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Current Publications Count: 1,031
| Title | Author | Year | Journal | Volume | Issue | Pages | DOI | Accession number | Keywords | Abstract | All authors/Notes | Link | Epub date |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Predicting the presence of coronary plaques featuring high-risk characteristics using polygenic risk scores and targeted proteomics in patients with suspected coronary artery disease | Møller, PL. et al. | 2024 | Genome Med. | ||||||||||
| Integrative multi-omics analysis identifies genetically supported druggable targets and immune cell specificity for myasthenia gravis | Li, J. et al. | 2024 | J Transl Med. | ||||||||||
| Characterization of sexual dimorphism in ANGPTL4 levels and function | Deng, M. et al. | 2024 | J Lipid Res. | ||||||||||
| TREM1 disrupts myeloid bioenergetics and cognitive function in aging and Alzheimer disease mouse models | Wilson, EN. et al. | 2024 | Nat Neurosci. | ||||||||||
| Cancer biomarkers: Emerging trends and clinical implications for personalized treatment | Passaro, A. et al. | 2024 | Cell | ||||||||||
| Three decades of advancements in osteoarthritis research: insights from transcriptomic, proteomic, and metabolomic studies | Rai, MF. et al. | 2024 | Osteoarthritis Cartilage | ||||||||||
| Enlarged perivascular spaces are associated with white matter injury, cognition and inflammation in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy | Karvelas, N. et al. | 2024 | Brain Commun. | ||||||||||
| Signaling Pathways Associated with Prior Cardiovascular Events in Hypertrophic Cardiomyopathy | Lee, C. et al. | 2024 | J Card Fail. | ||||||||||
| Signaling Pathways in Hypertrophic Cardiomyopathy: Will Proteomic Profiling Guide the Future? | Aurora, L. et al. | 2024 | J Card Fail. | ||||||||||
| Plasma proteins and persistent post-surgical pelvic pain among adolescents and young adults with endometriosis | Sasamoto, N. et al. | 2024 | Am J Obstet Gynecol. | ||||||||||
| Plasma Proteome-Based Test for First-Line Treatment Selection in Metastatic Non-Small Cell Lung Cancer | Christopoulos, P. et al. | 2024 | JCO Precis Oncol. | ||||||||||
| Exercise‐Dependent Modulation of Immunological Response Pathways in Endurance Athletes With and Without Atrial Fibrillation | Dorian, D. et al. | 2024 | J Am Heart Assoc. | ||||||||||
| The potential of the proteome to predict fracture | Chai, RC. et al. | 2024 | J Bone Miner Res. | ||||||||||
| Accelerated Aging in Cancer Survivors: Cellular Senescence, Frailty, and Possible Opportunities for Interventions | Wang, S. et al. | 2024 | Int. J. Mol. Sci. | ||||||||||
| Plasma proteomic signature of human longevity | Liu, X. et al. | 2024 | Aging Cell | ||||||||||
| Plasma proteomic profile of abdominal obesity in older adults, Plasma proteomic profile of abdominal obesity in older adults | Sathyan, S. et al. | 2024 | Obesity (Silver Spring) | ||||||||||
| Associations of plasma proteomics and age-related outcomes with brain age in a diverse cohort | Casanova, R. et al. | 2024 | Geroscience | ||||||||||
| Evolving role of semaglutide in NAFLD: in combination, weekly and oral administration | Koureta, E. et al. | 2024 | Front. Pharmacol. | ||||||||||
| Smoking changes adaptive immunity with persistent effects | Saint-André, V. et al. | 2024 | Nature | ||||||||||
| Nanoparticle enrichment mass-spectrometry proteomics identifies protein-altering variants for precise pQTL mapping | Suhre, K. et al. | 2024 | Nat Commun. | ||||||||||
| Which neuroimaging and fluid biomarkers method is better in theranostic of Alzheimer’s disease? An umbrella review | Mohammadi, H. et al. | 2024 | IBRO Neuroscience Reports | ||||||||||
| Plasma Ferritin Levels, Incident Heart Failure, and Cardiac Structure and Function: The ARIC Study | Aboelsaad IAF. et al. | 2025 | JACC Heart Fail. | ||||||||||
| Human host defence peptide LL-37 suppresses TNFα- mediated matrix metalloproteinases MMP9 and MMP13, in human bronchial epithelial cells | Altieri, A. et al. | 2024 | J Innate Immun. | ||||||||||
| Comprehensive proteomics of CSF, plasma, and urine identify DDC and other biomarkers of early Parkinson's disease | Rutledge, J. et al. | 2024 | Acta Neuropathol. | ||||||||||
| Multi-omics Analyses Identify AKR1A1 as a Biomarker for Diabetic Kidney Disease | Li, D. et al. | 2024 | Diabetes | ||||||||||
| Circulating Proteome Analysis Identifies Reduced Inflammation After Initiation of Hemodynamic Support with Either Veno-Arterial Extracorporeal Membrane Oxygenation or Impella in Patients with Cardiogenic Shock | Diakos, NA. et al. | 2024 | J Cardiovasc Transl Res. | ||||||||||
| Proteomic Associations of Adverse Outcomes in Human Heart Failure | Dib, MJ. et al. | 2024 | J Am Heart Assoc. | ||||||||||
| Proteome-wide mendelian randomization investigates potential associations in heart failure and its etiology: emphasis on PCSK9 | Lin, L. et al. | 2024 | BMC Med Genomics | ||||||||||
| Deep phenotyping of post-infectious myalgic encephalomyelitis/chronic fatigue syndrome | Walitt, B. et al. | 2024 | Nat Commun. | ||||||||||
| Genetic investigation into the broad health implications of caffeine: evidence from phenome-wide, proteome-wide and metabolome-wide Mendelian randomization | Zagkos, L. et al. | 2024 | BMC Med. | ||||||||||
| An omics-based machine learning approach to predict diabetes progression: a RHAPSODY study | Slieker, RC. et al. | 2024 | Diabetologia | ||||||||||
| A Cross-Sectional Study of Protein Changes Associated with Dementia in Non-Obese Weight Matched Women with and without Polycystic Ovary Syndrome | Butler, AE. et al. | 2024 | Int J Mol Sci. | ||||||||||
| Proteomic profiles of cytokines and chemokines in moderate to severe depression: Implications for comorbidities and biomarker discovery | Watson, KT. et al. | 2024 | Brain, Behavior, & Immunity - Health | ||||||||||
| Enhancing cardiovascular risk prediction through proteomics? | Singh, B. et al. | 2024 | Cardiovasc Res. | ||||||||||
| Proteomic insights into modifiable risk of venous thromboembolism and cardiovascular comorbidities | Yuan, S. et al. | 2024 | J Thromb Haemost. | ||||||||||
| Imatinib treatment improves hyperglycaemic dysregulation in severe COVID-19: a secondary analysis of blood biomarkers in a randomised controlled trial | Duijvelaar, E. et al. | 2024 | Critical Care | ||||||||||
| Non-invasive diagnosis of non-alcoholic fatty liver disease: Current status and future perspective | Wang, JL. et al. | 2024 | Heliyon | ||||||||||
| Aptamer proteomics for biomarker discovery in heart failure with reduced ejection fraction | Zhang, L.et. al. | 2022 | Circulation | ||||||||||
| Large-scale circulating proteome association study (CPAS) meta-analysis identifies circulating proteins and pathways predicting incident hip fractures | Austin, TR. et al. | 2024 | JBMR | ||||||||||
| Liquid Biopsy Proteomics in Ophthalmology | Wolf, J. et al. | 2024 | J. Proteome Res. | ||||||||||
| Discovery of sparse, reliable omic biomarkers with Stabl | Hedou, J. et al. | 2024 | Nat Biotechnol. | ||||||||||
| Development and Validation of a Protein Risk Score for Mortality in Heart Failure : A Community Cohort Study | Kuku, KO. et al. | 2024 | Ann Intern Med. | ||||||||||
| Human Nutrition Research in the Data Era: Results of 11 Reports on the Effects of a Multiple-Micronutrient- Intervention Study | Kaput, J. et al. | 2024 | Nutrients | ||||||||||
| Immune-mediated thrombocytopenia and IL-6-mediated thrombocytosis observed in idiopathic multicentric Castleman disease | Rubenstein, AI. et al. | 2024 | Br J Haematol. | ||||||||||
| Associations between genetically predicted plasma protein levels and Alzheimer's disease risk: a study using genetic prediction models | Zhu, J. et al. | 2024 | Alzheimers Res Ther. | ||||||||||
| Proteomic Associations Of N-terminal-pro Hormone Bnp In Heart Failure With Preserved Ejection Fraction In Two Cohorts | Azzo, JD. et al. | 2024 | J Card Fail. | ||||||||||
| Proteomic Correlates And Prognostic Significance Of Kidney Injury In Heart Failure With Preserved Ejection Fraction | Salman, O. et al. | 2024 | J Card Fail. | ||||||||||
| Proteomic associations with forced expiratory volume: a Mendelian randomisation study | Axelsson, GT. et al. | 2024 | Respir. Res. | ||||||||||
| N-terminal titin fragment: a non-invasive, pharmacodynamic biomarker for microdystrophin efficacy | Boehler, JF. et al. | 2024 | Skeletal Muscle | ||||||||||
| Large scale plasma proteomics identifies novel proteins and protein networks associated with heart failure development | Shah, AM. et al. | 2024 | Nat. Commun. | ||||||||||
| Therapeutic targets for diabetic kidney disease: proteome-wide Mendelian randomization and colocalization analyses | Zhang, W. et al. | 2024 | Diabetes | ||||||||||
| Blood DNA methylation profiling identifies cathepsin Z dysregulation in pulmonary arterial hypertension | Ulrich, A. et al. | 2024 | Nat. Commun. | ||||||||||
| Chloride Intracellular Channel Protein 1 (CLIC1) Is a Critical Host Cellular Factor for Influenza A Virus Replication | Rashid, M. et al. | 2024 | Viruses | ||||||||||
| Multi-Omics Approach to Improved Diagnosis and Treatment of Atopic Dermatitis and Psoriasis | Rusiñol, L. et al. | 2024 | Int. J. Mol. Sci. | ||||||||||
| Genetic insights into associations of multisite chronic pain with common diseases and biomarkers using data from the UK Biobank | Chen, Y. et al. | 2024 | Br J Anaesth. | ||||||||||
| A Cross-Sectional Study of Alzheimer-Related Proteins in Women with Polycystic Ovary Syndrome | Butler, AE. et al. | 2024 | Int J Mol Sci. | ||||||||||
| Persistent complement dysregulation with signs of thromboinflammation in active Long Covid | Cervia-Hasler, C. et al. | 2024 | Science | ||||||||||
| An Aptamer-Based Proteomic Analysis of Plasma from Cats (Felis catus) with Clinical Feline Infectious Peritonitis | Curtis, BE. et al. | 2024 | Viruses | ||||||||||
| Plasma protein signatures of adult asthma | Smilnak, GJ. et al. | 2024 | Allergy | ||||||||||
| Proteomics to predict relapse in patients with myelodysplastic neoplasms undergoing allogeneic hematopoietic cell transplantation | Guru Murthy, GS. et al. | 2024 | Biomark Res. | ||||||||||
| Prediction of Cardiac Death in Patients with Hypertrophic Cardiomyopathy Using Plasma Adipokine Levels | Akita, K. et al. | 2024 | NMCD | ||||||||||
| Proteomics for heart failure risk stratification: a systematic review | Kuku, KO. et al. | 2024 | BMC Med. | ||||||||||
| Genetic inhibition of angiopoietin-like protein-3, lipids, and cardiometabolic risk | Gobeil, E. et al. | 2024 | Eur Heart J. | ||||||||||
| Differential peripheral immune signatures elicited by vegan versus ketogenic diets in humans | Link, VM. et al. | 2024 | Nat Med. | ||||||||||
| Longitudinal plasma proteomics reveals biomarkers of alveolar-capillary barrier disruption in critically ill COVID-19 patients | Duijvelaar, E. et al. | 2024 | Nat Commun. | ||||||||||
| A polygenic risk score of atrial fibrillation improves prediction of lifetime risk for heart failure | Alkis, T. et al. | 2024 | ESC Heart Fail. | ||||||||||
| Proteome-Wide Mendelian Randomization identifies causal plasma proteins in lung cancer | Li, H. et al. | 2024 | iScience | ||||||||||
| Proteomic Biomarkers of Quantitative Interstitial Abnormalities in COPDGene and CARDIA Lung Study | Choi, B. et al. | 2024 | Am J Respir Crit Care Med. | ||||||||||
| Large-Scale Proteomics Identifies Novel Biomarkers and Circulating Risk Factors for Aortic Stenosis | Shelbaya, K. et al. | 2024 | J Am Coll Cardiol. | ||||||||||
| Proteomic Associations of NT-proBNP (N-Terminal Pro-B-Type Natriuretic Peptide) in Heart Failure With Preserved Ejection Fraction | Azzo, JD. et al. | 2024 | Circ Heart Fail. | ||||||||||
| Transcriptome-wide association study of the plasma proteome reveals cis and trans regulatory mechanisms underlying complex traits | Wittich, H. et al. | 2024 | Am J Hum Genet. | ||||||||||
| Identifying novel proteins for suicide attempt by integrating proteomes from brain and blood with genome-wide association data | Zhao, H. et al. | 2024 | Neuropsychopharmacology | ||||||||||
| Modulating fast skeletal muscle contraction protects skeletal muscle in animal models of Duchenne muscular dystrophy | Russell, AJ. et al. | 2024 | J Clin Invest. | ||||||||||
| Mechanistically based blood proteomic markers in the TGF-β pathway stratify risk of hepatocellular cancer in patients with cirrhosis | Xiang, X. et al. | 2024 | Genes Cancer | ||||||||||
| Association of Plasma YKL-40 With MRI, CSF, and Cognitive Markers of Brain Health and Dementia | Pase, MP. et al. | 2024 | Neurology | ||||||||||
| Untargeted Serum Proteomics Profiling in Female Patients with Idiopathic Scoliosis | Carry, P. et al. | 2024 | MRA | ||||||||||
| Recent developments in mass-spectrometry-based targeted proteomics of clinical cancer biomarkers | Wenk, D. et al. | 2024 | Clin Proteomics | ||||||||||
| Serum/Plasma Proteome in Non-Malignant Liver Disease | Fu, L. et al. | 2024 | Int. J. Mol. Sci. | ||||||||||
| High serum proteinase-3 levels predict poor progression-free survival and lower efficacy of bevacizumab in metastatic colorectal cancer | Furuya, K. et al. | 2024 | BMC Cancer | ||||||||||
| Lessons and Applications of Omics Research in Diabetes Epidemiology | Yu, G. et al. | 2024 | Curr Diab Rep. | ||||||||||
| Plasma Proteome-Wide Mendelian Randomization Analysis Reveals Biomarkers and Therapeutic Targets for Different Stages of COVID-19 | Krishnamoorthy, S. et al. | 2024 | Transboundary and Emerging Diseases | ||||||||||
| Special Issue “Deployment of Proteomics Approaches in Biomedical Research” | Fernández-Irigoyen, J. et al. | 2024 | Int. J. Mol. Sci. | ||||||||||
| Proteomic Analysis of Bronchoalveolar Lavage Fluid from Children with Bronchiolitis Obliterans Syndrome Identifies Potential Treatment Strategies | Strecker, L. et al. | 2024 | Transplantation and Cellular Therapy | ||||||||||
| Mapping the human brain proteome: opportunities, challenges, and clinical potential | Cartas-Cejudo, P. et al. | 2024 | Expert Rev Proteomics | ||||||||||
| Plasma SOMAmer proteomics of postoperative delirium | Leung, JM. et al. | 2024 | Brain Behav. | ||||||||||
| Spatial multi-omics: novel tools to study the complexity of cardiovascular diseases | Kiessling, P. et al. | 2024 | Genome Med. | ||||||||||
| Harnessing the power of proteomics in precision diabetes medicine | Kurgan, N. et al. | 2024 | Diabetologia | ||||||||||
| Multi-proteomic Biomarker Risk Scores for Predicting Risk and Guiding Therapy in Patients with Coronary Artery Disease | Gold, ME. et al. | 2023 | Curr Cardiol Rep. | ||||||||||
| Proteomic Analysis of the Senescence Associated Secretory Phenotype (SASP): GDF-15, IGFBP-2, and Cystatin-C Are Associated with Multiple Aging Traits | Evans, DS. et al. | 2023 | J Gerontol A Biol Sci Med Sci. | ||||||||||
| Proteome-wide Mendelian randomization highlights AIF1 and HLA-DQA2 as targets for primary sclerosing cholangitis | Chen, L. et al. | 2023 | Hepatol Int. | ||||||||||
| Multiplex electrochemical aptasensors for detection of endothelial dysfunction: Ready for prime time? | Grabowska, I. et al. | 2023 | TrAC | ||||||||||
| Vitamin D status affects proteomic profile of HDL associated proteins and inflammatory mediators in dyslipidemia | Mousa, H. et al. | 2023 | J Nutr Biochem. | ||||||||||
| Common and specific proteins and pathways in heart and cerebral ischemia | Palà, E. et al. | 2023 | J Stroke Cerebrovasc Dis. | ||||||||||
| Screening Plasma Proteins for the Putative Drug Targets for Carpal Tunnel Syndrome | Han, BX. et al. | 2023 | Cell Mol Neurobiol. | ||||||||||
| Growth Differentiation Factor 15 and Risk of Bleeding Events: The Atherosclerosis Risk in Communities Study | Mathews, L. et al. | 2023 | J Am Heart Assoc. | ||||||||||
| Plasma Protein Biomarkers of Healthy Dietary Patterns: Results from the Atherosclerosis Risk in Communities Study and the Framingham Heart Study | Du, S.et al. | 2023 | J Nutr. | ||||||||||
| Alterations in the Circulating Proteome Associated with Albuminuria | Kiernan, E. et al. | 2023 | J Am Soc Nephrol. | ||||||||||
| Proteomics Analysis of Genetic Liability of Abdominal Aortic Aneurysm Identifies Plasma Neogenin and Kit Ligand: The ARIC Study | Steffen, BT. et al. | 2023 | Arterioscler Thromb Vasc Biol. | ||||||||||
| Growth Differentiation Factor 15 and the Subsequent Risk of Atrial Fibrillation: The Atherosclerosis Risk in Communities Study | Chen, M. et al. | 2022 | Clin Chem. | ||||||||||
| Proteins Associated with Risk of Kidney Function Decline in the General Population | Grams, ME. et al. | 2021 | J Am Soc Nephrol. | ||||||||||
| Predicting disease course in ulcerative colitis using stool proteins identified through an aptamer-based screen | Soomro, S. et al. | 2021 | Nat Commun. | ||||||||||
| Immune Complex–Driven Generation of Human Macrophages with Anti-Inflammatory and Growth-Promoting Activity | Dalby, E. et al. | 2020 | J Immunol. | ||||||||||
| Strong impact on plasma protein profiles by precentrifugation delay but not by repeated freeze-thaw cycles, as analyzed using multiplex proximity extension assays | Shen, Q. et al. | 2018 | Clin Chem Lab Med. | ||||||||||
| Genetically predicted circulating protein biomarkers and ovarian cancer risk | Considine, DPC. et al. | 2021 | Gynecol Oncol. | ||||||||||
| Enhanced epigenetic profiling of classical human monocytes reveals a specific signature of healthy aging in the DNA methylome | Shchukina, I. et al. | 2021 | Nat Aging | ||||||||||
| Lymphadenopathy in IgG4-related disease: a phenotype of severe activity and poor prognosis, with eotaxin-3 as a new biomarker | Takanashi, S. et al. | 2021 | Rheumatology (Oxford) | ||||||||||
| Agreement of aptamer proteomics with standard methods for measuring venous thrombosis biomarkers | Faquih, T. et al. | 2021 | Res Pract Thromb Haemost. | ||||||||||
| A genome-wide meta-analysis yields 46 new loci associating with biomarkers of iron homeostasis | Bell, S. et al. | 2021 | Commun Biol | ||||||||||
| The relationship of soluble neuropilin-1 to severe COVID-19 risk factors in polycystic ovary syndrome | Moin, ASM. et al. | 2021 | Metabol Open. | ||||||||||
| Plasma heat shock protein response to euglycemia in type 2 diabetes | Atkin, AS. et al. | 2021 | BMJ Open Diabetes Res Care. | ||||||||||
| Hypoglycaemia in type 2 diabetes exacerbates amyloid‐related proteins associated with dementia | Moin, ASM. et al. | 2021 | Diabetes Obes Metab. | ||||||||||
| Soluble receptor for advanced glycation end products (sRAGE) as a biomarker of COPD | Pratte, KA. et al. | 2021 | Respir Res. | ||||||||||
| Amyloid-related protein changes associated with dementia differ according to severity of hypoglycemia | Moin, ASM. et al. | 2021 | BMJ Open Diabetes Res Care. | ||||||||||
| Change in circulating proteins during treatment of pulmonary exacerbation in patients with cystic fibrosis | Wagner, BD. et al. | 2021 | Health Sci Rep. | ||||||||||
| CARD10 cleavage by MALT1 restricts lung carcinoma growth in vivo | Israël, L. et al. | 2021 | Oncogenesis | ||||||||||
| The complement pathway is activated in people with human immunodeficiency virus and is associated with non-AIDS comorbidities | Vujkovic-Cvijin, I. et al. | 2021 | J Infect Dis. | ||||||||||
| Platelet glycoprotein Ib α‐chain as a putative therapeutic target for juvenile idiopathic arthritis: A Mendelian randomization study | Luo, S. et al. | 2021 | Arthritis Rheumatol. | ||||||||||
| A neuronal blood marker is associated with mortality in old age | Kaeser, SA. et al. | 2021 | Nat Aging | ||||||||||
| Integrative biochemical, proteomics, and metabolomics cerebrospinal fluid biomarkers predict clinical conversion to multiple sclerosis | Probert, F. et al. | 2021 | Brain Commun. | ||||||||||
| Identification of macrophage activation-related biomarkers in obese type 2 diabetes that may be indicative of enhanced respiratory risk in COVID-19 | Moin, ASM. et al. | 2021 | Sci Rep. | ||||||||||
| Parenteral lipid emulsions induce unique ileal fatty acid and metabolomic profiles but do not increase the risk of necrotizing enterocolitis in preterm pigs | Yakah, W. et al. | 2021 | Am J Physiol Gastrointest Liver Physiol. | ||||||||||
| Distinctive clinical presentation and pathogenic specificities of anti-AK5 encephalitis | Muñiz-Castrillo, S. et al. | 2021 | Brain | ||||||||||
| HMGB1 release by cholangiocytes governs biliary atresia pathogenesis and correlates with increases in afflicted infants | Mohanty, SK. et al. | 2021 | Hepatology | ||||||||||
| Proteomic profiling reveals biomarkers and pathways in type 2 diabetes risk | Ngo, D. et al. | 2021 | JCI Insight | ||||||||||
| Detection of pro angiogenic and inflammatory biomarkers in patients with CKD | Jalal, D. et al. | 2021 | Sci Rep. | ||||||||||
| Serum levels of ACE2 are higher in patients with obesity and diabetes | Emilsson, V. et al. | 2021 | Obes Sci Pract. | ||||||||||
| Characterization of the plasma proteomic profile of frailty phenotype | Landino, K. et al. | 2021 | Geroscience | ||||||||||
| Twelve new genomic loci associated with bone mineral density | Liu, L. et al. | 2020 | Front Endocrinol. | ||||||||||
| Dysregulated antibody, natural killer cell and immune mediator profiles in autoimmune thyroid diseases | Martin, TC. et al. | 2020 | Cells | ||||||||||
| Glycerol-3-phosphate is an FGF23 regulator derived from the injured kidney | Simic, P. et al. | 2020 | J Clin Invest. | ||||||||||
| Identification of plasma proteome signatures associated with ATN framework using SOMAscan | Fong, TG. et al. | 2020 | Ann Surg. | ||||||||||
| Deciphering the plasma proteome of type 2 diabetes | Elhadad, MA. et al. | 2020 | Diabetes | ||||||||||
| Serum LOX-1 is a novel prognostic biomarker of colorectal cancer | Nakashima-Nakasuga, C. et al. | 2020 | Int J Clin Oncol. | ||||||||||
| Tumor-associated macrophages promote ovarian cancer cell migration by secreting transforming growth factor beta induced (TGFBI) and tenascin C | Steitz, AM. et al. | 2020 | Cell Death Dis | ||||||||||
| Intense light pretreatment improves hemodynamics, barrier function and inflammation in a murine model of hemorrhagic shock lung. | Oyama, Y. et al. | 2020 | Mil Med. | ||||||||||
| Characterization and proteome of circulating extracellular vesicles as potential biomarkers for NASH | Povero, D. et al. | 2020 | Hepatol Commun. | ||||||||||
| Functional genomic analyses uncover APOE-mediated regulation of brain and cerebrospinal fluid beta-amyloid levels in Parkinson disease | Ibanez, L. et al. | 2020 | Acta Neuropathol Commun. | ||||||||||
| Plasma proteomic signatures predict dementia and cognitive impairment | Tanaka, T. et al. | 2020 | Alzheimers Dement (N Y). | ||||||||||
| Application of protein set enrichment analysis to correlation of protein functional sets with mass spectral features and multivariate proteomic tests | Grigorieva, J. et al. | 2020 | Clinical Mass Spectrometry | ||||||||||
| Epigenetic modulation by apabetalone counters cytokine-driven acute phase response in vitro, in mice and in patients with cardiovascular disease | Wasiak, S. et al. | 2020 | Cardiovasc Ther. | ||||||||||
| Elevated plasma frowth and differentiation factor 15 predicts incident anemia in older adults aged 60 years and older | Yamaguchi, Y. et al. | 2020 | J Gerontol A Biol Sci Med Sci. | ||||||||||
| Evaluation of associations between genetically predicted circulating protein biomarkers and breast cancer risk | Shu, X. et al. | 2020 | Int J Cancer. | ||||||||||
| Associations between genetically predicted blood protein biomarkers and pancreatic cancer risk | Zhu, J. et al. | 2020 | Cancer Epidemiol Biomarkers Prev. | ||||||||||
| Plasma-Derived Extracellular Vesicles Convey Protein Signatures That Reflect Pathophysiology in Lung and Pancreatic Adenocarcinomas | Fahrmann, JF. et al. | 2020 | Cancers (Basel). | ||||||||||
| Proteome-wide assessment of diabetes mellitus in Qatari identifies IGFBP-2 as a risk factor already with early glycaemic disturbances | Noordam, R. et al. | 2020 | Arch Biochem Biophys. | ||||||||||
| MFGE8, ALB, APOB, APOE, SAA1, A2M, and C3 as novel biomarkers for stress cardiomyopathy | Pan, XY. et al. | 2020 | Cardiovasc Ther. | ||||||||||
| DNA methylation during human adipogenesis and the impact of fructose | Tini, G. et al. | 2020 | Genes Nutr | ||||||||||
| Integrated lipidomics and proteomics network analysis highlights lipid and immunity pathways associated with Alzheimer’s disease | Xu, J. et al. | 2020 | Transl Neurodegener. | ||||||||||
| Time-dependent cytokine and chemokine changes in mouse cerebral cortex following a mild traumatic brain injury | Tweedie, D. et al. | 2020 | eLife | ||||||||||
| Identifying protein–metabolite networks associated with COPD phenotypes | Mastey, E. et al. | 2020 | Metabolites | ||||||||||
| An atlas of genetic correlations between psychiatric disorders and human blood plasma proteome | Cheng, S. et al. | 2020 | Eur Psychiatry. | ||||||||||
| HIV-associated gut dysbiosis is independent of sexual practice and correlates with noncommunicable diseases | Vujkovic-Cvijin, I. et al. | 2020 | Nat Commun. | ||||||||||
| Definition and independent validation of a proteomic-classifier in ovarian cancer | Kasimir-Bauer, s.et al. | 2020 | Cancers (Basel). | ||||||||||
| Urine biomarkers of renal renin–angiotensin system activity: Exploratory analysis in humans with and without obstructive sleep apnea | Hanly, PJ. et al. | 2020 | Physiol Rep. | ||||||||||
| Aptamer-based proteomic platform identifies novel protein predictors of incident heart failure and echocardiographic traits | Nayor, M. et al. | 2020 | Circ Heart Fail | ||||||||||
| Significant polyomic and functional upregulation of the PAPP-A/IGFBP-4/5/IGF-1 axis in chronic rhinosinusitis with nasal polyps | Mueller, SK. et al. | 2020 | Int Forum Allergy Rhinol. | ||||||||||
| Unexpected effects of systemic steroids on the CRSwNP proteome: Is protein upregulation more important than inhibition? | Workman, AD. et al. | 2020 | Int Forum Allergy Rhinol. | ||||||||||
| Increased apolipoprotein E and decreased TNF‐α in the cerebrospinal fluid of nondemented APOE‐ε4 carriers | Sasayama, D. et al. | 2020 | Neuropsychopharmacol Rep | ||||||||||
| Aging hallmarks exhibit organ-specific temporal signatures | Schaum, N. et al. | 2020 | Nature | ||||||||||
| Upregulation of systemic inflammatory pathways following anterior cruciate ligament injury relates to both cartilage and muscular changes: A pilot study | Hunt, ER. et al. | 2020 | J Orthop Res. | ||||||||||
| Transcriptomic and proteomic analyses reveal the potential mode of action of chondrocyte sheets in hyaline cartilage regeneration | Toyoda, E. et al. | 2019 | Int J Mol Sci | ||||||||||
| Profiling of the plasma proteome across different stages of human heart failure | Egerstedt, A. et al. | 2019 | Nat Commun. | ||||||||||
| Airway host-microbiome interactions in chronic obstructive pulmonary disease | Wang, Z. et al. | 2019 | Respir Res. | ||||||||||
| “T2-high” in severe asthma related to blood eosinophil, exhaled nitric oxide and serum periostin | Pavlidis, S. et al. | 2019 | Eur Respir J. | ||||||||||
| Whole genome sequence association with E-selectin levels reveals loss-of-function variant in African Americans | Polfus, LM. et al. | 2019 | Hum Mol Genet | ||||||||||
| Transcriptomic and proteomic pathways of diabetic and non-diabetic mitochondrial transplantation | Doulamis, IP. et al. | 2019 | Sci Rep. | ||||||||||
| Extending the information content of the MALDI analysis of biological fluids via multi-million shot analysis | Tsypin, M. et al. | 2019 | PLoS ONE | ||||||||||
| Epithelial IL-6 trans-signaling defines a new asthma phenotype with increased airway inflammation | Jevnikar, Z. et al. | 2019 | J Allergy Clin Immunol. | ||||||||||
| Modulation of Wnt/β-catenin signaling promotes blood-brain barrier phenotype in cultured brain endothelial cells | Laksitorini, MD. et al. | 2019 | Sci Rep. | ||||||||||
| Reduced plasma levels of small HDL particles transporting fibrinolytic proteins in pulmonary arterial hypertension | Harbaum, L. et al. | 2019 | Thorax | ||||||||||
| Necuparanib, a multitargeting heparan sulfate mimetic, targets tumor and stromal compartments in pancreatic cancer | MacDonald, A. et al. | 2019 | Mol Cancer Ther. | ||||||||||
| An SFTPC BRICHOS mutant links epithelial ER stress and spontaneous lung fibrosis | Katzen, J. et al. | 2019 | JCI Insight | ||||||||||
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| Frailty Resilience Score: A Novel Measure of Frailty Resilience Associated with Protection from Frailty and Survival | Milman, S. et al. | 2023 | J Gerontol A Biol Sci Med Sci. | 05/29/2023 | |||||||||
| New Markers for Management of Mesothelioma | Nash, A. et al. | 2023 | Semin Respir Crit Care Med. | 05/30/2023 | |||||||||
| MS-based proteomics of body fluids: The end of the beginning | Bader, JM. et al. | 2023 | Mol Cell Proteomics | 05/18/2023 | |||||||||
| Biomarkers of ageing: Current state-of-art, challenges, and opportunities | Chen, R. et al. | 2023 | MedComm – Future Medicine | 06/18/2023 | |||||||||
| Mass Spectrometry-based Proteomics of Epithelial Ovarian Cancers: a Clinical Perspective | Quian, L. et al. | 2023 | Mol Cell Proteomics | 05/18/2023 | |||||||||
| The Human Gastric Juice: A Promising Source for Gastric Cancer Biomarkers | Felipez, N. et al. | 2023 | Int J Mol Sci. | ||||||||||
| A Question of Frame: The Role of the Bone Marrow Stromal Niche in Myeloid Malignancies | Tomasoni, C. et al. | 2023 | Hemasphere | 05/23/2023 | |||||||||
| Proteomics approaches to long COVID: status and outlooks | Liang, X. et al. | 2023 | Life Medicine | ||||||||||
| Machine learning algorithm improves detection of NASH (NAS-based) and at-risk NASH, a development and validation study | Lee J. et al. | 2023 | Hepatology | ||||||||||
| (Bio-)Sensors for Skin Grafts and Skin Flaps Monitoring | Ozsoylu, D. et al. | 2023 | Sensors and Actuators Report | ||||||||||
| Association between Organochlorine Pesticides and Vitamin D in Female Subjects | Brennan, E. et al. | 2023 | Biomedicines | 05/15/2023 | |||||||||
| A blood and bronchoalveolar lavage protein signature of rapid FEV1 decline in smoking-associated COPD | DiLillo, K. et al. | 2023 | Sci Rep. | 05/22/2023 | |||||||||
| Canonical correlation analysis for multi-omics: Application to cross-cohort analysis | Jiang, MZ. et al. | 2023 | PLoS Genet. | 05/22/2023 | |||||||||
| Sex-based differences in cardiovascular proteomic profiles and their associations with adverse outcomes in patients with chronic heart failure | de Bakker, M. et al. | 2023 | Biol Sex Differ. | 05/17/2023 | |||||||||
| Identification of serum biomarkers for necrotizing enterocolitis using aptamer-based proteomics | Mackay, S. | 2023 | Front Pediatr. | 05/31/2023 | |||||||||
| HFrEF subphenotypes based on 4210 repeatedly measured circulating proteins are driven by different biological mechanisms | Petersen, TB. et al. | 2023 | EBioMedicine | 06/14/2023 | |||||||||
| Elevated plasma complement factor H related 5 protein is associated with venous thromboembolism | Iglesias, MJ. et al. | 2023 | Nat Commun | 06/07/2023 | |||||||||
| Renoprotective effects of genetically proxied fibroblast growth factor 21: Mendelian randomization, proteome-wide and metabolome-wide association study | Giontella, A. et al. | 2023 | Metabolism | 06/09/2023 | |||||||||
| Sequence variants affecting voice pitch in humans | Gisladottir, R. et al. | 2023 | Sci Adv. | ||||||||||
| Deficit of homozygosity among 1.52 million individuals and genetic causes of recessive lethality | Oddsson, A. et al. | 2023 | Nat Commun. | 06/10/2023 | |||||||||
| Cardiopulmonary Phenotypes and Protein Signatures in Children With Down Syndrome | DeBoer, E. et al. | 2023 | Clinical Pediatr. (Phila). | 06/12/2023 | |||||||||
| Magnetically Detected Protein Binding Using Spin-Labeled Slow Off-Rate Modified Aptamers | Lu, S. et al. | 2023 | ACS Sens. | 06/10/2023 | |||||||||
| Large scale proteomic studies create novel privacy considerations | Hill, AC. et al. | 2023 | Sci Rep. | The authors of this paper sought to demonstrate the need for similar privacy protections in proteomic research as genomic research already has. Since the discovery that single nucleotide polymorphisms (SNPs) can genetically distinguish individuals, multiple privacy protection policies regarding genetic information have been passed in the United States. Notably, these policies only explicitly address genetic information, leaving proteomics in a grey area and legally unprotected. The authors use limited proteome profiles without peptide sequencing to link specific individuals by using prior independent knowledge of QTLs The authors used the COPDGene and Jackson Heart studies to train a model to predict genotypes based on SomaScan proteomic measurements. The model was validated using the MESA, SPIROMICS, and splits from the COPDGene and Jackson Heart studies. The model identified independent subjects of European ancestry with 83-92% accuracy and African American subjects with ~90% accuracy. The authors determined that the minimum number of protein-pQTL pairs necessary to match a proteome to a genome is 100 pairs. The authors assessed whether newer and larger proteome assays were more or less accurate at identifying genetic profiles. To do so, they split the COPDGene subjects who had 5k data into a 50/50 train-test split and generated a new list of protein-QTL pairs. These protein-QTL pairs were also used to match proteomes and genomes of participants in the ARIC study who have 5k SomaScan data. Identification accuracy improved to_>_98% in COPDGene and ARIC participants. This study is the first to demonstrate on a large scale that proteomic data are not identity protected because an individual proteome can be matched to a specific genome with high accuracy even without protein sequence information. | 06/07/2023 | ||||||||
| Plasma proteomic profiles of pain subtypes in adolescentsand young adults with endometriosis | Sasamoto, S. et al. | 2023 | Hum Reprod | 05/17/2023 | |||||||||
| Evaluation of a New Aptamer-Based Array for Soluble Suppressor of Tumorgenicity (ST2) and N-terminal Pro-B-Type Natriuretic Peptide (NTproBNP) in Heart Failure Patients | Debbs, J. et al. | 2023 | J Cardiovasc Transl Res. | In this study, SomaScan and ELISA assays were used to measure NTproBNP and ST2 and the results and predictive performance of the two methods were compared. N-terminal pro-B-type natriuretic peptide (NTproBNP) and soluble suppressor of tumorgenicity 2 (ST2) are the two most widely used and recommended biomarkers used for the diagnosis and prognosis of heart failure. The SomaScan assay allows for the rapid detection of thousands of proteins simultaneously, including NTproBNP and ST2. Here, the authors wished to test the accuracy of the SomaScan method for detecting NTproBNP and ST2 by comparing the performance to commercial ELISA assays. EDTA plasma samples from participants from the Henry Ford Pharmacogenomic Registry who met Framingham criterion for HF and had an ejection fraction < 50% were analyzed. When ST2 results were compared, the two methods had similar hazard ratios and were statistically significant for predicting all-cause mortality both with and without adjustment to the MAGGIC score for heart failure. Similar results were seen for predicting cardiovascular mortality. The two methods for measuring ST2 had a Spearman correlation of 0.71 and a Pearson correlation of 0.74. To determine whether addition of each assay method for ST2 improved the accuracy of the MAGGIC model for predicting heart failure, ROC curves were generated. The addition of the ELISA ST2 resulted in an AUC of 0.69 and was statistically significant (p = 0.035), while the addition of the SomaScan ST2 resulted in an AUC of 0.68 but was not statistically significant (p = 0.121). When NTproBNP results were compared, the two methods also had similar hazard ratios for all-cause mortality and were statistically significant for predicting all-cause mortality both with and without adjustment to the MAGGIC score for heart failure. Similar results were also seen for predicting cardiovascular mortality. The two methods for NTproBNP had a Spearman correlation of 0.95 and a Pearson correlation of 0.88. The MAGGIC score model was not significantly improved with addition of either method for measuring NTproBNP. This study shows that SomaScan results correlate well with commercial ELISA-based assays for NTproBNP and ST2 and have comparable prognostic abilities for predicting heart failure survival, showing the potential for proteomics and multimarker diagnostic methods in health care. | 05/16/2023 | ||||||||
| Plasma proteomic risk markers of incident type 2 diabetes reflect physiologically distinct components of glucose-insulin homeostasis | Cronje, H. et al. | 2023 | Diabetes | In this study, the authors used the SomaScan 5k to conduct a large-scale proteomics association study of incident type 2 diabetes and longitudinal glucose trajectories. The Cardiovascular Health Study (CHS) is a population-based prospective study investigating cardiovascular disease risk factors in adults aged 65 years or older. The Health, Risk Factors, Exercise Training and Genetics (HERITAGE) is a 20-week, single-arm exercise intervention study investigating genetic and cardiometabolic contributors to endurance exercise response in participants recruited within family units. Plasma samples from CHS and HERITAGE studies were run on the SomaScan v4.0. Cox proportional hazard regression models were used to test associations of aptamers with incident type 2 diabetes. Linear mixed-effect models were used to assess associations of aptamers with 6-year longitudinal fasting glucose levels. Authors also assessed aptamer specificity. 51 proteins were associated with incident type 2 diabetes and all but two of the associated aptamers had published cis pQTLs; 12 have been validated by mass spectrometry, and 7 had strong (P > 0.70) correlations with Olink measurements. Protein associations with longitudinal glucose levels largely reflected those observed in the incident diabetes analyses. In the base model, 59 additional associations were statistically significant. Prospective protein associations were identified in a complementary analysis of multiple glucose homeostasis traits using intravenous glucose tolerance test (IVGTT). 52 significantly associated proteins from the main model were selected and their associations with the following four IVGTT traits in HERITAGE were tested: insulin sensitivity index, acute insulin response to glucose, disposition index, and glucose effectiveness. Insulin sensitivity index, acute insulin response to glucose, disposition index, and glucose effectiveness were respectively associated with 39, 9, 39, and 8 proteins. 90% of significantly associated proteins were associated with at least one IVGTT trait. The study overall observed three patterns of association: 1. Proteins reflecting higher insulin sensitivity were also markers of decreased diabetes risk and vice versa; 2. Proteins relating to pancreatic function had associations with diabetes and insulin secretion but not insulin sensitivity; 3. In the insulin-independent glucometabolic pathways, b-Glucuronidase (GUSB) was most strongly associated with incident diabetes. It is hypothesized that before the onset of overt diabetes, GUSB may be upregulated to compensate for hyperglycemia as the body becomes more insulin resistant. | 05/01/2023 | ||||||||
| The role of inflammation in anxiety and depression in the European U-BIOPRED asthma cohorts | Hou, R. et al. | 2023 | Brain Behav Immun. | In this study, the authors use data and samples from the largest European asthma cohort, the Unbiased Biomarkers for the Prediction of Respiratory Disease Outcomes (U-BIOPRED) study, and utilize the largest proteomic assay on the market, SomaScan, to address the underlying mechanism between inflammation, asthma, anxiety, and depression. Studies have shown that people with asthma are more likely to experience anxiety, psychological distress, and depression which can lead to poor disease management and lower quality of life. Evidence suggests that inflammation is the link between asthma, anxiety, and depression; however, studies have been limited by small sample sizes, poor study design, and a limited number of available inflammatory markers. Here, behavioral data and serum samples from 198 non-smoking patients with severe asthma (SAn), 65 smoking patients with severe asthma (SAs), 61 non-smoking patients with mild-to-moderate asthma (MMA), and 20 healthy nonsmokers (HC) from the U-BIOPRED were analyzed. Average Hospital Anxiety and Depression Scale (HADS) scores for anxiety, depression, and HADS total scores from this cohort revealed a significantly higher levels in the SAn and SAs groups compared to the MMA and HC groups. Proteomic analysis of inflammatory markers revealed significantly higher levels of IL6, CCL18, MCP1, CCL17, and IL8 in the SAn and SAs groups. When looking at correlations between HADS scores and inflammatory markers, significant positive correlations were found between the depression score and IL6, MCP1, CCL18, and CCL17, the anxiety score and CCL17, and the total score and IL6, CCL18, and CCL17. Correlations between inflammatory markers for air flow obstruction and HADS scores were also analyzed, revealing a small negative correlation between eosinophil count and FeNO with depression and total HADS scores in the SAs group. The findings from this study confirmed higher rates of anxiety and depression in patients with severe asthma and using SomaScan found that certain inflammatory cytokines were significantly different in those patients, pointing to a possible underlying mechanism. | 05/03/2023 | ||||||||
| Identification of biomarkers for glycaemic deterioration in type 2 diabetes | Slieker, RC. et al. | 2023 | Nat Commun. | This study aimed to identify biomarkers for glycemic deteroriation in three type 2 diabetes cohorts encompassing 2,973 individuals across three molecular classes: metabolites, lipids and proteins. This represents the first study to use a multiomic approach for biomarker discovery and report systematically how metabolites of different classes impact progression of T2D. Individuals from three cohorts, DCS, GoDARTS and ANDIS were included. Protein data was generated using SomaScan 1.3k. In the 1195 investigated plasma proteins, the levels of 98 were nominally associated with time to insulin in the base model. The protein with the strongest association with time to insulin was GDF-15. Mendelian randomization was performed on six of the identified proteins to investigate casual associations. GDF15 is causally associated with diabetes progression and found a possible causal association for IL-18Ra and FAS. Metabolics data was generated using UHLPC-MS/MS. Two metabolites, Aminoadipic Acid (AADA) and Homocitrulline (Hcit) were significantly associated with diabetes progression. Lipid data was generated using mass spec. Nine lipids were associated with diabetes progression of which eight were associated with increased risk which all belonged to the Triacylglycerol (TAG) class. SomaStrengths: Biomarker identification, top proteins validated using ELISA | 05/03/2023 | ||||||||
| Predicting progression to Alzheimer's disease with human hippocampal progenitors exposed to serum | Maruszak, A. et al. | 2023 | Brain | In this study, the authors develop an in vitro model and a proteomic model using SomaScan data to predict progression of mild cognitive impairment (MCI) to Alzheimer’s disease using serum samples. Early intervention for Alzheimer’s disease is key and changes in hippocampal neurogenesis (HN) have been shown to be promising early markers for Alzheimer’s disease progression; however, results from previous studies have conflicting results on the directionality of those changes. Longitudinal studies are needed to address those discrepancies but are limited by the availability of viable techniques to study living human brains. In this study, an in vitro method to measure changes in HN is developed as a proxy by examining cell proliferation and differentiation of a human hippocampal progenitor cell line treated with longitudinal serum samples from MCI converters and non-converters. Cells treated with serum from MCI converters lead to decreased proliferation, increased cell death and increased neurogenesis. Using this in vitro system, a model was developed combining cell number, markers for cell proliferation, markers for cell differentiation, and education in years that was able to predict progression from MCI to Alzheimer’s with an AUC of 0.967 and an ability to predict disease progression up to 3.5 years before clinical diagnosis. Next, proteomics was employed to similarly explore development of a predictive model for conversion from MCI to Alzheimer’s. Samples were analyzed on SomaScan to measure 3620 unique proteins (4006 different protein epitopes) and, using machine learning, a panel of 15 proteins was identified that could distinguish between serum samples from MCI converters and non-converters with an AUC of 0.77. Pathway and network analysis was also performed on the differentially expressed proteins from the SomaScan data. Canonical pathways identified included Coagulation, Acute phase response signaling, Extrinsic prothrombin activation pathway, FXR/RXR activation, Notch signaling, Superpathway of methionine degradation, and Wnt/_-catenin Signaling. The top three networks identified were “Hematological System Development and Function, Organismal Functions, Organismal Injury and Abnormalities”, “Cell Death and Survival, Embryonic Development, Organismal Development”, and “Cell-to-Cell Signaling and Interaction, Cellular Function and Maintenance, Inflammatory Response”. This study demonstrates promising in vitro serum based models for predicting Alzheimer’s disease progression and provides insights into the underlying mechanisms of the disease in relation to changes in HN. | 05/02/2023 | ||||||||
| High density lipoprotein-associated proteins in non-obese women with and without polycystic ovary syndrome | Butler, A. et al. | 2023 | Front Endocrinol. | 04/26/2023 | |||||||||
| Circulating proteins to predict COVID-19 severity | Su CY. et al. | 2023 | Sci Rep. | 04/17/2023 | |||||||||
| Quantitative proteomic screening uncovers candidate diagnostic and monitoring serum biomarkers of ankylosing spondylitis | Hwang M. et al. | 2023 | Arthritis Res Ther. | 04/11/2023 | |||||||||
| A proteo-transcriptomic map of non-alcoholic fatty liver disease signatures | Govaere O. et al. | 2023 | Nat Metab. | 04/10/2023 | |||||||||
| The 2022 Report on the Human Proteome from the HUPO Human Proteome Project | Omenn G. et al. | 2023 | J Proteome Res. | 04/07/2023 | |||||||||
| An atlas of genetic scores to predict multi-omic traits | Xu Y. et al. | 2023 | Nature | ||||||||||
| Unbiased Human Kidney Tissue Proteomics Identifies Matrix Metalloproteinase 7 as a Kidney Disease Biomarker | Hirohama D. et al. | 2023 | J Am Soc Nephrol. | 04/05/2023 | |||||||||
| Pregnancy-specific responses to COVID-19 revealed by high-throughput proteomics of human plasma | Gomez-Lopez, N. et al. | 2023 | Commun Med (Lond) | 04/04/2023 | |||||||||
| Plasma Proteomic Associations With Incident Ischemic Stroke in Older Adults: The Cardiovascular Health Study | Kalani R. et al. | 2023 | Neurology | 04/04/2023 | |||||||||
| Identification of Protein Biomarkers of the Dietary Approaches to Stop Hypertension Diet in Randomized Feeding Studies and Validation in an Observational Study | Kim H. et al. | 2023 | J Am Heart Assoc. | 04/04/2023 | |||||||||
| Proteomic cardiovascular risk assessment in chronic kidney disease | Deo R. et al. | 2023 | Eur Heart J. | 04/23/2023 | |||||||||
| Proteome and genome integration analysis of obesity | Zhao Q. et al. | 2023 | Chinese Medical Journal | 03/31/2023 | |||||||||
| Supportive Evidence For The Potential For Novel Biodiscovery In Osteoarthritis Through The Stepup Oa Consortium | Perry TA. et al. | 2023 | Osteoarthritis and Cartilage | ||||||||||
| Integrated Analysis of Tracheobronchial Fluid from Before and After Cardiopulmonary Bypass Reveals Activation of the Integrated Stress Response and Altered Pulmonary Microvascular Permeability | Habet V. et al. | 2023 | Yale J Biol Med. | 03/31/2023 | |||||||||
| Biomarkers for staging fibrosis and non-alcoholic steatohepatitis in non-alcoholic fatty liver disease (the LITMUS project): a comparative diagnostic accuracy study | Vali Y. et al. | 2023 | Lancet Gastroenterol Hepatol. | 03/20/2023 | |||||||||
| Associations between MICA and MICB genetic variants, protein levels, and colorectal cancer: Atherosclerosis Risk in Communities (ARIC) | Wang S. et al. | 2023 | Cancer Epidemiol Biomarkers Prev. | 03/23/2023 | |||||||||
| Lung proteome and metabolome endotype in HIV-associated obstructive lung disease | Samorodnitsky S.et al. | 2023 | ERJ Open Res. | 03/20/2023 | |||||||||
| Plasma gelsolin levels are associated with diabetes, sex, race, and poverty | Hooten NN et al. | 2023 | J Transl Med. | 03/10/2023 | |||||||||
| HDL-Associated Proteins in Subjects with Polycystic Ovary Syndrome: A Proteomic Study | Butler A. et al. | 2023 | Cells | 03/09/2023 | |||||||||
| Proteomic basis of mortality resilience mediated by FOXO3 longevity genotype | Donlon T. et al. | 2023 | Geroscience | 03/07/2023 | |||||||||
| Coagulation factor dysregulation in polycystic ovary syndrome is an epiphenomenon of obesity | Moin ASM. et al. | 2023 | Clin Endocrinol. (Oxf) | 03/01/2023 | |||||||||
| Exhaled biomarkers in adults with non-productive cough | Emilsson OI, et al. | 2023 | Respir Res. | 03/01/2023 | |||||||||
| SOMAscan Proteomics Identifies Novel Plasma Proteins in Amyotrophic Lateral Sclerosis Patients | Berrone, E. et al. | 2023 | Int J Mol Sci. | 01/18/2023 | |||||||||
| APOL1 Kidney Risk Variants and Proteomics | Chen, TK. et al. | 2022 | Clin J Am Soc Nephrol. | 05/17/2022 | |||||||||
| HLA-A, HSPA5, IGFBP5 and PSMA2 Are Restriction Factors for Zika Virus Growth in Astrocytic Cells | Sher, A. et al. | 2022 | Viruses | 12/29/2022 | |||||||||
| Plasma proteomic profiles of pain subtypes in adolescents and young adults with endometriosis | Naoko Sasamoto | 2023 | Human Reproduction | What are the similarities and differences in the systemic proteomic profiles by endometriosis-associated pain subtypes among adolescents and young adults with endometriosis? | Naoko Sasamoto, Long Ngo, Allison F Vitonis, Simon T Dillon, Christine B Sieberg, Stacey A Missmer, Towia A Libermann, Kathryn L Terry | 05/17/2023 | |||||||
| Analytical validation of the PROphet computational model for clinical benefit prediction and decision-making tool in metastatic NSCLC | Itamar Sela | 2023 | bioRxiv | https://doi.org/10.1101/2023.04.20.537648 | Itamar Sela, Coren Lahav, Ben Yellin, Yehonatan Elon, Michal Harel | 04/24/2023 | |||||||
| Circulating proteins to predict COVID-19 severity | Chen-Yang Su | 2023 | Scientific Reports | 13 | 6236 | https://doi.org/10.1038/s41598-023-31850-y | Predicting COVID-19 severity is difficult, and the biological pathways involved are not fully understood. To approach this problem, we measured 4701 circulating human protein abundances in two independent cohorts totaling 986 individuals. We then trained prediction models including protein abundances and clinical risk factors to predict COVID-19 severity in 417 subjects and tested these models in a separate cohort of 569 individuals. For severe COVID-19, a baseline model including age and sex provided an area under the receiver operator curve (AUC) of 65% in the test cohort. Selecting 92 proteins from the 4701 unique protein abundances improved the AUC to 88% in the training cohort, which remained relatively stable in the testing cohort at 86%, suggesting good generalizability. Proteins selected from different COVID-19 severity were enriched for cytokine and cytokine receptors, but more than half of the enriched pathways were not immune-related. Taken together, these findings suggest that circulating proteins measured at early stages of disease progression are reasonably accurate predictors of COVID-19 severity. Further research is needed to understand how to incorporate protein measurement into clinical care. | Chen-Yang Su, Sirui Zhou, Edgar Gonzalez-Kozlova, Guillaume Butler-Laporte, Elsa Brunet-Ratnasingham, Tomoko Nakanishi, Wonseok Jeon, David R. Morrison, Laetitia Laurent, Jonathan Afilalo, Marc Afilalo, Danielle Henry, Yiheng Chen, Julia Carrasco-Zanini, Yossi Farjoun, Maik Pietzner, Nofar Kimchi, Zaman Afrasiabi, Nardin Rezk, Meriem Bouab, Louis Petitjean, Charlotte Guzman, Xiaoqing Xue, Chris Tselios, Branka Vulesevic, Olumide Adeleye, Tala Abdullah, Noor Almamlouk, Yara Moussa, Chantal DeLuca, Naomi Duggan, Erwin Schurr, Nathalie Brassard, Madeleine Durand, Diane Marie Del Valle, Ryan Thompson, Mario A. Cedillo, Eric Schadt, Kai Nie, Nicole W. Simons, Konstantinos Mouskas, Nicolas Zaki, Manishkumar Patel, Hui Xie, Jocelyn Harris, Robert Marvin, Esther Cheng, Kevin Tuballes, Kimberly Argueta, Ieisha Scott, The Mount Sinai COVID-19 Biobank Team, Celia M. T. Greenwood, Clare Paterson, Michael A. Hinterberg, Claudia Langenberg, Vincenzo Forgetta, Joelle Pineau, Vincent Mooser, Thomas Marron, Noam D. Beckmann, Seunghee Kim-schulze, Alexander W. Charney, Sacha Gnjatic, Daniel E. Kaufmann, Miriam Merad & J. Brent Richards | 04/17/2023 | ||||
| Multi-omics identify falling LRRC15 as a COVID-19 severity marker and persistent pro-thrombotic signals in convalescence | Gisby J S, et al. | 2022 | Nature Communications | Patients with end-stage kidney disease (ESKD) are at high risk of severe COVID19. Here, we perform longitudinal blood sampling of ESKD haemodialysis patients with COVID-19, collecting samples pre-infection, serially during infection, and after clinical recovery. Using plasma proteomics, and RNAsequencing and flow cytometry of immune cells, we identify transcriptomic and proteomic signatures of COVID-19 severity, and find distinct temporal molecular profiles in patients with severe disease. | Jack S. Gisby, Norzawani B. Buiang, Artemis Papadaki, Candice L. Clarke, Talat H. Malik, Nicholas Medjeral-Thomas, Damiola Pinheiro, Page M. Mortimer, Shanice Lewis, Eleanor Sandhu, Stephen P McAdoo, Maria F. Prendecki, Michelle Willicombe, Matthew C. Pickering, Marina Botto, David C Thomas, James E. Peters | 12/15/2022 | |||||||
| Siglec-7 is a predictive biomarker for the efficacy of cancer vaccination against metastatic colorectal cancer | Yamada K, et al. | 2021 | Oncol Lett | 21 | 1 | 10 | https://doi.org/10.3892/ol.2020.12271 | biomarker; colorectal cancer; peptide vaccine; protein expression analysis; sialic acid-binding immunoglobulin type lectin-7. | Cancer immunotherapy, including vaccination, is considered a major scientific and medical breakthrough. However, cancer immunotherapy does not result in durable objective responses against colorectal cancer (CRC). To improve the efficacy of immunotherapy, the present study investigated several biomarkers for selecting patients who were expected to respond well to immunotherapy. Firstly, a comprehensive proteomic analysis was performed using tumor tissue lysates from patients enrolled in a phase II study, in which five human leukocyte antigen (HLA)-A*24:02-restricted peptides were administered. Sialic acid-binding immunoglobulin type lectin (Siglec)-7 was identified as a potential predictive biomarker. Subsequently, this biomarker was validated using western blot analysis, and immunofluorescence using tissue samples from the patients enrolled in the phase II study. The expression levels of Siglec-7 detected by immunofluorescence were quantified and their association with overall survival (OS) in patients treated with the peptide vaccine was examined. Furthermore, considering the important role of tumor-infiltrating lymphocytes (TILs) for CRC prognosis, the densities of CD3+, CD4+, CD8+ and forkhead box P3 (FOXP3)+ T cells in CRC tissues were examined and compared with Siglec-7 expression. The mean expression levels of Siglec-7 were significantly higher in patients with poor prognosis, with an OS of ≤2 years, as shown in comprehensive proteomic analysis (P=0.016) and western blot analysis (P=0.025). Immunofluorescence analysis demonstrated that Siglec-7 was expressed in intratumoral macrophages. The OS in patients with high Siglec-7 expression was significantly shorter than in that in patients with low Siglec-7 expression (P=0.017) in the HLA-A*24:02-matched patients. However, this difference was not observed in the HLA-unmatched patients. There was no significant difference in OS between patients according to the numbers of TILs, nor significant correlation between TILs and Siglec-7 expression. In conclusion, Siglec-7 expression in macrophages in tumor tissue may be a novel predictive biomarker for the efficacy of immunotherapy against metastatic CRC. | Yamada K, Hazama S, Suzuki N, Xu M, Nakagami Y, Fujiwara N, Tsunedomi R, Yoshida S, Tomochika S, Matsukuma S, Matsui H, Tokumitsu Y, Kanekiyo S, Shindo Y, Watanabe Y, Iida M, Takeda S, Ioka T, Ueno T, Ogihara H, Hamamoto Y, Hoshii Y, Kawano H, Fujita T, Kawakami Y, Nagano H. | 11/03/2021 | ||
| High-Multiplex Aptamer-Based Serum Proteomics to Identify Candidate Serum Biomarkers of Oral Squamous Cell Carcinoma | Blatt S, et al. | 2023 | Cancers | 15 | 7 | 2071 | https://doi.org/10.3390/cancers15072071 | oral cancer; SOMAscan; proteomics; liquid biopsy; biomarker; serum; prognosis; therapy | Improved serological biomarkers are needed for the early detection, risk stratification and treatment surveillance of patients with oral squamous cell carcinoma (OSCC). We performed an exploratory study using advanced, highly specific, DNA-aptamer-based serum proteomics (SOMAscan, 1305-plex) to identify distinct proteomic changes in patients with OSCC pre- vs. post-resection and compared to healthy controls. A total of 63 significantly differentially expressed serum proteins (each p < 0.05) were found that could discriminate between OSCC and healthy controls with 100% accuracy. Furthermore, 121 proteins were detected that were significantly altered between pre- and post-resection sera, and 12 OSCC-associated proteins reversed to levels equivalent to healthy controls after resection. Of these, 6 were increased and 6 were decreased relative to healthy controls, highlighting the potential relevance of these proteins as OSCC tumor markers. Pathway analyses revealed potential pathophysiological mechanisms associated with OSCC. Hence, quantitative proteome analysis using SOMAscan technology is promising and may aid in the development of defined serum marker assays to predict tumor occurrence, progression and recurrence in OSCC, and to guide personalized therapies. | Blatt, S.; Kämmerer, P.W.; Krüger, M.; Surabattula, R.; Thiem, D.G.E.; Dillon, S.T.; Al-Nawas, B.; Libermann, T.A.; Schuppan, D. | 03/30/2023 | ||
| Effect of pegbelfermin on NASH and fibrosis-related biomarkers and correlation with histological response in the FALCON 1 trial | Elizabeth A. Brown, et al. | 2023 | JHEP Reports | FALCON 1 was a phase IIb study of pegbelfermin in patients with non-alcoholic steatohepatitis (NASH) and stage 3 fibrosis. This FALCON 1 post hoc analysis aimed to further assess the effect of pegbelfermin on NASH-related biomarkers, correlations between histological assessments and non-invasive biomarkers, and concordance between the week 24 histologically assessed primary endpoint response and biomarkers. | EA Brown, A Minnich, AJ Sanyal, R Loomba | 04/01/2023 | |||||||
| A proteomic approach for investigating the pleiotropic effects of statins in the atherosclerosis risk in communities (ARIC) study | Bruno Bohn, et al. | 2023 | Journal of Proteomics | Statins are prescribed to reduce LDL-c and risk of CVD. Statins have pleiotropic effects, affecting pathophysiological functions beyond LDL-c reduction. We compared the proteome of statin users and nonusers (controls). We hypothesized that statin use is associated with proteins unrelated to lipid metabolism. | B Bohn, PL Lutsey, W Tang, JS Pankow, FL Norby | 02/10/2023 | |||||||
| Circulatory proteins relate cardiovascular disease to cognitive performance: A mendelian randomisation study | Jian Huang, et al. | 2023 | Front Genet | Mechanistic research suggests synergistic effects of cardiovascular disease (CVD) and dementia pathologies on cognitive decline. Interventions targeting proteins relevant to shared mechanisms underlying CVD and dementia could also be used for the prevention of cognitive impairment. | J Huang, D Gill, V Zuber, PM Matthews, P Elliott | 02/17/2023 | |||||||
| High dimensional proteomics identifies organ injury patterns associated with outcomes in human trauma | Li, Shimena | 2023 | J Trauma Acute Care Surg | High-throughput proteomics allow researchers to simultaneously explore the roles of thousands of biomarkers in the pathophysiology of diabetes. We conducted proteomic association studies of incident type 2 diabetes and physiologic responses to an intravenous glucose tolerance test (IVGTT) to identify novel protein contributors to glucose homeostasis and diabetes risk. | 02/07/2023 | ||||||||
| Human influenza virus infection elicits distinct patterns of monocyte and dendritic cell mobilization in blood and the nasopharynx | Sindhu Vangeti, et al. | 2023 | Elife | uring respiratory viral infections, the precise roles of monocytes and dendritic cells (DCs) in the nasopharynx in limiting infection and influencing disease severity are incompletely described. We studied circulating and nasopharyngeal monocytes and DCs in healthy controls (HCs) and in patients with mild to moderate infections (primarily influenza A virus [IAV]). | Sindhu Vangeti, Sara Falck-Jones, Meng Yu, Björn Österberg, Sang Liu, Muhammad Asghar, Klara Sondén, Clare Paterson, Penn Whitley, Jan Albert, Niclas Johansson, Anna Färnert, Anna Smed-Sörensen | 02/08/2023 | |||||||
| Preclinical Serological Signatures are Associated with Complicated Crohn's Disease Phenotype at Diagnosis | Choung, RS. et al. | 2023 | Clinical Gastroenterology and Hepatology | At diagnosis, up to one-third of patients with Crohn’s disease (CD) have a complicated phenotype with stricturing (B2) or penetrating (B3) behavior or require early surgery. We evaluated protein biomarkers and antimicrobial antibodies in serum archived years before CD diagnosis to assess whether complicated diagnoses were associated with a specific serological signature. | 02/11/2023 | ||||||||
| PSMA2 knockdown impacts expression of proteins involved in immune and cellular stress responses in human lung cells | Rashid MU, et al. | 2023 | Biochim Biophys Acta Mol Basis | No study yet has reported PSMA2 knockdown (KD) effects on the cellular proteome. METHODS: We used SOMAScan, an aptamer-based multiplexed technique, to measure >1300 human proteins to determine the impact of PSMA2 KD on A549 human lung epithelial cells. ... | Meng Yu, | 12/01/2022 | |||||||
| Cross-sectional proteomic expression in Parkinson's disease-related proteins in drug-naive patients vs healthy controls with longitudinal clinical follow-up | Abdi IY, et al. | 2023 | Neurobiol Dis | There is an urgent need to find reliable and accessible blood-based biomarkers for early diagnosis of Parkinson's disease (PD) correlating with clinical symptoms and displaying predictive potential to improve future clinical trials. This led us to a conduct large-scale proteomics approach using an advanced high-throughput proteomics technology to create a proteomic profile for PD. Over 1300 proteins were measured in serum samples from a de novo Parkinson's (DeNoPa) cohort made up of 85 deep clinically phenotyped drug-naïve de novo PD patients and 93 matched healthy controls (HC) with longitudinal clinical follow-up available of up to 8 years. | Björn Österberg, | 01/10/2023 | |||||||
| Adjudicated myocarditis and multisystem illness trajectory in healthcare workers post-COVID-19. | Sykes R, et al. | 2023 | Open Heart | We investigated the associations of healthcare worker status with multisystem illness trajectory in hospitalised post-COVID-19 individuals. | Muhammad Asghar, | 02/10/2023 | |||||||
| PSMA2 knockdown impacts expression of proteins involved in immune and cellular stress responses in human lung cells | Rashid MU, et al. | 2022 | Biochim Biophys Acta Mol Basis | Proteasome subunit alpha type-2 (PSMA2) is a critical component of the 20S proteasome, which is the core particle of the 26S proteasome complex and is involved in cellular protein quality control by recognizing and recycling defective proteins. PSMA2 expression dysregulation has been detected in different human diseases and viral infections. No study yet has reported PSMA2 knockdown (KD) effects on the cellular proteome. | Penn Whitley, | 12/05/2022 | |||||||
| Multi-omics studies in historically excluded populations: the road to equity | G Yang, et al. | 2022 | Clinical Pharmacology & Therapeutics | Over the past few decades, genomewide association studies (GWASs) have identified the specific genetics variants contributing to many complex diseases by testing millions of genetic variations across the human genome against a variety of phenotypes. However, GWASs are limited in their ability to uncover mechanistic insight given that most significant associations are found in non-coding region of the genome. | Jan Albert, | 12/10/2022 | |||||||
| Proteomic profiling of serum identifies a molecular signature that correlates with clinical outcomes in COPD | R Dagher, et al. | 2022 | Plos One | Novel biomarkers related to main clinical hallmarks of Chronic obstructive pulmonary disease (COPD), a heterogeneous disorder with pulmonary and extra-pulmonary manifestations, were investigated by profiling the serum levels of 1305 proteins using Slow Off-rate Modified Aptamers (SOMA)scan technology. | Niclas Johansson, | 12/08/2022 | |||||||
| Radiation therapy induces innate immune responses in patients treated for prostate cancers | AK Cheema, et al. | 2022 | Clinical Cancer Research | Radiation therapy (RT) is a curative therapeutic modality used to treat cancers as a single agent or in combination with surgery and chemotherapy. Advanced RT technologies enable treatment with large fractions and highly conformal radiation doses to effect free-radical damage to cellular DNA leading to cell cycle arrest, cell death, and innate immune response (IIR) stimulation. | Anna Färnert, | 12/01/2022 | |||||||
| Molecular models of multiple sclerosis severity identify heterogeneity of pathogenic mechanisms | P Kosa, et al. | 2022 | Nature Communication | While autopsy studies identify many abnormalities in the central nervous system (CNS) of subjects dying with neurological diseases, without their quantification in living subjects across the lifespan, pathogenic processes cannot be differentiated from epiphenomena. Using machine learning (ML), we searched for likely pathogenic mechanisms of multiple sclerosis (MS). | Anna Smed-Sörensen | 12/12/2022 | |||||||
| Mendelian randomization and genetic colocalization infer the effects of the multi-tissue proteome on 211 complex disease-related phenotypes | C Yang, et al. | 2022 | Genome Medicine | Human proteins are widely used as drug targets. Integration of large-scale protein-level genome-wide association studies (GWAS) and disease-related GWAS has thus connected genetic variation to disease mechanisms via protein. Previous proteome-by-phenome-wide Mendelian randomization (MR) studies have been mainly focused on plasma proteomes. | C Yang, AM Fagan, RJ Perrin, H Rhinn, O Harari | 12/12/2022 | |||||||
| Comparison of Proteomic Measurements Across Platforms in the Atherosclerosis Risk in Communities (ARIC) Study. | Rooney Mary, et al. | 2022 | Clin Chem | The plasma proteome can be quantified using different types of highly multiplexed technologies, including aptamer-based and proximity-extension immunoassay methods. There has been limited characterization of how these protein measurements correlate across platforms and with absolute measures from targeted immunoassays. | Rooney MR, Chen J, Ballantyne CM, Hoogeveen RC, Tang O, Grams ME, Tin A, Ndumele CE, Zannad F, Couper DJ, Tang W, Selvin E, Coresh J. | 12/12/2022 | |||||||
| Predicting AT(N) pathologies in Alzheimer's disease from blood-based proteomic data using neural networks. | Zhang Y, et al. | 2022 | Front Aging Neurosci | Blood-based biomarkers represent a promising approach to help identify early Alzheimer's disease (AD). Previous research has applied traditional machine learning (ML) to analyze plasma omics data and search for potential biomarkers, but the most modern ML methods based on deep learning has however been scarcely explored. In the current study, we aim to harness the power of state-of-the-art deep learning neural networks (NNs) to identify plasma proteins that predict amyloid, tau, and neurodegeneration (AT[N]) pathologies in AD. | Zhang Y, Ghose U, Buckley NJ, Engelborghs S, Sleegers K, Frisoni GB, Wallin A, Lleó A, Popp J, Martinez-Lage P, Legido-Quigley C, Barkhof F, Zetterberg H, Visser PJ, Bertram L, Lovestone S, Nevado-Holgado AJ, Shi L. | 11/29/2022 | |||||||
| Defining the serum proteomic signature of hepatic steatosis, inflammation, ballooning and fibrosis in nonalcoholic fatty liver disease. | Sanyal AJ, et al. | 2022 | J Hepatol | Despite recent progress, non-invasive tests for the diagnostic assessment and monitoring of non-alcoholic fatty liver disease (NAFLD) remain an unmet need. Herein, we aimed to identify diagnostic signatures of the key histological features of NAFLD. | Sanyal AJ, Williams SA, Lavine JE, Tetri B, Alexander L, Ostroff R, Biegel H, Kowdley K, Chalasani N, Dasarathy S, Diehl AM, Loomba R, Hameed B, Behling C, Kleiner DE, Karpen SJ, Williams J, Jia Y, Yates KP, Tonascia J. | 12/14/2022 | |||||||
| Plasma proteomics reveals early, broad release of chemokine, cytokine, TNF, and interferon mediators following trauma with delayed increases in a subset of chemokines and cytokines in patients that remain critically ill. | Bonaroti J, et al. | 2022 | Front Immunol | Severe injury is known to cause a systemic cytokine storm that is associated with adverse outcomes. However, a comprehensive assessment of the time-dependent changes in circulating levels of a broad spectrum of protein immune mediators and soluble immune mediator receptors in severely injured trauma patients remains uncharacterized. | Bonaroti J, Billiar I, Moheimani H, Wu J, Namas R, Li S, Kar UK, Vodovotz Y, Neal MD, Sperry JL, Billiar TR. | 11/30/2022 | |||||||
| Aptamer proteomics of serum exosomes from patients with Primary Raynaud's and patients with Raynaud's at risk of evolving into Systemic Sclerosis. | Piera-Velazquez S, et al. | 2022 | PLoS One | A major unmet need for Systemic Sclerosis (SSc) clinical management is the lack of biomarkers for the early diagnosis of patients with Raynaud's Phenomenon at high risk of evolving into SSc. | Piera-Velazquez S, Dillon ST, Gu X, Libermann TA, Jimenez SA. | 12/22/2022 | |||||||
| Biomarkers of haemodynamic severity of systemic sclerosis-associated pulmonary arterial hypertension by serum proteome analysis. | Sanges S, et al. | 2022 | Ann Rheum Dis | To mine the serum proteome of patients with systemic sclerosis-associated pulmonary arterial hypertension (SSc-PAH) and to detect biomarkers that may assist in earlier and more effective diagnosis and treatment. | Sanges S, Rice L, Tu L, Valenzi E, Cracowski JL, Montani D, Mantero JC, Ternynck C, Marot G, Bujor AM, Hachulla E, Launay D, Humbert M, Guignabert C, Lafyatis R. | 12/05/2022 | |||||||
| Classical and alternate complement factor overexpression in non-obese weight matched women with polycystic ovary syndrome does not correlate with vitamin D. | Abu Saleh Md Moin, et al. | 2022 | Front Endocrinol (Lausanne) | Women with polycystic ovary syndrome (PCOS) exhibit complement factor expression changes that may be obesity-driven rather than an intrinsic facet of PCOS; furthermore, complement changes have been associated with vitamin D deficiency, a common feature of PCOS. Therefore, complement pathway proteins and vitamin D levels may be linked in PCOS. | Abu Saleh Md Moin 1, Thozhukat Sathyapalan 2, Alexandra E Butler 1, Stephen L Atkin 1 | 12/31/2022 | |||||||
| Differential Proteins Expression Distinguished Between Patients With Infectious and Noninfectious Uveitis. | Pesutti CL, et al. | 2023 | Ocul Immunol Inflamm | We investigated the aqueous humor proteome and associated plasma proteome in patients with infectious or noninfectious uveitis. | Pessuti CL, Medley QG, Li N, Huang CL, Loureiro J, Banks A, Zhang Q, Costa DF, Ribeiro KS, Nascimento H, Muccioli C, Commodaro AG, Huang Q, Belfort R Jr. | 01/13/2023 | |||||||
| Abstract A022: Proteomic age acceleration associated with all-cause mortality in cancer survivors in the Atherosclerosis Risk in Communities (ARIC) Study.[R] | Shuo Wang, et al. | 2023 | Cancer Research | Longer lifespan and improved cancer treatment led to a rapid rise in the number of cancer survivors. However, many cancer survivors have physiological dysregulations at earlier chronological ages than those without cancer, suggesting that cancer survivors’ biological age is higher than their chronological age, i.e., they have accelerated aging. Cancer survivors’ biological age may be estimated by a novel proteomic aging clock (PAC). | Shuo Wang | 01/15/2023 | |||||||
| Perinatal Mood and Anxiety Disorders: biomarker discovery using plasma proteomics. | Accortt E, et al. | 2023 | Am J Obstet Gynecol | Perinatal mood and anxiety disorders encompass a range of mental health disorders that occur during pregnancy and up to 1 year postpartum, affecting approximately 20% of women. Traditional risk factors, such as a history of depression and pregnancy complications including preeclampsia, are known. Their predictive utility, however, is not specific or sensitive enough to inform clinical decision-making or prevention strategies for perinatal mood and anxiety disorders. Better diagnostic and prognostic models are needed for early identification and referral to treatment. | Accortt E, Mirocha J, Zhang D, Kilpatrick SJ, Libermann T, Karumanchi SA. | 01/14/2023 | |||||||
| Proteomic Predictors of Incident Diabetes: Results From the Atherosclerosis Risk in Communities (ARIC) Study | Rooney Mary, et al. | 2023 | Diabetes Care | The plasma proteome preceding diabetes can improve our understanding of diabetes pathogenesis. | 01/27/2023 | ||||||||
| Identification of a possible proteomic biomarker in Parkinson's disease: discovery and replication in blood, brain and cerebrospinal fluid. | Winchester L, et al. | 2022 | Brain Commun | Biomarkers to aid diagnosis and delineate the progression of Parkinson's disease are vital for targeting treatment in the early phases of the disease. Here, we aim to discover a multi-protein panel representative of Parkinson's and make mechanistic inferences from protein expression profiles within the broader objective of finding novel biomarkers. | Winchester L, Barber I, Lawton M, Ash J, Liu B, Evetts S, Hopkins-Jones L, Lewis S, Bresner C, Malpartida AB, Williams N, Gentlemen S, Wade-Martins R, Ryan B, Holgado-Nevado A, Hu M, Ben-Shlomo Y, Grosset D, Lovestone S. | 12/28/2022 | |||||||
| Exocrine Proteins Including Trypsin(ogen) as a Key Biomarker in Type 1 Diabetes. | Bakinowska L, et al. | 2023 | Diabetes Care | Diabetes | Proteomic profiling can identify useful biomarkers. Monozygotic (MZ) twins discordant for a condition represent an ideal test population. We aimed to investigate and validate proteomic profiling in twins with type 1 diabetes and in other well-characterized cohorts. | Bakinowska L, Vartak T, Phuthego T, Taylor M, Chandler K, Jerram ST, Williams S, Feldmann M, Johnson DG, Patel KA, Williams AJK, Long AE, Leslie RD, Gillespie KM; Action LADA Consortium and BOX Study Group. | 01/26/2023 | ||||||
| Analytical and Biological Variability of a Commercial Modified Aptamer Assay in Plasma Samples of Patients with Chronic Kidney Disease. | Dubin RF, et al. | 2023 | J Appl Lab Med | We carried out a study of the aptamer proteomic assay, SomaScan V4, to evaluate the analytical and biological variability of the assay in plasma samples of patients with moderate to severe chronic kidney disease (CKD). | Dubin RF, Deo R, Ren Y, Lee H, Shou H, Feldman H, Kimmel P, Waikar SS, Rhee EP, Tin A, Chen J, Coresh J, Go AS, Kelly T, Rao PS, Chen TK, Segal MR, Ganz P. | 01/27/2023 | |||||||
| Proteomic aptamer analysis reveals serum markers that characterize preclinical systemic sclerosis (SSc) patients at risk for progression toward definite SSc. | Bellocchi C et al. | 2023 | Arthritis Res Ther. | Bellocchi C, Assassi S, Lyons M, Marchini M, Mohan C, Santaniello A, Beretta L. | |||||||||
| Abstract WMP101: Plasma Proteomic Determinants Of White Matter Hyperintensities And Covert Brain Infarction In The Cardiovascular Health Study | Sharma, M, et al. | 2023 | Stroke | Identification of novel biomarkers of cerebral small vessel disease is critical to elucidate pathophysiology and guide therapeutic development for prevention. We evaluated plasma proteomic associations of clinically asymptomatic … | M Sharma, WT Longstreth, R Kalani, B Psaty, M Elkind | ||||||||
| Aptamer-Based Plasma Proteomics Nominates Biomarkers Of Neurological Severity, Stroke Diagnosis And Age | A Natu | 2023 | Stroke | Plasma protein biomarkers measured in the hyperacute setting that are associated with stroke diagnosis or with clinical neurological severity, can be diagnostically and prognostically meaningful in patient care. We hypothesized that … | A Natu, P Kumar, MR Frankel, S RANGARAJU | ||||||||
| Proteomic Mediators of Overall Cardiovascular Health on All-Cause Mortality | T Tanaka | 2023 | Nutrients | … The hybridization controls, viral proteins, and flagged SOMAmer Reagents were removed, resulting in a total of 1301 SOMAmer Reagents that were used in the final analysis. Some of the SOMAmer Reagents are designed to capture multiplex … | T Tanaka, SA Talegawkar, Y Jin, J Candia, G Fantoni… - Nutrients, 2023 | ||||||||
| Broadly neutralizing aptamers to SARS-CoV-2: a diverse panel of modified DNA antiviral agents. | Gelinas AD | 2023 | Mol Ther Nucleic Acids | Gelinas AD, Tan TK, Liu S, Jaramillo JG, Chadwick J, Harding AC, Zhang C, Ream BE, Chase CN, Otis MR, Lee T, Schneider DJ, James WS, Janjic N. | |||||||||
| Novel biomarkers and emerging tools to identify causal molecular pathways in hypertension and associated cardiovascular diseases. | Jozefczuk E, et al. | 2023 | Kardiol Pol | Józefczuk E, Guzik TJ, Siedlinski M. | |||||||||
| CXCL13 is a predictive biomarker in idiopathic multicentric Castleman disease | Pierson SK, et al. | 2022 | Nat Commun | 13 | 1 | 7236 | https://www.doi.org/10.1038/s41467-022-34873-7 | 36,433,996 | Humans *Castleman Disease/drug therapy Biomarkers Healthy Volunteers Immunotherapy Chemokine CXCL13 | Idiopathic multicentric Castleman disease (iMCD) is a rare and poorly-understood cytokine storm-driven inflammatory disorder. Interleukin-6 (IL-6) is a known disease driver in some patients, but anti-IL-6 therapy with siltuximab is not effective in all patients, and biomarkers indicating success at an early time point following treatment initiation are lacking. Here we show, by comparison of levels of 1,178 proteins in sera of healthy participants (N = 42), patients with iMCD (N = 88), and with related diseases (N = 60), a comprehensive landscape of candidate disease mediators and predictors of siltuximab response. C-X-C Motif Chemokine Ligand-13 (CXCL13) is identified and validated as the protein most prominently up-regulated in iMCD. Early and significant decrease in CXCL13 levels clearly distinguishes siltuximab responders from non-responders; a 17% reduction by day 8 following siltuximab therapy initiation is predictive of response at later time points. Our study thus suggests that CXCL13 is a predictive biomarker of response to siltuximab in iMCD. | Pierson, Sheila K Katz, Laura Williams, Reece Mumau, Melanie Gonzalez, Michael Guzman, Stacy Rubenstein, Ayelet Oromendia, Ana B Beineke, Philip Fossa, Alexander van Rhee, Frits Fajgenbaum, David C eng R01HL141408/U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ England Nat Commun. 2022 Nov 24;13(1):7236. doi: 10.1038/s41467-022-34873-7.I | 11/27/2022 | |
| The Childhood Acute Illness and Nutrition (CHAIN) network nested case-cohort study protocol: a multi-omics approach to understanding mortality among children in sub-Saharan Africa and South Asia | Njunge JM, et al. | 2022 | Gates Open Res | 6 | 77 | https://www.doi.org/10.12688/gatesopenres.13635.2 | 36,415,883 | Case-Cohort Children Lmic Mortality Omics Systems Biology | Introduction: Many acutely ill children in low- and middle-income settings have a high risk of mortality both during and after hospitalisation despite guideline-based care. Understanding the biological mechanisms underpinning mortality may suggest optimal pathways to target for interventions to further reduce mortality. The Childhood Acute Illness and Nutrition (CHAIN) Network ( www.chainnnetwork.org) Nested Case-Cohort Study (CNCC) aims to investigate biological mechanisms leading to inpatient and post-discharge mortality through an integrated multi-omic approach. Methods and analysis; The CNCC comprises a subset of participants from the CHAIN cohort (1278/3101 hospitalised participants, including 350 children who died and 658 survivors, and 270/1140 well community children of similar age and household location) from nine sites in six countries across sub-Saharan Africa and South Asia. Systemic proteome, metabolome, lipidome, lipopolysaccharides, haemoglobin variants, toxins, pathogens, intestinal microbiome and biomarkers of enteropathy will be determined. Computational systems biology analysis will include machine learning and multivariate predictive modelling with stacked generalization approaches accounting for the different characteristics of each biological modality. This systems approach is anticipated to yield mechanistic insights, show interactions and behaviours of the components of biological entities, and help develop interventions to reduce mortality among acutely ill children. Ethics and dissemination. The CHAIN Network cohort and CNCC was approved by institutional review boards of all partner sites. Results will be published in open access, peer reviewed scientific journals and presented to academic and policy stakeholders. Data will be made publicly available, including uploading to recognised omics databases. Trial registration NCT03208725. | Njunge, James M Tickell, Kirkby Diallo, Abdoulaye Hama Sayeem Bin Shahid, Abu Sadat Mohammad Gazi, Md Amran Saleem, Ali Kazi, Zaubina Ali, Syed Tigoi, Caroline Mupere, Ezekiel Lancioni, Christina L Yoshioka, Emily Chisti, Mohammod Jobayer Mburu, Moses Ngari, Moses Ngao, Narshion Gichuki, Bonface Omer, Elisha Gumbi, Wilson Singa, Benson Bandsma, Robert Ahmed, Tahmeed Voskuijl, Wieger Williams, Thomas N Macharia, Alex Makale, Johnstone Mitchel, Anna Williams, Jessica Gogain, Joe Janjic, Nebojsa Mandal, Rupasri Wishart, David S Wu, Hang Xia, Lei Routledge, Michael Gong, Yun Yun Espinosa, Camilo Aghaeepour, Nima Liu, Jie Houpt, Eric Lawley, Trevor D Browne, Hilary Shao, Yan Rwigi, Doreen Kariuki, Kevin Kaburu, Timothy Uhlig, Holm H Gartner, Lisa Jones, Kelsey Koulman, Albert Walson, Judd Berkley, James eng Gates Open Res. 2022 Nov 3;6:77. doi: 10.12688/gatesopenres.13635.2. eCollection 2022.I | 11/25/2022 | ||
| Thirty novel sequence variants impacting human intracranial volume | Nawaz MS, et al. | 2022 | Brain Commun | 4 | 6 | fcac271 | https://www.doi.org/10.1093/braincomms/fcac271 | 36,415,660 | Mendelian randomization brain structure genetic correlation genome-wide association study intracranial volume | Intracranial volume, measured through magnetic resonance imaging and/or estimated from head circumference, is heritable and correlates with cognitive traits and several neurological disorders. We performed a genome-wide association study meta-analysis of intracranial volume (n = 79 174) and found 64 associating sequence variants explaining 5.0% of its variance. We used coding variation, transcript and protein levels, to uncover 12 genes likely mediating the effect of these variants, including GLI3 and CDK6 that affect cranial synostosis and microcephaly, respectively. Intracranial volume correlates genetically with volumes of cortical and sub-cortical regions, cognition, learning, neonatal and neurological traits. Parkinson's disease cases have greater and attention deficit hyperactivity disorder cases smaller intracranial volume than controls. Our Mendelian randomization studies indicate that intracranial volume associated variants either increase the risk of Parkinson's disease and decrease the risk of attention deficit hyperactivity disorder and neuroticism or correlate closely with a confounder. | Nawaz, Muhammad Sulaman Einarsson, Gudmundur Bustamante, Mariana Gisladottir, Rosa S Walters, G Bragi Jonsdottir, Gudrun A Skuladottir, Astros Th Bjornsdottir, Gyda Magnusson, Sigurdur H Asbjornsdottir, Bergrun Unnsteinsdottir, Unnur Sigurdsson, Engilbert Jonsson, Palmi V Palmadottir, Vala Kolbrun Gudjonsson, Sigurjon A Halldorsson, Gisli H Ferkingstad, Egil Jonsdottir, Ingileif Thorleifsson, Gudmar Holm, Hilma Thorsteinsdottir, Unnur Sulem, Patrick Gudbjartsson, Daniel F Stefansson, Hreinn Thorgeirsson, Thorgeir E Ulfarsson, Magnus O Stefansson, Kari eng England Brain Commun. 2022 Oct 25;4(6):fcac271. doi: 10.1093/braincomms/fcac271. eCollection 2022.I | 11/24/2022 | |
| Are EPB41 and alpha-synuclein diagnostic biomarkers of sport-related concussion?Findings from the NCAA and Department of Defense CARE Consortium | Vorn R, et al. | 2022 | J Sport Health Sci | epub ahead of print | https://www.doi.org/10.1016/j.jshs.2022.11.007 | 36,403,906 | Biomarkers College athletes Concussion Mild traumatic brain injury Sport injury | BACKGROUND: Current protein biomarkers are only moderately predictive at identifying individuals with mild traumatic brain injury or concussion. Therefore, more accurate diagnostic markers are needed for sport-related concussion (SRC). METHODS: This was a multicenter, prospective, case-control study of athletes who provided blood samples and were diagnosed with a concussion or were a matched non-concussed control within the NCAA-DoD Concussion Assessment, Research, and Education (CARE) Consortium conducted between 2015 and 2019. The blood was collected within 48 h of injury to identify protein abnormalities at the acute and subacute timepoints. Athletes with concussion were divided into 6 h post-injury (0-6 h post-injury) and after 6 h post-injury (7-48 hours post-injury) groups. We applied a highly multiplexed proteomic technique that used a DNA aptamers assay to target 1305 proteins in plasma samples from athletes with and without SRC. RESULTS: A total of 140 athletes with concussion (79.3% male; aged 18.71 +/- 1.10 years, mean +/- SD) and 21 non-concussed athletes (76.2% male; 19.14 +/- 1.10 years) were included in this study. We identified 338 plasma proteins that significantly differed in abundance (319 upregulated and 19 downregulated) in concussed athletes compared to non-concussed athletes. The top 20 most differentially abundant proteins discriminated concussed athletes from non-concussed athletes with an area under the curve (AUC) of 0.954 (95% confidence interval: 0.922_0.986). Specifically, after 6 h of injury, the individual AUC of plasma erythrocyte membrane protein band 4.1 (EPB41) and alpha-synuclein (SNCA) were 0.956 and 0.875, respectively. The combination of EPB41 and SNCA provided the best AUC (1.000), which suggests this combination of candidate plasma biomarkers is best for diagnosing concussion in athletes after 6 h of injury. CONCLUSION: Our data suggest that proteomic profiling may provide novel diagnostic protein markers and that a combination of EPB41 and SNCA is the most predictive biomarker of concussion after 6 h of injury. | Vorn, Rany Devoto, Christina Meier, Timothy B Lai, Chen Yun, Sijung Broglio, Steven P Mithani, Sara McAllister, Thomas W Giza, Christopher C Kim, Hyung-Suk Huber, Daniel Harezlak, Jaroslaw Cameron, Kenneth L McGinty, Gerald Jackson, Jonathan Guskiewicz, Kevin M Mihalik, Jason P Brooks, Alison Duma, Stefan Rowson, Steven Nelson, Lindsay D Pasquina, Paul McCrea, Michael A Gill, Jessica M eng China J Sport Health Sci. 2022 Nov 17:S2095-2546(22)00114-4. doi: 10.1016/j.jshs.2022.11.007.I | 11/21/2022 | |||
| Metabolic and proteomic signatures of type 2 diabetes subtypes in an Arab population | Zaghlool SB, et al. | 2022 | Nat Commun | 13 | 1 | 7121 | https://www.doi.org/10.1038/s41467-022-34754-z | 36,402,758 | Humans *Diabetes Mellitus, Type 2/genetics/metabolism Proteomics Arabs *Diabetes Mellitus, Type 1 Insulin | Type 2 diabetes (T2D) has a heterogeneous etiology influencing its progression, treatment, and complications. A data driven cluster analysis in European individuals with T2D previously identified four subtypes: severe insulin deficient (SIDD), severe insulin resistant (SIRD), mild obesity-related (MOD), and mild age-related (MARD) diabetes. Here, the clustering approach was applied to individuals with T2D from the Qatar Biobank and validated in an independent set. Cluster-specific signatures of circulating metabolites and proteins were established, revealing subtype-specific molecular mechanisms, including activation of the complement system with features of autoimmune diabetes and reduced 1,5-anhydroglucitol in SIDD, impaired insulin signaling in SIRD, and elevated leptin and fatty acid binding protein levels in MOD. The MARD cluster was the healthiest with metabolomic and proteomic profiles most similar to the controls. We have translated the T2D subtypes to an Arab population and identified distinct molecular signatures to further our understanding of the etiology of these subtypes. | Zaghlool, Shaza B Halama, Anna Stephan, Nisha Gudmundsdottir, Valborg Gudnason, Vilmundur Jennings, Lori L Thangam, Manonanthini Ahlqvist, Emma Malik, Rayaz A Albagha, Omar M E Abou-Samra, Abdul Badi Suhre, Karsten eng NPRP11C-0115-180010/Qatar Foundation (Qatar Foundation for Education, Science and Community Development)/ England Nat Commun. 2022 Nov 19;13(1):7121. doi: 10.1038/s41467-022-34754-z.I | 11/20/2022 | |
| Multi-platform proteomic analysis of Alzheimer's disease cerebrospinal fluid and plasma reveals network biomarkers associated with proteostasis and the matrisome | Dammer EB, et al. | 2022 | Alzheimers Res Ther | 14 | 1 | 174 | https://www.doi.org/10.1186/s13195-022-01113-5 | 36,384,809 | Humans *Alzheimer Disease/cerebrospinal fluid Proteomics Proteostasis Amyloid beta-Peptides/cerebrospinal fluid Biomarkers/cerebrospinal fluid | Robust and accessible biomarkers that can capture the heterogeneity of Alzheimer's disease and its diverse pathological processes are urgently needed. Here, we undertook an investigation of Alzheimer's disease cerebrospinal fluid (CSF) and plasma from the same subjects (n=18 control, n=18 AD) using three different proteomic platforms-SomaLogic SomaScan, Olink proximity extension assay, and tandem mass tag-based mass spectrometry-to assess which protein markers in these two biofluids may serve as reliable biomarkers of AD pathophysiology observed from unbiased brain proteomics studies. Median correlation of overlapping protein measurements across platforms in CSF (r~0.7) and plasma (r~0.6) was good, with more variability in plasma. The SomaScan technology provided the most measurements in plasma. Surprisingly, many proteins altered in AD CSF were found to be altered in the opposite direction in plasma, including important members of AD brain co-expression modules. An exception was SMOC1, a key member of the brain matrisome module associated with amyloid-beta deposition in AD, which was found to be elevated in both CSF and plasma. Protein co-expression analysis on greater than 7000 protein measurements in CSF and 9500 protein measurements in plasma across all proteomic platforms revealed strong changes in modules related to autophagy, ubiquitination, and sugar metabolism in CSF, and endocytosis and the matrisome in plasma. Cross-platform and cross-biofluid proteomics represents a promising approach for AD biomarker development. | Dammer, Eric B Ping, Lingyan Duong, Duc M Modeste, Erica S Seyfried, Nicholas T Lah, James J Levey, Allan I Johnson, Erik C B eng K08 AG068604/AG/NIA NIH HHS/ P30 AG066511/AG/NIA NIH HHS/ U54 AG065187/AG/NIA NIH HHS/ England Alzheimers Res Ther. 2022 Nov 17;14(1):174. doi: 10.1186/s13195-022-01113-5.I | 11/18/2022 | |
| Proteomic signatures for identification of impaired glucose tolerance | Carrasco-Zanini J, et al. | 2022 | Nat Med | 28 | 11 | 2293-2300 | https://www.doi.org/10.1038/s41591-022-02055-z | 36,357,677 | Humans *Glucose Intolerance/diagnosis *Diabetes Mellitus, Type 2/diagnosis Blood Glucose/metabolism Proteomics Glucose Tolerance Test Fasting | The implementation of recommendations for type 2 diabetes (T2D) screening and diagnosis focuses on the measurement of glycated hemoglobin (HbA1c) and fasting glucose. This approach leaves a large number of individuals with isolated impaired glucose tolerance (iIGT), who are only detectable through oral glucose tolerance tests (OGTTs), at risk of diabetes and its severe complications. We applied machine learning to the proteomic profiles of a single fasted sample from 11,546 participants of the Fenland study to test discrimination of iIGT defined using the gold-standard OGTTs. We observed significantly improved discriminative performance by adding only three proteins (RTN4R, CBPM and GHR) to the best clinical model (AUROC = 0.80 (95% confidence interval: 0.79-0.86), P = 0.004), which we validated in an external cohort. Increased plasma levels of these candidate proteins were associated with an increased risk for future T2D in an independent cohort and were also increased in individuals genetically susceptible to impaired glucose homeostasis and T2D. Assessment of a limited number of proteins can identify individuals likely to be missed by current diagnostic strategies and at high risk of T2D and its complications. | Carrasco-Zanini, Julia Pietzner, Maik Lindbohm, Joni V Wheeler, Eleanor Oerton, Erin Kerrison, Nicola Simpson, Missy Westacott, Matthew Drolet, Dan Kivimaki, Mika Ostroff, Rachel Williams, Stephen A Wareham, Nicholas J Langenberg, Claudia eng MC_UU_12015/1/RCUK | Medical Research Council (MRC)/ R024227/RCUK | Medical Research Council (MRC)/ MC_PC_13046/RCUK | Medical Research Council (MRC)/ 220044/Z/19/Z/Wellcome Trust (Wellcome)/ 221854/Z/20/Z/Wellcome Trust (Wellcome)/ 311492/Academy of Finland (Suomen Akatemia)/ 339568/Academy of Finland (Suomen Akatemia)/ Nat Med. 2022 Nov;28(11):2293-2300. doi: 10.1038/s41591-022-02055-z. Epub 2022 Nov 10.I | 11/11/2022 | |
| Identifying causal serum protein-cardiometabolic trait relationships using whole genome sequencing | Png G, et al. | 2022 | Hum Mol Genet | epub ahead of print | https://www.doi.org/10.1093/hmg/ddac275 | 36,349,687 | Cardiometabolic diseases, such as type 2 diabetes and cardiovascular disease, have a high public health burden. Understanding the genetically-determined regulation of proteins that are dysregulated in disease can help to dissect the complex biology underpinning them. Here, we perform a protein quantitative trait locus (pQTL) analysis of 255 serum proteins relevant to cardiometabolic processes in 2893 individuals. Meta-analysing whole-genome sequencing (WGS) data from two Greek cohorts, MANOLIS (n = 1356; 22.5x WGS) and Pomak (n = 1537; 18.4x WGS), we detect 302 independently-associated pQTL variants for 171 proteins, including 12 rare variants (minor allele frequency [MAF] < 1%). We additionally find 15 pQTL variants that are rare in non-Finnish European populations, but have drifted up in frequency in the discovery cohorts here. We identify proteins causally associated with cardiometabolic traits, including MEP1B for high-density lipoprotein levels; and describe a knock-out Mep1b mouse model. Our findings furnish insights into the genetic architecture of the serum proteome, identify new protein-disease relationships, and demonstrate the importance of isolated populations in pQTL analysis. | Png, Grace Gerlini, Raffaele Hatzikotoulas, Konstantinos Barysenka, Andrei Rayner, N William Klaric, Lucija Rathkolb, Birgit Aguilar-Pimentel, Juan A Rozman, Jan Fuchs, Helmut Gailus-Durner, Valerie Tsafantakis, Emmanouil Karaleftheri, Maria Dedoussis, George Pietrzik, Claus Wilson, James F Angelis, Martin Hrabe Becker-Pauly, Christoph Gilly, Arthur Zeggini, Eleftheria eng England Hum Mol Genet. 2022 Nov 9:ddac275. doi: 10.1093/hmg/ddac275.I | 11/10/2022 | ||||
| Omics-based biomarkers discovery for Alzheimer's disease | Aerqin Q, et al. | 2022 | Cell Mol Life Sci | 79 | 12 | 585 | https://www.doi.org/10.1007/s00018-022-04614-6 | 36,348,101 | Humans *Alzheimer Disease/diagnosis/genetics/pathology Metabolomics Biomarkers Proteomics Genomics Alzheimer's disease Epigenomics Transcriptomics | Alzheimer's disease (AD) is the most common neurodegenerative disorders presenting with the pathological hallmarks of amyloid plaques and tau tangles. Over the past few years, great efforts have been made to explore reliable biomarkers of AD. High-throughput omics are a technology driven by multiple levels of unbiased data to detect the complex etiology of AD, and it provides us with new opportunities to better understand the pathophysiology of AD and thereby identify potential biomarkers. Through revealing the interaction networks between different molecular levels, the ultimate goal of multi-omics is to improve the diagnosis and treatment of AD. In this review, based on the current AD pathology and the current status of AD diagnostic biomarkers, we summarize how genomics, transcriptomics, proteomics and metabolomics are all conducing to the discovery of reliable AD biomarkers that could be developed and used in clinical AD management. | Aerqin, Qiaolifan Wang, Zuo-Teng Wu, Kai-Min He, Xiao-Yu Dong, Qiang Yu, Jin-Tai eng 82071201/National Natural Science Foundation of China/ 81971032/National Natural Science Foundation of China/ No.2018SHZDZX01/Shanghai Municipal Science and Technology Major Project/ 2022QD002/Doctoral Scientific Research Start-up Foundation from Henan University of Technology/ 3030277001/Excellence 2025 Talent Cultivation Program at Fudan University/ Review Switzerland Cell Mol Life Sci. 2022 Nov 8;79(12):585. doi: 10.1007/s00018-022-04614-6.I | 11/09/2022 | |
| Novel plasma and brain proteins that are implicated in multiple sclerosis | Lin X, et al. | 2022 | Brain | epub ahead of print | https://www.doi.org/10.1093/brain/awac420 | 36,346,149 | Multiple sclerosis biomarkers proteomics transcriptomics | Understanding how variations in the plasma and brain proteome contribute to multiple sclerosis susceptibility can provide important insights to guide drug repurposing and therapeutic development for multiple sclerosis. However, the role of genetically predicted protein abundance in multiple sclerosis remains largely unknown. Integrating plasma proteomics (n = 3,301) and brain proteomics (n = 376 discovery; n = 152 replication) into multiple sclerosis genome-wide association studies (n = 14,802 cases and 26,703 controls), we employed summary-based methods to identify candidate proteins involved in multiple sclerosis susceptibility. Next, we evaluated associations of the corresponding genes with multiple sclerosis at tissue-level using large gene expression quantitative trait data from whole-blood (n = 31,684) and brain (n = 1,194) tissue. Further, to assess transcriptional profiles for candidate proteins at cell-level, we examined gene expression patterns in immune cell types (dataset 1: n = 73 cases and 97 controls; dataset 2: n = 31 cases and 31 controls) for identified plasma proteins, and in brain cell types (dataset 1: n = 4 cases and 5 controls; dataset 2: n = 5 cases and 3 controls) for identified brain proteins. In a longitudinal multiple sclerosis cohort (n = 203 cases followed up to 15 years), we also assessed the corresponding gene-level associations with the outcome of disability worsening. We identified 39 novel proteins associated with multiple sclerosis risk. Based on five identified plasma proteins, four available corresponding gene candidates showed consistent associations with multiple sclerosis risk in whole-blood, and we found TAPBPL upregulation in multiple sclerosis B cells, CD8+ T cells and natural killer cells compared to controls. Among the 34 candidate brain proteins, 18 were replicated in a smaller cohort and 14 of 21 available corresponding gene candidates also showed consistent associations with multiple sclerosis risk in brain tissue. In cell-specific analysis, six identified brain candidates showed consistent differential gene expression in neuron and oligodendrocyte cell clusters. Based on the 39 protein-coding genes, we found 23 genes that were associated with disability worsening in multiple sclerosis cases. The findings present a set of candidate protein biomarkers for multiple sclerosis, reinforced by high concordance in downstream transcriptomics findings at tissue-level. This study also highlights the heterogeneity of cell-specific transcriptional profiles for the identified proteins, and that numerous candidates were also implicated in disease progression. Together, these findings can serve as an important anchor for future studies of disease mechanisms and therapeutic development. | Lin, Xin Yang, Yuanhao Gresle, Melissa Cuellar-Partida, Gabriel Han, Xikun Stankovich, Jim Fuh-Ngwa, Valery Charlesworth, Jac Burdon, Kathryn P Butzkueven, Helmut Taylor, Bruce V Zhou, Yuan eng England Brain. 2022 Nov 8:awac420. doi: 10.1093/brain/awac420.I | 11/09/2022 | |||
| Macrophage migration inhibitory factor promotes glucocorticoid resistance of neutrophilic inflammation in a murine model of severe asthma | Allam V, et al. | 2022 | Thorax | epub ahead of print | https://www.doi.org/10.1136/thorax-2021-218555 | 36,344,253 | asthma asthma mechanisms cytokine biology have nothing to disclose. EFM reports grants from Janssen, Bristol Myers Squibb, UCB, Merck Serono and Eli Lilly outside the submitted work. In addition, EFM has patents 7,709,514 and 7,863,313 issued. KFC has received honoraria for participating in advisory board meetings of GlaxoSmithKline, AstraZeneca, Novartis, Merck, Boehringer Ingelheim and TEVA regarding treatments for asthma and chronic obstructive pulmonary disease and has also been renumerated for speaking engagements. IA and PS report grants from the public private European Union Innovative Medicines Initiative during the conduct of the study. RD reports receiving fees for lectures at symposia organised by Novartis, AstraZeneca and TEVA consultation for TEVA and Novartis as member of advisory boards and participation in a scientific discussion about asthma organised by GlaxoSmithKline. RD is a cofounder and current consultant and has shares in Synairgen, a University of Southampton spin-out company. | BACKGROUND: Severe neutrophilic asthma is resistant to treatment with glucocorticoids. The immunomodulatory protein macrophage migration inhibitory factor (MIF) promotes neutrophil recruitment to the lung and antagonises responses to glucocorticoids. We hypothesised that MIF promotes glucocorticoid resistance of neutrophilic inflammation in severe asthma. METHODS: We examined whether sputum MIF protein correlated with clinical and molecular characteristics of severe neutrophilic asthma in the Unbiased Biomarkers for the Prediction of Respiratory Disease Outcomes (U-BIOPRED) cohort. We also investigated whether MIF regulates neutrophilic inflammation and glucocorticoid responsiveness in a murine model of severe asthma in vivo. RESULTS: MIF protein levels positively correlated with the number of exacerbations in the previous year, sputum neutrophils and oral corticosteroid use across all U-BIOPRED subjects. Further analysis of MIF protein expression according to U-BIOPRED-defined transcriptomic-associated clusters (TACs) revealed increased MIF protein and a corresponding decrease in annexin-A1 protein in TAC2, which is most closely associated with airway neutrophilia and NLRP3 inflammasome activation. In a murine model of severe asthma, treatment with the MIF antagonist ISO-1 significantly inhibited neutrophilic inflammation and increased glucocorticoid responsiveness. Coimmunoprecipitation studies using lung tissue lysates demonstrated that MIF directly interacts with and cleaves annexin-A1, potentially reducing its biological activity. CONCLUSION: Our data suggest that MIF promotes glucocorticoid-resistance of neutrophilic inflammation by reducing the biological activity of annexin-A1, a potent glucocorticoid-regulated protein that inhibits neutrophil accumulation at sites of inflammation. This represents a previously unrecognised role for MIF in the regulation of inflammation and points to MIF as a potential therapeutic target for the management of severe neutrophilic asthma. | Allam, Venkata Sita Rama Raju Pavlidis, Stelios Liu, Gang Kermani, Nazanin Zounemat Simpson, Jennifer To, Joyce Donnelly, Sheila Guo, Yi-Ke Hansbro, Philip M Phipps, Simon Morand, Eric F Djukanovic, Ratko Sterk, Peter Chung, Kian Fan Adcock, Ian Harris, James Sukkar, Maria B eng England Thorax. 2022 Nov 7:thoraxjnl-2021-218555. doi: 10.1136/thorax-2021-218555.I | 11/08/2022 | |||
| Vascular endothelial-cadherin as a marker of endothelial injury in preclinical Alzheimer disease | Tarawneh R, et al. | 2022 | Ann Clin Transl Neurol | epub ahead of print | https://www.doi.org/10.1002/acn3.51685 | 36,342,663 | OBJECTIVE: Endothelial dysfunction is an early and prevalent pathology in Alzheimer disease (AD). We here investigate the value of vascular endothelial-cadherin (VEC) as a cerebrospinal fluid (CSF) marker of endothelial injury in preclinical AD. METHODS: Cognitively normal participants (Clinical Dementia Rating [CDR] 0) from the Knight Washington University-ADRC were included in this study (n = 700). Preclinical Alzheimer's Cognitive Composite (PACC) scores, CSF VEC, tau, p-tau181, Abeta42/Abeta40, neurofilament light-chain (NFL) levels, and magnetic resonance imaging (MRI) assessments of white matter injury (WMI) were obtained from all participants. A subset of participants underwent brain amyloid imaging using positron emission tomography (amyloid-PET) (n = 534). Linear regression examined associations of CSF VEC with PACC and individual cognitive scores in preclinical AD. Mediation analyses examined whether CSF VEC mediated effects of CSF amyloid and tau markers on cognition in preclinical AD. RESULTS: CSF VEC levels significantly correlated with PACC and individual cognitive scores in participants with amyloid (A+T+/-N+/-; n = 558) or those with amyloid and tau pathologies (A+T+N+/-; n = 259), after adjusting for covariates. CSF VEC also correlated with CSF measures of amyloid, tau, and neurodegeneration and global amyloid burden on amyloid-PET scans in our cohort. Importantly, our findings suggest that CSF VEC mediates associations of CSF Abeta42/Abeta40, p-tau181, and global amyloid burden with cognitive outcomes in preclinical AD. INTERPRETATION: Our results support the utility of CSF VEC as a marker of endothelial injury in AD and highlight the importance of endothelial injury as an early pathology that contributes to cognitive impairment in even the earliest preclinical stages. | Tarawneh, Rawan Kasper, Rachel S Sanford, Jessie Phuah, Chia-Ling Hassenstab, Jason Cruchaga, Carlos eng 3962/The Foundation for Barnes-Jewish Hospital/ P50AG05681/National Institutes of Health and National Institute of Aging/ RF1AG053303/National Institutes of Health and National Institute of Aging/ Neuro-Genomics and Informatics Center/ P30AG066444/National Institutes of Health and National Institute of Aging/ Charleston Conference on Alzheimer's Disease/ P01AG03991/National Institutes of Health and National Institute of Aging/ RF1AG058501/National Institutes of Health and National Institute of Aging/ Hope Center for Neurological Disorders/ U01AG058922/National Institutes of Health and National Institute of Aging/ Chan Zuckerberg Initiative/ P19-00559/Centene Corporation/ R21 AG067755/AG/NIA NIH HHS/ K23 NS110927/NS/NINDS NIH HHS/ Washington University-Centene ARCH Personalized Medicine Initiative/ P30NS048056/National Institutes of Health and National Institute of Aging/ P30 AG066444/AG/NIA NIH HHS/ P20AG068077/National Institutes of Health and National Institute of Aging/ P01AG026276/National Institutes of Health and National Institute of Aging/ R01AG044546/National Institutes of Health and National Institute of Aging/ P01 AG003991/AG/NIA NIH HHS/ P50 AG005681/AG/NIA NIH HHS/ P01 AG026276/AG/NIA NIH HHS/ University of New Mexico Grand Challenges Initiative/ Washington University School of Medicine/ R21-AG067755-01A1/National Institutes of Health and National Institute of Aging/ Ann Clin Transl Neurol. 2022 Nov 7. doi: 10.1002/acn3.51685.I | 11/08/2022 | ||||
| Plasma proteomic signature of decline in gait speed and grip strength | Liu X, et al. | 2022 | Aging Cell | epub ahead of print | e13736 | https://www.doi.org/10.1111/acel.13736 | 36,333,824 | aging gait speed grip strength physical function proteomics | The biological mechanisms underlying decline in physical function with age remain unclear. We examined the plasma proteomic profile associated with longitudinal changes in physical function measured by gait speed and grip strength in community-dwelling adults. We applied an aptamer-based platform to assay 1154 plasma proteins on 2854 participants (60% women, aged 76 years) in the Cardiovascular Health Study (CHS) in 1992-1993 and 1130 participants (55% women, aged 54 years) in the Framingham Offspring Study (FOS) in 1991-1995. Gait speed and grip strength were measured annually for 7 years in CHS and at cycles 7 (1998-2001) and 8 (2005-2008) in FOS. The associations of individual protein levels (log-transformed and standardized) with longitudinal changes in gait speed and grip strength in two populations were examined separately by linear mixed-effects models. Meta-analyses were implemented using random-effects models and corrected for multiple testing. We found that plasma levels of 14 and 18 proteins were associated with changes in gait speed and grip strength, respectively (corrected p < 0.05). The proteins most strongly associated with gait speed decline were GDF-15 (Meta-analytic p = 1.58 x 10(-15) ), pleiotrophin (1.23 x 10(-9) ), and TIMP-1 (5.97 x 10(-8) ). For grip strength decline, the strongest associations were for carbonic anhydrase III (1.09 x 10(-7) ), CDON (2.38 x 10(-7) ), and SMOC1 (7.47 x 10(-7) ). Several statistically significant proteins are involved in the inflammatory responses or antagonism of activin by follistatin pathway. These novel proteomic biomarkers and pathways should be further explored as future mechanisms and targets for age-related functional decline. | Liu, Xiaojuan Pan, Stephanie Xanthakis, Vanessa Vasan, Ramachandran S Psaty, Bruce M Austin, Thomas R Newman, Anne B Sanders, Jason L Wu, Chenkai Tracy, Russell P Gerszten, Robert E Odden, Michelle C eng 75N92019D00031/HL/NHLBI NIH HHS/ 75N92021D00006/HL/NHLBI NIH HHS/ HHSN268200800007C/HL/NHLBI NIH HHS/ HHSN268201200036C/HL/NHLBI NIH HHS/ HHSN268201500001I/HL/NHLBI NIH HHS/ HHSN268201800001C/HL/NHLBI NIH HHS/ N01HC55222/HL/NHLBI NIH HHS/ N01HC85079/HL/NHLBI NIH HHS/ N01HC85080/HL/NHLBI NIH HHS/ N01HC85081/HL/NHLBI NIH HHS/ N01HC85082/HL/NHLBI NIH HHS/ N01HC85083/HL/NHLBI NIH HHS/ N01HC85086/HL/NHLBI NIH HHS/ NO1-HC-25195/HL/NHLBI NIH HHS/ R01HL144483/HL/NHLBI NIH HHS/ U01HL080295/HL/NHLBI NIH HHS/ U01HL130114/HL/NHLBI NIH HHS/ R01AG023629/AG/NIA NIH HHS/ England Aging Cell. 2022 Nov 4:e13736. doi: 10.1111/acel.13736.I | 11/06/2022 | ||
| Integrated proteomic and metabolomic modules identified as biomarkers of mortality in the Atherosclerosis Risk in Communities study and the African American Study of Kidney Disease and Hypertension | Zhou L, et al. | 2022 | Hum Genomics | 16 | 1 | 53 | https://www.doi.org/10.1186/s40246-022-00425-9 | 36,329,547 | Humans Aged Middle Aged African Americans/genetics *Cardiovascular Diseases Cross-Sectional Studies Proteomics Risk Factors Biomarkers *Hypertension/epidemiology/genetics Metabolomics *Kidney Diseases *Atherosclerosis/genetics *Diabetes Mellitus Chronic kidney disease Cluster analysis Dimensionality reduction Mortality | BACKGROUND: Proteins and metabolites are essential for many biological functions and often linked through enzymatic or transport reactions. Individual molecules have been associated with all-cause mortality. Many of these are correlated and might jointly represent pathways or endophenotypes involved in diseases. RESULTS: We present an integrated analysis of proteomics and metabolomics via a local dimensionality reduction clustering method. We identified 224 modules of correlated proteins and metabolites in the Atherosclerosis Risk in Communities (ARIC) study, a general population cohort of older adults (N = 4046, mean age 75.7, mean eGFR 65). Many of the modules displayed strong cross-sectional associations with demographic and clinical characteristics. In comprehensively adjusted analyses, including fasting plasma glucose, history of cardiovascular disease, systolic blood pressure and kidney function among others, 60 modules were associated with mortality. We transferred the network structure to the African American Study of Kidney Disease and Hypertension (AASK) (N = 694, mean age 54.5, mean mGFR 46) and identified mortality associated modules relevant in this disease specific cohort. The four mortality modules relevant in both the general population and CKD were all a combination of proteins and metabolites and were related to diabetes / insulin secretion, cardiovascular disease and kidney function. Key components of these modules included N-terminal (NT)-pro hormone BNP (NT-proBNP), Sushi, Von Willebrand Factor Type A, EGF And Pentraxin (SVEP1), and several kallikrein proteases. CONCLUSION: Through integrated biomarkers of the proteome and metabolome we identified functions of (patho-) physiologic importance related to diabetes, cardiovascular disease and kidney function. | Zhou, Linda Surapaneni, Aditya Rhee, Eugene P Yu, Bing Boerwinkle, Eric Coresh, Josef Grams, Morgan E Schlosser, Pascal eng K24 HL155861/HL/NHLBI NIH HHS/ R01 DK124399/DK/NIDDK NIH HHS/ R01 DK108803/DK/NIDDK NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't England Hum Genomics. 2022 Nov 3;16(1):53. doi: 10.1186/s40246-022-00425-9.I | 11/05/2022 | |
| The 2022 Report on the Human Proteome from the HUPO Human Proteome Project | Omenn GS, et al. | 2022 | J Proteome Res | epub ahead of print | https://www.doi.org/10.1021/acs.jproteome.2c00498 | 36,318,223 | Biology and Disease-HPP (B/D-HPP) Grand Challenge Project Human Protein Atlas Human Proteome Project (HPP) Mass Spectrometry Interactive Virtual Environment (MassIVE) PeptideAtlas Ribo-Seq chromosome-centric HPP (C-HPP) missing proteins (MP) neXtProt protein existence (PE metrics) non-MS PE1 proteins small open reading frames (smORFs) uncharacterized protein existence 1 (uPE1) | The 2022 Metrics of the Human Proteome from the HUPO Human Proteome Project (HPP) show that protein expression has now been credibly detected (neXtProt PE1 level) for 18_407 (93.2%) of the 19_750 predicted proteins coded in the human genome, a net gain of 50 since 2021 from data sets generated around the world and reanalyzed by the HPP. Conversely, the number of neXtProt PE2, PE3, and PE4 missing proteins has been reduced by 78 from 1421 to 1343. This represents continuing experimental progress on the human proteome parts list across all the chromosomes, as well as significant reclassifications. Meanwhile, applying proteomics in a vast array of biological and clinical studies continues to yield significant findings and growing integration with other omics platforms. We present highlights from the Chromosome-Centric HPP, Biology and Disease-driven HPP, and HPP Resource Pillars, compare features of mass spectrometry and Olink and Somalogic platforms, note the emergence of translation products from ribosome profiling of small open reading frames, and discuss the launch of the initial HPP Grand Challenge Project, A Function for Each Protein"." | Omenn, Gilbert S Lane, Lydie Overall, Christopher M Pineau, Charles Packer, Nicolle H Cristea, Ileana M Lindskog, Cecilia Weintraub, Susan T Orchard, Sandra Roehrl, Michael H A Nice, Edouard Liu, Siqi Bandeira, Nuno Chen, Yu-Ju Guo, Tiannan Aebersold, Ruedi Moritz, Robert L Deutsch, Eric W eng Review J Proteome Res. 2022 Nov 1. doi: 10.1021/acs.jproteome.2c00498.I | 11/02/2022 | |||
| Evaluating the Utility of Proteomics for the Identification of Circulating Pharmacodynamic Biomarkers of IFNbeta-1a Biologics | Hyland PL, et al. | 2022 | Clin Pharmacol Ther | epub ahead of print | https://www.doi.org/10.1002/cpt.2778 | 36,308,070 | Proteomics has the potential to identify pharmacodynamic (PD) biomarkers for similarity assessment of proposed biosimilars without relying on clinical efficacy end points. In this study, with 36 healthy participants randomized to therapeutic doses of interferon-beta 1a products (IFNbeta-1a) or pegylated-IFNbeta-1a (pegIFNbeta-1a) approved to treat multiple sclerosis or placebo, we evaluated the utility of a proteomic assay that profiles > 7,000 plasma proteins. IFNbeta-1a and pegIFNbeta-1a resulted in 248 and 528 differentially expressed protein analytes, respectively, between treatment and placebo groups over the time course. Thirty-one proteins were prioritized based on a maximal fold change >/= 2 from baseline, baseline adjusted area under the effect curve (AUEC) and overlap between the 2 products. Of these, the majority had a significant AUEC compared with placebo in response to either product; 8 proteins showed > 4-fold maximal change from baseline. We identified previously reported candidates, beta-2microglobulin and interferon-induced GTP-binding protein (Mx1) with ~ 50% coefficient of variation (CV) for AUEC, and many new candidates (including I-TAC, C1QC, and IP-10) with CVs ranging from 26%-129%. Upstream regulator analysis of differentially expressed proteins predicted activation of IFNbeta1 signaling as well as other cytokine, enzyme, and transcription signaling networks by both products. Although independent replication is required to confirm present results, our study demonstrates the utility of proteomics for the identification of individual and composite candidate PD biomarkers that may be leveraged to support clinical pharmacology studies for biosimilar approvals, especially when biologics have complex mechanisms of action or do not have previously characterized PD biomarkers. | Hyland, Paula L Chekka, Lakshmi Manasa S Samarth, Deepti P Rosenzweig, Barry A Decker, Erica Mohamed, Esraa G Guo, Yan Matta, Murali K Sun, Qin Wheeler, William Sanabria, Carlos Weaver, James L Schrieber, Sarah J Florian, Jeffry Wang, Yow-Ming Strauss, David G eng Clin Pharmacol Ther. 2022 Oct 29. doi: 10.1002/cpt.2778.I | 10/30/2022 | ||||
| Components of the Complement Cascade Differ in Polycystic Ovary Syndrome | Butler AE, et al. | 2022 | Int J Mol Sci | 23 | 20 | https://www.doi.org/10.3390/ijms232012232 | 36,293,087 | Female Humans Properdin/metabolism Complement Factor H Complement Factor B/metabolism *Mannose-Binding Lectin CD55 Antigens *Polycystic Ovary Syndrome Complement Factor D *Insulin Resistance Cohort Studies Proteomics Complement C1q Complement C3b Fibrinogen Cytokines C3 complement factors factor B polycystic ovary syndrome properdin | Complement pathway proteins are reported to be increased in polycystic ovary syndrome (PCOS) and may be affected by obesity and insulin resistance. To investigate this, a proteomic analysis of the complement system was undertaken, including inhibitory proteins. In this cohort study, plasma was collected from 234 women (137 with PCOS and 97 controls). SOMALogic proteomic analysis was undertaken for the following complement system proteins: C1q, C1r, C2, C3, C3a, iC3b, C3b, C3d, C3adesArg, C4, C4a, C4b, C5, C5a, C5b-6 complex, C8, properdin, factor B, factor D, factor H, factor I, mannose-binding protein C (MBL), complement decay-accelerating factor (DAF) and complement factor H-related protein 5 (CFHR5). The alternative pathway of the complement system was primarily overexpressed in PCOS, with increased C3 (p < 0.05), properdin and factor B (p < 0.01). In addition, inhibition of this pathway was also seen in PCOS, with an increase in CFHR5, factor H and factor I (p < 0.01). Downstream complement factors iC3b and C3d, associated with an enhanced B cell response, and C5a, associated with an inflammatory cytokine release, were increased (p < 0.01). Hyperandrogenemia correlated positively with properdin and iC3b, whilst insulin resistance (HOMA-IR) correlated with iC3b and factor H (p < 0.05) in PCOS. BMI correlated positively with C3d, factor B, factor D, factor I, CFHR5 and C5a (p < 0.05). This comprehensive evaluation of the complement system in PCOS revealed the upregulation of components of the complement system, which appears to be offset by the concurrent upregulation of its inhibitors, with these changes accounted for in part by BMI, hyperandrogenemia and insulin resistance. | Butler, Alexandra E Moin, Abu Saleh Md Sathyapalan, Thozhukat Atkin, Stephen L eng Switzerland Int J Mol Sci. 2022 Oct 13;23(20):12232. doi: 10.3390/ijms232012232.I | 10/28/2022 | ||
| Testican-2 is Associated with Reduced Risk of Incident ESKD | Wen D, et al. | 2022 | J Am Soc Nephrol | epub ahead of print | https://www.doi.org/10.1681/ASN.2022020216 | 36,288,905 | Background: Testican-2 was recently identified as a podocyte-derived protein that is released into circulation by the kidneys and is positively correlated with estimated glomerular filtration rate (eGFR) and eGFR slope. However, whether higher testican-2 levels are associated with lower risk of end stage kidney disease (ESKD) is unknown. Methods: Aptamer-based proteomics assessed blood testican-2 levels among participants in the African American Study of Kidney Disease and Hypertension (AASK, n=703), the Chronic Renal Insufficiency Cohort (CRIC) study (n=3,196), and the Atherosclerosis Risk in Communities (ARIC) study (n=4,378). We compared baseline characteristics by testican-2 tertile and used Cox proportional hazards models to study the association of testican-2 with incident ESKD. Results: Higher testican-2 levels were associated with higher measured GFR (mGFR) in AASK, higher eGFR in the CRIC and ARIC studies, and lower albuminuria in all cohorts. Baseline testican-2 levels were significantly associated with incident ESKD in Cox proportional hazards models adjusted for age, sex, and race (Model 1) and Model 1 + mGFR or eGFR + comorbidities (Model 2). In Model 3 (Model 2 + proteinuria), the associations between testican-2 (per SD increase) and incident ESKD were: AASK (HR = 0.84 [0.72, 0.98], P = 0.023), CRIC (HR = 0.95 [0.89, 1.02], P = 0.14), ARIC (HR = 0.54 [0.36, 0.83], P = 0.0044), and meta-analysis (HR = 0.92 [0.86, 0.98], P = 0.0073). Conclusions: Across three cohorts spanning >8,000 individuals, testican-2 is associated with kidney health and prognosis, with higher levels associated with reduced risk of ESKD. | Wen, Donghai Zhou, Linda Zheng, Zihe Surapaneni, Aditya Ballantyne, Christie Hoogeveen, Ron Shlipak, Michael Waikar, Sushrut Vasan, Ramachandra Kimmel, Paul Dubin, Ruth Deo, Rajat Feldman, Harold Ganz, Peter Coresh, Josef Grams, Morgan Rhee, Eugene eng J Am Soc Nephrol. 2022 Oct 26:ASN.2022020216. doi: 10.1681/ASN.2022020216.I | 10/27/2022 | ||||
| Multiomics study of nonalcoholic fatty liver disease | Sveinbjornsson G, et al. | 2022 | Nat Genet | 54 | 11 | 1652-1663 | https://www.doi.org/10.1038/s41588-022-01199-5 | 36,280,732 | Humans *Non-alcoholic Fatty Liver Disease/genetics Proteomics Genome-Wide Association Study Liver/metabolism Liver Cirrhosis/genetics/metabolism/pathology *Liver Neoplasms/genetics/metabolism | Nonalcoholic fatty liver (NAFL) and its sequelae are growing health problems. We performed a genome-wide association study of NAFL, cirrhosis and hepatocellular carcinoma, and integrated the findings with expression and proteomic data. For NAFL, we utilized 9,491 clinical cases and proton density fat fraction extracted from 36,116 liver magnetic resonance images. We identified 18 sequence variants associated with NAFL and 4 with cirrhosis, and found rare, protective, predicted loss-of-function variants in MTARC1 and GPAM, underscoring them as potential drug targets. We leveraged messenger RNA expression, splicing and predicted coding effects to identify 16 putative causal genes, of which many are implicated in lipid metabolism. We analyzed levels of 4,907 plasma proteins in 35,559 Icelanders and 1,459 proteins in 47,151 UK Biobank participants, identifying multiple proteins involved in disease pathogenesis. We show that proteomics can discriminate between NAFL and cirrhosis. The present study provides insights into the development of noninvasive evaluation of NAFL and new therapeutic options. | Sveinbjornsson, Gardar Ulfarsson, Magnus O Thorolfsdottir, Rosa B Jonsson, Benedikt A Einarsson, Eythor Gunnlaugsson, Gylfi Rognvaldsson, Solvi Arnar, David O Baldvinsson, Magnus Bjarnason, Ragnar G Eiriksdottir, Thjodbjorg Erikstrup, Christian Ferkingstad, Egil Halldorsson, Gisli H Helgason, Hannes Helgadottir, Anna Hindhede, Lotte Hjorleifsson, Grimur Jones, David Knowlton, Kirk U Lund, Sigrun H Melsted, Pall Norland, Kristjan Olafsson, Isleifur Olafsson, Sigurdur Oskarsson, Gudjon R Ostrowski, Sisse Rye Pedersen, Ole Birger Snaebjarnarson, Auethunn S Sigurdsson, Emil Steinthorsdottir, Valgerdur Schwinn, Michael Thorgeirsson, Gudmundur Thorleifsson, Gudmar Jonsdottir, Ingileif Bundgaard, Henning Nadauld, Lincoln Bjornsson, Einar S Rulifson, Ingrid C Rafnar, Thorunn Norddahl, Gudmundur L Thorsteinsdottir, Unnur Sulem, Patrick Gudbjartsson, Daniel F Holm, Hilma Stefansson, Kari eng Nat Genet. 2022 Nov;54(11):1652-1663. doi: 10.1038/s41588-022-01199-5. Epub 2022 Oct 24.I | 10/26/2022 | |
| Circulating Proteins Influencing Psychiatric Disease: A Mendelian Randomization Study | Lu T, et al. | 2022 | Biol Psychiatry | epub ahead of print | https://www.doi.org/10.1016/j.biopsych.2022.08.015 | 36,280,454 | Blood-brain barrier Circulating proteins Genome-wide association studies Mendelian randomization Psychiatric diseases Quantitative trait loci | BACKGROUND: There is a pressing need for novel drug targets for psychiatric disorders. Circulating proteins are potential candidates because they are relatively easy to measure and modulate and play important roles in signaling. METHODS: We performed two-sample Mendelian randomization analyses to estimate the associations between circulating protein abundances and risk of 10 psychiatric disorders. Genetic variants associated with 1611 circulating protein abundances identified in 6 large-scale proteomic studies were used as genetic instruments. Effects of the circulating proteins on psychiatric disorders were estimated by Wald ratio or inverse variance-weighted ratio tests. Horizontal pleiotropy, colocalization, and protein-altering effects were examined to validate the assumptions of Mendelian randomization. RESULTS: Nine circulating protein-to-disease associations withstood multiple sensitivity analyses. Among them, 2 circulating proteins had associations replicated in 3 proteomic studies. A 1 standard deviation increase in the genetically predicted circulating TIMP4 level was associated with a reduced risk of anorexia nervosa (minimum odds ratio [OR] = 0.83; 95% CI, 0.76-0.91) and bipolar disorder (minimum OR = 0.88; 95% CI, 0.82-0.94). A 1 standard deviation increase in the genetically predicted circulating ESAM level was associated with an increased risk of schizophrenia (maximum OR = 1.32; 95% CI, 1.22-1.43). In addition, 58 suggestive protein-to-disease associations warrant validation with observational or experimental evidence. For instance, a 1 standard deviation increase in the ERLEC1-201-to-ERLEC1-202 splice variant ratio was associated with a reduced risk of schizophrenia (OR = 0.94; 95% CI, 0.90-0.97). CONCLUSIONS: Prioritized circulating proteins appear to influence the risk of psychiatric disease and may be explored as intervention targets. | Lu, Tianyuan Forgetta, Vincenzo Greenwood, Celia M T Zhou, Sirui Richards, J Brent eng Biol Psychiatry. 2022 Aug 22:S0006-3223(22)01524-4. doi: 10.1016/j.biopsych.2022.08.015.I | 10/25/2022 | |||
| Plasma proteome profiling identifies changes associated to AD but not to FTD | Mofrad RB, et al. | 2022 | Acta Neuropathol Commun | 10 | 1 | 148 | https://www.doi.org/10.1186/s40478-022-01458-w | 36,273,219 | Humans Female Middle Aged Aged Male *Frontotemporal Dementia/diagnosis/genetics Proteome Proteomics *Frontotemporal Lobar Degeneration/diagnosis/pathology *Pick Disease of the Brain Biomarkers Ad Alzheimer's disease Ftd Frontotemporal dementia Plasma biomarkers Somascan | BACKGROUND: Frontotemporal dementia (FTD) is caused by frontotemporal lobar degeneration (FTLD), characterized mainly by inclusions of Tau (FTLD-Tau) or TAR DNA binding43 (FTLD-TDP) proteins. Plasma biomarkers are strongly needed for specific diagnosis and potential treatment monitoring of FTD. We aimed to identify specific FTD plasma biomarker profiles discriminating FTD from AD and controls, and between FTD pathological subtypes. In addition, we compared plasma results with results in post-mortem frontal cortex of FTD cases to understand the underlying process. METHODS: Plasma proteins (n = 1303) from pathologically and/or genetically confirmed FTD patients (n = 56; FTLD-Tau n = 16; age = 58.2 +/- 6.2; 44% female, FTLD-TDP n = 40; age = 59.8 +/- 7.9; 45% female), AD patients (n = 57; age = 65.5 +/- 8.0; 39% female), and non-demented controls (n = 148; 61.3 +/- 7.9; 41% female) were measured using an aptamer-based proteomic technology (SomaScan). In addition, exploratory analysis in post-mortem frontal brain cortex of FTD (n = 10; FTLD-Tau n = 5; age = 56.2 +/- 6.9, 60% female, and FTLD-TDP n = 5; age = 64.0 +/- 7.7, 60% female) and non-demented controls (n = 4; age = 61.3 +/- 8.1; 75% female) were also performed. Differentially regulated plasma and tissue proteins were identified by global testing adjusting for demographic variables and multiple testing. Logistic lasso regression was used to identify plasma protein panels discriminating FTD from non-demented controls and AD, or FTLD-Tau from FTLD-TDP. Performance of the discriminatory plasma protein panels was based on predictions obtained from bootstrapping with 1000 resampled analysis. RESULTS: Overall plasma protein expression profiles differed between FTD, AD and controls (6 proteins; p = 0.005), but none of the plasma proteins was specifically associated to FTD. The overall tissue protein expression profile differed between FTD and controls (7-proteins; p = 0.003). There was no difference in overall plasma or tissue expression profile between FTD subtypes. Regression analysis revealed a panel of 12-plasma proteins discriminating FTD from AD with high accuracy (AUC: 0.99). No plasma protein panels discriminating FTD from controls or FTD pathological subtypes were identified. CONCLUSIONS: We identified a promising plasma protein panel as a minimally-invasive tool to aid in the differential diagnosis of FTD from AD, which was primarily associated to AD pathophysiology. The lack of plasma profiles specifically associated to FTD or its pathological subtypes might be explained by FTD heterogeneity, calling for FTD studies using large and well-characterize cohorts. | Mofrad, R Babapour Del Campo, M Peeters, C F W Meeter, L H H Seelaar, H Koel-Simmelink, M Ramakers, I H G B Middelkoop, H A M De Deyn, P P Claassen, J A H R van Swieten, J C Bridel, C Hoozemans, J J M Scheltens, P van der Flier, W M Pijnenburg, Y A L Teunissen, Charlotte E eng 733050206/ZONMW_/ZonMw/Netherlands ToBike4Alzheimer/Alzheimer Nederland/ England Acta Neuropathol Commun. 2022 Oct 22;10(1):148. doi: 10.1186/s40478-022-01458-w.I | 10/24/2022 | |
| Association of mTORC1_dependent circulating protein levels with cataract formation: a mendelian randomization study | Cai Y, et al. | 2022 | BMC Genomics | 23 | 1 | 719 | https://www.doi.org/10.1186/s12864-022-08925-7 | 36,271,348 | Humans *Cataract/genetics Eukaryotic Initiation Factor-4A Eukaryotic Initiation Factor-4E/genetics *Eukaryotic Initiation Factor-4G Genome-Wide Association Study Mechanistic Target of Rapamycin Complex 1/genetics Mendelian Randomization Analysis Polymorphism, Single Nucleotide Sirolimus TOR Serine-Threonine Kinases/genetics Cataract Circulating Eif4ebp Mendelian randomization mTOR | BACKGROUND: The mechanistic target of rapamycin (mTOR) signal pathway plays a critical regulating role in the occurrence and development of cataract. However, the role of mTORC1 downstream proteins, including ribosomal protein S6K (RP-S6K), eukaryotic initiation factor 4E-binding protein (EIF4EBP), eukaryotic initiation factor 4G (EIF-4G), eukaryotic initiation factor 4E (EIF-4E), and eukaryotic initiation factor 4A (EIF-4A), in regulating cataract development is still unknown. Herein, we conducted a mendelian randomization (MR) study to understand the function of mTORC1 signaling in the process of cataract development. RESULTS: The causal estimate was evaluated with inverse-variance weighted (IVW) estimate, weighted median estimator, MR-Egger and MR robust adjusted profile score (MR. RAPS). The single-nucleotide polymorphisms (SNPs), P<5 x 10(- 6) and r(2)<0.05, were selected to genetically predict the RP-S6K, EIF4EBP, EIF-4E, EIF-4A, and EIF-4G. We included a total of 26,758 cases and 189,604 controls in this MR study. The study revealed causal association between circulating EIF4EBP (OR 1.09, 95% confidence interval 1.03,1.16, P = 0.004), RP-S6K (OR 1.04, 95% confidence interval 1.01, 1.08, P = 0.02) and cataract formation with IVW estimate. Whereas after correcting outliers, MR robust adjusted profile score (MR. RAPS) shows consistent result with IVW for EIF4EBP (OR = 1.08, 95%CI:1.05-1.11, P = 0.007). The observation strengthened the confidence in the true causal associations. However, no association was found for circulating EIF-4E (OR 1.03, 95% confidence interval 0.97, 1.09, P = 0.31), EIF-4A (OR 1.02, 95% confidence interval 0.98, 1.07, P = 0.34), and EIF-4G (OR 1.02, 95% confidence interval 0.94, 1.01, P = 0.64) levels with cataract formation. No evidence of heterogeneity and unbalanced horizontal pleiotropy was detected. CONCLUSION: The MR study suggests that EIF4EBP is a high-risk factor for cataract development. There may be a potential causal association between the mTORC1/EIF4EBP axis and cataract. This research highlights the potential mechanism for cataract development and a genetic target to prevent as well as treat cataracts. | Cai, Yingjun Liu, Kangcheng Wu, Pengfei Yuan, Ruolan He, Fei Zou, Jing eng NO. 2022JJ40855/Jing Zou/ England BMC Genomics. 2022 Oct 21;23(1):719. doi: 10.1186/s12864-022-08925-7.I | 10/23/2022 | |
| Molecular subclasses of preeclampsia characterized by a longitudinal maternal proteomics study: distinct biomarkers, disease pathways and options for prevention | Than NG, et al. | 2022 | J Perinat Med | epub ahead of print | https://www.doi.org/10.1515/jpm-2022-0433 | 36,253,935 | great obstetrical syndromes liquid biopsy omics personalized medicine prenatal diagnosis screening | OBJECTIVES: The heterogeneous nature of preeclampsia is a major obstacle to early screening and prevention, and a molecular taxonomy of disease is needed. We have previously identified four subclasses of preeclampsia based on first-trimester plasma proteomic profiles. Herein, we expanded this approach by using a more comprehensive panel of proteins profiled in longitudinal samples. METHODS: Proteomic data collected longitudinally from plasma samples of women who developed preeclampsia (n=109) and of controls (n=90) were available from our previous report on 1,125 proteins. Consensus clustering was performed to identify subgroups of patients with preeclampsia based on data from five gestational-age intervals by using select interval-specific features. Demographic, clinical, and proteomic differences among clusters were determined. Differentially abundant proteins were used to identify cluster-specific perturbed KEGG pathways. RESULTS: Four molecular clusters with different clinical phenotypes were discovered by longitudinal proteomic profiling. Cluster 1 involves metabolic and prothrombotic changes with high rates of early-onset preeclampsia and small-for-gestational-age neonates; Cluster 2 includes maternal anti-fetal rejection mechanisms and recurrent preeclampsia cases; Cluster 3 is associated with extracellular matrix regulation and comprises cases of mostly mild, late-onset preeclampsia; and Cluster 4 is characterized by angiogenic imbalance and a high prevalence of early-onset disease. CONCLUSIONS: This study is an independent validation and further refining of molecular subclasses of preeclampsia identified by a different proteomic platform and study population. The results lay the groundwork for novel diagnostic and personalized tools of prevention. | Than, Nandor Gabor Romero, Roberto Gyorffy, Daniel Posta, Mate Bhatti, Gaurav Done, Bogdan Chaemsaithong, Piya Jung, Eunjung Suksai, Manaphat Gotsch, Francesca Gallo, Dahiana M Bosco, Mariachiara Kim, Bomi Kim, Yeon Mee Chaiworapongsa, Tinnakorn Rossi, Simona W Szilagyi, Andras Erez, Offer Tarca, Adi L Papp, Zoltan eng Germany J Perinat Med. 2022 Oct 18. doi: 10.1515/jpm-2022-0433.I | 10/19/2022 | |||
| A Network of Serum Proteins Predict the Need for Systemic Immunomodulatory Therapy at Diagnosis in Noninfectious Uveitis | Kuiper JJW, et al. | 2022 | Ophthalmol Sci | 2 | 3 | 100175 | https://www.doi.org/10.1016/j.xops.2022.100175 | 36,245,752 | IMT, immunomodulatory therapy Network-based medicine Neutrophils Noninfectious uveitis Proteomics Systemic immunomodulatory therapy | PURPOSE: Early identification of patients with noninfectious uveitis requiring steroid-sparing immunomodulatory therapy (IMT) is currently lacking in objective molecular biomarkers. We evaluated the proteomic signature of patients at the onset of disease and associated proteomic clusters with the need for IMT during the course of the disease. DESIGN: Multicenter cohort study. PARTICIPANTS: Two hundred thirty treatment-free patients with active noninfectious uveitis. METHODS: We used aptamer-based proteomics (n = 1305 proteins) and a bioinformatic pipeline as a molecular stratification tool to define the serum protein network of a Dutch discovery cohort (n = 78) of patients and healthy control participants and independently validated our results in another Dutch cohort (n = 111) and a United States cohort (n = 67). Multivariate Cox analysis was used to assess the relationship between the protein network and IMT use. MAIN OUTCOME MEASURES: Serum protein levels and use of IMT. RESULTS: Network-based analyses revealed a tightly coexpressed serum cluster (n = 85 proteins) whose concentration was consistently low in healthy control participants (n = 26), but varied among patients with noninfectious uveitis (n = 52). Patients with high levels of the serum cluster at disease onset showed a significantly increased need for IMT during follow-up, independent of anatomic location of uveitis (hazard ratio, 3.42; 95% confidence interval, 1.22-9.5; P = 0.019). The enrichment of neutrophil-associated proteins in the protein cluster led to our finding that the neutrophil count could serve as a clinical proxy for this proteomic signature (correlation: r = 0.57, P = 0.006). In an independent Dutch cohort (n = 111), we confirmed that patients with relatively high neutrophil count at diagnosis (> 5.2 x 10(9)/L) had a significantly increased chance of requiring IMT during follow-up (hazard ratio, 3.2; 95% confidence interval, 1.5-6.8; P = 0.002). We validated these findings in a third cohort of 67 United States patients. CONCLUSIONS: A serum protein signature correlating with neutrophil levels was highly predictive for IMT use in noninfectious uveitis. We developed a routinely available tool that may serve as a novel objective biomarker to aid in clinical decision-making for noninfectious uveitis. | Kuiper, Jonas J W Verhagen, Fleurieke H Hiddingh, Sanne Wennink, Roos A W Hansen, Anna M Casey, Kerry A Hoefer, Imo E Haitjema, Saskia Drylewicz, Julia Yakin, Mehmet Sen, H Nida Radstake, Timothy R D J de Boer, Joke H eng Netherlands Ophthalmol Sci. 2022 May 31;2(3):100175. doi: 10.1016/j.xops.2022.100175. eCollection 2022 Sep.I | 10/18/2022 | |
| Assessment of variability in the plasma 7k SomaScan proteomics assay | Candia J, et al. | 2022 | Sci Rep | 12 | 1 | 17147 | https://www.doi.org/10.1038/s41598-022-22116-0 | 36,229,504 | Biomarkers/metabolism Humans *Proteomics/methods | SomaScan is a high-throughput, aptamer-based proteomics assay designed for the simultaneous measurement of thousands of proteins with a broad range of endogenous concentrations. In its most current version, the 7k SomaScan assay v4.1 is capable of measuring 7288 human proteins. In this work, we present an extensive technical assessment of this platform based on a study of 2050 samples across 22 plates. Included in the study design were inter-plate technical duplicates from 102 human subjects, which allowed us to characterize different normalization procedures, evaluate assay variability by multiple analytical approaches, present signal-over-background metrics, and discuss potential specificity issues. By providing detailed performance assessments on this wide range of technical aspects, we aim for this work to serve as a valuable resource for the growing community of SomaScan users. | Candia, Julian Daya, Gulzar N Tanaka, Toshiko Ferrucci, Luigi Walker, Keenan A eng ZIAAG000971-14/AG/NIA NIH HHS/ ZIAAG000349-01/AG/NIA NIH HHS/ England Sci Rep. 2022 Oct 13;12(1):17147. doi: 10.1038/s41598-022-22116-0.I | 10/14/2022 | |
| The severity and duration of Hypoglycemia affect platelet-derived protein responses in Caucasians | Moin ASM, et al. | 2022 | Cardiovasc Diabetol | 21 | 1 | 202 | https://www.doi.org/10.1186/s12933-022-01639-w | 36,203,210 | Blood Glucose/metabolism CD40 Ligand *Diabetes Mellitus, Type 2/diagnosis Humans *Hypoglycemia Plasminogen Plasminogen Activator Inhibitor 1 Thromboplastin von Willebrand Factor Hypoglycemia Inflammation Platelet-associated proteins Type 2 diabetes conflict of interest or competing interests to declare. | OBJECTIVE: Severe hypoglycemia is associated with increased cardiovascular death risk, and platelet responses to hypoglycemia (hypo) have been described. However, the impact of deep transient hypo (deep-hypo) versus prolonged milder hypo (mild-hypo) on platelet response is unclear. RESEARCH DESIGN AND METHODS: Two hypo studies were compared; firstly, mild-hypo in 18-subjects (10 type-2-diabetes (T2D), 8 controls), blood glucose to 2.8mmoL/L (50 mg/dL) for 1-hour; secondly deep-hypo in 46-subjects (23 T2D, 23 controls), blood glucose to < 2.2mmoL/L (< 40 mg/dL) transiently. Platelet-related protein (PRP) responses from baseline to after 1-hour of hypo (mild-hypo) or at deep-hypo were compared, and at 24-hours post-hypo. Slow Off-rate Modified Aptamer (SOMA)-scan plasma protein measurement was used to determine PRP changes for 13 PRPs. RESULTS: In controls, from baseline to hypo, differences were seen for four PRPs, three showing increased %change in deep-hypo (Plasminogen activator inhibitor-1(PAI-1), CD40 ligand (CD40LG) and Protein-S), one showing increased %change in mild-hypo (von Willebrand factor (vWF)); at 24-hours in controls, %change for Protein-S remained increased in deep-hypo, whilst % change for vWF and plasminogen were increased in mild-hypo. In T2D, from baseline to hypo, differences were seen for 4 PRPs, three showing increased %change in deep-hypo (PAI-1, platelet glycoprotein VI and Tissue factor), one showing increased %change in mild-hypo (CD40LG); at 24-hours in T2D, %change for CD40LG remained increased, together with vWF, in deep-hypo. CONCLUSION: Both mild-hypo and deep-hypo showed marked PRP changes that continued up to 24-hours, showing that both the severity and duration of hypoglycemia are likely important and that any degree of hypoglycemia may be detrimental for increased cardiovascular risk events through PRP changes. | Moin, Abu Saleh Md Sathyapalan, Thozhukat Atkin, Stephen L Butler, Alexandra E eng England Cardiovasc Diabetol. 2022 Oct 6;21(1):202. doi: 10.1186/s12933-022-01639-w.I | 10/07/2022 | |
| Comment on A proteomic surrogate for cardiovascular outcomes that is sensitive to multiple mechanisms of change in risk"" | Kivimaki M, et al. | 2022 | Sci Transl Med | 14 | 665 | eabq4810 | https://www.doi.org/10.1126/scitranslmed.abq4810 | 36,197,964 | *Decision Making *Proteomics | A 27-protein signature has been proposed to predict cardiovascular disease, but its applicability in clinical decision-making remains unclear. | Kivimaki, Mika Hingorani, Aroon D Lindbohm, Joni V eng 221854/Z/20/Z/WT_/Wellcome Trust/United Kingdom MR/R024227/1/MRC_/Medical Research Council/United Kingdom DH_/Department of Health/United Kingdom Comment Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Sci Transl Med. 2022 Oct 5;14(665):eabq4810. doi: 10.1126/scitranslmed.abq4810. Epub 2022 Oct 5.I | 10/06/2022 | |
| Response to comment on A proteomic surrogate for cardiovascular outcomes that is sensitive to multiple mechanisms of change in risk"" | Williams SA, et al. | 2022 | Sci Transl Med | 14 | 665 | eadd1355 | https://www.doi.org/10.1126/scitranslmed.add1355 | 36,197,965 | *Cardiovascular Diseases *Decision Making Humans Proteomics | A 27-protein signature has been proposed to predict cardiovascular disease, and its applicability in some clinical decision-making situations is discussed. | Williams, Stephen A Ganz, Peter eng Comment Sci Transl Med. 2022 Oct 5;14(665):eadd1355. doi: 10.1126/scitranslmed.add1355. Epub 2022 Oct 5.I | 10/06/2022 | |
| Proteomic analysis of diabetes genetic risk scores identifies complement C2 and neuropilin-2 as predictors of type 2 diabetes: the Atherosclerosis Risk in Communities (ARIC) Study | Steffen BT, et al. | 2022 | Diabetologia | epub ahead of print | https://www.doi.org/10.1007/s00125-022-05801-7 | 36,194,249 | Beta cell Diabetes Genetic risk score Insulin resistance Mendelian Proteomics | AIMS/HYPOTHESIS: Genetic predisposition to type 2 diabetes is well-established, and genetic risk scores (GRS) have been developed that capture heritable liabilities for type 2 diabetes phenotypes. However, the proteins through which these genetic variants influence risk have not been thoroughly investigated. This study aimed to identify proteins and pathways through which type 2 diabetes risk variants may influence pathophysiology. METHODS: Using a proteomics data-driven approach in a discovery sample of 7241 White participants in the Atherosclerosis Risk in Communities Study (ARIC) cohort and a replication sample of 1674 Black ARIC participants, we interrogated plasma levels of 4870 proteins and four GRS of specific type 2 diabetes phenotypes related to beta cell function, insulin resistance, lipodystrophy, BMI/blood lipid abnormalities and a composite score of all variants combined. RESULTS: Twenty-two plasma proteins were identified in White participants after Bonferroni correction. Of the 22 protein-GRS associations that were statistically significant, 10 were replicated in Black participants and all but one were directionally consistent. In a secondary analysis, 18 of the 22 proteins were found to be associated with prevalent type 2 diabetes and ten proteins were associated with incident type 2 diabetes. Two-sample Mendelian randomisation indicated that complement C2 may be causally related to greater type 2 diabetes risk (inverse variance weighted estimate: OR 1.65 per SD; p=7.0 x 10(-3)), while neuropilin-2 was inversely associated (OR 0.44 per SD; p=8.0 x 10(-3)). CONCLUSIONS/INTERPRETATION: Identified proteins may represent viable intervention or pharmacological targets to prevent, reverse or slow type 2 diabetes progression, and further research is needed to pursue these targets. | Steffen, Brian T Tang, Weihong Lutsey, Pamela L Demmer, Ryan T Selvin, Elizabeth Matsushita, Kunihiro Morrison, Alanna C Guan, Weihua Rooney, Mary R Norby, Faye L Pankratz, Nathan Couper, David Pankow, James S eng UL1RR025005/NH/NIH HHS/ R01 HL059367/HL/NHLBI NIH HHS/ R01HL134320/HL/NHLBI NIH HHS/ U01HG004402/HG/NHGRI NIH HHS/ T32 HL007779/HL/NHLBI NIH HHS/ Germany Diabetologia. 2022 Oct 4. doi: 10.1007/s00125-022-05801-7.I | 10/05/2022 | |||
| Renin: Measurements, Correlates, and Associations with Long-Term Adverse Kidney Outcomes | Blum MF, et al. | 2022 | Am J Hypertens | epub ahead of print | https://www.doi.org/10.1093/ajh/hpac112 | 36,190,914 | aptamer chronic kidney disease end stage kidney disease kidney mortality renin | BACKGROUND: The association of renin with adverse kidney outcomes is largely unknown, and renin measurement strategies vary. We aimed to measure the clinical correlates of different renin measurements and the association between renin and incident chronic kidney disease (CKD), end-stage kidney disease (ESKD), and mortality. METHODS: We performed a prospective cohort analysis 9420 participants in the Atherosclerosis Risk in Communities (ARIC) study followed from 1996-1998 through 2019. We estimated longitudinal associations of renin measured using SomaScan modified nucleotide aptamer assay with incident CKD, ESKD, and death using Cox proportional hazards models. Using samples from a subsequent study visit, we compared SomaScan renin with plasma renin activity (PRA) and renin level from Olink, and estimated associations with covariates using univariate and multivariable regression. RESULTS: Higher SomaScan renin levels were associated with higher risk of incident CKD (hazard ratio per two-fold higher [HR], 1.14; 95% confidence interval [CI], 1.09 to 1.20), ESKD (HR, 1.20; 95% CI, 1.03 to 1.41), and mortality (HR, 1.08; 95% CI, 1.04 to 1.13) in analyses adjusted for demographic, clinical, and socioeconomic covariates. SomaScan renin was moderately correlated with PRA (r=0.61) and highly correlated with Olink renin (r=0.94). SomaScan renin and PRA had similar clinical correlates except for divergent associations with age and beta blocker use, both of which correlated positively with SomaScan renin but negatively with PRA. CONCLUSIONS: SomaScan aptamer-based renin level was associated with higher risk of CKD, ESKD, and mortality. It was moderately correlated with PRA, sharing generally similar clinical covariate associations. | Blum, Matthew F Chen, Jingsha Surapaneni, Aditya Turner, Stephen T Ballantyne, Christie M Welling, Paul A Kottgen, Anna Coresh, Josef Crews, Deidra C Grams, Morgan E eng Am J Hypertens. 2022 Oct 3:hpac112. doi: 10.1093/ajh/hpac112.I | 10/04/2022 | |||
| Altered methylation pattern in EXOC4 is associated with stroke outcome: an epigenome-wide association study | Cullell N, et al. | 2022 | Clin Epigenetics | 14 | 1 | 124 | https://www.doi.org/10.1186/s13148-022-01340-5 | 36,180,927 | *Brain Ischemia/genetics CpG Islands DNA Methylation Epigenesis, Genetic Epigenome Genome-Wide Association Study Humans Rna *Stroke/genetics c-Mer Tyrosine Kinase/genetics | BACKGROUND AND PURPOSE: The neurological course after stroke is highly variable and is determined by demographic, clinical and genetic factors. However, other heritable factors such as epigenetic DNA methylation could play a role in neurological changes after stroke. METHODS: We performed a three-stage epigenome-wide association study to evaluate DNA methylation associated with the difference between the National Institutes of Health Stroke Scale (NIHSS) at baseline and at discharge (DeltaNIHSS) in ischaemic stroke patients. DNA methylation data in the Discovery (n = 643) and Replication (n = 62) Cohorts were interrogated with the 450 K and EPIC BeadChip. Nominal CpG sites from the Discovery (p value < 10(-06)) were also evaluated in a meta-analysis of the Discovery and Replication cohorts, using a random-fixed effect model. Metabolic pathway enrichment was calculated with methylGSA. We integrated the methylation data with 1305 plasma protein expression levels measured by SOMAscan in 46 subjects and measured RNA expression with RT-PCR in a subgroup of 13 subjects. Specific cell-type methylation was assessed using EpiDISH. RESULTS: The meta-analysis revealed an epigenome-wide significant association in EXOC4 (p value = 8.4 x 10(-08)) and in MERTK (p value = 1.56 x 10(-07)). Only the methylation in EXOC4 was also associated in the Discovery and in the Replication Cohorts (p value = 1.14 x 10(-06) and p value = 1.3 x 10(-02), respectively). EXOC4 methylation negatively correlated with the long-term outcome (coefficient = - 4.91) and showed a tendency towards a decrease in EXOC4 expression (rho = - 0.469, p value = 0.091). Pathway enrichment from the meta-analysis revealed significant associations related to the endocytosis and deubiquitination processes. Seventy-nine plasma proteins were differentially expressed in association with EXOC4 methylation. Pathway analysis of these proteins showed an enrichment in natural killer (NK) cell activation. The cell-type methylation analysis in blood also revealed a differential methylation in NK cells. CONCLUSIONS: DNA methylation of EXOC4 is associated with a worse neurological course after stroke. The results indicate a potential modulation of pathways involving endocytosis and NK cells regulation. | Cullell, Natalia Soriano-Tarraga, Carolina Gallego-Fabrega, Cristina Carcel-Marquez, Jara Muino, Elena Llucia-Carol, Laia Lledos, Miquel Esteller, Manel de Moura, Manuel Castro Montaner, Joan Rosell, Anna Delgado, Pilar Marti-Fabregas, Joan Krupinski, Jerzy Roquer, Jaume Jimenez-Conde, Jordi Fernandez-Cadenas, Israel eng Meta-Analysis Research Support, Non-U.S. Gov't Germany Clin Epigenetics. 2022 Sep 30;14(1):124. doi: 10.1186/s13148-022-01340-5.I | 10/01/2022 | |
| Proteomics of Coagulopathy Following Injury Reveals Limitations of Using Laboratory Assessment to Define Trauma-Induced Coagulopathy to Predict Massive Transfusion | Moore HB, et al. | 2022 | Ann Surg Open | 3 | 2 | e167 | https://www.doi.org/10.1097/as9.0000000000000167 | 36,177,090 | OBJECTIVE: Trauma-induced coagulopathy (TIC) is provoked by multiple mechanisms and is perceived to be one driver of massive transfusions (MT). Single laboratory values using prothrombin time (INR) or thrombelastography (TEG) are used to clinically define this complex process. We used a proteomics approach to test whether current definitions of TIC (INR, TEG, or clinical judgement) are sufficient to capture the majority of protein changes associated with MT. METHODS: Eight level-I trauma centers contributed blood samples from patients available early after injury. TIC was defined as INR >1.5 (INR-TIC), TEG maximum amplitude <50mm (TEG-TIC), or clinical judgement (Clin-TIC) by the trauma surgeon. MT was defined as > 10 units of red blood cells in 24 hours or > 4 units RBC/hour during the first 4 hr. SomaLogic proteomic analysis of 1,305 proteins was performed. Pathways associated with proteins dysregulated in patients with each TIC definition and MT were identified. RESULTS: Patients (n=211) had a mean injury severity score of 24, with a MT and mortality rate of 22% and 12%, respectively. We identified 578 SOMAscan analytes dysregulated among MT patients, of which INR-TIC, TEG-TIC, and Clin-TIC patients showed dysregulation only in 25%, 3%, and 4% of these, respectively. TIC definitions jointly failed to show changes in 73% of the protein levels associated with MT, and failed to identify 26% of patients that received a massive transfusion. INR-TIC and TEG-TIC patients showed dysregulation of proteins significantly associated with complement activity. Proteins dysregulated in Clin-TIC or massive transfusion patients were not significantly associated with any pathway. CONCLUSION: These data indicate there are unexplored opportunities to identify patients at risk for massive bleeding. Only a small subset of proteins that are dysregulated in patients receiving MT are statistically significantly dysregulated among patients whose TIC is defined based solely on laboratory measurements or clinical assessment. | Moore, Hunter B Neal, Matthew D Bertolet, Marnie Joughin, Brian A Yaffe, Michael B Barrett, Christopher D Bird, Molly A Tracy, Russell P Moore, Ernest E Sperry, Jason L Zuckerbraun, Brian S Park, Myung S Cohen, Mitchell J Wisniewski, Stephen R Morrissey, James H eng R00 HL151887/HL/NHLBI NIH HHS/ R35 GM119526/GM/NIGMS NIH HHS/ R35 HL135823/HL/NHLBI NIH HHS/ K99 HL151887/HL/NHLBI NIH HHS/ UM1 HL120877/HL/NHLBI NIH HHS/ Ann Surg Open. 2022 Jun;3(2):e167. doi: 10.1097/as9.0000000000000167. Epub 2022 May 25.I | 10/01/2022 | ||
| The dynamic changes and sex differences of 147 immune-related proteins during acute COVID-19 in 580 individuals | Butler-Laporte G, et al. | 2022 | Clin Proteomics | 19 | 1 | 34 | https://www.doi.org/10.1186/s12014-022-09371-z | 36,171,541 | Covid-19 Immunity Proteomics SOMAscan the Founder of 5 Prime Sciences. The Lady Davis Institute has previously received funding from GlaxoSmithKline, Eli Lilly, and Biogen for research programs at Dr. Richards' laboratory unrelated to this manuscript. C.P. and M.H. are employees of SomaLogic. | INTRODUCTION: Severe COVID-19 leads to important changes in circulating immune-related proteins. To date it has been difficult to understand their temporal relationship and identify cytokines that are drivers of severe COVID-19 outcomes and underlie differences in outcomes between sexes. Here, we measured 147 immune-related proteins during acute COVID-19 to investigate these questions. METHODS: We measured circulating protein abundances using the SOMAscan nucleic acid aptamer panel in two large independent hospital-based COVID-19 cohorts in Canada and the United States. We fit generalized additive models with cubic splines from the start of symptom onset to identify protein levels over the first 14 days of infection which were different between severe cases and controls, adjusting for age and sex. Severe cases were defined as individuals with COVID-19 requiring invasive or non-invasive mechanical respiratory support. RESULTS: 580 individuals were included in the analysis. Mean subject age was 64.3 (sd 18.1), and 47% were male. Of the 147 proteins, 69 showed a significant difference between cases and controls (p < 3.4 x 10(-4)). Three clusters were formed by 108 highly correlated proteins that replicated in both cohorts, making it difficult to determine which proteins have a true causal effect on severe COVID-19. Six proteins showed sex differences in levels over time, of which 3 were also associated with severe COVID-19: CCL26, IL1RL2, and IL3RA, providing insights to better understand the marked differences in outcomes by sex. CONCLUSIONS: Severe COVID-19 is associated with large changes in 69 immune-related proteins. Further, five proteins were associated with sex differences in outcomes. These results provide direct insights into immune-related proteins that are strongly influenced by severe COVID-19 infection. | Butler-Laporte, Guillaume Gonzalez-Kozlova, Edgar Su, Chen-Yang Zhou, Sirui Nakanishi, Tomoko Brunet-Ratnasingham, Elsa Morrison, David Laurent, Laetitia Afilalo, Jonathan Afilalo, Marc Henry, Danielle Chen, Yiheng Carrasco-Zanini, Julia Farjoun, Yossi Pietzner, Maik Kimchi, Nofar Afrasiabi, Zaman Rezk, Nardin Bouab, Meriem Petitjean, Louis Guzman, Charlotte Xue, Xiaoqing Tselios, Chris Vulesevic, Branka Adeleye, Olumide Abdullah, Tala Almamlouk, Noor Moussa, Yara DeLuca, Chantal Duggan, Naomi Schurr, Erwin Brassard, Nathalie Durand, Madeleine Del Valle, Diane Marie Thompson, Ryan Cedillo, Mario A Schadt, Eric Nie, Kai Simons, Nicole W Mouskas, Konstantinos Zaki, Nicolas Patel, Manishkumar Xie, Hui Harris, Jocelyn Marvin, Robert Cheng, Esther Tuballes, Kevin Argueta, Kimberly Scott, Ieisha Greenwood, Celia M T Paterson, Clare Hinterberg, Michael Langenberg, Claudia Forgetta, Vincenzo Mooser, Vincent Marron, Thomas Beckmann, Noam Kenigsberg, Ephraim Charney, Alexander W Kim-Schulze, Seunghee Merad, Miriam Kaufmann, Daniel E Gnjatic, Sacha Richards, J Brent eng England Clin Proteomics. 2022 Sep 28;19(1):34. doi: 10.1186/s12014-022-09371-z.I | 09/29/2022 | |
| Differences and commonalities in the genetic architecture of protein quantitative trait loci in European and Arab populations | Thareja G, et al. | 2022 | Hum Mol Genet | epub ahead of print | https://www.doi.org/10.1093/hmg/ddac243 | 36,168,886 | Polygenic scores (PGS) can identify individuals at risk of adverse health events and guide genetics-based personalized medicine. However, it is not clear how well PGS translate between different populations, limiting their application to well-studied ethnicities. Proteins are intermediate traits linking genetic predisposition and environmental factors to disease, with numerous blood circulating protein levels representing functional readouts of disease-related processes. We hypothesized that studying the genetic architecture of a comprehensive set of blood-circulating proteins between a European and an Arab population could shed fresh light on the translatability of PGS to understudied populations. We therefore conducted a genome-wide association study with whole-genome sequencing data using 1301 proteins measured on the SOMAscan aptamer-based affinity proteomics platform in 2935 samples of Qatar Biobank and evaluated the replication of protein quantitative traits (pQTLs) from European studies in an Arab population. Then, we investigated the colocalization of shared pQTL signals between the two populations. Finally, we compared the performance of protein PGS derived from a Caucasian population in a European and an Arab cohort. We found that the majority of shared pQTL signals (81.8%) colocalized between both populations. About one-third of the genetic protein heritability was explained by protein PGS derived from a European cohort, with protein PGS performing ~ 20% better in Europeans when compared to Arabs. Our results are relevant for the translation of PGS to non-Caucasian populations, as well as for future efforts to extend genetic research to understudied populations. | Thareja, Gaurav Belkadi, Aziz Arnold, Matthias Albagha, Omar M E Graumann, Johannes Schmidt, Frank Grallert, Harald Peters, Annette Gieger, Christian Consortium, The Qatar Genome Program Research Suhre, Karsten eng England Hum Mol Genet. 2022 Sep 28:ddac243. doi: 10.1093/hmg/ddac243.I | 09/29/2022 | ||||
| Unique and shared systemic biomarkers for emphysema in Alpha-1 Antitrypsin deficiency and chronic obstructive pulmonary disease | Serban KA, et al. | 2022 | EBioMedicine | 84 | 104262 | https://www.doi.org/10.1016/j.ebiom.2022.104262 | 36,155,958 | Biomarkers Humans Myosins Pharmaceutical Preparations *Pulmonary Disease, Chronic Obstructive/diagnosis/etiology *Pulmonary Emphysema/diagnosis/etiology *Somatomedins *alpha 1-Antitrypsin Deficiency/complications/diagnosis/genetics Alpha-1 antitrypsin deficiency Emphysema Plasma biomarker Protein score SomaScan Committee, Alpha-1 Foundation Medical Advisory and Scientific Committee, ATS - RCMB Website Committee, National Jewish Health IBC committee (all unpaid) KAP does not report any potential conflict of interest CS reports grants or contracts from Adverum, Arrowhead, AstraZeneca, CSA Medical, Grifols, Nuvaira, Takeda, Vertex consulting fees from AstraZenca, Dicerna, Glaxo Smith Kline, Inhibrx, Morair, UpToDate, Vertex has received honoraria for presentations from the American Thoracic Society has received support for travel from CSL Behring serves as the Medical Director for AlphaNet RAS reports grants or contracts from Vertex, NIH/NCATS, Alpha-1 Foundation, consulting fees from Grifols, CSL Behring, Vertex, Intellia, Inhibrx, Takeda, Evolve Biologics, has received travel support from CSL Behring has served on the Advisory Board of Arrowhead Pharmaceuticals, and serves as the Medical Director for AlphaNet and on the board of directors for Global Implementation Solutions, Osteogenesis Imperfecta Foundation, Alpha-1 Foundation, and AlphaNet AMT reports grants or contracts from Vertex, Grifols, and CSl Behring has received consulting fees from CSL Behring, Inhibrix, Z-factor, and Takeda, has received honoraria for lectures from Glaxo Smith Kline and AstraZeneca TB does not report any potential conflict of interest DAS does not report any potential conflict of interest LM does not report any potential conflict of interest NH does not report any potential conflict of interest EKS reports grants or contracts from Glaxo Smith Kline, Bayer BDH does not report any potential conflict of interest CPH reports grants or contracts from Alpha-1 Foundation, Bayer, Boehringer-Ingelheim, and Vertex, consulting fees from AstraZeneca and Takeda DLD has received honoraria for lectures from Novartis and financial support from Bayer towards the institution MHC reports grants or contracts from Glaxo Smith Kline, Bayer, consulting fees from AstraZeneca and Genentech, honoraria for presentations from Illumina, RPB does not report any potential conflict of interest. | BACKGROUND: Alpha-1 Antitrypsin (AAT) deficiency (AATD), the most common genetic cause of emphysema presents with unexplained phenotypic heterogeneity in affected subjects. Our objectives to identify unique and shared AATD plasma biomarkers with chronic obstructive pulmonary disease (COPD) may explain AATD phenotypic heterogeneity. METHODS: The plasma or serum of 5,924 subjects from four AATD and COPD cohorts were analyzed on SomaScan V4.0 platform. Using multivariable linear regression, inverse variance random-effects meta-analysis, and Least Absolute Shrinkage and Selection Operator (LASSO) regression we tested the association between 4,720 individual proteins or combined in a protein score with emphysema measured by 15th percentile lung density (PD15) or diffusion capacity (DLCO) in distinct AATD genotypes (Pi*ZZ, Pi*SZ, Pi*MZ) and non-AATD, PiMM COPD subjects. AAT SOMAmer accuracy for identifying AATD was tested using receiver operating characteristic curve analysis. FINDINGS: In PiZZ AATD subjects, 2 unique proteins were associated with PD15 and 98 proteins with DLCO. Of those, 68 were also associated with DLCO in COPD also and enriched for three cellular component pathways: insulin-like growth factor, lipid droplet, and myosin complex. PiMZ AATD subjects shared similar proteins associated with DLCO as COPD subjects. Our emphysema protein score included 262 SOMAmers and predicted emphysema in AATD and COPD subjects. SOMAmer AAT level <7.99 relative fluorescence unit (RFU) had 100% sensitivity and specificity for identifying Pi*ZZ, but it was lower for other AATD genotypes. INTERPRETATION: Using SomaScan, we identified unique and shared plasma biomarkers between AATD and COPD subjects and generated a protein score that strongly associates with emphysema in COPD and AATD. Furthermore, we discovered unique biomarkers associated with DLCO and emphysema in PiZZ AATD. FUNDING: This work was supported by a grant from the Alpha-1 Foundation to RPB. COPDGene was supported by Award U01 HL089897 and U01 HL089856 from the National Heart, Lung, and Blood Institute. Proteomics for COPDGene was supported by NIH 1R01HL137995. GRADS was supported by Award U01HL112707, U01 HL112695 from the National Heart, Lung, and Blood Institute, and UL1TRR002535 to CCTSI; QUANTUM-1 was supported by the National Heart Lung and Blood Institute, the Office of Rare Diseases through the Rare Lung Disease Clinical Research Network (1 U54 RR019498-01, Trapnell PI), and the Alpha-1 Foundation. COPDGene is also supported by the COPD Foundation through contributions made to an Industry Advisory Board that has included AstraZeneca, Bayer Pharmaceuticals, Boehringer-Ingelheim, Genentech, GlaxoSmithKline, Novartis, Pfizer, and Sunovion. | Serban, K A Pratte, K A Strange, C Sandhaus, R A Turner, A M Beiko, T Spittle, D A Maier, L Hamzeh, N Silverman, E K Hobbs, B D Hersh, C P DeMeo, D L Cho, M H Bowler, R P eng K08 HL141770/HL/NHLBI NIH HHS/ Meta-Analysis Netherlands EBioMedicine. 2022 Oct;84:104262. doi: 10.1016/j.ebiom.2022.104262. Epub 2022 Sep 22.I | 09/27/2022 | ||
| Human Plasma Proteome During Normal Pregnancy | Tarca AL, et al. | 2022 | J Proteome Res | 21 | 11 | 2687-2702 | https://www.doi.org/10.1021/acs.jproteome.2c00391 | 36,154,181 | Humans Pregnancy Female *Proteome/genetics/metabolism *Placenta/metabolism Longitudinal Studies Gestational Age aptamer biomarker machine learning proteomic standards single-cell RNA signature | The human plasma proteome is underexplored despite its potential value for monitoring health and disease. Herein, using a recently developed aptamer-based platform, we profiled 7288 proteins in 528 plasma samples from 91 normal pregnancies (Gene Expression Omnibus identifier GSE206454). The coefficient of variation was <20% for 93% of analytes (median 7%), and a cross-platform correlation for selected key angiogenic and anti-angiogenic proteins was significant. Gestational age was associated with changes in 953 proteins, including highly modulated placenta- and decidua-specific proteins, and they were enriched in biological processes including regulation of growth, angiogenesis, immunity, and inflammation. The abundance of proteins corresponding to RNAs specific to populations of cells previously described by single-cell RNA-Seq analysis of the placenta was highly modulated throughout gestation. Furthermore, machine learning-based prediction of gestational age and of time from sampling to term delivery compared favorably with transcriptomic models (mean absolute error of 2 weeks). These results suggested that the plasma proteome may provide a non-invasive readout of placental cellular dynamics and serve as a blueprint for investigating obstetrical disease. | Tarca, Adi L Romero, Roberto Bhatti, Gaurav Gotsch, Francesca Done, Bogdan Gudicha, Dereje W Gallo, Dahiana M Jung, Eunjung Pique-Regi, Roger Berry, Stanley M Chaiworapongsa, Tinnakorn Gomez-Lopez, Nardhy eng J Proteome Res. 2022 Nov 4;21(11):2687-2702. doi: 10.1021/acs.jproteome.2c00391. Epub 2022 Sep 26.I | 09/27/2022 | |
| Multi-Omic Admission-Based Prognostic Biomarkers Identified by Machine Learning Algorithms Predict Patient Recovery and 30-Day Survival in Trauma Patients | Abdelhamid SS, et al. | 2022 | Metabolites | 12 | 9 | 774 | https://www.doi.org/10.3390/metabo12090774 | 36,144,179 | biomarkers machine learning multi-omics prognostic proteomics trauma equity stake in Haima Therapeutics. He has received research support and/or honoraria from Haemonetics, Instrumentation Laboratories, Janssen Pharmaceuticals, and Meredian. T.R.B. is a stakeholder in Immunetrics. Other authors declare no conflict of interests. | Admission-based circulating biomarkers for the prediction of outcomes in trauma patients could be useful for clinical decision support. It is unknown which molecular classes of biomolecules can contribute biomarkers to predictive modeling. Here, we analyzed a large multi-omic database of over 8500 markers (proteomics, metabolomics, and lipidomics) to identify prognostic biomarkers in the circulating compartment for adverse outcomes, including mortality and slow recovery, in severely injured trauma patients. Admission plasma samples from patients (n = 129) enrolled in the Prehospital Air Medical Plasma (PAMPer) trial were analyzed using mass spectrometry (metabolomics and lipidomics) and aptamer-based (proteomics) assays. Biomarkers were selected via Least Absolute Shrinkage and Selection Operator (LASSO) regression modeling and machine learning analysis. A combination of five proteins from the proteomic layer was best at discriminating resolvers from non-resolvers from critical illness with an Area Under the Receiver Operating Characteristic curve (AUC) of 0.74, while 26 multi-omic features predicted 30-day survival with an AUC of 0.77. Patients with traumatic brain injury as part of their injury complex had a unique subset of features that predicted 30-day survival. Our findings indicate that multi-omic analyses can identify novel admission-based prognostic biomarkers for outcomes in trauma patients. Unique biomarker discovery also has the potential to provide biologic insights. | Abdelhamid, Sultan S Scioscia, Jacob Vodovotz, Yoram Wu, Junru Rosengart, Anna Sung, Eunseo Rahman, Syed Voinchet, Robert Bonaroti, Jillian Li, Shimena Darby, Jennifer L Kar, Upendra K Neal, Matthew D Sperry, Jason Das, Jishnu Billiar, Timothy R eng T32 HL098036/HL/NHLBI NIH HHS/ R38 HL150207/HL/NHLBI NIH HHS/ R35 GM127027/GM/NIGMS NIH HHS/ R35GM119526/NH/NIH HHS/ DP2AI164325/National Institute of Allergy and Infectious Diseases/ R35-GM-127027/NH/NIH HHS/ R35 GM119526/GM/NIGMS NIH HHS/ DP2 AI164325/AI/NIAID NIH HHS/ Switzerland Metabolites. 2022 Aug 23;12(9):774. doi: 10.3390/metabo12090774.I | 09/24/2022 | |
| Prediction of Total-Body and Partial-Body Exposures to Radiation Using Plasma Proteomic Expression Profiles | Sproull M, et al. | 2022 | Radiat Res | epub ahead of print | https://www.doi.org/10.1667/RADE-22-00074.1 | 36,136,739 | There is a need to identify new biomarkers of radiation exposure for not only systemic total-body irradiation (TBI) but also to characterize partial-body irradiation and organ specific radiation injury. In the current study, we sought to develop novel biodosimetry models of radiation exposure using TBI and organ specific partial-body irradiation to only the brain, lung or gut using a multivariate proteomics approach. Subset panels of significantly altered proteins were selected to build predictive models of radiation exposure in a variety of sample cohort configurations relevant to practical field application of biodosimetry diagnostics during future radiological or nuclear event scenarios. Female C57BL/6 mice, 8-15 weeks old, received a single total-body or partial-body dose of 2 or 8 Gy TBI or 2 or 8 Gy to only the lung or gut, or 2, 8 or 16 Gy to only the brain using a Pantak X-ray source. Plasma was collected by cardiac puncture at days 1, 3 and 7 postirradiation for total-body exposures and only the lung and brain exposures, and at days 3, 7 and 14 postirradiation for gut exposures. Plasma was then screened using the aptamer-based SOMAscan proteomic assay technology, for changes in expression of 1,310 protein analytes. A subset panel of protein biomarkers which demonstrated significant changes (P < 0.01) in expression after irradiation were used to build predictive models of radiation exposure using different sample cohorts. Model 1 compared controls vs. all pooled irradiated samples, which included TBI and all organ specific partial irradiation. Model 2 compared controls vs. TBI vs. partial irradiation (with all organ specific partial exposure pooled within the partial-irradiated group), and model 3 compared controls vs. each individual organ specific partial-body exposure separately (brain, gut and lung). Detectable values were obtained for all 1,310 proteins included in the SOMAscan assay for all samples. Each model algorithm built using a unique sample cohort was validated with a training set of samples and tested with a separate new sample series. Overall predictive accuracies of 89%, 78% and 55% resulted for models 1-3, respectively, representing novel predictive panels of radiation responsive proteomic biomarkers. Though relatively high overall predictive accuracies were achieved for models 1 and 2, all three models showed limited accuracy at differentiating between the controls and partial-irradiated body samples. In our study we were able to identify novel panels of radiation responsive proteins useful for predicting radiation exposure and to create predictive models of partial-body exposure including organ specific radiation exposures. This proof-of-concept study also illustrates the inherent physiological limitations of distinguishing between small-body exposures and the unirradiated using proteomic biomarkers of radiation exposure. As use of biodosimetry diagnostics in future mass casualty settings will be complicated by the heterogeneity of partial-body exposure received in the field, further work remains in adapting these diagnostic tools for practical use. | Sproull, M Kawai, T Krauze, A Shankavaram, U Camphausen, K eng Radiat Res. 2022 Sep 22. doi: 10.1667/RADE-22-00074.1.I | 09/23/2022 | ||||
| Proteomic Analysis of Effects of Spironolactone in Heart Failure With Preserved Ejection Fraction | Javaheri A, et al. | 2022 | Circ Heart Fail | 15 | 9 | e009693 | https://www.doi.org/10.1161/CIRCHEARTFAILURE.121.009693 | 36,126,144 | Apelin/pharmacology/therapeutic use *Biological Products/pharmacology/therapeutic use Caspases/pharmacology/therapeutic use *Heart Failure Humans *Insulins/therapeutic use Liver X Receptors Mineralocorticoid Receptor Antagonists/therapeutic use Phospholipid Transfer Proteins/pharmacology/therapeutic use Proteome Proteomics Spironolactone/adverse effects Stroke Volume/physiology Treatment Outcome Americas caspase glycoprotein heart failure spironolactone | BACKGROUND: The TOPCAT trial (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist Trial) suggested clinical benefits of spironolactone treatment among patients with heart failure with preserved ejection fraction enrolled in the Americas. However, a comprehensive assessment of biologic pathways impacted by spironolactone therapy in heart failure with preserved ejection fraction has not been performed. METHODS: We conducted aptamer-based proteomic analysis utilizing 5284 modified aptamers to 4928 unique proteins on plasma samples from TOPCAT participants from the Americas (n=164 subjects with paired samples at baseline and 1 year) to identify proteins and pathways impacted by spironolactone therapy in heart failure with preserved ejection fraction. Mean percentage change from baseline was calculated for each protein. Additionally, we conducted pathway analysis of proteins altered by spironolactone. RESULTS: Spironolactone therapy was associated with proteome-wide significant changes in 7 proteins. Among these, CARD18 (caspase recruitment domain-containing protein 18), PKD2 (polycystin 2), and PSG2 (pregnancy-specific glycoprotein 2) were upregulated, whereas HGF (hepatic growth factor), PLTP (phospholipid transfer protein), IGF2R (insulin growth factor 2 receptor), and SWP70 (switch-associated protein 70) were downregulated. CARD18, a caspase-1 inhibitor, was the most upregulated protein by spironolactone (-0.5% with placebo versus +66.5% with spironolactone, P<0.0001). The top canonical pathways that were significantly associated with spironolactone were apelin signaling, stellate cell activation, glycoprotein 6 signaling, atherosclerosis signaling, liver X receptor activation, and farnesoid X receptor activation. Among the top pathways, collagens were a consistent theme that increased in patients receiving placebo but decreased in patients randomized to spironolactone. CONCLUSIONS: Proteomic analysis in the TOPCAT trial revealed proteins and pathways altered by spironolactone, including the caspase inhibitor CARD18 and multiple pathways that involved collagens. In addition to effects on fibrosis, our studies suggest potential antiapoptotic effects of spironolactone in heart failure with preserved ejection fraction, a hypothesis that merits further exploration. | Javaheri, Ali Diab, Ahmed Zhao, Lei Qian, Chenao Cohen, Jordana B Zamani, Payman Kumar, Anupam Wang, Zhaoqing Ebert, Christina Maranville, Joseph Kvikstad, Erika Basso, Michael van Empel, Vanessa Richards, A Mark Doughty, Robert N Rietzschel, Ernst Kammerhoff, Karl Gogain, Joseph Schafer, Peter Seiffert, Dietmar A Gordon, David A Ramirez-Valle, Francisco Mann, Douglas L Cappola, Thomas P Chirinos, Julio A eng R01 HL155599/HL/NHLBI NIH HHS/ U01 TR003734/TR/NCATS NIH HHS/ R03 HL146874/HL/NHLBI NIH HHS/ K24 AG070459/AG/NIA NIH HHS/ R01 HL104106/HL/NHLBI NIH HHS/ R01 HL121510/HL/NHLBI NIH HHS/ R56 HL136730/HL/NHLBI NIH HHS/ R01 AG058969/AG/NIA NIH HHS/ R01 HL153646/HL/NHLBI NIH HHS/ U01 HL160277/HL/NHLBI NIH HHS/ K08 HL138262/HL/NHLBI NIH HHS/ R33 HL146390/HL/NHLBI NIH HHS/ P01 HL094307/HL/NHLBI NIH HHS/ R01 HL157264/HL/NHLBI NIH HHS/ R01 HL155344/HL/NHLBI NIH HHS/ Randomized Controlled Trial Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Circ Heart Fail. 2022 Sep;15(9):e009693. doi: 10.1161/CIRCHEARTFAILURE.121.009693. Epub 2022 Aug 9.I | 09/21/2022 | |
| Inflammatory Markers in Non-Obese Women with Polycystic Ovary Syndrome Are Not Elevated and Show No Correlation with Vitamin D Metabolites | Moin ASM, et al. | 2022 | Nutrients | 14 | 17 | https://www.doi.org/10.3390/nu14173540 | 36,079,796 | Aged Biomarkers Female Humans Inflammation/complications *Insulin Resistance Obesity *Polycystic Ovary Syndrome Vitamin D Vitamins inflammation matrix metalloproteinases polycystic ovary syndrome vitamin D3 | INTRODUCTION: Chronic low-grade inflammation is a characteristic of women with polycystic ovary syndrome (PCOS), although this may be obesity-driven rather than an intrinsic facet of PCOS; furthermore, vitamin D deficiency, another common feature of PCOS, is reported to have an association with increased inflammation. Therefore, circulating inflammatory protein levels and circulating levels of vitamin D may be linked in PCOS, though it is unclear which vitamin D metabolites may be important. METHODS: We measured plasma levels of 24 inflammatory proteins and 12 matrix metalloproteinases (proteins modulated by the inflammatory process) by slow off-rate modified aptamer (SOMA)-scan plasma protein measurement in weight and aged-matched non-obese non-insulin resistant PCOS (n = 24) and control (n = 24) women. Inflammatory proteins and matrix metalloproteinases were correlated to 25-hydroxy vitamin D(3) (25(OH)D(3)), its epimer 25-hydroxy-3epi-vitamin D (3epi25(OH)D) and the active 1,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)) as measured by gold standard isotope-dilution liquid chromatography tandem mass spectrometry. RESULTS: PCOS women had both an elevated free androgen index and circulating anti-mullerian hormone, though insulin resistance was comparable to controls. C-reactive protein, as a standard circulatory marker of inflammation, was comparable between cohorts. Levels of circulating inflammatory proteins and matrix metalloproteinases were not different between the PCOS and control women, with no correlation of 25(OH)D(3,) 1,25(OH)(2)D(3) or 3epi25(OH)D with any of the inflammatory proteins. CONCLUSION: In a non-obese PCOS population matched for age and insulin resistance, circulating inflammatory proteins and matrix metalloproteinases were not elevated and did not correlate with 25(OH)D(3,) its epimer 3epi25(OH)D or 1,25(OH)(2)D(3) in either control or PCOS women, indicating that the inflammatory response is absent and the vitamin D-metabolite independent in non-obese women with PCOS. | Moin, Abu Saleh Md Sathyapalan, Thozhukat Atkin, Stephen L Butler, Alexandra E eng Switzerland Nutrients. 2022 Aug 27;14(17):3540. doi: 10.3390/nu14173540.I | 09/10/2022 | ||
| The associations between plasma soluble Trem1 and neurological diseases: a Mendelian randomization study | Shi X, et al. | 2022 | J Neuroinflammation | 19 | 1 | 218 | https://www.doi.org/10.1186/s12974-022-02582-z | 36,068,612 | *Alzheimer Disease/genetics *Amyotrophic Lateral Sclerosis Genome-Wide Association Study Humans Mendelian Randomization Analysis/methods *Parkinson Disease/genetics Polymorphism, Single Nucleotide/genetics Triggering Receptor Expressed on Myeloid Cells-1/genetics Alzheimer's disease Epilepsy Mendelian randomization Neurological diseases sTrem1 | BACKGROUND: Triggering receptor expressed on myeloid cell 1 (Trem1) is an important regulator of cellular inflammatory responses. Neuroinflammation is a common thread across various neurological diseases. Soluble Trem1 (sTrem1) in plasma is associated with the development of central nervous system disorders. However, the extent of any causative effects of plasma sTrem1 on the risk of these disorders is still unclear. METHOD: Genetic variants for plasma sTrem1 levels were selected as instrumental variables. Summary-level statistics of neurological disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), epilepsy, cerebrovascular diseases, and migraine were collected from genome-wide association studies (GWASs). Whether plasma sTrem1 was causally associated with neurological disorders was assessed using a two-sample Mendelian randomization (MR) analysis, with false discovery rate (FDR)-adjusted methods applied. RESULTS: We inferred suggestive association of higher plasma sTrem1 with the risk of AD (odds ratio [OR] per one standard deviation [SD] increase = 1.064, 95% CI 1.012-1.119, P = 0.014, P(FDR) = 0.056). Moreover, there was significant association between plasma sTrem1 level and the risk of epilepsy (OR per one SD increase = 1.044, 95% CI 1.016-1.072, P = 0.002, P(FDR) = 0.032), with a modest statistical power of 41%. Null associations were found for plasma sTrem1 with other neurological diseases and their subtypes. CONCLUSIONS: Taken together, this study indicates suggestive association between plasma sTrem1 and AD. Moreover, higher plasma sTrem1 was associated with the increased risk of epilepsy. The findings support the hypothesis that sTrem1 may be a vital element on the causal pathway to AD and epilepsy. | Shi, Xiaolei Wei, Tao Hu, Yachun Wang, Meng Tang, Yi eng 2021-2023/Guangzhou Municipal Key Discipline in Medicine/ 2019B030316001/Science and Technology Plan Project of Guangdong Province/ JQ19024/Beijing Natural Science Foundation/ 81970996/National Natural Science Foundation of China/ Z191100006619046/Beijing Municipal Science & Technology Commission/ DFL20220703/Beijing Hospitals Authority's Ascent Plan/ England J Neuroinflammation. 2022 Sep 6;19(1):218. doi: 10.1186/s12974-022-02582-z.I | 09/07/2022 | |
| Is an MRI-derived anatomical measure of dementia risk also a measure of brain aging? | Casanova R, et al. | 2022 | Geroscience | epub ahead of print | https://www.doi.org/10.1007/s11357-022-00650-z | 36,050,589 | Aging Alzheimer's disease Deficit accumulation index Machine learning Mortality Proteomics | Machine learning methods have been applied to estimate measures of brain aging from neuroimages. However, only rarely have these measures been examined in the context of biologic age. Here, we investigated associations of an MRI-based measure of dementia risk, the Alzheimer's disease pattern similarity (AD-PS) scores, with measures used to calculate biological age. Participants were those from visit 5 of the Atherosclerosis Risk in Communities Study with cognitive status adjudication, proteomic data, and AD-PS scores available. The AD-PS score estimation is based on previously reported machine learning methods. We evaluated associations of the AD-PS score with all-cause mortality. Sensitivity analyses using only cognitively normal (CN) individuals were performed treating CNS-related causes of death as competing risk. AD-PS score was examined in association with 32 proteins measured, using a Somalogic platform, previously reported to be associated with age. Finally, associations with a deficit accumulation index (DAI) based on a count of 38 health conditions were investigated. All analyses were adjusted for age, race, sex, education, smoking, hypertension, and diabetes. The AD-PS score was significantly associated with all-cause mortality and with levels of 9 of the 32 proteins. Growth/differentiation factor 15 (GDF-15) and pleiotrophin remained significant after accounting for multiple-testing and when restricting the analysis to CN participants. A linear regression model showed a significant association between DAI and AD-PS scores overall. While the AD-PS scores were created as a measure of dementia risk, our analyses suggest that they could also be capturing brain aging. | Casanova, Ramon Anderson, Andrea M Barnard, Ryan T Justice, Jamie N Kucharska-Newton, Anna Windham, Beverly Gwen Palta, Priya Gottesman, Rebecca F Mosley, Thomas H Hughes, Timothy M Wagenknecht, Lynne E Kritchevsky, Stephen B eng grant R01 HL134320/HL/NHLBI NIH HHS/ U01 AG024904/AG/NIA NIH HHS/ Switzerland Geroscience. 2022 Sep 2. doi: 10.1007/s11357-022-00650-z.I | 09/02/2022 | |||
| Neurocognitive trajectory and proteomic signature of inherited risk for Alzheimer's disease | Paranjpe MD, et al. | 2022 | PLoS Genet | 18 | 9 | e1010294 | https://www.doi.org/10.1371/journal.pgen.1010294 | 36,048,760 | Adult Aged *Alzheimer Disease/pathology Biomarkers Cross-Sectional Studies Genome-Wide Association Study Humans Middle Aged Proteomics | For Alzheimer's disease-a leading cause of dementia and global morbidity-improved identification of presymptomatic high-risk individuals and identification of new circulating biomarkers are key public health needs. Here, we tested the hypothesis that a polygenic predictor of risk for Alzheimer's disease would identify a subset of the population with increased risk of clinically diagnosed dementia, subclinical neurocognitive dysfunction, and a differing circulating proteomic profile. Using summary association statistics from a recent genome-wide association study, we first developed a polygenic predictor of Alzheimer's disease comprised of 7.1 million common DNA variants. We noted a 7.3-fold (95% CI 4.8 to 11.0; p < 0.001) gradient in risk across deciles of the score among 288,289 middle-aged participants of the UK Biobank study. In cross-sectional analyses stratified by age, minimal differences in risk of Alzheimer's disease and performance on a digit recall test were present according to polygenic score decile at age 50 years, but significant gradients emerged by age 65. Similarly, among 30,541 participants of the Mass General Brigham Biobank, we again noted no significant differences in Alzheimer's disease diagnosis at younger ages across deciles of the score, but for those over 65 years we noted an odds ratio of 2.0 (95% CI 1.3 to 3.2; p = 0.002) in the top versus bottom decile of the polygenic score. To understand the proteomic signature of inherited risk, we performed aptamer-based profiling in 636 blood donors (mean age 43 years) with very high or low polygenic scores. In addition to the well-known apolipoprotein E biomarker, this analysis identified 27 additional proteins, several of which have known roles related to disease pathogenesis. Differences in protein concentrations were consistent even among the youngest subset of blood donors (mean age 33 years). Of these 28 proteins, 7 of the 8 proteins with concentrations available were similarly associated with the polygenic score in participants of the Multi-Ethnic Study of Atherosclerosis. These data highlight the potential for a DNA-based score to identify high-risk individuals during the prolonged presymptomatic phase of Alzheimer's disease and to enable biomarker discovery based on profiling of young individuals in the extremes of the score distribution. | Paranjpe, Manish D Chaffin, Mark Zahid, Sohail Ritchie, Scott Rotter, Jerome I Rich, Stephen S Gerszten, Robert Guo, Xiuqing Heckbert, Susan Tracy, Russ Danesh, John Lander, Eric S Inouye, Michael Kathiresan, Sekar Butterworth, Adam S Khera, Amit V eng NIHR BTRU-2014- 10024/DH_/Department of Health/United Kingdom MR/L003120/1/MRC_/Medical Research Council/United Kingdom SP/09/002/BHF_/British Heart Foundation/United Kingdom RG/13/13/30194/BHF_/British Heart Foundation/United Kingdom RG/18/13/33946/BHF_/British Heart Foundation/United Kingdom CSO_/Chief Scientist Office/United Kingdom 75N92020D00001/HL/NHLBI NIH HHS/ HHSN268201500003I/HL/NHLBI NIH HHS/ N01HC95159/HL/NHLBI NIH HHS/ N01HC95160/HL/NHLBI NIH HHS/ N01HC95161/HL/NHLBI NIH HHS/ N01HC95162/HL/NHLBI NIH HHS/ N01HC95163/HL/NHLBI NIH HHS/ N01HC95164/HL/NHLBI NIH HHS/ N01HC95165/HL/NHLBI NIH HHS/ N01HC95166/HL/NHLBI NIH HHS/ N01 HC095167/HC/NHLBI NIH HHS/ N01HC95168/HL/NHLBI NIH HHS/ N01HC95169/HL/NHLBI NIH HHS/ 75N92020D00005/HL/NHLBI NIH HHS/ 75N92020D00002/HL/NHLBI NIH HHS/ 75N92020D00003/HL/NHLBI NIH HHS/ 75N92020D00006/HL/NHLBI NIH HHS/ 75N92020D00004/HL/NHLBI NIH HHS/ 75N92020D00007/HL/NHLBI NIH HHS/ N02 HL64278/HL/NHLBI NIH HHS/ R01 HL133870/HL/NHLBI NIH HHS/ R01 HL132320/HL/NHLBI NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't PLoS Genet. 2022 Sep 1;18(9):e1010294. doi: 10.1371/journal.pgen.1010294. eCollection 2022 Sep.I | 09/02/2022 | |
| Highly sensitive protein detection by aptamer-based single-molecule kinetic fingerprinting | Chatterjee T, et al. | 2022 | Biosens Bioelectron | 216 | 114639 | https://www.doi.org/10.1016/j.bios.2022.114639 | 36,037,714 | Antibodies, Monoclonal *Aptamers, Nucleotide/chemistry Biomarkers *Biosensing Techniques Humans Interleukin-8 Ligands *Nucleic Acids Reproducibility of Results SELEX Aptamer Technique/methods Vascular Endothelial Growth Factor A Analyte detection Aptamer Kinetic fingerprinting Protein biomarkers Sensitivity Single molecule fluorescence microscopy interests/personal relationships which may be considered as potential competing interests: N.G.W and A.J.-B are cofounder of aLight Sciences, Inc., which seeks to commercialize the SiMREPS technology. A.J.-B is an employee of aLight Sciences, Inc. N.G.W and A.J.-B are co-inventors of patent applications related to the SiMREPS technology. | Sensitive assays of protein biomarkers play critical roles in clinical diagnostics and biomedical research. Such assays typically employ immunoreagents such as monoclonal antibodies that suffer from several drawbacks, including relatively tedious production, significant batch-to-batch variability, and challenges in site-specific, stoichiometric modification with fluorophores or other labels. One proposed alternative to such immunoreagents, nucleic acid aptamers generated by systematic evolution of ligand by exponential enrichment (SELEX), can be chemically synthesized with much greater ease, precision, and reproducibility than antibodies. However, most aptamers exhibit relatively poor affinity, yielding low sensitivity in the assays employing them. Recently, single molecule recognition through equilibrium Poisson sampling (SiMREPS) has emerged as a platform for detecting proteins and other biomarkers with high sensitivity without requiring high-affinity detection probes. In this manuscript, we demonstrate the applicability and advantages of aptamers as detection probes in SiMREPS as applied to two clinically relevant biomarkers, VEGF(165) and IL-8, using a wash-free protocol with limits of detection in the low femtomolar range (3-9 fM). We show that the kinetics of existing RNA aptamers can be rationally optimized for use as SiMREPS detection probes by mutating a single nucleotide in the conserved binding region or by shortening the aptamer sequence. Finally, we demonstrate the detection of endogenous IL-8 from human serum at a concentration below the detection limit of commercial ELISAs. | Chatterjee, Tanmay Johnson-Buck, Alexander Walter, Nils G eng England Biosens Bioelectron. 2022 Nov 15;216:114639. doi: 10.1016/j.bios.2022.114639. Epub 2022 Aug 22.I | 08/30/2022 | ||
| Markers of endothelial glycocalyx dysfunction in Clarkson disease | Xie Z, et al. | 2022 | J Transl Med | 20 | 1 | 380 | https://www.doi.org/10.1186/s12967-022-03587-1 | 36,038,904 | Biomarkers *Capillary Leak Syndrome/diagnosis/pathology/therapy Endothelial Cells/pathology Glycocalyx Humans Proteomics Capillary leak Endothelium Glyocalcyx | BACKGROUND: Clarkson disease (monoclonal gammopathy-associated idiopathic systemic capillary leak syndrome, ISCLS) is a rare idiopathic condition marked by transient, relapsing-remitting episodes of systemic microvascular hyper-permeability, which liberates plasma fluid and macromolecules into the peripheral tissues. This pathology manifests clinically as the abrupt onset of hypotensive shock, hemoconcentration, and hypoalbuminemia. METHODS: We analysed endothelial glycocalyx (eGCX)-related markers in plasma from patients with ISCLS during acute disease flares and convalescence by ELISA and comprehensive proteomic profiling. We evaluated eGCX-related components and gene expression in cultured endothelial cells using RNA-sequencing, real-time PCR, and fluorescence staining. RESULTS: Serum levels of eGCX-related core components including hyaluronic acid (HA) and the core proteoglycan soluble syndecan-1 (sCD138) were elevated at baseline and during acute ISCLS flares. Serial measurements demonstrated that sCD138 levels peaked during the recovery (post-leak) phase of the illness. Proteomic analysis of matched acute and convalescent ISCLS plasma revealed increased abundance of eGCX-related proteins, including glypicans, thrombospondin-1 (TSP-1), and eGCX-degrading enzymes in acute compared to remission plasma. Abundance of endothelial cell damage markers did not differ in acute and baseline plasma. Expression of several eGCX-related genes and surface carbohydrate content in endothelial cells from patients with ISCLS did not differ significantly from that observed in healthy control cells. CONCLUSIONS: eGCX dysfunction, but not endothelial injury, may contribute to clinical symptoms of acute ISCLS. Serum levels of of eGCX components including sCD138 may be measured during acute episodes of ISCLS to monitor clinical status and therapeutic responses. | Xie, Zhihui Borset, Magne Sveen, Kjell Boe, Ole Wilhelm Chan, Eunice C Lack, Justin B Hornick, Katherine M Verlicchi, Franco Eisch, A Robin Melchio, Remo Dudek, Arkadiusz Z Druey, Kirk M eng Z01-AI-001083/Division of Intramural Research, National Institute of Allergy and Infectious Diseases/ Research Support, N.I.H., Intramural England J Transl Med. 2022 Aug 29;20(1):380. doi: 10.1186/s12967-022-03587-1.I | 08/30/2022 | |
| Recent developments of aptamer-based lateral flow assays for point-of-care (POC) diagnostics | Jaisankar A, et al. | 2022 | Anal Biochem | 655 | 114874 | https://www.doi.org/10.1016/j.ab.2022.114874 | 36,027,971 | Antibodies *Aptamers, Nucleotide Biological Assay *Biosensing Techniques Humans Point-of-Care Systems SELEX Aptamer Technique Aptamer-based LFA Aptamers Lateral flow assay Selex Sensors of interest. | In the field of lateral flow assay (LFA), the application of aptamer as a bioreceptor has been implemented to overcome the limitations of antibodies, such as tedious in vivo processes, short shelf-life, and functionalization issues. To address these limitations aptamer-based LFA (ALFA) is preferred to antibody-based LFA that produces higher sensitivity and specificity. In principle, aptamers have a strong affinity towards their targets like small, large, and non-immunogenic molecules because of their high affinity, sensitivity, low dissociation constant, cost-effectiveness, and flexible nature. Thus, ALFA can be considered an efficient biosensor model for its superior portability, rapid detection with quick turnaround time, and usability by a non-technical person at any location with simple visual output. This review concisely overviews ALFA, its principles, formats, aptamer selection process, and biomedical applications. In addition, the critical components to design, develop, test, and amplify signals to create ALFA are discussed in brief. In addition, the aspects of conceptualization of ALFA product transforming from bench-side laboratory design and fabrication to commercial market are addressed in detail. | Jaisankar, Abinaya Krishnan, Sasirekha Rangasamy, Loganathan eng Research Support, Non-U.S. Gov't Review Anal Biochem. 2022 Oct 15;655:114874. doi: 10.1016/j.ab.2022.114874. Epub 2022 Aug 24.I | 08/27/2022 | ||
| Blood-biomarkers and devices for atrial fibrillation screening: Lessons learned from the AFRICAT (Atrial Fibrillation Research In CATalonia) study | Pala E, et al. | 2022 | PLoS One | 17 | 8 | e0273571 | https://www.doi.org/10.1371/journal.pone.0273571 | 35,998,199 | *Atrial Fibrillation Biomarkers Electrocardiography, Ambulatory Humans Prospective Studies Spain | BACKGROUND AND OBJECTIVE: AFRICAT is a prospective cohort study intending to develop an atrial fibrillation (AF) screening program through the combination of blood markers, rhythm detection devices, and long-term monitoring in our community. In particular, we aimed to validate the use of NT-proBNP, and identify new blood biomarkers associated with AF. Also, we aimed to compare AF detection using various wearables and long-term Holter monitoring. METHODS: 359 subjects aged 65-75 years with hypertension and diabetes were included in two phases: Phase I (n = 100) and Phase II (n = 259). AF diagnosis was performed by baseline 12-lead ECG, 4 weeks of Holter monitoring (NuuboTM), and/or medical history. An aptamer array including 1310 proteins was measured in the blood of 26 patients. Candidates were selected according to p-value, logFC and biological function to be tested in verification and validation phases. Several screening devices were tested and compared: AliveCor, Watch BP, MyDiagnostick and Fibricheck. RESULTS: AF was present in 34 subjects (9.47%). The aptamer array revealed 41 proteins with differential expression in AF individuals. TIMP-2 and ST-2 were the most promising candidates in the verification analysis, but none of them was further validated. NT-proBNP (log-transformed) (OR = 1.934; p<0.001) was the only independent biomarker to detect AF in the whole cohort. Compared to an ECG, WatchBP had the highest sensitivity (84.6%) and AUC (0.895 [0.780-1]), while MyDiagnostick showed the highest specificity (97.10%). CONCLUSION: The inclusion and monitoring of a cohort of primary care patients for AF detection, together with the testing of biomarkers and screening devices provided useful lessons about AF screening in our community. An AF screening strategy using rhythm detection devices and short monitoring periods among high-risk patients with high NT-proBNP levels could be feasible. | Pala, Elena Bustamante, Alejandro Clua-Espuny, Josep Lluis Acosta, Juan Gonzalez-Loyola, Felipe Santos, Sara Dos Ribas-Segui, Domingo Ballesta-Ors, Juan Penalba, Anna Giralt, Marina Lechuga-Duran, Inigo Gentille-Lorente, Delicia Pedrote, Alonso Munoz, Miguel Angel Montaner, Joan eng Research Support, Non-U.S. Gov't PLoS One. 2022 Aug 23;17(8):e0273571. doi: 10.1371/journal.pone.0273571. eCollection 2022.I | 08/24/2022 | |
| Proteomic profiling platforms head to head: Leveraging genetics and clinical traits to compare aptamer- and antibody-based methods | Katz DH, et al. | 2022 | Sci Adv | 8 | 33 | eabm5164 | https://www.doi.org/10.1126/sciadv.abm5164 | 35,984,888 | Adult Antibodies/chemistry Aptamers, Peptide/chemistry Humans Longitudinal Studies Phenotype *Proteome *Proteomics/methods | High-throughput proteomic profiling using antibody or aptamer-based affinity reagents is used increasingly in human studies. However, direct analyses to address the relative strengths and weaknesses of these platforms are lacking. We assessed findings from the SomaScan1.3K (N = 1301 reagents), the SomaScan5K platform (N = 4979 reagents), and the Olink Explore (N = 1472 reagents) profiling techniques in 568 adults from the Jackson Heart Study and 219 participants in the HERITAGE Family Study across four performance domains: precision, accuracy, analytic breadth, and phenotypic associations leveraging detailed clinical phenotyping and genetic data. Across these studies, we show evidence supporting more reliable protein target specificity and a higher number of phenotypic associations for the Olink platform, while the Soma platforms benefit from greater measurement precision and analytic breadth across the proteome. | Katz, Daniel H Robbins, Jeremy M Deng, Shuliang Tahir, Usman A Bick, Alexander G Pampana, Akhil Yu, Zhi Ngo, Debby Benson, Mark D Chen, Zsu-Zsu Cruz, Daniel E Shen, Dongxiao Gao, Yan Bouchard, Claude Sarzynski, Mark A Correa, Adolfo Natarajan, Pradeep Wilson, James G Gerszten, Robert E eng HHSN268201100037C/HL/NHLBI NIH HHS/ R01 NR019628/NR/NINR NIH HHS/ R01 HL127564/HL/NHLBI NIH HHS/ U24 DK112340/DK/NIDDK NIH HHS/ HHSN268201800014C/HL/NHLBI NIH HHS/ R01 HL142711/HL/NHLBI NIH HHS/ RF1 AG063507/AG/NIA NIH HHS/ R01 HL117626/HL/NHLBI NIH HHS/ HHSN268201800011I/HB/NHLBI NIH HHS/ R01 HL146462/HL/NHLBI NIH HHS/ P30 GM118430/GM/NIGMS NIH HHS/ HHSN268201800012I/HB/NHLBI NIH HHS/ HHSN268201800012C/HL/NHLBI NIH HHS/ DP5 OD029586/OD/NIH HHS/ R01 HL120393/HL/NHLBI NIH HHS/ R01 HL047327/HL/NHLBI NIH HHS/ KL2 TR002542/TR/NCATS NIH HHS/ R01 HL047323/HL/NHLBI NIH HHS/ HHSN268201800014I/HB/NHLBI NIH HHS/ U01 HL120393/HL/NHLBI NIH HHS/ R01 DK081572/DK/NIDDK NIH HHS/ HHSN268201800001C/HL/NHLBI NIH HHS/ HHSN268201800013I/MD/NIMHD NIH HHS/ R01 HL132320/HL/NHLBI NIH HHS/ HHSN268201800011C/HL/NHLBI NIH HHS/ T32 HL007374/HL/NHLBI NIH HHS/ HHSN268201800015I/HB/NHLBI NIH HHS/ K23 HL150327/HL/NHLBI NIH HHS/ F32 HL150992/HL/NHLBI NIH HHS/ HHSN268201800010I/HB/NHLBI NIH HHS/ R01 HL047317/HL/NHLBI NIH HHS/ K08 HL145095/HL/NHLBI NIH HHS/ R01 HL045670/HL/NHLBI NIH HHS/ Sci Adv. 2022 Aug 19;8(33):eabm5164. doi: 10.1126/sciadv.abm5164. Epub 2022 Aug 19.I | 08/20/2022 | |
| Long-term changes in plasma proteomic profiles in premenopausal and postmenopausal Black and White women: the Atherosclerosis Risk in Communities study | Appiah D, et al. | 2022 | Menopause | 29 | 10 | 1150-1160 | https://www.doi.org/10.1097/GME.0000000000002031 | 35,969,495 | *Atherosclerosis Cholesterol Cross-Sectional Studies Female Humans Lipids Menopause Middle Aged *Postmenopause/physiology Premenopause/physiology Proteomics | OBJECTIVE: The activity, localization, and turnover of proteins within cells and plasma may contribute to physiologic changes during menopause and may influence disease occurrence. We examined cross-sectional differences and long-term changes in plasma proteins between premenopausal and naturally postmenopausal women. METHODS: We used data from 4,508 (19% Black) women enrolled in the Atherosclerosis Risk in Communities study. SOMAscan multiplexed aptamer technology was used to measure 4,697 plasma proteins. Linear regression models were used to compare differences in proteins at baseline (1993-1995) and 18-year change in proteins from baseline to 2011-2013. RESULTS: At baseline, 472 women reported being premenopausal and 4,036 women reported being postmenopausal, with average ages of 52.3 and 61.4 years, respectively. A greater proportion of postmenopausal women had diabetes (15 vs 9%), used hypertension (38 vs 27%) and lipid-lowering medications (10 vs 3%), and had elevated total cholesterol and waist girth. In multivariable adjusted models, 38 proteins differed significantly between premenopausal and postmenopausal women at baseline, with 29 of the proteins also showing significantly different changes between groups over the 18-year follow-up as the premenopausal women also reached menopause. These proteins were associated with various molecular/cellular functions (cellular development, growth, proliferation and maintenance), physiological system development (skeletal and muscular system development, and cardiovascular system development and function), and diseases/disorders (hematological and metabolic diseases and developmental disorders). CONCLUSIONS: We observed significantly different changes between premenopausal and postmenopausal women in several plasma proteins that reflect many biological processes. These processes may help to understand disease development during the postmenopausal period. | Appiah, Duke Schreiner, Pamela J Pankow, James S Brock, Guy Tang, Weihong Norby, Faye L Michos, Erin D Ballantyne, Christie M Folsom, Aaron R eng HHSN268201700002C/HL/NHLBI NIH HHS/ HHSN268201700001I/HL/NHLBI NIH HHS/ HHSN268201700004I/HL/NHLBI NIH HHS/ HHSN268201700004C/HL/NHLBI NIH HHS/ R01 HL134320/HL/NHLBI NIH HHS/ HHSN268201700003I/HL/NHLBI NIH HHS/ HHSN268201700005C/HL/NHLBI NIH HHS/ HHSN268201700001C/HL/NHLBI NIH HHS/ HHSN268201700003C/HL/NHLBI NIH HHS/ HHSN268201700002I/HL/NHLBI NIH HHS/ HHSN268201700005I/HL/NHLBI NIH HHS/ Research Support, N.I.H., Extramural Menopause. 2022 Oct 1;29(10):1150-1160. doi: 10.1097/GME.0000000000002031. Epub 2022 Aug 20.I | 08/16/2022 | |
| ELF5 is a potential respiratory epithelial cell-specific risk gene for severe COVID-19 | Pietzner M, et al. | 2022 | Nat Commun | 13 | 1 | 4484 | https://www.doi.org/10.1038/s41467-022-31999-6 | 35,970,849 | Angiotensin-Converting Enzyme 2/genetics *COVID-19/genetics *DNA-Binding Proteins/genetics Epithelial Cells/metabolism Humans Peptidyl-Dipeptidase A/metabolism Respiratory System SARS-CoV-2 *Transcription Factors/genetics | Despite two years of intense global research activity, host genetic factors that predispose to a poorer prognosis of COVID-19 infection remain poorly understood. Here, we prioritise eight robust (e.g., ELF5) or suggestive but unreported (e.g., RAB2A) candidate protein mediators of COVID-19 outcomes by integrating results from the COVID-19 Host Genetics Initiative with population-based plasma proteomics using statistical colocalisation. The transcription factor ELF5 (ELF5) shows robust and directionally consistent associations across different outcome definitions, including a >4-fold higher risk (odds ratio: 4.88; 95%-CI: 2.47-9.63; p-value < 5.0 x 10(-6)) for severe COVID-19 per 1 s.d. higher genetically predicted plasma ELF5. We show that ELF5 is specifically expressed in epithelial cells of the respiratory system, such as secretory and alveolar type 2 cells, using single-cell RNA sequencing and immunohistochemistry. These cells are also likely targets of SARS-CoV-2 by colocalisation with key host factors, including ACE2 and TMPRSS2. In summary, large-scale human genetic studies together with gene expression at single-cell resolution highlight ELF5 as a risk gene for severe COVID-19, supporting a role of epithelial cells of the respiratory system in the adverse host response to SARS-CoV-2. | Pietzner, Maik Chua, Robert Lorenz Wheeler, Eleanor Jechow, Katharina Willett, Julian D S Radbruch, Helena Trump, Saskia Heidecker, Bettina Zeberg, Hugo Heppner, Frank L Eils, Roland Mall, Marcus A Richards, J Brent Sander, Leif-Erik Lehmann, Irina Lukassen, Soren Wareham, Nicholas J Conrad, Christian Langenberg, Claudia eng MC_UU_12015/1/MRC_/Medical Research Council/United Kingdom MC_PC_13046/MRC_/Medical Research Council/United Kingdom MC_UU_00006/1/MRC_/Medical Research Council/United Kingdom 365825/CIHR/Canada 409511/CIHR/Canada 100558/CIHR/Canada 169303/CIHR/Canada C18281/A29019/CRUK_/Cancer Research UK/United Kingdom WT_/Wellcome Trust/United Kingdom DH_/Department of Health/United Kingdom Research Support, Non-U.S. Gov't England Nat Commun. 2022 Aug 15;13(1):4484. doi: 10.1038/s41467-022-31999-6.I | 08/16/2022 | |
| Neuroblastoma suppressor of tumorigenicity 1 is a circulating protein associated with progression to end-stage kidney disease in diabetes | Kobayashi H, et al. | 2022 | Sci Transl Med | 14 | 657 | eabj2109 | https://www.doi.org/10.1126/scitranslmed.abj2109 | 35,947,673 | Cell Cycle Proteins/*blood *Diabetes Mellitus, Type 2/complications Disease Progression Humans *Kidney Failure, Chronic *Neuroblastoma Proteomics Transforming Growth Factor beta | Circulating proteins associated with transforming growth factor-beta (TGF-beta) signaling are implicated in the development of diabetic kidney disease (DKD). It remains to be comprehensively examined which of these proteins are involved in the pathogenesis of DKD and its progression to end-stage kidney disease (ESKD) in humans. Using the SOMAscan proteomic platform, we measured concentrations of 25 TGF-beta signaling family proteins in four different cohorts composed in total of 754 Caucasian or Pima Indian individuals with type 1 or type 2 diabetes. Of these 25 circulating proteins, we identified neuroblastoma suppressor of tumorigenicity 1 (NBL1, aliases DAN and DAND1), a small secreted protein known to inhibit members of the bone morphogenic protein family, to be most strongly and independently associated with progression to ESKD during 10-year follow-up in all cohorts. The extent of damage to podocytes and other glomerular structures measured morphometrically in 105 research kidney biopsies correlated strongly with circulating NBL1 concentrations. Also, in vitro exposure to NBL1 induced apoptosis in podocytes. In conclusion, circulating NBL1 may be involved in the disease process underlying progression to ESKD, and its concentration in circulation may identify subjects with diabetes at increased risk of progression to ESKD. | Kobayashi, Hiroki Looker, Helen C Satake, Eiichiro D'Addio, Francesca Wilson, Jonathan M Saulnier, Pierre Jean Md Dom, Zaipul I O'Neil, Kristina Ihara, Katsuhito Krolewski, Bozena Badger, Hannah S Petrazzuolo, Adriana Corradi, Domenico Galecki, Andrzej Wilson, Parker C Najafian, Behzad Mauer, Michael Niewczas, Monika A Doria, Alessandro Humphreys, Benjamin D Duffin, Kevin L Fiorina, Paolo Nelson, Robert G Krolewski, Andrzej S eng P30 DK036836/DK/NIDDK NIH HHS/ R01 DK041526/DK/NIDDK NIH HHS/ R01 DK110350/DK/NIDDK NIH HHS/ R01 DK126799/DK/NIDDK NIH HHS/ Research Support, N.I.H., Extramural Research Support, N.I.H., Intramural Research Support, Non-U.S. Gov't Sci Transl Med. 2022 Aug 10;14(657):eabj2109. doi: 10.1126/scitranslmed.abj2109. Epub 2022 Aug 10.I | 08/11/2022 | |
| High Dimensional Immune Profiling of Smoldering Multiple Myeloma Distinguishes Distinct Tumor Microenvironments | Fernandez N, et al. | 2022 | Clin Lymphoma Myeloma Leuk | 22 | 11 | 853-862 | https://www.doi.org/10.1016/j.clml.2022.07.001 | 35,945,129 | Humans *Smoldering Multiple Myeloma Tumor Microenvironment *Monoclonal Gammopathy of Undetermined Significance/pathology *Multiple Myeloma/pathology Plasma Cells/pathology Disease Progression | BACKGROUND: Multiple myeloma (MM) is a malignancy of plasma cells that arises from premalignant Monoclonal Gammopathy of Undetermined Significance (MGUS) and often progresses through an asymptomatic Smoldering (SMM) phase. Understanding the interactions between abnormal clonal plasma cells and the tumor microenvironment (TME) in the early disease states (MGUS, SMM) may inform risk assessment and therapy. PATIENTS AND METHODS: We performed high dimensional immunologic analysis of bone marrow specimens from 73 subjects with SMM by mass cytometry and T cell receptor sequencing of CD138-depleted bone marrow (BM) mononuclear cells, and proteomics and seromic profiling of BM plasma. Analysis of individual assay data identified self-organizing subgroups of SMM patients. We then applied novel bioinformatic methods to integrate data from pairs, trios, and quartets of assays. RESULTS: Mass cytometry, TCRSeq and proteomics identified three taxa (sing. taxon) of subjects that shared common characteristics across all three assays. Differential levels of BM plasma pleiotropin (PTN) and BM T cells and their productive clonality emerged as strong distinguishing factors among these taxa. CONCLUSION: These results suggest that the continuum from MGUS to MM does not consist of a single pathway in the TME, and that complex interactions between myeloma cells and the TME may ultimately determine progression and inform clinical management. | Fernandez, Nicolas Perumal, Deepak Rahman, Adeeb Kim-Schulze, Seunghee Yesil, Jen Auclair, Daniel Adams, Homer 3rd Parekh, Samir Gnjatic, Sacha Cho, Hearn Jay eng Research Support, Non-U.S. Gov't Clin Lymphoma Myeloma Leuk. 2022 Nov;22(11):853-862. doi: 10.1016/j.clml.2022.07.001. Epub 2022 Jul 16.I | 08/10/2022 | |
| Proteomic Profiling of Plasma Biomarkers Associated With Return to Sport Following Concussion: Findings From the NCAA and Department of Defense CARE Consortium | Vorn R, et al. | 2022 | Front Neurol | 13 | 901238 | https://www.doi.org/10.3389/fneur.2022.901238 | 35,928,129 | biomarker concussion proteomic return to sport (RTS) sport injuries research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. | OBJECTIVE: To investigate the plasma proteomic profiling in identifying biomarkers related to return to sport (RTS) following a sport-related concussion (SRC). METHODS: This multicenter, prospective, case-control study was part of a larger cohort study conducted by the NCAA-DoD Concussion Assessment, Research, and Education (CARE) Consortium, athletes (n = 140) with blood collected within 48 h of injury and reported day to asymptomatic were included in this study, divided into two groups: (1) recovery <14-days (n = 99) and (2) recovery >/=14-days (n = 41). We applied a highly multiplexed proteomic technique that uses DNA aptamers assay to target 1,305 proteins in plasma samples from concussed athletes with <14-days and >/=14-days. RESULTS: We identified 87 plasma proteins significantly dysregulated (32 upregulated and 55 downregulated) in concussed athletes with recovery >/=14-days relative to recovery <14-days groups. The significantly dysregulated proteins were uploaded to Ingenuity Pathway Analysis (IPA) software for analysis. Pathway analysis showed that significantly dysregulated proteins were associated with STAT3 pathway, regulation of the epithelial mesenchymal transition by growth factors pathway, and acute phase response signaling. CONCLUSION: Our data showed the feasibility of large-scale plasma proteomic profiling in concussed athletes with a <14-days and >/= 14-days recovery. These findings provide a possible understanding of the pathophysiological mechanism in neurobiological recovery. Further study is required to determine whether these proteins can aid clinicians in RTS decisions. | Vorn, Rany Mithani, Sara Devoto, Christina Meier, Timothy B Lai, Chen Yun, Sijung Broglio, Steven P McAllister, Thomas W Giza, Christopher C Kim, Hyung-Suk Huber, Daniel Harezlak, Jaroslaw Cameron, Kenneth L McGinty, Gerald Jackson, Jonathan Guskiewicz, Kevin M Mihalik, Jason P Brooks, Alison Duma, Stefan Rowson, Steven Nelson, Lindsay D Pasquina, Paul McCrea, Michael A Gill, Jessica M eng Switzerland Front Neurol. 2022 Jul 19;13:901238. doi: 10.3389/fneur.2022.901238. eCollection 2022.I | 08/06/2022 | ||
| Serum proteomic profiling of rheumatoid arthritis-interstitial lung disease with a comparison to idiopathic pulmonary fibrosis | Wu X, et al. | 2022 | Thorax | epub ahead of print | https://www.doi.org/10.1136/thorax-2021-217822 | 35,907,639 | Interstitial Fibrosis Rheumatoid lung disease interest, all outside the submitted work: ST reports medical advisory group membership of Novo Nordisk and board membership at Droobi Health, Qatar. RG receives grant support from Canon Medical Systems. HH reports grants from Canon Medical Systems and Konica Minolta, and personal fees from Mitsubishi Chemical Co and Canon Medical Systems Inc. MN reports grants from AstraZeneca, Daiichi Sankyo, Canon Medical Systems, Merck investigator studies program personal fees from Daiichi Sankyo and AstraZeneca. MEW receives research support from Amgen, Bristol Myers Squibb and Eli Lilly and consultation fees from AbbVie, Aclaris, Amgen, Arena, Bayer, Bristol Myers Squibb, Corvitas, Eqrx, Genosco, GSK, Gilead, Horizon, Johnson & Johnson, Kiniksa, Lilly, Novartis, Pfizer, Rami Therapeutics, R Pharma, Roche, Sanofi, Scipher, Sci Rhom, Set Point and Tremeau. He holds stock/stock options of CanFite, Inmedix, Vorso and Scipher. NAS reports grants and other support from Bristol-Myers Squibb, grants from Mallinckrodt, Sanofi, Crescendo Biosciences, Lilly and Amgen. PFD reports grants from Bristol-Myers Squibb and Genentech, and other support from Boehringer Ingelheim. AMKC is a cofounder and equity stock holder for Proterris, which develops therapeutic uses for carbon monoxide, and also has a use patent on CO and a patent in chronic obstructive pulmonary disease. EYK is a member of the steering committees for and receives no financial remuneration from NCT04409834 (Prevention of arteriovenous thrombotic events in critically ill COVID-19 patients, TIMI group) and REMAP-CAP ACE2 renin-angiotensin system modulation domain, and receives unrelated research funding from Bayer AG, Roche Pharma Research and Early Development, Windtree Therapeutics, the US National Institutes of Health, the US Agency for International Development, the American Heart Association, American Lung Association and the Bell Family Fund. IOR reports grants from Genentech. FJM reports personal fees, non-financial support and other support from AstraZeneca, other support from Afferent/Merck, personal fees, non-financial support and other support from Boehringer Ingelheim, other support from Bristol Myers Squibb, other support from Chiesi, personal fees and non-financial support from the Canadian Respiratory Society, personal fees and non-financial support from CME Outfitters, personal fees and non-financial support from CSL Behring, personal fees from Dartmouth University, personal fees from France Foundation, personal fees from Gala, personal fees and non-financial support from Genentech, grants, personal fees, non-financial support and other support from GlaxoSmithKline, personal fees and non-financial support from Inova Fairfax, personal fees and non-financial support from MD Magazine, personal fees and non-financial support from NYP Methodist Hospital Brooklyn, personal fees and non-financial support from Miller Communications, personal fees and non-financial support from National Association for Continuing Education/Integritas, other support from Nitto, personal fees and non-financial support from Novartis, personal fees from New York University, personal fees and non-financial support from Patara/Respivant, personal fees from Pearl, personal fees and non-financial support from Peer View, personal fees from Physicians Education Resource, personal fees from ProMedior, personal fees and non-financial support from Rare Diseases Healthcare Communications, personal fees from Rockpointe Communications, personal fees and non-financial support from Sanofi/Regeneron, other support from Biogen, personal fees and non-financial support from Sunovion, personal fees and non-financial support from Teva, other support from two XAR, personal fees from University of Birmingham Alabama, personal fees from UpToDate, non-financial support from Veracyte, personal fees from Vindico, personal fees and non-financial support from WebMD/MedScape, non-financial support and other support from Zambon, non-financial support from ProTerrix Bio, and personal fees from IQVIA, Raziel, Abvie and Verona. TJD has received grant support from Bristol Myers Squibb, consulting fees from Boehringer Ingelheim and L.E.K. consulting, and has been part of a clinical trial funded by Genentech. The remaining authors have reported no conflicts of interest. | Although interstitial lung disease (ILD) causes significant morbidity and mortality in rheumatoid arthritis (RA), it is difficult to predict the development or progression of ILD, emphasising the need for improved discovery through minimally invasive diagnostic tests. Aptamer-based proteomic profiling was used to assess 1321 proteins from 159 patients with rheumatoid arthritis with interstitial lung disease (RA-ILD), RA without ILD, idiopathic pulmonary fibrosis and healthy controls. Differential expression and gene set enrichment analyses revealed molecular signatures that are strongly associated with the presence and severity of RA-ILD and provided insight into unexplored pathways of disease. These warrant further study as non-invasive diagnostic tools and future therapeutic targets. | Wu, Xiaoping Jeong, Yunju Poli de Frias, Sergio Easthausen, Imaani Hoffman, Katherine Oromendia, Clara Taheri, Shahrad Esposito, Anthony J Quesada Arias, Luisa Ayaub, Ehab A Maurer, Rie Gill, Ritu R Hatabu, Hiroto Nishino, Mizuki Frits, Michelle L Iannaccone, Christine K Weinblatt, Michael E Shadick, Nancy A Dellaripa, Paul F Choi, Augustine M K Kim, Edy Y Rosas, Ivan O Martinez, Fernando J Doyle, Tracy J eng F32 HL151132/HL/NHLBI NIH HHS/ K23 HL119558/HL/NHLBI NIH HHS/ L30 HL149048/HL/NHLBI NIH HHS/ R03 HL148484/HL/NHLBI NIH HHS/ England Thorax. 2022 Jul 30:thoraxjnl-2021-217822. doi: 10.1136/thorax-2021-217822.I | 07/31/2022 | |||
| Proteomic Biomarkers of the Apnea Hypopnea Index and Obstructive Sleep Apnea: Insights into the Pathophysiology of Presence, Severity, and Treatment Response | Cederberg KLJ, et al. | 2022 | Int J Mol Sci | 23 | 14 | https://www.doi.org/10.3390/ijms23147983 | 35,887,329 | Biomarkers Continuous Positive Airway Pressure Humans Polysomnography *Proteomics *Sleep Apnea, Obstructive/complications/diagnosis/therapy apnea-hypopnea index machine learning obstructive sleep apnea proteomics treatment Hedou, Dr. Jing Zhang, Dr. Ling Lin, Dr. Suresh Kotagal, Dr. Adam Blackman, Dr. Clete Kushida, and Dr. Nayia Petousi declare no conflict of interest. Dr. Chris Turnbull declares consulting fees from Bayer and honoraria from Stowood, outside the scope of this work. Dr. Schneider reports personal fees from Jazz Pharmaceuticals, personal fees from Harmony Biosciences, personal fees from Eisai, outside the submitted work. Dr. Leary is an employee of Jazz Pharmaceuticals who, in the course of her employment, has received stock options exercisable for, and other stock awards of, ordinary shares of Jazz Pharmaceuticals plc. Dr. Anne Marie Morse has received consulting fees from Jazz Pharmaceuticals, Harmony Biosciences, and Avadel, outside the scope of this work. Dr. Paula Schweitzer has received consulting fees from Apnimed and Jazz Pharmaceuticals her institution has received research funding from Apnimed, Avadel, Harmony Biosciences, Inspire Medical, and Suven Life Sciences, all outside the scope of this work. Dr. Richard Bogan is a shareholder in WaterMark Medical and Healthy Humming, LLC serves on the Board of Directors for WaterMark Medical is a consultant to Jazz, Harmony Biosciences, Takeda, Avadel, and Oventus has industry funded research for Avadel, BresoTec, Idorsia, Suven, Jazz, Balance, Vanda, Merck, Eisai, Philips, Fresca, Takeda, Liva Nova, Roche, Sommetrics, NLS, Sanofi, Apnimed and is on the Speakers Bureau for Jazz, Eisai, Harmony, Idorsia all outside the scope of this work. Dr. Yo-El Ju reports consulting fees from Applied Cognition, outside the scope of this work. Dr. Emmanuel Mignot occasionally consults and has received contracts from Jazz Pharmaceuticals, Orexia/Centessa, Tekeda, Dreem, and ActiGraph has received grant/clinical trial funding from Haromony, Tekeda, Apple, Humani, Sunovion, Indorsia, Eisai is and has been a Principal Investigator on clinical trials using sodium oxybate and Solriamfetol, Jazz Pharmaceutical products, for the treatment of Type 1 narcolepsy all outside the scope of this work. | Obstructive sleep apnea (OSA), a disease associated with excessive sleepiness and increased cardiovascular risk, affects an estimated 1 billion people worldwide. The present study examined proteomic biomarkers indicative of presence, severity, and treatment response in OSA. Participants (n = 1391) of the Stanford Technology Analytics and Genomics in Sleep study had blood collected and completed an overnight polysomnography for scoring the apnea-hypopnea index (AHI). A highly multiplexed aptamer-based array (SomaScan) was used to quantify 5000 proteins in all plasma samples. Two separate intervention-based cohorts with sleep apnea (n = 41) provided samples pre- and post-continuous/positive airway pressure (CPAP/PAP). Multivariate analyses identified 84 proteins (47 positively, 37 negatively) associated with AHI after correction for multiple testing. Of the top 15 features from a machine learning classifier for AHI >/= 15 vs. AHI < 15 (Area Under the Curve (AUC) = 0.74), 8 were significant markers of both AHI and OSA from multivariate analyses. Exploration of pre- and post-intervention analysis identified 5 of the 84 proteins to be significantly decreased following CPAP/PAP treatment, with pathways involving endothelial function, blood coagulation, and inflammatory response. The present study identified PAI-1, tPA, and sE-Selectin as key biomarkers and suggests that endothelial dysfunction and increased coagulopathy are important consequences of OSA, which may explain the association with cardiovascular disease and stroke. | Cederberg, Katie L J Hanif, Umaer Peris Sempere, Vicente Hedou, Julien Leary, Eileen B Schneider, Logan D Lin, Ling Zhang, Jing Morse, Anne M Blackman, Adam Schweitzer, Paula K Kotagal, Suresh Bogan, Richard Kushida, Clete A Ju, Yo-El S Petousi, Nayia Turnbull, Chris D Mignot, Emmanuel The Stages Cohort Investigator Group eng N/A/Oxford Radcliffe Hospital Charitable Funds/ KL2TR000450/NH/NIH HHS/ T32HL110952/NH/NIH HHS/ N/A/ResMed UK/ K23NS089922/NH/NIH HHS/ UL1 TR002345/TR/NCATS NIH HHS/ N/A/Bryte Foundation/ N/A/National Institute for Health Research/ N/A/Philips Respironics/ N/A/Klarman Family Foundation/ UL1TR000448/Washington University Institute of Clinical and Translational Sciences/ UL1RR024992/NH/NIH HHS/ Switzerland Int J Mol Sci. 2022 Jul 20;23(14):7983. doi: 10.3390/ijms23147983.I | 07/28/2022 | ||
| Associations between circulating proteins and risk of breast cancer by intrinsic subtypes: a Mendelian randomisation analysis | Shu X, et al. | 2022 | Br J Cancer | 127 | 8 | 1507-1514 | https://www.doi.org/10.1038/s41416-022-01923-2 | 35,882,941 | Biomarkers, Tumor/genetics/metabolism *Breast Neoplasms/pathology Female Humans Mendelian Randomization Analysis *Protein Disulfide Reductase (Glutathione) Receptors, Phospholipase A2 *Triple Negative Breast Neoplasms | BACKGROUND: The aetiologic role of circulating proteins in the development of breast cancer subtypes is not clear. We aimed to examine the potential causal effects of circulating proteins on the risk of breast cancer by intrinsic-like subtypes within the Mendelian randomisation (MR) framework. METHODS: MR was performed using summary statistics from two sources: the INTERVAL protein quantitative trait loci (pQTL) Study (1890 circulating proteins and 3301 healthy individuals) and the Breast Cancer Association Consortium (BCAC; 106,278 invasive cases and 91,477 controls). The inverse-variance (IVW)-weighted method was used as the main analysis to evaluate the associations between genetically predicted proteins and the risk of five different intrinsic-like breast cancer subtypes and the weighted median MR method, the Egger regression, the MR-PRESSO, and the MRLocus method were performed as secondary analysis. RESULTS: We identified 98 unique proteins significantly associated with the risk of one or more subtypes (Benjamini-Hochberg false discovery rate < 0.05). Among them, 51 were potentially specific to luminal A-like subtype, 14 to luminal B/Her2-negative-like, 11 to triple negative, 3 to luminal B-like, and 2 to Her2-enriched-like breast cancer (n(total) = 81). Associations for three proteins (ICAM1, PLA2R1 and TXNDC12) showed evident heterogeneity across the subtypes. For example, higher levels of genetically predicted ICAM1 (per unit of increase) were associated with an increased risk of luminal B/HER2-negative-like cancer (OR = 1.06, 95% CI = 1.03-1.08, BH-FDR = 2.43 x 10(-4)) while inversely associated with triple-negative breast cancer with borderline significance (OR = 0.97, 95% CI = 0.95-0.99, BH-FDR = 0.065, P(heterogeneity) < 0.005). CONCLUSIONS: Our study found potential causal associations with the risk of subtypes of breast cancer for 98 proteins. Associations of ICAM1, PLA2R1 and TXNDC12 varied substantially across the subtypes. The identified proteins may partly explain the heterogeneity in the aetiology of distinct subtypes of breast cancer and facilitate the personalised risk assessment of the malignancy. | Shu, Xiang Zhou, Qin Sun, Xiaohui Flesaker, Michelle Guo, Xingyi Long, Jirong Robson, Mark E Shu, Xiao-Ou Zheng, Wei Bernstein, Jonine L eng R00 CA230205/CA/NCI NIH HHS/ K99 CA230205/CA/NCI NIH HHS/ R25 CA214255/CA/NCI NIH HHS/ R01 CA202981/CA/NCI NIH HHS/ R01 CA235553/CA/NCI NIH HHS/ P30 CA008748/CA/NCI NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't England Br J Cancer. 2022 Nov;127(8):1507-1514. doi: 10.1038/s41416-022-01923-2. Epub 2022 Jul 26.I | 07/27/2022 | |
| Comparative Analysis of Alzheimer's Disease Cerebrospinal Fluid Biomarkers Measurement by Multiplex SOMAscan Platform and Immunoassay-Based Approach | Timsina J, et al. | 2022 | J Alzheimers Dis | 89 | 1 | 193-207 | https://www.doi.org/10.3233/JAD-220399 | 35,871,346 | *Alzheimer Disease/cerebrospinal fluid/diagnosis Amyloid beta-Peptides/cerebrospinal fluid Biomarkers/cerebrospinal fluid Humans Immunoassay Neurogranin/cerebrospinal fluid ROC Curve tau Proteins/cerebrospinal fluid Alzheimer's disease SOMAscan assays cerebrospinal fluid biomarkers correlation | BACKGROUND: The SOMAscan assay has an advantage over immunoassay-based methods because it measures a large number of proteins in a cost-effective manner. However, the performance of this technology compared to the routinely used immunoassay techniques needs to be evaluated. OBJECTIVE: We performed comparative analyses of SOMAscan and immunoassay-based protein measurements for five cerebrospinal fluid (CSF) proteins associated with Alzheimer's disease (AD) and neurodegeneration: NfL, Neurogranin, sTREM2, VILIP-1, and SNAP-25. METHODS: We compared biomarkers measured in ADNI (N = 689), Knight-ADRC (N = 870), DIAN (N = 115), and Barcelona-1 (N = 92) cohorts. Raw protein values were transformed using z-score in order to combine measures from the different studies. sTREM2 and VILIP-1 had more than one analyte in SOMAscan; all available analytes were evaluated. Pearson's correlation coefficients between SOMAscan and immunoassays were calculated. Receiver operating characteristic curve and area under the curve were used to compare prediction accuracy of these biomarkers between the two platforms. RESULTS: Neurogranin, VILIP-1, and NfL showed high correlation between SOMAscan and immunoassay measures (r > 0.9). sTREM2 had a fair correlation (r > 0.6), whereas SNAP-25 showed weak correlation (r = 0.06). Measures in both platforms provided similar predicted performance for all biomarkers except SNAP-25 and one of the sTREM2 analytes. sTREM2 showed higher AUC for SOMAscan based measures. CONCLUSION: Our data indicate that SOMAscan performs as well as immunoassay approaches for NfL, Neurogranin, VILIP-1, and sTREM2. Our study shows promise for using SOMAscan as an alternative to traditional immunoassay-based measures. Follow-up investigation will be required for SNAP-25 and additional established biomarkers. | Timsina, Jigyasha Gomez-Fonseca, Duber Wang, Lihua Do, Anh Western, Dan Alvarez, Ignacio Aguilar, Miquel Pastor, Pau Henson, Rachel L Herries, Elizabeth Xiong, Chengjie Schindler, Suzanne E Fagan, Anne M Bateman, Randall J Farlow, Martin Morris, John C Perrin, Richard J Moulder, Krista Hassenstab, Jason Voglein, Jonathan Chhatwal, Jasmeer Mori, Hiroshi Sung, Yun Ju Cruchaga, Carlos eng R01 AG044546/AG/NIA NIH HHS/ RF1 AG053303/AG/NIA NIH HHS/ RF1 AG074007/AG/NIA NIH HHS/ P01 AG003991/AG/NIA NIH HHS/ RF1 AG058501/AG/NIA NIH HHS/ P30 AG066444/AG/NIA NIH HHS/ P01 AG026276/AG/NIA NIH HHS/ U19 AG032438/AG/NIA NIH HHS/ Comparative Study Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. Netherlands J Alzheimers Dis. 2022;89(1):193-207. doi: 10.3233/JAD-220399.I | 07/25/2022 | |
| Identification of 969 protein quantitative trait loci in an African American population with kidney disease attributed to hypertension | Surapaneni A, et al. | 2022 | Kidney Int | 102 | 5 | 1167-1177 | https://www.doi.org/10.1016/j.kint.2022.07.005 | 35,870,639 | Humans Quantitative Trait Loci African Americans/genetics Proteome Genome-Wide Association Study Polymorphism, Single Nucleotide *Hypertension/genetics *Kidney Diseases/genetics Genetic Predisposition to Disease pQTL protein quantitative trait loci | Investigations into the causal underpinnings of disease processes can be aided by the incorporation of genetic information. Genetic studies require populations varied in both ancestry and prevalent disease in order to optimize discovery and ensure generalizability of findings to the global population. Here, we report the genetic determinants of the serum proteome in 466 African Americans with chronic kidney disease attributed to hypertension from the richly phenotyped African American Study of Kidney Disease and Hypertension (AASK) study. Using the largest aptamer-based protein profiling platform to date (6,790 proteins or protein complexes), we identified 969 genetic associations with 900 unique proteins; including 52 novel cis (local) associations and 379 novel trans (distant) associations. The genetic effects of previously published cis-protein quantitative trait loci (pQTLs) were found to be highly reproducible, and we found evidence that our novel genetic signals colocalize with gene expression and disease processes. Many trans- pQTLs were found to reflect associations mediated by the circulating cis protein, and the common trans-pQTLs are enriched for processes involving extracellular vesicles, highlighting a plausible mechanism for distal regulation of the levels of secreted proteins. Thus, our study generates a valuable resource of genetic associations linking variants to protein levels and disease in an understudied patient population to inform future studies of drug targets and physiology. | Surapaneni, Aditya Schlosser, Pascal Zhou, Linda Liu, Celina Chatterjee, Nilanjan Arking, Dan E Dutta, Diptavo Coresh, Josef Rhee, Eugene P Grams, Morgan E eng Kidney Int. 2022 Nov;102(5):1167-1177. doi: 10.1016/j.kint.2022.07.005. Epub 2022 Jul 21.I | 07/24/2022 | |
| The circulating proteomic signature of alcohol-associated liver disease | Luther J, et al. | 2022 | JCI Insight | 7 | 14 | https://www.doi.org/10.1172/jci.insight.159775 | 35,866,482 | Biomarkers Humans *Liver Diseases, Alcoholic/metabolism Proteome *Proteomics Hepatitis Hepatology Proteomics | Despite being a leading cause of advanced liver disease, alcohol-associated liver disease (ALD) has no effective medical therapies. The circulating proteome, which comprises proteins secreted by different cells and tissues in the context of normal physiological function or in the setting of disease and illness, represents an attractive target for uncovering novel biology related to the pathogenesis of ALD. In this work, we used the aptamer-based SomaScan proteomics platform to quantify the relative concentration of over 1300 proteins in a well-characterized cohort of patients with the spectrum of ALD. We found a distinct circulating proteomic signature that correlated with ALD severity, including over 600 proteins that differed significantly between ALD stages, many of which have not previously been associated with ALD to our knowledge. Notably, certain proteins that were markedly dysregulated in patients with alcohol-associated hepatitis were also altered, to a lesser degree, in patients with subclinical ALD and may represent early biomarkers for disease progression. Taken together, our work highlights the vast and distinct changes in the circulating proteome across the wide spectrum of ALD, identifies potentially novel biomarkers and therapeutic targets, and provides a proteomic resource atlas for ALD researchers and clinicians. | Luther, Jay Vannier, Augustin Gl Schaefer, Esperance A Goodman, Russell P eng K08 DK115881/DK/NIDDK NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't JCI Insight. 2022 Jul 22;7(14):e159775. doi: 10.1172/jci.insight.159775.I | 07/23/2022 | ||
| Proteomic biomarkers of Kleine-Levin syndrome | Hedou J, et al. | 2022 | Sleep | 45 | 9 | https://www.doi.org/10.1093/sleep/zsac097 | 35,859,339 | Biomarkers *Cognitive Dysfunction *Disorders of Excessive Somnolence Humans *Kleine-Levin Syndrome Proteomics Csf Kleine-Levine syndrome aptamers brain immunity hypersomnia microglia serum | STUDY OBJECTIVES: Kleine-Levin syndrome (KLS) is characterized by relapsing-remitting episodes of hypersomnia, cognitive impairment, and behavioral disturbances. We quantified cerebrospinal fluid (CSF) and serum proteins in KLS cases and controls. METHODS: SomaScan was used to profile 1133 CSF proteins in 30 KLS cases and 134 controls, while 1109 serum proteins were profiled in serum from 26 cases and 65 controls. CSF and serum proteins were both measured in seven cases. Univariate and multivariate analyses were used to find differentially expressed proteins (DEPs). Pathway and tissue enrichment analyses (TEAs) were performed on DEPs. RESULTS: Univariate analyses found 28 and 141 proteins differentially expressed in CSF and serum, respectively (false discovery rate <0.1%). Upregulated CSF proteins included IL-34, IL-27, TGF-b, IGF-1, and osteonectin, while DKK4 and vWF were downregulated. Pathway analyses revealed microglial alterations and disrupted blood-brain barrier permeability. Serum profiles show upregulation of Src-family kinases (SFKs), proteins implicated in cellular growth, motility, and activation. TEA analysis of up- and downregulated proteins revealed changes in brain proteins (p < 6 x 10-5), notably from the pons, medulla, and midbrain. A multivariate machine-learning classifier performed robustly, achieving a receiver operating curve area under the curve of 0.90 (95% confidence interval [CI] = 0.78-1.0, p = 0.0006) in CSF and 1.0 (95% CI = 1.0-1.0, p = 0.0002) in serum in validation cohorts, with some commonality across tissues, as the model trained on serum sample also discriminated CSF samples of controls versus KLS cases. CONCLUSIONS: Our study identifies proteomic KLS biomarkers with diagnostic potential and provides insight into biological mechanisms that will guide future research in KLS. | Hedou, Julien Cederberg, Katie L Ambati, Aditya Lin, Ling Farber, Neal Dauvilliers, Yves Quadri, Mohammed Bourgin, Patrice Plazzi, Giuseppe Andlauer, Olivier Hong, Seung-Chul Huang, Yu-Shu Leu-Semenescu, Smaranda Arnulf, Isabelle Taheri, Shahrad Mignot, Emmanuel eng S10 OD023452/OD/NIH HHS/ R01MH080957/NH/NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Sleep. 2022 Sep 8;45(9):zsac097. doi: 10.1093/sleep/zsac097.I | 07/22/2022 | ||
| High Dimensional Multiomics Reveals Unique Characteristics of Early Plasma Administration in Polytrauma Patients With TBI | Wu J, et al. | 2022 | Ann Surg | 276 | 4 | 673-683 | https://www.doi.org/10.1097/SLA.0000000000005610 | 35,861,072 | *Brain Injuries, Traumatic/therapy *Emergency Medical Services/methods Humans *Multiple Trauma/therapy Plasma Proteomics | OBJECTIVES: The authors sought to identify causal factors that explain the selective benefit of prehospital administration of thawed plasma (TP) in traumatic brain injury (TBI) patients using mediation analysis of a multiomic database. BACKGROUND: The Prehospital Air Medical Plasma (PAMPer) Trial showed that patients with TBI and a pronounced systemic response to injury [defined as endotype 2 (E2)], have a survival benefit from prehospital administration of TP. An interrogation of high dimensional proteomics, lipidomics and metabolomics previously demonstrated unique patterns in circulating biomarkers in patients receiving prehospital TP, suggesting that a deeper analysis could reveal causal features specific to TBI patients. METHODS: A novel proteomic database (SomaLogic Inc., aptamer-based assay, 7K platform) was generated using admission blood samples from a subset of patients (n=149) from the PAMPer Trial. This proteomic dataset was combined with previously reported metabolomic and lipidomic datasets from these same patients. A 2-step analysis was performed to identify factors that promote survival in E2-TBI patients who had received early TP. First, features were selected using both linear and multivariate-latent-factor regression analyses. Then, the selected features were entered into the causal mediation analysis. RESULTS: Causal mediation analysis of observable features identified 16 proteins and 41 lipids with a high proportion of mediated effect (>50%) to explain the survival benefit of early TP in E2-TBI patients. The multivariate latent-factor regression analyses also uncovered 5 latent clusters of features with a proportion effect >30%, many in common with the observable features. Among the observable and latent features were protease inhibitors known to inhibit activated protein C and block fibrinolysis (SERPINA5 and CPB2), a clotting factor (factor XI), as well as proteins involved in lipid transport and metabolism (APOE3 and sPLA(2)-XIIA). CONCLUSIONS: These findings suggest that severely injured patients with TBI process exogenous plasma differently than those without TBI. The beneficial effects of early TP in E2-TBI patients may be the result of improved blood clotting and the effect of brain protective factors independent of coagulation. | Wu, Junru Moheimani, Hamed Li, Shimena Kar, Upendra K Bonaroti, Jillian Miller, Richard S Daley, Brian J Harbrecht, Brian G Claridge, Jeffrey A Gruen, Danielle S Phelan, Herbert A Guyette, Francis X Neal, Matthew D Das, Jishnu Sperry, Jason L Billiar, Timothy R eng R35 GM127027/GM/NIGMS NIH HHS/ R01 HL141080/HL/NHLBI NIH HHS/ R38 HL150207/HL/NHLBI NIH HHS/ T32 GM008516/GM/NIGMS NIH HHS/ R35 GM119526/GM/NIGMS NIH HHS/ DP2 AI164325/AI/NIAID NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. Ann Surg. 2022 Oct 1;276(4):673-683. doi: 10.1097/SLA.0000000000005610. Epub 2022 Jul 19.I | 07/22/2022 | |
| Development and Validation of Prediction Models of Adverse Kidney Outcomes in the Population With and Without Diabetes | Grams ME, et al. | 2022 | Diabetes Care | 45 | 9 | 2055-2063 | https://www.doi.org/10.2337/dc22-0698 | 35,856,507 | Albuminuria *Diabetes Mellitus/epidemiology Glomerular Filtration Rate Humans Kidney *Renal Insufficiency *Renal Insufficiency, Chronic/epidemiology | OBJECTIVE: To predict adverse kidney outcomes for use in optimizing medical management and clinical trial design. RESEARCH DESIGN AND METHODS: In this meta-analysis of individual participant data, 43 cohorts (N = 1,621,817) from research studies, electronic medical records, and clinical trials with global representation were separated into development and validation cohorts. Models were developed and validated within strata of diabetes mellitus (presence or absence) and estimated glomerular filtration rate (eGFR; >/=60 or <60 mL/min/1.73 m2) to predict a composite of >/=40% decline in eGFR or kidney failure (i.e., receipt of kidney replacement therapy) over 2-3 years. RESULTS: There were 17,399 and 24,591 events in development and validation cohorts, respectively. Models predicting >/=40% eGFR decline or kidney failure incorporated age, sex, eGFR, albuminuria, systolic blood pressure, antihypertensive medication use, history of heart failure, coronary heart disease, atrial fibrillation, smoking status, and BMI, and, in those with diabetes, hemoglobin A1c, insulin use, and oral diabetes medication use. The median C-statistic was 0.774 (interquartile range [IQR] = 0.753, 0.782) in the diabetes and higher-eGFR validation cohorts; 0.769 (IQR = 0.758, 0.808) in the diabetes and lower-eGFR validation cohorts; 0.740 (IQR = 0.717, 0.763) in the no diabetes and higher-eGFR validation cohorts; and 0.750 (IQR = 0.731, 0.785) in the no diabetes and lower-eGFR validation cohorts. Incorporating the previous 2-year eGFR slope minimally improved model performance, and then only in the higher-eGFR cohorts. CONCLUSIONS: Novel prediction equations for a decline of >/=40% in eGFR can be applied successfully for use in the general population in persons with and without diabetes with higher or lower eGFR. | Grams, Morgan E Brunskill, Nigel J Ballew, Shoshana H Sang, Yingying Coresh, Josef Matsushita, Kunihiro Surapaneni, Aditya Bell, Samira Carrero, Juan J Chodick, Gabriel Evans, Marie Heerspink, Hiddo J L Inker, Lesley A Iseki, Kunitoshi Kalra, Philip A Kirchner, H Lester Lee, Brian J Levin, Adeera Major, Rupert W Medcalf, James Nadkarni, Girish N Naimark, David M J Ricardo, Ana C Sawhney, Simon Sood, Manish M Staplin, Natalie Stempniewicz, Nikita Stengel, Benedicte Sumida, Keiichi Traynor, Jamie P van den Brand, Jan Wen, Chi-Pang Woodward, Mark Yang, Jae Won Wang, Angela Yee-Moon Tangri, Navdeep Chalmers, John Hsu, Chi-Yuan Anderson, Amanda Rao, Panduranga Feldman, Harold Chang, Alex R Ho, Kevin Green, Jamie Siddiqui, Moneeza Palmer, Colin Shalev, Varda Metzger, Marie Flamant, Martin Houillier, Pascal Haymann, Jean-Philippe Cuddeback, John Ciemins, Elizabeth Kovesdy, Csaba P Trevisan, Marco Elinder, Carl Gustaf Wettermark, Bjorn Kalra, Philip Chinnadurai, Rajkumar Tollitt, James Green, Darren Gansevoort, Ron T Gutierrez, Orlando Konta, Tsuneo Kottgen, Anna Levey, Andrew S Polkinghorne, Kevan Schaffner, Elke Zhang, Luxia Chen, Jingsha eng R01 DK100446/DK/NIDDK NIH HHS/ Meta-Analysis Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Diabetes Care. 2022 Sep 1;45(9):2055-2063. doi: 10.2337/dc22-0698.I | 07/21/2022 | |
| Exploring the genetic relationship between deep vein thrombosis and plasma protein: a new research idea | Luo P, et al. | 2022 | Expert Rev Hematol | 15 | 9 | 867-873 | https://www.doi.org/10.1080/17474086.2022.2104707 | 35,857,435 | Blood Proteins/genetics Chromogranins Complement Factor B Humans Mendelian Randomization Analysis Proteome *Venous Thrombosis/genetics Deep venous thrombosis (DVT) causality genetic correlation genetics plasma protein | BACKGROUND: The aim of this article is to scan and analyze the genetic correlation between plasma proteome and deep venous thrombosis (DVT), and to explore the correlation between plasma protein and DVT. RESEARCH DESIGN AND METHODS: GWAS data of DVT and plasma proteins were analyzed with linkage disequilibrium scores, and plasma proteins that were genetically associated with DVT were screened out. To ascertain the causal link between potential plasma proteins and DVT, a Mendelian randomized (MR) study was used. This study used STRING to examine the pathogenesis of DVT in connection with the gene encoding plasma protein. RESULTS: Several suggestive plasma proteins were detected for DVT, such as Complement factor B (P value=0.0177), Chromogranin-A (P value=0.0158). Through MR analysis, we found that there was a significant positive causal relationship between Chromogranin-A (exposure) and DVT(outcome) (beta=-0.0117, P<0.0001). Our STRING analysis revealed that hsa04610 was associated with coagulation cascade in the KEGG pathway of Complement factor B(P<0.0001), which was based on GO and KEGG analysis of 8 selected plasma proteins. CONCLUSIONS: A genetic link between plasma protein and DVT was thoroughly investigated. Our findings provide a fresh perspective on the genetics and pathogenesis of DVT. | Luo, Pan Xu, Jiawen Xu, Ke Jing, Wensen Liu, Lin Xu, Peng eng Research Support, Non-U.S. Gov't England Expert Rev Hematol. 2022 Sep;15(9):867-873. doi: 10.1080/17474086.2022.2104707. Epub 2022 Aug 1.I | 07/21/2022 | |
| Genome-wide screening identifies DNA methylation sites that regulate the blood proteome | Nikpay M, et al. | 2022 | Epigenomics | epub ahead of print | https://www.doi.org/10.2217/epi-2022-0119 | 35,852,134 | DNA methylation Mendelian randomization biomarker epigenomics functional interaction proteomics | Background: Identifying DNA methylation sites that regulate the blood proteome is important for biomedical purposes. Materials & methods: Here the authors performed a genome-wide search to find DNA methylation sites that impact proteins. Results: The authors identified 165 methylation sites associated with 138 proteins. The authors noted hotspot genomic regions that control the levels of several proteins. For example, methylation of the ABO locus impacted 37 proteins and contributed to cardiometabolic comorbidities, including the severity of SARS-CoV-2 infection. The authors made these findings publicly available as a Unix software that identifies methylation sites that cause disease and reveals the underlying proteins. The authors underlined the software application by showing that components of innate immunity contribute to systolic blood pressure. Conclusion: This study provides a catalog of DNA methylation sites that regulate the proteome, and the results are available as freeware for biological insight. Our lifestyle choices and interactions with the world around us are continuously printed in our DNA through a biochemical process known as epigenomic modification. Excessive epigenomic modification at a DNA site may cause disease. To prevent or treat disease, it is important to find such sites and remove the excessive epigenomic modification with medications or lifestyle changes. Here the authors searched for DNA sites that undergo epigenomic modification. The authors also investigated the mechanism whereby these sites cause disease. The authors found that there are DNA sites where reverting the epigenomic modification could have a big impact on the body. The authors have made these findings publicly available. eng | Nikpay, Majid Ravati, Sepehr McPherson, Ruth eng FDN-154308/CAPMC/CIHR/Canada England Epigenomics. 2022 Jul 19. doi: 10.2217/epi-2022-0119.I | 07/20/2022 | |||
| Genome- and transcriptome-wide association studies show that pulmonary embolism is associated with bone-forming proteins | Feng R, et al. | 2022 | Expert Rev Hematol | 15 | 10 | 951-958 | https://www.doi.org/10.1080/17474086.2022.2103534 | 35,848,930 | Humans *Transcriptome Genome-Wide Association Study RNA, Messenger/genetics *Pulmonary Embolism/genetics Defensins/genetics Genetic Predisposition to Disease Polymorphism, Single Nucleotide Bmp Gwas Ldsc Pulmonary embolism Twas | BACKGROUND: Pulmonary embolism (PE) is a leading cause of death in stroke patients and a severe health burden worldwide. There is a pressing need to understand the mechanisms by which it occurs and to identify at-risk patients efficiently and accurately. METHODS: First, based on data from GWAS in European populations, we performed a linkage disequilibrium score regression (LDSC) analysis of plasma proteins and PE in 3,283 individuals and additionally analyzed the genetic association between PE and fracture. Then, we performed a TWAS on PE GWAS data using skeletal muscle and blood for gene expression references. Finally, we validated the genetic correlation between PE and human plasma proteins by co-matching the genes encoding the identified proteins and those identified using TWAS with the differentially expressed genes obtained from mRNA expression profiling of PE. RESULTS: We identified five plasma proteins associated with PE, including hydroxycarboxylic acid receptor 2, defensin 118, and bone morphogenetic protein (BMP) 7, as well as a relationship between PE and fracture. Comparison of genes encoding these proteins with genes obtained from TWAS and then with differentially expressed genes obtained from PE mRNA expression profiling revealed that PE was highly correlated with the BMP family of genes. | Feng, Ruoyang Lu, Mengnan Yang, Yanni Luo, Pan Liu, Lin Xu, Ke Xu, Peng eng England Expert Rev Hematol. 2022 Oct;15(10):951-958. doi: 10.1080/17474086.2022.2103534. Epub 2022 Sep 25.I | 07/19/2022 | |
| The amniotic fluid proteome predicts imminent preterm delivery in asymptomatic women with a short cervix | Gudicha DW, et al. | 2022 | Sci Rep | 12 | 1 | 11781 | https://www.doi.org/10.1038/s41598-022-15392-3 | 35,821,507 | Amniotic Fluid/metabolism Cervix Uteri/diagnostic imaging Female Humans Infant, Newborn Matrix Metalloproteinase 8/metabolism *Obstetric Labor, Premature/metabolism Pregnancy *Premature Birth/metabolism Proteome/metabolism Retrospective Studies | Preterm birth, the leading cause of perinatal morbidity and mortality, is associated with increased risk of short- and long-term adverse outcomes. For women identified as at risk for preterm birth attributable to a sonographic short cervix, the determination of imminent delivery is crucial for patient management. The current study aimed to identify amniotic fluid (AF) proteins that could predict imminent delivery in asymptomatic patients with a short cervix. This retrospective cohort study included women enrolled between May 2002 and September 2015 who were diagnosed with a sonographic short cervix (< 25 mm) at 16-32 weeks of gestation. Amniocenteses were performed to exclude intra-amniotic infection; none of the women included had clinical signs of infection or labor at the time of amniocentesis. An aptamer-based multiplex platform was used to profile 1310 AF proteins, and the differential protein abundance between women who delivered within two weeks from amniocentesis, and those who did not, was determined. The analysis included adjustment for quantitative cervical length and control of the false-positive rate at 10%. The area under the receiver operating characteristic curve was calculated to determine whether protein abundance in combination with cervical length improved the prediction of imminent preterm delivery as compared to cervical length alone. Of the 1,310 proteins profiled in AF, 17 were differentially abundant in women destined to deliver within two weeks of amniocentesis independently of the cervical length (adjusted p-value < 0.10). The decreased abundance of SNAP25 and the increased abundance of GPI, PTPN11, OLR1, ENO1, GAPDH, CHI3L1, RETN, CSF3, LCN2, CXCL1, CXCL8, PGLYRP1, LDHB, IL6, MMP8, and PRTN3 were associated with an increased risk of imminent delivery (odds ratio > 1.5 for each). The sensitivity at a 10% false-positive rate for the prediction of imminent delivery by a quantitative cervical length alone was 38%, yet it increased to 79% when combined with the abundance of four AF proteins (CXCL8, SNAP25, PTPN11, and MMP8). Neutrophil-mediated immunity, neutrophil activation, granulocyte activation, myeloid leukocyte activation, and myeloid leukocyte-mediated immunity were biological processes impacted by protein dysregulation in women destined to deliver within two weeks of diagnosis. The combination of AF protein abundance and quantitative cervical length improves prediction of the timing of delivery compared to cervical length alone, among women with a sonographic short cervix. | Gudicha, Dereje W Romero, Roberto Gomez-Lopez, Nardhy Galaz, Jose Bhatti, Gaurav Done, Bogdan Jung, Eunjung Gallo, Dahiana M Bosco, Mariachiara Suksai, Manaphat Diaz-Primera, Ramiro Chaemsaithong, Piya Gotsch, Francesca Berry, Stanley M Chaiworapongsa, Tinnakorn Tarca, Adi L eng Contract No. HHSN275201300006C/HD/NICHD NIH HHS/ Research Support, N.I.H., Extramural Research Support, N.I.H., Intramural England Sci Rep. 2022 Jul 11;12(1):11781. doi: 10.1038/s41598-022-15392-3.I | 07/14/2022 | |
| Serum Protein Signatures Using Aptamer-Based Proteomics for Minimal Change Disease and Membranous Nephropathy | Muruve DA, et al. | 2022 | Kidney Int Rep | 7 | 7 | 1539-1556 | https://www.doi.org/10.1016/j.ekir.2022.04.006 | 35,812,291 | membranous nephropathy minimal change disease proteomics systems biology | INTRODUCTION: Minimal change disease (MCD) and membranous nephropathy (MN) are glomerular diseases (glomerulonephritis [GN]) that present with the nephrotic syndrome. Although circulating PLA2R antibodies have been validated as a biomarker for MN, the diagnosis of MCD and PLA2R-negative MN still relies on the results of kidney biopsy or empirical corticosteroids in children. We aimed to identify serum protein biomarker signatures associated with MCD and MN pathogenesis using aptamer-based proteomics. METHODS: Quantitative SOMAscan proteomics was applied to the serum of adult patients with MCD (n = 15) and MN (n = 37) and healthy controls (n = 20). Associations between the 1305 proteins detected with SOMAscan were assessed using multiple statistical tests, expression pattern analysis, and systems biology analysis. RESULTS: A total of 208 and 244 proteins were identified that differentiated MCD and MN, respectively, with high statistical significance from the healthy controls (Benjamin-Hochberg [BH] P < 0.0001). There were 157 proteins that discriminated MN from MCD (BH P < 0.05). In MCD, 65 proteins were differentially expressed as compared with MN and healthy controls. When compared with MCD and healthy controls, 44 discriminatory proteins were specifically linked to MN. Systems biology analysis of these signatures identified cell death and inflammation as key pathways differentiating MN from MCD and healthy controls. Dysregulation of fatty acid metabolism pathways was confirmed in both MN and MCD as compared with the healthy subjects. CONCLUSION: SOMAscan represents a promising proteomic platform for biomarker development in GN. Validation of a greater number of discovery biomarkers in larger patient cohorts is needed before these data can be translated for clinical care. | Muruve, Daniel A Debiec, Hanna Dillon, Simon T Gu, Xuesong Plaisier, Emmanuelle Can, Handan Otu, Hasan H Libermann, Towia A Ronco, Pierre eng Kidney Int Rep. 2022 Apr 14;7(7):1539-1556. doi: 10.1016/j.ekir.2022.04.006. eCollection 2022 Jul.I | 07/12/2022 | |
| Proteomics and Population Biology in the Cardiovascular Health Study (CHS): design of a study with mentored access and active data sharing | Austin TR, et al. | 2022 | Eur J Epidemiol | 37 | 7 | 755-765 | https://www.doi.org/10.1007/s10654-022-00888-z | 35,790,642 | Biomarkers Cohort Studies Female Humans *Information Dissemination Male Prospective Studies *Proteomics/methods Cardiovascular Disease Cohort Study Genomics Proteomics funded by Johnson & Johnson. Elkind receives study drug in kind from the BMS-Pfizer Alliance for Eliquis(R) and funding from Roche for a NIH-funded stroke prevention trial royalties from UpToDate for chapters on stroke and serves as an unpaid Officer of the American Heart Association. Floyd has consulted for Shionogi Inc. Kizer has stock ownership in Abbott, Bristol Myers Squibb, Johnson & Johnson, Medtronic, Merck and Pfizer. Odden is a consultant for Cricket Health, Inc. | BACKGROUND: In the last decade, genomic studies have identified and replicated thousands of genetic associations with measures of health and disease and contributed to the understanding of the etiology of a variety of health conditions. Proteins are key biomarkers in clinical medicine and often drug-therapy targets. Like genomics, proteomics can advance our understanding of biology. METHODS AND RESULTS: In the setting of the Cardiovascular Health Study (CHS), a cohort study of older adults, an aptamer-based method that has high sensitivity for low-abundance proteins was used to assay 4979 proteins in frozen, stored plasma from 3188 participants (61% women, mean age 74 years). CHS provides active support, including central analysis, for seven phenotype-specific working groups (WGs). Each CHS WG is led by one or two senior investigators and includes 10 to 20 early or mid-career scientists. In this setting of mentored access, the proteomic data and analytic methods are widely shared with the WGs and investigators so that they may evaluate associations between baseline levels of circulating proteins and the incidence of a variety of health outcomes in prospective cohort analyses. We describe the design of CHS, the CHS Proteomics Study, characteristics of participants, quality control measures, and structural characteristics of the data provided to CHS WGs. We additionally highlight plans for validation and replication of novel proteomic associations. CONCLUSION: The CHS Proteomics Study offers an opportunity for collaborative data sharing to improve our understanding of the etiology of a variety of health conditions in older adults. | Austin, Thomas R McHugh, Caitlin P Brody, Jennifer A Bis, Joshua C Sitlani, Colleen M Bartz, Traci M Biggs, Mary L Bansal, Nisha Buzkova, Petra Carr, Steven A deFilippi, Christopher R Elkind, Mitchell S V Fink, Howard A Floyd, James S Fohner, Alison E Gerszten, Robert E Heckbert, Susan R Katz, Daniel H Kizer, Jorge R Lemaitre, Rozenn N Longstreth, W T McKnight, Barbara Mei, Hao Mukamal, Kenneth J Newman, Anne B Ngo, Debby Odden, Michelle C Vasan, Ramachandran S Shojaie, Ali Simon, Noah Smith, George Davey Davies, Neil M Siscovick, David S Sotoodehnia, Nona Tracy, Russell P Wiggins, Kerri L Zheng, Jie Psaty, Bruce M eng U01HL080295/HL/NHLBI NIH HHS/ HL144483/HL/NHLBI NIH HHS/ U01 HL080295/HL/NHLBI NIH HHS/ U01 HL130114/HL/NHLBI NIH HHS/ HHSN268200800007C/HL/NHLBI NIH HHS/ N01HC55222/HL/NHLBI NIH HHS/ N01HC85086/HL/NHLBI NIH HHS/ RF1 AG063507/AG/NIA NIH HHS/ K01 AG071689/AG/NIA NIH HHS/ WT_/Wellcome Trust/United Kingdom U01HL130114/HL/NHLBI NIH HHS/ N01HC85080/HL/NHLBI NIH HHS/ N01HC85081/HL/NHLBI NIH HHS/ HHSN268201200036C/HL/NHLBI NIH HHS/ R01 HL144483/HL/NHLBI NIH HHS/ HHSN268201800001C/HL/NHLBI NIH HHS/ R01 HL132320/HL/NHLBI NIH HHS/ R01AG023629/AG/NIA NIH HHS/ 75N92021D00006/HL/NHLBI NIH HHS/ N01HC85082/HL/NHLBI NIH HHS/ N01HC85083/HL/NHLBI NIH HHS/ RF1AG063507/AG/NIA NIH HHS/ R01HL132320/HL/NHLBI NIH HHS/ N01HC85079/HL/NHLBI NIH HHS/ R01 AG023629/AG/NIA NIH HHS/ Netherlands Eur J Epidemiol. 2022 Jul;37(7):755-765. doi: 10.1007/s10654-022-00888-z. Epub 2022 Jul 5.I | 07/06/2022 | |
| Placenta-derived proteins across gestation in healthy pregnancies-a novel approach to assess placental function? | Degnes ML, et al. | 2022 | BMC Med | 20 | 1 | 227 | https://www.doi.org/10.1186/s12916-022-02415-z | 35,773,701 | Biomarkers *Cesarean Section Cross-Sectional Studies Female Humans Placenta Pregnancy *Proteomics Aptamer Four vessel sampling Human Proteomics SomaLogic | BACKGROUND: Placenta-derived proteins in the systemic maternal circulation are suggested as potential biomarkers for placental function. However, the identity and longitudinal patterns of such proteins are largely unknown due to the inaccessibility of the human placenta and limitations in assay technologies. We aimed to identify proteins derived from and taken up by the placenta in the maternal circulation. Furthermore, we aimed to describe the longitudinal patterns across gestation of placenta-derived proteins as well as identify placenta-derived proteins that can serve as reference curves for placental function. METHODS: We analyzed proteins in plasma samples collected in two cohorts using the Somalogic 5000-plex platform. Antecubital vein samples were collected at three time points (gestational weeks 14-16, 22-24, and 30-32) across gestation in 70 healthy pregnancies in the longitudinal STORK cohort. In the cross sectional 4-vessel cohort, blood samples were collected simultaneously from the maternal antecubital vein (AV), radial artery (RA), and uterine vein (UV) during cesarean section in 75 healthy pregnancies. Placenta-derived proteins and proteins taken up by the placenta were identified using venoarterial differences (UV-RA). Placenta-derived proteins were defined as placenta-specific by comparison to the venoarterial difference in the antecubital vein-radial artery (AV-RA). These proteins were described longitudinally based on the STORK cohort samples using a linear mixed effects model per protein. Using a machine learning algorithm, we identified placenta-derived proteins that could predict gestational age, meaning that they closely tracked gestation, and were potential read-outs of placental function. RESULTS: Among the nearly 5000 measured proteins, we identified 256 placenta-derived proteins and 101 proteins taken up by the placenta (FDR < 0.05). Among the 256 placenta-derived proteins released to maternal circulation, 101 proteins were defined as placenta-specific. These proteins formed two clusters with distinct developmental patterns across gestation. We identified five placenta-derived proteins that closely tracked gestational age when measured in the systemic maternal circulation, termed a placental proteomic clock." CONCLUSIONS: Together, these data may serve as a first step towards a reference for the healthy placenta-derived proteome that can be measured in the systemic maternal circulation and potentially serve as biomarkers of placental function. The "placental proteomic clock" represents a novel concept that warrants further investigation. Deviations in the proteomic pattern across gestation of such proteomic clock proteins may serve as an indication of placental dysfunction." | Degnes, Maren-Helene Langeland Westerberg, Ane Cecilie Zucknick, Manuela Powell, Theresa L Jansson, Thomas Henriksen, Tore Roland, Marie Cecilie Paasche Michelsen, Trond Melbye eng Research Support, Non-U.S. Gov't England BMC Med. 2022 Jul 1;20(1):227. doi: 10.1186/s12916-022-02415-z.I | 07/01/2022 | |
| Circulating proteomic profiles associated with endometriosis in adolescents and young adults | Sasamoto N, et al. | 2022 | Hum Reprod | 37 | 9 | 2042-2053 | https://www.doi.org/10.1093/humrep/deac146 | 35,770,801 | Adolescent Adult Boston Cohort Studies Cross-Sectional Studies *Endometriosis/metabolism Female Humans Observational Studies as Topic Proteomics United States Young Adult adolescents angiogenesis endometriosis lesion color | STUDY QUESTION: What are the systemic molecular profiles of endometriosis diagnosed in adolescents and young adults? SUMMARY ANSWER: Significant enrichment and increased activation of proteins related to angiogenesis and cell migration pathways were observed in endometriosis cases compared to controls (P-value < 2.4 x 10-8). WHAT IS KNOWN ALREADY: Little is known about the pathophysiology of adolescent endometriosis despite the fact that over 50% of adults with endometriosis report onset of severe pelvic pain during adolescence. STUDY DESIGN, SIZE, DURATION: A cross-sectional analysis using data on 142 laparoscopically confirmed endometriosis cases and 74 controls from the observational longitudinal cohort of Women's Health Study: From Adolescence to Adulthood (A2A). PARTICIPANTS/MATERIALS, SETTING, METHODS: We measured 1305 plasma protein levels using the validated, multiplex aptamer-based proteomics discovery platform, SOMAscan. We calculated odds ratios and 95% CIs using logistic regression adjusting for age, BMI, fasting status and hormone use at blood draw for differentially expressed proteins (P < 0.05). Ingenuity Pathway Analysis and STRING analysis were performed to identify biological pathways and protein interactions. We also examined proteins and pathways associated with superficial peritoneal lesion colors (i.e. red, vascularized, white, blue/black, brown). MAIN RESULTS AND THE ROLE OF CHANCE: Average age at blood draw was 18 years for endometriosis cases and 22 years for controls. We identified 63 proteins associated with endometriosis with type-I error set at 0.05, and absolute fold change >1.2, revealing significant enrichment of dysregulated proteins in biological pathways associated with endometriosis. Increased activation of pathways related to angiogenesis and cell migration was observed in plasma from endometriosis cases compared to controls (P-value < 2.4 x 10-8). Furthermore, when we examined proteins and pathways associated with lesion colors, vascularized lesions were associated with upregulation of pathways related to immune cell migration/activation and inflammation, whereas white, blue/black and brown lesions were associated with downregulation of these pathways. LIMITATIONS, REASONS FOR CAUTION: Validation of our results in independent datasets and mechanistic studies are warranted to further our understanding of the pathophysiological characteristics of this common but understudied patient population. WIDER IMPLICATIONS OF THE FINDINGS: To our knowledge, this was the first study to comprehensively examine circulating proteins in predominantly adolescents and young adult women with and without endometriosis. Results from this study provide novel biological insight that will build toward further research to elucidate endometriosis pathophysiology during the earlier course of the disease trajectory. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by the Department of Defense (W81XWH1910318) and the 2017 Boston Center for Endometriosis Trainee Award. Financial support for establishment of and data collection within the A2A cohort were provided by the J. Willard and Alice S. Marriott Foundation. N.S., A.F.V., S.A.M., K.L.T. have received funding from Marriott Family Foundation. S.A.M. and K.L.T. are supported by NICHD (R01 HD94842). S.A.M. serves as an advisory board member for AbbVie and Roche; neither are related to this study. The authors report no conflict of interest. TRIAL REGISTRATION NUMBER: N/A. | Sasamoto, Naoko Ngo, Long Vitonis, Allison F Dillon, Simon T Missmer, Stacey A Libermann, Towia A Terry, Kathryn L eng Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. England Hum Reprod. 2022 Aug 25;37(9):2042-2053. doi: 10.1093/humrep/deac146.I | 07/01/2022 | |
| CCL17 acts as a novel therapeutic target in pathological cardiac hypertrophy and heart failure | Zhang Y, et al. | 2022 | J Exp Med | 219 | 8 | https://www.doi.org/10.1084/jem.20200418 | 35,687,056 | Angiotensin II Animals Cardiomegaly Chemokine CCL17/metabolism Chemokines/metabolism Fibrosis *Heart Failure Humans Ligands Mice Mice, Inbred C57BL Myocardium/pathology Myocytes, Cardiac/metabolism *Proteomics | Circulating proteomic signatures of age are closely associated with aging and age-related diseases; however, the utility of changes in secreted proteins in identifying therapeutic targets for diseases remains unclear. Serum proteomic profiling of an age-stratified healthy population and further community-based cohort together with heart failure patients study demonstrated that circulating C-C motif chemokine ligand 17 (CCL17) level increased with age and correlated with cardiac dysfunction. Subsequent animal experiments further revealed that Ccll7-KO significantly repressed aging and angiotensin II (Ang II)-induced cardiac hypertrophy and fibrosis, accompanied by the plasticity and differentiation of T cell subsets. Furthermore, the therapeutic administration of an anti-CCL17 neutralizing antibody inhibited Ang II-induced pathological cardiac remodeling. Our findings reveal that chemokine CCL17 is identifiable as a novel therapeutic target in age-related and Ang II-induced pathological cardiac hypertrophy and heart failure. | Zhang, Yang Ye, Yicong Tang, Xiaoqiang Wang, Hui Tanaka, Toshiko Tian, Ran Yang, Xufei Wang, Lun Xiao, Ying Hu, Xiaomin Jin, Ye Pang, Haiyu Du, Tian Liu, Honghong Sun, Lihong Xiao, Shuo Dong, Ruijia Ferrucci, Luigi Tian, Zhuang Zhang, Shuyang eng 2021-I2M-1-003/Chinese Academy of Medical Sciences Initiative for Innovative Medicine/ 7192155/Beijing Natural Science Foundation/ 2016YFC0901500/National Key Research and Development Program of China/ PX2021028/Beijing Hospital Authority/ 81970426/National Natural Science Foundation of China/ AG/NIA NIH HHS/ Research Support, Non-U.S. Gov't J Exp Med. 2022 Aug 1;219(8):e20200418. doi: 10.1084/jem.20200418. Epub 2022 Jun 10.I | 06/11/2022 | ||
| Serologic Biomarkers of Progression Toward Diagnosis of Rheumatoid Arthritis in Active Component Military Personnel | Loza MJ, et al. | 2022 | Arthritis Rheumatol | 74 | 11 | 1766-1775 | https://www.doi.org/10.1002/art.42260 | 35,671,369 | Humans *Military Personnel Proteomics Programmed Cell Death 1 Receptor *Arthritis, Rheumatoid Biomarkers *Arthritis, Reactive | OBJECTIVE: To identify a panel of serum biomarkers that could specifically identify imminent cases of rheumatoid arthritis (RA) before diagnosis. METHODS: Serum samples were collected at 4 time points from active component US military personnel, including 157 anti-citrullinated protein antibody (ACPA)-seropositive and 50 ACPA-seronegative RA subjects, 100 reactive arthritis (ReA) subjects, and 76 healthy controls. The cohorts were split into 2 phases, with samples tested on independent proteomic platforms for each phase. Classification models of RA diagnosis based on samples obtained within 6 months prior to diagnosis were developed both in univariate analyses and by multivariate random forest modeling of training sample sets and testing sample sets from each phase. RESULTS: Increases in serum analytes, including C-reactive protein levels, serum amyloid A, and soluble programmed cell death 1 (PD-1), were observed in seropositive RA subjects at the time point closest to diagnosis, up to several years before diagnosis. Only a small fraction of RA subjects had levels above the 95th percentile of healthy control levels until the time period within 6 months of diagnosis. For classification of RA diagnosis using samples obtained within 6 months prior to diagnosis, soluble PD-1 provided superior specificity compared to ReA cases (>89%), with a sensitivity of 48% for RA classification. An 8-analyte model provided superior sensitivity (69%), with comparable specificity relative to ReA (>82%). CONCLUSION: Our findings demonstrate that imminent RA diagnosis could be classified with high specificity, relative to healthy controls and ReA cases, using a panel of cytokines measured in serum samples collected within 6 months before actual diagnosis. | Loza, Matthew J Nagpal, Sunil Cole, Suzanne Laird, Renee M Alcala, Ashley Rao, Navin L Riddle, Mark S Porter, Chad K eng Research Support, Non-U.S. Gov't Arthritis Rheumatol. 2022 Nov;74(11):1766-1775. doi: 10.1002/art.42260. Epub 2022 Oct 7.I | 06/08/2022 | |
| Cystatin SN is a potent upstream initiator of epithelial-derived type 2 inflammation in chronic rhinosinusitis | Nocera AL, et al. | 2022 | J Allergy Clin Immunol | 150 | 4 | 872-881 | https://www.doi.org/10.1016/j.jaci.2022.04.034 | 35,660,375 | Allergens Animals Chronic Disease Cysteine Proteinase Inhibitors Cytokines Inflammation Mice *Nasal Polyps/pathology Peptide Hydrolases Proteomics *Rhinitis/metabolism *Salivary Cystatins/genetics/metabolism *Sinusitis/pathology Epithelium P-glycoprotein cystatin SA cystatin SN exome posttranslational modification sinonasal mucus transcriptome from the MEEI Curing Kids Fund, Cook Medical, Medtronics has consultant arrangements with Olympus, Medtronics, 3D Matrix, Third Wave Therapeutics, Bear-ENT, and Karl Storz has provided expert testimony on ear, nose, and throat-related cases has a patent for P-gp and cystatin inhibition for chronic rhinosinusitis and receives royalties from this patent and has stock and/or stock options in Interscope, Inquis Medical, and Diceros Therapeutics. The rest of the authors declare that they have no relevant conflicts of interest. | BACKGROUND: Cystatin SN (CST1) and cystatin SA (CST2) are cysteine protease inhibitors that protect against allergen, viral, and bacterial proteases. Cystatins are overexpressed in the setting of allergic rhinitis and chronic rhinosinusitis with nasal polyps (CRSwNP); however, their role in promoting type 2 inflammation remains poorly characterized. OBJECTIVE: The purpose of this study was to use integrated poly-omics and a murine exposure model to explore the link between cystatin overexpression in CRSwNP and type 2 inflammation. METHODS: In this institutional review board- and institutional animal care and use committee-approved study, we compared tissue, exosome, and mucus CST1 and CST2 between CRSwNP and controls (n = 10 per group) by using matched whole exome sequencing, transcriptomic, proteomic, posttranslational modification, histologic, functional, and bioinformatic analyses. C57/BL6 mice were dosed with 3.9 mug/mL of CST1 or PBS intranasally for 5 to 18 days in the presence or absence of epithelial ABCB1a knockdown. Inflammatory cytokines were quantified by using Quansys multiplex assays or ELISAs. RESULTS: Of the 1305 proteins quantified, CST1 and CST2 were among the most overexpressed protease inhibitors in tissue, exosome, and mucus samples; they were localized to the epithelial layer. Multiple posttranslational modifications were identified in the polyp tissue. Exosomal CST1 and CST2 were strongly and significantly correlated with eosinophils and Lund-Mackay scores. Murine type 2 cytokine secretion and T(H)2 cell infiltration increased in a time-dependent manner following CST1 exposure and was abrogated by epithelial knockdown of ABCB1a, a regulator of epithelial cytokine secretion. CONCLUSION: CST1 is a potent upstream initiator of epithelial-derived type 2 inflammation in CRSwNP. Therapeutic strategies targeting CST activity and its associated posttranslational modifications deserve further interrogation. | Nocera, Angela L Mueller, Sarina K Workman, Alan D Wu, Dawei McDonnell, Kristen Sadow, Peter M Amiji, Mansoor M Bleier, Benjamin S eng P01 CA240239/CA/NCI NIH HHS/ R01 NS108968/NS/NINDS NIH HHS/ Research Support, N.I.H., Extramural J Allergy Clin Immunol. 2022 Oct;150(4):872-881. doi: 10.1016/j.jaci.2022.04.034. Epub 2022 May 31.I | 06/07/2022 | |
| A novel non-invasive method allowing for discovery of pathologically relevant proteins from small airways | Ostling J, et al. | 2022 | Clin Proteomics | 19 | 1 | 20 | https://www.doi.org/10.1186/s12014-022-09348-y | 35,668,386 | Asthma Biomarker Breath Exhaled air Non-invasive Non-volatiles Precision medicine Proteomics Small airways of the PExA method, and boardmember and chairholder of PExA AB. Emilia Viklund is reporting a minor chairhold in PExA AB. Dr Ostling reports personal fees from PExA AB during the conduct of the study and Employed by PExA AB while writing the manuscript but not during the planning and completion of the study. | BACKGROUND: There is a lack of early and precise biomarkers for personalized respiratory medicine. Breath contains an aerosol of droplet particles, which are formed from the epithelial lining fluid when the small airways close and re-open during inhalation succeeding a full expiration. These particles can be collected by impaction using the PExA((R)) method (Particles in Exhaled Air), and are derived from an area of high clinical interest previously difficult to access, making them a potential source of biomarkers reflecting pathological processes in the small airways. RESEARCH QUESTION: Our aim was to investigate if PExA method is useful for discovery of biomarkers that reflect pathology of small airways. METHODS AND ANALYSIS: Ten healthy controls and 20 subjects with asthma, of whom 10 with small airway involvement as indicated by a high lung clearance index (LCI >/= 2.9 z-score), were examined in a cross-sectional design, using the PExA instrument. The samples were analysed with the SOMAscan proteomics platform (SomaLogic Inc.). RESULTS: Two hundred-seven proteins were detected in up to 80% of the samples. Nine proteins showed differential abundance in subjects with asthma and high LCI as compared to healthy controls. Two of these were less abundant (ALDOA4, C4), and seven more abundant (FIGF, SERPINA1, CD93, CCL18, F10, IgM, IL1RAP). sRAGE levels were lower in ex-smokers (n = 14) than in never smokers (n = 16). Gene Ontology (GO) annotation database analyses revealed that the PEx proteome is enriched in extracellular proteins associated with extracellular exosome-vesicles and innate immunity. CONCLUSION: The applied analytical method was reproducible and allowed identification of pathologically interesting proteins in PEx samples from asthmatic subjects with high LCI. The results suggest that PEx based proteomics is a novel and promising approach to study respiratory diseases with small airway involvement. | Ostling, Jorgen Van Geest, Marleen Olsson, Henric K Dahlen, Sven-Erik Viklund, Emilia Gustafsson, Per M Mirgorodskaya, Ekaterina Olin, Anna-Carin eng England Clin Proteomics. 2022 Jun 6;19(1):20. doi: 10.1186/s12014-022-09348-y.I | 06/07/2022 | |
| Genetic architecture of band neutrophil fraction in Iceland | Oskarsson GR, et al. | 2022 | Commun Biol | 5 | 1 | 525 | https://www.doi.org/10.1038/s42003-022-03462-1 | 35,650,273 | Genome-Wide Association Study Granulocytes/metabolism Humans Iceland Neutrophils/metabolism *Pelger-Huet Anomaly/genetics | The characteristic lobulated nuclear morphology of granulocytes is partially determined by composition of nuclear envelope proteins. Abnormal nuclear morphology is primarily observed as an increased number of hypolobulated immature neutrophils, called band cells, during infection or in rare envelopathies like Pelger-Huet anomaly. To search for sequence variants affecting nuclear morphology of granulocytes, we performed a genome-wide association study using band neutrophil fraction from 88,101 Icelanders. We describe 13 sequence variants affecting band neutrophil fraction at nine loci. Five of the variants are at the Lamin B receptor (LBR) locus, encoding an inner nuclear membrane protein. Mutations in LBR are linked to Pelger-Huet anomaly. In addition, we identify cosegregation of a rare stop-gain sequence variant in LBR and Pelger Huet anomaly in an Icelandic eight generation pedigree, initially reported in 1963. Two of the other loci include genes which, like LBR, play a role in the nuclear membrane function and integrity. These GWAS results highlight the role proteins of the inner nuclear membrane have as important for neutrophil nuclear morphology. | Oskarsson, Gudjon R Magnusson, Magnus K Oddsson, Asmundur Jensson, Brynjar O Fridriksdottir, Run Arnadottir, Gudny A Katrinardottir, Hildigunnur Rognvaldsson, Solvi Halldorsson, Gisli H Sveinbjornsson, Gardar Ivarsdottir, Erna V Stefansdottir, Lilja Ferkingstad, Egil Norland, Kristjan Tragante, Vinicius Saemundsdottir, Jona Jonasdottir, Aslaug Jonasdottir, Adalbjorg Sigurjonsdottir, Svanhvit Petursdottir, Karen O Davidsson, Olafur B Rafnar, Thorunn Holm, Hilma Olafsson, Isleifur Onundarson, Pall T Vidarsson, Brynjar Sigurdardottir, Olof Masson, Gisli Gudbjartsson, Daniel F Jonsdottir, Ingileif Norddahl, Gudmundur L Thorsteinsdottir, Unnur Sulem, Patrick Stefansson, Kari eng England Commun Biol. 2022 Jun 1;5(1):525. doi: 10.1038/s42003-022-03462-1.I | 06/02/2022 | |
| Aptamers Targeting Cardiac Biomarkers as an Analytical Tool for the Diagnostics of Cardiovascular Diseases: A Review | Komarova N, et al. | 2022 | Biomedicines | 10 | 5 | https://www.doi.org/10.3390/biomedicines10051085 | 35,625,822 | aptamer biosensor cardiac biomarkers cardiovascular disease detection diagnostics | The detection of cardiac biomarkers is used for diagnostics, prognostics, and the risk assessment of cardiovascular diseases. The analysis of cardiac biomarkers is routinely performed with high-sensitivity immunological assays. Aptamers offer an attractive alternative to antibodies for analytical applications but, to date, are not widely practically implemented in diagnostics and medicinal research. This review summarizes the information on the most common cardiac biomarkers and the current state of aptamer research regarding these biomarkers. Aptamers as an analytical tool are well established for troponin I, troponin T, myoglobin, and C-reactive protein. For the rest of the considered cardiac biomarkers, the isolation of novel aptamers or more detailed characterization of the known aptamers are required. More attention should be addressed to the development of dual-aptamer sandwich detection assays and to the studies of aptamer sensing in alternative biological fluids. The universalization of aptamer-based biomarker detection platforms and the integration of aptamer-based sensing to clinical studies are demanded for the practical implementation of aptamers to routine diagnostics. Nevertheless, the wide usage of aptamers for the diagnostics of cardiovascular diseases is promising for the future, with respect to both point-of-care and laboratory testing. | Komarova, Natalia Panova, Olga Titov, Alexey Kuznetsov, Alexander eng 21-79-10175/Russian Science Foundation/ Review Switzerland Biomedicines. 2022 May 6;10(5):1085. doi: 10.3390/biomedicines10051085.I | 05/29/2022 | ||
| Results of untargeted analysis using the SOMAscan proteomics platform indicates novel associations of circulating proteins with risk of progression to kidney failure in diabetes | Kobayashi H, et al. | 2022 | Kidney Int | 102 | 2 | 370-381 | https://www.doi.org/10.1016/j.kint.2022.04.022 | 35,618,095 | Biomarkers/metabolism *Diabetes Mellitus, Type 2/complications *Diabetic Nephropathies/complications/etiology Disease Progression Endostatins Humans Lectins, C-Type Proteomics/methods *Renal Insufficiency circulating biomarker diabetes diabetic kidney disease end-stage kidney disease proteomics analysis patent for predicting risk of ESRD | This study applies a large proteomics panel to search for new circulating biomarkers associated with progression to kidney failure in individuals with diabetic kidney disease. Four independent cohorts encompassing 754 individuals with type 1 and type 2 diabetes and early and late diabetic kidney disease were followed to ascertain progression to kidney failure. During ten years of follow-up, 227 of 754 individuals progressed to kidney failure. Using the SOMAscan proteomics platform, we measured baseline concentration of 1129 circulating proteins. In our previous publications, we analyzed 334 of these proteins that were members of specific candidate pathways involved in diabetic kidney disease and found 35 proteins strongly associated with risk of progression to kidney failure. Here, we examined the remaining 795 proteins using an untargeted approach. Of these remaining proteins, 11 were significantly associated with progression to kidney failure. Biological processes previously reported for these proteins were related to neuron development (DLL1, MATN2, NRX1B, KLK8, RTN4R and ROR1) and were implicated in the development of kidney fibrosis (LAYN, DLL1, MAPK11, MATN2, endostatin, and ROR1) in cellular and animal studies. Specific mechanisms that underlie involvement of these proteins in progression of diabetic kidney disease must be further investigated to assess their value as targets for kidney-protective therapies. Using multivariable LASSO regression analysis, five proteins (LAYN, ESAM, DLL1, MAPK11 and endostatin) were found independently associated with risk of progression to kidney failure. Thus, our study identified proteins that may be considered as new candidate prognostic biomarkers to predict risk of progression to kidney failure in diabetic kidney disease. Furthermore, three of these proteins (DLL1, ESAM, and MAPK11) were selected as candidate biomarkers when all SOMAscan results were evaluated. | Kobayashi, Hiroki Looker, Helen C Satake, Eiichiro Saulnier, Pierre Jean Md Dom, Zaipul I O'Neil, Kristina Ihara, Katsuhito Krolewski, Bozena Galecki, Andrzej T Niewczas, Monika A Wilson, Jonathan M Doria, Alessandro Duffin, Kevin L Nelson, Robert G Krolewski, Andrzej S eng ZIA DK069062/ImNIH/Intramural NIH HHS/ R01 DK126799/DK/NIDDK NIH HHS/ P30 DK036836/DK/NIDDK NIH HHS/ R01 DK110350/DK/NIDDK NIH HHS/ R01 DK041526/DK/NIDDK NIH HHS/ Research Support, N.I.H., Extramural Research Support, N.I.H., Intramural Research Support, Non-U.S. Gov't Kidney Int. 2022 Aug;102(2):370-381. doi: 10.1016/j.kint.2022.04.022. Epub 2022 May 23.I | 05/27/2022 | |
| Association between vascular endothelial growth factor-mediated blood-brain barrier dysfunction and stress-induced depression | Matsuno H, et al. | 2022 | Mol Psychiatry | 27 | 9 | 3822-3832 | https://www.doi.org/10.1038/s41380-022-01618-3 | 35,618,888 | Animals Mice Blood-Brain Barrier/metabolism Vascular Endothelial Growth Factor A/metabolism Endothelial Cells/metabolism *Depressive Disorder, Major/metabolism Depression *Brain Diseases/pathology Mice, Inbred BALB C Capillary Permeability/physiology | Several lines of evidence suggest that stress induces the neurovascular dysfunction associated with increased blood-brain barrier (BBB) permeability, which could be an important pathology linking stress and psychiatric disorders, including major depressive disorder (MDD). However, the detailed mechanism resulting in BBB dysfunction associated in the pathophysiology of MDD still remains unclear. Herein, we demonstrate the role of vascular endothelial growth factor (VEGF), a key mediator of vascular angiogenesis and BBB permeability, in stress-induced BBB dysfunction and depressive-like behavior development. We implemented an animal model of depression, chronic restraint stress (RS) in BALB/c mice, and found that the BBB permeability was significantly increased in chronically stressed mice. Immunohistochemical and electron microscopic observations revealed that increased BBB permeability was associated with both paracellular and transcellular barrier alterations in the brain endothelial cells. Pharmacological inhibition of VEGF receptor 2 (VEGFR2) using a specific monoclonal antibody (DC101) prevented chronic RS-induced BBB permeability and anhedonic behavior. Considered together, these results indicate that VEGF/VEGFR2 plays a crucial role in the pathogenesis of depression by increasing the BBB permeability, and suggest that VEGFR2 inhibition could be a potential therapeutic strategy for the MDD subtype associated with BBB dysfunction. | Matsuno, Hitomi Tsuchimine, Shoko O'Hashi, Kazunori Sakai, Kazuhisa Hattori, Kotaro Hidese, Shinsuke Nakajima, Shingo Chiba, Shuichi Yoshimura, Aya Fukuzato, Noriko Kando, Mayumi Tatsumi, Megumi Ogawa, Shintaro Ichinohe, Noritaka Kunugi, Hiroshi Sohya, Kazuhiro eng 17K01983/MEXT | Japan Society for the Promotion of Science (JSPS)/ 20K07985/MEXT | Japan Society for the Promotion of Science (JSPS)/ 19K17102/MEXT | Japan Society for the Promotion of Science (JSPS)/ 16KT0199/MEXT | Japan Society for the Promotion of Science (JSPS)/ 19ak0101043h0205/Japan Agency for Medical Research and Development (AMED)/ 19ak0101044h0404/Japan Agency for Medical Research and Development (AMED)/ England Mol Psychiatry. 2022 Sep;27(9):3822-3832. doi: 10.1038/s41380-022-01618-3. Epub 2022 May 26.I | 05/27/2022 | |
| Stability and reproducibility of proteomic profiles in epidemiological studies: comparing the Olink and SOMAscan platforms | Haslam DE, et al. | 2022 | Proteomics | 22 | 13 | e2100170 | https://www.doi.org/10.1002/pmic.202100170 | 35,598,103 | Epidemiologic Studies Follow-Up Studies Humans *Proteomics Reproducibility of Results *Specimen Handling Aptamers biomarkers epidemiology studies laboratory methods and tools multiplexing systems biology | Limited data exist on the performance of high-throughput proteomics profiling in epidemiological settings, including the impact of specimen collection and within-person variability over time. Thus, the Olink (972 proteins) and SOMAscan7Kv4.1 (7322 proteoforms of 6596 proteins) assays were utilized to measure protein concentrations in archived plasma samples from the Nurses' Health Studies and Health Professionals Follow-Up Study. Spearman's correlation coefficients (r) and intraclass correlation coefficients (ICCs) were used to assess agreement between (1) 42 triplicate samples processed immediately, 24-h or 48-h after blood collection from 14 participants; and (2) 80 plasma samples from 40 participants collected 1-year apart. When comparing samples processed immediately, 24-h, and 48-h later, 55% of assays had an ICC/r >/= 0.75 and 87% had an ICC/r >/= 0.40 in Olink compared to 44% with an ICC/r >/= 0.75 and 72% with an ICC/r >/= 0.40 in SOMAscan7K. For both platforms, >90% of the assays were stable (ICC/r >/= 0.40) in samples collected 1-year apart. Among 817 proteins measured with both platforms, Spearman's correlations were high (r > 0.75) for 14.7% and poor (r < 0.40) for 44.8% of proteins. High-throughput proteomics profiling demonstrated reproducibility in archived plasma samples and stability after delayed processing in epidemiological studies, yet correlations between proteins measured with the Olink and SOMAscan7K platforms were highly variable. | Haslam, Danielle E Li, Jun Dillon, Simon T Gu, Xuesong Cao, Yin Zeleznik, Oana A Sasamoto, Naoko Zhang, Xuehong Eliassen, A Heather Liang, Liming Stampfer, Meir J Mora, Samia Chen, Zsu-Zsu Terry, Kathryn L Gerszten, Robert E Hu, Frank B Chan, Andrew T Libermann, Towia A Bhupathiraju, Shilpa N eng P30 CA006516/NH/NIH HHS/ R01 CA49449/NH/NIH HHS/ T32 CA009001/NH/NIH HHS/ U01 CA167552/NH/NIH HHS/ U01 CA176726/NH/NIH HHS/ UM1 CA186107/NH/NIH HHS/ CRUK_/Cancer Research UK/United Kingdom R01 CA67262/NH/NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. Germany Proteomics. 2022 Jul;22(13-14):e2100170. doi: 10.1002/pmic.202100170. Epub 2022 May 31.I | 05/23/2022 | |
| Validation of disease-specific biomarkers for the early detection of bronchopulmonary dysplasia | Kindt ASD, et al. | 2022 | Pediatr Res | epub ahead of print | https://www.doi.org/10.1038/s41390-022-02093-w | 35,595,912 | OBJECTIVE: To demonstrate and validate the improvement of current risk stratification for bronchopulmonary dysplasia (BPD) early after birth by plasma protein markers (sialic acid-binding Ig-like lectin 14 (SIGLEC-14), basal cell adhesion molecule (BCAM), angiopoietin-like 3 protein (ANGPTL-3)) in extremely premature infants. METHODS AND RESULTS: Proteome screening in first-week-of-life plasma samples of n = 52 preterm infants <32 weeks gestational age (GA) on two proteomic platforms (SomaLogic((R)), Olink-Proteomics((R))) confirmed three biomarkers with significant predictive power: BCAM, SIGLEC-14, and ANGPTL-3. We demonstrate high sensitivity (0.92) and specificity (0.86) under consideration of GA, show the proteins' critical contribution to the predictive power of known clinical risk factors, e.g., birth weight and GA, and predicted the duration of mechanical ventilation, oxygen supplementation, as well as neonatal intensive care stay. We confirmed significant predictive power for BPD cases when switching to a clinically applicable method (enzyme-linked immunosorbent assay) in an independent sample set (n = 25, p < 0.001) and demonstrated disease specificity in different cohorts of neonatal and adult lung disease. CONCLUSION: While successfully addressing typical challenges of clinical biomarker studies, we demonstrated the potential of BCAM, SIGLEC-14, and ANGPTL-3 to inform future clinical decision making in the preterm infant at risk for BPD. TRIAL REGISTRATION: Deutsches Register Klinische Studien (DRKS) No. 00004600; https://www.drks.de . IMPACT: The urgent need for biomarkers that enable early decision making and personalized monitoring strategies in preterm infants with BPD is challenged by targeted marker analyses, cohort size, and disease heterogeneity. We demonstrate the potential of the plasma proteins BCAM, SIGLEC-14, and ANGPTL-3 to identify infants with BPD early after birth while improving the predictive power of clinical variables, confirming the robustness toward proteome assays and proving disease specificity. Our comprehensive analysis enables a phase-III clinical trial that allows full implementation of the biomarkers into clinical routine to enable early risk stratification in preterms with BPD. | Kindt, Alida S D Forster, Kai M Cochius-den Otter, Suzan C M Flemmer, Andreas W Hauck, Stefanie M Flatley, Andrew Kamphuis, Juliette Karrasch, Stefan Behr, Jurgen Franz, Axel Hartel, Christoph Krumsiek, Jan Tibboel, Dick Hilgendorff, Anne eng Pediatr Res. 2022 May 20. doi: 10.1038/s41390-022-02093-w.I | 05/21/2022 | ||||
| Mendelian randomization analysis of plasma levels of CD209 and MICB proteins and the risk of varicose veins of lower extremities | Shadrina AS, et al. | 2022 | PLoS One | 17 | 5 | e0268725 | https://www.doi.org/10.1371/journal.pone.0268725 | 35,594,287 | Genome-Wide Association Study Humans Lower Extremity/pathology *Mendelian Randomization Analysis Polymorphism, Single Nucleotide *Varicose Veins/genetics/pathology | Varicose veins of lower extremities (VVs) are a highly prevalent condition, the pathogenesis of which is still not fully elucidated. Mendelian randomization (MR) can provide useful preliminary information on the traits that are potentially causally related to the disease. The aim of the present study is to replicate the effects of the plasma levels of MHC class I polypeptide-related sequence B (MICB) and cluster of differentiation 209 (CD209) proteins reported in a previous hypothesis-free MR study. We conducted MR analysis using a fixed effects inverse-variance weighted meta-analysis of Wald ratios method. For MICB and CD209, we used data from a large-scale genome-wide association study (GWAS) for plasma protein levels (N = 3,301). For VVs, we used GWAS data obtained in the FinnGen project (N = 128,698), the eMERGE network (phase 3, N = 48,429), and the UK Biobank data available in the Gene ATLAS (N = 452,264). The data used in the study were obtained in individuals of European descent. The results for MICB did not pass criteria for statistical significance and replication. The results for CD209 passed all statistical significance thresholds, indicating that the genetically predicted increase in CD209 level is associated with increased risk of VVs (betaMR (SE) = 0.07 (0.01), OR (95% CI) = 1.08 (1.05-1.10), P-value = 5.9 x10-11 in the meta-analysis of three cohorts). Our findings provide further support that CD209 can potentially be involved in VVs. In future studies, independent validation of our results using data from more powerful GWASs for CD209 measured by different methods would be beneficial. | Shadrina, Alexandra S Elgaeva, Elizaveta E Stanaway, Ian B Jarvik, Gail P Namjou, Bahram Wei, Wei-Qi Glessner, Joe Hakonarson, Hakon Suri, Pradeep Tsepilov, Yakov A eng U01 HG008676/HG/NHGRI NIH HHS/ U01 HG008657/HG/NHGRI NIH HHS/ U01 HG008684/HG/NHGRI NIH HHS/ U01 HG008679/HG/NHGRI NIH HHS/ U01 HG008666/HG/NHGRI NIH HHS/ U01 HG008680/HG/NHGRI NIH HHS/ U01 HG008673/HG/NHGRI NIH HHS/ U01 HG008685/HG/NHGRI NIH HHS/ U01 HG006379/HG/NHGRI NIH HHS/ U01 HG008664/HG/NHGRI NIH HHS/ U01 HG008701/HG/NHGRI NIH HHS/ U01 HG008672/HG/NHGRI NIH HHS/ P30 AR072572/AR/NIAMS NIH HHS/ Meta-Analysis Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't PLoS One. 2022 May 20;17(5):e0268725. doi: 10.1371/journal.pone.0268725. eCollection 2022.I | 05/21/2022 | |
| Effects of age, amyloid, sex, and APOE epsilon4 on the CSF proteome in normal cognition | Wesenhagen KEJ, et al. | 2022 | Alzheimers Dement (Amst) | 14 | 1 | e12286 | https://www.doi.org/10.1002/dad2.12286 | 35,571,963 | INTRODUCTION: It is important to understand which biological processes change with aging, and how such changes are associated with increased Alzheimer's disease (AD) risk. We studied how cerebrospinal fluid (CSF) proteomics changed with age and tested if associations depended on amyloid status, sex, and apolipoprotein E E4 genotype. METHODS: We included 277 cognitively intact individuals aged 46 to 89 years from Alzheimer's Disease Neuroimaging Initiative, European Medical Information Framework for Alzheimer's Disease Multimodal Biomarker Discovery, and Metabolic Syndrome in Men. In total, 1149 proteins were measured with liquid chromatography mass spectrometry with multiple reaction monitoring/Rules-Based Medicine, tandem mass tag mass spectrometry, and SOMAscan. We tested associations between age and protein levels in linear models and tested enrichment for Reactome pathways. RESULTS: Levels of 252 proteins increased with age independently of amyloid status. These proteins were associated with immune and signaling processes. Levels of 21 proteins decreased with older age exclusively in amyloid abnormal participants and these were enriched for extracellular matrix organization. DISCUSSION: We found amyloid-independent and -dependent CSF proteome changes with older age, perhaps representing physiological aging and early AD pathology. | Wesenhagen, Kirsten E J Gobom, Johan Bos, Isabelle Vos, Stephanie J B Martinez-Lage, Pablo Popp, Julius Tsolaki, Magda Vandenberghe, Rik Freund-Levi, Yvonne Verhey, Frans Lovestone, Simon Streffer, Johannes Dobricic, Valerija Bertram, Lars Blennow, Kaj Pikkarainen, Maria Hallikainen, Merja Kuusisto, Johanna Laakso, Markku Soininen, Hilkka Scheltens, Philip Zetterberg, Henrik Teunissen, Charlotte E Visser, Pieter Jelle Tijms, Betty M eng Alzheimers Dement (Amst). 2022 May 6;14(1):e12286. doi: 10.1002/dad2.12286. eCollection 2022.I | 05/17/2022 | ||
| Whole-exome sequencing identifies rare genetic variants associated with human plasma metabolites | Bomba L, et al. | 2022 | Am J Hum Genet | 109 | 6 | 1038-1054 | https://www.doi.org/10.1016/j.ajhg.2022.04.009 | 35,568,032 | *Exome/genetics Gene Frequency/genetics Humans Prospective Studies Whole Exome Sequencing/methods Whole Genome Sequencing Wes Wgs drug targets endophenotypes loss-of-function metabolomics metabolon proteomics rare genetic variant sequencing non-financial support from Merck Sharp & Dohme (MSD) grants, personal fees, and non-financial support from Novartis grants from Pfizer and grants from AstraZeneca outside the submitted work. John Danesh sits on the International Cardiovascular and Metabolic Advisory Board for Novartis (since 2010) the Steering Committee of UK Biobank (since 2011) the MRC International Advisory Group (ING) member, London (since 2013) the MRC High Throughput Science 'Omics Panel Member, London (since 2013) the Scientific Advisory Committee for Sanofi (since 2013) the International Cardiovascular and Metabolism Research and Development Portfolio Committee for Novartis and the AstraZeneca Genomics Advisory Board (2018). Adam Butterworth reports institutional grants from AstraZeneca, Bayer, Biogen, BioMarin, Bioverativ, Merk and Sanofi. During the course of the project Praveen Surendran became an employee of GSK, Lorenzo Bomba became an employee of BioMarin, Mohd Karim became an employee of Variant Bio and Qi Guo became an employee of BenevolentAI. | Metabolite levels measured in the human population are endophenotypes for biological processes. We combined sequencing data for 3,924 (whole-exome sequencing, WES, discovery) and 2,805 (whole-genome sequencing, WGS, replication) donors from a prospective cohort of blood donors in England. We used multiple approaches to select and aggregate rare genetic variants (minor allele frequency [MAF] < 0.1%) in protein-coding regions and tested their associations with 995 metabolites measured in plasma by using ultra-high-performance liquid chromatography-tandem mass spectrometry. We identified 40 novel associations implicating rare coding variants (27 genes and 38 metabolites), of which 28 (15 genes and 28 metabolites) were replicated. We developed algorithms to prioritize putative driver variants at each locus and used mediation and Mendelian randomization analyses to test directionality at associations of metabolite and protein levels at the ACY1 locus. Overall, 66% of reported associations implicate gene targets of approved drugs or bioactive drug-like compounds, contributing to drug targets' validating efforts. | Bomba, Lorenzo Walter, Klaudia Guo, Qi Surendran, Praveen Kundu, Kousik Nongmaithem, Suraj Karim, Mohd Anisul Stewart, Isobel D Langenberg, Claudia Danesh, John Di Angelantonio, Emanuele Roberts, David J Ouwehand, Willem H Dunham, Ian Butterworth, Adam S Soranzo, Nicole eng Am J Hum Genet. 2022 Jun 2;109(6):1038-1054. doi: 10.1016/j.ajhg.2022.04.009. Epub 2022 May 13.I | 05/15/2022 | |
| Analytical Considerations of Large-Scale Aptamer-Based Datasets for Translational Applications | Jiang W, et al. | 2022 | Cancers (Basel) | 14 | 9 | https://www.doi.org/10.3390/cancers14092227 | 35,565,358 | aptamers bioinformatics biomarkers proteomics translational | The development and advancement of aptamer technology has opened a new realm of possibilities for unlocking the biocomplexity available within proteomics. With ultra-high-throughput and multiplexing, alongside remarkable specificity and sensitivity, aptamers could represent a powerful tool in disease-specific research, such as supporting the discovery and validation of clinically relevant biomarkers. One of the fundamental challenges underlying past and current proteomic technology has been the difficulty of translating proteomic datasets into standards of practice. Aptamers provide the capacity to generate single panels that span over 7000 different proteins from a singular sample. However, as a recent technology, they also present unique challenges, as the field of translational aptamer-based proteomics still lacks a standardizing methodology for analyzing these large datasets and the novel considerations that must be made in response to the differentiation amongst current proteomic platforms and aptamers. We address these analytical considerations with respect to surveying initial data, deploying proper statistical methodologies to identify differential protein expressions, and applying datasets to discover multimarker and pathway-level findings. Additionally, we present aptamer datasets within the multi-omics landscape by exploring the intersectionality of aptamer-based proteomics amongst genomics, transcriptomics, and metabolomics, alongside pre-existing proteomic platforms. Understanding the broader applications of aptamer datasets will substantially enhance current efforts to generate translatable findings for the clinic. | Jiang, Will Jones, Jennifer C Shankavaram, Uma Sproull, Mary Camphausen, Kevin Krauze, Andra V eng ZID BC010990/ImNIH/Intramural NIH HHS/ ZID BC 010990/CA/NCI NIH HHS/ Review Switzerland Cancers (Basel). 2022 Apr 29;14(9):2227. doi: 10.3390/cancers14092227.I | 05/15/2022 | ||
| Assay-related differences in SuPAR levels: implications for measurement and data interpretation | Vasbinder A, et al. | 2022 | J Nephrol | 3-Jan | https://www.doi.org/10.1007/s40620-022-01344-7 | 35,567,697 | Olink Quantikine SOMAScan Soluble urokinase plasminogen activator receptor Virogates suPARnostic | Vasbinder, Alexi Raffield, Laura Marie Gao, Yan Engstrom, Gunnar Quyyumi, Arshed Ali Reiner, Alexander Paul Reiser, Jochen Hayek, Salim Salim eng KL2TR002490/TR/NCATS NIH HHS/ T32 HL007853/HL/NHLBI NIH HHS/ U01-DK119083/DK/NIDDK NIH HHS/ U-M G024231/University of Michigan Frankel Cardiovascular Center/ HHSN268201800014C/HL/NHLBI NIH HHS/ R01HL153384/HL/NHLBI NIH HHS/ HHSN268201800013I/MD/NIMHD NIH HHS/ HHSN268201800011C/HL/NHLBI NIH HHS/ KL2 TR002490/TR/NCATS NIH HHS/ T32HL129982/HL/NHLBI NIH HHS/ HHSN268201800015I/HB/NHLBI NIH HHS/ HHSN268201800010I/HB/NHLBI NIH HHS/ HHSN268201800011I/HB/NHLBI NIH HHS/ R01 DK109720/DK/NIDDK NIH HHS/ HHSN268201800012I/HB/NHLBI NIH HHS/ R01 HL132947/HL/NHLBI NIH HHS/ HHSN268201800012C/HL/NHLBI NIH HHS/ T32-HL007853/HL/NHLBI NIH HHS/ HHSN268201800014I/HB/NHLBI NIH HHS/ R01HL132947/HL/NHLBI NIH HHS/ R01-DK109720/DK/NIDDK NIH HHS/ Letter Italy J Nephrol. 2022 May 14:1-3. doi: 10.1007/s40620-022-01344-7.I | 05/15/2022 | ||||
| Proteomic Analysis of Plasma Markers in Patients Maintained on Antipsychotics: Comparison to Patients Off Antipsychotics and Normal Controls | Engelke R, et al. | 2022 | Front Psychiatry | 13 | 809071 | https://www.doi.org/10.3389/fpsyt.2022.809071 | 35,546,954 | antipsychotics biomarkers bipolar disorder metabolic syndrome proteomics schizophrenia declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. | BACKGROUND: Schizophrenia (SZ) and bipolar disorder (BD) share many features: overlap in mood and psychotic symptoms, common genetic predisposition, treatment with antipsychotics (APs), and similar metabolic comorbidities. The pathophysiology of both is still not well defined, and no biomarkers can be used clinically for diagnosis and management. This study aimed to assess the plasma proteomics profile of patients with SZ and BD maintained on APs compared to those who had been off APs for 6 months and to healthy controls (HCs). METHODS: We analyzed the data using functional enrichment, random forest modeling to identify potential biomarkers, and multivariate regression for the associations with metabolic abnormalities. RESULTS: We identified several proteins known to play roles in the differentiation of the nervous system like NTRK2, CNTN1, ROBO2, and PLXNC1, which were downregulated in AP-free SZ and BD patients but were normalized" in those on APs. Other proteins (like NCAM1 and TNFRSF17) were "normal" in AP-free patients but downregulated in patients on APs, suggesting that these changes are related to medication's effects. We found significant enrichment of proteins involved in neuronal plasticity, mainly in SZ patients on APs. Most of the proteins associated with metabolic abnormalities were more related to APs use than having SZ or BD. The biomarkers identification showed specific and sensitive results for schizophrenia, where two proteins (PRL and MRC2) produced adequate results. CONCLUSIONS: Our results confirmed the utility of blood samples to identify protein signatures and mechanisms involved in the pathophysiology and treatment of SZ and BD." | Engelke, Rudolf Ouanes, Sami Ghuloum, Suhaila Chamali, Rifka Kiwan, Nancy Sarwath, Hina Schmidt, Frank Suhre, Karsten Al-Amin, Hassen eng Switzerland Front Psychiatry. 2022 Apr 25;13:809071. doi: 10.3389/fpsyt.2022.809071. eCollection 2022.I | 05/14/2022 | ||
| Plasma Proteomics of COVID-19-Associated Cardiovascular Complications: Implications for Pathophysiology and Therapeutics | Roh JD, et al. | 2022 | JACC Basic Transl Sci | 7 | 5 | 425-441 | https://www.doi.org/10.1016/j.jacbts.2022.01.013 | 35,530,264 | ADAMTS13, A Disintegrin And Metalloproteinase with a Thrombospondin type 1 motif, member 13 Covid-19 FSTL3, follistatin-like 3 NT-proBNP, N-terminal pro-B-type natriuretic peptide SASP, senescence associated secretory phenotype TGFbeta, transforming growth factor beta hsTnT, high sensitivity troponin T myocardial injury proteomics senescence R35HL15531 [to Dr Rosenzweig] R01HL092577, R01HL128914, and K24HL105780 [to Dr Ellinor] R01HL134893, R01HL140224, K24HL153669 [to Dr Ho] T32HL094301 [to Dr Weber] K08HL140200 [to Dr Rhee] and K76AG064328 [to Dr Roh]), the Fondation Leducq (14CVD01 [to Dr Ellinor]), the American Heart Association (18SFRN34110082 [to Dr Ellinor]), a Sarnoff Cardiovascular Research Foundation Fellowship award (to Dr Trager), the Fred and Ines Yeatts Fund for Innovative Research (to Dr Roh), the Hassenfeld Scholars Award (to Dr Roh), Fast Grants, Emergent Ventures, Mercatus Center at George Mason University (to Dr Martinot), and a research grant from Bayer AG to the Broad Institute (to Drs Ellinor and Ho). Dr Ellinor is supported by a grant from Bayer AG to the Broad Institute focused on the genetics and therapeutics of cardiovascular diseases and has served on advisory boards or consulted for Bayer AG, Quest Diagnostics, MyoKardia and Novartis. Dr Ho has received research grants from Bayer AG and Gilead Sciences and has received research supplies from EcoNugenics. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. | To gain insights into the mechanisms driving cardiovascular complications in COVID-19, we performed a case-control plasma proteomics study in COVID-19 patients. Our results identify the senescence-associated secretory phenotype, a marker of biological aging, as the dominant process associated with disease severity and cardiac involvement. FSTL3, an indicator of senescence-promoting Activin/TGFbeta signaling, and ADAMTS13, the von Willebrand Factor-cleaving protease whose loss-of-function causes microvascular thrombosis, were among the proteins most strongly associated with myocardial stress and injury. Findings were validated in a larger COVID-19 patient cohort and the hamster COVID-19 model, providing new insights into the pathophysiology of COVID-19 cardiovascular complications with therapeutic implications. | Roh, Jason D Kitchen, Robert R Guseh, J Sawalla McNeill, Jenna N Aid, Malika Martinot, Amanda J Yu, Andy Platt, Colin Rhee, James Weber, Brittany Trager, Lena E Hastings, Margaret H Ducat, Sarah Xia, Peng Castro, Claire Singh, Abhilasha Atlason, Bjarni Churchill, Timothy W Di Carli, Marcelo F Ellinor, Patrick T Barouch, Dan H Ho, Jennifer E Rosenzweig, Anthony eng K08 HL140200/HL/NHLBI NIH HHS/ R01 AG061034/AG/NIA NIH HHS/ JACC Basic Transl Sci. 2022 May;7(5):425-441. doi: 10.1016/j.jacbts.2022.01.013. Epub 2022 May 4.I | 05/10/2022 | |
| Proteomics in thrombosis research | Edfors F, et al. | 2022 | Res Pract Thromb Haemost | 6 | 3 | e12706 | https://www.doi.org/10.1002/rth2.12706 | 35,494,505 | Vte biomarker mass spectrometry plasma protein proteome proteomics thrombosis venous thromboembolism | A State of the Art lecture titled Proteomics in Thrombosis Research" was presented at the ISTH Congress in 2021. In clinical practice, there is a need for improved plasma biomarker-based tools for diagnosis and risk prediction of venous thromboembolism (VTE). Analysis of blood, to identify plasma proteins with potential utility for such tools, could enable an individualized approach to treatment and prevention. Technological advances to study the plasma proteome on a large scale allows broad screening for the identification of novel plasma biomarkers, both by targeted and nontargeted proteomics methods. However, assay limitations need to be considered when interpreting results, with orthogonal validation required before conclusions are drawn. Here, we review and provide perspectives on the application of affinity- and mass spectrometry-based methods for the identification and analysis of plasma protein biomarkers, with potential application in the field of VTE. We also provide a future perspective on discovery strategies and emerging technologies for targeted proteomics in thrombosis research. Finally, we summarize relevant new data on this topic, presented during the 2021 ISTH Congress." | Edfors, Fredrik Iglesias, Maria Jesus Butler, Lynn M Odeberg, Jacob eng Res Pract Thromb Haemost. 2022 Apr 25;6(3):e12706. doi: 10.1002/rth2.12706. eCollection 2022 Mar.I | 05/03/2022 | |
| Lymphocyte activation gene-3-associated protein networks are associated with HDL-cholesterol and mortality in the Trans-omics for Precision Medicine program | Manichaikul A, et al. | 2022 | Commun Biol | 5 | 1 | 362 | https://www.doi.org/10.1038/s42003-022-03304-0 | 35,501,457 | *Atherosclerosis Cholesterol, HDL Chromatin Humans Lymphocyte Activation Membrane Proteins *Precision Medicine | Deficiency of the immune checkpoint lymphocyte activation gene-3 (LAG3) protein is significantly associated with both elevated HDL-cholesterol (HDL-C) and myocardial infarction risk. We determined the association of genetic variants within +/-500 kb of LAG3 with plasma LAG3 and defined LAG3-associated plasma proteins with HDL-C and clinical outcomes. Whole genome sequencing and plasma proteomics were obtained from the Multi-Ethnic Study of Atherosclerosis (MESA) and the Framingham Heart Study (FHS) cohorts as part of the Trans-Omics for Precision Medicine program. In situ Hi-C chromatin capture was performed in EBV-transformed cell lines isolated from four MESA participants. Genetic association analyses were performed in MESA using multivariate regression models, with validation in FHS. A LAG3-associated protein network was tested for association with HDL-C, coronary heart disease, and all-cause mortality. We identify an association between the LAG3 rs3782735 variant and plasma LAG3 protein. Proteomics analysis reveals 183 proteins significantly associated with LAG3 with four proteins associated with HDL-C. Four proteins discovered for association with all-cause mortality in FHS shows nominal associations in MESA. Chromatin capture analysis reveals significant cis interactions between LAG3 and C1S, LRIG3, TNFRSF1A, and trans interactions between LAG3 and B2M. A LAG3-associated protein network has significant associations with HDL-C and mortality. | Manichaikul, Ani Lin, Honghuang Kang, Chansuk Yang, Chaojie Rich, Stephen S Taylor, Kent D Guo, Xiuqing Rotter, Jerome I Craig Johnson, W Cornell, Elaine Tracy, Russell P Peter Durda, J Liu, Yongmei Vasan, Ramachandran S Adrienne Cupples, L Gerszten, Robert E Clish, Clary B Jain, Deepti Conomos, Matthew P Blackwell, Thomas Papanicolaou, George J Rodriguez, Annabelle eng N01HC95169/HL/NHLBI NIH HHS/ 75N92020D00007/HL/NHLBI NIH HHS/ R01 HL071251/HL/NHLBI NIH HHS/ 75N92020D00005/HL/NHLBI NIH HHS/ N01HC95165/HL/NHLBI NIH HHS/ N01HC95159/HL/NHLBI NIH HHS/ N01HC95163/HL/NHLBI NIH HHS/ 75N92020D00002/HL/NHLBI NIH HHS/ UL1 RR033176/RR/NCRR NIH HHS/ R01 HL131862/HL/NHLBI NIH HHS/ UL1 TR000040/TR/NCATS NIH HHS/ R01 HL117626/HL/NHLBI NIH HHS/ N01HC95161/HL/NHLBI NIH HHS/ 75N92020D00001/HL/NHLBI NIH HHS/ UL1 TR001881/TR/NCATS NIH HHS/ 75N92019D00031/HL/NHLBI NIH HHS/ R01 HL120393/HL/NHLBI NIH HHS/ R01 HL071259/HL/NHLBI NIH HHS/ N01HC95168/HL/NHLBI NIH HHS/ HHSN268201500014C/HL/NHLBI NIH HHS/ N01HC95162/HL/NHLBI NIH HHS/ R01 HL071051/HL/NHLBI NIH HHS/ 75N92020D00004/HL/NHLBI NIH HHS/ UL1 TR001420/TR/NCATS NIH HHS/ HHSN268201500001I/HL/NHLBI NIH HHS/ R01 HL105756/HL/NHLBI NIH HHS/ R01 HL071205/HL/NHLBI NIH HHS/ R01 HL071258/HL/NHLBI NIH HHS/ N01HC95167/HL/NHLBI NIH HHS/ 75N92020D00003/HL/NHLBI NIH HHS/ N01HC25195/HL/NHLBI NIH HHS/ U54 HG003067/HG/NHGRI NIH HHS/ HHSN268201500003I/HL/NHLBI NIH HHS/ N01HC95164/HL/NHLBI NIH HHS/ R01 HL092577/HL/NHLBI NIH HHS/ 75N92020D00006/HL/NHLBI NIH HHS/ UL1 TR001079/TR/NCATS NIH HHS/ N01HC95166/HL/NHLBI NIH HHS/ R01 HL071250/HL/NHLBI NIH HHS/ N01HC95160/HL/NHLBI NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't England Commun Biol. 2022 May 2;5(1):362. doi: 10.1038/s42003-022-03304-0.I | 05/03/2022 | |
| Plasma proteome analyses in individuals of European and African ancestry identify cis-pQTLs and models for proteome-wide association studies | Zhang J, et al. | 2022 | Nat Genet | 54 | 5 | 593-602 | https://www.doi.org/10.1038/s41588-022-01051-w | 35,501,419 | Genetic Predisposition to Disease Genome-Wide Association Study *Gout/genetics Humans Polymorphism, Single Nucleotide *Proteome/genetics | Improved understanding of genetic regulation of the proteome can facilitate identification of the causal mechanisms for complex traits. We analyzed data on 4,657 plasma proteins from 7,213 European American (EA) and 1,871 African American (AA) individuals from the Atherosclerosis Risk in Communities study, and further replicated findings on 467 AA individuals from the African American Study of Kidney Disease and Hypertension study. Here, we identified 2,004 proteins in EA and 1,618 in AA, with most overlapping, which showed associations with common variants in cis-regions. Availability of AA samples led to smaller credible sets and notable number of population-specific cis-protein quantitative trait loci. Elastic Net produced powerful models for protein prediction in both populations. An application of proteome-wide association studies to serum urate and gout implicated several proteins, including IL1RN, revealing the promise of the drug anakinra to treat acute gout flares. Our study demonstrates the value of large and diverse ancestry study to investigate the genetic mechanisms of molecular phenotypes and their relationship with complex traits. | Zhang, Jingning Dutta, Diptavo Kottgen, Anna Tin, Adrienne Schlosser, Pascal Grams, Morgan E Harvey, Benjamin Yu, Bing Boerwinkle, Eric Coresh, Josef Chatterjee, Nilanjan eng R01 HG010480/HG/NHGRI NIH HHS/ R01 AR073178/AR/NIAMS NIH HHS/ R01 DK124399/DK/NIDDK NIH HHS/ R01 HL148218/HL/NHLBI NIH HHS/ R01 HL134320/HL/NHLBI NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Nat Genet. 2022 May;54(5):593-602. doi: 10.1038/s41588-022-01051-w. Epub 2022 May 2.I | 05/03/2022 | |
| Clinical applications of plasma proteomics and peptidomics: Towards precision medicine | He B, et al. | 2022 | Proteomics Clin Appl | 16 | 6 | e2100097 | https://www.doi.org/10.1002/prca.202100097 | 35,490,333 | Humans *Proteomics/methods Proteome/metabolism Precision Medicine/methods *COVID-19/diagnosis Biomarkers/metabolism biomarkers human proteome project peptidomics plasma precision medicine proteomics | In the context of precision medicine, disease treatment requires individualized strategies based on the underlying molecular characteristics to overcome therapeutic challenges posed by heterogeneity. For this purpose, it is essential to develop new biomarkers to diagnose, stratify, or possibly prevent diseases. Plasma is an available source of biomarkers that greatly reflects the physiological and pathological conditions of the body. An increasing number of studies are focusing on proteins and peptides, including many involving the Human Proteome Project (HPP) of the Human Proteome Organization (HUPO), and proteomics and peptidomics techniques are emerging as critical tools for developing novel precision medicine preventative measures. Excitingly, the emerging plasma proteomics and peptidomics toolbox exhibits a huge potential for studying pathogenesis of diseases (e.g., COVID-19 and cancer), identifying valuable biomarkers and improving clinical management. However, the enormous complexity and wide dynamic range of plasma proteins makes plasma proteome profiling challenging. Herein, we summarize the recent advances in plasma proteomics and peptidomics with a focus on their emerging roles in COVID-19 and cancer research, aiming to emphasize the significance of plasma proteomics and peptidomics in clinical applications and precision medicine. | He, Bo Huang, Zhao Huang, Canhua Nice, Edouard C eng 2020YFC2002705/National Key Research and Development Project of China/ 82103168/the National Natural Science Foundation of China/ 82102738/the National Natural Science Foundation of China/ Review Germany Proteomics Clin Appl. 2022 Nov;16(6):e2100097. doi: 10.1002/prca.202100097. Epub 2022 May 11.I | 05/02/2022 | |
| Proteomics of lung tissue reveals differences in inflammation and alveolar-capillary barrier response between atelectasis and aerated regions | Rashid A, et al. | 2022 | Sci Rep | 12 | 1 | 7065 | https://www.doi.org/10.1038/s41598-022-11045-7 | 35,487,970 | *Acute Lung Injury/metabolism Humans Inflammation/metabolism Lipopolysaccharides/metabolism Lung/metabolism Proteomics *Pulmonary Atelectasis/metabolism | Atelectasis is a frequent clinical condition, yet knowledge is limited and controversial on its biological contribution towards lung injury. We assessed the regional proteomics of atelectatic versus normally-aerated lung tissue to test the hypothesis that immune and alveolar-capillary barrier functions are compromised by purely atelectasis and dysregulated by additional systemic inflammation (lipopolysaccharide, LPS). Without LPS, 130 proteins were differentially abundant in atelectasis versus aerated lung, mostly (n = 126) with less abundance together with negatively enriched processes in immune, endothelial and epithelial function, and Hippo signaling pathway. Instead, LPS-exposed atelectasis produced 174 differentially abundant proteins, mostly (n = 108) increased including acute lung injury marker RAGE and chemokine CCL5. Functional analysis indicated enhanced leukocyte processes and negatively enriched cell-matrix adhesion and cell junction assembly with LPS. Additionally, extracellular matrix organization and TGF-beta signaling were negatively enriched in atelectasis with decreased adhesive glycoprotein THBS1 regardless of LPS. Concordance of a subset of transcriptomics and proteomics revealed overlap of leukocyte-related gene-protein pairs and processes. Together, proteomics of exclusively atelectasis indicates decreased immune response, which converts into an increased response with LPS. Alveolar-capillary barrier function-related proteomics response is down-regulated in atelectasis irrespective of LPS. Specific proteomics signatures suggest biological mechanistic and therapeutic targets for atelectasis-associated lung injury. | Rashid, Azman Zeng, Congli Motta-Ribeiro, Gabriel Dillon, Simon T Libermann, Towia A Lessa, Marcos Adriano Bagchi, Aranya Hutchinson, John Vidal Melo, Marcos F eng R01 HL121228/NH/NIH HHS/ Research Support, N.I.H., Extramural England Sci Rep. 2022 Apr 29;12(1):7065. doi: 10.1038/s41598-022-11045-7.I | 04/30/2022 | |
| Harnessing Big Data to Advance Treatment and Understanding of Pulmonary Hypertension | Rhodes CJ, et al. | 2022 | Circ Res | 130 | 9 | 1423-1444 | https://www.doi.org/10.1161/CIRCRESAHA.121.319969 | 35,482,840 | *Big Data Humans *Hypertension, Pulmonary/diagnosis/drug therapy/genetics Machine Learning Precision Medicine/methods big data information dissemination phenotype precision medicine pulmonary arterial hypertension Maron discloses Consultant roles for Actelion Pharmaceuticals and Tenax, and a Grant / Contract from Deerfield Company. | Pulmonary hypertension is a complex disease with multiple causes, corresponding to phenotypic heterogeneity and variable therapeutic responses. Advancing understanding of pulmonary hypertension pathogenesis is likely to hinge on integrated methods that leverage data from health records, imaging, novel molecular -omics profiling, and other modalities. In this review, we summarize key data sets generated thus far in the field and describe analytical methods that hold promise for deciphering the molecular mechanisms that underpin pulmonary vascular remodeling, including machine learning, network medicine, and functional genetics. We also detail how genetic and subphenotyping approaches enable earlier diagnosis, refined prognostication, and optimized treatment prediction. We propose strategies that identify functionally important molecular pathways, bolstered by findings across multi-omics platforms, which are well-positioned to individualize drug therapy selection and advance precision medicine in this highly morbid disease. | Rhodes, Christopher J Sweatt, Andrew J Maron, Bradley A eng K23 HL151892/HL/NHLBI NIH HHS/ R01 HL139613/HL/NHLBI NIH HHS/ R01 HL153502/HL/NHLBI NIH HHS/ R01 HL155096/HL/NHLBI NIH HHS/ FS/15/59/31839/BHF_/British Heart Foundation/United Kingdom Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Review Circ Res. 2022 Apr 29;130(9):1423-1444. doi: 10.1161/CIRCRESAHA.121.319969. Epub 2022 Apr 28.I | 04/29/2022 | |
| Multiomics analysis of rheumatoid arthritis yields sequence variants that have large effects on risk of the seropositive subset | Saevarsdottir S, et al. | 2022 | Ann Rheum Dis | 81 | 8 | 1085-1095 | https://www.doi.org/10.1136/annrheumdis-2021-221754 | 35,470,158 | *Arthritis, Rheumatoid/genetics Genetic Predisposition to Disease/genetics *Genome-Wide Association Study Humans Interferon-alpha Janus Kinases/genetics Protein Tyrosine Phosphatase, Non-Receptor Type 22/genetics Proteomics STAT Transcription Factors/genetics Signal Transduction/genetics autoantibodies polymorphism, genetic rheumatoid arthritis competing financial interests as employees. OAA is a consultant to HealthLytix. The following coauthors report the following but unrelated to the current report: Karolinska Institutet, with JA as principal investigator, has entered into agreements with the following entities, mainly but not exclusively for safety monitoring of rheumatology immunomodulators: Abbvie, BMS, Eli Lilly, Janssen, MSD, Pfizer, Roche, Samsung Bioepis and Sanofi, unrelated to the present study. SB has ownerships in Intomics A/S, Hoba Therapeutics Aps, Novo Nordisk A/S, Lundbeck A/S and managing board memberships in Proscion A/S and Intomics A/S. BG has received research grants from AbbVie, Bristol Myers-Squibb and Pfizer OH has received research grants from AbbVie, Novartis and Pfizer, DVJ has received speaker and consultation fees from AbbVie, Janssen, Lilly, MSD, Novartis, Pfizer, Roche and UCB, AGL has received speaking and/or consulting fees from AbbVie, Janssen, Lilly, MSD, Novartis, Pfizer, Roche and UCB and CT has received consulting fees from Roche, speaker fees from Abbvie, Bristol Myers-Squibb, Nordic Drugs, Pfizer and Roche, and an unrestricted grant from Bristol Myers-Squibb. | OBJECTIVES: To find causal genes for rheumatoid arthritis (RA) and its seropositive (RF and/or ACPA positive) and seronegative subsets. METHODS: We performed a genome-wide association study (GWAS) of 31 313 RA cases (68% seropositive) and ~1 million controls from Northwestern Europe. We searched for causal genes outside the HLA-locus through effect on coding, mRNA expression in several tissues and/or levels of plasma proteins (SomaScan) and did network analysis (Qiagen). RESULTS: We found 25 sequence variants for RA overall, 33 for seropositive and 2 for seronegative RA, altogether 37 sequence variants at 34 non-HLA loci, of which 15 are novel. Genomic, transcriptomic and proteomic analysis of these yielded 25 causal genes in seropositive RA and additional two overall. Most encode proteins in the network of interferon-alpha/beta and IL-12/23 that signal through the JAK/STAT-pathway. Highlighting those with largest effect on seropositive RA, a rare missense variant in STAT4 (rs140675301-A) that is independent of reported non-coding STAT4-variants, increases the risk of seropositive RA 2.27-fold (p=2.1x10(-9)), more than the rs2476601-A missense variant in PTPN22 (OR=1.59, p=1.3x10(-160)). STAT4 rs140675301-A replaces hydrophilic glutamic acid with hydrophobic valine (Glu128Val) in a conserved, surface-exposed loop. A stop-mutation (rs76428106-C) in FLT3 increases seropositive RA risk (OR=1.35, p=6.6x10(-11)). Independent missense variants in TYK2 (rs34536443-C, rs12720356-C, rs35018800-A, latter two novel) associate with decreased risk of seropositive RA (ORs=0.63-0.87, p=10(-9)-10(-27)) and decreased plasma levels of interferon-alpha/beta receptor 1 that signals through TYK2/JAK1/STAT4. CONCLUSION: Sequence variants pointing to causal genes in the JAK/STAT pathway have largest effect on seropositive RA, while associations with seronegative RA remain scarce. | Saevarsdottir, Saedis Stefansdottir, Lilja Sulem, Patrick Thorleifsson, Gudmar Ferkingstad, Egil Rutsdottir, Gudrun Glintborg, Bente Westerlind, Helga Grondal, Gerdur Loft, Isabella C Sorensen, Signe Bek Lie, Benedicte A Brink, Mikael Arlestig, Lisbeth Arnthorsson, Asgeir Orn Baecklund, Eva Banasik, Karina Bank, Steffen Bjorkman, Lena I Ellingsen, Torkell Erikstrup, Christian Frei, Oleksandr Gjertsson, Inger Gudbjartsson, Daniel F Gudjonsson, Sigurjon A Halldorsson, Gisli H Hendricks, Oliver Hillert, Jan Hogdall, Estrid Jacobsen, Soren Jensen, Dorte Vendelbo Jonsson, Helgi Kastbom, Alf Kockum, Ingrid Kristensen, Salome Kristjansdottir, Helga Larsen, Margit H Linauskas, Asta Hauge, Ellen-Margrethe Loft, Anne G Ludviksson, Bjorn R Lund, Sigrun H Markusson, Thorsteinn Masson, Gisli Melsted, Pall Moore, Kristjan H S Munk, Heidi Nielsen, Kaspar R Norddahl, Gudmundur L Oddsson, Asmundur Olafsdottir, Thorunn A Olason, Pall I Olsson, Tomas Ostrowski, Sisse Rye Horslev-Petersen, Kim Rognvaldsson, Solvi Sanner, Helga Silberberg, Gilad N Stefansson, Hreinn Sorensen, Erik Sorensen, Inge J Turesson, Carl Bergman, Thomas Alfredsson, Lars Kvien, Tore K Brunak, Soren Steinsson, Kristjan Andersen, Vibeke Andreassen, Ole A Rantapaa-Dahlqvist, Solbritt Hetland, Merete Lund Klareskog, Lars Askling, Johan Padyukov, Leonid Pedersen, Ole Bv Thorsteinsdottir, Unnur Jonsdottir, Ingileif Stefansson, Kari (SRQb) eng Research Support, Non-U.S. Gov't England Ann Rheum Dis. 2022 Aug;81(8):1085-1095. doi: 10.1136/annrheumdis-2021-221754. Epub 2022 Apr 25.I | 04/27/2022 | |
| Proteomics of human biological fluids for biomarker discoveries: technical advances and recent applications | Dayon L, et al. | 2022 | Expert Rev Proteomics | 19 | 2 | 131-151 | https://www.doi.org/10.1080/14789450.2022.2070477 | 35,466,824 | Biomarkers/metabolism *Body Fluids/metabolism Humans Proteome/metabolism *Proteomics/methods Automation Ms biofluid biomarker cohort human mass spectrometry plasma proteomics | INTRODUCTION: Biological fluids are routine samples for diagnostic testing and monitoring. Blood samples are typically measured because of their moderate invasive collection and high information content on health and disease. Several body fluids, such as cerebrospinal fluid (CSF), are also studied and suited to specific pathologies. Over the last two decades, proteomics has quested to identify protein biomarkers but with limited success. Recent technologies and refined pipelines have accelerated the profiling of human biological fluids. AREAS COVERED: We review proteomic technologies for the identification of biomarkers. These are based on antibodies/aptamers arrays or mass spectrometry (MS), but new ones are emerging. Advances in scalability and throughput have allowed to better design studies and cope with the limited sample size that has until now prevailed due to technological constraints. With these enablers, plasma/serum, CSF, saliva, tears, urine, and milk proteomes have been further profiled; we provide a non-exhaustive picture of some recent highlights (mainly covering literature from the last 5 years in the Scopus database) using MS-based proteomics. EXPERT OPINION: While proteomics has been in the shadow of genomics for years, proteomic tools and methodologies have reached certain maturity. They are now better suited to discover innovative and robust biofluid biomarkers. | Dayon, Loic Cominetti, Ornella Affolter, Michael eng Research Support, Non-U.S. Gov't Review England Expert Rev Proteomics. 2022 Feb;19(2):131-151. doi: 10.1080/14789450.2022.2070477. Epub 2022 May 5.I | 04/26/2022 | |
| Identifying causal genes for stroke via integrating the proteome and transcriptome from brain and blood | Wu BS, et al. | 2022 | J Transl Med | 20 | 1 | 181 | https://www.doi.org/10.1186/s12967-022-03377-9 | 35,449,099 | Bayes Theorem Brain/metabolism Genetic Predisposition to Disease *Genome-Wide Association Study Humans Polymorphism, Single Nucleotide/genetics Proteome/genetics/metabolism *Stroke/complications Transcriptome/genetics Bayesian colocalization Mendelian randomization Proteome-wide association study Stroke Transcriptome-wide association study | BACKGROUND: Genome-wide association studies (GWAS) have revealed numerous loci associated with stroke. However, the underlying mechanisms at these loci in the pathogenesis of stroke and effective stroke drug targets are elusive. Therefore, we aimed to identify causal genes in the pathogenesis of stroke and its subtypes. METHODS: Utilizing multidimensional high-throughput data generated, we integrated proteome-wide association study (PWAS), transcriptome-wide association study (TWAS), Mendelian randomization (MR), and Bayesian colocalization analysis to prioritize genes that contribute to stroke and its subtypes risk via affecting their expression and protein abundance in brain and blood. RESULTS: Our integrative analysis revealed that ICA1L was associated with small-vessel stroke (SVS), according to robust evidence at both protein and transcriptional levels based on brain-derived data. We also identified NBEAL1 that was causally related to SVS via its cis-regulated brain expression level. In blood, we identified 5 genes (MMP12, SCARF1, ABO, F11, and CKAP2) that had causal relationships with stroke and stroke subtypes. CONCLUSIONS: Together, via using an integrative analysis to deal with multidimensional data, we prioritized causal genes in the pathogenesis of SVS, which offered hints for future biological and therapeutic studies. | Wu, Bang-Sheng Chen, Shu-Fen Huang, Shu-Yi Ou, Ya-Nan Deng, Yue-Ting Chen, Shi-Dong Dong, Qiang Yu, Jin-Tai eng Research Support, Non-U.S. Gov't England J Transl Med. 2022 Apr 21;20(1):181. doi: 10.1186/s12967-022-03377-9.I | 04/23/2022 | |
| Effects of ivacaftor on systemic inflammation and the plasma proteome in people with CF and G551D | Hoppe JE, et al. | 2022 | J Cyst Fibros | epub ahead of print | https://www.doi.org/10.1016/j.jcf.2022.03.012 | 35,440,409 | CFTR modulation Extrapulmonary Inflammation Proteomics Foundation, outside the submitted work, SMR reports grants, personal fees, non-financial support and other from Vertex Pharmaceuticals Inc., during the conduct of the study grants and personal fees from Novartis, grants and personal fees from Bayer, grants from Translate Bio, non-financial support from Proteostasis, grants, personal fees and non-financial support from Galapagos/Abbvie, grants, personal fees and other from Synedgen/Synspira, grants from Eloxx, grants and personal fees from Celtaxsys, grants, personal fees, non-financial support and other from Vertex Pharmaceuticals Inc, personal fees from Renovion, grants and personal fees from Arrowhead, grants and other from Ionis, grants from Astra Zenica, personal fees from Cystetic Medicines, personal fees from Arcturus, outside the submitted work EMD reports other from EvoEndoscopy (formerly Triple Endoscopy), outside the submitted work and is a consultant for Boehringer Ingelheim, not related to this work. SDS reports grants from the Cystic Fibrosis Foundation that funds the work under consideration, and grants from the Cystic Fibrosis Foundation and National Institutes of Health funding activities outside the submitted work. BDW, JKH and SLH have nothing to disclose. | BACKGROUND: Ivacaftor is a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator for people with CF and the G551D mutation. We aimed to investigate the biology of CFTR modulation and systemic effects of CFTR restoration by examining changes in circulating measurements of inflammation and growth and novel proteins with ivacaftor treatment. METHODS: Blood samples from 64 CF subjects with G551D-CFTR were analyzed for inflammatory and growth-related proteins at baseline, 1 and 6 months after ivacaftor initiation. In 30 subjects, plasma was assayed for 1,322 proteins using the SomaScan proteomic platform at baseline and 6 months post-ivacaftor. Correlations with clinical outcomes were assessed. MEASUREMENTS AND MAIN RESULTS: Significant reductions in high mobility group box-1 protein (HMGB-1), calprotectin, serum amyloid A, and granulocyte colony-stimulating factor (G-CSF), and an increase in insulin-like growth factor (IGF-1) occurred 1 month after ivacaftor. This treatment effect was sustained at 6 months for HMGB-1 and calprotectin. Correcting for multiple comparisons in the proteomic analysis, 9 proteins (albumin, afamin, leptin, trypsin, pancreatic stone protein [PSP], pituitary adenylate cyclase-activating polypeptide-38, repulsive guidance molecule A [RGMA], calreticulin, GTPase KRas) changed significantly with ivacaftor. Proteins changing with treatment are involved in lipid digestion and transport and extracellular matrix organization biological processes. Reductions in calprotectin and G-CSF and increases in calreticulin, and RGMA correlated with improved lung function, while increasing IGF-1, leptin and afamin and decreasing PSP correlated with increased weight. CONCLUSIONS: Ivacaftor led to changes in inflammatory, lipid digestion, and extracellular matrix proteins, lending insights into the extrapulmonary effects of CFTR modulation. | Hoppe, Jordana E Wagner, Brandie D Kirk Harris, J Rowe, Steven M Heltshe, Sonya L DeBoer, Emily M Sagel, Scott D eng P30 DK072482/DK/NIDDK NIH HHS/ P30 DK089507/DK/NIDDK NIH HHS/ UL1 TR002535/TR/NCATS NIH HHS/ UL1 TR003096/TR/NCATS NIH HHS/ Netherlands J Cyst Fibros. 2022 Apr 16:S1569-1993(22)00089-3. doi: 10.1016/j.jcf.2022.03.012.I | 04/21/2022 | |||
| The Proteomic Profile of Interstitial Lung Abnormalities | Axelsson GT, et al. | 2022 | Am J Respir Crit Care Med | 206 | 3 | 337-346 | https://www.doi.org/10.1164/rccm.202110-2296OC | 35,438,610 | Genetic Predisposition to Disease Humans Lung *Lung Diseases, Interstitial/epidemiology/genetics Prospective Studies Proteomics *Respiratory System Abnormalities Tomography, X-Ray Computed biomarkers idiopathic pulmonary fibrosis interstitial lung abnormalities interstitial lung disease | Rationale: Knowledge on biomarkers of interstitial lung disease is incomplete. Interstitial lung abnormalities (ILAs) are radiologic changes that may present in its early stages. Objectives: To uncover blood proteins associated with ILAs using large-scale proteomics methods. Methods: Data from two prospective cohort studies, the AGES-Reykjavik (Age, Gene/Environment Susceptibility-Reykjavik) study (N = 5,259) for biomarker discovery and the COPDGene (Genetic Epidemiology of COPD) study (N = 4,899) for replication, were used. Blood proteins were measured using DNA aptamers, targeting more than 4,700 protein analytes. The association of proteins with ILAs and ILA progression was assessed with regression modeling, as were associations with genetic risk factors. Adaptive Least Absolute Shrinkage and Selection Operator models were applied to bootstrap data samples to discover sets of proteins predictive of ILAs and their progression. Measurements and Main Results: Of 287 associations, SFTPB (surfactant protein B) (odds ratio [OR], 3.71 [95% confidence interval (CI), 3.20-4.30]; P = 4.28 x 10(-67)), SCGB3A1 (Secretoglobin family 3A member 1) (OR, 2.43 [95% CI, 2.13-2.77]; P = 8.01 x 10(-40)), and WFDC2 (WAP four-disulfide core domain protein 2) (OR, 2.42 [95% CI, 2.11-2.78]; P = 4.01 x 10(-36)) were most significantly associated with ILA in AGES-Reykjavik and were replicated in COPDGene. In AGES-Reykjavik, concentrations of SFTPB were associated with the rs35705950 MUC5B (mucin 5B) promoter polymorphism, and SFTPB and WFDC2 had the strongest associations with ILA progression. Multivariate models of ILAs in AGES-Reykjavik, ILAs in COPDGene, and ILA progression in AGES-Reykjavik had validated areas under the receiver operating characteristic curve of 0.880, 0.826, and 0.824, respectively. Conclusions: Novel, replicated associations of ILA, its progression, and genetic risk factors with numerous blood proteins are demonstrated as well as machine-learning-based models with favorable predictive potential. Several proteins are revealed as potential markers of early fibrotic lung disease. | Axelsson, Gisli Thor Gudmundsson, Gunnar Pratte, Katherine A Aspelund, Thor Putman, Rachel K Sanders, Jason L Gudmundsson, Elias F Hatabu, Hiroto Gudmundsdottir, Valborg Gudjonsson, Alexander Hino, Takuya Hida, Tomoyuki Hobbs, Brian D Cho, Michael H Silverman, Edwin K Bowler, Russell P Launer, Lenore J Jennings, Lori L Hunninghake, Gary M Emilsson, Valur Gudnason, Vilmundur eng R01CA203636/NH/NIH HHS/ R01 HL113264/NH/NIH HHS/ U01 HL089856/NH/NIH HHS/ R01 HL137927/NH/NIH HHS/ U01 HL089856/HL/NHLBI NIH HHS/ R01 HL137927/HL/NHLBI NIH HHS/ R01 HL129937/HL/NHLBI NIH HHS/ HHSN27120120022C/NH/NIH HHS/ R01 133135/NH/NIH HHS/ N01-AG-1-2100/NH/NIH HHS/ K08 HL136928/NH/NIH HHS/ 5U01CA209414-03/NH/NIH HHS/ R01 HL111024/NH/NIH HHS/ R01 HL152735/NH/NIH HHS/ P01 HL114501/NH/NIH HHS/ P50HL084948/HL/NHLBI NIH HHS/ R01 135142/NH/NIH HHS/ R01 137927/NH/NIH HHS/ R01 HL135142/NH/NIH HHS/ R21HL129917/HL/NHLBI NIH HHS/ K08 HL140087/NH/NIH HHS/ R01 HL137995/NH/NIH HHS/ R01 HL137995/HL/NHLBI NIH HHS/ U01 HL089897/HL/NHLBI NIH HHS/ R01 HL130974/NH/NIH HHS/ Research Support, N.I.H., Extramural Research Support, N.I.H., Intramural Research Support, Non-U.S. Gov't Am J Respir Crit Care Med. 2022 Aug 1;206(3):337-346. doi: 10.1164/rccm.202110-2296OC.I | 04/20/2022 | |
| Chemical Modifications for a Next Generation of Nucleic Acid Aptamers | Chan KY, et al. | 2022 | Chembiochem | 23 | 15 | e202200006 | https://www.doi.org/10.1002/cbic.202200006 | 35,416,400 | Antibodies *Aptamers, Nucleotide/metabolism Ligands *Nucleic Acids SELEX Aptamer Technique/methods Selex Xna aptamers chemical modifications nucleic acids | In the past three decades, in vitro systematic evolution of ligands by exponential enrichment (SELEX) has yielded many aptamers for translational applications in both research and clinical settings. Despite their promise as an alternative to antibodies, the low success rate of SELEX ( approximately 30 %) has been a major bottleneck that hampers the further development of aptamers. One hurdle is the lack of chemical diversity in nucleic acids. To address this, the aptamer chemical repertoire has been extended by introducing exotic chemical groups, which provide novel binding functionalities. This review will focus on how modified aptamers can be selected and evolved, with illustration of some successful examples. In particular, unique chemistries are exemplified. Various strategies of incorporating modified building blocks into the standard SELEX protocol are highlighted, with a comparison of the differences between pre-SELEX and post-SELEX modifications. Nucleic acid aptamers with extended functionality evolved from non-natural chemistries will open up new vistas for function and application of nucleic acids. | Chan, Kwing Yeung Kinghorn, Andrew Brian Hollenstein, Marcel Tanner, Julian Alexander eng Research Support, Non-U.S. Gov't Review Germany Chembiochem. 2022 Aug 3;23(15):e202200006. doi: 10.1002/cbic.202200006. Epub 2022 Apr 29.I | 04/14/2022 | |
| Severe iatrogenic hypoglycaemia modulates the fibroblast growth factor protein response | Nandakumar M, et al. | 2022 | Diabetes Obes Metab | 24 | 8 | 1483-1497 | https://www.doi.org/10.1111/dom.14716 | 35,415,885 | Case-Control Studies *Diabetes Mellitus, Type 2 *Fibroblast Growth Factors/metabolism Humans *Hypoglycemia/chemically induced/complications Iatrogenic Disease fibroblast growth factors hypoglycaemia proteomics type 2 diabetes | INTRODUCTION: There is evidence that fibroblast growth factor (FGF) levels may be implicated in hypoglycaemia, with FGF19 being a potential contributor to insulin-independent pathways driving postprandial hypoglycaemia following bariatric surgery and basic FGF (FGF2) being elevated following mild hypoglycaemia occurring after the glucose tolerance test. However, their response following severe iatrogenic hypoglycaemia is unknown and therefore this pilot exploratory study was undertaken. METHODS: A case-control study of aged-matched type 2 diabetes (T2D; n = 23) and control (n = 23) subjects who underwent a hyperinsulinaemic clamp, initially to euglycaemia in T2D (5 mmol/L; 90 mg/dl), and then to hypoglycaemia (<2 mmol/L; <36 mg/dl) with subsequent follow-up time course to 24 h. FGF and FGF receptor proteins were determined by Slow Off-rate Modified Aptamer (SOMA)-scan plasma protein measurement. RESULTS: At baseline, FGF12 (p = .006) was higher and FGF20 (p = .004) was lower in T2D versus controls. At hypoglycaemia, FGF7 was lower in T2D. Post-hypoglycaemic levels of FGF18, FGF19, FGF20 and FGF23 were lower while FGF12 and FGF16 were higher in T2D versus control at different time points. No differences between T2D and controls were seen for FGF1, FGF2, FGF4, FGF6, FGF8, FGF9, FGF10, FGF21 or any of the FGF receptors. At 24 h post-hypoglycaemia, FGF20 (p = .01) differed between controls and T2D, while the levels for the other proteins measured returned to baseline. None of the FGF proteins altered from baseline to euglycaemia when clamped in T2D subjects. FGF23 negatively correlated with fasting blood glucose, but no FGFs correlated with body mass index in T2D. CONCLUSION: Severe transient hypoglycaemia modulated FGF7, 16, 19, 20 and 23 (known to be associated with diabetes), together with FGF18 and 12, not previously reported to be associated with diabetes but that may be important in the pathophysiology of hypoglycaemia; FGF20 remained low at 24 h. Taken together, these data suggest that recurrent hypoglycaemia may contribute to the development of complications through changes in FGF proteins. | Nandakumar, Manjula Moin, Abu Saleh Md Ramanjaneya, Manjunath Qaissi, Ahmed Al Sathyapalan, Thozhukat Atkin, Stephen L Butler, Alexandra E eng England Diabetes Obes Metab. 2022 Aug;24(8):1483-1497. doi: 10.1111/dom.14716. Epub 2022 May 3.I | 04/14/2022 | |
| Epidermal growth factor receptor signaling in precancerous keratinocytes promotes neighboring head and neck cancer squamous cell carcinoma cancer stem cell-like properties and phosphoinositide 3-kinase inhibitor insensitivity | Nguyen KA, et al. | 2022 | Mol Carcinog | 61 | 7 | 664-676 | https://www.doi.org/10.1002/mc.23409 | 35,417,043 | *Carcinoma, Squamous Cell/genetics Cell Line, Tumor ErbB Receptors/metabolism *Head and Neck Neoplasms/drug therapy Humans Keratinocytes/metabolism Neoplastic Stem Cells/pathology Phosphatidylinositol 3-Kinase/metabolism Phosphatidylinositol 3-Kinases/metabolism Phosphoinositide-3 Kinase Inhibitors *Precancerous Conditions Receptors, Fibroblast Growth Factor Squamous Cell Carcinoma of Head and Neck/drug therapy Tumor Microenvironment Egfr Hnscc Pi3k cancer stem cell resistance squamous cell carcinoma | Head and neck squamous cell carcinoma (HNSCC) is commonly associated with tobacco and alcohol consumption that induce a precancerous field," with phosphoinositide 3-kinase (PI3K) signaling being a common driver. However, the preclinical effectiveness of PI3K inhibitors has not necessarily translated to remarkable benefit in HNSCC patients. Thus, we sought to determine how precancerous keratinocytes influence HNSCC proliferation, cancer stem cell (CSC) maintenance, and response to PI3K inhibitors. We used the NOK keratinocyte cell line as a model of preneoplastic keratinocytes because it harbors two frequent genetic events in HNSCC, CDKN2A promoter methylation and TP53 mutation, but does not form tumors. NOK cell coculture or NOK cell-conditioned media promoted HNSCC proliferation, PI3K inhibitor resistance, and CSC phenotypes. SOMAscan-targeted proteomics determined the relative levels of >1300 analytes in the media conditioned by NOK cells and HNSCC cells +/- PI3K inhibitor. These results demonstrated that NOK cells release abundant levels of ligands that activate epidermal growth factor receptor (EGFR) and fibroblast growth factor receptor (FGFR), two receptor tyrosine kinases with oncogenic activity. Inhibition of EGFR, but not FGFR, blunted PI3K inhibitor resistance and CSC phenotypes induced by NOK cells. Our results demonstrate that precancerous keratinocytes can directly support neighboring HNSCC by activating EGFR. Importantly, PI3K inhibitor sensitivity was not necessarily a cancer cell-intrinsic property, and the tumor microenvironment impacts therapeutic response and supports CSCs. Additionally, combined inhibition of EGFR with PI3K inhibitor diminished EGFR activation induced by PI3K inhibitor and potently inhibited cancer cell proliferation and CSC maintenance." | Nguyen, Khoa A Keith, Madison J Keysar, Stephen B Hall, Spencer C Bimali, Anamol Jimeno, Antonio Wang, Xiao-Jing Young, Christian D eng P50 CA261605/CA/NCI NIH HHS/ R01 DE024371/DE/NIDCR NIH HHS/ I01 BX003232/BX/BLRD VA/ IK6 BX005962/BX/BLRD VA/ P30 CA046934/CA/NCI NIH HHS/ R01 DE028420/DE/NIDCR NIH HHS/ R01 DE027329/DE/NIDCR NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. Mol Carcinog. 2022 Jul;61(7):664-676. doi: 10.1002/mc.23409. Epub 2022 Apr 13.I | 04/14/2022 | |
| Ad26.COV2.S prevents upregulation of SARS-CoV-2 induced pathways of inflammation and thrombosis in hamsters and rhesus macaques | Aid M, et al. | 2022 | PLoS Pathog | 18 | 4 | e1009990 | https://www.doi.org/10.1371/journal.ppat.1009990 | 35,395,058 | Ad26COVS1 Animals Antibodies, Neutralizing *covid-19 COVID-19 Vaccines Cricetinae Humans Inflammation Macaca mulatta SARS-CoV-2 Spike Glycoprotein, Coronavirus *Thrombosis Up-Regulation | Syrian golden hamsters exhibit features of severe disease after SARS-CoV-2 WA1/2020 challenge and are therefore useful models of COVID-19 pathogenesis and prevention with vaccines. Recent studies have shown that SARS-CoV-2 infection stimulates type I interferon, myeloid, and inflammatory signatures similar to human disease and that weight loss can be prevented with vaccines. However, the impact of vaccination on transcriptional programs associated with COVID-19 pathogenesis and protective adaptive immune responses is unknown. Here we show that SARS-CoV-2 WA1/2020 challenge in hamsters stimulates myeloid and inflammatory programs as well as signatures of complement and thrombosis associated with human COVID-19. Notably, immunization with Ad26.COV2.S, an adenovirus serotype 26 vector (Ad26)-based vaccine expressing a stabilized SARS-CoV-2 spike protein, prevents the upregulation of these pathways, such that the mRNA expression profiles of vaccinated hamsters are comparable to uninfected animals. Using proteomics profiling, we validated these findings in rhesus macaques challenged with SARS-CoV-2 WA1/2020 or SARS-CoV-2 B.1.351. Finally, we show that Ad26.COV2.S vaccination induces T and B cell signatures that correlate with binding and neutralizing antibody responses weeks following vaccination. These data provide insights into the molecular mechanisms of Ad26.COV2.S protection against severe COVID-19 in animal models. | Aid, Malika Vidal, Samuel J Piedra-Mora, Cesar Ducat, Sarah Chan, Chi N Bondoc, Stephen Colarusso, Alessandro Starke, Carly E Nekorchuk, Michael Busman-Sahay, Kathleen Estes, Jacob D Martinot, Amanda J Barouch, Dan H eng P51 OD011092/OD/NIH HHS/ Research Support, Non-U.S. Gov't PLoS Pathog. 2022 Apr 8;18(4):e1009990. doi: 10.1371/journal.ppat.1009990. eCollection 2022 Apr.I | 04/09/2022 | |
| Mining the Plasma Proteome for Insights into the Molecular Pathology of Pulmonary Arterial Hypertension | Harbaum L, et al. | 2022 | Am J Respir Crit Care Med | 205 | 12 | 1449-1460 | https://www.doi.org/10.1164/rccm.202109-2106OC | 35,394,406 | Blood Proteins/genetics Familial Primary Pulmonary Hypertension Humans *Hypertension, Pulmonary Netrins Pathology, Molecular Proteome *Pulmonary Arterial Hypertension Thrombospondins Mendelian randomization case-control studies genome protein quantitative trait loci | Rationale: Pulmonary arterial hypertension (PAH) is characterized by structural remodeling of pulmonary arteries and arterioles. Underlying biological processes are likely reflected in a perturbation of circulating proteins. Objectives: To quantify and analyze the plasma proteome of patients with PAH using inherited genetic variation to inform on underlying molecular drivers. Methods: An aptamer-based assay was used to measure plasma proteins in 357 patients with idiopathic or heritable PAH, 103 healthy volunteers, and 23 relatives of patients with PAH. In discovery and replication subgroups, the plasma proteomes of PAH and healthy individuals were compared, and the relationship to transplantation-free survival in PAH was determined. To examine causal relationships to PAH, protein quantitative trait loci (pQTL) that influenced protein levels in the patient population were used as instruments for Mendelian randomization (MR) analysis. Measurements and Main Results: From 4,152 annotated plasma proteins, levels of 208 differed between patients with PAH and healthy subjects, and 49 predicted long-term survival. MR based on cis-pQTL located in proximity to the encoding gene for proteins that were prognostic and distinguished PAH from health estimated an adverse effect for higher levels of netrin-4 (odds ratio [OR], 1.55; 95% confidence interval [CI], 1.16-2.08) and a protective effect for higher levels of thrombospondin-2 (OR, 0.83; 95% CI, 0.74-0.94) on PAH. Both proteins tracked the development of PAH in previously healthy relatives and changes in thrombospondin-2 associated with pulmonary arterial pressure at disease onset. Conclusions: Integrated analysis of the plasma proteome and genome implicates two secreted matrix-binding proteins, netrin-4 and thrombospondin-2, in the pathobiology of PAH. | Harbaum, Lars Rhodes, Christopher J Wharton, John Lawrie, Allan Karnes, Jason H Desai, Ankit A Nichols, William C Humbert, Marc Montani, David Girerd, Barbara Sitbon, Olivier Boehm, Mario Novoyatleva, Tatyana Schermuly, Ralph T Ghofrani, H Ardeschir Toshner, Mark Kiely, David G Howard, Luke S Swietlik, Emilia M Graf, Stefan Pietzner, Maik Morrell, Nicholas W Wilkins, Martin R eng R01HL158686/NIH/NHLBI/ R01 HL156993/HL/NHLBI NIH HHS/ FS/13/48/30453/BHF_/British Heart Foundation/United Kingdom FS/15/59/31839/BHF_/British Heart Foundation/United Kingdom R24 HL105333/HL/NHLBI NIH HHS/ SP/12/12/29836/BHF_/British Heart Foundation/United Kingdom K01HL143137/NIH/NHLBI/ R01 HL158686/HL/NHLBI NIH HHS/ RE/18/4/34215/BHF_/British Heart Foundation/United Kingdom R01 HL136603/HL/NHLBI NIH HHS/ MR/K020919/1/MRC_/Medical Research Council/United Kingdom DH_/Department of Health/United Kingdom FS/18/52/33808/BHF_/British Heart Foundation/United Kingdom Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Am J Respir Crit Care Med. 2022 Jun 15;205(12):1449-1460. doi: 10.1164/rccm.202109-2106OC.I | 04/09/2022 | |
| Patterns and Persistence of Perioperative Plasma and Cerebrospinal Fluid Neuroinflammatory Protein Biomarkers After Elective Orthopedic Surgery Using SOMAscan | Dillon ST, et al. | 2022 | Anesth Analg | epub ahead of print | https://www.doi.org/10.1213/ANE.0000000000005991 | 35,389,379 | BACKGROUND: The neuroinflammatory response to surgery can be characterized by peripheral acute plasma protein changes in blood, but corresponding, persisting alterations in cerebrospinal fluid (CSF) proteins remain mostly unknown. Using the SOMAscan assay, we define acute and longer-term proteome changes associated with surgery in plasma and CSF. We hypothesized that biological pathways identified by these proteins would be in the categories of neuroinflammation and neuronal function and define neuroinflammatory proteome changes associated with surgery in older patients. METHODS: SOMAscan analyzed 1305 proteins in blood plasma (n = 14) and CSF (n = 15) samples from older patients enrolled in the Role of Inflammation after Surgery for Elders (RISE) study undergoing elective hip and knee replacement surgery with spinal anesthesia. Systems biology analysis identified biological pathways enriched among the surgery-associated differentially expressed proteins in plasma and CSF. RESULTS: Comparison of postoperative day 1 (POD1) to preoperative (PREOP) plasma protein levels identified 343 proteins with postsurgical changes (P < .05; absolute value of the fold change [|FC|] > 1.2). Comparing postoperative 1-month (PO1MO) plasma and CSF with PREOP identified 67 proteins in plasma and 79 proteins in CSF with altered levels (P < .05; |FC| > 1.2). In plasma, 21 proteins, primarily linked to immune response and inflammation, were similarly changed at POD1 and PO1MO. Comparison of plasma to CSF at PO1MO identified 8 shared proteins. Comparison of plasma at POD1 to CSF at PO1MO identified a larger number, 15 proteins in common, most of which are regulated by interleukin-6 (IL-6) or transforming growth factor beta-1 (TGFB1) and linked to the inflammatory response. Of the 79 CSF PO1MO-specific proteins, many are involved in neuronal function and neuroinflammation. CONCLUSIONS: SOMAscan can characterize both short- and long-term surgery-induced protein alterations in plasma and CSF. Acute plasma protein changes at POD1 parallel changes in PO1MO CSF and suggest 15 potential biomarkers for longer-term neuroinflammation that warrant further investigation. | Dillon, Simon T Otu, Hasan H Ngo, Long H Fong, Tamara G Vasunilashorn, Sarinnapha M Xie, Zhongcong Kunze, Lisa J Vlassakov, Kamen V Abdeen, Ayesha Lange, Jeffrey K Earp, Brandon E Cooper, Zara R Schmitt, Eva M Arnold, Steven E Hshieh, Tammy T Jones, Richard N Inouye, Sharon K Marcantonio, Edward R Libermann, Towia A eng R01 AG051658/AG/NIA NIH HHS/ R03 AG061582/AG/NIA NIH HHS/ K24 AG035075/AG/NIA NIH HHS/ K01 AG057836/AG/NIA NIH HHS/ P01 AG031720/AG/NIA NIH HHS/ R21 AG057955/AG/NIA NIH HHS/ R24 AG054259/AG/NIA NIH HHS/ Anesth Analg. 2022 Apr 7:10.1213/ANE.0000000000005991. doi: 10.1213/ANE.0000000000005991.I | 04/08/2022 | ||||
| A proteomic surrogate for cardiovascular outcomes that is sensitive to multiple mechanisms of change in risk | Williams SA, et al. | 2022 | Sci Transl Med | 14 | 639 | eabj9625 | https://www.doi.org/10.1126/scitranslmed.abj9625 | 35,385,337 | Biomarkers *Cardiovascular Diseases *Heart Failure/drug therapy Humans *Myocardial Infarction/drug therapy Proteomics *Stroke/complications | A reliable, individualized, and dynamic surrogate of cardiovascular risk, synoptic for key biologic mechanisms, could shorten the path for drug development, enhance drug cost-effectiveness and improve patient outcomes. We used highly multiplexed proteomics to address these objectives, measuring about 5000 proteins in each of 32,130 archived plasma samples from 22,849 participants in nine clinical studies. We used machine learning to derive a 27-protein model predicting 4-year likelihood of myocardial infarction, stroke, heart failure, or death. The 27 proteins encompassed 10 biologic systems, and 12 were associated with relevant causal genetic traits. We independently validated results in 11,609 participants. Compared to a clinical model, the ratio of observed events in quintile 5 to quintile 1 was 6.7 for proteins versus 2.9 for the clinical model, AUCs (95% CI) were 0.73 (0.72 to 0.74) versus 0.64 (0.62 to 0.65), c-statistics were 0.71 (0.69 to 0.72) versus 0.62 (0.60 to 0.63), and the net reclassification index was +0.43. Adding the clinical model to the proteins only improved discrimination metrics by 0.01 to 0.02. Event rates in four predefined protein risk categories were 5.6, 11.2, 20.0, and 43.4% within 4 years; median time to event was 1.71 years. Protein predictions were directionally concordant with changed outcomes. Adverse risks were predicted for aging, approaching an event, anthracycline chemotherapy, diabetes, smoking, rheumatoid arthritis, cancer history, cardiovascular disease, high systolic blood pressure, and lipids. Reduced risks were predicted for weight loss and exenatide. The 27-protein model has potential as a universal" surrogate end point for cardiovascular risk." | Williams, Stephen A Ostroff, Rachel Hinterberg, Michael A Coresh, Josef Ballantyne, Christie M Matsushita, Kunihiro Mueller, Christian E Walter, Joan Jonasson, Christian Holman, Rury R Shah, Svati H Sattar, Naveed Taylor, Roy Lean, Michael E Kato, Shintaro Shimokawa, Hiroaki Sakata, Yasuhiko Nochioka, Kotaro Parikh, Chirag R Coca, Steven G Omland, Torbjorn Chadwick, Jessica Astling, David Hagar, Yolanda Kureshi, Natasha Loupy, Kelsey Paterson, Clare Primus, Jeremy Simpson, Missy Trujillo, Nelson P Ganz, Peter eng R01 HL134320/HL/NHLBI NIH HHS/ HHSN268201700001I/HL/NHLBI NIH HHS/ HHSN268201700002I/HL/NHLBI NIH HHS/ HHSN268201700003I/HL/NHLBI NIH HHS/ HHSN268201700004I/HL/NHLBI NIH HHS/ HHSN268201700005I/HL/NHLBI NIH HHS/ R01 HL087641/HL/NHLBI NIH HHS/ R01 HL086694/HL/NHLBI NIH HHS/ U01 HG004402/HG/NHGRI NIH HHS/ R01 HL085757/HL/NHLBI NIH HHS/ U01 DK106962/DK/NIDDK NIH HHS/ R01 HL129856/HL/NHLBI NIH HHS/ U01 DK108809/DK/NIDDK NIH HHS/ R01 AG052964/AG/NIA NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Sci Transl Med. 2022 Apr 6;14(639):eabj9625. doi: 10.1126/scitranslmed.abj9625. Epub 2022 Apr 6.I | 04/07/2022 | |
| Diagnostic Accuracy of Blood-Based Biomarker Panels: A Systematic Review | Hardy-Sosa A, et al. | 2022 | Front Aging Neurosci | 14 | 683689 | https://www.doi.org/10.3389/fnagi.2022.683689 | 35,360,215 | Alzheimer's disease (AD) biomarker panel blood-based biomarker diagnosis preclinical AD commercial or financial relationships that could be construed as a potential conflict of interest. | BACKGROUND: Because of high prevalence of Alzheimer's disease (AD) in low- and middle-income countries (LMICs), there is an urgent need for inexpensive and minimally invasive diagnostic tests to detect biomarkers in the earliest and asymptomatic stages of the disease. Blood-based biomarkers are predicted to have the most impact for use as a screening tool and predict the onset of AD, especially in LMICs. Furthermore, it has been suggested that panels of markers may perform better than single protein candidates. METHODS: Medline/Pubmed was searched to identify current relevant studies published from January 2016 to December 2020. We included all full-text articles examining blood-based biomarkers as a set of protein markers or panels to aid in AD's early diagnosis, prognosis, and characterization. RESULTS: Seventy-six articles met the inclusion criteria for systematic review. Majority of the studies reported plasma and serum as the main source for biomarker determination in blood. Protein-based biomarker panels were reported to aid in AD diagnosis and prognosis with better accuracy than individual biomarkers. Conventional (amyloid-beta and tau) and neuroinflammatory biomarkers, such as amyloid beta-42, amyloid beta-40, total tau, phosphorylated tau-181, and other tau isoforms, were the most represented. We found the combination of amyloid beta-42/amyloid beta-40 ratio and APOEepsilon4 status to be most represented with high accuracy for predicting amyloid beta-positron emission tomography status. CONCLUSION: Assessment of Alzheimer's disease biomarkers in blood as a non-invasive and cost-effective alternative will potentially contribute to early diagnosis and improvement of therapeutic interventions. Given the heterogeneous nature of AD, combination of markers seems to perform better in the diagnosis and prognosis of the disease than individual biomarkers. | Hardy-Sosa, Anette Leon-Arcia, Karen Llibre-Guerra, Jorge J Berlanga-Acosta, Jorge Baez, Saiyet de la C Guillen-Nieto, Gerardo Valdes-Sosa, Pedro A eng Switzerland Front Aging Neurosci. 2022 Mar 11;14:683689. doi: 10.3389/fnagi.2022.683689. eCollection 2022.I | 04/02/2022 | ||
| Acceptability and experience of a personalised proteomic risk intervention for type 2 diabetes in primary care: qualitative interview study with patients and healthcare providers | Honey S, et al. | 2022 | Prim Health Care Res Dev | 23 | e24 | https://www.doi.org/10.1017/S1463423621000591 | 35,361,303 | *Diabetes Mellitus, Type 2/prevention & control Health Personnel Humans Primary Health Care Proteomics Qualitative Research behaviour change pre-diabetes proteomic risk assessment type 2 diabetes | AIM: We explored the acceptability of a personalised proteomic risk intervention for patients at increased risk of type 2 diabetes and their healthcare providers, as well as their experience of participating in the delivery of proteomic-based risk feedback in UK primary care. BACKGROUND: Advances in proteomics now allow the provision of personalised proteomic risk reports, with the intention of achieving positive behaviour change. This technology has the potential to encourage behaviour change in people at risk of developing type 2 diabetes. METHODS: A semi-structured interview study was carried out with patients at risk of type 2 diabetes and their healthcare providers in primary care in the North of England. Participants (n = 17) and healthcare provider (n = 4) were interviewed either face to face or via telephone. Data were analysed using thematic analysis. This qualitative study was nested within a single-arm pilot trial and undertaken in primary care. FINDINGS: The personalised proteomic risk intervention was generally acceptable and the experience was positive. The personalised nature of the report was welcomed, especially the way it provided a holistic approach to risks of organ damage and lifestyle factors. Insights were provided as to how this may change behaviour. Some participants reported difficulties in understanding the format of the presentation of risk and expressed surprise at receiving risk estimates for conditions other than type 2 diabetes. Personalised proteomic risk interventions have the potential to provide holistic and comprehensive assessments of risk factors and lifestyle factors which may lead to positive behaviour change. | Honey, Stephanie Neal, Richard D Messenger, Michael Smith, Samuel G eng DH_/Department of Health/United Kingdom Research Support, Non-U.S. Gov't England Prim Health Care Res Dev. 2022 Apr 1;23:e24. doi: 10.1017/S1463423621000591.I | 04/02/2022 | ||
| Translation of aptamers toward clinical diagnosis and commercialization | Liu S, et al. | 2022 | Biosens Bioelectron | 208 | 114168 | https://www.doi.org/10.1016/j.bios.2022.114168 | 35,364,525 | *Aptamers, Nucleotide *Biosensing Techniques Point-of-Care Testing SELEX Aptamer Technique Aptamer Aptasensor Clinical diagnostic Point-of-care test Translation | The dominance of antibodies in diagnostics has gradually changed following the discovery of aptamers in the early 1990s. Aptamers offer inherent advantages over traditional antibodies, including higher specificity, higher affinity, smaller size, greater stability, ease of manufacture, and low immunogenicity, rendering them the best candidates for point-of-care testing (POCT). In the past 20 years, the research community and pharmaceutical companies have made great efforts to promote the development of aptamer technology. Macugen(R) (pegaptanib) was the first aptamer drug approved by the US Food and Drug Administration (FDA), and various aptamer-based diagnostics show great promise in preclinical research and clinical trials. In this review, we introduce recent literature, ongoing clinical trials, commercial reagents of aptamer-based diagnostics, discuss the FDA regulatory mechanisms, and highlight the prospects and challenges in translating these studies into viable clinical diagnostic tools. | Liu, Shan Xu, Yixin Jiang, Xin Tan, Hong Ying, Binwu eng Review England Biosens Bioelectron. 2022 Jul 15;208:114168. doi: 10.1016/j.bios.2022.114168. Epub 2022 Mar 16.I | 04/02/2022 | ||
| Plasma Growth and Differentiation Factor 15 Predict Longitudinal Changes in Bone Parameters in Women, but Not in Men | Osawa Y, et al. | 2022 | J Gerontol A Biol Sci Med Sci | 77 | 10 | 1951-1958 | https://www.doi.org/10.1093/gerona/glac079 | 35,363,860 | Aged Aged, 80 and over Bone Density/physiology *Bone Diseases, Metabolic *Calcium Female Growth Differentiation Factor 15 Humans Male Parathyroid Hormone Radius/physiology Tibia/diagnostic imaging/physiology Cortical bone Growth/differentiation factor 15 Osteopenia Sex difference Trabecular bone | Bone fragility can progress with aging, but biomarkers to detect emerging osteopenia have not been fully elucidated. Growth/differentiation factor 15 (GDF-15) has pleiotropic roles in a broad range of age-related conditions, but its association with osteopenia is unknown. We examined the relationship between plasma GDF-15 levels and rate of change in bone parameters over 9 years of follow-up in 596 adults in the InCHIANTI study (baseline age, 65-94 years; women, 52.4%; mean follow-up, 7.0 +/- 3.0 years). Plasma GDF-15 concentrations were measured using the 1.3k HTS SOMAscan assay. Eight bone parameters were measured in the right tibia by peripheral quantitative computed tomography; total bone density, trabecular bone density, medullary plus trabecular bone density, cortical bone density, total bone area, cortical bone area, medullary bone area, and minimum moment of inertia (mMOI). We ran sex-specific linear mixed-effect models with random intercepts and slopes adjusted for age, age-squared, education, body mass index, the rate of change in weight, smoking, sedentary behavior, cross-sectional areas of calf muscles and fat, 25-hydroxyvitamin D, parathyroid hormone, calcium, diabetes mellitus, and follow-up time. We found a significant association of baseline GDF-15 x time" in models predicting cortical bone density and the mMOI in women, suggesting that the rates of decline in these bone parameters increased with higher GDF-15 (false discovery rate <0.05). Higher plasma levels GDF-15 predicted an accelerated decline in bone parameters in women, but was less associated in men. Furthermore studies are needed to understand the mechanisms underlying these sex differences." | Osawa, Yusuke Tanaka, Toshiko Semba, Richard D Fantoni, Giovanna Moaddel, Ruin Candia, Julian Simonsick, Eleanor M Bandinelli, Stefania Ferrucci, Luigi eng R21 HL112662/HL/NHLBI NIH HHS/ R01 MD009164/MD/NIMHD NIH HHS/ 21K10505/JSPS/ 263MD9164/AG/NIA NIH HHS/ R01 AG027012/AG/NIA NIH HHS/ R01 AG057723/AG/NIA NIH HHS/ Research Support, N.I.H., Extramural Research Support, N.I.H., Intramural Research Support, Non-U.S. Gov't J Gerontol A Biol Sci Med Sci. 2022 Oct 6;77(10):1951-1958. doi: 10.1093/gerona/glac079.I | 04/02/2022 | |
| A genome-wide meta-analysis identifies 50 genetic loci associated with carpal tunnel syndrome | Skuladottir AT, et al. | 2022 | Nat Commun | 13 | 1 | 1598 | https://www.doi.org/10.1038/s41467-022-29133-7 | 35,332,129 | Anthropometry *Carpal Tunnel Syndrome/genetics Genetic Loci Genome-Wide Association Study Humans Phenotype | Carpal tunnel syndrome (CTS) is the most common entrapment neuropathy and has a largely unknown underlying biology. In a genome-wide association study of CTS (48,843 cases and 1,190,837 controls), we found 53 sequence variants at 50 loci associated with the syndrome. The most significant association is with a missense variant (p.Glu366Lys) in SERPINA1 that protects against CTS (P = 2.9 x 10(-24), OR = 0.76). Through various functional analyses, we conclude that at least 22 genes mediate CTS risk and highlight the role of 19 CTS variants in the biology of the extracellular matrix. We show that the genetic component to the risk is higher in bilateral/recurrent/persistent cases than nonrecurrent/nonpersistent cases. Anthropometric traits including height and BMI are genetically correlated with CTS, in addition to early hormonal-replacement therapy, osteoarthritis, and restlessness. Our findings suggest that the components of the extracellular matrix play a key role in the pathogenesis of CTS. | Skuladottir, Astros Th Bjornsdottir, Gyda Ferkingstad, Egil Einarsson, Gudmundur Stefansdottir, Lilja Nawaz, Muhammad Sulaman Oddsson, Asmundur Olafsdottir, Thorunn A Saevarsdottir, Saedis Walters, G Bragi Magnusson, Sigurdur H Bjornsdottir, Anna Sveinsson, Olafur A Vikingsson, Arnor Hansen, Thomas Folkmann Jacobsen, Rikke Louise Erikstrup, Christian Schwinn, Michael Brunak, Soren Banasik, Karina Ostrowski, Sisse Rye Troelsen, Anders Henkel, Cecilie Pedersen, Ole Birger Jonsdottir, Ingileif Gudbjartsson, Daniel F Sulem, Patrick Thorgeirsson, Thorgeir E Stefansson, Hreinn Stefansson, Kari eng Meta-Analysis Research Support, Non-U.S. Gov't England Nat Commun. 2022 Mar 24;13(1):1598. doi: 10.1038/s41467-022-29133-7.I | 03/26/2022 | |
| Proteomic Studies of Psoriasis | Sobolev VV, et al. | 2022 | Biomedicines | 10 | 3 | https://www.doi.org/10.3390/biomedicines10030619 | 35,327,421 | Lc-ms/ms SOMAscan biomarkers comorbidities mass spectrometry predisposition proximity extension assay psoriasis risk factors | In this review paper, we discuss the contribution of proteomic studies to the discovery of disease-specific biomarkers to monitor the disease and evaluate available treatment options for psoriasis. Psoriasis is one of the most prevalent skin disorders driven by a Th17-specific immune response. Although potential patients have a genetic predisposition to psoriasis, the etiology of the disease remains unknown. During the last two decades, proteomics became deeply integrated with psoriatic research. The data obtained in proteomic studies facilitated the discovery of novel mechanisms and the verification of many experimental hypotheses of the disease pathogenesis. The detailed data analysis revealed multiple differentially expressed proteins and significant changes in proteome associated with the disease and drug efficacy. In this respect, there is a need for proteomic studies to characterize the role of the disease-specific biomarkers in the pathogenesis of psoriasis, develop clinical applications to choose the most efficient treatment options and monitor the therapeutic response. | Sobolev, Vladimir V Soboleva, Anna G Denisova, Elena V Pechatnikova, Eva A Dvoryankova, Eugenia Korsunskaya, Irina M Mezentsev, Alexandre eng Review Switzerland Biomedicines. 2022 Mar 7;10(3):619. doi: 10.3390/biomedicines10030619.I | 03/26/2022 | ||
| Diagnostic and Prognostic Protein Biomarkers of beta-Cell Function in Type 2 Diabetes and Their Modulation with Glucose Normalization | Moin ASM, et al. | 2022 | Metabolites | 12 | 3 | https://www.doi.org/10.3390/metabo12030196 | 35,323,639 | biomarkers diagnostic euglycemia glucose variability prognostic type 2 diabetes | Development of type-2 diabetes(T2D) is preceded by beta-cell dysfunction and loss. However, accurate measurement of beta-cell function remains elusive. Biomarkers have been reported to predict beta-cell functional decline but require validation. Therefore, we determined whether reported protein biomarkers could distinguish patients with T2D (onset < 10-years) from controls. A prospective, parallel study in T2D (n = 23) and controls (n = 23) was undertaken. In T2D subjects, insulin-induced blood glucose normalization from baseline 7.6 +/- 0.4 mmol/L (136.8 +/- 7.2 mg/dL) to 4.5 +/- 0.07 mmol/L (81 +/- 1.2 mg/dL) was maintained for 1-h. Controls were maintained at 4.9 +/- 0.1 mmol/L (88.2 +/- 1.8 mg/dL). Slow Off-rate Modified Aptamer (SOMA) -scan plasma protein measurement determined a 43-protein panel reported as diagnostic and/or prognostic for T2D. At baseline, 9 proteins were altered in T2D. Three of 13 prognostic/diagnostic proteins were lower in T2D: Adiponectin (p < 0.0001), Endocan (p < 0.05) and Mast/stem cell growth factor receptor-Kit (KIT) (p < 0.01). Two of 14 prognostic proteins [Cathepsin-D (p < 0.05) and Cadherin-E (p < 0.005)], and four of 16 diagnostic proteins [Kallikrein-4 (p = 0.001), Aminoacylase-1 (p = 0.001), Insulin-like growth factor-binding protein-4 (IGFBP4) (p < 0.05) and Reticulon-4 receptor (RTN4R) (p < 0.001)] were higher in T2D. Protein levels were unchanged following glucose normalization in T2D. Our results suggest that a focused biomarker panel may be useful for assessing beta-cell dysfunction and may complement clinical decision-making on insulin therapy. Unchanged post-glucose normalization levels indicate these are not acute-phase proteins or affected by glucose variability. | Moin, Abu Saleh Md Sathyapalan, Thozhukat Atkin, Stephen L Butler, Alexandra E eng Switzerland Metabolites. 2022 Feb 22;12(3):196. doi: 10.3390/metabo12030196.I | 03/25/2022 | ||
| Proteins and pathways in atrial fibrillation and atrial cardiomyopathy underlying cryptogenic stroke | Pala E, et al. | 2022 | Int J Cardiol Heart Vasc | 39 | 100977 | https://www.doi.org/10.1016/j.ijcha.2022.100977 | 35,281,755 | Atrial cardiomyopathy Atrial fibrillation Atrial function Biomarkers Cryptogenic stroke personal relationships that could have appeared to influence the work reported in this paper. | BACKGROUND: Atrial fibrillation (AF) is one of the most prevalent causes of cryptogenic stroke. Also, apart from AF itself, structural and remodelling changes in the atria might be an underlying cause of cryptogenic stroke. We aimed to discover circulating proteins and reveal pathways altered in AF and atrial cardiomyopathy, measured by left atrial volume index (LAVI) and peak atrial longitudinal strain (PALS), in patients with cryptogenic stroke. METHODS: An aptamer array (including 1310 proteins) was measured in the blood of 20 cryptogenic stroke patients monitored during 28 days with a Holter device as a case-control study of the Crypto-AF cohort. Protein levels were compared between patients with (n = 10) and without AF (n = 10) after stroke, and the best candidates were tested in 111 patients from the same cohort (44 patients with AF and 67 without AF). In addition, in the first 20 patients, proteins were explored according to PALS and LAVI values. RESULTS: Forty-six proteins were differentially expressed in AF cases. Of those, four proteins were tested in a larger sample size. Only DPP7, presenting lower levels in AF patients, was further validated. Fifty-seven proteins correlated with LAVI, and 270 correlated with PALS. NT-proBNP was common in all the discovery analyses performed. Interestingly, many proteins and pathways were altered in patients with low PALS. CONCLUSIONS: Multiple proteins and pathways related to AF and atrial cardiomyopathy have been revealed. The role of DPP7 as a biomarker for stroke aetiology should be further explored. Moreover, the present study may be considered hypothesis-generating. | Pala, Elena Pagola, Jorge Juega, Jesus Francisco-Pascual, Jaume Penalba, Anna Rodriguez, Maite De Lera Alfonso, Mercedes Arenillas, Juan F Cabezas, Juan Antonio Moniche, Francisco de Torres, Reyes Perez-Sanchez, Soledad Gonzalez-Alujas, Teresa Molina, Carlos A Bustamante, Alejandro Montaner, Joan eng Ireland Int J Cardiol Heart Vasc. 2022 Mar 7;39:100977. doi: 10.1016/j.ijcha.2022.100977. eCollection 2022 Apr.I | 03/15/2022 | ||
| Diabetes, GDF-15 and incident heart failure: the atherosclerosis risk in communities study | Echouffo-Tcheugui JB, et al. | 2022 | Diabetologia | 65 | 6 | 955-963 | https://www.doi.org/10.1007/s00125-022-05678-6 | 35,275,240 | Adult *Atherosclerosis/epidemiology Biomarkers *Diabetes Mellitus/epidemiology Female Growth Differentiation Factor 15 *Heart Failure/epidemiology/etiology Humans Male Middle Aged Risk Factors Growth differentiation factor-15 Heart failure Prediction Type 2 diabetes | AIMS/HYPOTHESIS: Elevated circulating growth differentiation factor-15 (GDF-15), a marker of cellular stress, is associated with both heart failure (HF) and diabetes. However, it is unclear to what extent GDF-15 is associated with HF among individuals with and without diabetes. METHODS: We evaluated 10,570 participants free of HF at Visit 3 (1993-1995) of the Atherosclerosis Risk in Communities study. We used Cox regression to evaluate the joint associations of GDF-15 and diabetes with incident HF. Models were adjusted for traditional cardiovascular risk factors. RESULTS: Among a total of 10,570 individuals (mean age of 60.0 years, 54% women, 27% black adults), elevated GDF-15 (>/=75th percentile) was more common in people with diabetes compared with those without diabetes (32.8% vs 23.6%, p<0.0001). During 23 years of follow-up, there were 2429 incident HF events. GDF-15 (in quartiles) was independently associated with HF among those with and without diabetes, with a stronger association among individuals with diabetes (p-for-diabetes-GDF-15 interaction = 0.034): HR for highest vs lowest GDF-15 quartile (reference): 1.64 (95% CI 1.41, 1.91) among those without diabetes and 1.72 (95% CI 1.32, 2.23) among those with diabetes. Individuals with diabetes and elevated GDF-15 had the highest risk of incident HF (HR 2.46; 95% CI 1.99, 3.03). After accounting for HF risk factors, GDF-15 provided additional prognostic information among participants with diabetes (DeltaC statistic for model with vs model without GDF-15: +0.008, p = 0.001) and among those without diabetes (+0.006, p<0.0001). CONCLUSIONS/INTERPRETATION: In a community-based sample of US adults, GDF-15 provided complementary prognostic information on the HF risk, especially among individuals with diabetes. | Echouffo-Tcheugui, Justin B Daya, Natalie Ndumele, Chiadi E Matsushita, Kunihiro Hoogeveen, Ron C Ballantyne, Christie M Coresh, Josef Shah, Amil M Selvin, Elizabeth eng R01 DK089174/DK/NIDDK NIH HHS/ R01 HL143224/HL/NHLBI NIH HHS/ K24 HL152008/HL/NHLBI NIH HHS/ R01 HL150342/HL/NHLBI NIH HHS/ 75N92022D00003/HL/NHLBI NIH HHS/ 75N92022D00005/HL/NHLBI NIH HHS/ R01 HL148218/HL/NHLBI NIH HHS/ K23 HL153774/HL/NHLBI NIH HHS/ 75N92022D00001/HL/NHLBI NIH HHS/ 75N92022D00002/HL/NHLBI NIH HHS/ K24 HL152440/HL/NHLBI NIH HHS/ R01 HL135008/HL/NHLBI NIH HHS/ 75N92022D00004/HL/NHLBI NIH HHS/ R01 HL146907/HL/NHLBI NIH HHS/ R01 HL134320/HL/NHLBI NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Germany Diabetologia. 2022 Jun;65(6):955-963. doi: 10.1007/s00125-022-05678-6. Epub 2022 Mar 11.I | 03/12/2022 | |
| Elucidating mechanisms of genetic cross-disease associations at the PROCR vascular disease locus | Stacey D, et al. | 2022 | Nat Commun | 13 | 1 | 1222 | https://www.doi.org/10.1038/s41467-022-28729-3 | 35,264,566 | Antigens, CD/genetics Crosses, Genetic Endothelial Cells/metabolism Endothelial Protein C Receptor/genetics Humans Protein C/metabolism Receptors, Cell Surface/genetics *Thrombosis/genetics *Venous Thromboembolism/genetics | Many individual genetic risk loci have been associated with multiple common human diseases. However, the molecular basis of this pleiotropy often remains unclear. We present an integrative approach to reveal the molecular mechanism underlying the PROCR locus, associated with lower coronary artery disease (CAD) risk but higher venous thromboembolism (VTE) risk. We identify PROCR-p.Ser219Gly as the likely causal variant at the locus and protein C as a causal factor. Using genetic analyses, human recall-by-genotype and in vitro experimentation, we demonstrate that PROCR-219Gly increases plasma levels of (activated) protein C through endothelial protein C receptor (EPCR) ectodomain shedding in endothelial cells, attenuating leukocyte-endothelial cell adhesion and vascular inflammation. We also associate PROCR-219Gly with an increased pro-thrombotic state via coagulation factor VII, a ligand of EPCR. Our study, which links PROCR-219Gly to CAD through anti-inflammatory mechanisms and to VTE through pro-thrombotic mechanisms, provides a framework to reveal the mechanisms underlying similar cross-phenotype associations. | Stacey, David Chen, Lingyan Stanczyk, Paulina J Howson, Joanna M M Mason, Amy M Burgess, Stephen MacDonald, Stephen Langdown, Jonathan McKinney, Harriett Downes, Kate Farahi, Neda Peters, James E Basu, Saonli Pankow, James S Tang, Weihong Pankratz, Nathan Sabater-Lleal, Maria de Vries, Paul S Smith, Nicholas L Gelinas, Amy D Schneider, Daniel J Janjic, Nebojsa Samani, Nilesh J Ye, Shu Summers, Charlotte Chilvers, Edwin R Danesh, John Paul, Dirk S eng MR/L003120/1/MRC_/Medical Research Council/United Kingdom BRC-1215-20014/DH_/Department of Health/United Kingdom MR/P502091/1/MRC_/Medical Research Council/United Kingdom UL1 RR025005/RR/NCRR NIH HHS/ NIHR133788/DH_/Department of Health/United Kingdom R01 HL059367/HL/NHLBI NIH HHS/ R01 HL086694/HL/NHLBI NIH HHS/ RG/18/13/33946/BHF_/British Heart Foundation/United Kingdom R01 HL105756/HL/NHLBI NIH HHS/ RG/19/9/34655/BHF_/British Heart Foundation/United Kingdom HHSN268201700002C/HL/NHLBI NIH HHS/ HHSN268201700001I/HL/NHLBI NIH HHS/ HHSN268201700004I/HL/NHLBI NIH HHS/ RG/16/4/32218/BHF_/British Heart Foundation/United Kingdom R01 HL134894/HL/NHLBI NIH HHS/ MR/S004068/2/MRC_/Medical Research Council/United Kingdom RE/13/6/30180/BHF_/British Heart Foundation/United Kingdom U01 HG004402/HG/NHGRI NIH HHS/ HHSN268201700005C/HL/NHLBI NIH HHS/ HHSN268201700001C/HL/NHLBI NIH HHS/ HHSN268201700003C/HL/NHLBI NIH HHS/ HHSN268201700004C/HL/NHLBI NIH HHS/ WT_/Wellcome Trust/United Kingdom HHSN268201700002I/HL/NHLBI NIH HHS/ HHSN268201700005I/HL/NHLBI NIH HHS/ CSO_/Chief Scientist Office/United Kingdom R01 HL087641/HL/NHLBI NIH HHS/ HHSN268201700003I/HL/NHLBI NIH HHS/ RG/13/13/30194/BHF_/British Heart Foundation/United Kingdom SP/19/2/344612/BHF_/British Heart Foundation/United Kingdom England Nat Commun. 2022 Mar 9;13(1):1222. doi: 10.1038/s41467-022-28729-3.I | 03/11/2022 | |
| Proteome-Wide Analysis Using SOMAscan Identifies and Validates Chitinase-3-Like Protein 1 as a Risk and Disease Marker of Delirium Among Older Adults Undergoing Major Elective Surgery | Vasunilashorn SM, et al. | 2022 | J Gerontol A Biol Sci Med Sci | 77 | 3 | 484-493 | https://www.doi.org/10.1093/gerona/glaa326 | 35,239,952 | Aged Biomarkers Case-Control Studies *Chitinase-3-Like Protein 1/genetics *Delirium/diagnosis/etiology Elective Surgical Procedures Humans Interleukin-6 *Postoperative Cognitive Complications/diagnosis/genetics Proteome Inflammation Postoperative Proteomics | BACKGROUND: Delirium (an acute change in cognition) is a common, morbid, and costly syndrome seen primarily in aging adults. Despite increasing knowledge of its epidemiology, delirium remains a clinical diagnosis with no established biomarkers to guide diagnosis or management. Advances in proteomics now provide opportunities to identify novel markers of risk and disease progression for postoperative delirium and its associated long-term consequences (eg, long-term cognitive decline and Alzheimer's disease [AD]). METHODS: In a nested matched case-control study (18 delirium/no-delirium pairs) within the Successful Aging after Elective Surgery study (N = 556), we evaluated the association of 1305 plasma proteins preoperatively [PREOP] and on postoperative day 2 [POD2]) with delirium using SOMAscan. Generalized linear models were applied to enzyme-linked immunosorbant assay (ELISA) validation data of one protein across the full cohort. Multi-protein modeling included delirium biomarkers identified in prior work (C-reactive protein, interleukin-6 [IL6]). RESULTS: We identified chitinase-3-like-protein-1 (CHI3L1/YKL-40) as the sole delirium-associated protein in both a PREOP and a POD2 predictor model, a finding confirmed by ELISA. Multi-protein modeling found high PREOP CHI3L1/YKL-40 and POD2 IL6 increased the risk of delirium (relative risk [95% confidence interval] Quartile [Q]4 vs Q1: 2.4[1.2-5.0] and 2.1[1.1-4.1], respectively). CONCLUSIONS: Our identification of CHI3L1/YKL-40 in postoperative delirium parallels reports of CHI3L1/YKL-40 and its association with aging, mortality, and age-related conditions including AD onset and progression. This highlights the type 2 innate immune response, involving CHI3L1/YKL-40, as an underlying mechanism of postoperative delirium, a common, morbid, and costly syndrome that threatens the independence of older adults. | Vasunilashorn, Sarinnapha M Dillon, Simon T Chan, Noel Y Fong, Tamara G Joseph, Marie Tripp, Bridget Xie, Zhongcong Ngo, Long H Lee, Chun Geun Elias, Jack A Otu, Hasan H Inouye, Sharon K Marcantonio, Edward R Libermann, Towia A eng R01 AG051658/AG/NIA NIH HHS/ R01 AG041274/AG/NIA NIH HHS/ K24 AG035075/AG/NIA NIH HHS/ K01 AG057836/AG/NIA NIH HHS/ R21 AG057955/AG/NIA NIH HHS/ R21 AG048600/AG/NIA NIH HHS/ R03 AG061582/AG/NIA NIH HHS/ ALZ/Alzheimer's Association/ R01AG051658/AG/NIA NIH HHS/ R24 AG054259/AG/NIA NIH HHS/ P01 AG031720/AG/NIA NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't J Gerontol A Biol Sci Med Sci. 2022 Mar 3;77(3):484-493. doi: 10.1093/gerona/glaa326.I | 03/04/2022 | |
| Connecting Genomics and Proteomics to Identify Protein Biomarkers for Adult and Youth-Onset Type 2 Diabetes: A Two-Sample Mendelian Randomization Study | Ghanbari F, et al. | 2022 | Diabetes | 71 | 6 | 1324-1337 | https://www.doi.org/10.2337/db21-1046 | 35,234,851 | Adolescent Adult Biomarkers Child *Diabetes Mellitus, Type 2/metabolism Genome-Wide Association Study Genomics Humans *Mendelian Randomization Analysis Polymorphism, Single Nucleotide Proteomics | Type 2 diabetes shows an increasing prevalence in both adults and children. Identification of biomarkers for both youth and adult-onset type 2 diabetes is crucial for development of screening tools or drug targets. In this study, using two-sample Mendelian randomization (MR), we identified 22 circulating proteins causally linked to adult type 2 diabetes and 11 proteins with suggestive evidence for association with youth-onset type 2 diabetes. Among these, colocalization analysis further supported a role in type 2 diabetes for C-type mannose receptor 2 (MR odds ratio [OR] 0.85 [95% CI 0.79-0.92] per genetically predicted SD increase in protein level), MANS domain containing 4 (MR OR 0.90 [95% CI 0.88-0.92]), sodium/potassium-transporting ATPase subunit beta2 (MR OR 1.10 [95% CI 1.06-1.15]), endoplasmic reticulum oxidoreductase 1beta (MR OR 1.09 [95% CI 1.05-1.14]), spermatogenesis-associated protein 20 (MR OR 1.12 [95% CI 1.06-1.18]), haptoglobin (MR OR 0.96 [95% CI 0.94-0.98]), and alpha1-3-N-acetylgalactosaminyltransferase and alpha1-3-galactosyltransferase (MR OR 1.04 [95% CI 1.03-1.05]). Our findings support a causal role in type 2 diabetes for a set of circulating proteins, which represent promising type 2 diabetes drug targets. | Ghanbari, Faegheh Yazdanpanah, Nahid Yazdanpanah, Mojgan Richards, J Brent Manousaki, Despoina eng Diabetes. 2022 Jun 1;71(6):1324-1337. doi: 10.2337/db21-1046.I | 03/03/2022 | |
| Advances in proteomic profiling of pediatric kidney diseases | Cummins TD, et al. | 2022 | Pediatr Nephrol | 37 | 10 | 2255-2265 | https://www.doi.org/10.1007/s00467-022-05497-2 | 35,220,505 | Adult Biomarkers Child Glomerular Filtration Rate Humans *Kidney Diseases/diagnosis Proteomics Renal Dialysis *Renal Insufficiency, Chronic Biomarker Chronic kidney disease Mass spectrometry Pediatric glomerular disease Proteomics conflicts of interest to declare. | Chronic kidney disease (CKD) can progress to kidney failure and require dialysis or transplantation, while early diagnosis can alter the course of disease and lead to better outcomes in both pediatric and adult patients. Significant CKD comorbidities include the manifestation of cardiovascular disease, heart failure, coronary disease, and hypertension. The pathogenesis of chronic kidney diseases can present as subtle and especially difficult to distinguish between different glomerular pathologies. Early detection of adult and pediatric CKD and detailed mechanistic understanding of the kidney damage can be helpful in delaying or curtailing disease progression via precise intervention toward diagnosis and prognosis. Clinically, serum creatinine and albumin levels can be indicative of CKD, but often are a lagging indicator only significantly affected once kidney function has severely diminished. The evolution of proteomics and mass spectrometry technologies has begun to provide a powerful research tool in defining these mechanisms and identifying novel biomarkers of CKD. Many of the same challenges and advances in proteomics apply to adult and pediatric patient populations. Additionally, proteomic analysis of adult CKD patients can be transferred directly toward advancing our knowledge of pediatric CKD as well. In this review, we highlight applications of proteomics that have yielded such biomarkers as PLA2R, SEMA3B, and other markers of membranous nephropathy as well as KIM-1, MCP-1, and NGAL in lupus nephritis among other potential diagnostic and prognostic markers. The potential for improving the clinical toolkit toward better treatment of pediatric kidney diseases is significantly aided by current and future development of proteomic applications. | Cummins, Timothy D Korte, Erik A Bhayana, Sagar Merchant, Michael L Barati, Michelle T Smoyer, William E Klein, Jon B eng R01 DK110077/DK/NIDDK NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Review Germany Pediatr Nephrol. 2022 Oct;37(10):2255-2265. doi: 10.1007/s00467-022-05497-2. Epub 2022 Feb 26.I | 02/28/2022 | |
| Specialized interferon action in COVID-19 | Galbraith MD, et al. | 2022 | Proc Natl Acad Sci U S A | 119 | 11 | https://www.doi.org/10.1073/pnas.2116730119 | 35,217,532 | Blood/*metabolism COVID-19/blood/*immunology Case-Control Studies Datasets as Topic Humans Inpatients Interferons/*blood *Proteome *Transcriptome Covid-19 CyTOF SARS-CoV-2 cytokine interferon Board for Eli Lilly. | The impacts of interferon (IFN) signaling on COVID-19 pathology are multiple, with both protective and harmful effects being documented. We report here a multiomics investigation of systemic IFN signaling in hospitalized COVID-19 patients, defining the multiomics biosignatures associated with varying levels of 12 different type I, II, and III IFNs. The antiviral transcriptional response in circulating immune cells is strongly associated with a specific subset of IFNs, most prominently IFNA2 and IFNG. In contrast, proteomics signatures indicative of endothelial damage and platelet activation associate with high levels of IFNB1 and IFNA6. Seroconversion and time since hospitalization associate with a significant decrease in a specific subset of IFNs. Additionally, differential IFN subtype production is linked to distinct constellations of circulating myeloid and lymphoid immune cell types. Each IFN has a unique metabolic signature, with IFNG being the most associated with activation of the kynurenine pathway. IFNs also show differential relationships with clinical markers of poor prognosis and disease severity. For example, whereas IFNG has the strongest association with C-reactive protein and other immune markers of poor prognosis, IFNB1 associates with increased neutrophil to lymphocyte ratio, a marker of late severe disease. Altogether, these results reveal specialized IFN action in COVID-19, with potential diagnostic and therapeutic implications. | Galbraith, Matthew D Kinning, Kohl T Sullivan, Kelly D Araya, Paula Smith, Keith P Granrath, Ross E Shaw, Jessica R Baxter, Ryan Jordan, Kimberly R Russell, Seth Dzieciatkowska, Monika Reisz, Julie A Gamboni, Fabia Cendali, Francesca Ghosh, Tusharkanti Guo, Kejun Wilson, Cara C Santiago, Mario L Monte, Andrew A Bennett, Tellen D Hansen, Kirk C Hsieh, Elena W Y D'Alessandro, Angelo Espinosa, Joaquin M eng K23 AR070897/AR/NIAMS NIH HHS/ P30 CA046934/CA/NCI NIH HHS/ P30 DK048520/DK/NIDDK NIH HHS/ R01 AI150305/AI/NIAID NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Proc Natl Acad Sci U S A. 2022 Mar 15;119(11):e2116730119. doi: 10.1073/pnas.2116730119.I | 02/27/2022 | ||
| Biological Age Acceleration Is Lower in Women With Ischemic Stroke Compared to Men | Gallego-Fabrega C, et al. | 2022 | Stroke | 53 | 7 | 2320-2330 | https://www.doi.org/10.1161/STROKEAHA.121.037419 | 35,209,739 | Acceleration Aging Child, Preschool DNA Methylation *Epigenesis, Genetic Female Genetic Markers Humans *Ischemic Stroke Male Proteomics ischemic stroke men women | BACKGROUND: Stroke onset in women occurs later in life compared with men. The underlying mechanisms of these differences have not been established. Epigenetic clocks, based on DNA methylation (DNAm) profiles, are the most accurate biological age estimate. Epigenetic age acceleration (EAA) measures indicate whether an individual is biologically younger or older than expected. Our aim was to analyze whether sexual dichotomy at age of stroke onset is conditioned by EAA. METHODS: We used 2 DNAm datasets from whole blood samples of case-control genetic studies of ischemic stroke (IS), a discovery cohort of 374 IS patients (N women=163, N men=211), from GRECOS (Genotyping Recurrence Risk of Stroke) and SEDMAN (Dabigatran Study in the Early Phase of Stroke, New Neuroimaging Markers and Biomarkers) studies and a replication cohort of 981 IS patients (N women=411, N men=570) from BASICMAR register. We compared chronological age, 2 DNAm-based biomarkers of aging and intrinsic and extrinsic epigenetic age acceleration EAA (IEAA and extrinsic EAA, respectively), in IS as well as in individual IS etiologic subtypes. Horvath and Hannum epigenetic clocks were used to assess the aging rate. A proteomic study using the SOMAScan multiplex assay was performed on 26 samples analyzing 1305 proteins. RESULTS: Women present lower Hannum-extrinsic EAA values, whereas men have higher Hannum-extrinsic EAA values (women=-0.64, men=1.24, P=1.34x10(-2)); the same tendency was observed in the second cohort (women=-0.57, men=0.79, P=0.02). These differences seemed to be specific to cardioembolic and undetermined stroke subtypes. Additionally, 42 blood protein levels were associated with Hannum-extrinsic EAA (P<0.05), belonging to the immune effector process (P=1.54x10(-6)) and platelet degranulation (P<8.74x10(-6)) pathways. CONCLUSIONS: This study shows that sex-specific underlying biological mechanisms associated with stroke onset could be due to differences in biological age acceleration between men and women. | Gallego-Fabrega, Cristina Muino, Elena Cullell, Natalia Carcel-Marquez, Jara Lazcano, Uxue Soriano-Tarraga, Carolina Lledos, Miquel Llucia-Carol, Laia Aguilera-Simon, Ana Marin, Rebeca Prats-Sanchez, Luis Camps-Renom, Pol Delgado-Mederos, Raquel Martin-Campos, Jesus M Delgado, Pilar Marti-Fabregas, Joan Montaner, Joan Krupinski, Jerzy Jimenez-Conde, J Roquer, Jaume Fernandez-Cadenas, Israel eng Research Support, Non-U.S. Gov't Stroke. 2022 Jul;53(7):2320-2330. doi: 10.1161/STROKEAHA.121.037419. Epub 2022 Feb 25.I | 02/26/2022 | |
| Proteomic profiling identifies novel proteins for genetic risk of severe COVID-19: the Atherosclerosis Risk in Communities Study | Steffen BT, et al. | 2022 | Hum Mol Genet | 31 | 14 | 2452-2461 | https://www.doi.org/10.1093/hmg/ddac024 | 35,212,764 | *COVID-19/genetics *Genetic Predisposition to Disease Genome-Wide Association Study Humans Proteomics Risk Factors | BACKGROUND: Genome-wide association studies have identified six genetic variants associated with severe COVID-19, yet the mechanisms through which they may affect disease remains unclear. We investigated proteomic signatures related to COVID-19 risk variants rs657152 (ABO), rs10735079 (OAS1/OAS2/OAS3), rs2109069 (DPP9), rs74956615 (TYK2), rs2236757 (IFNAR2) and rs11385942 (SLC6A20/LZTFL1/CCR9/FYCO1/CXCR6/XCR1) as well as their corresponding downstream pathways that may promote severe COVID-19 in risk allele carriers and their potential relevancies to other infection outcomes. METHODS: A DNA aptamer-based array measured 4870 plasma proteins among 11 471 participants. Linear regression estimated associations between the COVID-19 risk variants and proteins with correction for multiple comparisons, and canonical pathway analysis was conducted. Cox regression assessed associations between proteins identified in the main analysis and risk of incident hospitalized respiratory infections (2570 events) over a 20.7-year follow-up. RESULTS: The ABO variant rs657152 was associated with 84 proteins in 7241 white participants with 24 replicated in 1671 Black participants. The TYK2 variant rs74956615 was associated with ICAM-1 and -5 in white participants with ICAM-5 replicated in Black participants. Of the 84 proteins identified in the main analysis, seven were significantly associated with incident hospitalized respiratory infections including Ephrin type-A receptor 4 (hazard ratio (HR): 0.87; P = 2.3 x 10-11) and von Willebrand factor type A (HR: 1.17; P = 1.6x10-13). CONCLUSIONS: Novel proteomics signatures and pathways for COVID-19-related risk variants TYK2 and ABO were identified. A subset of these proteins predicted greater risk of incident hospitalized pneumonia and respiratory infections. Further studies to examine these proteins in COVID-19 patients are warranted. | Steffen, Brian T Pankow, James S Lutsey, Pamela L Demmer, Ryan T Misialek, Jeffrey R Guan, Weihua Cowan, Logan T Coresh, Josef Norby, Faye L Tang, Weihong eng T32 HL007779/HL/NHLBI NIH HHS/ R01 HL134320/HL/NHLBI NIH HHS/ U01 HG004402/HG/NHGRI NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't England Hum Mol Genet. 2022 Jul 21;31(14):2452-2461. doi: 10.1093/hmg/ddac024.I | 02/26/2022 | |
| Comparison of Aptamer-Based and Antibody-Based Assays for Protein Quantification in Chronic Kidney Disease | Lopez-Silva C, et al. | 2022 | Clin J Am Soc Nephrol | 17 | 3 | 350-360 | https://www.doi.org/10.2215/CJN.11700921 | 35,197,258 | Biomarkers Cystatin C Female Glomerular Filtration Rate Humans Interleukin-8 Male Receptors, Tumor Necrosis Factor Receptors, Urokinase Plasminogen Activator *Renal Insufficiency *Renal Insufficiency, Chronic AASK (African American Study of Kidney Disease and Hypertension) antibodies biological assay chronic inflammation chronic kidney disease end-stage renal disease mortality | BACKGROUND AND OBJECTIVES: Novel aptamer-based technologies can identify >7000 analytes per sample, offering a high-throughput alternative to traditional immunoassays in biomarker discovery. However, the specificity for distinct proteins has not been thoroughly studied in the context of CKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We assessed the use of SOMAscan, an aptamer-based technology, for the quantification of eight immune activation biomarkers and cystatin C among 498 African American Study of Kidney Disease and Hypertension (AASK) participants using immunoassays as the gold standard. We evaluated correlations of serum proteins as measured by SOMAscan versus immunoassays with each other and with iothalamate-measured GFR. We then compared associations between proteins measurement with risks of incident kidney failure and all-cause mortality. RESULTS: Six biomarkers (IL-8, soluble TNF receptor superfamily member 1B [TNFRSF1B], cystatin C, soluble TNF receptor superfamily member 1A [TNFRSF1A], IL-6, and soluble urokinase-type plasminogen activator receptor [suPAR]) had non-negligible correlations (r=0.94, 0.93, 0.89, 0.85, 0.46, and 0.23, respectively) between SOMAscan and immunoassay measurements, and three (IL-10, IFN-gamma, and TNF-alpha) were uncorrelated (r=0.08, 0.07, and 0.02, respectively). Of the six biomarkers with non-negligible correlations, TNFRSF1B, cystatin C, TNFRSF1A, and suPAR were negatively correlated with measured GFR and associated with higher risk of kidney failure. IL-8, TNFRSF1B, cystatin C, TNFRSF1A, and suPAR were associated with a higher risk of mortality via both methods. On average, immunoassay measurements were more strongly associated with adverse outcomes than their SOMAscan counterparts. CONCLUSIONS: SOMAscan is an efficient and relatively reliable technique for quantifying IL-8, TNFRSF1B, cystatin C, and TNFRSF1A in CKD and detecting their potential associations with clinical outcomes. PODCAST: This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2022_02_23_CJN11700921.mp3. | Lopez-Silva, Carolina Surapaneni, Aditya Coresh, Josef Reiser, Jochen Parikh, Chirag R Obeid, Wassim Grams, Morgan E Chen, Teresa K eng U01 DK048689/DK/NIDDK NIH HHS/ P20 RR011104/RR/NCRR NIH HHS/ P30 DK079310/DK/NIDDK NIH HHS/ U01 DK106962/DK/NIDDK NIH HHS/ K08 DK117068/DK/NIDDK NIH HHS/ M01 RR000071/RR/NCRR NIH HHS/ P20 RR011145/RR/NCRR NIH HHS/ K24 HL155861/HL/NHLBI NIH HHS/ R01 DK057867/DK/NIDDK NIH HHS/ M01 RR000052/RR/NCRR NIH HHS/ UL1 RR029887/RR/NCRR NIH HHS/ K24 DK002818/DK/NIDDK NIH HHS/ M01 RR000827/RR/NCRR NIH HHS/ M01 RR000080/RR/NCRR NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Clin J Am Soc Nephrol. 2022 Mar;17(3):350-360. doi: 10.2215/CJN.11700921. Epub 2022 Feb 23.I | 02/25/2022 | |
| Protein prediction for trait mapping in diverse populations | Schubert R, et al. | 2022 | PLoS One | 17 | 2 | e0264341 | https://www.doi.org/10.1371/journal.pone.0264341 | 35,202,437 | Atherosclerosis/ethnology/*genetics Female Gene Frequency *Genetic Association Studies Humans Male *Models, Genetic Pilot Projects Polymorphism, Single Nucleotide Proteins/*genetics Proteome/*genetics Quantitative Trait Loci | Genetically regulated gene expression has helped elucidate the biological mechanisms underlying complex traits. Improved high-throughput technology allows similar interrogation of the genetically regulated proteome for understanding complex trait mechanisms. Here, we used the Trans-omics for Precision Medicine (TOPMed) Multi-omics pilot study, which comprises data from Multi-Ethnic Study of Atherosclerosis (MESA), to optimize genetic predictors of the plasma proteome for genetically regulated proteome-wide association studies (PWAS) in diverse populations. We built predictive models for protein abundances using data collected in TOPMed MESA, for which we have measured 1,305 proteins by a SOMAscan assay. We compared predictive models built via elastic net regression to models integrating posterior inclusion probabilities estimated by fine-mapping SNPs prior to elastic net. In order to investigate the transferability of predictive models across ancestries, we built protein prediction models in all four of the TOPMed MESA populations, African American (n = 183), Chinese (n = 71), European (n = 416), and Hispanic/Latino (n = 301), as well as in all populations combined. As expected, fine-mapping produced more significant protein prediction models, especially in African ancestries populations, potentially increasing opportunity for discovery. When we tested our TOPMed MESA models in the independent European INTERVAL study, fine-mapping improved cross-ancestries prediction for some proteins. Using GWAS summary statistics from the Population Architecture using Genomics and Epidemiology (PAGE) study, which comprises approximately 50,000 Hispanic/Latinos, African Americans, Asians, Native Hawaiians, and Native Americans, we applied S-PrediXcan to perform PWAS for 28 complex traits. The most protein-trait associations were discovered, colocalized, and replicated in large independent GWAS using proteome prediction model training populations with similar ancestries to PAGE. At current training population sample sizes, performance between baseline and fine-mapped protein prediction models in PWAS was similar, highlighting the utility of elastic net. Our predictive models in diverse populations are publicly available for use in proteome mapping methods at https://doi.org/10.5281/zenodo.4837327. | Schubert, Ryan Geoffroy, Elyse Gregga, Isabelle Mulford, Ashley J Aguet, Francois Ardlie, Kristin Gerszten, Robert Clish, Clary Van Den Berg, David Taylor, Kent D Durda, Peter Johnson, W Craig Cornell, Elaine Guo, Xiuqing Liu, Yongmei Tracy, Russell Conomos, Matthew Blackwell, Tom Papanicolaou, George Lappalainen, Tuuli Mikhaylova, Anna V Thornton, Timothy A Cho, Michael H Gignoux, Christopher R Lange, Leslie Lange, Ethan Rich, Stephen S Rotter, Jerome I Manichaikul, Ani Im, Hae Kyung Wheeler, Heather E eng R15 HG009569/HG/NHGRI NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't PLoS One. 2022 Feb 24;17(2):e0264341. doi: 10.1371/journal.pone.0264341. eCollection 2022.I | 02/25/2022 | |
| Protein and miRNA profile of circulating extracellular vesicles in patients with primary sclerosing cholangitis | Povero D, et al. | 2022 | Sci Rep | 12 | 1 | 3027 | https://www.doi.org/10.1038/s41598-022-06809-0 | 35,194,091 | Adult Aged Biomarkers/blood Cholangitis, Sclerosing/*diagnosis Extracellular Vesicles/*genetics/*metabolism Female Gene Expression Humans Interleukin-13 Receptor alpha1 Subunit/*genetics/*metabolism Liver Cirrhosis/diagnosis Male MicroRNAs/*genetics/*metabolism Middle Aged Young Adult | Primary sclerosing cholangitis (PSC) is an idiopathic and heterogenous cholestatic liver disease characterized by chronic inflammation and fibrosis of the biliary tree. Currently, no effective therapies are available for this condition, whose incidence is rising. At present, specificity and sensitivity of current serum markers used to diagnose PSC are limited and often unreliable. In this study, we characterize circulating extracellular vesicles and provide supporting data on their potential use as novel surrogate biomarkers for PSC. EVs are membrane surrounded structures, 100-1000 nm in size, released by cells under various conditions and which carry a variety of bioactive molecules, including small non-coding RNAs, lipids and proteins. In recent years, a large body of evidence has pointed to diagnostic implications of EVs and relative cargo in various human diseases. We isolated EVs from serum of well-characterized patients with PSC or control subjects by differential centrifugation and size-exclusion chromatography. A complete characterization identified elevated levels of circulating EVs in PSC patients compared to healthy control subjects (2000 vs. 500 Calcein-FITC + EVs/muL). Tissue and cell specificity of circulating EVs was assessed by identification of liver-specific markers and cholangiocyte marker CK-19. Further molecular characterization identified 282 proteins that were differentially regulated in PSC-derived compared to healthy control-EVs. Among those, IL-13Ra1 was the most significantly and differentially expressed protein in PSC-derived EVs and correlated with the degree of liver fibrosis. In addition to protein profiling, we performed a miRNA-sequencing analysis which identified 11 among established, liver-specific (e.g., miR-122 and miR-192) and novel miRNAs. One of the newly identified miRNAs, miR-4645-3p, was significantly up-regulated fourfold in PSC-derived EVs compared to circulating EVs isolated from healthy controls. This study provides supporting evidence of the potential role of circulating EVs and associated protein and miRNA cargo as surrogate noninvasive and reliable biomarker for PSC. | Povero, Davide Tameda, Masahiko Eguchi, Akiko Ren, Wenhua Kim, Jihoon Myers, Robert Goodman, Zachary D Harrison, Stephen A Sanyal, Arun J Bosch, Jaime Ohno-Machado, Lucila Feldstein, Ariel E eng Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't England Sci Rep. 2022 Feb 22;12(1):3027. doi: 10.1038/s41598-022-06809-0.I | 02/24/2022 | |
| Identification of Distinct Inflammatory Programs and Biomarkers in Systemic Juvenile Idiopathic Arthritis and Related Lung Disease by Serum Proteome Analysis | Chen G, et al. | 2022 | Arthritis Rheumatol | 74 | 7 | 1271-1283 | https://www.doi.org/10.1002/art.42099 | 35,189,047 | *Arthritis, Juvenile/complications Biomarkers Humans *Lung Diseases/epidemiology *Macrophage Activation Syndrome Matrix Metalloproteinase 7 Proteome | OBJECTIVE: Recent observations in systemic juvenile idiopathic arthritis (JIA) suggest an increasing incidence of high-mortality interstitial lung disease often characterized by a variant of pulmonary alveolar proteinosis (PAP). Co-occurrence of macrophage activation syndrome (MAS) and PAP in systemic JIA suggests a shared pathology, but patients with lung disease associated with systemic JIA (designated SJIA-LD) also commonly experience features of drug reaction such as atypical rashes and eosinophilia. This study was undertaken to investigate immunopathology and identify biomarkers in systemic JIA, MAS, and SJIA-LD. METHODS: We used SOMAscan to measure ~1,300 analytes in sera from healthy controls and patients with systemic JIA, MAS, SJIA-LD, or other related diseases. We verified selected findings by enzyme-linked immunosorbent assay and lung immunostaining. Because the proteome of a sample may reflect multiple states (systemic JIA, MAS, or SJIA-LD), we used regression modeling to identify subsets of altered proteins associated with each state. We tested key findings in a validation cohort. RESULTS: Proteome alterations in active systemic JIA and MAS overlapped substantially, including known systemic JIA biomarkers such as serum amyloid A and S100A9, and novel elevations in the levels of heat-shock proteins and glycolytic enzymes. Interleukin-18 levels were elevated in all systemic JIA groups, particularly MAS and SJIA-LD. We also identified an MAS-independent SJIA-LD signature notable for elevated levels of intercellular adhesion molecule 5 (ICAM-5), matrix metalloproteinase 7 (MMP-7), and allergic/eosinophilic chemokines, which have been previously associated with lung damage. Immunohistochemistry localized ICAM-5 and MMP-7 in the lungs of patients with SJIA-LD. The ability of ICAM-5 to distinguish SJIA-LD from systemic JIA/MAS was independently validated. CONCLUSION: Serum proteins support a systemic JIA-to-MAS continuum; help distinguish systemic JIA, systemic JIA/MAS, and SJIA-LD; and suggest etiologic hypotheses. Select biomarkers, such as ICAM-5, could aid in early detection and management of SJIA-LD. | Chen, Guangbo Deutsch, Gail H Schulert, Grant S Zheng, Hong Jang, SoRi Trapnell, Bruce Lee, Pui Y Macaubas, Claudia Ho, Katherine Schneider, Corinne Saper, Vivian E de Jesus, Adriana Almeida Krasnow, Mark A Grom, Alexei Goldbach-Mansky, Raphaela Khatri, Purvesh Mellins, Elizabeth D Canna, Scott W eng R01 HD098428/HD/NICHD NIH HHS/ R01 AR061297/AR/NIAMS NIH HHS/ R01 AR066551/AR/NIAMS NIH HHS/ U19 AI109662/AI/NIAID NIH HHS/ R01 AI125197/AI/NIAID NIH HHS/ U19 AI057229/AI/NIAID NIH HHS/ K22 AI123366/AI/NIAID NIH HHS/ Research Support, N.I.H., Extramural Research Support, N.I.H., Intramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. Arthritis Rheumatol. 2022 Jul;74(7):1271-1283. doi: 10.1002/art.42099. Epub 2022 May 31.I | 02/22/2022 | |
| Immunopathological signatures in multisystem inflammatory syndrome in children and pediatric COVID-19 | Sacco K, et al. | 2022 | Nat Med | 28 | 5 | 1050-1062 | https://www.doi.org/10.1038/s41591-022-01724-3 | 35,177,862 | *COVID-19/complications/genetics Child Humans SARS-CoV-2 Systemic Inflammatory Response Syndrome/genetics T-Lymphocytes | Pediatric Coronavirus Disease 2019 (pCOVID-19) is rarely severe; however, a minority of children infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) might develop multisystem inflammatory syndrome in children (MIS-C), with substantial morbidity. In this longitudinal multi-institutional study, we applied multi-omics (analysis of soluble biomarkers, proteomics, single-cell gene expression and immune repertoire analysis) to profile children with COVID-19 (n = 110) and MIS-C (n = 76), along with pediatric healthy controls (pHCs; n = 76). pCOVID-19 was characterized by robust type I interferon (IFN) responses, whereas prominent type II IFN-dependent and NF-kappaB-dependent signatures, matrisome activation and increased levels of circulating spike protein were detected in MIS-C, with no correlation with SARS-CoV-2 PCR status around the time of admission. Transient expansion of TRBV11-2 T cell clonotypes in MIS-C was associated with signatures of inflammation and T cell activation. The association of MIS-C with the combination of HLA A*02, B*35 and C*04 alleles suggests genetic susceptibility. MIS-C B cells showed higher mutation load than pCOVID-19 and pHC. These results identify distinct immunopathological signatures in pCOVID-19 and MIS-C that might help better define the pathophysiology of these disorders and guide therapy. | Sacco, Keith Castagnoli, Riccardo Vakkilainen, Svetlana Liu, Can Delmonte, Ottavia M Oguz, Cihan Kaplan, Ian M Alehashemi, Sara Burbelo, Peter D Bhuyan, Farzana de Jesus, Adriana A Dobbs, Kerry Rosen, Lindsey B Cheng, Aristine Shaw, Elana Vakkilainen, Mikko S Pala, Francesca Lack, Justin Zhang, Yu Fink, Danielle L Oikonomou, Vasileios Snow, Andrew L Dalgard, Clifton L Chen, Jinguo Sellers, Brian A Montealegre Sanchez, Gina A Barron, Karyl Rey-Jurado, Emma Vial, Cecilia Poli, Maria Cecilia Licari, Amelia Montagna, Daniela Marseglia, Gian Luigi Licciardi, Francesco Ramenghi, Ugo Discepolo, Valentina Lo Vecchio, Andrea Guarino, Alfredo Eisenstein, Eli M Imberti, Luisa Sottini, Alessandra Biondi, Andrea Mato, Sayonara Gerstbacher, Dana Truong, Meng Stack, Michael A Magliocco, Mary Bosticardo, Marita Kawai, Tomoki Danielson, Jeffrey J Hulett, Tyler Askenazi, Manor Hu, Shaohui Cohen, Jeffrey I Su, Helen C Kuhns, Douglas B Lionakis, Michail S Snyder, Thomas M Holland, Steven M Goldbach-Mansky, Raphaela Tsang, John S Notarangelo, Luigi D eng ZIA AI001270/ImNIH/Intramural NIH HHS/ Research Support, N.I.H., Extramural Research Support, N.I.H., Intramural Research Support, Non-U.S. Gov't Nat Med. 2022 May;28(5):1050-1062. doi: 10.1038/s41591-022-01724-3. Epub 2022 Feb 17.I | 02/19/2022 | |
| Proteomics technologies for cancer liquid biopsies | Ding Z, et al. | 2022 | Mol Cancer | 21 | 1 | 53 | https://www.doi.org/10.1186/s12943-022-01526-8 | 35,168,611 | Early Detection of Cancer Humans Liquid Biopsy *Neoplasms/diagnosis/genetics Proteome/metabolism *Proteomics/methods Antibody arrays Aptamer Cancer liquid biopsy Mass spectrometry (MS) Proteomics Proximity extension assay (PEA) Reverse phase protein arrays (RPPA) declare no conflicts of interests and no competing interests of this work. | Alterations in DNAs could not reveal what happened in proteins. The accumulated alterations of DNAs would change the manifestation of proteins. Therefore, as is the case in cancer liquid biopsies, deep proteome profiling will likely provide invaluable and clinically relevant information in real-time throughout all stages of cancer progression. However, due to the great complexity of proteomes in liquid biopsy samples and the limitations of proteomic technologies compared to high-plex sequencing technologies, proteomic discoveries have yet lagged behind their counterpart, genomic technologies. Therefore, novel protein technologies are in urgent demand to fulfill the goals set out for biomarker discovery in cancer liquid biopsies.Notably, conventional and innovative technologies are being rapidly developed for proteomic analysis in cancer liquid biopsies. These advances have greatly facilitated early detection, diagnosis, prognosis, and monitoring of cancer evolution, adapted or adopted in response to therapeutic interventions. In this paper, we review the high-plex proteomics technologies that are capable of measuring at least hundreds of proteins simultaneously from liquid biopsy samples, ranging from traditional technologies based on mass spectrometry (MS) and antibody/antigen arrays to innovative technologies based on aptamer, proximity extension assay (PEA), and reverse phase protein arrays (RPPA). | Ding, Zhiyong Wang, Nan Ji, Ning Chen, Zhe-Sheng eng Research Support, Non-U.S. Gov't Review England Mol Cancer. 2022 Feb 15;21(1):53. doi: 10.1186/s12943-022-01526-8.I | 02/17/2022 | |
| Creatine kinase-(MB) and hepcidin as candidate biomarkers for early diagnosis of pulmonary tuberculosis: a proof-of-concept study in Lambarene, Gabon | Essone PN, et al. | 2022 | Infection | 50 | 4 | 897-905 | https://www.doi.org/10.1007/s15010-022-01760-8 | 35,133,607 | Biomarkers Creatine Kinase, MB Form Early Diagnosis Gabon Hepcidins Humans *Mycobacterium tuberculosis ROC Curve Sensitivity and Specificity *Tuberculosis/diagnosis *Tuberculosis, Pulmonary/diagnosis Creatine kinase-MB Diagnosis Hepcidin Tuberculosis | BACKGROUND: The present study aimed to evaluate the diagnostic utility of creatine kinase-MB (CK-MB), hepcidin (HEPC), phospholipase A2 group IIA (PLa2G2A), and myosin-binding protein C (MYBPC1) for tuberculosis (TB). These four biomarkers are differentially regulated between quiescent Mycobacterium tuberculosis (Mtb) infected individuals (non-progressors to TB disease) and Mtb-infected TB disease progressors 6 months before the onset of symptoms. METHODS: We enrolled samples from patients experiencing moderate-to-severe pulmonary infections diseases including 23 TB cases confirmed by smear microscopy and culture, and 34 TB-negative cases. For each participant, the serum levels of the four biomarkers were measured using ELISA. RESULTS: The levels of CK-MB and HEPC were significantly reduced in patients with active TB disease. CK-MB median level was 2045 pg/ml (1455-4000 pg/ml) in active TB cases and 3245 pg/ml (1645-4000 pg/ml) in non-TB pulmonary diseases. Using the receiver operating characteristic curve (ROC) analysis, HEPC and CK-MB had the Area Under the Curve (AUC) of 79% (95% CI 67-91%) and 81% (95% CI 69-93%), respectively. Both markers correlated with TB diagnosis as a single marker. PLa2G2A and MYBPC1 with AUCs of 48% (95% CI 36-65%) and 62% (95% CI 48-76%) did not performed well as single biomarkers. The three markers'model (CK-MB-HEPC-PLa2G2A) had the highest diagnostic accuracy at 82% (95% CI 56-82%) after cross-validation. CONCLUSION: CK-MB and HEPC levels were statistically different between confirmed TB cases and non-TB cases. This study yields promising results for the rapid diagnosis of TB disease using a single marker or three biomarkers model. | Essone, Paulin N Adegbite, Bayode R Mbadinga, Marien J M Mbouna, Armel V Lotola-Mougeni, Fabrice Alabi, Ayodele Edoa, Jean R Lell, Bertrand Alabi, Abraham S Adegnika, Ayola A Ramharter, Michael Siawaya, Joel F D Grobusch, Martin P Kremsner, Peter G Agnandji, Selidji T eng EDCTP-TMA-SF-1946-VARSAF/European and Developing Countries Clinical Trials Partnership/ Germany Infection. 2022 Aug;50(4):897-905. doi: 10.1007/s15010-022-01760-8. Epub 2022 Feb 8.I | 02/09/2022 | |
| Placental proteins with predicted roles in fetal development decrease in premature infants | Schreiner C, et al. | 2022 | Pediatr Res | 92 | 5 | 1316-1324 | https://www.doi.org/10.1038/s41390-022-01942-y | 35,132,128 | Female Humans Infant, Newborn Pregnancy Fetal Blood Fetal Development *Infant, Premature Placenta/metabolism *Pregnancy Proteins | BACKGROUND: Emerging evidence from animal experiments indicate that factors secreted by the placenta are critical for normal fetal organ development. Our objective was to characterize the umbilical vein and artery proteome in preterm infants and identify proteins that decrease in the neonatal circulation following delivery. METHODS: Cord blood at delivery and neonatal blood at 48-72 h of life was collected in 25 preterm infants. Plasma protein abundance was determined using the SomaLogic platform. RESULTS: When comparing protein levels of umbilical venous to arterial cord blood, 434 proteins were significantly higher indicating placental secretion into the fetal circulation. Moreover, when comparing neonatal blood to umbilical vein levels, 142 proteins were significantly lower. These proteins included Endoplasmic reticulum resident protein 29, CD59, Fibroblast growth factor 2 and Dynactin subunit 2, which are involved in brain development and prevention of brain damage as well as Fibroblast growth factor 1 which prevents lung fibrosis. CONCLUSIONS: The late second trimester human placenta secretes proteins into the fetal circulation which decrease following delivery. Many of these proteins are predicted to be important in the development of fetal organs. Further studies are needed to directly link placental proteins to organ development and poor outcomes in preterm infants. IMPACT: Prematurity remains a leading cause of morbidity and mortality requiring the development of novel treatments. Emerging evidence from animal studies suggest that factors secreted from the placenta may be critical in the development of the fetus. We report that the preterm human placenta secretes an array of proteins into the fetal circulation. Some of these proteins are predicted to be involved in the development of the brain and the lung. When born prematurely, infants are deprived of these placental proteins, which may contribute to their poor outcomes. | Schreiner, Cynthia Powell, Theresa L Palmer, Claire Jansson, Thomas eng R21 HD104914/HD/NICHD NIH HHS/ Pediatr Res. 2022 Nov;92(5):1316-1324. doi: 10.1038/s41390-022-01942-y. Epub 2022 Feb 7.I | 02/09/2022 | |
| Defining the effects of traffic-related air pollution on the human plasma proteome using an aptamer proteomic array: A dose-dependent increase in atherosclerosis-related proteins | Mookherjee N, et al. | 2022 | Environ Res | 209 | 112803 | https://www.doi.org/10.1016/j.envres.2022.112803 | 35,120,890 | *Air Pollutants/analysis/toxicity *Air Pollution/adverse effects/analysis *Atherosclerosis/chemically induced/etiology/metabolism Humans Proteome Proteomics Random Allocation Vehicle Emissions/analysis/toxicity Air pollution Atherosclerosis Biomarkers Diesel exhaust | BACKGROUND: Traffic-related air pollution (TRAP) is a critical risk factor and major contributor to respiratory and cardiovascular disease (CVD). The effects of TRAP beyond the lungs can be related to changes in circulatory proteins. However, such TRAP-mediated changes have not been defined in an unbiased manner using a controlled human model. OBJECTIVE: To detail global protein changes (the proteome) in plasma following exposure to inhaled diesel exhaust (DE), a paradigm of TRAP, using controlled human exposures. METHODS: In one protocol, ex-smokers and never-smokers were exposed to filtered air (FA) and DE (300 mug PM(2.5)/m(3)), on order-randomized days, for 2 h. In a second protocol, independent never-smoking participants were exposed to lower concentrations of DE (20, 50 or 150 mug PM(2.5)/m(3)) and FA, for 4 h, on order-randomized days. Each exposure was separated by 4 weeks of washout. Plasma samples obtained 24 h post-exposure from ex-smokers (n = 6) were first probed using Slow off-rate modified aptamer proteomic array. Plasma from never-smokers (n = 11) was used for independent assessment of proteins selected from the proteomics study by immunoblotting. RESULTS: Proteomics analyses revealed that DE significantly altered 342 proteins in plasma of ex-smokers (n = 6). The top 20 proteins therein were primarily associated with inflammation and CVD. Plasma from never-smokers (n = 11) was used for independent assessment of 6 proteins, amongst the top 10 proteins increased by DE in the proteomics study, for immunoblotting. The abundance of all six proteins (fractalkine, apolipoproteins (APOB and APOM), IL18R1, MIP-3 and MMP-12) was significantly increased by DE in plasma of these never-smokers. DE-mediated increase was shown to be concentration-dependent for fractalkine, APOB and MMP-12, all biomarkers of atherosclerosis, which correlated with plasma levels of IL-6, a subclinical marker of CVD, in independent participants. CONCLUSION: This investigation details changes in the human plasma proteome due to TRAP. We identify specific atherosclerosis-related proteins that increase concentration-dependently across a range of TRAP levels applicable worldwide. | Mookherjee, Neeloffer Ryu, Min Hyung Hemshekhar, Mahadevappa Orach, Juma Spicer, Victor Carlsten, Christopher eng Netherlands Environ Res. 2022 Jun;209:112803. doi: 10.1016/j.envres.2022.112803. Epub 2022 Feb 1.I | 02/06/2022 | ||
| Rare SLC13A1 variants associate with intervertebral disc disorder highlighting role of sulfate in disc pathology | Bjornsdottir G, et al. | 2022 | Nat Commun | 13 | 1 | 634 | https://www.doi.org/10.1038/s41467-022-28167-1 | 35,110,524 | 3' Untranslated Regions Bone and Bones/metabolism Genome-Wide Association Study Humans Intervertebral Disc/*metabolism Intervertebral Disc Degeneration/*genetics Intervertebral Disc Displacement/*genetics Sodium Sulfate Cotransporter/*genetics/*metabolism Sulfates/*metabolism Symporters/genetics/metabolism | Back pain is a common and debilitating disorder with largely unknown underlying biology. Here we report a genome-wide association study of back pain using diagnoses assigned in clinical practice; dorsalgia (119,100 cases, 909,847 controls) and intervertebral disc disorder (IDD) (58,854 cases, 922,958 controls). We identify 41 variants at 33 loci. The most significant association (OR(IDD) = 0.92, P = 1.6 x 10(-39); OR(dorsalgia) = 0.92, P = 7.2 x 10(-15)) is with a 3'UTR variant (rs1871452-T) in CHST3, encoding a sulfotransferase enzyme expressed in intervertebral discs. The largest effects on IDD are conferred by rare (MAF = 0.07 - 0.32%) loss-of-function (LoF) variants in SLC13A1, encoding a sodium-sulfate co-transporter (LoF burden OR = 1.44, P = 3.1 x 10(-11)); variants that also associate with reduced serum sulfate. Genes implicated by this study are involved in cartilage and bone biology, as well as neurological and inflammatory processes. | Bjornsdottir, Gyda Stefansdottir, Lilja Thorleifsson, Gudmar Sulem, Patrick Norland, Kristjan Ferkingstad, Egil Oddsson, Asmundur Zink, Florian Lund, Sigrun H Nawaz, Muhammad S Bragi Walters, G Skuladottir, Astros Th Gudjonsson, Sigurjon A Einarsson, Gudmundur Halldorsson, Gisli H Bjarnadottir, Valgerdur Sveinbjornsson, Gardar Helgadottir, Anna Styrkarsdottir, Unnur Gudmundsson, Larus J Pedersen, Ole B Hansen, Thomas Folkmann Werge, Thomas Banasik, Karina Troelsen, Anders Skou, Soren T Thorner, Lise Wegner Erikstrup, Christian Nielsen, Kaspar Rene Mikkelsen, Susan Jonsdottir, Ingileif Bjornsson, Aron Olafsson, Ingvar H Ulfarsson, Elfar Blondal, Josep Vikingsson, Arnor Brunak, Soren Ostrowski, Sisse R Ullum, Henrik Thorsteinsdottir, Unnur Stefansson, Hreinn Gudbjartsson, Daniel F Thorgeirsson, Thorgeir E Stefansson, Kari eng Research Support, Non-U.S. Gov't England Nat Commun. 2022 Feb 2;13(1):634. doi: 10.1038/s41467-022-28167-1.I | 02/04/2022 | |
| Linking Genetics and Proteomics: Gene-Protein Associations Built on Diversity | Schunkert H, et al. | 2022 | Circulation | 145 | 5 | 371-374 | https://www.doi.org/10.1161/CIRCULATIONAHA.121.058303 | 35,100,019 | Genome-Wide Association Study *Genomics Humans *Proteomics Editorials cardiovascular disease ethnic diversity genomics proteomics | Schunkert, Heribert Mayr, Manuel eng SP/17/10/33219/BHF_/British Heart Foundation/United Kingdom RG/16/14/32397/BHF_/British Heart Foundation/United Kingdom CH/16/3/32406/BHF_/British Heart Foundation/United Kingdom Comment Editorial Research Support, Non-U.S. Gov't Circulation. 2022 Feb;145(5):371-374. doi: 10.1161/CIRCULATIONAHA.121.058303. Epub 2022 Jan 31.I | 02/01/2022 | ||
| Aptamer-Based Screen of Neuropsychiatric Lupus Cerebrospinal Fluid Reveals Potential Biomarkers That Overlap With the Choroid Plexus Transcriptome | Vanarsa K, et al. | 2022 | Arthritis Rheumatol | 74 | 7 | 1223-1234 | https://www.doi.org/10.1002/art.42080 | 35,099,126 | *Biomarkers/cerebrospinal fluid Choroid Plexus/metabolism Complement C3/metabolism Humans Immunoglobulin M/metabolism Lipocalin-2/metabolism *Lupus Vasculitis, Central Nervous System/cerebrospinal fluid/diagnosis Macrophage Colony-Stimulating Factor/metabolism Proteomics Transcriptome | OBJECTIVE: As no gold-standard diagnostic test exists for neuropsychiatric systemic lupus erythematosus (NPSLE), we undertook this study to execute a broad screen of NPSLE cerebrospinal fluid (CSF) using an aptamer-based platform. METHODS: CSF was obtained from NPSLE patients and subjected to proteomic assay using the aptamer-based screen. Potential biomarkers were identified and validated in independent NPSLE cohorts in comparison to other neurologic diseases. RESULTS: Forty proteins out of the 1,129 screened were found to be elevated in NPSLE CSF. Based on enzyme-linked immunosorbent assay validation, CSF levels of angiostatin, alpha2-macroglobulin, DAN, fibronectin, hepatocellular carcinoma clone 1, IgM, lipocalin 2, macrophage colony-stimulating factor (M-CSF), and serine protease inhibitor G1 were significantly elevated in a predominantly White NPSLE cohort (n = 24), compared to patients with other neurologic diseases (n = 54), with CSF IgM (area under the curve [AUC] 0.95) and M-CSF (AUC 0.91) being the most discriminatory proteins. In a second Hong Kong-based NPSLE cohort, CSF IgM (AUC 0.78) and lipocalin 2 (AUC 0.85) were the most discriminatory proteins. Several CSF proteins exhibited high diagnostic specificity for NPSLE in both cohorts. Elevated CSF complement C3 was associated with an acute confusional state. Eleven molecules elevated in NPSLE CSF exhibited concordant elevation in the choroid plexus, suggesting shared origins. CONCLUSION: Lipocalin 2, M-CSF, IgM, and complement C3 emerge as promising CSF biomarkers of NPSLE with diagnostic potential. | Vanarsa, Kamala Sasidharan, Prashanth Duran, Valeria Gokaraju, Sirisha Nidhi, Malavika Titus, Anto Sam Crosslee Louis Sam Soomro, Sanam Stock, Ariel D Der, Evan Putterman, Chaim Greenberg, Benjamin Mok, Chi Chiu Hanly, John G Mohan, Chandra eng R01 AR074096/GF/NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Arthritis Rheumatol. 2022 Jul;74(7):1223-1234. doi: 10.1002/art.42080. Epub 2022 May 18.I | 02/01/2022 | |
| Coding and regulatory variants are associated with serum protein levels and disease | Emilsson V, et al. | 2022 | Nat Commun | 13 | 1 | 481 | https://www.doi.org/10.1038/s41467-022-28081-6 | 35,079,000 | Aged Blood Proteins/*genetics Disease/classification/*genetics Exome/*genetics Female *Genetic Predisposition to Disease *Genotype Humans Iceland Male *Polymorphism, Single Nucleotide Proteome/*metabolism | Circulating proteins can be used to diagnose and predict disease-related outcomes. A deep serum proteome survey recently revealed close associations between serum protein networks and common disease. In the current study, 54,469 low-frequency and common exome-array variants were compared to 4782 protein measurements in the serum of 5343 individuals from the AGES Reykjavik cohort. This analysis identifies a large number of serum proteins with genetic signatures overlapping those of many diseases. More specifically, using a study-wide significance threshold, we find that 2021 independent exome array variants are associated with serum levels of 1942 proteins. These variants reside in genetic loci shared by hundreds of complex disease traits, highlighting serum proteins' emerging role as biomarkers and potential causative agents of a wide range of diseases. | Emilsson, Valur Gudmundsdottir, Valborg Gudjonsson, Alexander Jonmundsson, Thorarinn Jonsson, Brynjolfur G Karim, Mohd A Ilkov, Marjan Staley, James R Gudmundsson, Elias F Launer, Lenore J Lindeman, Jan H Morton, Nicholas M Aspelund, Thor Lamb, John R Jennings, Lori L Gudnason, Vilmundur eng N01AG12100/AG/NIA NIH HHS/ 206194/WT_/Wellcome Trust/United Kingdom R01 AG065596/AG/NIA NIH HHS/ WT_/Wellcome Trust/United Kingdom HHSN271201200022C/DA/NIDA NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't England Nat Commun. 2022 Jan 25;13(1):481. doi: 10.1038/s41467-022-28081-6.I | 01/27/2022 | |
| A genome-wide association study of serum proteins reveals shared loci with common diseases | Gudjonsson A, et al. | 2022 | Nat Commun | 13 | 1 | 480 | https://www.doi.org/10.1038/s41467-021-27850-z | 35,078,996 | Aged Aged, 80 and over Blood Proteins/*genetics Cohort Studies Disease/classification/*genetics Female *Genetic Predisposition to Disease *Genome, Human Genome-Wide Association Study/*methods Humans Iceland Male *Polymorphism, Single Nucleotide *Quantitative Trait Loci | With the growing number of genetic association studies, the genotype-phenotype atlas has become increasingly more complex, yet the functional consequences of most disease associated alleles is not understood. The measurement of protein level variation in solid tissues and biofluids integrated with genetic variants offers a path to deeper functional insights. Here we present a large-scale proteogenomic study in 5,368 individuals, revealing 4,035 independent associations between genetic variants and 2,091 serum proteins, of which 36% are previously unreported. The majority of both cis- and trans-acting genetic signals are unique for a single protein, although our results also highlight numerous highly pleiotropic genetic effects on protein levels and demonstrate that a protein's genetic association profile reflects certain characteristics of the protein, including its location in protein networks, tissue specificity and intolerance to loss of function mutations. Integrating protein measurements with deep phenotyping of the cohort, we observe substantial enrichment of phenotype associations for serum proteins regulated by established GWAS loci, and offer new insights into the interplay between genetics, serum protein levels and complex disease. | Gudjonsson, Alexander Gudmundsdottir, Valborg Axelsson, Gisli T Gudmundsson, Elias F Jonsson, Brynjolfur G Launer, Lenore J Lamb, John R Jennings, Lori L Aspelund, Thor Emilsson, Valur Gudnason, Vilmundur eng HHSN271201200022C/DA/NIDA NIH HHS/ N01AG12100/AG/NIA NIH HHS/ R01 AG065596/AG/NIA NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't England Nat Commun. 2022 Jan 25;13(1):480. doi: 10.1038/s41467-021-27850-z.I | 01/27/2022 | |
| Using the Plasma Proteome for Risk Stratifying Patients with Pulmonary Arterial Hypertension | Rhodes CJ, et al. | 2022 | Am J Respir Crit Care Med | 205 | 9 | 1102-1111 | https://www.doi.org/10.1164/rccm.202105-1118OC | 35,081,018 | Area Under Curve Biomarkers Familial Primary Pulmonary Hypertension Humans Natriuretic Peptide, Brain Peptide Fragments Prognosis Proteome *Pulmonary Arterial Hypertension clinical outcomes | Rationale: NT-proBNP (N-terminal pro-brain natriuretic peptide), a biomarker of cardiac origin, is used to risk stratify patients with pulmonary arterial hypertension (PAH). Its limitations include poor sensitivity to early vascular pathology. Other biomarkers of vascular or systemic origin may also be useful in the management of PAH. Objectives: Identify prognostic proteins in PAH that complement NT-proBNP and clinical risk scores. Methods: An aptamer-based assay (SomaScan version 4) targeting 4,152 proteins was used to measure plasma proteins in patients with idiopathic, heritable, or drug-induced PAH from the UK National Cohort of PAH (n = 357) and the French EFORT (Evaluation of Prognostic Factors and Therapeutic Targets in PAH) study (n = 79). Prognostic proteins were identified in discovery-replication analyses of UK samples. Proteins independent of 6-minute-walk distance and NT-proBNP entered least absolute shrinkage and selection operator modeling, and the best combination in a single score was evaluated against clinical targets in EFORT. Measurements and Main Results: Thirty-one proteins robustly informed prognosis independent of NT-proBNP and 6-minute-walk distance in the UK cohort. A weighted combination score of six proteins was validated at baseline (5-yr mortality; area under the curve [AUC], 0.73; 95% confidence interval [CI], 0.63-0.85) and follow-up in EFORT (AUC, 0.84; 95% CI, 0.75-0.94; P = 9.96 x 10(-6)). The protein score risk stratified patients independent of established clinical targets and risk equations. The addition of the six-protein model score to NT-proBNP improved prediction of 5-year outcomes from AUC 0.762 (0.702-0.821) to 0.818 (0.767-0.869) by receiver operating characteristic analysis (P = 0.00426 for difference in AUC) in the UK replication and French samples combined. Conclusions: The plasma proteome informs prognosis beyond established factors in PAH and may provide a more sensitive measure of therapeutic response. | Rhodes, Christopher J Wharton, John Swietlik, Emilia M Harbaum, Lars Girerd, Barbara Coghlan, J Gerry Lordan, James Church, Colin Pepke-Zaba, Joanna Toshner, Mark Wort, Stephen J Kiely, David G Condliffe, Robin Lawrie, Allan Graf, Stefan Montani, David Boucly, Athenais Sitbon, Olivier Humbert, Marc Howard, Luke S Morrell, Nicholas W Wilkins, Martin R eng FS/15/59/31839/BHF_/British Heart Foundation/United Kingdom MR/K020919/1/MRC_/Medical Research Council/United Kingdom FS/13/48/30453/BHF_/British Heart Foundation/United Kingdom FS/18/52/33808/BHF_/British Heart Foundation/United Kingdom RE/18/4/34215/BHF_/British Heart Foundation/United Kingdom SP/12/12/29836/BHF_/British Heart Foundation/United Kingdom DH_/Department of Health/United Kingdom SP/18/10/33975/BHF_/British Heart Foundation/United Kingdom Research Support, Non-U.S. Gov't Am J Respir Crit Care Med. 2022 May 1;205(9):1102-1111. doi: 10.1164/rccm.202105-1118OC.I | 01/27/2022 | |
| Comparison of Proteomic Expression Profiles after Radiation Exposure across Four Different Species | Sproull M, et al. | 2022 | Radiat Res | 197 | 4 | 315-323 | https://www.doi.org/10.1667/RADE-21-00182.1 | 35,073,400 | Animals Biomarkers/metabolism Dose-Response Relationship, Radiation Histones Humans Mice Mice, Inbred C57BL *Proteomics *Radiation Exposure/adverse effects/analysis Swine Swine, Miniature | There is a need to identify biomarkers of radiation exposure for use in development of circulating biodosimeters for radiation exposure and for clinical use as markers of radiation injury. Most research approaches for biomarker discovery rely on a single animal model. The current study sought to take advantage of a novel aptamer-based proteomic assay which has been validated for use in many species to characterize changes to the blood proteome after total-body irradiation (TBI) across four different mammalian species including humans. Plasma was collected from C57BL6 mice, Sinclair minipigs, and Rhesus non-human primates (NHPs) receiving a single dose of TBI at a range of 3.3 Gy to 4.22 Gy at 24 h postirradiation. NHP and minipig models were irradiated using a 60Co source at a dose rate of 0.6 Gy/min, the C57BL6 mouse model using an X-ray source at a dose rate of 2.28 Gy/min and clinical samples from a photon source at 10 cGy/min. Plasma was collected from human patients receiving a single dose of 2 Gy TBI collected 6 h postirradiation. Plasma was screened using the aptamer-based SomaLogic SomaScan(R) proteomic assay technology to evaluate changes in the expression of 1,310 protein analytes. Confirmatory analysis of protein expression of biomarker HIST1H1C, was completed using plasma from C57BL6 mice receiving a 2, 3.5 or 8 Gy TBI collected at days 1, 3, and 7 postirradiation by singleplex ELISA. Summary of key pathways with altered expression after radiation exposure across all four mammalian species was determined using Ingenuity Pathway Analysis (IPA). Detectable values were obtained for all 1,310 proteins in all samples included in the SomaScan assay. A subset panel of protein biomarkers which demonstrated significant (p < 0.05) changes in expression of at least 1.3-fold after radiation exposure were characterized for each species. IPA of significantly altered proteins yielded a variety of top disease and biofunction pathways across species with the organismal injury and abnormalities pathway held in common for all four species. The HIST1H1C protein was shown to be radiation responsive within the human, NHP and murine species within the SomaScan dataset and was shown to demonstrate dose dependent upregulation at 2, 3.5 and 8 Gy at 24 h postirradiation in a separate murine cohort by ELISA. The SomaScan proteomics platform is a useful screening tool to evaluate changes in biomarker expression across multiple mammalian species. In our study, we were able to identify a novel biomarker of radiation exposure, HIST1H1C, and characterize panels of radiation responsive proteins and functional proteomic pathways altered by radiation exposure across murine, minipig, NHP and human species. Our study demonstrates the efficacy of using a multispecies approach for biomarker discovery. | Sproull, Mary Nishita, Denise Chang, Polly Moroni, Maria Citrin, Deborah Shankavaram, Uma Camphausen, Kevin eng Z99 CA999999/ImNIH/Intramural NIH HHS/ Research Support, N.I.H., Extramural Research Support, N.I.H., Intramural Radiat Res. 2022 Apr 1;197(4):315-323. doi: 10.1667/RADE-21-00182.1.I | 01/25/2022 | |
| Association of Circulating Proteins with Death or Lung Transplant in Patients with Idiopathic Pulmonary Fibrosis in the IPF-PRO Registry Cohort | Todd JL, et al. | 2022 | Lung | 200 | 1 | 18-Nov | https://www.doi.org/10.1007/s00408-021-00505-y | 35,066,606 | Cohort Studies Humans *Idiopathic Pulmonary Fibrosis *Lung Transplantation Proteomics Registries Biomarkers Interstitial lung diseases Observational study Proteomics RO, HM and SMP are employees of the Duke Clinical Research Institute, which was funded by Boehringer Ingelheim Pharmaceuticals, Inc to conduct this research. JR reports grants and personal fees from Boehringer Ingelheim and grants from Genentech, Galapagos, Syneos Health, Bellerophon Therapeutics, FibroGen, and the National Institutes of Health. JAL reports personal fees from Biogen, Boehringer Ingelheim, Galecto, Roche/Genentech and Veracyte. JAdA reports personal fees from Boehringer Ingelheim. MG reports personal fees, non-financial support, and other support from the France Foundation grants, non-financial support and other support from Boehringer Ingelheim and the Pulmonary Fibrosis Foundation and personal fees from Genentech. HH is on a speaker panel for Boehringer Ingelheim. IN reports personal fees from Boehringer Ingelheim, Genentech, and ImmuneWorks. JAB has no disclosures. KRF reports grants and personal fees from Boehringer Ingelheim and Roche/Genentech and personal fees from FibroGen, Sanofi, Genzyme, and Veracyte. TBL was an employee of Boehringer Ingelheim at the time this study was conducted. CH is an employee of Boehringer Ingelheim. | Idiopathic pulmonary fibrosis (IPF) is a progressive and ultimately fatal disease with a variable clinical course. Biomarkers that predict patient outcomes are needed. We leveraged data from 300 patients in the multicenter IPF-PRO Registry to determine associations between circulating proteins and the composite outcome of respiratory death or lung transplant. Plasma collected at enrollment was analyzed using aptamer-based proteomics (1305 proteins). Over a median follow-up of 30.4 months, there were 76 respiratory deaths and 26 lung transplants. In unadjusted univariable analyses, 61 proteins were significantly associated with the outcome (hazard ratio > 2 or < 0.5, corrected p | Todd, Jamie L Neely, Megan L Overton, Robert Mulder, Hillary Roman, Jesse Lasky, Joseph A de Andrade, Joao A Gulati, Mridu Huang, Howard Leonard, Thomas B Hesslinger, Christian Noth, Imre Belperio, John A Flaherty, Kevin R Palmer, Scott M eng UL1 TR001863/TR/NCATS NIH HHS/ Multicenter Study Research Support, Non-U.S. Gov't Lung. 2022 Feb;200(1):11-18. doi: 10.1007/s00408-021-00505-y. Epub 2022 Jan 23.I | 01/24/2022 | |
| Proteins in the pathway from high red blood cell width distribution to all-cause mortality | Osawa Y, et al. | 2022 | EBioMedicine | 76 | 103816 | https://www.doi.org/10.1016/j.ebiom.2022.103816 | 35,065,420 | Adult Aged Aged, 80 and over Aging *Erythrocyte Indices *Erythrocytes Female Humans Middle Aged Prognosis Proteomics Risk Factors Young Adult Insulin-like growth factor-binding protein 2 Mortality Red blood cell distribution width | BACKGROUND: The pathophysiological mechanisms underlying the association between red blood cell distribution width (RDW) and all-cause mortality are unknown. We conducted a data-driven discovery investigation to identify plasma proteins that mediate the association between RDW and time to death in community-dwelling adults. METHODS: At baseline, 962 adults (women, 54.4%; age range, 21-98 years) participated in the InCHIANTI, Aging in the Chianti Area" study, and proteomics data were generated from their plasma specimens. Of these, 623 participants had proteomics data available at the 9-year follow-up. For each visit, a total of 1301 plasma proteins were measured using SOMAscan technology. Complete data on vital status were available up to the 15-year follow-up period. Protein-specific exponential distribution accelerated failure time, and linear regression analyses adjusted for possible covariates were used for mortality and mediation analyses, respectively (survival data analysis). FINDINGS: Baseline values of EGFR, GHR, NTRK3, SOD2, KLRF1, THBS2, TIMP1, IGFBP2, C9, APOB, and LRP1B mediated the association between baseline RDW and all-cause mortality. Changes in IGFBP2 and C7 over 9 years mediated the association between changes in RDW and 6-year all-cause mortality. INTERPRETATION: Cellular senescence may contribute to the association between RDW and mortality. FUNDING: This study was funded by grants from the National Institutes of Health (NIH) and the National Institute on Aging (NIA) contract and was supported by the Intramural Research Program of the NIA, NIH. The InCHIANTI study was supported as a 'targeted project' by the Italian Ministry of Health and in part by the U.S. NIA." | Osawa, Yusuke Tanaka, Toshiko Semba, Richard D Fantoni, Giovanna Moaddel, Ruin Candia, Julian Simonsick, Eleanor M Bandinelli, Stefania Ferrucci, Luigi eng R01 AG027012/AG/NIA NIH HHS/ R01 AG057723/AG/NIA NIH HHS/ R21 HL112662/HL/NHLBI NIH HHS/ R01 MD009164/MD/NIMHD NIH HHS/ R01 HL111271/HL/NHLBI NIH HHS/ Netherlands EBioMedicine. 2022 Feb;76:103816. doi: 10.1016/j.ebiom.2022.103816. Epub 2022 Jan 19.I | 01/23/2022 | ||
| Aptamers: Potential Diagnostic and Therapeutic Agents for Blood Diseases | Aljohani MM, et al. | 2022 | Molecules | 27 | 2 | https://www.doi.org/10.3390/molecules27020383 | 35,056,696 | *Aptamers, Nucleotide aptamers blood diseases diagnostic therapeutic | Aptamers are RNA/DNA oligonucleotide molecules that specifically bind to a targeted complementary molecule. As potential recognition elements with promising diagnostic and therapeutic applications, aptamers, such as monoclonal antibodies, could provide many treatment and diagnostic options for blood diseases. Aptamers present several superior features over antibodies, including a simple in vitro selection and production, ease of modification and conjugation, high stability, and low immunogenicity. Emerging as promising alternatives to antibodies, aptamers could overcome the present limitations of monoclonal antibody therapy to provide novel diagnostic, therapeutic, and preventive treatments for blood diseases. Researchers in several biomedical areas, such as biomarker detection, diagnosis, imaging, and targeted therapy, have widely investigated aptamers, and several aptamers have been developed over the past two decades. One of these is the pegaptanib sodium injection, an aptamer-based therapeutic that functions as an anti-angiogenic medicine, and it is the first aptamer approved by the U.S. Food and Drug Administration (FDA) for therapeutic use. Several other aptamers are now in clinical trials. In this review, we highlight the current state of aptamers in the clinical trial program and introduce some promising aptamers currently in pre-clinical development for blood diseases. | Aljohani, Maher M Cialla-May, Dana Popp, Jurgen Chinnappan, Raja Al-Kattan, Khaled Zourob, Mohammed eng Review Switzerland Molecules. 2022 Jan 7;27(2):383. doi: 10.3390/molecules27020383.I | 01/22/2022 | ||
| Recent Developments in Clinical Plasma Proteomics-Applied to Cardiovascular Research | Palstrom NB, et al. | 2022 | Biomedicines | 10 | 1 | https://www.doi.org/10.3390/biomedicines10010162 | 35,052,841 | affinity proteomics cardiovascular disease mass spectrometry-based proteomics plasma proteomics | The human plasma proteome mirrors the physiological state of the cardiovascular system, a fact that has been used to analyze plasma biomarkers in routine analysis for the diagnosis and monitoring of cardiovascular diseases for decades. These biomarkers address, however, only a very limited subset of cardiovascular diseases, such as acute myocardial infarct or acute deep vein thrombosis, and clinical plasma biomarkers for the diagnosis and stratification cardiovascular diseases that are growing in incidence, such as heart failure and abdominal aortic aneurysm, do not exist and are urgently needed. The discovery of novel biomarkers in plasma has been hindered by the complexity of the human plasma proteome that again transforms into an extreme analytical complexity when it comes to the discovery of novel plasma biomarkers. This complexity is, however, addressed by recent achievements in technologies for analyzing the human plasma proteome, thereby facilitating the possibility for novel biomarker discoveries. The aims of this article is to provide an overview of the recent achievements in technologies for proteomic analysis of the human plasma proteome and their applications in cardiovascular medicine. | Palstrom, Nicolai Bjodstrup Matthiesen, Rune Rasmussen, Lars Melholt Beck, Hans Christian eng Review Switzerland Biomedicines. 2022 Jan 12;10(1):162. doi: 10.3390/biomedicines10010162.I | 01/22/2022 | ||
| The amniotic fluid proteome changes with gestational age in normal pregnancy: a cross-sectional study | Bhatti G, et al. | 2022 | Sci Rep | 12 | 1 | 601 | https://www.doi.org/10.1038/s41598-021-04050-9 | 35,022,423 | Adult Amniotic Fluid/*metabolism Cross-Sectional Studies Female *Gestational Age Humans Pregnancy/*metabolism *Proteome Retrospective Studies Young Adult | The cell-free transcriptome in amniotic fluid (AF) has been shown to be informative of physiologic and pathologic processes in pregnancy; however, the change in AF proteome with gestational age has mostly been studied by targeted approaches. The objective of this study was to describe the gestational age-dependent changes in the AF proteome during normal pregnancy by using an omics platform. The abundance of 1310 proteins was measured on a high-throughput aptamer-based proteomics platform in AF samples collected from women during midtrimester (16-24 weeks of gestation, n = 15) and at term without labor (37-42 weeks of gestation, n = 13). Only pregnancies without obstetrical complications were included in the study. Almost 25% (320) of AF proteins significantly changed in abundance between the midtrimester and term gestation. Of these, 154 (48.1%) proteins increased, and 166 (51.9%) decreased in abundance at term compared to midtrimester. Tissue-specific signatures of the trachea, salivary glands, brain regions, and immune system were increased while those of the gestational tissues (uterus, placenta, and ovary), cardiac myocytes, and fetal liver were decreased at term compared to midtrimester. The changes in AF protein abundance were correlated with those previously reported in the cell-free AF transcriptome. Intersecting gestational age-modulated AF proteins and their corresponding mRNAs previously reported in the maternal blood identified neutrophil-related protein/mRNA pairs that were modulated in the same direction. The first study to utilize an aptamer-based assay to profile the AF proteome modulation with gestational age, it reveals that almost one-quarter of the proteins are modulated as gestation advances, which is more than twice the fraction of altered plasma proteins (~ 10%). The results reported herein have implications for future studies focused on discovering biomarkers to predict, monitor, and diagnose obstetrical diseases. | Bhatti, Gaurav Romero, Roberto Gomez-Lopez, Nardhy Chaiworapongsa, Tinnakorn Jung, Eunjung Gotsch, Francesca Pique-Regi, Roger Pacora, Percy Hsu, Chaur-Dong Kavdia, Mahendra Tarca, Adi L eng HHSN275201300006C/HD/NICHD NIH HHS/ Research Support, N.I.H., Intramural England Sci Rep. 2022 Jan 12;12(1):601. doi: 10.1038/s41598-021-04050-9.I | 01/14/2022 | |
| Epigenetic scores for the circulating proteome as tools for disease prediction | Gadd DA, et al. | 2022 | Elife | 11 | https://www.doi.org/10.7554/eLife.71802 | 35,023,833 | Adolescent Adult Aged Aged, 80 and over Aging Biomarkers Cardiovascular Diseases/*diagnosis DNA Methylation/*genetics Diabetes Mellitus/*diagnosis Epigenesis, Genetic Epigenomics/*methods Female Humans Life Style Male Middle Aged Neoplasms/*diagnosis Proteome/*genetics Risk Factors Scotland Young Adult biomarker epidemiology epigenetic genetics genomics global health human morbiditiy prediction proteomics CH, PV, SC, KE, AM, KS No competing interests declared, RH has received consultant fees from Illumina, RM has received speaker fees from Illumina and is an advisor to the Epigenetic Clock Development Foundation | Protein biomarkers have been identified across many age-related morbidities. However, characterising epigenetic influences could further inform disease predictions. Here, we leverage epigenome-wide data to study links between the DNA methylation (DNAm) signatures of the circulating proteome and incident diseases. Using data from four cohorts, we trained and tested epigenetic scores (EpiScores) for 953 plasma proteins, identifying 109 scores that explained between 1% and 58% of the variance in protein levels after adjusting for known protein quantitative trait loci (pQTL) genetic effects. By projecting these EpiScores into an independent sample (Generation Scotland; n = 9537) and relating them to incident morbidities over a follow-up of 14 years, we uncovered 137 EpiScore-disease associations. These associations were largely independent of immune cell proportions, common lifestyle and health factors, and biological aging. Notably, we found that our diabetes-associated EpiScores highlighted previous top biomarker associations from proteome-wide assessments of diabetes. These EpiScores for protein levels can therefore be a valuable resource for disease prediction and risk stratification. Although our genetic code does not change throughout our lives, our genes can be turned on and off as a result of epigenetics. Epigenetics can track how the environment and even certain behaviors add or remove small chemical markers to the DNA that makes up the genome. The type and location of these markers may affect whether genes are active or silent, this is, whether the protein coded for by that gene is being produced or not. One common epigenetic marker is known as DNA methylation. DNA methylation has been linked to the levels of a range of proteins in our cells and the risk people have of developing chronic diseases. Blood samples can be used to determine the epigenetic markers a person has on their genome and to study the abundance of many proteins. Gadd, Hillary, McCartney, Zaghlool et al. studied the relationships between DNA methylation and the abundance of 953 different proteins in blood samples from individuals in the German KORA cohort and the Scottish Lothian Birth Cohort 1936. They then used machine learning to analyze the relationship between epigenetic markers found in people's blood and the abundance of proteins, obtaining epigenetic scores or 'EpiScores' for each protein. They found 109 proteins for which DNA methylation patterns explained between at least 1% and up to 58% of the variation in protein levels. Integrating the 'EpiScores' with 14 years of medical records for more than 9000 individuals from the Generation Scotland study revealed 137 connections between EpiScores for proteins and a future diagnosis of common adverse health outcomes. These included diabetes, stroke, depression, Alzheimer's dementia, various cancers, and inflammatory conditions such as rheumatoid arthritis and inflammatory bowel disease. Age-related chronic diseases are a growing issue worldwide and place pressure on healthcare systems. They also severely reduce quality of life for individuals over many years. This work shows how epigenetic scores based on protein levels in the blood could predict a person's risk of several of these diseases. In the case of type 2 diabetes, the EpiScore results replicated previous research linking protein levels in the blood to future diagnosis of diabetes. Protein EpiScores could therefore allow researchers to identify people with the highest risk of disease, making it possible to intervene early and prevent these people from developing chronic conditions as they age. eng | Gadd, Danni A Hillary, Robert F McCartney, Daniel L Zaghlool, Shaza B Stevenson, Anna J Cheng, Yipeng Fawns-Ritchie, Chloe Nangle, Cliff Campbell, Archie Flaig, Robin Harris, Sarah E Walker, Rosie M Shi, Liu Tucker-Drob, Elliot M Gieger, Christian Peters, Annette Waldenberger, Melanie Graumann, Johannes McRae, Allan F Deary, Ian J Porteous, David J Hayward, Caroline Visscher, Peter M Cox, Simon R Evans, Kathryn L McIntosh, Andrew M Suhre, Karsten Marioni, Riccardo E eng BB/F019394/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom 216767/Z/19/Z/WT_/Wellcome Trust/United Kingdom 221890/Z/20/Z/WT_/Wellcome Trust/United Kingdom G0700704/MRC_/Medical Research Council/United Kingdom P2C HD042849/HD/NICHD NIH HHS/ MR/R024065/1/MRC_/Medical Research Council/United Kingdom MC_UU_00007/10/MRC_/Medical Research Council/United Kingdom WT_/Wellcome Trust/United Kingdom MR/L023784/2/MRC_/Medical Research Council/United Kingdom MR/M013111/1/MRC_/Medical Research Council/United Kingdom RF1 AG073593/AG/NIA NIH HHS/ 104036/Z/14/Z/WT_/Wellcome Trust/United Kingdom 220857/Z/20/Z/WT_/Wellcome Trust/United Kingdom 203771/Z/16/Z/WT_/Wellcome Trust/United Kingdom 108890/Z/15/Z/WT_/Wellcome Trust/United Kingdom DH_/Department of Health/United Kingdom R01 AG054628/AG/NIA NIH HHS/ P30 AG066614/AG/NIA NIH HHS/ G1001245/MRC_/Medical Research Council/United Kingdom G0701120/MRC_/Medical Research Council/United Kingdom MR/K026992/1/MRC_/Medical Research Council/United Kingdom CZD/16/6/CSO_/Chief Scientist Office/United Kingdom Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't England Elife. 2022 Jan 13;11:e71802. doi: 10.7554/eLife.71802.I | 01/14/2022 | |||
| Acute serum protein and cytokine response of single dose of prednisone in adult volunteers | Roy R, et al. | 2022 | Steroids | 178 | 108953 | https://www.doi.org/10.1016/j.steroids.2021.108953 | 35,026,285 | Blood Proteins *Cytokines/genetics Glucocorticoids/therapeutic use Humans Prednisone/pharmacology *Receptors, Glucocorticoid/genetics/metabolism Tumor Necrosis Factor Ligand Superfamily Member 15 Volunteers Young Adult Corticosteroids Il-10 Il-8 Pharmacodynamic biomarkers Prednisone | Pharmacological glucocorticoids are the most prescribed anti-inflammatory medications, and are chemical variants of cortisol, the circadian and stress hormone. Both endogenous and pharmacological glucocorticoids bind the glucocorticoid receptor (NR3C1) with high affinity, and both then bind downstream gene promoter elements (GRE) to drive positive gene transcription of many proteins. Glucocorticoid/GR complexes also bind distinct negative gene promoter elements (nGRE) to inhibit expression of genes involved in NF-kappaB innate immunity signaling. We sought to define the acute response of a single dose of prednisone (0.2 mg/kg) in young adult volunteers, with blood samples taken at baseline, 2, 3, 4 and 6 h post-oral dose. To control for circadian morning cortisol hitting the same molecular pathways, a day of blood draws was done without oral prednisone (same time of day), one day prior to drug day. Serum samples were processed for steroid hormone profiles (mass spectrometry; 9 steroidal hormones), proteomics (SOMAscan aptamer panels, 1,305 proteins), and inflammatory markers (Meso Scale Discovery; 10 pro-inflammatory cytokines). The pharmacological effect of the prednisone dose was shown by significant declines of adrenal steroids by 3 h after dosing. IL-10 showed drug-related increase to 4 hrs, then decrease to 6 hrs. IL-8 showed drug-related decrease in serum by 4 h, consistent with direct negative action of GR/ligand on IL-8 gene promoter. Proteomics data showed beta-2 microglobulin, TNFSF15, TSH, CST3, NBL1 to show time-related decreases with prednisone, while CXCL13 showed increases, although these require validation. In summary, a single low dose of prednisone leads to broad suppression of the adrenal axis within 3 h, and down-regulation of inflammatory serum proteins by 6 h. | Roy, Runia Soldin, Steven J Stolze, Brian Barbieri, Marissa Tawalbeh, Shefa M Rouhana, Nicole Fronczek, Ann E Nagaraju, Kanneboyina van den Anker, John Dang, Utkarsh J Hoffman, Eric P eng U54 HD090254/HD/NICHD NIH HHS/ Research Support, N.I.H., Extramural Steroids. 2022 Feb;178:108953. doi: 10.1016/j.steroids.2021.108953. Epub 2022 Jan 10.I | 01/14/2022 | ||
| Influenza A Virus Uses PSMA2 for Downregulation of the NRF2-Mediated Oxidative Stress Response | Rashid MU, et al. | 2022 | J Virol | 96 | 5 | e0199021 | https://www.doi.org/10.1128/jvi.01990-21 | 35,019,712 | Down-Regulation *Host-Pathogen Interactions/genetics Humans Immune Evasion/genetics *Influenza A virus/genetics/immunology *Influenza, Human/immunology/virology NF-E2-Related Factor 2/genetics Oxidative Stress *Proteasome Endopeptidase Complex/genetics/metabolism Proteomics Reactive Oxygen Species/metabolism Virus Replication/genetics Nrf-2 Psma2 host protein influenza A virus proteasome | Influenza A virus (IAV), an obligatory intracellular parasite, uses host cellular molecules to complete its replication cycle and suppress immune responses. Proteasome subunit alpha type 2 (PSMA2) is a cellular protein highly expressed in IAV-infected human lung epithelial A549 cells. PSMA2 is part of the 20S proteasome complex that degrades or recycles defective proteins and involves proteolytic modification of many cellular regulatory proteins. However, the role of PSMA2 in IAV replication is not well understood. In this study, PSMA2 knockdown (KD) in A549 cells caused a significant reduction in extracellular progeny IAV, but intracellular viral protein translation and viral RNA transcription were not affected. This indicates that PSMA2 is a critical host factor for IAV maturation. To better understand the interplay between PSMA2 KD and IAV infection at the proteomic level, we used the SomaScan 1.3K version, which measures 1,307 proteins to analyze alterations induced by these treatments. We found seven cellular signaling pathways, including phospholipase C signaling, Pak signaling, and nuclear factor erythroid 2p45-related factor 2 (NRF2)-mediated oxidative stress response signaling, that were inhibited by IAV infection but significantly activated by PSMA2 KD. Further analysis of NRF2-mediated oxidative stress response signaling indicated IAV inhibits accumulation of reactive oxygen species (ROS), but ROS levels significantly increased during IAV infection in PSMA2 KD cells. However, IAV infection caused significantly higher NFR2 nuclear translocation that was inhibited in PSMA2 KD cells. This indicates that PSMA2 is required for NRF2-mediated ROS neutralization and that IAV uses PSMA2 to escape viral clearance via the NRF2-mediated cellular oxidative response. IMPORTANCE Influenza A virus (IAV) remains one of the most significant infectious agents, responsible for 3 million to 5 million illnesses each year and more than 50 million deaths during the 20th century. The cellular processes that promote and inhibit IAV infection and pathogenesis remain only partially understood. PSMA2 is a critical component of the 20S proteasome and ubiquitin-proteasome system, which is important in the replication of numerous viruses. This study examined host protein responses to IAV infection alone, PSMA2 knockdown alone, and IAV infection in the presence of PSMA2 knockdown and determined that interfering with PSMA2 function affected IAV maturation. These results help us better understand the importance of PSMA2 in IAV replication and may pave the way for designing additional IAV antivirals targeting PSMA2 or the host proteasome for the treatment of seasonal flu. | Rashid, Mahamud-Ur Gao, Ang Coombs, Kevin M eng MOP-106713/CIHR/Canada Research Support, Non-U.S. Gov't J Virol. 2022 Mar 9;96(5):e0199021. doi: 10.1128/jvi.01990-21. Epub 2022 Jan 12.I | 01/13/2022 | |
| Genetics of Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay (ARSACS) and Role of Sacsin in Neurodegeneration | Bagaria J, et al. | 2022 | Int J Mol Sci | 23 | 1 | https://www.doi.org/10.3390/ijms23010552 | 35,008,978 | Alleles Amino Acid Substitution Animals Brain/metabolism/pathology Disease Management Gene Expression Regulation Genetic Association Studies *Genetic Predisposition to Disease Genotype Heat-Shock Proteins/chemistry/*genetics/metabolism Humans Mitochondria/metabolism Muscle Spasticity/*diagnosis/*genetics/therapy Mutation Neurodegenerative Diseases/diagnosis/*etiology *Phenotype Protein Interaction Domains and Motifs Spinocerebellar Ataxias/*congenital/diagnosis/genetics/therapy Arsacs ataxia neurodegeneration sacsin | Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is an early-onset neurodegenerative disease that was originally discovered in the population from the Charlevoix-Saguenay-Lac-Saint-Jean (CSLSJ) region in Quebec. Although the disease progression of ARSACS may start in early childhood, cases with later onset have also been observed. Spasticity and ataxia could be common phenotypes, and retinal optic nerve hypermyelination is detected in the majority of patients. Other symptoms, such as pes cavus, ataxia and limb deformities, are also frequently observed in affected individuals. More than 200 mutations have been discovered in the SACS gene around the world. Besides French Canadians, SACS genetics have been extensively studied in Tunisia or Japan. Recently, emerging studies discovered SACS mutations in several other countries. SACS mutations could be associated with pathogenicity either in the homozygous or compound heterozygous stages. Sacsin has been confirmed to be involved in chaperon activities, controlling the microtubule balance or cell migration. Additionally, sacsin may also play a crucial role in regulating the mitochondrial functions. Through these mechanisms, it may share common mechanisms with other neurodegenerative diseases. Further studies are needed to define the exact functions of sacsin. This review introduces the genetic mutations discovered in the SACS gene and discusses its pathomechanisms and its possible involvement in other neurodegenerative diseases. | Bagaria, Jaya Bagyinszky, Eva An, Seong Soo A eng 2021R1A6A1A03038996/National Research Foundation of Korea/ 2020R1A2B5B01002463/National Research Foundation/ Review Switzerland Int J Mol Sci. 2022 Jan 4;23(1):552. doi: 10.3390/ijms23010552.I | 01/12/2022 | ||
| Effects of colchicine on lipolysis and adipose tissue inflammation in adults with obesity and metabolic syndrome | Levine JA, et al. | 2022 | Obesity (Silver Spring) | 30 | 2 | 358-368 | https://www.doi.org/10.1002/oby.23341 | 34,978,374 | Adipose Tissue/metabolism Adult Biomarkers/metabolism Colchicine/metabolism/pharmacology/therapeutic use Humans Inflammation/metabolism Insulin/metabolism *Insulin Resistance Lipolysis *Metabolic Syndrome/metabolism Obesity/complications/drug therapy/metabolism | OBJECTIVE: The aim of this study was to examine whether colchicine's anti-inflammatory effects would improve measures of lipolysis and distribution of leukocyte populations in subcutaneous adipose tissue (SAT). METHODS: A secondary analysis was conducted for a double-blind, randomized, placebo-controlled pilot study in which 40 adults with obesity and metabolic syndrome (MetS) were randomized to colchicine 0.6 mg or placebo twice daily for 3 months. Non-insulin-suppressible (l(0) ), insulin-suppressible (l(2) ), and maximal (l(0) +l(2) ) lipolysis rates were calculated by minimal model analysis. Body composition was determined by dual-energy x-ray absorptiometry. SAT leukocyte populations were characterized by flow cytometry analysis from biopsied samples obtained before and after the intervention. RESULTS: Colchicine treatment significantly decreased l(2) and l(0) +l(2) versus placebo (p < 0.05). These changes were associated with a significant reduction in markers of systemic inflammation, including high-sensitivity C-reactive protein, resistin, and circulating monocytes and neutrophils (p < 0.01). Colchicine did not significantly alter SAT leukocyte population distributions (p > 0.05). CONCLUSIONS: In adults with obesity and MetS, colchicine appears to improve insulin regulation of lipolysis and reduce markers of systemic inflammation independent of an effect on local leukocyte distributions in SAT. Further studies are needed to better understand the mechanisms by which colchicine affects adipose tissue metabolic pathways in adults with obesity and MetS. | Levine, Jordan A Sarrafan-Chaharsoughi, Zahra Patel, Tushar P Brady, Sheila M Chivukula, K Karthik Miller, Emily Han, Jung Min Periwal, Vipul Wolska, Anna Remaley, Alan T Dagur, Pradeep K Biancotto, Angelique Babyak, Ashley Fantoni, Giovanna Yanovski, Jack A Demidowich, Andrew P eng Z99 HD999999/ImNIH/Intramural NIH HHS/ ZIA HD000641/ImNIH/Intramural NIH HHS/ Randomized Controlled Trial Research Support, N.I.H., Intramural Obesity (Silver Spring). 2022 Feb;30(2):358-368. doi: 10.1002/oby.23341. Epub 2022 Jan 3.I | 01/04/2022 | |
| Serum Proteomics Uncovers Biomarkers of Clinical Portal Hypertension in Children With Biliary Atresia | Osborn J, et al. | 2022 | Hepatol Commun | 6 | 5 | 995-1004 | https://www.doi.org/10.1002/hep4.1878 | 34,962,102 | *Biliary Atresia/complications Biomarkers Child Endothelial Cells Humans *Hypertension, Portal/diagnosis Infant Proteomics | Children with biliary atresia (BA) often develop portal hypertension (PHT) and its complications, which are associated with high morbidity and mortality. The goal of this study was to identify serum biomarkers of PHT by using large-scale proteomics. We applied the slow off-rate modified aptamer scan (SOMAscan) to measure 1,305 proteins in serum samples of children with BA with and without clinical evidence of PHT in validation and discovery cohorts enrolled in the Biliary Atresia Study of Infants and Children. Serum proteomics data was analyzed using logistic regression to identify protein(s) with an area under the receiver operating characteristic curve (AUROC) >/= 0.90. Immunostaining was used to characterize the cellular localization of the new biomarker proteins in liver tissues. We identified nine proteins in the discovery cohort (n = 40 subjects) and five proteins in the validation cohort (n = 80 subjects) that individually or in combination predicted clinical PHT with AUROCs >/= 0.90. Merging the two cohorts, we found that semaphorin 6B (SEMA6B) alone and three other protein combinations (SEMA6B+secreted frizzle protein 3 [SFRP3], SEMA6B+COMM domain containing 7 [COMMD7], and vascular cell adhesion molecule 1 [VCAM1]+BMX nonreceptor tyrosine kinase [BMX]) had AUROCs >/= 0.90 in both cohorts, with high positive- and negative-predictive values. Immunostaining of the new protein biomarkers showed increased expression in hepatic endothelial cells, cholangiocytes, and immune cells within portal triads in BA livers with clinical PHT compared to healthy livers. Conclusion: Large-scale proteomics identified SEMA6B, SFRP3, COMMD7, BMX, and VCAM1 as biomarkers highly associated with clinical PHT in BA. The expression of the biomarkers in hepatic epithelial, endothelial, and immune cells support their potential role in the pathophysiology of PHT. | Osborn, Julie Mourya, Reena Thanekar, Unmesha Su, Weizhe Fei, Lin Shivakumar, Pranavkumar Bezerra, Jorge A eng T32 DK007727/DK/NIDDK NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Hepatol Commun. 2022 May;6(5):995-1004. doi: 10.1002/hep4.1878. Epub 2021 Dec 27.I | 12/29/2021 | |
| Proteomic analysis of serum in workers exposed to diesel engine exhaust | Rahman ML, et al. | 2022 | Environ Mol Mutagen | 63 | 1 | 18-28 | https://www.doi.org/10.1002/em.22469 | 34,894,159 | *Air Pollutants, Occupational/analysis/toxicity Carbon/analysis/metabolism Cross-Sectional Studies Group IB Phospholipases A2/metabolism Humans Inflammation/metabolism *Occupational Exposure/adverse effects/analysis Proteomics RNA-Binding Proteins/analysis Vehicle Emissions/analysis/toxicity SOMAscan carcinogenesis diesel engine exhaust elemental carbon lung cancer | Diesel engine exhaust (DEE) is classified as a Group 1 human carcinogen. Using a targeted proteomics approach, we aimed to identify proteins associated with DEE and characterize these markers to understand the mechanisms of DEE-induced carcinogenicity. In this cross-sectional molecular epidemiology study, we measured elemental carbon (EC) using a personal air monitor and quantified 1317 targeted proteins in the serum using the SOMAScan assay (SOMALogic) among 19 diesel exposed factory workers and 19 unexposed controls. We used linear regressions to identify proteins associated with DEE and examined their exposure-response relationship across levels of EC using linear trend tests. We further examined pathway enrichment of DEE-related proteins using MetaCore. Occupational exposure to DEE was associated with altered levels of 22 serum proteins (permutation p < .01). Of these, 13 proteins (CXCL11, HAPLN1, FLT4, CD40LG, PES1, IGHE.IGK..IGL, TNFSF9, PGD, NAGK, CCL25, CCL4L1, PDXK, and PLA2G1B) showed an exposure-response relationship with EC (p trend < .01), with serum levels of all but PLA2G1B declining with increasing air levels of EC. For instance, C-X-C Motif Chemokine Ligand 11 (CXCL11) showed the most significant association with DEE (beta = -0.25; permutation p = .00004), where mean serum levels were 4121.1, 2356.7, and 2298.8 relative fluorescent units among the unexposed, lower exposed (median, range : 56.9, 40.2-62.1 mug/m(3) EC), and higher exposed (median, range of EC: 72.9, 66.9-107.7 mug/m(3) EC) groups, respectively (p trend = .0005). Pathway analysis suggested that these proteins are enriched in pathways related to inflammation and immune regulation. Our study suggests that DEE exposure is associated with altered serum proteins, which play a role in inflammation and immune regulation. | Rahman, Mohammad L Bassig, Bryan A Dai, Yufei Hu, Wei Wong, Jason Y Y Blechter, Batel Hosgood, H Dean Ren, Danzhi Duan, Huawei Niu, Yong Xu, Jun Fu, Wei Meliefste, Kees Zhou, Baosen Yang, Jufang Ye, Meng Jia, Xiaowei Meng, Tao Bin, Ping Silverman, Debra T Vermeulen, Roel Rothman, Nathaniel Zheng, Yuxin Lan, Qing eng Research Support, N.I.H., Intramural Research Support, Non-U.S. Gov't Environ Mol Mutagen. 2022 Jan;63(1):18-28. doi: 10.1002/em.22469. Epub 2021 Dec 28.I | 12/12/2021 | |
| Whole Genome Sequence Analysis of the Plasma Proteome in Black Adults Provides Novel Insights Into Cardiovascular Disease | Katz DH, et al. | 2022 | Circulation | 145 | 5 | 357-370 | https://www.doi.org/10.1161/CIRCULATIONAHA.121.055117 | 34,814,699 | Adult Blacks Cardiovascular Diseases/*epidemiology/*genetics Female Genome-Wide Association Study/*methods Humans Male Proteome/*metabolism cardiovascular disease genetics proteomics race and ethnicity | BACKGROUND: Plasma proteins are critical mediators of cardiovascular processes and are the targets of many drugs. Previous efforts to characterize the genetic architecture of the plasma proteome have been limited by a focus on individuals of European descent and leveraged genotyping arrays and imputation. Here we describe whole genome sequence analysis of the plasma proteome in individuals with greater African ancestry, increasing our power to identify novel genetic determinants. METHODS: Proteomic profiling of 1301 proteins was performed in 1852 Black adults from the Jackson Heart Study using aptamer-based proteomics (SomaScan). Whole genome sequencing association analysis was ascertained for all variants with minor allele count >/=5. Results were validated using an alternative, antibody-based, proteomic platform (Olink) as well as replicated in the Multi-Ethnic Study of Atherosclerosis and the HERITAGE Family Study (Health, Risk Factors, Exercise Training and Genetics). RESULTS: We identify 569 genetic associations between 479 proteins and 438 unique genetic regions at a Bonferroni-adjusted significance level of 3.8x10(-11). These associations include 114 novel locus-protein relationships and an additional 217 novel sentinel variant-protein relationships. Novel cardiovascular findings include new protein associations at the APOE gene locus including ZAP70 (sentinel single nucleotide polymorphism [SNP] rs7412-T, beta=0.61+/-0.05, P=3.27x10(-30)) and MMP-3 (beta=-0.60+/-0.05, P=1.67x10(-32)), as well as a completely novel pleiotropic locus at the HPX gene, associated with 9 proteins. Further, the associations suggest new mechanisms of genetically mediated cardiovascular disease linked to African ancestry; we identify a novel association between variants linked to APOL1-associated chronic kidney and heart disease and the protein CKAP2 (rs73885319-G, beta=0.34+/-0.04, P=1.34x10(-17)) as well as an association between ATTR amyloidosis and RBP4 levels in community-dwelling individuals without heart failure. CONCLUSIONS: Taken together, these results provide evidence for the functional importance of variants in non-European populations, and suggest new biological mechanisms for ancestry-specific determinants of lipids, coagulation, and myocardial function. | Katz, Daniel H Tahir, Usman A Bick, Alexander G Pampana, Akhil Ngo, Debby Benson, Mark D Yu, Zhi Robbins, Jeremy M Chen, Zsu-Zsu Cruz, Daniel E Deng, Shuliang Farrell, Laurie Sinha, Sumita Schmaier, Alec A Shen, Dongxiao Gao, Yan Hall, Michael E Correa, Adolfo Tracy, Russell P Durda, Peter Taylor, Kent D Liu, Yongmei Johnson, W Craig Guo, Xiuqing Yao, Jie Ida Chen, Yii-Der Manichaikul, Ani W Jain, Deepti Bouchard, Claude Sarzynski, Mark A Rich, Stephen S Rotter, Jerome I Wang, Thomas J Wilson, James G Natarajan, Pradeep Gerszten, Robert E (Trans-Omics for Precision Medicine) eng R01 NR019628/NR/NINR NIH HHS/ DP5 OD029586/OD/NIH HHS/ R01 DK081572/DK/NIDDK NIH HHS/ R01 HL142711/HL/NHLBI NIH HHS/ R01 HL132320/HL/NHLBI NIH HHS/ R01 HL133870/HL/NHLBI NIH HHS/ T32 HL007374/HL/NHLBI NIH HHS/ F32 HL150992/HL/NHLBI NIH HHS/ K08 HL145095/HL/NHLBI NIH HHS/ U01 DK062413/DK/NIDDK NIH HHS/ KL2 TR002542/TR/NCATS NIH HHS/ K08 HL141601/HL/NHLBI NIH HHS/ RF1 AG063507/AG/NIA NIH HHS/ K23 DK127073/DK/NIDDK NIH HHS/ R01 HL146462/HL/NHLBI NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Circulation. 2022 Feb;145(5):357-370. doi: 10.1161/CIRCULATIONAHA.121.055117. Epub 2021 Nov 24.I | 11/25/2021 | |
| Liquid biomarkers for fibrotic NASH - progress in a complex field | Schuppan D, et al. | 2022 | J Hepatol | 76 | 1 | 7-May | https://www.doi.org/10.1016/j.jhep.2021.11.005 | 34,801,249 | Biomarkers Fibrosis Humans *Non-alcoholic Fatty Liver Disease/diagnosis Companion biomarker Nafld fibrogenesis liver biopsy liver fibrosis prediction serum marker arrangement or affiliation with any organization that may have a direct influence on their work. Please refer to the accompanying ICMJE disclosure forms for further details. | Schuppan, Detlef Myneni, Sudharani Surabattula, Rambabu eng Comment Editorial Research Support, Non-U.S. Gov't Netherlands J Hepatol. 2022 Jan;76(1):5-7. doi: 10.1016/j.jhep.2021.11.005. Epub 2021 Nov 17.I | 11/22/2021 | ||
| Identification of blood-based biomarkers for diagnosis and prognosis of Parkinson's disease: A systematic review of proteomics studies | Chelliah SS, et al. | 2022 | Ageing Res Rev | 73 | 101514 | https://www.doi.org/10.1016/j.arr.2021.101514 | 34,798,300 | Biomarkers Dopaminergic Neurons Humans *Parkinson Disease/diagnosis Prognosis Proteomics Apolipoprotein A-I Apolipoproteins Blood-based biomarkers Parkinson's disease Systematic review | Parkinson's Disease (PD), a neurodegenerative disorder, is characterised by the loss of motor function and dopamine neurons. Therapeutic avenues remain a challenge due to lack of accuracy in early diagnosis, monitoring of disease progression and limited therapeutic options. Proteomic platforms have been utilised to discover biomarkers for numerous diseases, a tool that may benefit the diagnosis and monitoring of disease progression in PD patients. Therefore, this systematic review focuses on analysing blood-based candidate biomarkers (CB) identified via proteomics platforms for PD. This study systematically reviewed articles across six databases (EMBASE, Cochrane, Ovid Medline, Scopus, Science Direct and PubMed) published between 2010 and 2020. Of the 504 articles identified, 12 controlled-PD studies were selected for further analysis. A total of 115 candidate biomarkers (CB) were identified across selected 12-controlled studies, of which 23 CB were found to be replicable in more than two cohorts. Using the PANTHER Go-Slim classification system and STRING network, the gene function and protein interactions between biomarkers were analysed. Our analysis highlights Apolipoprotein A-I (ApoA-I), which is essential in lipid metabolism, oxidative stress, and neuroprotection demonstrates high replicability across five cohorts with consistent downregulation across four cohorts. Since ApoA-I was highly replicable across blood fractions, proteomic platforms and continents, its relationship with cholesterol, statin and oxidative stress as PD biomarker, its role in the pathogenesis of PD is discussed in this paper. The present study identified ApoA-I as a potential biomarker via proteomics analysis of PD for the early diagnosis and prediction of disease progression. | Chelliah, Shalini Sundramurthi Bhuvanendran, Saatheeyavaane Magalingam, Kasthuri Bai Kamarudin, Muhamad Noor Alfarizal Radhakrishnan, Ammu Kutty eng Research Support, Non-U.S. Gov't Review Systematic Review England Ageing Res Rev. 2022 Jan;73:101514. doi: 10.1016/j.arr.2021.101514. Epub 2021 Nov 16.I | 11/20/2021 | ||
| Proteome-wide associations with short- and long-term weight loss and regain after Roux-en-Y gastric bypass surgery | Yousri NA, et al. | 2022 | Obesity (Silver Spring) | 30 | 1 | 129-141 | https://www.doi.org/10.1002/oby.23303 | 34,796,696 | Body Mass Index Follow-Up Studies *Gastric Bypass/methods Humans *Obesity, Morbid/complications/surgery Proteome Retrospective Studies Treatment Outcome Weight Loss | OBJECTIVE: Gastric bypass surgery results in long-term weight loss. Small studies have examined protein changes during rapid weight loss (up to 1 or 2 years post surgery). This study tested whether short-term changes were maintained after 12 years. METHODS: A 12-year follow-up, protein-wide association study of 1,297 SomaLogic aptamer-based plasma proteins compared short- (2-year) and long-term (12-year) protein changes in 234 individuals who had gastric bypass surgery with 144 nonintervened individuals with severe obesity. RESULTS: There were 51 replicated 12-year protein changes that differed between the surgery and nonsurgery groups. Adjusting for change in BMI, only 12 proteins remained significant, suggesting that BMI change was the primary reason for most protein changes and not non-BMI-related surgical effects. Protein changes were related to BMI changes during both weight-loss and weight-regain periods. The significant proteins were associated primarily with lipid, uric acid, or resting energy expenditure clinical variables and metabolic pathways. Eight protein changes were associated with 12-year diabetes remission, including apolipoprotein M, sex hormone binding globulin, and adiponectin (p < 3.5 x 10(-5) ). CONCLUSIONS: This study showed that most short-term postsurgical changes in proteins were maintained at 12 years. Systemic protection pathways, including inflammation, complement, lipid, and adipocyte pathways, were related to the long-term benefits of gastric bypass surgery. | Yousri, Noha A Engelke, Rudolf Sarwath, Hina McKinlay, Rodrick D Simper, Steven C Adams, Ted D Schmidt, Frank Suhre, Karsten Hunt, Steven C eng M01 RR000064/RR/NCRR NIH HHS/ R01 DK055006/DK/NIDDK NIH HHS/ Research Support, N.I.H., Extramural Research Support, N.I.H., Intramural Research Support, Non-U.S. Gov't Obesity (Silver Spring). 2022 Jan;30(1):129-141. doi: 10.1002/oby.23303. Epub 2021 Nov 18.I | 11/20/2021 | |
| Clinically Relevant Circulating Protein Biomarkers for Type 1 Diabetes: Evidence From a Two-Sample Mendelian Randomization Study | Yazdanpanah N, et al. | 2022 | Diabetes Care | 45 | 1 | 169-177 | https://www.doi.org/10.2337/dc21-1049 | 34,758,976 | Biomarkers *Diabetes Mellitus, Type 1/genetics *Epstein-Barr Virus Infections Genome-Wide Association Study/methods Herpesvirus 4, Human Humans Mendelian Randomization Analysis/methods Polymorphism, Single Nucleotide | OBJECTIVE: To identify circulating proteins influencing type 1 diabetes susceptibility using Mendelian randomization (MR). RESEARCH DESIGN AND METHODS: We used a large-scale two-sample MR study, using cis genetic determinants (protein quantitative trait loci [pQTL]) of up to 1,611 circulating proteins from five large genome-wide association studies, to screen for causal associations of these proteins with type 1 diabetes risk in 9,684 case subjects with type 1 diabetes and 15,743 control subjects. Further, pleiotropy-robust MR methods were used in sensitivity analyses using both cis and trans-pQTL. RESULTS: We found that a genetically predicted SD increase in signal regulatory protein gamma (SIRPG) level was associated with increased risk of type 1 diabetes risk (MR odds ratio [OR] 1.66 [95% 1.36-2.03]; P = 7.1 x 10-7). The risk of type 1 diabetes increased almost twofold per genetically predicted standard deviation (SD) increase in interleukin-27 Epstein-Barr virus-induced 3 (IL27-EBI3) protein levels (MR OR 1.97 [95% CI 1.48-2.62]; P = 3.7 x 10-6). However, an SD increase in chymotrypsinogen B1 (CTRB1) was associated with decreased risk of type 1 diabetes (MR OR 0.84 [95% CI 0.77-0.90]; P = 6.1 x 10-6). Sensitivity analyses using MR methods testing for pleiotropy while including trans-pQTL showed similar results. While the MR-Egger suggested no pleotropic effect (P value MR-Egger intercept = 0.31), there was evidence of pleiotropy in MR-PRESSO (P value global test = 0.006). CONCLUSIONS: We identified three novel circulating protein biomarkers associated with type 1 diabetes risk using an MR approach. These biomarkers are promising targets for development of drugs and/or of screening tools for early prediction of type 1 diabetes. | Yazdanpanah, Nahid Yazdanpanah, Mojgan Wang, Ye Forgetta, Vincenzo Pollak, Michael Polychronakos, Constantin Richards, J Brent Manousaki, Despoina eng Research Support, Non-U.S. Gov't Diabetes Care. 2022 Jan 1;45(1):169-177. doi: 10.2337/dc21-1049.I | 11/12/2021 | |
| ADAMTSL2 protein and a soluble biomarker signature identify at-risk non-alcoholic steatohepatitis and fibrosis in adults with NAFLD | Corey KE, et al. | 2022 | J Hepatol | 76 | 1 | 25-33 | https://www.doi.org/10.1016/j.jhep.2021.09.026 | 34,600,973 | ADAMTS Proteins/*analysis Adult Area Under Curve Biomarkers/analysis Biopsy/methods/statistics & numerical data Case-Control Studies Cohort Studies Female Humans Liver Cirrhosis/blood/*diagnosis/pathology Logistic Models Male Massachusetts Middle Aged Non-alcoholic Fatty Liver Disease/*diagnosis/pathology Prospective Studies ROC Curve Adamtsl2 biomarker fibrosis non-alcoholic fatty liver disease non-alcoholic steatohepatitis proteomics of Novartis. KEC serves on the scientific advisory board for Novo Nordisk and BMS and has received grant funding from Boehringer-Ingelheim, BMS and Novartis. All other authors have no conflicts of interest to declare. Please refer to the accompanying ICMJE disclosure forms for further details. | BACKGROUND & AIMS: Identifying fibrosis in non-alcoholic fatty liver disease (NAFLD) is essential to predict liver-related outcomes and guide treatment decisions. A protein-based signature of fibrosis could serve as a valuable, non-invasive diagnostic tool. This study sought to identify circulating proteins associated with fibrosis in NAFLD. METHODS: We used aptamer-based proteomics to measure 4,783 proteins in 2 cohorts (Cohort A and B). Targeted, quantitative assays coupling aptamer-based protein pull down and mass spectrometry (SPMS) validated the profiling results in a bariatric and NAFLD cohort (Cohort C and D, respectively). Generalized linear modeling-logistic regression assessed the ability of candidate proteins to classify fibrosis. RESULTS: From the multiplex profiling, 16 proteins differed significantly by fibrosis in cohorts A (n = 62) and B (n = 98). Quantitative and robust SPMS assays were developed for 8 proteins and validated in Cohorts C (n = 71) and D (n = 84). The A disintegrin and metalloproteinase with thrombospondin motifs like 2 (ADAMTSL2) protein accurately distinguished non-alcoholic fatty liver (NAFL)/non-alcoholic steatohepatitis (NASH) with fibrosis stage 0-1 (F0-1) from at-risk NASH with fibrosis stage 2-4, with AUROCs of 0.83 and 0.86 in Cohorts C and D, respectively, and from NASH with significant fibrosis (F2-3), with AUROCs of 0.80 and 0.83 in Cohorts C and D, respectively. An 8-protein panel distinguished NAFL/NASH F0-1 from at-risk NASH (AUROCs 0.90 and 0.87 in Cohort C and D, respectively) and NASH F2-3 (AUROCs 0.89 and 0.83 in Cohorts C and D, respectively). The 8-protein panel and ADAMTSL2 protein had superior performance to the NAFLD fibrosis score and fibrosis-4 score. CONCLUSION: The ADAMTSL2 protein and an 8-protein soluble biomarker panel are highly associated with at-risk NASH and significant fibrosis; they exhibited superior diagnostic performance compared to standard of care fibrosis scores. LAY SUMMARY: Non-alcoholic fatty liver disease (NAFLD) is one of the most common causes of liver disease worldwide. Diagnosing NAFLD and identifying fibrosis (scarring of the liver) currently requires a liver biopsy. Our study identified novel proteins found in the blood which may identify fibrosis without the need for a liver biopsy. | Corey, Kathleen E Pitts, Rebecca Lai, Michelle Loureiro, Joseph Masia, Ricard Osganian, Stephanie A Gustafson, Jenna L Hutter, Matthew M Gee, Denise W Meireles, Ozanan R Witkowski, Elan R Richards, Shola M Jacob, Jaison Finkel, Nancy Ngo, Debby Wang, Thomas J Gerszten, Robert E Ukomadu, Chinweike Jennings, Lori L eng P30 DK040561/DK/NIDDK NIH HHS/ R03 DK113349/DK/NIDDK NIH HHS/ R01 HL132320/HL/NHLBI NIH HHS/ R01 HL133870/HL/NHLBI NIH HHS/ R01 DK114144/DK/NIDDK NIH HHS/ Research Support, N.I.H., Extramural Netherlands J Hepatol. 2022 Jan;76(1):25-33. doi: 10.1016/j.jhep.2021.09.026. Epub 2021 Oct 1.I | 10/04/2021 | |
| The Plasma Proteome Fingerprint Associated with Circulating Carotenoids and Retinol in Older Adults | Yamaguchi Y, et al. | 2022 | J Nutr | 152 | 1 | 40-48 | https://www.doi.org/10.1093/jn/nxab340 | 34,550,359 | Carotenoids Lutein *Proteome Proteomics *Vitamin A Zeaxanthins beta Carotene carotene carotenoid cryptoxanthin lycopene protein retinol zeaxanthin | BACKGROUND: Although diets rich in carotenoids are associated with reduced risks of cardiovascular disease, age-related macular degeneration, disability, and other adverse aging outcomes, the underlying biological mechanisms are not fully elucidated. OBJECTIVES: To characterize the plasma proteome fingerprint associated with circulating carotenoid and retinol concentrations in older adults. METHODS: In 728 adults >/=65 y participating in the Invecchiare in Chianti (InCHIANTI) Study, plasma alpha-carotene, beta-carotene, beta-cryptoxanthin, lutein, zeaxanthin, and lycopene were measured using HPLC. The SOMAscan assay was used to measure 1301 plasma proteins. Multivariable linear regression models were used to examine the relationship of individual carotenoids and retinol with plasma proteins. A false discovery rate approach was used to deal with multiple comparisons using a q-value < 0.05. RESULTS: Plasma beta-carotene, beta-cryptoxanthin, lutein, zeaxanthin, and lycopene were associated with 85, 39, 4, 2, and 5 plasma proteins, respectively, in multivariable linear regression models adjusting for potential confounders (q < 0.05). No proteins were associated with alpha-carotene or retinol. Two or more carotenoids were positively associated with ferritin, 6-phosphogluconate dehydrogenase (decarboxylating), hepcidin, thrombospondin-2, and choline/ethanolamine kinase. The proteins associated with circulating carotenoids were related to energy metabolism, sirtuin signaling, inflammation and oxidative stress, iron metabolism, proteostasis, innate immunity, and longevity. CONCLUSIONS: The plasma proteomic fingerprint associated with elevated circulating carotenoids in older adults provides insight into the mechanisms underlying the protective role of carotenoids on health. | Yamaguchi, Yuko Zampino, Marta Tanaka, Toshiko Bandinelli, Stefania Moaddel, Ruin Fantoni, Giovanna Candia, Julian Ferrucci, Luigi Semba, Richard D eng R01 AG057723/AG/NIA NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't J Nutr. 2022 Jan 11;152(1):40-48. doi: 10.1093/jn/nxab340.I | 09/23/2021 | |
| Pediatric and adult dilated cardiomyopathy are distinguished by distinct biomarker profiles | Gropler MRF, et al. | 2022 | Pediatr Res | 92 | 1 | 206-215 | https://www.doi.org/10.1038/s41390-021-01698-x | 34,404,929 | Biomarkers *Cardiomyopathy, Dilated/diagnosis Humans Phenotype Prospective Studies | BACKGROUND: Emerging evidence suggests that pediatric and adult dilated cardiomyopathy (DCM) represent distinct diseases. Few diagnostic tools exist for pediatric cardiologists to assess clinical status and prognosis. We hypothesized that pediatric DCM would have a unique biomarker profile compared to adult DCM and controls. METHODS: We utilized a DNA aptamer array (SOMAScan) to compare biomarker profiles between pediatric and adult DCM. We simultaneously measured 1310 plasma proteins and peptides from 39 healthy children (mean age 3 years, interquartile range (IQR) 1-14), 39 ambulatory subjects with pediatric DCM (mean age 2.7 years, IQR 1-13), and 40 ambulatory adults with DCM (mean age 53 years, IQR 46-63). RESULTS: Pediatric and adult DCM patients displayed distinct biomarker profiles, despite similar clinical characteristics. We identified 20 plasma peptides and proteins that were increased in pediatric DCM compared to age- and sex-matched controls. Unbiased multidimensionality reduction analysis suggested previously unrecognized heterogeneity among pediatric DCM subjects. Biomarker profile analysis identified four subgroups of pediatric DCM with distinguishing clinical characteristics. CONCLUSIONS: These findings support the emerging concept that pediatric and adult DCM are distinct disease entities, signify the need to develop pediatric-specific biomarkers for disease prognostication, and challenge the paradigm that pediatric DCM should be viewed as a single disease. IMPACT: Pediatric and adult DCM patients displayed distinct biomarker profiles, despite similar clinical characteristics and outcomes. Our findings suggest that pediatric DCM may be a heterogeneous disease with various sub-phenotypes, including differing biomarker profiles and clinical findings. These data provide prerequisite information for future prospective studies that validate the identified pediatric DCM biomarkers, address their diagnostic accuracy and prognostic significance, and explore the full extent of heterogeneity amongst pediatric DCM patients. | Gropler, Melanie R F Lipshultz, Steven E Wilkinson, James D Towbin, Jeffrey A Colan, Steven D Canter, Charles E Lavine, Kory J Simpson, Kathleen E eng R01 HL151438/HL/NHLBI NIH HHS/ UL1 TR000448/TR/NCATS NIH HHS/ R01 HL138466/HL/NHLBI NIH HHS/ R01 HL139714/HL/NHLBI NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Pediatr Res. 2022 Jul;92(1):206-215. doi: 10.1038/s41390-021-01698-x. Epub 2021 Aug 17.I | 08/19/2021 | |
| Plasma proteins, cognitive decline, and 20-year risk of dementia in the Whitehall II and Atherosclerosis Risk in Communities studies | Lindbohm JV, et al. | 2022 | Alzheimers Dement | 18 | 4 | 612-624 | https://www.doi.org/10.1002/alz.12419 | 34,338,426 | *Alzheimer Disease *Atherosclerosis/epidemiology Blood Proteins *Cognitive Dysfunction/epidemiology *Dementia/epidemiology Humans Prospective Studies tau Proteins cognitive decline cohort study dementia longitudinal study proteomics the hypothesis and study design and SomaLogic, Inc. provided expertise in plasma proteins and funded the SOMAscan assays. Joni V. Lindbohm and Pyry N. Sipila have received personal lecture fees from the University of Helsinki. Nina Mars reports no conflicts of interest. Keenan A. Walker reports personal lecture fee from the Boston University Medical Center and holds the Programming Chair at the National Academy of Neuropsychology. Eric J. Brunner reports Osaka University research capacity building grant paid to employer. Archana Singh-Manoux reports no conflicts of interest. Gill Livingston reports no conflicts of interest. Kalle Saksela reports no conflicts of interest. Jane E. Ferrie reports no conflicts of interest. Ruth C. Lovering reports personal lecture fees from the University College London, funding from a COST action grant, and is a member of the executive committee for the International Society of Biocuration (a voluntary role and no payment has been or will be made). Stephen A. Williams is employee of SomaLogic Inc., which has a commercial interest in the results and co-inventor on multiple patents for specific proteomic models of disease. None of these patents relate to dementia (the topic of the manuscript). Aroon D. Hingorani reports no conflicts of interest. Rebecca F. Gottesman reports personal lecture fees for speaking at University of Michigan grand rounds, University of Alabama McKnight lecture, and the American College of Cardiology conference. Rebecca F. Gottesman is the secretary for the American Neurological Association. Henrik Zetterberg reports that he has served on the scientific advisory boards for Denali, Roche Diagnostics, Wave, Samumed, Siemens Healthineers, Pinteon Therapeutics, and CogRx has given lectures in symposia sponsored by Fujirebio, Alzecure, and Biogen and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program. Henrik Zetterberg is also the chair of the Alzheimer's Association Global Biomarker Standardization Consortium and the Alzheimer's Association Biolfluid-Based Biomarker Professional Interest Area. Mika Kivimaki reports no conflicts of interest. | INTRODUCTION: Plasma proteins affect biological processes and are common drug targets but their role in the development of Alzheimer's disease and related dementias remains unclear. We examined associations between 4953 plasma proteins and cognitive decline and risk of dementia in two cohort studies with 20-year follow-ups. METHODS: In the Whitehall II prospective cohort study proteins were measured using SOMAscan technology. Cognitive performance was tested five times over 20 years. Linkage to electronic health records identified incident dementia. The results were replicated in the Atherosclerosis Risk in Communities (ARIC) study. RESULTS: Fifteen non-amyloid/non-tau-related proteins were associated with cognitive decline and dementia, were consistently identified in both cohorts, and were not explained by known dementia risk factors. Levels of six of the proteins are modifiable by currently approved medications for other conditions. DISCUSSION: This study identified several plasma proteins in dementia-free people that are associated with long-term risk of cognitive decline and dementia. | Lindbohm, Joni V Mars, Nina Walker, Keenan A Singh-Manoux, Archana Livingston, Gill Brunner, Eric J Sipila, Pyry N Saksela, Kalle Ferrie, Jane E Lovering, Ruth C Williams, Stephen A Hingorani, Aroon D Gottesman, Rebecca F Zetterberg, Henrik Kivimaki, Mika eng RG/16/11/32334/BHF_/British Heart Foundation/United Kingdom UL1 RR025005/RR/NCRR NIH HHS/ U01 HL096917/HL/NHLBI NIH HHS/ 221854/Z/20/Z/WT_/Wellcome Trust/United Kingdom R01 HL086694/HL/NHLBI NIH HHS/ U01 HL096902/HL/NHLBI NIH HHS/ U01 HG004402/HG/NHGRI NIH HHS/ MR/R024227/1/MRC_/Medical Research Council/United Kingdom RG/13/2/30098/BHF_/British Heart Foundation/United Kingdom HHSN268201700001I/HL/NHLBI NIH HHS/ HHSN268201700004I/HL/NHLBI NIH HHS/ U01 HL096814/HL/NHLBI NIH HHS/ R56 AG056477/AG/NIA NIH HHS/ MR/S011676/1/MRC_/Medical Research Council/United Kingdom R01 HL087641/HL/NHLBI NIH HHS/ HHSN268201700003I/HL/NHLBI NIH HHS/ R01 AG056477/AG/NIA NIH HHS/ U01 HL096812/HL/NHLBI NIH HHS/ K23 AG064122/AG/NIA NIH HHS/ HHSN268201700002C/HL/NHLBI NIH HHS/ RF1 AG062553/AG/NIA NIH HHS/ HHSN268201700005C/HL/NHLBI NIH HHS/ HHSN268201700001C/HL/NHLBI NIH HHS/ HHSN268201700003C/HL/NHLBI NIH HHS/ U01 HL096899/HL/NHLBI NIH HHS/ HHSN268201700004C/HL/NHLBI NIH HHS/ WT_/Wellcome Trust/United Kingdom K24 AG052573/AG/NIA NIH HHS/ HHSN268201700002I/HL/NHLBI NIH HHS/ HHSN268201700005I/HL/NHLBI NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Alzheimers Dement. 2022 Apr;18(4):612-624. doi: 10.1002/alz.12419. Epub 2021 Aug 2.I | 08/03/2021 | |
| Identification and Evaluation of Serum Protein Biomarkers That Differentiate Psoriatic Arthritis From Rheumatoid Arthritis | Mc Ardle A, et al. | 2022 | Arthritis Rheumatol | 74 | 1 | 81-91 | https://www.doi.org/10.1002/art.41899 | 34,114,357 | Adult Arthritis, Psoriatic/*blood/*diagnosis Arthritis, Rheumatoid/*blood/*diagnosis Biomarkers/blood Blood Proteins/*analysis Cross-Sectional Studies Diagnosis, Differential Female Humans Male Middle Aged | OBJECTIVE: To identify serum protein biomarkers that might distinguish patients with early inflammatory arthritis (IA) with psoriatic arthritis (PsA) from those with rheumatoid arthritis (RA) and may be used to support appropriate early intervention. METHODS: The serum proteome of patients with PsA and patients with RA was interrogated using nano-liquid chromatography mass spectrometry (nano-LC-MS/MS) (n = 64 patients), an aptamer-based assay (SomaScan) targeting 1,129 proteins (n = 36 patients), and a multiplexed antibody assay (Luminex) for 48 proteins (n = 64 patients). Multiple reaction monitoring (MRM) assays were developed to evaluate the performance of putative markers using the discovery cohort (n = 60 patients) and subsequently an independent cohort of PsA and RA patients (n = 167). RESULTS: Multivariate machine learning analysis of the protein discovery data from the 3 platforms revealed that it was possible to differentiate PsA patients from RA patients with an area under the curve (AUC) of 0.94 for nano-LC-MS/MS, 0.69 for bead-based immunoassay measurements, and 0.73 for aptamer-based analysis. Subsequently, in the separate verification and evaluation studies, random forest models revealed that a subset of proteins measured by MRM could differentiate PsA and RA patients with AUCs of 0.79 and 0.85, respectively. CONCLUSION: We present a serum protein biomarker panel that can separate patients with early-onset IA with PsA from those with RA. With continued evaluation and refinement using additional and larger patient cohorts, including those with other arthropathies, we suggest that the panel identified here could contribute to improved clinical decision making. | Mc Ardle, Angela Kwasnik, Anna Szentpetery, Agnes Hernandez, Belinda Parnell, Andrew de Jager, Wilco de Roock, Sytze FitzGerald, Oliver Pennington, Stephen R eng 305266/FP7 Health/ Research Support, Non-U.S. Gov't Arthritis Rheumatol. 2022 Jan;74(1):81-91. doi: 10.1002/art.41899. Epub 2021 Nov 23.I | 06/12/2021 | |
| An Approach to Biomarker Discovery of Cannabis Use Utilizing Proteomic, Metabolomic, and Lipidomic Analyses | Hinckley JD, et al. | 2022 | Cannabis Cannabinoid Res | 7 | 1 | 65-77 | https://www.doi.org/10.1089/can.2020.0002 | 33,998,853 | Adult Analgesics Biomarkers Cannabinoid Receptor Agonists *Cannabis Chromatography, Liquid/methods Dronabinol/analysis Female *Hallucinogens Humans Lipidomics Lipids Male Proteomics Substance Abuse Detection/methods Tandem Mass Spectrometry Myc proto-oncogene cannabis markers | Introduction: Relatively little is known about the molecular pathways influenced by cannabis use in humans. We used a multi-omics approach to examine protein, metabolomic, and lipid markers in plasma differentiating between cannabis users and nonusers to understand markers associated with cannabis use. Methods: Eight discordant twin pairs and four concordant twin pairs for cannabis use completed a blood draw, urine and plasma toxicology testing, and provided information about their past 30-day cannabis use and other substance use patterns. The 24 twins were all non-Hispanic whites. Sixty-six percent were female. Median age was 30 years. Fifteen participants reported that they had used cannabis in the last 30 days, including eight participants that used every day or almost every day (29-30 of 30 days). Of these 15 participants, plasma 11-nor-9-carboxy-Delta(9)-tetrahydrocannabinol (THC-COOH) and total tetrahydrocannabinol (THC) concentrations were detectable in 12 participants. Among the eight heavy users" the amount of total THC (sum of THC and its metabolites) and plasma THC-COOH concentrations varied widely, with ranges of 13.1-1713 ng/mL and 2.7-284 ng/mL, respectively. A validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay measured plasma THC-COOH, THC, and other cannabinoids and metabolites. Plasma THC-COOH was used as the primary measure. Expression levels of 1305 proteins were measured using SOMAScan assay, and 34 lipid mediators and 314 metabolites were measured with LC-MS/MS. Analyses examined associations between markers and THC-COOH levels with and without taking genetic relatedness into account. Results: Thirteen proteins, three metabolites, and two lipids were identified as associated with THC-COOH levels. Myc proto-oncogene was identified as associated with THC-COOH levels in both molecular insight and potential marker analyses. Five pathways (interleukin-6 production, T lymphocyte regulation, apoptosis, kinase signaling pathways, and nuclear factor kappa-light-chain-enhancer of activated B cells) were linked with molecules identified in these analyses. Conclusions: THC-COOH levels are associated with immune system-related pathways. This study presents a feasible approach to identify additional molecular markers associated with THC-COOH levels." | Hinckley, Jesse D Saba, Laura Raymond, Kristen Bartels, Karsten Klawitter, Jost Christians, Uwe Hopfer, Christian eng P30 DA044223/DA/NIDA NIH HHS/ K24 DA032555/DA/NIDA NIH HHS/ Research Support, N.I.H., Extramural Twin Study Cannabis Cannabinoid Res. 2022 Feb;7(1):65-77. doi: 10.1089/can.2020.0002. Epub 2020 Jun 19.I | 05/18/2021 | |
| Proteomic signatures predict preeclampsia in individual cohorts but not across cohorts - implications for clinical biomarker studies | Ghaemi MS, et al. | 2022 | J Matern Fetal Neonatal Med | 35 | 25 | 5621-5628 | https://www.doi.org/10.1080/14767058.2021.1888915 | 33,653,202 | Female Humans Pregnancy *Proteomics/methods *Pre-Eclampsia/diagnosis Proteome/metabolism Biomarkers Blood Proteins Biomarker gestational age preeclampsia proteomics | BACKGROUND: Early identification of pregnant women at risk for preeclampsia (PE) is important, as it will enable targeted interventions ahead of clinical manifestations. The quantitative analyses of plasma proteins feature prominently among molecular approaches used for risk prediction. However, derivation of protein signatures of sufficient predictive power has been challenging. The recent availability of platforms simultaneously assessing over 1000 plasma proteins offers broad examinations of the plasma proteome, which may enable the extraction of proteomic signatures with improved prognostic performance in prenatal care. OBJECTIVE: The primary aim of this study was to examine the generalizability of proteomic signatures predictive of PE in two cohorts of pregnant women whose plasma proteome was interrogated with the same highly multiplexed platform. Establishing generalizability, or lack thereof, is critical to devise strategies facilitating the development of clinically useful predictive tests. A second aim was to examine the generalizability of protein signatures predictive of gestational age (GA) in uncomplicated pregnancies in the same cohorts to contrast physiological and pathological pregnancy outcomes. STUDY DESIGN: Serial blood samples were collected during the first, second, and third trimesters in 18 women who developed PE and 18 women with uncomplicated pregnancies (Stanford cohort). The second cohort (Detroit), used for comparative analysis, consisted of 76 women with PE and 90 women with uncomplicated pregnancies. Multivariate analyses were applied to infer predictive and cohort-specific proteomic models, which were then tested in the alternate cohort. Gene ontology (GO) analysis was performed to identify biological processes that were over-represented among top-ranked proteins associated with PE. RESULTS: The model derived in the Stanford cohort was highly significant (p = 3.9E-15) and predictive (AUC = 0.96), but failed validation in the Detroit cohort (p = 9.7E-01, AUC = 0.50). Similarly, the model derived in the Detroit cohort was highly significant (p = 1.0E-21, AUC = 0.73), but failed validation in the Stanford cohort (p = 7.3E-02, AUC = 0.60). By contrast, proteomic models predicting GA were readily validated across the Stanford (p = 1.1E-454, R = 0.92) and Detroit cohorts (p = 1.1.E-92, R = 0.92) indicating that the proteomic assay performed well enough to infer a generalizable model across studied cohorts, which makes it less likely that technical aspects of the assay, including batch effects, accounted for observed differences. CONCLUSIONS: Results point to a broader issue relevant for proteomic and other omic discovery studies in patient cohorts suffering from a clinical syndrome, such as PE, driven by heterogeneous pathophysiologies. While novel technologies including highly multiplex proteomic arrays and adapted computational algorithms allow for novel discoveries for a particular study cohort, they may not readily generalize across cohorts. A likely reason is that the prevalence of pathophysiologic processes leading up to the same" clinical syndrome can be distributed differently in different and smaller-sized cohorts. Signatures derived in individual cohorts may simply capture different facets of the spectrum of pathophysiologic processes driving a syndrome. Our findings have important implications for the design of omic studies of a syndrome like PE. They highlight the need for performing such studies in diverse and well-phenotyped patient populations that are large enough to characterize subsets of patients with shared pathophysiologies to then derive subset-specific signatures of sufficient predictive power." | Ghaemi, Mohammad S Tarca, Adi L Romero, Roberto Stanley, Natalie Fallahzadeh, Ramin Tanada, Athena Culos, Anthony Ando, Kazuo Han, Xiaoyuan Blumenfeld, Yair J Druzin, Maurice L El-Sayed, Yasser Y Gibbs, Ronald S Winn, Virginia D Contrepois, Kevin Ling, Xuefeng B Wong, Ronald J Shaw, Gary M Stevenson, David K Gaudilliere, Brice Aghaeepour, Nima Angst, Martin S eng R01 HL139844/HL/NHLBI NIH HHS/ R35 GM138353/GM/NIGMS NIH HHS/ England J Matern Fetal Neonatal Med. 2022 Dec;35(25):5621-5628. doi: 10.1080/14767058.2021.1888915. Epub 2021 Mar 2.I | 03/04/2021 | |
| Prospects for the application of aptamer based assay platforms in pathogen detection | Banu K, et al. | 2022 | Biocybernetics and Biomedical Engineering | 42 | 3 | 934-949 | https://www.doi.org/10.1016/j.bbe.2022.07.005 | Aptamer SELEX Biosensor Microfluidics Flow-cytometry | Aptamer-based diagnostics platforms for animal, human, plant and environmental pathogens are gaining importance as they are rapid, user-friendly, sensitive and selective. However, most of the aptamer-based platforms have not yet become commercially available. The increasing number of publications signifies the applications of aptamer-based platform and their potential. Herein, the present review is to describe, a brief overview of the development of various aptamer-based platforms and their applicability for the sensitive detection of pathogens. In this review, several aptamer-based platforms such as Enzyme linked immunosorbent assay (ELISA)-like assay, Apta blot, Apta Polymerase Chain Reaction (PCR), Apta array, Aptamer-based Lateral Flow Assays (LFA), Aptamer based fluorescence assay, Flowcytometry-based assay, Apta affinity chromatography, microfluidics-based platforms, and various aptasensor have been discussed. Most of the platforms are highlighted will encourage researchers to focus on developing pathogen detection platform for various applications. | Banu, Kauser Mondal, Bhairab Rai, Bhawana Monica, N. Hanumegowda, Raju | |||
| Identification of PCSK9-like human gene knockouts using metabolomics, proteomics, and whole-genome sequencing in a consanguineous population | Belkadi A, et al. | 2022 | Cell Genomics | epub ahead of print | 100218 | https://www.doi.org/10.1016/j.xgen.2022.100218 | human gene knockouts metabolomics proteomics whole-genome sequencing consanguineous population drug target validation, drug target identification | Summary Natural human knockouts of genes associated with desirable outcomes, such as PCSK9 with low levels of LDL-cholesterol, can lead to the discovery of new drug targets and treatments. Rare loss-of-function variants are more likely to be found in the homozygous state in consanguineous populations, and deep molecular phenotyping of blood samples from homozygous carriers can help to discriminate between silent and functional variants. Here, we combined whole-genome sequencing with proteomics and metabolomics for 2,935 individuals from the Qatar Biobank (QBB) to evaluate the power of this approach for finding genes of clinical and pharmaceutical interest. As proof-of-concept, we identified a homozygous carrier of a very rare PCSK9 variant with extremely low circulating PCSK9 levels and low LDL. Our study demonstrates that the chances of finding such variants are about 168 times higher in QBB compared with GnomAD and emphasizes the potential of consanguineous populations for drug discovery. | Belkadi, Aziz Thareja, Gaurav Abbaszadeh, Fatemeh Badii, Ramin Fauman, Eric Albagha, Omar M. E. Suhre, Karsten | ||||
| Proteome-Wide Analysis Using SOMAscan Identifies and Validates Epidermal Growth Factor as a Disease Marker of Collagenous Gastritis | Curci D, et al. | 2022 | Gastro Hep Advances | 1 | 5 | 689-702 | https://www.doi.org/10.1016/j.gastha.2022.04.016 | Collagenous Gastritis Proteomics Biomarker Epidermal Growth Factor | Collagenous gastritis (CG) is a rare disorder characterized by increased subepithelial collagen deposition and inflammatory infiltrates. The mechanisms involved in CG pathogenesis are poorly understood, and no CG-associated biomarkers have been identified. This proteomics study identified serum biomarkers and pathogenic pathways to provide new knowledge about the pathobiology of CG, a disease reported in less than 100 patients. | Curci, Debora Dillon, Simon T. Gu, Xuesong Winter, Harland Libermann, Towia A. | |||
| Prioritization of drug targets for neurodegenerative diseases by integrating genetic and proteomic data from brain and blood | Ge Y-J, et al. | 2022 | Biological Psychiatry | epub ahead of print | https://www.doi.org/10.1016/j.biopsych.2022.11.002 | drug discovery genetics Mendelian randomization neurodegenerative disease omics proteomics | Background Neurodegenerative diseases are among the most prevalent and devastating neurological disorders, with few effective prevention and treatment strategies. We aimed to integrate genetic and proteomic data to prioritize drug targets for neurodegenerative diseases. Methods We screened human proteomes through Mendelian randomization to identify causal mediators of Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), frontotemporal dementia, and Lewy body dementia. For instruments, we used brain and blood protein quantitative trait loci (pQTLs) identified from one GWAS with 376 individuals and another with 3,301, respectively. Causal associations were subsequently validated by sensitivity analyses and colocalization. The safety and druggability of identified targets were also evaluated. Results Our analyses showed targeting BIN1, GRN, and RET levels in blood, as well as ACE, ICA1L, MAP1S, SLC20A2, and TOM1L2 levels in brain might reduce AD risk, while ICA1L, SLC20A2, and TOM1L2 were not recommended as prioritized drugs due to the identified potential side-effects. Brain CD38, DGKQ, GPNMB, and SEC23IP were candidate targets for PD. Among them, GPNMB was the most promising target for PD with their causal relationship evidenced by studies on both brain and blood tissues. Interventions targeting FCRL3, LMAN2, MAPK3 in blood and DHRS11, FAM120B, SHMT1, TSFM in brain might affect MS risk. The risk of ALS might be reduced by medications targeting DHRS11, PSMB3, SARM1, and SCFD1 in brain. Conclusions Our study prioritized 22 proteins as targets for neurodegenerative diseases and provided preliminary evidence for drug development. Further studies are warranted to validate these targets. | Ge, Yi-Jun Ou, Ya-Nan Deng, Yue-Ting Wu, Bang-Sheng Yang, Liu Zhang, Ya-Ru Chen, Shi-Dong Huang, Yu-Yuan Dong, Qiang Tan, Lan Yu, Jin-Tai | |||||
| Immune system-wide Mendelian randomization and triangulation analyses support autoimmunity as a modifiable component in dementia-causing diseases | Lindbohm JV, et al. | 2022 | Nature Aging | 2 | 10 | 956-972 | https://www.doi.org/10.1038/s43587-022-00293-x | Immune system and blood–brain barrier dysfunction are implicated in the development of Alzheimer’s and other dementia-causing diseases, but their causal role remains unknown. We performed Mendelian randomization for 1,827_immune system- and blood–brain barrier-related biomarkers and identified 127_potential causal risk factors for dementia-causing diseases. Pathway analyses linked these biomarkers to amyloid-_, tau and _-synuclein pathways and to autoimmunity-related processes. A phenome-wide analysis using Mendelian randomization-based polygenic risk score in the FinnGen study (n_=_339,233) for the biomarkers indicated shared genetic background for dementias and autoimmune diseases. This association was further supported by human leukocyte antigen analyses. In inverse-probability-weighted analyses that simulate randomized controlled drug trials in observational data, anti-inflammatory methotrexate treatment reduced the incidence of Alzheimer’s disease in high-risk individuals (hazard ratio compared with no treatment, 0.64, 95% confidence interval 0.49–0.88, P_=_0.005). These converging results from different lines of human research suggest that autoimmunity is a modifiable component in dementia-causing diseases. | Lindbohm, Joni V. Mars, Nina Sipilä, Pyry N. Singh-Manoux, Archana Runz, Heiko Livingston, Gill Seshadri, Sudha Xavier, Ramnik Hingorani, Aroon D. Ripatti, Samuli Kivimäki, Mika | ||||
| Limited proteolysis–mass spectrometry reveals aging-associated changes in cerebrospinal fluid protein abundances and structures | Shuken SR, et al. | 2022 | Nature Aging | 2 | 5 | 379-388 | https://www.doi.org/10.1038/s43587-022-00196-x | Cerebrospinal fluid (CSF) proteins and their structures have been implicated in aging and neurodegenerative diseases. In the present study, we used limited proteolysis–mass spectrometry (LiP–MS) to screen for new aging-associated changes in the CSF proteome using a modified analysis. We found 38 protein groups that change in abundance with aging, predominantly immunoglobulins of the IgM subclass. We discovered six high-confidence candidates that underwent structural changes with aging, of which Kng1, Itih2, Lp-PLA2 and 14-3-3 proteins have binding partners or chemical forms known previously to change in the brains of patients with Alzheimer’s disease. Orthogonal validation by western blotting identified that the LiP–MS hit Cd5l forms a covalent complex with IgM in mouse and human CSF, the abundance of which increases with aging. In human CSF, SOMAmer probe signals for all six LiP–MS hits were associated with cognitive function and/or biomarkers of neurodegeneration, especially 14-3-3 proteins YWHAB and YWHAZ. Together, our findings show that LiP–MS can uncover age-related structural changes in CSF with relevance to neurodegeneration. | Shuken, Steven R. Rutledge, Jarod Iram, Tal Losada, Patricia Moran Wilson, Edward N. Andreasson, Katrin I. Leib, Ryan D. Wyss-Coray, Tony | ||||
| Differential Proteomics of Cardiovascular Risk and Coronary Artery Disease in Humans | Ferrannini E, et al. | 2021 | Front Cardiovasc Med | 8 | 790289 | https://www.doi.org/10.3389/fcvm.2021.790289 | 35,187,107 | atrial myosin regulatory light chain 2 cardiovascular risk factors coronary artery disease protein shisa-3 homolog proteomics Sankyo outside the submitted work. SW is an employee and shareholder of SomaLogic Inc., Boulder, Colorado, USA. AMag reports personal fees from Bayer, Fresenius, and Novartis outside the submitted work. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. | BACKGROUND: Proteomics of atypical phenotypes may help unravel cardiovascular disease mechanisms. AIM: We aimed to prospectively screen the proteome of four types of individuals: with or without coronary artery disease (CAD), each with or without multiple risk factors. Associations with individual risk factors and circulating biomarkers were also tested to provide a functional context to the protein hits. MATERIALS AND METHODS: The CAPIRE study (ClinicalTrials.gov Identifier: NCT02157662) is a cross-sectional study aimed at identifying possible new mechanisms promoting or protecting against atherothrombosis. Quantification (by aptamer technology), ranking (using partial least squares), and correlations (by multivariate regression) of ~5000 plasma proteins were performed in consecutive individuals aged 45-75 years, without previous cardiovascular disease, undergoing computed tomography angiography for suspected CAD, showing either >5/16 atherosclerotic segments (CAD(+)) or completely clean arteries (CAD(-)) and either /=3 risk factors (RF(-)) (based on history, blood pressure, glycemia, lipids, and smoking). RESULTS: Of 544 individuals, 39% were atypical (93 CAD(+)/RF(-); 120 CAD(-)/RF(+)) and 61% typical (102 CAD(+)/RF(+); 229 CAD(-)/RF(-)). In the comparison with CAD(+)/RF(-) adjusted for sex and age, CAD(-)/RF(+) was associated with increased atrial myosin regulatory light chain 2 (MYO) and C-C motif chemokine-22 (C-C-22), and reduced protein shisa-3 homolog (PS-3) and platelet-activating factor acetylhydrolase (PAF-AH). Extending the analysis to the entire cohort, an additional 8 proteins were independently associated with CAD or RF; by logistic regression, the 12-protein panel alone discriminated the four groups with AUC(ROC)'s of 0.72-0.81 (overall p = 1.0e(-38)). Among them, insulin-like growth factor binding protein-3 is positively associated with RF, lower BMI, and HDL-cholesterol, renin with CAD higher glycated hemoglobin HbA(1c), and smoking. CONCLUSIONS: In a CCTA-based cohort, four proteins, involved in opposing vascular processes (healing vs. adverse remodeling), are specifically associated with low CAD burden in high CV-risk individuals (high MYO and C-C-22) and high CAD burden in low-risk subjects (high PS-3 and PAF-AH), in interaction with BMI, smoking, diabetes, HDL-cholesterol, and HbA(1c). These findings could contribute to a deeper understanding of the atherosclerotic process beyond traditional risk profile assessment and potentially constitute new treatment targets. | Ferrannini, Ele Manca, Maria Laura Ferrannini, Giulia Andreotti, Felicita Andreini, Daniele Latini, Roberto Magnoni, Marco Williams, Stephen A Maseri, Attilio Maggioni, Aldo P eng Switzerland Front Cardiovasc Med. 2022 Feb 4;8:790289. doi: 10.3389/fcvm.2021.790289. eCollection 2021.I | 02/22/2022 | ||
| Integrated Multi-Omics for Novel Aging Biomarkers and Antiaging Targets | Wu L, et al. | 2021 | Biomolecules | 12 | 1 | https://www.doi.org/10.3390/biom12010039 | 35,053,186 | Aging/genetics Biomarkers *Genomics/methods Humans Metabolomics/methods *Proteomics/methods aging aging biomarkers aging clock antiaging targets multi-omics | Aging is closely related to the occurrence of human diseases; however, its exact biological mechanism is unclear. Advancements in high-throughput technology provide new opportunities for omics research to understand the pathological process of various complex human diseases. However, single-omics technologies only provide limited insights into the biological mechanisms of diseases. DNA, RNA, protein, metabolites, and microorganisms usually play complementary roles and perform certain biological functions together. In this review, we summarize multi-omics methods based on the most relevant biomarkers in single-omics to better understand molecular functions and disease causes. The integration of multi-omics technologies can systematically reveal the interactions among aging molecules from a multidimensional perspective. Our review provides new insights regarding the discovery of aging biomarkers, mechanism of aging, and identification of novel antiaging targets. Overall, data from genomics, transcriptomics, proteomics, metabolomics, integromics, microbiomics, and systems biology contribute to the identification of new candidate biomarkers for aging and novel targets for antiaging interventions. | Wu, Lei Xie, Xinqiang Liang, Tingting Ma, Jun Yang, Lingshuang Yang, Juan Li, Longyan Xi, Yu Li, Haixin Zhang, Jumei Chen, Xuefeng Ding, Yu Wu, Qingping eng Research Support, Non-U.S. Gov't Review Switzerland Biomolecules. 2021 Dec 28;12(1):39. doi: 10.3390/biom12010039.I | 01/22/2022 | ||
| Multi-omic analysis in injured humans: Patterns align with outcomes and treatment responses | Wu J, et al. | 2021 | Cell Rep Med | 2 | 12 | 100478 | https://www.doi.org/10.1016/j.xcrm.2021.100478 | 35,028,617 | Brain Injuries, Traumatic/*genetics/*therapy Cluster Analysis Cohort Studies *Genomics Humans Metabolome Plasma Proteome/metabolism Time Factors Treatment Outcome PAMPer trial endotype host response metabolomics multi-omics outcome proteomics systemic storm thawed plasma trauma Avita Medical and Spectral MD. M.D.N. holds an equity stake in Haima Therapeutics. He has received research support and/or honoraria from Haemonetics, Instrumentation Laboratories, and Janssen Pharmaceuticals. T.R.B. is a stakeholder in Immunetrics. Other authors declare no conflict of interests. | Trauma is a leading cause of death and morbidity worldwide. Here, we present the analysis of a longitudinal multi-omic dataset comprising clinical, cytokine, endotheliopathy biomarker, lipidome, metabolome, and proteome data from severely injured humans. A systemic storm" pattern with release of 1,061 markers, together with a pattern suggestive of the "massive consumption" of 892 constitutive circulating markers, is identified in the acute phase post-trauma. Data integration reveals two human injury response endotypes, which align with clinical trajectory. Prehospital thawed plasma rescues only endotype 2 patients with traumatic brain injury (30-day mortality: 30.3 versus 75.0%; p = 0.0015). Ubiquitin carboxy-terminal hydrolase L1 (UCHL1) was identified as the most predictive circulating biomarker to identify endotype 2-traumatic brain injury (TBI) patients. These response patterns refine the paradigm for human injury, while the datasets provide a resource for the study of critical illness, trauma, and human stress responses." | Wu, Junru Vodovotz, Yoram Abdelhamid, Sultan Guyette, Francis X Yaffe, Michael B Gruen, Danielle S Cyr, Anthony Okonkwo, David O Kar, Upendra K Krishnamoorthi, Neha Voinchet, Robert G Billiar, Isabel M Yazer, Mark H Namas, Rami A Daley, Brian J Miller, Richard S Harbrecht, Brian G Claridge, Jeffrey A Phelan, Herbert A Zuckerbraun, Brian S Johansson, Par I Stensballe, Jakob Morrissey, James H Tracy, Russell P Wisniewski, Stephen R Neal, Matthew D Sperry, Jason L Billiar, Timothy R eng T32 GM008516/GM/NIGMS NIH HHS/ UM1 HL120877/HL/NHLBI NIH HHS/ R35 GM119526/GM/NIGMS NIH HHS/ R35 GM127027/GM/NIGMS NIH HHS/ R01 HL141080/HL/NHLBI NIH HHS/ Research Support, N.I.H., Extramural Research Support, U.S. Gov't, Non-P.H.S. Cell Rep Med. 2021 Dec 21;2(12):100478. doi: 10.1016/j.xcrm.2021.100478. eCollection 2021 Dec 21.I | 01/15/2022 | |
| Blood Levels of the SMOC1 Hepatokine Are Not Causally Linked with Type 2 Diabetes: A Bidirectional Mendelian Randomization Study | Ghodsian N, et al. | 2021 | Nutrients | 13 | 12 | https://www.doi.org/10.3390/nu13124208 | 34,959,760 | Blood Glucose/metabolism Body Mass Index Case-Control Studies Diabetes Mellitus, Type 2/blood/*genetics Fasting/blood Gene Expression/physiology Genome-Wide Association Study Glycated Hemoglobin A/metabolism Humans Insulin/blood Insulin Resistance/genetics Liver/metabolism Mendelian Randomization Analysis Non-alcoholic Fatty Liver Disease/blood/*genetics Osteonectin/*blood Polymorphism, Single Nucleotide Risk Factors Waist-Hip Ratio Mendelian randomization Smoc1 hepatokine type 2 diabetes research contracts from Pfizer, Ionis Pharmaceuticals and Silence Therapeutics. | Hepatokines are liver-derived proteins that may influence metabolic pathways such as insulin sensitivity. Recently, Sparc-related modular calcium-binding protein 1 (SMOC1) was identified as glucose-responsive hepatokine that is dysregulated in the setting of non-alcoholic fatty liver disease (NAFLD). While SMOC1 may influence glucose-insulin homeostasis in rodents, it is unknown if SMOC1 is influenced by NAFLD in humans. It is also unknown if SMOC1 is causally associated with metabolic and disease traits in humans. Therefore, we aimed to determine the effect of NAFLD on SMOC1 gene expression in the liver and aimed to explore the potential causal associations of SMOC1 levels with NAFLD, T2D, and glycemic traits in humans. Using an RNA sequencing dataset from a cohort of 216 patients with NAFLD, we assessed SMOC1 expression levels across the NAFLD spectrum. We performed a series of bidirectional inverse-variance weighted Mendelian randomization (MR) analyses on blood SMOC1 levels using two sources of genome-wide association studies (GWAS) (Fenland study, n = 10,708 and INTERVAL study, n = 3301). We utilized GWAS summary statistics for NAFLD in 8434 cases and 770,180 controls, as well as publicly available GWAS for type 2 diabetes (T2D), body mass index (BMI), waist-to-hip ratio (WHR), fasting blood insulin (FBI), fasting blood glucose (FBG), homeostatic Model Assessment of Insulin Resistance (HOMA-B and HOMA-IR), and hemoglobin A1c (HbA1C). We found that SMOC1 expression showed no significant differences across NAFLD stages. We also identified that the top single-nucleotide polymorphism associated with blood SMOC1 levels, was associated with SMOC1 gene expression in the liver, but not in other tissues. Using MR, we did not find any evidence that genetically predicted NAFLD, T2D, and glycemic traits influenced SMOC1 levels. We also did not find evidence that blood SMOC1 levels were causally associated with T2D, NAFLD, and glycemic traits. In conclusion, the hepatokine SMOC1 does not appear to be modulated by the presence of NAFLD and may not regulate glucose-insulin homeostasis in humans. Results of this study suggest that blood factors regulating metabolism in rodents may not always translate to human biology. | Ghodsian, Nooshin Gagnon, Eloi Bourgault, Jerome Gobeil, Emilie Manikpurage, Hasanga D Perrot, Nicolas Girard, Arnaud Mitchell, Patricia L Arsenault, Benoit J eng Switzerland Nutrients. 2021 Nov 24;13(12):4208. doi: 10.3390/nu13124208.I | 12/29/2021 | ||
| Large-scale plasma proteomics can reveal distinct endotypes in chronic obstructive pulmonary disease and severe asthma | Suzuki M, et al. | 2021 | Clin Transl Allergy | 11 | 10 | e12091 | https://www.doi.org/10.1002/clt2.12091 | 34,962,717 | Bpco Copd Epoc asma severa asthme severe endotipos endotypen endotypes exosomas exosome exosomen exosomes proteomic proteomics proteomica proteomique schweres Asthma severe asthma ______ ______ _______ ____ Masaru Suzuki has received lecture fees from AstraZeneca, Boehringer Ingelheim, Novartis, and GlaxoSmithKline. Satoshi Konno has received grants from AstraZeneca, Boehringer Ingelheim, KYORIN Pharmaceutical, Novartis, and Japan Allergy Foundation during the conduct of the study, and has received lecture fees from AstraZeneca and Boehringer Ingelheim. Masaharu Nishimura has received grants from AstraZeneca, Boehringer Ingelheim, KYORIN Pharmaceutical, and MSD during the conduct of the study. John J. Cole, Hironi Makita, and Hiroki Kimura have no relevant conflicts of interest. | BACKGROUND: Chronic airway diseases including chronic obstructive pulmonary disease (COPD) and asthma are heterogenous in nature and endotypes within are underpinned by complex biology. This study aimed to investigate the utility of proteomic profiling of plasma combined with bioinformatic mining, and to define molecular endotypes and expand our knowledge of the underlying biology in chronic respiratory diseases. METHODS: The plasma proteome was evaluated using an aptamer-based affinity proteomics platform (SOMAscan(R)), representing 1238 proteins in 34 subjects with stable COPD and 51 subjects with stable but severe asthma. For each disease, we evaluated a range of clinical/demographic characteristics including bronchodilator reversibility, blood eosinophilia levels, and smoking history. We applied modified bioinformatic approaches used in the evaluation of RNA transcriptomics. RESULTS: Subjects with COPD and severe asthma were distinguished from each other by 365 different protein abundancies, with differential pathway networks and upstream modulators. Furthermore, molecular endotypes within each disease could be defined. The protein groups that defined these endotypes had both known and novel biology including groups significantly enriched in exosomal markers derived from immune/inflammatory cells. Finally, we observed associations to clinical characteristics that previously have been under-explored. CONCLUSION: This investigational study evaluating the plasma proteome in clinically-phenotyped subjects with chronic airway diseases provides support that such a method can be used to define molecular endotypes and pathobiological mechanisms that underpins these endotypes. It provided new concepts about the complexity of molecular pathways that define these diseases. In the longer term, such information will help to refine treatment options for defined groups. | Suzuki, Masaru Cole, John J Konno, Satoshi Makita, Hironi Kimura, Hiroki Nishimura, Masaharu Maciewicz, Rose A eng KYORIN Pharmaceutical/ Pfizer/ Boehringer Ingelheim/ Ministry of Health, Labor, and Welfare, Japan/ AstraZeneca/ Japan Allergy Foundation/ 17390239/Ministry of Education, Science, Culture and Sports of Japan/ 2139053/Ministry of Education, Science, Culture and Sports of Japan/ 24249049/Ministry of Education, Science, Culture and Sports of Japan/ England Clin Transl Allergy. 2021 Dec;11(10):e12091. doi: 10.1002/clt2.12091.I | 12/29/2021 | |
| Discovery of Novel Proteomic Biomarkers for the Prediction of Kidney Recovery from Dialysis-Dependent AKI Patients | Daniels JR, et al. | 2021 | Kidney360 | 2 | 11 | 1716-1727 | https://www.doi.org/10.34067/kid.0002642021 | 34,913,041 | *Acute Kidney Injury/diagnosis Biomarkers/urine Humans Kidney/metabolism *Proteomics Renal Dialysis/methods | BACKGROUND: AKI requiring dialysis (AKI-D) is associated with prolonged hospitalization, mortality, and progressive CKD among survivors. Previous studies have examined only select urine or serum biomarkers for predicting kidney recovery from AKI. METHODS: Serum samples collected on day 8 of randomized RRT from 72 patients enrolled in the Veteran's Affairs/National Institutes of Health Acute Renal Failure Trial Network study were analyzed by the SOMAscan proteomic platform to profile 1305 proteins in each sample. Of these patients, 38 recovered kidney function and dialysis was discontinued, whereas another 34 patients remained on dialysis by day 28. RESULTS: Differential serum levels of 119 proteins, with 53 higher and 66 lower, were detected in samples from patients who discontinued dialysis, compared with patients who remained on dialysis by day 28. Patients were classified into tertiles on the basis of SOMAscan protein measurements for the 25 proteins most differentially expressed. The association of serum levels of each protein with kidney recovery was further evaluated using logistic regression analysis. Higher serum levels of CXCL11, CXCL2/CXCL3, CD86, Wnt-7a, BTK, c-Myc, TIMP-3, CCL5, ghrelin, PDGF-C, survivin, CA2, IL-9, EGF, and neuregulin-1, and lower levels of soluble CXCL16, IL1RL1, stanniocalcin-1, IL-6, and FGF23 when classified in tertiles were significantly associated with better kidney recovery. This significant association persisted for each of these proteins after adjusting for potential confounding risk factors including age, sex, cardiovascular SOFA score, congestive heart failure, diabetes, modality of intensive dialysis treatment, cause of AKI, baseline serum creatinine, day 8 urine volume, and estimated 60-day mortality risk. CONCLUSIONS: These results suggest concerted changes between survival-related proteins and immune-regulatory chemokines in regulating angiogenesis, endothelial and epithelial remodeling, and kidney cell regeneration, illustrating potential mechanisms of kidney recovery. Thus, this study identifies potential novel predictive biomarkers of kidney recovery in patients with AKI-D. | Daniels, Jaclyn R Ma, Jennie Z Cao, Zhijun Beger, Richard D Sun, Jinchun Schnackenberg, Laura Pence, Lisa Choudhury, Devasmita Palevsky, Paul M Portilla, Didier Yu, Li-Rong eng FD999999/ImFDA/Intramural FDA HHS/ R01 DK075976/DK/NIDDK NIH HHS/ R01 DK122624/DK/NIDDK NIH HHS/ Research Support, N.I.H., Extramural Research Support, U.S. Gov't, Non-P.H.S. Kidney360. 2021 Nov 25;2(11):1716-1727. doi: 10.34067/kid.0002642021.I | 12/17/2021 | |
| An inflammatory aging clock (iAge) based on deep learning tracks multimorbidity, immunosenescence, frailty and cardiovascular aging | Sayed N, et al. | 2021 | Nat Aging | 1 | 598-615 | https://www.doi.org/10.1038/s43587-021-00082-y | 34,888,528 | While many diseases of aging have been linked to the immunological system, immune metrics capable of identifying the most at-risk individuals are lacking. From the blood immunome of 1,001 individuals aged 8-96 years, we developed a deep-learning method based on patterns of systemic age-related inflammation. The resulting inflammatory clock of aging (iAge) tracked with multimorbidity, immunosenescence, frailty and cardiovascular aging, and is also associated with exceptional longevity in centenarians. The strongest contributor to iAge was the chemokine CXCL9, which was involved in cardiac aging, adverse cardiac remodeling and poor vascular function. Furthermore, aging endothelial cells in human and mice show loss of function, cellular senescence and hallmark phenotypes of arterial stiffness, all of which are reversed by silencing CXCL9. In conclusion, we identify a key role of CXCL9 in age-related chronic inflammation and derive a metric for multimorbidity that can be utilized for the early detection of age-related clinical phenotypes. | Sayed, Nazish Huang, Yingxiang Nguyen, Khiem Krejciova-Rajaniemi, Zuzana Grawe, Anissa P Gao, Tianxiang Tibshirani, Robert Hastie, Trevor Alpert, Ayelet Cui, Lu Kuznetsova, Tatiana Rosenberg-Hasson, Yael Ostan, Rita Monti, Daniela Lehallier, Benoit Shen-Orr, Shai S Maecker, Holden T Dekker, Cornelia L Wyss-Coray, Tony Franceschi, Claudio Jojic, Vladimir Haddad, Francois Montoya, Jose G Wu, Joseph C Davis, Mark M Furman, David eng P30 AG059307/AG/NIA NIH HHS/ P30 AG066515/AG/NIA NIH HHS/ U19 AI057229/AI/NIAID NIH HHS/ U19 AI090019/AI/NIAID NIH HHS/ P50 AG047366/AG/NIA NIH HHS/ P30 DK116074/DK/NIDDK NIH HHS/ UL1 TR003142/TR/NCATS NIH HHS/ UL1 RR025744/RR/NCRR NIH HHS/ K01 HL135455/HL/NHLBI NIH HHS/ Nat Aging. 2021 Jul;1:598-615. doi: 10.1038/s43587-021-00082-y. Epub 2021 Jul 12.I | 12/11/2021 | |||
| Exercise plasma boosts memory and dampens brain inflammation via clusterin | De Miguel Z, et al. | 2021 | Nature | 600 | 7,889 | 494-499 | https://www.doi.org/10.1038/s41586-021-04183-x | 34,880,498 | *Alzheimer Disease/metabolism Animals Clusterin/genetics/metabolism *Encephalitis Endothelial Cells/metabolism Humans Mice Proteomics | Physical exercise is generally beneficial to all aspects of human and animal health, slowing cognitive ageing and neurodegeneration(1). The cognitive benefits of physical exercise are tied to an increased plasticity and reduced inflammation within the hippocampus(2-4), yet little is known about the factors and mechanisms that mediate these effects. Here we show that 'runner plasma', collected from voluntarily running mice and infused into sedentary mice, reduces baseline neuroinflammatory gene expression and experimentally induced brain inflammation. Plasma proteomic analysis revealed a concerted increase in complement cascade inhibitors including clusterin (CLU). Intravenously injected CLU binds to brain endothelial cells and reduces neuroinflammatory gene expression in a mouse model of acute brain inflammation and a mouse model of Alzheimer's disease. Patients with cognitive impairment who participated in structured exercise for 6 months had higher plasma levels of CLU. These findings demonstrate the existence of anti-inflammatory exercise factors that are transferrable, target the cerebrovasculature and benefit the brain, and are present in humans who engage in exercise. | De Miguel, Zurine Khoury, Nathalie Betley, Michael J Lehallier, Benoit Willoughby, Drew Olsson, Niclas Yang, Andrew C Hahn, Oliver Lu, Nannan Vest, Ryan T Bonanno, Liana N Yerra, Lakshmi Zhang, Lichao Saw, Nay Lui Fairchild, J Kaci Lee, Davis Zhang, Hui McAlpine, Patrick L Contrepois, Kevin Shamloo, Mehrdad Elias, Joshua E Rando, Thomas A Wyss-Coray, Tony eng R01 AG071783/AG/NIA NIH HHS/ P30 AG066515/AG/NIA NIH HHS/ F32 AG067652/AG/NIA NIH HHS/ R01 AG047820/AG/NIA NIH HHS/ P01 AG036695/AG/NIA NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. England Nature. 2021 Dec;600(7889):494-499. doi: 10.1038/s41586-021-04183-x. Epub 2021 Dec 8.I | 12/10/2021 | |
| Proteomic Approaches to Defining Remission and the Risk of Relapse in Rheumatoid Arthritis | O'Neil LJ, et al. | 2021 | Front Immunol | 12 | 729681 | https://www.doi.org/10.3389/fimmu.2021.729681 | 34,867,950 | Adult Aged Antirheumatic Agents/therapeutic use Arthritis, Rheumatoid/*blood/*classification/drug therapy Biomarkers/blood Blood Proteins/*analysis Female Humans Male Middle Aged Proteomics Recurrence Remission Induction disease activity outcomes research rheumatoid arthritis treatment commercial or financial relationships that could be construed as a potential conflict of interest. | OBJECTIVES: Patients with Rheumatoid Arthritis (RA) are increasingly achieving stable disease remission, yet the mechanisms that govern ongoing clinical disease and subsequent risk of future flare are not well understood. We sought to identify serum proteomic alterations that dictate clinically important features of stable RA, and couple broad-based proteomics with machine learning to predict future flare. METHODS: We studied baseline serum samples from a cohort of stable RA patients (RETRO, n = 130) in clinical remission (DAS28<2.6) and quantified 1307 serum proteins using the SOMAscan platform. Unsupervised hierarchical clustering and supervised classification were applied to identify proteomic-driven clusters and model biomarkers that were associated with future disease flare after 12 months of follow-up and RA medication withdrawal. Network analysis was used to define pathways that were enriched in proteomic datasets. RESULTS: We defined 4 proteomic clusters, with one cluster (Cluster 4) displaying a lower mean DAS28 score (p = 0.03), with DAS28 associating with humoral immune responses and complement activation. Clustering did not clearly predict future risk of flare, however an XGboost machine learning algorithm classified patients who relapsed with an AUC (area under the receiver operating characteristic curve) of 0.80 using only baseline serum proteomics. CONCLUSIONS: The serum proteome provides a rich dataset to understand stable RA and its clinical heterogeneity. Combining proteomics and machine learning may enable prediction of future RA disease flare in patients with RA who aim to withdrawal therapy. | O'Neil, Liam J Hu, Pingzhao Liu, Qian Islam, Md Mohaiminul Spicer, Victor Rech, Juergen Hueber, Axel Anaparti, Vidyanand Smolik, Irene El-Gabalawy, Hani S Schett, Georg Wilkins, John A eng Multicenter Study Randomized Controlled Trial Research Support, Non-U.S. Gov't Switzerland Front Immunol. 2021 Nov 18;12:729681. doi: 10.3389/fimmu.2021.729681. eCollection 2021.I | 12/07/2021 | ||
| Large-scale integration of the plasma proteome with genetics and disease | Ferkingstad E, et al. | 2021 | Nat Genet | 53 | 12 | 1712-1721 | https://www.doi.org/10.1038/s41588-021-00978-w | 34,857,953 | Biomarkers/blood Blood Proteins/*genetics/metabolism Disease/*genetics Female Gene Frequency Genetic Variation Genome-Wide Association Study Humans Male Middle Aged Proteome/*genetics Quantitative Trait Loci | The plasma proteome can help bridge the gap between the genome and diseases. Here we describe genome-wide association studies (GWASs) of plasma protein levels measured with 4,907 aptamers in 35,559 Icelanders. We found 18,084 associations between sequence variants and levels of proteins in plasma (protein quantitative trait loci; pQTL), of which 19% were with rare variants (minor allele frequency (MAF) < 1%). We tested plasma protein levels for association with 373 diseases and other traits and identified 257,490 associations. We integrated pQTL and genetic associations with diseases and other traits and found that 12% of 45,334 lead associations in the GWAS Catalog are with variants in high linkage disequilibrium with pQTL. We identified 938 genes encoding potential drug targets with variants that influence levels of possible biomarkers. Combining proteomics, genomics and transcriptomics, we provide a valuable resource that can be used to improve understanding of disease pathogenesis and to assist with drug discovery and development. | Ferkingstad, Egil Sulem, Patrick Atlason, Bjarni A Sveinbjornsson, Gardar Magnusson, Magnus I Styrmisdottir, Edda L Gunnarsdottir, Kristbjorg Helgason, Agnar Oddsson, Asmundur Halldorsson, Bjarni V Jensson, Brynjar O Zink, Florian Halldorsson, Gisli H Masson, Gisli Arnadottir, Gudny A Katrinardottir, Hildigunnur Juliusson, Kristinn Magnusson, Magnus K Magnusson, Olafur Th Fridriksdottir, Run Saevarsdottir, Saedis Gudjonsson, Sigurjon A Stacey, Simon N Rognvaldsson, Solvi Eiriksdottir, Thjodbjorg Olafsdottir, Thorunn A Steinthorsdottir, Valgerdur Tragante, Vinicius Ulfarsson, Magnus O Stefansson, Hreinn Jonsdottir, Ingileif Holm, Hilma Rafnar, Thorunn Melsted, Pall Saemundsdottir, Jona Norddahl, Gudmundur L Lund, Sigrun H Gudbjartsson, Daniel F Thorsteinsdottir, Unnur Stefansson, Kari eng Nat Genet. 2021 Dec;53(12):1712-1721. doi: 10.1038/s41588-021-00978-w. Epub 2021 Dec 2.I | 12/04/2021 | |
| High-throughput mediation analysis of human proteome and metabolome identifies mediators of post-bariatric surgical diabetes control | Dreyfuss JM, et al. | 2021 | Nat Commun | 12 | 1 | 6951 | https://www.doi.org/10.1038/s41467-021-27289-2 | 34,845,204 | Animals Biomarkers/blood Blood Glucose/metabolism Body Mass Index Carrier Proteins/blood/genetics Diabetes Mellitus, Type 2/*blood/genetics/pathology/surgery Dipeptidases/blood/genetics Fasting/physiology *Gastric Bypass Gene Expression Regulation Glycated Hemoglobin A/genetics/metabolism Hepatocytes/metabolism/pathology Human Growth Hormone/blood/genetics Humans Insulin-Like Growth Factor Binding Protein 1/blood/genetics Insulin-Like Growth Factor Binding Protein 2/blood/genetics Liver/*metabolism/pathology *Metabolome Obesity/*blood/genetics/pathology/surgery Primary Cell Culture *Proteome Rats Retrospective Studies | To improve the power of mediation in high-throughput studies, here we introduce High-throughput mediation analysis (Hitman), which accounts for direction of mediation and applies empirical Bayesian linear modeling. We apply Hitman in a retrospective, exploratory analysis of the SLIMM-T2D clinical trial in which participants with type 2 diabetes were randomized to Roux-en-Y gastric bypass (RYGB) or nonsurgical diabetes/weight management, and fasting plasma proteome and metabolome were assayed up to 3 years. RYGB caused greater improvement in HbA1c, which was mediated by growth hormone receptor (GHR). GHR's mediation is more significant than clinical mediators, including BMI. GHR decreases at 3 months postoperatively alongside increased insulin-like growth factor binding proteins IGFBP1/BP2; plasma GH increased at 1 year. Experimental validation indicates (1) hepatic GHR expression decreases in post-bariatric rats; (2) GHR knockdown in primary hepatocytes decreases gluconeogenic gene expression and glucose production. Thus, RYGB may induce resistance to diabetogenic effects of GH signaling.Trial Registration: Clinicaltrials.gov NCT01073020. | Dreyfuss, Jonathan M Yuchi, Yixing Dong, Xuehong Efthymiou, Vissarion Pan, Hui Simonson, Donald C Vernon, Ashley Halperin, Florencia Aryal, Pratik Konkar, Anish Sebastian, Yinong Higgs, Brandon W Grimsby, Joseph Rondinone, Cristina M Kasif, Simon Kahn, Barbara B Foster, Kathleen Seeley, Randy Goldfine, Allison Djordjilovic, Vera Patti, Mary Elizabeth eng RC1 DK086918/DK/NIDDK NIH HHS/ P01 DK117821/DK/NIDDK NIH HHS/ U01 DK114156/DK/NIDDK NIH HHS/ P30 DK036836/DK/NIDDK NIH HHS/ P30 DK057521/DK/NIDDK NIH HHS/ R56 DK095451/DK/NIDDK NIH HHS/ R01 DK043051/DK/NIDDK NIH HHS/ Randomized Controlled Trial Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't England Nat Commun. 2021 Nov 29;12(1):6951. doi: 10.1038/s41467-021-27289-2.I | 12/01/2021 | |
| Heat Shock-Related Protein Responses and Inflammatory Protein Changes Are Associated with Mild Prolonged Hypoglycemia | Moin ASM, et al. | 2021 | Cells | 10 | 11 | https://www.doi.org/10.3390/cells10113109 | 34,831,332 | Adult Biomarkers/metabolism Case-Control Studies Diabetes Mellitus, Type 2/blood/metabolism Dinoprost/analogs & derivatives/metabolism Female Heat-Shock Proteins/blood *Heat-Shock Response Humans Hypoglycemia/blood/*metabolism Inflammation/*metabolism Male Middle Aged Oxidative Stress Protein Interaction Mapping Proteins/*metabolism Ubiquitin-Conjugating Enzymes/metabolism heat shock proteins hypoglycemia inflammatory proteins type 2 diabetes | Mild hypoglycemia is common in clinical practice. Severe hypoglycemia results in heat shock protein and associate co-chaperone changes. Whether mild prolonged hypoglycemia elicits a similar response with inflammatory and oxidative-stress responses compared with a severe hypoglycemic event is unclear; therefore, this pilot exploratory study was undertaken. We performed a case-control induced hypoglycemia clamp study, maintaining blood glucose at 2.8 mmol/L (50 mg/dL) for 1 h in 17 subjects (T2D (n = 10); controls (n = 7)). Blood sampling was performed at baseline, hypoglycemia, and 24 h; slow off-rate modified aptamer (SOMA)-scan plasma protein analysis of HSP-related proteins, inflammatory stress markers, and oxidative stress markers was performed. In total, 16 HSPs were analyzed. At baseline, TLR4:MD-2 complex was elevated (p = 0.01), whilst HSPA8 was lower (p < 0.05) in T2D. At hypoglycemia, UBE2N, STIP1, and UBE2L3 increased (all p < 0.05), whilst TLR4:MD-2 and HSPA8 decreased (p < 0.05) in T2D versus baseline. In follow-up after hypoglycemia, HSPs normalized to baseline by 24 h, except UBE2L3 (p < 0.05), which was decreased in controls versus baseline. Correlation of altered inflammatory markers with HSPs revealed the following: at baseline, TLR4:MD-2 correlated with CXCL10 (p < 0.01) and SIGLEC1 (p < 0.05) in controls; HSPA8 negatively correlated with IL5 (p < 0.05) in T2D. A negative correlation between urinary isoprostane 8-iso PGF2alpha, a marker of oxidative stress, and HSPA1A was seen at 24 h in T2D only (p < 0.05). In conclusion, the HSP changes seen for mild prolonged hypoglycemia were similar to those previously reported for a severe event. However, mild prolonged hypoglycemia appeared to elicit an increased inflammatory response that was associated with heat shock and related proteins. | Moin, Abu Saleh Md Nandakumar, Manjula Kahal, Hassan Sathyapalan, Thozhukat Atkin, Stephen L Butler, Alexandra E eng Clinical Trial Switzerland Cells. 2021 Nov 10;10(11):3109. doi: 10.3390/cells10113109.I | 11/28/2021 | ||
| The Use of 'Omics for Diagnosing and Predicting Progression of Chronic Kidney Disease: A Scoping Review | Govender MA, et al. | 2021 | Front Genet | 12 | 682929 | https://www.doi.org/10.3389/fgene.2021.682929 | 34,819,944 | Sub-Saharan Africa biomarkers chronic kidney disease diabetes diagnosis early detection hypertension 'omics commercial or financial relationships that could be construed as a potential conflict of interest. | Globally, chronic kidney disease (CKD) contributes substantial morbidity and mortality. Recently, various 'omics platforms have provided insight into the molecular basis of kidney dysfunction. This scoping review is a synthesis of the current literature on the use of different 'omics platforms to identify biomarkers that could be used to detect early-stage CKD, predict disease progression, and identify pathways leading to CKD. This review includes 123 articles published from January 2007 to May 2021, following a structured selection process. The most common type of 'omic platform was proteomics, appearing in 55 of the studies and two of these included a metabolomics component. Most studies (n = 91) reported on CKD associated with diabetes mellitus. Thirteen studies that provided information on the biomarkers associated with CKD and explored potential pathways involved in CKD are discussed. The biomarkers that are associated with risk or early detection of CKD are SNPs in the MYH9/APOL1 and UMOD genes, the proteomic CKD273 biomarker panel and metabolite pantothenic acid. Pantothenic acid and the CKD273 biomarker panel were also involved in predicting CKD progression. Retinoic acid pathway genes, UMOD, and pantothenic acid provided insight into potential pathways leading to CKD. The biomarkers were mainly used to detect CKD and predict progression in high-income, European ancestry populations, highlighting the need for representative 'omics research in other populations with disparate socio-economic strata, including Africans, since disease etiologies may differ across ethnic groups. To assess the transferability of findings, it is essential to do research in diverse populations. | Govender, Melanie A Brandenburg, Jean-Tristan Fabian, June Ramsay, Michele eng Review Switzerland Front Genet. 2021 Nov 8;12:682929. doi: 10.3389/fgene.2021.682929. eCollection 2021.I | 11/26/2021 | ||
| Synergistic insights into human health from aptamer- and antibody-based proteomic profiling | Pietzner M, et al. | 2021 | Nat Commun | 12 | 1 | 6822 | https://www.doi.org/10.1038/s41467-021-27164-0 | 34,819,519 | Adult Alzheimer Disease/genetics Antibodies/metabolism Aptamers, Peptide/metabolism Cohort Studies Female Humans Male Membrane Glycoproteins/genetics Middle Aged Phenotype Protein Interaction Mapping Protein Interaction Maps/genetics Proteome/*genetics/metabolism Proteomics/*methods *Quantitative Trait Loci Receptors, Immunologic/genetics | Affinity-based proteomics has enabled scalable quantification of thousands of protein targets in blood enhancing biomarker discovery, understanding of disease mechanisms, and genetic evaluation of drug targets in humans through protein quantitative trait loci (pQTLs). Here, we integrate two partly complementary techniques-the aptamer-based SomaScan((R)) v4 assay and the antibody-based Olink assays-to systematically assess phenotypic consequences of hundreds of pQTLs discovered for 871 protein targets across both platforms. We create a genetically anchored cross-platform proteome-phenome network comprising 547 protein-phenotype connections, 36.3% of which were only seen with one of the two platforms suggesting that both techniques capture distinct aspects of protein biology. We further highlight discordance of genetically predicted effect directions between assays, such as for PILRA and Alzheimer's disease. Our results showcase the synergistic nature of these technologies to better understand and identify disease mechanisms and provide a benchmark for future cross-platform discoveries. | Pietzner, Maik Wheeler, Eleanor Carrasco-Zanini, Julia Kerrison, Nicola D Oerton, Erin Koprulu, Mine Luan, Jian'an Hingorani, Aroon D Williams, Steve A Wareham, Nicholas J Langenberg, Claudia eng MC_UU_00006/1/MRC_/Medical Research Council/United Kingdom MC_PC_13046/MRC_/Medical Research Council/United Kingdom AA/18/6/34223/BHF_/British Heart Foundation/United Kingdom WT_/Wellcome Trust/United Kingdom MC_UU_12015/1/MRC_/Medical Research Council/United Kingdom MR/V033867/1/MRC_/Medical Research Council/United Kingdom Observational Study Research Support, Non-U.S. Gov't England Nat Commun. 2021 Nov 24;12(1):6822. doi: 10.1038/s41467-021-27164-0.I | 11/26/2021 | |
| Proteomics and Risk of Atrial Fibrillation in Older Adults (From the Atherosclerosis Risk in Communities [ARIC] Study) | Norby FL, et al. | 2021 | Am J Cardiol | 161 | 42-50 | https://www.doi.org/10.1016/j.amjcard.2021.08.064 | 34,794,617 | Atherosclerosis/*blood/complications/epidemiology Atrial Fibrillation/*blood/complications/epidemiology Biomarkers/blood Female Follow-Up Studies Humans Incidence Male Middle Aged Natriuretic Peptide, Brain/*blood Peptide Fragments/*blood Protein Precursors Proteomics/*methods Risk Assessment/*methods Risk Factors Time Factors United States/epidemiology | Plasma proteomic profiling may aid in the discovery of novel biomarkers upstream of the development of atrial fibrillation (AF). We used data from the Atherosclerosis Risk in Communities study to examine the relation between large-scale proteomics and incident AF in a cohort of older-aged adults in the United States. We quantified 4,877 plasma proteins in Atherosclerosis Risk in Communities participants at visit 5 (2011-2013) using an aptamer-based proteomic profiling platform. We used Cox proportional hazards models to assess the association between protein levels and incident AF, and explored relation of selected protein biomarkers using annotated pathway analysis. Our study included 4,668 AF-free participants (mean age 75 +/- 5 years; 59% female; 20% Black race) with proteomic measures. A total of 585 participants developed AF over a mean follow-up of 5.7 +/- 1.7 years. After adjustment for clinical factors associated with AF, N-terminal pro-B-type natriuretic peptide (NT-proBNP) was associated with the risk of incident AF (hazard ratio, 1.82; 95% CI, 1.68 to 1.98; p, 2.91 x 10(-45) per doubling of NT-proBNP). In addition, 36 other proteins were also significantly associated with incident AF after Bonferroni correction. We further adjusted for medication use and estimated glomerular filtration rate and found 17 proteins, including angiopoietin-2 and transgelin, that remained significantly associated with incident AF. Pathway analyses implicated the inhibition of matrix metalloproteases as the top canonical pathway in AF pathogenesis. In conclusion, using a large-scale proteomic platform, we identified both novel and established proteins associated with incident AF and explored mechanistic pathways of AF development. | Norby, Faye L Tang, Weihong Pankow, James S Lutsey, Pamela L Alonso, Alvaro Steffan, Brian Chen, Lin Y Zhang, Michael Shippee, Nathan D Ballantyne, Christie M Boerwinkle, Eric Coresh, Josef Folsom, Aaron R eng 16EIA26410001/AHA/American Heart Association-American Stroke Association/ HHSN268201700002C/HL/NHLBI NIH HHS/ HHSN268201700001I/HL/NHLBI NIH HHS/ HHSN268201700004C/HL/NHLBI NIH HHS/ HHSN268201700003I/HL/NHLBI NIH HHS/ R01 HL126637/HL/NHLBI NIH HHS/ K24 HL148521/HL/NHLBI NIH HHS/ HHSN268201700004I/HL/NHLBI NIH HHS/ HHSN268201700005C/HL/NHLBI NIH HHS/ HHSN268201700001C/HL/NHLBI NIH HHS/ HHSN268201700003C/HL/NHLBI NIH HHS/ R01 HL141288/HL/NHLBI NIH HHS/ HHSN268201700002I/HL/NHLBI NIH HHS/ HHSN268201700005I/HL/NHLBI NIH HHS/ Multicenter Study Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Am J Cardiol. 2021 Dec 15;161:42-50. doi: 10.1016/j.amjcard.2021.08.064.I | 11/20/2021 | ||
| The Proteomic Signature of Recombinant Growth Hormone in Recreational Athletes | Esefeld M, et al. | 2021 | J Endocr Soc | 5 | 12 | bvab156 | https://www.doi.org/10.1210/jendso/bvab156 | 34,765,854 | antidoping glucose metabolism human growth hormone proteomics | OBJECTIVE: Administration of human growth hormone (hGH) is prohibited in competitive sport and its detection in an athlete's sample triggers an adverse analytical finding. However, the biological processes that are modulated by recombinant hGH are not well characterized and associated blood serum proteins may constitute new biomarkers for hGH misuse. METHODS: Thirty-five recreational athletes were enrolled in a study to investigate the time- and dose-dependent response of serum protein levels to recombinant hGH administration. Participants were randomly assigned to 4 groups, receiving 1 of 3 different doses of recombinant hGH or a placebo. Bio samples were collected at 22 time points over a period of 13 weeks, starting 4 weeks before treatment, during 3 weeks of treatment, and at 6 weeks' follow-up. A total of 749 serum samples were analyzed for 1305 protein markers using the SOMAscan proteomics platform. RESULTS: We identified 66 proteins that significantly associated with recombinant hGH administration and dosage, including well known hGH targets, such as IGF1, but also previously unknown hGH-related proteins (eg, protease inhibitors, WFIKKN1, and chemokines, CCL2). Network analysis revealed changes in specific biological pathways, mainly related to the immune system and glucose metabolism. CONCLUSION: Our analysis suggests that hGH administration affects biological processes more strongly than previously acknowledged. Some of the proteins were dysregulated even after hGH treatment and could potentially be developed into biomarkers for hGH misuse. Moreover, our findings suggest new roles for hGH-associated proteins in the etiology of hGH-related diseases and may indicate new risks that may be associated with hGH misuse. | Esefeld, Max Pastor, Antoni de la Torre, Rafael Barroso, Osquel Aikin, Reid Sarwath, Hina Engelke, Rudolf Schmidt, Frank Suhre, Karsten eng J Endocr Soc. 2021 Nov 2;5(12):bvab156. doi: 10.1210/jendso/bvab156. eCollection 2021 Dec 1.I | 11/13/2021 | |
| Cross-validation of SARS-CoV-2 responses in kidney organoids and clinical populations | Helms L, et al. | 2021 | JCI Insight | 6 | 24 | https://www.doi.org/10.1172/jci.insight.154882 | 34,767,537 | Acute Kidney Injury/etiology/*urine Adult Aged Angiotensin-Converting Enzyme 2/genetics Animals Apoptosis Bowman Capsule/cytology/virology COVID-19/complications/*urine Chlorocebus aethiops Female Gene Knockout Techniques Hospital Mortality Hospitalization Humans Kidney/metabolism/pathology/*virology Kidney Tubules, Proximal/metabolism/pathology/*virology Male Middle Aged Organoids/metabolism/*virology Podocytes/virology Polycystic Kidney Diseases Protein Kinase D2/genetics Proteome Receptors, Coronavirus/genetics Reproducibility of Results SARS-CoV-2/*pathogenicity Transcriptome Vero Cells Viral Tropism Virus Replication Covid-19 Genetic diseases Molecular pathology Nephrology iPS cells human kidney organoid differentiation and modeling of disease in this system (patent applications US 63/253,797 15/756,846 62/213,740 62/672,470 62/739,637 and PCT/US2019/032754). | Kidneys are critical target organs of COVID-19, but susceptibility and responses to infection remain poorly understood. Here, we combine SARS-CoV-2 variants with genome-edited kidney organoids and clinical data to investigate tropism, mechanism, and therapeutics. SARS-CoV-2 specifically infects organoid proximal tubules among diverse cell types. Infections produce replicating virus, apoptosis, and disrupted cell morphology, features of which are revealed in the context of polycystic kidney disease. Cross-validation of gene expression patterns in organoids reflects proteomic signatures of COVID-19 in the urine of critically ill patients indicating interferon pathway upregulation. SARS-CoV-2 viral variants alpha, beta, gamma, kappa, and delta exhibit comparable levels of infection in organoids. Infection is ameliorated in ACE2-/- organoids and blocked via treatment with de novo-designed spike binder peptides. Collectively, these studies clarify the impact of kidney infection in COVID-19 as reflected in organoids and clinical populations, enabling assessment of viral fitness and emerging therapies. | Helms, Louisa Marchiano, Silvia Stanaway, Ian B Hsiang, Tien-Ying Juliar, Benjamin A Saini, Shally Zhao, Yan Ting Khanna, Akshita Menon, Rajasree Alakwaa, Fadhl Mikacenic, Carmen Morrell, Eric D Wurfel, Mark M Kretzler, Matthias Harder, Jennifer L Murry, Charles E Himmelfarb, Jonathan Ruohola-Baker, Hannele Bhatraju, Pavan K Gale, Michael Jr Freedman, Benjamin S eng R21 AI158788/AI/NIAID NIH HHS/ P51 OD010425/OD/NIH HHS/ K23 DK116967/DK/NIDDK NIH HHS/ UH3 TR002158/TR/NCATS NIH HHS/ T90 DE021984/DE/NIDCR NIH HHS/ R24 HD000836/HD/NICHD NIH HHS/ F31 DK130550/DK/NIDDK NIH HHS/ U01 AI151698/AI/NIAID NIH HHS/ TL1 TR002318/TR/NCATS NIH HHS/ UC2 DK126006/DK/NIDDK NIH HHS/ UG3 TR003288/TR/NCATS NIH HHS/ UG3 TR002158/TR/NCATS NIH HHS/ K23 HL144916/HL/NHLBI NIH HHS/ R01 DK117914/DK/NIDDK NIH HHS/ R01 DK130386/DK/NIDDK NIH HHS/ R01 DK124063/DK/NIDDK NIH HHS/ U01 DK127553/DK/NIDDK NIH HHS/ Research Support, N.I.H., Extramural Research Support, U.S. Gov't, Non-P.H.S. JCI Insight. 2021 Dec 22;6(24):e154882. doi: 10.1172/jci.insight.154882.I | 11/13/2021 | ||
| A brain proteomic signature of incipient Alzheimer's disease in young APOE epsilon4 carriers identifies novel drug targets | Roberts JA, et al. | 2021 | Sci Adv | 7 | 46 | eabi8178 | https://www.doi.org/10.1126/sciadv.abi8178 | 34,757,788 | Aptamer-based proteomics revealed differentially abundant proteins in Alzheimer's disease (AD) brains in the Baltimore Longitudinal Study of Aging and Religious Orders Study (mean age, 89 +/- 9 years). A subset of these proteins was also differentially abundant in the brains of young APOE epsilon4 carriers relative to noncarriers (mean age, 39 +/- 6 years). Several of these proteins represent targets of approved and experimental drugs for other indications and were validated using orthogonal methods in independent human brain tissue samples as well as in transgenic AD models. Using cell culture-based phenotypic assays, we showed that drugs targeting the cytokine transducer STAT3 and the Src family tyrosine kinases, YES1 and FYN, rescued molecular phenotypes relevant to AD pathogenesis. Our findings may accelerate the development of effective interventions targeting the earliest molecular triggers of AD. | Roberts, Jackson A Varma, Vijay R An, Yang Varma, Sudhir Candia, Julian Fantoni, Giovanna Tiwari, Vinod Anerillas, Carlos Williamson, Andrew Saito, Atsushi Loeffler, Tina Schilcher, Irene Moaddel, Ruin Khadeer, Mohammed Lovett, Jacqueline Tanaka, Toshiko Pletnikova, Olga Troncoso, Juan C Bennett, David A Albert, Marilyn S Yu, Kaiwen Niu, Mingming Haroutunian, Vahram Zhang, Bin Peng, Junmin Croteau, Deborah L Resnick, Susan M Gorospe, Myriam Bohr, Vilhelm A Ferrucci, Luigi Thambisetty, Madhav eng P30 AG072975/AG/NIA NIH HHS/ P30 AG066507/AG/NIA NIH HHS/ RF1 AG057440/AG/NIA NIH HHS/ U01 AG046170/AG/NIA NIH HHS/ R01 AG053987/AG/NIA NIH HHS/ P30 AG010161/AG/NIA NIH HHS/ R01 AG015819/AG/NIA NIH HHS/ Sci Adv. 2021 Nov 12;7(46):eabi8178. doi: 10.1126/sciadv.abi8178. Epub 2021 Nov 10.I | 11/11/2021 | ||
| Ultrasensitive detection of blood biomarkers of Alzheimer's and Parkinson's diseases: a systematic review | Singh K, et al. | 2021 | Biomark Med | 15 | 17 | 1693-1708 | https://www.doi.org/10.2217/bmm-2021-0219 | 34,743,546 | Alzheimer Disease/*blood/*diagnosis Biomarkers/*blood Case-Control Studies Humans Longitudinal Studies Parkinson Disease/*blood/*diagnosis Publication Bias Publications Risk Alzheimer's disease Meso Scale Discovery Parkinson's disease Simoa SOMAscan biomarkers meta-analysis systematic review | Purpose: Neurodegenerative disorders are a global health burden with costly and invasive diagnoses relying on brain imaging technology or CSF-based biomarkers. Therefore, considerable efforts to identify blood-biomarkers for Alzheimer's (AD) and Parkinson's diseases (PD) are ongoing. Objectives: This review evaluates the blood biomarkers for AD and PD for their diagnostic value. Methods: This study systematically reviewed articles published between July 1984 and February 2021. Among 1266 papers, we selected 42 studies for a systematic review and 23 studies for meta-analysis. Results & conclusion: Our analysis highlights P-tau181, T-tau and Nfl as promising blood biomarkers for AD diagnosis. Nfl levels were consistently raised in 16 AD and three PD cohorts. P-tau181 and T-tau were also significantly increased in 12 and eight AD cohorts, respectively. | Singh, Kailash Cheung, Bernard My Xu, Aimin eng Meta-Analysis Research Support, Non-U.S. Gov't Systematic Review England Biomark Med. 2021 Dec;15(17):1693-1708. doi: 10.2217/bmm-2021-0219. Epub 2021 Nov 8.I | 11/09/2021 | |
| Dysregulated expression levels of APH1B in peripheral blood are associated with brain atrophy and amyloid-beta deposition in Alzheimer's disease | Park YH, et al. | 2021 | Alzheimers Res Ther | 13 | 1 | 183 | https://www.doi.org/10.1186/s13195-021-00919-z | 34,732,252 | *Alzheimer Disease/diagnostic imaging/genetics/pathology *Amyloid beta-Protein Precursor/metabolism Atrophy/pathology Brain/diagnostic imaging/pathology *Endopeptidases/genetics Genetic Predisposition to Disease Genome-Wide Association Study Humans *Membrane Proteins/genetics Transcriptome Alzheimer's disease Blood Expression Expression quantitative trait locus Imaging Transcriptome board. | BACKGROUND: The interaction between the brain and periphery might play a crucial role in the development of Alzheimer's disease (AD). METHODS: Using blood transcriptomic profile data from two independent AD cohorts, we performed expression quantitative trait locus (cis-eQTL) analysis of 29 significant genetic loci from a recent large-scale genome-wide association study to investigate the effects of the AD genetic variants on gene expression levels and identify their potential target genes. We then performed differential gene expression analysis of identified AD target genes and linear regression analysis to evaluate the association of differentially expressed genes with neuroimaging biomarkers. RESULTS: A cis-eQTL analysis identified and replicated significant associations in seven genes (APH1B, BIN1, FCER1G, GATS, MS4A6A, RABEP1, TRIM4). APH1B expression levels in the blood increased in AD and were associated with entorhinal cortical thickness and global cortical amyloid-beta deposition. CONCLUSION: An integrative analysis of genetics, blood-based transcriptomic profiles, and imaging biomarkers suggests that APH1B expression levels in the blood might play a role in the pathogenesis of AD. | Park, Young Ho Pyun, Jung-Min Hodges, Angela Jang, Jae-Won Bice, Paula J Kim, SangYun Saykin, Andrew J Nho, Kwangsik eng U01 AG072177/AG/NIA NIH HHS/ R01 LM011360/LM/NLM NIH HHS/ U01 AG068057/AG/NIA NIH HHS/ DH_/Department of Health/United Kingdom U01 AG024904/AG/NIA NIH HHS/ R03 AG054936/AG/NIA NIH HHS/ UL1 TR001108/TR/NCATS NIH HHS/ R01 LM012535/LM/NLM NIH HHS/ P50 GM115318/GM/NIGMS NIH HHS/ K01 AG049050/AG/NIA NIH HHS/ CIHR/Canada Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. England Alzheimers Res Ther. 2021 Nov 3;13(1):183. doi: 10.1186/s13195-021-00919-z.I | 11/05/2021 | |
| Integrated plasma proteomics and lung transcriptomics reveal novel biomarkers in idiopathic pulmonary fibrosis | Sivakumar P, et al. | 2021 | Respir Res | 22 | 1 | 273 | https://www.doi.org/10.1186/s12931-021-01860-3 | 34,689,792 | Biomarkers/blood Blood Proteins/*analysis Case-Control Studies *Gene Expression Profiling Humans Idiopathic Pulmonary Fibrosis/*blood/diagnosis/*genetics Lung/*chemistry *Proteome *Proteomics *Transcriptome Biomarkers Chemokines Extracellular matrix Idiopathic pulmonary fibrosis Mast cells | BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease with a significant unmet medical need. Development of transformational therapies for IPF is challenging in part to due to lack of robust predictive biomarkers of prognosis and treatment response. Importantly, circulating biomarkers of IPF are limited and none are in clinical use. METHODS: We previously reported dysregulated pathways and new disease biomarkers in advanced IPF through RNA sequencing of lung tissues from a cohort of transplant-stage IPF patients (n = 36) in comparison to normal healthy donors (n = 19) and patients with acute lung injury (n = 11). Here we performed proteomic profiling of matching plasma samples from these cohorts through the Somascan-1300 SomaLogics platform. RESULTS: Comparative analyses of lung transcriptomic and plasma proteomic signatures identified a set of 34 differentially expressed analytes (fold change (FC) >/= +/- 1.5, false discovery ratio (FDR) | Sivakumar, Pitchumani Ammar, Ron Thompson, John Ryan Luo, Yi Streltsov, Denis Porteous, Mary McCoubrey, Carly Cantu, Edward 3rd Beers, Michael F Jarai, Gabor Christie, Jason D eng I01 BX001176/BX/BLRD VA/ R01 HL145408/HL/NHLBI NIH HHS/ U01 HL152970/HL/NHLBI NIH HHS/ England Respir Res. 2021 Oct 24;22(1):273. doi: 10.1186/s12931-021-01860-3.I | 10/26/2021 | |
| Advances and Utility of the Human Plasma Proteome | Deutsch EW, et al. | 2021 | J Proteome Res | 20 | 12 | 5241-5263 | https://www.doi.org/10.1021/acs.jproteome.1c00657 | 34,672,606 | Aging/genetics COVID-19/genetics Databases, Protein Hemostasis/genetics Humans Mass Spectrometry *Proteome/genetics Proteomics/*trends DNA aptamers (Somascan) Human Plasma Proteome Project Human Proteome Project PeptideAtlas blood plasma proteomics proximity extension assays (PEA by Olink) interest(s): Krishnan K. Palaniappan is an employee of Freenome. Philipp E. Geyer is an employee of OmicEra Diagnostics GmbH. All other authors declare no competing financial interest. | The study of proteins circulating in blood offers tremendous opportunities to diagnose, stratify, or possibly prevent diseases. With recent technological advances and the urgent need to understand the effects of COVID-19, the proteomic analysis of blood-derived serum and plasma has become even more important for studying human biology and pathophysiology. Here we provide views and perspectives about technological developments and possible clinical applications that use mass-spectrometry(MS)- or affinity-based methods. We discuss examples where plasma proteomics contributed valuable insights into SARS-CoV-2 infections, aging, and hemostasis and the opportunities offered by combining proteomics with genetic data. As a contribution to the Human Proteome Organization (HUPO) Human Plasma Proteome Project (HPPP), we present the Human Plasma PeptideAtlas build 2021-07 that comprises 4395 canonical and 1482 additional nonredundant human proteins detected in 240 MS-based experiments. In addition, we report the new Human Extracellular Vesicle PeptideAtlas 2021-06, which comprises five studies and 2757 canonical proteins detected in extracellular vesicles circulating in blood, of which 74% (2047) are in common with the plasma PeptideAtlas. Our overview summarizes the recent advances, impactful applications, and ongoing challenges for translating plasma proteomics into utility for precision medicine. | Deutsch, Eric W Omenn, Gilbert S Sun, Zhi Maes, Michal Pernemalm, Maria Palaniappan, Krishnan K Letunica, Natasha Vandenbrouck, Yves Brun, Virginie Tao, Sheng-Ce Yu, Xiaobo Geyer, Philipp E Ignjatovic, Vera Moritz, Robert L Schwenk, Jochen M eng R24 GM127667/GM/NIGMS NIH HHS/ U19 AG023122/AG/NIA NIH HHS/ U24 CA210967/CA/NCI NIH HHS/ R01 GM087221/GM/NIGMS NIH HHS/ P30 ES017885/ES/NIEHS NIH HHS/ S10 OD026936/OD/NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Review J Proteome Res. 2021 Dec 3;20(12):5241-5263. doi: 10.1021/acs.jproteome.1c00657. Epub 2021 Oct 21.I | 10/22/2021 | |
| Mapping the proteo-genomic convergence of human diseases | Pietzner M, et al. | 2021 | Science | 374 | 6,569 | eabj1541 | https://www.doi.org/10.1126/science.abj1541 | 34,648,354 | Aging Alternative Splicing Blood Proteins/*genetics/metabolism COVID-19/genetics Connective Tissue Diseases/genetics Disease/etiology/*genetics Drug Development Female Gallstones/genetics Genetic Association Studies Genetic Variation *Genome, Human Genome-Wide Association Study *Genomics Humans Internet Male Phenotype Proteins/*genetics/metabolism *Proteome Quantitative Trait Loci Sex Characteristics | Characterization of the genetic regulation of proteins is essential for understanding disease etiology and developing therapies. We identified 10,674 genetic associations for 3892 plasma proteins to create a cis-anchored gene-protein-disease map of 1859 connections that highlights strong cross-disease biological convergence. This proteo-genomic map provides a framework to connect etiologically related diseases, to provide biological context for new or emerging disorders, and to integrate different biological domains to establish mechanisms for known gene-disease links. Our results identify proteo-genomic connections within and between diseases and establish the value of cis-protein variants for annotation of likely causal disease genes at loci identified in genome-wide association studies, thereby addressing a major barrier to experimental validation and clinical translation of genetic discoveries. | Pietzner, Maik Wheeler, Eleanor Carrasco-Zanini, Julia Cortes, Adrian Koprulu, Mine Worheide, Maria A Oerton, Erin Cook, James Stewart, Isobel D Kerrison, Nicola D Luan, Jian'an Raffler, Johannes Arnold, Matthias Arlt, Wiebke O'Rahilly, Stephen Kastenmuller, Gabi Gamazon, Eric R Hingorani, Aroon D Scott, Robert A Wareham, Nicholas J Langenberg, Claudia eng MC_UU_00006/1/MRC_/Medical Research Council/United Kingdom R01 HG011138/HG/NHGRI NIH HHS/ RF1 AG059093/AG/NIA NIH HHS/ U01 AG061359/AG/NIA NIH HHS/ RF1 AG057452/AG/NIA NIH HHS/ MR/V033867/1/MRC_/Medical Research Council/United Kingdom R35 HG010718/HG/NHGRI NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Science. 2021 Nov 12;374(6569):eabj1541. doi: 10.1126/science.abj1541. Epub 2021 Nov 12.I | 10/15/2021 | |
| Plasma P-selectin is an early marker of thromboembolism in COVID-19 | Fenyves BG, et al. | 2021 | Am J Hematol | 96 | 12 | E468-E471 | https://www.doi.org/10.1002/ajh.26372 | 34,622,480 | Aged Biomarkers/blood COVID-19/*blood/complications/diagnosis Female Humans Male P-Selectin/*blood Prospective Studies SARS-CoV-2/isolation & purification Thromboembolism/*blood/diagnosis/etiology | Fenyves, Bank G Mehta, Arnav Kays, Kyle R Beakes, Caroline Margolin, Justin Goldberg, Marcia B Hacohen, Nir Filbin, Michael R eng UL1 TR 002541-01/NH/NIH HHS/ David P. Ryan, MD Endowed Chair in Cancer Research/ UL1 TR002541/TR/NCATS NIH HHS/ Rosztoczy Foundation/ Massachusetts General Hospital/ U19 AI082630/AI/NIAID NIH HHS/ U19 AI082630/NH/NIH HHS/ American Lung Association/ T32 CA071345/CA/NCI NIH HHS/ Letter Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Am J Hematol. 2021 Dec 1;96(12):E468-E471. doi: 10.1002/ajh.26372. Epub 2021 Oct 16.I | 10/09/2021 | ||
| Vitamin D association with the renin angiotensin system in polycystic ovary syndrome | Butler AE, et al. | 2021 | J Steroid Biochem Mol Biol | 214 | 105965 | https://www.doi.org/10.1016/j.jsbmb.2021.105965 | 34,619,249 | Adult Angiotensin-Converting Enzyme 2/*blood Angiotensinogen/*blood Blood Pressure Female Humans Polycystic Ovary Syndrome/*blood/physiopathology Renin/*blood Renin-Angiotensin System Vitamin D/blood Vitamin D Deficiency/*blood/physiopathology Vitamins/blood Young Adult ACE2 protein Angiotensinogen Polycystic ovary syndrome Renin Vitamin D | Vitamin D deficiency is a negative endocrine renin-angiotensin system (RAS) modulator and PCOS women are often vitamin D deficient, leading to RAS overactivation in PCOS. A cross-sectional study was performed in 99 PCOS and 68 control women who presented sequentially. Circulating plasma levels of RAS proteins (Angiotensin-converting enzyme 2 (ACE2), renin and angiotensinogen) were measured by Slow Off-rate Modified Aptamer (SOMA)-scan and 25-hydroxyvitamin D [25(OH)D] was measured by tandem mass spectroscopy. The RAS system was found to be overactivated in the PCOS women compared to non-PCOS control women with increased renin and decreased angiotensinogen (p < 0.05); 25-hydroxyvitamin D was also significantly lower in the PCOS group (p < 0.0001). In PCOS women, plasma renin was increased in vitamin D deficient and insufficient groups compared with the vitamin D sufficient group (p < 0.005), but did not differ across non-PCOS control subgroups. In non-PCOS controls, plasma ACE2 decreased from vitamin D insufficiency to deficiency (p < 0.05). Angiotensinogen was not different across the vitamin D sufficiency, insufficiency and deficiency strata for either PCOS or non-PCOS controls. These data show that RAS activation through increased plasma renin levels was seen in vitamin D insufficient and deficient PCOS subjects compared to non-PCOS control women. In addition, decreased plasma ACE2 levels were seen in vitamin D deficiency in non-PCOS controls, which may predispose these vitamin D deficient subjects to increased cardiovascular risk and susceptibility to infectious agents such as COVID-19 where this is a risk factor. | Butler, Alexandra E Moin, Abu Saleh Md Sathyapalan, Thozhukat Atkin, Stephen L eng England J Steroid Biochem Mol Biol. 2021 Nov;214:105965. doi: 10.1016/j.jsbmb.2021.105965. Epub 2021 Oct 5.I | 10/08/2021 | ||
| Proteomic Biomarker Analysis of Serum from Japanese Field Mice (Apodemus Speciosus) Collected within the Fukushima Difficult-to-return Zone | Sproull M, et al. | 2021 | Health Phys | 121 | 6 | 564-573 | https://www.doi.org/10.1097/HP.0000000000001467 | 34,618,712 | Animals Cesium Radioisotopes/analysis *Fukushima Nuclear Accident Japan Mice Murinae Proteomics Radiation Dosage *Radiation Monitoring | The environmental impact of the Fukushima Daiichi nuclear power plant accident is a source of ongoing concern as there is uncertainty regarding the effects of chronic radiation exposure on local plant and animal life from Fukushima-derived radionuclides. In the current study, changes in proteomic biomarker expression due to chronic environmentally-derived radiation exposures was examined in wild field mice. Serum from 10 wild field mice (Apodemus speciosus) native to the Fukushima difficult-to-return zone and from eight wild field mice native to the Soma area (control) were collected. External dose estimations were completed using measurements of ambient radiation levels and calculating 137Cs concentrations in soil. Internal dose was estimated by counting whole mice using an HPGe detector. Age of the mice was estimated using molar wear. Serum was screened using the aptamer-based SOMAscan proteomic assay technology for changes in expression of 1,310 protein analytes. A subset panel of protein biomarkers that demonstrated significant changes in expression between control and exposed mice was determined and analyzed using Ingenuity Pathway Analysis (IPA). Control animals had a calculated lifetime dose range from 0.001 to 0.007 Gy, and exposed animals had a calculated lifetime dose range from 0.01 to 0.64 Gy. No discernable effect of dose rate was seen as relative dose rate correlated with dose for all samples. Detectable values were obtained for all 1,310 proteins included in the SOMAscan assay. Subset panels of proteins demonstrating significant (p < 0.05) changes in expression with either an upregulated or downregulated 1.5-fold change over control were identified for both the sample cohort inclusive of all exposed samples and the sample cohort restricted to samples from animals receiving low" dose exposures. These panels of proteins from exposed animals were analyzed using IPA, which highlighted changes in key biological pathways related to injury, respiratory, renal, urological, and gastrointestinal disease, and cancer. Significant changes in expression of proteomic biomarkers were seen in the serum of wild field mice that received environmental exposure to Fukushima-derived radionuclides. Our findings demonstrate novel biomarkers of radiation exposure in wildlife within the Fukushima difficult-to-return zone." | Sproull, Mary Hayes, Joshua Ishiniwa, Hiroko Nanba, Kenji Shankavaram, Uma Camphausen, Kevin Johnson, Thomas E eng T42 OH009229/OH/NIOSH CDC HHS/ T42OH009229/ACL/ACL HHS/ ZIA SC010373/ImNIH/Intramural NIH HHS/ ZID BC010990/ImNIH/Intramural NIH HHS/ Research Support, N.I.H., Extramural Research Support, N.I.H., Intramural Research Support, Non-U.S. Gov't Health Phys. 2021 Dec 1;121(6):564-573. doi: 10.1097/HP.0000000000001467.I | 10/08/2021 | |
| Identification of plasma proteins relating to brain neurodegeneration and vascular pathology in cognitively normal individuals | Shi L, et al. | 2021 | Alzheimers Dement (Amst) | 13 | 1 | e12240 | https://www.doi.org/10.1002/dad2.12240 | 34,604,499 | mediation neurodegeneration plasma proteomics sex-related difference vascular damage SOBP2021). R.E.M. is an advisor to the Epigenetic Clock Development Foundation and has received a speaker fee from Illumina. A.C. is member of Edinburgh MVM Research Ethics Committee. J.M.W is involved in European Stroke Organisation Guideline on Covert Small Vessel Disease 2021 and European Stroke Organisation Chair of Conference Planning Group 2021 and 2022. D.S. helped to set up CAPE study. A.M. received speaker fees from Janssen and Illumina. S.L. is an employee of Janssen Medical UK and Co-founder of Akrivia Health Ltd. He is also named as an inventor on biomarker intellectual property protected by Proteome Sciences and Kings College London unrelated to the current study and within the past 5 years has advised for Optum labs, Merck, SomaLogic, and been the recipient of funding from AstraZeneca and other companies via the IMI funding scheme. N.B. is a member of Mehta Family Centre for Engineering in Medicine, Kanpur, India as well as the editorial board of Stem Cells. A.N.H. is the main PI of a project funded by J&J, and another projects funded by GSK, all unrelated to this study. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. | INTRODUCTION: This study aims to first discover plasma proteomic biomarkers relating to neurodegeneration (N) and vascular (V) damage in cognitively normal individuals and second to discover proteins mediating sex-related difference in N and V pathology. METHODS: Five thousand and thirty-two plasma proteins were measured in 1061 cognitively normal individuals (628 females and 433 males), nearly 90% of whom had magnetic resonance imaging measures of hippocampal volume (as N) and white matter hyperintensities (as V). RESULTS: Differential protein expression analysis and co-expression network analysis revealed different proteins and modules associated with N and V, respectively. Furthermore, causal mediation analysis revealed four proteins mediated sex-related difference in N and one protein mediated such difference in V damage. DISCUSSION: Once validated, the identified proteins could help to select cognitively normal individuals with N and V pathology for Alzheimer's disease clinical trials and provide targets for further mechanistic studies on brain sex differences, leading to sex-specific therapeutic strategies. | Shi, Liu Buchanan, Colin R Cox, Simon R Hillary, Robert F Marioni, Riccardo E Campbell, Archie Hayward, Caroline Stolicyn, Aleks Whalley, Heather C Harris, Mathew A Waymont, Jennifer Waiter, Gordon Backhouse, Ellen Wardlaw, Joanna M Steele, Douglas Mcintosh, Andrew Lovestone, Simon Buckley, Noel J Nevado-Holgado, Alejo J eng MR/S010351/1/MRC_/Medical Research Council/United Kingdom R01 AG054628/AG/NIA NIH HHS/ U19 AG063744/AG/NIA NIH HHS/ MC_PC_17209/MRC_/Medical Research Council/United Kingdom MC_UU_00007/10/MRC_/Medical Research Council/United Kingdom RF1 AG057452/AG/NIA NIH HHS/ WT_/Wellcome Trust/United Kingdom Alzheimers Dement (Amst). 2021 Sep 27;13(1):e12240. doi: 10.1002/dad2.12240. eCollection 2021.I | 10/05/2021 | |
| Influence of renin-angiotensin-aldosterone system inhibitors on plasma levels of angiotensin-converting enzyme 2 | Zimmermann T, et al. | 2021 | ESC Heart Fail | 8 | 2 | 1717-1721 | https://www.doi.org/10.1002/ehf2.13249 | 34,596,976 | Aged Angiotensin Receptor Antagonists *Angiotensin-Converting Enzyme 2 Angiotensin-Converting Enzyme Inhibitors *covid-19 Female Humans Male Proteomics Renin-Angiotensin System SARS-CoV-2 Ace Ace2 Arb Covid-19 Plasma levels Raas SARS-CoV-2 Gesellschaft Basel. Dr. Walter reports research grants from the Swiss Heart Foundation (FF19097 and F18111) and the Swiss Academy of Medical Sciences and Bangerter Foundation. Dr. Mueller has received research grants from the Swiss National Science Foundation, the Swiss Heart Foundation, the KTI, the European Union, the Cardiovascular Research Foundation Basel, the University Hospital Basel, Abbott, Astra Zeneca, Beckman Coulter, Biomerieux, BRAHMS, Critical Diagnostics, Roche, Siemens, Singulex, and Sphingotec, as well as speaker/consulting honoraria from Abbott, Alere, Astra Zeneca, Bayer, Biomerieux, Boehringer Ingelheim, BMS, BRAHMS, Cardiorentis, Novartis, Roche, Sanofi, Siemens, and Singulex. All other authors declare that they have no conflict of interest with this study. All authors critically reviewed the manuscript and approved the final version for submission. The sponsors had no role in the design and conduct of the study collection, management, analysis, and interpretation of the data preparation or approval of the manuscript. | AIMS: Concern has been raised that treatment with angiotensin-converting enzyme inhibitors and angiotensin receptor blockers may increase the expression of angiotensin-converting enzyme 2 (ACE2), which acts as the entry receptor for SARS-CoV-2, and lead to an increased risk of death from SARS-CoV-2. We aimed to address this concern by evaluating the in vivo relationship of treatment with ACE inhibitors and angiotensin receptor blockers (ARB) with circulating plasma concentrations of ACE2 in a large cohort of patients with established cardiovascular disease (n = 1864) or cardiovascular risk factors (n = 2144) but without a history of heart failure. METHODS AND RESULTS: Angiotensin-converting enzyme 2 was measured in 4008 patients (median age 68, 33% women, 31% on ACE-inhibitors, 31% on ARB) using the SOMAscan proteomic platform (SomaLogic Inc, Colorado, USA). Plasma concentration of ACE2 was comparable in 1250 patients on ACE inhibitors (mean 5.99) versus patients without ACE inhibitors (mean 5.98, P = 0.54). Similarly, plasma concentration of ACE2 was comparable in 1260 patients on ARB (mean 5.99) versus patients without ARB (mean 5.98, P = 0.50). Plasma concentration of ACE2 was comparable in 2474 patients on either ACE inhibitors or ARB (mean 5.99) versus patients without ACE inhibitors or ARB (mean 5.98, P = 0.31). Multivariable quantile regression model analysis confirmed the lack of association between treatment with ACE inhibitors or ARB and ACE2 concentrations. Body mass index showed the only positive association with ACE2 plasma concentration (effect 0.015, 95% confidence interval 0.002 to 0.028, P = 0.024). CONCLUSIONS: In a large cohort of patients with established cardiovascular disease or cardiovascular risk factors but without heart failure, ACE inhibitors and ARB were not associated with higher plasma concentrations of ACE2. | Zimmermann, Tobias Walter, Joan Elias Lopez-Ayala, Pedro Strebel, Ivo Amrein, Melissa Koechlin, Michael Honegger, Ursina Mueller, Christian eng Research Support, Non-U.S. Gov't England ESC Heart Fail. 2021 Apr;8(2):1717-1721. doi: 10.1002/ehf2.13249. Epub 2021 Feb 19.I | 10/02/2021 | |
| Polygenic Risk Scores for Kidney Function and Their Associations with Circulating Proteome, and Incident Kidney Diseases | Yu Z, et al. | 2021 | J Am Soc Nephrol | 32 | 12 | 3161-73 | https://www.doi.org/10.1681/ASN.2020111599 | 34,548,389 | chronic kidney disease end stage kidney disease epidemiology and outcomes genetics and development glomerular filtration rate kidney disease | BACKGROUND: Genome-wide association studies (GWAS) have revealed numerous loci for kidney function (eGFR). The relationship between polygenic predictors of eGFR, risk of incident adverse kidney outcomes, and the plasma proteome is not known. METHODS: We developed a genome-wide polygenic risk score (PRS) for eGFR by applying the LDpred algorithm to summary statistics generated from a multiethnic meta-analysis of CKDGen Consortium GWAS (n=765,348) and UK Biobank GWAS (90% of the cohort; n=451,508), followed by best-parameter selection using the remaining 10% of UK Biobank data (n=45,158). We then tested the association of the PRS in the Atherosclerosis Risk in Communities (ARIC) study (n=8866) with incident CKD, ESKD, kidney failure, and AKI. We also examined associations between the PRS and 4877 plasma proteins measured at middle age and older adulthood and evaluated mediation of PRS associations by eGFR. RESULTS: The developed PRS showed a significant association with all outcomes. Hazard ratios per 1 SD lower PRS ranged from 1.06 (95% CI, 1.01 to 1.11) to 1.33 (95% CI, 1.28 to 1.37). The PRS was significantly associated with 132 proteins at both time points. The strongest associations were with cystatin C, collagen alpha-1(XV) chain, and desmocollin-2. Most proteins were higher at lower kidney function, except for five proteins, including testican-2. Most correlations of the genetic PRS with proteins were mediated by eGFR. CONCLUSIONS: A PRS for eGFR is now sufficiently strong to capture risk for a spectrum of incident kidney diseases and broadly influences the plasma proteome, primarily mediated by eGFR. | Yu, Zhi Jin, Jin Tin, Adrienne Kottgen, Anna Yu, Bing Chen, Jingsha Surapaneni, Aditya Zhou, Linda Ballantyne, Christie M Hoogeveen, Ron C Arking, Dan E Chatterjee, Nilanjan Grams, Morgan E Coresh, Josef eng MC_PC_17228/MRC_/Medical Research Council/United Kingdom R01 HG010480/HG/NHGRI NIH HHS/ U01 HL096917/HL/NHLBI NIH HHS/ K24 HL155861/HL/NHLBI NIH HHS/ U01 DK106981/DK/NIDDK NIH HHS/ R01 DK124399/DK/NIDDK NIH HHS/ R01 HL134320/HL/NHLBI NIH HHS/ MC_QA137853/MRC_/Medical Research Council/United Kingdom J Am Soc Nephrol. 2021 Sep 21;32(12):3161-73. doi: 10.1681/ASN.2020111599.I | 09/23/2021 | |
| Towards Building a Quantitative Proteomics Toolbox in Precision Medicine: A Mini-Review | Correa Rojo A, et al. | 2021 | Front Physiol | 12 | 723510 | https://www.doi.org/10.3389/fphys.2021.723510 | 34,512,391 | bioinformatics biomarker discovery clinical diagnostics precision medicine protein quantitative trait loci quantitative proteomics targeted techniques commercial or financial relationships that could be construed as a potential conflict of interest. | Precision medicine as a framework for disease diagnosis, treatment, and prevention at the molecular level has entered clinical practice. From the start, genetics has been an indispensable tool to understand and stratify the biology of chronic and complex diseases in precision medicine. However, with the advances in biomedical and omics technologies, quantitative proteomics is emerging as a powerful technology complementing genetics. Quantitative proteomics provide insight about the dynamic behaviour of proteins as they represent intermediate phenotypes. They provide direct biological insights into physiological patterns, while genetics accounting for baseline characteristics. Additionally, it opens a wide range of applications in clinical diagnostics, treatment stratification, and drug discovery. In this mini-review, we discuss the current status of quantitative proteomics in precision medicine including the available technologies and common methods to analyze quantitative proteomics data. Furthermore, we highlight the current challenges to put quantitative proteomics into clinical settings and provide a perspective to integrate proteomics data with genomics data for future applications in precision medicine. | Correa Rojo, Alejandro Heylen, Dries Aerts, Jan Thas, Olivier Hooyberghs, Jef Ertaylan, Gokhan Valkenborg, Dirk eng Review Switzerland Front Physiol. 2021 Aug 26;12:723510. doi: 10.3389/fphys.2021.723510. eCollection 2021.I | 09/14/2021 | ||
| Slow Off-Rate Modified Aptamer (SOMAmer) Proteomic Analysis of Patient-Derived Malignant Glioma Identifies Distinct Cellular Proteomes | Thanasupawat T, et al. | 2021 | Int J Mol Sci | 22 | 17 | https://www.doi.org/10.3390/ijms22179566 | 34,502,484 | Aptamers, Nucleotide/*chemistry Brain Neoplasms/*metabolism/pathology Glioma/*metabolism/pathology Humans Neoplasm Proteins/*metabolism Proteome/*metabolism *Proteomics Tumor Cells, Cultured SOMAmers glioblastoma glioma patient cell isolates proteomic clusters | Malignant gliomas derive from brain glial cells and represent >75% of primary brain tumors. This includes anaplastic astrocytoma (grade III; AS), the most common and fatal glioblastoma multiforme (grade IV; GBM), and oligodendroglioma (ODG). We have generated patient-derived AS, GBM, and ODG cell models to study disease mechanisms and test patient-centered therapeutic strategies. We have used an aptamer-based high-throughput SOMAscan((R)) 1.3K assay to determine the proteomic profiles of 1307 different analytes. SOMAscan((R)) proteomes of AS and GBM self-organized into closely adjacent proteomes which were clearly distinct from ODG proteomes. GBM self-organized into four proteomic clusters of which SOMAscan((R)) cluster 4 proteome predicted a highly inter-connected proteomic network. Several up- and down-regulated proteins relevant to glioma were successfully validated in GBM cell isolates across different SOMAscan((R)) clusters and in corresponding GBM tissues. Slow off-rate modified aptamer proteomics is an attractive analytical tool for rapid proteomic stratification of different malignant gliomas and identified cluster-specific SOMAscan((R)) signatures and functionalities in patient GBM cells. | Thanasupawat, Thatchawan Glogowska, Aleksandra Pascoe, Christopher Krishnan, Sai Nivedita Munir, Maliha Begum, Farhana Beiko, Jason Krcek, Jerry Del Bigio, Marc R Pitz, Marshall Shen, Yaoqing Spicer, Victor Coombs, Kevin M Wilkins, John Hombach-Klonisch, Sabine Klonisch, Thomas eng Switzerland Int J Mol Sci. 2021 Sep 3;22(17):9566. doi: 10.3390/ijms22179566.I | 09/11/2021 | ||
| Evolving A RIG-I Antagonist: A Modified DNA Aptamer Mimics Viral RNA | Ren X, et al. | 2021 | J Mol Biol | 433 | 21 | 167227 | https://www.doi.org/10.1016/j.jmb.2021.167227 | 34,487,794 | Antigens, Viral/*chemistry/metabolism Aptamers, Nucleotide/*chemistry/metabolism Binding Sites Cloning, Molecular Crystallography, X-Ray DEAD Box Protein 58/*chemistry/genetics/metabolism Escherichia coli/genetics/metabolism Gene Expression Genetic Vectors/chemistry/metabolism Humans Immunologic Factors/*chemistry/metabolism Kinetics Models, Molecular Molecular Mimicry Mutation Nucleic Acid Conformation Protein Binding Protein Conformation, alpha-Helical Protein Conformation, beta-Strand Protein Interaction Domains and Motifs RNA, Viral/*chemistry/metabolism Receptors, Immunologic/*chemistry/genetics/metabolism Recombinant Proteins/chemistry/genetics/metabolism SELEX Aptamer Technique DNA structure in-vitro innate immunity molecular recognition nucleic acid folding | Vertebrate organisms express a diversity of protein receptors that recognize and respond to the presence of pathogenic molecules, functioning as an early warning system for infection. As a result of mutation or dysregulated metabolism, these same innate immune receptors can be inappropriately activated, leading to inflammation and disease. One of the most important receptors for detection and response to RNA viruses is called RIG-I, and dysregulation of this protein is linked with a variety of disease states. Despite its central role in inflammatory responses, antagonists for RIG-I are underdeveloped. In this study, we use invitro selection from a pool of modified DNA aptamers to create a high affinity RIG-I antagonist. A high resolution crystal structure of the complex reveals molecular mimicry between the aptamer and the 5'-triphosphate terminus of viral ligands, which bind to the same amino acids within the CTD recognition platform of the RIG-I receptor. Our study suggests a powerful, generalizable strategy for generating immunomodulatory drugs and mechanistic tool compounds. | Ren, Xiaoming Gelinas, Amy D Linehan, Melissa Iwasaki, Akiko Wang, Wenshuai Janjic, Nebojsa Pyle, Anna Marie eng Research Support, Non-U.S. Gov't Netherlands J Mol Biol. 2021 Oct 15;433(21):167227. doi: 10.1016/j.jmb.2021.167227. Epub 2021 Sep 3.I | 09/07/2021 | |
| Radicava/Edaravone Findings in Biomarkers From Amyotrophic Lateral Sclerosis (REFINE-ALS): Protocol and Study Design | Berry J, et al. | 2021 | Neurol Clin Pract | 11 | 4 | e472-e479 | https://www.doi.org/10.1212/CPJ.0000000000000968 | 34,476,128 | OBJECTIVES: To identify putative biomarkers that may serve as quantifiable, biological, nonclinical measures of the pharmacodynamic effect of edaravone in amyotrophic lateral sclerosis (ALS) and to report real-world treatment outcomes. METHODS: This is a prospective, observational, longitudinal, multicenter (up to 40 sites) US study (Clinicaltrials.gov; NCT04259255) with at least 200 patients with ALS who will receive edaravone for 24 weeks (6 cycles; Food and Drug Administration-approved regimen). All participants must either be treatment naive for edaravone or be more than 1 month without receiving any edaravone dose before screening. Biomarker quantification and other assessments will be performed at baseline (before cycle 1) and during cycles 1, 3, and 6. Selected biomarkers of oxidative stress, inflammation, neuronal injury and death, and muscle injury, as well as biomarker discovery panels (EpiSwitch and SOMAscan), will be evaluated and, when feasible, compared with biobanked samples. Clinical efficacy assessments will include the ALS Functional Rating Scale-Revised, King's clinical staging, ALS Assessment Questionnaire-40, Appel ALS Score (Rating Scale), slow vital capacity, hand-held dynamometry and grip strength, and time to specified states of disease progression or death. DNA samples will also be collected for potential genomic evaluation. The predicted rates of progression and survival, and their potential correlations with biomarkers, will be evaluated. Adverse events related to the study will be reported. RESULTS: The study is estimated to be completed in 2022 with an interim analysis planned. CONCLUSIONS: Findings may help to further the understanding of the pharmacodynamic effect of edaravone, including changes in biomarkers, in response to treatment. | Berry, James Brooks, Benjamin Genge, Angela Heiman-Patterson, Terry Appel, Stanley Benatar, Michael Bowser, Robert Cudkowicz, Merit Gooch, Clifton Shefner, Jeremy Westra, Jurjen Agnese, Wendy Merrill, Charlotte Nelson, Sally Apple, Stephen eng Neurol Clin Pract. 2021 Aug;11(4):e472-e479. doi: 10.1212/CPJ.0000000000000968.I | 09/04/2021 | ||
| Serum Proteomics of Older Patients Undergoing Major Cardiac Surgery: Identification of Biomarkers Associated With Postoperative Delirium | Rhee J, et al. | 2021 | Front Aging Neurosci | 13 | 699763 | https://www.doi.org/10.3389/fnagi.2021.699763 | 34,456,709 | Il-6 Pde3a SOMAscan Timp-1 TruCulture cardiopulmonary bypass postoperative delirium proteomics commercial or financial relationships that could be construed as a potential conflict of interest. | BACKGROUND: Postoperative delirium (POD) is an acute altered mental state commonly encountered after cardiac surgery. The pathophysiological mechanisms underlying POD remain unclear. We aimed to identify circulating proteins significantly altered after major cardiac surgery with cardiopulmonary bypass (CPB). We also aimed to enable inferences on associations with POD. METHODS: Serum and whole blood samples were collected before CPB (n = 16 patients; n = 8 with POD) and again from the same patients on postoperative day 1. All patients were clinically evaluated for POD on postoperative days 1-3. An aptamer-based proteomics platform (SOMAscan) was used to quantify serum protein abundance in patients with POD compared with non-POD controls. We also performed a lipopolysaccharide (LPS)-based in vitro functional analysis (TruCulture) on whole blood samples from patients with POD and non-POD controls to approximate surgical stress. Cytokine levels were determined using a Luminex immunoassay. RESULTS: Cardiac surgery with CPB resulted in a significant (p(adj) < 0.01) change in 48.8% (637 out of 1,305) of proteins detected by SOMAscan. Gene set enrichment showed that the most impacted biological processes involved myeloid cell activation. Specifically, activation and degranulation of neutrophils were the top five highest-scoring processes. Pathway analyses with the Kyoto Encyclopedia of Genes and Genomes (KEGG) showed that metabolic enzymes, particularly those of glycolysis, were elevated in serum concentration after surgery. Several proteins were significantly increased postoperatively in patients diagnosed with POD relative to the non-POD controls, with interleukin-6 (IL-6) showing the greatest fold-change. LPS stimulation of whole blood samples confirmed these findings. Linear regression analysis showed a highly significant correlation between Confusion Assessment Method (CAM) scores and CPB-mediated changes in cGMP-inhibited 3',5'-cyclic phosphodiesterase A (PDE3A). CONCLUSIONS: Cardiac surgery with CPB resulted in inflammasome changes accompanied by unexpected increases in metabolic pathways. In exploratory analyses, we found that POD was associated with changes in the expression level of various proteins, most notably IL-6 and PDE3A. This study and ongoing protein biomarker studies will likely help quantify risk or confirm the diagnosis for POD and increase understanding of its pathophysiological mechanisms. | Rhee, James Kuznetsov, Alexandra McKay, Tina Lyons, Margaret Houstis, Nicholas Mekkonen, Jennifer Ethridge, Breanna Ibala, Reine Hahm, Eunice Gitlin, Jacob Guseh, J Sawalla Kitchen, Robert Rosenzweig, Anthony Shaefi, Shahzad Flaczyk, Adam Qu, Jason Akeju, Oluwaseun eng R01 DK125786/DK/NIDDK NIH HHS/ R35 HL155318/HL/NHLBI NIH HHS/ T32 HL007208/HL/NHLBI NIH HHS/ R03 AG060179/AG/NIA NIH HHS/ R01 AG053582/AG/NIA NIH HHS/ R01 AG061034/AG/NIA NIH HHS/ K08 GM134220/GM/NIGMS NIH HHS/ K08 HL140200/HL/NHLBI NIH HHS/ R21 EB030756/EB/NIBIB NIH HHS/ Switzerland Front Aging Neurosci. 2021 Aug 11;13:699763. doi: 10.3389/fnagi.2021.699763. eCollection 2021.I | 08/31/2021 | ||
| DNA Damage, n-3 Long-Chain PUFA Levels and Proteomic Profile in Brazilian Children and Adolescents | Barros TT, et al. | 2021 | Nutrients | 13 | 8 | https://www.doi.org/10.3390/nu13082483 | 34,444,642 | Adolescent Brazil Child Class I Phosphatidylinositol 3-Kinases/blood Class Ia Phosphatidylinositol 3-Kinase/blood Cross-Sectional Studies Cyclin C/blood Cyclin-Dependent Kinase 8/blood *DNA Damage Docosahexaenoic Acids/*blood Eicosapentaenoic Acid/*blood Fatty Acids, Omega-3/*blood Female Humans Hydrolases/blood Inflammation/metabolism Male Protein Kinase C beta/blood Proteomics DNA damage adolescents fatty acids proteomic of the Nestle group. J.K. works for Vydiant, a for-profit company. S.M. is on the faculty of the Department of Chemistry and Pharmaceutical Sciences, Amsterdam Institute for Molecular and Life Sciences, Vrije Universiteite Amsterdam. | Fatty acids play a significant role in maintaining cellular and DNA protection and we previously found an inverse relationship between blood levels of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) and DNA damage. The aim of this study was to explore differences in proteomic profiles, for 117 pro-inflammatory proteins, in two previously defined groups of individuals with different DNA damage and EPA and DHA levels. Healthy children and adolescents (n = 140) aged 9 to 13 years old in an urban area of Brazil were divided by k-means cluster test into two clusters of DNA damage (tail intensity) using the comet assay (cluster 1 = 5.9% +/- 1.2 and cluster 2 = 13.8% +/- 3.1) in our previous study. The cluster with higher DNA damage and lower levels of DHA (6.2 +/- 1.6 mg/dL; 5.4 +/- 1.3 mg/dL, p = 0.003) and EPA (0.6 +/- 0.2 mg/dL; 0.5 +/- 0.1 mg/dL, p < 0.001) presented increased expression of the proteins CDK8-CCNC, PIK3CA-PIK3R1, KYNU, and PRKCB, which are involved in pro-inflammatory pathways. Our findings support the hypothesis that low levels of n-3 long-chain PUFA may have a less protective role against DNA damage through expression of pro-inflammatory proteins, such as CDK8-CCNC, PIK3CA-PIK3R1, KYNU, and PRKCB. | Barros, Tamiris Trevisan de Venancio, Vinicius de Paula Hernandes, Livia Cristina Antunes, Lusania Maria Greggi Hillesheim, Elaine Salomao, Roberta Garcia Mathias, Mariana Giaretta Coelho-Landell, Carolina Almeida Toffano, Roseli Borges Donega Almada, Maria Olimpia Ribeiro do Vale Camelo-Junior, Jose Simon Moco, Sofia Cominetti, Ornella Ued, Fabio da Veiga Kaput, Jim Monteiro, Jacqueline Pontes eng 2012/20421-8/Fundacao de Amparo a Pesquisa do Estado de Sao Paulo/ 131224/2015-8/Conselho Nacional de Desenvolvimento Cientifico e Tecnologico/ RDHS 000054/Nestle Institute of Health Sciences/ Switzerland Nutrients. 2021 Jul 21;13(8):2483. doi: 10.3390/nu13082483.I | 08/28/2021 | ||
| Validation of Chemokine Biomarkers in Duchenne Muscular Dystrophy | Ogundele M, et al. | 2021 | Life (Basel) | 11 | 8 | https://www.doi.org/10.3390/life11080827 | 34,440,571 | Becker muscular dystrophy Duchenne muscular dystrophy chemokines disease severity inflammatory biomarkers validation studies | Duchenne muscular dystrophy (DMD) is a progressive muscle disease involving complex skeletal muscle pathogenesis. The pathogenesis is triggered by sarcolemma instability due to the lack of dystrophin protein expression, leading to Ca(2+) influx, muscle fiber apoptosis, inflammation, muscle necrosis, and fibrosis. Our lab recently used two high-throughput multiplexing techniques (e.g., SomaScan((R)) aptamer assay and tandem mass tag-(TMT) approach) and identified a series of serum protein biomarkers tied to different pathobiochemical pathways. In this study, we focused on validating the circulating levels of three proinflammatory chemokines (CCL2, CXCL10, and CCL18) that are believed to be involved in an early stage of muscle pathogenesis. We used highly specific and reproducible MSD ELISA assays and examined the association of these chemokines with DMD pathogenesis, age, disease severity, and response to glucocorticoid treatment. As expected, we confirmed that these three chemokines were significantly elevated in serum and muscle samples of DMD patients relative to age-matched healthy controls (p-value < 0.05, CCL18 was not significantly altered in muscle samples). These three chemokines were not significantly elevated in Becker muscular dystrophy (BMD) patients, a milder form of dystrophinopathy, when compared in a one-way ANOVA to a control group but remained significantly elevated in the age-matched DMD group (p < 0.05). CCL2 and CCL18 but not CXCL10 declined with age in DMD patients, whereas all three chemokines remained unchanged with age in BMD and controls. Only CCL2 showed significant association with time to climb four steps in the DMD group (r = 0.48, p = 0.038) and neared significant association with patients' reported outcome in the BMD group (r = 0.39, p = 0.058). Furthermore, CCL2 was found to be elevated in a serum of the mdx mouse model of DMD, relative to wild-type mouse model. This study suggests that CCL2 might be a suitable candidate biomarker for follow-up studies to demonstrate its physiological significance and clinical utility in DMD. | Ogundele, Michael Zhang, Jesslyn S Goswami, Mansi V Barbieri, Marissa L Dang, Utkarsh J Novak, James S Hoffman, Eric P Nagaraju, Kanneboyina Cinrg-Dnhs Investigators Hathout, Yetrib eng R01 AR061875/AR/NIAMS NIH HHS/ P50HD090254/NH/NIH HHS/ W81XWH-16-1-0557/U.S. Department of Defense/ Switzerland Life (Basel). 2021 Aug 13;11(8):827. doi: 10.3390/life11080827.I | 08/28/2021 | ||
| Discovery and validation of a novel subgroup and therapeutic target in idiopathic multicentric Castleman disease | Pierson SK, et al. | 2021 | Blood Adv | 5 | 17 | 3445-3456 | https://www.doi.org/10.1182/bloodadvances.2020004016 | 34,438,448 | *Castleman Disease/drug therapy *Herpesvirus 8, Human Humans Interleukin-6 Proteomics Signal Transduction United States | Idiopathic multicentric Castleman disease (iMCD) is a poorly understood hematologic disorder involving cytokine-induced polyclonal lymphoproliferation, systemic inflammation, and potentially fatal multiorgan failure. Although the etiology of iMCD is unknown, interleukin-6 (IL-6) is an established disease driver in approximately one-third of patients. Anti-IL-6 therapy, siltuximab, is the only US Food and Drug Administration-approved treatment. Few options exist for siltuximab nonresponders, and no validated tests are available to predict likelihood of response. We procured and analyzed the largest-to-date cohort of iMCD samples, which enabled classification of iMCD into disease categories, discovery of siltuximab response biomarkers, and identification of therapeutic targets for siltuximab nonresponders. Proteomic quantification of 1178 analytes was performed on serum of 88 iMCD patients, 60 patients with clinico-pathologically overlapping diseases (human herpesvirus-8-associated MCD, N = 20; Hodgkin lymphoma, N = 20; rheumatoid arthritis, N = 20), and 42 healthy controls. Unsupervised clustering revealed iMCD patients have heterogeneous serum proteomes that did not cluster with clinico-pathologically overlapping diseases. Clustering of iMCD patients identified a novel subgroup with superior response to siltuximab, which was validated using a 7-analyte panel (apolipoprotein E, amphiregulin, serum amyloid P-component, inactivated complement C3b, immunoglobulin E, IL-6, erythropoietin) in an independent cohort. Enrichment analyses and immunohistochemistry identified Janus kinase (JAK)/signal transducer and activator of transcription 3 signaling as a candidate therapeutic target that could potentially be targeted with JAK inhibitors in siltuximab nonresponders. Our discoveries demonstrate the potential for accelerating discoveries for rare diseases through multistakeholder collaboration. | Pierson, Sheila K Shenoy, Sushila Oromendia, Ana B Gorzewski, Alexander M Langan Pai, Ruth-Anne Nabel, Christopher Shield Ruth, Jason R Parente, Sophia A T Arenas, Daniel J Guilfoyle, Mary Reddy, Manjula Weinblatt, Michael Shadick, Nancy Bower, Mark Pria, Alessia Dalla Masaki, Yasufumi Katz, Laura Mezey, Jason Beineke, Philip Lee, David Tendler, Craig Kambayashi, Taku Fossa, Alexander van Rhee, Frits Fajgenbaum, David C eng R01 HL141408/HL/NHLBI NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Blood Adv. 2021 Sep 14;5(17):3445-3456. doi: 10.1182/bloodadvances.2020004016.I | 08/27/2021 | |
| Smoking induces sex-specific changes in the small airway proteome | Kokelj S, et al. | 2021 | Respir Res | 22 | 1 | 234 | https://www.doi.org/10.1186/s12931-021-01825-6 | 34,429,114 | Cigarette Smoking/genetics/*metabolism/pathology Cohort Studies Female Humans Lung/*metabolism/pathology Male Middle Aged Proteomics/*methods *Sex Characteristics *Smokers Spirometry/methods Tobacco Smoking/*genetics/metabolism/pathology Copd Exhaled particles Inflammation Proteomics Respiratory tract lining fluid Small airways Smoking personal fees from PExA AB during the conduct of the study and was employed by PExA AB while writing the manuscript, but not during the planning and completion of the study. HKO and BG are full-time employees of AstraZeneca. | INTRODUCTION: Cigarette smoke triggers many cellular and signaling responses in the lung and the resulting inflammation plays a central role in smoke-related lung diseases, such as COPD. We explored the effects of smoking on the small airway proteome in samples obtained by collection of exhaled particles with the aim to identify specific proteins dysregulated by smoking. METHODS: Exhaled particles were obtained from 38 current smokers, 47 former smokers and 22 healthy controls with the PExA method. 120 ng of sample was collected from individual subjects and analyzed with the SOMAscan proteomics platform. General linear model-based statistics were performed. RESULTS: Two hundred and three proteins were detected in at least half of 107 total samples. Active smoking exerted a significant impact on the protein composition of respiratory tract lining fluid (RTLF), with 81 proteins altered in current smokers compared to never smokers (p < 0.05, q < 0.124). Among the proteins most clearly discriminating between current and never smokers were sRAGE, FSTL3, SPOCK2 and protein S, all of them being less abundant in current smokers. Analysis stratified for sex unveiled sex differences with more pronounced proteomic alterations due to active smoking in females than males. Proteins whose abundance was altered by active smoking in women were to a larger extent related to the complement system. The small airway protein profile of former smokers appeared to be more similar to that observed in never smokers. CONCLUSIONS: The study shows that smoking has a strong impact on protein expression in the small airways, and that smoking affects men and women differently, suggesting PExA sampling combined with high sensitivity protein analysis offers a promising platform for early detection of COPD and identification of novel COPD drug targets. | Kokelj, Spela Ostling, Jorgen Georgi, Benjamin Fromell, Karin Ekdahl, Kristina Nilsson Olsson, Henric K Olin, Anna-Carin eng 2016-00639/Forskningsradet om Halsa, Arbetsliv och Valfard/ 21080209/Hjart-Lungfonden/ 2016-2075-5.1/Vetenskapsradet/ 2016-04519/Linneuniversitetet/ England Respir Res. 2021 Aug 24;22(1):234. doi: 10.1186/s12931-021-01825-6.I | 08/26/2021 | |
| Genetically Predicted Glucose-Dependent Insulinotropic Polypeptide (GIP) Levels and Cardiovascular Disease Risk Are Driven by Distinct Causal Variants in the GIPR Region | Bowker N, et al. | 2021 | Diabetes | 70 | 11 | 2706-2719 | https://www.doi.org/10.2337/db21-0103 | 34,426,508 | Adult Aged Cardiovascular Diseases/*blood Diabetes Mellitus, Type 2/*blood/genetics/metabolism Female Finland Gastric Inhibitory Polypeptide/*blood/genetics/metabolism *Genetic Predisposition to Disease Genetic Variation Genome-Wide Association Study Genotype Humans Male Middle Aged Receptors, Gastrointestinal Hormone/genetics/*metabolism Risk Factors United Kingdom | There is considerable interest in GIPR agonism to enhance the insulinotropic and extrapancreatic effects of GIP, thereby improving glycemic and weight control in type 2 diabetes (T2D) and obesity. Recent genetic epidemiological evidence has implicated higher GIPR-mediated GIP levels in raising coronary artery disease (CAD) risk, a potential safety concern for GIPR agonism. We therefore aimed to quantitatively assess whether the association between higher GIPR-mediated fasting GIP levels and CAD risk is mediated via GIPR or is instead the result of linkage disequilibrium (LD) confounding between variants at the GIPR locus. Using Bayesian multitrait colocalization, we identified a GIPR missense variant, rs1800437 (G allele; E354), as the putatively causal variant shared among fasting GIP levels, glycemic traits, and adiposity-related traits (posterior probability for colocalization [PP(coloc)] > 0.97; PP explained by the candidate variant [PP(explained)] = 1) that was independent from a cluster of CAD and lipid traits driven by a known missense variant in APOE (rs7412; distance to E354 approximately 770 Kb; R (2) with E354 = 0.004; PP(coloc) > 0.99; PP(explained) = 1). Further, conditioning the association between E354 and CAD on the residual LD with rs7412, we observed slight attenuation in association, but it remained significant (odds ratio [OR] per copy of E354 after adjustment 1.03; 95% CI 1.02, 1.04; P = 0.003). Instead, E354's association with CAD was completely attenuated when conditioning on an additional established CAD signal, rs1964272 (R (2) with E354 = 0.27), an intronic variant in SNRPD2 (OR for E354 after adjustment for rs1964272: 1.01; 95% CI 0.99, 1.03; P = 0.06). We demonstrate that associations with GIP and anthropometric and glycemic traits are driven by genetic signals distinct from those driving CAD and lipid traits in the GIPR region and that higher E354-mediated fasting GIP levels are not associated with CAD risk. These findings provide evidence that the inclusion of GIPR agonism in dual GIPR/GLP1R agonists could potentiate the protective effect of GLP-1 agonists on diabetes without undue CAD risk, an aspect that has yet to be assessed in clinical trials. | Bowker, Nicholas Hansford, Robert Burgess, Stephen Foley, Christopher N Auyeung, Victoria P W Erzurumluoglu, A Mesut Stewart, Isobel D Wheeler, Eleanor Pietzner, Maik Gribble, Fiona Reimann, Frank Bhatnagar, Pallav Coghlan, Matthew P Wareham, Nicholas J Langenberg, Claudia eng MC_UU_00014/3/MRC_/Medical Research Council/United Kingdom DH_/Department of Health/United Kingdom C864/A14136/CRUK_/Cancer Research UK/United Kingdom MC_PC_13046/MRC_/Medical Research Council/United Kingdom G0401527/MRC_/Medical Research Council/United Kingdom 106262/Z/14/Z/WT_/Wellcome Trust/United Kingdom G1000143/MRC_/Medical Research Council/United Kingdom 14136/CRUK_/Cancer Research UK/United Kingdom WT_/Wellcome Trust/United Kingdom MC_UU_00006/1/MRC_/Medical Research Council/United Kingdom MC_UU_12012/3/MRC_/Medical Research Council/United Kingdom 106263/Z/14/Z/WT_/Wellcome Trust/United Kingdom MR/N003284/1/MRC_/Medical Research Council/United Kingdom MC_UU_12015/1/MRC_/Medical Research Council/United Kingdom MC_PC_13048/MRC_/Medical Research Council/United Kingdom Research Support, Non-U.S. Gov't Diabetes. 2021 Nov;70(11):2706-2719. doi: 10.2337/db21-0103. Epub 2021 Aug 23.I | 08/25/2021 | |
| Group IIA secreted phospholipase A2 is associated with the pathobiology leading to COVID-19 mortality | Snider JM, et al. | 2021 | J Clin Invest | 131 | 19 | https://www.doi.org/10.1172/JCI149236 | 34,428,181 | Adolescent Adult Aged Aged, 80 and over COVID-19/*blood/*mortality Child Disease-Free Survival Female Group II Phospholipases A2/*blood Humans Male Middle Aged SARS-CoV-2/*metabolism Severity of Illness Index Survival Rate Covid-19 Cellular immune response Inflammation Molecular pathology officer of MicroRid Technologies Inc. | There is an urgent need to identify the cellular and molecular mechanisms responsible for severe COVID-19 that results in death. We initially performed both untargeted and targeted lipidomics as well as focused biochemical analyses of 127 plasma samples and found elevated metabolites associated with secreted phospholipase A2 (sPLA2) activity and mitochondrial dysfunction in patients with severe COVID-19. Deceased COVID-19 patients had higher levels of circulating, catalytically active sPLA2 group IIA (sPLA2-IIA), with a median value that was 9.6-fold higher than that for patients with mild disease and 5.0-fold higher than the median value for survivors of severe COVID-19. Elevated sPLA2-IIA levels paralleled several indices of COVID-19 disease severity (e.g., kidney dysfunction, hypoxia, multiple organ dysfunction). A decision tree generated by machine learning identified sPLA2-IIA levels as a central node in the stratification of patients who died from COVID-19. Random forest analysis and least absolute shrinkage and selection operator-based (LASSO-based) regression analysis additionally identified sPLA2-IIA and blood urea nitrogen (BUN) as the key variables among 80 clinical indices in predicting COVID-19 mortality. The combined PLA-BUN index performed significantly better than did either one alone. An independent cohort (n = 154) confirmed higher plasma sPLA2-IIA levels in deceased patients compared with levels in plasma from patients with severe or mild COVID-19, with the PLA-BUN index-based decision tree satisfactorily stratifying patients with mild, severe, or fatal COVID-19. With clinically tested inhibitors available, this study identifies sPLA2-IIA as a therapeutic target to reduce COVID-19 mortality. | Snider, Justin M You, Jeehyun Karen Wang, Xia Snider, Ashley J Hallmark, Brian Zec, Manja M Seeds, Michael C Sergeant, Susan Johnstone, Laurel Wang, Qiuming Sprissler, Ryan Carr, Tara F Lutrick, Karen Parthasarathy, Sairam Bime, Christian Zhang, Hao Helen Luberto, Chiara Kew, Richard R Hannun, Yusuf A Guerra, Stefano McCall, Charles E Yao, Guang Del Poeta, Maurizio Chilton, Floyd H eng I01 BX002624/BX/BLRD VA/ P30 ES006694/ES/NIEHS NIH HHS/ R01 AI125770/AI/NIAID NIH HHS/ P01 CA097132/CA/NCI NIH HHS/ UL1 TR001420/TR/NCATS NIH HHS/ R01 AI136934/AI/NIAID NIH HHS/ Clinical Trial Multicenter Study Observational Study Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't J Clin Invest. 2021 Oct 1;131(19):e149236. doi: 10.1172/JCI149236.I | 08/25/2021 | ||
| Cognitive stimulation in the workplace, plasma proteins, and risk of dementia: three analyses of population cohort studies | Kivimaki M, et al. | 2021 | BMJ | 374 | n1804 | https://www.doi.org/10.1136/bmj.n1804 | 34,407,988 | Aged Aged, 80 and over Blood Proteins/analysis Dementia/blood/*epidemiology Europe/epidemiology Female Humans Incidence Male Neuropsychological Tests Occupational Diseases/blood/*epidemiology/psychology Occupations/*statistics & numerical data Proportional Hazards Models Prospective Studies Risk Factors Sedentary Behavior United Kingdom/epidemiology United States/epidemiology Workplace/*psychology | OBJECTIVES: To examine the association between cognitively stimulating work and subsequent risk of dementia and to identify protein pathways for this association. DESIGN: Multicohort study with three sets of analyses. SETTING: United Kingdom, Europe, and the United States. PARTICIPANTS: Three associations were examined: cognitive stimulation and dementia risk in 107 896 participants from seven population based prospective cohort studies from the IPD-Work consortium (individual participant data meta-analysis in working populations); cognitive stimulation and proteins in a random sample of 2261 participants from one cohort study; and proteins and dementia risk in 13 656 participants from two cohort studies. MAIN OUTCOME MEASURES: Cognitive stimulation was measured at baseline using standard questionnaire instruments on active versus passive jobs and at baseline and over time using a job exposure matrix indicator. 4953 proteins in plasma samples were scanned. Follow-up of incident dementia varied between 13.7 to 30.1 years depending on the cohort. People with dementia were identified through linked electronic health records and repeated clinical examinations. RESULTS: During 1.8 million person years at risk, 1143 people with dementia were recorded. The risk of dementia was found to be lower for participants with high compared with low cognitive stimulation at work (crude incidence of dementia per 10 000 person years 4.8 in the high stimulation group and 7.3 in the low stimulation group, age and sex adjusted hazard ratio 0.77, 95% confidence interval 0.65 to 0.92, heterogeneity in cohort specific estimates I(2)=0%, P=0.99). This association was robust to additional adjustment for education, risk factors for dementia in adulthood (smoking, heavy alcohol consumption, physical inactivity, job strain, obesity, hypertension, and prevalent diabetes at baseline), and cardiometabolic diseases (diabetes, coronary heart disease, stroke) before dementia diagnosis (fully adjusted hazard ratio 0.82, 95% confidence interval 0.68 to 0.98). The risk of dementia was also observed during the first 10 years of follow-up (hazard ratio 0.60, 95% confidence interval 0.37 to 0.95) and from year 10 onwards (0.79, 0.66 to 0.95) and replicated using a repeated job exposure matrix indicator of cognitive stimulation (hazard ratio per 1 standard deviation increase 0.77, 95% confidence interval 0.69 to 0.86). In analysis controlling for multiple testing, higher cognitive stimulation at work was associated with lower levels of proteins that inhibit central nervous system axonogenesis and synaptogenesis: slit homologue 2 (SLIT2, fully adjusted beta -0.34, P<0.001), carbohydrate sulfotransferase 12 (CHSTC, fully adjusted beta -0.33, P<0.001), and peptidyl-glycine alpha-amidating monooxygenase (AMD, fully adjusted beta -0.32, P<0.001). These proteins were associated with increased dementia risk, with the fully adjusted hazard ratio per 1 SD being 1.16 (95% confidence interval 1.05 to 1.28) for SLIT2, 1.13 (1.00 to 1.27) for CHSTC, and 1.04 (0.97 to 1.13) for AMD. CONCLUSIONS: The risk of dementia in old age was found to be lower in people with cognitively stimulating jobs than in those with non-stimulating jobs. The findings that cognitive stimulation is associated with lower levels of plasma proteins that potentially inhibit axonogenesis and synaptogenesis and increase the risk of dementia might provide clues to underlying biological mechanisms. | Kivimaki, Mika Walker, Keenan A Pentti, Jaana Nyberg, Solja T Mars, Nina Vahtera, Jussi Suominen, Sakari B Lallukka, Tea Rahkonen, Ossi Pietilainen, Olli Koskinen, Aki Vaananen, Ari Kalsi, Jatinderpal K Goldberg, Marcel Zins, Marie Alfredsson, Lars Westerholm, Peter J M Knutsson, Anders Theorell, Tores Ervasti, Jenni Oksanen, Tuula Sipila, Pyry N Tabak, Adam G Ferrie, Jane E Williams, Stephen A Livingston, Gill Gottesman, Rebecca F Singh-Manoux, Archana Zetterberg, Henrik Lindbohm, Joni V eng MR/R024227/1/MRC_/Medical Research Council/United Kingdom MR/S011676/1/MRC_/Medical Research Council/United Kingdom P30 AG066507/AG/NIA NIH HHS/ Meta-Analysis Research Support, Non-U.S. Gov't England BMJ. 2021 Aug 18;374:n1804. doi: 10.1136/bmj.n1804.I | 08/20/2021 | ||
| A proteome-wide genetic investigation identifies several SARS-CoV-2-exploited host targets of clinical relevance | Anisul M, et al. | 2021 | Elife | 10 | https://www.doi.org/10.7554/eLife.69719 | 34,402,426 | 2',5'-Oligoadenylate Synthetase/genetics COVID-19/genetics/immunology/physiopathology/*virology Cell Adhesion Molecules *Genome-Wide Association Study Humans Lectins, C-Type Proteome Receptors, Cell Surface SARS-CoV-2/*physiology Scavenger Receptors, Class A/genetics Severity of Illness Index fas Receptor/genetics Covid-19 apoptosis epidemiology genetic colocalization genetics genomics global health human mendelian randomization proteins partnership currently involving the Wellcome Sanger Institute, EMBL-EBI, BMS, GSK, and Sanofi. Research is funded by financial and in-kind contributions from each of the partners. JS none, ES Open Targets is a pre-competitive partnership currently involving the Wellcome Sanger Institute, EMBL-EBI, BMS, GSK, and Sanofi. Research is funded by financial and in-kind contributions from each of the partners. ES is also a full-time employee of Bristol-Myers Squibb. MH Dr Holmes has consulted for Boehringer Ingelheim, and in adherence to the University of Oxford's Clinical Trial Service Unit & Epidemiological Studies Unit (CSTU) staff policy, did not accept personal honoraria or other payments from pharmaceutical companies. JM JM is a full-time employee of Bristol-Myers Squibb and retains stock or stock options in Bristol-Myers Squibb. The author has no other competing interests to declare. TG TG received grants from Biogen and GlaxoSmithKline. The author has no other competing interests to declare. ID Open Targets is a pre-competitive partnership currently involving the Wellcome Sanger Institute, EMBL-EBI, BMS, GSK, and Sanofi. Research is funded by financial and in-kind contributions from each of the partners. ID also received travel costs within the last 36 months from Takeda for speaking at their Reverse Translation Symposium. The author has no other competing interests to declare. | BACKGROUND: The virus SARS-CoV-2 can exploit biological vulnerabilities (e.g. host proteins) in susceptible hosts that predispose to the development of severe COVID-19. METHODS: To identify host proteins that may contribute to the risk of severe COVID-19, we undertook proteome-wide genetic colocalisation tests, and polygenic (pan) and cis-Mendelian randomisation analyses leveraging publicly available protein and COVID-19 datasets. RESULTS: Our analytic approach identified several known targets (e.g. ABO, OAS1), but also nominated new proteins such as soluble Fas (colocalisation probability >0.9, p=1 x 10(-4)), implicating Fas-mediated apoptosis as a potential target for COVID-19 risk. The polygenic (pan) and cis-Mendelian randomisation analyses showed consistent associations of genetically predicted ABO protein with several COVID-19 phenotypes. The ABO signal is highly pleiotropic, and a look-up of proteins associated with the ABO signal revealed that the strongest association was with soluble CD209. We demonstrated experimentally that CD209 directly interacts with the spike protein of SARS-CoV-2, suggesting a mechanism that could explain the ABO association with COVID-19. CONCLUSIONS: Our work provides a prioritised list of host targets potentially exploited by SARS-CoV-2 and is a precursor for further research on CD209 and FAS as therapeutically tractable targets for COVID-19. FUNDING: MAK, JSc, JH, AB, DO, MC, EMM, MG, ID were funded by Open Targets. J.Z. and T.R.G were funded by the UK Medical Research Council Integrative Epidemiology Unit (MC_UU_00011/4). JSh and GJW were funded by the Wellcome Trust Grant 206194. This research was funded in part by the Wellcome Trust [Grant 206194]. For the purpose of open access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission. Individuals who become infected with the virus that causes COVID-19 can experience a wide variety of symptoms. These can range from no symptoms or minor symptoms to severe illness and death. Key demographic factors, such as age, gender and race, are known to affect how susceptible an individual is to infection. However, molecular factors, such as unique gene mutations and gene expression levels can also have a major impact on patient responses by affecting the levels of proteins in the body. Proteins that are too abundant or too scarce may mean the difference between dying from or surviving COVID-19. Identifying the molecular factors in a host that affect how viruses can infect individuals, evade immune defences or trigger severe illness, could provide new ways to treat patients with COVID-19. Such factors are likely to remain constant, even when the virus mutates into new strains. Hence, insights would likely apply across all virus strains, including current strains, such as alpha and delta, and any new strains that may emerge in the future. Using such a 'natural experiment' approach, Karim et al. compared the genetic profiles of over 30,000 COVID-19 patients and a million healthy individuals. Nine proteins were found to have an impact on COVID-19 infection and disease severity. Four proteins were ranked as top priorities for potential treatment targets. One protein, called CD209 (also known as DC-SIGN), is involved in how the virus enters the host cells, and had one of the strongest associations with COVID-19. Two proteins, called IL-6R and FAS, were involved in the immune response and could be responsible for the immune over-activation often seen in severe COVID-19. Finally, one protein, called OAS1, formed part of the body's innate antiviral defence system and appeared to reduce susceptibility to COVID-19. Knowing more about the proteins that influence the severity of COVID-19 opens up new ways to predict, protect and treat patients who may have severe or fatal reactions to infection. Indeed, one of the identified proteins (IL-6R) had already been targeted in recent clinical trials with some encouraging results. Considering CD209 as a potential receptor for the virus could provide another avenue for therapeutics, similar to previously successful approaches to block the virus' known interaction with a receptor protein. Ultimately, this research could supply an entirely new set of treatment options to help combat the COVID-19 pandemic. eng | Anisul, Mohd Shilts, Jarrod Schwartzentruber, Jeremy Hayhurst, James Buniello, Annalisa Shaikho Elhaj Mohammed, Elmutaz Zheng, Jie Holmes, Michael Ochoa, David Carmona, Miguel Maranville, Joseph Gaunt, Tom R Emilsson, Valur Gudnason, Vilmundur McDonagh, Ellen M Wright, Gavin J Ghoussaini, Maya Dunham, Ian eng Wellcome Trust/United Kingdom MC_UU_00011/4/MRC_/Medical Research Council/United Kingdom 206194/WT_/Wellcome Trust/United Kingdom Research Support, Non-U.S. Gov't England Elife. 2021 Aug 17;10:e69719. doi: 10.7554/eLife.69719.I | 08/18/2021 | |||
| Distinct Molecular Signatures of Clinical Clusters in People With Type 2 Diabetes: An IMI-RHAPSODY Study | Slieker RC, et al. | 2021 | Diabetes | 70 | 11 | 2683-2693 | https://www.doi.org/10.2337/db20-1281 | 34,376,475 | Cluster Analysis Cohort Studies Cross-Sectional Studies Diabetes Mellitus, Type 2/*metabolism Humans Insulin Resistance | Type 2 diabetes is a multifactorial disease with multiple underlying aetiologies. To address this heterogeneity, investigators of a previous study clustered people with diabetes according to five diabetes subtypes. The aim of the current study is to investigate the etiology of these clusters by comparing their molecular signatures. In three independent cohorts, in total 15,940 individuals were clustered based on five clinical characteristics. In a subset, genetic (N = 12,828), metabolomic (N = 2,945), lipidomic (N = 2,593), and proteomic (N = 1,170) data were obtained in plasma. For each data type, each cluster was compared with the other four clusters as the reference. The insulin-resistant cluster showed the most distinct molecular signature, with higher branched-chain amino acid, diacylglycerol, and triacylglycerol levels and aberrant protein levels in plasma were enriched for proteins in the intracellular PI3K/Akt pathway. The obese cluster showed higher levels of cytokines. The mild diabetes cluster with high HDL showed the most beneficial molecular profile with effects opposite of those seen in the insulin-resistant cluster. This study shows that clustering people with type 2 diabetes can identify underlying molecular mechanisms related to pancreatic islets, liver, and adipose tissue metabolism. This provides novel biological insights into the diverse aetiological processes that would not be evident when type 2 diabetes is viewed as a homogeneous disease. | Slieker, Roderick C Donnelly, Louise A Fitipaldi, Hugo Bouland, Gerard A Giordano, Giuseppe N Akerlund, Mikael Gerl, Mathias J Ahlqvist, Emma Ali, Ashfaq Dragan, Iulian Elders, Petra Festa, Andreas Hansen, Michael K van der Heijden, Amber A Mansour Aly, Dina Kim, Min Kuznetsov, Dmitry Mehl, Florence Klose, Christian Simons, Kai Pavo, Imre Pullen, Timothy J Suvitaival, Tommi Wretlind, Asger Rossing, Peter Lyssenko, Valeriya Legido Quigley, Cristina Groop, Leif Thorens, Bernard Franks, Paul W Ibberson, Mark Rutter, Guy A Beulens, Joline W J 't Hart, Leen M Pearson, Ewan R eng WT_/Wellcome Trust/United Kingdom 102820/Z/13/Z/WT_/Wellcome Trust/United Kingdom WT098424AIA/WT_/Wellcome Trust/United Kingdom 212625/Z/18/Z/WT_/Wellcome Trust/United Kingdom MR/R022259/1/MRC_/Medical Research Council/United Kingdom MR/J0003042/1/MRC_/Medical Research Council/United Kingdom MR/L020149/1/MRC_/Medical Research Council/United Kingdom Research Support, Non-U.S. Gov't Diabetes. 2021 Nov;70(11):2683-2693. doi: 10.2337/db20-1281. Epub 2021 Aug 10.I | 08/12/2021 | |
| The COVIDome Explorer researcher portal | Sullivan KD, et al. | 2021 | Cell Rep | 36 | 7 | 109527 | https://www.doi.org/10.1016/j.celrep.2021.109527 | 34,348,131 | Access to Information Adult COVID-19/*genetics/immunology/*metabolism Case-Control Studies Data Mining *Databases, Genetic Datasets as Topic Female Gene Expression Profiling Humans Male *Metabolome Metabolomics Middle Aged *Proteome Proteomics *Transcriptome Young Adult Covid-19 Crp Sars data portal immune system infection inflammation metabolism multi-omics serpins for Elly Lilly and has provided consulting services to Gilead Sciences Inc. J.M.E. also serves on the Cell Reports Advisory Board. The remaining authors declare no competing interests. | COVID-19 pathology involves dysregulation of diverse molecular, cellular, and physiological processes. To expedite integrated and collaborative COVID-19 research, we completed multi-omics analysis of hospitalized COVID-19 patients, including matched analysis of the whole-blood transcriptome, plasma proteomics with two complementary platforms, cytokine profiling, plasma and red blood cell metabolomics, deep immune cell phenotyping by mass cytometry, and clinical data annotation. We refer to this multidimensional dataset as the COVIDome. We then created the COVIDome Explorer, an online researcher portal where the data can be analyzed and visualized in real time. We illustrate herein the use of the COVIDome dataset through a multi-omics analysis of biosignatures associated with C-reactive protein (CRP), an established marker of poor prognosis in COVID-19, revealing associations between CRP levels and damage-associated molecular patterns, depletion of protective serpins, and mitochondrial metabolism dysregulation. We expect that the COVIDome Explorer will rapidly accelerate data sharing, hypothesis testing, and discoveries worldwide. | Sullivan, Kelly Daniel Galbraith, Matthew Dominic Kinning, Kohl Thomas Bartsch, Kyle William Levinsky, Nik Caldwell Araya, Paula Smith, Keith Patrick Granrath, Ross Erich Shaw, Jessica Rose Baxter, Ryan Michael Jordan, Kimberly Rae Russell, Seth Aaron Dzieciatkowska, Monika Ewa Reisz, Julie Ann Gamboni, Fabia Cendali, Francesca Isabelle Ghosh, Tusharkanti Monte, Andrew Albert Bennett, Tellen Demeke Miller, Michael George Hsieh, Elena Wen-Yuan D'Alessandro, Angelo Hansen, Kirk Charles Espinosa, Joaquin Maximiliano eng R01 HL146442/HL/NHLBI NIH HHS/ RM1 GM131968/GM/NIGMS NIH HHS/ P30 DK048520/DK/NIDDK NIH HHS/ R01 AI150305/AI/NIAID NIH HHS/ UL1 TR002535/TR/NCATS NIH HHS/ P30 CA046934/CA/NCI NIH HHS/ K23 AR070897/AR/NIAMS NIH HHS/ R35 GM124939/GM/NIGMS NIH HHS/ R01 HL148151/HL/NHLBI NIH HHS/ R21 HL150032/HL/NHLBI NIH HHS/ R01 HL149714/HL/NHLBI NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Cell Rep. 2021 Aug 17;36(7):109527. doi: 10.1016/j.celrep.2021.109527. Epub 2021 Jul 28.I | 08/05/2021 | |
| Comparison of proteomic methods in evaluating biomarker-AKI associations in cardiac surgery patients | Liu RX, et al. | 2021 | Transl Res | 238 | 49-62 | https://www.doi.org/10.1016/j.trsl.2021.07.005 | 34,343,625 | Acute Kidney Injury/*blood Aged Aged, 80 and over Aptamers, Peptide Biomarkers/*blood Blood Chemical Analysis/methods Blood Proteins/*analysis Cardiac Surgical Procedures/*adverse effects Female Humans Immunoassay/methods Male Middle Aged Preoperative Period Proteomics/*methods | Although immunoassays are the most widely used protein measurement method, aptamer-based methods such as the SomaScan platform can quantify up to 7000 proteins per biosample, creating new opportunities for unbiased discovery. However, there is limited research comparing the consistency of biomarker-disease associations between immunoassay and aptamer-based platforms. In a substudy of the TRIBE-AKI cohort, preoperative and postoperative plasma samples from 294 patients with previous immunoassay measurements were analyzed using the SomaScan platform. Inter-platform Spearman correlations (r(s)) and biomarker-AKI associations were compared across 30 preoperative and 34 postoperative immunoassay-aptamer pairs. Possible factors contributing to inter-platform differences were examined including target protein characteristics, immunoassay, and SomaScan coefficients of variation, other assay characteristics, and sample storage time. The median r(s) was 0.54 (interquartile range [IQR] 0.34-0.83) in postoperative samples and 0.41 (IQR 0.21-0.69) in preoperative samples. We observed a trend of greater r(s) in biomarkers with greater concentrations; the Spearman correlation between the concentration of protein and the inter-platform correlation was 0.64 in preoperative pairs and 0.53 in postoperative pairs. Of proteins measured by immunoassays, we observed significant biomarker-AKI associations for 13 proteins preop and 24 postop; of all corresponding aptamers, 8 proteins preop and 12 postop. All proteins significantly associated with AKI as measured by SomaScan were also significantly associated with AKI as measured by immunoassay. All biomarker-AKI odds ratios were significantly different (P < 0.05) between platforms in 14% of aptamer-immunoassay pairs, none of which had high (r(s) > 0.50) inter-platform correlations. Although similar biomarker-disease associations were observed overall, biomarkers with high physiological concentrations tended to have the highest-confidence inter-platform operability in correlations and biomarker-disease associations. Aptamer assays provide excellent precision and an unprecedented coverage and promise for disease associations but interpretation of results should keep in mind a broad range of correlations with immunoassays. | Liu, Richard X Thiessen-Philbrook, Heather R Vasan, Ramachandran S Coresh, Josef Ganz, Peter Bonventre, Joseph V Kimmel, Paul L Parikh, Chirag R eng R01 HL085757/HL/NHLBI NIH HHS/ HHSN268201500001C/HL/NHLBI NIH HHS/ UL1 TR001863/TR/NCATS NIH HHS/ P30 DK079310/DK/NIDDK NIH HHS/ U01 DK106962/DK/NIDDK NIH HHS/ RF1 AG063507/AG/NIA NIH HHS/ R01 DK072381/DK/NIDDK NIH HHS/ UH3 DK114866/DK/NIDDK NIH HHS/ HHSN268201500001I/HL/NHLBI NIH HHS/ R01 HL132320/HL/NHLBI NIH HHS/ U01 DK082185/DK/NIDDK NIH HHS/ N01HC25195/HL/NHLBI NIH HHS/ 75N92019D00031/HL/NHLBI NIH HHS/ Comparative Study Multicenter Study Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Transl Res. 2021 Dec;238:49-62. doi: 10.1016/j.trsl.2021.07.005. Epub 2021 Jul 31.I | 08/04/2021 | ||
| New candidate blood biomarkers potentially associated with white matter hyperintensities progression | Jimenez-Balado J, et al. | 2021 | Sci Rep | 11 | 1 | 14324 | https://www.doi.org/10.1038/s41598-021-93498-w | 34,253,757 | Aged Biomarkers/*metabolism Blood-Brain Barrier/metabolism Humans Hypertension/*metabolism Magnetic Resonance Imaging Matrix Metalloproteinase 9/metabolism Middle Aged Neutral Ceramidase/genetics/metabolism Proto-Oncogene Proteins c-met/metabolism White Matter/*metabolism | We aimed to discover blood biomarkers associated with longitudinal changes in white matter hyperintensities (WMH). This study was divided into a discovery phase and a replication phase. Subjects in both studies were patients with hypertension, aged 50-70, who underwent two magnetic resonance imaging (MRI) sessions and blood extractions over a 4-year follow-up period. In the discovery phase, we screened 1305 proteins in 12 subjects with WMH progression and in 12 matched control subjects. We found that 41 proteins were differentially expressed: 13 were upregulated and 28 were downregulated. We subsequently selected three biomarkers for replication in baseline and follow-up samples in 80 subjects with WMH progression and in 80 control subjects. The selected protein candidates for the replication were MMP9 (matrix metalloproteinase-9), which was higher in cases, MET (hepatocyte growth factor receptor) and ASAH2 (neutral ceramidase), which were both lower in cases of WMH progression. Baseline biomarker concentrations did not predict WMH progression. In contrast, patients with WMH progression presented a steeper decline in MET over time. Furthermore, cases showed higher MMP9 and lower ASAH2 levels than controls at the follow-up. These results indicate that MMP9, MET, and ASAH2 are potentially associated with the progression of WMH, and could therefore be interesting candidates to validate in future studies. | Jimenez-Balado, Joan Pizarro, Jesus Riba-Llena, Iolanda Penalba, Anna Faura, Julia Pala, Elena Montaner, Joan Hernandez-Guillamon, Mar Delgado, Pilar eng Research Support, Non-U.S. Gov't England Sci Rep. 2021 Jul 12;11(1):14324. doi: 10.1038/s41598-021-93498-w.I | 07/14/2021 | |
| Soluble Neuropilin-1 Response to Hypoglycemia in Type 2 Diabetes: Increased Risk or Protection in SARS-CoV-2 Infection? | Moin ASM, et al. | 2021 | Front Endocrinol (Lausanne) | 12 | 665134 | https://www.doi.org/10.3389/fendo.2021.665134 | 34,248,841 | ADAM Proteins/*metabolism Aged Angiotensin-Converting Enzyme 2/*metabolism Angiotensins/metabolism Covid-19 Diabetes Mellitus, Type 2/*metabolism Female Glucose Clamp Technique Humans Hypoglycemia/*metabolism Male Membrane Proteins/*metabolism Middle Aged Neuropilin-1/*metabolism Protective Factors Renin/metabolism Risk Factors SARS-CoV-2 Semaphorin-3A/*metabolism Vascular Endothelial Growth Factor A/*metabolism ACE inhibitors Adam9 Neuropilin-1 type 2 diabetes commercial or financial relationships that could be construed as a potential conflict of interest. | INTRODUCTION: Neuropilin-1(NRP1) is a cofactor that enhances SARS-CoV-2 coronavirus cell infectivity when co-expressed with angiotensin-converting enzyme 2(ACE2). The Renin-Angiotensin System (RAS) is activated in type 2 diabetes (T2D); therefore, the aim of this study was to determine if hypoglycaemia-induced stress in T2D would potentiate serum NRP1(sNRP1) levels, reflecting an increased risk for SARS-CoV-2 infection. METHODS: A case-control study of aged-matched T2D (n = 23) and control (n = 23) subjects who underwent a hyperinsulinemic clamp over 1-hour to hypoglycemia(<40mg/dl) with subsequent timecourse of 4-hours and 24-hours. Slow Off-rate Modified Aptamer (SOMA)-scan plasma protein measurement determined RAS-related proteins: renin (REN), angiotensinogen (AGT), ACE2, soluble NRP1(sNRP1), NRP1 ligands (Vascular endothelial growth factor, VEGF and Class 3 Semaphorins, SEM3A) and NRP1 proteolytic enzyme (A Disintegrin and Metalloproteinase 9, ADAM9). RESULTS: Baseline RAS overactivity was present with REN elevated and AGT decreased in T2D (p<0.05); ACE2 was unchanged. Baseline sNRP1, VEGF and ADAM9 did not differ between T2D and controls and remained unchanged in response to hypoglycaemia. However, 4-hours post-hypoglycemia, sNRP1, VEGF and ADAM9 were elevated in T2D(p<0.05). SEMA3A was not different at baseline; at hypoglycemia, SEMA3A decreased in controls only. Post-hypoglycemia, SEMA3A levels were higher in T2D versus controls. sNRP1 did not correlate with ACE2, REN or AGT. T2D subjects stratified according to ACE inhibitor (ACEi) therapies showed no difference in sNRP1 levels at either glucose normalization or hypoglycaemia. CONCLUSION: Hypoglycemia potentiated both plasma sNRP1 level elevation and its ligands VEGF and SEMA3A, likely through an ADAM9-mediated mechanism that was not associated with RAS overactivity or ACEi therapy; however, whether this is protective or promotes increased risk for SARS-CoV-2 infection in T2D is unclear. CLINICAL TRIAL REGISTRATION: https://clinicaltrials.gov, identifier NCT03102801. | Moin, Abu Saleh Md Al-Qaissi, Ahmed Sathyapalan, Thozhukat Atkin, Stephen L Butler, Alexandra E eng Switzerland Front Endocrinol (Lausanne). 2021 Jun 23;12:665134. doi: 10.3389/fendo.2021.665134. eCollection 2021.I | 07/13/2021 | ||
| Type 2 Diabetes Coagulopathy Proteins May Conflict With Biomarkers Reflective of COVID-19 Severity | Moin ASM, et al. | 2021 | Front Endocrinol (Lausanne) | 12 | 658304 | https://www.doi.org/10.3389/fendo.2021.658304 | 34,248,840 | Aged Biomarkers/metabolism Blood Coagulation Blood Coagulation Factors/*metabolism COVID-19/*metabolism Case-Control Studies Complement Activation Diabetes Mellitus, Type 2/*metabolism Factor IX/metabolism Female Glucose Clamp Technique Heparin Cofactor II/metabolism Humans Hypoglycemia/*metabolism Kininogens/metabolism Male Middle Aged Peptides/metabolism Platelet Activation Platelet Factor 4/metabolism Prospective Studies Protein C/metabolism Proteomics SARS-CoV-2 Severity of Illness Index Thrombospondin 1/metabolism beta-Thromboglobulin/metabolism Covid-19 biomarkers hypoglycemia type 2 diabetes commercial or financial relationships that could be construed as a potential conflict of interest. | OBJECTIVE: Detailed proteomic analysis in a cohort of patients with differing severity of COVID-19 disease identified biomarkers within the complement and coagulation cascades as biomarkers for disease severity has been reported; however, it is unclear if these proteins differ sufficiently from other conditions to be considered as biomarkers. METHODS: A prospective, parallel study in T2D (n = 23) and controls (n = 23). A hyperinsulinemic clamp was performed and normoglycemia induced in T2D [4.5 +/- 0.07 mmol/L (81 +/- 1.2 mg/dl)] for 1-h, following which blood glucose was decreased to | Moin, Abu Saleh Md Al-Qaissi, Ahmed Sathyapalan, Thozhukat Atkin, Stephen L Butler, Alexandra E eng Switzerland Front Endocrinol (Lausanne). 2021 Jun 25;12:658304. doi: 10.3389/fendo.2021.658304. eCollection 2021.I | 07/13/2021 | ||
| Genomic atlas of the proteome from brain, CSF and plasma prioritizes proteins implicated in neurological disorders | Yang C, et al. | 2021 | Nat Neurosci | 24 | 9 | 1302-1312 | https://www.doi.org/10.1038/s41593-021-00886-6 | 34,239,129 | Aged *Alzheimer Disease/genetics/metabolism Brain/*metabolism Cerebrospinal Fluid/*metabolism Female Gene Expression Regulation High-Throughput Screening Assays/methods Humans Male Middle Aged Plasma/*metabolism Proteome Proteomics/methods *Quantitative Trait Loci | Understanding the tissue-specific genetic controls of protein levels is essential to uncover mechanisms of post-transcriptional gene regulation. In this study, we generated a genomic atlas of protein levels in three tissues relevant to neurological disorders (brain, cerebrospinal fluid and plasma) by profiling thousands of proteins from participants with and without Alzheimer's disease. We identified 274, 127 and 32 protein quantitative trait loci (pQTLs) for cerebrospinal fluid, plasma and brain, respectively. cis-pQTLs were more likely to be tissue shared, but trans-pQTLs tended to be tissue specific. Between 48.0% and 76.6% of pQTLs did not co-localize with expression, splicing, DNA methylation or histone acetylation QTLs. Using Mendelian randomization, we nominated proteins implicated in neurological diseases, including Alzheimer's disease, Parkinson's disease and stroke. This first multi-tissue study will be instrumental to map signals from genome-wide association studies onto functional genes, to discover pathways and to identify drug targets for neurological diseases. | Yang, Chengran Farias, Fabiana H G Ibanez, Laura Suhy, Adam Sadler, Brooke Fernandez, Maria Victoria Wang, Fengxian Bradley, Joseph L Eiffert, Brett Bahena, Jorge A Budde, John P Li, Zeran Dube, Umber Sung, Yun Ju Mihindukulasuriya, Kathie A Morris, John C Fagan, Anne M Perrin, Richard J Benitez, Bruno A Rhinn, Herve Harari, Oscar Cruchaga, Carlos eng P30 AG066444/AG/NIA NIH HHS/ R01 AG064877/AG/NIA NIH HHS/ R01 AG057777/AG/NIA NIH HHS/ RF1 AG053303/AG/NIA NIH HHS/ RF1 AG044546/AG/NIA NIH HHS/ R01 NS118146/NS/NINDS NIH HHS/ U01 AG058922/AG/NIA NIH HHS/ R01 AG044546/AG/NIA NIH HHS/ P01 AG003991/AG/NIA NIH HHS/ P50 AG005681/AG/NIA NIH HHS/ P01 AG026276/AG/NIA NIH HHS/ RF1 AG058501/AG/NIA NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Nat Neurosci. 2021 Sep;24(9):1302-1312. doi: 10.1038/s41593-021-00886-6. Epub 2021 Jul 8.I | 07/10/2021 | |
| Effects of adiposity on the human plasma proteome: observational and Mendelian randomisation estimates | Goudswaard LJ, et al. | 2021 | Int J Obes (Lond) | 45 | 10 | 2221-2229 | https://www.doi.org/10.1038/s41366-021-00896-1 | 34,226,637 | Adiposity/*physiology Adult Body Mass Index Cohort Studies Female Humans Male Mendelian Randomization Analysis Middle Aged Prospective Studies Proteome/*analysis/metabolism Surveys and Questionnaires | BACKGROUND: Variation in adiposity is associated with cardiometabolic disease outcomes, but mechanisms leading from this exposure to disease are unclear. This study aimed to estimate effects of body mass index (BMI) on an extensive set of circulating proteins. METHODS: We used SomaLogic proteomic data from up to 2737 healthy participants from the INTERVAL study. Associations between self-reported BMI and 3622 unique plasma proteins were explored using linear regression. These were complemented by Mendelian randomisation (MR) analyses using a genetic risk score (GRS) comprised of 654 BMI-associated polymorphisms from a recent genome-wide association study (GWAS) of adult BMI. A disease enrichment analysis was performed using DAVID Bioinformatics 6.8 for proteins which were altered by BMI. RESULTS: Observationally, BMI was associated with 1576 proteins (P < 1.4 x 10(-5)), with particularly strong evidence for a positive association with leptin and fatty acid-binding protein-4 (FABP4), and a negative association with sex hormone-binding globulin (SHBG). Observational estimates were likely confounded, but the GRS for BMI did not associate with measured confounders. MR analyses provided evidence for a causal relationship between BMI and eight proteins including leptin (0.63 standard deviation (SD) per SD BMI, 95% CI 0.48-0.79, P = 1.6 x 10(-15)), FABP4 (0.64 SD per SD BMI, 95% CI 0.46-0.83, P = 6.7 x 10(-12)) and SHBG (-0.45 SD per SD BMI, 95% CI -0.65 to -0.25, P = 1.4 x 10(-5)). There was agreement in the magnitude of observational and MR estimates (R(2) = 0.33) and evidence that proteins most strongly altered by BMI were enriched for genes involved in cardiovascular disease. CONCLUSIONS: This study provides evidence for a broad impact of adiposity on the human proteome. Proteins strongly altered by BMI include those involved in regulating appetite, sex hormones and inflammation; such proteins are also enriched for cardiovascular disease-related genes. Altogether, results help focus attention onto new proteomic signatures of obesity-related disease. | Goudswaard, Lucy J Bell, Joshua A Hughes, David A Corbin, Laura J Walter, Klaudia Davey Smith, George Soranzo, Nicole Danesh, John Di Angelantonio, Emanuele Ouwehand, Willem H Watkins, Nicholas A Roberts, David J Butterworth, Adam S Hers, Ingeborg Timpson, Nicholas J eng 204813/WT_/Wellcome Trust/United Kingdom MR/L003120/1/MRC_/Medical Research Council/United Kingdom PG/16/3/31833/BHF_/British Heart Foundation/United Kingdom 102215/WT_/Wellcome Trust/United Kingdom A19169/CRUK_/Cancer Research UK/United Kingdom WT_/Wellcome Trust/United Kingdom MC_UU_12013/3/MRC_/Medical Research Council/United Kingdom MC_UU_00011/1/MRC_/Medical Research Council/United Kingdom 202802/WT_/Wellcome Trust/United Kingdom Observational Study Research Support, Non-U.S. Gov't England Int J Obes (Lond). 2021 Oct;45(10):2221-2229. doi: 10.1038/s41366-021-00896-1. Epub 2021 Jul 5.I | 07/07/2021 | |
| Crowdsourcing assessment of maternal blood multi-omics for predicting gestational age and preterm birth | Tarca AL, et al. | 2021 | Cell Rep Med | 2 | 6 | 100323 | https://www.doi.org/10.1016/j.xcrm.2021.100323 | 34,195,686 | Adult Asymptomatic Diseases Biomarkers/blood Blood Proteins/classification/*genetics/metabolism Cell-Free Nucleic Acids/blood/classification/*genetics Crowdsourcing/methods Female *Gestational Age Humans Infant, Newborn Longitudinal Studies Pre-Eclampsia/blood/diagnosis/*genetics Pregnancy Premature Birth/blood/diagnosis/*genetics Proteomics/methods ROC Curve *Transcriptome aptamers collaborative competition human transcriptome arrays machine learning plasma proteomics predictive modeling preterm labor and delivery spontaneous preterm birth whole blood transcriptomics patent, which involves the prediction of preterm birth using proteomics data. All of the other authors declare no competing interests. | Identification of pregnancies at risk of preterm birth (PTB), the leading cause of newborn deaths, remains challenging given the syndromic nature of the disease. We report a longitudinal multi-omics study coupled with a DREAM challenge to develop predictive models of PTB. The findings indicate that whole-blood gene expression predicts ultrasound-based gestational ages in normal and complicated pregnancies (r = 0.83) and, using data collected before 37 weeks of gestation, also predicts the delivery date in both normal pregnancies (r = 0.86) and those with spontaneous preterm birth (r = 0.75). Based on samples collected before 33 weeks in asymptomatic women, our analysis suggests that expression changes preceding preterm prelabor rupture of the membranes are consistent across time points and cohorts and involve leukocyte-mediated immunity. Models built from plasma proteomic data predict spontaneous preterm delivery with intact membranes with higher accuracy and earlier in pregnancy than transcriptomic models (AUROC = 0.76 versus AUROC = 0.6 at 27-33 weeks of gestation). | Tarca, Adi L Pataki, Balint Armin Romero, Roberto Sirota, Marina Guan, Yuanfang Kutum, Rintu Gomez-Lopez, Nardhy Done, Bogdan Bhatti, Gaurav Yu, Thomas Andreoletti, Gaia Chaiworapongsa, Tinnakorn Hassan, Sonia S Hsu, Chaur-Dong Aghaeepour, Nima Stolovitzky, Gustavo Csabai, Istvan Costello, James C eng KL2 TR003143/TR/NCATS NIH HHS/ HHSN275201300006C/HD/NICHD NIH HHS/ R35 GM133346/GM/NIGMS NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. Cell Rep Med. 2021 Jun 15;2(6):100323. doi: 10.1016/j.xcrm.2021.100323. eCollection 2021 Jun 15.I | 07/02/2021 | |
| Evaluating microbiome-directed fibre snacks in gnotobiotic mice and humans | Delannoy-Bruno O, et al. | 2021 | Nature | 595 | 7,865 | 91-95 | https://www.doi.org/10.1038/s41586-021-03671-4 | 34,163,075 | Adolescent Adult Animals Bacteroides/drug effects/isolation & purification Blood Proteins/analysis Dietary Fiber/*pharmacology Feces/*microbiology Female Gastrointestinal Microbiome/*drug effects *Germ-Free Life Humans Male Mice Mice, Inbred C57BL Middle Aged Obesity/microbiology Overweight/microbiology Proteome/analysis/drug effects *Snacks Young Adult | Changing food preferences brought about by westernization that have deleterious health effects(1,2)-combined with myriad forces that are contributing to increased food insecurity-are catalysing efforts to identify more nutritious and affordable foods(3). Consumption of dietary fibre can help to prevent cardiovascular disease, type 2 diabetes and obesity(4-6). A substantial number of reports have explored the effects of dietary fibre on the gut microbial community(7-9). However, the microbiome is complex, dynamic and exhibits considerable intra- and interpersonal variation in its composition and functions. The large number of potential interactions between the components of the microbiome makes it challenging to define the mechanisms by which food ingredients affect community properties. Here we address the question of how foods containing different fibre preparations can be designed to alter functions associated with specific components of the microbiome. Because a marked increase in snack consumption is associated with westernization, we formulated snack prototypes using plant fibres from different sustainable sources that targeted distinct features of the gut microbiomes of individuals with obesity when transplanted into gnotobiotic mice. We used these snacks to supplement controlled diets that were consumed by adult individuals with obesity or who were overweight. Fibre-specific changes in their microbiomes were linked to changes in their plasma proteomes indicative of an altered physiological state. | Delannoy-Bruno, Omar Desai, Chandani Raman, Arjun S Chen, Robert Y Hibberd, Matthew C Cheng, Jiye Han, Nathan Castillo, Juan J Couture, Garret Lebrilla, Carlito B Barve, Ruteja A Lombard, Vincent Henrissat, Bernard Leyn, Semen A Rodionov, Dmitry A Osterman, Andrei L Hayashi, David K Meynier, Alexandra Vinoy, Sophie Kirbach, Kyleigh Wilmot, Tara Heath, Andrew C Klein, Samuel Barratt, Michael J Gordon, Jeffrey I eng DK70977/NH/NIH HHS/ P01 DK078669/DK/NIDDK NIH HHS/ R01 DK070977/DK/NIDDK NIH HHS/ P30 DK056341/DK/NIDDK NIH HHS/ DK078669/NH/NIH HHS/ F30 DK124967/DK/NIDDK NIH HHS/ R01 DK124193/DK/NIDDK NIH HHS/ UL1 TR002345/TR/NCATS NIH HHS/ Clinical Trial Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't England Nature. 2021 Jul;595(7865):91-95. doi: 10.1038/s41586-021-03671-4. Epub 2021 Jun 23.I | 06/25/2021 | |
| Predicting the probability of death using proteomics | Eiriksdottir T, et al. | 2021 | Commun Biol | 4 | 1 | 758 | https://www.doi.org/10.1038/s42003-021-02289-6 | 34,145,379 | Adolescent Adult Aged Aged, 80 and over Biomarkers/*blood Blood Proteins/*analysis Female Frailty/*mortality Humans Iceland Kaplan-Meier Estimate Male Middle Aged Prognosis Proteomics/*methods Risk Risk Assessment Risk Factors Young Adult | Predicting all-cause mortality risk is challenging and requires extensive medical data. Recently, large-scale proteomics datasets have proven useful for predicting health-related outcomes. Here, we use measurements of levels of 4,684 plasma proteins in 22,913 Icelanders to develop all-cause mortality predictors both for short- and long-term risk. The participants were 18-101 years old with a mean follow up of 13.7 (sd. 4.7) years. During the study period, 7,061 participants died. Our proposed predictor outperformed, in survival prediction, a predictor based on conventional mortality risk factors. We could identify the 5% at highest risk in a group of 60-80 years old, where 88% died within ten years and 5% at the lowest risk where only 1% died. Furthermore, the predicted risk of death correlates with measures of frailty in an independent dataset. Our results show that the plasma proteome can be used to assess general health and estimate the risk of death. | Eiriksdottir, Thjodbjorg Ardal, Steinthor Jonsson, Benedikt A Lund, Sigrun H Ivarsdottir, Erna V Norland, Kristjan Ferkingstad, Egil Stefansson, Hreinn Jonsdottir, Ingileif Holm, Hilma Rafnar, Thorunn Saemundsdottir, Jona Norddahl, Gudmundur L Thorgeirsson, Gudmundur Gudbjartsson, Daniel F Sulem, Patrick Thorsteinsdottir, Unnur Stefansson, Kari Ulfarsson, Magnus O eng England Commun Biol. 2021 Jun 18;4(1):758. doi: 10.1038/s42003-021-02289-6.I | 06/20/2021 | |
| Plasma Proteomics of Renal Function: A Trans-ethnic Meta-analysis and Mendelian Randomization Study | Matias-Garcia P, et al. | 2021 | J Am Soc Nephrol | 32 | 7 | 1747-63 | https://www.doi.org/10.1681/ASN.2020071070 | 34,135,082 | BACKGROUND: Studies on the relationship between renal function and the human plasma proteome have identified several potential biomarkers. However, investigations have been conducted largely in European populations, and causality of the associations between plasma proteins and kidney function has never been addressed. METHODS: A cross-sectional study of 993 plasma proteins among 2,882 participants in four studies of European and admixed ancestries (KORA, INTERVAL, HUNT, QMDiab) identified trans-ethnic associations between eGFR/CKD and proteomic biomarkers. For the replicated associations, two-sample bidirectional Mendelian randomization (MR) was used to investigate potential causal relationships. Publicly available datasets and transcriptomic data from independent studies were used to examine the association between gene expression in kidney tissue and eGFR . RESULTS: Fifty-seven plasma proteins were associated with eGFR, including one novel protein. Twenty-three of these were additionally associated with CKD. The strongest inferred causal effect was the positive effect of eGFR on testican-2, in line with the known biological role of this protein and the expression of its protein-coding gene (SPOCK2) in renal tissue. We also observed suggestive evidence of an effect of melanoma inhibitory activity (MIA), carbonic anhydrase III, and cystatin-M on eGFR. CONCLUSIONS: In a discovery-replication setting, we identified 57 proteins trans-ethnically associated with eGFR. The revealed causal relationships are an important stepping-stone in establishing testican-2 as a clinically relevant physiological marker of kidney disease progression, and point to additional proteins warranting further investigation. | Matias-Garcia, Pamela Wilson, Rory Guo, Qi Zaghlool, Shaza Eales, James Xu, Xiaoguang Charchar, Fadi Dormer, John Maalmi, Haifa Schlosser, Pascal Elhadad, Mohamed Nano, Jana Sharma, Sapna Peters, Annette Fornoni, Alessia Mook-Kanamori, Dennis Winkelmann, Juliane Danesh, John Di Angelantonio, Emanuele Ouwehand, Willem Watkins, Nicholas Roberts, David Petrera, Agnese Graumann, Johannes Koenig, Wolfgang Hveem, Kristian Jonasson, Christian Kottgen, Anna Butterworth, Adam Prunotto, Marco Hauck, Stefanie Herder, Christian Suhre, Karsten Gieger, Christian Tomaszewski, Maciej Teumer, Alexander Waldenberger, Melanie eng PG/17/35/33001/BHF_/British Heart Foundation/United Kingdom RG/18/13/33946/BHF_/British Heart Foundation/United Kingdom CH/12/2/29428/BHF_/British Heart Foundation/United Kingdom RG/13/13/30194/BHF_/British Heart Foundation/United Kingdom PG/19/16/34270/BHF_/British Heart Foundation/United Kingdom J Am Soc Nephrol. 2021 Jun 16;32(7):1747-63. doi: 10.1681/ASN.2020071070.I | 06/18/2021 | ||
| Comprehensive aptamer-based screen of 1317 proteins uncovers improved stool protein markers of colorectal cancer | Li H, et al. | 2021 | J Gastroenterol | 56 | 7 | 659-672 | https://www.doi.org/10.1007/s00535-021-01795-y | 34,117,903 | *Aptamers, Nucleotide Area Under Curve Biomarkers/*analysis Colorectal Neoplasms/*diagnosis Cross-Sectional Studies Enzyme-Linked Immunosorbent Assay/methods *Feces Humans ROC Curve Statistics, Nonparametric Biomarker Colorectal cancer Stool | BACKGROUND: To screen and validate novel stool protein biomarkers of colorectal cancer (CRC). METHODS: A novel aptamer-based screen of 1317 proteins was used to uncover elevated proteins in the stool of patients with CRC, as compared to healthy controls (HCs) in a discovery cohort. Selected biomarker candidates from the discovery cohort were ELISA validated in three independent cross-sectional cohorts comprises 76 CRC patients, 15 adenoma patients, and 63 healthy controls, from two different ethnicities. The expression of the potential stool biomarkers within CRC tissue was evaluated using single-cell RNA-seq datasets. RESULTS: A total of 92 proteins were significantly elevated in CRC samples as compared to HCs in the discovery cohort. Among Caucasians, the 5 most discriminatory proteins among the 16 selected proteins, ordered by their ability to distinguish CRC from adenoma and healthy controls, were MMP9, haptoglobin, myeloperoxidase, fibrinogen, and adiponectin. Except myeloperoxidase, the others were significantly associated with depth of tumor invasion. The 8 stool proteins with the highest AUC values were also discriminatory in a second cohort of Indian CRC patients. Several of the stool biomarkers elevated in CRC were also expressed within CRC tissue, based on the single-cell RNA-seq analysis. CONCLUSIONS: Stool MMP9, fibrinogen, myeloperoxidase, and haptoglobin emerged as promising CRC stool biomarkers, outperforming stool Hemoglobin. Longitudinal studies are warranted to assess the clinical utility of these novel biomarkers in early diagnosis of CRC. | Li, Hao Vanarsa, Kamala Zhang, Ting Soomro, Sanam Cicalese, Pietro Antonio Duran, Valeria Dasari, Shobha Lee, Kyung Hyun Pedroza, Claudia Kisiel, John B Qin, Huanlong Bresalier, Robert S Chia, Nicholas Mohan, Chandra eng Japan J Gastroenterol. 2021 Jul;56(7):659-672. doi: 10.1007/s00535-021-01795-y. Epub 2021 Jun 12.I | 06/13/2021 | |
| Serum Proteomics and Plasma Fibulin-3 in Differentiation of Mesothelioma From Asbestos-Exposed Controls and Patients With Other Pleural Diseases | Tsim S, et al. | 2021 | J Thorac Oncol | 16 | 10 | 1705-1717 | https://www.doi.org/10.1016/j.jtho.2021.05.018 | 34,116,230 | *Asbestos Biomarkers, Tumor Calcium-Binding Proteins Extracellular Matrix Proteins GPI-Linked Proteins Humans *Lung Neoplasms/diagnosis *Mesothelioma/diagnosis/etiology *Pleural Neoplasms/diagnosis/etiology Proteomics Retrospective Studies Biomarker Fibulin-3 Mesothelin Mesothelioma SOMAscan | INTRODUCTION: Malignant pleural mesothelioma (MPM) is difficult to diagnose. An accurate blood biomarker could prompt specialist referral or be deployed in future screening. In earlier retrospective studies, SOMAscan proteomics (Somalogic, Boulder, CO) and fibulin-3 seemed highly accurate, but SOMAscan has not been validated prospectively and subsequent fibulin-3 data have been contradictory. METHODS: A multicenter prospective observational study was performed in 22 centers, generating a large intention-to-diagnose cohort. Blood sampling, processing, and diagnostic assessment were standardized, including a 1-year follow-up. Plasma fibulin-3 was measured using two enzyme-linked immunosorbent assays (CloudClone [used in previous studies] and BosterBio, Pleasanton, CA). Serum proteomics was measured using the SOMAscan assay. Diagnostic performance (sensitivity at 95% specificity, area under the curve [AUC]) was benchmarked against serum mesothelin (Mesomark, Fujirebio Diagnostics, Malvern, PA). Biomarkers were correlated against primary tumor volume, inflammatory markers, and asbestos exposure. RESULTS: A total of 638 patients with suspected pleural malignancy (SPM) and 110 asbestos-exposed controls (AECs) were recruited. SOMAscan reliably differentiated MPM from AECs (75% sensitivity, 88.2% specificity, validation cohort AUC 0.855) but was not useful in patients with differentiating non-MPM SPM. Fibulin-3 (by BosterBio after failed CloudClone validation) revealed 7.4% and 11.9% sensitivity at 95% specificity in MPM versus non-MPM SPM and AECs, respectively (associated AUCs 0.611 [0.557-0.664], p = 0.0015) and 0.516 [0.443-0.589], p = 0.671), both inferior to mesothelin. SOMAscan proteins correlated with inflammatory markers but not with asbestos exposure. Neither biomarker correlated with tumor volume. CONCLUSIONS: SOMAscan may prove useful as a future screening test for MPM in asbestos-exposed persons. Neither fibulin-3 nor SOMAscan should be used for diagnosis or pathway stratification. | Tsim, Selina Alexander, Laura Kelly, Caroline Shaw, Ann Hinsley, Samantha Clark, Stephen Evison, Matthew Holme, Jayne Cameron, Euan J Sharma, Davand Wright, Angela Grundy, Seamus Grieve, Douglas Ionescu, Alina Breen, David P Paramasivam, Elankumaran Psallidas, Ioannis Mukherjee, Dipak Chetty, Mahendran Cox, Giles Hart-Thomas, Alan Naseer, Rehan Edwards, John Daneshvar, Cyrus Panchal, Rakesh Munavvar, Mohammed Ostroff, Rachel Alexander, Leigh Hall, Holly Neilson, Matthew Miller, Crispin McCormick, Carol Thomson, Fiona Chalmers, Anthony J Maskell, Nick A Blyth, Kevin G eng A17196/CRUK_/Cancer Research UK/United Kingdom A31287/CRUK_/Cancer Research UK/United Kingdom A29801/CRUK_/Cancer Research UK/United Kingdom Multicenter Study Observational Study Research Support, Non-U.S. Gov't J Thorac Oncol. 2021 Oct;16(10):1705-1717. doi: 10.1016/j.jtho.2021.05.018. Epub 2021 Jun 9.I | 06/12/2021 | |
| Effect of TNFalpha stimulation on expression of kidney risk inflammatory proteins in human umbilical vein endothelial cells cultured in hyperglycemia | Md Dom ZI, et al. | 2021 | Sci Rep | 11 | 1 | 11133 | https://www.doi.org/10.1038/s41598-021-90496-w | 34,045,516 | Down-Regulation/drug effects Fibroblasts/drug effects/metabolism Human Umbilical Vein Endothelial Cells/*drug effects/metabolism Humans Hyperglycemia/*metabolism Inflammation/*metabolism Receptors, Tumor Necrosis Factor/*metabolism Tumor Necrosis Factor-alpha/*pharmacology Up-Regulation/drug effects | We recently identified a kidney risk inflammatory signature (KRIS), comprising 6 TNF receptors (including TNFR1 and TNFR2) and 11 inflammatory proteins. Elevated levels of these proteins in circulation were strongly associated with risk of the development of end-stage kidney disease (ESKD) during 10-year follow-up. It has been hypothesized that elevated levels of these proteins in circulation might reflect (be markers of) systemic exposure to TNFalpha. In this in vitro study, we examined intracellular and extracellular levels of these proteins in human umbilical vein endothelial cells (HUVECs) exposed to TNFalpha in the presence of hyperglycemia. KRIS proteins as well as 1300 other proteins were measured using the SOMAscan proteomics platform. Four KRIS proteins (including TNFR1) were down-regulated and only 1 protein (IL18R1) was up-regulated in the extracellular fraction of TNFalpha-stimulated HUVECs. In the intracellular fraction, one KRIS protein was down-regulated (CCL14) and 1 protein was up-regulated (IL18R1). The levels of other KRIS proteins were not affected by exposure to TNFalpha. HUVECs exposed to a hyperglycemic and inflammatory environment also showed significant up-regulation of a distinct set of 53 proteins (mainly in extracellular fraction). In our previous study, circulating levels of these proteins were not associated with progression to ESKD in diabetes. | Md Dom, Zaipul I Pipino, Caterina Krolewski, Bozena O'Neil, Kristina Satake, Eiichiro Krolewski, Andrzej S eng P30 DK036836/DK/NIDDK NIH HHS/ R01 DK041526/DK/NIDDK NIH HHS/ DK041526-27/NH/NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't England Sci Rep. 2021 May 27;11(1):11133. doi: 10.1038/s41598-021-90496-w.I | 05/29/2021 | |
| Human plasma proteomic profiles indicative of cardiorespiratory fitness | Robbins JM, et al. | 2021 | Nat Metab | 3 | 6 | 786-797 | https://www.doi.org/10.1038/s42255-021-00400-z | 34,045,743 | Biomarkers *Blood Proteins *Cardiorespiratory Fitness Exercise Humans Life Style Metabolic Networks and Pathways Oxygen Consumption *Proteome *Proteomics/methods | Maximal oxygen uptake (VO(2)max) is a direct measure of human cardiorespiratory fitness and is associated with health. However, the molecular determinants of interindividual differences in baseline (intrinsic) VO(2)max, and of increases of VO(2)max in response to exercise training (DeltaVO(2)max), are largely unknown. Here, we measure ~5,000 plasma proteins using an affinity-based platform in over 650 sedentary adults before and after a 20-week endurance-exercise intervention and identify 147 proteins and 102 proteins whose plasma levels are associated with baseline VO(2)max and DeltaVO(2)max, respectively. Addition of a protein biomarker score derived from these proteins to a score based on clinical traits improves the prediction of an individual's DeltaVO(2)max. We validate findings in a separate exercise cohort, further link 21 proteins to incident all-cause mortality in a community-based cohort and reproduce the specificity of ~75% of our key findings using antibody-based assays. Taken together, our data shed light on biological pathways relevant to cardiorespiratory fitness and highlight the potential additive value of protein biomarkers in identifying exercise responsiveness in humans. | Robbins, Jeremy M Peterson, Bennet Schranner, Daniela Tahir, Usman A Rienmuller, Theresa Deng, Shuliang Keyes, Michelle J Katz, Daniel H Beltran, Pierre M Jean Barber, Jacob L Baumgartner, Christian Carr, Steven A Ghosh, Sujoy Shen, Changyu Jennings, Lori L Ross, Robert Sarzynski, Mark A Bouchard, Claude Gerszten, Robert E eng R01 NR019628/NR/NINR NIH HHS/ P30 DK040561/DK/NIDDK NIH HHS/ R01 HL047327/HL/NHLBI NIH HHS/ R01 HL047323/HL/NHLBI NIH HHS/ U24 DK112340/DK/NIDDK NIH HHS/ U54 GM104940/GM/NIGMS NIH HHS/ R01 HL132320/HL/NHLBI NIH HHS/ R01 HL133870/HL/NHLBI NIH HHS/ R01 HL146462/HL/NHLBI NIH HHS/ P30 GM118430/GM/NIGMS NIH HHS/ R01 HL045670/HL/NHLBI NIH HHS/ K23 HL150327/HL/NHLBI NIH HHS/ R01 HL047317/HL/NHLBI NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Germany Nat Metab. 2021 Jun;3(6):786-797. doi: 10.1038/s42255-021-00400-z. Epub 2021 May 27.I | 05/29/2021 | |
| Proteomic signatures of inflammatory skin diseases: a focus on atopic dermatitis | Mikhaylov D, et al. | 2021 | Expert Rev Proteomics | 18 | 5 | 345-361 | https://www.doi.org/10.1080/14789450.2021.1935247 | 34,033,497 | Biomarkers *Dermatitis, Atopic/genetics Humans Inflammation Proteomics Skin Atopic dermatitis Olink SOMAscan mass spectrometry microbiome personalized medicine proteins two-dimensional gel electrophoresis | Introduction: Atopic dermatitis (AD) is a chronic inflammatory skin condition characterized by cutaneous and systemic inflammation and barrier abnormalities. Over the past few decades, proteomic studies have been increasingly applied to AD research to compliment transcriptomic evaluations. Proteomic analyses helped identify new biomarkers of AD, allowing investigation of both the cutaneous AD profile and the systemic inflammation associated with the disease.Areas covered: This review discusses key studies that utilized various proteomic technologies to analyze AD skin and/or blood, which facilitated discovery of biomarkers related to pathogenesis, disease severity, systemic inflammation, and therapeutic response. Moreover, this review summarizes proteomic studies that helped define various AD endotypes/phenotypes. A literature search was conducted by querying Scopus, Google Scholar, PubMed/Medline, and Clinicaltrials.gov up to January 2021.Expert opinion: Use of proteomics in AD has allowed for identification of novel AD-related protein biomarkers. This approach continues to evolve and is becoming increasingly common for the study of AD, in conjunction with other -omics platforms, as proteomics shifts to quicker and more sensitive methods for detection of potential protein biomarkers. Although many biomarkers have been identified thus far, future larger studies are necessary to further correlate these markers with clinical parameters. | Mikhaylov, Daniela Del Duca, Ester Guttman-Yassky, Emma eng Review England Expert Rev Proteomics. 2021 May;18(5):345-361. doi: 10.1080/14789450.2021.1935247. Epub 2021 Jun 4.I | 05/26/2021 | |
| SOMAscan Proteomics Identifies Serum Biomarkers Associated With Liver Fibrosis in Patients With NASH | Luo Y, et al. | 2021 | Hepatol Commun | 5 | 5 | 760-773 | https://www.doi.org/10.1002/hep4.1670 | 34,027,267 | Nonalcoholic steatohepatitis (NASH) is a major cause of liver-related morbidity and mortality worldwide. Liver fibrosis stage, a key component of NASH, has been linked to the risk of mortality and liver-related clinical outcomes. Currently there are no validated noninvasive diagnostics that can differentiate between fibrosis stages in patients with NASH; many existing tests do not reflect underlying disease pathophysiology. Noninvasive biomarkers are needed to identify patients at high-risk of NASH with advanced fibrosis. This was a retrospective study of patients with histologically proven NASH with fibrosis stages 0-4. The SOMAscan proteomics platform was used to quantify 1,305 serum proteins in a discovery cohort (n = 113). In patients with advanced (stages 3-4) versus early fibrosis (stages 0-2), 97 proteins with diverse biological functions were differentially expressed. Next, fibrosis-stage classification models were explored using a machine learning-based approach to prioritize the biomarkers for further evaluation. A four-protein model differentiated patients with stage 0-1 versus stage 2-4 fibrosis (area under the receiver operating characteristic curve [AUROC] = 0.74), while a 12-protein classifier differentiated advanced versus early fibrosis (AUROC = 0.83). Subsequently, the model's performance was validated in two independent cohorts (n = 71 and n = 32) with similar results (AUROC = 0.74-0.78). Our advanced fibrosis model performed similarly to or better than Fibrosis-4 index, aspartate aminotransferase-to-platelet ratio index, and nonalcoholic fatty liver disease (NAFLD) fibrosis score-based models for all three cohorts. Conclusion: A SOMAscan proteomics-based exploratory classifier for advanced fibrosis, consisting of biomarkers that reflect the complexity of NASH pathophysiology, demonstrated similar performance in independent validation cohorts and performed similarly or better than Fibrosis-4 index, aspartate aminotransferase-to-platelet ratio index, and NAFLD fibrosis score. Further studies are warranted to evaluate the clinical utility of these biomarker panels in patients with NAFLD. | Luo, Yi Wadhawan, Samir Greenfield, Alex Decato, Benjamin E Oseini, Abdul M Collen, Rebecca Shevell, Diane E Thompson, John Jarai, Gabor Charles, Edgar D Sanyal, Arun J eng Hepatol Commun. 2021 Jan 20;5(5):760-773. doi: 10.1002/hep4.1670. eCollection 2021 May.I | 05/25/2021 | ||
| Metabolic syndrome and the plasma proteome: from association to causation | Elhadad MA, et al. | 2021 | Cardiovasc Diabetol | 20 | 1 | 111 | https://www.doi.org/10.1186/s12933-021-01299-2 | 34,016,094 | Adult Aged Aged, 80 and over Apolipoprotein B-100/blood/genetics Apolipoprotein E2/blood/genetics Biomarkers/blood Blood Proteins/*analysis/genetics Cardiometabolic Risk Factors Cross-Sectional Studies Female Germany/epidemiology Humans Incidence Male Mendelian Randomization Analysis Metabolic Syndrome/*blood/diagnosis/epidemiology/genetics Middle Aged Norway/epidemiology Predictive Value of Tests Prevalence Prospective Studies *Proteome *Proteomics Proto-Oncogene Mas Proto-Oncogene Proteins c-ret/blood/genetics Risk Assessment Blood proteins Cardiovascular disease Diabetes mellitus Metabolic syndrome Proteomics Risk factors type 2 | BACKGROUND: The metabolic syndrome (MetS), defined by the simultaneous clustering of cardio-metabolic risk factors, is a significant worldwide public health burden with an estimated 25% prevalence worldwide. The pathogenesis of MetS is not entirely clear and the use of molecular level data could help uncover common pathogenic pathways behind the observed clustering. METHODS: Using a highly multiplexed aptamer-based affinity proteomics platform, we examined associations between plasma proteins and prevalent and incident MetS in the KORA cohort (n = 998) and replicated our results for prevalent MetS in the HUNT3 study (n = 923). We applied logistic regression models adjusted for age, sex, smoking status, and physical activity. We used the bootstrap ranking algorithm of least absolute shrinkage and selection operator (LASSO) to select a predictive model from the incident MetS associated proteins and used area under the curve (AUC) to assess its performance. Finally, we investigated the causal effect of the replicated proteins on MetS using two-sample Mendelian randomization. RESULTS: Prevalent MetS was associated with 116 proteins, of which 53 replicated in HUNT. These included previously reported proteins like leptin, and new proteins like NTR domain-containing protein 2 and endoplasmic reticulum protein 29. Incident MetS was associated with 14 proteins in KORA, of which 13 overlap the prevalent MetS associated proteins with soluble advanced glycosylation end product-specific receptor (sRAGE) being unique to incident MetS. The LASSO selected an eight-protein predictive model with an (AUC = 0.75; 95% CI = 0.71-0.79) in KORA. Mendelian randomization suggested causal effects of three proteins on MetS, namely apolipoprotein E2 (APOE2) (Wald-Ratio = - 0.12, Wald-p = 3.63e-13), apolipoprotein B (APOB) (Wald-Ratio = - 0.09, Wald-p = 2.54e-04) and proto-oncogene tyrosine-protein kinase receptor (RET) (Wald-Ratio = 0.10, Wald-p = 5.40e-04). CONCLUSIONS: Our findings offer new insights into the plasma proteome underlying MetS and identify new protein associations. We reveal possible casual effects of APOE2, APOB and RET on MetS. Our results highlight protein candidates that could potentially serve as targets for prevention and therapy. | Elhadad, Mohamed A Wilson, Rory Zaghlool, Shaza B Huth, Cornelia Gieger, Christian Grallert, Harald Graumann, Johannes Rathmann, Wolfgang Koenig, Wolfgang Sinner, Moritz F Hveem, Kristian Suhre, Karsten Thorand, Barbara Jonasson, Christian Waldenberger, Melanie Peters, Annette eng Multicenter Study Research Support, Non-U.S. Gov't England Cardiovasc Diabetol. 2021 May 20;20(1):111. doi: 10.1186/s12933-021-01299-2.I | 05/22/2021 | |
| Multiomic Profiling in Black and White Populations Reveals Novel Candidate Pathways in Left Ventricular Hypertrophy and Incident Heart Failure Specific to Black Adults | Katz DH, et al. | 2021 | Circ Genom Precis Med | 14 | 3 | e003191 | https://www.doi.org/10.1161/CIRCGEN.120.003191 | 34,019,435 | Adult *African Americans Aged Biomarkers/blood Chemokine CX3CL1/*blood Cystatin C/blood *Echocardiography Female *Heart Failure/blood/diagnostic imaging/physiopathology Humans *Hypertrophy, Left Ventricular/blood/diagnostic imaging/physiopathology Incidence Male Middle Aged Natriuretic Peptide, Brain/blood Peptide Fragments/blood Sex Factors *Whites continental population groups heart failure hospitalization hypertrophy, left ventricular proteomics | BACKGROUND: Increased left ventricular (LV) mass is associated with adverse cardiovascular events including heart failure (HF). Both increased LV mass and HF disproportionately affect Black individuals. To understand the underlying mechanisms, we undertook a proteomic screen in a Black cohort and compared the findings to results from a White cohort. METHODS: We measured 1305 plasma proteins using the SomaScan platform in 1772 Black participants (mean age, 56 years; 62% women) in JHS (Jackson Heart Study) with LV mass assessed by 2-dimensional echocardiography. Incident HF was assessed in 1600 participants. We then compared protein associations in JHS to those observed in White participants from FHS (Framingham Heart Study; mean age, 54 years; 56% women). RESULTS: In JHS, there were 110 proteins associated with LV mass and 13 proteins associated with incident HF hospitalization with false discovery rate <5% after multivariable adjustment. Several proteins showed expected associations with both LV mass and HF, including NT-proBNP (N-terminal pro-B-type natriuretic peptide; beta=0.04; P=2x10(-8); hazard ratio, 1.48; P=0.0001). The strongest association with LV mass was novel: LKHA4 (leukotriene-A4 hydrolase; beta=0.05; P=5x10(-15)). This association was confirmed on an alternate proteomics platform and further supported by related metabolomic data. Fractalkine/CX3CL1 (C-X3-C Motif Chemokine Ligand 1) showed a novel association with incident HF (hazard ratio, 1.32; P=0.0002). While established biomarkers such as cystatin C and NT-proBNP showed consistent associations in Black and White individuals, LKHA4 and fractalkine were significantly different between the two groups. CONCLUSIONS: We identified several novel biological pathways specific to Black adults hypothesized to contribute to the pathophysiologic cascade of LV hypertrophy and incident HF including LKHA4 and fractalkine. | Katz, Daniel H Tahir, Usman A Ngo, Debby Benson, Mark D Gao, Yan Shi, Xu Nayor, Matthew Keyes, Michelle J Larson, Martin G Hall, Michael E Correa, Adolfo Sinha, Sumita Shen, Dongxiao Herzig, Matthew Yang, Qiong Robbins, Jeremy M Chen, Zsu-Zsu Cruz, Daniel E Peterson, Bennet Vasan, Ramachandran S Wang, Thomas J Wilson, James G Gerszten, Robert E eng KL2 TR002542/TR/NCATS NIH HHS/ HHSN268201800014I/HB/NHLBI NIH HHS/ R01 DK081572/DK/NIDDK NIH HHS/ HHSN268201800014C/HL/NHLBI NIH HHS/ HHSN268201800013I/MD/NIMHD NIH HHS/ HHSN268201800011I/HB/NHLBI NIH HHS/ K08 HL145095/HL/NHLBI NIH HHS/ HHSN268201800012I/HB/NHLBI NIH HHS/ HHSN268201800012C/HL/NHLBI NIH HHS/ P30 DK040561/DK/NIDDK NIH HHS/ R01 HL132320/HL/NHLBI NIH HHS/ HHSN268201800011C/HL/NHLBI NIH HHS/ K23 HL138260/HL/NHLBI NIH HHS/ R01 HL133870/HL/NHLBI NIH HHS/ T32 HL007374/HL/NHLBI NIH HHS/ HHSN268201800015I/HB/NHLBI NIH HHS/ F32 HL150992/HL/NHLBI NIH HHS/ HHSN268201800010I/HB/NHLBI NIH HHS/ Clinical Trial Multicenter Study Circ Genom Precis Med. 2021 Jun;14(3):e003191. doi: 10.1161/CIRCGEN.120.003191. Epub 2021 May 21.I | 05/22/2021 | |
| Plasma Proteomic Profile Predicts Survival in Heart Failure With Reduced Ejection Fraction | Gui H, et al. | 2021 | Circ Genom Precis Med | 14 | 3 | e003140 | https://www.doi.org/10.1161/CIRCGEN.120.003140 | 33,999,650 | Aged Biomarkers/blood Disease-Free Survival Female *Heart Failure/blood/mortality Humans Male Natriuretic Peptide, Brain/*blood *Proteomics *Stroke Volume Survival Rate heart failure mortality plasma prognosis risk | BACKGROUND: It remains unclear whether the plasma proteome adds value to established predictors in heart failure (HF) with reduced ejection fraction (HFrEF). We sought to derive and validate a plasma proteomic risk score (PRS) for survival in patients with HFrEF (HFrEF-PRS). METHODS: Patients meeting Framingham criteria for HF with EF<50% were enrolled (N=1017) and plasma underwent SOMAscan profiling (4453 targets). Patients were randomly divided 2:1 into derivation and validation cohorts. The HFrEF-PRS was derived using Cox regression of all-cause mortality adjusted for clinical score and NT-proBNP (N-terminal pro-B-type natriuretic peptide), then was tested in the validation cohort. Risk stratification improvement was evaluated by C statistic, integrated discrimination index, continuous net reclassification index, and median improvement in risk score for 1-year and 3-year mortality. RESULTS: Participants' mean age was 68 years, 48% identified as Black, 35% were female, and 296 deaths occurred. In derivation (n=681), 128 proteins associated with mortality, 8 comprising the optimized HFrEF-PRS. In validation (n=336) the HFrEF-PRS associated with mortality (hazard ratio, 2.27 [95% CI, 1.84-2.82], P=6.3x10(-14)), Kaplan-Meier curves differed significantly between HFrEF-PRS quartiles (P=2.2x10(-6)), and it remained significant after adjustment for clinical score and NT-proBNP (hazard ratio, 1.37 [95% CI, 1.05-1.79], P=0.021). The HFrEF-PRS improved metrics of risk stratification (C statistic change, 0.009, P=0.612; integrated discrimination index, 0.041, P=0.010; net reclassification index=0.391, P=0.078; median improvement in risk score=0.039, P=0.016) and associated with cardiovascular death and HF phenotypes (eg, 6-minute walk distance, EF change). Most HFrEF-PRS proteins had little known connection to HFrEF. CONCLUSIONS: A plasma multiprotein score improved risk stratification in patients with HFrEF and identified novel candidates. | Gui, Hongsheng She, Ruicong Luzum, Jasmine Li, Jia Bryson, Timothy D Pinto, Yigal Sabbah, Hani N Williams, L Keoki Lanfear, David E eng R01 DK113003/DK/NIDDK NIH HHS/ R01 HL132154/HL/NHLBI NIH HHS/ P01 HL074237/HL/NHLBI NIH HHS/ K08 HL146990/HL/NHLBI NIH HHS/ R01 DK064695/DK/NIDDK NIH HHS/ R01 HL118267/HL/NHLBI NIH HHS/ R01 HL103871/HL/NHLBI NIH HHS/ R01 AI079139/AI/NIAID NIH HHS/ R01 HL141845/HL/NHLBI NIH HHS/ L30 HL110279/HL/NHLBI NIH HHS/ Randomized Controlled Trial Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Circ Genom Precis Med. 2021 Jun;14(3):e003140. doi: 10.1161/CIRCGEN.120.003140. Epub 2021 May 17.I | 05/18/2021 | |
| Novel Murine Biomarkers of Radiation Exposure Using An Aptamer-Based Proteomic Technology | Sproull M, et al. | 2021 | Front Pharmacol | 12 | 633131 | https://www.doi.org/10.3389/fphar.2021.633131 | 33,981,223 | biodosimetry biomarker medical countermeasure radiation somascan commercial or financial relationships that could be construed as a potential conflict of interest. | Purpose: There is a need to identify new biomarkers of radiation exposure both for use in the development of biodosimetry blood diagnostics for radiation exposure and for clinical use as markers of radiation injury. In the current study, a novel high-throughput proteomics screening approach was used to identify proteomic markers of radiation exposure in the plasma of total body irradiated mice. A subset panel of significantly altered proteins was selected to build predictive models of radiation exposure and received radiation dose useful for population screening in a future radiological or nuclear event. Methods: Female C57BL6 Mice of 8-14 weeks of age received a single total body irradiation (TBI) dose of 2, 3.5, 8 Gy or sham radiation and plasma was collected by cardiac puncture at days 1, 3, and 7 post-exposure. Plasma was then screened using the aptamer-based SOMAscan proteomic assay technology, for changes in expression of 1,310 protein analytes. A subset panel of protein biomarkers which demonstrated significant changes (p < 0.05) in expression following radiation exposure were used to build predictive models of radiation exposure and radiation dose. Results: Detectable values were obtained for all 1,310 proteins included in the SOMAscan assay. For the Control vs. Radiation model, the top predictive proteins were immunoglobulin heavy constant mu (IGHM), mitogen-activated protein kinase 14 (MAPK14), ectodysplasin A2 receptor (EDA2R) and solute carrier family 25 member 18 (SLC25A18). For the Control vs. Dose model, the top predictive proteins were cyclin dependent kinase 2/cyclin A2 (CDK2. CCNA2), E-selectin (SELE), BCL2 associated agonist of cell death (BAD) and SLC25A18. Following model validation with a training set of samples, both models tested with a new sample cohort had overall predictive accuracies of 85% and 73% for the Control vs. Radiation and Control vs. Dose models respectively. Conclusion: The SOMAscan proteomics platform is a useful screening tool to evaluate changes in biomarker expression. In our study we were able to identify a novel panel of radiation responsive proteins useful for predicting whether an animal had received a radiation exposure and to what dose they had received. Such diagnostic tools are needed for future medical management of radiation exposures. | Sproull, Mary Shankavaram, Uma Camphausen, Kevin eng Switzerland Front Pharmacol. 2021 Apr 26;12:633131. doi: 10.3389/fphar.2021.633131. eCollection 2021.I | 05/14/2021 | ||
| The CRTAC1 Protein in Plasma Is Associated With Osteoarthritis and Predicts Progression to Joint Replacement: A Large-Scale Proteomics Scan in Iceland | Styrkarsdottir U, et al. | 2021 | Arthritis Rheumatol | 73 | 11 | 2025-2034 | https://www.doi.org/10.1002/art.41793 | 33,982,893 | Adult Aged *Arthroplasty, Replacement Biomarkers/blood Calcium-Binding Proteins/*blood Case-Control Studies Disease Progression Female Humans Iceland Male Middle Aged Osteoarthritis/*blood/diagnosis/surgery Prospective Studies Proteomics | OBJECTIVE: Biomarkers for diagnosis and progression of osteoarthritis (OA) are lacking. This study was undertaken to identify circulating biomarkers for OA that could predict disease occurrence and/or progression to joint replacement. METHODS: Using the SomaScan platform, we measured 4,792 proteins in plasma from 37,278 individuals, of whom 12,178 individuals had OA and 2,524 had undergone joint replacement. We performed a case-control study for identification of potential protein biomarkers for hip, knee, and/or hand OA, and a prospective study for identification of biomarkers for joint replacement. RESULTS: Among the large panel of plasma proteins assessed, cartilage acidic protein 1 (CRTAC1) was the most strongly associated with both OA diagnosis (odds ratio 1.46 [95% confidence interval 1.41-1.52] for knee OA, odds ratio 1.36 [95% confidence interval 1.29-1.43] for hip OA, and odds ratio 1.33 [95% confidence interval 1.26-1.40] for hand OA) and progression to joint replacement (hazard ratio 1.40 [95% confidence interval 1.30-1.51] for knee replacement and hazard ratio 1.31 [95% confidence interval 1.19-1.45] for hip replacement). Patients with OA who were in the highest quintile of risk of joint replacement, based on known risk factors (i.e., age, sex, and body mass index) and plasma CRTAC1 level, were 16 times more likely to undergo knee replacement within 5 years of plasma sample collection than those in the lowest quintile, and 6.5 times more likely to undergo hip replacement. CRTAC1 was not associated with other types of inflammatory arthritis. A specific protein profile was identified in those patients who had undergone joint replacement prior to plasma sample collection. CONCLUSION: Through a hypothesis-free approach, we identified CRTAC1 in plasma as a novel promising candidate biomarker for OA that is both associated with occurrence of OA and predictive of progression to joint replacement. This biomarker might also be useful in the selection of suitable patients for clinical trial enrollment. | Styrkarsdottir, Unnur Lund, Sigrun H Saevarsdottir, Saedis Magnusson, Magnus I Gunnarsdottir, Kristbjorg Norddahl, Gudmundur L Frigge, Michael L Ivarsdottir, Erna V Bjornsdottir, Gyda Holm, Hilma Thorgeirsson, Gudmundur Rafnar, Thorunn Jonsdottir, Ingileif Ingvarsson, Thorvaldur Jonsson, Helgi Sulem, Patrick Thorsteinsdottir, Unnur Gudbjartsson, Daniel Stefansson, Kari eng Research Support, Non-U.S. Gov't Arthritis Rheumatol. 2021 Nov;73(11):2025-2034. doi: 10.1002/art.41793. Epub 2021 Sep 28.I | 05/14/2021 | |
| Longitudinal proteomic analysis of severe COVID-19 reveals survival-associated signatures, tissue-specific cell death, and cell-cell interactions | Filbin MR, et al. | 2021 | Cell Rep Med | 2 | 5 | 100287 | https://www.doi.org/10.1016/j.xcrm.2021.100287 | 33,969,320 | Ards COVID-19 severity T cell activation acute respiratory distress syndrome death versus survival intracellular death signatures longitudinal lung epithelial cells lung monocyte/macrophages pancreatic exocrine proteases plasma proteomics employees of Olink Proteomics. G.S.H. is an employee of Genentech (as of November 2020). L.L.J. is an employee and stockholder of Novartis. N.H. holds equity in BioNTech and is a consultant for Related Sciences. | Mechanisms underlying severe coronavirus disease 2019 (COVID-19) disease remain poorly understood. We analyze several thousand plasma proteins longitudinally in 306 COVID-19 patients and 78 symptomatic controls, uncovering immune and non-immune proteins linked to COVID-19. Deconvolution of our plasma proteome data using published scRNA-seq datasets reveals contributions from circulating immune and tissue cells. Sixteen percent of patients display reduced inflammation yet comparably poor outcomes. Comparison of patients who died to severely ill survivors identifies dynamic immune-cell-derived and tissue-associated proteins associated with survival, including exocrine pancreatic proteases. Using derived tissue-specific and cell-type-specific intracellular death signatures, cellular angiotensin-converting enzyme 2 (ACE2) expression, and our data, we infer whether organ damage resulted from direct or indirect effects of infection. We propose a model in which interactions among myeloid, epithelial, and T cells drive tissue damage. These datasets provide important insights and a rich resource for analysis of mechanisms of severe COVID-19 disease. | Filbin, Michael R Mehta, Arnav Schneider, Alexis M Kays, Kyle R Guess, Jamey R Gentili, Matteo Fenyves, Bank G Charland, Nicole C Gonye, Anna L K Gushterova, Irena Khanna, Hargun K LaSalle, Thomas J Lavin-Parsons, Kendall M Lilley, Brendan M Lodenstein, Carl L Manakongtreecheep, Kasidet Margolin, Justin D McKaig, Brenna N Rojas-Lopez, Maricarmen Russo, Brian C Sharma, Nihaarika Tantivit, Jessica Thomas, Molly F Gerszten, Robert E Heimberg, Graham S Hoover, Paul J Lieb, David J Lin, Brian Ngo, Debby Pelka, Karin Reyes, Miguel Smillie, Christopher S Waghray, Avinash Wood, Thomas E Zajac, Amanda S Jennings, Lori L Grundberg, Ida Bhattacharyya, Roby P Parry, Blair Alden Villani, Alexandra-Chloe Sade-Feldman, Moshe Hacohen, Nir Goldberg, Marcia B eng T32 CA071345/CA/NCI NIH HHS/ U19 AI082630/AI/NIAID NIH HHS/ UL1 TR001102/TR/NCATS NIH HHS/ UL1 TR002541/TR/NCATS NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Cell Rep Med. 2021 May 18;2(5):100287. doi: 10.1016/j.xcrm.2021.100287. Epub 2021 May 3.I | 05/11/2021 | |
| Integrated trajectories of the maternal metabolome, proteome, and immunome predict labor onset | Stelzer IA, et al. | 2021 | Sci Transl Med | 13 | 592 | https://www.doi.org/10.1126/scitranslmed.abd9898 | 33,952,678 | Biomarkers Female Humans *Labor Onset/immunology/metabolism Longitudinal Studies *Metabolome Pregnancy *Proteome | Estimating the time of delivery is of high clinical importance because pre- and postterm deviations are associated with complications for the mother and her offspring. However, current estimations are inaccurate. As pregnancy progresses toward labor, major transitions occur in fetomaternal immune, metabolic, and endocrine systems that culminate in birth. The comprehensive characterization of maternal biology that precedes labor is key to understanding these physiological transitions and identifying predictive biomarkers of delivery. Here, a longitudinal study was conducted in 63 women who went into labor spontaneously. More than 7000 plasma analytes and peripheral immune cell responses were analyzed using untargeted mass spectrometry, aptamer-based proteomic technology, and single-cell mass cytometry in serial blood samples collected during the last 100 days of pregnancy. The high-dimensional dataset was integrated into a multiomic model that predicted the time to spontaneous labor [R = 0.85, 95% confidence interval (CI) [0.79 to 0.89], P = 1.2 x 10(-40), N = 53, training set; R = 0.81, 95% CI [0.61 to 0.91], P = 3.9 x 10(-7), N = 10, independent test set]. Coordinated alterations in maternal metabolome, proteome, and immunome marked a molecular shift from pregnancy maintenance to prelabor biology 2 to 4 weeks before delivery. A surge in steroid hormone metabolites and interleukin-1 receptor type 4 that preceded labor coincided with a switch from immune activation to regulation of inflammatory responses. Our study lays the groundwork for developing blood-based methods for predicting the day of labor, anchored in mechanisms shared in preterm and term pregnancies. | Stelzer, Ina A Ghaemi, Mohammad S Han, Xiaoyuan Ando, Kazuo Hedou, Julien J Feyaerts, Dorien Peterson, Laura S Rumer, Kristen K Tsai, Eileen S Ganio, Edward A Gaudilliere, Dyani K Tsai, Amy S Choisy, Benjamin Gaigne, Lea P Verdonk, Franck Jacobsen, Danielle Gavasso, Sonia Traber, Gavin M Ellenberger, Mathew Stanley, Natalie Becker, Martin Culos, Anthony Fallahzadeh, Ramin Wong, Ronald J Darmstadt, Gary L Druzin, Maurice L Winn, Virginia D Gibbs, Ronald S Ling, Xuefeng B Sylvester, Karl Carvalho, Brendan Snyder, Michael P Shaw, Gary M Stevenson, David K Contrepois, Kevin Angst, Martin S Aghaeepour, Nima Gaudilliere, Brice eng R35 GM137936/GM/NIGMS NIH HHS/ R61 NS114926/NS/NINDS NIH HHS/ T32 GM099608/GM/NIGMS NIH HHS/ R35 GM138353/GM/NIGMS NIH HHS/ R01 AG058417/AG/NIA NIH HHS/ 2018100/DDCF/Doris Duke Charitable Foundation/ R01 HL139844/HL/NHLBI NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Sci Transl Med. 2021 May 5;13(592):eabd9898. doi: 10.1126/scitranslmed.abd9898.I | 05/07/2021 | ||
| Duodenal Microbiota in Stunted Undernourished Children with Enteropathy. Reply | Chen RY, et al. | 2021 | N Engl J Med | 384 | 18 | 1778 | https://www.doi.org/10.1056/NEJMc2030388 | 33,951,373 | Child Duodenum Humans *Intestinal Diseases *Microbiota | Chen, Robert Y Ahmed, Tahmeed Gordon, Jeffrey I eng Comment Letter N Engl J Med. 2021 May 6;384(18):1778. doi: 10.1056/NEJMc2030388.I | 05/06/2021 | ||
| Effect of longevity genetic variants on the molecular aging rate | Gurinovich A, et al. | 2021 | Geroscience | 43 | 3 | 1237-1251 | https://www.doi.org/10.1007/s11357-021-00376-4 | 33,948,810 | Aged, 80 and over Aging/genetics *Genome-Wide Association Study Genotype Humans *Longevity/genetics Proteomics Extreme human longevity Genetic variants Molecular aging rate SOMAscan array stock-holder of Regeneron Pharmaceuticals. | We conducted a genome-wide association study of 1320 centenarians from the New England Centenarian Study (median age = 104 years) and 2899 unrelated controls using >9 M genetic variants imputed to the HRC panel of ~65,000 haplotypes. The genetic variants with the most significant associations were correlated to 4131 proteins that were profiled in the serum of a subset of 224 study participants using a SOMAscan array. The genetic associations were replicated in a genome-wide association study of 480 centenarians and ~800 controls of Ashkenazi Jewish descent. The proteomic associations were replicated in a proteomic scan of approximately 1000 Ashkenazi Jewish participants from a third cohort. The analysis replicated a protein signature associated with APOE genotypes and confirmed strong overexpression of BIRC2 (p < 5E-16) and under-expression of APOB in carriers of the APOE2 allele (p < 0.05). The analysis also discovered and replicated associations between longevity variants and slower changes of protein biomarkers of aging, including a novel protein signature of rs2184061 (CDKN2A/CDKN2B in chromosome 9) that suggests a genetic regulation of GDF15. The analyses showed that longevity variants correlate with proteome signatures that could be manipulated to discover healthy-aging targets. | Gurinovich, Anastasia Song, Zeyuan Zhang, William Federico, Anthony Monti, Stefano Andersen, Stacy L Jennings, Lori L Glass, David J Barzilai, Nir Millman, Sofiya Perls, Thomas T Sebastiani, Paola eng R24 GM134210/GM/NIGMS NIH HHS/ U19 AG056278/AG/NIA NIH HHS/ U19-AG023122/AG/NIA NIH HHS/ T32 AG023475/AG/NIA NIH HHS/ R01 AG061155/AG/NIA NIH HHS/ S10 OD021728/OD/NIH HHS/ P30 AG038072/AG/NIA NIH HHS/ R01 AG061844/AG/NIA NIH HHS/ UH2AG064704/AG/NIA NIH HHS/ F31 DE029701/DE/NIDCR NIH HHS/ UH2 AG064704/AG/NIA NIH HHS/ U19 AG023122/AG/NIA NIH HHS/ R01 AG046949/AG/NIA NIH HHS/ P30AG038072/AG/NIA NIH HHS/ R01 AG044829/AG/NIA NIH HHS/ R01 AG057909/AG/NIA NIH HHS/ Research Support, N.I.H., Extramural Switzerland Geroscience. 2021 Jun;43(3):1237-1251. doi: 10.1007/s11357-021-00376-4. Epub 2021 May 4.I | 05/06/2021 | |
| Identification and Validation of Nutrient State-Dependent Serum Protein Mediators of Human CD4(+) T Cell Responsiveness | Han K, et al. | 2021 | Nutrients | 13 | 5 | https://www.doi.org/10.3390/nu13051492 | 33,924,911 | Adult Aged Blood Proteins/*metabolism CD4-Positive T-Lymphocytes/*metabolism Cells, Cultured Fasting/*metabolism Female Humans Inflammation/*blood Male Middle Aged Nutrients/*blood Obesity/*blood Pilot Projects Reproducibility of Results Young Adult CD4+ T cell activation Igfbp1 Il1rl1 Mfge8 Pyy SOMAscan fasting integrative bioinformatics refeeding | Intermittent fasting and fasting mimetic diets ameliorate inflammation. Similarly, serum extracted from fasted healthy and asthmatic subjects' blunt inflammation in vitro, implicating serum components in this immunomodulation. To identify the proteins orchestrating these effects, SOMAScan technology was employed to evaluate serum protein levels in healthy subjects following an overnight, 24-h fast and 3 h after refeeding. Partial least square discriminant analysis identified several serum proteins as potential candidates to confer feeding status immunomodulation. The characterization of recombinant IGFBP1 (elevated following 24 h of fasting) and PYY (elevated following refeeding) in primary human CD4(+) T cells found that they blunted and induced immune activation, respectively. Furthermore, integrated univariate serum protein analysis compared to RNA-seq analysis from peripheral blood mononuclear cells identified the induction of IL1RL1 and MFGE8 levels in refeeding compared to the 24-h fasting in the same study. Subsequent quantitation of these candidate proteins in lean versus obese individuals identified an inverse regulation of serum levels in the fasted subjects compared to the obese subjects. In parallel, IL1RL1 and MFGE8 supplementation promoted increased CD4(+) T responsiveness to T cell receptor activation. Together, these data show that caloric load-linked conditions evoke serological protein changes, which in turn confer biological effects on circulating CD4(+) T cell immune responsiveness. | Han, Kim Singh, Komudi Rodman, Matthew J Hassanzadeh, Shahin Baumer, Yvonne Huffstutler, Rebecca D Chen, Jinguo Candia, Julian Cheung, Foo Stagliano, Katherine E R Pirooznia, Mehdi Powell-Wiley, Tiffany M Sack, Michael N eng Validation Study Switzerland Nutrients. 2021 Apr 28;13(5):1492. doi: 10.3390/nu13051492.I | 05/01/2021 | ||
| Immune dysregulation and autoreactivity correlate with disease severity in SARS-CoV-2-associated multisystem inflammatory syndrome in children | Ramaswamy A, et al. | 2021 | Immunity | 54 | 5 | 1083-1095 e7 | https://www.doi.org/10.1016/j.immuni.2021.04.003 | 33,891,889 | Adolescent Alarmins/immunology Autoantibodies/immunology CD8-Positive T-Lymphocytes/immunology COVID-19/*immunology/*pathology Child Child, Preschool Cytotoxicity, Immunologic/genetics Endothelium/immunology/pathology Humans Killer Cells, Natural/immunology Myeloid Cells/immunology Plasma Cells/immunology Receptors, Antigen, T-Cell/genetics/immunology SARS-CoV-2/*immunology Severity of Illness Index Systemic Inflammatory Response Syndrome/*immunology/*pathology Mis-c SARS-CoV-2 Trbv11-2 alarmins cytotoxicity inflammation pediatric plasmablasts Squibb, Novartis, Sanofi, and Genentech. He has been a consultant for Bayer Pharmaceuticals, Bristol Myers Squibb, Compass Therapeutics, EMD Serono, Genentech, Juno Therapeutics, Novartis Pharmaceuticals, Proclara Biosciences, Sage Therapeutics, and Sanofi Genzyme. Further information regarding funding is available on: https://openpaymentsdata.cms.gov/physician/166753/general-payments. N.K. reports personal fees from Boehringer Ingelheim, Third Rock, Pliant, Samumed, NuMedii, Indalo, Theravance, LifeMax, Three Lake Partners, RohBar in the last 36 months, and Equity in Pliant. N.K. is also a recipient of a grant from Veracyte and non-financial support from Miragen. All outside the submitted work In addition, N.K. has patents on New Therapies in Pulmonary Fibrosis and ARDS (unlicensed) and Peripheral Blood Gene Expression as biomarkers in IPF (licensed to biotech). S.H.K. receives consulting fees from Northrop Grumman. K.B.H. receives consulting fees from Prellis Biologics. B.S. is a former SomaLogic, Inc. (Boulder, CO, USA) employee and a company shareholder. All other authors declared that they have no competing interests. | Multisystem inflammatory syndrome in children (MIS-C) is a life-threatening post-infectious complication occurring unpredictably weeks after mild or asymptomatic SARS-CoV-2 infection. We profiled MIS-C, adult COVID-19, and healthy pediatric and adult individuals using single-cell RNA sequencing, flow cytometry, antigen receptor repertoire analysis, and unbiased serum proteomics, which collectively identified a signature in MIS-C patients that correlated with disease severity. Despite having no evidence of active infection, MIS-C patients had elevated S100A-family alarmins and decreased antigen presentation signatures, indicative of myeloid dysfunction. MIS-C patients showed elevated expression of cytotoxicity genes in NK and CD8(+) T cells and expansion of specific IgG-expressing plasmablasts. Clinically severe MIS-C patients displayed skewed memory T cell TCR repertoires and autoimmunity characterized by endothelium-reactive IgG. The alarmin, cytotoxicity, TCR repertoire, and plasmablast signatures we defined have potential for application in the clinic to better diagnose and potentially predict disease severity early in the course of MIS-C. | Ramaswamy, Anjali Brodsky, Nina N Sumida, Tomokazu S Comi, Michela Asashima, Hiromitsu Hoehn, Kenneth B Li, Ningshan Liu, Yunqing Shah, Aagam Ravindra, Neal G Bishai, Jason Khan, Alamzeb Lau, William Sellers, Brian Bansal, Neha Guerrerio, Pamela Unterman, Avraham Habet, Victoria Rice, Andrew J Catanzaro, Jason Chandnani, Harsha Lopez, Merrick Kaminski, Naftali Dela Cruz, Charles S Tsang, John S Wang, Zuoheng Yan, Xiting Kleinstein, Steven H van Dijk, David Pierce, Richard W Hafler, David A Lucas, Carrie L eng UL1 TR001863/TR/NCATS NIH HHS/ R21 AI144315/AI/NIAID NIH HHS/ R01 AI104739/AI/NIAID NIH HHS/ K08 HL136898/HL/NHLBI NIH HHS/ T32 AI007019/AI/NIAID NIH HHS/ R21 LM012884/LM/NLM NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Immunity. 2021 May 11;54(5):1083-1095.e7. doi: 10.1016/j.immuni.2021.04.003. Epub 2021 Apr 13.I | 04/24/2021 | |
| Early Interleukin-22 and Neutrophil Proteins Are Correlated to Future Lung Damage in Children With Cystic Fibrosis | Renwick J, et al. | 2021 | Front Pediatr | 9 | 640184 | https://www.doi.org/10.3389/fped.2021.640184 | 33,869,115 | biomarkers bronchoalveolar lavage cystic fibrosis neutrophils proteomics commercial or financial relationships that could be construed as a potential conflict of interest. | Cystic Fibrosis (CF) lung damage begins early in life. Lung function decline is associated with pulmonary infections, neutrophil infiltration and inflammation. In CF, neutrophils have an altered phenotype. In this pilot study, we aimed to determine if signals of dysfunctional neutrophil responses were evident early in life and whether these signals may be associated with lung damage in later childhood. We examined the pulmonary protein profiles of 14 clinical stable infants and pre-school children with CF employing the aptamer-based affinity platform, SOMAscan(R). High resolution computed tomography (HRCT) was performed on all children after age 6 years and Brody score calculated. A Spearman's rank order correlation analysis and Benjamini-Hochberg adjustment was used to correlate protein concentrations in early life to Brody scores in later childhood. Early life concentrations of azurocidin and myeloperoxidase, were positively correlated with Brody score after age 6 (p = 0.0041 and p = 0.0182, respectively). Four other neutrophil associated proteins; Complement C3 (p = 0.0026), X-ray repair CCP 6 (p = 0.0059), C3a anaphylatoxin des Arginine (p = 0.0129) and cytokine receptor common subunit gamma (p = 0.0214) were all negatively correlated with Brody scores. Interestingly, patients with more severe lung damage after age 6 had significantly lower levels of IL-22 in early years of life (p = 0.0243). IL-22 has scarcely been reported to have implications in CF. Identification of early biomarkers that may predict more severe disease progression is particularly important for the future development of early therapeutic interventions in CF disease. We recommend further corroboration of these findings in prospective validation studies. | Renwick, Julie Reece, Emma Walsh, Jamie Walsh, Ross Persaud, Thara O'Leary, Cathal Donnelly, Seamas C Greally, Peter eng Switzerland Front Pediatr. 2021 Mar 31;9:640184. doi: 10.3389/fped.2021.640184. eCollection 2021.I | 04/20/2021 | ||
| Platelet Protein-Related Abnormalities in Response to Acute Hypoglycemia in Type 2 Diabetes | Moin ASM, et al. | 2021 | Front Endocrinol (Lausanne) | 12 | 651009 | https://www.doi.org/10.3389/fendo.2021.651009 | 33,859,620 | Aged Blood Platelet Disorders/*blood/*etiology Blood Platelets/*chemistry Blood Proteins/*analysis COVID-19/*blood/complications Case-Control Studies Diabetes Mellitus, Type 2/*blood/*complications Female Glucose Clamp Technique Humans Hypoglycemia/*blood/*complications Lipids/blood Male Middle Aged Platelet Activation Thromboembolism/blood/etiology Covid-19 SARS-CoV-2 obesity platelet type 2 diabetes commercial or financial relationships that could be construed as a potential conflict of interest. | INTRODUCTION: Patients with severe COVID-19 infections have coagulation abnormalities indicative of a hypercoagulable state, with thromboembolic complications and increased mortality. Platelets are recognized as mediators of inflammation, releasing proinflammatory and prothrombotic factors, and are hyperactivated in COVID-19 infected patients. Activated platelets have also been reported in type 2 diabetes (T2D) patients, putting these patients at higher risk for thromboembolic complications of COVID-19 infection. METHODS: A case-control study of T2D (n=33) and control subjects (n=30) who underwent a hyperinsulinemic clamp to induce normoglycemia in T2D subjects: T2D: baseline glucose 7.5 +/- 0.3mmol/l (135.1 +/- 5.4mg/dl), reduced to 4.5 +/- 0.07mmol/l (81 +/- 1.2mg/dl) with 1-hour clamp; Controls: maintained at 5.1 +/- 0.1mmol/l (91.9 +/- 1.8mg/dl). Slow Off-rate Modified Aptamer (SOMA)-scan plasma protein measurement was used to determine a panel of platelet proteins. RESULTS: Prothrombotic platelet proteins were elevated in T2D versus controls: platelet factor 4 (PF4, p<0.05); platelet glycoprotein VI (PGVI p<0.05); P-selectin (p<0.01) and plasminogen activator inhibitor I (PAI-1, p<0.01). In addition, the antithrombotic platelet-related proteins, plasmin (p<0.05) and heparin cofactor II (HCFII, p<0.05), were increased in T2D. Normalization of glucose in the T2D cohort had no effect on platelet protein levels. CONCLUSION: T2D patients have platelet hyperactivation, placing them at higher risk for thromboembolic events. When infected with COVID-19, this risk may be compounded, and their propensity for a more severe COVID-19 disease course increased. CLINICAL TRIAL REGISTRATION: https://clinicaltrials.gov/ct2/show/NCT03102801, identifier NCT03102801. | Moin, Abu Saleh Md Al-Qaissi, Ahmed Sathyapalan, Thozhukat Atkin, Stephen L Butler, Alexandra E eng Switzerland Front Endocrinol (Lausanne). 2021 Mar 30;12:651009. doi: 10.3389/fendo.2021.651009. eCollection 2021.I | 04/17/2021 | ||
| Actionable druggable genome-wide Mendelian randomization identifies repurposing opportunities for COVID-19 | Gaziano L, et al. | 2021 | Nat Med | 27 | 4 | 668-676 | https://www.doi.org/10.1038/s41591-021-01310-z | 33,837,377 | Angiotensin-Converting Enzyme 2/genetics/physiology COVID-19/drug therapy/*genetics *Drug Repositioning Genome-Wide Association Study Humans Interleukin-10 Receptor beta Subunit/genetics/physiology Mendelian Randomization Analysis/*methods Quantitative Trait Loci Receptor, Interferon alpha-beta/genetics/physiology *SARS-CoV-2 | Drug repurposing provides a rapid approach to meet the urgent need for therapeutics to address COVID-19. To identify therapeutic targets relevant to COVID-19, we conducted Mendelian randomization analyses, deriving genetic instruments based on transcriptomic and proteomic data for 1,263 actionable proteins that are targeted by approved drugs or in clinical phase of drug development. Using summary statistics from the Host Genetics Initiative and the Million Veteran Program, we studied 7,554 patients hospitalized with COVID-19 and >1 million controls. We found significant Mendelian randomization results for three proteins (ACE2, P = 1.6 x 10(-6); IFNAR2, P = 9.8 x 10(-11) and IL-10RB, P = 2.3 x 10(-14)) using cis-expression quantitative trait loci genetic instruments that also had strong evidence for colocalization with COVID-19 hospitalization. To disentangle the shared expression quantitative trait loci signal for IL10RB and IFNAR2, we conducted phenome-wide association scans and pathway enrichment analysis, which suggested that IFNAR2 is more likely to play a role in COVID-19 hospitalization. Our findings prioritize trials of drugs targeting IFNAR2 and ACE2 for early management of COVID-19. | Gaziano, Liam Giambartolomei, Claudia Pereira, Alexandre C Gaulton, Anna Posner, Daniel C Swanson, Sonja A Ho, Yuk-Lam Iyengar, Sudha K Kosik, Nicole M Vujkovic, Marijana Gagnon, David R Bento, A Patricia Barrio-Hernandez, Inigo Ronnblom, Lars Hagberg, Niklas Lundtoft, Christian Langenberg, Claudia Pietzner, Maik Valentine, Dennis Gustincich, Stefano Tartaglia, Gian Gaetano Allara, Elias Surendran, Praveen Burgess, Stephen Zhao, Jing Hua Peters, James E Prins, Bram P Angelantonio, Emanuele Di Devineni, Poornima Shi, Yunling Lynch, Kristine E DuVall, Scott L Garcon, Helene Thomann, Lauren O Zhou, Jin J Gorman, Bryan R Huffman, Jennifer E O'Donnell, Christopher J Tsao, Philip S Beckham, Jean C Pyarajan, Saiju Muralidhar, Sumitra Huang, Grant D Ramoni, Rachel Beltrao, Pedro Danesh, John Hung, Adriana M Chang, Kyong-Mi Sun, Yan V Joseph, Jacob Leach, Andrew R Edwards, Todd L Cho, Kelly Gaziano, J Michael Butterworth, Adam S Casas, Juan P eng MR/L003120/1/MRC_/Medical Research Council/United Kingdom RG/13/13/30194/BHF_/British Heart Foundation/United Kingdom MC_UU_12015/1/MRC_/Medical Research Council/United Kingdom 754490/EC | EU Framework Programme for Research and Innovation H2020 | H2020 Priority Excellent Science | H2020 Marie Sklodowska-Curie Actions (H2020 Excellent Science - Marie Sklodowska-Curie Actions)/ I01 CX001897/CX/CSRD VA/ MR/S004068/2/MRC_/Medical Research Council/United Kingdom MC_UU_00002/7/MRC_/Medical Research Council/United Kingdom I01 BX003362/BX/BLRD VA/ 204623/Z/16/Z/WT_/Wellcome Trust/United Kingdom MVP001/Department of Veteran Affairs/ RG/18/13/33946/BHF_/British Heart Foundation/United Kingdom MVP035/Office of Research and Development, VA/ Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S. Nat Med. 2021 Apr;27(4):668-676. doi: 10.1038/s41591-021-01310-z. Epub 2021 Apr 9.I | 04/11/2021 | |
| A Microbiota-Directed Food Intervention for Undernourished Children | Chen RY, et al. | 2021 | N Engl J Med | 384 | 16 | 1517-1528 | https://www.doi.org/10.1056/NEJMoa2023294 | 33,826,814 | Anthropometry Bangladesh Blood Proteins/analysis Body Weight *Dietary Supplements Feces/microbiology Female *Food, Formulated *Gastrointestinal Microbiome Growth Humans Infant *Infant Nutritional Physiological Phenomena Male Malnutrition/*diet therapy/microbiology Proteome Weight Gain | BACKGROUND: More than 30 million children worldwide have moderate acute malnutrition. Current treatments have limited effectiveness, and much remains unknown about the pathogenesis of this condition. Children with moderate acute malnutrition have perturbed development of their gut microbiota. METHODS: In this study, we provided a microbiota-directed complementary food prototype (MDCF-2) or a ready-to-use supplementary food (RUSF) to 123 slum-dwelling Bangladeshi children with moderate acute malnutrition between the ages of 12 months and 18 months. The supplementation was given twice daily for 3 months, followed by 1 month of monitoring. We obtained weight-for-length, weight-for-age, and length-for-age z scores and mid-upper-arm circumference values at baseline and every 2 weeks during the intervention period and at 4 months. We compared the rate of change of these related phenotypes between baseline and 3 months and between baseline and 4 months. We also measured levels of 4977 proteins in plasma and 209 bacterial taxa in fecal samples. RESULTS: A total of 118 children (59 in each study group) completed the intervention. The rates of change in the weight-for-length and weight-for-age z scores are consistent with a benefit of MDCF-2 on growth over the course of the study, including the 1-month follow-up. Receipt of MDCF-2 was linked to the magnitude of change in levels of 70 plasma proteins and of 21 associated bacterial taxa that were positively correlated with the weight-for-length z score (P<0.001 for comparisons of both protein and bacterial taxa). These proteins included mediators of bone growth and neurodevelopment. CONCLUSIONS: These findings provide support for MDCF-2 as a dietary supplement for young children with moderate acute malnutrition and provide insight into mechanisms by which this targeted manipulation of microbiota components may be linked to growth. (Supported by the Bill and Melinda Gates Foundation and the National Institutes of Health; ClinicalTrials.gov number, NCT04015999.). | Chen, Robert Y Mostafa, Ishita Hibberd, Matthew C Das, Subhasish Mahfuz, Mustafa Naila, Nurun N Islam, M Munirul Huq, Sayeeda Alam, M Ashraful Zaman, Mahabub U Raman, Arjun S Webber, Daniel Zhou, Cyrus Sundaresan, Vinaik Ahsan, Kazi Meier, Martin F Barratt, Michael J Ahmed, Tahmeed Gordon, Jeffrey I eng R01 DK030292/DK/NIDDK NIH HHS/ P30 DK056341/DK/NIDDK NIH HHS/ F30 DK124967/DK/NIDDK NIH HHS/ T32 GM007200/GM/NIGMS NIH HHS/ DK30292/DK/NIDDK NIH HHS/ Comparative Study Randomized Controlled Trial Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't N Engl J Med. 2021 Apr 22;384(16):1517-1528. doi: 10.1056/NEJMoa2023294. Epub 2021 Apr 7.I | 04/08/2021 | |
| Plasma Proteomic Profiling in Hypertrophic Cardiomyopathy Patients before and after Surgical Myectomy Reveals Post-Procedural Reduction in Systemic Inflammation | Larson A, et al. | 2021 | Int J Mol Sci | 22 | 5 | https://www.doi.org/10.3390/ijms22052474 | 33,804,404 | Adult Aged Biomarkers/*blood Cardiac Surgical Procedures/*methods Cardiomyopathy, Hypertrophic/metabolism/pathology/*surgery Female Humans Inflammation/blood/*prevention & control Male Middle Aged Proteome/*analysis aptamer cardiovascular disease hypertrophic cardiomyopathy myectomy surgery proteomics design of the study in the collection, analyses, or interpretation of data in the writing of the manuscript, or in the decision to publish the results. | Left Ventricular Outflow Tract (LVOT) obstruction occurs in approximately 70% of Hypertrophic Cardiomyopathy (HCM) patients and currently requires imaging or invasive testing for diagnosis, sometimes in conjunction with provocative physiological or pharmaceutical stimuli. To identify potential biomarkers of LVOT obstruction, we performed proteomics profiling of 1305 plasma proteins in 12 HCM patients with documented LVOT obstruction, referred for surgical myectomy. Plasma was collected at the surgical preoperative visit, approximately one month prior to surgery and then at the post-surgical visit, approximately 3 months later. Proteomic profiles were generated using the aptamer-based SOMAscan assay. Principal Component Analysis using the highest statistically significant proteins separated all preoperative samples from all postoperative samples. Further analysis revealed a set of 25 proteins that distinguished the preoperative and postoperative states with a paired t-test p-value of <0.01. Ingenuity Pathway analysis facilitated the generation of protein interaction networks and the elucidation of key upstream regulators of differentially expressed proteins, such as interferon-gamma, TGF-beta1, and TNF. Biological pathways affected by surgery included organ inflammation, migration, and motility of leukocytes, fibrosis, vasculogenesis, angiogenesis, acute coronary events, endothelial proliferation, eicosanoid metabolism, calcium flux, apoptosis, and morphology of the cardiovascular system. Our results indicate that surgical relief of dynamic outflow tract obstruction in HCM patients is associated with unique alterations in plasma proteomic profiles that likely reflect improvement in organ inflammation and physiological function. | Larson, Amy Libermann, Towia A Bowditch, Heather Das, Gaurav Diakos, Nikolaos Huggins, Gordon S Rastegar, Hassan Chen, Frederick Y Rowin, Ethan J Maron, Martin S Chin, Michael T eng UL1 TR002544/TR/NCATS NIH HHS/ F32HL147492/NH/NIH HHS/ UL1TR002544/NH/NIH HHS/ 18IPA34170294/American Heart Association/ Switzerland Int J Mol Sci. 2021 Mar 1;22(5):2474. doi: 10.3390/ijms22052474.I | 04/04/2021 | ||
| BET inhibition blocks inflammation-induced cardiac dysfunction and SARS-CoV-2 infection | Mills RJ, et al. | 2021 | Cell | 184 | 8 | 2167-2182 e22 | https://www.doi.org/10.1016/j.cell.2021.03.026 | 33,811,809 | Angiotensin-Converting Enzyme 2/metabolism Animals COVID-19/*complications/drug therapy Cardiotonic Agents/*therapeutic use Cell Cycle Proteins/*antagonists & inhibitors/metabolism Cell Line Cytokines/metabolism Female Heart Diseases/*drug therapy/etiology Human Embryonic Stem Cells Humans Inflammation/complications/drug therapy Mice Mice, Inbred C57BL Quinazolinones/*therapeutic use Transcription Factors/*antagonists & inhibitors/metabolism Bromodomain and extraterminal family inhibitors Covid-19 drug discovery heart inflammation organoids co-inventors on patents relating to cardiac organoid maturation and cardiac therapeutics. J.E.H. is co-inventor on licensed patents for engineered heart muscle. R.J.M., E.R.P., D.M.T., B.G., and J.E.H. are co-founders, scientific advisors, and stockholders in Dynomics. D.M.T. and B.G. are employees of Dynomics. C.H., D.G., L.F., J.J., M.S., N.C.W.W., and E.K. are employees of Resverlogix. S.J.N. received honoraria and research support from Resverlogix. QIMR Berghofer Medical Research Institute filed a patent on the use of BETi. | Cardiac injury and dysfunction occur in COVID-19 patients and increase the risk of mortality. Causes are ill defined but could be through direct cardiac infection and/or inflammation-induced dysfunction. To identify mechanisms and cardio-protective drugs, we use a state-of-the-art pipeline combining human cardiac organoids with phosphoproteomics and single nuclei RNA sequencing. We identify an inflammatory cytokine-storm", a cocktail of interferon gamma, interleukin 1beta, and poly(I:C), induced diastolic dysfunction. Bromodomain-containing protein 4 is activated along with a viral response that is consistent in both human cardiac organoids (hCOs) and hearts of SARS-CoV-2-infected K18-hACE2 mice. Bromodomain and extraterminal family inhibitors (BETi) recover dysfunction in hCOs and completely prevent cardiac dysfunction and death in a mouse cytokine-storm model. Additionally, BETi decreases transcription of genes in the viral response, decreases ACE2 expression, and reduces SARS-CoV-2 infection of cardiomyocytes. Together, BETi, including the Food and Drug Administration (FDA) breakthrough designated drug, apabetalone, are promising candidates to prevent COVID-19 mediated cardiac damage." | Mills, Richard J Humphrey, Sean J Fortuna, Patrick R J Lor, Mary Foster, Simon R Quaife-Ryan, Gregory A Johnston, Rebecca L Dumenil, Troy Bishop, Cameron Rudraraju, Rajeev Rawle, Daniel J Le, Thuy Zhao, Wei Lee, Leo Mackenzie-Kludas, Charley Mehdiabadi, Neda R Halliday, Christopher Gilham, Dean Fu, Li Nicholls, Stephen J Johansson, Jan Sweeney, Michael Wong, Norman C W Kulikowski, Ewelina Sokolowski, Kamil A Tse, Brian W C Devilee, Lynn Voges, Holly K Reynolds, Liam T Krumeich, Sophie Mathieson, Ellen Abu-Bonsrah, Dad Karavendzas, Kathy Griffen, Brendan Titmarsh, Drew Elliott, David A McMahon, James Suhrbier, Andreas Subbarao, Kanta Porrello, Enzo R Smyth, Mark J Engwerda, Christian R MacDonald, Kelli P A Bald, Tobias James, David E Hudson, James E eng Research Support, Non-U.S. Gov't Cell. 2021 Apr 15;184(8):2167-2182.e22. doi: 10.1016/j.cell.2021.03.026. Epub 2021 Mar 16.I | 04/04/2021 | |
| Advances in Aptamer-Based Biomarker Discovery | Huang J, et al. | 2021 | Front Cell Dev Biol | 9 | 659760 | https://www.doi.org/10.3389/fcell.2021.659760 | 33,796,540 | Cell-selex SOMAScan aptamer biomarker discovery human diseases commercial or financial relationships that could be construed as a potential conflict of interest. | The discovery and identification of biomarkers promote the rational and fast development of medical diagnosis and therapeutics. Clinically, the application of ideal biomarkers still is limited due to the suboptimal technology in biomarker discovery. Aptamers are single-stranded deoxyribonucleic acid or ribonucleic acid molecules and can selectively bind to varied targets with high affinity and specificity. Compared with antibody, aptamers have desirable advantages, such as flexible design, easy synthesis and convenient modification with different functional groups. Currently, different aptamer-based technologies have been developed to facilitate biomarker discovery, especially CELL-SELEX and SOMAScan technology. CELL-SELEX technology is mainly used to identify cell membrane surface biomarkers of various cells. SOMAScan technology is an unbiased biomarker detection method that can analyze numerous and even thousands of proteins in complex biological samples at the same time. It has now become a large-scale multi-protein biomarker discovery platform. In this review, we introduce the aptamer-based biomarker discovery technologies, and summarize and highlight the discovered emerging biomarkers recently in several diseases. | Huang, Jie Chen, Xinxin Fu, Xuekun Li, Zheng Huang, Yuhong Liang, Chao eng Review Switzerland Front Cell Dev Biol. 2021 Mar 16;9:659760. doi: 10.3389/fcell.2021.659760. eCollection 2021.I | 04/03/2021 | ||
| Replication study of plasma proteins relating to Alzheimer's pathology | Shi L, et al. | 2021 | Alzheimers Dement | 17 | 9 | 1452-1464 | https://www.doi.org/10.1002/alz.12322 | 33,792,144 | Aged *Alzheimer Disease/blood/pathology Amyloid beta-Peptides/*blood Apolipoprotein E4/blood/genetics Biomarkers/*blood *Blood Proteins Cognitive Dysfunction/blood/pathology Europe Female Humans Male Middle Aged *Proteomics tau Proteins/*blood ATN framework Alzheimer's disease biomarker dementia network analysis plasma proteomics replication | INTRODUCTION: This study sought to discover and replicate plasma proteomic biomarkers relating to Alzheimer's disease (AD) including both the ATN" (amyloid/tau/neurodegeneration) diagnostic framework and clinical diagnosis. METHODS: Plasma proteins from 972 subjects (372 controls, 409 mild cognitive impairment [MCI], and 191 AD) were measured using both SOMAscan and targeted assays, including 4001 and 25 proteins, respectively. RESULTS: Protein co-expression network analysis of SOMAscan data revealed the relation between proteins and "N" varied across different neurodegeneration markers, indicating that the ATN variants are not interchangeable. Using hub proteins, age, and apolipoprotein E epsilon4 genotype discriminated AD from controls with an area under the curve (AUC) of 0.81 and MCI convertors from non-convertors with an AUC of 0.74. Targeted assays replicated the relation of four proteins with the ATN framework and clinical diagnosis. DISCUSSION: Our study suggests that blood proteins can predict the presence of AD pathology as measured in the ATN framework as well as clinical diagnosis." | Shi, Liu Winchester, Laura M Westwood, Sarah Baird, Alison L Anand, Sneha N Buckley, Noel J Hye, Abdul Ashton, Nicholas J Bos, Isabelle Vos, Stephanie J B Kate, Mara Ten Scheltens, Philip Teunissen, Charlotte E Vandenberghe, Rik Gabel, Silvy Meersmans, Karen Engelborghs, Sebastiaan De Roeck, Ellen E Sleegers, Kristel Frisoni, Giovanni B Blin, Olivier Richardson, Jill C Bordet, Regis Molinuevo, Jose L Rami, Lorena Wallin, Anders Kettunen, Petronella Tsolaki, Magda Verhey, Frans Lleo, Alberto Sala, Isabel Popp, Julius Peyratout, Gwendoline Martinez-Lage, Pablo Tainta, Mikel Johannsen, Peter Freund-Levi, Yvonne Frolich, Lutz Dobricic, Valerija Legido-Quigley, Cristina Barkhof, Frederik Andreasson, Ulf Blennow, Kaj Zetterberg, Henrik Streffer, Johannes Lill, Christina M Bertram, Lars Visser, Pieter Jelle Kolb, Hartmuth C Narayan, Vaibhav A Lovestone, Simon Nevado-Holgado, Alejo J eng DH_/Department of Health/United Kingdom Research Support, Non-U.S. Gov't Alzheimers Dement. 2021 Sep;17(9):1452-1464. doi: 10.1002/alz.12322. Epub 2021 Mar 31.I | 04/02/2021 | |
| Proteomics in aging research: A roadmap to clinical, translational research | Moaddel R, et al. | 2021 | Aging Cell | 20 | 4 | e13325 | https://www.doi.org/10.1111/acel.13325 | 33,730,416 | Aging/*blood/genetics Animals Biomarkers/blood Gene Expression Regulation Geroscience/methods Humans Hypoxia-Inducible Factor 1, alpha Subunit/blood MAP Kinase Signaling System/*genetics Mitogen-Activated Protein Kinases/blood Prognosis Proteome/*metabolism Proteomics/*methods Translational Research, Biomedical/*methods aging geroscience human proteomics | The identification of plasma proteins that systematically change with age and, independent of chronological age, predict accelerated decline of health is an expanding area of research. Circulating proteins are ideal translational omics" since they are final effectors of physiological pathways and because physicians are accustomed to use information of plasma proteins as biomarkers for diagnosis, prognosis, and tracking the effectiveness of treatments. Recent technological advancements, including mass spectrometry (MS)-based proteomics, multiplexed proteomic assay using modified aptamers (SOMAscan), and Proximity Extension Assay (PEA, O-Link), have allowed for the assessment of thousands of proteins in plasma or other biological matrices, which are potentially translatable into new clinical biomarkers and provide new clues about the mechanisms by which aging is associated with health deterioration and functional decline. We carried out a detailed literature search for proteomic studies performed in different matrices (plasma, serum, urine, saliva, tissues) and species using multiple platforms. Herein, we identified 232 proteins that were age-associated across studies. Enrichment analysis of the 232 age-associated proteins revealed metabolic pathways previously connected with biological aging both in animal models and in humans, most remarkably insulin-like growth factor (IGF) signaling, mitogen-activated protein kinases (MAPK), hypoxia-inducible factor 1 (HIF1), cytokine signaling, Forkhead Box O (FOXO) metabolic pathways, folate metabolism, advance glycation end products (AGE), and receptor AGE (RAGE) metabolic pathway. Information on these age-relevant proteins, likely expanded and validated in longitudinal studies and examined in mechanistic studies, will be essential for patient stratification and the development of new treatments aimed at improving health expectancy." | Moaddel, Ruin Ubaida-Mohien, Ceereena Tanaka, Toshiko Lyashkov, Alexey Basisty, Nathan Schilling, Birgit Semba, Richard D Franceschi, Claudio Gorospe, Myriam Ferrucci, Luigi eng K99 AG065484/AG/NIA NIH HHS/ R01 AG057723/AG/NIA NIH HHS/ U01 AG060906/AG/NIA NIH HHS/ Research Support, N.I.H., Extramural Review England Aging Cell. 2021 Apr;20(4):e13325. doi: 10.1111/acel.13325. Epub 2021 Mar 17.I | 03/18/2021 | |
| Seroconversion stages COVID19 into distinct pathophysiological states | Galbraith MD, et al. | 2021 | Elife | 10 | https://www.doi.org/10.7554/eLife.65508 | 33,724,185 | Biomarkers COVID-19/*epidemiology/immunology/metabolism/*virology Comorbidity Complement Activation/immunology Complement System Proteins/immunology Hematopoiesis Homeostasis Hospitalization Humans Hypoalbuminemia Interferons/metabolism Models, Biological *SARS-CoV-2 *Seroconversion Seroepidemiologic Studies Signal Transduction Covid19 Sars antibodies complement cytokines human immunology inflammation interferons interests declared, KS is a co-inventor on two patents related to JAK inhibition in COVID19: U.S. Provisional Patent Application Serial No. 62/992,855 entitled 'JAK1 Inhibition For Modulation Of Overdrive Anti-Viral Response To COVID-19' U.S. Provisional Patent Application Serial No. 62/993,749 entitled 'Compounds and Methods for Inhibition or Modulation of Viral Hypercytokinemia'. JE Reviewing editor, eLife, is a co-inventor on two patents related to JAK inhibition in COVID19: U.S. Provisional Patent Application Serial No. 62/992,855 entitled 'JAK1 Inhibition For Modulation Of Overdrive Anti-Viral Response To COVID-19' U.S. Provisional Patent Application Serial No. 62/993,749 entitled 'Compounds and Methods for Inhibition or Modulation of Viral Hypercytokinemia'. | COVID19 is a heterogeneous medical condition involving diverse underlying pathophysiological processes including hyperinflammation, endothelial damage, thrombotic microangiopathy, and end-organ damage. Limited knowledge about the molecular mechanisms driving these processes and lack of staging biomarkers hamper the ability to stratify patients for targeted therapeutics. We report here the results of a cross-sectional multi-omics analysis of hospitalized COVID19 patients revealing that seroconversion status associates with distinct underlying pathophysiological states. Low antibody titers associate with hyperactive T cells and NK cells, high levels of IFN alpha, gamma and lambda ligands, markers of systemic complement activation, and depletion of lymphocytes, neutrophils, and platelets. Upon seroconversion, all of these processes are attenuated, observing instead increases in B cell subsets, emergency hematopoiesis, increased D-dimer, and hypoalbuminemia. We propose that seroconversion status could potentially be used as a biosignature to stratify patients for therapeutic intervention and to inform analysis of clinical trial results in heterogenous patient populations. | Galbraith, Matthew D Kinning, Kohl T Sullivan, Kelly D Baxter, Ryan Araya, Paula Jordan, Kimberly R Russell, Seth Smith, Keith P Granrath, Ross E Shaw, Jessica R Dzieciatkowska, Monika Ghosh, Tusharkanti Monte, Andrew A D'Alessandro, Angelo Hansen, Kirk C Benett, Tellen D Hsieh, Elena Wy Espinosa, Joaquin M eng RM1GM131968/GM/NIGMS NIH HHS/ R01 AI150305/AI/NIAID NIH HHS/ R01AI150305/National Institute of Allergy and Infectious Diseases/ R01HL149714/HL/NHLBI NIH HHS/ R01HL148151/HL/NHLBI NIH HHS/ 3R01AI150305-01S1/National Institute of Allergy and Infectious Diseases/ UL1TR002535/TR/NCATS NIH HHS/ R21HL150032/HL/NHLBI NIH HHS/ 3UL1TR002535-03S2/TR/NCATS NIH HHS/ R35GM124939/GM/NIGMS NIH HHS/ P30CA046934/CA/NCI NIH HHS/ R01AI145988/National Institute of Allergy and Infectious Diseases/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't England Elife. 2021 Mar 16;10:e65508. doi: 10.7554/eLife.65508.I | 03/17/2021 | |||
| Vitamin D Association With Macrophage-Derived Cytokines in Polycystic Ovary Syndrome: An Enhanced Risk of COVID-19 Infection? | Moin ASM, et al. | 2021 | Front Endocrinol (Lausanne) | 12 | 638621 | https://www.doi.org/10.3389/fendo.2021.638621 | 33,716,989 | Adult Biomarkers/analysis Blood Proteins/analysis Body Mass Index COVID-19/complications/*epidemiology/immunology Cross-Sectional Studies Cytokines/*metabolism Female Humans Macrophage Activation Macrophages/chemistry/*metabolism Polycystic Ovary Syndrome/complications/*epidemiology/immunology Risk Assessment Tandem Mass Spectrometry Vitamin D/blood Vitamin D Deficiency/complications/*epidemiology COVID-19 risk factors cytokines macrophage polycystic ovary disease vitamin D commercial or financial relationships that could be construed as a potential conflict of interest. | BACKGROUND: Women with polycystic ovary syndrome (PCOS) often have vitamin D deficiency, a known risk factor for severe COVID-19 disease. Alveolar macrophage-derived cytokines contribute to the inflammation underlying pulmonary disease in COVID-19. We sought to determine if basal macrophage activation, as a risk factor for COVID-19 infection, was present in PCOS and, if so, was further enhanced by vitamin D deficiency. METHODS: A cross-sectional study in 99 PCOS and 68 control women who presented sequentially. Plasma levels of a macrophage-derived cytokine panel were determined by Slow Off-rate Modified Aptamer (SOMA)-scan plasma protein measurement. Vitamin D was measured by tandem mass spectroscopy. RESULTS: Vitamin D was lower in PCOS women (p<0.0001) and correlated negatively with body mass index (BMI) in PCOS (r=0.28, p=0.0046). Basal macrophage activation markers CXCL5, CD163 and MMP9 were elevated, whilst protective CD200 was decreased (p<0.05); changes in these variables were related to, and fully accounted for, by BMI. PCOS and control women were then stratified according to vitamin D concentration. Vitamin D deficiency was associated with decreased CD80 and IFN-gamma in PCOS and IL-12 in both groups (p<0.05). These factors, important in initiating and maintaining the immune response, were again accounted for by BMI. CONCLUSION: Basal macrophage activation was higher in PCOS with macrophage changes related with increased infection risk associating with vitamin D; all changes were BMI dependent, suggesting that obese PCOS with vitamin D deficiency may be at greater risk of more severe COVID-19 infection, but that it is obesity-related rather than an independent PCOS factor. | Moin, Abu Saleh Md Sathyapalan, Thozhukat Butler, Alexandra E Atkin, Stephen L eng Switzerland Front Endocrinol (Lausanne). 2021 Feb 25;12:638621. doi: 10.3389/fendo.2021.638621. eCollection 2021.I | 03/16/2021 | ||
| Metabolic consequences of obesity on the hypercoagulable state of polycystic ovary syndrome | Moin ASM, et al. | 2021 | Sci Rep | 11 | 1 | 5320 | https://www.doi.org/10.1038/s41598-021-84586-y | 33,674,695 | Adult Biomarkers/*blood Body Mass Index Female Humans Inflammation/metabolism Insulin Resistance Obesity/*metabolism Polycystic Ovary Syndrome/*metabolism Risk Factors Young Adult | Polycystic ovary syndrome (PCOS) women have a hypercoagulable state; however, whether this is intrinsically due to PCOS or, alternatively, a consequence of its metabolic complications is unclear. We determined plasma coagulation pathway protein levels in PCOS (n = 146) and control (n = 97) women recruited to a PCOS biobank. Circulating levels of a panel of 18 clotting pathway proteins were determined by Slow Off-rate Modified Aptamer-scan plasma protein measurement. Cohorts were age matched, though PCOS had elevated body mass index (p < 0.001), insulin (p < 0.001) and C-reactive protein (CRP) (p < 0.0001). Eight pro-coagulation proteins were elevated in PCOS: plasminogen activator inhibitor-1 (p < 0.0001), fibrinogen (p < 0.01), fibrinogen gamma chain (p < 0.0001), fibronectin (p < 0.01), von Willebrand factor (p < 0.05), D-dimer (p < 0.0001), P-selectin (p < 0.05), and plasma kallikrein (p < 0.001). However, two anticoagulant proteins, vitamin K-dependent protein-S (p < 0.0001) and heparin cofactor-II (p < 0.001) were elevated and prothrombin was decreased (p < 0.05). CRP, as a marker of inflammation, and insulin resistance (HOMA-IR) correlated with 11 and 6 of the clotting proteins, respectively (p < 0.05). When matched for BMI < 25 (16 PCOS, 53 controls) HOMA-IR remained elevated (p < 0.05) and heparin cofactor-II was increased (p < 0.05). In a multivariate analysis accounting for inflammation, insulin resistance and BMI, there was no correlation of PCOS with any of the coagulation proteins. The hypercoagulable state in PCOS is not intrinsic to the disease as it can be fully accounted for by BMI, inflammation and insulin resistance. | Moin, Abu Saleh Md Sathyapalan, Thozhukat Diboun, Ilhame Elrayess, Mohamed A Butler, Alexandra E Atkin, Stephen L eng England Sci Rep. 2021 Mar 5;11(1):5320. doi: 10.1038/s41598-021-84586-y.I | 03/07/2021 | |
| Quantitative Proteomic Analysis of Diabetes Mellitus in Heart Failure With Preserved Ejection Fraction | Hanff TC, et al. | 2021 | JACC Basic Transl Sci | 6 | 2 | 89-99 | https://www.doi.org/10.1016/j.jacbts.2020.11.011 | 33,665,511 | ApoM, apolipoprotein M CI, confidence interval CILP2, cartilage intermediate layer protein 2 DM, diabetes mellitus HFpEF, heart failure with preserved ejection fraction HR, hazard ratio LASSO, least absolute shrinkage and selection operator apolipoprotein M diabetes heart failure mediation analysis proteomics Cohen is supported by K23-HL133843. Dr. Javaheri is supported by K08-HL138262. Dr. Zamani is supported by grant K23-HL-13055. Dr. Chirinos is supported by a research grant from Bristol-Myers Squibb and by grants R01-HL 121510- 01A1, R61-HL-146390, R01-AG058969, 1R01-HL104106, P01-HL094307, R03-HL146874-01, and R56-HL136730. Dr. Javaheri has been named co-inventor on the patent application for the use of fusion protein nanodiscs for the treatment of heart failure. Drs. Zhao, Walsh, Maranville, Wang, Adam, Ramirez-Valle, Schafer, Seiffert, Gordon, and Cvijic own stock in Bristol-Myers Squibb. Dr. Cappola has received research funding from Bristol-Myers Squibb. Dr. Zamani has consulted for Vyaire. Dr. Chirinos has been a consultant for Sanifit, Microsoft, Fukuda-Denshi, Bristol-Myers Squibb, OPKO Healthcare, Ironwood Pharmaceuticals, Pfizer, Akros Pharma, Merck, Bayer, JNJ, and Edwards Life Sciences and received research grants from National Institutes of Health, American College of Radiology Network, Fukuda Denshi, Bristol-Myers Squibb, and Microsoft, and has been named as inventor in a University of Pennsylvania patent for the use of inorganic nitrates/nitrites for the treatment of heart failure and preserved ejection fraction. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. | Diabetes mellitus (DM) is associated with a higher risk of heart failure hospitalization and mortality in patients with heart failure with preserved ejection fraction (HFpEF). Using SomaScan assays and proteomics analysis of plasma from participants in the TOPCAT (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist) trial and the Penn Heart Failure Study, this study identified 10 proteins with significantly different expression in patients with HFpEF and DM. Of these, apolipoprotein M was found to mediate 72% (95% CI: 36% to 100%; p < 0.001) of the association between DM and the risk of cardiovascular death, aborted cardiac arrest, and heart failure hospitalization. | Hanff, Thomas C Cohen, Jordana B Zhao, Lei Javaheri, Ali Zamani, Payman Prenner, Stuart B Rietzschel, Ernst Jia, Yi Walsh, Alice Maranville, Joseph Wang, Zhaoqing Adam, Leonard Ramirez-Valle, Francisco Schafer, Peter Seiffert, Dietmar Gordon, David A Cvijic, Mary E Cappola, Thomas P Chirinos, Julio A eng K08 HL138262/HL/NHLBI NIH HHS/ P30 DK056341/DK/NIDDK NIH HHS/ JACC Basic Transl Sci. 2021 Feb 10;6(2):89-99. doi: 10.1016/j.jacbts.2020.11.011. eCollection 2021 Feb.I | 03/06/2021 | |
| A Neanderthal OAS1 isoform protects individuals of European ancestry against COVID-19 susceptibility and severity | Zhou S, et al. | 2021 | Nat Med | 27 | 4 | 659-667 | https://www.doi.org/10.1038/s41591-021-01281-1 | 33,633,408 | 2',5'-Oligoadenylate Synthetase/genetics/*physiology Aged Aged, 80 and over Animals COVID-19/*etiology/genetics Case-Control Studies Female *Genetic Predisposition to Disease Humans Interleukin-10 Receptor beta Subunit/genetics Male Mendelian Randomization Analysis Middle Aged Neanderthals Protein Isoforms/physiology Quantitative Trait Loci *SARS-CoV-2 Severity of Illness Index Whites | To identify circulating proteins influencing Coronavirus Disease 2019 (COVID-19) susceptibility and severity, we undertook a two-sample Mendelian randomization (MR) study, rapidly scanning hundreds of circulating proteins while reducing bias due to reverse causation and confounding. In up to 14,134 cases and 1.2 million controls, we found that an s.d. increase in OAS1 levels was associated with reduced COVID-19 death or ventilation (odds ratio (OR) = 0.54, P = 7 x 10(-8)), hospitalization (OR = 0.61, P = 8 x 10(-8)) and susceptibility (OR = 0.78, P = 8 x 10(-6)). Measuring OAS1 levels in 504 individuals, we found that higher plasma OAS1 levels in a non-infectious state were associated with reduced COVID-19 susceptibility and severity. Further analyses suggested that a Neanderthal isoform of OAS1 in individuals of European ancestry affords this protection. Thus, evidence from MR and a case-control study support a protective role for OAS1 in COVID-19 adverse outcomes. Available pharmacological agents that increase OAS1 levels could be prioritized for drug development. | Zhou, Sirui Butler-Laporte, Guillaume Nakanishi, Tomoko Morrison, David R Afilalo, Jonathan Afilalo, Marc Laurent, Laetitia Pietzner, Maik Kerrison, Nicola Zhao, Kaiqiong Brunet-Ratnasingham, Elsa Henry, Danielle Kimchi, Nofar Afrasiabi, Zaman Rezk, Nardin Bouab, Meriem Petitjean, Louis Guzman, Charlotte Xue, Xiaoqing Tselios, Chris Vulesevic, Branka Adeleye, Olumide Abdullah, Tala Almamlouk, Noor Chen, Yiheng Chasse, Michael Durand, Madeleine Paterson, Clare Normark, Johan Frithiof, Robert Lipcsey, Miklos Hultstrom, Michael Greenwood, Celia M T Zeberg, Hugo Langenberg, Claudia Thysell, Elin Pollak, Michael Mooser, Vincent Forgetta, Vincenzo Kaufmann, Daniel E Richards, J Brent eng MC_UU_00006/1/MRC_/Medical Research Council/United Kingdom Research Support, Non-U.S. Gov't Nat Med. 2021 Apr;27(4):659-667. doi: 10.1038/s41591-021-01281-1. Epub 2021 Feb 25.I | 02/27/2021 | |
| Revealing the role of the human blood plasma proteome in obesity using genetic drivers | Zaghlool SB, et al. | 2021 | Nat Commun | 12 | 1 | 1279 | https://www.doi.org/10.1038/s41467-021-21542-4 | 33,627,659 | Adult Aged Body Mass Index Female Humans Lipid Metabolism/genetics/physiology Male Mendelian Randomization Analysis Middle Aged Obesity/genetics/*metabolism Proteome/*metabolism Proteomics/methods | Blood circulating proteins are confounded readouts of the biological processes that occur in different tissues and organs. Many proteins have been linked to complex disorders and are also under substantial genetic control. Here, we investigate the associations between over 1000 blood circulating proteins and body mass index (BMI) in three studies including over 4600 participants. We show that BMI is associated with widespread changes in the plasma proteome. We observe 152 replicated protein associations with BMI. 24 proteins also associate with a genome-wide polygenic score (GPS) for BMI. These proteins are involved in lipid metabolism and inflammatory pathways impacting clinically relevant pathways of adiposity. Mendelian randomization suggests a bi-directional causal relationship of BMI with LEPR/LEP, IGFBP1, and WFIKKN2, a protein-to-BMI relationship for AGER, DPT, and CTSA, and a BMI-to-protein relationship for another 21 proteins. Combined with animal model and tissue-specific gene expression data, our findings suggest potential therapeutic targets further elucidating the role of these proteins in obesity associated pathologies. | Zaghlool, Shaza B Sharma, Sapna Molnar, Megan Matias-Garcia, Pamela R Elhadad, Mohamed A Waldenberger, Melanie Peters, Annette Rathmann, Wolfgang Graumann, Johannes Gieger, Christian Grallert, Harald Suhre, Karsten eng Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't England Nat Commun. 2021 Feb 24;12(1):1279. doi: 10.1038/s41467-021-21542-4.I | 02/26/2021 | |
| Blood biomarker discovery for autism spectrum disorder: A proteomic analysis | Hewitson L, et al. | 2021 | PLoS One | 16 | 2 | e0246581 | https://www.doi.org/10.1371/journal.pone.0246581 | 33,626,076 | Algorithms Area Under Curve Autism Spectrum Disorder/*metabolism Biomarkers/metabolism Communication Humans Machine Learning Proteomics/*methods | Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by deficits in social communication and social interaction and restricted, repetitive patterns of behavior, interests, or activities. Given the lack of specific pharmacological therapy for ASD and the clinical heterogeneity of the disorder, current biomarker research efforts are geared mainly toward identifying markers for determining ASD risk or for assisting with a diagnosis. A wide range of putative biological markers for ASD is currently being investigated. Proteomic analyses indicate that the levels of many proteins in plasma/serum are altered in ASD, suggesting that a panel of proteins may provide a blood biomarker for ASD. Serum samples from 76 boys with ASD and 78 typically developing (TD) boys, 18 months-8 years of age, were analyzed to identify possible early biological markers for ASD. Proteomic analysis of serum was performed using SomaLogic's SOMAScanTM assay 1.3K platform. A total of 1,125 proteins were analyzed. There were 86 downregulated proteins and 52 upregulated proteins in ASD (FDR < 0.05). Combining three different algorithms, we found a panel of 9 proteins that identified ASD with an area under the curve (AUC) = 0.8599+/-0.0640, with specificity and sensitivity of 0.8217+/-0.1178 and 0.835+/-0.1176, respectively. All 9 proteins were significantly different in ASD compared with TD boys, and were significantly correlated with ASD severity as measured by ADOS total scores. Using machine learning methods, a panel of serum proteins was identified that may be useful as a blood biomarker for ASD in boys. Further verification of the protein biomarker panel with independent test sets is warranted. | Hewitson, Laura Mathews, Jeremy A Devlin, Morgan Schutte, Claire Lee, Jeon German, Dwight C eng Research Support, Non-U.S. Gov't PLoS One. 2021 Feb 24;16(2):e0246581. doi: 10.1371/journal.pone.0246581. eCollection 2021.I | 02/25/2021 | |
| Biomarker-focused multi-drug combination therapy and repurposing trial in mdx mice | Ziemba M, et al. | 2021 | PLoS One | 16 | 2 | e0246507 | https://www.doi.org/10.1371/journal.pone.0246507 | 33,617,542 | Aminoisobutyric Acids/therapeutic use Animals Biomarkers Disease Models, Animal Drug Repositioning Male Mice Mice, Inbred mdx Muscular Dystrophy, Animal/*drug therapy Muscular Dystrophy, Duchenne/*drug therapy Prednisolone/therapeutic use Pregnadienediols/therapeutic use Rituximab/therapeutic use | Duchenne muscular dystrophy is initiated by dystrophin deficiency, but downstream pathophysiological pathways such as membrane instability, NFkB activation, mitochondrial dysfunction, and induction of TGFbeta fibrosis pathways are thought to drive the disability. Dystrophin replacement strategies are hopeful for addressing upstream dystrophin deficiency; however, all methods to date use semi-functional dystrophin proteins that are likely to trigger downstream pathways. Thus, combination therapies that can target multiple downstream pathways are important in treating DMD, even for dystrophin-replacement strategies. We sought to define blood pharmacodynamic biomarkers of drug response in the mdx mouse model of Duchenne muscular dystrophy using a series of repurposed drugs. Four-week-old mdx mice were treated for four weeks with four different drugs singly and in combination: vehicle, prednisolone, vamorolone, rituximab, beta-aminoisobutyric acid (BAIBA) (11 treatment groups; n = 6/group). Blood was collected via cardiac puncture at study termination, and proteomic profiling was carried out using SOMAscan aptamer panels (1,310 proteins assayed). Prednisolone was tested alone and in combination with other drugs. It was found to have a good concordance of prednisolone-responsive biomarkers (56 increased by prednisolone, 39 decreased) focused on NFkappaB and TGFbeta cascades. Vamorolone shared 45 (80%) of increased biomarkers and 13 (33%) of decreased biomarkers with prednisolone. Comparison of published human corticosteroid-responsive biomarkers to our mdx data showed 14% (3/22) concordance between mouse and human. Rituximab showed fewer drug-associated biomarkers, with the most significant being human IgG. On the other hand, BAIBA treatment (high and low dose) showed a drug-associated increase in 40 serum proteins and decreased 5 serum proteins. Our results suggest that a biomarker approach could be employed for assessing drug combinations in both mouse and human studies. | Ziemba, Michael Barkhouse, Molly Uaesoontrachoon, Kitipong Giri, Mamta Hathout, Yetrib Dang, Utkarsh J Gordish-Dressman, Heather Nagaraju, Kanneboyina Hoffman, Eric P eng Research Support, Non-U.S. Gov't PLoS One. 2021 Feb 22;16(2):e0246507. doi: 10.1371/journal.pone.0246507. eCollection 2021.I | 02/23/2021 | |
| Multi-omics highlights ABO plasma protein as a causal risk factor for COVID-19 | Hernandez Cordero AI, et al. | 2021 | Hum Genet | 140 | 6 | 969-979 | https://www.doi.org/10.1007/s00439-021-02264-5 | 33,604,698 | ABO Blood-Group System/metabolism Blood Proteins/*metabolism COVID-19/*epidemiology/metabolism/virology Cohort Studies *Genetic Predisposition to Disease Genome-Wide Association Study Humans Lung/*metabolism Mendelian Randomization Analysis *Polymorphism, Single Nucleotide *Quantitative Trait Loci Risk Factors SARS-CoV-2/*isolation & purification | SARS-CoV-2 is responsible for the coronavirus disease 2019 (COVID-19) and the current health crisis. Despite intensive research efforts, the genes and pathways that contribute to COVID-19 remain poorly understood. We, therefore, used an integrative genomics (IG) approach to identify candidate genes responsible for COVID-19 and its severity. We used Bayesian colocalization (COLOC) and summary-based Mendelian randomization to combine gene expression quantitative trait loci (eQTLs) from the Lung eQTL (n = 1,038) and eQTLGen (n = 31,784) studies with published COVID-19 genome-wide association study (GWAS) data from the COVID-19 Host Genetics Initiative. Additionally, we used COLOC to integrate plasma protein quantitative trait loci (pQTL) from the INTERVAL study (n = 3,301) with COVID-19 loci. Finally, we determined any causal associations between plasma proteins and COVID-19 using multi-variable two-sample Mendelian randomization (MR). The expression of 18 genes in lung and/or blood co-localized with COVID-19 loci. Of these, 12 genes were in suggestive loci (P(GWAS) < 5 x 10(-05)). LZTFL1, SLC6A20, ABO, IL10RB and IFNAR2 and OAS1 had been previously associated with a heightened risk of COVID-19 (P(GWAS) < 5 x 10(-08)). We identified a causal association between OAS1 and COVID-19 GWAS. Plasma ABO protein, which is associated with blood type in humans, demonstrated a significant causal relationship with COVID-19 in the MR analysis; increased plasma levels were associated with an increased risk of COVID-19 and, in particular, severe COVID-19. In summary, our study identified genes associated with COVID-19 that may be prioritized for future investigations. Importantly, this is the first study to demonstrate a causal association between plasma ABO protein and COVID-19. | Hernandez Cordero, Ana I Li, Xuan Milne, Stephen Yang, Chen Xi Bosse, Yohan Joubert, Philippe Timens, Wim van den Berge, Maarten Nickle, David Hao, Ke Sin, Don D eng Germany Hum Genet. 2021 Jun;140(6):969-979. doi: 10.1007/s00439-021-02264-5. Epub 2021 Feb 19.I | 02/20/2021 | |
| A meta-analysis uncovers the first sequence variant conferring risk of Bell's palsy | Skuladottir AT, et al. | 2021 | Sci Rep | 11 | 1 | 4188 | https://www.doi.org/10.1038/s41598-021-82736-w | 33,602,968 | Adult Aged Bell Palsy/*genetics Facial Muscles/pathology Facial Nerve/pathology Facial Paralysis/genetics Female Genome-Wide Association Study/methods Humans Inflammation/genetics Male Middle Aged Movement/physiology Prospective Studies Risk | Bell's palsy is the most common cause of unilateral facial paralysis and is defined as an idiopathic and acute inability to control movements of the facial muscles on the affected side. While the pathogenesis remains unknown, previous studies have implicated post-viral inflammation and resulting compression of the facial nerve. Reported heritability estimates of 4-14% suggest a genetic component in the etiology and an autosomal dominant inheritance has been proposed. Here, we report findings from a meta-analysis of genome-wide association studies uncovering the first unequivocal association with Bell's palsy (rs9357446-A; P = 6.79 x 10(-23), OR = 1.23; N(cases) = 4714, N(controls) = 1,011,520). The variant also confers risk of intervertebral disc disorders (P = 2.99 x 10(-11), OR = 1.04) suggesting a common pathogenesis in part or a true pleiotropy. | Skuladottir, Astros Th Bjornsdottir, Gyda Thorleifsson, Gudmar Walters, G Bragi Nawaz, Muhammad Sulaman Moore, Kristjan Helgi Swerford Olason, Pall I Thorgeirsson, Thorgeir E Sigurpalsdottir, Brynja Sveinbjornsson, Gardar Eggertsson, Hannes P Magnusson, Sigurdur H Oddsson, Asmundur Bjornsdottir, Anna Vikingsson, Arnor Sveinsson, Olafur A Hrafnsdottir, Maria G Sigurdardottir, Gudrun R Halldorsson, Bjarni V Hansen, Thomas Folkmann Paarup, Helene Erikstrup, Christian Nielsen, Kaspar Klokker, Mads Bruun, Mie Topholm Sorensen, Erik Banasik, Karina Burgdorf, Kristoffer S Pedersen, Ole Birger Ullum, Henrik Jonsdottir, Ingileif Stefansson, Hreinn Stefansson, Kari eng R01 DE022905/DE/NIDCR NIH HHS/ Meta-Analysis Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't England Sci Rep. 2021 Feb 18;11(1):4188. doi: 10.1038/s41598-021-82736-w.I | 02/20/2021 | |
| In-Depth Analysis of the Plasma Proteome in ME/CFS Exposes Disrupted Ephrin-Eph and Immune System Signaling | Germain A, et al. | 2021 | Proteomes | 9 | 1 | https://www.doi.org/10.3390/proteomes9010006 | 33,572,894 | Me/cfs SOMAscan(R) adherens junction diagnosis ephrin-Eph pathway glucose immune metabolism plasma proteomics | Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a disabling disease with worldwide prevalence and limited therapies exclusively aimed at treating symptoms. To gain insights into the molecular disruptions in ME/CFS, we utilized an aptamer-based technology that quantified 4790 unique human proteins, allowing us to obtain the largest proteomics dataset yet available for this disease, detecting highly abundant proteins as well as rare proteins over a nine-log dynamic range. We report a pilot study of 20 ME/CFS patients and 20 controls, all females. Significant differences in the levels of 19 proteins between cohorts implicate pathways related to the extracellular matrix, the immune system and cell-cell communication. Outputs of pathway and cluster analyses robustly highlight the ephrin pathway, which is involved in cell-cell signaling and regulation of an expansive variety of biological processes, including axon guidance, angiogenesis, epithelial cell migration, and immune response. Receiver Operating Characteristic (ROC) curve analyses distinguish the plasma proteomes of ME/CFS patients from controls with a high degree of accuracy (Area Under the Curve (AUC) > 0.85), and even higher when using protein ratios (AUC up to 0.95), that include some protein pairs with established biological relevance. Our results illustrate the promise of plasma proteomics for diagnosing and deciphering the molecular basis of ME/CFS. | Germain, Arnaud Levine, Susan M Hanson, Maureen R eng U54 NS105541/NS/NINDS NIH HHS/ R01AI107762/National Institute of Allergy and Infectious Diseases/ Seed funds/Cornell University/ Switzerland Proteomes. 2021 Jan 29;9(1):6. doi: 10.3390/proteomes9010006.I | 02/13/2021 | ||
| Evaluating the effects of cardiometabolic exposures on circulating proteins which may contribute to severe SARS-CoV-2 | Richardson TG, et al. | 2021 | EBioMedicine | 64 | 103228 | https://www.doi.org/10.1016/j.ebiom.2021.103228 | 33,548,839 | Biomarkers/blood Body Mass Index C-Reactive Protein/genetics/metabolism COVID-19/*blood/genetics Cardiovascular Diseases/*blood/genetics Female Genome-Wide Association Study Humans Interleukin-1/blood/genetics Interleukin-6/blood/genetics Male SARS-CoV-2/genetics/*metabolism Severity of Illness Index Cardiometabolic risk factors Circulating proteins Covid19 Mendelian randomization SARS-CoV-2 research, and in adherence to the University of Oxford's Clinical Trial Service Unit & Epidemiological Studies Unit (CSTU) staff policy, did not accept personal honoraria or other payments from pharmaceutical companies. All other authors declare no conflicts of interest. | BACKGROUND: Developing insight into the pathogenesis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is of critical importance to overcome the global pandemic caused by coronavirus disease 2019 (covid-19). In this study, we have applied Mendelian randomization (MR) to systematically evaluate the effect of 10 cardiometabolic risk factors and genetic liability to lifetime smoking on 97 circulating host proteins postulated to either interact or contribute to the maladaptive host response of SARS-CoV-2. METHODS: We applied the inverse variance weighted (IVW) approach and several robust MR methods in a two-sample setting to systemically estimate the genetically predicted effect of each risk factor in turn on levels of each circulating protein. Multivariable MR was conducted to simultaneously evaluate the effects of multiple risk factors on the same protein. We also applied MR using cis-regulatory variants at the genomic location responsible for encoding these proteins to estimate whether their circulating levels may influence severe SARS-CoV-2. FINDINGS: In total, we identified evidence supporting 105 effects between risk factors and circulating proteins which were robust to multiple testing corrections and sensitivity analyzes. For example, body mass index provided evidence of an effect on 23 circulating proteins with a variety of functions, such as inflammatory markers c-reactive protein (IVW Beta=0.34 per standard deviation change, 95% CI=0.26 to 0.41, P = 2.19 x 10(-16)) and interleukin-1 receptor antagonist (IVW Beta=0.23, 95% CI=0.17 to 0.30, P = 9.04 x 10(-12)). Further analyzes using multivariable MR provided evidence that the effect of BMI on lowering immunoglobulin G, an antibody class involved in protection from infection, is substantially mediated by raised triglycerides levels (IVW Beta=-0.18, 95% CI=-0.25 to -0.12, P = 2.32 x 10(-08), proportion mediated=44.1%). The strongest evidence that any of the circulating proteins highlighted by our initial analysis influence severe SARS-CoV-2 was identified for soluble glycoprotein 130 (odds ratio=1.81, 95% CI=1.25 to 2.62, P = 0.002), a signal transductor for interleukin-6 type cytokines which are involved in inflammatory response. However, based on current case samples for severe SARS-CoV-2 we were unable to replicate findings in independent samples. INTERPRETATION: Our findings highlight several key proteins which are influenced by established exposures for disease. Future research to determine whether these circulating proteins mediate environmental effects onto risk of SARS-CoV-2 infection or covid-19 progression are warranted to help elucidate therapeutic strategies for severe covid-19 disease. FUNDING: The Medical Research Council, the Wellcome Trust, the British Heart Foundation and UK Research and Innovation. | Richardson, Tom G Fang, Si Mitchell, Ruth E Holmes, Michael V Davey Smith, George eng MC_UU_00011/1/MRC_/Medical Research Council/United Kingdom MR/S003886/1/MRC_/Medical Research Council/United Kingdom Evaluation Study Netherlands EBioMedicine. 2021 Feb;64:103228. doi: 10.1016/j.ebiom.2021.103228. Epub 2021 Feb 3.I | 02/07/2021 | ||
| A replication-competent adenovirus-vectored influenza vaccine induces durable systemic and mucosal immunity | Matsuda K, et al. | 2021 | J Clin Invest | 131 | 5 | https://www.doi.org/10.1172/JCI140794 | 33,529,172 | Adenoviruses, Human/*genetics/immunology/physiology Administration, Oral Adolescent Adult Antibodies, Neutralizing/blood Antibodies, Viral/blood Antigens, Viral/genetics Female *Genetic Vectors Hemagglutinin Glycoproteins, Influenza Virus/genetics/immunology Humans Immunity, Cellular Immunity, Humoral Immunity, Mucosal Influenza A Virus, H5N1 Subtype/genetics/immunology Influenza Vaccines/*administration & dosage/genetics/*immunology Influenza, Human/immunology/prevention & control Male Nasal Sprays Palatine Tonsil Virus Replication Virus Shedding Young Adult Adaptive immunity Beta cells Immunology Influenza Vaccines adenovirus type 4 SAR-CoV-2 vaccines and their use | BACKGROUNDTo understand the features of a replicating vaccine that might drive potent and durable immune responses to transgene-encoded antigens, we tested a replication-competent adenovirus type 4 encoding influenza virus H5 HA (Ad4-H5-Vtn) administered as an oral capsule or via tonsillar swab or nasal spray.METHODSViral shedding from the nose, mouth, and rectum was measured by PCR and culturing. H5-specific IgG and IgA antibodies were measured by bead array binding assays. Serum antibodies were measured by a pseudovirus entry inhibition, microneutralization, and HA inhibition assays.RESULTSAd4-H5-Vtn DNA was shed from most upper respiratory tract-immunized (URT-immunized) volunteers for 2 to 4 weeks, but cultured from only 60% of participants, with a median duration of 1 day. Ad4-H5-Vtn vaccination induced increases in H5-specific CD4+ and CD8+ T cells in the peripheral blood as well as increases in IgG and IgA in nasal, cervical, and rectal secretions. URT immunizations induced high levels of serum neutralizing antibodies (NAbs) against H5 that remained stable out to week 26. The duration of viral shedding correlated with the magnitude of the NAb response at week 26. Adverse events (AEs) were mild, and peak NAb titers were associated with overall AE frequency and duration. Serum NAb titers could be boosted to very high levels 2 to 5 years after Ad4-H5-Vtn vaccination with recombinant H5 or inactivated split H5N1 vaccine.CONCLUSIONReplicating Ad4 delivered to the URT caused prolonged exposure to antigen, drove durable systemic and mucosal immunity, and proved to be a promising platform for the induction of immunity against viral surface glycoprotein targets.TRIAL REGISTRATIONClinicalTrials.gov NCT01443936 and NCT01806909.FUNDINGIntramural and Extramural Research Programs of the NIAID, NIH (U19 AI109946) and the Centers of Excellence for Influenza Research and Surveillance (CEIRS), NIAID, NIH (contract HHSN272201400008C). | Matsuda, Kenta Migueles, Stephen A Huang, Jinghe Bolkhovitinov, Lyuba Stuccio, Sarah Griesman, Trevor Pullano, Alyssa A Kang, Byong H Ishida, Elise Zimmerman, Matthew Kashyap, Neena Martins, Kelly M Stadlbauer, Daniel Pederson, Jessica Patamawenu, Andy Wright, Nathaniel Shofner, Tulley Evans, Sean Liang, C Jason Candia, Julian Biancotto, Angelique Fantoni, Giovanna Poole, April Smith, Jon Alexander, Jeff Gurwith, Marc Krammer, Florian Connors, Mark eng HHSN272201400008C/AI/NIAID NIH HHS/ U19 AI109946/AI/NIAID NIH HHS/ Clinical Trial, Phase I Randomized Controlled Trial Research Support, N.I.H., Intramural Research Support, Non-U.S. Gov't J Clin Invest. 2021 Mar 1;131(5):e140794. doi: 10.1172/JCI140794.I | 02/03/2021 | ||
| Protein signatures of centenarians and their offspring suggest centenarians age slower than other humans | Sebastiani P, et al. | 2021 | Aging Cell | 20 | 2 | e13290 | https://www.doi.org/10.1111/acel.13290 | 33,512,769 | Aged Aged, 80 and over *Aging Blood Proteins/*metabolism Cellular Senescence Humans SomaLogic aging longevity protein senescence and stockholder of Regeneron Pharmaceuticals. | Using samples from the New England Centenarian Study (NECS), we sought to characterize the serum proteome of 77 centenarians, 82 centenarians' offspring, and 65 age-matched controls of the offspring (mean ages: 105, 80, and 79 years). We identified 1312 proteins that significantly differ between centenarians and their offspring and controls (FDR < 1%), and two different protein signatures that predict longer survival in centenarians and in younger people. By comparing the centenarian signature with 2 independent proteomic studies of aging, we replicated the association of 484 proteins of aging and we identified two serum protein signatures that are specific of extreme old age. The data suggest that centenarians acquire similar aging signatures as seen in younger cohorts that have short survival periods, suggesting that they do not escape normal aging markers, but rather acquire them much later than usual. For example, centenarian signatures are significantly enriched for senescence-associated secretory phenotypes, consistent with those seen with younger aged individuals, and from this finding, we provide a new list of serum proteins that can be used to measure cellular senescence. Protein co-expression network analysis suggests that a small number of biological drivers may regulate aging and extreme longevity, and that changes in gene regulation may be important to reach extreme old age. This centenarian study thus provides additional signatures that can be used to measure aging and provides specific circulating biomarkers of healthy aging and longevity, suggesting potential mechanisms that could help prolong health and support longevity. | Sebastiani, Paola Federico, Anthony Morris, Melody Gurinovich, Anastasia Tanaka, Toshiko Chandler, Kevin B Andersen, Stacy L Denis, Gerald Costello, Catherine E Ferrucci, Luigi Jennings, Lori Glass, David J Monti, Stefano Perls, Thomas T eng F31 DE029701/DE/NIDCR NIH HHS/ S10-OD021728/NIH Office of the Director/ R24-GM134210/GM/NIGMS NIH HHS/ R01 AG061844/AG/NIA NIH HHS/ UH2 AG064704/AG/NIA NIH HHS/ U19 AG023122/AG/NIA NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't England Aging Cell. 2021 Feb;20(2):e13290. doi: 10.1111/acel.13290. Epub 2021 Jan 29.I | 01/30/2021 | |
| Age-associated difference in circulating ACE2, the gateway for SARS-COV-2, in humans: results from the InCHIANTI study | AlGhatrif M, et al. | 2021 | Geroscience | 43 | 2 | 619-627 | https://www.doi.org/10.1007/s11357-020-00314-w | 33,462,706 | Aged Angiotensin Receptor Antagonists Angiotensin-Converting Enzyme 2 Angiotensin-Converting Enzyme Inhibitors/therapeutic use *covid-19 Humans Italy/epidemiology *Peptidyl-Dipeptidase A SARS-CoV-2 Ace2 Aging Covid-19 Cardiovascular disease | Levels of angiotensin-converting enzyme 2 (ACE2), the gateway for COVID-19 virus into the cells, have been implicated in worse COVID-19 outcomes associated with aging and cardiovascular disease (CVD). Data on age-associated differences in circulating ACE2 levels in humans and the role of CVD and medications is limited. We analyzed data from 967 participants of the InCHIANTI study, a community-dwelling cohort in the Chianti region, Italy. Relative abundance of ACE2 in plasma was assessed using a proteomics platform. CVD diagnoses, use of renin-angiotensin-aldosterone system (RAAS) antagonists: ACEi, ARBs, and aldosterone antagonists, were ascertained. Multiple linear analyses were performed to examine the independent association of ACE2 with age, CVD, and RAAS antagonist use. Age was independently associated with lower log (ACE2) in persons aged >/= 55 years (STD beta = - 0.12, p = 0.0002). ACEi treatment was also independently associated with significantly lower ACE2 levels, and ACE2 was inversely associated with weight, and positively associated with peripheral artery disease (PAD) status. There was a trend toward higher circulating ACE2 levels in hypertensive individuals, but it did not reach statistical significance. In a stratified analysis, the association between log (ACE2) and log (IL-6) was more evidenced in participants with PAD. Circulating ACE2 levels demonstrate curvilinear association with age, with older individuals beyond the sixth decade age having lower levels. ACEi was associated with greater circulating ACE2 levels. Interestingly, ACE2 was elevated in PAD and positively associated with inflammatory markers, suggesting compensatory upregulation in the setting of chronic inflammation. Further studies are needed to comprehensively characterize RAAS components with aging and disease, and assess its prognostic role in predicting COVID-19 outcomes. | AlGhatrif, Majd Tanaka, Toshiko Moore, Ann Zenobia Bandinelli, Stefania Lakatta, Edward G Ferrucci, Luigi eng Research Support, N.I.H., Intramural Switzerland Geroscience. 2021 Apr;43(2):619-627. doi: 10.1007/s11357-020-00314-w. Epub 2021 Jan 18.I | 01/20/2021 | |
| Circulating markers of NADH-reductive stress correlate with mitochondrial disease severity | Sharma R, et al. | 2021 | J Clin Invest | 131 | 2 | https://www.doi.org/10.1172/JCI136055 | 33,463,549 | Adolescent Adult Aged Aged, 80 and over Alanine/blood Biomarkers/blood Child Child, Preschool Female Growth Differentiation Factor 15/blood Humans Hydroxybutyrates/blood Lactic Acid/blood MELAS Syndrome/*blood/genetics Male Middle Aged Mutation Severity of Illness Index Genetics Intermediary metabolism Metabolism Mitochondria Monogenic diseases Ret Hs6st1 sE-selectin integrated stress response creatine pyruvate 2-hydroxybutyrate alpha-hydroxybutyrate lactoyl-amino acids hydroxy-fatty acids hydroxy-acylcarnitines | Mitochondrial disorders represent a large collection of rare syndromes that are difficult to manage both because we do not fully understand biochemical pathogenesis and because we currently lack facile markers of severity. The m.3243A>G variant is the most common heteroplasmic mitochondrial DNA mutation and underlies a spectrum of diseases, notably mitochondrial encephalomyopathy lactic acidosis and stroke-like episodes (MELAS). To identify robust circulating markers of m.3243A>G disease, we first performed discovery proteomics, targeted metabolomics, and untargeted metabolomics on plasma from a deeply phenotyped cohort (102 patients, 32 controls). In a validation phase, we measured concentrations of prioritized metabolites in an independent cohort using distinct methods. We validated 20 analytes (1 protein, 19 metabolites) that distinguish patients with MELAS from controls. The collection includes classic (lactate, alanine) and more recently identified (GDF-15, alpha-hydroxybutyrate) mitochondrial markers. By mining untargeted mass-spectra we uncovered 3 less well-studied metabolite families: N-lactoyl-amino acids, beta-hydroxy acylcarnitines, and beta-hydroxy fatty acids. Many of these 20 analytes correlate strongly with established measures of severity, including Karnofsky status, and mechanistically, nearly all markers are attributable to an elevated NADH/NAD+ ratio, or NADH-reductive stress. Our work defines a panel of organelle function tests related to NADH-reductive stress that should enable classification and monitoring of mitochondrial disease. | Sharma, Rohit Reinstadler, Bryn Engelstad, Kristin Skinner, Owen S Stackowitz, Erin Haller, Ronald G Clish, Clary B Pierce, Kerry Walker, Melissa A Fryer, Robert Oglesbee, Devin Mao, Xiangling Shungu, Dikoma C Khatri, Ashok Hirano, Michio De Vivo, Darryl C Mootha, Vamsi K eng F32 GM133047/GM/NIGMS NIH HHS/ P01 HD080642/HD/NICHD NIH HHS/ P30 DK040561/DK/NIDDK NIH HHS/ R01 AR050597/AR/NIAMS NIH HHS/ Clinical Trial Multicenter Study Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't J Clin Invest. 2021 Jan 19;131(2):e136055. doi: 10.1172/JCI136055.I | 01/20/2021 | ||
| Plasma protein expression profiles, cardiovascular disease, and religious struggles among South Asians in the MASALA study | Ngo LH, et al. | 2021 | Sci Rep | 11 | 1 | 961 | https://www.doi.org/10.1038/s41598-020-79429-1 | 33,441,605 | Aged Asian Americans/*psychology Biomarkers/blood/metabolism Blood Proteins/*metabolism Cardiovascular Diseases/*blood/*metabolism Case-Control Studies Cell Differentiation/physiology Female Humans Incidence Logistic Models Male Middle Aged Proteomics/methods Religion Risk Factors United States | Blood protein concentrations are clinically useful, predictive biomarkers of cardiovascular disease (CVD). Despite a higher burden of CVD among U.S. South Asians, no CVD-related proteomics study has been conducted in this sub-population. The aim of this study is to investigate the associations between plasma protein levels and CVD incidence, and to assess the potential influence of religiosity/spirituality (R/S) on significant protein-CVD associations, in South Asians from the MASALA Study. We used a nested case-control design of 50 participants with incident CVD and 50 sex- and age-matched controls. Plasma samples were analyzed by SOMAscan for expression of 1305 proteins. Multivariable logistic regression models and model selection using Akaike Information Criteria were performed on the proteins and clinical covariates, with further effect modification analyses conducted to assess the influence of R/S measures on significant associations between proteins and incident CVD events. We identified 36 proteins that were significantly expressed differentially among CVD cases compared to matched controls. These proteins are involved in immune cell recruitment, atherosclerosis, endothelial cell differentiation, and vascularization. A final multivariable model found three proteins (Contactin-5 [CNTN5], Low affinity immunoglobulin gamma Fc region receptor II-a [FCGR2A], and Complement factor B [CFB]) associated with incident CVD after adjustment for diabetes (AUC = 0.82). Religious struggles that exacerbate the adverse impact of stressful life events, significantly modified the effect of Contactin-5 and Complement factor B on risk of CVD. Our research is this first assessment of the relationship between protein concentrations and risk of CVD in a South Asian sample. Further research is needed to understand patterns of proteomic profiles across diverse ethnic communities, and the influence of resources for resiliency on proteomic signatures and ultimately, risk of CVD. | Ngo, Long H Austin Argentieri, M Dillon, Simon T Kent, Blake Victor Kanaya, Alka M Shields, Alexandra E Libermann, Towia A eng R01 HL093009/HL/NHLBI NIH HHS/ K24 HL112827/HL/NHLBI NIH HHS/ UL1 RR024131/NH/NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't England Sci Rep. 2021 Jan 13;11(1):961. doi: 10.1038/s41598-020-79429-1.I | 01/15/2021 | |
| Inhibition of the Complement Alternative Pathway by Chemically Modified DNA Aptamers That Bind with Picomolar Affinity to Factor B | Xu X, et al. | 2021 | J Immunol | 206 | 4 | 861-873 | https://www.doi.org/10.4049/jimmunol.2001260 | 33,419,768 | *Aptamers, Nucleotide/chemistry/immunology Complement C3/chemistry/immunology *Complement Factor B/chemistry/immunology *Complement Pathway, Alternative Humans | The complement system is a conserved component of innate immunity that fulfills diverse roles in defense and homeostasis. Inappropriate activation of complement contributes to many inflammatory diseases, however, which has led to a renewed emphasis on development of therapeutic complement inhibitors. Activation of complement component C3 is required for amplification of complement and is achieved through two multisubunit proteases called C3 convertases. Of these, the alternative pathway (AP) C3 convertase is responsible for a majority of the C3 activation products in vivo, which renders it an attractive target for inhibitor discovery. In this study, we report the identification and characterization of two related slow off-rate modified DNA aptamers (SOMAmer) reagents that inhibit formation of the AP C3 convertase by binding to the proprotease, factor B (FB). These aptamers, known as SL1102 (31 bases) and SL1103 (29 bases), contain uniform substitutions of 5-(N-2-naphthylethylcarboxyamide)-2'-deoxyuridine for deoxythymidine. SL1102 and SL1103 bind FB with K (d) values of 49 and 88 pM, respectively, and inhibit activation of C3 and lysis of rabbit erythrocytes under AP-specific conditions. Cocrystal structures of SL1102 (3.4 A) and SL1103 (3.1 A) bound to human FB revealed that SL1102 and SL1103 recognize a site at the juncture of the CCP1, CCP3, and vWF domains of FB. Consistent with these structures and previously published information, these aptamers inhibited FB binding to C3b and blocked formation of the AP C3 convertase. Together, these results demonstrate potent AP inhibition by modified DNA aptamers and expand the pipeline of FB-binding molecules with favorable pharmacologic properties. | Xu, Xin Zhang, Chi Denton, Dalton T O'Connell, Daniel Drolet, Daniel W Geisbrecht, Brian V eng R21 AI113552/AI/NIAID NIH HHS/ R21 NS104767/NS/NINDS NIH HHS/ Research Support, N.I.H., Extramural J Immunol. 2021 Feb 15;206(4):861-873. doi: 10.4049/jimmunol.2001260. Epub 2021 Jan 8.I | 01/10/2021 | |
| Association of endopeptidases, involved in SARS-CoV-2 infection, with microbial aggravation in sputum of severe asthma | Abdel-Aziz MI, et al. | 2021 | Allergy | 76 | 6 | 1917-1921 | https://www.doi.org/10.1111/all.14731 | 33,411,967 | *Asthma/diagnosis *covid-19 Endopeptidases Humans SARS-CoV-2 Sputum | Abdel-Aziz, Mahmoud I Kermani, Nazanin Zounemat Neerincx, Anne H Vijverberg, Susanne J H Guo, Yike Howarth, Peter Dahlen, Sven-Erik Djukanovic, Ratko Sterk, Peter J Kraneveld, Aletta D Maitland-van der Zee, Anke H Chung, Kian Fan Adcock, Ian M eng 115010/Innovative Medicines Initiative/ European Federation of Pharmaceutical Industries and Associations/ FP7/2007-2013/Seventh Framework Programme/ Letter Research Support, Non-U.S. Gov't Denmark Allergy. 2021 Jun;76(6):1917-1921. doi: 10.1111/all.14731. Epub 2021 Jan 25.I | 01/08/2021 | ||
| Broadly effective metabolic and immune recovery with C5 inhibition in CHAPLE disease | Ozen A, et al. | 2021 | Nat Immunol | 22 | 2 | 128-139 | https://www.doi.org/10.1038/s41590-020-00830-z | 33,398,182 | Antibodies, Monoclonal, Humanized/adverse effects/pharmacokinetics/*therapeutic use Biomarkers/blood CD55 Antigens/deficiency/genetics Complement Activation/*drug effects Complement C5/*antagonists & inhibitors/metabolism Complement Inactivating Agents/adverse effects/pharmacokinetics/*therapeutic use Energy Metabolism/*drug effects Genetic Predisposition to Disease Humans Hypoproteinemia/*drug therapy/genetics/immunology/metabolism Immunity, Innate/*drug effects Mutation Phenotype Protein-Losing Enteropathies/*drug therapy/genetics/immunology/metabolism Treatment Outcome | Complement hyperactivation, angiopathic thrombosis and protein-losing enteropathy (CHAPLE disease) is a lethal disease caused by genetic loss of the complement regulatory protein CD55, leading to overactivation of complement and innate immunity together with immunodeficiency due to immunoglobulin wasting in the intestine. We report in vivo human data accumulated using the complement C5 inhibitor eculizumab for the medical treatment of patients with CHAPLE disease. We observed cessation of gastrointestinal pathology together with restoration of normal immunity and metabolism. We found that patients rapidly renormalized immunoglobulin concentrations and other serum proteins as revealed by aptamer profiling, re-established a healthy gut microbiome, discontinued immunoglobulin replacement and other treatments and exhibited catch-up growth. Thus, we show that blockade of C5 by eculizumab effectively re-establishes regulation of the innate immune complement system to substantially reduce the pathophysiological manifestations of CD55 deficiency in humans. | Ozen, Ahmet Kasap, Nurhan Vujkovic-Cvijin, Ivan Apps, Richard Cheung, Foo Karakoc-Aydiner, Elif Akkelle, Bilge Sari, Sinan Tutar, Engin Ozcay, Figen Uygun, Dilara Kocacik Islek, Ali Akgun, Gamze Selcuk, Merve Sezer, Oya Balci Zhang, Yu Kutluk, Gunsel Topal, Erdem Sayar, Ersin Celikel, Cigdem Houwen, Roderick H J Bingol, Aysen Ogulur, Ismail Eltan, Sevgi Bilgic Snow, Andrew L Lake, Camille Fantoni, Giovanna Alba, Camille Sellers, Brian Chauvin, Samuel D Dalgard, Clifton L Harari, Olivier Ni, Yan G Wang, Ming-Dauh Devalaraja-Narashimha, Kishor Subramanian, Poorani Ergelen, Rabia Artan, Reha Guner, Sukru Nail Dalgic, Buket Tsang, John Belkaid, Yasmine Ertem, Deniz Baris, Safa Lenardo, Michael J eng R01 GM129325/GM/NIGMS NIH HHS/ Z01 AI000769/ImNIH/Intramural NIH HHS/ Observational Study Research Support, N.I.H., Extramural Research Support, N.I.H., Intramural Research Support, Non-U.S. Gov't Nat Immunol. 2021 Feb;22(2):128-139. doi: 10.1038/s41590-020-00830-z. Epub 2021 Jan 4.I | 01/06/2021 | |
| Proteomic Signatures of Lifestyle Risk Factors for Cardiovascular Disease: A Cross-Sectional Analysis of the Plasma Proteome in the Framingham Heart Study | Corlin L, et al. | 2021 | J Am Heart Assoc | 10 | 1 | e018020 | https://www.doi.org/10.1161/JAHA.120.018020 | 33,372,532 | *Alcohol Drinking/epidemiology/metabolism *Cardiovascular Diseases/blood/epidemiology/genetics Effect Modifier, Epidemiologic Exercise/*physiology Female Genome-Wide Association Study *Heart Disease Risk Factors Humans *Life Style Longitudinal Studies Male Middle Aged Mortality Proteomics/*methods Quantitative Trait Loci *Smoking/epidemiology/metabolism United States/epidemiology alcohol consumption lifestyle physical activity proteomics smoking | Background Proteomic biomarkers related to cardiovascular disease risk factors may offer insights into the pathogenesis of cardiovascular disease. We investigated whether modifiable lifestyle risk factors for cardiovascular disease are associated with distinctive proteomic signatures. Methods and Results We analyzed 1305 circulating plasma proteomic biomarkers (assayed using the SomaLogic platform) in 897 FHS (Framingham Heart Study) Generation 3 participants (mean age 46+/-8 years; 56% women; discovery sample) and 1121 FOS (Framingham Offspring Study) participants (mean age 52 years; 54% women; validation sample). Participants were free of hypertension, diabetes mellitus, and clinical cardiovascular disease. We used linear mixed effects models (adjusting for age, sex, body mass index, and family structure) to relate levels of each inverse-log transformed protein to 3 lifestyle factors (ie, smoking, alcohol consumption, and physical activity). A Bonferroni-adjusted P value indicated statistical significance (based on number of proteins and traits tested, P<4.2x10(-6) in the discovery sample; P<6.85x10(-4) in the validation sample). We observed statistically significant associations of 60 proteins with smoking (37/40 top proteins validated in FOS), 30 proteins with alcohol consumption (23/30 proteins validated), and 5 proteins with physical activity (2/3 proteins associated with the physical activity index validated). We assessed the associations of protein concentrations with previously identified genetic variants (protein quantitative trait loci) linked to lifestyle-related disease traits in the genome-wide-association study catalogue. The protein quantitative trait loci were associated with coronary artery disease, inflammation, and age-related mortality. Conclusions Our cross-sectional study from a community-based sample elucidated distinctive sets of proteins associated with 3 key lifestyle factors. | Corlin, Laura Liu, Chunyu Lin, Honghuang Leone, Dominick Yang, Qiong Ngo, Debby Levy, Daniel Cupples, L Adrienne Gerszten, Robert E Larson, Martin G Vasan, Ramachandran S eng P30 DK040561/DK/NIDDK NIH HHS/ N01HC25195/HL/NHLBI NIH HHS/ HHSN268201500001I/HL/NHLBI NIH HHS/ 75N92019D00031/HL/NHLBI NIH HHS/ RF1 AG063507/AG/NIA NIH HHS/ R01 HL132320/HL/NHLBI NIH HHS/ T32 HL125232/HL/NHLBI NIH HHS/ K12 HD092535/HD/NICHD NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't England J Am Heart Assoc. 2021 Jan 5;10(1):e018020. doi: 10.1161/JAHA.120.018020. Epub 2020 Dec 29.I | 12/30/2020 | |
| Platelet-derived growth factor BB: A potential diagnostic blood biomarker for differentiating bipolar disorder from major depressive disorder | Idemoto K, et al. | 2021 | J Psychiatr Res | 134 | 48-56 | https://www.doi.org/10.1016/j.jpsychires.2020.12.051 | 33,360,224 | Becaplermin Biomarkers *Bipolar Disorder/diagnosis/drug therapy Case-Control Studies Cross-Sectional Studies *Depressive Disorder, Major/diagnosis/drug therapy Humans Bipolar disorder Diagnostic biomarker Major depressive disorder Pdgf-bb Platelet-derived growth factor Sodium valproate | Bipolar disorder (BD) is frequently misdiagnosed as major depressive disorder (MDD) due to overlapping depressive symptoms. This study investigated whether serum platelet-derived growth factor BB (PDGF-BB) is a differential diagnostic biomarker for BD and MDD. An initial SOMAscan proteomics assay of 1311 proteins in small samples from patients with BD and MDD and healthy controls (HCs) suggested that serum levels of PDGF-BB differed between BD and MDD. We then conducted a two-step, exploratory, cross-sectional, case-control study at our institute and five sites that included a total of 549 participants (157 with BD, 144 with MDD, and 248 HCs). Clinical symptoms were assessed using the Hamilton Depression Rating Scale and the Young Mania Rating Scale. In the initial analysis at our institute, serum PDGF-BB levels in the MDD group (n = 36) were significantly lower than those in the BD (n = 39) and HC groups (n = 36). In the multicenter study, serum PDGF-BB levels in the MDD group were again significantly lower than those in the BD and HC groups, with no significant difference between the BD and HC groups. Treatment with sodium valproate was associated with significantly lower serum PDGF-BB levels in patients with BD. After controlling for confounding factors (sex, age, body mass index, clinical severity, and valproate medication), serum PDGF-BB levels were lower in the MDD group than in the BD group regardless of mood state. Our findings suggest that serum PDGF-BB may be a potential biomarker to differentiate BD and MDD. | Idemoto, Keita Ishima, Tamaki Niitsu, Tomihisa Hata, Tatsuki Yoshida, Sumiko Hattori, Kotaro Horai, Tadasu Otsuka, Ikuo Yamamori, Hidenaga Toda, Shigenobu Kameno, Yosuke Ota, Kiyomitsu Oda, Yasunori Kimura, Atsushi Hashimoto, Tasuku Mori, Norio Kikuchi, Mitsuru Minabe, Yoshio Hashimoto, Ryota Hishimoto, Akitoyo Nakagome, Kazuyuki Iyo, Masaomi Hashimoto, Kenji eng Multicenter Study Research Support, Non-U.S. Gov't England J Psychiatr Res. 2021 Feb;134:48-56. doi: 10.1016/j.jpsychires.2020.12.051. Epub 2020 Dec 21.I | 12/29/2020 | ||
| A Combined Proteomics and Mendelian Randomization Approach to Investigate the Effects of Aspirin-Targeted Proteins on Colorectal Cancer | Nounu A, et al. | 2021 | Cancer Epidemiol Biomarkers Prev | 30 | 3 | 564-575 | https://www.doi.org/10.1158/1055-9965.EPI-20-1176 | 33,318,029 | Aspirin/pharmacology/*therapeutic use Colorectal Neoplasms/*drug therapy Humans Mendelian Randomization Analysis/*methods Proteomics/*methods Risk Factors | BACKGROUND: Evidence for aspirin's chemopreventative properties on colorectal cancer (CRC) is substantial, but its mechanism of action is not well-understood. We combined a proteomic approach with Mendelian randomization (MR) to identify possible new aspirin targets that decrease CRC risk. METHODS: Human colorectal adenoma cells (RG/C2) were treated with aspirin (24 hours) and a stable isotope labeling with amino acids in cell culture (SILAC) based proteomics approach identified altered protein expression. Protein quantitative trait loci (pQTLs) from INTERVAL (N = 3,301) and expression QTLs (eQTLs) from the eQTLGen Consortium (N = 31,684) were used as genetic proxies for protein and mRNA expression levels. Two-sample MR of mRNA/protein expression on CRC risk was performed using eQTL/pQTL data combined with CRC genetic summary data from the Colon Cancer Family Registry (CCFR), Colorectal Transdisciplinary (CORECT), Genetics and Epidemiology of Colorectal Cancer (GECCO) consortia and UK Biobank (55,168 cases and 65,160 controls). RESULTS: Altered expression was detected for 125/5886 proteins. Of these, aspirin decreased MCM6, RRM2, and ARFIP2 expression, and MR analysis showed that a standard deviation increase in mRNA/protein expression was associated with increased CRC risk (OR: 1.08, 95% CI, 1.03-1.13; OR: 3.33, 95% CI, 2.46-4.50; and OR: 1.15, 95% CI, 1.02-1.29, respectively). CONCLUSIONS: MCM6 and RRM2 are involved in DNA repair whereby reduced expression may lead to increased DNA aberrations and ultimately cancer cell death, whereas ARFIP2 is involved in actin cytoskeletal regulation, indicating a possible role in aspirin's reduction of metastasis. IMPACT: Our approach has shown how laboratory experiments and population-based approaches can combine to identify aspirin-targeted proteins possibly affecting CRC risk. | Nounu, Aayah Greenhough, Alexander Heesom, Kate J Richmond, Rebecca C Zheng, Jie Weinstein, Stephanie J Albanes, Demetrius Baron, John A Hopper, John L Figueiredo, Jane C Newcomb, Polly A Lindor, Noralane M Casey, Graham Platz, Elizabeth A Le Marchand, Loic Ulrich, Cornelia M Li, Christopher I van Duijnhoven, Franzel J B Gsur, Andrea Campbell, Peter T Moreno, Victor Vodicka, Pavel Vodickova, Ludmila Brenner, Hermann Chang-Claude, Jenny Hoffmeister, Michael Sakoda, Lori C Slattery, Martha L Schoen, Robert E Gunter, Marc J Castellvi-Bel, Sergi Kim, Hyeong Rok Kweon, Sun-Seog Chan, Andrew T Li, Li Zheng, Wei Bishop, D Timothy Buchanan, Daniel D Giles, Graham G Gruber, Stephen B Rennert, Gad Stadler, Zsofia K Harrison, Tabitha A Lin, Yi Keku, Temitope O Woods, Michael O Schafmayer, Clemens Van Guelpen, Bethany Gallinger, Steven Hampel, Heather Berndt, Sonja I Pharoah, Paul D P Lindblom, Annika Wolk, Alicja Wu, Anna H White, Emily Peters, Ulrike Drew, David A Scherer, Dominique Bermejo, Justo Lorenzo Williams, Ann C Relton, Caroline L eng R01 CA067941/CA/NCI NIH HHS/ U01 HG004438/HG/NHGRI NIH HHS/ U01 HG004446/HG/NHGRI NIH HHS/ U10 CA037429/CA/NCI NIH HHS/ K05 CA154337/CA/NCI NIH HHS/ U01 CA164930/CA/NCI NIH HHS/ P30 CA076292/CA/NCI NIH HHS/ R01 CA042182/CA/NCI NIH HHS/ P50 CA127003/CA/NCI NIH HHS/ U01 CA067941/CA/NCI NIH HHS/ R01 CA059045/CA/NCI NIH HHS/ HHSN268201100001I/HL/NHLBI NIH HHS/ R01 CA197350/CA/NCI NIH HHS/ R01 CA076366/CA/NCI NIH HHS/ R35 CA197735/CA/NCI NIH HHS/ R01 CA072520/CA/NCI NIH HHS/ P01 CA087969/CA/NCI NIH HHS/ P30 CA015704/CA/NCI NIH HHS/ HHSN268201100004I/HL/NHLBI NIH HHS/ P30 CA006973/CA/NCI NIH HHS/ U24 CA074783/CA/NCI NIH HHS/ P01 CA055075/CA/NCI NIH HHS/ S10 OD028685/OD/NIH HHS/ R01 CA151993/CA/NCI NIH HHS/ HHSN268201100046C/HL/NHLBI NIH HHS/ P30 DK034987/DK/NIDDK NIH HHS/ R01 CA048998/CA/NCI NIH HHS/ U01 CA137088/CA/NCI NIH HHS/ 11975/CRUK_/Cancer Research UK/United Kingdom R01 CA189184/CA/NCI NIH HHS/ U01 CA167552/CA/NCI NIH HHS/ HHSN268201100003C/WH/WHI NIH HHS/ MC_UU_12013_2/MRC_/Medical Research Council/United Kingdom Z01 CP010200/ImNIH/Intramural NIH HHS/ U24 CA074794/CA/NCI NIH HHS/ R01 CA066635/CA/NCI NIH HHS/ R21 CA191312/CA/NCI NIH HHS/ U01 CA206110/CA/NCI NIH HHS/ HHSN268201200008C/HL/NHLBI NIH HHS/ C18281/A19169/CRUK_/Cancer Research UK/United Kingdom R01 CA137178/CA/NCI NIH HHS/ U01 CA074794/CA/NCI NIH HHS/ P30 CA008748/CA/NCI NIH HHS/ U01 CA167551/CA/NCI NIH HHS/ P30 CA014089/CA/NCI NIH HHS/ R01 CA081488/CA/NCI NIH HHS/ HHSN271201100004C/AG/NIA NIH HHS/ R01 CA201407/CA/NCI NIH HHS/ R01 CA063464/CA/NCI NIH HHS/ P01 CA033619/CA/NCI NIH HHS/ U01 CA086308/CA/NCI NIH HHS/ UM1 CA186107/CA/NCI NIH HHS/ HHSN268201100002C/WH/WHI NIH HHS/ R01 CA207371/CA/NCI NIH HHS/ R03 CA153323/CA/NCI NIH HHS/ T32 ES013678/ES/NIEHS NIH HHS/ R01 CA136726/CA/NCI NIH HHS/ P30 CA016058/CA/NCI NIH HHS/ UM1 CA167552/CA/NCI NIH HHS/ K05 CA152715/CA/NCI NIH HHS/ U01 CA122839/CA/NCI NIH HHS/ WT_/Wellcome Trust/United Kingdom HHSN268201100003I/HL/NHLBI NIH HHS/ HHSN268201100002I/HL/NHLBI NIH HHS/ U01 CA074783/CA/NCI NIH HHS/ U01 CA084968/CA/NCI NIH HHS/ KL2 TR000421/TR/NCATS NIH HHS/ MR/R017247/1/MRC_/Medical Research Council/United Kingdom UM1 CA182883/CA/NCI NIH HHS/ K07 CA190673/CA/NCI NIH HHS/ HHSN268201200008I/HL/NHLBI NIH HHS/ 217487/Z/19/Z/WT_/Wellcome Trust/United Kingdom U01 CA164973/CA/NCI NIH HHS/ R37 CA054281/CA/NCI NIH HHS/ HHSN268201100001C/WH/WHI NIH HHS/ HHSN268201100004C/WH/WHI NIH HHS/ R01 CA097325/CA/NCI NIH HHS/ HHSN268201700006C/HL/NHLBI NIH HHS/ U19 CA148107/CA/NCI NIH HHS/ U01 AG018033/AG/NIA NIH HHS/ Research Support, N.I.H., Extramural Research Support, N.I.H., Intramural Research Support, Non-U.S. Gov't Cancer Epidemiol Biomarkers Prev. 2021 Mar;30(3):564-575. doi: 10.1158/1055-9965.EPI-20-1176. Epub 2020 Dec 14.I | 12/16/2020 | |
| ANMerge: A Comprehensive and Accessible Alzheimer's Disease Patient-Level Dataset | Birkenbihl C, et al. | 2021 | J Alzheimers Dis | 79 | 1 | 423-431 | https://www.doi.org/10.3233/JAD-200948 | 33,285,634 | Aged Aged, 80 and over Alzheimer Disease/diagnostic imaging/genetics/metabolism/*physiopathology Cohort Studies *Datasets as Topic Female Gene Expression Profiling Genotype Humans Magnetic Resonance Imaging Male Proteomics AddNeuroMed Alzheimer's disease biomarkers cohort analysis data-driven science dataset dementia genome wide association studies multimodal (https://www.j-alz.com/manuscript-disclosures/20-0948r2 ). | BACKGROUND: Accessible datasets are of fundamental importance to the advancement of Alzheimer's disease (AD) research. The AddNeuroMed consortium conducted a longitudinal observational cohort study with the aim to discover AD biomarkers. During this study, a broad selection of data modalities was measured including clinical assessments, magnetic resonance imaging, genotyping, transcriptomic profiling, and blood plasma proteomics. Some of the collected data were shared with third-party researchers. However, this data was incomplete, erroneous, and lacking in interoperability. OBJECTIVE: To provide the research community with an accessible, multimodal, patient-level AD cohort dataset. METHODS: We systematically addressed several limitations of the originally shared resources and provided additional unreleased data to enhance the dataset. RESULTS: In this work, we publish and describe ANMerge, a new version of the AddNeuroMed dataset. ANMerge includes multimodal data from 1,702 study participants and is accessible to the research community via a centralized portal. CONCLUSION: ANMerge is an information rich patient-level data resource that can serve as a discovery and validation cohort for data-driven AD research, such as, for example, machine learning and artificial intelligence approaches. | Birkenbihl, Colin Westwood, Sarah Shi, Liu Nevado-Holgado, Alejo Westman, Eric Lovestone, Simon Hofmann-Apitius, Martin eng MC_PC_17215/MRC_/Medical Research Council/United Kingdom Department of Health (NIHR)/ Research Support, Non-U.S. Gov't Netherlands J Alzheimers Dis. 2021;79(1):423-431. doi: 10.3233/JAD-200948.I | 12/09/2020 | |
| Genetics meets proteomics: perspectives for large population-based studies | Suhre K, et al. | 2021 | Nat Rev Genet | 22 | 1 | 19-37 | https://www.doi.org/10.1038/s41576-020-0268-2 | 32,860,016 | Biomarkers/analysis Blood Proteins/*analysis *Genome-Wide Association Study Humans Phenotype Proteome/*genetics *Proteomics | Proteomic analysis of cells, tissues and body fluids has generated valuable insights into the complex processes influencing human biology. Proteins represent intermediate phenotypes for disease and provide insight into how genetic and non-genetic risk factors are mechanistically linked to clinical outcomes. Associations between protein levels and DNA sequence variants that colocalize with risk alleles for common diseases can expose disease-associated pathways, revealing novel drug targets and translational biomarkers. However, genome-wide, population-scale analyses of proteomic data are only now emerging. Here, we review current findings from studies of the plasma proteome and discuss their potential for advancing biomedical translation through the interpretation of genome-wide association analyses. We highlight the challenges faced by currently available technologies and provide perspectives relevant to their future application in large-scale biobank studies. | Suhre, Karsten McCarthy, Mark I Schwenk, Jochen M eng Research Support, Non-U.S. Gov't Review England Nat Rev Genet. 2021 Jan;22(1):19-37. doi: 10.1038/s41576-020-0268-2. Epub 2020 Aug 28.I | 08/30/2020 | |
| Association of a Serum Protein Signature With Rheumatoid Arthritis Development | O'Neil LJ, et al. | 2021 | Arthritis Rheumatol | 73 | 1 | 78-88 | https://www.doi.org/10.1002/art.41483 | 32,770,634 | Adolescent Adult Aged Anti-Citrullinated Protein Antibodies/immunology Arthritis, Rheumatoid/*blood/immunology *Asymptomatic Diseases Calreticulin/blood Disease Progression Female Humans *Indians, North American Interleukin-1/blood/immunology Lectins/blood Longitudinal Studies *Machine Learning Male Middle Aged *Proteomics Rheumatoid Factor/immunology Toll-Like Receptor 2/blood/immunology Tumor Necrosis Factor-alpha/blood/immunology Young Adult | OBJECTIVE: The pathophysiologic events that precede the onset of rheumatoid arthritis (RA) remain incompletely understood. This study was undertaken to identify changes in the serum proteome that precede the onset of RA, with the aim of providing new insights into the pathogenic mechanisms that lead to its development. METHODS: In a cohort of first-degree relatives of Indigenous North American RA patients, the SomaScan proteomics platform was used to determine the levels of 1,307 proteins in multiple longitudinal serum samples from 17 individuals who were followed up prospectively to the time of disease onset. Proteomic signatures from this group of individuals (designated the progressor group) were compared to those in a group of individuals who were considered at risk of developing RA, stratified as either positive (n = 63) or negative (n = 47) for anti-citrullinated protein antibodies (ACPAs) (designated the at-risk group). Machine learning was used to identify a protein signature that could accurately classify those individuals at highest risk of future RA development. RESULTS: A preclinical proteomic signature that differentiated RA progressors from at-risk individuals, irrespective of ACPA status, was identified (area under the curve 0.913, accuracy 91.2%). Importantly, the predictive preclinical proteomic signature was present not only in serum samples obtained close to the onset of RA, but also in serum samples obtained a median of 30.9 months prior to onset. Network analysis implicated the activation of Toll-like receptor 2 and production of tumor necrosis factor and interleukin-1 as key events that precede RA progression. CONCLUSION: Alterations in the serum proteome in the preclinical phase of RA can emerge years prior to the onset of disease. Our findings suggest that the serum proteome provides a rich source of proteins serving both to classify at-risk individuals and to identify molecular pathways involved in the development of clinically detectable RA. | O'Neil, Liam J Spicer, Victor Smolik, Irene Meng, Xiaobo Goel, Rishi R Anaparti, Vidyanand Wilkins, John El-Gabalawy, Hani S eng MOP 77700/CIHR/Canada Research Support, Non-U.S. Gov't Arthritis Rheumatol. 2021 Jan;73(1):78-88. doi: 10.1002/art.41483. Epub 2020 Nov 10.I | 08/10/2020 | |
| Identification of Plasma Proteome Signatures Associated With Surgery Using SOMAscan | Fong TG, et al. | 2021 | Ann Surg | 273 | 4 | 732-742 | https://www.doi.org/10.1097/SLA.0000000000003283 | 30,946,084 | Aged Biomarkers/blood C-Reactive Protein/metabolism *Elective Surgical Procedures Enzyme-Linked Immunosorbent Assay Female Humans Length of Stay Male Postoperative Complications/*blood Proteome/*metabolism Proteomics/*methods | OBJECTIVES: To characterize the proteomic signature of surgery in older adults and association with postoperative outcomes. SUMMARY OF BACKGROUND DATA: Circulating plasma proteins can reflect the physiological response to and clinical outcomes after surgery. METHODS: Blood plasma from older adults undergoing elective surgery was analyzed for 1305 proteins using SOMAscan. Surgery-associated proteins underwent Ingenuity Pathways Analysis. Selected surgery-associated proteins were independently validated using Luminex or enzyme-linked immunosorbent assay methods. Generalized linear models estimated correlations with postoperative outcomes. RESULTS: Plasma from a subcohort (n = 36) of the Successful Aging after Elective Surgery (SAGES) study was used for SOMAscan. Systems biology analysis of 110 proteins with Benjamini-Hochberg (BH) corrected P value /=1.5 between postoperative day 2 (POD2) and preoperative (PREOP) identified functional pathways with major effects on pro-inflammatory proteins. Chitinase-3-like protein 1 (CHI3L1), C-reactive protein (CRP), and interleukin-6 (IL-6) were independently validated in separate validation cohorts from SAGES (n = 150 for CRP, IL-6; n = 126 for CHI3L1). Foldchange CHI3L1 and IL-6 were associated with increased postoperative complications [relative risk (RR) 1.50, 95% confidence interval (95% CI) 1.21-1.85 and RR 1.63, 95% CI 1.18-2.26, respectively], length of stay (RR 1.35, 95% CI 0.77-1.92 and RR 0.98, 95% CI 0.52-1.45), and risk of discharge to postacute facility (RR 1.15, 95% CI 1.04-1.26 and RR 1.11, 95% CI 1.04-1.18); POD2 and PREOP CRP difference was associated with discharge to postacute facility (RR 1.14, 95% CI 1.04-1.25). CONCLUSION: SOMAscan can identify novel and clinically relevant surgery-induced protein changes. Ultimately, proteomics may provide insights about pathways by which surgical stress contributes to postoperative outcomes. | Fong, Tamara G Chan, Noel Y Dillon, Simon T Zhou, Wenxiao Tripp, Bridget Ngo, Long H Otu, Hasan H Inouye, Sharon K Vasunilashorn, Sarinnapha M Cooper, Zara Xie, Zhongcong Marcantonio, Edward R Libermann, Towia A eng R01 AG051658/AG/NIA NIH HHS/ R03 AG061582/AG/NIA NIH HHS/ K24 AG035075/AG/NIA NIH HHS/ K07 AG041835/AG/NIA NIH HHS/ K01 AG057836/AG/NIA NIH HHS/ T32 AT000051/AT/NCCIH NIH HHS/ P01 AG031720/AG/NIA NIH HHS/ UL1 TR001102/TR/NCATS NIH HHS/ R21 AG057955/AG/NIA NIH HHS/ R24 AG054259/AG/NIA NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Ann Surg. 2021 Apr 1;273(4):732-742. doi: 10.1097/SLA.0000000000003283.I | 04/05/2019 | |
| Cellular and plasma proteomic determinants of COVID-19 and non-COVID-19 pulmonary diseases relative to healthy aging | Arthur L, et al. | 2021 | Nature Aging | 1 | 6 | 535-549 | https://www.doi.org/10.1038/s43587-021-00067-x | We examine the cellular and soluble determinants of coronavirus disease 2019 (COVID-19) relative to aging by performing mass cytometry in parallel with clinical blood testing and plasma proteomic profiling of ~4,700 proteins from 71 individuals with pulmonary disease and 148 healthy donors (25–80 years old). Distinct cell populations were associated with age (GZMK+CD8+ T cells and CD25low CD4+ T cells) and with COVID-19 (TBET_EOMES_ CD4+ T cells, HLA-DR+CD38+ CD8+ T cells and CD27+CD38+ B cells). A unique population of TBET+EOMES+ CD4+ T cells was associated with individuals with COVID-19 who experienced moderate, rather than severe or lethal, disease. Disease severity correlated with blood creatinine and urea nitrogen levels. Proteomics revealed a major impact of age on the disease-associated plasma signatures and highlighted the divergent contribution of hepatocyte and muscle secretomes to COVID-19 plasma proteins. Aging plasma was enriched in matrisome proteins and heart/aorta smooth muscle cell-specific proteins. These findings reveal age-specific and disease-specific changes associated with COVID-19, and potential soluble mediators of the physiological impact of COVID-19. | Arthur, Laura Esaulova, Ekaterina Mogilenko, Denis A. Tsurinov, Petr Burdess, Samantha Laha, Anwesha Presti, Rachel Goetz, Brian Watson, Mark A. Goss, Charles W. Gurnett, Christina A. Mudd, Philip A. Beers, Courtney O’Halloran, Jane A. Artyomov, Maxim N. | ||||
| Hypoglycemia-induced changes in complement pathways in type 2 diabetes | Moin ASM, et al. | 2021 | Atherosclerosis Plus | 46 | 35-45 | https://www.doi.org/10.1016/j.athplu.2021.11.002 | Hypoglycemia Type 2 diabetes Complement proteins Proteomics | An association between hypoglycaemia and adverse cardiovascular events has been suggested from longitudinal and retrospective cohort studies. The complement pathway proteins in hypoglycemia are not well studied. Here, we hypothesized that these circulating proteins would be elevated in response to hypoglycemia in type 2 diabetes (T2D) through the inflammatory response. | Moin, Abu Saleh Md Nandakumar, Manjula Diboun, Ilhame Al-Qaissi, Ahmed Sathyapalan, Thozhukat Atkin, Stephen L. Butler, Alexandra E. | ||||
| Large-scale plasma proteomic analysis identifies proteins and pathways associated with dementia risk | Walker KA, et al. | 2021 | Nature Aging | 1 | 5 | 473-489 | https://www.doi.org/10.1038/s43587-021-00064-0 | The plasma proteomic changes that precede the onset of dementia could yield insights into disease biology and highlight new biomarkers and avenues for intervention. We quantified 4,877 plasma proteins in nondemented older adults in the Atherosclerosis Risk in Communities cohort and performed a proteome-wide association study of dementia risk over five years (n_=_4,110; 428 incident cases). Thirty-eight proteins were associated with incident dementia after Bonferroni correction. Of these, 16 were also associated with late-life dementia risk when measured in plasma collected nearly 20 years earlier, during mid-life. Two-sample Mendelian randomization causally implicated two dementia-associated proteins (SVEP1 and angiostatin) in Alzheimer’s disease. SVEP1, an immunologically relevant cellular adhesion protein, was found to be part of larger dementia-associated protein networks, and circulating levels were associated with atrophy in brain regions vulnerable to Alzheimer’s pathology. Pathway analyses for the broader set of dementia-associated proteins implicated immune, lipid, metabolic signaling and hemostasis pathways in dementia pathogenesis. | Walker, Keenan A. Chen, Jingsha Zhang, Jingning Fornage, Myriam Yang, Yunju Zhou, Linda Grams, Morgan E. Tin, Adrienne Daya, Natalie Hoogeveen, Ron C. Wu, Aozhou Sullivan, Kevin J. Ganz, Peter Zeger, Scott L. Gudmundsson, Elias F. Emilsson, Valur Launer, Lenore J. Jennings, Lori L. Gudnason, Vilmundur Chatterjee, Nilanjan Gottesman, Rebecca F. Mosley, Thomas H. Boerwinkle, Eric Ballantyne, Christie M. Coresh, Josef | ||||
| Functional Network Profiles in ARSACS Disclosed by Aptamer-Based Proteomic Technology | Morani F, et al. | 2020 | Front Neurol | 11 | 603774 | https://www.doi.org/10.3389/fneur.2020.603774 | 33,584,503 | Arsacs SomaLogic technology engulfment of cells neuroinflammation proteomic analysis sacsin synaptogenesis commercial or financial relationships that could be construed as a potential conflict of interest. | Although the genetic basis of autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) has been uncovered, our poor understanding of disease mechanisms requires new light on functional pathways and modifying factors to improve early diagnostic strategies and offer alternative treatment options in a rare condition with no cure. Investigation of the pathologic state combining disease models and quantitative omic approach might improve biomarkers discovery with possible implications in patients' diagnoses. In this study, we analyzed proteomics data obtained using the SomaLogic technology, comparing cell lysates from ARSACS patients and from a SACS KO SH-SY5Y neuroblastoma cell model. Single-stranded deoxyoligonucleotides, selected in vitro from large random libraries, bound and quantified molecular targets related to the neuroinflammation signaling pathway and to neuronal development. Changes in protein levels were further analyzed by bioinformatics and network approaches to identify biomarkers of ARSACS and functional pathways impaired in the disease. We identified novel significantly dysregulated biological processes related to neuroinflammation, synaptogenesis, and engulfment of cells in patients and in KO cells compared with controls. Among the differential expressed proteins found in this work, we identified several proteins encoded by genes already known to be mutated in other forms of neurodegeneration. This finding suggests that common dysfunctional networks could be therapeutic targets for future investigations. | Morani, Federica Doccini, Stefano Chiorino, Giovanna Fattori, Fabiana Galatolo, Daniele Sciarrillo, Elisa Gemignani, Federica Zuchner, Stephan Bertini, Enrico Silvio Santorelli, Filippo Maria eng Switzerland Front Neurol. 2021 Jan 27;11:603774. doi: 10.3389/fneur.2020.603774. eCollection 2020.I | 02/16/2021 | ||
| Intense light as anticoagulant therapy in humans | Oyama Y, et al. | 2020 | PLoS One | 15 | 12 | e0244792 | https://www.doi.org/10.1371/journal.pone.0244792 | 33,382,840 | Animals Blood Coagulation/*physiology Blood Platelets/*metabolism Humans Light Male Mice Myocardial Ischemia/blood/*metabolism Myocardial Reperfusion Injury/blood/*metabolism Period Circadian Proteins/genetics/*metabolism *Phototherapy Platelet Aggregation/physiology Proteomics | Blood coagulation is central to myocardial ischemia and reperfusion (IR) injury. Studies on the light elicited circadian rhythm protein Period 2 (PER2) using whole body Per2-/- mice found deficient platelet function and reduced clotting which would be expected to protect from myocardial IR-injury. In contrast, intense light induction of PER2 protected from myocardial IR-injury while Per2 deficiency was detrimental. Based on these conflicting data, we sought to evaluate the role of platelet specific PER2 in coagulation and myocardial ischemia and reperfusion injury. We demonstrated that platelets from mice with tissue-specific deletion of Per2 in the megakaryocyte lineage (Per2loxP/loxP-PF4-CRE) significantly clot faster than platelets from control mice. We further found increases in infarct sizes or plasma troponin levels in Per2loxP/loxP-PF4-CRE mice when compared to controls. As intense light increases PER2 protein in human tissues, we also performed translational studies and tested the effects of intense light therapy on coagulation in healthy human subjects. Our human studies revealed that intense light therapy repressed procoagulant pathways in human plasma samples and significantly reduced the clot rate. Based on these results we conclude that intense light elicited PER2 has an inhibitory function on platelet aggregation in mice. Further, we suggest intense light as a novel therapy to prevent or treat clotting in a clinical setting. | Oyama, Yoshimasa Shuff, Sydney Davizon-Castillo, Pavel Clendenen, Nathan Eckle, Tobias eng R01 HL122472/HL/NHLBI NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't PLoS One. 2020 Dec 31;15(12):e0244792. doi: 10.1371/journal.pone.0244792. eCollection 2020.I | 01/01/2021 | |
| Identification of Potential Serum Protein Biomarkers and Pathways for Pancreatic Cancer Cachexia Using an Aptamer-Based Discovery Platform | Narasimhan A, et al. | 2020 | Cancers (Basel) | 12 | 12 | https://www.doi.org/10.3390/cancers12123787 | 33,334,063 | biomarkers cachexia humans neoplasms pancreatic adenocarcinoma paracrine communication proteome weight loss | Patients with pancreatic ductal adenocarcinoma (PDAC) suffer debilitating and deadly weight loss, known as cachexia. Development of therapies requires biomarkers to diagnose, and monitor cachexia; however, no such markers are in use. Via Somascan, we measured ~1300 plasma proteins in 30 patients with PDAC vs. 11 controls. We found 60 proteins specific to local PDAC, 46 to metastatic, and 67 to presence of >5% cancer weight loss (FC >/= |1.5|, p /= |0.50|, p | Narasimhan, Ashok Shahda, Safi Kays, Joshua K Perkins, Susan M Cheng, Lijun Schloss, Katheryn N H Schloss, Daniel E I Koniaris, Leonidas G Zimmers, Teresa A eng No number/Heroes Foundation/ R01-CA122596/CA/NCI NIH HHS/ No number/Lustgarten Foundation/ No number/Lilly Endowment/ R01-CA194593/CA/NCI NIH HHS/ No number/IUPUI Signature Center for Pancreatic Cancer Research/ I01 BX004177/BX/BLRD VA/ R01-DK096167/DK/NIDDK NIH HHS/ P30-CA082709/CA/NCI NIH HHS/ I01 CX002046/CX/CSRD VA/ Switzerland Cancers (Basel). 2020 Dec 15;12(12):3787. doi: 10.3390/cancers12123787.I | 12/19/2020 | ||
| A Plasma Proteomic Signature of Skeletal Muscle Mitochondrial Function | Zampino M, et al. | 2020 | Int J Mol Sci | 21 | 24 | https://www.doi.org/10.3390/ijms21249540 | 33,333,910 | Adult Aged Aged, 80 and over Energy Metabolism/physiology Female Gene Ontology Humans Inflammation/blood Magnetic Resonance Spectroscopy Male Middle Aged Mitochondria/*metabolism Muscle, Skeletal/*metabolism Oxidative Stress/physiology Plasma/*metabolism Proteome/*metabolism Proteomics Reactive Oxygen Species/metabolism SOMAscan aptamers inflammation mitochondria oxidative capacity phosphorous magnetic resonance spectroscopy plasma skeletal muscle | Although mitochondrial dysfunction has been implicated in aging, physical function decline, and several age-related diseases, an accessible and affordable measure of mitochondrial health is still lacking. In this study we identified the proteomic signature of muscular mitochondrial oxidative capacity in plasma. In 165 adults, we analyzed the association between concentrations of plasma proteins, measured using the SOMAscan assay, and skeletal muscle maximal oxidative phosphorylation capacity assessed as post-exercise phosphocreatine recovery time constant (tau(PCr)) by phosphorous magnetic resonance spectroscopy. Out of 1301 proteins analyzed, we identified 87 proteins significantly associated with tau(PCr), adjusting for age, sex, and phosphocreatine depletion. Sixty proteins were positively correlated with better oxidative capacity, while 27 proteins were correlated with poorer capacity. Specific clusters of plasma proteins were enriched in the following pathways: homeostasis of energy metabolism, proteostasis, response to oxidative stress, and inflammation. The generalizability of these findings would benefit from replication in an independent cohort and in longitudinal analyses. | Zampino, Marta Tanaka, Toshiko Ubaida-Mohien, Ceereena Fantoni, Giovanna Candia, Julian Semba, Richard D Ferrucci, Luigi eng R01 AG057723/AG/NIA NIH HHS/ R01 AG057723/NH/NIH HHS/ Switzerland Int J Mol Sci. 2020 Dec 15;21(24):9540. doi: 10.3390/ijms21249540.I | 12/19/2020 | ||
| Genetic architecture of host proteins involved in SARS-CoV-2 infection | Pietzner M, et al. | 2020 | Nat Commun | 11 | 1 | 6397 | https://www.doi.org/10.1038/s41467-020-19996-z | 33,328,453 | ABO Blood-Group System/metabolism Aptamers, Peptide/blood/metabolism Blood Coagulation COVID-19/*genetics/*virology Drug Delivery Systems Female Gene Expression Regulation Host-Derived Cellular Factors/metabolism Host-Pathogen Interactions/*genetics Humans Internet Male Middle Aged Proteins/*genetics Quantitative Trait Loci/genetics SARS-CoV-2/*physiology | Understanding the genetic architecture of host proteins interacting with SARS-CoV-2 or mediating the maladaptive host response to COVID-19 can help to identify new or repurpose existing drugs targeting those proteins. We present a genetic discovery study of 179 such host proteins among 10,708 individuals using an aptamer-based technique. We identify 220 host DNA sequence variants acting in cis (MAF 0.01-49.9%) and explaining 0.3-70.9% of the variance of 97 of these proteins, including 45 with no previously known protein quantitative trait loci (pQTL) and 38 encoding current drug targets. Systematic characterization of pQTLs across the phenome identified protein-drug-disease links and evidence that putative viral interaction partners such as MARK3 affect immune response. Our results accelerate the evaluation and prioritization of new drug development programmes and repurposing of trials to prevent, treat or reduce adverse outcomes. Rapid sharing and detailed interrogation of results is facilitated through an interactive webserver ( https://omicscience.org/apps/covidpgwas/ ). | Pietzner, Maik Wheeler, Eleanor Carrasco-Zanini, Julia Raffler, Johannes Kerrison, Nicola D Oerton, Erin Auyeung, Victoria P W Luan, Jian'an Finan, Chris Casas, Juan P Ostroff, Rachel Williams, Steve A Kastenmuller, Gabi Ralser, Markus Gamazon, Eric R Wareham, Nicholas J Hingorani, Aroon D Langenberg, Claudia eng MC_UU_00006/1/MRC_/Medical Research Council/United Kingdom R01 HG011138/HG/NHGRI NIH HHS/ FC001134/MRC_/Medical Research Council/United Kingdom DH_/Department of Health/United Kingdom U19 AG063744/AG/NIA NIH HHS/ MC_PC_13046/MRC_/Medical Research Council/United Kingdom AA/18/6/34223/BHF_/British Heart Foundation/United Kingdom RF1 AG059093/AG/NIA NIH HHS/ U01 AG061359/AG/NIA NIH HHS/ MC_UU_12015/1/MRC_/Medical Research Council/United Kingdom RF1 AG058942/AG/NIA NIH HHS/ R35 HG010718/HG/NHGRI NIH HHS/ FC001134/WT_/Wellcome Trust/United Kingdom FC001134/CRUK_/Cancer Research UK/United Kingdom RF1 AG057452/AG/NIA NIH HHS/ WT_/Wellcome Trust/United Kingdom Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't England Nat Commun. 2020 Dec 16;11(1):6397. doi: 10.1038/s41467-020-19996-z.I | 12/18/2020 | |
| Transcriptomic profiling across the nonalcoholic fatty liver disease spectrum reveals gene signatures for steatohepatitis and fibrosis | Govaere O, et al. | 2020 | Sci Transl Med | 12 | 572 | https://www.doi.org/10.1126/scitranslmed.aba4448 | 33,268,509 | *Diabetes Mellitus, Type 2/pathology Humans Liver/pathology Liver Cirrhosis/genetics/pathology *Non-alcoholic Fatty Liver Disease/genetics/pathology Transcriptome/genetics | The mechanisms that drive nonalcoholic fatty liver disease (NAFLD) remain incompletely understood. This large multicenter study characterized the transcriptional changes that occur in liver tissue across the NAFLD spectrum as disease progresses to cirrhosis to identify potential circulating markers. We performed high-throughput RNA sequencing on a discovery cohort comprising histologically characterized NAFLD samples from 206 patients. Unsupervised clustering stratified NAFLD on the basis of disease activity and fibrosis stage with differences in age, aspartate aminotransferase (AST), type 2 diabetes mellitus, and carriage of PNPLA3 rs738409, a genetic variant associated with NAFLD. Relative to early disease, we consistently identified 25 differentially expressed genes as fibrosing steatohepatitis progressed through stages F2 to F4. This 25-gene signature was independently validated by logistic modeling in a separate replication cohort (n = 175), and an integrative analysis with publicly available single-cell RNA sequencing data elucidated the likely relative contribution of specific intrahepatic cell populations. Translating these findings to the protein level, SomaScan analysis in more than 300 NAFLD serum samples confirmed that circulating concentrations of proteins AKR1B10 and GDF15 were strongly associated with disease activity and fibrosis stage. Supporting the biological plausibility of these data, in vitro functional studies determined that endoplasmic reticulum stress up-regulated expression of AKR1B10, GDF15, and PDGFA, whereas GDF15 supplementation tempered the inflammatory response in macrophages upon lipid loading and lipopolysaccharide stimulation. This study provides insights into the pathophysiology of progressive fibrosing steatohepatitis, and proof of principle that transcriptomic changes represent potentially tractable and clinically relevant markers of disease progression. | Govaere, Olivier Cockell, Simon Tiniakos, Dina Queen, Rachel Younes, Ramy Vacca, Michele Alexander, Leigh Ravaioli, Federico Palmer, Jeremy Petta, Salvatore Boursier, Jerome Rosso, Chiara Johnson, Katherine Wonders, Kristy Day, Christopher P Ekstedt, Mattias Oresic, Matej Darlay, Rebecca Cordell, Heather J Marra, Fabio Vidal-Puig, Antonio Bedossa, Pierre Schattenberg, Jorn M Clement, Karine Allison, Michael Bugianesi, Elisabetta Ratziu, Vlad Daly, Ann K Anstee, Quentin M eng Multicenter Study Research Support, Non-U.S. Gov't Sci Transl Med. 2020 Dec 2;12(572):eaba4448. doi: 10.1126/scitranslmed.aba4448.I | 12/04/2020 | ||
| Activity of ibrutinib plus R-CHOP in diffuse large B-cell lymphoma: Response, pharmacodynamic, and biomarker analyses of a phase Ib study | Schaffer M, et al. | 2020 | Cancer Treat Res Commun | 25 | 100235 | https://www.doi.org/10.1016/j.ctarc.2020.100235 | 33,188,997 | Adenine/*analogs & derivatives/pharmacology/therapeutic use Antineoplastic Combined Chemotherapy Protocols/pharmacology/*therapeutic use Biomarkers, Tumor/*metabolism Cyclophosphamide/pharmacology/therapeutic use Disease-Free Survival Doxorubicin/pharmacology/therapeutic use Female Humans Lymphoma, Large B-Cell, Diffuse/*drug therapy Male Middle Aged Piperidines/pharmacology/*therapeutic use Prednisone/pharmacology/therapeutic use Prognosis Rituximab/pharmacology/therapeutic use Vincristine/pharmacology/therapeutic use Biomarkers Diffuse large b-cell lymphoma Ibrutinib Phase Ib R-chop Response to treatment | INTRODUCTION: This unplanned post-hoc analysis was based on data from the phase Ib DBL1002 study (NCT01569750) and evaluated the association between molecular biomarkers and clinical response to combined treatment with ibrutinib plus rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in diffuse large B-cell lymphoma (DLBCL) subtypes. METHODS: DLBCL subtyping was conducted using immunohistochemistry. Next-generation sequencing using immunoglobulin H primers assessed minimal residual disease (MRD). A quantitative assay evaluated Bruton's tyrosine kinase (BTK) occupancy by ibrutinib in peripheral blood mononuclear cells. Targeted DNA sequencing examined genetic variants by DLBCL subtype. Secreted protein expression was evaluated with a SomaLogic analyte panel. RESULTS: Among 21 patients with DLBCL (median age 53.5 years), 17 achieved a complete response (CR) and 4 a partial response (PR). Of the 11 subtyped patients, 9 had a CR (5/7 germinal center B-cell-like [GCB] and 4/4 non-GCB) and 2 had a PR (both GCB). Nine of 12 patients tested for MRD achieved early (cycle 2 day 1) MRD negativity; most had a CR. There was near-complete BTK occupancy at 4 h postdose. Mutation analysis (n = 19) revealed variants including CREBBP, KMT2D, LRP1B, BCL2, and TNFRSF14; only 1 CD79B and TP53 each; no CARD11 or MYD88. CONCLUSIONS: In this study, first-line ibrutinib plus R-CHOP benefited patients with DLBCL, with good overall response rate and early MRD negativity. With a caveat of small sample size, our results showed that a favorable genetic profile and younger patient age may be important to beneficial clinical outcome with ibrutinib plus R-CHOP in DLBCL. | Schaffer, Michael Chaturvedi, Shalini Davis, Cuc de Jong, Jan Aquino, Regina Oki, Yasuhiro Fourneau, Nele Younes, Anas Balasubramanian, Sriram eng Clinical Trial, Phase I Research Support, Non-U.S. Gov't England Cancer Treat Res Commun. 2020;25:100235. doi: 10.1016/j.ctarc.2020.100235. Epub 2020 Nov 1.I | 11/15/2020 | ||
| Modified aptamers as reagents to characterize recombinant human erythropoietin products | Jankowski W, et al. | 2020 | Sci Rep | 10 | 1 | 18593 | https://www.doi.org/10.1038/s41598-020-75713-2 | 33,122,796 | Aptamers, Nucleotide/*chemistry Biosimilar Pharmaceuticals/chemistry Erythropoietin/*chemistry Humans Indicators and Reagents/*chemistry Marketing/methods Protein Conformation Recombinant Proteins/*chemistry | Reliable and reproducible monitoring of the conformational state of therapeutic protein products remains an unmet technological need. This need is amplified by the increasing number of biosimilars entering the drug development pipeline as many branded biologics are reaching the end of their market exclusivity period. Availability of methods to better characterize protein conformation may improve detection of counterfit and unlicensed therapeutic proteins. In this study, we report the use of a set of modified DNA aptamers with enhanced chemical diversity to probe the conformational state of 12 recombinant human erythropoietin (rHuEPO) therapeutic protein products; one FDA-licensed rHuEPO originator biological product, three rHuEPO products that are approved for marketing in the US or EU as biosimilars, and eight rHuEPO products that are not approved for marketing in the US or EU. We show that several of these modified aptamers are able to distinguish rHuEPO reference products or approved biosimilars from non-licensed rHuEPO products on the basis of differences in binding kinetics and equilibrium affinity constants. These reagents exhibit sensitivity to the conformational integrity of various forms of rHuEPO and as such represent powerful, simple-to-use analytical tools to monitor the conformational integrity of therapeutic-proteins during manufacture and to screen for and identify both substandard and counterfeit products. | Jankowski, Wojciech Lagasse, H A Daniel Chang, William C McGill, Joseph Jankowska, Katarzyna I Gelinas, Amy D Janjic, Nebojsa Sauna, Zuben E eng Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S. England Sci Rep. 2020 Oct 29;10(1):18593. doi: 10.1038/s41598-020-75713-2.I | 10/31/2020 | |
| Proteomic Signatures of Heart Failure in Relation to Left Ventricular Ejection Fraction | Adamo L, et al. | 2020 | J Am Coll Cardiol | 76 | 17 | 1982-1994 | https://www.doi.org/10.1016/j.jacc.2020.08.061 | 33,092,734 | Blood Proteins/*analysis Female Heart Failure/*blood/etiology Humans Male Matched-Pair Analysis Middle Aged Myocardial Ischemia/blood *Proteomics Registries Signal Transduction *Stroke Volume Wnt Signaling Pathway heart failure left ventricular ejection fraction proteomics | BACKGROUND: There is a growing recognition of the inherent limitations of the use of the left ventricular ejection fraction (LVEF) to accurately phenotype patients with heart failure (HF). OBJECTIVES: The authors sought to identify unique proteomic signatures for patients with HF with reduced ejection fraction (HFrEF), HF with a midrange LVEF (HFmrEF), and HF with preserved ejection fraction (HFpEF), as well as to identify molecular differences between patients with ischemic and nonischemic HF. METHODS: We used high-content aptamer-based proteomics technology (SOMAscan) to interrogate the blood proteome of age- and sex-matched patients with HF within different LVEF groups. RESULTS: Within the Washington University Heart Failure Registry, we identified age/sex-matched patients within 3 LVEF categories: HFrEF (LVEF <40%), HFmrEF (LVEF 40% to 50%), and HFpEF (LVEF >50%). We found that patients with HFrEF, HFmrEF, and HFpEF had unique variations in circulating proteins that reflected distinct biological pathophysiologies. Bioinformatics analysis revealed that there were biological themes that were unique to patients with HFrEF, HFpEF, or HFmrEF. Comparative analyses of patients with HFmrEF with improved LVEF and patients with HFmrEF with unchanged LVEF revealed marked differences between these 2 patient populations and indicated that patients with recovered LVEF are more similar to patients with HFpEF than to patients with HFrEF. Moreover, there were marked differences in the proteomic signatures of patients with ischemic and nonischemic HF. CONCLUSIONS: Viewed together, these findings suggest that it may be possible to use high-content multiplexed proteomics assays in combination with the clinical assessment of LVEF to more accurately identify clinical phenotypes of patients with HF. | Adamo, Luigi Yu, Jinsheng Rocha-Resende, Cibele Javaheri, Ali Head, Richard D Mann, Douglas L eng RC2 HL102222/HL/NHLBI NIH HHS/ I01 BX005065/BX/BLRD VA/ UL1 TR000448/TR/NCATS NIH HHS/ K08 HL138262/HL/NHLBI NIH HHS/ UL1 TR002345/TR/NCATS NIH HHS/ U10 HL110309/HL/NHLBI NIH HHS/ P30 CA091842/CA/NCI NIH HHS/ K08 HL145108/HL/NHLBI NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't J Am Coll Cardiol. 2020 Oct 27;76(17):1982-1994. doi: 10.1016/j.jacc.2020.08.061.I | 10/24/2020 | |
| Plasma proteomic profile of age, health span, and all-cause mortality in older adults | Sathyan S, et al. | 2020 | Aging Cell | 19 | 11 | e13250 | https://www.doi.org/10.1111/acel.13250 | 33,089,916 | Aged Aging/*physiology Female Humans Male Mortality/*trends Plasma/cytology/*metabolism Proteomics/*methods SomaScan(R) assay aging proteomics weighted gene co-expression network analysis | Aging is a complex trait characterized by a diverse spectrum of endophenotypes. By utilizing the SomaScan((R)) proteomic platform in 1,025 participants of the LonGenity cohort (age range: 65-95, 55.7% females), we found that 754 of 4,265 proteins were associated with chronological age. Pleiotrophin (PTN; beta[SE] = 0.0262 [0.0012]; p = 3.21 x 10(-86) ), WNT1-inducible-signaling pathway protein 2 (WISP-2; beta[SE] = 0.0189 [0.0009]; p = 4.60 x 10(-82) ), chordin-like protein 1 (CRDL1; beta[SE] = 0.0203[0.0010]; p = 1.45 x 10(-77) ), transgelin (TAGL; beta[SE] = 0.0215 [0.0011]; p = 9.70 x 10(-71) ), and R-spondin-1(RSPO1; beta[SE] = 0.0208 [0.0011]; p = 1.09 x 10(-70) ), were the proteins most significantly associated with age. Weighted gene co-expression network analysis identified two of nine modules (clusters of highly correlated proteins) to be significantly associated with chronological age and demonstrated that the biology of aging overlapped with complex age-associated diseases and other age-related traits. The correlation between proteomic age prediction based on elastic net regression and chronological age was 0.8 (p < 2.2E-16). Pathway analysis showed that inflammatory response, organismal injury and abnormalities, cell and organismal survival, and death pathways were associated with aging. The present study made novel associations between a number of proteins and aging, constructed a proteomic age model that predicted mortality, and suggested possible proteomic signatures possessed by a cohort enriched for familial exceptional longevity. | Sathyan, Sanish Ayers, Emmeline Gao, Tina Weiss, Erica F Milman, Sofiya Verghese, Joe Barzilai, Nir eng R01 AG046949/AG/NIA NIH HHS/ R01 AG057909/AG/NIA NIH HHS/ P01 AG021654/AG/NIA NIH HHS/ R01 AG061155/AG/NIA NIH HHS/ R01 AG044829/AG/NIA NIH HHS/ P30 DK020541/DK/NIDDK NIH HHS/ P30 AG038072/AG/NIA NIH HHS/ K23 AG051148/AG/NIA NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't England Aging Cell. 2020 Nov;19(11):e13250. doi: 10.1111/acel.13250. Epub 2020 Oct 22.I | 10/23/2020 | |
| Vascular Disease and Thrombosis in SARS-CoV-2-Infected Rhesus Macaques | Aid M, et al. | 2020 | Cell | 183 | 5 | 1354-1366 e13 | https://www.doi.org/10.1016/j.cell.2020.10.005 | 33,065,030 | Aged, 80 and over Animals Bronchoalveolar Lavage C-Reactive Protein/analysis COVID-19/blood/*complications/*immunology/pathology Complement Activation Cytokines/blood Female Humans Inflammation/blood/immunology/virology Lung/pathology Macaca mulatta Macrophages/immunology Male Platelet Activation SARS-CoV-2/*genetics Thrombosis/blood/*complications/pathology Transcriptome Vascular Diseases/blood/*complications/pathology IFNalpha SARS-CoV-2 coagulation collagen complement macrophage platelet thrombosis vWF vascular | The COVID-19 pandemic has led to extensive morbidity and mortality throughout the world. Clinical features that drive SARS-CoV-2 pathogenesis in humans include inflammation and thrombosis, but the mechanistic details underlying these processes remain to be determined. In this study, we demonstrate endothelial disruption and vascular thrombosis in histopathologic sections of lungs from both humans and rhesus macaques infected with SARS-CoV-2. To define key molecular pathways associated with SARS-CoV-2 pathogenesis in macaques, we performed transcriptomic analyses of bronchoalveolar lavage and peripheral blood and proteomic analyses of serum. We observed macrophage infiltrates in lung and upregulation of macrophage, complement, platelet activation, thrombosis, and proinflammatory markers, including C-reactive protein, MX1, IL-6, IL-1, IL-8, TNFalpha, and NF-kappaB. These results suggest a model in which critical interactions between inflammatory and thrombosis pathways lead to SARS-CoV-2-induced vascular disease. Our findings suggest potential therapeutic targets for COVID-19. | Aid, Malika Busman-Sahay, Kathleen Vidal, Samuel J Maliga, Zoltan Bondoc, Stephen Starke, Carly Terry, Margaret Jacobson, Connor A Wrijil, Linda Ducat, Sarah Brook, Olga R Miller, Andrew D Porto, Maciel Pellegrini, Kathryn L Pino, Maria Hoang, Timothy N Chandrashekar, Abishek Patel, Shivani Stephenson, Kathryn Bosinger, Steven E Andersen, Hanne Lewis, Mark G Hecht, Jonathan L Sorger, Peter K Martinot, Amanda J Estes, Jacob D Barouch, Dan H eng U54 CA225088/CA/NCI NIH HHS/ P51 OD011092/OD/NIH HHS/ P51 OD011132/OD/NIH HHS/ U01 CA260476/CA/NCI NIH HHS/ S10 OD025002/OD/NIH HHS/ S10 OD026799/OD/NIH HHS/ U24 AI118672/AI/NIAID NIH HHS/ UM1 AI124377/AI/NIAID NIH HHS/ U19 AI128751/AI/NIAID NIH HHS/ R01 AI129797/AI/NIAID NIH HHS/ R01 AI149670/AI/NIAID NIH HHS/ UM1 AI126603/AI/NIAID NIH HHS/ K08 AI135098/AI/NIAID NIH HHS/ R01 OD024917/OD/NIH HHS/ Case Reports Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Cell. 2020 Nov 25;183(5):1354-1366.e13. doi: 10.1016/j.cell.2020.10.005. Epub 2020 Oct 9.I | 10/17/2020 | |
| Comparison of Serum Pharmacodynamic Biomarkers in Prednisone-Versus Deflazacort-Treated Duchenne Muscular Dystrophy Boys | Tawalbeh S, et al. | 2020 | J Pers Med | 10 | 4 | https://www.doi.org/10.3390/jpm10040164 | 33,053,810 | Duchenne muscular dystrophy corticosteroids deflazacort glucocorticoids pharmacodynamic biomarkers prednisone safety | Prednisone (Pred) and Deflazacort (Dfz) are commonly used glucocorticoids (GCs) for Duchenne muscular dystrophy (DMD) treatment and management. While GCs are known to delay the loss of ambulation and motor abilities, chronic use can result in onerous side effects, e.g., weight gain, growth stunting, loss of bone density, etc. Here, we use the CINRG Duchenne natural history study to gain insight into comparative safety of Pred versus Dfz treatment through GC-responsive pharmacodynamic (PD) biomarkers. Longitudinal trajectories of SOMAscan((R)) protein data obtained on serum of DMD boys aged 4 to 10 (Pred: n = 7; Dfz: n = 8) were analyzed after accounting for age and time on treatment. Out of the pre-specified biomarkers, seventeen candidate proteins were differentially altered between the two drugs (p < 0.05). These include IGFBP-2 and AGER associated with diabetes complications, and MMP-3 associated with extracellular remodeling. As a follow-up, IGFBP-2, MMP-3, and IGF-I were quantified with an ELISA using a larger sample size of DMD biosamples (Dfz: n = 17, Pred: n = 12; up to 76 sera samples) over a longer treatment duration. MMP-3 and IGFBP-2 validated the SOMAscan((R)) signal, however, IGF-I did not. This study identified GC-responsive biomarkers, some associated with safety, that highlight differential PD response between Dfz and Pred. | Tawalbeh, Shefa Samsel, Alison Gordish-Dressman, Heather Hathout, Yetrib Investigators, Cinrg-Dnhs Dang, Utkarsh J eng W81XWH-16-1-0557/U.S. Department of Defense/ P50HD090254/Eunice Kennedy Shriver National Institute of Child Health and Human Development/ Switzerland J Pers Med. 2020 Oct 12;10(4):164. doi: 10.3390/jpm10040164.I | 10/16/2020 | ||
| The Evolution of the Cardiovascular Biomarker Study | Wang TJ | 2020 | Circulation | 142 | 15 | 1422-1424 | https://www.doi.org/10.1161/CIRCULATIONAHA.120.049682 | 33,044,857 | Biomarkers Humans *Myocardial Infarction Editorials gene expression profiling heart failure myocardial infarction transcriptome | Wang, Thomas J eng Comment Editorial Circulation. 2020 Oct 13;142(15):1422-1424. doi: 10.1161/CIRCULATIONAHA.120.049682. Epub 2020 Oct 12.I | 10/13/2020 | ||
| Serum protein biomarkers for juvenile dermatomyositis: a pilot study | Tawalbeh SM, et al. | 2020 | BMC Rheumatol | 4 | 52 | https://www.doi.org/10.1186/s41927-020-00150-7 | 33,015,544 | Biomarkers Juvenile dermatomyositis Pharmacodynamic biomarkers Serum proteomics SomaScan(R) | BACKGROUND: Blood accessible biomarkers to assess disease activity and their response to therapies in Juvenile Dermatomyositis (JDM) are urgently needed. This pilot study aims to identify serum protein biomarkers associated with clinical disease activity in untreated JDM and their response to medical therapy. METHODS: SomaScan(R) technology screened JDM patients for 1305 proteins at three points: 1) before start of treatment, 2) while on therapy, and 3) after treatment tapering when patients were clinically inactive. To define disease associated biomarkers, SomaScan(R) data from untreated JDM patients (n = 8) were compared to SomaScan(R) data from an independent age-matched healthy control group (n = 12). Longitudinal analysis defined treatment responsive proteins at three time points: untreated (7 samples), treated (7 samples), and clinically inactive (6 samples). To confirm the SomaScan(R) data, a subset of nine candidate proteins (CXCL11, IL-17B, IL-17D, IL-22, CXCL10, MCP-1, ANGPT2, MIF, IL-23) were tested by ELISA after adding 2 JDM (one untreated, one clinically inactive) serum samples to the same group of JDM girls (8 untreated, 7 treated; 7 clinically inactive) as well as with 17 age, gender, matched healthy controls. RESULTS: Comparison of untreated JDM versus healthy controls identified 202 elevated and 49 decreased serum proteins in JDM patients with an adjusted p-value < 0.001. Only 82 out of 251 identified biomarker candidates responded to treatment while 12 out of these 82 proteins returned to their original untreated disease levels upon therapy tapering. The ELISA testing of the untreated samples for nine candidate proteins confirmed previously known biomarkers (CXCL10 or IP-10, CXCL11 or I-TAC and MCP-1) and identified novel biomarkers including IL-22, Angiopoetin-2, and IL-17B in a cross-sectional analysis comparing 8 untreated JDM and 17 age/gender matched controls. The subsequent longitudinal data by ELISA were not concordant for some biomarkers (IL-22 and IL-17B), but the other biomarkers either normalized or rebounded concordantly. CONCLUSIONS: Blood accessible protein biomarkers reflecting JDM pathophysiology were identified; some of them rebounded after therapy was tapered. Further studies bridging these biomarkers to specific clinical features of JDM are required to confirm the clinical utility of these serum protein biomarkers. | Tawalbeh, Shefa M Marin, Wilfredo Morgan, Gabrielle A Dang, Utkarsh J Hathout, Yetrib Pachman, Lauren M eng England BMC Rheumatol. 2020 Oct 1;4:52. doi: 10.1186/s41927-020-00150-7. eCollection 2020.I | 10/06/2020 | ||
| Clinical and Proteomic Correlates of Plasma ACE2 (Angiotensin-Converting Enzyme 2) in Human Heart Failure | Chirinos JA, et al. | 2020 | Hypertension | 76 | 5 | 1526-1536 | https://www.doi.org/10.1161/HYPERTENSIONAHA.120.15829 | 32,981,365 | Academic Medical Centers Analysis of Variance Angiotensin-Converting Enzyme 2 Biomarkers/metabolism Covid-19 Cohort Studies Coronavirus Infections/*epidemiology/prevention & control Disease Outbreaks/*statistics & numerical data *Disease Progression Female Heart Failure/*enzymology/*physiopathology Humans Linear Models Male Middle Aged Pandemics/prevention & control Peptidyl-Dipeptidase A/*blood Pneumonia, Viral/*epidemiology/prevention & control Prognosis Proportional Hazards Models Proteomics/methods Retrospective Studies Sensitivity and Specificity Severity of Illness Index United States heart failure proteomics renin-angiotensin system | ACE2 (angiotensin-converting enzyme 2) is a key component of the renin-angiotensin-aldosterone system. Yet, little is known about the clinical and biologic correlates of circulating ACE2 levels in humans. We assessed the clinical and proteomic correlates of plasma (soluble) ACE2 protein levels in human heart failure. We measured plasma ACE2 using a modified aptamer assay among PHFS (Penn Heart Failure Study) participants (n=2248). We performed an association study of ACE2 against approximately 5000 other plasma proteins measured with the SomaScan platform. Plasma ACE2 was not associated with ACE inhibitor and angiotensin-receptor blocker use. Plasma ACE2 was associated with older age, male sex, diabetes mellitus, a lower estimated glomerular filtration rate, worse New York Heart Association class, a history of coronary artery bypass surgery, and higher pro-BNP (pro-B-type natriuretic peptide) levels. Plasma ACE2 exhibited associations with 1011 other plasma proteins. In pathway overrepresentation analyses, top canonical pathways associated with plasma ACE2 included clathrin-mediated endocytosis signaling, actin cytoskeleton signaling, mechanisms of viral exit from host cells, EIF2 (eukaryotic initiation factor 2) signaling, and the protein ubiquitination pathway. In conclusion, in humans with heart failure, plasma ACE2 is associated with various clinical factors known to be associated with severe coronavirus disease 2019 (COVID-19), including older age, male sex, and diabetes mellitus, but is not associated with ACE inhibitor and angiotensin-receptor blocker use. Plasma ACE2 protein levels are prominently associated with multiple cellular pathways involved in cellular endocytosis, exocytosis, and intracellular protein trafficking. Whether these have a causal relationship with ACE2 or are relevant to novel coronavirus-2 infection remains to be assessed in future studies. | Chirinos, Julio A Cohen, Jordana B Zhao, Lei Hanff, Thomas Sweitzer, Nancy Fang, James Corrales-Medina, Vicente Anmar, Ron Morley, Michael Zamani, Payman Bhattacharya, Priyanka Brandimarto, Jeff Jia, Yi Basso, Michael D Wang, Zhaoqing Ebert, Christina Ramirez-Valle, Francisco Schafer, Peter H Seiffert, Dietmar Gordon, David A Cappola, Thomas eng Multicenter Study Research Support, Non-U.S. Gov't Hypertension. 2020 Nov;76(5):1526-1536. doi: 10.1161/HYPERTENSIONAHA.120.15829. Epub 2020 Sep 28.I | 09/29/2020 | |
| Causal association between mTOR-dependent EIF-4E and EIF-4A circulating protein levels and type 2 diabetes: a Mendelian randomization study | Soliman GA, et al. | 2020 | Sci Rep | 10 | 1 | 15737 | https://www.doi.org/10.1038/s41598-020-71987-8 | 32,978,410 | Databases, Genetic Diabetes Mellitus, Type 2/genetics/*metabolism Eukaryotic Initiation Factor-4A/blood/*genetics Eukaryotic Initiation Factor-4E/blood/*genetics Eukaryotic Initiation Factor-4G/blood/genetics Eukaryotic Initiation Factors/blood/genetics Genetic Association Studies Humans Mechanistic Target of Rapamycin Complex 1/metabolism Mendelian Randomization Analysis *Polymorphism, Single Nucleotide Signal Transduction | The mammalian Target of Rapamycin complex 1 (mTORC1) nutrient-sensing pathway is a central regulator of cell growth and metabolism and is dysregulated in diabetes. The eukaryotic translation initiation factor 4E (EIF-4E) protein, a key regulator of gene translation and protein function, is controlled by mTORC1 and EIF-4E Binding Proteins (EIF4EBPs). Both EIF4EBPs and ribosomal protein S6K kinase (RP-S6K) are downstream effectors regulated by mTORC1 but converge to regulate two independent pathways. We investigated whether the risk of type 2 diabetes varied with genetically predicted EIF-4E, EIF-4A, EIF-4G, EIF4EBP, and RP-S6K circulating levels using Mendelian Randomization. We estimated the causal role of EIF-4F complex, EIF4EBP, and S6K in the circulation on type 2 diabetes, based on independent single nucleotide polymorphisms strongly associated (p = 5 x 10(-6)) with EIF-4E (16 SNPs), EIF-4A (11 SNPs), EIF-4G (6 SNPs), EIF4EBP2 (12 SNPs), and RP-S6K (16 SNPs). The exposure data were obtained from the INTERVAL study. We applied these SNPs for each exposure to publically available genetic associations with diabetes from the DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) case (n = 26,676) and control (n = 132,532) study (mean age 57.4 years). We meta-analyzed SNP-specific Wald-estimates using inverse variance weighting with multiplicative random effects and conducted sensitivity analysis. Mendelian Randomization (MR-Base) R package was used in the analysis. The PhenoScanner curated database was used to identify disease associations with SNP gene variants. EIF-4E is associated with a lowered risk of type 2 diabetes with an odds ratio (OR) 0.94, 95% confidence interval (0.88, 0.99, p = 0.03) with similar estimates from the weighted median and MR-Egger. Similarly, EIF-4A was associated with lower risk of type 2 diabetes with odds ratio (OR) 0.90, 95% confidence interval (0.85, 0.97, p = 0.0003). Sensitivity analysis using MR-Egger and weighed median analysis does not indicate that there is a pleiotropic effect. This unbiased Mendelian Randomization estimate is consistent with a protective causal association of EIF-4E and EIF-4A on type 2 diabetes. EIF-4E and EIF-4A may be targeted for intervention by repurposing existing therapeutics to reduce the risk of type 2 diabetes. | Soliman, Ghada A Schooling, C Mary eng Research Support, Non-U.S. Gov't England Sci Rep. 2020 Sep 25;10(1):15737. doi: 10.1038/s41598-020-71987-8.I | 09/27/2020 | |
| Plasma Biomarkers of Reticular Pseudodrusen and the Risk of Progression to Advanced Age-Related Macular Degeneration | Lynch AM, et al. | 2020 | Transl Vis Sci Technol | 9 | 10 | 12 | https://www.doi.org/10.1167/tvst.9.10.12 | 32,974,084 | Biomarkers Humans *Macular Degeneration/diagnosis Proteins Proteomics *Retinal Drusen/diagnosis aptamer-based proteomics intermediate age-related macular degeneration reticular pseudodrusen SomaLogic (E, I) J.L. Patnaik, None M.T. Mathias, None F.S. Siringo, None N. Mandava, SomaLogic (C) | PURPOSE: To determine, using an aptamer-based technology in patients with intermediate age-related macular degeneration (AMD), (1) if there is a difference in plasma levels of 4979 proteins in patients with and without reticular pseudodrusen (RPD), and (2) if plasma levels of proteins are related to time to conversion to advanced AMD. METHODS: Patients with intermediate AMD and RPD were identified from an AMD registry. Relative concentrations of each protein were log (base 2) transformed and compared between patients with and without RPD using linear regression. A Cox proportional hazards survival model was fit to each aptamer to quantify associations with time to conversion. A pathway analysis was conducted in converters versus non-converters using the Reactome database. RESULTS: Of the 109 intermediate AMD patients, 39 had bilateral RPD (36%). Two proteins, TCL1A and CNDP1, were lower in patients in the intermediate AMD group with RPD. Twenty-one patients converted to advanced AMD with a median time to conversion of 25.2 months (range, 2.3-48.5 months) and median follow-up time in non-converters of 26.4 months (range, 0.03-49.7 months). Several proteins (lysozyme C, TFF3, RNAS6, and SAP3) distinguished patients who converted from those who did not convert to advanced AMD. The top conversion pathways included tumor necrosis factors bind their physiological receptors, digestion and absorption, signaling by activin, and signaling by TGF-beta family members. CONCLUSIONS: We identified a protein signature related to RPD, as well as to conversion to advanced AMD. The pathway analysis suggests that dysfunction of critical systemic pathways may have links to conversion to advanced AMD. TRANSLATIONAL RELEVANCE: Biomarkers identified in plasma likely reflect systemic alterations in protein expression in patients with intermediate AMD. | Lynch, Anne M Wagner, Brandie D Palestine, Alan G Janjic, Nebojsa Patnaik, Jennifer L Mathias, Marc T Siringo, Frank S Mandava, Naresh eng Research Support, Non-U.S. Gov't Transl Vis Sci Technol. 2020 Sep 11;9(10):12. doi: 10.1167/tvst.9.10.12. eCollection 2020 Sep.I | 09/26/2020 | |
| Circulating testican-2 is a podocyte-derived marker of kidney health | Ngo D, et al. | 2020 | Proc Natl Acad Sci U S A | 117 | 40 | 25026-25035 | https://www.doi.org/10.1073/pnas.2009606117 | 32,958,645 | African Americans/genetics Aptamers, Peptide Biomarkers/*metabolism Female Glomerular Filtration Rate/genetics Humans Hypertension/genetics/pathology Kidney/*metabolism/pathology Kidney Function Tests Kidney Glomerulus/metabolism Male Middle Aged Podocytes/metabolism/pathology Proteoglycans/*genetics/metabolism *Proteomics chronic kidney disease proteomics testican-2 receive research support from Vertex, and are inventors on patents related to APOL1 diagnostics and therapeutics. | In addition to their fundamental role in clearance, the kidneys release select molecules into the circulation, but whether any of these anabolic functions provides insight on kidney health is unknown. Using aptamer-based proteomics, we characterized arterial (A)-to-renal venous (V) gradients for >1,300 proteins in 22 individuals who underwent invasive sampling. Although most of the proteins that changed significantly decreased from A to V, consistent with renal clearance, several were found to increase, the most significant of which was testican-2. To assess the clinical implications of these physiologic findings, we examined proteomic data in the Jackson Heart Study (JHS), an African-American cohort (n = 1,928), with replication in the Framingham Heart Study (FHS), a White cohort (n = 1,621). In both populations, testican-2 had a strong, positive correlation with estimated glomerular filtration rate (eGFR). In addition, higher baseline testican-2 levels were associated with a lower rate of eGFR decline in models adjusted for age, gender, hypertension, type 2 diabetes, body mass index, baseline eGFR, and albuminuria. Glomerular expression of testican-2 in human kidneys was demonstrated by immunohistochemistry, immunofluorescence, and electron microscopy, while single-cell RNA sequencing of human kidneys showed expression of the cognate gene, SPOCK2, exclusively in podocytes. In vitro, testican-2 increased glomerular endothelial tube formation and motility, raising the possibility that its secretion has a functional role within the glomerulus. Taken together, our findings identify testican-2 as a podocyte-derived biomarker of kidney health and prognosis. | Ngo, Debby Wen, Donghai Gao, Yan Keyes, Michelle J Drury, Erika R Katz, Dan H Benson, Mark D Sinha, Sumita Shen, Dongxiao Farrell, Laurie A Peterson, Bennet D Friedman, David J Elmariah, Sammy Young, Bessie A Smith, J Gustav Yang, Qiong Vasan, Ramachandran S Larson, Martin G Correa, Adolfo Humphreys, Benjamin D Wang, Thomas J Pollak, Martin R Wilson, James G Gerszten, Robert E Rhee, Eugene P eng HHSN268201800012C/HL/NHLBI NIH HHS/ R01 NR017399/NR/NINR NIH HHS/ HHSN268201500001C/HL/NHLBI NIH HHS/ HHSN268201800014C/HL/NHLBI NIH HHS/ HHSN268201800013I/MD/NIMHD NIH HHS/ R01 HL133870/HL/NHLBI NIH HHS/ 75N92019D00031/HL/NHLBI NIH HHS/ U01 DK106981/DK/NIDDK NIH HHS/ HHSN268201500001I/HL/NHLBI NIH HHS/ R01 HL132320/HL/NHLBI NIH HHS/ HHSN268201800011C/HL/NHLBI NIH HHS/ N01HC25195/HL/NHLBI NIH HHS/ HHSN268201800015I/HB/NHLBI NIH HHS/ K08 HL145095/HL/NHLBI NIH HHS/ T32 DK007540/DK/NIDDK NIH HHS/ Research Support, N.I.H., Extramural Proc Natl Acad Sci U S A. 2020 Oct 6;117(40):25026-25035. doi: 10.1073/pnas.2009606117. Epub 2020 Sep 21.I | 09/23/2020 | |
| Proteomics for personalized cardiovascular risk assessment: in pursuit of the Holy Grail | Ganz P, et al. | 2020 | Eur Heart J | 41 | 41 | 4008-4010 | https://www.doi.org/10.1093/eurheartj/ehaa661 | 32,901,246 | *Cardiovascular Diseases Heart Disease Risk Factors Humans Plasma Primary Prevention *Proteomics Risk Factors | Ganz, Peter Deo, Rajat Dubin, Ruth F eng U01 DK108809/DK/NIDDK NIH HHS/ Comment Editorial Research Support, N.I.H., Extramural England Eur Heart J. 2020 Nov 1;41(41):4008-4010. doi: 10.1093/eurheartj/ehaa661.I | 09/10/2020 | ||
| Targeting myostatin/activin A protects against skeletal muscle and bone loss during spaceflight | Lee SJ, et al. | 2020 | Proc Natl Acad Sci U S A | 117 | 38 | 23942-23951 | https://www.doi.org/10.1073/pnas.2014716117 | 32,900,939 | Activin Receptors, Type II/genetics/metabolism Activins/*metabolism Animals Bone Resorption/*metabolism Female Male Mice Mice, Inbred C57BL Mice, Knockout Muscle, Skeletal/*metabolism Muscular Atrophy/metabolism *Myostatin/genetics/metabolism Signal Transduction *Space Flight activin bone microgravity myostatin skeletal muscle | Among the physiological consequences of extended spaceflight are loss of skeletal muscle and bone mass. One signaling pathway that plays an important role in maintaining muscle and bone homeostasis is that regulated by the secreted signaling proteins, myostatin (MSTN) and activin A. Here, we used both genetic and pharmacological approaches to investigate the effect of targeting MSTN/activin A signaling in mice that were sent to the International Space Station. Wild type mice lost significant muscle and bone mass during the 33 d spent in microgravity. Muscle weights of Mstn(-/-) mice, which are about twice those of wild type mice, were largely maintained during spaceflight. Systemic inhibition of MSTN/activin A signaling using a soluble form of the activin type IIB receptor (ACVR2B), which can bind each of these ligands, led to dramatic increases in both muscle and bone mass, with effects being comparable in ground and flight mice. Exposure to microgravity and treatment with the soluble receptor each led to alterations in numerous signaling pathways, which were reflected in changes in levels of key signaling components in the blood as well as their RNA expression levels in muscle and bone. These findings have implications for therapeutic strategies to combat the concomitant muscle and bone loss occurring in people afflicted with disuse atrophy on Earth as well as in astronauts in space, especially during prolonged missions. | Lee, Se-Jin Lehar, Adam Meir, Jessica U Koch, Christina Morgan, Andrew Warren, Lara E Rydzik, Renata Youngstrom, Daniel W Chandok, Harshpreet George, Joshy Gogain, Joseph Michaud, Michael Stoklasek, Thomas A Liu, Yewei Germain-Lee, Emily L eng R01 AG052962/AG/NIA NIH HHS/ R01 AR060636/AR/NIAMS NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Proc Natl Acad Sci U S A. 2020 Sep 22;117(38):23942-23951. doi: 10.1073/pnas.2014716117. Epub 2020 Sep 8.I | 09/10/2020 | |
| Prioritizing Candidates of Post-Myocardial Infarction Heart Failure Using Plasma Proteomics and Single-Cell Transcriptomics | Chan MY, et al. | 2020 | Circulation | 142 | 15 | 1408-1421 | https://www.doi.org/10.1161/CIRCULATIONAHA.119.045158 | 32,885,678 | Aged Aged, 80 and over Animals Blood Proteins/*biosynthesis Female *Gene Expression Profiling *Gene Expression Regulation *Heart Failure/blood/genetics Humans Male Mice Middle Aged *Myocardial Infarction/blood/complications *Proteomics *Single-Cell Analysis heart failure myocardial infarction proteomics transcriptome | BACKGROUND: Heart failure (HF) is the most common long-term complication of acute myocardial infarction (MI). Understanding plasma proteins associated with post-MI HF and their gene expression may identify new candidates for biomarker and drug target discovery. METHODS: We used aptamer-based affinity-capture plasma proteomics to measure 1305 plasma proteins at 1 month post-MI in a New Zealand cohort (CDCS [Coronary Disease Cohort Study]) including 181 patients post-MI who were subsequently hospitalized for HF in comparison with 250 patients post-MI who remained event free over a median follow-up of 4.9 years. We then correlated plasma proteins with left ventricular ejection fraction measured at 4 months post-MI and identified proteins potentially coregulated in post-MI HF using weighted gene co-expression network analysis. A Singapore cohort (IMMACULATE [Improving Outcomes in Myocardial Infarction through Reversal of Cardiac Remodelling]) of 223 patients post-MI, of which 33 patients were hospitalized for HF (median follow-up, 2.0 years), was used for further candidate enrichment of plasma proteins by using Fisher meta-analysis, resampling-based statistical testing, and machine learning. We then cross-referenced differentially expressed proteins with their differentially expressed genes from single-cell transcriptomes of nonmyocyte cardiac cells isolated from a murine MI model, and single-cell and single-nucleus transcriptomes of cardiac myocytes from murine HF models and human patients with HF. RESULTS: In the CDCS cohort, 212 differentially expressed plasma proteins were significantly associated with subsequent HF events. Of these, 96 correlated with left ventricular ejection fraction measured at 4 months post-MI. Weighted gene co-expression network analysis prioritized 63 of the 212 proteins that demonstrated significantly higher correlations among patients who developed post-MI HF in comparison with event-free controls (data set 1). Cross-cohort meta-analysis of the IMMACULATE cohort identified 36 plasma proteins associated with post-MI HF (data set 2), whereas single-cell transcriptomes identified 15 gene-protein candidates (data set 3). The majority of prioritized proteins were of matricellular origin. The 6 most highly enriched proteins that were common to all 3 data sets included well-established biomarkers of post-MI HF: N-terminal B-type natriuretic peptide and troponin T, and newly emergent biomarkers, angiopoietin-2, thrombospondin-2, latent transforming growth factor-beta binding protein-4, and follistatin-related protein-3, as well. CONCLUSIONS: Large-scale human plasma proteomics, cross-referenced to unbiased cardiac transcriptomics at single-cell resolution, prioritized protein candidates associated with post-MI HF for further mechanistic and clinical validation. | Chan, Mark Y Efthymios, Motakis Tan, Sock Hwee Pickering, John W Troughton, Richard Pemberton, Christopher Ho, Hee-Hwa Prabath, Joseph-Francis Drum, Chester L Ling, Lieng Hsi Soo, Wern-Miin Chai, Siang-Chew Fong, Alan Oon, Yen-Yee Loh, Joshua P Lee, Chi-Hang Foo, Roger S Y Ackers-Johnson, Matthew Andrew Pilbrow, Anna Richards, A Mark eng Clinical Trial Multicenter Study Research Support, Non-U.S. Gov't Circulation. 2020 Oct 13;142(15):1408-1421. doi: 10.1161/CIRCULATIONAHA.119.045158. Epub 2020 Sep 4.I | 09/05/2020 | |
| Renin-Angiotensin System overactivation in polycystic ovary syndrome, a risk for SARS-CoV-2 infection? | Moin ASM, et al. | 2020 | Metabol Open | 7 | 100052 | https://www.doi.org/10.1016/j.metop.2020.100052 | 32,838,280 | ACE2 protein Angiotensinogen Polycystic ovary syndrome Renin | BACKGROUND: The SARS-CoV-2 coronavirus gains entry to target cells via the angiotensin-converting enzyme 2 (ACE2) receptor present on cells in blood vessels, lungs, heart, intestines, and kidneys. Renin-Angiotensin System (RAS) overactivity has also been described in metabolic syndrome, type 2 diabetes (T2D) and obesity, conditions shared by women with polycystic ovary syndrome (PCOS) We hypothesized that RAS overactivity may be present in PCOS. METHODS: We determined plasma levels of RAS-related proteins in a cohort of age matched control women (n = 97) and women with PCOS (n = 146). Plasma levels of RAS-related proteins (ACE2, Renin and Angiotensinogen (AGT)) were determined by Slow Off-rate Modified Aptamer (SOMA)-scan plasma protein measurement. RESULTS: PCOS women had a higher BMI (p < 0.001), systolic (p < 0.0001) and diastolic (p < 0.05) blood pressure, waist circumference (p < 0.0001), testosterone (p < 0.0001), free androgen index (p < 0.0001) and CRP (p < 0.0001). Renin was elevated in PCOS (p < 0.05) and angiotensinogen was lower in PCOS (p < 0.05), indicating overactivity of the RAS system in PCOS. ACE2 levels were lower in PCOS (p < 0.05), suggesting that PCOS women are at risk for development of hypertension. CONCLUSION: RAS proteins levels differed between PCOS and control women, suggesting that the insulin resistance inherent in PCOS may predispose these women to more severe COVID-19 infection. | Moin, Abu Saleh Md Sathyapalan, Thozhukat Atkin, Stephen L Butler, Alexandra E eng England Metabol Open. 2020 Sep;7:100052. doi: 10.1016/j.metop.2020.100052. Epub 2020 Aug 18.I | 08/25/2020 | ||
| Dickkopf-1 Overexpression in vitro Nominates Candidate Blood Biomarkers Relating to Alzheimer's Disease Pathology | Shi L, et al. | 2020 | J Alzheimers Dis | 77 | 3 | 1353-1368 | https://www.doi.org/10.3233/JAD-200208 | 32,831,200 | Aged Alzheimer Disease/*blood/genetics/*pathology Biomarkers/blood Female Gene Expression HEK293 Cells Humans Intercellular Signaling Peptides and Proteins/biosynthesis/*blood/genetics Male Middle Aged ATN framework Dickkopf-1 SomaScan Wnt signaling replication (https://www.j-alz.com/manuscript-disclosures/20-0208r3). | BACKGROUND: Previous studies suggest that Dickkopf-1 (DKK1), an inhibitor of Wnt signaling, plays a role in amyloid-induced toxicity and hence Alzheimer's disease (AD). However, the effect of DKK1 expression on protein expression, and whether such proteins are altered in disease, is unknown. OBJECTIVE: We aim to test whether DKK1 induced protein signature obtained in vitro were associated with markers of AD pathology as used in the amyloid/tau/neurodegeneration (ATN) framework as well as with clinical outcomes. METHODS: We first overexpressed DKK1 in HEK293A cells and quantified 1,128 proteins in cell lysates using aptamer capture arrays (SomaScan) to obtain a protein signature induced by DKK1. We then used the same assay to measure the DKK1-signature proteins in human plasma in two large cohorts, EMIF (n = 785) and ANM (n = 677). RESULTS: We identified a 100-protein signature induced by DKK1 in vitro. Subsets of proteins, along with age and apolipoprotein E varepsilon4 genotype distinguished amyloid pathology (A + T-N-, A+T+N-, A+T-N+, and A+T+N+) from no AD pathology (A-T-N-) with an area under the curve of 0.72, 0.81, 0.88, and 0.85, respectively. Furthermore, we found that some signature proteins (e.g., Complement C3 and albumin) were associated with cognitive score and AD diagnosis in both cohorts. CONCLUSIONS: Our results add further evidence for a role of DKK regulation of Wnt signaling in AD and suggest that DKK1 induced signature proteins obtained in vitro could reflect theATNframework as well as predict disease severity and progression in vivo. | Shi, Liu Winchester, Laura M Liu, Benjamine Y Killick, Richard Ribe, Elena M Westwood, Sarah Baird, Alison L Buckley, Noel J Hong, Shengjun Dobricic, Valerija Kilpert, Fabian Franke, Andre Kiddle, Steven Sattlecker, Martina Dobson, Richard Cuadrado, Antonio Hye, Abdul Ashton, Nicholas J Morgan, Angharad R Bos, Isabelle Vos, Stephanie J B Ten Kate, Mara Scheltens, Philip Vandenberghe, Rik Gabel, Silvy Meersmans, Karen Engelborghs, Sebastiaan De Roeck, Ellen E Sleegers, Kristel Frisoni, Giovanni B Blin, Olivier Richardson, Jill C Bordet, Regis Molinuevo, Jose L Rami, Lorena Wallin, Anders Kettunen, Petronella Tsolaki, Magda Verhey, Frans Lleo, Alberto Alcolea, Daniel Popp, Julius Peyratout, Gwendoline Martinez-Lage, Pablo Tainta, Mikel Johannsen, Peter Teunissen, Charlotte E Freund-Levi, Yvonne Frolich, Lutz Legido-Quigley, Cristina Barkhof, Frederik Blennow, Kaj Rasmussen, Katrine Laura Nordestgaard, Borge Gronne Frikke-Schmidt, Ruth Nielsen, Sune Fallgaard Soininen, Hilkka Vellas, Bruno Kloszewska, Iwona Mecocci, Patrizia Zetterberg, Henrik Morgan, B Paul Streffer, Johannes Visser, Pieter Jelle Bertram, Lars Nevado-Holgado, Alejo J Lovestone, Simon eng MR/L011859/1/MRC_/Medical Research Council/United Kingdom MC_PC_17214/MRC_/Medical Research Council/United Kingdom DH_/Department of Health/United Kingdom MC_PC_17215/MRC_/Medical Research Council/United Kingdom MR/L023784/2/MRC_/Medical Research Council/United Kingdom 171/ALZS_/Alzheimer's Society/United Kingdom Multicenter Study Research Support, Non-U.S. Gov't Netherlands J Alzheimers Dis. 2020;77(3):1353-1368. doi: 10.3233/JAD-200208.I | 08/25/2020 | |
| Increased Levels of Coagulation Factor XI in Plasma Are Related to Alzheimer's Disease Diagnosis | Begic E, et al. | 2020 | J Alzheimers Dis | 77 | 1 | 375-386 | https://www.doi.org/10.3233/JAD-200358 | 32,804,133 | Aged Aged, 80 and over Alzheimer Disease/*blood/*diagnosis Biomarkers/blood Cohort Studies *Databases, Factual Factor XI/*metabolism Female Humans Male Alzheimer's disease biomarkers blood coagulation blood coagulation factor xi cognitive impairment | BACKGROUND: Alzheimer's disease is a complex disorder of unclear etiology that develops in the elderly population. It is a debilitating, progressive neurodegeneration for which disease-modifying therapies do not exist. Previous studies have suggested that, for a subset of patients, dysregulation in hemostasis might be one of the molecular mechanisms that ultimately leads to the development of neurodegeneration resulting in cognitive decline that represents the most prominent symptomatic characteristic of Alzheimer's disease. OBJECTIVE: To examine a relationship between factors that are part of coagulation and anticoagulation pathways with cognitive decline that develops during Alzheimer's disease. METHODS: SOMAscan assay was used to measure levels of coagulation/anticoagulation factors V, VII, IX, X, Xa, XI, antithrombin III, protein S, protein C, and activated protein C in plasma samples obtained from three groups of subjects: 1) subjects with stable cognitively healthy function, 2) subjects with stable mild cognitive impairment, and 3) subjects diagnosed with probable Alzheimer's disease. RESULTS: Our results show that protein levels of coagulation factor XI are significantly increased in patients who are diagnosed with probable Alzheimer's disease compared with cognitively healthy subjects or patients diagnosed with mild cognitive impairment. Furthermore, our results demonstrate that significant predictors of Alzheimer's-type diagnosis are factors IX and XI-an increase in both factors is associated with a reduction in cognitive function. CONCLUSION: Our study justifies further investigations of biological pathways involving coagulation/anticoagulation factors in relation to dementia, including dementia resulting from Alzheimer's-type neurodegeneration. | Begic, Edin Hadzidedic, Suncica Obradovic, Slobodan Begic, Zijo Causevic, Mirsada eng Netherlands J Alzheimers Dis. 2020;77(1):375-386. doi: 10.3233/JAD-200358.I | 08/18/2020 | |
| Plasma proteomic profile of frailty | Sathyan S, et al. | 2020 | Aging Cell | 19 | 9 | e13193 | https://www.doi.org/10.1111/acel.13193 | 32,762,010 | Aged Female Frail Elderly/*statistics & numerical data Frailty/*genetics Humans Plasma/*metabolism Proteomics/*methods SomaScan(R) assay aging cumulative frailty score frailty frailty prediction proteomics | Frailty is a state of decreased physiological reserve and increased vulnerability to adverse outcomes in aging, and is characterized by dysregulation across various biological pathways. Frailty may manifest biologically as alteration in protein expression, possibly regulated at genetic, transcriptional and epigenetic levels. In this study, we examined the proteomic profile associated with frailty defined by an established cumulative frailty index (FI). Using the SomaScan((R)) assay, 4265 proteins were measured in plasma, of which 55 were positively associated and 88 were negatively associated with the FI. The proteins most strongly associated with frailty were fatty acid-binding proteins, including fatty acid-binding protein (FABP) (p = 1.96 x 10(-19) ) and FABPA (p = 8.10 x 10(-16) ), leptin (p = 1.43 x 10(-14) ), and ANTR2 (p = 7.95 x 10(-20) ). Pathway analysis with the top 143 frailty-associated proteins revealed enrichment for proteins in pathways related to lipid metabolism, musculoskeletal development and function, cell-to-cell signaling and interaction, cellular assembly, and organization. Frailty prediction model constructed with elastic net regression utilizing 110 proteins demonstrated a correlation between predicted frailty and observed frailty (r = 0.57, p < 2.2 x 10(-16) ). Predicted frailty was also more strongly correlated with chronological age (r = 0.54, p < 2.2 x 10(-16) ) than observed frailty (r = 0.37, p = 1.2 x 10(-15) ). This study identified novel proteins and pathways related to frailty that may offer improved frailty phenotyping and prediction. | Sathyan, Sanish Ayers, Emmeline Gao, Tina Milman, Sofiya Barzilai, Nir Verghese, Joe eng R01 AG057909/AG/NIA NIH HHS/ P30AG038072/The Nathan Shock Center of Excellence for the Biology of Aging/International K23AG051148/AG/NIA NIH HHS/ R01AG044829/AG/NIA NIH HHS/ P30 DK020541/DK/NIDDK NIH HHS/ R01AG057909/AG/NIA NIH HHS/ R01AG061155/AG/NIA NIH HHS/ R01AG046949/AG/NIA NIH HHS/ P30 AG038072/AG/NIA NIH HHS/ P01AG021654/AG/NIA NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't England Aging Cell. 2020 Sep;19(9):e13193. doi: 10.1111/acel.13193. Epub 2020 Aug 6.I | 08/08/2020 | |
| ZIKV Infection Induces DNA Damage Response and Alters the Proteome of Gastrointestinal Cells | Glover K, et al. | 2020 | Viruses | 12 | 7 | https://www.doi.org/10.3390/v12070771 | 32,708,879 | Caco-2 Cells/metabolism/virology *DNA Damage Gastrointestinal Tract/metabolism/*virology Gene Expression Regulation, Viral Humans Proteome/*metabolism Zika Virus Infection/metabolism/*pathology SomaScan aptamers bioinformatics dysregulated proteins flavivirus gastrointestinal disease proteomics design of the study in the collection, analyses, or interpretation of data in the writing of the manuscript, or in the decision to publish the results. | The zika virus (ZIKV) is a neurotropic virus that causes congenital abnormalities in babies when they are infected in utero. Some studies have reported these congenital abnormalities result from ZIKV attacking neural progenitor cells within the brain which differentiate into neurons, oligodendrocytes, and astrocytes. Each of these glial cells play important roles during development of the fetal brain. In addition to ZIKV-induced congenital abnormalities, infected patients experience gastrointestinal complications. There are presently no reports investigating the role of this virus at the proteomic level in gastrointestinal associated cells, so we conducted an in vitro proteomic study of ZIKV-induced changes in Caco-2, a colon-derived human cell line which is known to be permissive to ZIKV infection. We used SomaScan, a new aptamer-based proteomic tool to identify host proteins that are dysregulated during ZIKV infection at 12, 24, and 48 h post-infection. Bioinformatic analyses predicted that dysregulation of differentially-regulated host proteins results in various gastrointestinal diseases. Validation of the clinical relevance of these promising protein targets will add to the existing knowledge of ZIKV biology. These potential proteins may be useful targets towards the development of therapeutic interventions. | Glover, Kathleen Coombs, Kevin M eng Research Support, Non-U.S. Gov't Switzerland Viruses. 2020 Jul 17;12(7):771. doi: 10.3390/v12070771.I | 07/28/2020 | ||
| Identification of a unique temporal signature in blood and BAL associated with IPF progression | Norman KC, et al. | 2020 | Sci Rep | 10 | 1 | 12049 | https://www.doi.org/10.1038/s41598-020-67956-w | 32,694,604 | Aged Biomarkers/blood/*metabolism Blood Proteins Bronchoalveolar Lavage Fluid Disease Progression Disease Susceptibility Female Gene Expression Humans Idiopathic Pulmonary Fibrosis/etiology/*metabolism/pathology Male Middle Aged Protein Interaction Mapping Proteomics/methods | Idiopathic pulmonary fibrosis (IPF) is a progressive and heterogeneous interstitial lung disease of unknown origin with a low survival rate. There are few treatment options available due to the fact that mechanisms underlying disease progression are not well understood, likely because they arise from dysregulation of complex signaling networks spanning multiple tissue compartments. To better characterize these networks, we used systems-focused data-driven modeling approaches to identify cross-tissue compartment (blood and bronchoalveolar lavage) and temporal proteomic signatures that differentiated IPF progressors and non-progressors. Partial least squares discriminant analysis identified a signature of 54 baseline (week 0) blood and lung proteins that differentiated IPF progression status by the end of 80 weeks of follow-up with 100% cross-validation accuracy. Overall we observed heterogeneous protein expression patterns in progressors compared to more homogenous signatures in non-progressors, and found that non-progressors were enriched for proteomic processes involving regulation of the immune/defense response. We also identified a temporal signature of blood proteins that was significantly different at early and late progressor time points (p < 0.0001), but not present in non-progressors. Overall, this approach can be used to generate new hypothesis for mechanisms associated with IPF progression and could readily be translated to other complex and heterogeneous diseases. | Norman, Katy C O'Dwyer, David N Salisbury, Margaret L DiLillo, Katarina M Lama, Vibha N Xia, Meng Gurczynski, Stephen J White, Eric S Flaherty, Kevin R Martinez, Fernando J Murray, Susan Moore, Bethany B Arnold, Kelly B eng K23 HL141539/HL/NHLBI NIH HHS/ R00 HL139996/HL/NHLBI NIH HHS/ L30 HL138825/HL/NHLBI NIH HHS/ R01 HL144849/HL/NHLBI NIH HHS/ R35 HL144481/HL/NHLBI NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't England Sci Rep. 2020 Jul 21;10(1):12049. doi: 10.1038/s41598-020-67956-w.I | 07/23/2020 | |
| Impact of Kidney Function on the Blood Proteome and on Protein Cardiovascular Risk Biomarkers in Patients With Stable Coronary Heart Disease | Yang J, et al. | 2020 | J Am Heart Assoc | 9 | 15 | e016463 | https://www.doi.org/10.1161/JAHA.120.016463 | 32,696,702 | Aged Biomarkers/*blood Cohort Studies Coronary Disease/*blood/complications Female *Glomerular Filtration Rate Heart Disease Risk Factors Humans Male Middle Aged *Proteome Renal Insufficiency, Chronic/*blood/complications cardiovascular disease chronic kidney disease proteomics | Background Chronic kidney disease (CKD) confers increased cardiovascular risk, not fully explained by traditional factors. Proteins regulate biological processes and inform the risk of diseases. Thus, in 938 patients with stable coronary heart disease from the Heart and Soul cohort, we quantified 1054 plasma proteins using modified aptamers (SOMAscan) to: (1) discern how reduced glomerular filtration influences the circulating proteome, (2) learn of the importance of kidney function to the prognostic information contained in recently identified protein cardiovascular risk biomarkers, and (3) identify novel and even unique cardiovascular risk biomarkers among individuals with CKD. Methods and Results Plasma protein levels were correlated to estimated glomerular filtration rate (eGFR) using Spearman-rank correlation coefficients. Cox proportional hazard models were used to estimate the association between individual protein levels and the risk of the cardiovascular outcome (first among myocardial infarction, stroke, heart failure hospitalization, or mortality). Seven hundred and nine (67.3%) plasma proteins correlated with eGFR at P<0.05 (rho 0.06-0.74); 218 (20.7%) proteins correlated with eGFR moderately or strongly (rho 0.2-0.74). Among the previously identified 196 protein cardiovascular biomarkers, just 87 remained prognostic after correction for eGFR. Among patients with CKD (eGFR <60 mL/min per 1.73 m(2)), we identified 21 protein cardiovascular risk biomarkers of which 8 are unique to CKD. Conclusions CKD broadly alters the composition of the circulating proteome. We describe protein biomarkers capable of predicting cardiovascular risk independently of glomerular filtration, and those that are prognostic of cardiovascular risk specifically in patients with CKD and even unique to patients with CKD. | Yang, Joseph Brody, Edward N Murthy, Ashwin C Mehler, Robert E Weiss, Sophie J DeLisle, Robert K Ostroff, Rachel Williams, Stephen A Ganz, Peter eng R01 HL129856/HL/NHLBI NIH HHS/ U01 DK108809/DK/NIDDK NIH HHS/ R01 AG052964/AG/NIA NIH HHS/ R01 HL079235/HL/NHLBI NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. England J Am Heart Assoc. 2020 Aug 4;9(15):e016463. doi: 10.1161/JAHA.120.016463. Epub 2020 Jul 22.I | 07/23/2020 | |
| Evaluation of a novel blood microsampling device for clinical trial sample collection and protein biomarker analysis | Xing J, et al. | 2020 | Bioanalysis | 12 | 13 | 919-935 | https://www.doi.org/10.4155/bio-2020-0063 | 32,686,955 | Adult Biomarkers/blood Blood Proteins/*analysis Covid-19 Clinical Trials as Topic Coronavirus Infections/blood Enzyme-Linked Immunosorbent Assay Female Hemolysis Humans Male Middle Aged Pandemics Phlebotomy/*instrumentation Pneumonia, Viral/blood Proteomics/instrumentation Young Adult Dbs SomaScan Tap Vams biomarkers microsampling patient-centric sampling proteomics sampling device | Aim: Evaluation of a novel microsampling device for its use in clinical sample collection and biomarker analysis. Methodology: Matching samples were collected from 16 healthy donors (ten females, six males; age 42 +/- 20) via K2EDTA touch activated phlebotomy (TAP) device and phlebotomy. The protein profile differences between sampling groups was evaluated using aptamer-based proteomic assay SomaScan and selected ELISA. Conclusion: Somascan signal concordance between phlebotomy- and TAP-generated samples was studied and comparability of protein abundances between these blood sample collection methods was demonstrated. Statistically significant correlation in selected ELISA assays also confirmed the TAP device applicability to the quantitative analysis of protein biomarkers in clinical trials. | Xing, Jinming Loureiro, Joseph Patel, Michael T Mikhailov, Dmitri Gusev, Arkady I eng Evaluation Study England Bioanalysis. 2020 Jul;12(13):919-935. doi: 10.4155/bio-2020-0063. Epub 2020 Jul 20.I | 07/21/2020 | |
| Metabolic profiling shows pre-existing mitochondrial dysfunction contributes to muscle loss in a model of ICU-acquired weakness | Kemp PR, et al. | 2020 | J Cachexia Sarcopenia Muscle | 11 | 5 | 1321-1335 | https://www.doi.org/10.1002/jcsm.12597 | 32,677,363 | Aged *Hand Strength Humans Intensive Care Units Male Middle Aged *Mitochondria Quadriceps Muscle Stroke Volume *Ventricular Function, Left Aortic surgery Cortisol Metabolomics Mitochondrial dysfunction Muscle wasting grants, personal fees, and non-financial support from GSK, personal fees from BI, personal fees from Silence therapeutics, personal fees from Cell catapult, outside the submitted work all other authors have no conflicts of interest. | BACKGROUND: Surgery can lead to significant muscle loss, which increases recovery time and associates with increased mortality. Muscle loss is not uniform, with some patients losing significant muscle mass and others losing relatively little, and is likely to be accompanied by marked changes in circulating metabolites and proteins. Determining these changes may help understand the variability and identify novel therapeutic approaches or markers of muscle wasting. METHODS: To determine the association between muscle loss and circulating metabolites, we studied 20 male patients (median age, 70.5, interquartile range, 62.5-75) undergoing aortic surgery. Muscle mass was determined before and 7 days after surgery and blood samples were taken before surgery, and 1, 3, and 7 days after surgery. The circulating metabolome and proteome were determined using commercial services (Metabolon and SomaLogic). RESULTS: Ten patients lost more than 10% of the cross-sectional area of the rectus femoris (RF(CSA) ) and were defined as wasting. Metabolomic analysis showed that 557 circulating metabolites were altered following surgery (q < 0.05) in the whole cohort and 104 differed between wasting and non-wasting patients (q < 0.05). Weighted genome co-expression network analysis, identified clusters of metabolites, both before and after surgery, that associated with muscle mass and function (r = -0.72, p = 6 x 10(-4) with RF(CSA) on Day 0, P = 3 x 10(-4) with RF(CSA) on Day 7 and r = -0.73, P = 5 x 10(-4) with hand-grip strength on Day 7). These clusters were mainly composed of acyl carnitines and dicarboxylates indicating that pre-existing mitochondrial dysfunction contributes to muscle loss following surgery. Surgery elevated cortisol to the same extent in wasting and non-wasting patients, but the cortisol:cortisone ratio was higher in the wasting patients (Day 3 P = 0.043 and Day 7 P = 0.016). Wasting patients also showed a greater increase in circulating nucleotides 3 days after surgery. Comparison of the metabolome with inflammatory markers identified by SOMAscan(R) showed that pre-surgical mitochondrial dysfunction was associated with growth differentiation factor 15 (GDF-15) (r = 0.79, P = 2 x 10(-4) ) and that GDF-15, interleukin (IL)-8), C-C motif chemokine 23 (CCL-23), and IL-15 receptor subunit alpha (IL-15RA) contributed to metabolic changes in response to surgery. CONCLUSIONS: We show that pre-existing mitochondrial dysfunction and reduced cortisol inactivation contribute to muscle loss following surgery. The data also implicate GDF-15 and IL-15RA in mitochondrial dysfunction. | Kemp, Paul R Paul, Richard Hinken, Aaron C Neil, David Russell, Alan Griffiths, Mark J eng DH_/Department of Health/United Kingdom Research Support, Non-U.S. Gov't Germany J Cachexia Sarcopenia Muscle. 2020 Oct;11(5):1321-1335. doi: 10.1002/jcsm.12597. Epub 2020 Jul 16.I | 07/18/2020 | |
| Chemical Modification of Aptamers for Increased Binding Affinity in Diagnostic Applications: Current Status and Future Prospects | Elskens JP, et al. | 2020 | Int J Mol Sci | 21 | 12 | https://www.doi.org/10.3390/ijms21124522 | 32,630,547 | Aptamers, Nucleotide/*chemistry/*therapeutic use Humans Ligands Pathology, Molecular/methods SELEX Aptamer Technique/*methods/trends Selex aptamer chemical modifications diagnostic applications enhanced binding affinity | Aptamers are short single stranded DNA or RNA oligonucleotides that can recognize analytes with extraordinary target selectivity and affinity. Despite their promising properties and diagnostic potential, the number of commercial applications remains scarce. In order to endow them with novel recognition motifs and enhanced properties, chemical modification of aptamers has been pursued. This review focuses on chemical modifications, aimed at increasing the binding affinity for the aptamer's target either in a non-covalent or covalent fashion, hereby improving their application potential in a diagnostic context. An overview of current methodologies will be given, thereby distinguishing between pre- and post-SELEX (Systematic Evolution of Ligands by Exponential Enrichment) modifications. | Elskens, Jan P Elskens, Joke M Madder, Annemieke eng 1S96218N/Fonds Wetenschappelijk Onderzoek/ G054819N/Fonds Wetenschappelijk Onderzoek/ Review Switzerland Int J Mol Sci. 2020 Jun 25;21(12):4522. doi: 10.3390/ijms21124522.I | 07/08/2020 | ||
| Aptamer based proteomic pilot study reveals a urine signature indicative of pediatric urinary tract infections | Dong L, et al. | 2020 | PLoS One | 15 | 7 | e0235328 | https://www.doi.org/10.1371/journal.pone.0235328 | 32,628,701 | Adolescent Aptamers, Nucleotide/*chemistry Biomarkers/urine Child Child, Preschool Female Humans Male Pilot Projects Prospective Studies Proteomics/*methods *Support Vector Machine Urinalysis/*methods Urinary Tract Infections/*diagnosis/urine | OBJECTIVE: Current urinary tract infection (UTI) diagnostic strategies that rely on leukocyte esterase have limited accuracy. We performed an aptamer-based proteomics pilot study to identify urine protein levels that could differentiate a culture proven UTI from culture negative samples, regardless of pyuria status. METHODS: We analyzed urine from 16 children with UTIs, 8 children with culture negative pyuria and 8 children with negative urine culture and no pyuria. The urine levels of 1,310 proteins were quantified using the Somascan platform and normalized to urine creatinine. Machine learning with support vector machine (SVM)-based feature selection was performed to determine the combination of urine biomarkers that optimized diagnostic accuracy. RESULTS: Eight candidate urine protein biomarkers met filtering criteria. B-cell lymphoma protein, C-X-C motif chemokine 6, C-X-C motif chemokine 13, cathepsin S, heat shock 70kDA protein 1A, mitogen activated protein kinase, protein E7 HPV18 and transgelin. AUCs ranged from 0.91 to 0.95. The best prediction was achieved by the SVMs with radial basis function kernel. CONCLUSIONS: Biomarkers panel can be identified by the emerging technologies of aptamer-based proteomics and machine learning that offer the potential to increase UTI diagnostic accuracy, thereby limiting unneeded antibiotics. | Dong, Liang Watson, Joshua Cao, Sha Arregui, Samuel Saxena, Vijay Ketz, John Awol, Abduselam K Cohen, Daniel M Caterino, Jeffrey M Hains, David S Schwaderer, Andrew L eng R01 AG050801/AG/NIA NIH HHS/ R01 DK117934/DK/NIDDK NIH HHS/ R01 DK106286/DK/NIDDK NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Validation Study PLoS One. 2020 Jul 6;15(7):e0235328. doi: 10.1371/journal.pone.0235328. eCollection 2020.I | 07/07/2020 | |
| An expanded repertoire of intensity-dependent exercise-responsive plasma proteins tied to loci of human disease risk | Guseh JS, et al. | 2020 | Sci Rep | 10 | 1 | 10831 | https://www.doi.org/10.1038/s41598-020-67669-0 | 32,616,758 | Adult Blood Pressure Blood Proteins/*metabolism Coronary Artery Disease/etiology/prevention & control Exercise/*physiology Female Genetic Loci Genome-Wide Association Study Humans Male *Proteomics Quantitative Trait Loci Risk Young Adult | Routine endurance exercise confers numerous health benefits, and high intensity exercise may accelerate and magnify many of these benefits. To date, explanatory molecular mechanisms and the influence of exercise intensity remain poorly understood. Circulating factors are hypothesized to transduce some of the systemic effects of exercise. We sought to examine the role of exercise and exercise intensity on the human plasma proteome. We employed an aptamer-based method to examine 1,305 plasma proteins in 12 participants before and after exercise at two physiologically defined intensities (moderate and high) to determine the proteomic response. We demonstrate that the human plasma proteome is responsive to acute exercise in an intensity-dependent manner with enrichment analysis suggesting functional biological differences between the moderate and high intensity doses. Through integration of available genetic data, we estimate the effects of acute exercise on exercise-associated traits and find proteomic responses that may contribute to observed clinical effects on coronary artery disease and blood pressure regulation. In sum, we provide supportive evidence that moderate and high intensity exercise elicit different signaling responses, that exercise may act in part non-cell autonomously through circulating plasma proteins, and that plasma protein dynamics can simulate some the beneficial and adverse effects of acute exercise. | Guseh, J Sawalla Churchill, Timothy W Yeri, Ashish Lo, Claire Brown, Marcel Houstis, Nicholas E Aragam, Krishna G Lieberman, Daniel E Rosenzweig, Anthony Baggish, Aaron L eng R01AG061034/NH/NIH HHS/ 16SFRN31720000/AHA/American Heart Association-American Stroke Association/ R01 HL125869/NH/NIH HHS/ HL007208/NH/NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't England Sci Rep. 2020 Jul 2;10(1):10831. doi: 10.1038/s41598-020-67669-0.I | 07/04/2020 | |
| Serum biomarkers associated with baseline clinical severity in young steroid-naive Duchenne muscular dystrophy boys | Dang UJ, et al. | 2020 | Hum Mol Genet | 29 | 15 | 2481-2495 | https://www.doi.org/10.1093/hmg/ddaa132 | 32,592,467 | Biomarkers/*blood Child Child, Preschool Dystrophin/*blood Humans Male Muscular Dystrophy, Duchenne/*blood/drug therapy/pathology Oligonucleotides Phenotype Pregnadienediols/administration & dosage Severity of Illness Index Steroids/metabolism | Duchenne muscular dystrophy (DMD) is caused by loss of dystrophin in muscle, and while all patients share the primary gene and biochemical defect, there is considerable patient-patient variability in clinical symptoms. We sought to develop multivariate models of serum protein biomarkers that explained observed variation, using functional outcome measures as proxies for severity. Serum samples from 39 steroid-naive DMD boys 4 to <7 years enrolled into a clinical trial of vamorolone were studied (NCT02760264). Four assessments of gross motor function were carried out for each participant over a 6-week interval, and their mean was used as response for biomarker models. Weighted correlation network analysis was used for unsupervised clustering of 1305 proteins quantified using SOMAscan(R) aptamer profiling to define highly representative and connected proteins. Multivariate models of biomarkers were obtained for time to stand performance (strength phenotype; 17 proteins) and 6 min walk performance (endurance phenotype; 17 proteins) including some shared proteins. Identified proteins were tested with associations of mRNA expression with histological severity of muscle from dystrophinopathy patients (n = 28) and normal controls (n = 6). Strong associations predictive of both clinical and histological severity were found for ERBB4 (reductions in both blood and muscle with increasing severity), SOD1 (reductions in muscle and increases in blood with increasing severity) and CNTF (decreased levels in blood and muscle with increasing severity). We show that performance of DMD boys was effectively modeled with serum proteins, proximal strength associated with growth and remodeling pathways and muscle endurance centered on TGFbeta and fibrosis pathways in muscle. | Dang, Utkarsh J Ziemba, Michael Clemens, Paula R Hathout, Yetrib Conklin, Laurie S Hoffman, Eric P eng R44 NS095423/NS/NINDS NIH HHS/ Clinical Trial Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't England Hum Mol Genet. 2020 Aug 29;29(15):2481-2495. doi: 10.1093/hmg/ddaa132.I | 06/28/2020 | |
| Mechanisms of Sodium-Glucose Cotransporter 2 Inhibition: Insights From Large-Scale Proteomics | Ferrannini E, et al. | 2020 | Diabetes Care | 43 | 9 | 2183-2189 | https://www.doi.org/10.2337/dc20-0456 | 32,527,800 | Aged Benzhydryl Compounds/*pharmacology Biomarkers/analysis/blood Blood Proteins/drug effects/metabolism Female Glucose/metabolism Glucosides/*pharmacology Humans Hypoglycemic Agents/pharmacology Male Middle Aged Prospective Studies Proteome/analysis/*drug effects/metabolism Proteomics/methods Signal Transduction/drug effects Sodium-Glucose Transporter 2 Inhibitors/*pharmacology | OBJECTIVE: To assess the effects of empagliflozin, a selective sodium-glucose cotransporter 2 (SGLT2) inhibitor, on broad biological systems through proteomics. RESEARCH DESIGN AND METHODS: Aptamer-based proteomics was used to quantify 3,713 proteins in 144 paired plasma samples obtained from 72 participants across the spectrum of glucose tolerance before and after 4 weeks of empagliflozin 25 mg/day. The biology of the plasma proteins significantly changed by empagliflozin (at false discovery rate-corrected P < 0.05) was discerned through Ingenuity Pathway Analysis. RESULTS: Empagliflozin significantly affected levels of 43 proteins, 6 related to cardiomyocyte function (fatty acid-binding protein 3 and 4 [FABPA], neurotrophic receptor tyrosine kinase, renin, thrombospondin 4, and leptin receptor), 5 to iron handling (ferritin heavy chain 1, transferrin receptor protein 1, neogenin, growth differentiation factor 2 [GDF2], and beta2-microglobulin), and 1 to sphingosine/ceramide metabolism (neutral ceramidase), a known pathway of cardiovascular disease. Among the protein changes achieving the strongest statistical significance, insulin-like binding factor protein-1 (IGFBP-1), transgelin-2, FABPA, GDF15, and sulphydryl oxidase 2 precursor were increased, while ferritin, thrombospondin 3, and Rearranged during Transfection (RET) were decreased by empagliflozin administration. CONCLUSIONS: SGLT2 inhibition is associated, directly or indirectly, with multiple biological effects, including changes in markers of cardiomyocyte contraction/relaxation, iron handling, and other metabolic and renal targets. The most significant differences were detected in protein species (GDF15, ferritin, IGFBP-1, and FABP) potentially related to the clinical and metabolic changes that were actually measured in the same patients. These novel results may inform further studies using targeted proteomics and a prospective design. | Ferrannini, Ele Murthy, Ashwin C Lee, Yong-Ho Muscelli, Elza Weiss, Sophie Ostroff, Rachel M Sattar, Naveed Williams, Stephen A Ganz, Peter eng Research Support, Non-U.S. Gov't Diabetes Care. 2020 Sep;43(9):2183-2189. doi: 10.2337/dc20-0456. Epub 2020 Jun 11.I | 06/13/2020 | |
| Novel Insights Into the Effects of Interleukin 6 Antagonism in Non-ST-Segment-Elevation Myocardial Infarction Employing the SOMAscan Proteomics Platform | George MJ, et al. | 2020 | J Am Heart Assoc | 9 | 12 | e015628 | https://www.doi.org/10.1161/JAHA.119.015628 | 32,515,246 | Acute-Phase Proteins Aged Antibodies, Monoclonal, Humanized/*therapeutic use Aptamers, Nucleotide Blood Proteins/*metabolism Carrier Proteins/blood Chemokines, CC/blood Female Follow-Up Studies Hepcidins/blood High-Throughput Screening Assays Humans Insulin-Like Growth Factor Binding Protein 4/blood Male Membrane Glycoproteins/blood Middle Aged Myeloblastin/blood Non-ST Elevated Myocardial Infarction/blood/diagnosis/*drug therapy Norway *Proteome *Proteomics Randomized Controlled Trials as Topic Receptors, Interleukin-6/*antagonists & inhibitors Time Factors Treatment Outcome inflammation interleukin myocardial infarction proteomics | Background Interleukin 6 concentration is associated with myocardial injury, heart failure, and mortality after myocardial infarction. In the Norwegian tocilizumab non-ST-segment-elevation myocardial infarction trial, the first randomized trial of interleukin 6 blockade in myocardial infarction, concentration of both C-reactive protein and troponin T were reduced in the active treatment arm. In this follow-up study, an aptamer-based proteomic approach was employed to discover additional plasma proteins modulated by tocilizumab treatment to gain novel insights into the effects of this therapeutic approach. Methods and Results Plasma from percutaneous coronary intervention-treated patients, 24 in the active intervention and 24 in the placebo-control arm, drawn 48 hours postrandomization were randomly selected for analysis with the SOMAscan assay. Employing slow off-rate aptamers, the relative abundance of 1074 circulating proteins was measured. Proteins identified as being significantly different between groups were subsequently measured by enzyme immunoassay in the whole trial cohort (117 patients) at all time points (days 1-3 [7 time points] and 3 and 6 months). Five proteins identified by the SOMAscan assay, and subsequently confirmed by enzyme immunoassay, were significantly altered by tocilizumab administration. The acute-phase proteins lipopolysaccharide-binding protein, hepcidin, and insulin-like growth factor-binding protein 4 were all reduced during the hospitalization phase, as was the monocyte chemoattractant C-C motif chemokine ligand 23. Proteinase 3, released primarily from neutrophils, was significantly elevated. Conclusions Employing the SOMAscan aptamer-based proteomics platform, 5 proteins were newly identified that are modulated by interleukin 6 antagonism and may mediate the therapeutic effects of tocilizumab in non-ST-segment-elevation myocardial infarction. | George, Marc J Kleveland, Ola Garcia-Hernandez, Jorge Palmen, Jutta Lovering, Ruth Wiseth, Rune Aukrust, Pal Engmann, Jorgen Damas, Jan Kristian Hingorani, Aroon D Gullestad, Lars Casas, Juan P Ueland, Thor eng DH_/Department of Health/United Kingdom WT_/Wellcome Trust/United Kingdom Research Support, Non-U.S. Gov't England J Am Heart Assoc. 2020 Jun 16;9(12):e015628. doi: 10.1161/JAHA.119.015628. Epub 2020 Jun 9.I | 06/10/2020 | |
| Integrative phenotyping of glycemic responders upon clinical weight loss using multi-omics | Valsesia A, et al. | 2020 | Sci Rep | 10 | 1 | 9236 | https://www.doi.org/10.1038/s41598-020-65936-8 | 32,514,005 | Adipose Tissue/*metabolism Area Under Curve Body Composition Diet, Reducing Down-Regulation Fatty Acid Elongases/genetics/metabolism *Genomics Humans Intra-Abdominal Fat/physiology Ketone Bodies/*blood Lipids/analysis Phenotype *Proteomics ROC Curve Weight Loss/*physiology | Weight loss aims to improve glycemic control in obese but strong variability is observed. Using a multi-omics approach, we investigated differences between 174 responders and 201 non-responders, that had lost >8% body weight following a low-caloric diet (LCD, 800 kcal/d for 8 weeks). The two groups were comparable at baseline for body composition, glycemic control, adipose tissue transcriptomics and plasma ketone bodies. But they differed significantly in their response to LCD, including improvements in visceral fat, overall insulin resistance (IR) and tissue-specific IR. Transcriptomics analyses found down-regulation in key lipogenic genes (e.g. SCD, ELOVL5) in responders relative to non-responders; metabolomics showed increase in ketone bodies; while proteomics revealed differences in lipoproteins. Findings were consistent between genders; with women displaying smaller improvements owing to a better baseline metabolic condition. Integrative analyses identified a plasma omics model that was able to predict non-responders with strong performance (on a testing dataset, the Receiving Operating Curve Area Under the Curve (ROC AUC) was 75% with 95% Confidence Intervals (CI) [67%, 83%]). This model was based on baseline parameters without the need for intrusive measurements and outperformed clinical models (p = 0.00075, with a +14% difference on the ROC AUCs). Our approach document differences between responders and non-responders, with strong contributions from liver and adipose tissues. Differences may be due to de novo lipogenesis, keto-metabolism and lipoprotein metabolism. These findings are useful for clinical practice to better characterize non-responders both prior and during weight loss. | Valsesia, Armand Chakrabarti, Anirikh Hager, Jorg Langin, Dominique Saris, Wim H M Astrup, Arne Blaak, Ellen E Viguerie, Nathalie Masoodi, Mojgan eng Multicenter Study Randomized Controlled Trial Research Support, Non-U.S. Gov't England Sci Rep. 2020 Jun 8;10(1):9236. doi: 10.1038/s41598-020-65936-8.I | 06/10/2020 | |
| Zika virus dysregulates human Sertoli cell proteins involved in spermatogenesis with little effect on tight junctions | Rashid MU, et al. | 2020 | PLoS Negl Trop Dis | 14 | 6 | e0008335 | https://www.doi.org/10.1371/journal.pntd.0008335 | 32,511,241 | Animals Chlorocebus aethiops Humans Male Proteomics Semen/virology Sertoli Cells/*immunology/virology Signal Transduction *Spermatogenesis Tight Junctions/*immunology/virology Vero Cells Virus Replication Zika Virus Zika Virus Infection/*immunology | Zika virus (ZIKV), a neglected tropical disease until its re-emergence in 2007, causes microcephaly in infants and Guillain-Barre syndrome in adults. Its re-emergence and spread to more than 80 countries led the World Health Organization in 2016 to declare a Public Health Emergency. ZIKV is mainly transmitted by mosquitos, but can persist in infected human male semen for prolonged periods and may be sexually transmitted. Testicular Sertoli cells support ZIKV replication and may be a reservoir for persistent ZIKV infection. Electrical impedance analyses indicated ZIKV infection rapidly disrupted Vero cell monolayers but had little effect upon human Sertoli cells (HSerC). We determined ZIKV-induced proteomic changes in HSerC using an aptamer-based multiplexed technique (SOMAscan) targeting >1300 human proteins. ZIKV infection caused differential expression of 299 proteins during three different time points, including 5 days after infection. Dysregulated proteins are involved in different bio-functions, including cell death and survival, cell cycle, maintenance of cellular function, cell signaling, cellular assembly, morphology, movement, molecular transport, and immune response. Many signaling pathways important for maintenance of HSerC function and spermatogenesis were highly dysregulated. These included IL-6, IGF1, EGF, NF-kappaB, PPAR, ERK/MAPK, and growth hormone signaling. Down-regulation of the PPAR signaling pathway might impact cellular energy supplies. Upstream molecule analysis also indicated microRNAs involved in germ cell development were downregulated by infection. Overall, this study leads to a better understanding of Sertoli cellular mechanisms used by ZIKV during persistent infection and possible ZIKV impacts on spermatogenesis. | Rashid, Mahamud-Ur Zahedi-Amiri, Ali Glover, Kathleen K M Gao, Ang Nickol, Michaela E Kindrachuk, Jason Wilkins, John A Coombs, Kevin M eng 950-231498/CIHR/Canada Research Support, Non-U.S. Gov't PLoS Negl Trop Dis. 2020 Jun 8;14(6):e0008335. doi: 10.1371/journal.pntd.0008335. eCollection 2020 Jun.I | 06/09/2020 | |
| A fully joint Bayesian quantitative trait locus mapping of human protein abundance in plasma | Ruffieux H, et al. | 2020 | PLoS Comput Biol | 16 | 6 | e1007882 | https://www.doi.org/10.1371/journal.pcbi.1007882 | 32,492,067 | *Bayes Theorem Biomarkers/blood Blood Proteins/*genetics Genome-Wide Association Study Humans *Quantitative Trait Loci | Molecular quantitative trait locus (QTL) analyses are increasingly popular to explore the genetic architecture of complex traits, but existing studies do not leverage shared regulatory patterns and suffer from a large multiplicity burden, which hampers the detection of weak signals such as trans associations. Here, we present a fully multivariate proteomic QTL (pQTL) analysis performed with our recently proposed Bayesian method LOCUS on data from two clinical cohorts, with plasma protein levels quantified by mass-spectrometry and aptamer-based assays. Our two-stage study identifies 136 pQTL associations in the first cohort, of which >80% replicate in the second independent cohort and have significant enrichment with functional genomic elements and disease risk loci. Moreover, 78% of the pQTLs whose protein abundance was quantified by both proteomic techniques are confirmed across assays. Our thorough comparisons with standard univariate QTL mapping on (1) these data and (2) synthetic data emulating the real data show how LOCUS borrows strength across correlated protein levels and markers on a genome-wide scale to effectively increase statistical power. Notably, 15% of the pQTLs uncovered by LOCUS would be missed by the univariate approach, including several trans and pleiotropic hits with successful independent validation. Finally, the analysis of extensive clinical data from the two cohorts indicates that the genetically-driven proteins identified by LOCUS are enriched in associations with low-grade inflammation, insulin resistance and dyslipidemia and might therefore act as endophenotypes for metabolic diseases. While considerations on the clinical role of the pQTLs are beyond the scope of our work, these findings generate useful hypotheses to be explored in future research; all results are accessible online from our searchable database. Thanks to its efficient variational Bayes implementation, LOCUS can analyze jointly thousands of traits and millions of markers. Its applicability goes beyond pQTL studies, opening new perspectives for large-scale genome-wide association and QTL analyses. Diet, Obesity and Genes (DiOGenes) trial registration number: NCT00390637. | Ruffieux, Helene Carayol, Jerome Popescu, Radu Harper, Mary-Ellen Dent, Robert Saris, Wim H M Astrup, Arne Hager, Jorg Davison, Anthony C Valsesia, Armand eng MC_UU_00002/10/MRC_/Medical Research Council/United Kingdom Research Support, Non-U.S. Gov't PLoS Comput Biol. 2020 Jun 3;16(6):e1007882. doi: 10.1371/journal.pcbi.1007882. eCollection 2020 Jun.I | 06/04/2020 | |
| Colchicine's effects on metabolic and inflammatory molecules in adults with obesity and metabolic syndrome: results from a pilot randomized controlled trial | Demidowich AP, et al. | 2020 | Int J Obes (Lond) | 44 | 8 | 1793-1799 | https://www.doi.org/10.1038/s41366-020-0598-3 | 32,461,554 | Adult Anti-Inflammatory Agents/pharmacology/*therapeutic use Betacoronavirus/drug effects C-Reactive Protein Covid-19 Colchicine/pharmacology/*therapeutic use Coronavirus Infections/drug therapy/*immunology Double-Blind Method Female Humans Interleukin-6 Male Metabolic Syndrome/*complications/drug therapy/*immunology Middle Aged Obesity/complications/drug therapy/*immunology Pandemics Pilot Projects Pneumonia, Viral/drug therapy/*immunology SARS-CoV-2 Treatment Outcome Young Adult | OBJECTIVE: Recent clinical trials have demonstrated that colchicine may have metabolic and cardiovascular and benefits in at-risk patients; however, the mechanisms through which colchicine may improve outcomes are still unclear. We sought to examine colchicine's effects on circulating inflammatory and metabolic molecules in adults with obesity and metabolic syndrome (MetS). METHODS: Blood samples were collected pre- and post-intervention during a double-blind randomized controlled trial in which 40 adults with obesity and MetS were randomized to colchicine 0.6 mg or placebo twice-daily for 3 months. Serum samples were analyzed for 1305 circulating factors using the SomaScan Platform. The Benjamini-Hochberg procedure was used to adjust the false discovery rate (FDR) for multiple testing. RESULTS: At baseline, age (48.0 +/- 13.8 vs. 44.7 +/- 10.3 years) and BMI (39.8 +/- 6.4 vs. 41.8 +/- 8.2 kg/m(2)) were not different between groups. After controlling for the FDR, 34 molecules were significantly changed by colchicine. Colchicine decreased concentrations of multiple inflammatory molecules, including C-reactive protein, interleukin 6, and resistin, in addition to vascular-related proteins (e.g., oxidized low-density lipoprotein receptor, phosphodiesterase 5A). Conversely, relative to placebo, colchicine significantly increased concentrations of eight molecules including secreted factors associated with metabolism and anti-thrombosis. CONCLUSIONS: In adults with obesity, colchicine significantly affected concentrations of proteins involved in the innate immune system, endothelial function and atherosclerosis, uncovering new mechanisms behind its cardiometabolic effects. Further research is warranted to investigate whether colchicine's IL-6 suppressive effects may be beneficial in COVID-19. | Demidowich, Andrew P Levine, Jordan A Apps, Richard Cheung, Foo K Chen, Jinguo Fantoni, Giovanna Patel, Tushar P Yanovski, Jack A eng ZIA HD000641/ImNIH/Intramural NIH HHS/ Randomized Controlled Trial England Int J Obes (Lond). 2020 Aug;44(8):1793-1799. doi: 10.1038/s41366-020-0598-3. Epub 2020 May 27.I | 05/29/2020 | |
| Proteomic and Metabolomic Correlates of Healthy Dietary Patterns: The Framingham Heart Study | Walker ME, et al. | 2020 | Nutrients | 12 | 5 | https://www.doi.org/10.3390/nu12051476 | 32,438,708 | Cross-Sectional Studies Diet Surveys Diet, Healthy/*statistics & numerical data Diet, Mediterranean/*statistics & numerical data Dietary Approaches To Stop Hypertension/*statistics & numerical data Eating/*physiology Female Humans Linear Models Longitudinal Studies Male *Metabolome Metabolomics Middle Aged Proteome/*analysis Proteomics biomarker diet quality dietary patterns metabolomic proteomic | Data on proteomic and metabolomic signatures of healthy dietary patterns are limited. We evaluated the cross-sectional association of serum proteomic and metabolomic markers with three dietary patterns: the Alternative Healthy Eating Index (AHEI), the Dietary Approaches to Stop Hypertension (DASH) diet; and a Mediterranean-style (MDS) diet. We examined participants from the Framingham Offspring Study (mean age; 55 years; 52% women) who had complete proteomic (n = 1713) and metabolomic (n = 2284) data; using food frequency questionnaires to derive dietary pattern indices. Proteins and metabolites were quantified using the SomaScan platform and liquid chromatography/tandem mass spectrometry; respectively. We used multivariable-adjusted linear regression models to relate each dietary pattern index (independent variables) to each proteomic and metabolomic marker (dependent variables). Of the 1373 proteins; 103 were associated with at least one dietary pattern (48 with AHEI; 83 with DASH; and 8 with MDS; all false discovery rate [FDR] | Walker, Maura E Song, Rebecca J Xu, Xiang Gerszten, Robert E Ngo, Debby Clish, Clary B Corlin, Laura Ma, Jiantao Xanthakis, Vanessa Jacques, Paul F Vasan, Ramachandran S eng P30 DK040561/DK/NIDDK NIH HHS/ HHSN268201500001I/HL/NHLBI NIH HHS/ P30 DK020579/HL/NHLBI NIH HHS/ 75N92019D00031/HL/NHLBI NIH HHS/ P20 HL113444/HL/NHLBI NIH HHS/ R01 HL132320/HL/NHLBI NIH HHS/ P30 DK020579/DK/NIDDK NIH HHS/ U01 AG049505/AG/NIA NIH HHS/ 5T32HL125232/HL/NHLBI NIH HHS/ RF1 AG063507/AG/NIA NIH HHS/ Evaluation Study Switzerland Nutrients. 2020 May 19;12(5):1476. doi: 10.3390/nu12051476.I | 05/23/2020 | ||
| CDH6 and HAGH protein levels in plasma associate with Alzheimer's disease in APOE epsilon4 carriers | Ahmad S, et al. | 2020 | Sci Rep | 10 | 1 | 8233 | https://www.doi.org/10.1038/s41598-020-65038-5 | 32,427,856 | Alzheimer Disease/*metabolism Apolipoprotein E4/genetics/*metabolism Biomarkers/blood Cadherins/*metabolism *Genetic Carrier Screening Humans Thiolester Hydrolases/*metabolism | Many Alzheimer's disease (AD) genes including Apolipoprotein E (APOE) are found to be expressed in blood-derived macrophages and thus may alter blood protein levels. We measured 91 neuro-proteins in plasma from 316 participants of the Rotterdam Study (incident AD = 161) using Proximity Extension Ligation assay. We studied the association of plasma proteins with AD in the overall sample and stratified by APOE. Findings from the Rotterdam study were replicated in 186 AD patients of the BioFINDER study. We further evaluated the correlation of these protein biomarkers with total tau (t-tau), phosphorylated tau (p-tau) and amyloid-beta (Abeta) 42 levels in cerebrospinal fluid (CSF) in the Amsterdam Dementia Cohort (N = 441). Finally, we conducted a genome-wide association study (GWAS) to identify the genetic variants determining the blood levels of AD-associated proteins. Plasma levels of the proteins, CDH6 (beta = 0.638, P = 3.33 x 10(-4)) and HAGH (beta = 0.481, P = 7.20 x 10(-4)), were significantly elevated in APOE epsilon4 carrier AD patients. The findings in the Rotterdam Study were replicated in the BioFINDER study for both CDH6 (beta = 1.365, P = 3.97 x 10(-3)) and HAGH proteins (beta = 0.506, P = 9.31 x 10(-7)) when comparing cases and controls in APOE epsilon4 carriers. In the CSF, CDH6 levels were positively correlated with t-tau and p-tau in the total sample as well as in APOE epsilon4 stratum (P < 1 x 10(-3)). The HAGH protein was not detected in CSF. GWAS of plasma CDH6 protein levels showed significant association with a cis-regulatory locus (rs111283466, P = 1.92 x 10(-9)). CDH6 protein is implicated in cell adhesion and synaptogenesis while HAGH protein is related to the oxidative stress pathway. Our findings suggest that these pathways may be altered during presymptomatic AD and that CDH6 and HAGH may be new blood-based biomarkers. | Ahmad, Shahzad Milan, Marta Del Campo Hansson, Oskar Demirkan, Ayse Agustin, Ruiz Saez, Maria E Giagtzoglou, Nikolaos Cabrera-Socorro, Alfredo Bakker, Margot H M Ramirez, Alfredo Hankemeier, Thomas Stomrud, Erik Mattsson-Carlgren, Niklas Scheltens, Philip van der Flier, Wiesje M Ikram, M Arfan Malarstig, Anders Teunissen, Charlotte E Amin, Najaf van Duijn, Cornelia M eng Research Support, Non-U.S. Gov't England Sci Rep. 2020 May 19;10(1):8233. doi: 10.1038/s41598-020-65038-5.I | 05/20/2020 | |
| Circulating Protein Signatures and Causal Candidates for Type 2 Diabetes | Gudmundsdottir V, et al. | 2020 | Diabetes | 69 | 8 | 1843-1853 | https://www.doi.org/10.2337/db19-1070 | 32,385,057 | Aged Aged, 80 and over Case-Control Studies Diabetes Mellitus, Type 2/blood/*genetics Female Genetic Predisposition to Disease/genetics Genotype Humans Male Mendelian Randomization Analysis Polymorphism, Single Nucleotide/genetics | The increasing prevalence of type 2 diabetes poses a major challenge to societies worldwide. Blood-based factors like serum proteins are in contact with every organ in the body to mediate global homeostasis and may thus directly regulate complex processes such as aging and the development of common chronic diseases. We applied a data-driven proteomics approach, measuring serum levels of 4,137 proteins in 5,438 elderly Icelanders, and identified 536 proteins associated with prevalent and/or incident type 2 diabetes. We validated a subset of the observed associations in an independent case-control study of type 2 diabetes. These protein associations provide novel biological insights into the molecular mechanisms that are dysregulated prior to and following the onset of type 2 diabetes and can be detected in serum. A bidirectional two-sample Mendelian randomization analysis indicated that serum changes of at least 23 proteins are downstream of the disease or its genetic liability, while 15 proteins were supported as having a causal role in type 2 diabetes. | Gudmundsdottir, Valborg Zaghlool, Shaza B Emilsson, Valur Aspelund, Thor Ilkov, Marjan Gudmundsson, Elias F Jonsson, Stefan M Zilhao, Nuno R Lamb, John R Suhre, Karsten Jennings, Lori L Gudnason, Vilmundur eng HHSN271201200022C/DA/NIDA NIH HHS/ N01AG12100/AG/NIA NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Diabetes. 2020 Aug;69(8):1843-1853. doi: 10.2337/db19-1070. Epub 2020 May 8.I | 05/10/2020 | |
| Comparison of Proteomic Assessment Methods in Multiple Cohort Studies | Raffield LM, et al. | 2020 | Proteomics | 20 | 12 | e1900278 | https://www.doi.org/10.1002/pmic.201900278 | 32,386,347 | Adult Aged Aged, 80 and over Cohort Studies Female Humans Immunoassay/methods Male Middle Aged Myocardial Infarction/blood/*metabolism Proteome/*metabolism Proteomics/*methods Pulmonary Disease, Chronic Obstructive/blood/*metabolism Smokers/*statistics & numerical data antibody microarrays biomarkers multiplexings from MedImmune Corporation, Ltd., for a project outside the scope for this work. CE is an employee of AstraZeneca and owns stock options. | Novel proteomics platforms, such as the aptamer-based SOMAscan platform, can quantify large numbers of proteins efficiently and cost-effectively and are rapidly growing in popularity. However, comparisons to conventional immunoassays remain underexplored, leaving investigators unsure when cross-assay comparisons are appropriate. The correlation of results from immunoassays with relative protein quantification is explored by SOMAscan. For 63 proteins assessed in two chronic obstructive pulmonary disease (COPD) cohorts, subpopulations and intermediate outcome measures in COPD Study (SPIROMICS), and COPDGene, using myriad rules based medicine multiplex immunoassays and SOMAscan, Spearman correlation coefficients range from -0.13 to 0.97, with a median correlation coefficient of approximately 0.5 and consistent results across cohorts. A similar range is observed for immunoassays in the population-based Multi-Ethnic Study of Atherosclerosis and for other assays in COPDGene and SPIROMICS. Comparisons of relative quantification from the antibody-based Olink platform and SOMAscan in a small cohort of myocardial infarction patients also show a wide correlation range. Finally, cis pQTL data, mass spectrometry aptamer confirmation, and other publicly available data are integrated to assess relationships with observed correlations. Correlation between proteomics assays shows a wide range and should be carefully considered when comparing and meta-analyzing proteomics data across assays and studies. | Raffield, Laura M Dang, Hong Pratte, Katherine A Jacobson, Sean Gillenwater, Lucas A Ampleford, Elizabeth Barjaktarevic, Igor Basta, Patricia Clish, Clary B Comellas, Alejandro P Cornell, Elaine Curtis, Jeffrey L Doerschuk, Claire Durda, Peter Emson, Claire Freeman, Christine M Guo, Xiuqing Hastie, Annette T Hawkins, Gregory A Herrera, Julio Johnson, W Craig Labaki, Wassim W Liu, Yongmei Masters, Brett Miller, Michael Ortega, Victor E Papanicolaou, George Peters, Stephen Taylor, Kent D Rich, Stephen S Rotter, Jerome I Auer, Paul Reiner, Alex P Tracy, Russell P Ngo, Debby Gerszten, Robert E O'Neal, Wanda K Bowler, Russell P (TOPMed) eng N01HC95163/HL/NHLBI NIH HHS/ 75N93020D00002/AI/NIAID NIH HHS/ N01HC95169/HL/NHLBI NIH HHS/ N01 HC095162/HC/NHLBI NIH HHS/ N01HC95164/HL/NHLBI NIH HHS/ R01 HL132320/HL/NHLBI NIH HHS/ 75N98020D00007/OD/NIH HHS/ N01 HC095164/HC/NHLBI NIH HHS/ 75N95020D00004/DA/NIDA NIH HHS/ N01 HC095163/HC/NHLBI NIH HHS/ 75N95020D00003/DA/NIDA NIH HHS/ T32 HL007749/HL/NHLBI NIH HHS/ HHSN268201500003C/HL/NHLBI NIH HHS/ HHSN268200900019C/HL/NHLBI NIH HHS/ 75N90020D00002/CL/CLC NIH HHS/ R01 HL132947/HL/NHLBI NIH HHS/ P30 DK040561/DK/NIDDK NIH HHS/ N01HC95160/HL/NHLBI NIH HHS/ R01 HL120393/HL/NHLBI NIH HHS/ U54 HG003067/HG/NHGRI NIH HHS/ N01 HC095168/HC/NHLBI NIH HHS/ UL1 TR001079/TR/NCATS NIH HHS/ 75N96020D00002/ES/NIEHS NIH HHS/ P30 ES005605/ES/NIEHS NIH HHS/ 75N95020D00002/DA/NIDA NIH HHS/ 75N99020D00003/OF/ORFDO NIH HHS/ U01 HL089897/HL/NHLBI NIH HHS/ N01 HC095165/HC/NHLBI NIH HHS/ N01HC95162/HL/NHLBI NIH HHS/ N01HC95168/HL/NHLBI NIH HHS/ U01 HL089856/HL/NHLBI NIH HHS/ 75N90020D00003/CL/CLC NIH HHS/ 75N96020D00003/ES/NIEHS NIH HHS/ HHSN268200900015C/HL/NHLBI NIH HHS/ T32 HL129982/HL/NHLBI NIH HHS/ HHSN268200900016C/HL/NHLBI NIH HHS/ N01 HC095169/HC/NHLBI NIH HHS/ P30 DK063491/DK/NIDDK NIH HHS/ 75N99020D00002/OF/ORFDO NIH HHS/ I01 CX000911/CX/CSRD VA/ HHSN268201800001C/HL/NHLBI NIH HHS/ 75N99020D00006/OF/ORFDO NIH HHS/ N01 HC095159/HC/NHLBI NIH HHS/ N01HC95165/HL/NHLBI NIH HHS/ U01 HL137880/HL/NHLBI NIH HHS/ N01HC95159/HL/NHLBI NIH HHS/ N01 HC095161/HC/NHLBI NIH HHS/ 75N95020D00007/DA/NIDA NIH HHS/ N01HC95161/HL/NHLBI NIH HHS/ UL1 TR001420/TR/NCATS NIH HHS/ 75N95020D00005/DA/NIDA NIH HHS/ R01 HL133870/HL/NHLBI NIH HHS/ HHSN268201500003I/HL/NHLBI NIH HHS/ 75N92021D00006/HL/NHLBI NIH HHS/ HHSN268200900018C/HL/NHLBI NIH HHS/ 75N99020D00005/OF/ORFDO NIH HHS/ N01 HC095166/HC/NHLBI NIH HHS/ N01HC95167/HL/NHLBI NIH HHS/ 75N99020D00007/OF/ORFDO NIH HHS/ HHSN268200900017C/HL/NHLBI NIH HHS/ HHSN268200900020C/HL/NHLBI NIH HHS/ HHSN268200900013C/HL/NHLBI NIH HHS/ UL1 TR000040/TR/NCATS NIH HHS/ R01 HL117626/HL/NHLBI NIH HHS/ N01HC95166/HL/NHLBI NIH HHS/ Merit Review I01 CX000911/VA/VA/ HHSN268200900014C/HL/NHLBI NIH HHS/ N01 HC095167/HC/NHLBI NIH HHS/ 75N99020D00004/OF/ORFDO NIH HHS/ N01 HC095160/HC/NHLBI NIH HHS/ Comparative Study Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Germany Proteomics. 2020 Jun;20(12):e1900278. doi: 10.1002/pmic.201900278.I | 05/10/2020 | |
| Aptamers and Antisense Oligonucleotides for Diagnosis and Treatment of Hematological Diseases | Giudice V, et al. | 2020 | Int J Mol Sci | 21 | 9 | https://www.doi.org/10.3390/ijms21093252 | 32,375,354 | Animals *Aptamers, Nucleotide Clinical Trials as Topic Disease Management Drug Evaluation, Preclinical *Genetic Therapy/methods Hematologic Diseases/*diagnosis/etiology/mortality/*therapy Humans *Molecular Diagnostic Techniques *Oligonucleotides, Antisense SELEX Aptamer Technique Treatment Outcome antisense oligonucleotides aptamers diagnosis hematology treatment | Aptamers or chemical antibodies are single-stranded DNA or RNA oligonucleotides that bind proteins and small molecules with high affinity and specificity by recognizing tertiary or quaternary structures as antibodies. Aptamers can be easily produced in vitro through a process known as systemic evolution of ligands by exponential enrichment (SELEX) or a cell-based SELEX procedure. Aptamers and modified aptamers, such as slow, off-rate, modified aptamers (SOMAmers), can bind to target molecules with less polar and more hydrophobic interactions showing slower dissociation rates, higher stability, and resistance to nuclease degradation. Aptamers and SOMAmers are largely employed for multiplex high-throughput proteomics analysis with high reproducibility and reliability, for tumor cell detection by flow cytometry or microscopy for research and clinical purposes. In addition, aptamers are increasingly used for novel drug delivery systems specifically targeting tumor cells, and as new anticancer molecules. In this review, we summarize current preclinical and clinical applications of aptamers in malignant and non-malignant hematological diseases. | Giudice, Valentina Mensitieri, Francesca Izzo, Viviana Filippelli, Amelia Selleri, Carmine eng Review Switzerland Int J Mol Sci. 2020 May 4;21(9):3252. doi: 10.3390/ijms21093252.I | 05/08/2020 | ||
| Type I IFN response associated with mTOR activation in the TAFRO subtype of idiopathic multicentric Castleman disease | Pai RL, et al. | 2020 | JCI Insight | 5 | 9 | https://www.doi.org/10.1172/jci.insight.135031 | 32,376,796 | Adolescent Adult Aged *CD8-Positive T-Lymphocytes/cytology/immunology Castleman Disease/*immunology Female Humans Interferon Type I/*immunology *Killer Cells, Natural/cytology/immunology Longitudinal Studies Male Middle Aged *Monocytes/cytology/immunology TOR Serine-Threonine Kinases/*immunology Cellular immune response Cytokines Hematology Immunology T cells ACCELERATE study (formerly sponsored by Janssen Pharmaceuticals) and study drug from Pfizer for NCT03933904 without corresponding financial support. FVR receives research support from Janssen Pharmaceuticals and consultant fees from EUSA Pharma. There is a pending provisional patent application based on the work in this paper. | The TAFRO clinical subtype of idiopathic multicentric Castleman disease (iMCD-TAFRO) is a rare hematologic illness involving episodic disease flares of thrombocytopenia, anasarca, fever, reticulin myelofibrosis, renal dysfunction, and organomegaly (TAFRO) and progressive multiple organ dysfunction. We previously showed that the mTOR signaling pathway is elevated in lymph nodes of iMCD-TAFRO patients and that an mTOR inhibitor is effective in a small cohort of patients. However, the upstream mechanisms, cell types, and mediators involved in disease pathogenesis remain unknown. Here, we developed a targeted approach to identify candidate cellular drivers and mechanisms in iMCD-TAFRO through cellular and transcriptomic studies. Using paired iMCD-TAFRO PBMC samples collected during flare and remission, we identified T cell activation and alterations in NK cell and monocyte subset frequencies during iMCD-TAFRO flare. These changes were associated with increased Type I IFN (IFN-I) response gene signatures across CD8+ T cells, NK cells, and monocytes. Finally, we found that IFN-beta stimulation of monocytes and T cells from iMCD-TAFRO patient remission samples induced increased mTOR activation compared with healthy donors, and this was abrogated with either mTORC1 or JAK1/2 inhibition. The data presented here support a potentially novel role for IFN-I signaling as a driver of increased mTOR signaling in iMCD-TAFRO. | Pai, Ruth-Anne Langan Japp, Alberto Sada Gonzalez, Michael Rasheed, Rozena F Okumura, Mariko Arenas, Daniel Pierson, Sheila K Powers, Victoria Layman, Awo Akosua Kesewa Kao, Charlly Hakonarson, Hakon van Rhee, Frits Betts, Michael R Kambayashi, Taku Fajgenbaum, David C eng R01 HL141408/HL/NHLBI NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't JCI Insight. 2020 May 7;5(9):e135031. doi: 10.1172/jci.insight.135031.I | 05/08/2020 | ||
| Proteomic biomarkers of sleep apnea | Ambati A, et al. | 2020 | Sleep | 43 | 11 | https://www.doi.org/10.1093/sleep/zsaa086 | 32,369,590 | Biomarkers Cross-Sectional Studies Humans Polysomnography *Proteomics Receptors, Cell Surface *Sleep Apnea Syndromes apnea oxygen saturation proteomics serum sleep-disordered breathing | STUDY OBJECTIVES: Obstructive sleep apnea (OSA) is characterized by recurrent partial to complete upper airway obstructions during sleep, leading to repetitive arousals and oxygen desaturations. Although many OSA biomarkers have been reported individually, only a small subset have been validated through both cross-sectional and intervention studies. We sought to profile serum protein biomarkers in OSA in unbiased high throughput assay. METHODS: A highly multiplexed aptamer array (SomaScan) was used to profile 1300 proteins in serum samples from 713 individuals in the Stanford Sleep Cohort, a patient-based registry. Outcome measures derived from overnight polysomnography included Obstructive Apnea Hypopnea Index (OAHI), Central Apnea Index (CAI), 2% Oxygen Desaturation index, mean and minimum oxygen saturation indices during sleep. Additionally, a separate intervention-based cohort of 16 individuals was used to assess proteomic profiles pre- and post-intervention with positive airway pressure. RESULTS: OAHI was associated with 65 proteins, predominantly pathways of complement, coagulation, cytokine signaling, and hemostasis which were upregulated. CAI was associated with two proteins including Roundabout homolog 3 (ROBO3), a protein involved in bilateral synchronization of the pre-Botzinger complex and cystatin F. Analysis of pre- and post intervention samples revealed IGFBP-3 protein to be increased while LEAP1 (Hepicidin) to be decreased with intervention. An OAHI machine learning classifier (OAHI >=15 vs OAHI<15) trained on SomaScan protein measures alone performed robustly, achieving 76% accuracy in a validation dataset. CONCLUSIONS: Multiplex protein assays offer diagnostic potential and provide new insights into the biological basis of sleep disordered breathing. | Ambati, Aditya Ju, Yo-El Lin, Ling Olesen, Alexander N Koch, Henriette Hedou, Julien Jacques Leary, Eileen B Sempere, Vicente Peris Mignot, Emmanuel Taheri, Shahrad eng K23 NS089922/NS/NINDS NIH HHS/ KL2 RR024994/RR/NCRR NIH HHS/ UL1 TR002345/TR/NCATS NIH HHS/ KL2 TR000450/TR/NCATS NIH HHS/ KL2 TR002346/TR/NCATS NIH HHS/ UL1 TR000448/TR/NCATS NIH HHS/ Research Support, N.I.H., Extramural Sleep. 2020 Nov 12;43(11):zsaa086. doi: 10.1093/sleep/zsaa086.I | 05/06/2020 | ||
| Comprehensive aptamer-based screening identifies a spectrum of urinary biomarkers of lupus nephritis across ethnicities | Stanley S, et al. | 2020 | Nat Commun | 11 | 1 | 2197 | https://www.doi.org/10.1038/s41467-020-15986-3 | 32,366,845 | Activated-Leukocyte Cell Adhesion Molecule/urine Adult African Americans/statistics & numerical data Aptamers, Peptide/*metabolism Asians/statistics & numerical data Biomarkers/*urine E-Selectin/analysis Female Humans Lupus Nephritis/*diagnosis/ethnology/urine Properdin/urine Proteins/*analysis Sensitivity and Specificity Vascular Cell Adhesion Molecule-1/urine Whites/statistics & numerical data Young Adult | Emerging urinary biomarkers continue to show promise in evaluating lupus nephritis (LN). Here, we screen urine from active LN patients for 1129 proteins using an aptamer-based platform, followed by ELISA validation in two independent cohorts comprised of 127 inactive lupus, 107 active LN, 67 active non-renal lupus patients and 74 healthy controls, of three different ethnicities. Urine proteins that best distinguish active LN from inactive disease are ALCAM, PF-4, properdin, and VCAM-1 among African-Americans, sE-selectin, VCAM-1, BFL-1 and Hemopexin among Caucasians, and ALCAM, VCAM-1, TFPI and PF-4 among Asians. Most of these correlate significantly with disease activity indices in the respective ethnic groups, and surpass conventional metrics in identifying active LN, with better sensitivity, and negative/positive predictive values. Several elevated urinary molecules are also expressed within the kidneys in LN, based on single-cell RNAseq analysis. Longitudinal studies are warranted to assess the utility of these biomarkers in tracking lupus nephritis. | Stanley, Samantha Vanarsa, Kamala Soliman, Samar Habazi, Deena Pedroza, Claudia Gidley, Gabriel Zhang, Ting Mohan, Shree Der, Evan Suryawanshi, Hemant Tuschl, Thomas Buyon, Jill Putterman, Chaim Mok, Chi Chiu Petri, Michelle Saxena, Ramesh Mohan, Chandra eng R01 AR043727/AR/NIAMS NIH HHS/ R01 AR069572/AR/NIAMS NIH HHS/ R01 AR074096/AR/NIAMS NIH HHS/ P30 DK079328/DK/NIDDK NIH HHS/ Research Support, N.I.H., Extramural England Nat Commun. 2020 May 4;11(1):2197. doi: 10.1038/s41467-020-15986-3.I | 05/06/2020 | |
| Single-Molecule Super-Resolution Microscopy Reveals Heteromeric Complexes of MET and EGFR upon Ligand Activation | Harwardt MIE, et al. | 2020 | Int J Mol Sci | 21 | 8 | https://www.doi.org/10.3390/ijms21082803 | 32,316,583 | Cell Line, Tumor Cell Membrane/*metabolism Epidermal Growth Factor/pharmacology ErbB Receptors/metabolism HeLa Cells Hepatocyte Growth Factor/pharmacology Humans Ligands Multiprotein Complexes/metabolism Proto-Oncogene Proteins c-met/*metabolism Signal Transduction Single Molecule Imaging/*methods DNA-paint Egfr Met receptor cross-interaction receptor tyrosine kinases single-molecule localization microscopy single-particle tracking | Receptor tyrosine kinases (RTKs) orchestrate cell motility and differentiation. Deregulated RTKs may promote cancer and are prime targets for specific inhibitors. Increasing evidence indicates that resistance to inhibitor treatment involves receptor cross-interactions circumventing inhibition of one RTK by activating alternative signaling pathways. Here, we used single-molecule super-resolution microscopy to simultaneously visualize single MET and epidermal growth factor receptor (EGFR) clusters in two cancer cell lines, HeLa and BT-20, in fixed and living cells. We found heteromeric receptor clusters of EGFR and MET in both cell types, promoted by ligand activation. Single-protein tracking experiments in living cells revealed that both MET and EGFR respond to their cognate as well as non-cognate ligands by slower diffusion. In summary, for the first time, we present static as well as dynamic evidence of the presence of heteromeric clusters of MET and EGFR on the cell membrane that correlates with the relative surface expression levels of the two receptors. | Harwardt, Marie-Lena I E Schroder, Mark S Li, Yunqing Malkusch, Sebastian Freund, Petra Gupta, Shashi Janjic, Nebojsa Strauss, Sebastian Jungmann, Ralf Dietz, Marina S Heilemann, Mike eng 91069/Volkswagen Foundation/ SFB1177/Deutsche Forschungsgemeinschaft/ Ub-Net/Hessisches Ministerium fur Wissenschaft und Kunst/ DynaMem/Hessisches Ministerium fur Wissenschaft und Kunst/ Switzerland Int J Mol Sci. 2020 Apr 17;21(8):2803. doi: 10.3390/ijms21082803.I | 04/23/2020 | ||
| Reduced Apolipoprotein M and Adverse Outcomes Across the Spectrum of Human Heart Failure | Chirinos JA, et al. | 2020 | Circulation | 141 | 18 | 1463-1476 | https://www.doi.org/10.1161/CIRCULATIONAHA.119.045323 | 32,237,898 | Aged Apolipoproteins M/*blood Biomarkers/blood Down-Regulation Female Heart Failure/*blood/diagnosis/mortality/therapy Humans Lipoproteins, HDL/blood Lysophospholipids/blood Male Middle Aged Prognosis *Proteome Proteomics Randomized Controlled Trials as Topic Registries Risk Assessment Risk Factors Sphingosine/analogs & derivatives/blood Time Factors United States apolipoproteins M heart failure lipoproteins, HDL sphingosine-1-phosphate survival | BACKGROUND: Apo (apolipoprotein) M mediates the physical interaction between high-density lipoprotein (HDL) particles and sphingosine-1-phosphate (S1P). Apo M exerts anti-inflammatory and cardioprotective effects in animal models. METHODS: In a subset of PHFS (Penn Heart Failure Study) participants (n=297), we measured apo M by Enzyme-Linked ImmunoSorbent Assay (ELISA). We also measured total S1P by liquid chromatography-mass spectrometry and isolated HDL particles to test the association between apo M and HDL-associated S1P. We confirmed the relationship between apo M and outcomes using modified aptamer-based apo M measurements among 2170 adults in the PHFS and 2 independent cohorts: the Washington University Heart Failure Registry (n=173) and a subset of TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist Trial; n=218). Last, we examined the relationship between apo M and approximately 5000 other proteins (SomaScan assay) to identify biological pathways associated with apo M in heart failure. RESULTS: In the PHFS, apo M was inversely associated with the risk of death (standardized hazard ratio, 0.56 [95% CI, 0.51-0.61]; P<0.0001) and the composite of death/ventricular assist device implantation/heart transplantation (standardized hazard ratio, 0.62 [95% CI, 0.58-0.67]; P<0.0001). This relationship was independent of HDL cholesterol or apo AI levels. Apo M remained associated with death (hazard ratio, 0.78 [95% CI, 0.69-0.88]; P<0.0001) and the composite of death/ventricular assist device/heart transplantation (hazard ratio, 0.85 [95% CI, 0.76-0.94]; P=0.001) in models that adjusted for multiple confounders. This association was present in both heart failure with reduced and preserved ejection fraction and was replicated in the Washington University cohort and a cohort with heart failure with preserved ejection fraction only (TOPCAT). The S1P and apo M content of isolated HDL particles strongly correlated (R=0.81, P<0.0001). The top canonical pathways associated with apo M were inflammation (negative association), the coagulation system (negative association), and liver X receptor/retinoid X receptor activation (positive association). The relationship with inflammation was validated with multiple inflammatory markers measured with independent assays. CONCLUSIONS: Reduced circulating apo M is independently associated with adverse outcomes across the spectrum of human heart failure. Further research is needed to assess whether the apo M/S1P axis is a suitable therapeutic target in heart failure. | Chirinos, Julio A Zhao, Lei Jia, Yi Frej, Cecilia Adamo, Luigi Mann, Douglas Shewale, Swapnil V Millar, John S Rader, Daniel J French, Benjamin Brandimarto, Jeff Margulies, Kenneth B Parks, John S Wang, Zhaoqing Seiffert, Dietmar A Fang, James Sweitzer, Nancy Chistoffersen, Christina Dahlback, Bjorn Car, Bruce D Gordon, David A Cappola, Thomas P Javaheri, Ali eng U10 HL110338/HL/NHLBI NIH HHS/ R01 HL107594/HL/NHLBI NIH HHS/ P01 HL094307/HL/NHLBI NIH HHS/ RC2 HL102222/HL/NHLBI NIH HHS/ P30 DK056341/DK/NIDDK NIH HHS/ T32 HL007081/HL/NHLBI NIH HHS/ R01 HL104106/HL/NHLBI NIH HHS/ R61 HL146390/HL/NHLBI NIH HHS/ R56 HL136730/HL/NHLBI NIH HHS/ R01 AG058969/AG/NIA NIH HHS/ R01 HL119962/HL/NHLBI NIH HHS/ K08 HL138262/HL/NHLBI NIH HHS/ HHSN268201100026C/HL/NHLBI NIH HHS/ R01 HL121510/HL/NHLBI NIH HHS/ Multicenter Study Observational Study Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Circulation. 2020 May 5;141(18):1463-1476. doi: 10.1161/CIRCULATIONAHA.119.045323. Epub 2020 Apr 2.I | 04/03/2020 | |
| Modified nucleotides may have enhanced early RNA catalysis | Wolk SK, et al. | 2020 | Proc Natl Acad Sci U S A | 117 | 15 | 8236-8242 | https://www.doi.org/10.1073/pnas.1809041117 | 32,229,566 | Evolution, Molecular RNA/genetics/metabolism RNA, Catalytic/genetics/*metabolism Ribonucleotides/*metabolism RNA world catalytic RNA modified nucleotides | The modern version of the RNA World Hypothesis begins with activated ribonucleotides condensing (nonenzymatically) to make RNA molecules, some of which possess (perhaps slight) catalytic activity. We propose that noncanonical ribonucleotides, which would have been inevitable under prebiotic conditions, might decrease the RNA length required to have useful catalytic function by allowing short RNAs to possess a more versatile collection of folded motifs. We argue that modified versions of the standard bases, some with features that resemble cofactors, could have facilitated that first moment in which early RNA molecules with catalytic capability began their evolutionary path toward self-replication. | Wolk, Steven K Mayfield, Wesley S Gelinas, Amy D Astling, David Guillot, Jessica Brody, Edward N Janjic, Nebojsa Gold, Larry eng Proc Natl Acad Sci U S A. 2020 Apr 14;117(15):8236-8242. doi: 10.1073/pnas.1809041117. Epub 2020 Mar 30.I | 04/02/2020 | |
| Autophagy Modulators Profoundly Alter the Astrocyte Cellular Proteome | Sher AA, et al. | 2020 | Cells | 9 | 4 | https://www.doi.org/10.3390/cells9040805 | 32,225,060 | Astrocytes/*cytology/drug effects/*metabolism Astrocytoma/genetics/pathology *Autophagy/drug effects Biomarkers, Tumor/metabolism Cell Line, Tumor Cell Survival/drug effects Cytokines/metabolism Gene Expression Regulation, Neoplastic/drug effects Humans Macrolides/pharmacology Microtubule-Associated Proteins/metabolism Proteome/*metabolism Sequestosome-1 Protein/metabolism Sirolimus/pharmacology BafilomycinA1 Rapamycin aptamers autophagy bioinformatics cell responses | Autophagy is a key cellular process that involves constituent degradation and recycling during cellular development and homeostasis. Autophagy also plays key roles in antimicrobial host defense and numerous pathogenic organisms have developed strategies to take advantage of and/or modulate cellular autophagy. Several pharmacologic compounds, such as BafilomycinA1, an autophagy inducer, and Rapamycin, an autophagy inhibitor, have been used to modulate autophagy, and their effects upon notable autophagy markers, such as LC3 protein lipidation and Sequestosome-1/p62 alterations are well defined. We sought to understand whether such autophagy modulators have a more global effect upon host cells and used a recently developed aptamer-based proteomic platform (SOMAscan((R))) to examine 1305 U-251 astrocytic cell proteins after the cells were treated with each compound. These analyses, and complementary cytokine array analyses of culture supernatants after drug treatment, revealed substantial perturbations in the U-251 astrocyte cellular proteome. Several proteins, including cathepsins, which have a role in autophagy, were differentially dysregulated by the two drugs as might be expected. Many proteins, not previously known to be involved in autophagy, were significantly dysregulated by the compounds, and several, including lactadherin and granulins, were up-regulated by both drugs. These data indicate that these two compounds, routinely used to help dissect cellular autophagy, have much more profound effects upon cellular proteins. | Sher, Affan Ali Gao, Ang Coombs, Kevin M eng Research Support, Non-U.S. Gov't Switzerland Cells. 2020 Mar 26;9(4):805. doi: 10.3390/cells9040805.I | 04/01/2020 | ||
| Increased mTOR activation in idiopathic multicentric Castleman disease | Arenas DJ, et al. | 2020 | Blood | 135 | 19 | 1673-1684 | https://www.doi.org/10.1182/blood.2019002792 | 32,206,779 | Adolescent Adult Aged Biomarkers, Tumor/*metabolism Case-Control Studies Castleman Disease/metabolism/*pathology Child Child, Preschool Cohort Studies Female Follow-Up Studies *Gene Expression Regulation, Neoplastic Humans Infant Interleukin-6/*metabolism Male Middle Aged Prognosis Proteome/*analysis/metabolism Ribosomal Protein S6 Kinases/*metabolism Signal Transduction TOR Serine-Threonine Kinases/*metabolism Young Adult | Idiopathic multicentric Castleman disease (iMCD) is a rare and poorly understood hematologic disorder characterized by lymphadenopathy, systemic inflammation, cytopenias, and life-threatening multiorgan dysfunction. Interleukin-6 (IL-6) inhibition effectively treats approximately one-third of patients. Limited options exist for nonresponders, because the etiology, dysregulated cell types, and signaling pathways are unknown. We previously reported 3 anti-IL-6 nonresponders with increased mTOR activation who responded to mTOR inhibition with sirolimus. We investigated mTOR signaling in tissue and serum proteomes from iMCD patients and controls. mTOR activation was increased in the interfollicular space of iMCD lymph nodes (N = 26) compared with control lymph nodes by immunohistochemistry (IHC) for pS6, p4EBP1, and p70S6K, known effectors and readouts of mTORC1 activation. IHC for pS6 also revealed increased mTOR activation in iMCD compared with Hodgkin lymphoma, systemic lupus erythematosus, and reactive lymph nodes, suggesting that the mTOR activation in iMCD is not just a product of lymphoproliferation/inflammatory lymphadenopathy. Further, the degree of mTOR activation in iMCD was comparable to autoimmune lymphoproliferative syndrome, a disease driven by mTOR hyperactivation that responds to sirolimus treatment. Gene set enrichment analysis of serum proteomic data from iMCD patients (n = 88) and controls (n = 42) showed significantly enriched mTORC1 signaling. Finally, functional studies revealed increased baseline mTOR pathway activation in peripheral monocytes and T cells from iMCD remission samples compared with healthy controls. IL-6 stimulation augmented mTOR activation in iMCD patients, which was abrogated with JAK1/2 inhibition. These findings support mTOR activation as a novel therapeutic target for iMCD, which is being investigated through a trial of sirolimus (NCT03933904). | Arenas, Daniel J Floess, Katherine Kobrin, Dale Pai, Ruth-Anne Langan Srkalovic, Maya B Tamakloe, Mark-Avery Rasheed, Rozena Ziglar, Jasira Khor, Johnson Parente, Sophia A T Pierson, Sheila K Martinez, Daniel Wertheim, Gerald B Kambayashi, Taku Baur, Joseph Teachey, David T Fajgenbaum, David C eng R01 HL141408/HL/NHLBI NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Blood. 2020 May 7;135(19):1673-1684. doi: 10.1182/blood.2019002792.I | 03/25/2020 | |
| Placenta accreta spectrum: biomarker discovery using plasma proteomics | Shainker SA, et al. | 2020 | Am J Obstet Gynecol | 223 | 3 | 433 e1-433 e14 | https://www.doi.org/10.1016/j.ajog.2020.03.019 | 32,199,927 | Adult Biomarkers/blood Case-Control Studies Female Humans Placenta Accreta/*blood Pregnancy Pregnancy Trimester, Third *Prenatal Diagnosis Proteomics Vascular Endothelial Growth Factors/*blood antithrombin III diagnosis placenta accreta spectrum placentation plasma protein soluble Tie2 soluble VEGF receptor 2 | BACKGROUND: Many cases of placenta accreta spectrum are not diagnosed antenatally, despite identified risk factors and improved imaging methods. Identification of plasma protein biomarkers could further improve the antenatal diagnosis of placenta accreta spectrum . OBJECTIVE: The purpose of this study was to determine if women with placenta accreta spectrum have a distinct plasma protein profile compared with control subjects. STUDY DESIGN: We obtained plasma samples before delivery from 16 participants with placenta accreta spectrum and 10 control subjects with similar gestational ages (35.1 vs 35.5 weeks gestation, respectively). We analyzed plasma samples with an aptamer-based proteomics platform for alterations in 1305 unique proteins. Heat maps of the most differentially expressed proteins (T test, P<.01) were generated with matrix visualization and analysis software. Principal component analysis was performed with the use of all 1305 proteins and the top 21 dysregulated proteins. We then confirmed dysregulated proteins using enzyme-linked immunosorbent assay and report significant differences between placenta accreta spectrum and control cases (Wilcoxon-rank sum test, P<.05). RESULTS: Many of the top 50 proteins that significantly dysregulated in participants with placenta accreta spectrum were inflammatory cytokines, factors that regulate vascular remodeling, and extracellular matrix proteins that regulate invasion. Placenta accreta spectrum, with the use of the top 21 proteins, distinctly separated the placenta accreta spectrum cases from control cases (P<.01). Using enzyme-linked immunosorbent assay, we confirmed 4 proteins that were dysregulated in placenta accreta spectrum compared with control cases: median antithrombin III concentrations (240.4 vs 150.3 mg/mL; P=.002), median plasminogen activator inhibitor 1 concentrations (4.1 vs 7.1 ng/mL; P<.001), soluble Tie2 (13.5 vs 10.4 ng/mL; P=.02), soluble vascular endothelial growth factor receptor 2 (9.0 vs 5.9 ng/mL; P=.003). CONCLUSION: Participants with placenta accreta spectrum had a unique and distinct plasma protein signature. | Shainker, Scott A Silver, Robert M Modest, Anna M Hacker, Michele R Hecht, Jonathan L Salahuddin, Saira Dillon, Simon T Ciampa, Erin J D'Alton, Mary E Otu, Hasan H Abuhamad, Alfred Z Einerson, Brett D Branch, D Ware Wylie, Blair J Libermann, Towia A Karumanchi, S Ananth eng Evaluation Study Research Support, Non-U.S. Gov't Am J Obstet Gynecol. 2020 Sep;223(3):433.e1-433.e14. doi: 10.1016/j.ajog.2020.03.019. Epub 2020 Mar 19.I | 03/23/2020 | |
| Proteomic profiling of HTLV-1 carriers and ATL patients reveals sTNFR2 as a novel diagnostic biomarker for acute ATL | Guerrero CLH, et al. | 2020 | Blood Adv | 4 | 6 | 1062-1071 | https://www.doi.org/10.1182/bloodadvances.2019001429 | 32,196,559 | Adult Cytokines Flow Cytometry *Human T-lymphotropic virus 1/genetics Humans *Leukemia-Lymphoma, Adult T-Cell/diagnosis Proteomics Receptors, Tumor Necrosis Factor, Type II | Adult T-cell leukemia/lymphoma (ATL) is a human T-cell leukemia virus type 1 (HTLV-1)-associated T-cell malignancy with generally poor prognosis. Although only approximately 5% of HTLV-1 carriers progress to ATL, early diagnosis is challenging because of the lack of ATL biomarkers. In this study, we analyzed blood plasma profiles of asymptomatic HTLV-1 carriers (ACs); untreated ATL patients, including acute, lymphoma, smoldering, and chronic types; and ATL patients in remission. Through SOMAscan, expression levels of 1305 plasma proteins were analyzed in 85 samples (AC, n = 40; ATL, n = 40; remission, n = 5). Using gene set enrichment analysis and gene ontology, overrepresented pathways in ATL vs AC included angiogenesis, inflammation by cytokines and chemokines, interleukin-6 (IL-6)/JAK/STAT3, and notch signaling. In selecting candidate biomarkers, we focused on soluble tumor necrosis factor 2 (sTNFR2) because of its active role in enriched pathways, extreme significance (Welch's t test P < .00001), high discrimination capacity (area under the curve >0.90), and novelty in ATL research. Quantification of sTNFR2 in 102 plasma samples (AC, n = 30; ATL, n = 68; remission, n = 4) using enzyme-linked immunosorbent assay showed remarkable elevations in acute ATL, at least 10 times those of AC samples, and return of sTNFR2 to AC state levels after achieving remission. Flow cytometry and immunostaining validated the expression of TNFR2 in ATL cells. No correlation between sIL-2 and sTNFR2 levels in acute ATL was found, suggesting the possibility of sTNFR2 as an independent biomarker. Our findings represent the first extensive blood-based proteomic analysis of ATL, suggesting the potential clinical utility of sTNFR2 in diagnosing acute ATL. | Guerrero, Carmina Louise Hugo Yamashita, Yoshiko Miyara, Megumi Imaizumi, Naoki Kato, Megumi Sakihama, Shugo Hayashi, Masaki Miyagi, Takashi Karimata, Kaori Uchihara, Junnosuke Ohshiro, Kazuiku Todoroki, Junpei Nakachi, Sawako Morishima, Satoko Karube, Kennosuke Tanaka, Yuetsu Masuzaki, Hiroaki Fukushima, Takuya eng Research Support, Non-U.S. Gov't Blood Adv. 2020 Mar 24;4(6):1062-1071. doi: 10.1182/bloodadvances.2019001429.I | 03/21/2020 | |
| Effect of induced hypoglycemia on inflammation and oxidative stress in type 2 diabetes and control subjects | Kahal H, et al. | 2020 | Sci Rep | 10 | 1 | 4750 | https://www.doi.org/10.1038/s41598-020-61531-z | 32,179,763 | Adult Biomarkers/blood Blood Glucose C-Reactive Protein Case-Control Studies Diabetes Mellitus, Type 2/diagnosis/*drug therapy Female Humans Hypoglycemia/diagnosis/*etiology Hypoglycemic Agents/*adverse effects Inflammation Male Middle Aged *Oxidative Stress Time Factors | Intensive diabetes control has been associated with increased mortality in type 2 diabetes (T2DM); this has been suggested to be due to increased hypoglycemia. We measured hypoglycemia-induced changes in endothelial parameters, oxidative stress markers and inflammation at baseline and after a 24-hour period in type 2 diabetic (T2DM) subjects versus age-matched controls. Case-control study: 10 T2DM and 8 control subjects. Blood glucose was reduced from 5 (90 mg/dl) to hypoglycemic levels of 2.8 mmol/L (50 mg/dl) for 1 hour by incremental hyperinsulinemic clamps using baseline and 24 hour samples. Measures of endothelial parameters, oxidative stress and inflammation at baseline and at 24-hours post hypoglycemia were performed: proteomic (Somalogic) analysis for inflammatory markers complemented by C-reactive protein (hsCRP) measurement, and proteomic markers and urinary isoprostanes for oxidative measures, together with endothelial function. Between baseline and 24 -hours after hypoglycemia, 15 of 140 inflammatory proteins differed in T2DM whilst only 1 of 140 differed in controls; all returned to baseline at 24-hours. However, elevated hsCRP levels were seen at 24-hours in T2DM (2.4 mg/L (1.2-5.4) vs. 3.9 mg/L (1.8-6.1), Baseline vs 24-hours, P < 0.05). In patients with T2DM, between baseline and 24-hour after hypoglycemia, only one of 15 oxidative stress proteins differed and this was not seen in controls. An increase (P = 0.016) from baseline (73.4 ng/mL) to 24 hours after hypoglycemia (91.7 ng/mL) was seen for urinary isoprostanes. Hypoglycemia resulted in inflammatory and oxidative stress markers being elevated in T2DM subjects but not controls 24-hours after the event. | Kahal, Hassan Halama, Anna Aburima, Ahmed Bhagwat, Aditya M Butler, Alexandra E Graumann, Johannes Suhre, Karsten Sathyapalan, Thozhukat Atkin, Stephen L eng Research Support, Non-U.S. Gov't England Sci Rep. 2020 Mar 16;10(1):4750. doi: 10.1038/s41598-020-61531-z.I | 03/18/2020 | |
| Multimodal immune phenotyping of maternal peripheral blood in normal human pregnancy | Apps R, et al. | 2020 | JCI Insight | 5 | 7 | https://www.doi.org/10.1172/jci.insight.134838 | 32,163,376 | Adolescent Adult Biomarkers/blood Female *Gestational Age Humans Immunophenotyping Leukocytes/*immunology/metabolism Middle Aged Pregnancy/blood/*immunology Pregnancy Trimester, First/blood/*immunology Cellular immune response Immunology Obstetrics/gynecology Proteomics Reproductive Biology exists. | Changes in maternal immunity during pregnancy can result in an altered immune state, and as a natural perturbation, this provides an opportunity to understand functional interactions of the immune system in vivo. We report characterization of maternal peripheral immune phenotypes for 33 longitudinally sampled normal pregnancies, using clinical measurements of complete blood counts and major immune cell populations, as well as high parameter flow cytometry for 30 leukocyte antigens characterizing 79 cell populations, and monitoring of 1305 serum proteins using the SomaLogic platform. Cellular analyses characterized transient changes in T cell polarization and more persistent alterations in T and B cell subset frequencies and activation. Serum proteomic analysis identified a potentially novel set of 7 proteins that are predictive of gestational age: DDR1, PLAU, MRC1, ACP5, ROBO2, IGF2R, and GNS. We further show that gestational age can be predicted from the parameters obtained by complete blood count tests and clinical flow cytometry characterizing 5 major immune cell populations. Inferring gestational age from this routine clinical phenotyping data could be useful in resource-limited settings that lack obstetric ultrasound. Overall, both the cellular and proteomic analyses validate previously reported phenotypic immunological changes of pregnancy and uncover potentially new alterations and predictive markers. | Apps, Richard Kotliarov, Yuri Cheung, Foo Han, Kyu Lee Chen, Jinguo Biancotto, Angelique Babyak, Ashley Zhou, Huizhi Shi, Rongye Barnhart, Lisa Osgood, Sharon M Belkaid, Yasmine Holland, Steven M Tsang, John S Zerbe, Christa S eng Clinical Trial Research Support, N.I.H., Intramural JCI Insight. 2020 Apr 9;5(7):e134838. doi: 10.1172/jci.insight.134838.I | 03/13/2020 | ||
| Plasma proteomic signature of the risk of developing mobility disability: A 9-year follow-up | Osawa Y, et al. | 2020 | Aging Cell | 19 | 4 | e13132 | https://www.doi.org/10.1111/acel.13132 | 32,157,804 | Aged Aged, 80 and over Biomarkers/blood Cathepsins/*blood Disabled Persons/*psychology Female Follow-Up Studies Growth Differentiation Factor 15/*blood Humans Middle Aged *Proteomics Risk Factors Thrombospondins/*blood Walking/*psychology cathepsin S growth/differentiation factor 15 mobility disability proteomics thrombospondin-2 | INTRODUCTION: Mobility disability is a powerful indicator of poor health in older adults. The biological and pathophysiological mechanism underlying the development of mobility disability remains unknown. This study conducted a data-driven discovery phase investigation to identify plasma proteins that predict the incidence of mobility disability in community-dwelling older adults without mobility disability at baseline. METHODS: We investigated 660 women and men, aged 71.9 +/- 6.0 (60-94) years, who participated in the Invecchiare in Chianti, Aging in the Chianti Area" study and completed the 400-m walk at fast pace (400-m walk) at enrollment. Median follow-up time was 8.57 [interquartile, 3.20-9.08] years. SOMAscan technology was used to measure 1,301 plasma proteins at enrollment. The incident of mobility disability was defined as inability to complete the 400-m walk. Protein-specific Cox proportional hazard model was adjusted for sex, age, and other important covariates. RESULTS: Plasma levels of 75 proteins predicted mobility disability (p < .05). Significant proteins were enriched for the KEGG "PI3K-Akt signaling," "phagosomes," and "cytokine-cytokine receptor interaction" pathways. After multiple comparison adjustment, plasma cathepsin S (CTSS; hazard ratio [HR] 1.33, 95% CI: 1.17, 1.51, q = 0.007), growth/differentiation factor 15 (GDF15; HR: 1.45, 95% CI: 1.23, 1.72, q = 0.007), and thrombospondin-2 (THBS2; HR: 1.44, 95% CI: 1.22, 1.69, q = 0.007) remained significantly associated with high risk of losing mobility. CONCLUSION: CTSS, GDF15, and THBS2 are novel blood biomarkers associated with new mobility disability in community-dwelling individuals. Overall, our analysis suggests that cellular senescence and inflammation should be targeted for prevention of mobility disability." | Osawa, Yusuke Semba, Richard D Fantoni, Giovanna Candia, Julian Biancotto, Angelique Tanaka, Toshiko Bandinelli, Stefania Ferrucci, Luigi eng R01HL111271/The National Institutes of Health/International R01 AG027012/AG/NIA NIH HHS/ R01AG057723/The National Institutes of Health/International R21HL112662/The National Institutes of Health/International 263MD9164/AG/NIA NIH HHS/ Research Support, N.I.H., Extramural England Aging Cell. 2020 Apr;19(4):e13132. doi: 10.1111/acel.13132. Epub 2020 Mar 10.I | 03/12/2020 | |
| Using the circulating proteome to assess type I interferon activity in systemic lupus erythematosus | Smith MA, et al. | 2020 | Sci Rep | 10 | 1 | 4462 | https://www.doi.org/10.1038/s41598-020-60563-9 | 32,157,125 | Antibodies, Monoclonal, Humanized/*pharmacology Autoantibodies/*blood Biomarkers/*blood Gene Expression Profiling Humans Interferon Type I/*metabolism Lupus Erythematosus, Systemic/*blood/drug therapy/genetics Proteome/*analysis Severity of Illness Index | Type I interferon (IFN) drives pathology in systemic lupus erythematosus (SLE) and can be tracked via IFN-inducible transcripts in blood. Here, we examined whether measurement of circulating proteins, which enter the bloodstream from inflamed tissues, also offers insight into global IFN activity. Using a novel protocol we generated 1,132 aptamer-based protein measurements from anti-dsDNA(pos) SLE blood samples and derived an IFN protein signature (IFNPS) that approximates the IFN 21-gene signature (IFNGS). Of 82 patients with SLE, IFNPS was elevated for 89% of IFNGS-high patients (49/55) and 26% of IFNGS-low patients (7/27). IFNGS-high/IFNPS-high patients exhibited activated NK, CD4, and CD8 T cells, while IFNPS-high only patients did not. IFNPS correlated with global disease activity in lymphopenic and non-lymphopenic patients and decreased following type I IFN neutralisation with anifrolumab in the SLE phase IIb study, MUSE. In summary, we developed a protein signature that reflects IFNGS and identifies a new subset of patients with SLE who have IFN activity. | Smith, Michael A Chiang, Chia-Chien Zerrouki, Kamelia Rahman, Saifur White, Wendy I Streicher, Katie Rees, William A Schiffenbauer, Adam Rider, Lisa G Miller, Frederick W Manna, Zerai Hasni, Sarfaraz Kaplan, Mariana J Siegel, Richard Sinibaldi, Dominic Sanjuan, Miguel A Casey, Kerry A eng Research Support, Non-U.S. Gov't England Sci Rep. 2020 Mar 10;10(1):4462. doi: 10.1038/s41598-020-60563-9.I | 03/12/2020 | |
| Coronary Artery Disease and Type 2 Diabetes: A Proteomic Study | Ferrannini G, et al. | 2020 | Diabetes Care | 43 | 4 | 843-851 | https://www.doi.org/10.2337/dc19-1902 | 31,988,066 | Aged Cohort Studies Computed Tomography Angiography Coronary Angiography/methods Coronary Artery Disease/diagnosis/epidemiology/*metabolism Diabetes Mellitus, Type 2/complications/diagnosis/epidemiology/*metabolism Diabetic Angiopathies/diagnosis/epidemiology/metabolism Female Humans Male Middle Aged Prevalence Proteome/*analysis/metabolism *Proteomics/methods Risk Factors Tomography, X-Ray Computed/methods | OBJECTIVE: Coronary artery disease (CAD) is a major challenge in patients with type 2 diabetes (T2D). Coronary computed tomography angiography (CCTA) provides a detailed anatomic map of the coronary circulation. Proteomics are increasingly used to improve diagnostic and therapeutic algorithms. We hypothesized that the protein panel is differentially associated with T2D and CAD. RESEARCH DESIGN AND METHODS: In CAPIRE (Coronary Atherosclerosis in Outlier Subjects: Protective and Novel Individual Risk Factors Evaluation-a cohort of 528 individuals with no previous cardiovascular event undergoing CCTA), participants were grouped into CAD(-) (clean coronaries) and CAD(+) (diffuse lumen narrowing or plaques). Plasma proteins were screened by aptamer analysis. Two-way partial least squares was used to simultaneously rank proteins by diabetes status and CAD. RESULTS: Though CAD(+) was more prevalent among participants with T2D (HbA(1c) 6.7 +/- 1.1%) than those without diabetes (56 vs. 30%, P < 0.0001), CCTA-based atherosclerosis burden did not differ. Of the 20 top-ranking proteins, 15 were associated with both T2D and CAD, and 3 (osteomodulin, cartilage intermediate-layer protein 15, and HTRA1) were selectively associated with T2D only and 2 (epidermal growth factor receptor and contactin-1) with CAD only. Elevated renin and GDF15, and lower adiponectin, were independently associated with both T2D and CAD. In multivariate analysis adjusting for the Framingham risk panel, patients with T2D were protected" from CAD if female (P = 0.007), younger (P = 0.021), and with lower renin levels (P = 0.02). CONCLUSIONS: We concluded that 1) CAD severity and quality do not differ between participants with T2D and without diabetes; 2) renin, GDF15, and adiponectin are shared markers by T2D and CAD; 3) several proteins are specifically associated with T2D or CAD; and 4) in T2D, lower renin levels may protect against CAD." | Ferrannini, Giulia Manca, Maria Laura Magnoni, Marco Andreotti, Felicita Andreini, Daniele Latini, Roberto Maseri, Attilio Maggioni, Aldo P Ostroff, Rachel M Williams, Stephen A Ferrannini, Ele eng Research Support, Non-U.S. Gov't Diabetes Care. 2020 Apr;43(4):843-851. doi: 10.2337/dc19-1902. Epub 2020 Jan 27.I | 01/29/2020 | |
| Highly multiplexed proteomic assessment of human bone marrow in acute myeloid leukemia | Celik H, et al. | 2020 | Blood Adv | 4 | 2 | 367-379 | https://www.doi.org/10.1182/bloodadvances.2019001124 | 31,985,806 | Bone Marrow/*pathology Case-Control Studies Cellular Microenvironment Chemokines/analysis Chemokines, CC/metabolism Cytokines/analysis Gene Expression Regulation, Leukemic Humans Interleukin-8/metabolism Leukemia, Myeloid, Acute/*pathology Neoplasm Proteins/analysis Proteomics/*methods | Acute myeloid leukemia (AML) is a genetically heterogeneous disease that is characterized by abnormal clonal proliferation of myeloid progenitor cells found predominantly within the bone marrow (BM) and blood. Recent studies suggest that genetic and phenotypic alterations in the BM microenvironment support leukemogenesis and allow leukemic cells to survive and evade chemotherapy-induced death. However, despite substantial evidence indicating the role of tumor-host interactions in AML pathogenesis, little is known about the complex microenvironment of the BM. To address this, we performed novel proteomic profiling of the noncellular compartment of the BM microenvironment in patients with AML (n = 10) and age- and sex-matched healthy control subjects (n = 10) using an aptamer-based, highly multiplexed, affinity proteomics platform (SOMAscan). We show that proteomic assessment of blood or RNA-sequencing of BM are suboptimal alternate screening strategies to determine the true proteomic composition of the extracellular soluble compartment of AML patient BM. Proteomic analysis revealed that 168 proteins significantly differed in abundance, with 91 upregulated and 77 downregulated in leukemic BM. A highly connected signaling network of cytokines and chemokines, including IL-8, was found to be the most prominent proteomic signature associated with AML in the BM microenvironment. We report the first description of significantly elevated levels of the myelosuppressive chemokine CCL23 (myeloid progenitor inhibitory factor-1) in both AML and myelodysplastic syndrome patients and perform functional experiments supportive of a role in the suppression of normal hematopoiesis. This unique paired RNA-sequencing and proteomics data set provides innovative mechanistic insights into AML and healthy aging and should serve as a useful public resource. | Celik, Haydar Lindblad, Katherine E Popescu, Bogdan Gui, Gege Goswami, Meghali Valdez, Janet DeStefano, Christin Lai, Catherine Thompson, Julie Ghannam, Jack Y Fantoni, Giovanna Biancotto, Angelique Candia, Julian Cheung, Foo Sukumar, Gauthaman Dalgard, Clifton L Smith, Richard H Larochelle, Andre Dillon, Laura W Hourigan, Christopher S eng ZIA HL006163/Intramural NIH HHS/ Blood Adv. 2020 Jan 28;4(2):367-379. doi: 10.1182/bloodadvances.2019001124.I | 01/28/2020 | |
| Early angiogenic proteins associated with high risk for bronchopulmonary dysplasia and pulmonary hypertension in preterm infants | Arjaans S, et al. | 2020 | Am J Physiol Lung Cell Mol Physiol | 318 | 4 | L644-L654 | https://www.doi.org/10.1152/ajplung.00131.2019 | 31,967,847 | Adult Angiogenic Proteins/*metabolism Biomarkers/metabolism Bronchopulmonary Dysplasia/*etiology/*metabolism Female Gestational Age Humans Hypertension, Pulmonary/*etiology/*metabolism Infant, Extremely Premature/*metabolism Lung/metabolism Male Prospective Studies Proteomics/methods Vascular Diseases/metabolism SOMAmer angiogenesis aptamers biomarkers bronchopulmonary dysplasia lung development proteomics pulmonary hypertension related to this current work: laboratory research grants from United Therapeutics, Shire Pharmaceuticals, and Actelion. None of the other authors has any conflicts of interest, financial or otherwise, to disclose. | Early pulmonary vascular disease in preterm infants is associated with the subsequent development of bronchopulmonary dysplasia (BPD) and pulmonary hypertension (PH); however, mechanisms that contribute to or identify infants with increased susceptibility for BPD and/or PH are incompletely understood. Therefore, we tested if changes in circulating angiogenic peptides during the first week of life are associated with the later development of BPD and/or PH. We further sought to determine alternate peptides and related signaling pathways with the risk for BPD or PH. We prospectively enrolled infants with gestational age <34 wk and collected blood samples during their first week of life. BPD and PH were assessed at 36 wk postmenstrual age. Samples were assayed for each of the 1,121 peptides included in the SOMAscan scan technology, with subsequent pathway analysis. Of 102 infants in the study, 82 had BPD, and 13 had PH. Multiple angiogenic proteins (PF-4, VEGF121, ANG-1, bone morphogenetic protein 10 [BMP10], hepatocyte growth factor (HGF), ANG-2) were associated with the subsequent diagnosis of BPD; and FGF-19, PF-4, connective tissue activating peptide (CTAP)-III, and PDGF-AA levels were associated with BPD severity. Early increases in BMP10 was strongly associated with the late risk for BPD and PH. We found that early alterations of circulating angiogenic peptides and others were associated with the subsequent development of BPD. We further identified peptides that were associated with BPD severity and BPD-associated PH, including BMP10. We speculate that proteomic biomarkers during the first week of life may identify infants at risk for BPD and/or PH to enhance care and research. | Arjaans, Sanne Wagner, Brandie D Mourani, Peter M Mandell, Erica W Poindexter, Brenda B Berger, Rolf M F Abman, Steven H eng K23 RR021921/RR/NCRR NIH HHS/ R01 HL068702/HL/NHLBI NIH HHS/ Observational Study Research Support, N.I.H., Extramural Am J Physiol Lung Cell Mol Physiol. 2020 Apr 1;318(4):L644-L654. doi: 10.1152/ajplung.00131.2019. Epub 2020 Jan 22.I | 01/23/2020 | |
| Protein biomarkers for incident deep venous thrombosis in critically ill adolescents: An exploratory study | Tala JA, et al. | 2020 | Pediatr Blood Cancer | 67 | 4 | e28159 | https://www.doi.org/10.1002/pbc.28159 | 31,904,170 | Adolescent Biomarkers/*blood *Critical Illness Female Follow-Up Studies Humans Incidence Intensive Care Units Male Prognosis Prospective Studies Proteins/*analysis Risk Factors United States/epidemiology Venous Thrombosis/blood/*diagnosis/epidemiology adolescents biomarkers bleeding deep venous thrombosis proteins | BACKGROUND: There are no tests to identify critically ill children at high risk of deep venous thrombosis (DVT). In this exploratory study, we aimed to identify proteins that are associated with incident DVT in critically ill adolescents. PROCEDURE: Plasma samples were obtained from critically ill adolescents within 24 hours after initiation of cardiopulmonary support. The adolescents were followed with ultrasound to detect the development of DVT of the lower extremity and clinically for bleeding. Thrombin-antithrombin complex and prothrombin fragment 1+2 were measured using immunosorbent assays, whereas procoagulation and anticoagulation factors were measured using multiplex assays. Plasma samples were also analyzed using SOMAscan, an aptamer-based capture assay. The associations between DVT and the log-transformed level of the proteins were assessed using logistic regression adjusting for the presence of femoral venous catheter and severity of illness. Associations were expressed as odds ratio (OR) for every log-fold increase in level of the protein with 95% confidence interval (CI). RESULTS: Plasma from 59 critically ill adolescents, of whom 9 developed incident DVT, was analyzed. The median age of the adolescents was 15.1 years (interquartile range, 14.0-16.7 years). Higher levels of thrombin-antithrombin complex (OR: 31.54; 95% CI: 2.09-475.92) and lower levels of factor XIII (OR: 0.03; 95% CI: 0.002-0.44) were associated with DVT. CD36, MIC-1, and EpoR were marginally associated with DVT. Only factor XIII was associated with clinically relevant bleeding (OR: 0.27; 95% CI: 0.08-0.97). CONCLUSIONS: We identified candidate protein biomarkers for incident DVT. We plan to validate our findings in adequately powered studies. | Tala, Joana A Polikoff, Lee A Pinto, Matthew G Li, Simon Trakas, Erin Miksa, Michael Gertz, Shira Faustino, Edward Vincent S eng 14CRP20490002/AHA/American Heart Association-American Stroke Association/ Multicenter Study Research Support, Non-U.S. Gov't Pediatr Blood Cancer. 2020 Apr;67(4):e28159. doi: 10.1002/pbc.28159. Epub 2020 Jan 6.I | 01/07/2020 | |
| Epigenetics meets proteomics in an epigenome-wide association study with circulating blood plasma protein traits | Zaghlool SB, et al. | 2020 | Nat Commun | 11 | 1 | 15 | https://www.doi.org/10.1038/s41467-019-13831-w | 31,900,413 | Adult Aged Aged, 80 and over Blood Proteins/*genetics Chemokine CXCL10/genetics Cohort Studies CpG Islands DNA Methylation Epigenome Epigenomics Female GPI-Linked Proteins/genetics Germany Humans Inflammation/*genetics Intracellular Signaling Peptides and Proteins/genetics Male Middle Aged Proteomics Receptors, IgG/genetics | DNA methylation and blood circulating proteins have been associated with many complex disorders, but the underlying disease-causing mechanisms often remain unclear. Here, we report an epigenome-wide association study of 1123 proteins from 944 participants of the KORA population study and replication in a multi-ethnic cohort of 344 individuals. We identify 98 CpG-protein associations (pQTMs) at a stringent Bonferroni level of significance. Overlapping associations with transcriptomics, metabolomics, and clinical endpoints suggest implication of processes related to chronic low-grade inflammation, including a network involving methylation of NLRC5, a regulator of the inflammasome, and associated pQTMs implicating key proteins of the immune system, such as CD48, CD163, CXCL10, CXCL11, LAG3, FCGR3B, and B2M. Our study links DNA methylation to disease endpoints via intermediate proteomics phenotypes and identifies correlative networks that may eventually be targeted in a personalized approach of chronic low-grade inflammation. | Zaghlool, Shaza B Kuhnel, Brigitte Elhadad, Mohamed A Kader, Sara Halama, Anna Thareja, Gaurav Engelke, Rudolf Sarwath, Hina Al-Dous, Eman K Mohamoud, Yasmin A Meitinger, Thomas Wilson, Rory Strauch, Konstantin Peters, Annette Mook-Kanamori, Dennis O Graumann, Johannes Malek, Joel A Gieger, Christian Waldenberger, Melanie Suhre, Karsten eng Research Support, Non-U.S. Gov't England Nat Commun. 2020 Jan 3;11(1):15. doi: 10.1038/s41467-019-13831-w.I | 01/05/2020 | |
| Biomarker discovery in cardiac allograft vasculopathy using targeted aptamer proteomics | Almufleh A, et al. | 2020 | Clin Transplant | 34 | 1 | e13765 | https://www.doi.org/10.1111/ctr.13765 | 31,815,308 | Allografts Biomarkers Coronary Angiography *Coronary Artery Disease/diagnosis/etiology Female *Heart Transplantation/adverse effects Humans Male Middle Aged Prospective Studies Proteomics aptamer proteomic profiling cardiac allograft vasculopathy serum biomarkers | Cardiac allograft vasculopathy (CAV) limits long-term survival after heart transplantation. Non-invasive evaluation is challenging, and currently, there is no validated biomarker for CAV diagnosis or prognostication. To identify potential candidate CAV biomarkers, we utilized the Slow Off-rate Modified Aptamer (SOMAscan) assay, which evaluates over 1000 serum proteins, including many relevant to biological pathways in CAV. We evaluated three heart transplant patient groups according to angiographic ISHLT CAV grade: CAV(1-2) (mild-moderate CAV), CAV(3) (severe CAV), and CAV(0) (normal control). SOMAscan assays were performed and proteins quantitated. Comparisons of proteins between study groups were performed using one-way ANOVA (false discovery rate q-value < 0.10). Thirty-one patients (12 mild-moderate CAV, 9 severe CAV, 10 controls) were included: 81% male, median age 57 years and median 1.1 years post-transplant. Compared to controls, patients with mild-moderate CAV had similar characteristics, while patients with severe CAV had longer time from transplant and increased allosensitization. Statistical/bioinformatics analysis identified 14 novel biomarkers for CAV, including 4 specific for mild-moderate CAV. These proteins demonstrated important actions including apoptosis, inflammation, and platelet/coagulation activation. Upon preliminary receiver operating characteristics curve analysis, our protein biomarkers showed moderate-to-high discriminative ability for CAV (area under curve: 0.72 to 0.94). These candidate biomarkers are being validated in prospective studies. | Almufleh, Aws Zhang, Liyong Mielniczuk, Lisa M Stadnick, Ellamae Davies, Ross A Du, Qiujiang Rayner, Katey Liu, Peter P Chih, Sharon eng CIHR/Canada Research Support, Non-U.S. Gov't Denmark Clin Transplant. 2020 Jan;34(1):e13765. doi: 10.1111/ctr.13765. Epub 2019 Dec 30.I | 12/10/2019 | |
| Serum Protein Changes in Pediatric Sepsis Patients Identified With an Aptamer-Based Multiplexed Proteomic Approach | Shubin NJ, et al. | 2020 | Crit Care Med | 48 | 1 | e48-e57 | https://www.doi.org/10.1097/CCM.0000000000004083 | 31,714,400 | Aptamers, Peptide Blood Proteins/*analysis Child Cohort Studies Humans Proteomics/*methods Retrospective Studies Sepsis/*blood/*diagnosis/genetics | OBJECTIVES: Sepsis, a life-threatening organ dysfunction caused by a dysregulated host response to infection, is a leading cause of death and disability among children worldwide. Identifying sepsis in pediatric patients is difficult and can lead to treatment delay. Our objective was to assess the host proteomic response to infection utilizing an aptamer-based multiplexed proteomics approach to identify novel serum protein changes that might help distinguish between pediatric sepsis and infection-negative systemic inflammation and hence can potentially improve sensitivity and specificity of the diagnosis of sepsis over current clinical criteria approaches. DESIGN: Retrospective, observational cohort study. SETTING: PICU and cardiac ICU, Seattle Children's Hospital, Seattle, WA. PATIENTS: A cohort of 40 children with clinically overt sepsis and 30 children immediately postcardiopulmonary bypass surgery (infection-negative systemic inflammation control subjects) was recruited. Children with sepsis had a confirmed or suspected infection, two or more systemic inflammatory response syndrome criteria, and at least cardiovascular and/or pulmonary organ dysfunction. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Serum samples from 35 of the sepsis and 28 of the bypass surgery subjects were available for screening with an aptamer-based proteomic platform that measures 1,305 proteins to search for large-scale serum protein expression pattern changes in sepsis. A total of 111 proteins were significantly differentially expressed between the sepsis and control groups, using the linear models for microarray data (linear modeling) and Boruta (decision trees) R packages, with 55 being previously identified in sepsis patients. Weighted gene correlation network analysis helped identify 76 proteins that correlated highly with clinical sepsis traits, 27 of which had not been previously reported in sepsis. CONCLUSIONS: The serum protein changes identified with the aptamer-based multiplexed proteomics approach used in this study can be useful to distinguish between sepsis and noninfectious systemic inflammation. | Shubin, Nicholas J Navalkar, Krupa Sampson, Dayle Yager, Thomas D Cermelli, Silvia Seldon, Therese Sullivan, Erin Zimmerman, Jerry J Permut, Lester C Piliponsky, Adrian M eng Observational Study Crit Care Med. 2020 Jan;48(1):e48-e57. doi: 10.1097/CCM.0000000000004083.I | 11/13/2019 | |
| Atopic Dermatitis Endotypes Based on Allergen Sensitization, Reactivity to Staphylococcus aureus Antigens, and Underlying Systemic Inflammation | Leonard A, et al. | 2020 | J Allergy Clin Immunol Pract | 8 | 1 | 236-247 e3 | https://www.doi.org/10.1016/j.jaip.2019.08.013 | 31,430,591 | Allergens *Dermatitis, Atopic/diagnosis Humans Inflammation Proteomics *Staphylococcus aureus Allergy Atopic dermatitis | BACKGROUND: Atopic dermatitis (AD) is a chronic inflammatory disease with significant local and systemic inflammation and barrier disruption. AD is associated with increased risk of allergen sensitization and skin colonization by Staphylococcus aureus. The heterogeneity of AD is unknown, and its complexity suggests its subdivision into several endotypes. OBJECTIVE: To evaluate allergy-driven endotypic differences in patients with AD and identify proteomic signatures to distinguish between inflammatory responses. To perform proteomic profiling of allergen sensitivity, antibody levels to S aureus antigens, and circulating inflammatory mediators to characterize AD subsets in 76 subjects with moderate to severe AD and 39 healthy controls (HCs). METHODS: Sera were collected from 76 subjects with moderate to severe AD and 39 HCs with no history of skin disease. Serum was tested for levels of total serum immunoglobulin E (IgE) and allergen-specific IgE using a panel of 119 allergens as well as IgE antibodies against S aureus antigens, and was profiled for more than 1100 proteins by SOMAscan to detect differential expression of inflammatory mediators. RESULTS: Total serum IgE levels were significantly (P < .001) elevated in subjects with AD versus controls. A greater percentage of subjects with AD were allergic compared with HCs, and patients with AD tested positive to a greater number of allergens than did HCs. IgE was upregulated across 4 allergen subsets (food, perennial, seasonal, and mixed), and each allergen subset was associated with a distinct inflammatory signature marked by a specific suite of upregulated proteins. Finally, IgE antibodies against S aureus toxic shock syndrome toxin-1 were significantly upregulated in subjects with seasonal allergy (P = .0430) and perennial allergy (P = .00032). CONCLUSIONS: Overall, this study addresses the heterogeneity of AD by characterizing subsets of AD on the basis of allergen sensitization. It also demonstrates the differential systemic inflammation and S aureus-specific antibody responses associated with the allergenic endotypes. These unique proteomic signatures may be valuable for precise disease characterization and subsequent personalized treatment. | Leonard, Alexandra Wang, Jingya Yu, Li Liu, Hao Estrada, Yeriel Greenlees, Lydia McPhee, Roderick Ruzin, Alexey Guttman-Yassky, Emma Howell, Michael D eng Research Support, Non-U.S. Gov't J Allergy Clin Immunol Pract. 2020 Jan;8(1):236-247.e3. doi: 10.1016/j.jaip.2019.08.013. Epub 2019 Aug 17.I | 08/21/2019 | |
| Elevated Plasma Growth and Differentiation Factor 15 Is Associated With Slower Gait Speed and Lower Physical Performance in Healthy Community-Dwelling Adults | Semba RD, et al. | 2020 | J Gerontol A Biol Sci Med Sci | 75 | 1 | 175-180 | https://www.doi.org/10.1093/gerona/glz071 | 30,874,790 | Adult Aged Aged, 80 and over Aging/*physiology Biomarkers/blood Female Follow-Up Studies Gait/*physiology Geriatric Assessment/*methods Growth Differentiation Factor 15/*blood Healthy Volunteers Humans *Independent Living Male Middle Aged Physical Functional Performance Prospective Studies Sarcopenia/*blood/epidemiology/physiopathology Walking Speed/*physiology Young Adult Aging Growth and differentiation factor 15 Physical performance Sarcopenia Skeletal muscle | BACKGROUND: Growth and differentiation factor 15 (GDF-15) has been associated with obesity, muscle wasting, and cachexia. The receptor for GDF-15 was recently identified in the brainstem and regulates food intake and metabolism. The relationship of plasma GDF-15 with the age-associated decline of muscle mass and strength, gait speed, and physical performance in adults has not been well characterized. METHODS: Plasma GDF-15, grip strength, 6-m gait speed, 400-m walking test time, lower extremity physical performance score, appendicular lean mass, and fat mass were measured in 194 healthy adult participants, aged 22-93 years, of the Baltimore Longitudinal Study of Aging. RESULTS: Plasma GDF-15 concentrations increased with age (p < .001) and were higher in whites compared with blacks and Asians (p = .04). Adults with higher plasma GDF-15 had slower 6-m gait speed, longer 400-m walking time, and lower physical performance score in multivariable analyses adjusting for age and race. Plasma GDF-15 was not associated with grip strength, appendicular lean mass, or fat mass. CONCLUSIONS: Elevated plasma GDF-15 is associated with slower gait speed, higher 400-m walking time, and lower physical performance in very healthy community-dwelling adults. The relationship between plasma GDF-15 and sarcopenia-related outcomes may be stronger in the population not selected to be healthy, and this hypothesis should be tested in a representative population. | Semba, Richard D Gonzalez-Freire, Marta Tanaka, Toshiko Biancotto, Angelique Zhang, Pingbo Shardell, Michelle Moaddel, Ruin Ferrucci, Luigi eng R01 AG027012/AG/NIA NIH HHS/ R01 EY024596/EY/NEI NIH HHS/ R01 AG057723/AG/NIA NIH HHS/ R56 AG052973/AG/NIA NIH HHS/ Multicenter Study Research Support, N.I.H., Extramural Research Support, N.I.H., Intramural J Gerontol A Biol Sci Med Sci. 2020 Jan 1;75(1):175-180. doi: 10.1093/gerona/glz071.I | 03/16/2019 | |
| Joint Fluid Proteome after Anterior Cruciate Ligament Rupture Reflects an Acute Posttraumatic Inflammatory and Chondrodegenerative State | King JD, et al. | 2020 | Cartilage | 11 | 3 | 329-337 | https://www.doi.org/10.1177/1947603518790009 | 30,033,738 | Adolescent Anterior Cruciate Ligament/metabolism Anterior Cruciate Ligament Injuries/*metabolism Arthrocentesis Biomarkers/metabolism Cytokines/metabolism Female Humans Inflammation Knee Joint/*metabolism Male Osteoarthritis, Knee/*metabolism Proteome/*metabolism Proteomics Randomized Controlled Trials as Topic Rupture/metabolism Signal Transduction/genetics Synovial Fluid/*metabolism Young Adult anterior cruciate ligament biomarker osteoarthritis pathway analysis proteome conflicts of interest with respect to the research, authorship, and/or publication of this article. | OBJECTIVE: The purpose of this study was to evaluate changes in the synovial fluid proteome following acute anterior cruciate ligament (ACL) injury. DESIGN: This study represents a secondary analysis of synovial fluid samples collected from the placebo group of a previous randomized trial. Arthrocentesis was performed twice on 6 patients with an isolated acute ACL tear at a mean of 6 and 14 days postinjury. Synovial fluid was analyzed by a highly multiplexed assay of 1129 proteins (SOMAscan version 3, SomaLogic, Inc., Boulder, CO). Pathway analysis using DAVID was performed; genes included met 3 criteria: significant change between the 2 study time points using a paired t test, significant change between the 2 study time points using a Mann-Whitney nonparametric test, and significant Benjamini post hoc analysis. RESULTS: Fifteen analytes demonstrated significant increases between time points. Five of the 15 have been previously associated with the onset and/or severity of rheumatoid arthritis, including apoliopoprotein E and isoform E3, vascular cell adhesion protein 1, interleukin-34, and cell surface glycoprotein CD200 receptor 1. Chondrodegenerative enzymes and products of cartilage degeneration all increased over time following injury: MMP-1 (P = 0.08, standardized response mean [SRM] = 1.00), MMP-3 (P = 0.05, SRM = 0.90), ADAM12 (P = 0.03, SRM = 1.31), aggrecan (P = 0.08, SRM = 1.13), and CTX-II (P = 0.07, SRM = 0.56). Notable pathways that were differentially expressed following injury were the cytokine-cytokine receptor interaction and osteoclast differentiation pathways. CONCLUSIONS: The proteomic results and pathway analysis demonstrated a pattern of cartilage degeneration, not only consistent with previous findings but also changes consistent with an inflammatory arthritogenic process post-ACL injury. | King, John D Rowland, Grant Villasante Tezanos, Alejandro G Warwick, James Kraus, Virginia B Lattermann, Christian Jacobs, Cale A eng K23 AR060275/AR/NIAMS NIH HHS/ R24 HD050846/HD/NICHD NIH HHS/ UL1 TR000117/TR/NCATS NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Cartilage. 2020 Jul;11(3):329-337. doi: 10.1177/1947603518790009. Epub 2018 Jul 22.I | 07/24/2018 | |
| Circulating proteomic signature of early death in heart failure patients with reduced ejection fraction | Cuvelliez M, et al. | 2019 | Sci Rep | 9 | 1 | 19202 | https://www.doi.org/10.1038/s41598-019-55727-1 | 31,844,116 | Cardiovascular System/metabolism Cause of Death Extracellular Matrix/metabolism Female Heart Failure/*blood/metabolism/*mortality Humans Male Middle Aged Proteome/*metabolism Proteomics/methods Risk Factors | Heart failure (HF) remains a main cause of mortality worldwide. Risk stratification of patients with systolic chronic HF is critical to identify those who may benefit from advanced HF therapies. The aim of this study is to identify plasmatic proteins that could predict the early death (within 3 years) of HF patients with reduced ejection fraction hospitalized in CHRU de Lille. The subproteome targeted by an aptamer-based technology, the Slow Off-rate Modified Aptamer (SOMA) scan assay of 1310 proteins, was profiled in blood samples from 168 HF patients, and 203 proteins were significantly modulated between patients who died of cardiovascular death and patients who were alive after 3 years of HF evaluation (Wilcoxon test, FDR 5%). A molecular network was built using these 203 proteins, and the resulting network contained 2281 molecules assigned to 34 clusters annotated to biological pathways by Gene Ontology. This network model highlighted extracellular matrix organization as the main mechanism involved in early death in HF patients. In parallel, an adaptive Least Absolute Shrinkage and Selection Operator (LASSO) was performed on these 203 proteins, and six proteins were selected as candidates to predict early death in HF patients: complement C3, cathepsin S and F107B were decreased and MAPK5, MMP1 and MMP7 increased in patients who died of cardiovascular causes compared with patients living 3 years after HF evaluation. This proteomic signature of 6 circulating plasma proteins allows the identification of systolic HF patients with a risk of early death. | Cuvelliez, Marie Vandewalle, Vincent Brunin, Maxime Beseme, Olivia Hulot, Audrey de Groote, Pascal Amouyel, Philippe Bauters, Christophe Marot, Guillemette Pinet, Florence eng Research Support, Non-U.S. Gov't England Sci Rep. 2019 Dec 16;9(1):19202. doi: 10.1038/s41598-019-55727-1.I | 12/18/2019 | |
| Blood proteome profiling using aptamer-based technology for rejection biomarker discovery in transplantation | Shubin AV, et al. | 2019 | Sci Data | 6 | 1 | 314 | https://www.doi.org/10.1038/s41597-019-0324-y | 31,819,064 | *Aptamers, Nucleotide Biomarkers/blood Blood Proteins/*analysis Graft Rejection/blood/*diagnosis Humans *Proteome Proteomics/*methods *Transplantation | Face transplantation is a promising solution for patients with devastating facial injuries who lack other satisfactory treatment options. At the same time, this type of transplantation is accompanied with high risks of acute transplant rejection. The limitations of traditional skin biopsy and the need to frequently monitor the condition of face transplant call for less invasive biomarkers to better diagnose and treat acute rejection. Discovery of peripheral serum proteins accurately reflecting the transplant status would represent a reasonable solution to meet this demand. However, to date, there is no clinical data available to address the feasibility of this approach. In this study, we used the next generation aptamer-based SOMAscan proteomics platform to profile 1305 proteins of peripheral blood serum in twenty-four samples taken from 6 patients during no-rejection, nonsevere rejection, and severe rejection episodes. Also, we provide a detailed description of biosample processing and all steps to generate and analyze the SOMAscan dataset with hope it will assist in performing biomarker discovery in other transplantation centers using this platform. | Shubin, Andrey V Kollar, Branislav Dillon, Simon T Pomahac, Bohdan Libermann, Towia A Riella, Leonardo V eng W81XWH-16-1-0647/U.S. Department of Health & Human Services | Office of the Assistant Secretary for Health (OASH)/International P30 CA006516/CA/NCI NIH HHS/ Dataset Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. England Sci Data. 2019 Dec 9;6(1):314. doi: 10.1038/s41597-019-0324-y.I | 12/11/2019 | |
| Predicting health and life span with the deep plasma proteome | Emilsson V, et al. | 2019 | Nat Med | 25 | 12 | 1815-1816 | https://www.doi.org/10.1038/s41591-019-0677-y | 31,806,904 | Aging/*blood/genetics Humans Longevity/*genetics Proteome/*genetics | Emilsson, Valur Gudnason, Vilmundur Jennings, Lori L eng Nat Med. 2019 Dec;25(12):1815-1816. doi: 10.1038/s41591-019-0677-y.I | 12/07/2019 | ||
| Undulating changes in human plasma proteome profiles across the lifespan | Lehallier B, et al. | 2019 | Nat Med | 25 | 12 | 1843-1850 | https://www.doi.org/10.1038/s41591-019-0673-2 | 31,806,903 | Adolescent Adult Aged Aged, 80 and over Aging/*blood/genetics Animals Blood Proteins/*genetics Chronic Disease Female Humans Longevity/*genetics Male Mice Middle Aged Proteome/*genetics Risk Factors Young Adult | Aging is a predominant risk factor for several chronic diseases that limit healthspan(1). Mechanisms of aging are thus increasingly recognized as potential therapeutic targets. Blood from young mice reverses aspects of aging and disease across multiple tissues(2-10), which supports a hypothesis that age-related molecular changes in blood could provide new insights into age-related disease biology. We measured 2,925 plasma proteins from 4,263 young adults to nonagenarians (18-95 years old) and developed a new bioinformatics approach that uncovered marked non-linear alterations in the human plasma proteome with age. Waves of changes in the proteome in the fourth, seventh and eighth decades of life reflected distinct biological pathways and revealed differential associations with the genome and proteome of age-related diseases and phenotypic traits. This new approach to the study of aging led to the identification of unexpected signatures and pathways that might offer potential targets for age-related diseases. | Lehallier, Benoit Gate, David Schaum, Nicholas Nanasi, Tibor Lee, Song Eun Yousef, Hanadie Moran Losada, Patricia Berdnik, Daniela Keller, Andreas Verghese, Joe Sathyan, Sanish Franceschi, Claudio Milman, Sofiya Barzilai, Nir Wyss-Coray, Tony eng RG/13/13/30194/BHF_/British Heart Foundation/United Kingdom K99 NS112458/NS/NINDS NIH HHS/ R01 AG061155/AG/NIA NIH HHS/ R01 AG044829/AG/NIA NIH HHS/ DP1 AG053015/AG/NIA NIH HHS/ P30 AG038072/AG/NIA NIH HHS/ T32 AG047126/AG/NIA NIH HHS/ F32 AG055255/AG/NIA NIH HHS/ R01 AG045034/AG/NIA NIH HHS/ R01 AG057909/AG/NIA NIH HHS/ P50 AG047366/AG/NIA NIH HHS/ K23 AG051148/AG/NIA NIH HHS/ R00 NS112458/NS/NINDS NIH HHS/ RG/18/13/33946/BHF_/British Heart Foundation/United Kingdom Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Nat Med. 2019 Dec;25(12):1843-1850. doi: 10.1038/s41591-019-0673-2. Epub 2019 Dec 5.I | 12/07/2019 | |
| Plasma protein patterns as comprehensive indicators of health | Williams SA, et al. | 2019 | Nat Med | 25 | 12 | 1851-1857 | https://www.doi.org/10.1038/s41591-019-0665-2 | 31,792,462 | Adipose Tissue/metabolism Blood Proteins/*genetics Body Composition/*genetics/physiology *Exercise Female Humans Intra-Abdominal Fat/metabolism Life Style Liver/metabolism Male *Precision Medicine Risk Factors | Proteins are effector molecules that mediate the functions of genes(1,2) and modulate comorbidities(3-10), behaviors and drug treatments(11). They represent an enormous potential resource for personalized, systemic and data-driven diagnosis, prevention, monitoring and treatment. However, the concept of using plasma proteins for individualized health assessment across many health conditions simultaneously has not been tested. Here, we show that plasma protein expression patterns strongly encode for multiple different health states, future disease risks and lifestyle behaviors. We developed and validated protein-phenotype models for 11 different health indicators: liver fat, kidney filtration, percentage body fat, visceral fat mass, lean body mass, cardiopulmonary fitness, physical activity, alcohol consumption, cigarette smoking, diabetes risk and primary cardiovascular event risk. The analyses were prospectively planned, documented and executed at scale on archived samples and clinical data, with a total of ~85 million protein measurements in 16,894 participants. Our proof-of-concept study demonstrates that protein expression patterns reliably encode for many different health issues, and that large-scale protein scanning(12-16) coupled with machine learning is viable for the development and future simultaneous delivery of multiple measures of health. We anticipate that, with further validation and the addition of more protein-phenotype models, this approach could enable a single-source, individualized so-called liquid health check. | Williams, Stephen A Kivimaki, Mika Langenberg, Claudia Hingorani, Aroon D Casas, J P Bouchard, Claude Jonasson, Christian Sarzynski, Mark A Shipley, Martin J Alexander, Leigh Ash, Jessica Bauer, Tim Chadwick, Jessica Datta, Gargi DeLisle, Robert Kirk Hagar, Yolanda Hinterberg, Michael Ostroff, Rachel Weiss, Sophie Ganz, Peter Wareham, Nicholas J eng MR/R024227/1/MRC_/Medical Research Council/United Kingdom MC_UU_12015/1/MRC_/Medical Research Council/United Kingdom RF1 AG062553/AG/NIA NIH HHS/ MR/S011676/1/MRC_/Medical Research Council/United Kingdom R01 HL146462/HL/NHLBI NIH HHS/ R01 AG056477/AG/NIA NIH HHS/ R01 HL045670/HL/NHLBI NIH HHS/ RG/10/12/28456/BHF_/British Heart Foundation/United Kingdom SP/13/6/30554/BHF_/British Heart Foundation/United Kingdom Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Nat Med. 2019 Dec;25(12):1851-1857. doi: 10.1038/s41591-019-0665-2. Epub 2019 Dec 2.I | 12/04/2019 | |
| Multi-platform Affinity Proteomics Identify Proteins Linked to Metastasis and Immune Suppression in Ovarian Cancer Plasma | Graumann J, et al. | 2019 | Front Oncol | 9 | 1150 | https://www.doi.org/10.3389/fonc.2019.01150 | 31,737,572 | SOMAscan aptamer assay Spint2 affinity proteomics metastasis ovarian carcinoma proximity extension assay (PEA) | A central reason behind the poor clinical outcome of patients with high-grade serous carcinoma (HGSC) of the ovary is the difficulty in reliably detecting early occurrence or recurrence of this malignancy. Biomarkers that provide reliable diagnosis of this disease are therefore urgently needed. Systematic proteomic methods that identify HGSC-associated molecules may provide such biomarkers. We applied the antibody-based proximity extension assay (PEA) platform (Olink) for the identification of proteins that are upregulated in the plasma of OC patients. Using binders targeting 368 different plasma proteins, we compared 20 plasma samples from HGSC patients (OC-plasma) with 20 plasma samples from individuals with non-malignant gynecologic disorders (N-plasma). We identified 176 proteins with significantly higher levels in OC-plasma compared to N-plasma by PEA (p < 0.05 by U-test; Benjamini-Hochberg corrected), which are mainly implicated in immune regulation and metastasis-associated processes, such as matrix remodeling, adhesion, migration and proliferation. A number of these proteins have not been reported in previous studies, such as BCAM, CDH6, DDR1, N2DL-2 (ULBP2), SPINT2, and WISP-1 (CCN4). Of these SPINT2, a protease inhibitor mainly derived from tumor cells within the HGSC microenvironment, showed the highest significance (p < 2 x 10(-7)) similar to the previously described IL-6 and PVRL4 (NECTIN4) proteins. Results were validated by means of the aptamer-based 1.3 k SOMAscan proteomic platform, which revealed a high inter-platform correlation with a median Spearman rho of 0.62. Likewise, ELISA confirmed the PEA data for 10 out of 12 proteins analyzed, including SPINT2. These findings suggest that in contrast to other entities SPINT2 does not act as a tumor suppressor in HGSC. This is supported by data from the PRECOG and KM-Plotter meta-analysis databases, which point to a tumor-type-specific inverse association of SPINT2 gene expression with survival. Our data also demonstrate that both the PEA and SOMAscan affinity proteomics platforms bear considerable potential for the unbiased discovery of novel disease-associated biomarkers. | Graumann, Johannes Finkernagel, Florian Reinartz, Silke Stief, Thomas Brodje, Dorte Renz, Harald Jansen, Julia M Wagner, Uwe Worzfeld, Thomas Pogge von Strandmann, Elke Muller, Rolf eng Switzerland Front Oncol. 2019 Nov 1;9:1150. doi: 10.3389/fonc.2019.01150. eCollection 2019.I | 11/19/2019 | ||
| Aptamer Profiling of A549 Cells Infected with Low-Pathogenicity and High-Pathogenicity Influenza Viruses | Coombs KM, et al. | 2019 | Viruses | 11 | 11 | https://www.doi.org/10.3390/v11111028 | 31,694,171 | A549 Cells/metabolism/*virology Aptamers, Nucleotide/*analysis Cell Line Humans Influenza A Virus, H1N1 Subtype/pathogenicity Influenza A Virus, H5N1 Subtype/pathogenicity Influenza A Virus, H7N9 Subtype/pathogenicity Influenza A virus/*pathogenicity Proteome Proteomics/methods Virulence RNA virus infection SOMAScan(R) aptamers emerging viruses proteomics | Influenza A viruses (IAVs) are important animal and human emerging and re-emerging pathogens that are responsible for yearly seasonal epidemics and sporadic pandemics. IAVs cause a wide range of clinical illnesses, from relatively mild infections by seasonal strains, to acute respiratory distress during infections with highly pathogenic avian IAVs (HPAI). For this study, we infected A549 human lung cells with lab prototype A/PR/8/34 (H1N1) (PR8), a seasonal H1N1 (RV733), the 2009 pandemic H1N1 (pdm09), or with two avian strains, an H5N1 HPAI strain or an H7N9 strain that has low pathogenicity in birds but high pathogenicity in humans. We used a newly-developed aptamer-based multiplexed technique (SOMAscan((R))) to examine >1300 human lung cell proteins affected by the different IAV strains, and identified more than 500 significantly dysregulated cellular proteins. Our analyses indicated that the avian strains induced more profound changes in the A549 global proteome compared to all tested low-pathogenicity H1N1 strains. The PR8 strain induced a general activation, primarily by upregulating many immune molecules, the seasonal RV733 and pdm09 strains had minimal effect upon assayed molecules, and the avian strains induced significant downregulation, primarily in antimicrobial response, cardiovascular and post-translational modification systems. | Coombs, Kevin M Simon, Philippe F McLeish, Nigel J Zahedi-Amiri, Ali Kobasa, Darwyn eng MOP-106713/CIHR/Canada Research Support, Non-U.S. Gov't Switzerland Viruses. 2019 Nov 5;11(11):1028. doi: 10.3390/v11111028.I | 11/07/2019 | ||
| Effects of codon optimization on coagulation factor IX translation and structure: Implications for protein and gene therapies | Alexaki A, et al. | 2019 | Sci Rep | 9 | 1 | 15449 | https://www.doi.org/10.1038/s41598-019-51984-2 | 31,664,102 | *Codon Factor IX/*chemistry/*genetics Genetic Code *Genetic Therapy HEK293 Cells Humans *Protein Biosynthesis Protein Conformation | Synonymous codons occur with different frequencies in different organisms, a phenomenon termed codon usage bias. Codon optimization, a common term for a variety of approaches used widely by the biopharmaceutical industry, involves synonymous substitutions to increase protein expression. It had long been presumed that synonymous variants, which, by definition, do not alter the primary amino acid sequence, have no effect on protein structure and function. However, a critical mass of reports suggests that synonymous codon variations may impact protein conformation. To investigate the impact of synonymous codons usage on protein expression and function, we designed an optimized coagulation factor IX (FIX) variant and used multiple methods to compare its properties to the wild-type FIX upon expression in HEK293T cells. We found that the two variants differ in their conformation, even when controlling for the difference in expression levels. Using ribosome profiling, we identified robust changes in the translational kinetics of the two variants and were able to identify a region in the gene that may have a role in altering the conformation of the protein. Our data have direct implications for codon optimization strategies, for production of recombinant proteins and gene therapies. | Alexaki, Aikaterini Hettiarachchi, Gaya K Athey, John C Katneni, Upendra K Simhadri, Vijaya Hamasaki-Katagiri, Nobuko Nanavaty, Puja Lin, Brian Takeda, Kazuyo Freedberg, Daron Monroe, Dougald McGill, Joseph R Peters, Robert Kames, Jacob M Holcomb, David D Hunt, Ryan C Sauna, Zuben E Gelinas, Amy Janjic, Nebojsa DiCuccio, Michael Bar, Haim Komar, Anton A Kimchi-Sarfaty, Chava eng R15 HL121779/HL/NHLBI NIH HHS/ HL121779/U.S. Department of Health & Human Services | NIH | Office of Extramural Research, National Institutes of Health (OER)/International Research Support, N.I.H., Extramural Research Support, U.S. Gov't, Non-P.H.S. Research Support, U.S. Gov't, P.H.S. England Sci Rep. 2019 Oct 29;9(1):15449. doi: 10.1038/s41598-019-51984-2.I | 10/31/2019 | |
| Comparison of Urine and Plasma Biomarker Concentrations Measured by Aptamer-Based versus Immunoassay Methods in Cardiac Surgery Patients | Kukova LZ, et al. | 2019 | J Appl Lab Med | 4 | 3 | 331-342 | https://www.doi.org/10.1373/jalm.2018.028621 | 31,659,071 | Aged Biomarkers/*blood/*urine Cardiac Surgical Procedures Comorbidity Female Heart Diseases/*blood/diagnosis/surgery/*urine Humans Immunoassay/*methods/*standards Male Middle Aged | BACKGROUND: Protein detection assays are invaluable tools in the field of biomarker discovery. However, only immunoassays are widely used and can measure 10-20 analytes per biosample. The novel SOMAmer-based assay uses nucleotide aptamer technology to measure over 1300 analytes per biosample. We compared the SOMAmer-based platform to traditional approaches to quantify analytes in a clinical setting with paired samples before and after cardiac surgery. METHODS: In a substudy of the Translational Research Investigating Biomarker Endpoints in Acute Kidney Injury cohort, 54 individuals with acute kidney injury after cardiac surgery were identified. Preoperative and postoperative plasma and urine samples that had been previously evaluated for biomarker concentrations via immunoassays were analyzed via SOMAmer-based assay. RESULTS: Spearman correlations were estimated when >50% of biomarker values were within detectable ranges by immunoassay (plasma biomarkers: preoperative, 26/33; postoperative, 31/33; urine biomarkers: preoperative, 13/16; postoperative, 16/16). Overall, 27% of reportable plasma preoperative biomarkers displayed correlations >/=0.75 between immunoassay and SOMAmer measurements; 23% displayed correlations of 0.50-0.75, and 50% displayed correlations <0.50. In urine these values were 15%, 39%, and 46%, respectively. Forty-two percent of reportable plasma postoperative biomarkers displayed correlations >/=0.75, 16% displayed correlations 0.50-0.75, and 42% displayed correlations <0.50. In urine, these values were 19%, 25%, and 56%, respectively. CONCLUSIONS: In cardiac surgery patients, the SOMAmer-based assay detects proteins with moderate to strong correlation to current immunoassay methods. The correlations in urine are weaker than those in plasma. SOMAmer-based assay technology should be further evaluated in multiple settings as a high-throughput screening tool for biomarker discovery. | Kukova, Lidiya Z Mansour, Sherry G Coca, Steven G de Fontnouvelle, Christina A Thiessen-Philbrook, Heather R Shlipak, Michael G El-Khoury, Joe M Parikh, Chirag R eng K24 DK090203/DK/NIDDK NIH HHS/ P30 DK079310/DK/NIDDK NIH HHS/ R01 HL085757/HL/NHLBI NIH HHS/ R01 DK096549/DK/NIDDK NIH HHS/ U01 DK082185/DK/NIDDK NIH HHS/ Research Support, N.I.H., Extramural England J Appl Lab Med. 2019 Nov;4(3):331-342. doi: 10.1373/jalm.2018.028621. Epub 2019 May 28.I | 10/30/2019 | |
| Targeting Unique Epitopes on Highly Similar Proteins GDF-11 and GDF-8 with Modified DNA Aptamers | Ochsner UA, et al. | 2019 | Biochemistry | 58 | 46 | 4632-4640 | https://www.doi.org/10.1021/acs.biochem.9b00760 | 31,638,376 | Amino Acid Sequence Aptamers, Nucleotide/*chemistry Base Sequence Binding Sites Bone Morphogenetic Proteins/*analysis Epitopes/analysis Growth Differentiation Factors/*analysis Humans Indicators and Reagents Myostatin/*analysis Recombinant Proteins/analysis SELEX Aptamer Technique | The mature forms of the TGF-beta family members GDF-11 and GDF-8 are highly similar 25 kDa homodimers with 90% amino acid sequence identity and 99% similarity. Cross-reactivity of GDF-11 and GDF-8 binding reagents is common, making it difficult to attribute distinct roles of these two proteins in biology. We report the selection of GDF-11 and GDF-8 specific SOMAmer (Slow Off-rate Modified Aptamer) reagents aided by a combination of positive selection for one protein coupled with counter-selection against the other. We identified GDF-11 specific SOMAmer reagents from four modified DNA libraries that showed a high affinity (K(d) range 0.05-1.2 nM) for GDF-11 but did not bind to GDF-8 (K(d) > 1 muM). Conversely, we identified one SOMAmer reagent for GDF-8 from one of the modified libraries that demonstrated excellent affinity (K(d) = 0.23 nM) and specificity. In contrast, standard protocols that utilized only positive selection produced binding reagents with similar affinity for both proteins. High affinity and specificity were efficiently encoded in minimal sequences of 21 nucleotides for GDF-11 and 24 nucleotides for GDF-8. Further characterization in pull-down, competition, sandwich-binding, and kinetic studies revealed robust binding under a wide range of buffer and assay conditions. For highly similar proteins like GDF-11 and GDF-8, our method of selection coupled with counter-selection was essential for identification of high-affinity, specific reagents that have the potential to elucidate the fundamental distinction of these growth factors in biology. | Ochsner, Urs A Green, Louis S Rice, Taylor P Olivas, Edgar Janjic, Nebojsa Katilius, Evaldas eng Biochemistry. 2019 Nov 19;58(46):4632-4640. doi: 10.1021/acs.biochem.9b00760. Epub 2019 Nov 7.I | 10/23/2019 | |
| Reproducibility and Variability of Protein Analytes Measured Using a Multiplexed Modified Aptamer Assay | Tin A, et al. | 2019 | J Appl Lab Med | 4 | 1 | 30-39 | https://www.doi.org/10.1373/jalm.2018.027086 | 31,639,705 | Aged Atherosclerosis/*blood/diagnosis Blood Proteins/*analysis Equipment Design Female Glomerular Filtration Rate/physiology Humans Male Middle Aged Prospective Studies Proteomics/*instrumentation Reproducibility of Results | BACKGROUND: There is growing interest in the use of multiplexed aptamer-based assays for large-scale proteomic studies. However, the analytic, short- and long-term variation of the measured proteins is largely uncharacterized. METHODS: We quantified 4001 plasma protein analytes from 42 participants in the Atherosclerosis Risk in Communities (ARIC) Study in split samples and at multiple visits using a multiplexed modified aptamer assay. We calculated the CV, Spearman correlation, and intraclass correlation (ICC) between split samples and evaluated the short-term (4-9 weeks) and long-term (approximately 20 years) variability using paired t-tests with log-transformed protein concentrations and Bonferroni-corrected significance thresholds. We performed principal component (PC) analysis of protein analyte concentrations and evaluated their associations with age, sex, race, and estimated glomerular filtration rate (eGFR). RESULTS: The mean baseline age was 57 years at the first visit, 43% of participants were male and 57% were white. Among 3693 protein analytes that passed quality control, half (n = 1846) had CVs < 5.0%, Spearman correlations > 0.89, and ICCs > 0.96 among the split samples. Over the short term, only 1 analyte had a statistically significant difference between the 2 time points, whereas, over approximately 20 years, 866 analytes (23.4%) had statistically significant differences (P < 1.4 x 10(-5), 681 increased, 185 decreased). PC1 had high correlations with age (-0.73) and eGFR (0.60). PC2 had moderate correlation with male sex (0.18) and white race (0.31). CONCLUSIONS: Multiplexed modified aptamer technology can assay thousands of proteins with excellent precision. Our results support the potential for large-scale studies of the plasma proteome over the lifespan. | Tin, Adrienne Yu, Bing Ma, Jianzhong Masushita, Kunihiro Daya, Natalie Hoogeveen, Ron C Ballantyne, Christie M Couper, David Rebholz, Casey M Grams, Morgan E Alonso, Alvaro Mosley, Thomas Heiss, Gerardo Ganz, Peter Selvin, Elizabeth Boerwinkle, Eric Coresh, Josef eng HHSN268201100009C/HL/NHLBI NIH HHS/ HHSN268201700002I/HL/NHLBI NIH HHS/ N01HC55020/HL/NHLBI NIH HHS/ HHSN268201100005C/HL/NHLBI NIH HHS/ HHSN268201100006C/HL/NHLBI NIH HHS/ HHSN268201100007C/HL/NHLBI NIH HHS/ HHSN268201100008C/HL/NHLBI NIH HHS/ HHSN268201100011C/HL/NHLBI NIH HHS/ HHSN268201100012C/HL/NHLBI NIH HHS/ U01 HL096812/HL/NHLBI NIH HHS/ U01 HL096814/HL/NHLBI NIH HHS/ U01 HL096899/HL/NHLBI NIH HHS/ U01 HL096902/HL/NHLBI NIH HHS/ U01 HL096917/HL/NHLBI NIH HHS/ R01 HL134320/HL/NHLBI NIH HHS/ K01 DK107782/DK/NIDDK NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't England J Appl Lab Med. 2019 Jul;4(1):30-39. doi: 10.1373/jalm.2018.027086. Epub 2019 Jan 22.I | 10/23/2019 | |
| Characterization of Parkinson's disease using blood-based biomarkers: A multicohort proteomic analysis | Posavi M, et al. | 2019 | PLoS Med | 16 | 10 | e1002931 | https://www.doi.org/10.1371/journal.pmed.1002931 | 31,603,904 | Aged Algorithms Amidohydrolases/blood Biomarkers/*blood Carrier Proteins/blood Disease Progression Extracellular Matrix Proteins/blood Female Humans Longitudinal Studies Male Middle Aged Neurodegenerative Diseases Osteopontin/blood Parkinson Disease/*blood Proportional Hazards Models Proteoglycans/blood *Proteomics Reproducibility of Results | BACKGROUND: Parkinson's disease (PD) is a progressive neurodegenerative disease affecting about 5 million people worldwide with no disease-modifying therapies. We sought blood-based biomarkers in order to provide molecular characterization of individuals with PD for diagnostic confirmation and prediction of progression. METHODS AND FINDINGS: In 141 plasma samples (96 PD, 45 neurologically normal control [NC] individuals; 45.4% female, mean age 70.0 years) from a longitudinally followed Discovery Cohort based at the University of Pennsylvania (UPenn), we measured levels of 1,129 proteins using an aptamer-based platform. We modeled protein plasma concentration (log10 of relative fluorescence units [RFUs]) as the effect of treatment group (PD versus NC), age at plasma collection, sex, and the levodopa equivalent daily dose (LEDD), deriving first-pass candidate protein biomarkers based on p-value for PD versus NC. These candidate proteins were then ranked by Stability Selection. We confirmed findings from our Discovery Cohort in a Replication Cohort of 317 individuals (215 PD, 102 NC; 47.9% female, mean age 66.7 years) from the multisite, longitudinally followed National Institute of Neurological Disorders and Stroke Parkinson's Disease Biomarker Program (PDBP) Cohort. Analytical approach in the Replication Cohort mirrored the approach in the Discovery Cohort: each protein plasma concentration (log10 of RFU) was modeled as the effect of group (PD versus NC), age at plasma collection, sex, clinical site, and batch. Of the top 10 proteins from the Discovery Cohort ranked by Stability Selection, four associations were replicated in the Replication Cohort. These blood-based biomarkers were bone sialoprotein (BSP, Discovery false discovery rate [FDR]-corrected p = 2.82 x 10-2, Replication FDR-corrected p = 1.03 x 10-4), osteomodulin (OMD, Discovery FDR-corrected p = 2.14 x 10-2, Replication FDR-corrected p = 9.14 x 10-5), aminoacylase-1 (ACY1, Discovery FDR-corrected p = 1.86 x 10-3, Replication FDR-corrected p = 2.18 x 10-2), and growth hormone receptor (GHR, Discovery FDR-corrected p = 3.49 x 10-4, Replication FDR-corrected p = 2.97 x 10-3). Measures of these proteins were not significantly affected by differences in sample handling, and they did not change comparing plasma samples from 10 PD participants sampled both on versus off dopaminergic medication. Plasma measures of OMD, ACY1, and GHR differed in PD versus NC but did not differ between individuals with amyotrophic lateral sclerosis (ALS, n = 59) versus NC. In the Discovery Cohort, individuals with baseline levels of GHR and ACY1 in the lowest tertile were more likely to progress to mild cognitive impairment (MCI) or dementia in Cox proportional hazards analyses adjusting for age, sex, and disease duration (hazard ratio [HR] 2.27 [95% CI 1.04-5.0, p = 0.04] for GHR, and HR 3.0 [95% CI 1.24-7.0, p = 0.014] for ACY1). GHR's association with cognitive decline was confirmed in the Replication Cohort (HR 3.6 [95% CI 1.20-11.1, p = 0.02]). The main limitations of this study were its reliance on the aptamer-based platform for protein measurement and limited follow-up time available for some cohorts. CONCLUSIONS: In this study, we found that the blood-based biomarkers BSP, OMD, ACY1, and GHR robustly associated with PD across multiple clinical sites. Our findings suggest that biomarkers based on a peripheral blood sample may be developed for both disease characterization and prediction of future disease progression in PD. | Posavi, Marijan Diaz-Ortiz, Maria Liu, Benjamine Swanson, Christine R Skrinak, R Tyler Hernandez-Con, Pilar Amado, Defne A Fullard, Michelle Rick, Jacqueline Siderowf, Andrew Weintraub, Daniel McCluskey, Leo Trojanowski, John Q Dewey, Richard B Jr Huang, Xuemei Chen-Plotkin, Alice S eng P30 AG010124/AG/NIA NIH HHS/ U01 NS082151/NS/NINDS NIH HHS/ T32 AG000255/AG/NIA NIH HHS/ U24 NS095871/NS/NINDS NIH HHS/ P50 NS053488/NS/NINDS NIH HHS/ R01 NS115139/NS/NINDS NIH HHS/ U19 AG062418/AG/NIA NIH HHS/ U01 NS112008/NS/NINDS NIH HHS/ U01 NS082134/NS/NINDS NIH HHS/ U01 NS082148/NS/NINDS NIH HHS/ U01 NS097056/NS/NINDS NIH HHS/ Multicenter Study Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't PLoS Med. 2019 Oct 11;16(10):e1002931. doi: 10.1371/journal.pmed.1002931. eCollection 2019 Oct.I | 10/12/2019 | |
| Dual-platform affinity proteomics identifies links between the recurrence of ovarian carcinoma and proteins released into the tumor microenvironment | Finkernagel F, et al. | 2019 | Theranostics | 9 | 22 | 6601-6617 | https://www.doi.org/10.7150/thno.37549 | 31,588,238 | Ascites/metabolism/pathology Biomarkers, Tumor/analysis/metabolism Blood Proteins/analysis Cystadenocarcinoma, Serous/metabolism/mortality/*pathology Extracellular Vesicles/metabolism/pathology Female Humans Kaplan-Meier Estimate Ovarian Neoplasms/metabolism/mortality/*pathology Proteomics/*methods Recurrence *Tumor Microenvironment | The peritoneal fluid (ascites), replete with abundant tumor-promoting factors and extracellular vesicles (EVs) reflecting the tumor secretome, plays an essential role in ovarian high-grade serous carcinoma (HGSC) metastasis and immune suppression. A comprehensive picture of mediators impacting HGSC progression is, however, not available. Methods: Proteins in ascites from HGSC patients were quantified by the aptamer-based SOMAscan affinity proteomic platform. SOMAscan data were analyzed by bioinformatic methods to reveal clinically relevant links and functional connections, and were validated using the antibody-based proximity extension assay (PEA) Olink platform. Mass spectrometry was used to identify proteins in extracellular microvesicles released by HGSC cells. Results: Consistent with the clinical features of HGSC, 779 proteins in ascites identified by SOMAscan clustered into groups associated either with metastasis and a short relapse-free survival (RFS), or with immune regulation and a favorable RFS. In total, 346 proteins were linked to OC recurrence in either direction. Reanalysis of 214 of these proteins by PEA revealed an excellent median Spearman inter-platform correlation of rho=0.82 for the 46 positively RFS-associated proteins in both datasets. Intriguingly, many proteins strongly associated with clinical outcome were constituents of extracellular vesicles. These include proteins either linked to a poor RFS, such as HSPA1A, BCAM and DKK1, or associated with a favorable outcome, such as the protein kinase LCK. Finally, based on these data we defined two protein signatures that clearly classify short-term and long-term relapse-free survivors. Conclusion: The ascites secretome points to metastasis-promoting events and an anti-tumor response as the major determinants of the clinical outcome of HGSC. Relevant proteins include both bone fide secreted and vesicle-encapsulated polypeptides, many of which have previously not been linked to HGSC recurrence. Besides a deeper understanding of the HGSC microenvironment our data provide novel potential tools for HGSC patient stratification. Furthermore, the first large-scale inter-platform validation of SOMAscan and PEA will be invaluable for other studies using these affinity proteomics platforms. | Finkernagel, Florian Reinartz, Silke Schuldner, Maximiliane Malz, Alexandra Jansen, Julia M Wagner, Uwe Worzfeld, Thomas Graumann, Johannes von Strandmann, Elke Pogge Muller, Rolf eng Research Support, Non-U.S. Gov't Australia Theranostics. 2019 Aug 22;9(22):6601-6617. doi: 10.7150/thno.37549. eCollection 2019.I | 10/08/2019 | |
| Transcatheter aortic valve replacements alter circulating serum factors to mediate myofibroblast deactivation | Aguado BA, et al. | 2019 | Sci Transl Med | 11 | 509 | https://www.doi.org/10.1126/scitranslmed.aav3233 | 31,511,425 | Aortic Valve/drug effects/metabolism/pathology Cell Cycle Female Humans Hydrogels/pharmacology Inflammation Mediators/metabolism MAP Kinase Signaling System Male Myofibroblasts/metabolism/*pathology Phenotype Reproducibility of Results Serum/*metabolism Sex Characteristics Signal Transduction/drug effects *Transcatheter Aortic Valve Replacement Transcriptome/drug effects/genetics | The transcatheter aortic valve replacement (TAVR) procedure has emerged as a minimally invasive treatment for patients with aortic valve stenosis (AVS). However, alterations in serum factor composition and biological activity after TAVR remain unknown. Here, we quantified the systemic inflammatory effects of the TAVR procedure and hypothesized that alterations in serum factor composition would modulate valve and cardiac fibrosis. Serum samples were obtained from patients with AVS immediately before their TAVR procedure (pre-TAVR) and about 1 month afterward (post-TAVR). Aptamer-based proteomic profiling revealed alterations in post-TAVR serum composition, and ontological analysis identified inflammatory macrophage factors implicated in myofibroblast activation and deactivation. Hydrogel biomaterials used as valve matrix mimics demonstrated that post-TAVR serum reduced myofibroblast activation of valvular interstitial cells relative to pre-TAVR serum from the same patient. Transcriptomics and curated network analysis revealed a shift in myofibroblast phenotype from pre-TAVR to post-TAVR and identified p38 MAPK signaling as one pathway involved in pre-TAVR-mediated myofibroblast activation. Post-TAVR serum deactivated valve and cardiac myofibroblasts initially exposed to pre-TAVR serum to a quiescent fibroblast phenotype. Our in vitro deactivation data correlated with patient disease severity measured via echocardiography and multimorbidity scores, and correlations were dependent on hydrogel stiffness. Sex differences in cellular responses to male and female sera were also observed and may corroborate clinical observations regarding sex-specific TAVR outcomes. Together, alterations in serum composition after TAVR may lead to an antifibrotic fibroblast phenotype, which suggests earlier interventions may be beneficial for patients with advanced AVS to prevent further disease progression. | Aguado, Brian A Schuetze, Katherine B Grim, Joseph C Walker, Cierra J Cox, Anne C Ceccato, Tova L Tan, Aik-Choon Sucharov, Carmen C Leinwand, Leslie A Taylor, Matthew R G McKinsey, Timothy A Anseth, Kristi S eng R01 GM029090/GM/NIGMS NIH HHS/ 16SFRN31400013/AHA/American Heart Association-American Stroke Association/ R01 HL127240/HL/NHLBI NIH HHS/ R01 HL139968/HL/NHLBI NIH HHS/ T32 HL007822/HL/NHLBI NIH HHS/ R01 HL142935/HL/NHLBI NIH HHS/ R00 HL148542/HL/NHLBI NIH HHS/ R01 DE016523/DE/NIDCR NIH HHS/ R01 HL132353/HL/NHLBI NIH HHS/ F32 HL137256/HL/NHLBI NIH HHS/ K99 HL148542/HL/NHLBI NIH HHS/ F31 HL142223/HL/NHLBI NIH HHS/ R01 HL119533/HL/NHLBI NIH HHS/ R01 HL116848/HL/NHLBI NIH HHS/ P30 DK048520/DK/NIDDK NIH HHS/ R21 AR067469/AR/NIAMS NIH HHS/ R01 HL147558/HL/NHLBI NIH HHS/ T32 GM065103/GM/NIGMS NIH HHS/ R01 DK119594/DK/NIDDK NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. Sci Transl Med. 2019 Sep 11;11(509):eaav3233. doi: 10.1126/scitranslmed.aav3233.I | 09/13/2019 | ||
| Genome-wide association meta-analyses and fine-mapping elucidate pathways influencing albuminuria | Teumer A, et al. | 2019 | Nat Commun | 10 | 1 | 4130 | https://www.doi.org/10.1038/s41467-019-11576-0 | 31,511,532 | Albuminuria/*genetics Animals *Chromosome Mapping Creatinine/urine Diabetes Mellitus/genetics/urine Drosophila melanogaster/genetics Gene Expression Regulation Genetic Loci Genetic Predisposition to Disease *Genome-Wide Association Study Humans *Meta-Analysis as Topic Phenomics Risk Factors | Increased levels of the urinary albumin-to-creatinine ratio (UACR) are associated with higher risk of kidney disease progression and cardiovascular events, but underlying mechanisms are incompletely understood. Here, we conduct trans-ethnic (n = 564,257) and European-ancestry specific meta-analyses of genome-wide association studies of UACR, including ancestry- and diabetes-specific analyses, and identify 68 UACR-associated loci. Genetic correlation analyses and risk score associations in an independent electronic medical records database (n = 192,868) reveal connections with proteinuria, hyperlipidemia, gout, and hypertension. Fine-mapping and trans-Omics analyses with gene expression in 47 tissues and plasma protein levels implicate genes potentially operating through differential expression in kidney (including TGFB1, MUC1, PRKCI, and OAF), and allow coupling of UACR associations to altered plasma OAF concentrations. Knockdown of OAF and PRKCI orthologs in Drosophila nephrocytes reduces albumin endocytosis. Silencing fly PRKCI further impairs slit diaphragm formation. These results generate a priority list of genes and pathways for translational research to reduce albuminuria. | Teumer, Alexander Li, Yong Ghasemi, Sahar Prins, Bram P Wuttke, Matthias Hermle, Tobias Giri, Ayush Sieber, Karsten B Qiu, Chengxiang Kirsten, Holger Tin, Adrienne Chu, Audrey Y Bansal, Nisha Feitosa, Mary F Wang, Lihua Chai, Jin-Fang Cocca, Massimiliano Fuchsberger, Christian Gorski, Mathias Hoppmann, Anselm Horn, Katrin Li, Man Marten, Jonathan Noce, Damia Nutile, Teresa Sedaghat, Sanaz Sveinbjornsson, Gardar Tayo, Bamidele O van der Most, Peter J Xu, Yizhe Yu, Zhi Gerstner, Lea Arnlov, Johan Bakker, Stephan J L Baptista, Daniela Biggs, Mary L Boerwinkle, Eric Brenner, Hermann Burkhardt, Ralph Carroll, Robert J Chee, Miao-Li Chee, Miao-Ling Chen, Mengmeng Cheng, Ching-Yu Cook, James P Coresh, Josef Corre, Tanguy Danesh, John de Borst, Martin H De Grandi, Alessandro de Mutsert, Renee de Vries, Aiko P J Degenhardt, Frauke Dittrich, Katalin Divers, Jasmin Eckardt, Kai-Uwe Ehret, Georg Endlich, Karlhans Felix, Janine F Franco, Oscar H Franke, Andre Freedman, Barry I Freitag-Wolf, Sandra Gansevoort, Ron T Giedraitis, Vilmantas Gogele, Martin Grundner-Culemann, Franziska Gudbjartsson, Daniel F Gudnason, Vilmundur Hamet, Pavel Harris, Tamara B Hicks, Andrew A Holm, Hilma Foo, Valencia Hui Xian Hwang, Shih-Jen Ikram, M Arfan Ingelsson, Erik Jaddoe, Vincent W V Jakobsdottir, Johanna Josyula, Navya Shilpa Jung, Bettina Kahonen, Mika Khor, Chiea-Chuen Kiess, Wieland Koenig, Wolfgang Korner, Antje Kovacs, Peter Kramer, Holly Kramer, Bernhard K Kronenberg, Florian Lange, Leslie A Langefeld, Carl D Lee, Jeannette Jen-Mai Lehtimaki, Terho Lieb, Wolfgang Lim, Su-Chi Lind, Lars Lindgren, Cecilia M Liu, Jianjun Loeffler, Markus Lyytikainen, Leo-Pekka Mahajan, Anubha Maranville, Joseph C Mascalzoni, Deborah McMullen, Barbara Meisinger, Christa Meitinger, Thomas Miliku, Kozeta Mook-Kanamori, Dennis O Muller-Nurasyid, Martina Mychaleckyj, Josyf C Nauck, Matthias Nikus, Kjell Ning, Boting Noordam, Raymond Connell, Jeffrey O' Olafsson, Isleifur Palmer, Nicholette D Peters, Annette Podgornaia, Anna I Ponte, Belen Poulain, Tanja Pramstaller, Peter P Rabelink, Ton J Raffield, Laura M Reilly, Dermot F Rettig, Rainer Rheinberger, Myriam Rice, Kenneth M Rivadeneira, Fernando Runz, Heiko Ryan, Kathleen A Sabanayagam, Charumathi Saum, Kai-Uwe Schottker, Ben Shaffer, Christian M Shi, Yuan Smith, Albert V Strauch, Konstantin Stumvoll, Michael Sun, Benjamin B Szymczak, Silke Tai, E-Shyong Tan, Nicholas Y Q Taylor, Kent D Teren, Andrej Tham, Yih-Chung Thiery, Joachim Thio, Chris H L Thomsen, Hauke Thorsteinsdottir, Unnur Tonjes, Anke Tremblay, Johanne Uitterlinden, Andre G van der Harst, Pim Verweij, Niek Vogelezang, Suzanne Volker, Uwe Waldenberger, Melanie Wang, Chaolong Wilson, Otis D Wong, Charlene Wong, Tien-Yin Yang, Qiong Yasuda, Masayuki Akilesh, Shreeram Bochud, Murielle Boger, Carsten A Devuyst, Olivier Edwards, Todd L Ho, Kevin Morris, Andrew P Parsa, Afshin Pendergrass, Sarah A Psaty, Bruce M Rotter, Jerome I Stefansson, Kari Wilson, James G Susztak, Katalin Snieder, Harold Heid, Iris M Scholz, Markus Butterworth, Adam S Hung, Adriana M Pattaro, Cristian Kottgen, Anna eng MC_PC_17228/MRC_/Medical Research Council/United Kingdom R01 HL120393/HL/NHLBI NIH HHS/ U01 HL130114/HL/NHLBI NIH HHS/ U01 HL120393/HL/NHLBI NIH HHS/ R01 HL105756/HL/NHLBI NIH HHS/ T32 HL129982/HL/NHLBI NIH HHS/ K12 HD043483/HD/NICHD NIH HHS/ I01 BX003360/BX/BLRD VA/ P30 DK116074/DK/NIDDK NIH HHS/ MC_QA137853/MRC_/Medical Research Council/United Kingdom Research Support, Non-U.S. Gov't England Nat Commun. 2019 Sep 11;10(1):4130. doi: 10.1038/s41467-019-11576-0.I | 09/13/2019 | |
| Discovery and validation of plasma proteomic biomarkers relating to brain amyloid burden by SOMAscan assay | Shi L, et al. | 2019 | Alzheimers Dement | 15 | 11 | 1478-1488 | https://www.doi.org/10.1016/j.jalz.2019.06.4951 | 31,495,601 | Age Factors Aged *Alzheimer Disease/genetics/metabolism Amyloid/*metabolism Apolipoprotein E4/genetics/metabolism Biomarkers/*blood Brain/*metabolism Europe Female Humans Male Middle Aged *Proteomics Amyloid beta Causal relationship Plasma proteomics Replication SOMAscan assay Tau | INTRODUCTION: Plasma proteins have been widely studied as candidate biomarkers to predict brain amyloid deposition to increase recruitment efficiency in secondary prevention clinical trials for Alzheimer's disease. Most such biomarker studies are targeted to specific proteins or are biased toward high abundant proteins. METHODS: 4001 plasma proteins were measured in two groups of participants (discovery group = 516, replication group = 365) selected from the European Medical Information Framework for Alzheimer's disease Multimodal Biomarker Discovery study, all of whom had measures of amyloid. RESULTS: A panel of proteins (n = 44), along with age and apolipoprotein E (APOE) epsilon4, predicted brain amyloid deposition with good performance in both the discovery group (area under the curve = 0.78) and the replication group (area under the curve = 0.68). Furthermore, a causal relationship between amyloid and tau was confirmed by Mendelian randomization. DISCUSSION: The results suggest that high-dimensional plasma protein testing could be a useful and reproducible approach for measuring brain amyloid deposition. | Shi, Liu Westwood, Sarah Baird, Alison L Winchester, Laura Dobricic, Valerija Kilpert, Fabian Hong, Shengjun Franke, Andre Hye, Abdul Ashton, Nicholas J Morgan, Angharad R Bos, Isabelle Vos, Stephanie J B Buckley, Noel J Kate, Mara Ten Scheltens, Philip Vandenberghe, Rik Gabel, Silvy Meersmans, Karen Engelborghs, Sebastiaan De Roeck, Ellen E Sleegers, Kristel Frisoni, Giovanni B Blin, Olivier Richardson, Jill C Bordet, Regis Molinuevo, Jose L Rami, Lorena Wallin, Anders Kettunen, Petronella Tsolaki, Magda Verhey, Frans Lleo, Alberto Alcolea, Daniel Popp, Julius Peyratout, Gwendoline Martinez-Lage, Pablo Tainta, Mikel Johannsen, Peter Teunissen, Charlotte E Freund-Levi, Yvonne Frolich, Lutz Legido-Quigley, Cristina Barkhof, Frederik Blennow, Kaj Zetterberg, Henrik Baker, Susan Morgan, B Paul Streffer, Johannes Visser, Pieter Jelle Bertram, Lars Lovestone, Simon Nevado-Holgado, Alejo J eng MC_PC_17215/MRC_/Medical Research Council/United Kingdom MR/L023784/2/MRC_/Medical Research Council/United Kingdom Research Support, Non-U.S. Gov't Alzheimers Dement. 2019 Nov;15(11):1478-1488. doi: 10.1016/j.jalz.2019.06.4951. Epub 2019 Sep 5.I | 09/10/2019 | |
| Proteomics in gastroparesis: unique and overlapping protein signatures in diabetic and idiopathic gastroparesis | Grover M, et al. | 2019 | Am J Physiol Gastrointest Liver Physiol | 317 | 5 | G716-G726 | https://www.doi.org/10.1152/ajpgi.00115.2019 | 31,482,734 | Adult Aged Complement C2/genetics/metabolism Diabetes Complications/*genetics/metabolism/physiopathology Endothelial Cells/metabolism Female Fibroblasts/metabolism Gastric Emptying Gastroparesis/etiology/*genetics/metabolism/physiopathology Humans Macrophages/metabolism Male Middle Aged Prostaglandin-Endoperoxide Synthases/genetics/metabolism Protein Kinase C/genetics/metabolism Proteome/*genetics/metabolism diabetes immune cells inflammation macrophages | Macrophage-based immune dysregulation plays a critical role in development of delayed gastric emptying in diabetic mice. Loss of anti-inflammatory macrophages and increased expression of genes associated with pro-inflammatory macrophages has been reported in full-thickness gastric biopsies from gastroparesis patients. We aimed to determine broader protein expression (proteomics) and protein-based signaling pathways in gastric biopsies of diabetic (DG) and idiopathic gastroparesis (IG) patients. Additionally, we determined correlations between protein expressions, gastric emptying, and symptoms. Full-thickness gastric antrum biopsies were obtained from nine DG patients, seven IG patients, and five nondiabetic controls. Aptamer-based SomaLogic tissue scan that quantitatively identifies 1,305 human proteins was used. Protein fold changes were computed, and differential expressions were calculated using Limma. Ingenuity pathway analysis and correlations were carried out. Multiple-testing corrected P < 0.05 was considered statistically significant. Seventy-three proteins were differentially expressed in DG, 132 proteins were differentially expressed in IG, and 40 proteins were common to DG and IG. In both DG and IG, Role of Macrophages, Fibroblasts and Endothelial Cells" was the most statistically significant altered pathway [DG false discovery rate (FDR) = 7.9 x 10(-9); IG FDR = 6.3 x 10(-12)]. In DG, properdin expression correlated with GCSI bloating (r = -0.99, FDR = 0.02) and expressions of prostaglandin G/H synthase 2, protein kinase C-zeta type, and complement C2 correlated with 4 h gastric retention (r = -0.97, FDR = 0.03 for all). No correlations were found between proteins and symptoms or gastric emptying in IG. Protein expression changes suggest a central role of macrophage-driven immune dysregulation in gastroparesis, specifically, complement activation in diabetic gastroparesis.NEW & NOTEWORTHY This study uses SOMAscan, a novel proteomics assay for determination of altered proteins and associated molecular pathways in human gastroparesis. Seventy-three proteins were changed in diabetic gastroparesis, 132 in idiopathic gastroparesis compared with controls. Forty proteins were common in both. Macrophage-based immune dysregulation pathway was most significantly affected in both diabetic and idiopathic gastroparesis. Proteins involved in the complement and prostaglandin synthesis pathway were associated with symptoms and gastric emptying delay in diabetic gastroparesis." | Grover, Madhusudan Dasari, Surendra Bernard, Cheryl E Chikkamenahalli, Lakshmikanth L Yates, Katherine P Pasricha, Pankaj J Sarosiek, Irene McCallum, Richard Koch, Kenneth L Abell, Thomas L Kuo, Braden Shulman, Robert J Gibbons, Simon J McKenzie, Travis J Kellogg, Todd A Kendrick, Michael L Tonascia, James Hamilton, Frank A Parkman, Henry P Farrugia, Gianrico eng U24 DK074008/DK/NIDDK NIH HHS/ U01 DK073975/DK/NIDDK NIH HHS/ K23 DK103911/DK/NIDDK NIH HHS/ P30 DK089502/DK/NIDDK NIH HHS/ U01 DK073974/DK/NIDDK NIH HHS/ U01 DK074035/DK/NIDDK NIH HHS/ U01 DK073983/DK/NIDDK NIH HHS/ U01 DK112194/DK/NIDDK NIH HHS/ U01 DK112193/DK/NIDDK NIH HHS/ U01 DK074007/DK/NIDDK NIH HHS/ R03 DK120745/DK/NIDDK NIH HHS/ Research Support, N.I.H., Extramural Am J Physiol Gastrointest Liver Physiol. 2019 Nov 1;317(5):G716-G726. doi: 10.1152/ajpgi.00115.2019. Epub 2019 Sep 4.I | 09/05/2019 | |
| Stability of the Human Plasma Proteome to Pre-analytical Variability as Assessed by an Aptamer-Based Approach | Daniels JR, et al. | 2019 | J Proteome Res | 18 | 10 | 3661-3670 | https://www.doi.org/10.1021/acs.jproteome.9b00320 | 31,442,052 | Adult Aptamers, Peptide Blood Preservation/methods Blood Specimen Collection/methods Complement Activation Healthy Volunteers Humans Plasma/*chemistry *Protein Stability Proteome/analysis Proteomics/*methods aptamer technology biomarkers human blood plasma pre-analytical variability proteomics quality assessment | Variable processing and storage of whole blood and/or plasma are potential confounders in biomarker development and clinical assays. The goal of the study was to investigate how pre-analytical variables impact the human plasma proteome. Whole blood obtained from 16 apparently healthy individuals was collected in six EDTA tubes and processed randomly under six pre-analytical variable conditions including blood storage at 0 degrees C or RT for 6 h (B6h0C or B6hRT) before processing to plasma, plasma storage at 4 degrees C or RT for 24 h (P24h4C or P24hRT), low centrifugal force at 1300 x g, (Lowxg), and immediate processing to plasma under 2500 x g (control) followed by plasma storage at -80 degrees C. An aptamer-based proteomic assay was performed to identify significantly changed proteins (fold change >/=1.2, P < 0.05, and false discovery rate < 0.05) relative to the control from a total of 1305 proteins assayed. Pre-analytical conditions Lowxg and B6h0C resulted in the most plasma proteome changes with 200 and 148 proteins significantly changed, respectively. Only 36 proteins were changed under B6hRT. Conditions P24h4C and P24hRT yielded changes of 28 and 75 proteins, respectively. The complement system was activated in vitro under the conditions B6hRT, P24h4C, and P24hRT. The results suggest that particular pre-analytical variables should be controlled for clinical measurement of specific biomarkers. | Daniels, Jaclyn R Cao, Zhijun Maisha, Mackean Schnackenberg, Laura K Sun, Jinchun Pence, Lisa Schmitt, Thomas C Kamlage, Beate Rogstad, Sarah Beger, Richard D Yu, Li-Rong eng FD999999/ImFDA/Intramural FDA HHS/ Research Support, Non-U.S. Gov't J Proteome Res. 2019 Oct 4;18(10):3661-3670. doi: 10.1021/acs.jproteome.9b00320. Epub 2019 Sep 12.I | 08/24/2019 | |
| Disease-specific and glucocorticoid-responsive serum biomarkers for Duchenne Muscular Dystrophy | Hathout Y, et al. | 2019 | Sci Rep | 9 | 1 | 12167 | https://www.doi.org/10.1038/s41598-019-48548-9 | 31,434,957 | Biomarkers/*blood Blood Proteins/*metabolism Case-Control Studies Cell Adhesion Molecules/metabolism Child Child, Preschool Cross-Sectional Studies Extracellular Matrix Proteins/metabolism Glucocorticoids/*therapeutic use Humans Muscular Dystrophy, Duchenne/*drug therapy/pathology | Extensive biomarker discoveries for DMD have occurred in the past 7 years, and a vast array of these biomarkers were confirmed in independent cohorts and across different laboratories. In these previous studies, glucocorticoids and age were two major confounding variables. In this new study, using SomaScan technology and focusing on a subset of young DMD patients who were not yet treated with glucocorticoids, we identified 108 elevated and 70 decreased proteins in DMD relative to age matched healthy controls (p value < 0.05 after adjusting for multiple testing). The majority of the elevated proteins were muscle centric followed by cell adhesion, extracellular matrix proteins and a few pro-inflammatory proteins. The majority of decreased proteins were of cell adhesion, however, some had to do with cell differentiation and growth factors. Subsequent treatment of this group of DMD patients with glucocorticoids affected two major groups of pharmacodynamic biomarkers. The first group consisted of 80 serum proteins that were not associated with DMD and either decreased or increased following treatment with glucocorticoids, and therefore were reflective of a broader effect of glucocorticoids. The second group consisted of 17 serum proteins that were associated with DMD and these tended to normalize under treatment, thus reflecting physiologic effects of glucocorticoid treatment in DMD. In summary, we have identified a variety of circulating protein biomarkers that reflect the complex nature of DMD pathogenesis and response to glucocorticoids. | Hathout, Yetrib Liang, Chen Ogundele, Michael Xu, Ganggang Tawalbeh, Shefa M Dang, Utkarsh J Hoffman, Eric P Gordish-Dressman, Heather Conklin, Laurie S van den Anker, John N Clemens, Paula R Mah, Jean K Henricson, Erik McDonald, Craig eng U54HD090245/U.S. Department of Health & Human Services | NIH | Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)/International Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. England Sci Rep. 2019 Aug 21;9(1):12167. doi: 10.1038/s41598-019-48548-9.I | 08/23/2019 | |
| Guidelines for CSF Processing and Biobanking: Impact on the Identification and Development of Optimal CSF Protein Biomarkers | Hok AHYS, et al. | 2019 | Methods Mol Biol | 2044 | 27-50 | https://www.doi.org/10.1007/978-1-4939-9706-0_2 | 31,432,404 | *Biological Specimen Banks Biomarkers/cerebrospinal fluid Blood/metabolism *Cerebrospinal Fluid Cerebrospinal Fluid Proteins/*metabolism Early Diagnosis Freezing Humans Immunoassay Nervous System Diseases/*cerebrospinal fluid/diagnosis Protein Stability Proteome/genetics/*metabolism Proteomics Reproducibility of Results Serum/chemistry/metabolism Specimen Handling/*standards Workflow Biobanking Biomarkers Csf Guidelines Neurology Pre-analytical confounding factors Reproducibility Stability | The field of neurological diseases strongly needs biomarkers for early diagnosis and optimal stratification of patients in clinical trials or to monitor disease progression. Cerebrospinal fluid (CSF) is one of the main sources for the identification of novel protein biomarkers for neurological diseases. Despite the enormous efforts employed to identify novel CSF biomarkers, the high variability observed across different studies has hampered their validation and implementation in clinical practice. Such variability is partly caused by the effect of different pre-analytical confounding factors on protein stability, highlighting the importance to develop and comply with standardized operating procedures. In this chapter, we describe the international consensus pre-analytical guidelines for CSF processing and biobanking that have been established during the last decade, with a special focus on the influence of pre-analytical confounders on the global CSF proteome. In addition, we provide novel results on the influence of different delayed storage and freeze/thaw conditions on the CSF proteome using two novel large multiplex protein arrays (SOMAscan and Olink). Compliance to consensus guidelines will likely facilitate the successful development and implementation of CSF protein biomarkers in both research and clinical settings, ultimately facilitating the successful development of disease-modifying therapies. | Hok-A-Hin, Yanaika S Willemse, Eline A J Teunissen, Charlotte E Del Campo, Marta eng Methods Mol Biol. 2019;2044:27-50. doi: 10.1007/978-1-4939-9706-0_2.I | 08/23/2019 | ||
| Application of an Aptamer-Based Proteomics Assay (SOMAscan) in Rat Cerebrospinal Fluid | Simats A, et al. | 2019 | Methods Mol Biol | 2044 | 221-231 | https://www.doi.org/10.1007/978-1-4939-9706-0_13 | 31,432,415 | Animals Aptamers, Nucleotide Biomarkers/*cerebrospinal fluid/metabolism Cerebrospinal Fluid Proteins/*analysis/metabolism Humans Oligonucleotide Array Sequence Analysis Proteome/*metabolism Proteomics/*methods Rats Software Aptamer Csf Multiplex Proteome Rat SOMAscan | The exploration of the cerebrospinal fluid (CSF) through proteomics techniques might help in the search of molecular biomarkers relevant to neurological pathologies. Aiming this, we describe here a commercially available multiplexed proteomics technology based on the use of modified aptamers (SOMAscan assay). From our experience in exploring the rat CSF proteome, we detail the basic principles of this oligonucleotide-based proteomics approach, as well as the main data-processing steps to obtain relative quantitative values for proteins that could discriminate among different brain conditions, as an attempt in the search of neurological biomarkers. Finally, we give some tips on performing the SOMAscan assay and key recommendations on the verification analyses of the resulting candidate biomarkers. | Simats, Alba Ramiro, Laura Montaner, Joan Garcia-Berrocoso, Teresa eng Research Support, Non-U.S. Gov't Methods Mol Biol. 2019;2044:221-231. doi: 10.1007/978-1-4939-9706-0_13.I | 08/23/2019 | ||
| Pulmonary Aptamer Signatures in Children's Interstitial and Diffuse Lung Disease | Deterding RR, et al. | 2019 | Am J Respir Crit Care Med | 200 | 12 | 1496-1504 | https://www.doi.org/10.1164/rccm.201903-0547OC | 31,409,098 | Biomarkers/metabolism Bronchoalveolar Lavage Fluid/*chemistry Case-Control Studies Child Child, Preschool Diagnosis, Differential Female Humans Hyperplasia Infant Lung Diseases, Interstitial/*diagnosis/*metabolism Male Neuroendocrine Cells/pathology Proteomics neuroendocrine pediatric surfactant | Rationale: Biomarker signatures are needed in children with children's interstitial and diffuse lung disease (chILD) to improve diagnostic approaches, increase our understanding of disease pathogenesis, monitor disease progression, and develop new treatment strategies. Proteomic technology using SOMAmer (Slow Off-rate Modified Aptamer) nucleic acid-based protein-binding reagents allows for biomarker discovery.Objectives: We hypothesized that proteins and protein pathways in BAL fluid (BALF) would distinguish children with neuroendocrine cell hyperplasia of infancy (NEHI), surfactant dysfunction mutations, and other chILD diagnoses and control subjects.Methods: BALF was collected for clinical indications and banked in patients with chILD and disease control subjects using standardized protocols over 10 years. BALF supernatant was analyzed using an aptamer assay to measure 1,129 protein levels. Protein levels were compared between groups using an ANOVA and adjusted for multiple comparisons using false discovery rate. Proteins were classified into pathways. Hierarchical clustering was used to define endotypes in the group of children with NEHI.Measurements and Main Results: After correcting for multiple testing, children with NEHI (n = 22) had 202 aptamers that were significantly different (P < 0.05) in BALF compared with control subjects (n = 9). Children with surfactant mutation (n = 8) had 51 aptamers significantly different (P < 0.05) in BALF compared with control subjects (n = 9). Proteins associated with pulmonary fibrosis and inflammation were associated with the surfactant dysfunction group but not the NEHI group. Using hierarchical clustering analysis, two distinct NEHI endotypes were identified.Conclusions: Distinct proteins and protein pathways can be determined from BALF of children with chILD, and these hold promise to further our understanding of chILD. | Deterding, Robin R Wagner, Brandie D Harris, J Kirk DeBoer, Emily M eng UL1 TR001082/TR/NCATS NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Am J Respir Crit Care Med. 2019 Dec 15;200(12):1496-1504. doi: 10.1164/rccm.201903-0547OC.I | 08/15/2019 | |
| Identifying and targeting pathogenic PI3K/AKT/mTOR signaling in IL-6-blockade-refractory idiopathic multicentric Castleman disease | Fajgenbaum DC, et al. | 2019 | J Clin Invest | 129 | 10 | 4451-4463 | https://www.doi.org/10.1172/JCI126091 | 31,408,438 | Adolescent Adult *Castleman Disease/drug therapy/metabolism/pathology Female Humans Interleukin-6/*metabolism Male Middle Aged Phosphatidylinositol 3-Kinases/*metabolism Proteomics Proto-Oncogene Proteins c-akt/*metabolism Signal Transduction/*drug effects Sirolimus/*pharmacology TOR Serine-Threonine Kinases/*metabolism Cytokines Hematology Immunology Lymphomas Janssen Pharmaceuticals. TSU is a coinventor on US patent 10,001,483 B2, assigned to the U.S. Government, with a portion of royalties going to employee-inventors under PL 99-502. TSU has research support through Cooperative Research and Development Agreements with the National Cancer Institute, Celgene Corporation, and Merck, and through a clinical trial agreement from Roche and the Fred Hutchinson Cancer Research Center. | BACKGROUND: Idiopathic multicentric Castleman disease (iMCD) is a hematologic illness involving cytokine-induced lymphoproliferation, systemic inflammation, cytopenias, and life-threatening multi-organ dysfunction. The molecular underpinnings of interleukin-6(IL-6)-blockade refractory patients remain unknown; no targeted therapies exist. In this study, we searched for therapeutic targets in IL-6-blockade refractory iMCD patients with the thrombocytopenia, anasarca, fever/elevated C-reactive protein, reticulin myelofibrosis, renal dysfunction, organomegaly (TAFRO) clinical subtype. METHODS: We analyzed tissues and blood samples from three IL-6-blockade refractory iMCD-TAFRO patients. Cytokine panels, quantitative serum proteomics, flow cytometry of PBMCs, and pathway analyses were employed to identify novel therapeutic targets. To confirm elevated mTOR signaling, a candidate therapeutic target from the above assays, immunohistochemistry was performed for phosphorylated S6, a read-out of mTOR activation, in three iMCD lymph node tissue samples and controls. Proteomic, immunophenotypic, and clinical response assessments were performed to quantify the effects of administration of the mTOR inhibitor, sirolimus. RESULTS: Studies of three IL-6-blockade refractory iMCD cases revealed increased CD8+ T cell activation, VEGF-A, and PI3K/Akt/mTOR pathway activity. Administration of sirolimus significantly attenuated CD8+ T cell activation and decreased VEGF-A levels. Sirolimus induced clinical benefit responses in all three patients with durable and ongoing remissions of 66, 19, and 19 months. CONCLUSION: This precision medicine approach identifies PI3K/Akt/mTOR signaling as the first pharmacologically-targetable pathogenic process in IL-6-blockade refractory iMCD. Prospective evaluation of sirolimus in treatment-refractory iMCD is planned (NCT03933904). FUNDING: Castleman's Awareness & Research Effort/Castleman Disease Collaborative Network, Penn Center for Precision Medicine, University Research Foundation, Intramural NIH funding, and National Heart Lung and Blood Institute. | Fajgenbaum, David C Langan, Ruth-Anne Japp, Alberto Sada Partridge, Helen L Pierson, Sheila K Singh, Amrit Arenas, Daniel J Ruth, Jason R Nabel, Christopher S Stone, Katie Okumura, Mariko Schwarer, Anthony Jose, Fabio Freire Hamerschlak, Nelson Wertheim, Gerald B Jordan, Michael B Cohen, Adam D Krymskaya, Vera Rubenstein, Arthur Betts, Michael R Kambayashi, Taku van Rhee, Frits Uldrick, Thomas S eng R01 HL141408/HL/NHLBI NIH HHS/ ZIA BC011700/ImNIH/Intramural NIH HHS/ Case Reports Research Support, Non-U.S. Gov't J Clin Invest. 2019 Aug 13;129(10):4451-4463. doi: 10.1172/JCI126091.I | 08/14/2019 | |
| A serum protein signature of APOE genotypes in centenarians | Sebastiani P, et al. | 2019 | Aging Cell | 18 | 6 | e13023 | https://www.doi.org/10.1111/acel.13023 | 31,385,390 | Adult Aged Aged, 80 and over Alzheimer Disease/blood/*genetics/metabolism Apolipoproteins E/blood/*genetics/metabolism Cohort Studies Female Fluorescence Genotype Humans Male Middle Aged Prospective Studies Proteomics Young Adult Apoe SomaLogic centenarian cognitive function genotypes protein | The discovery of treatments to prevent or delay dementia and Alzheimer's disease is a priority. The gene APOE is associated with cognitive change and late-onset Alzheimer's disease, and epidemiological studies have provided strong evidence that the e(2) allele of APOE has a neuroprotective effect, it is associated with increased longevity and an extended healthy lifespan in centenarians. In this study, we correlated APOE genotype data of 222 participants of the New England Centenarian Study, including 75 centenarians, 82 centenarian offspring, and 65 controls, comprising 55 carriers of APOE e(2) , with aptamer-based serum proteomics (SomaLogic technology) of 4,785 human proteins corresponding to 4,137 genes. We discovered a signature of 16 proteins that associated with different APOE genotypes and replicated the signature in three independent studies. We also show that the protein signature tracks with gene expression profiles in brains of late-onset Alzheimer's disease versus healthy controls. Finally, we show that seven of these proteins correlate with cognitive function patterns in longitudinally collected data. This analysis in particular suggests that Baculoviral IAP repeat containing two (BIRC2) is a novel biomarker of neuroprotection that associates with the neuroprotective allele of APOE. Therefore, targeting APOE e(2) molecularly may preserve cognitive function. | Sebastiani, Paola Monti, Stefano Morris, Melody Gurinovich, Anastasia Toshiko, Tanaka Andersen, Stacy L Sweigart, Benjamin Ferrucci, Luigi Jennings, Lori L Glass, David J Perls, Thomas T eng ICS110.1/RF97.71/Italian Ministry of Health/International R21 AG056630/AG/NIA NIH HHS/ R01 AG061844/AG/NIA NIH HHS/ Novartis Institute for Biomedical Research (NIBR)/International UH2 AG064704/AG/NIA NIH HHS/ U19 AG023122/AG/NIA NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't England Aging Cell. 2019 Dec;18(6):e13023. doi: 10.1111/acel.13023. Epub 2019 Aug 5.I | 08/07/2019 | |
| Plasma proteome in multiple sclerosis disease progression | Malekzadeh A, et al. | 2019 | Ann Clin Transl Neurol | 6 | 9 | 1582-1594 | https://www.doi.org/10.1002/acn3.771 | 31,364,818 | Adult Biomarkers/blood Brain/*diagnostic imaging Disease Progression Female Humans Magnetic Resonance Imaging Male Middle Aged Multiple Sclerosis, Chronic Progressive/diagnostic imaging/*metabolism Multiple Sclerosis, Relapsing-Remitting/diagnostic imaging/*metabolism Prognosis Proteome/*metabolism | BACKGROUND: The pathophysiology of multiple sclerosis disease progression remains undetermined. The aim of this study was to identify differences in plasma proteome during different stages of MS disease progression. METHODS: We used a multiplex aptamer proteomics platform (Somalogic) for sensitive detection of 1129 proteins in plasma. MS patients were selected and categorized based on baseline and a 4-year follow-up EDSS (delta EDSS) scores; relapse-onset (RO) slow progression (n = 31), RO with rapid progression (n = 29), primary progressive (n = 30), and healthy controls (n = 20). The relation of baseline plasma protein levels with delta EDSS and different MRI progression parameters were assessed using linear regression models. RESULTS: Regression analyses of plasma proteins with delta EDSS showed six significant associations. Strong associations were found for the proteins LGLAS8 (P = 7.64 x 10(-5) , q = 0.06), CCL3 (P = 0.0001, q = 0.06), and RGMA (P = 0.0005, q = 0.09). In addition, associations of plasma proteins were found with percentage brain volume for C3 (P = 2,08 x 10(-9) , q = 1,70 x 10(-6) ), FGF9 (P = 3,42 x 10(-9) , q = 1,70 x 10(-6) ), and EHMT2 (P = 0.0007, q = 0.01). Most of the significant markers were associated with cell-cell and cell-extracellular matrix adhesion, immune system communication, immune system activation, and complement pathways. CONCLUSIONS: Our results revealed eight novel biomarkers related to clinical and radiological progression in MS. These results indicate that changes in immune system, complement pathway and ECM remodeling proteins contribute to MS progression and may therefore be further explored for use in prognosis of MS. | Malekzadeh, Arjan Leurs, Cyra van Wieringen, Wessel Steenwijk, Martijn D Schoonheim, Menno M Amann, Michael Naegelin, Yvonne Kuhle, Jens Killestein, Joep Teunissen, Charlotte E eng 14-358e/Dutch MS Research Foundation/International PA 0186/Primary Progressive MS Alliance/International Research Support, Non-U.S. Gov't Ann Clin Transl Neurol. 2019 Sep;6(9):1582-1594. doi: 10.1002/acn3.771. Epub 2019 Jul 31.I | 08/01/2019 | |
| Apabetalone (RVX-208) reduces vascular inflammation in vitro and in CVD patients by a BET-dependent epigenetic mechanism | Tsujikawa LM, et al. | 2019 | Clin Epigenetics | 11 | 1 | 102 | https://www.doi.org/10.1186/s13148-019-0696-z | 31,300,040 | Cardiovascular Diseases/*drug therapy/metabolism Cell Adhesion/drug effects Cell Adhesion Molecules/genetics Cell Cycle Proteins/antagonists & inhibitors/*metabolism Cell Line Clinical Trials, Phase II as Topic Epigenesis, Genetic/drug effects Gene Expression Profiling Gene Expression Regulation/drug effects Human Umbilical Vein Endothelial Cells Humans Proteomics/methods Quinazolinones/*administration & dosage/pharmacology THP-1 Cells Transcription Factors/antagonists & inhibitors/*metabolism Vasculitis/*drug therapy/genetics Adhesion Apabetalone Atherosclerosis Brd4 Bromodomain Cvd Diabetes Epigenetics Huvec THP-1 monocytes Vascular inflammation endothelium company. | BACKGROUND: Apabetalone (RVX-208) is a bromodomain and extraterminal protein inhibitor (BETi) that in phase II trials reduced the relative risk (RR) of major adverse cardiac events (MACE) in patients with cardiovascular disease (CVD) by 44% and in diabetic CVD patients by 57% on top of statins. A phase III trial, BETonMACE, is currently assessing apabetalone's ability to reduce MACE in statin-treated post-acute coronary syndrome type 2 diabetic CVD patients with low high-density lipoprotein C. The leading cause of MACE is atherosclerosis, driven by dysfunctional lipid metabolism and chronic vascular inflammation (VI). In vitro studies have implicated the BET protein BRD4 as an epigenetic driver of inflammation and atherogenesis, suggesting that BETi may be clinically effective in combating VI. Here, we assessed apabetalone's ability to regulate inflammation-driven gene expression and cell adhesion in vitro and investigated the mechanism by which apabetalone suppresses expression. The clinical impact of apabetalone on mediators of VI was assessed with proteomic analysis of phase II CVD patient plasma. RESULTS: In vitro, apabetalone prevented inflammatory (TNFalpha, LPS, or IL-1beta) induction of key factors that drive endothelial activation, monocyte recruitment, adhesion, and plaque destabilization. BRD4 abundance on inflammatory and adhesion gene promoters and enhancers was reduced by apabetalone. BRD2-4 degradation by MZ-1 also prevented TNFalpha-induced transcription of monocyte and endothelial cell adhesion molecules and inflammatory mediators, confirming BET-dependent regulation. Transcriptional regulation by apabetalone translated into a reduction in monocyte adhesion to an endothelial monolayer. In a phase II trial, apabetalone treatment reduced the abundance of multiple VI mediators in the plasma of CVD patients (SOMAscan(R) 1.3 k). These proteins correlate with CVD risk and include adhesion molecules, cytokines, and metalloproteinases. Ingenuity(R) Pathway Analysis (IPA(R)) predicted that apabetalone inhibits pro-atherogenic regulators and pathways and prevents disease states arising from leukocyte recruitment. CONCLUSIONS: Apabetalone suppressed gene expression of VI mediators in monocytes and endothelial cells by inhibiting BET-dependent transcription induced by multiple inflammatory stimuli. In CVD patients, apabetalone treatment reduced circulating levels of VI mediators, an outcome conducive with atherosclerotic plaque stabilization and MACE reduction. Inhibition of inflammatory and adhesion molecule gene expression by apabetalone is predicted to contribute to MACE reduction in the phase III BETonMACE trial. | Tsujikawa, Laura M Fu, Li Das, Shovon Halliday, Christopher Rakai, Brooke D Stotz, Stephanie C Sarsons, Christopher D Gilham, Dean Daze, Emily Wasiak, Sylwia Studer, Deborah Rinker, Kristina D Sweeney, Michael Johansson, Jan O Wong, Norman C W Kulikowski, Ewelina eng Research Support, Non-U.S. Gov't Germany Clin Epigenetics. 2019 Jul 12;11(1):102. doi: 10.1186/s13148-019-0696-z.I | 07/14/2019 | |
| The nucleolus functions as a phase-separated protein quality control compartment | Frottin F, et al. | 2019 | Science | 365 | 6,451 | 342-347 | https://www.doi.org/10.1126/science.aaw9157 | 31,296,649 | Cell Nucleolus/*metabolism HEK293 Cells HSP70 Heat-Shock Proteins/metabolism Humans Nuclear Proteins/*chemistry Nucleophosmin Phase Transition *Protein Folding Proteome Tissue Culture Techniques | The nuclear proteome is rich in stress-sensitive proteins, which suggests that effective protein quality control mechanisms are in place to ensure conformational maintenance. We investigated the role of the nucleolus in this process. In mammalian tissue culture cells under stress conditions, misfolded proteins entered the granular component (GC) phase of the nucleolus. Transient associations with nucleolar proteins such as NPM1 conferred low mobility to misfolded proteins within the liquid-like GC phase, avoiding irreversible aggregation. Refolding and extraction of proteins from the nucleolus during recovery from stress was Hsp70-dependent. The capacity of the nucleolus to store misfolded proteins was limited, and prolonged stress led to a transition of the nucleolar matrix from liquid-like to solid, with loss of reversibility and dysfunction in quality control. Thus, we suggest that the nucleolus has chaperone-like properties and can promote nuclear protein maintenance under stress. | Frottin, F Schueder, F Tiwary, S Gupta, R Korner, R Schlichthaerle, T Cox, J Jungmann, R Hartl, F U Hipp, M S eng Research Support, Non-U.S. Gov't Science. 2019 Jul 26;365(6451):342-347. doi: 10.1126/science.aaw9157. Epub 2019 Jul 11.I | 07/13/2019 | |
| Effects of microbiota-directed foods in gnotobiotic animals and undernourished children | Gehrig JL, et al. | 2019 | Science | 365 | 6,449 | https://www.doi.org/10.1126/science.aau4732 | 31,296,738 | Animals Bangladesh Blood Proteins/analysis Child Nutrition Disorders/*diet therapy/metabolism/*microbiology Child, Preschool *Gastrointestinal Microbiome *Germ-Free Life *Host Microbial Interactions Humans Infant *Infant Nutritional Physiological Phenomena | To examine the contributions of impaired gut microbial community development to childhood undernutrition, we combined metabolomic and proteomic analyses of plasma samples with metagenomic analyses of fecal samples to characterize the biological state of Bangladeshi children with severe acute malnutrition (SAM) as they transitioned, after standard treatment, to moderate acute malnutrition (MAM) with persistent microbiota immaturity. Host and microbial effects of microbiota-directed complementary food (MDCF) prototypes targeting weaning-phase bacterial taxa underrepresented in SAM and MAM microbiota were characterized in gnotobiotic mice and gnotobiotic piglets colonized with age- and growth-discriminatory bacteria. A randomized, double-blind controlled feeding study identified a lead MDCF that changes the abundances of targeted bacteria and increases plasma biomarkers and mediators of growth, bone formation, neurodevelopment, and immune function in children with MAM. | Gehrig, Jeanette L Venkatesh, Siddarth Chang, Hao-Wei Hibberd, Matthew C Kung, Vanderlene L Cheng, Jiye Chen, Robert Y Subramanian, Sathish Cowardin, Carrie A Meier, Martin F O'Donnell, David Talcott, Michael Spears, Larry D Semenkovich, Clay F Henrissat, Bernard Giannone, Richard J Hettich, Robert L Ilkayeva, Olga Muehlbauer, Michael Newgard, Christopher B Sawyer, Christopher Head, Richard D Rodionov, Dmitry A Arzamasov, Aleksandr A Leyn, Semen A Osterman, Andrei L Hossain, Md Iqbal Islam, Munirul Choudhury, Nuzhat Sarker, Shafiqul Alam Huq, Sayeeda Mahmud, Imteaz Mostafa, Ishita Mahfuz, Mustafa Barratt, Michael J Ahmed, Tahmeed Gordon, Jeffrey I eng P30 AR057235/AR/NIAMS NIH HHS/ P30 AR074992/AR/NIAMS NIH HHS/ P30 DK056341/DK/NIDDK NIH HHS/ P30 DK020579/DK/NIDDK NIH HHS/ T32 GM007200/GM/NIGMS NIH HHS/ P30 DK052574/DK/NIDDK NIH HHS/ UL1 TR002345/TR/NCATS NIH HHS/ P30 CA091842/CA/NCI NIH HHS/ Randomized Controlled Trial Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Science. 2019 Jul 12;365(6449):eaau4732. doi: 10.1126/science.aau4732.I | 07/13/2019 | ||
| Application of Proteomics Profiling for Biomarker Discovery in Hypertrophic Cardiomyopathy | Shimada YJ, et al. | 2019 | J Cardiovasc Transl Res | 12 | 6 | 569-579 | https://www.doi.org/10.1007/s12265-019-09896-z | 31,278,493 | Aged Biomarkers/blood Blood Proteins/*analysis Cardiomyopathy, Hypertrophic/*blood/diagnosis Case-Control Studies Female High-Throughput Screening Assays Humans Least-Squares Analysis Male Middle Aged Predictive Value of Tests Protein Interaction Maps *Proteomics Biomarker discovery Hypertrophic cardiomyopathy Proteomics member of MyoKardia. The other authors have no conflict of interest related to this article. | High-throughput proteomics profiling has never been applied to discover biomarkers in patients with hypertrophic cardiomyopathy (HCM). The objective was to identify plasma protein biomarkers that can distinguish HCM from controls. We performed a case-control study of patients with HCM (n = 15) and controls (n = 22). We carried out plasma proteomics profiling of 1129 proteins using the SOMAscan assay. We used the sparse partial least squares discriminant analysis to identify 50 most discriminant proteins. We also determined the area under the curve (AUC) of the receiver operating characteristic curve using the Monte Carlo cross validation with balanced subsampling. The average AUC was 0.94 (95% confidence interval, 0.82-1.00) and the discriminative accuracy was 89%. In HCM, 13 out of the 50 proteins correlated with troponin I and 12 with New York Heart Association class. Proteomics profiling can be used to elucidate protein biomarkers that distinguish HCM from controls. | Shimada, Yuichi J Hasegawa, Kohei Kochav, Stephanie M Mohajer, Pouya Jung, Jeeyoun Maurer, Mathew S Reilly, Muredach P Fifer, Michael A eng 18CDA34110245/AHA/American Heart Association-American Stroke Association/ UL1 TR001873/TR/NCATS NIH HHS/ Research Support, Non-U.S. Gov't J Cardiovasc Transl Res. 2019 Dec;12(6):569-579. doi: 10.1007/s12265-019-09896-z. Epub 2019 Jul 5.I | 07/07/2019 | |
| Fine-Mapping of the Human Blood Plasma N-Glycome onto Its Proteome | Suhre K, et al. | 2019 | Metabolites | 9 | 7 | https://www.doi.org/10.3390/metabo9070122 | 31,247,951 | Hilic-uplc N-glycosylation SOMAscan aptamers glycomics population study proteomics Ivo Ugrina and Gordan Lauc are working for or have stakes in Genos Ltd., a private company specialized in glycomics analyses. The other authors have nothing to disclose. The funders had no role in the design of the study in the collection, analyses, or interpretation of data in the writing of the manuscript or in the decision to publish the results. The statements made herein are solely the responsibility of the authors. | Most human proteins are glycosylated. Attachment of complex oligosaccharides to the polypeptide part of these proteins is an integral part of their structure and function and plays a central role in many complex disorders. One approach towards deciphering this human glycan code is to study natural variation in experimentally well characterized samples and cohorts. High-throughput capable large-scale methods that allow for the comprehensive determination of blood circulating proteins and their glycans have been recently developed, but so far, no study has investigated the link between both traits. Here we map for the first time the blood plasma proteome to its matching N-glycome by correlating the levels of 1116 blood circulating proteins with 113 N-glycan traits, determined in 344 samples from individuals of Arab, South-Asian, and Filipino descent, and then replicate our findings in 46 subjects of European ancestry. We report protein-specific N-glycosylation patterns, including a correlation of core fucosylated structures with immunoglobulin G (IgG) levels, and of trisialylated, trigalactosylated, and triantennary structures with heparin cofactor 2 (SERPIND2). Our study reveals a detailed picture of protein N-glycosylation and suggests new avenues for the investigation of its role and function in the associated complex disorders. | Suhre, Karsten Trbojevic-Akmacic, Irena Ugrina, Ivo Mook-Kanamori, Dennis O Spector, Tim Graumann, Johannes Lauc, Gordan Falchi, Mario eng Biomedical Research Program' funds at Weill Cornell Medicine in Qatar/Qatar Foundation/ Switzerland Metabolites. 2019 Jun 26;9(7):122. doi: 10.3390/metabo9070122.I | 06/30/2019 | ||
| Neutrophil activation in systemic capillary leak syndrome (Clarkson disease) | Xie Z, et al. | 2019 | J Cell Mol Med | 23 | 8 | 5119-5127 | https://www.doi.org/10.1111/jcmm.14381 | 31,210,423 | Adult Blood Proteins/*genetics Capillary Leak Syndrome/*blood/genetics/pathology Endothelial Cells Endothelium, Vascular/metabolism Female Humans Male Middle Aged Neutrophil Activation/*genetics Neutrophils/metabolism *Proteomics neutrophils proteomics vascular leak | Systemic capillary leak syndrome (SCLS; Clarkson disease) is a rare orphan disorder characterized by transient yet recurrent episodes of hypotension and peripheral oedema due to diffuse vascular leakage of fluids and proteins into soft tissues. Humoral mediators, cellular responses and genetic features accounting for the clinical phenotype of SCLS are virtually unknown. Here, we searched for factors altered in acute SCLS plasma relative to matched convalescent samples using multiplexed aptamer-based proteomic screening. Relative amounts of 612 proteins were changed greater than twofold and 81 proteins were changed at least threefold. Among the most enriched proteins in acute SCLS plasma were neutrophil granule components including bactericidal permeability inducing protein, myeloperoxidase and matrix metalloproteinase 8. Neutrophils isolated from blood of subjects with SCLS or healthy controls responded similarly to routine pro-inflammatory mediators. However, acute SCLS sera activated neutrophils relative to remission sera. Activated neutrophil supernatants increased permeability of endothelial cells from both controls and SCLS subjects equivalently. Our results suggest systemic neutrophil degranulation during SCLS acute flares, which may contribute to the clinical manifestations of acute vascular leak. | Xie, Zhihui Kuhns, Douglas B Gu, Xuesong Otu, Hasan H Libermann, Towia A Gallin, John I Parikh, Samir M Druey, Kirk M eng Research Support, N.I.H., Intramural England J Cell Mol Med. 2019 Aug;23(8):5119-5127. doi: 10.1111/jcmm.14381. Epub 2019 Jun 18.I | 06/19/2019 | |
| The prediction of early preeclampsia: Results from a longitudinal proteomics study | Tarca AL, et al. | 2019 | PLoS One | 14 | 6 | e0217273 | https://www.doi.org/10.1371/journal.pone.0217273 | 31,163,045 | Adult Female Humans Longitudinal Studies *Models, Biological Pre-Eclampsia/*blood Predictive Value of Tests Pregnancy Pregnancy Proteins/*blood *Proteomics | OBJECTIVES: To identify maternal plasma protein markers for early preeclampsia (delivery <34 weeks of gestation) and to determine whether the prediction performance is affected by disease severity and presence of placental lesions consistent with maternal vascular malperfusion (MVM) among cases. STUDY DESIGN: This longitudinal case-control study included 90 patients with a normal pregnancy and 33 patients with early preeclampsia. Two to six maternal plasma samples were collected throughout gestation from each woman. The abundance of 1,125 proteins was measured using high-affinity aptamer-based proteomic assays, and data were modeled using linear mixed-effects models. After data transformation into multiples of the mean values for gestational age, parsimonious linear discriminant analysis risk models were fit for each gestational-age interval (8-16, 16.1-22, 22.1-28, 28.1-32 weeks). Proteomic profiles of early preeclampsia cases were also compared to those of a combined set of controls and late preeclampsia cases (n = 76) reported previously. Prediction performance was estimated via bootstrap. RESULTS: We found that 1) multi-protein models at 16.1-22 weeks of gestation predicted early preeclampsia with a sensitivity of 71% at a false-positive rate (FPR) of 10%. High abundance of matrix metalloproteinase-7 and glycoprotein IIbIIIa complex were the most reliable predictors at this gestational age; 2) at 22.1-28 weeks of gestation, lower abundance of placental growth factor (PlGF) and vascular endothelial growth factor A, isoform 121 (VEGF-121), as well as elevated sialic acid binding immunoglobulin-like lectin 6 (siglec-6) and activin-A, were the best predictors of the subsequent development of early preeclampsia (81% sensitivity, FPR = 10%); 3) at 28.1-32 weeks of gestation, the sensitivity of multi-protein models was 85% (FPR = 10%) with the best predictors being activated leukocyte cell adhesion molecule, siglec-6, and VEGF-121; 4) the increase in siglec-6, activin-A, and VEGF-121 at 22.1-28 weeks of gestation differentiated women who subsequently developed early preeclampsia from those who had a normal pregnancy or developed late preeclampsia (sensitivity 77%, FPR = 10%); 5) the sensitivity of risk models was higher for early preeclampsia with placental MVM lesions than for the entire early preeclampsia group (90% versus 71% at 16.1-22 weeks; 87% versus 81% at 22.1-28 weeks; and 90% versus 85% at 28.1-32 weeks, all FPR = 10%); and 6) the sensitivity of prediction models was higher for severe early preeclampsia than for the entire early preeclampsia group (84% versus 71% at 16.1-22 weeks). CONCLUSION: We have presented herein a catalogue of proteome changes in maternal plasma proteome that precede the diagnosis of preeclampsia and can distinguish among early and late phenotypes. The sensitivity of maternal plasma protein models for early preeclampsia is higher in women with underlying vascular placental disease and in those with a severe phenotype. | Tarca, Adi L Romero, Roberto Benshalom-Tirosh, Neta Than, Nandor Gabor Gudicha, Dereje W Done, Bogdan Pacora, Percy Chaiworapongsa, Tinnakorn Panaitescu, Bogdan Tirosh, Dan Gomez-Lopez, Nardhy Draghici, Sorin Hassan, Sonia S Erez, Offer eng HHSN275201300006C/HD/NICHD NIH HHS/ Clinical Trial Research Support, N.I.H., Extramural Research Support, N.I.H., Intramural Research Support, Non-U.S. Gov't PLoS One. 2019 Jun 4;14(6):e0217273. doi: 10.1371/journal.pone.0217273. eCollection 2019.I | 06/05/2019 | |
| Circulating Biomarkers of Testosterone's Anabolic Effects on Fat-Free Mass | Huang G, et al. | 2019 | J Clin Endocrinol Metab | 104 | 9 | 3768-78 | https://www.doi.org/10.1210/jc.2019-00505 | 31,120,518 | BACKGROUND: Biomarkers that predict response to anabolic therapies could expedite the development of function promoting anabolic drugs. This study aimed to identify serum biomarkers that are responsive to testosterone administration and associated with increases in fat-free mass (FFM). METHODS: Serum samples were obtained from the 5alpha-Reductase Trial, a randomized trial that compared the effects of graded doses of testosterone enanthate for 20-weeks in healthy men randomized to placebo or dutasteride (dual SRD5A inhibitor). Testosterone's effects on FFM or strength measures did not differ between placebo vs dutasteride groups. Accordingly, 54 subjects treated with testosterone plus placebo were included in the Discovery Cohort, and 48 randomized to dutasteride were included in the Validation Cohort. 1162 biomarkers were evaluated using pre-specified criteria. RESULTS: In the Discovery Cohort, testosterone administration increased PRO-C3 and PRO-C6 levels in a dose- and concentration-dependent manner; increases in these biomarkers from baseline to week-12 were associated with changes in FFM from baseline to week-20 (PRO-C3: r2=0.437, p<0.001; PRO-C6: r2=0.434, p<0.001). Changes in PRO-C3 and PRO-C6 levels were significantly associated with changes in chest press strength (PRO-C3: r2=0.394, p<0.001; PRO-C6: r2=0.530, p<0.001). In the SOMAscan, changes in insulin-like growth factor binding protein-6 (IGFBP6) and Glypican 3 (GPC3) were associated with changes in total and free testosterone levels and FFM. These findings were replicated in the Validation Cohort. CONCLUSION: PRO-C3, PRO-C6, IGFBP6 and GPC3 fulfilled the pre-specified criteria for biomarkers of testosterone-induced muscle anabolism: changes in these biomarkers were associated with changes in total and free testosterone concentrations and with testosterone-induced gains in FFM. | Huang, Grace Rocha, Guilherme V Pencina, Karol M Cox, Karen Krishnan, Venkatesh Henriksen, Kim Mitchell, Peter Sissons, Sean E Li, Zhuoying Nedergaard, Anders F Karsdal, Morten A Sun, Shu Storer, Thomas W Basaria, Shehzad Bhasin, Shalender eng K08 HL132122/HL/NHLBI NIH HHS/ R01 HD043348/HD/NICHD NIH HHS/ J Clin Endocrinol Metab. 2019 May 23;104(9):3768-78. doi: 10.1210/jc.2019-00505.I | 05/24/2019 | ||
| Characterization of Glycolytic Enzymes and Pyruvate Kinase M2 in Type 1 and 2 Diabetic Nephropathy | Gordin D, et al. | 2019 | Diabetes Care | 42 | 7 | 1263-1273 | https://www.doi.org/10.2337/dc18-2585 | 31,076,418 | Aged Aged, 80 and over Autopsy Biomarkers/blood Case-Control Studies Cohort Studies Diabetes Mellitus, Type 1/blood/*complications/metabolism/pathology Diabetes Mellitus, Type 2/blood/*complications/metabolism/pathology Diabetic Nephropathies/blood/*metabolism/pathology Disease Progression Enzymes/analysis/*metabolism Female Glomerular Filtration Rate Glucose/*metabolism Humans Kidney/metabolism/pathology/physiopathology Kidney Glomerulus/metabolism/pathology/physiopathology Male Metabolic Networks and Pathways/physiology Metabolomics/methods Middle Aged Mitochondria/metabolism Proteomics/methods Pyruvate Kinase/*metabolism Renal Insufficiency, Chronic/complications/metabolism/pathology/physiopathology | OBJECTIVE: Elevated glycolytic enzymes in renal glomeruli correlated with preservation of renal function in the Medalist Study, individuals with >/=50 years of type 1 diabetes. Specifically, pyruvate kinase M2 (PKM2) activation protected insulin-deficient diabetic mice from hyperglycemia-induced glomerular pathology. This study aims to extend these findings in a separate cohort of individuals with type 1 and type 2 diabetes and discover new circulatory biomarkers for renal protection through proteomics and metabolomics of Medalists' plasma. We hypothesize that increased glycolytic flux and improved mitochondrial biogenesis will halt the progression of diabetic nephropathy. RESEARCH DESIGN AND METHODS: Immunoblots analyzed selected glycolytic and mitochondrial enzymes in postmortem glomeruli of non-Medalists with type 1 diabetes (n = 15), type 2 diabetes (n = 19), and no diabetes (n = 5). Plasma proteomic (SOMAscan) (n = 180) and metabolomic screens (n = 214) of Medalists with and without stage 3b chronic kidney disease (CKD) were conducted and significant markers validated by ELISA. RESULTS: Glycolytic (PKM1, PKM2, and ENO1) and mitochondrial (MTCO2) enzymes were significantly elevated in glomeruli of CKD- versus CKD+ individuals with type 2 diabetes. Medalists' plasma PKM2 correlated with estimated glomerular filtration rate (r (2) = 0.077; P = 0.0002). Several glucose and mitochondrial enzymes in circulation were upregulated with corresponding downregulation of toxic metabolites in CKD-protected Medalists. Amyloid precursor protein was also significantly upregulated, tumor necrosis factor receptors downregulated, and both confirmed by ELISA. CONCLUSIONS: Elevation of enzymes involved in the metabolism of intracellular free glucose and its metabolites in renal glomeruli is connected to preserving kidney function in both type 1 and type 2 diabetes. The renal profile of elevated glycolytic enzymes and reduced toxic glucose metabolites is reflected in the circulation, supporting their use as biomarkers for endogenous renal protective factors in people with diabetes. | Gordin, Daniel Shah, Hetal Shinjo, Takanori St-Louis, Ronald Qi, Weier Park, Kyoungmin Paniagua, Samantha M Pober, David M Wu, I-Hsien Bahnam, Vanessa Brissett, Megan J Tinsley, Liane J Dreyfuss, Jonathan M Pan, Hui Dong, Yutong Niewczas, Monika A Amenta, Peter Sadowski, Thorsten Kannt, Aimo Keenan, Hillary A King, George L eng DP3 DK094333/DK/NIDDK NIH HHS/ T32 DK007260/DK/NIDDK NIH HHS/ P30 DK036836/DK/NIDDK NIH HHS/ R24 DK083957/DK/NIDDK NIH HHS/ DP3 DK112192/DK/NIDDK NIH HHS/ UL1 RR025758/RR/NCRR NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Diabetes Care. 2019 Jul;42(7):1263-1273. doi: 10.2337/dc18-2585. Epub 2019 May 10.I | 05/12/2019 | |
| Accelerating Biomarker Discovery Through Electronic Health Records, Automated Biobanking, and Proteomics | Wells QS, et al. | 2019 | J Am Coll Cardiol | 73 | 17 | 2195-2205 | https://www.doi.org/10.1016/j.jacc.2019.01.074 | 31,047,008 | Academic Medical Centers Acceleration Aged Automation/*methods Biological Specimen Banks/organization & administration Biomarkers/blood Cohort Studies Electronic Health Records/*organization & administration Female Heart Failure/*blood/diagnosis Humans Male Middle Aged Proportional Hazards Models Prospective Studies Proteomics/*organization & administration Reproducibility of Results Risk Assessment Sensitivity and Specificity Thrombospondins/*blood biomarkers electronic health records heart failure proteomics | BACKGROUND: Circulating biomarkers can facilitate diagnosis and risk stratification for complex conditions such as heart failure (HF). Newer molecular platforms can accelerate biomarker discovery, but they require significant resources for data and sample acquisition. OBJECTIVES: The purpose of this study was to test a pragmatic biomarker discovery strategy integrating automated clinical biobanking with proteomics. METHODS: Using the electronic health record, the authors identified patients with and without HF, retrieved their discarded plasma samples, and screened these specimens using a DNA aptamer-based proteomic platform (1,129 proteins). Candidate biomarkers were validated in 3 different prospective cohorts. RESULTS: In an automated manner, plasma samples from 1,315 patients (31% with HF) were collected. Proteomic analysis of a 96-patient subset identified 9 candidate biomarkers (p < 4.42 x 10(-5)). Two proteins, angiopoietin-2 and thrombospondin-2, were associated with HF in 3 separate validation cohorts. In an emergency department-based registry of 852 dyspneic patients, the 2 biomarkers improved discrimination of acute HF compared with a clinical score (p < 0.0001) or clinical score plus B-type natriuretic peptide (p = 0.02). In a community-based cohort (n = 768), both biomarkers predicted incident HF independent of traditional risk factors and N-terminal pro-B-type natriuretic peptide (hazard ratio per SD increment: 1.35 [95% confidence interval: 1.14 to 1.61; p = 0.0007] for angiopoietin-2, and 1.37 [95% confidence interval: 1.06 to 1.79; p = 0.02] for thrombospondin-2). Among 30 advanced HF patients, concentrations of both biomarkers declined (80% to 84%) following cardiac transplant (p < 0.001 for both). CONCLUSIONS: A novel strategy integrating electronic health records, discarded clinical specimens, and proteomics identified 2 biomarkers that robustly predict HF across diverse clinical settings. This approach could accelerate biomarker discovery for many diseases. | Wells, Quinn S Gupta, Deepak K Smith, J Gustav Collins, Sean P Storrow, Alan B Ferguson, Jane Smith, Maya Landenhed Pulley, Jill M Collier, Sarah Wang, Xiaoming Roden, Dan M Gerszten, Robert E Wang, Thomas J eng S10 OD017985/OD/NIH HHS/ K23 HL128928/HL/NHLBI NIH HHS/ R01 HL140074/HL/NHLBI NIH HHS/ K12 HL109019/HL/NHLBI NIH HHS/ R01 HL132320/HL/NHLBI NIH HHS/ R01 HL133870/HL/NHLBI NIH HHS/ Comparative Study Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't J Am Coll Cardiol. 2019 May 7;73(17):2195-2205. doi: 10.1016/j.jacc.2019.01.074.I | 05/03/2019 | |
| A signature of circulating inflammatory proteins and development of end-stage renal disease in diabetes | Niewczas MA, et al. | 2019 | Nat Med | 25 | 5 | 805-813 | https://www.doi.org/10.1038/s41591-019-0415-5 | 31,011,203 | Adult Aged Biomarkers/blood Blood Proteins/genetics/metabolism Cohort Studies Diabetes Mellitus, Type 1/blood/complications/genetics Diabetes Mellitus, Type 2/blood/complications/genetics Diabetic Nephropathies/*blood/*etiology/genetics Disease Progression Female Humans Inflammation Mediators/blood Kidney Failure, Chronic/*blood/*etiology/genetics Male Middle Aged Prognosis Prospective Studies Proteomics Receptors, Tumor Necrosis Factor/blood/genetics Risk Factors | Chronic inflammation is postulated to be involved in the development of end-stage renal disease in diabetes, but which specific circulating inflammatory proteins contribute to this risk remain unknown. To study this, we examined 194 circulating inflammatory proteins in subjects from three independent cohorts with type 1 and type 2 diabetes. In each cohort, we identified an extremely robust kidney risk inflammatory signature (KRIS), consisting of 17 proteins enriched in tumor necrosis factor-receptor superfamily members, that was associated with a 10-year risk of end-stage renal disease. All these proteins had a systemic, non-kidney source. Our prospective study findings provide strong evidence that KRIS proteins contribute to the inflammatory process underlying end-stage renal disease development in both types of diabetes. These proteins point to new therapeutic targets and new prognostic tests to identify subjects at risk of end-stage renal disease, as well as biomarkers to measure responses to treatment of diabetic kidney disease. | Niewczas, Monika A Pavkov, Meda E Skupien, Jan Smiles, Adam Md Dom, Zaipul I Wilson, Jonathan M Park, Jihwan Nair, Viji Schlafly, Andrew Saulnier, Pierre-Jean Satake, Eiichiro Simeone, Christopher A Shah, Hetal Qiu, Chengxiang Looker, Helen C Fiorina, Paolo Ware, Carl F Sun, Jennifer K Doria, Alessandro Kretzler, Matthias Susztak, Katalin Duffin, Kevin L Nelson, Robert G Krolewski, Andrzej S eng DP3 DK108220/DK/NIDDK NIH HHS/ DP3 DK112177/DK/NIDDK NIH HHS/ R01 DK087635/DK/NIDDK NIH HHS/ P30 DK036836/DK/NIDDK NIH HHS/ R01 DK076077/DK/NIDDK NIH HHS/ P30 DK081943/DK/NIDDK NIH HHS/ R01 DK041526/DK/NIDDK NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Nat Med. 2019 May;25(5):805-813. doi: 10.1038/s41591-019-0415-5. Epub 2019 Apr 22.I | 04/24/2019 | |
| Influenza a virus-triggered autophagy decreases the pluripotency of human-induced pluripotent stem cells | Zahedi-Amiri A, et al. | 2019 | Cell Death Dis | 10 | 5 | 337 | https://www.doi.org/10.1038/s41419-019-1567-4 | 31,000,695 | A549 Cells *Autophagy/drug effects Cell Differentiation Embryonic Development Humans Induced Pluripotent Stem Cells/cytology/*metabolism/virology Influenza A virus/*physiology Macrolides/pharmacology Metabolic Networks and Pathways Nanog Homeobox Protein/metabolism Proteome/analysis Proteomics SOXB1 Transcription Factors/metabolism Sirolimus/pharmacology Virus Replication | Maternal influenza infection during pregnancy was reported multiple times as the possible cause of many defects and congenital anomalies. Apart from several cases of influenza-related miscarriage during various trimesters of pregnancy, some epidemiological data suggest a link between maternal influenza infection and genetic abnormalities in offspring. However, there are no reports yet describing how maternal influenza alters cellular pathways at early stages of development to result in congenital defects in the fetus. In the present study, using proteomic approaches, we utilized human-induced pluripotent stem cells (hiPSCs) for modeling intrablastocyst infection with influenza virus to not only investigate the vulnerability and responses of pluripotent stem cells to this virus but also to determine the possible impacts of influenza on pluripotency and signaling pathways controlling differentiation and embryogenesis. Our data indicated viral protein production in influenza A virus (IAV)-infected hiPSCs. However, viral replication was restricted in these cells, but cell viability and pluripotency were negatively affected. These events occurred simultaneously with an excessive level of IAV-induced autophagy as well as cytopathic effects. Quantitative SOMAscan screening also indicated that changes in the proteome of hiPSCs corresponded to abnormal differentiation in these cells. Taken together, our results showed that IAV-modulated reduction in hiPSC pluripotency is associated with significant activation of autophagy. Further investigations are required to explore the role of IAV-induced autophagy in leading pluripotent stem cells toward abnormal differentiation and impaired development in early stages of embryogenesis. | Zahedi-Amiri, Ali Sequiera, Glen L Dhingra, Sanjiv Coombs, Kevin M eng MOP-106713/CIHR/Canada MOP-142265/CIHR/Canada Research Support, Non-U.S. Gov't England Cell Death Dis. 2019 Apr 18;10(5):337. doi: 10.1038/s41419-019-1567-4.I | 04/20/2019 | |
| Discovery and validation of a prognostic proteomic signature for tuberculosis progression: A prospective cohort study | Penn-Nicholson A, et al. | 2019 | PLoS Med | 16 | 4 | e1002781 | https://www.doi.org/10.1371/journal.pmed.1002781 | 30,990,820 | Adolescent Biomarkers/analysis/*blood/metabolism Child Cohort Studies Diagnostic Tests, Routine/methods Disease Progression Female Humans Longitudinal Studies Male Point-of-Care Testing Prognosis Prospective Studies Proteome/*analysis/metabolism Proteomics Tuberculosis/blood/*diagnosis/pathology | BACKGROUND: A nonsputum blood test capable of predicting progression of healthy individuals to active tuberculosis (TB) before clinical symptoms manifest would allow targeted treatment to curb transmission. We aimed to develop a proteomic biomarker of risk of TB progression for ultimate translation into a point-of-care diagnostic. METHODS AND FINDINGS: Proteomic TB risk signatures were discovered in a longitudinal cohort of 6,363 Mycobacterium tuberculosis-infected, HIV-negative South African adolescents aged 12-18 years (68% female) who participated in the Adolescent Cohort Study (ACS) between July 6, 2005 and April 23, 2007, through either active (every 6 months) or passive follow-up over 2 years. Forty-six individuals developed microbiologically confirmed TB disease within 2 years of follow-up and were selected as progressors; 106 nonprogressors, who remained healthy, were matched to progressors. Over 3,000 human proteins were quantified in plasma with a highly multiplexed proteomic assay (SOMAscan). Three hundred sixty-one proteins of differential abundance between progressors and nonprogressors were identified. A 5-protein signature, TB Risk Model 5 (TRM5), was discovered in the ACS training set and verified by blind prediction in the ACS test set. Poor performance on samples 13-24 months before TB diagnosis motivated discovery of a second 3-protein signature, 3-protein pair-ratio (3PR) developed using an orthogonal strategy on the full ACS subcohort. Prognostic performance of both signatures was validated in an independent cohort of 1,948 HIV-negative household TB contacts from The Gambia (aged 15-60 years, 66% female), longitudinally followed up for 2 years between March 5, 2007 and October 21, 2010, sampled at baseline, month 6, and month 18. Amongst these contacts, 34 individuals progressed to microbiologically confirmed TB disease and were included as progressors, and 115 nonprogressors were included as controls. Prognostic performance of the TRM5 signature in the ACS training set was excellent within 6 months of TB diagnosis (area under the receiver operating characteristic curve [AUC] 0.96 [95% confidence interval, 0.93-0.99]) and 6-12 months (AUC 0.76 [0.65-0.87]) before TB diagnosis. TRM5 validated with an AUC of 0.66 (0.56-0.75) within 1 year of TB diagnosis in the Gambian validation cohort. The 3PR signature yielded an AUC of 0.89 (0.84-0.95) within 6 months of TB diagnosis and 0.72 (0.64-0.81) 7-12 months before TB diagnosis in the entire South African discovery cohort and validated with an AUC of 0.65 (0.55-0.75) within 1 year of TB diagnosis in the Gambian validation cohort. Signature validation may have been limited by a systematic shift in signal magnitudes generated by differences between the validation assay when compared to the discovery assay. Further validation, especially in cohorts from non-African countries, is necessary to determine how generalizable signature performance is. CONCLUSIONS: Both proteomic TB risk signatures predicted progression to incident TB within a year of diagnosis. To our knowledge, these are the first validated prognostic proteomic signatures. Neither meet the minimum criteria as defined in the WHO Target Product Profile for a progression test. More work is required to develop such a test for practical identification of individuals for investigation of incipient, subclinical, or active TB disease for appropriate treatment and care. | Penn-Nicholson, Adam Hraha, Thomas Thompson, Ethan G Sterling, David Mbandi, Stanley Kimbung Wall, Kirsten M Fisher, Michelle Suliman, Sara Shankar, Smitha Hanekom, Willem A Janjic, Nebojsa Hatherill, Mark Kaufmann, Stefan H E Sutherland, Jayne Walzl, Gerhard De Groote, Mary Ann Ochsner, Urs Zak, Daniel E Scriba, Thomas J eng U01 AI115619/AI/NIAID NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Validation Study PLoS Med. 2019 Apr 16;16(4):e1002781. doi: 10.1371/journal.pmed.1002781. eCollection 2019 Apr.I | 04/17/2019 | |
| Zika Virus Infection Disrupts Astrocytic Proteins Involved in Synapse Control and Axon Guidance | Sher AA, et al. | 2019 | Front Microbiol | 10 | 596 | https://www.doi.org/10.3389/fmicb.2019.00596 | 30,984,137 | RNA virus infection SOMAScan aptamers astrocytic dysregulation proteomics virus-host interaction | The first human Zika virus (ZIKV) outbreak was reported in Micronesia in 2007, followed by one in Brazil in 2015. Recent studies have reported cases in Europe, Oceania and Latin America. In 2016, ZIKV transmission was also reported in the US and the World Health Organization declared it a Public Health Emergency of International Concern. Because various neurological conditions are associated with ZIKV, such as microcephaly, Guillain-Barre syndrome, and other disorders of both the central and peripheral nervous systems, including encephalopathy, (meningo)encephalitis and myelitis, and because of the lack of reliable patient diagnosis, numerous ongoing studies seek to understand molecular mechanisms underlying ZIKV pathogenesis. Astrocytes are one of the most abundant cells in the CNS. They control axonal guidance, synaptic signaling, neurotransmitter trafficking and maintenance of neurons, and are targeted by ZIKV. In this study, we used a newly developed multiplexed aptamer-based technique (SOMAScan) to examine > 1300 human astrocyte cell proteins. We identified almost 300 astrocyte proteins significantly dysregulated by ZIKV infection that span diverse functions and signaling pathways, including protein translation, synaptic control, cell migration and differentiation. | Sher, Affan A Glover, Kathleen K M Coombs, Kevin M eng Switzerland Front Microbiol. 2019 Mar 26;10:596. doi: 10.3389/fmicb.2019.00596. eCollection 2019.I | 04/16/2019 | ||
| Plasma FGF-19 Levels are Increased in Patients with Post-Bariatric Hypoglycemia | Mulla CM, et al. | 2019 | Obes Surg | 29 | 7 | 2092-2099 | https://www.doi.org/10.1007/s11695-019-03845-0 | 30,976,983 | Adult Bariatric Surgery/*adverse effects Blood Glucose/metabolism Blood Proteins/analysis/metabolism Case-Control Studies Female Fibroblast Growth Factors/*blood Gastric Bypass/adverse effects Gastrointestinal Hormones/blood Glucagon-Like Peptide 1/blood Glucagon-Like Peptide-1 Receptor/antagonists & inhibitors Humans Hypoglycemia/*blood/diet therapy/drug therapy/*etiology Male Meals Middle Aged Obesity, Morbid/blood/*surgery Peptide Fragments/therapeutic use Postoperative Complications/*blood/diet therapy/drug therapy Proteome/analysis Proteomics Up-Regulation Bile acids Fgf-19 Gastric bypass Hypoglycemia Pharmaceuticals, has received investigator-initiated grant support from Janssen Pharmaceuticals, Medimmune, Sanofi, Astra-Zeneca, Jenesis, and Nuclea, has been a site investigator for XOMA, and acknowledges clinical trial research trial product support from Ethicon, Covidien, NovoNordisk, Nestle, and Dexcom within the past 5 years. Dr. Patti and Dr. Goldfine disclose a patent application for plasma proteins contributing to hypoglycemia. Dr. Mulla, Dr. Dreyfuss, Dr. Houten, Dr. Pan, Dr. Pober, Dr. Wewer Albrechtsen, Dr. Svane, Dr. Schmidt, Dr. Holst, Dr. Craig and Dr. McLaughlin declare no potential competing interests. | BACKGROUND: Hypoglycemia is an increasingly recognized complication of bariatric surgery. Mechanisms contributing to glucose lowering remain incompletely understood. We aimed to identify differentially abundant plasma proteins in patients with post-bariatric hypoglycemia (PBH) after Roux-en-Y gastric bypass (RYGB), compared to asymptomatic post-RYGB. METHODS: Proteomic analysis of blood samples collected after overnight fast and mixed meal challenge in individuals with PBH, asymptomatic RYGB, severe obesity, or overweight recruited from outpatient hypoglycemia or bariatric clinics. RESULTS: The top-ranking differentially abundant protein at 120 min after mixed meal was fibroblast growth factor 19 (FGF-19), an intestinally derived hormone regulated by bile acid-FXR signaling; levels were 2.4-fold higher in PBH vs. asymptomatic post-RYGB (mean + SEM, 1094 +/- 141 vs. 428 +/- 45, P < 0.001, FDR < 0.01). FGF-19 ELISA confirmed 3.5-fold higher concentrations in PBH versus asymptomatic (360 +/- 70 vs. 103 +/- 18, P = 0.025). To explore potential links between increased FGF-19 and GLP-1, residual samples from other human studies in which GLP-1 was modulated were assayed. FGF-19 levels did not change in response to infusion of GLP-1 and PYY in overweight/obese individuals. Infusion of the GLP-1 receptor antagonist exendin 9-39 in recently operated asymptomatic post-RYGB did not alter FGF-19 levels after mixed meal. By contrast, GLP-1 receptor antagonist infusion yielded a significant increase in FGF-19 levels after oral glucose in individuals with PBH. While plasma bile acids did not differ between PBH and asymptomatic post-RYGB, these data suggest unique interrelationships between GLP-1 and FGF-19 in PBH. CONCLUSIONS: Taken together, these data support FGF-19 as a potential contributor to insulin-independent pathways driving postprandial hypoglycemia in PBH. | Mulla, Christopher M Goldfine, Allison B Dreyfuss, Jonathan M Houten, Sander Pan, Hui Pober, David M Wewer Albrechtsen, Nicolai J Svane, Maria S Schmidt, Julie B Holst, Jens Juul Craig, Colleen M McLaughlin, Tracey L Patti, Mary-Elizabeth eng L30 TR001569/TR/NCATS NIH HHS/ P30 DK036836/DK/NIDDK NIH HHS/ KL2 TR001083/TR/NCATS NIH HHS/ RC1 DK086918/DK/NIDDK NIH HHS/ UL1 TR001085/TR/NCATS NIH HHS/ UL1 TR001102/TR/NCATS NIH HHS/ R56 DK095451/DK/NIDDK NIH HHS/ R44 DK107114/DK/NIDDK NIH HHS/ T32 DK007260/DK/NIDDK NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Obes Surg. 2019 Jul;29(7):2092-2099. doi: 10.1007/s11695-019-03845-0.I | 04/13/2019 | |
| Stress Hyperglycemia in Critically Ill Patients: Insight Into Possible Molecular Pathways | Bar-Or D, et al. | 2019 | Front Med (Lausanne) | 6 | 54 | https://www.doi.org/10.3389/fmed.2019.00054 | 30,972,338 | Warburg effect dipeptidyl peptidase IV glycolysis hyperglycemia oxidative phosphorylation sepsis | Severe sepsis, systemic inflammatory response syndrome (SIRS), and traumatic brain injury are frequently associated with hyperglycemia in non-diabetic patients. In patients suffering from any of these conditions, hyperglycemia at admission to an intensive care unit (ICU) is directly correlated with increased mortality or morbidity. Although there was initial enthusiasm for insulin treatment to blood glucose levels below 110 mg/dL in these patients, recent understanding suggests that the potential for hypoglycemic complications make this approach potentially dangerous. More moderate glucose control seems to be more beneficial than the aggressive glucose lowering initially suggested. An important publication has shown that hyperlactatemia accompanying hyperglycemia could be the real culprit in bad outcomes. This suggests that coupling moderate glucose lowering with therapeutic agents which might treat the underlying metabolic disturbances in these conditions may be a better strategy. The key metabolic disturbance in these three conditions seems to be persistent glycolysis as an energy source even in the presence of adequate tissue oxygenation (the Warburg Effect). We look at recent advances in understanding aerobic glycolysis and possibly the action of DPP4 on incretins resulting in insulin dysregulation and suggest key metabolic pathways involved in hyperglycemia regulation. | Bar-Or, David Rael, Leonard T Madayag, Robert M Banton, Kaysie L Tanner, Allen 2nd Acuna, David L Lieser, Mark J Marshall, Gary T Mains, Charles W Brody, Edward eng Switzerland Front Med (Lausanne). 2019 Mar 27;6:54. doi: 10.3389/fmed.2019.00054. eCollection 2019.I | 04/12/2019 | ||
| Cancer protein biomarker discovery based on nucleic acid aptamers | Xiong H, et al. | 2019 | Int J Biol Macromol | 132 | 190-202 | https://www.doi.org/10.1016/j.ijbiomac.2019.03.165 | 30,926,499 | Animals Aptamers, Nucleotide/metabolism Biomarkers, Tumor/*metabolism Cell Membrane/metabolism Humans Neoplasm Proteins/*metabolism SELEX Aptamer Technique/*methods Cancer biomarker Nucleic acid aptamer Protein | Identification of biomarkers is essential for diagnosis, targeted therapy and prognosis evaluation of diseases, especially cancers. Currently, the number of ideal clinical biomarkers is still limited partially because of lacking efficient methods in biomarker discovery. Nucleic acid aptamers are artificial single-stranded DNA or RNA sequences that can selectively bind to various targets with high specificity and affinity. Moreover, aptamers possess desirable advantages, including easy synthesis, convenient modification, relative chemical stability and low immunogenicity. Recently, different aptamer-based strategies have been developed to facilitate the discovery of biomarkers. Based on cell-SELEX technology, the selected aptamers can be used to identify cell-surface protein biomarkers of different cancer cells. SOMAscan can analyze thousands of proteins of different biological samples, which becomes a multiplexed protein biomarker discovery platform. Additionally, secreted protein biomarkers can be discovered by aptamers screened through secretome SELEX. In order to facilitate the identification of target proteins, several covalent cross-linking strategies have been developed, such as aptamer-based affinity labeling (ABAL), DNA-templated aptamer and protein-aptamer template (PAT). In this review, we mainly highlight the emerging nucleic acid aptamer-based biomarker discovery strategies and demonstrate their unique technological advantages in discovering cancer biomarkers. The challenges and perspectives of aptamer-based methods are also discussed. | Xiong, Hongjie Yan, Jianhua Cai, Shundong He, Qunye Peng, Dongming Liu, Zhenbao Liu, Yanfei eng Review Netherlands Int J Biol Macromol. 2019 Jul 1;132:190-202. doi: 10.1016/j.ijbiomac.2019.03.165. Epub 2019 Mar 26.I | 03/31/2019 | ||
| A Novel Proteomics Approach to Identify Serum and Urinary Biomarkers and Pathways that Associate with Lower Urinary Tract Symptoms in Men and Women: Pilot Results of the Symptoms of Lower Urinary Tract Dysfunction Research Network (LURN) Study | Helfand BT, et al. | 2019 | Urology | 129 | 35-42 | https://www.doi.org/10.1016/j.urology.2019.03.014 | 30,922,973 | Adult Aged Biomarkers/blood/urine Cohort Studies Feasibility Studies Female Humans Lower Urinary Tract Symptoms/*blood/diagnosis/*urine Male Middle Aged Pilot Projects *Proteomics Symptom Assessment | OBJECTIVES: To assess the feasibility of a novel proteomics approach to identify biomarkers associated with lower urinary tract symptoms (LUTS) within serum and urine, because many clinical factors contribute to LUTS in men and women. These factors confound clinicians' abilities to reliably evaluate and treat LUTS. Previous studies identified candidate LUTS biomarkers, but none are clinically utilized. METHODS: Eighteen male and 18 female symptoms of lower urinary tract dysfunction research network (LURN) observational cohort study participants with LUTS (measured on the LUTS Tool questionnaire) were randomly selected. Twelve male and 12 female controls with minimal or no LUTS were recruited and matched for clinico-demographic characteristics. The SomaScan Assay (SomaLogic) was used to measure the abundance of 1305 proteins contained within urine and serum. Statistical analyses were performed to evaluate reproducibility of assays, compare protein abundances, and estimate effect size. RESULTS: SomaScan assay results were more reproducible in serum than in urine. Within serum, there were many more differentially abundant proteins between cases and controls in males than in females. An enrichment/pathway analysis of the affected proteins in male and female subjects demonstrated that the enriched Gene Ontology processes were related to prostate morphogenesis in men and growth and inflammation in women. CONCLUSION: The pilot study results support that the etiology and pathophysiologic mechanisms underlying LUTS may be sex-specific. While further studies involving larger numbers of subjects are warranted, our results support the feasibility of a novel proteomic approach to identify biomarkers for diagnostic classification of LUTS. | Helfand, Brian T Andreev, Victor P Siddiqui, Nazema Y Liu, Gang Erickson, Bradley A Helmuth, Margaret E Lutgendorf, Susan K Lai, H Henry Kirkali, Ziya eng U01 DK100017/DK/NIDDK NIH HHS/ U01 DK097780/DK/NIDDK NIH HHS/ UL1 TR001422/TR/NCATS NIH HHS/ K23 DK110417/DK/NIDDK NIH HHS/ U01 DK100011/DK/NIDDK NIH HHS/ U01 DK097772/DK/NIDDK NIH HHS/ U01 DK097776/DK/NIDDK NIH HHS/ U24 DK099879/DK/NIDDK NIH HHS/ K12 DK100024/DK/NIDDK NIH HHS/ U01 DK099932/DK/NIDDK NIH HHS/ U01 DK097779/DK/NIDDK NIH HHS/ U01 DK099879/DK/NIDDK NIH HHS/ Observational Study Urology. 2019 Jul;129:35-42. doi: 10.1016/j.urology.2019.03.014. Epub 2019 Mar 25.I | 03/30/2019 | ||
| Fatigue in Sjogren's Syndrome: A Search for Biomarkers and Treatment Targets | Bodewes ILA, et al. | 2019 | Front Immunol | 10 | 312 | https://www.doi.org/10.3389/fimmu.2019.00312 | 30,863,411 | Adult Aged Biomarkers/blood/*metabolism Blood Proteins/*metabolism Fatigue/diagnosis/*metabolism/therapy Female Humans Interferons/blood/metabolism Male Middle Aged Proteome/*metabolism Proteomics/*methods ROC Curve Signal Transduction Sjogren's Syndrome/diagnosis/*metabolism/therapy Up-Regulation Young Adult SOMAscan Sjogren's syndrome fatigue interferon proteomics | Background: Primary Sjogren's syndrome (pSS) is a systemic autoimmune disease, where patients often suffer from fatigue. Biological pathways underlying fatigue are unknown. In this study aptamer-based SOMAscan technology is used to identify potential biomarkers and treatment targets for fatigue in pSS. Methods: SOMAscan(R) Assay 1.3k was performed on serum samples of healthy controls (HCs) and pSS patients characterized for interferon upregulation and fatigue. Differentially expressed proteins (DEPs) between pSS patients and HC or fatigued and non-fatigued pSS patients were validated and discriminatory capacity of markers was tested using independent technology. Results: Serum concentrations of over 1,300 proteins were compared between 63 pSS patients and 20 HCs resulting in 58 upregulated and 46 downregulated proteins. Additionally, serum concentrations of 30 interferon positive (IFNpos) and 30 interferon negative (IFNneg) pSS patients were compared resulting in 25 upregulated and 13 downregulated proteins. ELISAs were performed for several DEPs between pSS patients and HCs or IFNpos and IFNneg all showing a good correlation between protein levels measured by ELISA and relative fluorescence units (RFU) measured by the SOMAscan. Comparing 22 fatigued and 23 non-fatigued pSS patients, 16 serum proteins were differentially expressed, of which 14 were upregulated and 2 were downregulated. Top upregulated DEPs included neuroactive synaptosomal-associated protein 25 (SNAP-25), alpha-enolase (ENO1) and ubiquitin carboxyl-terminal hydrolase isozyme L1 (UCHL1). Furthermore, the proinflammatory mediator IL36a and several complement factors were upregulated in fatigued compared to non-fatigued pSS patients. ROC analysis indicated that DEPs showed good capacity to discriminate fatigued and non-fatigued pSS patients. Conclusion: In this study we validated the use of aptamer-based proteomics and identified a novel set of proteins which were able to distinguish fatigued from non-fatigued pSS patients and identified a so-called fatigue signature."" | Bodewes, Iris L A van der Spek, Peter J Leon, Leticia G Wijkhuijs, Annemarie J M van Helden-Meeuwsen, Cornelia G Tas, Liselotte Schreurs, Marco W J van Daele, Paul L A Katsikis, Peter D Versnel, Marjan A eng Research Support, Non-U.S. Gov't Switzerland Front Immunol. 2019 Feb 26;10:312. doi: 10.3389/fimmu.2019.00312. eCollection 2019.I | 03/14/2019 | ||
| Proteomics Profiling and Risk of New-Onset Atrial Fibrillation: Framingham Heart Study | Ko D, et al. | 2019 | J Am Heart Assoc | 8 | 6 | e010976 | https://www.doi.org/10.1161/JAHA.118.010976 | 30,841,775 | Atrial Fibrillation/blood/*epidemiology/genetics Biomarkers/blood Blood Proteins/genetics/*metabolism Female Follow-Up Studies *Forecasting Genome-Wide Association Study/*methods Humans Incidence Longitudinal Studies Male Middle Aged Polymorphism, Genetic Prospective Studies Proteomics/*methods Risk Factors United States/epidemiology atrial fibrillation biomarker proteomics risk | Background Prior studies relating proteomics markers to incident AF screened for limited numbers of proteins. Methods and Results We performed proteomics assays among participants from the Framingham Heart Study Offspring attending their fifth examination. Plasma protein levels (n=1373) were measured by the SOMAscan proteomic profiling platform. We used robust inference for the Cox proportional hazards model to relate each protein level with incident AF. In addition, we examined the association between AF-related genetic loci and levels of proteins associated with AF. Our study included 1885 participants (mean age 55+/-10 years, 54% women) who had proteomic profiles measured. A total of 349 participants developed AF during follow-up (mean follow-up 18.3 years). We observed that 8 proteins were significantly associated with incident AF after adjusting for age, sex, technical covariates, and correction for multiple testing ( P<0.05/1373=3.6x10(-5)). After additional adjustments for clinical factors associated with AF, ADAMTS13 and N-terminal pro-B-type natriuretic peptide remained significantly associated with the risk of incident AF (hazard ratio, 0.78; 95% CI, 0.70-0.88; and 1.44; 95% CI, 1.22-1.70, respectively; P<3.6x10(-5) for both). None of the 8 proteins were encoded by genes at AF-related genetic loci previously identified by genome-wide association studies. Conclusions We identified 8 proteins associated with risk of incident AF after adjustment for age and sex; 2 proteins were associated with AF after adjustment for AF risk factors. Future studies are needed to replicate our findings, identify whether the markers are mechanistically related to AF development, and whether they are clinically useful for identification of future AF risk. | Ko, Darae Benson, Mark D Ngo, Debby Yang, Qiong Larson, Martin G Wang, Thomas J Trinquart, Ludovic McManus, David D Lubitz, Steven A Ellinor, Patrick T Vasan, Ramachandran S Gerszten, Robert E Benjamin, Emelia J Lin, Honghuang eng UL1 TR001430/TR/NCATS NIH HHS/ R01 HL092577/HL/NHLBI NIH HHS/ R01 HL128914/HL/NHLBI NIH HHS/ R01 HL137734/HL/NHLBI NIH HHS/ N01HC25195/HL/NHLBI NIH HHS/ R01 HL137794/HL/NHLBI NIH HHS/ K08 HL145095/HL/NHLBI NIH HHS/ R01 HL126911/HL/NHLBI NIH HHS/ R01 HL139731/HL/NHLBI NIH HHS/ P30 DK040561/DK/NIDDK NIH HHS/ K24 HL105780/HL/NHLBI NIH HHS/ UH3 TR000921/TR/NCATS NIH HHS/ R01 DK108159/DK/NIDDK NIH HHS/ R01 HL135219/HL/NHLBI NIH HHS/ R01 HL132320/HL/NHLBI NIH HHS/ HHSN268201500001I/HL/NHLBI NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. England J Am Heart Assoc. 2019 Mar 19;8(6):e010976. doi: 10.1161/JAHA.118.010976.I | 03/08/2019 | |
| Activin type II receptor signaling in cardiac aging and heart failure | Roh JD, et al. | 2019 | Sci Transl Med | 11 | 482 | https://www.doi.org/10.1126/scitranslmed.aau8680 | 30,842,316 | Activin Receptors, Type II/*metabolism Activins/blood Adult Aged Aged, 80 and over Aging/blood/*metabolism Animals Constriction, Pathologic Disease Models, Animal Follistatin-Related Proteins/metabolism Frailty Heart Failure/blood/*metabolism/pathology/physiopathology Heart Ventricles/pathology/physiopathology Humans Ligands Male Mice, Inbred C57BL Middle Aged Myocardium/*metabolism/*pathology Myocytes, Cardiac/metabolism Pressure Proteasome Endopeptidase Complex/metabolism Proteolysis Rats Sarcoplasmic Reticulum Calcium-Transporting ATPases Severity of Illness Index *Signal Transduction Systole | Activin type II receptor (ActRII) ligands have been implicated in muscle wasting in aging and disease. However, the role of these ligands and ActRII signaling in the heart remains unclear. Here, we investigated this catabolic pathway in human aging and heart failure (HF) using circulating follistatin-like 3 (FSTL3) as a potential indicator of systemic ActRII activity. FSTL3 is a downstream regulator of ActRII signaling, whose expression is up-regulated by the major ActRII ligands, activin A, circulating growth differentiation factor-8 (GDF8), and GDF11. In humans, we found that circulating FSTL3 increased with aging, frailty, and HF severity, correlating with an increase in circulating activins. In mice, increasing circulating activin A increased cardiac ActRII signaling and FSTL3 expression, as well as impaired cardiac function. Conversely, ActRII blockade with either clinical-stage inhibitors or genetic ablation reduced cardiac ActRII signaling while restoring or preserving cardiac function in multiple models of HF induced by aging, sarcomere mutation, or pressure overload. Using unbiased RNA sequencing, we show that activin A, GDF8, and GDF11 all induce a similar pathologic profile associated with up-regulation of the proteasome pathway in mammalian cardiomyocytes. The E3 ubiquitin ligase, Smurf1, was identified as a key downstream effector of activin-mediated ActRII signaling, which increased proteasome-dependent degradation of sarcoplasmic reticulum Ca(2+) ATPase (SERCA2a), a critical determinant of cardiomyocyte function. Together, our findings suggest that increased activin/ActRII signaling links aging and HF pathobiology and that targeted inhibition of this catabolic pathway holds promise as a therapeutic strategy for multiple forms of HF. | Roh, Jason D Hobson, Ryan Chaudhari, Vinita Quintero, Pablo Yeri, Ashish Benson, Mark Xiao, Chunyang Zlotoff, Daniel Bezzerides, Vassilios Houstis, Nicholas Platt, Colin Damilano, Federico Lindman, Brian R Elmariah, Sammy Biersmith, Michael Lee, Se-Jin Seidman, Christine E Seidman, Jonathan G Gerszten, Robert E Lach-Trifilieff, Estelle Glass, David J Rosenzweig, Anthony eng R01 AG061034/AG/NIA NIH HHS/ R01 AR060636/AR/NIAMS NIH HHS/ R01 HL080494/HL/NHLBI NIH HHS/ R01 HL132320/HL/NHLBI NIH HHS/ UH3 TR000901/TR/NCATS NIH HHS/ 14FTF20440012/AHA_/American Heart Association-American Stroke Association/ UH2 TR000901/TR/NCATS NIH HHS/ R01 HL122987/HL/NHLBI NIH HHS/ K08 HL145095/HL/NHLBI NIH HHS/ R01 HL135886/HL/NHLBI NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Sci Transl Med. 2019 Mar 6;11(482):eaau8680. doi: 10.1126/scitranslmed.aau8680.I | 03/08/2019 | ||
| SOMAscan-based proteomic measurements of plasma brain natriuretic peptide are decreased in mild cognitive impairment and in Alzheimer's dementia patients | Begic E, et al. | 2019 | PLoS One | 14 | 2 | e0212261 | https://www.doi.org/10.1371/journal.pone.0212261 | 30,763,368 | Aged Aged, 80 and over Alzheimer Disease/*blood Biomarkers/blood Cognitive Dysfunction/*blood Female Humans Male Natriuretic Peptide, Brain/*blood Proteomics | Alzheimer's disease represents the most common age-related neurodegenerative disorder and a leading cause of progressive cognitive impairment. Predicting cognitive decline is challenging but would be invaluable in an increasingly aging population which also experiences a rising cardiovascular risk. In order to examine whether plasma measurements of one of the established biomarkers of heart failure, brain natriuretic peptide (BNP), reflect a decline in cognitive function, associated with Alzheimer's disease neurodegeneration, BNP levels were analysed, by using a novel assay called a SOMAscan, in 1. cognitively healthy, control subjects; 2. subjects with mild cognitive impairment, and 3. subjects with Alzheimer's disease. The results of our study show that the levels of the BNP were significantly different between the three types of diagnoses (p < 0.05), whereby subjects with mild cognitive impairment had the lowest mean BNP value, and healthy subjects had the highest BNP value. Importantly, our results show that the levels of the BNP are influenced by the presence of at least one APOE4 allele in the healthy (p < 0.05) and in the Alzheimer's disease groups of subjects (p < 0.1). As the levels of the BNP appear to be independent of the APOE4 genotype in subjects with mild cognitive impairment, the results of our study support inclusion of measurements of plasma levels of the BNP in the list of the core Alzheimer's disease biomarkers for identification of the mild cognitive impairment group of patients. In addition, the results of our study warrant further investigations into molecular links between Alzheimer's disease-type cognitive decline and cardiovascular disorders. | Begic, Edin Hadzidedic, Suncica Kulaglic, Ajla Ramic-Brkic, Belma Begic, Zijo Causevic, Mirsada eng Research Support, Non-U.S. Gov't PLoS One. 2019 Feb 14;14(2):e0212261. doi: 10.1371/journal.pone.0212261. eCollection 2019.I | 02/15/2019 | |
| Proteomic Profiles in Advanced Age-Related Macular Degeneration Using an Aptamer-Based Proteomic Technology | Lynch AM, et al. | 2019 | Transl Vis Sci Technol | 8 | 1 | 14 | https://www.doi.org/10.1167/tvst.8.1.14 | 30,697,465 | aptamer-based technologies geographic atrophy neovascular AMD proteomics | PURPOSE: To explore top-ranked plasma proteins related to neovascular age-related macular degeneration (AMD) and geographic atrophy (GA), and explore pathways related to neovascular AMD and GA. METHODS: We conducted a pilot study of patients with neovascular AMD (n = 10), GA (n = 10), and age-matched cataract controls (n = 10) who were recruited into an AMD registry. We measured 4001 proteins in ethylenediaminetetraacetic acid plasma samples using an aptamer-based proteomic technology. Relative concentrations of each of 4001 proteins were log (base 2) transformed and compared between cases of neovascular AMD and GA versus controls using linear regression. Pathway analysis was conducted using pathways downloaded from Reactome. RESULTS: In this pilot study, higher levels of vinculin and lower levels of CD177 were found in patients with neovascular AMD compared with controls. Neuregulin-4 was higher and soluble intercellular adhesion molecule-1 was lower in patients with GA compared with controls. For neovascular AMD, cargo trafficking to the periciliary membrane, fibroblast growth factor receptor 3b ligand binding and activation, and vascular endothelial growth factor-related pathways were in the top ranked pathways. The top-ranked pathways for GA included several related to ErbB4 signaling. CONCLUSIONS: We found different proteins and different pathways associated with neovascular AMD and GA. Vinculin and some of the top-ranked pathways have been previously associated with AMD, whereas others have not been described. TRANSLATIONAL RELEVANCE: Biomarkers identified in plasma likely reflect systemic alterations in protein expression and may improve our understanding of the mechanisms leading to AMD. | Lynch, Anne M Wagner, Brandie D Weiss, Sophie J Wall, Kirsten M Palestine, Alan G Mathias, Marc T Siringo, Frank S Cathcart, Jennifer N Patnaik, Jennifer L Drolet, Daniel W Janjic, Nebojsa Mandava, Naresh eng Transl Vis Sci Technol. 2019 Jan 25;8(1):14. doi: 10.1167/tvst.8.1.14. eCollection 2019 Jan.I | 01/31/2019 | |
| Aging Disrupts Muscle Stem Cell Function by Impairing Matricellular WISP1 Secretion from Fibro-Adipogenic Progenitors | Lukjanenko L, et al. | 2019 | Cell Stem Cell | 24 | 3 | 433-446 e7 | https://www.doi.org/10.1016/j.stem.2018.12.014 | 30,686,765 | Adipocytes/cytology/*metabolism Adipogenesis Aging/*metabolism Animals CCN Intercellular Signaling Proteins/deficiency/*metabolism Cells, Cultured Humans Mice Mice, Inbred C57BL Mice, Knockout Muscle, Skeletal/cytology/*metabolism Proto-Oncogene Proteins/deficiency/*metabolism Stem Cells/cytology/*metabolism Ccn4 Wisp1 aging fibro-adipogenic progenitors matricellular signaling muscle stem cells regeneration satellite cell skeletal muscle stem cell niche or were employees of the Nestle Institute of Health Sciences / Nestec S.A., Switzerland. L.L. and J.N.F. are inventors of patent WO2017207678A1 assigned to Nestec S.A. | Research on age-related regenerative failure of skeletal muscle has extensively focused on the phenotypes of muscle stem cells (MuSCs). In contrast, the impact of aging on regulatory cells in the MuSC niche remains largely unexplored. Here, we demonstrate that aging impairs the function of mouse fibro-adipogenic progenitors (FAPs) and thereby indirectly affects the myogenic potential of MuSCs. Using transcriptomic profiling, we identify WNT1 Inducible Signaling Pathway Protein 1 (WISP1) as a FAP-derived matricellular signal that is lost during aging. WISP1 is required for efficient muscle regeneration and controls the expansion and asymmetric commitment of MuSCs through Akt signaling. Transplantation of young FAPs or systemic treatment with WISP1 restores the myogenic capacity of MuSCs in aged mice and rescues skeletal muscle regeneration. Our work establishes that loss of WISP1 from FAPs contributes to MuSC dysfunction in aged skeletal muscles and demonstrates that this mechanism can be targeted to rejuvenate myogenesis. | Lukjanenko, Laura Karaz, Sonia Stuelsatz, Pascal Gurriaran-Rodriguez, Uxia Michaud, Joris Dammone, Gabriele Sizzano, Federico Mashinchian, Omid Ancel, Sara Migliavacca, Eugenia Liot, Sophie Jacot, Guillaume Metairon, Sylviane Raymond, Frederic Descombes, Patrick Palini, Alessio Chazaud, Benedicte Rudnicki, Michael A Bentzinger, C Florian Feige, Jerome N eng R01 AR044031/AR/NIAMS NIH HHS/ FDN-148387/CIHR/Canada Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Cell Stem Cell. 2019 Mar 7;24(3):433-446.e7. doi: 10.1016/j.stem.2018.12.014. Epub 2019 Jan 24.I | 01/29/2019 | |
| Human PAH is characterized by a pattern of lipid-related insulin resistance | Hemnes AR, et al. | 2019 | JCI Insight | 4 | 1 | https://www.doi.org/10.1172/jci.insight.123611 | 30,626,738 | Cardiology Hypertension Insulin Proteomics Pulmonology Therapeutics, and Complexa. MEP has served as a consultant to Gilead. CJR has served as consultant to Actelion and United Therapeutics. | BACKGROUND: Pulmonary arterial hypertension (PAH) is a deadly disease of the small pulmonary vasculature with an increased prevalence of insulin resistance (IR). Insulin regulates both glucose and lipid homeostasis. We sought to quantify glucose- and lipid-related IR in human PAH, testing the hypothesis that lipoprotein indices are more sensitive indices of IR in PAH. METHODS: Oral glucose tolerance testing in PAH patients and triglyceride-matched (TG-matched) controls and proteomic, metabolomics, and lipoprotein analyses were performed in PAH and controls. Results were validated in an external cohort and in explanted human PAH lungs. RESULTS: PAH patients were similarly glucose intolerant or IR by glucose homeostasis metrics compared with control patients when matched for the metabolic syndrome. Using the insulin-sensitive lipoprotein index, TG/HDL ratio, PAH patients were more commonly IR than controls. Proteomic and metabolomic analysis demonstrated separation between PAH and controls, driven by differences in lipid species. We observed a significant increase in long-chain acylcarnitines, phosphatidylcholines, insulin metabolism-related proteins, and in oxidized LDL receptor 1 (OLR1) in PAH plasma in both a discovery and validation cohort. PAH patients had higher lipoprotein axis-related IR and lipoprotein-based inflammation scores compared with controls. PAH patient lung tissue showed enhanced OLR1 immunostaining within plexiform lesions and oxidized LDL accumulation within macrophages. CONCLUSIONS: IR in PAH is characterized by alterations in lipid and lipoprotein homeostasis axes, manifest by elevated TG/HDL ratio, and elevated circulating medium- and long-chain acylcarnitines and lipoproteins. Oxidized LDL and its receptor OLR1 may play a role in a proinflammatory phenotype in PAH. FUNDING: NIH DK096994, HL060906, UL1 RR024975-01, UL1 TR000445-06, DK020593, P01 HL108800-01A1, and UL1 TR002243; American Heart Association 13FTF16070002. | Hemnes, Anna R Luther, J Matthew Rhodes, Christopher J Burgess, Jason P Carlson, James Fan, Run Fessel, Joshua P Fortune, Niki Gerszten, Robert E Halliday, Stephen J Hekmat, Rezzan Howard, Luke Newman, John H Niswender, Kevin D Pugh, Meredith E Robbins, Ivan M Sheng, Quanhu Shibao, Cyndya A Shyr, Yu Sumner, Susan Talati, Megha Wharton, John Wilkins, Martin R Ye, Fei Yu, Chang West, James Brittain, Evan L eng UL1 TR000445/TR/NCATS NIH HHS/ P30 DK040561/DK/NIDDK NIH HHS/ P60 DK020593/DK/NIDDK NIH HHS/ R01 HL060906/HL/NHLBI NIH HHS/ R01 DK096994/DK/NIDDK NIH HHS/ R01 HL146588/HL/NHLBI NIH HHS/ P30 DK020593/DK/NIDDK NIH HHS/ T32 HL087738/HL/NHLBI NIH HHS/ UL1 TR002243/TR/NCATS NIH HHS/ R01 HL142720/HL/NHLBI NIH HHS/ FS/15/59/31839/BHF_/British Heart Foundation/United Kingdom K08 HL121174/HL/NHLBI NIH HHS/ UL1 RR024975/RR/NCRR NIH HHS/ P01 HL108800/HL/NHLBI NIH HHS/ JCI Insight. 2019 Jan 10;4(1):e123611. doi: 10.1172/jci.insight.123611.I | 01/11/2019 | ||
| Vero Cell Proteomic Changes Induced by Zika Virus Infection | Glover KKM, et al. | 2019 | Proteomics | 19 | 4 | e1800309 | https://www.doi.org/10.1002/pmic.201800309 | 30,578,658 | Animals Chlorocebus aethiops *Proteomics Vero Cells Virus Replication Zika Virus/*physiology Zika Virus Infection/*metabolism RNA virus infection SOMAScan aptamers proteomics | The re-emergence and the recent spread of the Zika virus (ZIKV) has raised significant global concerns due to lack of information in patient diagnosis and management. Thus, in addition to gaining more basic information about ZIKV biology, appropriate interventions and management strategies are being sought to control ZIKV-associated diseases and its spread. This study's objective is to identify host cell proteins that are significantly dysregulated during ZIKV infection. SOMAScan, a novel aptamer-based assay, is used to simultaneously screen >1300 host proteins to detect ZIKV-induced host protein dysregulation at multiple time points during infection. A total of 125 Vero cell host proteins, including cytokines such as CXCL11 and CCL5, interferon stimulated gene 15, and translation initiation factors EIF5A and EIF4G2, are significantly dysregulated after ZIKV infection. Bioinformatic analyses of 77 host proteins, that are significantly dysregulated >/=1.25-fold, identify several activated biological processes, including the JAK/STAT, Tec kinase, and complement cascade pathways. | Glover, Kathleen K M Gao, Ang Zahedi-Amiri, Ali Coombs, Kevin M eng CIHR/Canada Research Support, Non-U.S. Gov't Germany Proteomics. 2019 Feb;19(4):e1800309. doi: 10.1002/pmic.201800309. Epub 2019 Jan 23.I | 12/24/2018 | |
| A combined score of clinical factors and serum proteins can predict time to recurrence in high grade serous ovarian cancer | Mysona D, et al. | 2019 | Gynecol Oncol | 152 | 3 | 574-580 | https://www.doi.org/10.1016/j.ygyno.2018.12.015 | 30,578,005 | Cystadenocarcinoma, Serous/*blood/pathology/surgery Cytoreduction Surgical Procedures Disease-Free Survival Female Humans Middle Aged Neoplasm Grading Neoplasm Proteins/*blood Neoplasm Recurrence, Local/*blood/pathology Ovarian Neoplasms/*blood/pathology/surgery Predictive Value of Tests Progression-Free Survival Prospective Studies Biomarkers Ovarian neoplasm Prognosis Serum proteomics | OBJECTIVE: To investigate the utility of a combined panel of protein biomarkers and clinical factors to predict recurrence in serous ovarian cancer patients. METHODS: Women at Augusta University diagnosed with ovarian cancer were enrolled between 2005 and 2015 (n_=_71). Blood was drawn at enrollment and follow-up visits. Patient serum collected at remission was analyzed using the SOMAscan array (n_=_35) to measure levels of 1129 proteins. The best 26 proteins were confirmed using Luminex assays in the same 35 patients and in an additional 36 patients (n(total)_=_71) as orthogonal validation. The data from these 26 proteins was combined with clinical factors using an elastic net multivariate model to find an optimized combination predictive of progression-free survival (PFS). RESULTS: Of the 26 proteins, Brain Derived Neurotrophic Factor and Platelet Derived Growth Factor molecules were significant for predicting PFS on both univariate and multivariate analyses. All 26 proteins were combined with clinical factors using the elastic net algorithm. Ten components were determined to predict PFS (HR of 6.55, p-value 1.12_x_10(-6), CI 2.57-16.71). This model was named the serous high grade ovarian cancer (SHOC) score. CONCLUSION: The SHOC score can predict patient prognosis in remission. This tool will hopefully lead to early intervention and consolidation therapy strategies in remission patients destined to recur. | Mysona, David Pyrzak, Adam Purohit, Sharad Zhi, Wenbo Sharma, Ashok Tran, Lynn Tran, Paul Bai, Shan Rungruang, Bunja Ghamande, Sharad She, Jin-Xiong eng F30 DK121461/DK/NIDDK NIH HHS/ Observational Study Research Support, Non-U.S. Gov't Gynecol Oncol. 2019 Mar;152(3):574-580. doi: 10.1016/j.ygyno.2018.12.015. Epub 2018 Dec 18.I | 12/24/2018 | |
| Multiomics modeling of the immunome, transcriptome, microbiome, proteome and metabolome adaptations during human pregnancy | Ghaemi MS, et al. | 2019 | Bioinformatics | 35 | 1 | 95-103 | https://www.doi.org/10.1093/bioinformatics/bty537 | 30,561,547 | Computational Biology Female Humans *Metabolome *Microbiota *Pregnancy *Proteome *Transcriptome | MOTIVATION: Multiple biological clocks govern a healthy pregnancy. These biological mechanisms produce immunologic, metabolomic, proteomic, genomic and microbiomic adaptations during the course of pregnancy. Modeling the chronology of these adaptations during full-term pregnancy provides the frameworks for future studies examining deviations implicated in pregnancy-related pathologies including preterm birth and preeclampsia. RESULTS: We performed a multiomics analysis of 51 samples from 17 pregnant women, delivering at term. The datasets included measurements from the immunome, transcriptome, microbiome, proteome and metabolome of samples obtained simultaneously from the same patients. Multivariate predictive modeling using the Elastic Net (EN) algorithm was used to measure the ability of each dataset to predict gestational age. Using stacked generalization, these datasets were combined into a single model. This model not only significantly increased predictive power by combining all datasets, but also revealed novel interactions between different biological modalities. Future work includes expansion of the cohort to preterm-enriched populations and in vivo analysis of immune-modulating interventions based on the mechanisms identified. AVAILABILITY AND IMPLEMENTATION: Datasets and scripts for reproduction of results are available through: https://nalab.stanford.edu/multiomics-pregnancy/. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. | Ghaemi, Mohammad Sajjad DiGiulio, Daniel B Contrepois, Kevin Callahan, Benjamin Ngo, Thuy T M Lee-McMullen, Brittany Lehallier, Benoit Robaczewska, Anna Mcilwain, David Rosenberg-Hasson, Yael Wong, Ronald J Quaintance, Cecele Culos, Anthony Stanley, Natalie Tanada, Athena Tsai, Amy Gaudilliere, Dyani Ganio, Edward Han, Xiaoyuan Ando, Kazuo McNeil, Leslie Tingle, Martha Wise, Paul Maric, Ivana Sirota, Marina Wyss-Coray, Tony Winn, Virginia D Druzin, Maurice L Gibbs, Ronald Darmstadt, Gary L Lewis, David B Partovi Nia, Vahid Agard, Bruno Tibshirani, Robert Nolan, Garry Snyder, Michael P Relman, David A Quake, Stephen R Shaw, Gary M Stevenson, David K Angst, Martin S Gaudilliere, Brice Aghaeepour, Nima eng K01 LM012381/LM/NLM NIH HHS/ CIHR 321510/CIHR/Canada U19 AI057229/AI/NIAID NIH HHS/ R01 HL139844/HL/NHLBI NIH HHS/ K12 HL120001/HL/NHLBI NIH HHS/ P30 DK116074/DK/NIDDK NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't England Bioinformatics. 2019 Jan 1;35(1):95-103. doi: 10.1093/bioinformatics/bty537.I | 12/19/2018 | |
| Cerebrospinal fluid biomarkers link toxic astrogliosis and microglial activation to multiple sclerosis severity | Masvekar R, et al. | 2019 | Mult Scler Relat Disord | 28 | 34-43 | https://www.doi.org/10.1016/j.msard.2018.11.032 | 30,553,167 | Adolescent Adult Aged Astrocytes/metabolism Biomarkers/cerebrospinal fluid Cell Culture Techniques Cells, Cultured Cluster Analysis Female Gliosis/*cerebrospinal fluid Humans Male Microglia/metabolism Middle Aged Multiple Sclerosis/*cerebrospinal fluid Prospective Studies Severity of Illness Index Young Adult CNS tissue destruction CSF biomarkers MS severity Microglial activation Multiple sclerosis Toxic astrogliosis | BACKGROUND: Once multiple sclerosis (MS) reaches the progressive stage, immunomodulatory treatments have limited efficacy. This suggests that processes other than activation of innate immunity may at least partially underlie disability progression during late stages of MS. Pathology identified these alternative processes as aberrant activation of astrocytes and microglia, and subsequent degeneration of oligodendrocytes and neurons. However, we mostly lack biomarkers that could measure central nervous system (CNS) cell-specific intrathecal processes in living subjects. This prevents differentiating pathogenic processes from an epiphenomenon. Therefore, we sought to develop biomarkers of CNS cell-specific processes and link them to disability progression in MS. METHODS: In a blinded manner, we measured over 1000 proteins in the cerebrospinal fluid (CSF) of 431 patients with neuroimmunological diseases and healthy volunteers using modified DNA-aptamers (SOMAscan(R)). We defined CNS cell type-enriched clusters using variable cluster analysis, combined with in vitro modeling. Differences between diagnostic categories were identified in the training cohort (n_=_217) and their correlation to disability measures were assessed; results were validated in an independent validation cohort (n_=_214). RESULTS: Astrocyte cluster 8 (MMP7, SERPINA3, GZMA and CLIC1) and microglial cluster 2 (DSG2 and TNFRSF25) were reproducibly elevated in MS and had a significant and reproducible correlation with MS severity suggesting their pathogenic role. In vitro studies demonstrated that proteins of astrocyte cluster 8 are noticeably released upon stimulation with proinflammatory stimuli and overlap with the phenotype of recently described neuro-toxic (A1) astrocytes. CONCLUSION: Microglial activation and toxic astrogliosis are associated with MS disease process and may partake in CNS tissue destruction. This hypothesis should be tested in new clinical trials. | Masvekar, Ruturaj Wu, Tianxia Kosa, Peter Barbour, Christopher Fossati, Valentina Bielekova, Bibiana eng ZIA NS003055-11/Intramural NIH HHS/ Clinical Trial Netherlands Mult Scler Relat Disord. 2019 Feb;28:34-43. doi: 10.1016/j.msard.2018.11.032. Epub 2018 Dec 5.I | 12/16/2018 | ||
| Metabolic and proteomic signatures of hypoglycaemia in type 2 diabetes | Halama A, et al. | 2019 | Diabetes Obes Metab | 21 | 4 | 909-919 | https://www.doi.org/10.1111/dom.13602 | 30,525,282 | Adult Amino Acids/metabolism Bile Acids and Salts/metabolism Blood Glucose/metabolism Case-Control Studies Diabetes Mellitus, Type 2/*metabolism Fatty Acids/metabolism Female Glucose Clamp Technique Healthy Volunteers Humans Hypoglycemia/*metabolism Inflammation/metabolism Lipid Metabolism Male *Metabolomics Middle Aged *Proteomics Steroids/metabolism clinical physiology glucose metabolism hypoglycaemia type 2 diabetes | AIMS: To determine the biochemical changes that underlie hypoglycaemia in a healthy control group and in people with type 2 diabetes (T2D). MATERIALS AND METHODS: We report a hypoglycaemic clamp study in seven healthy controls and 10 people with T2D. Blood was withdrawn at four time points: at baseline after an overnight fast; after clamping to euglycaemia at 5 mmol/L; after clamping to hypoglycaemia at 2.8 mmol/L; and 24 hours later, after overnight fast. Deep molecular phenotyping using non-targeted metabolomics and the SomaLogic aptamer-based proteomics platform was performed on collected samples. RESULTS: A total of 955 metabolites and 1125 proteins were identified, with significant alterations in >90 molecules. A number of metabolites significantly increased during hypoglycaemia, but only cortisol, adenosine-3',5'-cyclic monophosphate (cyclic AMP), and pregnenolone sulphate, were independent of insulin. By contrast, identified protein changes were triggered by hypoglycaemia rather than insulin. The T2D group had significantly higher levels of fatty acids including 10-nonadecenoate, linolenate and dihomo-linoleate during hypoglycaemia compared with the control group. Molecules contributing to cardiovascular complications such as fatty-acid-binding protein-3 and pregnenolone sulphate were altered in the participants with T2D during hypoglycaemia. Almost all molecules returned to baseline at 24 hours. CONCLUSIONS: The present study provides a comprehensive description of molecular events that are triggered by insulin-induced hypoglycaemia. We identified deregulated pathways in T2D that may play a role in the pathophysiology of hypoglycaemia-induced cardiovascular complications. | Halama, Anna Kahal, Hassan Bhagwat, Aditya M Zierer, Jonas Sathyapalan, Thozhukat Graumann, Johannes Suhre, Karsten Atkin, Stephen L eng Research Support, Non-U.S. Gov't England Diabetes Obes Metab. 2019 Apr;21(4):909-919. doi: 10.1111/dom.13602. Epub 2018 Dec 27.I | 12/14/2018 | |
| Osteitis is associated with dysregulated pro-osteoblastic activity in patients with nasal polyps | Wu D, et al. | 2019 | Laryngoscope | 129 | 3 | E102-E109 | https://www.doi.org/10.1002/lary.27581 | 30,537,181 | Adult Bone Morphogenetic Proteins/*metabolism Case-Control Studies Down-Regulation Female Humans Male Middle Aged Nasal Polyps/*metabolism Osteitis/*metabolism Osteoblasts/*metabolism Prospective Studies Rhinitis/*metabolism Signal Transduction Sinusitis/*metabolism Osteitis bone morphogenetic protein pathway chronic rhinosinusitis nasal polyps | OBJECTIVES/HYPOTHESIS: The overlying inflammatory mucosa plays a crucial role in the initiation of osteitis; however, the molecular mechanism is unclear. The objective of this study was to explore the bone morphogenetic protein (BMP) pathway and to correlate the expression of key signaling molecules with the degree of osteitis in patients with chronic rhinosinusitis with nasal polyps (CRSwNP). STUDY DESIGN: Prospective experimental analysis. METHODS: This was an institutional review board-approved study in which mucosal samples were obtained from sites of osteitis in CRSwNP and compared to nonosteitic healthy controls (n = 10/group). Protein expression of key BMP pathway was quantified by aptamer-based protein array and confirmed by a set of selected mRNA analyses. Degree of osteitis was assessed using both Kennedy Osteitis Score and Global Osteitis Score (GOS). RESULTS: Pro-osteoblastic expression of BMP7 (fold change [FC] = -1.18, P = .017) and BMP9 (FC = -1.32, P = .023), their receptors, BMP receptor type-1A (BMPR1A) (FC = -2.56, P = .005) and BMP receptor type-2 (FC = -1.28, P = .022), and two enhancers of BMP signaling pathway, the repulsive guidance molecule domain family member B (FC = -1.13, P = .008) and the chordin-like protein 1 (FC = -1.18, P = .027), were all significantly downregulated in CRSwNP. Conversely, the pro-osteoclastic factor, tartrate-resistant acid phosphatase type 5 (ACP5) (FC = 2.36, P = .001), was significantly increased in CRSwNP. GOS was inversely correlated with levels of BMP7 (r = -0.684, P = .005) and BMPR1A (r = -0.864, P = .005) and positively correlated with levels of ACP5 (r = 0.815, P = .004). The FCs among the proteins studied significantly and positively correlated with the FCs of their mRNA expression (r = 0.908, P = .002). CONCLUSIONS: Downregulated pro-osteoblastic mucosal BMP signaling is strongly and significantly associated with increased osteitis in CRSwNP. LEVEL OF EVIDENCE: NA Laryngoscope, 129:E102-E109, 2019. | Wu, Dawei Nocera, Angela L Mueller, Sarina K Finn, Kristen Libermann, Towia A Bleier, Benjamin S eng Laryngoscope. 2019 Mar;129(3):E102-E109. doi: 10.1002/lary.27581. Epub 2018 Dec 11.I | 12/12/2018 | |
| Candidate early predictive plasma protein markers of doxorubicin-induced chronic cardiotoxicity in B6C3F(1) mice | Desai VG, et al. | 2019 | Toxicol Appl Pharmacol | 363 | 164-173 | https://www.doi.org/10.1016/j.taap.2018.11.016 | 30,517,846 | Administration, Intravenous Animals Antibiotics, Antineoplastic/*toxicity Biomarkers/blood Cardiotoxicity/*blood/etiology/prevention & control Dexrazoxane/administration & dosage Doxorubicin/administration & dosage/*toxicity Heart/drug effects Male Mice Myocardium/pathology Protective Agents/administration & dosage Proteome/analysis/drug effects Proteomics Receptor, Notch1/blood Risk Assessment/methods von Willebrand Factor/analysis Biomarkers Cardiotoxicity Dexrazoxane Doxorubicin Mouse Plasma SOMAscan Proteomic Assay | Cardiotoxicity is a serious adverse effect of doxorubicin (DOX) treatment in cancer patients. Currently, there is a lack of sensitive biomarkers to predict the risk of DOX-induced cardiotoxicity. Using SOMAmer-based proteomic technology, 1129 proteins were profiled to identify potential early biomarkers of cardiotoxicity in plasma from male B6C3F(1) mice given a weekly intravenous dose of 3_mg/kg DOX or saline (SAL) for 2, 3, 4, 6, or 8_weeks (6, 9, 12, 18, or 24_mg/kg cumulative DOX doses, respectively). Also, a group of mice received the cardio-protectant, dexrazoxane (DXZ; 60_mg/kg; intraperitoneal) 30_min before a weekly DOX or SAL dose. Proteomic analysis in plasma collected a week after the last dose showed a significant >/=1.2-fold change in level of 18 proteins in DOX-treated mice compared to SAL-treated counterparts during 8-week exposure. Of these, neurogenic locus notch homolog protein 1 (NOTCH1), von Willebrand factor (vWF), mitochondrial glutamate carrier 2, Wnt inhibitory factor 1, legumain, and mannan-binding lectin serine protease 1 were increased in plasma at 6_mg/kg cumulative DOX dose, prior to the release of myocardial injury marker, cardiac troponin I at 12_mg/kg and higher cumulative doses. These six proteins also remained significantly elevated following myocardial injury or pathology at 24_mg/kg. Pretreatment of mice with DXZ significantly attenuated DOX-induced elevated levels of only NOTCH1 and vWF with mitigation of cardiotoxicity. This suggests NOTCH1 and vWF as candidate early biomarkers of DOX cardiotoxicity, which may help in addressing a clinically important question of identifying cancer patients at risk for cardiotoxicity. | Desai, Varsha G Lee, Taewon Moland, Carrie L Vijay, Vikrant Han, Tao Lewis, Sherry M Herman, Eugene H Fuscoe, James C eng Research Support, U.S. Gov't, P.H.S. Toxicol Appl Pharmacol. 2019 Jan 15;363:164-173. doi: 10.1016/j.taap.2018.11.016. Epub 2018 Dec 2.I | 12/06/2018 | ||
| Noninvasive exosomal proteomic biosignatures, including cystatin SN, peroxiredoxin-5, and glycoprotein VI, accurately predict chronic rhinosinusitis with nasal polyps | Mueller SK, et al. | 2019 | Int Forum Allergy Rhinol | 9 | 2 | 177-186 | https://www.doi.org/10.1002/alr.22226 | 30,485,711 | Adult Chronic Disease Exosomes/*metabolism Female Humans Male Middle Aged Nasal Polyps/*diagnosis Peroxiredoxins/*metabolism Platelet Membrane Glycoproteins/*metabolism Predictive Value of Tests Prognosis Proteome Rhinitis/*diagnosis Salivary Cystatins/*metabolism Sinusitis/*diagnosis Transcriptome Young Adult and platelet glycoprotein VI biosignature chronic rhinosinusitis cystatin-SN exosome mucus nasal polyps peroxiredoxin-5 proteomics | BACKGROUND: Exosomes are secreted epithelial-derived vesicles that contain a conserved protein array representative of their parent cell. Exosomes may be reproducibly and noninvasively purified from nasal mucus. The exosomal proteome can be quantified using SOMAscan(TM) , a highly multiplexed, aptamer-based proteomic platform. The purpose of this study was to determine whether chronic rhinosinusitis with nasal polyps (CRSwNP) has a unique predictive exosomal proteomic biosignature. METHODS: Exosomes were isolated from whole mucus sampled from control and CRSwNP patients (n = 20 per group) by differential ultracentrifugation. The SOMAscan(TM) platform was used to simultaneously quantify 1310 biologically relevant human proteins. Matched tissue and whole mucus proteomes were also analyzed. Differential protein expression and discriminatory power were calculated using the unweighted pair group method with arithmetic-mean and principal component analysis, respectively. Bioinformatic analysis was performed using Ingenuity Pathway, MetaCore, and GeneMANIA analyses. RESULTS: The exosomal proteome demonstrated 123 significantly (p < 0.05) differentially regulated proteins in CRSwNP relative to control. Eighty of these proteins overlapped with the matched CRSwNP tissue proteome as compared with only 4 among matched whole mucus samples. Forty-three significantly dysregulated pathway networks overlapped between the exosomal and tissue proteome in CRSwNP as compared with only 3 among matched whole mucus samples. The best-performing protein set (cystatin-SN, peroxiredoxin-5, and glycoprotein VI) achieved an area under the curve (AUC) value of up to 99%. CONCLUSION: Our data contribute a significant advance in the development of a reproducible, noninvasive, serial, and quantitative liquid biopsy" for rhinosinusitis. The exosomal proteomic approach has revealed a unique biosignature associated with CRSwNP, which outperforms whole mucus sampling, and thus provides a method of noninvasive disease detection and proposes new potential therapeutic targets." | Mueller, Sarina K Nocera, Angela L Dillon, Simon T Gu, Xuesong Wendler, Olaf Otu, Hasan H Libermann, Towia A Bleier, Benjamin S eng Int Forum Allergy Rhinol. 2019 Feb;9(2):177-186. doi: 10.1002/alr.22226. Epub 2018 Nov 28.I | 11/30/2018 | |
| High-Throughput Identification of the Plasma Proteomic Signature of Inflammatory Bowel Disease | Di Narzo AF, et al. | 2019 | J Crohns Colitis | 13 | 4 | 462-471 | https://www.doi.org/10.1093/ecco-jcc/jjy190 | 30,445,421 | C-Reactive Protein/metabolism Case-Control Studies Colitis, Ulcerative/*blood/genetics/metabolism Crohn Disease/*blood/genetics/metabolism Databases, Genetic Humans Intestinal Mucosa/metabolism Proteome/genetics/*metabolism Proteomics/*methods RNA, Messenger/*blood/metabolism Severity of Illness Index *Transcriptome Proteomics differential expression analysis inflammatory bowel disease proteomic quantitative trait loci | BACKGROUND: The molecular aetiology of inflammatory bowel disease [IBD] and its two subtypes, ulcerative colitis [UC] and Crohn's disease [CD], have been carefully investigated at genome and transcriptome levels. Recent advances in high-throughput proteome quantification has enabled comprehensive large-scale plasma proteomics studies of IBD. METHODS: The study used two cohorts: [1] The CERTIFI-cohort: 42 samples from the CERTIFI trial of anti-TNFalpha-refractory CD patients; [2] the PROgECT-UNITI-HCs cohort: 46 UC samples of the PROgECT study, 84 CD samples of the UNITI I and UNITI II studies, and 72 healthy controls recruited in Mount Sinai Hospital, New York, USA. The plasma proteome for these two cohorts was quantified using high-throughput platforms. RESULTS: For the PROgECT-UNITI-HCs cohort, we measured a total of 1310 proteins. Of these, 493 proteins showed different plasma levels in IBD patients to the plasma levels in controls at 10% false discovery rate [FDR], among which 11 proteins had a fold change greater than 2. The proteins upregulated in IBD were associated with immunity functionality, whereas the proteins downregulated in IBD were associated with nutrition and metabolism. The proteomic profiles were very similar between UC and CD. In the CERTIFI cohort, 1014 proteins were measured, and it was found that the plasma protein level had little correlation with the blood or intestine transcriptomes. CONCLUSIONS: We report the largest proteomics study to date on IBD and controls. A large proportion of plasma proteins are altered in IBD, which provides insights into the disease aetiology and indicates a potential for biomarker discovery. | Di Narzo, Antonio F Brodmerkel, Carrie Telesco, Shannon E Argmann, Carmen Peters, Lauren A Li, Katherine Kidd, Brian Dudley, Joel Cho, Judy Schadt, Eric E Kasarskis, Andrew Dobrin, Radu Hao, Ke eng S10 OD018522/OD/NIH HHS/ U01 DK062422/DK/NIDDK NIH HHS/ U24 DK062429/DK/NIDDK NIH HHS/ England J Crohns Colitis. 2019 Mar 30;13(4):462-471. doi: 10.1093/ecco-jcc/jjy190.I | 11/18/2018 | |
| Exosome swarms eliminate airway pathogens and provide passive epithelial immunoprotection through nitric oxide | Nocera AL, et al. | 2019 | J Allergy Clin Immunol | 143 | 4 | 1525-1535 e1 | https://www.doi.org/10.1016/j.jaci.2018.08.046 | 30,442,371 | Exosomes/*immunology Humans Immunity, Innate/*immunology Nasal Mucosa/*immunology/metabolism Nitric Oxide/metabolism Nitric Oxide Synthase Type II/metabolism Pseudomonas Infections/immunology Cd81 Exosome epithelium innate immunity nitric oxide proteomics sinonasal mucus | BACKGROUND: Nasal mucosa-derived exosomes (NMDEs) harbor immunodefensive proteins and are capable of rapid interepithelial protein transfer. OBJECTIVES: We sought to determine whether mucosal exposure to inhaled pathogens stimulates a defensive swarm of microbiocidal exosomes, which also donate their antimicrobial cargo to adjacent epithelial cells. METHODS: We performed an institutional review board-approved study of healthy NMDE secretion after Toll-like receptor (TLR) 4 stimulation by LPS (12.5 mug/mL) in the presence of TLR4 inhibitors. Interepithelial transfer of exosomal nitric oxide (NO) synthase and nitric oxide was measured by using ELISAs and NO activity assays. Exosomal antimicrobial assays were performed with Pseudomonas aeruginosa. Proteomic analyses were performed by using SOMAscan. RESULTS: In vivo and in vitro LPS exposure induced a 2-fold increase in NMDE secretion along with a 2-fold increase in exosomal inducible nitric oxide synthase expression and function through TLR4 and inhibitor of nuclear factor kappaB kinase activation. LPS stimulation increased exosomal microbiocidal activity against P aeruginosa by almost 2 orders of magnitude. LPS-stimulated exosomes induced a 4-fold increase in NO production within autologous epithelial cells with protein transfer within 5 minutes of contact. Pathway analysis of the NMDE proteome revealed 44 additional proteins associated with NO signaling and innate immune function. CONCLUSIONS: We provide direct in vivo evidence for a novel exosome-mediated innate immunosurveillance and defense mechanism of the human upper airway. These findings have implications for lower airway innate immunity, delivery of airway therapeutics, and host microbiome regulation. | Nocera, Angela L Mueller, Sarina K Stephan, Jules R Hing, Loretta Seifert, Philip Han, Xue Lin, Derrick T Amiji, Mansoor M Libermann, Towia Bleier, Benjamin S eng P30 EY003790/EY/NEI NIH HHS/ Research Support, N.I.H., Extramural J Allergy Clin Immunol. 2019 Apr;143(4):1525-1535.e1. doi: 10.1016/j.jaci.2018.08.046. Epub 2018 Nov 12.I | 11/18/2018 | |
| Novel Application of Aptamer Proteomic Analysis in Cystic Fibrosis Bronchoalveolar Lavage Fluid | DeBoer EM, et al. | 2019 | Proteomics Clin Appl | 13 | 3 | e1800085 | https://www.doi.org/10.1002/prca.201800085 | 30,431,231 | Adolescent Aptamers, Nucleotide/*metabolism *Bronchoalveolar Lavage Fluid Case-Control Studies Child Child, Preschool Cystic Fibrosis/*metabolism Female Humans Infant Male Proteomics/*methods Young Adult Pseudomonas aeruginosa inflammation pediatrics | PURPOSE: Biomarkers are needed in cystic fibrosis (CF) to understand disease progression, assess response to therapy, and enrich enrollment for clinical trials. Aptamer-based proteomics have proven useful in blood samples. The aim is to evaluate proteins in bronchoalveolar lavage fluid (BALF) in CF children compared to controls and identify endotypes during CF exacerbations. EXPERIMENTAL DESIGN: BALF is collected clinically from 50 patients with CF and nine disease controls, processed, and stored per protocol. BALF supernatants are analyzed for 1129 proteins by aptamer approach (SOMAscan proteomics platform). Proteins are compared across groups and used for pathway analysis. Endotypes are identified within the CF group. RESULTS: CF BALF has increased concentrations of neutrophil elastase, myeloperoxidase, and decreased concentration of protein folding and host defense proteins. Pathways that distinguished CF subjects included interferon gamma signaling, membrane trafficking, and phospholipid metabolism. In the CF group, unbiased analysis of proteins identified two distinct endotypes that differed based on BALF white blood cell and neutrophil counts and detection of CF pathogens. CONCLUSIONS AND CLINICAL RELEVANCE: Proteomic analysis of the CF airway demonstrates a complex environment of proteins and pathways. This work provides evidence that aptamer-based proteomics can differentiate between groups and can determine endotypes within CF. | DeBoer, Emily M Wagner, Brandie D Popler, Jonathan Harris, Jonathan Kirk Zemanick, Edith T Accurso, Frank J Sagel, Scott D Deterding, Robin R eng UL1 TR001082/TR/NCATS NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Germany Proteomics Clin Appl. 2019 May;13(3):e1800085. doi: 10.1002/prca.201800085. Epub 2019 Jan 3.I | 11/16/2018 | |
| Beyond Autoantibodies: Biologic Roles of Human Autoreactive B Cells in Rheumatoid Arthritis Revealed by RNA-Sequencing | Mahendra A, et al. | 2019 | Arthritis Rheumatol | 71 | 4 | 529-541 | https://www.doi.org/10.1002/art.40772 | 30,407,753 | Arthritis, Rheumatoid/blood/*genetics/*immunology Autoantibodies/*genetics/immunology B-Lymphocytes/*immunology Cytokines/blood/immunology ErbB Receptors/blood/immunology Humans Leukocytes, Mononuclear/immunology Receptors, Interleukin-15/blood/immunology Sequence Analysis, RNA Signal Transduction/immunology Transcriptome/*immunology | OBJECTIVE: To obtain the comprehensive transcriptome profile of human citrulline-specific B cells from patients with rheumatoid arthritis (RA). METHODS: Citrulline- and hemagglutinin-specific B cells were sorted by flow cytometry using peptide-streptavidin conjugates from the peripheral blood of RA patients and healthy individuals. The transcriptome profile of the sorted cells was obtained by RNA-sequencing, and expression of key protein molecules was evaluated by aptamer-based SOMAscan assay and flow cytometry. The ability of these proteins to effect differentiation of osteoclasts and proliferation and migration of synoviocytes was examined by in vitro functional assays. RESULTS: Citrulline-specific B cells, in comparison to citrulline-negative B cells, from patients with RA differentially expressed the interleukin-15 receptor alpha (IL-15Ralpha) gene as well as genes related to protein citrullination and cyclic AMP signaling. In analyses of an independent cohort of cyclic citrullinated peptide-seropositive RA patients, the expression of IL-15Ralpha protein was enriched in citrulline-specific B cells from the patients' peripheral blood, and surprisingly, all B cells from RA patients were capable of producing the epidermal growth factor ligand amphiregulin (AREG). Production of AREG directly led to increased migration and proliferation of fibroblast-like synoviocytes, and, in combination with anti-citrullinated protein antibodies, led to the increased differentiation of osteoclasts. CONCLUSION: To the best of our knowledge, this is the first study to document the whole transcriptome profile of autoreactive B cells in any autoimmune disease. These data identify several genes and pathways that may be targeted by repurposing several US Food and Drug Administration-approved drugs, and could serve as the foundation for the comparative assessment of B cell profiles in other autoimmune diseases. | Mahendra, Ankit Yang, Xingyu Abnouf, Shaza Adolacion, Jay R T Park, Daechan Soomro, Sanam Roszik, Jason Coarfa, Cristian Romain, Gabrielle Wanzeck, Keith Bridges, S Louis Jr Aggarwal, Amita Qiu, Peng Agarwal, Sandeep K Mohan, Chandra Varadarajan, Navin eng RP130570/Cancer Prevention and Research Institute of Texas/International CA160591/ Department of Defense/International R01 CA174385/CA/NCI NIH HHS/ RP180466/Cancer Prevention and Research Institute of Texas/International E-1774/Welch Foundation/International 1705464/National Science Foundation/International 509800/Melanoma Research Alliance/International Evaluation Study Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. Arthritis Rheumatol. 2019 Apr;71(4):529-541. doi: 10.1002/art.40772. Epub 2019 Feb 23.I | 11/09/2018 | |
| The human placental proteome secreted into the maternal and fetal circulations in normal pregnancy based on 4-vessel sampling | Michelsen TM, et al. | 2019 | FASEB J | 33 | 2 | 2944-2956 | https://www.doi.org/10.1096/fj.201801193R | 30,335,547 | Adult Cohort Studies Female Fetal Development Fetus/*metabolism Humans *Maternal-Fetal Exchange Placenta/*metabolism Pregnancy Pregnancy Proteins/*metabolism Protein Interaction Maps Proteome/*analysis Specimen Handling/*methods placental physiology pregnancy proteins proteomics trophoblast | We sought to identify proteins secreted by the human placenta into the maternal and fetal circulations. Blood samples from the maternal radial artery and uterine vein and umbilical artery and vein were obtained during cesarean section in 35 healthy women with term pregnancy. Slow off-rate modified aptamer (SOMA) protein-binding technology was used to quantify 1310 known proteins. The uteroplacental and umbilical venoarterial concentration differences were calculated. Thirty-four proteins were significantly secreted by the placenta into the maternal circulation, including placental growth factor, growth/differentiation factor 15, and matrix metalloproteinase 12. There were 341 proteins significantly secreted by the placenta into the fetal circulation. Only 7 proteins were secreted into both the fetal and maternal circulations, suggesting a distinct directionality in placental protein release. We examined changes across gestation in the proteins found to be significantly secreted by the placenta into the maternal circulation using serial blood samples from healthy women. Among the 34 proteins secreted into the maternal circulation, 8 changed significantly across gestation. The identified profiles of secreted placental proteins will allow us to identify novel minimally invasive biomarkers for human placental function across gestation and discover previously unknown proteins secreted by the human placenta that regulate maternal physiology and fetal development.-Michelsen, T. M., Henriksen, T., Reinhold, D., Powell, T. L., Jansson, T. The human placental proteome secreted into the maternal and fetal circulations in normal pregnancy based on 4-vessel sampling. | Michelsen, Trond M Henriksen, Tore Reinhold, Dominik Powell, Theresa L Jansson, Thomas eng Research Support, Non-U.S. Gov't FASEB J. 2019 Feb;33(2):2944-2956. doi: 10.1096/fj.201801193R. Epub 2018 Oct 18.I | 10/20/2018 | |
| Assessing the Genetic Correlations Between Blood Plasma Proteins and Osteoporosis: A Polygenic Risk Score Analysis | Liang X, et al. | 2019 | Calcif Tissue Int | 104 | 2 | 171-181 | https://www.doi.org/10.1007/s00223-018-0483-4 | 30,306,195 | Absorptiometry, Photon Adult Aged Blood Proteins/analysis/*genetics Bone Density/*genetics Female Femur Neck/anatomy & histology/diagnostic imaging Genetic Predisposition to Disease/ethnology Genome-Wide Association Study Genotype Humans Male Middle Aged Multifactorial Inheritance/*genetics Organ Size Osteoporosis/blood/epidemiology/*genetics Polymorphism, Single Nucleotide Radius/anatomy & histology/diagnostic imaging Research Design Risk Factors Spine/anatomy & histology/diagnostic imaging Whites/genetics/statistics & numerical data Blood plasma proteins Osteoporosis Polygenic risk score analysis Miao Ding, Bolun Cheng, Shiqiang Cheng, Mei Ma, Lu Zhang, Hui Shen, Qing Tian, Xiong Guo, Feng Zhang, and Hong-Wen Deng declare that they have no conflicts of interest. | Osteoporosis is a common metabolic bone disease. The impact of global blood plasma proteins on the risk of osteoporosis remains elusive now. We performed a large-scale polygenic risk score (PRS) analysis to evaluate the potential effects of blood plasma proteins on the development of osteoporosis in 2286 Caucasians, including 558 males and 1728 females. Bone mineral density (BMD) and bone areas at ulna & radius, hip, and spine were measured using Hologic 4500W DXA. BMD/bone areas values were adjusted for age, sex, height, and weight as covariates. Genome-wide SNP genotyping of 2286 Caucasian subjects was performed using Affymetrix Human SNP Array 6.0. The 267 blood plasma proteins-associated SNP loci and their genetic effects were obtained from recently published genome-wide association study (GWAS) using a highly multiplexed aptamer-based affinity proteomics platform. The polygenetic risk score (PRS) of study subjects for each blood plasma protein was calculated from the genotypes data of the 2286 Caucasian subjects by PLINK software. Pearson correlation analysis of individual PRS values and BMD/bone area value was performed using R. Additionally, gender-specific analysis also was performed by Pearson correlation analysis. 267 blood plasma proteins were analyzed in this study. For BMD, we observed association signals between 41 proteins and BMD, mainly including whole body total BMD versus Factor H (p value = 9.00 x 10(-3)), whole body total BMD versus BGH3 (p value = 1.40 x 10(-2)), spine total BMD versus IGF-I (p value = 2.15 x 10(-2)), and spine total BMD versus SAP (p value = 3.90 x 10(-2)). As for bone areas, association evidence was observed between 45 blood plasma proteins and bone areas, such as ferritin versus spine area (p value = 1.90 x 10(-2)), C4 versus hip area (p value = 1.25 x 10(-2)), and hemoglobin versus right ulna and radius area (p value = 2.70 x 10(-2)). Our study results suggest the modest impact of blood plasma proteins on the variations of BMD/bone areas, and identify several candidate blood plasma proteins for osteoporosis. | Liang, Xiao Du, Yanan Wen, Yan Liu, Li Li, Ping Zhao, Yan Ding, Miao Cheng, Bolun Cheng, Shiqiang Ma, Mei Zhang, Lu Shen, Hui Tian, Qing Guo, Xiong Zhang, Feng Deng, Hong-Wen eng R01 MH118695/MH/NIMH NIH HHS/ R01 AR059781/AR/NIAMS NIH HHS/ R01 GM109068/GM/NIGMS NIH HHS/ R01 AR057049/AR/NIAMS NIH HHS/ U19 AG055373/AG/NIA NIH HHS/ P20 GM109036/GM/NIGMS NIH HHS/ R01 MH104680/MH/NIMH NIH HHS/ R01 MH107354/MH/NIMH NIH HHS/ R01 EB020407/EB/NIBIB NIH HHS/ R01 EB006841/EB/NIBIB NIH HHS/ R01 AR069055/AR/NIAMS NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Calcif Tissue Int. 2019 Feb;104(2):171-181. doi: 10.1007/s00223-018-0483-4. Epub 2018 Oct 10.I | 10/12/2018 | |
| A Framework for Multi-Omic Prediction of Treatment Response to Biologic Therapy for Psoriasis | Foulkes AC, et al. | 2019 | J Invest Dermatol | 139 | 1 | 100-107 | https://www.doi.org/10.1016/j.jid.2018.04.041 | 30,030,151 | Adult Biological Therapy/*methods Etanercept/*therapeutic use Female Follow-Up Studies *Gene Expression Regulation Humans Immunosuppressive Agents/therapeutic use Male Pilot Projects Prognosis Prospective Studies Psoriasis/*drug therapy/genetics/metabolism RNA, Messenger/*genetics Skin | Biologic therapies have shown high efficacy in psoriasis, but individual response varies and is poorly understood. To inform biomarker discovery in the Psoriasis Stratification to Optimise Relevant Therapy (i.e., PSORT) study, we evaluated a comprehensive array of omics platforms across three time points and multiple tissues in a pilot investigation of 10 patients with severe psoriasis, treated with the tumor necrosis factor (TNF) inhibitor, etanercept. We used RNA sequencing to analyze mRNA and small RNA transcriptome in blood, lesional and nonlesional skin, and the SOMAscan platform to investigate the serum proteome. Using an integrative systems biology approach, we identified signals of treatment response in genes and pathways associated with TNF signaling, psoriasis pathology, and the major histocompatibility complex region. We found association between clinical response and TNF-regulated genes in blood and skin. Using a combination of differential expression testing, upstream regulator analysis, clustering techniques, and predictive modeling, we show that baseline samples are indicative of patient response to biologic therapies, including signals in blood, which have traditionally been considered unreliable for inference in dermatology. In conclusion, our pilot study provides both an analytical framework and empirical basis to estimate power for larger studies, specifically the ongoing PSORT study, which we show as powered for biomarker discovery and patient stratification. | Foulkes, Amy C Watson, David S Carr, Daniel F Kenny, John G Slidel, Timothy Parslew, Richard Pirmohamed, Munir Anders, Simon Reynolds, Nick J Griffiths, Christopher E M Warren, Richard B Barnes, Michael R eng R13 AR009431/AR/NIAMS NIH HHS/ MR/1011808/1/MRC_/Medical Research Council/United Kingdom MR/L016311/1/MRC_/Medical Research Council/United Kingdom MR/N005872/1/MRC_/Medical Research Council/United Kingdom DH_/Department of Health/United Kingdom MR/L006758/1/MRC_/Medical Research Council/United Kingdom Observational Study Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't J Invest Dermatol. 2019 Jan;139(1):100-107. doi: 10.1016/j.jid.2018.04.041. Epub 2018 Jul 17.I | 07/22/2018 | |
| Balanced Event Prediction Through Sampled Survival Analysis | Datta G, et al. | 2019 | Systems Medicine | 2 | 1 | 28-38 | https://www.doi.org/10.1089/sysm.2018.0015 | Abstract Class imbalance can present a major issue in time-to-event analyses for instances where the number of individuals diagnosed with a disease are far outnumbered by those who remain undiagnosed within a specified time frame. An example of this is the incidence rate of myocardial infarction (MI) among patients with stable coronary heart disease, where MI events are typically sparse over the course of a study. This imbalance may result in inaccurate risk predictions for individuals who are more likely to be having an MI event. In this study, we combine sampling with the Cox proportional hazards model in a cross-validation framework to balance predictive performance. This approach leverages advantages provided by classification tools and the statistical power of survival models in examining time-to-event data. To demonstrate the effectiveness of this modeling approach, we use high-dimensional proteomic data (obtained using the SOMAScan? assay) to identify patients likely to experience an MI event within 4 years of a blood draw. In our data set, 8.1% of patients experienced an MI within 4 years, making this a severely class-imbalanced data set. Cox proportional hazards elastic net regression models were developed using sampling techniques, allowing us to identify and select features that more accurately identify individuals at higher risk of MI. The resulting Cox elastic net regression models created on the sampled data (both upsampled and downsampled) were superior to three other competing models: elastic net logistic regression and support vector machine models developed on downsampled data, and a Cox proportional hazards elastic net developed on the full data. These results, and additional simulation results, demonstrate the effectiveness of combining sampling with survival analysis techniques for improved predictive performance in a biomedical application. Class imbalance can present a major issue in time-to-event analyses for instances where the number of individuals diagnosed with a disease are far outnumbered by those who remain undiagnosed within a specified time frame. An example of this is the incidence rate of myocardial infarction (MI) among patients with stable coronary heart disease, where MI events are typically sparse over the course of a study. This imbalance may result in inaccurate risk predictions for individuals who are more likely to be having an MI event. In this study, we combine sampling with the Cox proportional hazards model in a cross-validation framework to balance predictive performance. This approach leverages advantages provided by classification tools and the statistical power of survival models in examining time-to-event data. To demonstrate the effectiveness of this modeling approach, we use high-dimensional proteomic data (obtained using the SOMAScan? assay) to identify patients likely to experience an MI event within 4 years of a blood draw. In our data set, 8.1% of patients experienced an MI within 4 years, making this a severely class-imbalanced data set. Cox proportional hazards elastic net regression models were developed using sampling techniques, allowing us to identify and select features that more accurately identify individuals at higher risk of MI. The resulting Cox elastic net regression models created on the sampled data (both upsampled and downsampled) were superior to three other competing models: elastic net logistic regression and support vector machine models developed on downsampled data, and a Cox proportional hazards elastic net developed on the full data. These results, and additional simulation results, demonstrate the effectiveness of combining sampling with survival analysis techniques for improved predictive performance in a biomedical application. | Datta, Gargi Alexander, Leigh E. Hinterberg, Michael A. Hagar, Yolanda | ||||
| Clinical Validation of a Protein Biomarker Panel for Non-Small Cell Lung Cancer | Jung YJ, et al. | 2018 | J Korean Med Sci | 33 | 53 | e342 | https://www.doi.org/10.3346/jkms.2018.33.e342 | 30,595,683 | Adult Aged Area Under Curve Biomarkers, Tumor/*blood Blood Proteins/*metabolism Carcinoma, Non-Small-Cell Lung/*diagnosis/pathology Female Humans Lung Neoplasms/*diagnosis/pathology Male Middle Aged Neoplasm Staging ROC Curve Republic of Korea Sensitivity and Specificity Smoking Aptamer Computed Tomography Lung Cancer Screening Lung Nodule conflict: Kim Y, Jung JH, and Seok M are employees of Aptamer Sciences Inc. Although the present study used AptoDetectTM-Lung, a product of Aptamer Sciences Inc., the 3 co-researchers did not involve study design and data analysis that made any biased influence. The whole study was free from conflicts of interest. These facts do not alter the authors' adherence to Journal Korean Medical Science policies on the sharing of data and material. Jung YJ, Oh IJ, Lee W, Park CK, Lim JH, Kim YC, Kim WS, and Choi CM have no conflict of interest to disclose. | We validated the diagnostic performance of a previously developed blood-based 7-protein biomarker panel, AptoDetect-Lung (Aptamer Sciences Inc., Pohang, Korea) using modified aptamer-based proteomic technology for lung cancer detection. Non-small cell lung cancer (NSCLC), 200 patients and benign nodule controls, 200 participants were enrolled. In a high-risk population corresponding to >/= 55 years of age and >/= 30 pack-years, the diagnostic performance was improved, showing 73.3% sensitivity and 90.5% specificity with an area under the curve of 0.88. AptoDetect-Lung (Aptamer Sciences Inc.) offers the best validated performance to discriminate NSCLC from benign nodule controls in a high-risk population and could play a complementary role in lung cancer screening. | Jung, Young Ju Oh, In-Jae Kim, Youndong Jung, Jong Ha Seok, Minkyoung Lee, Woochang Park, Cheol Kyu Lim, Jung-Hwan Kim, Young-Chul Kim, Woo-Sung Choi, Chang-Min eng Korea (South) J Korean Med Sci. 2018 Dec 13;33(53):e342. doi: 10.3346/jkms.2018.33.e342. eCollection 2018 Dec 31.I | 01/01/2019 | |
| Probing the Virtual Proteome to Identify Novel Disease Biomarkers | Mosley JD, et al. | 2018 | Circulation | 138 | 22 | 2469-2481 | https://www.doi.org/10.1161/CIRCULATIONAHA.118.036063 | 30,571,344 | Adult Aged Aged, 80 and over Biomarkers/*blood Carotid Artery Diseases/*diagnosis/genetics Female *Genome-Wide Association Study Genotype Humans Lectins, C-Type/analysis Male Middle Aged Odds Ratio Phenotype Polymorphism, Single Nucleotide Proteome/*analysis Proteomics Receptor, Platelet-Derived Growth Factor beta/blood atherosclerosis biomarkers electronic health records | BACKGROUND: Proteomic approaches allow measurement of thousands of proteins in a single specimen, which can accelerate biomarker discovery. However, applying these technologies to massive biobanks is not currently feasible because of the practical barriers and costs of implementing such assays at scale. To overcome these challenges, we used a virtual proteomic" approach, linking genetically predicted protein levels to clinical diagnoses in >40 000 individuals. METHODS: We used genome-wide association data from the Framingham Heart Study (n=759) to construct genetic predictors for 1129 plasma protein levels. We validated the genetic predictors for 268 proteins and used them to compute predicted protein levels in 41 288 genotyped individuals in the Electronic Medical Records and Genomics (eMERGE) cohort. We tested associations for each predicted protein with 1128 clinical phenotypes. Lead associations were validated with directly measured protein levels and either low-density lipoprotein cholesterol or subclinical atherosclerosis in the MDCS (Malmo Diet and Cancer Study; n=651). RESULTS: In the virtual proteomic analysis in eMERGE, 55 proteins were associated with 89 distinct diagnoses at a false discovery rate q<0.1. Among these, 13 associations involved lipid (n=7) or atherosclerosis (n=6) phenotypes. We tested each association for validation in MDCS using directly measured protein levels. At Bonferroni-adjusted significance thresholds, levels of apolipoprotein E isoforms were associated with hyperlipidemia, and circulating C-type lectin domain family 1 member B and platelet-derived growth factor receptor-beta predicted subclinical atherosclerosis. Odds ratios for carotid atherosclerosis were 1.31 (95% CI, 1.08-1.58; P=0.006) per 1-SD increment in C-type lectin domain family 1 member B and 0.79 (0.66-0.94; P=0.008) per 1-SD increment in platelet-derived growth factor receptor-beta. CONCLUSIONS: We demonstrate a biomarker discovery paradigm to identify candidate biomarkers of cardiovascular and other diseases." | Mosley, Jonathan D Benson, Mark D Smith, J Gustav Melander, Olle Ngo, Debby Shaffer, Christian M Ferguson, Jane F Herzig, Matthew S McCarty, Catherine A Chute, Christopher G Jarvik, Gail P Gordon, Adam S Palmer, Melody R Crosslin, David R Larson, Eric B Carrell, David S Kullo, Iftikhar J Pacheco, Jennifer A Peissig, Peggy L Brilliant, Murray H Kitchner, Terrie E Linneman, James G Namjou, Bahram Williams, Marc S Ritchie, Marylyn D Borthwick, Kenneth M Kiryluk, Krzysztof Mentch, Frank D Sleiman, Patrick M Karlson, Elizabeth W Verma, Shefali S Zhu, Yineng Vasan, Ramachandran S Yang, Qiong Denny, Josh C Roden, Dan M Gerszten, Robert E Wang, Thomas J eng U01 HG006385/HG/NHGRI NIH HHS/ UL1 TR000445/TR/NCATS NIH HHS/ U01 HG008657/HG/NHGRI NIH HHS/ U01 HG006382/HG/NHGRI NIH HHS/ R01 LM010685/LM/NLM NIH HHS/ S10 RR025141/RR/NCRR NIH HHS/ U01 HG006389/HG/NHGRI NIH HHS/ T32 HL007208/HL/NHLBI NIH HHS/ U01 HG006828/HG/NHGRI NIH HHS/ 16FTF30130005/AHA/American Heart Association-American Stroke Association/ U01 HG008685/HG/NHGRI NIH HHS/ U01 HG006379/HG/NHGRI NIH HHS/ U01 HG006830/HG/NHGRI NIH HHS/ P30 EY008126/EY/NEI NIH HHS/ U01 HG006380/HG/NHGRI NIH HHS/ R01 HL132320/HL/NHLBI NIH HHS/ P50 GM115305/GM/NIGMS NIH HHS/ P30 CA068485/CA/NCI NIH HHS/ R01 HL133870/HL/NHLBI NIH HHS/ U01 HG006388/HG/NHGRI NIH HHS/ U01 HG006378/HG/NHGRI NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Circulation. 2018 Nov 27;138(22):2469-2481. doi: 10.1161/CIRCULATIONAHA.118.036063.I | 12/21/2018 | |
| Proteomic analysis of heart failure hospitalization among patients with chronic kidney disease: The Heart and Soul Study | Dubin RF, et al. | 2018 | PLoS One | 13 | 12 | e0208042 | https://www.doi.org/10.1371/journal.pone.0208042 | 30,557,359 | Aged Aged, 80 and over Angiopoietin-2/blood Biomarkers/blood Extracellular Matrix Proteins/blood Female Glomerular Filtration Rate Heart Failure/blood/*diagnosis/etiology/therapy Hospitalization/statistics & numerical data Humans Male Middle Aged Prognosis Proteomics Receptor, Notch1/blood Renal Insufficiency, Chronic/blood/*complications Risk Assessment Tartrate-Resistant Acid Phosphatase/blood | BACKGROUND: Patients with chronic kidney disease (CKD) are at increased risk for heart failure (HF). We aimed to investigate differences in proteins associated with HF hospitalizations among patients with and without CKD in the Heart and Soul Study. METHODS AND RESULTS: We measured 1068 unique plasma proteins from baseline samples of 974 participants in The Heart and Soul Study who were followed for HF hospitalization over a median of 7 years. We sequentially applied forest regression and Cox survival analyses to select prognostic proteins. Among participants with CKD, four proteins were associated with HF at Bonferroni-level significance (p<2.5x10(-4)): Angiopoietin-2 (HR[95%CI] 1.45[1.33, 1.59]), Spondin-1 (HR[95%CI] 1.13 [1.06, 1.20]), tartrate-resistant acid phosphatase type 5 (HR[95%CI] 0.65[0.53, 0.78]) and neurogenis locus notch homolog protein 1 (NOTCH1) (HR[95%CI] 0.67[0.55, 0.80]). These associations persisted at p<0.01 after adjustment for age, estimated glomerular filtration and history of HF. CKD was a significant interaction term in the associations of NOTCH1 and Spondin-1 with HF. Pathway analysis showed a trend for higher representation of the Cardiac Hypertrophy and Complement/Coagulation pathways among proteins prognostic of HF in the CKD sub-group. CONCLUSIONS: These results suggest that markers of heart failure differ between patients with and without CKD. Further research is needed to validate novel markers in cohorts of patients with CKD and adjudicated HF events. | Dubin, Ruth F Whooley, Mary Pico, Alexander Ganz, Peter Schiller, Nelson B Meyer, Craig eng R01 HL079235/HL/NHLBI NIH HHS/ U01 DK108809/DK/NIDDK NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't PLoS One. 2018 Dec 17;13(12):e0208042. doi: 10.1371/journal.pone.0208042. eCollection 2018.I | 12/18/2018 | |
| No Plasmatic Proteomic Signature at Clinical Disease Onset Associated With 11 Year Clinical, Cognitive and MRI Outcomes in Relapsing-Remitting Multiple Sclerosis Patients | Bridel C, et al. | 2018 | Front Mol Neurosci | 11 | 371 | https://www.doi.org/10.3389/fnmol.2018.00371 | 30,429,773 | Mri cognition multiple sclerosis prognosis proteomics | Background: The clinical course of relapsing-remitting multiple sclerosis (RRMS) is highly heterogeneous and prognostic biomarkers at time of diagnosis are lacking. Objective: We investigated the predictive value of the plasma proteome at time of diagnosis in RRMS patients. Methods: The plasma proteome was interrogated using a novel aptamer-based proteomics platform, which allows to measure the levels of a predefined set of 1310 proteins. Results: In 67 clinically and radiologically well characterized RRMS patients, we found no association between the plasma proteome at diagnosis and clinical, cognitive or MRI outcomes after 11 years. Conclusions: Proteomics studies on cerebrospinal fluid may be better suited to identify prognostic biomarkers in early RRMS. | Bridel, Claire Eijlers, Anand J C van Wieringen, Wessel N Koel-Simmelink, Marleen Leurs, Cyra E Schoonheim, Menno M Killestein, Joep Teunissen, Charlotte E eng Switzerland Front Mol Neurosci. 2018 Oct 31;11:371. doi: 10.3389/fnmol.2018.00371. eCollection 2018.I | 11/16/2018 | ||
| Serum biomarkers of glucocorticoid response and safety in anti-neutrophil cytoplasmic antibody-associated vasculitis and juvenile dermatomyositis | Conklin LS, et al. | 2018 | Steroids | 140 | 159-166 | https://www.doi.org/10.1016/j.steroids.2018.10.008 | 30,352,204 | Adolescent Adult Aged Aged, 80 and over Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis/*blood/*drug therapy Biomarkers/blood Child Child, Preschool Dermatomyositis/*blood/*drug therapy Female Glucocorticoids/*adverse effects/*pharmacology/therapeutic use Humans Male Middle Aged Proteomics *Safety Treatment Outcome Young Adult Anti-inflammatory Biomarker Glucocorticoids Juvenile dermatomyositis Vasculitis BioPharma. KN, and EPH are co-founders of ReveraGen and own founder shares. LSC, JMD, JvdA own stock options of ReveraGen. | Glucocorticoids are standard of care for many chronic inflammatory conditions, including juvenile dermatomyositis (JDM) and anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). We sought to define pharmacodynamic biomarkers of therapeutic efficacy and safety concerns of glucocorticoid treatment for these two disorders. Previous proteomic profiling of patients with Duchenne muscular dystrophy (DMD) and inflammatory bowel disease (IBD) treated with glucocorticoids identified candidate biomarkers for efficacy and safety concerns of glucocorticoids. Serial serum samples from patients with AAV (n_=_30) and JDM (n_=_12) were obtained during active disease, and after treatment with glucocorticoids. For AAV, 8 of 11 biomarkers of the anti-inflammatory response to glucocorticoids were validated (P-value | Conklin, Laurie S Merkel, Peter A Pachman, Lauren M Parikh, Hemang Tawalbeh, Shefa Damsker, Jesse M Cuthbertson, David D Morgan, Gabrielle A Monach, Paul A Hathout, Yetrib Nagaraju, Kanneboyina van den Anker, John McAlear, Carol A Hoffman, Eric P eng K26 OD011171/OD/NIH HHS/ U54 RR019497/RR/NCRR NIH HHS/ R56 NS097229/NS/NINDS NIH HHS/ U54 HD090254/HD/NICHD NIH HHS/ P30 AR072579/AR/NIAMS NIH HHS/ P50 HD090254/HD/NICHD NIH HHS/ R43 AR073547/AR/NIAMS NIH HHS/ U54 AR057319/AR/NIAMS NIH HHS/ R43 AR073541/AR/NIAMS NIH HHS/ R21 AI128248/AI/NIAID NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. Steroids. 2018 Dec;140:159-166. doi: 10.1016/j.steroids.2018.10.008. Epub 2018 Oct 21.I | 10/24/2018 | ||
| Aptamer-based proteomics of serum and plasma in acquired aplastic anemia | Giudice V, et al. | 2018 | Exp Hematol | 68 | 38-50 | https://www.doi.org/10.1016/j.exphem.2018.09.008 | 30,312,735 | Adolescent Adult Aged Anemia, Aplastic/*blood/diagnosis/drug therapy/immunology Aptamers, Nucleotide/*metabolism Benzoates/therapeutic use Biomarkers Blood Proteins/*analysis Child Child, Preschool Female Humans Hydrazines/therapeutic use Immunosuppressive Agents/therapeutic use Male Middle Aged Molecular Targeted Therapy Proteomics/*methods Pyrazoles/therapeutic use Receptors, Thrombopoietin/antagonists & inhibitors Young Adult | Single-stranded oligonucleotides containing deoxyuridine are aptamers (SOMAmers) that can bind proteins with high specificity and affinity and slow dissociation rates. SOMAscan, an aptamer-based proteomic technology, allows measurement of more than 1,300 proteins simultaneously for the identification of new disease biomarkers. The aim of the present study was to identify new serum and plasma protein markers for diagnosis of acquired aplastic anemia (AA) and response to immunosuppressive therapies (IST). SOMAscan was used to screen 1,141 serum proteins in 28 AA patients before and after therapy and 1,317 plasma proteins in seven SAA patients treated with standard IST and a thrombopoietin receptor agonist. From our analysis, 19 serum and 28 plasma proteins were identified as possible candidate diagnostic and prognostic markers. A custom immunobead-based multiplex assay with five selected serum proteins (BMP-10, CCL17, DKK1, HGF, and SELL) was used for validation in a verification set (n_=_65) of samples obtained before and after IST and in a blinded validation cohort at baseline (n_=_16). After technical validation, four biomarkers were employed to predict diagnosis (accuracy, 88%) and long-term response to IST (accuracy, 79%). In conclusion, SOMAscan is a powerful tool for the identification of new biomarkers. We propose further larger studies to validate new candidate serum and plasma diagnostic and prognostic markers of AA. | Giudice, Valentina Biancotto, Angelique Wu, Zhijie Cheung, Foo Candia, Julian Fantoni, Giovanna Kajigaya, Sachiko Rios, Olga Townsley, Danielle Feng, Xingmin Young, Neal S eng Z01 HL002315-21/Intramural NIH HHS/ Z01 HL002315-22/Intramural NIH HHS/ Z01 HL002315-23/Intramural NIH HHS/ Evaluation Study Research Support, N.I.H., Intramural Netherlands Exp Hematol. 2018 Dec;68:38-50. doi: 10.1016/j.exphem.2018.09.008. Epub 2018 Oct 9.I | 10/13/2018 | ||
| Validation of a Novel Modified Aptamer-Based Array Proteomic Platform in Patients with End-Stage Renal Disease | Han Z, et al. | 2018 | Diagnostics (Basel) | 8 | 4 | https://www.doi.org/10.3390/diagnostics8040071 | 30,297,602 | SOMAscan biomarker end-stage renal disease validation | End stage renal disease (ESRD) is characterized by complex metabolic abnormalities, yet the clinical relevance of specific biomarkers remains unclear. The development of multiplex diagnostic platforms is creating opportunities to develop novel diagnostic and therapeutic approaches. SOMAscan is an innovative multiplex proteomic platform which can measure >1300 proteins. In the present study, we performed SOMAscan analysis of plasma samples and validated the measurements by comparison with selected biomarkers. We compared concentrations of SOMAscan-measured prostate specific antigen (PSA) between males and females, and validated SOMAscan concentrations of fibroblast growth factor 23 (FGF23), FGF receptor 1 (FGFR1), and FGFR4 using Enzyme-Linked immunosorbent assay (ELISA). The median (25th and 75th percentile) SOMAscan PSA level in males and females was 4304.7 (1815.4 to 7259.5) and 547.8 (521.8 to 993.4) relative fluorescence units (p = 0.002), respectively, suggesting biological plausibility. Pearson correlation between SOMAscan and ELISA was high for FGF23 (R = 0.95, p < 0.001) and FGFR4 (R = 0.69, p < 0.001), indicating significant positive correlation, while a weak correlation was found for FGFR1 (R = 0.13, p = 0.16). In conclusion, there is a good to near-perfect correlation between SOMAscan and standard immunoassays for FGF23 and FGFR4, but not for FGFR1. This technology may be useful to simultaneously measure a large number of plasma proteins in ESRD, and identify clinically important prognostic markers to predict outcomes. | Han, Zhongji Xiao, Zhousheng Kalantar-Zadeh, Kamyar Moradi, Hamid Shafi, Tariq Waikar, Sushrut S Quarles, L Darryl Yu, Zhi Tin, Adrienne Coresh, Josef Kovesdy, Csaba P eng IK2 CX001043/CX/CSRD VA/ Switzerland Diagnostics (Basel). 2018 Oct 8;8(4):71. doi: 10.3390/diagnostics8040071.I | 10/10/2018 | ||
| Increased levels of circulating MMP3 correlate with severe rejection in face transplantation | Kollar B, et al. | 2018 | Sci Rep | 8 | 1 | 14915 | https://www.doi.org/10.1038/s41598-018-33272-7 | 30,297,859 | Acute Disease Adult Biomarkers/blood Biopsy Cluster Analysis Facial Transplantation/*adverse effects Female Graft Rejection/*blood Humans Male Matrix Metalloproteinase 3/*blood Middle Aged Reproducibility of Results Up-Regulation | Face transplantation is a viable treatment option for carefully selected patients with devastating injuries to the face. However, acute rejection episodes occur in more than 80% of recipients in the first postoperative year. Unfortunately, neither a correlation between histological grades of rejection and anti-rejection treatment nor systemic surrogate markers of rejection in face transplantation are established in clinical routine. Therefore, we utilized next generation aptamer-based SOMAscan proteomics platform for non-invasive rejection biomarker discovery. Longitudinal serum samples from face transplant recipients with long-term follow-up were included in this study. From the 1,310 proteins analyzed by SOMAscan, a 5-protein signature (MMP3, ACY1, IL1R2, SERPINA4, CPB2) was able to discriminate severe rejection from both no-rejection and nonsevere rejection samples. Technical validation on ELISA platform showed high correlation with the SOMAscan data for the MMP3 protein (r(s) = 0.99). Additionally, MMP3 levels were significantly increased during severe rejection as compared to no-rejection (p = 0.0009) and nonsevere rejection (p = 0.0173) episodes. Pathway analyses revealed significant activation of the metallopeptidase activity during severe face transplant rejection. This pilot study demonstrates the feasibility of SOMAscan to identify non-invasive candidate biomarkers of rejection in face transplantation. Further validation in a larger independent patient cohort is needed. | Kollar, Branislav Shubin, Andrey Borges, Thiago J Tasigiorgos, Sotirios Win, Thet Su Lian, Christine G Dillon, Simon T Gu, Xuesong Wyrobnik, Iris Murphy, George F Pomahac, Bohdan Libermann, Towia A Riella, Leonardo V eng P30 CA006516/CA/NCI NIH HHS/ Research Support, N.I.H., Extramural Research Support, U.S. Gov't, Non-P.H.S. England Sci Rep. 2018 Oct 8;8(1):14915. doi: 10.1038/s41598-018-33272-7.I | 10/10/2018 | |
| Aptamer-based search for correlates of plasma and serum water T(2): implications for early metabolic dysregulation and metabolic syndrome | Patel V, et al. | 2018 | Biomark Res | 6 | 28 | https://www.doi.org/10.1186/s40364-018-0143-x | 30,237,882 | Classification and regression tree analysis Glucokinase regulatory protein Hepatocyte growth factor Insulin resistance Metabolic syndrome Nuclear magnetic resonance relaxometry Random forests Receptor tyrosine kinase FLT3 SOMAscan aptamer assay Transverse relaxation time constant of the University of North Texas Health Science Center, Fort Worth (Protocol 2013-205). All enrolled subjects gave prior consent to participate by signing an IRB-approved consent form, after being made aware of benefits and risks of participation.Not applicable.The University of North Texas Health Science Center, Fort Worth has pending patent applications for the use of plasma and serum water T2 for metabolic health screening, with D.P.C as an inventor.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | BACKGROUND: Metabolic syndrome is a cluster of abnormalities that increases the risk for type 2 diabetes and atherosclerosis. Plasma and serum water T(2) from benchtop nuclear magnetic resonance relaxometry are early, global and practical biomarkers for metabolic syndrome and its underlying abnormalities. In a prior study, water T(2) was analyzed against ~ 130 strategically selected proteins and metabolites to identify associations with insulin resistance, inflammation and dyslipidemia. In the current study, the analysis was broadened ten-fold using a modified aptamer (SOMAmer) library, enabling an unbiased search for new proteins correlated with water T(2) and thus, metabolic health. METHODS: Water T(2) measurements were recorded using fasting plasma and serum from non-diabetic human subjects. In parallel, plasma samples were analyzed using a SOMAscan assay that employed modified DNA aptamers to determine the relative concentrations of 1310 proteins. A multi-step statistical analysis was performed to identify the biomarkers most predictive of water T(2). The steps included Spearman rank correlation, followed by principal components analysis with variable clustering, random forests for biomarker selection, and regression trees for biomarker ranking. RESULTS: The multi-step analysis unveiled five new proteins most predictive of water T(2): hepatocyte growth factor, receptor tyrosine kinase FLT3, bone sialoprotein 2, glucokinase regulatory protein and endothelial cell-specific molecule 1. Three of the five strongest predictors of water T(2) have been previously implicated in cardiometabolic diseases. Hepatocyte growth factor has been associated with incident type 2 diabetes, and endothelial cell specific molecule 1, with atherosclerosis in subjects with diabetes. Glucokinase regulatory protein plays a critical role in hepatic glucose uptake and metabolism and is a drug target for type 2 diabetes. By contrast, receptor tyrosine kinase FLT3 and bone sialoprotein 2 have not been previously associated with metabolic conditions. In addition to the five most predictive biomarkers, the analysis unveiled other strong correlates of water T(2) that would not have been identified in a hypothesis-driven biomarker search. CONCLUSIONS: The identification of new proteins associated with water T(2) demonstrates the value of this approach to biomarker discovery. It provides new insights into the metabolic significance of water T(2) and the pathophysiology of metabolic syndrome. | Patel, Vipulkumar Dwivedi, Alok K Deodhar, Sneha Mishra, Ina Cistola, David P eng England Biomark Res. 2018 Sep 17;6:28. doi: 10.1186/s40364-018-0143-x. eCollection 2018.I | 09/22/2018 | ||
| Habitual aerobic exercise and circulating proteomic patterns in healthy adults: relation to indicators of healthspan | Santos-Parker JR, et al. | 2018 | J Appl Physiol (1985) | 125 | 5 | 1646-1659 | https://www.doi.org/10.1152/japplphysiol.00458.2018 | 30,236,049 | Adult Aged Aging/*blood Biomarkers Exercise/*physiology Female Healthy Aging/*blood Humans Male Middle Aged *Proteome Young Adult SomaLogic blood pressure inflammation weighted correlation network analysis | Habitual aerobic exercise enhances physiological function and reduces risk of morbidity and mortality throughout life, but the underlying molecular mechanisms are largely unknown. The circulating proteome reflects the intricate network of physiological processes maintaining homeostasis and may provide insight into the molecular transducers of the health benefits of physical activity. In this exploratory study, we assessed the plasma proteome (SOMAscan proteomic assay; 1,129 proteins) of healthy sedentary or aerobic exercise-trained young women and young and older men ( n = 47). Using weighted correlation network analysis to identify clusters of highly co-expressed proteins, we characterized 10 distinct plasma proteomic modules (patterns). In healthy young (24 +/- 1 yr) men and women, 4 modules were associated with aerobic exercise status and 1 with participant sex. In healthy young and older (64 +/- 2 yr) men, 5 modules differed with age, but 2 of these were partially preserved at young adult levels in older men who exercised; among all men, 4 modules were associated with exercise status, including 3 of the 4 identified in young adults. Exercise-linked proteomic patterns were related to pathways involved in wound healing, regulation of apoptosis, glucose-insulin and cellular stress signaling, and inflammation/immune responses. Importantly, several of the exercise-related modules were associated with physiological and clinical indicators of healthspan, including diastolic blood pressure, insulin resistance, maximal aerobic capacity, and vascular endothelial function. Overall, these findings provide initial insight into circulating proteomic patterns modulated by habitual aerobic exercise in healthy young and older adults, the biological processes involved, and their relation to indicators of healthspan. NEW & NOTEWORTHY This is the first study to assess the relation between plasma proteomic patterns and aerobic exercise status in healthy adults. Weighted correlation network analysis identified 10 distinct proteomic modules, including 5 patterns specific for exercise status. Additionally, 5 modules differed with aging in men, two of which were preserved in older exercising men. Exercise-associated modules included proteins related to inflammation, stress pathways, and immune function and correlated with clinical and physiological indicators of healthspan. | Santos-Parker, Jessica R Santos-Parker, Keli S McQueen, Matthew B Martens, Christopher R Seals, Douglas R eng R37 AG013038/AG/NIA NIH HHS/ UL1 TR001082/TR/NCATS NIH HHS/ T32 AG000279/AG/NIA NIH HHS/ Comparative Study Research Support, N.I.H., Extramural J Appl Physiol (1985). 2018 Nov 1;125(5):1646-1659. doi: 10.1152/japplphysiol.00458.2018. Epub 2018 Sep 20.I | 09/22/2018 | |
| Phase IIa trial in Duchenne muscular dystrophy shows vamorolone is a first-in-class dissociative steroidal anti-inflammatory drug | Conklin LS, et al. | 2018 | Pharmacol Res | 136 | 140-150 | https://www.doi.org/10.1016/j.phrs.2018.09.007 | 30,219,580 | Administration, Oral Anti-Inflammatory Agents/blood/*pharmacology/*therapeutic use Biomarkers/blood Blood Glucose/analysis Child Child, Preschool Humans Hydrocortisone/blood Insulin/blood Male Muscular Dystrophy, Duchenne/*drug therapy/metabolism Pregnadienediols/blood/*pharmacology/*therapeutic use | We report a first-in-patient study of vamorolone, a first-in-class dissociative steroidal anti-inflammatory drug, in Duchenne muscular dystrophy. This 2-week, open-label Phase IIa multiple ascending dose study (0.25, 0.75, 2.0, and 6.0 mg/kg/day) enrolled 48 boys with Duchenne muscular dystrophy (4 to <7 years), with outcomes including clinical safety, pharmacokinetics and pharmacodynamic biomarkers. The study design included pharmacodynamic biomarkers in three contexts of use: 1. Secondary outcomes for pharmacodynamic safety (insulin resistance, adrenal suppression, bone turnover); 2. Exploratory outcomes for drug mechanism of action; 3. Exploratory outcomes for expanded pharmacodynamic safety. Vamorolone was safe and well-tolerated through the highest dose tested (6.0 mg/kg/day) and pharmacokinetics of vamorolone were similar to prednisolone. Using pharmacodynamic biomarkers, the study demonstrated improved safety of vamorolone versus glucocorticoids as shown by reduction of insulin resistance, beneficial changes in bone turnover (loss of increased bone resorption and decreased bone formation only at the highest dose level), and a reduction in adrenal suppression. Exploratory biomarkers of pharmacodynamic efficacy showed an anti-inflammatory mechanism of action and a beneficial effect on plasma membrane stability, as demonstrated by a dose-responsive decrease in serum creatine kinase activity. With an array of pre-selected biomarkers in multiple contexts of use, we demonstrate the development of the first dissociative steroid that preserves anti-inflammatory efficacy and decreases steroid-associated safety concerns. Ongoing extension studies offer the potential to bridge exploratory efficacy biomarkers to clinical outcomes. | Conklin, Laurie S Damsker, Jesse M Hoffman, Eric P Jusko, William J Mavroudis, Panteleimon D Schwartz, Benjamin D Mengle-Gaw, Laurel J Smith, Edward C Mah, Jean K Guglieri, Michela Nevo, Yoram Kuntz, Nancy McDonald, Craig M Tulinius, Mar Ryan, Monique M Webster, Richard Castro, Diana Finkel, Richard S Smith, Andrea L Morgenroth, Lauren P Arrieta, Adrienne Shimony, Maya Jaros, Mark Shale, Phil McCall, John M Hathout, Yetrib Nagaraju, Kanneboyina van den Anker, John Ward, Leanne M Ahmet, Alexandra Cornish, Michaelyn R Clemens, Paula R eng R44 NS095423/NS/NINDS NIH HHS/ U34 AR068616/AR/NIAMS NIH HHS/ U54 HD090257/HD/NICHD NIH HHS/ U54 HD090254/HD/NICHD NIH HHS/ P50 HD090254/HD/NICHD NIH HHS/ Clinical Trial, Phase II Multicenter Study Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. Netherlands Pharmacol Res. 2018 Oct;136:140-150. doi: 10.1016/j.phrs.2018.09.007. Epub 2018 Sep 13.I | 09/17/2018 | ||
| Scanning" into the Future: The Promise of SOMAScan Technology for Kidney Disease" | Coca SG | 2018 | Kidney Int Rep | 3 | 5 | 1020-1022 | https://www.doi.org/10.1016/j.ekir.2018.06.009 | 30,197,965 | Coca, Steven G eng R01 HL085757/HL/NHLBI NIH HHS/ U01 DK106962/DK/NIDDK NIH HHS/ R01 DK096549/DK/NIDDK NIH HHS/ U01 DK082185/DK/NIDDK NIH HHS/ R01 DK112258/DK/NIDDK NIH HHS/ Editorial Kidney Int Rep. 2018 Jun 30;3(5):1020-1022. doi: 10.1016/j.ekir.2018.06.009. eCollection 2018 Sep.I | 09/11/2018 | |||
| Aptamer-Based Proteomics Identifies Mortality-Associated Serum Biomarkers in Dialysis-Dependent AKI Patients | Yu LR, et al. | 2018 | Kidney Int Rep | 3 | 5 | 1202-1213 | https://www.doi.org/10.1016/j.ekir.2018.04.012 | 30,197,987 | acute kidney injury aptamers biomarkers | INTRODUCTION: Currently, no effective therapies exist to reduce the high mortality associated with dialysis-dependent acute kidney injury (AKI-D). Serum biomarkers may be useful in understanding the pathophysiological processes involved with AKI and the severity of injury, and point to novel therapeutic targets. METHODS: Study day 1 serum samples from 100 patients and day 8 samples from 107 patients enrolled in the Veteran's Affairs/National Institutes of Health Acute Renal Failure Trial Network study were analyzed by the slow off-rate modified aptamers scan proteomic platform to profile 1305 proteins in each sample. Patients in each cohort were classified into tertiles based on baseline biomarker measurements. Cox regression analyses were performed to examine the relationships between serum levels of each biomarker and mortality. RESULTS: Changes in the serum levels of 54 proteins, 33 of which increased and 21 of which decreased, were detected when comparing samples of patients who died in the first 8 days versus patients who survived >8 days. Among the 33 proteins that increased, higher serum levels of fibroblast growth factor-23 (FGF23), tissue plasminogen activator (tPA), neutrophil collagenase (matrix metalloproteinase-8), and soluble urokinase plasminogen activator receptor, when stratified by tertiles, were associated with higher mortality. The association with mortality persisted for each of these proteins after adjusting for other potential risk factors, including age, sex, cardiovascular sequential organ failure assessment score, congestive heart failure, and presence of diabetes. Upper tertile levels of FGF23, tPA, and interleukin-6 on day 8 were associated with increased mortality; however, FGF23 barely lost significance after multivariable adjustment. CONCLUSIONS: Our results underscore an emerging proteomics tool capable of identifying low-abundance serum proteins important not only in the pathogenesis of AKI-D, but which is also helpful in discriminating AKI-D patients with high mortality. | Yu, Li-Rong Sun, Jinchun Daniels, Jaclyn R Cao, Zhijun Schnackenberg, Laura Choudhury, Devasmita Palevsky, Paul M Ma, Jennie Z Beger, Richard D Portilla, Didier eng R01 DK075976/DK/NIDDK NIH HHS/ Y01 DK003508/DK/NIDDK NIH HHS/ Kidney Int Rep. 2018 May 3;3(5):1202-1213. doi: 10.1016/j.ekir.2018.04.012. eCollection 2018 Sep.I | 09/11/2018 | |
| Improving probes for super-resolution | Moore RP, et al. | 2018 | Nat Methods | 15 | 9 | 659-660 | https://www.doi.org/10.1038/s41592-018-0120-1 | 30,171,240 | *DNA Microscopy, Fluorescence *Oligonucleotides | Moore, Regan P Legant, Wesley R eng Comment Nat Methods. 2018 Sep;15(9):659-660. doi: 10.1038/s41592-018-0120-1.I | 09/02/2018 | ||
| A proteomic signature that reflects pancreatic beta-cell function | Curran AM, et al. | 2018 | PLoS One | 13 | 8 | e0202727 | https://www.doi.org/10.1371/journal.pone.0202727 | 30,161,145 | Adult Area Under Curve Body Mass Index Calcineurin/metabolism Cell Line Female Glucose Tolerance Test Humans Insulin Secretion/drug effects Insulin-Secreting Cells/cytology/*metabolism Interleukin-17/genetics/metabolism/pharmacology Linear Models Male Metabolic Networks and Pathways Proteome/*metabolism *Proteomics ROC Curve Young Adult beta-Endorphin/metabolism | AIM: Proteomics has the potential to enhance early identification of beta-cell dysfunction, in conjunction with monitoring the various stages of type 2 diabetes onset. The most routine method of assessing pancreatic beta-cell function is an oral glucose tolerance test, however this method is time consuming and carries a participant burden. The objectives of this research were to identify protein signatures and pathways related to pancreatic beta-cell function in fasting blood samples. METHODS: Beta-cell function measures were calculated for MECHE study participants who completed an oral glucose tolerance test and had proteomic data (n = 100). Information on 1,129 protein levels was obtained using the SOMAscan assay. Receiver operating characteristic curves were used to assess discriminatory ability of proteins of interest. Subsequent in vitro experiments were performed using the BRIN-BD11 pancreatic beta-cell line. Replication of findings were achieved in a second human cohort where possible. RESULTS: Twenty-two proteins measured by aptamer technology were significantly associated with beta-cell function/HOMA-IR while 17 proteins were significantly associated with the disposition index (p | Curran, Aoife M Scott-Boyer, Marie Pier Kaput, Jim Ryan, Miriam F Drummond, Elaine Gibney, Eileen R Gibney, Michael J Roche, Helen M Brennan, Lorraine eng Research Support, Non-U.S. Gov't PLoS One. 2018 Aug 30;13(8):e0202727. doi: 10.1371/journal.pone.0202727. eCollection 2018.I | 08/31/2018 | |
| Classification of prostate cancer using a protease activity nanosensor library | Dudani JS, et al. | 2018 | Proc Natl Acad Sci U S A | 115 | 36 | 8954-8959 | https://www.doi.org/10.1073/pnas.1805337115 | 30,126,988 | Animals *Biomarkers, Tumor/biosynthesis/genetics *Gene Expression Profiling *Gene Library Heterografts Humans Male Mice Mice, Nude Neoplasm Transplantation *Neoplasms, Experimental/classification/genetics/metabolism *Prostatic Neoplasms/classification/genetics/metabolism activity-based nanosensors diagnostic biomarkers prognostic biomarkers prostate cancer proteolytic enzymes patent application related to this work. A.D.W. is currently an employee of Glympse Bio. S.N.B. is a shareholder of and consultant to Glympse Bio. | Improved biomarkers are needed for prostate cancer, as the current gold standards have poor predictive value. Tests for circulating prostate-specific antigen (PSA) levels are susceptible to various noncancer comorbidities in the prostate and do not provide prognostic information, whereas physical biopsies are invasive, must be performed repeatedly, and only sample a fraction of the prostate. Injectable biosensors may provide a new paradigm for prostate cancer biomarkers by querying the status of the prostate via a noninvasive readout. Proteases are an important class of enzymes that play a role in every hallmark of cancer; their activities could be leveraged as biomarkers. We identified a panel of prostate cancer proteases through transcriptomic and proteomic analysis. Using this panel, we developed a nanosensor library that measures protease activity in vitro using fluorescence and in vivo using urinary readouts. In xenograft mouse models, we applied this nanosensor library to classify aggressive prostate cancer and to select predictive substrates. Last, we coformulated a subset of nanosensors with integrin-targeting ligands to increase sensitivity. These targeted nanosensors robustly classified prostate cancer aggressiveness and outperformed PSA. This activity-based nanosensor library could be useful throughout clinical management of prostate cancer, with both diagnostic and prognostic utility. | Dudani, Jaideep S Ibrahim, Maria Kirkpatrick, Jesse Warren, Andrew D Bhatia, Sangeeta N eng P30 CA014051/CA/NCI NIH HHS/ P30 ES002109/ES/NIEHS NIH HHS/ HHMI/Howard Hughes Medical Institute/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. Proc Natl Acad Sci U S A. 2018 Sep 4;115(36):8954-8959. doi: 10.1073/pnas.1805337115. Epub 2018 Aug 20.I | 08/22/2018 | |
| Modified aptamers enable quantitative sub-10-nm cellular DNA-PAINT imaging | Strauss S, et al. | 2018 | Nat Methods | 15 | 9 | 685-688 | https://www.doi.org/10.1038/s41592-018-0105-0 | 30,127,504 | Aptamers, Nucleotide/*chemistry Green Fluorescent Proteins/chemistry Limit of Detection Microscopy, Fluorescence/methods | Although current implementations of super-resolution microscopy are technically approaching true molecular-scale resolution, this has not translated to imaging of biological specimens, because of the large size of conventional affinity reagents. Here we introduce slow off-rate modified aptamers (SOMAmers) as small and specific labeling reagents for use with DNA points accumulation in nanoscale topography (DNA-PAINT). To demonstrate the achievable resolution, specificity, and multiplexing capability of SOMAmers, we labeled and imaged both transmembrane and intracellular targets in fixed and live cells. | Strauss, Sebastian Nickels, Philipp C Strauss, Maximilian T Jimenez Sabinina, Vilma Ellenberg, Jan Carter, Jeffrey D Gupta, Shashi Janjic, Nebojsa Jungmann, Ralf eng 680241/ERC_/European Research Council/International Research Support, Non-U.S. Gov't Nat Methods. 2018 Sep;15(9):685-688. doi: 10.1038/s41592-018-0105-0. Epub 2018 Aug 20.I | 08/22/2018 | |
| Serum biomarker for diagnostic evaluation of pulmonary arterial hypertension in systemic sclerosis | Rice LM, et al. | 2018 | Arthritis Res Ther | 20 | 1 | 185 | https://www.doi.org/10.1186/s13075-018-1679-8 | 30,115,106 | Aged Aged, 80 and over Biomarkers/*blood Early Diagnosis Female Follistatin-Related Proteins/*blood Humans Hypertension, Pulmonary/blood/*diagnosis/*etiology Male Middle Aged Midkine/*blood Scleroderma, Systemic/blood/*complications Sensitivity and Specificity Biomarkers Classification Proteomic Pulmonary arterial hypertension Scleroderma tissue and serum samples were enrolled with signed informed written consent by the institutional review board of Boston University. CONSENT FOR PUBLICATION: The manuscript does not contain any individual person's data in any form. COMPETING INTERESTS: The authors declare that they have no competing interests. PUBLISHER'S NOTE: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | BACKGROUND: Systemic sclerosis-associated pulmonary arterial hypertension (SSc-PAH) is one of the leading causes of death in SSc. Identification of a serum-based proteomic diagnostic biomarker for SSc-PAH would allow for rapid non-invasive screening and could positively impact patient survival. Identification and validation of novel proteins could potentially facilitate the identification of SSc-PAH, and might also point to important protein mediators in pathogenesis. METHODS: Thirteen treatment-naive SSc-PAH patients had serum collected at time of diagnosis and were used as the discovery cohort for the protein-expression biomarker. Two proteins, Midkine and Follistatin-like 3 (FSTL3) were then validated by enzyme-linked immunosorbent assays. Midkine and FSTL3 were tested in combination to identify SSc-PAH and were validated in two independent cohorts of SSc-PAH (n = 23, n = 11). RESULTS: Eighty-two proteins were found to be differentially regulated in SSc-PAH sera. Two proteins (Midkine and FSTL3) were also shown to be elevated in publicly available data and their expression was evaluated in independent cohorts. In the validation cohorts, the combination of Midkine and FSTL3 had an area under the receiver operating characteristic curve (AUC) of 0.85 and 0.92 with respective corresponding measures of sensitivity of 76% and 91%, and specificity measures of 76% and 80%. CONCLUSIONS: These findings indicate that there is a clear delineation between overall protein expression in sera from SSc patients and those with SSc-PAH. The combination of Midkine and FSTL3 can serve as an SSc-PAH biomarker and are potential drug targets for this rare disease population. | Rice, Lisa M Mantero, Julio C Stratton, Eric A Warburton, Rod Roberts, Kari Hill, Nicholas Simms, Robert W Domsic, Robyn Farber, Harrison W Layfatis, Robert eng R01 AR051089/AR/NIAMS NIH HHS/ P50 AR060780/AR/NIAMS NIH HHS/ P30 AR061271/AR/NIAMS NIH HHS/ Research Support, N.I.H., Extramural England Arthritis Res Ther. 2018 Aug 16;20(1):185. doi: 10.1186/s13075-018-1679-8.I | 08/18/2018 | |
| Genome-wide mapping of plasma protein QTLs identifies putatively causal genes and pathways for cardiovascular disease | Yao C, et al. | 2018 | Nat Commun | 9 | 1 | 3268 | https://www.doi.org/10.1038/s41467-018-05512-x | 30,111,768 | Adult Blood Proteins/*genetics Cardiovascular Diseases/*genetics/metabolism Chromosome Mapping Female Gene Expression Profiling Genetic Predisposition to Disease/*genetics *Genome-Wide Association Study Humans Male Middle Aged Polymorphism, Single Nucleotide Quantitative Trait Loci/*genetics Risk Factors Signal Transduction/genetics | Identifying genetic variants associated with circulating protein concentrations (protein quantitative trait loci; pQTLs) and integrating them with variants from genome-wide association studies (GWAS) may illuminate the proteome's causal role in disease and bridge a knowledge gap regarding SNP-disease associations. We provide the results of GWAS of 71 high-value cardiovascular disease proteins in 6861 Framingham Heart Study participants and independent external replication. We report the mapping of over 16,000 pQTL variants and their functional relevance. We provide an integrated plasma protein-QTL database. Thirteen proteins harbor pQTL variants that match coronary disease-risk variants from GWAS or test causal for coronary disease by Mendelian randomization. Eight of these proteins predict new-onset cardiovascular disease events in Framingham participants. We demonstrate that identifying pQTLs, integrating them with GWAS results, employing Mendelian randomization, and prospectively testing protein-trait associations holds potential for elucidating causal genes, proteins, and pathways for cardiovascular disease and may identify targets for its prevention and treatment. | Yao, Chen Chen, George Song, Ci Keefe, Joshua Mendelson, Michael Huan, Tianxiao Sun, Benjamin B Laser, Annika Maranville, Joseph C Wu, Hongsheng Ho, Jennifer E Courchesne, Paul Lyass, Asya Larson, Martin G Gieger, Christian Graumann, Johannes Johnson, Andrew D Danesh, John Runz, Heiko Hwang, Shih-Jen Liu, Chunyu Butterworth, Adam S Suhre, Karsten Levy, Daniel eng G0800270/MRC_/Medical Research Council/United Kingdom RG/13/13/30194/BHF_/British Heart Foundation/United Kingdom MR/L003120/1/MRC_/Medical Research Council/United Kingdom 268834/ERC_/European Research Council/International K99 HL136875/HL/NHLBI NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't England Nat Commun. 2018 Aug 15;9(1):3268. doi: 10.1038/s41467-018-05512-x.I | 08/17/2018 | |
| Proteomics: Clinical and research applications in respiratory diseases | Norman KC, et al. | 2018 | Respirology | 23 | 11 | 993-1003 | https://www.doi.org/10.1111/resp.13383 | 30,105,802 | *Biomedical Research/methods/trends Epigenesis, Genetic Humans Inventions Protein Processing, Post-Translational *Proteomics/methods/trends *Respiratory Tract Diseases/genetics/metabolism/physiopathology application clinical lung disease proteomics research | The proteome is the study of the protein content of a definable component of an organism in biology. However, the tissue-specific expression of proteins and the varied post-translational modifications, splice variants and protein-protein complexes that may form, make the study of protein a challenging yet vital tool in answering many of the unanswered questions in medicine and biology to date. Indeed, the spatial, temporal and functional composition of proteins in the human body has proven difficult to elucidate for many years. Given the effect of microRNA and epigenetic regulation on silencing and enhancing gene transcription, the study of protein arguably provides more accurate information on homeostasis and perturbation in health and disease. There have been significant advances in the field of proteomics in recent years, with new technologies and platforms available to the research community. In this review, we briefly discuss some of these new technologies and developments in the context of respiratory disease. We also discuss the types of data science approaches to analyses and interpretation of the large volumes of data generated in proteomic studies. We discuss the application of these technologies with regard to respiratory disease and highlight the potential for proteomics in generating major advances in the understanding of respiratory pathophysiology into the future. | Norman, Katy C Moore, Bethany B Arnold, Kelly B O'Dwyer, David N eng K99 HL139996/HL/NHLBI NIH HHS/ HL127805/GF/NIH HHS/ AI117229/GF/NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Review Australia Respirology. 2018 Nov;23(11):993-1003. doi: 10.1111/resp.13383. Epub 2018 Aug 13.I | 08/15/2018 | |
| Highly multiplexed proteomic analysis reveals significant tissue and exosomal coagulation pathway derangement in chronic rhinosinusitis with nasal polyps | Mueller SK, et al. | 2018 | Int Forum Allergy Rhinol | 8 | 12 | 1438-1444 | https://www.doi.org/10.1002/alr.22189 | 30,091,854 | Adult Blood Coagulation Blood Coagulation Disorders/*metabolism Chronic Disease Exosomes/*metabolism Female Fibrinogen/metabolism Fibronectins/metabolism Humans Male Middle Aged Mucus Nasal Polyps/*metabolism Proteomics Rhinitis/diagnosis/*metabolism Sinusitis/diagnosis/*metabolism Up-Regulation von Willebrand Factor/metabolism biomarker chronic rhinosinusitis microarray nasal polyps sinusitis | BACKGROUND: The coagulation pathway has been previously implicated in the etiopathogenesis of chronic rhinosinusitis with nasal polyps (CRSwNP) through analysis of individual proteins within the cascade. The purpose of this study was to: (1) apply a large-scale proteomic approach to confirm these previous findings; and (2) correlate the protein aberrations between tissue and exosomes to establish exosomal proteomics as a method to probe the pathophysiology of CRSwNP. METHODS: This investigation was an internal review board-approved study in which matched tissue and mucus exosomal proteomes were compared between control and CRSwNP (n = 10/group) using an aptamer-based proteomic array and confirmed using whole transcriptome sequencing. Protein expression and the correlation between samples were calculated using Student's t-test and Benjamini-Hochberg procedures followed by the application of Ingenuity Pathway and MetaCore bioinformatics analyses. RESULTS: Among all protein pathways, the coagulation cascade was the most significantly associated with CRSwNP (p = 2.85e-8). Among the 13 significantly altered coagulation-related tissue proteins, fibronectin and fibrinogen gamma chains were the most overexpressed in CRSwNP relative to control (fold change [FC], 2.59; p = 0.006; and FC, 2.38; p < 0.001, respectively), whereas von Willebrand factor was the most underexpressed (FC, -3.06; p < 0.001). The exosomal fibrinolysis and coagulation pathway proteomes exhibited strong inverse and significant correlations with the tissue findings (r = -0.86; p = 0.013; and r = -0.79; p = 0.007, respectively). CONCLUSION: Our proteomic analysis confirmed that the coagulation pathway is highly significantly deranged within nasal polyp tissue. The correlation between tissue- and mucus-derived exosomal fibrinolysis and coagulation protein alterations were strong, inverse, and highly significant. This lends further support to the emerging concept of exosomal proteomic analysis as a method to study chronic sinonasal inflammation. | Mueller, Sarina K Nocera, Angela L Dillon, Simon T Wu, Dawei Libermann, Towia A Bleier, Benjamin S eng Int Forum Allergy Rhinol. 2018 Dec;8(12):1438-1444. doi: 10.1002/alr.22189. Epub 2018 Aug 9.I | 08/10/2018 | |
| Cytokines IL-17, TNF and IFN-gamma Alter the Expression of Antimicrobial Peptides and Proteins Disparately: A Targeted Proteomics Analysis using SOMAscan Technology | Altieri A, et al. | 2018 | Vaccines (Basel) | 6 | 3 | https://www.doi.org/10.3390/vaccines6030051 | 30,087,279 | Host defence peptides antimicrobial peptides bronchial epithelial cells cytokines inflammation | Antimicrobial peptides, also known as host defence peptides, are immunomodulatory molecules required to resolve infections. Antimicrobial peptides and proteins (APPs) are important in the control of infections in the lungs. Despite evidence that APPs exhibit a wide range of immune functions and modulate inflammation, the effect of inflammatory cytokines on the expression of APPs is not completely defined. In this study, we profiled the expression of 39 different APPs in human bronchial epithelial cells (HBEC) using Slow Off-rate Modified Aptamer (SOMAmer)-based protein array, in the presence and absence of three different inflammatory cytokines (IL-17, TNF and IFN-gamma). Expression of 13 different APPs was altered in response to IL-17, TNF or IFN-gamma. Independent validations of selected proteins from the proteomics screen i.e., those that were significantly enhanced by >2-fold change (p < 0.01) using western blots conclusively demonstrated that inflammatory cytokines alter the expression of APPs differentially. For example, the abundance of cathepsin S was enhanced by only IFN-gamma, whereas lipocalin-2 was increased by IL-17 alone. Abundance of elafin increased in presence of IL-17 or TNF, but decreased in response to IFN-gamma. Whereas the abundance of cathepsin V decreased following stimulation with IL-17, TNF and IFN-gamma. The results of this study demonstrate that inflammatory cytokines alter the expression of APPs disparately. This suggests that the composition of the inflammatory cytokine milieu may influence APPs abundance and thus alter the processes required for infection control and regulation of inflammation in the lungs. | Altieri, Anthony Piyadasa, Hadeesha Recksiedler, Breann Spicer, Victor Mookherjee, Neeloffer eng Switzerland Vaccines (Basel). 2018 Aug 7;6(3):51. doi: 10.3390/vaccines6030051.I | 08/09/2018 | ||
| Co-regulatory networks of human serum proteins link genetics to disease | Emilsson V, et al. | 2018 | Science | 361 | 6,404 | 769-773 | https://www.doi.org/10.1126/science.aaq1327 | 30,072,576 | Aptamers, Nucleotide Blood Proteins/*analysis/*genetics Cardiovascular Diseases/*genetics Genetic Predisposition to Disease Genetic Variation Humans Iceland Metabolic Diseases/*genetics Metabolic Networks and Pathways Proteome/*analysis/*genetics Proteomics/*methods | Proteins circulating in the blood are critical for age-related disease processes; however, the serum proteome has remained largely unexplored. To this end, 4137 proteins covering most predicted extracellular proteins were measured in the serum of 5457 Icelanders over 65 years of age. Pairwise correlation between proteins as they varied across individuals revealed 27 different network modules of serum proteins, many of which were associated with cardiovascular and metabolic disease states, as well as overall survival. The protein modules were controlled by cis- and trans-acting genetic variants, which in many cases were also associated with complex disease. This revealed co-regulated groups of circulating proteins that incorporated regulatory control between tissues and demonstrated close relationships to past, current, and future disease states. | Emilsson, Valur Ilkov, Marjan Lamb, John R Finkel, Nancy Gudmundsson, Elias F Pitts, Rebecca Hoover, Heather Gudmundsdottir, Valborg Horman, Shane R Aspelund, Thor Shu, Le Trifonov, Vladimir Sigurdsson, Sigurdur Manolescu, Andrei Zhu, Jun Olafsson, Orn Jakobsdottir, Johanna Lesley, Scott A To, Jeremy Zhang, Jia Harris, Tamara B Launer, Lenore J Zhang, Bin Eiriksdottir, Gudny Yang, Xia Orth, Anthony P Jennings, Lori L Gudnason, Vilmundur eng N01AG12100/AG/NIA NIH HHS/ R01 DK104363/DK/NIDDK NIH HHS/ HHSN271201200022C/DA/NIDA NIH HHS/ Z99 AG999999/ImNIH/Intramural NIH HHS/ Z01 AG007380-02/ImNIH/Intramural NIH HHS/ Research Support, N.I.H., Intramural Research Support, Non-U.S. Gov't Science. 2018 Aug 24;361(6404):769-773. doi: 10.1126/science.aaq1327. Epub 2018 Aug 2.I | 08/04/2018 | |
| Multi-omics monitoring of drug response in rheumatoid arthritis in pursuit of molecular remission | Tasaki S, et al. | 2018 | Nat Commun | 9 | 1 | 2755 | https://www.doi.org/10.1038/s41467-018-05044-4 | 30,013,029 | Antibodies, Monoclonal, Humanized/therapeutic use Antirheumatic Agents/*therapeutic use Arthritis, Rheumatoid/*drug therapy/genetics/immunology/pathology Biomarkers, Pharmacological/blood Blood Proteins/*genetics/immunology Case-Control Studies Cell Count Gene Expression Regulation Humans Infliximab/therapeutic use Lymphocytes/drug effects/immunology/pathology Methotrexate/*therapeutic use Monocytes/drug effects/immunology/pathology Neutrophils/drug effects/immunology/pathology Proteomics/methods Remission Induction Severity of Illness Index *Transcriptome Treatment Outcome | Sustained clinical remission (CR) without drug treatment has not been achieved in patients with rheumatoid arthritis (RA). This implies a substantial difference between CR and the healthy state, but it has yet to be quantified. We report a longitudinal monitoring of the drug response at multi-omics levels in the peripheral blood of patients with RA. Our data reveal that drug treatments alter the molecular profile closer to that of HCs at the transcriptome, serum proteome, and immunophenotype level. Patient follow-up suggests that the molecular profile after drug treatments is associated with long-term stable CR. In addition, we identify molecular signatures that are resistant to drug treatments. These signatures are associated with RA independently of known disease severity indexes and are largely explained by the imbalance of neutrophils, monocytes, and lymphocytes. This high-dimensional phenotyping provides a quantitative measure of molecular remission and illustrates a multi-omics approach to understanding drug response. | Tasaki, Shinya Suzuki, Katsuya Kassai, Yoshiaki Takeshita, Masaru Murota, Atsuko Kondo, Yasushi Ando, Tatsuya Nakayama, Yusuke Okuzono, Yuumi Takiguchi, Maiko Kurisu, Rina Miyazaki, Takahiro Yoshimoto, Keiko Yasuoka, Hidekata Yamaoka, Kunihiro Morita, Rimpei Yoshimura, Akihiko Toyoshiba, Hiroyoshi Takeuchi, Tsutomu eng England Nat Commun. 2018 Jul 16;9(1):2755. doi: 10.1038/s41467-018-05044-4.I | 07/18/2018 | |
| Endothelial Microparticles and Systemic Complement Activation in Patients With Chronic Kidney Disease | Jalal D, et al. | 2018 | J Am Heart Assoc | 7 | 14 | https://www.doi.org/10.1161/JAHA.117.007818 | 30,006,493 | Adult Aged Brachial Artery/diagnostic imaging/physiopathology Case-Control Studies Cell-Derived Microparticles/*metabolism Complement Activation Complement C4a/metabolism Complement C5a/metabolism Complement Factor B/*metabolism Complement Factor D/*metabolism Complement Membrane Attack Complex/metabolism *Complement Pathway, Alternative Complement System Proteins/metabolism Endothelial Cells Endothelium, Vascular/*physiopathology Female Glomerular Filtration Rate Humans Kidney Transplantation Male Middle Aged Pilot Projects Proteomics Renal Insufficiency, Chronic/*metabolism/physiopathology/surgery Severity of Illness Index Vasodilation Microparticles complement activation chronic kidney disease | BACKGROUND: Endothelial microparticles are associated with chronic kidney disease (CKD) and complement activation. We hypothesized that the complement pathway is activated in patients with CKD via endothelial microparticles and that complement activation correlates with endothelial dysfunction in CKD. METHODS AND RESULTS: We analyzed complement data of 30 healthy subjects, 30 patients with stage III/IV CKD, and 30 renal transplant recipients with stage III/IV CKD, evaluating the potential correlation of complement fragments with brachial artery flow-mediated dilation, Chronic Kidney Disease Epidemiology Collaboration glomerular filtration rate, and urinary albumin/creatinine ratio. Endothelial microparticles were characterized via proteomic analysis and compared between study groups. Complement fragment Ba was significantly increased in CKD and post-kidney transplant CKD. Plasma Ba levels correlated significantly with lower brachial artery flow-mediated dilation, lower Chronic Kidney Disease Epidemiology Collaboration glomerular filtration rate, and higher urinary albumin/creatinine ratio. Factor D levels were significantly higher in the plasma microparticles of patients with CKD versus healthy controls. Plasma microparticles isolated from patients with CKD and containing factor D activated the alternative pathway in vitro. CONCLUSION: The alternative complement pathway is activated in CKD and correlates with endothelial dysfunction and markers of CKD. Future studies are needed to evaluate whether endothelial microparticles with increased factor D play a pathologic role in CKD-associated vascular disease. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02230202. | Jalal, Diana Renner, Brandon Laskowski, Jennifer Stites, Erik Cooper, James Valente, Karissa You, Zhiying Perrenoud, Loni Le Quintrec, Moglie Muhamed, Ismaeel Christians, Uwe Klawitter, Jelena Lindorfer, Margaret A Taylor, Ronald P Holers, V Michael Thurman, Joshua M eng R01 DK076690/DK/NIDDK NIH HHS/ R01 DK113586/DK/NIDDK NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't England J Am Heart Assoc. 2018 Jul 13;7(14):e007818. doi: 10.1161/JAHA.117.007818.I | 07/15/2018 | ||
| Plasma proteomic signature of age in healthy humans | Tanaka T, et al. | 2018 | Aging Cell | 17 | 5 | e12799 | https://www.doi.org/10.1111/acel.12799 | 29,992,704 | Adult Aged Aged, 80 and over Aging/*blood Female *Health Humans Male Middle Aged Molecular Sequence Annotation *Proteomics Reproducibility of Results Young Adult *aging *aptamers *healthy aging *humans *plasma | To characterize the proteomic signature of chronological age, 1,301 proteins were measured in plasma using the SOMAscan assay (SomaLogic, Boulder, CO, USA) in a population of 240 healthy men and women, 22-93 years old, who were disease- and treatment-free and had no physical and cognitive impairment. Using a p | Tanaka, Toshiko Biancotto, Angelique Moaddel, Ruin Moore, Ann Zenobia Gonzalez-Freire, Marta Aon, Miguel A Candia, Julian Zhang, Pingbo Cheung, Foo Fantoni, Giovanna Semba, Richard D Ferrucci, Luigi eng England Aging Cell. 2018 Oct;17(5):e12799. doi: 10.1111/acel.12799. Epub 2018 Jul 11.I | 07/12/2018 | |
| Genomic atlas of the human plasma proteome | Sun BB, et al. | 2018 | Nature | 558 | 7,708 | 73-79 | https://www.doi.org/10.1038/s41586-018-0175-2 | 29,875,488 | Blood Proteins/*genetics Female *Genomics Hepatocyte Growth Factor/genetics Humans Inflammatory Bowel Diseases/genetics Male Mutation, Missense/genetics Myeloblastin/genetics Positive Regulatory Domain I-Binding Factor 1/genetics Proteome/*genetics Proto-Oncogene Proteins/genetics Quantitative Trait Loci/genetics Vasculitis/genetics alpha 1-Antitrypsin/genetics | Although plasma proteins have important roles in biological processes and are the direct targets of many drugs, the genetic factors that control inter-individual variation in plasma protein levels are not well understood. Here we characterize the genetic architecture of the human plasma proteome in healthy blood donors from the INTERVAL study. We identify 1,927 genetic associations with 1,478 proteins, a fourfold increase on existing knowledge, including trans associations for 1,104 proteins. To understand the consequences of perturbations in plasma protein levels, we apply an integrated approach that links genetic variation with biological pathway, disease, and drug databases. We show that protein quantitative trait loci overlap with gene expression quantitative trait loci, as well as with disease-associated loci, and find evidence that protein biomarkers have causal roles in disease using Mendelian randomization analysis. By linking genetic factors to diseases via specific proteins, our analyses highlight potential therapeutic targets, opportunities for matching existing drugs with new disease indications, and potential safety concerns for drugs under development. | Sun, Benjamin B Maranville, Joseph C Peters, James E Stacey, David Staley, James R Blackshaw, James Burgess, Stephen Jiang, Tao Paige, Ellie Surendran, Praveen Oliver-Williams, Clare Kamat, Mihir A Prins, Bram P Wilcox, Sheri K Zimmerman, Erik S Chi, An Bansal, Narinder Spain, Sarah L Wood, Angela M Morrell, Nicholas W Bradley, John R Janjic, Nebojsa Roberts, David J Ouwehand, Willem H Todd, John A Soranzo, Nicole Suhre, Karsten Paul, Dirk S Fox, Caroline S Plenge, Robert M Danesh, John Runz, Heiko Butterworth, Adam S eng MR/L003120/1/MRC_/Medical Research Council/United Kingdom RG/13/13/30194/BHF_/British Heart Foundation/United Kingdom MR/S004068/1/MRC_/Medical Research Council/United Kingdom MR/S003746/1/MRC_/Medical Research Council/United Kingdom SP/12/12/29836/BHF_/British Heart Foundation/United Kingdom MC_UU_00002/7/MRC_/Medical Research Council/United Kingdom 1508647/MRC_/Medical Research Council/United Kingdom 204623/Z/16/Z/WT_/Wellcome Trust/United Kingdom RG/16/4/32218/BHF_/British Heart Foundation/United Kingdom MR/P013880/1/MRC_/Medical Research Council/United Kingdom England Nature. 2018 Jun;558(7708):73-79. doi: 10.1038/s41586-018-0175-2. Epub 2018 Jun 6.I | 06/08/2018 | |
| Benefit of Apabetalone on Plasma Proteins in Renal Disease | Wasiak S, et al. | 2018 | Kidney Int Rep | 3 | 3 | 711-721 | https://www.doi.org/10.1016/j.ekir.2017.12.001 | 29,854,980 | bromodomain cardiovascular disease chronic kidney disease epigenetics inflammation proteomics | INTRODUCTION: Apabetalone, a small molecule inhibitor, targets epigenetic readers termed BET proteins that contribute to gene dysregulation in human disorders. Apabetalone has in vitro and in vivo anti-inflammatory and antiatherosclerotic properties. In phase 2 clinical trials, this drug reduced the incidence of major adverse cardiac events in patients with cardiovascular disease. Chronic kidney disease is associated with a progressive loss of renal function and a high risk of cardiovascular disease. We studied the impact of apabetalone on the plasma proteome in patients with impaired kidney function. METHODS: Subjects with stage 4 or 5 chronic kidney disease and matched controls received a single dose of apabetalone. Plasma was collected for pharmacokinetic analysis and for proteomics profiling using the SOMAscan 1.3k platform. Proteomics data were analyzed with Ingenuity Pathway Analysis to identify dysregulated pathways in diseased patients, which were targeted by apabetalone. RESULTS: At baseline, 169 plasma proteins (adjusted P value <0.05) were differentially enriched in renally impaired patients versus control subjects, including cystatin C and beta(2) microglobulin, which correlate with renal function. Bioinformatics analysis of the plasma proteome revealed a significant activation of 42 pathways that control immunity and inflammation, oxidative stress, endothelial dysfunction, vascular calcification, and coagulation. At 12 hours postdose, apabetalone countered the activation of pathways associated with renal disease and reduced the abundance of disease markers, including interleukin-6, plasminogen activator inhibitor-1, and osteopontin. CONCLUSION: These data demonstrated plasma proteome dysregulation in renally impaired patients and the beneficial impact of apabetalone on pathways linked to chronic kidney disease and its cardiovascular complications. | Wasiak, Sylwia Tsujikawa, Laura M Halliday, Christopher Stotz, Stephanie C Gilham, Dean Jahagirdar, Ravi Kalantar-Zadeh, Kamyar Robson, Richard Sweeney, Michael Johansson, Jan O Wong, Norman C Kulikowski, Ewelina eng Kidney Int Rep. 2017 Dec 8;3(3):711-721. doi: 10.1016/j.ekir.2017.12.001. eCollection 2018 May.I | 06/02/2018 | |
| Stability and reproducibility of proteomic profiles measured with an aptamer-based platform | Kim CH, et al. | 2018 | Sci Rep | 8 | 1 | 8382 | https://www.doi.org/10.1038/s41598-018-26640-w | 29,849,057 | Adult Aging/metabolism Aptamers, Nucleotide/*metabolism Body Mass Index Fasting Female Humans Male Proteomics/*methods Reproducibility of Results | The feasibility of SOMAscan, a multiplex, high sensitivity proteomics platform, for use in studies using archived plasma samples has not yet been assessed. We quantified 1,305 proteins from plasma samples donated by 16 Nurses' Health Study (NHS) participants, 40 NHSII participants, and 12 local volunteers. We assessed assay reproducibility using coefficients of variation (CV) from duplicate samples and intra-class correlation coefficients (ICC) and Spearman correlation coefficients (r) of samples processed (i.e., centrifuged and aliquoted into separate components) immediately, 24, and 48 hours after collection, as well as those of samples collected from the same individuals 1 year apart. CVs were <20% for 99% of proteins overall and <10% for 92% of proteins in heparin samples compared to 66% for EDTA samples. We observed ICC or Spearman r (comparing immediate vs. 24-hour delayed processing) >/=0.75 for 61% of proteins, with some variation by anticoagulant (56% for heparin and 70% for EDTA) and protein class (ranging from 49% among kinases to 83% among hormones). Within-person stability over 1 year was good (ICC or Spearman r >/= 0.4) for 91% of proteins. These results demonstrate the feasibility of SOMAscan for analyses of archived plasma samples. | Kim, Claire H Tworoger, Shelley S Stampfer, Meir J Dillon, Simon T Gu, Xuesong Sawyer, Sherilyn J Chan, Andrew T Libermann, Towia A Eliassen, A Heather eng UM1 CA176726/CA/NCI NIH HHS/ R01 CA163451/CA/NCI NIH HHS/ P30 CA006516/CA/NCI NIH HHS/ T32 CA009001/CA/NCI NIH HHS/ R01 CA137178/CA/NCI NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't England Sci Rep. 2018 May 30;8(1):8382. doi: 10.1038/s41598-018-26640-w.I | 06/01/2018 | |
| Cerebrospinal Fluid Protein Changes in Preeclampsia | Ciampa E, et al. | 2018 | Hypertension | 72 | 1 | 219-226 | https://www.doi.org/10.1161/HYPERTENSIONAHA.118.11153 | 29,844,151 | Adult Biomarkers/cerebrospinal fluid Cerebrospinal Fluid Proteins/*cerebrospinal fluid Enzyme-Linked Immunosorbent Assay Female Humans Pre-Eclampsia/*cerebrospinal fluid Pregnancy Prognosis Proteomics/*methods activin brain cerebrospinal fluid proteins hypertension preeclampsia proteomics | The molecular mechanisms underlying seizure susceptibility in preeclampsia are unknown. We hypothesized that altered expression of distinct proteins in the cerebrospinal fluid (CSF) may reflect pathophysiological changes in the central nervous system that contribute to the neurological manifestations of severe preeclampsia. We obtained CSF samples from 13 patients with preeclampsia and 14 control patients during spinal anesthesia before delivery and analyzed them by SOMAscan, an aptamer-based proteomics platform for alterations in 1310 protein levels. Ingenuity Pathway Analysis was conducted to highlight relationships between preeclampsia-specific proteins found to be significantly altered. For 2 of the target proteins, we validated the difference in CSF concentrations by ELISA. SOMAscan revealed 82 proteins, whose expression levels were significantly different (P<0.05) in CSF from patients with preeclampsia versus controls. Principal component analysis achieved perfect separation of the preeclampsia and control groups in 2 dimensions. The differentially expressed proteins converge around 4 signaling molecules: TGF-beta (transforming growth factor-beta), VEGFA (vascular endothelial growth factor A), angiotensinogen, and IL-6 (interleukin-6). Within the TGF-beta pathway, upregulation of activin A (301.6+/-47.4 versus 151.6+/-20.5 pg/mL; P=0.0074) and follistatin-related gene (5129+/-347 versus 3016+/-188 pg/mL; P<0.0001) in preeclampsia was confirmed by ELISA. In summary, signaling pathways important for vascular remodeling, inflammation, and neuronal growth, signaling, and electrophysiology were well represented among the proteins found to be altered in CSF in patients with preeclampsia. | Ciampa, Erin Li, Yunping Dillon, Simon Lecarpentier, Edouard Sorabella, Laura Libermann, Towia A Karumanchi, S Ananth Hess, Philip E eng Research Support, Non-U.S. Gov't Hypertension. 2018 Jul;72(1):219-226. doi: 10.1161/HYPERTENSIONAHA.118.11153. Epub 2018 May 29.I | 05/31/2018 | |
| Mistimed food intake and sleep alters 24-hour time-of-day patterns of the human plasma proteome | Depner CM, et al. | 2018 | Proc Natl Acad Sci U S A | 115 | 23 | E5390-E5399 | https://www.doi.org/10.1073/pnas.1714813115 | 29,784,788 | Adult Circadian Clocks Circadian Rhythm/physiology Eating/*physiology Healthy Volunteers Humans Male Melatonin/metabolism Plasma/chemistry/metabolism Proteome/*metabolism Sleep/*physiology Wakefulness/physiology Work Schedule Tolerance/physiology circadian rhythm eating at night peripheral clocks personalized medicine shift work Philips Inc. and Somalogics, Inc. K.P.W. has received grants/research support from CurAegis Technologies (formerly known as Torvec, Inc.), Philips Inc., and Somalogics, Inc. K.P.W. has received consulting fees or has served as a paid member of the scientific advisory boards for CurAegis Technologies, the NIH, and Circadian Therapeutics. K.P.W. has received speaker honoraria from the American Academy of Sleep Medicine, the American College of Chest Physicians, the American Diabetes Association, The Obesity Society, and Philips, Inc. K.P.W. holds stock options for CurAegis Technologies. | Proteomics holds great promise for understanding human physiology, developing health biomarkers, and precision medicine. However, how much the plasma proteome varies with time of day and is regulated by the master circadian suprachiasmatic nucleus brain clock, assessed here by the melatonin rhythm, is largely unknown. Here, we assessed 24-h time-of-day patterns of human plasma proteins in six healthy men during daytime food intake and nighttime sleep in phase with the endogenous circadian clock (i.e., circadian alignment) versus daytime sleep and nighttime food intake out of phase with the endogenous circadian clock (i.e., circadian misalignment induced by simulated nightshift work). We identified 24-h time-of-day patterns in 573 of 1,129 proteins analyzed, with 30 proteins showing strong regulation by the circadian cycle. Relative to circadian alignment, the average abundance and/or 24-h time-of-day patterns of 127 proteins were altered during circadian misalignment. Altered proteins were associated with biological pathways involved in immune function, metabolism, and cancer. Of the 30 circadian-regulated proteins, the majority peaked between 1400 hours and 2100 hours, and these 30 proteins were associated with basic pathways involved in extracellular matrix organization, tyrosine kinase signaling, and signaling by receptor tyrosine-protein kinase erbB-2. Furthermore, circadian misalignment altered multiple proteins known to regulate glucose homeostasis and/or energy metabolism, with implications for altered metabolic physiology. Our findings demonstrate the circadian clock, the behavioral wake-sleep/food intake-fasting cycle, and interactions between these processes regulate 24-h time-of-day patterns of human plasma proteins and help identify mechanisms of circadian misalignment that may contribute to metabolic dysregulation. | Depner, Christopher M Melanson, Edward L McHill, Andrew W Wright, Kenneth P Jr eng P30 DK048520/DK/NIDDK NIH HHS/ F32 DK111161/DK/NIDDK NIH HHS/ UL1 TR001082/TR/NCATS NIH HHS/ R01 HL132150/HL/NHLBI NIH HHS/ R21 DK092624/DK/NIDDK NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Proc Natl Acad Sci U S A. 2018 Jun 5;115(23):E5390-E5399. doi: 10.1073/pnas.1714813115. Epub 2018 May 21.I | 05/23/2018 | |
| Characterization of the rat cerebrospinal fluid proteome following acute cerebral ischemia using an aptamer-based proteomic technology | Simats A, et al. | 2018 | Sci Rep | 8 | 1 | 7899 | https://www.doi.org/10.1038/s41598-018-26237-3 | 29,784,938 | Acute Disease Animals Aptamers, Nucleotide/*genetics Biomarkers/*cerebrospinal fluid Brain/*metabolism/pathology Brain Ischemia/*cerebrospinal fluid/genetics/pathology Humans Male Proteome/*analysis Proteomics/*methods Rats Rats, Wistar Stroke/*cerebrospinal fluid/genetics/pathology | The limited accessibility to the brain has turned the cerebrospinal fluid (CSF) into a valuable source that may contribute to the complete understanding of the stroke pathophysiology. Here we have described the CSF proteome in the hyper-acute phase of cerebral ischemia by performing an aptamer-based proteomic assay (SOMAscan) in CSF samples collected before and 30 min after male Wistar rats had undergone a 90 min Middle Cerebral Artery Occlusion (MCAO) or sham-surgery. Proteomic results indicated that cerebral ischemia acutely increased the CSF levels of 716 proteins, mostly overrepresented in leukocyte chemotaxis and neuronal death processes. Seven promising candidates were further evaluated in rat plasma and brain (CKB, CaMK2A, CaMK2B, CaMK2D, PDXP, AREG, CMPK). The 3 CaMK2 family-members and CMPK early decreased in the infarcted brain area and, together with AREG, co-localized with neurons. Conversely, CKB levels remained consistent after the insult and specifically matched with astrocytes. Further exploration of these candidates in human plasma revealed the potential of CKB and CMPK to diagnose stroke, while CaMK2B and CMPK resulted feasible biomarkers of functional stroke outcome. Our findings provided insights into the CSF proteome following cerebral ischemia and identified new outstanding proteins that might be further considered as potential biomarkers of stroke. | Simats, Alba Garcia-Berrocoso, Teresa Ramiro, Laura Giralt, Dolors Gill, Natalia Penalba, Anna Bustamante, Alejandro Rosell, Anna Montaner, Joan eng Research Support, Non-U.S. Gov't England Sci Rep. 2018 May 21;8(1):7899. doi: 10.1038/s41598-018-26237-3.I | 05/23/2018 | |
| Tracking disease progression non-invasively in Duchenne and Becker muscular dystrophies | Spitali P, et al. | 2018 | J Cachexia Sarcopenia Muscle | 9 | 4 | 715-726 | https://www.doi.org/10.1002/jcsm.12304 | 29,682,908 | Adult Aged Biomarkers Computational Biology/methods Cross-Sectional Studies Disease Progression Follow-Up Studies Humans Middle Aged Muscle, Skeletal/diagnostic imaging/pathology/physiopathology Muscular Dystrophy, Duchenne/*diagnosis Proteome Proteomics/methods Young Adult Becker muscular dystrophy Biomarker Duchenne muscular dystrophy Longitudinal analysis Proteomics Sarcopenia | BACKGROUND: Analysis of muscle biopsies allowed to characterize the pathophysiological changes of Duchenne and Becker muscular dystrophies (D/BMD) leading to the clinical phenotype. Muscle tissue is often investigated during interventional dose finding studies to show in situ proof of concept and pharmacodynamics effect of the tested drug. Less invasive readouts are needed to objectively monitor patients' health status, muscle quality, and response to treatment. The identification of serum biomarkers correlating with clinical function and able to anticipate functional scales is particularly needed for personalized patient management and to support drug development programs. METHODS: A large-scale proteomic approach was used to identify serum biomarkers describing pathophysiological changes (e.g. loss of muscle mass), association with clinical function, prediction of disease milestones, association with in vivo (31) P magnetic resonance spectroscopy data and dystrophin levels in muscles. Cross-sectional comparisons were performed to compare DMD patients, BMD patients, and healthy controls. A group of DMD patients was followed up for a median of 4.4 years to allow monitoring of individual disease trajectories based on yearly visits. RESULTS: Cross-sectional comparison enabled to identify 10 proteins discriminating between healthy controls, DMD and BMD patients. Several proteins (285) were able to separate DMD from healthy, while 121 proteins differentiated between BMD and DMD; only 13 proteins separated BMD and healthy individuals. The concentration of specific proteins in serum was significantly associated with patients' performance (e.g. BMP6 serum levels and elbow flexion) or dystrophin levels (e.g. TIMP2) in BMD patients. Analysis of longitudinal trajectories allowed to identify 427 proteins affected over time indicating loss of muscle mass, replacement of muscle by adipose tissue, and cardiac involvement. Over-representation analysis of longitudinal data allowed to highlight proteins that could be used as pharmacodynamic biomarkers for drugs currently in clinical development. CONCLUSIONS: Serum proteomic analysis allowed to not only discriminate among DMD, BMD, and healthy subjects, but it enabled to detect significant associations with clinical function, dystrophin levels, and disease progression. | Spitali, Pietro Hettne, Kristina Tsonaka, Roula Charrout, Mohammed van den Bergen, Janneke Koeks, Zaida Kan, Hermien E Hooijmans, Melissa T Roos, Andreas Straub, Volker Muntoni, Francesco Al-Khalili-Szigyarto, Cristina Koel-Simmelink, Marleen J A Teunissen, Charlotte E Lochmuller, Hanns Niks, Erik H Aartsma-Rus, Annemieke eng Department of Health/United Kingdom Research Support, Non-U.S. Gov't Germany J Cachexia Sarcopenia Muscle. 2018 Aug;9(4):715-726. doi: 10.1002/jcsm.12304. Epub 2018 Apr 16.I | 04/24/2018 | |
| Plasma proteomics identifies a 'chemokine storm' in idiopathic multicentric Castleman disease | Pierson SK, et al. | 2018 | Am J Hematol | 93 | 7 | 902-912 | https://www.doi.org/10.1002/ajh.25123 | 29,675,946 | Adult Antibodies, Monoclonal/therapeutic use Castleman Disease/blood/*etiology Chemokine CXCL13/metabolism Chemokines/*metabolism Female Humans Interleukin-6/immunology Male Middle Aged Plasma/*chemistry Proteomics/*methods Up-Regulation | Human Herpesvirus-8 (HHV-8)-negative/idiopathic multicentric Castleman disease (iMCD) is a poorly understood disease involving polyclonal lymphoproliferation with dysmorphic germinal centers, constitutional symptoms, and multi-organ failure. Patients can experience thrombocytopenia, anasarca, reticulin fibrosis, renal dysfunction, organomegaly, and normal immunoglobulin levels, - iMCD-TAFRO. Others experience thrombocytosis, milder effusions, and hypergammaglobulinemia, -iMCD-Not Otherwise Specified (iMCD-NOS). Though the etiology is unknown in both subtypes, iMCD symptoms and disease progression are believed to be driven by a cytokine storm, often including interleukin-6 (IL-6). However, approximately two-thirds of patients do not respond to anti-IL-6 therapy; alternative drivers and signaling pathways are not known for anti-IL-6 nonresponders. To identify potential mediators of iMCD pathogenesis, we quantified 1129 proteins in 13 plasma samples from six iMCD patients during flare and remission. The acute phase reactant NPS-PLA2 was the only significantly increased protein (P = .017); chemokines and complement were significantly enriched pathways. Chemokines represented the greatest proportion of upregulated cytokines, suggesting that iMCD involves a chemokine storm. The chemokine CXCL13, which is essential in homing B cells to germinal centers, was the most upregulated cytokine across all patients (log2 fold-change = 3.22). Expression of CXCL13 was also significantly increased in iMCD lymph node germinal centers compared to controls in a stromal meshwork pattern. We observed distinct proteomic profiles between the two iMCD-TAFRO patients, who both failed anti-IL-6-therapy, and the four iMCD-NOS patients, in whom all three treated with anti-IL-6-therapy responded, suggesting that differing mechanisms may exist. This study reveals proteomic differences between flare and remission and the potential to molecularly define iMCD subgroups. | Pierson, Sheila K Stonestrom, Aaron J Shilling, Dustin Ruth, Jason Nabel, Christopher S Singh, Amrit Ren, Yue Stone, Katie Li, Hongzhe van Rhee, Frits Fajgenbaum, David C eng Research Support, Non-U.S. Gov't Am J Hematol. 2018 Jul;93(7):902-912. doi: 10.1002/ajh.25123. Epub 2018 May 16.I | 04/21/2018 | |
| Plasma from some cancer patients inhibits adenoviral Ad5f35 vector transduction of dendritic cells | Jin P, et al. | 2018 | Cytotherapy | 20 | 5 | 728-739 | https://www.doi.org/10.1016/j.jcyt.2018.03.001 | 29,655,599 | Adenoviridae/*genetics Adult Aged Cytokines/metabolism Dendritic Cells/*metabolism Female Gene Expression Regulation Genetic Vectors/*metabolism Humans Middle Aged Monocytes/cytology/metabolism Neoplasms/*blood Plasma/*metabolism Principal Component Analysis Receptor, ErbB-2/metabolism Tissue Donors *Transduction, Genetic adHER2/neu cancer immunotherapy dendritic cells (DCs) | BACKGROUND: Pooled AB serum is often used as a media supplement for cell culture but it has the potential to transmit infectious diseases. To avoid this risk, we used autologous plasma as a media supplement for manufacturing dendritic cells (DCs) for cancer immunotherapy. We noticed inconsistencies in the DCs and investigated their nature and cause. METHODS: Adenovirus human epidural growth factor receptor 2 (adHER2/neu) DCs for 21 patients were manufactured from autologous peripheral blood monocytes that were treated with granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin (IL)-4 for 3 days, transduced with Ad5f35HER2ECTM and then treated with lipopolysaccharide and interferon (IFN)-gamma for 1 day. The cells were cultured in RPMI-1640 supplemented with either 10% heat inactivated autologous or AB plasma. RESULTS: Twenty-eight adHER2/neu DCs were manufactured for 21 patients using autologous plasma and 68 were manufactured for 20 of those patients using AB plasma. The expression of human epidural growth factor receptor 2 (HER2/neu) was less for DCs manufactured with autologous plasma (70.3 +/- 33.3% versus 86.1 +/- 22.8%; P <0.01). Manufacturing adHER2/neu DCs using monocytes from three healthy subjects and plasma from one patient with low HER2/neu expression (18%) resulted in low HER2/neu expression by all three DCs (13%, 16% and 23%). Analysis of the levels of 1322 proteins in eight plasma samples associated with low HER2/neu expression and in 12 associated with high HER2/neu expression revealed that the levels of 14 predicted HER2/neu transduction efficiency. CONCLUSION: The manufacture of adHER2/neu DC using autologous plasma as a media supplement resulted in inconsistent HER2/neu expression. It is likely that variability in the levels of multiple proteins in autologous plasma contributed to low HER2/neu expression. | Jin, Ping Chen, Wenjing Ren, Jiaqiang Chen, Steven Wood, Lauren Zhao, Yingdong Remaley, Alan Pham, Chauha Lian, Sheena Liu, Shutong Liu, Hui Highfill, Steven Berzofsky, Jay A Stroncek, David F eng ZIA CL002119-09/Intramural NIH HHS/ ZIA CL002120-09/Intramural NIH HHS/ Research Support, N.I.H., Intramural England Cytotherapy. 2018 May;20(5):728-739. doi: 10.1016/j.jcyt.2018.03.001. Epub 2018 Apr 11.I | 04/16/2018 | |
| Analysis of circulating angiopoietin-like protein 3 and genetic variants in lipid metabolism and liver health: the DiOGenes study | Hess AL, et al. | 2018 | Genes Nutr | 13 | 7 | https://www.doi.org/10.1186/s12263-018-0597-3 | 29,619,113 | Angiopoietin-like protein 3 Lipid metabolism Lipoprotein lipase Liver markers Liver steatosis Protein quantitative trait locus Single nucleotide polymorphisms countries, confirming that the study protocol was in accordance with the Declaration of Helsinki.Not applicable.AA is an advisor to or a member of advisory boards for a number of food and pharmaceutical producers: Basic Research, USA Beachbody, USA BioCare Copenhagen, Denmark Crossfit, USA Dutch Beer Institute, Netherlands Feast Kitchen A/S, Denmark Gelesis, USA Groupe Ethique et Sante, France McCain Foods Limited, USA Nestle Research Center, Switzerland Novo Nordisk, Denmark Pfizer, Germany Saniona, Denmark Sanofi-Aventis, Germany S-Biotek, Denmark Scandinavian Airlines System, Denmark TetraPak, Sweden Weight Watchers, USA and from Zaluvida, Switzerland. AA does not own stock in, or have other ownership interests in, any of the companies to which he provides scientific advice, or in any nutrition company other than those companies whose stock is held by various mutual fund retirement accounts. Recent research at the University of Copenhagen, Denmark, has been funded by unrestricted grants from or contracts with DC-Ingredients, Denmark Danish Dairy Foundation Global Dairy Platform and Gelesis AS, USA. AA receives payment as associate editor of The American Journal of Clinical Nutrition and as a member of the editorial committee of Annual Review of Nutrition. AA is a recipient of honoraria as speaker for a wide range of Danish and international concerns and of royalties from textbooks and from popular diet and cookery books. AA is a co-inventor of a number of patents, including Methods of inducing weight loss, treating obesity and preventing weight gain (licensee Gelesis, USA) and Biomarkers for predicting degree of weight loss (licensee Nestec SA, CH), owned by the University of Copenhagen, in accordance with Danish law. AA is a co-founder and co-owner of the University of Copenhagen spin-out companies Mobile Fitness A/S, Personalized Weight Management Research Consortium ApS (Gluco-diet.dk), and Flaxslim ApS, where he is also a member of the board. AA is not an advocate or activist for specific diets and is not strongly committed to any specific diet, e.g., veganism, Atkins diet, gluten-free diet, high animal protein diet, or dietary supplements. AV, JC, and JH are full-time employees at Nestle Institute of Health Sciences. The remaining authors declare that they have no competing interests.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | BACKGROUND: Angiopoietin-like protein 3 (ANGPTL3), a liver-derived protein, plays an important role in the lipid and lipoprotein metabolism. Using data available from the DiOGenes study, we assessed the link with clinical improvements (weight, plasma lipid, and insulin levels) and changes in liver markers, alanine aminotransferase, aspartate aminotransferase (AST), adiponectin, fetuin A and B, and cytokeratin 18 (CK-18), upon low-calorie diet (LCD) intervention. We also examined the role of genetic variation in determining the level of circulating ANGPTL3 and the relation between the identified genetic markers and markers of hepatic steatosis. METHODS: DiOGenes is a multicenter, controlled dietary intervention where obese participants followed an 8-week LCD (800 kcal/day, using a meal replacement product). Plasma ANGPTL3 and liver markers were measured using the SomaLogic (Boulder, CO) platform. Protein quantitative trait locus (pQTL) analyses assessed the link between more than four million common variants and the level of circulating ANGPTL3 at baseline and changes in levels during the LCD intervention. RESULTS: Changes in ANGPTL3 during weight loss showed only marginal association with changes in triglycerides (nominal p = 0.02) and insulin (p = 0.04); these results did not remain significant after correcting for multiple testing. However, significant association (after multiple-testing correction) were observed between changes in ANGPTL3 and AST during weight loss (p = 0.004) and between ANGPTL3 and CK-18 (baseline p = 1.03 x 10(-7), during weight loss p = 1.47 x 10(-13)). Our pQTL study identified two loci significantly associated with changes in ANGPTL3. One of these loci (the APOA4-APOA5-ZNF259-BUD13 gene cluster) also displayed significant association with changes in CK-18 levels during weight loss (p = 0.007). CONCLUSION: We clarify the link between circulating levels of ANGPTL3 and specific markers of liver function. We demonstrate that changes in ANGPLT3 and CK-18 during LCD are under genetic control from trans-acting variants. Our results suggest an extended function of ANGPTL3 in the inflammatory state of liver steatosis and toward liver metabolic processes. | Hess, Anne Lundby Carayol, Jerome Blaedel, Trine Hager, Jorg Di Cara, Alessandro Astrup, Arne Saris, Wim H M Larsen, Lesli Hingstrup Valsesia, Armand eng Germany Genes Nutr. 2018 Apr 2;13:7. doi: 10.1186/s12263-018-0597-3. eCollection 2018.I | 04/06/2018 | ||
| Slow Off-Rate Modified Aptamer (SOMAmer) as a Novel Reagent in Immunoassay Development for Accurate Soluble Glypican-3 Quantification in Clinical Samples | Duo J, et al. | 2018 | Anal Chem | 90 | 8 | 5162-5170 | https://www.doi.org/10.1021/acs.analchem.7b05277 | 29,605,994 | Aptamers, Nucleotide/*chemistry Carcinoma, Hepatocellular/*diagnosis Chromatography, Liquid Glypicans/*analysis Humans *Immunoassay Liver Neoplasms/*diagnosis Recombinant Proteins/analysis Solubility Tandem Mass Spectrometry | Accurate quantification of soluble glypican-3 in clinical samples using immunoassays is challenging, because of the lack of appropriate antibody reagents to provide a full spectrum measurement of all potential soluble glypican-3 fragments in vivo. Glypican-3 SOMAmer (slow off-rate modified aptamer) is a novel reagent that binds, with high affinity, to a far distinct epitope of glypican-3, when compared to all available antibody reagents generated in-house. This paper describes an integrated analytical approach to rational selection of key reagents based on molecular characterization by epitope mapping, with the focus on our work using a SOMAmer as a new reagent to address development challenges with traditional antibody reagents for the soluble glypican-3 immunoassay. A qualified SOMAmer-based assay was developed and used for soluble glypican-3 quantification in hepatocellular carcinoma (HCC) patient samples. The assay demonstrated good sensitivity, accuracy, and precision. Data correlated with those obtained using the traditional antibody-based assay were used to confirm the clinically relevant soluble glypican-3 forms in vivo. This result was reinforced by a liquid chromatography tandem mass spectrometry (LC-MS/MS) assay quantifying signature peptides generated from trypsin digestion. The work presented here offers an integrated strategy for qualifying aptamers as an alternative affinity platform for immunoassay reagents that can enable speedy assay development, especially when traditional antibody reagents cannot meet assay requirements. | Duo, Jia Chiriac, Camelia Huang, Richard Y-C Mehl, John Chen, Guodong Tymiak, Adrienne Sabbatini, Peter Pillutla, Renuka Zhang, Yan eng Anal Chem. 2018 Apr 17;90(8):5162-5170. doi: 10.1021/acs.analchem.7b05277. Epub 2018 Apr 6.I | 04/03/2018 | |
| Sperm cell purification from mock forensic swabs using SOMAmer affinity reagents | Katilius E, et al. | 2018 | Forensic Sci Int Genet | 35 | 13-Sep | https://www.doi.org/10.1016/j.fsigen.2018.03.011 | 29,609,058 | Cell Separation DNA/*isolation & purification DNA Fingerprinting Epithelial Cells/cytology Female Forensic Genetics Humans Indicators and Reagents Male Specimen Handling/instrumentation Spermatozoa/*cytology Affinity reagents Cell elution DNA typing Detergents Forensic science Selex SOMAmers Sex offenses Sperm purification | We have demonstrated a proof of concept with affinity-based purification of sperm cells from mock forensic samples using SOMAmer reagents, DNA-based affinity reagents developed by SomaLogic, Inc. SOMAmer reagents were selected in vitro using whole-cell SELEX to bind specifically with intact, detergent-treated sperm cells. Successful separation of sperm from epithelial cells and their debris was demonstrated using buccal swabs with added semen. Primarily male DNA profiles were generated from sperm cells eluted from the types of cotton swabs typically used for rape kit evidence collection. The quality of sperm DNA isolated from samples purified using SOMAmers is comparable to existing commercially available differential extraction-based methods at higher sperm concentrations. This purification method is simple, offers relatively rapid (<2hr) sperm purification, and can potentially be automated using robotic workstations. This work serves as proof of concept that demonstrates the first use of SOMAmer reagents as affinity ligands to bind sperm cells. With further development, this technique can potentially be used for high-throughput sexual assault forensic casework. | Katilius, Evaldas Carmel, Andrew B Koss, Heidi O'Connell, Dan Smith, Breanna C Sanders, Glenn M LaBerge, Greggory S eng Research Support, U.S. Gov't, Non-P.H.S. Netherlands Forensic Sci Int Genet. 2018 Jul;35:9-13. doi: 10.1016/j.fsigen.2018.03.011. Epub 2018 Mar 27.I | 04/03/2018 | ||
| Integrative Omics: Harnessing the Proteome to Maximize the Potential of the Genome | McGarrah RW, et al. | 2018 | Circulation | 137 | 11 | 1173-1175 | https://www.doi.org/10.1161/CIRCULATIONAHA.117.032807 | 29,530,892 | *Cardiovascular Diseases Genomics Humans *Proteome Proteomics Risk Factors Editorials biomarkers cardiovascular diseases genetics genome-wide association study | McGarrah, Robert W Shah, Svati H eng Comment Editorial Circulation. 2018 Mar 13;137(11):1173-1175. doi: 10.1161/CIRCULATIONAHA.117.032807.I | 03/14/2018 | ||
| Combined use of protein biomarkers and network analysis unveils deregulated regulatory circuits in Duchenne muscular dystrophy | Parolo S, et al. | 2018 | PLoS One | 13 | 3 | e0194225 | https://www.doi.org/10.1371/journal.pone.0194225 | 29,529,088 | Case-Control Studies Female Gene Expression Regulation Humans Male Muscle, Skeletal/metabolism Muscular Dystrophy, Duchenne/diagnosis/genetics/*metabolism *Protein Interaction Mapping *Protein Interaction Maps *Proteome *Proteomics/methods Signal Transduction Workflow | Although the genetic basis of Duchenne muscular dystrophy has been known for almost thirty years, the cellular and molecular mechanisms characterizing the disease are not completely understood and an efficacious treatment remains to be developed. In this study we analyzed proteomics data obtained with the SomaLogic technology from blood serum of a cohort of patients and matched healthy subjects. We developed a workflow based on biomarker identification and network-based pathway analysis that allowed us to describe different deregulated pathways. In addition to muscle-related functions, we identified other biological processes such as apoptosis, signaling in the immune system and neurotrophin signaling as significantly modulated in patients compared with controls. Moreover, our network-based analysis identified the involvement of FoxO transcription factors as putative regulators of different pathways. On the whole, this study provided a global view of the molecular processes involved in Duchenne muscular dystrophy that are decipherable from serum proteome. | Parolo, Silvia Marchetti, Luca Lauria, Mario Misselbeck, Karla Scott-Boyer, Marie-Pier Caberlotto, Laura Priami, Corrado eng Research Support, Non-U.S. Gov't PLoS One. 2018 Mar 12;13(3):e0194225. doi: 10.1371/journal.pone.0194225. eCollection 2018.I | 03/13/2018 | |
| Harnessing the Power of Proteomics to Assess Drug Safety and Guide Clinical Trials | Lam MPY, et al. | 2018 | Circulation | 137 | 10 | 1011-1014 | https://www.doi.org/10.1161/CIRCULATIONAHA.117.032876 | 29,506,994 | Biomarkers Early Diagnosis *Proteomics *Quinolines Editorials clinical trials drugs proteomics | Assessing drug safety and efficacy is costly, and many promising candidates can present unwanted side effects. Can new developments in proteomic biomarkers help provide timely monitoring of efficacy and protect participant safety? In this issue, Williams et al. tackled this question with a retrospective study on whether patients treated with torcetrapib in the ILLUMINATE trial showed signs of increased cardiovascular risks early in the trial. | Lam, Maggie P Y Ge, Ying eng R00 HL127302/HL/NHLBI NIH HHS/ R01 HL096971/HL/NHLBI NIH HHS/ R01 HL109810/HL/NHLBI NIH HHS/ Comment Editorial Research Support, N.I.H., Extramural Circulation. 2018 Mar 6;137(10):1011-1014. doi: 10.1161/CIRCULATIONAHA.117.032876.I | 03/07/2018 | |
| Proteomic analysis reveals distinctive protein profiles involved in CD8(+) T cell-mediated murine autoimmune cholangitis | Zhang W, et al. | 2018 | Cell Mol Immunol | 15 | 8 | 756-767 | https://www.doi.org/10.1038/cmi.2017.149 | 29,375,127 | Adoptive Transfer Analysis of Variance Animals Autoimmune Diseases/blood/*immunology Blood Proteins/*analysis CD8-Positive T-Lymphocytes/*immunology/*metabolism Cholangitis/blood/*immunology Disease Models, Animal Female Liver/metabolism Mice Mice, Inbred C57BL Natural Killer T-Cells/metabolism Proteomics/*methods Receptor, Transforming Growth Factor-beta Type II/metabolism Spleen/metabolism Cd8 autoimmune cholangitis dnTGFbetaRII mice proteomic analysis | Autoimmune cholangitis arises from abnormal innate and adaptive immune responses in the liver, and T cells are critical drivers in this process. However, little is known about the regulation of their functional behavior during disease development. We previously reported that mice with T cell-restricted expression of a dominant negative form of transforming growth factor beta receptor type II (dnTGFbetaRII) spontaneously develop an autoimmune cholangitis that resembles human primary biliary cholangitis (PBC). Adoptive transfer of CD8(+) but not CD4(+) T cells into Rag1(-/-) mice reproduced the disease, demonstrating a critical role for CD8(+) T cells in PBC pathogenesis. Herein, we used SOMAscan technology to perform proteomic analysis of serum samples from dnTGFbetaRII and B6 control mice at different ages. In addition, we analyzed CD8 protein profiles after adoptive transfer of splenic CD8(+) cells into Rag1(-/-) recipients. The use of the unique SOMAscan aptamer technology revealed critical and distinct profiles of CD8 cells, which are key to biliary mediation. In total, 254 proteins were significantly increased while 216 proteins were significantly decreased in recipient hepatic CD8(+) cells compared to donor splenic CD8(+) cells. In contrast to donor splenic CD8(+) cells, recipient hepatic CD8(+) cells expressed distinct profiles for proteins involved in chemokine signaling, focal adhesion, T cell receptor and natural killer cell-mediated cytotoxicity pathways. | Zhang, Weici Zhang, Ren Zhang, Jun Sun, Ying Leung, Patrick Sc Yang, Guo-Xiang Shuai, Zongwen Ridgway, William M Gershwin, M Eric eng P30 DK078392/DK/NIDDK NIH HHS/ R01 DK090019/DK/NIDDK NIH HHS/ Research Support, N.I.H., Extramural China Cell Mol Immunol. 2018 Aug;15(8):756-767. doi: 10.1038/cmi.2017.149. Epub 2018 Jan 29.I | 01/30/2018 | |
| Adrenomedullin surges are linked to acute episodes of the systemic capillary leak syndrome (Clarkson disease) | Xie Z, et al. | 2018 | J Leukoc Biol | 103 | 4 | 749-759 | https://www.doi.org/10.1002/JLB.5A0817-324R | 29,360,169 | Acute Disease Adrenomedullin/*metabolism Aged Biomarkers/*metabolism Capillary Leak Syndrome/metabolism/*pathology Case-Control Studies Cells, Cultured Endothelium, Vascular/metabolism/*pathology Female Gene Expression Profiling Gene Expression Regulation Humans Leukocytes, Mononuclear/metabolism/*pathology Male Middle Aged Monocytes/metabolism/*pathology adrenomedullin angiogenesis endothelium vascular leak | BACKGROUND: Systemic Capillary Leak Syndrome (SCLS) is an extremely rare and life-threatening vascular disorder of unknown etiology. SCLS is characterized by abrupt and transient episodes of hypotensive shock and edema due to plasma leakage into peripheral tissues. The disorder has garnered attention recently because its initial presentation resembles more common vascular disorders including systemic anaphylaxis, sepsis, and acute infections with the Ebola/Marburg family of filoviruses. Although approximately 70-85% of patients with SCLS have a concurrent monoclonal gammopathy of unknown significance (MGUS), any contribution of the paraprotein to acute flares is unknown. PROCEDURE: To identify circulating factors that might trigger acute SCLS crises, we profiled transcriptomes of paired peripheral blood mononuclear cell fractions obtained from patients during acute attacks and convalescent intervals by microarray. RESULTS: This study uncovered 61 genes that were significantly up- or downregulated more than 2.5-fold in acute samples relative to respective baselines. One of the most upregulated genes was ADM, which encodes the vasoactive peptide adrenomedullin. A stable ADM protein surrogate (pro-ADM) was markedly elevated in SCLS acute sera compared to remission samples or sera from healthy controls. Monocytes and endothelial cells (ECs) from SCLS subjects expressed significantly more ADM in response to proinflammatory stimuli compared to healthy control cells. Application of ADM to ECs elicited protective effects on vascular barrier function, suggesting a feedback protective mechanism in SCLS. CONCLUSIONS: Since ADM has established hypotensive effects, differentiating between these dual actions of ADM is crucial for therapeutic applications aimed at more common diseases associated with increased ADM levels. | Xie, Zhihui Chen, Wei-Sheng Yin, Yuzhi Chan, Eunice C Terai, Kaoru Long, Lauren M Myers, Timothy G Dudek, Arkadiusz Z Druey, Kirk M eng ZIA AI001083-08/Intramural NIH HHS/ Research Support, N.I.H., Intramural J Leukoc Biol. 2018 Apr;103(4):749-759. doi: 10.1002/JLB.5A0817-324R. Epub 2018 Jan 23.I | 01/24/2018 | |
| Deep molecular phenotypes link complex disorders and physiological insult to CpG methylation | Zaghlool SB, et al. | 2018 | Hum Mol Genet | 27 | 6 | 1106-1121 | https://www.doi.org/10.1093/hmg/ddy006 | 29,325,019 | Basic Helix-Loop-Helix Transcription Factors/genetics Carrier Proteins/genetics Computational Biology/methods *CpG Islands *DNA Methylation Epigenesis, Genetic Female Genetic Association Studies/methods Genome, Human Genome-Wide Association Study/methods Glucose Metabolism Disorders/*genetics Humans Lipids/blood Male Metabolome Obesity/*genetics Repressor Proteins/genetics Tobacco Smoking/*genetics | Epigenetic regulation of cellular function provides a mechanism for rapid organismal adaptation to changes in health, lifestyle and environment. Associations of cytosine-guanine di-nucleotide (CpG) methylation with clinical endpoints that overlap with metabolic phenotypes suggest a regulatory role for these CpG sites in the body's response to disease or environmental stress. We previously identified 20 CpG sites in an epigenome-wide association study (EWAS) with metabolomics that were also associated in recent EWASs with diabetes-, obesity-, and smoking-related endpoints. To elucidate the molecular pathways that connect these potentially regulatory CpG sites to the associated disease or lifestyle factors, we conducted a multi-omics association study including 2474 mass-spectrometry-based metabolites in plasma, urine and saliva, 225 NMR-based lipid and metabolite measures in blood, 1124 blood-circulating proteins using aptamer technology, 113 plasma protein N-glycans and 60 IgG-glyans, using 359 samples from the multi-ethnic Qatar Metabolomics Study on Diabetes (QMDiab). We report 138 multi-omics associations at these CpG sites, including diabetes biomarkers at the diabetes-associated TXNIP locus, and smoking-specific metabolites and proteins at multiple smoking-associated loci, including AHRR. Mendelian randomization suggests a causal effect of metabolite levels on methylation of obesity-associated CpG sites, i.e. of glycerophospholipid PC(O-36: 5), glycine and a very low-density lipoprotein (VLDL-A) on the methylation of the obesity-associated CpG loci DHCR24, MYO5C and CPT1A, respectively. Taken together, our study suggests that multi-omics-associated CpG methylation can provide functional read-outs for the underlying regulatory response mechanisms to disease or environmental insults. | Zaghlool, Shaza B Mook-Kanamori, Dennis O Kader, Sara Stephan, Nisha Halama, Anna Engelke, Rudolf Sarwath, Hina Al-Dous, Eman K Mohamoud, Yasmin A Roemisch-Margl, Werner Adamski, Jerzy Kastenmuller, Gabi Friedrich, Nele Visconti, Alessia Tsai, Pei-Chien Spector, Tim Bell, Jordana T Falchi, Mario Wahl, Annika Waldenberger, Melanie Peters, Annette Gieger, Christian Pezer, Marija Lauc, Gordan Graumann, Johannes Malek, Joel A Suhre, Karsten eng Wellcome Trust/United Kingdom Research Support, Non-U.S. Gov't England Hum Mol Genet. 2018 Mar 15;27(6):1106-1121. doi: 10.1093/hmg/ddy006.I | 01/13/2018 | |
| The Impact of the Glomerular Filtration Rate on the Human Plasma Proteome | Christensson A, et al. | 2018 | Proteomics Clin Appl | 12 | 3 | e1700067 | https://www.doi.org/10.1002/prca.201700067 | 29,281,176 | Aged Blood Proteins/*metabolism Female *Glomerular Filtration Rate Humans Male Middle Aged *Proteomics Sex Characteristics | PURPOSE: The application of proteomics in chronic kidney disease (CKD) can potentially uncover biomarkers and pathways that are predictive of disease. EXPERIMENTAL DESIGN: Within this context, this study examines the relationship between the human plasma proteome and glomerular filtration rate (GFR) as measured by iohexol clearance in a cohort from Sweden (n = 389; GFR range: 8-100 mL min(-1) /1.73 m(2) ). A total of 2893 proteins are quantified using a modified aptamer assay. RESULTS: A large proportion of the proteome is associated with GFR, reinforcing the concept that CKD affects multiple physiological systems (individual protein-GFR correlations listed here). Of these, cystatin C shows the most significant correlation with GFR (rho = -0.85, p = 1.2 x 10(-97) ), establishing strong validation for the use of this biomarker in CKD diagnostics. Among the other highly significant protein markers are insulin-like growth factor-binding protein 6, neuroblastoma suppressor of tumorigenicity 1, follistatin-related protein 3, trefoil factor 3, and beta-2 microglobulin. These proteins may indicate an imbalance in homeostasis across a variety of cellular processes, which may be underlying renal dysfunction. CONCLUSIONS AND CLINICAL RELEVANCE: Overall, this study represents the most extensive characterization of the plasma proteome and its relation to GFR to date, and suggests the diagnostic and prognostic value of proteomics for CKD across all stages. | Christensson, Anders Ash, Jessica A DeLisle, Robert K Gaspar, Fraser W Ostroff, Rachel Grubb, Anders Lindstrom, Veronica Bruun, Laila Williams, Steve A eng Research Support, Non-U.S. Gov't Germany Proteomics Clin Appl. 2018 May;12(3):e1700067. doi: 10.1002/prca.201700067. Epub 2018 Jan 31.I | 12/28/2017 | |
| A proteomic clock of human pregnancy | Aghaeepour N, et al. | 2018 | Am J Obstet Gynecol | 218 | 3 | 347 e1-347 e14 | https://www.doi.org/10.1016/j.ajog.2017.12.208 | 29,277,631 | Adult Algorithms Biomarkers/blood CD4-Positive T-Lymphocytes/metabolism Female Gene Ontology *Gestational Age Glypicans/blood Granulins/blood Humans Janus Kinases/blood Models, Theoretical Placental Lactogen/blood Postpartum Period/*blood Predictive Value of Tests Pregnancy/*blood Pregnancy Trimesters/*blood Proteome/*metabolism STAT Transcription Factors/blood STAT5 Transcription Factor/blood Signal Transduction Janus kinase/signal transducer and activator of transcription Luminex Somalogic T cell alpha-fetoprotein antibody aptamer chrionic somatomammotropin hormore cross-validation elastic net gestational age glypican 3 granulins macrophage colony-stimulating factor 1 receptor plasma protein polymeric immunoglobulin receptor pregnancy prolactin proteome protooncogene tyrosine-protein kinase receptor Ret somamer | BACKGROUND: Early detection of maladaptive processes underlying pregnancy-related pathologies is desirable because it will enable targeted interventions ahead of clinical manifestations. The quantitative analysis of plasma proteins features prominently among molecular approaches used to detect deviations from normal pregnancy. However, derivation of proteomic signatures sufficiently predictive of pregnancy-related outcomes has been challenging. An important obstacle hindering such efforts were limitations in assay technology, which prevented the broad examination of the plasma proteome. OBJECTIVE: The recent availability of a highly multiplexed platform affording the simultaneous measurement of 1310 plasma proteins opens the door for a more explorative approach. The major aim of this study was to examine whether analysis of plasma collected during gestation of term pregnancy would allow identifying a set of proteins that tightly track gestational age. Establishing precisely timed plasma proteomic changes during term pregnancy is a critical step in identifying deviations from regular patterns caused by fetal and maternal maladaptations. A second aim was to gain insight into functional attributes of identified proteins and link such attributes to relevant immunological changes. STUDY DESIGN: Pregnant women participated in this longitudinal study. In 2 subsequent sets of 21 (training cohort) and 10 (validation cohort) women, specific blood specimens were collected during the first (7-14 weeks), second (15-20 weeks), and third (24-32 weeks) trimesters and 6 weeks postpartum for analysis with a highly multiplexed aptamer-based platform. An elastic net algorithm was applied to infer a proteomic model predicting gestational age. A bootstrapping procedure and piecewise regression analysis was used to extract the minimum number of proteins required for predicting gestational age without compromising predictive power. Gene ontology analysis was applied to infer enrichment of molecular functions among proteins included in the proteomic model. Changes in abundance of proteins with such functions were linked to immune features predictive of gestational age at the time of sampling in pregnancies delivering at term. RESULTS: An independently validated model consisting of 74 proteins strongly predicted gestational age (P = 3.8 x 10(-14), R = 0.97). The model could be reduced to 8 proteins without losing its predictive power (P = 1.7 x 10(-3), R = 0.91). The 3 top ranked proteins were glypican 3, chorionic somatomammotropin hormone, and granulins. Proteins activating the Janus kinase and signal transducer and activator of transcription pathway were enriched in the proteomic model, chorionic somatomammotropin hormone being the top-ranked protein. Abundance of chorionic somatomammotropin hormone strongly correlated with signal transducer and activator of transcription-5 signaling activity in CD4 T cells, the endogenous cell-signaling event most predictive of gestational age. CONCLUSION: Results indicate that precisely timed changes in the plasma proteome during term pregnancy mirror a proteomic clock. Importantly, the combined use of several plasma proteins was required for accurate prediction. The exciting promise of such a clock is that deviations from its regular chronological profile may assist in the early diagnoses of pregnancy-related pathologies, and point to underlying pathophysiology. Functional analysis of the proteomic model generated the novel hypothesis that chrionic somatomammotropin hormone may critically regulate T-cell function during pregnancy. | Aghaeepour, Nima Lehallier, Benoit Baca, Quentin Ganio, Ed A Wong, Ronald J Ghaemi, Mohammad S Culos, Anthony El-Sayed, Yasser Y Blumenfeld, Yair J Druzin, Maurice L Winn, Virginia D Gibbs, Ronald S Tibshirani, Rob Shaw, Gary M Stevenson, David K Gaudilliere, Brice Angst, Martin S eng Research Support, Non-U.S. Gov't Validation Study Am J Obstet Gynecol. 2018 Mar;218(3):347.e1-347.e14. doi: 10.1016/j.ajog.2017.12.208. Epub 2017 Dec 24.I | 12/27/2017 | |
| Genetic Architecture of the Cardiovascular Risk Proteome | Benson MD, et al. | 2018 | Circulation | 137 | 11 | 1158-1172 | https://www.doi.org/10.1161/CIRCULATIONAHA.117.029536 | 29,258,991 | Aged Apolipoproteins E/genetics/metabolism Blood Proteins/*genetics/metabolism Cardiovascular Diseases/blood/diagnosis/*genetics Databases, Genetic Female Gene Expression Profiling Genetic Predisposition to Disease *Genetic Variation Genome-Wide Association Study Hep G2 Cells Heredity Humans Male Mendelian Randomization Analysis Middle Aged Phenotype Protein Phosphatase 2C/genetics/metabolism Quantitative Trait Loci Risk Factors Apoe cardiovascular genomics genome-wide analysis proteomics systems biology exists. | BACKGROUND: We recently identified 156 proteins in human plasma that were each associated with the net Framingham Cardiovascular Disease Risk Score using an aptamer-based proteomic platform in Framingham Heart Study Offspring participants. Here we hypothesized that performing genome-wide association studies and exome array analyses on the levels of each of these 156 proteins might identify genetic determinants of risk-associated circulating factors and provide insights into early cardiovascular pathophysiology. METHODS: We studied the association of genetic variants with the plasma levels of each of the 156 Framingham Cardiovascular Disease Risk Score-associated proteins using linear mixed-effects models in 2 population-based cohorts. We performed discovery analyses on plasma samples from 759 participants of the Framingham Heart Study Offspring cohort, an observational study of the offspring of the original Framingham Heart Study and their spouses, and validated these findings in plasma samples from 1421 participants of the MDCS (Malmo Diet and Cancer Study). To evaluate the utility of this strategy in identifying new biological pathways relevant to cardiovascular disease pathophysiology, we performed studies in a cell-model system to experimentally validate the functional significance of an especially novel genetic association with circulating apolipoprotein E levels. RESULTS: We identified 120 locus-protein associations in genome-wide analyses and 41 associations in exome array analyses, the majority of which have not been described previously. These loci explained up to 66% of interindividual plasma protein-level variation and, on average, accounted for 3 times the amount of variation explained by common clinical factors, such as age, sex, and diabetes mellitus status. We described overlap among many of these loci and cardiovascular disease genetic risk variants. Finally, we experimentally validated a novel association between circulating apolipoprotein E levels and the transcription factor phosphatase 1G. Knockdown of phosphatase 1G in a human liver cell model resulted in decreased apolipoprotein E transcription and apolipoprotein E protein levels in cultured supernatants. CONCLUSIONS: We identified dozens of novel genetic determinants of proteins associated with the Framingham Cardiovascular Disease Risk Score and experimentally validated a new role for phosphatase 1G in lipoprotein biology. Further, genome-wide and exome array data for each protein have been made publicly available as a resource for cardiovascular disease research. | Benson, Mark D Yang, Qiong Ngo, Debby Zhu, Yineng Shen, Dongxiao Farrell, Laurie A Sinha, Sumita Keyes, Michelle J Vasan, Ramachandran S Larson, Martin G Smith, J Gustav Wang, Thomas J Gerszten, Robert E eng P30 DK040561/DK/NIDDK NIH HHS/ N01 HC025195/HC/NHLBI NIH HHS/ T32 HL007208/HL/NHLBI NIH HHS/ K01 GM103817/GM/NIGMS NIH HHS/ HHSN268201000033C/HL/NHLBI NIH HHS/ R01 HL132320/HL/NHLBI NIH HHS/ R01 HL133870/HL/NHLBI NIH HHS/ N01HC25195/HL/NHLBI NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Validation Study Circulation. 2018 Mar 13;137(11):1158-1172. doi: 10.1161/CIRCULATIONAHA.117.029536. Epub 2017 Dec 19.I | 12/21/2017 | |
| Application of Large-Scale Aptamer-Based Proteomic Profiling to Planned Myocardial Infarctions | Jacob J, et al. | 2018 | Circulation | 137 | 12 | 1270-1277 | https://www.doi.org/10.1161/CIRCULATIONAHA.117.029443 | 29,222,138 | Ablation Techniques *Aptamers, Nucleotide Biomarkers/blood Blood Proteins/genetics/*metabolism Cardiomyopathy, Hypertrophic/*blood/genetics/pathology/surgery Case-Control Studies Feasibility Studies High-Throughput Screening Assays Humans Myocardium/*metabolism/pathology Predictive Value of Tests Prognosis Proteomics/*methods Reproducibility of Results ST Elevation Myocardial Infarction/*blood/genetics/pathology Time Factors cardiovascular disease myocardial infarction proteins | BACKGROUND: Emerging proteomic technologies using novel affinity-based reagents allow for efficient multiplexing with high-sample throughput. To identify early biomarkers of myocardial injury, we recently applied an aptamer-based proteomic profiling platform that measures 1129 proteins to samples from patients undergoing septal alcohol ablation for hypertrophic cardiomyopathy, a human model of planned myocardial injury. Here, we examined the scalability of this approach using a markedly expanded platform to study a far broader range of human proteins in the context of myocardial injury. METHODS: We applied a highly multiplexed, expanded proteomic technique that uses single-stranded DNA aptamers to assay 4783 human proteins (4137 distinct human gene targets) to derivation and validation cohorts of planned myocardial injury, individuals with spontaneous myocardial infarction, and at-risk controls. RESULTS: We found 376 target proteins that significantly changed in the blood after planned myocardial injury in a derivation cohort (n=20; P<1.05E-05, 1-way repeated measures analysis of variance, Bonferroni threshold). Two hundred forty-seven of these proteins were validated in an independent planned myocardial injury cohort (n=15; P<1.33E-04, 1-way repeated measures analysis of variance); >90% were directionally consistent and reached nominal significance in the validation cohort. Among the validated proteins that were increased within 1 hour after planned myocardial injury, 29 were also elevated in patients with spontaneous myocardial infarction (n=63; P<6.17E-04). Many of the novel markers identified in our study are intracellular proteins not previously identified in the peripheral circulation or have functional roles relevant to myocardial injury. For example, the cardiac LIM protein, cysteine- and glycine-rich protein 3, is thought to mediate cardiac mechanotransduction and stress responses, whereas the mitochondrial ATP synthase F(0) subunit component is a vasoactive peptide on its release from cells. Last, we performed aptamer-affinity enrichment coupled with mass spectrometry to technically verify aptamer specificity for a subset of the new biomarkers. CONCLUSIONS: Our results demonstrate the feasibility of large-scale aptamer multiplexing at a level that has not previously been reported and with sample throughput that greatly exceeds other existing proteomic methods. The expanded aptamer-based proteomic platform provides a unique opportunity for biomarker and pathway discovery after myocardial injury. | Jacob, Jaison Ngo, Debby Finkel, Nancy Pitts, Rebecca Gleim, Scott Benson, Mark D Keyes, Michelle J Farrell, Laurie A Morgan, Thomas Jennings, Lori L Gerszten, Robert E eng P30 DK040561/DK/NIDDK NIH HHS/ T32 HL007208/HL/NHLBI NIH HHS/ K01 GM103817/GM/NIGMS NIH HHS/ HHSN268201000033C/HL/NHLBI NIH HHS/ R01 HL132320/HL/NHLBI NIH HHS/ R01 HL133870/HL/NHLBI NIH HHS/ Comparative Study Research Support, N.I.H., Extramural Validation Study Circulation. 2018 Mar 20;137(12):1270-1277. doi: 10.1161/CIRCULATIONAHA.117.029443. Epub 2017 Dec 8.I | 12/10/2017 | |
| Chemotherapy-induced differential cell cycle arrest in B-cell lymphomas affects their sensitivity to Wee1 inhibition | Wang X, et al. | 2018 | Haematologica | 103 | 3 | 466-476 | https://www.doi.org/10.3324/haematol.2017.175992 | 29,217,775 | Animals Antineoplastic Agents/pharmacology Apoptosis/drug effects Cell Cycle Checkpoints/*drug effects Cell Cycle Proteins/*antagonists & inhibitors Cells, Cultured Cytarabine/pharmacology DNA Damage/drug effects Doxorubicin/pharmacology Drug Synergism Humans Lymphoma, B-Cell/drug therapy/*pathology Mice Nuclear Proteins/*antagonists & inhibitors Protein-Tyrosine Kinases/*antagonists & inhibitors | Chemotherapeutic agents, e.g., cytarabine and doxorubicin, cause DNA damage. However, it remains unknown whether such agents differentially regulate cell cycle arrest in distinct types of B-cell lymphomas, and whether this phenotype can be exploited for developing new therapies. We treated various types of B cells, including primary and B lymphoma cells, with cytarabine or doxorubicin, and determined DNA damage responses, cell cycle regulation and sensitivity to a Wee1 inhibitor. We found that cyclin A2/B1 upregulation appears to be an intrinsic programmed response to DNA damage; however, different types of B cells arrest in distinct phases of the cell cycle. The Wee1 inhibitor significantly enhanced the apoptosis of G2 phase-arrested B-cell lymphomas by inducing premature entry into mitosis and mitotic catastrophe, whereas it did not affect G1/S-phase-arrested lymphomas. Cytarabine-induced G1-arrest can be converted to G2-arrest by doxorubicin treatment in certain B-cell lymphomas, which correlates with newly acquired sensitivity to the Wee1 inhibitor. Consequently, the Wee1 inhibitor together with cytarabine or doxorubicin inhibited tumor growth in vitro and in vivo more effectively, providing a potential new therapy for treating B-cell lymphomas. We propose that the differential cell cycle arrest can be exploited to enhance the chemosensitivity of B-cell lymphomas. | Wang, Xiaoguang Chen, Zhangguo Mishra, Ameet K Silva, Alexa Ren, Wenhua Pan, Zenggang Wang, Jing H eng R01 CA166325/CA/NCI NIH HHS/ Italy Haematologica. 2018 Mar;103(3):466-476. doi: 10.3324/haematol.2017.175992. Epub 2017 Dec 7.I | 12/09/2017 | |
| Vitamin B12 deficiency and impaired expression of amnionless during aging | Pannerec A, et al. | 2018 | J Cachexia Sarcopenia Muscle | 9 | 1 | 41-52 | https://www.doi.org/10.1002/jcsm.12260 | 29,159,972 | Adult Aged Aged, 80 and over Aging Animals Biomarkers/*blood Female Humans Longitudinal Studies Male Membrane Proteins Methylmalonic Acid/*blood Middle Aged Proteins/*metabolism Rats Rats, Wistar Vitamin B 12/*blood Vitamin B 12 Deficiency/*physiopathology Amnionless Cobalamin Frailty Methylmalonic acid Sarcopenia Vitamin B12 | BACKGROUND: Physical frailty and loss of mobility in elderly individuals lead to reduced independence, quality of life, and increased mortality. Vitamin B12 deficiency has been linked to several age-related chronic diseases, including in the musculo-skeletal system, where vitamin B12 deficiency is generally believed to be linked to poor nutritional intake. In the present study, we asked whether aging and frailty associate with altered vitamin B12 homeostasis in humans and investigated the underlying molecular mechanisms using preclinical models. METHODS: We analysed a subset of the Singapore Longitudinal Aging Study and stratified 238 participants based on age and Fried frailty criteria. Levels of methyl-malonic acid (MMA), a marker for vitamin B12 deficiency, and amnionless, the vitamin B12 co-receptor that anchors the vitamin B12 transport complex to the membrane of epithelial cells, were measured in plasma. In addition, vitamin B12 levels and the molecular mechanisms of vitamin B12 uptake and excretion were analysed in ileum, kidney, liver, and blood using a rat model of natural aging where nutritional intake is fully controlled. RESULTS: We demonstrate that aging and frailty are associated with a higher prevalence of functional vitamin B12 deficiency that can be detected by increased levels of MMA in blood (rho = 0.25; P = 0.00013). The decline in circulating vitamin B12 levels is recapitulated in a rat model of natural aging where food composition and intake are stable. At the molecular level, these perturbations involve altered expression of amnionless in the ileum and kidney. Interestingly, we demonstrate that amnionless can be detected in serum where its levels increase during aging in both rodents and human (P = 3.3e-07 and 9.2e-07, respectively). Blood amnionless levels negatively correlate with vitamin B12 in rats (r(2) = 0.305; P = 0.0042) and positively correlate with the vitamin B12 deficiency marker MMA in humans (rho = 0.22; P = 0.00068). CONCLUSIONS: Our results demonstrate that aging and frailty cause intrinsic vitamin B12 deficiencies, which can occur independently of nutritional intake. Mechanistically, vitamin B12 deficiency involves the physio-pathological decline of both the intestinal uptake and the renal reabsorption system for vitamin B12. Finally, amnionless is a novel biomarker which can detect perturbed vitamin B12 bioavailability during aging and physical frailty. | Pannerec, Alice Migliavacca, Eugenia De Castro, Antonio Michaud, Joris Karaz, Sonia Goulet, Laurence Rezzi, Serge Ng, Tze Pin Bosco, Nabil Larbi, Anis Feige, Jerome N eng Germany J Cachexia Sarcopenia Muscle. 2018 Feb;9(1):41-52. doi: 10.1002/jcsm.12260. Epub 2017 Nov 21.I | 11/22/2017 | |
| Diet-resistant obesity is characterized by a distinct plasma proteomic signature and impaired muscle fiber metabolism | Thrush AB, et al. | 2018 | Int J Obes (Lond) | 42 | 3 | 353-362 | https://www.doi.org/10.1038/ijo.2017.286 | 29,151,592 | Biomarkers/blood Blood Proteins/analysis/*metabolism Case-Control Studies Diet Exosomes/metabolism Female Humans Middle Aged Muscle Fibers, Skeletal/*metabolism Muscle, Skeletal/metabolism/physiopathology *Obesity/blood/diet therapy/epidemiology/metabolism Proteome/analysis/*metabolism Treatment Failure | BACKGROUND/OBJECTIVES: Inter-individual variability in weight loss during obesity treatment is complex and poorly understood. Here we use whole body and tissue approaches to investigate fuel oxidation characteristics in skeletal muscle fibers, cells and distinct circulating protein biomarkers before and after a high fat meal (HFM) challenge in those who lost the most (obese diet-sensitive; ODS) vs the least (obese diet-resistant; ODR) amount of weight in a highly controlled weight management program. SUBJECTS/METHODS: In 20 weight stable-matched ODS and ODR women who previously completed a standardized clinical weight loss program, we analyzed whole-body energetics and metabolic parameters in vastus lateralis biopsies and plasma samples that were obtained in the fasting state and 6 h after a defined HFM, equivalent to 35% of total daily energy requirements. RESULTS: At baseline (fasting) and post-HFM, muscle fatty acid oxidation and maximal oxidative phosphorylation were significantly greater in ODS vs ODR, as was reactive oxygen species emission. Plasma proteomics of 1130 proteins pre and 1, 2, 5 and 6 h after the HFM demonstrated distinct group and interaction differences. Group differences identified S-formyl glutathione hydratase, heat shock 70 kDA protein 1A/B (HSP72), and eukaryotic translation initiation factor 5 (eIF5) to be higher in ODS vs ODR. Group-time differences included aryl hydrocarbon interacting protein (AIP), peptidylpropyl isomerase D (PPID) and tyrosine protein-kinase Fgr, which increased in ODR vs ODS over time. HSP72 levels correlated with muscle oxidation and citrate synthase activity. These proteins circulate in exosomes; exosomes isolated from ODS plasma increased resting, leak and maximal respiration rates in C2C12 myotubes by 58%, 21% and 51%, respectively, vs those isolated from ODR plasma. CONCLUSIONS: Findings demonstrate distinct muscle metabolism and plasma proteomics in fasting and post-HFM states corresponding in diet-sensitive vs diet-resistant obese women. | Thrush, A B Antoun, G Nikpay, M Patten, D A DeVlugt, C Mauger, J-F Beauchamp, B L Lau, P Reshke, R Doucet, E Imbeault, P Boushel, R Gibbings, D Hager, J Valsesia, A Slack, R S Al-Dirbashi, O Y Dent, R McPherson, R Harper, M-E eng MOP57810/CIHR/Canada MOP136936/CIHR/Canada Research Support, Non-U.S. Gov't England Int J Obes (Lond). 2018 Mar;42(3):353-362. doi: 10.1038/ijo.2017.286. Epub 2017 Nov 20.I | 11/21/2017 | |
| Non-invasive assessment of non-alcoholic fatty liver disease: Clinical prediction rules and blood-based biomarkers | Vilar-Gomez E, et al. | 2018 | J Hepatol | 68 | 2 | 305-315 | https://www.doi.org/10.1016/j.jhep.2017.11.013 | 29,154,965 | Biomarkers/*blood Decision Support Techniques Humans *Liver Cirrhosis/blood/diagnosis/etiology *Non-alcoholic Fatty Liver Disease/blood/complications/diagnosis Prognosis Apri Fib-4 Nafld Nash | The correct identification of patients at increased risk of non-alcoholic steatohepatitis (NASH) and advanced fibrosis is a critical step in the assessment of non-alcoholic fatty liver disease (NAFLD). Since liver biopsy is invasive, expensive and prone to sampling error, several clinical prediction rules and blood-based biomarkers have been developed as attractive and affordable alternatives for identification of patients at high risk of NASH and advanced fibrosis. Current biomarkers constitute predictive models (e.g. NAFLD fibrosis score, FIB-4 index and BARD score) or direct measures of inflammation (e.g. circulating keratin 18 fragments), or fibrosis (e.g. FibroTest(R), ELF or Pro-C3 tests). In the clinical setting, biomarkers may discriminate between patients with NASH or advanced fibrosis, predict dynamic changes in NASH/fibrosis over time, and provide long-term prognostic information. Although clinically useful, current biomarker predictions may be influenced by hepatic and extrahepatic conditions (e.g. age, patient comorbidities, and fibrosis or NASH prevalence), which may lead to inaccurate estimates in small subsamples of patients. No highly sensitive and specific tests are available to differentiate NASH from simple steatosis. However, diagnostic accuracy can be improved by combining blood biomarkers. NAFLD fibrosis score and FIB-4 index are both cost-effective and highly sensitive tools to exclude patients with advanced fibrosis. Moreover, their higher scores may identify patients at higher risk of non-liver- and liver-related morbidity and mortality. More expensive tests such as FibroTest or ELF are more specific for detection of patients with significant and advanced fibrosis. Recent efforts have concentrated on omics" approaches for developing and validating novel biomarkers. Herein, we describe currently available clinical prediction rules and blood-based biomarkers for identifying NASH and advanced fibrosis in patients with NAFLD, discussing their advantages and disadvantages, as well as their potential clinical utility for predicting dynamic changes over time and identifying patients at increased risk of adverse outcomes." | Vilar-Gomez, Eduardo Chalasani, Naga eng Review Netherlands J Hepatol. 2018 Feb;68(2):305-315. doi: 10.1016/j.jhep.2017.11.013. Epub 2017 Dec 2.I | 11/21/2017 | |
| Identification of novel systemic sclerosis biomarkers employing aptamer proteomic analysis | Wermuth PJ, et al. | 2018 | Rheumatology (Oxford) | 57 | 10 | 1698-1706 | https://www.doi.org/10.1093/rheumatology/kex404 | 29,140,474 | Biomarkers/analysis Humans Proteomics/*methods Scleroderma, Systemic/*diagnosis | There is an important unmet need for clinically validated non-invasive biomarkers for SSc diagnosis, assessment of disease activity, extent of internal organ involvement, therapeutic response and prognosis. There is also an unmet need for biomarkers to accurately differentiate primary RP from recent onset RP evolving into SSc. The lack of sensitive and specific biomarkers for SSc and SSc-associated RP is a limitation for the optimal clinical management of these patients. The development of highly sensitive and specific proteomic analysis employing aptamers and the expansion in the number of proteins that can be specifically identified by aptamer proteomics have opened new horizons for biomarker discovery. Here, we review the background and rationale for aptamer proteomic analysis for the identification of novel non-invasive biomarkers for SSc and recent onset RP evolving into SSc. Large scale application of aptamer proteomic platforms for this purpose will be of substantial value for the precision and personalized medical care of SSc patients. These studies will be placed in context by comparison with proteomic biomarker studies performed for other rheumatological inflammatory and autoimmune diseases. | Wermuth, Peter J Piera-Velazquez, Sonsoles Jimenez, Sergio A eng Review England Rheumatology (Oxford). 2018 Oct 1;57(10):1698-1706. doi: 10.1093/rheumatology/kex404.I | 11/16/2017 | |
| Early Identification of Bronchopulmonary Dysplasia Using Novel Biomarkers by Proteomic Screening | Forster K, et al. | 2018 | Am J Respir Crit Care Med | 197 | 8 | 1076-1080 | https://www.doi.org/10.1164/rccm.201706-1218LE | 29,053,024 | Age Factors Biomarkers/*blood Bronchopulmonary Dysplasia/*blood/*diagnosis *Early Diagnosis Female Gestational Age Humans Infant, Newborn Infant, Premature/*blood Male Proteomics/*methods | Forster, Kai Sass, Steffen Ehrhardt, Harald Mous, Daphne S Rottier, Robbert J Oak, Prajakta Schulze, Andreas Flemmer, Andreas W Gronbach, Judith Hubener, Christoph Desai, Tushar Eickelberg, Oliver Theis, Fabian J Hilgendorff, Anne eng Comparative Study Letter Research Support, Non-U.S. Gov't Am J Respir Crit Care Med. 2018 Apr 15;197(8):1076-1080. doi: 10.1164/rccm.201706-1218LE.I | 10/21/2017 | ||
| Improving Assessment of Drug Safety Through Proteomics: Early Detection and Mechanistic Characterization of the Unforeseen Harmful Effects of Torcetrapib | Williams SA, et al. | 2018 | Circulation | 137 | 10 | 999-1010 | https://www.doi.org/10.1161/CIRCULATIONAHA.117.028213 | 28,974,520 | Aged Aldosterone/metabolism Anticholesteremic Agents/*adverse effects/therapeutic use Biomarkers, Pharmacological Case-Control Studies Cholesterol Ester Transfer Proteins/antagonists & inhibitors Drug-Related Side Effects and Adverse Reactions/*metabolism/mortality Early Diagnosis Female Heart Failure/etiology/*metabolism/mortality Humans Male Middle Aged Myocardial Infarction/etiology/*metabolism/mortality Prognosis Prospective Studies Proteomics Quinolines/*adverse effects/therapeutic use Stroke/etiology/*metabolism/mortality Survival Analysis aptamers biomarkers peptides precision medicine prescription drugs proteins | BACKGROUND: Early detection of adverse effects of novel therapies and understanding of their mechanisms could improve the safety and efficiency of drug development. We have retrospectively applied large-scale proteomics to blood samples from ILLUMINATE (Investigation of Lipid Level Management to Understand its Impact in Atherosclerotic Events), a trial of torcetrapib (a cholesterol ester transfer protein inhibitor), that involved 15 067 participants at high cardiovascular risk. ILLUMINATE was terminated at a median of 550 days because of significant absolute increases of 1.2% in cardiovascular events and 0.4% in mortality with torcetrapib. The aims of our analysis were to determine whether a proteomic analysis might reveal biological mechanisms responsible for these harmful effects and whether harmful effects of torcetrapib could have been detected early in the ILLUMINATE trial with proteomics. METHODS: A nested case-control analysis of paired plasma samples at baseline and at 3 months was performed in 249 participants assigned to torcetrapib plus atorvastatin and 223 participants assigned to atorvastatin only. Within each treatment arm, cases with events were matched to controls 1:1. Main outcomes were a survey of 1129 proteins for discovery of biological pathways altered by torcetrapib and a 9-protein risk score validated to predict myocardial infarction, stroke, heart failure, or death. RESULTS: Plasma concentrations of 200 proteins changed significantly with torcetrapib. Their pathway analysis revealed unexpected and widespread changes in immune and inflammatory functions, as well as changes in endocrine systems, including in aldosterone function and glycemic control. At baseline, 9-protein risk scores were similar in the 2 treatment arms and higher in participants with subsequent events. At 3 months, the absolute 9-protein derived risk increased in the torcetrapib plus atorvastatin arm compared with the atorvastatin-only arm by 1.08% (P=0.0004). Thirty-seven proteins changed in the direction of increased risk of 49 proteins previously associated with cardiovascular and mortality risk. CONCLUSIONS: Heretofore unknown effects of torcetrapib were revealed in immune and inflammatory functions. A protein-based risk score predicted harm from torcetrapib within just 3 months. A protein-based risk assessment embedded within a large proteomic survey may prove to be useful in the evaluation of therapies to prevent harm to patients. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00134264. | Williams, Stephen A Murthy, Ashwin C DeLisle, Robert K Hyde, Craig Malarstig, Anders Ostroff, Rachel Weiss, Sophie J Segal, Mark R Ganz, Peter eng R01 AG052964/AG/NIA NIH HHS/ R01 HL129856/HL/NHLBI NIH HHS/ U01 DK108809/DK/NIDDK NIH HHS/ Randomized Controlled Trial Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Circulation. 2018 Mar 6;137(10):999-1010. doi: 10.1161/CIRCULATIONAHA.117.028213. Epub 2017 Oct 3.I | 10/05/2017 | |
| Serum proteomic assessment of the progression of fracture healing | Hussein AI, et al. | 2018 | J Orthop Res | 36 | 4 | 1153-1163 | https://www.doi.org/10.1002/jor.23754 | 28,971,515 | Animals Biomarkers/*blood Bone and Bones/pathology Femoral Fractures/diagnostic imaging/pathology *Fracture Healing Male Mice, Inbred C57BL *Proteome Radiography animal models: preclinical studies fracture healing microarray serum biomarkers | A targeted proteomic analysis of murine serum over a 35-day course of fracture healing was carried out to determine if serum proteomic changes could be used to monitor the biological progression of fracture healing. Transverse, closed femoral fractures where generated and stabilized with intramedullary fixation. A single stranded DNA aptamer-based multiplexed proteomic approach was used to assay 1,310 proteins. The transcriptomic profiles for genes matching the 1,310 proteins were obtained by microarray analysis of callus mRNA. Of the 1,310 proteins analyzed, 850 proteins showed significant differences among the time points (p-value <0.05). Ontology assessment associated these proteins with osteoblasts, monocyte/macrophage lineages, mesenchymal stem cell lines, hepatic tissues, and lymphocytes. Temporal clustering of these data identified proteins associated with inflammation, cartilage formation and bone remodeling stages of healing. VEGF, Wnt, and TGF-betasignaling pathways were restricted to the period of cartilage formation. Comparison of the proteomic and transcriptomic profiles showed that 87.5% of proteins in serum had concordant expression to their mRNA expression in the callus, while 12.5% of the protein and mRNA expression patterns were discordant. The discordant proteins that were elevated in the serum but down regulated in callus mRNA expression were related to clotting functions, allograft rejection, and complement function. While proteins down regulated in the serum and elevated in callus mRNA were associated with osteoblast function, NF-kb, and activin signaling. These data show the serum proteome may be used to monitor the different biological stages of fracture healing and have translational potential in assessing human fracture healing. (c) 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1153-1163, 2018. | Hussein, Amira I Mancini, Christian Lybrand, Kyle E Cooke, Margaret E Matheny, Heather E Hogue, Brenna L Tornetta, Paul 3rd Gerstenfeld, Louis C eng R01 AR059741/AR/NIAMS NIH HHS/ R21 AR067900/AR/NIAMS NIH HHS/ TL1 TR001410/TR/NCATS NIH HHS/ UL1 TR001430/TR/NCATS NIH HHS/ Research Support, N.I.H., Extramural J Orthop Res. 2018 Apr;36(4):1153-1163. doi: 10.1002/jor.23754. Epub 2017 Nov 22.I | 10/04/2017 | |
| Toll-like receptor 3 blockade in rhinovirus-induced experimental asthma exacerbations: A randomized controlled study | Silkoff PE, et al. | 2018 | J Allergy Clin Immunol | 141 | 4 | 1220-1230 | https://www.doi.org/10.1016/j.jaci.2017.06.027 | 28,734,844 | Adolescent Adult Aged Anti-Inflammatory Agents/*therapeutic use Antibodies, Monoclonal/*therapeutic use Asthma/diagnosis/*drug therapy/immunology/*virology Disease Progression Double-Blind Method Female Healthy Volunteers Humans Male Middle Aged Picornaviridae Infections/*complications/drug therapy/immunology *Rhinovirus Severity of Illness Index Toll-Like Receptor 3/*antagonists & inhibitors Treatment Outcome Young Adult Asthma Toll-like receptor 3 inflammation viral infection | BACKGROUND: Human rhinoviruses (HRVs) commonly precipitate asthma exacerbations. Toll-like receptor 3, an innate pattern recognition receptor, is triggered by HRV, driving inflammation that can worsen asthma. OBJECTIVE: We sought to evaluate an inhibitory mAb to Toll-like receptor 3, CNTO3157, on experimental HRV-16 inoculation in healthy subjects and asthmatic patients. METHODS: In this double-blind, multicenter, randomized, parallel-group study in North America and Europe, healthy subjects and patients with mild-to-moderate stable asthma received single or multiple doses of CNTO3157 or placebo, respectively, and were then inoculated with HRV-16 within 72 hours. All subjects were monitored for respiratory symptoms, lung function, and nasal viral load. The primary end point was maximal decrease in FEV(1) during 10 days after inoculation. RESULTS: In asthmatic patients (n = 63) CNTO3157 provided no protection against FEV(1) decrease (least squares mean: CNTO3157 [n = 30] = -7.08% [SE, 8.15%]; placebo [n = 25] = -5.98% [SE, 8.56%]) or symptoms after inoculation. In healthy subjects (n = 12) CNTO3157 versus placebo significantly attenuated upper (P = .03) and lower (P = .02) airway symptom scores, with area-under-the-curve increases of 9.1 (15.1) versus 34.9 (17.6) and 13.0 (18.4) versus 50.4 (25.9) for the CNTO3157 (n = 8) and placebo (n = 4) groups, respectively, after inoculation. All of the severe and 4 of the nonserious asthma exacerbations occurred while receiving CNTO3157. CONCLUSION: In summary, CNTO3157 was ineffective in attenuating the effect of HRV-16 challenge on lung function, asthma control, and symptoms in asthmatic patients but suppressed cold symptoms in healthy subjects. Other approaches, including blockade of multiple pathways or antiviral agents, need to be sought for this high unmet medical need. | Silkoff, Philip E Flavin, Susan Gordon, Robert Loza, Mathew J Sterk, Peter J Lutter, Rene Diamant, Zuzana Turner, Ronald B Lipworth, Brian J Proud, David Singh, Dave Eich, Andreas Backer, Vibeke Gern, James E Herzmann, Christian Halperin, Scott A Mensinga, Tjeert T Del Vecchio, Alfred M Branigan, Patrick San Mateo, Lani Baribaud, Frederic Barnathan, Elliot S Johnston, Sebastian L eng G1000758/MRC_/Medical Research Council/United Kingdom Multicenter Study Randomized Controlled Trial Research Support, Non-U.S. Gov't J Allergy Clin Immunol. 2018 Apr;141(4):1220-1230. doi: 10.1016/j.jaci.2017.06.027. Epub 2017 Jul 20.I | 07/25/2017 | |
| Proteomic Profiles Associated with Early Echocardiogram Evidence of Pulmonary Vascular Disease in Preterm Infants | Wagner BD, et al. | 2018 | Am J Respir Crit Care Med | 197 | 3 | 394-397 | https://www.doi.org/10.1164/rccm.201703-0654LE | 28,650,220 | Biomarkers/blood Bronchopulmonary Dysplasia/*blood/diagnostic imaging/physiopathology Cohort Studies Echocardiography, Doppler/*methods Female Follow-Up Studies Humans Hypertension, Pulmonary/*blood/diagnostic imaging/physiopathology Infant, Newborn *Infant, Premature Male Prospective Studies Proteomics Risk Assessment Vascular Diseases/*blood/diagnostic imaging | Wagner, Brandie D Babinec, Ana E Carpenter, Charlie Gonzalez, Samantha O'Brien, Grace Rollock, Kara Williamson, Kayla Mourani, Peter M Abman, Steven H eng R01 HL085703/HL/NHLBI NIH HHS/ UL1 TR000154/TR/NCATS NIH HHS/ K23 RR021921/RR/NCRR NIH HHS/ R25 HL131486/HL/NHLBI NIH HHS/ R01 HL068702/HL/NHLBI NIH HHS/ Observational Study Research Support, N.I.H., Extramural Am J Respir Crit Care Med. 2018 Feb 1;197(3):394-397. doi: 10.1164/rccm.201703-0654LE.I | 06/27/2017 | ||
| Sputum transcriptomics reveal upregulation of IL-1 receptor family members in patients with severe asthma | Rossios C, et al. | 2018 | J Allergy Clin Immunol | 141 | 2 | 560-570 | https://www.doi.org/10.1016/j.jaci.2017.02.045 | 28,528,200 | Adult Animals Asthma/*immunology/pathology Eosinophils/immunology/pathology Female *Gene Expression Profiling Humans Male Mice Middle Aged Neutrophils/immunology/pathology Receptors, Interleukin-1/*immunology Sputum/*immunology Th2 Cells/immunology/pathology Up-Regulation/*immunology C-reactive protein IL-1alpha IL-1beta IL-33 receptor Severe asthma T(h)2 eosinophil exhaled nitric oxide inflammasome neutrophil | BACKGROUND: Sputum analysis in asthmatic patients is used to define airway inflammatory processes and might guide therapy. OBJECTIVE: We sought to determine differential gene and protein expression in sputum samples from patients with severe asthma (SA) compared with nonsmoking patients with mild/moderate asthma. METHODS: Induced sputum was obtained from nonsmoking patients with SA, smokers/ex-smokers with severe asthma, nonsmoking patients with mild/moderate asthma (MMAs), and healthy nonsmoking control subjects. Differential cell counts, microarray analysis of cell pellets, and SOMAscan analysis of sputum analytes were performed. CRID3 was used to inhibit the inflammasome in a mouse model of SA. RESULTS: Eosinophilic and mixed neutrophilic/eosinophilic inflammation were more prevalent in patients with SA compared with MMAs. Forty-two genes probes were upregulated (>2-fold) in nonsmoking patients with severe asthma compared with MMAs, including IL-1 receptor (IL-1R) family and nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain containing 3 (NRLP3) inflammasome members (false discovery rate < 0.05). The inflammasome proteins nucleotide-binding oligomerization domain, leucine rich repeat and pyrin domain containing 1 (NLRP1), NLRP3, and nucleotide-binding oligomerization domain (NOD)-like receptor C4 (NLRC4) were associated with neutrophilic asthma and with sputum IL-1beta protein levels, whereas eosinophilic asthma was associated with an IL-13-induced T(H)2 signature and IL-1 receptor-like 1 (IL1RL1) mRNA expression. These differences were sputum specific because no activation of NLRP3 or enrichment of IL-1R family genes in bronchial brushings or biopsy specimens in patients with SA was observed. Expression of NLRP3 and of the IL-1R family genes was validated in the Airway Disease Endotyping for Personalized Therapeutics cohort. Inflammasome inhibition using CRID3 prevented airway hyperresponsiveness and airway inflammation (both neutrophilia and eosinophilia) in a mouse model of severe allergic asthma. CONCLUSION: IL1RL1 gene expression is associated with eosinophilic SA, whereas NLRP3 inflammasome expression is highest in patients with neutrophilic SA. T(H)2-driven eosinophilic inflammation and neutrophil-associated inflammasome activation might represent interacting pathways in patients with SA. | Rossios, Christos Pavlidis, Stelios Hoda, Uruj Kuo, Chih-Hsi Wiegman, Coen Russell, Kirsty Sun, Kai Loza, Matthew J Baribaud, Frederic Durham, Andrew L Ojo, Oluwaseun Lutter, Rene Rowe, Anthony Bansal, Aruna Auffray, Charles Sousa, Ana Corfield, Julie Djukanovic, Ratko Guo, Yike Sterk, Peter J Chung, Kian Fan Adcock, Ian M (U-BIOPRED) eng G1000758/MRC_/Medical Research Council/United Kingdom Department of Health/United Kingdom Clinical Trial Multicenter Study Research Support, Non-U.S. Gov't J Allergy Clin Immunol. 2018 Feb;141(2):560-570. doi: 10.1016/j.jaci.2017.02.045. Epub 2017 May 18.I | 05/22/2017 | |
| The differential plasma proteome of obese and overweight individuals undergoing a nutritional weight loss and maintenance intervention | Oller Moreno S, et al. | 2018 | Proteomics Clin Appl | 12 | 1 | https://www.doi.org/10.1002/prca.201600150 | 28,371,297 | Adiponectin/blood/genetics Adult Biomarkers/blood Blood Proteins/*genetics/metabolism Body Mass Index C-Reactive Protein/genetics/metabolism Diet, Reducing/methods Female Humans *Insulin Resistance Leukocyte L1 Antigen Complex/blood/genetics Longitudinal Studies Male Middle Aged Obesity/blood/*diet therapy/genetics/pathology Pregnancy Proteins/blood/genetics Proteoglycans/blood/genetics Proteome/*genetics/metabolism Serum Amyloid A Protein/genetics/metabolism Sex Hormone-Binding Globulin/genetics/metabolism Tandem Mass Spectrometry Weight Loss/physiology Weight Reduction Programs/*methods Biomarker Diabetes Large-scale study Mass spectrometry Obesity | PURPOSE: The nutritional intervention program DiOGenes" focuses on how obesity can be prevented and treated from a dietary perspective. We generated differential plasma proteome profiles in the DiOGenes cohort to identify proteins associated with weight loss and maintenance and explore their relation to body mass index, fat mass, insulin resistance, and sensitivity. EXPERIMENTAL DESIGN: Relative protein quantification was obtained at baseline and after combined weight loss/maintenance phases using isobaric tagging and MS/MS. A Welch t-test determined proteins differentially present after intervention. Protein relationships with clinical variables were explored using univariate linear models, considering collection center, gender and age as confounding factors. RESULTS: Four hundred and seventy three subjects were measured at baseline and end of the intervention; 39 proteins were longitudinally differential. Proteins with largest changes were sex hormone-binding globulin, adiponectin, C-reactive protein, calprotectin, serum amyloid A, and proteoglycan 4 (PRG4), whose association with obesity and weight loss is known. We identified new putative biomarkers for weight loss/maintenance. Correlation between PRG4 and proline-rich acidic protein 1 variation and Matsuda insulin sensitivity increment was showed. CONCLUSION AND CLINICAL RELEVANCE: MS-based proteomic analysis of a large cohort of non-diabetic overweight and obese individuals concomitantly identified known and novel proteins associated with weight loss and maintenance." | Oller Moreno, Sergio Cominetti, Ornella Nunez Galindo, Antonio Irincheeva, Irina Corthesy, John Astrup, Arne Saris, Wim H M Hager, Jorg Kussmann, Martin Dayon, Loic eng Clinical Trial Multicenter Study Research Support, Non-U.S. Gov't Germany Proteomics Clin Appl. 2018 Jan;12(1). doi: 10.1002/prca.201600150. Epub 2017 May 15.I | 04/04/2017 | ||
| Protein quantitative trait locus study in obesity during weight-loss identifies a leptin regulator | Carayol J, et al. | 2017 | Nat Commun | 8 | 1 | 2084 | https://www.doi.org/10.1038/s41467-017-02182-z | 29,234,017 | Adolescent Adult *Body Mass Index Female Gene Regulatory Networks Humans Leptin/*genetics/metabolism Male Middle Aged Obesity/diet therapy/*genetics/metabolism Polynucleotide Adenylyltransferase Proteins/genetics/*metabolism Proteomics/methods *Quantitative Trait Loci Regulatory Elements, Transcriptional Weight Loss/genetics Young Adult | Thousands of genetic variants have been associated with complex traits through genome-wide association studies. However, the functional variants or mechanistic consequences remain elusive. Intermediate traits such as gene expression or protein levels are good proxies of the metabolic state of an organism. Proteome analysis especially can provide new insights into the molecular mechanisms of complex traits like obesity. The role of genetic variation in determining protein level variation has not been assessed in obesity. To address this, we design a large-scale protein quantitative trait locus (pQTL) analysis based on a set of 1129 proteins from 494 obese subjects before and after a weight loss intervention. This reveals 55 BMI-associated cis-pQTLs and trans-pQTLs at baseline and 3 trans-pQTLs after the intervention. We provide evidence for distinct genetic mechanisms regulating BMI-associated proteins before and after weight loss. Finally, by functional analysis, we identify and validate FAM46A as a trans regulator for leptin. | Carayol, Jerome Chabert, Christian Di Cara, Alessandro Armenise, Claudia Lefebvre, Gregory Langin, Dominique Viguerie, Nathalie Metairon, Sylviane Saris, Wim H M Astrup, Arne Descombes, Patrick Valsesia, Armand Hager, Jorg eng Multicenter Study Randomized Controlled Trial Research Support, Non-U.S. Gov't England Nat Commun. 2017 Dec 12;8(1):2084. doi: 10.1038/s41467-017-02182-z.I | 12/14/2017 | |
| A degradation fragment of type X collagen is a real-time marker for bone growth velocity | Coghlan RF, et al. | 2017 | Sci Transl Med | 9 | 419 | https://www.doi.org/10.1126/scitranslmed.aan4669 | 29,212,713 | Adult Animals Bone Development/*physiology Collagen Type X/*metabolism Enzyme-Linked Immunosorbent Assay Female Fracture Healing/*physiology Humans Male Mice Young Adult | Despite its importance as a key parameter of child health and development, growth velocity is difficult to determine in real time because skeletal growth is slow and clinical tools to accurately detect very small increments of growth do not exist. We report discovery of a marker for skeletal growth in infants and children. The intact trimeric noncollagenous 1 (NC1) domain of type X collagen, the marker we designated as CXM for Collagen X Marker, is a degradation by-product of endochondral ossification that is released into the circulation in proportion to overall growth plate activity. This marker corresponds to the rate of linear bone growth at time of measurement. Serum concentrations of CXM plotted against age show a pattern similar to well-established height growth velocity curves and correlate with height growth velocity calculated from incremental height measurements in this study. The CXM marker is stable once collected and can be accurately assayed in serum, plasma, and dried blood spots. CXM testing may be useful for monitoring growth in the pediatric population, especially responses of infants and children with genetic and acquired growth disorders to interventions that target the underlying growth disturbances. The utility of CXM may potentially extend to managing other conditions such as fracture healing, scoliosis, arthritis, or cancer. | Coghlan, Ryan F Oberdorf, Jon A Sienko, Susan Aiona, Michael D Boston, Bruce A Connelly, Kara J Bahney, Chelsea LaRouche, Jeremie Almubarak, Sarah M Coleman, Daniel T Girkontaite, Irute von der Mark, Klaus Lunstrum, Gregory P Horton, William A eng Sci Transl Med. 2017 Dec 6;9(419):eaan4669. doi: 10.1126/scitranslmed.aan4669.I | 12/08/2017 | ||
| A Pilot Characterization of the Human Chronobiome | Skarke C, et al. | 2017 | Sci Rep | 7 | 1 | 17141 | https://www.doi.org/10.1038/s41598-017-17362-6 | 29,215,023 | Adult Blood Pressure Blood Proteins/metabolism *Circadian Rhythm Heart Rate Humans Hydrocortisone/metabolism Male *Metabolome *Microbiota Mouth/metabolism Pilot Projects *Proteome Saliva/metabolism Time Factors *Transcriptome | Physiological function, disease expression and drug effects vary by time-of-day. Clock disruption in mice results in cardio-metabolic, immunological and neurological dysfunction; circadian misalignment using forced desynchrony increases cardiovascular risk factors in humans. Here we integrated data from remote sensors, physiological and multi-omics analyses to assess the feasibility of detecting time dependent signals - the chronobiome - despite the noise" attributable to the behavioral differences of free-living human volunteers. The majority (62%) of sensor readouts showed time-specific variability including the expected variation in blood pressure, heart rate, and cortisol. While variance in the multi-omics is dominated by inter-individual differences, temporal patterns are evident in the metabolome (5.4% in plasma, 5.6% in saliva) and in several genera of the oral microbiome. This demonstrates, despite a small sample size and limited sampling, the feasibility of characterizing at scale the human chronobiome "in the wild". Such reference data at scale are a prerequisite to detect and mechanistically interpret discordant data derived from patients with temporal patterns of disease expression, to develop time-specific therapeutic strategies and to refine existing treatments." | Skarke, Carsten Lahens, Nicholas F Rhoades, Seth D Campbell, Amy Bittinger, Kyle Bailey, Aubrey Hoffmann, Christian Olson, Randal S Chen, Lihong Yang, Guangrui Price, Thomas S Moore, Jason H Bushman, Frederic D Greene, Casey S Grant, Gregory R Weljie, Aalim M FitzGerald, Garret A eng P30 ES013508/ES/NIEHS NIH HHS/ UL1 RR024134/RR/NCRR NIH HHS/ UL1 TR000003/TR/NCATS NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't England Sci Rep. 2017 Dec 7;7(1):17141. doi: 10.1038/s41598-017-17362-6.I | 12/08/2017 | |
| Large-scale proteomics identifies MMP-7 as a sentinel of epithelial injury and of biliary atresia | Lertudomphonwanit C, et al. | 2017 | Sci Transl Med | 9 | 417 | https://www.doi.org/10.1126/scitranslmed.aan8462 | 29,167,395 | Animals Biliary Atresia/*metabolism/pathology Biomarkers/metabolism Cholestasis/metabolism/pathology Disease Models, Animal Humans Matrix Metalloproteinase 7/genetics/*metabolism Proteomics/*methods | Biliary atresia is a progressive infantile cholangiopathy of complex pathogenesis. Although early diagnosis and surgery are the best predictors of treatment response, current diagnostic approaches are imprecise and time-consuming. We used large-scale, quantitative serum proteomics at the time of diagnosis of biliary atresia and other cholestatic syndromes (serving as disease controls) to identify biomarkers of disease. In a discovery cohort of 70 subjects, the lead biomarker was matrix metalloproteinase-7 (MMP-7), which retained high distinguishing features for biliary atresia in two validation cohorts. Notably, the diagnostic performance reached 95% when MMP-7 was combined with gamma-glutamyltranspeptidase (GGT), a marker of cholestasis. Using human tissue and an experimental model of biliary atresia, we found that MMP-7 is primarily expressed by cholangiocytes, released upon epithelial injury, and promotes the experimental disease phenotype. Thus, we propose that serum MMP-7 (alone or in combination with GGT) is a diagnostic biomarker for biliary atresia and may serve as a therapeutic target. | Lertudomphonwanit, Chatmanee Mourya, Reena Fei, Lin Zhang, Yue Gutta, Sridevi Yang, Li Bove, Kevin E Shivakumar, Pranavkumar Bezerra, Jorge A eng P30 DK078392/DK/NIDDK NIH HHS/ R01 DK064008/DK/NIDDK NIH HHS/ R01 DK083781/DK/NIDDK NIH HHS/ U01 DK062497/DK/NIDDK NIH HHS/ Sci Transl Med. 2017 Nov 22;9(417):eaan8462. doi: 10.1126/scitranslmed.aan8462.I | 11/24/2017 | ||
| Sequential inflammatory processes define human progression from M. tuberculosis infection to tuberculosis disease | Scriba TJ, et al. | 2017 | PLoS Pathog | 13 | 11 | e1006687 | https://www.doi.org/10.1371/journal.ppat.1006687 | 29,145,483 | Adolescent Child Disease Progression Humans Inflammation/complications/immunology/therapy *Mycobacterium tuberculosis T-Lymphocytes/*immunology Tuberculosis/*microbiology/*therapy Vaccines/therapeutic use | Our understanding of mechanisms underlying progression from Mycobacterium tuberculosis infection to pulmonary tuberculosis disease in humans remains limited. To define such mechanisms, we followed M. tuberculosis-infected adolescents longitudinally. Blood samples from forty-four adolescents who ultimately developed tuberculosis disease (progressors") were compared with those from 106 matched controls, who remained healthy during two years of follow up. We performed longitudinal whole blood transcriptomic analyses by RNA sequencing and plasma proteome analyses using multiplexed slow off-rate modified DNA aptamers. Tuberculosis progression was associated with sequential modulation of immunological processes. Type I/II interferon signalling and complement cascade were elevated 18 months before tuberculosis disease diagnosis, while changes in myeloid inflammation, lymphoid, monocyte and neutrophil gene modules occurred more proximally to tuberculosis disease. Analysis of gene expression in purified T cells also revealed early suppression of Th17 responses in progressors, relative to M. tuberculosis-infected controls. This was confirmed in an independent adult cohort who received BCG re-vaccination; transcript expression of interferon response genes in blood prior to BCG administration was associated with suppression of IL-17 expression by BCG-specific CD4 T cells 3 weeks post-vaccination. Our findings provide a timeline to the different immunological stages of disease progression which comprise sequential inflammatory dynamics and immune alterations that precede disease manifestations and diagnosis of tuberculosis disease. These findings have important implications for developing diagnostics, vaccination and host-directed therapies for tuberculosis. TRIAL REGISTRATION: Clincialtrials.gov, NCT01119521." | Scriba, Thomas J Penn-Nicholson, Adam Shankar, Smitha Hraha, Tom Thompson, Ethan G Sterling, David Nemes, Elisa Darboe, Fatoumatta Suliman, Sara Amon, Lynn M Mahomed, Hassan Erasmus, Mzwandile Whatney, Wendy Johnson, John L Boom, W Henry Hatherill, Mark Valvo, Joe De Groote, Mary Ann Ochsner, Urs A Aderem, Alan Hanekom, Willem A Zak, Daniel E eng D43 TW000231/TW/FIC NIH HHS/ N01AI70022/AI/NIAID NIH HHS/ R01 AI087915/AI/NIAID NIH HHS/ N01AI95383/AI/NIAID NIH HHS/ U19 AI106761/AI/NIAID NIH HHS/ Clinical Trial PLoS Pathog. 2017 Nov 16;13(11):e1006687. doi: 10.1371/journal.ppat.1006687. eCollection 2017 Nov.I | 11/18/2017 | |
| Divergent roles for Clusterin in Lung Injury and Repair | Habiel DM, et al. | 2017 | Sci Rep | 7 | 1 | 15444 | https://www.doi.org/10.1038/s41598-017-15670-5 | 29,133,960 | Aged Animals Apoptosis Bleomycin/adverse effects Case-Control Studies Cell Line Clusterin/blood/genetics/*metabolism Cytoplasm/metabolism DNA Breaks, Double-Stranded DNA Mismatch Repair Datasets as Topic Disease Models, Animal Epithelial Cells/pathology Extracellular Space/metabolism Female Fibrosis Gene Expression Profiling Gene Knockdown Techniques Humans Idiopathic Pulmonary Fibrosis/blood/chemically induced/genetics/*pathology Lung/drug effects/*pathology Male Mice Mice, Inbred C57BL Mice, Knockout Middle Aged Pulmonary Disease, Chronic Obstructive/blood/*pathology RNA, Small Interfering/metabolism Respiratory Mucosa/cytology/pathology | Lung fibrosis is an unabated wound healing response characterized by the loss and aberrant function of lung epithelial cells. Herein, we report that extracellular Clusterin promoted epithelial cell apoptosis whereas intracellular Clusterin maintained epithelium viability during lung repair. Unlike normal and COPD lungs, IPF lungs were characterized by significantly increased extracellular Clusterin whereas the inverse was evident for intracellular Clusterin. In vitro and in vivo studies demonstrated that extracellular Clusterin promoted epithelial cell apoptosis while intercellular Clusterin modulated the expression of the DNA repair proteins, MSH2, MSH6, OGG1 and BRCA1. The fibrotic response in Clusterin deficient (CLU-/-) mice persisted after bleomycin and it was associated with increased DNA damage, reduced DNA repair responses, and elevated cellular senescence. Remarkably, this pattern mirrored that observed in IPF lung tissues. Together, our results show that cellular localization of Clusterin leads to divergent effects on epithelial cell regeneration and lung repair during fibrosis. | Habiel, David M Camelo, Ana Espindola, Milena Burwell, Timothy Hanna, Richard Miranda, Elena Carruthers, Alan Bell, Matthew Coelho, Ana Lucia Liu, Hao Pilataxi, Fernanda Clarke, Lori Grant, Ethan Lewis, Arthur Moore, Bethany Knight, Darryl A Hogaboam, Cory M Murray, Lynne A eng R01 HL123899/HL/NHLBI NIH HHS/ RC2 HL101740/HL/NHLBI NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't England Sci Rep. 2017 Nov 13;7(1):15444. doi: 10.1038/s41598-017-15670-5.I | 11/15/2017 | |
| Trisomy 21 causes changes in the circulating proteome indicative of chronic autoinflammation | Sullivan KD, et al. | 2017 | Sci Rep | 7 | 1 | 14818 | https://www.doi.org/10.1038/s41598-017-13858-3 | 29,093,484 | Adolescent Adult Child Child, Preschool Chronic Disease Complement System Proteins/analysis Cytokines/blood Down Syndrome/*blood/complications Female Humans Infant Inflammation/*blood/complications Male Proteome/*analysis Receptors, Growth Factor/blood Trisomy Young Adult | Trisomy 21 (T21) causes Down syndrome (DS), but the mechanisms by which T21 produces the different disease spectrum observed in people with DS are unknown. We recently identified an activated interferon response associated with T21 in human cells of different origins, consistent with overexpression of the four interferon receptors encoded on chromosome 21, and proposed that DS could be understood partially as an interferonopathy. However, the impact of T21 on systemic signaling cascades in living individuals with DS is undefined. To address this knowledge gap, we employed proteomics approaches to analyze blood samples from 263 individuals, 165 of them with DS, leading to the identification of dozens of proteins that are consistently deregulated by T21. Most prominent among these proteins are numerous factors involved in immune control, the complement cascade, and growth factor signaling. Importantly, people with DS display higher levels of many pro-inflammatory cytokines (e.g. IL-6, MCP-1, IL-22, TNF-alpha) and pronounced complement consumption, resembling changes seen in type I interferonopathies and other autoinflammatory conditions. Therefore, these results are consistent with the hypothesis that increased interferon signaling caused by T21 leads to chronic immune dysregulation, and justify investigations to define the therapeutic value of immune-modulatory strategies in DS. | Sullivan, Kelly D Evans, Donald Pandey, Ahwan Hraha, Thomas H Smith, Keith P Markham, Neil Rachubinski, Angela L Wolter-Warmerdam, Kristine Hickey, Francis Espinosa, Joaquin M Blumenthal, Thomas eng Research Support, Non-U.S. Gov't England Sci Rep. 2017 Nov 1;7(1):14818. doi: 10.1038/s41598-017-13858-3.I | 11/03/2017 | |
| Assessment of Variability in the SOMAscan Assay | Candia J, et al. | 2017 | Sci Rep | 7 | 1 | 14248 | https://www.doi.org/10.1038/s41598-017-14755-5 | 29,079,756 | Adult Aptamers, Nucleotide/*metabolism Blood Proteins/*metabolism Calibration Female Humans Male Middle Aged Proteomics/*methods Reproducibility of Results | SOMAscan is an aptamer-based proteomics assay capable of measuring 1,305 human protein analytes in serum, plasma, and other biological matrices with high sensitivity and specificity. In this work, we present a comprehensive meta-analysis of performance based on multiple serum and plasma runs using the current 1.3 k assay, as well as the previous 1.1 k version. We discuss normalization procedures and examine different strategies to minimize intra- and interplate nuisance effects. We implement a meta-analysis based on calibrator samples to characterize the coefficient of variation and signal-over-background intensity of each protein analyte. By incorporating coefficient of variation estimates into a theoretical model of statistical variability, we also provide a framework to enable rigorous statistical tests of significance in intervention studies and clinical trials, as well as quality control within and across laboratories. Furthermore, we investigate the stability of healthy subject baselines and determine the set of analytes that exhibit biologically stable baselines after technical variability is factored in. This work is accompanied by an interactive web-based tool, an initiative with the potential to become the cornerstone of a regularly updated, high quality repository with data sharing, reproducibility, and reusability as ultimate goals. | Candia, Julian Cheung, Foo Kotliarov, Yuri Fantoni, Giovanna Sellers, Brian Griesman, Trevor Huang, Jinghe Stuccio, Sarah Zingone, Adriana Ryan, Brid M Tsang, John S Biancotto, Angelique eng Research Support, N.I.H., Extramural Research Support, N.I.H., Intramural England Sci Rep. 2017 Oct 27;7(1):14248. doi: 10.1038/s41598-017-14755-5.I | 10/29/2017 | |
| Molecular-based diagnosis of multiple sclerosis and its progressive stage | Barbour C, et al. | 2017 | Ann Neurol | 82 | 5 | 795-812 | https://www.doi.org/10.1002/ana.25083 | 29,059,494 | Adolescent Adult Aged Biomarkers/cerebrospinal fluid Case-Control Studies Cell Line Cerebrospinal Fluid Proteins/*metabolism Diagnosis, Differential Female Humans Male Middle Aged Multiple Sclerosis, Chronic Progressive/*cerebrospinal fluid/*diagnosis Multiple Sclerosis, Relapsing-Remitting/*cerebrospinal fluid/*diagnosis Young Adult | OBJECTIVE: Biomarkers aid diagnosis, allow inexpensive screening of therapies, and guide selection of patient-specific therapeutic regimens in most internal medicine disciplines. In contrast, neurology lacks validated measurements of the physiological status, or dysfunction(s) of cells of the central nervous system (CNS). Accordingly, patients with chronic neurological diseases are often treated with a single disease-modifying therapy without understanding patient-specific drivers of disability. Therefore, using multiple sclerosis (MS) as an example of a complex polygenic neurological disease, we sought to determine whether cerebrospinal fluid (CSF) biomarkers are intraindividually stable, cell type-, disease- and/or process-specific, and responsive to therapeutic intervention. METHODS: We used statistical learning in a modeling cohort (n = 225) to develop diagnostic classifiers from DNA-aptamer-based measurements of 1,128 CSF proteins. An independent validation cohort (n = 85) assessed the reliability of derived classifiers. The biological interpretation resulted from in vitro modeling of primary or stem cell-derived human CNS cells and cell lines. RESULTS: The classifier that differentiates MS from CNS diseases that mimic MS clinically, pathophysiologically, and on imaging achieved a validated area under the receiver operating characteristic curve (AUROC) of 0.98, whereas the classifier that differentiates relapsing-remitting from progressive MS achieved a validated AUROC of 0.91. No classifiers could differentiate primary progressive from secondary progressive MS better than random guessing. Treatment-induced changes in biomarkers greatly exceeded intraindividual and technical variabilities of the assay. INTERPRETATION: CNS biological processes reflected by CSF biomarkers are robust, stable, disease specific, or even disease stage specific. This opens opportunities for broad utilization of CSF biomarkers in drug development and precision medicine for CNS disorders. Ann Neurol 2017;82:795-812. | Barbour, Christopher Kosa, Peter Komori, Mika Tanigawa, Makoto Masvekar, Ruturaj Wu, Tianxia Johnson, Kory Douvaras, Panagiotis Fossati, Valentina Herbst, Ronald Wang, Yue Tan, Keith Greenwood, Mark Bielekova, Bibiana eng Z99 NS999999/Intramural NIH HHS/ ZIA NS003055-02/Intramural NIH HHS/ Ann Neurol. 2017 Nov;82(5):795-812. doi: 10.1002/ana.25083.I | 10/24/2017 | |
| Efficacy of individualised diets in patients with irritable bowel syndrome: a randomised controlled trial | Ali A, et al. | 2017 | BMJ Open Gastroenterol | 4 | 1 | e000164 | https://www.doi.org/10.1136/bmjgast-2017-000164 | 29,018,540 | Dietary Factors Irritable Bowel Syndrome Quality Of Life | BACKGROUND: Patients with irritable bowel syndrome (IBS) are often placed on diets guided by food intolerance assays, although these have not been validated. We assessed the effects of individualised diets in patients with IBS guided by a leucocyte activation test. METHODS: This is a parallel-group, double-blind, randomised controlled trial of 58 adults with IBS seen at an academic health centre in Northeast USA. Peripheral venous blood was analysed using a leucocyte activation test; individual foods were reported to produce positive or negative results. Participants were randomised to a 4-week diet with either individualised guidance to eliminate foods with positive assay results and allow foods with negative assay results (intervention), or with individualised guidance, matched in rigour and complexity, to eliminate foods with negative assay results and allow foods with positive assay results (comparison). The primary outcome was between-group differences in the IBS Global Improvement Scale (GIS). Secondary outcomes included reductions in IBS Symptom Severity Scale (SSS) scores and increases in IBS Adequate Relief (AR) and Quality of Life (QOL) scores. An aptamer-based proteomic analysis was conducted in strong responders. RESULTS: The intervention group had significantly greater increases in mean GIS score after 4 weeks (0.86 vs comparison; 95% CI 0.05 to 1.67; p=0.04) and 8 weeks (1.22 vs comparison; 95% CI 0.22 to 2.22; p=0.02). The intervention group also had significantly greater reductions in mean SSS score at 4 weeks (-61.78 vs comparison; 95% CI -4.43 to -119.14; p=0.04) and 8 weeks (-66.42 vs comparison; 95% CI -5.75 to -127.09; p=0.03). There were no significant differences between intervention and comparison groups in mean AR or QOL scores. A reduction in neutrophil elastase concentration was associated with reduced symptoms. CONCLUSIONS: Elimination diets guided by leucocyte activation tests reduced symptoms. These findings could lead to insights into the pathophysiology of IBS. TRIAL REGISTRATION NUMBER: NCT02186743. | Ali, Ather Weiss, Theresa R McKee, Douglas Scherban, Alisa Khan, Sumiya Fields, Maxine R Apollo, Damian Mehal, Wajahat Z eng UL1 TR000142/TR/NCATS NIH HHS/ England BMJ Open Gastroenterol. 2017 Sep 20;4(1):e000164. doi: 10.1136/bmjgast-2017-000164. eCollection 2017.I | 10/12/2017 | |
| Structural basis for IL-1alpha recognition by a modified DNA aptamer that specifically inhibits IL-1alpha signaling | Ren X, et al. | 2017 | Nat Commun | 8 | 1 | 810 | https://www.doi.org/10.1038/s41467-017-00864-2 | 28,993,621 | Aptamers, Nucleotide/*chemistry/metabolism/*pharmacology Binding, Competitive Crystallography, X-Ray Deoxyuridine/chemistry Human Umbilical Vein Endothelial Cells Humans Hydrophobic and Hydrophilic Interactions Interleukin-1alpha/*chemistry/genetics/*metabolism Interleukin-1beta/metabolism Models, Molecular Receptors, Interleukin-1/metabolism SELEX Aptamer Technique Signal Transduction/drug effects | IL-1alpha is an essential cytokine that contributes to inflammatory responses and is implicated in various forms of pathogenesis and cancer. Here we report a naphthyl modified DNA aptamer that specifically binds IL-1alpha and inhibits its signaling pathway. By solving the crystal structure of the IL-1alpha/aptamer, we provide a high-resolution structure of this critical cytokine and we reveal its functional interaction interface with high-affinity ligands. The non-helical aptamer, which represents a highly compact nucleic acid structure, contains a wealth of new conformational features, including an unknown form of G-quadruplex. The IL-1alpha/aptamer interface is composed of unusual polar and hydrophobic elements, along with an elaborate hydrogen bonding network that is mediated by sodium ion. IL-1alpha uses the same interface to interact with both the aptamer and its cognate receptor IL-1RI, thereby suggesting a novel route to immunomodulatory therapeutics.The cytokine interleukin 1alpha (IL-1alpha) plays an important role in inflammatory processes. Here the authors use SELEX to generate a modified DNA aptamer which specifically binds IL-1alpha, present the structure of the IL-1alpha/aptamer complex and show that this aptamer inhibits the IL-1alpha signaling pathway. | Ren, Xiaoming Gelinas, Amy D von Carlowitz, Ira Janjic, Nebojsa Pyle, Anna Marie eng P41 GM103403/GM/NIGMS NIH HHS/ S10 RR029205/RR/NCRR NIH HHS/ HHMI/Howard Hughes Medical Institute/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. England Nat Commun. 2017 Oct 9;8(1):810. doi: 10.1038/s41467-017-00864-2.I | 10/11/2017 | |
| Antiinflammatory effects of aprepitant coadministration with cART regimen containing ritonavir in HIV-infected adults | Spitsin S, et al. | 2017 | JCI Insight | 2 | 19 | https://www.doi.org/10.1172/jci.insight.95893 | 28,978,797 | Adult Aged Anti-HIV Agents/administration & dosage/adverse effects/blood/*therapeutic use Anti-Inflammatory Agents/administration & dosage/adverse effects/blood/*therapeutic use Aprepitant/administration & dosage/adverse effects/blood/*therapeutic use Drug Administration Schedule Drug Therapy, Combination Female HIV Infections/blood/*drug therapy/virology Humans Inflammation Mediators/metabolism Male Middle Aged Ritonavir/*therapeutic use Viral Load | BACKGROUND: HIV-infected individuals, even well controlled with combined antiretroviral therapy (cART), have systemic inflammation and comorbidities. Substance P (SP) is an undecapeptide, which mediates neurotransmission and inflammation through its cognate neurokinin 1 receptor (NK1R). Plasma SP levels are elevated in HIV-infected individuals. The FDA-approved antiemetic aprepitant, an NK1R antagonist, has anti-HIV effects and antiinflammatory actions. We evaluated the safety, pharmacokinetics, and antiinflammatory properties of aprepitant in HIV-positive individuals receiving cART. METHODS: We conducted a phase 1B study of 12 HIV-positive individuals on a ritonavir-containing regimen (HIV viral load less than 40 copies/ml and CD4 > 400 cells/mul). Participants received open-label aprepitant 375 mg per day for 28 days and were followed for an additional 30 days. Changes in plasma levels of proinflammatory markers were assessed using flow cytometry, ELISA, luminex, and SOMAscan assays. RESULTS: The mean peak aprepitant plasma concentration was 30.7 +/- 15.3 mug/ml at day 14 and 23.3 +/- 12.3 mug/ml at day 28. Aprepitant treatment resulted in decreased plasma SP levels and affected 176 plasma proteins (56 after FDR) and several metabolic pathways, including inflammation and lipid metabolism. No change in soluble CD163 was observed. Aprepitant treatment was associated with a moderate increases in total and HDL cholesterol and affected select hematologic and metabolic markers, which returned to baseline levels 30 days after aprepitant treatment was stopped. There were 12 mild and 10 moderate adverse events (AE). CONCLUSIONS: Aprepitant is safe and well tolerated. The antiinflammatory properties of aprepitant make it a possible adjunctive therapy for comorbid conditions associated with HIV infection. TRIAL REGISTRATION: ClinicalTrials.gov (NCT02154360). FUNDING: This research was funded by NIH UO1 MH090325, P30 MH097488, and PO1 MH105303. | Spitsin, Sergei Tebas, Pablo Barrett, Jeffrey S Pappa, Vasiliki Kim, Deborah Taylor, Deanne Evans, Dwight L Douglas, Steven D eng P01 MH105303/MH/NIMH NIH HHS/ P30 MH097488/MH/NIMH NIH HHS/ U01 MH090325/MH/NIMH NIH HHS/ UM1 AI069534/AI/NIAID NIH HHS/ Clinical Trial, Phase I Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't JCI Insight. 2017 Oct 5;2(19):e95893. doi: 10.1172/jci.insight.95893.I | 10/06/2017 | ||
| Pharmacokinetic Properties of DNA Aptamers with Base Modifications | Gupta S, et al. | 2017 | Nucleic Acid Ther | 27 | 6 | 345-353 | https://www.doi.org/10.1089/nat.2017.0683 | 28,961,063 | Animals Aptamers, Nucleotide/administration & dosage/blood/*chemistry/*pharmacokinetics Base Sequence Drug Design Hydrophobic and Hydrophilic Interactions Ligands Linear Models Male Polyethylene Glycols/*chemistry/metabolism Rats Rats, Sprague-Dawley SELEX Aptamer Technique/methods Statistics, Nonparametric Uracil/*chemistry/metabolism aptamer pharmacokinetics modified nucleotides plasma clearance side chains N.J. are employees and stakeholders of SomaLogic, Inc. T.S., M.H., and Y.I. are employees and stakeholders of Otsuka Pharmaceutical Co., Ltd. | The addition of novel side chains at the 5-position of uracil is an effective means to increase chemical diversity of aptamers and hence the success rate for discovery of high-affinity ligands to protein targets. Such modifications also increase nuclease resistance, which is useful in a range of applications, especially for therapeutics. In this study, we assess the impact of these side chains on plasma pharmacokinetics of modified aptamers conjugated to a 40 kDa polyethylene glycol. We show that clearance from plasma depends on relative hydrophobicity: side chains with a negative cLogP (more hydrophilic) result in slower plasma clearance compared with side chains with a positive cLogP (more hydrophobic). We show that clearance increases with the number of side chains in sequences of >/=28 synthons, but this effect is dramatically diminished in shorter sequences. These results serve as a guide for the design of new therapeutic aptamers with diversity-enhancing side chains. | Gupta, Shashi Drolet, Daniel W Wolk, Steven K Waugh, Sheela M Rohloff, John C Carter, Jeffery D Mayfield, Wesley S Otis, Matthew R Fowler, Catherine R Suzuki, Tomoki Hirota, Masao Ishikawa, Yuichi Schneider, Daniel J Janjic, Nebojsa eng Nucleic Acid Ther. 2017 Dec;27(6):345-353. doi: 10.1089/nat.2017.0683. Epub 2017 Sep 29.I | 09/30/2017 | |
| Cerebrospinal fluid extracellular vesicle enrichment for protein biomarker discovery in neurological disease; multiple sclerosis | Welton JL, et al. | 2017 | J Extracell Vesicles | 6 | 1 | 1369805 | https://www.doi.org/10.1080/20013078.2017.1369805 | 28,959,386 | Extracellular vesicles biomarkers cerebrospinal fluid multiple sclerosis proteomics size exclusion chromatography | The discovery of disease biomarkers, along with the use of liquid biopsies" as a minimally invasive source of biomarkers, continues to be of great interest. In inflammatory diseases of the central nervous system (CNS), cerebrospinal fluid (CSF) is the most obvious biofluid source. Extracellular vesicles (EVs) are also present in CSF and are thought to be potential "biomarker treasure chests". However, isolating these CSF-derived EVs remains challenging. This small-scale pilot study developed and tested a protocol to enrich for CSF-EVs, both in relapsing remitting multiple sclerosis (RRMS) CSF and controls. These were subsequently compared, using an aptamer based proteomics array, SOMAscan. EVs were enriched from RRMS patient (n = 4) and non-demyelinating control (idiopathic intracranial hypertension (IIH) (n = 3)) CSF using precipitation and mini size-exclusion chromatography (SEC). EV-enriched fractions were selected using pre-defined EV characteristics, including increased levels of tetraspanins. EVs and paired CSF were analysed by SOMAscan, providing relative abundance data for 1128 proteins. CSF-EVs were characterised, revealing exosome-like features: rich in tetraspanins CD9 and CD81, size ~100 nm, and exosome-like morphology by TEM. Sufficient quantities of, SOMAscan compatible, EV material was obtained from 5 ml CSF for proteomics analysis. Overall, 348 and 580 proteins were identified in CSF-EVs and CSF, respectively, of which 50 were found to be significantly (t-test) and exclusively enriched in RRMS CSF-EVs. Selected proteins, Plasma kallikrein and Apolipoprotein-E4, were further validated by western blot and appeared increased in CSF-EVs compared to CSF. Functional enrichment analysis of the 50 enriched proteins revealed strong associations with biological processes relating to MS pathology and also extracellular regions, consistent with EV enrichment. This pilot study demonstrates practicality for EV enrichment in CSF derived from patients with MS and controls, allowing detailed analysis of protein profiles that may offer opportunities to identify novel biomarkers and therapeutic approaches in CNS inflammatory diseases." | Welton, Joanne L Loveless, Samantha Stone, Timothy von Ruhland, Chris Robertson, Neil P Clayton, Aled eng MR/L010305/1/MRC_/Medical Research Council/United Kingdom J Extracell Vesicles. 2017 Sep 3;6(1):1369805. doi: 10.1080/20013078.2017.1369805. eCollection 2017.I | 09/30/2017 | |
| Sexual Dimorphism, Age, and Fat Mass Are Key Phenotypic Drivers of Proteomic Signatures | Curran AM, et al. | 2017 | J Proteome Res | 16 | 11 | 4122-4133 | https://www.doi.org/10.1021/acs.jproteome.7b00501 | 28,950,061 | Adipose Tissue Age Factors Female Humans Male *Phenotype Proteomics/*methods Sex Characteristics age biomarker fat mass pathway phenotype protein proteomics sex | Validated protein biomarkers are needed for assessing health trajectories, predicting and subclassifying disease, and optimizing diagnostic and therapeutic clinical decision-making. The sensitivity, specificity, accuracy, and precision of single or combinations of protein biomarkers may be altered by differences in physiological states limiting the ability to translate research results to clinically useful diagnostic tests. Aptamer based affinity assays were used to test whether low abundant serum proteins differed based on age, sex, and fat mass in a healthy population of 94 males and 102 females from the MECHE cohort. The findings were replicated in 217 healthy male and 377 healthy female participants in the DiOGenes consortium. Of the 1129 proteins in the panel, 141, 51, and 112 proteins (adjusted p < 0.1) were identified in the MECHE cohort and significantly replicated in DiOGenes for sexual dimorphism, age, and fat mass, respectively. Pathway analysis classified a subset of proteins from the 3 phenotypes to the complement and coagulation cascades pathways and to immune and coagulation processes. These results demonstrated that specific proteins were statistically associated with dichotomous (male vs female) and continuous phenotypes (age, fat mass), which may influence the identification and use of biomarkers of clinical utility for health diagnosis and therapeutic strategies. | Curran, Aoife M Fogarty Draper, Colleen Scott-Boyer, Marie-Pier Valsesia, Armand Roche, Helen M Ryan, Miriam F Gibney, Michael J Kutmon, Martina Evelo, Chris T Coort, Susan L Astrup, Arne Saris, Wim H Brennan, Lorraine Kaput, Jim eng Research Support, Non-U.S. Gov't J Proteome Res. 2017 Nov 3;16(11):4122-4133. doi: 10.1021/acs.jproteome.7b00501. Epub 2017 Oct 4.I | 09/28/2017 | |
| Attenuated PDGF signaling drives alveolar and microvascular defects in neonatal chronic lung disease | Oak P, et al. | 2017 | EMBO Mol Med | 9 | 11 | 1504-1520 | https://www.doi.org/10.15252/emmm.201607308 | 28,923,828 | Animals Animals, Newborn Cells, Cultured Chronic Disease Fibroblasts/cytology/metabolism Haploinsufficiency Human Umbilical Vein Endothelial Cells Humans Infant, Newborn Lung/metabolism Lung Diseases/metabolism/*pathology/prevention & control Mice Mice, Inbred C57BL Oxygen/metabolism Platelet-Derived Growth Factor/*metabolism/pharmacology/therapeutic use Receptor, Platelet-Derived Growth Factor alpha/antagonists & inhibitors/genetics/metabolism Respiration, Artificial Signal Transduction/drug effects Vascular Endothelial Growth Factor A/metabolism PDGF-Ralpha Vegf-a bronchopulmonary dysplasia neonatal chronic lung disease transforming growth factor-beta | Neonatal chronic lung disease (nCLD) affects a significant number of neonates receiving mechanical ventilation with oxygen-rich gas (MV-O(2)). Regardless, the primary molecular driver of the disease remains elusive. We discover significant enrichment for SNPs in the PDGF-Ralpha gene in preterms with nCLD and directly test the effect of PDGF-Ralpha haploinsufficiency on the development of nCLD using a preclinical mouse model of MV-O(2) In the context of MV-O(2), attenuated PDGF signaling independently contributes to defective septation and endothelial cell apoptosis stemming from a PDGF-Ralpha-dependent reduction in lung VEGF-A. TGF-beta contributes to the PDGF-Ralpha-dependent decrease in myofibroblast function. Remarkably, endotracheal treatment with exogenous PDGF-A rescues both the lung defects in haploinsufficient mice undergoing MV-O(2) Overall, our results establish attenuated PDGF signaling as an important driver of nCLD pathology with provision of PDGF-A as a protective strategy for newborns undergoing MV-O(2). | Oak, Prajakta Pritzke, Tina Thiel, Isabella Koschlig, Markus Mous, Daphne S Windhorst, Anita Jain, Noopur Eickelberg, Oliver Foerster, Kai Schulze, Andreas Goepel, Wolfgang Reicherzer, Tobias Ehrhardt, Harald Rottier, Robbert J Ahnert, Peter Gortner, Ludwig Desai, Tushar J Hilgendorff, Anne eng Research Support, Non-U.S. Gov't England EMBO Mol Med. 2017 Nov;9(11):1504-1520. doi: 10.15252/emmm.201607308.I | 09/20/2017 | |
| An immune clock of human pregnancy | Aghaeepour N, et al. | 2017 | Sci Immunol | 2 | 15 | https://www.doi.org/10.1126/sciimmunol.aan2946 | 28,864,494 | The maintenance of pregnancy relies on finely tuned immune adaptations. We demonstrate that these adaptations are precisely timed, reflecting an immune clock of pregnancy in women delivering at term. Using mass cytometry, the abundance and functional responses of all major immune cell subsets were quantified in serial blood samples collected throughout pregnancy. Cell signaling-based Elastic Net, a regularized regression method adapted from the elastic net algorithm, was developed to infer and prospectively validate a predictive model of interrelated immune events that accurately captures the chronology of pregnancy. Model components highlighted existing knowledge and revealed previously unreported biology, including a critical role for the interleukin-2-dependent STAT5ab signaling pathway in modulating T cell function during pregnancy. These findings unravel the precise timing of immunological events occurring during a term pregnancy and provide the analytical framework to identify immunological deviations implicated in pregnancy-related pathologies. | Aghaeepour, Nima Ganio, Edward A Mcilwain, David Tsai, Amy S Tingle, Martha Van Gassen, Sofie Gaudilliere, Dyani K Baca, Quentin McNeil, Leslie Okada, Robin Ghaemi, Mohammad S Furman, David Wong, Ronald J Winn, Virginia D Druzin, Maurice L El-Sayed, Yaser Y Quaintance, Cecele Gibbs, Ronald Darmstadt, Gary L Shaw, Gary M Stevenson, David K Tibshirani, Robert Nolan, Garry P Lewis, David B Angst, Martin S Gaudilliere, Brice eng K23 GM111657/GM/NIGMS NIH HHS/ U19 AI057229/AI/NIAID NIH HHS/ Sci Immunol. 2017 Sep 1;2(15):eaan2946. doi: 10.1126/sciimmunol.aan2946.I | 09/03/2017 | |||
| Identification of novel biomarkers to monitor beta-cell function and enable early detection of type 2 diabetes risk | Belongie KJ, et al. | 2017 | PLoS One | 12 | 8 | e0182932 | https://www.doi.org/10.1371/journal.pone.0182932 | 28,846,711 | Adult Biomarkers/blood Blood Glucose/*metabolism Case-Control Studies Cross-Sectional Studies Diabetes Mellitus, Type 2/blood/*diagnosis Early Diagnosis Female Glucose Clamp Technique Glucose Intolerance/*blood Glucose Tolerance Test Humans Insulin/blood Insulin Resistance/*physiology Insulin-Secreting Cells/*metabolism Male Middle Aged Risk Factors | A decline in beta-cell function is a prerequisite for the development of type 2 diabetes, yet the level of beta-cell function in individuals at risk of the condition is rarely measured. This is due, in part, to the fact that current methods for assessing beta-cell function are inaccurate, prone to error, labor-intensive, or affected by glucose-lowering therapy. The aim of the current study was to identify novel circulating biomarkers to monitor beta-cell function and to identify individuals at high risk of developing beta-cell dysfunction. In a nested case-control study from the Relationship between Insulin Sensitivity and Cardiovascular disease (RISC) cohort (n = 1157), proteomics and miRNA profiling were performed on fasting plasma samples from 43 individuals who progressed to impaired glucose tolerance (IGT) and 43 controls who maintained normal glucose tolerance (NGT) over three years. Groups were matched at baseline for age, gender, body mass index (BMI), insulin sensitivity (euglycemic clamp) and beta-cell glucose sensitivity (mathematical modeling). Proteomic profiling was performed using the SomaLogic platform (Colorado, USA); miRNA expression was performed using a modified RT-PCR protocol (Regulus Therapeutics, California, USA). Results showed differentially expressed proteins and miRNAs including some with known links to type 2 diabetes, such as adiponectin, but also novel biomarkers and pathways. In cross sectional analysis at year 3, the top differentially expressed biomarkers in people with IGT/ reduced beta-cell glucose sensitivity were adiponectin, alpha1-antitrypsin (known to regulate adiponectin levels), endocan, miR-181a, miR-342, and miR-323. At baseline, adiponectin, cathepsin D and NCAM.L1 (proteins expressed by pancreatic beta-cells) were significantly lower in those that progressed to IGT. Many of the novel prognostic biomarker candidates were within the epithelial-mesenchymal transition (EMT) pathway: for example, Noggin, DLL4 and miR-181a. Further validation studies are required in additional clinical cohorts and in patients with type 2 diabetes, but these results identify novel pathways and biomarkers that may have utility in monitoring beta-cell function and/ or predicting future decline, allowing more targeted efforts to prevent and intercept type 2 diabetes. | Belongie, Kirstine J Ferrannini, Ele Johnson, Kjell Andrade-Gordon, Patricia Hansen, Michael K Petrie, John R eng PLoS One. 2017 Aug 28;12(8):e0182932. doi: 10.1371/journal.pone.0182932. eCollection 2017.I | 08/29/2017 | |
| Activation of Inflammatory and Pro-Thrombotic Pathways in Acute Stress Cardiomyopathy | Fitzgibbons TP, et al. | 2017 | Front Cardiovasc Med | 4 | 49 | https://www.doi.org/10.3389/fcvm.2017.00049 | 28,824,923 | acute myocardial infarction coagulation inflammation stress cardiomyopathy women | Stress cardiomyopathy (SCM) is a unique cardiac disorder that more often occurs in women. SCM presents in a similar fashion as acute myocardial infarction (AMI), with chest pain, ECG changes, and congestive heart failure. The primary distinguishing feature is the absence of thrombotic coronary occlusion in SCM. How this reduction in cardiac function occurs in the absence of coronary occlusion remains unknown. Therefore, we tested the hypothesis that a targeted proteomic comparison of patients with acute SCM and AMI might identify relevant mechanistic differences. Blood was drawn in normal controls (n = 6), women with AMI (n = 12), or women with acute SCM (n = 15). Two-week follow-up samples were available in AMI (n = 4) and SCM patients (n = 11). Relative concentrations of 1,310 serum proteins were measured in each of the 48 samples using the SOMAscan assay. Women with AMI had greater myocyte necrosis, as reflected by a higher peak troponin I concentration (AMI 32.03 +/- 29.46 vs. SCM 2.68 +/- 2.6 ng/ml, p < 0.05). AMI and SCM patients had equivalent reductions in left ventricular ejection fraction [LVEF (%) 39 +/- 12 vs. 37 +/- 12, p = 0.479]. In follow-up, women with SCM had a greater improvement in cardiac function [LVEF (%) 60 +/- 7 vs. 45 +/- 13, p < 0.001]. No differentially expressed proteins were detected (absolute log2-fold change >1; q < 0.05) between AMI and SCM in the acute or recovery phase. However, when we compared normal controls to patients with AMI, there was differential expression of 35 proteins. When we compared normal controls to patients with SCM, 45 proteins were differentially expressed. In comparison to normal controls, biological processes such as complement, coagulation, and inflammation were activated in both AMI and SCM. There were four proteins that showed a non-significant trend to be increased in acute SCM vs. AMI (netrin-1, follistatin-like 3, kallikrein 7, kynureninase). Despite a lesser degree of myocardial necrosis than AMI, SCM is characterized by a similar activation of inflammatory, complement, and coagulation pathways. These findings may explain reported thromboembolic complications in the short term and elevated risk of mortality in the long term of SCM. | Fitzgibbons, Timothy P Edwards, Yvonne J K Shaw, Peter Iskandar, Aline Ahmed, Mohamed Bote, Josiah Shah, Tejen Sinha, Sumita Gerszten, Robert E Keaney, John F Jr Zile, Michael R Aurigemma, Gerard P eng Switzerland Front Cardiovasc Med. 2017 Aug 3;4:49. doi: 10.3389/fcvm.2017.00049. eCollection 2017.I | 08/22/2017 | ||
| Interleukin 1 Receptor-Like 1 Protein (ST2) is a Potential Biomarker for Cardiomyopathy in Duchenne Muscular Dystrophy | Anderson J, et al. | 2017 | Pediatr Cardiol | 38 | 8 | 1606-1612 | https://www.doi.org/10.1007/s00246-017-1703-9 | 28,821,969 | Adolescent Adult Biomarkers/*blood Cardiomyopathies/*blood/etiology Case-Control Studies Enzyme-Linked Immunosorbent Assay Humans Interleukin-1 Receptor-Like 1 Protein/*blood Linear Models Male Muscular Dystrophy, Duchenne/blood/*complications Stroke Volume Young Adult Biomarkers Cardiomyopathy Duchenne muscular dystrophy ST2 interest. Haeri Seol declares that she has no conflict of interest. Heather Gordish-Dressman declares that she has no conflict of interest. Yetrib Hathout declares that he has no conflict of interest. Christopher Spurney declares that he has no conflict of interest. | Duchenne muscular dystrophy (DMD) is a rare, fatal X-linked disorder characterized by the lack of dystrophin, a key sarcolemma muscle protein. Cardiac failure is a significant cause of death in DMD subjects. The purpose of our research was to identify potential cardiac serum biomarkers associated with DMD cardiomyopathy. This is an observational, case-controlled study using subjects from the CINRG DMD natural history study with cardiomyopathy (ejection fraction (EF) <55%; shortening fraction (SF) <28%), subjects without cardiomyopathy (EF >/= 55%; SF >/= 28%) compared to normal healthy volunteer subjects. The DMD with cardiomyopathy group had significantly lower average EF and SF (EF = 45 +/- 10/SF = 25 +/- 2%) than the DMD without cardiomyopathy group (EF = 58 +/- 5% and SF = 32 +/- 3%; p < 0.01). Among a selected set of potential biomarkers for cardiomyopathy (MMP9, BNP, GAL3, CRP, LEP, TNC, TLR4 and ST2) we validated ST2 as significantly elevated in the serum of DMD cardiomyopathy group (35,798 +/- 4884 pg/mL) compared to normal controls (9940 +/- 2680 pg/mL; p < 0.01; n = 6). Matrix metallopeptidase 9 (MMP9) levels were found significantly increased in both DMD groups compared to controls (p < 0.01). No significant differences were seen in BNP, GAL3, CRP, LEP, TNC or TLR4 levels. Increased ST2 levels were found in serum of DMD subjects compared to healthy volunteers and further elevated in DMD subjects with cardiomyopathy. Future studies correlating cardiomyopathy with ST2 levels may allow for improved non-invasive monitoring of cardiac disease in DMD subjects. | Anderson, Julia Seol, Haeri Gordish-Dressman, Heather Hathout, Yetrib Spurney, Christopher F eng W81XWH-09-1-0592/US Dept of Defense/ R01AR062380/NH/NIH HHS/ U54 HD090257/HD/NICHD NIH HHS/ 1R01AR061875/NH/NIH HHS/ U54 MD007587/MD/NIMHD NIH HHS/ R01 AR062380/AR/NIAMS NIH HHS/ UL1 RR024992/RR/NCRR NIH HHS/ G12RR003051/NH/NIH HHS/ G12 RR003051/RR/NCRR NIH HHS/ H133B031118/US Dept of Education/ NIDDR/ UL1RR024992/NH/NIH HHS/ UL1 TR002345/TR/NCATS NIH HHS/ U54 RR026139/RR/NCRR NIH HHS/ U54HD053177/NH/NIH HHS/ UL1RR031988/NH/NIH HHS/ R24HD050846/NH/NIH HHS/ U54RR026139/NH/NIH HHS/ U54 HD053177/HD/NICHD NIH HHS/ UL1 RR031988/RR/NCRR NIH HHS/ R24 HD050846/HD/NICHD NIH HHS/ UL1 TR000448/TR/NCATS NIH HHS/ H133B090001/US Dept of Education/ NIDDR/ R01 AR061875/AR/NIAMS NIH HHS/ Observational Study Pediatr Cardiol. 2017 Dec;38(8):1606-1612. doi: 10.1007/s00246-017-1703-9. Epub 2017 Aug 18.I | 08/20/2017 | |
| Discovery and Validation of a Six-Marker Serum Protein Signature for the Diagnosis of Active Pulmonary Tuberculosis | De Groote MA, et al. | 2017 | J Clin Microbiol | 55 | 10 | 3057-3071 | https://www.doi.org/10.1128/JCM.00467-17 | 28,794,177 | Antigens, Bacterial/blood Biomarkers/blood Blood Proteins/*analysis Complement C9/*metabolism Fructose-Bisphosphate Aldolase/*blood Gelsolin/*blood Humans Mycobacterium tuberculosis/genetics/immunology Proteoglycans/*blood Proteomics Sensitivity and Specificity Serpins/*blood Tuberculosis, Pulmonary/*diagnosis/microbiology aptamer biomarker tuberculosis | New non-sputum biomarker tests for active tuberculosis (TB) diagnostics are of the highest priority for global TB control. We performed in-depth proteomic analysis using the 4,000-plex SOMAscan assay on 1,470 serum samples from seven countries where TB is endemic. All samples were from patients with symptoms and signs suggestive of active pulmonary TB that were systematically confirmed or ruled out for TB by culture and clinical follow-up. HIV coinfection was present in 34% of samples, and 25% were sputum smear negative. Serum protein biomarkers were identified by stability selection using L1-regularized logistic regression and by Kolmogorov-Smirnov (KS) statistics. A naive Bayes classifier using six host response markers (HR6 model), including SYWC, kallistatin, complement C9, gelsolin, testican-2, and aldolase C, performed well in a training set (area under the sensitivity-specificity curve [AUC] of 0.94) and in a blinded verification set (AUC of 0.92) to distinguish TB and non-TB samples. Differential expression was also highly significant (P < 10(-20)) for previously described TB markers, such as IP-10, LBP, FCG3B, and TSP4, and for many novel proteins not previously associated with TB. Proteins with the largest median fold changes were SAA (serum amyloid protein A), NPS-PLA2 (secreted phospholipase A2), and CA6 (carbonic anhydrase 6). Target product profiles (TPPs) for a non-sputum biomarker test to diagnose active TB for treatment initiation (TPP#1) and for a community-based triage or referral test (TPP#2) have been published by the WHO. With 90% sensitivity and 80% specificity, the HR6 model fell short of TPP#1 but reached TPP#2 performance criteria. In conclusion, we identified and validated a six-marker signature for active TB that warrants diagnostic development on a patient-near platform. | De Groote, Mary A Sterling, David G Hraha, Thomas Russell, Theresa M Green, Louis S Wall, Kirsten Kraemer, Stephan Ostroff, Rachel Janjic, Nebojsa Ochsner, Urs A eng Research Support, Non-U.S. Gov't J Clin Microbiol. 2017 Oct;55(10):3057-3071. doi: 10.1128/JCM.00467-17. Epub 2017 Aug 9.I | 08/11/2017 | |
| Potential of High-Affinity, Slow Off-Rate Modified Aptamer Reagents for Mycobacterium tuberculosis Proteins as Tools for Infection Models and Diagnostic Applications | Russell TM, et al. | 2017 | J Clin Microbiol | 55 | 10 | 3072-3088 | https://www.doi.org/10.1128/JCM.00469-17 | 28,794,178 | Acyltransferases/*analysis Antigens, Bacterial/*analysis/immunology Aptamers, Peptide/*metabolism Bacterial Proteins/analysis/*blood/*urine Humans Immunologic Tests/methods Mycobacterium tuberculosis/*immunology Protein Binding/physiology Tuberculosis, Pulmonary/*diagnosis/microbiology Mycobacterium tuberculosis aptamer biomarker immunodiagnostics proteomics | Direct pathogen detection in blood to diagnose active tuberculosis (TB) has been difficult due to low levels of circulating antigens or due to the lack of specific, high-affinity binding reagents and reliable assays with adequate sensitivity. We sought to determine whether slow off-rate modified aptamer (SOMAmer) reagents with subnanomolar affinity for Mycobacterium tuberculosis proteins (antigens 85A, 85B, 85C, GroES, GroEL2, DnaK, CFP10, KAD, CFP2, RplL, and Tpx) could be useful to diagnose tuberculosis. When incorporated into the multiplexed, array-based proteomic SOMAscan assay, limits of detection reached the subpicomolar range in 40% serum. Binding to native M. tuberculosis proteins was confirmed by using M. tuberculosis culture filtrate proteins and fractions from infected macrophages and via affinity capture assays and subsequent mass spectrometry. Comparison of serum from culture-positive pulmonary TB patients and TB suspects systematically ruled out for TB revealed small but statistically significant (P < 0.0001) differences in the median M. tuberculosis signals and in specific pathogen markers, such as antigen 85B. Samples where many M. tuberculosis aptamers produced high signals were rare exceptions. In concentrated, protein-normalized urine from TB patients and non-TB controls, the CFP10 (EsxB) SOMAmer yielded the most significant differential signals (P < 0.0276), particularly in TB patients with HIV coinfection. In conclusion, direct M. tuberculosis antigen detection proved difficult even with a sensitive method such as SOMAscan, likely due to their very low, subpicomolar abundance. The observed differences between cases and controls had limited diagnostic utility in serum and urine, but further evaluation of M. tuberculosis SOMAmers using other platforms and sample types is warranted. | Russell, Theresa M Green, Louis S Rice, Taylor Kruh-Garcia, Nicole A Dobos, Karen De Groote, Mary A Hraha, Thomas Sterling, David G Janjic, Nebojsa Ochsner, Urs A eng Research Support, Non-U.S. Gov't J Clin Microbiol. 2017 Oct;55(10):3072-3088. doi: 10.1128/JCM.00469-17. Epub 2017 Aug 9.I | 08/11/2017 | |
| Aging and sarcopenia associate with specific interactions between gut microbes, serum biomarkers and host physiology in rats | Siddharth J, et al. | 2017 | Aging (Albany NY) | 9 | 7 | 1698-1720 | https://www.doi.org/10.18632/aging.101262 | 28,783,713 | Aging/*physiology Animals Bacteria/classification Biomarkers/blood *Gastrointestinal Microbiome/physiology Genome, Bacterial Genomics Host-Pathogen Interactions Rats *Sarcopenia aging lipidomics microbiome muscle physiology proteomics sarcopenia Sciences SA. | The microbiome has been demonstrated to play an integral role in the maintenance of many aspects of health that are also associated with aging. In order to identify areas of potential exploration and intervention, we simultaneously characterized age-related alterations in gut microbiome, muscle physiology and serum proteomic and lipidomic profiles in aged rats to define an integrated signature of the aging phenotype. We demonstrate that aging skews the composition of the gut microbiome, in particular by altering the Sutterella to Barneseilla ratio, and alters the metabolic potential of intestinal bacteria. Age-related changes of the gut microbiome were associated with the physiological decline of musculoskeletal function, and with molecular markers of nutrient processing/availability, and inflammatory/immune status in aged versus adult rats. Altogether, our study highlights that aging leads to a complex interplay between the microbiome and host physiology, and provides candidate microbial species to target physical and metabolic decline during aging by modulating gut microbial ecology. | Siddharth, Jay Chakrabarti, Anirikh Pannerec, Alice Karaz, Sonia Morin-Rivron, Delphine Masoodi, Mojgan Feige, Jerome N Parkinson, Scott James eng Research Support, Non-U.S. Gov't Aging (Albany NY). 2017 Jul 17;9(7):1698-1720. doi: 10.18632/aging.101262.I | 08/08/2017 | |
| The prediction of late-onset preeclampsia: Results from a longitudinal proteomics study | Erez O, et al. | 2017 | PLoS One | 12 | 7 | e0181468 | https://www.doi.org/10.1371/journal.pone.0181468 | 28,738,067 | Biomarkers/blood/metabolism Case-Control Studies Female Gestational Age Humans Longitudinal Studies Placenta Growth Factor/blood/metabolism Pre-Eclampsia/blood/*etiology/*metabolism Pregnancy Pregnancy Proteins/metabolism Prospective Studies Proteome/*metabolism Proteomics/methods Risk Factors Signal Transduction/physiology Vascular Endothelial Growth Factor A/blood/metabolism | BACKGROUND: Late-onset preeclampsia is the most prevalent phenotype of this syndrome; nevertheless, only a few biomarkers for its early diagnosis have been reported. We sought to correct this deficiency using a high through-put proteomic platform. METHODS: A case-control longitudinal study was conducted, including 90 patients with normal pregnancies and 76 patients with late-onset preeclampsia (diagnosed at >/=34 weeks of gestation). Maternal plasma samples were collected throughout gestation (normal pregnancy: 2-6 samples per patient, median of 2; late-onset preeclampsia: 2-6, median of 5). The abundance of 1,125 proteins was measured using an aptamers-based proteomics technique. Protein abundance in normal pregnancies was modeled using linear mixed-effects models to estimate mean abundance as a function of gestational age. Data was then expressed as multiples of-the-mean (MoM) values in normal pregnancies. Multi-marker prediction models were built using data from one of five gestational age intervals (8-16, 16.1-22, 22.1-28, 28.1-32, 32.1-36 weeks of gestation). The predictive performance of the best combination of proteins was compared to placental growth factor (PIGF) using bootstrap. RESULTS: 1) At 8-16 weeks of gestation, the best prediction model included only one protein, matrix metalloproteinase 7 (MMP-7), that had a sensitivity of 69% at a false positive rate (FPR) of 20% (AUC = 0.76); 2) at 16.1-22 weeks of gestation, MMP-7 was the single best predictor of late-onset preeclampsia with a sensitivity of 70% at a FPR of 20% (AUC = 0.82); 3) after 22 weeks of gestation, PlGF was the best predictor of late-onset preeclampsia, identifying 1/3 to 1/2 of the patients destined to develop this syndrome (FPR = 20%); 4) 36 proteins were associated with late-onset preeclampsia in at least one interval of gestation (after adjustment for covariates); 5) several biological processes, such as positive regulation of vascular endothelial growth factor receptor signaling pathway, were perturbed; and 6) from 22.1 weeks of gestation onward, the set of proteins most predictive of severe preeclampsia was different from the set most predictive of the mild form of this syndrome. CONCLUSIONS: Elevated MMP-7 early in gestation (8-22 weeks) and low PlGF later in gestation (after 22 weeks) are the strongest predictors for the subsequent development of late-onset preeclampsia, suggesting that the optimal identification of patients at risk may involve a two-step diagnostic process. | Erez, Offer Romero, Roberto Maymon, Eli Chaemsaithong, Piya Done, Bogdan Pacora, Percy Panaitescu, Bogdan Chaiworapongsa, Tinnakorn Hassan, Sonia S Tarca, Adi L eng HHSN275201300006C/HD/NICHD NIH HHS/ PLoS One. 2017 Jul 24;12(7):e0181468. doi: 10.1371/journal.pone.0181468. eCollection 2017.I | 07/25/2017 | |
| Diagnosis and prognosis-review of biomarkers for mesothelioma | Sun HH, et al. | 2017 | Ann Transl Med | 5 | 11 | 244 | https://www.doi.org/10.21037/atm.2017.06.60 | 28,706,912 | Mesothelioma asbestos biomarker diagnosis prognosis | Malignant pleural mesothelioma (MPM) is an aggressive disease arising in pleural cell lining and is associated with asbestos exposure. Today, there is a rising incidence of MPM reaching 3,000 annual cases nationally, primarily from the large population occupationally exposed to asbestos between 1940 and 1980. With a prolonged latency period, presenting clinically 10 to 40 years after exposure, MPM is often diagnosed in late stages and presents median survival time of less than 12 months. There is a serious need for improvement in prognostic and diagnostic tools for MPM. Recent investigation and discovery of various biomarkers has shown promise, including Osteopontin, Fibulin-3, Soluble Mesothelin-Related Proteins (SMRP), High Mobility Group Box 1 (HMGB1), micro-RNA's, peripheral blood-based markers, and Slow Off-rate Modified Aptamer (SOMAmer) proteomic assays. In this review, we explore these current major biomarkers and their prognostic and diagnostic potential, highlighting the most recent large studies and developments for each. While progress has been made in mesothelioma research, many questions remain unanswered. Increased international cooperation is necessary for improving validity of results for current biomarkers through repeated investigation and increasing cohort sizes, as well as for the continued search for new and better markers. | Sun, Huan H Vaynblat, Allen Pass, Harvey I eng Review China Ann Transl Med. 2017 Jun;5(11):244. doi: 10.21037/atm.2017.06.60.I | 07/15/2017 | |
| Identification of unique proteomic signatures in allergic and non-allergic skin disease | Wang J, et al. | 2017 | Clin Exp Allergy | 47 | 11 | 1456-1467 | https://www.doi.org/10.1111/cea.12979 | 28,703,865 | Case-Control Studies Cluster Analysis Dermatitis, Atopic/*immunology/*metabolism Dermatitis, Contact/immunology/metabolism Female Humans Immunoglobulin E/blood/immunology Inflammation Mediators/blood/metabolism Male *Proteome *Proteomics/methods Skin Diseases/etiology/*metabolism atopic dermatitis biomarkers clinical immunology contact dermatitis dermatology psoriasis | BACKGROUND: Atopic dermatitis (AD), psoriasis (PS), and contact dermatitis (CD) are common skin diseases, characterized by barrier disruption and systemic inflammation, with unique epidermal signatures and common inflammatory pathways identified by transcriptomic profiling. This study profiled proteomic signatures in serum from subjects with AD, PS, and CD compared with healthy controls (HC). OBJECTIVE: Identify unique proteomic signatures to distinguish between inflammatory diseases with similar epidermal disruption and overlapping epithelial inflammation. METHODS: Sera from 20 subjects with moderate to severe AD, 10 subjects with CD, 12 subjects with moderate to severe PS, 10 subjects with both AD and CD, and 10 HC with no history of skin disease was analysed using high-throughput proteomic analysis that detects expression of 1129 protein targets. Protein expression was compared between disease and HC, and across diseases for statistical significance (fold change>/=1.5 and false discovery rate | Wang, J Suarez-Farinas, M Estrada, Y Parker, M L Greenlees, L Stephens, G Krueger, J Guttman-Yassky, E Howell, M D eng England Clin Exp Allergy. 2017 Nov;47(11):1456-1467. doi: 10.1111/cea.12979. Epub 2017 Aug 11.I | 07/14/2017 | |
| Aptamer-based proteomic profiling for prognostication in pulmonary arterial hypertension | Giannitsis E, et al. | 2017 | Lancet Respir Med | 5 | 9 | 671-672 | https://www.doi.org/10.1016/S2213-2600(17)30209-6 | 28,624,387 | Familial Primary Pulmonary Hypertension Gene Expression Profiling Humans *Hypertension, Pulmonary *Proteomics | Giannitsis, Evangelos Mueller-Hennessen, Matthias Katus, Hugo A eng Comment England Lancet Respir Med. 2017 Sep;5(9):671-672. doi: 10.1016/S2213-2600(17)30209-6. Epub 2017 Jun 15.I | 06/19/2017 | ||
| Plasma proteome analysis in patients with pulmonary arterial hypertension: an observational cohort study | Rhodes CJ, et al. | 2017 | Lancet Respir Med | 5 | 9 | 717-726 | https://www.doi.org/10.1016/S2213-2600(17)30161-3 | 28,624,389 | Adult Aged Arterial Pressure Biomarkers/blood Blood Proteins/*analysis Cohort Studies Familial Primary Pulmonary Hypertension/*blood/mortality Female Humans Hypertension/*blood/mortality Male Middle Aged Proteome/*analysis Risk Assessment Risk Factors | BACKGROUND: Idiopathic and heritable pulmonary arterial hypertension form a rare but molecularly heterogeneous disease group. We aimed to measure and validate differences in plasma concentrations of proteins that are associated with survival in patients with idiopathic or heritable pulmonary arterial hypertension to improve risk stratification. METHODS: In this observational cohort study, we enrolled patients with idiopathic or heritable pulmonary arterial hypertension from London (UK; cohorts 1 and 2), Giessen (Germany; cohort 3), and Paris (France; cohort 4). Blood samples were collected at routine clinical appointment visits, clinical data were collected within 30 days of blood sampling, and biochemical data were collected within 7 days of blood sampling. We used an aptamer-based assay of 1129 plasma proteins, and patient clinical details were concealed to the technicians. We identified a panel of prognostic proteins, confirmed with alternative targeted assays, which we evaluated against the established prognostic risk equation for pulmonary arterial hypertension derived from the REVEAL registry. All-cause mortality was the primary endpoint. FINDINGS: 20 proteins differentiated survivors and non-survivors in 143 consecutive patients with idiopathic or heritable pulmonary arterial hypertension with 2 years' follow-up (cohort 1) and in a further 75 patients with 2.5 years' follow-up (cohort 2). Nine proteins were both prognostic independent of plasma NT-proBNP concentrations and confirmed by targeted assays. The functions of these proteins relate to myocardial stress, inflammation, pulmonary vascular cellular dysfunction and structural dysregulation, iron status, and coagulation. A cutoff-based score using the panel of nine proteins provided prognostic information independent of the REVEAL equation, improving the C statistic from area under the curve 0.83 (for REVEAL risk score, 95% CI 0.77-0.89; p<0.0001) to 0.91 (for panel and REVEAL 0.87-0.96; p<0.0001) and improving reclassification indices without detriment to calibration. Poor survival was preceded by an adverse change in panel score in paired samples from 43 incident patients with pulmonary arterial hypertension in cohort 3 (p=0.0133). The protein panel was validated in 93 patients with idiopathic or heritable pulmonary arterial hypertension in cohort 4, with 4.4 years' follow-up and improved risk estimates, providing complementary information to the clinical risk equation. INTERPRETATION: A combination of nine circulating proteins identifies patients with pulmonary arterial hypertension with a high risk of mortality, independent of existing clinical assessments, and might have a use in clinical management and the evaluation of new therapies. FUNDING: National Institute for Health Research, Wellcome Trust, British Heart Foundation, Assistance Publique-Hopitaux de Paris, Inserm, Universite Paris-Sud, and Agence Nationale de la Recherche. | Rhodes, Christopher J Wharton, John Ghataorhe, Pavandeep Watson, Geoffrey Girerd, Barbara Howard, Luke S Gibbs, J Simon R Condliffe, Robin Elliot, Charles A Kiely, David G Simonneau, Gerald Montani, David Sitbon, Olivier Gall, Henning Schermuly, Ralph T Ghofrani, H Ardeschir Lawrie, Allan Humbert, Marc Wilkins, Martin R eng WT_/Wellcome Trust/United Kingdom FS/13/48/30453/BHF_/British Heart Foundation/United Kingdom PG/11/116/29288/BHF_/British Heart Foundation/United Kingdom RG/10/16/28575/BHF_/British Heart Foundation/United Kingdom Multicenter Study Observational Study England Lancet Respir Med. 2017 Sep;5(9):717-726. doi: 10.1016/S2213-2600(17)30161-3. Epub 2017 Jun 15.I | 06/19/2017 | |
| GDF15 is a heart-derived hormone that regulates body growth | Wang T, et al. | 2017 | EMBO Mol Med | 9 | 8 | 1150-1164 | https://www.doi.org/10.15252/emmm.201707604 | 28,572,090 | Animals *Child Development Child, Preschool Growth Differentiation Factor 15/*metabolism Growth Hormone/*antagonists & inhibitors Humans Mice, Inbred C57BL Mice, Knockout Models, Animal Myocytes, Cardiac/*metabolism Signal Transduction Gdf15 body growth failure to thrive heart disease heart-derived hormone | The endocrine system is crucial for maintaining whole-body homeostasis. Little is known regarding endocrine hormones secreted by the heart other than atrial/brain natriuretic peptides discovered over 30 years ago. Here, we identify growth differentiation factor 15 (GDF15) as a heart-derived hormone that regulates body growth. We show that pediatric heart disease induces GDF15 synthesis and secretion by cardiomyocytes. Circulating GDF15 in turn acts on the liver to inhibit growth hormone (GH) signaling and body growth. We demonstrate that blocking cardiomyocyte production of GDF15 normalizes circulating GDF15 level and restores liver GH signaling, establishing GDF15 as a bona fide heart-derived hormone that regulates pediatric body growth. Importantly, plasma GDF15 is further increased in children with concomitant heart disease and failure to thrive (FTT). Together these studies reveal a new endocrine mechanism by which the heart coordinates cardiac function and body growth. Our results also provide a potential mechanism for the well-established clinical observation that children with heart diseases often develop FTT. | Wang, Ting Liu, Jian McDonald, Caitlin Lupino, Katherine Zhai, Xiandun Wilkins, Benjamin J Hakonarson, Hakon Pei, Liming eng P50 MH096891/MH/NIMH NIH HHS/ R01 DK111495/DK/NIDDK NIH HHS/ U01 HG008684/HG/NHGRI NIH HHS/ P30 DK019525/DK/NIDDK NIH HHS/ K08 DK099379/DK/NIDDK NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. England EMBO Mol Med. 2017 Aug;9(8):1150-1164. doi: 10.15252/emmm.201707604.I | 06/03/2017 | |
| Downregulation of the Complement Cascade In Vitro, in Mice and in Patients with Cardiovascular Disease by the BET Protein Inhibitor Apabetalone (RVX-208) | Wasiak S, et al. | 2017 | J Cardiovasc Transl Res | 10 | 4 | 337-347 | https://www.doi.org/10.1007/s12265-017-9755-z | 28,567,671 | Animals Cardiovascular Diseases/blood/*drug therapy/genetics/immunology Cells, Cultured Complement Activation/*drug effects Complement Inactivating Agents/adverse effects/*therapeutic use Complement System Proteins/genetics/immunology/*metabolism Cytokines/immunology/metabolism Gene Expression Profiling Hepatocytes/*drug effects/immunology/metabolism Humans Immunity, Innate/drug effects Mice, SCID Primary Cell Culture Proteins/*antagonists & inhibitors/genetics/metabolism Proteomics Quinazolines/adverse effects/*therapeutic use Quinazolinones Signal Transduction/drug effects Biomarker Bromodomain Bromodomain and extraterminal protein Cardiovascular disease major acute cardiac event Complement cascade Epigenetics Inflammation Innate immunity standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000. Informed consent was obtained from all patients for being included in the study. ANIMAL STUDIES: All institutional and national guidelines for the care and use of laboratory animals were followed and approved by the appropriate institutional committees. DISCLOSURE: Authors are employees and shareholders of Resverlogix Corp. SOURCES OF FUNDING: This work was supported by Resverlogix Corp. | Apabetalone (RVX-208) is an epigenetic regulator developed to treat cardiovascular disease (CVD) that targets BET proteins. Through transcriptional regulation RVX-208 modulates pathways that underlie CVD including reverse cholesterol transport, vascular inflammation, coagulation, and complement. Using transcriptomics and proteomics we show that complement is one of the top pathways downregulated by RVX-208 in primary human hepatocytes (PHH) and in plasma from CVD patients. RVX-208 reduces basal and cytokine-driven expression of complement factors in PHH and in chimeric mice with humanized livers. Plasma proteomics of CVD patients shows that RVX-208 decreases complement proteins and regulators, including complement activators SAP and CRP. Circulating activated fragments C5a, C3b, and C5b-C6 are reduced by 51, 32, and 10%, respectively, indicating decreased activity of complement in patients. As complement components are linked to CVD and metabolic syndrome, including major acute cardiac events, modulating their levels and activity by RVX-208 may alleviate risks associated with these diseases. | Wasiak, Sylwia Gilham, Dean Tsujikawa, Laura M Halliday, Christopher Calosing, Cyrus Jahagirdar, Ravi Johansson, Jan Sweeney, Michael Wong, Norman C Kulikowski, Ewelina eng J Cardiovasc Transl Res. 2017 Aug;10(4):337-347. doi: 10.1007/s12265-017-9755-z. Epub 2017 May 31.I | 06/02/2017 | |
| Fifteen new risk loci for coronary artery disease highlight arterial-wall-specific mechanisms | Howson JMM, et al. | 2017 | Nat Genet | 49 | 7 | 1113-1119 | https://www.doi.org/10.1038/ng.3874 | 28,530,674 | Arteries/*pathology Atherosclerosis/genetics Cell Adhesion/genetics Chemotaxis, Leukocyte/genetics Coronary Artery Disease/*genetics/pathology/physiopathology Energy Metabolism/genetics Female Genetic Predisposition to Disease *Genome-Wide Association Study Genotype Histone Code Humans Male Muscle, Smooth, Vascular/pathology Polymorphism, Single Nucleotide Quantitative Trait Loci Risk Factors | Coronary artery disease (CAD) is a leading cause of morbidity and mortality worldwide. Although 58 genomic regions have been associated with CAD thus far, most of the heritability is unexplained, indicating that additional susceptibility loci await identification. An efficient discovery strategy may be larger-scale evaluation of promising associations suggested by genome-wide association studies (GWAS). Hence, we genotyped 56,309 participants using a targeted gene array derived from earlier GWAS results and performed meta-analysis of results with 194,427 participants previously genotyped, totaling 88,192 CAD cases and 162,544 controls. We identified 25 new SNP-CAD associations (P < 5 x 10(-8), in fixed-effects meta-analysis) from 15 genomic regions, including SNPs in or near genes involved in cellular adhesion, leukocyte migration and atherosclerosis (PECAM1, rs1867624), coagulation and inflammation (PROCR, rs867186 (p.Ser219Gly)) and vascular smooth muscle cell differentiation (LMOD1, rs2820315). Correlation of these regions with cell-type-specific gene expression and plasma protein levels sheds light on potential disease mechanisms. | Howson, Joanna M M Zhao, Wei Barnes, Daniel R Ho, Weang-Kee Young, Robin Paul, Dirk S Waite, Lindsay L Freitag, Daniel F Fauman, Eric B Salfati, Elias L Sun, Benjamin B Eicher, John D Johnson, Andrew D Sheu, Wayne H H Nielsen, Sune F Lin, Wei-Yu Surendran, Praveen Malarstig, Anders Wilk, Jemma B Tybjaerg-Hansen, Anne Rasmussen, Katrine L Kamstrup, Pia R Deloukas, Panos Erdmann, Jeanette Kathiresan, Sekar Samani, Nilesh J Schunkert, Heribert Watkins, Hugh Do, Ron Rader, Daniel J Johnson, Julie A Hazen, Stanley L Quyyumi, Arshed A Spertus, John A Pepine, Carl J Franceschini, Nora Justice, Anne Reiner, Alex P Buyske, Steven Hindorff, Lucia A Carty, Cara L North, Kari E Kooperberg, Charles Boerwinkle, Eric Young, Kristin Graff, Mariaelisa Peters, Ulrike Absher, Devin Hsiung, Chao A Lee, Wen-Jane Taylor, Kent D Chen, Ying-Hsiang Lee, I-Te Guo, Xiuqing Chung, Ren-Hua Hung, Yi-Jen Rotter, Jerome I Juang, Jyh-Ming J Quertermous, Thomas Wang, Tzung-Dau Rasheed, Asif Frossard, Philippe Alam, Dewan S Majumder, Abdulla Al Shafi Di Angelantonio, Emanuele Chowdhury, Rajiv Chen, Yii-Der Ida Nordestgaard, Borge G Assimes, Themistocles L Danesh, John Butterworth, Adam S Saleheen, Danish eng K99 HL130580/HL/NHLBI NIH HHS/ P30 ES010126/ES/NIEHS NIH HHS/ MR/L003120/1/MRC_/Medical Research Council/United Kingdom G0800270/MRC_/Medical Research Council/United Kingdom R56 DK104806/DK/NIDDK NIH HHS/ UL1 TR000124/TR/NCATS NIH HHS/ K23 DK088942/DK/NIDDK NIH HHS/ T32 HL098049/HL/NHLBI NIH HHS/ 1508647/MRC_/Medical Research Council/United Kingdom R21 HL123677/HL/NHLBI NIH HHS/ S10 OD020069/OD/NIH HHS/ SP/02/002/14543/BHF_/British Heart Foundation/United Kingdom CH/12/2/29428/BHF_/British Heart Foundation/United Kingdom SP/09/002/27676/BHF_/British Heart Foundation/United Kingdom P30 DK063491/DK/NIDDK NIH HHS/ 268834/ERC_/European Research Council/International RG/08/014/24067/BHF_/British Heart Foundation/United Kingdom RG/14/5/30893/BHF_/British Heart Foundation/United Kingdom Meta-Analysis Nat Genet. 2017 Jul;49(7):1113-1119. doi: 10.1038/ng.3874. Epub 2017 May 22.I | 05/23/2017 | |
| Multiomic disease signatures converge to cytotoxic CD8 T cells in primary Sjogren's syndrome | Tasaki S, et al. | 2017 | Ann Rheum Dis | 76 | 8 | 1458-1466 | https://www.doi.org/10.1136/annrheumdis-2016-210788 | 28,522,454 | ADAM Proteins/genetics/immunology/metabolism Adult Aged CD8-Positive T-Lymphocytes/immunology/metabolism Computational Biology *Epigenomics Female *Gene Expression Profiling Genome-Wide Association Study Humans *Immunophenotyping Male Middle Aged *Proteomics RNA, Messenger/*metabolism Sjogren's Syndrome/genetics/*immunology/metabolism T-Lymphocytes, Cytotoxic/*immunology/metabolism Transcriptome Disease Activity Gene Polymorphism Sjgren's Syndrome | OBJECTIVES: Multiomics study was conducted to elucidate the crucial molecular mechanisms of primary Sjogren's syndrome (SS) pathology. METHODS: We generated multiple data set from well-defined patients with SS, which includes whole-blood transcriptomes, serum proteomes and peripheral immunophenotyping. Based on our newly generated data, we performed an extensive bioinformatic investigation. RESULTS: Our integrative analysis identified SS gene signatures (SGS) dysregulated in widespread omics layers, including epigenomes, mRNAs and proteins. SGS predominantly involved the interferon signature and ADAMs substrates. Besides, SGS was significantly overlapped with SS-causing genes indicated by a genome-wide association study and expression trait loci analyses. Combining the molecular signatures with immunophenotypic profiles revealed that cytotoxic CD8 -T cells- were associated with SGS. Further, we observed the activation of SGS in cytotoxic CD8 T cells isolated from patients with SS. CONCLUSIONS: Our multiomics investigation identified gene signatures deeply associated with SS pathology and showed the involvement of cytotoxic CD8 T cells. These integrative relations across multiple layers will facilitate our understanding of SS at the system level. | Tasaki, Shinya Suzuki, Katsuya Nishikawa, Ayumi Kassai, Yoshiaki Takiguchi, Maiko Kurisu, Rina Okuzono, Yuumi Miyazaki, Takahiro Takeshita, Masaru Yoshimoto, Keiko Yasuoka, Hidekata Yamaoka, Kunihiro Ikeura, Kazuhiro Tsunoda, Kazuyuki Morita, Rimpei Yoshimura, Akihiko Toyoshiba, Hiroyoshi Takeuchi, Tsutomu eng England Ann Rheum Dis. 2017 Aug;76(8):1458-1466. doi: 10.1136/annrheumdis-2016-210788. Epub 2017 May 18.I | 05/20/2017 | |
| Proteomic profiling identifies novel circulating markers associated with bronchiectasis in cystic fibrosis | DeBoer EM, et al. | 2017 | Proteomics Clin Appl | 11 | 10 | https://www.doi.org/10.1002/prca.201600147 | 28,452,194 | Adolescent Biomarkers/blood Body Mass Index Bronchiectasis/*blood/*complications/diagnostic imaging/metabolism Child Cystic Fibrosis/*complications Disease Progression Female Humans Lung/physiopathology Male *Proteomics Tomography, X-Ray Computed Cystic fibrosis Extracellular matrix Lung Injury | PURPOSE: Evaluate bronchiectasis change over 1 year in children with cystic fibrosis (CF) and find blood proteins associated with bronchiectasis. EXPERIMENTAL DESIGN: Pilot study of CF children who had chest computed tomography (CT) scans and blood collected during times of clinical stability. Blood plasma was analyzed for 1129 proteins using SOMAmer(R), the SOMAscan proteomics platform. Bronchiectasis was measured on two CT scans collected 1 year apart. Spearman's rank estimated the correlations between outcomes. Clinical relevance was defined as |r| >0.40. RESULTS: There were 26 children included: mean age 11.3 years (SD 2.4 years), mean Brody Bronchiectasis score 0.65 (SD 0.83), mean airway count 14.3 (SD 5.7) per CT slice. Brody bronchiectasis change over 1 year ranged from -1.0 to 1.9 and airway count change over one year ranged from -7.7 to 13.5 airways per slice. Proteins related to inflammation and extracellular matrix degradation were associated with cross-sectional and longitudinal structural changes. CONCLUSIONS AND CLINICAL RELEVANCE: Imaging outcomes were more strongly correlated with circulating proteins than age or spirometry values. The unique SOMAscan proteomic platform identifies several novel proteins in blood that are associated with bronchiectasis and that may serve as clinically useful biomarkers in children with CF. | DeBoer, Emily M Kroehl, Miranda E Wagner, Brandie D Accurso, Frank J Harris, J Kirk Lynch, David A Sagel, Scott D Deterding, Robin R eng KL2 TR001080/TR/NCATS NIH HHS/ Research Support, N.I.H., Extramural Germany Proteomics Clin Appl. 2017 Sep;11(9-10). doi: 10.1002/prca.201600147. Epub 2017 May 29.I | 04/30/2017 | ||
| The influence of insulin resistance on cerebrospinal fluid and plasma biomarkers of Alzheimer's pathology | Westwood S, et al. | 2017 | Alzheimers Res Ther | 9 | 1 | 31 | https://www.doi.org/10.1186/s13195-017-0258-6 | 28,441,961 | Alzheimer Disease/*blood/*cerebrospinal fluid Amyloid beta-Peptides/*blood/*cerebrospinal fluid Animals Apolipoprotein E4/*blood/*cerebrospinal fluid Biomarkers/blood/cerebrospinal fluid Humans *Insulin Resistance Male Middle Aged Reproducibility of Results Sensitivity and Specificity Alzheimer's disease Cerebrospinal fluid biomarkers Diabetes mellitus Insulin resistance Plasma biomarkers Proteomics | BACKGROUND: Insulin resistance (IR) has previously been associated with an increased risk of developing Alzheimer's disease (AD), although the relationship between IR and AD is not yet clear. Here, we examined the influence of IR on AD using plasma and cerebrospinal fluid (CSF) biomarkers related to IR and AD in cognitively healthy men. We also aimed to characterise the shared protein signatures between IR and AD. METHODS: Fifty-eight cognitively healthy men, 28 IR and 30 non-IR (age and APOE epsilon4 matched), were drawn from the Metabolic Syndrome in Men study in Kuopio, Finland. CSF AD biomarkers (amyloid beta-peptide (Abeta), total tau and tau phosphorylated at the Thr181 epitope) were examined with respect to IR. Targeted proteomics using ELISA and Luminex xMAP assays were performed to assess the influence of IR on previously identified CSF and plasma protein biomarker candidates of AD pathology. Furthermore, CSF and plasma SOMAscan was performed to discover proteins that associate with IR and CSF AD biomarkers. RESULTS: CSF AD biomarkers did not differ between IR and non-IR groups, although plasma insulin correlated with CSF Abeta/tau across the whole cohort. In total, 200 CSF and 487 plasma proteins were differentially expressed between IR and non-IR subjects, and significantly enriched pathways, many of which have been previously implicated in AD, were identified. CSF and plasma proteins significantly associated with CSF AD biomarkers were also discovered, and those sensitive to both IR and AD were identified. CONCLUSIONS: These data indicate that IR is not directly related to the level of CSF AD pathology in cognitively healthy men. Proteins that associated with both AD and IR are potential markers indicative of shared pathology. | Westwood, Sarah Liu, Benjamine Baird, Alison L Anand, Sneha Nevado-Holgado, Alejo J Newby, Danielle Pikkarainen, Maria Hallikainen, Merja Kuusisto, Johanna Streffer, Johannes R Novak, Gerald Blennow, Kaj Andreasson, Ulf Zetterberg, Henrik Smith, Ulf Laakso, Markku Soininen, Hilkka Lovestone, Simon eng G0801464/MRC_/Medical Research Council/United Kingdom Review England Alzheimers Res Ther. 2017 Apr 26;9(1):31. doi: 10.1186/s13195-017-0258-6.I | 04/27/2017 | |
| The peripheral blood proteome signature of idiopathic pulmonary fibrosis is distinct from normal and is associated with novel immunological processes | O'Dwyer DN, et al. | 2017 | Sci Rep | 7 | 46560 | https://www.doi.org/10.1038/srep46560 | 28,440,314 | Adult Aged Aged, 80 and over *Blood Proteins/immunology/metabolism Female Humans *Idiopathic Pulmonary Fibrosis/blood/immunology Male Middle Aged *Proteome/immunology/metabolism | Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal interstitial pneumonia. The disease pathophysiology is poorly understood and the etiology remains unclear. Recent advances have generated new therapies and improved knowledge of the natural history of IPF. These gains have been brokered by advances in technology and improved insight into the role of various genes in mediating disease, but gene expression and protein levels do not always correlate. Thus, in this paper we apply a novel large scale high throughput aptamer approach to identify more than 1100 proteins in the peripheral blood of well-characterized IPF patients and normal volunteers. We use systems biology approaches to identify a unique IPF proteome signature and give insight into biological processes driving IPF. We found IPF plasma to be altered and enriched for proteins involved in defense response, wound healing and protein phosphorylation when compared to normal human plasma. Analysis also revealed a minimal protein signature that differentiated IPF patients from normal controls, which may allow for accurate diagnosis of IPF based on easily-accessible peripheral blood. This report introduces large scale unbiased protein discovery analysis to IPF and describes distinct biological processes that further inform disease biology. | O'Dwyer, David N Norman, Katy C Xia, Meng Huang, Yong Gurczynski, Stephen J Ashley, Shanna L White, Eric S Flaherty, Kevin R Martinez, Fernando J Murray, Susan Noth, Imre Arnold, Kelly B Moore, Bethany B eng UL1 TR000433/TR/NCATS NIH HHS/ K24 HL111316/HL/NHLBI NIH HHS/ R01 HL091745/HL/NHLBI NIH HHS/ R01 HL130796/HL/NHLBI NIH HHS/ R01 HL115618/HL/NHLBI NIH HHS/ T32 AI007413/AI/NIAID NIH HHS/ Clinical Trial Multicenter Study Observational Study Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't England Sci Rep. 2017 Apr 25;7:46560. doi: 10.1038/srep46560.I | 04/26/2017 | ||
| Human knockouts and phenotypic analysis in a cohort with a high rate of consanguinity | Saleheen D, et al. | 2017 | Nature | 544 | 7,649 | 235-239 | https://www.doi.org/10.1038/nature22034 | 28,406,212 | 1-Alkyl-2-acetylglycerophosphocholine Esterase/deficiency/genetics Apolipoprotein C-III/deficiency/genetics Cohort Studies *Consanguinity Coronary Disease/blood/genetics Cytochrome P450 Family 2/genetics *DNA Mutational Analysis Dietary Fats/pharmacology Exome/genetics Fasting/blood Female *Gene Deletion Gene Frequency Genes/*genetics Genetic Association Studies/*methods *Homozygote Humans Interleukin-8/blood Male Middle Aged Myocardial Infarction/blood/genetics Neuregulins/genetics Pakistan Pedigree *Phenotype Phosphoproteins/genetics Postprandial Period RNA Splice Sites/genetics Reverse Genetics/methods Sodium-Hydrogen Exchangers/genetics Triglycerides/blood | A major goal of biomedicine is to understand the function of every gene in the human genome. Loss-of-function mutations can disrupt both copies of a given gene in humans and phenotypic analysis of such 'human knockouts' can provide insight into gene function. Consanguineous unions are more likely to result in offspring carrying homozygous loss-of-function mutations. In Pakistan, consanguinity rates are notably high. Here we sequence the protein-coding regions of 10,503 adult participants in the Pakistan Risk of Myocardial Infarction Study (PROMIS), designed to understand the determinants of cardiometabolic diseases in individuals from South Asia. We identified individuals carrying homozygous predicted loss-of-function (pLoF) mutations, and performed phenotypic analysis involving more than 200 biochemical and disease traits. We enumerated 49,138 rare (<1% minor allele frequency) pLoF mutations. These pLoF mutations are estimated to knock out 1,317 genes, each in at least one participant. Homozygosity for pLoF mutations at PLA2G7 was associated with absent enzymatic activity of soluble lipoprotein-associated phospholipase A2; at CYP2F1, with higher plasma interleukin-8 concentrations; at TREH, with lower concentrations of apoB-containing lipoprotein subfractions; at either A3GALT2 or NRG4, with markedly reduced plasma insulin C-peptide concentrations; and at SLC9A3R1, with mediators of calcium and phosphate signalling. Heterozygous deficiency of APOC3 has been shown to protect against coronary heart disease; we identified APOC3 homozygous pLoF carriers in our cohort. We recruited these human knockouts and challenged them with an oral fat load. Compared with family members lacking the mutation, individuals with APOC3 knocked out displayed marked blunting of the usual post-prandial rise in plasma triglycerides. Overall, these observations provide a roadmap for a 'human knockout project', a systematic effort to understand the phenotypic consequences of complete disruption of genes in humans. | Saleheen, Danish Natarajan, Pradeep Armean, Irina M Zhao, Wei Rasheed, Asif Khetarpal, Sumeet A Won, Hong-Hee Karczewski, Konrad J O'Donnell-Luria, Anne H Samocha, Kaitlin E Weisburd, Benjamin Gupta, Namrata Zaidi, Mozzam Samuel, Maria Imran, Atif Abbas, Shahid Majeed, Faisal Ishaq, Madiha Akhtar, Saba Trindade, Kevin Mucksavage, Megan Qamar, Nadeem Zaman, Khan Shah Yaqoob, Zia Saghir, Tahir Rizvi, Syed Nadeem Hasan Memon, Anis Hayyat Mallick, Nadeem Ishaq, Mohammad Rasheed, Syed Zahed Memon, Fazal-Ur-Rehman Mahmood, Khalid Ahmed, Naveeduddin Do, Ron Krauss, Ronald M MacArthur, Daniel G Gabriel, Stacey Lander, Eric S Daly, Mark J Frossard, Philippe Danesh, John Rader, Daniel J Kathiresan, Sekar eng P30 DK043351/DK/NIDDK NIH HHS/ RG/08/014/24067/BHF_/British Heart Foundation/United Kingdom MR/P02811X/1/MRC_/Medical Research Council/United Kingdom R01 GM104371/GM/NIGMS NIH HHS/ MR/P013880/1/MRC_/Medical Research Council/United Kingdom U54 HG003067/HG/NHGRI NIH HHS/ R01 HL107816/HL/NHLBI NIH HHS/ MR/L003120/1/MRC_/Medical Research Council/United Kingdom Wellcome Trust/United Kingdom RG/16/4/32218/BHF_/British Heart Foundation/United Kingdom Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. England Nature. 2017 Apr 12;544(7649):235-239. doi: 10.1038/nature22034.I | 04/14/2017 | |
| Paracrine signals regulate human liver organoid maturation from induced pluripotent stem cells | Asai A, et al. | 2017 | Development | 144 | 6 | 1056-1064 | https://www.doi.org/10.1242/dev.142794 | 28,275,009 | Animals Bile Acids and Salts/metabolism Biological Transport Biomarkers/metabolism *Cell Differentiation Cell Polarity Coculture Techniques Gene Expression Regulation Hepatocytes/cytology/ultrastructure Human Umbilical Vein Endothelial Cells/cytology/metabolism Humans Induced Pluripotent Stem Cells/*cytology/metabolism Liver/*cytology Mesenchymal Stem Cells/cytology/metabolism Mice Morphogenesis/genetics Organ Specificity/genetics Organoids/*cytology/metabolism *Paracrine Communication Proteins/analysis Abcb11 Hepatocyte differentiation Liver development Regeneration Tissue engineering | A self-organizing organoid model provides a new approach to study the mechanism of human liver organogenesis. Previous animal models documented that simultaneous paracrine signaling and cell-to-cell surface contact regulate hepatocyte differentiation. To dissect the relative contributions of the paracrine effects, we first established a liver organoid using human induced pluripotent stem cells (iPSCs), mesenchymal stem cells (MSCs) and human umbilical vein endothelial cells (HUVECs) as previously reported. Time-lapse imaging showed that hepatic-specified endoderm iPSCs (HE-iPSCs) self-assembled into three-dimensional organoids, resulting in hepatic gene induction. Progressive differentiation was demonstrated by hepatic protein production after in vivo organoid transplantation. To assess the paracrine contributions, we employed a Transwell system in which HE-iPSCs were separately co-cultured with MSCs and/or HUVECs. Although the three-dimensional structure did not form, their soluble factors induced a hepatocyte-like phenotype in HE-iPSCs, resulting in the expression of bile salt export pump. In conclusion, the mesoderm-derived paracrine signals promote hepatocyte maturation in liver organoids, but organoid self-organization requires cell-to-cell surface contact. Our in vitro model demonstrates a novel approach to identify developmental paracrine signals regulating the differentiation of human hepatocytes. | Asai, Akihiro Aihara, Eitaro Watson, Carey Mourya, Reena Mizuochi, Tatsuki Shivakumar, Pranavkumar Phelan, Kieran Mayhew, Christopher Helmrath, Michael Takebe, Takanori Wells, James Bezerra, Jorge A eng P30 DK078392/DK/NIDDK NIH HHS/ England Development. 2017 Mar 15;144(6):1056-1064. doi: 10.1242/dev.142794.I | 03/10/2017 | |
| Selection of DNA aptamers with two modified bases | Gawande BN, et al. | 2017 | Proc Natl Acad Sci U S A | 114 | 11 | 2898-2903 | https://www.doi.org/10.1073/pnas.1615475114 | 28,265,062 | *Aptamers, Nucleotide Cell Line, Tumor Deoxyribonucleases/metabolism Gene Library Humans Ligands PCSK9 Inhibitors Proprotein Convertase 9/chemistry/genetics *SELEX Aptamer Technique Pcsk9 Psma Selex SOMAmer modified aptamer SomaLogic, Inc. SOMAmer reagent is a registered trademark of SomaLogic, Inc. | The nucleobases comprising DNA and RNA aptamers provide considerably less chemical diversity than protein-based ligands, limiting their versatility. The introduction of novel functional groups at just one of the four bases in modified aptamers has recently led to dramatic improvement in the success rate of identifying nucleic acid ligands to protein targets. Here we explore the benefits of additional enhancement in physicochemical diversity by selecting modified DNA aptamers that contain amino-acid-like modifications on both pyrimidine bases. Using proprotein convertase subtilisin/kexin type 9 as a representative protein target, we identify specific pairwise combinations of modifications that result in higher affinity, metabolic stability, and inhibitory potency compared with aptamers with single modifications. Such doubly modified aptamers are also more likely to be encoded in shorter sequences and occupy nonoverlapping epitopes more frequently than aptamers with single modifications. These highly modified DNA aptamers have broad utility in research, diagnostic, and therapeutic applications. | Gawande, Bharat N Rohloff, John C Carter, Jeffrey D von Carlowitz, Ira Zhang, Chi Schneider, Daniel J Janjic, Nebojsa eng Proc Natl Acad Sci U S A. 2017 Mar 14;114(11):2898-2903. doi: 10.1073/pnas.1615475114. Epub 2017 Mar 6.I | 03/08/2017 | |
| A multi-component classifier for nonalcoholic fatty liver disease (NAFLD) based on genomic, proteomic, and phenomic data domains | Wood GC, et al. | 2017 | Sci Rep | 7 | 43238 | https://www.doi.org/10.1038/srep43238 | 28,266,614 | Bariatric Surgery Biomarkers/*analysis *Decision Support Techniques Genomics/*methods Humans Non-alcoholic Fatty Liver Disease/*classification/*pathology Obesity/*complications/surgery Proteomics/*methods ROC Curve | Non-alcoholic fatty liver disease (NAFLD) represents a spectrum of conditions that include steatohepatitis and fibrosis that are thought to emanate from hepatic steatosis. Few robust biomarkers or diagnostic tests have been developed for hepatic steatosis in the setting of obesity. We have developed a multi-component classifier for hepatic steatosis comprised of phenotypic, genomic, and proteomic variables using data from 576 adults with extreme obesity who underwent bariatric surgery and intra-operative liver biopsy. Using a 443 patient training set, protein biomarker discovery was performed using the highly multiplexed SOMAscan((R)) proteomic assay, a set of 19 clinical variables, and the steatosis predisposing PNPLA3 rs738409 single nucleotide polymorphism genotype status. The most stable markers were selected using a stability selection algorithm with a L(1)-regularized logistic regression kernel and were then fitted with logistic regression models to classify steatosis, that were then tested against a 133 sample blinded verification set. The highest area under the ROC curve (AUC) for steatosis of PNPLA3 rs738409 genotype, 8 proteins, or 19 phenotypic variables was 0.913, whereas the final classifier that included variables from all three domains had an AUC of 0.935. These data indicate that multi-domain modeling has better predictive power than comprehensive analysis of variables from a single domain. | Wood, G Craig Chu, Xin Argyropoulos, George Benotti, Peter Rolston, David Mirshahi, Tooraj Petrick, Anthony Gabrielson, John Carey, David J DiStefano, Johanna K Still, Christopher D Gerhard, Glenn S eng R01 DK091601/DK/NIDDK NIH HHS/ Evaluation Study Research Support, N.I.H., Extramural England Sci Rep. 2017 Mar 7;7:43238. doi: 10.1038/srep43238.I | 03/08/2017 | ||
| The maternal plasma proteome changes as a function of gestational age in normal pregnancy: a longitudinal study | Romero R, et al. | 2017 | Am J Obstet Gynecol | 217 | 1 | 67 e1-67 e21 | https://www.doi.org/10.1016/j.ajog.2017.02.037 | 28,263,753 | Adult Biomarkers/blood Blood Proteins/*analysis Female *Gestational Age Humans Longitudinal Studies Pregnancy Pregnancy Complications/blood *Pregnancy Outcome Prospective Studies Proteome/*analysis Proteomics/methods C-C motif-28 aptamer biomarker carbonic anhydrase-6 dual-specificity mitogen-activated protein kinase kinase-4 glypican-3 high-throughput biology interleukin-1 receptor 4 placental growth factor pregnancy-associated plasma protein A prolactin proteins sialic acid-binding immunoglobulin-type lectin-6 | OBJECTIVE: Pregnancy is accompanied by dramatic physiological changes in maternal plasma proteins. Characterization of the maternal plasma proteome in normal pregnancy is an essential step for understanding changes to predict pregnancy outcome. The objective of this study was to describe maternal plasma proteins that change in abundance with advancing gestational age and determine biological processes that are perturbed in normal pregnancy. STUDY DESIGN: A longitudinal study included 43 normal pregnancies that had a term delivery of an infant who was appropriate for gestational age without maternal or neonatal complications. For each pregnancy, 3 to 6 maternal plasma samples (median, 5) were profiled to measure the abundance of 1125 proteins using multiplex assays. Linear mixed-effects models with polynomial splines were used to model protein abundance as a function of gestational age, and the significance of the association was inferred via likelihood ratio tests. Proteins considered to be significantly changed were defined as having the following: (1) >1.5-fold change between 8 and 40 weeks of gestation; and (2) a false discovery rate-adjusted value of P < .1. Gene ontology enrichment analysis was used to identify biological processes overrepresented among the proteins that changed with advancing gestation. RESULTS: The following results were found: (1) Ten percent (112 of 1125) of the profiled proteins changed in abundance as a function of gestational age; (2) of the 1125 proteins analyzed, glypican-3, sialic acid-binding immunoglobulin-type lectin-6, placental growth factor, C-C motif-28, carbonic anhydrase 6, prolactin, interleukin-1 receptor 4, dual-specificity mitogen-activated protein kinase 4, and pregnancy-associated plasma protein-A had more than a 5-fold change in abundance across gestation (these 9 proteins are known to be involved in a wide range of both physiological and pathological processes, such as growth regulation, embryogenesis, angiogenesis immunoregulation, inflammation etc); and (3) biological processes associated with protein changes in normal pregnancy included defense response, defense response to bacteria, proteolysis, and leukocyte migration (false discovery rate, 10%). CONCLUSION: The plasma proteome of normal pregnancy demonstrates dramatic changes in both the magnitude of changes and the fraction of the proteins involved. Such information is important to understand the physiology of pregnancy and the development of biomarkers to differentiate normal vs abnormal pregnancy and determine the response to interventions. | Romero, Roberto Erez, Offer Maymon, Eli Chaemsaithong, Piya Xu, Zhonghui Pacora, Percy Chaiworapongsa, Tinnakorn Done, Bogdan Hassan, Sonia S Tarca, Adi L eng HHSN275201300006C/HD/NICHD NIH HHS/ ZIA HD002400-26/Intramural NIH HHS/ Research Support, N.I.H., Extramural Research Support, N.I.H., Intramural Am J Obstet Gynecol. 2017 Jul;217(1):67.e1-67.e21. doi: 10.1016/j.ajog.2017.02.037. Epub 2017 Mar 3.I | 03/07/2017 | |
| Identification of serum protein biomarkers for utrophin based DMD therapy | Guiraud S, et al. | 2017 | Sci Rep | 7 | 43697 | https://www.doi.org/10.1038/srep43697 | 28,252,048 | Animals *Biomarkers *Blood Proteins Disease Models, Animal Enzyme-Linked Immunosorbent Assay Humans Mice Mice, Transgenic Muscular Dystrophy, Animal Muscular Dystrophy, Duchenne/blood/genetics/therapy Proteome Proteomics/methods Translational Research, Biomedical Utrophin/*blood/therapeutic use | Despite promising therapeutic avenues, there is currently no effective treatment for Duchenne muscular dystrophy (DMD), a lethal monogenic disorder caused by the loss of the large cytoskeletal protein, dystrophin. A highly promising approach to therapy, applicable to all DMD patients irrespective to their genetic defect, is to modulate utrophin, a functional paralogue of dystrophin, able to compensate for the primary defects of DMD restoring sarcolemmal stability. One of the major difficulties in assessing the effectiveness of therapeutic strategies is to define appropriate outcome measures. In the present study, we utilised an aptamer based proteomics approach to profile 1,310 proteins in plasma of wild-type, mdx and Fiona (mdx overexpressing utrophin) mice. Comparison of the C57 and mdx sera revealed 83 proteins with statistically significant >2 fold changes in dystrophic serum abundance. A large majority of previously described biomarkers (ANP32B, THBS4, CAMK2A/B/D, CYCS, CAPNI) were normalised towards wild-type levels in Fiona animals. This work also identified potential mdx markers specific to increased utrophin (DUS3, TPI1) and highlights novel mdx biomarkers (GITR, MYBPC1, HSP60, SIRT2, SMAD3, CNTN1). We define a panel of putative protein mdx biomarkers to evaluate utrophin based strategies which may help to accelerate their translation to the clinic. | Guiraud, Simon Edwards, Benjamin Squire, Sarah E Babbs, Arran Shah, Nandini Berg, Adam Chen, Huijia Davies, Kay E eng MR/N010698/1/MRC_/Medical Research Council/United Kingdom Research Support, Non-U.S. Gov't England Sci Rep. 2017 Mar 2;7:43697. doi: 10.1038/srep43697.I | 03/03/2017 | ||
| Connecting genetic risk to disease end points through the human blood plasma proteome | Suhre K, et al. | 2017 | Nat Commun | 8 | 14357 | https://www.doi.org/10.1038/ncomms14357 | 28,240,269 | Alleles Blood Proteins/*metabolism Complement System Proteins/metabolism Drug Delivery Systems *Endpoint Determination Gene Regulatory Networks *Genetic Predisposition to Disease Genetic Variation Genome, Human Genome-Wide Association Study Glycoproteins/metabolism Heme/metabolism Humans Molecular Sequence Annotation Pharmacogenetics Protein Processing, Post-Translational/genetics Proteome/genetics/*metabolism Quantitative Trait Loci RNA Splicing/genetics RNA, Messenger/genetics/metabolism Reproducibility of Results Risk Factors | Genome-wide association studies (GWAS) with intermediate phenotypes, like changes in metabolite and protein levels, provide functional evidence to map disease associations and translate them into clinical applications. However, although hundreds of genetic variants have been associated with complex disorders, the underlying molecular pathways often remain elusive. Associations with intermediate traits are key in establishing functional links between GWAS-identified risk-variants and disease end points. Here we describe a GWAS using a highly multiplexed aptamer-based affinity proteomics platform. We quantify 539 associations between protein levels and gene variants (pQTLs) in a German cohort and replicate over half of them in an Arab and Asian cohort. Fifty-five of the replicated pQTLs are located in trans. Our associations overlap with 57 genetic risk loci for 42 unique disease end points. We integrate this information into a genome-proteome network and provide an interactive web-tool for interrogations. Our results provide a basis for novel approaches to pharmaceutical and diagnostic applications. | Suhre, Karsten Arnold, Matthias Bhagwat, Aditya Mukund Cotton, Richard J Engelke, Rudolf Raffler, Johannes Sarwath, Hina Thareja, Gaurav Wahl, Annika DeLisle, Robert Kirk Gold, Larry Pezer, Marija Lauc, Gordan El-Din Selim, Mohammed A Mook-Kanamori, Dennis O Al-Dous, Eman K Mohamoud, Yasmin A Malek, Joel Strauch, Konstantin Grallert, Harald Peters, Annette Kastenmuller, Gabi Gieger, Christian Graumann, Johannes eng Research Support, Non-U.S. Gov't England Nat Commun. 2017 Feb 27;8:14357. doi: 10.1038/ncomms14357.I | 02/28/2017 | ||
| Development and Characterization of an HPV Type-16 Specific Modified DNA Aptamer for the Improvement of Potency Assays | Trausch JJ, et al. | 2017 | Anal Chem | 89 | 6 | 3554-3561 | https://www.doi.org/10.1021/acs.analchem.6b04852 | 28,233,502 | Antigen-Antibody Reactions Antigens, Viral/*immunology Aptamers, Nucleotide/chemical synthesis/chemistry/*immunology Enzyme-Linked Immunosorbent Assay Epitopes/*immunology Human papillomavirus 16/*immunology Humans Papillomavirus Vaccines/*immunology | Measuring vaccine potency is critical for vaccine release and is often accomplished using antibody-based ELISAs. Antibodies can be associated with significant drawbacks that are often overlooked including lot-to-lot variability, problems with cell-line maintenance, limited stability, high cost, and long discovery lead times. Here, we address many of these issues through the development of an aptamer, known as a slow off-rate modified DNA aptamer (SOMAmer), which targets a vaccine antigen in the human papillomavirus (HPV) vaccine Gardasil. The aptamer, termed HPV-07, was selected to bind the Type 16 virus-like-particle (VLP) formed by the self-assembling capsid protein L1. It is capable of binding with high sensitivity (EC(50) of 0.1 to 0.4 mug/mL depending on assay format) while strongly discriminating against other VLP types. The aptamer competes for binding with the neutralizing antibody H16.V5, indicating at least partial recognition of a neutralizing and clinically relevant epitope. This makes it a useful reagent for measuring both potency and stability. When used in an ELISA format, the aptamer displays both high precision (intermediate precision of 6.3%) and a large linear range spanning from 25% to 200% of a typical formulation. To further exploit the advantages of aptamers, a simplified mix and read assay was also developed. This assay format offers significant time and resource reductions compared to a traditional ELISA. These results show aptamers are suitable reagents for biological potency assays, and we expect that their implementation could improve upon current assay formats. | Trausch, Jeremiah J Shank-Retzlaff, Mary Verch, Thorsten eng Research Support, Non-U.S. Gov't Anal Chem. 2017 Mar 21;89(6):3554-3561. doi: 10.1021/acs.analchem.6b04852. Epub 2017 Mar 8.I | 02/25/2017 | |
| The impact of micronutrient status on health: correlation network analysis to understand the role of micronutrients in metabolic-inflammatory processes regulating homeostasis and phenotypic flexibility | van den Broek TJ, et al. | 2017 | Genes Nutr | 12 | 5 | https://www.doi.org/10.1186/s12263-017-0553-7 | 28,194,237 | Carotenoids Glucose Inflammation Lipid Metabolic challenge test Phenotypic flexibility Systems biology Vitamins | BACKGROUND: Vitamins and carotenoids are key micronutrients facilitating the maintenance of health, as evidenced by the increased risk of disease with low intake. Optimal phenotypic flexibility, i.e., the ability to respond to a physiological challenge, is an essential indicator of health status. Therefore, health can be measured by applying a challenge test and monitoring the response of relevant phenotypic processes. In this study, we assessed the correlation of three fat-soluble vitamins, (i.e., vitamin A or retinol, vitamin D(3), two homologues of vitamin E) and four carotenoids (i.e., alpha-carotene, beta-carotene, beta-cryptoxanthin, and lycopene), with characteristics of metabolic and inflammatory parameters at baseline and in response to a nutritional challenge test (NCT) in a group of 36 overweight and obese male subjects, using proteomics and metabolomics platforms. The phenotypic flexibility concept implies that health can be measured by the ability to adapt to a NCT, which may offer a more sensitive way to assess changes in health status of healthy subjects. RESULTS: Correlation analyses of results after overnight fasting revealed a rather evenly distributed network in a number of relatively strong correlations per micronutrient, with minor overlap between correlation profiles of each compound. Correlation analyses of challenge response profiles for metabolite and protein parameters with micronutrient status revealed a network that is more skewed towards alpha-carotene and gamma-tocopherol suggesting a more prominent role for these micronutrients in the maintenance of phenotypic flexibility. Comparison of the networks revealed that there is merely overlap of two parameters (inositol and oleic acid (C18:1)) affirming that there is a specific biomarker response profile upon NCT. CONCLUSIONS: Our study shows that applying the challenge test concept is able to reveal previously unidentified correlations between specific micronutrients and health-related processes, with potential relevance for maintenance of health that were not observed by correlating homeostatic measurements. This approach will contribute to insights on the influence of micronutrients on health and help to create efficient micronutrient intervention programs. | van den Broek, Tim J Kremer, Bas H A Marcondes Rezende, Marisa Hoevenaars, Femke P M Weber, Peter Hoeller, Ulrich van Ommen, Ben Wopereis, Suzan eng Germany Genes Nutr. 2017 Feb 8;12:5. doi: 10.1186/s12263-017-0553-7. eCollection 2017.I | 02/15/2017 | ||
| High-Throughput Characterization of Blood Serum Proteomics of IBD Patients with Respect to Aging and Genetic Factors | Di Narzo AF, et al. | 2017 | PLoS Genet | 13 | 1 | e1006565 | https://www.doi.org/10.1371/journal.pgen.1006565 | 28,129,359 | Adult Aging/*blood Biomarkers/blood Case-Control Studies Female *Genetic Predisposition to Disease Hepatocyte Growth Factor/blood High-Throughput Screening Assays Humans Inflammatory Bowel Diseases/*blood/epidemiology/genetics Male Middle Aged Polymorphism, Single Nucleotide Proteome/genetics/*metabolism Proto-Oncogene Proteins/blood Quantitative Trait Loci | To date, no large scale, systematic description of the blood serum proteome has been performed in inflammatory bowel disease (IBD) patients. By using microarray technology, a more complete description of the blood proteome of IBD patients is feasible. It may help to achieve a better understanding of the disease. We analyzed blood serum profiles of 1128 proteins in IBD patients of European descent (84 Crohn's Disease (CD) subjects and 88 Ulcerative Colitis (UC) subjects) as well as 15 healthy control subjects, and linked protein variability to patient age (all cohorts) and genetic components (genotype data generated from CD patients). We discovered new, previously unreported aging-associated proteomic traits (such as serum Albumin level), confirmed previously reported results from different tissues (i.e., upregulation of APOE with aging), and found loss of regulation of MMP7 in CD patients. In carrying out a genome wide genotype-protein association study (proteomic Quantitative Trait Loci, pQTL) within the CD patients, we identified 41 distinct proteomic traits influenced by cis pQTLs (underlying SNPs are referred to as pSNPs). Significant overlaps between pQTLs and cis eQTLs corresponding to the same gene were observed and in some cases the QTL were related to inflammatory disease susceptibility. Importantly, we discovered that serum protein levels of MST1 (Macrophage Stimulating 1) were regulated by SNP rs3197999 (p = 5.96E-10, FDR<5%), an accepted GWAS locus for IBD. Filling the knowledge gap of molecular mechanisms between GWAS hits and disease susceptibility requires systematically dissecting the impact of the locus at the cell, mRNA expression, and protein levels. The technology and analysis tools that are now available for large-scale molecular studies can elucidate how alterations in the proteome driven by genetic polymorphisms cause or provide protection against disease. Herein, we demonstrated this directly by integrating proteomic and pQTLs with existing GWAS, mRNA expression, and eQTL datasets to provide insights into the biological processes underlying IBD and pinpoint causal genetic variants along with their downstream molecular consequences. | Di Narzo, Antonio F Telesco, Shannon E Brodmerkel, Carrie Argmann, Carmen Peters, Lauren A Li, Katherine Kidd, Brian Dudley, Joel Cho, Judy Schadt, Eric E Kasarskis, Andrew Dobrin, Radu Hao, Ke eng Research Support, Non-U.S. Gov't PLoS Genet. 2017 Jan 27;13(1):e1006565. doi: 10.1371/journal.pgen.1006565. eCollection 2017 Jan.I | 01/28/2017 | |
| Genome-wide quantitative trait loci mapping of the human cerebrospinal fluid proteome | Sasayama D, et al. | 2017 | Hum Mol Genet | 26 | 1 | 44-51 | https://www.doi.org/10.1093/hmg/ddw366 | 28,031,287 | Biomarkers/*cerebrospinal fluid *Genome, Human Genome-Wide Association Study Humans Mental Disorders/cerebrospinal fluid/*genetics/pathology Phenotype Polymorphism, Single Nucleotide/*genetics Protein Array Analysis Proteome/*genetics Proteomics/methods Quantitative Trait Loci/*genetics | Cerebrospinal fluid (CSF) is virtually the only one accessible source of proteins derived from the central nervous system (CNS) of living humans and possibly reflects the pathophysiology of a variety of neuropsychiatric diseases. However, little is known regarding the genetic basis of variation in protein levels of human CSF. We examined CSF levels of 1,126 proteins in 133 subjects and performed a genome-wide association analysis of 514,227 single nucleotide polymorphisms (SNPs) to detect protein quantitative trait loci (pQTLs). To be conservative, Spearman's correlation was used to identify an association between genotypes of SNPs and protein levels. A total of 421 cis and 25 trans SNP-protein pairs were significantly correlated at a false discovery rate (FDR) of less than 0.01 (nominal P < 7.66 x 10-9). Cis-only analysis revealed additional 580 SNP-protein pairs with FDR < 0.01 (nominal P < 2.13 x 10-5). pQTL SNPs were more likely, compared to non-pQTL SNPs, to be a disease/trait-associated variants identified by previous genome-wide association studies. The present findings suggest that genetic variations play an important role in the regulation of protein expression in the CNS. The obtained database may serve as a valuable resource to understand the genetic bases for CNS protein expression pattern in humans. | Sasayama, Daimei Hattori, Kotaro Ogawa, Shintaro Yokota, Yuuki Matsumura, Ryo Teraishi, Toshiya Hori, Hiroaki Ota, Miho Yoshida, Sumiko Kunugi, Hiroshi eng Research Support, Non-U.S. Gov't England Hum Mol Genet. 2017 Jan 1;26(1):44-51. doi: 10.1093/hmg/ddw366.I | 12/30/2016 | |
| A moderate increase in dietary zinc reduces DNA strand breaks in leukocytes and alters plasma proteins without changing plasma zinc concentrations | Zyba SJ, et al. | 2017 | Am J Clin Nutr | 105 | 2 | 343-351 | https://www.doi.org/10.3945/ajcn.116.135327 | 28,003,206 | Adult Blood Proteins/*metabolism Body Composition Body Mass Index Cation Transport Proteins/blood DNA Damage/*drug effects Diet Edible Grain/chemistry *Food, Fortified Humans Leukocytes/drug effects/metabolism Male Metallothionein/blood Middle Aged Oxidative Stress/drug effects Phytic Acid/administration & dosage/blood Proteomics Young Adult Zinc/*administration & dosage/*blood DNA repair antioxidant inflammation zinc biomarkers zinc fortification | BACKGROUND: Food fortification has been recommended to improve a population's micronutrient status. Biofortification techniques modestly elevate the zinc content of cereals, but few studies have reported a positive impact on functional indicators of zinc status. OBJECTIVE: We determined the impact of a modest increase in dietary zinc that was similar to that provided by biofortification programs on whole-body and cellular indicators of zinc status. DESIGN: Eighteen men participated in a 6-wk controlled consumption study of a low-zinc, rice-based diet. The diet contained 6 mg Zn/d for 2 wk and was followed by 10 mg Zn/d for 4 wk. To reduce zinc absorption, phytate was added to the diet during the initial period. Indicators of zinc homeostasis, including total absorbed zinc (TAZ), the exchangeable zinc pool (EZP), plasma and cellular zinc concentrations, zinc transporter gene expression, and other metabolic indicators (i.e., DNA damage, inflammation, and oxidative stress), were measured before and after each dietary-zinc period. RESULTS: TAZ increased with increased dietary zinc, but plasma zinc concentrations and EZP size were unchanged. Erythrocyte and leukocyte zinc concentrations and zinc transporter expressions were not altered. However, leukocyte DNA strand breaks decreased with increased dietary zinc, and the level of proteins involved in DNA repair and antioxidant and immune functions were restored after the dietary-zinc increase. CONCLUSIONS: A moderate 4-mg/d increase in dietary zinc, similar to that which would be expected from zinc-biofortified crops, improves zinc absorption but does not alter plasma zinc. The repair of DNA strand breaks improves, as do serum protein concentrations that are associated with the DNA repair process. This trial was registered at clinicaltrials.gov as NCT02861352. | Zyba, Sarah J Shenvi, Swapna V Killilea, David W Holland, Tai C Kim, Elijah Moy, Adrian Sutherland, Barbara Gildengorin, Virginia Shigenaga, Mark K King, Janet C eng Randomized Controlled Trial Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Am J Clin Nutr. 2017 Feb;105(2):343-351. doi: 10.3945/ajcn.116.135327. Epub 2016 Dec 21.I | 12/23/2016 | |
| Highly Multiplexed Proteomic Analysis of Quantiferon Supernatants To Identify Biomarkers of Latent Tuberculosis Infection | De Groote MA, et al. | 2017 | J Clin Microbiol | 55 | 2 | 391-402 | https://www.doi.org/10.1128/JCM.01646-16 | 27,852,671 | Adolescent Adult Biomarkers/*analysis Emigrants and Immigrants Enzyme-Linked Immunospot Assay/methods Female Humans Immunologic Factors/*analysis Interferon-gamma Release Tests/methods Latent Tuberculosis/*diagnosis Male Middle Aged Proteome/*analysis Proteomics/*methods Tuberculin Test/methods United States Young Adult biomarkers diagnosis immunity latent infection proteomics tuberculosis | The tests for diagnosing latent tuberculosis infection (LTBI) are limited by a poor predictive value for identifying people at the highest risk for progressing to active tuberculosis (TB) and have various sensitivities and specificities in different populations. Identifying a more robust signature for LTBI is important for TB prevention and elimination. A pilot study was conducted with samples from immigrants to the United States that were screened for LTBI by the three commercially approved tests, namely, the tuberculin skin test (TST), the Quantiferon-TB Gold in-tube (QFT-GIT), and the T-SPOT.TB (T-SPOT). QFT-GIT supernatants from 13 people with concordant positive results and 26 people with concordant negative results were analyzed via the highly multiplexed SOMAscan proteomic assay. The proteins in the stimulated supernatants that distinguished LTBI from controls included interleukin-2 (IL-2), monocyte chemotactic protein 2 (MCP-2), interferon gamma inducible protein-10 (IP-10), interferon gamma (IFN-gamma), tumor necrosis factor superfamily member 14 (TNFSF14, also known as LIGHT), monokine induced by gamma interferon (MIG), and granzyme B (P <0.00001). In addition, antigen stimulation increased the expression of heparin-binding EGF-like growth factor (HB-EGF) and activin AB in LTBI samples. In nil tubes, LIGHT was the most significant marker (P <0.0001) and was elevated in LTBI subjects. Other prominent markers in nonstimulated QFT-GIT supernatants were the complement-3 components C3b, iC3b, and C3d, which were upregulated in LTBI and markedly decreased upon stimulation. We found known and novel proteins that warrant further studies for developing improved tests for LTBI, for predicting progression to active disease, and for discriminating LTBI from active TB. | De Groote, Mary Ann Higgins, Michael Hraha, Thomas Wall, Kirsten Wilson, Michael L Sterling, David G Janjic, Nebojsa Reves, Randall Ochsner, Urs A Belknap, Robert eng J Clin Microbiol. 2017 Feb;55(2):391-402. doi: 10.1128/JCM.01646-16. Epub 2016 Nov 16.I | 11/18/2016 | |
| Development of a Protein Biomarker Panel to Detect Non-Small-Cell Lung Cancer in Korea | Jung YJ, et al. | 2017 | Clin Lung Cancer | 18 | 2 | e99-e107 | https://www.doi.org/10.1016/j.cllc.2016.09.012 | 27,836,219 | Adenocarcinoma/blood/*diagnosis Antigens, Neoplasm/blood Aptamers, Peptide/metabolism Area Under Curve Bayes Theorem Biomarkers, Tumor/*blood Carcinoma, Large Cell/blood/*diagnosis Carcinoma, Non-Small-Cell Lung/blood/*diagnosis Carcinoma, Squamous Cell/blood/*diagnosis Case-Control Studies Early Detection of Cancer Female Humans Keratin-19/blood Lung Neoplasms/blood/*diagnosis Male Middle Aged Neoplasm Staging Prognosis Proteomics/*methods Aptamer Biomarker Cyfra 21-1 Lung cancer screening Lung nodule | BACKGROUND: Lung cancer screening using low-dose computed tomography reduces lung cancer mortality. However, the high false-positive rate, cost, and potential harms highlight the need for complementary biomarkers. We compared the diagnostic performance of modified aptamer-based protein biomarkers with Cyfra 21-1. PATIENTS AND METHODS: Participants included 100 patients diagnosed with lung cancer, and 100 control subjects from Asan Medical Center (Seoul, Korea). We investigated candidate biomarkers with new modified aptamer-based proteomic technology and developed a 7-protein panel that discriminates lung cancer from controls. A naive Bayesian classifier was trained using sera from 75 lung cancers and 75 controls. An independent set of 25 cases and 25 controls was used to verify performance of this classifier. The panel results were compared with Cyfra 21-1 to evaluate the diagnostic accuracy for lung nodules detected by computed tomography. RESULTS: We derived a 7-protein biomarker classifier from the initial train set comprising: EGFR1, MMP7, CA6, KIT, CRP, C9, and SERPINA3. This classifier distinguished lung cancer cases from controls with an area under the curve (AUC) of 0.82 in the train set and an AUC of 0.77 in the verification set. The 7-marker naive Bayesian classifier resulted in 91.7% specificity with 75.0% sensitivity for the subset of individuals with lung nodules. The AUC of the classifier for lung nodules was 0.88, whereas Cyfra 21-1 had an AUC of 0.72. CONCLUSION: We have developed a protein biomarker panel to identify lung cancers from controls with a high accuracy. This integrated noninvasive approach to the evaluation of lung nodules deserves further prospective validation among larger cohorts of patients with lung nodules in screening strategy. | Jung, Young Ju Katilius, Evaldas Ostroff, Rachel M Kim, Youndong Seok, Minkyoung Lee, Sujin Jang, Seongsoo Kim, Woo Sung Choi, Chang-Min eng Comparative Study Research Support, Non-U.S. Gov't Clin Lung Cancer. 2017 Mar;18(2):e99-e107. doi: 10.1016/j.cllc.2016.09.012. Epub 2016 Oct 5.I | 11/12/2016 | |
| Complementarity of SOMAscan to LC-MS/MS and RNA-seq for quantitative profiling of human embryonic and mesenchymal stem cells | Billing AM, et al. | 2017 | J Proteomics | 150 | 86-97 | https://www.doi.org/10.1016/j.jprot.2016.08.023 | 27,613,379 | Adult Aptamers, Peptide/analysis/metabolism Biomarkers/metabolism Cells, Cultured Chromatography, Liquid Embryonic Stem Cells/*metabolism Gene Expression Profiling/*methods Genomics/methods Humans Male Mesenchymal Stem Cells/*metabolism Proteomics/*methods RNA/analysis *Sequence Analysis, RNA Tandem Mass Spectrometry/*methods Young Adult Embryonic stem cells Mesenchymal stem cells Quantitative LC-MS/MS RNA-seq SOMAscan assay | Dynamic range limitations are challenging to proteomics, particularly in clinical samples. Affinity proteomics partially overcomes this, yet suffers from dependence on reagent quality. SOMAscan, an aptamer-based platform for over 1000 proteins, avoids that issue using nucleic acid binders. Targets include low expressed proteins not easily accessible by other approaches. Here we report on the potential of SOMAscan for the study of differently sourced mesenchymal stem cells (MSC) in comparison to LC-MS/MS and RNA sequencing. While targeting fewer analytes, SOMAscan displays high precision and dynamic range coverage, allowing quantification of proteins not measured by the other platforms. Expression between cell types (ESC and MSC) was compared across techniques and uncovered the expected large differences. Sourcing was investigated by comparing subtypes: bone marrow-derived, standard in clinical studies, and ESC-derived MSC, thought to hold similar potential but devoid of inter-donor variability and proliferating faster in vitro. We confirmed subtype-equivalency, as well as vesicle and extracellular matrix related processes in MSC. In contrast, the proliferative nature of ESC was captured less by SOMAscan, where nuclear proteins are underrepresented. The complementary of SOMAscan allowed the comprehensive exploration of CD markers and signaling molecules, not readily accessible otherwise and offering unprecedented potential in subtype characterization. SIGNIFICANCE: Mesenchymal stem cells (MSC) represent promising stem cell-derived therapeutics as indicated by their application in >500 clinical trials currently registered with the NIH. Tissue-derived MSC require invasive harvesting and imply donor-to-donor differences, to which embryonic stem cell (ESC)-derived MSC may provide an alternative and thus warrant thorough characterization. In continuation of our previous study where we compared in depth embryonic stem cells (ESC) and MSC from two sources (bone marrow and ESC-derived), we included the aptamer-based SOMAscan assay, complementing LC-MS/MS and RNA-seq data. Furthermore, SOMAscan, a targeted proteomics platform developed for analyzing clinical samples, has been benchmarked against established analytical platforms (LC-MS/MS and RNA-seq) using stem cell comparisons as a model. | Billing, Anja M Ben Hamidane, Hisham Bhagwat, Aditya M Cotton, Richard J Dib, Shaima S Kumar, Pankaj Hayat, Shahina Goswami, Neha Suhre, Karsten Rafii, Arash Graumann, Johannes eng Netherlands J Proteomics. 2017 Jan 6;150:86-97. doi: 10.1016/j.jprot.2016.08.023. Epub 2016 Sep 6.I | 10/25/2016 | ||
| Proteomic study of hepatocellular carcinoma using a novel modified aptamer-based array (SOMAscan) platform | Qiao Z, et al. | 2017 | Biochim Biophys Acta Proteins Proteom | 1865 | 4 | 434-443 | https://www.doi.org/10.1016/j.bbapap.2016.09.011 | 27,663,888 | Aptamers, Nucleotide/*chemistry *Carcinoma, Hepatocellular/genetics/metabolism Female *Gene Expression Regulation, Neoplastic Humans *Liver Neoplasms/genetics/metabolism Male *Neoplasm Proteins/biosynthesis/genetics Oligonucleotide Array Sequence Analysis/*methods Hepatocellular carcinoma SOMAscan Vascular invasion | Vascular invasion is a pathological hallmark of hepatocellular carcinoma (HCC), associated with poor prognosis; it is strongly related to the early recurrence and poor survival after curative resection. In order to determine the proteomic backgrounds of HCC carcinogenesis and vascular invasion, we employed a novel modified aptamer-based array (SOMAscan) platform. SOMAscan is based on the Slow Off-rate Modified Aptamers (SOMAmers), which rely on the natural 3D folding of single-stranded DNA-based protein affinity reagents. Currently, the expression level of 1129 proteins can be assessed quantitatively. Correlation matrix analysis showed that the overall proteomic features captured by SOMAscan differ between tumor and non-tumor tissues. Non-tumor tissues were shown to have more homogeneous proteome backgrounds than tumor tissues. A comparative study identified 68 proteins with differential expression between tumor and non-tumor tissues, together with eight proteins associated with vascular invasion. Gene Ontology analysis showed that the extracellular space and extracellular region proteins were predominantly detected. Network analysis revealed the linkage of seven proteins, AKT1, MDM2, PTEN, FGF1, MAPK8, PRKCB, and FN1, which were categorized as the components of Pathways in cancer" in pathway analysis. The results of SOMAscan analysis were not concordant with those obtained by western blotting; only the determined FN1 levels were concordant between the two platforms. We demonstrated that the proteome captured by SOMAscan includes the proteins relevant to carcinogenesis and vascular invasion in HCC. The identified proteins may serve as candidates for the future studies of disease mechanisms and clinical applications." | Qiao, Zhiwei Pan, Xiaoqing Parlayan, Cuneyd Ojima, Hidenori Kondo, Tadashi eng Research Support, Non-U.S. Gov't Netherlands Biochim Biophys Acta Proteins Proteom. 2017 Apr;1865(4):434-443. doi: 10.1016/j.bbapap.2016.09.011. Epub 2016 Sep 20.I | 09/25/2016 | |
| A Proteome-Derived Longitudinal Pharmacodynamic Biomarker for Diffuse Systemic Sclerosis Skin | Rice LM, et al. | 2017 | J Invest Dermatol | 137 | 1 | 62-70 | https://www.doi.org/10.1016/j.jid.2016.08.027 | 27,640,094 | Adult Biomarkers/blood Case-Control Studies Cytokines/*metabolism Enzyme-Linked Immunosorbent Assay Female Humans Linear Models Longitudinal Studies Male Middle Aged Pharmacogenomic Testing Proteome/*metabolism Reproducibility of Results Scleroderma, Diffuse/*blood/drug therapy/physiopathology Severity of Illness Index | In this study we systematically investigated alterations in the serum proteome of patients with diffuse cutaneous systemic sclerosis and identified differentially expressed proteins that correlated with disease severity. Our goal was to identify a combination of serum proteins that would provide a biological measure for the extent of skin disease and that could be combined into a longitudinal pharmacodynamic biomarker. We found that 16% of the sera proteins analyzed by SOMAscan aptamer technology, from two cohorts of patients with diffuse cutaneous systemic sclerosis, were identified as differentially regulated between diffuse cutaneous systemic sclerosis and controls and correlated with modified Rodnan skin score. This dataset showed tumor necrosis factor-alpha, IFN-gamma, transforming growth factor-beta, and IL-13 as potential upstream regulators of the serum protein patterns in the sera of patients with diffuse cutaneous systemic sclerosis. By ELISA, two analytes (ST2 and Spondin-1) best described longitudinal change in modified Rodnan skin score, using linear mixed models. This model was then validated in three independent cohorts. In this study we discovered a large array of proteins not previously associated with systemic sclerosis that provide insight into pathogenesis and potential targets for therapeutic intervention. Furthermore, we show that two of these proteins can be combined to form a robust longitudinal biomarker that might be used in clinical trials to assess changes in diffuse cutaneous systemic sclerosis skin disease over time. | Rice, Lisa M Mantero, Julio C Stifano, Giuseppina Ziemek, Jessica Simms, Robert W Gordon, Jessica Domsic, Robyn Lafyatis, Robert eng UL1 TR000157/TR/NCATS NIH HHS/ P30 AR061271/AR/NIAMS NIH HHS/ P50 AR060780/AR/NIAMS NIH HHS/ R01 AR051089/AR/NIAMS NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't J Invest Dermatol. 2017 Jan;137(1):62-70. doi: 10.1016/j.jid.2016.08.027. Epub 2016 Sep 14.I | 09/19/2016 | |
| Selection of aptamers to Neisseria meningitidis and Streptococcus pneumoniae surface specific proteins and affinity assay using thin film AlN resonators | Escolano JM, et al. | 2017 | Sensors and Actuators B: Chemical | 246 | 591-596 | https://www.doi.org/10.1016/j.snb.2017.02.098 | Meningitis SOMAmer AlN gravimetric biosensor PavA FHbp | The first steps in the development of an aptasensor for bacterial meningitis diagnosis in real time are described: slow off-rate modified aptamers (SOMAmer) selection, gravimetric sensor fabrication and functionalization of its active surface. SOMAmers polyclonal populations were generated to surface specific proteins PavA (S. pneumoniae) and FHbp (N. meningitidis) by systematic evolution of ligands by exponential enrichment method (SELEX). After eight rounds, they were tested by direct enzyme-linked oligonucleotide assays (ELONA) and by high frequency (1.4GHz) gravimetric sensors based on thin film AlN resonators operating in shear mode. The sensing surface of the resonators was functionalized using a silane-glutaraldehyde based protocol and the binding of PavA and FHbp was measured in real time. The SOMAmers polyclonal populations showing the best ELONA results have been also tested using gravimetric sensors and the binding to the protein functionalized surface was measured in real time showing positive results. These first steps towards the development of an aptasensor for the targeted bacteria demonstrate the potential of the method for sensitive, rapid, and cost effective detection of bacterial meningitis. | Escolano, José M. Díaz-Durán, Bárbara DeMiguel-Ramos, Mario Olivares, Jimena Geday, Morten A. Iborra, Enrique | ||||
| Diagnostic and Prognostic Biomarkers in the Rational Assessment of Mesothelioma (DIAPHRAGM) study: protocol of a prospective, multicentre, observational study | Tsim S, et al. | 2016 | BMJ Open | 6 | 11 | e013324 | https://www.doi.org/10.1136/bmjopen-2016-013324 | 27,884,852 | Biomarkers, Tumor/blood Cross-Sectional Studies Extracellular Matrix Proteins/*blood GPI-Linked Proteins/*blood Humans Lung Neoplasms/*blood/*diagnostic imaging Magnetic Resonance Imaging Mesothelin Mesothelioma/*blood/*diagnostic imaging Mesothelioma, Malignant Prognosis Prospective Studies Proteomics/methods ROC Curve Research Design Scotland Biomarker Diagnosis Mesothelioma | INTRODUCTION: Malignant pleural mesothelioma (MPM) is an asbestos-related cancer, which is difficult to diagnose. Thoracoscopy is frequently required but is not widely available. An accurate, non-invasive diagnostic biomarker would allow early specialist referral, limit diagnostic delays and maximise clinical trial access. Current markers offer insufficient sensitivity and are not routinely used. The SOMAmer proteomic classifier and fibulin-3 have recently demonstrated sensitivity and specificity exceeding 90% in retrospective studies. DIAPHRAGM (Diagnostic and Prognostic Biomarkers in the Rational Assessment of Mesothelioma) is a suitably powered, multicentre, prospective observational study designed to determine whether these markers provide clinically useful diagnostic and prognostic information. METHODS AND ANALYSIS: Serum and plasma (for SOMAscan and fibulin-3, respectively) will be collected at presentation, prior to pleural biopsy/pleurodesis, from 83 to 120 patients with MPM, at least 480 patients with non-MPM pleural disease and 109 asbestos-exposed controls. Final numbers of MPM/non-MPM cases will depend on the incidence of MPM in the study population (estimated at 13-20%). Identical sampling and storage protocols will be used in 22 recruiting centres and histological confirmation sought in all cases. Markers will be measured using the SOMAscan proteomic assay (SomaLogic) and a commercially available fibulin-3 ELISA (USCN Life Science). The SE in the estimated sensitivity and specificity will be <5% for each marker and their performance will be compared with serum mesothelin. Blood levels will be compared with paired pleural fluid levels and MPM tumour volume (using MRI) in a nested substudy. The prognostic value of each marker will be assessed and a large bioresource created. ETHICS AND DISSEMINATION: The study has been approved by the West of Scotland Research Ethics Committee (Ref: 13/WS/0240). A Trial Management Group meets on a monthly basis. Results will be published in peer-reviewed journals, presented at international meetings and disseminated to patient groups. TRIAL REGISTRATION NUMBER: ISRCTN10079972, Pre-results. | Tsim, Selina Kelly, Caroline Alexander, Laura McCormick, Carol Thomson, Fiona Woodward, Rosie Foster, John E Stobo, David B Paul, Jim Maskell, Nick A Chalmers, Anthony Blyth, Kevin G eng ETM/285/CSO_/Chief Scientist Office/United Kingdom Multicenter Study Observational Study England BMJ Open. 2016 Nov 24;6(11):e013324. doi: 10.1136/bmjopen-2016-013324.I | 11/26/2016 | |
| The Relationship of Novel Plasma Proteins in the Early Neonatal Period With Retinopathy of Prematurity | Lynch AM, et al. | 2016 | Invest Ophthalmol Vis Sci | 57 | 11 | 5076-5082 | https://www.doi.org/10.1167/iovs.16-19653 | 27,679,852 | PURPOSE: Retinopathy of prematurity (ROP) is a vision-threatening disease associated with abnormal retinal vascular development. Proteins from the insulin-like growth factor pathway are related to ROP. However, there is a paucity of research on the role of other proteins in ROP. The aim of this study was to identify plasma proteins related to clinically significant ROP. METHODS: We measured 1121 plasma proteins in the early neonatal period in infants at risk for ROP using an aptamer-based proteomic technology. The primary aim of the study was to compare plasma protein concentrations in infants who did (n = 12) and did not (n = 23) subsequently develop clinically significant ROP using logistic regression. As a secondary aim, we examined patterns in the proteins across categories of clinically significant, low-grade, and no ROP groups. RESULTS: Lower levels of 16 proteins were associated with an increased risk of clinically significant ROP. In this group, superoxide dismutase (Mn), mitochondrial (MnSOD), and chordin-like protein 1 (CRDL1) were highly ranked. Other proteins in this group included: C-C motif chemokine 14 (HCC-1), prolactin, insulin-like growth factor-binding protein 7 (IGFBP-7), and eotaxin. Higher levels of 12 proteins were associated with a higher risk for ROP. Fibroblast growth factor 19 (FGF-19) was the top-ranked protein target followed by hepatocyte growth factor-like protein (MSP), luteinizing hormone (LH), cystatin M, plasminogen, and proprotein convertase subtilisin/kexin type 9 (PCSK9). We also noted different patterns in the trend of concentrations of proteins across the clinically significant, low-grade, and no ROP groups. CONCLUSIONS: We discovered plasma proteins with novel associations with clinically significant ROP (MnSOD, CRDL1, PCSK9), proteins with links to established ROP signaling pathways (IGFBP-7), and proteins such as MnSOD that may be a target for future therapeutic interventions. | Lynch, Anne M Wagner, Brandie D Mandava, Naresh Palestine, Alan G Mourani, Peter M McCourt, Emily A Oliver, Scott C N Abman, Steven H eng R01 HL085703/HL/NHLBI NIH HHS/ UL1 TR001082/TR/NCATS NIH HHS/ Invest Ophthalmol Vis Sci. 2016 Sep 1;57(11):5076-5082. doi: 10.1167/iovs.16-19653.I | 09/30/2016 | ||
| Identification of Pathway-Specific Serum Biomarkers of Response to Glucocorticoid and Infliximab Treatment in Children with Inflammatory Bowel Disease | Heier CR, et al. | 2016 | Clin Transl Gastroenterol | 7 | 9 | e192 | https://www.doi.org/10.1038/ctg.2016.49 | 27,628,422 | OBJECTIVE: Serum biomarkers may serve to predict early response to therapy, identify relapse, and facilitate drug development in inflammatory bowel disease (IBD). Biomarkers are particularly important in children, in whom achieving early remission and minimizing procedures are especially beneficial. METHODS: We profiled protein and micro RNA (miRNA) in serum from patients pre- and post-therapy, to identify molecular markers of pharmacodynamic effect. Serum was obtained from children with IBD before and after treatment with either corticosteroids (prednisone; n=12) or anti-tumor necrosis factor-alpha biologic (infliximab; n=7). Over 1,100 serum proteins were assayed using aptamer-based SOMAscan proteomics, and 22 miRNAs analyzed by quantitative real time PCR. Concordance of longitudinal changes between the groups was used to identify markers responsive to treatment. Bioinformatic analysis was used to build insight into mechanisms of changes in response to treatment. RESULTS: We identified 18 proteins and three miRNAs responsive to both prednisone and infliximab. Eight markers that decreased are associated with inflammation and have gene promoters regulated by nuclear factor (NF)-kappaB. Several that increased are associated with resolving inflammation and tissue damage. We also identified six markers that appear to be steroid-specific, three of which have glucocorticoid receptor binding elements in their promoter region. CONCLUSIONS: Serum markers regulated by the inflammatory transcription factor NF-kappaB are potential candidates for pharmacodynamic biomarkers that, if correlated with later outcomes like endoscopic or histologic healing, could be used to monitor treatment, optimize dosing, and enhance drug development. The pharmacodynamic biomarkers identified here hold potential to improve both clinical care and drug development. Further studies are warranted to investigate these markers as early predictors of response, or possibly surrogate outcomes. | Heier, Christopher R Fiorillo, Alyson A Chaisson, Ellen Gordish-Dressman, Heather Hathout, Yetrib Damsker, Jesse M Hoffman, Eric P Conklin, Laurie S eng K99 HL130035/HL/NHLBI NIH HHS/ L40 AR068727/AR/NIAMS NIH HHS/ R00 HL130035/HL/NHLBI NIH HHS/ Clin Transl Gastroenterol. 2016 Sep 15;7(9):e192. doi: 10.1038/ctg.2016.49.I | 09/16/2016 | ||
| Serum pharmacodynamic biomarkers for chronic corticosteroid treatment of children | Hathout Y, et al. | 2016 | Sci Rep | 6 | 31727 | https://www.doi.org/10.1038/srep31727 | 27,530,235 | Adolescent Adrenal Cortex Hormones/adverse effects/blood/*therapeutic use Anti-Inflammatory Agents/adverse effects/*therapeutic use Biomarkers/blood Blood Proteins/metabolism Case-Control Studies Child Child, Preschool Cross-Sectional Studies Female Humans Inflammation Mediators/blood Inflammatory Bowel Diseases/*blood/*drug therapy Longitudinal Studies Male Muscular Dystrophy, Duchenne/*blood/*drug therapy Proteome/metabolism | Corticosteroids are extensively used in pediatrics, yet the burden of side effects is significant. Availability of a simple, fast, and reliable biochemical read out of steroidal drug pharmacodynamics could enable a rapid and objective assessment of safety and efficacy of corticosteroids and aid development of corticosteroid replacement drugs. To identify potential corticosteroid responsive biomarkers we performed proteome profiling of serum samples from DMD and IBD patients with and without corticosteroid treatment using SOMAscan aptamer panel testing 1,129 proteins in <0.1 cc of sera. Ten pro-inflammatory proteins were elevated in untreated patients and suppressed by corticosteroids (MMP12, IL22RA2, CCL22, IGFBP2, FCER2, LY9, ITGa1/b1, LTa1/b2, ANGPT2 and FGG). These are candidate biomarkers for anti-inflammatory efficacy of corticosteroids. Known safety concerns were validated, including elevated non-fasting insulin (insulin resistance), and elevated angiotensinogen (salt retention). These were extended by new candidates for metabolism disturbances (leptin, afamin), stunting of growth (growth hormone binding protein), and connective tissue remodeling (MMP3). Significant suppression of multiple adrenal steroid hormones was also seen in treated children (reductions of 17-hydroxyprogesterone, corticosterone, 11-deoxycortisol and testosterone). A panel of new pharmacodynamic biomarkers for corticosteroids in children was defined. Future studies will need to bridge specific biomarkers to mechanism of drug action, and specific clinical outcomes. | Hathout, Yetrib Conklin, Laurie S Seol, Haeri Gordish-Dressman, Heather Brown, Kristy J Morgenroth, Lauren P Nagaraju, Kanneboyina Heier, Christopher R Damsker, Jesse M van den Anker, John N Henricson, Erik Clemens, Paula R Mah, Jean K McDonald, Craig Hoffman, Eric P eng R44 NS095423/NS/NINDS NIH HHS/ R01 AR062380/AR/NIAMS NIH HHS/ R00 HL130035/HL/NHLBI NIH HHS/ L40 AR068727/AR/NIAMS NIH HHS/ R01 AR061875/AR/NIAMS NIH HHS/ P50 AR060836/AR/NIAMS NIH HHS/ U54 HD071601/HD/NICHD NIH HHS/ K99 HL130035/HL/NHLBI NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. England Sci Rep. 2016 Aug 17;6:31727. doi: 10.1038/srep31727.I | 08/18/2016 | ||
| Incorporation of Slow Off-Rate Modified Aptamers Reagents in Single Molecule Array Assays for Cytokine Detection with Ultrahigh Sensitivity | Wu D, et al. | 2016 | Anal Chem | 88 | 17 | 8385-9 | https://www.doi.org/10.1021/acs.analchem.6b02451 | 27,529,794 | Antibodies/immunology Aptamers, Nucleotide/*chemistry Cytokines/*blood/immunology Enzyme-Linked Immunosorbent Assay Humans Indicators and Reagents/*chemistry Kinetics | Slow off-rate modified aptamers (SOMAmers) are attractive protein recognition reagents due to their high binding affinities, stable chemical structures, easy production, and established selection process. Here, biotinylated SOMAmer reagents were incorporated into single molecule array (Simoa)-based assays in place of traditional detection antibodies for six cytokine targets. Optimization and validation were conducted for TNF-alpha as a demonstration using a capture antibody/detection-SOMAmer detection scheme to highlight the performance of this approach. The optimized assay has a broad dynamic range (>4 log10 units) and an ultralow detection limit of 0.67 fM (0.012 pg/mL). These results show comparable sensitivity to our antibody pair-based Simoa assays, and tens to thousands-fold enhancement in sensitivity compared with conventional ELISAs. High recovery percentages were observed in a spike-recovery test using human sera, demonstrating the feasibility of this novel Simoa assay in detecting TNF-alpha in clinically relevant samples. Detection SOMAmers were also used to detect other cytokines, such as IFN-gamma, IL-1beta, IL-2, IL-6, and IL-10, in human samples. Although not yet demonstrated, in principle it should be possible to eventually replace both the capture and detector antibodies with corresponding SOMAmer pairs in sandwich immunoassays. The combination of the ultrasensitive Simoa platform with the higher reliability of SOMAmer binding reagents will greatly benefit both biomarker discovery and disease diagnostic fields. | Wu, Danlu Katilius, Evaldas Olivas, Edgar Dumont Milutinovic, Milena Walt, David R eng Letter Research Support, U.S. Gov't, Non-P.H.S. Anal Chem. 2016 Sep 6;88(17):8385-9. doi: 10.1021/acs.analchem.6b02451. Epub 2016 Aug 23.I | 08/17/2016 | |
| Six-SOMAmer Index Relating to Immune, Protease and Angiogenic Functions Predicts Progression in IPF | Ashley SL, et al. | 2016 | PLoS One | 11 | 8 | e0159878 | https://www.doi.org/10.1371/journal.pone.0159878 | 27,490,795 | Aged Area Under Curve Biomarkers/blood Cathepsins/metabolism Cysteine Endopeptidases/metabolism Disease Progression Disease-Free Survival Female Humans Idiopathic Pulmonary Fibrosis/immunology/metabolism/*pathology Inducible T-Cell Co-Stimulator Protein/metabolism Lectins/metabolism Logistic Models Male Middle Aged Peptide Hydrolases/*metabolism Proportional Hazards Models ROC Curve *Severity of Illness Index Smoking Vascular Endothelial Growth Factor Receptor-2/metabolism | RATIONALE: Biomarkers in easily accessible compartments like peripheral blood that can predict disease progression in idiopathic pulmonary fibrosis (IPF) would be clinically useful regarding clinical trial participation or treatment decisions for patients. In this study, we used unbiased proteomics to identify relevant disease progression biomarkers in IPF. METHODS: Plasma from IPF patients was measured using an 1129 analyte slow off-rate modified aptamer (SOMAmer) array, and patient outcomes were followed over the next 80 weeks. Receiver operating characteristic (ROC) curves evaluated sensitivity and specificity for levels of each biomarker and estimated area under the curve (AUC) when prognostic biomarker thresholds were used to predict disease progression. Both logistic and Cox regression models advised biomarker selection for a composite disease progression index; index biomarkers were weighted via expected progression-free days lost during follow-up with a biomarker on the unfavorable side of the threshold. RESULTS: A six-analyte index, scaled 0 to 11, composed of markers of immune function, proteolysis and angiogenesis [high levels of ficolin-2 (FCN2), cathepsin-S (Cath-S), legumain (LGMN) and soluble vascular endothelial growth factor receptor 2 (VEGFsR2), but low levels of inducible T cell costimulator (ICOS) or trypsin 3 (TRY3)] predicted better progression-free survival in IPF with a ROC AUC of 0.91. An index score >/= 3 (group >/= 2) was strongly associated with IPF progression after adjustment for age, gender, smoking status, immunomodulation, forced vital capacity % predicted and diffusing capacity for carbon monoxide % predicted (HR 16.8, 95% CI 2.2-126.7, P = 0.006). CONCLUSION: This index, derived from the largest proteomic analysis of IPF plasma samples to date, could be useful for clinical decision making in IPF, and the identified analytes suggest biological processes that may promote disease progression. | Ashley, Shanna L Xia, Meng Murray, Susan O'Dwyer, David N Grant, Ethan White, Eric S Flaherty, Kevin R Martinez, Fernando J Moore, Bethany B eng R01 HL115618/HL/NHLBI NIH HHS/ T32 AI007413/AI/NIAID NIH HHS/ UL1 TR000433/TR/NCATS NIH HHS/ PLoS One. 2016 Aug 4;11(8):e0159878. doi: 10.1371/journal.pone.0159878. eCollection 2016.I | 08/05/2016 | |
| Identifying Low-Abundance Biomarkers: Aptamer-Based Proteomics Potentially Enables More Sensitive Detection in Cardiovascular Diseases | Gramolini A, et al. | 2016 | Circulation | 134 | 4 | 286-9 | https://www.doi.org/10.1161/CIRCULATIONAHA.116.022940 | 27,444,931 | *Biomarkers Biomarkers, Tumor Cardiovascular Diseases/diagnosis Humans *Proteomics Editorials biomarkers cohort studies diagnosis prognosis proteomics | Gramolini, Anthony Lau, Edward Liu, Peter P eng CIHR/Canada Comment Editorial Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Circulation. 2016 Jul 26;134(4):286-9. doi: 10.1161/CIRCULATIONAHA.116.022940.I | 07/23/2016 | ||
| Aptamer-Based Proteomic Profiling Reveals Novel Candidate Biomarkers and Pathways in Cardiovascular Disease | Ngo D, et al. | 2016 | Circulation | 134 | 4 | 270-85 | https://www.doi.org/10.1161/CIRCULATIONAHA.116.021803 | 27,444,932 | Acute Coronary Syndrome/blood Adult Aptamers, Nucleotide/*metabolism Biomarkers/*blood Blood Proteins/*analysis Cardiomyopathy, Hypertrophic/*blood/complications Chromatography, Liquid DNA, Single-Stranded/metabolism Female Humans Longitudinal Studies Male Middle Aged Myocardial Infarction/*blood/etiology Phenotype Proteomics/*methods Reproducibility of Results Sensitivity and Specificity Tandem Mass Spectrometry aptamer, nucleotides cardiovascular diseases mass spectrometry myocardial infarction proteomics | BACKGROUND: Single-stranded DNA aptamers are oligonucleotides of approximately 50 base pairs in length selected for their ability to bind proteins with high specificity and affinity. Emerging DNA aptamer-based technologies may address limitations of existing proteomic techniques, including low sample throughput, which have hindered proteomic analyses of large cohorts. METHODS: To identify early biomarkers of myocardial injury, we applied an aptamer-based proteomic platform that measures 1129 proteins to a clinically relevant perturbational model of planned myocardial infarction (PMI), patients undergoing septal ablation for hypertrophic cardiomyopathy. Blood samples were obtained before and at 10 and 60 minutes after PMI, and protein changes were assessed by repeated-measures analysis of variance. The generalizability of our PMI findings was evaluated in a spontaneous myocardial infarction cohort (Wilcoxon rank-sum). We then tested the platform's ability to detect associations between proteins and Framingham Risk Score components in the Framingham Heart Study, performing regression analyses for each protein versus each clinical trait. RESULTS: We found 217 proteins that significantly changed in the peripheral vein blood after PMI in a derivation cohort (n=15; P<5.70E-5). Seventy-nine of these proteins were validated in an independent PMI cohort (n=15; P<2.30E-4); >85% were directionally consistent and reached nominal significance. We detected many protein changes that are novel in the context of myocardial injury, including Dickkopf-related protein 4, a WNT pathway inhibitor (peak increase 124%, P=1.29E-15) and cripto, a growth factor important in cardiac development (peak increase 64%, P=1.74E-4). Among the 40 validated proteins that increased within 1 hour after PMI, 23 were also elevated in patients with spontaneous myocardial infarction (n=46; P<0.05). Framingham Heart Study analyses revealed 156 significant protein associations with the Framingham Risk Score (n=899), including aminoacylase 1 (beta=0.3386, P=2.54E-22) and trigger factor 2 (beta=0.2846, P=5.71E-17). Furthermore, we developed a novel workflow integrating DNA-based immunoaffinity with mass spectrometry to analytically validate aptamer specificity. CONCLUSIONS: Our results highlight an emerging proteomics tool capable of profiling >1000 low-abundance analytes with high sensitivity and high precision, applicable both to well-phenotyped perturbational studies and large human cohorts, as well. | Ngo, Debby Sinha, Sumita Shen, Dongxiao Kuhn, Eric W Keyes, Michelle J Shi, Xu Benson, Mark D O'Sullivan, John F Keshishian, Hasmik Farrell, Laurie A Fifer, Michael A Vasan, Ramachandran S Sabatine, Marc S Larson, Martin G Carr, Steven A Wang, Thomas J Gerszten, Robert E eng U24 CA160034/CA/NCI NIH HHS/ R01HL132320//International T32 HL007208/HL/NHLBI NIH HHS/ K01 GM103817/GM/NIGMS NIH HHS/ HHSN268201000033C/HL/NHLBI NIH HHS/ R01 HL132320/HL/NHLBI NIH HHS/ N01HC25195/HL/NHLBI NIH HHS/ Research Support, N.I.H., Extramural Circulation. 2016 Jul 26;134(4):270-85. doi: 10.1161/CIRCULATIONAHA.116.021803.I | 07/23/2016 | |
| An evaluation of an aptamer for use as an affinity reagent with MS: PCSK9 as an example protein | Gupta V, et al. | 2016 | Bioanalysis | 8 | 15 | 1557-1564 | https://www.doi.org/10.4155/bio-2016-0046 | 27,397,798 | Antibodies, Immobilized/chemistry Antibodies, Monoclonal/chemistry Aptamers, Nucleotide/*chemistry Chromatography, Affinity/*methods Humans Magnets/chemistry Mass Spectrometry/*methods Proprotein Convertase 9/analysis/*blood Ms method development proteins | BACKGROUND: For quantitative immunoaffinity IA-LC-MS, the utility of antibodies has been demonstrated many times but the utility of aptamers as affinity reagents is unproven. METHODS: Immunoaffinity reagents including a monoclonal antibody and an aptamer were coupled to magnetic beads and used as part of an enrichment strategy for PCSK9 quantitation in plasma. RESULTS: With limited method development, we have established a comparison of an anti-PCSK9 aptamer with an anti-PCSK9 monoclonal antibody. The background that results from a tryptic digest of affinity enrichment in plasma was demonstrated for each reagent using high-resolution full scan MS. The assay recovery was demonstrated for multiple concentrations of aptamer in plasma with different concentrations of PCSK9 protein. CONCLUSION: The aptamer achieved comparable enrichment to the antibody, but with lower peptide background, thus demonstrating the potential use of aptamers for IA-LC-MS. | Gupta, Vinita Lassman, Michael E McAvoy, Thomas Lee, Anita Yh Chappell, Derek L Laterza, Omar F eng Comparative Study England Bioanalysis. 2016 Aug;8(15):1557-1564. doi: 10.4155/bio-2016-0046. Epub 2016 Jul 11.I | 07/12/2016 | |
| Loss of fibronectin from the aged stem cell niche affects the regenerative capacity of skeletal muscle in mice | Lukjanenko L, et al. | 2016 | Nat Med | 22 | 8 | 897-905 | https://www.doi.org/10.1038/nm.4126 | 27,376,579 | Aging/*metabolism Animals Blotting, Western Extracellular Matrix/metabolism Fibronectins/*genetics/metabolism Flow Cytometry Focal Adhesion Protein-Tyrosine Kinases/*metabolism Integrins/metabolism Mice Muscle, Skeletal/cytology/*metabolism Polymerase Chain Reaction Regeneration/*genetics *Stem Cell Niche p38 Mitogen-Activated Protein Kinases/*metabolism | Age-related changes in the niche have long been postulated to impair the function of somatic stem cells. Here we demonstrate that the aged stem cell niche in skeletal muscle contains substantially reduced levels of fibronectin (FN), leading to detrimental consequences for the function and maintenance of muscle stem cells (MuSCs). Deletion of the gene encoding FN from young regenerating muscles replicates the aging phenotype and leads to a loss of MuSC numbers. By using an extracellular matrix (ECM) library screen and pathway profiling, we characterize FN as a preferred adhesion substrate for MuSCs and demonstrate that integrin-mediated signaling through focal adhesion kinase and the p38 mitogen-activated protein kinase pathway is strongly de-regulated in MuSCs from aged mice because of insufficient attachment to the niche. Reconstitution of FN levels in the aged niche remobilizes stem cells and restores youth-like muscle regeneration. Taken together, we identify the loss of stem cell adhesion to FN in the niche ECM as a previously unknown aging mechanism. | Lukjanenko, Laura Jung, M Juliane Hegde, Nagabhooshan Perruisseau-Carrier, Claire Migliavacca, Eugenia Rozo, Michelle Karaz, Sonia Jacot, Guillaume Schmidt, Manuel Li, Liangji Metairon, Sylviane Raymond, Frederic Lee, Umji Sizzano, Federico Wilson, David H Dumont, Nicolas A Palini, Alessio Fassler, Reinhard Steiner, Pascal Descombes, Patrick Rudnicki, Michael A Fan, Chen-Ming von Maltzahn, Julia Feige, Jerome N Bentzinger, C Florian eng F31 HD075345/HD/NICHD NIH HHS/ R01 AR060042/AR/NIAMS NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Nat Med. 2016 Aug;22(8):897-905. doi: 10.1038/nm.4126. Epub 2016 Jul 4.I | 07/05/2016 | |
| Proteomics analysis of vesicles isolated from plasma and urine of prostate cancer patients using a multiplex, aptamer-based protein array | Welton JL, et al. | 2016 | J Extracell Vesicles | 5 | 31209 | https://www.doi.org/10.3402/jev.v5.31209 | 27,363,484 | plasma protein array proteomics urine prostate | Proteomics analysis of biofluid-derived vesicles holds enormous potential for discovering non-invasive disease markers. Obtaining vesicles of sufficient quality and quantity for profiling studies has, however, been a major problem, as samples are often replete with co-isolated material that can interfere with the identification of genuine low abundance, vesicle components. Here, we used a combination of ultracentrifugation and size-exclusion chromatography to isolate and analyse vesicles of plasma or urine origin. We describe a sample-handling workflow that gives reproducible, quality vesicle isolations sufficient for subsequent protein profiling. Using a semi-quantitative aptamer-based protein array, we identified around 1,000 proteins, of which almost 400 were present at comparable quantities in plasma versus urine vesicles. Significant differences were, however, apparent with elements like HSP90, integrin alphaVbeta5 and Contactin-1 more prevalent in urinary vesicles, while hepatocyte growth factor activator, prostate-specific antigen-antichymotrypsin complex and many others were more abundant in plasma vesicles. This was also applied to a small set of specimens collected from men with metastatic prostate cancer, highlighting several proteins with the potential to indicate treatment refractory disease. The study provides a practical platform for furthering protein profiling of vesicles in prostate cancer, and, hopefully, many other disease scenarios. | Welton, Joanne Louise Brennan, Paul Gurney, Mark Webber, Jason Paul Spary, Lisa Kate Carton, David Gil Falcon-Perez, Juan Manuel Walton, Sean Peter Mason, Malcolm David Tabi, Zsuzsanna Clayton, Aled eng J Extracell Vesicles. 2016 Jun 29;5:31209. doi: 10.3402/jev.v5.31209. eCollection 2016.I | 07/02/2016 | ||
| Development and Validation of a Protein-Based Risk Score for Cardiovascular Outcomes Among Patients With Stable Coronary Heart Disease | Ganz P, et al. | 2016 | JAMA | 315 | 23 | 2532-41 | https://www.doi.org/10.1001/jama.2016.5951 | 27,327,800 | Aged Blood Proteins/*analysis Cause of Death Coronary Artery Disease/*blood Female Heart Failure/etiology Humans Male Myocardial Infarction/etiology Norway Prospective Studies Proteomics *Risk Assessment San Francisco Stroke/etiology | IMPORTANCE: Precise stratification of cardiovascular risk in patients with coronary heart disease (CHD) is needed to inform treatment decisions. OBJECTIVE: To derive and validate a score to predict risk of cardiovascular outcomes among patients with CHD, using large-scale analysis of circulating proteins. DESIGN, SETTING, AND PARTICIPANTS: Prospective cohort study of participants with stable CHD. For the derivation cohort (Heart and Soul study), outpatients from San Francisco were enrolled from 2000 through 2002 and followed up through November 2011 ( | Ganz, Peter Heidecker, Bettina Hveem, Kristian Jonasson, Christian Kato, Shintaro Segal, Mark R Sterling, David G Williams, Stephen A eng R01 HL079235/HL/NHLBI NIH HHS/ Evaluation Study Multicenter Study Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. Validation Study JAMA. 2016 Jun 21;315(23):2532-41. doi: 10.1001/jama.2016.5951.I | 06/22/2016 | |
| Using Aptamer-Based Technology to Probe the Plasma Proteome for Cardiovascular Disease Prediction | Sabatine MS | 2016 | JAMA | 315 | 23 | 2525-6 | https://www.doi.org/10.1001/jama.2016.6110 | 27,327,798 | Blood Proteins/*analysis Coronary Artery Disease/*blood Female Humans Male *Risk Assessment | Sabatine, Marc S eng Comment Editorial JAMA. 2016 Jun 21;315(23):2525-6. doi: 10.1001/jama.2016.6110.I | 06/22/2016 | ||
| Identification of definitive serum biomarkers associated with disease activity in primary Sjogren's syndrome | Nishikawa A, et al. | 2016 | Arthritis Res Ther | 18 | 1 | 106 | https://www.doi.org/10.1186/s13075-016-1006-1 | 27,180,164 | Adult Aged Biomarkers/*blood Enzyme-Linked Immunosorbent Assay Female High-Throughput Screening Assays/methods Humans Male Middle Aged Proteomics/methods Sjogren's Syndrome/*blood Biomarker Disease activity Proteomics Serum protein Sjogren's syndrome | BACKGROUND: In this study, we sought to identify definitive biomarkers associated with disease activity in primary Sjogren's syndrome (pSS). METHODS: Serum protein concentrations in pSS patients and healthy controls (HCs) were comprehensively screened using high-throughput proteomic analysis, and differentially expressed proteins were extracted. Correlation between differentially expressed proteins and European League Against Rheumatism Sjogren's Syndrome Disease Activity Index (ESSDAI) scores was analyzed and disease activity-associated biomarkers were identified. These biomarkers were validated by enzyme-linked immunosorbent assay (ELISA) in a separate pSS cohort. RESULTS: The serum concentrations of 1100 proteins were compared between 30 pSS patients and 30 HCs, with 82 differentially expressed proteins identified as pSS-associated proteins. Of these 82 proteins, 9 were identified as disease activity-associated biomarkers. These nine biomarkers underwent validation by ELISA in a separate pSS validation cohort (n = 58), with five proteins (CXCL13, TNF-R2, CD48, B-cell activating factor (BAFF), and PD-L2) subsequently being confirmed as candidate biomarkers. Of these five candidate biomarkers, CXCL13 exhibited the most significant correlation with the lymphadenopathy, glandular, and pulmonary domains of the ESSDAI. CXCL13, TNF-R2 and CD48 exhibited a positive correlation with the biological domain of the ESSDAI. TNF-R2 exhibited the most negative correlation with uptake in the submandibular gland on technetium 99m-pertechnetate salivary gland scintigraphy. CONCLUSIONS: Our approach successfully identified serum biomarkers associated with disease activity in pSS patients. These markers might be potential therapeutic targets in pSS patients. | Nishikawa, Ayumi Suzuki, Katsuya Kassai, Yoshiaki Gotou, Yuumi Takiguchi, Maiko Miyazaki, Takahiro Yoshimoto, Keiko Yasuoka, Hidekata Yamaoka, Kunihiro Morita, Rimpei Yoshimura, Akihiko Takeuchi, Tsutomu eng Research Support, Non-U.S. Gov't England Arthritis Res Ther. 2016 May 14;18(1):106. doi: 10.1186/s13075-016-1006-1.I | 05/18/2016 | |
| A cross sectional study of two independent cohorts identifies serum biomarkers for facioscapulohumeral muscular dystrophy (FSHD) | Petek LM, et al. | 2016 | Neuromuscul Disord | 26 | 7 | 405-13 | https://www.doi.org/10.1016/j.nmd.2016.04.012 | 27,185,459 | Adolescent Adult Aged Biomarkers/blood Cohort Studies Cost of Illness Cross-Sectional Studies Disease Progression Female Humans Magnetic Resonance Imaging Male Middle Aged Muscular Dystrophy, Facioscapulohumeral/*blood/diagnostic imaging Proteome Proteomics Severity of Illness Index Young Adult Biomarker Carbonic anhydrase Creatine kinase D4z4 Dux4 Fshd Facioscapulohumeral Muscular dystrophy Troponin | Measuring the severity and progression of facioscapulohumeral muscular dystrophy (FSHD) is particularly challenging because muscle weakness progresses over long periods of time and can be sporadic. Biomarkers are essential for measuring disease burden and testing treatment strategies. We utilized the sensitive, specific, high-throughput SomaLogic proteomics platform of 1129 proteins to identify proteins with levels that correlate with FSHD severity in a cross-sectional study of two independent cohorts. We discovered biomarkers that correlate with clinical severity and disease burden measured by magnetic resonance imaging. Sixty-eight proteins in the Rochester cohort (n = 48) and 51 proteins in the Seattle cohort (n = 30) had significantly different levels in FSHD-affected individuals when compared with controls (p-value | Petek, Lisa M Rickard, Amanda M Budech, Christopher Poliachik, Sandra L Shaw, Dennis Ferguson, Mark R Tawil, Rabi Friedman, Seth D Miller, Daniel G eng R01 AR064197/AR/NIAMS NIH HHS/ Multicenter Study Validation Study England Neuromuscul Disord. 2016 Jul;26(7):405-13. doi: 10.1016/j.nmd.2016.04.012. Epub 2016 Apr 22.I | 05/18/2016 | |
| readat: An R package for reading and working with SomaLogic ADAT files | Cotton RJ, et al. | 2016 | BMC Bioinformatics | 17 | 1 | 201 | https://www.doi.org/10.1186/s12859-016-1007-8 | 27,146,037 | Adult Aged Chorionic Gonadotropin/*blood Cohort Studies Cross-Sectional Studies Female Follicle Stimulating Hormone/*blood Humans Internet Male Middle Aged Prostate-Specific Antigen/*blood Proteomics/*methods Software Adat Bioconductor Dynamic range Proteomics R SomaLogic | BACKGROUND: SomaLogic's SOMAscan assay platform allows the analysis of the relative abundance of over 1300 proteins directly from biological matrices such as blood plasma and serum. The data resulting from the assay is provided in a proprietary text-based format not easily imported into R. RESULTS: readat is an R package for working with the SomaLogic ADAT file format. It provides functionality for importing, transforming and annotating data from these files. The package is free, open source, and available on Bioconductor and Bitbucket. CONCLUSIONS: readat integrates into both Bioconductor and traditional R workflows, rendering it easy to make use of ADAT files. | Cotton, Richard J Graumann, Johannes eng Evaluation Study England BMC Bioinformatics. 2016 May 4;17(1):201. doi: 10.1186/s12859-016-1007-8.I | 05/06/2016 | |
| Respiratory Mucosal Proteome Quantification in Human Influenza Infections | Marion T, et al. | 2016 | PLoS One | 11 | 4 | e0153674 | https://www.doi.org/10.1371/journal.pone.0153674 | 27,088,501 | Case-Control Studies Humans Influenza A virus/*isolation & purification/pathogenicity Influenza, Human/*diagnosis/metabolism/virology Nasal Cavity/*metabolism/virology Proteome/*analysis Proteomics/*methods Respiratory Mucosa/*metabolism/virology Viral Load | Respiratory influenza virus infections represent a serious threat to human health. Underlying medical conditions and genetic make-up predispose some influenza patients to more severe forms of disease. To date, only a few studies have been performed in patients to correlate a selected group of cytokines and chemokines with influenza infection. Therefore, we evaluated the potential of a novel multiplex micro-proteomics technology, SOMAscan, to quantify proteins in the respiratory mucosa of influenza A and B infected individuals. The analysis included but was not limited to quantification of cytokines and chemokines detected in previous studies. SOMAscan quantified more than 1,000 secreted proteins in small nasal wash volumes from infected and healthy individuals. Our results illustrate the utility of micro-proteomic technology for analysis of proteins in small volumes of respiratory mucosal samples. Furthermore, when we compared nasal wash samples from influenza-infected patients with viral load >/= 2(8) and increased IL-6 and CXCL10 to healthy controls, we identified 162 differentially-expressed proteins between the two groups. This number greatly exceeds the number of DEPs identified in previous studies in human influenza patients. Most of the identified proteins were associated with the host immune response to infection, and changes in protein levels of 151 of the DEPs were significantly correlated with viral load. Most important, SOMAscan identified differentially expressed proteins heretofore not associated with respiratory influenza infection in humans. Our study is the first report for the use of SOMAscan to screen nasal secretions. It establishes a precedent for micro-proteomic quantification of proteins that reflect ongoing response to respiratory infection. | Marion, Tony Elbahesh, Husni Thomas, Paul G DeVincenzo, John P Webby, Richard Schughart, Klaus eng HHSN266200700005C/AI/NIAID NIH HHS/ HHSN272201400006C/AI/NIAID NIH HHS/ HHSN266200700005C/PHS HHS/ HHSN272201400006C/PHS HHS/ Comparative Study Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. PLoS One. 2016 Apr 18;11(4):e0153674. doi: 10.1371/journal.pone.0153674. eCollection 2016.I | 04/19/2016 | |
| Clinical utility of serum biomarkers in Duchenne muscular dystrophy | Hathout Y, et al. | 2016 | Clin Proteomics | 13 | 9 | https://www.doi.org/10.1186/s12014-016-9109-x | 27,051,355 | Biomarkers Clinical outcomes Duchenne muscular dystrophy Mass spectrometry Pharmacodynamic biomarkers Proteins SomaScan Surrogate biomarkers miRNA | Assessments of disease progression and response to therapies in Duchenne muscular dystrophy (DMD) patients remain challenging. Current DMD patient assessments include complex physical tests and invasive procedures such as muscle biopsies, which are not suitable for young children. Defining alternative, less invasive and objective outcome measures to assess disease progression and response to therapy will aid drug development and clinical trials in DMD. In this review we highlight advances in development of non-invasive blood circulating biomarkers as a means to assess disease progression and response to therapies in DMD. | Hathout, Yetrib Seol, Haeri Han, Meng Hsuan J Zhang, Aiping Brown, Kristy J Hoffman, Eric P eng U54 HD090257/HD/NICHD NIH HHS/ P30 HD040677/HD/NICHD NIH HHS/ R01 AR062380/AR/NIAMS NIH HHS/ P50 AR060836/AR/NIAMS NIH HHS/ U54 HD071601/HD/NICHD NIH HHS/ Review England Clin Proteomics. 2016 Apr 5;13:9. doi: 10.1186/s12014-016-9109-x. eCollection 2016.I | 04/07/2016 | ||
| Embracing proteins: structural themes in aptamer-protein complexes | Gelinas AD, et al. | 2016 | Curr Opin Struct Biol | 36 | 122-32 | https://www.doi.org/10.1016/j.sbi.2016.01.009 | 26,919,170 | Aptamers, Nucleotide/*chemistry/metabolism Binding Sites Hydrophobic and Hydrophilic Interactions Ligands *Models, Molecular Nucleic Acid Conformation Nucleotide Motifs Protein Binding Protein Conformation Proteins/*chemistry/metabolism Structure-Activity Relationship | Understanding the structural rules that govern specific, high-affinity binding characteristic of aptamer-protein interactions is important in view of the increasing use of aptamers across many applications. From the modest number of 16 aptamer-protein structures currently available, trends are emerging. The flexible phosphodiester backbone allows folding into precise three-dimensional structures using known nucleic acid motifs as scaffolds that orient specific functional groups for target recognition. Still, completely novel motifs essential for structure and function are found in modified aptamers with diversity-enhancing side chains. Aptamers and antibodies, two classes of macromolecules used as affinity reagents with entirely different backbones and composition, recognize protein epitopes of similar size and with comparably high shape complementarity. | Gelinas, Amy D Davies, Douglas R Janjic, Nebojsa eng Review England Curr Opin Struct Biol. 2016 Feb;36:122-32. doi: 10.1016/j.sbi.2016.01.009. Epub 2016 Feb 24.I | 02/27/2016 | ||
| Fit for the Eye: Aptamers in Ocular Disorders | Drolet DW, et al. | 2016 | Nucleic Acid Ther | 26 | 3 | 127-46 | https://www.doi.org/10.1089/nat.2015.0573 | 26,757,406 | Aptamers, Nucleotide/*therapeutic use Eye Diseases/genetics/*therapy Humans Ligands Ophthalmology/*trends SELEX Aptamer Technique/*trends | For any new class of therapeutics, there are certain types of indications that represent a natural fit. For nucleic acid ligands in general, and aptamers in particular, the eye has historically been an attractive site for therapeutic intervention. In this review, we recount the discovery and early development of three aptamers designated for use in ophthalmology, one approved (Macugen), and two in late-stage development (Fovista and Zimura). Every one of these molecules was originally intended for other indications. Key improvements in technology, specifically with regard to libraries used for in vitro selection and subsequent chemical optimization of aptamers, have played an important role in allowing the identification of development candidates with suitable properties. The lessons learned from the selection of these molecules are valuable for informing us about the many remaining opportunities for aptamer-based therapeutics in ophthalmology as well as for identifying additional indications for which aptamers as a class of therapeutics have distinct advantages. | Drolet, Daniel W Green, Louis S Gold, Larry Janjic, Nebojsa eng Review Nucleic Acid Ther. 2016 Jun;26(3):127-46. doi: 10.1089/nat.2015.0573. Epub 2016 Jan 12.I | 01/13/2016 | |
| Serum proteomic analysis identifies interleukin 16 as a biomarker for clinical response during early treatment of rheumatoid arthritis | Murota A, et al. | 2016 | Cytokine | 78 | 87-93 | https://www.doi.org/10.1016/j.cyto.2015.12.002 | 26,700,586 | Abatacept/therapeutic use Adult Aged Antibodies, Monoclonal, Humanized/therapeutic use Antirheumatic Agents/*therapeutic use Arthritis, Rheumatoid/*blood/*drug therapy Biomarkers/blood Blood Proteins/*analysis/immunology Blood Sedimentation Female Humans Infliximab/therapeutic use Interleukin-16/*blood Male Matrix Metalloproteinase 3/blood Methotrexate/therapeutic use Middle Aged *Proteomics Statistics as Topic Treatment Outcome Biomarker Interleukin-16 Proteomics Rheumatoid arthritis Serum protein | OBJECTIVES: To conduct a comprehensive quantitative proteomics analysis of novel serum protein biomarkers based on synovitis status associated with matrix metalloproteinase-3 (MMP-3) and to determine the clinical significance of these biomarkers in rheumatoid arthritis (RA). METHODS: Patients with untreated RA (n=28), primary Sjogren's syndrome (pSS) (n=30), and healthy controls (HCs) (n=30) were enrolled for the screening assay. A total of 1128 serum proteins were analyzed using the SOMAscan assay. Serum levels of MMP-3 and interleukin (IL)-16 were measured using a latex turbidimetric immunoassay and ELISA at baseline and 12weeks after treatment with methotrexate (MTX) for MTX-naive RA patients (n=28) or with the biologics tocilizumab (TCZ) (n=7), abatacept (ABT) (n=11) or infliximab (n=22) for MTX-inadequate response (IR) RA patients. Correlation analysis was conducted using Spearman's rank correlation method. RESULTS: Proteomics showed that serum IL-16 levels were most positively correlated with those of MMP-3 (rho=0.51, p<0.01) and were significantly increased in patients with untreated active RA compared to HCs (p<0.01) or those with pSS (p<0.01). IL-16 levels decreased following treatment in both the MTX-naive and MTX-IR groups. Regarding clinical response, fluctuations in IL-16 levels were positively associated with changes in clinical indicators, particularly the Clinical Disease Activity Index (rho=0.89, p<0.01) in the TCZ and ABT-treated group. However, no similar correlation was noted in MMP-3 and acute phase reactants in any groups. CONCLUSIONS: IL-16 was a more effective clinical parameter than MMP-3, C-reactive protein, or erythrocyte sedimentation rate in both MTX-naive and MTX-IR RA patients. IL-16 might be a useful biomarker for evaluating clinical response in RA patients. | Murota, Atsuko Suzuki, Katsuya Kassai, Yoshiaki Miyazaki, Takahiro Morita, Rimpei Kondo, Yasushi Takeshita, Masaru Niki, Yasuo Yoshimura, Akihiko Takeuchi, Tsutomu eng Research Support, Non-U.S. Gov't England Cytokine. 2016 Feb;78:87-93. doi: 10.1016/j.cyto.2015.12.002. Epub 2015 Dec 14.I | 12/25/2015 | ||
| Longitudinal Protein Changes in Blood Plasma Associated with the Rate of Cognitive Decline in Alzheimer's Disease | Sattlecker M, et al. | 2016 | J Alzheimers Dis | 49 | 4 | 1105-14 | https://www.doi.org/10.3233/JAD-140669 | 26,599,049 | Aged Alzheimer Disease/*blood/*psychology Biomarkers/blood *Cognition/physiology Cognitive Dysfunction/blood/psychology Disease Progression Female Follow-Up Studies Humans Linear Models Longitudinal Studies Male Mental Status Schedule Neuropsychological Tests Alzheimer's disease cognitive decline complement cascade cytokine-cytokine receptor interaction plasma proteins | Biomarkers of Alzheimer's disease (AD) progression are needed to support the development of urgently needed disease modifying drugs. We employed a SOMAscan assay for quantifying 1,001 proteins in blood samples from 90 AD subjects, 37 stable mild cognitive impaired (MCI) subjects, 39 MCI subjects converting to AD within a year and 69 controls at baseline and one year follow up. We used linear mixed effects models to identify proteins changing significantly over one year with the rate of cognitive decline, which was quantified as the reduction in Mini Mental State Examination (MMSE) scores. Additionally, we investigated proteins changing differently across disease groups and during the conversion from MCI to AD. We found that levels of proteins belonging to the complement cascade increase significantly in fast declining AD patients. Longitudinal changes in the complement cascade might be a surrogate biomarker for disease progression. We also found that members of the cytokine-cytokine receptor interaction pathway change during AD when compared to healthy aging subjects. | Sattlecker, Martina Khondoker, Mizanur Proitsi, Petroula Williams, Stephen Soininen, Hilkka Kloszewska, Iwona Mecocci, Patrizia Tsolaki, Magda Vellas, Bruno Lovestone, Simon Dobson, Richard Jb eng 167/ALZS_/Alzheimer's Society/United Kingdom 171/ALZS_/Alzheimer's Society/United Kingdom G0801464/MRC_/Medical Research Council/United Kingdom Research Support, Non-U.S. Gov't Netherlands J Alzheimers Dis. 2016;49(4):1105-14. doi: 10.3233/JAD-140669.I | 11/26/2015 | |
| Chemically Modified Interleukin-6 Aptamer Inhibits Development of Collagen-Induced Arthritis in Cynomolgus Monkeys | Hirota M, et al. | 2016 | Nucleic Acid Ther | 26 | 1 | 44843 | https://www.doi.org/10.1089/nat.2015.0567 | 26,579,954 | Amino Acid Sequence Animals Aptamers, Peptide/*chemistry Arthritis, Experimental/chemically induced/*prevention & control Cells, Cultured Collagen/*adverse effects Female Humans Interleukin-6/*blood/chemistry Macaca fascicularis Molecular Sequence Data Phosphorylation STAT3 Transcription Factor/metabolism Sequence Homology, Amino Acid T-Lymphocytes/metabolism | Interleukin-6 (IL-6) is a potent mediator of inflammatory and immune responses, and a validated target for therapeutic intervention of inflammatory diseases. Previous studies have shown that SL1026, a slow off-rate modified aptamer (SOMAmer) antagonist of IL-6, neutralizes IL-6 signaling in vitro. In the present study, we show that SL1026 delays the onset and reduces the severity of rheumatoid symptoms in a collagen-induced arthritis model in cynomolgus monkeys. SL1026 (1 and 10 mg/kg), administered q.i.d., delayed the progression of arthritis and the concomitant increase in serum IL-6 levels compared to the untreated control group. Furthermore, SL1026 inhibited IL-6-induced STAT3 phosphorylation ex vivo in T lymphocytes from human blood and IL-6-induced C-reactive protein and serum amyloid A production in human primary hepatocytes. Importantly, SOMAmer treatment did not elicit an immune response, as evidenced by the absence of anti-SOMAmer antibodies in plasma of treated monkeys. These results demonstrate that SOMAmer antagonists of IL-6 may be attractive agents for the treatment of IL-6-mediated diseases, including rheumatoid arthritis. | Hirota, Masao Murakami, Ikuo Ishikawa, Yuichi Suzuki, Tomoki Sumida, Shun-ichiro Ibaragi, Shigeru Kasai, Hayato Horai, Naoto Drolet, Daniel W Gupta, Shashi Janjic, Nebojsa Schneider, Daniel J eng Nucleic Acid Ther. 2016 Feb;26(1):10-9. doi: 10.1089/nat.2015.0567. Epub 2015 Nov 18.I | 11/19/2015 | |
| The relationship of circulating proteins in early pregnancy with preterm birth | Lynch AM, et al. | 2016 | Am J Obstet Gynecol | 214 | 4 | 517 e1-517 e8 | https://www.doi.org/10.1016/j.ajog.2015.11.001 | 26,576,488 | Adult Biomarkers/blood Blood Proteins/*metabolism Case-Control Studies Cohort Studies Female Humans Logistic Models Pregnancy Pregnancy Trimester, First/*blood Premature Birth/*blood Proteomics coagulation cascade complement system early pregnancy preterm birth Hospital Colorado innovations grant to develop Kids Personalized Protein Signatures (KIPPS) panels for children using the SomaLogic technology. In addition she serves on the Joint Steering Committee for KIPPS. The other co-authors report no conflict of interest. | BACKGROUND: Preterm birth (PTB) (< 37 completed weeks' gestation) is a pathological outcome of pregnancy and a major global health problem. Babies born preterm have an elevated risk for long-term adverse medical and neurodevelopmental sequelae. Substantial evidence implicates intrauterine infection and/or inflammation in PTB. However, these are often relatively late findings in the process, when PTB is inevitable. Identification of earlier markers of PTB may make successful intervention possible. Although select proteins, notably those related to the inflammatory pathways, have been associated with PTB, there has been a lack of research into the role of other protein pathways in the development of PTB. The purpose of this study was to investigate, using a previously described biomarker discovery approach, a subset of circulating proteins and their association with PTB focusing on samples from early pregnancy. OBJECTIVES: The objectives of the study were as follows: (1) to perform a large-scale biomarker discovery, utilizing an innovative platform to identify proteins associated with preterm birth in plasma taken between 10 and 15 weeks' gestation and, (2) to determine which protein pathways are most strongly associated with preterm birth. To address these aims, we measured 1129 proteins in a plasma sample from early pregnancy using a multiplexed aptamer-based proteomic technology developed in Colorado by SomaLogic. STUDY DESIGN: Using a nested case-control approach, we measured proteins at a single time point in early pregnancy in 41 women who subsequently delivered preterm and 88 women who had term uncomplicated deliveries. We measured 1129 proteins using a multiplexed aptamer-based proteomic technology developed by SomaLogic. Logistic regressions and random forests were used to compare protein levels. RESULTS: The complement factors B and H and the coagulation factors IX and IX ab were the highest-ranking proteins distinguishing cases of preterm birth from term controls. The top 3 pathways associated with preterm birth were the complement cascade, the immune system, and the clotting cascade. CONCLUSION: Using a discovery approach, these data provide further confirmation that there is an association of immune- and coagulation-related events in early pregnancy with preterm birth. Thus, plasma protein profiles at 10-15 weeks of gestation are related to the development of preterm birth later in pregnancy. | Lynch, Anne M Wagner, Brandie D Deterding, Robin R Giclas, Patricia C Gibbs, Ronald S Janoff, Edward N Holers, V Michael Santoro, Nanette F eng K23 HD049684/HD/NICHD NIH HHS/ R21 HD068961/HD/NICHD NIH HHS/ 5 K23 HD4984-04/HD/NICHD NIH HHS/ R21 HD68961-01A1/HD/NICHD NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Am J Obstet Gynecol. 2016 Apr;214(4):517.e1-517.e8. doi: 10.1016/j.ajog.2015.11.001. Epub 2015 Nov 11.I | 11/19/2015 | |
| Developing clinically relevant biomarkers in inflammatory arthritis: A multiplatform approach for serum candidate protein discovery | McArdle A, et al. | 2016 | Proteomics Clin Appl | 10 | 6 | 691-8 | https://www.doi.org/10.1002/prca.201500046 | 26,332,844 | Adult Arthritis, Psoriatic/blood/*diagnosis/pathology Arthritis, Rheumatoid/blood/*diagnosis/pathology Biomarkers/metabolism Blood Proteins/*metabolism Chromatography, Liquid Diagnosis, Differential Female Gene Expression Gene Expression Profiling Humans Immunoassay Male Middle Aged Tandem Mass Spectrometry Lc-ms/ms Luminex Multiplexing Psoriatic and Rhuematoid Arthritis SOMAscan | PURPOSE: To identify candidate biomarkers that have the potential to distinguish between patients with psoriatic arthritis (PsA) or rheumatoid arthritis (RA) and explore the value of combining different protein discovery platforms for the development of a multiplexed protein biomarker panel. EXPERIMENTAL DESIGN: Serum samples from 32 patients (PsA; n = 16 and RA; n = 16) defined as active, early onset, and treatment naive were analyzed using unbiased label-free LC-MS/MS, a microsphere bead-based immunoassay (Luminex xMAP) and an aptamer-based assay (SOMAscan). RESULTS: LC-MS/MS was used to quantify 324 proteins, while the Luminex xMAP targeted 48 proteins and SOMAscan supported the measurement of 1129 proteins. The combined data from these techniques gave reproducible quantification of 1501 proteins in total. Of these, 42 (LC-MS/MS), 3 (Luminex xMAP), and 127 (SOMAscan) proteins were found to be differentially expressed between PsA and RA (p < 0.05). CONCLUSION AND CLINICAL RELEVANCE: Using three different and potentially complementary proteomic platforms we identified a total of 172 proteins that are differentially expressed in patients with PsA compared to RA. These proteins collectively represent candidates for inclusion in a protein signature that could be developed as a diagnostic test to discriminate patients with PsA from RA and therefore be of clinical utility. | McArdle, Angela Qasim Butt, Aisha Szentpetery, Agnes de Jager, Wilco de Roock, Sytze FitzGerald, Oliver Pennington, Stephen R eng Research Support, Non-U.S. Gov't Germany Proteomics Clin Appl. 2016 Jun;10(6):691-8. doi: 10.1002/prca.201500046. Epub 2015 Nov 9.I | 09/04/2015 | |
| SELEX: How It Happened and Where It will Go | Gold L | 2015 | J Mol Evol | 81 | 6 | 140-3 | https://www.doi.org/10.1007/s00239-015-9705-9 | 26,480,964 | *Aptamers, Nucleotide History, 20th Century SELEX Aptamer Technique/*history United States | Gold, Larry eng Autobiography Bibliography Historical Article Germany J Mol Evol. 2015 Dec;81(5-6):140-3. doi: 10.1007/s00239-015-9705-9. Epub 2015 Oct 20.I | 10/21/2015 | ||
| Influence of 5-N-carboxamide modifications on the thermodynamic stability of oligonucleotides | Wolk SK, et al. | 2015 | Nucleic Acids Res | 43 | 19 | 9107-22 | https://www.doi.org/10.1093/nar/gkv981 | 26,438,535 | Amides/chemistry Circular Dichroism Deoxyuridine/*analogs & derivatives Models, Molecular Nuclear Magnetic Resonance, Biomolecular Nucleic Acid Denaturation Nucleotide Motifs Oligonucleotides/*chemistry *Thermodynamics | We have recently shown that the incorporation of modified nucleotides such as 5-N-carboxamide-deoxyuridines into random nucleic acid libraries improves success rates in SELEX experiments and facilitates the identification of ligands with slow off-rates. Here we report the impact of these modifications on the thermodynamic stability of both duplexes and intramolecular 'single-stranded' structures. Within duplexes, large, hydrophobic naphthyl groups were destabilizing relative to the all natural DNA duplex, while the hydrophilic groups exhibited somewhat improved duplex stability. All of the significant changes in stability were driven by opposing contributions from the enthalpic and entropic terms. In contrast, both benzyl and naphthyl modifications stabilized intramolecular single-stranded structures relative to their natural DNA analogs, consistent with the notion that intramolecular folding allows formation of novel, stabilizing hydrophobic interactions. Imino proton NMR data provided evidence that elements of the folded structure form at temperatures well below the Tm, with a melting transition that is distinctly less cooperative when compared to duplex DNA. Although there are no data to suggest that the unmodified DNA sequences fold into structures similar to their modified analogs, this still represents clear evidence that these modifications impart thermodynamic stability to the folded structure not achievable with unmodified DNA. | Wolk, Steven K Shoemaker, Richard K Mayfield, Wes S Mestdagh, Andrew L Janjic, Nebojsa eng Research Support, Non-U.S. Gov't England Nucleic Acids Res. 2015 Oct 30;43(19):9107-22. doi: 10.1093/nar/gkv981. Epub 2015 Oct 4.I | 10/07/2015 | |
| Association of growth differentiation factor 11/8, putative anti-ageing factor, with cardiovascular outcomes and overall mortality in humans: analysis of the Heart and Soul and HUNT3 cohorts | Olson KA, et al. | 2015 | Eur Heart J | 36 | 48 | 3426-34 | https://www.doi.org/10.1093/eurheartj/ehv385 | 26,294,790 | Age Factors Aged Bone Morphogenetic Proteins/*metabolism Coronary Disease/blood/mortality Female Growth Differentiation Factor 9/*metabolism Growth Differentiation Factors/*metabolism Heart Failure/blood/mortality Humans Hypertrophy, Left Ventricular/blood/*mortality Male Myocardial Ischemia/blood/*mortality Prognosis Prospective Studies Risk Factors Stroke/blood/mortality Ageing Cardiovascular outcomes Epidemiology Growth differentiation factor 11 and 8 Hypertrophy | AIMS: Growth differentiation factor 11 and/or its homologue growth differentiation factor 8 (GDF11/8) reverses age-related cardiac hypertrophy and vascular ageing in mice. We investigated whether GDF11/8 associates with cardiovascular outcomes, left ventricular hypertrophy (LVH), or age in humans. METHODS AND RESULTS: We measured plasma GDF11/8 levels in 928 participants with stable ischaemic heart disease in the Heart and Soul study. We adjudicated heart failure hospitalization, stroke, myocardial infarction, death, and their composite endpoint. Left ventricular hypertrophy was evaluated by echocardiography. We used multivariable Cox proportional hazards models to compare rates of cardiovascular events and death across GDF11/8 quartiles and logistic regression models to evaluate the association between GDF11/8 and LVH. Four hundred and fifty participants (48.5%) experienced a cardiovascular event or death during 8.9 years of follow-up. The adjusted risk of the composite endpoint was lower in the highest compared with the lowest GDF11/8 quartile [hazard ratio (HR), 0.45; 95% confidence interval (CI), 0.33-0.60; P < 0.001]. We replicated this relationship of GDF11/8 to adverse events in 971 participants in the HUNT3 cohort (adjusted HR, 0.34; 95% CI, 0.23-0.51; P < 0.001). Left ventricular hypertrophy was present in 368 participants (39.7%) at baseline. Participants in the highest quartile of GDF11/8 were less likely to have LVH than those in the lowest quartile (adjusted OR, 0.55; 95% CI, 0.35-0.86; P = 0.009). GDF11/8 levels were lower in older individuals (P < 0.001). CONCLUSION: In patients with stable ischaemic heart disease, higher GDF11/8 levels are associated with lower risk of cardiovascular events and death. Our findings suggest that GDF11/8 has similar cardioprotective properties in humans to those demonstrated in mice. | Olson, Kristoff A Beatty, Alexis L Heidecker, Bettina Regan, Mathilda C Brody, Edward N Foreman, Trudi Kato, Shintaro Mehler, Robert E Singer, Britta S Hveem, Kristian Dalen, Havard Sterling, David G Lawn, Richard M Schiller, Nelson B Williams, Stephen A Whooley, Mary A Ganz, Peter eng KL2TR000143/TR/NCATS NIH HHS/ R01 H L079235/PHS HHS/ Multicenter Study Observational Study Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. Research Support, U.S. Gov't, P.H.S. England Eur Heart J. 2015 Dec 21;36(48):3426-34. doi: 10.1093/eurheartj/ehv385. Epub 2015 Aug 20.I | 08/22/2015 | |
| Proteomic methods for biomarker discovery and validation. Are we there yet? | Hathout Y | 2015 | Expert Rev Proteomics | 12 | 4 | 329-31 | https://www.doi.org/10.1586/14789450.2015.1064771 | 26,186,709 | *Biomarkers Chromatography, Liquid *Proteomics Tandem Mass Spectrometry SomaScan antibody bead arrays biomarkers biomarkers validation proteomics targeted mass spectrometry | Noninvasive molecular biomarkers are becoming attractive tools to monitor disease progression, aid drug development programs and use as surrogate outcome measures in clinical trials. Cutting edge proteomic methods to assay biomarkers in body fluids have been developed in the past few years, but transitioning them to clinical practice has been slow and depends on the qualification of both the method and the biomarker. | Hathout, Yetrib eng Editorial Validation Study England Expert Rev Proteomics. 2015 Aug;12(4):329-31. doi: 10.1586/14789450.2015.1064771.I | 07/18/2015 | |
| Increased cerebrospinal fluid fibrinogen in major depressive disorder | Hattori K, et al. | 2015 | Sci Rep | 5 | 11412 | https://www.doi.org/10.1038/srep11412 | 26,081,315 | Brain/pathology Case-Control Studies Depressive Disorder, Major/*cerebrospinal fluid/diagnosis Diffusion Magnetic Resonance Imaging Female Fibrinogen/*cerebrospinal fluid Humans Male White Matter/pathology | Major depressive disorder (MDD) presumably includes heterogeneous subgroups with differing pathologies. To obtain a marker reflecting such a subgroup, we analyzed the cerebrospinal fluid (CSF) levels of fibrinogen, which has been reported to be elevated in the plasma of patients with MDD. Three fibrinogen-related proteins were measured using aptamer-based analyses and CSF samples of 30 patients with MDD and 30 controls. The numbers of patients with an excessively high level (>99 percentile of the controls) was significantly increased (17 to 23%). Measurement reproducibility of these results was confirmed by an ELISA for fibrinogen (Pearson's r = 0.77). In an independent sample set from 36 patients and 30 controls, using the ELISA, results were similar (22%). When these two sample sets were combined, the number of patients with a high fibrinogen level was significantly increased (15/66; odds ratio 8.53; 95% confidence interval 1.9-39.1, p = 0.0011). By using diffusion tensor imaging, we found white matter tracts abnormalities in patients with a high fibrinogen level but not those patients with a normal fibrinogen level, compared with controls. Plasma fibrinogen levels were similar among the diagnostic groups. Our results point to a subgroup of MDD represented by increased CSF fibrinogen and white matter tract abnormalities. | Hattori, Kotaro Ota, Miho Sasayama, Daimei Yoshida, Sumiko Matsumura, Ryo Miyakawa, Tomoko Yokota, Yuuki Yamaguchi, Shinobu Noda, Takamasa Teraishi, Toshiya Hori, Hiroaki Higuchi, Teruhiko Kohsaka, Shinichi Goto, Yu-ichi Kunugi, Hiroshi eng Research Support, Non-U.S. Gov't England Sci Rep. 2015 Jun 17;5:11412. doi: 10.1038/srep11412.I | 06/18/2015 | ||
| Plasma protein biomarkers of Alzheimer's disease endophenotypes in asymptomatic older twins: early cognitive decline and regional brain volumes | Kiddle SJ, et al. | 2015 | Transl Psychiatry | 5 | 6 | e584 | https://www.doi.org/10.1038/tp.2015.78 | 26,080,319 | Aged Alzheimer Disease/*blood/pathology Asymptomatic Diseases Biomarkers/blood Brain/*pathology *Endophenotypes Entorhinal Cortex/pathology Female Humans Intracellular Signaling Peptides and Proteins/*blood MAP Kinase Kinase 4/*blood Male Middle Aged Neuropsychological Tests Organ Size Protein Serine-Threonine Kinases/*blood Twins/*genetics/psychology | There is great interest in blood-based markers of Alzheimer's disease (AD), especially in its pre-symptomatic stages. Therefore, we aimed to identify plasma proteins whose levels associate with potential markers of pre-symptomatic AD. We also aimed to characterise confounding by genetics and the effect of genetics on blood proteins in general. Panel-based proteomics was performed using SOMAscan on plasma samples from TwinsUK subjects who are asymptomatic for AD, measuring the level of 1129 proteins. Protein levels were compared with 10-year change in CANTAB-paired associates learning (PAL; n = 195), and regional brain volumes (n = 34). Replication of proteins associated with regional brain volumes was performed in 254 individuals from the AddNeuroMed cohort. Across all the proteins measured, genetic factors were found to explain ~26% of the variability in blood protein levels on average. The plasma level of the mitogen-activated protein kinase (MAPK) MAPKAPK5 protein was found to positively associate with the 10-year change in CANTAB-PAL in both the individual and twin difference context. The plasma level of protein MAP2K4 was found to suggestively associate negatively (Q < 0.1) with the volume of the left entorhinal cortex. Future studies will be needed to assess the specificity of MAPKAPK5 and MAP2K4 to eventual conversion to AD. | Kiddle, S J Steves, C J Mehta, M Simmons, A Xu, X Newhouse, S Sattlecker, M Ashton, N J Bazenet, C Killick, R Adnan, J Westman, E Nelson, S Soininen, H Kloszewska, I Mecocci, P Tsolaki, M Vellas, B Curtis, C Breen, G Williams, S C R Lovestone, S Spector, T D Dobson, R J B eng 171/ALZS_/Alzheimer's Society/United Kingdom MR/L011859/1/MRC_/Medical Research Council/United Kingdom 086904 /Z/08/Z/WT_/Wellcome Trust/United Kingdom Research Support, Non-U.S. Gov't Transl Psychiatry. 2015 Jun 16;5(6):e584. doi: 10.1038/tp.2015.78.I | 06/17/2015 | |
| Large-scale serum protein biomarker discovery in Duchenne muscular dystrophy | Hathout Y, et al. | 2015 | Proc Natl Acad Sci U S A | 112 | 23 | 7153-8 | https://www.doi.org/10.1073/pnas.1507719112 | 26,039,989 | Adolescent Adult Biomarkers/*blood Blood Proteins/*metabolism Case-Control Studies Child Child, Preschool Cohort Studies Humans Male Muscular Dystrophy, Duchenne/*blood Young Adult SOMAmer SOMAscan biomarkers muscular dystrophy proteomics SomaLogic, Inc E.B., R.K.D., B.M., M.N., B.S., F.S., D.S., and S.W. are employees and stakeholders in SomaLogic, Inc. Y.M.K. has been affiliated with the Eli Lilly and Co. since October 2012. | Serum biomarkers in Duchenne muscular dystrophy (DMD) may provide deeper insights into disease pathogenesis, suggest new therapeutic approaches, serve as acute read-outs of drug effects, and be useful as surrogate outcome measures to predict later clinical benefit. In this study a large-scale biomarker discovery was performed on serum samples from patients with DMD and age-matched healthy volunteers using a modified aptamer-based proteomics technology. Levels of 1,125 proteins were quantified in serum samples from two independent DMD cohorts: cohort 1 (The Parent Project Muscular Dystrophy-Cincinnati Children's Hospital Medical Center), 42 patients with DMD and 28 age-matched normal volunteers; and cohort 2 (The Cooperative International Neuromuscular Research Group, Duchenne Natural History Study), 51 patients with DMD and 17 age-matched normal volunteers. Forty-four proteins showed significant differences that were consistent in both cohorts when comparing DMD patients and healthy volunteers at a 1% false-discovery rate, a large number of significant protein changes for such a small study. These biomarkers can be classified by known cellular processes and by age-dependent changes in protein concentration. Our findings demonstrate both the utility of this unbiased biomarker discovery approach and suggest potential new diagnostic and therapeutic avenues for ameliorating the burden of DMD and, we hope, other rare and devastating diseases. | Hathout, Yetrib Brody, Edward Clemens, Paula R Cripe, Linda DeLisle, Robert Kirk Furlong, Pat Gordish-Dressman, Heather Hache, Lauren Henricson, Erik Hoffman, Eric P Kobayashi, Yvonne Monique Lorts, Angela Mah, Jean K McDonald, Craig Mehler, Bob Nelson, Sally Nikrad, Malti Singer, Britta Steele, Fintan Sterling, David Sweeney, H Lee Williams, Steve Gold, Larry eng UL1RR031988/RR/NCRR NIH HHS/ U54 RR026139/RR/NCRR NIH HHS/ U54HD053177/HD/NICHD NIH HHS/ R01AR062380/AR/NIAMS NIH HHS/ UL1 TR000075/TR/NCATS NIH HHS/ P50AR060836/AR/NIAMS NIH HHS/ P30 HD040677/HD/NICHD NIH HHS/ R01 AR062380/AR/NIAMS NIH HHS/ R24HD050846/HD/NICHD NIH HHS/ UL1RR024992/RR/NCRR NIH HHS/ 2U54HD053177/HD/NICHD NIH HHS/ UL1 RR024992/RR/NCRR NIH HHS/ G12RR003051/RR/NCRR NIH HHS/ G12 RR003051/RR/NCRR NIH HHS/ U54 HD053177/HD/NICHD NIH HHS/ UL1 RR031988/RR/NCRR NIH HHS/ P30HD040677/HD/NICHD NIH HHS/ U54RR026139/RR/NCRR NIH HHS/ R24 HD050846/HD/NICHD NIH HHS/ U54 AR052646/AR/NIAMS NIH HHS/ UL1 TR000448/TR/NCATS NIH HHS/ R01 AR061875/AR/NIAMS NIH HHS/ P50 AR060836/AR/NIAMS NIH HHS/ UL1TR000075/TR/NCATS NIH HHS/ R01 AR055100/AR/NIAMS NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. Proc Natl Acad Sci U S A. 2015 Jun 9;112(23):7153-8. doi: 10.1073/pnas.1507719112. Epub 2015 May 26.I | 06/04/2015 | |
| Non-helical DNA Triplex Forms a Unique Aptamer Scaffold for High Affinity Recognition of Nerve Growth Factor | Jarvis TC, et al. | 2015 | Structure | 23 | 7 | 1293-304 | https://www.doi.org/10.1016/j.str.2015.03.027 | 26,027,732 | Amino Acid Sequence Base Sequence Binding Sites Crystallography, X-Ray DNA/*chemistry Humans Hydrophobic and Hydrophilic Interactions Molecular Sequence Data Nerve Growth Factor/*chemistry/physiology Protein Binding Protein Structure, Secondary SELEX Aptamer Technique | Discerning the structural building blocks of macromolecules is essential for understanding their folding and function. For a new generation of modified nucleic acid ligands (called slow off-rate modified aptamers or SOMAmers), we previously observed essential functions of hydrophobic aromatic side chains in the context of well-known nucleic acid motifs. Here we report a 2.45-A resolution crystal structure of a SOMAmer complexed with nerve growth factor that lacks any known nucleic acid motifs, instead adopting a configuration akin to a triangular prism. The SOMAmer utilizes extensive hydrophobic stacking interactions, non-canonical base pairing and irregular purine glycosidic bond angles to adopt a completely non-helical, compact S-shaped structure. Aromatic side chains contribute to folding by creating an unprecedented intercalating zipper-like motif and a prominent hydrophobic core. The structure provides compelling rationale for potent inhibitory activity of the SOMAmer and adds entirely novel motifs to the repertoire of structural elements uniquely available to SOMAmers. | Jarvis, Thale C Davies, Douglas R Hisaminato, Akihiko Resnicow, Daniel I Gupta, Shashi Waugh, Sheela M Nagabukuro, Akira Wadatsu, Takashi Hishigaki, Haretsugu Gawande, Bharat Zhang, Chi Wolk, Steven K Mayfield, Wesley S Nakaishi, Yuichiro Burgin, Alex B Stewart, Lance J Edwards, Thomas E Gelinas, Amy D Schneider, Daniel J Janjic, Nebojsa eng Structure. 2015 Jul 7;23(7):1293-304. doi: 10.1016/j.str.2015.03.027. Epub 2015 May 28.I | 06/02/2015 | |
| Rapid Slow Off-Rate Modified Aptamer (SOMAmer)-Based Detection of C-Reactive Protein Using Isotachophoresis and an Ionic Spacer | Eid C, et al. | 2015 | Anal Chem | 87 | 13 | 6736-43 | https://www.doi.org/10.1021/acs.analchem.5b00886 | 26,024,067 | Aptamers, Nucleotide/*chemistry C-Reactive Protein/*analysis Ions *Isotachophoresis | We present an on-chip electrophoretic assay for rapid protein detection with a SOMAmer (Slow Off-Rate Modified Aptamer) reagent. We used isotachophoresis (ITP) coupled with an ionic spacer to both react and separate SOMAmer-protein complex from free SOMAmer reagent. ITP accelerates the reaction kinetics as the ionic spacer concurrently separates the reaction products. We developed a numerical and analytical model to describe ITP spacer assays, which involve low-mobility, nonfocusing targets that are recruited into the ITP zone by higher-mobility, ITP-focused probes. We demonstrated a proof-of-concept of this assay using C-reactive protein (CRP) in buffer, and achieved a 2 nM limit of detection (LOD) with a combined 20 min assay time (10 min off-chip preparation of reagents and 10 min on-chip run). Our findings suggest that this approach has potential as a simple and rapid alternative to other homogeneous immunoassays. We also explore the extension of this assay to a diluted serum sample spiked with CRP, where we observe decreased sensitivity (an LOD of 25 nM in 20-fold diluted serum). We describe the challenges in extending this assay to complex samples and achieving higher sensitivity and specificity for clinical applications. | Eid, Charbel Palko, James W Katilius, Evaldas Santiago, Juan G eng Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. Anal Chem. 2015 Jul 7;87(13):6736-43. doi: 10.1021/acs.analchem.5b00886. Epub 2015 Jun 16.I | 05/30/2015 | |
| Blood Protein Markers of Neocortical Amyloid-beta Burden: A Candidate Study Using SOMAscan Technology | Voyle N, et al. | 2015 | J Alzheimers Dis | 46 | 4 | 947-61 | https://www.doi.org/10.3233/JAD-150020 | 25,881,911 | Aged Aged, 80 and over Aging/blood/pathology Alzheimer Disease/*blood/*pathology Amyloid beta-Peptides/*metabolism Aniline Compounds/metabolism Apolipoproteins E/genetics Australia Blood Proteins/*metabolism Cohort Studies Female Humans Male Middle Aged Neocortex/*metabolism Positron-Emission Tomography Proteins Proteomics Thiazoles/metabolism Alzheimer's disease amyloid plaques blood positron emission tomography scan | BACKGROUND: Four previously reported studies have tested for association of blood proteins with neocortical amyloid-beta burden (NAB). If shown to be robust, these proteins could have utility as a blood test for enrichment in clinical trials of Alzheimer's disease (AD) therapeutics. OBJECTIVE: This study aimed to investigate whether previously identified blood proteins also show evidence for association with NAB in serum samples from the Australian Imaging, Biomarker and Lifestyle Flagship Study of Ageing (AIBL). The study considers candidate proteins seen in cohorts other than AIBL and candidates previously discovered in the AIBL cohort. METHODS: Our study used the SOMAscan platform for protein quantification in blood serum. Linear and logistic regressions were used to model continuous NAB and dichotomized NAB respectively using single proteins as a predictor. Multiple protein models were built using stepwise regression techniques and support vectors machines. Age and APOEvarepsilon4 carriage were used as covariates for all analysis. RESULTS: Of the 41 proteins previously reported, 15 AIBL candidates and 20 non-AIBL candidates were available for testing. Of these candidates, pancreatic polypeptide (PPY) and IgM showed a significant association with NAB. Notably, IgM was found to associate with continuous NAB across cognitively normal control subjects. CONCLUSIONS: We have further demonstrated the association of PPY and IgM with NAB, despite technical differences between studies. There are several reasons for a lack of significance for the other candidates including platform differences and the use of serum rather than plasma samples. To investigate the possibility of technical differences causing lack of replication, further studies are required. | Voyle, Nicola Baker, David Burnham, Samantha C Covin, Antonia Zhang, Zhanpan Sangurdekar, Dipen P Tan Hehir, Cristina A Bazenet, Chantal Lovestone, Simon Kiddle, Steven Dobson, Richard J B eng 122/ALZS_/Alzheimer's Society/United Kingdom 171/ALZS_/Alzheimer's Society/United Kingdom MR/L011859/1/MRC_/Medical Research Council/United Kingdom Research Support, Non-U.S. Gov't Netherlands J Alzheimers Dis. 2015;46(4):947-61. doi: 10.3233/JAD-150020.I | 04/18/2015 | |
| Practical synthesis of cytidine-5-carboxamide-modified nucleotide reagents | Rohloff JC, et al. | 2015 | Nucleosides Nucleotides Nucleic Acids | 34 | 3 | 180-98 | https://www.doi.org/10.1080/15257770.2014.978011 | 25,710,355 | Cytidine/analogs & derivatives/*chemical synthesis/chemistry Oligonucleotides/*chemical synthesis/chemistry Solid-Phase Synthesis Techniques Aptamer Selex cytidine-5-carboxamide modified nucleotide | Chemically-modified derivatives of cytidine, bearing a 5-(N-substituted-carboxamide) functional group, are new reagents for use in aptamer discovery via the SELEX process (Systematic Evolution of Ligands by EXponential enrichment). Herein, we disclose a practical synthesis of 5-(N-benzylcarboxamide)-2'-deoxycytidine, and the corresponding 5-(N-1-naphthylmethylcarboxamide)- and 5-(N-3-phenylpropylcarboxamide)-2'-deoxycytidine analogs, as both the suitably-protected 3'-O-cyanoethylphosphoramidite reagents (CEP; gram scale) and the 5'-O-triphosphate reagents (TPP; milligram-scale). The key step in the syntheses is a mild, palladium(0)-catalyzed carboxyamidation of an unprotected 5-iodo-cytidine. Use of the CEP reagents for solid-phase oligonucleotide synthesis was demonstrated and incorporation of the TPP reagents by KOD polymerase in a primer extension assay confirmed the utility of these reagents for SELEX. Finally, the carboxyamidation reaction was also used to prepare the nuclease-resistant sugar-variants: 5-(N-benzylcarboxamide)-2'-O-methyl-cytidine and 5-(N-3-phenylpropylcarboxamide)-2'-deoxy-2'-fluoro-cytidine. | Rohloff, John C Fowler, Catherine Ream, Brian Carter, Jeffrey D Wardle, Greg Fitzwater, Tim eng Nucleosides Nucleotides Nucleic Acids. 2015;34(3):180-98. doi: 10.1080/15257770.2014.978011.I | 02/25/2015 | |
| Circulating Proteomic Signatures of Chronological Age | Menni C, et al. | 2015 | J Gerontol A Biol Sci Med Sci | 70 | 7 | 809-16 | https://www.doi.org/10.1093/gerona/glu121 | 25,123,647 | Adult Aged Aged, 80 and over Aging/*blood Biomarkers/blood Carrier Proteins/blood Cohort Studies Cytokines/blood Eye Proteins/blood Female Humans Insulin-Like Growth Factor Binding Protein 6/blood Male Matrix Metalloproteinase 12/blood Middle Aged Nerve Tissue Proteins/blood Phenotype *Proteomics *Registries Twins United Kingdom Aging Aptamers. Blood biomarkers Early development Nucleotide Proteomics | To elucidate the proteomic features of aging in plasma, the subproteome targeted by the SOMAscan assay was profiled in blood samples from 202 females from the TwinsUK cohort. Findings were replicated in 677 independent individuals from the AddNeuroMed, Alzheimer's Research UK, and Dementia Case Registry cohorts. Results were further validated using RNAseq data from whole blood in TwinsUK and the most significant proteins were tested for association with aging-related phenotypes after adjustment for age. Eleven proteins were associated with chronological age and were replicated at protein level in an independent population. These were further investigated at gene expression level in 384 females from the TwinsUK cohort. The two most strongly associated proteins were chordin-like protein 1 (meta-analysis beta [SE] = 0.013 [0.001], p = 3.66 x 10(-46)) and pleiotrophin (0.012 [0.005], p = 3.88 x 10(-41)). Chordin-like protein 1 was also significantly correlated with birthweight (0.06 [0.02], p = 0.005) and with the individual Framingham 10-years cardiovascular risk scores in TwinsUK (0.71 [0.18], p = 9.9 x 10(-5)). Pleiotrophin is a secreted growth factor with a plethora of functions in multiple tissues and known to be a marker for cardiovascular risk and osteoporosis. Our study highlights the importance of proteomics to identify some molecular mechanisms involved in human health and aging. | Menni, Cristina Kiddle, Steven J Mangino, Massimo Vinuela, Ana Psatha, Maria Steves, Claire Sattlecker, Martina Buil, Alfonso Newhouse, Stephen Nelson, Sally Williams, Stephen Voyle, Nicola Soininen, Hilkka Kloszewska, Iwona Mecocci, Patrizia Tsolaki, Magda Vellas, Bruno Lovestone, Simon Spector, Tim D Dobson, Richard Valdes, Ana M eng 171/ALZS_/Alzheimer's Society/United Kingdom G0801464/MRC_/Medical Research Council/United Kingdom MR/L011859/1/MRC_/Medical Research Council/United Kingdom MR/M004422/1/MRC_/Medical Research Council/United Kingdom Twin Study J Gerontol A Biol Sci Med Sci. 2015 Jul;70(7):809-16. doi: 10.1093/gerona/glu121. Epub 2014 Aug 14.I | 08/16/2014 | |
| A candidate plasma protein classifier to identify Alzheimer's disease | Zhao X, et al. | 2015 | J Alzheimers Dis | 43 | 2 | 549-63 | https://www.doi.org/10.3233/JAD-141149 | 25,114,072 | Aged Aged, 80 and over Alzheimer Disease/*blood/cerebrospinal fluid/*diagnosis Amyloid beta-Peptides/cerebrospinal fluid Area Under Curve Blood Proteins/*classification/*metabolism Female Humans Male Middle Aged Peptide Fragments/cerebrospinal fluid Predictive Value of Tests Principal Component Analysis Proteomics Reproducibility of Results tau Proteins/cerebrospinal fluid Alzheimer's disease aptamers biomarkers blood proteome | Biomarkers currently used in the aid for the diagnosis of Alzheimer's disease (AD) are cerebrospinal fluid (CSF) protein markers and brain neuroimaging markers. These biomarkers, however, either involve semi-invasive procedures or are costly to measure. Thus, AD biomarkers from more easily accessible body fluids, such as plasma, are very enticing. Using an aptamer-based proteomic technology, we profiled 1,129 plasma proteins of AD patients and non-demented control individuals. A 5-protein classifier for AD identification was constructed in the discovery study with excellent 10-fold cross-validation performance (90.1% sensitivity, 84.2% specificity, 87.9% accuracy, and AUC as 0.94). In an independent validation study, the classifier was applied and correctly predicted AD with 100.0% sensitivity, 80.0% specificity, and 90.0% accuracy, matching or outperforming the CSF Abeta42 and tau biomarkers whose performance were assessed in individual-matched CSF samples obtained at the same visit as plasma sample collection. Moreover, the classifier also correctly predicted mild cognitive impairment, an early pre-dementia state of the disease, with 96.7% sensitivity, 80.0% specificity, and 92.5% accuracy. These studies demonstrate that plasma proteins could be used effectively and accurately to contribute to the clinical diagnosis of AD. Although additional and more diverse cohorts are needed for further validation of the robustness, including the support of postmortem diagnosis, the 5-protein classifier appears to be a promising blood test to contribute diagnosis of AD. | Zhao, Xuemei Lejnine, Serguei Spond, Jeffrey Zhang, Chunsheng Ramaraj, T C Holder, Daniel J Dai, Hongyue Weiner, Russell Laterza, Omar F eng Research Support, Non-U.S. Gov't Netherlands J Alzheimers Dis. 2015;43(2):549-63. doi: 10.3233/JAD-141149.I | 08/13/2014 | |
| Improved preparation of 2_M triethylammonium bicarbonate | Carlson M, et al. | 2015 | Green Chem Lett Rev | 8 | 4 | 37-39 | https://www.doi.org/10.1080/17518253.2015.1091039 | The widely used chromatographic eluent, aqueous triethylammonium bicarbonate, can be efficiently prepared as 2 M stock solution by carbonation of a mixture of triethylamine and water in a commercially available pressure reactor (20–25 psi). This improved process reduces carbon dioxide waste emissions by ca. 90% compared to traditional gas bubbling at atmospheric pressure. | Carlson, M. Carter, J. D. Rohloff, J. | ||||
| DTC-and-Me: Patient, Provider, Proteins and Regulators | Steele FR, et al. | 2014 | J Pers Med | 4 | 1 | 79-87 | https://www.doi.org/10.3390/jpm4010079 | 25,562,144 | The yet-unrealized potential for more personalized" Direct-to-Consumer (DTC) tests to fundamentally alter the practice and economics of healthcare is undeniable. However, there are also many challenges to be met, including the herculean task of ensuring that the information provided by such tests is scientifically sound and, ideally, medically actionable. We consider recent events in DTC testing and suggest a "thought experiment" of an approach that could ultimately meet the needs of patients, providers and regulatory authorities." | Steele, Fintan R Gold, Larry eng Switzerland J Pers Med. 2014 Mar 18;4(1):79-87. doi: 10.3390/jpm4010079.I | 01/07/2015 | ||
| Nucleic Acid Ligands With Protein-like Side Chains: Modified Aptamers and Their Use as Diagnostic and Therapeutic Agents | Rohloff JC, et al. | 2014 | Mol Ther Nucleic Acids | 3 | 10 | e201 | https://www.doi.org/10.1038/mtna.2014.49 | 25,291,143 | Limited chemical diversity of nucleic acid libraries has long been suspected to be a major constraining factor in the overall success of SELEX (Systematic Evolution of Ligands by EXponential enrichment). Despite this constraint, SELEX has enjoyed considerable success over the past quarter of a century as a result of the enormous size of starting libraries and conformational richness of nucleic acids. With judicious introduction of functional groups absent in natural nucleic acids, the diversity gap" between nucleic acid-based ligands and protein-based ligands can be substantially bridged, to generate a new class of ligands that represent the best of both worlds. We have explored the effect of various functional groups at the 5-position of uracil and found that hydrophobic aromatic side chains have the most profound influence on the success rate of SELEX and allow the identification of ligands with very low dissociation rate constants (named Slow Off-rate Modified Aptamers or SOMAmers). Such modified nucleotides create unique intramolecular motifs and make direct contacts with proteins. Importantly, SOMAmers engage their protein targets with surfaces that have significantly more hydrophobic character compared with conventional aptamers, thereby increasing the range of epitopes that are available for binding. These improvements have enabled us to build a collection of SOMAmers to over 3,000 human proteins encompassing major families such as growth factors, cytokines, enzymes, hormones, and receptors, with additional SOMAmers aimed at pathogen and rodent proteins. Such a large and growing collection of exquisite affinity reagents expands the scope of possible applications in diagnostics and therapeutics." | Rohloff, John C Gelinas, Amy D Jarvis, Thale C Ochsner, Urs A Schneider, Daniel J Gold, Larry Janjic, Nebojsa eng Review Mol Ther Nucleic Acids. 2014 Oct 7;3(10):e201. doi: 10.1038/mtna.2014.49.I | 10/08/2014 | ||
| Validation of a blood protein signature for non-small cell lung cancer | Mehan MR, et al. | 2014 | Clin Proteomics | 11 | 1 | 32 | https://www.doi.org/10.1186/1559-0275-11-32 | 25,114,662 | Biomarker Diagnosis Lung cancer Preanalytic variability Proteomic SOMAmer Sample bias Squamous cell carcinoma | BACKGROUND: CT screening for lung cancer is effective in reducing mortality, but there are areas of concern, including a positive predictive value of 4% and development of interval cancers. A blood test that could manage these limitations would be useful, but development of such tests has been impaired by variations in blood collection that may lead to poor reproducibility across populations. RESULTS: Blood-based proteomic profiles were generated with SOMAscan technology, which measured 1033 proteins. First, preanalytic variability was evaluated with Sample Mapping Vectors (SMV), which are panels of proteins that detect confounders in protein levels related to sample collection. A subset of well collected serum samples not influenced by preanalytic variability was selected for discovery of lung cancer biomarkers. The impact of sample collection variation on these candidate markers was tested in the subset of samples with higher SMV scores so that the most robust markers could be used to create disease classifiers. The discovery sample set (n = 363) was from a multi-center study of 94 non-small cell lung cancer (NSCLC) cases and 269 long-term smokers and benign pulmonary nodule controls. The analysis resulted in a 7-marker panel with an AUC of 0.85 for all cases (68% adenocarcinoma, 32% squamous) and an AUC of 0.93 for squamous cell carcinoma in particular. This panel was validated by making blinded predictions in two independent cohorts (n = 138 in the first validation and n = 135 in the second). The model was recalibrated for a panel format prior to unblinding the second cohort. The AUCs overall were 0.81 and 0.77, and for squamous cell tumors alone were 0.89 and 0.87. The estimated negative predictive value for a 15% disease prevalence was 93% overall and 99% for squamous lung tumors. The proteins in the classifier function in destruction of the extracellular matrix, metabolic homeostasis and inflammation. CONCLUSIONS: Selecting biomarkers resistant to sample processing variation led to robust lung cancer biomarkers that performed consistently in independent validations. They form a sensitive signature for detection of lung cancer, especially squamous cell histology. This non-invasive test could be used to improve the positive predictive value of CT screening, with the potential to avoid invasive evaluation of nonmalignant pulmonary nodules. | Mehan, Michael R Williams, Stephen A Siegfried, Jill M Bigbee, William L Weissfeld, Joel L Wilson, David O Pass, Harvey I Rom, William N Muley, Thomas Meister, Michael Franklin, Wilbur Miller, York E Brody, Edward N Ostroff, Rachel M eng P50 CA058187/CA/NCI NIH HHS/ P50 CA090440/CA/NCI NIH HHS/ England Clin Proteomics. 2014 Aug 1;11(1):32. doi: 10.1186/1559-0275-11-32. eCollection 2014.I | 08/13/2014 | |
| Investigation of novel circulating proteins, germ line single-nucleotide polymorphisms, and molecular tumor markers as potential efficacy biomarkers of first-line sunitinib therapy for advanced renal cell carcinoma | Motzer RJ, et al. | 2014 | Cancer Chemother Pharmacol | 74 | 4 | 739-50 | https://www.doi.org/10.1007/s00280-014-2539-0 | 25,100,134 | Adult Angiogenesis Inhibitors/administration & dosage/adverse effects/pharmacokinetics Angiopoietin-2/*blood Antigens, Neoplasm/blood/genetics Biomarkers, Tumor/blood/genetics Carbonic Anhydrase IX Carbonic Anhydrases/blood/genetics *Carcinoma, Renal Cell/drug therapy/genetics/metabolism/pathology Disease-Free Survival Drug Administration Schedule Drug Monitoring/methods Drug Screening Assays, Antitumor Female Humans Hypoxia-Inducible Factor 1, alpha Subunit/blood/genetics *Indoles/administration & dosage/adverse effects/pharmacokinetics *Kidney Neoplasms/drug therapy/genetics/metabolism/pathology Male Matrix Metalloproteinase 2/*blood Polymorphism, Single Nucleotide Prognosis *Pyrroles/administration & dosage/adverse effects/pharmacokinetics Sunitinib Treatment Outcome Vascular Endothelial Growth Factor A/*genetics Vascular Endothelial Growth Factor Receptor-3/*genetics *Von Hippel-Lindau Tumor Suppressor Protein/blood/genetics | PURPOSE: Sunitinib is a first-line advanced renal cell carcinoma (RCC) standard of care. In a randomized phase II trial comparing sunitinib treatment schedules, separate exploratory biomarker analyses investigated the correlations of efficacy with selected serum, germ line single-nucleotide polymorphism (SNP), or tumor markers. METHODS: Advanced RCC patients received first-line sunitinib 50 mg/day on the approved 4-week-on-2-week-off schedule (n = 146) or 37.5 mg/day continuous dosing (n = 146). The following correlation analyses were performed: (1) response evaluation criteria in solid tumors-defined tumor response with serum soluble protein levels via two distinct multiplex (n < 1,000) platforms; (2) response and time-to-event outcomes with germ line SNPs in vascular endothelial growth factor (VEGF)-A and VEGF receptor (VEGFR)3 genes; and (3) response and time-to-event outcomes with tumor immunohistochemistry status for hypoxia-inducible factor 1-alpha (HIF-1alpha) and carbonic anhydrase-IX or tumor Von Hippel-Lindau (VHL) gene inactivation status. RESULTS: Lower baseline angiopoietin-2 (Ang-2) and higher baseline matrix metalloproteinase-2 (MMP-2) levels were identified by both platforms as statistically significantly associated with tumor response. There were no significant correlations between VEGF-A or VEGFR3 SNPs and outcomes. Progression-free survival was longer for HIF-1alpha percent of tumor expression groups 0-2 (HIF-1alpha low) versus 3-4 (HIF-1alpha high; p = 0.034). There were no significant correlations between outcomes and each VHL inactivation mechanism [mutation (86% of VHL-inactive patients), methylation (14%), and large deletion (7%)] or mechanisms combined. CONCLUSIONS: Serum Ang-2 and MMP-2 and tumor HIF-1alpha were identified as relevant baseline biomarkers of sunitinib activity in advanced RCC, warranting further research into their prognostic versus predictive value. | Motzer, Robert J Hutson, Thomas E Hudes, Gary R Figlin, Robert A Martini, Jean-Francois English, Patricia A Huang, Xin Valota, Olga Williams, J Andrew eng Clinical Trial, Phase II Multicenter Study Randomized Controlled Trial Research Support, Non-U.S. Gov't Germany Cancer Chemother Pharmacol. 2014 Oct;74(4):739-50. doi: 10.1007/s00280-014-2539-0. Epub 2014 Aug 7.I | 08/08/2014 | |
| Specific capture and detection of Staphylococcus aureus with high-affinity modified aptamers to cell surface components | Baumstummler A, et al. | 2014 | Lett Appl Microbiol | 59 | 4 | 422-31 | https://www.doi.org/10.1111/lam.12295 | 24,935,714 | Antibody Affinity Aptamers, Peptide/chemistry/*metabolism Bacterial Proteins/chemistry/*metabolism Cell Membrane/chemistry/*metabolism Gene Expression Regulation, Bacterial Protein Binding Sensitivity and Specificity Staphylococcus aureus/genetics/*metabolism Staphylococcus aureus aptamer cell capture cell surface protein A staining | Slow off-rate modified aptamer (SOMAmer) reagents were generated to several Staphylococcus aureus cell surface-associated proteins via SELEX with multiple modified DNA libraries using purified recombinant or native proteins. High-affinity binding agents with sub-nanomolar Kd 's were obtained for staphylococcal protein A (SpA), clumping factors (ClfA, ClfB), fibronectin-binding proteins (FnbA, FnbB) and iron-regulated surface determinants (Isd). Further screening revealed several SOMAmers that specifically bound to Staph. aureus cells from all strains that were tested, but not to other staphylococci or other bacteria. SpA and ClfA SOMAmers proved useful for the selective capture and enrichment of Staph. aureus cells, as shown by culture and PCR, leading to improved limits of detection and efficient removal of PCR inhibitors. Detection of Staph. aureus cells was enhanced by several orders of magnitude when the bacterial cell surface was coated with SOMAmers followed by qPCR of the SOMAmers. Furthermore, fluorescence-labelled SpA SOMAmers demonstrated their utility as direct detection agents in flow cytometry. Significance and impact of the study: Monitoring for microbial contamination of food, water, nonsterile products or the environment is typically based on culture, PCR or antibodies. Aptamers that bind with high specificity and affinity to well-conserved cell surface epitopes represent a promising novel type of reagents to detect bacterial cells without the need for culture or cell lysis, including for the capture and enrichment of bacteria present at low cell densities and for the direct detection via qPCR or fluorescent staining. | Baumstummler, A Lehmann, D Janjic, N Ochsner, U A eng Research Support, Non-U.S. Gov't England Lett Appl Microbiol. 2014 Oct;59(4):422-31. doi: 10.1111/lam.12295. Epub 2014 Jul 2.I | 06/18/2014 | |
| Genetic associations with micronutrient levels identified in immune and gastrointestinal networks | Morine MJ, et al. | 2014 | Genes Nutr | 9 | 4 | 408 | https://www.doi.org/10.1007/s12263-014-0408-4 | 24,879,315 | The discovery of vitamins and clarification of their role in preventing frank essential nutrient deficiencies occurred in the early 1900s. Much vitamin research has understandably focused on public health and the effects of single nutrients to alleviate acute conditions. The physiological processes for maintaining health, however, are complex systems that depend upon interactions between multiple nutrients, environmental factors, and genetic makeup. To analyze the relationship between these factors and nutritional health, data were obtained from an observational, community-based participatory research program of children and teens (age 6-14) enrolled in a summer day camp in the Delta region of Arkansas. Assessments of erythrocyte S-adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH), plasma homocysteine (Hcy) and 6 organic micronutrients (retinol, 25-hydroxy vitamin D3, pyridoxal, thiamin, riboflavin, and vitamin E), and 1,129 plasma proteins were performed at 3 time points in each of 2 years. Genetic makeup was analyzed with 1 M SNP genotyping arrays, and nutrient status was assessed with 24-h dietary intake questionnaires. A pattern of metabolites (met_PC1) that included the ratio of erythrocyte SAM/SAH, Hcy, and 5 vitamins were identified by principal component analysis. Met_PC1 levels were significantly associated with (1) single-nucleotide polymorphisms, (2) levels of plasma proteins, and (3) multilocus genotypes coding for gastrointestinal and immune functions, as identified in a global network of metabolic/protein-protein interactions. Subsequent mining of data from curated pathway, network, and genome-wide association studies identified genetic and functional relationships that may be explained by gene-nutrient interactions. The systems nutrition strategy described here has thus associated a multivariate metabolite pattern in blood with genes involved in immune and gastrointestinal functions. | Morine, Melissa J Monteiro, Jacqueline Pontes Wise, Carolyn Teitel, Candee Pence, Lisa Williams, Anna Ning, Baitang McCabe-Sellers, Beverly Champagne, Catherine Turner, Jerome Shelby, Beatrice Bogle, Margaret Beger, Richard D Priami, Corrado Kaput, Jim eng Germany Genes Nutr. 2014 Jul;9(4):408. doi: 10.1007/s12263-014-0408-4. Epub 2014 May 31.I | 06/01/2014 | ||
| Alzheimer's disease biomarker discovery using SOMAscan multiplexed protein technology | Sattlecker M, et al. | 2014 | Alzheimers Dement | 10 | 6 | 724-34 | https://www.doi.org/10.1016/j.jalz.2013.09.016 | 24,768,341 | Aged Aged, 80 and over Alzheimer Disease/*blood Atrophy/etiology Biomarkers/*blood Blood Proteins/*metabolism Brain/pathology Cognitive Dysfunction/blood Cohort Studies Female Humans Logistic Models *Magnetic Resonance Imaging Male *Proteomics ROC Curve Alzheimer's disease Blood biomarkers Proteins Rate of progression SOMAscan sMRI | Blood proteins and their complexes have become the focus of a great deal of interest in the context of their potential as biomarkers of Alzheimer's disease (AD). We used a SOMAscan assay for quantifying 1001 proteins in blood samples from 331 AD, 211 controls, and 149 mild cognitive impaired (MCI) subjects. The strongest associations of protein levels with AD outcomes were prostate-specific antigen complexed to alpha1-antichymotrypsin (AD diagnosis), pancreatic prohormone (AD diagnosis, left entorhinal cortex atrophy, and left hippocampus atrophy), clusterin (rate of cognitive decline), and fetuin B (left entorhinal atrophy). Multivariate analysis found that a subset of 13 proteins predicted AD with an accuracy of area under the curve of 0.70. Our replication of previous findings provides further evidence that levels of these proteins in plasma are truly associated with AD. The newly identified proteins could be potential biomarkers and are worthy of further investigation. | Sattlecker, Martina Kiddle, Steven J Newhouse, Stephen Proitsi, Petroula Nelson, Sally Williams, Stephen Johnston, Caroline Killick, Richard Simmons, Andrew Westman, Eric Hodges, Angela Soininen, Hilkka Kloszewska, Iwona Mecocci, Patrizia Tsolaki, Magda Vellas, Bruno Lovestone, Simon Dobson, Richard J B eng 167/ALZS_/Alzheimer's Society/United Kingdom 171/ALZS_/Alzheimer's Society/United Kingdom G0801464/MRC_/Medical Research Council/United Kingdom MR/L011859/1/MRC_/Medical Research Council/United Kingdom Research Support, Non-U.S. Gov't Alzheimers Dement. 2014 Nov;10(6):724-34. doi: 10.1016/j.jalz.2013.09.016. Epub 2014 Apr 25.I | 04/29/2014 | |
| Methylation potential associated with diet, genotype, protein, and metabolite levels in the Delta Obesity Vitamin Study | Monteiro JP, et al. | 2014 | Genes Nutr | 9 | 3 | 403 | https://www.doi.org/10.1007/s12263-014-0403-9 | 24,760,553 | Micronutrient research typically focuses on analyzing the effects of single or a few nutrients on health by analyzing a limited number of biomarkers. The observational study described here analyzed micronutrients, plasma proteins, dietary intakes, and genotype using a systems approach. Participants attended a community-based summer day program for 6-14 year old in 2 years. Genetic makeup, blood metabolite and protein levels, and dietary differences were measured in each individual. Twenty-four-hour dietary intakes, eight micronutrients (vitamins A, D, E, thiamin, folic acid, riboflavin, pyridoxal, and pyridoxine) and 3 one-carbon metabolites [homocysteine (Hcy), S-adenosylmethionine (SAM), and S-adenosylhomocysteine (SAH)], and 1,129 plasma proteins were analyzed as a function of diet at metabolite level, plasma protein level, age, and sex. Cluster analysis identified two groups differing in SAM/SAH and differing in dietary intake patterns indicating that SAM/SAH was a potential marker of nutritional status. The approach used to analyze genetic association with the SAM/SAH metabolites is called middle-out: SNPs in 275 genes involved in the one-carbon pathway (folate, pyridoxal/pyridoxine, thiamin) or were correlated with SAM/SAH (vitamin A, E, Hcy) were analyzed instead of the entire 1M SNP data set. This procedure identified 46 SNPs in 25 genes associated with SAM/SAH demonstrating a genetic contribution to the methylation potential. Individual plasma metabolites correlated with 99 plasma proteins. Fourteen proteins correlated with body mass index, 49 with group age, and 30 with sex. The analytical strategy described here identified subgroups for targeted nutritional interventions. | Monteiro, Jacqueline Pontes Wise, Carolyn Morine, Melissa J Teitel, Candee Pence, Lisa Williams, Anna McCabe-Sellers, Beverly Champagne, Catherine Turner, Jerome Shelby, Beatrice Ning, Baitang Oguntimein, Joan Taylor, Lauren Toennessen, Terri Priami, Corrado Beger, Richard D Bogle, Margaret Kaput, Jim eng Germany Genes Nutr. 2014 May;9(3):403. doi: 10.1007/s12263-014-0403-9. Epub 2014 Apr 24.I | 04/25/2014 | ||
| Systematic selection of modified aptamer pairs for diagnostic sandwich assays | Ochsner UA, et al. | 2014 | Biotechniques | 56 | 3 | 125-8, 130, 132-3 | https://www.doi.org/10.2144/000114134 | 24,641,476 | Affinity Labels/chemistry *Aptamers, Nucleotide/chemistry Humans Molecular Diagnostic Techniques Protein Binding Proteins/chemistry/*isolation & purification Recombinant Proteins/chemistry/isolation & purification SELEX Aptamer Technique/*methods Selex aptamer diagnostics epitope selection modified nucleotides sandwich assay | Protein diagnostic applications typically require pairs of analyte-specific reagents for capture and detection. We developed methods for the systematic isolation of slow off-rate modified aptamer (SOMAmer) reagents that bind to different epitopes and allow efficient pair-wise screening of multiple ligands. SOMAmers were generated via a second systematic evolution of ligands by exponential enrichment (SELEX), using complexes of target proteins with a primary, non-amplifiable SOMAmer and employing different modified nucleotides (e.g., naphthylmethyl- or tryptaminocarbonyl-dU) to favor alternate binding epitopes. Non-competing binding of primary and secondary SOMAmers was tested in radiolabel competition and sandwich binding assays. Multiplexed high-throughput screening for sandwich pairs utilized the Luminex platform, with primary SOMAmers as capture agents attached to different types of LumAvidin beads, which were then pooled for testing the secondary SOMAmers individually as detection agents. Functional SOMAmer pairs were obtained for Clostridium difficile binary toxin (CdtA) and for a panel of human proteins (ANGPT2, TSP2, CRDL1, MATN2, GPVI, C7, PLG) that had been previously identified as promising markers for cardiovascular risk. The equilibrium dissociation constants (Kd values) ranged from 0.02-2.7 nM, and the detection limits were in the low picomolar range for these proteins in SOMAmer sandwich assays. These results indicate that SOMAmer pairs hold promise for the development of rapid tests or specific diagnostic panels. | Ochsner, Urs A Green, Louis S Gold, Larry Janjic, Nebojsa eng England Biotechniques. 2014 Mar 1;56(3):125-8, 130, 132-3. doi: 10.2144/000114134. eCollection 2014.I | 03/20/2014 | |
| Aptamer-based proteomic signature of intensive phase treatment response in pulmonary tuberculosis | Nahid P, et al. | 2014 | Tuberculosis (Edinb) | 94 | 3 | 187-96 | https://www.doi.org/10.1016/j.tube.2014.01.006 | 24,629,635 | Adult Antitubercular Agents/*therapeutic use Bacterial Proteins/*metabolism Biomarkers/metabolism Drug Therapy, Combination Female Humans Male Middle Aged Pilot Projects Prospective Studies Proteomics/methods SELEX Aptamer Technique/methods Treatment Outcome Tuberculosis, Pulmonary/blood/*drug therapy Young Adult Biomarkers Logistic regression model Multiplex analysis Proteomics SOMAscan Treatment response Tuberculosis of SomaLogic. MAD is a paid SomaLogic consultant. | BACKGROUND: New drug regimens of greater efficacy and shorter duration are needed for tuberculosis (TB) treatment. The identification of accurate, quantitative, non-culture based markers of treatment response would improve the efficiency of Phase 2 TB drug testing. METHODS: In an unbiased biomarker discovery approach, we applied a highly multiplexed, aptamer-based, proteomic technology to analyze serum samples collected at baseline and after 8 weeks of treatment from 39 patients with pulmonary TB from Kampala, Uganda enrolled in a Centers for Disease Control and Prevention (CDC) TB Trials Consortium Phase 2B treatment trial. RESULTS: We identified protein expression differences associated with 8-week culture status, including Coagulation Factor V, SAA, XPNPEP1, PSME1, IL-11 Ralpha, HSP70, Galectin-8, alpha2-Antiplasmin, ECM1, YES, IGFBP-1, CATZ, BGN, LYNB, and IL-7. Markers noted to have differential changes between responders and slow-responders included nectin-like protein 2, EphA1 (Ephrin type-A receptor 1), gp130, CNDP1, TGF-b RIII, MRC2, ADAM9, and CDON. A logistic regression model combining markers associated with 8-week culture status revealed an ROC curve with AUC = 0.96, sensitivity = 0.95 and specificity = 0.90. Additional markers showed differential changes between responders and slow-responders (nectin-like protein), or correlated with time-to-culture-conversion (KLRK1). CONCLUSIONS: Serum proteins involved in the coagulation cascade, neutrophil activity, immunity, inflammation, and tissue remodeling were found to be associated with TB treatment response. A quantitative, non-culture based, five-marker signature predictive of 8-week culture status was identified in this pilot study. | Nahid, Payam Bliven-Sizemore, Erin Jarlsberg, Leah G De Groote, Mary A Johnson, John L Muzanyi, Grace Engle, Melissa Weiner, Marc Janjic, Nebojsa Sterling, David G Ochsner, Urs A eng R01 AI104589/AI/NIAID NIH HHS/ 1R01AI104589/AI/NIAID NIH HHS/ Clinical Trial, Phase II Multicenter Study Randomized Controlled Trial Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S. Scotland Tuberculosis (Edinb). 2014 May;94(3):187-96. doi: 10.1016/j.tube.2014.01.006. Epub 2014 Feb 7.I | 03/19/2014 | |
| Proteomics analysis of cancer exosomes using a novel modified aptamer-based array (SOMAscan) platform | Webber J, et al. | 2014 | Mol Cell Proteomics | 13 | 4 | 1050-64 | https://www.doi.org/10.1074/mcp.M113.032136 | 24,505,114 | Biomarkers, Tumor/metabolism Cell Line, Tumor Exosomes/genetics/*metabolism Genes, Essential Humans Male Microarray Analysis/*methods Nanotechnology Prostatic Neoplasms/*metabolism Proteomics/*methods | We have used a novel affinity-based proteomics technology to examine the protein signature of small secreted extracellular vesicles called exosomes. The technology uses a new class of protein binding reagents called SOMAmers(R) (slow off-rate modified aptamers) and allows the simultaneous precise measurement of over 1000 proteins. Exosomes were highly purified from the Du145 prostate cancer cell line, by pooling selected fractions from a continuous sucrose gradient (within the density range of 1.1 to 1.2 g/ml), and examined under standard conditions or with additional detergent treatment by the SOMAscan array (version 3.0). Lysates of Du145 cells were also prepared, and the profiles were compared. Housekeeping proteins such as cyclophilin-A, LDH, and Hsp70 were present in exosomes, and we identified almost 100 proteins that were enriched in exosomes relative to cells. These included proteins of known association with cancer exosomes such as MFG-E8, integrins, and MET, and also those less widely reported as exosomally associated, such as ROR1 and ITIH4. Several proteins with no previously known exosomal association were confirmed as exosomally expressed in experiments using individual SOMAmer(R) reagents or antibodies in micro-plate assays. Western blotting confirmed the SOMAscan-identified enrichment of exosomal NOTCH-3, L1CAM, RAC1, and ADAM9. In conclusion, we describe here over 300 proteins of hitherto unknown association with prostate cancer exosomes and suggest that the SOMAmer(R)-based assay technology is an effective proteomics platform for exosome-associated biomarker discovery in diverse clinical settings. | Webber, Jason Stone, Timothy C Katilius, Evaldas Smith, Breanna C Gordon, Bridget Mason, Malcolm D Tabi, Zsuzsanna Brewis, Ian A Clayton, Aled eng G2012-03/PCUK_/Prostate Cancer UK/United Kingdom CRUK_/Cancer Research UK/United Kingdom Research Support, Non-U.S. Gov't Mol Cell Proteomics. 2014 Apr;13(4):1050-64. doi: 10.1074/mcp.M113.032136. Epub 2014 Feb 6.I | 02/08/2014 | |
| Crystal structure of interleukin-6 in complex with a modified nucleic acid ligand | Gelinas AD, et al. | 2014 | J Biol Chem | 289 | 12 | 8720-34 | https://www.doi.org/10.1074/jbc.M113.532697 | 24,415,767 | Aptamers, Nucleotide/*chemistry/*pharmacology Crystallography, X-Ray Drug Discovery Humans Interleukin-6/*chemistry/*metabolism Ligands Models, Molecular Protein Conformation Recombinant Proteins/chemistry/metabolism SELEX Aptamer Technique Aptamers DNA Structure G-quartet Interleukin Molecular Evolution Nucleic Acid Chemistry Protein-Nucleic Acid Interaction Selex | IL-6 is a secreted cytokine that functions through binding two cell surface receptors, IL-6Ralpha and gp130. Because of its involvement in the progression of several chronic inflammatory diseases, IL-6 is a target of pharmacologic interest. We have recently identified a novel class of ligands called SOMAmers (S low Off-rate Modified Aptamers) that bind IL-6 and inhibit its biologic activity. SOMAmers exploit the chemical diversity of protein-like side chains assembled on flexible nucleic acid scaffolds, resulting in an expanded repertoire of intra- and intermolecular interactions not achievable with conventional aptamers. Here, we report the co-crystal structure of a high affinity SOMAmer (Kd = 0.20 nm) modified at the 5-position of deoxyuridine in a complex with IL-6. The SOMAmer, comprised of a G-quartet domain and a stem-loop domain, engages IL-6 in a clamp-like manner over an extended surface exhibiting close shape complementarity with the protein. The interface is characterized by substantial hydrophobic interactions overlapping the binding surfaces of the IL-6Ralpha and gp130 receptors. The G-quartet domain retains considerable binding activity as a disconnected autonomous fragment (Kd = 270 nm). A single substitution from our diversely modified nucleotide library leads to a 37-fold enhancement in binding affinity of the G-quartet fragment (Kd = 7.4 nm). The ability to probe ligand surfaces in this manner is a powerful tool in the development of new therapeutic reagents with improved pharmacologic properties. The SOMAmer.IL-6 structure also expands our understanding of the diverse structural motifs achievable with modified nucleic acid libraries and elucidates the nature with which these unique ligands interact with their protein targets. | Gelinas, Amy D Davies, Douglas R Edwards, Thomas E Rohloff, John C Carter, Jeffrey D Zhang, Chi Gupta, Shashi Ishikawa, Yuichi Hirota, Masao Nakaishi, Yuichiro Jarvis, Thale C Janjic, Nebojsa eng J Biol Chem. 2014 Mar 21;289(12):8720-34. doi: 10.1074/jbc.M113.532697. Epub 2014 Jan 12.I | 01/15/2014 | |
| Chemically modified DNA aptamers bind interleukin-6 with high affinity and inhibit signaling by blocking its interaction with interleukin-6 receptor | Gupta S, et al. | 2014 | J Biol Chem | 289 | 12 | 8706-19 | https://www.doi.org/10.1074/jbc.M113.532580 | 24,415,766 | Amino Acid Sequence Animals Anti-Inflammatory Agents/chemistry/metabolism/*pharmacology Aptamers, Nucleotide/chemistry/metabolism/*pharmacology Base Sequence CHO Cells Cricetulus Drug Discovery Humans Interleukin-6/*antagonists & inhibitors/chemistry/*immunology/metabolism Macaca fascicularis Mice Molecular Sequence Data Rats Receptors, Interleukin-6/*immunology SELEX Aptamer Technique/methods Serum/metabolism Aptamers Cell Signaling Interleukin Molecular Evolution Nuclease Stability Nucleic Acid Chemistry Protein-DNA Interaction Selex SOMAmer | Interleukin-6 (IL-6) is a pleiotropic cytokine that regulates immune and inflammatory responses, and its overproduction is a hallmark of inflammatory diseases. Inhibition of IL-6 signaling with the anti-IL-6 receptor antibody tocilizumab has provided some clinical benefit to patients; however, direct cytokine inhibition may be a more effective option. We used the systematic evolution of ligands by exponential enrichment (SELEX) process to discover slow off-rate modified aptamers (SOMAmers) with hydrophobic base modifications that inhibit IL-6 signaling in vitro. Two classes of IL-6 SOMAmers were isolated from modified DNA libraries containing 40 random positions and either 5-(N-benzylcarboxamide)-2'-deoxyuridine (Bn-dU) or 5-[N-(1-naphthylmethyl)carboxamide]-2'-deoxyuridine (Nap-dU) replacing dT. These modifications facilitate the high affinity binding interaction with IL-6 and provide resistance against degradation by serum endonucleases. Post-SELEX optimization of one Bn-dU and one Nap-dU SOMAmer led to improvements in IL-6 binding (10-fold) and inhibition activity (greater than 20-fold), resulting in lead SOMAmers with sub-nanomolar affinity (Kd = 0.2 nm) and potency (IC50 = 0.2 nm). Although similar in inhibition properties, the two SOMAmers have unique sequences and different ortholog specificities. Furthermore, these SOMAmers were stable in human serum in vitro for more than 48 h. Both SOMAmers prevented IL-6 signaling by blocking the interaction of IL-6 with its receptor and inhibited the proliferation of tumor cells in vitro as effectively as tocilizumab. This new class of IL-6 inhibitor may be an effective therapeutic alternative for patients suffering from inflammatory diseases. | Gupta, Shashi Hirota, Masao Waugh, Sheela M Murakami, Ikuo Suzuki, Tomoki Muraguchi, Masahiro Shibamori, Masafumi Ishikawa, Yuichi Jarvis, Thale C Carter, Jeffrey D Zhang, Chi Gawande, Bharat Vrkljan, Michael Janjic, Nebojsa Schneider, Daniel J eng J Biol Chem. 2014 Mar 21;289(12):8706-19. doi: 10.1074/jbc.M113.532580. Epub 2014 Jan 12.I | 01/15/2014 | |
| Beyond antibodies: new affinity reagents to unlock the proteome | Lollo B, et al. | 2014 | Proteomics | 14 | 6 | 638-44 | https://www.doi.org/10.1002/pmic.201300187 | 24,395,722 | Animals Antibodies/analysis Aptamers, Nucleotide/*chemistry Humans Protein Array Analysis/methods Proteome/*analysis Proteomics/*methods Aptamer Biomarker Protein arrays SOMAmer SOMAscan | Antibodies have been the workhorse reagents of protein capture and quantification since their 1959 debut in the RIAs developed by Yalow and Berson. However, there are technical challenges to the use of antibodies in highly multiplexed arrays aimed at measuring hundreds or even thousands of proteins at one time. We describe here a recently developed class of synthetic protein-binding reagents (slow off-rate modified aptamer). We discuss the chemical makeup and protein binding specifications of slow off-rate modified aptamer reagents, compare them to traditional aptamers and antibodies, briefly describe the novel proteomic assay that takes advantage of their unique properties, and provide several examples of their multiple applications to biomarker discovery and validation across a range of biomedical science questions. | Lollo, Bridget Steele, Fintan Gold, Larry eng Germany Proteomics. 2014 Mar;14(6):638-44. doi: 10.1002/pmic.201300187. Epub 2014 Feb 20.I | 01/08/2014 | |
| Candidate blood proteome markers of Alzheimer's disease onset and progression: a systematic review and replication study | Kiddle SJ, et al. | 2014 | J Alzheimers Dis | 38 | 3 | 515-31 | https://www.doi.org/10.3233/JAD-130380 | 24,121,966 | Alzheimer Disease/*blood/*diagnosis Biomarkers/*blood Blood Proteins/*metabolism Disease Progression Humans Proteome Alzheimer's disease biomarkers blood magnetic resonance imaging nucleotide aptamers | A blood-based protein biomarker, or set of protein biomarkers, that could predict onset and progression of Alzheimer's disease (AD) would have great utility; potentially clinically, but also for clinical trials and especially in the selection of subjects for preventative trials. We reviewed a comprehensive list of 21 published discovery or panel-based (> 100 proteins) blood proteomics studies of AD, which had identified a total of 163 candidate biomarkers. Few putative blood-based protein biomarkers replicate in independent studies but we found that some proteins do appear in multiple studies; for example, four candidate biomarkers are found to associate with AD-related phenotypes in five independent research cohorts in these 21 studies: alpha-1-antitrypsin, alpha-2-macroglobulin, apolipoprotein E, and complement C3. Using SomaLogic's SOMAscan proteomics technology, we were able to conduct a large-scale replication study for 94 of the 163 candidate biomarkers from these 21 published studies in plasma samples from 677 subjects from the AddNeuroMed (ANM) and the Alzheimer's Research UK/Maudsley BRC Dementia Case Registry at King's Health Partners (ARUK/DCR) research cohorts. Nine of the 94 previously reported candidates were found to associate with AD-related phenotypes (False Discovery Rate (FDR) q-value < 0.1). These proteins show sufficient replication to be considered for further investigation as a biomarker set. Overall, we show that there are some signs of a replicable signal in the range of proteins identified in previous studies and we are able to further replicate some of these. This suggests that AD pathology does affect the blood proteome with some consistency. | Kiddle, Steven J Sattlecker, Martina Proitsi, Petroula Simmons, Andrew Westman, Eric Bazenet, Chantal Nelson, Sally K Williams, Stephen Hodges, Angela Johnston, Caroline Soininen, Hilkka Kloszewska, Iwona Mecocci, Patrizia Tsolaki, Magda Vellas, Bruno Newhouse, Stephen Lovestone, Simon Dobson, Richard J B eng 171/ALZS_/Alzheimer's Society/United Kingdom MR/L011859/1/MRC_/Medical Research Council/United Kingdom Research Support, Non-U.S. Gov't Review Systematic Review Netherlands J Alzheimers Dis. 2014;38(3):515-31. doi: 10.3233/JAD-130380.I | 10/15/2013 | |
| Interaction with both ZNRF3 and LGR4 is required for the signalling activity of R-spondin | Xie Y, et al. | 2013 | EMBO Rep | 14 | 12 | 1120-6 | https://www.doi.org/10.1038/embor.2013.167 | 24,165,923 | Amino Acid Motifs Binding Sites HEK293 Cells Humans Protein Binding Receptors, G-Protein-Coupled/*metabolism Thrombospondins/chemistry/*metabolism Ubiquitin-Protein Ligases/*metabolism *Wnt Signaling Pathway | R-spondin proteins sensitize cells to Wnt signalling and act as potent stem cell growth factors. Various membrane proteins have been proposed as potential receptors of R-spondin, including LGR4/5, membrane E3 ubiquitin ligases ZNRF3/RNF43 and several others proteins. Here, we show that R-spondin interacts with ZNRF3/RNF43 and LGR4 through distinct motifs. Both LGR4 and ZNRF3 binding motifs are required for R-spondin-induced LGR4/ZNRF3 interaction, membrane clearance of ZNRF3 and activation of Wnt signalling. Importantly, Wnt-inhibitory activity of ZNRF3, but not of a ZNRF3 mutant with reduced affinity to R-spondin, can be strongly suppressed by R-spondin, suggesting that R-spondin primarily functions by binding and inhibiting ZNRF3. Together, our results support a dual receptor model of R-spondin action, where LGR4/5 serve as the engagement receptor whereas ZNRF3/RNF43 function as the effector receptor. | Xie, Yang Zamponi, Raffaella Charlat, Olga Ramones, Melissa Swalley, Susanne Jiang, Xiaomo Rivera, Daniel Tschantz, William Lu, Bo Quinn, Lisa Dimitri, Chris Parker, Jefferson Jeffery, Doug Wilcox, Sheri K Watrobka, Mike LeMotte, Peter Granda, Brian Porter, Jeffrey A Myer, Vic E Loew, Andreas Cong, Feng eng England EMBO Rep. 2013 Dec;14(12):1120-6. doi: 10.1038/embor.2013.167. Epub 2013 Oct 29.I | 10/30/2013 | |
| Measurement of cetuximab and panitumumab-unbound serum EGFR extracellular domain using an assay based on slow off-rate modified aptamer (SOMAmer) reagents | Park NJ, et al. | 2013 | PLoS One | 8 | 8 | e71703 | https://www.doi.org/10.1371/journal.pone.0071703 | 23,990,977 | Antibodies, Monoclonal/administration & dosage/*metabolism Antibodies, Monoclonal, Humanized/administration & dosage/*metabolism Antineoplastic Agents/administration & dosage/metabolism Aptamers, Nucleotide/genetics/metabolism Binding Sites Binding, Competitive Biomarkers/blood Cetuximab Clinical Laboratory Techniques/*methods Enzyme-Linked Immunosorbent Assay ErbB Receptors/antagonists & inhibitors/*blood/metabolism Humans Panitumumab Polymerase Chain Reaction Receptor, ErbB-2/antagonists & inhibitors/blood/metabolism Receptor, ErbB-3/antagonists & inhibitors/blood/metabolism Receptor, ErbB-4 Reproducibility of Results | BACKGROUND: Response to cetuximab (Erbitux(R)) and panitumumab (Vectibix(R)) varies among individuals, and even those who show response ultimately gain drug resistance. One possible etiologic factor is differential interaction between the drug and target. We describe the development of an assay based on Slow Off-rate Modified Aptamer (SOMAmer()) reagents that can distinguish drug-bound from unbound epidermal growth factor receptor (EGFR). METHODS: This quantitative assay uses a SOMAmer reagent specific for EGFR extracellular domain (ECD) as a capturing reagent. Captured SOMAmer is quantitated using PCR. Linearity and accuracy (recovery) of the assay were assessed using normal sera and purified EGFR ECD. RESULTS: This EGFR ECD assay showed linearity between 2.5 and 600 ng/mL. Average recovery was 101%. The assay detected EGFR but showed little cross-reactivity to other ErbB proteins: 0.4% for ErbB2, 6.9% for ErbB3, and 1.3% for ErbB4. Preincubation of normal serum with either cetuximab or panitumumab resulted in a dose-dependent decrease in EGFR ECD levels measured using the SOMAmer assay; preincubation did not affect measurement with an ELISA. CONCLUSIONS: This SOMAmer-based serum EGFR ECD assay accurately and specifically measures EGFR in serum. Detection of significant amounts of drug-unbound EGFR in patients undergoing cetuximab or panitumumab treatment could be an indicator of poor drug response. Further studies are needed to evaluate the utility of the assay as an indicator of drug efficacy or as a guide to dosing. | Park, Noh Jin Wang, Xiuqiang Diaz, Angelica Goos-Root, Dana M Bock, Christopher Vaught, Jonathan D Sun, Weimin Strom, Charles M eng PLoS One. 2013 Aug 21;8(8):e71703. doi: 10.1371/journal.pone.0071703. eCollection 2013.I | 08/31/2013 | |
| Detection of Clostridium difficile toxins A, B and binary toxin with slow off-rate modified aptamers | Ochsner UA, et al. | 2013 | Diagn Microbiol Infect Dis | 76 | 3 | 278-85 | https://www.doi.org/10.1016/j.diagmicrobio.2013.03.029 | 23,680,240 | Aptamers, Nucleotide Bacterial Proteins/analysis/*chemistry/metabolism Clostridioides difficile/*metabolism Culture Media, Conditioned/analysis Enterocolitis, Pseudomembranous/diagnosis/microbiology Enterotoxins/analysis/*chemistry/metabolism Enzyme-Linked Immunosorbent Assay Humans Limit of Detection Peptide Fragments/chemistry Protein Binding SELEX Aptamer Technique | Rapid and accurate diagnostic tests for Clostridium difficile infections (CDI) are crucial for management of patients with suspected CDI and for infection control. Enzyme immunoassays for detection of the toxins are routinely used but lack adequate sensitivity. We generated slow off-rate modified aptamers (SOMAmer reagents) via in vitro selection (SELEX) that bind toxins A, B and binary toxin with high affinity and specificity. Using SOMAmers alone or in conjunction with antibodies, we have developed toxin assays with a 1 pmol/L (300 pg/mL) limit of detection and a 3 log dynamic range. SOMAmers proved useful as capture or detection agents in equilibrium solution binding radioassays, pull-down capture assays, dot blots, and plate- or membrane-based sandwich assays, thus represent a promising alternative to antibodies in diagnostic applications. SOMAmers detected toxins A, B and binary toxin in culture supernatants from toxigenic C. difficile, including a BI/NAP1 strain and historic strains. | Ochsner, Urs A Katilius, Evaldas Janjic, Nebojsa eng Research Support, Non-U.S. Gov't Diagn Microbiol Infect Dis. 2013 Jul;76(3):278-85. doi: 10.1016/j.diagmicrobio.2013.03.029. Epub 2013 May 13.I | 05/18/2013 | |
| Growth differentiation factor 11 is a circulating factor that reverses age-related cardiac hypertrophy | Loffredo FS, et al. | 2013 | Cell | 153 | 4 | 828-39 | https://www.doi.org/10.1016/j.cell.2013.04.015 | 23,663,781 | *Aging Animals Blood Pressure Bone Morphogenetic Proteins/*metabolism Cardiomegaly/*metabolism Female Forkhead Transcription Factors/metabolism Growth Differentiation Factors/*metabolism Humans Hypertrophy, Left Ventricular/metabolism Induced Pluripotent Stem Cells/cytology/metabolism Male Mice Mice, Inbred C57BL Myocytes, Cardiac/cytology/*metabolism *Parabiosis | The most common form of heart failure occurs with normal systolic function and often involves cardiac hypertrophy in the elderly. To clarify the biological mechanisms that drive cardiac hypertrophy in aging, we tested the influence of circulating factors using heterochronic parabiosis, a surgical technique in which joining of animals of different ages leads to a shared circulation. After 4 weeks of exposure to the circulation of young mice, cardiac hypertrophy in old mice dramatically regressed, accompanied by reduced cardiomyocyte size and molecular remodeling. Reversal of age-related hypertrophy was not attributable to hemodynamic or behavioral effects of parabiosis, implicating a blood-borne factor. Using modified aptamer-based proteomics, we identified the TGF-beta superfamily member GDF11 as a circulating factor in young mice that declines with age. Treatment of old mice to restore GDF11 to youthful levels recapitulated the effects of parabiosis and reversed age-related hypertrophy, revealing a therapeutic opportunity for cardiac aging. | Loffredo, Francesco S Steinhauser, Matthew L Jay, Steven M Gannon, Joseph Pancoast, James R Yalamanchi, Pratyusha Sinha, Manisha Dall'Osso, Claudia Khong, Danika Shadrach, Jennifer L Miller, Christine M Singer, Britta S Stewart, Alex Psychogios, Nikolaos Gerszten, Robert E Hartigan, Adam J Kim, Mi-Jeong Serwold, Thomas Wagers, Amy J Lee, Richard T eng 5U01 HL100402/HL/NHLBI NIH HHS/ 1R01 AG033053/AG/NIA NIH HHS/ K99 HL112905/HL/NHLBI NIH HHS/ 1R01 AG040019/AG/NIA NIH HHS/ DP2 OD004345/OD/NIH HHS/ R00 HL112905/HL/NHLBI NIH HHS/ 1DP2 OD004345/OD/NIH HHS/ K08 DK090147/DK/NIDDK NIH HHS/ P30DK036836/DK/NIDDK NIH HHS/ R01 AG033053/AG/NIA NIH HHS/ R01 AG032977/AG/NIA NIH HHS/ HHMI/Howard Hughes Medical Institute/ R01 AG040019/AG/NIA NIH HHS/ U01 HL100402/HL/NHLBI NIH HHS/ P30 DK036836/DK/NIDDK NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Cell. 2013 May 9;153(4):828-39. doi: 10.1016/j.cell.2013.04.015.I | 05/15/2013 | |
| Elucidating novel serum biomarkers associated with pulmonary tuberculosis treatment | De Groote MA, et al. | 2013 | PLoS One | 8 | 4 | e61002 | https://www.doi.org/10.1371/journal.pone.0061002 | 23,637,781 | Adult Biomarkers/*blood C-Reactive Protein/metabolism Female Humans Male Middle Aged Phospholipases A2/blood Proteomics Serum Amyloid A Protein/metabolism Tuberculosis, Pulmonary/*therapy | In an unbiased approach to biomarker discovery, we applied a highly multiplexed proteomic technology (SOMAscan, SomaLogic, Inc, Boulder, CO) to understand changes in proteins from paired serum samples at enrollment and after 8 weeks of TB treatment from 39 patients with pulmonary TB from Kampala, Uganda enrolled in the Center for Disease Control and Prevention's Tuberculosis Trials Consortium (TBTC) Study 29. This work represents the first large-scale proteomic analysis employing modified DNA aptamers in a study of active tuberculosis (TB). We identified multiple proteins that exhibit significant expression differences during the intensive phase of TB therapy. There was enrichment for proteins in conserved networks of biological processes and function including antimicrobial defense, tissue healing and remodeling, acute phase response, pattern recognition, protease/anti-proteases, complement and coagulation cascade, apoptosis, immunity and inflammation pathways. Members of cytokine pathways such as interferon-gamma, while present, were not as highly represented as might have been predicted. The top proteins that changed between baseline and 8 weeks of therapy were TSP4, TIMP-2, SEPR, MRC-2, Antithrombin III, SAA, CRP, NPS-PLA2, LEAP-1, and LBP. The novel proteins elucidated in this work may provide new insights for understanding TB disease, its treatment and subsequent healing processes that occur in response to effective therapy. | De Groote, Mary A Nahid, Payam Jarlsberg, Leah Johnson, John L Weiner, Marc Muzanyi, Grace Janjic, Nebojsa Sterling, David G Ochsner, Urs A eng Research Support, Non-U.S. Gov't PLoS One. 2013 Apr 18;8(4):e61002. doi: 10.1371/journal.pone.0061002. Print 2013.I | 05/03/2013 | |
| Highly multiplexed proteomic platform for biomarker discovery, diagnostics, and therapeutics | Mehan MR, et al. | 2013 | Adv Exp Med Biol | 735 | 283-300 | https://www.doi.org/10.1007/978-1-4614-4118-2_20 | 23,402,035 | Animals Biomarkers/*analysis Blood Proteins/chemistry Complement Inactivating Agents/pharmacology Complement System Proteins/physiology *Diagnosis Drug Therapy/*methods Humans Proteins/chemistry Proteomics/*methods | Progression from health to disease is accompanied by complex changes in protein expression in both the circulation and affected tissues. Large-scale comparative interrogation of the human proteome can offer insights into disease biology as well as lead to the discovery of new biomarkers for diagnostics, new targets for therapeutics, and can identify patients most likely to benefit from treatment. Although genomic studies provide an increasingly sharper understanding of basic biological and pathobiological processes, they ultimately only offer a prediction of relative disease risk, whereas proteins offer an immediate assessment of real-time" health and disease status. We have recently developed a new proteomic technology, based on modified aptamers, for biomarker discovery that is capable of simultaneously measuring more than a thousand proteins from small volumes of biological samples such as plasma, tissues, or cells. Our technology is enabled by SOMAmers (Slow Off-rate Modified Aptamers), a new class of protein binding reagents that contain chemically modified nucleotides that greatly expand the physicochemical diversity of nucleic acid-based ligands. Such modifications introduce functional groups that are absent in natural nucleic acids but are often found in protein-protein, small molecule-protein, and antibody-antigen interactions. The use of these modifications expands the range of possible targets for SELEX (Systematic Evolution of Ligands by EXponential Enrichment), results in improved binding properties, and facilitates selection of SOMAmers with slow dissociation rates. Our assay works by transforming protein concentrations in a mixture into a corresponding DNA signature, which is then quantified on current commercial DNA microarray platforms. In essence, we take advantage of the dual nature of SOMAmers as both folded binding entities with defined shapes and unique nucleic acid sequences recognizable by specific hybridization probes. Currently, our assay is capable of simultaneously measuring 1,030 proteins, extending to sub-pM detection limits, an average dynamic range of each analyte in the assay of > 3 logs, an overall dynamic range of at least 7 logs, and a throughput of one million analytes per week. Our collection includes SOMAmers that specifically recognize most of the complement cascade proteins. We have used this assay to identify potential biomarkers in a range of diseases such as malignancies, cardiovascular disorders, and inflammatory conditions. In this chapter, we describe the application of our technology to discovering large-scale protein expression changes associated with chronic kidney disease and non-small cell lung cancer. With this new proteomics technology-which is fast, economical, highly scalable, and flexible--we now have a powerful tool that enables whole-proteome proteomics, biomarker discovery, and advancing the next generation of evidence-based, "personalized" diagnostics and therapeutics." | Mehan, Michael R Ostroff, Rachel Wilcox, Sheri K Steele, Fintan Schneider, Daniel Jarvis, Thale C Baird, Geoffrey S Gold, Larry Janjic, Nebojsa eng Review Adv Exp Med Biol. 2013;735:283-300. doi: 10.1007/978-1-4614-4118-2_20.I | 02/14/2013 | ||
| Unique motifs and hydrophobic interactions shape the binding of modified DNA ligands to protein targets | Davies DR, et al. | 2012 | Proc Natl Acad Sci U S A | 109 | 49 | 19971-6 | https://www.doi.org/10.1073/pnas.1213933109 | 23,139,410 | Amino Acid Motifs/genetics Aptamers, Nucleotide/*chemistry/*metabolism Becaplermin Crystallography, X-Ray DNA Primers/genetics *Hydrophobic and Hydrophilic Interactions *Models, Molecular Molecular Sequence Data Molecular Structure Phosphorylation Protein Binding Proto-Oncogene Proteins c-sis/chemistry/*metabolism SELEX Aptamer Technique/*methods Sequence Analysis, DNA Transition Temperature | Selection of aptamers from nucleic acid libraries by in vitro evolution represents a powerful method of identifying high-affinity ligands for a broad range of molecular targets. Nevertheless, a sizeable fraction of proteins remain difficult targets due to inherently limited chemical diversity of nucleic acids. We have exploited synthetic nucleotide modifications that confer protein-like diversity on a nucleic acid scaffold, resulting in a new generation of binding reagents called SOMAmers (Slow Off-rate Modified Aptamers). Here we report a unique crystal structure of a SOMAmer bound to its target, platelet-derived growth factor B (PDGF-BB). The SOMAmer folds into a compact structure and exhibits a hydrophobic binding surface that mimics the interface between PDGF-BB and its receptor, contrasting sharply with mainly polar interactions seen in traditional protein-binding aptamers. The modified nucleotides circumvent the intrinsic diversity constraints of natural nucleic acids, thereby greatly expanding the structural vocabulary of nucleic acid ligands and considerably broadening the range of accessible protein targets. | Davies, Douglas R Gelinas, Amy D Zhang, Chi Rohloff, John C Carter, Jeffrey D O'Connell, Daniel Waugh, Sheela M Wolk, Steven K Mayfield, Wesley S Burgin, Alex B Edwards, Thomas E Stewart, Lance J Gold, Larry Janjic, Nebojsa Jarvis, Thale C eng Proc Natl Acad Sci U S A. 2012 Dec 4;109(49):19971-6. doi: 10.1073/pnas.1213933109. Epub 2012 Nov 8.I | 11/10/2012 | |
| Early detection of malignant pleural mesothelioma in asbestos-exposed individuals with a noninvasive proteomics-based surveillance tool | Ostroff RM, et al. | 2012 | PLoS One | 7 | 10 | e46091 | https://www.doi.org/10.1371/journal.pone.0046091 | 23,056,237 | Adult Aged Aged, 80 and over Asbestos Biomarkers, Tumor/blood Carcinogens Case-Control Studies Cohort Studies Enzyme-Linked Immunosorbent Assay Female Humans Lectins/blood Male Mesothelioma/chemically induced/*diagnosis/metabolism Middle Aged Pleural Neoplasms/chemically induced/*diagnosis/metabolism Principal Component Analysis Proteomics/*methods Public Health Surveillance/*methods Reproducibility of Results Sensitivity and Specificity Young Adult | BACKGROUND: Malignant pleural mesothelioma (MM) is an aggressive, asbestos-related pulmonary cancer that is increasing in incidence. Because diagnosis is difficult and the disease is relatively rare, most patients present at a clinically advanced stage where possibility of cure is minimal. To improve surveillance and detection of MM in the high-risk population, we completed a series of clinical studies to develop a noninvasive test for early detection. METHODOLOGY/PRINCIPAL FINDINGS: We conducted multi-center case-control studies in serum from 117 MM cases and 142 asbestos-exposed control individuals. Biomarker discovery, verification, and validation were performed using SOMAmer proteomic technology, which simultaneously measures over 1000 proteins in unfractionated biologic samples. Using univariate and multivariate approaches we discovered 64 candidate protein biomarkers and derived a 13-marker random forest classifier with an AUC of 0.99+/-0.01 in training, 0.98+/-0.04 in independent blinded verification and 0.95+/-0.04 in blinded validation studies. Sensitivity and specificity at our pre-specified decision threshold were 97%/92% in training and 90%/95% in blinded verification. This classifier accuracy was maintained in a second blinded validation set with a sensitivity/specificity of 90%/89% and combined accuracy of 92%. Sensitivity correlated with pathologic stage; 77% of Stage I, 93% of Stage II, 96% of Stage III and 96% of Stage IV cases were detected. An alternative decision threshold in the validation study yielding 98% specificity would still detect 60% of MM cases. In a paired sample set the classifier AUC of 0.99 and 91%/94% sensitivity/specificity was superior to that of mesothelin with an AUC of 0.82 and 66%/88% sensitivity/specificity. The candidate biomarker panel consists of both inflammatory and proliferative proteins, processes strongly associated with asbestos-induced malignancy. SIGNIFICANCE: The SOMAmer biomarker panel discovered and validated in these studies provides a solid foundation for surveillance and diagnosis of MM in those at highest risk for this disease. | Ostroff, Rachel M Mehan, Michael R Stewart, Alex Ayers, Deborah Brody, Edward N Williams, Stephen A Levin, Stephen Black, Brad Harbut, Michael Carbone, Michele Goparaju, Chandra Pass, Harvey I eng U01 CA111295/CA/NCI NIH HHS/ 2U01CA111295-04/CA/NCI NIH HHS/ Multicenter Study Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't PLoS One. 2012;7(10):e46091. doi: 10.1371/journal.pone.0046091. Epub 2012 Oct 3.I | 10/12/2012 | |
| Life's simple measures: unlocking the proteome | Brody E, et al. | 2012 | J Mol Biol | 422 | 5 | 595-606 | https://www.doi.org/10.1016/j.jmb.2012.06.021 | 22,721,953 | Aptamers, Nucleotide/*analysis/*metabolism Body Fluids/*chemistry Protein Binding Proteome/*analysis SELEX Aptamer Technique/*methods | Using modified nucleotides and selecting for slow off-rates in the SELEX procedure, we have evolved a special class of aptamers, called SOMAmers (slow off-rate modified aptamers), which bind tightly and specifically to proteins in body fluids. We use these in a novel assay that yields 1:1 complexes of the SOMAmers with their cognate proteins in body fluids. Measuring the SOMAmer concentrations of the resultant complexes reflects the concentration of the proteins in the fluids. This is simply done by hybridization to complementary sequences on solid supports, but it can also be done by any other DNA quantification technology (including NexGen sequencing). We use measurements of over 1000 proteins in under 100 muL of serum or plasma to answer important medical questions, two of which are reviewed here. A number of bioinformatics methods have guided our discoveries, including principal component analysis. We use various methods to evaluate sample handling procedures in our clinical samples and can identify many parameters that corrupt proteomics analysis. | Brody, Edward Gold, Larry Mehan, Mike Ostroff, Rachel Rohloff, John Walker, Jeff Zichi, Dom eng Netherlands J Mol Biol. 2012 Oct 5;422(5):595-606. doi: 10.1016/j.jmb.2012.06.021. Epub 2012 Jun 19.I | 06/23/2012 | |
| Identification of cis-regulatory variation influencing protein abundance levels in human plasma | Lourdusamy A, et al. | 2012 | Hum Mol Genet | 21 | 16 | 3719-26 | https://www.doi.org/10.1093/hmg/dds186 | 22,595,970 | Aged Aged, 80 and over Aptamers, Nucleotide Blood Proteins/*genetics Female Genetic Predisposition to Disease Genome-Wide Association Study Humans Male Middle Aged *Polymorphism, Single Nucleotide Proteomics/methods Quantitative Trait Loci *Regulatory Sequences, Nucleic Acid | Proteins are central to almost all cellular processes, and dysregulation of expression and function is associated with a range of disorders. A number of studies in human have recently shown that genetic factors significantly contribute gene expression variation. In contrast, very little is known about the genetic basis of variation in protein abundance in man. Here, we assayed the abundance levels of proteins in plasma from 96 elderly Europeans using a new aptamer-based proteomic technology and performed genome-wide local (cis-) regulatory association analysis to identify protein quantitative trait loci (pQTL). We detected robust cis-associations for 60 proteins at a false discovery rate of 5%. The most highly significant single nucleotide polymorphism detected was rs7021589 (false discovery rate, 2.5 x 10(-12)), mapped within the gene coding sequence of Tenascin C (TNC). Importantly, we identified evidence of cis-regulatory variation for 20 previously disease-associated genes encoding protein, including variants with strong evidence of disease association show significant association with protein abundance levels. These results demonstrate that common genetic variants contribute to the differences in protein abundance levels in human plasma. Identification of pQTLs will significantly enhance our ability to discover and comprehend the biological and functional consequences of loci identified from genome-wide association study of complex traits. This is the first large-scale genetic association study of proteins in plasma measured using a novel, highly multiplexed slow off-rate modified aptamer (SOMAmer) proteomic platform. | Lourdusamy, Anbarasu Newhouse, Stephan Lunnon, Katie Proitsi, Petra Powell, John Hodges, Angela Nelson, Sally K Stewart, Alex Williams, Stephen Kloszewska, Iwona Mecocci, Patrizia Soininen, Hilkka Tsolaki, Magda Vellas, Bruno Lovestone, Simon Dobson, Richard eng K01 AG030514/AG/NIA NIH HHS/ P30 AG010129/AG/NIA NIH HHS/ U01 AG024904/AG/NIA NIH HHS/ U19 AG010483/AG/NIA NIH HHS/ Research Support, Non-U.S. Gov't England Hum Mol Genet. 2012 Aug 15;21(16):3719-26. doi: 10.1093/hmg/dds186. Epub 2012 May 16.I | 05/19/2012 | |
| Protein signature of lung cancer tissues | Mehan MR, et al. | 2012 | PLoS One | 7 | 4 | e35157 | https://www.doi.org/10.1371/journal.pone.0035157 | 22,509,397 | Aged Apoptosis/genetics Biomarkers, Tumor/blood/genetics/metabolism Carcinoma, Non-Small-Cell Lung/blood/genetics/*metabolism Female *Gene Expression Regulation, Neoplastic Humans Inflammation/genetics Lung Neoplasms/blood/genetics/*metabolism Male Middle Aged Neoplasm Invasiveness/genetics Neoplasm Metastasis Neovascularization, Pathologic/genetics Proteome/*analysis | Lung cancer remains the most common cause of cancer-related mortality. We applied a highly multiplexed proteomic technology (SOMAscan) to compare protein expression signatures of non small-cell lung cancer (NSCLC) tissues with healthy adjacent and distant tissues from surgical resections. In this first report of SOMAscan applied to tissues, we highlight 36 proteins that exhibit the largest expression differences between matched tumor and non-tumor tissues. The concentrations of twenty proteins increased and sixteen decreased in tumor tissue, thirteen of which are novel for NSCLC. NSCLC tissue biomarkers identified here overlap with a core set identified in a large serum-based NSCLC study with SOMAscan. We show that large-scale comparative analysis of protein expression can be used to develop novel histochemical probes. As expected, relative differences in protein expression are greater in tissues than in serum. The combined results from tissue and serum present the most extensive view to date of the complex changes in NSCLC protein expression and provide important implications for diagnosis and treatment. | Mehan, Michael R Ayers, Deborah Thirstrup, Derek Xiong, Wei Ostroff, Rachel M Brody, Edward N Walker, Jeffrey J Gold, Larry Jarvis, Thale C Janjic, Nebojsa Baird, Geoffrey S Wilcox, Sheri K eng PLoS One. 2012;7(4):e35157. doi: 10.1371/journal.pone.0035157. Epub 2012 Apr 11.I | 04/18/2012 | |
| Advances in human proteomics at high scale with the SOMAscan proteomics platform | Gold L, et al. | 2012 | N Biotechnol | 29 | 5 | 543-9 | https://www.doi.org/10.1016/j.nbt.2011.11.016 | 22,155,539 | Biomarkers/metabolism DNA/*metabolism Humans Proteins/metabolism Proteomics/*instrumentation/methods/*trends | In 1997, while still working at NeXstar Pharmaceuticals, several of us made a proteomic bet. We thought then, and continue to think, that proteomics offers a chance to identify disease-specific biomarkers and improve healthcare. However, interrogating proteins turned out to be a much harder problem than interrogating nucleic acids. Consequently, the 'omics' revolution has been fueled largely by genomics. High-scale proteomics promises to transform medicine with personalized diagnostics, prevention, and treatment. We have now reached into the human proteome to quantify more than 1000 proteins in any human matrix - serum, plasma, CSF, BAL, and also tissue extracts - with our new SOMAmer-based proteomics platform. The surprising and pleasant news is that we have made unbiased protein biomarker discovery a routine and fast exercise. The downstream implications of the platform are substantial. | Gold, Larry Walker, Jeffrey J Wilcox, Sheri K Williams, Stephen eng Review Netherlands N Biotechnol. 2012 Jun 15;29(5):543-9. doi: 10.1016/j.nbt.2011.11.016. Epub 2011 Dec 7.I | 12/14/2011 | |
| Age-dependent changes in the cerebrospinal fluid proteome by slow off-rate modified aptamer array | Baird GS, et al. | 2012 | Am J Pathol | 180 | 2 | 446-56 | https://www.doi.org/10.1016/j.ajpath.2011.10.024 | 22,122,984 | Adult Aged Aged, 80 and over Aging/genetics/*metabolism Aptamers, Nucleotide/*metabolism Biomarkers/cerebrospinal fluid Cerebrospinal Fluid Proteins/*analysis Female Humans Male Middle Aged Protein Array Analysis/*methods Proteome/genetics/*metabolism Young Adult | An important precondition for the successful development of diagnostic assays of cerebrospinal fluid (CSF) biomarkers of age-related neurodegenerative diseases is an understanding of the dynamic nature of the CSF proteome during the normal aging process. In this study, a novel proteomic technology was used to quantify hundreds of proteins simultaneously in the CSF from 90 cognitively normal adults 21 to 85 years of age. SomaLogic's highly multiplexed proteomic platform can measure more than 800 proteins simultaneously from small volumes of biological fluids using novel slow off-rate modified aptamer (SOMAmer) protein affinity reagents with sensitivity, specificity, and dynamic ranges that meet or exceed those of enzyme-linked immunosorbent assays. In the first application of this technology to CSF, we detected 248 proteins that possessed signals greater than twofold over background. Several novel correlations between detected protein concentrations and age were discovered that indicate that both inflammation and response to injury in the central nervous system may increase with age. Applying this powerful proteomic approach to CSF provides potential new insight into the aging of the human central nervous system that may have utility in discovering new disease-related changes in the CSF proteome. | Baird, Geoffrey S Nelson, Sally K Keeney, Tracy R Stewart, Alex Williams, Stephen Kraemer, Stephan Peskind, Elaine R Montine, Thomas J eng P50 AG005136/AG/NIA NIH HHS/ AG05136/AG/NIA NIH HHS/ Research Support, N.I.H., Extramural Research Support, U.S. Gov't, Non-P.H.S. Am J Pathol. 2012 Feb;180(2):446-56. doi: 10.1016/j.ajpath.2011.10.024. Epub 2011 Nov 26.I | 11/30/2011 | |
| Aptamers and the RNA world, past and present | Gold L, et al. | 2012 | Cold Spring Harb Perspect Biol | 4 | 3 | https://www.doi.org/10.1101/cshperspect.a003582 | 21,441,582 | Aptamers, Nucleotide/*chemistry Biomarkers/blood/chemistry History, 20th Century Humans Proteomics/methods RNA/*chemistry/physiology SELEX Aptamer Technique/*history | Aptamers and the SELEX process were discovered over two decades ago. These discoveries have spawned a productive academic and commercial industry. The collective results provide insights into biology, past and present, through an in vitro evolutionary exploration of the nature of nucleic acids and their potential roles in ancient life. Aptamers have helped usher in an RNA renaissance. Here we explore some of the evolution of the aptamer field and the insights it has provided for conceptualizing an RNA world, from its nascence to our current endeavor employing aptamers in human proteomics to discover biomarkers of health and disease. | Gold, Larry Janjic, Nebojsa Jarvis, Thale Schneider, Dan Walker, Jeffrey J Wilcox, Sheri K Zichi, Dom eng Historical Article Review Cold Spring Harb Perspect Biol. 2012 Mar 1;4(3):a003582. doi: 10.1101/cshperspect.a003582.I | 03/29/2011 | ||
| From SOMAmer-based biomarker discovery to diagnostic and clinical applications: a SOMAmer-based, streamlined multiplex proteomic assay | Kraemer S, et al. | 2011 | PLoS One | 6 | 10 | e26332 | https://www.doi.org/10.1371/journal.pone.0026332 | 22,022,604 | Automation Biological Assay/*methods Biomarkers/*analysis Case-Control Studies *Diagnostic Techniques and Procedures Humans Limit of Detection Nucleic Acids/metabolism Oligonucleotides/chemistry/*metabolism Proteomics/*methods Reproducibility of Results Titrimetry | Recently, we reported a SOMAmer-based, highly multiplexed assay for the purpose of biomarker identification. To enable seamless transition from highly multiplexed biomarker discovery assays to a format suitable and convenient for diagnostic and life-science applications, we developed a streamlined, plate-based version of the assay. The plate-based version of the assay is robust, sensitive (sub-picomolar), rapid, can be highly multiplexed (upwards of 60 analytes), and fully automated. We demonstrate that quantification by microarray-based hybridization, Luminex bead-based methods, and qPCR are each compatible with our platform, further expanding the breadth of proteomic applications for a wide user community. | Kraemer, Stephan Vaught, Jonathan D Bock, Christopher Gold, Larry Katilius, Evaldas Keeney, Tracy R Kim, Nancy Saccomano, Nicholas A Wilcox, Sheri K Zichi, Dom Sanders, Glenn M eng Research Support, Non-U.S. Gov't PLoS One. 2011;6(10):e26332. doi: 10.1371/journal.pone.0026332. Epub 2011 Oct 17.I | 10/25/2011 | |
| Rapid histochemistry using slow off-rate modified aptamers with anionic competition | Gupta S, et al. | 2011 | Appl Immunohistochem Mol Morphol | 19 | 3 | 273-8 | https://www.doi.org/10.1097/PAI.0b013e3182008c29 | 21,217,521 | Aptamers, Peptide/chemistry/*metabolism Breast Neoplasms/*diagnosis/metabolism/pathology Carcinoma/*diagnosis/metabolism/pathology Epidermal Growth Factor/metabolism Female Fluorescent Dyes/chemistry/*metabolism Humans *Molecular Diagnostic Techniques Protein Binding Sensitivity and Specificity | Immunohistochemistry is used in both research and clinical settings to identify proteins in tissue samples. Despite the power and versatility of immunohistochemistry, limitations are imposed by the slow diffusion of antibodies through tissue and the need for secondary staining or signal amplification. Aptamers can circumvent these limitations, but their application has been hindered by nonspecific binding to cellular components, particularly in the nucleus. Here we describe unique slow off-rate modified aptamers that facilitate rapid and selective binding to target proteins in tissue. Specifically, we have developed a fluorescent aptamer that binds to the human epidermal growth factor receptor 2 (HER2) in breast carcinomas quickly and specifically, and we have shown that the slow off-rate of the aptamer from the HER2 protein contributes to its selectivity. These findings open the door to aptamer histochemistry applications in both research and clinical settings, including intraoperative diagnostics in which speed and accuracy are paramount. | Gupta, Shashi Thirstrup, Derek Jarvis, Thale C Schneider, Daniel J Wilcox, Sheri K Carter, Jeff Zhang, Chi Gelinas, Amy Weiss, Allison Janjic, Nebojsa Baird, Geoffrey S eng Research Support, Non-U.S. Gov't Appl Immunohistochem Mol Morphol. 2011 May;19(3):273-8. doi: 10.1097/PAI.0b013e3182008c29.I | 01/11/2011 | |
| Unlocking biomarker discovery: large scale application of aptamer proteomic technology for early detection of lung cancer | Ostroff RM, et al. | 2010 | PLoS One | 5 | 12 | e15003 | https://www.doi.org/10.1371/journal.pone.0015003 | 21,170,350 | Algorithms Autoantibodies/chemistry Biomarkers/*metabolism Biomarkers, Tumor/*metabolism Carcinoma, Non-Small-Cell Lung/*metabolism Case-Control Studies Cohort Studies Early Detection of Cancer/*methods Humans Lung Neoplasms/*metabolism Mass Spectrometry/methods Models, Statistical Proteomics/*methods Sensitivity and Specificity Smoking/adverse effects | BACKGROUND: Lung cancer is the leading cause of cancer deaths worldwide. New diagnostics are needed to detect early stage lung cancer because it may be cured with surgery. However, most cases are diagnosed too late for curative surgery. Here we present a comprehensive clinical biomarker study of lung cancer and the first large-scale clinical application of a new aptamer-based proteomic technology to discover blood protein biomarkers in disease. METHODOLOGY/PRINCIPAL FINDINGS: We conducted a multi-center case-control study in archived serum samples from 1,326 subjects from four independent studies of non-small cell lung cancer (NSCLC) in long-term tobacco-exposed populations. Sera were collected and processed under uniform protocols. Case sera were collected from 291 patients within 8 weeks of the first biopsy-proven lung cancer and prior to tumor removal by surgery. Control sera were collected from 1,035 asymptomatic study participants with >/= 10 pack-years of cigarette smoking. We measured 813 proteins in each sample with a new aptamer-based proteomic technology, identified 44 candidate biomarkers, and developed a 12-protein panel (cadherin-1, CD30 ligand, endostatin, HSP90alpha, LRIG3, MIP-4, pleiotrophin, PRKCI, RGM-C, SCF-sR, sL-selectin, and YES) that discriminates NSCLC from controls with 91% sensitivity and 84% specificity in cross-validated training and 89% sensitivity and 83% specificity in a separate verification set, with similar performance for early and late stage NSCLC. CONCLUSIONS/SIGNIFICANCE: This study is a significant advance in clinical proteomics in an area of high unmet clinical need. Our analysis exceeds the breadth and dynamic range of proteome interrogated of previously published clinical studies of broad serum proteome profiling platforms including mass spectrometry, antibody arrays, and autoantibody arrays. The sensitivity and specificity of our 12-biomarker panel improves upon published protein and gene expression panels. Separate verification of classifier performance provides evidence against over-fitting and is encouraging for the next development phase, independent validation. This careful study provides a solid foundation to develop tests sorely needed to identify early stage lung cancer. | Ostroff, Rachel M Bigbee, William L Franklin, Wilbur Gold, Larry Mehan, Mike Miller, York E Pass, Harvey I Rom, William N Siegfried, Jill M Stewart, Alex Walker, Jeffrey J Weissfeld, Joel L Williams, Stephen Zichi, Dom Brody, Edward N eng U01 CA085070/CA/NCI NIH HHS/ P50 CA058187/CA/NCI NIH HHS/ P50-CA58187/CA/NCI NIH HHS/ P50 CA090440/CA/NCI NIH HHS/ 5P30CA016056/CA/NCI NIH HHS/ U01 CA086137-10/CA/NCI NIH HHS/ U01-CA85070/CA/NCI NIH HHS/ U01 CA086137/CA/NCI NIH HHS/ 5U01CA086137/CA/NCI NIH HHS/ P30 CA016056/CA/NCI NIH HHS/ Multicenter Study Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't PLoS One. 2010 Dec 7;5(12):e15003. doi: 10.1371/journal.pone.0015003.I | 12/21/2010 | |
| Aptamer-based multiplexed proteomic technology for biomarker discovery | Gold L, et al. | 2010 | PLoS One | 5 | 12 | e15004 | https://www.doi.org/10.1371/journal.pone.0015004 | 21,165,148 | Aged *Aptamers, Nucleotide Biomarkers/*metabolism Evidence-Based Medicine Female Gene Library Genetic Techniques Glomerular Filtration Rate Humans Kidney Failure, Chronic/metabolism Kinetics Male Mass Spectrometry/methods Middle Aged Nucleic Acid Hybridization Oligonucleotide Array Sequence Analysis Proteome Proteomics/*methods Reproducibility of Results | BACKGROUND: The interrogation of proteomes (proteomics") in a highly multiplexed and efficient manner remains a coveted and challenging goal in biology and medicine. METHODOLOGY/PRINCIPAL FINDINGS: We present a new aptamer-based proteomic technology for biomarker discovery capable of simultaneously measuring thousands of proteins from small sample volumes (15 microL of serum or plasma). Our current assay measures 813 proteins with low limits of detection (1 pM median), 7 logs of overall dynamic range (~100 fM-1 microM), and 5% median coefficient of variation. This technology is enabled by a new generation of aptamers that contain chemically modified nucleotides, which greatly expand the physicochemical diversity of the large randomized nucleic acid libraries from which the aptamers are selected. Proteins in complex matrices such as plasma are measured with a process that transforms a signature of protein concentrations into a corresponding signature of DNA aptamer concentrations, which is quantified on a DNA microarray. Our assay takes advantage of the dual nature of aptamers as both folded protein-binding entities with defined shapes and unique nucleotide sequences recognizable by specific hybridization probes. To demonstrate the utility of our proteomics biomarker discovery technology, we applied it to a clinical study of chronic kidney disease (CKD). We identified two well known CKD biomarkers as well as an additional 58 potential CKD biomarkers. These results demonstrate the potential utility of our technology to rapidly discover unique protein signatures characteristic of various disease states. CONCLUSIONS/SIGNIFICANCE: We describe a versatile and powerful tool that allows large-scale comparison of proteome profiles among discrete populations. This unbiased and highly multiplexed search engine will enable the discovery of novel biomarkers in a manner that is unencumbered by our incomplete knowledge of biology, thereby helping to advance the next generation of evidence-based medicine." | Gold, Larry Ayers, Deborah Bertino, Jennifer Bock, Christopher Bock, Ashley Brody, Edward N Carter, Jeff Dalby, Andrew B Eaton, Bruce E Fitzwater, Tim Flather, Dylan Forbes, Ashley Foreman, Trudi Fowler, Cate Gawande, Bharat Goss, Meredith Gunn, Magda Gupta, Shashi Halladay, Dennis Heil, Jim Heilig, Joe Hicke, Brian Husar, Gregory Janjic, Nebojsa Jarvis, Thale Jennings, Susan Katilius, Evaldas Keeney, Tracy R Kim, Nancy Koch, Tad H Kraemer, Stephan Kroiss, Luke Le, Ngan Levine, Daniel Lindsey, Wes Lollo, Bridget Mayfield, Wes Mehan, Mike Mehler, Robert Nelson, Sally K Nelson, Michele Nieuwlandt, Dan Nikrad, Malti Ochsner, Urs Ostroff, Rachel M Otis, Matt Parker, Thomas Pietrasiewicz, Steve Resnicow, Daniel I Rohloff, John Sanders, Glenn Sattin, Sarah Schneider, Daniel Singer, Britta Stanton, Martin Sterkel, Alana Stewart, Alex Stratford, Suzanne Vaught, Jonathan D Vrkljan, Mike Walker, Jeffrey J Watrobka, Mike Waugh, Sheela Weiss, Allison Wilcox, Sheri K Wolfson, Alexey Wolk, Steven K Zhang, Chi Zichi, Dom eng Research Support, Non-U.S. Gov't PLoS One. 2010 Dec 7;5(12):e15004. doi: 10.1371/journal.pone.0015004.I | 12/18/2010 | |
| High-content affinity-based proteomics: unlocking protein biomarker discovery | Brody EN, et al. | 2010 | Expert Rev Mol Diagn | 10 | 8 | 1013-22 | https://www.doi.org/10.1586/erm.10.89 | 21,080,818 | *Aptamers, Nucleotide Biomarkers/*analysis/*chemistry Enzyme-Linked Immunosorbent Assay/methods Genetic Variation Humans Mass Spectrometry Molecular Diagnostic Techniques Proteins/*analysis/chemistry *Proteomics SELEX Aptamer Technique | Single protein biomarkers measured with antibody-based affinity assays are the basis of molecular diagnostics in clinical practice today. There is great hope in discovering new protein biomarkers and combinations of protein biomarkers for advancing medicine through monitoring health, diagnosing disease, guiding treatment, and developing new therapeutics. The goal of high-content proteomics is to unlock protein biomarker discovery by measuring many (thousands) or all ( approximately 23,000) proteins in the human proteome in an unbiased, data-driven approach. High-content proteomics has proven technically difficult due to the diversity of proteins, the complexity of relevant biological samples, such as blood and tissue, and large concentration ranges (in the order of 10(12) in blood). Mass spectrometry and affinity methods based on antibodies have dominated approaches to high-content proteomics. For technical reasons, neither has achieved adequate simultaneous performance and high-content. Here we review antibody-based protein measurement, multiplexed antibody-based protein measurement, and limitations of antibodies for high-content proteomics due to their inherent cross-reactivity. Finally, we review a new affinity-based proteomic technology developed from the ground up to solve the problem of high content with high sensitivity and specificity. Based on a new generation of slow off-rate modified aptamers (SOMAmers), this technology is unlocking biomarker discovery. | Brody, Edward N Gold, Larry Lawn, Richard M Walker, Jeffrey J Zichi, Dom eng Research Support, Non-U.S. Gov't Review England Expert Rev Mol Diagn. 2010 Nov;10(8):1013-22. doi: 10.1586/erm.10.89.I | 11/18/2010 | |
| Expanding the chemistry of DNA for in vitro selection | Vaught JD, et al. | 2010 | J Am Chem Soc | 132 | 12 | 4141-51 | https://www.doi.org/10.1021/ja908035g | 20,201,573 | Aptamers, Nucleotide/*chemistry/genetics/metabolism Base Sequence Gene Library Humans Molecular Sequence Data Molecular Structure Polymerase Chain Reaction Tumor Necrosis Factor Receptor Superfamily, Member 9/*chemistry/genetics/metabolism | Six new 5-position modified dUTP derivatives connected by a unique amide linkage were synthesized and tested for compatibility with the enzymatic steps of in vitro selection. Six commercially available DNA polymerases were tested for their ability to efficiently incorporate each of these dUTP derivatives during PCR. It was not possible to perform PCR under standard conditions using any of the modified dUTP derivatives studied. In contrast, primer extension reactions of random templates, as well as defined sequence templates, were successful. KOD XL and D. Vent DNA polymerases were found to be the most efficient at synthesizing full-length primer extension product, with all of the dUTP derivatives tested giving yields similar to those obtained with TTP. Several of these modified dUTPs were then used in an in vitro selection experiment comparing the use of modified dUTP derivatives with TTP for selecting aptamers to a protein target (necrosis factor receptor superfamily member 9, TNFRSF9) that had previously been found to be refractory to in vitro selection using DNA. Remarkably, selections employing modified DNA libraries resulted in the first successful isolation of DNA aptamers able to bind TNFRSF9 with high affinity. | Vaught, Jonathan D Bock, Chris Carter, Jeff Fitzwater, Tim Otis, Matt Schneider, Dan Rolando, Justin Waugh, Sheela Wilcox, Sheri K Eaton, Bruce E eng Research Support, U.S. Gov't, Non-P.H.S. J Am Chem Soc. 2010 Mar 31;132(12):4141-51. doi: 10.1021/ja908035g.I | 03/06/2010 | |
| The stability of the circulating human proteome to variations in sample collection and handling procedures measured with an aptamer-based proteomics array | Ostroff R, et al. | 2010 | J Proteomics | 73 | 3 | 649-66 | https://www.doi.org/10.1016/j.jprot.2009.09.004 | 19,755,178 | Algorithms Aptamers, Peptide/chemistry Blood Coagulation/physiology Blood Preservation/adverse effects/methods Blood Proteins/analysis/*metabolism Blood Specimen Collection/adverse effects/*methods/standards Cluster Analysis Freezing/adverse effects Humans Models, Biological Observer Variation Protein Array Analysis/instrumentation/methods *Protein Stability Proteome/*analysis/*metabolism Proteomics/instrumentation/methods SELEX Aptamer Technique/instrumentation/*methods Time Factors | Blood-based protein biomarkers hold great promise to advance medicine with applications that detect and diagnose diseases and aid in their treatment. We are developing such applications with our proteomics technology that combines high-content with low limits of detection. Biomarker discovery relies heavily on archived blood sample collections. Blood is dynamic and changes with different sampling procedures potentially confounding biomarker studies. In order to better understand the effects of sampling procedures on the circulating proteome, we studied three sample collection variables commonly encountered in archived sample sets. These variables included (1) three different sample tube types, PPT plasma, SST serum, and Red Top serum, (2) the time from venipuncture to centrifugation, and (3) the time from centrifugation to freezing. We profiled 498 proteins for each of 240 samples and compared the results by ANOVA. The results found no significant variation in the measurements for most proteins (approximately 99%) when the two sample processing times tested were 2h or less, regardless of sample tube type. Even at the longest timepoints, 20 h, approximately 82% of the proteins, on average for the three collection tube types, showed no significant change. These results are encouraging for proteomic biomarker discovery. | Ostroff, Rachel Foreman, Trudi Keeney, Tracy R Stratford, Suzanne Walker, Jeffrey J Zichi, Dom eng Evaluation Study Research Support, Non-U.S. Gov't Netherlands J Proteomics. 2010 Jan 3;73(3):649-66. doi: 10.1016/j.jprot.2009.09.004. Epub 2009 Sep 13.I | 09/17/2009 | |
| Proteomics and diagnostics: Let's Get Specific, again | Zichi D, et al. | 2008 | Curr Opin Chem Biol | 12 | 1 | 78-85 | https://www.doi.org/10.1016/j.cbpa.2008.01.016 | 18,275,862 | Animals Antibodies/immunology Aptamers, Peptide/metabolism *Diagnosis Humans Protein Array Analysis Proteomics/*methods Sensitivity and Specificity | DNA array technology has changed all discussions about proteomics. Whole genome arrays allow unbiased experimentation, and the surprises that flow from those approaches. 'Whole proteome' proteomics is not possible today, and might never be possible unless experiments are guided by careful evaluation of reagent specificity. In this paper we explore some possible ways to increase the content of proteomic analysis. | Zichi, Dom Eaton, Bruce Singer, Britta Gold, Larry eng Review England Curr Opin Chem Biol. 2008 Feb;12(1):78-85. doi: 10.1016/j.cbpa.2008.01.016. Epub 2008 Mar 7.I | 02/16/2008 | |
| Processing of photoaptamer microarrays | Petach H, et al. | 2004 | Methods Mol Biol | 264 | 101-10 | https://www.doi.org/10.1385/1-59259-759-9:101 | 15,020,783 | Cross-Linking Reagents/metabolism Endostatins/metabolism Fluorescent Dyes/metabolism *Light Nucleic Acids/*metabolism Protein Array Analysis/instrumentation/*methods Protein Binding | Photoaptamers are single-stranded nucleic acids selected for their high affinity to specific proteins of interest. Photoaptamer microarrays capture and quantify proteins from complex samples using a unique protocol that leverages both high-affinity capture with covalent retention of analytes. The initial capture of proteins from solution is similar to the well-known antibody capture, but the secondary binding event" affected by photoaptamers is a covalent crosslink between the photoaptamer capture agent and the protein analyte. The nature of this specific covalent reaction allows a unique microarray processing that is described in detail in this chapter." | Petach, Helen Ostroff, Rachel Greef, Chad Husar, Gregory M eng Methods Mol Biol. 2004;264:101-10. doi: 10.1385/1-59259-759-9:101.I | 03/17/2004 | ||
| Sensitivity and specificity of photoaptamer probes | Smith D, et al. | 2003 | Mol Cell Proteomics | 2 | 1 | 8-Nov | https://www.doi.org/10.1074/mcp.m200059-mcp200 | 12,601,078 | Bromodeoxyuridine/*pharmacology Cross-Linking Reagents/*pharmacology Escherichia coli/metabolism HIV Envelope Protein gp120/chemistry Kinetics Oligonucleotide Array Sequence Analysis Peptides/*chemistry Protein Array Analysis Protein Binding Proteomics/methods Sensitivity and Specificity | The potential of photoaptamers as proteomic probes was investigated. Photoaptamers are defined as aptamers that bear photocross-linking functionality, in this report, 5-bromo-2'-deoxyuridine. A key question regarding the use of photoaptamer probes is the specificity of the cross-linking reaction. The specificity of three photoaptamers was explored by comparing their reactions with target proteins and non-target proteins. The range of target/non-target specificity varies from 100- to >10(6)-fold with most values >10(4)-fold. The contributions of the initial binding step and the photocross-linking step were evaluated for each reaction. Photocross-linking never degraded specificity and significantly increased aptamer specificity in some cases. The application of photoaptamer technology to proteomics was investigated in microarray format. Immobilized anti-human immunodeficiency virus-gp120 aptamer was able to detect subnanomolar concentrations of target protein in 5% human serum. The levels of sensitivity and specificity displayed by photoaptamers, combined with other advantageous properties of aptamers, should facilitate development of protein chip technology. | Smith, Drew Collins, Brian D Heil, James Koch, Tad H eng Research Support, Non-U.S. Gov't Mol Cell Proteomics. 2003 Jan;2(1):11-8. doi: 10.1074/mcp.m200059-mcp200.I | 02/26/2003 | |
| One, two, infinity: genomes filled with aptamers | Gold L, et al. | 2002 | Chem Biol | 9 | 12 | 1259-64 | https://www.doi.org/10.1016/s1074-5521(02)00286-7 | 12,498,875 | Evolution, Molecular Gene Expression Regulation/genetics Genome Oligonucleotides/*genetics/therapeutic use RNA/chemistry/genetics | Gold, Larry Brody, Ed Heilig, Joe Singer, Britta eng Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S. Chem Biol. 2002 Dec;9(12):1259-64. doi: 10.1016/s1074-5521(02)00286-7.I | 12/25/2002 | ||
| Dimensionality is the issue: use of photoaptamers in protein microarrays | Petach H, et al. | 2002 | Curr Opin Biotechnol | 13 | 4 | 309-14 | https://www.doi.org/10.1016/s0958-1669(02)00329-4 | 12,323,351 | Electrophoresis, Gel, Two-Dimensional/*methods Enzyme-Linked Immunosorbent Assay/*methods Indicators and Reagents/chemistry Ligands Molecular Probes Photochemistry/*methods Protein Array Analysis/*methods/trends Proteins/*analysis/*chemistry Proteomics/methods Sensitivity and Specificity | The development of high-density arrays for proteomics has become a goal of SomaLogic, many other companies, and a wide variety of academic entities. Unfortunately, the word proteomics has come to mean virtually everything. We define proteomics as being derived from arrays of analyte-specific reagents (ASRs) used to measure (something about) proteins. As the density of the ASRs on a chip increases toward the number of proteins in an organism, the concept of proteomics moves toward comprehensive proteomics. At issue then, is what constitutes an ASR, and what differences between them lead toward more or less biological information from a high-density panel of ASRs. | Petach, Helen Gold, Larry eng Review England Curr Opin Biotechnol. 2002 Aug;13(4):309-14. doi: 10.1016/s0958-1669(02)00329-4.I | 09/27/2002 | |
| Interlocking structural motifs mediate molecular discrimination by a theophylline-binding RNA | Zimmermann GR, et al. | 1997 | Nat Struct Biol | 4 | 8 | 644-9 | https://www.doi.org/10.1038/nsb0897-644 | 9,253,414 | Bronchodilator Agents/*chemistry Caffeine/chemistry Cytosine/chemistry Magnetic Resonance Spectroscopy Models, Molecular Molecular Sequence Data *Nucleic Acid Conformation RNA/*chemistry Sensitivity and Specificity Theophylline/*chemistry | To visualize the interplay of RNA structural interactions in a ligand binding site, we have determined the solution structure of a high affinity RNA-theophylline complex using NMR spectroscopy. The structure provides insight into the ability of this in vitro selected RNA to discriminate theophylline from the structurally similar molecule caffeine. Numerous RNA structural motifs combine to form a well-ordered binding pocket where an intricate network of hydrogen bonds and stacking interactions lock the theophylline into the complex. Two internal loops interact to form the binding site which consists of a sandwich of three base triples. The complex also contains novel base-zipper and 1-3-2 stacking motifs, in addition to an adenosine platform and a reversed sugar. An important feature of the RNA is that many of the conserved core residues participate in multiple overlapping tertiary interactions. This complex illustrates how interlocking structural motifs can be assembled into a highly specific ligand-binding site that possesses high levels of affinity and molecular discrimination. | Zimmermann, G R Jenison, R D Wick, C L Simorre, J P Pardi, A eng Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S. Nat Struct Biol. 1997 Aug;4(8):644-9. doi: 10.1038/nsb0897-644.I | 08/01/1997 | |
| Let's get specific: the relationship between specificity and affinity | Eaton BE, et al. | 1995 | Chem Biol | 2 | 10 | 633-8 | https://www.doi.org/10.1016/1074-5521(95)90023-3 | 9,383,468 | Animals Drug Design Humans Protein Binding Receptors, Drug/*chemistry Surface Properties | The factors that lead to high-affinity binding are a good fit between the surfaces of the two molecules in their ground state and charge complementarity. Exactly the same factors give high specificity for a target. We argue that selection for high-affinity binding automatically leads to highly specific binding. This principle can be used to simplify screening approaches aimed at generating useful drugs. | Eaton, B E Gold, L Zichi, D A eng Review Chem Biol. 1995 Oct;2(10):633-8. doi: 10.1016/1074-5521(95)90023-3.I | 10/01/1995 | |
| High-resolution molecular discrimination by RNA | Jenison RD, et al. | 1994 | Science | 263 | 5,152 | 1425-9 | https://www.doi.org/10.1126/science.7510417 | 7,510,417 | Base Sequence Binding Sites Binding, Competitive DNA, Complementary/chemistry Hydrogen Bonding Magnetic Resonance Spectroscopy Molecular Sequence Data Molecular Structure Nucleic Acid Conformation RNA/chemistry/*metabolism Sequence Analysis, DNA Theophylline/chemistry/*metabolism Xanthines/chemistry/metabolism | Species of RNA that bind with high affinity and specificity to the bronchodilator theophylline were identified by selection from an oligonucleotide library. One RNA molecule binds to theophylline with a dissociation constant Kd of 0.1 microM. This binding affinity is 10,000-fold greater than the RNA molecule's affinity for caffeine, which differs from theophylline only by a methyl group at nitrogen atom N-7. Analysis by nuclear magnetic resonance indicates that this RNA molecule undergoes a significant change in its conformation or dynamics upon theophylline binding. Binding studies of compounds chemically related to theophylline have revealed structural features required for the observed binding specificity. These results demonstrate the ability of RNA molecules to exhibit an extremely high degree of ligand recognition and discrimination. | Jenison, R D Gill, S C Pardi, A Polisky, B eng AI01051/AI/NIAID NIH HHS/ AI33098/AI/NIAID NIH HHS/ RR03283/RR/NCRR NIH HHS/ Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S. Science. 1994 Mar 11;263(5152):1425-9. doi: 10.1126/science.7510417.I | 03/11/1994 | |
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