Digital Commons Network^™

Health And Disease Markers Correlate With Gut Microbiome Composition Across Thousands Of People., Ohad Manor, Chengzhen L Dai, Sergey A Kornilov, Brett Smith, Nathan D Price, Jennifer C Lovejoy, Sean M Gibbons, Andrew T Magis

Articles, Abstracts, and Reports

Variation in the human gut microbiome can reflect host lifestyle and behaviors and influence disease biomarker levels in the blood. Understanding the relationships between gut microbes and host phenotypes are critical for understanding wellness and disease. Here, we examine associations between the gut microbiota and ~150 host phenotypic features across ~3,400 individuals. We identify major axes of taxonomic variance in the gut and a putative diversity maximum along the Firmicutes-to-Bacteroidetes axis. Our analyses reveal both known and unknown associations between microbiome composition and host clinical markers and lifestyle factors, including host-microbe associations that are composition-specific. These results suggest potential opportunities …

Aml Risk Stratification Models Utilizing Eln-2017 Guidelines And Additional Prognostic Factors: A Swog Report., Era L Pogosova-Agadjanyan, Anna Moseley, Megan Othus, Frederick R Appelbaum, Thomas R Chauncey, I-Ming L Chen, Harry P Erba, John E Godwin, Isaac C Jenkins, Min Fang, Mike Huynh, Kenneth J Kopecky, Alan F List, Jasmine Naru, Jerald P Radich, Emily Stevens, Brooke E Willborg, Cheryl L Willman, Brent L Wood, Qing Zhang, Soheil Meshinchi, Derek L Stirewalt

Articles, Abstracts, and Reports

Background: The recently updated European LeukemiaNet risk stratification guidelines combine cytogenetic abnormalities and genetic mutations to provide the means to triage patients with acute myeloid leukemia for optimal therapies. Despite the identification of many prognostic factors, relatively few have made their way into clinical practice.

Methods: In order to assess and improve the performance of the European LeukemiaNet guidelines, we developed novel prognostic models using the biomarkers from the guidelines, age, performance status and select transcript biomarkers. The models were developed separately for mononuclear cells and viable leukemic blasts from previously untreated acute myeloid leukemia patients (discovery cohort,

Results: Models …

Precision Medicine In Pancreatic Disease-Knowledge Gaps And Research Opportunities: Summary Of A National Institute Of Diabetes And Digestive And Kidney Diseases Workshop., Mark E Lowe, Dana K Andersen, Richard M Caprioli, Jyoti Choudhary, Zobeida Cruz-Monserrate, Anil K Dasyam, Christopher E Forsmark, Fred S Gorelick, Joe W Gray, Mark Haupt, Kimberly A Kelly, Kenneth P Olive, Sylvia K Plevritis, Noa Rappaport, Holger R Roth, Hanno Steen, S Joshua Swamidass, Temel Tirkes, Aliye Uc, Kirill Veselkov, David C Whitcomb, Aida Habtezion

Articles, Abstracts, and Reports

A workshop on research gaps and opportunities for Precision Medicine in Pancreatic Disease was sponsored by the National Institute of Diabetes and Digestive Kidney Diseases on July 24, 2019, in Pittsburgh. The workshop included an overview lecture on precision medicine in cancer and 4 sessions: (1) general considerations for the application of bioinformatics and artificial intelligence; (2) omics, the combination of risk factors and biomarkers; (3) precision imaging; and (4) gaps, barriers, and needs to move from precision to personalized medicine for pancreatic disease. Current precision medicine approaches and tools were reviewed, and participants identified knowledge gaps and research needs …

The Current State Of Molecular Testing In The Treatment Of Patients With Solid Tumors, 2019., Wafik S El-Deiry, Richard M Goldberg, Heinz-Josef Lenz, Anthony F Shields, Geoffrey T Gibney, Antoinette R Tan, Jubilee Brown, Burton Eisenberg, Elisabeth I Heath, Surasak Phuphanich, Edward Kim, Andrew J Brenner, John L Marshall

Articles, Abstracts, and Reports

The world of molecular profiling has undergone revolutionary changes over the last few years as knowledge, technology, and even standard clinical practice have evolved. Broad molecular profiling is now nearly essential for all patients with metastatic solid tumors. New agents have been approved based on molecular testing instead of tumor site of origin. Molecular profiling methodologies have likewise changed such that tests that were performed on patients a few years ago are no longer complete and possibly inaccurate today. As with all rapid change, medical providers can quickly fall behind or struggle to find up-to-date sources to ensure he or …

Heart Failure Symptom Biology In Response To Ventricular Assist Device Implantation., Christopher S Lee, James O Mudd, Karen S Lyons, Quin E Denfeld, Corrine Y Jurgens, Bradley E Aouizerat, Jill M Gelow, Christopher V Chien, Emily Aarons, Kathleen L Grady

Articles, Abstracts, and Reports

BACKGROUND: We have a limited understanding of the biological underpinnings of symptoms in heart failure (HF), particularly in response to left ventricular assist device (LVAD) implantation.

OBJECTIVE: The aim of this study was to quantify the degree to which symptoms and biomarkers change in parallel from before implantation through the first 6 months after LVAD implantation in advanced HF.

METHODS: This was a prospective cohort study of 101 patients receiving an LVAD for the management of advanced HF. Data on symptoms (dyspnea, early and subtle symptoms [HF Somatic Perception Scale], pain severity [Brief Pain Inventory], wake disturbance [Epworth Sleepiness Scale], …

Sitc 2018 Workshop Report: Immuno-Oncology Biomarkers: State Of The Art., Lisa H Butterfield, Mary L Disis, Bernard A Fox, David R Kaufman, Samir N Khleif, Ena Wang

Articles, Abstracts, and Reports

Identification of biomarkers in cancer immunotherapy that predict therapeutic response and/or limit adverse events are a critical need in the field. To address recent progress and hurdles around cancer biomarker development and utilization, the Society for Immunotherapy of Cancer (SITC) convened a workshop, "Immuno-Oncology Biomarkers: State of the Art," on May 16-17, 2018. Topics discussed included challenges in handling biospecimens, identification and validation of new biomarkers, data sharing, and collaborating across disciplines to advance biomarker development. Panel discussions followed session presentations to help foster participant conversation and discuss future projects and collaborations. The results of the Workshop include the development …

Perspectives In Melanoma: Meeting Report From The Melanoma Bridge (30 November-2 December, 2017, Naples, Italy)., Paolo A Ascierto, Igor Puzanov, Sanjiv S Agarwala, Carlo Bifulco, Gerardo Botti, Corrado Caracò, Gennaro Ciliberto, Michael A Davies, Reinhard Dummer, Soldano Ferrone, Thomas F Gajewski, Claus Garbe, Jason J Luke, Francesco M Marincola, Giuseppe Masucci, Janice M Mehnert, Nicola Mozzillo, Giuseppe Palmieri, Michael A Postow, Stephen P Schoenberger, Ena Wang, Magdalena Thurin

Articles, Abstracts, and Reports

Metastatic melanoma represents a challenging clinical situation and, until relatively recently, there was an absence of effective treatment options. However, in 2011, the advanced melanoma treatment landscape was revolutionised with the approval of the anti-cytotoxic T-lymphocyte-associated protein-4 checkpoint inhibitor ipilimumab and the selective BRAF kinase inhibitor vemurafenib, both of which significantly improved overall survival. Since then, availability of new immunotherapies, especially the anti-programmed death-1 checkpoint inhibitors, as well as other targeted therapies, have further improved outcomes for patients with advanced melanoma. Seven years on from the first approval of these novel therapies, evidence for the use of various immune-based and …

Perspectives In Immunotherapy: Meeting Report From The Immunotherapy Bridge (29-30 November, 2017, Naples, Italy)., Paolo A Ascierto, James Brugarolas, Luigi Buonaguro, Lisa H Butterfield, David Carbone, Bruno Daniele, Robert Ferris, Bernard A Fox, Jérôme Galon, Cesare Gridelli, Howard L Kaufman, Christopher A Klebanoff, Ignacio Melero, Paul Nathan, Chrystal M Paulos, Marco Ruella, Ryan Sullivan, Hassane Zarour, Igor Puzanov

Articles, Abstracts, and Reports

Immunotherapy represents the third important wave in the history of the systemic treatment of cancer after chemotherapy and targeted therapy and is now established as a potent and effective treatment option across several cancer types. The clinical success of anti-cytotoxic T-lymphocyte-associated antigen (CTLA)-4, first, and anti-programmed death (PD)-1/PD-ligand (L)1 agents in melanoma and other cancers a few years later, has encouraged increasing focus on the development of other immunotherapies (e.g. monoclonal antibodies with other immune targets, adoptive cell transfer, and vaccines), with over 3000 immuno-oncology trials ongoing, involving hundreds of research institutes across the globe. The potential use of these …

Applying Genomics In Heart Transplantation., Brendan J Keating, Alexandre C Pereira, Michael Snyder, Brian D. Piening

Articles, Abstracts, and Reports

While advances in patient care and immunosuppressive pharmacotherapies have increased the lifespan of heart allograft recipients, there are still significant comorbidities post-transplantation and 5-year survival rates are still significant, at approximately 70%. The last decade has seen massive strides in genomics and other omics fields, including transcriptomics, with many of these advances now starting to impact heart transplant clinical care. This review summarizes a number of the key advances in genomics which are relevant for heart transplant outcomes, and we highlight the translational potential that such knowledge may bring to patient care within the next decade.

Lower Serum Iga Is Associated With Copd Exacerbation Risk In Spiromics., Nirupama Putcha, Gabriel G Paul, Antoine Azar, Robert A Wise, Wanda K O'Neal, Mark T Dransfield, Prescott G Woodruff, Jeffrey L Curtis, Alejandro P Comellas, M Bradley Drummond, Allison A. Lambert, Laura M Paulin, Ashraf Fawzy, Richard E Kanner, Robert Paine, Meilan K Han, Fernando J Martinez, Russell P Bowler, R Graham Barr, Nadia N Hansel

Articles, Abstracts, and Reports

BACKGROUND: Decreased but measurable serum IgA levels (≤70 mg/dL) have been associated with risk for infections in some populations, but are unstudied in COPD. This study tested the hypothesis that subnormal serum IgA levels would be associated with exacerbation risk in COPD.

METHODS: Data were analyzed from 1,049 COPD participants from the observational cohort study SPIROMICS (535 (51%) women; mean age 66.1 (SD 7.8), 338 (32%) current smokers) who had baseline serum IgA measured using the Myriad RBM biomarker discovery platform. Exacerbation data was collected prospectively (mean 944.3 (SD 281.3) days), and adjusted linear, logistic and zero-inflated negative binomial regressions …

Differential Impact Of Serial Measurement Of Nonplatelet Thromboxane Generation On Long-Term Outcome After Cardiac Surgery., Nikolaos Kakouros, Tyler J Gluckman, John V Conte, Thomas S Kickler, Katherine Laws, Bruce A Barton, Jeffrey J Rade

Articles, Abstracts, and Reports

BACKGROUND: Systemic thromboxane generation, not suppressible by standard aspirin therapy and likely arising from nonplatelet sources, increases the risk of atherothrombosis and death in patients with cardiovascular disease. In the RIGOR (Reduction in Graft Occlusion Rates) study, greater nonplatelet thromboxane generation occurred early compared with late after coronary artery bypass graft surgery, although only the latter correlated with graft failure. We hypothesize that a similar differential association exists between nonplatelet thromboxane generation and long-term clinical outcome.

METHODS AND RESULTS: Five-year outcome data were analyzed for 290 RIGOR subjects taking aspirin with suppressed platelet thromboxane generation. Multivariable modeling was performed to …

A Two-Biomarker Model Predicts Mortality In The Critically Ill With Sepsis., Carmen Mikacenic, Brenda L Price, Susanna Harju-Baker, D Shane O'Mahony, Cassianne Robinson-Cohen, Frank Radella, William O Hahn, Ronit Katz, David C Christiani, Jonathan Himmelfarb, W Conrad Liles, Mark M Wurfel

Articles, Abstracts, and Reports

RATIONALE: Improving the prospective identification of patients with systemic inflammatory response syndrome (SIRS) and sepsis at low risk for organ dysfunction and death is a major clinical challenge.

OBJECTIVES: To develop and validate a multibiomarker-based prediction model for 28-day mortality in critically ill patients with SIRS and sepsis.

METHODS: A derivation cohort (n = 888) and internal test cohort (n = 278) were taken from a prospective study of critically ill intensive care unit (ICU) patients meeting two of four SIRS criteria at an academic medical center for whom plasma was obtained within 24 hours. The validation cohort (n = …

Pretreatment Ethyl Glucuronide Levels Predict Response To A Contingency Management Intervention For Alcohol Use Disorders Among Adults With Serious Mental Illness., Michael Gerard Mcdonell, Emily Leickly, Sterling Mcpherson, Jordan Skalisky, Katherine Hirchak, Oladunni Oluwoye, Debra Srebnik, John Michael Roll, Richard Kirkland Ries

Articles, Abstracts, and Reports

BACKGROUND AND OBJECTIVES: This study investigated if pretreatment ethyl glucuronide (EtG) levels corresponding to light (100 ng/mL), heavy (500 ng/mL), and very heavy (1,000 ng/mL) drinking predicted longest duration of alcohol abstinence (LDA) and proportion of EtG-negative urine tests in outpatients receiving a 12-week EtG-based contingency management (CM) intervention for alcohol dependence.

METHODS: Participants were 40 adults diagnosed with alcohol use disorders and serious mental illness who submitted up to 12 urine samples for EtG analysis during a 4-week observation period and were then randomized to 12-weeks of CM for alcohol abstinence and addiction treatment attendance. Alcohol use outcomes during …

High Agreement Between Benchtop And Point-Of-Care Dipcard Tests For Ethyl Glucuronide., Emily Leickly, Jordan Skalisky, Sterling Mcpherson, Michael F Orr, Michael G Mcdonell

Articles, Abstracts, and Reports

No abstract provided.

A Wellness Study Of 108 Individuals Using Personal, Dense, Dynamic Data Clouds., Nathan D Price, Andrew T Magis, John C Earls, Gustavo Glusman, Roie Levy, Christopher Lausted, Daniel T Mcdonald, Ulrike Kusebauch, Christopher L Moss, Yong Zhou, Shizhen Qin, Robert L Moritz, Kristin Brogaard, Gilbert S Omenn, Jennifer C Lovejoy, L Hood

Articles, Abstracts, and Reports

Personal data for 108 individuals were collected during a 9-month period, including whole genome sequences; clinical tests, metabolomes, proteomes, and microbiomes at three time points; and daily activity tracking. Using all of these data, we generated a correlation network that revealed communities of related analytes associated with physiology and disease. Connectivity within analyte communities enabled the identification of known and candidate biomarkers (e.g., gamma-glutamyltyrosine was densely interconnected with clinical analytes for cardiometabolic disease). We calculated polygenic scores from genome-wide association studies (GWAS) for 127 traits and diseases, and used these to discover molecular correlates of polygenic risk (e.g., genetic risk …

Ccr4 Is A Determinant Of Melanoma Brain Metastasis., Anat Klein, Orit Sagi-Assif, Tsipi Meshel, Alona Telerman, Sivan Izraely, Shlomit Ben-Menachem, Jagadeesh Bayry, Diego M Marzese, Shuichi Ohe, Dave S B Hoon, Neta Erez, Isaac P Witz

Articles, Abstracts, and Reports

We previously identified the chemokine receptor CCR4 as part of the molecular signature of melanoma brain metastasis. The aim of this study was to determine the functional significance of CCR4 in melanoma brain metastasis. We show that CCR4 is more highly expressed by brain metastasizing melanoma cells than by local cutaneous cells from the same melanoma. Moreover, we found that the expression of CCR4 is significantly higher in paired clinical specimens of melanoma metastases than in samples of primary tumors from the same patients. Notably, the expression of the CCR4 ligands, Ccl22 and Ccl17 is upregulated at the earliest stages …

Biomarkers Of Acute Stroke Etiology (Base) Study Methodology., Edward C Jauch, Andrew D Barreto, Joseph P Broderick, Doug M Char, Brett L Cucchiara, Thomas G Devlin, Alison J Haddock, William J Hicks, Brian C Hiestand, Glen C Jickling, Jeff June, David S Liebeskind, Ted J Lowenkopf, Joseph B Miller, John O'Neill, Tim L Schoonover, Frank R Sharp, W Frank Peacock

Articles, Abstracts, and Reports

Acute ischemic stroke affects over 800,000 US adults annually, with hundreds of thousands more experiencing a transient ischemic attack. Emergent evaluation, prompt acute treatment, and identification of stroke or TIA (transient ischemic attack) etiology for specific secondary prevention are critical for decreasing further morbidity and mortality of cerebrovascular disease. The Biomarkers of Acute Stroke Etiology (BASE) study is a multicenter observational study to identify serum markers defining the etiology of acute ischemic stroke. Observational trial of patients presenting to the hospital within 24 h of stroke onset. Blood samples are collected at arrival, 24, and 48 h later, and RNA …

Optimal Nutrition And The Ever-Changing Dietary Landscape: A Conference Report., A Shao, A Drewnowski, D C Willcox, L Krämer, Christopher G Lausted, M Eggersdorfer, J Mathers, J D Bell, R K Randolph, R Witkamp, J C Griffiths

Articles, Abstracts, and Reports

The field of nutrition has evolved rapidly over the past century. Nutrition scientists and policy makers in the developed world have shifted the focus of their efforts from dealing with diseases of overt nutrient deficiency to a new paradigm aimed at coping with conditions of excess-calories, sedentary lifestyles and stress. Advances in nutrition science, technology and manufacturing have largely eradicated nutrient deficiency diseases, while simultaneously facing the growing challenges of obesity, non-communicable diseases and aging. Nutrition research has gone through a necessary evolution, starting with a reductionist approach, driven by an ambition to understand the mechanisms responsible for the effects …

Differentiated State Of Initiating Tumor Cells Is Key To Distinctive Immune Responses Seen In H-Ras, Michael A Podolsky, Jacob T Bailey, Andrew J Gunderson, Carrie J Oakes, Kyle Breech, Adam B Glick

Articles, Abstracts, and Reports

Heterogeneity in tumor immune responses is a poorly understood yet critical parameter for successful immunotherapy. In two doxycycline-inducible models where oncogenic H-RasG12V is targeted either to the epidermal basal/stem cell layer with a Keratin14-rtTA transgene (K14Ras), or committed progenitor/suprabasal cells with an Involucrin-tTA transgene (InvRas), we observed strikingly distinct tumor immune responses. On threshold doxycycline levels yielding similar Ras expression, tumor latency, and numbers, tumors from K14Ras mice had an immunosuppressed microenvironment, whereas InvRas tumors had a proinflammatory microenvironment. On a Rag1-/- background, InvRas mice developed fewer and smaller tumors that regressed over time, whereas K14Ras mice developed more …

Cell Population Structure Prior To Bifurcation Predicts Efficiency Of Directed Differentiation In Human Induced Pluripotent Cells., Rhishikesh Bargaje, Kalliopi Trachana, Martin N Shelton, Christopher S Mcginnis, Joseph X Zhou, Cora Chadick, Savannah Cook, Christopher Cavanaugh, Sui Huang, Leroy Hood

Articles, Abstracts, and Reports

Steering the differentiation of induced pluripotent stem cells (iPSCs) toward specific cell types is crucial for patient-specific disease modeling and drug testing. This effort requires the capacity to predict and control when and how multipotent progenitor cells commit to the desired cell fate. Cell fate commitment represents a critical state transition or "tipping point" at which complex systems undergo a sudden qualitative shift. To characterize such transitions during iPSC to cardiomyocyte differentiation, we analyzed the gene expression patterns of 96 developmental genes at single-cell resolution. We identified a bifurcation event early in the trajectory when a primitive streak-like cell population …