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The Proceedings of the 15th Annual Research Day Department of Medicine May 1 & 2, 2017 Pages Schedule of Events 3 - 4 Keynote Speaker: Pages Tadataka Yamada, MD 5 Pages Oral Presenters: May 1, 2017 6 - 25 Pages Oral Presenters: May 2, 2017 26 - 41 Pages List of Judges 42 - 44 Poser Author Index & Abstracts: Pages 45 - 103 Residents - May 1, 2017 Poser Author Index & Abstracts: Pages Session A – May 2, 2017 104 -204 Poser Author Index & Abstracts: Pages Session B – May 2, 2017 205 -298 Pages Acknowledgments 299 2 | Page CLINCAL RESEARCH: RESIDENTS MAY 1 - UNIVERSITY CLUB 5:00 pm Registration & Poster Viewing 5:15 pm Welcome & Opening Remarks Mark Gladwin, MD Chair, Department of Medicine Director, Vascular Medicine Institute Professor of Medicine, Division of PACCM Alison Morris MD, MS Vice Chair, Clinical Research Professor of Medicine Director, University of Pittsburgh HIV Lung Research Center UPMC Chair, Translational Pulmonary and Critical Care Medicine 5:30-6:30 pm Oral Presentations Sokratis Apostolidis, MD Emily Guhl, MD Shelly Kakar, DO Yijia Li, MD 6:30-7:30 pm Poster Viewing Session & Discussion 7:30-8:00 pm Keynote Speaker Introduction Tadataka Yamada, MD “An M.D. Degree – A Life Full of Options” Venture Partner with Frazier Healthcare Partners 8:00 pm Awards Presentation 3 | Page RESEARCH DAY MAY 2 – BIOMEDICAL SCIENCE TOWER SOUTH FOYER & S-100 9:00 am Registration & Continental Breakfast Available 9:30-11:30 am Session A: Poster Viewing & Judging 11:30 am Lunch Available 12:00-1:00 pm Keynote Speaker Tadataka Yamada, MD “Lessons from Global Health” Venture Partner with Frazier Healthcare Partners 1:15-3:15 pm Session B: Poster Viewing & Judging 3:30-4:30 pm Oral Presentations Jill Allenbaugh, MD Neelesh Nadkarni, MD, PhD, FRCPC Natasha Parekh, MD Francois Yu, PhD 4:30 pm Awards Presentation 4 | Page Keynote Speaker Tadataka Yamada, MD Dr. Tadataka Yamada is a Venture Partner with Frazier Healthcare Partners. Prior to joining Frazier he was Executive Vice-President, Chief Medical & Scientific Officer and a Board Member of Takeda Pharmaceuticals. Dr. Yamada has served as President of the Bill & Melinda Gates Foundation Global Health Program. In this position, he oversaw grants totaling more than $9 billion in programs directed at applying technologies to address major health challenges of the developing world including TB, HIV, malaria and other infectious diseases, malnutrition and maternal and child health. He was formerly Chairman, Research and Development and a Member of the Board of Directors of GlaxoSmithKline and before that he was Chair of the Department of Internal Medicine and Physician-in-Chief at the University of Michigan Medical Center. Dr. Yamada holds a bachelor's degree in history from Stanford University and obtained his M.D. from New York University School of Medicine. In recognition of his contributions to medicine and science he has been elected to membership in the National Academy of Medicine (US), the Academy of Medical Sciences (UK) and the National Academy of Medicine (Mexico) and he has received an honorary appointment as Knight Commander of the Most Excellent Order of the British Empire (KBE). He is a Past-President of the Association of American Physicians and of the American Gastroenterological Association and he has served as a member of the President's Council of Advisors on Science and Technology and the Advisory Committee to the Director of the National Institutes of Health. He is currently Vice Chair of the Council of the National Academy of Medicine and serves on the Board of Directors of the Clinton Health Access Initiative. 5 | Page Oral Presenter – May 1, 2017 Sokratis Apostolidis, MD Resident - International Scholar Bio: Sokratis is a PGY-2 Internal Medicine resident in the IST scholars’ track of the UPMC Internal Medicine Residency program. He was born and raised in Greece and completed his medical school studies in the University of Athens. Halfway through his medical training, he became drawn to immunology and rheumatologic diseases and shortly after his graduation, he joined the Rheumatology Lab of Dr. Tsokos in Beth Israel Deaconess Medical Center. As a post-doctoral fellow in Boston, he performed research on lupus nephritis and the role of the Protein Phosphatase 2a in Systemic Lupus Erythematosus pathogenesis. His research work on autoimmunity and immune tolerance has been published in the Journal of Immunology, Journal of Biological Chemistry and Nature Immunology. During his internal medicine residency, his research interests focus on identifying the underlying mechanisms contributing to vascular injury in scleroderma patients. Presentation: Single cell RNA sequencing reveals a signature of endothelial injury in scleroderma skin. Background: Vascular injury is a hallmark event in the pathogenesis of Systemic Sclerosis (SSc). Endothelial dysfunction happens early in the course of the disease and drives some of the most prominent clinical manifestations of scleroderma, including Raynaud’s phenomenon, telangiectasias and gastric antral vascular ectasias, pulmonary arterial hypertension and scleroderma renal crisis. The exact mechanisms that lead to endothelial cell injury and propagate the vasculopathy in scleroderma are not well understood. Single cell RNA sequencing provides a robust platform for cellular identification, allows gene expression analysis at the single cell level and accounts for cellular heterogeneity. Methods: The study was completed in the Scleroderma Center of UPMC in collaboration with the Boston University Scleroderma Center and the Broad Institute of Boston. Scleroderma patients and healthy matched controls at UPMC and Boston University Scleroderma Centers were 6 | Page recruited. Skin biopsies were obtained and the tissues were digested to form single cell suspensions. We then implemented single cell FACS-sorting and subsequent RNA sequencing of the isolated cells from scleroderma and healthy control skin. The analysis was performed using R software. We used t-distributed stochastic neighbor embedding (t-SNE) with k-means clustering to identify the various cell types. We performed pathway analysis using Gene Set Enrichment Analysis (GSEA) and Ingenuity Pathway Analysis (IPA). Finally, we independently verified distinct markers using immunohistochemistry on skin biopsies and qPCR in primary endothelial cells isolated from skin of scleroderma patients and healthy controls. Results: In order to be able to visualize and ultimately define the various cell subsets in the dataset, we used t-distributed stochastic neighbor embedding (t-SNE), a method of unsupervised learning for dimensionality reduction. 2D projection of the t-SNE coupled with k-means clustering effectively reduced the dimensionality of the data revealing clustering patterns that had the potential to represent distinct cellular populations, as shown in Figure 1. Figure 1. 7 | Page The purpose of our analysis was to identify endothelial cells. In order to define the cluster that represents the endothelial cell population in our dataset, we employed known endothelial cell markers, such as Von Willebrand factor (gene name VWF), platelet endothelial cell adhesion molecule (gene name PECAM1) and vascular endothelial cadherin (CDH5). We overlaid the expression of these genes on the t-SNE projection plot and were able to positively identify the endothelial cells among the sorted single cells from healthy and scleroderma skin. Cluster 4 in Figure 1 is the cluster that represents the endothelial cells based on the expression of the abovementioned genes (the expression of the genes is not depicted in Figure 1). After defining the endothelial cells in our dataset, we focused our analysis on the endothelial cell subpopulation and identified differentially expressed genes between healthy control ECs and SSc ECs. As it can be seen in Figure 2, the two fold upregulated genes (top bin) contains already established markers of endothelial injury and activation including the Apelin receptor APLNR and stabilin-1 (gene name STAB1), as well as previously identified markers of endothelial injury and negative regulation of angiogenesis in scleroderma, such as THBS1 and VWF. It also includes components of the extracellular matrix, such as the heparin sulfate proteoglycan 2 (gene name HSPG2) that was previously shown to be implicated in fibrotic processes including scleroderma- associated fibrosis, wound healing and to be regulated in a TGF-β dependent manner. In order to highlight pathways that are enriched in our dataset and to find gene signatures that are positively or negatively regulated in scleroderma endothelial cells compared to their healthy counterparts, we used Gene Set Enrichment Analysis (GSEA) (45) and Ingenuity Pathway Analysis (IPA, Qiagen). Using GSEA we were able to demonstrate that the SSc endothelial cell expression profile is enriched in processes associated with extracellular matrix (ECM) generation as well as epithelial-to-mesenchymal transition (EMT). In addition, using Ingenuity Pathway, we found that scleroderma endothelial cells show enrichment in pathways associated with inhibition of angiogenesis, acute phase response, complement activation and matrix metalloproteinases (Figure 3). 8 | Page Figure 2. 9 | Page Figure 3. Finally, two of the top differentially expressed genes, HSPG2 and APLNR, were independently verified. Primary endothelial cells isolated from scleroderma skin expressed higher 10 | Page levels of APLNR compared to endothelial cells isolated from healthy skin. HSPG2
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