Research Report 2018

A Message from Executive Vice President Gilbert White, II, MD, Chief Scientific Officer

2018 was another strong year for research. Grant and Yan Qing Ma were promoted to Investigator. revenues for the year were $16.1 M, another record Lisa Baumann-Kreuziger, Lynn Malec, and Matt for us and exceeding our 2018 budget by $1 M. Karafin were promoted to Associate Investigator. New NIH R-type grants or competitive renewals Jorge DiPaola of the University of Colorado, David were obtained by Bob Montgomery and by Sandy Lillicrap and Paula James from Queens University in Haberichter. Peter Newman successfully competed Kingston, Canada, James O’Donnell from the Royal for a $6.9 M 7-year R35 Career award from NHLBI. College of Surgeons of Ireland, and Amy Shapiro Karin Hoffmeister received a new $4.8 M K12 award from the Indiana Hemophilia and Thrombosis Center in Glycobiology, one of four in the US together with in Indianapolis were appointed as adjunct Senior Johns Hopkins, Harvard, and UCSD. Gil White is the Investigators at the BRI. PI on a new $1.5 M OT2 consortium grant from NIH that is part of the NIH Precision Medicine Initiative. A Individual accomplishments during the year were new F-type award went to Puja Agrawal in Sid Rao’s numerous. We celebrated Hardy Weiler’s and Pam lab. Altogether, there were 11 new NIH grants in 2018 Christopherson’s 20th year with the organization. that totaled $17.5 M. Nan Zhu received the second Alan Mast chaired the 2018 Hemostasis Gordon R. Douglas Ziegler Innovation Award for her work Conference. Irene Hernandez in Hardy Weiler’s lab related to the pathogenesis of acute myelogenous received Excellence in Action recognition from Versiti. leukemia. Matt Karafin, Josh Field, Peter Newman, Dick Aster received the BizTimes Media Health Care Karin Hoffmeister, and Subra Malarkannan received Heroes Lifetime Achievement Award, recognizing funding for Versiti Moonshot projects. his advancements in . Karin Hoffmeister chaired the Megakaryocyte and John Pulikkan joined the faculty as Associate Scientific Committee and the Committee Program Investigator in the stem cell group. John came from the at the annual meeting of the American Society of University of Massachusetts Medical School from the Hematology (ASH). Hervé Falet also serves on the lab of Lucio Castilla, a former scholar of the Leukemia Megakaryocyte and Platelet Scientific Committee. and Lymphoma Society. His research focuses on Peter Newman serves on the Investment and Audit chromatin dynamics and understanding the regulatory Committee of ASH. Alan Mast, Karin Hoffmeister, pathways that are deregulated in hematopoietic stem Magda Chrzanowska, Debra Newman, Roy and progenitor cells in acute myeloid leukemia in order Silverstein and Bob Montgomery continue to serve to better understand the development of leukemia. on NIH review panels. Peter Newman continues His overall goal is to develop novel therapeutic to serve as Associate Editor of Arteriosclerosis, strategies for the treatment of leukemia. Jieqing Zhu Thrombosis, and Vascular Biology (ATVB). Hardy

Research Report 2018 1 Continued: A Message from Executive Vice President Gilbert White, II, MD, Chief Scientific Officer

Weiler and Roy Silverstein serve on the ATVB Editorial University, on November 8th. His talk was titled “T Zheng in Demin Wang’s lab was the 2018 Doolittle Board. Alan Mast is a new Associate Editor of the Cell Exhaustion and PD-a Immunotherapy”. All four Fellow and Saravanan Subramaniam in Hardy Weiler’s Journal of Thrombosis and Haemostasis. Magda lectures were outstanding and examples of cutting lab was the Gallagher Fellow. Waseem Anani in Karin Chrzanowska is on the Editorial Board of Plos One. edge science and translation. Hoffmeister’s lab was named the first Jaqueline and Bonnie Dittel is Associate Editor of Arlen Fredrick Scholar. New Directors Fellows were and on the Editorial Boards of the Journal of The 1st Annual Great Lakes Translational Glycomics Heather Ashwood in Karin Hoffmeister’s lab and Neuroimmunology and Brain, Behavior, and . Symposium was held May 31st at the Blood Amy Siebert-McKenzie in Alan Mast’s lab, bringing Subra Malarkannan is Associate Editor of Frontiers in Research Institute (BRI) and was organized by Karin to 6 the number who have been supported through . Qizhen Shi is on the Editorial Board of Hoffmeister. Featuring speakers from GlycoMimetics, the contributions of Scott and Genevieve Harkness. Molecular Therapy, Methods and Clinical Development. Inc, Washington University in St. Louis, Virginia Chao Yang in Subra Malarkannan’s lab received the Peter Newman is Co-Editor of the 3rd Edition of Commonwealth University, Roswell Park Cancer inaugural J. Evan Sadler Graduate Scholar Award, as and Gil White is Co-Editor of the 6th Edition of Center, Brigham and Women’s Hospital, and Medical voted by the BRI graduate students and postdoctoral Thrombosis and Hemostasis. Six students completed College of Wisconsin (MCW), it was attended by more fellows. Moua Yang in Roy Silverstein’s lab received the their PhD degrees in 2018: Michael Reimer from Sid than 60 individuals. The 12th Annual Center for Human Mary Rodes Gibson Memorial Award in Hemostasis Rao’s lab, Aye Myat Myat Thinn from Jieqing Zhu’s Immunology Symposium was held October 25th at and Thrombosis for the highest scoring abstract at lab, David Schauder from Weiguo Cui’s lab, Alex Abel the BRI. The symposium, titled “B Cells and Broadly the American Society of Hematology meeting. Five from Subra Malarkannan’s lab, Erin Wesley from Matt Neutralizing ,” featured renowned speakers new graduate students selected the BRI as their place Riese’s lab, and Moua Yang from Roy Silverstein’s lab. from Harvard University, Scripps Research Institute, to train: Paytsar Topchyan and Christine Nguyen Vanderbilt University, the Feinstein Institute for Medical in Weiguo Cui’s lab, Yaling Wu in Demin Wang’s lab, The 16th Annual Aster Lecture was delivered on Research, and Sanofi Pharmaceuticals. This year’s Savannah Neu in Bonnie Dittel’s lab, and Yuanhua Cai August 15th by Dr. Olja Finn, Distinguished Professor meeting was hosted by Demin Wang and Renren Wen. in Qizhen Shi’s lab. of Immunology and Surgery at the University of Pittsburgh. Her talk was titled “Vaccines in the The Scientific Advisory Board reviewed part of the Sadly, we lost a long-time and beloved colleague Prevention of Non-Viral Cancers”. The 17th Annual Vascular Biology program in October. Overall, there when Joan Gill passed away on May 9, 2018. Joan Mosesson Lecture was delivered on October 4th was high enthusiasm for this group of investigators. In was internationally renowned in the world of bleeding by Dr. Bjorn Dahlback, Senior Professor in the their summary comments, the Board described the disorders and made a number of lasting contributions Department of Laboratory Medicine at Lund University need for continued succession planning, space for through her work with von Willebrand disease and in Malmo, Sweden. His talk was on “Novel Insights continued expansion, attention to retention, and the hemophilia. One of the first women in the field, Joan into the Regulation of Blood Coagulation by FV success of the mentoring program. They also reported served as an example to countless young women in Isoforms, TFPI alpha and Protein S”. The 2nd Annual some faculty anxiety regarding a perceived emphasis hematology and was the face of bleeding disorders Jacqueline Fredrick Lecture, selected and hosted by on cell therapies and uncertainty regarding changes in care in the State of Wisconsin. the graduate students and postdoctoral fellows at the leadership. BRI, was given on September 20th by Melanie Cobb, At years’ end, there were 38 trainees in the BRI. All of Browning Chair in Medical Science in the Department our T32 Training Grant positions were filled in 2018: of Pharmacology at the UT Southwestern Medical Tyce Kearl in Subra Malarkannan’s lab, Alyssa Moroi Center. The talk was titled “Catching a Few Good in Peter Newman’s lab followed by Lauren Pommert in WNKs”. The 2nd Annual R. Douglas Ziegler Innovation Sid Rao’s lab, Nate Schloemer in Subra Malarkannan’s Lecture was by Dr. Rafi Ahmed, Director of the highly lab followed by Amy Siebert-McKenzie in Alan Mast’s Gilbert C. White, II, MD innovative Harrington Discovery Institute at Emory lab, and Jesse Sundlov in Peter Newman’s lab. Yongwei Chief Scientific Officer

2 Research By The Numbers – 2018

10 $122.4 5 New NIH Million New Diagnostic Grants New Applications Tests Developed

$16.1 33 Million 1 Start-Up Company Investigators Research Formed Revenues

$614+ 2 13 Thousand Patents Filed Core Labs Average Funding per Investigator

Research Report 2018 3 Transfusion Medicine

Transfusion Medicine research has a long history at Versiti, reflecting its basic mission to provide a safe and effective supply of blood products for patients who require transfusion.

Effective transfusion therapy requires knowledge of the biology and physiology of blood, satisfactory methods for collecting and storing blood cells with maximum preservation of function, and an understanding of the many diseases in which transfusion of blood components can be beneficial.

Research conducted by the Transfusion Medicine group addresses each of these areas. Investigators in the Transfusion Medicine Program study basic biology and clinical implications of a range of transfusion-related issues. CEO Emeritus and Senior Investigator, Blood Research Institute Richard H. Aster, MD Professor, Department of Medicine, Medical College of Wisconsin (MCW) MD, University of Michigan 1957 Hematology, Harvard University 1965 Faculty, Harvard 1964-1970 Started at Versiti: 1971

cell destruction and improved understanding of the Funding molecular basis for these conditions. RO1-HL-13629-47 National Heart Lung and Blood Awards, Honors and Service Institute. Renewed June 1, 2017 • Founder: GTI Diagnostics (subsidiary of VBRIF) Publications • Karl Landsteiner Award, American Association of Blood 1. Curtis BR, Hsu YS, Podoltsev N, Lacy J, Curtis S, Banks (AABB) Samuel MS, Zutavern K, DeSimone RA, Bougie DW, • Henry Stratton Medal for translational research, Aster RH. Patients treated with oxaliplatin are at risk for American Society of Hematology thrombocytopenia caused by multiple drug-dependent antibodies. Blood. 2018 Mar 29;131(13):1486-1489. • Distinguished Service Award, Medical College of PMID: 29439950 Wisconsin (MCW) 2. Dhakal B, Kreuziger LB, Rein L, Kleman A, Fraser • Reviewer for the journals Blood, New England Journal R, Aster RH, Hari P, Padmanabhan A. Disease of Medicine, Lancet, Nature, Science Translational burden, complication rates, and health-care costs Medicine and Transfusion of heparin-induced thrombocytopenia in the USA: • Grant reviewer (Transfusion Medicine), Center for a population-based study. Lancet Haematol. 2018 Scientific Review, National Institutes of Health May;5(5):e220-e231. PMID: 29703336

Research Interests Immune destruction of red blood cells, white blood cells, and platelets is a major cause of morbidity and mortality in patients. Dr. Aster’s work is aimed at understanding the causes of blood cell destruction by , drug-induced antibodies, and antibodies triggered by or exposure to fetal blood cells during pregnancy. Recent studies in his laboratory have shown that metabolites generated in the body following exposure to various drugs can induce antibodies that cause platelet destruction and bleeding and provide new insights into the cause of “idiosyncratic” drug-sensitivity reactions. Findings made in these and related studies are defining new methods for detection to improve diagnosis and treatment in patients with antibody-induced blood

Research Report 2018 5 Director, Platelet & Immunology Lab, Versiti Brian Curtis, PhD, Senior Director, Versiti Product Development and Clinical Lab, Versiti Investigator, Blood Research Institute, Versiti Assistant Adjunct Professor, Clinical and Translational Science Institute, Medical College of Wisconsin D(ABMLI), MT(ASCP) PhD, University of Wisconsin-Milwaukee SBB, Investigator Started at Versiti: 1991

antibodies that destroy her child’s platelets. Recent work PMID: 29439950 in the Curtis lab has allowed for improved diagnosis of 2. Thinn AMM, Wang Z, Zhou D, Zhao Y, Curtis BR, Zhu J. FNAIT. Autonomous conformational regulation of β3 integrin and the conformation-dependent property of HPA-1a Awards, Honors and Service alloantibodies. Proc Natl Acad Sci U S A. 2018 Sep • Member, Editorial Board, Transfusion 2017 25;115(39):E9105-E9114. PMID: 30209215 • Member, ISBT Nomenclature 3. Rachel Petermann, Tamam Bakchoul, Brian Curtis, Working Party, 1997 Francois Mullier, Shigeki Miyata, Donald M. Arnold. Investigations for Fetal and Neonatal Alloimmune • Member, AABB Molecular Testing Standards Thrombocytopenia (FNAIT): Recommendations from Committee, 2012 the Platelet Immunology Scientific Subcommittee. J • Member, ISBT International Granulocyte Thromb Haemost 2018; Dec;16(12):2526-2529. doi: Immunobiology Workshop Steering Committee, 2014 10.1111/jth.14294. • Co-Chair, ISTH Platelet Immunology SSC, 2015 1 3 • Member, AABB Selection of Abstracts Program Unit Transfer Lysate

• Member, ASH Scientific Committee on Transfusion 2 Medicine, 2016 Lyse Incubate then wash • Member, Platelet Advisory Board, Ionis beads Pharmaceuticals, 2016 Incubate then wash platelets PE-anti-human IgG Research Interests • Co-chair, ISBT Platelet Immunobiology Working Party, Antibody Subcommittee on Quality, 2018 2 Glycoprotein Antibodies specific for carried on blood Incubate platelets and white blood cells () cause with Bead anti-IgG, 5 Wash beads thrombocytopenia and (low neutrophil Funding count) in various immune disorders and can be difficult “Development of a New and Improved Diagnostic Assay Negative result Positive result to identify. Work in Dr. Curtis’ laboratory has led to for Antibody Detection in Patients with Suspected improved methods for detecting such antibodies and to Heparin-Induced Thrombocytopenia (HIT)”. Strategic y new understanding of the blood disorders in which they ensi t

Investment Fund, Versiti (Co-PI). t are involved. Dr. Curtis serves as Director of the Platelet n and Neutrophil Immunology Reference Laboratory of e I Versiti and applies his research findings to improve Publications en c es c the effectiveness with which this laboratory enhances 1. Curtis BR, Hsu YS, Podoltsev N, Lacy J, Curtis S, medical care for patients referred for diagnostic testing. Samuel MS, Zutavern K, DeSimone RA, Bougie DW, luo r

One particular area of expertise for the lab is in diagnosis Aster RH. Patients treated with oxaliplatin are at risk for ead F B of Fetal and Neonatal Alloimmune Thrombocytopenia thrombocytopenia caused by multiple drug-dependent

(FNAIT), a disorder in which a pregnant mother can make antibodies. Blood. 2018 Mar 29;131(13):1486-1489. PE-anti-human IgG – Fluorescence Intensity 6 Versiti Blood Research Institute

Senior Investigator, Versiti Blood Research Institute, Versiti Gregory Denomme, PhD Senior Director of Immunohematology and Innovation, Versiti PhD, Microbiology and Immunology, University of Western Ontario, 1993 Started at Versiti: 2009

Awards, Honors and Service 4. Levitt RN, Gourri E, Gassner C, Banez-Sese G, Salam A, Denomme GA, Yang E. Molecular characterization and • Working Party member, Red Blood Cell multidisciplinary management of Gerbich hemolytic Immunogenetics and Blood Group Terminology disease of the newborn. Pediatr Blood Cancer. 2018 • International Society for Blood Transfusion Jun;65(6):e27014. PMID: 29469208 • Editorial Board Member, International Journal of 5. Yazer MH, Anani WQ, Denomme GA, Karafin MS, Clinical Transfusion Medicine Sayers M, Shaz BH; Biomedical Excellence for Safer Transfusion (BEST) Collaborative. Trends in antigen- • Editorial Board Member, Transfusion negative red blood cell distributions by racial or ethnic groups in the United States. Transfusion. 2018 Funding Jan;58(1):145-150. PMID: 29023750 Designer blood cells: CRISPR/cas9 alteration of red blood cell and platelet antigens. G. Denomme (Principal Investigator) B. Curtis, P. Newman (Senior Investigator). Versiti Strategic Funding 2019.

Publications Antibody mediated lysis of PNH red blood cell clone 1. Storry JR, Clausen FB, Castilho L, Chen Q, Daniels

G, Denomme G, et al. International Society of Blood Inhibits deposition of Transfusion Working Party on Red Cell Immunogenetics DAF complement C3b on red blood cell surface and Blood Group Terminology: Report of the Dubai, Research Interests Copenhagen and Toronto meetings. Vox Sang Inhibits formation of Dr. Denomme is Senior Director of Versiti’s 2019;114:95-102 MIRL membrane attack Immunohematology and Transfusion Service Laboratory, complex 2. Compernolle V, Chou ST, Tanael S, Savage W, Howard a division of Versiti Clinical Laboratories. He is an J, Josephson CD, Odame I, Hogan C, Denomme G, immunology and immunohematology-trained scientist Shehata N; International Collaboration for Transfusion with interests in the immune response to red cell Medicine Guidelines. Red blood cell specifications for antigens, the expression of blood groups, and bench- patients with hemoglobinopathies: a systematic review to-bedside studies in immunohematology. His work and guideline. Transfusion. 2018 Jun;58(6):1555-1566. integrates immunogenetics with transfusion medicine to Review. PMID: 29697146 explore the genetic basis of blood group expression and the functional polymorphisms underlying the pathology 3. Flegel WA, Chen Q, Castilho L, Keller MA, Klapper of immune-mediated red cell . EB, Lane WJ, Pirenne F, Stack G, St-Louis M, Tormey CA, Waxman DA, Weinstock C, Wendel S, Denomme GA. Molecular immunohaematology round table discussions at the AABB Annual Meeting, Orlando 2016. Blood Transfus. 2018 Feb 14:1-12. PMID: 29517973

Research Report 2018 7 Investigator, Blood Research Institute, Versiti Hervé Falet, PhD Assistant Professor, Medical College of Wisconsin PhD, Paris Descartes University, 1997 Postdoctoral fellowship, Brigham and Women’s Hospital and Harvard Medical School, 2001 Started at Versiti: 2016

of mortality, mostly due to bleeding. regulates hepatic thrombopoietin production via JAK2- Blood platelets are produced in the bone marrow by STAT3 signaling. Nat Med. 2015;21(1):47-54. PMID: megakaryocytes in a unique process that requires 25485912 extensive intracellular membrane rearrangements. These 2. Bender M, Giannini S, Grozovsky R, Jönsson T, include the formation of the demarcation membrane Christensen H, Pluthero FG, Ko A, Mullally A, Kahr system, the surface-connected membrane extension WHA, Hoffmeister KM, Falet H. Dynamin 2-dependent that invaginates into the cell body and further develops to endocytosis is required for normal megakaryocyte provide membranes for future platelets. development in mice. Blood. 2015;125(6):1014-1024. PMID: 25468568 At the Blood Research Institute, Dr. Falet investigates the roles of novel membrane binding and deforming 3. Begonja AJ, Pluthero FG, Suphamungmee W, Giannini proteins in the formation and organization of the S, Christensen H, Leung R, Lo R, Nakamura F, Lehman megakaryocyte demarcation membrane system. He W, Plomann M, Hoffmeister KM, Kahr WHA, Hartwig anticipates that his studies will yield basic information JH, Falet H. FlnA binding to PACSIN2 F-BAR domain related to megakaryocyte and platelet biology, and lead regulates membrane tubulation in megakaryocytes and to the development of new approaches to reestablish platelets. Blood. 2015;126(1):80-88. PMID: 25838348 thrombopoiesis in the setting of thrombocytopenia (low platelet count). Awards, Honors and Service • Bridge Grant Award, American Society of Hematology Research Interests 2015-2016 Dr. Hervé Falet received his master’s and doctoral • Outstanding Graduate School Educator Award, degree from Paris Descartes University and completed Graduate School of Biomedical Sciences, Medical his postdoctoral fellowship at Brigham and Women’s College of Wisconsin 2018 Hospital and Harvard Medical School. He joined the Blood • Member, Scientific Committee on Megakaryocytes and Research Institute faculty in 2016. His primary research Platelets, American Society of Hematology 2019-2022 interests are associated with blood platelet production (thrombopoiesis) and function. Funding Platelets circulate in blood at a concentration of 150,000- 450,000/µl that is maintained by a fine balance between National Institutes of Health R01 HL126743 “Endocytosis production and clearance. At sites of vascular injury, in Platelet and Megakaryocyte Biology” platelets respond to external stimuli by rapidly changing “Platelet Fireworks”, showing Dnm2-null platelets on shape and recruiting other platelets. Deficient platelet Publications a fibrinogen surface after GPVI activation. production, due to genetic causes, secondary to cancer 1. Grozovsky R, Begonja AJ, Liu K, Visner G, Hartwig JH, Winner, 2019 Platelets cover competition. therapy, or from unknown etiology, poses significant risks Falet H, Hoffmeister KM. The Ashwell-Morell receptor

8 Versiti Blood Research Institute Senior Medical Director, Versiti Joshua Field, MD, MS Investigator, Blood Research Institute Professor of Medicine, Medical College of Wisconsin Medical Director, Adult Sickle Cell Disease Clinic, Froedtert Hospital MD, Carver College of Medicine, University of Iowa, Iowa City, IA 2001 Started at Versiti: 2010

Awards, Honors and Service 2. Yu JC, Lin G, Field JJ, Linden J. Induction of antiinflammatory purinergic signaling in activated • Member, American Society of Hematology Guidelines human iNKT cells. JCI Insight. 2018 Sep 6;3(17). PMID: on Sickle Cell Disease Committee 2017 30185656 • Chair, Acute Pain Taxonomy Project for American Pain 3. AAAPT Diagnostic Criteria for Acute Sickle Cell Society/American Association for Pain Management Disease Pain. Field JJ, Ballas SK, Campbell CM, Crosby 2017 LE, Dampier C, Darbari DS, McClish DK, Smith WR, • Thomas A. Smallwood Award, Froedtert Hospital, WI “In Zempsky WT. J Pain. 2018 Dec 19. recognition of Patient Care Excellence 2017 • American Society of Hematology: Committee on Quality, Washington, DC, 2016-present • Ad hoc reviewer: K01 Diversity Review, NHLBI, Bethesda, MD, 2018 Funding “A Phase 1 Open-Label, Dose-Escalation/Dose-Expansion fMRI Safety and Tolerability Study of INCB059872 in Subjects Cingulate Cortex with Sickle Cell Disease” Incyte Corporation 11/01/2017 – Medial 10/31/2019 Frontal Gyrus Precuneus Research Interests “C1701-202 A Randomized, Placebo-controlled, Phase 2 Study to Evaluate the Safety and Pharmacodynamics Dr. Field is concerned with clinical aspects and of Once-daily Oral IW-1701 in Patients with Stable Amygdala optimization of treatment for adults with sickle cell Sickle Cell Disease” Ironwood Pharmaceuticals, Inc. disease (SCD). He was the principal investigator on 06/01-2018-present. a multi-center trial to evaluate effectiveness of the PAG adenosine2A receptor agonist regadenoson, an inhibitor Pain Centers of that may be useful for treatment of blood Publications vessel occlusion in SCD, as well as a trial to evaluate the 1. Lanzkron S, Little J, Field J, Shows JR, Wang H, Seufert cysteinyl leukotriene receptor antagonist, montelukast. R. Brooks J, Varadhan R, Haywood C Jr, Saheed M, Dr. Field also examined a novel imaging modality, Huang CY, Griffin B, Frymark S, Piehet A, Robertson D, Peripheral contrast-enhanced ultrasound, for the measurement of Proudford M, Kincaid A, Green C, Burgess L, Wallace Nerves microvascular blood flow in patients with SCD. Currently, PAIN Spinal Cord M, Segal J. Increased Acute Care Utilization in a Dr. Field is pursuing a study to taper opioids in patients Prospective Cohort of Adults with Sickle Cell Disease. INJURY/ with SCD and measure effects on functional MRI imaging INFLAMMATION Blood Adv 2018 Sep 25;2(18):2412-2417. PMID: Opioids of the brain. 30254105 Vascular Occlusion

Research Report 2018 9 Marqus Valentine Marqus Valentine has beaten sickle cell disease – and the odds. Many sickle cell disease patients do not live into adulthood. Marqus has made it into his 30s thanks to the generosity of blood donors, who have helped him receive more than 500 life-saving donations during his life. He’s grateful to blood donors and is now giving back to help other sickle cell patients in need.

“SC got scary for me when I was in high school because I could understand that I might not come out of the hospital.” Senior Medical Director, Versiti Jerome Gottschall, MD Senior Investigator, Blood Research Institute, Versiti Professor of Pathology, Department of Pathology, Medical College of Wisconsin MD, Ohio State University College of Medicine, 1974 Started at Versiti: 1979

blood products in distinct clinical settings. Dr. Gottschall EL; National Heart, Lung, and Blood Institute (NHLBI) also is concerned with the clinical aspects of immune Recipient Epidemiology and Donor Evaluation Study-III hemolytic anemia and in the status of iron levels in repeat (REDS-III). Contemporary Risk Factors and Outcomes blood donors. In 2015, Dr. Gottschall participated as of Transfusion-Associated Circulatory Overload. Crit co-author on two important articles, published in Lancet Care Med. 2018 Apr;46(4):577-585. PMID: 29300236 Haematology and Transfusion, about the importance 4. Van Buren NL, Gorlin JB, Reed RC, Gottschall JL, Nelson of red cell genotyping for transfusion medicine. An avid SC. Ceftriaxone-induced drug reaction mimicking athlete throughout his entire life, Dr. Gottschall says acute splenic sequestration crisis in a child with sports have taught him three critical life skills that he uses hemoglobin SC disease. Transfusion. Apr;58(4):879- in his medical work and throughout his life: discipline; 883 PMID: 29473172 persistence; and setting goals. 5. Wei S, Gonzalez Rodriguez E, Chang R, Holcomb JB, Awards, Honors and Service Kao LS, Wade CE; PROPPR Study Group…Gottschall, JL. Elevated Syndecan-1 after Trauma and Risk • Member, College of American Pathologists of Sepsis: A Secondary Analysis of Patients from • Member, American Association of Blood Banks the Pragmatic, Randomized Optimal Platelet and (AABB) Plasma Ratios (PROPPR) Trial. J Am Coll Surg. 2018 Dec;227(6):587-595. PMID: 30243993 • Member, American Society of Hematology Publications 1. Gehrie EA, Roubinian NH, Chowdhury D, Brambilla Research Interests DJ, Murphy EL, Gottschall JL, Wu Y, Ness PM, Strauss Dr. Gottschall is a Co-Principal Investigator on the RG, Hendrickson JE; NHLBI Recipient Epidemiology- Recipient Epidemiology and Donor Evaluation Study- Donor Evaluation Study (REDS-III). A multicentre III (REDS III) sponsored by the National Heart Lung study investigating vital sign changes occurring in and Blood Institute in which Versiti is one of several complicated and uncomplicated transfusions. Vox participating organizations. REDS III includes studies Sang. 2018 Feb;113(2):160-169. PMID: 29277907 on blood safety, blood availability, HIV transmission and 2. Glisch C, Jawa Z, Brener A, Carpenter E, Gottschall other transfusion-related studies. REDS III will utilize J, Treml A, Karafin MS. Evaluation of a two-sample large donor, component and recipient databases to process for prevention of ABO mistransfusions in a high help answer important transfusion-related questions. volume academic hospital. BMJ Open Qual. 2018 Jul Among subjects to be studied are alloimmunization 15;7(3):e000270. PMID: 30057954 ( against transfused blood cells), impact of on donor iron levels, benefits of red 3. Roubinian NH, Hendrickson JE, Triulzi DJ, Gottschall cell transfusion in the elderly, and transfusion of various JL, Michalkiewicz M, Chowdhury D, Kor DJ, Looney MR, Matthay MA, Kleinman SH, Brambilla D, Murphy

Research Report 2018 11 Medical Director, Medical Sciences Institute, Versiti Matthew Karafin, MD Associate Investigator, Blood Research Institute, Versiti Associate Professor of Pathology, Medical College of Wisconsin MD, Carver College of Medicine, University of Iowa, Iowa City, IA, 2007 Transfusion Medicine Fellowship, Johns Hopkins Hospital, 2011 Anatomical and Clinical Pathology Residency, Johns Hopkins Hospital, 2012 MS, Medical College of Wisconsin, Milwaukee, WI, 2015 Started at Versiti: 2012

• Member, College of American Pathologists (CAP) Donor Evaluation Study-III (REDS-III). Risk factors • Member American Society of Hematology (ASH) for red blood cell alloimmunization in the Recipient Epidemiology and Donor Evaluation Study (REDS-III) • Member, American Society for Clinical Pathology database. Br J Haematol. 2018 Jun;181(5):672-681. (ASCP) PMID: 9675950 • Member, Alpha Omega Alpha (AOA) Funding HHSN268201100003I (Mast) 03/15/2011 – 03/14/2020 NIH/NHLBI $511,520 “Recipient Epidemiology and Donor Evaluation Study III (REDS III)” (Co-I) 1K23HL136787-01A1 (Karafin) 12/15/2017 – 12/15/2022 NIH/NHLBI $165,000 “The Effects of Older Red Cell Units in Adults with Sickle Cell Disease”(PI) Publications 1. Karafin MS, Fu X, D’Alessandro A, Thomas T, Hod EA, Zimring JC, Field JJ, Francis RO. The clinical impact of glucose-6-phosphate dehydrogenase deficiency in patients with sickle cell disease. Curr Opin Hematol. Research Interests 2018 Nov;25(6):494-499. PMID: 30239377 Dr. Karafin’s research interests include the use of red cell 2. Karafin MS, Singh M, Ceesay M, Koduri S, Zhang L, transfusion for patients with sickle cell disease, etiology Simpson P, Field JJ. Dyspareunia is associated with and prevention of red cell alloimmunization, benefits chronic pain in premenopausal women with sickle and risks of red cell storage for patients with sickle cell cell disease. Hematology. 2018 Jan 29:1-6. PMID: disease, benefits and risks of red cell transfusions in the 29376481 elderly, and the etiology and prevention of transfusion 3. Karafin MS, Singavi A, Hussain J, Wandersee N, Heinrich reactions. T, Hurley RW, Zhang L, Simpson P, Field JJ. Predictive factors of daily opioid use and quality of life in adults Awards, Honors and Service with sickle cell disease. Hematology. 2018 May 31:1-8. PMID: 29848208 • Member, American Society for (ASFA) 4. Karafin MS, Westlake M, Hauser RG, Tormey CA, • Member, American Association of Blood Banks Norris PJ, Roubinian NH, Wu Y, Triulzi DJ, Kleinman S, (AABB): Chair, Molecular Testing Accreditation Hendrickson JE; NHLBI Recipient Epidemiology and Program Unit Committee

12 Versiti Blood Research Institute Associate Investigator, Blood Research Institute Anand Padmanabhan, Medical Director, Therapeutic Services, Versiti Associate Professor of Pathology, Medical College of Wisconsin MD, Thanjavur Medical College, Thanjavur, TN, India, 2000 MD, PhD, PhD, Brown University, 2006 Started at Versiti: 2010

Awards, Honors and Service 2. Dhakal B, Baumann-Kreuziger L, Rein L, Kleman A, Fraser R, Hari P and Padmanabhan A*. Disease • American Society for Apheresis Lecturer Award, 2018 burden, complication rates, and health-care costs • Editor, Journal of Clinical Apheresis (JCA), of heparin-induced thrombocytopenia in the USA: 08/2015-present a population-based study. Lancet Haematol. 2018 May;5(5):e220-e231 • Chair, JCA Writing Committee on the Use of Apheresis in Human Disease, (2016-present) 3. Pandya K, Davis G, Johnson E and Padmanabhan A. Serotonin Release Assay (SRA)-Negative HIT, a newly • Member, American Association of Blood Banks (AABB) recognized entity: Implications for diagnosis and • Member, American Society for Apheresis (ASFA) management. Thrombosis Research, 2018 Dec;172:169- • Member, American Society of Hematology (ASH) 171. 4. Irani M, Siegal E, Jella A, Aster RH and Padmanabhan Publications: A. Use of Intravenous to Treat Spontaneous Heparin-induced Thrombocytopenia. 1. Jones CG, Pechauer SM, Curtis BR, Bougie DW, Aster Transfusion. Epub ahead of print, Transfusion, Dec 2018 RH and Padmanabhan A*. IgG in Normal Plasma Inhibits HIT Antibody-mediated Platelet Activation: Implications for Plasma Exchange in HIT. Blood 2018 Figure: Model showing how we think HIT antibodies Feb 8;131(6):703-706.* Corresponding Author actually cause platelet activation in HIT (from Padmanabhan et al, Blood 2015) Research Interests Heparin is widely used to prevent and treat thrombosis, but some patients given this otherwise useful anticoagulant become immunized and produce antibodies that cause thrombocytopenia (heparin- induced thrombocytopenia, HIT). Many affected individuals experience thrombosis, which can be life threatening. Dr. Padmanabhan is engaged in studies to define the properties of heparin-induced antibodies that are most likely to cause thrombosis. Findings made are expected to advance the understanding of HIT and to improve laboratory diagnosis and treatment of this dangerous disorder.

Research Report 2018 13 Glycomics Center

The Glycomics Center, led by faculty member Dr. Karin Hoffmeister, opened its doors in 2016 for the Blood Research Institute. Analogous to Genomics and Proteomics, Glycomics focuses on defining the structures and functions of complex carbohydrates (sugars), as found in glycoproteins, glycolipids, and glycosaminoglycans.

Complex carbohydrates are important in many physiological processes and alterations in glycosylation are associated with vast numbers of blood related and unrelated diseases and disorders. The specific focus of the Center is to harness genomic with glycomic approaches with an emphasis on exploring transcriptional and epigenetic regulatory mechanisms of carbohydrate synthesis in health and disease. The data will help to understand and predict molecular mechanisms of carbohydrate expression and recognition by proteins important in human biology and disease. The Center will bring together scientists at BloodCenter of Wisconsin and other institutions to understand the role that sugars play in biology. Senior Investigator, Blood Research Institute, Versiti Karin Hoffmeister, MD Professor of Biochemistry, Medical College of Wisconsin Director of Translational Glycomics Center Lecturer on Medicine, Harvard Medical School, Brigham and Women’s Hospital Associate Professor of Pediatrics, Boston Children’s Hospital MD, Technical University of Aachen, Aachen, Germany, 1993 Doctor of Medicine, Doctoral Research Program, Technical University of Aachen, 1995 Started at Versiti: 2016

functions. Dr. Hoffmeister’s studies expand toward defining glycosyltransferases cell-specific transcriptional regulatory mechanisms during hematopoiesis to combine phenotypic surface carbohydrate expression with genomic and epigenetic data in hematopoietic cells. Awards, Honors and Service • Member, Hemostasis and Thrombosis Study Section • Member, Transfusion Medicine Study Section, special panel • Member, American Society of Hematology • Chair Megakaryocytes and Platelet Scientific Committee Funding RO1 HL089224-10 “Carbohydrate Mediated Platelet Clearance” PO1 HL 107146-06 “Biosynthesis and Function of Research Interests Lactosaminyl Glycans in Hematopoiesis” Dr. Hoffmeister investigates how glycans regulate U54 HL119145-04 “Novel Approaches for Platelet Storage hematopoiesis and end-effector blood cells, including B-Bic Drive” platelets. The general theme of Dr. Hoffmeister’s research K12 HL141954-01 “Glycans in Blood Hematopoiesis and is to better understand the role of carbohydrates in Disease” hematopoietic stem cells, megakaryocytes and platelet function, survival, and interaction with other blood Publications cells. Carbohydrate biosynthesis in nucleated cells is a highly regulated process involving several hundred 1. Hoffmeister KM. TPO-logy accepted. Blood. 2018 Aug glycosyltransferases. Correct glycan biosynthesis 9;132(6):555-557. PMID: 30093383 depends on the correct architecture and topology of the endoplasmic reticulum (ER) and Golgi apparatus. During maturation, differentiation and inflammation programmed remodeling of cell surface glycans takes place by the regulated expression of specific glycosyltransferases to regulate different biological Thrombosis, Hemostasis & Vascular Biology

The Thrombosis, Hemostasis and Vascular Biology Program is concerned with cellular and molecular mechanisms of normal blood clotting, pathological thrombosis, and events impacting the integrity of the blood vessels that transport blood throughout our body.

Studies conducted in the laboratories of the BRI range from basic scientific investigations of blood coagulation and platelet function, to the pathophysiology, treatment, and diagnosis of bleeding and clotting disorders. Executive Vice President, Medical Sciences Institute and Chief Medical Officer, Versiti Thomas C Abshire, MD Senior Investigator, Blood Research Institute Professor of Pediatrics, Medicine and the CTSI, Medical College of Wisconsin MD, Tulane University School of Medicine, 1979 Pediatrics, David Grant USAF Medical Center, Travis AFB, CA 1979-82 Pediatric Hematology, University of Colorado Health Science Center, 1985-88 Started at Versiti: 2009

Awards, Honors, and Service disease in the United States: perspective from the Zimmerman program. Ann Blood. 2018 Jan;3. pii: 7. • Member, American Society of Hematology PMID: 30135959 • Past President, Hemostasis and Thrombosis Research 2. Holm E, Carlsson KS, Lövdahl S, Lail AE, Abshire Society (HTRS) TC, Berntorp E. Bleeding-related hospitalization in • Best Doctors in America 2009-2018 patients with von Willebrand disease and the impact of prophylaxis: Results from national registers in Sweden • CTSI of SE WI Board of Directors compared with normal controls and participants in the von Willebrand Disease Prophylaxis Network. Funding Haemophilia 2018 Jul;24(4):628-633. PMID: 29626372 5R01HL112614-05 Montgomery/Abshire (Multiple PIs) 3. Malec L, Abshire T, Jobe S, White G. rFIXFc for 12/14/2013 – 11/30/2018 NIH/NHLBI “Comparative Induction in a Severe Hemophilia Effectiveness in the Diagnosis of VWD” B Patient with an Inhibitor and Prior History of ITI Related Nephrotic Syndrome. Haemophilia. 2018 Publications Jul;24(4):e294-e296. PMID: 30024646 1. Flood VH, Abshire TC, Christopherson PA, Friedman KD, Cox Gill J, Montgomery RR, Haberichter SL; Zimmerman Program Investigators. Von Willebrand

Plateletessel nteraction Research Interests One of Dr. Abshire’s major research interests involves Adesion Areation ibrin lot conducting clinical trials in patients with bleeding and thrombotic disorders with the aim of defining disease Unactivated Platelets characteristics and evaluating new approaches to Activated GPIIbIIIa Fibrinogen Fibrin treatment. A recent focus is the evaluation of mild Platelets bleeding conditions in both children and adults, particularly those affected by von Willebrand Disease (VWD). With Robert Montgomery, MD, Dr. Abshire and GPIb a team of investigators from 12 centers across North VWF America have just finished the fifth year of a study funded by the NIH entitled “Comparative Effectiveness in the Endothelial Collagen Actiated Platelets Diagnosis of VWD” which is focusing on new diagnoses of Cells 1. Alpha granules 2. Dense granules VWD and how to better define this bleeding disorder from -VWF -ATP, ADP a clinical, laboratory and molecular basis. -FV, FXI -Ca++ -Fibrinogen

Research Report 2018 17 Associate Medical Director/Associate Investigator, Blood Research Institute, Versiti Lisa Baumann Kreuziger, Assistant Professor, Dept. of Medicine, Division of Hematology/Oncology, Medical College of Wisconsin MD, University of Wisconsin School of Medicine and Public Health, 2006 MD, MS Started at Versiti: 2013

patients will develop thrombotic complications including 2. Baumann Kreuziger L, Slaughter MS, Sundareswaran stroke or LVAD failure. Dr. Baumann-Kreuziger was K, Mast AE. Clinical Relevance of Histopathologic awarded a pilot grant from the Clinical and Translational Analysis of HeartMate II Thrombi. ASAIO J. 2018 Nov/ Sciences Institute to evaluate potential mechanisms of Dec;64(6):754-759. PMID: 29461277 thrombosis in patients with left ventricular assist devices. 3. Moyer GC, Bannow BS, Thornburg C, Rosovsky R, Wang TF, Woller S, Thornhill D, Kreuziger LB. A Survey Awards, Honors and Service of Oral Anticoagulant Preferences in the Treatment • Top Patient Experience Recognition, Froedtert Hospital of Challenging Patient Populations. Clin Appl Thromb 2018 Hemost. 2018 Oct 2:1076029618804080. PMID: 30278766. Leuk Lymphoma. 2018 Jun;59(6):1348- • Medical Student Teaching Pin, 2018 1355. PMID: 28905668 • American Society of Hematology Thrombophilia 4. Baumann Kreuziger LM, Massicotte MP. Adult and Guideline panel 2018 pediatric mechanical circulation: a guide for the hematologist. Hematology Am Soc Hematol Educ Funding Program. 2018 Nov 30;2018(1):507-515. PMID: “Evaluating thrombi composition and persistent 30504351 coagulation activation in the pathophysiology of left ventricular assist device (LVAD) thrombosis” NIH $80,000 (PI) 7/2015 – 6/2019 “Direct Oral Anticoagulants (DOACs) versus LMWH Research Interests +/- warfarin for VTE in cancer: A Randomized Venous thromboembolism occurs in more than a half Effectiveness Trial (CANVAS)” Alliance Foundation million Americans every year. Anticoagulation after (PI) 05/27/2017 – present venous thrombosis can prevent recurrence but is associated with a risk of bleeding. Dr. Baumann-Kreuziger “Post-Thrombotic Syndrome and Predictors of aims to define the best treatment course for cancer Recurrence in Catheter-Related Thrombosis” patients with thrombosis associated with catheters and determine if a biomarker can be used to predict Publications recurrence. Identification of a biomarker would allow 1. Baumann Kreuziger L, Karkouti K, Tweddell J, anticoagulation to be individualized based on each Massicotte MP. Antithrombotic Therapy Management patient’s risk profile. Patients with heart failure who of Adult and Pediatric Cardiac Surgery Patients. J require implanted left ventricular assist devices (LVADs) Thromb Haemost. 2018 Nov;16(11):2133-2146. Review. are another group that is at high risk for bleeding and PMID: 30153372 thrombotic complications. Despite use of anticoagulant and antiplatelet medications, approximately 10% of LVAD

18 Versiti Blood Research Institute Investigator, Blood Research Institute Magdalena Associate Professor in Pharmacology and Toxicology, Medical College of Wisconsin Research Member, Medical College of Wisconsin Cancer Center Medical College of Wisconsin Cardiovascular Center Chrzanowska, PhD, PhD, University of North Carolina at Chapel Hill, 1996 MSc, Jagiellonian University, Krakow, Poland, 1991 FAHA Started at Versiti: 2005

the blood vessel wall in atherosclerotic disease. In 2016, Center: Atherosclerosis, Thrombosis and Vascular Dr. Chrzanowska succeeded in obtaining the renewal of Biology Signature Program 2011- present grant support from the National Institutes of Health for • Member, Medical College of Wisconsin Cancer Center, her work. Cancer Cell Biology Research Program - 2011 - Present The complications of cardiovascular disease remain • NIH Vascular Cell and Molecular Biology Study Section major killers of the American population. The – 2015-2019 maintenance of normal cardiovascular function is critically dependent on vascular endothelium – cells that line blood vessels. Dr. Chrzanowska’s research Funding is focused on understanding molecular mechanisms NIH/NHLB R01 - HL111582-05 Chrzanowska-Wodnicka, underlying critical endothelial cell functions, such as M, (PI) 4/16/12 - 6/30/20 “Rap1 in endothelial preventing blood leakage, selective transfer of cells and homeostasis” substances to and from the blood stream, regulation of blood pressure, and restorative and pathogenic new blood Publications vessel growth. 1. Lakshmikanthan S, Sobczak M, Li Calzi S, Shaw L, Dr. Chrzanowska’s recent research revealed new Grant MB, Chrzanowska-Wodnicka M. Rap1B promotes mechanisms through which endothelial cells respond VEGF-induced endothelial permeability and is required to the flow of blood and how defects in these responses for dynamic regulation of endothelial barrier. J Cell Sci. contribute to atherosclerosis in an in vivo disease model. 2018 Jan 10;131(1). PMID: 29222111 These are the first necessary steps in developing new strategies to restore endothelial function to prevent Research Interests the progression of atherosclerosis. Furthermore, these Endothelial cells (EC) cover the inner surface of blood studies provided novel insights into mechanisms vessels and perform many critical functions, such as through which endothelial cells maintain barrier under preventing leakage of blood cells and plasma from the normal conditions. Importantly, Dr. Chrzanowska’s circulation, preventing inappropriate blood clotting, studies identified potential novel therapeutic targets for regulating selective transfer of cells and substances into pathological vascular hyper-permeability associated with and out of blood vessels, and maintaining the correct early diabetes. blood pressure. Importantly, EC can adapt their functions to their Awards, Honors and Service environment, by sensing blood flow and the presence of • American Heart Association, ATVB Council – 2019 AHA inflammatory signals. Scientific Sessions Programming Committee 2018 Dr. Chrzanowska studies how a protein, designated Rap1, • Affiliate Member, Clinical and Translational Science regulates the response of EC to changes in blood flow and Institute of SE Wisconsin 2011-present inflammation. Her work helps understand the processes • Member, Medical College of Wisconsin Cardiovascular causing hypertension and the narrowing and hardening of

Research Report 2018 19 Associate Professor of Pediatric Hematology, Medical College of Wisconsin Veronica H. Flood, MD Associate Investigator, Blood Research Institute, Versiti MD, Tufts University School of Medicine, 1999 Started at Versiti: 2016

vessel injury, the VWF-collagen interaction is an important • Co-Chair, Von Willebrand Disease Management component of hemostasis. She also is interested in the Guideline Panel, ASH/ISTH/NHF/WFH genetics of von Willebrand disease (VWD). Through • Outstanding Medical Student Teacher, Medical College collaboration with Dr. Robert Montgomery and the of Wisconsin, 2017-2018 Zimmerman Program for the Molecular and Clinical Biology of VWD, Dr. Flood has worked on characterizing genetic changes in VWD, with particular attention to Funding variants that affect platelet and collagen binding. Dr. R01 HL126810 “Mechanism of Type 4 Collagen Flood has been funded by the National Heart Lung and Interactions with Von Willebrand Factor” (PI) Blood Institute since 2010, initially through a K08 award R01 HL112614 “Comparative Effectiveness in the and subsequently transitioned to independent funding Diagnosis of VWD” (Co-I) through an R01 grant. Awards, Honors and Service Publications 1. Flood, V.H., Johnsen, J.M., Kochelek, C., Slobodianuk, • Standing member, NIH Study Section, National Heart, T.L., Christopherson, P.A., Haberichter, S.L., Udani, R., Lung, and Blood Institute, Mentored Patient-Oriented Bellissimo, D.B., Friedman, K.D., Montgomery, R.R. Research review panel Common VWF Sequence Variants Associated with • Vice-Chair, Mentored Research Award Committee Higher VWF and FVIII Are Less Frequent in Subjects ,Hemostasis and Thrombosis Research Society Diagnosed with Type 1 VWD. Res Pract Thromb Haemost 2(2):390-398, 2018. Research Interests 2. *Alaqzam, T., Stanley, A.C., Simpson, P.M., Flood, V.H., Menon, S. Treatment Modalities in Adolescents Who Dr. Flood is a pediatric hematologist and researcher Present With Heavy Menstrual Bleeding. J Pediatr at the Medical College of Wisconsin in Milwaukee. She Adolesc Gynecol 31(5);451-458, 2018. received her medical degree from Tufts University School of Medicine, and went on to complete a residency in 3. *Keesler, D.A., Flood, V.H. Current Issues in Diagnosis pediatrics at Phoenix Children’s Hospital and a fellowship and Treatment of von Willebrand Disease. Research in pediatric hematology/oncology at Oregon Health and and Practice in Thrombosis and Haemostasis, 2(1):34- Science University. 41, 2018. She began her research career as an undergraduate 4. Flood, V.H., Abshire, T.C., Christopherson, P.A., studying primate genetics in the Department of Friedman, K.D., Gill, J.C., Montgomery, R.R., Anthropology at Harvard University. Her academic career Haberichter, S.L., the Zimmerman Program in hemostasis research includes work on the biology of Investigators. Von Willebrand Disease in the United von Willebrand factor (VWF). Dr. Flood is interested in how States: Perspective from the Zimmerman Program. VWF interacts with two of its main partners, platelet GPlb Ann Blood 2018;3:7. and collagen. Since collagen is exposed at sites of blood * First author a trainee.

20 Versiti Blood Research Institute Medical Director Hemostasis Reference Lab, Diagnostic Labs, Versiti Kenneth Friedman, MD Associate Investigator Blood Research Institute, Versiti Assistant Medical Director Comprehensive Center for Bleeding Disorders Associate Professor of Internal Medicine and Pathology, Medical College of Wisconsin MD, SUNY Upstate Medical University, Syracuse, NY 1980 Started at Versiti: 1997

markers. Dr. Friedman’s other area of interest relates 4. St Ledger K, Feussner A, Kalina U, Horn C, Metzner HJ, to utilization of plasma and genetic markers to better Bensen-Kennedy D, Blackman N, Veldman A, Stowers understand the mechanisms underlying the bleeding that A, Friedman KD. International comparative field occurs in patients with defects of von Willebrand factor. study evaluating the assay performance of AFSTYLA in plasma samples at clinical hemostasis laboratories. Awards, Honors and Service J Thromb Haemost. 2018 Mar;16(3):555-564. PMID: 9274194 • Co-Director, National Marrow Donor Program – Versiti Branch 2017 • Best Doctors in America 2018 • Medical Director of the Apheresis Center for the NMDP site in Milwaukee 2018 • Ad hoc Reviewer, Journal of Thrombosis and Hemostasis, Blood, and Transfusion and Transplantation 2018 Publications 1. Flood VH, Johnsen JM, Kochelek C, Slobodianuk TL, Christopherson PA, Haberichter SL, Udani R, Bellissimo DB, Friedman KD, Montgomery RR. Common VWF Research Interests sequence variants associated with higher VWF and FVIII are less frequent in subjects diagnosed with Thrombotic microangiopathies are a collection of type 1 VWD. Res Pract Thromb Haemost. 2018 Jan diseases characterized by formation of platelet/ 23;2(2):390-398. PMID: 30046743 protein aggregates that obstruct the microcirculation, resulting in multi-organ dysfunction. Microthrombi in 2. Flood VH, Abshire TC, Christopherson PA, Friedman thrombotic thrombocytopenic purpura are rich in von KD, Cox Gill J, Montgomery RR, Haberichter SL; Willebrand factor as a consequence of deficiency of Zimmerman Program Investigators. Von Willebrand the von Willebrand factor control enzyme ADAMTS13. disease in the United States: perspective from the Alternatively in atypical hemolytic uremic syndrome, Zimmerman program. Ann Blood. 2018 Jan;3. pii: 7. the microthrombi are rich in fibrin as a consequence of PMID: 30135959 disordered complement regulation and endothelial cell 3. Friedman KD, Powell JS, Bensen-Kennedy D. injury. The current focus of Dr. Friedman’s research of Response: The coagulation laboratory monitoring of thrombotic microangiopathies is the evaluation of patient AFSTYLA single-chain FVIII concentrate. Haemophilia. plasma and genetic samples in order to identify patterns 2018 May;24(3):e129-e131.PMID: 29603512 of disease, underlying risk factors and prognostic

Research Report 2018 21 Alex & Braxton Woltring

“We were fortunate blood was available to treat our daughter. Now, we can look forward to her future,” says Adelaide’s mom, Katie.

Thanks to BloodCenter’s innovative research, Adelaide is living a normal, healthy life. Adelaide has von Willebrand disease. At age 5, she had multiple spontaneous bleeds and received blood transfusions that helped save her life. (1943-2018) Joan Cox Gill, MD Senior Investigator, Blood Research Institute, Versiti Director, Comprehensive Center for Bleeding Disorders Professor, Pediatrics and Medicine, Medical College of Wisconsin MD, Medical College of Wisconsin 1976 Started at Versiti: 1991

Hemophilia Foundation Regional Committee to (HTCN) Study Investigators. Risk factors associated investigate treatment guidelines in hemophilia and with invasive orthopaedic interventions in males with other bleeding disorders and was leading several haemophilia enrolled in the Universal Data Collection pharmaceutical contract research studies to evaluate program from 2000 to 2010. Haemophilia. 2018 replacement therapy products for patients with Nov;24(6):964-970. PMID: 29957840 hemophilia and von Willebrand disease. Her colleagues at the Blood Research Institute, the Medical College of Wisconsin and the Great Lakes Hemophilia Foundation will miss her wise counsel and her unstinting advocacy for patients with bleeding and clotting disorders. Awards, Honors and Service • Member, Science Committee, CDC Public Health Surveillance for Bleeding Disorders 2017 • Best Doctors in America 2017 • Medical Expert Panel; Federal Division of Vaccine Compensation 2017 Publications 1. Flood VH, Abshire TC, Christopherson PA, Friedman Research Interests KD, Cox Gill J, Montgomery RR, Haberichter SL; The Blood Research Institute and Medical College of Zimmerman Program Investigators. Von Willebrand Wisconsin lost a valued colleague and friend with the disease in the United States: perspective from the passing of Joan Cox Gill in 2018. Dr. Gill devoted her entire Zimmerman program. Ann Blood. 2018 Jan;3. pii: 7. career to clinical research concerning the diagnosis PMID: 30135959 and treatment of bleeding and clotting disorders in 2. Sood SL, Cheng D, Ragni M, Kessler CM, Quon D, both adult and pediatric populations. As of 2018, she Shapiro AD, Key NS, Manco-Johnson MJ, Cuker A, was co-investigator of a study to evaluate the ability of Kempton C, Wang TF, Eyster ME, Kuriakose P, von bleeding questionnaires to predict surgical bleeding Drygalski A, Gill JC, Wheeler A, Kouides P, Escobar MA, in tonsillectomies and molar tooth extractions; co- Leissinger C, Galdzicka S, Corson M, Watson C, Konkle principal investigator of a study to characterize the BA. A cross-sectional analysis of cardiovascular disease pharmacogenetics of the anticoagulant warfarin in in the hemophilia population. Blood Adv. 2018 Jun pediatric patients with thrombosis; and an investigator 12;2(11):1325-1333. PMID: 29895623 and member of the science and advisory committees of the CDC national study of the complications of 3. Tobase P, Lane H, Siddiqi AE, Soucie JM, Ingram-Rich R, hemophilia. She was also chair of the Great Lakes Ward S, Gill JC; Hemophilia Treatment Center Network Research Report 2018 23 Investigator, Blood Research Institute, Versiti Sandra Haberichter, PhD Director of Hemostasis Reference Laboratory, Versiti Associate Professor of Pediatrics, Medical College of Wisconsin PhD, University of Wisconsin-Milwaukee, 1998 Fellowship, Blood Research Institute, Versiti, 1998-2003 Started at Versiti: 1998

defining the molecular basis for accelerated clearance Publications of VWF in patients with this form of VWD. Knowledge gained in these studies is expected to improve laboratory 1. Flood VH, Johnsen JM, Kochelek C, Slobodianuk TL, diagnosis and treatment of this common bleeding Christopherson PA, Haberichter SL, Udani R, Bellissimo disorder. DB, Friedman KD, Montgomery RR. Common VWF sequence variants associated with higher VWF and Awards, Honors and Service FVIII are less frequent in subjects diagnosed with type 1 VWD. Res Pract Thromb Haemost. 2018 Jan • Member, American Society of Hematology 2018 23;2(2):390-398. PMID: 30046743 • Chair, ISTH SSC scientific committee on von Willebrand 3. Jacobi PM, Kanaji S, Jakab D, Gehrand AL, Johnsen JM, Factor 2018 Haberichter SL. Von Willebrand Factor Propeptide to • Member, International Society on Thrombosis and Antigen Ratio Identifies Platelet Activation and Reduced Haemostasis 2018 VWF Survival Phenotype in Mice. J Thromb Haemost. 2018 Feb;113(2):160-169. PMID: 29285851 Funding 4. Kanaji S, Orje JN, Kanaji T, Kamikubo Y, Morodomi Y, Chen Y, Zarpellon A, Eberhardt J, Forli S, Fahs SA, R01 HL136430 “VWF- Mechanisms of Regulation” Sood R, Haberichter SL, Montgomery RR, Ruggeri ZM. Humanized GPIbα-von Willebrand factor interaction in the mouse. Blood Adv. 2018 Oct 9;2(19):2522-2532. PMID: 30287479 Research Interests The plasma protein von Willebrand factor (VWF) plays 33 Increased VWF clearance is prevalent in a critical role in enabling blood platelets to interact with 30 moderately severe type 1 VWD. damaged blood vessels and stop bleeding. Genetically 27 76% 38% 7% determined abnormalities of VWF function and synthesis 24 VWFpp/VWF:Ag < 3 predicts reduced cause von Willebrand Disease (VWD), a source of abnormal bleeding that affects about one percent of the 21 Increased synthesis/secretion phenotype (blue). general population. Dr. Haberichter’s work is aimed at 18 Clearance characterizing various genetic defects that cause VWD 15 (VWFpp/VWF:Ag>3) VWFpp/VWF:Ag > 3 predicts increased plasma and defining how these defects affect the structure and 12 VWF clearance (green). function of the large, highly complex VWF molecule.

VWFpp/VWF:Ag 9 Recent findings have shown that low VWF levels in Reduced 76% of subjects with VWF:Ag ≤ 10 IU/dL and 6 patients with a sub-type of VWD, designated Type 1C, Secretion 38% of subjects with VWF:Ag = 11-20 IU/dL decrease VWF levels by shortening the survival of VWF in 3 have an increased VWF clearance phenotype the circulation and have led to a novel laboratory assay 0 (type 1C). to diagnose this condition. Her current work is aimed at 0 10 20 30 40 50 VWF:Ag (IU/dL) 24 Versiti Blood Research Institute Medical Director, Comprehensive Center for Bleeding Disorders (CCBD) Shawn Jobe, MD, PhD Associate Investigator, Blood Research Institute, Versiti Associate Professor, Department of Pediatrics and Cell Biology, Neurobiology, and Anatomy PhD, Medical College of Wisconsin, 1998 MD, Medical College of Wisconsin, 1999 Started at Versiti: 2013

and prevention of thrombosis in aging-related diseases. Clin North Am. 2018 Jun;65(3):561-578. Review. PMID: Platelet procoagulant activity also is important in the 29803283 prevention of bleeding. In other work, researchers in Dr. 5. Yang M, Kholmukhamedov A, Schulte ML, Cooley BC, Jobe’s lab are investigating how procoagulant platelets Scoggins NO, Wood JP, Cameron SJ, Morrell CN, Jobe might work to prevent bleeding in patients with severe SM, Silverstein RL. Platelet CD36 signaling through hemophilia. ERK5 promotes caspase-dependent procoagulant activity and fibrin deposition in vivo. Blood Adv. 2018 Awards, Honors and Service Nov 13;2(21):2848-2861. PMID: 30381401 • Standing member American Heart Association Thrombosis/Hemostasis Study Section • National Hemophilia Foundation Clinical Fellowship Advisory Board • Member International Society on Thrombosis and Hemostasis Publications 1. Kholmukhamedov A, Janecke R, Choo HJ, Jobe SM. The mitochondrial calcium uniporter regulates procoagulant platelet formation. J Thromb Haemost. Research Interests 2018 Nov;16(11):2315-2321. PMID: 30179298 2. Malec L, Abshire T, Jobe S, White G. rFIXFc for Platelets are required to stop bleeding, but inappropriate Immune Tolerance Induction in a Severe Hemophilia platelet adhesion and activation results in thrombosis. B Patient with an Inhibitor and Prior History of ITI Dr. Jobe’s group is working to understand how platelet Related Nephrotic Syndrome. Haemophilia. 2018 activation is regulated. They have identified a novel Jul;24(4):e294-e296. PMID: 30024646 platelet mitochondrial mechanism that transforms the platelet’s function from proaggregatory to 3. Sakurai Y, Hardy ET, Ahn B, Tran R, Fay ME, Ciciliano procoagulant. Work in Dr. Jobe’s lab currently is focused JC, Mannino RG, Myers DR, Qiu Y, Carden MA, Baldwin on understanding how platelet mitochondrially-mediated WH, Meeks SL, Gilbert GE, Jobe SM, Lam WA. A events are regulated and how they function to regulate microengineered vascularized bleeding model that hemostasis and thrombosis. Changes in mitochondrial integrates the principal components of hemostasis. metabolism are linked closely with many diseases Nat Commun. 2018 Feb 6;9(1):509. PMID: 29410404 associated with aging including diabetes, atherosclerosis 4. Sharma R, Perez Botero J, Jobe SM. Congenital and hypertension. Insights gained from these studies Disorders of Platelet Function and Number. Pediatr are expected to provide novel avenues for the treatment

Research Report 2018 25 Investigator, Blood Research Institute, Versiti Yan-Qing Ma, PhD PhD, Chinese Academy of Sciences, 2004 Started at Versiti: 2011

activation process. An important objective is to identify Publications novel inhibitors of platelet function that can be useful for treatment and prevention of thrombosis. 1. Cao Z, Suo X, Chu Y, Xu Z, Bao Y, Miao C, Deng W, Mao K, Gao J, Xu Z, Ma YQ. Peptides derived from the Awards, Honors and Service integrin β cytoplasmic tails inhibit angiogenesis. Cell Commun Signal. 2018 Jul 3; 16(1):38. PMID: 29970081 • Member, American Heart association 2. Xu Z, Ni B, Cao Z, Zielonka J, Gao J, Chen F, • Member, American Society of Hematology Kalyanaraman B, White GC, Ma YQ. Kindlin-3 negatively • Member, International Society on Thrombosis and regulates the release of neutrophil extracellular traps. Hemostasis J Leukoc Biol. 2018 Sep; 104(3):597-602. PMID: 29656482 Funding R01 HL131654 “Kindlin-3 Signaling in Blood Cells”

Kindlin-3 signaling in platelets and neutrophils

Research Interests Integrins comprise an extensive family of cell membrane proteins that are essential for cell-cell communication and signaling. In blood platelets, the integrin allb/ ß3 undergoes complex intracellular and extracellular structural changes that enable these cells to adhere to damaged blood vessels and to each other to control bleeding. This process must be carefully regulated to enable hemostasis to be achieved without causing a clot to be propagated inappropriately. Dr. Ma’s current work is aimed at understanding intracellular signaling cascades in platelets that control structural changes in integrin allb/ß3 during platelet activation. A particular goal is to define how kindlin-3, a key integrin activator in platelets, coordinates with upstream binding partners and creates a signaling network that regulates the platelet 26 Versiti Blood Research Institute Associate Medical Director of the Center for Comprehensive Bleeding Disorders, Versiti Lynn Malec, MD, MSc MD, UW Madison School of Medicine and Public Health, 2006 MSc, University of Pittsburgh, Institute for Clinical Research Education, 2014 Started at Versiti: 2016

Dr. Malec’s current research interests involve the PINK: An ATHN-LINKED Observational Study into the investigation of inhibitor prevention and eradication in Pink” 2017-2019 (Principal Investigator) $100,000 patients with hemophilia and the impact of prophylactic Children’s Hospital of Wisconsin Hematology/Oncology/ use in this patient population. She currently is Transplant Pilot Project Funding Program “Pilot Study investigating the role that recombinant factor VIII Fc of Whole Genome Sequencing in Brother Cohorts fusion protein (rFVIIIFc) has in immune tolerance with Severe Hemophilia A to identify Candidate Genes induction and is conducting a multi-site observational Implicated in Inhibitor Development 2018-2019 (Principal study to evaluate the efficacy and safety of rFVlllFc for Investigator) $75,000 ITI. Additionally, Dr. Malec was successful in competing for funding amongst a qualified pool of national junior Bioverativ Investigator Initiated Funding Program investigators and received the DREAM Award through “Hemophilia Inhibitor Response to Eloctate” 2016-2020 Hemostasis and Thrombosis Research Society (HTRS) (Principal Investigator) $74,000 to explore the impact of extended half-life products in preventing joint bleeds and joint damage in patients with Publications hemophilia. Dr. Malec is engaged in the care of adult 1. Malec L, Abshire T, Jobe S, White GC. rFIXFc for and pediatric patients with disorders of hemostasis Immune Tolerance Induction in a Severe Hemophilia and thrombosis, as well as other benign hematologic B Patient with an Inhibitor and Prior History of ITI conditions. Related Nephrotic Syndrome. Haemophilia. 2018 Jul;24(4):e294-e296. PMID: 30024646 Awards, Honors and Service 2. Malec LM, Cooper J, Rudolph J, Michaels MG, Ragni MV. • Treasurer, Hemostasis and Thrombosis Research Prophylactic rtPA in the Prevention of Line-associated Research Interests Society, 2018-present Thrombosis and Infection in Short Bowel Syndrome. J • Working Group Member, National Heart, Lung, and Pediatr Gastroenterol Nutr. 2018 Jun;66(6):972-975. Dr. Lynn Malec developed an interest in hemostasis Blood Institute (NHLBI) State of the Science Workshop PMID: 29135819 during her Internal Medicine and Pediatrics residency Factor VIII Inhibitors: Generating a National Blueprint at the University of Pittsburgh. This interest flourished for Future Research, 2018. during her fellowship in Pediatric Hematology/Oncology at Children’s Hospital of Pittsburgh during which time • Learning Action Network Member, Foundation for gained further expertise in the care of, and research Women and Girls with Bleeding Disorders 2014-present involving, patients with congenital bleeding disorders across the age spectrum. During her fellowship, she Funding pursued a Master’s of Science in Clinical Research DREAM Award: Mentored Research Award sponsored by through the University of Pittsburgh Institute for Clinical Hemostasis and Thrombosis Research Society (HTRS) Research Education. This rigorous training furthered and the American Thrombosis Hemostasis Network her interest in clinical research involving patients with (ATHN) “Is Prophylaxis Putting Hemophilic Joints in the bleeding disorders.

Research Report 2018 27 Senior Investigator, Blood Research Institute, Versiti Alan Mast, MD, PhD Medical Director, Medical Services, Versiti Walter A. Schroeder Endowed Chair for Blood Research Associate Professor, Department of Pathology, Medical College of Wisconsin Associate Professor, Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin MD, Duke University, 1991 PhD, Duke University, 1991 Started at Versiti: 2003

indicating that younger donors will benefit from additional • Member, American Society of Hematology Committee safety measures to protect them from iron depletion. for Scientific Affairs, 2018 In his basic research, Dr. Mast studies a protein • Co-Chair, American Society of Hematology Working designated “tissue factor pathway inhibitor (TFPI).” Group on Innovations in Clinical Trials, 2018 This protein plays a critical role in preventing blood • Member, American Society of Hematology Media from clotting inside blood vessels. His basic research Experts Subcommittee, 2018 program has made several important discoveries about the molecular interactions between TFPI and blood coagulation proteins. These have led to new ideas about Funding how bleeding and clotting disorders occur. TFPI alters REDS-III NHLBI bleeding severity in hemophilia. Dr. Mast’s laboratory is TFPI R01 NHLBI working to develop new pharmaceutical agents that block Novo Nordisk Research Grant TFPI as a treatment for hemophilia. Publications Awards, Honors and Service 1. Ellery PER, Hilden I, Sejling K, Loftager M, Martinez • Member, NIH Thrombosis and Hemostasis Study ND, Maroney SA, Mast AE. Correlates of plasma Section, 2018 and platelet tissue factor pathway inhibitor, factor V, and Protein S. Res Pract Thromb Haemost. 2018 Jan;2(1):93-104. PMID: 29354797 2. Maroney SA, Peterson JA, Zwifelhofer W, Martinez Research Interests ND, Yan K, Bercovitz RS, Woods RK, Mast AE. Plasma Proteolytic Cascade Activation during Neonatal Blood donation removes a large amount of iron that is Cardiopulmonary Bypass Surgery. Thromb Haemost. contained in red blood cells. Therefore, many regular 2018 Sep;118(9):1545-1555. PMID: 30086574 blood donors become iron deficient. In his clinical research, Dr. Mast studies the effect of blood donations 3. Peterson JA, Maroney SA, Zwifelhofer W, Wood JP, on iron metabolism and iron deficiency in the donor. Yan K, Bercovitz RS, Woods RK, Mast AE. Heparin- His clinical research program has found that recovery protamine balance after neonatal cardiopulmonary of iron stores following blood donation takes more than bypass surgery. J Thromb Haemost. 2018 six months, emphasizing the need for blood donors to Oct;16(10):1973-1983. PMID: 30016577 take iron pills following each donation. A study found that 4. Tanratana P, Ellery P, Westmark P, Mast AE, Sheehan JP. taking 19 mg iron (the amount of iron in a typical multiple Elevated Plasma Factor IXa Activity in Premenopausal vitamin with iron) for 60 days following each donation is Women on Hormonal Contraception. Arterioscler a simple and effective means for donors to replace iron Thromb Vasc Biol. 2018 Jan;38(1):266-274. PMID: lost during blood donation. A study of teenage blood 29097362 donors found that teenagers are more susceptible to iron deficiency following blood donation than are adults, 28 Versiti Blood Research Institute Senior Investigator, Blood Research Institute, Versiti Robert Montgomery, MD Attending Physician, Children’s Hospital of Wisconsin Professor of the Clinical and Translational Science Institute, Medical College of Wisconsin Professor of Pediatric Hematology & Population Health – Epidemiology, MCW Research Member, Hematologic Malignancy & Transplantation Research Program, MCW MD, University of Pittsburgh Medical School, 1969 Started at Versiti: 1980

approach could be used as an alternative to using FVIII Funding by-passing therapeutics that can sometimes run into more than $1M/yr. No one would have predicted that RO1 HL139847 “Molecular Interactions of FVIII and VWF” gene therapy could work in these individuals. Two other PO1 HL144457 “Zimmerman Program on the Biology of projects are directed at the molecular (DNA) causes of VWD” VWD. RO1 HL112614 “Comparative Effectiveness in the Awards, Honors and Service Diagnosis of VWD” • Executive Secretary, Hemophilia (and Thrombosis) Publications Research Society of North America 1. Flood VH, Abshire TC, Christopherson PA, Friedman • Member, Medical and Scientific Advisory Board KD, Cox Gill J, Montgomery RR, Haberichter SL; National Hemophilia Foundation Zimmerman Program Investigators. Von Willebrand • Chair, Fellowship Review Program, National Hemophilia disease in the United States: perspective from the Foundation Zimmerman program. Ann Blood. 2018 Jan;3. pii: 7. PMID: 30135959 2. Flood VH, Johnsen JM, Kochelek C, Slobodianuk TL, Christopherson PA, Haberichter SL, Udani R, Bellissimo DB, Friedman KD, Montgomery RR. Common VWF sequence variants associated with higher VWF and FVIII are less frequent in subjects diagnosed with Research Interests type 1 VWD. Res Pract Thromb Haemost. 2018 Jan 23;2(2):390-398. PMID: 30046743 Hemophilia and von Willebrand Disease (VWD) are Clot two major hereditary bleeding disorders that Dr. Aggregation 3. Kanaji S, Orje JN, Kanaji T, Kamikubo Y, Morodomi Platelet Montgomery’s laboratory studies. The abnormal protein Y, Chen Y, Zarpellon A, Eberhardt J, Forli S, Fahs SA, in hemophilia is Factor VIII (FVIII) and in VWD is von Sood R, Haberichter SL, Montgomery RR, Ruggeri ZM. αIIbβ3 Ib-IX Willebrand factor (VWF). Although these are regulated by αIIbβ3 Humanized GPIbα-von Willebrand factor interaction in different genes, the two proteins bind together and help 3 the mouse. Blood Adv. 2018 Oct 9;2(19):2522-2532. Adhesion PMID: 30287479 C1 orchestrate the cessation of bleeding. In hemophilia Dr. C1 Montgomery is exploring a unique form of gene therapy 4. Swystun LL, Lai JD, Notley C, Georgescu I, Paine AS, D’D3 in which FVIII is induced to be synthesized and stored in A3 A1 Mewburn J, Nesbitt K, Schledzewski K, Géraud C, platelets where it binds to VWF. This is not its normal site Kzhyshkowska J, Goerdt S, Hopman W, Montgomery to be synthesized, but the platelet targets it to be released RR, James PD, Lillicrap D. The endothelial cell at the site where a blood vessel is damaged. This therapy receptor stabilin-2 regulates VWF-FVIII complex can be effective even if the patient has begun to mount an Initiation half-life and immunogenicity. J Clin Invest. 2018 Aug immune response that normally blocks FVIII (this occurs Collagen 1/3 Collagen 4/6 31;128(9):4057-4073. PMID: 30124466 in 30% of hemophilia patients). Gene therapy using this Research Report 2018 29 Senior Investigator, Blood Research Institute, Versiti Debra Newman, PhD Professor, Department of Pharmacology & Toxicology/Department of Microbiology and Molecular Biology, Medical College of Wisconsin PhD, Biology, Marquette 1989 Started at Versiti: 1989

A major focus of research in Dr. Newman’s laboratory is Publications Platelet Endothelial Cell Adhesion Molecule-1 (PECAM-1), which inhibits responses of many circulating blood 1. Bercovitz RS, Shewmake AC, Newman DK, Niebler cells, including platelets and T cells. T cells are immune RA, Scott JP, Stuth E, Simpson PM, Yan K, Woods RK. cells that play an important role in clearing infections Validation of a definition of excessive postoperative and eradicating tumors. Dr. Newman has recently bleeding in infants undergoing cardiac surgery with discovered that PECAM-1 works with another potent T cardiopulmonary bypass. J Thorac Cardiovasc Surg. cell suppressor, Transforming Growth Factor ß (TFGß), 2018 May;155(5):2112-2124. PMID: 29338867 to inhibit anti-tumor responses. Her current work 2. Liao D, Mei H, Hu Y, Newman DK, Newman PJ. CRISPR- is dedicated to developing a better understanding of mediated deletion of the PECAM-1 cytoplasmic domain how PECAM-1 expression is regulated in T cells and of increases receptor lateral mobility and strengthens how PECAM-1 and TGFß work together to inhibit T cell endothelial cell junctional integrity. Life Sci. 2018 Jan responses. This research will help improve T cell-based 15;193:186-193. PMID: 29122551 therapies for treatment of cancer. 3. Newman DK. G6b-B: the “Y’s” and wherefores. Blood. Awards, Honors and Service 2018 Sep 27;132(13):1359-1360. PMID: 30262581 4. Newman DK, Fu G, McOlash L, Schauder D, Newman • Member, Program Project Grant Review Parent PJ, Cui W, Rao S, Johnson BD, Gershan JA, Riese MJ. Committee, National Heart, Lung & Blood Institute, Frontline Science: PECAM-1 (CD31) expression in National Institutes of Health 2017 - present naïve and memory, but not acutely activated, CD8+ T • Ad hoc Manuscript Reviewer: Proceedings of the cells. J Leukoc Biol. 2018 Nov;104(5):883-893. PMID: Research Interests National Academy of Sciences: USA; Science Reports; 30063264 Science Translational Medicine; Science Signaling; 5. Scott JP, Niebler RA, Stuth EAE, Newman DK, Tweddell Platelets are important in early wound healing, where Journal of Experimental Medicine; Blood; Journal JS, Bercovitz RS, Benson DW, Cole R, Simpson PM, Yan they initially stick to damaged blood vessels and then of Cell Biology; Journal of Biological Chemistry; K, Woods RK. Rotational Thromboelastometry Rapidly aggregate with one another to form a platelet plug. American Journal of Physiology: Heart and Circulatory Predicts Thrombocytopenia and Hypofibrinogenemia Excessive bleeding occurs when platelet counts are Physiology; Arteriosclerosis, Thrombosis and Vascular During Neonatal Cardiopulmonary Bypass. low, or when platelets don’t function well. Newborns Biology; Circulation Research; Journal of Thrombosis who undergo heart surgery for congenital heart defects and Hemostasis; Thrombosis and Haemostasis; 6. World J Pediatr Congenit Heart Surg. 2018 Jul;9(4):424- experience very severe bleeding. In Dr. Newman’s lab, Thrombosis Research; Journal of Immunology; 433. PMID: 29945504 they are trying to find out how much decreases in platelet Journal of Cell Science; Human Immunology; BMC 7. Wesley EM, Xin G, McAllister D, Malarkannan S, count and function that occur during heart surgery Immunology; Transfusion; The Anatomical Record; Free Newman DK, Dwinell MB, Cui W, Johnson BD, Riese contribute to severe bleeding in newborn heart surgery Radical Biology and Medicine; Molecular Biology of the MJ. Diacylglycerol kinase ζ (DGKζ) and Casitas patients. This research will help physicians administer the Cell; Cell Adhesion and Migration; PLoS One b-lineage proto-oncogene b-deficient mice have similar right number of platelets at the right time to effectively functional outcomes in T cells but DGKζ-deficient mice control bleeding in this at risk population. Funding have increased T cell activation and tumor clearance. Immunohorizons. 2018 Apr 1;2(4):107-118. PMID: NIH R35- HL139937 (Co-Investigator) 30027154

30 Versiti Blood Research Institute Vice President for Research, Versiti Peter Newman, PhD Associate Director/Senior Investigator, Versiti Blood Research Institute Professor, Department of Pharmacology, Medical College of Wisconsin Professor, Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin PhD, St. Louis University, 1983 Started at Versiti: 1983

technology to generate megakaryocyte progenitor cells, • Chair, NIH Special Emphasis Panel, Consortium Linking megakaryocytes, and platelets from induced pluripotent Oncology with Thrombosis 2018 stem cells to create platelet alloantigen-specific cell lines • Editor, Arteriosclerosis, Thrombosis and Vascular capable of long-term self-renewal, cryopreservation, and Biology (Journal of the American Heart Association) distribution. 2012-present Awards, Honors and Service • Chair, BloodWorks Northwest Scientific Advisory Board 2012-present • R35 Outstanding Investigator Award, NIH National Heart, Lung, and Blood Institute 2018-25 Funding • Distinguished Career Award, International Society of 2018-2025 - NIH Grant R35 HL139937 (Outstanding Thrombosis and Haemostasis 2013 Investigator Award) Publications rid 1. Liao D, Mei H, Hu Y, Newman DK, Newman PJ. CRISPR- mediated deletion of the PECAM-1 cytoplasmic domain increases receptor lateral mobility and strengthens endothelial cell junctional integrity. Life Sci. 2018 Jan 15;193:186-193. PMID: 29122551 2. Newman DK, Fu G, McOlash L, Schauder D, Newman Research Interests PJ, Cui W, Rao S, Johnson BD, Gershan JA, Riese MJ. Frontline Science: PECAM-1 (CD31) expression in Peter Newman’s laboratory divides its attention between s naïve and memory, but not acutely activated, CD8+ T exploring the structure and function of the vascular cell 3 cells. J Leukoc Biol. 2018 Nov;104(5):883-893. PMID: adhesion and signaling receptor, PECAM-1, in platelets 30063264 and endothelial cells, and the generation of antigenically- distinct megakaryocytes and platelets from induced 3. Zhi H, Ahlen MT, Thinn AMM, Weiler H, Curtis BR, pluripotent stem (iPS) cells - both funded by a newly- Skogen B, Zhu J, Newman PJ. High-resolution mapping received, 7-year, $7M Outstanding Investigator Award of the polyclonal immune response to the human from the National Heart, Lung, and Blood Institute of platelet alloantigen HPA-1a (PlA1). Blood Adv. 2018 Nov the National Institutes of Health. Techniques range from eu 13;2(21):3001-3011. PMID: 30413435 Ser 33 CRISPR-mediated gene editing to protein crystallography 469 to the development of animal models of platelet alloimmunity. Projects range from investigating the Gln470 molecular basis of PECAM-1-mediated homophilic binding and the role of carbohydrate residues in this process to exploiting recent advances in CRISPR gene editing Research Report 2018 31 Investigator, Blood Research Institute, Versiti Qizhen Shi, MD, PhD Professor of Pediatric Hematology, Medical College of Wisconsin MD, Fujian Medical University, Fuzhou, China, 1990 PhD, Fujian Medical University, Fuzhou, China, 1998 Molecular Hematology Fellowship, Medical College of Wisconsin 2000 – 2006 Started at Versiti: 2010

aimed at understanding why platelet-derived FVIII can Funding still be effective in hemophilia A even in the presence of inhibitors. In a separate line of research, Dr. Shi’s team R01 HL102035 “Platelet Derived FVIII Gene Therapy of found that that FVIII’s carrier protein, VWF, can modulate Hemophilia A” the antigenicity of FVIII, attenuating FVIII memory NHF Bridge Award “Investigation of VWF as an immune responses in hemophilia A mice. These studies immunomodulator of the immunogenic response towards provide important information about the impact of VWF FVIII”. on FVIII immune responses, which will aid the design Bayer Hemophilia Award “Platelet gene therapy of murine of more effective protocols to prevent FVIII immune hemophilia B with pre-existing anti-FIX immunity”. responses and to induce FVIII immune tolerance in patients with hemophilia A. Biotest Research Grant “The impact of VWF on FVIII immune response in hemophilia A with inhibitors”. Awards, Honors and Service • Reviewer for the Poster Award. The 21st Annual Publications Meeting of American Society of Gene and Cell Therapy 1. Luo X, Chen J, Schroeder JA, Allen KP, Baumgartner (ASGCT), May 2018, Chicago, IL. CK, Malarkannan S, Hu J, Williams CB, Shi Q. Platelet • Moderator, the Oral Session of Blood Coagulation Gene Therapy Promotes Targeted and Fibrinolytic Factors: The Clotting System in by and Induction of Antigen-Specific Inflammation, Immunity, and Cancer. The 60th Regulatory T Cells. Front Immunol. 2018 Sep 6;9:1950. American Society of Hematology (ASH) Annual PMID: 30237796 Research Interests Meeting, December 2018, San Diego, CA. 2. Shi Q. Platelet-Targeted Gene Therapy for Hemophilia. • Editorial board member, Molecular Therapy – Methods Mol Ther Methods Clin Dev. 2018 Feb 7;9:100-108. Development of inhibitory antibodies (inhibitors) against & Clinical Development 2017-present Review. PMID: 29520365 FVIII is a significant problem in the clinical care of patients with hemophilia A. One primary focus of Dr. Shi’s research is to develop a gene therapy approach for the treatment of hemophilia A, including hemophilia A with inhibitors. Dr. Shi’s studies have shown that engineering blood stem cells to have FVIII made and stored in platelets can solve all the problems for hemophilia A. These studies show platelet-targeted gene therapy can efficiently correct the bleeding phenotype in hemophilia A mice even in the presence of neutralizing antibodies. Furthermore, platelet gene therapy can induce profound antigen- specific immune tolerance through peripheral clonal deletion of antigen-specific CD4 T cells and expansion of antigen-specific regulatory T cells. These studies are 32 Versiti Blood Research Institute Senior Investigator, Blood Research Institute, Versiti Roy Silverstein, MD John and Linda Mellowes Professor and Chair, Department of Medicine, Medical College of Wisconsin MD, Emory University School of Medicine 1979 Started at Versiti: 2011

leading to atherosclerosis. The remarkable diversity of SM, Silverstein RL. Platelet CD36 signaling through CD36 functions suggests that further work will have ERK5 promotes caspase-dependent procoagulant implications for treatment and/or prevention of arterial activity and fibrin deposition in vivo. Blood Adv. 2018 disease, thrombosis and cancer. Nov 13;2(21):2848-2861. PMID: 30381401 Awards, Honors and Service • Past-President, Central Society for Clinical and Translational Research 2018 • President-elect, American Society of Hematology 2018 • Chair, AICS study section for NIH 2018 • Editorial Boards: J. Clinical Investigation and J. Experimental Medicine Funding R01 HL142152: “ERK5 and CD36 link oxidative stress to platelet dysfunction and ischemic injury” R01 HL126645: “MRP-14, CD36 and Thrombosis” Advancing a Healthier Wisconsin Endowment Pre Research Interests Program Project Pilot Program: Metabolic Control of Inflammation in Atherosclerosis by Research by Dr. Silverstein’s group concerns basic Scavenger Receptors” mechanisms underlying common vascular diseases, especially thrombosis, atherosclerosis and neoplastic Publications angiogenesis, with particular emphasis on the role of a cellular receptor designated CD36 expressed on 1. Chen Y, Silverstein RL. Platelet metabolism meets platelets, endothelial cells, and other thrombosis. Blood. 2018 Sep 13;132(11):1089-1091. tissues. Recent work has shown that CD36 acts as PMID: 30213838 a negative regulator of new blood vessel formation 2. Silverstein RL. Oxidized Lipid Uptake by Scavenger (angiogenesis), a process critical to tumor growth. Receptor CD36 (Cluster of Differentiation 36) CD36 also enables the recognition by platelets and Modulates Endothelial Surface Properties and May macrophages of danger signals generated in the body Contribute to Atherogenesis. Arterioscler Thromb as the result of inflammation, oxidant stress, diabetes Vasc Biol. 2018 Jan;38(1):4-5. PMID: 29282244 and cancer, and may play a role in the pro-thrombotic state associated with these conditions as well as in 3. Yang M, Kholmukhamedov A, Schulte ML, Cooley BC, accumulation of cholesterol in blood vessel walls, Scoggins NO, Wood JP, Cameron SJ, Morrell CN, Jobe Research Report 2018 33 Senior Investigator, Blood Research Institute, Versiti Hartmut Weiler, PhD Associate Professor, Department of Physiology, Medical College of Wisconsin Director, Transgenic Core Facility, Human Molecular Genetics Center, MCW Dr.rer.nat., Technische Hochschule Darmstadt Germany, 1989 Started at Versiti: 1997

oalation factors relate Funding te fnction of stem cells “Protein C pathway function in Hematopoiesis” -- NHLBI -- 1R01HL117132 “Regulation of Innate Immunity by Coagulation Receptors” -- NHLBI -- 1RO1 HL133348 tem isse “Coagulation Factor Signaling in Malaria” -- NIH/NIAID ells eair -- R01HL130678 “Serpin Regulation of Coagulation Proteases” -- NHLBI lood oalation actors -- R01HL062565 “Protein C Pathway Mitigation of Radiation-Induced Vascular Dysfunction” -- NIAID --U01AI133561 Publications 1. Slobodianuk TL, Kochelek C, Foeckler J, Kalloway S, Weiler H, Flood VH. Defective collagen binding and increased bleeding in a murine model of von Willebrand elate te Protect riin disease affecting collagen IV binding. J Thromb fnction of te ematooietic bacterial sesis Haemost. 2018 Dec 18. doi: 10.1111/jth.14341. [Epub lacenta stem stem cells from and treatin ahead of print] PMID: 30565388 Research Interests cells and blood radiation inry alaria 2. Bergmeier W, Antoniak S, Conway EM, Denis CV, essels Activation of the blood clotting system serves to stop George LA, Isermann B, Key NS, Krishnaswamy S, Lam bleeding when a blood vessel is injured, but it also is WA, Lillicrap D, Liu J, Looney MR, López JA, Maas C, a natural part of the body’s response to infections, Peyvandi F, Ruf W, Sood AK, Versteeg HH, Wolberg AS, inflammation, and cancer, and plays an important role in altered rodents serving as models for human disease. Wong PC, Wood JP, Weiler H: Advances in Clinical and embryonic development. In 2018, the National Institutes Basic Science of Coagulation: Illustrated abstracts of of Health supported work in Dr. Weiler’s laboratory to the 9th Chapel Hill Symposium on Hemostasis. Res develop innovative therapeutic interventions targeting Awards, Honors and Service Pract Thromb Haemost. 2018 Apr 12;2(3):407-428. blood coagulation pathways in diseases such as • 9th Symposium on Hemostasis, April 12-14, 2018; PMID: 30046746; PMCID: PMC6046595. severe sepsis, malaria, and bone marrow failure after Chapel Hill NC. Co-Chair/Organizer. exposure to lethal doses of radiation. Dr. Weiler holds 3. Zhi H, Ahlen MT, Thinn AMM, Weiler H, Curtis BR, the Ziegler Family Chair for Research, and also directs • NIH reviewer Special Emphasis Panel/Scientific Review Skogen B, Zhu J, Newman PJ. High-resolution mapping the joint Transgenic Core Facility of the Medical College Group 2018/05 ZRG1 VH-J (08) S, July 20-21, 2018 of the polyclonal immune response to the human of Wisconsin (MCW) and the Versiti Blood Research (SBRI, STTR) platelet alloantigen HPA-1a (PlA1). Blood Adv. 2018 Institute. The facility provides a wide range of genome Nov 13;2(21):3001-3011. PMID: 30413435; PMCID: editing services facilitating the generation of genetically PMC6234362 34 Versiti Blood Research Institute Senior Investigator/Director, Blood Research Institute, Versiti Gilbert White, II, MD Richard H. and Sara E. Aster Chair for Medical Research Professor, Dept. of Medicine, Biochemistry, and Pharmacology & Toxicology, Medical College of Wisconsin MD, University of North Carolina, Chapel Hill, 1971 Started at Versiti: 2004

Understanding how Rap 1b modulates platelet function • Chair, American Society of Hematology (ASH) Bridge will enable development of methods to selectively Grant Review Program 2018 manipulate intracellular signaling pathways so as to • Member, International Society of Thrombosis and prevent thrombosis without provoking hemorrhage in Hemostasis (ISTH) Awards & Honors Committee 2018 patients with impending heart attacks or strokes. Funding UL1 TR001435 “Clinical and Translational Science Institute, NCATS UG3 OD023190 “All of US – Wisconsin, NIH Office of Director T32 HL07209 “Research Training in Hematology and Transfusion Medicine”, NHLBI T32 GM080202 “Medical Scientist Training Program”, NIGMS Publications 1. Malec L, Abshire T, Jobe S, White G. rFIXFc for Immune Tolerance Induction in a Severe Hemophilia B Patient with an Inhibitor and Prior History of ITI Research Interests Related Nephrotic Syndrome. Haemophilia. 2018 Work by Dr. White’s group is aimed at understanding Jul;24(4):e294-e296. PMID: 30024646 signaling pathways involved in the hemostatic responses 2. Xu Z, Ni B, Cao Z, Zielonka J, Gao J, Chen F, by blood platelets. A longtime focus is the role of an Kalyanaraman B, White GC, Ma YQ. Kindlin-3 negatively intracellular protein, Rap 1b, which is present in high regulates the release of neutrophil extracellular traps. concentrations in platelets and is critical for platelet J Leukoc Biol. 2018 Sep;104(3):597-602. PMID: aggregation and the activation of integrins that are 29656482 critical for the platelet-platelet interactions needed to Awards, Honors and Service form a hemostatic plug. Rap 1b also appears to be a • Board of Directors, National Hemophilia Foundation critical target for cyclic AMP-dependent protein kinase • Board of Directors, Great Lakes Hemophilia Foundation (PKA) and phosphorylation of Rap 1b by PKA is involved in the inhibition of platelets by drugs that target the PKA • Board of Directors, Versiti Blood Research Foundation pathway. Thus, Rap 1b may function as a unique and • Editorial Board, Haemophilia 2018 critical bi-directional modulator of platelet activation. • Co-Editor, 6th edition of Thrombosis and Hemostasis

Research Report 2018 35 Investigator, Blood Research Institute, Versiti Jieqing Zhu, PhD Associate Professor, Department of Biochemistry, Medical College of Wisconsin PhD, Institute of Microbiology, Chinese Academy of Sciences, Beijing 2003 Immune Disease Institute, Harvard Medical School, Boston 2009 Started at Versiti: 2011

surface, which provides new information of conformation- Publications dependent integrin activation. 1. Thinn AMM, Wang Z, Zhou D, Zhao Y, Curtis BR, Zhu J. Autonomous conformational regulation of β integrin Awards, Honors and Service 3 and the conformation-dependent property of HPA-1a • Member, American Society of Hematology (ASH) 2018 alloantibodies. Proc Natl Acad Sci U S A. 2018 Sep • Member, American Society for Biochemistry and 25;115(39):E9105-E9114. PMID: 30209215 Molecular Biology (ASBMB) 2018 2. Thinn AMM, Wang Z, Zhu J. The membrane-distal • Editorial Boards: Scientific Reports regions of integrin α cytoplasmic domains contribute differently to integrin inside-out activation. Sci Rep. Funding 2018 Mar 22;8(1):5067. PMID: 29568062 3. Zhou D, Thinn AMM, Zhao Y, Wang Z, Zhu J. Structure R01 HL131836 “Structural Transition of Cellular Integrins of an extended β integrin. Blood. 2018 Aug and Applications Thereof” 3 30;132(9):962-972. PMID: 30018079 R35 HL139937 (PI: P. Newman) “Basic investigation 4. Zhu J. Csk/CD148 and platelet SFK activation: a and translational applications concerning the cell and balancing act! Blood. 2018 Mar 8;131(10):1042-1043. molecular biology of blood and vascular cells” PMID: 29519930

Research Interests Membrane protein complexes designated “integrins” function as cell surface receptors to regulate cell-cell and cell-matrix interactions critical for organ development, hemostasis, antigen recognition, cellular homing to specific body sites and inflammation. Dr. Zhu is using structural biology, biochemistry and cell biology techniques to investigate how particular structural domains of integrins function in integrin activation. These studies will guide the development of small molecule or antibody inhibitors of integrin function that can be useful in the treatment and prevention of thrombosis and a range of other conditions. Recent studies have revealed the previously unappreciated function of α integrin cytoplasmic domain in integrin activation and signaling, and the structural basis of integrin extension on the cell 36 Versiti Blood Research Institute Immunology

Immunobiology has been a cornerstone of research at Versiti since 1947, going back to the early days of immunohematology. Studies by Versiti investigators led to the identification of some of the first antigen systems specific to red blood cells.

Versiti investigators facilitated the first bone marrow transplant from an unrelated donor to successfully treat bone marrow failure (aplastic anemia) and played key roles in creation of the National Marrow Donor Program. Vice President and Medical Director, Diagnostic Laboratories Matthew Anderson, MD, Associate Investigator, Blood Research Institute, Versiti Assistant Professor, Pathology, Medical College of Wisconsin Member, Human and Molecular Genetics Center, Medical College of Wisconsin PhD MD, Medical College of Wisconsin, 2006 PhD, Medical College of Wisconsin, 2004 Started at Versiti: 2013

plans to develop next-generation sequencing assays to analyze other genes important for the immune response to transplants and to monitor patients for rejection. Awards, Honors and Service • Member, American Society for and Immunogenetics (ASHI) • Member, Assocation for Molecular Pathology • Fellow, College of American Pathologists Publications 1. Perez Botero J, Dugan SN, Anderson MW. ANKRD26- Related Thrombocytopenia. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2018. 2018 Jun 21. PMID: 29927566

A Strategies for HL Research Interests ! genotyping Dr. Anderson’s research interests include the use of high-throughput sequencing technologies for clinical A: Standard methods for diagnostics and biomarker discovery, with a focus on HLA genotyping typically transplantation. Human leukocyte antigens (HLA) are sequence only 1-3 exons of key molecular determinants of the adaptive immune B" the HLA gene (exon 2 in this response and also control the host immune response example). to hematopoietic and solid-organ transplants. Clinically, the success of a transplant critically depends on a high degree of similarity between the HLA molecules of the B: Next-generation sequencing donor and recipient. Dr. Anderson’s group has recently methods utilize overlapping created a novel bioinformatics approach to directly DNA fragments to sequence compare HLA gene sequences from hematopoietic the entire HLA gene. transplant donor and recipients, demonstrating that transplant pairs highly matched at a genetic level show improved transplant outcome (in press). In the future, he 38 Versiti Blood Research Institute #$%&'()*+!")#$"%&'%()*+#),-.)&%/+"01'/&!23))!"$/4$#4)5%"6+4()*+#),-.)&%/+"01'/&)"01'7$880)(%9:%/7%) +/80);<=)%>+/( +*)"6%),-.)&%/%)%?>+/@)'/)"6'()%>$518%"332)A) %><"&%/%#$"'+/)(%9:%/7'/&)5%"6+4() :"'8'B%)+C%#8$11'/&)DA.)*#$&5%/"()"+)(%9:%/7%)"6%)%/"'#%),-.)&%/%2)) Investigator, Blood Research Institute, Versiti Weiguo Cui, MD, PhD Assistant Professor, Department of Microbiology and Immunology, Medical College of Wisconsin MD/PhD, Tianjin Medical University, China, 2004 Dept. of Immunobiology, Yale University School of Medicine, 2012 Started at Versiti: 2012

Awards, Honors and Service Drobyski WR, Tarakanova V, Craft J, Cui W. Single- cell RNA sequencing unveils an IL-10-producing • ACS Research Scholar Grant (RSG) helper subset that sustains • Ad hoc review, IHD study section, NIH during persistent infection. Nat Commun. 2018 Nov 28;9(1):5037. • Method of manufacturing dual-specific t-cells for use in cancer immunotherapy. Weiguo Cui. US Patent (US 2. Newman DK, Fu G, McOlash L, Schauder D, Newman 2018/0334651). Nov. 22, 2018. PJ, Cui W, Rao S, Johnson BD, Gershan JA, Riese MJ. Frontline Science: PECAM-1 (CD31) expression in naïve Funding and memory, but not acutely activated, CD8+ T cells. J Leukoc Biol. 2018 Nov;104(5):883-893. 5R01AI125741-0 Cui (PI) 05/16/2016-04/30/2021 NIH/ NIAID “The cellular and transcriptional control of CD8 T 3. Wesley EM, Xin G, McAllister D, Malarkannan S, cell functional adaptation to chronic viruses.” Newman DK, Dwinell MB, Cui W, Johnson BD, Riese MJ. Diacylglycerol kinase ζ (DGKζ) and Casitas RSG-17-186-01(PI) 01/01/2018 – 12/31/2021/ACS b-lineage proto-oncogene b-deficient mice have similar “Harnessing BATF-Boosted Anti-tumor CD8 T Cells in functional outcomes in T cells but DGKζ-deficient mice Cancer Immunotherapy” have increased T cell activation and tumor clearance. Immunohorizons. 2018 Apr 1;2(4):107-118. Publications 1. Xin G, Zander R, Schauder DM, Chen Y, Weinstein JS,

Research Interests Following infection, induction of a subset of , designated memory T cells, is critical for achieving protection against exposure to bacteria and viruses. Dr. Cui’s studies are aimed at improving the understanding of memory T cell development. His current work is focused on the study of epigenetic changes that take place in lymphocytes during the response to an acute infection. An immediate goal is to identify specific chromosomal structures that influence T cell memory. Findings made will improve basic understanding of the immune response and have implications for the treatment and prevention of infectious diseases.

Research Report 2018 39 Senior Investigator, Blood Research Institute, Versiti Bonnie Dittel, PhD Medical College of Wisconsin, Department of Microbiology and Immunology PhD, University of Minnesota Postdoctoral Training, Yale University Started at Versiti: 2000

autoimmunity. Dr. Dittel also is investigating how immune Medical College of Wisconsin, Cancer Center pilot cells propagate EAE by studying the mechanisms grant, Can chronic lymphocytic leukemia (CLL) exhibit whereby they open the blood-brain barrier and induce regulatory function? Principal Investigator neuronal damage. Findings made are expected to suggest new approaches for treating MS and other immune Publications disorders affecting the nervous system. 1. Lopez, L., N. Aparicio, M.R. Pazos, M.T. Grande, M.A. Barreda-Manso, I. Benito-Cuesta, C. Vazquez, N., M. Awards, Honors and Service Amores, G. Ruiz-Perez, E. Garcia-Garcia, M. Betaka, • Journal of Neuroimmunology, Editorial Board R.M. Tolon, B.N. Dittel, C.J. Hillard and J. Romero. • Autoimmunity, Associate Editor 2018. Cannabinoid CB2 receptors in the mouse brain: relevance for Alzheimer’s disease. J. Neuroinflamm. • Brain, Behavior, and Immunity, Editorial Board 15:158. • NINDS, Clinical Neuroimmunology and Brain Tumors, 2. Ray, A., Khalil, M., Pulakanti, K.L., Burns, R.T., Gurski, ad hoc member C.J., Basu, S., Wang, D., Rao, S. and Dittel, B.N. Mature • NINDS, ZRG1 BDCN-G 03 M, Member Conflict: IgDlow/- B cells maintain tolerance by promoting Neuroimmunology, Neuroinflammation and homeostasis. Nat. Commun. doi. org/10.1038/s41467-018-08122-9 • Brain Tumors, Chair • NIAID, Cellular and Molecular Immunology B, ad hoc member Research Interests Funding Autoimmunity occurs when the 1R56AI122655 - 01A1, NIAID, Mechanisms mounts an inappropriate attack on one’s own body of a novel regulatory B cell subset, Principal tissues. Dr. Dittel’s laboratory is concerned with immune Investigator regulation that occurs during multiple sclerosis (MS), the most prevalent autoimmune disorder affecting the 1R56AI129348-01A1, NIAID, B cell-mediated central nervous system (CNS). For this work, she is immune regulation, Principal Investigator utilizing a mouse model of MS designated experimental RG 1501-03034-National Multiple Sclerosis autoimmune encephalomyelitis (EAE). Current studies Society, Characterization of a Novel are aimed at understanding how key cells of the immune Regulatory B Cell Subset that Attenuates system (T and B lymphocytes) interact to influence the EAE, Principal Investigator autoimmune process that causes damage to CNS tissue. In recent studies we have identified a new subset of B Teva Investigator Sponsored Studies, Teva lymphocytes (BDL) that induce the proliferation of a Pharmaceuticals, Access the ability of critical subset of T lymphocytes designated T regulatory Copaxone to enhance the regulatory activity cells (Treg) via GITRL that are essential for controlling of a novel B cell subset, Principal Investigator 40 Versiti Blood Research Institute Senior Investigator, Blood Research Institute, Versiti Jack Gorski, PhD Assistant Professor, Microbiology and Immunology, Medical College of Wisconsin PhD, University of Cincinnati, 1976 Started at Versiti: 1986

among older persons in the US can be tracked utilizing the tools of molecular biology. Findings made in this work will advance basic understanding of the human response and its relation to autoimmunity, tissue transplantation and infectious disease. Awards, Honors, and Service • Director, Center for Human Immunology, Blood Research Institute

Many peptides One peptide TCR Snuggle up Research Interests Viral and start an The immune response is a complicated process involving Peptide direct and indirect communication between many immune specialized types of cells. Dr. Gorski studies this process HLA response at a molecular level. Recent studies have provided new insights into how the immune system recognizes One HLA Many HLA and generates a response against protein fragments (peptides) from germs or viruses. He is the inventor of Many TCR One TCR innovative methods to characterize genetic differences H ar between individuals that determine which protein W At e fragments can be recognized, and how to measure the range of unique immune cells that recognize these protein the RuLes fragments. Dr. Gorski currently studies how immune responses are affected by aging , how T cell responses e? differ between healthy children and children with an One peptide: HLA Many peptide: HLA HEr autoimmune disease, and how the spread of influenza Research Report 2018 41 Senior Investigator and Gardetto Chair for Immunology and Immunotherapy, Blood Research Institute Subramaniam Professor of Medicine, Microbiology & Immunology, and Pediatrics, Medical College of Wisconsin PhD Madurai Kamaraj University, Madurai, TN, India, 1991 Malarkannan, PhD Started at Versiti: 2000

Awards, Honors and Service MACC Fund, “Targeting Pediatric Cancer with ‘Next-Gen’ CARs”AHW, Honing inflammatory responses in cancer • Ad hoc Reviewer, NIAID, ZRG-IMM-U-81, NIH, 2017- treatment with designer CAR-T cells. 2018 Ann’s Hope Foundation, Requirement of metabolic • Chair, NIAID, ZRG1 IMM-F-02 Study Section, NIH, 2018 reprogramming in NK cells during the clearance of • External Member, Grant Review Committee, Infections melanoma. and Immunity Board, UK Medical Research Council (MRC), Extramural Program, UK, 2018 Publications 1. Abel AM, Tiwari AA, Gerbec ZJ, Siebert JR, Yang C, Funding Schloemer NJ, Dixon KJ, Thakar MS, Malarkannan S. R01 AI102893, “Molecular Mechanisms of Signaling Co- IQ Domain-Containing GTPase-Activating Protein 1 Ordination in Innate Lymphocytes” Regulates Cytoskeletal Reorganization and Facilitates NKG2D-Mediated Mechanistic Target of Rapamycin R01 CA179363, Molecular Signature of Inflammation” Complex 1 Activation and Gene Translation R38 HL143561, Stimulating access to Research in in Natural Killer Cells. Front Immunol. 2018 May Residency (StARR). 28;9:1168. PMID: 29892299 2. Abel AM, Yang C, Thakar MS, Malarkannan S. Natural Killer Cells: Development, Maturation, and Clinical Utilization. Front Immunol. 2018 Aug 13;9:1869. Review. PMID: 30150991 Research Interests 3. Nanbakhsh A, Best B, Riese M, Rao S, Wang L, Medin Natural Killer (NK) cells are a type of that J, Thakar MS, Malarkannan S Dextran Enhances the specializes in killing virus-infected and malignant cells. Lentiviral Transduction Efficiency of Murine and Human Due to this specialty, there is a great deal of interest in Primary NK Cells. J Vis Exp. 2018 Jan 15;(131) PMID: using NK cells for therapeutic purposes. Dr. Malarkannan’s 29364266 group studies basic, translational, and clinical aspects 4. Yang C, Tsaih SW, Lemke A, Flister MJ, Thakar MS, of NK cells. Using single-cell sequencing, his group has Malarkannan S. mTORC1 and mTORC2 differentially determined the developmental heterogeneity of human promote development. Elife. 2018 NK cells in healthy individuals and patients with rare May 29;7. pii: e35619. doi: 10.7554/eLife.35619. PMID: inherited diseases. The group’s studies have identified 29809146 pathways that influence target cell killing and associated inflammatory changes. This work may show how these pathways can be manipulated to maximize the killing effect and minimize the adverse effects of NK cell therapy. This constitutes a new form of transfusion therapy for treatment of malignant conditions. 42 Versiti Blood Research Institute Associate Professor, Departments of Medicine (Division of Heme/Onc), Microbiology and Immunology, and Surgery, Matthew Riese, MD, PhD Medical College of Wisconsin Associate Investigator, Blood Research Institute, Versiti PhD, Medical College of Wisconsin, 2002 MD, Medical College of Wisconsin, 2004 Started at Versiti: 2012

Awards, Honors and Service 3. Bajor DL, Mick R, Riese MJ, Huang AC, Sullivan B, Richman LP, Torigan DA, George SM, Stelekati E, Chen • Member, American Association for Cancer Research F, Melenhorst JJ, Lacey SF, Xu X, Wherry EJ, Gangadhar 2018 TC, Amaravadi, RK, Schuchter LM, and Vonderheide • Member, American Society of Clinical Oncology 2018 RH.Clinical response and immune activation with CD40 agonism and CTLA-4 blockade in patients with • Member, Society for Leukocyte Biology 2018 metastatic melanoma. Oncoimmunology. 2018 Aug 20; 7(10). PMID: 30288340 Funding 4. Newman DK, Fu G, McOlash L, Schauder D, Newman Bristol-Myers Squibb. 9/1/2016-6/1/2019. “Studies of PJ, Cui W, Rao S, Johnson BD, Gershan JA, Riese MJ. novel compounds in mice models.” (PI-Riese) Frontline Science: PECAM-1 (CD31) expression in MCW Cancer Center. 11/1/2017-10/31/2019. “Optimizing naïve and memory, but not acutely activated, CD8+ T Cancer Adoptive Cellular Therapies with Epigenetic cells. J Leukoc Biol. 2018 Nov;104(5):883-893. PMID: Strategies.” (PI-Riese, co-PI Rao). 30063264 Advancing a Healthier Wisconsin. 1/1/2018-12/31/2019. “Engineering Inflammation-free CAR Therapy.” (PI- Malarkannan, co-PI Riese). Function of Inhibitory Checkpoints MCW Center of Immunology. 12/1/2018-11/30/2019. in CD8+ T cells

“Unbiased Genomic Analysis of the Pancreatic Cancer TCR CD28 Immune Microenvironment.” (PI-Riese). Extracellular Intracellular Research Interests checkpoints checkpoints

Immunotherapies for the treatment of malignancy have Publications CTLA4: DGKζ: DGKζ Naive Activation Naive Activation recently begun to demonstrate impressive success in 1. Nanbakhsh A, Best B, Riese M, Rao S, Wang L, Medin Block: +++ MARCKs kinase Block: +++ achieving long-term disease control and eradication; J, Thakar MS, Malarkannan S Dextran Enhances the Exhaustion Exhaustion Enforcement: + Enforcement: - however, the therapies work in a minority of patients. The Lentiviral Transduction Efficiency of Murine and Human CTLA4 Riese lab is investigating ways to improve upon existing Primary NK Cells. J Vis Exp. 2018 Jan 15;(131) PMID: Inhibit naive T cell Activation cancer immunotherapies by targeting “off” switches 29364266 inside T cells, the cells responsible for killing cancer 2. Wesley EM, Xin G, McAllister D, Malarkannan S, cells. His studies have incorporated both oncology and Inhibit exhausted T cells Newman DK, Dwinell MB, Cui W, Johnson BD, Riese PD-1 chemistry and have allowed him to blend medicine and MJ. Diacylglycerol kinase ζ (DGKζ) and Casitas research throughout his career. b-lineage proto-oncogene b-deficient mice have similar PD-1: EF hands kinase DGKα: functional outcomes in T cells but DGK -deficient mice Naive Activation Naive Activation ζ Block: +/- DGKα Block: + have increased T cell activation and tumor clearance. Exhaustion Exhaustion Immunohorizons. 2018 Apr 1;2(4):107-118. PMID: Enforcement: +++ Enforcement: +++ 30027154

Research Report 2018 43 Senior Investigator, and John B. and Judith A. Gardetto Chair for Cancer Research Demin Wang, PhD Blood Research Institute, Versiti Adjunct Faculty, Department of Microbiology and Immunology, Medical College of Wisconsin PhD, University of Tennessee, 1995 Employed at Versiti: 2000

the possibility of production and have led • Committee Chair and Speaker, 12th annual Center to the findings that antibodies causing heparin-induced for Human Immunology Symposium, Milwaukee, thrombocytopenia and thrombosis (HIT) are produced Wisconsin, 2018 by a subset of B lymphocytes designated marginal zone • Invited Speaker, International Conference on Blood B cells when self-tolerance is broken. Work in these Research, Shanghai, China, 2018 fields is expected to provide an improved understanding of autoantibody formation in human disease and • Workshop Chair, Lymphocytes, Activation suggest new approaches to prevention and treatment of and , including HIV and Other autoimmunity. Infections: B Cells and Innate Immune Cells, 58th Annual meeting, American, Society of Hematology Awards, Honors, and Service (ASH), San Diego, California, 2018 • Editorial Board, Blood, 2017-present Funding • Member, ZRG1 IMM-S (02), Special Emphasis Panel, R01 AI079087 “PLCγs in B cell biology and autoimmunity” NHLBI, NIH, 2018 R01 HL130724 “B cell responses in heparin-induced • Reviewer, American Society of Hematology (ASH), San thrombocytopenia” Diego, CA, 2018 MCW Bridge Award (R01 HL136527) “PLCγ signaling in early B lymphopoiesis” inal transdction Publications Research Interests 1. Zeng H, Yu M, Tan H, Li Y, Su W, Shi H, Dhungana Y, Guy cell recrsor mmatre cell atre cell Dr. Wang is concerned with self-renewal and H C, Neale G, Cloer C, Peng J, Wang D*, Chi H*. Discrete differentiation of cells (hematopoietic stem cells, HSCs) roles and bifurcation of PTEN signaling and mTORC1- Atoimmnity that give rise to blood cells and to the subset of white -recrsor leemia mediated anabolic metabolism underlie IL-7-driven B blood cells (B lymphocytes) that produce antibodies. lymphopoiesis. Science Adv. 2018 Jan 31;4(1):eaar5701. His studies are designed to identify and functionally tside cell PMID: 29399633. *Co-corresponding authorship characterize signaling molecules and pathways that are 2. Zhang M, Dong Y, Hu F, Yang D, Zhao Q, Lv C, Wang Y, Xia critical to HSC and B cell biology. Recent studies have inal transdction C, Weng Q, Liu X, Li C, Zhou P, Wang T, Guan Y, Guo R, identified a novel and critical signal transduction pathway cascades of molecle interactions Liu L, Geng Y, Wu H, Du J, Hu Z, Xu S, Chen J, He A, Liu that controls the development of normal early B cells issin B, Wang D, Yang YG, Wang J. Transcription factor Hoxb5 omonents and the formation of B-precursor acute lymphoblastic nside cell reprograms B cells into functional T lymphocytes. Nat leukemia. These findings further our understanding of B Immunol. 2018 Mar;19(3):279-290. PMID: 29434353 cell development and transformation, and suggest new 3. Wen R, Wang D. Identification of PTPRJ as a novel approaches to the treatment of leukemia. Furthermore, Ncles ene ression inherited thrombocytopenia gene. Blood (in press). recent studies have identified new mechanisms that regulate induction of tolerance in B cells, thereby limiting 44 Versiti Blood Research Institute Associate Investigator, Blood Research Institute, Versiti Renren Wen, PhD PhD, University of Tennessee Medical School, Memphis 1996 St. Jude Children’s Research Hospital, Memphis 1996-2000 Started at Versiti: 2000

on studying two signaling molecules: phospholipase of these two type of antibodies and the B cell type that gamma, mutations of which have been associated with generates these antibodies. Her study of HIT at a clonal human autoinflammatory diseases and T cell lymphomas, level would potentially lead to novel and improved and Bcl10, mutations of which have been associated with diagnosis and HIT treatment. Her study also suggests human B cell lymphomas. Her work will potentially lead that the antibodies involved in HIT may play roles in to better understanding of the molecular pathogenesis cardiovascular diseases beyond HIT. of immune deficiency, autoimmunity, and cancer development. Awards, Honors and Service Dr. Wen also works on heparin-induced thrombocytopenia • Member, American Society of Microbiology (HIT), a disease that is caused by clinical administration of heparin, which in some patients can result in limb- and • Member, American Association for the Advancement of life-threatening thrombosis. It is believed that heparin Science complexed with a self-protein PF4 induces PF4/heparin antibodies, some of which causes HIT. Through cloning Funding human antibodies in HIT patients, Dr. Wen observed the 5R01 AI079087-08 Wang (PI) 06/15/2008 – 08/31/2019 existence of two types of antibodies to PF4/heparin, NIH/NIAID “PLCγs in B Cell Biology and Autoimmunity” those that can activate platelets and those that cannot. Role: Co-Investigator Her current work is focused on identifying the underlying molecular mechanisms that differentiate the function R01 HL130724 Wang (PI) 12/01/2016-11/30/2020 “B cell responses in heparin-induced thrombocytopenia” Role: Co-Investigator Research Interests R01 AI083636-06 Salomon (PI) 05/08/2017- 04/30/2022 “Phosphoproteomic Analysis of Feedback T and B lymphocytes are two important cell types in Networks in T Cell Signaling” Role: Co-investigator our . Whereas B cells secrete antibodies that are essential for protection against extracellular pathogens, T cells are critical for the control of infection by intracellular pathogens, and for enabling B lymphocytes to efficiently produce antibodies. However, aberrant signaling in B and T cells can lead to abnormal development and activation of B and T cells, resulting in immune deficiency, autoimmunity, or cancer development. Dr. Wen’s work is aimed at more fully understanding the molecular events that govern development of T cells to maturity and defining pathways that are critical for T cell functions. More specifically, her work has been focused

Research Report 2018 45 Stem Cells

Research in Stem Cell Biology and Hematopoiesis is aimed at understanding the many factors that regulate the normal process of how blood cells are formed (hematopoiesis), as well as understanding disease mechanisms that lead to abnormal hematopoiesis, which either could lead to a failure of healthy blood cell production or cause leukemia.

Studies in this area are bringing Versiti into the fields of regenerative medicine, and cancer biology. These studies reflect an ongoing commitment to expanding foundational research into areas that will fundamentally improve the understanding and treatment of currently incurable blood diseases.

Stem Cell Biology investigators are using cutting-edge technology to characterize molecular mechanisms involved in regulation of hematopoietic stem cells and their maturation into mature red cells, white cells and platelets. Assistant Professor, Department of Internal Medicine, Division of Hematology and Oncology, Karen Carlson, MD PhD Medical College of Wisconsin MD/PhD University of Wisconsin-Madison, 2004 Hematology/Oncology Fellowship: New York Presbyterian, Weill-Cornell Medical Center, 2011 Started at Versiti: 2016

extracellular matrix (ECM), and in particular, the Funding glycoprotein laminin-ɣ1, regulates neurovascular units in hematopoietic adult stem cell niches. She also is using “Bone Marrow Failure in Mice Deficient for the 3-dimensional image reconstructions to understand Extracellular Matrix Component, Laminin-gamma1” how human acute myelogenous leukemia (AML) traffics (1K08HL127187-03) — NHLBI (NIH) PI – April 1, 2015 – through the bone marrow vascular niches during March 31, 2020 remission induction chemotherapy. “Acute myelogenous leukemia interface with the Dr. Carlson’s long-term goal is to apply what she learns hematopoietic niche” MCW Cancer Center – PI – about the basic biology of the bone marrow extracellular December 1, 2017 – November 30, 2018 matrix to develop niche-targeted therapies that will help her patients with hematopoietic diseases. Publications 1. Schneidewend R, Hosking P, Brazauskas R, Awards, Honors and Service Peterson J, Beaudin C, Michaelis L, Atallah E, Hari P, • Best Doctors designation 2018 Carlson K. Early Fluorescence in situ Hybridization Assessment during Acute Myeloid Leukemia • Member, American Society of Matrix Biology 2018 Induction Chemotherapy. Acta Haematol. 2018 Mar • Member, American Society of Biochemistry and 29;139(3):171-175. PMID: 29597188 Molecular Biology 2018 • Member, International Society of Experimental Hematology 2018 Research Interests • Member, American Society of Hematology 2018 Dr. Karen-Sue Carlson is a board certified clinical hematologist. She joined the faculty at the Medical College of Wisconsin as an Assistant Professor of Medicine in the Division of Hematology and Oncology in 2013, and was appointed Assistant Investigator at the Blood Research Institute in 2016. She maintains an active clinical focus on diseases of disordered hematopoiesis including aplastic anemia, acute and chronic leukemias, and myelodysplastic and myeloproliferative syndromes at the Medical College of Wisconsin. At the Blood Research Institute, her research focuses on extracellular matrix regulation of adult stem cell homeostasis. Using murine models, Dr. Carlson studies how

Research Report 2018 47 Associate Investigator, Blood Research Institute, Versiti John Pulikkan, PhD PhD, Ludwig Maximilians University of Munich, Munich, Germany, 2008 Postdoctoral Associate, University of Massachusetts Medical School, Worcester, MA, 2010-2018 Started at Versiti: 2018

Awards, Honors and Service • Member, American Society for Hematology 2018 • Young Investigator Grant, Alex’s Lemonade Stand Publications Foundation for Childhood Cancer 2014 1. Pulikkan JA, Hegde M, Ahmed H, Belaghzal H, Illendula • Discovery Grant, Lauri Strauss Leukemia Foundation A, Yu J, O’Hagen K, Ou J, Muller-Tidow C, Wolfe SA, Zhu 2014 LJ, Dekker J, Bushweller JH, Castilla LH. CBFβ-SMMHC • Scholar Award in Basic Research, American Society of inhibition triggers apoptosis by disrupting MYC Hematology (ASH) 2013 chromatin dynamics in acute myeloid leukemia. Cell • Member, American Association for Cancer Research 2018 Jun 28;174(1):172-186. PMID: 29958106 (AACR) 2018 2. Pulikkan JA and Castilla LH. Pre-leukemia in inv(16) • Member, International Society for Stem Cell Research acute myeloid leukemia development. Frontiers in (ISSCR) 2018 Oncology 2018 Apr 26: 8(129): 1-7. PMID: 29755956

Research Interests The past decade of leukemia research has indicated in a comprehensive understanding of the role of genetic and epigenetic changes in leukemogenesis. However, only recently has the three-dimensional genome architecture been implicated in leukemogenesis. While much is known about transcription factor deregulation in AML, our understanding of chromatin structure and how transcription factors regulate higher-order genome architecture is limited. Our lab is interested in understanding the interplay between transcription factors (RUNX1 and C/EBPα) and chromatin dynamics in myeloid differentiation and how this is altered in AML. Our goal is to identify and characterize novel therapeutic targets, and translate them to the clinic with academic and pharmaceutical collaborations. 48 Versiti Blood Research Institute Associate Investigator, Blood Research Institute, Versiti Sridhar Rao, MD, PhD MD, University of Chicago, Pritzker School of Medicine, 2001 PhD, University of Chicago, 1999 Started at Versiti: 2010

developed. In Dr. Rao’s lab, they have focused on how Funding mutations in a specific group of genes, termed the cohesin complex, cause AML. Recent work indicates National Cancer Institute- R01 “Cohesin Mutations in that mutations in the cohesin complex promote bone AML” marrow cells to divide abnormally, and this predisposes Midwest Athletes Against Childhood Cancer (MACC them to acquire additional mutations which ultimately Fund) cause leukemia. Because the cohesin mutation likely Hyundai Hope on Wheels (HHOW) Impact Award occurs early in the process, targeting these mutations could lead to new therapies. Dr. Rao is currently working on different targeted therapy agents already in clinical Publications trial to determine if they could be used to treat patients 1. Stoltz KP, Jondle CN, Pulakanti K, Sylvester PA, Urrutia with cohesin-mutated AML. He has also expanded his R, Rao S, Tarakanova VL. Tumor suppressor Interferon research interest into Ewing’s Sarcoma, in which cohesin Regulatory Factor 1 selectively blocks expression of mutations have also recently been identified. endogenous retrovirus. Virology. 2018 Oct 17;526:52- 60. PMID: 30342302 Awards, Honors and Service 2. Volk A, Liang K, Suraneni P, Li X, Zhao J, Bulic M, • Member, American Society of Hematology 2018 Marshall S, Pulakanti K, Malinge S, Taub J, Ge Y, Rao S, Bartom E, Shilatifard A, Crispino JD. A CHAF1B- • Member, American Society for Blood & Marrow Dependent Molecular Switch in Hematopoiesis Transplantation (ASBMT) 2018 and Leukemia Pathogenesis. Cancer Cell. 2018 Nov • Member, International Society for Stem Cell Research 12;34(5):707-723.e7. PMID: 30423293 Research Interests (ISSCR) 2018 Acute Myelogenous Leukemia (AML) is a common Normal malignancy, but despite modern chemotherapy, the oesin ites of ncreased majority of patients relapse. Dr. Rao’s laboratory focuses romatin Accessibility on how altered gene expression causes diseases such N AA as cancer. His long-term goal is to understand how gene ccancy expression derangements can be targeted to develop less toxic, more effective chemotherapies to treat blood- tant oesin derived cancer. Additional PRC2 tations Dr. Rao’s laboratory focuses on Acute Myelogenous HoxA7/9 Leukemia (AML) because it represents a significant clinical challenge, with up to 50% of patients relapsing. nanced elfeneal Recent data has indicated a large number of genes tem ell (>200) can be mutated in AML, making it difficult to enes eemic istal is elatory lement ells understand how specific, targeted therapies can be Proimal Promoter Taken from Fisher et al, Leukemia, 2017 Research Report 2018 49 Associate Investigator, Blood Research Institute, Versiti Nan Zhu, PhD Assistant Professor, Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin PhD, Boston University, Boston, MA, 2007 Started at Versiti: 2015

their role in normal and malignant stem cell function Awards, Honors and Service and understanding the precise underlying molecular mechanism. In 2016, Dr. Zhu’s study on JMJD1C, an • American Society of Hematology, Scholar Award epigenetic regulator, demonstrated that it is important for LSC function but dispensable for HSC function, thus a Funding potential therapeutic target. Dr. Zhu’s lab is studying the ASH Scholar “Understanding Molecular Mechanism of molecular mechanism of how JMJD1C functions in AML. JMJD1C Function in AML” The ultimate goal of our research is to identify therapeutic targets and developed targeted therapy in AML based on knowledge gained from our research.

Research Interests Research in Dr. Zhu’s laboratory focuses on understanding epigenetic regulation in normal and malignant hematopoiesis with emphasis on the role of such regulation in hematopoietic stem cells (HSC) as well as leukemia stem cells (LSC). Epigenetic regulation refers to changes in gene activities that are independent of the underlying gene sequences. Epigenetic regulators play an important role in normal development and differentiation. More recently, they emerge as important players in the development of cancer as evident by recurrent mutations across a spectrum of cancers. Dr. Zhu’s lab has previously screened and identified several epigenetic regulators as important for the maintenance of acute myeloid leukemia (AML). Currently, Dr. Zhu is working on elucidating

50 Versiti Blood Research Institute Martha Sullivan What she thought was a common cold turned out to be life-threatening for Martha Sullivan. A late night trip to the ER led to doctors discovering that she had leukemia. The next day, Martha began chemotherapy. She received multiple blood and platelet transfusions to help prepare her body for a bone marrow transplant. Just four months after her diagnosis, Martha’s match was found and she underwent the transplant that helped save her life.

“Because of blood and bone marrow donors, I am a leukemia survivor,” says Martha. “Every day is a new beginning, so love life!” Core Laboratories

such as a QuantStudio 6 Flex Real-time PCR system for The Thrombosis Core maintains a spinning disk confocal rapid measurement of gene activity. Both 10X Genomics microscope system for in vivo studies on thrombosis. and Fluidigm systems are available for molecular analysis This core also features an in vitro flow system designed of single cells. to recapitulate the in vivo conditions of flowing blood in the vasculature (VenaFlux system from Cellix Ltd; Zeiss The Protein Chemistry Core synthesizes peptides inverted microscope with phase contrast, fluorescence using a microwave-enhanced Liberty 1 synthesizer and and incubation capabilities). offers peptide purification and a variety of post synthesis peptide modifications. The Core aids investigators The Histology Core specializes in tissue preparation, with protein purifications using AKTA and Agilent cutting of fixed and frozen sections and various staining chromatography systems. techniques. This core is staffed by a histology technician with 30 years of experience in experimental and clinical The Hybridoma Core produces murine and rat histology. monoclonal antibodies for research and diagnostic purposes. The Gene Editing Core is available as a resource for researchers that want to make targeted mutations in cells The Flow Cytometry Core utilizes two Becton Dickinson using recently developed CRISPR technology. LSR II multicolor cytometers, one BD FACS Celesta, one BD Accuri cytometer, a BD FACSAria high-speed cell The Computational Biology Core is led by a PhD sorter, and a BD FACS Melody cell sorter. scientist who collaborates with BRI investigators to analyze and interpret their next generation sequencing The Microscopic Imaging Core includes the confocal/ data. The Core provides not only data analysis but also multiphoton laboratory featuring an Olympus FV1000- integration and development of new computational MPEconfocal, multiphoton microscope as well as an methods to analyze and integrate genome wide data sets. inverted Nikon TE200, a Nikon Eclipse Ti2 inverted Modern biomedical research requires access to a wide fluorescence microscope, a Zeiss Axioscope and a The joint BRI/MCW Transgenic Core aids in the range of specialized technologies. The Versiti Blood Zeiss Lumar V12 stereo microscope with fluorescence generation of genetically altered animal models for the Research Institute maintains cutting-edge technology capabilities. A PhD Imaging Specialist manages the study of human disease. platforms that give researchers from the BRI, and its Microscopic Imaging Core. affiliates on the Medical College of Wisconsin (MCW) The Clinical Trials Research Office (CTRO) supports campus, access to state-of-the-art equipment and The Biophysics Core is equipped with a BIAcore 3000 the work of our Clinical Investigators, interfacing with expertise. These centralized core laboratories are a Plasmon Resonance Spectrometer and an Octet Red 96 the other research support services at the BRI. Services shared resource and are staffed by technical specialists from forte BIO that enables scientists to study protein- provided by the CTRO include but are not limited to that support individual research projects. Currently, the protein interactions in real time. clinical trial design and activation, study coordination and management, data collection, adverse event reporting, BRI is home to 13 different core laboratories. The Viral Vector Core is shared between the BRI and regulatory support and compliance, budgeting and MCW and specializes in vectors based on lentivirus, The Molecular Cell Biology Core offers DNA contract negotiation, and financial management. sequencing using both capillary-based and next- adenovirus and adeno-associated virus needed generation platforms and quantitative assays for DNA for research in the field of gene therapy and other and RNA utilizing several different instrument platforms, experimental applications.

52 Versiti Blood Research Institute Versiti Blood Research Institute Foundation

In 2018, the Versiti Blood Research Institute Mike and Ginny McBride Foundation welcomed Kelley McCaskill as Vice President of Philanthropy. Kelley brings more than The Versiti Blood Research Institute’s research 20 years’ experience to this role and is excited was instrumental in ensuring that Ginny’s kidney about the opportunity to engage with researchers transplant was a success. and donors who are part of the Blood Research Ginny has polycystic kidney and liver disease (PKD), Institute (BRI) community. an inherited disorder. The day after we celebrated th Two events that highlighted the important research our 50 wedding anniversary, she started on kidney taking place at the Blood Research Institute dialysis. After 22 months of dialysis treatments, included Research and Roses, where we welcomed her nephew Brad called to say he wanted to give nearly 100 people to the BRI gardens to learn about her one of his kidneys. While Brad’s kidney wasn’t T-Cell Therapy from Dr. Matthew Riese, an Associate a perfect match, investigators at the Versiti Blood Investigator with the BRI. Research Institute had developed a process that made it possible for Ginny to receive his kidney. The 2018 Imagine Gala was held at the Prior to the transplant, Ginny had to have several Intercontinental Hotel and was a great success. Co- treatments to strengthen her chairs Brenda and Tony Garbo and the Stollenwerk antibodies, ensuring that if there was any sign that Family welcomed 250 guests who bid on silent and her body was rejecting Brad’s kidney, her antibodies live auction items, heard from Tia, a sickle cell and would “win the fight.” Ginny’s kidney transplant was bone marrow patient, and learned about emerging performed at Froedtert Hospital in July, 2014. research in the fields of Stem Cell and Cell Therapy Research – areas that have grown quickly at the BRI When we learned about Versiti Blood Research with support of the community. Institute’s Campaign for a Center for Stem Cell and Cellular Therapy Research and building project, As the Foundation works to expand awareness there was no question we wanted to be involved. It of the Versiti Blood Research Institute in our was their research that had such a huge impact on community and beyond, we appreciate all that you the success of Ginny’s kidney transplant. do for us. You are our best advocates – sharing with your networks the important, life-changing work We believe “the best use of one’s life is to invest that happens at the BRI. in something that will outlast life.” Versiti Blood Research Institute’s cutting edge research will If you’d like to learn more about how you can help, continue to impact people’s lives long after our please contact the Foundation office at 414-937- passing. 6799. Mike McBride

Research Report 2018 53 Intellectual Property

Novel Approaches to Help Patients Mission Statement Basic and applied biomedical research studies The Technology Transfer Office supports Versiti’s are aimed primarily at understanding normal and organizational mission of bringing life-saving abnormal biology. This aids disease diagnosis, solutions to the patient through a departmental treatment and prevention. Research findings impact focus on placing innovations into the hands of patients and patient care when companies develop customers and colleagues. products and services from new discoveries. Intellectual property and patents help to differentiate and protect these new markets. Federal Background guidelines encourage protection of grant-supported discoveries through patents and other mechanisms Inventor Tibor Greenwalt and colleagues discovered that have the potential to transform research a white cell filtration method for blood in the 1960s. findings into products and services that benefit the Patent activity increased in the 1980s with the health of the public. discovery of the human platelet antigen system. Currently, the Technology Transfer Office provides The Technology Transfer Office of Versiti helps intellectual property, contract management, and to identify, protect, and commercially partner business management administrative services for discoveries to serve patient needs. Net revenues the organization. A cross functional team called generated support further research. In 2018, the Technology Transfer Review Group provides two new patents were filed, and royalty revenue executive oversight for this function. totaled $457,864. Versiti has more than 50 license agreements with industry partners. The number of new licenses executed in 2018 was twice the national average for institutes with the same sized research budget.

54 Versiti Blood Research Institute Leadership 2018

Versiti Board of Versiti Blood Versiti Leadership Research Administration

Directors Research Institute Foundation Board Chris Miskel, President & Tony Watkins, Executive Tina Koplinski, MS, CRA Dale Kent, Chair Chief Executive Officer Vice President and Chief Director of Research Administration Financial Officer Blood Research Institute L. Alan (Skip) Whaley, Robert Wawrzyn, Chair Thomas Abshire, MD, Vice Chair Executive Vice President, Jim Weidner, Executive Brenda Garbo, Vice Chair William Cashdollar, PhD Medical Sciences Institute Vice President & Chief Mitchell Watt, Secretary Director Core Research Lab Guy Crane, Secretary Human Resources Officer & Chief Medical Officer Blood Research Institute James Rauh, Treasurer Richard Gallagher, Brian Bautista, Executive Gilbert C. White, II, MD, Cathy Buck Treasurer Vice President and Chief Executive Vice President Susan Knight, MBA, CNMT, FACHE Senior Director Richard Fotsch Andy Anderson, MD, MBA Operating Officer and Chief Scientific Officer, Versiti; Director, Blood Medical Sciences Institute Lynne Briggs, Vice Fred Geilfuss Emery Harlan Research Institute President & Chief Laura Savatski, MBA, CLP, RTTP Thomas J. Hauske, Jr. Sarah Joerres, MD Information Officer Technology Transfer Officer Gregory Larkin, MD Dale Kent Gitesh Dubal, Executive Blood Research Institute Robert H. Manegold Robert H. Manegold Vice President and Chief Marketing Officer Jeff McDonald Ron Miller Colleen McCarthy, Chief of Chris Miskel Chris Miskel Staff and Vice President, John Perras James Rauh Organ and Tissue Donation E. Randall Wright John R. Raymond, Sr., MD Kelley McCaskill, Vice Peter D. Ziegler Johan C. R. Segerdahl President, Philanthropy Kristin Severson Meg McElligott, Vice President & Chief Quality John J. Stollenwerk Officer Julia Syburg Brad Pietz, Executive Gilbert C. White, II, MD Vice President & Chief Laboratory Officer Michael H. White Bart Reuter, Executive Vice Peter D. Ziegler President & Chief Legal & Compliance Officer

Research Report 2018 55 Advisory Boards 2018

2018 Scientific Advisory Board Robert Flaumenhaft, MD, PhD Steven Pipe, MD Professor, Division of Hemostasis and Thrombosis Professor of Pediatrics and Pathology Gail Bishop, PhD Beth Israel Deaconess Medical Center Laurence A. Boxer Research Professor of Pediatrics and Holden Chair of Cancer Biology Communicable Diseases Professor of Microbiology & International Medicine Assoc. J. Evan Sadler, MD, PhD Pediatric Medical Director, Hemophilia and Coagulation Director for Basic Science Research Chief, Division of Hematology Disorders Program Holden Comprehensive Cancer Center Ira M. Lang Professor of Medicine Director, Special Coagulation Laboratory Director, Center for Immunology & Immune-Based Professor of Biochemistry and of Molecular Biophysics University of Michigan Disorders Washington University School of Medicine – St. Louis The University of Iowa Sean Stowell, MD PhD Brad Schwartz, MD Medical Director, Center for Apheresis, Emory Hospital David Bodine, Phd Chief Executive Officer Center for Transfusion and Cellular Therapies Chief and Senior Investigator Morgridge Institute for Research Emory University School of Medicine National Human Genome Research Institute Professor of Medicine and Biomolecular Chemistry Genetics and Molecular Biology Branch University of Wisconsin National Institutes of Health 2018 T32 Advisory Board Nancy Speck, PhD Lawrence Brass, MD, PhD Chair, Department of Cell and Developmental Biology Douglas B. Cines, MD Professor of Medicine and Pharmacology Investigator, Abramson Family Center Cancer Professor of Medicine Hematology-Oncology Division Research Institute Professor of Pathology and Laboratory Medicine Associate Dean and Director, Combined Degree and The Perelman School of Medicine Director of Coagulation Laboratory and Office of Faculty Physician University of Pennsylvania Development Scholars Program University of Pennsylvania Perelman School of Medicine University of Pennsylvania School of Medicine Philadelphia, PA 2018 External Advisory Board/Medical Mary M. Horowitz, MD, MS John L. Cleveland, PhD Sciences Institute Robert A. Uihlein, Jr. Professor of Hematologic Research Associate Center Director, Division of Basic Science Director H. Lee Moffitt Cancer Center & Research Institute Paul M. Ness, MD CIBMTR® Director, Transfusion Medicine, Department of Pathology Associate Director, Cancer, Genomic Sciences and Charles T. Esmon, PhD Johns Hopkins School of Medicine Precision Medicine Center Member and Head of Coagulation Biology Medical College of Wisconsin, Milwaukee, WI Oklahoma Medical Research Foundation Barbara Konkle, MD Professor of Pathology and Biochemistry & Director, Clinical and Translational Research and James C. Zimring, MD, PhD Molecular Biology Medical Director, Hemostasis Reference Laboratory Director, Bloodworks NW Research Institute Oklahoma Medical Research Foundation Puget Sound Blood Center Chief Scientific Officer , Bloodworks NW Professor of Medicine Professor of Laboratory Medicine and Hematology University of Washington School of Medicine University of Washington School of Medicine, Seattle, WA

56 Versiti Blood Research Institute Donors 2018

Donors by giving level (all 2018 Julia and John Syburg Lynn and Anthony Baudo Community Fund Inc Fund donations received) Anthony and Jolene Watkins Julianne and Rick Bauer Ted and Mary Kellner BioLegend Gilbert and Judy White Joan Brengel Tina and Jim Koplinski Blood Centers of America Inc $100,000+ Peter and Joan Ziegler Lynne and John Briggs Mary Ann and Charles LaBahn Thomas and Elissa Bolger Stollenwerk Family Charitable William and Nancy Cashdollar Melinda and Donald Lanham John and Olive Bryson Foundation $2,500 - $4,999 Cedar Street Charitable Nathaniel and Amy Marshall Gregory and Jennifer Bucholc Four-Four Foundation Inc Foundation Meg and Brian McElligott Cathy and Greg Buck Richard and Patsy Aster Cleary Gull Inc Mediware Information Systems Corning Life Sciences Direct Supply Inc $20,000 - $99,999 Elizabeth Cordero James and Betty Jo Nelsen Weiguo Cui Richard Fotsch and Hanna Sandra Cunningham Network For Good Bonnie and Jeffrey Dittel Dixon and Herta Benz Royston-Fotsch E. C. Styberg Foundation Peter and Debra Newman Gitesh and Neha Dubal Hauske Family Foundation Jacquelyn and Arlyn Fredrick Emil Ewald Family Foundation Inc OneBlood, Inc. Dean and Anne Fitzgerald Froedtert Health Inc Essen BioScience Ilke and Peter Panzer Amy Friemoth $10,000 - $19,999 Richard and Ann Gallagher Evan and Marion Helfaer Park Bank Foundation Inc Robert Fuelling and Dorothy Godfrey & Kahn SC Guy and Katherine Crane Foundation Karen and Keith Pierce Schneider-Fuelling Jerome and Hope Gottschall Foley & Lardner LLP James and Judith Rauh Barbara Fuldner Cream City 5k Greater Milwaukee Foundation’s Emtec David and Molly Fritz Laura Savatski GE United Way Campaign Betsy Barr Fund Brenda and Tony Garbo John Senatore Jack and Kathleen Gorski Fenwal Inc Harwood Engineering Francie Luke Silverman C. Frederick Geilfuss and Anne Kristin and Chuck Severson Greater Milwaukee Foundation - Consultants Hamilton Geilfuss Kevin and Linda Steiner David C. Scott Foundation Foundation Thomas and Katherine Hauske Burton Goodman GemPharmatech Andrea Stollenwerk Michael Hammerman Héma-Québec George and Julie Mosher Family David and Patricia Stroik Charles Hauske J P Morgan Charitable Giving Joan and Fred Brengel Family Fund - Meier Foundation Foundation Marilyn and Robert Teper Karin Hoffmeister and Herve Foundation, Inc. Tricia Gervasi The John Oster Family Falet Jewish Community Foundation - Dale and Linda Kent Laura Miller Memorial Glycotech Corp Foundation Inc Austin Jelcick Kolaga Family Charitable Trust Peter and Beth Gottsacker Family James and Leigh Ann Tidey Jewish Community Fdn - Ronald Meijer Moderna Therapeutics Play 4 Cade Charitable Fund United Way of Greater Milwaukee D Miller & Susan Angel Miller Robert and Janet Montgomery Greater Milwaukee Foundation’s Vilter Foundation Inc Mary Ann Kampe Barbara Stein Donna and Joel Nettesheim Thomas J. Bliffert Foundation Asher and Susan Nichols Family Michelle Waite Kapco Kathleen and Joseph Puca Fund Robert and Susan Wawrzyn Ken and Kathy Klein Thomas Savage $5,000 - $9,999 Greater Milwaukee Foundation’s Jim and Rosie Weidner Jim Koetje Stalle Reality Group Cottrell Balding Fund West Bend Mutual Insurance Co. Jeff and Donna Landsman Thomas and Diane Abshire Trinity Trust Greater Milwaukee Foundation’s William and Sandy Heitz Family Arthur and Nancy Laskin David V. Uihlein Foundation Norbert and Dorothy Whittle Randall Family Fund Foundation James Marshall Sarah and Jeffrey Joerres John Hach Louise Wilson Tom and Amy Marshall Collin and Kirsten Johnson $1,000 - $2,499 Jon and Ann Hammes Wintrust Financial Corp Paradise Memorial Funeral Home Kohl’s John Adamson and Annette von Troy Heinritz Sharon Ziegler Christopher Parsons Ladish Company Foundation Drygalski Herb Kohl Philanthropies PeproTech Inc John and Linda Mellowes Bernard and Bess Alberg Mehraboon Irani $500 - $999 Matthew Roethle Chris and Nicole Miskel Amicus Therapeutics Inc Janice and Raymond Perry Sanofi Foundation for North John and JoEllen Stollenwerk Benevity Community Impact Research Report 2018 57 America Emergency Medicine Adrienne Pfarr Lihui Yin Betty Schuett Specialists SC Brad and Dina Pietz Erin Yttre Schwab Charitable Fund Mason Fisher Mary Lou Rice Mei Yu Anna and Conor Squier Randolph and Pamela Grace and Andrew Robbins Janice and Larry Zahorik State Farm Companies Frank Samuel Sauseda Nanyan Zhang Foundation Froedtert South Inc Elizabeth Senglaub Adam Ziebell STEMCELL Technologies Thomas R Fox Family Carl Sokol Jane Ziemanski Inc. Foundation Jen Souvignier Jackie Zigan David Tampa Kimberly Gerber The Bartolotta Restaurant Mark Zogg Roberta Thorpe Christine Gostomski- Group Joe and Sue Zuern Margery Uihlein Megna Irina Vasilev Lynn Zwitter Wenthe-Davidson David and Kerry Grosse Willard and Mary Walker Stacey and Donald Zysk Engineering Co Judy Guelig and Alvan Mary Anne and Ronald Alan and Elizabeth Whaley Bachtell Wawrzyn Mark & Julia Winkler Petri TJ Hauske Michelle and Michael Fund Bradley Heberlein Weber Ryan Heinritz Karen and Gene Wenzel $250 - $499 Therese Jensen Jieqing Zhu Susan and Dan Johnson Russ Weber Matthew and Cindy Donna Kleczka Carmel Wendorff Anderson Carine Krull David Wenninger John and Francine Arnold Nona Kyle Weybridge Company LTD Aurora Health Care Inc Daniel Loy Bryan and Jennie Joe Balsanek Michael and Laurie Wiedmeyer Lisa Baumann Kreuziger Mahoney George and Bonnie Brian and Thrisha Bautista Kelley McCaskill Wiedmeyer Bio-Techne Mehran Mehrabi Paul and Patricia Williams Bryan Blanke William and Barbara Mielke June Williams David and Suzanne Boerke Ronald and Susan Miller Laura and Carl Wise Jeffrey and Kelly Bradford MilliporeSigma Mary B Wisniewski and B Brady Corporation Alex Minella Scott Wisniewski Calvin and JoAnne Heidi Mohs Esther and Fred Wiviott Brockmann Mosquito Joe of Waukesha Steven and Diane David Brumder County Wojciechowicz Martha Cates Chris Nicholson Bill and Diane Wolf Jason Clarin Josh North Shirley Wolf Jim and Olga Clouthier Tom Olejniczak Erin Wolslager Janeen Coyle Deborah Oseland Kevin Wolslager Molly Duffy Melissa Paul Kristi and Joe Wright

58 Versiti Blood Research Institute Publications 2018

1. Abel AM, Tiwari AA, Gerbec ZJ, Siebert JR, Yang C, AK, Versteeg HH, Wolberg AS, Wong PC, Wood JP, Weiler Regulates the Formation of Hepatic Progenitor Cells from Schloemer NJ, Dixon KJ, Thakar MS, Malarkannan S. IQ H. Advances in Clinical and Basic Science of Coagulation: Human iPSC-Derived Endoderm by Facilitating Efficient Domain-Containing GTPase-Activating Protein 1 Regulates Illustrated abstracts of the 9th Chapel Hill Symposium Recruitment of RNA Pol II. Genes (Basel). 2018 Dec Cytoskeletal Reorganization and Facilitates NKG2D- on Hemostasis. Res Pract Thromb Haemost. 2018 Apr 28;10(1). PMID: 30597922 Mediated Mechanistic Target of Rapamycin Complex 1 12;2(3):407-428. PMID: 30046746 18. Dhakal B, Kreuziger LB, Rein L, Kleman A, Fraser R, Activation and Cytokine Gene Translation in Natural Killer 10. Best B, Moran P, Ren B. VEGF/PKD-1 signaling mediates Aster RH, Hari P, Padmanabhan A. Disease burden, Cells. Front Immunol. 2018 May 28;9:1168. PMID: 29892299 arteriogenic gene expression and angiogenic responses complication rates, and health-care costs of heparin- 2. Abel AM, Yang C, Thakar MS, Malarkannan S. Natural Killer in reversible human microvascular endothelial cells with induced thrombocytopenia in the USA: a population-based Cells: Development, Maturation, and Clinical Utilization. extended lifespan. Mol Cell Biochem. 2018 Sep;446(1- study. Lancet Haematol. 2018 May;5(5):e220-e231. PMID: Front Immunol. 2018 Aug 13;9:1869. Review. PMID: 2):199-207. PMID: 29380239 29703336 30150991 11. Cao Z, Suo X, Chu Y, Xu Z, Bao Y, Miao C, Deng W, Mao K, 19. Ellery PER, Hilden I, Sejling K, Loftager M, Martinez ND, 3. Agrawal P, Heimbruch KE, Rao S. Genome-Wide Maps Gao J, Xu Z, Ma YQ. Peptides derived from the integrin β Maroney SA, Mast AE. Correlates of plasma and platelet of Transcription Regulatory Elements and Transcription cytoplasmic tails inhibit angiogenesis. Cell Commun Signal. tissue factor pathway inhibitor, factor V, and Protein S. Enhancers in Development and Disease. Compr Physiol. 2018 Jul 3;16(1):38. PMID: 29970081 Res Pract Thromb Haemost. 2018 Jan;2(1):93-104. PMID: 2018 Dec 13;9(1):439-455. PMID: 30549021 29354797 12. Chen Y, Silverstein RL. Platelet metabolism meets 4. Alaqzam TS, Stanley AC, Simpson PM, Flood VH, Menon thrombosis. Blood. 2018 Sep 13;132(11):1089-1091. PMID: 20. Epperla N, Kleman A, Karafin M, Foy P. Re-treatment versus S. Treatment Modalities in Adolescents Who present With 30213838 extended treatment strategy of systemic bevacizumab in Heavy Menstrual Bleeding. J Pediatr Adolesc Gynecol. 2018 hereditary hemorrhagic telangiectasia: which is better? 13. Cloutier N, Allaeys I, Marcoux G, Machlus KR, Mailhot B, Mar 7. pii: S1083-3188(18)30171-2. PMID: 29524595 Ann Hematol. 2018 Sep;97(9):1727-1729. PMID: 29656313 Zufferey A, Levesque T, Becker Y, Tessandier N, Melki I, Zhi 5. Balogun RA, Schwartz J, Dunbar N, Padmanabhan A; H, Poirier G, Rondina MT, Italiano JE, Flamand L, McKenzie 21. Flegel WA, Chen Q, Castilho L, Keller MA, Klapper EB, Lane American Society for Apheresis (ASFA) Special Issue SE, Cote F, Nieswandt B, Khan WI, Flick MJ, Newman PJ, WJ, Pirenne F, Stack G, St-Louis M, Tormey CA, Waxman Writing Committee. In response to Peeding and Karp, “The Lacroix S, Fortin PR, Boilard E. Platelets release pathogenic DA, Weinstock C, Wendel S, Denomme GA. Molecular definition of severe systemic lupus erythematosus needs serotonin and return to circulation after - immunohaematology round table discussions at the AABB clarification in the next ASFA guidelines”. J Clin Apher. 2018 mediated sequestration. Proc Natl Acad Sci U S A. 2018 Feb Annual Meeting, Orlando 2016. Blood Transfus. 2018 Feb Oct;33(5):624. PMID: 30187957 13;115(7):E1550-E1559. PMID: 29386381 14:1-12. PMID: 29517973 6. Baumann Kreuziger L, Karkouti K, Tweddell J, Massicotte 14. Compernolle V, Chou ST, Tanael S, Savage W, Howard J, 22. Flood VH, Abshire TC, Christopherson PA, Friedman KD, MP. Antithrombotic Therapy Management of Adult and Josephson CD, Odame I, Hogan C, Denomme G, Shehata Cox Gill J, Montgomery RR, Haberichter SL; Zimmerman Pediatric Cardiac Surgery Patients. J Thromb Haemost. N; International Collaboration for Transfusion Medicine Program Investigators. Von Willebrand disease in the United 2018 Nov;16(11):2133-2146. Review. PMID: 30153372 Guidelines. Red blood cell specifications for patients with States: perspective from the Zimmerman program. Ann hemoglobinopathies: a systematic review and guideline. Blood. 2018 Jan;3. pii: 7. PMID: 30135959 7. Baumann Kreuziger L, Slaughter MS, Sundareswaran K, Transfusion. 2018 Jun;58(6):1555-1566. Review. PMID: Mast AE. Clinical Relevance of Histopathologic Analysis of 23. Flood VH, Johnsen JM, Kochelek C, Slobodianuk TL, 29697146 HeartMate II Thrombi. ASAIO J. 2018 Nov/Dec;64(6):754- Christopherson PA, Haberichter SL, Udani R, Bellissimo DB, 759. PMID: 29461277 15. Curtis BR, Hsu YS, Podoltsev N, Lacy J, Curtis S, Samuel MS, Friedman KD, Montgomery RR. Common VWF sequence Zutavern K, DeSimone RA, Bougie DW, Aster RH. Patients variants associated with higher VWF and FVIII are less 8. Bercovitz RS, Shewmake AC, Newman DK, Niebler RA, Scott treated with oxaliplatin are at risk for thrombocytopenia frequent in subjects diagnosed with type 1 VWD. Res Pract JP, Stuth E, Simpson PM, Yan K, Woods RK. Validation of caused by multiple drug-dependent antibodies. Blood. 2018 Thromb Haemost. 2018 Jan 23;2(2):390-398. PMID: a definition of excessive postoperative bleeding in infants Mar 29;131(13):1486-1489. PMID: 29439950 30046743 undergoing cardiac surgery with cardiopulmonary bypass. J Thorac Cardiovasc Surg. 2018 May;155(5):2112-2124. 16. DeLisle J. Is This a Blood Transfusion Reaction? Don’t 24. Friedman KD, Powell JS, Bensen-Kennedy D. Response: PMID: 29338867 Hesitate; Check It Out. J Infus Nurs. 2018 Jan/Feb;41(1):43- The coagulation laboratory monitoring of AFSTYLA 51. PMID: 29293197 single-chain FVIII concentrate. Haemophilia. 2018 9. Bergmeier W, Antoniak S, Conway EM, Denis CV, George LA, May;24(3):e129-e131. PMID: 29603512 Isermann B, Key NS, Krishnaswamy S, Lam WA, Lillicrap D, 17. DeLaForest A, Di Furio F, Jing R, Ludwig-Kubinski A, Liu J, Looney MR, López JA, Maas C, Peyvandi F, Ruf W, Sood Twaroski K, Urick A, Pulakanti K, Rao S, Duncan SA. HNF4A

Research Report 2018 59 25. Gehrie EA, Roubinian NH, Chowdhury D, Brambilla DJ, abstract available. PMID: 29259003 Griffin B, Frymark S, Piehet A, Robertson D, Proudford M, Murphy EL, Gottschall JL, Wu Y, Ness PM, Strauss RG, Kincaid A, Green C, Burgess L, Wallace M, Segal J. Increased 33. Kanaji S, Orje JN, Kanaji T, Kamikubo Y, Morodomi Y, Hendrickson JE; NHLBI Recipient Epidemiology-Donor Acute Care Utilization in a Prospective Cohort of Adults with Chen Y, Zarpellon A, Eberhardt J, Forli S, Fahs SA, Sood R, Evaluation Study (REDS-III). A multicentre study Sickle Cell Disease. Blood Adv 2018 Sep 25;2(18):2412-2417. Haberichter SL, Montgomery RR, Ruggeri ZM. Humanized investigating vital sign changes occurring in complicated PMID: 30254105 GPIbα-von Willebrand factor interaction in the mouse. Blood and uncomplicated transfusions. Vox Sang. 2018 Adv. 2018 Oct 9;2(19):2522-2532. PMID: 30287479 42. Levitt RN, Gourri E, Gassner C, Banez-Sese G, Salam A, Feb;113(2):160-169. PMID: 29277907 Denomme GA, Yang E. Molecular characterization and 34. Karafin MS, Fu X, D’Alessandro A, Thomas T, Hod EA, 26. Glisch C, Jawa Z, Brener A, Carpenter E, Gottschall multidisciplinary management of Gerbich hemolytic Zimring JC, Field JJ, Francis RO. The clinical impact J, Treml A, Karafin MS. Evaluation of a two-sample disease of the newborn. Pediatr Blood Cancer. 2018 of glucose-6-phosphate dehydrogenase deficiency in process for prevention of ABO mistransfusions in a high Jun;65(6):e27014. PMID: 29469208 patients with sickle cell disease. Curr Opin Hematol. 2018 volume academic hospital. BMJ Open Qual. 2018 Jul Nov;25(6):494-499. PMID: 30239377 43. Liao D, Mei H, Hu Y, Newman DK, Newman PJ. CRISPR- 15;7(3):e000270. PMID: 30057954 mediated deletion of the PECAM-1 cytoplasmic domain 35. Karafin MS, Singh M, Ceesay M, Koduri S, Zhang L, 27. Graminske S, Puca K, Schmidt A, Brooks S, Boerner A, increases receptor lateral mobility and strengthens Simpson P, Field JJ. Dyspareunia is associated with chronic Heldke S, de Arruda Indig M, Brucks M, Kossor D. In vitro endothelial cell junctional integrity. Life Sci. 2018 Jan pain in premenopausal women with sickle cell disease. evaluation of di(2-ethylhexyl)terephthalate-plasticized 15;193:186-193. PMID: 29122551 Hematology. 2018 Jan 29:1-6. PMID: 29376481 polyvinyl chloride blood bags for red blood cell storage in 44. Lindholm PF, Kwaan HC, Ramsey G, Curtis BR, Fryer AS-1 and PAGGSM additive solutions. Transfusion. 2018 36. Karafin MS, Singavi A, Hussain J, Wandersee N, Heinrich T, J. Severe thrombocytopenia in a patient following liver May;58(5):1100-1107. PMID: 29574766 Hurley RW, Zhang L, Simpson P, Field JJ. Predictive factors transplantation caused by HPA-1a antibodies produced by of daily opioid use and quality of life in adults with sickle cell 28. Hoffmeister KM. TPO-logy accepted. Blood. 2018 Aug the liver donor. Am J Hematol. 2018 Jan;93(1):150-153. disease. Hematology. 2018 May 31:1-8. PMID: 29848208 9;132(6):555-557. PMID: 30093383 PMID: 29044602 37. Karafin MS, Westlake M, Hauser RG, Tormey CA, Norris PJ, 29. Holm E, Carlsson KS, Lövdahl S, Lail AE, Abshire TC, 45. López A, Aparicio N, Pazos MR, Grande MT, Barreda-Manso Roubinian NH, Wu Y, Triulzi DJ, Kleinman S, Hendrickson Berntorp E. Bleeding-related hospitalization in patients MA, Benito-Cuesta I, Vázquez C, Amores M, Ruiz-Pérez G, JE; NHLBI Recipient Epidemiology and Donor Evaluation with von Willebrand disease and the impact of prophylaxis: García-García E, Beatka M, Tolón RM, Dittel BN, Hillard CJ, Study-III (REDS-III). Risk factors for red blood cell Results from national registers in Sweden compared Romero J. Cannabinoid CB2 receptors in the mouse brain: alloimmunization in the Recipient Epidemiology and Donor with normal controls and participants in the von relevance for Alzheimer’s disease. J Neuroinflammation. Evaluation Study (REDS-III) database. Br J Haematol. 2018 Willebrand Disease Prophylaxis Network. Haemophilia 2018 May 24;15(1):158. PMID: 29793509 Jun;181(5):672-681. PMID: 9675950 2018 Jul;24(4):628-633. PMID: 29626372 46. Luo X, Chen J, Schroeder JA, Allen KP, Baumgartner CK, 38. Kholmukhamedov A, Janecke R, Choo HJ, Jobe 30. Jacobi PM, Kanaji S, Jakab D, Gehrand AL, Johnsen JM, Malarkannan S, Hu J, Williams CB, Shi Q. Platelet Gene SM. The mitochondrial calcium uniporter regulates Haberichter SL. Von Willebrand Factor Propeptide to Therapy Promotes Targeted Peripheral Tolerance by Clonal procoagulant platelet formation. J Thromb Haemost. 2018 Antigen Ratio Identifies Platelet Activation and Reduced Deletion and Induction of Antigen-Specific Regulatory T Nov;16(11):2315-2321. PMID: 30179298 VWF Survival Phenotype in Mice. J Thromb Haemost. 2018 Cells. Front Immunol. 2018 Sep 6;9:1950. PMID: 30237796 Feb;113(2):160-169. PMID: 29285851 39. Kreuziger LB, Massicotte MP. Adult and pediatric 47. Malec L, Abshire T, Jobe S, White G. rFIXFc for Immune mechanical circulation: a guide for the hematologist. 31. Jang Y, Gerbec ZJ, Won T, Choi B, Podsiad A, B Moore B, Tolerance Induction in a Severe Hemophilia B Patient with Hematology Am Soc Hematol Educ Program. 2018 Nov Malarkannan S, Laouar Y. Cutting Edge: Check Your Mice-A an Inhibitor and Prior History of ITI Related Nephrotic 30;2018(1):507-515. Review. PMID: 30504351 Point Mutation in the Ncr1 Locus Identified in CD45.1 Syndrome. Haemophilia. 2018 Jul;24(4):e294-e296. PMID: Congenic Mice with Consequences in Mouse Susceptibility 40. Lakshmikanthan S, Sobczak M, Li Calzi S, Shaw L, Grant 30024646 to Infection. J Immunol. 2018 Mar 15;200(6):1982-1987. MB, Chrzanowska-Wodnicka M. Rap1B promotes VEGF- 48. Malec LM, Cooper J, Rudolph J, Michaels MG, Ragni MV. PMID: 29440507 induced endothelial permeability and is required for Prophylactic rtPA in the Prevention of Line-associated dynamic regulation of endothelial barrier. 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60 Versiti Blood Research Institute 49. Maroney SA, Peterson JA, Zwifelhofer W, Martinez ND, Yan Nov;104(5):883-893. PMID: 30063264 2018 Apr;46(4):577-585. PMID: 29300236 K, Bercovitz RS, Woods RK, Mast AE. Plasma Proteolytic 58. Padmanabhan A. Cellular collection by apheresis. 66. Sakurai Y, Hardy ET, Ahn B, Tran R, Fay ME, Ciciliano Cascade Activation during Neonatal Cardiopulmonary Transfusion. 2018 Feb;58 Suppl 1:598-604. Review. PMID: JC, Mannino RG, Myers DR, Qiu Y, Carden MA, Baldwin Bypass Surgery. Thromb Haemost. 2018 Sep;118(9):1545- 29443409 WH, Meeks SL, Gilbert GE, Jobe SM, Lam WA. A 1555. PMID: 30086574 microengineered vascularized bleeding model that 59. Pandya KA, Johnson EG, Davis GA, Padmanabhan A. 50. Mescher C, Gilbertson D, Randall NM, Tarchand G, Tomaska integrates the principal components of hemostasis. Nat Serotonin release assay (SRA)-negative HIT, a newly J, Baumann Kreuziger L, Morrison VA. The impact of Agent Commun. 2018 Feb 6;9(1):509. 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57. Newman DK, Fu G, McOlash L, Schauder D, Newman PJ, National Heart, Lung, and Blood Institute (NHLBI) Recipient

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Xu Z, Ni B, Cao Z, Zielonka J, Gao J, Chen F, Kalyanaraman Adv. 2018 Jun 12;2(11):1325-1333. PMID: 29895623 Mar;118(3):502-513. PMID: 29452445 B, White GC, Ma YQ. Kindlin-3 negatively regulates the 74. St Ledger K, Feussner A, Kalina U, Horn C, Metzner HJ, 82. Tobase P, Lane H, Siddiqi AE, Soucie JM, Ingram-Rich R, release of neutrophil extracellular traps. J Leukoc Biol. 2018 Bensen-Kennedy D, Blackman N, Veldman A, Stowers Ward S, Gill JC; Hemophilia Treatment Center Network Sep;104(3):597-602. PMID: 29656482 A, Friedman KD. International comparative field study (HTCN) Study Investigators. Risk factors associated 90. Yang C, Tsaih SW, Lemke A, Flister MJ, Thakar MS, evaluating the assay performance of AFSTYLA in plasma with invasive orthopaedic interventions in males with Malarkannan S. mTORC1 and mTORC2 differentially samples at clinical hemostasis laboratories. J Thromb haemophilia enrolled in the Universal Data Collection promote natural killer cell development. Elife. 2018 Haemost. 2018 Mar;16(3):555-564. PMID: 9274194 program from 2000 to 2010. Haemophilia. 2018 May 29;7. pii: e35619. doi: 10.7554/eLife.35619. PMID: Nov;24(6):964-970. PMID: 29957840 75. Stoltz KP, Jondle CN, Pulakanti K, Sylvester PA, Urrutia 29809146 R, Rao S, Tarakanova VL. Tumor suppressor Interferon 83. Van Buren NL, Gorlin JB, Reed RC, Gottschall JL, Nelson SC. 91. Yang M, Kholmukhamedov A, Schulte ML, Cooley BC, Regulatory Factor 1 selectively blocks expression of Ceftriaxone-induced drug reaction mimicking acute splenic Scoggins NO, Wood JP, Cameron SJ, Morrell CN, Jobe endogenous retrovirus. Virology. 2018 Oct 17;526:52-60. sequestration crisis in a child with hemoglobin SC disease. SM, Silverstein RL. Platelet CD36 signaling through ERK5 PMID: 30342302 Transfusion. Apr;58(4):879-883 PMID: 29473172 promotes caspase-dependent procoagulant activity and 76. Subramaniam S, Kanse SM, Kothari H, Reinhardt C, 84. 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62 Versiti Blood Research Institute 96. Zeng Y, Hiti A, Moranville S, Vicent G, Chavira S, de Arruda Indig M, Graminske S, Boerner A, Schmidt A, Oreizy F, Chen A, Saleminik M, Mosqueda F, Lin A, Judge K. Human HLA-B27 typing using the BD™ HLA-B27 kit on the BD FACSVia™ system: A multicenter study. Cytometry B Clin Cytom. 2018 Sep;94(5):651-657. PMID: 29476701 97. Zhang M, Dong Y, Hu F, Yang D, Zhao Q, Lv C, Wang Y, Xia C, Weng Q, Liu X, Li C, Zhou P, Wang T, Guan Y, Guo R, Liu L, Geng Y, Wu H, Du J, Hu Z, Xu S, Chen J, He A, Liu B, Wang D, Yang YG, Wang J. Transcription factor Hoxb5 reprograms B cells into functional T lymphocytes. Nat Immunol. 2018 Mar;19(3):279-290. PMID: 29434353 98. Zhi H, Ahlen MT, Thinn AMM, Weiler H, Curtis BR, Skogen B, Zhu J, Newman PJ. High-resolution mapping of the polyclonal immune response to the human platelet alloantigen HPA-1a (PlA1). Blood Adv. 2018 Nov 13;2(21):3001-3011. PMID: 30413435 99. Zhou D, Thinn AMM, Zhao Y, Wang Z, Zhu J. Structure of an

extended β3 integrin. Blood. 2018 Aug 30;132(9):962-972. PMID: 30018079 100. Zhu J. Csk/CD148 and platelet SFK activation: a balancing act! Blood. 2018 Mar 8;131(10):1042-1043. PMID: 29519930

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