CTSA Translational Research Fellowship Opportunity in Comparative Cancer Genomics at Tufts Cummings School of Veterinary Medicine

Description of Fellowship Training Environment The purpose of this 2-year research fellowship opportunity is to provide residency-trained veterinary specialists with advanced instruction and mentoring in comparative cancer genomics. The Fellow will be involved in research aimed at dissecting the genomic landscape of specific canine tumors (osteosarcoma, hemangiosarcoma, lymphoma) and using those data to interrogate relevant molecular pathways for potential therapeutic intervention. The goal of the fellowship is to provide the trainee with a comprehensive set of tools that will support a future career as a clinician-scientist in the setting of academic medicine. Fellows will work within the laboratories of Drs. Cheryl London and Heather Gardner, gaining bench-based skill sets including cell- culture, a variety of assays to assess tumor cell phenotype (flow cytometry, assessment of proliferation/apoptosis, invasion assays, etc), DNA/RNA purification, PCR/RT-qPCR, cloning, gene editing (CRISPR), western blotting and chromatin immunoprecipitation (ChIP), among others. Additionally, the Fellow will learn basic tools associated with analysis of genomic data including R/R Studio and command-line based open-source software (DESeq2, EdgeR, SnpEff, etc.). The Fellow will obtain a visiting scientist position at the Broad Institute, permitting access to correlative genomics data and computational expertise within the Vertebrate Genomics Group (directed by Dr. Karlsson). The Research Fellow will devote at least 80% of their effort to benchtop research and analysis of data. The remaining 20% of time may be spent embedded within the Clinical Trials Office at the Cummings School to participate in ongoing translational oncology studies and/or engaging in clinical duties related to their research (i.e., sample collection, etc.). In this clinical setting, the Fellow will be responsible for assisting with all aspects of clinical trials conducted in oncology patients presenting to the Foster Hospital for Small Animals under the supervision of Dr. London. The Fellow will also have opportunities to rotate through the pediatric oncology service at the University of Massachusetts Medical School (with Dr. Shohet). Lastly, Jackson Laboratory is now a partner with Tufts University and we have initiated a large collaborative effort to develop and credential canine PDX models, with the goal of establishing a canine immune system in the mouse, much like humanized mouse systems. This is being undertaken at the JAX Farmington campus, a short drive from the Grafton Cummings School. The fellow will be involved, as appropriate, in working with the JAX faculty to evaluate the PDX tumors at the histologic and genomic levels.

Goals of the Fellowship 1. Gain expertise in a variety of laboratory techniques including cell culture, gene editing methods, cloning, western blotting, flow cytometry among others. 2. Become familiar with methods for genomic interrogation (RNAseq, whole exome sequencing, whole genome sequencing and CHiP sequencing) and associated analytic tools. 3. Develop fundamental knowledge regarding animal models of cancer, specifically mouse xenograft and PDX systems. 4. Demonstrate an understanding of how molecular techniques can be used to support comparative and translational research. 5. Improve communication and presentation skills in both small and large venues 6. Synthesize relevant literature and apply it to research questions including hypothesis generation and formulation of a research plan 7. Gain expertise in grant and paper writing 8. Develop tools to become comfortable working in a team science setting.

Fellowship Mentoring Team Heather Gardner, DVM, PhD, ACVIM(O), Primary Mentor: Assistant Research Professor, Cummings School of Veterinary Medicine at Tufts University. Dr. Gardner in a veterinary medical oncologist with broad training in clinical trials and comparative genomics. She has a number of active collaborations with the Broad Institute, the Translational Genomics Research Institute and the Children’s Hospital of Philadelphia. Her research efforts center on leveraging the canine tumor genome to inform comparative and translational research. Dr. Gardner will provide primary oversight to the Fellow. She has co-mentored research projects for several veterinary residents, undergraduate and graduate students. Cheryl London, DVM, PhD, ACVIM(O), Co-Mentor: Anne Engen and Dusty Professor in Comparative Oncology, Director of the Clinical Trials Office, Cummings School of Veterinary Medicine at Tufts University; Research Professor at the Graduate School of Biomedical Sciences and School of Medicine at Tufts University. Dr. London is an expert in the field of translational sciences and comparative medicine, using spontaneous models of cancer in dogs. She led the establishment of successful Veterinary Clinical Trials programs at both OSU and Tufts and she maintains an active research laboratory in the Immunology Department at Tufts School of Medicine. She is heavily involved in the Tufts Clinical and Translational Science Institute (CTSI), serving as Director of the Research Collaboration Team and the One Health Optional Module. Dr. London has been the primary mentor/research advisor for 8 MS students, 5 PhD students, 14 Medical Oncology Residents/Fellows, and 3 Postdoctoral Fellows. Several have gone on to advanced careers in industry and academics. Importantly, all of her prior PhD students were DVMs enrolled in a dual program; in each case their thesis work was undertaken during the course of their residency programs (two anatomic pathology, two clinical pathology, two medical oncology) and she is therefore familiar with the need to balance laboratory-based research with clinical responsibilities in the setting of veterinary medicine. Elinor Karlsson, PhD: Associate Professor in Bioinformatics and Integrative Biology at the University of Massachusetts Medical School; Director of the Vertebrate Genomics Group at the Broad Institute of MIT and Harvard. Dr. Karlsson has expertise in vertebrate genomics, with her research program spanning the genetics that drive canine behaviors to genomic alterations in canine cancers. She has extensive experience with various techniques to analyze genomics data, bioinformatics and integration of data from multiple genomics platforms within and across species. Dr. Karlsson has several active collaborations with Drs. Gardner and London, with studies spanning both genomics-based analytic techniques and clinical trials in pet dogs with cancer. These coordinated efforts supported successful R27 and R01 applications for which Dr. Karlsson is the PI and Drs. London and Gardner are co-PI/co-investigator. Jason Shohet, MD, PhD: Division Chief for Pediatric Hematology/Oncology at University of Massachusetts Medical School; Associate Professor of Pediatrics at University of Massachusetts Medical School. Dr. Shohet’s research focuses on the development of less toxic therapies for childhood cancers and cancer stem cell biology. As such, he provides a clinical context to assist with translation of experimental results and application to human patients. Wonyeong Kang, DVM, PhD: Associate Research Scientist, The Jackson Laboratory. Dr. Kang is leading an effort to generate a canine PDX core resource for future translational work. She plans to caninize these models to provide a better tool for immune-oncology studies. Dr. Kang will assist the Fellow with making connections to the community at JAX in Farmington CT engaged in canine comparative oncology work, ranging from the PDX models to generation of canine iPSCs and genomics of canine brain tumors. Norma Terrin, PhD: Scientific Director of the Biostatistics, Epidemiology and Research Design (BERD) Center within the Tufts Clinical and Translational Science Institute (CTSI) and Professor at Tufts University School of Medicine. Dr. Terrin will contribute her experience with respect to experimental design and statistical analysis, particularly with respect to animal model work.

Programmatic training opportunities available to the fellow: The mentoring team has designed a set of comprehensive training opportunities that take advantage of the complementary sets of expertise available to the Fellow and leverages ongoing partnerships between Tufts University/Tufts CTSI/Tufts Medical Center, the Broad Institute and The Jackson Laboratory. The following workshops and seminar series are available through Tufts CTSI, providing instruction in multiple facets of comparative and translational research: grant writing, comparative effectiveness research seminars, good clinical practice (GCP), developing and managing your research career, research design and data analysis. The CTSI has several resources to support training in team science that are geared to junior faculty as well. Through the visiting scientist appointment at the Broad Institute, the Fellow will be able to attend workshops and seminar series, including advanced informatics classes, yearly CRISPR focused short courses and monthly cancer program meetings, which brings together scientists from across the diverse landscape of Boston academic and industry stakeholders. Additional workshops are available through both the Broad Institute and Tufts CTSI for fellows interested in gaining skills in bioinformatics techniques related to their research. Lastly, the Fellow will have opportunities to spend time at both the University of Massachusetts Medical School Hospital and JAX Farmington to get hands on experience across pediatric oncology and mouse models. In summary, the proposed training program will provide a truly unique opportunity for intensive training across the spectrum of laboratory- based research, mouse modeling, translational and comparative clinical cancer trials and pediatric oncology.

Interested candidates should contact Dr. Heather Gardner at [email protected]. OMB No. 0925-0001 and 0925-0002 (Rev. 03/2020 Approved Through 02/28/2023)

BIOGRAPHICAL SKETCH Provide the following information for the Senior/key personnel and other significant contributors. Follow this format for each person. DO NOT EXCEED FIVE PAGES. NAME: Gardner, Heather L. eRA COMMONS USER NAME: HGARDNER POSITION TITLE: Research Assistant Professor EDUCATION/TRAINING INSTITUTION AND LOCATION DEGREE START COMPLETION FIELD OF STUDY DATE DATE Washington State University, Pullman BS 08/2001 05/2005 Zoology WA Washington State University, Pullman DVM 08/2007 05/2011 Veterinary Medicine WA Ohio State University, Columbus OH Residency 07/2014 07/2017 Medical Oncology Tufts University, Boston MA PhD 07/2017 05/2020 Genetics

A. PERSONAL STATEMENT I am a board certified veterinary medical oncologist with advanced training in comparative and translational clinical trials. I recently completed my PhD in Genetics at the Graduate School of Biomedical Sciences at Tufts University and am an assistant research professor at the Cummings School of Veterinary Medicine at Tufts University. Over the course of my clinical training from internship through medical oncology residency I have had the opportunity to be involved in several trials of novel therapeutics that generated data in support of subsequent human drug development (selinexor, acalabrutinib, among others). During my time at Tufts University I also had the opportunity to be involved in several Clinical and Translational Science Award One Health Alliance (COHA) efforts including the optimization of the Tufts veterinary electronic medical records for data modeling using the Observational Medical Outcomes Partnership (OMOPv5+) common data model. Additionally, I have assisted in the execution of the COHA website, which incorporates an online Research Workbench tool based on the OMOPv5+ common data model and serves as a portal for collaboration and distribution of knowledge. At Tufts University I established a number of collaborations within Tufts and its associated partners (Jackson Laboratory, Maine Medical Center), University of Massachusetts Medical School and the Broad Institute, facilitating a broadly engaged approach to building expertise in comparative oncology. My research centers on the biology and therapy of OS, with a specific focus on defining the genomic landscape of OS in dogs to more effectively leverage this spontaneous model for therapeutic development. Through this work I have gained skills in computational analysis of large-scale genomics datasets, advanced gene-editing methods and essential techniques in molecular biology, providing me with the expertise to provide mentorship in a fellowship. A few of my more recent book chapters and accepted publications are listed below.

a. Gardner HL, Sivaprakasam K, Briones N, Zismann V, Perdigones N, Richholt R, Liang W, Aldrich J, Trent JM, Shields P, Robinson N, Johnson J, Lana S, Houghton P, Fenger J, Lorch G, Janeway KA, London CA, Hendricks WPD. Canine osteosarcoma genome sequencing identified recurrent mutations in DMD and the histone methyltransferase gene SETD2. Commun Biol. 2019;2:266. doi: 10.1038/s42003-019- 0487-2. eCollection 2019. PubMed PMID: 31341965. b. Gardner HL, Fenger JM, London CA. Dogs as a Model for Cancer. Annu Rev Anim Biosci. 2016;4:199- 222. PMID: 26566160. c. Gardner HL*, Londhe P*, London CA. Leveraging Dogs with Spontaneous Cancer to Advance Drug Development. Animal Models in Cancer Drug Discovery. Elsevier. April 2019. *Contributed equally.

B. POSITIONS AND HONORS

Positions and Employment 2011-2012 Associate Veterinarian; VCA Alameda East, Denver, CO 2012-2013 Oncology Intern; University of Florida; Gainesville, FL 2013-2014 Clinical Trials Intern; The Ohio State University; Columbus, OH 2014-2017 Medical Oncology Resident; The Ohio State University; Columbus, OH 2020 - Assistant Research Professor; Cummings School of Veterinary Medicine at Tufts University; North Grafton, MA

Professional Memberships

2011 - Member, Veterinary Cancer Society 2011 - 2015 Member, American Veterinary Medical Association 2011 – 2012 Member, Denver Area Veterinary Medical Society 2011 Member, Washington State Veterinary Medical Association 2016 - Associate Member, American Association for Cancer Research 2017 - Diplomate, American College of Veterinary Internal Medicine (Oncology) 2017 - Broad Institute, Visiting Graduate Student/Scientist

Honors

2008 Dr. E.M. Gildow Scholarship 2009 Pet Memorial Scholarship 2010 Novartis Animal Health Scholarship 2011 Joyeux Noelle Scholarship 2011 Tacoma Kennel Club Scholarship 2011 Veterinary Cancer Society Award Membership 2016 Amiya K. Patnaik Memorial Award for Outstanding Poster Presentation in Basic Science 2017 3rd Place Award in College Graduate Student Seminar Course 2017 Sackler Student Enrichment Fund Award 2019 1st Place AVMA/AVMF Early Stage Investigator Award 2020 Dean’s Award

C. CONTRIBUTIONS TO SCIENCE

1. During my trials internship and oncology residency training I was extensively involved in multiple pre- and post- IND clinical trial efforts aimed at evaluating novel targeted therapeutics in spontaneous canine cancers. These studies provided key pieces of data regarding safety, biologic activity and pharmacokinetic/ and pharmacodynamic relationships in the setting of spontaneous canine cancer that ultimately positively impacted the subsequent development timeline. a. London C, Gardner HL, Rippy S, Post G, LaPerle K, Crew L, Lopresti-Morrow L, Garton AJ, McMahon G, LaVallee TM, Gedrich R. KTN0158, a humanized anti-KIT monoclonal antibody, demonstrates biologic activity against both normal and malignant canine mast cells. Clin Cancer Res. 2016;23(10):2565-2574. PMID: 27815356 b. Gardner HL*, Harrington BK*, Izumi R, Hamdy A, Rothbaum W, Coombes KR, Covey T, Kaptein A, Gulrajani M, Van Lith B, Krejsa C, Phelps MA, Russell DS, Zhang X, Urie BK, London CA, Byrd JC, Johnson AJ, Kisseberth WC. Preclinical evaluation of the novel BTK inhibitor acalabrutinib in canine models of B cell non-Hodgkin lymphoma. PLoS One. 2016;11(7):e0159607. PMID: 27434128 *Contributed equally c. London CA, Acquaviva J, Smith DL, Sequeira M, Shin Ogawa L, Gardner HL, Bernabe LF, Bear MD, Selting K, Proia DA. Consecutive day HSP90 inhibitor administration improves efficacy in murine models of KIT-driven malignancies and canine mast cell tumors. Clin Cancer Res. 2018 Dec 15;24(24):6396- 6407. doi: 10.1158/1078-0432.CCR-18-0703. Epub 2018 Aug 31. PubMed PMID: 30171047.

2. Throughout my clinical training I have participated in several studies evaluating the utility of the multi-targeted kinase inhibitor toceranib (Palladia) in the setting of canine cancer. As the first FDA approved cancer therapy for dogs, work with toceranib preceded and facilitated the development path of its closely related analog sunitinib (Sutent). These trials demonstrated that toceranib (and likely sunitinib as well) does not improve outcome in the microscopic metastatic disease setting, informing current and future treatment recommendations. Moreover, combination of toceranib with chemotherapy similarly did not improve outcomes in solid tumors. a. Gardner HL, London CA, Portela RA, Nguyen S, Rosenberg MP, Klein MK, Clifford C, Thamm DH, Vail DM, Bergman P, et al. Maintenance therapy with toceranib following doxorubicin-based chemotherapy for canine splenic hemangiosarcoma. BMC Vet Res. 2015;11:131. PMID: 26062540. b. Gardner HL*, London CA*, Mathie T, Stingle N, Portela R, Pennell ML, Clifford CA, Rosenberg MP, Vail DM, Williams LE, et al. Impact of toceranib/piroxicam/cyclophosphamide maintenance therapy on outcome of dogs with appendscular osteosarcoma following amputation and carboplatin chemotherapy: A multi-Institutional Study. PLoS One. 2015 9;10(4):e0124889. PMID: 25923466 *Contributed equally c. Rippy SB, Gardner HL, Nguyen SM, Warry EE, Portela RF, Drost WT, Hostnik ET, Green EM, Chew DJ, Peng J, et al. A pilot study of toceranib/vinblastine therapy for canine transitional cell carcinoma. BMC Vet Res. 2016;12(1):257. PubMed PMID: 27855679.

3. I have been actively involved in the work performed under the auspices of an NCI P01 grant (PI Peter Houghton) entitled “Studies of Childhood Sarcomas”. This included working closely with a co-investigator to interrogate the function of p63 isoforms in OS biology; assessment of LY5, a putative STAT3 inhibitor, in preclinical models; and sequencing of the canine OS tumor genome (also supported by an administrative supplement to the Dana Farber Cancer Institute P30 support grant). Collectively this body of work helped to define canine OS as a relevant large animal model of human disease and identified STAT3 as a therapeutic vulnerability in this cancer. a. Gardner HL*, Cam M*, Roberts RD, Fenger JM, Guttridge DC, London CA, Cam H. ΔNp63 mediates cellular survival and metastasis in canine osteosarcoma. Oncotarget. 2016;7(30):48533-48546. doi: 10.18632/oncotarget.10406. PubMed PMID: 27391430. *Contributed equally b. Gardner HL*, Yu Peter*, Roberts R, Cam H, Hariharan S, Ren L, LeBlanc AK, Xiao H, Lin J, et al. Target specificity, in vivo pharmacokinetics, and efficacy of the putative STAT3 inhibitor LY5 in osteosarcoma, Ewing’s sarcoma, and rhabdomyosarcoma. PLoS One. 2017 Jul 27;12(7):e0181885. doi: 10.1371/journal.pone.0181885. PubMed PMID: 28750090. *Contributed equally c. Gardner HL, Sivaprakasam K, Briones N, Zismann V, Perdigones N, Richholt R, Liang W, Aldrich J, Trent JM, Shields P, Robinson N, Johnson J, Lana S, Houghton P, Fenger J, Lorch G, Janeway KA, London CA, Hendricks WPD. Canine osteosarcoma genome sequencing identified recurrent mutations in DMD and the histone methyltransferase gene SETD2. Commun Biol. 2019;2:266. doi: 10.1038/s42003-019-0487-2. eCollection 2019. PubMed PMID: 31341965.

4. Over the course of my training through internship and residency I have participated in several clinical trials that were intended to bring new therapeutics to veterinary clinical oncology. In some instances they also supported the development path of the drug within veterinary medicine (verdinexor, RV1001) and in other instances they used existing therapeutics to assess therapeutic activity. Collectively, these studies have helped to advance treatment options for veterinary cancer patients. a. Gardner HL*, Sadowski AR*, Borgatti A, Wilson H, Vail D, Lachowicz J, Manley C, Turner A, Klein MK, Waite A, Sahora A,London CA. Phase II study of the Oral Selective Inhibitor of Nuclear Export (SINE) KPT-335 in 58 dogs with lymphoma. BMC Vet Res. 2018 Aug 24;14(1):250. doi: 10.1186/s12917-018- 1587-9. PubMed PMID: 30143046. *Contributed equally b. Gardner HL, Rippy SB, Bear MD, Cronin KL, Heeb H, Burr H, Cannon CM, Penmetsa KV, Viswanadha S, Vakkalanka S, London CA. Phase I/II evaluation of RV1001, a novel PI3Kδ inhibitor, in spontaneous canine lymphoma. PLoS One. 2018 Apr 24;13(4):e0195357. doi: 10.1371/journal.pone.0195357. eCollection 2018. PubMed PMID: 29689086; PubMed Central PMCID: PMC5915681. c. Schuh EM, Portela R, Gardner HL, Schoen C, London CA. Safety and efficacy of targeted hyperthermia treatment utilizing gold nanorod therapy in spontaneous canine neoplasia. BMC Vet Res. 2017 Oct 2;13(1):294. doi: 10.1186/s12917-017-1209-y. PubMed PMID: 28969639. d. Alexander CK, Cronin KL, Silver M, Gardner HL, London CA. The Addition of Metronomic Chemotherapy Does Not Improve Outcome for Canine Splenic Hemangiosarcoma. Small Anim Pract. 2019 Jan;60(1):32-37. doi: 10.1111/jsap.12926. Epub 2018 Sep 12. PubMed PMID: 30209807.

A complete list of my published work can be found in My Bibliography using the following link: https://www.ncbi.nlm.nih.gov/myncbi/heather.gardner.1/bibliography/public/.

D. ADDITIONAL INFORMATION:

Ongoing Research Support

K01 ORIP/NIH PI: Gardner (Co-Mentors: Hinds/Yelick) 03/01/20-02/30/25 Elucidating the therapeutic utility of targeting metabolic dependencies in osteosarcoma. This is a mentored training grant. I will use this funding to complete my PhD thesis and transition into an independent faculty member.

AKC Canine Health Foundation #02768 (Co-PI: Gardner) 04/01/20 – 03/31/23 Defining the functional consequences and therapeutic vulnerability of dystrophin alterations in canine osteosarcoma. The overarching goal of this application is to characterize the function of dystrophin in malignant bone biology and use these data to optimize subsequent therapeutic targeting in canine OS. This data will be critical to optimize subsequent in vivo efforts to detect mutant dystrophin in tumor samples and leverage that information to optimize therapeutic approaches in canine OS.

D19CA-083 Morris Animal Foundation (PI: London) 09/01/18-07/31/20 Interrogating the regulation, function and therapeutic potential of monocarboxylate transporters in osteosarcoma. The purpose of this proposal is to investigate the mechanisms by which STAT3 and FOXM1 regulate MCT1 and MCT4 expression and function in OS cell lines. Role: Co-Investigator

Animal Cancer Foundation (PI: London) 06/01/18-05/30/20 Interrogating the regulation, function and therapeutic potential of monocarboxylate transporters in osteosarcoma. The purpose of this proposal is to investigate the mechanisms by which STAT3 and FOXM1 regulate MCT1 and MCT4 expression and function in OS cell lines. Role: Co-Investigator

U54 TR002354 (PI: Selker, London – Director) 05/01/18-04/30/23 Tufts Clinical and Translational Science Institute Through research resources, services, and education, Tufts Clinical and Translational Science Institute supports the entire spectrum of clinical and translational research to help meet the promise and the public’s needs of biomedical science. This spectrum includes the translation of bench research into bedside care (“T1”), into effective clinical practice (“T2”), into wide care delivery and public health (“T3”), and into health policy (“T4”). This research will have impact on healthcare and the public’s health. Role: Co-Investigator

U01 CA224153 (MPI: London/Richards) NIH/NCI 12/01/17-11/30/22 Enhancing the efficacy of immunotherapy in DLBCL using rational combination approaches The purpose of this proposal is to use dogs with spontaneous naïve DLBCL to rapidly evaluate rational small molecule/immunotherapy combination approaches, with the ultimate goal of identifying the most effective combination to move forward in human patients with DLBCL. Role: Co-Investigator

OMB No. 0925-0001 and 0925-0002 (Rev. 03/2020 Approved Through 02/28/2023)

BIOGRAPHICAL SKETCH

NAME: London, Cheryl A. eRA COMMONS USER NAME (credential, e.g., agency login): calondon POSITION TITLE: Professor

EDUCATION/TRAINING (Begin with baccalaureate or other initial professional education, such as nursing, include postdoctoral training and residency training if applicable. Add/delete rows as necessary.) INSTITUTION AND LOCATION DEGREE Completion Date FIELD OF STUDY Bowdoin College, Brunswick, ME B.A. 05/1986 Biochemistry Tufts University, Boston, MA D.V.M. 05/1990 Veterinary Medicine University of Wisconsin, Madison, WI Residency 07/1994 Medical Oncology Harvard University, Boston, MA Ph.D. 06/1999 Immunology A. Personal Statement I am a veterinary medical oncologist with over 25 years of experience in translational and comparative oncology and drug development. As Director of the Clinical Trials Office at the Cummings School of Veterinary Medicine at Tufts, I am responsible for overseeing all studies in client owned animals with spontaneous disease. As Director of the One Health Program and Research Collaboration Team at the Tufts Clinical Translational Science Institute (CTSI), I am charged with expanding and integrating comparative medicine efforts across Tufts and its partners. Over the past 10 years I have worked to enhance comparative and translational research efforts across the veterinary/human interface, and have been intimately involved in the growth of the CTSA One Health Alliance (COHA) through leadership of the COHA Clinical Trials Subcommittee, development of the veterinary Observational Medical Outcomes Partnership (OMOPv5+) Common Data Model and more recently, the COHA web site that serves as a central hub for information, training and communication. I have ongoing collaborations with the Broad Institute, Dana Farber Cancer Institute, and Ohio State University as well as several projects with industry partners. Over the course of my career I have been the primary advisor for 15 House Officers, 8 MS students, 5 PhD students and 4 Postdoctoral Fellows. I have also mentored 8 undergraduate/professional students through summer research programs/internships. Lastly, 4 of my trainees have received SERCA K01 mentored training awards. My background in basic and clinical/translational research provide a rich set of experiences for ensuring that milestones outlined in this fellowship are achieved.

1. Gardner HL, Fenger JM, London CA. Dogs as a Model for Cancer. Annu Rev Anim Biosci. 2016; 4:199- 222. PMID: 26566160 2. LeBlanc AK, Breen M, Choyke P, Dewhirst M, Fan TM, Gustafson DL, Helman LJ, Kastan MB, Knapp DW, Levin WJ, London C, Mason N, Mazcko C, Olson PN, Page R, Teicher BA, Thamm DH, Trent JM, Vail DM, Khanna C. Perspectives from man's best friend: National Academy of Medicine's Workshop on Comparative Oncology. Sci Transl Med. 2016 Feb 3;8(324):324ps5. PMID: 26843188 3. London C, TedxOhioStateUniversity 2015: Of Mice, Dogs, and Men, http://vet.osu.edu/vmc-news/canine- cancer-clinical-trials-discussed-tedxohiostateuniversity-dr-cheryl-london B. Positions and Honors Positions 1995-98 Clinical Instructor, Oncology, Tufts School of Veterinary Medicine, N. Grafton, MA 1996-99 Research Fellow, Immunology Division, Brigham and Women’s Hospital, Boston, MA 1999-05 Assistant Professor, UC Davis School of Veterinary Medicine 2005-13 Associate Professor, Veterinary Biosciences, College of Veterinary Medicine, OSU 2007- Director, Veterinary Clinical Research Support Shared Resource, College of Vet Medicine, OSU 2013-16 Shackelford Professor, Veterinary Biosciences, College of Veterinary Medicine, OSU 2016- Associated Faculty Professor, College of Veterinary Medicine, OSU 2013-18 Director, Translational Therapeutics, Center for Clinical and Translational Sciences, OSU 2014-18 Director, Translational Therapeutics Think Tank, OSU 2016- Research Professor, School of Medicine, Tufts University, Boston, MA 2016- Director, Clinical Trials Office, Cummings School of Vet Medicine, Tufts University, Grafton, MA 2017- Director, One Health Program and Research Collaboration Team, Tufts CTSI, Boston, MA 2018- Anne Engen and Dusty Professor of Comparative Oncology, Cummings School, Grafton, MA 2020- Associate Dean for Research and Graduate Education

Honors 1993 Robert S. Brodey Award, for outstanding resident’s clinical research 1994 Miles Small Animal Resident of the Year Award 1994 Robert S. Brodey Award, for outstanding resident's basic research 1995-97 John Stauffer Graduate Fellowship 2003 Vintner Grant in Honor of Marc Beringer 2005-16 Shackelford Professor of Veterinary Medicine, OSU 2010 Pfizer Animal Health Research Award 2018 Pfizer Animal Health Research Award

C. Contributions to Science 1. During my residency in veterinary medical oncology, the contribution of KIT signaling to mast cell biology was just being explored. As dogs frequently develop neoplastic diseases of mast cells, I asked whether dog mast cell tumors (MCT) possess mutations in KIT that may contribute to tumor biology. During an externship in the laboratory of Dr. Stephen Galli at Harvard University in 1993, I identified the presence of internal tandem duplications in the juxtamembrane domain of KIT that resulted in ligand-independent KIT signaling. This was the first driver mutation found in canine spontaneous cancer, and my laboratory subsequently defined the role of mutant KIT in canine MCT biology and its utility as a biomarker for mast cell disease. a. London CA, Kisseberth WC, Galli SJ, Geissler EN, and Helfand SC. Expression of stem cell factor ligand (c-kit) by the malignant mast cells from spontaneous canine mast cell tumors. J Comp Path 115:399-414; 1996. PMID: 9004081 b. London CA, Galli SJ, Yuuki T, Hu Z-Q, Helfand SH, Geissler EN. Spontaneous canine mast cell tumors express tandem duplications in the proto-oncogene c-kit. Exp Hematol 27:689-697;1999. PMID: 10210327 c. Downing S, Chien MB, Kass PH, Moore PF, London CA. Prevalence and significance of Kit internal tandem duplications in canine mast cell tumor. Am J Vet Res 63:1718-1723; 2002. PMID: 12492288 d. Zadovoskaya R, Chien MB, London CA. Use of Kit internal tandem duplications to establish mast cell tumor clonality. J Vet Int Med. 18:915-917; 2004. PMID: 15638281

2. The characterization of KIT dysregulation in canine MCT provided an opportunity to evaluate the clinical utility of small molecule inhibitors in the setting of spontaneous disease. To this end, my laboratory worked with Sugen (now Pfizer) during the development and testing of the orally bioavailable multi-targeted kinase inhibitor sunitinib by interrogating the biologic activity of its companion drug toceranib. These studies were critical as earlier inhibitors developed by Sugen had failed both Phase 2 and 3 human clinical trials and there was concern that the newer orally bioavailable compounds would fail to meet clinical endpoints. My laboratory demonstrated inhibition of KIT signaling by toceranib in vitro and defined its safety and efficacy in a Phase 1 study in dogs with spontaneous cancers, providing clear evidence that that sunitinib would likely have biologic activity against KIT-driven malignancies in future human studies. Furthermore, my laboratory performed the first study that demonstrated direct in vivo target modulation (inhibition of KIT phosphorylation) following a single dose of inhibitor in a spontaneous model of disease. Sunitinib was approved for the treatment of imatinib-resistant GIST in 2006 and I led the subsequent pivotal study in dogs with MCT that resulted in the approval of toceranib for dogs with MCT, the first FDA approved cancer therapy in this species. a. Liao AT, Chien MB, Shenoy N, Mendel DB, McMahon G, Cherrington JM, London CA. Inhibition of constitutively active forms of mutant Kit by a multi-targeted indolinone kinase inhibitor. Blood 15:585-593; 2002. PMID: 12091352 b. London CA,, Hannah A, Zadovoskaya R, Chien MB, Rosenberg ME, Downing S, Post G, Shenoy N, Mendel DB, McMahon G, Cherrington JM. Phase I dose-escalating study of SU11654, a small molecule receptor tyrosine kinase inhibitor, in dogs with spontaneous malignancies. Clin Cancer Res 9:2755-2768; 2003. PMID:12855656 c. Pryer NK, Lee LB, Zadovoskaya R, Yu X, Sukbuntherng J, Cherrington JM, London CA. Proof of target for SU11654: Kit inhibition in canine mast cell tumors. Clin Cancer Res 9:5729-5734; 2003. PMID: 14654558 d. London CA, Malpais PB, Follis SL, Boucher JF, Rusk A, Rosenberg MP, Henry CJ, Mitchener KL, Klein MK, Hintermeister JG, Bergman PJ, Couto GC, Mauldin GN, Michels GM. Multicenter, placebo- controlled, double-blind, randomized study of oral Palladia (SU11654) in the treatment of dogs with recurrent mast cell tumors. Clin Cancer Res. 15(11):3856-65; 2009. PMID:1947073 3. To better define the biology of malignant mast cell disease, my laboratory developed a technique to generate normal mast cells from canine bone marrow resulting in the generation of a tremendously valuable resource for comparative biology. We demonstrated that canine mast cells possess gene expression profiles and functional properties that are much more comparable to human mast cells when compared to mouse mast cells. Furthermore, the ability to reliably generate canine mast cells enabled us to critically compare the molecular profiles and functional consequences of therapeutic interventions in both normal and malignant mast cell populations. Specifically, we defined the kinetics of HSP90-induced KIT target modulation by ganetespib (STA- 9090) prior to human clinical trials and identified KIT as a novel target of the HDAC inhibitor AR42. Lastly, we compared the microRNA profiles of normal and malignant canine mast cells, resulting in the identification of miR-9 as a mediator of invasive behavior and metastasis; a similar role for miR9 has been defined in metastatic human breast cancer. These data supported the development of an inducible mouse model of mast cell specific miR-9 overexpression, supporting the successful K01 application by Dr. Joelle Fenger, for whom I serve as mentor. a. Lin T-Z., London CA. Functional comparison of canine and murine bone marrow derived cultured mast cells. Vet Imm Immunopathol 114:320-34; 2006. PMID:17027994 b. Lin TY, Bear M, Du Z, Foley KP, Ying W, Barsoum J, London CA. The novel HSP90 inhibitor STA- 9090 exhibits activity against Kit dependent and independent malignant mast cell tumors. Exp Hematol. 36:1266-1277; 2008. PMCID: PMC3837096 c. Lin TY, Fenger J, Muharari S, Bear M, Kulp SK, Wang D, Chen CS, Kisseberth WC, London CA. AR- 42, a novel HDAC inhibitor, exhibits biologic activity against malignant mast cell lines via downregulation of constitutively activated Kit. Blood. May 27;115(21):4217-25; 2010. PMCID: PMC3398750 d. Fenger JM, Bear MD, Volinia S, Lin TY, Harrington BK, London CA, Kisseberth WC. Overexpression of miR-9 in mast cells is associated with invasive behavior and spontaneous metastasis. BMC Cancer. Feb 11;14:84. 2014. PMCID: PMC3933481 4. My laboratory has also focused on the comparative biology of canine and human osteosarcoma (OSA) with the ultimate goal of identifying common molecular pathways that provide a foundation for subsequent translational clinical trials. To this end we characterized the contribution of constitutive STAT3 activation to canine OSA, demonstrating that it plays a similar role in disease biology when compared to human OSA. Furthermore, we validated STAT3 as a relevant target for therapeutic intervention in both canine and human OSA. This work resulted in a strong collaborative effort with the OSU College of Pharmacy, OSU College of Medicine, and Nationwide Children’s Hospital to develop and test viable allosteric inhibitors capable of specifically targeting STAT3 (LLL12 and LY5). Importantly, our collaborative work contributed to a successful P01 application, “Studies of Childhood Sarcoma” that integrated in vitro studies, mouse models of disease and spontaneous canine cancer to accelerate and optimize translational efforts. More recently, we completed a comprehensive analysis of the canine osteosarcoma genome, identifying key mutations in SETD2 and DMD. a. Fossey SL, Liao AT, McCleese JK, Bear MD, Lin J, Li P, Kisseberth WK, London CA. Characterization of STAT3 Activation and Expression in Canine and Human Osteosarcoma. BMC Cancer. Mar 10; 9:81; 2009. PMCID: PMC2666757 b. Bid HK, Oswald D, Li C, London C, Lin J, Houghton PJ. Anti-angiogenic activity of a small molecule STAT3 inhibitor LLL12. PLoS One. 7(4):2012. PMCID: PMC3328460 c. Yu PY, Gardner HL, Roberts R, Cam H, Hariharan S, Ren L, LeBlanc AK, Xiao H, Lin J, Guttridge DC, Mo X, Bennett CE, Coss CC, Ling Y, Phelps MA, Houghton P, London CA Target specificity, in vivo pharmacokinetics, and efficacy of the putative STAT3 inhibitor LY5 in osteosarcoma, Ewing's sarcoma, and rhabdomyosarcoma. PLoS One 12(7):2017. PMCID: PMC5531494 d. Gardner HL, Sivaprakasam K, Briones N, Zismann V, Perdigones N, Richholt R, Liang W, Aldrich J, Trent JM, Shields P, Robinson N, Johnson J, Lana S, Houghton P, Fenger J, Lorch G, Janeway KA, London CA, Hendricks WPD. Canine osteosarcoma genome sequencing identified recurrent mutations in DMD and the histone methyltransferase gene SETD2. Commun Biol. 2019;2:266. doi: 10.1038/s42003-019- 0487-2. eCollection 2019. PubMed PMID: 31341965; PubMed Central PMCID: PMC6642146

5. A major focus of my scientific efforts has been to perform studies in the pre- and post-IND settings that facilitate and inform subsequent human clinical trials. Our work with ganetespib in dogs with spontaneous cancers demonstrated that biologic activity was associated with sustained drug plasma levels between 200-600 ng/ml and established surrogate biomarkers of HSP90 inhibition. A follow-on study to this work defined a dosing regimen for ganetespib that provided both superior downregulation of the HSP90 client protein KIT in canine mast cell tumors which was linked to improved biologic activity. Our clinical trial of the XPO-1 inhibitor verdinexor (KPT- 335) in dogs defined the expected adverse event profile and provided strong evidence of biologic activity in lymphoid malignancies, both of which were confirmed in subsequent human clinical trials of the closely related analog selinexor (KPT-335). Lastly, our work with the anti-KIT humanized MAb (KTN0158) in dogs with mast cell tumors was incorporated into the IND application and supported human clinical trials. a. London CA, Bear MD, McCleese J, Foley KP, Paalangara R, Inoue T, Ying W, Barsoum J. Phase I evaluation of STA-1474, a prodrug of the novel HSP90 inhibitor ganetespib, in dogs with spontaneous cancer. PLoS One. 6(11); 2011. PMCID: PMC3207826 b. London CA, Acquaviva J, Smith DL, Sequeira M, Shin Ogawa L, Gardner HL, Feo Bernabe L, Bear MD, Bechtel SA, Proia DA. Consecutive day HSP90 inhibitor administration improves efficacy in murine models of KIT-driven malignancies and canine mast cell tumors. Clin Cancer Res. 2018 Dec 15;24(24):6396-6407. doi: 10.1158/1078-0432.CCR-18-0703. PMID:30171047 PMCID: In progress. c. London CA, Bernabe LF, Barnard S, Kisseberth WC, Borgatti A, Henson M, Wilson H, Jensen K, Ito D, Modiano JF, Bear MD, Pennell ML, Saint-Martin JR, McCauley D, Kauffman M, Shacham S. Preclinical evaluation of the novel, orally bioavailable Selective Inhibitor of Nuclear Export (SINE) KPT 335 in spontaneous canine cancer: results of a phase I study. PLoS One. Feb 4;9(2); 2014. PMCID:PMC3913620 d. London C, Gardner HL, Rippy S, Post G, LaPerle K, Crew L, Lopresti-Morrow L, Garton AJ, McMahon G, LaVallee TM, Gedrich R. KTN0158, a humanized anti-KIT monoclonal antibody, demonstrates biologic activity against both normal and malignant canine mast cells. KTN0158, a humanized anti-KIT monoclonal antibody, demonstrates biologic activity against both normal and malignant canine mast cells. Clin Cancer Res. 2017 May 15;23(10):2565-2574. PMCID: PMC5418113

A complete list of my 132 publications can be found at the following link: https://www.ncbi.nlm.nih.gov/myncbi/cheryl.london.1/bibliography/public/

D. Additional Information: Research Support and/or Scholastic Performance Ongoing Research Support NIH U54 TR002354 Selker (PI) 05/01/2018-04/30/2023 Through research resources, services, and education, Tufts Clinical and Translational Science Institute supports the entire spectrum of clinical and translational research. This spectrum includes the translation of bench research into bedside care (“T1”), into effective clinical practice (“T2”), into wide care delivery and public health (“T3”), and into health policy (“T4”). Role: Director Research Collaboration Team, One Health Module

NIH U01CA224153 London (PI)/Richards (Co-PI) 12/01/2017-11/30/2022 Enhancing the efficacy of immunotherapy in DLBCL using rational combination approaches The purpose of this proposal is to use dogs with spontaneous naïve DLBCL to rapidly evaluate rational small molecule/immunotherapy combination approaches, with the ultimate goal of identifying the most effective combination to move forward in human patients with DLBCL.

NIH U01 CA224182 Dow (PI)/London (Co-PI) 12/01/2017-11/30/2022 Optimizing novel immunotherapy combinations targeting the tumor microenvironment in canine osteosarcoma The purpose of this proposal is to test four TME modifying immunotherapy combinations for anti-tumor and immune modulatory activity in dogs with macroscopic OS metastases, interrogating relevant biomarkers associated with responses to therapy, then using this information to conduct an adjuvant immunotherapy trial with the most active combination in dogs with microscopic metastatic OS.

PETCO Foundation London (PI) 03/01/2018-02/28/2021 Improving outcomes for dogs with hemangiosarcoma. The purpose of this proposal is to develop and validate a non-invasive blood based method that can be used for early detection of HSA and characterization of the genetic changes over time that drive resistance to therapy; and use this data to identify novel targets for therapy associated with resistance.

NIH 1R37 CA218570-01AI Karlsson (PI) London (Co-I) 02/01/2018-01/30/2021 Transforming family dogs into a powerful and accessible model for human cancer The purpose of this proposal is to combine the power of cell-free DNA sequencing, the enthusiasm of citizen- scientist pet owners, and the clinical experience of veterinarians. A research portal for collection of information on diagnosis, treatment, and outcome for thousands of dogs with cancer, will be created. New computational methodologies to identify genomic similarities between canine and human cancers will be developed.

AKC Canine Health Foundation London (PI) 02/01/2018-01/31/2021 Identification of novel synthetic lethal partners to optimize PI3K targeted therapies in canine hemangiosarcoma. The purpose of this study is to assess the expression and function of PI3K isoforms in canine HSA and use combined CRISPR/lenti-sh approaches to generate HSA lines deficient in specific isoforms for identification of synthetic lethal partners. We will assess tumors for mutations in the PI3K/AKT/mTOR pathway and use this data to design assays that leverage cell-free tumor DNA for monitoring of remission.

Animal Cancer Foundation London (PI) 09/01/2018-08/31/2020 Interrogating the regulation, function and therapeutic potential of monocarboxylate transporters (MCTs) in OS. The overarching goal of this proposal is to expand upon our previous findings and investigate how dysregulated STAT3 activation and altered FOXM1/MCT expression and can be targeted to modulate cellular metabolism, resulting in synthetic lethality in combination with standard cytotoxic chemotherapy.

Morris Animal Foundation D19CA-083 London (PI) 08/31/2018-09/01/2020 Interrogating the therapeutic potential of monocarboxylate transporters in osteosarcoma The overarching goal of this proposal is to investigate how dysregulated STAT3 activation and altered FOXM1/MCT expression and can be effectively targeted to modulate cellular metabolism, resulting in synthetic lethality in combination with other therapeutics.

NIH/NCI R01 CA225755 Lindblad-Toh (PI) London (Co-I) 06/06/2018-08/31/2022 Enhancing the dog as a model for human cancers: From genome sequence towards clinical trials We will generate a platinum CanFam4.0 genome and improved information of both gene and variant annotation and specifically focus on canine mammary tumors, lymphoma and osteosarcoma to characterize these tumor types in the dog population using several approaches to meet human standards. We will further set up a Scandinavian-wide veterinary oncology network for research collaboration.

NIH U01 CA224182 Jaffe (PI)/London (Co-PI) 07/01/2019-06/30/2024 Credentialing a Cross-Species Platform to Investigate Cancer Therapy-Associated Cardiovascular Toxicity The overarching goal of this application is to leverage a cross-species modeling platform that integrates data generated from mice, dogs with spontaneous cancer and human cancer patients to critically interrogate and then validate mechanistic drivers of and therapeutic strategies for both known and emergent CV toxicities.

Completed Research Support

UL1TR002544 (Administrative Supplement, PI: Selker) 07/01/2018-04/30/2019 The purpose of this supplement is to build additional functionalities within OMOPV5+ that support multi- investigator/multi-institution studies and develop an interactive and functional web site to support comparative medicine. Role: Project Director

P01CA165995 (PI: Houghton) 06/05/2013-05/31/2019 NCI NIH Studies of childhood sarcoma Project 2: STAT3 signaling in sarcoma (London) Core C: Comparative Animal Core (London) The purpose of this program project grant is to comprehensively understand the roles of three signaling pathways (NF-kB, STAT3, and insulin like growth factors) in childhood sarcomas.

3P30CA006516-51 (Administrative Supplement, PI: Benz) 09/01/2016-08/31/2018 A Multi-Institutional Approach to Interrogate and Improve Immunotherapy Outcomes in Osteosarcoma The purpose of this work was to support analysis of the canine osteosarcoma tumor genome as a prelude to future immunotherapy clinical trials in dogs with osteosarcoma. Role: Consortium Project Director

OMB No. 0925-0001 and 0925-0002 (Rev. 09/17 Approved Through 03/31/2020)

BIOGRAPHICAL SKETCH Provide the following information for the Senior/key personnel and other significant contributors. Follow this format for each person. DO NOT EXCEED FIVE PAGES. NAME: Karlsson, Elinor eRA COMMONS USER NAME (credential, e.g., agency login): elinorkarlsson POSITION TITLE: Associate Professor EDUCATION/TRAINING (Begin with baccalaureate or other initial professional education, such as nursing, include postdoctoral training and residency training if applicable. Add/delete rows as necessary.) INSTITUTION AND LOCATION DEGREE END DATE FIELD OF STUDY (if applicable) MM/YYYY Rice University, Houston, TX BA 05/1999 Biochemistry and cell biology Rice University, Houston, TX BFA 05/2000 Boston University, Boston, MA PHD 05/2008 Bioinformatics Harvard University, Cambridge, MA Postdoctoral Fellow 09/2014

A. Personal Statement My research is focused on using genomic technologies to gain new insight into common human diseases and to inform the development of new therapeutics. As a computational geneticist with over 16 years of experience in large-scale genomics and sequence analysis, I have developed and applied new methods for detecting genomic signatures of evolution and trait association in diverse mammalian species. As a graduate student, I led the first genome-wide association studies of complex diseases in dogs, finding significantly associated genes for canine compulsive disorder and osteosarcoma. During my postdoctoral fellowship at Harvard University, I combined different computational and experimental approaches to find biological pathways underlying naturally selected traits in both humans (cholera susceptibility) and in dogs (behavioral traits).

At U Mass Medical School, I lead a team of graduate students and postdoctoral scholars in the Bioinformatics and Integrative Biology Program. I am also Director of Vertebrate Genomics at the Broad Institute of MIT and Harvard, where I manage a team with deep expertise in genome sequencing and assembly. My projects include the 200 Mammals Project, an international collaboration focused on identifying highly conserved genomic positions, with single base resolution, and refining the mammalian phylogeny. I also launched the first large-scale citizen science based dog genetics project. To date, Darwin’s Dogs has enrolled over 22,000 dogs, with detailed phenotype information, enabling well-powered genetic association studies of complex traits. My research group also develops Barkbase.org, an NIH funded initiative that is generating and sharing epigenetic annotations of diverse dog tissue types as a resource for disease research.

My current research includes a large study focused on canine cancer genomics, and supported by an NIH NCI R37 award: "Transforming family dogs into a powerful and accessible model for human cancer", and the NIH NHGRI supported 200 Mammals Project, a comparative genomics project that identifying functional genomic elements using sequence conservation. 1. Megquier K, Turner-Maier J, Swofford R, Kim JH, Sarver AL, Wang C, Sakthikumar S, Johnson J, Koltookian M, Lewellen M, Scott MC, Graef AJ, Borst L, Tonomura N, Alfoldi J, Painter C, Thomas R, Karlsson EK, Breen M, Modiano JF, Elvers I, Lindblad-Toh K. Comparative genomics reveals shared mutational landscape in canine hemangiosarcoma and human angiosarcoma. Mol Cancer Res. 2019 Sep 30;PubMed PMID: 31570656. 2. Megquier K, Genereux DP, Hekman J, Swofford R, Turner-Maier J, Johnson J, Alonso J, Li X, Morrill K, Anguish LJ, Koltookian M, Logan B, Sharp CR, Ferrer L, Lindblad-Toh K, Meyers-Wallen VN, Hoffman A, Karlsson EK. BarkBase: Epigenomic Annotation of Canine Genomes. Genes (Basel). 2019 Jun 7;10(6)PubMed PMID: 31181663; PubMed Central PMCID: PMC6627511. 3. Noh HJ, Tang R, Flannick J, O'Dushlaine C, Swofford R, Howrigan D, Genereux DP, Johnson J, van Grootheest G, Grünblatt E, Andersson E, Djurfeldt DR, Patel PD, Koltookian M, M Hultman C, Pato MT, Pato CN, Rasmussen SA, Jenike MA, Hanna GL, Stewart SE, Knowles JA, Ruhrmann S, Grabe HJ, Wagner M, Rück C, Mathews CA, Walitza S, Cath DC, Feng G, Karlsson EK, Lindblad-Toh K. Integrating evolutionary and regulatory information with a multispecies approach implicates genes and pathways in obsessive-compulsive disorder. Nat Commun. 2017 Oct 17;8(1):774. PubMed PMID: 29042551; PubMed Central PMCID: PMC5645406. 4. Karlsson EK, Sigurdsson S, Ivansson E, Thomas R, Elvers I, Wright J, Howald C, Tonomura N, Perloski M, Swofford R, Biagi T, Fryc S, Anderson N, Courtay-Cahen C, Youell L, Ricketts SL, Mandlebaum S, Rivera P, von Euler H, Kisseberth WC, London CA, Lander ES, Couto G, Comstock K, Starkey MP, Modiano JF, Breen M, Lindblad-Toh K. Genome-wide analyses implicate 33 loci in heritable dog osteosarcoma, including regulatory variants near CDKN2A/B. Genome Biol. 2013 Dec 12;14(12):R132. PubMed PMID: 24330828; PubMed Central PMCID: PMC4053774.

B. Positions and Honors Positions and Employment 1999 - 2000 Scientific Programmer, Genome Sequencing Center, Baylor College of Medicine, Houston, MA 2001 - 2002 Database developer, CSI, Wellington 2002 - 2003 Data analyst, Center for Genome Research, Whitehead Institute, Cambridge, MA 2003 - 2008 Graduate Research Scientist, Bioinformatics, Boston Univ, Boston, MA 2003 - 2014 Research Affiliate, Broad Institute, Cambridge, MA 2008 - 2014 Postdoctoral Fellow, Systems Biology, Harvard Univ, Cambridge, MA 2014 - Visiting Scientist, Broad Institute, Cambridge, MA 2014 - 2019 Assistant Professor, Program in Bioinformatics and Integrative Biology, University of Massachusetts Medical School, Worcester, MA 2019 - Associate Professor, Program in Bioinformatics and Integrative Biology, University of Massachusetts Medical School, Worcester, MA

Other Experience and Professional Memberships 2017 - Advisory board member, Genomics Aoteoroa, New Zealand 2018 - Steering committee Member, g2p2pop Research Coordination Network 2018 - Member, Scientific advisory board, Fauna Bio 2018 - Founder & Chief Scientist , Darwin’s Ark Foundation

Honors 2005 Insight Award, RECOMB 2005 Graduate Research Fellowship, National Science Foundation 2009 Next-Gen Tomorrow's PIs, Genome Technology 2009 Postdoctoral Fellow, American Cancer Society 2013 Postdoctoral Fellow, Charles A. King Trust

C. Contribution to Science

1. I developed and applied new methods for detecting positive selection in the human genome. Prior to this, existing tests typically found large regions containing many genes and thousands of polymorphisms, and provided no information on the underlying selected phenotype. During my postdoctoral fellowship with Dr. Pardis Sabeti, I helped develop the Composite of Multiple Signals methodology, which combines different tests for natural selection to provide 20-100x better resolution and precise identification of top functional candidates. I then used this test to identify more than 300 signals of natural selection in the genomes of Bangladeshi individuals, and showed that many selected genes and pathways are associated with resistance to cholera. We performed a genome-wide study of natural selection in a population from the Ganges River Delta, the historic geographic epicenter of cholera, intersected the results with association studies and found a significant enrichment for potassium channel genes involved in cyclic adenosine monophosphate-mediated chloride secretion and for components of the innate immune system involved in nuclear factor κB (NF-κB) signaling. This work demonstrated that combining selection and association can identify genetic factors influencing susceptibility to infectious diseases.

a. Bourque DL, Bhuiyan TR, Genereux DP, Rashu R, Ellis CN, Chowdhury F, Khan AI, Alam NH, Paul A, Hossain L, Mayo-Smith LM, Charles RC, Weil AA, LaRocque RC, Calderwood SB, Ryan ET, Karlsson EK, Qadri F, Harris JB. Analysis of the Human Mucosal Response to Cholera Reveals Sustained Activation of Innate Immune Signaling Pathways. Infect Immun. 2018 Feb;86(2)PubMed PMID: 29133347; PubMed Central PMCID: PMC5778365. b. Ellis CN, LaRocque RC, Uddin T, Krastins B, Mayo-Smith LM, Sarracino D, Karlsson EK, Rahman A, Shirin T, Bhuiyan TR, Chowdhury F, Khan AI, Ryan ET, Calderwood SB, Qadri F, Harris JB. Comparative proteomic analysis reveals activation of mucosal innate immune signaling pathways during cholera. Infect Immun. 2015 Mar;83(3):1089-103. PubMed PMID: 25561705; PubMed Central PMCID: PMC4333457. c. Karlsson EK, Harris JB, Tabrizi S, Rahman A, Shlyakhter I, Patterson N, O'Dushlaine C, Schaffner SF, Gupta S, Chowdhury F, Sheikh A, Shin OS, Ellis C, Becker CE, Stuart LM, Calderwood SB, Ryan ET, Qadri F, Sabeti PC, Larocque RC. Natural selection in a bangladeshi population from the cholera- endemic ganges river delta. Sci Transl Med. 2013 Jul 3;5(192):192ra86. PubMed PMID: 23825302; PubMed Central PMCID: PMC4367964. d. Grossman SR, Shlyakhter I, Karlsson EK, Byrne EH, Morales S, Frieden G, Hostetter E, Angelino E, Garber M, Zuk O, Lander ES, Schaffner SF, Sabeti PC. A composite of multiple signals distinguishes causal variants in regions of positive selection. Science. 2010 Feb 12;327(5967):883-6. PubMed PMID: 20056855.

2. I developed and implemented new approaches for variant detection, genome assembly validation, and population genetic analysis for diverse species for various whole genome sequencing projects. My team led the sequencing, assembly and analysis of 130 new mammalian reference genomes, which are yielding new insight in growth and selection in the mamma lineage.

a. Beichman AC, Koepfli KP, Li G, Murphy W, Dobrynin P, Kilver S, Tinker MT, Murray MJ, Johnson J, Lindblad-Toh K, Karlsson EK, Lohmueller KE, Wayne RK. Aquatic adaptation and depleted diversity: a deep dive into the genomes of the sea otter and giant otter. Mol Biol Evol. 2019 Jun 18;PubMed PMID: 31212313. b. Hindle AG, Allen KN, Batten AJ, Hückstädt LA, Turner-Maier J, Schulberg SA, Johnson J, Karlsson E, Lindblad-Toh K, Costa DP, Bloch DB, Zapol WM, Buys ES. Low guanylyl cyclase activity in Weddell seals: implications for peripheral vasoconstriction and perfusion of the brain during diving. Am J Physiol Regul Integr Comp Physiol. 2019 Jun 1;316(6):R704-R715. PubMed PMID: 30892912; PubMed Central PMCID: PMC6620652. c. Herrera-Alvarez S, Karlsson E, Ryder OA, Lindblad-Toh K, Crawford A. How to make a rodent giant: Genomic basis and tradeoffs of gigantism in the capybara, the world's largest rodent. bioRxiv. 2018 September 03; d. Palkopoulou E, Lipson M, Mallick S, Nielsen S, Rohland N, Baleka S, Karpinski E, Ivancevic AM, To TH, Kortschak RD, Raison JM, Qu Z, Chin TJ, Alt KW, Claesson S, Dalén L, MacPhee RDE, Meller H, Roca AL, Ryder OA, Heiman D, Young S, Breen M, Williams C, Aken BL, Ruffier M, Karlsson E, Johnson J, Di Palma F, Alfoldi J, Adelson DL, Mailund T, Munch K, Lindblad-Toh K, Hofreiter M, Poinar H, Reich D. A comprehensive genomic history of extinct and living elephants. Proc Natl Acad Sci U S A. 2018 Mar 13;115(11):E2566-E2574. PubMed PMID: 29483247; PubMed Central PMCID: PMC5856550.

3. I developed methods for GWAS of complex diseases in dog breeds tailored to their unusual population structure that could identify associated genes and regulatory pathways, and pinpoint putative causal variants. I completed the first two GWAS of complex diseases in dog breeds using new methods tailored to their unusual population structure. By combining GWAS with scans for signals of selection, I was able to identify genes and regulatory pathways, and pinpoint putative causal variants, associated with two diseases shared between dogs and humans: obsessive compulsive disorder and osteosarcoma. Most recently, I established a new resource for dog genomics, BarkBase, which is modeled on the NIH Roadmap project and provides information on the epigenomic markers in diverse tissue types.

a. Megquier K, Genereux DP, Hekman J, Swofford R, Turner-Maier J, Johnson J, Alonso J, Li X, Morrill K, Anguish LJ, Koltookian M, Logan B, Sharp CR, Ferrer L, Lindblad-Toh K, Meyers-Wallen VN, Hoffman A, Karlsson EK. BarkBase: Epigenomic Annotation of Canine Genomes. Genes (Basel). 2019 Jun 7;10(6)PubMed PMID: 31181663; PubMed Central PMCID: PMC6627511. b. Noh HJ, Tang R, Flannick J, O'Dushlaine C, Swofford R, Howrigan D, Genereux DP, Johnson J, van Grootheest G, Grünblatt E, Andersson E, Djurfeldt DR, Patel PD, Koltookian M, M Hultman C, Pato MT, Pato CN, Rasmussen SA, Jenike MA, Hanna GL, Stewart SE, Knowles JA, Ruhrmann S, Grabe HJ, Wagner M, Rück C, Mathews CA, Walitza S, Cath DC, Feng G, Karlsson EK, Lindblad-Toh K. Integrating evolutionary and regulatory information with a multispecies approach implicates genes and pathways in obsessive-compulsive disorder. Nat Commun. 2017 Oct 17;8(1):774. PubMed PMID: 29042551; PubMed Central PMCID: PMC5645406. c. Tang R, Noh HJ, Wang D, Sigurdsson S, Swofford R, Perloski M, Duxbury M, Patterson EE, Albright J, Castelhano M, Auton A, Boyko AR, Feng G, Lindblad-Toh K, Karlsson EK. Candidate genes and functional noncoding variants identified in a canine model of obsessive-compulsive disorder. Genome Biol. 2014 Mar 14;15(3):R25. PubMed PMID: 24995881; PubMed Central PMCID: PMC4038740. d. Karlsson EK, Sigurdsson S, Ivansson E, Thomas R, Elvers I, Wright J, Howald C, Tonomura N, Perloski M, Swofford R, Biagi T, Fryc S, Anderson N, Courtay-Cahen C, Youell L, Ricketts SL, Mandlebaum S, Rivera P, von Euler H, Kisseberth WC, London CA, Lander ES, Couto G, Comstock K, Starkey MP, Modiano JF, Breen M, Lindblad-Toh K. Genome-wide analyses implicate 33 loci in heritable dog osteosarcoma, including regulatory variants near CDKN2A/B. Genome Biol. 2013 Dec 12;14(12):R132. PubMed PMID: 24330828; PubMed Central PMCID: PMC4053774.

4. I developed genetic tests designed to map strongly selected traits and tailored to a population's specific history, and applied these methods in dogs and in malaria. Genetic tests are often most powerful when tailored to a population's specific history. Dogs have an unusual history of domestication, artificial selection, and breed creation. For the dog genome project, I analyzed genetic diversity and haplotype structure in dog breeds, simulated association mapping, and developing a novel method for mapping strongly selected traits, that I applied both in dogs and in malaria (drug resistance loci). Following the dog genome project, I continued to develop new genetic approaches to investigate dog population history and identify functional genomic loci underlying canine phenotypes.

a. Grossman SR, Andersen KG, Shlyakhter I, Tabrizi S, Winnicki S, Yen A, Park DJ, Griesemer D, Karlsson EK, Wong SH, Cabili M, Adegbola RA, Bamezai RN, Hill AV, Vannberg FO, Rinn JL, Lander ES, Schaffner SF, Sabeti PC. Identifying recent adaptations in large-scale genomic data. Cell. 2013 Feb 14;152(4):703-13. PubMed PMID: 23415221; PubMed Central PMCID: PMC3674781. b. Van Tyne D, Park DJ, Schaffner SF, Neafsey DE, Angelino E, Cortese JF, Barnes KG, Rosen DM, Lukens AK, Daniels RF, Milner DA Jr, Johnson CA, Shlyakhter I, Grossman SR, Becker JS, Yamins D, Karlsson EK, Ndiaye D, Sarr O, Mboup S, Happi C, Furlotte NA, Eskin E, Kang HM, Hartl DL, Birren BW, Wiegand RC, Lander ES, Wirth DF, Volkman SK, Sabeti PC. Identification and functional validation of the novel antimalarial resistance locus PF10_0355 in Plasmodium falciparum. PLoS Genet. 2011 Apr;7(4):e1001383. PubMed PMID: 21533027; PubMed Central PMCID: PMC3080868. c. Grossman SR, Shlyakhter I, Karlsson EK, Byrne EH, Morales S, Frieden G, Hostetter E, Angelino E, Garber M, Zuk O, Lander ES, Schaffner SF, Sabeti PC. A composite of multiple signals distinguishes causal variants in regions of positive selection. Science. 2010 Feb 12;327(5967):883-6. PubMed PMID: 20056855. d. Lindblad-Toh K, Wade CM, Mikkelsen TS, Karlsson EK, Jaffe DB, Kamal M, Clamp M, Chang JL, Kulbokas EJ 3rd, Zody MC, Mauceli E, Xie X, Breen M, Wayne RK, Ostrander EA, Ponting CP, Galibert F, Smith DR, DeJong PJ, Kirkness E, … , Lander ES. Genome sequence, comparative analysis and haplotype structure of the domestic dog. Nature. 2005 Dec 8;438(7069):803-19. PubMed PMID: 16341006. 5. I designed the first whole genome SNP genotyping arrays for dogs and developed a two-stage gene mapping approach tailored to the population history of purebred dogs. I mapped loci underlying white coat color; hairlessness, the dorsal ridge and spinal defects in ridgeback breeds; hairlessness and canine obsessive compulsive disorder. For white coat color; hairlessness, the dorsal ridge I identified specific mutations underlying the trait.

a. Dodman NH, Karlsson EK, Moon-Fanelli A, Galdzicka M, Perloski M, Shuster L, Lindblad-Toh K, Ginns EI. A canine chromosome 7 locus confers compulsive disorder susceptibility. Mol Psychiatry. 2010 Jan;15(1):8-10. PubMed PMID: 20029408. b. Drögemüller C, Karlsson EK, Hytönen MK, Perloski M, Dolf G, Sainio K, Lohi H, Lindblad-Toh K, Leeb T. A mutation in hairless dogs implicates FOXI3 in ectodermal development. Science. 2008 Sep 12;321(5895):1462. PubMed PMID: 18787161. c. Karlsson EK, Baranowska I, Wade CM, Salmon Hillbertz NH, Zody MC, Anderson N, Biagi TM, Patterson N, Pielberg GR, Kulbokas EJ 3rd, Comstock KE, Keller ET, Mesirov JP, von Euler H, Kämpe O, Hedhammar A, Lander ES, Andersson G, Andersson L, Lindblad-Toh K. Efficient mapping of mendelian traits in dogs through genome-wide association. Nat Genet. 2007 Nov;39(11):1321-8. PubMed PMID: 17906626. d. Salmon Hillbertz NH, Isaksson M, Karlsson EK, Hellmén E, Pielberg GR, Savolainen P, Wade CM, von Euler H, Gustafson U, Hedhammar A, Nilsson M, Lindblad-Toh K, Andersson L, Andersson G. Duplication of FGF3, FGF4, FGF19 and ORAOV1 causes hair ridge and predisposition to dermoid sinus in Ridgeback dogs. Nat Genet. 2007 Nov;39(11):1318-20. PubMed PMID: 17906623.

D. Additional Information: Research Support and/or Scholastic Performance

Ongoing Research Support 1R01 MH110427-01, NIH Crowley, James (PI) 08/01/16-04/30/21 OCD: Novel Comparative Genomic Approaches to Identify Disease and Treatment Mechanisms The goals of this project are to do a comparative genomic analysis integrating human OCD genetic findings with canine compulsive disorder (CCD) genomic work. Role: Consortium PI

R37 CA218570-01A1, NIH Karlsson, Elinor (PI) 04/01/18-03/31/21 Transforming family dogs into a powerful and accessible model for human cancer This project aims to use new genomic technology and a direct-to-dog-owner citizen science approach to transform the scale and scope of translational cancer research possible using dogs as a model system. Role: PI

1R01 HG008742-01A1, NIH Karlsson, Elinor (PI) 09/28/16-02/29/20 The 200 mammals project: sequencing genomes by a novel cost-effective method, yielding a high resolution annotation of the human genome The Project goals are to (1) Select, collect, and sequence 150 mammals. (2) Assemble 150 mammals and align all 200 mammals. (3) Analyze and annotate 200 mammals. This work will yield both a wealth of new mammalian genomes and conservation tracks, and analyses to aid in the discovery of evolutionarily important and disease-causing variants. Role: CPI

BIOGRAPHICAL SKETCH Provide the following information for the Senior/key personnel and other significant contributors. Follow this format for each person. DO NOT EXCEED FIVE PAGES. NAME: Jason Matthew Shohet eRA COMMONS USER NAME (credential, e.g., agency login): JSHOHET

POSITION TITLE: Associate Professor

EDUCATION/TRAINING (Begin with baccalaureate or other initial professional education, such as nursing, include postdoctoral training and residency training if applicable. Add/delete rows as necessary.)

DEGREE Completion (if Date FIELD OF STUDY INSTITUTION AND LOCATION applicable) MM/YYYY

Reed College, Portland, OR BA 1981-1985 Chemistry Boston University, School of Medicine MD, PhD 1985-1993 Pathology Baylor College of Medicine, Houston, TX MD, PhD 1993-1995 Pediatric Residency Baylor College of Medicine, TCH, Houston, TX MD, PhD 1995-1996 Hem/Onc Fellowship University of Texas Southwestern Medical MD, PhD 1996-1999 Hem/Onc Fellowship Center, Dallas, TX

A. Personal Statement As a pediatric oncologist, my research goals are to develop more effective and less toxic therapies for childhood cancers with a special focus on neuroblastoma. I have recently relocated to assume the position as Division Chief for Pediatric Hematology/Oncology at University of Massachusetts Medical School in Worcester, Ma. This is after 19 years as head of the neuroblastoma research program at Texas Children’s Cancer Center, Baylor College of Medicine. The UMass Medical School and UMass Memorial Clinical organizations provides exceptional support and research infrastructure for basic and translational efforts. I am an affiliated member of the Cancer Biology program, the MD, PhD program and the division of Molecular, Cell and Cancer Biology headed by Dr. Michael Green. A major focus of my laboratory is characterizing the role of MYCN in neuroblastoma pathogenesis and tumor stem cell biology. Over the past 14 years, we have pursued mechanisms for MYCN mediated repression of p53 which is required for tumorigenesis. As part of this work we have characterized multiple direct transcriptional targets of MYCN which are either destabilize p53 (e.g. MDM2) or alter transcriptional pathways to promote proliferation and inhibit apoptosis (e.g. MCM7 or mir- 34a). This work has involved developing novel transgenic mouse models, optimized orthotopic xenografts and conditional cell lines for gain and loss of function studies of both microRNAs and coding genes. The laboratory also recently described a novel direct binding interaction of MYCN with p53 that reveals a novel oncogenic function for MYCN as a direct transcriptional cofactor for p53. Our laboratory also has defined a major cancer stem cell population in neuroblastoma based on expression of CD114 (the GCSF receptor). These cells are highly tumorigenic with distinct molecular signatures as defined by single cell sequencing. Ongoing efforts will expand the characterization of the phenotypic and molecular heterogeneity of neuroblastoma and how this impacts interactions with the immune microenvironment. The repression of immunosurveillance during tumor development and metastasis is a critical aspect cancer biology that is difficult to model in standard NSG /PDX systems. We are now adapting our xenograft systems to monitor tumor development in fully ‘humanized’ NSG mice developed by Dr. Dale Greiner and Dr. Michael Brehm at UMass Medical school. Our orthotopic models now permit us to better define how tumor/immune cell interactions change in response to chemotherapy and immunomodulatory treatments. Representative publications: 1. Agarwal, S, Milazzo, G., Rajapakshe, K, Bernardi, R. Chen Z., Barbieri, E, Koster, J, Perini, G. Coarfa, C. Shohet, J.M. MYCN acts as a direct co-regulator of p53 in MYCN amplified neuroblastoma, Oncotarget, 9(29), 20323-20338, April, 2018. PMCID: 5945521, PMID: 29755654 2. Slack A, Chen Z, Tonelli R, Pule M, Hunt L, Pession A, Shohet, J.M. The p53 regulatory gene MDM2 is a direct transcriptional target of MYCN in neuroblastoma. Proc. Natl. Acad. Sci. USA, 102(3), 731- 736, Jan 18, 2005. PMID: 15644444. 3. Zaowen Chen, Yunfu Lin, Eveline Barbieri, Sue Burlingame, John Hicks, Andrew Ludwig and Jason Shohet Mdm2 deficiency suppresses MYCN-driven neuroblastoma tumorigenesis in vivo., Neoplasia, 11(8):753-62, Aug 2009. PMID: 19649205 4. Shohet JM, Ghosh R, Coarfa C, Ludwig A, Benham A, Chen Z, Patterson DM, Barbieri E, Mestdagh P, Sikorski DN, Milosevic A, Kim ES, Gunaratne PH. A genome-wide search for MYCN binding sites reveals new oncogenic and tumor suppressor microRNAs associated with aggressive neuroblastoma. Cancer Res 71(11):3841-51, 2011. PMID: 21498633

B. Positions: 1999-2002 Instructor, Department of Pediatrics, Baylor College of Medicine, Houston, TX 2002-2012 Assistant Professor, Department of Pediatrics, Baylor College of Medicine, Houston, TX 2012- 2018 Associate Professor, Department of Pediatrics, Baylor College of Medicine, Houston, TX 2018-present Associate Professor, Department of Pediatrics, UMass Medical School, Worcester, MA.

Board Certifications American Board of Pediatrics since 1/1/99 (recertified 2005) Pediatric Hematology/Oncology as of 12/2002 (recertified 2012)

Other Experience and Professional Memberships 2010- Present Member AACR 2004- Present Member Children’s Oncology Group

National Committee Children’s Oncology Group- Neuroblastoma Biology and Therapeutics

Review Panels and Study Sections Review Panels and Study Sections 2010 – 2014 Alex’s Lemonade Stand Foundation 2010 Department of Defense 2011 Grant Reviewer: AACR – RSG and Fellowship applications 2013 NIH study section: Tumor Cell Biology (TCB) 2014 NIH study section: Cancer Molecular Pathobiology (CAMP) 2015 NIH Special emphasis panel 2016 NIH Special emphasis panel (PPQ) 2017 NIH Special emphasis panel (PPQ) 2018 NIH study section; Molecular Oncogenesis (MONC)

Honors and Awards 1993 Sidney Cooperband Award, Boston University 1997 American Cancer Society, Texas Division Fellowship Award 1997 Children’s Cancer Research Foundation Fellowship Award 1998 American Society of Pediatric Hematology and Oncology Young Investigator Award 2000 Fleming and Davenport Award for Clinical Research 2002 Molecular Medicine Scholars Award (Baylor) 2004 Advances in Neuroblastoma Research Conference (Genoa Italy) – Best basic science presentation 2006 Advances in Neuroblastoma Research Conference (Los Angeles) Plenary presentation 2008 Advances in Neuroblastoma Research Conference (Chiba, Japan) Plenary presentation 2010 Virginia and L.E. Simmons Family Foundation Collaborative Research Award

2012 Advances in Neuroblastoma Research Conference (Toronto, Canada) Plenary presentation 2014 Advances in Neuroblastoma Research Conference (Cologne, Germany) Plenary presentation

Ad Hoc Reviewer Editorial Responsibilities Assistant Editor- Scientific Reports 2015- present Journal Reviewer – as hoc: a. Nature Reviews Cancer b. Nature Medicine c. Cancer Research d. International Journal of Cancer Research e. Genes and Development f. Oncogene g. Molecular Cancer Therapeutics h. Cell Cycle i. International Journal of Oncology j. Journal of Biological Chemistry

C. Contribution to Science Since completing my Hematology oncology fellowship in 1999, I have focused understanding the molecular and cellular biology of neuroblastoma and the role of MYCN as the primary driver of this cancer. This neural crest derived malignancy remains a major cause of morbidity and mortality in pediatric oncology. Initially, we identified several important transcriptional targets of MYCN including MCM7 and MDM2 and confirmed the role of each of these molecules in tumorigenesis using transgenic animal models. I published several studies looking at the MYCN/MDM2/p53 signaling axis and the role of MDM2 inhibitors as in Neuroblastoma tumorigenesis. Pre-clinical studies from my laboratory have directly supported the clinical development of MDM2 inhibitors to activate p53 in wild type tumors.

a) Slack A, Chen Z, Tonelli R, Pule M, Hunt L, Pession A, Shohet, J.M. The p53 regulatory gene MDM2 is a direct transcriptional target of MYCN in neuroblastoma. Proc. Natl. Acad. Sci. USA, 102(3), 731- 736, Jan 18, 2005. PMID: 15644444. b) Slack, A, Lozano, G, Shohet, J.M., MDM2 as MYCN transcriptional target: implications for neuroblastoma pathogenesis, Cancer Letters, 228(1-2), 21-7, Oct. 18, 2005. PMID: 15927364 c) Barbieri, E., Mehta, P., Chen, Z., Zhang, L., Slack, A. , Berg, S., Shohet, JM. MDM2 inhibition sensitizes neuroblastoma to chemotherapy induced apoptotic cell death, Mol Cancer Ther, 5(9):2358-65, 2006. PMID: 16985070 d) Eveline Barbieri, Katleen De Preter, Mario Capasso, Peter Johansson, Tsz-Kwong Man, Zaowen Chen, Paris Stowers, Gian Paolo Tonini, Frank Speleman, and Jason M. Shohet. A p53 Drug Response Signature Identifies Prognostic Genes in High-Risk Neuroblastoma”. PLOS One. 2013 Nov 19;8(11):e79843

The theme of MYCN transcriptional regulation lead us to profile MYCN regulated microRNAs in neuroblastoma. Through these studies in our laboratory and with several collaborators, we have helped to establish microRNAs as both possible therapeutic tools and targets for neuroblastoma.

a) Wei JS, Song YK, Durinck S, chen QR, Cheuk AT, Tsang P, Zhang Q, Thiele CJ, Slack A, Shohet J, khan J., The MYCN oncogene is a direct target of miR-34a, Oncogene;27(39):5204-13, Sep 4, 2008. PMID: 18504438. PMCID: PMC2562938 b) Shohet, JM, Redefining functional MYCN gene signatures in neuroblastoma. 2012 Nov 20; 109(47):19041-2. PNAS, Epub 2012 Nov 8. PMID: 23139408

c) Ghosh R, Singh LC, Shohet JM, Gunaratne PH. A gold nanoparticle platform for the delivery of functional microRNAs into cancer cells. Biomaterials, Oct 27, 2013. pii: S0142-9612(12)01144-1. PMID: 23111335. d) Rihani A, Van Goethem A, Ongenaert M, De Brouwer S, Volders PJ, Agarwal S, De Preter K, Mestdagh P, Shohet J, Speleman F, Vandesompele J, Van Maerken T. Genome wide expression profiling of p53 regulated miRNAs in neuroblastoma. Sci Rep. 2015 Mar 12;5:9027. PMID: 25762502; PMCID: PMC4356961.

The role of MYCN as a transcription factor and a contributor to stem cell reprograming led us into the field of stem cell biology. Most recently, in two papers in cancer research we have characterized the G-CSF receptor as a marker for a novel cancer stem cell subpopulation in neuroblastoma. These exciting studies demonstrate that downstream STAT3 may be a major factor in neuroblastoma tumorigenesis and cancer relapse after therapy. Importantly, STAT3 and MYCN share multiple microRNA targets which may synergistically promote the stemness of this subpopulation.

a) Hsu DM, Agarwal S, Benham A, Coarfa C, Trahan DN, Chen Z, Stowers PN, Courtney AN, Lakoma A, Barbieri E, Metelitsa LS, Gunaratne P, Kim ES, Shohet J, G-CSF Receptor Positive Neuroblastoma Subpopulations Are Enriched in Chemotherapy-Resistant or Relapsed Tumors and Are Highly Tumorigenic. July 1, 2013; 73(13):4134-46. PMID: 23687340. PMCID: 4298227. b) Agarwal S, Lakoma A, Chen Z, Hicks J, Metelitsa LS, Kim ES, Shohet JM. G-CSF promotes neuroblastoma tumorigenicity and metastasis via STAT3-dependent cancer stem cell activation. Cancer Res. 2015. PMID: 25908586. NIHMSID: 687493. We have found that MYCN globally affects p53 transcriptional responses to genotoxic therapy (Argawal, et al 2018).

Complete List of Published Work in My Bibliography: click here to go to MY NCBI.nim.nih.gov

D. Research Support

Ongoing research support 1 R01 CA174808-01A1 (Shohet) 04/01/14-03/31/19 NCI (no cost extension 6/2020) Targeting the G-CSF/STAT3 signaling pathway in neuroblastoma cancer stem cells Major Goals of Project: Cancer stem cells (CSCs) may drive disease relapse which accounts for the majority of deaths in neuroblastoma (NB). We will determine how STAT3 signaling, downstream of the G- CSF growth factor, contributes to the tumorigenicity and maintenance of a novel G-CSF receptor + CSC- like NB subpopulation.

Hyundai Hope on Wheels Scholar Grant 04/1/2019-04/1/2021 Evaluation and Therapeutic Targeting of PRMT5 in high risk neuroblastoma $300,000 Major Goals of Project: determine the function of PRMT5 in neuroblastoma pathogenesis and the impact of novel small molecule inhibitors to tumor growth in vivo. Preclinical modeling of anti-PRMT5 inhibitors in combination with chemotherapy.

Children’s Neuroblastoma Research Foundation award 06/01/2019-06/01/202 Therapeutic targeting of YAP/TAZ signaling in high risk neuroblastoma $40,000

Completed research support (last 5 years) Cookies for Cancer Foundation ($200,000) 12/01/16 -12/1/18 Children’s Neuroblastoma Research Foundation ($75,000) 01/01/17 -12/30/17 Gilson -Longenbaugh Foundation ($150,000) 07/01/16 -06/30/17 Cookies for Cancer Foundation ($45,000) 12/01/15 -11/30/17

BIOGRAPHICAL SKETCH Provide the following information for the Senior/key personnel and other significant contributors. Follow this format for each person. DO NOT EXCEED FIVE PAGES. NAME: Won Yeong Kang eRA COMMONS USER NAME (credential, e.g., agency login): WONYEONGKANG POSITION TITLE: Associate Research Scientist EDUCATION/TRAINING (Begin with baccalaureate or other initial professional education, such as nursing, include postdoctoral training and residency training if applicable. Add/delete rows as necessary.) Completion DEGREE Date FIELD OF STUDY INSTITUTION AND LOCATION (if applicable) MM/YYYY

College of Veterinary Medicine, Jeju National University, B.S. 02/2008 Veterinary medicine South Korea

Doctor of Veterinary Medicine, National license of South D.V.M. 02/2008 Veterinary medicine Korea

Veterinary toxicology and biochemistry, College of M.S. 02/2010 Veterinary toxicology Veterinary Medicine, Jeju National University, South and biochemistry Korea Department of Health Sciences and Technology Ph.D. 02/2014 Translational research Sungkyunkwan University, South Korea

Samsung Medical Center, Seoul, South Korea Postdoc 07/2015 Translational research

EWHA Woman’s University, Seoul, South Korea Postdoc 03/2017 Translational research

A. Personal Statement

I've been dedicating on translational research by leading the research projects and patient derived xenograft (PDX) program. Also, I’ve been performing veterinary procedures to laboratory animals focusing on metabolic disease and cancer researches practically. My major in University was Veterinary Medicine and I was trained to study bio-functional screening and evaluation of therapeutic or natural compounds in animal disease models at veterinary research laboratory as an undergraduate researcher ever since 2004. I earned M.S. from the department of veterinary toxicology and biochemistry at Jeju National University in South Korea. This veterinary knowledge and practical technics have enabled me to joining in PDX model programs of Institute for Refractory Cancer Research, Samsung Medical Center. As a team leader, I led a Translational Research Organization (TRO) department consisting of in vivo, in vitro and histology cores and I conducted preclinical studies with pharmaceutical companies. I worked on developing a systematic and efficient flow of PDX programs from cancer patients to bench sides. The resources we collected/generated in PDX programs is critical for further scientific finding and interpret, so in order to increase the success rate of PDX and to maintain high quality of research resources, I applied various methods to optimize the human and canine cancer PDX program. I also led various research projects to validate the functions of novel cancer biomarkers and in total, I have authored/coauthored/corresponding-authored 26 publications.

1. Sa JK. et al. Identification of Genomic and Molecular Traits that Present Therapeutic Vulnerability to HGF-targeted therapy in Glioblastoma. Neuro Oncol. 2018. PMID: 29939324.

2. Cho SY. et al. Alterations in the Rho pathway contribute to Epstein-Barr virus-induced lymphomagenesis in immunosuppressed environments. Blood. 2018. PMCID: PMC5921963. 3. Cho SY. et al. A Novel Combination Treatment Targeting BCL-XL and MCL1 for KRAS/BRAF-mutated and BCL2L1-amplified Colorectal Cancers. Mol Cancer Ther. 2017. PMID: 28611106. 4. Cho YJ and Kang W. et al. Involvement of DDX6 gene in radio- and chemoresistance in glioblastoma. Int J Oncol. 2016. PMID: 26783102.

B. Positions and Honors

Positions and Employment

2010-2014 PDX team manager and Research project leader, Institute for Refractory Cancer Research, Samsung Medical Center, Seoul, South Korea 2014-2015 Team leader of PDX translational research organization in Institute for Refractory Cancer Research, Samsung Medical Center, Seoul, South Korea 2015-2017 PDX Team leader in Ewha-JAX International Research Center for Cancer Immunotherapy, EWHA Woman’s University, Seoul, South Korea 2017-Present Associate Research Scientist, The Jackson Laboratory, Farmington, CT

C. Contributions to Science

My contributions are in this field of cancer research is to accelerate the cancer translational research for through the clinical relevant preclinical researches and by developing the highly useful research resources including patient derived xenograft models and bio-bank for over last 8 years. These resources have been disseminating and utilizing for various cancer researches. I earned my Ph.D. to study about anti-angiogenic resistance in GBM patients. I found over expressed gene, TLN1, which was revealed first time in glioblastoma patients and studied the functions of TLN1 in terms of anti-angiogenic resistance. Eventually, I validated that the gene modification in glioblastoma PDX provided survival benefits with antiangiogenic therapeutics. I joined various research projects by utilizing multiple cancers xenograft models including PDX or cell line derived xenografts.

1. Lee JK. et al. USP1 targeting impedes GBM growth by inhibiting stem cell maintenance and radioresistance. Neuro Oncol. 2016. PMCID: PMC4677407. 2. Cho SY and Kang W. et al. An Integrative Approach to Precision Cancer Medicine Using Patient- Derived Xenografts. Mol Cells. 2016. PMCID: PMC4757806. 3. Kang W. et al. Talin1 targeting potentiates anti-angiogenic therapy by attenuating invasion and stem- like features of glioblastoma multiforme. Oncotarget. 2015 PMID: 26336988

I worked on the collaborating research projects with pharmaceutical companies while we validated the functions of the therapeutic compounds including anti-cancer metastatic compounds, telomerase inhibitor, and immunotherapy.

1. Lee SJ and Kang W. et al. Natural killer (NK) cells inhibit systemic metastasis of glioblastoma cells and have therapeutic effects against glioblastomas in the brain. BMC Cancer. 2015. PubMed PMID: 26704632; PubMed Central PMCID: PMC4690248. 2. Woo SR, Ham Y and Kang W. et al. KML001, a telomere-targeting drug, sensitizes glioblastoma cells to temozolomide chemotherapy and radiotherapy through DNA damage and apoptosis. Biomed Res Int. 2014. PMID: 25295271; PubMed Central PMCID: PMC4176651. 3. Kim DG. et al. Chemical inhibition of prometastatic lysyl-tRNA synthetase-laminin receptor interaction. Nat Chem Biol. 2014. PMCID: PMC4021855.

Complete List of Published Work in My Bibliography: https://www.ncbi.nlm.nih.gov/myncbi/14eogqxFwnxU-q/bibliography/public/

D. Research Support

Completed Research Support Projects remain ongoing but Dr. Kang’s effort is no longer on these projects.

1. HI13C2148 Lee (PI) The Ministry of Health & Welfare, South Korea The Korean Healthcare Technology R&D project through the Korean Health Industry Development Institute (KHIDI)

Role: Researcher, PDX project manager

2. 2015K1A4A3047851 Lee (PI) The Ministry of Science, ICT & Future Planning, South Korea The International Research & Development Program of the National Research Foundation of Korea (NRF)

Role: Researcher, Project manager

OMB No. 0925-0001 and 0925-0002 (Rev. 10/15 Approved Through 10/31/2018)

BIOGRAPHICAL SKETCH DO NOT EXCEED FIVE PAGES. NAME: TERRIN, NORMA

eRA COMMONS USER NAME (credential, e.g., agency login): nterrin

POSITION TITLE: Professor of Medicine EDUCATION/TRAINING (Begin with baccalaureate or other initial professional education, such as nursing, include postdoctoral training and residency training if applicable. Add/delete rows as necessary.)

INSTITUTION AND LOCATION DEGREE Completion Date FIELD OF STUDY (if applicable) MM/YYYY Sarah Lawrence College BA 05/1976 Mathematics Boston University MA 05/1984 Mathematics Boston University PHD 01/1990 Mathematics A. Personal Statement I am excited to serve as a mentor for Dr. Gardner’s K01 application. I have been active as an instructor and mentor in the Clinical and Translational Science (CTS) program at the Sackler School of Graduate Biomedical Sciences for over 15 years. I teach biostatistics and meta-analysis, and serve on the Fellowship Advisory Committee of the CTS program. I have mentored doctoral students, postdoctoral trainees, and junior faculty throughout my career. These include MS and PhD students in the CTS program at the Tufts Graduate School of Biomedical Sciences, K-awardees, and PhD students in clinical research, nursing, and statistical methods, totaling over 30 trainees. I frequently advise investigators on important aspects of study design and analysis, through my role as Scientific Director of the Biostatistics, Epidemiology, and Research Design (BERD) Center in the Tufts Clinical and Translational Science Institute (CTSI). I collaborate with clinical, basic science, health services, and translational researchers in areas including oncology, pediatrics, nephrology, HIV-AIDS, and pulmonary medicine. My methodological research has been funded by the National Science Foundation (NSF), the Agency for Healthcare Research and Quality (AHRQ), and the National Cancer Institute (NCI). B. Positions and Honors

Positions and Employment 1989 - 1995 Assistant Professor, Department of Statistics, Carnegie Mellon University, Pittsburgh, PA 1995 - 1997 Associate Professor, Department of Statistics, Carnegie Mellon University, Pittsburgh, PA 1995 - 1997 Visiting Associate Professor, Department of Statistics, Harvard University, Cambridge, MA 1996 - Senior Statistician, Biostatistics Research Center, Tufts Medical Center, Boston, MA 1998 - 2015 Associate Professor of Medicine, Tufts University School of Medicine, Boston, MA 2012 - Director, Biostatistics, Epidemiology, and Research Design (BERD) Center, Tufts Clinical and Translational Science Institute (CTSI), Boston, MA 2015 - Professor of Medicine, Tufts University School of Medicine, Boston, MA

Other Experience and Professional Memberships 2002 - Chair, PhD Qualifying Exam Committee, Clinical and Translational Science Program, Sackler School of Graduate Biomedical Sciences, Tufts University, Boston, MA 2002 - 2006 Member, Health Care Quality and Effectiveness Research (HCQER) study section of the Agency for Healthcare Research and Quality (AHRQ) 2007 - Statistics Editor, Clinical Infectious Diseases 2007- Elected member, Society for Research Synthesis Methods 2008 - 2014 Member, Scientific Review Committee of the Institutional Review Board, Tufts Medical Center, Boston, MA 2009 - Member, Editorial Board, Research Synthesis Methods Associate Editor, Quality of Life Research 2013 - 2015 Associate Editor, Quality of Life Research

C. Contribution to Science

1. Meta-Analysis: Methods and Applications. I raise questions about simplistic, yet pervasive, statistical methods for detecting publication and other forms of selection bias in systematic review. I was funded as Principal Investigator of an AHRQ R01 grant to study methods for dealing with publication bias in meta- analysis. One of my studies demonstrated that researchers cannot visually identify publication bias, and in another study I found that a popular adjustment method based on the funnel plot has poor statistical properties. I co-authored a 2006 BMJ paper, “Assessment of evidence-based methodologies: have we taken a short cut? The case study of funnel plots to detect publication bias” and a 2011 BMJ paper (with many prominent systematic review methodologists), “Recommendations for examining and interpreting funnel plot asymmetry in meta-analyses of randomised controlled trials.” Authors frequently cite these papers, as well as my first-author papers, when pressed to improperly “diagnose” bias with a funnel plot. I am a co-author of the “Expanded Guidance on Selected Quantitative Synthesis Topics,” published in 2013 by AHRQ and I contribute nationally to the field of meta-analysis as an elected member of the Society for Research Synthesis Methodology and through service on the editorial board of Research Synthesis Methodology.

a. Engels EA, Terrin N, Barza M, Lau J. Meta-analysis of diagnostic tests for acute sinusitis. J Clin Epidemiol. 2000 Aug;53(8):852-62. PubMed PMID: 10942869. b. Terrin N, Schmid CH, Lau J, Olkin I. Adjusting for publication bias in the presence of heterogeneity. Stat Med. 2003 Jul 15;22(13):2113-26. PubMed PMID: 12820277. c. Terrin N, Schmid CH, Lau J. In an empirical evaluation of the funnel plot, researchers could not visually identify publication bias. J Clin Epidemiol. 2005 Sep;58(9):894-901. PubMed PMID: 16085192. d. Mantha S, Karp R, Raghavan V, Terrin N, Bauer KA, Zwicker JI. Assessing the risk of venous thromboembolic events in women taking progestin-only contraception: a meta-analysis. BMJ. 2012 Aug 7;345:e4944. PubMed PMID: 22872710; PubMed Central PMCID: PMC3413580.

2. Mentoring. I have mentored doctoral students, postdoctoral trainees, and junior faculty over my entire career. These include MS students in the Clinical and Translational Science Program (CTSP) at the Sackler School of Graduate Biomedical Sciences, K-awardees, and PhD students in clinical research, nursing, and statistical methods, totaling over 30 trainees. Recent or current projects with high clinical impact include the work of a pediatric fellow who identified genotypes protective against withdrawal symptoms in infants exposed to narcotics prenatally, and the work of a K-23 trainee who studies HIV treatment adherence, patient tracking, and loss-to-follow-up in Namibia, a country where seasonal migration makes it difficult to maintain patients on therapy. As a member of the Advisory Committee of the CTSP since 2000, I have reviewed the MS and PhD thesis proposals and theses of nearly every graduate of the program, and I am consulted by other statistics mentors concerning advanced methodological issues in trainees’ research.

a. Miskulin DC, Meyer KB, Athienites NV, Martin AA, Terrin N, Marsh JV, Fink NE, Coresh J, Powe NR, Klag MJ, Levey AS. Comorbidity and other factors associated with modality selection in incident dialysis patients: the CHOICE Study. Choices for Healthy Outcomes in Caring for End-Stage Renal Disease. Am J Kidney Dis. 2002 Feb;39(2):324-36. PubMed PMID: 11840373. b. Mayer DK, Terrin NC, Kreps GL, Menon U, McCance K, Parsons SK, Mooney KH. Cancer survivors information seeking behaviors: a comparison of survivors who do and do not seek information about cancer. Patient Educ Couns. 2007 Mar;65(3):342-50. PubMed PMID: 17029864. c. Wachman EM, Hayes MJ, Brown MS, Paul J, Harvey-Wilkes K, Terrin N, Huggins GS, Aranda JV, Davis JM. Association of OPRM1 and COMT single-nucleotide polymorphisms with hospital length of stay and treatment of neonatal abstinence syndrome. JAMA. 2013 May 1;309(17):1821-7. PubMed PMID: 23632726; PubMed Central PMCID: PMC4432911. d. Hong SY, Fanelli TJ, Jonas A, Gweshe J, Tjituka F, Sheehan HM, Wanke C, Terrin N, Jordan MR, Tang AM. Household food insecurity associated with antiretroviral therapy adherence among HIV- infected patients in Windhoek, Namibia. J Acquir Immune Defic Syndr. 2014 Dec 1;67(4):e115-22. PubMed PMID: 25356779; PubMed Central PMCID: PMC4215168.

3. Prediction Models: Methods and Applications. My research on external validity of predictive models highlighted the necessity of external validation to test the transportability of predictive models. That work was later cited by Ewout W. Steyerberg, an internationally recognized authority on prediction modeling, in his textbook, “Clinical Prediction Models.” I collaborated on a study on equipoise in which we developed and demonstrated a method for ethical patient enrollment in clinical trials based on the quantification of uncertainty in prediction models. I am currently involved in a project that builds on those methods, to assess whether knee osteoarthritis patients with specific characteristics would be 1) better off with total knee replacement, 2) better off with a non-surgical intervention, or 3) in equipoise for an RCT.

a. Schmid C, Terrin N, Griffith J, D'Agostino SR, Selker H. Predictive performance of missing data methods for logistic regression, classification trees and neural networks. Journal of Statistical Computation and Simulation. 2001; 71(2):115--140. b. Savvides P, Terrin N, Erban J, Selker HP. Development and validation of a patient-specific predictive instrument for the need for dose reduction in chemotherapy for breast cancer: a potential decision aid for the use of myeloid growth factors. Support Care Cancer. 2003 May;11(5):313-20. PubMed PMID: 12720075. c. Terrin N, Schmid CH, Griffith JL, D'Agostino RB, Selker HP. External validity of predictive models: a comparison of logistic regression, classification trees, and neural networks. J Clin Epidemiol. 2003 Aug;56(8):721-9. PubMed PMID: 12954463. d. Selker HP, Ruthazer R, Terrin N, Griffith JL, Concannon T, Kent DM. Random treatment assignment using mathematical equipoise for comparative effectiveness trials. Clin Transl Sci. 2011 Feb;4(1):10-6. PubMed PMID: 21348950; PubMed Central PMCID: PMC3076795.

4. Patient Reported Outcomes: Methods and Applications. My research concerns appropriate statistical application of time-varying Health-Related Quality of Life (HRQL) data in survival models. I was Dual Principal Investigator of an R21 grant funded by the National Cancer Institute entitled “Innovative Statistical Methods for the Integration of Functional and Clinical Outcomes.” The project, the results of which were published in a 2013 invited paper in Quality of Life Research, used joint models for longitudinal and survival outcomes to assess the prognostic value of longitudinally measured HRQL. Also, as co- investigator of a study to document trajectories of HRQL in pediatric hematopoietic stem cell transplant patients (HSCT), I ensured that the analyses used cutting edge methods to address non-ignorable missing data and dual (self- and proxy) HRQL raters. I was also co-investigator of a clinical trial to test an internet- based intervention to support parents of HSCT patients. I serve as Associate Editor of the journal Quality of Life Research.

a. Chen C, Jeruss S, Chapman JS, Terrin N, Tighiouart H, Glassman E, Wilson JM, Parsons SK. Long- term functional impact of congenital diaphragmatic hernia repair on children. J Pediatr Surg. 2007 Apr;42(4):657-65. PubMed PMID: 17448762. b. Terrin N, Rodday AM, Tighiouart H, Chang G, Parsons SK. Parental emotional functioning declines with occurrence of clinical complications in pediatric hematopoietic stem cell transplant. Support Care Cancer. 2013 Mar;21(3):687-95. PubMed PMID: 22936494; PubMed Central PMCID: PMC3540150. c. Tickle-Degnen L, Saint-Hilaire M, Thomas CA, Habermann B, Martinez LS, Terrin N, Noubary F, Naumova EN. Emergence and evolution of social self-management of Parkinson's disease: study protocol for a 3-year prospective cohort study. BMC Neurol. 2014 May 2;14:95. PubMed PMID: 24885181; PubMed Central PMCID: PMC4016672. d. Terrin N, Rodday AM, Parsons SK. Joint models for predicting transplant-related mortality from quality of life data. Qual Life Res. 2015 Jan;24(1):31-9. PubMed PMID: 24129669; PubMed Central PMCID: PMC3989470.

5. Infectious Diseases and Other Clinical Applications. I collaborate with clinical and health services researchers in areas including infectious diseases, HIV-AIDS, pediatrics, nephrology, pulmonary medicine, oncology, surgery, health related quality of life, and health behavior. As Director of the Research Design Center/Biostatistics Research Center in the Tufts CTSI, I supervise 11 statisticians and epidemiologists doing similar work. I am a member of the Biostatistics Core of the Brown-Tufts Center for AIDS Research, and a co-investigator on a USAID contract to study assessment of malnutrition in resource-poor settings,

including malnutrition in people with HIV. Nationally and internationally, I contribute to the understanding of Infectious Diseases as Statistics Editor of the journal Clinical Infectious Diseases.

a. Carling P, Fung T, Killion A, Terrin N, Barza M. Favorable impact of a multidisciplinary antibiotic management program conducted during 7 years. Infect Control Hosp Epidemiol. 2003 Sep;24(9):699- 706. PubMed PMID: 14510254. b. McDermott AY, Terrin N, Wanke C, Skinner S, Tchetgen E, Shevitz AH. CD4+ cell count, viral load, and highly active antiretroviral therapy use are independent predictors of body composition alterations in HIV-infected adults: a longitudinal study. Clin Infect Dis. 2005 Dec 1;41(11):1662-70. PubMed PMID: 16267741. c. McMahon J, Wanke C, Terrin N, Skinner S, Knox T. Poverty, hunger, education, and residential status impact survival in HIV. AIDS Behav. 2011 Oct;15(7):1503-11. PubMed PMID: 20632079; PubMed Central PMCID: PMC3010417. d. Forrester JE, Rhee MS, McGovern BH, Sterling RK, Knox TA, Terrin N. The association of HIV viral load with indirect markers of liver injury. J Viral Hepat. 2012 Feb;19(2):e202-11. PubMed PMID: 22239520; PubMed Central PMCID: PMC3261587.

D. Additional Information: Research Support and/or Scholastic Performance

Ongoing Research Support 1R01 CA243542-01, NIH/NCI Jaffe (PI) 09/01/19-08/31/24 Credentialing a cross-species platform to investigate cancer therapy-associated cardiovascular toxicity The overarching goal of this proposal is to create a cross-species (dog, mice, human) model platform for the study of cancer therapy-associated cardiovascular toxicity. Role: Investigator

KL2TR002545, NIH/NCATS Freund (PI) 05/01/19-04/30/21 Tufts Clinical and Translational Science Institute (CTSI) Mentored Career Development This institutional career development award will support junior investigators in the developing their careers as team scientists and clinical translational investigators. Role: Mentor

U01 TR002271, NIH/NCATS Davis (PI) 08/15/18-07/31/23 Precision Medicine in the Diagnosis of Genetic Disorders in Neonates The overarching goal of this proposal is to examine the clinical utility and operational infrastructure of a neonatal gene panel in high-risk neonates in order to determine if it will provide a more timely diagnosis and better care at significantly lower cost than standard diagnostic care or WGS, establishing the foundation for a CTSA wide Neonatal Precision Medicine Program. Role: Investigator

UL1 TR002544, NIH Selker (PI) 05/01/18-04/30/23 Tufts Clinical and Translational Science Institute Through research resources, services, and education, Tufts Clinical and Translational Science Institute supports the entire spectrum of clinical and translational research to help meet the promise and the public’s needs of biomedical science. This spectrum includes the translation of bench research into bedside care (“T1”), into effective clinical practice (“T2”), into wide care delivery and public health (“T3”), and into health policy (“T4”). By doing this, we hope to support research that will have impact on healthcare and the public’s health. Role: Scientific Director of BERD

R21 NR017704, NIH/NINR Baleja (PI) 09/26/18-07/31/20 Diagnosis of Heart Failure Status Using Epidermal Metabolomics The primary goal of this proposal is to lay the groundwork for the use of epidermal metabolites to provide insight into any other disease that might manifest in the skin such as those associated with dry skin, cancer, or in-born errors of metabolism. Role: Investigator

1R01AG055443-01A1, NIH/NIA Ceglia (PI) 09/30/18-05/31/23 Impact of protein and alkali supplementation on skeletal muscle in older adults Major goal: To determine whether an alkaline salt supplement (potassium bicarbonate) can enhance the beneficial impact of a high protein diet on muscle performance and mass. Role: Investigator

Northeastern University NIH (multiple funds) Briesacher (PI) 08/21/17-08/20/20 NIH (multiple funds) Statistical service for Dr. Bresacher’s multiple grants. Role: Investigator

Completed Research Support Charles H. Hood Foundation Major Grant Initiative to Advance Child Health Davis (PI) 01/01/17-09/30/18 ESTABLISHING RISK IN NEONATAL ABSTINENCE SYNDROME Our long term goals are the development of a prediction tool to establish risk of significant NAS and a better assessment tool to guide earlier identification and treatment. Role: Investigator

R21 DA 041706, NIDA Davis (PI) 08/01/16-07/31/19 Establishing Risk in Neonatal Abstinence Syndrome The primary goal of this proposal is the development of a clinical prediction tool to establish risk of US. Neonatal abstinence syndrome (NAS). Role: Investigator

CE-1304-6173, PCORI / Lahey Clinic Ghogawala (PI) 10/01/18-03/31/19 Cervical Spondylotic Myelopathy Surgical Trial (CSM-S Trial) Role: Investigator

R01 MD 007735, NIH/NIMHD Freund (PI) 12/01/14-05/31/19 Insurance Instability and Disparities in Chronic Disease Outcomes To determine the effectiveness of Massachusetts Health Insurance Reform on reducing disparities in processes and outcomes of chronic conditions among Boston’s vulnerable populations. Role: Investigator

Finnegan Project – U. of Louisville Subcontract, Chiesi Farmaceutici Company Terrin (PI) 08/01/18-01/31/19 Multicenter Cross Validation Study of a Simplified Finnegan Scoring System The purpose of the study is to provide an independent statistical analysis of the sFNAS in a population of infants treated for NAS in a NIDA funded multisite clinical trial led by Tufts Medical Center.

1 U24 TR001609 Selker (PI) 02/12/17-06/30/18 JOHNS HOPKINS-TUFTS TRIAL INNOVATION CENTER The objective is streamlining and making efficient the processes by which clinical trials are conducted including operations, application of the best science and innovative and study design and execution. Role: Investigator

R01 FD 003899, FDA Davis (PI) 07/15/13-08/31/18 Phase 2 Study of rhCC10 to Prevent Neonatal Bronchopulmonary Dysplasia Randomized, double-blinded, placebo-controlled dose escalation study to examine safety and efficacy of rhCC10 in high risk preterm infants. Role: Investigator

UL1 TR001064, NIH Selker (PI) 05/01/15-04/30/18 Tufts Clinical and Translational Science Institute. Role: Director of BERD

R01 DA 032889, NIH/NIDA Davis (PI) 09/01/12-06/30/17 Improving Outcome in Neonatal Abstinence Syndrome. Role: Investigator