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Maturation And Substrate Processing Topography Of The Plasmodium Falciparum Invasion/Egress Protease Plasmepsin X, Sumit Mukherjee, Suong Nguyen, Eashan Sharma, Daniel E Goldberg

2020-Current year OA Pubs

The malaria parasite Plasmodium invades a host erythrocyte, multiplies within a parasitophorous vacuole (PV) and then ruptures the PV and erythrocyte membranes in a process known as egress. Both egress and invasion are controlled by effector proteins discharged from specialized secretory organelles. The aspartic protease plasmepsin X (PM X) regulates activity for many of these effectors, but it is unclear how PM X accesses its diverse substrates that reside in different organelles. PM X also autoprocesses to generate different isoforms. The function of this processing is not understood. We have mapped the self-cleavage sites and have constructed parasites with cleavage …

Enhancing Interprofessional Collaboration And Interprofessional Education In Women's Health, Laura Baecher-Lind, Angela C Fleming, Rashmi Bhargava, Susan M Cox, Elise N Everett, David A Forstein, Shireen Madani Sims, Helen K Morgan, Christopher M Morosky, Celeste S Royce, Tammy S Sonn, Jill M Sutton, Scott C Graziano

2020-Current year OA Pubs

This article is from the 'To The Point' series from the Association of Professors of Gynecology and Obstetrics Undergraduate Medical Education Committee. The purpose of this review is to provide an understanding of the differing yet complementary nature of interprofessional collaboration and interprofessional education as well as their importance to the specialty of Obstetrics and Gynecology. We provide a historical perspective of how interprofessional collaboration and interprofessional education have become key aspects of clinical and educational programs, enhancing both patient care and learner development. Opportunities to incorporate interprofessional education within women's health educational programs across organizations are suggested. This is …

A Multi-Layer Functional Genomic Analysis To Understand Noncoding Genetic Variation In Lipids, Shweta Ramdas, Jonathan Judd, Sarah E Graham, Stavroula Kanoni, Yuxuan Wang, Ida Surakka, Brandon Wenz, Shoa L Clarke, Alessandra Chesi, Andrew Wells, Konain Fatima Bhatti, Sailaja Vedantam, Thomas W Winkler, Adam E Locke, Eirini Marouli, Greg J M Zajac, Kuan-Han H Wu, Ioanna Ntalla, Qin Hui, Derek Klarin, Austin T Hilliard, Zeyuan Wang, Chao Xue, Gudmar Thorleifsson, Anna Helgadottir, Daniel F Gudbjartsson, Hilma Holm, Isleifur Olafsson, Mi Yeong Hwang, Sohee Han, Masato Akiyama, Saori Sakaue, Chikashi Terao, Masahiro Kanai, Wei Zhou, Ben M Brumpton, Humaira Rasheed, Aki S Havulinna, Yogasudha Veturi, Jennifer Allen Pacheco, Elisabeth A Rosenthal, Todd Lingren, Qiping Feng, Iftikhar J Kullo, Akira Narita, Jun Takayama, Hilary C Martin, Karen A Hunt, Bhavi Trivedi, Jeffrey Haessler, Franco Giulianini, Yuki Bradford, Jason E Miller, Archie Campbell, Kuang Lin, Iona Y Millwood, Asif Rasheed, George Hindy, Jessica D Faul, Wei Zhao, David R Weir, Constance Turman, Hongyan Huang, Mariaelisa Graff, Ananyo Choudhury, Dhriti Sengupta, Anubha Mahajan, Michael R Brown, Weihua Zhang, Ketian Yu, Ellen M Schmidt, Anita Pandit, Stefan Gustafsson, Xianyong Yin, Jian'an Luan, Jing-Hua Zhao, Fumihiko Matsuda, Hye-Mi Jang, Kyungheon Yoon, Carolina Medina-Gomez, Achilleas Pitsillides, Jouke Jan Hottenga, Andrew R Wood, Yingji Ji, Zishan Gao, Simon Haworth, Ruth E Mitchell, Jin Fang Chai, Mette Aadahl, Anne A Bjerregaard, Jie Yao, Ani Manichaikul, Wen-Jane Lee, Chao Agnes Hsiung, Helen R Warren, Julia Ramirez, Jette Bork-Jensen, Line L Kårhus, Anuj Goel, Maria Sabater-Lleal, Raymond Noordam, Pala Mauro, Floris Matteo, Aaron F Mcdaid, Pedro Marques-Vidal, Matthias Wielscher, Stella Trompet, Naveed Sattar, Line T Møllehave, Matthias Munz, Lingyao Zeng, Jianfeng Huang, Bin Yang, Alaitz Poveda, Azra Kurbasic, Sebastian Schönherr, Lukas Forer, Markus Scholz, Tessel E Galesloot, Jonathan P Bradfield, Sanni E Ruotsalainen, E Warwick Daw, Joseph M Zmuda, Jonathan S Mitchell, Christian Fuchsberger, Henry Christensen, Jennifer A Brody, Phuong Le, Mary F Feitosa, Mary K Wojczynski, Daiane Hemerich, Michael Preuss, Massimo Mangino, Paraskevi Christofidou, Niek Verweij, Jan W Benjamins, Jorgen Engmann, Tsao L Noah, Anurag Verma, Roderick C Slieker, Ken Sin Lo, Nuno R Zilhao, Marcus E Kleber, Graciela E Delgado, Shaofeng Huo, Daisuke D Ikeda, Hiroyuki Iha, Jian Yang, Jun Liu, Ayşe Demirkan, Hampton L Leonard, Jonathan Marten, Carina Emmel, Börge Schmidt, Laura J Smyth, Marisa Cañadas-Garre, Chaolong Wang, Masahiro Nakatochi, Andrew Wong, Nina Hutri-Kähönen, Xueling Sim, Rui Xia, Alicia Huerta-Chagoya, Juan Carlos Fernandez-Lopez, Valeriya Lyssenko, Suraj S Nongmaithem, Alagu Sankareswaran, Marguerite R Irvin, Christopher Oldmeadow, Han-Na Kim, Seungho Ryu, Paul R H J Timmers, Liubov Arbeeva, Rajkumar Dorajoo, Leslie A Lange, Gauri Prasad, Laura Lorés-Motta, Marc Pauper, Jirong Long, Xiaohui Li, Elizabeth Theusch, Fumihiko Takeuchi, Cassandra N Spracklen, Anu Loukola, Sailalitha Bollepalli, Sophie C Warner, Ya Xing Wang, Wen B Wei, Teresa Nutile, Daniela Ruggiero, Yun Ju Sung, Shufeng Chen, Fangchao Liu, Jingyun Yang, Katherine A Kentistou, Bernhard Banas, Anna Morgan, Karina Meidtner, Lawrence F Bielak, Jennifer A Smith, Prashantha Hebbar, Aliki-Eleni Farmaki, Edith Hofer, Maoxuan Lin, Maria Pina Concas, Simona Vaccargiu, Peter J Van Der Most, Niina Pitkänen, Brian E Cade, Sander W Van Der Laan, Kumaraswamy Naidu Chitrala, Stefan Weiss, Amy R Bentley, Ayo P Doumatey, Adebowale A Adeyemo, Jong Young Lee, Eva R B Petersen, Aneta A Nielsen, Hyeok Sun Choi, Maria Nethander, Sandra Freitag-Wolf, Lorraine Southam, Nigel W Rayner, Carol A Wang, Shih-Yi Lin, Jun-Sing Wang, Christian Couture, Leo-Pekka Lyytikäinen, Kjell Nikus, Gabriel Cuellar-Partida, Henrik Vestergaard, Bertha Hidalgo, Olga Giannakopoulou, Qiuyin Cai, Morgan O Obura, Jessica Van Setten, Karen Y He, Hua Tang, Natalie Terzikhan, Jae Hun Shin, Rebecca D Jackson, Alexander P Reiner, Lisa Warsinger Martin, Zhengming Chen, Liming Li, Takahisa Kawaguchi, Joachim Thiery, Joshua C Bis, Lenore J Launer, Huaixing Li, Mike A Nalls, Olli T Raitakari, Sahoko Ichihara, Sarah H Wild, Christopher P Nelson, Harry Campbell, Susanne Jäger, Toru Nabika, Fahd Al-Mulla, Harri Niinikoski, Peter S Braund, Ivana Kolcic, Peter Kovacs, Tota Giardoglou, Tomohiro Katsuya, Dominique De Kleijn, Gert J De Borst, Eung Kweon Kim, Hieab H H Adams, M Arfan Ikram, Xiaofeng Zhu, Folkert W Asselbergs, Adriaan O Kraaijeveld, Joline W J Beulens, Xiao-Ou Shu, Loukianos S Rallidis, Oluf Pedersen, Torben Hansen, Paul Mitchell, Alex W Hewitt, Mika Kähönen, Louis Pérusse, Claude Bouchard, Anke Tönjes, Yii-Der Ida Chen, Craig E Pennell, Trevor A Mori, Wolfgang Lieb, Andre Franke, Claes Ohlsson, Dan Mellström, Yoon Shin Cho, Hyejin Lee, Jian-Min Yuan, Woon-Puay Koh, Sang Youl Rhee, Jeong-Taek Woo, Iris M Heid, Klaus J Stark, Martina E Zimmermann, Henry Völzke, Georg Homuth, Michele K Evans, Alan B Zonderman, Ozren Polasek, Gerard Pasterkamp, Imo E Hoefer, Susan Redline, Katja Pahkala, Albertine J Oldehinkel, Harold Snieder, Ginevra Biino, Reinhold Schmidt, Helena Schmidt, Stefania Bandinelli, George Dedoussis, Thangavel Alphonse Thanaraj, Patricia A Peyser, Norihiro Kato, Matthias B Schulze, Giorgia Girotto, Carsten A Böger, Bettina Jung, Peter K Joshi, David A Bennett, Philip L De Jager, Xiangfeng Lu, Vasiliki Mamakou, Morris Brown, Mark J Caulfield, Patricia B Munroe, Xiuqing Guo, Marina Ciullo, Jost B Jonas, Nilesh J Samani, Jaakko Kaprio, Päivi Pajukanta, Teresa Tusié-Luna, Carlos A Aguilar-Salinas, Linda S Adair, Sonny Augustin Bechayda, H Janaka De Silva, Ananda R Wickremasinghe, Ronald M Krauss, Jer-Yuarn Wu, Wei Zheng, Anneke I Den Hollander, Dwaipayan Bharadwaj, Adolfo Correa, James G Wilson, Lars Lind, Chew-Kiat Heng, Amanda E Nelson, Yvonne M Golightly, James F Wilson, Brenda Penninx, Hyung-Lae Kim, John Attia, Rodney J Scott, D C Rao, Donna K Arnett, Mark Walker, Laura J Scott, Heikki A Koistinen, Giriraj R Chandak, Josep M Mercader, Clicerio Gonzalez Villalpando, Lorena Orozco, Myriam Fornage, E Shyong Tai, Rob M Van Dam, Terho Lehtimäki, Nish Chaturvedi, Mitsuhiro Yokota, Jianjun Liu, Dermot F Reilly, Amy Jayne Mcknight, Frank Kee, Karl-Heinz Jöckel, Mark I Mccarthy, Colin N A Palmer, Veronique Vitart, Caroline Hayward, Eleanor Simonsick, Cornelia M Van Duijn, Zi-Bing Jin, Fan Lu, Haretsugu Hishigaki, Xu Lin, Winfried März, Vilmundur Gudnason, Jean-Claude Tardif, Guillaume Lettre, Leen M T Hart, Petra J M Elders, Daniel J Rader, Scott M Damrauer, Meena Kumari, Mika Kivimaki, Pim Van Der Harst, Tim D Spector, Ruth J F Loos, Michael A Province, Esteban J Parra, Miguel Cruz, Bruce M Psaty, Ivan Brandslund, Peter P Pramstaller, Charles N Rotimi, Kaare Christensen, Samuli Ripatti, Elisabeth Widén, Hakon Hakonarson, Struan F A Grant, Lambertus Kiemeney, Jacqueline De Graaf, Markus Loeffler, Florian Kronenberg, Dongfeng Gu, Jeanette Erdmann, Heribert Schunkert, Paul W Franks, Allan Linneberg, J Wouter Jukema, Amit V Khera, Minna Männikkö, Marjo-Riitta Jarvelin, Zoltan Kutalik, Cucca Francesco, Dennis O Mook-Kanamori, Ko Willems Van Dijk, Hugh Watkins, David P Strachan, Niels Grarup, Peter Sever, Neil Poulter, Wayne Huey-Herng Sheu, Jerome I Rotter, Thomas M Dantoft, Fredrik Karpe, Matt J Neville, Nicholas J Timpson, Ching-Yu Cheng, Tien-Yin Wong, Chiea Chuen Khor, Hengtong Li, Charumathi Sabanayagam, Annette Peters, Christian Gieger, Andrew T Hattersley, Nancy L Pedersen, Patrik K E Magnusson, Dorret I Boomsma, Eco J C De Geus, L Adrienne Cupples, Joyce B J Van Meurs, Arfan Ikram, Mohsen Ghanbari, Penny Gordon-Larsen, Wei Huang, Young Jin Kim, Yasuharu Tabara, Nicholas J Wareham, Claudia Langenberg, Eleftheria Zeggini, Jaakko Tuomilehto, Johanna Kuusisto, Markku Laakso, Erik Ingelsson, Goncalo Abecasis, John C Chambers, Jaspal S Kooner, Paul S De Vries, Alanna C Morrison, Scott Hazelhurst, Michèle Ramsay, Kari E North, Martha Daviglus, Peter Kraft, Nicholas G Martin, John B Whitfield, Shahid Abbas, Danish Saleheen, Robin G Walters, Michael V Holmes, Corri Black, Blair H Smith, Aris Baras, Anne E Justice, Julie E Buring, Paul M Ridker, Daniel I Chasman, Charles Kooperberg, Gen Tamiya, Masayuki Yamamoto, David A Van Heel, Richard C Trembath, Wei-Qi Wei, Gail P Jarvik, Bahram Namjou, M Geoffrey Hayes, Marylyn D Ritchie, Pekka Jousilahti, Veikko Salomaa, Kristian Hveem, Bjørn Olav Åsvold, Michiaki Kubo, Yoichiro Kamatani, Yukinori Okada, Yoshinori Murakami, Bong-Jo Kim, Unnur Thorsteinsdottir, Kari Stefansson, Jifeng Zhang, Y Eugene Chen, Yuk-Lam Ho, Julie A Lynch, Philip S Tsao, Kyong-Mi Chang, Kelly Cho, Christopher J O'Donnell, John M Gaziano, Peter Wilson, Karen L Mohlke, Timothy M Frayling, Joel N Hirschhorn, Sekar Kathiresan, Michael Boehnke, Million Veterans Program, Global Lipids Genetics Consortium, Struan Grant, Pradeep Natarajan, Yan V Sun, Andrew P Morris, Panos Deloukas, Gina Peloso, Themistocles L Assimes, Cristen J Willer, Xiang Zhu, Christopher D Brown

Faculty, Staff and Student Publications

A major challenge of genome-wide association studies (GWASs) is to translate phenotypic associations into biological insights. Here, we integrate a large GWAS on blood lipids involving 1.6 million individuals from five ancestries with a wide array of functional genomic datasets to discover regulatory mechanisms underlying lipid associations. We first prioritize lipid-associated genes with expression quantitative trait locus (eQTL) colocalizations and then add chromatin interaction data to narrow the search for functional genes. Polygenic enrichment analysis across 697 annotations from a host of tissues and cell types confirms the central role of the liver in lipid levels and highlights the selective …

Risk Assessment With Low-Pass Whole-Genome Sequencing Of Cell-Free Dna Before Cd19 Car T-Cell Therapy For Large B-Cell Lymphoma, Hua-Jay J Cherng, Ryan Sun, Bryant Sugg, Russell Irwin, Haopeng Yang, Cao Cuong Le, Qing Deng, Luis Fayad, Nathan H Fowler, Simrit Parmar, Raphael Steiner, Fredrick Hagemeister, Ranjit Nair, Hun Ju Lee, Maria Rodriguez, Felipe Samaniego, Swaminathan P Iyer, Christopher R Flowers, Linghua Wang, Loretta J Nastoupil, Sattva S Neelapu, Sairah Ahmed, Paolo Strati, Michael R Green, Jason Westin

Faculty, Staff and Student Publications

Patients with relapsed or refractory large B-cell lymphomas (rrLBCL) can achieve long-term remission after CD19 chimeric antigen receptor T-cell therapy (CART19). However, more than half of recipients will experience treatment failure. Thus, approaches are needed to identify high-risk patients who may benefit from alternative or consolidative therapy. We evaluated low-pass whole-genome sequencing (lpWGS) of cell-free DNA (cfDNA) before CART19 as a new approach for risk stratification. We performed lpWGS on pretreatment plasma samples from 122 patients at time of leukapheresis who received standard-of-care CART19 for rrLBCL to define DNA copy number alterations (CNAs). In multivariable selection, high focal CNA score …

Primary Cutaneous Lymphoma: Recommendations For Clinical Trial Design And Staging Update From The Iscl, Usclc, And Eortc, Elise A Olsen, Sean Whittaker, Rein Willemze, Lauren Pinter-Brown, Francine Foss, Larisa Geskin, Lawrence Schwartz, Steven Horwitz, Joan Guitart, John Zic, Youn H Kim, Gary S Wood, Madeleine Duvic, Wei Ai, Michael Girardi, Alejandro Gru, Emmanuella Guenova, Emmilia Hodak, Richard Hoppe, Werner Kempf, Ellen Kim, Mary Jo Lechowicz, Pablo Ortiz-Romero, Evangelia Papadavid, Pietro Quaglino, Mark Pittelkow, H Miles Prince, Jose Antonio Sanches, Makoto Sugaya, Maarten Vermeer, Jasmine Zain, Robert Knobler, Rudolf Stadler, Martine Bagot, Julia Scarisbrick

Faculty, Staff and Student Publications

The number of patients with primary cutaneous lymphoma (PCL) relative to other non-Hodgkin lymphomas (NHLs) is small and the number of subtypes large. Although clinical trial guidelines have been published for mycosis fungoides/Sézary syndrome, the most common type of PCL, none exist for the other PCLs. In addition, staging of the PCLs has been evolving based on new data on potential prognostic factors, diagnosis, and assessment methods of both skin and extracutaneous disease and a desire to align the latter with the Lugano guidelines for all NHLs. The International Society for Cutaneous Lymphomas (ISCL), the United States Cutaneous LymphomaConsortium (USCLC), …

Left Sided Breast Cancer Is Associated With Aggressive Biology And Worse Outcomes Than Right Sided Breast Cancer, Yara Abdou, Medhavi Gupta, Mariko Asaoka, Kristopher Attwood, Opyrchal Mateusz, Shipra Gandhi, Kazuaki Takabe

2020-Current year OA Pubs

Breast cancer is more common on the left side than the right side. We aim to evaluate differences in clinicopathological and genomic characteristics based on laterality. We analyzed survival outcomes and clinical characteristics of 881,320 patients recorded by the Surveillance, Epidemiology, and End Results (SEER) program. The Cancer Genome Atlas (TCGA) was used to explore genomic and clinical features from 1,062 patients. Gene expression data was used to quantitate cytolytic activity and hallmark gene-sets were used for gene set enrichment analysis. An institutional retrospective review was conducted on 155 patients treated with neoadjuvant chemotherapy (NACT). Patient characteristics were summarized by …

Engineering Hyaluronic Acid For The Development Of New Treatment Strategies For Osteoarthritis, Yu Seon Kim, Farshid Guilak

2020-Current year OA Pubs

Osteoarthritis (OA) is a degenerative joint disease that is characterized by inflammation of the joints, degradation of cartilage, and the remodeling of other joint tissues. Due to the absence of disease-modifying drugs for OA, current clinical treatment options are often only effective at slowing down disease progression and focus mainly on pain management. The field of tissue engineering has therefore been focusing on developing strategies that could be used not only to alleviate symptoms of OA but also to regenerate the damaged tissue. Hyaluronic acid (HA), an integral component of both the synovial fluid and articular cartilage, has gained widespread …

The Use Of Objective Assessments In The Evaluation Of Technical Skills In Cardiothoracic Surgery: A Systematic Review, Nabil Hussein, Jef Van Den Eynde, Connor Callahan, Alvise Guariento, Can Gollmann-Tepeköylü, Malak Elbatarny, Mahmoud Loubani

2020-Current year OA Pubs

OBJECTIVES: With reductions in training time and intraoperative exposure, there is a need for objective assessments to measure trainee progression. This systematic review focuses on the evaluation of trainee technical skill performance using objective assessments in cardiothoracic surgery and its incorporation into training curricula.

METHODS: Databases (EBSCOHOST, Scopus and Web of Science) and reference lists of relevant articles for studies that incorporated objective assessment of technical skills of trainees/residents in cardiothoracic surgery were included. Data extraction included task performed; assessment setting and tool used; number/level of assessors; study outcome and whether the assessments were incorporated into training curricula. The methodological …

Online Randomised Factorial Trial Of Electronic Screening And Brief Intervention For Alcohol Use In Pregnancy: A Study Protocol, Steven J. Ondersma, Lisa Todd, Samantha Jablonski, Chaarushi Ahuja, Kathryn Gilstad-Hayden, Gregory Goyert, Amy M. Loree, Jaimee Heffner, Kimberly A. Yonkers

Center for Health Policy and Health Services Research Articles

INTRODUCTION: Approximately 1 in 7 pregnant women in the USA report past-month alcohol use. Strong evidence connects prenatal alcohol exposure with a range of adverse perinatal outcomes, including the spectrum of conditions known as fetal alcohol spectrum disorders. Screening and Brief Intervention (SBI) has been recommended for pregnant women but has proven difficult to implement. This study will test the efficacy of single-session technology-delivered SBI (electronic SBI) for alcohol use in pregnancy, while simultaneously evaluating the possible additional benefit of tailored text messages and/or booster sessions in a 3×2 factorial trial.

METHOD AND ANALYSIS: This full factorial trial will use …

Gonadal Sex Patterns P21-Induced Cellular Senescence In Mouse And Human Glioblastoma, Lauren Broestl, Nicole M Warrington, Lucia Grandison, Tamara Abou-Antoun, Olivia Tung, Saraswati Shenoy, Miranda M Tallman, Gina Rhee, Wei Yang, Jasmin Sponagel, Lihua Yang, Najla Kfoury-Beaumont, Cameron M Hill, Sulaiman A Qanni, Diane D Mao, Albert H Kim, Sheila A Stewart, Monica Venere, Jingqin Luo, Joshua B Rubin

2020-Current year OA Pubs

Males exhibit higher incidence and worse prognosis for the majority of cancers, including glioblastoma (GBM). Disparate survival may be related to sex-biased responses to treatment, including radiation. Using a mouse model of GBM, we show that female cells are more sensitive to radiation, and that senescence represents a major component of the radiation therapeutic response in both sexes. Correlation analyses revealed that the CDK inhibitor p21 and irradiation induced senescence were differentially regulated between male and female cells. Indeed, female cellular senescence was more sensitive to changes in p21 levels, a finding that was observed in wildtype and transformed murine …

Association Between Social Vulnerability Index And Cardiovascular Disease: A Behavioral Risk Factor Surveillance System Study, Vardhmaan Jain, Mahmoud Al Rifai, Safi U Khan, Ankur Kalra, Fatima Rodriguez, Zainab Samad, Yashashwi Pokharel, Arunima Misra, Laurence S Sperling, Jamal S Rana, Waqas Ullah, Ankit Medhekar, Salim S Virani

Division of Cardiology Faculty Papers

Background Social and environmental factors play an important role in the rising health care burden of cardiovascular disease. The Centers for Disease Control and Prevention developed the Social Vulnerability Index (SVI) from US census data as a tool for public health officials to identify communities in need of support in the setting of a hazardous event. SVI (ranging from a least vulnerable score of 0 to a most vulnerable score of 1) ranks communities on 15 social factors including unemployment, minoritized groups status, and disability, and groups them under 4 broad themes: socioeconomic status, housing and transportation, minoritized groups, and …

Polygenic Risk, Midlife Life's Simple 7, And Lifetime Risk Of Stroke, Emy A Thomas, Nitesh Enduru, Adrienne Tin, Eric Boerwinkle, Michael E Griswold, Thomas H Mosley, Rebecca F Gottesman, Myriam Fornage

Faculty, Staff and Student Publications

Background

Recent genetic discoveries in stroke have unleashed the potential of using genetic information for risk prediction and health interventions aimed at disease prevention. We sought to estimate the lifetime risk of stroke (LTRS) by levels of genetic risk and to investigate whether optimal cardiovascular health can offset the negative impact of high genetic risk on lifetime risk of stroke.

Methods and Results

Study participants were 11 568 middle‐aged adults (56% women, 23% Black adults), who were free of stroke at baseline and were followed up for a median of 28 years. The remaining LTRS was estimated according to levels …

Association Between Social Vulnerability Index And Cardiovascular Disease: A Behavioral Risk Factor Surveillance System Study, Vardhmaan Jain, Mahmoud Al Rifai, Safi U Khan, Ankur Kalra, Fatima Rodriguez, Zainab Samad, Yashashwi Pokharel, Arunima Misra, Laurence S Sperling, Jamal S Rana, Waqas Ullah, Ankit Medhekar, Salim S Virani

Faculty, Staff and Students Publications

Background Social and environmental factors play an important role in the rising health care burden of cardiovascular disease. The Centers for Disease Control and Prevention developed the Social Vulnerability Index (SVI) from US census data as a tool for public health officials to identify communities in need of support in the setting of a hazardous event. SVI (ranging from a least vulnerable score of 0 to a most vulnerable score of 1) ranks communities on 15 social factors including unemployment, minoritized groups status, and disability, and groups them under 4 broad themes: socioeconomic status, housing and transportation, minoritized groups, and …

Sex And Gender Differences In Symptoms Of Early Psychosis: A Systematic Review And Meta-Analysis, Brooke Carter, Jared Wootten, Suzanne Archie, Amanda L Terry, Kelly K. Anderson

Epidemiology and Biostatistics Publications

First-episode psychosis (FEP) can be quite variable in clinical presentation, and both sex and gender may account for some of this variability. Prior literature on sex or gender differences in symptoms of psychosis have been inconclusive, and a comprehensive summary of evidence on the early course of illness is lacking. The objective of this study was to conduct a systematic review and meta-analysis of the literature to summarize prior evidence on the sex and gender differences in the symptoms of early psychosis. We conducted an electronic database search (MEDLINE, Scopus, PsycINFO, and CINAHL) from 1990 to present to identify quantitative …

Structural Plasticity Can Produce Metaplasticity, Wenli Zhao, Shuo Han, Na Qiu, Wenbo Feng, Mengjie Lu, Wenru Zhang, Mu Wang, Qingtong Zhou, Shutian Chen, Wei Xu, Juan Du, Xiaojing Chu, Cuiying Yi, Antao Dai, Liaoyuan Hu, Michelle Y Shen, Yaping Sun, Qing Zhang, Yingli Ma, Wenge Zhong, Dehua Yang, Ming-Wei Wang, Beili Wu, Qiang Zhao

Faculty, Staff and Student Publications

Somatostatin receptors (SSTRs) play versatile roles in inhibiting the secretion of multiple hormones such as growth hormone and thyroid-stimulating hormone, and thus are considered as targets for treating multiple tumors. Despite great progress made in therapeutic development against this diverse receptor family, drugs that target SSTRs still show limited efficacy with preferential binding affinity and conspicuous side-effects. Here, we report five structures of SSTR2 and SSTR4 in different states, including two crystal structures of SSTR2 in complex with a selective peptide antagonist and a non-peptide agonist, respectively, a cryo-electron microscopy (cryo-EM) structure of Gi1-bound SSTR2 in the presence of the …

Snmmi/Acr/Asnc/Scmr Joint Credentialing Statement For Cardiac Pet/Mri: Endorsed By The American Heart Association, Terrence D Ruddy, Mouaz Al-Mallah, James A Arrighi, John P Bois, David A Bluemke, Marcelo F Di Carli, Vasken Dilsizian, Robert J Gropler, Hossein Jadvar, Saurabh Malhotra, Matthier Pelletier-Galarneau, Thomas H Schindler, Pamela K Woodard, Panithaya Chareonthaitawee

2020-Current year OA Pubs

No abstract provided.

Phase I Trial Of The Dll3/Cd3 Bispecific T-Cell Engager Bi 764532 In Dll3-Positive Small-Cell Lung Cancer And Neuroendocrine Carcinomas, Martin Wermke, Enriqueta Felip, Valentina Gambardella, Yasutoshi Kuboki, Daniel Morgensztern, Zohra Oum' Hamed, Meiruo Liu, Matus Studeny, Taofeek K Owonikoko

2020-Current year OA Pubs

Poorly differentiated neuroendocrine carcinomas such as small-cell lung cancer (SCLC) have poor survival and high relapse rates. DLL3 is found on these carcinomas and has become a target of increasing interest in recent years. The bispecific DLL3/CD3 T-cell engager BI 764532 has been shown to induce complete tumor regression in a human T cell-engrafted mouse model. Here, we describe the study design of a first-in-human, phase I, multicenter, open-label, non-randomized, dose-escalation study in patients with SCLC or other DLL3-positive neuroendocrine carcinomas. The study will determine the maximum tolerated dose and evaluate safety, tolerability, pharmacokinetics and preliminary efficacy of BI 764532 …

Charting The Proteome Landscape In Major Psychiatric Disorders: From Biomarkers To Biological Pathways Towards Drug Discovery, Brisa S Fernandes, Yulin Dai, Peilin Jia, Zhongming Zhao

Faculty, Staff and Student Publications

Schizophrenia (SZ), bipolar disorder (BD), and major depressive disorder (MDD) are major mental disorders that affect a significant proportion of the global population. Advancing our knowledge of the pathophysiology of these disorders and identifying biomarkers are urgent needs for developing objective diagnostic tests and new therapeutics. In this study, we performed a systematic review and then extracted, curated, and analyzed proteomics data from published studies, aiming to assess the proteome in peripheral blood of individuals with SZ, BD, or MDD. Then, we performed pathway and network analyses to illuminate the biological themes concatenated by the differentially expressed proteins by systematically …

Genome-Wide Bidirectional Crispr Screens Identify Mucins As Host Factors Modulating Sars-Cov-2 Infection, Scott B Biering, Sylvia A Sarnik, Eleanor Wang, James R Zengel, Sarah R Leist, Alexandra Schäfer, Varun Sathyan, Padraig Hawkins, Kenichi Okuda, Cyrus Tau, Aditya R Jangid, Connor V Duffy, Jin Wei, Rodney C Gilmore, Mia Madel Alfajaro, Madison S Strine, Xammy Nguyenla, Erik Van Dis, Carmelle Catamura, Livia H Yamashiro, Julia A Belk, Adam Begeman, Jessica C Stark, D Judy Shon, Douglas M Fox, Shahrzad Ezzatpour, Emily Huang, Nico Olegario, Arjun Rustagi, Allison S Volmer, Alessandra Livraghi-Butrico, Eddie Wehri, Richard R Behringer, Dong-Joo Cheon, Julia Schaletzky, Hector C Aguilar, Andreas S Puschnik, Brian Button, Benjamin A Pinsky, Catherine A Blish, Ralph S Baric, Wanda K O'Neal, Carolyn R Bertozzi, Craig B Wilen, Richard C Boucher, Jan E Carette, Sarah A Stanley, Eva Harris, Silvana Konermann, Patrick D Hsu

Faculty, Staff and Student Publications

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes a range of symptoms in infected individuals, from mild respiratory illness to acute respiratory distress syndrome. A systematic understanding of host factors influencing viral infection is critical to elucidate SARS-CoV-2-host interactions and the progression of Coronavirus disease 2019 (COVID-19). Here, we conducted genome-wide CRISPR knockout and activation screens in human lung epithelial cells with endogenous expression of the SARS-CoV-2 entry factors ACE2 and TMPRSS2. We uncovered proviral and antiviral factors across highly interconnected host pathways, including clathrin transport, inflammatory signaling, cell-cycle regulation, and transcriptional and epigenetic regulation. We further identified mucins, a …

A Genome-Wide Association Study Of Obstructive Heart Defects Among Participants In The National Birth Defects Prevention Study, Sara R Rashkin, Mario Cleves, Gary M Shaw, Wendy N Nembhard, Eirini Nestoridi, Mary M Jenkins, Paul A Romitti, Xiang-Yang Lou, Marilyn L Browne, Laura E Mitchell, Andrew F Olshan, Kevin Lomangino, Sudeepa Bhattacharyya, John S Witte, Charlotte A Hobbs

Faculty, Staff and Student Publications

Obstructive heart defects (OHDs) share common structural lesions in arteries and cardiac valves, accounting for ~25% of all congenital heart defects. OHDs are highly heritable, resulting from interplay among maternal exposures, genetic susceptibilities, and epigenetic phenomena. A genome-wide association study was conducted in National Birth Defects Prevention Study participants (N

Insights From A Large-Scale Whole-Genome Sequencing Study Of Systolic Blood Pressure, Diastolic Blood Pressure, And Hypertension, Tanika N Kelly, Xiao Sun, Karen Y He, Michael R Brown, Sarah A Gagliano Taliun, Jacklyn N Hellwege, Marguerite R Irvin, Xuenan Mi, Jennifer A Brody, Nora Franceschini, Xiuqing Guo, Shih-Jen Hwang, Paul S De Vries, Yan Gao, Arden Moscati, Girish N Nadkarni, Lisa R Yanek, Tali Elfassy, Jennifer A Smith, Ren-Hua Chung, Amber L Beitelshees, Amit Patki, Stella Aslibekyan, Brandon M Blobner, Juan M Peralta, Themistocles L Assimes, Walter R Palmas, Chunyu Liu, Adam P Bress, Zhijie Huang, Lewis C Becker, Chii-Min Hwa, Jeffrey R O'Connell, Jenna C Carlson, Helen R Warren, Sayantan Das, Ayush Giri, Lisa W Martin, W Craig Johnson, Ervin R Fox, Erwin P Bottinger, Alexander C Razavi, Dhananjay Vaidya, Lee-Ming Chuang, Yen-Pei C Chang, Take Naseri, Deepti Jain, Hyun Min Kang, Adriana M Hung, Vinodh Srinivasasainagendra, Beverly M Snively, Dongfeng Gu, May E Montasser, Muagututi'a Sefuiva Reupena, Benjamin D Heavner, Jonathon Lefaive, James E Hixson, Kenneth M Rice, Fei Fei Wang, Jonas B Nielsen, Jianfeng Huang, Alyna T Khan, Wei Zhou, Jovia L Nierenberg, Cathy C Laurie, Nicole D Armstrong, Mengyao Shi, Yang Pan, Adrienne M Stilp, Leslie Emery, Quenna Wong, Nicola L Hawley, Ryan L Minster, Joanne E Curran, Patricia B Munroe, Daniel E Weeks, Kari E North, Russell P Tracy, Eimear E Kenny, Daichi Shimbo, Aravinda Chakravarti, Stephen S Rich, Alex P Reiner, John Blangero, Susan Redline, Braxton D Mitchell, Dabeeru C Rao, Yii-Der Ida Chen, Sharon L R Kardia, Robert C Kaplan, Rasika A Mathias, Jiang He, Bruce M Psaty, Myriam Fornage, Ruth J F Loos, Adolfo Correa, Eric Boerwinkle, Jerome I Rotter, Charles Kooperberg, Todd L Edwards, Gonçalo R Abecasis, Xiaofeng Zhu, Daniel Levy, Donna K Arnett, Alanna C Morrison, Samoan Obesity, Lifestyle, And Genetic Adaptations Study (Olaga) Group,‡ Nhlbi Trans-Omics For Precision Medicine Topmed) Consortium

Faculty, Staff and Student Publications

BACKGROUND: The availability of whole-genome sequencing data in large studies has enabled the assessment of coding and noncoding variants across the allele frequency spectrum for their associations with blood pressure.

METHODS: We conducted a multiancestry whole-genome sequencing analysis of blood pressure among 51 456 Trans-Omics for Precision Medicine and Centers for Common Disease Genomics program participants (stage-1). Stage-2 analyses leveraged array data from UK Biobank (N=383 145), Million Veteran Program (N=318 891), and Reasons for Geographic and Racial Differences in Stroke (N=10 643) participants, along with whole-exome sequencing data from UK Biobank (N=199 631) participants.

RESULTS: Two blood pressure signals …

Mortality Among Patients With Covid-19 And Different Interstitial Lung Disease Subtypes: A Multicenter Cohort Study., Joy Zhao, Brandon Metra, Gautam George, Jesse Roman, Joseph Mallon, Baskaran Sundaram, Michael Li, Ross Summer

Division of Pulmonary, Allergy, and Critical Care Medicine Faculty Papers

No abstract provided.

Impact Of Somatic Mutations On Survival Outcomes In Patients With Anaplastic Thyroid Carcinoma, Jennifer Rui Wang, Matthew Montierth, Li Xu, Maitrayee Goswami, Xiao Zhao, Gilbert Cote, Wenyi Wang, Priyanka Iyer, Ramona Dadu, Naifa L Busaidy, Stephen Y Lai, Neil D Gross, Renata Ferrarotto, Charles Lu, Gary Brandon Gunn, Michelle D Williams, Mark Routbort, Mark E Zafereo, Maria E Cabanillas

Faculty, Staff and Student Publications

PURPOSE: Anaplastic thyroid carcinoma (ATC) uniformly present with aggressive disease, but the mutational landscape of tumors varies. We aimed to determine whether tumor mutations affect survival outcomes in ATC.

MATERIALS AND METHODS: Patients who underwent mutation sequencing using targeted gene panels between 2005 and 2019 at a tertiary referral center were included. Associations between mutation status and survival outcomes were assessed using Cox proportional hazards models.

RESULTS: A total of 202 patients were included, where 122 died of ATC (60%). The median follow-up was 31 months (interquartile range, 18-45 months). The most common mutations were in

CONCLUSION: Mutation analysis provides …

Gene Therapy For Fibrodysplasia Ossificans Progressiva: Feasibility And Obstacles, Elisabeth M W Eekhoff, Ruben D De Ruiter, Bernard J Smilde, Ton Schoenmaker, Teun J De Vries, Coen Netelenbos, Edward C Hsiao, Christiaan Scott, Nobuhiko Haga, Zvi Grunwald, Carmen L De Cunto, Maja Di Rocco, Patricia L R Delai, Robert J Diecidue, Vrisha Madhuri, Tae-Joon Cho, Rolf Morhart, Clive S Friedman, Michael Zasloff, Gerard Pals, Jae-Hyuck Shim, Guangping Gao, Frederick Kaplan, Robert J Pignolo, Dimitra Micha

Department of Anesthesiology Faculty Papers

Fibrodysplasia ossificans progressiva (FOP) is a rare and devastating genetic disease, in which soft connective tissue is converted into heterotopic bone through an endochondral ossification process. Patients succumb early as they gradually become trapped in a second skeleton of heterotopic bone. Although the underlying genetic defect is long known, the inherent complexity of the disease has hindered the discovery of effective preventions and treatments. New developments in the gene therapy field have motivated its consideration as an attractive therapeutic option for FOP. However, the immune system's role in FOP activation and the as-yet unknown primary causative cell, are crucial issues …

Immune Checkpoint Inhibitors In Luminal Gastrointestinal Malignancies: Going Beyond Msi-H/Dmmr, Tmb And Pd-L1, Daniel S. Lefler, Adam E. Snook, Babar Bashir

Department of Medical Oncology Faculty Papers

In luminal gastrointestinal tumors, immune checkpoint inhibitors (ICIs) targeting PD-1, PD-L1 and CTLA-4 have been investigated in multiple settings. The indications for these drugs are primarily dependent on specific biomarkers that imply immunogenicity: overexpression of PD-L1, tumor mutational burden, loss of mismatch repair proteins (dMMR) and/or high microsatellite instability status. Although these markers can be both predictive and prognostic, there is variability in how they are measured and used to guide therapies. Moreover, the use of ICIs can be further refined with a better understanding of the tumor microenvironment and interactions with other available therapies. The purpose of this review …

Clinical Activity Of Mitogen-Activated Protein Kinase-Targeted Therapies In Patients With Non-V600 Braf-Mutant Tumors, Matthew Dankner, Yifan Wang, Rouhi Fazelzad, Benny Johnson, Caroline A Nebhan, Ibiayi Dagogo-Jack, Nathaniel J Myall, Georg Richtig, Jillian W P Bracht, Marco Gerlinger, Eiji Shinozaki, Takayuki Yoshino, Daisuke Kotani, Jason R Fangusaro, Oliver Gautschi, Julien Mazieres, Jeffrey A Sosman, Scott Kopetz, Vivek Subbiah, Michael A Davies, Anna L Groover, Ryan J Sullivan, Keith T Flaherty, Douglas B Johnson, Andrea Benedetti, David W Cescon, Anna Spreafico, George Zogopoulos, April A N Rose

Faculty, Staff and Student Publications

Purpose: Non-V600 mutations comprise approximately 35% of all BRAF mutations in cancer. Many of these mutations have been identified as oncogenic drivers and can be classified into three classes according to molecular characteristics. Consensus treatment strategies for class 2 and 3 BRAF mutations have not yet been established.

Methods: We performed a systematic review and meta-analysis with published reports of individual patients with cancer harboring class 2 or 3 BRAF mutations from 2010 to 2021, to assess treatment outcomes with US Food and Drug Administration-approved mitogen-activated protein kinase (MAPK) pathway targeted therapy (MAPK TT) according to BRAF class, cancer type, …

Selinexor In Advanced, Metastatic Dedifferentiated Liposarcoma: A Multinational, Randomized, Double-Blind, Placebo-Controlled Trial, Mrinal M Gounder, Albiruni Abdul Razak, Neeta Somaiah, Sant Chawla, Javier Martin-Broto, Giovanni Grignani, Scott M Schuetze, Bruno Vincenzi, Andrew J Wagner, Bartosz Chmielowski, Robin L Jones, Richard F Riedel, Silvia Stacchiotti, Elizabeth T Loggers, Kristen N Ganjoo, Axel Le Cesne, Antoine Italiano, Xavier Garcia Del Muro, Melissa Burgess, Sophie Piperno-Neumann, Christopher Ryan, Mary F Mulcahy, Charles Forscher, Nicolas Penel, Scott Okuno, Anthony Elias, Lee Hartner, Tony Philip, Thierry Alcindor, Bernd Kasper, Peter Reichardt, Lore Lapeire, Jean-Yves Blay, Christine Chevreau, Claudia Maria Valverde Morales, Gary K Schwartz, James L Chen, Hari Deshpande, Elizabeth J Davis, Garth Nicholas, Stefan Gröschel, Helen Hatcher, Florence Duffaud, Antonio Casado Herráez, Roberto Diaz Beveridge, Giuseppe Badalamenti, Mikael Eriksson, Christian Meyer, Margaret Von Mehren, Brian A Van Tine, Katharina Götze, Filomena Mazzeo, Alexander Yakobson, Aviad Zick, Alexander Lee, Anna Estival Gonzalez, Andrea Napolitano, Mark A Dickson, Dayana Michel, Changting Meng, Lingling Li, Jianjun Liu, Osnat Ben-Shahar, Dane R Van Domelen, Christopher J Walker, Hua Chang, Yosef Landesman, Jatin J Shah, Sharon Shacham, Michael G Kauffman, Steven Attia

Faculty, Staff and Student Publications

Purpose: Antitumor activity in preclinical models and a phase I study of patients with dedifferentiated liposarcoma (DD-LPS) was observed with selinexor. We evaluated the clinical benefit of selinexor in patients with previously treated DD-LPS whose sarcoma progressed on approved agents.

Methods: SEAL was a phase II-III, multicenter, randomized, double-blind, placebo-controlled study. Patients age 12 years or older with advanced DD-LPS who had received two-five lines of therapy were randomly assigned (2:1) to selinexor (60 mg) or placebo twice weekly in 6-week cycles (crossover permitted). The primary end point was progression-free survival (PFS). Patients who received at least one dose of …

Electrophysiological Alterations Driving Pain-Associated Spontaneous Activity In Human Sensory Neuron Somata Parallel Alterations Described In Spontaneously Active Rodent Nociceptors, Robert Y North, Max A Odem, Yan Li, Claudio Esteves Tatsui, Ryan M Cassidy, Patrick M Dougherty, Edgar T Walters

Faculty, Staff and Student Publications

Neuropathic pain in rodents can be driven by ectopic spontaneous activity (SA) generated by sensory neurons in dorsal root ganglia (DRG). The recent demonstration that SA in dissociated human DRG neurons is associated with reported neuropathic pain in patients enables a detailed comparison of pain-linked electrophysiological alterations driving SA in human DRG neurons to alterations that distinguish SA in nociceptors from SA in low-threshold mechanoreceptors (LTMRs) in rodent neuropathy models. Analysis of recordings from dissociated somata of patient-derived DRG neurons showed that SA and corresponding pain in both sexes were significantly associated with the three functional electrophysiological alterations sufficient to …

3’Utr Shortening Of Has2 Promotes Hyaluronan Hyper-Synthesis And Bioenergetic Dysfunction In Pulmonary Hypertension, Victor Tseng, Scott D Collum, Ayed Allawzi, Kathryn Crotty, Samantha Yeligar, Aaron Trammell, M Ryan Smith, Bum-Yong Kang, Roy L Sutliff, Jennifer L Ingram, Soma S S K Jyothula, Rajarajan A Thandavarayan, Howard J Huang, Eva S Nozik, Eric J Wagner, C Michael Hart, Harry Karmouty-Quintana

Faculty, Staff and Student Publications

Pulmonary hypertension (PH) comprises a diverse group of disorders that share a common pathway of pulmonary vascular remodeling leading to right ventricular failure. Development of anti-remodeling strategies is an emerging frontier in PH therapeutics that requires a greater understanding of the interactions between vascular wall cells and their extracellular matrices. The ubiquitous matrix glycan, hyaluronan (HA), is markedly elevated in lungs from patients and experimental models with PH. Herein, we identified HA synthase-2 (HAS2) in the pulmonary artery smooth muscle cell (PASMC) layer as a predominant locus of HA dysregulation. HA upregulation involves depletion of NUDT21, a master regulator of …

Dynamic Expression Of Schlafen 11 (Slfn11) In Circulating Tumour Cells As A Liquid Biomarker In Small Cell Lung Cancer, Bingnan Zhang, C Allison Stewart, Qi Wang, Robert J Cardnell, Pedro Rocha, Junya Fujimoto, Luisa M Solis Soto, Runsheng Wang, Veronica Novegil, Peter Ansell, Lei He, Luisa Fernandez, Adam Jendrisak, Cole Gilbertson, Joseph D Schonhoft, Jiyun Byun, Joshua Jones, Amanda K L Anderson, Ana Aparicio, Hai Tran, Marcelo V Negrao, Jianjun Zhang, Wei-Lien Wang, Ignacio I Wistuba, Jing Wang, Rick Wenstrup, Lauren A Byers, Carl M Gay

Faculty, Staff and Student Publications

Introduction: Small cell lung cancer (SCLC) is an aggressive malignancy with no established biomarkers. Schlafen 11(SLFN11), a DNA/RNA helicase that sensitises cancer cells to DNA-damaging agents, has emerged as a promising predictive biomarker for several drug classes including platinum and PARP inhibitors. Detection of SLFN11 in circulating tumour cells (CTCs) may provide a valuable alternative to tissue sampling.

Methods: SLFN11 expression was evaluated in tumour samples and characterised in circulating tumour cells (CTC) longitudinally to determine its potential role as a biomarker of response.

Results: Among 196 SCLC tumours, 51% expressed SLFN11 by IHC. In addition, 20/29 extra-thoracic high-grade neuroendocrine …