Medical Genetics Commons^™

Miracle Of Microrna-Driven Cancer Nanotherapeutics, Goknur Kara, Banu Arun, George A Calin, Bulent Ozpolat

Faculty, Staff and Student Publications

MicroRNAs (miRNAs) are non-protein-coding RNA molecules 20-25 nucleotides in length that can suppress the expression of genes involved in numerous physiological processes in cells. Accumulating evidence has shown that dysregulation of miRNA expression is related to the pathogenesis of various human diseases and cancers. Thus, stragegies involving either restoring the expression of tumor suppressor miRNAs or inhibiting overexpressed oncogenic miRNAs hold potential for targeted cancer therapies. However, delivery of miRNAs to tumor tissues is a challenging task. Recent advances in nanotechnology have enabled successful tumor-targeted delivery of miRNA therapeutics through newly designed nanoparticle-based carrier systems. As a result, miRNA therapeutics …

Identification Of The Nrf2 Transcriptional Network As A Therapeutic Target For Trigeminal Neuropathic Pain, Chirag Vasavda, Risheng Xu, Jason Liew, Ruchita Kothari, Ryan S Dhindsa, Evan R Semenza, Bindu D Paul, Dustin P Green, Mark F Sabbagh, Joseph Y Shin, Wuyang Yang, Adele M Snowman, Lauren K Albacarys, Abhay Moghekar, Carlos A Pardo-Villamizar, Mark Luciano, Judy Huang, Chetan Bettegowda, Shawn G Kwatra, Xinzhong Dong, Michael Lim, Solomon H Snyder

Duncan NRI Faculty and Staff Publications

Trigeminal neuralgia, historically dubbed the "suicide disease," is an exceedingly painful neurologic condition characterized by sudden episodes of intense facial pain. Unfortunately, the only U.S. Food and Drug Administration (FDA)-approved medication for trigeminal neuralgia carries substantial side effects, with many patients requiring surgery. Here, we identify the NRF2 transcriptional network as a potential therapeutic target. We report that cerebrospinal fluid from patients with trigeminal neuralgia accumulates reactive oxygen species, several of which directly activate the pain-transducing channel TRPA1. Similar to our patient cohort, a mouse model of trigeminal neuropathic pain also exhibits notable oxidative stress. We discover that stimulating the …

The Value Of In Vivo Reflectance Confocal Microscopy As An Assessment Tool In Chemotherapy-Induced Peripheral Neuropathy: A Pilot Study, Sabrina R Ramnarine, Patrick M Dougherty, Roman Rolke, Linda J Williams, Christi Alessi-Fox, Andrew J Coleman, Caterina Longo, Lesley A Colvin, Marie T Fallon

Faculty, Staff and Student Publications

Background: There is a lack of standardized objective and reliable assessment tools for chemotherapy-induced peripheral neuropathy (CIPN). In vivo reflectance confocal microscopy (RCM) imaging offers a non-invasive method to identify peripheral neuropathy markers, namely Meissner's corpuscles (MC). This study investigated the feasibility and value of RCM in CIPN.

Patients and methods: Reflectance confocal microscopy was performed on the fingertip to evaluate MC density in 45 healthy controls and 9 patients with cancer (prior, during, and post-chemotherapy). Quantification was completed by 2 reviewers (one blinded), with maximum MC count/3 × 3 mm image reported. Quantitative Sensory Testing (QST; thermal and mechanical …

Adaptation And Dosimetric Commissioning Of A Synchrotron-Based Proton Beamline For Flash Experiments, Ming Yang, Xiaochun Wang, Fada Guan, Uwe Titt, Kiminori Iga, Dadi Jiang, Takeshi Takaoka, Satoshi Tootake, Tadashi Katayose, Masumi Umezawa, Emil Schüler, Steven Frank, Steven H Lin, Narayan Sahoo, Albert C Koong, Radhe Mohan, X Ronald Zhu

Faculty, Staff and Student Publications

Objective. Irradiation with ultra-high dose rates (>40 Gy s^-1), also known as FLASH irradiation, has the potential to shift the paradigm of radiation therapy because of its reduced toxicity to normal tissues compared to that of conventional irradiations. The goal of this study was to (1) achieve FLASH irradiation conditions suitable for pre-clinicalin vitroandin vivobiology experiments using our synchrotron-based proton beamline and (2) commission the FLASH irradiation conditions achieved.

Approach. To achieve these suitable FLASH conditions, we made a series of adaptations to our proton beamline, including modifying the spill length …

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 …

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), …

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 …

Robust And Efficient Assessment Of Potency (Reap) As A Quantitative Tool For Dose-Response Curve Estimation, Shouhao Zhou, Xinyi Liu, Xinying Fang, Vernon M Chinchilli, Michael Wang, Hong-Gang Wang, Nikolay V Dokholyan, Chan Shen, J Jack Lee

Faculty, Staff and Student Publications

The median-effect equation has been widely used to describe the dose-response relationship and identify compounds that activate or inhibit specific disease targets in contemporary drug discovery. However, the experimental data often contain extreme responses, which may significantly impair the estimation accuracy and impede valid quantitative assessment in the standard estimation procedure. To improve the quantitative estimation of the dose-response relationship, we introduce a novel approach based on robust beta regression. Substantive simulation studies under various scenarios demonstrate solid evidence that the proposed approach consistently provides robust estimation for the median-effect equation, particularly when there are extreme outcome observations. Moreover, simulation …

Muscle And Adipose Tissue Segmentations At The Third Cervical Vertebral Level In Patients With Head And Neck Cancer, Kareem A Wahid, Brennan Olson, Rishab Jain, Aaron J Grossberg, Dina El-Habashy, Cem Dede, Vivian Salama, Moamen Abobakr, Abdallah S R Mohamed, Renjie He, Joel Jaskari, Jaakko Sahlsten, Kimmo Kaski, Clifton D Fuller, Mohamed A Naser

Faculty, Staff and Student Publications

The accurate determination of sarcopenia is critical for disease management in patients with head and neck cancer (HNC). Quantitative determination of sarcopenia is currently dependent on manually-generated segmentations of skeletal muscle derived from computed tomography (CT) cross-sectional imaging. This has prompted the increasing utilization of machine learning models for automated sarcopenia determination. However, extant datasets currently do not provide the necessary manually-generated skeletal muscle segmentations at the C3 vertebral level needed for building these models. In this data descriptor, a set of 394 HNC patients were selected from The Cancer Imaging Archive, and their skeletal muscle and adipose tissue was …

Weight Maintenance, A Prognostic Factor That Mediates The Incidence Of Dementia: From Genetics To Etiologies, Sunny Chen

All Dissertations

Objectives: Alzheimer’s disease-related dementia is a devastating neurodegenerative disease that affects millions of people. The goal of this work is to investigate biological mechanisms such as weight loss and mitochondrial function that can serve as prognostic factors for dementia, healthy aging, and longevity.

Methodologies: This work consists of two separate systematic literature reviews, and an investigational study. The first review examined existing studies on weight trends in dementia. The second review investigated the role of mitochondria and its associated gene TOMM40 in aging. The third paper included a nested case control analysis of weight change patterns before and …

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 …

Unlocking The Pediatric Transcriptome: A Combinatorial Approach For Total Rna Analysis, William Schleif

All Dissertations

The transcriptome is an oft-studied target in the pursuit to better understand the functional elements of the human genome as part of genomic research. The transcriptome possesses its own unique set of challenges that hamper utilization of RNA-based discoveries and translation into actionable findings. Scientific progress thus far has expanded annotated reference genes for protein-coding and non-coding (nc) regulatory transcripts, yet much of the variation from splicing events or retention of other regions remain an open challenge, especially in children. This dissertation explores the current state of diagnostic and methodological barriers in front of the full unlocking of the transcriptome, …

Genetics And Genomics Education Among Physician Assistants, Wesley Patterson

All Dissertations

This dissertation comprises five chapters to describe genetics and genomics education among physician assistant/associate (PA) students and practicing PAs. Chapter I introduces the gap in supply and demand of genetic services, the need for non-genetics healthcare providers to fill the gap, and the PA profession as a solution.

Chapter II is a rapid literature review that summarizes the available literature regarding genetics and genomics education for PAs. A paucity of literature exists to describe the current state of PA genetics-genomics education. The few studies retrieved describe content being taught in PA programs, the number of genetics-genomics contact hours PA students …

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 …

Ankle2-Related Microcephaly: A Variable Microcephaly Syndrome Resembling Zika Infection, Ajay X Thomas, Nichole Link, Laurie A Robak, Gail Demmler-Harrison, Emily C Pao, Audrey E Squire, Savannah Michels, Julie S Cohen, Anne Comi, Paolo Prontera, Alberto Verrotti Di Pianella, Giuseppe Di Cara, Livia Garavelli, Stefano Giuseppe Caraffi, Carlo Fusco, Roberta Zuntini, Kendall C Parks, Elliott H Sherr, Mais O Hashem, Sateesh Maddirevula, Fowzan S Alkuraya, Isphana A F Contractar, Jennifer E Neil, Christopher A Walsh, Hugo J Bellen, Hsiao-Tuan Chao, Robin D Clark, Ghayda M Mirzaa

Duncan NRI Faculty and Staff Publications

Objective: This study delineates the clinical and molecular spectrum of ANKLE2-related microcephaly (MIC), as well as highlights shared pathological mechanisms between ANKLE2 and the Zika virus.

Methods: We identified 12 individuals with MIC and variants in ANKLE2 with a broad range of features. Probands underwent thorough phenotypic evaluations, developmental assessments, and anthropometric measurements. Brain imaging studies were systematically reviewed for developmental abnormalities. We functionally interrogated a subset of identified ANKLE2 variants in Drosophila melanogaster.

Results: All individuals had MIC (z-score ≤ -3), including nine with congenital MIC. We identified a broad range of brain abnormalities including simplified cortical gyral pattern, …

Ablation Of Long Noncoding Rna Malat1 Activates Antioxidant Pathway And Alleviates Sepsis In Mice, Jingshu Chen, Shu Tang, Sui Ke, James J Cai, Daniel Osorio, Andrei Golovko, Benjamin Morpurgo, Shaodong Guo, Yuxiang Sun, Melanie Winkle, George A Calin, Yanan Tian

Faculty, Staff and Student Publications

The metastasis-associated lung adenocarcinoma transcript1 (MALAT1) is a long noncoding RNA (lncRNA) and is known for its role in cancer development and prognosis. In this study, we report that MALAT1 plays an important role in regulating acute inflammatory responses in sepsis. In patient samples, MALAT1 expression was positively correlated with severity of sepsis. In cultured macrophages, LPS treatment significantly induced MALAT1 expression, while genetic ablation of MALAT1 greatly reduced proinflammatory cytokine levels. Furthermore, MALAT1-ablated mice had significantly increased survival rates in cecal ligation and puncture (CLP)-induced sepsis and LPS-induced endotoxemia. One novel and salient feature of MALAT1-ablated mice is greatly …

Sexual Orientation And Gender Identity Data Collection In Oncology Practice: Findings Of An Asco Survey, Charles S Kamen, Mandi L Pratt-Chapman, Stephen C Meersman, Gwendolyn P Quinn, Matthew B Schabath, Shail Maingi, Janette K Merrill, Elizabeth Garrett-Mayer, Melinda Kaltenbaugh, Caroline Schenkel, Shine Chang

Faculty, Staff and Student Publications

Purpose: Lack of collection of sexual orientation and gender identity (SOGI) data in oncology practices limits assessment of sexual and gender minority (SGM) cancer patients' experiences and restricts opportunities to improve health outcomes of SGM patients. Despite national calls for routine SOGI data collection, individual-level and institutional barriers hinder progress. This study aimed to identify these barriers in oncology.

Methods: An online survey of ASCO members and others assessed SOGI data collection in oncology practices, institutional characteristics related to SOGI data collection, respondents' attitudes about SOGI data and SGM patients, and respondent demographics. Logistic regression calculated adjusted odds ratios (ORs) …

Acylcarnitines And Genetic Variation In Fat Oxidation Genes In Hiv-Infected, Antiretroviral-Treated Children With And Without Myopathy, Brian Kirmse, Charlotte Hobbs, Lisa Aaron, Grace Montepiedra, Marshall Summar, Paige L Williams, Caitlin J Smith, Russell Van Dyke, Chunli Yu, Kelli K Ryckman, William Borkowsky

Faculty, Staff and Student Publications

BACKGROUND: Mitochondrial toxicity resulting in myopathy and lactic acidosis has been described in antiretroviral (ARV)-exposed patients. We hypothesized that myopathy in HIV-infected, ARV-treated children would be associated with metabolic (acylcarnitines) and genetic (variants in metabolic genes) markers of dysfunctional fatty acid oxidation (FAO).

METHODS: Acylcarnitine profiles (ACP) were analyzed for 74 HIV-infected children on nucleoside reverse transcriptase inhibitor (NRTI)-containing ARV. Thirty-seven participants with ≥2 creatine kinase measurements >500 IU (n = 18) or evidence of echocardiographic cardiomyopathy (n = 19) were matched with 37 participants without myopathy. Single nucleotide polymorphisms (SNPs) in FAO genes were also evaluated.

RESULTS: Abnormal ACP …

Clinical Research In Ovarian Cancer: Consensus Recommendations From The Gynecologic Cancer Intergroup, Ignace Vergote, Antonio Gonzalez-Martin, Domenica Lorusso, Charlie Gourley, Mansoor Raza Mirza, Jean-Emmanuel Kurtz, Aikou Okamoto, Kathleen Moore, Frédéric Kridelka, Iain Mcneish, Alexander Reuss, Bénédicte Votan, Andreas Du Bois, Sven Mahner, Isabelle Ray-Coquard, Elise C Kohn, Jonathan S Berek, David S P Tan, Nicoletta Colombo, Rongyu Zang, Nicole Concin, Dearbhaile O'Donnell, Alejandro Rauh-Hain, C Simon Herrington, Christian Marth, Andres Poveda, Keiichi Fujiwara, Gavin C E Stuart, Amit M Oza, Michael A Bookman, Participants Of The 6th Gynecologic Cancer Intergroup (Gcig) Ovarian Cancer Consensus Conference On Clinical Research

Faculty, Staff and Student Publications

The Gynecologic Cancer InterGroup (GCIG) sixth Ovarian Cancer Conference on Clinical Research was held virtually in October, 2021, following published consensus guidelines. The goal of the consensus meeting was to achieve harmonisation on the design elements of upcoming trials in ovarian cancer, to select important questions for future study, and to identify unmet needs. All 33 GCIG member groups participated in the development, refinement, and adoption of 20 statements within four topic groups on clinical research in ovarian cancer including first line treatment, recurrent disease, disease subgroups, and future trials. Unanimous consensus was obtained for 14 of 20 statements, with …

Novel Mitochondria-Targeting Compounds Selectively Kill Human Leukemia Cells, Svetlana B Panina, Jingqi Pei, Natalia Baran, Elissa Tjahjono, Shraddha Patel, Gheath Alatrash, Sergej Konoplev, Leonid A Stolbov, Vladimir V Poroikov, Marina Konopleva, Natalia V Kirienko

Faculty, Staff and Student Publications

Acute myeloid leukemia (AML) is a heterogeneous group of aggressive hematological malignancies commonly associated with treatment resistance, high risk of relapse, and mitochondrial dysregulation. We identified six mitochondria-affecting compounds (PS compounds) that exhibit selective cytotoxicity against AML cells in vitro. Structure-activity relationship studies identified six analogs from two original scaffolds that had over an order of magnitude difference between LD50 in AML and healthy peripheral blood mononuclear cells. Mechanistically, all hit compounds reduced ATP and selectively impaired both basal and ATP-linked oxygen consumption in leukemic cells. Compounds derived from PS127 significantly upregulated production of reactive oxygen species (ROS) in AML …

Advances In Head And Neck Cancer Pain, Y Ye, D D Jensen, C T Viet, H L Pan, W M Campana, M Amit, M D Boada

Faculty, Staff and Student Publications

Head and neck cancer (HNC) affects over 890,000 people annually worldwide and has a mortality rate of 50%. Aside from poor survival, HNC pain impairs eating, drinking, and talking in patients, severely reducing quality of life. Different pain phenotype in patients (allodynia, hyperalgesia, and spontaneous pain) results from a combination of anatomical, histopathological, and molecular differences between cancers. Poor pathologic features (e.g., perineural invasion, lymph node metastasis) are associated with increased pain. The use of syngeneic/immunocompetent animal models, as well as a new mouse model of perineural invasion, provides novel insights into the pathobiology of HNC pain. Glial and immune …

Preventing Cholesterol-Induced Perk (Protein Kinase Rna-Like Endoplasmic Reticulum Kinase) Signaling In Smooth Muscle Cells Blocks Atherosclerotic Plaque Formation, Abhijnan Chattopadhyay, Pujun Guan, Suravi Majumder, Kaveeta Kaw, Zhen Zhou, Chen Zhang, Siddharth K Prakash, Anita Kaw, L Maximillian Buja, Callie S Kwartler, Dianna M Milewicz

Faculty, Staff and Student Publications

BACKGROUND: Vascular smooth muscle cells (SMCs) undergo complex phenotypic modulation with atherosclerotic plaque formation in hyperlipidemic mice, which is characterized by de-differentiation and heterogeneous increases in the expression of macrophage, fibroblast, osteogenic, and stem cell markers. An increase of cellular cholesterol in SMCs triggers similar phenotypic changes in vitro with exposure to free cholesterol due to cholesterol entering the endoplasmic reticulum, triggering endoplasmic reticulum stress and activating Perk (protein kinase RNA-like endoplasmic reticulum kinase) signaling.

METHODS: We generated an SMC-specific

RESULTS: SMC-specific deletion of Perk reduces atherosclerotic plaque formation in male hyperlipidemic mice by 80%. Single-cell transcriptomic data identify 2 …

Unilateral Radiation Therapy For Tonsillar Cancer: Treatment Outcomes In The Era Of Human Papillomavirus, Positron-Emission Tomography, And Intensity Modulated Radiation Therapy, Nicolette Taku, Gregory Chronowski, G Brandon Gunn, William H Morrison, Neil D Gross, Amy C Moreno, Renata Ferrarotto, Steven J Frank, C David Fuller, Ryan P Goepfert, Jack Phan, Stephen Y Lai, Jay P Reddy, David I Rosenthal, Adam S Garden

Faculty, Staff and Student Publications

Purpose: The goal of this study was to evaluate disease, survival, and toxic effects after unilateral radiation therapy treatment for tonsillar cancer.

Methods and materials: A retrospective study was performed of patients treated at our institution within the period from 2000 to 2018. Summary statistics were used to assess the cohort by patient characteristics and treatments delivered. The Kaplan-Meier method was used to determine survival outcomes.

Results: The cohort comprised 403 patients, including 343 (85%) with clinical and/or radiographic evidence of ipsilateral cervical nodal disease and 181 (45%) with multiple involved nodes. Human papillomavirus was detected in 294 (73%) tumors. …

Aapm Task Group Report 303 Endorsed By The Abs: Mri Implementation In Hdr Brachytherapy-Considerations From Simulation To Treatment, Joann Prisciandaro, Jacqueline Esthappan Zoberi, Gil'ad Cohen, Yusung Kim, Perry Johnson, Eric Paulson, William Song, Ken-Pin Hwang, Beth Erickson, Sushil Beriwal, Christian Kirisits, Firas Mourtada

Faculty, Staff and Student Publications

The task group (TG) on magnetic resonance imaging (MRI) implementation in high-dose-rate (HDR) brachytherapy (BT)-Considerations from simulation to treatment, TG 303, was constituted by the American Association of Physicists in Medicine's (AAPM's) Science Council under the direction of the Therapy Physics Committee, the Brachytherapy Subcommittee, and the Working Group on Brachytherapy Clinical Applications. The TG was charged with developing recommendations for commissioning, clinical implementation, and on-going quality assurance (QA). Additionally, the TG was charged with describing HDR BT workflows and evaluating practical consideration that arise when implementing MR imaging. For brevity, the report is focused on the treatment of gynecologic …

Pulmonary Fibrosis Model Using Micro-Ct Analyzable Human Psc-Derived Alveolar Organoids Containing Alveolar Macrophage-Like Cells, Seri Choi, Jiwoong Choi, Seongmin Cheon, Jihong Song, Seung-Yeon Kim, Ji-Eun Kim, Dae-Hwan Nam, Gohar Manzar, Su-Man Kim, Hyung-Sik Kang, Kee K Kim, Sang Hoon Jeong, Ju-Han Lee, Eun-Kee Park, Minseob Lee, Hyang-Ae Lee, Ki-Suk Kim, Han-Jin Park, Won Keun Oh, Chungoo Park, Chang Hyun Lee, Eun-Mi Kim

Faculty, Staff and Student Publications

Human lung organoids (hLOs) are useful for disease modelling and drug screening. However, a lack of immune cells in hLOs limits the recapitulation of in vivo cellular physiology. Here, we generated hLOs containing alveolar macrophage (AMφ)-like cells derived from pluripotent stem cells (PSC). To bridge hLOs with advanced human lung high-resolution X-ray computed tomography (CT), we acquired quantitative micro-CT images. Three hLO types were observed during differentiation. Among them, alveolar hLOs highly expressed not only lung epithelial cell markers but also AMφ-specific markers. Furthermore, CD68

Vorinostat Combined With Busulfan, Fludarabine, And Clofarabine Conditioning Regimen For Allogeneic Hematopoietic Stem Cell Transplantation In Patients With Acute Leukemia: Long-Term Study Outcomes, Gheath Alatrash, Chantal Saberian, Roland Bassett, Peter F Thall, Celina Ledesma, Yoshimi Lu, May Daher, Benigno C Valdez, Jitesh Kawedia, Uday Popat, Rohtesh Mehta, Betul Oran, Yago Nieto, Amanda Olson, Paolo Anderlini, David Marin, Chitra Hosing, Amin M Alousi, Elizabeth J Shpall, Gabriela Rondon, Julianne Chen, Muzaffar Qazilbash, Richard E Champlin, Partow Kebriaei

Faculty, Staff and Student Publications

Conditioning regimens play a major role in determining disease outcomes following allogeneic hematopoietic stem cell transplantation (allo-HSCT). The use of i.v. busulfan (Bu) as part of conditioning chemotherapy has been shown to be effective in controlling disease relapse; however, disease relapse remains a major cause of death following allo-HSCT. This study was conducted to determine the long-term outcomes of vorinostat with i.v. Bu plus dual nucleoside analogs clofarabine (Clo) and fludarabine (Flu) in the conditioning regimen for patients undergoing allo-HSCT. This was a rapid dose escalation phase I/II study designed to determine whether the addition of vorinostat would improve the …

Discovery Of A Drug To Treat Airway Mucus Hypersecretion, Burton F Dickey, Ying Lai, Manfred Frick, Axel T Brunger

Faculty, Staff and Student Publications

No abstract provided.

Racial And Ethnic Trends And Disparities In Nsclc, Kristin M Primm, Hui Zhao, Daphne C Hernandez, Shine Chang

Faculty, Staff and Student Publications

Introduction: Detailed evaluations of racial and ethnic trends and disparities in NSCLC outcomes are lacking, and it remains unclear whether recent advances in screening and targeted therapies for NSCLC have benefited all population groups equally.

Methods: Using the Surveillance, Epidemiology, and End Results 18-registry data, we evaluated trends in overall and stage-specific NSCLC incidence (2007-2018) among patients aged 55 to 79 years by sex and race and ethnicity. Overall and stage-specific 2-year cause-specific survival rates were calculated by sex and race and ethnicity. Health Disparities software calculated absolute (difference) and relative (ratio) disparity measures comparing racial and ethnic groups with …

Pathways And Barriers To Careers In Academic Clinical Cancer Prevention: A Qualitative Study, Melissa Y Kok, Janelle C Chavez, Pompeyo R Quesada, Oluwapelumi T Adegoke, Shine Chang

Faculty, Staff and Student Publications

National surveys document steady declines over time in interest in academic medicine and cancer prevention careers (Am J Prev Med 54(3):444-8, 2018). Through interviews with 16 academic cancer prevention physicians at one comprehensive cancer center, this study identifies motivations and barriers to physician careers in academic cancer prevention and proposes recommendations to increase recruitment. Participants reported that cancer prevention was vague to them early in training, impairing career exploration. Further, without role models and opportunities to learn about cancer prevention, many were ignorant of career options. Many had incorrect views about cancer prevention practice being mainly within the scope of …