Medicine and Health Sciences Commons^™

Multi-Ancestry Genetic Study Of Type 2 Diabetes Highlights The Power Of Diverse Populations For Discovery And Translation, Anubha Mahajan, Cassandra N Spracklen, Weihua Zhang, Maggie C Y Ng, Lauren E Petty, Hidetoshi Kitajima, Grace Z Yu, Sina Rüeger, Leo Speidel, Young Jin Kim, Momoko Horikoshi, Josep M Mercader, Daniel Taliun, Sanghoon Moon, Soo-Heon Kwak, Neil R Robertson, Nigel W Rayner, Marie Loh, Bong-Jo Kim, Joshua Chiou, Irene Miguel-Escalada, Pietro Della Briotta Parolo, Kuang Lin, Fiona Bragg, Michael H Preuss, Fumihiko Takeuchi, Jana Nano, Xiuqing Guo, Amel Lamri, Masahiro Nakatochi, Robert A Scott, Jung-Jin Lee, Alicia Huerta-Chagoya, Mariaelisa Graff, Jin-Fang Chai, Esteban J Parra, Jie Yao, Lawrence F Bielak, Yasuharu Tabara, Yang Hai, Valgerdur Steinthorsdottir, James P Cook, Mart Kals, Niels Grarup, Ellen M Schmidt, Ian Pan, Tamar Sofer, Matthias Wuttke, Chloe Sarnowski, Christian Gieger, Darryl Nousome, Stella Trompet, Jirong Long, Meng Sun, Lin Tong, Wei-Min Chen, Meraj Ahmad, Raymond Noordam, Victor J Y Lim, Claudia H T Tam, Yoonjung Yoonie Joo, Chien-Hsiun Chen, Laura M Raffield, Cécile Lecoeur, Bram Peter Prins, Aude Nicolas, Lisa R Yanek, Guanjie Chen, Richard A Jensen, Salman Tajuddin, Edmond K Kabagambe, Ping An, Anny H Xiang, Hyeok Sun Choi, Brian E Cade, Jingyi Tan, Jack Flanagan, Fernando Abaitua, Linda S Adair, Adebowale Adeyemo, Carlos A Aguilar-Salinas, Masato Akiyama, Sonia S Anand, Alain Bertoni, Zheng Bian, Jette Bork-Jensen, Ivan Brandslund, Jennifer A Brody, Chad M Brummett, Thomas A Buchanan, Mickaël Canouil, Juliana C N Chan, Li-Ching Chang, Miao-Li Chee, Ji Chen, Shyh-Huei Chen, Yuan-Tsong Chen, Zhengming Chen, Lee-Ming Chuang, Mary Cushman, Swapan K Das, H Janaka De Silva, George Dedoussis, Latchezar Dimitrov, Ayo P Doumatey, Shufa Du, Qing Duan, Kai-Uwe Eckardt, Leslie S Emery, Daniel S Evans, Michele K Evans, Krista Fischer, James S Floyd, Ian Ford, Myriam Fornage, Oscar H Franco, Timothy M Frayling, Barry I Freedman, Christian Fuchsberger, Pauline Genter, Hertzel C Gerstein, Vilmantas Giedraitis, Clicerio González-Villalpando, Maria Elena González-Villalpando, Mark O Goodarzi, Penny Gordon-Larsen, David Gorkin, Myron Gross, Yu Guo, Sophie Hackinger, Sohee Han, Andrew T Hattersley, Christian Herder, Annie-Green Howard, Willa Hsueh, Mengna Huang, Wei Huang, Yi-Jen Hung, Mi Yeong Hwang, Chii-Min Hwu, Sahoko Ichihara, Mohammad Arfan Ikram, Martin Ingelsson, Md Tariqul Islam, Masato Isono, Hye-Mi Jang, Farzana Jasmine, Guozhi Jiang, Jost B Jonas, Marit E Jørgensen, Torben Jørgensen, Yoichiro Kamatani, Fouad R Kandeel, Anuradhani Kasturiratne, Tomohiro Katsuya, Varinderpal Kaur, Takahisa Kawaguchi, Jacob M Keaton, Abel N Kho, Chiea-Chuen Khor, Muhammad G Kibriya, Duk-Hwan Kim, Katsuhiko Kohara, Jennifer Kriebel, Florian Kronenberg, Johanna Kuusisto, Kristi Läll, Leslie A Lange, Myung-Shik Lee, Nanette R Lee, Aaron Leong, Liming Li, Yun Li, Ruifang Li-Gao, Symen Ligthart, Cecilia M Lindgren, Allan Linneberg, Ching-Ti Liu, Jianjun Liu, Adam E Locke, Tin Louie, Jian'an Luan, Andrea O Luk, Xi Luo, Jun Lv, Valeriya Lyssenko, Vasiliki Mamakou, K Radha Mani, Thomas Meitinger, Andres Metspalu, Andrew D Morris, Girish N Nadkarni, Jerry L Nadler, Michael A Nalls, Uma Nayak, Suraj S Nongmaithem, Ioanna Ntalla, Yukinori Okada, Lorena Orozco, Sanjay R Patel, Mark A Pereira, Annette Peters, Fraser J Pirie, Bianca Porneala, Gauri Prasad, Sebastian Preissl, Laura J Rasmussen-Torvik, Alexander P Reiner, Michael Roden, Rebecca Rohde, Kathryn Roll, Charumathi Sabanayagam, Maike Sander, Kevin Sandow, Naveed Sattar, Sebastian Schönherr, Claudia Schurmann, Mohammad Shahriar, Jinxiu Shi, Dong Mun Shin, Daniel Shriner, Jennifer A Smith, Wing Yee So, Alena Stančáková, Adrienne M Stilp, Konstantin Strauch, Ken Suzuki, Atsushi Takahashi, Kent D Taylor, Barbara Thorand, Gudmar Thorleifsson, Unnur Thorsteinsdottir, Brian Tomlinson, Jason M Torres, Fuu-Jen Tsai, Jaakko Tuomilehto, Teresa Tusie-Luna, Miriam S Udler, Adan Valladares-Salgado, Rob M Van Dam, Jan B Van Klinken, Rohit Varma, Marijana Vujkovic, Niels Wacher-Rodarte, Eleanor Wheeler, Eric A Whitsel, Ananda R Wickremasinghe, Ko Willems Van Dijk, Daniel R Witte, Chittaranjan S Yajnik, Ken Yamamoto, Toshimasa Yamauchi, Loïc Yengo, Kyungheon Yoon, Canqing Yu, Jian-Min Yuan, Salim Yusuf, Liang Zhang, Wei Zheng, Finngen, Emerge Consortium, Leslie J Raffel, Michiya Igase, Eli Ipp, Susan Redline, Yoon Shin Cho, Lars Lind, Michael A Province, Craig L Hanis, Patricia A Peyser, Erik Ingelsson, Alan B Zonderman, Bruce M Psaty, Ya-Xing Wang, Charles N Rotimi, Diane M Becker, Fumihiko Matsuda, Yongmei Liu, Eleftheria Zeggini, Mitsuhiro Yokota, Stephen S Rich, Charles Kooperberg, James S Pankow, James C Engert, Yii-Der Ida Chen, Philippe Froguel, James G Wilson, Wayne H H Sheu, Sharon L R Kardia, Jer-Yuarn Wu, M Geoffrey Hayes, Ronald C W Ma, Tien-Yin Wong, Leif Groop, Dennis O Mook-Kanamori, Giriraj R Chandak, Francis S Collins, Dwaipayan Bharadwaj, Guillaume Paré, Michèle M Sale, Habibul Ahsan, Ayesha A Motala, Xiao-Ou Shu, Kyong-Soo Park, J Wouter Jukema, Miguel Cruz, Roberta Mckean-Cowdin, Harald Grallert, Ching-Yu Cheng, Erwin P Bottinger, Abbas Dehghan, E-Shyong Tai, Josée Dupuis, Norihiro Kato, Markku Laakso, Anna Köttgen, Woon-Puay Koh, Colin N A Palmer, Simin Liu, Goncalo Abecasis, Jaspal S Kooner, Ruth J F Loos, Kari E North, Christopher A Haiman, Jose C Florez, Danish Saleheen, Torben Hansen, Oluf Pedersen, Reedik Mägi, Claudia Langenberg, Nicholas J Wareham, Shiro Maeda, Takashi Kadowaki, Juyoung Lee, Iona Y Millwood, Robin G Walters, Kari Stefansson, Simon R Myers, Jorge Ferrer, Kyle J Gaulton, James B Meigs, Karen L Mohlke, Anna L Gloyn, Donald W Bowden, Jennifer E Below, John C Chambers, Xueling Sim, Michael Boehnke, Jerome I Rotter, Mark I Mccarthy, Andrew P Morris

Faculty, Staff and Student Publications

We assembled an ancestrally diverse collection of genome-wide association studies (GWAS) of type 2 diabetes (T2D) in 180,834 affected individuals and 1,159,055 controls (48.9% non-European descent) through the Diabetes Meta-Analysis of Trans-Ethnic association studies (DIAMANTE) Consortium. Multi-ancestry GWAS meta-analysis identified 237 loci attaining stringent genome-wide significance (P < 5 × 10-9), which were delineated to 338 distinct association signals. Fine-mapping of these signals was enhanced by the increased sample size and expanded population diversity of the multi-ancestry meta-analysis, which localized 54.4% of T2D associations to a single variant with >50% posterior probability. This improved fine-mapping enabled systematic assessment of candidate causal genes and molecular mechanisms through which T2D associations are mediated, laying the foundations for functional investigations. Multi-ancestry genetic risk scores enhanced transferability of T2D prediction across diverse populations. Our study provides a step toward more effective clinical translation of T2D GWAS …

Natural Killer Cells In Liver Transplantation: Can We Harness The Power Of The Immune Checkpoint To Promote Tolerance?, Jennifer Halma, Stephen Pierce, Rebecca Mclennan, Todd Bradley, Ryan T. Fischer

Manuscripts, Articles, Book Chapters and Other Papers

The roles that natural killer (NK) cells play in liver disease and transplantation remain ill-defined. Reports on the matter are often contradictory, and the mechanisms elucidated are complex and dependent on the context of the model tested. Moreover, NK cell attributes, such as receptor protein expression and function differ among species, make study of primate or rodent transplant models challenging. Recent insights into NK function and NK-mediated therapy in the context of cancer therapy may prove applicable to transplantation. Of specific interest are immune checkpoint molecules and the mechanisms by which they modulate NK cells in the tumor micro-environment. In …

Building Capacity For Cancer Research In The Era Of Covid-19: Implementation And Results From An International Virtual Clinical Research Training Program In Zambia, Kevin Diao, Dorothy C Lombe, Catherine K Mwaba, Juliana Wu, Darya A Kizub, Carrie A Cameron, Elizabeth Y Chiao, Susan C Msadabwe, Lilie L Lin

Faculty, Staff and Student Publications

Purpose: The incidence of cancer in sub-Saharan Africa is increasing rapidly, yet cancer research in the region continues to lag. One contributing factor is limited exposure to clinical research among trainees. We describe implementation and results of a virtual clinical research training program for Zambian clinical oncology fellows developed jointly by the Cancer Diseases Hospital in Zambia and the MD Anderson Cancer Center to address this need.

Methods: The clinical research training program consisted of 14 weekly virtual lectures, development of research questions by Zambian clinical oncology fellows, assignment of faculty and peer mentors, longitudinal mentorship of research protocols, and …

Chromatin State Dynamics Confers Specific Therapeutic Strategies In Enhancer Subtypes Of Colorectal Cancer, Elias Orouji, Ayush T Raman, Anand K Singh, Alexey Sorokin, Emre Arslan, Archit K Ghosh, Jonathan Schulz, Christopher Terranova, Shan Jiang, Ming Tang, Mayinuer Maitituoheti, Scot C Callahan, Praveen Barrodia, Katarzyna Tomczak, Yingda Jiang, Zhiqin Jiang, Jennifer S Davis, Sukhen Ghosh, Hey Min Lee, Laura Reyes-Uribe, Kyle Chang, Yusha Liu, Huiqin Chen, Ali Azhdarinia, Jeffrey Morris, Eduardo Vilar, Kendra S Carmon, Scott E Kopetz, Kunal Rai

Faculty, Staff and Student Publications

Objective: Enhancer aberrations are beginning to emerge as a key epigenetic feature of colorectal cancers (CRC), however, a comprehensive knowledge of chromatin state patterns in tumour progression, heterogeneity of these patterns and imparted therapeutic opportunities remain poorly described.

Design: We performed comprehensive epigenomic characterisation by mapping 222 chromatin profiles from 69 samples (33 colorectal adenocarcinomas, 4 adenomas, 21 matched normal tissues and 11 colon cancer cell lines) for six histone modification marks: H3K4me3 for Pol II-bound and CpG-rich promoters, H3K4me1 for poised enhancers, H3K27ac for enhancers and transcriptionally active promoters, H3K79me2 for transcribed regions, H3K27me3 for polycomb repressed regions and …

Whole Exome Sequencing Identifies Potential Candidate Genes For Spina Bifida Derived From Mouse Models, Chunyan Wang, Steve Seltzsam, Bixia Zheng, Chen-Han Wilfred Wu, Camille Nicolas-Frank, Kirollos Yousef, Kit Sing Au, Nina Mann, Dalia Pantel, Sophia Schneider, Luca Schierbaum, Thomas M Kitzler, Dervla M Connaughton, Youying Mao, Rufeng Dai, Makiko Nakayama, Jameela A Kari, Sherif El Desoky, Mohammed Shalaby, Loai A Eid, Hazem S Awad, Velibor Tasic, Shrikant M Mane, Richard P Lifton, Michelle A Baum, Shirlee Shril, Carlos R Estrada, Friedhelm Hildebrandt

Faculty, Staff and Student Publications

Spina bifida (SB) is the second most common nonlethal congenital malformation. The existence of monogenic SB mouse models and human monogenic syndromes with SB features indicate that human SB may be caused by monogenic genes. We hypothesized that whole exome sequencing (WES) allows identification of potential candidate genes by (i) generating a list of 136 candidate genes for SB, and (ii) by unbiased exome-wide analysis. We generated a list of 136 potential candidate genes from three categories and evaluated WES data of 50 unrelated SB cases for likely deleterious variants in 136 potential candidate genes, and for potential SB candidate …

Venetoclax Combined With Induction Chemotherapy In Patients With Newly Diagnosed Acute Myeloid Leukaemia: A Post-Hoc, Propensity Score-Matched, Cohort Study, Curtis A Lachowiez, Patrick K Reville, Hagop Kantarjian, Elias Jabbour, Gautam Borthakur, Naval Daver, Sanam Loghavi, Ken Furudate, Lianchun Xiao, Sherry Pierce, Nicholas J Short, Abhishek Maiti, Musa Yilmaz, Koji Sasaki, Koichi Takahashi, Marina Konopleva, Naveen Pemmaraju, Uday Popat, Elizabeth Shpall, Guillermo Garcia-Manero, Farhad Ravandi, Courtney D Dinardo, Tapan M Kadia

Faculty, Staff and Student Publications

Background: Venetoclax combined with intensive chemotherapy has been shown to be safe with promising activity in fit patients with newly diagnosed acute myeloid leukaemia. The aim of this study was to compare the activity of venetoclax plus intensive chemotherapy with intensive chemotherapy alone.

Methods: This was a post-hoc propensity score matched analysis of prospective clinical trials (NCT03214562, NCT02115295, and NCT01289457) in patients at The University of Texas MD Anderson Cancer Center, Texas, USA between March 29, 2010, and June 15, 2021. Eligible patients were aged 18 years and older, and had newly diagnosed acute myeloid leukaemia …

New Practical Aspects Of Sweet Syndrome, Tejas P Joshi, Sarah K Friske, David A Hsiou, Madeleine Duvic

Faculty, Staff and Student Publications

Sweet syndrome (SS), or acute febrile neutrophilic dermatosis, is an inflammatory, non-infectious skin reaction characterized clinically by tender, erythematous papules/plaques/pustules/nodules commonly appearing on the upper limbs, trunk, and head and neck; histologically, SS is characterized by dense neutrophilic infiltrate in the dermis. SS is accompanied by fever; an elevation of inflammatory markers (e.g., erythrocyte sedimentation rate, C reactive protein) in serum may also be observed. Although most cases of SS are idiopathic, SS also occurs in the setting of malignancy or following administration of an associated drug. SS has also been reported in association with pregnancy and a burgeoning list …

Molecular, Histological, And Clinical Characteristics Of Oligodendrogliomas: A Multi-Institutional Retrospective Study, Antonio Dono, Kristin Alfaro-Munoz, Yuanqing Yan, Carlos A Lopez-Garcia, Zaid Soomro, Garret Williford, Takeshi Takayasu, Lindsay Robell, Nazanin K Majd, John De Groot, Yoshua Esquenazi, Carlos Kamiya-Matsuoka, Leomar Y Ballester

Faculty, Staff and Student Publications

Background: Reports suggest that phosphatidylinositol 3-kinase pathway alterations confer increased risk of progression and poor prognosis in oligodendroglioma, IDH-mutant, and 1p/19q-codeleted molecular oligodendrogliomas (mODG). However, factors that affect prognosis in mODG have not been thoroughly studied. In addition, the benefits of adjuvant radiation and temozolomide (TMZ) in mODGs remain to be determined.

Objective: To evaluate the role of PIK3CA mutations in mODGs.

Methods: One hundred seven mODGs (2008-2019) diagnosed at 2 institutions were included. A retrospective review of clinical characteristics, molecular alterations, treatments, and outcomes was performed.

Results: The median age was 37 years, and 61 patients (57%) were male. …

Genetic Correlates In Patients With Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia Treated With Hyper-Cvad Plus Dasatinib Or Ponatinib, Yuya Sasaki, Hagop M Kantarjian, Nicholas J Short, Feng Wang, Ken Furudate, Hidetaka Uryu, Rebecca Garris, Nitin Jain, Koji Sasaki, Farhad Ravandi, Marina Konopleva, Guillermo Garcia-Manero, Latasha Little, Curtis Gumbs, Li Zhao, P Andrew Futreal, Koichi Takahashi, Elias Jabbour

Faculty, Staff and Student Publications

Recurring genetic abnormalities have been identified in Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL). Among them, IKZF1 deletion was associated with poor prognosis in patients treated with imatinib-based or dasatinib-based regimens. However, the molecular determinants for clinical outcomes in ponatinib-treated patients remain unknown. We systematically analyzed genetic alterations in adults with Ph-positive ALL uniformly treated in clinical trials with dasatinib-based regimens or a ponatinib-based regimen and investigated the molecular determinants for treatment outcomes using pretreatment specimens collected from adults with Ph-positive ALL treated with Hyper-CVAD plus dasatinib or ponatinib. DNA sequencing and SNP microarray were performed and recurrent genetic abnormalities …

Landscape Of Notch1 Mutations And Co-Occurring Biomarker Alterations In Chronic Lymphocytic Leukemia, Fatima Zahra Jelloul, Richard Yang, Sofia Garces, Rashmi Kanagal-Shamanna, Chi Y Ok, Sanam Loghavi, Mark J Routbort, Zhuang Zuo, C Cameron Yin, Kristen Floyd, Roland L Bassett, William Wierda, Nitin Jain, Philip Thompson, Rajyalakshmi Luthra, L Jeffrey Medeiros, Keyur P Patel

Faculty, Staff and Student Publications

NOTCH1 is one of the most frequently mutated genes in chronic lymphocytic leukemia and has emerged as a marker of poor prognosis. In addition to coding NOTCH1 mutations involving exon 34, non-coding NOTCH1 mutations involving the 3' UTR have been described in a limited number of chronic lymphocytic leukemia (CLL) patients and were associated with adverse outcomes. In this study, 1574 CLL patients were assessed using targeted sequencing with a 29 gene panel and the results were correlated with prognostic characteristics. NOTCH1 mutations were detected in 252 (16%) patients, including both coding (220/252, 14%), non-coding (24/252, 1.5%) and a mixture …

Free Cholesterol Bioavailability And Atherosclerosis, Rei J Abe, Jun-Ichi Abe, Minh T H Nguyen, Elizabeth A Olmsted-Davis, Abrar Mamun, Priyanka Banerjee, John P Cooke, Longhou Fang, Henry Pownall, Nhat-Tu Le

Faculty, Staff and Student Publications

Purpose of review: As both a cholesterol acceptor and carrier in the reverse cholesterol transport (RCT) pathway, high-density lipoprotein (HDL) is putatively atheroprotective. However, current pharmacological therapies to increase plasma HDL cholesterol (HDL-c) concentration have paradoxically failed to prevent or reduce atherosclerosis and cardiovascular disease (CVD). Given that free cholesterol (FC) transfer between surfaces of lipoproteins and cells is reversible, excess plasma FC can be transferred to the cells of peripheral tissue sites resulting in atherosclerosis. Here, we summarize potential mechanisms contributing to this paradox and highlight the role of excess free cholesterol (FC) bioavailability in atherosclerosis vs. atheroprotection.

Recent …

Differential Ets1 Binding To T:G Mismatches Within A Cpg Dinucleotide Contributes To C-To-T Somatic Mutation Rate Of The Idh2 Hotspot At Codon Arg140, Jie Yang, Esha Gupta, John R Horton, Robert M Blumenthal, Xing Zhang, Xiaodong Cheng

Faculty, Staff and Student Publications

Cytosine to thymine (C>T) somatic mutation is highly enriched in certain types of cancer, and most commonly occurs via deamination of a 5-methylcytosine (5mC) to thymine, in the context of a CpG dinucleotide. In theory, deamination should occur at equal rates to both 5mC nucleotides on opposite strands. In most cases, the resulting T:G or G:T mismatch can be repaired by thymine DNA glycosylase activities. However, while some hotspot-associated CpG mutations have approximately equal numbers of mutations that resulted either from C>T or G>A in a CpG dinucleotide, many showed strand bias, being skewed toward C>T …

Barriers And Facilitators Of Implementing Automated Radiotherapy Planning: A Multisite Survey Of Low- And Middle-Income Country Radiation Oncology Providers, Gwendolyn J Mcginnis, Matthew S Ning, Beth M Beadle, Nanette Joubert, William Shaw, Christoph Trauernich, Hannah Simonds, Surbhi Grover, Carlos E Cardenas, Laurence E Court, Grace L Smith

Faculty, Staff and Student Publications

Purpose: Global access to radiotherapy (RT) is inequitable, with obstacles to implementing modern technologies in low- and middle- income countries (LMICs). The Radiation Planning Assistant (RPA) is a web-based automated RT planning software package intended to increase accessibility of high-quality RT planning. We surveyed LMIC RT providers to identify barriers and facilitators of future RPA deployment and uptake.

Methods: RT providers underwent a pilot RPA teaching session in sub-Saharan Africa (Botswana, South Africa, and Tanzania) and Central America (Guatemala). Thirty providers (30 of 33, 90.9% response rate) participated in a postsession survey.

Results: Respondents included physicians (n = 10, 33%), …

Activity Of Decitabine As Maintenance Therapy In Core Binding Factor Acute Myeloid Leukemia, Jayastu Senapati, Mahran Shoukier, Guillermo Garcia-Manero, Xuemei Wang, Keyur Patel, Tapan Kadia, Farhad Ravandi, Naveen Pemmaraju, Maro Ohanian, Naval Daver, Courtney Dinardo, Yesid Alvarado, Jeffrey Aldrich, Gautam Borthakur

Faculty, Staff and Student Publications

Background: Posttherapy measurable residual disease (MRD) positivity in core binding factor acute myeloid leukemia (CBF-AML) is associated with shorter relapse-free survival (RFS). Elimination of MRD measured via quantitative reverse transcription polymerase chain reaction (qRTPCR) for disease specific transcripts can potentially lead to better outcomes in CBF-AML.

Methods: We prospectively monitored the MRD using qRTPCR and flow cytometry on bone marrow samples in patients with newly diagnosed CBF-AML who received decitabine (DAC) maintenance therapy after fludarabine/cytarabine/G-CSF (FLAG)-based induction/consolidation regimen. Negative qRTPCR (CMR) was defined as fusion transcript <0.01%.

Results: Thirty-one patients with CBF-AML including 14 with t(8;21) and 17 with inv(16) received …

Association Of Flame-Retardant Clothing With Mycosis Fungoides: A Retrospective Analysis, Katherine E Park, Vignesh Ramachandran, Jessica Tran, Tejas P Joshi, Naveen Garg, Madeleine Duvic

Faculty, Staff and Student Publications

Introduction: Mycosis fungoides (MF), the most prevalent form of cutaneous T-cell lymphoma (CTCL), has been associated with a variety of environmental and occupational exposures. Flame-retardant clothing (FRC), in contrast to flame-resistant clothing, is chemically treated and may constitute a previously unrecognized occupational hazard.

Objectives: To report an association between FRC and MF.

Methods: After encountering several young male patients whose onset of MF coincided with the occupational use of FRC and occupation as fire fighters, we did a retrospective search. Additional biopsy proven MF patients with use of FRC were identified by the EPIC electronic medical record using the search …

Home Cooking Quality Assessment Tool Validation Using Community Science And Crowdsourcing Approaches, Margaret Raber, Nalini Ranjit, Larkin L Strong, Karen Basen-Engquist

Faculty, Staff and Student Publications

Objective: To refine a measure of home cooking quality (defined as the usage level of practices with the potential to influence the nutrient content of prepared foods) and conduct a construct validation of the revised tool, the Healthy Cooking Questionnaire 2 (HCQ2).

Design: Two validation approaches are described: (1) a community science approach used to refine and validate Healthy Cooking Questionnaire (HCQ) constructs, and (2) responses to the revised HCQ (HCQ2) in a sample of Amazon Mechanical Turk (MTurk) workers to determine questionnaire comprehension.

Setting: The Community Scientist Program at the University of Texas MD Anderson Cancer Center facilitated discussion …

Ovarian Cancer Reporting Lexicon For Computed Tomography (Ct) And Magnetic Resonance (Mr) Imaging Developed By The Sar Uterine And Ovarian Cancer Disease-Focused Panel And The Esur Female Pelvic Imaging Working Group, Atul B Shinagare, Elizabeth A Sadowski, Hyesun Park, Olga R Brook, Rosemarie Forstner, Sumer K Wallace, Jeanne M Horowitz, Neil Horowitz, Marcia Javitt, Priyanka Jha, Aki Kido, Yulia Lakhman, Susanna I Lee, Lucia Manganaro, Katherine E Maturen, Stephanie Nougaret, Liina Poder, Gaiane M Rauch, Caroline Reinhold, Evis Sala, Isabelle Thomassin-Naggara, Herbert Alberto Vargas, Aradhana Venkatesan, Olivera Nikolic, Andrea G Rockall

Faculty, Staff and Student Publications

Objectives: Imaging evaluation is an essential part of treatment planning for patients with ovarian cancer. Variation in the terminology used for describing ovarian cancer on computed tomography (CT) and magnetic resonance (MR) imaging can lead to ambiguity and inconsistency in clinical radiology reports. The aim of this collaborative project between Society of Abdominal Radiology (SAR) Uterine and Ovarian Cancer (UOC) Disease-focused Panel (DFP) and the European Society of Uroradiology (ESUR) Female Pelvic Imaging (FPI) Working Group was to develop an ovarian cancer reporting lexicon for CT and MR imaging.

Methods: Twenty-one members of the SAR UOC DFP and ESUR FPI …

The Microrna-183/96/182 Cluster Inhibits Lung Cancer Progression And Metastasis By Inducing An Interleukin-2-Mediated Antitumor Cd8+ Cytotoxic T-Cell Response, Samrat T Kundu, B Leticia Rodriguez, Laura A Gibson, Amanda N Warner, Mabel G Perez, Rakhee Bajaj, Jared J Fradette, Caleb A Class, Luisa M Solis, Frank R Rojas Alvarez, Ignacio I Wistuba, Lixia Diao, Fengju Chen, Mohit Sachdeva, Jing Wang, David G Kirsch, Chad J Creighton, Don L Gibbons

Faculty, Staff and Student Publications

Here, Kundu et al. investigated the role of the microRNA-183/96/182 cluster (m96cl) in lung cancer and used a novel conditional m96cl mouse to establish that loss of m96cl accelerated the growth of K-Ras mutant autochthonous lung adenocarcinomas. Overall, the authors identified a novel mechanistic role of the m96cl in the suppression of lung cancer growth and metastasis by inducing an IL2-mediated systemic CD8+ CTL immune response.

Definitive Radiotherapy For Extracranial Oligoprogressive Metastatic Renal Cell Carcinoma As A Strategy To Defer Systemic Therapy Escalation, Brian De, Aradhana M Venkatesan, Pavlos Msaouel, Amol J Ghia, Jing Li, Debra N Yeboa, Quynh-Nhu Nguyen, Andrew J Bishop, Eric Jonasch, Amishi Y Shah, Matthew T Campbell, Jennifer Wang, Amado J Zurita-Saavedra, Jose A Karam, Christopher G Wood, Surena F Matin, Nizar M Tannir, Chad Tang

Faculty, Staff and Student Publications

Objective: To study whether delivering definitive radiotherapy (RT) to sites of oligoprogression in metastatic renal cell carcinoma (mRCC) enabled deferral of systemic therapy (ST) changes without compromising disease control or survival.

Patients and methods: We identified patients with mRCC who received RT to three or fewer sites of extracranial progressive disease between 2014 and 2019 at a large tertiary cancer centre. Inclusion criteria were: (1) controlled disease for ≥3 months before oligoprogression, (2) all oligoprogression sites treated with a biologically effective dose of ≥100 Gy, and (3) availability of follow-up imaging. Time-to-event end-points were calculated from the start of RT. …

Rhoa-Rock Competes With Yap To Regulate Amoeboid Breast Cancer Cell Migration In Response To Lymphatic-Like Flow, Amina Mohammadalipour, Miguel F Diaz, Megan Livingston, Adesuwa Ewere, Allen Zhou, Paulina D Horton, Loretta T Olamigoke, John M Lamar, John P Hagan, Hyun J Lee, Pamela L Wenzel

Faculty, Staff and Student Publications

Lymphatic drainage generates force that induces prostate cancer cell motility via activation of Yes-associated protein (YAP), but whether this response to fluid force is conserved across cancer types is unclear. Here, we show that shear stress corresponding to fluid flow in the initial lymphatics modifies taxis in breast cancer, whereas some cell lines use rapid amoeboid migration behavior in response to fluid flow, a separate subset decrease movement. Positive responders displayed transcriptional profiles characteristic of an amoeboid cell state, which is typical of cells advancing at the edges of neoplastic tumors. Regulation of the HIPPO tumor suppressor pathway and YAP …

Home Cooking Quality Assessment Tool Validation Using Community Science And Crowdsourcing Approaches, Margaret Raber, Nalini Ranjit, Larkin L Strong, Karen Basen-Engquist

Faculty, Staff and Student Publications

Objective: To refine a measure of home cooking quality (defined as the usage level of practices with the potential to influence the nutrient content of prepared foods) and conduct a construct validation of the revised tool, the Healthy Cooking Questionnaire 2 (HCQ2).

Design: Two validation approaches are described: (1) a community science approach used to refine and validate Healthy Cooking Questionnaire (HCQ) constructs, and (2) responses to the revised HCQ (HCQ2) in a sample of Amazon Mechanical Turk (MTurk) workers to determine questionnaire comprehension.

Setting: The Community Scientist Program at the University of Texas MD Anderson Cancer Center facilitated discussion …

Curated Variation Benchmarks For Challenging Medically Relevant Autosomal Genes, Justin Wagner, Nathan D Olson, Lindsay Harris, Jennifer Mcdaniel, Haoyu Cheng, Arkarachai Fungtammasan, Yih-Chii Hwang, Richa Gupta, Aaron M Wenger, William J Rowell, Ziad M Khan, Jesse Farek, Yiming Zhu, Aishwarya Pisupati, Medhat Mahmoud, Chunlin Xiao, Byunggil Yoo, Sayed Mohammad Ebrahim Sahraeian, Danny E Miller, David Jáspez, José M Lorenzo-Salazar, Adrián Muñoz-Barrera, Luis A Rubio-Rodríguez, Carlos Flores, Giuseppe Narzisi, Uday Shanker Evani, Wayne E Clarke, Joyce Lee, Christopher E Mason, Stephen E Lincoln, Karen H Miga, Mark T W Ebbert, Alaina Shumate, Heng Li, Chen-Shan Chin, Justin M Zook, Fritz J Sedlazeck

Faculty, Staff and Students Publications

The repetitive nature and complexity of some medically relevant genes poses a challenge for their accurate analysis in a clinical setting. The Genome in a Bottle Consortium has provided variant benchmark sets, but these exclude nearly 400 medically relevant genes due to their repetitiveness or polymorphic complexity. Here, we characterize 273 of these 395 challenging autosomal genes using a haplotype-resolved whole-genome assembly. This curated benchmark reports over 17,000 single-nucleotide variations, 3,600 insertions and deletions and 200 structural variations each for human genome reference GRCh37 and GRCh38 across HG002. We show that false duplications in either GRCh37 or GRCh38 result in …

Transcriptome-Wide Identification Of Rna-Binding Protein Binding Sites Using Seclip-Seq, Steven M Blue, Brian A Yee, Gabriel A Pratt, Jasmine R Mueller, Samuel S Park, Alexander A Shishkin, Anne C Starner, Eric L Van Nostrand, Gene W Yeo

Faculty, Staff and Students Publications

Discovery of interaction sites between RNA-binding proteins (RBPs) and their RNA targets plays a critical role in enabling our understanding of how these RBPs control RNA processing and regulation. Cross-linking and immunoprecipitation (CLIP) provides a generalizable, transcriptome-wide method by which RBP/RNA complexes are purified and sequenced to identify sites of intermolecular contact. By simplifying technical challenges in prior CLIP methods and incorporating the generation of and quantitative comparison against size-matched input controls, the single-end enhanced CLIP (seCLIP) protocol allows for the profiling of these interactions with high resolution, efficiency and scalability. Here, we present a step-by-step guide to the seCLIP …

Signal-To-Noise Analysis Can Inform The Likelihood That Incidentally Identified Variants In Sarcomeric Genes Are Associated With Pediatric Cardiomyopathy, Leonie M Kurzlechner, Edward G Jones, Amy M Berkman, Hanna J Tadros, Jill A Rosenfeld, Yaping Yang, Hari Tunuguntla, Hugh D Allen, Jeffrey J Kim, Andrew P Landstrom

Faculty, Staff and Students Publications

Background: Hypertrophic cardiomyopathy (HCM) is the most common heritable cardiomyopathy and can predispose individuals to sudden death. Most pediatric HCM patients host a known pathogenic variant in a sarcomeric gene. With the increase in exome sequencing (ES) in clinical settings, incidental variants in HCM-associated genes are being identified more frequently. Diagnostic interpretation of incidental variants is crucial to enhance clinical patient management. We sought to use amino acid-level signal-to-noise (S:N) analysis to establish pathogenic hotspots in sarcomeric HCM-associated genes as well as to refine the 2015 American College of Medical Genetics (ACMG) criteria to predict incidental variant pathogenicity.

Methods and …

Enpp1 Variants In Patients With Gaci And Pxe Expand The Clinical And Genetic Heterogeneity Of Heritable Disorders Of Ectopic Calcification., Douglas Ralph, Yvonne Nitschke, Michael A Levine, Matthew Caffet, Tamara Wurst, Amir Hossein Saeidian, Leila Youssefian, Hassan Vahidnezhad, Sharon F Terry, Frank Rutsch, Jouni Uitto, Qiaoli Li

Department of Medicine Faculty Papers

Pseudoxanthoma elasticum (PXE) and generalized arterial calcification of infancy (GACI) are clinically distinct genetic entities of ectopic calcification associated with differentially reduced circulating levels of inorganic pyrophosphate (PPi), a potent endogenous inhibitor of calcification. Variants in ENPP1, the gene mutated in GACI, have not been associated with classic PXE. Here we report the clinical, laboratory, and molecular evaluations of ten GACI and two PXE patients from five and two unrelated families registered in GACI Global and PXE International databases, respectively. All patients were found to carry biallelic variants in ENPP1. Among ten ENPP1 variants, one homozygous variant demonstrated uniparental disomy …

Comparison Of Five Supervised Feature Selection Algorithms Leading To Top Features And Gene Signatures From Multi-Omics Data In Cancer, Tapas Bhadra, Saurav Mallik, Neaj Hasan, Zhongming Zhao

Faculty, Staff and Student Publications

BACKGROUND: As many complex omics data have been generated during the last two decades, dimensionality reduction problem has been a challenging issue in better mining such data. The omics data typically consists of many features. Accordingly, many feature selection algorithms have been developed. The performance of those feature selection methods often varies by specific data, making the discovery and interpretation of results challenging.

METHODS AND RESULTS: In this study, we performed a comprehensive comparative study of five widely used supervised feature selection methods (mRMR, INMIFS, DFS, SVM-RFE-CBR and VWMRmR) for multi-omics datasets. Specifically, we used five representative datasets: gene expression …

Dance Of The Golgi: Understanding Golgi Dynamics In Cancer Metastasis, Rakhee Bajaj, Amanda N Warner, Jared F Fradette, Don L Gibbons

Faculty, Staff and Student Publications

The Golgi apparatus is at the center of protein processing and trafficking in normal cells. Under pathological conditions, such as in cancer, aberrant Golgi dynamics alter the tumor microenvironment and the immune landscape, which enhances the invasive and metastatic potential of cancer cells. Among these changes in the Golgi in cancer include altered Golgi orientation and morphology that contribute to atypical Golgi function in protein trafficking, post-translational modification, and exocytosis. Golgi-associated gene mutations are ubiquitous across most cancers and are responsible for modifying Golgi function to become pro-metastatic. The pharmacological targeting of the Golgi or its associated genes has been …

A Patient-Derived Ipsc Model To Study Glutamate Deficiency By Shank-3 Mutation In Autism Spectrum Disorder, Tiffany Berry, Courtney Caccia

Biology Student Scholarship

Tiffany Berry ’22, Majors: Biology and Psychology

Courtney Caccia ’22, Majors: Biology and Psychology

Faculty Mentor: Dr. Charles Toth, Biology

The use of human stem cell lines derived from persons with Autism Spectrum Disorder (ASD) provides a unique opportunity to model brain growth and potential to regain brain activity for treatment. Our lab has previously used stem cells to derive 3D cardiomyocytes to examine cardiovascular disease as well as kidney organoids and macrophages to study kidney disease. Using techniques our lab has learned using these stem cell models have prepared us to examine cell communication in mutated neurons. We will …

Markers Of Kidney Function, Genetic Variation Related To Cognitive Function, And Cognitive Performance In The Uk Biobank, Erin L Richard, Linda K Mcevoy, Ian J Deary, Gail Davies, Steven Y Cao, Eyal Oren, John E Alcaraz, Andrea Z Lacroix, Jan Bressler, Rany M Salem

Faculty, Staff and Student Publications

BACKGROUND: Chronic kidney disease has been linked to worse cognition. However, this association may be dependent on the marker of kidney function used, and studies assessing modification by genetics are lacking. This study examined associations between multiple measures of kidney function and assessed effect modification by a polygenic score for general cognitive function.

METHODS: In this cross-sectional study of up to 341,208 European ancestry participants from the UK Biobank study, we examined associations between albuminuria and estimated glomerular filtration rate based on creatinine (eGFRcre) or cystatin C (eGFRcys) with cognitive performance on tests of verbal-numeric reasoning, reaction time and visual …

Accessory Genomes Drive Independent Spread Of Carbapenem-Resistant Klebsiella Pneumoniae Clonal Groups 258 And 307 In Houston, Tx, William C Shropshire, An Q Dinh, Michelle Earley, Lauren Komarow, Diana Panesso, Kirsten Rydell, Sara I Gómez-Villegas, Hongyu Miao, Carol Hill, Liang Chen, Robin Patel, Bettina C Fries, Lilian Abbo, Eric Cober, Sara Revolinski, Courtney L Luterbach, Henry Chambers, Vance G Fowler, Robert A Bonomo, Samuel A Shelburne, Barry N Kreiswirth, David Van Duin, Blake M Hanson, Cesar A Arias

Faculty, Staff and Student Publications

Carbapenem-resistant Klebsiella pneumoniae (CRKp) is an urgent public health threat. Worldwide dissemination of CRKp has been largely attributed to clonal group (CG) 258. However, recent evidence indicates the global emergence of a CRKp CG307 lineage. Houston, TX, is the first large city in the United States with detected cocirculation of both CRKp CG307 and CG258. We sought to characterize the genomic and clinical factors contributing to the parallel endemic spread of CG258 and CG307. CRKp isolates were collected as part of the prospective, Consortium on Resistance against Carbapenems in Klebsiella and other Enterobacterales 2 …