Biomedical Informatics Commons^™

Evaluating The Proportion Of Isolated Cases Among A Spectrum Of Birth Defects In A Population-Based Registry, Peter H Langlois, Lisa Marengo, Philip J Lupo, Margaret Drummond-Borg, A J Agopian, Wendy N Nembhard, Mark A Canfield

Faculty, Staff and Students Publications

INTRODUCTION: Because the etiology and outcomes of birth defects may differ by the presence vs. absence of co-occurring anomalies, epidemiologic studies often attempt to classify cases into isolated versus non-isolated groupings. This report describes a computer algorithm for such classification and presents results using data from the Texas Birth Defects Registry (TBDR).

METHODS: Each of the 1,041 birth defects coded by the TBDR was classified as chromosomal, syndromic, minor, or "needs review" by a group of three clinical geneticists. A SAS program applied those classifications to each birth defect in a case (child/fetus), and then hierarchically combined them to obtain …

Ultrahigh Resolution Lipid Mass Spectrometry Imaging Of High-Grade Serous Ovarian Cancer Mouse Models, Xin Ma, Andro Botros, Sylvia R Yun, Eun Young Park, Olga Kim, Soojin Park, Thu-Huyen Pham, Ruihong Chen, Murugesan Palaniappan, Martin M Matzuk, Jaeyeon Kim, Facundo M Fernández

Faculty, Staff and Students Publications

No effective screening tools for ovarian cancer (OC) exist, making it one of the deadliest cancers among women. Considering that little is known about the detailed progression and metastasis mechanism of OC at a molecular level, it is crucial to gain more insights into how metabolic and signaling alterations accompany its development. Herein, we present a comprehensive study using ultra-high-resolution Fourier transform ion cyclotron resonance matrix-assisted laser desorption/ionization (MALDI) mass spectrometry imaging (MSI) to investigate the spatial distribution and alterations of lipids in ovarian tissues collected from double knockout (n = 4) and triple mutant mouse models (n …

Factors Associated With Nonsyndromic Anotia And Microtia, Texas, 1999–2014, Jeremy M Schraw, J P Woodhouse, Renata H Benjamin, Charles J Shumate, Joanne Nguyen, Mark A Canfield, A J Agopian, Philip J Lupo

Faculty, Staff and Students Publications

BACKGROUND: Few risk factors have been identified for nonsyndromic anotia/microtia (A/M).

METHODS: We obtained data on cases and a reference population of all livebirths in Texas for 1999-2014 from the Texas Birth Defects Registry (TBDR) and Texas vital records. We estimated prevalence ratios (PRs) and 95% confidence intervals (CIs) for A/M (any, isolated, nonisolated, unilateral, and bilateral) using Poisson regression. We evaluated trends in prevalence rates using Joinpoint regression.

RESULTS: We identified 1,322 cases, of whom 982 (74.3%) had isolated and 1,175 (88.9%) had unilateral A/M. Prevalence was increased among males (PR: 1.3, 95% CI: 1.2-1.4), offspring of women with …

Oocyte-Specific Wee1-Like Protein Kinase 2 Is Dispensable For Fertility In Mice, Kaori Nozawa, Zian Liao, Yuhkoh Satouh, Ting Geng, Masahito Ikawa, Diana Monsivais, Martin M Matzuk

Faculty, Staff and Students Publications

Wee1-like protein kinase 2 (WEE2) is an oocyte-specific protein tyrosine kinase involved in the regulation of oocyte meiotic arrest in humans. As such, it has been proposed as a candidate for non-hormonal female contraception although pre-clinical models have not been reported. Therefore, we developed two novel knockout mouse models using CRISPR/Cas9 to test loss-of-function of Wee2 on female fertility. A frameshift mutation at the Wee2 translation start codon in exon 2 had no effect on litter size, litter production, or the ability of oocytes to maintain prophase I arrest. Because of the lack of a reproductive phenotype, we additionally generated …

Disease Modeling Of Adamts9-Related Nephropathy Using Kidney Organoids Reveals Its Roles In Tubular Cells And Podocytes, Seyoung Yu, Yo Jun Choi, John Hoon Rim, Hye-Youn Kim, Nasim Bekheirnia, Sarah Jane Swartz, Hongzheng Dai, Shen Linda Gu, Soyeon Lee, Ryuichi Nishinakamura, Friedhelm Hildebrandt, Mir Reza Bekheirnia, Heon Yung Gee

Faculty, Staff and Students Publications

INTRODUCTION: Mutations in ADAMTS9 cause nephronophthisis-related ciliopathies (NPHP-RC), which are characterized by multiple developmental defects and kidney diseases. Patients with NPHP-RC usually have normal glomeruli and negligible or no proteinuria. Herein, we identified novel compound-heterozygous ADAMTS9 variants in two siblings with NPHP-RC who had glomerular manifestations, including proteinuria.

METHODS: To investigate whether ADAMTS9 dysfunction causes NPHP and glomerulopathy, we differentiated ADAMTS9 knockout human induced pluripotent stem cells (hiPSCs) into kidney organoids. Single-cell RNA sequencing was utilized to elucidate the gene expression profiles from the ADAMTS9 knockout kidney organoids.

RESULTS:ADAMTS9 knockout had no effect on nephron differentiation; however, it reduced …

Human Health During Space Travel: State-Of-The-Art Review, Chayakrit Krittanawong, Nitin Kumar Singh, Richard A Scheuring, Emmanuel Urquieta, Eric M Bershad, Timothy R Macaulay, Scott Kaplin, Carly Dunn, Stephen F Kry, Thais Russomano, Marc Shepanek, Raymond P Stowe, Andrew W Kirkpatrick, Timothy J Broderick, Jean D Sibonga, Andrew G Lee, Brian E Crucian

Faculty, Staff and Student Publications

The field of human space travel is in the midst of a dramatic revolution. Upcoming missions are looking to push the boundaries of space travel, with plans to travel for longer distances and durations than ever before. Both the National Aeronautics and Space Administration (NASA) and several commercial space companies (e.g., Blue Origin, SpaceX, Virgin Galactic) have already started the process of preparing for long-distance, long-duration space exploration and currently plan to explore inner solar planets (e.g., Mars) by the 2030s. With the emergence of space tourism, space travel has materialized as a potential new, exciting frontier of business, hospitality, …

Rare Diseases And Space Health: Optimizing Synergies From Scientific Questions To Care, Maria Puscas, Gabrielle Martineau, Gurjot Bhella, Penelope E Bonnen, Phil Carr, Robyn Lim, John Mitchell, Matthew Osmond, Emmanuel Urquieta, Jaime Flamenbaum, Giuseppe Iaria, Yann Joly, Étienne Richer, Joan Saary, David Saint-Jacques, Nicole Buckley, Etienne Low-Decarie

Faculty, Staff and Students Publications

Knowledge transfer among research disciplines can lead to substantial research progress. At first glance, astronaut health and rare diseases may be seen as having little common ground for such an exchange. However, deleterious health conditions linked to human space exploration may well be considered as a narrow sub-category of rare diseases. Here, we compare and contrast research and healthcare in the contexts of rare diseases and space health and identify common barriers and avenues of improvement. The prevalent genetic basis of most rare disorders contrasts sharply with the occupational considerations required to sustain human health in space. Nevertheless small sample …

Concurrent Mutations In Sf3b1 And Phf6 In Myeloid Neoplasms, Zhuang Zuo, L Jeffrey Medeiros, Sofia Garces, Mark J Routbort, Chi Young Ok, Sanam Loghavi, Rashmi Kanagal-Shamanna, Fatima Zahra Jelloul, Guillermo Garcia-Manero, Kelly S Chien, Keyur P Patel, Rajyalakshmi Luthra, C Cameron Yin

Faculty, Staff and Student Publications

It has been reported that gene mutations in SF3B1 and PHF6 are mutually exclusive. However, this observation has never been rigorously assessed. We report the clinicopathologic and molecular genetic features of 21 cases of myeloid neoplasms with double mutations in SF3B1 and PHF6, including 9 (43%) with myelodysplastic syndrome, 5 (24%) with acute myeloid leukemia, 4 (19%) with myeloproliferative neoplasms, and 3 (14%) with myelodysplastic/myeloproliferative neoplasms. Multilineage dysplasia with ring sideroblasts, increased blasts, and myelofibrosis are common morphologic findings. All cases but one had diploid or non-complex karyotypes. SF3B1 mutations were detected in the first analysis of all the …

Author Correction: A Nanoengineered Topical Transmucosal Cisplatin Delivery System Induces Anti-Tumor Response In Animal Models And Patients With Oral Cancer, Manijeh Goldberg, Aaron Manzi, Amritpreet Birdi, Brandon Laporte, Peter Conway, Stefanie Cantin, Vasudha Mishra, Alka Singh, Alexander T Pearson, Eric R Goldberg, Sam Goldberger, Benjamin Flaum, Rifat Hasina, Nyall R London, Gary L Gallia, Chetan Bettegowda, Simon Young, Vlad Sandulache, James Melville, Jonathan Shun, Sonya E O'Neill, Erkin Aydin, Alex Zhavoronkov, Anxo Vidal, Atenea Soto, Maria Jose Alonso, Ari J Rosenberg, Mark W Lingen, Anil D'Cruz, Nishant Agrawal, Evgeny Izumchenko

Faculty, Staff and Student Publications

No abstract provided.

Egfr Is A Master Switch Between Immunosuppressive And Immunoactive Tumor Microenvironment In Inflammatory Breast Cancer, Xiaoping Wang, Takashi Semba, Ganiraju C Manyam, Jing Wang, Shan Shao, Francois Bertucci, Pascal Finetti, Savitri Krishnamurthy, Lan Thi Hanh Phi, Troy Pearson, Steven J Van Laere, Jared K Burks, Evan N Cohen, James M Reuben, Fei Yang, Hu Min, Nicholas Navin, Van Ngu Trinh, Toshiaki Iwase, Harsh Batra, Yichao Shen, Xiang Zhang, Debu Tripathy, Naoto T Ueno

Faculty, Staff and Student Publications

Inflammatory breast cancer (IBC), the most aggressive breast cancer subtype, is driven by an immunosuppressive tumor microenvironment (TME). Current treatments for IBC have limited efficacy. In a clinical trial (NCT01036087), an anti-EGFR antibody combined with neoadjuvant chemotherapy produced the highest pathological complete response rate ever reported in patients with IBC having triple-negative receptor status. We determined the molecular and immunological mechanisms behind this superior clinical outcome. Using novel humanized IBC mouse models, we discovered that EGFR-targeted therapy remodels the IBC TME by increasing cytotoxic T cells and reducing immunosuppressive regulatory T cells and M2 macrophages. These changes were due to …

Histopathological Tumour Response Scoring In Resected Pancreatic Cancer Following Neoadjuvant Therapy: International Interobserver Study (Isgpp-1), Boris V Janssen, Stijn Van Roessel, Susan Van Dieren, Onno De Boer, Volkan Adsay, Olca Basturk, Lodewijk Brosens, Fiona Campbell, Deyali Chatterjee, Angela Chou, Claudio Doglioni, Irene Esposito, Roger Feakins, Talia L Fuchs, Noriyoshi Fukushima, Anthony J Gill, Seung-Mo Hong, Ralph H Hruban, Jeffrey Kaplan, Alyssa Krasinkas, Claudio Luchini, Chanjuan Shi, Aatur Singhi, Elizabeth Thompson, Marie-Louise F Velthuysen, Marc G Besselink, Joanne Verheij, Huamin Wang, Caroline Verbeke, Arantza Fariña

Faculty, Staff and Student Publications

Background: Most tumour response scoring systems for resected pancreatic cancer after neoadjuvant therapy score tumour regression. However, whether treatment-induced changes, including tumour regression, can be identified reliably on haematoxylin and eosin-stained slides remains unclear. Moreover, no large study of the interobserver agreement of current tumour response scoring systems for pancreatic cancer exists. This study aimed to investigate whether gastrointestinal/pancreatic pathologists can reliably identify treatment effect on tumour by histology, and to determine the interobserver agreement for current tumour response scoring systems.

Methods: Overall, 23 gastrointestinal/pancreatic pathologists reviewed digital haematoxylin and eosin-stained slides of pancreatic cancer or treated tumour bed. The …

Consensus Opinion From An International Group Of Experts On Measurable Residual Disease In Hairy Cell Leukemia, Farhad Ravandi, Robert J Kreitman, Enrico Tiacci, Leslie Andritsos, Versha Banerji, Jacqueline C Barrientos, Seema A Bhat, James S Blachly, Alessandro Broccoli, Timothy Call, Dai Chihara, Claire Dearden, Judit Demeter, Sasha Dietrich, Monica Else, Narendranath Epperla, Brunangelo Falini, Francesco Forconi, Douglas E Gladstone, Alessandro Gozzetti, Sunil Iyengar, James B Johnston, Jeffrey Jorgensen, Gunnar Juliusson, Francesco Lauria, Gerard Lozanski, Sameer A Parikh, Jae H Park, Aaron Polliack, Graeme Quest, Tadeusz Robak, Kerry A Rogers, Alan Saven, John F Seymour, Tamar Tadmor, Martin S Tallman, Constantine S Tam, Philip A Thompson, Xavier Troussard, Clive S Zent, Thorsten Zenz, Pier Luigi Zinzani, Bernhard Wörmann, Kanti Rai, Michael Grever

Faculty, Staff and Student Publications

A significant body of literature has been generated related to the detection of measurable residual disease (MRD) at the time of achieving complete remission (CR) in patients with hairy cell leukemia (HCL). However, due to the indolent nature of the disease as well as reports suggesting long-term survival in patients treated with a single course of a nucleoside analog albeit without evidence of cure, the merits of detection of MRD and attempts to eradicate it have been debated. Studies utilizing novel strategies in the relapse setting have demonstrated the utility of achieving CR with undetectable MRD (uMRD) in prolonging the …

Mir21 Modulates The Hippo Signaling Pathway Via Interference With Pp2a Bβ To Inhibit Trophoblast Invasion And Cause Preeclampsia, Mingyu Hu, Yangxi Zheng, Jiujiang Liao, Li Wen, Juan Cheng, Jiayu Huang, Biao Huang, Li Lin, Yao Long, Yue Wu, Xuan Ye, Yong Fu, Hongbo Qi, Philip N Baker, Chao Tong

Faculty, Staff and Student Publications

Preeclampsia (PE) is a pregnancy-specific disorder attributed to deficient extravillous trophoblast (EVT) invasion into the uterus, but the mechanism of EVT invasion remains unclear. In this study, we found significantly elevated expression of microRNA 21 (miR21), which negatively regulates trophoblast invasion and migration, in preeclamptic placentae. Whole-genome RNA sequencing revealed that PPP2R2B, which encodes PP2A Bβ, and the Hippo pathway are downstream targets of miR21. The effects of miR21 on trophoblast mobility were abolished in LATS1T1079A/S909A and YAP-5SA mutants. Moreover, we found that PP2A Bβ dephosphorylates LATS1 via direct protein-protein interactions and thus modulates the phosphorylation and subcellular distribution …

Egfr-Phosphorylated Gdh1 Harmonizes With Rsk2 To Drive Creb Activation And Tumor Metastasis In Egfr-Activated Lung Cancer, Jihoon Kang, Jaemoo Chun, Jung Seok Hwang, Chaoyun Pan, Jie Li, Austin C Boese, Isabelle Young, Courteney M Malin, Yibin Kang, Don L Gibbons, Gabriel Sica, Haian Fu, Suresh S Ramalingam, Lingtao Jin, Sumin Kang

Faculty, Staff and Student Publications

The cancer metastasis process involves dysregulated oncogenic kinase signaling, but how this orchestrates metabolic networks and signal cascades to promote metastasis is largely unclear. Here we report that inhibition of glutamate dehydrogenase 1 (GDH1) and ribosomal S6 kinase 2 (RSK2) synergistically attenuates cell invasion, anoikis resistance, and immune escape in lung cancer and more evidently in tumors harboring epidermal growth factor receptor (EGFR)-activating or EGFR inhibitor-resistant mutations. Mechanistically, GDH1 is activated by EGFR through phosphorylation at tyrosine 135 and, together with RSK2, enhances the cAMP response element-binding protein (CREB) activity via CaMKIV signaling, thereby promoting metastasis. Co-targeting RSK2 and GDH1 …

Efficacy Of Cabozantinib In Metastatic Mit Family Translocation Renal Cell Carcinomas, Jonathan Thouvenin, Omar Alhalabi, Maria Carlo, Lucia Carril-Ajuria, Laure Hirsch, Nieves Martinez-Chanza, Sylvie Négrier, Luca Campedel, Dylan Martini, Delphine Borchiellini, Jad Chahoud, Massimo Lodi, Philippe Barthélémy, Elshad Hasanov, Andrew W Hahn, Thierry Gil, Srinivas R Viswanathan, Ziad Bakouny, Pavlos Msaouel, Mehmet Asim Bilen, Toni K Choueiri, Laurence Albiges, Nizar M Tannir, Gabriel G Malouf

Faculty, Staff and Student Publications

Background: MiT family translocation renal cell carcinoma (TRCC) is a rare and aggressive subgroup of renal cell carcinoma harboring high expression of c-MET. While TRCC response rates to VEGF receptor tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors are limited, efficacy of cabozantinib (a VEGFR, MET, and AXL inhibitor) in this subgroup is unclear.

Methods: We performed a multicenter, retrospective, international cohort study of patients with TRCC treated with cabozantinib. The main objectives were to estimate response rate according to RECIST 1.1 and to analyze progression-free survival (PFS) and overall survival (OS).

Results: Fifty-two patients with metastatic TRCC treated in …

Prognostic Significance Of P16 And Its Relationship With Human Papillomavirus Status In Patients With Penile Squamous Cell Carcinoma: Results Of 5 Years Follow-Up, Jad Chahoud, Niki M Zacharias, Rachel Pham, Wei Qiao, Ming Guo, Xin Lu, Angelita Alaniz, Luis Segarra, Magaly Martinez-Ferrer, Frederico Omar Gleber-Netto, Curtis R Pickering, Priya Rao, Curtis A Pettaway

Faculty, Staff and Student Publications

Penile Squamous Cell Carcinoma (PSCC) is associated with high-risk human papillomavirus (HR-HPV). The immunohistochemical (IHC) test for p16INK4a (p16) is highly correlated with HR-HPV expression in other SCCs. To investigate whether the expression of p16 IHC or HR-HPV is associated with survival in PSCC, we conducted a single institution analysis of 143 patients with a diagnosis of PSCC and, available tissue were tested for p16 IHC staining patterns, histological subtype, tumor grade, and lymphovascular invasion (LVI) by an experienced pathologist. HR-HPV status using the Cobas PCR Assay or the RNAScope high-risk HPV in situ hybridization kit were also assessed. Patient …

Author Correction: Disrupted Ca2+ Homeostasis And Immunodeficiency In Patients With Functional Ip3 Receptor Subtype 3 Defects, Julika Neumann, Erika Van Nieuwenhove, Lara E Terry, Frederik Staels, Taylor R Knebel, Kirsten Welkenhuyzen, Kourosh Ahmadzadeh, Mariah R Baker, Margaux Gerbaux, Mathijs Willemsen, John S Barber, Irina I Serysheva, Liesbeth De Waele, François Vermeulen, Susan Schlenner, Isabelle Meyts, David I Yule, Geert Bultynck, Rik Schrijvers, Stephanie Humblet-Baron, Adrian Liston

Faculty, Staff and Student Publications

This corrects the article "Disrupted Ca²⁺ homeostasis and immunodeficiency in patients with functional IP₃ receptor subtype 3 defects" on page 11.

Executive Summary Of The American Radium Society Appropriate Use Criteria For Management Of Uterine Clear Cell And Serous Carcinomas, Tracy Sherertz, Anuja Jhingran, Matthew Biagioli, David Gaffney, Mohamed Elshaikh, Robert L Coleman, Matthew Harkenrider, Elizabeth A Kidd, Shruti Jolly, Catheryn Yashar, Lorraine Portelance, Andrew Wahl, Aradhana Venkatesan, Linna Li, William Small, American Radium Society

Faculty, Staff and Student Publications

Background: Uterine clear cell and serous carcinomas have a high propensity for locoregional and distant spread, tend to be more advanced at presentation, and carry a higher risk of recurrence and death than endometrioid cancers. Limited prospective data exist to guide evidence-based management of these rare malignancies.

Objective: The American Radium Society sought to summarize evidence-based guidelines developed by a multidisciplinary expert panel that help to guide the management of uterine clear cell and serous carcinomas.

Methods: The American Radium Society Appropriate Use Criteria presented in this manuscript were developed by a multidisciplinary expert panel using an extensive analysis of …

Federated Learning Enables Big Data For Rare Cancer Boundary Detection, Sarthak Pati, Ujjwal Baid, Brandon Edwards, Micah Sheller, Shih-Han Wang, G Anthony Reina, Patrick Foley, Alexey Gruzdev, Deepthi Karkada, Christos Davatzikos, Chiharu Sako, Satyam Ghodasara, Michel Bilello, Suyash Mohan, Philipp Vollmuth, Gianluca Brugnara, Chandrakanth J Preetha, Felix Sahm, Klaus Maier-Hein, Maximilian Zenk, Martin Bendszus, Wolfgang Wick, Evan Calabrese, Jeffrey Rudie, Javier Villanueva-Meyer, Soonmee Cha, Madhura Ingalhalikar, Manali Jadhav, Umang Pandey, Jitender Saini, John Garrett, Matthew Larson, Robert Jeraj, Stuart Currie, Russell Frood, Kavi Fatania, Raymond Y Huang, Ken Chang, Carmen Balaña, Jaume Capellades, Josep Puig, Johannes Trenkler, Josef Pichler, Georg Necker, Andreas Haunschmidt, Stephan Meckel, Gaurav Shukla, Spencer Liem, Gregory S Alexander, Joseph Lombardo, Joshua D Palmer, Adam E Flanders, Adam P Dicker, Haris I Sair, Craig K Jones, Archana Venkataraman, Meirui Jiang, Tiffany Y So, Cheng Chen, Pheng Ann Heng, Qi Dou, Michal Kozubek, Filip Lux, Jan Michálek, Petr Matula, Miloš Keřkovský, Tereza Kopřivová, Marek Dostál, Václav Vybíhal, Michael A Vogelbaum, J Ross Mitchell, Joaquim Farinhas, Joseph A Maldjian, Chandan Ganesh Bangalore Yogananda, Marco C Pinho, Divya Reddy, James Holcomb, Benjamin C Wagner, Benjamin M Ellingson, Timothy F Cloughesy, Catalina Raymond, Talia Oughourlian, Akifumi Hagiwara, Chencai Wang, Minh-Son To, Sargam Bhardwaj, Chee Chong, Marc Agzarian, Alexandre Xavier Falcão, Samuel B Martins, Bernardo C A Teixeira, Flávia Sprenger, David Menotti, Diego R Lucio, Pamela Lamontagne, Daniel Marcus, Benedikt Wiestler, Florian Kofler, Ivan Ezhov, Marie Metz, Rajan Jain, Matthew Lee, Yvonne W Lui, Richard Mckinley, Johannes Slotboom, Piotr Radojewski, Raphael Meier, Roland Wiest, Derrick Murcia, Eric Fu, Rourke Haas, John Thompson, David Ryan Ormond, Chaitra Badve, Andrew E Sloan, Vachan Vadmal, Kristin Waite, Rivka R Colen, Linmin Pei, Murat Ak, Ashok Srinivasan, J Rajiv Bapuraj, Arvind Rao, Nicholas Wang, Ota Yoshiaki, Toshio Moritani, Sevcan Turk, Joonsang Lee, Snehal Prabhudesai, Fanny Morón, Jacob Mandel, Konstantinos Kamnitsas, Ben Glocker, Luke V M Dixon, Matthew Williams, Peter Zampakis, Vasileios Panagiotopoulos, Panagiotis Tsiganos, Sotiris Alexiou, Ilias Haliassos, Evangelia I Zacharaki, Konstantinos Moustakas, Christina Kalogeropoulou, Dimitrios M Kardamakis, Yoon Seong Choi, Seung-Koo Lee, Jong Hee Chang, Sung Soo Ahn, Bing Luo, Laila Poisson, Ning Wen, Pallavi Tiwari, Ruchika Verma, Rohan Bareja, Ipsa Yadav, Jonathan Chen, Neeraj Kumar, Marion Smits, Sebastian R Van Der Voort, Ahmed Alafandi, Fatih Incekara, Maarten M J Wijnenga, Georgios Kapsas, Renske Gahrmann, Joost W Schouten, Hendrikus J Dubbink, Arnaud J P E Vincent, Martin J Van Den Bent, Pim J French, Stefan Klein, Yading Yuan, Sonam Sharma, Tzu-Chi Tseng, Saba Adabi, Simone P Niclou, Olivier Keunen, Ann-Christin Hau, Martin Vallières, David Fortin, Martin Lepage, Bennett Landman, Karthik Ramadass, Kaiwen Xu, Silky Chotai, Lola B Chambless, Akshitkumar Mistry, Reid C Thompson, Yuriy Gusev, Krithika Bhuvaneshwar, Anousheh Sayah, Camelia Bencheqroun, Anas Belouali, Subha Madhavan, Thomas C Booth, Alysha Chelliah, Marc Modat, Haris Shuaib, Carmen Dragos, Aly Abayazeed, Kenneth Kolodziej, Michael Hill, Ahmed Abbassy, Shady Gamal, Mahmoud Mekhaimar, Mohamed Qayati, Mauricio Reyes, Ji Eun Park, Jihye Yun, Ho Sung Kim, Abhishek Mahajan, Mark Muzi, Sean Benson, Regina G H Beets-Tan, Jonas Teuwen, Alejandro Herrera-Trujillo, Maria Trujillo, William Escobar, Ana Abello, Jose Bernal, Jhon Gómez, Joseph Choi, Stephen Baek, Yusung Kim, Heba Ismael, Bryan Allen, John M Buatti, Aikaterini Kotrotsou, Hongwei Li, Tobias Weiss, Michael Weller, Andrea Bink, Bertrand Pouymayou, Hassan F Shaykh, Joel Saltz, Prateek Prasanna, Sampurna Shrestha, Kartik M Mani, David Payne, Tahsin Kurc, Enrique Pelaez, Heydy Franco-Maldonado, Francis Loayza, Sebastian Quevedo, Pamela Guevara, Esteban Torche, Cristobal Mendoza, Franco Vera, Elvis Ríos, Eduardo López, Sergio A Velastin, Godwin Ogbole, Mayowa Soneye, Dotun Oyekunle, Olubunmi Odafe-Oyibotha, Babatunde Osobu, Mustapha Shu'aibu, Adeleye Dorcas, Farouk Dako, Amber L Simpson, Mohammad Hamghalam, Jacob J Peoples, Ricky Hu, Anh Tran, Danielle Cutler, Fabio Y Moraes, Michael A Boss, James Gimpel, Deepak Kattil Veettil, Kendall Schmidt, Brian Bialecki, Sailaja Marella, Cynthia Price, Lisa Cimino, Charles Apgar, Prashant Shah, Bjoern Menze, Jill S Barnholtz-Sloan, Jason Martin, Spyridon Bakas

Faculty, Staff and Student Publications

Although machine learning (ML) has shown promise across disciplines, out-of-sample generalizability is concerning. This is currently addressed by sharing multi-site data, but such centralization is challenging/infeasible to scale due to various limitations. Federated ML (FL) provides an alternative paradigm for accurate and generalizable ML, by only sharing numerical model updates. Here we present the largest FL study to-date, involving data from 71 sites across 6 continents, to generate an automatic tumor boundary detector for the rare disease of glioblastoma, reporting the largest such dataset in the literature (n = 6, 314). We demonstrate a 33% delineation improvement for the surgically …

Treatment Of Epilepsy Using A Targeted P38Γ Kinase Gene Therapy, Nicolle Morey, Magdalena Przybyla, Julia Van Der Hoven, Yazi D Ke, Fabien Delerue, Janet Van Eersel, Lars M Ittner

Faculty, Staff and Student Publications

Hyperphosphorylated microtubule-associated protein tau has been implicated in dementia, epilepsy, and other neurological disorders. In contrast, site-specific phosphorylation of tau at threonine 205 (T205) by the kinase p38γ was shown to disengage tau from toxic pathways, serving a neuroprotective function in Alzheimer's disease. Using a viral-mediated gene delivery approach in different mouse models of epilepsy, we show that p38γ activity-enhancing treatment reduces seizure susceptibility, restores neuronal firing patterns, reduces behavioral deficits, and ameliorates epilepsy-induced deaths. Furthermore, we show that p38γ-mediated phosphorylation of tau at T205 is essential for this protection in epilepsy, as a lack of this critical interaction reinstates …

Identifying And Minimizing Underspecification In Breast Cancer Subtyping, Jonathan Cheuk-Kiu Tang

Master's Theses

In the realm of biomedical technology, both accuracy and consistency are crucial to the development and deployment of these tools. While accuracy is easy to measure, consistency metrics are not so simple to measure, especially in the scope of biomedicine where prediction consistency can be difficult to achieve. Typically, biomedical datasets contain a significantly larger amount of features compared to the amount of samples, which goes against ordinary data mining practices. As a result, predictive models may fail to find valid pathways for prediction during training on such datasets. This concept is known as underspecification.

Underspecification has been more accepted …

Structural Variants Drive Context-Dependent Oncogene Activation In Cancer, Zhichao Xu, Dong-Sung Lee, Sahaana Chandran, Victoria T Le, Rosalind Bump, Jean Yasis, Sofia Dallarda, Samantha Marcotte, Benjamin Clock, Nicholas Haghani, Chae Yun Cho, Kadir C Akdemir, Selene Tyndale, P Andrew Futreal, Graham Mcvicker, Geoffrey M Wahl, Jesse R Dixon

Faculty, Staff and Student Publications

Higher-order chromatin structure is important for the regulation of genes by distal regulatory sequences. Structural variants (SVs) that alter three-dimensional (3D) genome organization can lead to enhancer-promoter rewiring and human disease, particularly in the context of cancer3. However, only a small minority of SVs are associated with altered gene expression4,5, and it remains unclear why certain SVs lead to changes in distal gene expression and others do not. To address these questions, we used a combination of genomic profiling and genome engineering to identify sites of recurrent changes in 3D genome structure in cancer and determine the effects of specific …

Germline Variants Associated With Toxicity To Immune Checkpoint Blockade, Stefan Groha, Sarah Abou Alaiwi, Wenxin Xu, Vivek Naranbhai, Amin H Nassar, Ziad Bakouny, Talal El Zarif, Renee Maria Saliby, Guihong Wan, Ahmad Rajeh, Elio Adib, Pier V Nuzzo, Andrew L Schmidt, Chris Labaki, Biagio Ricciuti, Joao Victor Alessi, David A Braun, Sachet A Shukla, Tanya E Keenan, Eliezer Van Allen, Mark M Awad, Michael Manos, Osama Rahma, Leyre Zubiri, Alexandra-Chloe Villani, Benjamin Fairfax, Christian Hammer, Zia Khan, Kerry Reynolds, Yevgeniy Semenov, Deborah Schrag, Kenneth L Kehl, Matthew L Freedman, Toni K Choueiri, Alexander Gusev

Faculty, Staff and Student Publications

Immune checkpoint inhibitors (ICIs) have yielded remarkable responses but often lead to immune-related adverse events (irAEs). Although germline causes for irAEs have been hypothesized, no individual variant associated with developing irAEs has been identified. We carried out a genome-wide association study of 1,751 patients on ICIs across 12 cancer types. We investigated two irAE phenotypes: (1) high-grade (3-5) and (2) all-grade events. We identified 3 genome-wide significant associations (P < 5 × 10-8) in the discovery cohort associated with all-grade irAEs: rs16906115 near IL7 (combined P = 3.6 × 10-11; hazard ratio (HR) = 2.1); rs75824728 near IL22RA1 (combined P = 3.5 × 10-8; HR = 1.8); and rs113861051 on 4p15 (combined P = 1.2 × 10-8, HR = 2.0); rs16906115 was replicated in 3 independent studies. The association near IL7 colocalized with the gain of a new cryptic exon for IL7, a critical regulator of lymphocyte homeostasis. Patients carrying the IL7 germline variant exhibited significantly increased lymphocyte stability after ICI initiation, which was itself predictive of downstream irAEs and improved survival.

Distinct Germline Genetic Susceptibility Profiles Identified For Common Non-Hodgkin Lymphoma Subtypes, Sonja I Berndt, Joseph Vijai, Yolanda Benavente, Nicola J Camp, Alexandra Nieters, Zhaoming Wang, Karin E Smedby, Geffen Kleinstern, Henrik Hjalgrim, Caroline Besson, Christine F Skibola, Lindsay M Morton, Angela R Brooks-Wilson, Lauren R Teras, Charles Breeze, Joshua Arias, Hans-Olov Adami, Demetrius Albanes, Kenneth C Anderson, Stephen M Ansell, Bryan Bassig, Nikolaus Becker, Parveen Bhatti, Brenda M Birmann, Paolo Boffetta, Paige M Bracci, Paul Brennan, Elizabeth E Brown, Laurie Burdett, Lisa A Cannon-Albright, Ellen T Chang, Brian C H Chiu, Charles C Chung, Jacqueline Clavel, Pierluigi Cocco, Graham Colditz, Lucia Conde, David V Conti, David G Cox, Karen Curtin, Delphine Casabonne, Immaculata De Vivo, Arjan Diepstra, W Ryan Diver, Ahmet Dogan, Christopher K Edlund, Lenka Foretova, Joseph F Fraumeni, Attilio Gabbas, Hervé Ghesquières, Graham G Giles, Sally Glaser, Martha Glenn, Bengt Glimelius, Jian Gu, Thomas M Habermann, Christopher A Haiman, Corinne Haioun, Jonathan N Hofmann, Theodore R Holford, Elizabeth A Holly, Amy Hutchinson, Aalin Izhar, Rebecca D Jackson, Ruth F Jarrett, Rudolph Kaaks, Eleanor Kane, Laurence N Kolonel, Yinfei Kong, Peter Kraft, Anne Kricker, Annette Lake, Qing Lan, Charles Lawrence, Dalin Li, Mark Liebow, Brian K Link, Corrado Magnani, Marc Maynadie, James Mckay, Mads Melbye, Lucia Miligi, Roger L Milne, Thierry J Molina, Alain Monnereau, Rebecca Montalvan, Kari E North, Anne J Novak, Kenan Onel, Mark P Purdue, Kristin A Rand, Elio Riboli, Jacques Riby, Eve Roman, Gilles Salles, Douglas W Sborov, Richard K Severson, Tait D Shanafelt, Martyn T Smith, Alexandra Smith, Kevin W Song, Lei Song, Melissa C Southey, John J Spinelli, Anthony Staines, Deborah Stephens, Heather J Sutherland, Kaitlyn Tkachuk, Carrie A Thompson, Hervé Tilly, Lesley F Tinker, Ruth C Travis, Jenny Turner, Celine M Vachon, Claire M Vajdic, Anke Van Den Berg, David J Van Den Berg, Roel C H Vermeulen, Paolo Vineis, Sophia S Wang, Elisabete Weiderpass, George J Weiner, Stephanie Weinstein, Nicole Wong Doo, Yuanqing Ye, Meredith Yeager, Kai Yu, Anne Zeleniuch-Jacquotte, Yawei Zhang, Tongzhang Zheng, Elad Ziv, Joshua Sampson, Nilanjan Chatterjee, Kenneth Offit, Wendy Cozen, Xifeng Wu, James R Cerhan, Stephen J Chanock, Susan L Slager, Nathaniel Rothman

Faculty, Staff and Student Publications

Lymphoma risk is elevated for relatives with common non-Hodgkin lymphoma (NHL) subtypes, suggesting shared genetic susceptibility across subtypes. To evaluate the extent of mutual heritability among NHL subtypes and discover novel loci shared among subtypes, we analyzed data from eight genome-wide association studies within the InterLymph Consortium, including 10,629 cases and 9,505 controls. We utilized Association analysis based on SubSETs (ASSET) to discover loci for subsets of NHL subtypes and evaluated shared heritability across the genome using Genome-wide Complex Trait Analysis (GCTA) and polygenic risk scores. We discovered 17 genome-wide significant loci (P<5 >× 10−8) for subsets of NHL subtypes, …

Direct Cd32 T-Cell Cytotoxicity: Implications For Breast Cancer Prognosis And Treatment, Giuseppe Sconocchia, Giulia Lanzilli, Valeriana Cesarini, Domenico A Silvestris, Katayoun Rezvani, Roberto Arriga, Sara Caratelli, Ken Chen, Jinzhuang Dou, Carlo Cenciarelli, Gabriele Toietta, Silvia Baldari, Tommaso Sconocchia, Francesca De Paolis, Anna Aureli, Giandomenica Iezzi, Maria Irno Consalvo, Francesco Buccisano, Maria I Del Principe, Luca Maurillo, Adriano Venditti, Alessio Ottaviani, Giulio C Spagnoli

Faculty, Staff and Student Publications

The FcγRII (CD32) ligands are IgFc fragments and pentraxins. The existence of additional ligands is unknown. We engineered T cells with human chimeric receptors resulting from the fusion between CD32 extracellular portion and transmembrane CD8α linked to CD28/ζ chain intracellular moiety (CD32-CR). Transduced T cells recognized three breast cancer (BC) and one colon cancer cell line among 15 tested in the absence of targeting antibodies. Sensitive BC cell conjugation with CD32-CR T cells induced CD32 polarization and down-regulation, CD107a release, mutual elimination, and proinflammatory cytokine production unaffected by human IgGs but enhanced by cetuximab. CD32-CR T cells protected immunodeficient mice …

Statistical Process Control To Monitor Use Of A Web-Based Autoplanning Tool, Hunter Mehrens, Raphael Douglas, Mary Gronberg, Kelly Nealon, Joy Zhang, Laurence Court

Faculty, Staff and Student Publications

PURPOSE: To investigate the use of statistical process control (SPC) for quality assurance of an integrated web-based autoplanning tool, Radiation Planning Assistant (RPA).

METHODS: Automatically generated plans were downloaded and imported into two treatment planning systems (TPSs), RayStation and Eclipse, in which they were recalculated using fixed monitor units. The recalculated plans were then uploaded back to the RPA, and the mean dose differences for each contour between the original RPA and the TPSs plans were calculated. SPC was used to characterize the RPA plans in terms of two comparisons: RayStation TPS versus RPA and Eclipse TPS versus RPA for …

Radiomics In Abdominopelvic Solid-Organ Oncologic Imaging: Current Status, Xiaoyang Liu, Mohamed G Elbanan, Antonio Luna, Masoom A Haider, Andrew D Smith, Carl F Sabottke, Bradley M Spieler, Baris Turkbey, David Fuentes, Ahmed Moawad, Serageldin Kamel, Natally Horvat, Khaled M Elsayes

Faculty, Staff and Student Publications

Radiomics is the process of extraction of high-throughput quantitative imaging features from medical images. These features represent noninvasive quantitative biomarkers that go beyond the traditional imaging features visible to the human eye. This article first reviews the steps of the radiomics pipeline, including image acquisition, ROI selection and image segmentation, image preprocessing, feature extraction, feature selection, and model development and application. Current evidence for the application of radiomics in abdominopelvic solid-organ cancers is then reviewed. Applications including diagnosis, subtype determination, treatment response assessment, and outcome prediction are explored within the context of hepatobiliary and pancreatic cancer, renal cell carcinoma, prostate …

Clinically Significant Metachronous Colorectal Pathology Detected Among Young-Onset Colorectal Cancer Survivors: Implications For Post-Resection Surveillance Guidelines, Oliver Peacock, Eduardo Vilar, Montserrat Guraieb-Trueba, Selvi Thirumurthi, George J Chang, Y Nancy You

Faculty, Staff and Student Publications

No abstract provided.

Utility Of Measurable Residual Disease For Predicting Treatment Outcomes With Bcr- And Bcl2-Targeted Therapies In Patients With Cll, William G Wierda, Thomas J Kipps, Othman Al-Sawaf, Brenda Chyla, Juliana M L Biondo, Yong Mun, Yanwen Jiang, John F Seymour

Faculty, Staff and Student Publications

Inhibitors targeting B-cell receptor (BCR) signaling pathway proteins and B-cell lymphoma-2 (BCL2) in chronic lymphocytic leukemia (CLL) are recommended in the first-line and relapsed/refractory disease settings. Measurable residual disease (MRD) is an important prognostic tool in patients treated with the BCL2-targeted agent, venetoclax. We explored the relationship between MRD status and progression-free (PFS)/overall survival (OS) in patients with CLL, following treatment with novel BCR- and BCL2-targeted agents. Compared with chemoimmunotherapy, higher rates of undetectable (u)MRD were achieved with BCL2-targeted therapies; achieving uMRD status was associated with longer PFS and OS than MRD-positivity. Continuous treatment with BCR-targeted agents did not achieve …

Implications Of Ras Mutational Status In Subsets Of Patients With Newly Diagnosed Acute Myeloid Leukemia Across Therapy Subtypes, Daniel Rivera, Kunhwa Kim, Rashmi Kanagal-Shamanna, Gautam Borthakur, Guillermo Montalban-Bravo, Naval Daver, Courtney Dinardo, Nicholas J Short, Musa Yilmaz, Naveen Pemmaraju, Koichi Takahashi, Elias J Jabbour, Sherry Pierce, Marina Konopleva, Kapil Bhalla, Guillermo Garcia-Manero, Farhad Ravandi, Hagop Kantarjian, Tapan M Kadia

Faculty, Staff and Student Publications

Activating mutations in RAS have been reported in about 10-15% of patients with AML; previous studies have not identified a prognostic significance. However, RAS mutations have emerged as a potential resistance mechanism to treatment with inhibitors of FLT3, IDH, and BCL2. We aimed to determine the characteristics and outcomes of patients with RAS-mutated (RAS-mut) AML across therapy subsets of 1410 patients newly diagnosed (ND AML). RAS-mut was observed in 273 (20%) patients. Overall, patients with RAS-mut AML had an estimated 3-year survival rate of 38% vs. 28% in those with RAS wild type (RAS-wt), p = .01. Among patients with …