Digital Commons Network^™

Systemic Sclerosis Associated Interstitial Lung Disease: A Conceptual Framework For Subclinical, Clinical And Progressive Disease, David Roofeh, Kevin K Brown, Ella A Kazerooni, Donald Tashkin, Shervin Assassi, Fernando Martinez, Athol U Wells, Ganesh Raghu, Christopher P Denton, Lorinda Chung, Anna-Maria Hoffmann-Vold, Oliver Distler, Kerri A Johannson, Yannick Allanore, Eric L Matteson, Leticia Kawano-Dourado, John D Pauling, James R Seibold, Elizabeth R Volkmann, Simon L F Walsh, Chester V Oddis, Eric S White, Shaney L Barratt, Elana J Bernstein, Robyn T Domsic, Paul F Dellaripa, Richard Conway, Ivan Rosas, Nitin Bhatt, Vivien Hsu, Francesca Ingegnoli, Bashar Kahaleh, Puneet Garcha, Nishant Gupta, Surabhi Khanna, Peter Korsten, Celia Lin, Stephen C Mathai, Vibeke Strand, Tracy J Doyle, Virginia Steen, Donald F Zoz, Juan Ovalles-Bonilla, Ignasi Rodriguez-Pinto, Padmanabha D Shenoy, Andrew Lewandoski, Elizabeth Belloli, Alain Lescoat, Vivek Nagaraja, Wen Ye, Suiyuan Huang, Toby Maher, Dinesh Khanna

Faculty, Staff and Students Publications

OBJECTIVES: To establish a framework by which experts define disease subsets in systemic sclerosis associated interstitial lung disease (SSc-ILD).

METHODS: A conceptual framework for subclinical, clinical and progressive ILD was provided to 83 experts, asking them to use the framework and classify actual SSc-ILD patients. Each patient profile was designed to be classified by at least four experts in terms of severity and risk of progression at baseline; progression was based on 1-year follow-up data. A consensus was reached if ≥75% of experts agreed. Experts provided information on which items were important in determining classification.

RESULTS: Forty-four experts (53%) completed …

Very-Long-Chain Fatty Acids Induce Glial-Derived Sphingosine-1-Phosphate Synthesis, Secretion, And Neuroinflammation, Hyung-Lok Chung, Qi Ye, Ye-Jin Park, Zhongyuan Zuo, Jung-Wan Mok, Oguz Kanca, Sudhir Gopal Tattikota, Shenzhao Lu, Nobert Perrimon, Hyun Kyoung Lee, Hugo J Bellen

Faculty, Staff and Students Publications

VLCFAs (very-long-chain fatty acids) are the most abundant fatty acids in myelin. Hence, during demyelination or aging, glia are exposed to higher levels of VLCFA than normal. We report that glia convert these VLCFA into sphingosine-1-phosphate (S1P) via a glial-specific S1P pathway. Excess S1P causes neuroinflammation, NF-κB activation, and macrophage infiltration into the CNS. Suppressing the function of S1P in fly glia or neurons, or administration of Fingolimod, an S1P receptor antagonist, strongly attenuates the phenotypes caused by excess VLCFAs. In contrast, elevating the VLCFA levels in glia and immune cells exacerbates these phenotypes. Elevated VLCFA and S1P are also …

Adiposity-Associated Atrial Fibrillation: Molecular Determinants, Mechanisms, And Clinical Significance, Monika Gawałko, Arnela Saljic, Na Li, Issam Abu-Taha, Thomas Jespersen, Dominik Linz, Stanley Nattel, Jordi Heijman, Anke Fender, Dobromir Dobrev

Faculty, Staff and Students Publications

Obesity is an important contributing factor to the pathophysiology of atrial fibrillation (AF) and its complications by causing systemic changes, such as altered haemodynamic, increased sympathetic tone, and low-grade chronic inflammatory state. In addition, adipose tissue is a metabolically active organ that comprises various types of fat deposits with discrete composition and localization that show distinct functions. Fatty tissue differentially affects the evolution of AF, with highly secretory active visceral fat surrounding the heart generally having a more potent influence than the rather inert subcutaneous fat. A variety of proinflammatory, profibrotic, and vasoconstrictive mediators are secreted by adipose tissue, particularly …

Higher Risk Of Short Term Covid-19 Vaccine Adverse Events In Myositis Patients With Autoimmune Comorbidities: Results From The Covad Study, Mrinalini Dey, Naveen R, Elena Nikiphorou, Parikshit Sen, Sreoshy Saha, James B Lilleker, Vishwesh Agarwal, Sinan Kardes, Jessica Day, Marcin Milchert, Mrudula Joshi, Tamer Gheita, Babur Salim, Tsvetelina Velikova, Abraham Edgar Gracia-Ramos, Ioannis Parodis, Albert Selva O'Callaghan, Minchul Kim, Tulika Chatterjee, Ai Lyn Tan, Ashima Makol, Arvind Nune, Lorenzo Cavagna, Miguel A Saavedra, Samuel Katsuyuki Shinjo, Nelly Ziade, Johannes Knitza, Masataka Kuwana, Oliver Distler, Bhupen Barman, Yogesh Preet Singh, Rajiv Ranjan, Avinash Jain, Sapan C Pandya, Rakesh Kumar Pilania, Aman Sharma, Manesh M Manoj, Vikas Gupta, Chengappa G Kavadichanda, Pradeepta Sekhar Patro, Sajal Ajmani, Sanat Phatak, Rudra Prosad Goswami, Abhra Chandra Chowdhury, Ashish Jacob Mathew, Padnamabha Shenoy, Ajay Asranna, Keerthi Talari Bommakanti, Anuj Shukla, Arunkumar R Pande, Kunal Chandwar, John D Pauling, Chris Wincup, Döndü Üsküdar Cansu, Erick Adrian Zamora Tehozol, Jorge Rojas Serrano, Ignacio García-De La Torre, Nicoletta Del Papa, Gianluca Sambataro, Atzeni Fabiola, Marcello Govoni, Simone Parisi, Elena Bartoloni Bocci, Gian Domenico Sebastiani, Enrico Fusaro, Marco Sebastiani, Luca Quartuccio, Franco Franceschini, Pier Paolo Sainaghi, Giovanni Orsolini, Rossella De Angelis, Maria Giovanna Danielli, Vincenzo Venerito, Lisa S Traboco, Leonardo Santos Hoff, Suryo Anggoro Kusumo Wibowo, Stylianos Tomaras, Daman Langguth, Vidya Limaye, Merrilee Needham, Nilesh Srivastav, Akira Yoshida, Ran Nakashima, Shinji Sato, Naoki Kimura, Yuko Kaneko, Jesús Loarce-Martos, Sergio Prieto-González, Albert Gil-Vila, Raquel Arànega Gonzalez, Hector Chinoy, Vikas Agarwal, Rohit Aggarwal, Latika Gupta

Faculty, Staff and Student Publications

No abstract provided.

Association Of Mitochondrial Dna Copy Number With Brain Mri Markers And Cognitive Function: A Meta-Analysis Of Community-Based Cohorts, Yuankai Zhang, Xue Liu, Kerri L Wiggins, Nuzulul Kurniansyah, Xiuqing Guo, Amanda L Rodrigue, Wei Zhao, Lisa R Yanek, Scott M Ratliff, Achilleas Pitsillides, Juan Sebastian Aguirre Patiño, Tamar Sofer, Dan E Arking, Thomas R Austin, Alexa S Beiser, John Blangero, Eric Boerwinkle, Jan Bressler, Joanne E Curran, Lifang Hou, Timothy M Hughes, Sharon L R Kardia, Lenore J Launer, Daniel Levy, Thomas H Mosley, Ilya M Nasrallah, Stephen S Rich, Jerome I Rotter, Sudha Seshadri, Wassim Tarraf, Kevin A González, Vasan Ramachandran, Kristine Yaffe, Paul A Nyquist, Bruce M Psaty, Charles S Decarli, Jennifer A Smith, David C Glahn, Hector M González, Joshua C Bis, Myriam Fornage, Susan R Heckbert, Annette L Fitzpatrick, Chunyu Liu, Claudia L Satizabal

Faculty, Staff and Student Publications

BACKGROUND AND OBJECTIVES: Previous studies suggest that lower mitochondrial DNA (mtDNA) copy number (CN) is associated with neurodegenerative diseases. However, whether mtDNA CN in whole blood is related to endophenotypes of Alzheimer disease (AD) and AD-related dementia (AD/ADRD) needs further investigation. We assessed the association of mtDNA CN with cognitive function and MRI measures in community-based samples of middle-aged to older adults.

METHODS: We included dementia-free participants from 9 diverse community-based cohorts with whole-genome sequencing in the Trans-Omics for Precision Medicine (TOPMed) program. Circulating mtDNA CN was estimated as twice the ratio of the average coverage of mtDNA to nuclear …

Assessing Gaps In Motherhood After Cancer: Development And Psychometric Testing Of The Survivorship Oncofertility Barriers Scale, Aubri Hoffman, Chloe Josephine Denham, Shuangshuang Fu, Tito Mendoza, Roni Nitecki, Kirsten A Jorgensen, Jose Garcia, Kelly Lamiman, Terri L Woodard, J Alejandro Rauh-Hain

Faculty, Staff and Student Publications

Objective: With a growing population of young cancer survivors, there is an increasing need to address the gaps in evidence regarding cancer survivors' obstetric outcomes, fertility care access, and experiences. As part of a large research program, this study engaged survivors and experts in co-developing and testing the validity, reliability, acceptability, and feasibility of a scale to assess survivor-reported barriers to motherhood after cancer.

Methods: Scale items were developed based on literature and expert review of 226 reproductive health items, and six experience and focus groups with 26 survivors of breast and gynecological cancers. We then invited 128 survivors to …

An Exploratory Simulation Study And Prediction Model On Human Brain Behavior And Activity Using An Integration Of Deep Neural Network And Biosensor Rabi Antenna, Nhat Truong Pham, Montree Bunruangses, Phichai Youplao, Anita Garhwal, Kanad Ray, Arup Roy, Sarawoot Boonkirdram, Preecha Yupapin, Muhammad Arif Jalil, Jalil Ali, Shamim Kaiser, Mufti Mahmud, Saurav Mallik, Zhongming Zhao

Faculty, Staff and Student Publications

The plasmonic antenna probe is constructed using a silver rod embedded in a modified Mach-Zehnder interferometer (MZI) ad-drop filter. Rabi antennas are formed when space-time control reaches two levels of system oscillation and can be used as human brain sensor probes. Photonic neural networks are designed using brain-Rabi antenna communication, and transmissions are connected via neurons. Communication signals are carried by electron spin (up and down) and adjustable Rabi frequency. Hidden variables and deep brain signals can be obtained by external detection. A Rabi antenna has been developed by simulation using computer simulation technology (CST) software. Additionally, a communication device …

Inferring Evolutionary Trajectories From Cross-Sectional Transcriptomic Data To Mirror Lung Adenocarcinoma Progression, Kexin Huang, Yun Zhang, Haoran Gong, Zhengzheng Qiao, Tiangang Wang, Weiling Zhao, Liyu Huang, Xiaobo Zhou

Faculty, Staff and Student Publications

Lung adenocarcinoma (LUAD) is a deadly tumor with dynamic evolutionary process. Although much endeavors have been made in identifying the temporal patterns of cancer progression, it remains challenging to infer and interpret the molecular alterations associated with cancer development and progression. To this end, we developed a computational approach to infer the progression trajectory based on cross-sectional transcriptomic data. Analysis of the LUAD data using our approach revealed a linear trajectory with three different branches for malignant progression, and the results showed consistency in three independent cohorts. We used the progression model to elucidate the potential molecular events in LUAD …

Prevalence Of Sars-Cov-2 Antibodies By Rural-Urban Residential Status In Texas, Breanna Bailey Ellis

Dissertations and Theses (Open Access)

Understanding the health disparities associated with SARS-CoV-2 antibody status across Texas is essential. These differences can guide healthcare professionals and local public health officials to identify vulnerable populations needing COVID-19 prevention and treatment resources. This study aims to contribute to the literature by determining if rural and urban geographical locations are disproportionately impacted by SARS-CoV-2 infection and vaccination in the state of Texas. I utilized the Texas Coronavirus Antibody REsponse Survey (Texas CARES), a large ongoing prospective population-based survey among 5–90-year-olds from the Texas general population that began collecting seroprevalence data in October 2020 (1). Participants in the survey are …

Elucidating Mechanisms Involved In Host Microbial-Tumor Interactions, Vidhi Chandra

Dissertations and Theses (Open Access)

Cancer is a rising cause of mortality worldwide. Microbiota is the collection of micro-organisms that live inside our bodies and can impact the host health and disease by interacting with the immune and metabolic systems. The relationship between the microbiota and cancer is complex. Gut and intratumoral microbiota can affect cancer development and progression by influencing patient outcomes and therapy responsiveness in several cancer types. Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer surrounded by a highly immuno-suppressive tumor microenvironment (TME) which limits efficacy of most available therapies. The tumoral niche provides a privileged microenvironment for microbial colonization that can …

Unique Transcriptional Profiles Underlie Osteosarcomagenesis Driven By Different P53 Mutants, Dhruv Chachad

Dissertations and Theses (Open Access)

Missense mutations in the DNA binding domain of the Trp53 gene are characterized as structural (p53R172H) or contact (p53R245W) mutations based on their effect on the conformation of the protein. These mutations show gain-of-function activities such as increased metastatic incidence as compared to p53 loss, often mediated by their interaction with a repertoire of transcription factors. These interactions are largely context specific. In order to understand the mechanisms by which these mutations drive osteosarcoma progression, we created a mouse model, wherein either the p53 structural mutant p53R172H, or the contact mutant, p53R245W, are expressed specifically in …

Pregnant Black/African Americans' Experiences In Prenatal Genetic Counseling, Latonya Alexander

Dissertations and Theses (Open Access)

Pregnant Black/African American patients have faced systematic racism in the U.S. healthcare system embodied in the high maternal morbidity and mortality rates. Patients have the desire to feel heard and connected with their healthcare providers. Prenatal genetic counselors are not only trained to provide education to individuals, couples, and families who may be seeking genetic counseling, but also to use psychosocial skills with patients. Previous studies with majority of White participants have described how psychosocial skills build patient trust. Therefore, this study aimed to determine what factors made pregnant Black/African American patients feel heard and trustful with their prenatal genetic …

Mincle-Gsdmd-Mediated Release Of Il-1Β Small Extracellular Vesicles From Hepatic Macrophages In Ethanol-Induced Liver Injury, Quanri Zhang, Weiwei Liu, Katarzyna Bulek, Han Wang, Megan R Mcmullen, Xiaoqin Wu, Nicole Welch, Renliang Zhang, Jaividhya Dasarathy, Srinivasan Dasarathy, Laura E Nagy, Xiaoxia Li

Faculty, Staff and Student Publications

BACKGROUND: Macrophage-inducible C-type lectin (Mincle) is expressed on hepatic macrophages and senses ethanol (EtOH)-induced danger signals released from dying hepatocytes and promotes IL-1β production. However, it remains unclear what and how EtOH-induced Mincle ligands activate downstream signaling events to mediate IL-1β release and contribute to alcohol-associated liver disease (ALD). In this study, we investigated the association of circulating β-glucosylceramide (β-GluCer), an endogenous Mincle ligand, with severity of ALD and examined the mechanism by which β-GluCer engages Mincle on hepatic macrophages to release IL-1β in the absence of cell death and exacerbates ALD.

METHOD AND RESULTS: Concentrations of β-GluCer were increased …

Fully Human Monoclonal Antibody Targeting Activated Adam10 On Colorectal Cancer Cells, Nayanendu Saha, Du-San Baek, Rachelle P Mendoza, Dorothea Robev, Yan Xu, Yehuda Goldgur, M Jason De La Cruz, Elisa De Stanchina, Peter W Janes, Kai Xu, Dimiter S Dimitrov, Dimitar B Nikolov

Faculty, Staff and Student Publications

Metastasis and chemoresistance in colorectal cancer are mediated by certain poorly differentiated cancer cells, known as cancer stem cells, that are maintained by Notch downstream signaling initiated upon Notch cleavage by the metalloprotease ADAM10. It has been shown that ADAM10 overexpression correlates with aberrant signaling from Notch, erbBs, and other receptors, as well as a more aggressive metastatic phenotype, in a range of cancers including colon, gastric, prostate, breast, ovarian, uterine, and leukemia. ADAM10 inhibition, therefore, stands out as an important and new approach to deter the progression of advanced CRC. For targeting the ADAM10 substrate-binding region, which is located …

Efficacy Of Alternative Dose Regimens Of Exemestane In Postmenopausal Women With Stage 0 To Ii Estrogen Receptor-Positive Breast Cancer: A Randomized Clinical Trial, Davide Serrano, Sara Gandini, Parjhitham Thomas, Katherine D Crew, Nagi B Kumar, Lana A Vornik, J Jack Lee, Paolo Veronesi, Giuseppe Viale, Aliana Guerrieri-Gonzaga, Matteo Lazzeroni, Harriet Johansson, Mauro D'Amico, Flavio Guasone, Stefano Spinaci, Bjørn-Erik Bertelsen, Gunnar Mellgren, Isabelle Bedrosian, Diane Weber, Tawana Castile, Eileen Dimond, Brandy M Heckman-Stoddard, Eva Szabo, Powel H Brown, Andrea Decensi, Bernardo Bonanni

Faculty, Staff and Student Publications

IMPORTANCE: Successful therapeutic cancer prevention requires definition of the minimal effective dose. Aromatase inhibitors decrease breast cancer incidence in high-risk women, but use in prevention and compliance in adjuvant settings are hampered by adverse events.

OBJECTIVE: To compare the noninferiority percentage change of estradiol in postmenopausal women with estrogen receptor-positive breast cancer given exemestane, 25 mg, 3 times weekly or once weekly vs a standard daily dose with a noninferiority margin of -6%.

DESIGN, SETTING, AND PARTICIPANTS: This multicenter, presurgical, double-blind phase 2b randomized clinical trial evaluated 2 alternative dosing schedules of exemestane. Postmenopausal women with estrogen receptor-positive breast cancer …

Comparison Of Reconstructed Prompt Gamma Emissions Using Maximum Likelihood Estimation And Origin Ensemble Algorithms For A Compton Camera System Tailored To Proton Range Monitoring, Ingrid Valencia Lozano, George Dedes, Steve Peterson, Dennis Mackin, Andreas Zoglauer, Sam Beddar, Stephen Avery, Jerimy Polf, Katia Parodi

Faculty, Staff and Student Publications

Compton-based prompt gamma (PG) imaging is being investigated by several groups as a potential solution for in vivo range monitoring in proton therapy. The performance of this technique depends on the detector system as well as the ability of the reconstruction method to obtain good spatial resolution to establish a quantitative correlation between the PG emission and the proton beam range in the patient. To evaluate the feasibility of PG imaging for range monitoring, we quantitatively evaluated the emission distributions reconstructed by a Maximum Likelihood Expectation Maximization (MLEM) and a Stochastic Origin Ensemble (SOE) algorithm. To this end, we exploit …

A Parathyroid Hormone/Salt-Inducible Kinase Signaling Axis Controls Renal Vitamin D Activation And Organismal Calcium Homeostasis, Sung-Hee Yoon, Mark B Meyer, Carlos Arevalo, Murat Tekguc, Chengcheng Zhang, Jialiang S Wang, Christian D Castro Andrade, Katelyn Strauss, Tadatoshi Sato, Nancy A Benkusky, Seong Min Lee, Rebecca Berdeaux, Marc Foretz, Thomas B Sundberg, Ramnik J Xavier, Charles H Adelmann, Daniel J Brooks, Anthony Anselmo, Ruslan I Sadreyev, Ivy A Rosales, David E Fisher, Navin Gupta, Ryuji Morizane, Anna Greka, J Wesley Pike, Michael Mannstadt, Marc N Wein

Faculty, Staff and Student Publications

The renal actions of parathyroid hormone (PTH) promote 1,25-vitamin D generation; however, the signaling mechanisms that control PTH-dependent vitamin D activation remain unknown. Here, we demonstrated that salt-inducible kinases (SIKs) orchestrated renal 1,25-vitamin D production downstream of PTH signaling. PTH inhibited SIK cellular activity by cAMP-dependent PKA phosphorylation. Whole-tissue and single-cell transcriptomics demonstrated that both PTH and pharmacologic SIK inhibitors regulated a vitamin D gene module in the proximal tubule. SIK inhibitors increased 1,25-vitamin D production and renal Cyp27b1 mRNA expression in mice and in human embryonic stem cell–derived kidney organoids. Global- and kidney-specific Sik2/Sik3 mutant mice showed Cyp27b1 upregulation, …

A Protocol For A Cluster Randomized Trial Of Care Delivery Models To Improve The Quality Of Smoking Cessation And Shared Decision Making For Lung Cancer Screening, Lisa M Lowenstein, Ya-Chen Tina Shih, Jennifer Minnix, Maria A Lopez-Olivo, Kristin G Maki, George Kypriotakis, Viola B Leal, Sanjay S Shete, James Fox, Shawn P Nishi, Paul M Cinciripini, Robert J Volk

Faculty, Staff and Student Publications

BACKGROUND: Patients eligible for lung cancer screening (LCS) are those at high risk of lung cancer due to their smoking histories and age. While screening for LCS is effective in lowering lung cancer mortality, primary care providers are challenged to meet beneficiary eligibility for LCS from the Centers for Medicare & Medicaid Services, including a patient counseling and shared decision-making (SDM) visit with the use of patient decision aid(s) prior to screening.

METHODS: We will use an effectiveness-implementation type I hybrid design to: 1) identify effective, scalable smoking cessation counseling and SDM interventions that are consistent with recommendations, can be …

P53 And Ovarian Carcinoma Survival: An Ovarian Tumor Tissue Analysis Consortium Study, Martin Köbel, Eun-Young Kang, Ashley Weir, Peter F Rambau, Cheng-Han Lee, Gregg S Nelson, Prafull Ghatage, Nicola S Meagher, Marjorie J Riggan, Jennifer Alsop, Michael S Anglesio, Matthias W Beckmann, Christiani Bisinotto, Michelle Boisen, Jessica Boros, Alison H Brand, Angela Brooks-Wilson, Michael E Carney, Penny Coulson, Madeleine Courtney-Brooks, Kara L Cushing-Haugen, Cezary Cybulski, Suha Deen, Mona A El-Bahrawy, Esther Elishaev, Ramona Erber, Sian Fereday, Aocs Group, Anna Fischer, Simon A Gayther, Arantzazu Barquin-Garcia, Aleksandra Gentry-Maharaj, C Blake Gilks, Helena Gronwald, Marcel Grube, Paul R Harnett, Holly R Harris, Andreas D Hartkopf, Arndt Hartmann, Alexander Hein, Joy Hendley, Brenda Y Hernandez, Yajue Huang, Anna Jakubowska, Mercedes Jimenez-Linan, Michael E Jones, Catherine J Kennedy, Tomasz Kluz, Jennifer M Koziak, Jaime Lesnock, Jenny Lester, Jan Lubiński, Teri A Longacre, Maria Lycke, Constantina Mateoiu, Bryan M Mccauley, Valerie Mcguire, Britta Ney, Alexander Olawaiye, Sandra Orsulic, Ana Osorio, Luis Paz-Ares, Teresa Ramón Y Cajal, Joseph H Rothstein, Matthias Ruebner, Minouk J Schoemaker, Mitul Shah, Raghwa Sharma, Mark E Sherman, Yurii B Shvetsov, Naveena Singh, Helen Steed, Sarah J Storr, Aline Talhouk, Nadia Traficante, Chen Wang, Alice S Whittemore, Martin Widschwendter, Lynne R Wilkens, Stacey J Winham, Javier Benitez, Andrew Berchuck, David D Bowtell, Francisco J Candido Dos Reis, Ian Campbell, Linda S Cook, Anna Defazio, Jennifer A Doherty, Peter A Fasching, Renée T Fortner, María J García, Marc T Goodman, Ellen L Goode, Jacek Gronwald, David G Huntsman, Beth Y Karlan, Linda E Kelemen, Stefan Kommoss, Nhu D Le, Stewart G Martin, Usha Menon, Francesmary Modugno, Paul Dp Pharoah, Joellen M Schildkraut, Weiva Sieh, Annette Staebler, Karin Sundfeldt, Anthony J Swerdlow, Susan J Ramus, James D Brenton

Faculty, Staff and Student Publications

Our objective was to test whether p53 expression status is associated with survival for women diagnosed with the most common ovarian carcinoma histotypes (high-grade serous carcinoma [HGSC], endometrioid carcinoma [EC], and clear cell carcinoma [CCC]) using a large multi-institutional cohort from the Ovarian Tumor Tissue Analysis (OTTA) consortium. p53 expression was assessed on 6,678 cases represented on tissue microarrays from 25 participating OTTA study sites using a previously validated immunohistochemical (IHC) assay as a surrogate for the presence and functional effect of TP53 mutations. Three abnormal expression patterns (overexpression, complete absence, and cytoplasmic) and the normal (wild type) pattern were …

High-Dose Once-Daily Thoracic Radiotherapy In Limited-Stage Small-Cell Lung Cancer: Calgb 30610 (Alliance)/Rtog 0538, Jeffrey Bogart, Xiaofei Wang, Gregory Masters, Junheng Gao, Ritsuko Komaki, Laurie E Gaspar, John Heymach, James Bonner, Charles Kuzma, Saiama Waqar, William Petty, Thomas E Stinchcombe, Jeffrey D Bradley, Everett Vokes

Faculty, Staff and Student Publications

PURPOSE: Although level 1 evidence supports 45-Gy twice-daily radiotherapy as standard for limited-stage small-cell lung cancer, most patients receive higher-dose once-daily regimens in clinical practice. Whether increasing radiotherapy dose improves outcomes remains to be prospectively demonstrated.

METHODS: This phase III trial, CALGB 30610/RTOG 0538 (ClinicalTrials.gov identifier: NCT00632853), was conducted in two stages. In the first stage, patients with limited-stage disease were randomly assigned to receive 45-Gy twice-daily, 70-Gy once-daily, or 61.2-Gy concomitant-boost radiotherapy, starting with either the first or second (of four total) chemotherapy cycles. In the second stage, allocation to the 61.2-Gy arm was discontinued following planned interim toxicity …

Combining Mendelian Randomization And Network Deconvolution For Inference Of Causal Networks With Gwas Summary Data, Zhaotong Lin, Haoran Xue, Wei Pan

Faculty, Staff and Student Publications

Mendelian randomization (MR) has been increasingly applied for causal inference with observational data by using genetic variants as instrumental variables (IVs). However, the current practice of MR has been largely restricted to investigating the total causal effect between two traits, while it would be useful to infer the direct causal effect between any two of many traits (by accounting for indirect or mediating effects through other traits). For this purpose we propose a two-step approach: we first apply an extended MR method to infer (i.e. both estimate and test) a causal network of total effects among multiple traits, then we …

Philadelphia-Like Genetic Rearrangements In Adults With B-Cell All: Refractoriness To Chemotherapy And Response To Tyrosine Kinase Inhibitor In Abl Class Rearrangements, Jayastu Senapati, Elias Jabbour, Marina Konopleva, Nicholas J Short, Guilin Tang, Naval Daver, Partow Kebriaei, Tapan Kadia, Naveen Pemmaraju, Koichi Takahashi, Courtney Dinardo, Koji Sasaki, Gautam Borthakur, Beenu Thakral, Rashmi Kanagal-Shamanna, Keyur Patel, Farhad Ravandi, Kathryn Roberts, Charles Mullighan, Hagop Kantarjian, Nitin Jain

Faculty, Staff and Student Publications

PURPOSE: Philadelphia-like (Ph-like) B-cell ALL is a high-risk subtype of B-cell ALL that shares a gene expression profile with Ph-positive ALL, but without a

PATIENTS AND METHODS: We performed a retrospective review of patients with B-cell ALL treated at MD Anderson Cancer Center to identify recurrent genetic fusions commonly seen in Ph-like ALL and focus on patients treated with TKI.

RESULTS: We identified 23 patients with recurrent genetic fusions commonly seen in Ph-like ALL; 14 had

CONCLUSION: Understanding the genomics of B-cell ALL is important for disease prognostication and for precise treatment planning. Besides conventional cytogenetics and directed FISH testing, …

Prospective Study Of Perioperative Circulating Tumor Dna Dynamics In Patients Undergoing Hepatectomy For Colorectal Liver Metastases, Timothy E Newhook, Michael J Overman, Yun Shin Chun, Arvind Dasari, Ching-Wei D Tzeng, Hop S Tran Cao, Victoria Raymond, Christine Parseghian, Benny Johnson, Yujiro Nishioka, Yoshikuni Kawaguchi, Abhineet Uppal, Timothy J Vreeland, Ariel Jaimovich, Elsa M Arvide, Jenilette V Cristo, Steven H Wei, Kanwal P Raghav, Van K Morris, Jeffrey E Lee, Scott Kopetz, Jean-Nicolas Vauthey

Faculty, Staff and Student Publications

OBJECTIVE: To evaluate the association of perioperative ctDNA dynamics on outcomes after hepatectomy for CLM.

SUMMARY BACKGROUND DATA: Prognostication is imprecise for patients undergoing hepatectomy for CLM, and ctDNA is a promising biomarker. However, clinical implications of perioperative ctDNA dynamics are not well established.

METHODS: Patients underwent curative-intent hepatectomy after preoperative chemotherapy for CLM (2013-2017) with paired prehepatectomy/postoperative ctDNA analyses via plasma-only assay. Positivity was determined using a proprietary variant classifier. Primary endpoint was recurrence-free survival (RFS). Median follow-up was 55 months.

RESULTS: Forty-eight patients were included. ctDNA was detected before and after surgery (ctDNA+/+) in 14 (29%), before but …

Neural Network Based Ensemble Model To Predict Radiation Induced Lymphopenia After Concurrent Chemo-Radiotherapy For Non-Small Cell Lung Cancer From Two Institutions, Yejin Kim, Ibrahim Chamseddine, Yeona Cho, Jin Sung Kim, Radhe Mohan, Nadya Shusharina, Harald Paganetti, Steven Lin, Hong In Yoon, Seungryong Cho, Clemens Grassberger

Faculty, Staff and Student Publications

The use of adjuvant Immune Checkpoint Inhibitors (ICI) after concurrent chemo-radiation therapy (CCRT) has become the standard of care for locally advanced non-small cell lung cancer (LA-NSCLC). However, prolonged radiotherapy regimens are known to cause radiation-induced lymphopenia (RIL), a long-neglected toxicity that has been shown to correlate with response to ICIs and survival of patients treated with adjuvant ICI after CCRT. In this study, we aim to develop a novel neural network (NN) approach that integrates patient characteristics, treatment related variables, and differential dose volume histograms (dDVH) of lung and heart to predict the incidence of RIL at the end …

Genome-Wide Analysis Of Structural Variants In Parkinson Disease, Kimberley J Billingsley, Jinhui Ding, Pilar Alvarez Jerez, Anastasia Illarionova, Kristin Levine, Francis P Grenn, Mary B Makarious, Anni Moore, Daniel Vitale, Xylena Reed, Dena Hernandez, Ali Torkamani, Mina Ryten, John Hardy, Uk Brain Expression Consortium (Ukbec), Ruth Chia, Sonja W Scholz, Bryan J Traynor, Clifton L Dalgard, Debra J Ehrlich, Toshiko Tanaka, Luigi Ferrucci, Thomas G Beach, Geidy E Serrano, John P Quinn, Vivien J Bubb, Ryan L Collins, Xuefang Zhao, Mark Walker, Emma Pierce-Hoffman, Harrison Brand, Michael E Talkowski, Bradford Casey, Mark R Cookson, Androo Markham, Mike A Nalls, Medhat Mahmoud, Fritz J Sedlazeck, Cornelis Blauwendraat, J Raphael Gibbs, Andrew B Singleton

Faculty, Staff and Students Publications

OBJECTIVE: Identification of genetic risk factors for Parkinson disease (PD) has to date been primarily limited to the study of single nucleotide variants, which only represent a small fraction of the genetic variation in the human genome. Consequently, causal variants for most PD risk are not known. Here we focused on structural variants (SVs), which represent a major source of genetic variation in the human genome. We aimed to discover SVs associated with PD risk by performing the first large-scale characterization of SVs in PD.

METHODS: We leveraged a recently developed computational pipeline to detect and genotype SVs from 7,772 …

Hemato-Vascular Specification Requires Arnt1 And Arnt2 Genes In Zebrafish Embryos, Hailey E Edwards, Mary Jane Elizalde, Jaclyn P Souder, Daniel A Gorelick

Faculty, Staff and Students Publications

During embryonic development, a subset of cells in the mesoderm germ layer are specified as hemato-vascular progenitor cells, which then differentiate into endothelial cells and hematopoietic stem and progenitor cells. In zebrafish, the transcription factor npas4l (cloche) is required for the specification of hemato-vascular progenitor cells. However, it is unclear whether npas4l is the sole factor at the top of the hemato-vascular specification cascade. Here, we show that arnt1 and arnt2 genes are required for hemato-vascular specification. We found that arnt1;arnt2 double mutant zebrafish embryos, but not arnt1 or arnt2 single mutants, lack blood cells and most endothelial cells. arnt1/2 …

Interaction Modules That Impart Specificity To Disordered Protein, Katerina Cermakova, H Courtney Hodges

Faculty, Staff and Students Publications

Intrinsically disordered regions (IDRs) are especially enriched among proteins that regulate chromatin and transcription. As a result, mechanisms that influence specificity of IDR-driven interactions have emerged as exciting unresolved issues for understanding gene regulation. We review the molecular elements frequently found within IDRs that confer regulatory specificity. In particular, we summarize the differing roles of disordered low-complexity regions (LCRs) and short linear motifs (SLiMs) towards selective nuclear regulation. Examination of IDR-driven interactions highlights SLiMs as organizers of selectivity, with widespread roles in gene regulation and integration of cellular signals. Analysis of recurrent interactions between SLiMs and folded domains suggests diverse …

Bladder Mucosal Cystitis Cystica Lesions Are Tertiary Lymphoid Tissues That Correlate With Recurrent Urinary Tract Infection Frequency In Postmenopausal Women, Marianne M Ligon, Brooke Liang, Stacy M Lenger, Priyanka Parameswaran, Siobhan Sutcliffe, Jerry L Lowder, Indira U Mysorekar

Faculty, Staff and Students Publications

PURPOSE: We identify correlates and clinical outcomes of cystitis cystica, a poorly understood chronic inflammatory bladder change, in women with recurrent urinary tract infections.

MATERIALS AND METHODS: A retrospective, observational cohort of women with recurrent urinary tract infections who underwent cystoscopy (n=138) from 2015 to 2018 were identified using electronic medical records. Cystitis cystica status was abstracted from cystoscopy reports and correlations were identified by logistic regression. Urinary tract infection-free survival time associated with cystitis cystica was evaluated by Cox proportional hazards regression. Exact logistic regression was used to identify factors associated with changes to cystitis cystica lesions on repeat …

Middle Meningeal Artery Embolization For Chronic Subdural Hematoma: Predictors Of Clinical And Radiographic Failure From 636 Embolizations, Mohamed M Salem, Okkes Kuybu, Alex Nguyen Hoang, Ammad A Baig, Mirhojjat Khorasanizadeh, Cordell Baker, Joshua C Hunsaker, Aldo A Mendez, Gustavo Cortez, Jason M Davies, Sandra Narayanan, C Michael Cawley, Howard A Riina, Justin M Moore, Alejandro M Spiotta, Alexander A Khalessi, Brian M Howard, Ricardo Hanel, Omar Tanweer, Elad I Levy, Ramesh Grandhi, Michael J Lang, Adnan H Siddiqui, Peter Kan, Christopher S Ogilvy, Bradley A Gross, Ajith J Thomas, Brian T Jankowitz, Jan-Karl Burkhardt

Faculty, Staff and Students Publications

Background

Knowledge regarding predictors of clinical and radiographic failures of middle meningeal artery (MMA) embolization (MMAE) treatment for chronic subdural hematoma (CSDH) is limited.

Purpose

To identify predictors of MMAE treatment failure for CSDH.

Materials and Methods

In this retrospective study, consecutive patients who underwent MMAE for CSDH from February 2018 to April 2022 at 13 U.S. centers were included. Clinical failure was defined as hematoma reaccumulation and/or neurologic deterioration requiring rescue surgery. Radiographic failure was defined as a maximal hematoma thickness reduction less than 50% at last imaging (minimum 2 weeks of head CT follow-up). Multivariable logistic regression models …

Effect Of Quality Of Life On Radiation Adherence For Patients With Cervical Cancer In An Urban Safety Net Health System, Alison K Yoder, Elizabeth Dong, Xiaoman Yu, Alfredo Echeverria, Shelly Sharma, Jane Montealegre, Michelle S Ludwig

Faculty, Staff and Students Publications

PURPOSE: Outcomes for patients undergoing chemoradiation for cervical cancer are dependent on adherence to radiation therapy (RT). In other diseases, quality of life (QoL) is associated with treatment adherence, but the association between QoL and RT adherence for patients with cervical cancer remains unclear.

METHODS AND MATERIALS: This prospective study included patients undergoing RT for cervical cancer from 2017 to 2021 at an urban safety net hospital. The Functional Assessment of Cancer Therapy-Cervical Cancer Version 4 was used to assess QoL based on 5 subscales (physical, functional, social and emotional, and cervical-cancer specific). The survey was administered at radiation consult, …