Medical Specialties Commons^™

Left Ventricular Diastolic Dysfunction With Elevated Filling Pressures Is Associated With Embolic Stroke Of Undetermined Source And Atrial Fibrillation, Zubair Bashir, Liqi Shu, Yuqian Guo, Edward W Chen, Shuyuan Wang, Eric D Goldstein, Maheen Rana, Narendra Kala, Xing Dai, Daniel Mandel, Shadi Yaghi, Phinnara Has, Mingxing Xie, Tao Wang, James Simmons, Christopher Song, Philip Haines

Faculty, Staff and Student Publications

Background/Objectives: Left ventricular diastolic dysfunction (LVDD) and elevated left ventricular filling pressure (LVFP) are strong predictors of clinical outcomes across various populations. However, their diagnostic utility in embolic stroke of undetermined source (ESUS) remains unclear. We hypothesized that LVDD with elevated LVFP (based on echocardiography) was more likely to be prevalent in ESUS compared to non-cardioembolic stroke (NCE) and to be associated with atrial fibrillation (AF) on follow-up monitoring.

Methods: This is a single-center retrospective study that included adult patients with a diagnosis of acute ischemic stroke between January 2016 and June 2017. LV function was assessed by …

Multicenter Pivotal Study Of The Alterra Adaptive Prestent For The Treatment Of Pulmonary Regurgitation, V Vivian Dimas, Vasilis Babaliaros, Dennis Kim, D Scott Lim, Gareth Morgan, Thomas K Jones, Aimee K Armstrong, Darren Berman, Jamil Aboulhosn, Vaikom S Mahadevan, Matthew J Gillespie, David Balzer, Thomas Zellers, Xiao Yu, Girish Shirali, Anitha Parthiban, Jonathan Leipsic, Philipp Blanke, Evan Zahn, Shabana Shahanavaz

Faculty, Staff and Students Publications

Background: A dilated native right ventricular outflow tract (RVOT) presents unique challenges for transcatheter management using balloon-expandable valves. The Alterra Adaptive Prestent was designed to expand transcatheter therapy to treat patients with dilated RVOTs.

Objectives: The aim of this study was to report 2-year outcomes of the main cohort of the ALTERRA (Multicenter Study of Congenital Pulmonic Valve Dysfunction Studying the SAPIEN 3 THV With the Alterra Adaptive Prestent) pivotal trial using the prestent with transcatheter pulmonary valve replacement.

Methods: The prestent device used with the 29 mm SAPIEN 3 transcatheter heart valve (THV) was evaluated for the management of …

Memory Modulation: Dominance Of Negative Visual Context Over Neutral Verbal Memory, Stas Kozak, Noa Herz, Maya Tocker, Yair Bar-Haim, Nitzan Censor

Department of Neurology Faculty Papers

Neutral memories can be modulated via intentional memory control paradigms such as directed forgetting. In addition, previous studies have shown that neutral visual memories can be modulated indirectly, via remember and forget instructions towards competing verbal memories. Here we show that direct modulation of neutral verbal memory strength is impaired by negative visual context, and that negative visual context is resistant to indirect memory modulation. Participants were directly instructed to intentionally remember or forget newly encoded neutral verbal information. Importantly, this verbal information was interleaved with embedded negative visual context. Results showed that negative visual context eliminated the well-documented effect …

Regular Nonsteroidal Anti-Inflammatory Drug Use Increases Stress Fracture Risk In The General Population: A Retrospective Case-Control Study, Alexandra Ciuciu, Chris Mulholland, Michael A. Bozzi, Chris C. Frymoyer, Leonardo Cavinatto, David Yaron, Marc I. Harwood, Jeremy D. Close, Christopher J. Mehallo, Ryan E. Tomlinson

Department of Orthopaedic Surgery Faculty Papers

Previous studies have shown that the use of nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with increased stress fracture risk. This phenomenon has been studied predominantly in high-activity individuals, so data regarding the general population are limited despite the substantial economic and resource burden of stress fracture injuries within the general US population. Furthermore, our preclinical studies demonstrate that regular use of NSAIDs also diminishes the intrinsic ability of bone to resist fracture. To determine the association of regular NSAID use with stress fractures in the general population, we surveyed subjects presenting with either stress fracture or uncomplicated ankle sprain to …

Long Covid Among Undocumented Latino Immigrant Populations In The Emergency Department., Karen P. Reyes, Zubaid Rafique, Brian Chinnock, Vijaya Arun Kumar, Michael Gottlieb, Kristin L. Rising, Robert M. Rodriguez

Department of Emergency Medicine Faculty Papers

Although many investigators have examined post–COVID-19 condition (long COVID) and its effects in the general population, to our knowledge, no studies have investigated its effect on one of the largest underserved US populations: undocumented Latino immigrants.¹ This group comprises 7% of the US population and has high rates of uninsurance, limited access to primary care, and language barriers when seeking health care.^2-4 Anti-immigrant political rhetoric and immigrants’ fear of discovery of their undocumented status when accessing health care make evaluation of this population more challenging.⁵ We leveraged emergency departments (EDs) as the primary health care …

Impact Of Age On Pharmacogenomics And Treatment Outcomes Of B-Cell Acute Lymphoblastic Leukemia, Satoshi Yoshimura, Zhenhua Li, Yoshihiro Gocho, Wenjian Yang, Kristine R Crews, Shawn H R Lee, Kathryn G Roberts, Charles G Mullighan, Mary V Relling, Jiyang Yu, Allen E J Yeoh, Mignon L Loh, Caner Saygin, Mark R Litzow, Sima Jeha, Seth E Karol, Hiroto Inaba, Ching-Hon Pui, Marina Konopleva, Nitin Jain, Wendy Stock, Elisabeth Paietta, Elias Jabbour, Steven M Kornblau, William E Evans, Jun J Yang

Faculty, Staff and Student Publications

Purpose: Acute lymphoblastic leukemia (ALL) can occur across all age groups, with a strikingly higher cure rate in children compared with adults. However, the pharmacological basis of age-related differences in ALL treatment response remains unclear.

Methods: Studying 767 children and 309 adults with newly diagnosed B-cell ALL enrolled on frontline trials at St Jude Children's Research Hospital, MD Anderson Cancer Center, the Alliance for Clinical Trials in Oncology, and the ECOG-ACRIN Cancer Research Group, we determined the ex vivo sensitivity of leukemia cells to 21 drugs. Twenty-three ALL molecular subtypes were identified using RNA sequencing. We systematically characterized the associations …

Larp1 Haploinsufficiency Is Associated With An Autosomal Dominant Neurodevelopmental Disorder, James Chettle, Raymond J Louie, Olivia Larner, Robert Best, Kevin Chen, Josephine Morris, Zinaida Dedeic, Anna Childers, R Curtis Rogers, Barbara R Dupont, Cindy Skinner, Sébastien Küry, Kevin Uguen, Marc Planes, Danielle Monteil, Megan Li, Aviva Eliyahu, Lior Greenbaum, Nofar Mor, Thomas Besnard, Bertrand Isidor, Benjamin Cogné, Alyssa Blesson, Anne Comi, Ingrid M Wentzensen, Blake Vuocolo, Seema R Lalani, Roberta Sierra, Lori Berry, Kent Carter, Stephan J Sanders, Sarah P Blagden

Faculty, Staff and Students Publications

Autism spectrum disorder (ASD) is a neurodevelopmental disorder (NDD) that affects approximately 4% of males and 1% of females in the United States. While causes of ASD are multi-factorial, single rare genetic variants contribute to around 20% of cases. Here, we report a case series of seven unrelated probands (6 males, 1 female) with ASD or another variable NDD phenotype attributed to de novo heterozygous loss of function or missense variants in the gene LARP1 (La ribonucleoprotein 1). LARP1 encodes an RNA-binding protein that post-transcriptionally regulates the stability and translation of thousands of mRNAs, including those regulating cellular metabolism and …

Pandemic Perspectives From Detained Youth During Covid-19: Bridging The Knowledge Gap For Future Safeguards., April Mcneill-Johnson, Zuri Hudson, Brittany Moore, Dumebi Okocha, Megha Ramaswamy, Kimberly Randell

Manuscripts, Articles, Book Chapters and Other Papers

Despite the worsening health disparities among youth in detention during the COVID-19 pandemic, there has been minimal exploration into the pandemic experiences of detained youth and opportunities for pandemic mitigation. This paper analyzes the perspectives of youth in detention on the pandemic, including the effect of the pandemic on their detention experience and their perceptions about COVID-19 vaccination. The study used purposive sampling to recruit 16 participants (aged 14-17 years) from two juvenile detention centers in the urban Midwest. We conducted semi-structured interviews and analyzed verbatim transcripts using a hybrid deductive-inductive approach and thematic analysis. Four themes emerged: 1) personal …

Phase I/Ii Study Of Bms-986156 With Ipilimumab Or Nivolumab With Or Without Stereotactic Ablative Radiotherapy In Patients With Advanced Solid Malignancies, Joe Y Chang, Xinyan Xu, Girish S Shroff, Nathan I Comeaux, Wei Li, Jordi Rodon Ahnert, Daniel D Karp, Ecaterina E Dumbrava, Vivek Verma, Aileen Chen, James Welsh, David S Hong

Faculty, Staff and Student Publications

Background: BMS-986156 is an agonist of the glucocorticoid-induced tumor necrosis factor receptor (TNFR)-related protein (GITR) and promotes increased effector T-cell activation. Combined anti-GITR, anti-programmed death-1, anti-cytotoxic T-lymphocyte-associated protein 4 antibodies and radiotherapy improve tumor control in preclinical studies. Herein we describe the results of the safety and efficacy of BMS-986156+ipilimumab or nivolumab with/without stereotactic ablative radiotherapy (SABR) in patients with advanced solid cancers (NCT04021043).

Methods: This open-label, multigroup, single-center phase I/II study enrolled patients with histologically-confirmed stage IV solid cancers resistant to standard treatments. Group 1 (G1, n=20) received four cycles of ipilimumab (3 mg/kg) plus BMS-986156 (30 …

Forecasting The Effects Of Smoking Prevalence Scenarios On Years Of Life Lost And Life Expectancy From 2022 To 2050: A Systematic Analysis For The Global Burden Of Disease Study 2021, Gbd 2021 Tobacco Forecasting Collaborators

Faculty, Staff and Students Publications

BACKGROUND: Smoking is the leading behavioural risk factor for mortality globally, accounting for more than 175 million deaths and nearly 4·30 billion years of life lost (YLLs) from 1990 to 2021. The pace of decline in smoking prevalence has slowed in recent years for many countries, and although strategies have recently been proposed to achieve tobacco-free generations, none have been implemented to date. Assessing what could happen if current trends in smoking prevalence persist, and what could happen if additional smoking prevalence reductions occur, is important for communicating the effect of potential smoking policies.

METHODS: In this analysis, we use …

Alliance A061202: Ixazomib, Pomalidomide, And Dexamethasone For Patients With Lenalidomide-Refractory Mm In First Relapse., Peter Voorhees, Vera Suman, Yvonne Efebera, Noopur Raje, Sascha Tuchman, Cesar Rodriguez, Jacob Laubach, Misty Bova-Solem, Destin Carlisle, Saad Usmani, Philip Mccarthy, Paul G Richardson

Oncology Articles

Optimal therapy for the growing number of patients with lenalidomide (LEN)-refractory multiple myeloma in their first relapse remains poorly defined. We therefore undertook a randomized phase 2 study to evaluate the efficacy and safety of combining the oral proteasome inhibitor ixazomib (IXA) with pomalidomide (POM) and dexamethasone (DEX) in this patient population. The overall response rate (ORR) for POM-DEX was 43.6%, and for IXA-POM-DEX, it was 63.2%. The depth of response, measured by the attainment of at least a very good partial response, favored triplet therapy over doublet therapy (28.9% vs 5.1%; P = .0063). A preplanned interim analysis after …

Impact Of Cancer Therapy On Clonal Hematopoiesis Mutations And Subsequent Clinical Outcomes, Kevin T Nead, Taebeom Kim, Lijin Joo, Tina L Mcdowell, Justin W Wong, Irenaeus C C Chan, Elizabeth Brock, Jing Zhao, Ting Xu, Chad Tang, Chang-Lung Lee, Jun-Ichi Abe, Kelly L Bolton, Zhongxing Liao, Paul A Scheet, Steven H Lin

Faculty, Staff and Student Publications

Exposure to cancer therapies is associated with an increased risk of clonal hematopoiesis (CH). The objective of our study was to investigate the genesis and evolution of CH after cancer therapy. In this prospective study, we undertook error-corrected duplex DNA sequencing in blood samples collected before and at 2 time points after chemoradiation in patients with esophageal or lung cancer recruited from 2013 to 2018. We applied a customized workflow to identify the earliest changes in CH mutation count and clone size and determine their association with clinical outcomes. Our study included 29 patients (87 samples). Their median age was …

The Impact Of A Web-Based Prognostic Calculator On Prognostic Confidence In Outpatient Palliative Care, David Hui, John P Maxwell, Allison De La Rosa, Kristofer Jennings, Marieberta Vidal, Akhila Reddy, Ahsan Azhar, Rony Dev, Kimberson Tanco, Yvonne Heung, Marvin Delgado-Guay, Donna Zhukovsky, Joseph Arthur, Suresh Reddy, Sriram Yennu, Amy Ontai, Eduardo Bruera

Faculty, Staff and Student Publications

Purpose: Clinicians are often uncertain about their prognostic estimates, which may impede prognostic communication and clinical decision-making. We assessed the impact of a web-based prognostic calculator on physicians' prognostic confidence.

Methods: In this prospective study, palliative care physicians estimated the prognosis of patients with advanced cancer in an outpatient clinic using the temporal, surprise, and probabilistic approaches for 6 m, 3 m, 2 m, 1 m, 2 w, 1 w, and 3 d. They then reviewed information from www.predictsurvival.com , which calculated survival estimates from seven validated prognostic scores, including the Palliative Prognostic Score, Palliative Prognostic Index, and Palliative Performance …

Ct Strain Metrics Allow For Earlier Diagnosis Of Bronchiolitis Obliterans Syndrome After Hematopoietic Cell Transplant, Husham Sharifi, Christopher D Bertini, Mansour Alkhunaizi, Maria Hernandez, Zayan Musa, Carlos Borges, Ihsan Turk, Lara Bashoura, Burton F Dickey, Guang-Shing Cheng, Gregory Yanik, Craig J Galban, Huawei Henry Guo, Myrna C B Godoy, Joseph M Reinhardt, Eric A Hoffman, Mario Castro, Gabriela Rondon, Amin M Alousi, Richard E Champlin, Elizabeth J Shpall, Ying Lu, Samuel Peterson, Keshav Datta, Mark R Nicolls, Joe Hsu, Ajay Sheshadri

Faculty, Staff and Student Publications

Bronchiolitis obliterans syndrome (BOS) after hematopoietic cell transplantation (HCT) is associated with substantial morbidity and mortality. Quantitative computed tomography (qCT) can help diagnose advanced BOS meeting National Institutes of Health (NIH) criteria (NIH-BOS) but has not been used to diagnose early, often asymptomatic BOS (early BOS), limiting the potential for early intervention and improved outcomes. Using pulmonary function tests (PFTs) to define NIH-BOS, early BOS, and mixed BOS (NIH-BOS with restrictive lung disease) in patients from 2 large cancer centers, we applied qCT to identify early BOS and distinguish between types of BOS. Patients with transient impairment or healthy lungs …

Gender And Sexuality Awareness In Medical Education And Practice: Mixed Methods Study, Rola Khamisy-Farah, Eden Biras, Rabie Shehadeh, Ruba Tuma, Hisham Atwan, Anna Siri, Manlio Converti, Francesco Chirico, Łukasz Szarpak, Carlo Biz, Raymond Farah, Nicola Bragazzi

Faculty, Staff and Students Publications

BACKGROUND: The integration of gender and sexuality awareness in health care is increasingly recognized as vital for patient outcomes. Despite this, there is a notable lack of comprehensive data on the current state of physicians' training and perceptions in these areas, leading to a gap in targeted educational interventions and optimal health care delivery.

OBJECTIVE: The study's aim was to explore the experiences and perceptions of attending and resident physicians regarding the inclusion of gender and sexuality content in medical school curricula and professional practice in Israel.

METHODS: This cross-sectional survey targeted a diverse group of physicians across various specializations …

Immunologic Signatures Of Response And Resistance To Nivolumab With Ipilimumab In Advanced Metastatic Cancer, Apostolia M Tsimberidou, Farah A Alayli, Kwame Okrah, Alexandra Drakaki, Danny N Khalil, Shivaani Kummar, Saad A Khan, F Stephen Hodi, David Y Oh, Christopher R Cabanski, Shikha Gautam, Stefanie L Meier, Meelad Amouzgar, Shannon M Pfeiffer, Robin Kageyama, Enjun Yang, Marko Spasic, Michael T Tetzlaff, Wai Chin Foo, Travis J Hollmann, Yanyun Li, Matthew Adamow, Phillip Wong, Jonni S Moore, Sharlene Velichko, Richard O Chen, Dinesh Kumar, Samantha Bucktrout, Ramy Ibrahim, Ute Dugan, Lisa Salvador, Vanessa M Hubbard-Lucey, Jill O'Donnell-Tormey, Sandra Santulli-Marotto, Lisa H Butterfield, Diane M Da Silva, Justin Fairchild, Theresa M Lavallee, Lacey J Padrón, Padmanee Sharma

Faculty, Staff and Student Publications

Identifying pan-tumor biomarkers that predict responses to immune checkpoint inhibitors (ICI) is critically needed. In the AMADEUS clinical trial (NCT03651271), patients with various advanced solid tumors were assessed for changes in intratumoral CD8 percentages and their response to ICI. Patients were grouped based on tumoral CD8 levels: those with CD8 <15% (CD8-low) received nivolumab (anti-PD-1) plus ipilimumab (anti-CTLA4) and those with CD8 ≥15% (CD8-high) received nivolumab monotherapy. 79 patients (72 CD8-low and 7 CD8-high) were treated. The disease control rate was 25.0% (18/72; 95% CI: 15.8–35.2) in CD8-low and 14.3% (1/7; 95% CI: 1.1–43.8) in CD8-high. Tumors from 35.9% (14/39; 95% CI: 21.8–51.4) of patients converted from CD8 <15% pretreatment to ≥15% after treatment. Multiomic analyses showed that CD8-low responders had an inflammatory tumor microenvironment pretreatment, enhanced by an influx of CD8 T cells, CD4 T cells, B cells, and macrophages upon treatment. These findings reveal crucial pan-cancer immunological features for ICI response in patients with metastatic disease.

Implementation Study Of The Carra Uveitis Consensus Treatment Plans: Feasibility For Clinical Practice And Applicability For Research., Margaret H. Chang, Fatima Barbar-Smiley, Shoghik Akoghlanian, Joanne Drew, Sheila T. Angeles-Han, Megan Quinlan-Waters, John F. Bohnsack, Ashley M. Cooper, Barbara Edelheit, Jennifer Twachtman-Bassett, Melissa A. Lerman, Kabita Nanda, C Egla Rabinovich, Mindy S. Lo, Carra Uveitis Workgroup And The Carra Registry Investigators

Manuscripts, Articles, Book Chapters and Other Papers

BACKGROUND: Chronic anterior uveitis (CAU) carries a significant risk for eye complications and vision loss. The Childhood Arthritis and Rheumatology Research Alliance (CARRA) introduced consensus treatment plans (CTPs) to standardize treatment for CAU and facilitate future comparative effectiveness studies. Two CTPs were developed to address: 1) initiation of methotrexate (MTX) in patients with CAU naïve to steroid-sparing therapy, and 2) initiation of a TNF inhibitor (TNFi) in patients with severe uveitis or uveitis refractory to MTX. We evaluated implementation of the uveitis CTPs using existing CARRA Registry infrastructure and assessed feasibility of the CTPs for comparative effectiveness research.

METHODS: This …

Alzheimer’S Disease Risk Gene Cd2ap Is A Dose-Sensitive Determinant Of Synaptic Structure And Plasticity, Matea Pavešković, Ruth B De-Paula, Shamsideen A Ojelade, Evelyne K Tantry, Mikhail Y Kochukov, Suyang Bao, Surabi Veeraragavan, Alexandra R Garza, Snigdha Srivastava, Si-Yuan Song, Masashi Fujita, Duc M Duong, David A Bennett, Philip L De Jager, Nicholas T Seyfried, Mary E Dickinson, Jason D Heaney, Benjamin R Arenkiel, Joshua M Shulman

Duncan NRI Faculty and Staff Publications

CD2-Associated protein (CD2AP) is a candidate susceptibility gene for Alzheimer's disease, but its role in the mammalian central nervous system remains largely unknown. We show that CD2AP protein is broadly expressed in the adult mouse brain, including within cortical and hippocampal neurons, where it is detected at pre-synaptic terminals. Deletion of Cd2ap altered dendritic branching and spine density, and impaired ubiquitin-proteasome system activity. Moreover, in mice harboring either one or two copies of a germline Cd2ap null allele, we noted increased paired-pulse facilitation at hippocampal Schaffer-collateral synapses, consistent with a haploinsufficient requirement for pre-synaptic release. Whereas conditional Cd2ap knockout in …

Trβ Activation Confers At2-To-At1 Cell Differentiation And Anti-Fibrosis During Lung Repair Via Klf2 And Cebpa, Xin Pan, Lan Wang, Juntang Yang, Yingge Li, Min Xu, Chenxi Liang, Lulu Liu, Zhongzheng Li, Cong Xia, Jiaojiao Pang, Mengyuan Wang, Meng Li, Saiya Guo, Peishuo Yan, Chen Ding, Ivan O Rosas, Guoying Yu

Faculty, Staff and Students Publications

Aberrant repair underlies the pathogenesis of pulmonary fibrosis while effective strategies to convert fibrosis to normal regeneration are scarce. Here, we found that thyroid hormone is decreased in multiple models of lung injury but is essential for lung regeneration. Moreover, thyroid hormone receptor α (TRα) promotes cell proliferation, while TRβ fuels cell maturation in lung regeneration. Using a specific TRβ agonist, sobetirome, we demonstrate that the anti-fibrotic effects of thyroid hormone mainly rely on TRβ in mice. Cellularly, TRβ activation enhances alveolar type-2 (AT2) cell differentiation into AT1 cell and constrains AT2 cell hyperplasia. Molecularly, TRβ activation directly regulates the …

Increased Myositis And Possible Myocarditis In Melanoma Patients Treated With Immune Checkpoint Inhibitors In The Covid-19 Era, Allison L. Gradone, Vincent T Ma, Alexi Vasbinder, Leslie A Fecher, Sarah Yentz, Salim S Hayek, Christopher D Lao

Department of Medical Oncology Faculty Papers

BACKGROUND: Immune checkpoint inhibitor (ICI)-mediated myocarditis results in significant morbidity and mortality. At our institution, we noted an increased incidence of ICI-mediated myocarditis cases, leading to further investigation in our database of advanced melanoma patients treated with ICI therapy.

METHODS: A single-center, retrospective cohort analysis of patients with advanced melanoma identified cases of ICI-mediated myocarditis and myositis.

RESULTS: 366 patients with advanced melanoma received a dose of ICI from September 2014 to October 2019. Of these patients, there were 0 cases of ICI-mediated myocarditis (0%, 95% CI 0%-1.0%) and 2 cases of ICI-mediated myositis (0.55%, 95% CI 0.07%-1.96%). From November …

Biologic And Clinical Analysis Of Childhood Gamma Delta T-All Identifies Lmo2/Stag2 Rearrangements As Extremely High Risk, Shunsuke Kimura, Chun Shik Park, Lindsey E Montefiori, Ilaria Iacobucci, Petri Pölönen, Qingsong Gao, Elizabeth D Arnold, Andishe Attarbaschi, Anthony Brown, Barbara Buldini, Kenneth J Caldwell, Yunchao Chang, Chelsey Chen, Cheng Cheng, Zhongshan Cheng, John Choi, Valentino Conter, Kristine R Crews, Hester A De Groot-Kruseman, Takao Deguchi, Mariko Eguchi, Hannah E Muhle, Sarah Elitzur, Gabriele Escherich, Burgess B Freeman, Zhaohui Gu, Katie Han, Keizo Horibe, Toshihiko Imamura, Sima Jeha, Motohiro Kato, Kean H Chiew, Tanya Khan, Michal Kicinski, Stefan Köhrer, Steven M Kornblau, Rishi S Kotecha, Chi-Kong Li, Yen-Chun Liu, Franco Locatelli, Selina M Luger, Elisabeth M Paietta, Atsushi Manabe, Hanne V Marquart, Riccardo Masetti, Mellissa Maybury, Pauline Mazilier, Jules P P Meijerink, Sharnise Mitchell, Takako Miyamura, Andrew S Moore, Koichi Oshima, Katarzyna Pawinska-Wasikowska, Rob Pieters, Mollie S Prater, Shondra M Pruett-Miller, Ching-Hon Pui, Chunxu Qu, Michaela Reiterova, Noemi Reyes, Kathryn G Roberts, Jacob M Rowe, Atsushi Sato, Kjeld Schmiegelow, Martin Schrappe, Shuhong Shen, Szymon Skoczeń, Orietta Spinelli, Jan Stary, Michael Svaton, Masatoshi Takagi, Junko Takita, Yanjing Tang, David T Teachey, Paul G Thomas, Daisuke Tomizawa, Jan Trka, Elena Varotto, Tiffaney L Vincent, Jun J Yang, Allen E J Yeoh, Yinmei Zhou, Martin Zimmermann, Hiroto Inaba, Charles G Mullighan

Faculty, Staff and Student Publications

Acute lymphoblastic leukemia expressing the gamma delta T-cell receptor (γδ T-ALL) is a poorly understood disease. We studied 200 children with γδ T-ALL from 13 clinical study groups to understand the clinical and genetic features of this disease. We found age and genetic drivers were significantly associated with outcome. γδ T-ALL diagnosed in children under 3 years of age was extremely high-risk and enriched for genetic alterations that result in both LMO2 activation and STAG2 inactivation. Mechanistically, using patient samples and isogenic cell lines, we show that inactivation of STAG2 profoundly perturbs chromatin organization by altering enhancer-promoter looping, resulting in …

Multi-Ancestry Gwas Meta-Analyses Of Lung Cancer Reveal Susceptibility Loci And Elucidate Smoking-Independent Genetic Risk, Bryan R Gorman, Sun-Gou Ji, Michael Francis, Anoop K Sendamarai, Yunling Shi, Poornima Devineni, Uma Saxena, Elizabeth Partan, Andrea K Devito, Jinyoung Byun, Younghun Han, Xiangjun Xiao, Don D Sin, Wim Timens, Jennifer Moser, Sumitra Muralidhar, Rachel Ramoni, Rayjean J Hung, James D Mckay, Yohan Bossé, Ryan Sun, Christopher I Amos, Va Million Veteran Program, Saiju Pyarajan

Faculty, Staff and Student Publications

Lung cancer remains the leading cause of cancer mortality, despite declining smoking rates. Previous lung cancer GWAS have identified numerous loci, but separating the genetic risks of lung cancer and smoking behavioral susceptibility remains challenging. Here, we perform multi-ancestry GWAS meta-analyses of lung cancer using the Million Veteran Program cohort (approximately 95% male cases) and a previous study of European-ancestry individuals, jointly comprising 42,102 cases and 181,270 controls, followed by replication in an independent cohort of 19,404 cases and 17,378 controls. We then carry out conditional meta-analyses on cigarettes per day and identify two novel, replicated loci, including the 19p13.11 …

Whole-Exome Sequencing Uncovers The Genetic Complexity Of Bicuspid Aortic Valve In Families With Early-Onset Complications, Sara Mansoorshahi, Anji T Yetman, Malenka M Bissell, Yuli Y Kim, Hector I Michelena, Julie De Backer, Laura Muiño Mosquera, Dawn S Hui, Anthony Caffarelli, Maria G Andreassi, Ilenia Foffa, Dongchuan Guo, Rodolfo Citro, Margot De Marco, Justin T Tretter, Shaine A Morris, Simon C Body, Jessica X Chong, Michael J Bamshad, Dianna M Milewicz, Siddharth K Prakash

Faculty, Staff and Student Publications

Bicuspid aortic valve (BAV) is the most common congenital heart lesion with an estimated population prevalence of 1%. We hypothesize that specific gene variants predispose to early-onset complications of BAV (EBAV). We analyzed whole-exome sequences (WESs) to identify rare coding variants that contribute to BAV disease in 215 EBAV-affected families. Predicted damaging variants in candidate genes with moderate or strong supportive evidence to cause developmental cardiac phenotypes were present in 107 EBAV-affected families (50% of total), including genes that cause BAV (9%) or heritable thoracic aortic disease (HTAD, 19%). After appropriate filtration, we also identified 129 variants in 54 candidate …

The Cochlear Dose And The Age At Radiotherapy Predict Severe Hearing Loss After Passive Scattering Proton Therapy And Cisplatin In Children With Medulloblastoma, Mohammad H Abu-Arja, Austin L Brown, Jack M Su, M Fatih Okcu, Holly B Lindsay, Susan L Mcgovern, Mary Frances Mcaleer, David R Grosshans, Murali M Chintagumpala, Arnold C Paulino

Faculty, Staff and Student Publications

Background: Hearing loss (HL) is associated with worse neurocognitive outcomes among patients with medulloblastoma. We aimed to identify risk factors associated with severe HL and to evaluate the generalizability of a published HL calculator among patients treated with passive scattering proton therapy (PSPT) and cisplatin.

Methods: We identified patients aged 3-21 years who were treated at our centers between 2007 and 2022. Audiograms were graded using the International Society of Pediatric Oncology (SIOP) Boston scale. Time to grades 3-4 HL was evaluated using Kaplan-Meier and multivariable Cox models to estimate hazard ratios and 95% confidence intervals (CI).

Results: Seventy-nine patients …

Identification Of A Single-Dose, Low-Flip-Angle-Based Cbv Threshold For Fractional Tumor Burden Mapping In Recurrent Glioblastoma, Aliya Anil, Ashley M Stokes, John P Karis, Laura C Bell, Jennifer Eschbacher, Kristofer Jennings, Melissa A Prah, Leland S Hu, Jerrold L Boxerman, Kathleen M Schmainda, C Chad Quarles

Faculty, Staff and Student Publications

Background and purpose: DSC-MR imaging can be used to generate fractional tumor burden (FTB) maps via application of relative CBV thresholds to spatially differentiate glioblastoma recurrence from posttreatment radiation effects (PTRE). Image-localized histopathology was previously used to validate FTB maps derived from a reference DSC-MR imaging protocol by using preload, a moderate flip angle (MFA, 60°), and postprocessing leakage correction. Recently, a DSC-MR imaging protocol with a low flip angle (LFA, 30°) with no preload was shown to provide leakage-corrected relative CBV (rCBV) equivalent to the reference protocol. This study aimed to identify the rCBV thresholds for the LFA protocol …

A Ligation-Independent Sequencing Method Reveals Trna-Derived Rnas With Blocked 3′ Termini, Alessandro Scacchetti, Emily J Shields, Natalie A Trigg, Grace S Lee, Jeremy E Wilusz, Colin C Conine, Roberto Bonasio

Faculty, Staff and Students Publications

Despite the numerous sequencing methods available, the diversity in RNA size and chemical modification makes it difficult to capture all RNAs in a cell. We developed a method that combines quasi-random priming with template switching to construct sequencing libraries from RNA molecules of any length and with any type of 3' modifications, allowing for the sequencing of virtually all RNA species. Our ligation-independent detection of all types of RNA (LIDAR) is a simple, effective tool to identify and quantify all classes of coding and non-coding RNAs. With LIDAR, we comprehensively characterized the transcriptomes of mouse embryonic stem cells, neural progenitor …

Penicillin Susceptibility Among Staphylococcus Aureus Skin And Soft Tissue Infections At A Children’S Hospital, J Chase Mcneil, Lauren M Sommer, Marritta Joseph, Kristina G Hulten, Sheldon L Kaplan

Faculty, Staff and Students Publications

Shortly after its introduction into clinical practice, Staphylococcus aureus isolates gained resistance to penicillin via the acquisition of β-lactamases. A number of centers have recently described an increase in the proportion of invasive methicillin-susceptible S. aureus (MSSA), which are also susceptible to penicillin (PSSA). Little data are available regarding the prevalence or impact of PSSA in skin and soft tissue infections (SSTI). Community-acquired MSSA SSTI isolates were obtained through a surveillance study at Texas Children’s Hospital from January 2017 to December 2021. A total of 200 random isolates underwent PCR for blaZ β-lactamase; blaZ-negative isolates then underwent penicillin susceptibility …

In Acute Severe Ulcerative Colitis Patients Who Receive Rescue Therapy, Prior Maintenance Therapy And Day 3 C-Reactive Protein After Rescue Therapy Are Associated With 12-Month Colectomy Risk, Jared A Sninsky, Ana-Maria Staicu, Edward L Barnes

Faculty, Staff and Students Publications

No abstract provided.

Default Mode Network Electrophysiological Dynamics And Causal Role In Creative Thinking, Eleonora Bartoli, Ethan Devara, Huy Q Dang, Rikki Rabinovich, Raissa K Mathura, Adrish Anand, Bailey R Pascuzzi, Joshua Adkinson, Yoed N Kenett, Kelly R Bijanki, Sameer A Sheth, Ben Shofty

Faculty, Staff and Students Publications

The default mode network (DMN) is a widely distributed, intrinsic brain network thought to play a crucial role in internally directed cognition. The present study employs stereo-EEG in 13 human patients, obtaining high resolution neural recordings across multiple canonical DMN regions during two processes that have been associated with creative thinking: spontaneous and divergent thought. We probe these two DMN-associated higher cognitive functions through mind wandering and alternate uses tasks, respectively. Our results reveal DMN recruitment during both tasks, as well as a task-specific dissociation in spatiotemporal response dynamics. When compared to the fronto-parietal network, DMN activity was characterized by …

Microfluidic Affinity Selection Of B-Lineage Cells From Peripheral Blood For Minimal Residual Disease Monitoring In Pediatric B-Type Acute Lymphoblastic Leukemia Patients., Malgorzata A. Witek, Nicholas E. Larkey, Alena Bartakova, Mateusz L. Hupert, Shalee Mog, Jami K. Cronin, Judy Vun, Keith August, Steven A. Soper

Manuscripts, Articles, Book Chapters and Other Papers

Assessment of minimal residual disease (MRD) is the most powerful predictor of outcome in B-type acute lymphoblastic leukemia (B-ALL). MRD, defined as the presence of leukemic cells in the blood or bone marrow, is used for the evaluation of therapy efficacy. We report on a microfluidic-based MRD (MF-MRD) assay that allows for frequent evaluation of blood for the presence of circulating leukemia cells (CLCs). The microfluidic chip affinity selects B-lineage cells, including CLCs using anti-CD19 antibodies poised on the wall of the microfluidic chip. Affinity-selected cells are released from the capture surface and can be subjected to immunophenotyping to enumerate …