Medical Specialties Commons^™

A Study Of Dietary Patterns Derived By Cluster Analysis And Their Association With Metabolic Dysfunction-Associated Steatotic Liver Disease Severity Among Hispanic Patients, Xiaotao Zhang, Carrie R Daniel, Valeria Soltero, Ximena Vargas, Shilpa Jain, Fasiha Kanwal, Aaron P Thrift, Maya Balakrishnan

Faculty, Staff and Student Publications

Introduction: Diet is a modifiable metabolic dysfunction-associated steatotic liver disease (MASLD) risk factor, but few studies have been conducted among Hispanic patients, despite the fact that MASLD prevalence and severity are highest among this ethnic subgroup. We aimed to identify prevalent dietary patterns among Hispanic patients using cluster analysis and to investigate associations with MASLD severity.

Methods: This cross-sectional analysis included 421 Harris County MASLD Cohort participants who self-reported Hispanic ethnicity and completed baseline food frequency questionnaires. All included patients had MASLD, diagnosed per standard clinical criteria. K-means analysis was used to identify clusters of patients sharing similar dietary habits. …

Lung Cancer In Ever- And Never-Smokers: Findings From Multi-Population Gwas Studies, Yafang Li, Xiangjun Xiao, Jianrong Li, Younghun Han, Chao Cheng, Gail F Fernandes, Shannon E Slewitzke, Susan M Rosenberg, Meng Zhu, Jinyoung Byun, Yohan Bossé, James D Mckay, Demetrios Albanes, Stephen Lam, Adonina Tardon, Chu Chen, Stig E Bojesen, Maria T Landi, Mattias Johansson, Angela Risch, Heike Bickeböller, H-Erich Wichmann, David C Christiani, Gad Rennert, Susanne M Arnold, Gary E Goodman, John K Field, Michael P A Davies, Sanjay Shete, Loïc Le Marchand, Geoffrey Liu, Rayjean J Hung, Angeline S Andrew, Lambertus A Kiemeney, Ryan Sun, Shanbeh Zienolddiny, Kjell Grankvist, Mikael Johansson, Neil E Caporaso, Angela Cox, Yun-Chul Hong, Philip Lazarus, Matthew B Schabath, Melinda C Aldrich, Ann G Schwartz, Ivan Gorlov, Kristen S Purrington, Ping Yang, Yanhong Liu, Joan E Bailey-Wilson, Susan M Pinney, Diptasri Mandal, James C Willey, Colette Gaba, Paul Brennan, Jun Xia, Hongbing Shen, Christopher I Amos

Faculty, Staff and Student Publications

BACKGROUND: Clinical, molecular, and genetic epidemiology studies displayed remarkable differences between ever- and never-smoking lung cancer.

METHODS: We conducted a stratified multi-population (European, East Asian, and African descent) association study on 44,823 ever-smokers and 20,074 never-smokers to identify novel variants that were missed in the non-stratified analysis. Functional analysis including expression quantitative trait loci (eQTL) colocalization and DNA damage assays, and annotation studies were conducted to evaluate the functional roles of the variants. We further evaluated the impact of smoking quantity on lung cancer risk for the variants associated with ever-smoking lung cancer.

RESULTS: Five novel independent loci, GABRA4, intergenic …

Bi-Allelic Variants In Celsr3 Are Implicated In Central Nervous System And Urinary Tract Anomalies, Jil D Stegmann, Jeshurun C Kalanithy, Gabriel C Dworschak, Nina Ishorst, Enrico Mingardo, Filipa M Lopes, Yee Mang Ho, Phillip Grote, Tobias T Lindenberg, Öznur Yilmaz, Khadija Channab, Steve Seltzsam, Shirlee Shril, Friedhelm Hildebrandt, Felix Boschann, André Heinen, Angad Jolly, Katherine Myers, Kim Mcbride, Mir Reza Bekheirnia, Nasim Bekheirnia, Marcello Scala, Manuela Morleo, Vincenzo Nigro, Annalaura Torella, Tudp Consortium, Michele Pinelli, Valeria Capra, Andrea Accogli, Silvia Maitz, Alice Spano, Rory J Olson, Eric W Klee, Brendan C Lanpher, Se Song Jang, Jong-Hee Chae, Philipp Steinbauer, Dietmar Rieder, Andreas R Janecke, Julia Vodopiutz, Ida Vogel, Jenny Blechingberg, Jennifer L Cohen, Kacie Riley, Victoria Klee, Laurence E Walsh, Matthias Begemann, Miriam Elbracht, Thomas Eggermann, Arzu Stoppe, Kyra Stuurman, Marjon Van Slegtenhorst, Tahsin Stefan Barakat, Maureen S Mulhern, Tristan T Sands, Cheryl Cytrynbaum, Rosanna Weksberg, Federica Isidori, Tommaso Pippucci, Giulia Severi, Francesca Montanari, Michael C Kruer, Somayeh Bakhtiari, Hossein Darvish, Heiko Reutter, Gregor Hagelueken, Matthias Geyer, Adrian S Woolf, Jennifer E Posey, James R Lupski, Benjamin Odermatt, Alina C Hilger

Faculty, Staff and Students Publications

CELSR3 codes for a planar cell polarity protein. We describe twelve affected individuals from eleven independent families with bi-allelic variants in CELSR3. Affected individuals presented with an overlapping phenotypic spectrum comprising central nervous system (CNS) anomalies (7/12), combined CNS anomalies and congenital anomalies of the kidneys and urinary tract (CAKUT) (3/12) and CAKUT only (2/12). Computational simulation of the 3D protein structure suggests the position of the identified variants to be implicated in penetrance and phenotype expression. CELSR3 immunolocalization in human embryonic urinary tract and transient suppression and rescue experiments of Celsr3 in fluorescent zebrafish reporter lines further support an …

Biallelic Variants In Slc4a10 Encoding A Sodium-Dependent Bicarbonate Transporter Lead To A Neurodevelopmental Disorder, Reza Maroofian, Mina Zamani, Rauan Kaiyrzhanov, Lutz Liebmann, Ehsan Ghayoor Karimiani, Barbara Vona, Antje K Huebner, Daniel G Calame, Vinod K Misra, Saeid Sadeghian, Reza Azizimalamiri, Mohammad Hasan Mohammadi, Jawaher Zeighami, Sogand Heydaran, Mehran Beiraghi Toosi, Javad Akhondian, Meisam Babaei, Narges Hashemi, Rhonda E Schnur, Mohnish Suri, Jonas Setzke, Matias Wagner, Theresa Brunet, Christopher M Grochowski, Lisa Emrick, Wendy K Chung, Ute A Hellmich, Miriam Schmidts, James R Lupski, Hamid Galehdari, Mariasavina Severino, Henry Houlden, Christian A Hübner

Faculty, Staff and Students Publications

PURPOSE: SLC4A10 encodes a plasma membrane-bound transporter, which mediates Na+-dependent HCO3− import, thus mediating net acid extrusion. Slc4a10 knockout mice show collapsed brain ventricles, an increased seizure threshold, mild behavioral abnormalities, impaired vision, and deafness.

METHODS: Utilizing exome/genome sequencing in families with undiagnosed neurodevelopmental disorders and international data sharing, 11 patients from 6 independent families with biallelic variants in SLC4A10 were identified. Clinico-radiological and dysmorphology assessments were conducted. A minigene assay, localization studies, intracellular pH recordings, and protein modeling were performed to study the possible functional consequences of the variant alleles.

RESULTS: The families harbor 8 segregating ultra-rare biallelic SLC4A10 …

Foxp1 Haploinsufficiency Contributes To The Development Of Congenital Diaphragmatic Hernia, Katherine E Pendleton, Andres Hernandez-Garcia, Jennifer M Lyu, Ian M Campbell, Chad A Shaw, Julie Vogt, Frances A High, Patricia K Donahoe, Wendy K Chung, Daryl A Scott

Faculty, Staff and Students Publications

FOXP1 encodes a transcription factor involved in tissue regulation and cell-type-specific functions. Haploinsufficiency of FOXP1 is associated with a neurodevelopmental disorder: autosomal dominant mental retardation with language impairment with or without autistic features. More recently, heterozygous FOXP1 variants have also been shown to cause a variety of structural birth defects including central nervous system (CNS) anomalies, congenital heart defects, congenital anomalies of the kidney and urinary tract, cryptorchidism, and hypospadias. In this report, we present a previously unpublished case of an individual with congenital diaphragmatic hernia (CDH) who carries an approximately 3.8 Mb deletion. Based on this deletion, and deletions …

Novel Avenues Of Tau Research, Claire E Sexton, Gal Bitan, Kathryn R Bowles, Miroslaw Brys, Luc Buée, Mahmoud Bukar Maina, Claire D Clelland, Ann D Cohen, John F Crary, Jeffrey L Dage, Kristophe Diaz, Bess Frost, Li Gan, Alison M Goate, Lawrence I Golbe, Oskar Hansson, Celeste M Karch, Hartmuth C Kolb, Renaud La Joie, Suzee E Lee, Diana Matallana, Bruce L Miller, Chiadi U Onyike, Yakeel T Quiroz, Jessica E Rexach, Jonathan D Rohrer, Amy Rommel, Ghazaleh Sadri-Vakili, Suzanne E Schindler, Julie A Schneider, Reisa A Sperling, Charlotte E Teunissen, Stacie C Weninger, Susan L Worley, Hui Zheng, Maria C Carrillo

Faculty, Staff and Students Publications

INTRODUCTION: The pace of innovation has accelerated in virtually every area of tau research in just the past few years.

METHODS: In February 2022, leading international tau experts convened to share selected highlights of this work during Tau 2022, the second international tau conference co-organized and co-sponsored by the Alzheimer's Association, CurePSP, and the Rainwater Charitable Foundation.

RESULTS: Representing academia, industry, and the philanthropic sector, presenters joined more than 1700 registered attendees from 59 countries, spanning six continents, to share recent advances and exciting new directions in tau research.

DISCUSSION: The virtual meeting provided an opportunity to foster cross-sector collaboration …

Role Of Non-Chromosomal Birth Defects On The Risk Of Developing Childhood Hodgkin Lymphoma: A Children’S Oncology Group Study, Erin C Peckham-Gregory, Lucas Maschietto Boff, Jeremy M Schraw, Logan G Spector, Amy M Linabery, Erik B Erhardt, Karina B Ribeiro, Carl E Allen, Michael E Scheurer, Philip J Lupo

Faculty, Staff and Students Publications

Background: Non-chromosomal birth defects are an important risk factor for several childhood cancers. However, these associations are less clear for Hodgkin lymphoma (HL). Therefore, we sought to more fully elucidate the association between non-chromosomal birth defects and HL risk.

Procedure: Information on cases (n = 517) diagnosed with HL (ages of 0-14) at Children's Oncology Group Institutions for the period of 1989-2003 was obtained. Control children without a history of cancer (n = 784) were identified using random digit dialing and individually matched to cases on sex, race/ethnicity, age, and geographic location. Parents completed comprehensive interviews and answered questions including …

Cub Domains Are Not Required For Ovch2 Function In Sperm Maturation In The Mouse Epididymis, Katarzyna Kent, Kaori Nozawa, Courtney Sutton, Frey Daniel, Masahito Ikawa, Thomas X Garcia, Martin M Matzuk

Faculty, Staff and Students Publications

BACKGROUND: Ovochymase 2 (Ovch2) is an epididymis-specific gene that is required for male fertility. While a multitude of reproductive tract-specific genes required for male fertility have been identified, OVCH2 is thus far the first protein required for male fertility that contains Complement C1r/C1s, Uegf, Bmp1 (CUB) domains located in tandem in the C-terminus of the protein. Identifying the functional significance of this unique domain has implications in better understanding fertility and infertility and as a potential contraceptive target.

OBJECTIVE: The goals of these studies were to understand the influence and requirement of OVCH2 CUB domains in the localization and functional …

Tex46 Knockout Male Mice Are Sterile Secondary To Sperm Head Malformations And Failure To Penetrate Through The Zona Pellucida, Yoshitaka Fujihara, Haruhiko Miyata, Ferheen Abbasi, Tamara Larasati, Kaori Nozawa, Zhifeng Yu, Masahito Ikawa, Martin M Matzuk

Faculty, Staff and Students Publications

Each year, infertility affects 15% of couples worldwide, with 50% of cases attributed to men. It is assumed that sperm head shape is important for sperm-zona pellucida (ZP) penetration but research has yet to elucidate why. We generated testis expressed 46 (Tex46) knockout mice to investigate the essential roles of TEX46 in mammalian reproduction. We used RT-PCR to demonstrate that Tex46 was expressed exclusively in the male reproductive tract in mice and humans. We created Tex46−/− mice using the Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-CRISPR-associated protein 9 (Cas9) system and analyzed their fertility. Tex46 null spermatozoa …

Retrograde Endocannabinoid Signaling At Inhibitory Synapses In Vivo, Barna Dudok, Linlin Z Fan, Jordan S Farrell, Shreya Malhotra, Jesslyn Homidan, Doo Kyung Kim, Celestine Wenardy, Charu Ramakrishnan, Yulong Li, Karl Deisseroth, Ivan Soltesz

Faculty, Staff and Students Publications

Endocannabinoid (eCB)-mediated suppression of inhibitory synapses has been hypothesized, but this has not yet been demonstrated to occur in vivo because of the difficulty in tracking eCB dynamics and synaptic plasticity during behavior. In mice navigating a linear track, we observed location-specific eCB signaling in hippocampal CA1 place cells, and this was detected both in the postsynaptic membrane and the presynaptic inhibitory axons. All-optical in vivo investigation of synaptic responses revealed that postsynaptic depolarization was followed by a suppression of inhibitory synaptic potentials. Furthermore, interneuron-specific cannabinoid receptor deletion altered place cell tuning. Therefore, rapid, postsynaptic, activity-dependent eCB signaling modulates inhibitory …

Long-Term Follow-Up For Recipients Of Genetically Modified Cells: A Team Effort, Helen E Heslop

Faculty, Staff and Students Publications

No abstract provided.

Community Recommendations On Cryoem Data Archiving And Validation, Gerard J Kleywegt, Paul D Adams, Sarah J Butcher, Catherine L Lawson, Alexis Rohou, Peter B Rosenthal, Sriram Subramaniam, Maya Topf, Sanja Abbott, Philip R Baldwin, John M Berrisford, Gérard Bricogne, Preeti Choudhary, Tristan I Croll, Radostin Danev, Sai J Ganesan, Timothy Grant, Aleksandras Gutmanas, Richard Henderson, J Bernard Heymann, Juha T Huiskonen, Andrei Istrate, Takayuki Kato, Gabriel C Lander, Shee Mei Lok, Steven J Ludtke, Garib N Murshudov, Ryan Pye, Grigore D Pintilie, Jane S Richardson, Carsten Sachse, Osman Salih, Sjors H W Scheres, Gunnar F Schroeder, Carlos Oscar S Sorzano, Scott M Stagg, Zhe Wang, Rangana Warshamanage, John D Westbrook, Martyn D Winn, Jasmine Y Young, Stephen K Burley, Jeffrey C Hoch, Genji Kurisu, Kyle Morris, Ardan Patwardhan, Sameer Velankar

Faculty, Staff and Students Publications

In January 2020, a workshop was held at EMBL-EBI (Hinxton, UK) to discuss data requirements for the deposition and validation of cryoEM structures, with a focus on single-particle analysis. The meeting was attended by 47 experts in data processing, model building and refinement, validation, and archiving of such structures. This report describes the workshop's motivation and history, the topics discussed, and the resulting consensus recommendations. Some challenges for future methods-development efforts in this area are also highlighted, as is the implementation to date of some of the recommendations.

Post-Mastectomy Pain Syndrome: A Review Article And Emerging Treatment Modalities, Jay D Shah, Kennedy Kirkpatrick, Krishna Shah

Faculty, Staff and Students Publications

Post-mastectomy pain syndrome (PMPS) is a syndrome broadly applied to the development of chronic pain after surgical breast intervention (i.e., lumpectomy and mastectomy). The incidence of PMPS is likely underreported, and this has contributed to a paucity of high-level evidence related to the treatment of the aforementioned condition. A drive to reduce the burden of opioid use has led to pain management physicians trialing a variety of strategies to help patients manage PMPS. This review discusses the latest evidence behind treatment options for PMPS, exploring medications as well as interventional techniques (e.g., nerve blocks, radiofrequency ablation, neuromodulation, and intrathecal drug …

Determining A Urinary-Specific Antibiogram And Risk Factors Of Trimethoprim/Sulfamethoxazole, Ciprofloxacin And Multidrug Resistance Among Enterobacterales In Primary Care, Marissa Valentine-King, Michael A Hansen, Roger Zoorob, Matthew Schlueter, Jennifer L Matas, Samuel E Willis, Lisa C K Danek, Kenneth Muldrew, Mohammad Zare, Forrest Hudson, Robert L Atmar, Andrew Chou, Barbara W Trautner, Larissa Grigoryan

Faculty, Staff and Student Publications

Background: Risk factors for ciprofloxacin or MDR in primary care urine specimens are not well defined.

Objectives: We created a primary care-specific antibiogram for Escherichia coli isolates from cases with complicated and uncomplicated urinary tract infection (UTI) and evaluated risk factors for ciprofloxacin, trimethoprim/sulfamethoxazole and MDR among Enterobacterales.

Methods: We conducted a cross-sectional study to determine resistance and risk factors by collecting urine cultures from all patients (≥18 years) presenting with provider-suspected UTI at two primary care, safety-net clinics in Houston, TX, USA between November 2018 and March 2020.

Results: Among 1262 cultures, 308 cultures grew 339 uropathogens. Patients with …

Mechanisms Of Sleep Disturbances In Long-Term Cancer Survivors: A Childhood Cancer Survivor Study Report, Lauren C Daniel, Huiqi Wang, Tara M Brinkman, Kathy Ruble, Eric S Zhou, Oxana Palesh, Robyn Stremler, Rebecca Howell, Daniel A Mulrooney, Valerie M Crabtree, Sogol Mostoufi-Moab, Kevin Oeffinger, Joseph Neglia, Yutaka Yasui, Gregory T Armstrong, Kevin Krull

Faculty, Staff and Student Publications

Background: Sleep problems following childhood cancer treatment may persist into adulthood, exacerbating cancer-related late effects and putting survivors at risk for poor physical and psychosocial functioning. This study examines sleep in long-term survivors and their siblings to identify risk factors and disease correlates.

Methods: Childhood cancer survivors (≥5 years from diagnosis; n = 12 340; 51.5% female; mean [SD] age = 39.4 [9.6] years) and siblings (n = 2395; 57.1% female; age = 44.6 [10.5] years) participating in the Childhood Cancer Survivor Study completed the Pittsburgh Sleep Quality Index (PSQI). Multivariable Poisson-error generalized estimating equation compared prevalence of binary sleep …

Pan-Cancer Proteogenomics Characterization Of Tumor Immunity, Francesca Petralia, Weiping Ma, Tomer M Yaron, Francesca Pia Caruso, Nicole Tignor, Joshua M Wang, Daniel Charytonowicz, Jared L Johnson, Emily M Huntsman, Giacomo B Marino, Anna Calinawan, John Erol Evangelista, Myvizhi Esai Selvan, Shrabanti Chowdhury, Dmitry Rykunov, Azra Krek, Xiaoyu Song, Berk Turhan, Karen E Christianson, David A Lewis, Eden Z Deng, Daniel J B Clarke, Jeffrey R Whiteaker, Jacob J Kennedy, Lei Zhao, Rossana Lazcano Segura, Harsh Batra, Maria Gabriela Raso, Edwin Roger Parra, Rama Soundararajan, Ximing Tang, Yize Li, Xinpei Yi, Shankha Satpathy, Ying Wang, Maciej Wiznerowicz, Tania J González-Robles, Antonio Iavarone, Sara J C Gosline, Boris Reva, Ana I Robles, Alexey I Nesvizhskii, D R Mani, Michael A Gillette, Robert J Klein, Marcin Cieslik, Bing Zhang, Amanda G Paulovich, Robert Sebra, Zeynep H Gümüş, Galen Hostetter, David Fenyö, Gilbert S Omenn, Lewis C Cantley, Avi Ma'ayan, Alexander J Lazar, Michele Ceccarelli, Pei Wang, Clinical Proteomic Tumor Analysis Consortium

Faculty, Staff and Student Publications

Despite the successes of immunotherapy in cancer treatment over recent decades, less than <10%-20% cancer cases have demonstrated durable responses from immune checkpoint blockade. To enhance the efficacy of immunotherapies, combination therapies suppressing multiple immune evasion mechanisms are increasingly contemplated. To better understand immune cell surveillance and diverse immune evasion responses in tumor tissues, we comprehensively characterized the immune landscape of more than 1,000 tumors across ten different cancers using CPTAC pan-cancer proteogenomic data. We identified seven distinct immune subtypes based on integrative learning of cell type compositions and pathway activities. We then thoroughly categorized unique genomic, epigenetic, transcriptomic, and proteomic changes associated with each subtype. Further leveraging the deep phosphoproteomic data, we studied kinase activities in different immune subtypes, which revealed potential subtype-specific therapeutic targets. Insights from this work will facilitate the development of future immunotherapy strategies and enhance precision targeting with existing agents.

Impact Of Electronic Cigarettes On Pediatric, Adolescent And Young Adult Leukemia Patients, Sanila Sarkar, Lea M Stitzlein, Joya Chandra

Faculty, Staff and Student Publications

Electronic cigarettes, which deliver an aerosolized, nicotine-containing product upon inhalation, are a public health issue that continue to gain popularity among adolescents and young adults in the United States. Use of electronic cigarettes is wide, and extends to pediatric patients with multiple comorbidities, including childhood cancer, leaving them vulnerable to further negative health outcomes. Acute leukemias are the most common type of cancer in pediatric populations, and treatment outcomes for these patients are improving; consequently, there is an increased emphasis on the effect of behavioral lifestyle factors on quality of life in survivorship. The rate of electronic cigarette use is …

Paired Single-B-Cell Transcriptomics And Receptor Sequencing Reveal Activation States And Clonal Signatures That Characterize B Cells In Acute Myeloid Leukemia, Shengnan Guo, Gopi S Mohan, Bofei Wang, Tianhao Li, Naval Daver, Yuting Zhao, Patrick K Reville, Dapeng Hao, Hussein A Abbas

Faculty, Staff and Student Publications

BACKGROUND: Acute myeloid leukemia (AML) is associated with a dismal prognosis. Immune checkpoint blockade (ICB) to induce antitumor activity in AML patients has yielded mixed results. Despite the pivotal role of B cells in antitumor immunity, a comprehensive assessment of B lymphocytes within AML's immunological microenvironment along with their interaction with ICB remains rather constrained.

METHODS: We performed an extensive analysis that involved paired single-cell RNA and B-cell receptor (BCR) sequencing on 52 bone marrow aspirate samples. These samples included 6 from healthy bone marrow donors (normal), 24 from newly diagnosed AML patients (NewlyDx), and 22 from 8 relapsed or …

Iterative Patient Testing Of A Stimuli-Responsive Swallowing Activity Sensor To Promote Extended User Engagement During The First Year After Radiation: Multiphase Remote And In-Person Observational Cohort Study, Eileen H Shinn, Adam S Garden, Susan K Peterson, Dylan J Leupi, Minxing Chen, Rachel Blau, Laura Becerra, Tarek Rafeedi, Julian Ramirez, Daniel Rodriquez, Finley Vanfossen, Sydney Zehner, Patrick P Mercier, Joseph Wang, Kate Hutcheson, Ehab Hanna, Darren J Lipomi

Faculty, Staff and Student Publications

BACKGROUND: Frequent sensor-assisted monitoring of changes in swallowing function may help improve detection of radiation-associated dysphagia before it becomes permanent. While our group has prototyped an epidermal strain/surface electromyography sensor that can detect minute changes in swallowing muscle movement, it is unknown whether patients with head and neck cancer would be willing to wear such a device at home after radiation for several months.

OBJECTIVE: We iteratively assessed patients' design preferences and perceived barriers to long-term use of the prototype sensor.

METHODS: In study 1 (questionnaire only), survivors of pharyngeal cancer who were 3-5 years post treatment and part of …

Experience With A Hybrid Recruitment Approach Of Patient-Facing Web Portal Screening And Subsequent Phone And Medical Record Review For A Neurosurgical Intervention Trial For Chronic Ischemic Stroke Disability (Pisces Iii), Brad J Kolls, Keith W Muir, Sean I Savitz, Lawrence R Wechsler, Julie G Pilitsis, Scott Rahimi, Richard L Beckman, Vincent Holmes, Peng R Chen, David S Albers, Daniel T Laskowitz

Faculty, Staff and Student Publications

BACKGROUND: Recruitment of participants is the greatest risk to completion of most clinical trials, with 20-40% of trials failing to reach the targeted enrollment. This is particularly true of trials of central nervous system (CNS) therapies such as intervention for chronic stroke. The PISCES III trial was an invasive trial of stereotactically guided intracerebral injection of CTX0E03, a fetal derived neural stem cell line, in patients with chronic disability due to ischemic stroke. We report on the experience using a novel hybrid recruitment approach of a patient-facing portal to self-identify and perform an initial screen for general trial eligibility (tier …

Hmzdupfinder: A Robust Computational Approach For Detecting Intragenic Homozygous Duplications From Exome Sequencing Data, Haowei Du, Zain Dardas, Angad Jolly, Christopher M Grochowski, Shalini N Jhangiani, He Li, Donna Muzny, Jawid M Fatih, Gozde Yesil, Nursel H Elçioglu, Alper Gezdirici, Dana Marafi, Davut Pehlivan, Daniel G Calame, Claudia M B Carvalho, Jennifer E Posey, Tomasz Gambin, Zeynep Coban-Akdemir, James R Lupski

Faculty, Staff and Students Publications

Homozygous duplications contribute to genetic disease by altering gene dosage or disrupting gene regulation and can be more deleterious to organismal biology than heterozygous duplications. Intragenic exonic duplications can result in loss-of-function (LoF) or gain-of-function (GoF) alleles that when homozygosed, i.e. brought to homozygous state at a locus by identity by descent or state, could potentially result in autosomal recessive (AR) rare disease traits. However, the detection and functional interpretation of homozygous duplications from exome sequencing data remains a challenge. We developed a framework algorithm, HMZDupFinder, that is designed to detect exonic homozygous duplications from exome sequencing (ES) data. The …

Protein-Folding Chaperones Predict Structure-Function Relationships And Cancer Risk In Brca1 Mutation Carriers, Brant Gracia, Patricia Montes, Angelica Maria Gutierrez, Banu Arun, Georgios Ioannis Karras

Faculty, Staff and Student Publications

Predicting the risk of cancer mutations is critical for early detection and prevention, but differences in allelic severity of human carriers confound risk predictions. Here, we elucidate protein folding as a cellular mechanism driving differences in mutation severity of tumor suppressor BRCA1. Using a high-throughput protein-protein interaction assay, we show that protein-folding chaperone binding patterns predict the pathogenicity of variants in the BRCA1 C-terminal (BRCT) domain. HSP70 selectively binds 94% of pathogenic BRCA1-BRCT variants, most of which engage HSP70 more than HSP90. Remarkably, the magnitude of HSP70 binding linearly correlates with loss of folding and function. We identify a prevalent …

Gamma Delta T Cells In Acute Myeloid Leukemia: Biology And Emerging Therapeutic Strategies, Adishwar Rao, Akriti Agrawal, Gautam Borthakur, Venkata Lokesh Battula, Abhishek Maiti

Faculty, Staff and Student Publications

γδ T cells play an important role in disease control in acute myeloid leukemia (AML) and have become an emerging area of therapeutic interest. These cells represent a minor population of T lymphocytes with intrinsic abilities to recognize antigens in a major histocompatibility complex-independent manner and functionally straddle the innate and adaptive immunity interface. AML shows high expression of phosphoantigens and UL-16 binding proteins that activate the Vδ2 and Vδ1 subtypes of γδ T cells, respectively, leading to γδ T cell-mediated cytotoxicity. Insights from murine models and clinical data in humans show improved overall survival, leukemia-free survival, reduced risk of …

Prognostic Risk Signature In Patients With Acute Myeloid Leukemia Treated With Hypomethylating Agents And Venetoclax, Alex Bataller, Alexandre Bazinet, Courtney D Dinardo, Abhishek Maiti, Gautam Borthakur, Naval G Daver, Nicholas J Short, Elias J Jabbour, Ghayas C Issa, Naveen Pemmaraju, Musa Yilmaz, Guillermo Montalban-Bravo, Koichi Takahashi, Sanam Loghavi, Guillermo Garcia-Manero, Farhad Ravandi, Hagop M Kantarjian, Tapan M Kadia

Faculty, Staff and Student Publications

Hypomethylating agents (HMAs) and venetoclax (Ven) represent the standard of care for patients with acute myeloid leukemia (AML) who are ineligible for intensive chemotherapy. However, the European LeukemiaNet (ELN) risk classifications have been validated for patients treated with intensive therapy. In this study, we validate a recently proposed new molecular prognostic risk signature (mPRS) for patients with AML treated with HMAs and Ven. This classification allocated patients to favorable, intermediate (N/KRAS or FLT3-internal tandem duplication mutations), and lower (TP53 mutations) benefit groups. We retrospectively analyzed 159 patients treated with HMA and Ven. The mPRS classification allocated 74 (47%), 31 (19%), …

Bridging Therapy With Axicabtagene Ciloleucel For Large B-Cell Lymphoma: Results From The Us Lymphoma Car-T Consortium, Michael D Jain, Miriam T Jacobs, Feng Gao, Loretta J Nastoupil, Jay Y Spiegel, Yi Lin, Saurabh Dahiya, Matthew Lunning, Lazaros Lekakis, Patrick Reagan, Olalekan Oluwole, Joseph Mcguirk, Abhinav Deol, Alison R Sehgal, Andre Goy, Brian T Hill, Charalambos Andreadis, Javier Munoz, Julio C Chavez, N Nora Bennani, Aaron P Rapoport, Julie M Vose, David Miklos, Sattva S Neelapu, Frederick L Locke, Armin Ghobadi

Faculty, Staff and Student Publications

During the manufacturing period of autologous chimeric antigen receptor (CAR) T-cell therapy, patients may experience a decline in their condition due to cancer progression. In this study, we investigated the impact of bridging therapy (BT) on the outcome of patients with relapsed/refractory large B-cell lymphoma who received antilymphoma treatment between leukapheresis and axicabtagene ciloleucel (axi-cel) infusion. We conducted our analysis using data from the multicenter US Lymphoma CAR-T Consortium, with a median follow-up of 33 months (range, 4.3-42.1). Out of the 298 patients who underwent leukapheresis, 275 patients received axi-cel. A total 52% of patients (n = 143) who received …

Differential Upregulation Of Th1/Th17-Associated Proteins And Pd-L1 In Granulomatous Mycosis Fungoides, Mario L Marques-Piubelli, Jesus Navarrete, Debora A Ledesma, Courtney W Hudgens, Rossana N Lazcano, Ali Alani, Auris Huen, Madeleine Duvic, Priyadharsini Nagarajan, Phyu P Aung, Ignacio I Wistuba, Jonathan L Curry, Roberto N Miranda, Carlos A Torres-Cabala

Faculty, Staff and Student Publications

Granulomatous Mycosis Fungoides (GMF) is a rare form of mycosis fungoides (MF) characterized by a granulomatous infiltrate associated with the neoplastic lymphoid population and is considered to have a worse prognosis compared with regular MF. The upregulation of the T helper (Th) axis, especially Th17, plays an important role in the pathogenesis of several inflammatory/infectious granulomatous cutaneous diseases, but its role in GMF is still not elucidated to date. In this study, we evaluated the immunohistochemical expression of Th1 (Tbet), Th2 (GATA-3), Th17 (RORγT), T regulatory (Foxp3), and immune checkpoint (IC) (PD-1 and PD-L1) markers in a cohort of patients …

A Phase 1/2 Study Of Mini-Hyper-Cvd Plus Venetoclax In Patients With Relapsed/Refractory Acute Lymphoblastic Leukemia, Nicholas J Short, Elias Jabbour, Nitin Jain, Jayastu Senapati, Lewis Nasr, Fadi G Haddad, Zhenhua Li, Yu-Chih Hsiao, Jun J Yang, Naveen Pemmaraju, Maro Ohanian, William G Wierda, Guillermo Montalban-Bravo, Gautam Borthakur, Lina Han, Lianchun Xiao, Xuelin Huang, Regina Abramova, Min Zhao, Rebecca Garris, Marina Konopleva, Farhad Ravandi, Hagop Kantarjian

Faculty, Staff and Student Publications

Preclinical studies suggest that Bcl-2 inhibition with venetoclax has antileukemic activity in acute lymphoblastic leukemia (ALL) and may synergize with conventional chemotherapy. We designed a phase 1/2 clinical trial to evaluate the safety and efficacy of low-intensity chemotherapy in combination with venetoclax in adults with relapsed or refractory ALL. Patients received the mini-hyper-CVD regimen (dose-attenuated hyperfractionated cyclophosphamide, vincristine, and dexamethasone alternating with methotrexate and cytarabine) in combination with venetoclax (200 mg or 400 mg daily) on days 1 to 14 in cycle 1 and on days 1 to 7 in consolidation cycles. Twenty-two patients were treated. The median number of …

Mortality After Major Cardiovascular Events In Survivors Of Childhood Cancer, Wendy Bottinor, Cindy Im, David R Doody, Saro H Armenian, Alexander Arynchyn, Borah Hong, Rebecca M Howell, David R Jacobs, Kirsten K Ness, Kevin C Oeffinger, Alexander P Reiner, Gregory T Armstrong, Yutaka Yasui, Eric J Chow

Faculty, Staff and Student Publications

Background: Adult survivors of childhood cancer are at risk for cardiovascular events.

Objectives: In this study, we sought to determine the risk for mortality after a major cardiovascular event among childhood cancer survivors compared with noncancer populations.

Methods: All-cause and cardiovascular cause-specific mortality risks after heart failure (HF), coronary artery disease (CAD), or stroke were compared among survivors and siblings in the Childhood Cancer Survivor Study (CCSS) and participants in the Coronary Artery Risk Development in Young Adults (CARDIA) study. Cox proportional hazard regression models were used to estimate HRs and 95% CIs between groups, adjusted for demographic and clinical …

Loss Of The Endoplasmic Reticulum Protein Tmem208 Affects Cell Polarity, Development, And Viability, Debdeep Dutta, Oguz Kanca, Rishi V Shridharan, Paul C Marcogliese, Benjamin Steger, Marie Morimoto, F Graeme Frost, Ellen Macnamara, Michael F Wangler, Shinya Yamamoto, Andreas Jenny, David Adams, May C Malicdan, Hugo J Bellen

Faculty, Staff and Students Publications

Nascent proteins destined for the cell membrane and the secretory pathway are targeted to the endoplasmic reticulum (ER) either posttranslationally or cotranslationally. The signal-independent pathway, containing the protein TMEM208, is one of three pathways that facilitates the translocation of nascent proteins into the ER. The in vivo function of this protein is ill characterized in multicellular organisms. Here, we generated a CRISPR-induced null allele of the fruit fly ortholog

Grit And Second Language Learning Engagement: The Mediating Role Of Affect Balance, Chenggang Wu, Xiaoyong Tian, Hui Jin

Faculty, Staff and Student Publications

The study of the relationship between key psychological attributes of learners and their engagement in second language (L2) learning helps to understand the critical personality mechanisms influencing language learning. The present study examined the L2 learning engagement from the perspectives of grit (i.e., consistent efforts and interests devoted to a long-term goal) and affect balance (a notion that takes into account both positive and negative emotions concurrently, assessing and evaluating which side holds more significance or influence). A cohort of English L2 learners (