Medical Genetics Commons^™

Preclinical Efficacy Of Targeting Epigenetic Mechanisms In Aml With 3q26 Lesions And Evi1 Overexpression, Christine E Birdwell, Warren Fiskus, Tapan M Kadia, Christopher P Mill, Koji Sasaki, Naval Daver, Courtney D Dinardo, Naveen Pemmaraju, Gautam Borthakur, John A Davis, Kaberi Das, Sunil Sharma, Stephen Horrigan, Xinjia Ruan, Xiaoping Su, Joseph D Khoury, Hagop Kantarjian, Kapil N Bhalla

Faculty, Staff and Student Publications

AML with chromosomal alterations involving 3q26 overexpresses the transcription factor (TF) EVI1, associated with therapy refractoriness and inferior overall survival in AML. Consistent with a CRISPR screen highlighting BRD4 dependency, treatment with BET inhibitor (BETi) repressed EVI1, LEF1, c-Myc, c-Myb, CDK4/6, and MCL1, and induced apoptosis of AML cells with 3q26 lesions. Tegavivint (TV, BC-2059), known to disrupt the binding of nuclear β-catenin and TCF7L2/LEF1 with TBL1, also inhibited co-localization of EVI1 with TBL1 and dose-dependently induced apoptosis in AML cell lines and patient-derived (PD) AML cells with 3q26.2 lesions. TV treatment repressed EVI1, attenuated enhancer activity at ERG, TCF7L2, …

Targeting Hypoxia-Inducible Factors: Therapeutic Opportunities And Challenges, Xiaoyi Yuan, Wei Ruan, Bentley Bobrow, Peter Carmeliet, Holger K Eltzschig

Faculty, Staff and Student Publications

Hypoxia-inducible factors (HIFs) are highly conserved transcription factors that are crucial for adaptation of metazoans to limited oxygen availability. Recently, HIF activation and inhibition have emerged as therapeutic targets in various human diseases. Pharmacologically desirable effects of HIF activation include erythropoiesis stimulation, cellular metabolism optimization during hypoxia and adaptive responses during ischaemia and inflammation. By contrast, HIF inhibition has been explored as a therapy for various cancers, retinal neovascularization and pulmonary hypertension. This Review discusses the biochemical mechanisms that control HIF stabilization and the molecular strategies that can be exploited pharmacologically to activate or inhibit HIFs. In addition, we examine …

A Phase 1 Trial Of 8-Chloro-Adenosine In Relapsed/Refractory Acute Myeloid Leukemia: An Evaluation Of Safety And Pharmacokinetics, Vinod Pullarkat, Lisa S Chen, Joycelynne Palmer, Jianying Zhang, Timothy W Synold, Ralf Buettner, Le Xuan Truong Nguyen, Guido Marcucci, Ni-Chun Tsai, Yan Wang, James O'Hearn, Varsha Gandhi, Steven T Rosen

Faculty, Staff and Student Publications

Background: This study evaluated the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of 8-chloro-adenosine (8-Cl-Ado) in patients with relapsed/refractory acute myeloid leukemia (AML).

Methods: 8-Cl-Ado was administered daily for 5 days; the starting dose was 100 mg/m2 , the highest dose tested was 800 mg/m2 . The end points were toxicity, disease response, and PK/PD measurements.

Results: The predominant nonhematologic toxicity was cardiac with grade ≥3 toxicity. Plasma PK in all patients suggested heterogeneity among patients, yet, some dose-dependency for the accumulation of 8-Cl-Ado. Two 8-Cl-Ado metabolites accumulated at similar levels to 8-Cl-Ado. Cellular PK in eight patients indicated accumulation of …

Case Series: Stenotrophomonas Maltophilia In Pediatric Oncology Patients, Sanila Sarkar, Lea M Stitzlein, Emily Rav, Miriam B Garcia, Shehla Razvi, Michael Chang, Ramia Zakhour

Faculty, Staff and Student Publications

Background: Stenotrophomonas maltophilia is a bacterial pathogen that can be fatal in hospitalized and immunocompromised patients with mortality as high as 69%. Pediatric cancer patients often have risk factors that are common for this infection, making them particularly susceptible. Managing S. maltophilia is especially challenging as it has inherent resistance to several antibiotics. Furthermore, soft tissue infections in neutropenic patients may deviate from the typical clinical presentation of S. maltophilia.

Case details: This case series describes an in-depth examination of three cases involving immunocompromised pediatric patients with S. maltophilia infections. Each case exhibited a distinct clinical presentation, encompassing infection of …

The Status And Challenges For Prostate Stereotactic Body Radiation Therapy Treatments In United States Proton Therapy Centers: An Nrg Oncology Practice Survey, Jiajian Shen, Paige A Taylor, Carlos E Vargas, Minglei Kang, Jatinder Saini, Jun Zhou, Peilong Wang, Wei Liu, Charles B Simone, Ying Xiao, Liyong Lin

Faculty, Staff and Student Publications

Purpose: To report the current practice pattern of the proton stereotactic body radiation therapy (SBRT) for prostate treatments.

Materials and methods: A survey was designed to inquire about the practice of proton SBRT treatment for prostate cancer. The survey was distributed to all 30 proton therapy centers in the United States that participate in the National Clinical Trial Network in February, 2023. The survey focused on usage, patient selection criteria, prescriptions, target contours, dose constraints, treatment plan optimization and evaluation methods, patient-specific QA, and image-guided radiation therapy (IGRT) methods.

Results: We received responses from 25 centers (83% participation). Only 8 …

Comprehensive Analysis Identifies Variability In Pi3k Pathway Alterations In Triple-Negative Breast Cancer Subtypes, Reva K Basho, Li Zhao, Jason B White, Lei Huo, Roland L Bassett, Elizabeth A Mittendorf, Alastair Thompson, Jennifer K Litton, Naoto Ueno, Banu Arun, Bora Lim, Vicente Valero, Debu Tripathy, Jianhua Zhang, Beatriz E Adrada, Lumarie Santiago, Elizabeth Ravenberg, Sahil Seth, Clinton Yam, Stacy L Moulder, Senthil Damodaran

Faculty, Staff and Student Publications

Purpose: The PI3K pathway is frequently altered in triple-negative breast cancer (TNBC). Limited cell line and human data suggest that TNBC tumors characterized as mesenchymal (M) and luminal androgen receptor (LAR) subtypes have increased incidence of alterations in the PI3K pathway. The impact of PI3K pathway alterations across TNBC subtypes is poorly understood.

Methods: Pretreatment tumor was evaluated from operable TNBC patients enrolled on a clinical trial of neoadjuvant therapy (NAT; A Robust TNBC Evaluation fraMework to Improve Survival [ClinicalTrials.gov identifier: NCT02276443]). Tumors were characterized into seven TNBC subtypes per Pietenpol criteria (basal-like 1, basal-like 2, immunomodulatory, M, mesenchymal …

Management Of Incomplete Microcirculatory Reperfusion After Endovascular Thrombectomy: Focus On Inhibition Of The Glycoprotein Iib/Iiia Receptor Pathway, Neeharika Krothapalli, Thomas Ortel, Devin Mcbride, Adam De Havenon, Lauren H Sansing, David Hasan, Brian Mac Grory

Faculty, Staff and Student Publications

Endovascular thrombectomy (EVT) is one of the most effective therapies for acute ischemic stroke attributable to large-vessel occlusion but, despite successful treatment, there remains a significant number of patients with disability. The phenomenon of incomplete microcirculatory reperfusion or no reflow is thought to underlie a substantial proportion of cases with unfavorable outcome. This phenomenon likely arises from platelet aggregation and endothelial edema impacting the cerebral microvasculature, vessels that are below the resolution of digital subtraction angiography. Although incomplete microcirculatory reperfusion prevents tissue recovery and poses a significant clinical challenge, there are multiple therapeutic options administered early after recanalization that have …

Outcomes In 14 Live Births Resulting From Pegvaliase-Treated Pregnancies In Pku-Affected Females, Caide Bier, Kaelin Dickey, Brittan Bibb, Angela Crutcher, Rebecca Sponberg, Richard Chang, Monica Boyer, Laura Davis-Keppen, Cindy Matthes, Michelle Tharp, Danielle Vice, Erin Cooney, Megan Morand, Joseph Ray, Melissa Lah, Markey Mcnutt, Hans C Andersson

Faculty, Staff and Student Publications

Background: Adults with PKU have difficulty maintaining plasma phenylalanine (Phe) in the range that is safe for neurologic function. Elevated plasma Phe is a risk factor for congenital anomalies and developmental delay in offspring resulting from pregnancies with poor Phe control in women with PKU. Enzyme supplementation with pegvaliase allows adults with PKU to eat an unrestricted diet and have plasma Phe levels in a safe range for pregnancy but pegvaliase has not been approved for use in pregnant females with PKU. We report the results of chart review of 14 living offspring of females affected with PKU who were …

The Fatigue-Inducing Effects Of Cancer And Its Therapy Are Characterized By Decreased Physical Activity In The Absence Of Any Motivational Deficit, Thien T Phan, Kiersten S Scott, Brandon Chelette, A Phillip West, Robert Dantzer

Faculty, Staff and Student Publications

Although cancer and its therapy are well known to be associated with fatigue, the exact nature of cancer-related fatigue remains ill-defined. We previously reported that fatigue-like behavior induced independently by tumor growth and by the chemotherapeutic agent cisplatin is characterized by reduced voluntary wheel running and an intact motivation to expand effort for food rewards. The present set of experiments was initiated to characterize the functional consequences of fatigue induced by chemoradiotherapy in tumor-bearing mice and relate them to changes in the expression of genes coding for inflammation, mitochondria dynamics and metabolism. Two syngeneic murine models of cancer were selected …

Genome-Wide Gene-Environment Interaction Analyses To Understand The Relationship Between Red Meat And Processed Meat Intake And Colorectal Cancer Risk, Mariana C Stern, Joel Sanchez Mendez, Andre E Kim, Mireia Obón-Santacana, Ferran Moratalla-Navarro, Vicente Martín, Victor Moreno, Yi Lin, Stephanie A Bien, Conghui Qu, Yu-Ru Su, Emily White, Tabitha A Harrison, Jeroen R Huyghe, Catherine M Tangen, Polly A Newcomb, Amanda I Phipps, Claire E Thomas, Eric S Kawaguchi, Juan Pablo Lewinger, John L Morrison, David V Conti, Jun Wang, Duncan C Thomas, Elizabeth A Platz, Kala Visvanathan, Temitope O Keku, Christina C Newton, Caroline Y Um, Anshul Kundaje, Anna Shcherbina, Neil Murphy, Marc J Gunter, Niki Dimou, Nikos Papadimitriou, Stéphane Bézieau, Franzel J B Van Duijnhoven, Satu Männistö, Gad Rennert, Alicja Wolk, Michael Hoffmeister, Hermann Brenner, Jenny Chang-Claude, Yu Tian, Loïc Le Marchand, Michelle Cotterchio, Konstantinos K Tsilidis, D Timothy Bishop, Yohannes Adama Melaku, Brigid M Lynch, Daniel D Buchanan, Cornelia M Ulrich, Jennifer Ose, Anita R Peoples, Andrew J Pellatt, Li Li, Matthew A M Devall, Peter T Campbell, Demetrius Albanes, Stephanie J Weinstein, Sonja I Berndt, Stephen B Gruber, Edward Ruiz-Narvaez, Mingyang Song, Amit D Joshi, David A Drew, Jessica L Petrick, Andrew T Chan, Marios Giannakis, Ulrike Peters, Li Hsu, W James Gauderman

Faculty, Staff and Student Publications

Background: High red meat and/or processed meat consumption are established colorectal cancer risk factors. We conducted a genome-wide gene-environment (GxE) interaction analysis to identify genetic variants that may modify these associations.

Methods: A pooled sample of 29,842 colorectal cancer cases and 39,635 controls of European ancestry from 27 studies were included. Quantiles for red meat and processed meat intake were constructed from harmonized questionnaire data. Genotyping arrays were imputed to the Haplotype Reference Consortium. Two-step EDGE and joint tests of GxE interaction were utilized in our genome-wide scan.

Results: Meta-analyses confirmed positive associations between increased consumption of red meat and …

Identification Of Pancreatic Cancer Germline Risk Variants With Effects That Are Modified By Smoking, Huili Zhu, Jaihee Choi, Naishu Kui, Tianzhong Yang, Peng Wei, Donghui Li, Ryan Sun

Faculty, Staff and Student Publications

Purpose: Pancreatic cancer (PC) is a deadly disease most often diagnosed in late stages. Identification of high-risk subjects could both contribute to preventative measures and help diagnose the disease at earlier timepoints. However, known risk factors, assessed independently, are currently insufficient for accurately stratifying patients. We use large-scale data from the UK Biobank (UKB) to identify genetic variant-smoking interaction effects and show their importance in risk assessment.

Methods: We draw data from 15,086,830 genetic variants and 315,512 individuals in the UKB. There are 765 cases of PC. Crucially, robust resampling corrections are used to overcome well-known challenges in hypothesis testing …

Personal History Of Cancer As A Risk Factor For Second Primary Lung Cancer: Implications For Lung Cancer Screening, Sara Nofal, Jiangong Niu, Paul Resong, Jeff Jin, Kelly W Merriman, Xiuning Le, Hormuzd Katki, John Heymach, Mara B Antonoff, Edwin Ostrin, Jia Wu, Jianjun Zhang, Iakovos Toumazis

Faculty, Staff and Student Publications

Background: Personal history of cancer is an independent risk factor for lung cancer but is omitted from existing lung cancer screening eligibility criteria. In this study, we assess the lung cancer risk among cancer survivors and discuss potential implications for screening.

Methods: This was a retrospective, secondary analysis of data from the Surveillance, Epidemiology and End Results (SEER) registry and the MD Anderson Cancer Center (MDACC). We estimated the standardized incidence ratios (SIRs) for lung cancer by site of first primary cancer using data from SEER. We assessed the lung cancer risk among head and neck cancer survivors from MDACC …

Systematic Evaluation Of Mri-Based Characterization Of Tumor-Associated Vascular Morphology And Hemodynamics Via A Dynamic Digital Phantom, Chengyue Wu, David A Hormuth, Ty Easley, Federico Pineda, Gregory S Karczmar, Thomas E Yankeelov

Faculty, Staff and Student Publications

Purpose: Validation of quantitative imaging biomarkers is a challenging task, due to the difficulty in measuring the ground truth of the target biological process. A digital phantom-based framework is established to systematically validate the quantitative characterization of tumor-associated vascular morphology and hemodynamics based on dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI).

Approach: A digital phantom is employed to provide a ground-truth vascular system within which 45 synthetic tumors are simulated. Morphological analysis is performed on high-spatial resolution DCE-MRI data (spatial/temporal resolution = 30 to 300μm/60s" role="presentation" style="box-sizing: inherit; display: inline-block; line-height: 0; font-size: 18.08px; font-size-adjust: none; overflow-wrap: normal; word-spacing: normal; text-wrap-mode: …

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 …

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 …

Transient Generalized Osteosclerosis In A Newborn Mimicking Congenital Osteopetrosis With Negative Comprehensive Genetic Workup: A Case Report, Jeffrey Hauck, Amanda Gerard, James E Crowe, Caridad A Martinez, Keren Machol

Faculty, Staff and Students Publications

We present a newborn with transient generalized osteosclerosis and negative genetic workup. The etiology of this condition is unknown. Given overlapping radiologic signs with severe forms of osteopetrosis, familiarity with this condition is crucial for correct diagnosis and management.

Cognitive, Emotional, And Other Non-Motor Symptoms Of Spinocerebellar Ataxias, Chi-Ying R Lin, Sheng-Han Kuo, Puneet Opal

Faculty, Staff and Students Publications

Purpose of review: Spinocerebellar ataxias (SCAs) are autosomal dominant degenerative syndromes that present with ataxia and brain stem abnormalities. This review describes the cognitive and behavioral symptoms of SCAs in the context of recent knowledge of the role of the cerebellum in higher intellectual function.

Recent findings: Recent studies suggest that patients with spinocerebellar ataxia can display cognitive deficits even early in the disease. These have been given the term cerebellar cognitive affective syndrome (CCAS). CCAS can be tracked using newly developed rating scales. In addition, patients with spinocerebellar ataxia also display impulsive and compulsive behavior, depression, anxiety, fatigue, and …

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 …

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 …

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 …

Building Effective Mentoring Relationships During Clinical Ethics Fellowships: Pedagogy, Programs, And People, Trevor M Bibler, Ryan H Nelson, Bryanna Moore, Janet Malek, Mary A Majumder

Center for Medical Ethics and Health Policy Staff Publications

How should clinical ethicists be trained? Scholars have stated that clinical ethics fellowships create well-trained, competent ethicists. While this appears intuitive, few features of fellowship programs have been publicly discussed, let alone debated. In this paper, we examine how fellowships can foster effective mentoring relationships. These relationships provide the foundation for the fellow's transition from novice to competent professional. In this essay, we begin by discussing our pedagogical commitments. Next, we describe the structures our program has created to assist our fellows in becoming competent ethicists. We then outline the kinds of knowledge, skills, and professional attributes mentors should possess. …

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 …

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. …

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 …

The Card8 Inflammasome Dictates Hiv/Siv Pathogenesis And Disease Progression, Qiankun Wang, Kolin M Clark, Ritudhwaj Tiwari, Nagarajan Raju, Gregory K Tharp, Jeffrey Rogers, R Alan Harris, Muthuswamy Raveendran, Steven E Bosinger, Tricia H Burdo, Guido Silvestri, Liang Shan

Faculty, Staff and Students Publications

While CD4+ T-cell depletion is key to disease progression in people living with HIV and SIV-infected macaques, the mechanisms underlying this depletion remain incompletely understood, with most cell death involving uninfected cells. In contrast, SIV infection of “natural” hosts such as sooty mangabeys do not cause CD4+ depletion and AIDS despite high-level viremia. Here, we report that the CARD8 inflammasome is activated immediately after HIV entry by the viral protease encapsulated in incoming virions. Sensing of HIV protease activity by CARD8 leads to rapid pyroptosis of quiescent cells without productive infection, while T-cell activation abolishes CARD8 function and increases permissiveness …

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 …

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

Evidence Review And Considerations For Use Of First Line Genome Sequencing To Diagnose Rare Genetic Disorders, Kristen M Wigby, Deanna Brockman, Gregory Costain, Caitlin Hale, Stacie L Taylor, John Belmont, David Bick, David Dimmock, Susan Fernbach, John Greally, Vaidehi Jobanputra, Shashikant Kulkarni, Elizabeth Spiteri, Ryan J Taft

Center for Medical Ethics and Health Policy Staff Publications

Early use of genome sequencing (GS) in the diagnostic odyssey can reduce suffering and improve care, but questions remain about which patient populations are most amenable to GS as a first-line diagnostic test. To address this, the Medical Genome Initiative conducted a literature review to identify appropriate clinical indications for GS. Studies published from January 2011 to August 2022 that reported on the diagnostic yield (DY) or clinical utility of GS were included. An exploratory meta-analysis using a random effects model evaluated DY based on cohort size and diagnosed cases per cohort. Seventy-one studies met inclusion criteria, comprising over 13,000 …