Digital Commons Network^™

The Association Of Self-Reported Sleep And Circadian Measures With Glycemic Control And Diabetes Complications Among Young Adults With Type 2 Diabetes, Dorit Koren, Kristen L Knutson, Brian K Burke, Kimberly L Drews, Fida Bacha, Lorraine Katz, Marsha D Marcus, Siripoom Mckay, Kristen Nadeau, Babak Mokhlesi, Today Study Group

Children’s Nutrition Research Center Staff Publications

We aim to examine the association of sleep duration, sleep quality, late chronotype, and circadian misalignment with glycemic control and risk of complications in young adults with youth-onset type 2 diabetes followed in the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study. Self-reported sleep duration, quality, timing, and circadian misalignment were assessed via a modified Pittsburgh Sleep Quality Index (PSQI) questionnaire, and chronotype was assessed via the Morningness-Eveningness Questionnaire (MEQ). We examined diabetes complications including loss of glycemic control (defined as hemoglobin A1c ≥8%), hypertension, dyslipidemia, albuminuria, and diabetic peripheral neuropathy. Multivariable logistic regression models were …

Propofol Enhancement Of Slow Wave Sleep To Target The Nexus Of Geriatric Depression And Cognitive Dysfunction: Protocol For A Phase I Open Label Trial, Rachel Lynn Rios, Michael Green, S Kendall Smith, Mohammadmehdi Kafashan, Shinung Ching, Nuri B Farber, Nan Lin, Brendan P Lucey, Charles F Reynolds, Eric J Lenze, Ben Julian Agustin Palanca, Swiped Study Team

2020-Current year OA Pubs

INTRODUCTION: Late-life treatment-resistant depression (LL-TRD) is common and increases risk for accelerated ageing and cognitive decline. Impaired sleep is common in LL-TRD and is a risk factor for cognitive decline. Slow wave sleep (SWS) has been implicated in key processes including synaptic plasticity and memory. A deficiency in SWS may be a core component of depression pathophysiology. The anaesthetic propofol can induce electroencephalographic (EEG) slow waves that resemble SWS. Propofol may enhance SWS and oral antidepressant therapy, but relationships are unclear. We hypothesise that propofol infusions will enhance SWS and improve depression in older adults with LL-TRD. This hypothesis has …

Variant-Specific Pathophysiological Mechanisms Of Aff3 Differently Influence Transcriptome Profiles, Sissy Bassani, Jacqueline Chrast, Giovanna Ambrosini, Norine Voisin, Frédéric Schütz, Alfredo Brusco, Fabio Sirchia, Lydia Turban, Susanna Schubert, Rami Abou Jamra, Jan-Ulrich Schlump, Desiree Demille, Pinar Bayrak-Toydemir, Gary Rex Nelson, Kristen Nicole Wong, Laura Duncan, Mackenzie Mosera, Christian Gilissen, Lisenka E L M Vissers, Rolph Pfundt, Rogier Kersseboom, Hilde Yttervik, Geir Åsmund Myge Hansen, Marie Falkenberg Smeland, Kameryn M Butler, Michael J Lyons, Claudia M B Carvalho, Chaofan Zhang, James R Lupski, Lorraine Potocki, Leticia Flores-Gallegos, Rodrigo Morales-Toquero, Florence Petit, Binnaz Yalcin, Annabelle Tuttle, Houda Zghal Elloumi, Lane Mccormick, Mary Kukolich, Oliver Klaas, Judit Horvath, Marcello Scala, Michele Iacomino, Francesca Operto, Federico Zara, Karin Writzl, Aleš Maver, Maria K Haanpää, Pia Pohjola, Harri Arikka, Anneke J A Kievit, Camilla Calandrini, Christian Iseli, Nicolas Guex, Alexandre Reymond

Faculty, Staff and Students Publications

BACKGROUND: We previously described the KINSSHIP syndrome, an autosomal dominant disorder associated with intellectual disability (ID), mesomelic dysplasia and horseshoe kidney, caused by de novo variants in the degron of AFF3. Mouse knock-ins and overexpression in zebrafish provided evidence for a dominant-negative mode of action, wherein an increased level of AFF3 resulted in pathological effects.

METHODS: Evolutionary constraints suggest that other modes-of-inheritance could be at play. We challenged this hypothesis by screening ID cohorts for individuals with predicted-to-be damaging variants in AFF3. We used both animal and cellular models to assess the deleteriousness of the identified variants.

RESULTS: We identified …

A Technology-Assisted Web Application For Consumer Access To A Nonprescription Statin Medication, Steven E Nissen, Howard G Hutchinson, Kathy Wolski, Karol Watson, Seth S Martin, Erin D Michos, William S Weintraub, Melanie Morris, Leslie Cho, Luke Laffin, Douglas Jacoby, Christie M Ballantyne, Jan Ekelund, Filip Birve, Venu Menon, Michelle Strzelecki, Paul M Ridker

Faculty, Staff and Students Publications

Background: Although statins reduce adverse cardiovascular outcomes, less than one-half of eligible patients receive treatment. A nonprescription statin has the potential to improve access to statins.

Objectives: This study sought to assess concordance between clinician and consumer assessment of eligibility for nonprescription statin treatment using a technology assisted self-selection Web application (Web App) and evaluate effect on low-density lipoprotein cholesterol (LDL-C) levels.

Methods: This study was a prospective actual use 6-month study to evaluate use of a Web App to qualify participants without a medical background for a moderate-intensity statin based on current guidelines. Participants entered demographic information, cholesterol values, …

Cosmetic Penile Enhancement Procedures: An Smsna Position Statement, Landon Trost, Daniel N Watter, Serge Carrier, Mohit Khera, Faysal A Yafi, Helen L Bernie, Matthew Ziegelmann, Tobias Köhler

Faculty, Staff and Students Publications

Background: Penile cosmetic enhancement procedures have been performed for many years with varying success. However, they have historically been relegated to niche areas of sexual medicine, with limited data, and have not achieved mainstream adoption. More recently, the topic has been increasingly discussed within academic congresses due to availability of novel techniques, therapies, and procedures. Given their distinctive nature, the Sexual Medicine Society of North America (SMSNA) felt that it was pertinent to develop formal position statements to help guide both patients and sexual medicine providers on the current state of the scientific literature and to give recommendations for future …

Factors Associated With Intention To Implement Sbi And Sud Treatment: A Survey Of Primary Care Clinicians In Texas Enrolled In An Online Course, Alicia Kowalchuk, Tiffany G Ostovar-Kermani, Kylie Schaper, Larissa Grigoryan, Jacqueline M Hirth, Maria Carmenza Mejia, Kiara K Spooner, Roger J Zoorob

Faculty, Staff and Students Publications

BACKGROUND: Substance use disorder (SUD) presents a range of public health challenges and consequences. Despite the prevention potential of screening and brief intervention (SBI) in the primary care setting, implementation is low. The purpose of this study was to assess associations of primary care clinicians' knowledge of SBI and SUD treatment, subjective norms, and perceived behavioral control with intention to incorporate SBI and SUD treatment into regular clinical practice.

METHODS: This online survey was administered to primary care clinicians who practice in Texas between March 1, 2021, and February 5, 2023. Survey questions were mapped to factors in the Theory …

Thbs1 Regulates Skeletal Muscle Mass In A Tgfβ-Smad2/3-Atf4-Dependent Manner, Davy Vanhoutte, Tobias G Schips, Rachel A Minerath, Jiuzhou Huo, Naga Swathi Sree Kavuri, Vikram Prasad, Suh-Chin Lin, Michael J Bround, Michelle A Sargent, Christopher M Adams, Jeffery D Molkentin

Faculty, Staff and Students Publications

Loss of muscle mass is a feature of chronic illness and aging. Here, we report that skeletal muscle-specific thrombospondin-1 transgenic mice (Thbs1 Tg) have profound muscle atrophy with age-dependent decreases in exercise capacity and premature lethality. Mechanistically, Thbs1 activates transforming growth factor β (TGFβ)-Smad2/3 signaling, which also induces activating transcription factor 4 (ATF4) expression that together modulates the autophagy-lysosomal pathway (ALP) and ubiquitin-proteasome system (UPS) to facilitate muscle atrophy. Indeed, myofiber-specific inhibition of TGFβ-receptor signaling represses the induction of ATF4, normalizes ALP and UPS, and partially restores muscle mass in Thbs1 Tg mice. Similarly, myofiber-specific deletion of Smad2 and Smad3 …

The Impact Of The Optn Policy Change On Patients With A Durable Left Ventricular Assist Device And Chronic Kidney Disease: Analysis Of The Unos Database, Eric D. Warner, Christopher Pritting, Sawan Dutta, Matt Bierowski, Waqas Ullah, Yevgeniy Brailovsky, Michelle Kittleson, René J. Alvarez, J. Eduardo Rame, Alexander Hajduczok, Vineeta Kumar, Danial Ahmad, Vakhtang Tchantchaleishvili, Indranee N. Rajapreyar

Division of Cardiology Faculty Papers

BACKGROUND: The Organ Procurement and Transplantation Network (OPTN) implemented modifications in 2018 to the adult heart transplant allocation system to better stratify the most medically urgent transplant candidates. We evaluated the impact of these changes on patients supported by a durable left ventricular assist device (LVAD) with chronic kidney disease (CKD).

OBJECTIVE: To evaluate the impact of the OPTN policy change on patients supported by durable left ventricular assist devices (LVAD) with chronic kidney disease (CKD).

METHODS: We performed an analysis of patients from the United Network of Organ Sharing Database supported by durable LVAD listed for a heart transplant …

Therapeutic Strategies Against Metabolic Imbalance In A Male Mouse Model With 5-Ht2cr Loss-Of-Function, Hailan Liu, Zhaoxun Liu, Hueyxian Kelly Wong, Nathan Xu, Qingzhuo Liu, Yongxiang Li, Yao Liu, Hueyzhong Wong, Megan E Burt, Sanika V Jossy, Junying Han, Yang He

Faculty, Staff and Students Publications

The serotonin 2C receptor (5-HT2CR)-melanocortin pathway plays well-established roles in the regulation of feeding behavior and body weight homeostasis. Dysfunctions in this system, such as loss-of-function mutations in the Htr2c gene, can lead to hyperphagia and obesity. In this study, we aimed to investigate the potential therapeutic strategies for ameliorating hyperphagia, hyperglycemia, and obesity associated with a loss-of-function mutation in the Htr2c gene (Htr2cF327L/Y). We demonstrated that reexpressing functional 5-HT2CR solely in hypothalamic pro-opiomelanocortin (POMC) neurons is sufficient to reduce food intake and body weight in Htr2cF327L/Y mice subjected to a high-fat diet (HFD). In addition, 5-HT2CR expression restores the …

Generation Of Oviductal Glycoprotein 1 Cre Mouse Model For The Study Of Secretory Epithelial Cells Of The Oviduct, Emily A Mcglade, Jiude Mao, Kalli K Stephens, Andrew M Kelleher, Lisette A Maddison, Miranda L Bernhardt, Francesco J Demayo, John P Lydon, Wipawee Winuthayanon

Faculty, Staff and Students Publications

The epithelial cell lining of the oviduct plays an important role in oocyte pickup, sperm migration, preimplantation embryo development, and embryo transport. The oviduct epithelial cell layer comprises ciliated and nonciliated secretory cells. The ciliary function has been shown to support gamete and embryo movement in the oviduct, yet secretory cell function has not been well characterized. Therefore, our goal was to generate a secretory cell-specific Cre recombinase mouse model to study the role of the oviductal secretory cells. A knock-in mouse model, Ovgp1Cre:eGFP, was created by expressing Cre from the endogenous Ovgp1 (oviductal glycoprotein 1) locus, with enhanced green …

Brain Cell-Type Shifts In Alzheimer’S Disease, Autism, And Schizophrenia Interrogated Using Methylomics And Genetics, Chloe X Yap, Daniel D Vo, Matthew G Heffel, Arjun Bhattacharya, Cindy Wen, Yuanhao Yang, Kathryn E Kemper, Jian Zeng, Zhili Zheng, Zhihong Zhu, Eilis Hannon, Dorothea Seiler Vellame, Alice Franklin, Christa Caggiano, Brie Wamsley, Daniel H Geschwind, Noah Zaitlen, Alexander Gusev, Bogdan Pasaniuc, Jonathan Mill, Chongyuan Luo, Michael J Gandal

Faculty, Staff and Student Publications

Few neuropsychiatric disorders have replicable biomarkers, prompting high-resolution and large-scale molecular studies. However, we still lack consensus on a more foundational question: whether quantitative shifts in cell types-the functional unit of life-contribute to neuropsychiatric disorders. Leveraging advances in human brain single-cell methylomics, we deconvolve seven major cell types using bulk DNA methylation profiling across 1270 postmortem brains, including from individuals diagnosed with Alzheimer's disease, schizophrenia, and autism. We observe and replicate cell-type compositional shifts for Alzheimer's disease (endothelial cell loss), autism (increased microglia), and schizophrenia (decreased oligodendrocytes), and find age- and sex-related changes. Multiple layers of evidence indicate that endothelial …

Biobank-Wide Association Scan Identifies Risk Factors For Late-Onset Alzheimer's Disease And Endophenotypes, Donghui Yan, Carlos Cruchaga, Et Al.

2020-Current year OA Pubs

Rich data from large biobanks, coupled with increasingly accessible association statistics from genome-wide association studies (GWAS), provide great opportunities to dissect the complex relationships among human traits and diseases. We introduce BADGERS, a powerful method to perform polygenic score-based biobank-wide association scans. Compared to traditional approaches, BADGERS uses GWAS summary statistics as input and does not require multiple traits to be measured in the same cohort. We applied BADGERS to two independent datasets for late-onset Alzheimer's disease (AD; n=61,212). Among 1738 traits in the UK biobank, we identified 48 significant associations for AD. Family history, high cholesterol, and numerous traits …

Estimating The Likelihood Of Epilepsy From Clinically Noncontributory Electroencephalograms Using Computational Analysis: A Retrospective, Multisite Case–Control Study, Luke Tait, Lydia E. Staniaszek, Elizabeth Galizia, David Martin-Lopez, Matthew C. Walker, Al Anzari Abdul Azeez, Kay Meiklejohn, David Allen, Chris Price, Sophie Georgiou, Manny Bagary, Sakh Khalsa, Francesco Manfredonia, Phil Tittensor, Charlotte Lawthom, Benjamin B. Howes, Rohit Shankar, John R. Terry, Wessel Woldman

Peninsula Medical School

Objective: This study was undertaken to validate a set of candidate biomarkers of seizure susceptibility in a retrospective, multisite case–control study, and to determine the robustness of these biomarkers derived from routinely collected electroencephalography (EEG) within a large cohort (both epilepsy and common alternative conditions such as nonepileptic attack disorder). Methods: The database consisted of 814 EEG recordings from 648 subjects, collected from eight National Health Service sites across the UK. Clinically noncontributory EEG recordings were identified by an experienced clinical scientist (N = 281; 152 alternative conditions, 129 epilepsy). Eight computational markers (spectral [n = 2], network-based [n = …

Accessibility, Relevance, And Impact Of A Symptom Monitoring Tool For Home Hospice Care: Theory Elaboration And Qualitative Assessment, Karla T Washington, Debra Parker Oliver, Allison K Donehower, Patrick White, Jacquelyn J Benson, Patrick G Lyons, George Demiris

2020-Current year OA Pubs

BACKGROUND: Early users found Engagement and Visualization to Improve Symptoms in Oncology Care (ENVISION), a web-based application designed to improve home management of hospice patients' symptoms and support patients' and family caregivers' well-being, to be generally useful and easy to use. However, they also raised concerns about potential challenges users with limited technological proficiency might experience.

OBJECTIVE: We sought to concurrently accomplish two interrelated study aims: (1) to develop a conceptual framework of digital inclusivity for health information systems and (2) to apply the framework in evaluating the digital inclusivity of the ENVISION application.

METHODS: We engaged ENVISION users (N=34) …

Neurodevelopmental Outcomes After Late Preterm Antenatal Corticosteroids: The Alps Follow-Up Study, Cynthia Gyamfi-Bannerman, Rebecca G Clifton, Alan T N Tita, Sean C Blackwell, Monica Longo, Jessica A De Voest, T Michael O'Shea, Sabine Z Bousleiman, Felecia Ortiz, Dwight J Rouse, Torri D Metz, George R Saade, Kara M Rood, Kent D Heyborne, John M Thorp, Geeta K Swamy, William A Grobman, Kelly S Gibson, Yasser Y El-Sayed, George A Macones, Eunice Kennedy Shriver Maternal-Fetal Medicine Units Network

Faculty, Staff and Student Publications

Importance: The Antenatal Late Preterm Steroids (ALPS) trial changed clinical practice in the United States by finding that antenatal betamethasone at 34 to 36 weeks decreased short-term neonatal respiratory morbidity. However, the trial also found increased risk of neonatal hypoglycemia after betamethasone. This follow-up study focused on long-term neurodevelopmental outcomes after late preterm steroids.

Objective: To evaluate whether administration of late preterm (34-36 completed weeks) corticosteroids affected childhood neurodevelopmental outcomes.

Design, setting, and participants: Prospective follow-up study of children aged 6 years or older whose birthing parent had enrolled in the multicenter randomized clinical trial, conducted at 13 centers that …

Graded Decisions In The Human Brain, Tao Xie, Markus Adamek, Hohyun Cho, Matthew A Adamo, Anthony L Ritaccio, Jon T Willie, Peter Brunner, Jan Kubanek

2020-Current year OA Pubs

Decision-makers objectively commit to a definitive choice, yet at the subjective level, human decisions appear to be associated with a degree of uncertainty. Whether decisions are definitive (i.e., concluding in all-or-none choices), or whether the underlying representations are graded, remains unclear. To answer this question, we recorded intracranial neural signals directly from the brain while human subjects made perceptual decisions. The recordings revealed that broadband gamma activity reflecting each individual's decision-making process, ramped up gradually while being graded by the accumulated decision evidence. Crucially, this grading effect persisted throughout the decision process without ever reaching a definite bound at the …

The Macrophage Landscape Across The Lifespan Of A Human Cardiac Allograft, Xiao Li, Diwakar Turaga, Rich G Li, Chang-Ru Tsai, Julianna N Quinn, Yi Zhao, Ruby Wilson, Katherine Carlson, Jun Wang, Joseph A Spinner, Edward J Hickey, Iki Adachi, James F Martin

Faculty, Staff and Student Publications

Background: Much of our knowledge of organ rejection after transplantation is derived from rodent models.

Methods: We used single-nucleus RNA sequencing to investigate the inflammatory myocardial microenvironment in human pediatric cardiac allografts at different stages after transplantation. We distinguished donor- from recipient-derived cells using naturally occurring genetic variants embedded in single-nucleus RNA sequencing data.

Results: Donor-derived tissue resident macrophages, which accompany the allograft into the recipient, are lost over time after transplantation. In contrast, monocyte-derived macrophages from the recipient populate the heart within days after transplantation and form 2 macrophage populations: recipient MP1 and recipient MP2. Recipient MP2s have cell …

Common Single-Base Insertions In The Vntr Of The Carboxyl Ester Lipase (Cel) Gene Are Benign And Also Likely To Arise Somatically In The Exocrine Pancreas, Ranveig S Brekke, Anny Gravdal, Khadija El Jellas, Grace E Curry, Jianguo Lin, Steven J Wilhelm, Solrun J Steine, Eric Mas, Stefan Johansson, Mark E Lowe, Bente B Johansson, Xunjun Xiao, Karianne Fjeld, Anders Molven

2020-Current year OA Pubs

The CEL gene encodes carboxyl ester lipase, a pancreatic digestive enzyme. CEL is extremely polymorphic due to a variable number tandem repeat (VNTR) located in the last exon. Single-base deletions within this VNTR cause the inherited disorder MODY8, whereas little is known about VNTR single-base insertions in pancreatic disease. We therefore mapped CEL insertion variants (CEL-INS) in 200 Norwegian patients with pancreatic neoplastic disorders. Twenty-eight samples (14.0%) carried CEL-INS alleles. Most common were insertions in repeat 9 (9.5%), which always associated with a VNTR length of 13 repeats. The combined INS allele frequency (0.078) was similar to that observed in …

Comparative Analysis Of In-Silico Tools In Identifying Pathogenic Variants In Dominant Inherited Retinal Diseases, Daniel C Brock, Meng Wang, Hafiz Muhammad Jafar Hussain, David E Rauch, Molly Marra, Mark E Pennesi, Paul Yang, Lesley Everett, Radwan S Ajlan, Jason Colbert, Fernanda Belga Ottoni Porto, Anna Matynia, Michael B Gorin, Robert K Koenekoop, Irma Lopez, Ruifang Sui, Gang Zou, Yumei Li, Rui Chen

Faculty, Staff and Students Publications

Inherited retinal diseases (IRDs) are a group of rare genetic eye conditions that cause blindness. Despite progress in identifying genes associated with IRDs, improvements are necessary for classifying rare autosomal dominant (AD) disorders. AD diseases are highly heterogenous, with causal variants being restricted to specific amino acid changes within certain protein domains, making AD conditions difficult to classify. Here, we aim to determine the top-performing in-silico tools for predicting the pathogenicity of AD IRD variants. We annotated variants from ClinVar and benchmarked 39 variant classifier tools on IRD genes, split by inheritance pattern. Using area-under-the-curve (AUC) analysis, we determined the …

Age-Related Brain Atrophy And The Positive Effects Of Behavioral Enrichment In Middle-Aged Beagles., Jessica A Noche, Hamsanandini Radhakrishnan, Margo F. Ubele, Kathy Boaz, Jennifer L Mefford, Erin D Jones, Hollie Y Van Rooyen, Jessica A Perpich, Katie Mccarty, Beverly Meacham, Jeffrey R. Smiley, Stasia A Bembenek Bailey, László G Puskás, David K. Powell, Lorena Sordo, Michael J Phelan, Christopher M. Norris, Elizabeth Head, Craig E L Stark

Neuroscience Faculty Publications

Aging dogs serve as a valuable preclinical model for Alzheimer's disease (AD) due to their natural age-related development of β-amyloid (Aβ) plaques, human-like metabolism, and large brains that are ideal for studying structural brain aging trajectories from serial neuroimaging. Here we examined the effects of chronic treatment with the calcineurin inhibitor (CNI) tacrolimus or the nuclear factor of activated T cells (NFAT)-inhibiting compound Q134R on age-related canine brain atrophy from a longitudinal study in middle-aged beagles (36 females, 7 males) undergoing behavioral enrichment. Annual MRI was analyzed using modern, automated techniques for region-of-interest-based and voxel-based volumetric assessments. We found that …

A Multi-Institutional Meningioma Mri Dataset For Automated Multi-Sequence Image Segmentation, Dominic Labella, Omaditya Khanna, Shan Mcburney-Lin, Ryan Mclean, Pierre Nedelec, Arif Rashid, Nourel Hoda Tahon, Talissa Altes, Ujjwal Baid, Radhika Bhalerao, Yaseen Dhemesh, Scott Floyd, Devon Godfrey, Fathi Hilal, Anastasia Janas, Anahita Kazerooni, Collin Kent, John Kirkpatrick, Florian Kofler, Kevin Leu, Nazanin Maleki, Bjoern Menze, Maxence Pajot, Zachary Reitman, Jeffrey Rudie, Rachit Saluja, Yury Velichko, Chunhao Wang, Pranav Warman, Nico Sollmann, David Diffley, Khanak Nandolia, Daniel Warren, Ali Hussain, John Pascal Fehringer, Yulia Bronstein, Lisa Deptula, Evan Stein, Mahsa Taherzadeh, Eduardo Portela De Oliveira, Aoife Haughey, Marinos Kontzialis, Luca Saba, Benjamin Turner, Melanie Brüßeler, Shehbaz Ansari, Athanasios Gkampenis, David Maximilian Weiss, Aya Mansour, Islam Shawali, Nikolay Yordanov, Joel Stein, Roula Hourani, Mohammed Yahya Moshebah, Ahmed Magdy Abouelatta, Tanvir Rizvi, Klara Willms, Dann Martin, Abdullah Okar, Gennaro D'Anna, Ahmed Taha, Yasaman Sharifi, Shahriar Faghani, Dominic Kite, Marco Pinho, Muhammad Ammar Haider, Michelle Alonso-Basanta, Javier Villanueva-Meyer, Andreas Rauschecker, Ayman Nada, Mariam Aboian, Adam Flanders, Spyridon Bakas, Evan Calabrese

Department of Radiology Faculty Papers

Meningiomas are the most common primary intracranial tumors and can be associated with significant morbidity and mortality. Radiologists, neurosurgeons, neuro-oncologists, and radiation oncologists rely on brain MRI for diagnosis, treatment planning, and longitudinal treatment monitoring. However, automated, objective, and quantitative tools for non-invasive assessment of meningiomas on multi-sequence MR images are not available. Here we present the BraTS Pre-operative Meningioma Dataset, as the largest multi-institutional expert annotated multilabel meningioma multi-sequence MR image dataset to date. This dataset includes 1,141 multi-sequence MR images from six sites, each with four structural MRI sequences (T2-, T2/FLAIR-, pre-contrast T1-, and post-contrast T1-weighted) accompanied by …

Integrative Molecular Analyses Of The Md Anderson Prostate Cancer Patient-Derived Xenograft (Mda Pca Pdx) Series, Nicolas Anselmino, Estefania Labanca, Peter D A Shepherd, Jiabin Dong, Jun Yang, Xiaofei Song, Subhiksha Nandakumar, Ritika Kundra, Cindy Lee, Nikolaus Schultz, Jianhua Zhang, John C Araujo, Ana M Aparicio, Sumit K Subudhi, Paul G Corn, Louis L Pisters, John F Ward, John W Davis, Elba S Vazquez, Geraldine Gueron, Christopher J Logothetis, Andrew Futreal, Patricia Troncoso, Yu Chen, Nora M Navone

Faculty, Staff and Student Publications

PURPOSE: Develop and deploy a robust discovery platform that encompasses heterogeneity, clinical annotation, and molecular characterization and overcomes the limited availability of prostate cancer models. This initiative builds on the rich MD Anderson (MDA) prostate cancer (PCa) patient-derived xenograft (PDX) resource to complement existing publicly available databases by addressing gaps in clinically annotated models reflecting the heterogeneity of potentially lethal and lethal prostate cancer.

EXPERIMENTAL DESIGN: We performed whole-genome, targeted, and RNA sequencing in representative samples of the same tumor from 44 PDXs derived from 38 patients linked to donor tumor metadata and corresponding organoids. The cohort includes models derived …

Oncology Patients’ Willingness To Report Their Medication Safety Concerns From Home: A Qualitative Study, Deema Bunni, Grace Walters, Misun Hwang, Katie Gahn, Heidi Mason, Milisa Manojlovich, Yang Gong, Yun Jiang

Faculty, Staff and Student Publications

Purpose: Oncology patients often struggle to manage their medications and related adverse events during transitions of care. They are expected to take an active role in self-monitoring and timely reporting of their medication safety events or concerns to clinicians. The purpose of this study was to explore the factors influencing oncology patients' willingness to report adverse events or concerns related to their medication after their transitions back home.

Methods: A qualitative interview study was conducted with adult patients with breast, prostate, lung, or colorectal cancer who experienced care transitions within the previous year. A semi-structured interview guide was developed to …

Ire1Α Determines Ferroptosis Sensitivity Through Regulation Of Glutathione Synthesis, Dadi Jiang, Youming Guo, Tianyu Wang, Liang Wang, Yuelong Yan, Ling Xia, Rakesh Bam, Zhifen Yang, Hyemin Lee, Takao Iwawaki, Boyi Gan, Albert C Koong

Faculty, Staff and Student Publications

Cellular sensitivity to ferroptosis is primarily regulated by mechanisms mediating lipid hydroperoxide detoxification. We show that inositol-requiring enzyme 1 (IRE1α), an endoplasmic reticulum (ER) resident protein critical for the unfolded protein response (UPR), also determines cellular sensitivity to ferroptosis. Cancer and normal cells depleted of IRE1α gain resistance to ferroptosis, while enhanced IRE1α expression promotes sensitivity to ferroptosis. Mechanistically, IRE1α's endoribonuclease activity cleaves and down-regulates the mRNA of key glutathione biosynthesis regulators glutamate-cysteine ligase catalytic subunit (GCLC) and solute carrier family 7 member 11 (SLC7A11). This activity of IRE1α is independent of its role in regulating the UPR and is …

Jag1/2 Maintain Esophageal Homeostasis And Suppress Foregut Tumorigenesis By Restricting The Basal Progenitor Cell Pool, Haidi Huang, Yu Jiang, Jiangying Liu, Dan Luo, Jianghong Yuan, Rongzi Mu, Xiang Yu, Donglei Sun, Jihong Lin, Qiyue Chen, Xinjing Li, Ming Jiang, Jianming Xu, Bo Chu, Chengqian Yin, Lei Zhang, Youqiong Ye, Bo Cao, Qiong Wang, Yongchun Zhang

Faculty, Staff and Students Publications

Basal progenitor cells are crucial for maintaining foregut (the esophagus and forestomach) homeostasis. When their function is dysregulated, it can promote inflammation and tumorigenesis. However, the mechanisms underlying these processes remain largely unclear. Here, we employ genetic mouse models to reveal that Jag1/2 regulate esophageal homeostasis and foregut tumorigenesis by modulating the function of basal progenitor cells. Deletion of Jag1/2 in mice disrupts esophageal and forestomach epithelial homeostasis. Mechanistically, Jag1/2 deficiency impairs activation of Notch signaling, leading to reduced squamous epithelial differentiation and expansion of basal progenitor cells. Moreover, Jag1/2 deficiency exacerbates the deoxycholic acid (DCA)-induced squamous epithelial injury and …

Third-Party Fecal Microbiota Transplantation For High-Risk Treatment-Naïve Acute Gvhd Of The Lower Gi Tract, Zachariah Defilipp, Ashish V Damania, Haesook T Kim, Chia-Chi Chang, Areej El-Jawahri, Steven L Mcafee, Aj S Bottoms, Vesselina Toncheva, Melissa M Smith, Maria Dolaher, Lindsey Perry, Meghan White, Brittany Diana, Sheila Connolly, Bimalangshu R Dey, Matthew J Frigault, Richard A Newcomb, Paul V O'Donnell, Thomas R Spitzer, Michael K Mansour, Daniela Weber, Nadim J Ajami, Elizabeth Hohmann, Robert R Jenq, Yi-Bin Chen

Faculty, Staff and Student Publications

Disruption of the intestinal microbiome is observed with acute graft-versus-host disease (GVHD) of the lower gastrointestinal (LGI) tract, and fecal microbiota transplantation (FMT) has successfully cured steroid-refractory cases. In this open-label, single-arm, pilot study, third-party, single-donor FMT was administered in combination with systemic corticosteroids to participants with high-risk acute LGI GVHD, with a focus on treatment-naïve cases. Participants were scheduled to receive 1 induction dose (15 capsules per day for 2 consecutive days), followed by 3 weekly maintenance doses, consisting of 15 capsules per dose. The primary end point of the study was feasibility, which would be achieved if ≥80% …

High All-Cause Mortality And Increasing Proportion Of Older Adults With Tuberculosis In Texas, 2008–2020, Belinda A Medrano, Miryoung Lee, Gretchen Gemeinhardt, Lana Yamba, Blanca I Restrepo

Faculty, Staff and Student Publications

Pulmonary tuberculosis (PTB) elimination efforts must consider the global growth of the ageing population. Here we used TB surveillance data from Texas, United States (2008-2020; total n = 10656) to identify unique characteristics and outcomes in older adults (OA, ≥65 years) with PTB, compared to young adults (YA, 18-39 years) or middle-aged adults (40-64 years). We found that the proportion of OA with PTB increased from 15% in 2008 to 24% in 2020 (trend p < 0.05). Diabetes was highly prevalent in OA (32%) but not associated with adverse outcomes. Death was 13-fold higher in OA compared to YA and was 7% at the time of diagnosis which suggests diagnostic delays. However, once TB was suspected, we found no differences in culture, smear, or nucleic acid detection of mycobacteria (although less lung cavitations) in OA. During treatment, OA had less drug-resistant TB, few adverse reactions and adhered with TB treatment. We recommend training healthcare workers to 'think TB' in OA, for prompt treatment initiation to diminish deaths. Furthermore, OA should be added as a priority group to the latent TB treatment guidelines by the World Health Organization, to prevent TB disease in this highly vulnerable group.

Targeting Cathepsin C Ameliorates Murine Acetaminophen-Induced Liver Injury, Jessica Raith, Malte Bachmann, Sina Gonther, Hendrik Stülb, Ali A Aghdassi, Christine T N Pham, Heiko Mühl

2020-Current year OA Pubs

Acetaminophen (APAP) overdosing is a major cause of acute liver failure worldwide and an established model for drug-induced acute liver injury (ALI). While studying gene expression during murine APAP-induced ALI by 3'mRNA sequencing (massive analysis of cDNA ends, MACE), we observed splenic mRNA accumulation encoding for the neutrophil serine proteases cathepsin G, neutrophil elastase, and proteinase-3 - all are hierarchically activated by cathepsin C (CtsC). This, along with increased serum levels of these proteases in diseased mice, concurs with the established phenomenon of myeloid cell mobilization during APAP intoxication.

Keratin 17 Modulates The Immune Topography Of Pancreatic Cancer, Lyanne Delgado-Coka, Michael Horowitz, Mariana Torrente-Goncalves, Lucia Roa-Peña, Cindy Leiton, Mahmudul Hasan, Sruthi Babu, Danielle Fassler, Jaymie Oentoro, Ji-Dong Bai, Emanuel Petricoin, Lynn Matrisian, Edik Matthew Blais, Natalia Marchenko, Felicia Allard, Wei Jiang, Brent Larson, Andrew Hendifar, Chao Chen, Shahira Abousamra, Dimitris Samaras, Tahsin Kurc, Joel Saltz, Luisa Escobar-Hoyos, Kenneth Shroyer

Kimmel Cancer Center Faculty Papers

BACKGROUND: The immune microenvironment impacts tumor growth, invasion, metastasis, and patient survival and may provide opportunities for therapeutic intervention in pancreatic ductal adenocarcinoma (PDAC). Although never studied as a potential modulator of the immune response in most cancers, Keratin 17 (K17), a biomarker of the most aggressive (basal) molecular subtype of PDAC, is intimately involved in the histogenesis of the immune response in psoriasis, basal cell carcinoma, and cervical squamous cell carcinoma. Thus, we hypothesized that K17 expression could also impact the immune cell response in PDAC, and that uncovering this relationship could provide insight to guide the development of …

Inhibition Of The Mptp And Lipid Peroxidation Is Additively Protective Against I/R Injury, Arielys Mendoza, Pooja Patel, Dexter Robichaux, Daniel Ramirez, Jason Karch

Faculty, Staff and Students Publications

Background: During myocardial ischemia/reperfusion (I/R) injury, high levels of matrix Ca2+ and reactive oxygen species (ROS) induce the opening of the mitochondrial permeability transition pore (mPTP), which causes mitochondrial dysfunction and ultimately necrotic death. However, the mechanisms of how these triggers individually or cooperatively open the pore have yet to be determined.

Methods: Here, we use a combination of isolated mitochondrial assays and in vivo I/R surgery in mice. We challenged isolated liver and heart mitochondria with Ca2+, ROS, and Fe2+ to induce mitochondrial swelling. Using inhibitors of the mPTP (cyclosporine A or ADP) lipid peroxidation (ferrostatin-1, MitoQ), we determined …