Medicine and Health Sciences Commons^™

Increasing Covid-19 Testing And Vaccination Uptake In The Take Care Texas Community-Based Randomized Trial: Adaptive Geospatial Analysis, Kehe Zhang, Jocelyn V Hunyadi, Marcia C De Oliveira Otto, Miryoung Lee, Zitong Zhang, Ryan Ramphul, Jose-Miguel Yamal, Ashraf Yaseen, Alanna C Morrison, Shreela Sharma, Mohammad Hossein Rahbar, Xu Zhang, Stephen Linder, Dritana Marko, Rachel White Roy, Deborah Banerjee, Esmeralda Guajardo, Michelle Crum, Belinda Reininger, Maria E Fernandez, Cici Bauer

Faculty, Staff and Student Publications

BACKGROUND: Geospatial data science can be a powerful tool to aid the design, reach, efficiency, and impact of community-based intervention trials. The project titled Take Care Texas aims to develop and test an adaptive, multilevel, community-based intervention to increase COVID-19 testing and vaccination uptake among vulnerable populations in 3 Texas regions: Harris County, Cameron County, and Northeast Texas.

OBJECTIVE: We aimed to develop a novel procedure for adaptive selections of census block groups (CBGs) to include in the community-based randomized trial for the Take Care Texas project.

METHODS: CBG selection was conducted across 3 Texas regions over a 17-month period …

Comparative Transcriptomics Reveals A Mixed Basal, Club, And Hillock Epithelial Cell Identity In Castration-Resistant Prostate Cancer, Samuel P Pitzen, Amber N Rudenick, Yinjie Qiu, Weijie Zhang, Sarah A Munro, Braedan M Mccluskey, Colleen Forster, Hannah E Bergom, Atef Ali, Ella Boytim, John T Lafin, Simon Linder, Mazlina Ismail, Wout Devlies, Conner J Sessions, Frank Claessens, Steven Joniau, Gerhardt Attard, Wilbert Zwart, Peter S Nelson, Eva Corey, Yuzhuo Wang, Joshua M Lang, Himisha Beltran, Douglas Strand, Emmanuel S Antonarakis, Justin Hwang, Paari Murugan, R Stephanie Huang, Scott M Dehm

Faculty, Staff and Student Publications

Inhibiting the androgen receptor (AR) is effective for treatment of advanced prostate cancers because of their AR-dependent luminal epithelial cell identity. Tumors progress during therapy to castration-resistant prostate cancer (CRPC) by restoring AR signaling and maintaining luminal identity or by converting through lineage plasticity to a neuroendocrine (NE) identity or double-negative CRPC (DNPC) lacking luminal or NE identities. Here, we show that DNPC cells express genes defining basal, club, and hillock epithelial cells from benign prostate. We identified KLF5 as a regulator of genes defining this mixed basal, club, and hillock cell identity in DNPC models. KLF5-mediated upregulation of

Bbox1 Restrains Tbk1-Mtorc1 Oncogenic Signaling In Clear Cell Renal Cell Carcinoma, Chengheng Liao, Lianxin Hu, Liwei Jia, Jin Zhou, Tao Wang, Kangsan Kim, Hua Zhong, Hongwei Yao, Lei Dong, Lei Guo, Qian Liang, Cheng Zhang, Fangzhou Zhao, Jun Fang, Hongyi Liu, Shina Li, Lin Xu, Jeremy M Simon, Srinivas Malladi, Payal Kapur, James Brugarolas, Ralph J Deberardinis, Qing Zhang

Faculty, Staff and Student Publications

Clear cell renal cell carcinoma (ccRCC), a metabolic disease originating from renal proximal convoluted tubule (PCT) epithelial cells, remains incompletely understood in terms of its initiating signaling events. Here, we identify γ-butyrobetaine hydroxylase 1 (BBOX1), a key enzyme in carnitine synthesis predominantly expressed in PCT cells, as a tumor suppressor in ccRCC. BBOX1 expression is lost during ccRCC malignant transformation, and its restoration reduces cell viability in physiological medium and inhibits xenograft tumor growth. Transcriptomic analyses reveal that BBOX1 suppresses critical metabolic pathways including mTORC1 signaling and glycolysis in ccRCC. Further, we identify TANK-binding kinase 1 (TBK1) as an essential …

Intensive Lifestyle Intervention, Cardiac Biomarkers, And Cardiovascular Outcomes In Diabetes: Look Ahead Cardiac Biomarker Ancillary Study, Kershaw V Patel, Zainali Chunawala, Subodh Verma, Matthew W Segar, Katelyn R Garcia, Chiadi E Ndumele, Thomas J Wang, James L Januzzi, Antoni Bayes-Genis, Javed Butler, Carolyn S P Lam, Christie M Ballantyne, James A De Lemos, Alain G Bertoni, Mark Espeland, Ambarish Pandey

Faculty, Staff and Students Publications

Background: N-terminal pro-B-type natriuretic peptide (NT-proBNP) and high-sensitivity cardiac troponin T (hs-cTnT) are associated with cardiovascular outcomes and are recommended for measurement in type 2 diabetes (T2D). However, the effects of an intensive lifestyle intervention (ILI) targeting weight loss on cardiac biomarkers and the prognostic association of changes in these biomarkers with risk of adverse cardiovascular outcomes in T2D are not well-established.

Objectives: This study sought to evaluate the effects of an ILI on cardiac biomarkers and the association of changes in cardiac biomarkers with risk of cardiovascular outcomes in T2D.

Methods: Participants of the Look AHEAD (Action for Health …

Phosphorylation Of Cryab Induces A Condensatopathy To Worsen Post-Myocardial Infarction Left Ventricular Remodeling, Moydul Islam, David R. Rawnsley, Xiucui Ma, Walter Navid, Chen Zhao, Xumin Guan, Layla Foroughi, John T. Murphy, Honora Navid, Carla J. Weinheimer, Attila Kovacs, Jessica Nigro, Aaradhya Diwan, Ryan P. Chang, Minu Kumari, Martin E. Young, Babak Razani, Kenneth B. Margulies, Mahmoud Abdellatif, Simon Sedej, Ali Javaheri, Douglas F. Covey, Kartik Mani, Abhinav Diwan

2020-Current year OA Pubs

Protein aggregates are emerging therapeutic targets in rare monogenic causes of cardiomyopathy and amyloid heart disease, but their role in more prevalent heart-failure syndromes remains mechanistically unexamined. We observed mislocalization of desmin and sarcomeric proteins to aggregates in human myocardium with ischemic cardiomyopathy and in mouse hearts with post-myocardial infarction ventricular remodeling, mimicking findings of autosomal-dominant cardiomyopathy induced by the R120G mutation in the cognate chaperone protein CRYAB. In both syndromes, we demonstrate increased partitioning of CRYAB phosphorylated on serine 59 to NP40-insoluble aggregate-rich biochemical fraction. While CRYAB undergoes phase separation to form condensates, the phosphomimetic mutation of serine 59 …

Assessing Dynamic Cognitive Function In The Daily Lives Of Youths With And Without Type 1 Diabetes: Usability Study, Mary Katherine Ray, Jorie Fleming, Andrew Aschenbrenner, Jason Hassenstab, Brooke Redwine, Carissa Burns, Ana Maria Arbelaez, Mary Ellen Vajravelu, Tamara Hershey

2020-Current year OA Pubs

BACKGROUND: Studies have shown a relationship between worse glycemic control and lower cognitive scores in youths with type 1 diabetes (T1D). However, most studies assess long-term glucose control (eg, years-decades) and cognition at a single time point. Understanding this relationship at a higher temporal resolution (eg, minutes-hours) and in naturalistic settings has potential clinical implications. Newer technology (eg, continuous glucose monitoring [CGM] and ecological momentary assessment) provides a unique opportunity to explore the glucose dynamics that influence dynamic cognition; that is, cognitive functions that fluctuate short-term and are influenced by environmental factors.

OBJECTIVE: Before we can assess this relationship, we …

A Neuronal Code For Object Representation And Memory In The Human Amygdala And Hippocampus, Runnan Cao, Peter Brunner, Puneeth N Chakravarthula, Krista L Wahlstrom, Cory Inman, Elliot H Smith, Xin Li, Adam N Mamelak, Nicholas J Brandmeir, Ueli Rutishauser, Jon T Willie, Shuo Wang

2020-Current year OA Pubs

How the brain encodes, recognizes, and memorizes general visual objects is a fundamental question in neuroscience. Here, we investigated the neural processes underlying visual object perception and memory by recording from 3173 single neurons in the human amygdala and hippocampus across four experiments. We employed both passive-viewing and recognition memory tasks involving a diverse range of naturalistic object stimuli. Our findings reveal a region-based feature code for general objects, where neurons exhibit receptive fields in the high-level visual feature space. This code can be validated by independent new stimuli and replicated across all experiments, including fixation-based analyses with large natural …

Lifespan In Rodents With Myt1l Heterozygous Mutation, Allyson Schreiber, Raylynn G Swift, Leslie Wilson, Kristen L Kroll, Joseph D Dougherty, Susan E Maloney

2020-Current year OA Pubs

MYT1L syndrome is a newly recognized disorder characterized by intellectual disability, speech and motor delay, neuroendocrine disruptions, ADHD, and autism. In order to study this gene and its association with these phenotypes, our lab recently created a Myt1l heterozygous mutant mouse inspired by a clinically relevant mutation. This model recapitulates several of the physical and neurologic abnormalities seen in humans with MYT1L syndrome, such as weight gain, microcephaly, and behavioral disruptions. The majority of patients with this syndrome are young, and little is known about the impact of age on health and mortality in these patients. Using a Myt1l mutant …

Swog S1815: A Phase Iii Randomized Trial Of Gemcitabine, Cisplatin, And Nab-Paclitaxel Versus Gemcitabine And Cisplatin In Newly Diagnosed, Advanced Biliary Tract Cancers, Rachna T Shroff, Benjamin Tan, Et Al.

2020-Current year OA Pubs

PURPOSE: SWOG S1815 was a randomized, open label phase III trial, evaluating gemcitabine, nab-paclitaxel, and cisplatin (GAP) versus gemcitabine and cisplatin (GC) in patients with newly diagnosed advanced biliary tract cancers (BTCs).

METHODS: Patients with newly diagnosed locally advanced unresectable or metastatic BTC, including intrahepatic cholangiocarcinoma (ICC) and extrahepatic cholangiocarcinoma (ECC) and gallbladder carcinoma (GBC), were randomly assigned 2:1 to either GAP (gemcitabine 800 mg/m

RESULTS: Among 452 randomly assigned participants, 441 were eligible and analyzable, 67% with ICC, 16% with GBC, and 17% with ECC. There was no significant difference in overall survival (OS) between GAP versus GC. Median …

Glucagon-Like Peptide-1 Receptor Agonists Improve Metabolic Dysfunction-Associated Steatotic Liver Disease Outcomes, Brandon Havranek, Rebecca Loh, Beatriz Torre, Rachel Redfield, Dina Halegoua-De Marzio

Division of Gastroenterology and Hepatology Faculty Papers

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the leading cause of chronic liver disease and is associated with significant cardiovascular morbidity and mortality. This study aims to investigate the association of glucagon-like peptide-1 (GLP-1) agonists with major cardiovascular events, clinically significant portal hypertension events, and all-cause mortality in patients with MASLD. A large, population-based retrospective cohort study was conducted using the TriNetX platform, which provided real-time access to electronic health records of 634,265 adult patients with MASLD/MASH. Propensity score matching (PSM) was employed to create two cohorts: A GLP-1 agonists group and a control group without GLP-1 agonists usage. Hazard …

Sex And Outcomes Of Patients With Microsatellite Instability-High And Braf V600e Mutated Metastatic Colorectal Cancer Receiving Immune Checkpoint Inhibitors, Vincenzo Nasca, Joseph Zhao, Javier Ros, Sara Lonardi, Koen Zwart, Romain Cohen, Marwan Fakih, Priya Jayachandran, Jeanine M L Roodhart, Jeroen Derksen, Rossana Intini, Francesca Bergamo, Giacomo Mazzoli, Filippo Ghelardi, Marta Ligero, Jitendra Jonnagaddala, Nicholas Hawkins, Robyn L Ward, Durgesh Wankhede, Hermann Brenner, Michael Hoffmeister, Marco Vitellaro, Lisa Salvatore, Claire Gallois, Pierre Laurent-Puig, Chiara Cremolini, Michael J Overman, Julien Taieb, David Tougeron, Thierry Andre, Jakob Nikolas Kather, Raghav Sundar, Javier Carmona, Elena Elez, Miriam Koopman, Filippo Pietrantonio

Faculty, Staff and Student Publications

Background: Immune checkpoint inhibitors (ICIs) are the gold standard therapy in patients with deficient mismatch repair (dMMR)/microsatellite instability-high (MSI-H) metastatic colorectal cancer (mCRC). A significant proportion of patients show resistance, making the identification of determinants of response crucial. Growing evidence supports the role of sex in determining susceptibility to anticancer therapies, but data is lacking for patients with MSI-H CRC.

Methods: In this real-world cohort comprising 624 patients with MSI-H mCRC receiving ICIs, we investigated the impact of sex on patients' outcomes, overall and according to RAS-BRAF mutational status or type of treatment (anti-PD-(L)1 with or without anti-CTLA-4 agents). We …

Tigit Inhibitor M6223 As Monotherapy Or In Combination With Bintrafusp Alfa In Patients With Advanced Solid Tumors: A First-In-Human, Phase 1, Dose-Escalation Trial, Aung Naing, Meredith Mckean, Anthony Tolcher, Anja Victor, Ping Hu, Wei Gao, Marco A F Nogueira Filho, Thomas Kitzing, Stephan Gleicher, Daniel Holland, Emilia Richter, Keyvan Tadjalli-Mehr, Lillian L Siu

Faculty, Staff and Student Publications

Background: M6223 is an intravenous (IV), Fc-competent, fully human, antagonistic, anti-T cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domains (TIGIT) antibody. Bintrafusp alfa (BA) is a bifunctional fusion protein that simultaneously blocks nonredundant immunosuppressive TGF-β and PD-(L)1 pathways.

Methods: This first-in-human, dose-escalation study in patients with advanced solid tumors (N=58; aged ≥18 years, ECOG PS≤1) evaluated M6223 alone (Part 1A, n=40; M6223 10-2400 mg every 2 weeks, n=32; M6223 2400 mg every 3 weeks, n=8) or with BA (Part 1B, n=18; M6223 300-1600 mg with BA 1200 mg; both every 2 weeks, intravenous). Primary objectives were safety, tolerability, …

A Targeted Gene Expression Biomarker Predicts Clinic Low-Risk Meningioma Recurrence, Minh P Nguyen, Ramin A Morshed, Mark W Youngblood, Haley K Perlow, Calixto-Hope G Lucas, Akash J Patel, Joshua D Palmer, Craig M Horbinski, Stephen T Magill, William C Chen, David R Raleigh

Duncan NRI Faculty and Staff Publications

Background: Despite reassuring clinical and histological features, low-grade meningiomas can recur after surgery. Targeted gene expression profiling improves risk stratification of meningiomas, but the utility of this approach for clinical low-risk meningiomas is incompletely understood.

Methods: This was a multicenter retrospective cohort study of meningiomas from patients who were treated at 4 institutions from 1992 to 2023. Adult patients with newly diagnosed or recurrent World Health Organization (WHO) grade 1 meningiomas that were treated with gross total resection (GTR) or subtotal resection (STR), or newly diagnosed WHO grade 2 meningiomas that were treated with GTR, were included. A 34-gene expression …

Long-Read Sequencing Of 945 Han Individuals Identifies Structural Variants Associated With Phenotypic Diversity And Disease Susceptibility, Jiao Gong, Huiru Sun, Kaiyuan Wang, Yanhui Zhao, Yechao Huang, Qinsheng Chen, Hui Qiao, Yang Gao, Jialin Zhao, Yunchao Ling, Ruifang Cao, Jingze Tan, Qi Wang, Yanyun Ma, Jing Li, Jingchun Luo, Sijia Wang, Jiucun Wang, Guoqing Zhang, Shuhua Xu, Feng Qian, Fang Zhou, Huiru Tang, Dali Li, Chinese Pangenome Consortium (Cpc), Fritz J Sedlazeck, Li Jin, Yuting Guan, Shaohua Fan

Faculty, Staff and Students Publications

Genomic structural variants (SVs) are a major source of genetic diversity in humans. Here, through long-read sequencing of 945 Han Chinese genomes, we identify 111,288 SVs, including 24.56% unreported variants, many with predicted functional importance. By integrating human population-level phenotypic and multi-omics data as well as two humanized mouse models, we demonstrate the causal roles of two SVs: one SV that emerges at the common ancestor of modern humans, Neanderthals, and Denisovans in GSDMD for bone mineral density and one modern-human-specific SV in WWP2 impacting height, weight, fat, craniofacial phenotypes and immunity. Our results suggest that the GSDMD SV could …

Contrast-Enhanced Magnetic Resonance Imaging Based Calf Muscle Perfusion And Machine Learning In Peripheral Artery Disease, Bijen Khagi, Tatiana Belousova, Christina M Short, Addison A Taylor, Jean Bismuth, Dipan J Shah, Gerd Brunner

Faculty, Staff and Students Publications

Peripheral artery disease (PAD) remains underdiagnosed and undertreated and is associated with an increased risk for adverse cardiovascular outcomes. Imaging provides an approach to identifying patients with PAD. However, the role of integrating imaging with machine learning to identify PAD patients and potentially assess disease severity remains understudied. A total of 56 participants, including 36 PAD patients with intermittent claudication and 20 matched controls, underwent contrast-enhanced magnetic resonance imaging (CE-MRI) calf muscle perfusion scanning. CE-MRI-derived dynamic muscle perfusion maps were developed to quantify alterations of the microvascular circulation in the calf muscles based on voxel contrast enhancement. These dynamic muscle …

Neuronal Network Activation Induced By Forniceal Deep Brain Stimulation In Mice, Bin Tang, Zhenyu Wu, Qi Wang, Jianrong Tang

Faculty, Staff and Students Publications

Background: The fimbria-fornix is a nerve fiber bundle that connects various structures of the limbic system in the brain and plays a key role in cognition. It has become a major target of deep brain stimulation (DBS) to treat memory impairment in both dementia patients and animal models of neurological diseases. Previously, we have reported the beneficial memory effects of chronic forniceal DBS in mouse models of intellectual disability disorders. In Rett syndrome and CDKL5 deficiency disorder models, DBS strengthens hippocampal synaptic plasticity, reduces dentate inhibitory transmission or increases adult hippocampal neurogenesis that aids memory. However, the underlying neuronal circuitry …

Motor Pool Selectivity Of Neuromuscular Degeneration In Type I Spinal Muscular Atrophy Is Conserved Between Human And Mouse, Justin C Lee, Wendy K Chung, David J Pisapia, Christopher E Henderson

Faculty, Staff and Students Publications

Spinal muscular atrophy (SMA) is caused by low levels of the survival motor neuron (SMN) protein. Even though SMN is ubiquitously expressed, the disease selectively affects motor neurons, leading to progressive muscle weakness. Even among motor neurons, certain motor units appear more clinically resistant to SMA. To quantitatively survey selective resistance, we studied extensive neuromuscular autopsies of Type I SMA patients and age-matched controls. We found highly divergent degrees of degeneration of neighboring motor units, even within individual cranial nerves or a single anatomical area such as the neck. Examination of a Type I SMA patient maintained on life support …

Bacterial Community Assembly Of Specific Pathogen-Free Neonatal Mice, Elizabeth A Kennedy, James S Weagley, Andrew H Kim, Avan Antia, Anna L Deveaux, Megan T Baldridge

2020-Current year OA Pubs

BACKGROUND: Neonatal mice are frequently used to model diseases that affect human infants. Microbial community composition has been shown to impact disease progression in these models. Despite this, the maturation of the early-life murine microbiome has not been well-characterized. We address this gap by characterizing the assembly of the bacterial microbiota of C57BL/6 and BALB/c litters from birth to adulthood across multiple independent litters.

RESULTS: The fecal microbiome of young pups is dominated by only a few pioneering bacterial taxa. These taxa are present at low levels in the microbiota of multiple maternal body sites, precluding a clear identification of …

Heterogeneous Clinical Phenotypes Of Sporadic Early-Onset Alzheimer's Disease: A Neuropsychological Data-Driven Approach, Deepti Putcha, Erik Musiek, Kyle Womack, Et Al.

2020-Current year OA Pubs

BACKGROUND: The clinical presentations of early-onset Alzheimer's disease (EOAD) and late-onset Alzheimer's disease are distinct, with EOAD having a more aggressive disease course with greater heterogeneity. Recent publications from the Longitudinal Early-Onset Alzheimer's Disease Study (LEADS) described EOAD as predominantly amnestic, though this phenotypic description was based solely on clinical judgment. To better understand the phenotypic range of EOAD presentation, we applied a neuropsychological data-driven method to subtype the LEADS cohort.

METHODS: Neuropsychological test performance from 169 amyloid-positive EOAD participants were analyzed. Education-corrected normative comparisons were made using a sample of 98 cognitively normal participants. Comparing the relative levels of …

Efficacy Of Zenocutuzumab In Nrg1 Fusion-Positive Cancer, Alison M Schram, Koichi Goto, Dong-Wan Kim, Teresa Macarulla, Antoine Hollebecque, Eileen M O'Reilly, Sai-Hong Ignatius Ou, Jordi Rodon, Sun Young Rha, Kazumi Nishino, Michaël Duruisseaux, Joon Oh Park, Cindy Neuzillet, Stephen V Liu, Benjamin A Weinberg, James M Cleary, Emiliano Calvo, Kumiko Umemoto, Misako Nagasaka, Christoph Springfeld, Tanios Bekaii-Saab, Grainne M O'Kane, Frans Opdam, Kim A Reiss, Andrew K Joe, Ernesto Wasserman, Viktoriya Stalbovskaya, Jim Ford, Shola Adeyemi, Lokesh Jain, Shekeab Jauhari, Alexander Drilon, Enrgy Investigators

Faculty, Staff and Student Publications

Background: Neuregulin 1 (NRG1) fusions are recurrent oncogenic drivers found in multiple solid tumors. NRG1 binds to human epidermal growth factor receptor 3 (HER3), leading to heterodimerization with HER2 and activation of downstream growth and proliferation pathways. The efficacy and safety of zenocutuzumab, a bispecific antibody against HER2 and HER3, in patients with NRG1 fusion-positive solid tumors are unclear.

Methods: In this registrational, phase 2 clinical study, we assigned patients with advanced NRG1 fusion-positive cancer involving any tumor type to receive zenocutuzumab at a dose of 750 mg intravenously every 2 weeks. The primary end point was overall …

Genomic And Phenotypic Correlates Of Mosaic Loss Of Chromosome Y In Blood, Yasminka A Jakubek, Xiaolong Ma, Adrienne M Stilp, Fulong Yu, Jason Bacon, Justin W Wong, Francois Aguet, Kristin Ardlie, Donna K Arnett, Kathleen Barnes, Joshua C Bis, Tom Blackwell, Lewis C Becker, Eric Boerwinkle, Russell P Bowler, Matthew J Budoff, April P Carson, Jiawen Chen, Michael H Cho, Josef Coresh, Nancy J Cox, Paul S De Vries, Dawn L Demeo, David W Fardo, Myriam Fornage, Xiuqing Guo, Michael E Hall, Nancy Heard-Costa, Bertha Hidalgo, Marguerite Ryan Irvin, Andrew D Johnson, Eric Jorgenson, Eimear E Kenny, Michael D Kessler, Daniel Levy, Yun Li, Joao A C Lima, Yongmei Liu, Adam E Locke, Ruth J F Loos, Mitchell J Machiela, Rasika A Mathias, Braxton D Mitchell, Joanne M Murabito, Josyf C Mychaleckyj, Kari E North, Peter Orchard, Stephen C J Parker, Yash Pershad, Patricia A Peyser, Katherine A Pratte, Bruce M Psaty, Laura M Raffield, Susan Redline, Stephen S Rich, Jerome I Rotter, Sanjiv J Shah, Jennifer A Smith, Aaron P Smith, Albert Smith, Margaret A Taub, Hemant K Tiwari, Russell Tracy, Bjoernar Tuftin, Alexander G Bick, Vijay G Sankaran, Alexander P Reiner, Paul Scheet, Paul L Auer

Faculty, Staff and Student Publications

Mosaic loss of Y (mLOY) is the most common somatic chromosomal alteration detected in human blood. The presence of mLOY is associated with altered blood cell counts and increased risk of Alzheimer disease, solid tumors, and other age-related diseases. We sought to gain a better understanding of genetic drivers and associated phenotypes of mLOY through analyses of whole-genome sequencing (WGS) of a large set of genetically diverse males from the Trans-Omics for Precision Medicine (TOPMed) program. We show that haplotype-based calling methods can be used with WGS data to successfully identify mLOY events. This approach enabled us to identify differences …

Differentiating Between Renal Medullary And Clear Cell Renal Carcinoma With A Machine Learning Radiomics Approach, Rahim Jiwani, Koustav Pal, Iwan Paolucci, Bruno Odisio, Kristy Brock, Nizar M Tannir, Daniel D Shapiro, Pavlos Msaouel, Rahul A Sheth

Faculty, Staff and Student Publications

Background: The objective of this study was to develop and validate a radiomics-based machine learning (ML) model to differentiate between renal medullary carcinoma (RMC) and clear cell renal carcinoma (ccRCC).

Methods: This retrospective Institutional Review Board -approved study analyzed CT images and clinical data from patients with RMC (n = 87) and ccRCC (n = 93). Patients without contrast-enhanced CT scans obtained before nephrectomy were excluded. A standard volumetric software package (MIM 7.1.4, MIM Software Inc.) was used for contouring, after which 949 radiomics features were extracted with PyRadiomics 3.1.0. Radiomics analysis was then performed with RadAR for differential radiomics …

Bi-Allelic Kics2 Mutations Impair Kicstor Complex-Mediated Mtorc1 Regulation, Causing Intellectual Disability And Epilepsy, Rebecca Buchert, Martin D Burkhalter, Chrisovalantou Huridou, Linda Sofan, Timo Roser, Kirsten Cremer, Javeria Raza Alvi, Stephanie Efthymiou, Tawfiq Froukh, Sughra Gulieva, Ulviyya Guliyeva, Moath Hamdallah, Muriel Holder-Espinasse, Rauan Kaiyrzhanov, Doreen Klingler, Mahmoud Koko, Lars Matthies, Joohyun Park, Marc Sturm, Ana Velic, Stephanie Spranger, Tipu Sultan, Hartmut Engels, Holger Lerche, Henry Houlden, Alistair T Pagnamenta, Ingo Borggraefe, Yvonne Weber, Penelope E Bonnen, Reza Maroofian, Olaf Riess, Jonasz J Weber, Melanie Philipp, Tobias B Haack

Faculty, Staff and Students Publications

Nutrient-dependent mTORC1 regulation upon amino acid deprivation is mediated by the KICSTOR complex, comprising SZT2, KPTN, ITFG2, and KICS2, recruiting GATOR1 to lysosomes. Previously, pathogenic SZT2 and KPTN variants have been associated with autosomal recessive intellectual disability and epileptic encephalopathy. We identified bi-allelic KICS2 variants in eleven affected individuals presenting with intellectual disability and epilepsy. These variants partly affected KICS2 stability, compromised KICSTOR complex formation, and demonstrated a deleterious impact on nutrient-dependent mTORC1 regulation of 4EBP1 and S6K. Phosphoproteome analyses extended these findings to show that KICS2 variants changed the mTORC1 proteome, affecting proteins that function in translation, splicing, and …

Dna-Binding Affinity And Specificity Determine The Phenotypic Diversity In Bcl11b-Related Disorders, Ivana Lessel, Anja Baresic, Ivan K Chinn, Jonathan May, Anu Goenka, Kate E Chandler, Jennifer E Posey, Alexandra Afenjar, Luisa Averdunk, Maria Francesca Bedeschi, Thomas Besnard, Rae Brager, Lauren Brick, Melanie Brugger, Theresa Brunet, Susan Byrne, Oscar De La Calle-Martín, Valeria Capra, Paul Cardenas, Céline Chappé, Hey J Chong, Benjamin Cogne, Erin Conboy, Heidi Cope, Thomas Courtin, Wallid Deb, Robertino Dilena, Christèle Dubourg, Magdeldin Elgizouli, Erica Fernandes, Kristi K Fitzgerald, Silvana Gangi, Jaya K George-Abraham, Muge Gucsavas-Calikoglu, Tobias B Haack, Medard Hadonou, Britta Hanker, Irina Hüning, Maria Iascone, Bertrand Isidor, Irma Järvelä, Jay J Jin, Alexander A L Jorge, Dragana Josifova, Ruta Kalinauskiene, Erik-Jan Kamsteeg, Boris Keren, Elena Kessler, Heike Kölbel, Mariya Kozenko, Christian Kubisch, Alma Kuechler, Suzanne M Leal, Juha Leppälä, Sharon M Luu, Gholson J Lyon, Suneeta Madan-Khetarpal, Margherita Mancardi, Elaine Marchi, Lakshmi Mehta, Beatriz Menendez, Chantal F Morel, Sue Moyer Harasink, Dayna-Lynn Nevay, Vincenzo Nigro, Sylvie Odent, Renske Oegema, John Pappas, Matthew T Pastore, Yezmin Perilla-Young, Konrad Platzer, Nina Powell-Hamilton, Rachel Rabin, Aisha Rekab, Raissa C Rezende, Leema Robert, Ferruccio Romano, Marcello Scala, Karin Poths, Isabelle Schrauwen, Jessica Sebastian, John Short, Richard Sidlow, Jennifer Sullivan, Katalin Szakszon, Queenie K G Tan, Undiagnosed Diseases Network, Matias Wagner, Dagmar Wieczorek, Bo Yuan, Nicole Maeding, Dirk Strunk, Amber Begtrup, Siddharth Banka, James R Lupski, Eva Tolosa, Davor Lessel

Faculty, Staff and Students Publications

BCL11B is a Cys2-His2 zinc-finger (C2H2-ZnF) domain-containing, DNA-binding, transcription factor with established roles in the development of various organs and tissues, primarily the immune and nervous systems. BCL11B germline variants have been associated with a variety of developmental syndromes. However, genotype-phenotype correlations along with pathophysiologic mechanisms of selected variants mostly remain elusive. To dissect these, we performed genotype-phenotype correlations of 92 affected individuals harboring a pathogenic or likely pathogenic BCL11B variant, followed by immune phenotyping, analysis of chromatin immunoprecipitation DNA-sequencing data, dual-luciferase reporter assays, and molecular modeling. These integrative analyses enabled us to define three clinical subtypes of BCL11B-related disorders. …

Punch Cd3-Ols: A Phase 3 Prospective Observational Cohort Study To Evaluate The Safety And Efficacy Of Fecal Microbiota, Live-Jslm (Rebyota) In Adults With Recurrent Clostridioides Difficile Infection, Paul Feuerstadt, Teena Chopra, Whitfield Knapple, Nicholas W Van Hise, Erik R Dubberke, Brian Baggott, Beth Guthmueller, Lindy Bancke, Michael Gamborg, Theodore S Steiner, Daniel Van Handel, Sahil Khanna

2020-Current year OA Pubs

BACKGROUND: The aim of this study was to evaluate the safety and efficacy of fecal microbiota, live-jslm (RBL; REBYOTA)-the first single-dose, broad consortia microbiota-based live biotherapeutic approved by the US Food and Drug Administration for preventing recurrent Clostridioides difficile infection (rCDI) in adults following standard-of-care (SOC) antibiotic treatment.

METHODS: PUNCH CD3-OLS was a prospective, phase 3, open-label study, conducted across the US and Canada. Participants were aged ≥18 years with documented rCDI and confirmed use of SOC antibiotics. Participants with comorbidities including inflammatory bowel disease and mild-to-moderate immunocompromising conditions could be enrolled. A single dose of RBL was rectally administered …

Snap Participation As A Moderator Of Food And Nutrition Security And Combined Cardiometabolic Conditions: A Mixed Regression Approach, Maha Almohamad, Ruosha Li, Natalia I Heredia, Jayna M Dave, Eric E Calloway, Anjail Sharrief, Shreela V Sharma

Faculty, Staff and Student Publications

Objectives: To examine the relationships between food security, nutrition security, Supplemental Nutrition Assistance Program (SNAP) participation, and cardiometabolic outcomes, including hypertension, hyperlipidemia, or diabetes, among low-income U.S. individuals.

Methods: A cross-sectional survey of 486 participants (April–June 2021) assessed food and nutrition security and cardiometabolic outcomes. Mixed-effects logistic regression models adjusted for covariates and included a random effect for state of residence. Moderation analyses evaluated SNAP participation’s impact.

Results: Very low food security was associated with higher odds of having at least one cardiometabolic condition, such as hypertension, hyperlipidemia, or diabetes (AOR = 1.96; 95% CI: 1.04–3.69; p = 0.04). SNAP …

Targeting Tiam1 Enhances Hippocampal-Dependent Learning And Memory In The Adult Brain And Promotes Nmda Receptor-Mediated Synaptic Plasticity And Function, Francisco A Blanco, Md Ali Bin Saifullah, Jinxuan X Cheng, Carlota Abella, Federico Scala, Karen Firozi, Sanyong Niu, Jin Park, Jeannie Chin, Kimberley F Tolias

Faculty, Staff and Students Publications

Excitatory synapses and the actin-rich dendritic spines on which they reside are indispensable for information processing and storage in the brain. In the adult hippocampus, excitatory synapses must balance plasticity and stability to support learning and memory. However, the mechanisms governing this balance remain poorly understood. Tiam1 is an actin cytoskeleton regulator prominently expressed in the dentate gyrus (DG) throughout life. Previously, we showed that Tiam1 promotes dentate granule cell synapse and spine stabilization during development, but its role in the adult hippocampus remains unclear. Here, we deleted Tiam1 from adult forebrain excitatory neurons (Tiam1^fKO) and assessed …

Neutralizing Antibody Immune Correlates For A Recombinant Protein Vaccine In The Covail Trial, Youyi Fong, Lauren Dang, Bo Zhang, Jonathan Fintzi, Shiyu Chen, Jing Wang, Nadine G Rouphael, Angela R Branche, David J Diemert, Ann R Falsey, Cecilia Losada, Lindsey R Baden, Sharon E Frey, Jennifer A Whitaker, Susan J Little, Satoshi Kamidani, Emmanuel B Walter, Richard M Novak, Richard Rupp, Lisa A Jackson, Chenchen Yu, Craig A Magaret, Cindy Molitor, Bhavesh Borate, Tara M Babu, Angelica C Kottkamp, Anne F Luetkemeyer, Lilly C Immergluck, Rachel M Presti, Martín Bäcker, Patricia L Winokur, Siham M Mahgoub, Paul A Goepfert, Dahlene N Fusco, Robert L Atmar, Christine M Posavad, Jinjian Mu, Mat Makowski, Mamodikoe K Makhene, Seema U Nayak, Paul C Roberts, Dean Follmann, Peter B Gilbert

Faculty, Staff and Students Publications

For COVAIL recipients of a coronavirus disease 2019 (COVID-19) Sanofi booster vaccine, neutralizing antibody titers were assessed as a correlate of risk (CoR) of COVID-19. Peak and exposure-proximal titers were inverse CoRs with covariate-adjusted hazard ratios (95% confidence intervals) 0.30 (0.11, 0.78) and 0.25 (0.07, 0.85) per 10-fold increase in weighted average titer.

Acute Mecp2 Loss In Adult Mice Reveals Transcriptional And Chromatin Changes That Precede Neurological Dysfunction And Inform Pathogenesis, Sameer S Bajikar, Jian Zhou, Ryan O'Hara, Harini P Tirumala, Mark A Durham, Alexander J Trostle, Michelle Dias, Yingyao Shao, Hu Chen, Wei Wang, Hari Krishna Yalamanchili, Ying-Wooi Wan, Laura A Banaszynski, Zhandong Liu, Huda Y Zoghbi

Faculty, Staff and Students Publications

Mutations in the X-linked methyl-CpG-binding protein 2 (MECP2) gene cause Rett syndrome, a severe childhood neurological disorder. MeCP2 is a well-established transcriptional repressor, yet upon its loss, hundreds of genes are dysregulated in both directions. To understand what drives such dysregulation, we deleted Mecp2 in adult mice, circumventing developmental contributions and secondary pathogenesis. We performed time series transcriptional, chromatin, and phenotypic analyses of the hippocampus to determine the immediate consequences of MeCP2 loss and the cascade of pathogenesis. We find that loss of MeCP2 causes immediate and bidirectional progressive dysregulation of the transcriptome. To understand what drives gene downregulation, we …

Large-Bore Mechanical Thrombectomy Versus Catheter-Directed Thrombolysis In The Management Of Intermediate-Risk Pulmonary Embolism: Primary Results Of The Peerless Randomized Controlled Trial., Wissam A Jaber, Carin F Gonsalves, Stefan Stortecky, Samuel Horr, Orestis Pappas, Ripal T Gandhi, Keith Pereira, Jay Giri, Sameer J Khandhar, Khawaja Afzal Ammar, David M Lasorda, Brian Stegman, Lucas Busch, David J Dexter, Ezana M Azene, Nikhil Daga, Fakhir Elmasri, Chandra R Kunavarapu, Mark E Rea, Joseph S Rossi, Joseph Campbell, Jonathan Lindquist, Adam Raskin, Jason C Smith, Thomas M Tamlyn, Gabriel A Hernandez, Parth Rali, Torrey R Schmidt, Jeffrey T Bruckel, Juan C Camacho, Jun Li, Samy Selim, Catalin Toma, Sukhdeep Singh Basra, Brian A Bergmark, Bhavraj Khalsa, David M Zlotnick, Jordan Castle, David J O'Connor, C Michael Gibson

Heart and Vascular Articles

BACKGROUND: There are a lack of randomized controlled trial data comparing outcomes of different catheter-based interventions for intermediate-risk pulmonary embolism.

METHODS: PEERLESS is a prospective, multicenter, randomized controlled trial that enrolled 550 patients with intermediate-risk pulmonary embolism with right ventricular dilatation and additional clinical risk factors randomized 1:1 to treatment with large-bore mechanical thrombectomy (LBMT) or catheter-directed thrombolysis (CDT). The primary end point was a hierarchal win ratio composite of the following (assessed at the sooner of hospital discharge or 7 days after the procedure): (1) all-cause mortality, (2) intracranial hemorrhage, (3) major bleeding, (4) clinical deterioration and/or escalation to …