Digital Commons Network^™

Mbnl Overexpression Rescues Cardiac Phenotypes In A Myotonic Dystrophy Type 1 Heart Mouse Model, Rong-Chi Hu, Yi Zhang, Larissa Nitschke, Sara J Johnson, Ayrea E Hurley, William R Lagor, Zheng Xia, Thomas A Cooper

Faculty, Staff and Students Publications

Myotonic dystrophy type 1 (DM1) is an autosomal dominant disease caused by a CTG repeat expansion in the dystrophia myotonica protein kinase (DMPK) gene. The expanded CUG repeat RNA (CUGexp RNA) transcribed from the mutant allele sequesters the muscleblind-like (MBNL) family of RNA-binding proteins, causing their loss of function and disrupting regulated pre-mRNA processing. We used a DM1 heart mouse model that inducibly expresses CUGexp RNA to test the contribution of MBNL loss to DM1 cardiac abnormalities and explored MBNL restoration as a potential therapy. AAV9-mediated overexpression of MBNL1 and/or MBNL2 significantly rescued DM1 cardiac phenotypes including conduction delays, contractile …

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 …

Unraveling Physiologic Mechanisms In Passive And Active Mechanoreceptor Stimulation, Halah Khan, Braden Ashcraft

Annual Research Symposium

No abstract provided.

A Galleria Mellonella Study: Protective Effects Of Sulforaphane On Immune Function In Binge Alcohol Exposure, Robert Kento Darby, Braydon Black, Vincent Tran, Dallen James, Scott Quimby

Annual Research Symposium

Alcohol is associated with increased mortality and morbidity. Pulmonary infections with opportunistic pathogens can occur in healthy humans; however, hazardous alcohol exposure like binge alcohol intoxication (≥ 0.08% BAC) is a major risk factor. We’ve previously investigated the efficacy of Sulforaphane (SFN) prophylaxis in protecting human and murine alveolar macrophage function against opportunistic infections when exposed to binge alcohol conditions in vitro. However, an in vivo model investigating SFN and hazardous alcohol exposure in the context of infection is not well understood. The aim of this study is to 1) establish a G. mellonella larvae model by determining the LD50 …

Axl Signaling In Cancer: From Molecular Insights To Targeted Therapies, Monika Yadav, Akansha Sharma, Ketki Patne, Saba Tabasum, Jyoti Suryavanshi, Laxminarayan Rawat, Marc Machaalani, Marc Eid, Rana Singh, Toni Choueiri, Soumitro Pal, Akash Sabarwal

Department of Microbiology and Immunology Faculty Papers

AXL, a member of the TAM receptor family, has emerged as a potential target for advanced-stage human malignancies. It is frequently overexpressed in different cancers and plays a significant role in various tumor-promoting pathways, including cancer cell proliferation, invasion, metastasis, epithelial-mesenchymal transition (EMT), angiogenesis, stemness, DNA damage response, acquired therapeutic resistance, immunosuppression, and inflammatory responses. Beyond oncology, AXL also facilitates viral infections, including SARS-CoV-2 and Zika highlighting its importance in both cancer and virology. In preclinical models, small-molecule kinase inhibitors targeting AXL have shown promising anti-tumorigenic potential. This review primarily focuses on the induction, regulation and biological functions of AXL …

A Deep Learning-Based System For Automatic Detection Of Emesis With High Accuracy In Suncus Murinus, Zengbing Lu, Yimeng Qiao, Xiaofei Huang, Dexuan Cui, Julia Y H Liu, Man Piu Ngan, Luping Liu, Zhixin Huang, Zi-Tong Li, Lingqing Yang, Aleena Khalid, Yingyi Deng, Sze Wa Chan, Longlong Tu, John A Rudd

Children’s Nutrition Research Center Staff Publications

Quantifying emesis in Suncus murinus (S. murinus) has traditionally relied on direct observation or reviewing recorded behaviour, which are laborious, time-consuming processes that are susceptible to operator error. With rapid advancements in deep learning, automated animal behaviour quantification tools with high accuracy have emerged. In this study, we pioneere the use of both three-dimensional convolutional neural networks and self-attention mechanisms to develop the Automatic Emesis Detection (AED) tool for the quantification of emesis in S. murinus, achieving an overall accuracy of 98.92%. Specifically, we use motion-induced emesis videos as training datasets, with validation results demonstrating an accuracy of 99.42% for …

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 …

Classification Of Non-Tcga Cancer Samples To Tcga Molecular Subtypes Using Compact Feature Sets, Kyle Ellrott, Christopher K Wong, Christina Yau, Mauro A A Castro, Jordan A Lee, Brian J Karlberg, Jasleen K Grewal, Vincenzo Lagani, Bahar Tercan, Verena Friedl, Toshinori Hinoue, Vladislav Uzunangelov, Lindsay Westlake, Xavier Loinaz, Ina Felau, Peggy I Wang, Anab Kemal, Samantha J Caesar-Johnson, Ilya Shmulevich, Alexander J Lazar, Ioannis Tsamardinos, Katherine A Hoadley, Cancer Genome Atlas Analysis Network, A Gordon Robertson, Theo A Knijnenburg, Christopher C Benz, Joshua M Stuart, Jean C Zenklusen, Andrew D Cherniack, Peter W Laird

Faculty, Staff and Student Publications

Molecular subtypes, such as defined by The Cancer Genome Atlas (TCGA), delineate a cancer's underlying biology, bringing hope to inform a patient's prognosis and treatment plan. However, most approaches used in the discovery of subtypes are not suitable for assigning subtype labels to new cancer specimens from other studies or clinical trials. Here, we address this barrier by applying five different machine learning approaches to multi-omic data from 8,791 TCGA tumor samples comprising 106 subtypes from 26 different cancer cohorts to build models based upon small numbers of features that can classify new samples into previously defined TCGA molecular subtypes-a …

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 …

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 …

The Application And Innovation Of Casgevy On Sickle Cell Disease, Emily Tackett, Le Thien Truc Pham, Hannah Salamie, Arin Wade, Allison Provenzale, Alexander Defranco, Ashley Jacob, Brianna Lu, Joshua Honaker, Amy Stockert

Pharmacy and Wellness Review

Casgevy, sickle cell anemia, SCA, sickle cell disease, SCD, CRISPR/Cas9, hydroxyurea, hemoglobin, Hb, l-glutamine, voxelotor, Crizanlizumab, Lyfgenia, stem cells, genetics, pharmacogenetics, pharmacogenomics

Probing For Intentions: The Early Readiness Potential Does Not Reflect Awareness Of Motor Preparation, Jake Gavenas, Aaron Schurger, Uri Maoz

Psychology Faculty Articles and Research

Voluntary actions are typically preceded by the readiness potential (RP), a negative midfrontal electroencephalography (EEG) deflection that begins ~2 s before movement. What cognitive and neural process the RP reflects and how it relates to conscious intention remain unclear due to conflicting findings. We investigated the neural basis and cognitive significance of the RP in a novel probe-based paradigm. Contrary to prior reports, we found that pre-probe RP buildups were not related to reported awareness of motor preparation. Computational modeling suggested that the best explanation for these results is via metacognitive access to stochastic accumulation. Reported preparation was also related …

Therapeutic Targeting Of The Janus Kinase/Signal Transducer And Activator Of Transcription Pathway In Cutaneous T-Cell Lymphoma, Alisha Kashyap, Julia Dai, Xiao Ni

Faculty, Staff and Student Publications

Background/Objectives: Cutaneous T-cell lymphoma (CTCL) is a rare group of non-Hodgkin lymphomas characterized by the clonal expansion of malignant T cells. While current treatments can alleviate symptoms and significant progress has been made in treating leukemic CTCL, a definitive cure remains elusive. Dysregulation of the Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway is a key driver of CTCL pathogenesis. As a result, therapeutic strategies targeting JAK/STAT signaling have gained momentum, with the increasing use of JAK inhibitors and other agents that effectively suppress this pathway. These immune-modulating therapies have broad effects on physiological processes, inflammation, and …

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 …

Proceedings Of The 1st Biannual Bridging The Gaps In Lung Cancer Conference, Narjust Florez, Sandip P Patel, Heather Wakelee, Lyudmila Bazhenova, Erminia Massarelli, Ravi Salgia, Brendon Stiles, Solange Peters, Jyoti Malhotra, Shirish M Gadgeel, Jorge J Nieva, Michelle Afkhami, Fred R Hirsch, Matthew Gubens, Tina Cascone, Benjamin Levy, Joshua Sabari, Hatim Husain, Patrick C Ma, Leah M Backhus, Puneeth Iyengar, Percy Lee, Russell Miller, Jacob Sands, Edward Kim

Faculty, Staff and Student Publications

Lung cancer is the leading cause of cancer death in the US and globally. The mortality from lung cancer has been declining, due to a reduction in incidence and advances in treatment. Although recent success in developing targeted and immunotherapies for lung cancer has benefitted patients, it has also expanded the complexity of potential treatment options for health care providers. To aid in reducing such complexity, experts in oncology convened a conference (Bridging the Gaps in Lung Cancer) to identify current knowledge gaps and controversies in the diagnosis, treatment, and outcomes of various lung cancer scenarios, as described here. Such …

Oncogenic Kras Mutations Confer A Unique Mechanotransduction Response To Peristalsis In Colorectal Cancer Cells, Abigail J Clevenger, Claudia A Collier, John Paul M Gorley, Sarah Colijn, Maygan K Mcfarlin, Spencer C Solberg, Scott Kopetz, Amber N Stratman, Shreya A Raghavan

Faculty, Staff and Student Publications

Colorectal cancer tumors start as polyps on the inner lining of the colorectum, in which they are exposed to the mechanics of peristalsis. Our previous work leveraged a custom-built peristalsis bioreactor to demonstrate that colonic peristalsis led to cancer stem cell enrichment in colorectal cancer cells. However, this malignant mechanotransductive response was confined to select colorectal cancer lines that harbored an oncogenic mutation in the Kirsten rat sarcoma virus (KRAS) gene. In this study, we explored the involvement of activating KRAS mutations on peristalsis-associated mechanotransduction in colorectal cancer. Peristalsis enriched cancer stem cell marker Leucine-rich repeat-containing G protein-coupled receptor 5 …

Differences In Provider Beliefs And Delivery Of The 5as For Cigarette And Non-Cigarette Tobacco Use Between Two Types Of Healthcare Centers Serving Rural And/Or Medically Underserved Areas Of Texas, Us, Ammar D Siddiqi, Brian J Carter, Maggie Britton, Tzuan A Chen, Isabel Martinez Leal, Asfand B Moosa, Teresa Williams, Kathleen Casey, Hector Sanchez, Lorraine R Reitzel

Faculty, Staff and Student Publications

Background/objectives: Rural populations in the US bear a disproportionate burden of cancer mortality, which may be partly due to their elevated tobacco use and the limited receipt of tobacco use interventions in rural healthcare settings. Here, we examine providers' use of the 5As (Ask, Advise, Assess, Assist, and Arrange), a brief tobacco cessation intervention, with their patients to assess intervention gaps.

Methods: Provider practices in substance use treatment centers (SUTCs) and medical healthcare centers (MHCs), each serving rural and/or medically underserved areas (MUAs) of Texas, were compared. In total, 347 providers from 10 SUTCs (n = 174) and 9 …

Design And Implementation Of An Action Plan For Justice, Equity, Diversity, And Inclusion Within The Clinical Genome Resource, Alice B Popejoy, Deborah I Ritter, Danielle Azzariti, Jonathan S Berg, Joanna E Bulkley, Mildred Cho, Claudia Gonzaga-Jauregui, Teri E Klein, Daphne O Martschenko, Akinyemi Oni-Orisan, Erin M Ramos, Heidi L Rehm, Erin R Riggs, Matthew W Wright, Michael Yudell, Sharon E Plon, Joannella Morales

Faculty, Staff and Students Publications

How might members of a large, multi-institutional research and resource consortium foster justice, equity, diversity, and inclusion as central to its mission, goals, governance, and culture? These four principles, often referred to as JEDI, can be aspirational-but to be operationalized, they must be supported by concrete actions, investments, and a persistent long-term commitment to the principles themselves, which often requires self-reflection and course correction. We present here the iterative design process implemented across the Clinical Genome Resource (ClinGen) that led to the development of an action plan to operationalize JEDI principles across three major domains, with specific deliverables and commitments …

Design And Implementation Of An Action Plan For Justice, Equity, Diversity, And Inclusion Within The Clinical Genome Resource, Alice B Popejoy, Deborah I Ritter, Danielle Azzariti, Jonathan S Berg, Joanna E Bulkley, Mildred Cho, Claudia Gonzaga-Jauregui, Teri E Klein, Daphne O Martschenko, Akinyemi Oni-Orisan, Erin M Ramos, Heidi L Rehm, Erin R Riggs, Matthew W Wright, Michael Yudell, Sharon E Plon, Joannella Morales

Faculty, Staff and Students Publications

How might members of a large, multi-institutional research and resource consortium foster justice, equity, diversity, and inclusion as central to its mission, goals, governance, and culture? These four principles, often referred to as JEDI, can be aspirational-but to be operationalized, they must be supported by concrete actions, investments, and a persistent long-term commitment to the principles themselves, which often requires self-reflection and course correction. We present here the iterative design process implemented across the Clinical Genome Resource (ClinGen) that led to the development of an action plan to operationalize JEDI principles across three major domains, with specific deliverables and commitments …

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 …

Characterizing Features Affecting Local Ancestry Inference Performance In Admixed Populations, Jessica Honorato-Mauer, Nirav N Shah, Adam X Maihofer, Clement C Zai, Sintia Belangero, Caroline M Nievergelt, Marcos Santoro, Elizabeth G Atkinson

Faculty, Staff and Students Publications

In recent years, significant efforts have been made to improve methods for genomic studies of admixed populations using local ancestry inference (LAI). Accurate LAI is crucial to ensure that downstream analyses accurately reflect the genetic ancestry of research participants. Here, we test analytic strategies for LAI to provide guidelines for optimal accuracy, focusing on admixed populations reflective of Latin America's primary continental ancestries-African (AFR), Amerindigenous (AMR), and European (EUR). Simulating linkage-disequilibrium-informed admixed haplotypes under a variety of 2- and 3-way admixture models, we implemented a standard LAI pipeline, testing the impact of reference panel composition, DNA data type, demography, 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. …

Bio-Primed Machine Learning To Enhance Discovery Of Relevant Biomarkers, David M Henke, Alexander Renwick, Joseph R Zoeller, Jitendra K Meena, Nicholas J Neill, Elizabeth A Bowling, Kristen L Meerbrey, Thomas F Westbrook, Lukas M Simon

Faculty, Staff and Students Publications

Precision medicine relies on identifying reliable biomarkers for gene dependencies to tailor individualized therapeutic strategies. The advent of high-throughput technologies presents unprecedented opportunities to explore molecular disease mechanisms but also challenges due to high dimensionality and collinearity among features. Traditional statistical methods often fall short in this context, necessitating novel computational approaches that harness the full potential of big data in bioinformatics. Here, we introduce a novel machine learning approach extending the Least Absolute Shrinkage and Selection Operator (LASSO) regression framework to incorporate biological knowledge, such as protein-protein interaction databases, into the regularization process. This bio-primed approach prioritizes variables that …

Antidiabetic Properties Of Prickly Pear (Opuntia Ficus-Indica) Fruit Extract, Kenzy Aidan Joseph Mckay

The Undergraduate Research Journal

Diabetes mellitus is a metabolic disorder that claims 1.5 million lives annually. Opuntia ficus-indica, commonly known as the prickly pear, has been commonly used in traditional folk medicine for its hypoglycemic properties. It has been claimed that it has antimicrobial and antioxidant properties as well. The plant is native to Mexico and is commonly found in the middle east and India and folk medicine from all of these areas have been using prickly pear medicinally for years. To test these claims an extract of locally sourced Opuntia ficus-indica was prepared using the flesh and seeds of the fruit. The …

Advanced External Beam Stereotactic Radiotherapy For Skull Base Reirradiation, He Wang, Fahed M Alsanea, Dong Joo Rhee, Xiaodong Zhang, Wei Liu, Jinzhong Yang, Zhifei Wen, Yao Zhao, Tyler D Williamson, Rachel A Hunter, Peter A Balter, Tina M Briere, Ronald X Zhu, Anna Lee, Amy C Moreno, Jay P Reddy, Adam S Garden, David I Rosenthal, Gary B Gunn, Jack Phan

Faculty, Staff and Student Publications

Background/objectives: Stereotactic body radiation therapy (SBRT) for skull base reirradiation is particularly challenging, as patients have already received substantial radiation doses to the region, and nearby normal organs may have approached their tolerance limit from prior treatments. In this study, we reviewed the characteristics and capabilities of four advanced external beam radiation delivery systems and four modern treatment planning systems and evaluated the treatment plan quality of each technique using skull base reirradiation patient cases.

Methods: SBRT plans were generated for sixteen skull base reirradiation patients using four modalities: the GK plan for the Elekta Leksell Gamma Knife Perfexion/ICON, the …

Brd7 Loss Reawakens Dormant Metastasis Initiating Cells In Lung By Forging An Immunosuppressive Niche, Jayanta Mondal, Junfeng Zhang, Feng Qing, Shunping Li, Dhiraj Kumar, Jason T Huse, Filippo G Giancotti

Faculty, Staff and Student Publications

Metastasis in cancer is influenced by epigenetic factors. Using an in vivo screen, we demonstrate that several subunits of the polybromo-associated BAF (PBAF) chromatin remodeling complex, particularly Brd7, are required for maintaining breast cancer metastatic dormancy in the lungs of female mice. Brd7 loss induces metastatic reawakening, along with modifications in epigenomic landscapes and upregulated oncogenic signaling. Breast cancer cells harboring Brd7 inactivation also reprogram the surrounding immune microenvironment by downregulating MHC-1 expression and promoting a pro-metastatic cytokine profile. Flow cytometric and single-cell analyses reveal increased levels of pro-tumorigenic inflammatory and transitional neutrophils, CD8+ exhausted T cells, and CD4+ stress …

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 …