Medical Genetics Commons^™

Mendelian Randomization With Incomplete Measurements On The Exposure In The Hispanic Community Health Study/Study Of Latinos, Yilun Li, Kin Yau Wong, Annie Green Howard, Penny Gordon-Larsen, Heather M Highland, Mariaelisa Graff, Kari E North, Carolina G Downie, Christy L Avery, Bing Yu, Kristin L Young, Victoria L Buchanan, Robert Kaplan, Lifang Hou, Brian Thomas Joyce, Qibin Qi, Tamar Sofer, Jee-Young Moon, Dan-Yu Lin

Faculty, Staff and Student Publications

Mendelian randomization has been widely used to assess the causal effect of a heritable exposure variable on an outcome of interest, using genetic variants as instrumental variables. In practice, data on the exposure variable can be incomplete due to high cost of measurement and technical limits of detection. In this paper, we propose a valid and efficient method to handle both unmeasured and undetectable values of the exposure variable in one-sample Mendelian randomization analysis with individual-level data. We estimate the causal effect of the exposure variable on the outcome using maximum likelihood estimation and develop an expectation maximization algorithm for …

Multiplex Immunofluorescence Captures Progressive Immune Exhaustion With Advancing Penile Squamous Cell Cancer Stage, Filip Ionescu, Jonathan Nguyen, Carlos Moran Segura, Mahati Paravathaneni, G Daniel Grass, Peter Johnstone, Niki M Zacharias, Curtis A Pettaway, Xin Lu, Youngchul Kim, Junmin Whiting, Jasreman Dhillon, Steven A Eschrich, Juskaran Chadha, Keerthi Gullapalli, Gabriel Roman Souza, Hiroko Miyagi, Brandon J Manley, Philippe E Spiess, Jad Chahoud

Faculty, Staff and Student Publications

Penile squamous cell carcinoma (PSCC) is a rare and deadly malignancy. Therapeutic advances have been stifled by a poor understanding of disease biology. Specifically, the immune microenvironment is an underexplored component in PSCC and the activity of immune checkpoint inhibitors observed in a subset of patients suggests immune escape may play an important role in tumorigenesis. Herein, we explored for the first time the immune microenvironment of 57 men with PSCC and how it varies with the presence of human papillomavirus (HPV) infection and across tumor stages using multiplex immunofluorescence of key immune cell markers. We observed an increase in …

Molecular And Clinical Effects Of Aromatase Inhibitor Therapy On Skeletal Muscle Function In Early-Stage Breast Cancer, Tara A Seibert, Lei Shi, Sandra Althouse, Richard Hoffman, Bryan P Schneider, Kristen A Russ, Cody A Altherr, Stuart J Warden, Theresa A Guise, Andrew R Coggan, Tarah J Ballinger

Faculty, Staff and Student Publications

We evaluated biochemical changes in skeletal muscle of women with breast cancer initiating aromatase inhibitors (AI), including oxidation of ryanodine receptor RyR1 and loss of stabilizing protein calstabin1, and detailed measures of muscle function. Fifteen postmenopausal women with stage I-III breast cancer planning to initiate AI enrolled. Quadriceps muscle biopsy, dual-energy x-ray absorptiometry, isokinetic dynamometry, Short Physical Performance Battery, grip strength, 6-min walk, patient-reported outcomes, and serologic measures of bone turnover were assessed before and after 6 months of AI. Post-AI exposure, oxidation of RyR1 significantly increased (0.23 ± 0.37 vs. 0.88 ± 0.80, p <  0.001) and RyR1-bound calstabin1 significantly decreased (1.69 ± 1.53 vs. 0.74 ± 0.85, p <  0.001), consistent with dysfunctional calcium channels in skeletal muscle. Grip strength significantly decreased at 6 months. No significant differences were seen in isokinetic dynamometry measures of muscle contractility, fatigue resistance, or muscle recovery post-AI exposure. However, there was significant correlation between oxidation of RyR1 with muscle power (r = 0.60, p = 0.02) and muscle fatigue (r = 0.57, p = 0.03). Estrogen deprivation therapy for breast cancer resulted in maladaptive changes in skeletal muscle, consistent with the biochemical signature of dysfunctional RyR1 calcium channels. Future studies will evaluate longer trajectories of muscle function change and include other high bone turnover states, such as bone metastases.

Delineating The Mechanism Of Fragility At Bcl6 Breakpoint Region Associated With Translocations In Diffuse Large B Cell Lymphoma, Vidya Gopalakrishnan, Urbi Roy, Shikha Srivastava, Khyati M Kariya, Shivangi Sharma, Saniya M Javedakar, Bibha Choudhary, Sathees C Raghavan

Faculty, Staff and Student Publications

BCL6 translocation is one of the most common chromosomal translocations in cancer and results in its enhanced expression in germinal center B cells. It involves the fusion of BCL6 with any of its twenty-six Ig and non-Ig translocation partners associated with diffuse large B cell lymphoma (DLBCL). Despite being discovered long back, the mechanism of BCL6 fragility is largely unknown. Analysis of the translocation breakpoints in 5' UTR of BCL6 reveals the clustering of most of the breakpoints around a region termed Cluster II. In silico analysis of the breakpoint cluster sequence identified sequence motifs that could potentially fold into …

Cell Membrane-Anchored And Tumor-Targeted Il-12 T-Cell Therapy Destroys Cancer-Associated Fibroblasts And Disrupts Extracellular Matrix In Heterogenous Osteosarcoma Xenograft Models, Jiemiao Hu, Alexander J Lazar, Davis Ingram, Wei-Lien Wang, Wendong Zhang, Zhiliang Jia, Dristhi Ragoonanan, Jian Wang, Xueqing Xia, Kris Mahadeo, Richard Gorlick, Shulin Li

Faculty, Staff and Student Publications

Background: The extracellular matrix (ECM) and cancer-associated fibroblasts (CAFs) play major roles in tumor progression, metastasis, and the poor response of many solid tumors to immunotherapy. CAF-targeted chimeric antigen receptor-T cell therapy cannot infiltrate ECM-rich tumors such as osteosarcoma.

Method: In this study, we used RNA sequencing to assess whether the recently invented membrane-anchored and tumor-targeted IL-12-armed (attIL12) T cells, which bind cell-surface vimentin (CSV) on tumor cells, could destroy CAFs to disrupt the ECM. We established an in vitro model of the interaction between osteosarcoma CAFs and attIL12-T cells to uncover the underlying mechanism by which attIL12-T cells penetrate …

Effects Of Kras Genetic Interactions On Outcomes In Cancers Of The Lung, Pancreas, And Colorectum, Isabella N Grabski, John V Heymach, Kenneth L Kehl, Scott Kopetz, Ken S Lau, Gregory J Riely, Deborah Schrag, Rona Yaeger, Rafael A Irizarry, Kevin M Haigis

Faculty, Staff and Student Publications

Background: KRAS is among the most commonly mutated oncogenes in cancer, and previous studies have shown associations with survival in many cancer contexts. Evidence from both clinical observations and mouse experiments further suggests that these associations are allele- and tissue-specific. These findings motivate using clinical data to understand gene interactions and clinical covariates within different alleles and tissues.

Methods: We analyze genomic and clinical data from the AACR Project GENIE Biopharma Collaborative for samples from lung, colorectal, and pancreatic cancers. For each of these cancer types, we report epidemiological associations for different KRAS alleles, apply principal component analysis (PCA) to …

Tfeb Drives Mtorc1 Hyperactivation And Kidney Disease In Tuberous Sclerosis Complex, Nicola Alesi, Damir Khabibullin, Dean M Rosenthal, Elie W Akl, Pieter M Cory, Michel Alchoueiry, Samer Salem, Melissa Daou, William F Gibbons, Jennifer A Chen, Long Zhang, Harilaos Filippakis, Laura Graciotti, Caterina Miceli, Jlenia Monfregola, Claudia Vilardo, Manrico Morroni, Chiara Di Malta, Gennaro Napolitano, Andrea Ballabio, Elizabeth P Henske

Duncan NRI Faculty and Staff Publications

Tuberous Sclerosis Complex (TSC) is caused by TSC1 or TSC2 mutations, leading to hyperactivation of mechanistic target of rapamycin complex 1 (mTORC1) and lesions in multiple organs including lung (lymphangioleiomyomatosis) and kidney (angiomyolipoma and renal cell carcinoma). Previously, we found that TFEB is constitutively active in TSC. Here, we generated two mouse models of TSC in which kidney pathology is the primary phenotype. Knockout of TFEB rescues kidney pathology and overall survival, indicating that TFEB is the primary driver of renal disease in TSC. Importantly, increased mTORC1 activity in the TSC2 knockout kidneys is normalized by TFEB knockout. In TSC2-deficient …

Product Attributes Of Car T-Cell Therapy Differentially Associate With Efficacy And Toxicity In Second-Line Large B-Cell Lymphoma (Zuma-7), Simone Filosto, Saran Vardhanabhuti, Miguel A Canales, Xavier Poiré, Lazaros J Lekakis, Sven De Vos, Craig A Portell, Zixing Wang, Christina To, Marco Schupp, Soumya Poddar, Tan Trinh, Carmen M Warren, Ethan G Aguilar, Justin Budka, Paul Cheng, Justin Chou, Adrian Bot, Rhine R Shen, Jason R Westin

Faculty, Staff and Student Publications

Treatment resistance and toxicities remain a risk following chimeric antigen receptor (CAR) T-cell therapy. Herein, we report pharmacokinetics, pharmacodynamics, and product and apheresis attributes associated with outcomes among patients with relapsed/refractory large B-cell lymphoma (LBCL) treated with axicabtagene ciloleucel (axi-cel) in ZUMA-7. Axi-cel peak expansion associated with clinical response and toxicity, but not response durability. In apheresis material and final product, a naive T-cell phenotype (CCR7+CD45RA+) expressing CD27 and CD28 associated with improved response durability, event-free survival, progression-free survival, and a lower number of prior therapies. This phenotype was not associated with high-grade cytokine release syndrome (CRS) or neurologic events. …

Polatuzumab Vedotin, Venetoclax, And An Anti-Cd20 Monoclonal Antibody In Relapsed/Refractory B-Cell Non-Hodgkin Lymphoma, Simona F Shaitelman, Wendy A Woodward

Faculty, Staff and Student Publications

Neoadjuvant chemotherapy plus immunotherapy for triple-negative breast cancer (TNBC) is associated with improved but incomplete response. In this issue of Cancer Cell, Shiao et al. characterize longitudinal biopsies from a window of opportunity study with single-cell RNA sequencing (scRNA-seq) and spatial proteomic profiling and elucidate synergy between radiotherapy (RT) and pembrolizumab.

Fusionneoantigen: : A Resource Of Fusion Gene-Specific Neoantigens, Himansu Kumar, Ruihan Luo, Jianguo Wen, Chengyuan Yang, Xiaobo Zhou, Pora Kim

Faculty, Staff and Student Publications

Among the diverse sources of neoantigens (i.e. single-nucleotide variants (SNVs), insertions or deletions (Indels) and fusion genes), fusion gene-derived neoantigens are generally more immunogenic, have multiple targets per mutation and are more widely distributed across various cancer types. Therefore, fusion gene-derived neoantigens are a potential source of highly immunogenic neoantigens and hold great promise for cancer immunotherapy. However, the lack of fusion protein sequence resources and knowledge prevents this application. We introduce 'FusionNeoAntigen', a dedicated resource for fusion-specific neoantigens, accessible at https://compbio.uth.edu/FusionNeoAntigen. In this resource, we provide fusion gene breakpoint crossing neoantigens focused on ∼43K fusion proteins of ∼16K in-frame …

Lung Cancer In Ever- And Never-Smokers: Findings From Multi-Population Gwas Studies, Yafang Li, Xiangjun Xiao, Jianrong Li, Younghun Han, Chao Cheng, Gail F. Fernandes, Shannon E. Slewitzke, Susan M. Rosenberg, Meng Zhu, Jinyoung Byun, Yohan Bossé, James D. Mckay, Demetrios Albanes, Stephan Lam, Adonina Tardon, Chu Chen, Stig E. Bojesen, Maria T. Landi, Mattias Johansson, Angela Risch, Heike Bickeböller, H-Erich Wichmann, David C. Christiani, Gad Rennert, Susanne M. Arnold, Gary E. Goodman, John K. Field, Diptasri Mandal, Et Al

School of Graduate Studies Faculty Publications

BACKGROUND: Clinical, molecular, and genetic epidemiology studies displayed remarkable differences between ever- and never-smoking lung cancer. METHODS: We conducted a stratified multi-population (European, East Asian, and African descent) association study on 44,823 ever-smokers and 20,074 never-smokers to identify novel variants that were missed in the non-stratified analysis. Functional analysis including eQTL colocalization and DNA damage assays, and annotation studies were conducted to evaluate the functional roles of the variants. We further evaluated the impact of smoking quantity on lung cancer risk for the variants associated with ever-smoking lung cancer. RESULTS: Five novel independent loci, GABRA4, inter-genic region 12q24.33, LRRC4C, LINC01088, …

Dimerization Of The 4ig Isoform Of B7-H3 In Tumor Cells Mediates Enhanced Proliferation And Tumorigenic Signaling, Margie N Sutton, Sarah E Glazer, Riccardo Muzzioli, Ping Yang, Seth T Gammon, David Piwnica-Worms

Faculty, Staff and Student Publications

B7-H3 (CD276) has two isoforms (2Ig and 4Ig), no confirmed cognate receptor, and physiological functions that remain elusive. While differentially expressed on many solid tumors correlating with poor survival, mechanisms of how B7-H3 signals in cis (tumor cell) versus in trans (immune cell co-regulator) to elicit pro-tumorigenic phenotypes remain poorly defined. Herein, we characterized a tumorigenic and signaling role for tumor cell-expressed 4Ig-B7-H3, the dominant human isoform, in gynecological cancers that could be abrogated upon CRISPR/Cas9 knockout of B7-H3; tumorigenesis was rescued upon re-expression of 4Ig-B7-H3. Size exclusion chromatography revealed dimerization states for the extracellular domains of both human 4Ig- …

Cov2var, A Function Annotation Database Of Sars-Cov-2 Genetic Variation, Yuzhou Feng, Jiahao Yi, Lin Yang, Yanfei Wang, Jianguo Wen, Weiling Zhao, Pora Kim, Xiaobo Zhou

Faculty, Staff and Student Publications

The COVID-19 pandemic, caused by the coronavirus SARS-CoV-2, has resulted in the loss of millions of lives and severe global economic consequences. Every time SARS-CoV-2 replicates, the viruses acquire new mutations in their genomes. Mutations in SARS-CoV-2 genomes led to increased transmissibility, severe disease outcomes, evasion of the immune response, changes in clinical manifestations and reducing the efficacy of vaccines or treatments. To date, the multiple resources provide lists of detected mutations without key functional annotations. There is a lack of research examining the relationship between mutations and various factors such as disease severity, pathogenicity, patient age, patient gender, cross-species …

Pancanqtlv20: A Comprehensive Resource For Expression Quantitative Trait Loci Across Human Cancers, Chengxuan Chen, Yuan Liu, Mei Luo, Jingwen Yang, Yamei Chen, Runhao Wang, Joseph Zhou, Yong Zang, Lixia Diao, Leng Han

Faculty, Staff and Student Publications

Expression quantitative trait locus (eQTL) analysis is a powerful tool used to investigate genetic variations in complex diseases, including cancer. We previously developed a comprehensive database, PancanQTL, to characterize cancer eQTLs using The Cancer Genome Atlas (TCGA) dataset, and linked eQTLs with patient survival and GWAS risk variants. Here, we present an updated version, PancanQTLv2.0 (https://hanlaboratory.com/PancanQTLv2/), with advancements in fine-mapping causal variants for eQTLs, updating eQTLs overlapping with GWAS linkage disequilibrium regions and identifying eQTLs associated with drug response and immune infiltration. Through fine-mapping analysis, we identified 58 747 fine-mapped eQTLs credible sets, providing mechanic insights of gene regulation in …

Contributions Of The Microbiome-Derived Metabolome For Risk Assessment And Prognostication Of Pancreatic Cancer, Ricardo A León-Letelier, Rongzhang Dou, Jody Vykoukal, Michele T Yip-Schneider, Anirban Maitra, Ehsan Irajizad, Ranran Wu, Jennifer B Dennison, Kim-An Do, Jianjun Zhang, C Max Schmidt, Samir Hanash, Johannes F Fahrmann

Faculty, Staff and Student Publications

Background: Increasing evidence implicates microbiome involvement in the development and progression of pancreatic ductal adenocarcinoma (PDAC). Studies suggest that reflux of gut or oral microbiota can lead to colonization in the pancreas, resulting in dysbiosis that culminates in release of microbial toxins and metabolites that potentiate an inflammatory response and increase susceptibility to PDAC. Moreover, microbe-derived metabolites can exert direct effector functions on precursors and cancer cells, as well as other cell types, to either promote or attenuate tumor development and modulate treatment response.

Content: The occurrence of microbial metabolites in biofluids thereby enables risk assessment and prognostication of PDAC, …

Class Ii Hla-Drb4 Is A Predictive Biomarker For Survival Following Immunotherapy In Metastatic Non-Small Cell Lung Cancer, Cindy Y Jiang, Lili Zhao, Michael D Green, Shashidhar Ravishankar, Andrea M H Towlerton, Anthony J Scott, Malini Raghavan, Matthew F Cusick, Edus H Warren, Nithya Ramnath

Faculty, Staff and Student Publications

Immune checkpoint inhibitors (ICI) are important treatment options for metastatic non-small cell lung cancer (mNSCLC). However, not all patients benefit from ICIs and can experience immune-related adverse events (irAEs). Limited understanding exists for germline determinants of ICI efficacy and toxicity, but Human Leukocyte Antigen (HLA) genes have emerged as a potential predictive biomarker. We performed HLA typing on 85 patients with mNSCLC, on ICI therapy and analyzed the impact of HLA Class II genotype on progression free survival (PFS), overall survival (OS), and irAEs. Most patients received pembrolizumab (83.5%). HLA-DRB4 genotype was seen in 34/85 (40%) and its presence correlated …

Mir126-Targeted-Nanoparticles Combined With Pi3k/Akt Inhibitor As A New Strategy To Overcome Melanoma Resistance, Maria Beatrice Arasi, Gabriele De Luca, Laura Chronopoulou, Francesca Pedini, Eleonora Petrucci, Michela Flego, Annarita Stringaro, Marisa Colone, Luca Pasquini, Massimo Spada, Valentina Lulli, Maria Chiara Perrotta, George Adrian Calin, Cleofe Palocci, Mauro Biffoni, Federica Felicetti, Nadia Felli

Faculty, Staff and Student Publications

Metastatic melanoma poses significant challenges as a highly lethal disease. Despite the success of molecular targeting using BRAFV600E inhibitors (BRAFis) and immunotherapy, the emergence of early recurrence remains an issue and there is the need for novel therapeutic approaches. This study aimed at creating a targeted delivery system for the oncosuppressor microRNA 126 (miR126) and testing its effectiveness in combination with a phosphatidylinositol 3-kinase (PI3K)/ protein kinase B (AKT) inhibitor for treating metastatic melanoma resistant to BRAFis. To achieve this, we synthesized chitosan nanoparticles containing a chemically modified miR126 sequence. These nanoparticles were further functionalized with an antibody specific to …

Targeting Dna Repair And Survival Signaling In Diffuse Intrinsic Pontine Gliomas To Prevent Tumor Recurrence, Monika Sharma, Ivana Barravecchia, Robert Teis, Jeanette Cruz, Rachel Mumby, Elizabeth K Ziemke, Carlos E Espinoza, Varunkumar Krishnamoorthy, Brian Magnuson, Mats Ljungman, Carl Koschmann, Joya Chandra, Christopher E Whitehead, Judith S Sebolt-Leopold, Stefanie Galban

Faculty, Staff and Student Publications

Therapeutic resistance remains a major obstacle to successful clinical management of diffuse intrinsic pontine glioma (DIPG), a high-grade pediatric tumor of the brain stem. In nearly all patients, available therapies fail to prevent progression. Innovative combinatorial therapies that penetrate the blood-brain barrier and lead to long-term control of tumor growth are desperately needed. We identified mechanisms of resistance to radiotherapy, the standard of care for DIPG. On the basis of these findings, we rationally designed a brain-penetrant small molecule, MTX-241F, that is a highly selective inhibitor of EGFR and PI3 kinase family members, including the DNA repair protein DNA-PK. Preliminary …

Serine Synthesis Via Reversed Shmt2 Activity Drives Glycine Depletion And Acetaminophen Hepatotoxicity In Masld, Alia Ghrayeb, Alexandra C Finney, Bella Agranovich, Daniel Peled, Sumit Kumar Anand, M Peyton Mckinney, Mahasen Sarji, Dongshan Yang, Natan Weissman, Shani Drucker, Sara Isabel Fernandes, Jonatan Fernández-García, Kyle Mahan, Zaid Abassi, Lin Tan, Philip L Lorenzi, James Traylor, Jifeng Zhang, Ifat Abramovich, Y Eugene Chen, Oren Rom, Inbal Mor, Eyal Gottlieb

Faculty, Staff and Student Publications

Metabolic dysfunction-associated steatotic liver disease (MASLD) affects one-third of the global population. Understanding the metabolic pathways involved can provide insights into disease progression and treatment. Untargeted metabolomics of livers from mice with early-stage steatosis uncovered decreased methylated metabolites, suggesting altered one-carbon metabolism. The levels of glycine, a central component of one-carbon metabolism, were lower in mice with hepatic steatosis, consistent with clinical evidence. Stable-isotope tracing demonstrated that increased serine synthesis from glycine via reverse serine hydroxymethyltransferase (SHMT) is the underlying cause for decreased glycine in steatotic livers. Consequently, limited glycine availability in steatotic livers impaired glutathione synthesis under acetaminophen-induced oxidative …

Integrated Multi-Omics Analyses Identify Anti-Viral Host Factors And Pathways Controlling Sars-Cov-2 Infection, Jiakai Hou, Yanjun Wei, Jing Zou, Roshni Jaffery, Long Sun, Shaoheng Liang, Ningbo Zheng, Ashley M Guerrero, Nicholas A Egan, Ritu Bohat, Si Chen, Caishang Zheng, Xiaobo Mao, S Stephen Yi, Ken Chen, Daniel J Mcgrail, Nidhi Sahni, Pei-Yong Shi, Yiwen Chen, Xuping Xie, Weiyi Peng

Faculty, Staff and Student Publications

Host anti-viral factors are essential for controlling SARS-CoV-2 infection but remain largely unknown due to the biases of previous large-scale studies toward pro-viral host factors. To fill in this knowledge gap, we perform a genome-wide CRISPR dropout screen and integrate analyses of the multi-omics data of the CRISPR screen, genome-wide association studies, single-cell RNA-Seq, and host-virus proteins or protein/RNA interactome. This study uncovers many host factors that are currently underappreciated, including the components of V-ATPases, ESCRT, and N-glycosylation pathways that modulate viral entry and/or replication. The cohesin complex is also identified as an anti-viral pathway, suggesting an important role of …

Unraveling The Intercellular Communication Disruption And Key Pathways In Alzheimer’S Disease: An Integrative Study Of Single-Nucleus Transcriptomes And Genetic Association, Andi Liu, Brisa S Fernandes, Citu Citu, Zhongming Zhao

Faculty, Staff and Student Publications

BACKGROUND: Recently, single-nucleus RNA-seq (snRNA-seq) analyses have revealed important cellular and functional features of Alzheimer's disease (AD), a prevalent neurodegenerative disease. However, our knowledge regarding intercellular communication mediated by dysregulated ligand-receptor (LR) interactions remains very limited in AD brains.

METHODS: We systematically assessed the intercellular communication networks by using a discovery snRNA-seq dataset comprising 69,499 nuclei from 48 human postmortem prefrontal cortex (PFC) samples. We replicated the findings using an independent snRNA-seq dataset of 56,440 nuclei from 18 PFC samples. By integrating genetic signals from AD genome-wide association studies (GWAS) summary statistics and whole genome sequencing (WGS) data, we prioritized …

Investigation Into Cardiac Myhc-Α 334-352-Specific Tcr Transgenic Mice Reveals A Role For Cytotoxic Cd4 T Cells In The Development Of Cardiac Autoimmunity, Meghna Sur, Mahima T. Rasquinha, Kiruthiga Mone, Chandirasegaran Massilamany, Ninaad Lasrado, Channabasavaiah B. Gurumurthy, Raymond A Sobel, Jay Reddy

Journal Articles: Genetics, Cell Biology & Anatomy

Myocarditis is one of the major causes of heart failure in children and young adults and can lead to dilated cardiomyopathy. Lymphocytic myocarditis could result from autoreactive CD4⁺ and CD8⁺ T cells, but defining antigen specificity in disease pathogenesis is challenging. To address this issue, we generated T cell receptor (TCR) transgenic (Tg) C57BL/6J mice specific to cardiac myosin heavy chain (Myhc)-α 334-352 and found that Myhc-α-specific TCRs were expressed in both CD4⁺ and CD8⁺ T cells. To investigate if the phenotype is more pronounced in a myocarditis-susceptible genetic background, we backcrossed with A/J mice. At …

Identifying Factors That Reduce Substance Use Liability, Victoria Allen, Nick Blanch, Sunday Wright, Kelci Straka-Mai, Aarushi Patel, Caleb Bridgwater, Lubidia Menjivar, Cate Vaughn, Courtney Blondino Phd, The Mid-Atlantic Twin Registry, Michael M. Vanyukov Phd, Hermine H.M. Maes Phd, Elizabeth Prom-Wormley Phd

IRBEH/Spit for Science Publications and Presentations

No abstract provided.

Application Of Genomics And Epigenetics In Disease And Syndrome Classification, Yanqi Dang, Wei Wang, Aiping Lyu, Lisheng Wang, Guang Ji

Research outputs 2022 to 2026

No abstract provided.

Systemic Treatment Of Recessive Dystrophic Epidermolysis Bullosa With Mesenchymal Stromal Cells: A Scoping Review Of The Literature And Conclusions For Future Clinical Research, Elke Niebergall-Roth, Kathrin Dieter, Markus H. Frank, Mark A. Kluth

Research outputs 2022 to 2026

Background: The ability of mesenchymal stromal cells (MSCs) to facilitate regenerative responses in inflamed and injured tissues, coupled with preclinical data suggesting potential to restore defective collagen VII at the dermo-epidermal junction, has raised the hope that MSCs may provide an effective disease-modifying therapy for patients suffering from recessive dystrophic epidermolysis bullosa (RDEB). Methods: We present a descriptive analysis of the clinical research on systemic MSC administration to RDEB patients available in PubMed, including six early-phase studies and one case report, involving 59 patients who received 1–3 intravenous infusions of MSCs from various sources. Results: Based on 133 MSC infusions, …

The Role Of Liver-Specific Transcription Factor Hnf4 In Reprogramming Of Fibroblasts, Mary Odubote

Masters Theses

The mammalian liver, a vital organ with complex functions, relies on a network of transcription factors to regulate gene expression. Fusion of hepatoma cells with fibroblasts often leads to gene extinction, silencing approximately 400 liver-enriched genes, including critical transcription factors such as HNF4. Previous studies revealed that ectopic expression of HNF4 in fibroblasts failed to prevent the extinction of SERPINA1, a liver-specific gene, upon subsequent fusion with hepatoma cells. Here, we sought to investigate the extent to which ectopic expression of HNF4 can reprogram fibroblast cells and prevent gene extinction in hybrid cells.

Using whole-genome expression analysis, we compared RAT1 …

Actin Depolymerization Of Tenocytes Promotes A Tendinosis-Like Gene Expression, Kameron Inguito, Ba, Valerie West, Karl Matthew Ebron, Justin Parreno, Phd

Alpha Omega Alpha Research Symposium Posters

Optimal cellular mechanotransduction is essential for tendon matrix homeostasis. We recently developed an in vivo rat model of tendinosis, where the plantaris tendon are overloaded through ablation of the synergistic Achilles tendon. Using this model we determined that tissue overload disrupts matrix-cell interactions, which results in under-stimulation of tendon cells (tenocytes) (Fig.1)

Using an ex vivo model of tendon stress deprivation by maintaining tail tendon fascicles in floating culture we showed that tenocyte under-stimulation results in destabilization of filamentous (F-)actin (Fig.2). F-actin destabilization coincides with tendinosis-like gene expression: downregulation of tenogenic genes (Col1, Tnc, asma, Scx), upregulation of chondrogenic (Acan, …

Rragd-Associated Autosomal Dominant Kidney Hypomagnesemia With Cardiomyopathy: A Review On The Clinical Manifestations And Therapeutic Options, Francesco Trepiccione, Irene Sambri, Barbara Ruggiero, Francesco Emma, Andrea Ballabio, Giulia Florio, Ines Vanderheyden, Anna Iervolino, François Jouret

Duncan NRI Faculty and Staff Publications

Background: A hereditary condition primarily affecting the kidneys and heart has newly been identified: the RRAGD-associated autosomal dominant kidney hypomagnesemia with cardiomyopathy (ADKH-RRAGD). This disorder is characterized by renal loss of magnesium and potassium, coupled with varying degrees of cardiac dysfunction. These range from arrhythmias to severe dilated cardiomyopathy, which may require heart transplantation. Mutations associated with RRAGD significantly disrupt the non-canonical branch of the mechanistic target of rapamycin complex 1 pathway. This disruption hinders the nuclear translocation and transcriptional activity of the transcription factor EB a crucial regulator of lysosomal and autophagic function.

Summary: All identified RRAGD variants compromise …

Emerging Unconventional Therapies For Glioblastoma Multiforme, Danielle Morang

Capstone Showcase

Glioblastoma multiforme (GBM) is the most prevalent and aggressive primary malignant brain tumor occurring in adults with a median survival of less than two years. It is a highly invasive tumor characterized by genetic heterogeneity, angiogenesis, and rapid proliferation. Patients undergo a multimodal treatment regimen consisting of surgical resection and chemoradiation therapy, yet GBM tumors almost always recur with a worsening prognosis. The molecular and genetic complexities of GBM pose a significant challenge for developing effective therapeutics. Thus, it is imperative to identify new therapeutic targets and explore novel treatment strategies to improve patients’ overall survival time and quality of …

Autochthonous Plasmodium Vivax Infections, Florida, Usa, 2023, Swamy Rakesh Adapa, Kami Kim, Liwang Cui

College of Medicine & TGH Faculty Publications

During May–July 2023, a cluster of 7 patients at local hospitals in Florida, USA, received a diagnosis of Plasmodium vivax malaria. Whole-genome sequencing of the organism from 4 patients and phylogenetic analysis with worldwide representative P. vivax genomes indicated probable single parasite introduction from Central/South America.