Medical Specialties Commons^™

The Immune System And Metabolic Products In Epilepsy And Glioma-Associated Epilepsy: Emerging Therapeutic Directions, Shashwat Tripathi, Cody L Nathan, Matthew C Tate, Craig M Horbinski, Jessica W Templer, Joshua M Rosenow, Timothy L Sita, Charles D James, Benjamin Deneen, Stephen D Miller, Amy B Heimberger

Faculty, Staff and Students Publications

Epilepsy has a profound impact on quality of life. Despite the development of new antiseizure medications (ASMs), approximately one-third of affected patients have drug-refractory epilepsy and are nonresponsive to medical treatment. Nearly all currently approved ASMs target neuronal activity through ion channel modulation. Recent human and animal model studies have implicated new immunotherapeutic and metabolomic approaches that may benefit patients with epilepsy. In this Review, we detail the proinflammatory immune landscape of epilepsy and contrast this with the immunosuppressive microenvironment in patients with glioma-related epilepsy. In the tumor setting, excessive neuronal activity facilitates immunosuppression, thereby contributing to subsequent glioma progression. …

Retrospective Analysis Of The Impact Of High- And Low-Quality Donor Livers For Patients With High-Acuity Illness, Ron K Varghese, Greta E Handing, Ashley E Montgomery, Abbas A Rana, John A Goss

Faculty, Staff and Students Publications

BACKGROUND Patients with high-acuity liver failure have increased access to marginal and split liver options, owing to historically high waitlist mortality rates. While most research states that donor liver quality has no impact on patients with high-acuity illness, there have been inconsistencies in recent research on how liver quality impacts post-transplant outcomes for these patients. We aimed to quantify donor liver quality with various post-transplantation patient outcomes for patients with high-acuity illness. MATERIAL AND METHODS Using the liver donor risk index (LDRI), model for end stage liver disease (MELD), and clinically relevant recipient factors, we used multivariate logistic regression to …

Integrating Genetic Regulation And Single-Cell Expression With Gwas Prioritizes Causal Genes And Cell Types For Glaucoma, Andrew R Hamel, Wenjun Yan, John M Rouhana, Aboozar Monovarfeshani, Xinyi Jiang, Puja A Mehta, Jayshree Advani, Yuyang Luo, Qingnan Liang, Skanda Rajasundaram, Arushi Shrivastava, Katherine Duchinski, Sreekar Mantena, Jiali Wang, Tavé Van Zyl, Louis R Pasquale, Anand Swaroop, Puya Gharahkhani, Anthony P Khawaja, Stuart Macgregor, Rui Chen, Veronique Vitart, Joshua R Sanes, Janey L Wiggs, Ayellet V Segrè

Faculty, Staff and Students Publications

Primary open-angle glaucoma (POAG), characterized by retinal ganglion cell death, is a leading cause of irreversible blindness worldwide. However, its molecular and cellular causes are not well understood. Elevated intraocular pressure (IOP) is a major risk factor, but many patients have normal IOP. Colocalization and Mendelian randomization analysis of >240 POAG and IOP genome-wide association study (GWAS) loci and overlapping expression and splicing quantitative trait loci (e/sQTLs) in 49 GTEx tissues and retina prioritizes causal genes for 60% of loci. These genes are enriched in pathways implicated in extracellular matrix organization, cell adhesion, and vascular development. Analysis of single-nucleus RNA-seq …

Developmental Basis Of Shh Medulloblastoma Heterogeneity, Maxwell P Gold, Winnie Ong, Andrew M Masteller, David R Ghasemi, Julie Anne Galindo, Noel R Park, Nhan C Huynh, Aneesh Donde, Veronika Pister, Raul A Saurez, Maria C Vladoiu, Grace H Hwang, Tanja Eisemann, Laura K Donovan, Adam D Walker, Joseph Benetatos, Christelle Dufour, Livia Garzia, Rosalind A Segal, Robert J Wechsler-Reya, Jill P Mesirov, Andrey Korshunov, Kristian W Pajtler, Scott L Pomeroy, Olivier Ayrault, Shawn M Davidson, Jennifer A Cotter, Michael D Taylor, Ernest Fraenkel

Faculty, Staff and Students Publications

Many genes that drive normal cellular development also contribute to oncogenesis. Medulloblastoma (MB) tumors likely arise from neuronal progenitors in the cerebellum, and we hypothesized that the heterogeneity observed in MBs with sonic hedgehog (SHH) activation could be due to differences in developmental pathways. To investigate this question, here we perform single-nucleus RNA sequencing on highly differentiated SHH MBs with extensively nodular histology and observed malignant cells resembling each stage of canonical granule neuron development. Through innovative computational approaches, we connect these results to published datasets and find that some established molecular subtypes of SHH MB appear arrested at different …

A Road Map For The Treatment Of Pediatric Diffuse Midline Glioma, Carl Koschmann, Wajd N Al-Holou, Marta M Alonso, Jamie Anastas, Pratiti Bandopadhayay, Tara Barron, Oren Becher, Rodrigo Cartaxo, Maria G Castro, Chan Chung, Madison Clausen, Derek Dang, Robert Doherty, Ryan Duchatel, Matthew Dun, Mariella Filbin, Andrea Franson, Stefanie Galban, Marc Garcia Moure, Hugh Garton, Pruthvi Gowda, Joana Graca Marques, Cynthia Hawkins, Allison Heath, Esther Hulleman, Sunjong Ji, Chris Jones, Lindsay Kilburn, Cassie Kline, Michael A Koldobskiy, Daniel Lim, Pedro R Lowenstein, Q Richard Lu, Joanna Lum, Stephen Mack, Suresh Magge, Bernard Marini, Donna Martin, Neena Marupudi, Dana Messinger, Rajen Mody, Meredith Morgan, Mateus Mota, Karin Muraszko, Sabine Mueller, Siva Kumar Natarajan, Javad Nazarian, Michael Niculcea, Nicholas Nuechterlein, Hideho Okada, Valerie Opipari, Manjunath P Pai, Sharmistha Pal, Erik Peterson, Timothy Phoenix, John R Prensner, Matthew Pun, G Praveen Raju, Zachary J Reitman, Adam Resnick, David Rogawski, Amanda Saratsis, Stefanie G Sbergio, Mark Souweidane, James M Stafford, Theophilos Tzaridis, Sujatha Venkataraman, Orazio Vittorio, Jack Wadden, Daniel Wahl, Robert J Wechsler-Reya, Viveka Nand Yadav, Xu Zhang, Qiang Zhang, Sriram Venneti

Faculty, Staff and Students Publications

Recent clinical trials for H3K27-altered diffuse midline gliomas (DMGs) have shown much promise. We present a consensus roadmap and identify three major barriers: (1) refinement of experimental models to include immune and brain-specific components; (2) collaboration among researchers, clinicians, and industry to integrate patient-derived data through sharing, transparency, and regulatory considerations; and (3) streamlining clinical efforts including biopsy, CNS-drug delivery, endpoint determination, and response monitoring. We highlight the importance of comprehensive collaboration to advance the understanding, diagnostics, and therapeutics for DMGs.

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. …

Vaccines: A Promising Therapy For Myelodysplastic Syndrome, Kriti Gera, Anjali Chauhan, Paul Castillo, Maryam Rahman, Akash Mathavan, Akshay Mathavan, Elizabeth Oganda-Rivas, Leighton Elliott, John R Wingard, Elias J Sayour

Faculty, Staff and Student Publications

Myelodysplastic neoplasms (MDS) define clonal hematopoietic malignancies characterized by heterogeneous mutational and clinical spectra typically seen in the elderly. Curative treatment entails allogeneic hematopoietic stem cell transplant, which is often not a feasible option due to older age and significant comorbidities. Immunotherapy has the cytotoxic capacity to elicit tumor-specific killing with long-term immunological memory. While a number of platforms have emerged, therapeutic vaccination presents as an appealing strategy for MDS given its promising safety profile and amenability for commercialization. Several preclinical and clinical trials have investigated the efficacy of vaccines in MDS; these include peptide vaccines targeting tumor antigens, whole …

The Irish National Chronic Obstructive Pulmonary Disease Quality Improvement Collaborative: An Adaptive Learning Collaborative, Orla Woods, Rachel Macdonell, John Brennan, Lucia Prihodova, Breda Cushen, Richard W Costello, Timothy J Mcdonnell

Faculty, Staff and Student Publications

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is the the most common disease-specific cause of adult emergency hospital admissions in Ireland. Preliminary groundwork indicated that treatment of acute exacerbations of COPD (AECOPD) in Ireland is not standardised between public hospitals. Applying Institute for Healthcare Improvement Breakthrough Series and Model for Improvement methodologies, Royal College of Physicians of Ireland designed and conducted a novel flexible and adaptive quality improvement (QI) collaborative which, using embedded evaluation, aimed to deliver QI teaching to enable teams to implement bespoke, locally applicable changes to improve and standardise acute COPD care at presentation, admission and discharge stages …

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.

Gut Epithelial Interleukin-17 Receptor A Signaling Can Modulate Distant Tumors Growth Through Microbial Regulation, Vidhi Chandra, Le Li, Olivereen Le Roux, Yu Zhang, Rian M Howell, Dhwani N Rupani, Seyda Baydogan, Haiyan D Miller, Erick Riquelme, Joseph Petrosino, Michael P Kim, Krishna P L Bhat, James R White, Jay K Kolls, Yuliya Pylayeva-Gupta, Florencia Mcallister

Faculty, Staff and Student Publications

Microbes influence cancer initiation, progression and therapy responsiveness. IL-17 signaling contributes to gut barrier immunity by regulating microbes but also drives tumor growth. A knowledge gap remains regarding the influence of enteric IL-17-IL-17RA signaling and their microbial regulation on the behavior of distant tumors. We demonstrate that gut dysbiosis induced by systemic or gut epithelial deletion of IL-17RA induces growth of pancreatic and brain tumors due to excessive development of Th17, primary source of IL-17 in human and mouse pancreatic ductal adenocarcinoma, as well as B cells that circulate to distant tumors. Microbial dependent IL-17 signaling increases DUOX2 signaling in …

Psychological Distress And Social Support Among Community Paediatric Palliative Care Programme Caregivers: Longitudinal Analysis, Esther Chui Yan Wong, Phillip Lung Wai Au-Doung, Yvonne Yuen Ling Chu, Sandy Sin Yuet Wong, Chi Kong Li, Yin Ting Cheung

Faculty, Staff and Students Publications

No abstract provided.

Variants In The Wdr44 Wd40-Repeat Domain Cause A Spectrum Of Ciliopathy By Impairing Ciliogenesis Initiation, Andrea Accogli, Saurabh Shakya, Taewoo Yang, Christine Insinna, Soo Yeon Kim, David Bell, Kirill R Butov, Mariasavina Severino, Marcello Niceta, Marcello Scala, Hyun Sik Lee, Taekyeong Yoo, Jimmy Stauffer, Huijie Zhao, Chiara Fiorillo, Marina Pedemonte, Maria C Diana, Simona Baldassari, Viktoria Zakharova, Anna Shcherbina, Yulia Rodina, Christina Fagerberg, Laura Sønderberg Roos, Jolanta Wierzba, Artur Dobosz, Amanda Gerard, Lorraine Potocki, Jill A Rosenfeld, Seema R Lalani, Tiana M Scott, Daryl Scott, Mahshid S Azamian, Raymond Louie, Hannah W Moore, Neena L Champaigne, Grace Hollingsworth, Annalaura Torella, Vincenzo Nigro, Rafal Ploski, Vincenzo Salpietro, Federico Zara, Simone Pizzi, Giovanni Chillemi, Marzia Ognibene, Erin Cooney, Jenny Do, Anders Linnemann, Martin J Larsen, Suzanne Specht, Kylie J Walters, Hee-Jung Choi, Murim Choi, Marco Tartaglia, Phillippe Youkharibache, Jong-Hee Chae, Valeria Capra, Sung-Gyoo Park, Christopher J Westlake

Faculty, Staff and Students Publications

WDR44 prevents ciliogenesis initiation by regulating RAB11-dependent vesicle trafficking. Here, we describe male patients with missense and nonsense variants within the WD40 repeats (WDR) of WDR44, an X-linked gene product, who display ciliopathy-related developmental phenotypes that we can model in zebrafish. The patient phenotypic spectrum includes developmental delay/intellectual disability, hypotonia, distinct craniofacial features and variable presence of brain, renal, cardiac and musculoskeletal abnormalities. We demonstrate that WDR44 variants associated with more severe disease impair ciliogenesis initiation and ciliary signaling. Because WDR44 negatively regulates ciliogenesis, it was surprising that pathogenic missense variants showed reduced abundance, which we link to misfolding of …

Mechanism Of Anion Exchange And Small-Molecule Inhibition Of Pendrin, Lie Wang, Anthony Hoang, Eva Gil-Iturbe, Arthur Laganowsky, Matthias Quick, Ming Zhou

Faculty, Staff and Students Publications

Pendrin (SLC26A4) is an anion exchanger that mediates bicarbonate (HCO3−) exchange for chloride (Cl−) and is crucial for maintaining pH and salt homeostasis in the kidney, lung, and cochlea. Pendrin also exports iodide (I−) in the thyroid gland. Pendrin mutations in humans lead to Pendred syndrome, causing hearing loss and goiter. Inhibition of pendrin is a validated approach for attenuating airway hyperresponsiveness in asthma and for treating hypertension. However, the mechanism of anion exchange and its inhibition by drugs remains poorly understood. We applied cryo-electron microscopy to determine structures of pendrin from Sus scrofa in the presence of either Cl−, …

Drmref: Comprehensive Reference Map Of Drug Resistance Mechanisms In Human Cancer, Xiaona Liu, Jiahao Yi, Tina Li, Jianguo Wen, Kexin Huang, Jiajia Liu, Grant Wang, Pora Kim, Qianqian Song, Xiaobo Zhou

Faculty, Staff and Student Publications

Drug resistance poses a significant challenge in cancer treatment. Despite the initial effectiveness of therapies such as chemotherapy, targeted therapy and immunotherapy, many patients eventually develop resistance. To gain deep insights into the underlying mechanisms, single-cell profiling has been performed to interrogate drug resistance at cell level. Herein, we have built the DRMref database (https://ccsm.uth.edu/DRMref/) to provide comprehensive characterization of drug resistance using single-cell data from drug treatment settings. The current version of DRMref includes 42 single-cell datasets from 30 studies, covering 382 samples, 13 major cancer types, 26 cancer subtypes, 35 treatment regimens and 42 drugs. All datasets in …

Current And Future Therapeutic Strategies For High-Grade Gliomas Leveraging The Interplay Between Epigenetic Regulators And Kinase Signaling Networks, Lea M Stitzlein, Jack T Adams, Erin N Stitzlein, Richard W Dudley, Joya Chandra

Faculty, Staff and Student Publications

Targeted therapies, including small molecule inhibitors directed against aberrant kinase signaling and chromatin regulators, are emerging treatment options for high-grade gliomas (HGG). However, when translating these inhibitors into the clinic, their efficacy is generally limited to partial and transient responses. Recent studies in models of high-grade gliomas reveal a convergence of epigenetic regulators and kinase signaling networks that often cooperate to promote malignant properties and drug resistance. This review examines the interplay between five well-characterized groups of chromatin regulators, including the histone deacetylase (HDAC) family, bromodomain and extraterminal (BET)-containing proteins, protein arginine methyltransferase (PRMT) family, Enhancer of zeste homolog 2 …

Sirtuin 2 Inhibition Modulates Chromatin Landscapes Genome-Wide To Induce Senescence In Atrx-Deficient Malignant Glioma, Prit Benny Malgulwar, Carla Danussi, Sharvari Dharmaiah, William Johnson, Anand Singh, Kunal Rai, Arvind Rao, Jason T Huse

Faculty, Staff and Student Publications

BACKGROUND: Functional inactivation of ATRX characterizes large subgroups of malignant gliomas in adults and children. ATRX deficiency in glioma induces widespread chromatin remodeling, driving transcriptional shifts and oncogenic phenotypes. Effective strategies to therapeutically target these broad epigenomic sequelae remain undeveloped.

METHODS: We utilized integrated multiomics and the Broad Institute Connectivity Map (CMAP) to identify drug candidates that could potentially revert ATRX-deficient transcriptional changes. We then employed disease-relevant experimental models to evaluate functional phenotypes, coupling these studies with epigenomic profiling to elucidate molecular mechanism(s).

RESULTS: CMAP analysis and transcriptional/epigenomic profiling implicated the Class III HDAC Sirtuin2 (SIRT2) as a central mediator …

Contextualizing The Revised Patient Perception Of Patient-Centeredness (Pppc-R) Scale In Primary Healthcare Settings: A Validity And Reliability Evaluation Study, Yiyuan Cai, Pengfei Guo, Jiong Tu, Mengyao Hu, Lingrui Liu, Bridget L Ryan, Jing Liao, Rubee Dev, Yiran Li, Tianyu Huang, Ruilin Wang, Li Kuang, Ruonan Huang, Xinfang Li, Edmundo Roberto Melipillán, Shuaixiang Zhao, Wenjun He, Xiaohui Wang, Nan Zhang, Dong Roman Xu

Faculty, Staff and Student Publications

BACKGROUND: An English version of the Patient Perception of Patient-Centeredness (PPPC) scale was recently revised, and it is necessary to test this instrument in different primary care populations.

AIM: This study aimed to assess the validity and reliability of a Chinese version of the PPPC scale.

DESIGN: A mixed method was used in this study. The Delphi method was used to collect qualitative and quantitative data to address the content validity of the PPPC scale by calculating the Content Validity Index, Content Validity Ratio, the adjusted Kappa, and the Item Impact Score. Confirmatory factor analysis (CFA) and exploratory factor analysis …

Surgical Management Of Choanal Atresia: Two Classic Cases And Review Of The Literature, Philipp Karschnia, Jorg Dietrich, Francesco Bruno, Antonio Dono, Stephanie T Juenger, Nico Teske, Jacob S Young, Tommaso Sciortino, Levin Häni, Martin Van Den Bent, Michael Weller, Michael A Vogelbaum, Ramin A Morshed, Alexander F Haddad, Annette M Molinaro, Nitin Tandon, Juergen Beck, Oliver Schnell, Lorenzo Bello, Shawn Hervey-Jumper, Niklas Thon, Stefan J Grau, Yoshua Esquenazi, Roberta Rudà, Susan M Chang, Mitchel S Berger, Daniel P Cahill, Joerg-Christian Tonn

Faculty, Staff and Student Publications

BACKGROUND: Resection of the contrast-enhancing (CE) tumor represents the standard of care in newly diagnosed glioblastoma. However, some tumors ultimately diagnosed as glioblastoma lack contrast enhancement and have a 'low-grade appearance' on imaging (non-CE glioblastoma). We aimed to (a) volumetrically define the value of non-CE tumor resection in the absence of contrast enhancement, and to (b) delineate outcome differences between glioblastoma patients with and without contrast enhancement.

METHODS: The RANO resect group retrospectively compiled a global, eight-center cohort of patients with newly diagnosed glioblastoma per WHO 2021 classification. The associations between postoperative tumor volumes and outcome were analyzed. Propensity score-matched …

Development Of A Rabbit Human Glioblastoma Model For Testing Of Endovascular Selective Intra-Arterial Infusion (Esia) Of Novel Stem Cell-Based Therapeutics, Peter Kan, Visish M Srinivasan, Joy Gumin, Roberto Garcia, Stephen R Chen, Jeremiah N Johnson, Dalis E Collins, Melissa M Chen, Daniel Ledbetter, Jason Huse, Zean Aaron Evan Luna, Ariadna Robledo, Viren Vasandani, Abhijit Rao, Sanjay K Singh, Elizabeth J Shpall, Juan Fueyo, Candelaria Gomez-Manzano, Frederick F Lang

Faculty, Staff and Student Publications

BACKGROUND: Endovascular selective intra-arterial (ESIA) infusion of cellular oncotherapeutics is a rapidly evolving strategy for treating glioblastoma. Evaluation of ESIA infusion requires a unique animal model. Our goal was to create a rabbit human GBM model to test IA infusions of cellular therapies and to test its usefulness by employing clinical-grade microcatheters and infusion methods to deliver mesenchymal stem cells loaded with an oncolytic adenovirus, Delta-24-RGD (MSC-D24).

METHODS: Rabbits were immunosuppressed with mycophenolate mofetil, dexamethasone, and tacrolimus. They underwent stereotactic xenoimplantation of human GBM cell lines (U87, MDA-GSC-17, and MDA-GSC-8-11) into the right frontal lobe. Tumor formation was confirmed on …

A Retrospective Genomic Landscape Of 661 Young Adult Glioblastomas Diagnosed Using 2016 Who Guidelines For Central Nervous System Tumors, James F Haberberger, Worthy Pegram, Nicholas Britt, Kelsie Schiavone, Eric Severson, Radwa Sharaf, Lee A Albacker, Erik Williams, Mirna Lechpammer, Amanda Hemmerich, Douglas Lin, Richard S P Huang, Matthew Hiemenz, Julia Elvin, Ryon Graf, Glenn Lesser, David Kram, Roy Strowd, Wenya Linda Bi, Lori A Ramkissoon, Michael B Cohen, Prasanth Reddy, James Creeden, Jeffrey S Ross, Brian M Alexander, Shakti H Ramkissoon

Faculty, Staff and Student Publications

The authors present a cohort of 661 young adult glioblastomas diagnosed using 2016 WHO World Health Organization Classification of Tumors of the Central Nervous System, utilizing comprehensive genomic profiling (CGP) to explore their genomic landscape and assess their relationship to currently defined disease entities. This analysis explored variants with evidence of pathogenic function, common copy number variants (CNVs), and several novel fusion events not described in literature. Tumor mutational burden (TMB) mutational signatures, anatomic location, and tumor recurrence are further explored. Using data collected from CGP, unsupervised machine-learning techniques were leveraged to identify 10 genomic classes in previously assigned young …

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- …

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 …

Fak Drives Resistance To Therapy In Hpv-Negative Head And Neck Cancer In A P53-Dependent Manner, Phillip M Pifer, Liangpeng Yang, Manish Kumar, Tongxin Xie, Mitchell Frederick, Andrew Hefner, Beth Beadle, David Molkentine, Jessica Molkentine, Annika Dhawan, Mohamed Abdelhakiem, Abdullah A Osman, Brian J Leibowitz, Jeffrey N Myers, Curtis R Pickering, Vlad C Sandulache, John Heymach, Heath D Skinner

Faculty, Staff and Student Publications

PURPOSE: Radiation and platinum-based chemotherapy form the backbone of therapy in human papillomavirus (HPV)-negative head and neck squamous cell carcinoma (HNSCC). We have correlated focal adhesion kinase (FAK/PTK2) expression with radioresistance and worse outcomes in these patients. However, the importance of FAK in driving radioresistance and its effects on chemoresistance in these patients remains unclear.

EXPERIMENTAL DESIGN: We performed an in vivo shRNA screen using targetable libraries to identify novel therapeutic sensitizers for radiation and chemotherapy.

RESULTS: We identified FAK as an excellent target for both radio- and chemosensitization. Because TP53 is mutated in over 80% of HPV-negative HNSCC, we …

Clinicalomicsdb: Exploring Molecular Associations Of Oncology Drug Responses In Clinical Trials, Chang In Moon, John Michael Elizarraras, Jonathan Thomas Lei, Byron Jia, Bing Zhang

Faculty, Staff and Students Publications

Matching patients to optimal treatment is challenging, in part due to the limited availability of real-world clinical datasets for predictive biomarker identification. The growing integration of omics profiling into clinical trials presents a new opportunity to tackle this challenge. Here, we introduce ClinicalOmicsDB, a web application for exploring molecular associations of oncology drug responses in clinical trials. This database includes transcriptomic data from 40 clinical trial studies, with 5913 patients spanning 11 cancer types. These studies include 67 treatment arms with a variety of chemotherapy, targeted therapy and immunotherapy drugs, and their combinations, which we organize based on an established …

Pharmacotherapy For Primary Biliary Cholangitis: An Assessment Of Medication Candidacy And Rates Of Treatment, Nicholas Macdonald, Rebecca Loh, Jonathan Fenkel, David Sass, Dina Halegoua-De Marzio

Division of Gastroenterology and Hepatology Faculty Papers

BACKGROUND: Ursodeoxycholic acid is the preferred first-line therapy for primary biliary cholangitis. Alternative therapies, such as obeticholic acid, are recommended for patients who cannot tolerate ursodeoxycholic acid or who have an inadequate response to ursodeoxycholic acid monotherapy. Prior investigations have suggested that as many as 30% of patients with primary biliary cholangitis may have never received treatment with ursodeoxycholic acid. No prior investigations have examined usage rates of obeticholic acid in the treatment of primary biliary cholangitis.

METHODS: All patients with an ICD-10 diagnosis of primary biliary cholangitis who had any records within the health system were included. A review …

Experiences Of Family Communication And Cascade Genetic Testing For Hereditary Cancer In Medically Underserved Populations-A Qualitative Study, Erica M Bednar, J Alejandro Rauh-Hain, Jose J Garcia, Norma De Aguinaga, Mary Anne Powell, Sylvia L Peral, Roni Nitecki, Kirsten Jorgensen, Natasha L Rudy, Karen H Lu, Charles A Leath, Isabel C Scarinci

Faculty, Staff and Student Publications

UNLABELLED: We sought to explore the intrafamilial communication and cascade genetic testing (CGT) experiences of patients with hereditary cancer from diverse, medically underserved populations and their relatives. Participants included patients receiving oncology care at an urban, safety net hospital in Texas or comprehensive cancer center in Alabama and their first-degree relatives. In-depth semi-structured qualitative interviews were completed wherein patients shared their experiences with genetic counseling (GC), genetic testing (GT), and communicating their results to relatives. Relatives shared their experiences receiving information from the patient and considering CGT. Interviews were transcribed, coded, and themes were identified. Of 25 participating patients, most …

Identifying Opportunities For Prevention Of Adverse Outcomes Following Female Genital Fistula Repair: Protocol For A Mixed-Methods Study In Uganda, Alison El Ayadi, Susan Obore, Fred Kirya, Suellen Miller, Abner Korn, Hadija Nalubwama, John Neuhaus, Monica Getahun, Patrick Eyul, Robert Twine, Erin Andrew, Justus Barageine

Department of Obstetrics and Gynecology Faculty Papers

BACKGROUND: Female genital fistula is a traumatic debilitating injury, frequently caused by prolonged obstructed labor, affecting between 500,000-2 million women in lower-resource settings. Vesicovaginal fistula causes urinary incontinence, and other morbidity may occur during fistula development. Women with fistula are stigmatized, limit social and economic engagement, and experience psychiatric morbidity. Improved surgical access has reduced fistula consequences yet post-repair risks impacting quality of life and well-being include fistula repair breakdown or recurrence and ongoing or changing urine leakage or incontinence. Limited evidence on risk factors contributing to adverse outcomes hinders interventions to mitigate adverse events. This study aims to quantify …

Proteogenomic Characterization Of Small Cell Lung Cancer Identifies Biological Insights And Subtype-Specific Therapeutic Strategies, Qian Liu, Jing Zhang, Chenchen Guo, Mengcheng Wang, Chenfei Wang, Yilv Yan, Liangdong Sun, Di Wang, Lele Zhang, Huansha Yu, Likun Hou, Chunyan Wu, Yuming Zhu, Gening Jiang, Hongwen Zhu, Yanting Zhou, Shanhua Fang, Tengfei Zhang, Liang Hu, Junqiang Li, Yansheng Liu, Hui Zhang, Bing Zhang, Li Ding, Ana I Robles, Henry Rodriguez, Daming Gao, Hongbin Ji, Hu Zhou, Peng Zhang

Faculty, Staff and Students Publications

We performed comprehensive proteogenomic characterization of small cell lung cancer (SCLC) using paired tumors and adjacent lung tissues from 112 treatment-naive patients who underwent surgical resection. Integrated multi-omics analysis illustrated cancer biology downstream of genetic aberrations and highlighted oncogenic roles of FAT1 mutation, RB1 deletion, and chromosome 5q loss. Two prognostic biomarkers, HMGB3 and CASP10, were identified. Overexpression of HMGB3 promoted SCLC cell migration via transcriptional regulation of cell junction-related genes. Immune landscape characterization revealed an association between ZFHX3 mutation and high immune infiltration and underscored a potential immunosuppressive role of elevated DNA damage response activity via inhibition of the …

Factors Associated With Blood Mercury Concentrations And Their Interactions With Three Glutathione S-Transferase Genes (Gstt1, Gstm1, And Gstp1): An Exposure Assessment Study Of Typically Developing Jamaican Children, Sheikh Farzana Zaman, Maureen Samms-Vaughan, Sepideh Saroukhani, Jan Bressler, Manouchehr Hessabi, Megan L Grove, Sydonnie Shakespeare Pellington, Katherine A Loveland, Mohammad H Rahbar

Faculty, Staff and Student Publications

BACKGROUND: Jamaican soil is abundant in heavy metals including mercury (Hg). Due to availability and ease of access, fish is a traditional dietary component in Jamaica and a significant source of Hg exposure. Mercury is a xenobiotic and known neuro-toxicant that affects children's neurodevelopment. Human glutathione S-transferase (GST) genes, including GSTT1, GSTM1, and GSTP1, affect Hg conjugation and elimination mechanisms.

METHODS: In this exposure assessment study we used data from 375 typically developing (TD) 2-8-year-old Jamaican children to explore the association between environmental Hg exposure, GST genes, and their interaction effects on blood Hg concentrations (BHgCs). We used multivariable general …

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, …