Digital Commons Network^™

Overnight 1-Mg Dst Serum Cortisol In Various Stages Of Chronic Kidney Disease-Normative Data And Underlying Mechanisms, Robin Garg, Saba Samad Memon, Anurag Lila, Vijaya Sarathi, Priyanka Patil, Tukaram Jamale, Sreyashi Bose, Manjiri Karlekar, Virendra Patil, Nalini Shah, Tushar Bandgar

Faculty, Staff and Student Publications

CONTEXT: Data on the overnight 1 mg-dexamethasone suppression test (ONDST) in renal dysfunction are limited.

OBJECTIVE: We aim to determine the normative range of ONDST cortisol across chronic kidney disease (CKD) stages and reasons for its alteration.

METHODS: Prospectively, 180 CKD (30 each in G2-G5/5D) patients and 30 healthy controls underwent ONDST 8 Am serum cortisol (chemiluminescent immunoassay [CLIA]). In an exploratory cohort, 45 (15 each: G3b/G4, G5/G5D, and healthy controls) individuals' blood biochemistry for basal (8 Am) cortisol and adrenocorticotropin (ACTH), post-ONDST 8 Am dexamethasone, ACTH, cortisol (CLIA and liquid chromatography-tandem mass spectrometry), and 4 Pm cortisol was collected. …

Expanded T Lymphocytes In The Cerebrospinal Fluid Of Multiple Sclerosis Patients Are Specific For Epstein-Barr-Virus-Infected B Cells, Assaf Gottlieb, H Phuong T Pham, Jerome G Saltarrelli, J William Lindsey

Faculty, Staff and Student Publications

Epstein-Barr virus (EBV) infection has long been associated with multiple sclerosis (MS), but the role of EBV in the pathogenesis of MS is not clear. Our hypothesis is that a major fraction of the expanded clones of T lymphocytes in the cerebrospinal fluid (CSF) are specific for autologous EBV-infected B cells. We obtained blood and CSF samples from eight relapsing-remitting patients in the process of diagnosis. We stimulated cells from the blood with autologous EBV-infected lymphoblastoid cell lines (LCL), EBV, varicella zoster virus, influenza, and candida and sorted the responding cells with flow cytometry after 6 d. We sequenced the …

Large Scale Plasma Proteomics Identifies Novel Proteins And Protein Networks Associated With Heart Failure Development, Amil M Shah, Peder L Myhre, Victoria Arthur, Pranav Dorbala, Humaira Rasheed, Leo F Buckley, Brian Claggett, Guning Liu, Jianzhong Ma, Ngoc Quynh Nguyen, Kunihiro Matsushita, Chiadi Ndumele, Adrienne Tin, Kristian Hveem, Christian Jonasson, Håvard Dalen, Eric Boerwinkle, Ron C Hoogeveen, Christie Ballantyne, Josef Coresh, Torbjørn Omland, Bing Yu

Faculty, Staff and Student Publications

Heart failure (HF) causes substantial morbidity and mortality but its pathobiology is incompletely understood. The proteome is a promising intermediate phenotype for discovery of novel mechanisms. We measured 4877 plasma proteins in 13,900 HF-free individuals across three analysis sets with diverse age, geography, and HF ascertainment to identify circulating proteins and protein networks associated with HF development. Parallel analyses in Atherosclerosis Risk in Communities study participants in mid-life and late-life and in Trøndelag Health Study participants identified 37 proteins consistently associated with incident HF independent of traditional risk factors. Mendelian randomization supported causal effects of 10 on HF, HF risk …

Beyond The Global Brain Differences: Intraindividual Variability Differences In 1q211 Distal And 15q112 Bp1-Bp2 Deletion Carriers, Rune Boen, Tobias Kaufmann, Dennis Van Der Meer, Oleksandr Frei, Ingrid Agartz, David Ames, Micael Andersson, Nicola J Armstrong, Eric Artiges, Joshua R Atkins, Jochen Bauer, Francesco Benedetti, Dorret I Boomsma, Henry Brodaty, Katharina Brosch, Randy L Buckner, Murray J Cairns, Vince Calhoun, Svenja Caspers, Sven Cichon, Aiden P Corvin, Benedicto Crespo-Facorro, Udo Dannlowski, Friederike S David, Eco J C De Geus, Greig I De Zubicaray, Sylvane Desrivières, Joanne L Doherty, Gary Donohoe, Stefan Ehrlich, Else Eising, Thomas Espeseth, Simon E Fisher, Andreas J Forstner, Lidia Fortaner-Uyà, Vincent Frouin, Masaki Fukunaga, Tian Ge, David C Glahn, Janik Goltermann, Hans J Grabe, Melissa J Green, Nynke A Groenewold, Dominik Grotegerd, Gøril Rolfseng Grøntvedt, Tim Hahn, Ryota Hashimoto, Jayne Y Hehir-Kwa, Frans A Henskens, Avram J Holmes, Asta K Håberg, Jan Haavik, Sebastien Jacquemont, Andreas Jansen, Christiane Jockwitz, Erik G Jönsson, Masataka Kikuchi, Tilo Kircher, Kuldeep Kumar, Stephanie Le Hellard, Costin Leu, David E Linden, Jingyu Liu, Robert Loughnan, Karen A Mather, Katie L Mcmahon, Allan F Mcrae, Sarah E Medland, Susanne Meinert, Clara A Moreau, Derek W Morris, Bryan J Mowry, Thomas W Mühleisen, Igor Nenadić, Markus M Nöthen, Lars Nyberg, Roel A Ophoff, Michael J Owen, Christos Pantelis, Marco Paolini, Tomas Paus, Zdenka Pausova, Karin Persson, Yann Quidé, Tiago Reis Marques, Perminder S Sachdev, Sigrid B Sando, Ulrich Schall, Rodney J Scott, Geir Selbæk, Elena Shumskaya, Ana I Silva, Sanjay M Sisodiya, Frederike Stein, Dan J Stein, Benjamin Straube, Fabian Streit, Lachlan T Strike, Alexander Teumer, Lea Teutenberg, Anbupalam Thalamuthu, Paul A Tooney, Diana Tordesillas-Gutierrez, Julian N Trollor, Dennis Van 'T Ent, Marianne B M Van Den Bree, Neeltje E M Van Haren, Javier Vázquez-Bourgon, Henry Völzke, Wei Wen, Katharina Wittfeld, Christopher R K Ching, Lars T Westlye, Paul M Thompson, Carrie E Bearden, Kaja K Selmer, Dag Alnæs, Ole A Andreassen, Ida E Sønderby, Enigma-Cnv Working Group

Faculty, Staff and Student Publications

Background: Carriers of the 1q21.1 distal and 15q11.2 BP1-BP2 copy number variants exhibit regional and global brain differences compared with noncarriers. However, interpreting regional differences is challenging if a global difference drives the regional brain differences. Intraindividual variability measures can be used to test for regional differences beyond global differences in brain structure.

Methods: Magnetic resonance imaging data were used to obtain regional brain values for 1q21.1 distal deletion (n = 30) and duplication (n = 27) and 15q11.2 BP1-BP2 deletion (n = 170) and duplication (n = 243) carriers and matched noncarriers (n = 2350). Regional intra-deviation scores, i.e., …

Qiditangshen Granules Alleviates Diabetic Nephropathy Podocyte Injury: A Network Pharmacology Study And Experimental Validation In Vivo And Vitro, Fei Gao, Ying Zhou, Borui Yu, Huidi Xie, Yang Shi, Xianhui Zhang, Hongfang Liu

Faculty, Staff and Student Publications

BACKGROUND: QiDiTangShen granules (QDTS), a traditional Chinese medicine (TCM) compound prescription, have remarkable efficacy in diabetic nephropathy (DN) patients, and their pharmacological mechanism needs further exploration.

METHODS: According to the active ingredients and targets of the QDTS in the TCMSP database, the network pharmacology of QDTS was investigated. The potential active ingredients were chosen based on the oral bioavailability and the drug similarity index. At the same time, targets for DN-related disease were obtained from GeneCards, OMIM, PharmGKB, TTD, and DrugBank. The TCM-component-target network and the protein-protein interaction (PPI) network were constructed with the Cytoscape and STRING platforms, respectively, and …

Coronary Flow Capacity And Survival Prediction After Revascularization: Physiological Basis And Clinical Implications, K Lance Gould, Nils P Johnson, Amanda E Roby, Linh Bui, Danai Kitkungvan, Monica B Patel, Tung Nguyen, Richard Kirkeeide, Mary Haynie, Salman A Arain, Konstantinos Charitakis, Abhijeet Dhoble, Richard Smalling, Angelo Nascimbene, Marwan Jumean, Sachin Kumar, Biswajit Kar, Stefano Sdringola, Anthony Estrera, Igor Gregoric, Dejian Lai, Ruosha Li, David Mcpherson, Jagat Narula

Faculty, Staff and Student Publications

BACKGROUND AND AIMS: Coronary flow capacity (CFC) is associated with an observed 10-year survival probability for individual patients before and after actual revascularization for comparison to virtual hypothetical ideal complete revascularization.

METHODS: Stress myocardial perfusion (mL/min/g) and coronary flow reserve (CFR) per pixel were quantified in 6979 coronary artery disease (CAD) subjects using Rb-82 positron emission tomography (PET) for CFC maps of artery-specific size-severity abnormalities expressed as percent left ventricle with prospective follow-up to define survival probability per-decade as fraction of 1.0.

RESULTS: Severely reduced CFC in 6979 subjects predicted low survival probability that improved by 42% after revascularization compared …

Brain Connectivity And Academic Skills In English Learners, Tehila Nugiel, Damion V Demeter, Mackenzie E Mitchell, Annacarolina Garza, Arturo E Hernandez, Jenifer Juranek, Jessica A Church

Faculty, Staff and Student Publications

English learners (ELs) are a rapidly growing population in schools in the United States with limited experience and proficiency in English. To better understand the path for EL's academic success in school, it is important to understand how EL's brain systems are used for academic learning in English. We studied, in a cohort of Hispanic middle-schoolers (n = 45, 22F) with limited English proficiency and a wide range of reading and math abilities, brain network properties related to academic abilities. We applied a method for localizing brain regions of interest (ROIs) that are group-constrained, yet individually specific, to test how …

Targeting Innate Immunity In Glioma Therapy, Andrew G Gillard, Dong Ho Shin, Lethan A Hampton, Andres Lopez-Rivas, Akhila Parthasarathy, Juan Fueyo, Candelaria Gomez-Manzano

Faculty, Staff and Student Publications

Currently, there is a lack of effective therapies for the majority of glioblastomas (GBMs), the most common and malignant primary brain tumor. While immunotherapies have shown promise in treating various types of cancers, they have had limited success in improving the overall survival of GBM patients. Therefore, advancing GBM treatment requires a deeper understanding of the molecular and cellular mechanisms that cause resistance to immunotherapy. Further insights into the innate immune response are crucial for developing more potent treatments for brain tumors. Our review provides a brief overview of innate immunity. In addition, we provide a discussion of current therapies …

Reactivation Of The G1 Enhancer Landscape Underlies Core Circuitry Addiction To Swi/Snf, Katerina Cermakova, Ling Tao, Milan Dejmek, Michal Sala, Matthew D Montierth, Yuen San Chan, Ivanshi Patel, Courtney Chambers, Mario Loeza Cabrera, Dane Hoffman, Ronald J Parchem, Wenyi Wang, Radim Nencka, Eveline Barbieri, H Courtney Hodges

Faculty, Staff and Student Publications

Several cancer core regulatory circuitries (CRCs) depend on the sustained generation of DNA accessibility by SWI/SNF chromatin remodelers. However, the window when SWI/SNF is acutely essential in these settings has not been identified. Here we used neuroblastoma (NB) cells to model and dissect the relationship between cell-cycle progression and SWI/SNF ATPase activity. We find that SWI/SNF inactivation impairs coordinated occupancy of non-pioneer CRC members at enhancers within 1 hour, rapidly breaking their autoregulation. By precisely timing inhibitor treatment following synchronization, we show that SWI/SNF is dispensable for survival in S and G2/M, but becomes acutely essential only during G1 phase. …

Covid-19 Convalescent Plasma Therapy Decreases Inflammatory Cytokines: A Randomized Controlled Trial, Feben Habtehyimer, Xianming Zhu, Andrew D Redd, Kelly A Gebo, Alison G Abraham, Eshan U Patel, Oliver Laeyendecker, Thomas J Gniadek, Reinaldo E Fernandez, Owen R Baker, Malathi Ram, Edward R Cachay, Judith S Currier, Yuriko Fukuta, Jonathan M Gerber, Sonya L Heath, Barry Meisenberg, Moises A Huaman, Adam C Levine, Aarthi Shenoy, Shweta Anjan, Janis E Blair, Daniel Cruser, Donald N Forthal, Laura L Hammitt, Seble Kassaye, Giselle S Mosnaim, Bela Patel, James H Paxton, Jay S Raval, Catherine G Sutcliffe, Matthew Abinante, Kevin S Oei, Valerie Cluzet, Marie Elena Cordisco, Benjamin Greenblatt, William Rausch, David Shade, Amy L Gawad, Sabra L Klein, Andrew Pekosz, Shmuel Shoham, Arturo Casadevall, Evan M Bloch, Daniel Hanley, Aaron A R Tobian, David J Sullivan

Faculty, Staff and Student Publications

This study examined the role that cytokines may have played in the beneficial outcomes found when outpatient individuals infected with SARS-CoV-2 were transfused with COVID-19 convalescent plasma (CCP) early in their infection. We found that the pro-inflammatory cytokine IL-6 decreased significantly faster in patients treated early with CCP. Participants with COVID-19 treated with CCP later in the infection did not have the same effect. This decrease in IL-6 levels after early CCP treatment suggests a possible role of inflammation in COVID-19 progression. The evidence of IL-6 involvement brings insight into the possible mechanisms involved in CCP treatment mitigating SARS-CoV-2 severity.

Enhancing Mitosis Quantification And Detection In Meningiomas With Computational Digital Pathology, Hongyan Gu, Chunxu Yang, Issa Al-Kharouf, Shino Magaki, Nelli Lakis, Christopher Kazu Williams, Sallam Mohammad Alrosan, Ellie Kate Onstott, Wenzhong Yan, Negar Khanlou, Inma Cobos, Xinhai Robert Zhang, Neda Zarrin-Khameh, Harry V Vinters, Xiang Anthony Chen, Mohammad Haeri

Faculty, Staff and Student Publications

Mitosis is a critical criterion for meningioma grading. However, pathologists' assessment of mitoses is subject to significant inter-observer variation due to challenges in locating mitosis hotspots and accurately detecting mitotic figures. To address this issue, we leverage digital pathology and propose a computational strategy to enhance pathologists' mitosis assessment. The strategy has two components: (1) A depth-first search algorithm that quantifies the mathematically maximum mitotic count in 10 consecutive high-power fields, which can enhance the preciseness, especially in cases with borderline mitotic count. (2) Implementing a collaborative sphere to group a set of pathologists to detect mitoses under each high-power …

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 …

Hypoxia-Activated Prodrug And Antiangiogenic Therapies Cooperatively Treat Pancreatic Cancer But Elicit Immunosuppressive G-Mdsc Infiltration, Arthur Liu, Seth T Gammon, Federica Pisaneschi, Akash Boda, Casey R Ager, David Piwnica-Worms, David S Hong, Michael A Curran

Faculty, Staff and Student Publications

We previously showed that ablation of tumor hypoxia can sensitize tumors to immune checkpoint blockade (ICB). Here, we used a Kras+/G12D TP53+/R172H Pdx1-Cre-derived (KPC-derived) model of pancreatic adenocarcinoma to examine the tumor response and adaptive resistance mechanisms involved in response to 2 established methods of hypoxia-reducing therapy: the hypoxia-activated prodrug TH-302 and vascular endothelial growth factor receptor 2 (VEGFR-2) blockade. The combination of both modalities normalized tumor vasculature, increased DNA damage and cell death, and delayed tumor growth. In contrast with prior cancer models, the combination did not alleviate overall tissue hypoxia or sensitize these KPC tumors to ICB therapy …

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 …

Toward Standardization, Harmonization, And Integration Of Social Determinants Of Health Data: A Texas Clinical And Translational Science Award Institutions Collaboration, Catherine K Craven, Linda Highfield, Mujeeb Basit, Elmer V Bernstam, Byeong Yeob Choi, Robert L Ferrer, Jonathan A Gelfond, Sandi L Pruitt, Vaishnavi Kannan, Paula K Shireman, Heidi Spratt, Kayla J Torres Morales, Chen-Pin Wang, Zhan Wang, Meredith N Zozus, Edward C Sankary, Susanne Schmidt

Faculty, Staff and Student Publications

INTRODUCTION: The focus on social determinants of health (SDOH) and their impact on health outcomes is evident in U.S. federal actions by Centers for Medicare & Medicaid Services and Office of National Coordinator for Health Information Technology. The disproportionate impact of COVID-19 on minorities and communities of color heightened awareness of health inequities and the need for more robust SDOH data collection. Four Clinical and Translational Science Award (CTSA) hubs comprising the Texas Regional CTSA Consortium (TRCC) undertook an inventory to understand what contextual-level SDOH datasets are offered centrally and which individual-level SDOH are collected in structured fields in each …

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 …

Levodopa Rescues Retinal Function In The Transgenic A53t Alpha-Synuclein Model Of Parkinson's Disease, Katie K N Tran, Vickie H Y Wong, Kirstan A Vessey, David I Finkelstein, Bang V Bui, Christine T O Nguyen

Faculty, Staff and Student Publications

BACKGROUND: Loss of substantia nigra dopaminergic cells and alpha-synuclein (α-syn)-rich intraneuronal deposits within the central nervous system are key hallmarks of Parkinson's disease (PD). Levodopa (L-DOPA) is the current gold-standard treatment for PD. This study aimed to evaluate

METHODS: Anaesthetised 6-month-old mice expressing human A53T alpha-synuclein (HOM) and wildtype (WT) control littermates were intraperitoneally given 20 mg/kg L-DOPA (50 mg levodopa, 2.5 mg benserazide) or vehicle saline (

RESULTS: We found that photoreceptor (a-wave) and bipolar cell (b-wave) ERG responses (

CONCLUSIONS: These findings deepen our understanding of dopamine and alpha-synuclein interactions in the retina and provide a high-throughput preclinical …

Modeling Methyl-Sensitive Transcription Factor Motifs With An Expanded Epigenetic Alphabet, Coby Viner, Charles A Ishak, James Johnson, Nicolas J Walker, Hui Shi, Marcela K Sjöberg-Herrera, Shu Yi Shen, Santana M Lardo, David J Adams, Anne C Ferguson-Smith, Daniel D De Carvalho, Sarah J Hainer, Timothy L Bailey, Michael M Hoffman

Faculty, Staff and Student Publications

BACKGROUND: Transcription factors bind DNA in specific sequence contexts. In addition to distinguishing one nucleobase from another, some transcription factors can distinguish between unmodified and modified bases. Current models of transcription factor binding tend not to take DNA modifications into account, while the recent few that do often have limitations. This makes a comprehensive and accurate profiling of transcription factor affinities difficult.

RESULTS: Here, we develop methods to identify transcription factor binding sites in modified DNA. Our models expand the standard A/C/G/T DNA alphabet to include cytosine modifications. We develop Cytomod to create modified genomic sequences and we also enhance …

Comparison Of Energy Budget Of Cockroach Nymph (Hemimetabolous) And Hornworm (Holometabolous) Under Food Restriction, Charles J Green, Chen Hou

Faculty, Staff and Student Publications

Animals with different life histories budget their intake energy differently when food availability is low. It has been shown previously that hornworm (larva of Manduca sexta), a holometabolous insect species with a short development stage, prioritizes growth at the price of metabolism under food restriction, but it is unclear how hemimetabolous insect species with a relatively long development period budget their intake energy under food scarcity. Here, we use orange head cockroaches (Eublaberus posticus) to investigate this question. We found that for both species under food restriction, rates of metabolism and growth were suppressed, but the degree …

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 …

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 …

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 …

Preclinical Repurposing Of Sitagliptin As A Drug Candidate For Colorectal Cancer By Targeting Cd24/Ctnnb1/Sox4-Centered Signaling Hub, Jing-Wen Shih, Alexander T H Wu, Ntlotlang Mokgautsi, Po-Li Wei, Yan-Jiun Huang

Faculty, Staff and Student Publications

Despite significant advances in treatment modalities, colorectal cancer (CRC) remains a poorly understood and highly lethal malignancy worldwide. Cancer stem cells (CSCs) and the tumor microenvironment (TME) have been shown to play critical roles in initiating and promoting CRC progression, metastasis, and treatment resistance. Therefore, a better understanding of the underlying mechanisms contributing to the generation and maintenance of CSCs is crucial to developing CSC-specific therapeutics and improving the current standard of care for CRC patients. To this end, we used a bioinformatics approach to identify increased CD24/SOX4 expression in CRC samples associated with poor prognosis. We also …

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 …

Cell State Of Origin Impacts Development Of Distinct Endometriosis-Related Ovarian Carcinoma Histotypes, Ian Beddows, Huihui Fan, Karolin Heinze, Benjamin K Johnson, Anna Leonova, Janine Senz, Svetlana Djirackor, Kathleen R Cho, Celeste Leigh Pearce, David G Huntsman, Michael S Anglesio, Hui Shen

Faculty, Staff and Student Publications

Clear cell ovarian carcinoma (CCOC) and endometrioid ovarian carcinoma (ENOC) are ovarian carcinoma histotypes, which are both thought to arise from ectopic endometrial (or endometrial-like) cells through an endometriosis intermediate. How the same cell type of origin gives rise to two morphologically and biologically different histotypes has been perplexing, particularly given that recurrent genetic mutations are common to both and present in nonmalignant precursors. We used RNA transcription analysis to show that the expression profiles of CCOC and ENOC resemble those of normal endometrium at secretory and proliferative phases of the menstrual cycle, respectively. DNA methylation at the promoter of …

Cell Cycle Arrest Induces Lipid Droplet Formation And Confers Ferroptosis Resistance, Hyemin Lee, Amber Horbath, Lavanya Kondiparthi, Jitendra Kumar Meena, Guang Lei, Shayani Dasgupta, Xiaoguang Liu, Li Zhuang, Pranavi Koppula, Mi Li, Iqbal Mahmud, Bo Wei, Philip L Lorenzi, Khandan Keyomarsi, Masha V Poyurovsky, Kellen Olszewski, Boyi Gan

Faculty, Staff and Student Publications

How cells coordinate cell cycling with cell survival and death remains incompletely understood. Here, we show that cell cycle arrest has a potent suppressive effect on ferroptosis, a form of regulated cell death induced by overwhelming lipid peroxidation at cellular membranes. Mechanistically, cell cycle arrest induces diacylglycerol acyltransferase (DGAT)-dependent lipid droplet formation to sequester excessive polyunsaturated fatty acids (PUFAs) that accumulate in arrested cells in triacylglycerols (TAGs), resulting in ferroptosis suppression. Consequently, DGAT inhibition orchestrates a reshuffling of PUFAs from TAGs to phospholipids and re-sensitizes arrested cells to ferroptosis. We show that some slow-cycling antimitotic drug-resistant cancer cells, such as …

Crispr-Cas9 Base Editing Of Pathogenic Camkiiδ Improves Cardiac Function In A Humanized Mouse Model, Simon Lebek, Xurde M Caravia, Leon G Straub, Damir Alzhanov, Wei Tan, Hui Li, John R Mcanally, Kenian Chen, Lin Xu, Philipp E Scherer, Ning Liu, Rhonda Bassel-Duby, Eric N Olson

Faculty, Staff and Student Publications

Cardiovascular diseases are the most common cause of worldwide morbidity and mortality, highlighting the necessity for advanced therapeutic strategies. Ca2+/calmodulin-dependent protein kinase IIδ (CaMKIIδ) is a prominent inducer of various cardiac disorders, which is mediated by 2 oxidation-sensitive methionine residues within the regulatory domain. We have previously shown that ablation of CaMKIIδ oxidation by CRISPR-Cas9 base editing enables the heart to recover function from otherwise severe damage following ischemia/reperfusion (IR) injury. Here, we extended this therapeutic concept toward potential clinical translation. We generated a humanized CAMK2D knockin mouse model in which the genomic sequence encoding the entire regulatory domain was …

Effect Of Acupuncture Vs Sham Acupuncture On Patients With Poststroke Motor Aphasia: A Randomized Clinical Trial, Boxuan Li, Shizhe Deng, Bifang Zhuo, Bomo Sang, Junjie Chen, Menglong Zhang, Guang Tian, Lili Zhang, Yuzheng Du, Peng Zheng, Gonglei Yue, Zhihong Meng

Faculty, Staff and Student Publications

IMPORTANCE: Motor aphasia is common among patients with stroke. Acupuncture is recommended as an alternative therapy for poststroke aphasia, but its efficacy remains uncertain.

OBJECTIVE: To investigate the effects of acupuncture on language function, neurological function, and quality of life in patients with poststroke motor aphasia.

DESIGN, SETTING, AND PARTICIPANTS: This multicenter, sham-controlled, randomized clinical trial was conducted in 3 tertiary hospitals in China from October 21, 2019, to November 13, 2021. Adult patients with poststroke motor aphasia were enrolled. Data analysis was performed from February to April 2023.

INTERVENTIONS: Eligible participants were randomly allocated (1:1) to manual acupuncture (MA) …

Descriptor: Synthetic Genomic Dataset With Diverse Ancestry (Syngen6), Xinyue Wang, Sitao Min, Jaideep Vaidya

Faculty, Staff and Student Publications

Advancements in genomic analysis techniques and data-driven research are driving precision medicine. However, in many cases, these advances are not equitable and do not help all subpopulations, since many existing genomic datasets lack diversity, limiting their applicability for studying populations beyond those of European ancestry. Thus, to advance genomic analysis and to allow for a fair benchmarking of novel proposed approaches, there is a significant demand for balanced and representative datasets. To address this issue, we developed,