Digital Commons Network^™

Gene Promoters Are Genomically Encoded To Facilitate Histone Exchange/Incorporation, Blaine Bartholomew

Faculty, Staff and Student Publications

Gene promoters are intrinsically hardwired not only to facilitate transcription preinitiation complex formation but also the release of paused RNA polymerase by H2A.Z. A new PLOS Biology study reveals poly (dA) tracts at promoters positively stimulate H2A.Z incorporation by the SWR complex in yeast.

Igtp: Learning Interpretable Cellular Embedding For Inferring Biological Mechanisms Underlying Single-Cell Transcriptomics, Kang-Lin Hsieh, Kai Zhang, Yan Chu, Lishan Yu, Xiaoyang Li, Nuo Hu, Isha Kawosa, Patrick G Pilié, Pratip K Bhattacharya, Degui Zhi, Xiaoqian Jiang, Zhongming Zhao, Yulin Dai

Faculty, Staff and Student Publications

Deep-learning models like Variational AutoEncoder have enabled low dimensional cellular embedding representation for large-scale single-cell transcriptomes and shown great flexibility in downstream tasks. However, biologically meaningful latent space is usually missing if no specific structure is designed. Here, we engineered a novel interpretable generative transcriptional program (iGTP) framework that could model the importance of transcriptional program (TP) space and protein-protein interactions (PPI) between different biological states. We demonstrated the performance of iGTP in a diverse biological context using gene ontology, canonical pathway, and different PPI curation. iGTP not only elucidated the ground truth of cellular responses but also surpassed other …

Glutamate Gating Of Ampa-Subtype Iglurs At Physiological Temperatures, Anish Kumar Mondal, Elisa Carrillo, Vasanthi Jayaraman, Edward C Twomey

Faculty, Staff and Student Publications

Ionotropic glutamate receptors (iGluRs) are tetrameric ligand-gated ion channels that mediate most excitatory neurotransmission1. iGluRs are gated by glutamate, where on glutamate binding, they open their ion channels to enable cation influx into postsynaptic neurons, initiating signal transduction1,2. The structural mechanics of how glutamate gating occurs in full-length iGluRs is not well understood. Here, using the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid subtype iGluR (AMPAR), we identify the glutamate-gating mechanism. AMPAR activation by glutamate is augmented at physiological temperatures. By preparing AMPARs for cryogenic-electron microscopy at these temperatures, we captured the glutamate-gating mechanism. Activation by glutamate initiates ion channel opening that involves all ion …

Amniotic Fluid Extracellular Vesicle And Cell-Free Rna Profiling Reveals Fetal Adaptations In Twin-Twin Transfusion Syndrome, Jacqueline G Parchem, Huihui Fan, Lovepreet K Mann, Kadeshia M Campbell, Sujuan Yang, Wencai Ma, Jong H Won, Jing Wang, Ramesha Papanna, Raghu Kalluri

Faculty, Staff and Student Publications

No abstract provided.

Effect Of Very Preterm Delivery On Outcomes Following In Utero Spina Bifida Repair, Michael V Zaretsky, Jagruti Anadkat, Kelly A Bennett, Yair J Blumenfeld, Chris Buchanan, Caitlin Clifford, Timothy Crombleholme, Samer Elbabaa, Stephen P Emery, William H Goodnight, Hanmin Lee, Joseph B Lillegard, Foong-Yen Lim, Francois I Luks, Virginia Lijewski, Jena L Miller, Ueli Moehrlen, Julie Moldenhauer, Anita J Moon-Grady, Mauro Schenone, Daniel W Skupski, Aimen F Shaaban, Kuojen Tsao, Tim Van Mieghem, Amy J Wagner

Faculty, Staff and Student Publications

Objective: In utero fetal spina bifida repair decreases the risk for cerebrospinal fluid (CSF) diversion including ventriculoperitoneal (VP) shunt placement, reverses hindbrain herniation, and improves motor function with a higher likelihood of independent ambulation. Unfortunately, in utero surgery can be complicated by preterm delivery. The goal of this study was to compare pregnancy and neonatal outcomes between individuals who delivered very preterm, and those who delivered later in gestation following in-utero spina bifida repair.

Methods: Data from the North American Fetal Therapy Network (NAFTNet) Fetal Myelomeningocele Consortium (fMMC) registry collected from 2011 to 2024 were analyzed. Three cohorts of patients …

Evidence For Biomolecular Condensates Formed By The Escherichia Coli Matp Protein In Spatiotemporal Regulation Of The Bacterial Cell Division Cycle, Inés Barros-Medina, Miguel Ángel Robles-Ramos, Marta Sobrinos-Sanguino, Juan Román Luque-Ortega, Carlos Alfonso, William Margolin, Germán Rivas, Begoña Monterroso, Silvia Zorrilla

Faculty, Staff and Student Publications

An increasing number of proteins involved in bacterial cell cycle events have been recently shown to form biomolecular condensates important for their functions that may play a role in development of antibiotic-tolerant persister cells. Here we report that the E. coli chromosomal Ter macrodomain organizer MatP, a division site selection protein coordinating chromosome segregation with cell division, formed biomolecular condensates in crowding cytomimetic systems preferentially localized at the membrane of microfluidics droplets. Condensates were antagonized and partially dislodged from the membrane by DNA sequences recognized by MatP (matS), which partitioned into them. FtsZ, a core component of the division machinery …

Multiparametric Mri Scoring System Of The Pancreas For The Diagnosis Of Chronic Pancreatitis, Temel Tirkes, Dhiraj Yadav, Darwin L Conwell, Xuandong Zhao, Anil K Dasyam, Vivek Gowdra Halappa, Aashish Patel, Zarine K Shah, Jordan Swensson, Naoki Takahashi, Sudhakar Venkatesh, Ashley Wachsman, Liang Li, Kristofer Jennings, Yunlong Yang, Phil A Hart, Stephen J Pandol, Walter G Park, Santhi Swaroop Vege, Mark Topazian, Paul R Territo, Scott A Persohn, Dana K Andersen, Evan L Fogel, Consortium For The Study Of Chronic Pancreatitis, Diabetes, And Pancreatic Cancer (Cpdpc)

Faculty, Staff and Student Publications

Background: Ductal features alone may not offer high diagnostic sensitivity or most accurate disease severity of chronic pancreatitis (CP).

Purpose: Diagnose CP based on multiparametric MRI and MRCP features.

Study type: Prospective.

Population: Between February 2019 and May 2021, 46 control (23 males, 49.3 ± 14.1 years), 45 suspected (20 males, 48.7 ± 12.5 years), and 46 definite (20 males, 53.7 ± 14.6 years) CP patients were enrolled at seven hospitals enrolled in the MINIMAP study. CP classification was based on imaging findings and clinical presentation.

Field strength and sequences: 1.5 T. T1-weighted (T1W) spoiled gradient echo, T1 map with …

Lefitolimod In Combination With Ipilimumab In Patients With Advanced Solid Tumors: A Phase I Trial, Mirella Nardo, Mohamed A Gouda, Matthew J Reilley, Amadeo B Biter, Joann Lim, Stacie A Bean, Ly M Nguyen, Priya R Bhosale, Casey R Ager, Coline A Couillault, Sarina A Piha-Paul, Siqing Fu, Apostolia M Tsimberidou, Timothy A Yap, Aung Naing, Jordi Rodon, Vivek Subbiah, Daniel D Karp, Michael A Curran, David S Hong

Faculty, Staff and Student Publications

Introduction: TLR9 agonists are immunomodulators that have been of interest for combined use with cancer immunotherapy. TLR9 agonists, such as lefitolimod (MGN1703), significantly increased Th1 response in preclinical models and have demonstrated efficacy in early clinical trials. This trial assessed the safety and preliminary efficacy of the combination of lefitolimod and ipilimumab in patients with advanced solid tumors.

Methods: This was a single-center, open-label, investigator-initiated phase I trial conducted at The University of Texas MD Anderson Cancer Center. Patients received leftolimod either subcutaneously (at escalating doses of 15-120 mg) or intratumorally (at the maximum feasible dose) in combination with ipilimumab …

Tumoral And Circulating Genomic Landscape Inform Survival Differences In Colorectal Carcinomatosis, Michael G White, Reed I Ayabe, Mohammad A Zeineddine, Fadl A Zeineddine, Abdelrahman M G Yousef, Mahmoud Yousef, Norman J Galbraith, J Bryan Iorgulescu, Christopher Scally, Keith Fournier, Timothy E Newhook, Nancy Y You, Jason Willis, Scott Kopetz, George J Chang, John Paul Shen, Abhineet Uppal

Faculty, Staff and Student Publications

Colorectal peritoneal metastases (CPM) are the third most common site of metastatic spread of colorectal cancer and are associated with worse survival than other sites of metastatic disease. In recent years tumoral circulating tumoral DNA (ctDNA) mutational status has been increasingly utilized in clinical decision making for metastatic colorectal cancer patients despite its utility in CPM being poorly understood. Here we describe standard of care performed mutational profiles and associated outcomes for unresectable CPM patients, with a contextual comparison to 160 unresected colorectal liver metastases (CLM) patients. Of 508 patients, 288 (57 %) had CPM alone and 220 (43 %) …

Using A Surgical Risk Predictor To Estimate Percutaneous Cryoablation Adverse Event Risk: A Single Center Comparative Analysis, Prisha Patel, Koustav Pal, Hadi Ahmed, Bill Tang, Iwan Paolucci, Mohammad Khavandi, Peiman Habibollahi, Ketan Shah, Steven Y Huang, Bruno C Odisio, Sanjay Gupta, Kamran Ahrar, Steven Yevich, Joshua D Kuban, Alda Tam, Rahul A Sheth

Faculty, Staff and Student Publications

Objective: To evaluate the relevance of established surgical risk calculators for predicting complications in patients undergoing percutaneous lung cryoablation (PLC).

Methods: The institution's database was queried for PLC procedures from March 2015 to May 2024, excluding those patients with concomitant local therapies or five or more lesions treated in a single setting. Demographics, frailty metrics as defined by the surgical literature, and procedural variables were collected. To evaluate the suitability of surgical risk estimate calculators, the requisite demographic data were input into the American College of Surgery surgical risk calculator; estimates for length of stay (LOS), serious complications, 30-day readmission, …

Natural History Models For Lung Cancer: A Scoping Review, Renu Sara Nargund, Sayaka Ishizawa, Maryam Eghbalizarch, Paul Yeh, Seyyed Mostafa Mousavi Janbeh Saray, Sara Nofal, Yimin Geng, Pianpian Cao, Edwin J Ostrin, Rafael Meza, Martin C Tammemägi, Robert J Volk, Maria A Lopez-Olivo, Iakovos Toumazis

Faculty, Staff and Student Publications

Introduction: Natural history models (NHMs) of lung cancer (LC) simulate the disease's natural progression providing a baseline for assessing the impact of interventions. NHMs have been increasingly used to inform public health policies, highlighting their utility. The objective of this scoping review was to summarize existing LC NHMs, identify their limitations, and propose a framework for future NHM development.

Methods: We searched MEDLINE, Embase, Web of Science, and IEEE Xplore from their inception to October 5, 2023, for peer-reviewed, full-length articles with an LC NHM. Model characteristics, their applications, data sources used, and limitations were extracted and narratively synthesized.

Results: …

Maternal Dysbiosis Produces Long-Lasting Behavioral Changes In Offspring, Jacob Hudobenko, Claudia M Di Gesù, Patrick R Mooz, Joseph Petrosino, Nagireddy Putluri, Bhanu P Ganesh, Kristen Rebeles, Frank W Blixt, Venugopal R Venna, Louise D Mccullough

Faculty, Staff and Student Publications

Advanced maternal age (AMA) is defined as a pregnancy in a woman older than 35 years of age. AMA increases the risk for both maternal and neonatal complications, including miscarriage and stillbirth. AMA has also been linked to neurodevelopmental and neuropsychiatric disorders in the offspring. Recent studies have found that age-associated compositional shifts in the gut microbiota contribute to altered microbial metabolism and enhanced inflammation in the host. We investigated the specific contribution of the maternal microbiome on pregnancy outcomes and offspring behavior by recolonizing young female mice with aged female microbiome prior to pregnancy. We discovered that pre-pregnancy colonization …

Interplay Between Skeletal Muscle Catabolism And Remodeling Of Arteriovenous Fistula By Yes-Associated Protein 1 (Yap1) Signaling, Yongdong Wu, Tae Hoon Lee, Owen H Cheng, Eric K Peden, Qingtian Li, Jun Wang, Fengzhang Huang, Marites P Melancon, David Sheikh-Hamad, Tao Wang, Luan Truong, William E Mitch, Ming Liang, Jizhong Cheng

Faculty, Staff and Student Publications

Key Points:

1. Atrophied muscle–derived myostatin stimulated mesenchymal stem cell differentiation and adverse arteriovenous (AV) fistula remodeling through yes-associated protein 1 (YAP1) activation.

2. Treatment with myostatin peptibody inhibited muscle wasting and blocked mesenchymal stem cell activation and AV fistula fibrosis.

3. A light-sensitive drug-release strategy was engineered for the periadventitial delivery of verteporfin to improve AV fistula patency.

Background: Arteriovenous (AV) fistulas are the preferred access for dialysis but have a high incidence of failure. The aim of this study was to understand the crosstalk between skeletal muscle catabolism and AV fistula maturation failure.

Methods: Skeletal muscle metabolism and AV fistula maturation …

Bilateral Germ Cell Tumor Of The Testis: Biological And Clinical Implications For A Stem Versus Genetic Origin Of Cancers, Jamaal C Jackson, Darren Sanchez, Aron Y Joon, Marcos R Estecio, Andrew C Johns, Amishi Y Shah, Matthew Campbell, John F Ward, Louis L Pisters, Charles C Guo, Miao Zhang, Niki M Zacharias, Shi-Ming Tu

Faculty, Staff and Student Publications

Germ cell tumors of the testis (GCTs) provide an ideal tumor model to investigate the cellular versus genetic origin of cancers. In this single institutional study, we evaluated 38 patients with bilateral GCT, including tumors that occurred simultaneously (synchronous) and those occurring at different times (metachronous). For nine of these patients, DNA was isolated from the right and left GCT to determine the genomic and epigenetic differences between tissues using whole-exome sequencing (WES) and reduced representation bisulfite sequencing (RRBS). We found that seminomas and non-seminomas are molecularly distinct based on DNA methylation and not due to synchronous or metachronous disease. …

The Effects Of Prescribed Medications On Depressive Symptoms And Neurocognitive Performance In People With Hiv, Asante R Kamkwalala, Avery Matthews, Ankita Garg, Upal Roy, Qing Ma, Maile Karris, Erin Sundermann, Ronald J Ellis, Patricia K Riggs, Mattia Trunfio, Jennifer Blanchard, David J Moore, Leah H Rubin, Scott L Letendre

Faculty, Staff and Student Publications

Background: Alterations in brain function and structure, such as depression and neurocognitive impairment, continue to occur in people with human immunodeficiency virus (HIV, PWH) taking suppressive antiretroviral therapy (ART). The lifespan of PWH has improved but the healthspan remains worse than people without HIV, in part because of aging-related diseases. As a result, polypharmacy is common and increases the risk of drug-drug interactions and adverse reactions.

Methods: This cross-sectional project investigated the relationship between 7 medication-related metrics (including anticholinergic burden), depressive symptoms, and neurocognitive performance in 491 PWH at a single center in the United States. All participants were taking …

Overcoming Barriers To Human Papillomavirus Vaccination In Guangdong Province, China, Shuaijing Zhang, Shiqi Li, Jingtai Ma, Guiyuan Ji, Zhifeng Li, Siyi Chen, Fenglin Zhang, Xingfen Yang, Jianpeng Xiao, Rong Cao, Chenggang Wu, Wei Wu

Faculty, Staff and Student Publications

Human papillomavirus (HPV) infection remains a critical public health challenge in China, particularly in Guangdong Province, where HPV-52, 16, and 58 genotypes predominate, and male infection rates exceed 40%. Despite the successful implementation of a government-funded school-based program that has achieved 88% HPV vaccine coverage among adolescent girls, several persistent barriers, including genotype mismatch (the free HPV vaccine covers < 50% of high-risk local strains), regional disparities (80% vs. 60% for first-dose coverage), and exclusion of males, thwart progress toward herd immunity. Financial sustainability risks pose an even more significant threat to the expansion of HPV vaccination programs, especially in Guangdong province where annual expenditures exceed CNY 200 million. This review delves into Guangdong's pioneering efforts and proposes practical solutions: accelerating domestic multivalent HPV vaccine development, adopting gender-neutral vaccination policies, and leveraging mobile clinics for remote populations. These strategies not only provide a roadmap for China but also serve as valuable insight for other LMICs striving to overcome HPV-related inequalities.

An Intranasally Administered Igm Protects Against Antigenically Distinct Subtypes Of Influenza A Viruses, Ashwin Kumar Ramesh, Jwala Priyadarsini Sivaccumar, Xiaohua Ye, Luona Yang, Hailong Guo, Chen-Ni Chin, Sha Ha, John W Shiver, William R Strohl, Yan Xu, Haijuan Du, Tongqing Zhou, Ningyan Zhang, Kai Xu, Xinli Liu, Tong-Ming Fu, Zhiqiang An

Faculty, Staff and Student Publications

Engineering broadly neutralizing monoclonal antibodies (mAbs) targeting the hemagglutinin (HA) of Influenza A virus (IAV) is a promising approach for intervention of seasonal flu. However, HA plasticity often leads to resistant strains that compromise mAb potency as bivalent IgGs. Here we hypothesize that multimerization of anti-IAV antibodies as IgMs can enhance coverage and neutralization potency. Here, we construct 18 IgM antibodies from known broadly neutralizing IgGs targeting different IAV HA epitopes and evaluate their breadth and potency of neutralization against distinct H1N1 and H3N2 IAVs. The IgM version of receptor binding site-specific IgG F045-092 shows increased breadth and antiviral potency …

Enhanced And Interpretable Prediction Of Multiple Cancer Types Using A Stacking Ensemble Approach With Shap Analysis, Shahid Mohammad Ganie, Pijush Kanti Dutta Pramanik, Zhongming Zhao

Faculty, Staff and Student Publications

Background: Cancer is a leading cause of death worldwide, and its early detection is crucial for improving patient outcomes. This study aimed to develop and evaluate ensemble learning models, specifically stacking, for the accurate prediction of lung, breast, and cervical cancers using lifestyle and clinical data.

Methods: 12 base learners were trained on datasets for lung, breast, and cervical cancer. Stacking ensemble models were then developed using these base learners. The models were evaluated for accuracy, precision, recall, F1-score, AUC-ROC, MCC, and kappa. An explainable AI technique, SHAP, was used to interpret model predictions.

Results: The stacking …

The Potential Of Brain Organoids In Addressing The Heterogeneity Of Synucleinopathies, Xiao-Jun Diao, Claudio Soto, Fei Wang, Yu Wang, Yun-Cheng Wu, Abhisek Mukherjee

Faculty, Staff and Student Publications

Synucleinopathies are a group of diseases characterized by neuronal and glial accumulation of α-synuclein (aSyn) linked with different clinical presentations, including Parkinson's disease (PD), Parkinson's disease with dementia (PDD), Dementia with Lewy Bodies (DLB) and Multiple system atrophy (MSA). Interestingly, the structure of the aSyn aggregates can vary across different synucleinopathies. Currently, it is unclear how the aSyn protein can aggregate into diverse structures and affect distinct cell types and various brain regions, leading to different clinical symptoms. Recent advances in induced pluripotent stem cells (iPSCs)-based brain organoids (BOs) technology provide an unprecedented opportunity to define the etiology of synucleinopathies …

Investigative Needle Core Biopsies Support Multimodal Deep-Data Generation In Glioblastoma, Kenny K H Yu, Sreyashi Basu, Gerard Baquer, Ryuhjin Ahn, Jennifer Gantchev, Sonali Jindal, Michael S Regan, Zaki Abou-Mrad, Michael C Prabhu, Marc J Williams, Alicia D D'Souza, Seth W Malinowski, Kelsey Hopland, Yuval Elhanati, Sylwia A Stopka, Alexei Stortchevoi, Charles Couturier, Zhong He, Jingjing Sun, Yulong Chen, Alexsandra B Espejo, Kin Hoe Chow, Smitha Yerrum, Pei-Lun Kao, Brittany Parker Kerrigan, Lisa Norberg, Douglas Nielsen, Vinay K Puduvalli, Jason Huse, Rameen Beroukhim, Betty Y S Kim, Sangeeta Goswami, Adrienne Boire, Sarah Frisken, Michael J Cima, Matthias Holdhoff, Calixto-Hope G Lucas, Chetan Bettegowda, Stuart S Levine, Tejus A Bale, Cameron Brennan, David A Reardon, Frederick F Lang, E Antonio Chiocca, Keith L Ligon, Forest M White, Padmanee Sharma, Viviane Tabar, Nathalie Y R Agar

Faculty, Staff and Student Publications

Glioblastoma (GBM) is an aggressive primary brain cancer with few effective therapies. Stereotactic needle biopsies are routinely used for diagnosis; however, the feasibility and utility of investigative biopsies to monitor treatment response remains ill-defined. Here, we demonstrate the depth of data generation possible from routine stereotactic needle core biopsies and perform highly resolved multi-omics analyses, including single-cell RNA sequencing, spatial transcriptomics, metabolomics, proteomics, phosphoproteomics, T-cell clonotype analysis, and MHC Class I immunopeptidomics on standard biopsy tissue obtained intra-operatively. We also examine biopsies taken from different locations and provide a framework for measuring spatial and genomic heterogeneity. Finally, we investigate the …

Improved Overall Survival In An Anti-Pd-L1 Treated Cohort Of Newly Diagnosed Glioblastoma Patients Is Associated With Distinct Immune, Mutation, And Gut Microbiome Features: A Single Arm Prospective Phase I/Ii Trial, Shiao-Pei Weathers, Xiqi Li, Haifeng Zhu, Ashish V Damania, Mark Knafl, Brian Mckinley, Heather Lin, Rebecca A Harrison, Nazanin K Majd, Barbara J O'Brien, Marta Penas-Prado, Monica Loghin, Carlos Kamiya-Matsuoka, W K Alfred Yung, Luisa M Solis Soto, Dipen M Maru, Ignacio Wistuba, Edwin R Parra Cuentas, Sharia Hernandez, Andrew Futreal, Jennifer A Wargo, Katja Schulze, Walter C Darbonne, Nadim J Ajami, Scott E Woodman, John F De Groot

Faculty, Staff and Student Publications

This phase I/II trial aims to evaluate the efficacy of concurrent atezolizumab with radiation therapy and temozolomide (TMZ) followed by adjuvant atezolizumab and TMZ in newly diagnosed glioblastoma (GBM) patients and to identify pre-treatment correlates with outcome (N = 60). Trial number: NCT03174197. The primary outcome was overall survival (OS) whereas secondary outcomes were retrospective global-omics analyses to identify pre-treatment immune and genetic tumor features that correlated with survival. Concurrent use of atezolizumab with radiation and TMZ demonstrated OS in line with published trials for newly diagnosed GBM. Tumor genomic (WES and/or targeted NGS panel), transcriptomic (RNAseq) and tissue microenvironment …

Building A Pre-Surgical Multiparametric-Mri-Based Morphologic, Qualitative, Semiquantitative, First And High-Order Radiomic Predictive Treatment Response Model For Undifferentiated Pleomorphic Sarcoma To Replace Recist, Raul F Valenzuela, Elvis Duran-Sierra, Mathew Antony, Behrang Amini, Sam Lo, Keila E Torres, Robert S Benjamin, Jingfei Ma, Ken-Pin Hwang, R Jason Stafford, Dejka Araujo, Andrew J Bishop, Ravin Ratan, Wei-Lien Wang, Jossue Espinoza, Pia V Valenzuela, Chengyue Wu, John E Madewell, William A Murphy, Colleen M Costelloe

Faculty, Staff and Student Publications

Background: Undifferentiated pleomorphic sarcoma (UPS) is the largest subgroup of soft-tissue sarcomas. It demonstrates post-therapeutic hemosiderin deposition, granulation tissue formation, fibrosis, and calcification. Our research aims to establish the multiparametric MRI (mp-MRI) value for predicting UPS treatment response.

Methods: An IRB-approved retrospective study included 33 extremity UPS patients with pre-operative mp-MRI, including diffusion-weighted imaging (DWI), contrast-enhanced susceptibility-weighted imaging (CE-SWI), and perfusion-weighted imaging with dynamic contrast-enhancement (PWI/DCE), and surgical resection between February 2021 and May 2023. Lesions were visually classified on CE-SWI into one of 6 morphology patterns. On PWI/DCE, lesions were classified into one of 6 patterns, and time-intensity curves …

Acute Brcaness Induction And Ar Pathway Blockage Through Cdk12/7/9 Degradation Enhances Parp Inhibitor Sensitivity In Prostate Cancer, Fu Gui, Baishan Jiang, Jie Jiang, Zhixiang He, Takuya Tsujino, Tomoaki Takai, Seiji Arai, Celine Pana, Jens Köllermann, Gary Andrew Bradshaw, Robyn Eisert, Marian Kalocsay, Anne Fassl, Steven P Balk, Adam S Kibel, Li Jia

Faculty, Staff and Student Publications

Current treatments for advanced prostate cancer (PCa) primarily target the androgen receptor (AR) pathway. However, the emergence of castration-resistant prostate cancer (CRPC) and resistance to AR pathway inhibitors (APPIs) remains ongoing challenges. Here, we present BSJ-5-63, a proteolysis-targeting chimera (PROTAC) targeting cyclin-dependent kinases (CDKs) CDK12, CDK7, and CDK9, offering a multipronged approach to CRPC therapy. BSJ-5-63 degrades CDK12, diminishing BRCA1 and BRCA2 expression and inducing a sustained "BRCAness" state. This sensitizes cancer cells to PARP inhibitors (PARPis) regardless of their homologous recombination repair (HRR) status. Furthermore, CDK7 and CDK9 degradation attenuates AR signaling, enhancing its therapeutic efficacy. Preclinical studies, including …

A Pioneering Artificial Intelligence Tool To Predict Treatment Outcomes In Ovarian Cancer Via Diagnostic Laparoscopy, Xiaotian Ma, Yu-Chun Hsu, Amma Asare, Kai Zhang, Deanna Glassman, Katelyn F Handley, Katherine Foster, Khwahish Sharma, Shannon Westin, Amir Jazaeri, Nicole D Fleming, Pratip K Bhattacharya, Xiaoqian Jiang, Anil K Sood, Shayan Shams

Faculty, Staff and Student Publications

Ovarian cancer is associated with high rates of patient mortality and morbidity. Laparoscopic assessment of tumor localization can be used for treatment planning in newly diagnosed high-grade serous ovarian carcinoma (HGSOC). While spread to multiple intra-abdominal areas is correlated with worse outcomes, whether other morphological tumor differences are also associated with patient outcomes is unknown. Given the large volume of visual information in laparoscopic videos, we investigated whether deep-learning models can capture implicit features and predict treatment outcomes. We developed a novel deep-learning framework using pre-treatment laparoscopic images to assess clinical outcomes following upfront standard treatment, defined as short progression-free …

The Dynamic Immune Behavior Of Primary And Metastatic Ovarian Carcinoma, Elaine Stur, Fuduan Peng, Pang-Ning Teng, Emine Bayraktar, Min Hu, Sara Corvigno, David J Brown, Sanghoon Lee, Kathleen N Moore, Nicholas W Bateman, Kathleen M Darcy, George L Maxwell, Thomas P Conrads, Nidhi Sahni, Ignacio Vázquez-García, Sohrab P Shah, Joseph Celestino, Nicole D Fleming, Nicholas E Navin, Linghua Wang, Anil K Sood

Faculty, Staff and Student Publications

Patients with high-grade serous ovarian carcinoma (HGSC) are usually diagnosed with advanced-stage disease, and the tumors often have immunosuppressive characteristics. Together, these factors are important for disease progression, drug resistance, and mortality. In this study, we used a combination of single-cell sequencing and spatial transcriptomics to identify the molecular mechanisms that lead to immunosuppression in HGSC. Primary tumors consistently showed a more active immune microenvironment than did omental tumors. In addition, we found that untreated primary tumors were mostly populated by dysfunctional CD4 and CD8 T cells in later stages of differentiation; this, in turn, was correlated with expression changes …

Idh Status Dictates Ohsv Mediated Metabolic Reprogramming Affecting Anti-Tumor Immunity, Upasana Sahu, Matthew P Mullarkey, Sara A Murphy, Joshua C Anderson, Vasanta Putluri, Abu Hena Mostafa Kamal, Jun Hyoung Park, Tae Jin Lee, Alexander L Ling, Benny A Kaipparettu, Ashok Sharma, Nagireddy Putluri, Pamela L Wenzel, Christopher D Willey, E Antonio Chiocca, James M Markert, Balveen Kaur

Faculty, Staff and Student Publications

Identification of isocitrate dehydrogenase (IDH) mutations has uncovered the crucial role of metabolism in gliomagenesis. Oncolytic herpes virus (oHSV) initiates direct tumor debulking by tumor lysis and activates anti-tumor immunity, however, little is known about the role of glioma metabolism in determining oHSV efficacy. Here we identify that oHSV rewires central carbon metabolism increasing glucose utilization towards oxidative phosphorylation and shuttling glutamine towards reductive carboxylation in IDH wildtype glioma. The switch in metabolism results in increased lipid synthesis and cellular ROS. PKC induces ACSL4 in oHSV treated cells leading to lipid peroxidation and ferroptosis. Ferroptosis is critical to launch an …

High-Grade Astrocytoma With Piloid Features: A Single-Institution Case Series And Literature Review, Eric A Goethe, Subhiksha Srinivasan, Swaminathan Kumar, Sujit S Prabhu, Maria A Gubbiotti, Sherise D Ferguson

Faculty, Staff and Student Publications

High-grade astrocytoma with piloid features (HGAP) is a recently described primary brain tumor and the first requiring a specific methylation pattern for diagnosis, as its histologic features are often compatible with other tumors such as glioblastoma (GBM). Characterized by molecular alterations in CDKN2A/B, NF1, BRAF, FGFR1, and ATRX, they may be located anywhere in the CNS but show a predilection for the posterior fossa. Reports are limited to retrospective case series, and the standard of care is not yet established. We performed a retrospective review of electronic medical records of all patients with HGAP at our institution. Records were queried …

Impact Of Antidiabetic Medication Type On A New Episode Of Depression: A Retrospective Cohort Study In Texas, Usa, Lin-Na Chou, Mukaila A Raji, Holly M Holmes, Yong-Fang Kuo

Faculty, Staff and Student Publications

Objectives: To examine the associations between antidiabetic medication type and a new episode of depression using 100% Texas Medicare database during 2009 and 2018.

Design: A retrospective cohort study.

Setting: A population-based study using the Texas Medicare data.

Interventions: 11 common antihyperglycaemic medication types, alone and in combinations: metformin-only, five non-metformin-containing regimens (dipeptidyl peptidase-4 inhibitor (DPP4i) only, sulfonylureas (SU) only, thiazolidinediones (TZD) only, SU/DPP4i and SU/TZD) and five metformin-containing combination treatments (metformin/DPP4i, metformin/SU, metformin/TZD, metformin/SU/DPP4i and metformin/SU/TZD).

Participants: This study included 59 057 type 2 diabetes (T2D) patients from a cohort of Texas Medicare beneficiaries who were aged ≥66 years, …

Ensemble Learning With Explainable Ai For Improved Heart Disease Prediction Based On Multiple Datasets, Shahid Mohammad Ganie, Pijush Kanti Dutta Pramanik, Zhongming Zhao

Faculty, Staff and Student Publications

Heart disease is one of the leading causes of death worldwide. Predicting and detecting heart disease early is crucial, as it allows medical professionals to take appropriate and necessary actions at earlier stages. Healthcare professionals can diagnose cardiac conditions more accurately by applying machine learning technology. This study aimed to enhance heart disease prediction using stacking and voting ensemble methods. Fifteen base models were trained on two different heart disease datasets. After evaluating various combinations, six base models were pipelined to develop ensemble models employing a meta-model (stacking) and a majority vote (voting). The performance of the stacking and voting …

Tobacco Smoking Functional Networks: A Whole-Brain Connectome Analysis In 24 539 Individuals, Yezhi Pan, Chuan Bi, Zhenyao Ye, Hwiyoung Lee, Jiaao Yu, Luba Yammine, Tianzhou Ma, Peter Kochunov, L Elliot Hong, Shuo Chen

Faculty, Staff and Student Publications

Introduction: Nicotine addiction, a multifaceted neuropsychiatric disorder, profoundly impacts brain functions through interactions with neural pathways. Despite its significance, the impact of tobacco smoking on the whole-brain functional connectome remains largely unexplored.

Aims and methods: We conducted a whole-brain analysis on 24 539 adults aged 40 and above from the United Kingdom Biobank cohort. Subjects were categorized into individuals who use nicotine and those who do not use nicotine based on current and chronic tobacco smoking information. Functional connectivity was assessed using resting-state functional magnetic resonance imaging. We employed a network analysis method to assess the systematic effects of tobacco …