Medical Specialties Commons^™

Epigenome Reprogramming Through H3k27 And H3k4 Trimethylation As A Resistance Mechanism To Dna Methylation Inhibition In Brafv600e-Mutated Colorectal Cancer, Hey Min Lee, Ajay Kumar Saw, Van K Morris, Stefania Napolitano, Christopher Bristow, Sanjana Srinivasan, Micheal Peoples, Alexey Sorokin, Preeti Kanikarla Marie, Jonathan Schulz, Anand K Singh, Christopher Terranova, Oluwadara Coker, Abhinav Jain, Scott Kopetz, Kunal Rai

Faculty, Staff and Student Publications

Purpose: BRAFV600E-mutated colorectal cancer exhibits a strong correlation with DNA hypermethylation, suggesting that this subgroup of tumors presents unique epigenomic phenotypes. Nonetheless, 5-azacitidine, which inhibits DNA methyltransferase activity, is not efficacious in BRAFV600E colorectal cancer in vivo.

Experimental design: We randomized and treated mice implanted with patient-derived tumor xenografts harboring BRAFV600E mutation with control, 5-azacitidine, vemurafenib (BRAF inhibitor), or the combination. Comprehensive epigenomic profiling was conducted on control and 5-azacitidine-treated tumor samples, including DNA methylation, histone modifications, chromatin accessibility, and gene expression. Combinations of epigenetic agents were explored in preclinical BRAFV600E colorectal cancer models.

Results: A profound reduction of DNA …

Sample Multiplexing For Retinal Single-Cell Rna Sequencing, Justin Ma, Ting-Kuan Chu, Maria Polo-Prieto, Yong H Park, Yumei Li, Rui Chen, Graeme Mardon, Benjamin J Frankfort, Nicholas M Tran

Faculty, Staff and Students Publications

Rare cell populations can be challenging to characterize using microfluidic single-cell RNA sequencing (scRNA-seq) platforms. Typically, the population of interest must be enriched and pooled from multiple biological specimens for efficient collection. However, these practices preclude the resolution of sample origin together with phenotypic data and are problematic in experiments in which biological or technical variation is expected to be high (e.g., disease models, genetic perturbation screens, or human samples). One solution is sample multiplexing whereby each sample is tagged with a unique sequence barcode that is resolved bioinformatically. We have established a scRNA-seq sample multiplexing pipeline for mouse retinal …

Oncolytic Virotherapies And Adjuvant Gut Microbiome Therapeutics To Enhance Efficacy Against Malignant Gliomas, Natalie M Meléndez-Vázquez, Candelaria Gomez-Manzano, Filipa Godoy-Vitorino

Faculty, Staff and Student Publications

Glioblastoma (GBM) is the most prevalent malignant brain tumor. Current standard-of-care treatments offer limited benefits for patient survival. Virotherapy is emerging as a novel strategy to use oncolytic viruses (OVs) for the treatment of GBM. These engineered and non-engineered viruses infect and lyse cancer cells, causing tumor destruction without harming healthy cells. Recent advances in genetic modifications to OVs have helped improve their targeting capabilities and introduce therapeutic genes, broadening the therapeutic window and minimizing potential side effects. The efficacy of oncolytic virotherapy can be enhanced by combining it with other treatments such as immunotherapy, chemotherapy, or radiation. Recent studies …

Evidence That Crispr-Cas9 Y537s-Mutant Expressing Breast Cancer Cells Activate Yes-Associated Protein 1 To Driving The Conversion Of Normal Fibroblasts Into Cancer-Associated Fibroblasts, Luca Gelsomino, Amanda Caruso, Emine Tasan, Adele Elisabetta Leonetti, Rocco Malivindi, Giuseppina Daniela Naimo, Francesca Giordano, Salvatore Panza, Guowei Gu, Benedetta Perrone, Cinzia Giordano, Loredana Mauro, Bruno Nardo, Gianfranco Filippelli, Daniela Bonofiglio, Ines Barone, Suzanne A W Fuqua, Stefania Catalano, Sebastiano Andò

Faculty, Staff and Students Publications

BACKGROUND: Endocrine therapy (ET) has improved the clinical outcomes of Estrogen receptor alpha-positive (ERɑ +) breast cancer (BC) patients, even though resistance to ET remains a clinical issue. Mutations in the hormone-binding domain of ERɑ represent an acquired intrinsic mechanism of ET resistance. However, the latter also depends on the multiple functional interactions between BC cells and the tumor microenvironment (TME). Here, we investigated how the most common Y537S-ERɑ mutation may influence the behavior of fibroblasts, the most prominent component of the TME.

METHODS: We conducted coculture experiments with normal human foreskin fibroblasts BJ1-hTERT (NFs), cancer-associated fibroblasts (CAFs), isolated from …

Observing The Impacts Of Different Diets On Clinical Outcomes In Patients With Alzheimer's Disease: A Scoping Review, Erjola Toska, Alessandra Ottley, Quinn Jackson, Rachel Fricker, Alexa Carleo, Gabriella Cutrali, Olivia D’Alessio, Raquel Rossman, Samuel Kruchakov, Abraham Edelstein, Lubov Nathanson

HCA-NSU MD Research Day

Observing the Impacts of Different Diets on Clinical Outcomes in patients with Alzheimer's disease: A Scoping Review Authors: Quinn Jackson, OMS-III; Rachel Fricker,OMS-III; Erjola Toska, OMS-III; Alessandra Ottley,OMS-III; Alexa Carleo,OMS-III; Gabriella Cutrali, OMS-III; Olivia D’Alessio, OMS-III; Raquel Rossman, OMS-III; Samuel Kruchakov, OMS-III; Abraham Edelstein,OMS-III; Lubov Nathanson, Ph.D. Program: Nova Southeastern University Dr. Kiran C. Patel College of Osteopathic Medicine, Florida Objectives: This study aimed to assess the literature published from 2013 to 2023 on the impact of diet on Alzheimer’s Disease (AD). Background: AD is primarily marked by β-amyloid plaques and neurofibrillary tangles, which impair neuronal synapses, leading to memory …

The Role Of Kctd13 In Androgen Receptor Ubiquitination​, Faith Abraham, Ahmed Chahdi, Phd, Carolina Jorgez, Phd, Abhishek Seth

HCA-NSU MD Research Day

The Role of KCTD13 in Androgen Receptor Ubiquitination Faith Abraham1, Ahmed Chahdi, PhD2, Caroline Jorgez, PhD3, and Abhishek Seth, MD2 1Class of 2024, Dr. Kiran C. Patel College of Osteopathic Medicine, 2Urology, Nemours Children’s Hospital, Orlando, FL 3Urology, Baylor College of Medicine, Houston, TX Objective: This study was conducted to determine the effect of the KCTD13 gene on major protein effectors of common genitourinary (GU) defects. Background: Hypospadias, characterized by the ventral positioning of the urethral opening, occurs in approximately 1 out of 125 live births. Cryptorchidism, or undescended testes (UDT), is the most common GU birth defect, affecting around …

Ar (Cag)N Microsatellite And Apex1 C444t>G (Pasp148glu) Polymorphisms As Independent Prognostic Biomarkers In Prostate Cancer: Insights From An Argentinian Cohort, Gaston Pascual, Agustina Sabater, Juan Bizzotto, Rocio Seniuk, Pablo Sanchis, Sabrina Ledesma-Bazan, Estefania Labanca, Carlos Scorticati, Osvaldo Mazza, Elba Vazquez, Ayelen Toro, Federico Prada, Geraldine Gueron, Javier Cotignola

Faculty, Staff and Student Publications

Background/objectives: Prostate cancer (PCa) is the leading malignancy and the third most common cause of cancer-related death in Argentinian men. Predicting outcomes in localized PCa remains difficult due to tumor heterogeneity. In this study, we assessed the impact of AR (CAG)n and APEX1 c.444T>G polymorphisms on biochemical relapse in Argentine patients with localized PCa.

Methods: We genotyped blood samples from 123 PCa patients for AR (CAG)n and APEX1 p.Asp148Glu (c.444T>G) polymorphisms. Associations with clinicopathological parameters and biochemical relapse-free survival (BRFS) were assessed.

Results: AR (CAG)20-23 was associated with a family history of breast/ovarian cancer (p = 0.0469). …

The Il-1Β Inhibitor Canakinumab In Previously Treated Lower-Risk Myelodysplastic Syndromes: A Phase 2 Clinical Trial, Juan Jose Rodriguez-Sevilla, Vera Adema, Kelly S Chien, Sanam Loghavi, Feiyang Ma, Hui Yang, Guillermo Montalban-Bravo, Xuelin Huang, Xavier Calvo, Joby Joseph, Kristy Bodden, Guillermo Garcia-Manero, Simona Colla

Faculty, Staff and Student Publications

In myelodysplastic syndromes (MDS), the IL-1β pathway is upregulated, and previous studies using mouse models of founder MDS mutations demonstrated that it enhances hematopoietic stem and progenitor cells' (HSPCs') aberrant differentiation towards the myeloid lineage at the expense of erythropoiesis. To evaluate whether targeting the IL-1β signaling pathway can rescue ineffective erythropoiesis in patients with MDS, we designed a phase 2 non-randomized single-arm clinical trial (NCT04239157) to assess the safety profile and efficacy of the IL-1β inhibitor canakinumab in previously treated lower-risk MDS patients. We enrolled 25 patients with a median age of 74 years; 60% were male, 16% had …

Long-Read Sequencing Of An Advanced Cancer Cohort Resolves Rearrangements, Unravels Haplotypes, And Reveals Methylation Landscapes, Kieran O'Neill, Erin Pleasance, Jeremy Fan, Vahid Akbari, Glenn Chang, Katherine Dixon, Veronika Csizmok, Signe Maclennan, Vanessa Porter, Andrew Galbraith, Cameron J Grisdale, Luka Culibrk, John H Dupuis, Richard Corbett, James Hopkins, Reanne Bowlby, Pawan Pandoh, Duane E Smailus, Dean Cheng, Tina Wong, Connor Frey, Yaoqing Shen, Eleanor Lewis, Luis F Paulin, Fritz J Sedlazeck, Jessica M T Nelson, Eric Chuah, Karen L Mungall, Richard A Moore, Robin Coope, Andrew J Mungall, Melissa K Mcconechy, Laura M Williamson, Kasmintan A Schrader, Stephen Yip, Marco A Marra, Janessa Laskin, Steven J M Jones

Faculty, Staff and Students Publications

The Long-Read Personalized OncoGenomics (POG) dataset comprises a cohort of 189 patient tumors and 41 matched normal samples sequenced using the Oxford Nanopore Technologies PromethION platform. This dataset from the POG program and the Marathon of Hope Cancer Centres Network includes DNA and RNA short-read sequence data, analytics, and clinical information. We show the potential of long-read sequencing for resolving complex cancer-related structural variants, viral integrations, and extrachromosomal circular DNA. Long-range phasing facilitates the discovery of allelically differentially methylated regions (aDMRs) and allele-specific expression, including recurrent aDMRs in the cancer genes RET and CDKN2A. Germline promoter methylation in MLH1 can …

Genetically Determined Telomere Length In Monoclonal Gammopathy Of Undetermined Significance, Multiple Myeloma Risk And Outcome, Matteo Giaccherini, Alyssa I Clay-Gilmour, Romano Liotti, Angelica Macauda, Manuel Gentiluomo, Elizabeth E Brown, Mitchell J Machiela, Stephen J Chanock, Michelle A T Hildebrandt, Aaron D Norman, Elisabet Manasanch, S Vincent Rajkumar, Jonathan N Hofmann, Sonja I Berndt, Parveen Bhatti, Graham G Giles, Elad Ziv, Shaji K Kumar, Nicola J Camp, Wendy Cozen, Susan L Slager, Federico Canzian, Federica Gemignani, Celine M Vachon, Daniele Campa

Faculty, Staff and Student Publications

No abstract provided.

Addition Of Metastasis-Directed Therapy To Systemic Therapy For Oligometastatic Pancreatic Ductal Adenocarcinoma (Extend): A Multicenter, Randomized Phase Ii Trial, Ethan B Ludmir, Alexander D Sherry, Bryan M Fellman, Suyu Liu, Tharakeswara Bathala, Cara Haymaker, Marina N Medina-Rosales, Alexandre Reuben, Emma B Holliday, Grace L Smith, Sonal S Noticewala, Sarah Nicholas, Tracy R Price, Rachael M Martin-Paulpeter, Luis A Perles, Sunyoung S Lee, Michael S Lee, Brandon G Smaglo, Ryan W Huey, Jason Willis, Dan Zhao, Lorenzo Cohen, Cullen M Taniguchi, Eugene J Koay, Matthew H G Katz, Robert A Wolff, Prajnan Das, Shubham Pant, Albert C Koong, Chad Tang

Faculty, Staff and Student Publications

Purpose: The EXTEND trial tested the hypothesis that adding comprehensive metastasis-directed therapy (MDT) to chemotherapy would improve progression-free survival (PFS) over chemotherapy alone among patients with oligometastatic pancreatic ductal adenocarcinoma (PDAC).

Methods: EXTEND (ClinicalTrials.gov identifier: NCT03599765) is a multicenter, phase II basket trial randomly assigning patients with ≤five metastases 1:1 to MDT plus systemic therapy versus systemic therapy. Disease progression was defined by radiologic criteria (RECIST v1.1), clinical progression, or death. The primary end point was PFS in the per-protocol population, evaluated after all patients achieved at least 6 months of follow-up. Exploratory end points included systemic immune response …

Validation Of A Prognostic Blood-Based Sphingolipid Panel For Men With Localized Prostate Cancer Followed On Active Surveillance, Justin R Gregg, Lisa Newcomb, Ranran Wu, Jennifer Dennison, John W Davis, Curtis Pettaway, Louis Pisters, John F Ward, Brian F Chapin, Lisly Chéry, Ahmet Urkmez, Andrew M Fang, Noel Higgason, Patricia Troncoso, Carrie R Daniel, Christopher Logothetis, Timothy C Thompson, Andrew W Hahn, Menghan Liu, Yingye Zheng, Dan W Lin, Samir Hanash, Ehsan Irajizad, Johannes Fahrmann

Faculty, Staff and Student Publications

Background: We previously reported that increases in circulating sphingolipids are associated with elevated risk of biopsy Gleason grade group (GG) upgrading in men on Active Surveillance (AS) for prostate cancer. Here, we aimed to validate these findings and establish a blood-based sphingolipid biomarker panel for identifying men on AS who are at high-risk of biopsy GG upgrading.

Methods: Men diagnosed with low- or intermediate-risk prostate cancer in one of two AS cohorts (CANARY PASS and MDACC) were followed for GG upgrading after diagnostic and confirmatory biopsy. The PASS cohort consisted of 544 patients whereas the MDACC Cohort consisted of 697 …

The Rna Receptor Rig-I Binding Synthetic Oligodeoxynucleotide Promotes Pneumonia Survival, Yongxing Wang, Vikram V Kulkarni, Jezreel Pantaleóngarcía, Michael K Longmire, Mathilde Lethier, Stephen Cusack, Scott E Evans

Faculty, Staff and Student Publications

Pneumonia is a worldwide threat to public health, demanding novel preventative and therapeutic strategies. The lung epithelium is a critical environmental interface that functions as a physical barrier to pathogen invasion while also actively sensing and responding to pathogens. We have reported that stimulating lung epithelial cells with a combination therapeutic consisting of a diacylated lipopeptide and a synthetic CpG oligodeoxynucleotide (ODN) induces synergistic pneumonia protection against a wide range of pathogens. We report here that mice deficient in TLR9, the previously described receptor for ODN, still displayed partial ODN-induced protection. This prompted us to seek an alternate ODN receptor, …

Unlocking Intracellular Oncology Targets: The Unique Role Of Antibody-Based T-Cell Receptor Mimic (Tcrm) Therapeutics In T-Cell Engagers (Tces) And Antibody-Drug Conjugates (Adcs), Jeffrey Molldrem, Dongxing Zha

Faculty, Staff and Student Publications

Effectively targeting intracellular tumor-associated proteins presents a formidable challenge in oncology, as they are traditionally considered inaccessible to conventional antibody-based therapies and CAR-T cell therapies. However, recent advancements in antibody engineering have revolutionized this field, offering promising new strategies to combat cancer. This review focuses on the innovative use of T-cell receptor mimic (TCRm) antibodies within the therapeutic frameworks of T-cell engagers (TCE) and antibody-drug conjugates (ADCs). TCRm antibodies, designed to recognize peptide-MHC complexes rather than cell surface proteins, integrate the capacity of T-cells to reach intracellular targets with the unique strengths of antibodies. When incorporated into T-cell engaging therapeutics, …

Genomic Insights For Personalised Care In Lung Cancer And Smoking Cessation: Motivating At-Risk Individuals Toward Evidence-Based Health Practices, Tony Chen, Giang Pham, Louis Fox, Nina Adler, Xiaoyu Wang, Jingning Zhang, Jinyoung Byun, Younghun Han, Gretchen R B Saunders, Dajiang Liu, Michael J Bray, Alex T Ramsey, James Mckay, Laura J Bierut, Christopher I Amos, Rayjean J Hung, Xihong Lin, Haoyu Zhang, Li-Shiun Chen

Faculty, Staff and Students Publications

BACKGROUND: Lung cancer and tobacco use pose significant global health challenges, necessitating a comprehensive translational roadmap for improved prevention strategies such as cancer screening and tobacco treatment, which are currently under-utilised. Polygenic risk scores (PRSs) may further motivate health behaviour change in primary care for lung cancer in diverse populations. In this work, we introduce the GREAT care paradigm, which integrates PRSs within comprehensive patient risk profiles to motivate positive health behaviour changes.

METHODS: We developed PRSs using large-scale multi-ancestry genome-wide association studies and standardised PRS distributions across all ancestries. We validated our PRSs in 561,776 individuals of diverse ancestry …

Real-World Impact Of Differences In The Who And Icc Classifications Of Non-Hodgkin Lymphoma: A Leo Cohort Study Analysis, Brooj Abro, Matthew J Maurer, Thomas M Habermann, W Richard Burack, Jennifer R Chapman, Jonathon B Cohen, Jonathan W Friedberg, Giorgio Inghirami, Brad S Kahl, Melissa C Larson, Brian K Link, Izidore S Lossos, Peter Martin, Timothy J Mcdonnell, Loretta J Nastoupil, Shaun M Riska, Sergei Syrbu, Francisco Vega, Kiran R Vij, Christopher R Flowers, James R Cerhan, David L Jaye, Andrew L Feldman

Faculty, Staff and Student Publications

Recent introduction of 2 different lymphoma classifications has raised concerns about consistency in diagnosis, management, and clinical trial enrollment. Data from a large cohort reflecting real-world clinical practice suggest that differences between the classifications will affect < 1% of non-Hodgkin lymphomas.

Probabilistic Presurgical Language Fmri Atlas Of Patients With Brain Tumors, Jian Ming Teo, Vinodh A Kumar, Jina Lee, Rami W Eldaya, Ping Hou, Mu-Lan Jen, Kyle R Noll, Peng Wei, Sherise D Ferguson, Sujit S Prabhu, Max Wintermark, Ho-Ling Liu

Faculty, Staff and Student Publications

Background and purpose: Patients with brain tumors have high intersubject variation in putative language regions, which may limit the utility of straightforward application of healthy subject brain atlases in clinical scenarios. The purpose of this study was to develop a probabilistic functional brain atlas that consolidates language functional activations of sentence completion and Silent Word Generation language paradigms using a large sample of patients with brain tumors.

Materials and methods: The atlas was developed using retrospectively collected fMRI data from patients with brain tumors who underwent their first standard-of-care presurgical language fMRI scan at our institution between July 18, 2015, …

Homozygous Variants In Wdr83os Lead To A Neurodevelopmental Disorder With Hypercholanemia, Scott Barish, Sheng-Jia Lin, Reza Maroofian, Alper Gezdirici, Hamoud Alhebby, Aurélien Trimouille, Marta Biderman Waberski, Tadahiro Mitani, Ilka Huber, Kristian Tveten, Øystein L Holla, Øyvind L Busk, Henry Houlden, Ehsan Ghayoor Karimiani, Mehran Beiraghi Toosi, Reza Shervin Badv, Paria Najarzadeh Torbati, Fatemeh Eghbal, Javad Akhondian, Ayat Al Safar, Abdulrahman Alswaid, Giovanni Zifarelli, Peter Bauer, Dana Marafi, Jawid M Fatih, Kevin Huang, Cassidy Petree, Daniel G Calame, Charlotte Von Der Lippe, Fowzan S Alkuraya, Sami Wali, James R Lupski, Gaurav K Varshney, Jennifer E Posey, Davut Pehlivan

Faculty, Staff and Students Publications

WD repeat domain 83 opposite strand (WDR83OS) encodes the 106-aa (amino acid) protein Asterix, which heterodimerizes with CCDC47 to form the PAT (protein associated with ER translocon) complex. This complex functions as a chaperone for large proteins containing transmembrane domains to ensure proper folding. Until recently, little was known about the role of WDR83OS or CCDC47 in human disease traits. However, biallelic variants in CCDC47 were identified in four unrelated families with trichohepatoneurodevelopmental syndrome, characterized by a neurodevelopmental disorder (NDD) with liver dysfunction. Three affected siblings in an additional family share a homozygous truncating WDR83OS variant and a phenotype of …

Large-Scale Application Of Clingen-Insight Apc-Specific Acmg/Amp Variant Classification Criteria Leads To Substantial Reduction In Vus, Xiaoyu Yin, Marcy Richardson, Andreas Laner, Xuemei Shi, Elisabet Ognedal, Valeria Vasta, Thomas V O Hansen, Marta Pineda, Deborah Ritter, Johan De Dunnen, Emadeldin Hassanin, Wencong Lyman Lin, Ester Borras, Karl Krahn, Margareta Nordling, Alexandra Martins, Khalid Mahmood, Emily Nadeau, Victoria Beshay, Carli Tops, Maurizio Genuardi, Tina Pesaran, Ian M Frayling, Gabriel Capellá, Andrew Latchford, Sean V Tavtigian, Carlo Maj, Sharon E Plon, Marc S Greenblatt, Finlay A Macrae, Isabel Spier, Stefan Aretz

Faculty, Staff and Students Publications

Pathogenic constitutional APC variants underlie familial adenomatous polyposis, the most common hereditary gastrointestinal polyposis syndrome. To improve variant classification and resolve the interpretative challenges of variants of uncertain significance (VUSs), APC-specific variant classification criteria were developed by the ClinGen-InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel (VCEP) based on the criteria of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP). A streamlined algorithm using the APC-specific criteria was developed and applied to assess all APC variants in ClinVar and the International Society for Gastrointestinal Hereditary Tumours (InSiGHT) international reference APC Leiden Open Variation …

Skn-1 Activation During Infection Of Caenorhabditis Elegans Requires Cdc-48 And Endoplasmic Reticulum Proteostasis, Carolaing Gabaldón, Ozgur Karakuzu, Danielle A Garsin

Faculty, Staff and Student Publications

During challenge of Caenorhabditis elegans with human bacterial pathogens such as Pseudomonas aeruginosa and Enterococcus faecalis, the elicited host response can be damaging if not properly controlled. The activation of Nrf (nuclear factor erythroid-related factor)/CNC (Cap-n-collar) transcriptional regulators modulates the response by upregulating genes that neutralize damaging molecules and promote repair processes. Activation of the C. elegans Nrf ortholog, SKN-1, is tightly controlled by a myriad of regulatory mechanisms, but a central feature is an activating phosphorylation accomplished by the p38 mitogen-activated kinase (MAPK) cascade. In this work, loss of CDC-48, an AAA+ ATPase, was observed to severely compromise SKN-1 …

Gpr56: Gpcr As A Guardian Against Ferroptosis, Yuelong Yan, Li Zhuang, Boyi Gan

Faculty, Staff and Student Publications

Transmembrane receptor proteins are proficient in sensing external signals and initiating downstream pathways to control cell survival. Lin et al. demonstrated that GPR56, a G-protein-coupled receptor, can be activated by its agonist to suppress ferroptosis-a form of cell death-and effectively mitigate ferroptosis-associated liver damage.

Mitral Annular Disjunction In Heritable Thoracic Aortic Disease: Insights From The Montalcino Aortic Consortium, Kishan L Asokan, Jennifer R Landes, Wannes Renders, Laura Muiño Mosquera, Julie De Backer, David W Jantzen, Anji T Yetman, Gisela Teixido-Tura, Arturo Evangelista, Richmond Jeremy, Edward G Jones, Shaine Morris, Tam Doan, Maral Ouzonian, Alan Braverman, Guillaume Jondeau, Olivier Milleron, Dianna M Milewicz, Siddharth K Prakash

Faculty, Staff and Student Publications

Background: Mitral annular disjunction (MAD), posterior displacement of the mitral valve leaflet hinge point, predisposes to arrhythmias or sudden cardiac death. We evaluated the burden of MAD, mitral valve prolapse (MVP), and mitral regurgitation (MR) by heritable thoracic aortic disease gene in a cross-sectional analysis of 2014-2023 data in the Montalcino Aortic Consortium registry.

Methods and results: MAD was determined by direct measurement of echocardiographic images. MR and MVP were defined according to current clinical guidelines. Associations were evaluated using χ2 or Fisher exact tests. MR and MVP were enriched in Montalcino Aortic Consortium participants (672) with pathogenic variants (PV) …

White Matter Hyperintensities And Mild Tbi In Post-9/11 Veterans And Service Members, David F Tate, Erin D Bigler, Gerald E York, Mary R Newsome, Brian A Taylor, Andrew R Mayer, Mary Jo Pugh, Angela P Presson, Zhining Ou, Elizabeth S Hovenden, Josephine Dimanche, Tracy J Abildskov, Rajan Agarwal, Heather G Belanger, Aaron M Betts, Timothy Duncan, Blessen C Eapen, Carlos A Jaramillo, Michael Lennon, Jennifer E Nathan, Randall S Scheibel, Matthew B Spruiell, William C Walker, Elisabeth A Wilde

Faculty, Staff and Student Publications

Introduction: The neurobehavioral significance of white matter hyperintensities (WMHs) seen on magnetic resonance imaging after traumatic brain injury (TBI) remains unclear, especially in Veterans and Service Members with a history of mild TBI (mTBI). In this study, we investigate the relation between WMH, mTBI, age, and cognitive performance in a large multisite cohort from the Long-term Impact of Military-relevant Brain Injury Consortium-Chronic Effects of Neurotrauma Consortium.

Materials and methods: The neuroimaging and neurobehavioral assessments for 1,011 combat-exposed, post-9/11 Veterans and Service Members (age range 22-69 years), including those with a history of at least 1 mTBI (n = 813; median …

Genetic Risk Factors Underlying White Matter Hyperintensities And Cortical Atrophy, Yash Patel, Jean Shin, Eeva Sliz, Ariana Tang, Aniket Mishra, Rui Xia, Edith Hofer, Hema Sekhar Reddy Rajula, Ruiqi Wang, Frauke Beyer, Katrin Horn, Max Riedl, Jing Yu, Henry Völzke, Robin Bülow, Uwe Völker, Stefan Frenzel, Katharina Wittfeld, Sandra Van Der Auwera, Thomas H Mosley, Vincent Bouteloup, Jean-Charles Lambert, Geneviève Chêne, Carole Dufouil, Christophe Tzourio, Jean-François Mangin, Rebecca F Gottesman, Myriam Fornage, Reinhold Schmidt, Qiong Yang, Veronica Witte, Markus Scholz, Markus Loeffler, Gennady V Roshchupkin, M Arfan Ikram, Hans J Grabe, Sudha Seshadri, Stephanie Debette, Tomas Paus, Zdenka Pausova

Faculty, Staff and Student Publications

White matter hyperintensities index structural abnormalities in the cerebral white matter, including axonal damage. The latter may promote atrophy of the cerebral cortex, a key feature of dementia. Here, we report a study of 51,065 individuals from 10 cohorts demonstrating that higher white matter hyperintensity volume associates with lower cortical thickness. The meta-GWAS of white matter hyperintensities-associated cortical 'atrophy' identifies 20 genome-wide significant loci, and enrichment in genes specific to vascular cell types, astrocytes, and oligodendrocytes. White matter hyperintensities-associated cortical 'atrophy' showed positive genetic correlations with vascular-risk traits and plasma biomarkers of neurodegeneration, and negative genetic correlations with cognitive functioning. …

Racial And Sociodemographic Disparities In The Use Of Targeted Therapies In Advanced Ovarian Cancer Patients With Medicare, Anne Knisely, Chi-Fang Wu, Alexa Kanbergs, Nuria Agusti, Kirsten A Jorgensen, Alexander Melamed, Sharon H Giordano, Jose Alejandro Rauh-Hain, Roni Nitecki Wilke

Faculty, Staff and Student Publications

Objective: To describe sociodemographic and racial disparities in receipt of poly ADP-ribose polymerase inhibitors (PARPi) and bevacizumab among insured patients with ovarian cancer.

Methods: This retrospective study used the Surveillance, Epidemiology, and End Results (SEER)-Medicare database to identify patients with advanced stage, high grade serous ovarian cancer diagnosed between 2010 and 2019. The primary outcome of interest was receipt of PARPi or bevacizumab at any time after diagnosis. χ2 tests were used to compare categorical variables. Factors independently associated with the receipt of PARPi and/or bevacizumab were identified using a multivariable logistic regression.

Results: The cohort included 6242 patients; 276 …

Obesity And Outcomes In Adoptive Cellular Therapy In Solid Tumors, Derrick L Tao, Mirella Nardo, Cheuk Hong Leung, Heather Y Lin, Lei Kang, Hung Le, Ecaterina E Dumbrava, David S Hong

Faculty, Staff and Student Publications

This cohort study investigates the association of obesity with adoptive cell therapy outcomes in patients with solid tumors.

Patient-Reported Convenience And Effectiveness Of Telehealth For Breast Cancer Management, Akshara Singareeka Raghavendra, Kristofer Jennings, Gil Guerra, Debu Tripathy, Meghan S Karuturi

Faculty, Staff and Student Publications

Background: Before the coronavirus disease 2019 (COVID-19) pandemic, telehealth was rarely used for breast cancer management at tertiary care centers. We sought to examine patient satisfaction, experiences, preferences, and perceived effectiveness and technical quality of telehealth visits in follow-up patients receiving routine outpatient care in the breast medical oncology practice at The University of Texas MD Anderson Cancer Center.

Methods: We administered a survey to 60 follow-up patients for a duration of 9 months (January 5, 2021 to October 27, 2021) who had at least one telehealth consultation during the COVID-19 pandemic, from April 10, 2020 to October 21, 2021. …

Fc-Enhanced Anti-Ctla-4, Anti-Pd-1, Doxorubicin, And Ultrasound-Mediated Blood-Brain Barrier Opening: A Novel Combinatorial Immunotherapy Regimen For Gliomas, Kwang-Soo Kim, Karl Habashy, Andrew Gould, Junfei Zhao, Hinda Najem, Christina Amidei, Ruth Saganty, Víctor A Arrieta, Crismita Dmello, Li Chen, Daniel Y Zhang, Brandyn Castro, Leah Billingham, Daniel Levey, Olivia Huber, Marilyn Marques, David A Savitsky, Benjamin M Morin, Miguel Muzzio, Michael Canney, Craig Horbinski, Peng Zhang, Jason Miska, Surya Padney, Bin Zhang, Raul Rabadan, Joanna J Phillips, Nicholas Butowski, Amy B Heimberger, Jian Hu, Roger Stupp, Dhan Chand, Catalina Lee-Chang, Adam M Sonabend

Faculty, Staff and Student Publications

Background: Glioblastoma is a highly aggressive brain cancer that is resistant to conventional immunotherapy strategies. Botensilimab, an Fc-enhanced anti-CTLA-4 antibody (FcE-aCTLA-4), has shown durable activity in "cold" and immunotherapy-refractory cancers.

Methods: We evaluated the efficacy and immune microenvironment phenotype of a mouse analogue of FcE-aCTLA-4 in treatment-refractory preclinical models of glioblastoma, both as a monotherapy and in combination with doxorubicin delivered via low-intensity pulsed ultrasound and microbubbles (LIPU/MB). Additionally, we studied 4 glioblastoma patients treated with doxorubicin, anti-PD-1 with concomitant LIPU/MB to investigate the novel effect of doxorubicin modulating FcγR expressions in tumor-associated macrophages/microglia (TAMs).

Results: FcE-aCTLA-4 demonstrated high-affinity binding …

Thrombosis, Brain Metastasis Formation, And The Perivascular Metastatic Niche-Novel Insights From The Tumor Microvascular Circulation, Christopher Alvarez-Breckenridge, Priscilla K Brastianos, Daniel P Cahill

Faculty, Staff and Student Publications

No abstract provided.

The Emerging Field Of Viroimmunotherapy For Pediatric Brain Tumors, Marc Garcia-Moure, Virginia Laspidea, Sumit Gupta, Andrew G Gillard, Soumen Khatua, Akhila Parthasarathy, Jiasen He, Frederick F Lang, Juan Fueyo, Marta M Alonso, Candelaria Gomez-Manzano

Faculty, Staff and Student Publications

Pediatric brain tumors are the most common solid tumors in children. Even to date, with the advances in multimodality therapeutic management, survival outcomes remain dismal in some types of tumors, such as pediatric-type diffuse high-grade gliomas or central nervous system embryonal tumors. Failure to understand the complex molecular heterogeneity and the elusive tumor and microenvironment interplay continues to undermine therapeutic efficacy. Developing a strategy that would improve survival for these fatal tumors remains unmet in pediatric neuro-oncology. Oncolytic viruses (OVs) are emerging as a feasible, safe, and promising therapy for brain tumors. The new paradigm in virotherapy implies that the …