Digital Commons Network^™

Secretory Leukocyte Protease Inhibitor Protects Against Severe Urinary Tract Infection In Mice, Anne L Rosen, Michael A Lint, Dayne H Voelker, Nicole M Gilbert, Christopher P Tomera, Jesús Santiago-Borges, Meghan A Wallace, Thomas J Hannan, Carey-Ann D Burnham, Scott J Hultgren, Andrew L Kau

2020-Current year OA Pubs

Millions suffer from urinary tract infections (UTIs) worldwide every year with women accounting for the majority of cases. Uropathogenic

Yersiniabactin Is A Quorum-Sensing Autoinducer And Siderophore In Uropathogenic Escherichia Coli, James R Heffernan, John A Wildenthal, Hung Tran, George L Katumba, William H Mccoy, Jeffrey P Henderson

2020-Current year OA Pubs

Siderophores are secreted ferric ion chelators used to obtain iron in nutrient-limited environmental niches, including human hosts. While all

Tumor- And Circulating-Free Dna Methylation Identifies Clinically Relevant Small Cell Lung Cancer Subtypes, Simon Heeke, Carl M Gay, Marcos R Estecio, Hai Tran, Benjamin B Morris, Bingnan Zhang, Ximing Tang, Maria Gabriela Raso, Pedro Rocha, Siqi Lai, Edurne Arriola, Paul Hofman, Veronique Hofman, Prasad Kopparapu, Christine M Lovly, Kyle Concannon, Luana Guimaraes De Sousa, Whitney Elisabeth Lewis, Kimie Kondo, Xin Hu, Azusa Tanimoto, Natalie I Vokes, Monique B Nilsson, Allison Stewart, Maarten Jansen, Ildikó Horváth, Mina Gaga, Vasileios Panagoulias, Yael Raviv, Danny Frumkin, Adam Wasserstrom, Aharona Shuali, Catherine A Schnabel, Yuanxin Xi, Lixia Diao, Qi Wang, Jianjun Zhang, Peter Van Loo, Jing Wang, Ignacio I Wistuba, Lauren A Byers, John V Heymach

Faculty, Staff and Student Publications

Small cell lung cancer (SCLC) is an aggressive malignancy composed of distinct transcriptional subtypes, but implementing subtyping in the clinic has remained challenging, particularly due to limited tissue availability. Given the known epigenetic regulation of critical SCLC transcriptional programs, we hypothesized that subtype-specific patterns of DNA methylation could be detected in tumor or blood from SCLC patients. Using genomic-wide reduced-representation bisulfite sequencing (RRBS) in two cohorts totaling 179 SCLC patients and using machine learning approaches, we report a highly accurate DNA methylation-based classifier (SCLC-DMC) that can distinguish SCLC subtypes. We further adjust the classifier for circulating-free DNA (cfDNA) to subtype …

Probiotic Limosilactobacillus Reuteri Dsm 17938 Changes Foxp3 Deficiency-Induced Dyslipidemia And Chronic Hepatitis In Mice, Erini Nessim Kostandy, Ji Ho Suh, Xiangjun Tian, Beanna Okeugo, Erin Rubin, Sara Shirai, Meng Luo, Christopher M Taylor, Kang Ho Kim, J Marc Rhoads, Yuying Liu

Faculty, Staff and Student Publications

The probiotic Limosilactobacillus reuteri DSM 17938 produces anti-inflammatory effects in scurfy (SF) mice, a model characterized by immune dysregulation, polyendocrinopathy, enteropathy, and X-linked inheritance (called IPEX syndrome in humans), caused by regulatory T cell (Treg) deficiency and is due to a Foxp3 gene mutation. Considering the pivotal role of lipids in autoimmune inflammatory processes, we investigated alterations in the relative abundance of lipid profiles in SF mice (± treatment with DSM 17938) compared to normal WT mice. We also examined the correlation between plasma lipids and gut microbiota and circulating inflammatory markers. We noted a significant upregulation of plasma lipids …

Insights From The Histopathologic Analysis Of Acquired And Genetic Thoracic Aortic Aneurysms And Dissections, L Maximilian Buja, Bihong Zhao, Humaira Sadaf, Michelle Mcdonald, Ana M Segura, Li Li, Alana Cecchi, Siddharth K Prakash, Rana O Afifi, Charles C Miller, Anthony L Estrera, Dianna M Milewicz

Faculty, Staff and Student Publications

OBJECTIVE: The purpose of this study was to apply contemporary consensus criteria developed by the Society for Cardiovascular Pathology and the Association for European Cardiovascular Pathology to the evaluation of aortic pathology, with the expectation that the additional pathologic information may enhance the understanding and management of aortic diseases.

METHODS: A scoring system was applied to ascending aortic specimens from 42 patients with heritable thoracic aortic disease and known genetic variations and from 86 patients from a single year, including patients with known genetic variations (n = 12) and patients with sporadic disease (n = 74).

RESULTS: The various types …

Probiotic Limosilactobacillus Reuteri Dsm 17938 Changes Foxp3 Deficiency-Induced Dyslipidemia And Chronic Hepatitis In Mice, Erini Nessim Kostandy, Ji Ho Suh, Xiangjun Tian, Beanna Okeugo, Erin Rubin, Sara Shirai, Meng Luo, Christopher M Taylor, Kang Ho Kim, J Marc Rhoads, Yuying Liu

Faculty, Staff and Student Publications

The probiotic Limosilactobacillus reuteri DSM 17938 produces anti-inflammatory effects in scurfy (SF) mice, a model characterized by immune dysregulation, polyendocrinopathy, enteropathy, and X-linked inheritance (called IPEX syndrome in humans), caused by regulatory T cell (Treg) deficiency and is due to a Foxp3 gene mutation. Considering the pivotal role of lipids in autoimmune inflammatory processes, we investigated alterations in the relative abundance of lipid profiles in SF mice (± treatment with DSM 17938) compared to normal WT mice. We also examined the correlation between plasma lipids and gut microbiota and circulating inflammatory markers. We noted a significant upregulation of plasma lipids …

Molecular-Guided Therapy For The Treatment Of Patients With Relapsed And Refractory Childhood Cancers: A Beat Childhood Cancer Research Consortium Trial., Giselle L Saulnier Sholler, Genevieve Bergendahl, Elizabeth C. Lewis, Jacqueline Kraveka, William Ferguson, Abhinav B. Nagulapally, Karl Dykema, Valerie I Brown, Michael S. Isakoff, Joseph Junewick, Deanna Mitchell, Jawhar Rawwas, William Roberts, Don Eslin, Javier Oesterheld, Randal K. Wada, Devang Pastakia, Virginia Harrod, Kevin Ginn, Raya Saab, Kevin Bielamowicz, Jason Glover, Eugenia Chang, Gina K. Hanna, Daniel Enriquez, Tyler Izatt, Rebecca F Halperin, Abigail Moore, Sara A. Byron, William P D Hendricks, Jeffrey M. Trent

Manuscripts, Articles, Book Chapters and Other Papers

BACKGROUND: Children with relapsed central nervous system (CNS tumors), neuroblastoma, sarcomas, and other rare solid tumors face poor outcomes. This prospective clinical trial examined the feasibility of combining genomic and transcriptomic profiling of tumor samples with a molecular tumor board (MTB) approach to make real‑time treatment decisions for children with relapsed/refractory solid tumors.

METHODS: Subjects were divided into three strata: stratum 1-relapsed/refractory neuroblastoma; stratum 2-relapsed/refractory CNS tumors; and stratum 3-relapsed/refractory rare solid tumors. Tumor samples were sent for tumor/normal whole-exome (WES) and tumor whole-transcriptome (WTS) sequencing, and the genomic data were used in a multi-institutional MTB to make real‑time treatment …

Matrin3 Mediates Differentiation Through Stabilizing Chromatin Loop-Domain Interactions And Yy1 Mediated Enhancer-Promoter Interactions, Tianxin Liu, Qian Zhu, Yan Kai, Trevor Bingham, Stacy Wang, Hye Ji Cha, Stuti Mehta, Thorsten M Schlaeger, Guo-Cheng Yuan, Stuart H Orkin

Faculty, Staff and Students Publications

Although emerging evidence indicates that alterations in proteins within nuclear compartments elicit changes in chromosomal architecture and differentiation, the underlying mechanisms are not well understood. Here we investigate the direct role of the abundant nuclear complex protein Matrin3 (Matr3) in chromatin architecture and development in the context of myogenesis. Using an acute targeted protein degradation platform (dTAG-Matr3), we reveal the dynamics of development-related chromatin reorganization. High-throughput chromosome conformation capture (Hi-C) experiments revealed substantial chromatin loop rearrangements soon after Matr3 depletion. Notably, YY1 binding was detected, accompanied by the emergence of novel YY1-mediated enhancer-promoter loops, which occurred concurrently with changes in …

Functional Epas1/ Hif2a Missense Variant Is Associated With Hematocrit In Andean Highlanders, Elijah S Lawrence, Wanjun Gu, Ryan J Bohlender, Cecilia Anza-Ramirez, Amy M Cole, James J Yu, Hao Hu, Erica C Heinrich, Katie A O'Brien, Carlos A Vasquez, Quinn T Cowan, Patrick T Bruck, Kysha Mercader, Mona Alotaibi, Tao Long, James E Hall, Esteban A Moya, Marco A Bauk, Jennifer J Reeves, Mitchell C Kong, Rany M Salem, Gustavo Vizcardo-Galindo, Jose-Luis Macarlupu, Rómulo Figueroa-Mujíca, Daniela Bermudez, Noemi Corante, Eduardo Gaio, Keolu P Fox, Veikko Salomaa, Aki S Havulinna, Andrew J Murray, Atul Malhotra, Frank L Powel, Mohit Jain, Alexis C Komor, Gianpiero L Cavalleri, Chad D Huff, Francisco C Villafuerte, Tatum S Simonson

Faculty, Staff and Student Publications

Hypoxia-inducible factor pathway genes are linked to adaptation in both human and nonhuman highland species. EPAS1, a notable target of hypoxia adaptation, is associated with relatively lower hemoglobin concentration in Tibetans. We provide evidence for an association between an adaptive EPAS1 variant (rs570553380) and the same phenotype of relatively low hematocrit in Andean highlanders. This Andean-specific missense variant is present at a modest frequency in Andeans and absent in other human populations and vertebrate species except the coelacanth. CRISPR-base-edited human cells with this variant exhibit shifts in hypoxia-regulated gene expression, while metabolomic analyses reveal both genotype and phenotype associations …

Patient And Public Involvement In Abortion Research: Reflections From The Shaping Abortion For Change (Sacha) Study, The Sacha Study Team N/A, Rebecca Blaylock, Maria Lewandowska, Charlotte Kelly, Becky Gunn, Rebecca Meiksin, Rachel H. Scott, Melissa J. Palmer, Kaye Wellings, Patricia A. Lohr, Rebecca S. French, Jill Shawe, Wendy Norman, Sharon Cameron, Clare Murphy, Geoffrey Wong, Paula Baraitser, Caroline Free, Annette Aronsson, Jennifer Reiter, Sally Sheldon, Louise Keogh, Rachel Scott, Natasha Salaria, Ona Mccarthy

School of Nursing and Midwifery

Patient and public involvement (PPI) is limited within abortion-related research. Possible reasons for this include concerns about engaging with a stigmatised patient group who value confidentiality and may be reluctant to re-engage with services. Structural barriers, including limited funding for abortion-related research, also prevent researchers from creating meaningful PPI opportunities. Here, we describe lessons learnt on undertaking PPI as part of the Shaping Abortion for Change (SACHA) Study, which sought to create an evidence base to guide new directions in abortion care in Britain. Two approaches to PPI were used: involving patients and the public in the oversight of the …

Srf-Deficient Astrocytes Provide Neuroprotection In Mouse Models Of Excitotoxicity And Neurodegeneration, Surya Chandra Rao Thumu, Monika Jain, Sumitha Soman, Soumen Das, Vijaya Verma, Arnab Nandi, David H Gutmann, Balaji Jayaprakash, Deepak Nair, James P Clement, Swananda Marathe, Narendrakumar Ramanan

2020-Current year OA Pubs

Reactive astrogliosis is a common pathological hallmark of CNS injury, infection, and neurodegeneration, where reactive astrocytes can be protective or detrimental to normal brain functions. Currently, the mechanisms regulating neuroprotective astrocytes and the extent of neuroprotection are poorly understood. Here, we report that conditional deletion of serum response factor (SRF) in adult astrocytes causes reactive-like hypertrophic astrocytes throughout the mouse brain. These

Development And Validation Of Parent-Reported Gastrointestinal Health Scale In Mecp2 Duplication Syndrome, Davut Pehlivan, Sukru Aras, Daniel G Glaze, Muharrem Ak, Bernhard Suter, Kathleen J Motil

Faculty, Staff and Students Publications

BACKGROUND/AIMS: We aimed to develop a validated patient-reported Gastrointestinal Health Scale (GHS) specific to MECP2 Duplication Syndrome (MDS) to be used in clinical trials.

METHODS: MDS parents completed a Gastrointestinal Health Questionnaire (GHQ) to investigate the most relevant and important items associated with gastrointestinal problems in MECP2-related disorders. Item reduction was executed according to EORTC guidelines. We performed reliability and validity studies for the finalized scale.

RESULTS: A total of 106 surveys were eligible for item reduction and validation processes. The initial 55 items were reduced to 38 items based on parent responses, expert opinion, and initial confirmatory factor analysis …

Design, Synthesis, X-Ray Crystallography, And Biological Activities Of Covalent, Non-Peptidic Inhibitors Of Sars-Cov-2 Main Protease, Md Ashraf-Uz-Zaman, Teck Khiang Chua, Xin Li, Yuan Yao, Bala Krishna Moku, Chandra Bhushan Mishra, Vasanthi Avadhanula, Pedro A Piedra, Yongcheng Song

Faculty, Staff and Students Publications

Highly contagious SARS-CoV-2 coronavirus has infected billions of people worldwide with flu-like symptoms since its emergence in 2019. It has caused deaths of several million people. The viral main protease (Mpro) is essential for SARS-CoV-2 replication and therefore a drug target. Several series of covalent inhibitors of Mpro were designed and synthesized. Structure-activity relationship studies show that 1) several chloroacetamide- and epoxide-based compounds targeting Cys145 are potent inhibitors with IC50 values as low as 0.49 μM, and 2) Cys44 of Mpro is not nucleophilic for covalent inhibitor design. High resolution X-ray studies revealed the protein-inhibitor interactions and mechanisms of inhibition. …

Processes For Identifying Caregivers And Screening For Caregiver And Patient Distress In Community Oncology: Results From Wf-1803cd., Chandylen L. Nightingale, Anna C. Snavely, Laurie E. Mclouth, Emily V. Dressler, Erin E. Kent, Christian S. Adonizio, Suzanne C. Danhauer, Rachel Cannady, Judith O. Hopkins, Heather Kehn, Kathryn E. Weaver, Katherine R. Sterba

Behavioral Science Faculty Publications

BACKGROUND: Despite their vital roles, informal caregivers of adult cancer patients are commonly overlooked in cancer care. This study describes processes for identifying cancer caregivers and processes for distress screening and management among caregivers and patients in the understudied community oncology setting.

METHODS: Supportive care leaders from the National Cancer Institute Community Oncology Research Program practices completed online survey questions regarding caregiver identification, caregiver and patient distress screening, and distress management strategies. We described practice group characteristics and prevalence of study outcomes. Multivariable logistic regression explored associations between practice group characteristics and caregiver identification in the electronic health record (EHR). …

Three-Year Follow-Up Analysis Of Axicabtagene Ciloleucel In Relapsed/Refractory Indolent Non-Hodgkin Lymphoma (Zuma-5), Sattva S Neelapu, Julio C Chavez, Alison R Sehgal, Narendranath Epperla, Matthew Ulrickson, Emmanuel Bachy, Pashna N Munshi, Carla Casulo, David G Maloney, Sven De Vos, Ran Reshef, Lori A Leslie, Olalekan O Oluwole, Ibrahim Yakoub-Agha, Rashmi Khanal, Joseph Rosenblatt, Ronald Korn, Weixin Peng, Christine Lui, Jacob Wulff, Rhine Shen, Soumya Poddar, A Scott Jung, Harry Miao, Sara Beygi, Caron A Jacobson

Faculty, Staff and Student Publications

Axicabtagene ciloleucel (axi-cel) is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy approved for relapsed/refractory (R/R) follicular lymphoma (FL). Approval was supported by the phase 2, multicenter, single-arm ZUMA-5 study of axi-cel for patients with R/R indolent non-Hodgkin lymphoma (iNHL; N = 104), including FL and marginal zone lymphoma (MZL). In the primary analysis (median follow-up, 17.5 months), the overall response rate (ORR) was 92% (complete response rate, 74%). Here, we report long-term outcomes from ZUMA-5. Eligible patients with R/R iNHL after ≥2 lines of therapy underwent leukapheresis, followed by lymphodepleting chemotherapy and axi-cel infusion (2 × 106 CAR …

The Mrna-Lnp Vaccines - The Good, The Bad And The Ugly?, Botond Z. Igyártó, Zhen Qin

Department of Microbiology and Immunology Faculty Papers

The mRNA-LNP vaccine has received much attention during the COVID-19 pandemic since it served as the basis of the most widely used SARS-CoV-2 vaccines in Western countries. Based on early clinical trial data, these vaccines were deemed safe and effective for all demographics. However, the latest data raise serious concerns about the safety and effectiveness of these vaccines. Here, we review some of the safety and efficacy concerns identified to date. We also discuss the potential mechanism of observed adverse events related to the use of these vaccines and whether they can be mitigated by alterations of this vaccine mechanism …

Strategies For Treating Acute Pain In Patients With Opioid Dependence: A Scoping Review Protocol., Sarah Levine, Megha Andrews, Benjamin H. Saracco, Matthew Salzman

Cooper Medical School of Rowan University Departmental Research

INTRODUCTION: People who are dependent on opioids experience acute pain similar to other individuals. However, treating acute pain in these patients renders unique challenges such as opioid-induced hyperalgesia, opioid tolerance, withdrawal and stigma from healthcare providers. Thus, it is crucial to identify effective strategies for treating acute pain in this population and to highlight gaps in knowledge to create a high standard of care. The main objective of the proposed scoping review is to identify current strategies for treating the acute pain in individuals with opioid dependence or use disorder.

METHODS AND ANALYSIS: MEDLINE via the PubMed interface, Embase and …

[Summary: International Consensus Statement On Nomenclature And Classification Of The Congenital Bicuspid Aortic Valve And Its Aortopathy, For Clinical, Surgical, Interventional And Research Purposes], Hector I Michelena, Alessandro Della Corte, Arturo Evangelista, Joseph J Maleszewski, William D Edwards, Mary J Roman, Richard B Devereux, Borja Fernández, Federico M Asch, Alex J Barker, Lilia M Sierra, Laurent De Kerchove, Susan M Fernandes, Paul W M Fedak, Evaldas Girdauskas, Victoria Delgado, Suhny Abbara, Emmanuel Lansac, Siddharth K Prakash, Malenka M Bissell, Bogdan A Popescu, Michael D Hope, Marta Sitges, Vinod H Thourani, Phillippe Pibarot, Krishnaswamy Chandrasekaran, Patrizio Lancellotti, Michael A Borger, John K Forrest, John Webb, Dianna M Milewicz, Raj Makkar, Martin B Leon, Stephen P Sanders, Michael Markl, Victor A Ferrari, William C Roberts, Jae-Kwan Song, Philipp Blanke, Charles S White, Samuel Siu, Lars G Svensson, Alan C Braverman, Joseph Bavaria, Thoralf M Sundt, Gebrine El Khoury, Ruggero De Paulis, Maurice Enriquez-Sarano, Jeroen J Bax, Catherine M Otto, Hans-Joachim Schäfers

Faculty, Staff and Student Publications

This consensus of nomenclature and classification for congenital bicuspid aortic valve and its aortopathy is evidence-based and intended for universal use by physicians (both pediatricians and adults), echocardiographers, advanced cardiovascular imaging specialists, interventional cardiologists, cardiovascular surgeons, pathologists, geneticists, and researchers spanning these areas of clinical and basic research. In addition, as long as new key and reference research is available, this international consensus may be subject to change based on evidence-based data1.

Examining Associations Between School-Level Determinants And The Implementation Of Physical Activity Opportunities, Derek W Craig, Timothy J Walker, Shreela V Sharma, Paula Cuccaro, Natalia I Heredia, Andjelka Pavlovic, Laura F Defina, Harold W Kohl, Maria E Fernandez

Faculty, Staff and Student Publications

School-based physical activity (PA) opportunities can help students engage in greater amounts of daily PA, meet PA guidelines, and lead to improved health and educational outcomes. However, we do not completely understand the organizational challenges to implementing these opportunities successfully. This exploratory study examined associations between school-level determinants and the implementation of school-based PA opportunities. We analyzed cross-sectional survey data from schools (n = 46) participating in the Healthy Zone School Program (HZSP) (Dallas, Texas, USA) during 2019-2020. Respondents completed an electronic survey that included measures of school-level determinants (e.g. culture, leadership, priority) and the implementation of school-based PA opportunities. …

Aspscr1-Tfe3 Reprograms Transcription By Organizing Enhancer Loops Around Hexameric Vcp/P97, Amir Pozner, Li Li, Shiv Prakash Verma, Shuxin Wang, Jared J Barrott, Mary L Nelson, Jamie S E Yu, Gian Luca Negri, Shane Colborne, Christopher S Hughes, Ju-Fen Zhu, Sydney L Lambert, Lara S Carroll, Kyllie Smith-Fry, Michael G Stewart, Sarmishta Kannan, Bodrie Jensen, Cini M John, Saif Sikdar, Hongrui Liu, Ngoc Ha Dang, Jennifer Bourdage, Jinxiu Li, Jeffery M Vahrenkamp, Katelyn L Mortenson, John S Groundland, Rosanna Wustrack, Donna L Senger, Franz J Zemp, Douglas J Mahoney, Jason Gertz, Xiaoyang Zhang, Alexander J Lazar, Martin Hirst, Gregg B Morin, Torsten O Nielsen, Peter S Shen, Kevin B Jones

Faculty, Staff and Student Publications

The t(X,17) chromosomal translocation, generating the ASPSCR1::TFE3 fusion oncoprotein, is the singular genetic driver of alveolar soft part sarcoma (ASPS) and some Xp11-rearranged renal cell carcinomas (RCCs), frustrating efforts to identify therapeutic targets for these rare cancers. Here, proteomic analysis identifies VCP/p97, an AAA+ ATPase with known segregase function, as strongly enriched in co-immunoprecipitated nuclear complexes with ASPSCR1::TFE3. We demonstrate that VCP is a likely obligate co-factor of ASPSCR1::TFE3, one of the only such fusion oncoprotein co-factors identified in cancer biology. Specifically, VCP co-distributes with ASPSCR1::TFE3 across chromatin in association with enhancers genome-wide. VCP presence, its hexameric assembly, and its …

Metabolic Model Predictions Enable Targeted Microbiome Manipulation Through Precision Prebiotics, Georgios Marinos, Inga K Hamerich, Reena Debray, Nancy Obeng, Carola Petersen, Jan Taubenheim, Johannes Zimmermann, Dana Blackburn, Buck S Samuel, Katja Dierking, Andre Franke, Matthias Laudes, Silvio Waschina, Hinrich Schulenburg, Christoph Kaleta

Faculty, Staff and Students Publications

While numerous health-beneficial interactions between host and microbiota have been identified, there is still a lack of targeted approaches for modulating these interactions. Thus, we here identify precision prebiotics that specifically modulate the abundance of a microbiome member species of interest. In the first step, we show that defining precision prebiotics by compounds that are only taken up by the target species but no other species in a community is usually not possible due to overlapping metabolic niches. Subsequently, we use metabolic modeling to identify precision prebiotics for a two-member Caenorhabditis elegans microbiome community comprising the immune-protective target species Pseudomonas …

Chimeric Antigen Receptor Macrophages Target And Resorb Amyloid Plaques, Alexander B. Kim, Qingli Xiao, Ping Yan, Qiuyun Pan, Gaurav Pandey, Susie Grathwohl, Ernesto Gonzales, Isabella Xu, Yoonho Cho, Hans Haecker, Slava Epelman, Abhinav Diwan, Jin-Moo Lee, Carl J Deselm

2020-Current year OA Pubs

Substantial evidence suggests a role for immunotherapy in treating Alzheimer's disease (AD). While the precise pathophysiology of AD is incompletely understood, clinical trials of antibodies targeting aggregated forms of β amyloid (Aβ) have shown that reducing amyloid plaques can mitigate cognitive decline in patients with early-stage AD. Here, we describe what we believe to be a novel approach to target and degrade amyloid plaques by genetically engineering macrophages to express an Aβ-targeting chimeric antigen receptor (CAR-Ms). When injected intrahippocampally, first-generation CAR-Ms have limited persistence and fail to significantly reduce plaque load, which led us to engineer next-generation CAR-Ms that secrete …

Efficacy Of Novel Agents Against Cellular Models Of Familial Platelet Disorder With Myeloid Malignancy (Fpd-Mm), Christopher P Mill, Warren C Fiskus, Courtney D Dinardo, Patrick Reville, John A Davis, Christine E Birdwell, Kaberi Das, Hanxi Hou, Koichi Takahashi, Lauren Flores, Xinjia Ruan, Xiaoping Su, Sanam Loghavi, Joseph D Khoury, Kapil N Bhalla

Faculty, Staff and Student Publications

Germline, mono-allelic mutations in RUNX1 cause familial platelet disorder (RUNX1-FPD) that evolves into myeloid malignancy (FPD-MM): MDS or AML. FPD-MM commonly harbors co-mutations in the second RUNX1 allele and/or other epigenetic regulators. Here we utilized patient-derived (PD) FPD-MM cells and established the first FPD-MM AML cell line (GMR-AML1). GMR-AML1 cells exhibited active super-enhancers of MYB, MYC, BCL2 and CDK6, augmented expressions of c-Myc, c-Myb, EVI1 and PLK1 and surface markers of AML stem cells. In longitudinally studied bone marrow cells from a patient at FPD-MM vs RUNX1-FPD state, we confirmed increased chromatin accessibility and mRNA expressions of MYB, MECOM and …

The Novel Phosphatase Nudt5 Is A Critical Regulator Of Triple-Negative Breast Cancer Growth, Jing Qian, Yanxia Ma, William M Tahaney, Cassandra L Moyer, Amanda Lanier, Jamal Hill, Darian Coleman, Negar Koupaei, Susan G Hilsenbeck, Michelle I Savage, Brent D G Page, Abhijit Mazumdar, Powel H Brown

Faculty, Staff and Student Publications

BACKGROUND: The most aggressive form of breast cancer is triple-negative breast cancer (TNBC), which lacks expression of the estrogen receptor (ER) and progesterone receptor (PR), and does not have overexpression of the human epidermal growth factor receptor 2 (HER2). Treatment options for women with TNBC tumors are limited, unlike those with ER-positive tumors that can be treated with hormone therapy, or those with HER2-positive tumors that can be treated with anti-HER2 therapy. Therefore, we have sought to identify novel targeted therapies for TNBC. In this study, we investigated the potential of a novel phosphatase, NUDT5, as a potential therapeutic target …

Gestational Diabetes Augments Group B Streptococcus Infection By Disrupting Maternal Immunity And The Vaginal Microbiota, Vicki Mercado-Evans, Marlyd E Mejia, Jacob J Zulk, Samantha Ottinger, Zainab A Hameed, Camille Serchejian, Madelynn G Marunde, Clare M Robertson, Mallory B Ballard, Simone H Ruano, Natalia Korotkova, Anthony R Flores, Kathleen A Pennington, Kathryn A Patras

Faculty, Staff and Student Publications

Group B Streptococcus (GBS) is a pervasive perinatal pathogen, yet factors driving GBS dissemination in utero are poorly defined. Gestational diabetes mellitus (GDM), a complication marked by dysregulated immunity and maternal microbial dysbiosis, increases risk for GBS perinatal disease. Using a murine GDM model of GBS colonization and perinatal transmission, we find that GDM mice display greater GBS in utero dissemination and subsequently worse neonatal outcomes. Dual-RNA sequencing reveals differential GBS adaptation to the GDM reproductive tract, including a putative glycosyltransferase (yfhO), and altered host responses. GDM immune disruptions include reduced uterine natural killer cell activation, impaired recruitment to placentae, …

Efficacy And Safety Of Autologous Tumor-Infiltrating Lymphocytes In Recurrent Or Refractory Ovarian Cancer, Colorectal Cancer, And Pancreatic Ductal Adenocarcinoma, Rodabe Amaria, Anne Knisely, David Vining, Scott Kopetz, Michael J Overman, Milind Javle, Mara B Antonoff, Ching-Wei D Tzeng, Robert A Wolff, Shubham Pant, Kathryn Lito, Kelly Rangel, Bryan Fellman, Ying Yuan, Karen H Lu, Donastas Sakellariou-Thompson, Cara L Haymaker, Marie-Andrée Forget, Patrick Hwu, Chantale Bernatchez, Amir A Jazaeri

Faculty, Staff and Student Publications

BACKGROUND: Tumor-infiltrating lymphocyte (TIL) therapy has shown efficacy in metastatic melanoma, non-small cell lung cancer, and other solid tumors. Our preclinical work demonstrated more robust CD8 predominant TIL production when agonistic anti-4-1BB and CD3 antibodies were used in early ex vivo TIL culture.

METHODS: Patients with treatment-refractory metastatic colorectal (CRC), pancreatic (PDAC) and ovarian (OVCA) cancers were eligible. Lymphodepleting chemotherapy was followed by infusion of ex vivo expanded TIL, manufactured at MD Anderson Cancer Center with IL-2 and agonistic stimulation of CD3 and 4-1BB (urelumab). Patients received up to six doses of high-dose IL-2 after TIL infusion. Primary endpoint was …

Tumor-Specific Polycistronic Mirna Delivered By Engineered Exosomes For The Treatment Of Glioblastoma, Malcolm F Mcdonald, Anwar Hossain, Eric N Momin, Irtiza Hasan, Sanjay Singh, Satoshi Adachi, Joy Gumin, Daniel Ledbetter, Jing Yang, Lihong Long, Marc Daou, Sricharan Gopakumar, Lynette M Phillips, Brittany Parker Kerrigan, Frederick F Lang

Faculty, Staff and Student Publications

Background: Glioblastoma (GBM) has poor prognosis due to ineffective agents and poor delivery methods. MicroRNAs (miRs) have been explored as novel therapeutics for GBM, but the optimal miRs and the ideal delivery strategy remain unresolved. In this study, we sought to identify the most effective pan-subtype anti-GBM miRs and to develop an improved delivery system for these miRs.

Methods: We conducted an unbiased screen of over 600 miRs against 7 glioma stem cell (GSC) lines representing all GBM subtypes to identify a set of pan-subtype-specific anti-GBM miRs and then used available TCGA GBM patient outcomes and miR expression data to …

Rapid And Accurate Remethylation Of Dna In Dnmt3a- Deficient Hematopoietic Cells With Restoration Of Dnmt3a Activity, Yang Li, Haley J Abel, Michelle Cai, Taylor A Lavalle, Tiankai Yin, Nichole M Helton, Amanda M Smith, Christopher A Miller, Timothy J Ley

2020-Current year OA Pubs

Here, we characterize the DNA methylation phenotypes of bone marrow cells from mice with hematopoietic deficiency of

Genetic Context Drives Age-Related Disparities In Synaptic Maintenance And Structure Across Cortical And Hippocampal Neuronal Circuits., Sarah E Heuer, Emily W Nickerson, Gareth R Howell, Erik B Bloss

Faculty Research 2024

The disconnection of neuronal circuitry through synaptic loss is presumed to be a major driver of age-related cognitive decline. Age-related cognitive decline is heterogeneous, yet whether genetic mechanisms differentiate successful from unsuccessful cognitive decline through maintenance or vulnerability of synaptic connections remains unknown. Previous work using rodent and primate models leveraged various techniques to imply that age-related synaptic loss is widespread on pyramidal cells in prefrontal cortex (PFC) circuits but absent on those in area CA1 of the hippocampus. Here, we examined the effect of aging on synapses on projection neurons forming a hippocampal-cortico-thalamic circuit important for spatial working memory …

Current Practices, Perceived Barriers, And Promising Implementation Strategies For Improving Quality Of Smoking Cessation Support In Accredited Cancer Programs Of The American College Of Surgeons., Jamie S. Ostroff, Eileen M. Reilly, Jessica L. Burris, Graham W. Warren, Rachel C. Shelton, Timothy W. Mullett, Just Ask Quality Improvement Task Force

Psychology Faculty Publications

PURPOSE: Persistent smoking is associated with poor outcomes in cancer care. It is strongly recommended that oncology care providers provide cessation support; however, there is limited information about smoking cessation assessment and treatment patterns in routine oncology practice.

METHODS: Leaders of the American College of Surgeons Commission on Cancer (CoC) and National Accreditation Program for Breast Centers (National Accredited Program for Breast Cancer) elected to participate in a national quality improvement initiative (Just ASK) focused on smoking assessment/treatment in cancer care. Online baseline survey responses were received from 762 accredited programs.

RESULTS: Most programs reported regularly asking about smoking (89.9%), …