Digital Commons Network^™

Psilocybin's Acute And Persistent Brain Effects: A Precision Imaging Drug Trial, Subha Subramanian, Travis Rick Reneau, Demetrius Perry, Ravi Chacko, Timothy O Laumann, Karin Flavin, Christine Horan, Julie Schweiger, Nicholas Metcalf, Eric J Lenze, Abraham Z Snyder, Nico U F Dosenbach, Ginger Nicol, Joshua S Siegel

2020-Current year OA Pubs

Psilocybin (PSIL) is a psychedelic drug and a promising experimental therapeutic for many psychiatric conditions. Precision functional mapping (PFM) combines densely repeated resting state fMRI sampling and individual-specific network mapping to improve signal-to-noise ratio (SNR) and effect size in brain imaging research. We present a randomized cross-over study in which PFM was used to characterize acute and persistent effects of psilocybin or methylphenidate (MTP) on brain networks. Seven healthy volunteers (mean age 34.1 years, SD = 9.8; n = 3 females, n = 6 Caucasians) underwent (1) extensive baseline imaging, (2) imaging beginning 60-90 minutes after drug exposure, and (3) …

A Cascading Effects Model Of Early Sensory Development In Autism, Natalie Russo, Carissa J. Cascio, Grace T. Baranek, Tiffany G. Woynaroski, Zachary J. Williams, Shulamite A. Green, Roseann Schaaf

Department of Occupational Therapy Faculty Papers

Autism has historically been defined by the presence of differences in social communication and restricted, repetitive patterns of behavior, interests, or activities (RRBs). Since 2013 when the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders was published, sensory features were added as one of the polythetic restricted and repetitive behavior diagnostic criteria of autism, though it has remained understudied. Here, we summarize theory and research to provide support for the perspective that early sensory functions and experiences play a primary role in autism and have downstream effects on social communication and repetitive behavioral features of autism. The …

177lu-Labeled Antibody-Drug Conjugate: A Dual-Mechanistic Treatment Modality In Solid Tumors, Aiko Yamaguchi, Chisato M Yamazaki, Yasuaki Anami, Summer Y Y Ha, Wei Xiong, Robert T Ta, Ningyan Zhang, H Charles Manning, Zhiqiang An, Kyoji Tsuchikama

The Brown Foundation: Institute of Molecular Medicine

To explore the potential of site-selectively radiolabeled antibody-drug conjugates (ADC) against solid tumors, we constructed and evaluated radiolabeled ADCs equipped with lutetium-177 (177Lu) and a membrane-permeable antimitotic agent. Site-selective 177Lu-labeled ADCs [anti-trophoblast cell-surface antigen 2 (TROP2) 177Lu-DTPA ADCs or anti-HER2 177Lu-DO3A ADCs], a 177Lu-labeled homogeneous radioimmunoconjugate (homogeneous RIC), and 177Lu-labeled conventional RIC (heterogeneous RIC) were constructed. We confirmed that 177Lu-labeled ADCs and the homogeneous RIC were obtained with high homogeneity and defined chelator/payload-to-antibody ratios. Next, we performed biodistribution studies and treatment efficacy studies in xenograft mouse models bearing orthotopic breast tumors. Compared with the heterogeneous RIC, the 177Lu-DTPA TROP2 ADC …

Advances In Molecular Imaging Of Vegfrs: Innovations In Imaging And Therapeutics, Hanieh Karimi, Sarah Lee, Wenqi Xu, Sigrid A. Langhans, David K. Johnson, Erik Stauff, Heidi H. Kecskemethy, Lauren W. Averill, Xuyi Yue

Department of Radiology Faculty Papers

Vascular endothelial growth factor receptors (VEGFRs) are key regulators of angiogenesis, lymphangiogenesis, and vascular permeability, playing essential roles in both physiological and pathological processes. The VEGFR family, including VEGFR-1, VEGFR-2, and VEGFR-3, interacts with structurally related VEGF ligands (VEGFA, VEGFB, VEGFC, VEGFD, and placental growth factor [PlGF]), activating downstream signaling pathways that mediate critical cellular processes, including proliferation, migration, and survival. Dysregulation of VEGFR signaling has been implicated in numerous diseases, such as cancer, cardiovascular conditions, and inflammatory disorders. Targeting VEGFRs with radiopharmaceuticals, such as radiolabeled peptides, antibodies, and specific tracers like 64Cu-bevacizumab and 89Zr-ramucirumab, has emerged as a powerful …

Refine: A Database Of Linked Clinical Data And Genomic Biomarkers In Renal Cell Carcinoma Patients Receiving Immunotherapy-Based Treatment Regimens, Jeffrey Zhong, Albert Jang, Bashar Abuqayas, Arnab Basu, David Benjamin, Vineel Bhatlapenumarthi, Mehmet Asim Bilen, Dhvani Buch, Mark Chang, Erica Chin, Sourat Darabi, Nagendra Dhanikonda, Pooja Ghatalia, Claud Grigg, Abby Grier, Tanya Jindal, Joannah Jung, Deepak Kilari, Hamsa Kumar, Suzanna Lee, Brittany Neelands, Chinmayi Pandya, Jeff Pawalek, Jaimee Staggers, Ahmet Yildirim, Yousef Zakharia, Kevin Zarrabi, Michael Zimmerman, George Sledge, David Spetzler, Andrew Elliott, Rana Mckay, Pedro Barata

Department of Medical Oncology Faculty Papers

The REnal cancer consortium for Focused Investigation of Novel biomarkers and Expression (REFINE) consortium represents an important initiative in integrating clinical data with molecular sequencing in patients with advanced renal cell carcinoma (RCC) treated with immunotherapy-based approaches. By leveraging real-world evidence and genomic analysis, this consortium aims to explore putative predictive biomarkers with the potential to inform personalized treatment strategies. Findings from the REFINE database may further contribute to our understanding of disease courses of immunotherapy-based approaches for various molecular subtypes of RCC, associations of race and ethnicity with RCC treatment and outcomes with representation of patient populations underrepresented in …

Olaparib And Radiotherapy Induce Type I Interferon- And Cd8+ T Cell-Dependent Sensitization To Immunotherapy In Pancreatic Cancer, Victoria M Valvo, Qiang Zhang, Long Jiang, Erin A Holcomb, Ashley N Pearson, Anna G Edmunds, Hailey G Faulkner, Jadyn G James, Akshay Tate, Amanda K Huber, Zhuwen Wang, Yupei Guo, David Karnak, Leslie A Parsels, Joshua D Parsels, Yu L Lei, Alnawaz Rehemtulla, Heng Lin, Eileen S Carpenter, Daniel R Wahl, Vaibhav Sahai, Theodore S Lawrence, Michael D Green, Meredith A Morgan

Faculty, Staff and Student Publications

PARP inhibitors sensitize pancreatic ductal adenocarcinoma (PDAC) to radiation by inducing DNA damage and replication stress. These mechanisms also have the potential to enhance radiation-induced type I interferon (T1IFN) mediated anti-tumoral immune responses. We hypothesized that the PARP inhibitor olaparib would also potentiate radiation-induced T1IFN to promote anti-tumor immune responses and sensitization of otherwise resistant PDAC to immunotherapy. To test this hypothesis, we assessed the effects of olaparib and radiation on T1IFN production and sensitivity to αPD-L1 immunotherapy, as well as on the tumor microenvironment by single-cell RNA sequencing (scRNA-seq). We found that olaparib enhanced T1IFN production following radiation and …

Eph Receptors Activate Myeloid Checkpoint Receptor Lilrb5 To Support Tumor Development, Yubo He, Chengcheng Zhang, Lingxiao Tan, Mi Deng, Xiaoye Liu, Ryan Huang, Xing Yang, Jingjing Xie, Qi Lou, Meng Fang, Caroline Smith, Samuel John, Wei Xiong, Xin Li, Cheryl Lewis, Jade Homsi, Ankit Gupta, Ningyan Zhang, Zhiqiang An, Cheng Cheng Zhang

Faculty, Staff and Student Publications

Immunosuppressive myeloid cells are critical obstacles to T cell-centered immune checkpoint blockade therapies, which have been successful in treating a fraction of patients with cancer. How tumor cells interact with myeloid cells to regulate immune responses and tumor development is unclear. In this study, we report that certain membrane tyrosine kinase Eph receptors, including EphA7 and EphB1, specifically bind the immune inhibitory receptors leukocyte Ig-like receptor family B 5 (LILRB5) and LILRB2. These Eph receptors induce LILRB5-mediated signaling activation, and LILRB5 also activates Eph receptor signaling. Activation of LILRB5 promoted immunosuppressive marker expression and inhibited activating marker expression on myeloid …

The Present And Future Of Precision Oncology And Tumor-Agnostic Therapeutic Approaches, Nakul M Shah, Funda Meric-Bernstam

Faculty, Staff and Student Publications

Precision oncology has transformed the treatment landscape for patients with advanced solid tumors. Tumor-agnostic therapies, those that have been approved based on genetic mutations or biomarkers across tumor histology types, are important examples of how the implementation of precision oncology can expand therapeutic options for patients, especially those with rare cancer types and treatment-refractory disease. In this review, we first discuss how advances in next-generation sequencing and molecular profiling have enabled the identification of shared actionable alterations. Subsequently, we explore the current landscape of tumor-agnostic therapies that have received approval from the Food and Drug Administration. We discuss the strengths …

Cross-Sectional Analysis Of Wound-Associated Soluble Factors In Early, Established, And Chronic Wounds Of Recessive Dystrophic Epidermolysis Bullosa Patients, Vitali Alexeev, Leonie Huitema, Taylor Phillips, Paras Patel, Mauricio Garza, Franziska Ringpfeil, Julio Salas-Alanis, Olga Igoucheva

Department of Dermatology and Cutaneous Biology Faculty Papers

BACKGROUND: Poorly healing wounds represent the primary health-related burden for hereditary recessive dystrophic epidermolysis bullosa (RDEB) patients. Contribution of wound-associated soluble constituents to wound progression remains not well defined.

OBJECTIVE: To conduct cross-sectional analysis of cytokine, chemokine, and growth factor in exudates from RDEB wounds and define changes associated with wound progression.

METHODS: Concentrations of selected cytokines, chemokines, and growth factors were evaluated by multiplex ELISA in eight blister fluids and 66 exudates from early, established, and chronic RDEB and five chronic venous ulcers (VU). A cross-sectional analysis was performed.

RESULTS: Our data demonstrated that proinflammatory CXCL8 and IL-1β tend …

Mesenchymal Stem Cells And Fibroblasts Contribute To Microvascular Proliferation In Glioblastoma And Are Correlated With Immunosuppression And Poor Outcome, Candice C Poon, Shelley M Herbrich, Yulong Chen, Anwar Hossain, Gregory N Fuller, Sonali Jindal, Sreyashi Basu, Daniel Ledbetter, Marc Macaluso, Lynnette M Phillips, Joy Gumin, Zhong He, Brittany C Parker Kerrigan, Sanjay K Singh, Pratishtha Singh, Mohammed Fayyad Zaman, Derek Ng Tang, Sangeeta Goswami, Frederick F Lang, Padmanee Sharma

Faculty, Staff and Student Publications

Microvascular proliferation (MVP) is a disease-defining hallmark of glioblastoma and other World Health Organization grade 4 gliomas. MVP also serves as a poor prognostic marker in various solid tumors. Despite its clinical significance, the mechanisms and biological consequences of MVP are controversial and remain unclear. In this study, we performed single-cell RNA sequencing on paired CD45-CD105+ vascular/perivascular stromal cells (PVSC) and CD45+CD105± immune cells from 16 primary glioma patient samples, both with and without MVP. This analysis revealed the presence of developmentally related mesenchymal stem cells alongside cancer-associated fibroblasts, pericytes, fibromyocytes, and smooth muscle cells within the CD45-CD105+ compartment. RNA …

Prediction Of Methotrexate Neurotoxicity Using Clinical, Sociodemographic, And Area-Based Information In Children With Acute Lymphoblastic Leukemia, Rachel D Harris, Olga A Taylor, Maria Monica Gramatges, Amy E Hughes, Mark Zobeck, Sandi Pruitt, M Brooke Bernhardt, Ashley Chavana, Van Huynh, Kathleen Ludwig, Laura Klesse, Kenneth Heym, Timothy Griffin, Rodrigo Erana, Juan Carlos Bernini, Ashley Choi, Yuu Ohno, Melissa A Richard, Alanna C Morrison, Han Chen, Bing Yu, Philip J Lupo, Karen R Rabin, Michael E Scheurer, Austin L Brown

Center for Medical Ethics and Health Policy Staff Publications

Background: Methotrexate is a critical component of pediatric acute lymphoblastic leukemia (ALL) therapy that can result in neurotoxicity which has been associated with an increased risk of relapse. We leveraged machine learning to develop a neurotoxicity risk prediction model in a diverse cohort of children with ALL.

Methods: We included children (age 2-20 years) diagnosed with ALL (2005-2019) and treated in Texas without pre-existing neurologic disease. Clinical information was obtained by medical record review. Neurotoxicity occurring post-induction and prior to maintenance therapy was defined as neurologic episodes occurring within 21 days of methotrexate. Suspected cases were independently confirmed by 2 …

Assessment Of Water Quality Among Handwashing And Drinking Water Stations In Schools In Belize, 2022, Anh N Ly, Alexandra Kossik, Ary Sosa, Uriel Sosa, Dian Maheia, Yolanda Gongora, Russell Manzanero, Francis Morey, Melissa Diaz-Musa, Dennis Nichols, Adrianna Maliga, Kelsey Mcdavid, Christina Craig, Gerhaldine Morazan, Matthew Lozier, Kristy O Murray

Faculty, Staff and Students Publications

Water quality assessments are critical for ensuring timely responses to water-related concerns, particularly in low-resource areas with limited water, sanitation, and hygiene (WASH) infrastructure. In collaboration with the Belize Ministry of Health and Wellness and the Ministry of Education, Culture, Science and Technology, we conducted a survey on WASH infrastructure and resources among 221 schools. We identified 65 schools across all six districts of Belize for water quality testing. Among these 65 schools, 83% had at least one water sample that did not meet the WHO's recommended free chlorine residual level for drinking water. Additionally, coliforms and Escherichia coli were …

Nonstructural Roles Of Junctophilin-2 In The Heart, Daniel F Hutchison, Satadru K Lahiri, Kurt W Prins, Xander H T Wehrens

Faculty, Staff and Students Publications

Junctophilin-2 (JPH2) is an essential structural protein that maintains the integrity of junctional membrane complexes (JMCs) in cardiomyocytes, thereby playing its canonical role in excitation-contraction (E-C) coupling. Recent studies reveal novel, nonstructural functions of JPH2 in cardiomyocytes, including regulation of mitochondrial function, lipid metabolism, nuclear signaling, and innate immune responses. Calpain-mediated cleavage of JPH2 generates nuclear fragments, which differentially modulate stress responses. Moreover, full-length JPH2 also localizes to the nucleus, where it forms phase-separated nuclear droplets during oxidative stress. Collectively, these findings highlight JPH2 as a multifunctional protein with critical roles beyond its canonical structural function in E-C coupling.

Impact Of Sociodemographic Determinants On Enrollment Into Contemporary Lymphoma Clinical Trials: A Systematic Review, Jun Yang Jiang, Ang Li, Alexis Romero, Christopher R Flowers, Chijioke Nze

Faculty, Staff and Students Publications

While the incidence and survival associated with lymphoma have improved in recent years, outcome disparities related to sociodemographic factors such as age, sex, race, ethnicity, socioeconomic status (SES), and other social determinants of health (SDOH) remain prevalent in the modern era. Clinical trials are crucial for further improving outcomes, yet not all sociodemographic groups are equally represented in contemporary lymphoma trials. We conducted a systematic review of the literature evaluating the impact of SDOH on enrollment into clinical trials in the United States and identified 21 relevant studies. We confirmed that Black and Hispanic individuals are underrepresented in lymphoma clinical …

Career Impact Of The National Interprofessional Fellowship In Patient Safety: An Alumni Evaluation, Bradley V Watts, Kathleen Carluzzo, Blake F Webb, Kelley Arredondo

Faculty, Staff and Students Publications

Background: There has been a proliferation of health professions training programmes focused on quality and patient safety, but little information regarding the outcomes of these programmes. The purpose of this study was to examine the impact of an interprofessional quality and patient safety curriculum on career outcomes of interprofessional healthcare learners for the Veterans Affairs Patient Safety Fellowship.

Method: We conducted a survey-based assessment of 117 alumni of the Interprofessional Fellowship in Patient Safety assessing their satisfaction with the training program and career impacts.

Results: 84 of 117 alumni were located and participated in the assessment. Fellows entered the training …

Linking Dna Methylation In Brain Regions To Alzheimer’S Disease Risk: A Mendelian Randomization Study, Hua Zhong, Jingjing Zhu, Shuai Liu, Dan Zhou, Quan Long, Chong Wu, Bingxin Zhao, Chao Cheng, Yaohua Yang, Qing Wu, Yong Wu, Changwei Li, Zhaoming Wang, Jianyong Wu, Xingyi Guo, Degui Zhi, Youping Deng, Lang Wu

Faculty, Staff and Students Publications

Aim: DNA methylation in brain regions represents a potential mechanism linking genetic variation to Alzheimer's disease (ad) risk, yet most studies have focused on blood-derived methylation markers. In this study, we conducted a systematic Mendelian randomization (MR) study to evaluate associations between predicted brain region-specific DNA methylation levels and ad risk, using methylation quantitative trait loci (mQTL) as genetic instruments.

Methods: We analyzed mQTLs from five human brain regions: cerebellum (CRBLM), frontal cortex (FCTX), causal pons (PONS), and temporal cortex (TCTX) from 600 individuals in Gibbs et al's study, as well as mQTLs from dorsolateral prefrontal cortex (DLPFC) of 543 …

Importance Of Outbreak Response Research In Bridging Knowledge Gaps On Emerging Infectious Diseases, Robert F Breiman, David Wang, Michael Diamond, Adrianus C M Boon, Et Al.

2020-Current year OA Pubs

An important outcome of the devastating 2014 West African Ebola virus disease outbreak and the 2020 COVID-19 pandemic has been the growing promotion of conducting research during outbreaks of emerging infectious diseases (EIDs) as a valuable and acceptable process of acquiring knowledge to enhance our ability to better prevent and control these diseases in the future. Recognising the unique opportunity during outbreaks to leverage increases in cases over a short time interval and in a circumscribed area, we articulate a systematic process of conducting EID outbreak response research, highlighting knowledge gaps that should be prioritised, and measures that can be …

Quality Over Quantity-Current Challenges Of Robotic Surgery In Poland, Marcin Kubiak, Jacek Doniec, S Vincent Grasso, Andrew Gumbs, Amir Nour Mohammadi, Katarzyna Sędłak, Zuzanna Pelc, Stanisław Góźdź, Wojciech Załuska, Artur Bachta, Paweł Rybojad, Kamil Torres, Timothy M Pawlik, Marek Zawadzki, Andrzej Budzyński, Karol Rawicz-Pruszyński

Rowan-Virtua School of Osteopathic Medicine Departmental Research

Since its introduction in 2010, a dynamic growth of robotic-assisted surgery (RAS) has been observed in Poland. The number of healthcare institutions implementing RAS has tripled in the last 36 months, with 80 surgical robots currently utilized on a national scale. While urological procedures dominate RAS utilization (73%), adoption in gynecology (12.2%) and gastrointestinal surgery (8.5%) is rising, driven by recent National Health Fund reimbursement policies. However, significant fragmentation and alarmingly low numbers of individual RAS procedures were identified: 47.7% of surgeons perform less than 40 cases annually. Parallel to expanding the robotic surgery reimbursement program, several standardized actions are …

Tumor Microenvironment Governs The Prognostic Landscape Of Immunotherapy For Head And Neck Squamous Cell Carcinoma: A Computational Model-Guided Analysis, Priyan Bhattacharya, Alban J Linnenbach, Andrew P. South, Ubaldo E. Martinez-Outshoorn, Joseph M. Curry, Jennifer M. Johnson, Larry A. Harshyne, Mỹ G. Mahoney, Adam J. Luginbuhl, Rajanikanth Vadigepalli

Department of Otolaryngology - Head and Neck Surgery Faculty Papers

Immune checkpoint inhibition (ICI) has emerged as a critical treatment strategy for squamous cell carcinoma of the head and neck (HNSCC) that halts the immune escape of the tumor cells. Increasing evidence suggests that the onset, progression, and lack of/no response of HNSCC to ICI are emergent properties arising from the interactions within the tumor microenvironment (TME). Deciphering how the diversity of cellular and molecular interactions leads to distinct HNSCC TME subtypes subsequently governing the ICI response remains largely unexplored. We developed a cellular-molecular model of the HNSCC TME that incorporates multiple cell types, cellular states, and transitions, and molecularly …

Comparison Between Pipeline Embolization Device (Ped) Versus Flow Redirection Endoluminal Device (Fred) For Intracranial Aneurysms: A Comprehensive Systematic Review And Meta-Analysis, Seyed Maroufi, Mohammad Fallahi, Muhammad Waqas, Othman Bin-Alamer, Manisha Koneru, Joanna Roy, Jane Khalife, Hamza Shaikh, Daniel Tonetti

Department of Neurosurgery Faculty Papers

OBJECTIVES: The performance of the Pipeline Embolization Device (PED) and relatively newer double-layered Flow Re-Direction Endoluminal Device (FRED) have been studied for the treatment of intracranial aneurysms, but direct comparisons between PED and FRED are limited. The current systematic review aims at comparing the efficacy and safety of PED and FRED.

METHODS: A systematic review of the literature was conducted according to the PRISMA guideline. PubMed, Embase, Scopus, Web of Science, and Cochrane Library were searched, and related records were identified. A meta-analysis of double-arm studies comparing PED and FRED was conducted on angiographic and clinical outcomes, retreatment rates, and …

Plasma Insulin-Like Growth Factor-Binding Protein-7 Is Positively Associated With Age, Obesity, Mortality, And Cancer In Postmenopausal Women, Melissa C Orenduff, Carl F Pieper, Emma H Allott, Michael F Coleman, Su Yon Jung, Mara Z Vitolins, Jenifer I Fenton, Chu Chen, Candyce H Kroenke, Fred K Tabung, Ana Barac, Electra D Paskett, Michael N Pollak, Jennifer Hays-Grudo, Shine Chang, Stephen D Hursting

Faculty, Staff and Student Publications

Background: Predictors of premature death and cancer development are needed to more precisely identify individuals who may warrant preventive intervention. Circulating insulin-like growth factor (IGF)-binding protein-7 (IGFBP7) and, to a lesser extent, the IGFBP7/IGF-1 ratio are emerging biomarkers of renal and cardiovascular morbidity. However, their relationships with aging, obesity, mortality, and cancer risk remain unclear.

Methods: This hypothesis-generating study investigated plasma IGFBP7, IGF-1, and their ratio as predictors of all-cause mortality and the incidence of any cancer (excluding nonmelanoma skin cancer), obesity-related cancer (composite of 13 cancer types), and breast cancer in a large longitudinal cohort of postmenopausal women. We …

Restoration Of The Tumor Suppressor Function Of Y220c-Mutant P53 By Rezatapopt, A Small-Molecule Reactivator, Anna M Puzio-Kuter, Lizhong Xu, Mary Kate Mcbrayer, Romyr Dominique, Hongju H Li, Bruce J Fahr, Alyssa M Brown, Amy E Wiebesiek, Brandon M Russo, Chris L Mulligan, Hong Yang, Josh Battaglia, Kimberly A Robell, Dafydd H Thomas, Kuo-Sen Huang, Alexander Solovyov, Benjamin D Greenbaum, Jonathan D Oliner, Thomas W Davis, Melissa L Dumble, Melissa L Johnson, Shunbin Xiong, Peirong Yang, Guillermina Lozano, Marc M Fellous, Binh T Vu, Alison M Schram, Arnold J Levine, Masha V Poyurovsky

Faculty, Staff and Student Publications

Restoration of the tumor suppressor function of tumor-associated p53 mutants, including the Y220C substitution, has posed a significant challenge for therapeutic discovery. In this study, we describe rezatapopt (PC14586), part of a series of compounds designed to reactivate the p53 Y220C mutant. These compounds restore p53 tumor suppressor function by correcting its conformation and enabling it to bind DNA and activate downstream target genes, thus inducing antiproliferative changes in tumor cells. Our findings are supported by biochemical and structural analysis, in vitro and in vivo transcriptomics, and functional data, revealing the recovery of multiple aspects of the wild-type p53 program. …

Comparison Of Open And Laparo-Endoscopic Repair Techniques For Patients With Bilateral Inguinal Hernias, Divyansh Agarwal, Tina Bharani, Nora Fullington, Lauren Ott, Kortney Hodgson, Daelyn Mcclain, Kaela Blake, Michael Reinhorn

Department of Surgery Faculty Papers

INTRODUCTION: For primary bilateral inguinal hernias, international guidelines favor a laparoscopic posterior mesh repair due to relatively lower risk of acute and chronic pain, faster recovery, and favorable biomechanical properties compared to open anterior approaches (Lichtenstein, plug and patch, etc.). However, studies comparing open mesh-based bilateral inguinal hernia repairs to bilateral laparoscopic and robotic mesh-based approaches are limited. The Abdominal Core Health Quality Collaborative (ACHQC) registry includes longitudinal data on bilateral inguinal hernia repairs performed via open as well as laparo-endoscopic approaches. We hypothesize that outcomes for bilateral inguinal hernia repair are similar between open and laparo-endoscopic approaches in the …

Mutant P53 Gain Of Function: Why Many See It, Why Some Do Not, Guillermina Lozano, Carol Prives, Kanaga Sabapathy

Faculty, Staff and Student Publications

Mutations in the TP53 tumor-suppressor gene in human cancer are unique in that 60% to 70% are of the missense variety, resulting in a full-length protein that is often highly expressed in patients' tumors. These missense mutant proteins often exhibit pro-oncogenic activities (referred to as gain of function) in mouse models and human cell lines and correlate with poor cancer prognosis in some cases.

A Novel Cardiomyopathy Phenotype Linked To A Chd7 Missense Variant, In Young Park, Chih-Wei Hsu, Karim Bouazoune, Christina E Espindola, Madeline Hannah Mclaughlin Armond, Cristian Coarfa, Sandra L Grimm, James F Martin, Donna M Martin, Cheryl Lyn Walker

Center for Medical Ethics and Health Policy Staff Publications

Loss of function in the chromatin remodeler CHD7 causes CHARGE syndrome, characterized by variable penetrance and diverse abnormalities. However, establishing genotype-phenotype correlations has been challenging, as most CHD7 inactivating mutations are null alleles. Through CHD7 missense variant analysis at potential phosphorylation sites, we identified T730 (T720 in mice) as a critical residue associated with pathogenesis. Using a CHD7 T730 missense variant (Chd7T720A) and a frameshift null allele (Chd7fs) in a mouse model, we found that Chd7fs/fs mice were non-viable, while Chd7fs/+ mice exhibited haploinsufficiency-related circling behavior. Notably, Chd7fs/T720A mice died before postnatal …

Correlations Within And Between Highly Multiplexed Proteomic Assays Of Human Plasma, Mary R Rooney, Jingsha Chen, Christie M Ballantyne, Ron C Hoogeveen, Eric Boerwinkle, Bing Yu, Keenan A Walker, Pascal Schlosser, Elizabeth Selvin, Nilanjan Chatterjee, David Couper, Morgan E Grams, Josef Coresh

Faculty, Staff and Students Publications

Introduction: The number of assays on proteomic platforms has grown rapidly. The leading platforms, SomaScan and Olink, have strengths and limitations. Comparisons of precision on the latest platforms-SomaScan 11k and Olink Explore HT-have not yet been established.

Methods: Among 102 participants in the Atherosclerosis Risk in Communities Study (mean age 74 years, 53% women, 47% Black), we used split plasma samples to measure platform precision. CV and Spearman correlations were calculated for each assay. Cross-platform agreement was assessed for overlapping proteins.

Results: SomaScan 11k demonstrated a median correlation of 0.85 for the 10 778 assays and a median CV of …

A Meta-Analysis And Systematic Review Of Cardiac Troponin I Vs T In Community Dwelling Adults: Is Specificity At Risk?, Yashika Parashar, Aya Awwad, Soahum Bagchi, Brian Claggett, Saman Asad Siddiqui, Ajari Winifred Ogheneochuko, Christie M Ballantyne, Christopher Defilippi

Faculty, Staff and Students Publications

Background: Cardiac troponin I and T measured by high-sensitivity assays (hs-cTn) are detectable in most ambulatory adults. Hs-cTnI and T may perform differently for prediction of cardiovascular (CV) events. In adults with myopathies and advanced age, hs-cTnT can lose CV specificity. We undertook a meta-analysis of ambulatory studies measuring hs-cTn to determine whether hs-cTnI is a superior predictor of CV outcomes.

Methods: Articles evaluating hs-cTnI or T for incident heart failure (HF), myocardial infarction (MI), CV, and all-cause death in ambulatory adults were screened. Adjusted HRs were extracted standardized as hs-cTn tertile 3 vs 1. Pooled effects were calculated, and …

Lipoprotein(A) And Heart Failure Among Black And White Participants In Atherosclerosis Risk In Communities Study, Framingham Offspring Study, And Multi-Ethnic Study Of Atherosclerosis: The Pooling Project, Sarah Nomura, Weihua Guan, Yixin Zhang, Geoffrey H Tison, Hiroaki Ikezaki, Margaret R Diffenderfer, Ching-Ti Liu, Ron C Hoogeveen, Christie M Ballantyne, Ernst J Schaefer, Michael Y Tsai

Faculty, Staff and Students Publications

Background: This study investigated Lp(a) (lipoprotein(a)) levels with heart failure (HF) incidence overall and ejection fraction (EF) subtypes among Black and White participants in a pooled analysis of MESA (Multi-Ethnic Study of Atherosclerosis), FOS (Framingham Offspring Study), and ARIC (Atherosclerosis Risk in Communities Study).

Methods: This study was conducted among 16 771 White and Black participants in ARIC (N=10 347), MESA (N=4150), and FOS (N=2274). Baseline was time of Lp(a) measurement (ARIC Visit 4: 1996-1998; MESA Visit 1: 2000-2002; FOS Cycle 6: 1995-1998). HF with reduced EF (HFrEF) was defined as EF < 50% and ≥50% as HF with preserved EF (HFpEF). Cox proportional hazards regression was used to evaluate associations between Lp(a) (log-transformed continuous, dichotomized at ≥30 mg/dL and ≥50 mg/dL, and quartiles) and HF (overall, HFpEF, HFrEF) in the overall population and stratified by race. Analyses were replicated excluding prior history of myocardial infarction.

Results: There were 2759 HF cases (HFpEF N=859; …

Xbp1s-Edem2 Prevents The Onset And Development Of Hfpef By Ameliorating Cardiac Lipotoxicity, Oveena Fonseka, Rida Raja, Claire Ross, Sanskruti R Gare, Jiayan Zhang, Susanne S Hille, Katharine King, Andrea Ruiz-Velasco, Namrita Kaur, Xinyi Chen, Jessica M Miller, Riham R E Abouleisa, Qinghui Ou, Zhiyong Zou, Xiangjun Zhao, Cristian Sotomayor-Flores, Derk Frank, Eileithyia Swanton, Martin R Pool, Sara Missaglia, Daniela Tavian, Gabriele G Schiattarella, Tao Wang, Luigi Venetucci, Christian Pinali, Martin K Rutter, Bernard D Keavney, Elizabeth J Cartwright, Tamer M A Mohamed, Oliver J Müller, Wei Liu

Center for Medical Ethics and Health Policy Staff Publications

Background: Morbidity and mortality of heart failure with preserved ejection fraction (HFpEF) is increased in metabolic disorders. However, options for preventing and treating these prevalent outcomes are limited. Intramyocardial lipotoxicity contributes to cardiac dysfunction. Here, we investigate the mechanisms underlying EDEM2 (endoplasmic reticulum degradation-enhancing alpha-mannosidase-like protein 2) regulation of cardiac lipid homeostasis and assess strategies that inhibit the incidence and progression of HFpEF.

Methods: Metabolic stress was induced in C57BL/6 male mice using a high-fat diet and Nω-nitro-L-arginine methyl ester. The recombinant adeno-associated virus 9 delivery system was used for loss- and gain-of-function studies. Palmitic acid and oleic acid …

Mitral Valve Surgery After Failed Transcatheter Intervention For Mitral Regurgitation: Surgical Techniques, Challenges And Outcomes, Mateo Marin-Cuartas, Syed Zaid, Jörg Kempfert, Michael A Borger, Serdar Akansel, Thilo Noack, David Holzhey, Tsuyoshi Kaneko, Isaac George, Gorav Ailawadi, Robert L Smith, Arnar Geirrson, Ahmed El-Eshmawi, Dimosthenis Pandis, Suzanne De Waha, Nikolaos Bonaros, Fabien Praz, Maurizio Taramasso, Michele De Bonis, Lenard Conradi, Christian Hagl, Nicolas Doll, Mahmoud Wehbe, Alexey Dashkevich, Manuela De La Cuesta, Jagdip Kang, Zara Dietze, Philipp Kiefer, Gilbert H L Tang

Faculty, Staff and Students Publications

Objectives: This review article aims to examine the surgical approach to patients with failed mitral transcatheter edge-to-edge repair (M-TEER), focusing on operative challenges, decision-making and contemporary outcome data. Technical considerations, including device removal and the management of complex mitral valve (MV) anatomy, are discussed.

Methods: We performed a comprehensive literature review and gathered the experience from high-volume centres in the surgical management of failed M-TEER.

Results: MV surgery after failed M-TEER is a complex but increasingly necessary procedure as the use of M-TEER grows. It occurs in up to 6% of patients, with a median age of 70-76 years at …