Digital Commons Network^™

Deep Learning Based Rapid X-Ray Fluorescence Signal Extraction And Image Reconstruction For Preclinical Benchtop X-Ray Fluorescence Computed Tomography Applications, Amrit Kaphle, Sandun Jayarathna, Sang Hyun Cho

Faculty, Staff and Student Publications

Recent research advances have resulted in an experimental benchtop X-ray fluorescence computed tomography (XFCT) system that likely meets the imaging dose/scan time constraints for benchtop XFCT imaging of live mice injected with gold nanoparticles (GNPs). For routine in vivo benchtop XFCT imaging, however, additional challenges, most notably the need for rapid/near-real-time handling of X-ray fluorescence (XRF) signal extraction and XFCT image reconstruction, must be successfully addressed. Here we propose a novel end-to-end deep learning (DL) framework that integrates a one-dimensional convolutional neural network (1D CNN) for rapid XRF signal extraction with a U-Net model for XFCT image reconstruction. We trained …

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 …

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 …

Atrial Fibrillation In An Elite Athlete: Continuous Ecg Monitoring Guiding Therapy And Return To Play., Sean M Muir, Auroa Badin, Anne R Albers, Kanny Grewal

Heart and Vascular Articles

BACKGROUND: The diagnosis of atrial fibrillation (AF) is increasing among elite athletes. This case highlights the novel use of an implantable loop recorder to guide treatment decisions for AF in an elite soccer player.

CASE SUMMARY: A 25-year-old professional soccer player who had received a diagnosis of asymptomatic AF during routine screening underwent cardioversion and continuous monitoring with an implantable loop recorder. A rising AF burden prompted ablation.

DISCUSSION: This case demonstrates the potential utility of advanced monitoring technologies for managing AF in athletes, particularly when symptoms are absent or minimal. Additional studies are needed to confirm whether continuous monitoring …

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 …

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 …

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.

Oxygen Saturation Targeting In The Neonatal Intensive Care Unit, Faeq Almudares, Bheru Gandhi, Jonathan Davies, Xanthi Couroucli, Natalie Villafranco, Nidhy Paulose Varghese, Milenka Cuevas Guaman, Charleta Guillory, Binoy Shivanna

Faculty, Staff and Students Publications

Oxygen (O2) is vital for cellular development, function, proliferation, and repair, underscoring its critical role in organogenesis. Both hypoxia (reduced tissue O2) and hyperoxia (excess tissue O2), when prolonged, can trigger inflammation and oxidative stress, contributing to acute and long-term cardiopulmonary and neurodevelopmental morbidity. In sick neonates, immature defense mechanisms and coexisting morbidities demand nuanced and sometimes opposing strategies for O2 saturation targets and therapeutic titration. Most current neonatal O2 targeting guidelines are based on animal models or small clinical studies, resulting in recommendations with limited evidence. This narrative review aims to provide an updated overview of the physiological roles …

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 …

Emerging Therapeutic Potential Of Fisetin For Nephrotoxicity, Kidney Injury, And Nephropathy: A Systematic Review, Saeed Mohajeri, Alizamen Salehifard Jouneghani, Saeid Heidari-Soureshjani, Catherine M.T. Sherwin, Faramarz Beigi

Pediatrics Faculty Publications

INTRODUCTION/OBJECTIVE: Kidney diseases cause high morbidity and mortality worldwide. This study investigated the mechanistic effects of Fisetin (FIS) on nephrotoxicity, kidney injury, and nephropathy induced by drugs, toxic chemicals, diabetes, lupus, diet, ureteral obstruction, and ischemic situations.

METHODS: To identify pertinent articles published before Oct 1, 2024, a comprehensive electronic search was performed across several databases, including MEDLINE/PubMed, Embase, Cochrane Library, Web of Science, and Scopus. After establishing clear inclusion and exclusion criteria, studies that met the research objectives were selected. Data were extracted and analyzed, documenting study characteristics, methodologies, and biological mechanisms.

RESULTS: Antioxidant benefits were evident with increased …

Racial And Ethnic Representation And Study Engagement In A Siteless Digital Clinical Trial Using A Smartwatch: Findings From The Apple Heart Study., Kaylin T. Nguyen, Jingzhi Yu, Haley Hedlin, Adam T. Phillips, Sumbul Desai, Lauren Cheung, Peter R Kowey, Sneha S. Jain, John S. Rumsfeld, Andrea M. Russo, Christopher B. Granger, Mellanie True Hills, Manisha Desai, Kenneth W. Mahaffey, Mintu P. Turakhia, Marco V. Perez

Department of Medicine Faculty Papers

OBJECTIVE: To evaluate differences in study engagement in diverse racial/ethnic groups that have been significantly underrepresented in atrial fibrillation and digital clinical trials.

PATIENTS AND METHODS: This was a secondary analysis of participants from the Apple Heart Study, a prospective, siteless, single-arm pragmatic clinical trial from November 29, 2017, to January 31, 2019. Black, Hispanic, Asian, and White participants were monitored using an irregular rhythm notification algorithm designed to detect atrial fibrillation on a smartwatch. Logistic regression was performed to evaluate the relationship between race/ethnicity and completion of the first study visit after an irregular rhythm notification, adjusting for demographic …

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 …

Pelvic Pain Symptoms And Inflammation Among Adolescents And Adults With And Without Endometriosis, Amy Shafrir, Ashley Laliberte, Britani Wallace, Allison F. Vitonis, Christine B. Sieberg, Marzieh Ghiasi, Larry I. Magpantay, Marta Epeldegui, Andrew Schrepf, Sawsan As-Sanie, Kathryn L. Terry, Stacey A. Missmer

Health Sciences Faculty Publications

We evaluated inflammatory markers among 389 surgically confirmed endometriosis cases and 505 controls from the Women's Health Study: From Adolescence to Adulthood (A2A) cohort. Participants reported dysmenorrhea, acyclic pelvic pain, dyspareunia, and pain with bowel movements. Using multiplex assays, we measured their levels of plasma interleukin (IL)-1β, -6, -8, -10, and -16, tumor necrosis factor (TNF)-α, monocyte chemotactic protein (MCP)-1 and -4, thymus and activation-regulated chemokine (TARC), and interferon gamma-induced protein (IP)-10. For each symptom, we computed biomarker-level geometric means (GMs) with 95% confidence intervals (95% CI) using multivariate linear regression among the endometriosis cases and controls, with interactions with …

Beyond The Surface: Mapping Dde's Metabolic Footprint On Adolescent Obesity, Zhenjiang Li, Shudi Pan, Brittney O Baumert, Jiawen Carmen Chen, Jesse A Goodrich, Hongxu Wang, Sarah Rock, Justin Ryder, Damaskini Valvi, Todd Jenkins, Stephanie Sisley, Xiangping Lin, Scott M Bartell, Thomas H Inge, Stavra Xanthakos, Brooklynn Mcneil, Anna R Robuck, Catherine E Mullins, Sandrah P Eckel, Rob S Mcconnell, Michele A La Merrill, Douglas I Walker, David V Conti, Lida Chatzi

Faculty, Staff and Students Publications

Background: Bariatric surgery is an intervention for severe obesity, leading to significant weight loss and metabolic improvements. However, the release of lipophilic chemicals accumulated in adipose tissue during weight loss presents a unique clinical challenge and research opportunity. Dichlorodiphenyldichloroethylene (DDE) is a persistent organic pollutant increasingly recognized as obesogen, while the biological mechanisms through which DDE influences body mass index (BMI) and waist circumference remain underexplored.

Objectives: We aimed to identify metabolic signatures mediating the association between DDE exposure and weight loss by plasma and adipose tissue metabolomics.

Methods: We conducted a longitudinal study involving 60 adolescents with severe obesity …

Time-Driven Activity-Based Costing For Cervical Myelopathy Surgery: A Step Towards Total Episode Costs, Kavantissa M. Keppetipola, Adam Leibold, Jay Trivedi, Ashmal Sami, Advith Sarikonda, D. Mitchell Self, Emily L. Isch, Steven R. Glener, Srinivas Prasad, Jack Jallo, Joshua E. Pelta-Heller, James Harrop, Alex R. Vaccaro, Ahilan Sivaganesan

Department of Neurosurgery Faculty Papers

INTRODUCTION: Time-driven activity-based costing (TDABC) is a highly accurate method for determining the true cost of delivering a healthcare service. However, TDABC is most often applied to a singular phase of care such as an outpatient visit or a surgical event. Here we broaden the scope by using TDABC to estimate the costs of surgically treating cervical myelopathy - from the moment of surgical scheduling until post-operative hospital discharge.

METHODS: In a single-center retrospective study at a large tertiary academic institution, TDABC was employed to measure pre-operative, intra-operative, and post-operative (inpatient) costs for 63 patients undergoing elective surgery for cervical …

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 …

In Situ Structure And Assembly Of The Abc-Type Tripartite Pump Macab-Tolc, Tong Huo, Wenfang Zhang, Zhili Yu, Wei Zheng, Yaoming Wu, Qiuyu Ren, Zekai Wan, Junli Cao, Zhao Wang, Xiaodong Shi

Faculty, Staff and Students Publications

The MacAB-TolC tripartite efflux pump is widely distributed in Gram-negative bacteria, extruding antibiotics and virulence factors that lead to multidrug resistance and pathogenicity. However, the in situ structure and assembly mechanism of MacAB-TolC remain unclear. Here, we resolve the in situ structures of the MacAB-TolC efflux pump in Escherichia coli by electron cryo-tomography and subtomogram averaging. In the cells without antibiotic treatment, we observe a fully assembled MacAB-TolC pump. When Escherichia coli cells are treated with erythromycin, in addition to the tripartite pumps, we also discover the emergence of MacA-TolC subcomplexes without MacB, indicating flexible binding of MacB in the …

Targeting Eya1 Phosphatase Activity In Mll-Rearranged Leukemia, Lola Badmus

Dissertations

MLL-rearranged (MLL-r) leukemia is an aggressive subset of acute leukemia, accounting for up to 10% of adult and 70% of infant AML and ALL cases. These leukemias are driven by MLL fusion proteins, which recruit epigenetic cofactors to dysregulate gene expression, leading to poor prognosis and resistance to conventional chemotherapy. Previous lab work identified EYA1’s role in leukemogenesis, establishing it as a therapeutic target in MLL-r leukemia. EYA1, is a transcriptional coactivator and protein tyrosine phosphatase (PTP). Originally a gout medication, benzbromarone (BBR), was identified in an NCI Diversity Set screen as an EYA1-specific PTP inhibitor. BBR provides a tool …

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 …

Posterior Predictive Design For Phase I Clinical Trials, Chenqi Fu, Shouhao Zhou, J Jack Lee

Faculty, Staff and Student Publications

Interval-based designs represent cutting-edge adaptive methodologies for phase I clinical trials to identify the maximum tolerated dose (MTD). These designs exhibit robust performance comparable to more intricate, model-based designs, and their pretabulated decision rule enables them to be implemented as simply as the conventional algorithm-based designs. In this paper, we introduce the posterior predictive (PoP) design, a novel interval-based design that leverages advanced Bayesian predictive hypothesis testing techniques for dose escalation and de-escalation. Our work moves beyond the existing model-assisted interval-based designs by achieving global optimality in dose transition. Theoretically, the global optimality ensures that the proposed design can consistently …

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 …

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 …

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 …

Phage-Induced Protection Against Lethal Bacterial Reinfection, Yikun Xing, Haroldo J Hernandez Santos, Ling Qiu, Samantha R Ritter, Jacob J Zulk, Rachel Lahowetz, Kathryn A Patras, Austen L Terwilliger, Anthony W Maresso

Faculty, Staff and Students Publications

Bacteriophages, or phages, are viruses that target and infect bacteria. Due to a worldwide rise in antimicrobial resistance (AMR), phages have been proposed as a promising alternative to antibiotics for the treatment of resistant bacterial infections. Up to this point in history, phage use in preclinical animal studies, clinical trials, and emergency-use compassionate care cases has centered around the original observation from 1915 showing phage as lytic agent, and thus a treatment that kills bacteria. Here, we describe an activity associated with phage therapy that extends beyond lytic activity that results in long-term protection against reinfection. This activity is potent, …

Adipocyte/Tumor Cell Crosstalk Via Igf-1/Txnip Axis Promotes Malignancy And Endocrine Resistance In Breast Cancer, Amanda Caruso, Felice Maria Accattatis, Cinzia Giordano, Luca Gelsomino, Piercarlo Del Console, Maria Francesca Fiorita, Balazs Gyorffy, Laura Bianchi, Alfonso Carleo, Rossana De Salvo, Bruno M Simões, Robert B Clarke, Lorenzo Memeo, Cristina Colarossi, Eleonora Aiello, Francesco Conforti, Suzanne A W Fuqua, Matilde Todaro, Giorgio Stassi, Catia Morelli, Diego Sisci, Daniela Bonofiglio, Stefania Catalano, Sebastiano Andò, Ines Barone

Faculty, Staff and Students Publications

Background: Despite significant improvements in the outcome of Estrogen Receptor (ER) α-positive breast cancer (BC) following the use of endocrine therapies, resistance remains a major challenge. Clinical studies proved that obesity, in addition to promote BC progression, is associated with a reduced efficacy to these treatments, but mechanisms remain unclear.

Methods: We used co-culture systems followed by validation through an ‘ex vivo’ model of human mammary obese (Ob) adipocytes and obese endocrine-resistant metastatic Patient-Derived Organoids (PDOs). Transcriptomics with MixOmics-MINT and MetaCore Functional Tools along with lentiviral and pharmacological approaches provide insights into mechanisms. Clinical relevance was investigated using public datasets, …

Education In Advance Care Planning: A Novel Equity-Based, Interprofessional Service-Learning Approach, Dorothy Yam, Sriya Kudaravalli, Elizabeth A. Mulvaney, Leslie Scheunemann, Grace W. Orsatti

Journal of Innovation in Health Sciences Education

Introduction: Despite health sciences graduate schools emphasizing service-learning and interprofessionalism, they often struggle to integrate these values into the curricula effectively. Advance care planning is inherently interdisciplinary and presents an opportunity to address equity gaps through service-learning. This report describes a novel interdisciplinary service-learning initiative for graduate student trainees, focused on advance care planning in underserved communities.

Methods: After targeted training, teams of medical, law, and social work students, and professionals from their respective fields, took part in two Life Planning Fairs in historically underserved neighborhoods in Pittsburgh, Pennsylvania. Using a form developed by the Allegheny County Bar Association …