Digital Commons Network^™

Pediatric Vs Adult Invasive Aspergillosis In Cancer And Hematopoietic Transplant Patients: Insights From A Matched Cohort At A Tertiary Cancer Center, Saliba Wehbe, Ramia Zakhour, Ray Hachem, Ying Jiang, Hiba Dagher, Roseen Salman, Anne-Marie Chaftari, Issam I Raad

Faculty, Staff and Student Publications

Background: Invasive aspergillosis (IA) is a life-threatening infection in immunocompromised patients, including those with hematologic malignancies and hematopoietic stem cell transplants. While adult IA has been well characterized, data on pediatric populations remain limited, and potential age-related differences are often overlooked in current management guidelines.

Methods: We conducted a retrospective matched cohort study at a tertiary cancer center, evaluating IA cases diagnosed over a 31-year period. Pediatric patients (≤18 years) with proven or probable IA were matched 1:3 with adult IA cases based on year of diagnosis, underlying disease, and history of hematopoietic cell transplantation. We compared demographics, clinical presentation, …

Peritoneal Delivery Of Capsinoids, Nonpungent Trpv1 Agonists, Induces Mild Hypothermia In Conscious Mice Through Trpv1 Activation Of Visceral Vagal Afferents, Alexander P Andersohn, Ting Wu, Andrea N Doan, Charles L Cantrell, Robert L Jarret, Sean P Marrelli

Faculty, Staff and Student Publications

Therapeutic hypothermia (TH) has demonstrated neuroprotection in instances of cardiac arrest and neonatal hypoxia/ischemia but faces different challenges in application to stroke due to the activation of cold defense mechanisms in conscious patients. This study examined the efficacy and specificity of capsinoids (a purified mixture of capsiate and dihydrocapsiate) to induce a sustained fall in core body temperature in conscious mice. Capsinoids function as TRPV1 agonists. However, unlike capsaicin, capsinoids are vulnerable to esterase-mediated breakdown, thus significantly restricting their action to the site of delivery. We showed that capsinoids delivered intraperitoneally (IP) to mice induced a TRPV1-dependent drop in core …

Targeting Gliomas With Beta-Amyloid-Specific Dyes: A Novel Approach For In Vivo Staining And Potential Therapeutic Applications, Lilia Kucheryavykh, Jescelica Ortiz Rivera, Boris Ermolinsky, Vassiliy Tsytsarev, Lynnette Cary, Janaina Alves, Adriana Reyes, Noelis De La Cruz-Rivera, Kevin Rosa Gonzalez, Felix Narvaez Irizarry

School of Integrative Biological & Chemical Sciences Faculty Publications

Gliomas, the most common primary brain tumors, present significant diagnostic and treatment challenges due to their infiltrative nature and heterogeneity. Our previous research revealed that glioma tumors in both animals and humans accumulate beta-amyloid protein (Aβ), detectable through immunohistochemical methods or staining with amyloid-specific dyes. We hypothesize that beta-amyloid-specific dyes could serve as glioma markers, potentially enabling the delineation of glioma tumors or targeted therapeutics delivery. In this study, the specificity and blood-brain barrier permeability of two fluorescent beta-amyloid-specific dyes, Brilliant Blue G (BBG) and BODIPY-based Amyloid Probe-1 (BAP-1), were evaluated in C57Bl/6 mouse glioma implantation models using GL261 and …

Signs, Symptoms, And Health-Related Quality Of Life In Melas: Measuring What’S Important From The Patient And Clinician Perspectives, Paolo Medrano, Benjamin Banderas, Marisa Brimmer, Lily Settel, Sari Berger, Alan Shields, Amy Goldstein, Amel Karaa, Austin Larson, Sumit Parikh, Fernando Scaglia, Karra Danyelle Harrington, Chris James Edgar, Pamela Ventola, Matthew Webster, Jennifer Chickering, Chad Gwaltney, Phebe Wilson, Chad Glasser

Faculty, Staff and Students Publications

Background and objectives: Mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) is a rare genetic syndrome mostly associated with pathogenic variants in mitochondrial DNA. As there is limited research on the life experience of patients with MELAS, this study aimed to develop an understanding of the patient experience of MELAS through qualitative interviews to identify, describe, and substantiate important and relevant signs, symptoms, and health-related quality-of-life (HRQoL) impact (S/S/I) concepts.

Methods: Clinician and patient interviews were conducted virtually using semi-structured interview guides. During 60-minute interviews with five experts in the United States, clinicians were asked for their perspective on …

A Novel Approach To Calculating Expected Total Fetal Lung Volume In Fetuses With Isolated Congenital Diaphragmatic Hernia And Fetal Growth Restriction: A Theoretical Computational Simulation, Morcos Hanna, Jonathan Davies, Amaryllis Fernandes, Pamela M Ketwaroo, Amy R Mehollin-Ray, Roopali Donepudi, Alice King, Joseph Hagan, Sundeep G Keswani, Sharada H Gowda, Caraciolo J Fernandes

Faculty, Staff and Students Publications

Objectives: Congenital diaphragmatic hernia (CDH) often coexists with fetal growth restriction (FGR). The observed-to-expected (O/E) total fetal lung volume (TFLV) is used to assess CDH severity, predict outcomes, and direct fetal interventions. Expected TFLV measurements traditionally rely only on gestation age (GA). This simulation assesses how incorporating weight-adjusted GA norms affects O/E TFLV calculations in patients with isolated CDH and FGR.

Methods: A simulated dataset (n=1,005) utilized published mean fetal weight and TFLV references. Computer-generated variables included observed weights (3rd-10th %ile), O/E TFLV (10-65 %), and percent liver herniation (0-42 %). GA estimates were corrected by weight and used to …

Female Cardioprotection In A Mouse Model Of Alcohol-Associated Cardiomyopathy, Joshua M. Edavettal, Meagan Donovan, Nicholas R. Harris, Xavier R. Chapa-Dubocq, Keishla M. Rodríguez-Graciani, Janos Paloczi, Liz Simon, Bysani Chandrasekar, Jason D. Gardner

School of Graduate Studies Faculty Publications

Chronic alcohol misuse is the leading cause of non-ischemic dilated cardiomyopathy, and the molecular mechanisms underlying the development of alcohol-associated cardiomyopathy (ACM), particularly regarding sex-specific susceptibility and mitochondrial contributions, are not fully known. In this study, we utilized a preclinical model of chronic + binge ethanol consumption to investigate sex differences in disease severity and mitochondrial function. Male and female C57BL/6J mice were fed ethanol or control liquid diets for 30 days, with 2 binge episodes on days 10 and 30. Cardiac morphology was assessed via echocardiography and cardiac function via left ventricular pressure-volume catheterization. Mitochondrial function was evaluated ex …

Bifurcated In-Stent In Situ Technique For Creation Of A Bifurcated Bridging Stent-Graft System To 2 Target Vessels Using A Single Directional Branch: A Report Of 2 Cases, Gustavo Paludetto, Lethicia Mesquita, Bruno Pagnin Schmid, Lucas Ruiter Kanamori, Dora Babocs, Thanila A Macedo, Gustavo S Oderich

Faculty, Staff and Students Publications

Objective: The objective of the study is to describe a novel bifurcated in-stent in situ technique (BIS2T) for creation of a bifurcated bridging stent-graft system to target 2 vessels using a single directional branch during complex endovascular aortic aneurysm.

Technique: The technique uses 3 balloon-expandable stent-grafts. The first supporting stent-graft is deployed from the directional branch into the first target vessel or aneurysm sac. A reentry catheter is used to create an in situ fenestration in the first stent-graft, which is predilatated with a 3 mm 0.014 inch angioplasty balloon. This is exchanged for a 0.035 inch 5 Fr catheter …

Overview Of Exosomal Non-Coding Rnas In Cardiovascular Disease Using High Throughput Sequencing, Mortaza Eivazi, Leila Abkhooie, Kamran Hosseini, Parnia Mobasheran, Tahereh Ebrahimi, Vahideh Tarhriz, Eric Lazartigues

School of Graduate Studies Faculty Publications

Non-coding RNAs including miRNAs, long-ncRNAs, and circular RNAs play crucial roles in cell-to-cell communication and epigenetic regulation. They control gene expression at multiple levels, including transcriptional, post-transcriptional, and translational, thereby influencing associated signaling pathways. Encapsulated within exosomes, micro-vesicles, and apoptotic bodies, ncRNAs can be transported between cells while being protected from harsh environmental conditions. Studies have shown various expression patterns across different cell types and in various physiological and pathological states. However, the precise correlations and extent of their contribution to diseases are still under investigation. Recent studies have reported the involvement of extracellular vesicle-associated ncRNAs in the pathogenesis of …

Thrombi From Stroke Due To Cardioembolic Etiology Have Higher Cd11b-Positive Cells Compared To Large Artery Atherosclerosis, Carson Finger, Gomana Emara, Gabriel S Chiu, Kelly Li, Sunil Sheth, Chunfeng Tan, Maria Parekh, Mehmet Enes Inam, Deepa Dongarwar, Bharti Manwani

Faculty, Staff and Student Publications

Identifying the underlying etiology of ischemic stroke is crucial for implementing effective stroke prevention measures. In the era of thrombectomy, ischemic stroke thrombus composition has gained considerable interest in the recent years. However, only a limited studies have analyzed the inflammatory milieu of the thrombus in association with stroke etiology. Atrial Fibrillation (AF), a common etiology of large strokes, is difficult to detect, but is known to be an inflammatory disease with a dominance of CD11b cell types (characterizes bone marrow derived myeloid cells such as monocytes, neutrophils, macrophages, and natural killer cells) in the atria. We hypothesized that thrombi …

Decreasing Barriers To The Utilization Of Cryopreserved Sperm In Male Cancer Survivors: An Expert Review And Guide, Megan V Alexander, Hailie Ciomperlik, Anna Claire Reynolds, Allyson Nevins, Luwam Ghidei, Jordan Kassab, Kevin Campbell, John Sullivan, Michael D Jochum, Laura Detti, Terri L Woodard, Larry I Lipshultz, Laurie J Mckenzie

Faculty, Staff and Students Publications

Cryopreservation of sperm offers male cancer patients a critical opportunity to preserve fertility prior to gonadotoxic treatments. Despite its increasing availability, utilization rates remain modest at typically less than ten percent. This expert review provides a framework for an optimal Oncofertility Patient Care Pathway, explores the multifaceted barriers to cryopreserved sperm use, and proposes specific solutions. We focus on key timepoints for intervention, including the post-treatment fertility care return visit, continued sperm cryopreservation while remote from family building, eventual readiness for family building, and posthumous considerations. Patients often face difficulty engaging in post-treatment reproductive follow-up, with one-third of patients missing …

Human Papillomavirus Vaccine Uptake In Ethnically Diverse Women Living With Systemic Lupus Erythematosus, Sebastian Bruera, Yinan Huang, Savannah Bowman, Maria E Suarez-Almazor, Grace H Lo, Maria A Lopez-Olivo, Elizabeth Chiao, Jennifer R Kramer, Frederick A Pereira, Sandeep K Agarwal

Faculty, Staff and Students Publications

Background: Women with systemic lupus erythematosus (SLE) are at an increased risk of infection from the human papillomavirus (HPV) and subsequently HPV-mediated malignancies and genital warts. The HPV vaccine is a highly effective intervention in preventing HPV infection and is recommended in SLE patients. We determined HPV vaccination rates and factors associated with decreased vaccination uptake in women living with SLE.

Methods: We conducted a cross-sectional study in which we enrolled women with SLE (aged 21–45) for whom the HPV vaccine is recommended for by the US Food and Drug Administration (FDA). The primary outcome was self-reported HPV vaccination as …

Using The Electronic Health Record To Facilitate Drug Allergy Delabeling., Matthew J Molloy, Adam P Yan, Averi E Wilson, Jonathan Beus, Lauren M Hess

Faculty, Staff and Students Publications

Purpose of review: There is a growing number of allergy delabeling programs across diverse clinical specialties and care settings. The electronic health record (EHR) can be leveraged to facilitate allergy delabeling. The purpose of this review is to describe EHR tools that have been used in allergy delabeling programs. We also provide recommendations for organizations considering EHR-based allergy delabeling workflows that incorporate clinical informatics best practices.

Recent findings: Recent literature describes several EHR tools used in delabeling. These tools can be organized around the steps of the allergy delabeling workflow: 1. Identify eligible patients, 2. Risk stratify, 3. Evaluation and …

Setdb1 Is Critically Required For Uveal Melanoma Growth And Represents A Promising Therapeutic Target, Imène Krossa, Céline Pisibon, Yann Cheli, Karine Bille, Mélanie Dalmasso, Sabah Hamadat, Chrystel Husser, Marie Irondelle, Julien Cherfils-Vicini, Frédéric Soysouvanh, Sacha Nahon-Esteve, Arnaud Martel, Sandra Lassalle, Jean-Pierre Caujolle, Célia Maschi, Stéphanie Baillif, Dan Hasson, Saul Carcamo, Andrerw E. Aplin, Irwin Davidson, Emily Bernstein, Valeria Naim, Robert Ballotti, Corine Bertolotto, Thomas Strub

Department of Pharmacology, Physiology, and Cancer Biology Faculty Papers

Metastatic uveal melanomas are highly resistant to all existing treatments. To identify actionable vulnerabilities, we conducted a CRISPR-Cas9 knockout screen using a library composed of chromatin regulators. We revealed that the lysine methyltransferase, SETDB1, plays a critical role in metastatic uveal melanoma cell proliferation and survival. Functionally, SETDB1 deficiency induces a DNA damage response, senescence-like state and growth arrest. Knockdown of SETDB1 is associated with a decreased expression of genes related to replication and cell cycle. Moreover, deficiency in CDC6, an essential regulator of DNA replication, phenocopies SETDB1 inhibition. Using a pre-clinical model, we further demonstrated that anti-SETDB1 therapy impairs …

Transdiagnostic Alterations In White Matter Microstructure Associated With Suicidal Thoughts And Behaviours In The Enigma Suicidal Thoughts And Behaviours Consortium, Laura S Van Velzen, Lejla Colic, Zuriel Ceja, Maria R Dauvermann, Luca M Villa, Hannah S Savage, Yara J Toenders, Niousha Dehestani, Alyssa H Zhu, Adrian I Campos, Lauren E Salminen, Martin Alda, Ingrid Agartz, Nina Alexander, Rosa Ayesa-Arriola, Elizabeth D Ballard, Nerisa Banaj, Carlotta Barkhau, Zeynep Başgöze, Jochen Bauer, Francesco Benedetti, Klaus Berger, Bianca Besteher, Katharina Brosch, Manuel Canal-Rivero, Simon Cervenka, Romain Colle, Colm G Connolly, Emmanuelle Corruble, Philippe Courtet, Baptiste Couvy-Duchesne, Benedicto Crespo-Facorro, Kathryn R Cullen, Udo Dannlowski, Jeremy Deverdun, Ana M Diaz-Zuluaga, Lorielle M F Dietze, Jennifer W Evans, Negar Fani, Kira Flinkenflügel, Naomi P Friedman, Ian H Gotlib, Nynke A Groenewold, Dominik Grotegerd, Tomas Hajek, Alexander S Hatoum, Marco Hermesdorf, Ian B Hickie, Yoshiyuki Hirano, Tiffany C Ho, Yuki Ikemizu, Frank Iorfino, Jonathan C Ipser, Yuko Isobe, Andrea P Jackowski, Fabrice Jollant, Tilo Kircher, Melissa Klug, Sheri-Michelle Koopowitz, Anna Kraus, Axel Krug, Emmanuelle Le Bars, Elisabeth J Leehr, Meng Li, Elizabeth T C Lippard, Carlos Lopez-Jaramillo, Ivan I Maximov, Andrew M Mcintosh, Katie A Mclaughlin, Sean R Mcwhinney, Susanne Meinert, Elisa Melloni, Philip B Mitchell, Benson Mwangi, Igor Nenadić, Stener Nerland, Emilie Olie, Victor Ortiz-García De La Foz, Pedro M Pan, Fabricio Pereira, Fabrizio Piras, Federica Piras, Sara Poletti, Andrew E Reineberg, Gloria Roberts, Rafael Romero-García, Matthew D Sacchet, Giovanni A Salum, Anca-Larisa Sandu, Carl M Sellgren, Eiji Shimizu, Harry R Smolker, Jair C Soares, J Douglas Steele, Frederike Stein, Dan J Stein, Benjamin Straube, Lea Teutenberg, Florian Thomas-Odenthal, Paula Usemann, Romain Valabregue, Johanna Valencia-Echeverry, Gerd Wagner, Gordon Waiter, Martin Walter, Heather C Whalley, Mon-Ju Wu, Tony T Yang, Carlos A Zarate, Andre Zugman, Giovana B Zunta-Soares, Kees Van Heeringen, Sanne J H Van Rooij, Nic Van Der Wee, Steven Van Der Werff, Paul M Thompson, Hilary P Blumberg, Anne-Laura Van Harmelen, Miguel E Rentería, Neda Jahanshad, Enigma Suicidal Thoughts And Behaviours Consortium, Lianne Schmaal

Faculty, Staff and Student Publications

Previous studies have suggested that alterations in white matter (WM) microstructure are implicated in suicidal thoughts and behaviours (STBs). However, findings of diffusion tensor imaging (DTI) studies have been inconsistent. In this large-scale mega-analysis conducted by the ENIGMA Suicidal Thoughts and Behaviours (ENIGMA-STB) consortium, we examined WM alterations associated with STBs. Data processing was standardised across sites, and resulting WM microstructure measures (fractional anisotropy (FA), axial diffusivity (AD), mean diffusivity and radial diffusivity) for 24 WM tracts and one global measure were pooled across 40 cohorts. We compared these measures among individuals with a psychiatric diagnosis and lifetime history of …

Distinct Spatiotemporal Patterns Of White Matter Hyperintensity Progression, Jinyong Chung, Gilsoon Park, Wi-Sun Ryu, Dawid Schellingerhout, Hang-Rai Kim, Dong-Seok Gwak, Elizabeth Haddad, Neda Jahanshad, Beom Joon Kim, Keun-Sik Hong, Hyerin Oh, Sang-Wuk Jeong, Joon-Tae Kim, Man Seok Park, Kang-Ho Choi, Kyungbok Lee, Tai Hwan Park, Sang-Soon Park, Jong-Moo Park, Kyusik Kang, Kyung-Ho Yu, Mi Sun Oh, Soo Joo Lee, Jae Guk Kim, Jae-Kwan Cha, Dae-Hyun Kim, Jun Lee, Moon-Ku Han, Yong-Jin Cho, Byung-Chul Lee, Philip M Bath, Joanna M Wardlaw, Hee-Joon Bae, Hosung Kim, Dong-Eog Kim

Faculty, Staff and Student Publications

White matter hyperintensity, a key imaging biomarker for brain health, has prognostic implications for stroke. Using a multicenter MRI dataset of 9179 stroke patients plus the UK Biobank (n = 36,210 low/high risk controls), we employ Subtype and Stage Inference modeling and identify three distinct white matter hyperintensity progression subtypes: fronto-parietal, radial, and temporo-occipital. Longitudinal validation confirms classification stability. The fronto-parietal subtype shows delayed onset and more hypertension, while the temporo-occipital subtype has more atrial fibrillation and coronary heart disease. The fronto-parietal and radial subtypes are linked to small vessel stroke, while the temporo-occipital subtype is linked to cardioembolism. The …

Leptin As A Key Driver For Organ Fibrogenesis, Xue-Nan Sun, Shiuhwei Chen, Shangang Zhao, Jan-Bernd Funcke, Megan Virostek, Line Pedersen, Chao Li, Chanmin Joung, Qian Lin, Yan Li, Ayanna Cobb, May-Yun Wang, Kyounghee Min, Lisandro Maya-Ramos, Giovanna Degasperi, Junquan Liu, Ningyan Zhang, Zhiqiang An, Diana R Tomchick, R Max Wynn, Da Young Oh, Philipp E Scherer

Faculty, Staff and Student Publications

Leptin, a hormone primarily secreted by adipocytes, regulates energy balance and systemic metabolism through its interaction with the leptin receptor (LEPR). Beyond these functions, leptin signaling has been implicated in the pathogenesis of tissue fibrosis. Here, we report the x-ray crystal structures of a leptin-neutralizing antibody (hLep3) in the unbound and leptin-bound states. The interaction of this antibody with leptin mimics the interaction of the LEPR with leptin, providing direct insights into the mechanism by which the antibody disrupts leptin signaling. We furthermore evaluate the therapeutic potential of neutralizing leptin with this antibody across distinct mouse models of fibrosis affecting …

Whole-Genome Sequencing Reveals Individual And Cohort Level Insights Into Chromosome 9p Syndromes, Yingxi Wang, Eleanor I Sams, Rachel Slaugh, Sandra Crocker, Emily Cordova Hurtado, Sophia Tracy, Ying-Chen Claire Hou, Christopher Markovic, Kostandin Valle, Victoria Tate, Khadija Belhassan, Elizabeth Appelbaum, Titilope Akinwe, Rodrigo T Starosta, Yang Cao, Amber Neilson, Yu Liu, Nathaniel Jensen, Reza Ghasemi, Tina Lindsay, Juana Manuel, Sophia Couteranis, Milinn Kremitzki, Jack Ustanik, Thomas Antonacci, Jeffrey K Ng, Andrew Emory, Laura Metz, Tracie Deluca, Katherine N Lyons, Toni Sinnwell, Brianne Thomeczek, Kymme Wang, Nick Sisneros, Megha Muraleedharan, Anantha Kethireddy, Marco Corbo, Harsha Gowda, Katherine A King, Christina A Gurnett, Susan K Dutcher, Catherine Gooch, Yang E Li, Matthew W Mitchell, Kevin A Peterson, Amjad Horani, Jill A Rosenfeld, Weimin Bi, Pawel Stankiewicz, Hsiao-Tuan Chao, Jennifer E Posey, Christopher M Grochowski, Zain Dardas, Erik G Puffenberger, Christopher E Pearson, Frank Kooy, Dale Annear, A Micheil Innes, Michael Heinz, Richard Head, Robert Fulton, Stephan Toutain, 9p-Arch, Lucinda Antonacci-Fulton, Xiaoxia Cui, Robi D Mitra, F Sessions Cole, Julie Neidich, Patricia I Dickson, Jeffrey Milbrandt, Tychele N Turner

Faculty, Staff and Students Publications

Background: Previous genomic efforts on chromosome 9p deletion and duplication syndromes have utilized low-resolution strategies (i.e., karyotypes, chromosome microarrays). These studies have provided important initial insights into these syndromes. This current study is the first large-scale whole-genome sequencing (WGS) study of 100 individuals from families with chromosome 9p syndromes.

Methods: Through the newly formed 9P-ARCH (Advanced Research in Chromosomal Health: Genomic, Phenotypic, and Functional Aspects of 9p-Related syndromes) research network, we assembled a cohort of individuals from families with chromosome 9p syndromes. WGS was applied to 100 individuals, and other genomic technologies were applied to a subset of individuals. To …

Lorbin: Efficient Binning Of Long-Read Metagenomes By Multiscale Adaptive Clustering And Evaluation, Wei Xue, Zuo Liu, Yaozhong Zhang, Waseem Raza, Yarong Li, Li Jiang, Ye Tao, Jun Qian, Jousset Alexandre, Fang-Jie Zhao, Yangchun Xu, Fritz Sedlazeck, Qirong Shen, Gaofei Jiang, Zhong Wei

Faculty, Staff and Students Publications

Long-read sequencing has transformed metagenomics and improved the quality of metagenome-assembled genomes (MAGs). However, current binning methods struggle with identifying unknown species and managing imbalanced species distributions. Here, we present LorBin, an unsupervised binner specially designed to reconstruct MAGs in natural microbiomes. LorBin deploys a two-stage multiscale adaptive DBSCAN and BIRCH clustering with evaluation decision models using single-copy genes to maximize MAG recovery. LorBin outperforms six competing binners in both simulated and real microbiomes, including oral, gut, and marine samples. LorBin generated 15-189% more high-quality MAGs with high serendipity and identified 2.4-17 times more novel taxa than state-of-the-art binning methods. …

Compromised Pressure-Generating Capacity Of Diaphragmatic Muscle And Its Interaction With The Lower Rib Cage At High Lung Volume During Airway Occlusion, Aladin M Boriek, Noralis Rodriguez-Santiago, Sanghyun Kim, Aubri Ford, Shari Wynd, Rolf D Hubmayr

Faculty, Staff and Students Publications

The pressure generating capacity of the diaphragm is generally thought to be compromised at high lung volume either due to loss of curvature or loss of its membrane tension. At a state of hyperinflation during airway occlusion at total lung capacity, the diaphragmatic muscle is forced to contract from an initial shorter length, the zone of apposition narrows, insertional force on the chest wall is reduced and abdominal compliance falls. We hypothesize that these altered mechanical conditions at high lung volume lead to a loss of the pressure generating capacity that is mediated by excessive muscle shortening rather than loss …

Racial Disparities In Clonal Hematopoiesis And Their Impact On Hematologic Malignancies, Zijian Zhang, Chao Cheng

Faculty, Staff and Students Publications

Clonal hematopoiesis of indeterminate potential (CHIP) is a known risk factor for hematologic malignancies (HM), but its distribution and clinical implications across diverse ancestries remain poorly characterized. In this study, we investigated CHIP and its progression to HM in a large, racially diverse cohort from the All of Us Research Program, comprising 245,388 participants. We identified 10,446 CHIP driver mutations in 9,476 individuals. Our analysis revealed clear racial disparities in CHIP prevalence and mutational profiles: African American (AA) individuals had higher odds of CHIP and exhibited distinct mutation patterns compared to White American (WA) individuals. Consistent with prior studies, CHIP …

Influence Of The Covid-19 Pandemic On Anatomy Higher Education Around The World, Sneh Patel, Santanu De

FDLA Journal

The Coronavirus Infectious Disease 2019 (COVID-19) disrupted the higher education sector worldwide in several disciplines, especially those in healthcare as well as science, technology, engineering, and mathematics (STEM) that require active, experiential learning via practical application of concepts centering around anatomy. Dynamic instructional and technological interventions took place rapidly in an effort to minimize the adverse repercussions of moving away from traditional means of education in these critical scientific fields. COVID-19 necessitated administrators, faculty, students, and interns at colleges, universities, medical/ healthcare science programs and residencies to pursue teaching, learning, and assessment of anatomy courses/curricula through innovative strategies without compromising …

Profound Opioid And Medetomidine Withdrawal: A Case Series And Narrative Review Of Available Literature, Phil Durney, Elise Paquin, Gamal Ftizpatrick, Drew Lockstein, Tareva Warrick-Stone, Do, Maeve Montesi, Sejal Patel, Jamal Rashid, Oluwarotimi Vaughan-Ogunlusi, Kelly Goodsell, Jennifer L. Kahoud, Christopher Martin, Keira Chism, Paul Goebel, Karen Alexander, Dennis Goodstein, Kory S. London

Division of Internal Medicine Faculty Papers & Presentations

Medetomidine, a potent central acting α2 agonist, has emerged as a fentanyl adulterant in the non-medical opioid supply. Its use has been linked to a novel withdrawal syndrome that is often resistant to conventional treatment protocols. Four cases are presented exemplifying extreme, but increasingly common forms of this withdrawal syndrome. A literature review is provided demonstrating both the paucity of available literature as well as potential avenues for treatment and future research. As adulterants continue to proliferate in the illicit drug supply, clinicians should anticipate atypical withdrawal phenotypes and consider early intervention.

Relationship Between Smoking And Psychiatric And Somatic Comorbidities In Older Age Bipolar Disorder: Lien Entre Le Tabagisme Et Les Affections Psychiatriques Et Somatiques Concomitantes Chez Les Personnes Âgées Atteintes De Trouble Bipolaire, Molly Howland, Arushi Mahajan, Peijun Chen, Osvaldo Almeida, Kürşat Altınbaş, Hilary Blumberg, Annemiek Dols, Nicole Fiorelli, Orestes Forlenza, Beny Lafer, Andrew Olagunju, Melis Orhan, Soham Rej, Martha Sajatovic, Matthew Schurr, Christian Simhandl, Jair Soares, Ashley Sutherland, Shang-Ying Tsai, Sara Weisenbach, Joy Yala, Farren Briggs

Faculty, Staff and Student Publications

Objective

Smoking has been associated with psychiatric and somatic comorbidities in bipolar disorder (BD) populations. However, studies in older age BD (OABD) populations are sparse. We hypothesized that among individuals with OABD, current and former smokers would have worse psychiatric and somatic comorbidities parameters compared to never smokers.

Method

Our study used baseline cross-sectional data from 27 international studies reporting data on adults 50 years old and older (N = 984). Smoking status was categorized into current smokers, former smokers, and never smokers. The distribution of demographic and clinical variables was assessed. The associations between smoking status and the …

Use Of The Selective Cytopheretic Device With Continuous Renal Replacement Therapy In Children: A Comparison Of Contemporary Cohorts, Natalja L Stanski, Jangdong Seo, Todd Jenkins, Kelli A Krallman, Shina Menon, H David Humes, David J Askenazi, Rajit K Basu, Ayse Akcan-Arikan, Stuart L Goldstein, Katja M Gist

Faculty, Staff and Students Publications

Introduction: The selective cytopheretic device (SCD) is a cell-directed extracorporeal therapy approved for use in children with acute kidney injury (AKI) receiving continuous renal replacement therapy (CRRT) with sepsis/sepsis-like conditions. We compared outcomes for children treated with SCD to a contemporary cohort of children treated with CRRT alone.

Methods: Secondary analysis and comparison of patients ≤22 years old and ≥10 kg from a multicenter registry of patients receiving CRRT for AKI and/or fluid overload (WE-ROCK; 2015-2021) to patients from two multicenter, prospective, interventional studies of children with AKI and multiple organ dysfunction (MODS) receiving SCD (SCD-PED-01/SCD-PED-02; 2016-2022).

Results: Eighteen patients …

Cdk4/6 Inhibitors In Breast Cancer-Who Should Receive Them?, Anran Chen, Ze-Yi Zheng, Meenakshi Anurag, Ahmed Elkhanany, Natalie C Chen, Eric C Chang

Faculty, Staff and Students Publications

More than 70% of breast cancers are estrogen receptor-positive (ER+). Endocrine therapy that blocks estrogen signaling remains the cornerstone of treatment, yet relapses continue to affect many patients. Cyclin-dependent kinases 4 and 6 (CDK4/6) regulate the G1-S phase transition in the cell cycle, and pharmacological inhibition of this pathway has been successfully leveraged to reduce recurrence. CDK4/6 inhibitors combined with endocrine therapy are now the standard of care, although determining the optimal patient population for treatment remains a key challenge. A newly published study provides important insight, showing that loss of the NF1/neurofibromin tumor suppressor confers greater sensitivity to CDK4/6 …

Xpert Mtb/Rif Ultra Assay For Tuberculosis Disease And Rifampicin Resistance In Children, Alexander W Kay, Maia Madison, Katie Scandrett, Tara Ness, Pauline Amuge, Leeberk Raja Inbaraj, Mukesh Kumar Sathya Narayanan, Lucia González Fernández, Michael Eisenhut, Nazir Ismail, Alexei Korobitsyn, Sabine E Verkuijl, Annemieke Brands, Kerri Viney, Tiziana Masini, Anna M Mandalakas, Karen R Steingart, Yemisi Takwoingi

Faculty, Staff and Students Publications

Background: In 2023, an estimated 1.3 million children (aged 0-14 years) became ill with tuberculosis, and 166,000 children (aged 0-15 years) died from the disease. Xpert MTB/RIF Ultra (Xpert Ultra) is a molecular World Health Organization (WHO)-recommended rapid diagnostic test that detects Mycobacterium tuberculosis complex and rifampicin resistance. This is an update of a Cochrane review first published in 2020 and last updated in 2022. Parts of the current update informed the 2024 WHO updated guidance for the diagnosis of tuberculosis.

Objectives: To assess the diagnostic accuracy of Xpert Ultra for detecting pulmonary tuberculosis, tuberculous meningitis, lymph node tuberculosis, and …

Rtx-303, An Orally Bioavailable Polθ Polymerase Inhibitor That Potentiates Parp Inhibitors In Brca Mutant Tumors, Gurushankar Chandramouly, William Fried, John Gordon, Douglas Ralph, Channita Keuk, Sangeeta Kumari, Mercy Ramanjulu, William Auerbacher, Leonid Minakhin, Taylor Tredinnick, Bernadette Tiberi, George Morton, Robert Betsch, Kathy Q. Cai, Umeshkumar M Vekariya, Mrityunjay Tyagi, Tomasz Skorski, Sergey Karakashev, Neil Johnson, Wayne E. Childers, Xiaojiang S. Chen, Richard T. Pomerantz

Department of Biochemistry and Molecular Biology Faculty Papers

DNA polymerase θ (Polθ) is a polymerase-helicase fusion protein that is synthetically lethal with homologous recombination (HR) factors, such as BRCA1/2, and confers resistance to PARP inhibitors (PARPi) and other genotoxic cancer therapies. Previously developed Polθ polymerase (Polθ-pol) inhibitors (Polθi) exhibited limited pharmacological activity and metabolic stability, warranting the development of a Polθi with improved drug-like properties. Here, we developed RTx-303, a selective allosteric small-molecule Polθ-pol inhibitor that exhibits 5.1 nM IC50, 88% oral bioavailability, and a prolonged half-life along with its equipotent metabolite. X-ray crystallography highlights the development of a solvent-exposed side-chain that is essential for the optimal drug-like …

A Quantitative, Bayesian-Informed Approach To Gene-Specific Variant Classification: Updated Expert Panel Recommendations Improve Classification Of Tp53 Germline Variants For Li-Fraumeni Syndrome, Cristina Fortuno, Megan N Frone, Jessica Mester, Miguel De La Hoya, Phuong L Mai, Tina Pesaran, Maria Isabel Achatz, Rebecca Bassett, Carolina Bustamante, Stephanie Crowley, Kelvin Cesar De Andrade, D Gareth Evans, Bingjian Feng, Laura Fuqua, Maria Isabel Harrell, Jessica N Hatton, Robert Huether, Chimene Kesserwan, Kristy Lee, Suzanne P Macfarland, Jamie L Maciaszek, Kara Maxwell, Kelly Mcgoldrick, Maureen Murphy, Bita Nehoray, Judith Penkert, Emilia Modolo Pinto, Sharon E Plon, Alison Schwartz-Levine, Ashley S Thompson, Wenyi Wang, Gerard P Zambetti, Kristin Zelley, Paul A James, Sharon A Savage, Christian P Kratz, Amanda B Spurdle

Faculty, Staff and Students Publications

Background: Germline pathogenic variants in TP53 cause Li-Fraumeni syndrome, with significantly elevated cancer risk from infancy. Accurate classification of TP53 variants is essential to guide clinical management and surveillance, yet many variants remain classified as variants of uncertain significance (VUS). To improve classification accuracy and reduce the proportion of VUS, the ClinGen TP53 Variant Curation Expert Panel (VCEP) has updated its specifications.

Methods: The updated specifications incorporate the latest ClinGen recommendations and methodological advances, providing greater granularity for multiple evidence types, and also introduce the novel use of variant allele fraction as evidence of pathogenicity, particularly in the context of …

Genome-Wide Association Study Of Childhood B-Cell Acute Lymphoblastic Leukemia Reveals Novel African Ancestry-Specific Susceptibility Loci, Cindy Im, Andrew R Raduski, Lauren J Mills, Kashi Raj Bhattarai, Robert J Mobley, Kelly R Barnett, Zhanni Lu, Kenneth Liao, Nathan Anderson, Rebecca A Johnson, Erica Langer, Anthony J Hooten, Alix E Seif, Kathrin M Bernt, Matthew Tsang, Brandon A Mamou, Luis Gil-De-Gómez, Julie A Wolfson, Danielle N Friedman, Neerav Shukla, Laura J Klesse, Erin L Marcotte, Lingyun Ji, Alice Dang, Minjie Luo, Yiming Zhong, Jalen Langie, Charleston W K Chiang, Adam De Smith, Joseph L Wiemels, Andrew Dewan, Xiaomei Ma, Catherine Metayer, Zhaoming Wang, Heather H Nelson, Nathan Pankratz, Tianzhong Yang, Saonli Basu, Lucie M Turcotte, Jun J Yang, Daniel Savic, Michael E Scheurer, Logan G Spector

Faculty, Staff and Students Publications

B-cell acute lymphoblastic leukemia (B-ALL) is the most common pediatric malignancy. Given racial/ethnic differences in incidence and outcomes, B-ALL genome-wide association studies among children of African ancestry are needed. Leveraging multi-institutional datasets with 840 African American children with B-ALL and 3360 controls, nine loci achieved genome-wide significance (P <  5 × 10−8) after meta-analysis. Two loci were established trans-ancestral susceptibility regions (IKZF1, ARID5B), while the remaining novel loci were specific to African populations. Five-year overall survival among children carrying novel risk alleles was significantly worse (83% versus 96% in non-carriers, P = 4.8 × 10−3). Novel risk variants were also associated with subtype-specific disease (P <  0.05), including higher susceptibility for a subtype overrepresented in African American children (TCF3-PBX1) and lower …

Computational Insights Into The Structural Basis For Reduced Hepatotoxicity Of Novel Nonopioid Analgesics, Claire Coderch, Hernan A. Bazán, Nicolas G. Bazan, Bhattacharjee Surjyadipta, Julio Alvarez-Builla, Beatriz De Pascual-Teresa

School of Graduate Studies Faculty Publications

Acetaminophen (ApAP) toxicity arises from the reactive intermediate N-acetyl-p-benzoquinone imine (NAPQI), a degradation product known to cause significant liver damage and kidney injury. This toxicity is a major concern associated with the widespread use of ApAP, a commonly used nonsteroidal anti-inflammatory drug. To address this important issue, a series of novel nonopioid analgesic candidates with reduced toxicity have been recently reported. However, the molecular and atomic-level mechanisms underlying their decreased toxicity remain largely unexplored. In this study, computational analyses is performed to investigate the dynamic behavior, physicochemical properties, and ligand-receptor interactions of these new chemical entities (NCEs). The findings provide …