Digital Commons Network^™

Prevalence And Clinical Impact Of Pseudohypercalcemia In Paraproteinemia: A Case And Cohort Study, Usman Sunusi, Li Chen, Nianyi Li, Jason K Y Lee, Irmeen Siddiqui, Erin Goodhue, Rongrong Huang, Jieli Li

Faculty, Staff and Students Publications

Background: Hypercalcemia is a common and serious complication of malignancy, often contributing to morbidity and mortality. In patients with paraproteinemia, elevated total calcium with normal ionized calcium, termed pseudohypercalcemia, can complicate diagnosis and lead to inappropriate treatment. While this phenomenon has been described in case reports, its prevalence and clinical impact in routine practice remain poorly defined.

Methods: We report a case of pseudohypercalcemia in a patient with IgG κ multiple myeloma and conducted a retrospective review of de-identified data to assess the prevalence and biochemical associations of pseudohypercalcemia in paraproteinemia. Available data included serum protein electrophoresis (SPEP), …

Fastk Post-Transcriptional Regulators – A ‘Fast-Track’ In Mitochondrial Gene Expression, Justin Van Riper, Bridget J Corsaro, Monica C Pillon

Faculty, Staff and Students Publications

Fas-activated serine/threonine kinase (FASTK) proteins comprise one of the largest families of mitochondrial post-transcriptional regulators. Members are classified based on their conserved C-terminus, which shows homology with the PD-(D/E)XK superfamily of endoribonucleases. However, it is still uncertain which of these FASTK members are catalytic. The six human FASTK homologs rely on their RNA-binding activity to regulate distinct stages of mitochondrial gene expression, including early processing of nascent RNA, 3'-end messenger RNA (mRNA) maturation, ribosomal RNA (rRNA) modification, mRNA stability, and translation. Genetic and genomic studies have highlighted the crucial role of FASTK proteins in balancing the mitochondrial transcriptome and controlling …

Translational Framework Linking Perfluoroheptanoic Acid (Pfhpa) Exposure To Metabolic Dysfunction Associated Steatotic Liver Disease In Adolescents, Brittney O Baumert, Ana C Maretti-Mira, Douglas I Walker, Zhenjiang Li, Nikos Stratakis, Hongxu Wang, Yinqi Zhao, Fabian Christoph Fischer, Qiran Jia, Damaskini Valvi, Scott M Bartell, Jiawen Carmen Chen, Thomas Inge, Justin R Ryder, Todd Jenkins, Stephanie Sisley, Stavra Xanthakos, David E Kleiner, Rohit Kohli, Sarah Rock, Sandrah P Eckel, Michele A La Merrill, Max M Aung, Matthew P Salomon, Rob Mcconnell, Jesse Goodrich, David V Conti, Lucy Golden-Mason, Lida Chatzi

Faculty, Staff and Students Publications

Background: The rising prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD), particularly among pediatric populations, requires identification of modifiable risk factors to control disease progression. Per- and polyfluoroalkyl substances (PFAS) have emerged as potential contributors to liver damage; however, their role in MASLD remains underexplored. This study aimed to develop a translational framework integrating human and in vitro data to elucidate the effect of PFAS on MASLD development.

Methods: We measured PFAS plasma levels in the Teen-LABS cohort (n = 136), comprising adolescents with obesity (mean age = 16.8 years) undergoing bariatric surgery. Plasma samples were also analyzed using proteomic …

Nasal Microbionts Differentially Colonize And Elicit Cytokines In Human Nasal Epithelial Organoids, Andrea I Boyd, Leah A Kafer, Isabel F Escapa, Amal Kambal, Hira Tariq, Susan G Hilsenbeck, Hoa Nguyen-Phuc, Anubama Rajan, Joshua M Lensmire, Kathryn A Patras, Pedro A Piedra, Sarah E Blutt, Katherine P Lemon

Faculty, Staff and Students Publications

Nasal colonization by Staphylococcus aureus or Streptococcus pneumoniae is associated with an increased risk of infection by these pathobionts, whereas nasal colonization by Dolosigranulum species is associated with health. Human nasal epithelial organoids (HNOs) differentiated at air-liquid interface (ALI) physiologically recapitulate human nasal respiratory epithelium with a robust mucociliary blanket. Due to their natural stem-like properties, HNO lines are a long-term experimental resource that offers genetic diversity based on the different donors. To develop HNOs as a new model system for bacterial nasal colonization, we reproducibly monocolonized HNOs differentiated at ALI with S. aureus, S. pneumoniae, or Dolosigranulum …

Short Term Hemodynamic Effects Of Atrial Fibrillation In A Closed-Loop Human Cardiac-Baroreflex System, Oluwasanmi Adeodu, Michelle Gee, Babak Mahmoudi, Rajanikanth Vadigepalli, Mayuresh V. Kothare

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Atrial fibrillation (AF) remains the leading cardiac cause of stroke and AF-related death rate in the United States has been increasing for over twenty years. While the effect of standalone AF on heart rate is well established, there is a lack of clarity on its impact on other critical hemodynamic metrics. This is ostensibly due to interaction with other common comorbidities, especially hypertension. In addition, AF has a complex relationship with the state of the baroreflex. Evidence indicates that baroreflex sensitivity (BRS), the ability of the intrinsic cardiac control system to initiate parasympathetic response, is suppressed during AF. Therefore, a …

Early Intratracheal Budesonide To Reduce Bronchopulmonary Dysplasia In Extremely Preterm Infants: The Budesonide In Babies (Bib) Randomized Clinical Trial, Namasivayam Ambalavanan, Waldemar A Carlo, Kayla J Nowak, Laura Elizabeth Wiener, Shirley S Cosby, Abhay J Bhatt, Kristi L Watterberg, Brenda B Poindexter, Martin Keszler, Carl T D'Angio, Luc P Brion, Vivek Narendran, Carrie A Rau, C Michael Cotten, Matthew M Laughon, Abhik Das, Matthew A Rysavy, Anna Maria Hibbs, Janell Fuller, Karen M Puopolo, Anup Katheria, Ravi M Patel, Jennifer R Bermick, Abbot R Laptook, Irina Prelipcean, Myra H Wyckoff, Ryan Moore, Stephanie L Merhar, Robin K Ohls, Bradley A Yoder, Marta Perez, Sarvin Ghavam, Lauritz R Meyer, Valerie Y Chock, Sara B Demauro, Wesley M Jackson, Deepali Handa, Michele C Walsh

Faculty, Staff and Student Publications

Importance: Extremely preterm infants are at high risk for bronchopulmonary dysplasia (BPD) and death. Multiple small randomized clinical trials showed that a combination of budesonide with surfactant compared with surfactant alone reduced BPD or death.

Objective: To determine if early intratracheal administration of a combination of budesonide (0.25 mg/kg) mixed with surfactant, compared with surfactant alone, reduces physiologic BPD or death by 36 weeks' postmenstrual age in extremely preterm infants.

Design, setting, and participants: This double-masked randomized clinical trial was conducted from April 2021 to June 2024 in the 17 centers of the United States Neonatal Research Network. Infants 22 …

Cd7 Regulates The Persistence Of Terminally Exhausted Cd8 T Cells During Chronic Infection, Sean Hyslop, Colby J Hofferek, Maria V Stegantseva, Emerald Kan, Kelli A Mccord, Victor M Alvarez, Amanda Y Xia, Jacob P Conarty, Andreas Wieland, William H Hudson

Faculty, Staff and Students Publications

CD8+ T cell exhaustion limits immune responses during cancer and chronic infection. We identify CD7 as a tissue-specific regulator of terminally exhausted CD8+ T cells during chronic infection. CD7 expression progressively increases during exhaustion, reaching its highest levels on a subset of CD101+Tim3low terminally exhausted cells that arise in the liver. Transcriptomic analysis revealed that CD7-deficient terminally exhausted cells display altered expression of co-stimulatory, translational, and effector genes, correlating with markedly reduced persistence and increased apoptotic susceptibility. Importantly, CD7 is preferentially upregulated on PD-1+CD39+ tumor-infiltrating lymphocytes (TILs) in human head and neck squamous cell carcinoma (HNSCC), suggesting CD7 may play …

The Roles Of Sirt1 In Breast And Gynecologic Malignancies, Jianmin Ding, Matthew T Ye, Songlin Zhang

Faculty, Staff and Students Publications

Sirtuin 1 (SIRT1), an NAD+-dependent histone deacetylase, exerts complex and context-dependent effects in breast and gynecological cancers. By deacetylating histone and non-histone proteins such as p53, FOXO, and NF-κB, SIRT1 regulates essential processes including DNA repair, apoptosis, metabolism, and stress response. In breast cancer, SIRT1 may act as a tumor suppressor in early stages by maintaining genomic stability but promotes epithelial–mesenchymal transition, metastasis, and chemoresistance in aggressive subtypes such as triple-negative breast cancer. Similarly, in gynecological cancers, SIRT1 displays dual roles: promoting proliferation via estrogen signaling and p53/FOXO1 inhibition in Type I endometrial cancer yet potentially supporting DNA repair in …

Selective Rna Sequestration In Biomolecular Condensates Directs Cell Fate Transitions, Patrizia Pessina, Mika Nevo, Junchao Shi, Srikanth Kodali, Eduard Casas, Yingzhi Cui, Alicia L Richards, Emily J Park, Xi Chen, Florencia Levin-Ferreyra, Alejandra Rivera Tostado, Erica Stevenson, Nevan J Krogan, Danielle L Swaney, Qilong Ying, Qi Chen, Justin Brumbaugh, Bruno Di Stefano

Faculty, Staff and Students Publications

Controlling stem cell differentiation is a longstanding goal in biomedical research. Here we explore how cell fate is influenced by RNA condensates, specifically P-bodies, which modulate gene expression posttranscriptionally. We profiled the transcriptomes of biomolecular condensates in diverse developmental contexts spanning multiple vertebrate species. Our analyses revealed conserved, cell type-specific sequestration of untranslated RNAs encoding cell fate regulators. P-body RNA contents do not reflect active gene expression in each cell type but are enriched for translationally repressed transcripts characteristic of the preceding developmental stage. Mechanistically, P-body contents are controlled by microRNAs and can be profoundly reshaped by perturbing AGO2 or …

Molecular And Cellular Characterization Of Planarian Stem Cell Microenvironments, Frederick G Mann, Carolyn E Brewster, Dung M Vuu, Mol Mir, Riley Galton, Shao-Fu Nien, Enya R Dewars, Carlos Guerrero-Hernández, Jason A Morrison, Mary C Mckinney, Lucinda E Maddera, Melainia L Mcclain, Kate E Hall, Seth Malloy, Shiyuan Chen, Brian D Slaughter, Sean A Mckinney, Stephanie H Nowotarski, Anoja Perera, Blair W Benham-Pyle, Alejandro Sánchez Alvarado

Faculty, Staff and Students Publications

Stem cell niches are essential for regulating stem cell self-renewal and differentiation during tissue repair and regeneration. However, the mechanisms supporting stem cell function in highly regenerative organisms, such as the freshwater planarian Schmidtea mediterranea, remain unclear. Using spatial transcriptomics, we identified two cell types associated with planarian stem cells: secretory cells we term "hecatonoblasts" and intestinal cells. Surprisingly, while hecatonoblasts were in close physical proximity to stem cells in the mesenchyme, they were dispensable for regeneration. In contrast, intestinal cells, despite lacking direct contact with stem cells, regulated both their position and function during regeneration. Electron microscopy revealed diverse …

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 …

Pharmacological Profiling In Cll Patients During Pirtobrutinib Therapy And Disease Progression, Shady I Tantawy, Burcu Aslan, Ganiraju Manyam, Lakesla R Iles, Natalia Timofeeva, Neetu Singh, Nitin Jain, Alessandra Ferrajoli, Philip A Thompson, Keyur P Patel, Sai Prasad Desikan, William G Wierda, Varsha Gandhi

Faculty, Staff and Student Publications

No abstract provided.

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 …

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 …

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 …

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 …

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 …

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 …

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. …

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 …

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 …

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 …

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 …

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 …

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 …