Medical Specialties Commons^™

Primary Intramedullary Spinal Melanocytomas: Case Report And Review Of Clinical Features, Diagnosis, And Management, Gil Kimchi, Samantha Varela, Juan Pablo Zuluaga-Garcia, Francisco Call-Orellana, Esteban Ramirez Ferrer, Romulo Augusto Andrade De Almeida, Maria A Gubbiotti, Isabella C Glitza, Andrew J Bishop, Jonathan D Grant, Robert Y North, Christopher A Alvarez-Breckenridge, Laurence D Rhines, Claudio E Tatsui

Faculty, Staff and Student Publications

Objective: Intramedullary melanocytomas are extremely rare spinal cord tumors with distinct histopathological and imaging characteristics. This report reviews the literature on this pathology and presents a representative case study, highlighting aspects of diagnosis and management.

Methods: A scoping review of PubMed, Web of Science, and Embase databases was conducted to identify reports on intramedullary melanocytomas, focusing on clinical presentation, imaging features, histopathology, treatment, and outcomes. Case reports and case series were included due to the rarity of these tumors.

Results: Twelve manuscripts met the inclusion criteria, including 15 patients. In the majority of patients, intramedullary melanocytomas present with progressive myelopathy …

Culture-Independent Meta-Pangenomics Enabled By Long-Read Metagenomics Reveals Associations With Pediatric Undernutrition, Jeremiah J Minich, Nicholas Allsing, M Omar Din, Michael J Tisza, Kenneth Maleta, Daniel Mcdonald, Nolan Hartwick, Allen Mamerto, Caitriona Brennan, Lauren Hansen, Justin Shaffer, Emily R Murray, Tiffany Duong, Rob Knight, Kevin Stephenson, Mark J Manary, Todd P Michael

Faculty, Staff and Students Publications

The human gut microbiome is linked to child malnutrition, yet traditional microbiome approaches lack resolution. We hypothesized that complete metagenome-assembled genomes (cMAGs), recovered through long-read (LR) DNA sequencing, would enable pangenome and microbial genome-wide association study (GWAS) analyses to identify microbial genetic associations with child linear growth. LR methods produced 44-64× more cMAGs per gigabase pair (Gbp) than short-read methods, with PacBio (PB) yielding the most accurate and cost-effective assemblies. In a Malawian longitudinal pediatric cohort, we generated 986 cMAGs (839 circular) from 47 samples and applied this database to an expanded set of 210 samples. Machine learning identified species …

Epigenetic Landscape In Lysosomal Storage Disorders: Mechanisms And Modulation, Andrés Felipe Leal, Harry Pachajoa, Shunji Tomatsu

Department of Pediatrics Faculty Papers

Lysosomal storage disorders (LSDs) are rare substrate-accumulating diseases primarily characterized by mutations in genes encoding proteins involved in lysosomal function, most of which have enzymatic activity. Resulting lysosomal dysfunction leads to the overaccumulation of non- or partially degraded substrates. While it is true that enzyme deficiency is the primary cause of LSDs, the epigenetic alterations in DNA methylation, miRNA expression, and histone modifications appear to be critical mechanisms involved in the pathogenesis of LSDs. As epigenetic marks are, in most cases, reversible, their study becomes vital to developing strategies aimed at reversing epigenome alterations. Although classical therapeutic alternatives aim to …

Reprogramming Tumor Microenvironment Via Systemic Delivery Of Tlr3 Agonist And Manganese Nanoparticle, Young Seok Cho, Xingwu Zhou, Xiaoqi Sun, Ziye Wan, Julia Crowther, Mariko Takahashi, Swetha Kodamasimham, Qi Wu, May Thazin Phoo, Youngseo Na, Kai Han, Zaiye Li, Anna Schwendeman, Steven P Schwendeman, Yu Leo Lei, James J Moon

Faculty, Staff and Student Publications

Toll-like receptor (TLR) agonists, as potent immunostimulatory adjuvants, play a critical role in linking the innate and adaptive immune responses. However, their antitumor effects as cancer immunotherapeutic agents have been limited. Here, we report our finding that manganese ion (Mn2+) potentiates various TLR agonists, leading to robust activation of the TLR pathway and the stimulator of interferon genes (STING) pathway among innate immune cells. In particular, we have observed robust antitumor efficacy after intratumoral administration of a TLR3 agonist and Mn2+. To achieve systemic codelivery of TLR3 agonist and Mn2+, we have developed a low-molecular-weight poly(inosinic:cytidylic acid)-Mn2+ coordination lipid nanoparticle …

Preclinical Efficacy Of Tasquinimod-Based Combinations In Advanced Myeloproliferative Neoplasms In Blastic Phase, Warren Fiskus, Lucia Masarova, Christopher P Mill, Christine E Birdwell, Kaberi Das, Hanxi Hou, John A Davis, Antrix Jain, Anna Malovannaya, Taghi Manshouri, Andrew Dunbar, Surbhi Sharma, Tapan M Kadia, Courtney D Dinardo, Prithviraj Bose, Naveen Pemmaraju, Sanam Loghavi, Xiaoping Su, Raajit K Rampal, Marie Törngren, Kapil N Bhalla

Faculty, Staff and Students Publications

The alarmins, S100A8 (A8) and S100A9 (A9), are low molecular weight proteins belonging to the S100 protein family. A8 and A9 are secreted into the extracellular space and plasma, in which they interact with Toll-like receptor 4, receptor for advanced glycation end products, and CD33. In these studies, we determined the preclinical efficacy of tasquinimod (TQ) against advanced myeloproliferative neoplasm (MPN) cell lines and patient-derived (PD) CD34+ blastic phase (BP; >5% blasts in the peripheral blood) MPN cells. TQ induced loss of viability in cell lines and PD MPN-BP cells, but not in normal CD34+ progenitor cells. In TQ-treated PD …

Differences In Dieting Behavior In Athletic Trainers, Emily Madrak, Ki L. Cole, Bridget M. Miller, Jennifer L. Volberding

Journal of Sports Medicine and Allied Health Sciences: Official Journal of the Ohio Athletic Trainers Association

Introduction: Athletic trainers (ATs) have a foundational knowledge in many facets of health, including optimization of wellness. Though ATs may be actively trying to improve their own health, societal pressure can have a large impact on behavior. The purpose of this study was to identify differences between gender and years-certified in diet patterns in ATs. Methods: A cross-sectional survey was distributed to 2500 National Athletic Training Association members, It included a demographics section and five-item researcher-created questions regarding diet. Chi-square tests of independence were used to determine the relationship. Results: Significance was determined for gender and question 2, “Have …

Comparing Lower Extremity Kinematics Using Trazer And Inertial Motion Capture Systems, Gabriella Juoza-Clark Spt, Joellen Carter Spt, Nikki Stam Spt, Kevin Robinson Pt, Dsc, Ocs

Journal of Sports Medicine and Allied Health Sciences: Official Journal of the Ohio Athletic Trainers Association

Introduction: This study assessed the validity of a non-immersive body motion tracking system (TRAZER) as an alternative to using Inertial Measurement Units (IMU)-based motion capture (MyoMotion) for lower extremity kinematic analysis. Methods: Twenty healthy participants (10 females, 10 males) with a mean age of 24.03 years (range: 20-33 years) and a mean BMI of 25.15 kg/m² (range: 18.45-32.23 kg/m²) performed double and single-leg squats. Data Analysis: Kinematic data from TRAZER and MyoMotion IMUs were compared using a mixed two-way ANOVA. Results: No significant differences were observed in knee flexion data across all movements (p > 0.05) and knee abduction during the …

Parameters Of Suspension Training On Core Performance: A Critically Appraised Topic, Sara Stiltner, Andrea Cripps

Journal of Sports Medicine and Allied Health Sciences: Official Journal of the Ohio Athletic Trainers Association

Clinical Scenario: The core is a functional unit connecting the upper and lower extremities consisting of abdominal, back, and hip musculature. A highly functional core is essential within the kinetic chain and aids in injury prevention and rehabilitation. Traditional means of core stability training are performed on a stable surface. An emerging mode of core training is suspension training (ST), which utilizes a movement paired with instability to challenge the core stabilizers and increase motor unit recruitment.The purpose of suspension training is to increase muscle activation in core stabilizer’s, while mimicking functional movements.It was the purpose of this research to …

Using External Visual Feedback Techniques To Improve Chronic Ankle Instability: A Critically Appraised Topic, Paxtyn Watkins, Bradlee Wells, Aric J. Warren

Journal of Sports Medicine and Allied Health Sciences: Official Journal of the Ohio Athletic Trainers Association

Introduction: Lateral ankle sprains (LAS) are among the most common musculoskeletal injury in physically active populations posing a substantial health burden. Individuals who sustain ankle sprains often have a diminished quality of life with prolonged symptoms, decreased levels of physical activity, and the propensity to develop chronic ankle instability (CAI). It is estimated that up to 40% of people who sustain an initial lateral ankle sprain will develop CAI. Many therapeutic interventions exist to help alleviate symptoms and the feeling of “giving out.” This critically appraised topic will examine multiple interventions that involve using external visual feedback methods to improve …

The Impact Of Athletic Retirement On Anxiety In Elite Athletes, A Critically Appraised Topic, Jordan Gorham, Emily Madrak

Journal of Sports Medicine and Allied Health Sciences: Official Journal of the Ohio Athletic Trainers Association

Though there is growing interest in athletic mental health, this interest appears to diminish significantly once an athlete enters athletic retirement. The abrupt transition can precipitate mental health struggles, exacerbated by the lack of adequate preparation for lifestyle after retirement and the attachment of athletic identity to their sport. Consequently, these circumstances may increase symptoms associated with poor mental health, with a specific focus on anxiety. As the athlete retires and moves into different stages of life, research notes that athletes with stronger athletic identities have poorer mental health than those who had weaker athletic identity^. While the scrutiny …

Comparing Position Specific Gps Normative Data In Professional Female Club Soccer, Andy Seraphin, Christi Edson, Cory Price, Barrett Jones, Amanda Jagielo, Justin Mullner

Journal of Sports Medicine and Allied Health Sciences: Official Journal of the Ohio Athletic Trainers Association

Objective: To establish normative ranges in common performance tests for professional women’s club soccer. Setting:1^st division professional women’s soccer club in the United States

Participants: Twenty-eight healthy professional women’s soccer players (Age: 27.8 ± 5.1 years; Body Mass: 66.2 ± 6.7 kg). Main Outcome Measures: Season GPS data was analyzed and metrics included minutes, total distance, high speed running, total accelerations, total decelerations, and maximum speed. Statistical analysis was performed to determine differences between positions. Results: Statistically significant differences were found across all metrics in comparison to overall mean. Differences in each metric may be due to a …

Genome-Wide Crispr Screens Identify Critical Targets To Enhance Car-Nk Cell Antitumor Potency, Alexander Biederstädt, Rafet Basar, Jeong-Min Park, Nadima Uprety, Rejeena Shrestha, Francia Reyes Silva, Merve Dede, John Watts, Sunil Acharya, Donghai Xiong, Bin Liu, May Daher, Hind Rafei, Pinaki Banerjee, Ping Li, Sanjida Islam, Huihui Fan, Mayra Shanley, Jingling Jin, Bijender Kumar, Vernikka Woods, Paul Lin, Silvia Tiberti, Ana Karen Nunez Cortes, Xin Ru Jiang, Inci Biederstädt, Patrick Zhang, Ye Li, Seema Rawal, Enli Liu, Luis Muniz-Feliciano, Gary M Deyter, Elizabeth J Shpall, Natalie Wall Fowlkes, Ken Chen, Katayoun Rezvani

Faculty, Staff and Student Publications

Adoptive cell therapy using engineered natural killer (NK) cells is a promising approach for cancer treatment, with targeted gene editing offering the potential to further enhance their therapeutic efficacy. However, the spectrum of actionable genetic targets to overcome tumor and microenvironment-mediated immunosuppression remains largely unexplored. We performed multiple genome-wide CRISPR screens in primary human NK cells and identified critical checkpoints regulating resistance to immunosuppressive pressures. Ablation of MED12, ARIH2, and CCNC significantly improved NK cell antitumor activity against multiple treatment-refractory human cancers in vitro and in vivo. CRISPR editing augmented both innate and CAR-mediated NK cell function, associated with enhanced …

Whole-Exome Sequencing-Based Linkage Analysis Of Multiple Myeloma (Mm) And Monoclonal Gammopathy Of Undetermined Significance (Mgus) Pedigrees, Alyssa I Clay-Gilmour, Nicola J Camp, Xiaomu Wei, Angel Earle, Aaron Norman, Jason Sinnwell, Delphine Demangel, Rosalie Griffin, Charles Dumontet, James Mckay, Ken Offit, Vijai Joseph, Siwei Chen, Daniel O'Brien, Vincent Rajkumar, Robert Klein, Shaji Kumar, Steve Lipkin, Celine M Vachon

Faculty, Staff and Student Publications

Background/objectives: Family history is a known risk factor for multiple myeloma (MM) and its precursor condition, monoclonal gammopathy of undetermined significance (MGUS). Previous genome-wide association studies (GWASs) have identified 35 common loci associated with MM risk and 21 associated with MGUS. The objective of this study was to identify less common and rare genetic loci predisposing to MM/MGUS through whole-exome sequencing (WES)-based linkage analysis.

Methods: Multipoint linkage analysis was conducted using the Multipoint Engine for Rapid Likelihood Inference (MERLIN) with the Lander-Green algorithm on germline WES data from 79 pedigrees with 2 or more affected relatives (120 MM, 86 MGUS, …

Development Of A Targeted Bioprotac Degrader Selective For Misfolded Sod1, Christen G Chisholm, Rachael Bartlett, Mikayla L Brown, Emma-Jayne Proctor, Natalie E Farrawell, Jody Gorman, Fabien Delerue, Lars M Ittner, Kara L Vine-Perrow, Heath Ecroyd, Neil R Cashman, Darren N Saunders, Luke Mcalary, Jeremy S Lum, Justin J Yerbury

Faculty, Staff and Student Publications

The accumulation of misfolded proteins underlies a broad range of neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Due to their dynamic nature, these misfolded proteins have proven challenging to target therapeutically. Here, we specifically target misfolded disease variants of the ALS-associated protein superoxide dismutase 1 (SOD1), using a biological proteolysis targeting chimera (BioPROTAC) composed of a SOD1-specific intrabody and an E3 ubiquitin ligase. Screening of intrabodies and E3 ligases for optimal BioPROTAC construction reveals a candidate capable of degrading multiple disease variants of SOD1, preventing their aggregation in cells. Using CRISPR/Cas9 technology to develop a BioPROTAC transgenic mouse line, we …

Mutational Landscape And Clinical Impact Of Spen Mutations In Patients With Chronic Lymphocytic Leukemia, Priyatharsini Nirmalanantham, Andrés E Quesada, Anindita Ghosh, Pei Lin, Chi Y Ok, Richard K Yang, Hong Fang, Sofia Garces, Rashmi Kanagal-Shamanna, Sanam Loghavi, Mark J Routbort, Cameron Cheng Yin, Wang Wei, Sarah Pasyar, Roland Bassett, Siba El Hussein, Nitin Jain, Jan Burger, William G Wierda, Sa Wang, Carlos Bueso-Ramos, Keyur P Patel, Leonard Jeffrey Medeiros, Fatima Zahra Jelloul

Faculty, Staff and Student Publications

Background/objectives: NOTCH1 is frequently mutated in chronic lymphocytic leukemia (CLL) and is a marker of poor prognosis. In addition to NOTCH1, mutations in the NOTCH1 regulatory pathway including SPEN have been described in a limited number of CLL cases and others have suggested that these mutations are also associated with adverse patient outcomes Methods: In this study, 1617 CLL cases were assessed using targeted sequencing and a 29-gene panel and the results were correlated with prognosis.

Results: SPEN mutations were detected in 48 (2.9%) CLL patients: 92.4% were deleterious (frameshift or truncating nonsense mutations) and the remaining (7.6%) were …

Distinct Tumor-Associated Macrophage Signatures Shape The Immune Microenvironment And Patient Prognosis In Renal Cell Carcinoma, Youngsoo Han, Aidan Shen, Cheng-Chi Chao, Lucas Yeung, Aliesha Garrett, Jianming Zeng, Satoru Kawakita, Jesse Wang, Zhaohui Wang, Alireza Hassani, Xiling Shen, Chongming Jiang

Faculty, Staff and Student Publications

Renal cell carcinoma (RCC) accounts for 90% of adult renal cancer cases and is characterized by significant heterogeneity within its tumor microenvironment. This study tests the hypothesis that tumor-associated macrophages (TAMs) influence RCC progression and patient response to treatment by investigating the prognostic implications of TAM signatures. Utilizing independent single-cell RNA sequencing data from RCC patients, we developed eight distinct TAM signatures reflective of TAM presence. A LASSO Cox regression model was constructed to predict survival outcomes, evaluated using the TCGA dataset, and validated across independent RCC cohorts. Model performance was assessed through Kaplan-Meier survival plots, receiver operating characteristic (ROC) …

Distinguishing Syndromic And Nonsyndromic Cleft Palate Through Analysis Of Protein-Altering De Novo Variants In 818 Trios, Kelsey R Robinson, Sarah W Curtis, Justin E Paschall, Wasiu Lanre Adeyemo, Terri H Beaty, Azeez Butali, Carmen J Buxó, David J Cutler, Michael P Epstein, Lord J J Gowans, Jacqueline T Hecht, Gary M Shaw, Lina Moreno Uribe, Jeffrey C Murray, Harrison Brand, Seth M Weinberg, Mary L Marazita, Kimberly F Doheny, Elizabeth J Leslie-Clarkson

Faculty, Staff and Student Publications

De novo variants (DNs) are sporadically occurring variants found in an offspring but absent in both parents. DNs most commonly arise in the germline and are not under selective pressure; therefore, they may be enriched for disease-causing alleles. In fact, DNs have been implicated in multiple rare genetic disorders. Cleft palate (CP) is a craniofacial congenital anomaly occurring in ∼1 in 1,700 live births. Genome-wide association studies have found fewer than a dozen CP-specific loci, while exome and targeted sequencing studies in family-based and case-control cohorts often lack statistical power to conclusively identify causal variants. We therefore hypothesized that CP …

Compadre: Combined Pedigree-Aware Distant Relatedness Estimation For Improved Pedigree Reconstruction, Grahame F Evans, James T Baker, Lauren E Petty, Alexander S Petty, Hannah G Polikowsky, Ryan J Bohlender, Hung-Hsin Chen, Che-Yu Chou, Kathryn Z Viljoen, Janet M Beilby, Shelly Jo Kraft, Wanying Zhu, Joshua M Landman, Autumn R Morrow, Dayi Bian, Alyssa C Scartozzi, Chad D Huff, Jennifer E Below

Faculty, Staff and Student Publications

Designing powerful and unbiased genomic studies requires accurate assessment of familial relatedness even when this information is not captured from participants. Characterization of pairwise degrees of relatedness from participants' genetic data enables reconstruction of pedigrees, and several pedigree reconstruction tools have emerged in the last decade. However, limitations of these tools include high computational burden in large datasets, reliance on external information, reduced accuracy in admixed populations, and most notably, an inability to accurately reconstruct pedigrees when only a subset of family members is represented in the genetic data. To improve pedigree reconstruction in large-scale data and in pedigrees with …

Menin Inhibitor Ds-1594b Drives Differentiation And Induces Synergistic Lethality In Combination With Venetoclax In Acute Myeloid Leukemia Cells With Rearranged Mixed-Lineage Leukemia And Mutated Nucleophosmin-1, Valerio Ciaurro, Vassilena Sharlandjieva, Anna Skwarska, Catherine Chahrour, Natalia Baran, Zhihong Zeng, Cassandra Ramage, Naval Daver, Bing Z Carter, Sovira Chaundhry, Palaniraja Thandapani, Maria Paola Martelli, Thomas A Milne, Marina Konopleva

Faculty, Staff and Student Publications

Mixed-lineage leukemia (MLL) rearrangements and Nucleophosmin-1 (NPM1) mutations are associated with acute leukemias whose pathogenesis is critically influenced by protein-protein interactions between menin and MLL. We hypothesized that targeting the menin-MLL interaction using DS-1594b and blocking the antiapoptotic BCL-2 protein using venetoclax may promote differentiation and enhance eradication of MLL-rearranged and NPM1-mutated leukemias models. We treated acute myeloid leukemia (AML) cell lines with MLL rearrangements, NPM1 mutations, other leukemias and primary samples from AML patients with venetoclax alone, DS- 1594b alone, and their combination. We measured proliferation, viability, apoptosis, and differentiation using a variety of cellular assays, Western blotting, and …

Prospective Phase Ii Clinical Trial Of Molecular Glioblastoma (Historical Grade 2 And 3 Idh Wildtype Gliomas) Preliminary Novel Exploratory Analyses: Treatment Intensification, Margin Reduction And Epigenetic Stratified Outcomes With Radiation Therapy And Chemotherapy, Debra Nana Yeboa, Benjamin T Whitfield, Ruitao Lin, Chinenye Lynette Ejezie, Todd A Swanson, Thomas H Beckham, Chenyang Wang, Brian De, Subha Perni, Martin C Tom, Jing Li, Susan L Mcgovern, Rebecca Harrison, Nazanin K Majd, Vinay K Puduvalli, Ashley E Aaroe, Monica Loghin, Barbara J O'Brien, Anuj D Patel, Chirag B Patel, Jeffrey S Wefel, Ceylan Altintas Taslicay, Maria Gule-Monroe, Arnold C Paulino, Mary Frances Mcaleer, David R Grosshans, Amol J Ghia, Wen Jiang, Caroline Chung, Moshe Maor, Cheng-Han Yang, Maria A Gubbiotti, Carlos Kamiya-Matsuoka, Leomar Y Ballester, Shiao-Pei Weathers, Jason T Huse

Faculty, Staff and Student Publications

Purpose: Molecular glioblastoma (molGBM) is a variant lacking the full histopathological profile of glioblastoma. We report a trial aimed at addressing the optimal management of this newly recognized rarer form of glioma.

Methods: In this phase II study, molGBM patients were treated with radiation to a dose of 60Gy to the gross tumor volume (GTV) only, and a single smaller margin potentially as low as 1cm to the clinical tumor volume (CTV). As the trial is ongoing, we report on important exploratory biomarker findings correlating with median overall survival (mOS). Analysis included Kaplan-Meier and univariable/multivariable cox proportional hazard models. Available …

Cofilin Inhibition Ameliorates Piezo2 And Ampa Dysfunction In A Mouse Model Of Angelman Syndrome, Luis O Romero, Manisha Bade, Elisa Carrillo, Sonia Paz-López, Syed A M Hasan, William James Antonisamy, Vasanthi Jayaraman, Zahoor A Shah, Valeria Vásquez, Julio F Cordero-Morales

Faculty, Staff and Student Publications

Angelman syndrome (AS) is a neurogenetic disorder characterized by motor coordination and cognitive deficits. In AS, hippocampal neurons show reduced filamentous (F-)actin, a decrease we also reported in dorsal root ganglia (DRG) neurons, along with impaired mechanosensitive ion channel activity. Currently, there are no pharmacological targets to prevent the decrease of F-actin in AS. Here, we utilize a first-in-class selective cofilin inhibitor (SZ-3) to restore PIEZO2 function in DRG neurons and glutamate-evoked currents in hippocampal neurons from AS mice. Using atomic force microscopy, we demonstrate that inhibiting cofilin, an actin-severing protein, with SZ-3 increases cellular stiffness by stabilizing the actin …

Targeting Gd2 With Naxitamab Overcomes Gd3 Synthase-Driven Immune Suppression In Triple-Negative Breast Cancer, Vivek Anand, Bolutyfe Oderinde, Maryam Siddiqui, Anudishi Tyagi, Jenny Borgman, Chong Wu, Michael Andreeff, V Lokesh Battula

Faculty, Staff and Student Publications

Gangliosides are acidic glycosphingolipids involved in cell-adhesion, signal-transduction and tumor progression. GD3 synthase (GD3S/ST8SIA1), a key enzyme in ganglioside biosynthesis, is upregulated in many cancers, including GD2+ breast cancer stem-like cells (BCSCs) in triple-negative breast cancer (TNBC). Here, we demonstrated the immunomodulatory role of GD3S and identified a fully humanized anti-GD2 antibody, naxitamab, as a therapeutic tool to target GD3S/GD2+ breast tumors. GD3S expression correlates with immune-checkpoint activation and reduced immune infiltration. Ectopic overexpression of GD3S suppressed macrophage-mediated phagocytosis and NK or T cell-induced cell death in BC cells. Lipidomic analysis identified GD2 as the major effector ganglioside …

Integrating Pathogenic Variants, Polygenic Risk Score, And Family History For Prostate Cancer Risk Estimation In Men Of African Ancestry, Fei Chen, Xin Sheng, Anqi Wang, Yili Xu, Raymond Hughley, Wei Xiong, Loreall Pooler, Peggy Wan, Susan M Gundell, Godfrey Kigozi, Gertrude Nakigozi, Fred Nalugoda, Joseph Kagaayi, Grace Nalwoga Kigozi, Stephen Mugamba, Emmanuel Kyasanku, James Nkale, Vitalis Ofumbi Olwa, Alexander Lubwama, Alex Daama, Resty Nakajugo, Ben Adusei, Mohamed Jalloh, Serigne Magueye Gueye, Andrew A Adjei, James Mensah, Pedro W Fernandez, Akindele Olupelumi Adebiyi, J Olufemi Ogunbiyi, Oseremen Inokhoife Aisuodionoe-Shadrach, Lindsay Petersen, Wenlong Carl Chen, Jo Mcbride, Jeannette T Bensen, James L Mohler, Jack A Taylor, Caroline Andrews, Mbaaga Kigongo, Amanya Colline, Vicky Kiddu, Juliet Namugambe, Shallot Owamaani, Kuteesa Job, Benon Joseph Masaba, Frank Asiimwe, Proscovia Muwanga, Joy Namulondo, Florence Nagawa, Charity Kayiraba, Martin Ogwang, Ronald Okidi, David Oweka, Elio Kitara, James Obonyo, Daniel Lajul, Paul Matovu, Precious Arinda Muheki, Johnson Natumanya, Emmanuel Agaba, Emmanuel Aculokin, Amos Twongyeirwe, George Mutema, Denis Bitamazire, Eboneé N Butler, Sue Ann Ingles, Benjamin A Rybicki, Janet L Stanford, Wei Zheng, Sonja I Berndt, Stephen J Chanock, Chad D Huff, Joseph Lachance, Luc Multigner, Burcu F Darst, Timothy R Rebbeck, Laurent Brureau, Stephen Watya, David V Conti, Christopher A Haiman

Faculty, Staff and Student Publications

BACKGROUND AND OBJECTIVE: The impact of germline pathogenic variants (PVs) in cancer predisposition genes on risk of prostate cancer (PCa) remains understudied in large populations of African ancestry. This study aims to characterize the range of genetic risk of PCa and aggressive disease phenotypes in men of African ancestry.

METHODS: We analyzed 7176 PCa cases and 4873 controls from seven countries across North America and Africa to assess the association between PVs in 37 cancer predisposition genes and the risk of overall, aggressive, and metastatic PCa. Genes significantly associated with PCa risk were used to estimate lifetime absolute risk based …

Incidence And Risk Factors For Pneumonitis Due To Trastuzumab Deruxtecan In Metastatic Breast Cancer: A Retrospective Cohort Study, Maria Azhar, Felipe Soto, Amber Su, Norma Alicia Vazquez Gonzalez, Kevin Bernal Medina, Alejandro Lizarraga Madrigal, Cesar Chavez Duran, Carlos Ignacio Rodriguez Reyna, Colin Chan, Girish S Shroff, Roland L Bassett, Sarah Pasyar, David Zhang, Vickie R Shannon, Mehmet Altan, Melissa P Mitchell, Funda Meric-Bernstam, Jason Mouabbi, Rashmi K Murthy, Saadia A Faiz, Lara Bashoura, Bora Lim, Ajay Sheshadri

Faculty, Staff and Student Publications

Background: Fam-trastuzumab deruxtecan (T-DXd) is an antibody-drug conjugate (ADC) that targets human epidermal growth factor receptor 2 (HER2) and delivers a topoisomerase inhibitor payload. T-DXd has been effectively used to treat metastatic breast cancer but causes pneumonitis in 10–15% of cases. Risk factors associated with T-DXd pneumonitis are not well described.

Research question: What are the major clinical risk factors for T-DXd pneumonitis?

Study design and methods: We conducted a retrospective study of women with metastatic breast cancer at our institution treated with T-DXd as standard of care between 2020 and 2024. We collected clinical data, including demographics, relevant review …

Pregnancy Outcomes In Women With Heritable Thoracic Aortic Disease: Data From The Eorp Esc Registry Of Pregnancy And Cardiac Disease (Ropac) Iii, Puck N J Peters, Johanna A Van Der Zande, Julie De Backer, Guillaume Jondeau, Osama Ahmad, Marjorie Richardson, Francesca M Comoglio, Heleen Van Der Zwaan, Siddharth K Prakash, Christina Christersson, Karishma P Ramlakhan, Roger Hall, Mark R Johnson, Jolien W Roos-Hesselink, Ropac Investigators

Faculty, Staff and Student Publications

Aims: The risk of pregnancy in women with heritable thoracic aortic disease (HTAD) is estimated to be high, but supporting data are scarce. The aim of this study is to prospectively investigate pregnancy outcomes to improve patient management and care.

Methods and results: The Registry of Pregnancy and Cardiac disease (ROPAC) III is a prospective global registry including pregnant women with known aortic pathology between 2018 and 2023. Cardiac, obstetric and fetal outcomes, beta-blocker use, and the impact of breastfeeding were investigated. Additionally, changes in aortic diameters were assessed. In total, 176 pregnancies in 170 women (mean age 32 years, …

Effects Of Combining Traditional East Asian And Conventional Western Medicine On Acute Stroke Outcomes, Dong-Seok Gwak, Jong-Sik Lee, Dawid Schellingerhout, Jinyong Chung, Hyerin Oh, Sang-Wuk Jeong, Ji Sung Lee, Hee-Joon Bae, Mikyung Kim, Dong-Jun Choi, Dong-Eog Kim

Faculty, Staff and Student Publications

Background: Traditional East Asian medicine (TM) is widely used in Korea and other East Asian countries. However, the effects of TM treatment on acute ischemic stroke (AIS) outcomes remain unclear, as previous studies lacked a sufficient sample size, a consecutive series design, or a prospective outcome capture approach. We aimed to investigate whether combining TM with conventional Western medicine (CM) treatments (C+TM) leads to better outcomes after AIS, relative to CM treatment alone.

Methods: We retrospectively analyzed 2157 consecutive patients with AIS from a prospectively collected registry (2011-2021) at our center and compared the CM and C+TM groups in terms …

Therapeutic Potential Of Prmt1 As A Critical Survival Dependency Target In Multiple Myeloma, Tabish Hussain, Sharad Awasthi, Farid Shahid, S Stephen Yi, Nidhi Sahni, C Marcelo Aldaz

Faculty, Staff and Student Publications

Multiple myeloma (MM) is a neoplasm of antibody-producing plasma cells and is the second most prevalent hematological malignancy worldwide. Development of drug resistance and disease relapse significantly impede the success of MM treatment, highlighting the critical need to discover novel therapeutic targets. In a custom CRISPR/Cas9 screen targeting 197 DNA damage response-related genes, Protein Arginine N-Methyltransferase 1 (PRMT1) emerged as a top hit, revealing it as a potential therapeutic vulnerability and survival dependency in MM cells. PRMT1, a major Type I PRMT enzyme, catalyzes the asymmetric transfer of methyl groups to arginine residues, influencing gene transcription and protein function through …

Serum Response Factor Is Essential For Endometrial Function And Prevention Of Inflammatory Fibrosis, Ryan M Marquardt, Sara A Grimm, San-Pin Wu, Peter F Lais, Shu-Yun Li, Xin Xu, Erin Smithberger, David Cunefare, Charan Ganta, David Olson, Eunhee M Jeong, Jae-Wook Jeong, Bruce A Lessey, John P Lydon, Francesco J Demayo

Faculty, Staff and Students Publications

Pregnancy requires a supportive uterine environment facilitated by steroid hormone–regulated differentiation of endometrial stromal fibroblasts into decidual cells and tight control of inflammation. Serum response factor (SRF) is a widely expressed transcription factor essential for mesenchymal cell growth and differentiation with noted roles in hormonal regulation of muscle tissues but little characterization in reproductive organs. Here, we reveal that endometrial SRF is dysregulated in human endometriosis and is critical for female reproductive success in mice through regulation of endometrial stromal and epithelial cells. Immunohistochemical analysis identified decreased endometrial SRF expression in infertile endometriosis patient tissues. RNAi-based SRF knockdown in human …

Disparate Leukemia Mutations Converge On Nuclear Phase-Separated Condensates, Gandhar K Datar, Elmira Khabusheva, Archish Anand, Joshua Beale, Marwa Sadek, Chun-Wei Chen, Evdokiia Potolitsyna, Nayara Alcantara-Contessoto, Guangyuan Liu, Josephine De La Fuente, Christina Dollinger, Anna Guzman, Alejandra Martell, Katharina Wohlan, Abhishek Maiti, Nicholas J Short, S Stephen Yi, Vibeke Andresen, Bjørn Tore Gjertsen, Brunangelo Falini, Rachel E Rau, Lorenzo Brunetti, Nidhi Sahni, Margaret A Goodell, Joshua A Riback

Faculty, Staff and Students Publications

During cancer development, mutations promote changes in gene expression that cause transformation. Leukemia associated with aberrant HOXA expression is driven by translocations of nucleoporin genes or KMT2A as well as mutations in NPM1. The mechanistic convergence of these disparate mutations remains elusive. Here, we demonstrate that mutant nucleophosmin 1 (NPM1c) forms nuclear condensates in human cell lines, mouse models, and primary patient samples. We show NPM1c phase separation is necessary and sufficient to recruit NUP98 and KMT2A to condensates. Through extensive mutagenesis and pharmacological destabilization of phase separation, we find that NPM1c condensates are necessary for regulating gene expression, promoting …

Early Ctdna Dynamics Inform First-Line Therapy In Patients With Extensive-Stage Small Cell Lung Cancer, Carmela Ciardullo, Luis Tobalina, T Hedley Carr, Philip Szekeres, Silvija Kraljevic, Lauren Averett Byers, Giulia Fabbri

Faculty, Staff and Student Publications

Purpose: Small cell lung cancer (SCLC) is an aggressive malignancy with a poor prognosis despite initial treatment responses. This study evaluates ctDNA for monitoring disease and assessing the efficacy of first-line therapy in patients with extensive-stage SCLC (1L ES-SCLC).

Experimental design: In the TAZMAN trial, 31 patients with 1L ES-SCLC received standard treatment with durvalumab and etoposide plus carboplatin or cisplatin. We analyzed 228 plasma samples from 27 of 31 patients using a liquid biopsy approach to detect somatic mutations and copy-number aberrations, while also accounting for clonal hematopoiesis mutations.

Results: Baseline ctDNA analysis detected somatic alterations in 96.3% of …