Digital Commons Network^™

Kras G12c And Kras G12d Respond To Lipid Metabolism In An Allele-Specific Manner, Neha Arora, Hong Liang, Walaa Kattan, Wantong Yao, Haoqiang Ying, Junchen Liu, Yong Zhou

Faculty, Staff and Student Publications

KRAS mutated at hotspots G12, G13, and Q61 possess profound allele-specific oncogenesis. Signaling of KRAS mutants is mostly compartmentalized to the proteolipid nanoclusters on the plasma membrane (PM), illustrating critical roles of spatiotemporal organization in KRAS cancer signaling. The activated GTP-bound KRAS molecules, including the wild type and mutants, have been traditionally thought to favor similar lipids. We recently reported distinct lipid sensing capabilities of different KRAS mutants, especially with KRASG12D favoring unsaturated lipids and KRASG12C gaining additional enrichment of saturated lipids. As such, KRAS mutants may respond to lipid acyl chain remodeling in an allele-specific manner. Lysophosphatidylcholine acyltransferase 1 …

Erk-Mediated Phosphorylation Of Yap Defines A Noncanonical Fgf Signaling Mechanism In Stem Cells, Xiaolei Zhao, Shannon Erhardt, Li Tang, Xiaotong Chen, Stephen M Farmer, Zixiu Cheng, Wen Chen, Ella Ziyuan Lu, Kihan Sung, Chang-Ru Tsai, Mingjie Zheng, Sheng Zhang, Yang Liu, Jianxin Wang, Min Li, James F Martin, Jun Wang

Faculty, Staff and Student Publications

While Fgf and Hippo-Yap signaling are fundamental for proper development, homeostasis, and disease, their crosstalk remains largely unknown. Here, we identified that Yap and Taz, canonical Hippo effectors, function as noncanonical effectors of Fgf signaling to maintain the proper function of neural crest (NC) lineages. NC cells are a multipotent stem cell population during vertebrate embryogenesis that contribute to numerous structures and diverse cell lineages, including craniofacial and cardiac tissues, neurons, and suture mesenchymal cells (SMCs), a specified cell population required for cranial bone growth and repair. We observed that activation of Fgf signaling in NC cells and NC-derived SMCs …

Cefepime Pharmacokinetics In Critically Ill Children With Multiple Organ Dysfunction Syndrome Using Volumetric Absorptive Microsampling, Victor Amajor, Amanda Bwint, Steven Shein, Janet Hume, Courtney Rowan, Leeanne Flygt, Matthew Malone, Erin Stenson, Scott Weiss, Matt Zinter, Sujatha Kannan, Mary Dahmer, Ryan Nofziger, Manjunath Pai, Athena Zuppa, Nathaniel Rhodes, Mark Hall, Marc Scheetz, Kevin Downes

Department of Pediatrics Faculty Papers

Up to half of critically ill children experience multiple organ dysfunction syndrome (MODS), which worsens outcomes and increases mortality risk. Cefepime is a broad-spectrum antibiotic commonly used in pediatric sepsis, but its pharmacokinetics during MODS has not been evaluated. We performed a prospective, observational study of critically ill children with MODS who were administered cefepime and collected up to 15 whole blood samples over 3 days using volumetric absorptive microsampling (VAMS). We performed nonlinear mixed-effects modeling to develop a population PK model for cefepime in children with MODS. We then reran our final population PK model using estimated plasma concentrations …

Current Practices And Variations Among Pediatric Severe Asthma Programs In The United States-The North American Severe Pediatric Asthma Consortium., Kristina Gaietto, Nadia Krupp, Avani V. Shah, Erhan Ararat, Samantha H. Averill, Sachin Baxi, Matejka Cernelc-Kohan, Jeffrey M. Chambliss, Heather De Keyser, Monica Federico, Bob Geng, Akilah A. Jefferson, Parisa Kaviany, Lila C. Kertz, Kirsten Kloepfer, Allyson Larkin, Sydney Leibel, Tanya Martinez-Fernandez, Samira Naime, Robert D. Pesek, Dinesh K. Pillai, Deepa Rastogi, Katherine Rivera-Spoljaric, Kristie R. Ross, Franziska J. Rosser, Tregony C. Simoneau, Jade Tam-Williams, Kelan G. Tantisira, William Anderson, Jonathan M. Gaffin, Theresa W. Guilbert, Erick Forno

Manuscripts, Articles, Book Chapters and Other Papers

BACKGROUND: Severe and difficult to treat asthma in children is a complex condition causing significant morbidity and associated healthcare costs. While treatment guidelines exist for severe asthma, optimal treatment approaches for the pediatric population are less well established. Furthermore, best practices regarding real world management and implementation of guidelines for the severe pediatric asthma population are lacking. In order to provide care for this population, institutions around the United States have developed multidisciplinary severe pediatric asthma programs (SPAPs). In recent years, the North American Severe Pediatric Asthma Consortium (NASPAC) was established as a mechanism for SPAPs to collaborate and share …

Relationship Between Sociodemographic Characteristics At Presentation And Outcomes Of Provoked Venous Thromboembolism In United States Children: A Secondary Analysis Of The Multinational Kids-Duration Of Therapy For Thrombosis Trial., Hope P. Wilson, Maua M. Alleyne, Sanjay Ahuja, Ernest Amankwah, Aisha Bruce, Shannon L. Carpenter, Fernando F. Corrales-Medina, Craig A. Mullen, Arun Panigrahi, Lakshmi Srivaths, Courtney D. Thornburg, Anupam Verma, Gary Woods, Neil A. Goldenberg, Madhvi Rajpurkar

Manuscripts, Articles, Book Chapters and Other Papers

BACKGROUND: Venous thromboembolism (VTE) is associated with adverse long-term sequelae, including recurrence and development of chronic venous insufficiency following limb deep vein thrombosis (postthrombotic syndrome [PTS]). Adult VTE studies have demonstrated that lower socioeconomic status, Black race, and Latinx ethnicity are associated with an increased risk of recurrence. Clinical trial-derived pediatric VTE data are limited.

OBJECTIVES: The objective of this study was to assess whether clinical features of provoked VTE and outcomes vary across sociodemographic characteristics and proxies for social determinants of health among children enrolled in the Kids-duration of therapy for thrombosis trial.

METHODS: We conducted a secondary analysis …

Biphasic Sleep Is A Feature Of Sleep Disturbance In Syngap1-Rd, Aida Doucoure, Het Patel, Mark A Abboud, Alice Sperry, Sarah K Wanigatunga, Deana Crocetti, Heather Volk, Adam P Spira, Stewart H Mostofsky, Vaishnav Krishnan, Constance Smith-Hicks

Faculty, Staff and Students Publications

Study objectives: Sleep problems are common in children with SYNGAP1-Related Disorder (SYNGAP1-RD). The use of devices that objectively estimate sleep are complicated by co-occurring sensory disorders in this population. We examined the feasibility and validity of wrist actigraphy to examine sleep and rest-activity rhythms (RAR).

Methods: Data from five children with SYNGAP1-RD and 42 typically developing children were analyzed. All children were asked to wear the Actiwatch-2 for 14 continuous days and caregivers were asked to complete a sleep diary and the Children Sleep Health Questionnaire (CSHQ). Parametric (alpha, beta, acrophase, amplitude, up/down mesor, mesor), nonparametric (intradaily variability, interdaily stability, …

Asynchronous Transitions From High-Risk Hepatoblastoma To Carcinoma, Xinjian Yu, Stephen Sarabia, Martin Urbicain, Sonal Somvanshi, Roma Patel, Priyanka Rao, Tuan M Tran, Yen-Ping Yeh, Keng-Shih Chang, Yi-Tzu Lo, Jessica Epps, Kathleen A Scorsone, Hua-Sheng Chiu, Emporia Faith Hollingsworth, Cintia R Perez, Mohammad Javad Najaf Panah, Barry Zorman, Jordan Muscal, Milton J Finegold, John A Goss, Rita Alaggio, Angshumoy Roy, Kevin E Fisher, Andras Heczey, Sarah Woodfield, Sanjeev Vasudevan, Kalyani Patel, Ting-Wen Chen, Dolores Lopez-Terrada, Pavel Sumazin

Faculty, Staff and Students Publications

Background & aims: Most pediatric hepatocellular tumors are classified as hepatoblastoma (HB) or hepatocellular carcinoma (HCC), yet a subset exhibits mixed histological and molecular features. These hepatoblastomas with carcinoma features (HBCs) include cases provisionally designated as hepatocellular neoplasm-not otherwise specified (HCN-NOS). Their biology remains poorly understood, with unresolved questions about their cellular composition and outcomes. It is unclear whether HBCs comprise hybrid cells with combined HB and HCC characteristics (HBC cells) or admixtures of distinct HB and HCC cells. We characterized the biology, etiology, cellular composition, and evolutionary dynamics of HBCs.

Methods: We performed multi-omics profiling - including single-nucleus RNA …

Blinded, Bias-Controlled Multi-Rater Evaluation Of Human-Versus-Ai Brain Metastasis Segmentation Using A Hybrid Foundation-Model Framework, Yiding Han, Enze Zhu, Mhd Hasan Ai Mekdash, Omar Awad, Piyush Pathak, Shixiao Liang, Daniel Allan Hamstra, Xizhe Zhang, Zaid Ali Siddiqui, Baozhou Sun

Faculty, Staff and Students Publications

Background: Accurate segmentation of brain metastases (BM) is essential for diagnosis, stereotactic radiosurgery planning, and longitudinal assessment. However, manual contouring is time-intensive, limiting clinical scalability, and exhibits substantial inter-observer variability. This variability complicates objective assessment of automated segmentation methods and challenges interpretation of model performance.

Purpose: To address these limitations, we developed TUM-SAM, a hybrid foundation-model framework for fully automated BM segmentation, and introduced a bias-controlled, blinded multi-rater evaluation paradigm to determine whether AI-based BM segmentation has reached expert-level performance and whether AI-generated contours are preferred by human experts under unbiased assessment.

Methods: TUM-SAM integrates nnU-Net-based lesion detection with a …

Medadl: High-Throughput Information Extraction Of Functional Status From Electronic Health Records To Advance Frailty Assessment In Older Adults, Sunyang Fu, Zhiyi Yue, Jennyly T Nguyen, Huipeng Liu, Jaerong Ahn, Vanessa Ramirez, Jude Des Bordes, Hongfang Liu, Min Ji Kwak, Nahid J Rianon

Faculty, Staff and Student Publications

Background: Functional status is essential for assessing frailty and planning care in older adults but is often under-documented in the structured fields of electronic health records. Manual chart review can capture functional status information but is labor-intensive and time-consuming. In this study, we developed and validated a scalable natural language processing (NLP) model to extract functional status information from unstructured electronic health record (EHR) notes.

Methods: This retrospective cohort study included 110 older adults seen at a geriatric osteoporosis clinic. A large language model-augmented symbolic NLP pipeline (MedADL) was developed to extract activities of daily living (ADL) and instrumental activities …

Functional Assessment Of A Convergent Gene Network Underlying Allergic Diseases And Ige., Pradeep Eranti, Raphaël Vernet, Christophe Linhard, Bing Ge, Laura Beaumier, Anne-Marie Madore, Sébastien Chanoine, Bénédicte L. Tremblay, Xiaojian Shao, Isabelle Pin, Mark Lathrop, Elin Grundberg, Valérie Siroux, Tomi Pastinen, Catherine Laprise, Emmanuelle Bouzigon, Florence Demenais

Manuscripts, Articles, Book Chapters and Other Papers

BACKGROUND: The relationships between allergic diseases (AD) and IgE levels are complex.

OBJECTIVE: We sought to identify genes associated with AD and IgE having close proximity in the interactome and to elucidate the associated biological mechanisms.

METHODS: We integrated a comprehensive interactome with data from genome-wide (GWAS) and epigenome-wide (EWAS) association studies of AD and IgE levels, respectively. We used the SigMod algorithm to identify gene modules enriched in AD- and IgE-associated signals. We performed a connectivity analysis of these two modules to characterize direct cross-trait connections. Finally, we conducted an in-depth functional analysis of the directly-connected AD and IgE …

A Phase-Ii Randomized Controlled Pilot Study Of Nicotinamide Riboside Supplementation In Older Adults With Amnestic Mild Cognitive Impairment, Christopher Martens, Kevin Decker, Theodore Deconne, Faria Sanjana, Fiona Horvat, Nicholas Rizzi, Catherine Awad, Elizabeth Habash, Joshua Hobson, Mary Kramer, Michael Armstrong, Nichole Reisdorph, Ryan Pohlig, Alyssa Lanzi, Curtis Johnson, Matthew Cohen, James Ellison

Department of Psychiatry and Human Behavior Faculty Papers

INTRODUCTION: Declining nicotinamide adenine dinucleotide (NAD+) may elevate risk of Alzheimer's disease.

METHODS: We conducted a 12-week double-blind, randomized, placebo-controlled pilot study to evaluate the safety, tolerability, and preliminary efficacy of the NAD+ precursor, nicotinamide riboside (NR), for enhancing cognitive function and cerebral blood flow (CBF) in adults with amnestic mild cognitive impairment (aMCI).

RESULTS: 42 participants completed the study (NR = 22, placebo = 20). Adherence was similar between groups with no serious adverse effects. Blood NAD+ increased twofold in the NR group. There were no improvements in cognitive function (primary outcome), total CBF, or blood pressure (secondary outcomes). …

Mechanisms Coordinating Exit From The Stem Cell State In Mammals, Emily J Park, Florencia Levin-Ferreyra, Bruno Di Stefano

Faculty, Staff and Students Publications

Differentiation requires coordinated exit from the stem cell state, during which gene regulatory networks sustaining self-renewal are dismantled, while lineage-specific programs are activated. This transition is governed by chromatin modifications, transcriptional networks, RNA processing, translational control, and metabolic rewiring that must operate with temporal precision. Despite significant progress in identifying individual regulatory components, understanding how these layers integrate to orchestrate irreversible cell fate commitment remains a fundamental challenge. This review examines common and unique regulatory principles governing stem cell exit, from totipotency during early embryogenesis to tissue-specific stem cell differentiation in adults. We synthesize recent findings on regulatory mechanisms across …

Modern Molecular Profiling Recontextualizes The Nrg/Rtog 0539 Trial And Reveals Hidden High-Risk And Radiotherapy-Resistant Meningiomas, Leeor S Yefet, Clifford Robinson, Et Al.

2020-Current year OA Pubs

BACKGROUND: Meningiomas exhibit clinical heterogeneity. Radiotherapy (RT) remains the only adjuvant therapy, but tumor-control is variable, and biomarkers are limited. NRG/RTOG-0539 is the first prospective phase 2 trial to stratify meningioma patients for adjuvant RT based on clinical risk. Here, we apply modern molecular tools to this cohort and identify correlates of RT response.

METHODS: Tumor tissue from 100 RTOG-0539 patients was profiled using DNA methylation arrays, RNA sequencing, and whole-exome sequencing. Recurrence scores, Molecular Groups, gene expression, and copy number alterations were compared across clinical groups and between RT responders and non-responders; non-response was defined as progression or death …

Enhancing Validation Of Case-Control Omics Signatures Through "Minimalist" Single-Subject Analysis (N-Of-1 Trials): Proof Of Concept In Sepsis, Liam S Wilson, Nima Pouladi, Rachel F Nelson, Elizabeth A Middleton, Neal D Tolley, Mahdieh Shabanian, Colleen Kenost, Robert A Campbell, Matthew T Rondina, Yves A Lussier

2020-Current year OA Pubs

OBJECTIVE: To evaluate if a single-subject study (S3) design, utilizing paired transcriptome samples from the same patient (eg, "sepsis" vs "recovered"), can replicate transcriptomic signatures from small case-control studies, addressing challenges in patient accrual for rare or sub-stratified diseases.

METHODS: We generated a sepsis gene signature (SGS) comprising 300 differentially expressed genes (DEGs; FDR <  5%) from a human sepsis case-control cohort using general linear models (GLMs). Reproducibility of SGS was assessed through three approaches applied to sub-sampled independent datasets: single-subject analyses (N-of-1-MixEnrich), anticipated to perform better; conventional paired-sample GLM analyses; and a traditional case-control GLM analysis.

RESULTS: SGS reproducibility in GLM analyses was inconsistent at smaller cohort sizes (∼80% reproducibility; n = 5) but stabilized at cohort sizes >6. Remarkably, the single-subject-study approach consistently reproduced SGS in each of the 18 subjects individually (100% reproducibility; n = 1).

DISCUSSION: Conventional GLMs are …

Mapping Dna Methylation Signatures To Identify Epigenetic Variation Across Subcortical Regions Of The Human Posttraumatic Stress Disorder Brain, Hongyu Li, Yujing Liu, Yiming Shi, Jiawei Wang, Tuan P Nguyen, Yuhan Xie, Wangjie Zheng, Youshu Cheng, Dianne A Cruz, Jennifer L Modliszewski, Rosemarie Terwilliger, Alexa-Nicole Sliby, José Jaime Martínez-Magaña, Janitza L Montalvo-Ortiz, John D Roache, Lynnette A Averill, Stacey Young-Mccaughan, Paulo R Shiroma, Bertrand R Huber, David A Lewis, Jill Glausier, Paul Holtzheimer, Matthew J Friedman, Jing Zhang, Alan L Peterson, Chadi G Abdallah, Amir Valizadeh, Xinyu Zhang, Ke Xu, John H Krystal, Ronald S Duman, Hongyu Zhao, David L Corcoran, Douglas E Williamson, Matthew J Girgenti

Staff and Researcher Publications

Background: Posttraumatic stress disorder (PTSD) is a mental disorder that may occur in the aftermath of severe psychological trauma. Epigenetic changes in the brain may play a critical role in understanding the neurobiology of PTSD by linking environmental traumatic stress exposure to lasting alterations in gene expression that shape neuronal function.

Methods: We examined 1,065,750 DNA methylation (DNAm) sites from 171 donors including neurotypical controls and PTSD and major depressive disorder (MDD) cases across 6 regions implicated in the fear circuitry of the brain. We performed RNA sequencing (RNA-seq) to examine changes in gene expression and linked these changes to …

Feasibility Of Using Electronic Medical Records To Identify Postdischarge Mental Health Screening Documentation In Trauma Patients., Kellie Girardot, Julie L Otte

Emergency Medicine and Trauma

BACKGROUND: Injury leads to long-term physical and mental health challenges, yet inpatient screening for post-traumatic stress disorder and depression remains inconsistent, and postdischarge mental health is poorly understood, particularly in less resourced trauma centers where emerging symptoms may go unrecognized.

OBJECTIVE: To evaluate the feasibility of using the electronic medical record to identify postdischarge mental health screening documentation in adult trauma patients within 6 months after discharge.

METHODS: This retrospective descriptive feasibility study was conducted at a midwestern US regional Level II trauma center serving a predominantly rural catchment area. Adult trauma patients admitted between January 1 and December 31, …

Crispr/Cas9-Based Genome Editing: Understanding Differences In Dna Repair Pathways, Profiles, And Outcomes, Samuel Effah, Shirley Barrera, Nahia Urturi Ortiz, Will Dampier, Michael Nonnemacher, Brian Wigdahl

Kimmel Cancer Center Faculty Papers

Over a decade of advances in Clustered Regularly Interspersed Short Palindromic Repeats (CRISPR) and CRISPR-associated protein 9 (Cas9)-based technologies have culminated in the first-ever FDA-approved CRISPR/Cas-based therapy. Aside from this approved therapy for sickle cell anemia, several CRISPR/Cas-based therapies are currently under development or testing for a range of chronic diseases, including viral diseases like human immunodeficiency virus type 1 (HIV-1) infection, genetic diseases like familial hypercholesterolemia, and cancer. The success of these therapies hinges on the effective delivery of CRISPR/Cas9 components to target regions, efficient Cas endonuclease editing, repair profiles generated, and their resulting outcomes. Here, we discuss the …

Oncocytic Intraductal Carcinoma Of The Parotid Gland With Strn::Alk Fusion, Reham H Soliman, Chris Shi, Kevin E Fisher, Hong Yu, Fouad El-Dana, Xu Cao, Li Liang, Pei Ying, Songlin Zhang

Faculty, Staff and Students Publications

Intraductal carcinoma (IDC) of the salivary gland is an uncommon epithelial neoplasm characterized by a predominantly intraductal or intracystic proliferation rimmed by a myoepithelial cell layer. Advances in molecular profiling have revealed recurrent gene fusions in IDC, most frequently involving RET, although fusions implicating other kinase genes have also been described. Among these, ALK rearrangements are rare and remain poorly characterized. Herein, we report a case of oncocytic IDC of the parotid gland harboring a STRN::ALK fusion, further expanding the molecular landscape of this tumor. Although this fusion has been previously reported in intercalated duct IDC, to our knowledge, this …

Comprehensive Prediction Analysis Of Novel Noncoding Regulatory Variants Identified In The Microrna Binding Regions In Complement System Genes, Anthony Shadid, Haydn E Rich, Kathryn D Hok, Marie-Francoise Doursout, Marcos I Restrepo, Nirmal K Banda, Lavanya Gunamalai, Pooja Shivshankar

The Brown Foundation: Institute of Molecular Medicine

The complement system is a central component of innate immunity that coordinates host defense, immune surveillance, and inflammatory responses through tightly regulated proteolytic cascades. Genetic variation within complement genes contributes substantially to interindividual differences in complement activity and disease susceptibility. While coding variants directly alter complement protein structure and function, the microRNA (miRNA)-mediated control and post-transcriptional regulation is not fully understood in shaping complement gene expression across immune and inflammatory mechanisms. Complement pathway genes exhibit extensive and heterogeneous 3'-untranslated regions (3'UTRs), which serve as primary platforms for miRNA binding and RNA-binding protein interactions. Both common and rare single-nucleotide polymorphisms within …

Fgfr3::Tacc3 Fusion And Notch1 Loss-Of-Function In A Case Of Hpv-Associated Sinonasal Squamous Cell Carcinoma: Diagnostic Challenge And Implications For Targeted Therapy, Xu Cao, Hong Yu, Reham Hamdy Abdulazim Soliman, Pei Ying, Songlin Zhang, Li Liang

Faculty, Staff and Students Publications

Sinonasal squamous cell carcinoma (SNSCC) comprises a heterogeneous group of tumors with emerging molecular subtypes. Human papillomavirus (HPV)-associated SNSCC is a distinct entity, although actionable genomic alterations beyond HPV-driven pathways remain underexplored. Distinguishing HPV-associated SNSCC from carcinoma ex inverted papilloma can be particularly challenging in limited biopsy specimens, as these lesions may appear morphologically similar. We report a case of HPV-associated SNSCC with concurrent FGFR3::TACC3 fusion and NOTCH1 p.C1416 stop-gain mutation.

Obesity And Keratoconus: A Mediation Study Based On The Chinese Keratoconus Cohort, Kaili Yang, Anqi Chang, Runqi Tu, Liyan Xu, Yuwei Gu, Qi Fan, Shanshan Yin, Yi Yuan, Yifan Wang, Chenchen Yin, Yonghao Zang, Changxiu Li, Chenjiu Pang, Daniela Oehring, Yibin Hao, Shengwei Ren

School of Health Professions

Purpose: Growing evidence indicates a strong association between obesity and keratoconus (KC), although the potential mediating factors remain largely unknown. This study aimed to explore the potential pathways through which corneal biomechanical and topographic parameters might link obesity and KC using structural equation modeling (SEM). Methods: This case-control study included 759 participants (363 patients with KC and 396 controls) from the Chinese Keratoconus (CKC) Cohort Study. Associations among body mass index (BMI), corneal biomechanical parameters, topographic parameters, and KC were analyzed using generalized linear regression models. SEM was used to construct latent variables for corneal biomechanical and topographic parameters. Three …

Chemotherapeutic Induction Of Cytosolic Single-Stranded Dna Accumulation Sensitizes Triple-Negative Breast Cancer To Immunotherapy, Yong Du, Li Yang, Hui Dai, Jianli Zhou, Zhicheng Zhou, Ruoxi Yuan, Rui Ye, Anh Thai Quynh Nguyen, Kishor Bhatia, Shiaw-Yih Lin

Faculty, Staff and Students Publications

Background: Despite the widespread adoption of chemoimmunotherapy in triple-negative breast cancer (TNBC), the mechanisms by which cytotoxic chemotherapy engages antitumor immunity remain poorly defined. Identifying tumor-intrinsic immunogenic programs that predict and enhance responsiveness to immune checkpoint blockade (ICB) is therefore of critical clinical importance.

Methods: Transcriptomic signatures of TREX1 deficiency were generated from CRISPR-engineered TNBC models and applied to multiple independent TNBC cohorts treated with chemoimmunotherapy. Cytosolic single-stranded DNA (ssDNA) accumulation was quantified using a flow cytometry-based assay to functionally screen chemotherapeutic agents. Immune activation and therapeutic efficacy were evaluated using in vitro assays, syngeneic mouse tumor models, flow cytometry, …

Plasma Gdf15 Affects Long-Term Dementia Risk And Alters Neuroimmune Signaling, Cassandra O Blew, Michael R Duggan, Dimitrios Tsitsipatis, Gabriela T Gomez, Zulema Rodriguez-Hernandez, Luke C Pilling, Jingsha Chen, Eva Jacobsen, Heather E Dark, Yifei Lu, Shannon M Drouin, Cassandra M Joynes, Minhao Yao, Murat Bilgel, Abhay Moghekar, Qu Tian, Julián Candia, Mary Kaileh, Aditi Gupta, Krystyna Mazan-Mamczarz, Myriam Gorospe, Alexey Lyashkov, Yevgeniya Lukyanenko, Mika Kivimaki, Philipp Frank, Lori L Jennings, Valborg Gudmundsdottir, Vilmundur Gudnason, Lenore J Launer, Naoto Kaneko, Shintaro Kato, Makio Furuichi, Masaki Shibayama, Masahisa Katsuno, Keita Hiraga, Yukiko Nishita, Rei Otsuka, James R Pike, Mary R Rooney, Pascal Schlosser, Yuhan Cui, Guray Erus, Christos Davatzikos, Rebecca F Gottesman, Iwao Waga, Priya Palta, Christie Ballantyne, Michael Griswold, Zhonghua Liu, Luigi Ferrucci, Allison B Herman, Keenan A Walker

Faculty, Staff and Students Publications

Growth/differentiation factor-15 (GDF15) is a secreted cytokine strongly associated with dementia risk. However, the extent to which GDF15 represents a biomarker and driver of dementia risk remains unclear. Across multiple cohorts, we demonstrated that plasma GDF15 is associated with greater dementia risk over 15- to 25-year follow-up periods when measured in midlife, with stronger associations observed for vascular, compared to Alzheimer's disease (AD), dementia. Two-sample Mendelian randomization supported plasma GDF15's mechanistic role in AD and related dementias, while cohort studies linked it to cerebral small vessel disease, neurodegeneration, phosphorylated tau, and a cerebrospinal fluid proteomic signature indicative of neuroimmune activation. …

Folr1-Targeted Actinium-225-Based Alpha-Particle Therapy Eliminates Ovarian Cancer, Neetu Singh, Esther Need, Ayden Berndt, Matthew Goff, Lydia J. Wilson, Firas Mourtada, Feng Guo, Tara Mastren, Taslim Al-Hilal, Anil K. Sood, Amit Maity, Scott C. Miller, Satoshi Minoshima, Shreya Goel, Sixiang Shi

Department of Radiation Oncology Faculty Papers

Despite the advancement in therapies, ovarian cancer treatment is challenging because of poor prognosis and high relapse associated with acquired resistance. Emerging targeted alpha particles, particularly actinium-225 (225Ac), for treating refractory cancers have opened avenues for improved therapeutic options. Here, we describe a successful example of folate receptor 1 (FOLR1)–targeted 225Ac alpha-particle therapy for treatment of ovarian cancer. Longitudinal positron emission tomography imaging demonstrated high tumor-specific uptake of αFOLR1 (anti-FOLR1 antibody) in SKOV3 xenografts. FOLR1-targeted 225Ac demonstrated high therapeutic efficacy, achieving marked tumor regression, 80% survival, and 40% complete tumor elimination. The therapy resulted in tumor-specific double-stranded DNA damage, and …

Adaptation Of The Transition Readiness Assessment Questionnaire For Pediatric-Onset Multiple Sclerosis: Protocol For A User-Centered Design Approach, Claudia Gambrah-Lyles, Aaron W Abrams, Sara Loud, Hollie Schmidt, Emily Blosberg, Melissa Wright, Kelsey E Poisson, Kristen S Fisher, Kimberly A O'Neill, Akash Virupakshaiah, John W Rose

Faculty, Staff and Students Publications

Background: Pediatric-onset multiple sclerosis (POMS) is a chronic, progressive neurologic condition requiring lifelong management and coordinated transition from pediatric to adult care. Evidence-based guidelines identify transition readiness assessment as a core component of successful transition; however, most POMS clinics do not formally assess readiness, and existing tools do not address POMS-specific challenges, such as fluctuating disability, complex treatment regimens, and cognitive impairment. This gap underscores the need for a transition readiness measure tailored to POMS.

Objective: This paper aims to describe a stakeholder-engaged, implementation science-guided protocol for adapting the Transition Readiness Assessment Questionnaire (TRAQ) version 6.0 to reflect the unique …

Meeting Report From The 2025 Cure Ocular Melanoma (Cure Om) Global Science Meeting, Amsterdam, The Netherlands, October 2025, Andrew E. Aplin, Katherina Alsina, Allison S. Betof, Joseph Birkett, Marcus O. Butler, George Cole, Rizwan Haq, Florian A. Karreth, Vinit B. Mahajan, Rahul Marpadga, Prithvi Mruthyunjaya, Paul Nathan, Jonas A. Nilsson, Gary Palmer, Joseph J. Sacco, Takami Sato, Sarah Stanhope, Pang-Ning Teng, Kyleigh Lipira

Department of Pharmacology, Physiology, and Cancer Biology Faculty Papers

The 2025 Cure Ocular Melanoma (CURE OM) Global Science Meeting took place in Amsterdam, The Netherlands on October 25th, 2025. Several promising drug candidates are in development; however, there is still an urgent need for better prevention, detection, and treatment of uveal melanoma. The purpose of this meeting was to promote international collaboration and idea exchange between scientists, industry, and patient advocates.

Rna G-Quadruplexes Function As A Tunable Switch Of Fus Phase Separation, Jenny L. Carey, Miyuki Hayashi, Emily A. Welebob, Laura R. Ganser, Huan Wang, Kerry Buckhaults, Jacquelyn A. Depierro, Zheng Shi, James Shorter, Sua Myong, Aaron R. Haeusler, Lin Guo

Department of Biochemistry and Molecular Biology Faculty Papers

Fused in sarcoma (FUS) undergoes liquid-liquid phase separation (LLPS) to support essential cellular functions, but aberrant phase transitions promote toxic aggregation in neurodegenerative disease. Short RNA oligonucleotides can reverse this behavior, yet the structural determinants that govern RNA activity remain poorly defined. Here, we identify RNA G-quadruplexes (rG4s) as tunable structural motifs that potently modulate FUS LLPS. rG4 activity depends on its concentration and is modulated by rG4 length and stability: increasing repeat number switches rG4s from inhibitor to nucleator of FUS assembly, whereas chemical modifications that stabilize rG4 enhance inhibitory function and render these activities resilient to ionic perturbation. …

Prmt5 As A Key Driver Of Stemness And Metastatic Potential In Triple-Negative Breast Cancer, Jae Jin Jeong, Mauli Maniar, Shahrzad Ghane, Sakshi Deshpande, Claire Ellis, Ashakumary Lakshmikuttyamma

College of Pharmacy Faculty Papers

Protein arginine methyltransferase 5 (PRMT5) mediates arginine methylation of a wide range of proteins and plays context-dependent oncogenic or tumor-suppressive roles. In cancer, PRMT5 represses several tumor suppressor genes, including E-cadherin, TP53BP1, ST7, PTEN, and RB (retinoblastoma). Elevated PRMT5 expression has been reported across multiple cancer types, notably triple-negative breast cancer (TNBC). In TNBC, high PRMT5 levels are associated with enhanced cancer stem cell self-renewal, increased tumor growth and metastasis, and reduced patient survival. Mechanistically, PRMT5 promotes breast cancer stem cell maintenance and proliferation through stabilization of the transcription factors KLF4 and KLF5. Disruption of the PRMT5-KLF4 axis results in …

Neddylation Maintains Oocyte Quality By Stabilizing Mitochondrial Transcription, Avery A Ahmed, Tessa E Steenwinkel, Bethany K Patton, Peixin Jiang, Matthew D Meyer, Jaspreet K Rishi, Mei Leng, Alexander B Saltzman, Elizabeth S Anaya, Momal Sharif, Laurie J Mckenzie, Laura Detti, Anna Malovannaya, Sean M Hartig, Stephanie A Pangas

Faculty, Staff and Students Publications

Age-related decline in oocyte quality increases the risk of infertility, miscarriage, and birth defects. Mitochondrial dysfunction is a key contributor to this decline. Here, we report that oocyte-specific deletion of Uba3, which encodes the catalytic subunit of the E1 NEDDylation-activating complex, causes sterility in mice. Fully grown, germinal vesicle–stage Uba3 conditional knockout oocytes exhibit mitochondrial dysfunction, including elevated reactive oxygen species, impaired oxidative phosphorylation, and depletion of mitochondrially encoded RNA transcripts. Proteomic analysis identified alterations in mitochondrial-associated proteins, including enrichment of mitochondrial matrix and respiratory chain components and reduced abundance of electron transport chain complexes. These defects were associated …

Non-Tobacco Nicotine Dependence Is Associated With Increased Complications Following Clavicle Open Reduction Internal Fixation, Akin A. Adio, Rahul K. Goyal, Abby Skiena, Mohammad Daher, John G. Horneff, Hafiz F. Kassam, Brian W. Hill, Joseph A. Abboud

Rothman Institute Papers

BACKGROUND: Tobacco dependence is well established to impair bone healing and increase postoperative complications. However, the independent effects of nicotine, separate from combustion-related factors, remain unclear. This study aimed to evaluate the impact of non-tobacco nicotine dependence (NTND) following open reduction and internal fixation (ORIF) of clavicle fractures, including midshaft and lateral fracture subtypes.

METHODS: A retrospective cohort study was performed using a large national database. Patients undergoing ORIF of clavicle fractures were identified using procedural and diagnostic codes. Patients with non-tobacco nicotine dependence (e.g., vaping, patches, or gum) were identified and propensity score matched to (1) patients without nicotine …