Medical Genetics Commons^™

Pimicotinib Versus Placebo For Tenosynovial Giant Cell Tumour (Maneuver): An International, Randomised, Placebo-Controlled, Phase 3 Trial, Hairong Xu, Xiaohui Niu, Vinod Ravi, Javier Martin-Broto, Albiruni Abdul Razak, Ramy Saleh, Yong Zhou, Jingnan Shen, Tang Liu, Kamlesh Kumar Sankhala, César Serrano, Silvia Stacchiotti, Jing Wang, Giacomo G Baldi, Yi Feng, Yingqi Hua, Tao Li, Piotr Rutkowski, Xiaojing Zhang, Gabriel Tinoco, Qingping Zou, Boyao Shan, Xiangyu Zhu, Hans Gelderblom

Faculty, Staff and Student Publications

Background: Tenosynovial giant cell tumour (TGCT) is a rare, locally aggressive neoplasm that affects otherwise healthy adults. There are few systemic treatment options, highlighting an unmet need. We report the results of part 1 of the MANEUVER trial, which aimed to evaluate the efficacy and safety of pimicotinib, a highly selective, potent, colony-stimulating factor-1 receptor inhibitor, in patients with TGCT.

Methods: MANEUVER is a randomised, placebo-controlled, phase 3 study done in 40 specialised hospitals in Asia, Europe, and North America. Patients aged 18 years and older with unresectable, symptomatic TGCT (patient-reported worse stiffness or worst pain of at least 4 …

Ccr7 Immune Cell Receptor Expression In Inflammatory Breast Cancer, Jennifer H Chen, Wintana Balema, Savitri Krishnamurthy, Alison N Lawrence, Natalie W Fowlkes, Richard A Larson, Surbhi Shivhare, Caren Sanchez, Megan M Rodriguez, Jangsoon Lee, Emilly S Villodre, Bisrat G Debeb, Naoto T Ueno, Steve Van Laere, Francois Bertucci, Hyunwoo Cho, Erik P Sulman, Bora Lim, Wendy A Woodward

Faculty, Staff and Student Publications

No abstract provided.

Patterns Of Failure Following Stereotactic Radiosurgery Salvage For Recurrent High-Grade Glioma, Shivani Bindal, Brandon Gonzalez, Antonio Dono, Roy Riascos, Jay-Jiguang Zhu, Sigmund Hsu, Nitin Tandon, Angel Blanco, Yoshua Esquenazi, Mark Amsbaugh

Faculty, Staff and Student Publications

Background and objectives: Re-irradiation with stereotactic radiosurgery (SRS) is an increasingly used treatment for recurrent high-grade glioma (HGG). We analyzed the patterns of failure after salvage SRS to better identify which patients would most benefit.

Methods: We reviewed all patients who received SRS for recurrent HGG over 12 years at our institution. Pattern of failure was defined by the distance of recurrence from the SRS isodose line. Overall-survival (OS), progression-free survival (PFS), and local-failure-free survival (LFS) were estimated using Kaplan-Meier methods, and regression model analysis was performed to analyze clinical predictors of failure.

Results: 146 patients with HGG underwent SRS …

Pan-Cancer Evolution Signatures Link Clonal Expansion To Dynamic Changes In The Tumor Immune Microenvironment, Xinyu Yang, Wei Liu, Geoff Macintyre, Peter Van Loo, Florian Markowetz, Peter Bailey, Ke Yuan

Faculty, Staff and Student Publications

Cancer is an evolutionary process characterized by profound intratumor heterogeneity (ITH), which can be quantified using in silico estimates of cancer cell fractions (CCFs) of tumor-specific somatic mutations. We demonstrate a data-driven approach based on CCF distributions to identify 4 robust pan-cancer evolutionary signatures from 4,146 tumors across 17 cancer types in The Cancer Genome Atlas (TCGA). These signatures define a continuum of cancer cell fractions reflecting neutral evolution, clonal expansion, and clonal fixation. Correlating evolutionary signatures with mutational and biological programs reveals that tumors enriched for clonal expansion and fixation are associated with immune evasion and distinct changes in …

The Efficacy And Safety Of Serratus Anterior Plane Block In Patients Undergoing Cardiac Surgery: A Systematic Review And Meta-Analysis, Xu-Bo Cui, Ming-Zhu Cui, Qiu-Ju Yang, Yang Liu, Meng-Qi Yi, Xiao-Yang Zhang, Yun-Tai Yao

Faculty, Staff and Student Publications

Background: Serratus anterior plane block (SAPB) is a widely used fascial block that reduces postoperative pain and perioperative opioid consumption. This meta-analysis assessed the efficacy and safety of SAPB in cardiac surgery patients.

Methods: We systematically searched PubMed, Web of Science, Cochrane Library, Embase, China National Knowledge Infrastructure, and Wanfang databases on May 10, 2024. Pooled relative risks and mean differences (MD) with 95% confidence intervals (CI) were calculated for dichotomous and continuous outcomes, respectively. Heterogeneity was assessed using the I2 statistic, and publication bias was evaluated using Egger test. Subgroup analyses were stratified by study design (randomized controlled trials …

Uncovering Hidden Prognostic Patterns In Colorectal Cancer Histology Using Unsupervised Learning: A Computational Pathology Study, Wen-Tong Zhou, Yong Liu, Gang Yu, Kuan-Song Wang, Chao Xu, Jonathan Greenbaum, Chong Wu, Lin-Dong Jiang, Christopher J Papasian, Hong-Mei Xiao, Hong-Wen Deng

Faculty, Staff and Student Publications

Colorectal cancer (CRC) remains a leading cause of cancer mortality globally, yet current histopathological diagnostics capture only limited features. This study aimed to discover subtle, prognostically significant histomorphological patterns in CRC tissues using unsupervised deep learning. We developed a framework integrating convolutional neural networks with deep clustering, trained on 23,341 image patches from 493 patients. We identified 30 distinct histomorphological clusters from CRC tissue images. Through univariate and multivariate survival analyses, three clusters (Cluster13, Cluster19, and Cluster24) were consistently associated with patient prognosis. These clusters were integrated with clinical factors (T stage, N stage, and differentiation degree) to construct a …

Telemedicine As A Gateway To Early-Phase Oncology Trials: Lessons From 14,000 Patients And Future Directions For Global Access And Equity, Carlos Torrado, Clark R Andersen, Lei Kang, Amanda L Brink, Taiwo Adesoye, Hung Le, Clover J Patterson, Anna Poullard, Jessica A Osburn, Harold N Tan, Mohamed A Gouda, Sheena Charles, Gabriele E Urschel, Tin-Yun Tang, David S Hong, Stephane Champiat, Aung Naing, Apostolia M Tsimberidou, Ecaterina E Dumbrava, Sarina A Piha-Paul, Jordi Rodon, Timothy A Yap, Paula R Pohlmann, Funda Meric-Bernstam, Siqing Fu

Faculty, Staff and Student Publications

Background: Telemedicine expanded rapidly during the COVID-19 pandemic, but its role in early-phase oncology trials remains uncertain. We evaluated its impact on recruitment, enrollment, equity, and access in a large phase I program.

Patients and methods: We retrospectively analyzed patients seen for first consultation in the MD Anderson Phase I Program (2016-2023). Recruitment (consent) and enrollment (treatment initiation) were compared by visit type, race/ethnicity, and geography across pre-pandemic (2016-2019), pandemic (2020-March 11, 2023), and post-public health emergency (PHE; March-December 2023) periods. A chart review of 400 patients validated findings.

Results: Of 14,085 patients, 7,247 were evaluated post-pandemic, with 36% (n …

Pkmζ-Kibra Interactions, Molecular Turnover, And Memory, Changchi Hsieh, David A Cano, Panayiotis Tsokas, James E Cottrell, André Antonio Fenton, Harel Shouval, Todd Charlton Sacktor

Faculty, Staff and Student Publications

How can the molecules that strengthen synaptic connections maintain memory in the face of molecular turnover? Our previous work showed that persistent interaction between the postsynaptic scaffolding protein, KIBRA, and the autonomously active PKC isoform, PKMζ, is crucial for maintaining synaptic long-term potentiation (LTP) and memory lasting at least a month. This duration is longer than the lifespans of individual KIBRA and PKMζ molecules. Biophysical modeling of the interaction suggests oligomers of KIBRA-PKMζ dimers, but not individual dimers or monomers, can overcome molecular turnover by continuously incorporating newly synthesized KIBRA and PKMζ, replacing those that have degraded. Here we used …

Complete Genome Sequence Of The Widely Used Coaggregation Fusobacterial Strain Pk1594, Bibek G C, Shiqi Xu, Chenggang Wu

Faculty, Staff and Student Publications

We report the complete genome sequence of the fusobacterial strain PK1594, widely used to study coaggregation between Fusobacterium nucleatum and oral bacteria. The assembly comprises a 2,357,192-bp chromosome and a 20,441-bp contig representing a duplicated 10,221-bp plasmid. znpA analysis indicates that PK1594 is Fusobacterium hwasookii rather than F. nucleatum.

Schistosome Esophageal Gland Factor Meg-82 Drives Host Cell Lysis And Interacts With Host Immune Proteins, Pallavi Yadav, Sabona B Simbassa, Ryan Sloan, Phillip A Newmark, Jayhun Lee

Faculty, Staff and Student Publications

Schistosomes are blood flukes that ingest large amounts of host blood during their intra-mammalian stage. The ingested blood contains leukocytes that can be harmful, yet the parasites survive inside the host for decades, reflecting superb immune evasion mechanisms that remain poorly understood. Our previous work discovered that FoxA, a forkhead transcription factor, drives the production of the esophageal gland, an anterior digestive organ essential for degrading ingested leukocytes and for in vivo survival. However, a comprehensive molecular makeup of the esophageal gland remains unclear. Importantly, the esophageal gland factors responsible for degrading ingested leukocytes, their mechanisms of action, and how …

International Consensus-Driven Recommendations For Patient-Reported Outcome Research Objectives In Early Phase Dose-Finding Oncology Trials: Optimise-Ror, Emily Alger, Olalekan Lee Aiyegbusi, Amylou C Dueck, Anna Minchom, Madeline Pe, John D Peipert, Claire Snyder, Stefan N Symeonides, Roger Wilson, Ethan Basch, Yu Qiao, Susan E Bates, Helen Bulbeck, Lizzie Dean, Massimo Di Maio, Aaron R Hansen, Olga Kholmanskikh, Ken Kobayashi, Dónal Landers, Christophe Le Tourneau, J Jack Lee, Brigette B Y Ma, Lynley V Marshall, Sheetal Patel, Joan Petrie, Gregory R Pond, Kieran Prior, Khadija R Rantell, John F Reeve, Olga Solovyeva, Nolan A Wages, Harald A Weber, Melanie J Calvert, Christina Yap

Faculty, Staff and Student Publications

Purpose: There is growing scientific interest in incorporating patient-reported outcomes (PROs) in early phase dose-finding oncology trials (DFOTs) to assess tolerability, inform dose selection, and guide later stage trial design. However, research indicates that PRO objectives in DFOTs are often unclear. The Incorporating Patient-Reported Outcomes in Dose-Finding Trials-Research Objectives Recommendations (OPTIMISE-ROR) project was established to support trialists to effectively incorporate PROs into DFOTs.

Methods: Using the Enhancing Quality and Transparency of Health Research (EQUATOR) Network's methodological framework, guideline development included the following: (1) a methodological review of published DFOTs incorporating PROs; (2) candidate item generation, refined through expert consultation; (3) …

Clinical Trial Success Rate In Lymphoma: Fate Of Trials And Agents From 2000 To 2019, Zhiping Luo, Meng Li, Brian C Primeaux, Rahul Shah, Ruitao Lin, Swaminathan P Iyer, Loretta J Nastoupil, Michael R Green, Jason R Westin, Christopher R Flowers, Dai Chihara

Faculty, Staff and Student Publications

Although previous studies have examined the drug development and clinical trial success rates in oncology, a comprehensive analysis of development success rate in lymphoma has not been performed. Therefore, we analyzed lymphoma trials initiated between 1 January 2000 and 31 December 2019, using the Trialtrove database and ClinicalTrials.gov. We identified phase 1, 2, and 3 trials that included patients with lymphoma and analyzed the transition rate of investigational agents across phases and their US Food and Drug Administration (FDA) approval rates to assess the efficiency and success of the clinical development process. A total of 1032 phase 1 trials and …

Dual Phagocytosis-Checkpoint Blockade Revitalizes Immune Surveillance In Mouse Models Of Glioblastoma, Jonghoon Ha, Yifan Wang, Yifan Ma, Annette Wu, Shiyan Dong, Seong Dong Jeong, Jared L Edwards, Mengyu Chang, Yen-Tzu Chang, Xiaotian Wang, Maurice Dufilho, Michelle Najarro Torres, Shannon Mccabe, Weiye Deng, Adam J Grippin, Jeffrey S Weinberg, Shaan M Raza, Franco Demonte, Ian E Mccutcheon, Sujit Prabhu, Sherise D Ferguson, Chibawanye I Ene, Kadir Akdemir, Sreyashi Basu, Sonali Jindal, Benjamin R Schrank, Jian Hu, Sangeeta Goswami, Vinay K Puduvalli, Frederick F Lang, Kristin Huntoon, Padmanee Sharma, Betty Y S Kim, Wen Jiang

Faculty, Staff and Student Publications

Macrophage-mediated phagocytosis of tumor cells elicits potent antitumor immunity. Nonetheless, sole-blockade of the anti-phagocytosis molecule CD47 has yielded insufficient therapeutic outcomes. Here, we report that glioblastoma (GBM) cells expressed abundant levels of phagocytosis checkpoint CD24. We further show that dual blockade of CD24 and CD47 synergistically enhances the pro-phagocytic activity of macrophages, thereby improving tumor antigen cross-presentation and activating the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway. This innate immune activation facilitates T cell infiltration into tumors and sensitizes tumors to anti-PD1 therapy, improving survival outcomes in murine GBM models, including immunosuppressive tumors reflecting human GBM-like features. Thus, our …

Microrna-625-3p Increases Chemosensitivity In Ovarian Cancer Cells Through Decreasing Ssx2ip-Mediated Cisplatin Export In Extracellular Vesicles, Chi-Lam Au-Yeung, Tetsushi Tsuruga, Marina A Talor, Yadira J Pacheco, Guangan He, Zahid H Siddik, Byeong J Cha, Suet-Ying Kwan, Kwong-Kwok Wong, Kay-Pong Yip, Samuel C Mok

Faculty, Staff and Student Publications

Introduction: Advanced-stage high-grade serous ovarian cancer (HGSC) is a disease that is difficult to manage due to its heterogeneous clinical behavior. No reliable prediction of response to chemotherapy is currently available and the overall survival rate remains poor. Herein, we sought to determine the molecular mechanisms by which microRNAs (miRNAs) confer chemoresistance in ovarian cancer and demonstrate the efficacy of targeting miRNAs to sensitize HGSC to cisplatin treatment.

Methods: Next-generation miRNA sequencing was performed using microdissected HGSC specimens to identify an miRNA signature for intrinsic chemoresistance, and miR-625-3p was selected for further study. The effects of miR-625-3p on cisplatin sensitivity …

Integrating The Glycemia Risk Index Into Clinical Practice And Research: A Consensus Report, Guillermo E Umpierrez, Viral N Shah, Veronica Brady, Mark A Clements, Juan Espinoza, Elizabeth Healey, Michael A Kohn, David M Maahs, Ralph Oiknine, Jane J Seley, Steven P Weitzman, David Kerr, Halis K Akturk, Grazia Aleppo, Mohammed E Al-Sofiani, Eda Cengiz, Francis J Doyle, Osagie Ebekozien, Steven V Edelman, Laya Ekhlaspour, Guido Freckmann, Lutz Heinemann, Irl B Hirsch, Victoria C Hsiao, Sun H Kim, Boris Kovatchev, Rayhan A Lal, Marcus Lind, Julia K Mader, Nestoras Mathioudakis, Tracey Mclaughlin, Sultan A Meo, Deborah A Osafehinti, Moshe Phillip, Priya Prahalad, David Scheinker, Michael P Snyder, Jing Wang, Jenise C Wong, Eugene E Wright, Mandy M Shao, Agatha F Scheideman, Ashley Y Dunova, David C Klonoff

Faculty, Staff and Student Publications

A panel of experts in the use of continuous glucose monitoring (CGM) data in the treatment of diabetes met in Burlingame, California on October 27, 2025 to discuss the utility of the glycemia risk index (GRI) for clinical care research and population health management. The GRI composite metric is a single number (on a 0-100 percentile scale-lower is better) based on an expert-determined weighting of the seven individual components in the existing ambulatory glucose profile (AGP). The GRI describes the quality of glycemia based on glucose values collected in a 14-day CGM tracing, thus providing additional insights into CGM profiles …

Cancers 2025: Growing With Quality, Samuel C Mok

Faculty, Staff and Student Publications

As we enter 2026, we take a moment to reflect on the progress of Cancers over the past year [...].

Assessing The Presence Of Biasing And Non-Biasing Unblinding In A Randomized Controlled Trial Of A Home-Use Tdcs Device: An Exploratory Analysis, Fredrik Hieronymus, Nathan T M Huneke, Daniel Månsson, Erik M Rehn, Melker Hagsäter, Rachel D Woodham, Jair C Soares, Allan H Young, Rodrigo M Vieira, Sudhakar Selvaraj, Cynthia Fu

Faculty, Staff and Student Publications

Background: Better-than-chance guessing of treatment assignment raises concerns about unblinding as this opens efficacy estimates up to being influenced by factors other than the true efficacy of the intervention. However, such accuracy does not necessarily indicate that efficacy estimates are biased.

Objective: To assess whether unblinding was biasing (impacting on efficacy estimates) or non-biasing (not impacting on efficacy estimates) in a sham-controlled trial of a home-use transcranial direct-current stimulation (tDCS) device, in which treatment allocation guesses at endpoint were unbalanced.

Methods: Interrelations between i) treatment allocation, ii) treatment allocation guesses, iii) adverse event reports, and iv) depressive symptom severity, as …

Childhood Maltreatment And Deviations From Normative Brain Structure: A Mega-Analysis Of 3,711 Individuals From The Enigma Mdd And Enigma Ptsd Working Groups, Haley R Wang, Zhen-Qi Liu, Elena Pozzi, Ahmed Hussain, Priyanka Sigar, Chadi Abdallah, Nina Alexander, Justin Baker, Jochen Bauer, Jennifer Urbano Blackford, Josh Cisler, Colm G Connolly, Andrew Cotton, Judith Daniels, Udo Dannlowski, Maria Densmore, Terri Deroon-Cassini, Danai Dima, Stefan Du Plessis, Amit Etkin, Negar Fani, Lukas Fisch, Jacklynn Fitzgerald, Thomas Frodl, Cynthia H Y Fu, Ali Saffet Gonul, Evan M Gordon, Ian Gotlib, Roberto Goya-Maldonado, Nynke A Groenewold, Dominik Grotegerd, Tim Hahn, J Paul Hamilton, Laura Han, Ilan Harpaz-Rotem, Courtney C Haswell, Ryan Herringa, Julia Herzog, Jonathan Ipser, Neda Jahanshad, Tanja Jovanovic, Milissa Kaufman, Tilo Kircher, Maximilian Konowski, Sheri-Michelle Koopowitz, Axel Krug, John Krystal, Ruth Lanius, Christine Larson, Amit Lazarov, Lauren Lebois, Elisabeth Leehr, Ifat Levy, Meng Li, Antje Manthey, Adi Maron-Katz, Andrew Mcintosh, Katie Mclaughlin, Susanne Meinert, Benson Mwangi, Steven M Nelson, Igor Nenadić, Yuval Neria, Richard Neufeld, Amar Ojha, Bunmi Olatunji, Elizabeth A Olson, Nils Opel, Matthew Peverill, Kerry Ressler, Marisa Ross, Isabelle Rosso, Matthew Sacchet, Kelly Sambrook, Christian Schmahl, Soraya Seedat, Martha E Shenton, Maurizio Sicorello, Anika Sierk, Jair C Soares, Dan J Stein, Frederike Stein, Murray B Stein, Benjamin Suarez-Jimenez, Jean Théberge, Sophia I Thomopoulos, Carissa Tomas, Paula Usemann, Leigh L Van Den Heuvel, Sanne Van Rooij, Henrik Walter, Martin Walter, Xin Wang, Heather Whalley, Nils R Winter, Mon-Ju Wu, Hong Xie, Tony Yang, Xi Zhu, Sigal Zilcha-Mano, Giovana B Zunta-Soares, Sophia Frangou, Paul M Thompson, Lauren Salminen, Delin Sun, Rajendra Morey, Jennifer S Stevens, Lianne Schmaal, Tiffany C Ho

Faculty, Staff and Student Publications

Background: Childhood maltreatment (CM), encompassing abuse and neglect, is highly prevalent and associated with elevated risk for Major Depressive Disorder (MDD), Posttraumatic Stress Disorder (PTSD), and other related conditions. The extent to which neuroanatomical alterations in MDD and PTSD are attributable to CM, however, is uncertain.

Methods: Here, we analyzed CM and whole-brain MRI data from 3,711 participants in the ENIGMA MDD and PTSD Working Groups (25 sites; 33.3±13.0 years; 59.9% female). Normative modeling estimated deviation z-scores for 14 subcortical volumes (SV), 68 cortical thickness (CT), and 68 surface area (SA) measures. To identify transdiagnostic effects, associations between CM and …

Medial Pulvinar Nucleus As A Causal Hub For Heteromodal Naming, Oscar Woolnough, Tessy Thomas, Kathryn M Snyder, Ellery Wheeler, Jay Gavvala, Nitin Tandon

Faculty, Staff and Student Publications

Our ability to retrieve the names of objects in our environment is a fundamental aspect of everyday life. This process requires a complex, dynamic network of cortical and subcortical interactions. While the cortical constituents of this network have been extensively studied with intracranial recordings, the subcortical nodes of the naming network are unclear. We probed the role of the left medial pulvinar nucleus in naming with direct intracranial recordings and stimulation in eight humans (three male, five female) as they named objects using pictures and auditory and written descriptions. We found a spectrotemporal signature of naming in the left medial …

Proteomic Profiling Of Pulmonary Function And Cardiovascular Disease Risk In The Atherosclerosis Risk In Communities Study, Yura Lee, Astrid M Manuel, Ngoc Quynh H Nguyen, Christine Ladd-Acosta, Alanna C Morrison, Kari E North, Eric Boerwinkle, Amil M Shah, Zhongming Zhao, Stephanie J London, Bing Yu

Faculty, Staff and Student Publications

Background: Pulmonary function is linked to cardiovascular disease risk; however, the underlying mechanisms remain unclear. We aimed to identify protein biomarkers associated with pulmonary function and examine their impact on incident chronic obstructive pulmonary disease, coronary heart disease, heart failure, and all-cause mortality.

Methods: Data from White and Black Americans in the Atherosclerosis Risk in Communities study (visit 2: N=11 354, mean age=57 years; visit 5: N=3517, mean age=75 years), a prospective cohort, were analyzed. Linear regression assessed associations between protein levels and pulmonary function measures, including forced expiratory volume in 1 second and forced vital capacity. The impact of …

Influence Of Body Composition On The Efficacy Of Nivolumab Plus Ipilimumab For Metastatic Clear Cell Renal Cell Carcinoma, Kabir Grewal, Maria Julia Moura Nascimento Santos, Pankaj Kumar Chauhan, Kai Yu, Nizar M Tannir, Sagar S Mukhida, Neha Venkatesh, Amishi Y Shah, Amado J Zurita, Andrew C Johns, Matthew T Campbell, Sangeeta Goswami, Jianjun Gao, Eric Jonasch, Jennifer L Mcquade, Omar Alhalabi, Pavlos Msaouel, Andrew W Hahn

Faculty, Staff and Student Publications

Background: Immune checkpoint inhibitor therapy (ICI) with nivolumab+ipilimumab is a first-line (1L) standard for metastatic clear cell renal cell carcinoma (ccRCC), yet outcomes remain heterogeneous. Increasing evidence suggests that host factors influence the tumor microenvironment and response to ICI. Although higher body mass index (BMI) has been associated with improved outcomes in several malignancies, BMI is an imprecise surrogate for underlying adipose and muscle compartments. We evaluated the association between body composition and outcomes with 1L nivolumab+ipilimumab in metastatic ccRCC.

Methods: We retrospectively analyzed patients with mccRCC treated with 1L nivolumab+ipilimumab at MD Anderson Cancer Center between June 2015 and …

Mechanometabolism Instructs Hematopoietic Stem Cell Specification, Paulina D Horton, Alina Syed, Michelle Winkler, Abishek B Vaidya, Michael Rariden, Neha Arora, Yong Zhou, Michihiro Kobayashi, Momoko Yoshimoto, Hyun Jung Lee, Hyun-Eui Kim, John P Hagan, Catherine Denicourt, Travis I Moore, Pamela L Wenzel

Faculty, Staff and Student Publications

Mechanical force generated by blood flow stimulates emergence of the first hematopoietic stem cells (HSCs) that populate the blood system. Force drives the transition of HSC precursors from an endothelial to hematopoietic identity, yet the molecular regulation of this fate switch remains poorly understood. We report that shear stress triggers adaptation in mitochondrial composition, ultrastructure, and function, which are essential for hematopoietic fate and engraftment potential. Shear stress remodels mitochondria in hemogenic endothelium by promoting mitochondrial gene transcription and protein synthesis. Laminar flow selectively initiates translation of 5' terminal polypyrimidine (5'TOP) motif-containing transcripts, which commonly encode ribosome and translation machinery. …

Ectopic B Lymphocyte Follicles Exacerbate Ischemic Brain Damage Via Mif-Cd74/Cxcr4 And Interferon Signaling, Sheng Yang, Hang Zhang, Lu-Lu Xu, Luo-Qi Zhou, Yun-Hui Chu, Lian Chen, Xiao-Wei Pang, Lu-Yang Zhang, Li-Fang Zhu, Ming-Hao Dong, Ke Shang, Jun Xiao, Long-Jun Wu, Wei Wang, Dai-Shi Tian, Chuan Qin

Faculty, Staff and Student Publications

Neuroinflammation, encompassing both innate and adaptive immune responses, plays a crucial role in ischemic stroke. Although B lymphocytes are central to adaptive immunity, their contributions to ischemic stroke remain poorly understood. Here, we demonstrated that B lymphocytes accumulate in ischemic lesions, forming germinal center-like structures at the later stage after stroke, which mainly depended on in situ proliferation. This accumulation correlated with worsened neuroinflammation and ischemic injury, whereas B cell depletion reduced chronic brain damage during stroke. Mechanistically, microglia recruited B cells into ischemic lesions through MIF-CD74/CXCR4 signaling during the early phase of stroke, while IFN-related pathways in B cells …

Dna Methylation Is Associated With Von Willebrand Factor And Coagulation Factor Viii Plasma Levels: The Atherosclerosis Risk In Communities Study, Julie Hahn, Jan Bressler, Myriam Fornage, Eric Boerwinkle, Nicholas L Smith, Alanna C Morrison, Paul S De Vries

Faculty, Staff and Student Publications

Background: Limited information is available on how DNA methylation of cytosine-phosphate-guanine (CpG) sites across the genome regulate circulating von Willebrand Factor (VWF) and factor VIII (FVIII) levels.

Methods: We performed an epigenome-wide association study to examine the association of leukocyte DNA methylation levels at 483,735 CpG sites with VWF antigen plasma levels and FVIII activity in 2,597 Black and 1,011 White participants from the Atherosclerosis Risk in Communities (ARIC) study. VWF antigen levels and FVIII activity were measured at the baseline exam, while DNA methylation was measured with the Infinium HumanMethylation450 BeadChip array at visit 2 or 3. Discovery analysis …

Poly(Adp-Ribose) Glycohydrolase Enforces P21 Degradation Via Deparylation To Promote Gastric Cancer Progression, Yangchan Hu, Qimei Bao, Yixing Huang, Yan Wang, Xin Zhao, Junjun Nan, Yuxin Meng, Mingcong Deng, Yuancong Li, Zirui Zhuang, Hanyi He, Dan Zu, Yuke Zhong, Chunkai Zhang, Bing Wang, Ran Li, Yanhua He, Qihan Wang, Min Liu, John A Tainer, Yin Shi, Xiangdong Cheng, Ji Jing, Zu Ye

Faculty, Staff and Student Publications

Dysregulation of cell cycle checkpoints is a cancer hallmark, with ubiquitination-controlled protein stability playing a pivotal role. Although p21, a key cyclin-dependent kinase inhibitor, is tightly regulated by ubiquitin-mediated degradation, the key upstream modulators of its ubiquitination remain incompletely defined. Here, we identify poly(ADP-ribose) glycohydrolase (PARG) as a regulator of p21 stability in gastric cancer (GC) cells. We show that PARG expression is markedly upregulated in GC tissues and correlates with poor patient prognosis. Functional assays revealed that genetic depletion of PARG triggers G2/M phase arrest and impairs GC cell proliferation. Mechanistically, we demonstrate that PARG loss enhances p21 PARylation, …

Selective Deletion Of Fgfr1 In Agrp Neurons Impairs Energy Homeostasis Under High-Fat Diet In Mice, Daniel Shookster, Shea O'Connell, Patel Darshan, Taylor Landry, Wyatt Bunner, Zhiying Jiang, Qingchun Tong, Hu Huang

Faculty, Staff and Student Publications

Background: The global obesity crisis and the limited success of current treatments underscore the need to identify novel regulatory pathways. While central administration of α-Klotho exerts anti-obesity effects in rodents through AgRP neurons, the intracellular signaling mechanisms that mediate this process remain undefined.

Methods: To define the role of FGFR1 within the α-Klotho signaling pathway in AgRP neurons, we performed a targeted deletion of the receptor in adult mice using an AAV-mediated CRISPR/Cas9 system alongside transgenic models.

Results: Deletion of FGFR1 in AgRP neurons disrupted energy homeostasis, promoting weight gain induced by a high-fat diet. Electrophysiological recordings revealed that FGFR1 …

Cd44v9 As A Therapeutic Target For Antibody-Drug Conjugate In Advanced Breast Cancer, Dileep R Reddy, Mckenna E Flynn, Yasuaki Anami, Zhaoxuan Yang, Jayden Aleman, Minji Seo, Kyoji Tsuchikama, Jennifer A Maynard, Naoto T Ueno, Jangsoon Lee

Faculty, Staff and Student Publications

Antibody-drug conjugates (ADCs) have revolutionized breast cancer therapy. HER2 is the only validated biomarker guiding ADC therapy in breast cancer. However, their clinical benefit remains confined to HER2- and TROP2-targeted therapies. Tumor heterogeneity and acquired resistance often limit durable responses, underscoring the need for novel, tumor-specific ADC targets. CD44 variant isoform 9 (CD44v9), a splice variant of the CD44 family, is largely absent in normal tissues but enriched in aggressive breast cancers, where it contributes to stemness, redox regulation, and therapy resistance. In this study, we developed a chimeric monoclonal antibody against CD44v9 (clone SUM24.1, IgG1) and conjugated it to …

Intraoperative Ultrasound Imaging Features Guiding Surgical Strategy In Spinal Cord Ependymoma Resection, Esteban Ramirez-Ferrer, Ian E Mccutcheon, Gil Kimchi, Behrang Amini, Romulo Andrade Almeida, Francisco Call-Orellana, Juan Pablo Zuluaga-Garcia, Robert Y North, Christopher A Alvarez-Breckenridge, Jeffrey S Weinberg, Laurence D Rhines, Claudio E Tatsui

Faculty, Staff and Student Publications

Background and objectives: Preoperative imaging provides surgeons with an initial estimate of tumor infiltration and the likelihood of achieving an en-bloc resection in spinal cord ependymomas, yet the definitive decision is made intraoperatively. This study characterizes the intraoperative ultrasound (iUS) features that guide real-time surgical strategy and are associated with successful en-bloc removal.

Methods: A retrospective review of iUS images obtained during resection of spinal cord ependymomas was performed. The presence of a peritumoral halo representing the transition zone between the tumor and the spinal cord, the dorsal sagittal area of the spinal cord overlying the tumoral poles, the presence …

Alpha 7 Nicotinic Acetylcholine Receptor Contributes To Long-Term Cognitive Recovery Following Ischemic Stroke, Dustin T Nguyen, Kate Mendoza, Cassandra Hall, Chunfeng Tan, Anjali Chauhan

Faculty, Staff and Student Publications

Stroke is associated with autonomic dysfunction and reduced acetylcholine (ACh), a neurotransmitter critical for cognition. ACh signals in part through the alpha-7 nicotinic acetylcholine receptor (α7nAChR), a ligand-gated ion channel involved in synaptic plasticity, learning, and memory. Impaired α7nAChR signaling has been linked to heightened neuroinflammation and poor acute stroke recovery. Here, we investigated whether α7nAChR contributes to post-stroke cognitive recovery in young male mice. Wild-type (WT) and α7nAChR knockout (α7n0KO) mice underwent 60-min middle cerebral artery occlusion (MCAO). In a pharmacology cohort, the α7nAChR agonist GTS-21 was administered immediately after reperfusion and then daily for 20 days. Cognitive performance …

Barriers To Occupational And Physical Therapy Utilization For Children With Cancer, Maria C Swartz, Shiming Zhang, Donna Kelly, Clark R Andersen, Keri Schadler, Alakh P Rajan, Eduardo Gonzalez Villarreal, Stephanie J Wells, Amy Heaton, Karen Moody

Faculty, Staff and Student Publications

Introduction: Occupational and physical therapy (OT/PT) referrals and utilization barriers for childhood cancer patients have not been adequately examined. The current study investigated factors influencing referrals to and utilization of OT/PT services among children with cancer at an NIH-designated cancer center.

Methods: This retrospective cohort study included pediatric cancer patients (up to 18.99 years) presenting to the center over a 33.5-month period. Variables that could influence referrals to OT/PT were extracted from the electronic medical record (EMR) including OT and PT referrals (inpatient and outpatient), OT and PT consult completion, age at diagnosis, cancer type, sex, race/ethnicity, insurance, cancer treatment, …