Digital Commons Network^™

Hierarchical Small Molecule Inhibition Of Myst Acetyltransferases, Xuemin Chen, Alexandra Castroverde, Minervo Perez, Ronald Holewinski, Kiall F Suazo, Rashmi Karki, Thorkell Andresson, Benjamin A Garcia, Jordan L Meier

2020-Current year OA Pubs

MYST lysine acetyltransferases (KATs) are a class of epigenetic enzymes critical for cellular function that constitute an emerging therapeutic target in cancer. Recently, several drug-like MYST inhibitors have been reported that show promise in preclinical models as well as in clinical trials of breast cancer. Understanding the specificity of these molecules is critical for their effective use as chemical probes. Here we apply an integrated profiling strategy to systematically define the potency and selectivity of drug-like MYST KAT inhibitors. First, we use optimized chemoproteomic profiling and histone acetylation biormarkers to study the industry-developed KAT inhibitor PF-9363. This reveals dose-dependent engagement …

Social Prescribing For Refugee Populations: A Rapid Realist Review Of International Evidence, Victoria Touzel, Doreen Reifegerste, Luisa Bartz, Anna-Lena Esser, Kerryn Husk

Peninsula Medical School

BackgroundSocial prescribing offers potential for addressing social determinants of health and supporting health equity among disadvantaged groups. However, evidence for refugee populations remains limited, despite this group facing profound social and systemic barriers. This rapid realist review synthesizes social prescribing and comparable social-capital based intervention evidence to address this gap.MethodsWe conducted a RAMESES-compliant rapid realist review supported by an expert advisory board. Searches across six databases (2014–2024) were supplemented by grey literature and citation chasing strategies. Eligible studies included refugee, asylum-seekers and forcibly displaced populations engaged in either formal social prescribing or comparably operationalized social-capital interventions. Synthesis developed Context-Mechanism-Outcome configurations …

Cd8+ T Cell Differentiation Into Nk-Like Effector Cells Drives Transplant Rejection, Dawei Zou, Stephanie G Yi, Yulin Dai, Luan Truong, Lillian W Gaber, Richard J Knight, Xiang Xiao, Rafik M Ghobrial, Xian C Li, Zhongming Zhao, Wenhao Chen, A Osama Gaber

Faculty, Staff and Student Publications

T cells are central drivers of transplant rejection, yet the differentiation fates underlying this process remain unclear. Using single-cell transcriptomic profiling of human kidney allograft biopsies, we identified a predominant infiltrating CD8+ T cell subset exhibiting killer cell lectin-like receptor (KLR)+ NK-like features. Mechanistic studies in mice showed that the KLR+ subset emerged de novo post-transplantation and dominated the CD8+ T cell infiltrate in rejecting allografts. These NK-like CD8+ T cells expressed high levels of interferon regulatory factor 4 (IRF4), and Irf4 deletion disrupted their differentiation and induced transplant acceptance. Therapeutically, either costimulation blockade or mTOR inhibition substantially reduced the …

Purine Metabolic Adaptation Protects The Endothelium From Disturbed Flow-Induced Dna Damage And Atherosclerosis, Qian Ma, Yongfeng Cai, Zhidan Zhang, Dingwei Zhao, Yuan Zhao, Peishan Xu, Tammy Lu, Wendy Zhang, Qiuhua Yang, Yaqi Zhou, Varadarajan Sudhahar, Tohru Fukai, Hanjoong Jo, Yiming Xu, Yuqing Huo

Faculty, Staff and Students Publications

Despite effective lipid-lowering therapies, atherosclerosis continues to be a leading cause of death, with considerable residual cardiovascular risk. Atherosclerotic lesions develop preferentially at arterial regions exposed to disturbed flow (d-flow), which induces genomic stress, endothelial injury, and barrier dysfunction. Hemodynamic forces are known to reprogram endothelial metabolism, but the role of de novo purine synthesis (DNPS), which supplies nucleotides for genome maintenance and whose terminal steps are catalyzed by the bifunctional enzyme ATIC, remains undefined in atherosclerosis. By integrating bulk and single-cell multiomics with in vitro flow systems and in vivo models, we show that d-flow upregulates DNPS and ATIC …

Diacylglycerol Kinase Eta As A Novel Target In Nras Mutant Melanoma, Haley P. Wilson, Casey D. Stefanski, Signe Caksa, Glenn L. Mersky, Scott D. Varney, Jelan I. Haj, Dan A. Erkes, Timothy J. Purwin, Vivian Chua, Andrew E. Aplin

Department of Pharmacology, Physiology, and Cancer Biology Faculty Papers

NRAS mutations occur in 10%-30% of cutaneous melanomas and are associated with high tumor mutational burden. Mutant NRAS signaling drives aberrant cell growth and proliferation, in part, through activation of the RAF-MEK-ERK1/2 kinase pathway; however, targeted therapies to this pathway have limited effectiveness in patients with NRAS mutant melanoma. The role of other targetable signaling pathways in NRAS mutant melanoma is poorly characterized. Here, we demonstrated that one isoform of diacylglycerol kinase, diacylglycerol kinase eta (DGKη), a lipid signaling regulator, was highly expressed in NRAS mutant melanoma patient samples. Knockdown of DGKH in NRAS mutant melanoma cell lines resulted in …

Computational Modeling Meets 3d Bioprinting: Emerging Synergies In Cardiovascular Disease Modeling, Tanmay Mukherjee, Mehdi Salar Amoli, Sarah Rezapourdamanab, Lama Rita El Shammas, Martin L Tomov, Emilio A Mendiola, Vahid Serpooshan, Reza Avazmohammadi

Faculty, Staff and Student Publications

Cardiovascular diseases (CVDs) remain the leading cause of death worldwide, underscoring the need for improved strategies in diagnosis, treatment, and disease modeling. Traditional in vitro models often fall short in replicating human CV physiology, prompting efforts to advance cardiac tissue engineering and computational modeling. Among these, three-dimensional (3D) bioprinting has emerged as a transformative tool, enabling the creation of biomimetic CV constructs that more faithfully replicate native tissue structure and function. However, challenges persist in achieving appropriate mechanical properties and long-term performance of engineered CV constructs. Computational modeling offers powerful solutions to assist with these challenges, providing predictive insights into …

Regional Variation Of Underlying Kidney Diseases In Children Undergoing Chronic Kidney Replacement Therapy Around The Globe., Dagmara Borzych-Dużałka, Marjolein Bonthuis, Uma Ali, Yok-Chin Yap, Michael Manno, Yihui Zhai, Reyner Loza, Seema Hashmi, Naye Choi, Kenza Soulami, Judith Exantus, Mohamed S. Al Riyami, Sameh Mabrouk, Marbella Ma Angeles, Cristina Zelaya-Camacho, Henny Adriani Puspitasari, Syed Saimul Huque, Francisco Cano, Kar Hui Ng, Sevcan A. Bakkaloğlu, Jerome Harambat, Kitty J. Jager, Bradley A. Warady, Franz Schaefer

Manuscripts, Articles, Book Chapters and Other Papers

BACKGROUND: There is a scarcity of information regarding the distribution of the diseases leading to kidney failure (KF) in children living in the emerging world. We used registry data to provide a global overview of the underlying disease spectrum in children commencing kidney replacement therapy (KRT).

METHODS: We analyzed KF causes among 23,620 children and adolescents commencing maintenance KRT in 80 countries, using data from the IPNA Global KRT Registry (including ESPN/ERA Registry), the International Pediatric Dialysis Network (IPDN), the United States Renal Data System (USRDS), and the Australia and New Zealand Dialysis and Transplant Registry (ANZDATA). The analysis considered …

Risk Factors For The Development Of Food Allergy In Infants And Children: A Systematic Review And Meta-Analysis, Nazmul Islam, Alexandro W L Chu, Falana Sheriff, Farid Foroutan, Gordon H Guyatt, Romina Brignardello-Petersen, Paul Oykhman, Alfonso Iorio, Ariel Izcovich, Katherine M Morrison, Yetiani Roldan Benitez, Rachel J Couban, Dorota Borovsky, Yiming Zhang, Leonardo Ologundudu, Keerthana Pasumarthi, Syed Fahad Farooq, Kyle Tong, Wang-Choi Tang, Haseeb Faisal, Muhammad Faran Khalid, Mohammad Saad Asif, Shannon French, Susan Waserman, R Sharon Chinthrajah, Hugh A Sampson, S Shahzad Mustafa, Jay A Lieberman, Kirsi M Järvinen, Sally Bailey, Philippe Bégin, Scott H Sicherer, Jennifer Gerdts, Melanie Carver, Lynda Mitchell, Kelly Cleary, Matthew J Greenhawt, Julie Wang, Aikaterini Anagnostou, Marcus S Shaker, Anita Chandra-Puri, Patricia C Fulkerson, Robert A Wood, Derek K Chu

Faculty, Staff and Students Publications

Importance: The incidence and risk (predictive) factors for early life food allergy development remain uncertain.

Objective: To estimate the incidence and quantify risk factors for food allergy development.

Data sources: MEDLINE and Embase were systematically searched to January 1, 2025. Data were analyzed from June 1, 2025, to November 25, 2025.

Study selection: Incidence estimates included studies confirming food allergy via food challenge. Risk factor analyses included cohort, case-control, and cross-sectional studies in any language assessing children younger than 6 years using multivariable analyses.

Data extraction and synthesis: Paired reviewers independently extracted data. Random-effects meta-analyses pooled incidence and adjusted odds …

Adhesion G Protein-Coupled Receptors, Tobias Langenhan, Garret R Anderson, Demet Araç, Gabriela Aust, Monserrat Avila-Zozaya, Sofie Morsing Bagger, Patrick Barth, Sandra Berndt, Stephen C Blacklow, Beatriz Blanco-Redondo, Antony A Boucard, James P Bridges, Lara-Sophie Brodmerkel, Kathleen M Caron, Yin Kwan Chung, Andrew N Dates, Virginea De Araujo Farias, Daniel Del Toro, Joseph G Duman, Felix B Engel, David M Favara, Caroline J Formstone, Chaoyu Fu, Alain Garcia De Las Bayonas, Anastasia Georgiadi, David E Gloriam, Randy A Hall, Jörg Hamann, Peter W Hildebrand, Cheng-Chih Hsiao, Bill X Huang, Jonathan A Javitch, Hee-Yong Kim, Robert J Kittel, Gunnar Kleinau, Richard Leduc, Ines Liebscher, Hsi-Hsien Lin, Joshua Linnert, Marie-Gabrielle Ludwig, David C Martinelli, Signe Mathiasen, Daniel Matúš, Mariam Melkumyan, Ana L Moreno-Salinas, Jan Mulder, Michael A Nash, Kasturi Pal, Daniel T Pederick, Nicole A Perry-Hauser, Xianhua Piao, Yu-Qi Ping, Dimitris G Placantonakis, Fabian Pohl, Simone Prömel, Mette M Rosenkilde, Laurent Sabbagh, Richard C Sando, Patrick Scheerer, Torsten Schöneberg, Elena Seiradake, Mareike Selcho, Florian Seufert, Abhishek K Singh, Georgios Skiniotis, Katja Spiess, Norbert Sträter, David Strutt, Thomas C Südhof, Jinpeng Sun, Gregory G Tall, Doreen Thor, Douglas G Tilley, Kimberley F Tolias, Mario Vallon, Erwin G Van Meir, Benoit Vanhollebeke, Giselle R Wiggin, Uwe Wolfrum, Jie Yan, Nathan A Zaidman, Yimin Zou, Nicole Scholz

Faculty, Staff and Students Publications

Adhesion G protein-coupled receptors (aGPCRs) constitute a structurally and functionally distinct group within the superfamily of GPCRs. In 2015, the International Union of Pharmacology invited the Adhesion GPCR Consortium to publish a comprehensive review about aGPCRs and establish a unified nomenclature. Since then, substantial progress has been made in delineating the biological roles, molecular architecture, biochemical properties, expression profiles, ligand repertoire, and activation and signaling strategies of aGPCRs. Commensurate with these advances, their relevance to human pathophysiology has become increasingly apparent. In a coordinated effort, the Adhesion GPCR Consortium has reviewed recent progress in this field and provides a comprehensive …

Adhesion G Protein-Coupled Receptors, Tobias Langenhan, Garret R Anderson, Demet Araç, Gabriela Aust, Monserrat Avila-Zozaya, Sofie Morsing Bagger, Patrick Barth, Sandra Berndt, Stephen C Blacklow, Beatriz Blanco-Redondo, Antony A Boucard, James P Bridges, Lara-Sophie Brodmerkel, Kathleen M Caron, Yin Kwan Chung, Andrew N Dates, Virginea De Araujo Farias, Daniel Del Toro, Joseph G Duman, Felix B Engel, David M Favara, Caroline J Formstone, Chaoyu Fu, Alain Garcia De Las Bayonas, Anastasia Georgiadi, David E Gloriam, Randy A Hall, Jörg Hamann, Peter W Hildebrand, Cheng-Chih Hsiao, Bill X Huang, Jonathan A Javitch, Hee-Yong Kim, Robert J Kittel, Gunnar Kleinau, Richard Leduc, Ines Liebscher, Hsi-Hsien Lin, Joshua Linnert, Marie-Gabrielle Ludwig, David C Martinelli, Signe Mathiasen, Daniel Matúš, Mariam Melkumyan, Ana L Moreno-Salinas, Jan Mulder, Michael A Nash, Kasturi Pal, Daniel T Pederick, Nicole A Perry-Hauser, Xianhua Piao, Yu-Qi Ping, Dimitris G Placantonakis, Fabian Pohl, Simone Prömel, Mette M Rosenkilde, Laurent Sabbagh, Richard C Sando, Patrick Scheerer, Torsten Schöneberg, Elena Seiradake, Mareike Selcho, Florian Seufert, Abhishek K Singh, Georgios Skiniotis, Katja Spiess, Norbert Sträter, David Strutt, Thomas C Südhof, Jinpeng Sun, Gregory G Tall, Doreen Thor, Douglas G Tilley, Kimberley F Tolias, Mario Vallon, Erwin G Van Meir, Benoit Vanhollebeke, Giselle R Wiggin, Uwe Wolfrum, Jie Yan, Nathan A Zaidman, Yimin Zou, Nicole Scholz

Faculty, Staff and Students Publications

Adhesion G protein-coupled receptors (aGPCRs) constitute a structurally and functionally distinct group within the superfamily of GPCRs. In 2015, the International Union of Pharmacology invited the Adhesion GPCR Consortium to publish a comprehensive review about aGPCRs and establish a unified nomenclature. Since then, substantial progress has been made in delineating the biological roles, molecular architecture, biochemical properties, expression profiles, ligand repertoire, and activation and signaling strategies of aGPCRs. Commensurate with these advances, their relevance to human pathophysiology has become increasingly apparent. In a coordinated effort, the Adhesion GPCR Consortium has reviewed recent progress in this field and provides a comprehensive …

Mif-Cd74 Signaling Drives Immune Modulation In Medulloblastoma, Benjamin Draper, Zhen You, Dean Thompson, Xu Guo, Alaide Morcavallo, Diego Chillon Pino, Carlos Lorenzo Gido Nery, Sumana Shrestha, Chantelle E Bowers, Courtney Himsworth, Alberto Delaidelli, Bethany Remeniuk, Sonia Morlando, Brandon Wade, Freya Gordon, Yara Sanchez-Corrales, Bei Hopkins, Natalie Monteiro, Darren Locke, Miao Liu, Jacob Torrejon Diaz, Kevin Greenslade, Barbara Martins Da Costa, Karen Barker, Colin Kwok, Olumide Ogunbiyi, Anya Fletcher, Stacey Richardson, Carlos Custodia, Rafael Roque, Thomas Jackson, Regan Barfoot, Sergi Castellano, Rebecca M Hill, Olivier Saulnier, Thomas S Jacques, Michael D Taylor, Claudia C Faria, Olivier Ayrault, Poul H Sorensen, John Anderson, Louis Chesler, L Frank Huang, Steven C Clifford, Laura K Donovan

Faculty, Staff and Students Publications

Background: Relapsed medulloblastoma remains a significant therapeutic challenge as it is near universally fatal. The tumor microenvironment of medulloblastoma plays a critical role in tumor progression, influencing tumor growth, immune evasion, and therapeutic resistance. We hypothesized that defining tumor-immune interactions in diagnostic and relapsed medulloblastoma may uncover mechanisms of immune evasion and identify novel therapeutic targets.

Methods: We analyzed paired primary and recurrent RNA-sequencing data from 140 medulloblastoma patients to profile immune cell composition and validate spatial relationships within the TME. To identify key tumor-immune interactions, we developed a novel algorithm to detect receptor-ligand pairs using single-cell RNA-sequencing data. These …

Fructose: Metabolic Signal And Modern Hazard, Richard J Johnson, Miguel A Lanaspa, Dean R Tolan, Marcus D Goncalves, Samir Softic, Kimber L Stanhope, Laura G Sánchez-Lozada, Mark A Herman, Joshua D Rabinowitz

Faculty, Staff and Students Publications

There is much interest in the role of sweeteners such as table sugar (sucrose) and high-fructose corn syrup in obesity and metabolic disease. Both sweeteners consist of glucose and fructose, two six-carbon isomeric sugars. Whereas glucose ingestion may promote obesity through its effects to stimulate insulin secretion, fructose has unique metabolic effects that promote triglyceride synthesis and fat accumulation. These effects arise from fructose's well-known role as a signal of metabolic plenty. Under modern conditions of overnutrition, chronic excess fructose drives features of metabolic syndrome. Emerging evidence further links fructose to cancer and dementia. Here we review the biochemical, molecular …

Noncanonical Clock Regulators Control Stress Responses In Digestive Diseases, Dishu Zhou, Roberto E López-Valiente, Samer G Mattar, Dongyin Guan

Faculty, Staff and Students Publications

The digestive system is essential for nutrient absorption, processing, and waste elimination. The expression of many genes and physiological processes within this system exhibits a 24-h rhythmicity. However, modern lifestyle factors, such as jet lag, shift work, and irregular eating patterns, significantly disrupt these rhythms, triggering various stress responses and contributing to numerous digestive disorders. Here, we focus on emerging studies on noncanonical clock regulators involved in stress responses, integrate these novel findings into the established model of the core circadian clock, and highlight recent advances in the development of novel therapeutics targeting these 24-h regulators. In addition, we discuss …

High-Penetrance Rare Variants Underlying Familial Lung Cancer Risk: Insights From Genetic Epidemiology Of Lung Cancer Consortium, Yanhong Liu, Yafang Li, Jinyoung Byun, Vikram R Shaw, Claudio Pikielny, Bo Peng, Chao Cheng, Spiridon Tsavachidis, Xiangjun Xiao, Dakai Zhu, Younghun Han, Ivan P Gorlov, Olga Y Gorlova, Michael Cole, Colette R Gaba, Erin L Crawford, Kristen Purrington, Ellen L Goode, Ping Yang, James Mckay, John K Field, Geoffrey Liu, Rayjean J Hung, Jun Xia, Jiyeon Choi, Matthew B Schabath, Jaclyn Lopiccolo, David C Christiani, Joan Bailey-Wilson, Ann G Schwartz, James C Willey, Diptasri Mandal, Susan M Pinney, Christopher I Amos

Faculty, Staff and Students Publications

Introduction: Rare, deleterious germline variants are key contributors to inherited lung cancer (LC) risk. The Genetic Epidemiology of LC Consortium (GELCC) has curated valuable high-risk LC families and is uniquely positioned to uncover rare, high-penetrance variants underlying familial LC (FLC).

Methods: We performed whole-genome and exome sequencing on germline DNA from 120 high-risk LC families (177 FLC cases, 309 unaffected relatives). We prioritized rare (allele frequency < 1% in the genome aggregation database), potentially deleterious variants present in two or more FLC cases. These variants were then validated in 10,085 sporadic LC (SLC) cases and 612,970 controls.

Results: We identified 118 candidate variants, 28 of which were validated in SLC with strong statistical support. We discovered a novel pathogenic axis of three truncating variants in GALNT6, MUC4, and ERBB3 genes, which …

A Covalent Allosteric Molecular Glue Suppresses Nrf2-Dependent Cancer Growth, Nilotpal Roy, Ilah Bok, Harit Panda, Dhaval P Bhatt, Emily M Wilkerson, Soma Saeidi, Paul Zolkind, Michael B Major, Et Al.

2020-Current year OA Pubs

UNLABELLED: The NRF2 transcription factor is constitutively active in cancer, in which it functions to maintain oxidative homeostasis and reprogram cellular metabolism. NRF2-active tumors exhibit NRF2 dependency and resistance to chemotherapy/radiotherapy (RT). In this study, we characterize VVD-065, a first-in-class NRF2 inhibitor that acts via an unprecedented allosteric molecular glue mechanism. In the absence of stress or mutation, NRF2 is rapidly degraded by the Kelch-like ECH-associated protein 1 (KEAP1)-cullin3 (CUL3) ubiquitin-ligase complex. VVD-065 specifically and covalently engages Cys151 on KEAP1, which in turn promotes KEAP1-CUL3 complex formation, leading to enhancement of NRF2 degradation. Previously reported Cys151-directed compounds decrease KEAP1-CUL3 interactions …

Promises, Pitfalls, And Paths Forward For The Pediatric Research Equity Act., Alexa L. Pagano, Danielle J. Green, Jennifer Goldman, Anjali Deshmukh

Manuscripts, Articles, Book Chapters and Other Papers

IMPORTANCE: Since its enactment in 2003, the Pediatric Research Equity Act (PREA) has significantly increased the number of pediatric drug studies performed and expanded pediatric drug labeling. Despite these advancements, many drugs used in children still lack pediatric-specific US Food and Drug Administration (FDA) labeling, even when pediatric studies are required by law. Recent legislative changes strengthened the FDA's enforcement authority over PREA. As these changes are implemented, persistent gaps in pediatric drug development warrant examination. Addressing these gaps may help ensure that children are systematically included in clinical research and that medications used in children are supported by rigorous …

Qualitative Beta-2-Adrenoceptor Signaling In The Regulation Of Human Airway Epithelia Mucin And Cytokine Production, Fred Graumuller, Diana Cervantes, Tung O. Chan, Niccolette Schaunaman, Dominic R. Villalba, Burton F. Dickey, Julia K. L. Walker, Hong Wei Chu, Raymond B. Penn

Division of Pulmonary, Allergy, and Critical Care Medicine Faculty Papers

BACKGROUND: Numerous in vivo studies have demonstrated beta-2-adrenoceptor (β2AR) -agonism as permissive in the development of allergic lung inflammation, and have implicated the arrestin-dependent signaling arm of the β2AR in mediating this effect. However, the specific cell type(s) mediating β2AR regulation of allergic lung inflammation remain unestablished.

METHODS: To explore the potential contribution of airway epithelia in this phenomenon, we compared the ability of ractopamine (RP), recently identified as a Gs-biased beta-agonist, to that of the unbiased/balanced beta-agonist albuterol (ALB), on IL-13-stimulated mucin and cytokine production in human airway epithelia cultures in air-liquid interface (HAE).

RESULTS: ALB, which activates both …

Risk Of Alzheimer Dementia After High-Dose Vs Standard-Dose Influenza Vaccination, Avram Samuel Bukhbinder, Yaobin Ling, Lauren Jhin, Elizabeth He, Kristofer Harris, Mya Rodriguez, Jenna Thomas, Gabriela Cruz, Kamal Phelps, Yejin Kim, Luyao Chen, Xiaoqian Jiang, Paul E Schulz

Faculty, Staff and Student Publications

Background and objectives: Previous studies, including large cohort analyses comparing vaccinated and unvaccinated adults, suggest that routine immunizations such as inactivated influenza vaccines (IIVs) may reduce Alzheimer dementia (AD) risk. Whether AD risk differs after high-dose IIV (H-IIV) vs standard-dose IIV (S-IIV) remains unexamined. We hypothesized that AD risk would be lower among adults ≥65 years after H-IIV compared with S-IIV.

Methods: This retrospective cohort study analyzed data spanning 2014-2019 from IQVIA PharMetrics Plus for Academics, a US health care claims database. Eligible participants were ≥65 years with ≥2 years of continuous medical and pharmaceutical coverage and no previous diagnostic …

High-Precision Automated Bone Age: A Clinically Useful Tool In Monitoring Of Treatment Effects In Children And Adolescents, Hans Henrik Thodberg, Lise Aksglaede, Anders Juul, Shanlee M. Davis, Judith L. Ross

Department of Pediatrics Faculty Papers

The clinical value of serial bone age (BA) determinations in children during growth is limited by the manual rater variability (precision 0.63 years). The objective of this work was to determine the precision of automated bone age and bone health index (BHI) measurements by BoneXpert and to establish the time interval at which the automated method can detect a significant treatment effect. The data were from a case-control trial (oxandrolone/placebo) following 90 boys with Klinefelter syndrome (KS) with five visits over 2 years, recording X-rays of both hands. The precision of BA was 0.08 years [0.07; 0.09] 95% CI, leading …

Inflammation- And Resolution-Programmed Myeloid Circuits Govern Therapeutic Resistance In Epithelial And Mesenchymal Triple-Negative Breast Cancer, Liqun Yu, Charlotte Rivas, Fengshuo Liu, Yichao Shen, Ling Wu, Zhan Xu, Yunfeng Ding, Xiaoxin Hao, Weijie Zhang, Hilda L Chan, Jun Liu, Bo Wei, Yang Gao, Luis Becerra-Dominguez, Yi-Hsuan Wu, Siyue Wang, Tobie D Lee, Xuan Li, Xiang Chen, David G Edwards, Xiang H-F Zhang

Faculty, Staff and Students Publications

Single-cell analysis of human triple-negative breast cancer revealed heterogeneous macrophage populations with opposing phenotypes - proinflammatory and proresolution of inflammation. Paradoxically, both subsets accumulated in therapy-refractory residual tumors but showed inverse correlations across patients, suggesting mutually exclusive resistance mechanisms. Inflammatory macrophages localized preferentially to epithelial-like tumors, whereas proresolution macrophages were enriched in mesenchymal-like tumors. Mouse models faithfully recapitulated these patterns. After chemoimmunotherapy, mesenchymal-like tumors expanded proresolution macrophages through phagocytosis/efferocytosis, ω-3 fatty acid uptake, and resolvin production. Macrophage-secreted C1q emerged as a principal antagonist of T cell function by targeting mitochondria and inducing metabolic dysfunction. By contrast, epithelial-like tumors accumulated inflammatory …

Dapk2 Regulates Pkm2 Phosphorylation At Threonine 45 To Facilitate Disturbed Flow-Induced Atherosclerosis, Shuai Guo, Long Xu, Yixin Chen, Yuan Zhao, Yuting Zhang, Runfa Yu, Kaixiang Cao, Litao Wang, Wenjia Ai, Jiang-Yun Luo, Lu Lu, Jun He, Yuan Zhou, Li Wang, Andrew H Baker, Yuqing Huo, Yiming Xu

Faculty, Staff and Students Publications

Background: Oscillatory shear stress (OSS), resulting from disturbed blood flow, is implicated in atherosclerotic plaque formation by incompletely understood mechanisms. This study aims to elucidate the involvement of death-associated protein kinase (DAPK) 2 in OSS-induced endothelial cell (EC) activation and atherosclerosis.

Methods: Publicly available resources, including genome-wide microarray, RNA sequencing, and single-cell RNA sequencing, were utilized to identify key OSS-sensitive regulatory factors. Techniques such as mass spectrometry, immunoprecipitation, proximity ligation assay, and RNA sequencing were employed to identify pyruvate kinase M2 (PKM2) as the binding protein of DAPK2 and determine the specific site of PKM2 phosphorylation by DAPK2. To assess …

Loss Of Znrf3/Rnf43 Unleashes Egrfr In Cancer, Fei Yue, Amy T Ku, Payton D Stevens, Megan N Michalski, Weiyu Jiang, Jianghua Tu, Zhongcheng Shi, Yongchao Dou, Yi Wang, Xin-Hua Feng, Galen Hostetter, Xiangwei Wu, Shixia Huang, Noah F Shroyer, Bing Zhang, Bart O Williams, Qingyun Liu, Xia Lin, Yi Li

Faculty, Staff and Students Publications

ZNRF3 and RNF43 are closely related transmembrane E3 ubiquitin ligases with significant roles in development and cancer. Conventionally, their biological functions have been associated with regulating WNT signaling receptor ubiquitination and degradation. However, our proteogenomic studies have revealed EGFR as the protein most negatively correlated with ZNRF3/RNF43 mRNA levels in multiple human cancers. Through biochemical investigations, we demonstrate that ZNRF3/RNF43 interact with EGFR via their extracellular domains, leading to EGFR ubiquitination and subsequent degradation facilitated by the E3 ligase RING domain. Overexpression of ZNRF3 reduces EGFR levels and suppresses cancer cell growth in vitro and in vivo, whereas knockout of …

Single-Cell Tcr Mapping Reveals Spatially Coordinated T Cell States In Head And Neck Cancer, Kelli A Mccord, Emerald Kan, Sean Hyslop, Amanda Y Xia, Colby J Hofferek, James S Lewis, Andreas Wieland, David J Hernandez, Vlad C Sandulache, William H Hudson

Faculty, Staff and Students Publications

Current spatial T cell receptor (TCR) profiling approaches lack the resolution needed to link clonal identity, transcriptional state, and spatial positioning of individual T cells in the tumor microenvironment. Here, we introduce a spatial TCR profiling strategy that resolves individual T cell clones together with their transcriptional states at single-cell resolution and applied the method to human head and neck squamous cell carcinoma. Presumed tumor-specific T cells were broadly dispersed throughout the tumor microenvironment, and cells of the same clone occupied distinct transcriptional states in different locations: Immune-rich regions contained more plastic or progenitor cells, whereas tumor-dense regions were enriched …

Constitutive Ampk Activation Prevents Hepatocellular Carcinoma Development Through Inhibition Of Hnf4Α Activity, Zhen Sun, Bernard Linares, Cassidy Urdiales, Fiyad Alsarmi, Boyuan Sang, Nagireddy Putluri, Jeanine L Van Nostrand

Faculty, Staff and Students Publications

Hepatocellular carcinoma (HCC) is a major cause of cancer-related mortality and is largely driven by metabolic disorders such as obesity and type 2 diabetes. The AMP-activated protein kinase (AMPK) is a master regulator of metabolism, and its activation has been proposed as a therapeutic strategy for treating metabolic disorders. However, although AMPK activity is down-regulated in HCC, the precise role of AMPK in HCC development has not been clearly delineated. Here, we investigated the ability of constitutive AMPK activation to prevent HCC development using a constitutively active AMPK transgenic mouse model and a pharmacological AMPK activator. We observed that AMPK …

A Multidomain Peptide Hydrogel-Liposome Composite For Controlled Release Of A Cyclic Dinucleotide In Oral Cancer, Joseph W R Swain, Andrea H Molina, Gemalene M Sunga, Danielle Chew-Martinez, Neeraja Dharmaraj, Alejandra Cobos Perez, Arghadip Dey, Ephraim J Vázquez-Rosado, Simon Young, Jeffrey D Hartgerink

Faculty, Staff and Student Publications

While immunotherapy is a promising treatment strategy for cancer, the majority of head and neck squamous cell carcinoma (HNSCC) patients treated with single-agent immunotherapy do not respond. Therefore, researchers are investigating combination treatments with immunostimulatory molecules that can maximize anti-tumor responses. Cyclic dinucleotides (CDNs) are STING agonists that hold promise in combination approaches, but they require frequent intratumoral administration when used in both preclinical models of HNSCC and clinical trials. To reduce administration frequency, we have created a peptide hydrogel–liposome composite system, K2-Lip(CDN), for local and prolonged availability of CDN. We investigated the loading limits of cationic liposomes in both …

A Prolonged Nightly Fasting Plus Telehealth Coaching Intervention (Pnf+) For Men On Androgen Deprivation Therapy For Pca: A Pilot Feasibility Randomized Controlled Trial, Kuang-Yi Wen, Julianne Freedman, Kevin K. Zarrabi, Rachel Slamon, Rita Smith, Jessica Liang, Patrick Mille, William J. Tester, William Kevin Kelly

Department of Medical Oncology Faculty Papers

Background/Objectives: This study aimed to assess the feasibility and acceptability of a 3-month health coaching intervention to promote PNF and healthy diet for men on ADT for PCa.

Methods: The study was carried out via a two-armed randomized controlled trial including 40 patients with PCa at a medical center in Philadelphia. During the 3-month period, the intervention group (PNF+) received health coaching utilizing an interactive text message system, and the control group received healthy eating text messages for the same duration. The outcome variables were feasibility and acceptability.

Results: The PNF+ group (n = 27) had high …

Distinct Effects Of Complement C4a And C4b Copy Numbers In Systemic Sclerosis Serological And Clinical Subtypes, Javier Martínez-López, Carlos Rangel-Peláez, Inmaculada Rodriguez-Martin, Alfredo Guillen-Del-Castillo, Carmen P Simeón-Aznar, José L Callejas, Oliver Distler, Susanna M Proudman, Mandana Nikpour, Nicolas Hunzelmann, Gianluca Moroncini, Jeska K De Vries-Bouwstra, Ariane L Herrick, Yannick Allanore, Marta E Alarcon-Riquelme, Lorenzo Beretta, Shervin Assassi, Christopher P Denton, Maureen D Mayes, Javier Martin, Marialbert Acosta-Herrera, Martin Kerick

Faculty, Staff and Student Publications

Objective: Complement component 4 (C4), encoded by C4A and C4B within the major histocompatibility complex (MHC) on chromosome 6, regulates the immune response and clears immune complexes. The variable copy number (CN) of C4 genes and retroviral human endogenous retrovirus K (HERV-K) element influence its function. Given the relationship of C4 CN with systemic sclerosis (SSc) risk, we assessed associations with SSc clinical and serologic subtypes.

Methods: We compared imputed C4 CNs across SSc subgroups (4,049 anticentromere positive [ACA+]; 2,200 anti-topoisomerase I [ATA+]; 577 anti-RNA polymerase [ARA+]; 1,078 triple-negative [TN] patients; 6,295 limited cutaneous SSc [lcSSc]; and 2,946 diffuse cutaneous …

Novel Variants Identified In Families With Snx27 -Related Neurodevelopmental Disorder, Aiding In Characterizing Its Genotypic And Phenotypic Spectrum, Tayyaba Shan, Abrar Hussain, Anushree Acharya, Mulazim Hussain, Yumei Li, Hafiz Muhammad Jafar Hussain, Kiran Afshan, Suzanne M Leal, Rui Chen, Asif Mir, Isabelle Schrauwen, Sabika Firasat

Faculty, Staff and Students Publications

Background:

Sorting Nexin 27 (SNX27), a key regulator of synaptic receptor trafficking and endosomal recycling, has been implicated in maintaining synaptic homeostasis and cognitive function. To date, variants in SNX27 have been reported in a small number of patients across three publications with severe neurodevelopmental phenotypes. However, the genetic and functional landscape of SNX27-related disorders remains poorly understood, and further evidence is needed to confirm its association with disease and to better delineate the associated phenotype.

Methods and Results:

Two unrelated Pakistani families with a total of five affected individuals segregating a neurodevelopmental disorder were investigated via exome …

Efficient In Vivo Pharmacological Inhibition Of Δfosb, An Ap-1 Transcription Factor, In The Brain, Sean Mcneme, Anil Kumar, Yun Young Yim, Brandon W Hughes, Corey St Romain, Yi Li, Ashwani Kumar, Qichao Bao, Molly Estill, Shanghua Fan, Nadeen Takatka, Earnest P Chen, Matthew Rivera, Haiying Chen, Alfred J Robison, Mischa Machius, Stephen J Haggarty, Jeannie Chin, Eric J Nestler, Jia Zhou, Gabby Rudenko

Faculty, Staff and Students Publications

ΔFOSB, an unusually stable member of the AP-1 family of transcription factors, mediates long-term maladaptations that play a key role in the pathogenesis of drug addiction, cognitive decline, dyskinesia, and several other chronic neurological and psychiatric conditions. We have recently identified that 2-phenoxybenzenesulfonic acid-containing compounds disrupt the binding of ΔFOSB to DNA in vitro in cell-based assays, and one such compound, JPC0661, disrupts ΔFOSB binding to genomic DNA in vivo in the mouse brain with partial efficiency. JPC0661 binds to a groove outside of the DNA-binding cleft of the ΔFOSB/JUND bZIP heterodimer in a cocrystal structure. Here, we generated a …

Comprehensive Profiling Of The Human Tear Fluid Mirnome Using Small Rna Sequencing, Garrett Jones, Drew Mayernik, Saleh Ahmed, Eliza Williams, Jeremy Altman, Tae Jin Lee, Amy Estes, Cintia S De Paiva, Pamela Martin, Shruti Sharma, Ashok Sharma

Faculty, Staff and Students Publications

Purpose: To generate a comprehensive profile of microRNAs (miRNAs) present in human tear fluid using next-generation sequencing (NGS), establish a reference miRNome for healthy human tear fluid, and investigate whether miRNA expression varies by sex, race, or age.

Methods: Tear samples were collected from 32 adults using Schirmer strips. RNA was isolated using the miRNeasy Serum/Plasma Kit, and cDNA libraries were prepared using the QIAseq miRNA Library Kit. Barcoded libraries were sequenced on the NovaSeq 6000 platform. Bioinformatic analyses included adapter trimming, alignment to miRBase, normalization with DESeq2, and functional annotation using multiMiR and clusterProfiler. Differential expression analysis was performed …