Digital Commons Network^™

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 …

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 …

Condensate State As Determinant Of Amyloid Pathology In Neurodegeneration, Lathan Lucas, Josephine C Ferreon, Allan Chris M Ferreon

Faculty, Staff and Students Publications

Neurodegenerative diseases arise when normally functional aggregation-prone proteins transition into stable cross-β amyloid fibrils. Although these fibrils share a conserved architecture, the pathways that lead to fibrillation vary across proteins and cellular environments. Liquid-liquid phase separation is now recognized as a central organizer of intracellular biochemistry that modulates protein aggregation. Physiological condensation can buffer aggregation by maintaining macromolecular solubility and providing partner interactions that compete against pathological protein-protein interactions. However, condensates can transform and age into gel-like states that can favor the emergence of β-rich oligomers and solid-state fibrils. Across six disease-linked proteins that include Tau, α-synuclein, amyloid-β, TDP-43, FUS, …

Reirradiation Treatment Effects In The Clinic (Retec) Proposal - Proof Of Concept Based On Spinal Cord Dose Tolerance For Reirradiation With Stereotactic Body Radiotherapy, Jimm Grimm, Anand Mahadevan, Olusola Obayomi-Davies, Scott G. Soltys, Arjun Sahgal, Kristin J. Redmond, Michael T. Milano, Wolfgang A. Tomé, Kenneth Brooks, Scott Dodd, John Austin Vargo, Gopal Subedi, Jinyu Xue, Bisher Ebid, Felix Ehret, Byung-Han Andrew Rhieu, Christoph Fürweger, Rachel Grimm, Alexander Muacevic, Vitali Moiseenko, Shalom Kalnicki, Mark Mclaughlin, Lawrence R. Kleinberg, John R. Adler, Iris C. Gibbs

College of Health Professions Faculty Papers

BACKGROUND: Since the inception of spinal radiosurgery decades ago, the factors influencing spinal cord recovery have remained unclear. Elucidating these factors would aid in reirradiation planning and delivery. We describe modeling reirradiation normal tissue complication probabilities (NTCP) from compiled published data, akin to the collaborative Quantitative Analysis of Normal Tissue Effects in the Clinic (QUANTEC) and High Dose per Fraction, Hypofractionated Treatment Effects in the Clinic (HyTEC) projects.

PURPOSE: Simple dose-time recovery factors for the spinal cord serve as a basis to propose the Reirradiation Treatment Effects in the Clinic (ReTEC) project. ReTEC aims to define human organ recovery factors …

Utility Of Right Ventricular Mass Ratios In Recipients With Pulmonary Hypertension: A United Network For Organ-Sharing Database Analysis, Matthew P. Weber, Danial Ahmad, Howard J. Eisen, Eugene Storozynsky, René J. Alvarez, J. Eduardo Rame, Keshava Rajagopal, John W. Entwistle, Charles Hoopes, Vakhtang Tchantchaleishvili

Division of Cardiology Faculty Papers

PURPOSE: There is a lack of data reviewing the role of predicted cardiac mass ratio (PCMR) in transplant recipients with pulmonary hypertension (PH). In particular, the right ventricular (RV) mass ratio (RVMR) is a component of PCMR not yet studied separately for this purpose. We aimed to review the relationship of PCMR and RVMR with PH in terms of post-transplant overall survival.

METHODS: The United Network for Organ-Sharing (UNOS) database was queried for primary heart transplant (HTx) patients from 2004 to 2023. Predicted RVMR was calculated for donors and recipients. A parsimonious multivariable model Cox model was formed for risk …

Epigenome-Wide Association Study Of Blood Proteome In The Atherosclerosis Risk In Communities Study, Yang Li, Aditya Surapaneni, Zulema Rodriguez-Hernandez, Pascal Schlosser, Eugene P Rhee, Eric Boerwinkle, Bing Yu, Megan L Grove, Kelly V Ruggles, Josef Coresh, Morgan Grams

Faculty, Staff and Student Publications

Characterizing the relationship between DNA methylation and circulating proteins is critical to understanding the epigenetic regulation of the human plasma proteome. Here, we performed an epigenome-wide association study of 5,032 circulating proteins in 1,449 White and 315 Black participants from the Atherosclerosis Risk in Communities cohort. We identified 12,500 significant protein quantitative trait methylation (pQTM)-protein associations involving 1,647 proteins. Among 7,796 unique pQTMs, 14.7% were classified as cis-pQTMs, which were enriched for fundamental cellular processes, whereas trans-pQTMs were predominantly linked to immune-related functions. Trans-pQTMs also exhibited stronger associations with demographic, lifestyle, and clinical traits as compared with cis-pQTMs. We identified …

An Innovative Curriculum To Empower Trainees And Faculty To Address Patient-Initiated Identity-Based Misconduct In The Clinical Learning Environment, Nkanyezi Ferguson, Lauren E. Hock, Patrick Barlow, Aisha S. Jamison, Marcy E. Rosenbaum, Nicole Del Castillo

Department of Medicine Faculty Papers

Introduction: Training residents and attending physicians on effective communication strategies to manage biased patient and visitor comments is lacking. The I-RESPOND toolkit curriculum provides strategies for addressing identity-based misconduct in the clinical setting. Methods: Resident physicians and faculty in 12 departments at a single academic center participated in the workshop between June 2021 and February 2022. The workshop consisted of interactive didactics, an introduction to the I-RESPOND toolkit, and opportunities to practice communication strategies with formative feedback. Retrospective pre/postworkshop survey instruments and a follow-up survey were used to evaluate the workshop and subsequent experiences. Results: Sixty-six (32%) of 204 participants …

Contributing Factors Of Contralateral Breast Cancer In Patients With Brca Mutation (On-Brca Ii Study, Korea-Bsg 11), Seon-Hi Shin, Sung Gwe Ahn, Jai Min Ryu, Sae Byul Lee, Hyung Seok Park, Eun-Shin Lee, Janghee Lee, Byeongju Kang, Sanghwa Kim, Eun Young Kim, Young-Joon Kang, Sun Young Min, Moohyun Lee, Se-Kang Kim, Hong-Kyu Kim, Chihwan David Cha

Faculty, Staff and Students Publications

Background: The cumulative risk of contralateral breast cancer (CBC) in BRCA1/2 carriers is remarkably higher than in non-carriers. This study aimed to investigate the clinicopathological predictors associated with the risk of metachronous CBC among breast cancer patients with BRCA1/2 mutations using correspondence analysis.

Methods: This retrospective study included patients who underwent BRCA testing between January 2008 and December 2018. The inclusion criterion was patients being between 20 and 80-years-old with invasive breast cancer (pT1-3, N0-3). We performed univariate and multivariate survival analyses to assess the risks associated with BRCA mutations, and conducted correspondence analysis to identify contributing factors for CBC …

Co-Occurrence Of Transcriptionally Distinct Persister Cell States Underpins Neoadjuvant Therapy Resistance In Triple-Negative Breast Cancer, Yu Zhang, Fatemeh Ahmadi Moughari, Ioanna Mavrommati, Nora J Doleschall, Kate Moore, Gareth Muirhead, Ram Rajaram Srinivasan, Ping Gong, Jonathan T Lei, Amy Fleming, Hwei Minn Khoo, Naomi Guppy, Gabrielle Elshtein, Mohammed Inayatullah, Vijay K Tiwari, Lacey E Dobrolecki, Michael T Lewis, Syed Haider, Rachael Natrajan

Faculty, Staff and Students Publications

Background

Although the addition of neoadjuvant immune checkpoint blockade to chemotherapy has improved patient outcome in early triple‑negative breast cancer (TNBC), some patients continue to have poor disease outcomes.

Methods

To characterise neoadjuvant chemotherapy (NAC) resistant cell populations that persist post-NAC, we created a high-resolution single-cell atlas of 129,433 cells from fourteen TNBC patient-derived xenograft (PDX) models with residual disease post-NAC. We identified transcriptionally distinct cancer subpopulations or cell states using unsupervised clustering and characterised‑ their regulatory network as well as clinical associations with treatment response, metastatic progression and survival. Findings were validated using multiple independent TNBC cohorts.

Results

Four …

Evapecognition: An 18-Year Dataset Of Great Ape Cognition, Alejandro Sánchez-Amaro, Sonja J Ebel Van Wijk, Carin Molenaar, Akzira Abuova, Lizbeth Mujica-Manrique, Sarah M Leisterer-Peoples, Bret Beheim, Luke Maurits, Anna Albiach-Serrano, Matthias Allritz, Nazli Altınok, Federica Amici, Alice Mi Auersperg, Filippo Aureli, Elisa Bandini, Jochen Barth, Leïla Benziad, Bettina E Bläsing, Manuel Bohn, Marie Bourjade, Juliane Bräuer, Marie-Hélène Broihanne, Sarah F Brosnan, Nereida Bueno-Guerra, Thomas Bugnyar, David Buttelmann, Frances Buttelmann, Trix Cacchione, Malinda Carpenter, Fernando Colmenares, Catherine Crockford, Katherine A Cronin, África De Las Heras, Arianna De Marco, Sarah E Detroy, Valérie Dufour, Shona Duguid, Robin I M Dunbar, Johanna Eckert, Jan M Engelmann, Joel Fagot, Julia Fischer, Sofia Ingrid Fredrika Forss, Martina Funk, György Gergely, Julia R Greenberg, Johannes Großmann, Sebastian Grüneisen, Marta Halina, Daniel Hanus, Sarah R Heilbronner, Christophe Heintz, Robert Hepach, Esther Herrmann, Satoshi Hirata, Alenka Hribar, Gabriele Janzen, Juliane Kaminski, Patricia Kanngiesser, Fumihiro Kano, Katharina C Kirchhofer, Hagen Knofe, Kathrin S Kopp, Christopher Krupenye, Isabelle Barbara Laumer, Stephen C Levinson, Ulf Liszkowski, Héctor M Manrique, Gema Martin-Ordas, Emma Suvi Mcewen, Richard T Moore, Enric Munar, Marcos Nadal, Christian Nawroth, Suska Nolte, Marie Pelé, Patrizia Potì, Hannes Rakoczy, Julia Riedel, Amélie Romain, Federico Rossano, Yvan I Russell, Gloria Sabbatini, Marie Schäfer, Marina Scheumann, Martin Schmelz, Benjamin Schmid, Vanesa Schmitt, Carla Sebastián-Enesco, Amanda Madeleine Seed, Chikako Suda-King, Tibor Tauzin, Sebastian Tempelmann, Claudio Tennie, Valentina Truppa, Jana Uher, Amrisha Vaish, Edwin J C Van Leeuwen, Elisabetta M Visalberghi, Christoph J Völter, Victoria Vonau, Claudia A F Wascher, Roman M Wittig, Wouter Wolf, Michael Tomasello, Katja Liebal, Josep Call, Daniel B M Haun

Faculty, Staff and Students Publications

The study of great ape cognition offers insights into the evolutionary origins of human intelligence, but is hindered by small sample sizes and restricted access to data. To address this, we present the EVApeCognition Dataset, a publicly available resource comprising 262 experimental datasets from 150 scientific publications from the Wolfgang Köhler Primate Research Center (2004-2021) in Leipzig, Germany. Eighty-one apes participated in 150 studies, with a majority (N = 78) participating in more than one study. Publication of the dataset aims to make these unique datasets accessible for future meta-analyses and correlational analyses, helping us better understand how our great …

Bi-Allelic Variants In Ap5z1 And Ap5b1 Lead To Retinal Degeneration, Hafiz Muhammad Jafar Hussain, Meng Wang, Paul Yang, Behnoosh Tasharrofi, Yumei Li, Rebecca Lynn Clark, Emma Fale-Olsen, Grace Waldow, Mohammad Keramatipour, Mostafa Asadollahi, Mark E Pennesi, Rui Chen

Faculty, Staff and Students Publications

Inherited retinal diseases (IRDs) comprise a diverse group of disorders that frequently lead to progressive vision impairment and blindness. Despite advances in genetic testing, a significant number of IRD cases remain genetically unsolved, often due to unidentified disease-associated genes or variants. This study reports additional cases for the newly discovered IRD genes of the AP-5 complex. A comprehensive ophthalmological evaluation was performed for all patients, including retinal imaging (multimodal imaging), visual field testing, and electroretinogram (ERG) testing. Whole-genome and -exome sequencing (WGS and WES) were performed for clinically unsolved IRD patients, and data were analyzed to identify underlying causal variants. …

Cerebellar Oligodendrocytic Α-Synuclein Pathology And Dentate Nucleus Neuronal Hypertrophy In Parkinson’S Disease, Diego Iacono, Hui Peng, John Paul Bouffard, Roger Kurlan

Department of Neurology Faculty Papers

Idiopathic Parkinson's disease (iPD) research has historically prioritized basal ganglia dysfunction and neuronal Lewy body pathology, often overlooking cerebellar and non-neuronal cells contributions. This study investigates cerebellar neuropathology in iPD, specifically focusing on neuronal and non-neuronal cells of the dentate nucleus (DN) and its adjacent white matter (DN-WM). We systematically assessed autopsy-confirmed iPD brains vs. age-matched controls using immunohistochemistry and stereology-based morphometry methods. The study evaluated α-synuclein pathology, other common age-related co-occurring pathologies (β-amyloid, Tau, neuroinflammation), myelin integrity (Luxol-Fast-Blue), and neuronal volumetric changes in the DN of the cerebellum. In iPD brains, we identified intracytoplasmic α-synuclein inclusions within oligodendrocytes across …

Multi-Trait Polygenic Scores For Copd And Copd Exacerbations Implicate Druggable Proteins, Chengyue Zhang, Iain R Konigsberg, Yixuan He, Jingzhou Zhang, Tinashe Chikowore, William B Feldman, Xiaowei Hu, Yi Ding, Bogdan Pasaniuc, Diana Chang, Qingwen Chen, Jessica A Lasky-Su, Julian Hecker, Martin D Tobin, Jing Chen, Sean Kalra, Katherine A Pratte, Hae Kyung Im, Emily S Wan, Ani Manichaikul, Edwin K Silverman, Russell P Bowler, Leslie A Lange, Victor E Ortega, Alicia R Martin, Michael H Cho, Matthew R Moll

Faculty, Staff and Student Publications

BACKGROUND

We constructed multi-trait polygenic risk scores (PRSs) predicting chronic obstructive pulmonary disease (COPD) and exacerbations, validated their performance in diverse cohorts, and identified PRS-related proteins for potential therapeutic targeting.

METHODS

PRSmix+, a multi-trait PRS framework, is used to train a composite PRS (PRSmulti) in COPDGene non-Hispanic White participants (n = 6,647). Associations of PRSmulti with COPD status (GOLD 2–4 vs. GOLD 0 or ICD) and exacerbation frequency were tested in COPDGene African American (n = 2,466), ECLIPSE (n = 1,858), Mass General Brigham Biobank (n = 15,152), and All of Us (n = 118,566). …

The Effects Of Orexin Receptor Antagonism During Early Withdrawal In Stimulant Use Disorder: Protocol For A Proof-Of-Concept Study, Heather Webber, Nikky Tran, Rita Blake, Sarah Goldman, Trevor George, Bill Bailey, Robert Suchting, Jin Yoon, Jessica Vincent, Michael Weaver, Joy Schmitz, Scott Lane

Faculty, Staff and Student Publications

Background: Stimulant use disorders (StimUDs), including cocaine and methamphetamine use disorders, remain a major public health concern in the United States with no US Food and Drug Administration (FDA)-approved pharmacological treatments. The early recovery period following stimulant use is marked by sleep disturbances, heightened stress reactivity, and dysregulated reward processing, contributing to high rates of resumption of use. Evidence from animal and human studies supports the orexin neuropeptide system as a promising therapeutic target for minimizing these disruptive mechanisms. Suvorexant, an FDA-approved dual orexin receptor antagonist for insomnia, has previously been shown to improve sleep, reduce stress, and attenuate craving …

Contraception In The Ed: Understanding Education And Opportunities For Clinicians To Advise Patients, Hannah B. Lewis, Teagan R. Mccarthy, Dara Kass, Jennifer L. Kahoud

Department of Emergency Medicine Faculty Papers

Introduction: The United States faces a high rate of unwanted pregnancies. Despite this, many people continue to face barriers to accessing contraception. The emergency department (ED) can help bridge these gaps, but emergency clinicians must first feel comfortable offering contraceptive services. In this study, we sought to determine emergency clinician comfort in prescribing contraceptives and educating patients on their use. We also gauged clinician interest in receiving education specifically geared toward contraceptive care.

Methods: We conducted an online survey of ED residents, attendings, and advanced practice clinicians at Thomas Jefferson Univerity Hospital and affiliates in both the urban and suburban …

What Are The Top 10 Global Research Priorities For Perianal Crohn's Disease? The Global Perianal Crohn's Disease Priority Setting Partnership, Theo Pelly, Parakkal Deepak, Et Al.

2020-Current year OA Pubs

BACKGROUND AND AIMS: Perianal Crohn's disease (pCD) is a debilitating condition with a prevalence of approximately 20% in patients within 10 years of diagnosis of CD. The condition significantly impacts patient quality of life, and there remain a number of unmet needs relating to its optimal management. A global Priority Setting Partnership (PSP) was established to identify the top 10 research priorities for pCD.

METHODS: The PSP followed standard James Lind Alliance (JLA) methodology. An initial survey was circulated to gather unanswered research questions from key stakeholders. From these responses, a longlist of summary questions was formed. These questions were …

Clingen Api Platform For Classification Of Human Genetic Variants, Neethu Shah, Tierra Farris, Arturo Alejandro Zuniga, Andrew R Jackson, Jessie Arce, Kevin Riehle, Christine G Preston, Mark E Mandell, Bryan Wulf, Gloria Cheung, Keyang Yu, Deborah I Ritter, Dubravka Jevtic, Miroslav Milinkov, Novak Martinovic, Nevena Vucinic, Aleksandar Mihajlovic, Alan F Rubin, Melissa S Cline, Marina Distefano, Malachi Griffith, Obi L Griffith, Matt W Wright, Teri E Klein, Sharon E Plon, Aleksandar Milosavljevic

Faculty, Staff and Students Publications

In this commentary, we describe how the Clinical Genome Resource's (ClinGen's) application programming interface-based microservices accelerate growth and dissemination of knowledge about human genetic variation. By exposing findable, accessible, interoperable, reusable, and AI-ready variant data, ClinGen lays a foundation for next-generation software applications, AI systems, and variant classification workflows.

Overlapping Mhc Class I/Ii Epitopes Program Cdc1-Like Differentiation Of Monocyte-Derived Dendritic Cells Via Mtorc1 Signaling Inhibition, S B Amanya, A Murthy, N Bisht, Z N Bullock, K J Ernste, J Vasquez-Perez, W Liu, A Trivedi, D Oyewole-Said, A Paul, L Umokoro, V Akhanov, M Samuel, Z Shi, M H Nguyen, S Huang, M Jeong, P Iakova, K A Jain, K Pham, D C Kraushaar, V Konduri, W K Decker

Faculty, Staff and Students Publications

Viral infection polarizes monocyte-derived dendritic cells (moDC) to initiate type 1 immunity. The availability of overlapping (homologous) MHC class I and II epitopes, an occurrence frequently and primarily associated with intracellular infection, significantly enhances this process; however, the underlying mechanism(s) are unclear. We demonstrate that moDC loaded with homologous MHC epitopes acquire a cDC1-like phenotype in a process governed by mTORC1. mTORC1 pathway inhibition leads to NF-κB-mediated expression of IL-12 and other type I immune polarizing genes. The observed cDC1-like gene signature was also significantly enhanced in clinical moDC vaccine products made through methodologies that enforced class I and II …

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 …

Relative Impact Of Multidomain Lifestyle Interventions On Deficit Accumulation Frailty Over 24 Months In The U.S. Pointer Trial, Mark A Espeland, Kayloni Olson, Christy C Tangney, Darren R Gitelman, Maryjo Cleveland, Amber A Thro, Yitbarek N Demesie, Heather M Snyder, Rachel A Whitmer, Pankaja Desai, Rifat Alam, Lucia Crivelli, Thomas M Holland, Olivia Preissle, Rema Raman, Michele K York, Laura D Baker

Faculty, Staff and Students Publications

Background: Multidomain lifestyle interventions hold promise as approaches to slow aging. Deficit accumulation frailty indices (FIs) are increasingly used to capture aging processes. Frailty is highly associated with increased mortality and chronic disease risk, but the degree to which multidomain lifestyle changes impact frailty is not clear.

Methods: The U.S. Study to Protect Brain Health through Lifestyle Intervention to Reduce Risk (U.S. POINTER) was a 2-year randomized clinical trial to compare two multidomain lifestyle interventions designed to increase exercise, improve diet, and promote social and cognitive stimulating activities and health monitoring. The Structured intervention incorporated greater structure, intensity, and accountability …

Structure-Preserving Multivariate Hypothesis Testing For Mass Spectrometry Imaging And Single-Cell Data, Keziah E Liebenberg, Erin Craig, Robert Tibshirani, Livia S Eberlin

Faculty, Staff and Students Publications

Motivation: Mass spectrometry imaging (MSI) and single-cell RNA sequencing (scRNA-seq) offer high-resolution views into tissue and cellular heterogeneity. However, conventional statistical analyses often treat sub-measurements (pixels or cells) as independent, ignoring their nested origin from individual samples. This assumption inflates the effective sample size, increases false discoveries, and undermines biological interpretation. Pixel- or cell-level averaging avoids this but sacrifices spatial or cellular resolution.

Results: We evaluated block-SAM on both simulated and real-world datasets. In DESI-MSI data from kidney, lung, and ovarian tumors, block-SAM consistently identified fewer-but more reliable-differential features compared to traditional-SAM. For example, in the kidney dataset, traditional-SAM identified …

The Ki-67 Proliferation Index And Recurrence Risk Of Intracranial Meningioma: A Multicenter, Retrospective Cohort Study Of 5,050 Patients, Christian Mirian, Lasse Rehné Jensen, Tareq A Juratli, Andrea Daniela Maier, Anders Broechner, Sverre H Torp, Helen A Shih, Ramin A Morshed, Jacob S Young, Stephen T Magill, Luca Bertero, Walter Stummer, Dorothee Cäcilia Spille, Benjamin Brokinkel, Soichi Oya, Satoru Miyawaki, Nobuhito Saito, Martin Proescholdt, Yasuhiro Kuroi, Konstantinos Gousias, Matthias Simon, Jennifer Moliterno, Ricardo Prat-Acin, Stéphane Goutagny, Vikram C Prabhu, John T Tsiang, Johannes Wach, Erdem Güresir, Junkoh Yamamoto, Young Zoon Kim, Joo Ho Lee, Daniel W Kim, Matthew Koshy, Karthikeyan Perumal, Mustafa K Baskaya, Donald M Cannon, Dennis C Shrieve, Chang-Ok Suh, Jong Hee Chang, Maria Kamenova, Sven Straumann, Jehuda Soleman, Ilker Y Eyüpoglu, Tony Catalan, Austin Lui, Philip V Theodosopoulos, Michael W Mcdermott, Fang Wang, Pedro Góes, Aria Jamshidi, Ricardo Komotar, Michael Ivan, Evan Luther, Luis Souhami, Marie-Christine Guiot, Tamás Csonka, Toshiki Endo, Olivia Claire Barrett, Randy Jensen, Tejpal Gupta, Akash J Patel, Tiemo J Klisch, Jun Won Kim, Francesco Maiuri, Valeria Barresi, María Dolores Tabernero, Simon Skyrman, Ian Law, David Scheie, Bjarne Winther Kristensen, Tina Nørgaard Munch, Torstein Meling, Kåre Fugleholm, Paul Blanche, Tiit Mathiesen

Faculty, Staff and Students Publications

Purpose: The Ki-67 proliferation index (Ki-67 PI) has been associated with meningioma recurrence, yet its clinical utility remains debated. Whether Ki-67 PI provides prognostic information across subgroups defined by both WHO grade and extent of resection remains to be investigated.

Methods: We analyzed 5,050 patients with intracranial meningiomas from the international PERNS cohort (42 centers, diagnosed between 1989-2019) who underwent surgical resection without postoperative radiotherapy. Ki-67 PI prognostic accuracy was assessed up to 10 years postoperatively by using ROC analyses and estimating its association with the risk of recurrence.

Results: Results demonstrated that the prognostic value of Ki-67 PI differed …

Untangling Impacts Of Socioeconomic Position, Chronic Disease, And Low-Level Pm2.5 Exposure On Mortality Among Native American Medicare Beneficiaries, Judy Wendt Hess, Wenyaw Chan

Faculty, Staff and Student Publications

Ambient fine particulate matter (PM2.5) is associated with increased mortality at concentrations below current regulatory standards. Studies of low-level exposure often rely on large administrative cohorts whose geographic and demographic composition may influence observed associations. In a prior analysis, we observed an association between long-term PM2.5 and all-cause mortality among Native American Medicare beneficiaries living in zip codes within the lowest decile of PM2.5 exposure. The present study, a case-control analysis of 1,713,399 low-PM2.5-exposed beneficiaries enrolled in traditional Medicare during 2015-2016, evaluated whether this association could be explained by geographic context, socioeconomic position (SEP), or baseline health status. We used …

Claudins Interact With Lilrb Immune Inhibitory Receptors To Promote Myeloid Immunosuppression In Cancer, Xiaoye Liu, Ryan Huang, Zhiqiang Ku, Jingjing Xie, Heyu Chen, Yubo He, Qi Lou, Chengcheng Zhang, Xing Yang, Cheryl Lewis, Jade Homsi, Ankit Gupta, Lei Dong, Kenian Chen, Annabel Tu, Liming Du, Hailong Yu, Qing Hu, Meng Fang, Bufan Li, A E M Adan Khan, Caroline Simith, Samuel John, Lin Xu, Ningyan Zhang, Zhiqiang An, Cheng Cheng Zhang

The Brown Foundation: Institute of Molecular Medicine

The mechanisms underlying tumor cell-myeloid cell interactions in the tumor microenvironment (TME) remain unclear, and predictive biomarkers for patient response to myeloid checkpoint blockade are lacking. This study identified specific binding between tight junction claudins (CLDNs) and leukocyte immunoglobulin-like receptor subfamily B2 (LILRB2) and LILRB5. In multiple human cancer cohorts, the spatial proximity of LILRB2-positive macrophages to CLDN-expressing cancer cells correlated with clinical outcomes, highlighting this spatial relationship as a potential biomarker. In syngeneic LILRB2-transgenic and humanized mouse models, CLDN18.2-LILRB2 interactions triggered bidirectional signaling, enhanced the immunosuppressive activity of myeloid cells, and accelerated tumor progression. These effects were reversed by …

Translationally-Relevant Tumor Resection Model For Murine Preclinical Models Of Oral Squamous Cell Carcinoma, Gemalene M Sunga, Alejandra Cobos Perez, Andrea H Molina, Nourhan Hussein, Neeraja Dharmaraj, Andrew Sikora, Simon Young

Faculty, Staff and Student Publications

Currently, the first-line treatment for the most common form of head and neck squamous cell carcinoma (HNSCC), oral cavity squamous cell carcinoma (OSCC), is surgical resection, followed by risk-adapted treatments, such as chemoradiotherapy. However, with the current standard of care and even the emergence of new treatments, such as checkpoint blockade, the overall survival for advanced, recurrent disease remains high, and the prevalence of head and neck cancer is projected to continue to increase in the coming years. Thus, deeper investigation into current standard-of-care modalities, in addition to novel therapeutics, is necessary to translate potential and promising treatment options to …

Implementing Measurement-Based Care In Virtual Mental Health Services For Rural Veterans: Provider Insights From A Pre-Implementation Evaluation, Amanda Heeren, Kimberly Mccoy, Lindsey Fuhrmeister, Natalie Suiter, Jan A Lindsay, Chloe Hoang, Laura Marsh, John Fortney, Carolyn Turvey

Faculty, Staff and Students Publications

Background

Measurement-Based Care (MBC) uses repeated standardized psychological assessments to monitor treatment progress and guide clinical decision-making. Although MBC improves outcomes when results are discussed collaboratively, adoption across the Veterans Health Administration (VHA) remains below 50%, particularly in virtual and rural settings. This pre-implementation evaluation explored provider perspectives to inform development of a digital MBC workflow for rural tele-mental health settings.

Methods

Using the Alacrity Center’s Discover, Design, Build, and Test model and User Centered Design, we conducted a pre-implementation survey of mental health providers at a VHA Medical Center providing care to rural and highly rural Veterans in South …

Regulation Of Mitochondrial Ros By C15orf48 In A Basal Cell Subpopulation Contributes To Chemotherapy Resistance In Tnbc, Yan Jiang, Noor M Abdulkareem, Amanda L Rinkenbaugh, Yuan Qi, Steven W Wall, Xiaomei Zhang, Jiansu Shao, Sabrina Jeter-Jones, Shirong Cai, Faiza Baameur Hancock, Gloria V Echeverria, Jeffrey T Chang, Helen Piwnica-Worms

Faculty, Staff and Students Publications

Systemic neoadjuvant chemotherapy, often combined with immunotherapy, is the standard of care for early-stage, non-breast cancer susceptibility gene (BRCA)-mutant triple negative breast cancer (TNBC). However, up to 70% of patients retain residual disease after treatment, which is linked to recurrence and mortality within 5 years. To define mechanisms of resistance, we performed single-cell RNA sequencing on orthotopic TNBC patient-derived xenografts during a cycle of treatment with doxorubicin and cyclophosphamide (AC). Clustering identified four tumor epithelial cell populations, with basal cells enriched in residual tumors. These basal cells up-regulated C15ORF48, a paralog of the mitochondrial cytochrome c oxidase associated subunit FA4 …

Organ Procurement Organization Utilization Of Portable Hypothermic Oxygenated Machine Perfusion In Liver Transplantation: The First Us Experience, Christine E. Haugen, Muhammad Bilal Moeen-Ud-Din, Abdalla M. Hadhoud, Achintya Kaw, James R. Butler, James V. Guarrera, Sherry Quire, Ralph C. Quillin

Department of Surgery Faculty Papers

BACKGROUND: Advanced machine perfusion techniques have increased the use of hard-to-place organs, effectively changing the liver transplantation landscape. Liver transplantation machine perfusion has been driven largely by industry or individual transplant centers. We describe the implementation of a portable, organ procurement organization-initiated hypothermic oxygenated machine perfusion strategy for liver transplantation as a proof of concept.

METHODS: Surgeons and staff at a regional organ procurement organization (Indiana Donor Network) were trained to use and cannulate liver allografts using a portable hypothermic oxygenated machine perfusion platform. We evaluated all liver transplantations recovered and placed on hypothermic oxygenated machine perfusion (N = 18) …

Nanog Proximity Proteomics Maps Neighborhood Hubs Linked To Mesenchymal Stem Cell Stemness And Chromatin Control, Kyoung-Jae Choi, Michail Tyryshkin, Harathi Jonnagaddala, Allan Chris M Ferreon, Marian Kalocsay, Josephine C Ferreon

Faculty, Staff and Students Publications

NANOG overexpression has been reported to reverse aging-associated decline in mesenchymal stem/stromal cell (MSC) function, but the molecular machinery engaged by NANOG in MSCs remains incompletely defined. Here, we applied APEX proximity labeling coupled with quantitative mass spectrometry to define the NANOG proximity interactome (proxeome) in human MSCs. Of 1040 quantified proteins, 828 were significantly enriched in the APEX-NANOG (H2O2 labeling) samples, consistent with a broad NANOG-centered neighborhood rather than a single stoichiometric complex. Enriched proteins encompass RNA-processing pathways (including splicing/RNP factors and selected m6A-related proteins), transcriptional coactivation and elongation control (Mediator and 7SK/P-TEFb regulators), chromatin repression/poising modules (Polycomb and …

Transcultural Headache Medicine: A Framework For Integrating Cultural Contexts Into Headache Science And Care - A Call To Action From The International Headache Society., Mario F. P. Peres, Giancarlo Lucchetti, Homero Vallada, Ivy L. Riso, Georgia K. Westenhofen, Marcelo Moraes Valença, Juliana Ramos De Andrade, K. C. Brennan, Morris Levin, Tsubasa Takizawa, Zhao Dong, Yonggang Wang, Wanakorn Rattanawong, Henry Riyanto Sofyan, Massimo Leone, Freda Dodd-Glover, Hsiangkuo Yuan, Abdulrazaq Albilali, Taoufik Alsaadi, Leonardo Caixeta, Anna P. Andreou, Peter J. Goadsby, Antoinette Maassenvandenbrink, Sait Ashina, Rami Burstein, Patricia Pozo-Rosich, Fayyaz Ahmed, Shuu-Jiun Wang

Department of Jefferson Headache Center Papers and Presentations

Headache disorders are among the most disabling neurological conditions, affecting over 1.5 billion people globally. Despite advances in pharmacological therapies, major inequities persist due to underdiagnosis, undertreatment and limited access to effective care, particularly in low- and middle-income countries. Social determinants of health, including cultural meanings, language and health beliefs, are increasingly recognized as key drivers of disparities in burden, diagnosis and treatment outcomes. Traditional medicine, used by more than 80% of the global population, remains first-line care in many regions and continues to influence therapeutic choices in high-income settings. Major systems such as Ayurveda, Traditional Chinese Medicine, Unani and …