Medicine and Health Sciences Commons^™

Surgical Revision In The Presence Of An S. Aureus Infection Increases Virulence Factor Expression And Activates A Multi-Tissue Inflammatory Response, Carly J. Smith, Arianna J. Moniodes, Amanda R. Watkins, Autumn G. Melvage, Thomas P. Thompson, Eirene Choi, Abigail A. Lucas, Brendan F. Gilmore, Thomas P. Schaer, Noreen J. Hickok, Theresa A. Freeman

Department of Orthopaedic Surgery Faculty Papers

Replacing implanted medical hardware due to infection often requires one or more revision surgeries. Each surgery triggers a tissue injury response and disrupts the established bacterial biofilm. However, the complex tissue response to reinjury and biofilm disturbance is not well understood. Our results show that with an existing infection, immunological niches such as the bone marrow, lymph nodes, and circulating blood further upregulate pro-inflammatory programs in response to revision. Rather than reducing bacterial burden, this heightened inflammation provokes virulence factor expression and tissue damage, including bone osteolysis and muscle fibrosis. While muscle fibrosis appears transient and begins resolving by 14 …

Clinical Outcomes Of Patients With Unsuccessful Mechanical Thrombectomy Versus Best Medical Management Of Medium Vessel Occlusion Stroke In The Middle Cerebral Artery Territory, Tobias D Faizy, Vivek Yedavalli, Hamza Adel Salim, Dhairya A Lakhani, Basel Musmar, Nimer Adeeb, Muhammed Amir Essibayi, Motaz Daraghma, Kareem El Naamani, Nils Henninger, Sri Hari Sundararajan, Anna Luisa Kuhn, Jane Khalife, Sherief Ghozy, Luca Scarcia, Leonard Ll Yeo, Benjamin Yq Tan, Robert W Regenhardt, Jeremy Josef Heit, Nicole M Cancelliere, Aymeric Rouchaud, Jens Fiehler, Sunil A Sheth, Ajit S Puri, Christian Dyzmann, Marco Colasurdo, Leonardo Renieri, João Pedro Filipe, Pablo Harker, Răzvan Alexandru Radu, Mohamad Abdalkader, Piers Klein, Thomas R Marotta, Julian Spears, Takahiro Ota, Ashkan Mowla, Pascal Jabbour, Arundhati Biswas, Frédéric Clarençon, James E Siegler, Thanh N Nguyen, Ricardo Varela, Amanda Baker, David Altschul, Nestor Gonzalez, Markus A Möhlenbruch, Vincent Costalat, Benjamin Gory, Christian Paul Stracke, Constantin Hecker, Gaultier Marnat, Hamza Shaikh, Christoph J Griessenauer, David S Liebeskind, Alessandro Pedicelli, Andrea Maria Alexandre, Illario Tancredi, Erwah Kalsoum, Max Wintermark, Boris Lubicz, Aman B Patel, Vitor Mendes Pereira, Adam A Dmytriw, Adrien Guenego, Mad-Mt Investigators

Faculty, Staff and Student Publications

Background: Current randomized controlled trials are investigating the efficacy and safety of mechanical thrombectomy (MT) in patients with medium vessel occlusion (MeVO) stroke. Whether best medical management (MM) is more efficient than unsuccessful vessel recanalization during MT remains unknown.

Methods: This was a retrospective cohort study using data from 37 academic centers across North America, Asia, and Europe between September 2017 and July 2021. Only patients with occlusion of the distal branches (M2 and M3) of the middle cerebral artery territory were included. Unsuccessful MT was defined as a modified Thrombolysis in Cerebral Infarction score of 0-2a. Propensity score matching …

Investigating The Polygenic Relationship Between Heavy Cannabis Use And Schizophrenia In The All Of Us Research Program, Isabelle Austin-Zimmerman, Hayley H A Thorpe, John J Meredith, Jibran Y Khokhar, Tian Ge, Marta Di Forti, Arpana Agrawal, Emma C Johnson, Sandra Sanchez-Roige

2020-Current year OA Pubs

BACKGROUND: Decades of research have identified a strong association between heavy cannabis use and schizophrenia (SCZ), with evidence of correlated genetic factors. However, many studies on the genetic relationship between cannabis use and psychosis have lacked data on both phenotypes within the same individuals, creating challenges due to unmeasured confounding. We aimed to address this by using multimodal data from the All of Us Research Program, which contains genetic data as well as information on SCZ diagnosis and cannabis use.

METHODS: We tested the association between cannabis use disorder (CUD) and SCZ polygenic scores (PGSs) with SCZ and heavy cannabis …

Adjudicated Cardiovascular Events In Patients With Covid-19: Association With Vaccination Status And Changes Over Time, Behnood Bikdeli, Darsiya Krishnathasan, Antoine Bejjani, Candrika D. Khairani, Nada Hamade, Umberto Campia, Julia Davies, Nicole Porio, Ali Assi, Andre Armero, Anthony Tristani, Marcos D. Ortiz-Rios, Victor Nauffal, Zaid I. Almarzooq, Eric Q. Wei, Bridget Mcgonagle, Mariana Pfeferman, Sina Rashedi, Alyssa Sato, Giovanni Scimeca, Valeria Zuluaga-Sánchez, Mehrdad Zarghami, Aditya Achanta, Sirus Jesudasen, Bruce C. Tiu, Geno J. Merli, Orly Leiva, John Fanikos, Aditya M. Sharma, Samantha M. Rizzo, Ruth B. Morrison, Alec Vishnevsky, Shiavax J. Rao, Sivan Naveh, Abdelghani El Rafei, James Welker, Marc P. Bonaca, Brett J. Carroll, Samuel Z. Goldhaber, Zhou Lan, Gregory Piazza, The Corona-Vte Network Investigators

Jefferson Hospital Staff Papers and Presentations

BACKGROUND: Patients with COVID-19 are at risk of thrombotic and cardiovascular complications. Existing risk estimates derive from early COVID-19 experiences. More recent event rates, temporal trends, and the association between vaccination status and cardiovascular outcomes remain unclear.

METHODS: The CORONA-VTE Network (COVID-19 Registry to Assess Frequency, Risk Factors, Management, and Outcomes of Arterial and Venous Thromboembolic Complications) multicenter registry included patients with COVID-19 from March 2020 to February 2024. A composite of venous and arterial thrombotic events and a composite of adjudicated cardiovascular events were assessed at 90 days after COVID-19 diagnosis. Time-to-first-event analyses were stratified by inpatients and outpatients …

Mbnl Loss Of Function In Smooth Muscle As A Model For Myotonic Dystrophy Associated Gastrointestinal Dysmotility, Janel A M Peterson, Jesus A Frias, Andrew N Miller, Krishnakant G Soni, Yi Zhang, Zheng Xia, John W Day, Geoffrey A Preidis, Thomas A Cooper

Faculty, Staff and Students Publications

Myotonic dystrophy type 1 (DM1) is the most common adult-onset muscular dystrophy and severely affects multiple organ systems, including the brain, heart, skeletal muscle, and gastrointestinal (GI) tract. Despite 80% of individuals with DM1 experiencing GI dysfunction that affects their daily life, the mechanisms of GI dysmotility in DM1 remain an understudied aspect of the disease. DM1 is caused by a CTG repeat expansion in the DMPK gene that, when expressed as an expanded CUG repeat RNA, sequesters and reduces the activity of the muscleblind-like (MBNL) RNA-binding protein family. We developed a mouse line with conditional, smooth muscle-specific knockout of …

Vesicle-Mediated Mitochondrial Clearance Presents An Actionable Metabolic Vulnerability In Triple-Negative Breast Cancer, Jody Vykoukal, Yihui Chen, Mingxin Zuo, Riccardo Ballarò, Monica J Hong, Hansini Krishna, Daniela B Rodriquez-Perera, Hiroyuki Katayama, Ehsan Irajizad, Ranran Wu, Ricardo A León-Letelier, Jennifer B Dennison, Angelica M Gutierrez, Adriana Paulucci-Holthauzen, Timothy C Thompson, Leona Rusling, Yining Cai, Fu Chung Hsiao, Soyoung Park, Banu Arun, Samir Hanash, Johannes F Fahrmann

Faculty, Staff and Student Publications

Selective autophagy of mitochondria is known to promote cancer cell survival and progression, including in triple-negative breast cancer (TNBC). Here, we apply an integrated multi-omics approach together with functional experimental analyses to investigate metabolic adaptations that support mitochondrial quality control in TNBC. We detail a mitochondrial quality control mechanism, complementary to mitophagy, that is enabled by a program of heightened extracellular sphingomyelin salvaging in TNBC coupled with extracellular vesicle-mediated intracellular clearance of mitochondrial damage. Targeting of this onco-metabolic pathway via repurposing of eliglustat, a selective small molecule inhibitor of glucosylceramide synthase, results in ceramide-mediated compensatory mitophagy and cancer cell death …

Accurate Imputation Of Pathway-Specific Gene Expression In Spatial Transcriptomics With Pasta, Ruoxing Li, Peng Yang, Mauro Di Pilato, Jianjun Zhang, Christopher R Flowers, Lulu Shang, Ziyi Li

Faculty, Staff and Student Publications

Mapping the entire transcriptome at single-cell resolution under its natural spatial context is essential for investigating the oncogenesis and progression of diseases. The recently emerged targeted in-situ technologies retain the spatial organization of cells at high resolution, although they remain limited in the number of genes that can be simultaneously measured. To overcome this obstacle, numerous computational methods have been developed to predict unmeasured gene expression in spatial transcriptomics data by leveraging scRNA-seq data. Most of these methods focus on the expression of individual genes and usually generate highly variable predictions. In this study, we introduce PASTA (PAthway-oriented Spatial gene …

Lung Adenocarcinoma Surfaceome Remodeling With Egfr Inhibitors Uncovers Placental Alkaline Phosphatase As A Target For Combination Therapy, Yihui Chen, Rongzhang Dou, Monica J Hong, Hanwen Xu, Jody Vykoukal, Ricardo A León-Letelier, Yining Cai, Soyoung Park, Ehsan Irajizad, Fu Chung Hsiao, Jennifer B Dennison, Edwin J Ostrin, Johannes F Fahrmann, Hiroyuki Katayama, Samir M Hanash

Faculty, Staff and Student Publications

Treatment of lung adenocarcinomas (LUADs) that exhibit activated epidermal growth factor receptor (EGFR) with EGFR tyrosine kinase inhibitors (TKIs) has limited efficacy. Assessment of the impact of EGFR TKI on the LUAD surfaceome remodeling reveals potential therapeutic targets. We identify placental type alkaline phosphatase (ALPP), which has restricted expression in normal tissues, among upregulated surface proteins following EGFR TKI treatment of both TKI sensitive as well as resistant cells. EGF treatment represses ALPP expression, whereas EGFR TKIs upregulate its expression through dephosphorylation and activation of FoxO3a, a transcriptional regulator that binds to the promoter region of ALPP. The combination of …

Holter Monitor Qt Dispersion And Qtc-Dispersion In Pediatric Long Qt Syndrome And Development Of A Diagnostic And Arrhythmia Risk Prediction Model, Hadeel Allam, Na Le Dang, Edita Karasalihovic, Nathan Miller, Lisa Roelle, William B Orr, Dustin Nash, Anthony G Pompa, Jennifer N A Silva

2020-Current year OA Pubs

BACKGROUND: Holter monitors can provide temporal QT analysis, allowing for calculation of QT dispersion and corrected QT dispersion over time. We describe the results of the QT dispersion and corrected QT dispersion over a 24-hour period in pediatric patients with long QT syndrome (LQTS), compared with a normal cohort, and develop 2 new machine learning models for diagnosis and arrhythmia risk prediction in LQTS.

METHODS: A single-center retrospective case-control study was conducted comparing patients with congenital LQTS and normal controls who underwent a clinically indicated Holter between January 2022 and May 2024. After identifying patients with cardiac events, 2 neural …

Baseline Ecg And Cardiovascular Outcomes In People With Hiv: Insights From Reprieve, Aya Awwad, Shashwatee Bagchi, Et Al.

2020-Current year OA Pubs

BACKGROUND: With antiretroviral therapy, people with HIV (PWH) have an increased burden of cardiovascular disease. The REPRIEVE (Randomized Trial to Prevent Vascular Events in HIV) trial demonstrated that pitavastatin reduces major adverse cardiovascular events (MACEs) among PWH at low to moderate traditional atherosclerotic risk. Electrocardiographic abnormalities are common in PWH, but little is known about their association with MACEs. We sought to examine whether baseline electrocardiographic abnormalities are associated with increased MACE risk among a global primary cardiovascular disease prevention cohort of PWH in REPRIEVE.

METHODS: In this observational analysis, entry electrocardiographic abnormalities were adjudicated and classified as major or …

Intracranial Injection Of Genetically Modified, Mosquito Non-Transmissible Zika Virus: Safety In Primates And Ramifications For Brain Tumor Therapy, Alec J Hirsch, Amanda De Andrade Costa, Emilie Russler-Germain, Ashwani Kesarwani, Yuping Li, Michael S Diamond, Milan G Chheda, Et Al.

2020-Current year OA Pubs

Glioblastomas (GBMs) are incurable brain tumors. Zika virus (ZIKV) has specificity in killing GBM stem cells, which drive treatment resistance. In mouse models of GBM, ZIKV also generates an anti-tumor inflammatory response and prolongs survival. To support clinical development and address safety concerns for intra-tumoral treatment, we assessed the effects of injection of an immune-sensitized ZIKV (Δ10 3'-UTR ZIKV), which cannot be transmitted by mosquitos, into non-tumor-bearing rhesus macaque brains. After injection, the primates showed no clinical signs of illness. Histologically, as expected, ZIKV infection elicited mild inflammation, which resolved within 2 weeks. No infectious virus was detected in the …

A Proteogenomic Gene Signature Defines Prognostic Subgroups Highlighting Pi3k/Akt/Mtor Signaling Pathway As A Therapeutic Vulnerability In Myeloid Malignancies, Fan He, Shuyang Lin, Bei Gao, Varun Ramesh, Alexander B Kim, Tim Kong, Daniel A C Fisher, Christopher T Letson, Molly Brakhane, Mary Fulbright, Yanbo Yu, Marco Sardiello, Jorge Di Paola, Stephen M Sykes, Stephen T Oh

2020-Current year OA Pubs

INTRODUCTION: Myeloid malignancies, including acute myeloid leukemia (AML) and myeloproliferative neoplasms (MPN), exhibit overlapping pathophysiology. Chronic MPNs can transform into secondary AML (sAML), which is associated with poor prognosis and limited treatment options. However, the process and prognostic significance of leukemic transformation remain incompletely understood.

METHOD: Through a two-sample bidirectional Mendelian randomization (MR) analysis, we showed that genetic liability to MPN significantly predicts the risk of developing AML, establishing MPN as the precursor to leukemia. To identify mediators of this risk, we integrated population-level plasma proteomics data, identifying 55 proteins associated with MPN. Upon integrative analysis with the BEAT-AML cohort, …

Radiogenomic Profiling Of Prostate Tumors Prior To External Beam Radiotherapy Converges On A Transcriptomic Signature Of Tgf-Β Activity Driving Tumor Recurrence, Anson T. Ku, Uma Shankavaram, Shana Y. Trostel, Hong Zhang, Sumeyra Kartal, Houssein A. Sater, Stephanie A. Harmon, Nicole V. Carrabba, Yang Liu, Hyunnam Ryu, James A. Proudfoot, Boon Hao Hong, Bradford J. Wood, Peter A. Pinto, Peter L. Choyke, Mack Roach, Howard M. Sandler, Stephanie L. Pugh, Kenneth L. Zeitzer, Lucas C. Mendez, Nirav S. Kapadia, William A. Hall, Anand B. Desai, Radka S. Stoyanova, Alan Pollack, Elai Davicioni, Melvin L. K. Chua, Baris Turkbey, Adam G. Sowalsky, Deborah E. Citrin

Einstein Health Papers

PURPOSE: Clinical risk grouping based on PSA, tumor grade, and disease extent guides treatment intensity for localized prostate cancer. However, many patients with intermediate- or high-risk disease treated with external beam radiotherapy (EBRT) and androgen deprivation therapy (ADT) still develop biochemical recurrence (BCR). Early identification of patients at high risk for BCR could enable personalized treatment strategies.

EXPERIMENTAL DESIGN: We prospectively enrolled 29 patients with intermediate- or high-risk prostate cancer undergoing EBRT and ADT. Pretreatment biopsies (n = 60) underwent whole-transcriptome microarray and whole-exome sequencing. Patients received multiparametric MRI at baseline and 6 months after treatment, with a median follow-up …

Extracellular Matrix-Mycaf Signatures Correlate With Resistance To Neoadjuvant Apd-L1 Immune Checkpoint Inhibition With Durvalumab + Metformin In Hpv+ Hnscc, Pablo Llerena, Hani Samarah, Kathryn Nunes, Zhao Lin, Kelly Bridgham, Sruti Tekumalla, Amiti Jain, Larry A. Harshyne, Sanket Kumar Shukla, Ioannis Vathiotis, Madalina Tuluc, Stacey Gargano, John R. Eisenbrey, Scott W Keith, David Cognetti, Voichita Bar-Ad, Adam J. Luginbuhl, Rita S. Axelrod, Rajanikanth Vadigepalli, Hushan Yang, Diana Whitaker-Menezes, Megan Roche, My G. Mahoney, Athanassios Argiris, Charalambos C. Solomides, Jennifer Johnson, Md, Mouadh Barbirou, Amanda Miller, Andrew P. South, Ramkrishna Mitra, Alban J Linnenbach, Ubaldo E. Martinez-Outshoorn, Joseph Curry

Department of Otolaryngology - Head and Neck Surgery Faculty Papers

PURPOSE: Immune checkpoint inhibitors (ICI) have demonstrated clinical benefit in head and neck squamous cell carcinoma (HNSCC); however, single-agent efficacy is limited, leaving significant unmet needs. Metformin may synergize with ICIs, offering promise to improve response rates. We leveraged multiomic data from a randomized, presurgical neoadjuvant trial (NCT03618654) evaluating a single infusion of the anti-PD-L1 ICI durvalumab with or without daily, standard dose metformin in previously untreated, nondiabetic patients with HNSCC to understand predictors of response and the effect of combination therapy.

PATIENTS AND METHODS: Clinical, pathologic, and correlative data were analyzed to investigate response and resistance mechanisms. We present …

Targeting Kinesin Family Member 20a Sensitizes Stem-Like Triple-Negative Breast Cancer Cells To Standard Chemotherapy, Yayoi Adachi, Weilong Chen, Cheng Zhang, Tao Wang, Nina Gildor, Rachel Shi, Haoyong Fu, Masashi Takeda, Qian Liang, Fangzhou Zhao, Hongyi Liu, Jun Fang, Jin Zhou, Hongwei Yao, Lianxin Hu, Shina Li, Lei Guo, Lin Xu, Ling Xie, Xian Chen, Chengheng Liao, Qing Zhang

Faculty, Staff and Student Publications

Triple-negative breast cancer (TNBC), being both aggressive and highly lethal, poses a major clinical challenge in terms of treatment. Its heterogeneity and lack of hormone receptors or HER2 expression further restrict the availability of targeted therapy. Breast cancer stem cells (BCSCs), known to fuel TNBC malignancy, are now being exploited as a vulnerability for TNBC treatment. Here, we dissected the transcriptome of BCSCs and identified kinesin family member 20A (KIF20A) as a key regulator of BCSC survival and TNBC tumorigenesis. Genetic depletion or pharmacological inhibition of KIF20A impairs BCSC viability and tumor initiation and development in vitro and in vivo. …

Itpr1 Autoantibody-Associated Autoimmunity As A Cause Of Newly Emerging Cognitive Decline Mimicking Alzheimer's Disease: Case Report And Brief Review Of The Literature, Nicolas Kunath, Hermod Arne Bollandsås Ramfjord, Elisabeth Volden Kvisvik, Marton Konyves-Kolonics, Gøril Rolfseng Grøntvedt, Irina I Serysheva, Lars Komorowski, Brigitte Wildemann, Sven Jarius

Faculty, Staff and Student Publications

Background: Since its first description in 2014, anti-inositol 1,4,5-trisphosphate receptor type 1 (ITPR1, also termed IP3R1) autoimmunity has been recognized as causing a clinically heterogeneous spectrum of symptoms. While first described in patients with autoimmune cerebellar ataxia, this facultative paraneoplastic disease has been associated also with peripheral neuropathy, dysautonomia, sleep disorders, neuropsychiatric/psychotic symptoms, and cognitive decline.

Methods: Retrospective case study.

Results: We report the case of a 58-year-old patient who was admitted with acute confusion, rapidly progressive cognitive decline, and hallucinations. A history of mild cognitive impairment over several years and low cerebrospinal fluid (CSF) amyloid beta-42 and elevated CSF …

Structural Basis For Genome-Wide Site-Specific Dna Recognition By Nuclear Factor Ia, Ci Zhu, Ding Xiao, Zhipu Luo, Jie Zhang, Shuang Liu, Yueyu Wang, Xi Chen, Hejin Xiao, Xiaofeng Li, Juyu Tang, Xianyang Fang, Jie Shen, He Song

2020-Current year OA Pubs

Nuclear Factor IA, a member of the long-studied Nuclear Factor I family of DNA-binding proteins, plays pivotal roles in development and metabolism. Dysregulation or loss of Nuclear Factor IA is associated with severe neurological defects in humans and disruptions in fatty acid metabolism linked to conditions such as osteoarthritis. Despite extensive study, the DNA recognition mechanism of Nuclear Factor I family proteins remains unresolved. Previous studies have proposed that these proteins dimerize via their DNA-binding domains to bind TGGCA-containing dyad sequences. In this study, we demonstrate that both full-length Nuclear Factor IA and its isolated DNA-binding domain are monomeric in …

Facts And Hopes Of Chimeric Antigen Receptor-Redirected Nk T Cells, Amy N Courtney, Xin Zhou, Gengwen Tian, Ying Wang, Leonid S Metelitsa, Gianpietro Dotti

Faculty, Staff and Students Publications

Chimeric antigen receptor (CAR)-engineered invariant NK T cells (CAR-NKT) are a novel cell platform for cancer immunotherapy. Unlike conventional T cells, NKTs are characterized by innate antitumor properties, minimal alloreactivity, and a unique ability to modulate the tumor microenvironment. This article provides a comprehensive overview of preclinical and early clinical studies evaluating CAR-NKTs in both autologous and allogeneic clinical settings. We discuss the contributions of CAR signaling domains, cytokine coexpression, and other functional measures that correlate with CAR-NKT persistence, function, and metabolic fitness. We also discuss the critical role of immunocompetent animal models in elucidating the interactions of CAR-NKTs with …

A Long Non-Coding Rna Leat1 Mediates The Hormone Responsiveness Of Efnb2 During Male Urogenital Development, Deidre Mattiske, Pascal Bernard, Paul E Gradie, Richard R Behringer, Paul A Overbeek, Rachel J O'Neill, Tiffany Phillips, Melanie Stewart, Neil Youngson, Gerard Tarulli, Andrew J Pask

Faculty, Staff and Students Publications

The novel long non-coding RNA (lncRNA) Leat1 is extraordinarily conserved in both its location (syntenic with EfnB2, an essential gene in anogenital patterning) and sequence. Here we show that Leat1 is upregulated following the production of testosterone from the developing testis in mice and interacts with EfnB2, positively regulating its expression. Leat1 expression is suppressed by estrogen, which in turn suppresses the expression of EfnB2. Moreover, the loss of Leat1 leads to reduced EfnB2, resulting in a severe hypospadias phenotype. The human LEAT1 gene is also co-expressed with EFNB2 in the developing human penis, suggesting a conserved function for this …

Transdiagnostic Links Of Reward Processing In Obsessive-Compulsive Disorder And Depression, Kevin M Wagner, Matti Cervin, Jessica S C Cheng, Jasmine Arriaga, Vanessa Zavala Cruz, Dayan Berrones, Josselyn S Muñoz, Renee M Frederick, Jacey L Anderberg, Belinda E Núñez Bracho, Victor R Adorno, Leonardo F Fontenelle, Andrew D Wiese, Latin American Trans-Ancestry Initiative For Ocd Genomics (Latino), Brazilian Obsessive-Compulsive Spectrum Disorder Working Group (Gttoc), James J Crowley, Eric A Storch

Faculty, Staff and Students Publications

Objectives: Transdiagnostic models aim to uncover shared mechanisms across mental disorders. Reward responsiveness (the ability to experience pleasure from rewarding stimuli) is a plausible, yet underexplored, transdiagnostic mechanism linking obsessive-compulsive disorder (OCD) and depression. This study used network analysis to (1) examine how key reward responsiveness domains are interlinked in individuals with OCD and (2) explore how each domain is uniquely associated with OCD and depression.

Methods: A total of 1345 individuals with a history of OCD symptoms (ages 18-88, 71 % women) from Latino communities in the United States (including Puerto Rico) and nine Latin American countries completed validated …

Methylation-Based Signature To Distinguish Indolent And Aggressive Prostate Cancer, Muheng Liao, Jace Webster, Amy Ly, Emily Rozycki, Christopher A Maher

2020-Current year OA Pubs

Prostate cancer management faces significant challenges in distinguishing indolent from aggressive disease, particularly since most patients are intermediate-risk and therefore hinders the ability to recommend standardized treatment recommendations. Moreover, current prognostic tools including Gleason scoring and tumor staging demonstrate limited accuracy for predicting disease progression and tumor recurrence. DNA methylation serves as a stable epigenetic modification that directly regulates gene expression, making it an ideal biomarker for cancer prognosis. Therefore, this study leveraged whole-genome enzymatic methylation sequencing on 120 patients to develop a novel prognostic signature for aggressive prostate cancer progression. We analyzed 20,849 differentially methylated regions (DMRs) and employed …

Biophysical Simulation Enables Segmentation And Nervous System Atlas Mapping For Image First Spatial Omics, Lina Mohammed Ali, Aldrin Kay Yuen Yim, Emanuel Gerbi, Thien Nguyen, Nicholas Tu, Faith Ikede, Remi Sampaleanu, Diana Grigore, Jason Waligorski, Colin Kremitzki, Liya Yuan, Wendy Dong, Robi Mitra, Jeffrey Milbrandt, William Buchser

2020-Current year OA Pubs

Spatial omics (SO) produces high-definition mapping of subcellular molecules within tissue samples. Mapping transcripts to anatomical regions requires segmentation, but this remains challenging in tissue cross-sections with tubular structures like axons in peripheral nerve or spinal cord. Neural networks could address misidentification but are hindered by the need for extensive human annotations. We present SiDoLa-NS (Simulate, Don't Label-Nervous System), an image-driven (top-down) approach to SO analysis in the nervous system. We utilize biophysical properties of tissue architectures to design synthetic images of tissue samples, eliminating reliance on manual annotation and enabling scalable training data generation. With synthetic samples, we trained …

Superior Transplant Recipient Outcome Prediction And Pathology Assessment Using Rapid Deep Learning Applied To Procurement Kidney Biopsies, Joseph P Gaut, Jon N Marsh, Ling Chen, Fan Zhang, Xiaobing Yu, Parker Wilson, Ta-Chiang Liu, S Joshua Swamidass

2020-Current year OA Pubs

Evaluating the suitability of deceased organ donor kidneys relies on clinical, laboratory, and biopsy data. Pathologist quantitation of glomerulosclerosis is a critical histologic parameter used in the decision to transplant. This is an arduous task with modest reproducibility and inconsistent correlation with graft outcomes. Prior work shows that deep learning methods automate glomerulosclerosis quantitation with performance superior to on-call pathologists. Extending beyond this prior work, in this study we find that deep learning glomerulosclerosis quantitation better correlates with graft outcomes. A customized and updated deep learning model was used to analyze 691 procurement biopsies of transplanted kidneys with an average …

Methodology For The Pediatric Dose Optimization For Seizures In Emergency Medical Services (Pedidose) Study, Manish I Shah, Kathleen M Adelgais, James M Chamberlain, Henry E Wang, Lindsey A Morgan, James J Riviello, Rana R Said, Joseph E Sullivan, Kimia F Ghaffari, Kathryn M Kothari, Mohsen Saidinejad, Robert A Lowe, Raymond L Fowler, Catherine R Counts, Claudia R Morris, Jonathan R Studnek, Nancy K Glober, Caleb E Ward, Brian M Clemency, Nicholas Patrick, Rachel D Munn, Graham M Brant-Zawadzki, Christian Martin-Gill, Daniel K Nishijima, Kevin Li, Neomi Sepulveda, John M Vanburen

Faculty, Staff and Student Publications

Background: Seizures are one of the most common reasons for emergency medical services (EMS) activation for children, and current EMS practice results in underdosing and delayed delivery of anti-seizure medication. A prehospital evidence-based guideline recommends using intranasal or intramuscular midazolam as first-line treatment for pediatric seizures. Despite attempts to implement these guidelines, one-third of children having a paramedic-witnessed seizure have ongoing seizures on emergency department (ED) arrival; this may be due to inadequate or delayed midazolam dosing. Replacing the error-prone, sequential calculations with age-based midazolam dosing may be simpler, faster, and more effective without compromising safety. The objective of this …

Protein-Nucleic Acid Language Model-Assisted Design Of Precise And Compact Adenine Base Editor, Jingxuan Ren, Jiawei Yao, Qiuyu Cao, Yinuo Li, Yang Li, Ziyi Zhang, Xiyu Ge, Shengfang Wang, Yang Zhang, Xiaogang Wang, Xiaohui Zhang

Faculty, Staff and Students Publications

Adenine base editors (ABEs) are powerful tools for gene therapy. However, efficient version of ABEs (e.g. ABE8e) always induce excessive bystander and off-target editing events and are large in size, hindering their potential in clinical disease treatment. Here, we develop a pre-trained Protein-Nucleic Acid Constrained Language Model to design ABE8e with high activity, reduced editing window and decreased size. By further engineering, the smallest ABE8e- PNLM-pcABE- with a 27% size reduction, exhibits high activity, precise 3-nt editing window, and reduced off-target events near background level in HEK293T cells. Compared to ABE8e, PNLM-pcABE has up to 133.5-fold precision improvement in pathogenic …

Cardiometabolic And Molecular Adaptations To 6-Month Intermittent Fasting In Middle-Aged Men And Women With Overweight: Secondary Outcomes Of A Randomized Controlled Trial, Ruteja A Barve, Nicola Veronese, Beatrice Bertozzi, Valeria Tosti, Maria Lastra Cagigas, Francesco Spelta, Edda Cava, Laura Piccio, Dayna S Early, Richard D Head, Luigi Fontana

2020-Current year OA Pubs

Intermittent fasting (IF) has gained attention as a potential intervention for cardiometabolic health, though its long-term effects remain unclear. In this randomized clinical trial, we assessed the impact of 6 months of IF on body composition, cardiovascular risk factors, and related molecular pathways in middle-aged (30-65 years) men and women with overweight (BMI 24.8-35 kg/m²). In this trial, 41 participants were randomized to either an intermittent fasting (IF) intervention or to maintain their habitual diet. The primary outcome (circulating CRP concentration) was previously reported; here, we present exploratory analyses focusing on metabolomic and transcriptomic responses. IF led to an 8% …

Concurrent Tb And Hiv Therapies Control Tb Reactivation During Co-Infection But Not Chronic Immune Activation, Riti Sharan, Yi Zou, Bindu Singh, Vinay Shivanna, Edward J Dick, Shannan Hall-Ursone, Xi Luo, Guanlin Guo, Shabaana A Khader, Xavier Alvarez, Jyothi Rengarajan, Zhao Lai, Smriti Mehra, Hulin Wu, Deepak Kaushal

Faculty, Staff and Student Publications

Most HIV-negative individuals exposed to Mycobacterium tuberculosis (Mtb) control infection as latent TB infection (LTBI), but HIV co-infection greatly increases progression to tuberculosis (TB), the leading cause of death in people living with HIV (PLHIV). Although combination antiretroviral therapy (cART) reduces LTBI reactivation, immune control of Mtb is not fully restored, as shown by persistent TB incidence in PLHIV on cART. In macaques, skewed pulmonary effector memory CD4⁺ T-cell (TEM) responses and new TB lesions persist despite cART. We hypothesize that concurrent anti-TB therapy with cART would improve bacterial control and immune restoration compared to cART alone. Using …

Agpat2 Acts At The Crossroads Of Lipid Biosynthesis And Drp1-Mediated Er Morphogenesis, Yoshihiro Adachi, Mauricio Torres, Allen H Hunter, Woo Jung Cho, Meixia Pan, Xianlin Han, Guangwei Du, Ling Qi, Miho Iijima, Hiromi Sesaki

Faculty, Staff and Student Publications

The morphology of the endoplasmic reticulum (ER), characterized by central sheets and peripheral tubules, is controlled by membrane-shaping proteins. However, the role of lipids in ER morphogenesis remains elusive, despite the ER being the major site for lipid synthesis. Here, by examining the role of eighteen phosphatidic acid (PA)-generating enzymes in ER morphology, we identify lysophosphatidic acid acyltransferase 2 (AGPAT2) as a critical factor in mouse and human cells. AGPAT2 produces PA in the glycerophospholipid/triacylglycerol biosynthesis pathway, and its mutations cause congenital generalized lipodystrophy. We find that AGPAT2-generated PA drives ER tubulation through gene knockout, 3D structural analysis by FIB-SEM, …

Measurable Imaging-Based Changes In Enhancement Of Intrahepatic Cholangiocarcinoma After Radiotherapy Reflect Physical Mechanisms Of Response, Brian De, Prashant Dogra, Mohamed Zaid, Dalia Elganainy, Kevin Sun, Ahmed M Amer, Charles Wang, Michael K Rooney, Enoch Chang, Hyunseon C Kang, Zhihui Wang, Priya Bhosale, Bruno C Odisio, Timothy E Newhook, Ching-Wei D Tzeng, Hop S Tran Cao, Yun S Chun, Jean-Nicholas Vauthey, Sunyoung S Lee, Ahmed Kaseb, Kanwal Raghav, Milind Javle, Bruce D Minsky, Sonal S Noticewala, Emma B Holliday, Grace L Smith, Albert C Koong, Prajnan Das, Vittorio Cristini, Ethan B Ludmir, Eugene J Koay

Faculty, Staff and Student Publications

Escalated doses of radiotherapy associate with improved local control and overall survival (OS) in intrahepatic cholangiocarcinoma (iCCA), but personalization remains limited because conventional size-based CT criteria correlate poorly with outcomes. We hypothesized that quantitative enhancement measurements would better predict clinical outcomes and guide individualized RT optimization. In a retrospective cohort of 154 patients, we analyzed pre- and post-RT CT scans using quantitative European Association for Study of Liver (qEASL) to derive viable tumor volumes, comparing enhancement-based metrics with size-based RECIST and linking them to outcomes via survival and mathematical modeling. Change in enhancement volume was strongly associated with OS after …

Stakeholder Criteria For Trust In Artificial Intelligence-Based Computer Perception Tools In Health Care: Qualitative Interview Study, Ansh Rai, Meghan E Hurley, John Herrington, Eric A Storch, Casey J Zampella, Julia Parrish-Morris, Anika Sonig, Gabriel Lázaro-Muñoz, Kristin Kostick-Quenet

Faculty, Staff and Students Publications

Background: Computer perception (CP) technologies hold significant promise for advancing precision mental health care systems, given their ability to leverage algorithmic analysis of continuous, passive sensing data from wearables and smartphones (eg, behavioral activity, geolocation, vocal features, and ambient environmental data) to infer clinically meaningful behavioral and physiological states. However, successful implementation critically depends on cultivating well-founded stakeholder trust.

Objective: This study aims to investigate, across adolescents, caregivers, clinicians, and developers, the contingencies under which CP technologies are deemed trustworthy in health care.

Methods: We conducted 80 semistructured interviews with a purposive sample of adolescents (n=20) diagnosed with autism, Tourette …