Digital Commons Network^™

Applying The Practical, Robust, Implementation And Sustainability Model (Prism) To A Community-Based Youth Participatory Action Research Program, Nicholas Szoko, Tyia K Wilson, Ebonie Slade, Ti'yanna Risher, Marquise Wheeler, Elizabeth Miller, Alison J Culyba

2020-Current year OA Pubs

BACKGROUND: Youth participatory action research (YPAR) represents an empowerment-based process in which youth identify and address issues in their schools and communities. YPAR has been applied in diverse settings, but evaluations of YPAR implementations using an implementation and dissemination science (IDS) framework are limited. Our goal was to use the Practical, Robust, Implementation & Sustainability Model (PRISM) to evaluate a multisite community-based YPAR program.

METHODS: We identified three community sites to implement Youth Leadership in Action (YLIA+), an eight session YPAR intervention. Any youth aged 13 and older was eligible to participate. Guided by PRISM, we collected data using: (1) …

Iodine-Promoted Oxidative Cross-Coupling For The Synthesis Of (E)-2-(3-Oxo-3-Phenylprop-1-En-1-Yl)-3-Phenylquinazolin-4(3 H)-One Via C-H Activation: Development Of Synthetic Tlx Agonists, Lingaiah Maram, Puhan Zhao, Thomas Koelblen, Lamees Hegazy, Thomas P Burris, Bahaa Elgendy

2020-Current year OA Pubs

We report the development of an efficient iodine-promoted oxidative cross-coupling reaction for the synthesis of (

Sulfated Dietary Fiber Protects Gut Microbiota From Antibiotics, Fuqing Wu, Xiaoqian Annie Yu, David Angeles-Albores, Susan E Erdman, Eric J Alm

Faculty, Staff and Student Publications

Background: Antibiotics, while essential for combating pathogens, also disrupt commensal bacteria, leading to gut microbiota imbalance and associated diseases. However, strategies to mitigate such collateral damage remain largely underexplored.

Result: In this study, we found that fucoidan, a marine polysaccharide derived from brown seaweed, provides broad-spectrum growth protection against multiple classes of antibiotics for human gut microbial isolates in vitro and for fecal communities ex vivo. This protective effect is dependent on the structural integrity, molecular weight, and sulfur content of the polysaccharide. Transcriptomic analysis showed that while fucoidan had minimal impact on baseline gene expression, it counteracted about 60% …

Development Of A Customizable Web-Based Dashboard For Remote Blood Pressure Monitoring: Feasibility And Usability Implementation Study, Joshua Wollen, Thuy Nguyen, Charles Coton, Gina Dewildt, Gabretta Cooksey, Audrey Cohen, Nicholas Hoang, Munachi Okpala, Michael Gonzalez, Mengxi Wang, Chigozirim Izeogu, Elmer Bernstam, Charles Green, Sean Savitz, Jose-Miguel Yamal, Anjail Sharrief

Faculty, Staff and Student Publications

Background: Effective blood pressure (BP) management is essential for several disease states, including secondary stroke prevention. Remote BP monitoring used in combination with an electronic data capture (EDC) system offers potential for improved BP control for patients. While such systems currently exist, there are many patient-, provider-, and system-specific challenges these systems currently do not address. In addition, such systems are rarely described transparently and comprehensively in the literature with enough detail to be reproduced by other clinicians.

Objective: This study aims to describe the development and design of a web-based EDC system tailored for remote BP monitoring and management …

Three Positively Charged Binding Sites On The Eastern Equine Encephalitis Virus E2 Glycoprotein Coordinate Heparan Sulfate- And Protein Receptor-Dependent Infection, Maria D H Alcorn, Chengqun Sun, Theron C Gilliland Jr, Tetyana Lukash, Christine M Crasto, Saravanan Raju, Michael S Diamond, Scott C Weaver, William B Klimstra

2020-Current year OA Pubs

Naturally circulating strains of eastern equine encephalitis virus (EEEV) bind heparan sulfate (HS) receptors and this interaction has been linked to neurovirulence. Previous studies associated EEEV-HS interactions with three positively charged amino acid clusters on the E2 glycoprotein. One of these sites has recently been reported to be critical for binding EEEV to the very-low-density lipoprotein receptor (VLDLR), an EEEV receptor protein. The proteins apolipoprotein E receptor 2 (ApoER2) isoforms 1 and 2, and LDLR have also been shown to function as EEEV receptors. Herein, we investigate the individual contribution of each HS interaction site to EEEV HS- and protein …

Increased Fungal Burden In The Gastrointestinal Tract Of Brain-Dead Organ Donors, Erika J Nachman, Colleen K Ardis, A Kyle B Ardis, Javier Nieto, Madeline M Bresson, Clare M Robertson, Maggie N Seale, Nora M Villafuerte, Zhe Lyu, Eva C Preisner, Heather A Danhof, Sara C Di Rienzi, Yolanda T Becker, Robert A Britton

Faculty, Staff and Students Publications

Approximately 3% of organ transplant recipients will be diagnosed with an invasive fungal infection (IFI), with 10%-47% being fatal. The source of IFI is typically not known, but Candida spp. cause the majority of IFI cases. We obtained intestines from two types of organ donors, brain-dead (BD) (n = 7) and donation after circulatory death (DCD) (n = 5), to sample microbes from the mucosal surface and the lumen. BD donors were parenterally fed and treated with corticosteroids in the days before procurement, whereas DCD donors were enterally fed and not given corticosteroids. We found fungi present in …

Rare Variants In Bmal1 Are Associated With A Neurodevelopmental Syndrome, Vishnu Anand Cuddapah, Dechun Chen, Bumsik Cho, Rebecca Moore, Mohnish Suri, Hana Safraou, Frederic Tran-Mau-Them, Ashley Wilson, Jacqueline Odgis, Atteeq U Rehman, Carol Saunders, Shiva Ganesan, Vaidehi Jobanputra, Stephen W Scherer, Ingo Helbig, Amita Sehgal

Duncan NRI Faculty and Staff Publications

Children with neurodevelopmental disorders exhibit highly penetrant sleep and circadian dysfunction, but the underlying mechanisms are unclear. We asked whether a subset of individuals with neurodevelopmental disorders might have genetic variants in genes known to drive circadian rhythms. Through international collaboration, we identified ten individuals with very rare genetic variants in BMAL1, a core component of the molecular clock. These individuals exhibited overlapping signs and symptoms including developmental delay, autism spectrum disorder, and variably penetrant marfanoid features. We functionally tested the identified BMAL1 variants in cell culture and in vivo and found disrupted BMAL1 function. These findings demonstrate that …

Survival To Hospital Discharge In The Fetus With Moderate To Severe Mitral Regurgitation Either In Isolation Or In Combination With Aortic Valve Stenosis Or Atresia, A Fetal Heart Society Collaborative Study, Betul Yilmaz Furtun, Kavitha Pundi, Anita Moon-Grady, Nicole Cresalia, Asela Nieuwsma, Sarah K Gelehrter, Bhawna Arya, Mary T Donofrio, Christopher Statile, Ann Kavanaugh-Mchugh, Lindsay Freud, Elijah Bolin, Megan Warner, Sowmya Balasubramanian, James Strainic, Carol Wittlieb-Weber, Nelangi M Pinto, Lisa Hornberger, Shaine A Morris

Faculty, Staff and Students Publications

Background: Case series report high mortality after fetal diagnosis of moderate to severe mitral regurgitation in combination with left atrial dilation, hydrops, or restrictive atrial septum. However, overall outcomes and specific high-risk features remain unclear.

Methods: We performed a multicenter retrospective cohort study of fetuses with ≥moderate mitral regurgitation and normal cardiac connections evaluated January 1, 2005 to January 31, 2016. Fetuses undergoing fetal cardiac intervention (FCI) were described separately. We assessed associations between fetal echocardiographic features and discharge mortality using mixed logistic regression and classification and regression tree modeling, stratified by studies performed < 28 and ≥28 weeks gestational age (GA).

Results: Of 67 fetuses, 96% had …

Real-Time Experiences Of Racism And Stress In Association With Postpartum Weight Retention: A Longitudinal Ecological Momentary Assessment Study, Dara M Méndez, Amanda L Tapia, Sarah A Sanders, Andrea D Casas, Marquita Smalls, Esa M Davis, Stephen L Rathbun, Tiffany L Gary-Webb, Lora E Burke, Serwaa S Omowale, Linda A Adodoadji, John J Gianakas, Y Lai, Maisa Feghali, Meredith L Wallace

Faculty, Staff and Student Publications

Racial inequities in postpartum weight have been documented with limited studies on the influences of racism and other forms of discrimination. In a prospective longitudinal study applying ecological momentary assessment (EMA) and ambulatory assessment of weight, we measured the association between discrimination, stress, and postpartum weight change. The Postpartum Mothers Mobile Study is a cohort of 313 pregnant and birthing individuals who were followed during their second and third trimesters through 1 year postpartum. They were recruited in clinical settings between 2017 and 2020 in a major city center in Pennsylvania. Measures of racism and gender-based discrimination were collected via …

Association Between Allostatic Load And Accelerated White Matter Brain Aging: Findings From The Uk Biobank, Li Feng, Zhenyao Ye, Zewen Du, Yezhi Pan, Travis Canida, Hongjie Ke, Song Liu, Shuo Chen, L Elliot Hong, Peter Kochunov, Jie Chen, David K Y Lei, Edmond Shenassa, Tianzhou Ma

Faculty, Staff and Student Publications

White matter (WM) brain age, a neuroimaging-derived biomarker indicating WM microstructural changes, helps predict dementia and neurodegenerative disorder risks. The cumulative effect of chronic stress on WM brain aging remains unknown. In this study, we assessed cumulative stress using a multi-system composite allostatic load (AL) index based on inflammatory, anthropometric, respiratory, lipidemia, and glucose metabolism measures, and investigated its association with WM brain age gap (BAG), computed from diffusion tensor imaging data using a machine learning model, among 22 951 European ancestries aged 40 to 69 (51.40% women) from UK Biobank. Linear regression, Mendelian randomization, along with inverse probability weighting, …

Genetic Overlap Between Functional Impairment And Depression And Anxiety Symptom Severity: Evidence From The Glad Study, Megan Skelton, Jessica Mundy, Abigail Ter Kuile, Brett Adey, Cherie Armour, Joshua Buckman, Jonathan Coleman, Molly Davies, Colette R. Hirsch, Matthew Hotopf, Ian Jones, Gursharan Kalsi, Georgina Krebs, Sang Hyuck Lee, Yuhao Lin, Andrew M. Mcintosh, Alicia J. Peel, Christopher Rayner, Katharine Rimes, Daniel J. Smith, Katherine N. Thompson, David Veale, James T.R. Walters, Christopher Hübel, Gerome Breen, Thalia C. Eley

School of Psychology

BACKGROUND: Functional impairment in daily activities, such as work and socializing, is part of the diagnostic criteria for major depressive disorder and most anxiety disorders. Despite evidence that symptom severity and functional impairment are partially distinct, functional impairment is often overlooked. To assess whether functional impairment captures diagnostically relevant genetic liability beyond that of symptoms, we aimed to estimate the heritability of, and genetic correlations between, key measures of current depression symptoms, anxiety symptoms, and functional impairment.

METHODS: In 17,130 individuals with lifetime depression or anxiety from the Genetic Links to Anxiety and Depression (GLAD) Study, we analyzed total scores …

Conservative Oxygen Therapy In Mechanically Ventilated Critically Ill Adult Patients: The Uk-Rox Randomized Clinical Trial, Uk-Rox Investigators, Daniel S Martin, Doug W Gould, Tasnin Shahid, James C Doidge, Alex Cowden, Zia Sadique, Julie Camsooksai, Walton N Charles, Miriam Davey, Amelia Francis-Johnson, Roger M Garrett, Michael P W Grocott, Joanne Jones, Lamprini Lampro, Diane M Mackle, B Ronan O'Driscoll, Alvin Richards-Belle, Anthony J Rostron, Tamás Szakmány, Alex Warren, Paul J Young, Kathryn M Rowan, David A Harrison, Paul R Mouncey

Peninsula Medical School

IMPORTANCE: Supplemental oxygen is frequently given to patients in intensive care units (ICUs); however, there is insufficient evidence to guide its therapeutic use and to minimize the potential harm caused by administering too little or too much.

OBJECTIVE: To determine whether reducing exposure to supplemental oxygen through a strategy of conservative oxygen therapy by using a peripheral oxygen saturation (Spo2) target of 90% (range, 88%-92%) reduces mortality at 90 days in mechanically ventilated adult patients receiving supplemental oxygen in the ICU.

DESIGN, SETTING, AND PARTICIPANTS: Multicenter, pragmatic, randomized clinical trial conducted in 97 ICUs in the UK including 16 500 …

Rare Variants In Bmal1 Are Associated With A Neurodevelopmental Syndrome, Vishnu Anand Cuddapah, Dechun Chen, Bumsik Cho, Rebecca Moore, Mohnish Suri, Hana Safraou, Frederic Tran-Mau-Them, Ashley Wilson, Jacqueline Odgis, Atteeq U. Rehman, Carol J. Saunders, Shiva Ganesan, Vaidehi Jobanputra, Stephen W. Scherer, Ingo Helbig, Amita Sehgal

Manuscripts, Articles, Book Chapters and Other Papers

Through international gene-matching efforts, we identified 10 individuals with ultrarare heterozygous variants, including 5 de novo variants, in BMAL1, a core component of the molecular clock. Instead of an isolated circadian phenotype seen with disease-causing variants in other molecular clock genes, all individuals carrying BMAL1 variants surprisingly share a clinical syndrome manifest as developmental delay and autism spectrum disorder, with variably penetrant sleep disturbances, seizures, and marfanoid habitus. Variants were functionally tested in cultured cells using a Per2-promoter driven luciferase reporter and revealed both loss-of-function and gain-of-function changes in circadian rhythms. The tested BMAL1 variants disrupted PER2 mRNA …

Interactive 3d Segmentation For Primary Gross Tumor Volume In Oropharyngeal Cancer, Mikko Saukkoriipi, Jaakko Sahlsten, Joel Jaskari, Lotta Orsmaa, Jari Kangas, Nastaran Rasouli, Roope Raisamo, Jussi Hirvonen, Helena Mehtonen, Jorma Järnstedt, Antti Mäkitie, Mohamed Naser, Clifton Fuller, Benjamin Kann, Kimmo Kaski

Faculty, Staff and Student Publications

Radiotherapy is the main treatment modality of oropharyngeal cancer (OPC), in which an accurate segmentation of primary gross tumor volume (GTVt) is essential but also challenging due to significant interobserver variability and the time consumed in manual tumor delineation. For such a challenge an interactive deep learning (DL) based approach offers the advantage of automatic high-performance segmentation with the flexibility for user correction when necessary. In this study, we investigate an interactive DL for GTVt segmentation in OPC by introducing a novel two-stage Interactive Click Refinement (2S-ICR) framework and implementing state-of-the-art algorithms. Using the 2021 HEad and neCK TumOR dataset …

Artificial Intelligence-Based Digital Pathology Using H&E-Stained Whole Slide Images In Immuno-Oncology: From Immune Biomarker Detection To Immunotherapy Response Prediction., Jessica Zhang, Horyun Choi, Yeseul Kim, Jonghanne Park, Sukjoo Cho, Eugene Kim, Allen Cho, Ju Young Lee, Jaeyoun Choi, Christmann Low, Chan Mi Jung, Emma J Yu, Jeffrey Chuang, Lee Cooper, Young Kwang Chae

Faculty Research 2025

Immuno-oncology and the advent of immunotherapies, in particular immune checkpoint inhibitors (ICIs), have fundamentally altered the way we treat cancer. Yet only a small subset of patients actually responds to ICIs, and many face significant adverse effects, making the accurate selection of patients for ICIs essential to the work of immuno-oncology. Immune biomarkers, such as programmed death-ligand 1, microsatellite instability/defective mismatch repair, and tumor mutational burden have been developed for patient selection and stratification for ICIs, though their predictive abilities remain limited. This is due to several challenges: lack of adequate tissue sampling, the time-consuming and subjective nature of manual …

Alternative To The Statistical Mass Confusion Of Testing For "No Effect", Josh L Morgan

2020-Current year OA Pubs

In cell biology, statistical analysis means testing the hypothesis that there was no effect. This weak form of hypothesis testing neglects effect size, is universally misinterpreted, and is disastrously prone to error when combined with high-throughput cell biology. The solution is for analysis of measurements to start and end with an interpretation of effect size. In this manuscript, I walk through some of the common critiques of significance testing and how they relate to experimental cell biology. I argue that careful consideration of effect size should be returned to its central position in the planning and discussion of cell biological …

An Ethanol-Induced Loss Of The Lipid Droplet-Associated Segregase Vcp/P97 Leads To Hepatic Steatosis, Sandhya Sen, Shaun Weller, Ryan J Schulze, Donglin Ding, Carol A Casey, Conrad Weihl, Mark A Mcniven

2020-Current year OA Pubs

The liver stores substantial numbers of neutral lipid organelles termed lipid droplets (LDs) that accumulate within hepatocytes in response to chronic ethanol (EtOH) consumption leading to hepatic steatosis. Mass spectrometry analysis of LDs isolated from EtOH-damaged rat livers revealed a substantial reduction in the valosin-containing protein ATPase (VCP/p97) that acts to remove targeted proteins from cellular membranes for degradation. Experimental disruption of VCP function resulted in an increase in LD content in hepatocytes and mouse livers along with a marked increase in LD-associated hydroxysteroid dehydrogenase (HSD17β13) known to contribute to hepatic steatosis. Surprisingly, treatment of hepatocytes with the proteasome inhibitor …

Detection Of Brain Cancer Using Genome-Wide Cell-Free Dna Fragmentomes, Dimitrios Mathios, Et Al.

2020-Current year OA Pubs

UNLABELLED: Diagnostic delays in patients with brain cancer are common and can impact patient outcome. Development of a blood-based assay for detection of brain cancers could accelerate brain cancer diagnosis. In this study, we analyzed genome-wide cell-free (cfDNA) fragmentomes, including fragmentation profiles and repeat landscapes, from the plasma of individuals with (n = 148) or without (n = 357) brain cancer. Machine learning analyses of cfDNA fragmentome features detected brain cancer across all-grade gliomas (AUC = 0.90; 95% confidence interval, 0.87-0.93), and these results were validated in an independent prospectively collected cohort. cfDNA fragmentome changes in patients with gliomas represented …

Comparative Outcomes Of Coil Embolization And Surgical Clipping In Elderly Patients With Subarachnoid Hemorrhage: A Systematic Review And Meta-Analysis, Yohanna Idsabella Rossi, Gabriel Bolner, Jonathan Costa Dall'acqua, Fabiana Dolovitsch De Oliveira, Lucas V. Zacaria, Taís L. Denicol, Michel Frudit, Natália Vasconcellos De Oliveira Souza

Department of Neurology Faculty Papers

BACKGROUND AND OBJECTIVES: Elderly patients with subarachnoid hemorrhage (SAH) face a disproportionately high burden of morbidity and mortality. While endovascular coiling is often favored in this population, direct comparisons with surgical clipping are limited. We conducted a meta-analysis to compare outcomes of clipping versus coiling in SAH patients aged ≥ 60 years.

METHODS: A systematic search of PubMed, Embase, and Cochrane databases identified studies comparing the two treatments in this age group. The primary outcome was a composite of unfavorable outcomes (modified Rankin Scale [mRS] > 2 and mortality). Secondary outcomes included mortality, favorable outcome (mRS 0-2), rebleeding, and hospital length …

The Effect Of Hcv On Methadone Dose During Pregnancy, Sarah Boudova, Neel S. Iyer, Danielle M. Tholey, Jonathan M. Fenkel, Rupsa C. Boelig

Department of Obstetrics and Gynecology Faculty Papers

Pregnancy is a time of high patient motivation to initiate treatment for opioid use disorder (OUD). Hepatic drug metabolism can be altered by pregnancy and hepatitis C virus (HCV) infection. We aimed to examine the impact of HCV during pregnancy on methadone dosing. Retrospective chart review of all pregnant patients with OUD admitted for initiation of methadone from 1/2020-6/2022. Associations were examined using Student's T-tests, chi-squared tests, Fisher's exact tests and univariate and multivariate linear regression. We identified 191 pregnancies initiated on methadone, of which 188 were screened for HCV. 111 (59.0%) were HCV Antibody (Ab)+, of whom 108 were …

Integrating Ctdna Analysis And Radiomics For Dynamic Risk Assessment In Localized Lung Cancer, Everett J Moding, Mohammad Shahrokh Esfahani, Cheng Jin, Angela B Hui, Barzin Y Nabet, Yufei Liu, Jacob J Chabon, Michael S Binkley, David M Kurtz, Emily G Hamilton, Aadel A Chaudhuri, Chih Long Liu, Zhe Li, Rene F Bonilla, Alice L Jiang, Brianna C Lau, Pablo Lopez, Jianzhong He, Yawei Qiao, Ting Xu, Luyang Yao, Saumil Gandhi, Zhongxing Liao, Millie Das, Kavitha J Ramchandran, Sukhmani K Padda, Joel W Neal, Heather A Wakelee, Michael F Gensheimer, Billy W Loo, Ruijiang Li, Steven H Lin, Ash A Alizadeh, Maximilian Diehn

Faculty, Staff and Student Publications

The complementarity and clinical utility of combining liquid biopsies and radiomic image analysis has not been demonstrated. Circulating tumor DNA (ctDNA) minimal residual disease after chemoradiotherapy (CRT) for non-small cell lung cancer (NSCLC) is highly prognostic, but on-treatment biomarkers are needed to enable response-adapted therapies. Here, we analyzed 418 patients with NSCLC undergoing CRT to develop and validate a novel dynamic risk model that accurately predicts ultimate progression-free survival during treatment. We optimize tissue-free variant calling from plasma samples to facilitate ctDNA monitoring and demonstrate the importance of accounting for persistent clonal hematopoiesis variants. We show that mid-CRT ctDNA concentration …

Nemvaleukin Alfa Monotherapy In Patients With Advanced Melanoma And Renal Cell Carcinoma: Results From The Phase 1/2 Non-Randomized Artistry-1 Trial, Emiliano Calvo, Valentina Boni, Olivier Dumas, Sang Joon Shin, Seth D Rosen, Arvind Chaudhry, Philip R Debruyne, Xiaomin He, Ulka N Vaishampayan, David F Mcdermott

School of Nursing and Midwifery

BACKGROUND: Despite improved outcomes with immune checkpoint inhibitors (ICIs) and their combinations in advanced solid tumors, a subset of patients remains unresponsive or progresses, highlighting an unmet need for novel treatments with durable benefit. Nemvaleukin alfa (nemvaleukin, ALKS 4230) demonstrated manageable safety and antitumor activity, alone and in combination with pembrolizumab, across heavily pretreated advanced solid tumors in the ARTISTRY-1 study. We report in-depth antitumor activity, safety, pharmacokinetics, and pharmacodynamics of nemvaleukin monotherapy at the recommended phase 2 dose (RP2D) in advanced melanoma and renal cell carcinoma (RCC) cohorts from ARTISTRY-1.

METHODS: ARTISTRY-1 was a three-part (A, B, and C), …

Stem Cell-Derived Corneal Epithelium: Engineering Barrier Function For Ocular Surface Repair, Emily Elizabeth Fresenko, Jian-Xing Ma, Matthew Giegengack, Atalie Carina Thompson, Anthony Atala, Andrew J W Huang, Yuanyuan Zhang

2020-Current year OA Pubs

The cornea, the transparent anterior window of the eye, critically refracts light and protects intraocular structures. Corneal pathologies, including trauma, infection, chemical injury, metabolic diseases, genetic conditions, and age-related degeneration, can lead to significant visual impairment. While penetrating keratoplasty or full-thickness corneal transplantation remains a standard and effective intervention for severe corneal dysfunction, limitations in donor tissue availability and the risk of immunogenic graft rejection necessitate alternative therapeutic strategies. Furthermore, for cases of isolated epithelial disfunction, a full-thickness cornea graft may not be required or effective. This review examines the potential of corneal epithelial constructs derived from autologous stem cells …

Enhancing Patient Positioning Accuracy: Evaluating Daily Cone Beam Computed Tomography In The Halcyon System., Duong Thanh Tai, Luong Tien Phat, Tran Trung Kien, Nguyen Ngoc Anh, Nguyen Xuan Hai, Peter Sandwall, David Bradley, James C L Chow

Oncology Articles

BACKGROUND: Precise patient positioning is crucial for successful radiotherapy, ensuring accurate delivery of radiation to tumors while minimizing exposure to healthy tissues. Positional errors can significantly impact treatment efficacy and increase side effects. This study evaluates the effectiveness of daily cone beam computed tomography (CBCT) imaging in the Halcyon system for detecting and correcting patient misalignments across various cancer types and treatment sites.

METHODS: A retrospective analysis was conducted on 411 patients treated with the Varian Halcyon linear accelerator from August 2022 to August 2024. Patients were grouped based on tumor location: Head and Neck (118 patients), Chest (188 patients), …

Sporadic Als Induced Pluripotent Stem Cell Derived Neurons Reveal Hallmarks Of Tdp-43 Loss Of Function, Jeffrey D Rothstein, Olivia Keeley, Caroline Warlick, Timothy M Miller, Cindy V Ly, Jonathan D Glass, Alyssa N Coyne

2020-Current year OA Pubs

Nuclear loss and cytoplasmic buildup of the RNA-binding protein TDP-43 is a hallmark of ALS and related disorders. While studies using artificial TDP-43 depletion in neurons have revealed changes in gene expression and splicing, their relevance to actual patients remained unclear. Induced pluripotent stem cell (iPSC)-derived neurons (iPSNs) from 180 individuals, including controls, C9orf72 ALS/FTD, and sporadic ALS (sALS) patients were used to generate and analyze ~32,500 qRT-PCR data points across 20 genes which identified variable, time-dependent signatures of TDP-43 loss of function in individual lines. Notably, the same changes were also seen in postmortem brain tissue from the same …

Inhibition Of Epithelial Cell Yap-Tead/Lox Signaling Attenuates Pulmonary Fibrosis In Preclinical Models, Darcy Elizabeth Wagner, Hani N Alsafadi, Nilay Mitash, Aurelien Justet, Qianjiang Hu, Ricardo Pineda, Claudia Staab-Weijnitz, Martina Korfei, Nika Gvazava, Kristin Wannemo, Ugochi Onwuka, Molly Mozurak, Adriana Estrada-Bernal, Juan Cala-Garcia, Katrin Mutze, Rita Costa, Deniz Bölükbas, John Stegmayr, Wioletta Skronska-Wasek, Stephan Klee, Chiharu Ota, Hoeke A Baarsma, Jingtao Wang, John Sembrat, Anne Hilgendorff, Jun Ding, Andreas Günther, Rachel Chambers, Ivan Rosas, Stijn De Langhe, Naftali Kaminski, Mareike Lehmann, Oliver Eickelberg, Melanie Königshoff

Faculty, Staff and Students Publications

Idiopathic pulmonary fibrosis (IPF) is a progressive and lethal disease characterized by excessive extracellular matrix deposition. Current IPF therapies slow disease progression but do not stop or reverse it. The (myo)fibroblasts are thought to be the main cellular contributors to excessive extracellular matrix production in IPF. Here we show that fibrotic alveolar type II cells regulate production and crosslinking of extracellular matrix via the co-transcriptional activator YAP. YAP leads to increased expression of Lysl oxidase (LOX) and subsequent LOX-mediated crosslinking by fibrotic alveolar type II cells. Pharmacological YAP inhibition via verteporfin reverses fibrotic alveolar type II cell reprogramming and LOX …

Quantile Index Predictors Using R Package Hyper.Gam, Tingting Zhan, Misung Yi, Inna Chervoneva

Department of Pharmacology, Physiology, and Cancer Biology Faculty Papers

MOTIVATION: Evaluation of single-cell protein expression from immunohistochemistry images is used increasingly in biomedical research. Many proteins are used solely for phenotyping cells in the tumor microenvironment. Other proteins with meaningfully quantitative expression levels provide so-called functional protein biomarkers. There is still a limited number of methods and software tools available for utilizing the entire distributions of single-cell expression levels.

RESULTS: We present the R package hyper.gam, providing a supervised learning framework for deriving biomarkers based on single-cell distribution quantiles. The single-cell data are first converted into sample quantile functions, which are then used as predictors in scalar-on-function regression models …

Trauma Resuscitation With Low-Titer Group O Whole Blood Or Products: Study Protocol For A Randomized Clinical Trial (The Troop Trial), Jan O Jansen, Claudia Pedroza, Luis Leon Novelo, Tianyao Hao, Gina R Dewildt, Charles F Coton, Kiran Mansoor, Shannon W Stephens, Marisa B Marques, James R Stubbs, Jillian R Richter, Henry E Wang, John B Holcomb, Stacia M Desantis

Faculty, Staff and Student Publications

Background: Hemorrhage is the most common cause of potentially preventable death after injury. Balanced transfusion with red blood cells, plasma, and platelets (component therapy, CT) has been shown to reduce mortality, and is the standard of care. Low-Titer Group O Whole Blood (LTOWB) is an attractive alternative to CT, but existing evidence comprises observational studies, and a small single center pilot randomized controlled trial, which evaluated a type of whole blood that is no longer in use. The aim of the "Trauma Resuscitation with Low-Titer Group O Whole Blood Or Products" (TROOP) trial is to compare the effectiveness and safety …

Rsph4a-Pcdx: An Index To Predict Lung Function Decline In Primary Ciliary Dyskinesia, Gabriel Román-Ríos, Gabriel Rosario-Ortiz, Marcos J Ramos-Benitez, Ricardo A Mosquera, Wilfredo De Jesús-Rojas

Faculty, Staff and Student Publications

Primary ciliary dyskinesia (PCD) is a rare, genetically heterogeneous disorder that impairs mucociliary clearance and leads to progressive lung disease. This study aimed to characterize lung function decline in a genetically homogeneous cohort of Puerto Rican patients with

Rna Sequencing And Immunohistochemistry Jointly Improve Tumor Biomarker Interpretation, Vladimir Kushnarev, Danil Stupichev, Suren Davitavyan, Kirill Kriukov, Basavaraja U Shanthappa, Anna Butusova, Sofia Menshikova, Anna Belozerova, Anastasia Shvyrkova, Arina Tkachuk, Olga Khatenkova, Linda Balabanian, Ekaterina Postovalova, Jochen K Lennerz, Funda Meric-Bernstam, Alexander Bagaev

Faculty, Staff and Student Publications

This study aimed to assess the correlation between RNA sequencing (RNA-seq) and immunohistochemistry (IHC) in detecting key cancer biomarkers across solid tumors, and then, to establish RNA-seq thresholds that accurately reflect clinical IHC classifications. Expression levels of nine biomarkers-ESR1, PGR, AR, MKI67, ERBB2, CD274, CDX2, KRT7, and KRT20-were analyzed in 365 formalin-fixed, paraffin-embedded samples from breast, lung, gastrointestinal, and other solid carcinomas. Correlations between RNA-seq data and IHC scores were determined using Spearman's correlation coefficients, with RNA-seq cut-offs established to distinguish positive from negative IHC scores. The results revealed strong correlations for most biomarkers, with coefficients ranging from 0.53 to …