Digital Commons Network^™

Implementation Of A Package Of Emergency Care Interventions And Clinical Outcomes, Corey B Bills, Paul Wesseh, Catherine Cooper, Taylor W Burkholder, Lane Epps, Michael Jaung, Emilie J Calvello Hynes, Alex Mayah, John K Shakpeh, Kayla Enriquez

Faculty, Staff and Students Publications

Importance: Investments in emergency care systems are vital to ensuring universal health coverage and improving health outcomes in low- and middle-income countries.

Objective: To assess whether a package of emergency care interventions is associated with improved patient mortality and clinical care quality.

Design, setting, and participants: This pre-post quality improvement study was conducted at a single urban referral hospital emergency unit (EU) in Monrovia, Liberia, to assess clinical and educational outcomes resulting from the implementation of a package of interventions from January 1, 2018, through June 30, 2019. Final analysis was performed in November 2023. Data from a random subset …

Natriuretic Peptide Cut Points For Heart Failure Classification In Individuals With And Without Obesity, Mandana Chitsazan, Juhi K Parekh, Leah B Kosyakovsky, Sophie M Nemeth, Emily S Lau, James L Januzzi, Thomas J Wang, Daniel Levy, Chiadi E Ndumele, Elizabeth Selvin, Christie M Ballantyne, Bruce M Psaty, John S Gottdiener, Jorge R Kizer, Christopher R Defilippi, Norrina B Allen, Rudolf A De Boer, Sanjiv J Shah, Jennifer E Ho

Faculty, Staff and Students Publications

Background: The 2022 American Heart Association/American College of Cardiology/Heart Failure Society of America guidelines introduced elevated natriuretic peptide (NP) levels as a criterion for defining stage B heart failure (HF), or pre-HF, to identify individuals at greatest risk for future HF. Given the known NP deficiency in obesity, we aimed to assess whether a single NP cut point would disproportionately up-classify individuals with versus without obesity to stage B HF.

Methods: Participants free of HF from 5 community-based cohorts were included. We examined the reclassification of individuals to stage B HF using the 2022 versus 2013 guidelines, stratified by obesity …

Pan-Uk Biobank Genome-Wide Association Analyses Enhance Discovery And Resolution Of Ancestry-Enriched Effects, Konrad J Karczewski, Rahul Gupta, Masahiro Kanai, Wenhan Lu, Kristin Tsuo, Ying Wang, Raymond K Walters, Patrick Turley, Shawneequa Callier, Nirav N Shah, Nikolas Baya, Duncan S Palmer, Jacqueline I Goldstein, Gopal Sarma, Matthew Solomonson, Nathan Cheng, Sam Bryant, Claire Churchhouse, Caroline M Cusick, Timothy Poterba, John Compitello, Daniel King, Wei Zhou, Cotton Seed, Hilary K Finucane, Mark J Daly, Benjamin M Neale, Elizabeth G Atkinson, Alicia R Martin

Faculty, Staff and Students Publications

Large biobanks, such as the UK Biobank (UKB), enable massive phenome by genome-wide association studies that elucidate genetic etiology of complex traits. However, individuals from diverse genetic ancestry groups are often excluded from association analyses due to concerns about population structure introducing false positive associations. Here, we generate mixed model associations and meta-analyses across genetic ancestry groups, inclusive of a larger fraction of the UKB than previous efforts, to produce freely-available summary statistics for 7,266 traits. We build a quality control and analysis framework informed by genetic architecture. Overall, we identify 14,676 significant loci (p < 5 × 10−8) in the meta-analysis that were not found in the EUR genetic ancestry group alone, including novel associations for example between CAMK2D and triglycerides. We also …

Adeno-Associated Virus-Mediated Silencing Of Sox4 Leads To Long-Term Amelioration Of Liver Phenotypes In Mouse Models Of Alagille Syndrome, Duncan Fox, Jun Xie, Jennifer L Burwinkel, Josh M Adams, Kashish Chetal, Marzieh Keivandarian, Yaniv Faingelernt, Sanjay Subramanian, Mario F Lopez, Anna L Peters, Nathan Salomonis, Neda Zarrin-Khameh, Guangping Gao, Stacey S Huppert, Hamed Jafar-Nejad

Faculty, Staff and Students Publications

Background & aims: In patients with Alagille syndrome (ALGS), bile duct paucity often leads to severe cholestatic phenotypes for which liver transplantation remains the only definitive treatment. No Food and Drug Administration-approved mechanism-based strategies exist to enhance biliary development in ALGS or other diseases with bile duct paucity. We aimed to identify a therapeutic target to address this unmet need.

Methods: Preclinical ALGS mouse models lacking 1 copy of Jag1 with or without conditional deletion of 1 or both copies of Sox9 were used. Sox4 levels were reduced genetically or with adeno-associated virus 8 (AAV8) vectors driving a Sox4-silencing sequence. …

Germline Cancer Predisposition Results From The National Cancer Institute-Children's Oncology Group Pediatric Match Trial, Sarah Scollon, Sharon E Plon, Steven Joffe, Jaclyn A Biegel, Shashikant Kulkarni, George Miles, David R Patton, Brent Coffey, Cynthia L Winter, Gregory J Tsongalis, Mark J Routbort, Nilsa C Ramirez, Lauren Saguilig, Jin Piao, Todd A Alonzo, Stacey L Berg, Elizabeth Fox, Brenda Weigel, Douglas S Hawkins, Jeffrey S Abrams, Margaret Mooney, Naoko Takebe, James V Tricoli, Katherine A Janeway, Nita L Seibel, D Williams Parsons

Faculty, Staff and Students Publications

Purpose: Precision oncology trials have generally focused on tumor testing to identify actionable alterations. The National Cancer Institute-Children's Oncology Group Pediatric MATCH trial incorporated return of germline results to assess feasibility of reporting in a cooperative group setting and characterize germline cancer predisposition in patients with refractory cancers.

Patients and methods: Tumor and blood DNA from patients 1-21 years of age with treatment-refractory solid tumors, non-Hodgkin lymphomas, or histiocytic disorders underwent cancer gene panel sequencing. Clinical germline reports returned to 151 study sites included pathogenic/likely pathogenic (P/LP) germline variants found in 38 cancer predisposition genes (CPGs). European Society of Medical …

Bi-Allelic Loss-Of-Function Variants In Poc5 Cause A Syndromic Retinal, Endocrine, And Neuromuscular Ciliopathy, Anneke T Vulto-Van Silfhout, Ingrid M Jazet, Suzanne Yzer, Jeroen Pas, Serwet Demirdas, Elisabeth F C Van Rossum, Alberta A H J Thiadens, Ronald Van Beek, Lonneke Haer-Wigman, Daniela Q C M Barge-Schaapveld, Charlotte Brasch-Andersen, Simon Frost, Miriam Bauwens, Elfride De Baere, Irina Balikova, Filip Van Den Broeck, Monika Weisz-Hubshman, Pascal Joset, Peter Miny, Isabel Filges, Susanne Kohl, Pietro De Angeli, Laura Kühlewein, Jan-Philipp Bodenbender, Tobias Haack, Karin Poths, Lidia Fernandez-Caballero, Marta Corton, Fiona Blanco Kelly, Carmen Ayuso, Peggy Martínez-Esteban, John Vissing, Jordi Díaz-Manera, Volker Straub, Ana Töpf, Siying Lin, Gavin Arno, William L Macken, Jennifer Spillane, Radha Ramachandran, Erik De Vrieze, Tjakko Van Ham, Susanne Roosing, Machteld M Oud

Faculty, Staff and Students Publications

Purpose: A homozygous loss-of-function (LoF) variant in POC5 was previously described in an individual with retinitis pigmentosa. We identified POC5 variants in 12 probands with a syndromic phenotype. We aim to define the phenotype spectrum and molecular mechanism associated with biallelic POC5 LoF variants.

Methods: We studied a cohort of 12 families with bi-allelic LoF POC5 variants and performed detailed phenotype analysis. POC5 localization studies were performed in 3 proband-derived fibroblast cell lines.

Results: Detailed phenotyping of probands with POC5 variants expands the phenotype spectrum beyond ocular manifestations. This syndrome causes not only rod-cone dystrophy but also diabetes mellitus with …

Hydrogen Sulfide Inhibits Recruitment Of Monocyte-Derived Tumor Associated Macrophages In Glioblastoma By Downregulating Cxcl12, Joseph Camarano, Morgan Roque, Gabrielle Gahn, Stephen Garrett Whipple, Danielle Terrell, Charles Ronkon, Jamie Toms, Anthony Sin, Bharat Guthikonda, Khatri Latha, Yuhui Yang, Xinggui Shen, Christopher G Kevil, Ganesh Rao, Sungho Lee

Faculty, Staff and Students Publications

Tumor associated macrophages (TAMs) directly contribute to the dismal prognosis of glioblastoma by preventing anti-tumor immunity and promoting tumor invasion and angiogenesis. Inhibiting TAM infiltration is a potential therapeutic strategy in glioblastoma, with several chemokine antagonists in early clinical development. Hydrogen sulfide, a gasotransmitter that regulates microglial accumulation in a wide range of CNS diseases, may be a novel therapeutic target to prevent TAM recruitment in glioblastoma. In this study, hydrogen sulfide concentrations were directly measured from 14 isocitrate dehydrogenase (IDH)-wildtype glioblastoma surgical samples and compared against overall survival as well as expression of TAM markers and chemokines. Effects of …

Corneal Sensory Nerve Regulation Of Tear Production Through Stimulation Of Transient Receptor Potential Melastatin 8 (Trpm8) Channel: A Potential New Approach For Treating Dry Eye Disease, Juana Gallar, Stephen Pflugfelder, Anat Galor, Preeya K Gupta, Pedram Hamrah

Faculty, Staff and Students Publications

The lacrimal functional unit (LFU) tightly controls the secretion of all tear components, thus playing a critical role in maintaining ocular surface homeostasis. Forming an exquisitely sensitive neural network across the ocular surface, corneal sensory nerves detect environmental stimuli (e.g., temperature, chemicals, and mechanical pressure) through transient receptor potential (TRP) ion channels. Among these, TRP melastatin 8 (TRPM8) is a key regulator of basal tear production. Stimulated by the small temperature reductions and tear film osmolarity increases that arise due to evaporative cooling, TRPM8 activates the LFU, leading to increased basal tear production. Here, we focus on reviewing the topical …

A Narrative Review Of The Ileal Pouch In Pediatric Inflammatory Bowel Disease And Familial Adenomatous Polyposis, Anitta Philip, Allyson Wyatt, Jose R Rodriguez, Brad Pasternak, Lisa Mcmahon, Kalyani Patel, Richard Kellermayer

Faculty, Staff and Students Publications

Ileal pouch-anal anastomosis is a surgical intervention in patients with medically refractory inflammatory bowel disease and familial adenomatous polyposis syndrome. Reported outcomes in children have been limited by both the retrospective nature and sample size of the investigations. In addition, there is a lack of consensus on surveillance guidelines in this patient population. Delay or lack of surveillance may increase the risk of complications (pouchitis, Crohn's disease-like inflammation, dysplasia, etc.). This narrative review aims to summarize the most recent literature (2013-2023) on short-term, long-term, and quality of life (QoL) outcomes in pediatric ileal pouch (J-pouch) patients. A proposed surveillance guidance …

Characterizing Measurement-Based Care In The Texas Youth Depression And Suicide Research Network (Tx-Ydsrn), Holli Slater, Yasmin Alzubi, Afsaneh Rezaeizadeh, Jennifer L Hughes, April Gorman, Taryn L Mayes, Joshua S Elmore, Eric A Storch, Sarah M Wakefield, Madhukar H Trivedi

Faculty, Staff and Students Publications

Integration of measurement-based care (MBC) into clinical practice has shown promise in improving treatment outcomes for depression. Yet, without a gold standard measure of MBC, assessing fidelity to the MBC model across various clinical settings is difficult. A central goal of the Texas Youth Depression and Suicide Research Network (TX-YDSRN) was to characterize MBC across the state of Texas through the development of a standardized tool to assess the use of MBC strategies when assessing depression, anxiety, side effects, and treatment adherence. A chart review of clinical visits indicated standardized depression measures (71.2%) and anxiety measures (64%) were being utilized …

Treatment-Related Adverse Events And Associated Outcomes In Patients With Advanced Urothelial Carcinoma Treated With Enfortumab Vedotin: Analysis Of The Unite Study, Amanda Nizam, Charles B Nguyen, Jinju Li, Emily C Zabor, Pavlos Msaouel, Cindy Y Jiang, Omar Alhalabi, Eugene Oh, Matthew P Davidsohn, Ilana B Epstein, Dimitra Rafailia Bakaloudi, Rafee Talukder, Tanya Jindal, Amy K Taylor, Michael J Glover, Ali Raza Khaki, Emily Lemke, Hannah Mabey, Bashar Abuqayas, Albert Jang, Jason R Brown, Sean T Evans, Cameron Pywell, Arnab Basu, Mehmet A Bilen, Pedro C Barata, Yousef Zakharia, Matthew I Milowsky, Deepak Kilari, Christopher J Hoimes, Sumit A Shah, Hamid Emamekhoo, Nancy B Davis, Shilpa Gupta, Petros Grivas, Joaquim Bellmunt, Matthew T Campbell, Ajjai S Alva, Vadim S Koshkin

Faculty, Staff and Students Publications

Introduction: Enfortumab vedotin-ejfv (EV), an antibody-drug conjugate approved for advanced urothelial carcinoma (aUC), has limited real-world safety data and no validated predictive biomarkers. Retrospective studies suggest higher objective response rates (ORR) among patients developing EV-related dermatologic toxicities, but survival implications remain unclear. This analysis assessed the safety of EV monotherapy and the impact of dermatologic and neurologic toxicities on efficacy outcomes in a multi-institutional cohort.

Materials and methods: UNITE is a multicenter, retrospective study across 16 US sites of patients with aUC treated with targeted agents, including EV. Primary endpoints were the incidence of EV treatment-related adverse events (TRAEs, any …

Nonprofit Hospital Ceo Compensation: Does Quality Matter?, Derek Jenkins, Marah Short, Vivian Ho

Faculty, Staff and Students Publications

Background: Past research has documented that increases in profits and health system size, as well as increases in the reward generosity for improving these metrics play an important role in explaining increases in nonprofit hospital CEO pay between 2012 and 2019.

Objectives: To test whether hospital quality measures play a supplemental role in determining CEO pay.

Research design: We estimated linear regressions for 2012 and 2019 of the log of CEO wages on system or independent hospital characteristics, including quality. The regressions were used to construct a Oaxaca decomposition of factors associated with CEO compensation.

Subjects: One thousand forty-seven nonprofit …

Prostaglandin E2 As A Mechanistic Biomarker Of Chronic Pancreatitis, Jami L Saloman, Bahiyyah Jefferson, Samuel Han, William E Fisher, Evan L Fogel, Phil A Hart, Liang Li, Walter G Park, Santhi Swaroop Vege, Dhiraj Yadav, Mark D Topazian, Darwin L Conwell

Faculty, Staff and Students Publications

Introduction: Chronic pancreatitis (CP) is a disease associated with chronic inflammation, fibrosis, and pain. There is a lack of tools available that facilitate early diagnosis, when intervention could prevent irreversible damage. Pilot data suggested prostaglandin E2 (PGE2) as a candidate biomarker for early CP. PGE2 activates signaling pathways that promote inflammation, pain, and fibrosis.

Methods: We assessed PGE2, metabolites, and downstream targets in pancreatic fluid collected endoscopically 0-10 (n = 110) and 10-20 (n = 111) minutes after intravenous secretin administration. PGE2 and metabolites were measured in plasma (n = 75) and urine (n = 71) from the same subjects. …

Covid-19 Booster Vaccine Messaging In Emergency Departments: A Cluster Randomized Clinical Trial, Melanie F Molina, Stephanie A Eucker, Kristin L Rising, Efrat R Kean, Zubaid Rafique, Heba Mesbah, David V Glidden, Mireya I Arreguin, Christopher Alvarez, Robert M Rodriguez

Faculty, Staff and Students Publications

Importance: Patient uptake of updated COVID-19 vaccines is crucial for reducing severe outcomes, yet national uptake remains low.

Objective: To determine if tailored messaging or simple inquiry about vaccine acceptance increases 30-day uptake of updated COVID-19 vaccines among emergency department (ED) patients.

Design, setting, and participants: This 3-arm, cluster randomized clinical trial conducted from January 29 to June 18, 2024, enrolled adult ED patients who had not received a COVID-19 vaccine in the prior 6 months across 6 EDs in San Francisco, California; Philadelphia, Pennsylvania; Houston, Texas; and Durham, North Carolina.

Interventions: Intervention M involved tailored messaging about updated COVID-19 …

Associations Of High Attenuation Area-Related Proteomic Biomarkers With Fibrotic Or Subpleural Interstitial Lung Abnormalities, John S Kim, Catherine L Debban, Daniel E Guzman, Riley T Hannan, Mary Salvatore, Claire Mcgroder, David Zhang, Anna J Podolanczuk, Daniel A Duprez, Shwu-Fan Ma, Yong Huang, Jeffrey M Sturek, Stephen S Rich, Jerome I Rotter, Rajat Deo, Ruth F Dubin, Janelle Vu Pugashetti, Jennifer M Wang, Meilan K Han, Justin M Oldham, Imre Noth, Prescott G Woodruff, Victor E Ortega, Julie C Fanburg-Smith, Edward B Stelow, Christopher A Moskaluk, Eric A Hoffman, Christine Kim Garcia, Russell P Bowler, Peter Ganz, R Graham Barr, Ani Manichaikul

Faculty, Staff and Student Publications

No abstract provided.

Molecular And Genetic Landscapes Of Retina And Brain Microglia In Neurodegenerative Diseases, Khang Ma, Rinki Ratnapriya

Faculty, Staff and Students Publications

Microglia-driven dysregulation has emerged as a significant underlying mechanism in many neurodegenerative diseases, such as age-related macular degeneration (AMD) and Alzheimer's disease (AD). Although both brain and retinal microglia originate from the yolk sac, it is uncertain whether they share molecular similarities or genetic and molecular foundations related to neurodegenerative diseases. In this study, we examine the transcriptomic and epigenetic profiles of retina and brain microglia through integrative analyses of single-nucleus RNA sequencing (snRNA-seq) and single-nucleus ATAC sequencing (snATAC-seq) from 97 independent human samples across 11 different studies. Our findings reveal that retina and brain microglia share similar expression and …

Transdiagnostic Correlates Of Family Accommodation In Anxious Youth, Whitney S Shepherd, Erika S Trent, Orri Smarason, Hannah N Sansone, Daphne M Ayton, Amanda Palo, Abigail E Candelari, Wayne K Goodman, Andrew G Guzick, Eric A Storch

Faculty, Staff and Students Publications

Anxiety disorders are common in children and cause significant impairment. Family accommodation, which refers to behavioral changes that family members make to temporarily alleviate a child’s anxiety, has been linked to child anxiety symptom severity. Although emotional vulnerabilities for anxiety such as emotion dysregulation, anxiety sensitivity, and distress intolerance have been associated with family accommodation, research concerning the relationship between these constructs among anxious youth is limited. We hypothesized that these variables would be uniquely and positively associated with family accommodation and would moderate the relationship between anxiety symptom severity and family accommodation. Treatment-seeking child–parent dyads (N = 90; …

Htlv-1 And Atll: Epidemiology, Oncogenesis, And Opportunities For Community-Informed Research In The United States, Adrian D. Altieri, Sean P. Reilly, Abu Mansalay, Alan Khoo, Nettie Johnson, Zafar K. Khan, Amy Leader, Pooja Jain, Pierluigi Porcu

Kimmel Cancer Center Faculty Papers

Human T-cell leukemia virus type 1 (HTLV-1), the first oncogenic human retrovirus, causes adult T-cell leukemia/lymphoma (ATLL), an aggressive neoplasm of mature CD4+ T-cells that is incurable in most patients and is associated with a median survival of less than 1 year. HTLV-1 also causes inflammatory disorders, including HTLV-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and uveitis. The estimated lifetime risks of ATLL and HAM/TSP in HTLV-1 carriers are 3-5% and 0.25-1.8%, respectively. Although there is uncertainty about other health effects of HTLV-1, a recent meta-analysis showed an association between HTLV-1 and cardiovascular, cerebrovascular, and metabolic diseases and a 57% increased risk …

Development Of A Leucine-Rich Repeat-Containing Protein 15-Targeted Radio-Immunotheranostic Approach To Deplete Pro-Tumorigenic Mechanisms And Immunotherapy Resistance, Claire M Storey, Abbie Hasson, Diane Abou, Daniel Thorek, Et Al.

2020-Current year OA Pubs

Leucine-rich repeat containing 15 (LRRC15) has emerged as an attractive biomarker and target for cancer therapy. Transforming growth factor-β (TGFβ) induces the expression of this plasma membrane protein specifically in aggressive and treatment resistant tumor cells derived from mesenchymal stem cells, with minimal expression observed in non-neoplastic tissues. We have developed a humanized monoclonal antibody, DUNP19, that specifically binds with high affinity to a phylogenetically conserved LRRC15 epitope and is rapidly internalized upon LRRC15 binding. In multiple subcutaneous and orthotopic tumor xenograft mouse models, Lutetium-177 labeled DUNP19 ([

The Critical Human Pathogen Acinetobacter Baumannii Exhibits Light-Regulated Circadian Rhythms, Valentín Permingeat, Bárbara Edith Perez Mora, María Laura Migliori, Natalia Arana, Julia Fernández, María Belén Allasia, Melisa Luciana Lamberti, Gisela Di Venanzio, Ramiro Esteban Rodriguez, Mario Federico Feldman, Diego Andrés Golombek, María Alejandra Mussi

2020-Current year OA Pubs

Acinetobacter baumannii is recognized as the paradigm of multidrug-resistant superbug, topping the WHO priority list of critical human pathogens. Interestingly, it senses and responds to blue light, which modulates global aspects of its physiology, including pathogenicity. We hypothesized that light could serve as a signal to synchronize the bacterial physiology to the host's behavior and/or to the environment. At environmental temperatures, light regulation is mainly governed by the photoreceptor BlsA. In this work, we identified the existence of daily rhythms in blsA promoter activity displaying a robust response to light, as well as endogenous circadian rhythms in A. baumannii. In …

Ebola Virus Vp35 Nnlns Motif Modulates Viral Rna Synthesis And Mib2-Mediated Signaling, Grace Uwase, Priya Luthra, Olivia A Vogel, Jyoti Batra, Bruno A La Rosa, Kathleen C F Sheehan, Oam Khatavkar, Jacqueline E Payton, Robert A Davey, Nevan J Krogan, Christopher F Basler, Daisy W Leung, Gaya K Amarasinghe

2020-Current year OA Pubs

Ebola virus (EBOV) is a nonsegmented, negative-sense virus (NNSV) with a single-stranded RNA genome. EBOV encodes for a limited number of proteins and thus depends on host factors to facilitate viral replication and pathogenesis. Of the virus-encoded proteins, multifunctional EBOV VP35 (eVP35) is necessary for host immune evasion and viral RNA synthesis. Previous proteomics studies identified an interaction between eVP35 and the host E3 ubiquitin ligase Mindbomb 2 (MIB2). Here, we show how an NNLNS (Asn-Asn-Leu-Asn-Ser) motif (residues 201 to 205) within eVP35 serves as a binding site for MIB2. This motif is critical for eVP35-dependent inhibition of MIB2-mediated interferon …

Life-Moms: Effects Of Multicomponent Lifestyle Randomized Control Trial On Physical Activity During Pregnancy In Women With Overweight And Obesity, Hannah E Cabre, Debra Haire-Joshu, Alison G Cahill, Samuel Klein, Et Al.

2020-Current year OA Pubs

BACKGROUND: This report details the effect of LIFE-Mom's multicomponent lifestyle interventions on physical activity (PA) and inactivity time across pregnancy (2nd and 3rd trimesters) and their effect on gestational weight gain (GWG) and maternal/neonatal outcomes, a pre-specified secondary analysis.

METHODS: Pregnant people with BMI ≥ 25 kg/m

RESULTS: Although there were statistically significant differences in vigorous activity between the intervention and control group (p = .024), there were no clinically meaningful differences in PA. In the combined sample, moderate to vigorous PA (MVPA) significantly decreased across pregnancy (mean ± SD: 72.9 ± 29.1 min/day vs 63.9 ± 28.1 min/day; p …

Design And Application Of A Tau Seed Amplification Assay For Screening Inhibitors Of Tau Seeding, Damian Gorski, Haley Evans, Tyler Allison, Carla Barria, Danielle Harrison, Victor Banerjee, Nicolas Mendez, Mohammad Shahnawaz, Sanne Kaalund, Jonas Folke, Susana Aznar, Paul Schultz, Fei Wang, Claudio Soto

Faculty, Staff and Student Publications

Background: Tau protein aggregates are a key pathological hallmark of Alzheimer's disease (AD) and are closely associated with cognitive decline and neurodegeneration. It is proposed that tau aggregates faithfully propagate throughout the brain by self-templating their disease-associated conformation onto natively-folded tau monomers, thereby inducing their aggregation and incorporation into growing fibrils. As such, the inhibition or modulation of tau seeding and aggregation represents a viable therapeutic strategy for AD and other tauopathies.

Methods: We have recently developed seed amplification assays (SAA) for the detection and amplification of small quantities of misfolded protein aggregates in various neurodegenerative diseases. In this article, …

Cyp1b1 Mediates Cigarette Smoke-Induced Lipid Accumulation In Alveolar Type 2 Cells, Yin Zhu, Siddhika Gamare, Francesca Polverino, Caroline A Owen, Payaningal R Somanath, Xiaoyun Wang, Duo Zhang

Faculty, Staff and Students Publications

Alterations in lipid profiles have been shown in patients with chronic obstructive pulmonary disease (COPD), but the underlying molecular mechanisms remain unclear. In this study, we aimed to investigate the role of cytochrome P450 family-1 subfamily B member 1 (CYP1B1) in cigarette smoke (CS)-induced lipid accumulation in alveolar type II epithelial (AT2) cells. We observed a steady increase in CYP1B1 protein levels in AT2 cells from COPD patients. Additionally, CS exposure induced CYP1B1 expression in AT2 cells of murine lungs. In vitro, treatment with cigarette smoke extract (CSE) not only upregulated CYP1B1 expression but also triggered lipid accumulation in AT2-like …

Cookie-Pro: Covalent Inhibitor Binding Kinetics Profiling On The Proteome Scale, Hanfeng Lin, Bin Yang, Lang Ding, Yen-Yu Yang, Matthew V Holt, Sung Yun Jung, Bing Zhang, Meng C Wang, Jin Wang

Faculty, Staff and Students Publications

Covalent inhibitors are an emerging class of therapeutics, but methods to comprehensively profile their binding kinetics and selectivity across the proteome have been limited. Here we introduce COOKIE-Pro (COvalent Occupancy KInetic Enrichment via Proteomics), an unbiased method for quantifying irreversible covalent inhibitor binding kinetics on a proteome-wide scale. COOKIE-Pro uses a two-step incubation process with mass spectrometry-based proteomics to determine kinact and KI values for covalent inhibitors against both on-target and off-target proteins. We validated COOKIE-Pro using BTK inhibitors spebrutinib and ibrutinib, accurately reproducing known kinetic parameters and identifying both expected and unreported off-targets. The method revealed that …

Engineered Exosomes With Krasg12d Specific Sirna In Pancreatic Cancer: A Phase I Study With Immunological Correlates, Valerie S Kalluri, Brandon G Smaglo, Krishnan K Mahadevan, Michelle L Kirtley, Kathleen M Mcandrews, Mayela Mendt, Sujuan Yang, Ana S Maldonado, Hikaru Sugimoto, Maria E Salvatierra, Luisa M Solis Soto, Cara Haymaker, Rick Finch, Mihai Gagea, Adam C Fluty, Steven J Ludtke, J Jack Lee, Abhinav K Jain, Gauri Varadhachary, Rachna T Shroff, Anirban Maitra, Elizabeth Shpall, Shubham Pant, Raghu Kalluri

Faculty, Staff and Students Publications

Oncogenic KRAS is amongst the key genetic drivers for initiation and maintenance of pancreatic ductal adenocarcinoma (PDAC). Here, we show that engineered exosomes with KrasG12D specific siRNA (iExoKrasG12D) reveal a biodistribution in pancreas with negligible toxicity in preclinical studies in mice and Rhesus macaques. Clinical testing of iExoKrasG12D in the iEXPLORE (iExoKrasG12D in Pancreatic Cancer) Phase I study employed a non-randomized single-arm classical 3 + 3 dose escalation design (Phase Ia), followed by an accelerated titration design (Phase Ib) (NCT03608631). The primary outcomes included safety, tolerability and target engagement, and the secondary outcomes aimed to assess disease control. …

Enhancing Stemm Education Through Advanced Technologies And Collaborative Programs, Zhongcheng Shi, Michael Nguyen, Yuan Yao, Debra D Murray, Rayne H Rouce, Veronica Ajewole, Huan Xie, Shixia Huang

Faculty and Staff Publications

Integrating advanced technologies into STEMM (Science, Technology, Engineering, Mathematics, and Medicine) education is essential for preparing a future-ready, diverse scientific workforce capable of addressing complex global challenges. This paper presents three interconnected programs-BRITE (Biotechnology Research Incubator for Teachers), ASPIRATION (AI-guided Scientist-Mentored Primary Literature Adaptation for STEMM Education), and C-REP (Cancer Research Education Program)-developed through collaborations with Advanced Technology Cores and multi-institutional participation, involving mentors ranging from core directors to graduate and medical students. While initially supported by internal funding, two of these initiatives have since secured NIH grant support. These initiatives provide immersive, hands-on training in genomics, proteomics, metabolomics, flow …

Uncovering The Pml::Rara Fusion In Cytogenetically Cryptic And Fish-Negative Acute Promyelocytic Leukemia-A Case Report And Comprehensive Literature Review, Busra Delikkaya, Jaime Eberle-Singh, Arianna Morton, Jerald Gong, Jinglan Liu

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

The PML::RARA fusion resulting from t(15;17) is the genetic hallmark of acute promyelocytic leukemia (APL), typically detected by cytogenetics and/or fluorescence in situ hybridization (FISH) studies. Rarely, APL patients present with normal cytogenetics and FISH findings, complicating diagnosis and delaying life-saving therapy. We report a 23-year-old male with clinical, morphologic and immunophenotypic features consistent with APL but negative for FISH studies. Despite prompt initiation of all-trans retinoic acid (ATRA) based on clinical suspicion, the patient succumbed to intracranial hemorrhage. Quantitative reverse transcriptase PCR (qRT-PCR) confirmed a long isoform PML::RARA fusion. A review of 34 published cytogenetics- and FISH-negative cases since …

Economics Of Corneal Cross-Linking For Keratoconus Treatment, Christopher J. Rapuano, Richard L. Lindstrom, Eric Donnenfeld, John P. Berdahl, Vance Thompson, David Kratochvil, John Carter

Wills Eye Hospital Papers

AIM: To optimize the real-world applicability of a health economic model estimating the cost-effectiveness of corneal cross-linking for the treatment of keratoconus in the United States.

MATERIALS AND METHODS: A previously reported discrete-event simulation (DES) model was adapted to reassess the cost-effectiveness of corneal cross-linking (CXL) from the US payer perspective. The simulation of keratoconus progression, which is a key driver of model outcomes, was remodeled to more accurately reflect the real-world relationship between age and the rate of disease progression. All costs were updated to reflect 2025 values. We simulated 4,000 eyes of 2,000 patients diagnosed with keratoconus to …

Serum Endotrophin Relates To Blood Pressure In Young South Asian Women But Not White Women: Evidence Of Ethnic Variation In Its Early Vascular Implications, Ravi Retnakaran, Dawei Bu, Jiajie Pu, Philip W Connelly, Anthony J Hanley, Ningyan Zhang, Zhiqiang An, Bernard Zinman, Philipp E Scherer

The Brown Foundation: Institute of Molecular Medicine

BACKGROUND: Endotrophin is a novel circulating fibroinflammatory protein that has recently been associated with cardiovascular disease (CVD) and all-cause mortality. However, little is known about its role early in the natural history of vascular disease nor whether it exhibits ethnicity-specific variation. Recognizing that South Asians have an elevated risk of ultimately developing CVD, we sought to address these questions by characterizing endotrophin and its physiologic correlates in young South Asian women as compared to White women.

METHODS: From a cohort recruited in pregnancy and followed to 1-year after delivery, we identified 40 participants of South Asian descent and 40 age- …