Medical Specialties Commons^™

Pfas Exposure And Postoperative Weight Regain In Adolescents After Bariatric Surgery: Findings From The Teen-Labs Study, Brittney O Baumert, Elizabeth Costello, Zhenjiang Li, Justin R Ryder, Thomas Inge, Todd Jenkins, Stephanie Sisley, Stavra A Xanthakos, Douglas I Walker, Nikos Stratakis, Damaskini Valvi, Scott M Bartell, Angela L Slitt, Rohit Kohli, Sarah Rock, Michele A La Merrill, Sandrah P Eckel, Max T Aung, Rob Mcconnell, David V Conti, Lida Chatzi

Faculty, Staff and Students Publications

Objective: Weight regain following bariatric surgery remains a clinical challenge, with limited understanding of contributing environmental factors. Per- and polyfluoroalkyl substances (PFAS), persistent chemicals linked to metabolic dysfunction, may influence long-term weight trajectories. This study aimed to evaluate associations between PFAS exposure and changes in BMI, percent weight loss, and waist circumference among adolescents after bariatric surgery.

Methods: We included 186 adolescents (mean age: 17.1 years; 76.3% female; 72.0% White) from the Teen-Longitudinal Assessment of Bariatric Surgery (Teen-LABS) cohort who underwent surgery between 2007 and 2012. Anthropometric measurements were collected at baseline and 6, 12, 36, and 60 months post …

Carbonic Anhydrase Inhibition Sensitizes Group 3 Medulloblastoma To Radiotherapy, Cory M Richman, Alexandra Rasnitsyn, Borja L Holgado, Maria Vladoiu, Namal Abeysundara, Sandra Majo, Sara Chabi, Lucie J Taunay, Hiromichi Suzuki, Ichiyo Shibahara, Joonas Haapasalo, Jonelle G Pallotta, Tajana Douglas, Kaitlin Kharas, Kyle Juraschka, Oliver Ocsenas, Sachin A Kumar, Kristiina Nordfors, Ana Guerreiro Stücklin, Raul A Suarez, Jiao Zhang, Xiaochong Wu, Craig Daniels, Livia Garzia, Jüri Reimand, Olivier Saulnier, Thomas E Merchant, Celio Pouponnot, David R Raleigh, Michael D Taylor, Pasqualino De Antonellis

Faculty, Staff and Students Publications

Group 3 (G3) medulloblastoma constitutes the most aggressive molecular subgroup, and nearly all patients present with metastases upon recurrence. Treatment for newly diagnosed medulloblastoma relies on a combination of maximal safe surgical resection, followed by chemotherapy and ionizing radiation, and no therapies have been shown to confer a survival benefit at the time of recurrence. Given the limited therapeutic options available for patients with medulloblastoma, especially at recurrence, and the incomplete understanding of the molecular mechanisms underlying resistance to treatment, we sought to uncover actionable targets and biomarkers that could help refine patient selection and treatment of newly diagnosed medulloblastoma …

Alternative Polyadenylation Contributes To Fibroblast Senescence In Pulmonary Fibrosis, Jingjing Huang, Maria Jose Gacha-Garay, Yu Wang, Scott D Collum, Rene A Girard, Hydia Puente, Seung-Hee Yoo, Rahat Hussain, Jayeshkumar Patel, Manish Patel, Eric J Wagner, Hari Krishnayalamanchili, Harry Karmouty-Quintana, Zheng Chen, Tingting Mills

Faculty, Staff and Students Publications

Idiopathic pulmonary fibrosis (IPF) is a prevalent and deadly age-related disease characterized by chronic, progressive, and irreversible fibrosis. A key effector cell population in the fibroproliferative response is the fibroblasts. Fibroblast cell senescence gradually worsens during aging, and the acquisition of a senescence-associated secretory phenotype (SASP) turns senescent fibroblasts into pro-inflammatory cells. However, the mechanism promoting senescence in IPF, especially at the post-transcriptional level, is poorly understood. We recently discovered that Nudix Hydrolase 21 (NUDT21, also named CFIm25), an RNA-binding protein, plays a critical role in regulating the expression of SASP factors through alternative polyadenylation (APA). APA allows adding poly(A) …

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 …

Analyzing The Learning Curve Of Vnotes Sacrocolpopexy By The Cumulative Summation Test: A Cohort Study, Wenyu Liu, Nannan Sun, Yuejiao Zhang, Yuyan Li, Weihao Lai, Youjun Zhou, Xiaoming Guan, Juan Liu

Faculty, Staff and Students Publications

Background: The learning curve of transvaginal natural orifice transluminal endoscopic sacrocolpopexy (vNOTES-SC) in the treat of pelvic organ prolapse (POP) is critical yet underexplored. Our objective is to describe the learning curve and surgical complications of vNOTES-SC, taking into account the factors that affect operative time and evaluate the long-term follow-up outcomes of this surgery.

Methods: We conducted a hospital-based cohort study involving patients who underwent vNOTES-SC from June 2017 to May 2024. All surgeries were performed by a single surgeon with over 20 years of surgical experience. This study employed cumulative summation test (CUSUM) analysis to quantify the learning …

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 …

Post-Deployment Monitoring Of Ai Performance In Intracranial Hemorrhage Detection By Chatgpt, Eric Rohren, Mohadese Ahmadzade, Sofia Colella, Nina Kottler, Sriyesh Krishnan, Jason Poff, Neelesh Rastogi, Walter Wiggins, Joyce Yee, Carlos Zuluaga, Phil Ramis, Mohammad Ghasemi-Rad

Faculty, Staff and Students Publications

Rationale and objectives: To evaluate the post-deployment performance of an artificial intelligence (AI) system (Aidoc) for intracranial hemorrhage (ICH) detection and assess the utility of ChatGPT-4 Turbo for automated AI monitoring.

Materials and methods: This retrospective study evaluated 332,809 head CT examinations from 37 radiology practices across the United States (December 2023-May 2024). Of these, 13,569 cases were flagged as positive for ICH by the Aidoc AI system. A HIPAA (Health Insurance Portability and Accountability Act) -compliant version of ChatGPT-4 Turbo was used to extract data from radiology reports. Ground truth was established through radiologists' review of 200 randomly selected …

Using Latent Patient-Centered Fear Extinction Profiles To Guide Treatment In Pediatric Ocd, Katherine M Ingram, Eric A Storch, Daniel A Geller, Brent J Small, Sabine Wilhelm, Joseph F Mcguire

Faculty, Staff and Students Publications

Background: While exposure with response prevention (ERP) is the frontline treatment for pediatric obsessive-compulsive disorder (OCD), not all patients benefit. Impairments in extinction learning are implicated in pediatric OCD's etiology and treatment, with impaired pre-treatment extinction learning associated with worse ERP outcomes. However, available methods for assessing patients' difficulties with fear extinction are costly and underdeveloped. In response, we used person-centered profiles to characterize latent fear extinction patterns among youth with OCD, and investigated the degree to which scores on common rating scales correspond to profile membership.

Methods: Youth with OCD (n=98) completed a diagnostic clinical battery followed by a …

Picalm Alzheimer’S Risk Allele Causes Aberrant Lipid Droplets In Microglia, Alena Kozlova, Siwei Zhang, Ari Sudwarts, Hanwen Zhang, Stanislau Smirnou, Seul Kee Byeon, Christina Thapa, Xiaotong Sun, Kimberley Stephenson, Xiaojie Zhao, Brendan Jamison, Moorthi Ponnusamy, Xin He, Julie A Schneider, Akhilesh Pandey, David A Bennett, Zhiping P Pang, Alan R Sanders, Hugo J Bellen, Gopal Thinakaran, Jubao Duan

Faculty, Staff and Students Publications

Despite genome-wide association studies (GWAS) of late-onset Alzheimer’s disease (LOAD) having identified many genetic risk loci1–3, the underlying disease mechanisms remain largely unclear. Determining causal disease variants and their LOAD-relevant cellular phenotypes has been a challenge. Here, using our approach for identifying functional GWAS risk variants showing allele-specific open chromatin, we systematically identified putative causal LOAD-risk variants in human induced pluripotent stem (iPS)-cell-derived neurons, astrocytes and microglia, and linked a PICALM LOAD-risk allele to a microglial-specific role of PICALM in lipid droplet (LD) accumulation. Allele-specific open-chromatin mapping revealed functional risk variants for 26 LOAD-risk loci, mostly …

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 …

Classifying A Distinct Form Of Diabetes In Lean Individuals With A History Of Undernutrition: An International Consensus Statement, Pradnyashree Wadivkar, Felix Jebasingh, Nihal Thomas, Chittaranjan S Yajnik, Allan Arthur Vaag, Davis Kibirige, Silver Bahendeka, Mandeep Bajaj, Michael S Boyne, Charlotte Bavuma, Jacko Abodo, Sarah Wild, Ullas Kolthur-Seetharam, Satinath Mukhopadhyay, Noel P Somasundaram, Peter Schwarz, Dirk L Christensen, Faruque Pathan, Angus G Jones, Sandeep Mathur, Sylvia Kehlenbrink, Meredith Hawkins, Vellore Declaration Signatories

Faculty, Staff and Students Publications

Since 1955, a form of diabetes in lean, young (BMI < 18·5 kg/m2, age < 30 years) individuals with a history suggestive of undernutrition from before birth and throughout childhood has been described in the literature. In 1985, WHO formally classified it as malnutrition-related diabetes, but subsequently removed the classification in 1999 over a disagreement as to whether undernutrition was a sufficient risk factor to cause this type of diabetes. Emerging evidence now strongly supports the distinct classification of this unique diabetes phenotype, which is characterised by substantial impairment of pancreatic insulin secretion, with normal hepatic and peripheral insulin sensitivity, an absence of ketoacidosis, and no islet cell autoantibodies. In this consensus statement, we synthesise this evidence to produce a set of common features of the disease, proposed pathogenetic mechanisms, and suggested management and prevention strategies. During a consensus meeting in Vellore, India, in January, 2025, type 5 diabetes was proposed as the nomenclature for this distinct form of diabetes, subsequently formalised at the International Diabetes Federation (IDF) World Diabetes Congress in April, 2025. We call upon the international diabetes community to recognise this distinct form of the disease, and to support the IDF's Type 5 Diabetes Working Group and its goals to promote more research into its phenotype, pathophysiology, and treatment, which will benefit millions of patients worldwide, particularly in low-income and middle-income countries.

Timing Of Cardiac Resynchronization Therapy Following Stable Medical Therapy In Patients With Heart Failure, Alessandro Villaschi, Christian Basile, Lina Benson, Paolo Gatti, William T Abraham, Michael Böhm, Biykem Bozkurt, Javed Butler, Gianluigi Condorelli, Cecilia Linde, Marco Metra, Wilfried Mullens, Peter Mol, Shelley Zieroth, Raffaele Scorza, Lars H Lund, Fredrik Gadler, Gianluigi Savarese

Faculty, Staff and Students Publications

Background: Guidelines' recommendations for cardiac resynchronization therapy (CRT) implantation in selected patients with heart failure (HF) exist. However, data on the best timing for CRT implantation after the achievement of stable medical therapy (SMT) and its association with outcomes are currently lacking.

Objectives: The aim of this study was to investigate the timing of CRT implantation after the achievement of SMT, associated patient profiles, and clinical outcomes in a real-world HF population.

Methods: Patients with HF treated with SMT derived from the Swedish ICD and Pacemaker Registry who received CRT between 2007 and 2020 were included in the study. Patient …

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. …

Examining The Relationship Between Dysphagia, Eating-Related Symptoms, And Diet Quality Among Oropharyngeal Cancer Patients During Critical Stages Of Cancer Survivorship: The U-Dine Study, Beatrice Manduchi, Vlad C Sandulache, Ji Yun Tark, Shreela Sharma, Ruosha Li, Emily Roller, Andrew Bevelhimer, Katherine A Hutcheson, Marcia C De Oliveira Otto

Faculty, Staff and Students Publications

Background: Diet quality is a modifiable factor impacting treatment outcomes in oropharyngeal cancer (OPC), yet the effect of dysphagia and self-reported eating-related symptoms remains unclear. This study examined their associations with diet quality in OPC patients.

Methods: A cross-sectional analysis was conducted with two parallel cohorts from MD Anderson Cancer Center and Michael E. DeBakey Veterans Affairs Medical Center as part of the Uncovering the Long-Term Impact of OPC and Dysphagia on Dietary Quality and Nutrition Among Cancer Survivors (U-DINE) Study. Participants at varying survivorship stages (prediagnosis, 3-6 and 18+ months posttreatment) were assessed for dysphagia (DIGEST scale) and six …

Nrf2 Hyperactivation As A Driver Of Radiotherapy Resistance And Suppressed Antitumor Immunity In Head And Neck Squamous Cell Carcinoma, Rutulkumar Patel, Kalil Saab, Lixia Luo, Yan Ma, Rashid Abdullah Osman, Nerissa T Williams, Jeffrey Everitt, Maciej J Zelazowski, Patricia Castro, William K Decker, William H Hudson, Jeffrey N Myers, Vlad C Sandulache, Mitchell J Frederick, Yvonne M Mowery, David G Kirsch

Faculty, Staff and Students Publications

Purpose: Alterations in the KEAP1/NFE2L2 (NRF2)/CUL3 pathway occur in ∼20% of human head and neck squamous cell carcinomas (HNSCC) and are associated with resistance to standard-of-care therapy. However, this pathway's role in radiotherapy resistance in HNSCC has not been well studied.

Experimental design: We generated genetically engineered mouse models and developed primary murine cancer cell lines harboring mutations commonly observed in human HNSCC, including inducible activation of PIK3CA and deletion of Trp53, with or without Keap1 loss. Primary tumors were initiated via 4-hydroxytamoxifen injection ± the tobacco carcinogen benzo[a]pyrene (BAP) into the oral buccal mucosa. Tumors were analyzed by Western …

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 …

Dominant Negative Atp5f1a Variants Disrupt Oxidative Phosphorylation Causing Neurological Disorders, Sara M Fielder, Marisa W Friederich, Daniella H Hock, Jessie R Zhang, Liana M Valin, Jill A Rosenfeld, Kevin T A Booth, Natasha J Brown, Rocio Rius, Tanavi Sharma, Liana N Semcesen, Kim C Worley, Lindsay C Burrage, Kayla Treat, Tara Samson, Sarah Govert, Sara Dacunha, Weimin Yuan, Jian Chen, Jacob Lesinski, Hieu Hoang, Stephanie A Morrison, Farah A Ladha, Roxanne A Van Hove, Cole R Michel, Richard Reisdorph, Eric Tycksen, Dustin Baldridge, Gary A Silverman, Claudia Soler-Alfonso, Erin Conboy, Francesco Vetrini, Lisa Emrick, William J Craigen, Undiagnosed Diseases Network, Stephen M Sykes, David A Stroud, Johan L K Van Hove, Tim Schedl, Stephen C Pak

Faculty, Staff and Students Publications

ATP5F1A encodes the α-subunit of complex V of the respiratory chain, which is responsible for mitochondrial ATP synthesis. We describe 6 probands with heterozygous de novo missense ATP5F1A variants that presented with developmental delay, intellectual disability, and movement disorders. All variants were located at the contact points between the α- and β-subunits. Functional studies in C. elegans revealed that the variants were damaging via a dominant negative genetic mechanism. Biochemical and proteomics studies of proband-derived cells showed a marked reduction in complex V abundance and activity. Mitochondrial physiology studies revealed increased oxygen consumption, yet decreased mitochondrial membrane potential and ATP …

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 …

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.

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 …

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. …

Current States In Understanding Oligodendroglia-Mediated Neurological Issues In Neurofibromatosis Type 1 (Nf1), Benjamin E Aghoghovwia, Cheng-En Shen, Sabiha Bano, Nandini Shyamala, Alesandra Echeandia Marrero, Khushboo Irshad, Samer Sharafaldin, Nicole M Brossier, Yuan Pan

Faculty, Staff and Student Publications

Neurofibromatosis type 1 (NF1) is among the most common neurogenetic disorders and is associated with an increased risk of developing tumors in the nervous system. Additionally, up to 80% of patients with NF1 experience neurological complications, including deficits in attention, memory, and executive function. Significant effort has been dedicated to studying how NF1 mutations autonomously dysregulate neuronal function. Increasing evidence indicates that NF1 mutations also dysregulate the oligodendroglial lineage that contributes to neurological issues in NF1. Here, we summarize our current understanding of how NF1 mutations impact the oligodendroglial lineage homeostasis and plasticity. We also discuss gaps in knowledge, potential …

Functional Outcomes In Pediatric Patients On Renal Replacement Therapy In A Worldwide Registry, Kristin J Dolan, Katja M Gist, Abby Basalely, Gabriella Bottari, Abhishek Chakraborty, Mihaela Damian, Dana Fuhrman, Denise C Hasson, Catherine Joseph, Dave Kwiatkowski, Susan Martin, Jenn Nhan, Nicolas Ollberding, David T Selewski, Danielle Soranno, Michelle C Starr, Amy Strong, Sameer Thadani, Huaiyu Zang, Ayse Akcan Arikan

Faculty, Staff and Students Publications

Background and hypothesis: Mortality rates of children supported with continuous renal replacement therapy (CRRT) have improved, yet morbidity remains high. We aimed to evaluate the functional outcomes of children receiving CRRT using Functional Status Scale (FSS). We hypothesized that children receiving CRRT will have worse FSS compared with their baseline and acquire new morbidity at hospital discharge and 6 and 12 months post-discharge, and that lack of renal recovery will contribute to worsening functional status.

Methods: This is a retrospective chart review from The Worldwide Exploration of Renal Replacement Outcomes Collaborate in Kidney Disease (WE-ROCK), an international multi-center registry. Twenty-eight …

Evaluation Of Image Quality In Mobile Cone-Beam Ct With Dose Modulation Using Automatic Exposure Control: A Phantom Study, Keita Okazaki, Wenchao Cao, Reza Taleei, Firas Mourtada, Jun Li, Karen Mooney, Pramila Rani Anne, Yingxuan Chen

Department of Radiation Oncology Faculty Papers

BACKGROUND: The integration of mobile cone-beam computed tomography (CBCT) into brachytherapy workflows offers clinical advantages such as immediate verification of applicator placement and adaptive treatment planning. These benefits require sufficient image quality to delineate applicators, target volumes, and organs at risk. A systematic evaluation of automatic exposure control (AEC) settings, radiation dose, and image quality is essential to ensure clinically acceptable imaging while minimizing patient exposure.

PURPOSE: This study evaluates the characteristics of AEC and its impact on image quality and radiation dose in a mobile CBCT system used for brachytherapy.

METHODS: The Elekta ImagingRing CBCT system was used to …

Acute Care Of Patients With Moderate Respiratory Distress: Recommendations From An American College Of Emergency Physicians Expert Panel., Christopher W Baugh, Jim F Neuenschwander, Jesslyn Lenox, Jennifer Hoh, Kara Ward, Sara Muramoto, John Casey, Antonio Anzueto, Hajirah Ishaq, Jared Mount, Peter M Deblieux

Ambulatory and Primary Care Articles

INTRODUCTION: Patients with respiratory distress are frequently encountered in the emergency department (ED). Efforts to assess, initiate treatments, and stabilize these patients require a systematic and rapid response. Emergency physicians need a comprehensive and efficient approach for evaluating, treating, and managing patients presenting to the ED with moderate respiratory distress.

METHODS: The American College of Emergency Physicians convened an expert panel of academic and community emergency physicians, critical care specialists, respiratory therapists, hospitalists, and pharmacists to develop and subsequently disseminate consensus recommendations regarding the diagnosis and treatment of patients with moderate respiratory distress presenting to the ED.

RESULTS: A digital …

Comparison Of Imaging Based Single-Cell Resolution Spatial Transcriptomics Profiling Platforms Using Formalin-Fixed Paraffin-Embedded Tumor Samples, Nejla Ozirmak Lermi, Max Molina Ayala, Sharia Hernandez, Wei Lu, Khaja Khan, Alejandra Serrano, Idania Lubo, Leticia Hamana, Katarzyna Tomczak, Sean Barnes, Jinzhuang Dou, Qingnan Liang, Rti Team, Maria Gabriela Raso, Ximing Tang, Mei Jiang, Beatriz Sanchez-Espiridion, Annikka Weissferdt, John Heymach, Jianjun Zhang, Boris Sepesi, Tina Cascone, Anne Tsao, Mehmet Altan, Reza Mehran, Don Gibbons, Ignacio Wistuba, Cara Haymaker, Ken Chen, Luisa M Solis Soto

Faculty, Staff and Student Publications

Imaging-based spatial transcriptomics (ST) is evolving as a pivotal technology in studying tumor biology and associated microenvironments. However, the strengths of the commercially available ST platforms in studying spatial biology have not been systematically evaluated using rigorously controlled experiments. We use serial 5 μm sections of formalin-fixed, paraffin-embedded surgically resected lung adenocarcinoma and pleural mesothelioma samples in tissue microarrays to compare the performance of the ST platforms (CosMx, MERFISH, and Xenium (uni/multi-modal)) in reference to bulk RNA sequencing, multiplex immunofluorescence, GeoMx, and hematoxylin and eosin staining data. In addition to an objective assessment of automatic cell segmentation and phenotyping, we …

Non-Invasive Detection Of Choroidal Melanoma Via Tear-Derived Protein Corona On Gold Nanoparticles: A Machine Learning Approach, Hakimeh Rakhshandeh, Ahmad Nasiraei, Hamid Riazi-Esfahani, Babak Masoomian, Fariba Ghassemi, Mojtaba Arjmand, Saeed Heidari Keshel, Fatemeh Atyabi, Rassoul Dinarvand

Wills Eye Hospital Papers

This study investigates the feasibility of using tear sample analysis, based on protein corona formation on gold nanoparticles combined with electrospray ionization mass spectrometry (ESI-MS) and machine learning techniques, as a non-invasive approach for the detection of choroidal melanoma. The aim is to assess whether protein-nanoparticle interactions can support early and reliable identification of this ocular condition. Tear samples were collected using Schirmer strips from six healthy individuals and six patients diagnosed with choroidal melanoma, with subsequent augmentation to 18 samples per group. Gold nanoparticles (AuNPs, ~ 20 nm) were synthesized via citrate reduction and incubated with tear samples to …