Medicine and Health Sciences Commons^™

The Epilepsy Centers Of Excellence At The Veterans Health Administration, Zulfi Haneef, Caleb A Casanova, Vincent Zhang, Jennifer R Bonds King, Rizwana Rehman, Nina I Garga, Glenn D Graham, Alan R Towne

Faculty, Staff and Students Publications

Introduction: The Veterans Health Administration (VHA) Epilepsy Centers of Excellence (ECoE) was established in 2008 to provide specialized care for veterans with epilepsy. Although established more than a decade ago, there has been no systematic evaluation of the ECoE's performance in key mission areas. We evaluated their performance in several key mission areas-clinical care, research, education, and outreach-since inception to evaluate their success in meeting the initial mandate.

Materials and methods: We analyzed available data from relevant literature, ECoE annual reports, and the ECoE website between 2011 and 2023. Clinical care is the primary mission of the ECoE and was …

"Holy Cow, Where Do I Sign Up?" Attitudes Of Military Veterans Toward Epigenomic Biomarker Toxic Exposure Testing, Stacey Pereira, Calvin Apodaca, Kyle Slominski, Rachele K Lipsky, Cristian Coarfa, Cheryl L Walker, Amy L Mcguire, Lea Steele, Drew A Helmer

Center for Medical Ethics and Health Policy Staff Publications

Introduction: After the Sergeant First Class Heath Robinson Honoring Our Promise to Address Comprehensive Toxics Promise to Address Comprehensive Toxics (PACT) Act in 2022, there has been a great interest in studying toxic exposures encountered during military service. Development of epigenomic biomarkers for exposures could facilitate understanding of exposure-related health effects, but such testing could also provide unwanted information.

Materials and methods: We explored attitudes toward epigenomic biomarker research and the potential to test for past exposures using semistructured interviews with Veterans (n = 22) who experienced potentially harmful exposures.

Results: Twenty Veterans said they would hypothetically want to receive …

Hydration Status And Acute Kidney Injury Biomarkers In Ncaa Female Soccer Athletes During Preseason Conditioning, Daniel E Newmire, Erica M Filep, Jordan B Wainwright, Heather E Webb, Darryn S Willoughby

Faculty, Staff and Students Publications

Exercise training in extreme temperatures concurrent with hypohydration status may potentiate the development of acute kidney injury (AKI) in young, healthy persons.

Background/Objectives: It is unknown how repeated training bouts in ambient higher temperatures and humidity may influence measures of AKI. The purpose of this study was to investigate hydration status and renal biomarkers related to AKI in NCAA Division I female soccer athletes during preseason conditioning.

Methods: A convenience sample of n = 21 athletes were recruited (mean ± SEM; age: 19.3 ± 0.25 y; height: 169.6 ± 1.36 cm; mass: 68.43 ± 2.46 kg; lean body …

Determining Falls Risk In People With Parkinson's Disease Using Wearable Sensors: A Systematic Review, Maeve Bradley, Sarah O'Loughlin, Eoghan Donlon, Amy Gallagher, Clodagh O'Keeffe, John Inocentes, Federica Ruggieri, Richard B Reilly, Richard Walsh, Tim Lynch, Daniel G Di Luca, Conor Fearon

2020-Current year OA Pubs

A prior history of falls remains the strongest predictor of future falls in individuals with Parkinson's disease (PD). There are limited biomarkers available to identify falls risk before falls begin to occur. The aim of this review is to investigate if features associated with falls risk may be detected by wearable sensors in patients with PD. A systematic search of the MEDLINE, EMBASE, Cochrane, and Cinahl databases was performed. Key quality criteria include sample size adequacy, data collection procedures, and the clarity of statistical analyses. The data from each included study were extracted into defined data extraction spreadsheets. Results were …

Letter Of Concern From The Association Of Academic Chairs Of Emergency Medicine Regarding Acgme Proposed Changes, Richard J Hamilton, Lance B Becker, Richard E Wolfe, D Adam Algren, Thomas Arnold, Michael Baumann, Ross P Berkeley, Terrell S Caffery, Chad M Cannon, Theodore J Corbin, Michael E Chansky, Harinder S Dhindsa, Charles L Emerman, David A Farcy, Chris Fox, Michael A Gibbs, Christopher S Goode, Steven Andy Godwin, Dietrich Jehle, David Johnson, Samuel M Keim, Babak Khazaeni, Barry J Knapp, Clint Hawthorne, John D Hoyle, Michael Christopher Kurz, Evan Leibner, Robert Mcnamara, Robert F Mccormack, Edward A Michelson, Chadwick Miller, Ashley Norse, Andrew Nugent, Brian J O'Neil, David T Overton, Edward A Panacek, William F Paolo, Denis R Pauzé, Amanda L Perez, Ralph J Riviello, Scott W Rodi, Peter S Pang, Juan A Gonzalez Sanchez, David Seaberg, Adam Schwartz, Stephen A Shiver, David P Sklar, Ben C Smith, Jeffrey R Stowell, Marc D Squillante, J Jeremy Thomas, Terry Vanden Hoek, Gregory A Volturo, E Lea Walters, Thomas E Wyatt, Donald M Yealy

Faculty, Staff and Student Publications

This letter, signed by over 50 academic chairs of emergency medicine, urges the ACGME to reconsider a proposed mandate requiring all emergency medicine residency programs to adopt a four-year training model. The authors argue that current three-year programs are supported by data demonstrating equivalent educational and clinical outcomes compared to four-year formats. They criticize the flawed survey methodology underpinning the proposal, note the loss of milestone-based training flexibility, and highlight the lack of added scholarly or clinical value in the fourth year. The letter also outlines negative consequences for fellowship participation, workforce development, trainee debt, and diversity. The signatories advocate …

Unveiling Endoscopic Procedures In Maude: An Etl-Llm Method, Yuheng Shi, Eric Yang, Yang Gong

Faculty, Staff and Student Publications

The increased dependence on patient safety studies using the MAUDE database underscores the critical need to define and standardize the methods for extracting and analyzing event reports. The lack of reproducible methods leads to an inconsistent understanding of reported events and diminishes their effectiveness in informing clinicians. Thus, an ETL pipeline combined with LLMs was proposed to standardize the identification and interpretation of the reports. Using endoscopic clip reports as an example, the ETL-LLM method demonstrates the effectiveness of extracting and analyzing categorical and narrative reports, helping uncover insights related to patient complications, surgical procedures, and device uses. This innovative …

Pneumococcal Colonization Dynamics Among Young Children With And Without Respiratory Symptoms During The First Year Of The Sars-Cov-2 Pandemic., Liset Olarte, Brian R. Lee, Dithi Banerjee, Douglas Swanson, Christopher J. Harrison, Rangaraj Selvarangan

Manuscripts, Articles, Book Chapters and Other Papers

BACKGROUND: Non-pharmaceutical interventions to mitigate the spread of SARS-CoV-2 were implemented across the United States in 2020. These public health measures might influence pneumococcal colonization in younger children and their subsequent risk of invasive pneumococcal disease. Our objective was to evaluate pneumococcal colonization rates in children ≤ 5 years of age with and without respiratory symptoms during the first 12 months of SARS-CoV-2 pandemic (April 2020 - March 2021).

STUDY DESIGN: This is a retrospective cross-sectional study evaluating pneumococcal colonization rates, density and serotype distribution across three study periods (April-July [Period 1], August-November [Period 2] and December-March [Period 3]) after …

Mis-Splicing-Derived Neoantigens And Cognate Tcrs In Splicing Factor Mutant Leukemias, Won Jun Kim, Edie I Crosse, Emma De Neef, Inaki Etxeberria, Erich Y Sabio, Eric Wang, Jan Philipp Bewersdorf, Kuan-Ting Lin, Sydney X Lu, Andrea Belleville, Nina Fox, Cynthia Castro, Pu Zhang, Takeshi Fujino, Jennifer Lewis, Jahan Rahman, Beatrice Zhang, Jacob H Winick, Alexander M Lewis, Robert F Stanley, Susan Dewolf, Brigita Meškauskaitė Urben, Meril Takizawa, Tobias Krause, Henrik Molina, Ronan Chaligne, Priya Koppikar, Jeffrey Molldrem, Mathieu Gigoux, Taha Merghoub, Anthony Daniyan, Smita S Chandran, Benjamin D Greenbaum, Christopher A Klebanoff, Robert K Bradley, Omar Abdel-Wahab

Faculty, Staff and Student Publications

Mutations in RNA splicing factors are prevalent across cancers and generate recurrently mis-spliced mRNA isoforms. Here we identified a series of bona fide neoantigens translated from highly stereotyped splicing alterations promoted by neomorphic, leukemia-associated somatic splicing machinery mutations. We utilized feature-barcoded peptide-MHC dextramers to isolate neoantigen-reactive T cell receptors (TCRs) from healthy donors, patients with active myeloid malignancy, and following curative allogeneic stem cell transplant. Neoantigen-reactive CD8+ T cells were present in the blood of patients with active cancer and had a distinct phenotype from virus-reactive T cells with evidence of impaired cytotoxic function. T cells engineered with TCRs recognizing …

Visualizing Data For Diabetes Management In Patient Portals, Eric Yang, Lakeidra Salazar, Usha Rijal, Yang Gong

Faculty, Staff and Student Publications

Effectively managing diabetes requires active patient engagement in monitoring crucial health metrics, such as HbA1c and glucose levels. However, many existing patient portals present this information in complex and confusing formats, hindering understanding and communication. This study established a prototype for a user-centered dashboard for diabetes management, designed to enhance patient comprehension and interaction with their health data by utilizing principles of relational data display. By applying Gestalt principles and theories of distributed representation, our dashboard optimizes data visualization through Google Looker Studio, ultimately reducing cognitive load and aiding patients in self-management. The findings emphasize the benefits of user-friendly and …

Encorafenib, Cetuximab, And Mfolfox6 In Braf-Mutated Colorectal Cancer, Elena Elez, Takayuki Yoshino, Lin Shen, Sara Lonardi, Eric Van Cutsem, Cathy Eng, Tae Won Kim, Harpreet Singh Wasan, Jayesh Desai, Fortunato Ciardiello, Rona Yaeger, Timothy S Maughan, Van K Morris, Christina Wu, Tiziana Usari, Robert Laliberte, Samuel S Dychter, Xiaosong Zhang, Josep Tabernero, Scott Kopetz, Breakwater Trial Investigators

Faculty, Staff and Student Publications

Background: First-line treatment with encorafenib plus cetuximab (EC) with or without chemotherapy (oxaliplatin, leucovorin, and fluorouracil [mFOLFOX6]) for BRAF V600E-mutated metastatic colorectal cancer, an aggressive subtype with a poor prognosis, was compared with standard care (chemotherapy with or without bevacizumab) in an open-label, phase 3 trial, which showed significance regarding one of the two primary end points, objective response according to blinded independent central review (odds ratio for EC+mFOLFOX6 vs. standard care, 2.44; one-sided P< 0.001). This result led to accelerated Food and Drug Administration approval of this investigational combination therapy for BRAF V600E-mutated metastatic colorectal cancer, including as first-line therapy. Data on progression-free survival (the second primary end point) and an updated interim analysis of overall …

A Conditional Point Cloud Diffusion Model For Deformable Liver Motion Tracking Via A Single Arbitrarily-Angled X-Ray Projection, Jiacheng Xie, Hua-Chieh Shao, Yunxiang Li, Shunyu Yan, Chenyang Shen, Jing Wang, You Zhang

Faculty, Staff and Student Publications

Objective. Deformable liver motion tracking using a single x-ray projection enables real-time motion monitoring and treatment intervention. We introduce a conditional point cloud diffusion (PCD) model-based framework for accurate and robust liver motion tracking from arbitrarily angled single x-ray projections. Approach. We propose a conditional PCD model for liver motion tracking (PCD-Liver), which estimates volumetric liver motion by solving deformable vector fields (DVFs) of a prior liver surface point cloud, based on a single x-ray image. It is a patient-specific model of two main components: a rigid alignment model to estimate the liver’s overall shifts, and a conditional PCD …

Mapping Mave Data For Use In Human Genomics Applications, Jeremy A Arbesfeld, Estelle Y Da, James S Stevenson, Kori Kuzma, Anika Paul, Tierra Farris, Benjamin J Capodanno, Sally B Grindstaff, Kevin Riehle, Nuno Saraiva-Agostinho, Jordan F Safer, Jonathan Casper, Maximilian Haeussler, Aleksandar Milosavljevic, Julia Foreman, Helen V Firth, Sarah E Hunt, Sumaiya Iqbal, Melissa S Cline, Alan F Rubin, Alex H Wagner

Faculty, Staff and Students Publications

Background: Experimental data from functional assays have a critical role in interpreting the impact of genetic variants. Assay data must be unambiguously mapped to a reference genome to make it accessible, but it is often reported relative to assay-specific sequences, complicating downstream use and integration of variant data across resources. To make multiplexed assays of variant effect (MAVE) data more broadly available to the research and clinical communities, the Atlas of Variant Effects Alliance mapped MAVE data from the MaveDB community database to human reference sequences, creating an extensive set of machine-readable homology mappings that are incorporated into widely used …

What Drives Clinic Follow-Up After Traumatic Spinal Injury? An Observational Cohort Study From Tanzania, Chibuikem A Ikwuegbuenyi, Julie Woodfield, Romani Roman Sabas, Sean Inzerillo, Noah Willett, Magalie Cadieux, Scott L Zuckerman, Francois Waterkeyn, Halinder S Mangat, Hamisi K Shabani, Roger Härtl

2020-Current year OA Pubs

OBJECTIVES: To evaluate factors associated with clinic follow-up after traumatic spinal injury (TSI) in Tanzania, focusing on demographic, injury-related and hospital variables. We hypothesised that socioeconomic and injury-specific factors would predict follow-up adherence.

DESIGN: Retrospective observational cohort study.

SETTING: Tertiary government referral centre for neurosurgery and orthopaedics in Dar es Salaam, Tanzania.

PARTICIPANTS: 443 adults with TSI admitted between September 2016 and October 2021. Inclusion criteria included survival to discharge and availability of the discharge date. Patients with missing data were excluded.

PRIMARY AND SECONDARY OUTCOME MEASURES: Primary outcomes were any clinic follow-up and 1-year follow-up post-discharge. Secondary outcome was …

Low Frequency, High Complexity: Assessing Skill Decay In Transesophageal Echocardiography Post-Simulation Training, Enyo Ablordeppey, Emily Terian, Collyn T Murray, Laura Wallace, Wendy Huang, Erica Blustein, Alexander Croft, Ernesto Romo, Mansi Agarwal, Daniel Theodoro

2020-Current year OA Pubs

INTRODUCTION: Resuscitative transesophageal echo (rTEE) is a promising adjunct to cardiac arrest resuscitation. However, it is a high-acuity diagnostic tool that is rarely used in this setting and its safety establishment is limited because of low occurrence. High-acuity, low occurrence skills such as rTEE during cardiac arrest inevitably decay. In this study we examined the content and percentage of rTEE skill decay following simulation-based education (SBE).

METHODS: Resuscitative TEE-naïve emergency physicians (EP) were trained using a combination of clinical exposure, web-based didactics, and monthly hands-on sessions with a high-fidelity rTEE simulator for four months. The COVID-19 pandemic created a natural …

Intratumoral Neutrophil-To-Lymphocyte Ratio Is Mirrored By Circulating Neutrophil-To-Lymphocyte Ratio In Non-Small Cell Lung Cancer, Kyle G Mitchell, Younghee Lee, Nathaniel Deboever, Marcelo V Negrao, Hai T Tran, Edwin Parra, Lauren Byers, Alexandre Reuben, Lorenzo Federico, Chantale Bernatchez, Jing Wang, Mara B Antonoff, Ara A Vaporciyan, Stephen G Swisher, Tina Cascone, Ignacio I Wistuba, John V Heymach, Don L Gibbons, Jianjun Zhang, Daniel J Mcgrail, Boris Sepesi, Cara L Haymaker

Faculty, Staff and Student Publications

Tumor-initiated emergency granulopoiesis results in expansion of the circulating neutrophil compartment and neutrophil recruitment into the tumor microenvironment (TME), which may in turn promote tumor progression. Although an elevated circulating neutrophil-to-lymphocyte ratio (cNLR) has repeatedly been demonstrated to be an adverse prognostic factor in patients with non-small cell lung cancer (NSCLC), whether this neutrophil expansion in circulation reflects a similar relative neutrophil abundance in the TME remains unclear. We sought to characterize the relationships between cNLR and the intratumoral neutrophil-to-lymphocyte ratio (tNLR), between tNLR and proteogenomic and immune features of NSCLC tumors, and between tNLR and prognosis.We analyzed tNLR (transcriptomic …

Differences In Arterial Events In Vascular Ehlers-Danlos, Loeys-Dietz, And Marfan Syndrome, Ernesto Calderon-Martinez, Walter V Velasco, Dongchuan Guo, Ellen H Hostetler, Zhang Xun, Sara Stephens, Sherene Shalhub, Julie De Backer, Maral Ouzounian, Scott A Lemaire, Olivier Milleron, Nadine Hanna, Pauline Arnaud, Maria Tchitchinadze, Siddharth K Prakash, Mark Lindsay, Julien Marcadier, Richmond Jeremy, Shaine A Morris, Anji T Yetman, Catherine Boileau, Alan C Braverman, Guillaume Jondeau, Dianna M Milewicz

Faculty, Staff and Students Publications

Background: Heritable thoracic aortic disease is due to altered genes that confer a highly penetrant risk for thoracic aortic aneurysm and dissection, and a subset of these genes also cause aneurysms and dissections of peripheral arteries beyond the aorta. Arterial aneurysms, dissections, and ruptures are associated with pathogenic variants (PVs) in COL3A1, which is responsible for vascular Ehlers-Danlos syndrome, but arterial events are rare in Marfan syndrome due to PVs in FBN1, and poorly characterized in Loeys-Dietz syndrome due to PVs in the transforming growth factor (TGF)-β pathway genes.

Objectives: This study sought to define the relative risk of arterial …

Modeling Reemergence Of Vaccine-Eliminated Infectious Diseases Under Declining Vaccination In The Us, Mathew V Kiang, Kate M Bubar, Yvonne Maldonado, Peter J Hotez, Nathan C Lo

Faculty, Staff and Students Publications

Importance: Widespread childhood vaccination has eliminated many infectious diseases in the US. However, vaccination rates are declining, and there are ongoing policy debates to reduce the childhood vaccine schedule, which may risk reemergence of previously eliminated infectious diseases.

Objective: To estimate the number of cases and complications in the US under scenarios of declining childhood vaccination for measles, rubella, poliomyelitis, and diphtheria.

Design, setting, and participants: A simulation model was used to assess the importation and dynamic spread of vaccine-preventable infectious diseases across 50 US states and the District of Columbia. The model was parameterized with data on area-specific estimates …

Cholesterol Metabolism Regulated By Camkk2-Creb Signaling Promotes Castration-Resistant Prostate Cancer, Chenchu Lin, Thomas L Pulliam, Jenny J Han, Jiaqian Xu, Carlos Vera Recio, Sandi R Wilkenfeld, Yan Shi, Manoj Kushwaha, Sarah Bench, Eduardo Ruiz, Sanjanaa Senthilkumar, Jayasurya Dileep, Peter D A Shepherd, Nora M Navone, Albert R Klekers, Elizabeth M Whitley, Michael M Ittmann, Livia S Eberlin, Wenyi Wang, Daniel E Frigo

Faculty, Staff and Student Publications

Castration-resistant prostate cancer (CRPC) remains an incurable disease in need of improved treatments. CAMKK2 is an emerging therapeutic target whose oncogenic effects in prostate cancer have, to date, been largely attributed to its activation of AMP-activated protein kinase (AMPK). Here, we demonstrate that CAMKK2 promotes prostate cancer growth through an alternative downstream pathway involving CAMKI and CREB. Unbiased transcriptomics identify CREB-mediated transcription as a CAMKK2-regulated process, findings that we validate using diverse molecular, genetic, and pharmacological approaches in vitro and in vivo. CAMKK2 promotes CREB phosphorylation/activation through CAMKIα independently of AMPK, CAMKIV, or other CAMKI isoforms. Functionally, the CREB family …

Apolipoprotein M Attenuates Age-Related Macular Degeneration Phenotypes Via Sphingosine-1-Phosphate Signaling And Lysosomal Lipid Catabolism, Tae Jun Lee, Andrea Santeford, Kristen M Pitts, Carla Valenzuela Ripoll, Ryo Terao, Zhen Guo, Mualla Ozcan, Dagmar Kratky, Christina Christoffersen, Ali Javaheri, Rajendra S Apte

2020-Current year OA Pubs

Age-related macular degeneration (AMD) is a leading cause of blindness in people over 50. AMD and cardiovascular disease share risk factors including age, impaired lipid metabolism, and extracellular lipid deposition. Because of its importance in age-related diseases, we hypothesize that apolipoprotein M (ApoM), a lipocalin that binds sphingosine-1-phosphate (S1P), might restore lipid homeostasis and retinal function in AMD. In support, we find that human patients with AMD demonstrate significantly reduced ApoM compared to controls. In mice with impaired retinal cholesterol efflux, ApoM improves retinal pigment epithelium (RPE) function and lipotoxicity in an S1P- and S1P receptor 3-dependent manner. Ultrastructural evidence …

Metabolic Control Of Glycosylation Forms For Establishing Glycan-Dependent Protein Interaction Networks, Xingyu Liu, Li Yi, Zongtao Lin, Siyu Chen, Shunyang Wang, Ying Sheng, Carlito B Lebrilla, Benjamin A Garcia, Yixuan Xie

2020-Current year OA Pubs

Protein-protein interactions (PPIs) are crucial for comprehending the molecular mechanisms and signaling pathways underlying diverse biological processes and disease progression. However, investigating PPIs involving membrane proteins is challenging due to the complexity and heterogeneity of glycosylation. To tackle this challenge, we developed an approach termed glycan-dependent affinity purification coupled with mass spectrometry (GAP-MS), specifically designed to characterize changes in glycoprotein PPIs under varying glycosylation conditions. GAP-MS integrates metabolic control of glycan profiles in cultured cells using small molecules referred to as glycan modifiers with affinity purification followed by mass spectrometry analysis (AP-MS). Here, GAP-MS was applied to characterize and compare …

A Road Map For Uniform, Comprehensive Long-Term Follow-Up After Curative Therapy For Sickle Cell Disease, Shalini Shenoy, Julie Kanter, Adetola Kassim, Courtney Fitzhugh, Elizabeth Stenger, Monica Bhatia, Lydia Pecker, Lakshmanan Krishnamurti, Allison A King

2020-Current year OA Pubs

An increasing number of allogeneic transplant and autologous gene modification transplant therapies seek to eradicate sickle hemoglobin and the consequent hemolysis, vasculopathy, functional compromise, morbidity, and mortality. Because these modalities are used in parallel, it is important to be able to define the spectrum and stability of correction, long-term effects, and the pros and cons of each modality. A comparison between interventions that will be sought by providers and patients undergoing intervention requires uniform assessments that evaluate disease- and intervention-related effects for informed decision-making. This expert summary outlines a pathway to functional evaluations with timing recommendations, provides broad management guidelines, …

Patterns Of Sialyl-Lewis X Expression Predict Gastric Histopathology, Nancy Vargas, Andrés Quiroga, Juan Pablo Chaves, Harold Bolaños, Ilke Nalbantoglu, Claudia Patricia Acosta Astaiza, Yuefeng Wu, José B Sáenz

2020-Current year OA Pubs

INTRODUCTION: Gastric cancer develops through a series of pre-cancerous changes over decades of chronic inflammation. Chronic atrophic gastritis (CAG) represents a critical transition in the progression to gastric cancer, though validated histologic markers are needed to more accurately detect and assess the extent of CAG. We previously identified sialyl-Lewis X (sLe

METHODS: We obtained gastric corpus and/or antrum biopsies from 149 adult patients with dyspepsia. Biopsies were stained with hematoxylin/eosin and a commercially available antibody to sLe

RESULTS: The majority of patients (70%) had gastric pathology (CNG or CAG ± IM). The presence of sLe

CONCLUSION: Patterns of sLe

Exploring Predictors Of Treatment Response To Glp-1 Receptor Agonists For Smoking Cessation, Luba Yammine, Constanza De Dios, Robert Suchting, Charles E Green, David A Nielsen, Consuelo Walss-Bass, Joy M Schmitz

Faculty, Staff and Student Publications

Introduction: Understanding predictors of smoking cessation medication efficacy facilitates the ability to enhance treatment effectiveness. In our pilot trial, exenatide, a glucagon-like peptide-1 receptor agonist, adjunct to nicotine patch improved smoking abstinence compared to nicotine patch alone. This secondary analysis explores potential baseline characteristics associated with differential treatment response to exenatide.

Aims and methods: The parent trial randomized (1:1) 84 smokers with prediabetes and/or overweight to once-weekly placebo or exenatide, 2 mg, subcutaneously. All participants received nicotine patch (21 mg) and brief smoking cessation counseling, with biologically confirmed 7-day point prevalence abstinence at week 6 (end-of-treatment) deemed the primary outcome. …

Cancer Immunotherapy Clinical Trials To Support Urgently Needed Access In Low- And Middle-Income Countries: A Report From The Sitc Global Access And Impact Committee, Jennifer Dent, Thomas A Odeny, Et Al.

2020-Current year OA Pubs

Cancer is rapidly on the rise as a cause of morbidity and mortality in low- and middle-income countries (LMICs). However, despite the increasing importance of immune checkpoint inhibitors (ICIs) as a pillar of cancer therapy, access in these settings lags well behind that in high-income countries (HICs). Increasing the evaluation of ICIs through local clinical trials and demonstration projects, and inclusion in multinational clinical trials is the first step to improving access. In particular, the epidemiology and clinical presentation of cancer in LMICs is often distinct from that in HICs, and the impact of immune checkpoint blockade in these settings …

Dysferlinopathy As Cause Of Long-Term Hyperckemia With Preserved Strength, Ikreet Cheema, Jacob Goodwin, Teerin Liewluck, Robert Charles Bucelli, Alan Pestronk, Margherita Milone

2020-Current year OA Pubs

BACKGROUND: Dysferlin (DYSF) has a crucial role in sarcolemmal repair. While DYSF mutations commonly manifest as limb-girdle muscular dystrophy (LGMDR2) or distal Miyoshi myopathy, atypical manifestations, such as asymptomatic hyperCKemia and pseudometabolic myopathy, are rarely reported. We describe clinical, serologic, radiologic, genetic, and muscle pathology findings of three patients with rare dysferlinopathy phenotypes and long-term follow up in one of them. We also review the literature pertinent to uncommon forms of dysferlinopathy presenting with hyperCKemia and pseudometabolic phenotype.

RESULTS: Patient 1 is a 51-year-old female with exercise-induced myalgia predominantly affecting calf muscles for 7 years. She had a 22-year history …

Protocol For Assessing Mobilization Of Peritoneal B Cells To The Pre-Metastatic Omentum In An Orthotopic Mouse Model Of Ovarian Cancer, Wonjae Lee, Hironari Akasaka, Honami Naora

Faculty, Staff and Student Publications

The omentum is a visceral adipose tissue that undergoes dynamic immunological changes prior to and following metastasis. Here, we present a protocol for assessing the mobilization of peritoneal B cells to the pre-metastatic omentum in a mouse ovarian cancer model. We describe steps for isolation and adoptive transfer of peritoneal donor B cells and their detection in the omentum of recipient mice. This protocol could be utilized to study the mobilization of peritoneal B cells to the omentum in other pathological contexts. For complete details on the use and execution of this protocol, please refer to Lee et al.

Characterization And Clinical Implications Of P53 Dysfunction In Patients With Myelodysplastic Syndromes, Matteo Zampini, Elena Riva, Luca Lanino, Elisabetta Sauta, Rita Antunes Dos Reis, Rosa Maria Andres Ejarque, Giulia Maggioni, Alberto Termanini, Alessandra Merlotti, Alessia Campagna, Lorenzo Dall'olio, Austin Kulasekararaj, Michela Calvi, Clara Di Vito, Arturo Bonometti, Daoud Rahal, Giorgio Croci, Emanuela Boveri, Umberto Gianelli, Maurilio Ponzoni, Rossella Caselli, Serena Albertazzi, Gabriele Todisco, Marta Ubezio, Laura Crisafulli, Alessandro Frigo, Enrico Lugli, Ettore Mosca, Pamela Acha, Serena Ghisletti, Francesco Nicassio, Armando Santoro, Maria Diez-Campelo, Francesc Solé, Lionel Ades, Uwe Platzbecker, Valeria Santini, Pierre Fenaux, Torsten Haferlach, David Sallman, Guillermo Garcia-Manero, Domenico Mavilio, Daniel Remondini, Gastone Castellani, Saverio D'Amico, Amer M Zeidan, Rami Komrokji, Shahram Kordasti, Francesca Ficara, Matteo Giovanni Della Porta, Calr Consortium

Faculty, Staff and Student Publications

Purpose: Tumor Protein 53 (p53) expressed from gene TP53 is a seminal tumor suppressor. We aimed to characterize mutational and nonmutational mechanisms of p53 dysfunction in myelodysplastic syndromes (MDS) and to investigate their clinical effect.

Patients and methods: We analyzed a cohort of 6,204 patients with MDS and subsets of patients with available information on RNA sequencing of tumor cells (n = 109), high-dimensional phenotype of immune cells (n = 77), and multiomics analysis (RNA sequencing and proteomics) on single cells (n = 15). An independent validation was performed on 914 patients.

Results: Biallelic TP53 inactivation was a powerful driver …

Usp37 Counteracts Hltf To Protect Damaged Replication Forks And Promote Survival Of Brca1-Deficient Cells And Parp Inhibitor Resistance, Mengfan Tang, Siting Li, Ziqiang Zhu, Chao Wang, Shuai Ding, Huimin Zhang, Min Huang, Sarah Keast, Zhen Chen, Ling Yin, Litong Nie, Dan Su, Xu Feng, Junjie Chen

Faculty, Staff and Student Publications

Poly(ADP-ribose) polymerase inhibitors (PARPi) have greatly improved survival of cancer patients harboring BRCA1 mutations. However, therapy resistance develops via either restoration of homologous recombination or replication fork stabilization. Therapeutic targets to overcome PARPi resistance are critically needed. We identified the deubiquitinase USP37 as a key determinant of PARPi toxicity in BRCA1-deficient cells via whole-genome CRISPR screens. USP37 ablation enhanced PARPi sensitivity in BRCA1-deficient cells and also overcame PARPi resistance due to 53BP1 loss. USP37 interacts with and deubiquitinates replication protein A (RPA) at stalled replication forks to limit excessive RPA accumulation, progressive RPA exhaustion, and the conversion of RPA-coated single-stranded …

Protocol To Analyze Trna And Rrna Processing Using Biotin-Labeled Probes, Sseu-Pei Hwang, Katherine Barondeau, Catherine Denicourt

Faculty, Staff and Student Publications

Mature tRNAs and rRNAs are derived from larger precursor transcripts through intricate endo- and exonuclease processing steps. Here, we present a protocol to analyze rRNA and tRNA processing using total RNA extracted from human cells. We describe steps for separating RNA by denaturing electrophoresis, followed by northern blotting. We detail procedures for detecting pre-rRNA intermediates or specific tRNA species using biotin-labeled probes imaged via fluorescence or chemiluminescence. This non-radioactive, high-sensitivity assay enables the investigation of rRNA and tRNA expression dynamics. For complete details on the use and execution of this protocol, please refer to Hwang et al.

Monoclonal Antibodies Targeting The Fimh Adhesin Protect Against Uropathogenic E. Coli Uti, Edward D B Lopatto, Jesús M Santiago-Borges, Denise A Sanick, Sameer Kumar Malladi, Philippe N Azimzadeh, Morgan W Timm, Isabella F Fox, Aaron J Schmitz, Jackson S Turner, Shaza M Sayed Ahmed, Lillian Ortinau, Nathaniel C Gualberto, Jerome S Pinkner, Karen W Dodson, Ali H Ellebedy, Andrew L Kau, Scott J Hultgren

2020-Current year OA Pubs

As antimicrobial resistance increases, urinary tract infections (UTIs) are expected to pose an increased burden in morbidity and expense on the health care system, increasing the need for alternative antibiotic-sparing treatments. Most UTIs are caused by uropathogenic