Digital Commons Network^™

Landscape And Clinicopathologic Features Of Ras Pathway Mutations In Chronic Myelomonocytic Leukemia, Guillermo Montalban-Bravo, Sanam Loghavi, Ziyi Li, Kelly Chien, Rashmi Kanagal-Shamanna, Alex Bataller, Anuya Natu, Mark Gurney, Alexandre Bazinet, Danielle Hammond, Koji Sasaki, Gautam Borthakur, Mahesh Swaminathan, Courtney Dinardo, Tapan Kadia, Farhad Ravandi, Naval Daver, Nicholas Short, Naveen Pemmaraju, Ghayas Issa, Terra L Lasho, Christy M Finke, Aref Al-Kali, Clifford Csizmar, Hassan Alkhateeb, Naseema Gangat, Abhishek A Mangaonkar, Carlos Bueso-Ramos, Ayalew Tefferi, Hagop Kantarjian, Guillermo Garcia-Manero, Mrinal M Patnaik

Faculty, Staff and Student Publications

RAS pathway (RASp) mutations induce proliferative features, and promote transformation in chronic myelomonocytic leukemia (CMML). However, the unique clonal landscape and hierarchy of distinct RASp mutations remain unexplored. To characterize the landscape, architecture, and implications of unique RASp mutations in CMML, we evaluated a cohort of 814 patients with CMML. We identified 461 RASp mutations among 342 patients (42%). N/KRAS and CBL mutations were the most common, frequently involved the P-loop or RING domains, respectively, and frequently appeared as dominant events (63% and 65%, respectively). BRAF, NF1, and PTPN11 mutations spanned throughout the gene structure, and frequently appeared as subclonal …

Optimizing Genetic Ancestry Adjustment In Dna Methylation Studies: A Comparative Analysis Of Approaches, Kira D Höffler, Seyma Katrinli, Matthew W Halvorsen, Anne-Kristin Stavrum, Kevin S O'Connell, Alexey Shadrin, Srdjan Djurovic, Ole A Andreassen, James J Crowley, Jan Haavik, Kristen Hagen, Gerd Kvale, Kerry Ressler, Bjarne Hansen, Jair C Soares, Gabriel R Fries, Alicia K Smith, Stéphanie Le Hellard

Faculty, Staff and Student Publications

Background: Genetic ancestry is an important factor to account for in DNA methylation studies because genetic variation influences DNA methylation patterns. One approach uses principal components (PCs) calculated from CpG sites that overlap with common SNPs to adjust for ancestry when genotyping data is not available. However, this method does not remove technical and biological variations, such as sex and age, prior to calculating the PCs. The first PC is therefore often associated with factors other than ancestry.

Methods: We developed and adapted the adapted EpiAnceR+ approach, which includes (1) residualizing the CpG data overlapping with common SNPs for control …

The Effect Of Telehealth-Based Medical Nutrition Therapy On Cardiovascular Disease Risk Factors In A Rural Population: A Secondary Analysis Of Outcomes Related To Nutrition, Health And Well-Being From The Healthy Rural Hearts Randomised Controlled Trial, Tracy L. Schumacher, Erin D. Clarke, Jaimee Herbert, Anna Jansson, Chris Oldmeadow, Megan E. Rollo, Penny Milson, Carissa Alderton, Leanne J. Brown, Jennifer T. May Phd, Rn, Anp-Bc, Annabelle Williams, Michelle Guppy, Shanthi Ramanathan, John Attia, Clare E. Collins

Publications

BACKGROUND: Adults in rural Australia are at elevated risk of cardiovascular disease (CVD). To date, no intervention trials have evaluated the impact of dietitian delivered nutrition therapy using telehealth exclusively in patients recruited in the primary care setting. The primary aim was to assess effectiveness of telehealth delivered Medical Nutrition Therapy (MNT) on change in dietary intake energy, reported as percent energy derived from nutrient-dense (core) foods. Secondary aims included assessment of the intervention effects on percentage weight loss, quality of life, health literacy and patient engagement in their health (patient activation).

METHODS: This was a secondary data analysis of …

Development And Validation Of Clinical Screening Systems For Cushing Disease In The United States, Jorge E. Salcedo-Sifuentes, Sonal Mehta, Carter M. Suryadevara, Marvin Bergsneider, Kevin C. J. Yuen, Paul A. Gardner, Julie M. Silverstein, Albert H. Kim, James J. Evans, Garni Barkhoudarian, Juan C. Fernandez-Miranda, William T. Couldwell, Robert C. Rennert, Varun R. Kshettry, Kyle C. Wu, Carolina Benjamin, Gabriel Zada, Michael R. Chicoine, Jamie J. Van Gompel, Michael P. Catalino, Michael Karsy, Adam Mamelak, Ildiko Torok, Trevor Low, Won Kim, Donato R. Pacione, Nidhi Agrawal

Department of Neurosurgery Faculty Papers

PURPOSE: Clinical screening systems (CSSs) for Cushing syndrome (CS) validated in Europe have not been evaluated for CS or Cushing disease (CD) in the United States (US). We aimed to evaluate existing CSSs in US patients and develop two new symptom-based CSSs to identify patients with high pre-test probability of disease warranting referral for definitive biochemical workup-one for broad CS screening and one specifically for CD.

METHODS: Data were obtained from the Registry of Adenomas of the Pituitary and Related Disorders (RAPID)-comprising 615 patients who underwent transnasal transsphenoidal resection for CD at one of 11 US pituitary centers, the Centers …

Just-In-Time Adaptive Intervention To Improve Hiv Prevention And Substance Use In Youth Experiencing Homelessness (My-Ride): Protocol For A Randomized Controlled Trial, Diane Santa Maria, Nikhil Padhye, Michael Businelle, Natasha Slesnick, Stefani Ricondo, Marguerita Lightfoot

Faculty, Staff and Students Publications

Background: Youth who are experiencing homelessness face a higher risk of HIV infection compared to their housed peers, and suicide and overdose remain the leading causes of death among homeless youth. Just-in-Time Adaptive Interventions (JITAIs) are gaining momentum for HIV prevention and substance use research. Yet, most interventions for homeless youth have not addressed modifiable real-time factors.

Objective: This paper describes the development and implementation of a randomized attention-controlled trial to assess the efficacy of motivating youth to reduce infections, disconnections, and emotional dysregulation (MY-RIDE), a JITAI to improve HIV prevention and substance use in homeless youth.

Methods: This study …

The Effect Of Type 2 Diabetes Genetic Predisposition On Non-Cardiovascular Comorbidities, Ana Luiza Arruda, Ozvan Bocher, Henry J Taylor, Davis Cammann, Satoshi Yoshiji, Xianyong Yin, Chi Zhao, Jingchun Chen, Alexis C Wood, Ken Suzuki, Josep M Mercader, Cassandra N Spracklen, James B Meigs, Marijana Vujkovic, George Davey Smith, Jerome I Rotter, Benjamin F Voight, Andrew P Morris, Eleftheria Zeggini

Faculty, Staff and Students Publications

Type 2 diabetes is associated with a range of non-cardiovascular non-oncologic comorbidities. To move beyond associations and evaluate causal effects between type 2 diabetes genetic predisposition and 21 comorbidities, we apply Mendelian randomization analysis using genome-wide association studies across multiple genetic ancestries. Additionally, leveraging eight mechanistic clusters of type 2 diabetes genetic profiles, each representing distinct biological pathways, we investigate causal links between cluster-stratified type 2 diabetes genetic predisposition and comorbidity risk. We identify causal effects of type 2 diabetes genetic predisposition driven by distinct genetic clusters. For example, the risk-increasing effects of type 2 diabetes genetic predisposition on cataracts …

Germline Determinants Of Toxicity And Efficacy In Patients With Large B-Cell Lymphoma Treated With Car T-Cell Therapy, Paolo Strati, Amanda Brandt, Anath C Lionel, Jared Henderson, Jason R Westin, Sherry Adkins, Elizabeth J Shpall, Partow Kebriaei, Jeremy Ramdial, Neeraj Saini, Sairah Ahmed, Christopher Flowers, Sattva S Neelapu, Michelle A T Hildebrandt

Faculty, Staff and Student Publications

Background: Recent data have suggested that germline genetic aberrations can affect outcomes in patients with large B-cell lymphoma (LBCL) treated with chimeric antigen receptor T-cell therapy (CART). However, a comprehensive analysis of germline determinants of response and toxicity after CART has not yet been described.

Methods: Genome-wide genotyping was performed in 170 patients with LBCL treated with standard of care axicabtagene ciloleucel. Polygenic risk score instruments for blood cell traits and inflammatory markers were obtained from the PGS Catalog and analyzed using PRSice-2. Exploratory gene-based and genome-wide association study analyses were performed. Genetic ancestry of the patients with LBCL was …

Sti Testing And Diagnosis Rates Among Patients With Mpox In 2 Populous Us Cities, 2022, Shauna H Gunaratne, Karen J Vigil, Simian Huang, Nina Kumenda, Jacob Mclean, Clare Delaurentis, Delivette Castor, Jason Zucker

Faculty, Staff and Student Publications

Background: Mpox is recognized as a sexually transmitted infection, and the 2022 epidemic and 2024 resurgence of mpox cases through sexual transmission highlighted the need for sexually transmitted infection (STI) testing. Our objective was to observe rates of STI testing and STI diagnoses in patients with confirmed mpox in Houston, Texas and New York City, New York (NY).

Methods: This was a retrospective cohort study involving manual review of confirmed mpox cases at three large clinical centers in Houston, Texas and New York City, NY. Descriptive statistics were calculated for rates of STI testing and new diagnoses of syphilis, chlamydia …

Hydroxyapatite Microspheres Induce Durable Pleurodesis And Are Rapidly Cleared By Pleural Osteoclasts, Yusuke Tanaka, Yuki Takahashi, Yuma Shindo, Lori B. Pitstick, Steven L. Teitelbaum, Wei Zou, Xiangning Wang, Jason C. Woods, Kathryn A. Wikenheiser-Brokamp, Francis X. Mccormack

2020-Current year OA Pubs

Talc pleurodesis is highly effective for preventing recurrence of pneumothorax and pleural effusion, but it can be complicated by dissemination, acute lung injury, lead exposure, and foreign body-induced chronic inflammation and pain. Our objective is to develop a safe, biodegradable, contaminant-free particle for pleurodesis. We used mouse models of pneumothorax and malignant pleural effusion to compare the efficacy and safety of pleurodesis with talc and hydroxyapatite microspheres (HAM). Intrapleural instillation of microspheres induced pleural adhesions, fibrosis, and symphysis as effectively as talc and resulted in more durable protection from experimental pneumothorax. HAM and talc both induced an osteoclastogenic, inflammatory, and …

Multicenter Stroke Preclinical Assessment Network Analysis Of Cardiovascular Risk Factor Subgroups Treated With The Poly(Adp-Ribose) Polymerase Inhibitor Veliparib, Raymond C Koehler, Karni Bedirian, Mu-Hsun Chen, Yanrong Shi, Suyi Cao, Brooklyn D Avery, Senthilkumar S Karuppagounder, Kazi Akhter, Adnan Bibic, Valina L Dawson, Ted M Dawson, Márcio A Diniz, Jessica Lamb, Karisma A Nagarkatti, Anjali Chauhan, Jaroslaw Aronowski, Louise D Mccullough, Andreia Lopes De Morais, Xuyan Jin, Cenk Ayata, Mariia Kumskova, Rakesh B Patel, Anil K Chauhan, Enrique C Leira, Pradip K Kamat, Mohammad B Khan, Krishnan M Dhandapani, David C Hess, Ligia S B Boisserand, Basavaraju G Sanganahalli, Lauren H Sansing, Patrick D Lyden

Faculty, Staff and Student Publications

Background: The Stroke Preclinical Assessment Network tested 6 therapeutic interventions initiated at the time of reperfusion after focal ischemic stroke in young mice, aging mice, obese mice, and spontaneously hypertensive rats. This randomized, controlled trial was conducted across 6 sites with concealed treatment and blinded neurobehavior assessments. The trial had an adaptive design with preset levels of efficacy and futility interrogated after each of 4 stages. The primary outcome was turning preference on the corner test at 1 month. The PARP (poly(ADP-ribose) polymerase) inhibitor, veliparib, was considered futile after the second stage when pooling all animal models (n=231 …

Impact Of Obicetrapib On Major Adverse Cardiovascular Events In High-Risk Patients: A Pooled Analysis, Stephen J Nicholls, Adam J Nelson, Kausik K Ray, Christie M Ballantyne, Marc Ditmarsch, Douglas Kling, Andrew Hsieh, Michael Szarek, John J Kastelein, Michael H Davidson

Faculty, Staff and Students Publications

Background: The cholesteryl ester transfer protein inhibitor obicetrapib decreases levels of atherogenic lipids and raises high-density lipoprotein cholesterol (HDL-C).

Objectives: In this study, we sought to determine the effect of obicetrapib on cardiovascular events.

Methods: The effects of 10 mg obicetrapib and placebo daily on major adverse cardiovascular event (MACE) rates were investigated in a pooled analysis of 354 patients with heterozygous familial hypercholesterolemia (HeFH) and 2,530 patients with atherosclerotic cardiovascular disease (ASCVD) over 365 days. The association between on-treatment lipids and MACE were also investigated.

Results: The cohort (mean age 66 years, 36% female, ASCVD 82%, HeFH 27%, diabetes …

Genetics-Nutrition Interactions Control Diurnal Enhancer-Promoter Dynamics And Liver Lipid Metabolism, Dishu Zhou, Ying Chen, Panpan Liu, Kun Zhu, Juliet Holder-Haynes, S Julie-Ann Lloyd, Cam Mong La, Inna I Astapova, Seunghee Choa, Ying Xiong, Hosung Bae, Marlene Aguilar, Hongyuan Yang, Yu A An, Zheng Sun, Mark A Herman, Xia Gao, Liming Pei, Cholsoon Jang, Joshua D Rabinowitz, Samer G Mattar, Yongyou Zhang, Dongyin Guan

Faculty, Staff and Student Publications

The circadian clock controls 24-h rhythmic processes. However, how genetic variations outside clock genes impact peripheral diurnal rhythms remains largely unknown. Here, we find that genetic variation contributes to different diurnal patterns of hepatic gene expression in both humans and mice. Nutritional challenges alter the rhythmicity of gene expression in mouse liver in a strain-specific manner. Remarkably, genetics and nutrition interdependently control more than 80% of rhythmic gene and enhancer-promoter interactions (E-PIs), with a noncanonical clock regulator, estrogen-related receptor gamma (ESRRγ), emerging as a top transcription factor during motif mining. Knockout of Esrrγ abolishes strain-specific metabolic processes in response to …

Genetic Underpinnings Of The Heterogeneous Impact Of Obesity On Lipid Levels And Cardiovascular Disease, Daeeun Kim, Heather M Highland, Roelof A J Smit, Micah R Hysong, Victoria L Buchanan, Kristin L Young, Chi Zhao, Cassandra N Spracklen, Tuomas O Kilpeläinen, Boya Guo, Burcu F Darst, Yanwei Cai, Zhe Wang, Jessica Lundin, Sonja I Berndt, Joann E Manson, Eirini Marouli, Leslie Lange, Ethan Lange, Myriam Fornage, Christopher R Gignoux, Christopher A Haiman, Stephen S Rich, Steven Buyske, Ruth J F Loos, Charles Kooperberg, Ulrike Peters, Christy L Avery, Penny Gordon-Larsen, Mariaelisa Graff, Laura M Raffield, Kari E North

Faculty, Staff and Student Publications

Background: Obesity is thought to increase cardiovascular disease (CVD) risk partly through dyslipidemia. Yet, obesity's effects on dyslipidemia are not uniform. Understanding the shared genetic basis between obesity and lipid traits can provide insight into this heterogeneity and its implications for CVD risk.

Methods: We examined local genetic correlations between three lipid measures [high-density lipoprotein cholesterol (HDL), low-density lipoprotein cholesterol (LDL), and triglycerides (TG)] and body mass index (BMI) using genome-wide association study summary statistics from European ancestry UK Biobank participants. We identified genomic loci with opposing genetic effects on obesity and dyslipidemia risk (protective BMI-lipid loci) and those with …

Inflammation And Mutational Burden Differentially Associated With Nivolumab Or Ipilimumab Combination Efficacy In Colorectal Cancer, Ming Lei, Michael J Overman, Jin Yao, Thierry André, Sara Lonardi, Heinz-Josef Lenz, Massimo Aglietta, Fabio Gelsomino, Ray Mcdermott, Ka Yeung Mark Wong, Michael A Morse, Eric Van Cutsem, Alain Hendlisz, Dana B Cardin, Bart Neyns, Andrew Hill, Anuradha Krishnamurthy, Franklin Chen, Samith Kochuparambil, Robert R Jenq, Sandzhar Abdullaev, Beilei He, Ruslan Novosiadly, Scott Kopetz

Faculty, Staff and Student Publications

Nivolumab alone and in combination with ipilimumab demonstrated durable clinical benefit in patients with previously treated microsatellite instability-high/mismatch repair-deficient metastatic colorectal cancer in the phase 2 CheckMate 142 study. Here, we report exploratory biomarker analyses from CheckMate 142 evaluating associations between various tissue biomarkers and the efficacy of nivolumab monotherapy and nivolumab plus ipilimumab combination in these patients. Higher expression of inflammation-related gene expression signatures is associated with improved response per investigator assessment and survival benefit with nivolumab monotherapy. In contrast, higher tumor mutational burden, tumor indel burden, and degrees of microsatellite instability are associated with improved response per investigator …

Assessing A Community Health Worker-Facilitated, Digitally Delivered, Family-Centered Diabetes Management Program: Single-Arm Quasi-Experimental Study, Zenong Yin, Vanessa L Errisuriz, Heather Cuevas, Bertha E Flores, Laura Delfausse, Christina Galvan, Jing Wang, Chengdong Li, Renata Morfin, Shiyu Li, Maysa Sapargeldiyeva, Giliane Yza Muyna, Minyu Zhang, Vanessa Sweet, Deborah Parra-Medina

Faculty, Staff and Student Publications

Background: The high prevalence of type 2 diabetes (T2D) and associated complications disproportionately affect low-income Latino populations, who also experience disparities in diabetes self-management (DSM), including poor medication adherence, physical activity, diet, and glycemic control.

Objective: This study examined, through an academic-community partnership, the effectiveness of ¡Salud, Salud! (an evidence-based, family-centered diabetes self-management education and support [DSMES] program) on primary (glycemic control and quality of life) and secondary (social, psychological, and behavioral factors related to T2D management) outcomes among low-income Latino adults with T2D or prediabetes.

Methods: In total, 81 adults (mean age 48.90 years, SD 12.57; n=57, 70.4%, female; …

Rescue Epilepsy Medication And Training: A Comparison Between Midazolam Use, Guidelines, Clinical Practice, And Possibilities In The Uk And Norway, Rohit Shankar

Peninsula Medical School

Objectives: Status epilepticus (SE) is a prolonged epileptic seizure carrying significant risk of long-term disability and death. Rescue therapies are prescribedfor prehospital administration to terminate SE. This study compared prescribingpractices of rescue therapies of midazolam in the UK and Norway.Methods: A cross-sectional, online, 21-item Likert-style survey was administeredto epilepsy professionals in the UK circulated via ILAE/ESNA and in Norway viaILAE/Epilepsinet using a non-discriminatory exponential snowballing techniqueleading to non-probability sampling. Data were collected anonymously and analyzed using descriptive statistics, Mann–Whitney, Chi-square, and Fisher's exact tests. Significance was accepted at p<0.05.Results: All 86 UK and 53 Norway respondents identified buccal midazolam as the first-line rescue medication choice in the community for prolonged and/or generalized tonic–clonic seizures. Norwegian respondents had significantly more experience in epilepsy-related work (p=0.002), were more likely to have a larger caseload on buccal midazolam (p<0.001), prescribed higher midazolam doses (p<0.001), and provided training yearly (p<0.001). UK respondents were more likely to delegate rescue medication prescribing to primary care (p=0.006) and reviewed emergency management plans more frequently (p=0.006). There was an inter-country difference in the period of midazolam non-use that respondents required before withdrawing from treatment plans (p<0.001). Concern about inappropriate use of buccal midazolam was similarly high in both countries.Significance: This study compared epilepsy professionals in two neighboringhigh-income countries. Findings suggest an urgent need for international guidelines to recommend best practices on prescribing doses and withdrawal of buccal midazolam. The potential abuse of buccal midazolam by patients and carers warrants further investigation.

Causal Ai-Based Clinical And Radiomic Analysis For Optimizing Patient Selection In Combined Immunotherapy And Sabr In Early-Stage Nsclc: A Secondary Analysis Of The Phase Ii I-Sabr Trial, Maliazurina B Saad, Eman Showkatian, Vivek Verma, Qasem Al-Tashi, Muhammad Aminu, Xinyan Xu, Muhamed Qayati Mohamed, Morteza Salehjahromi, Sheeba J Sujit, Yuliya Kitsel, Steven H Lin, Zhongxing Liao, Saumil Gandhi, David Qian, David Jaffray, Caroline Chung, Natalie I Vokes, Jianjun Zhang, J Jack Lee, John V Heymach, Jia Wu, Joe Y Chang

Faculty, Staff and Student Publications

Background: The recent phase II randomized stereotactic ablative radiotherapy with and without immunotherapy (I-SABR) trial has shown improved event-free survival (EFS) when adding immunotherapy to stereotactic ablative radiotherapy (SABR) for early-stage inoperable non-small cell lung cancer (NSCLC). However, optimizing patient selection thereof is critical, because not every patient benefits from immunotherapy. Leveraging the powerful use of artificial intelligence, this secondary analysis of the I-SABR trial developed a modeling system (named "I-SABR-SELECT") based on clinical and radiomic factors to address which patients should receive additional immunotherapy.

Methods: The discovery/validation cohorts were from the I-SABR trial, with external validation from the single-arm …

Risk Markers For Sudden Unexpected Death In Epilepsy: An Observational, Prospective, Multicentre Cohort Study, Manuela Ochoa-Urrea, Xi Luo, Laura Vilella, Nuria Lacuey, Shirin Jamal Omidi, Norma J Hupp, Blanca Talavera, Johnson P Hampson, M R Sandhya Rani, Shiqiang Tao, Xiaojin Li, Christina Y Miyake, Licong Cui, Jaison S Hampson, Ganne Chaitanya, Yash Shashank Vakilna, Rup K Sainju, Daniel Friedman, Maromi Nei, Luke Allen, Catherine A Scott, Joana Oliveira, Brian Gehlbach, Stephan U Schuele, Jennifer A Ogren, Ronald M Harper, Beate Diehl, Lisa M Bateman, George B Richerson, Jose-Miguel Yamal, Guo-Qiang Zhang, Orrin Devinsky, Samden D Lhatoo

Faculty, Staff and Student Publications

Background: Sudden unexpected death in epilepsy (SUDEP) is the leading cause of epilepsy-related mortality. Generalised-particularly nocturnal-convulsive seizures, longstanding epilepsy, and solitary living have been identified retrospectively as risk factors. No definitive electroclinical biomarkers have been prospectively ascertained. This study aimed to identify SUDEP risk markers using multimodality data with long-term follow-up.

Methods: This prospective, multicentre, observational cohort study, conducted at nine centres (eight in the USA and one in the UK), recruited children and adults with epilepsy who were undergoing prolonged video-electroencephalographic (EEG) monitoring. Inclusion criteria were diagnosis of epilepsy by an epilepsy specialist, with or without drug resistance; age …

Male Hypogonadism: Recommendations From The Fifth International Consultation On Sexual Medicine (Icsm 2024), Mohit Khera, Luiz Otavio Torres, Ethan D Grober, Abraham Morgentaler, Martin Miner, Thomas Hugh Jones, Jesse N Mills, Andrea Salonia

Faculty, Staff and Students Publications

Introduction: Male hypogonadism is a clinical condition combining low circulating testosterone (T) and specific signs and symptoms associated with impaired hormone production.

Objectives: To provide the 5th International Consultation for Sexual Medicine consensus paper with recommendations concerning management strategies for hypogonadism.

Outcomes: A narrative review combined with expert opinions on major topics concerning diagnosis of male hypogonadism; treatment options; T impact toward cardiovascular, metabolic, sexual, and reproductive health; and prostate cancer (PCa).

Methods: A consensus panel was held with leading Sexual Medicine experts during the 5th ICSM. Relevant English-language peer-reviewed literature was reviewed with a focus on research from but …

All-Optical Voltage Interrogation For Probing Synaptic Plasticity In Vivo, Jacques Carolan, Michelle A Land, Xiaoyu Lu, Maxime Beau, Dimitar Kostadinov, François St-Pierre, Beverley A Clark, Michael Häusser

Faculty, Staff and Students Publications

Measuring synaptic efficacy and defining the rules for induction of synaptic plasticity at identified connections in the mammalian brain is essential for understanding how synapses contribute to learning and memory. This requires new approaches to selectively evoke presynaptic activity and measure postsynaptic responses with high spatiotemporal resolution and high sensitivity over long periods in vivo. Here we develop an all-optical approach to probe synaptic plasticity at identified cerebellar synapses in awake, behaving mice. We developed and applied JEDI-2Psub, a genetically encoded voltage indicator with increased sensitivity around resting membrane potentials, to record subthreshold and suprathreshold activity in Purkinje cell (PC) …

Ambient Fine Particulate Matter, Residential Greenness, And Childhood Cancer Risk By Trimester Of Exposure In Minnesota 2000 To 2014: A Case-Control Study, Cassandra J Clark, David Haynes, Zhanni Lu, Jeannette M Sample, Laura A Mcguinn, Thanh T Hoang, Philip J Lupo, Michael E Scheurer, Erin L Marcotte, Lindsay A Williams

Faculty, Staff and Students Publications

Background: Outdoor air pollution is a suspected risk factor for childhood cancer, and there is some evidence that greenness may reduce cancer risk. We examined relationships between prenatal exposure to ambient fine particle air pollution [particulate matter < 2.5 µg/m3 (PM2.5)], greenness, and childhood cancer risk in Minnesota.

Methods: Cases included individuals born in the state of Minnesota and reported to the Minnesota Cancer Reporting System between 2000 and 2014 (n = 1272, ages 0-14 years at diagnosis) and birth year-matched cancer-free controls (n = 5245). We used Network Common Data Form to estimate monthly PM2.5 exposure and the normalized difference vegetation index for census tract-level greenness. We estimated ORs and …

A Mast Cell Receptor Mediates Post-Stroke Brain Inflammation Via A Dural-Brain Axis, Ruchita Kothari, Mostafa W Abdulrahim, Hyun Jong Oh, Daniel H Capuzzi, Collin B Kilgore, Sumil K Nair, Yaowu Zhang, Nathachit Limjunyawong, Sarbjit S Saini, Jennifer E Kim, Justin M Caplan, Fernanado L Gonzalez, Christopher M Jackson, Chetan Bettegowda, Judy Huang, Bhanu P Ganesh, Chunfeng Tan, Raymond C Koehler, Rafael J Tamargo, Louise D Mccullough, Risheng Xu, Xinzhong Dong

Faculty, Staff and Student Publications

The immune environment surrounding the brain plays a fundamental role in monitoring signs of injury. Insults, including ischemic stroke, can disrupt this balance and incite an exaggerated inflammatory response, yet the underlying mechanism remains unclear. Here, we show that the mast-cell-specific receptor Mrgprb2 regulates post-stroke brain inflammation from the meninges. Mrgprb2 causes meningeal mast cell degranulation after stroke, releasing immune mediators. This process recruits skull bone marrow neutrophils into the dura and further promotes neutrophil migration from the dura into the brain by cleaving the chemorepellent semaphorin 3a. We demonstrate that the human ortholog, MRGPRX2, is expressed in human meningeal …

Rare Variants In Prkci Cause Van Der Woude Syndrome And Other Features Of Peridermopathy, Kelsey Robinson, Sunil K Singh, Rachel B Walkup, Dorelle V Fawwal, Kendra M Vilfort, Amanda Koloskee, Azeez Fashina, Wasiu Lanre Adeyemo, Terri H Beaty, Azeez Butali, Carmen J Buxó, Wendy K Chung, David J Cutler, Michael P Epstein, Brooklynn Gasser, Lord J J Gowans, Jacqueline T Hecht, Anuj Mankad, Lina Moreno Uribe, Daryl A Scott, Gary M Shaw, Mary Ann Thomas, Seth M Weinberg, Eric C Liao, Harrison Brand, Mary L Marazita, Robert J Lipinski, Jeffrey C Murray, Robert A Cornell, Elizabeth J Leslie-Clarkson

Faculty, Staff and Student Publications

Van der Woude syndrome (VWS) is an autosomal dominant disorder characterized by lower lip pits and orofacial clefts (OFCs). With a prevalence of ∼1 in 35,000 live births, it is the most common form of syndromic clefting. Most VWS is attributed to variants in IRF6 (∼70%) or GRHL3 (∼5%), leaving up to 25% of individuals without a molecular diagnosis. Both IRF6 and GRHL3 function in a transcriptional regulatory network (TRN) governing differentiation of periderm, a single epithelial cell layer preventing pathological adhesions during palatogenesis. Periderm disruption can elicit a spectrum of phenotypes, including lip pits and OFCs, pterygia, and severe …

Genome-Wide Analysis Of Dna Methylation Signatures Linking Prenatal Exposure To The Chinese Great Famine And Blood Lipids In Late Adulthood: The Genomic Research Of The Chinese Famine (Grecf) Study, Huan Wang, Luqi Shen, Tingting Liu, Ruiyuan Zhang, Zhenghe Wang, Jingkai Wei, Ye Shen, Jinzhen Guo, Toni Miles, Changwei Li, Zhiyong Zou

Faculty, Staff and Student Publications

Background/objectives: Prenatal exposure to famine can lead to lasting health effects through changes in DNA methylation. This study aims to evaluate the impact of prenatal exposure to the Chinses Great Famine (1959-1961) on human epigenome and the subsequent influence on blood lipids.

Methods: We conducted an epigenome-wide association study (EWAS) of peripheral blood-based DNA methylation and prenatal exposure to the Chinese Great Famine as well as blood lipids among eight participants exposed to famine and eight sex-matched participants (born ≤ 3 years after the famine). Genome-wide DNA methylation sites were profiled using the Illumina EPIC BeadChip, which covers 850K methylation …

Concurrent Local Therapy Extends Clinical Benefit Of Tebentafusp In Metastatic Uveal Melanoma Patients, Tristan L. Lim, Kamaneh Montazeri, Eric Wehrenberg-Klee, Antoine Desilets, Rino S. Seedor, Marlana Orloff, Takami Sato, Michael Caplan, Mariam El-Ashmawy, Benjamin Izar, Shaheer Khan, Inderjit Mehmi, Aleigha Lawless, Theodore S. Hong, Omid Hamid, Richard D. Carvajal, Alexander Shoushtari, Ryan J. Sullivan

Kimmel Cancer Center Faculty Papers

BACKGROUND: Tebentafusp has significantly improved overall survival in HLA-A*02:01+ metastatic uveal melanoma (mUM) patients even in those with a best objective response of progressive disease. Thus, strategies to maintain tebentafusp therapy are critical. Here, we examine the efficacy and safety of adding concurrent local therapy (CLT) to tebentafusp upon radiological progression with tebentafusp alone.

PATIENTS AND METHODS: This multicenter retrospective study included mUM patients treated with tebentafusp and CLT, consisting of extrahepatic soft tissue irradiation and liver-directed therapies (LDTs). Efficacy of target and nontarget sites were assessed per RECIST version 1.1. PFS with tebentafusp alone (PFS1) was compared to that …

Escape Of Kdm6a From X Chromosome Is Detrimental To Ischemic Brains Via Irf5 Signaling, Conelius Ngwa, Afzal Misrani, Kanaka Valli Manyam, Yan Xu, Shaohua Qi, Romana Sharmeen, Juneyoung Lee, Long-Jun Wu, Louise Mccullough, Fudong Liu

The Brown Foundation: Institute of Molecular Medicine

The role of chromatin biology and epigenetics in disease progression is gaining increasing recognition. Genes that escape X chromosome inactivation (XCI) can impact neuroinflammation through epigenetic mechanisms. Our previous study has suggested that the X escapee genes Kdm6a and Kdm5c are involved in microglial activation after stroke in aged mice. However, the underlying mechanisms remain unclear. We hypothesized that Kdm6a/5c demethylate H3K27Me3/H3K4Me3 in microglia, respectively, and mediate the transcription of interferon regulatory factor 5 (IRF5) and IRF4, leading to microglial pro-inflammatory responses and exacerbated stroke injury. Aged (17–20 months) Kdm6a/5c microglial conditional knockout (CKO) female mice (one allele of the …

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.

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 …

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 …

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 …