Medicine and Health Sciences Commons^™

European And African Ancestry-Specific Plasma Protein-Qtl And Metabolite-Qtl Analyses Identify Ancestry-Specific T2d Effector Proteins And Metabolites, Chengran Yang, Priyanka Gorijala, Jigyasha Timsina, Lihua Wang, Menghan Liu, Ciyang Wang, William Brock, Yueyao Wang, Fumihiko Urano, Yun Ju Sung, Carlos Cruchaga

2020-Current year OA Pubs

In this study, we generated and integrated plasma proteomics and metabolomics with the genotype datasets of over 2300 European (EUR) and 400 African (AFR) ancestries to identify ancestry-specific multi-omics quantitative trait loci (QTLs). In total, we mapped 954 AFR pQTLs, 2848 EUR pQTLs, 65 AFR mQTLs, and 490 EUR mQTLs. We further applied these QTLs to ancestry-stratified type-2 diabetes (T2D) risk to pinpoint key proteins and metabolites underlying the disease-associated genetic loci. Using INTACT that combined trait-imputation and colocalization results, we nominated 270 proteins and 72 metabolites from the EUR set; seven proteins and one metabolite from the AFR set …

Regional Heterogeneity Of The Blood-Brain Barrier, Marie Blanchette, Kaja Bajc, Benjamin D Gastfriend, Caterina P Profaci, Nadine Ruderisch, Cayce E Dorrier, Guo Zhong, Raquel Cuevas-Diaz Duran, Sean S Harvey, Iris H Garcia-Pak, Lucija Pintarić, Manon Leclerc, Louise Reveret, Vincent Émond, Annette Wang, Deepti Pant, Linus T Tsai, Frédéric Calon, Nina Isoherranen, Sean P Palecek, Eric V Shusta, Jiaqian Wu, Richard Daneman

The Brown Foundation: Institute of Molecular Medicine

The blood-brain barrier (BBB), formed by specialized endothelial cells (ECs), regulates the extracellular composition of the central nervous system (CNS). Little is known about whether there are regional specializations of the BBB that may control the function of specific neural circuits. We use single cell RNA-seq to characterize ECs from nine CNS regions in male mice: cortex, hippocampus, cerebellum, spinal cord, striatum, thalamus, hypothalamus, midbrain, and medulla/pons. Although there is a core BBB transcriptional profile, there are significant regional specializations. Stra6, a retinoid transporter, is highly enriched in the BBB of the nucleus accumbens shell (ShNAc) and ventral cochlear nucleus, …

Subsets Of Follicular Lymphoma 3b Have Divergent Outcomes: Results From The Prospective Multicenter Mer And Leo Cohorts, Patrizia Mondello, David Russler-Germain, Brad Kahl, Et Al.

2020-Current year OA Pubs

Follicular lymphoma (FL) 3B is considered an aggressive lymphoma, however recent studies have challenged this paradigm. Additional controversy involves the clinical implication of pure FL3B (FL3Bp) vs FL3B with concurrent diffuse large B cell lymphoma (DLBCL) (FL3Bc). To address these questions, we performed a pooled study of the MER and LEO cohorts comparing 464 newly diagnosed, R-CHOP-treated patients with FL1-2 (n = 216), FL3A (n = 170), FL3B (n = 78) and 739 DLBCL. Among FL3B patients, 19 (24%) had FL3Bc and 59 (76%) FL3Bp. Baseline characteristics and outcomes were similar between the two FL3B subtypes. Compared to FL1-3A, FL3B …

Micbg406a Polymorphism Reduces Risk Of Mechanical Ventilation And Death During Viral Acute Lung Injury, Harry Pickering, Narges Alipanah-Lechner, Ernie Chen, Dylan Duchen, Holden T Maecker, Seunghee Kim-Schulze, Ruth R Montgomery, Chris Cotsapas, Hanno Steen, Florian Krammer, Charles R Langelier, Ofer Levy, Lindsey R Baden, Esther Melamed, Lauren Ir Ehrlich, Grace A Mccomsey, Rafick P Sekaly, Charles B Cairns, Elias K Haddad, Albert C Shaw, David A Hafler, David B Corry, Farrah Kheradmand, Mark A Atkinson, Scott C Brakenridge, Nelson I Agudelo Higuita, Jordan P Metcalf, Catherine L Hough, William B Messer, Bali Pulendran, Kari C Nadeau, Mark M Davis, Ana Fernandez Sesma, Viviana Simon, Monica Kraft, Chris Bime, David J Erle, Joanna Schaenmann, Al Ozonoff, Bjoern Peters, Steven H Kleinstein, Alison D Augustine, Joann Diray-Arce, Patrice M Becker, Nadine Rouphael, Matthew C Altman, Steve Bosinger, Walter Eckalbar, Carolyn S Calfee, Oscar A Aguilar, Elaine F Reed, John R Greenland, Daniel R Calabrese

Faculty, Staff and Students Publications

MHC class I polypeptide-related sequence B (MICB) is a ligand for NKG2D. We have shown NK cells are central to lung transplant acute lung injury (ALI) via NKG2D activation, and increased MICB in bronchoalveolar lavage predicts ALI severity. Separately, we found a MICB polymorphism (MICBG406A) is associated with decreased ALI risk. We hypothesized this polymorphism would protect against severe SARS-CoV-2 respiratory disease. We analyzed 1,036 patients hospitalized with SARS-CoV-2 infection from IMPACC. Associations between MICBG406A and outcomes were determined by linear regression or Cox proportional hazards models. We also measured immune profiles of peripheral blood and the upper and lower …

Generational Health Professional Perceptions About Artificial Intelligence Impact On Clinical Work, Karima Lalani, Kerryn Butler-Henderson, David T Marc, Susan H Fenton

Faculty, Staff and Student Publications

Whilst the evidence-base related to artificial intelligence (AI) has been growing in relation to its use and impact on healthcare, there is a lack of evidence related to the health workforce impact and no research examining the generational perceptions in relation to the health workforce and AI. This paper presents the results of a survey, which found generational differences in perceptions about the impact of AI on clinical jobs. Gen Z and Millennials were more likely to agree with statements that AI will improve their clinical decision-making skills/abilities, accomplish clinical tasks more quickly, and cause unemployment in their professional occupation. …

Amputation Trends Among People Who Use Drugs In The Context Of Philadelphia’S Increasingly Xylazine Adulterated Drug Supply, Rose Laurano, Monika Pogorzelska-Maziarz, Traci C. Green, Sara Beachy, Kristin L. Rising, Jeffrey K. Hom, Megan K. Reed

Jefferson Center for Connected Care Faculty Papers

BACKGROUND: Xylazine-adulterated fentanyl has rapidly spread across the United States and has been increasingly detected in overdose deaths in Philadelphia, PA through medical examiner reports, clinical testing, and widescale drug checking. Xylazine use has been associated with wounds which may lead to amputation, but the extent of this outcome has not been explored.

METHODS: Utilizing the 10th revision of the International Classification of Diseases (ICD-10) codes, we conducted a de-identified retrospective analysis of data for patients identified with opioid related disorders (ICD-10 code F11) admitted to four different hospitals in Philadelphia, PA between 2018 and 2023. Exposure to xylazine use …

Frontline Acalabrutinib, Lenalidomide And Rituximab For Advanced Stage Follicular Lymphoma With High Tumor Burden: Phase Ii Trial, Paolo Strati, Lei Feng, Jason R Westin, Ranjit Nair, Luis E Fayad, Maria A Rodriguez, Dai Chihara, Luis Malpica, Jared Henderson, Mariana Gallardo, Marissa Rivera, Iris Wang, Anastasiia Bolshakova, Anastasia Radko, David Kurtz, Stefan K Alig, Christopher R Flowers, Ash A Alizadeh, Sattva S Neelapu

Faculty, Staff and Student Publications

This phase II trial aims to determine the efficacy and safety of frontline acalabrutinib, lenalidomide and rituximab for patients with advanced stage follicular lymphoma (FL) and high tumor burden. The primary endpoint was best complete response (CR) rate; the secondary endpoints were overall response rate (ORR), duration of response measured as CR at 30 months (CR30), progression of disease at 24 months (POD24) rate, progression-free survival (PFS), overall survival and safety. Twenty-four patients with previously untreated FL were included in this phase 2 single arm study (NCT04404088). The most common grade 3-4 adverse events were neutropenia (58%) and …

Histologic And Immune Characterization Of Cutaneous Immune-Related Adverse Events Induced By Immune Checkpoint Inhibitors, Omar Pacha, Anisha B Patel, Jonathan L Curry, Cara L Haymaker, Nejla Ozirmak Lermi, Dzifa Yawa Duose, Ken Chen, Joud Hajjar, Aung Naing

Faculty, Staff and Student Publications

Background: Although immune checkpoint inhibitors (ICIs) are efficacious, they often cause immune-related adverse events (irAEs), most commonly cutaneous irAEs (CirAEs). The mechanisms underlying CirAEs remain unclear.

Methods: Attempting to better understand their mechanisms and histology we conducted a prospective study of 15 patients with advanced cancers treated with ICIs who developed grade 2 or higher CirAEs. Clinical and histologic characterization of biopsy specimens of CirAEs was performed. Histologic analysis of patient biopsy specimens were subdivided by epidermal reaction patterns that included spongiotic, lichenoid, and interface dermatitis patterns. A targeted RNA expression assay was used to identify immune markers in CirAE …

Discontinuation Rates And Predictors Of Medical Cannabis Cessation For Chronic Musculoskeletal Pain, Mohammad Khak, Sina Ramtin, Juliet Chung, Asif M. Ilyas, Ari Greis

Rothman Institute Papers

Medical cannabis (MC) is increasingly used as a treatment for chronic musculoskeletal pain, but there is limited data on factors influencing its discontinuation. This study aims to investigate the rates of MC discontinuation and explore factors influencing it in patients with chronic musculoskeletal pain. A retrospective analysis was conducted on 78 patients certified for medical cannabis over a 2 year period. Patient demographics, pain origin, and Global Physical Health (GPH) and Global Mental Health (GMH) scores were collected before intervention. Discontinuation rates were measured at three-month and one-year follow-up. Statistical analyses, including Fisher's Exact Test and two-sample t-tests, were performed …

Urinary Pneumococcal Serotype Detection Among Children With And Without Community-Acquired Pneumonia, Lilliam Ambroggio, Lindsay R Grant, Jillian M Cotter, Samuel R Dominguez, Daniel Olson, Sara R Saporta-Keating, Cody Bender, Mohammad Ali, Kathleen Grice, Gonzalo Lerner, Michael W Pride, Ashley Miller, Maria J Tort, Annaellis Vaughan, Elizabeth Temte, Alec Edid, Alejandro Cané, Kristina G Hulten, Jill Stein, Bradford D Gessner, Edwin J Asturias

Faculty, Staff and Students Publications

Background: Urinary antigen detection (UAD) assays can address diagnostic challenges with culture-based identification of S. pneumoniae. We aimed to evaluate the utility of Pfizer's UAD1 and UAD2 assays for pneumococcal serotype surveillance in children with community acquired pneumonia (CAP) or upper respiratory tract infections (URI).

Methods: From March 2021-December 2023, children 3 months to 5 years who presented to the Children's Hospital Colorado Emergency Department with respiratory symptoms were enrolled as CAP or URI; healthy children served as controls. Nasal swabs were tested for pneumococcus by PCR. UAD assays identified pneumococcal serotypes from urine. Groups were compared using descriptive statistics. …

Adipokines And Transitions In Metabolic Health Over Time: The Atherosclerosis Risk In Communities (Aric) Study, Bige Ozkan, Sui Zhang, Justin B Echouffo-Tcheugui, Roberta Florido, Vijay Nambi, Erin D Michos, Layla A Abushamat, Kunihiro Matsushita, Gary Gerstenblith, Roger S Blumenthal, Ron Hoogeveen, Christie M Ballantyne, Josef Coresh, Elizabeth Selvin, Chiadi E Ndumele

Faculty, Staff and Students Publications

Context: Transitions in metabolic health status over time are strongly linked to risk for cardiovascular events, particularly among individuals with obesity. Adipokines are proteins with metabolic effects, but their role in transitions in metabolic health status over time is unknown.

Objective: To evaluate the associations of adiponectin and leptin with metabolic risk transitions over time.

Methods: Among 8423 individuals who attended ARIC Visits 2 (1990-1992) and 4 (1996-1998), we evaluated prospective associations of Visit 2 levels of the adipokines adiponectin and leptin (per 1-SD higher) with 6-year transitions in metabolic health. Metabolic health was categorized as metabolically "healthy" [no metabolic …

Tet2-Mutant Myeloid Cells Mitigate Alzheimer’S Disease Progression Via Cns Infiltration And Enhanced Phagocytosis In Mice, Katie A Matatall, Trisha K Wathan, Minh Nguyen, Hu Chen, Alexandra Mcdonald, Guantong Qi, Julia A Belk, Marcus A Florez, Duy T Le, Temitope Olarinde, Caitlyn Vlasschaert, Marco M Buttigieg, Chih-Wei Fan, Saul Carcamo, Ruoqiong Cao, Daniel E Kennedy, Arushana A Maknojia, Apoorva Thatavarty, Josaura V Fernandez Sanchez, Hind Bouzid, Surabi Veeraragavan, Susan Crocker, Margaret A Goodell, Antony Rodriguez, Siddhartha Jaiswal, Michael J Rauh, Eirini P Papapetrou, Samuele G Marro, Katherine Y King

Faculty, Staff and Students Publications

Clonal hematopoiesis (CH) is associated with many age-related diseases, but its interaction with Alzheimer's disease (AD) remains unclear. Here, we show that TET2-mutant CH is associated with a 47% reduced risk of late-onset AD (LOAD) in the UK Biobank, whereas other drivers of CH do not confer protection. In a mouse model of AD, transplantation of Tet2-mutant bone marrow reduced cognitive decline and β-amyloid plaque formation, effects not observed with Dnmt3a-mutant marrow. Bone-marrow-derived microglia-like cells were detected at an increased rate in Tet2-mutant marrow recipients, and TET2-mutant human induced pluripotent stem cell (iPSC)-derived microglia were more phagocytic and hyperinflammatory than …

Artificial Transneurons Emulate Neuronal Activity In Different Areas Of Brain Cortex, Rivu Midya, Ambarish S Pawar, Debi P Pattnaik, Eric Mooshagian, Pavel Borisov, Thomas D Albright, Lawrence H Snyder, R Stanley Williams, J Joshua Yang, Alexander G Balanov, Sergei Gepshtein, Sergey E Savel'ev

2020-Current year OA Pubs

Rapid development of memristive elements emulating biological neurons creates new opportunities for brain-like computation at low energy consumption. A first step toward mimicking complex neural computations is the analysis of single neurons and their characteristics. Here we measure and model spiking activity in artificial neurons built using diffusive memristors. We compare activity of these artificial neurons with the spiking activity of biological neurons measured in sensory, pre-motor, and motor cortical areas of the monkey (male) brain. We find that artificial neurons can operate in diverse self-sustained and noise-induced spiking regimes that correspond to the activity of different types of cortical …

Feasibility And Preliminary Efficacy Of A Lymphedema And Fibrosis Self-Management Program For Head And Neck Cancer Survivors: A Pilot Randomized Controlled Trial, Jie Deng, Barbara Murphy, Lucy Andersen, Erin Mcmenamin, John Lukens, Joy Cohn, Karthik Rajasekaran, Ryan Quinn, Bryan Spinelli, Alexander Lin

Department of Physical Therapy Faculty Papers

OBJECTIVES: Survivors of head and neck cancer (HNC) are at high risk for developing lymphedema and fibrosis (LEF). Once diagnosed with LEF, survivors must engage in a lifelong program of self-care to minimize long-term adverse effects. However, evidence-based LEF self-management (SM) programs are lacking. To fill this void, we developed and pilot-tested a LEF-SM program for HNC survivors.

MATERIALS AND METHODS: The LEF-SM Program was developed using the Information-Motivation-Behavioral Skills model of health behavior change as a framework. The program was pilot tested in a three-group randomized controlled trial evaluating feasibility and preliminary efficacy. Fifty-nine participants were randomized to: Usual …

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

Faculty, Staff and Student Publications

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

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

Exploring Factors Affecting The Adoption And Use Of Digital Health Technologies Among Older Adults With Cancer: A Qualitative Study, Misun Hwang, Youmin Cho, Katie Gahn, Heidi Mason, Milisa Manojlovich, Yang Gong, Yun Jiang

Faculty, Staff and Student Publications

Purpose: Although digital health technologies (DHTs) are promising to improve health outcomes in older adults with cancer, the low adoption and limited use remain significant gaps in their effective digital health care. Little is known about their concerns about adopting and using DHTs in routine life, particularly in the continued use phase. This study aims to explore factors affecting the initial adoption and continued use of DHTs among older adults with cancer.

Methods: A secondary analysis of qualitative data was conducted based on interviews with 21 older adults (≥ 65 years) with breast, prostate, lung, or colorectal cancer. The transcripts …

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

2020-Current year OA Pubs

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

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

Drug Development Studies Supporting Zileuton As A Parenteral Adjuvant To Attenuate Antibiotic-Associated Nephrotoxicity, Cole S Hudson, James E Smith, Linh T Vuong, Nicholas S Teran, Nazanin Pouya, David Sheikh-Hamad, Xinli Liu, Shama Kajiji, Vincent H Tam

Faculty, Staff and Students Publications

Glycopeptide, polymyxin, and aminoglycoside antibiotics are among the most commonly used agents to treat drug-resistant bacterial infections; however, their clinical use is hindered by nephrotoxicity. We previously reported that zileuton has the potential to attenuate antibiotic-associated nephrotoxicity in an animal model. Here, we further report the development of a parenteral formulation and exploration of dosing strategies for zileuton. The solubility, stability, and multi-dose safety of two zileuton formulations were evaluated. Zileuton serum and renal tissue pharmacokinetics were evaluated after a single dose and compared to steady state after 10 days. Different dosing strategies of zileuton to attenuate vancomycin-, polymyxin B-, …

Hand Hygiene Knowledge, Attitudes, Practices, And Hand Dirtiness Of Primary School Students Before And After A Behavioral Change Intervention During The Covid-19 Pandemic, Belize 2022-2023, Anh N Ly, Christina Craig, Kelsey Mcdavid, Dian Maheia, Yolanda Gongora, Francis Morey, Russell Manzanero, Alexandra Medley, Allison Stewart, Allison Lino, Ramiro Quezada, Rosalva Blanco, Vickie Romero, Gerhaldine Morazan, Ella Hawes, Oluwadara Okeremi, Kanako Ishida, Matthew Lozier, Kristy O Murray

Faculty, Staff and Students Publications

Hand hygiene (HH) can prevent the spread of infectious diseases and school absenteeism. However, limited data exist on HH practices at schools. Our study assesses the impact of a pilot HH intervention in 12 schools in Belize during the coronavirus disease 2019 (COVID-19) pandemic. After a national assessment of existing water, sanitation, and hygiene resources (December 2021-January 2022), 12 pilot schools were selected to evaluate an HH intervention, which included environmental nudges and HH education. Baseline assessments occurred in March 2022, the HH intervention was implemented during October 2022-May 2023, and follow-up assessments were conducted in June 2023. Student knowledge, …

Rapid And Sustainable Deep Testosterone Reduction Predicts Effective Androgen Deprivation Therapy For Metastatic Hormone-Sensitive Prostate Cancer., Ze Wang, Haiyang Xiao, Chongliang Zheng, Jian Chen, Qiming Chen, Zhenzhen Chen, Dianzheng Zhang, Luofu Wang, Weihua Lan, Qiuli Liu, Jun Jiang

PCOM Scholarly Works

The testosterone (TT)/androgen receptor axis plays a crucial role in the initiation and progression of prostate cancer (PCa). We aimed to investigate the predictive value of serum TT levels on metastatic PCa progression. A total of 219 patients with metastatic PCa were included in this study. Analyses performed included Pearson's correlation test, Wilcoxon rank test, Chi-square test, Cox regression, and Kaplan-Meier analysis. High serum TT levels (> 405 ng/dL) before ADT treatment, deep testosterone reduction (DTR) within the first year of ADT, rapid DTR within 3 months of ADT, and sustained DTR in the first year of ADT are associated …

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

Faculty, Staff and Student Publications

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

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

Duncan NRI Faculty and Staff Publications

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

Rescue Of Male Infertility By Human Prss55 In Transgenic Mice Establishes A Contraceptive Research Model, Courtney M Sutton, Kohei Umezu, Daisuke Mashiko, Masahito Ikawa, Irina V Larina, Thomas X Garcia, Martin M Matzuk

Faculty, Staff and Students Publications

The development of non-hormonal male contraceptives requires validated preclinical models. This study investigated whether human orthologs of two mouse testis-specific serine proteases, PRSS55 and TMPRSS12, both essential for male fertility in mice, could functionally rescue the infertility phenotypes of their respective knockout mouse lines. We generated transgenic mouse lines expressing human PRSS55 with either an extracellularly or intracellularly positioned C-terminal 3xFLAG tag (RES GPI or RES TM), and a line expressing human TMPRSS12 with a C-terminal 3xFLAG tag (T12 RES), all on their respective mouse null backgrounds. Fertility was assessed through continuous mating trials, and sperm parameters were evaluated. Both …

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

Faculty, Staff and Students Publications

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

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

Results: Of 67 fetuses, 96% had …

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

Faculty, Staff and Students Publications

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

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

Faculty, Staff and Student Publications

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

Depletion Of Effector Regulatory T Cells Associates With Major Response To Induction Dual Immune Checkpoint Blockade, Xianli Jiang, Nils-Petter Rudqvist, Bo Jiang, Shengbin Ye, Shan He, Qingnan Liang, Jinzhuang Dou, Michelle D Williams, Joe Dan Dunn, Jason M Johnson, Keiko Akagi, Weihong Xiao, Shaoheng Liang, Satvik Elayavalli, Baohua Sun, Edwin R Parra, Renata Ferrarotto, Adam S Garden, Clifton David Fuller, Jay Reddy, Neil D Gross, Miriam N Lango, Cheuk Hong Leung, Suyu Liu, Diane D Liu, Meng Li, J Jack Lee, Michael A Curran, Jack Phan, Ken Chen, Maura L Gillison

Faculty, Staff and Student Publications

In a phase II trial, patients with local-regionally advanced human papillomavirus-positive oropharyngeal carcinoma (n = 35) received ipilimumab (anti-CTLA4) and nivolumab (anti-PD-1) as induction immunotherapy and concurrently with radiotherapy (NCT03799445). Coprimary endpoints included 6-month complete metabolic response rate (94%) and 2-year progression-free survival (84%). Induction yielded a 46% major histopathologic response rate. Single-cell profiling revealed responders had higher baseline intratumoral CD8+ T cells with a tumor-reactive, tissue-resident memory (TRM) phenotype and a treatment-related decrease in effector regulatory T (eTreg) cells. The eTreg decrease correlated with CD8+ T-cell clonotype transitioning from TRM to effector memory and IFNG+ effector cells. …

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

2020-Current year OA Pubs

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

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

2020-Current year OA Pubs

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

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

Oncology Articles

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

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