Medicine and Health Sciences Commons^™

Measurement Of Severe Acute Respiratory Syndrome Coronavirus 2 Antigens In Plasma Of Pediatric Patients With Acute Coronavirus Disease 2019 Or Multisystem Inflammatory Syndrome In Children Using An Ultrasensitive And Quantitative Immunoassay, George B Sigal, Tanya Novak, Anu Mathew, Janet Chou, Yubo Zhang, Navaratnam Manjula, Pradeepthi Bathala, Jessica Joe, Nikhil Padmanabhan, Daniel Romero, Gabriella Allegri-Machado, Jill Joerger, Laura L Loftis, Stephanie P Schwartz, Tracie C Walker, Julie C Fitzgerald, Keiko M Tarquinio, Matt S Zinter, Jennifer E Schuster, Natasha B Halasa, Melissa L Cullimore, Aline B Maddux, Mary A Staat, Katherine Irby, Heidi R Flori, Bria M Coates, Hillary Crandall, Shira J Gertz, Adrienne G Randolph, Nira R Pollock, Overcoming Covid-19 Investigators

Center for Medical Ethics and Health Policy Staff Publications

Background: Detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antigens in blood has high sensitivity in adults with acute coronavirus disease 2019 (COVID-19), but sensitivity in pediatric patients is unclear. Recent data suggest that persistent SARS-CoV-2 spike antigenemia may contribute to multisystem inflammatory syndrome in children (MIS-C). We quantified SARS-CoV-2 nucleocapsid (N) and spike (S) antigens in blood of pediatric patients with either acute COVID-19 or MIS-C using ultrasensitive immunoassays (Meso Scale Discovery).

Methods: Plasma was collected from inpatients (< 21 years) enrolled across 15 hospitals in 15 US states. Acute COVID-19 patients (n = 36) had a range of disease severity and positive nasopharyngeal SARS-CoV-2 RT-PCR within 24 hours of blood collection. Patients with MIS-C (n = 53) met CDC criteria and tested positive for SARS-CoV-2 (RT-PCR or serology). Controls were patients pre-COVID-19 (n = 67) or within 24 hours of negative RT-PCR (n = 43).

Results: Specificities of N and S assays were 95-97% and 100%, respectively. In acute COVID-19 patients, N/S plasma assays …

The Temporal Impulse Response Function In Infantile Nystagmus, Gal Avital, Felicia Kuperwaser, Andrew W Pountain, Keenan A Lacey, Erin E Zwack, Magdalena Podkowik, Bo Shopsin, Victor J Torres, Itai Yanai

Faculty, Staff and Student Publications

Innate immune recognition of bacterial pathogens is a key determinant of the ensuing systemic response, and host or pathogen heterogeneity in this early interaction can impact the course of infection. To gain insight into host response heterogeneity, we investigate macrophage inflammatory dynamics using primary human macrophages infected with Group B Streptococcus. Transcriptomic analysis reveals discrete cellular states within responding macrophages, one of which consists of four sub-states, reflecting inflammatory activation. Infection with six additional bacterial species—Staphylococcus aureus, Listeria monocytogenes, Enterococcus faecalis, Yersinia pseudotuberculosis, Shigella flexneri, and Salmonella enterica—recapitulates these states, though at …

Role Of Stem Cell Transplant In Cd30+ Ptcl Following Frontline Brentuximab Vedotin Plus Chp Or Chop In Echelon-2., Kerry J Savage, Steven M Horwitz, Ranjana Advani, Jacob Haaber Christensen, Eva Domingo-Domenech, Giuseppe Rossi, Franck Morschhauser, Onder Alpdogan, Cheolwon Suh, Kensei Tobinai, Andrei Shustov, Marek Trneny, Sam Yuen, Pier Luigi Zinzani, Lorenz Trümper, Tim Ilidge, Owen A O'Connor, Barbara Pro, Harry Miao, Veronica Bunn, Keenan Fenton, Michelle Fanale, Markus Puhlmann, Swaminathan Iyer

Department of Medical Oncology Faculty Papers

Peripheral T-cell lymphomas (PTCLs) are a heterogeneous group of aggressive non-Hodgkin lymphomas, the majority of which have high relapse rates following standard therapy. Despite use of consolidative stem cell transplant (SCT) following frontline therapy, there remains no consensus on its utility. The double-blind randomized phase 3 ECHELON-2 study (#NCT01777152; clinicaltrials.gov) demonstrated improved progression-free survival (PFS) and overall survival with frontline brentuximab vedotin plus cyclophosphamide, doxorubicin, and prednisone (A+CHP). Herein, we conducted an exploratory subgroups analysis of the impact of consolidative SCT on PFS in patients with previously untreated CD30+ PTCL (ALK- anaplastic large cell lymphoma [ALCL] and non-ALCL) …

Whole Genome Sequence Analysis Of Blood Lipid Levels In >66,000 Individuals, Margaret Sunitha Selvaraj, Xihao Li, Zilin Li, Akhil Pampana, David Y Zhang, Joseph Park, Stella Aslibekyan, Joshua C Bis, Jennifer A Brody, Brian E Cade, Lee-Ming Chuang, Ren-Hua Chung, Joanne E Curran, Lisa De Las Fuentes, Paul S De Vries, Ravindranath Duggirala, Barry I Freedman, Mariaelisa Graff, Xiuqing Guo, Nancy Heard-Costa, Bertha Hidalgo, Chii-Min Hwu, Marguerite R Irvin, Tanika N Kelly, Brian G Kral, Leslie Lange, Xiaohui Li, Martin Lisa, Steven A Lubitz, Ani W Manichaikul, Preuss Michael, May E Montasser, Alanna C Morrison, Take Naseri, Jeffrey R O'Connell, Nicholette D Palmer, Patricia A Peyser, Muagututia S Reupena, Jennifer A Smith, Xiao Sun, Kent D Taylor, Russell P Tracy, Michael Y Tsai, Zhe Wang, Yuxuan Wang, Wei Bao, John T Wilkins, Lisa R Yanek, Wei Zhao, Donna K Arnett, John Blangero, Eric Boerwinkle, Donald W Bowden, Yii-Der Ida Chen, Adolfo Correa, L Adrienne Cupples, Susan K Dutcher, Patrick T Ellinor, Myriam Fornage, Stacey Gabriel, Soren Germer, Richard Gibbs, Jiang He, Robert C Kaplan, Sharon L R Kardia, Ryan Kim, Charles Kooperberg, Ruth J F Loos, Karine A Viaud-Martinez, Rasika A Mathias, Stephen T Mcgarvey, Braxton D Mitchell, Deborah Nickerson, Kari E North, Bruce M Psaty, Susan Redline, Alexander P Reiner, Ramachandran S Vasan, Stephen S Rich, Cristen Willer, Jerome I Rotter, Daniel J Rader, Xihong Lin, Gina M Peloso, Pradeep Natarajan

Faculty, Staff and Student Publications

Blood lipids are heritable modifiable causal factors for coronary artery disease. Despite well-described monogenic and polygenic bases of dyslipidemia, limitations remain in discovery of lipid-associated alleles using whole genome sequencing (WGS), partly due to limited sample sizes, ancestral diversity, and interpretation of clinical significance. Among 66,329 ancestrally diverse (56% non-European) participants, we associate 428M variants from deep-coverage WGS with lipid levels; ~400M variants were not assessed in prior lipids genetic analyses. We find multiple lipid-related genes strongly associated with blood lipids through analysis of common and rare coding variants. We discover several associated rare non-coding variants, largely at Mendelian lipid …

Evolution And Modulation Of Antigen-Specific T Cell Responses In Melanoma Patients, Jani Huuhtanen, Liang Chen, Emmi Jokinen, Henna Kasanen, Tapio Lönnberg, Anna Kreutzman, Katriina Peltola, Micaela Hernberg, Chunlin Wang, Cassian Yee, Harri Lähdesmäki, Mark M Davis, Satu Mustjoki

Faculty, Staff and Student Publications

Analyzing antigen-specific T cell responses at scale has been challenging. Here, we analyze three types of T cell receptor (TCR) repertoire data (antigen-specific TCRs, TCR-repertoire, and single-cell RNA + TCRαβ-sequencing data) from 515 patients with primary or metastatic melanoma and compare it to 783 healthy controls. Although melanoma-associated antigen (MAA) -specific TCRs are restricted to individuals, they share sequence similarities that allow us to build classifiers for predicting anti-MAA T cells. The frequency of anti-MAA T cells distinguishes melanoma patients from healthy and predicts metastatic recurrence from primary melanoma. Anti-MAA T cells have stem-like properties and frequent interactions with regulatory …

Cue-Induced Cocaine Craving Enhances Psychosocial Stress And Vice Versa In Chronic Cocaine Users, Ann-Kathrin Kexel, Bruno Kluwe-Schiavon, Markus R Baumgartner, Etna J E Engeli, Monika Visentini, Clemens Kirschbaum, Erich Seifritz, Beate Ditzen, Leila M Soravia, Boris B Quednow

Faculty, Staff and Student Publications

Stress and craving, it has been found, contribute to the development and maintenance of and relapse in cocaine use disorder. Chronic cocaine users (CU), previous research has shown, display altered physiological responses to psychosocial stress and increased vegetative responding to substance-related cues. However, how psychosocial stress and cue-induced craving interact in relation to the CU's physiological responses remains largely unknown. We thus investigated the interaction between acute psychosocial stress and cocaine-cue-related reactivity in 47 CU and 38 controls. In a crossed and balanced design, the participants were randomly exposed to a video-based cocaine-cue paradigm and the Trier Social Stress Test …

Amyloid Β, Lipid Metabolism, Basal Cholinergic System, And Therapeutics In Alzheimer's Disease, Victoria Campos-Peña, Pavel Pichardo-Rojas, Talía Sánchez-Barbosa, Emma Ortíz-Islas, Citlali Ekaterina Rodríguez-Pérez, Pedro Montes, Gerardo Ramos-Palacios, Daniela Silva-Adaya, Rafael Valencia-Quintana, Jorge Francisco Cerna-Cortes, Danira Toral-Rios

2020-Current year OA Pubs

The presence of insoluble aggregates of amyloid β (Aβ) in the form of neuritic plaques (NPs) is one of the main features that define Alzheimer's disease. Studies have suggested that the accumulation of these peptides in the brain significantly contributes to extensive neuronal loss. Furthermore, the content and distribution of cholesterol in the membrane have been shown to have an important effect on the production and subsequent accumulation of Aβ peptides in the plasma membrane, contributing to dysfunction and neuronal death. The monomeric forms of these membrane-bound peptides undergo several conformational changes, ranging from oligomeric forms to beta-sheet structures, each …

Association Of Α-Klotho With Subclinical Carotid Atherosclerosis In Subjects With Type 1 Diabetes Mellitus, Esmeralda Castelblanco, Marta Hernández, Nuria Alonso, Aina Ribes-Betriu, Jordi Real, Minerva Granado-Casas, Joana Rossell, Marina Idalia Rojo-López, Adriana Silvia Dusso, Josep Julve, Didac Mauricio

2020-Current year OA Pubs

BACKGROUND: Compelling evidence suggests that the fibroblast growth factor 23 (FGF23) / α-klotho axis is impaired in subjects with diabetes mellitus. We examined the relationship between parameters related to calcium/phosphate homeostasis, including FGF23 and α-klotho, and subclinical carotid atherosclerosis burden in type 1 diabetes mellitus (T1D) subjects.

METHODS: This cross-sectional study involved 226 subjects with T1D and 147 age-, sex- and plaque-matched, non-diabetic (non-T1D) subjects, both with normal renal function. Carotid ultrasound was performed to determine the presence and burden of atheromatous plaques. Concentrations of the intact form of FGF23 and α-klotho were assessed by ELISA. Calcium, phosphate, parathyroid hormone, …

Collaborative Quality Improvement Strategy In Secondary Prevention Of Cardiovascular Disease In India: Findings From A Multi-Stakeholder, Qualitative Study Using Consolidated Framework For Implementation Research (Cfir), Kavita Singh, Mark D. Huffman, Leslie C M Johnson, Nikhil Tandon, Dorairaj Prabhakaran, Emily Mendenhall

2020-Current year OA Pubs

BACKGROUND: Cardiovascular disease (CVD) is highly prevalent in India, and little is known about the perception of patients and providers about a package of collaborative quality improvement (C-QIP) strategies consisting of provider-focused electronic health records-decision support system (EHR-DSS), non-physician health workers (NPHW), and patient-facing text messages to enhance the CVD care.

OBJECTIVE: To explore the barriers and enablers of the C-QIP strategy from the perspective of providers, health administrators, patients, and care givers in India.

METHODS: We conducted a qualitative study using the consolidated framework for implementation research (CFIR) to understand the challenges and facilitators of implementing C-QIP strategy to …

2021 Saem Consensus Conference Proceedings: Research Priorities For Developing Emergency Department Screening Tools For Social Risks And Needs, Jacqueline Furbacher, Callan Fockele, Ben Del Buono, Laura Janneck, Cooper March, Melanie Molina, Herbet C Duber, Kelly M Doran, Michelle P Lin, Richelle J Cooper, Payal Modi

Faculty, Staff and Student Publications

INTRODUCTION: The Emergency Department (ED) acts as a safety net for our healthcare system. While studies have shown increased prevalence of social risks and needs among ED patients, there are many outstanding questions about the validity and use of social risks and needs screening tools in the ED setting.

METHODS: In this paper, we present research gaps and priorities pertaining to social risks and needs screening tools used in the ED, identified through a consensus approach informed by literature review and external expert feedback as part of the 2021 SAEM Consensus Conference -- From Bedside to Policy: Advancing Social Emergency …

Vitamin C Supplementation For The Treatment Of Covid-19: A Systematic Review And Meta-Analysis, Monika Olczak-Pruc, Damian Swieczkowski, Jerzy R Ladny, Michal Pruc, Raul Juarez-Vela, Zubaid Rafique, Frank W Peacock, Lukasz Szarpak

Faculty, Staff and Students Publications

Since the outbreak of the coronavirus disease 2019 (COVID-19) pandemic, caused by the severe respiratory syndrome coronavirus 2 (SARS-CoV-2), millions of people have died, and the medical system has faced significant difficulties. Our purpose was to perform a meta-analysis to estimate the effect of vitamin C on in-hospital mortality and the ICU or hospital length of stay for patients diagnosed with COVID-19. We conducted a systematic review with meta-analysis in the following databases: PubMed, Web of Science, Scopus and Cochrane Central Register of Controlled Trials. We included studies that evaluated the effect of vitamin C supplementation, compared with standard treatment …

Occupational Characteristics Associated With Sars-Cov-2 Infection In The Uk Biobank During August-November 2020: A Cohort Study, Elizabeth L Yanik, Bradley A Evanoff, Ann Marie Dale, Yinjiao Ma, Karen E Walker-Bone

2020-Current year OA Pubs

BACKGROUND: Occupational exposures may play a key role in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection risk. We used a job-exposure matrix linked to the UK Biobank to measure occupational characteristics and estimate associations with a positive SARS-CoV-2 test.

METHODS: People reporting job titles at their baseline interview in England who were < 65 years of age in 2020 were included. Healthcare workers were excluded because of differential access to testing. Jobs were linked to the US Occupational Information Network (O*NET) job exposure matrix. O*NET-based scores were examined for occupational physical proximity, exposure to diseases/infection, working outdoors exposed to weather, and working outdoors under cover (score range = 1-5). Jobs were classified as remote work using two algorithms. SARS-CoV-2 test results were evaluated between August 5th-November 10th, 2020, when the UK was released from lockdown. Cox regression was used to calculate adjusted hazard ratios (aHRs), accounting for age, sex, race, education, neighborhood deprivation, assessment center, household size, and income.

RESULTS: We included 115,451 people with job titles, of whom 1746 tested positive for SARS-CoV-2. A one-point increase in physical proximity score was associated with 1.14 times higher risk of SARS-CoV-2 (95%CI = 1.05-1.24). A one-point increase in the exposure to diseases/infections score was associated with 1.09 …

Blood Culture Utilization Practices Among Febrile And/Or Hypothermic Inpatients, Kap Sum Foong, Satish Munigala, Stephanie Kern-Allely, David K Warren

2020-Current year OA Pubs

BACKGROUND: Predictors associated with the decision of blood culture ordering among hospitalized patients with abnormal body temperature are still underexplored, particularly non-clinical factors. In this study, we evaluated the factors affecting blood culture ordering in febrile and hypothermic inpatients.

METHODS: We performed a retrospective study of 15,788 adult inpatients with fever (≥ 38.3℃) or hypothermia (< 36.0℃) from January 2016 to December 2017. We evaluated the proportion of febrile and hypothermic episodes with an associated blood culture performed within 24h. Generalized Estimating Equations were used to determine independent predictors associated with blood culture ordering among febrile and hypothermic inpatients.

RESULTS: We identified 21,383 abnormal body temperature episodes among 15,788 inpatients (13,093 febrile and 8,290 hypothermic episodes). Blood cultures were performed in 36.7% (7,850/ 21,383) of these episodes. Predictors for blood culture ordering among inpatients with abnormal body temperature included fever ≥ 39℃ (adjusted …

A Dpagt1 Missense Variant Causes Degenerative Retinopathy Without Myasthenic Syndrome In Mice, Lillian F Hyde, Yang Kong, Lihong Zhao, Sriganesh Ramachandra Rao, Jieping Wang, Lisa Stone, Andrew Njaa, Gayle B. Collin, Mark P. Krebs, Bo Chang, Steven J Fliesler, Patsy M. Nishina, Juergen K. Naggert

Faculty Research 2022

Congenital disorders of glycosylation (CDG) are a heterogenous group of primarily autosomal recessive mendelian diseases caused by disruptions in the synthesis of lipid-linked oligosaccharides and their transfer to proteins. CDGs usually affect multiple organ systems and vary in presentation, even within families. There is currently no cure, and treatment is aimed at ameliorating symptoms and improving quality of life. Here, we describe a chemically induced mouse mutant,

Near-Peers Effectively Teach Clinical Documentation Skills To Early Medical Students, Anita Vijay Kusnoor, Rajeev Balchandani, Malford Tyson Pillow, Stephanie Sherman, Nadia Ismail

Faculty, Staff and Students Publications

Background: Composing the History of Present Illness (HPI), a key component of medical communication, requires critical thinking. Small group learning strategies have demonstrated superior effectiveness at developing critical thinking skills. Finding sufficient faculty facilitators for small groups remains a major gap in implementing these sessions. We hypothesized that "near-peer" teachers could effectively teach HPI documentation skills and fill the gap of small group facilitators. Here, we present a head-to-head comparison of near-peer and faculty teaching outcomes.

Methods: Second-year medical students in a single institution participated in an HPI Workshop as a clinical skills course requirement. Students were randomly assigned a …

Near-Peers Effectively Teach Clinical Documentation Skills To Early Medical Students, Anita Vijay Kusnoor, Rajeev Balchandani, Malford Tyson Pillow, Stephanie Sherman, Nadia Ismail

Faculty, Staff and Students Publications

BACKGROUND: Composing the History of Present Illness (HPI), a key component of medical communication, requires critical thinking. Small group learning strategies have demonstrated superior effectiveness at developing critical thinking skills. Finding sufficient faculty facilitators for small groups remains a major gap in implementing these sessions. We hypothesized that "near-peer" teachers could effectively teach HPI documentation skills and fill the gap of small group facilitators. Here, we present a head-to-head comparison of near-peer and faculty teaching outcomes.

METHODS: Second-year medical students in a single institution participated in an HPI Workshop as a clinical skills course requirement. Students were randomly assigned a …

Multi-Trait Genome-Wide Association Study Of Opioid Addiction: Oprm1 And Beyond, Nathan Gaddis, Arpana Agrawal, Paul W Jeffries, Kathleen Bucholz, Elliot C Nelson, Laura Bierut, Et Al.

2020-Current year OA Pubs

Opioid addiction (OA) is moderately heritable, yet only rs1799971, the A118G variant in OPRM1, has been identified as a genome-wide significant association with OA and independently replicated. We applied genomic structural equation modeling to conduct a GWAS of the new Genetics of Opioid Addiction Consortium (GENOA) data together with published studies (Psychiatric Genomics Consortium, Million Veteran Program, and Partners Health), comprising 23,367 cases and effective sample size of 88,114 individuals of European ancestry. Genetic correlations among the various OA phenotypes were uniformly high (r

Functional Genomics Of Complex Cancer Genomes., Francesca Menghi, Edison Liu

Faculty Research 2022

Cancer functional genomics is the study of how genetic, epigenetic, and transcriptional alterations affect cancer phenotypes, such as growth and therapeutic response. Here, we comment on how, taking advantage of next generation sequencing, functional genomics, often combined with systems biology approaches, has revealed novel cancer vulnerabilities beyond the original paradigm of one gene-one phenotype.

Risk Factors For Thoracic Aortic Dissection, Zhen Zhou, Alana C Cecchi, Siddharth K Prakash, Dianna M Milewicz

Faculty, Staff and Student Publications

Thoracic aortic aneurysms involving the root and/or the ascending aorta enlarge over time until an acute tear in the intimal layer leads to a highly fatal condition, an acute aortic dissection (AAD). These Stanford type A AADs, in which the tear occurs above the sinotubular junction, leading to the formation of a false lumen in the aortic wall that may extend to the arch and thoracoabdominal aorta. Type B AADs originate in the descending thoracic aorta just distal to the left subclavian artery. Genetic variants and various environmental conditions that disrupt the aortic wall integrity have been identified that increase …

Respiratory Virus Surveillance Among Children With Acute Respiratory Illnesses - New Vaccine Surveillance Network, United States, 2016-2021., Ariana Perez, Joana Y. Lively, Aaron Curns, Geoffrey A. Weinberg, Natasha B. Halasa, Mary Allen Staat, Peter G. Szilagyi, Laura S. Stewart, Monica M. Mcneal, Benjamin Clopper, Yingtao Zhou, Brett L. Whitaker, Elizabeth Lemasters, Elizabeth Harker, Janet A. Englund, Eileen J. Klein, Rangaraj Selvarangan, Christopher J. Harrison, Julie A. Boom, Leila C. Sahni, Marian G. Michaels, John V. Williams, Gayle E. Langley, Susan I. Gerber, Angela Campbell, Aron J. Hall, Brian Rha, Meredith Mcmorrow, New Vaccine Surveillance Network Collaborators

Manuscripts, Articles, Book Chapters and Other Papers

The New Vaccine Surveillance Network (NVSN) is a prospective, active, population-based surveillance platform that enrolls children with acute respiratory illnesses (ARIs) at seven pediatric medical centers. ARIs are caused by respiratory viruses including influenza virus, respiratory syncytial virus (RSV), human metapneumovirus (HMPV), human parainfluenza viruses (HPIVs), and most recently SARS-CoV-2 (the virus that causes COVID-19), which result in morbidity among infants and young children (1-6). NVSN estimates the incidence of pathogen-specific pediatric ARIs and collects clinical data (e.g., underlying medical conditions and vaccination status) to assess risk factors for severe disease and calculate influenza and COVID-19 vaccine effectiveness. Current NVSN …

Respiratory Virus Surveillance Among Children With Acute Respiratory Illnesses - New Vaccine Surveillance Network, United States, 2016-2021, Ariana Perez, Joana Y Lively, Aaron Curns, Geoffrey A Weinberg, Natasha B Halasa, Mary Allen Staat, Peter G Szilagyi, Laura S Stewart, Monica M Mcneal, Benjamin Clopper, Yingtao Zhou, Brett L Whitaker, Elizabeth Lemasters, Elizabeth Harker, Janet A Englund, Eileen J Klein, Rangaraj Selvarangan, Christopher J Harrison, Julie A Boom, Leila C Sahni, Marian G Michaels, John V Williams, Gayle E Langley, Susan I Gerber, Angela Campbell, Aron J Hall, Brian Rha, Meredith Mcmorrow

Faculty, Staff and Student Publications

The New Vaccine Surveillance Network (NVSN) is a prospective, active, population-based surveillance platform that enrolls children with acute respiratory illnesses (ARIs) at seven pediatric medical centers. ARIs are caused by respiratory viruses including influenza virus, respiratory syncytial virus (RSV), human metapneumovirus (HMPV), human parainfluenza viruses (HPIVs), and most recently SARS-CoV-2 (the virus that causes COVID-19), which result in morbidity among infants and young children (1-6). NVSN estimates the incidence of pathogen-specific pediatric ARIs and collects clinical data (e.g., underlying medical conditions and vaccination status) to assess risk factors for severe disease and calculate influenza and COVID-19 vaccine effectiveness. Current NVSN …

Critical Role Of Lncepat In Coupling Dysregulated Egfr Pathway And Histone H2a Deubiquitination During Glioblastoma Tumorigenesis, Linlin Li, Aidong Zhou, Yanjun Wei, Feng Liu, Peng Li, Runping Fang, Li Ma, Sicong Zhang, Longqiang Wang, Jinze Liu, Hope T Richard, Yiwen Chen, Hengbin Wang, Suyun Huang

Faculty, Staff and Student Publications

Histone 2A (H2A) monoubiquitination is a fundamental epigenetics mechanism of gene expression, which plays a critical role in regulating cell fate. However, it is unknown if H2A ubiquitination is involved in EGFR-driven tumorigenesis. In the current study, we have characterized a previously unidentified oncogenic lncRNA (lncEPAT) that mediates the integration of the dysregulated EGFR pathway with H2A deubiquitination in tumorigenesis. LncEPAT was induced by the EGFR pathway, and high-level lncEPAT expression positively correlated with the glioma grade and predicted poor survival of glioma patients. Mass spectrometry analyses revealed that lncEPAT specifically interacted with deubiquitinase USP16. LncEPAT inhibited USP16's recruitment to …

Infant Behavioral State And Stool Microbiome In Infants Receiving Lactocaseibacillus Rhamnosus Gg In Formula: Randomized Controlled Trial, Robert J Shulman, Maciej Chichlowski, Fabiola Gutierrez Orozco, Cheryl L Harris, Jennifer L Wampler, Nicholas A Bokulich, Carol Lynn Berseth

Faculty, Staff and Students Publications

BACKGROUND: Our aim was to evaluate infant behavioral state, stool microbiome profile and calprotectin in infants with infantile colic receiving a partially hydrolyzed protein formula with or without added Lacticaseibacillus (formerly Lactobacillus) rhamnosus GG (LGG).

METHODS: In this single-center, double-blind, controlled, parallel, prospective study, term infants (14-28 days of age) identified with colic (using modified Wessel's criteria: cried and/or fussed ≥ 3 h/day for ≥ 3 days/week, in a one-week period) were randomized to receive one of two formulas over a three-week feeding period: marketed partially hydrolyzed cow's milk-based infant formula (PHF, n = 35) or a similar formula with …

Spontaneous Activity Patterns In Human Motor Cortex Replay Evoked Activity Patterns For Hand Movements, Tomer Livne, Dohyun Kim, Nicholas V Metcalf, Lu Zhang, Lorenzo Pini, Gordon L Shulman, Maurizio Corbetta

2020-Current year OA Pubs

Spontaneous brain activity, measured with resting state fMRI (R-fMRI), is correlated among regions that are co-activated by behavioral tasks. It is unclear, however, whether spatial patterns of spontaneous activity within a cortical region correspond to spatial patterns of activity evoked by specific stimuli, actions, or mental states. The current study investigated the hypothesis that spontaneous activity in motor cortex represents motor patterns commonly occurring in daily life. To test this hypothesis 15 healthy participants were scanned while performing four different hand movements. Three movements (Grip, Extend, Pinch) were ecological involving grip and grasp hand movements; one control movement involving the …

Regulation Of Airway Smooth Muscle Cell Proliferation By Diacylglycerol Kinase: Relevance To Airway Remodeling In Asthma, Miguel Angel Hernandez-Lara, Santosh K Yadav, Sushrut D. Shah, Mariko Okumura, Yuichi Yokoyama, Raymond B. Penn,, Taku Kambayashi, Deepak A. Deshpande

Center for Translational Medicine Faculty Papers

Airway remodeling in asthma involves the hyperproliferation of airway smooth muscle (ASM) cells. However, the molecular signals that regulate ASM growth are not completely understood. Gq-coupled G protein-coupled receptor and receptor tyrosine kinase signaling regulate ASM cell proliferation via activation of phospholipase C, generation of inositol triphosphate (IP3) and diacylglycerol (DAG). Diacylglycerol kinase (DGK) converts DAG into phosphatidic acid (PA) and terminates DAG signaling while promoting PA-mediated signaling and function. Herein, we hypothesized that PA is a pro-mitogenic second messenger in ASM, and DGK inhibition reduces the conversion of DAG into PA resulting in inhibition of ASM cell proliferation. We …

Feasibility Of A Novel Non-Invasive Swab Technique For Serial Whole-Exome Sequencing Of Cervical Tumors During Chemoradiation Therapy, Julianna K Bronk, Chiraag Kapadia, Xiaogang Wu, Bhavana V Chapman, Rui Wang, Tatiana V Karpinets, Xingzhi Song, Andrew M Futreal, Jianhua Zhang, Ann H Klopp, Lauren E Colbert

Faculty, Staff and Student Publications

BACKGROUND: Clinically relevant genetic predictors of radiation response for cervical cancer are understudied due to the morbidity of repeat invasive biopsies required to obtain genetic material. Thus, we aimed to demonstrate the feasibility of a novel noninvasive cervical swab technique to (1) collect tumor DNA with adequate throughput to (2) perform whole-exome sequencing (WES) at serial time points over the course of chemoradiation therapy (CRT).

METHODS: Cervical cancer tumor samples from patients undergoing chemoradiation were collected at baseline, at week 1, week 3, and at the completion of CRT (week 5) using a noninvasive swab-based biopsy technique. Swab samples were …

Molecular Pathways Of Major Depressive Disorder Converge On The Synapse, Gabriel R Fries, Valeria A Saldana, Johannes Finnstein, Theo Rein

Faculty, Staff and Student Publications

Major depressive disorder (MDD) is a psychiatric disease of still poorly understood molecular etiology. Extensive studies at different molecular levels point to a high complexity of numerous interrelated pathways as the underpinnings of depression. Major systems under consideration include monoamines, stress, neurotrophins and neurogenesis, excitatory and inhibitory neurotransmission, mitochondrial dysfunction, (epi)genetics, inflammation, the opioid system, myelination, and the gut-brain axis, among others. This review aims at illustrating how these multiple signaling pathways and systems may interact to provide a more comprehensive view of MDD's neurobiology. In particular, considering the pattern of synaptic activity as the closest physical representation of mood, …

Integrating Transcriptomics, Metabolomics, And Gwas Helps Reveal Molecular Mechanisms For Metabolite Levels And Disease Risk, Xianyong Yin, Adam E Locke, Nathan O Stitziel, Et Al.

2020-Current year OA Pubs

Transcriptomics data have been integrated with genome-wide association studies (GWASs) to help understand disease/trait molecular mechanisms. The utility of metabolomics, integrated with transcriptomics and disease GWASs, to understand molecular mechanisms for metabolite levels or diseases has not been thoroughly evaluated. We performed probabilistic transcriptome-wide association and locus-level colocalization analyses to integrate transcriptomics results for 49 tissues in 706 individuals from the GTEx project, metabolomics results for 1,391 plasma metabolites in 6,136 Finnish men from the METSIM study, and GWAS results for 2,861 disease traits in 260,405 Finnish individuals from the FinnGen study. We found that genetic variants that regulate metabolite …

Safety And Immunogenicity Of The Na-Apr-1 Hookworm Vaccine In Infection-Naïve Adults, David J Diemert, Maria Zumer, Doreen Campbell, Shannon Grahek, Guangzhao Li, Jin Peng, Maria Elena Bottazzi, Peter Hotez, Jeffrey Bethony

Center for Medical Ethics and Health Policy Staff Publications

Background: The Necator americanus hemoglobinase, aspartic protease-1 (Na-APR-1), facilitates the ability of adult hookworms to parasitize the intestine of their human hosts. A recombinant version of APR-1 protected laboratory animals against hookworm infection by inducing neutralizing antibodies that block the protein's enzymatic activity and thereby impair blood feeding. A catalytically inactive version of the wild-type hemoglobinase (Na-APR-1(M74)) was expressed by infiltrating Nicotiana benthamiana tobacco plants with an Agrobacterium tumefaciens strain engineered to express the vaccine antigen, which was adjuvanted with aluminum hydroxide adjuvant (Alhydrogel).

Methods: An open-label dose-escalation Phase 1 clinical trial was conducted in 40 healthy, hookworm-naïve adult volunteers …

Diabetes Duration And Subclinical Myocardial Injury: The Atherosclerosis Risk In Communities Study (Aric), Carine E Hamo, Justin B Echouffo-Tcheugui, Sui Zhang, Roberta Florido, James S Pankow, Erin D Michos, Ronald Goldberg, Vijay Nambi, Gary Gerstenblith, Wendy S Post, Roger S Blumenthal, Christie Ballantyne, Elizabeth Selvin, Josef Coresh, Chiadi E Ndumele

Faculty, Staff and Students Publications

Background: Diabetes exerts adverse effects on the heart, and a longer diabetes duration is associated with greater heart failure risk. We studied diabetes duration and subclinical myocardial injury, as reflected by high-sensitivity cardiac troponin (hs-cTnT).

Methods: We analyzed 9052 participants without heart failure or coronary heart disease (mean age 63 years, 58% female, 21% Black, 15% with diabetes) at The Atherosclerosis Risk in Communities Study (ARIC) Visit 4 (1996 to 1998). Diabetes duration was calculated based on diabetes status at Visits 1 (1987 to 1989) through 4, or using self-reported age of diabetes diagnosis prior to Visit 1. We used …