Digital Commons Network^™

Utility Of Colposcopy For The Screening And Management Of Cervical Cancer In Africa: A Cross-Sectional Analysis Of Providers’ Training And Practices, Joël Fokom Domgue, Issimouha Dille, Freddy Gnangnon, Sharon Kapambwe, Celine Bouchard, Nomonde Mbatani, Elodie Gauroy, Nathalie Ledaga Ambounda, Robert Yu, Fatoumata Sidibe, Joseph Kamgno, Bangaly Traore, Pierre-Marie Tebeu, Gregory Halle-Ekane, Mohenou Isidore Diomande, Jean-Marie Dangou, Fabrice Lecuru, Isaac Adewole, Marie Plante, Partha Basu, Sanjay Shete

Faculty, Staff and Student Publications

Introduction: Cervical cancer is a public health issue in Africa with devastating socioeconomic consequences due to the lack of organized screening programs. The success of screening programs depends on the appropriate investigation and management of women who test positive for screening. Colposcopic assessment following positive screening results is a noteworthy issue in Africa. This study aimed to assess the utilization of colposcopy by providers in the region.

Methods: A cross-sectional study was conducted in 2021-2022 among healthcare providers involved in cervical cancer prevention activities in Africa. They were invited to report prior colposcopy training, whether they performed colposcopy and the …

Influenza Knowledge And Barriers To Vaccination In Immunosuppressed Patients In The Pediatric Rheumatology Clinic., Julia G. Harris, Leslie Favier, Jordan T. Jones, Maria Ibarra, Michael J. Holland, Emily Fox, Kelly Jensen, Ashley K. Sherman, Ashley M. Cooper

Manuscripts, Articles, Book Chapters and Other Papers

BACKGROUND: Most patients with a pediatric rheumatic disease are at increased risk of influenza due to immunosuppressive medication use. Despite initial quality improvement efforts, our influenza vaccination rate plateaued at 72%, which prompted a survey of patients and families to assess provider vaccine recommendations, influenza knowledge, and barriers to influenza vaccination.

METHODS: Patients on immunosuppressive medication or their parent were eligible to complete a survey between July 2019 and January 2020. Survey questions assessed demographics, rheumatology diagnosis, immunosuppressive medication(s), influenza vaccination recommendation, patient/parent influenza knowledge, and barriers to influenza vaccination. Influenza vaccination rates for immunosuppressed patients were acquired each influenza …

Transcriptomic Clustering Of Chronic Lymphocytic Leukemia: Molecular Subtypes Based On Bruton’S Tyrosine Kinase Expression Levels, Gorkem Kismali, Ganiraju Manyam, Nitin Jain, Cristina Ivan, Betty Lamothe, Mary L Ayres, Lakesla R Iles, William G Wierda, Varsha Gandhi

Faculty, Staff and Student Publications

Historically, CLL prognostication relied on disease burden, reflected in clinical stage. Later, chromosome abnormalities and genomics suggested several CLL subtypes which were aligned with response to therapy. Gene expression profiling data identified pathways associated with CLL progression. We hypothesized that transcriptome and proteome may identify functional omics associated with CLL nosology. As a test cohort, we utilized publicly available treatment-naïve CLL transcriptomics data (n = 130) and did consensus clustering that identified BTK-expression-based clusters. The BTK-High and BTK-Low clusters were validated in public and our in-house databases (n = >550 CLL patients). To associate with functional relevance, we took samples …

Centering Autonomy And Choice To Support Oral Prep Utilization Among People Who Inject Drugs: Qualitative Lessons From Hptn 094 Integra, Amaya Perez-Brumer, Rose Schmidt, Rebecca Kennedy, Jordan E Lake, Yolanda R Villarreal, Sydney Bornstein, Irene Kuo, Omar Nieto, Julie Franks, Cecile Denis, Nabila El-Bassel, Steve Shoptaw, Peter Davidson, Laramie R Smith

Faculty, Staff and Student Publications

Background: Oral Pre-exposure prophylaxis (PrEP) is effective in preventing HIV transmission. However, despite high rates of HIV risk behaviors among people who inject drugs (PWID), this population remains underserved by current HIV prevention efforts in the United States. To address this challenge, we conducted an in-depth exploration of perspectives on using oral PrEP among PWID engaged in the HIV Prevention Trials Network (HPTN) 094 INTEGRA Study.

Methods: Guided by the Practical, Robust, Implementation, and Sustainability Model (PRISM), our qualitative study drew on semi-structured interviews conducted as part of the embedded implementation science evaluation of HPTN 094 INTEGRA. Seventy-seven PWID participants …

Structural Variant Allelic Heterogeneity In Mecp2 Duplication Syndrome Provides Insight Into Clinical Severity And Variability Of Disease Expression, Davut Pehlivan, Jesse D Bengtsson, Sameer S Bajikar, Christopher M Grochowski, Ming Yin Lun, Mira Gandhi, Angad Jolly, Alexander J Trostle, Holly K Harris, Bernhard Suter, Sukru Aras, Melissa B Ramocki, Haowei Du, Michele G Mehaffey, Kyunghee Park, Ellen Wilkey, Cemal Karakas, Jesper J Eisfeldt, Maria Pettersson, Lynn Liu, Marwan S Shinawi, Virginia E Kimonis, Wojciech Wiszniewski, Kyle Mckenzie, Timo Roser, Angela M Vianna-Morgante, Alberto S Cornier, Ahmed Abdelmoity, James P Hwang, Shalini N Jhangiani, Donna M Muzny, Tadahiro Mitani, Kazuhiro Muramatsu, Shin Nabatame, Daniel G Glaze, Jawid M Fatih, Richard A Gibbs, Zhandong Liu, Anna Lindstrand, Fritz J Sedlazeck, James R Lupski, Huda Y Zoghbi, Claudia M B Carvalho

Faculty, Staff and Students Publications

BACKGROUND: MECP2 Duplication Syndrome, also known as X-linked intellectual developmental disorder Lubs type (MRXSL; MIM: 300260), is a neurodevelopmental disorder caused by copy number gains spanning MECP2. Despite varying genomic rearrangement structures, including duplications and triplications, and a wide range of duplication sizes, no clear correlation exists between DNA rearrangement and clinical features. We had previously demonstrated that up to 38% of MRXSL families are characterized by complex genomic rearrangements (CGRs) of intermediate complexity (2 ≤ copy number variant breakpoints < 5), yet the impact of these genomic structures on regulation of gene expression and phenotypic manifestations have not been investigated.

METHODS: To study the role of the genomic rearrangement structures on an individual's clinical phenotypic variability, we employed a comprehensive …

Structural Variant Allelic Heterogeneity In Mecp2 Duplication Syndrome Provides Insight Into Clinical Severity And Variability Of Disease Expression, Davut Pehlivan, Marwan S Shinawi, Et Al.

2020-Current year OA Pubs

BACKGROUND: MECP2 Duplication Syndrome, also known as X-linked intellectual developmental disorder Lubs type (MRXSL; MIM: 300260), is a neurodevelopmental disorder caused by copy number gains spanning MECP2. Despite varying genomic rearrangement structures, including duplications and triplications, and a wide range of duplication sizes, no clear correlation exists between DNA rearrangement and clinical features. We had previously demonstrated that up to 38% of MRXSL families are characterized by complex genomic rearrangements (CGRs) of intermediate complexity (2 ≤ copy number variant breakpoints <  5), yet the impact of these genomic structures on regulation of gene expression and phenotypic manifestations have not been investigated.

METHODS: To study the role of the genomic rearrangement structures on an individual's clinical phenotypic variability, we employed a comprehensive …

Primary Anorectal Mammary-Like Adenocarcinoma: A Potential Diagnostic Pitfall With Conventional Colorectal Adenocarcinoma, Margaret L Axelrod, Xiuli Liu, Pooja Navale

2020-Current year OA Pubs

Anogenital mammary-like glands (AGMLGs) are present in the anogenital region that bear striking morphologic and protein-expression similarities to mammary glands in the breast. AGMLGs can give rise to both benign and malignant lesions which mimic primary breast lesions. Herein, we report two mammary-type adenocarcinomas arising from AGMLGs, including one in the previously unreported site of the rectum. Recognition of mammary-type adenocarcinoma in the rectal and anogenital regions is crucial as clinical management options may differ compared to conventional colorectal adenocarcinomas.

Pathways From Socioeconomic Factors To Major Cardiovascular Events Among Postmenopausal Veteran And Nonveteran Women: Findings From The Women's Health Initiative, Hind A Beydoun, May A Beydoun, Rebecca L Kinney, Simin Liu, Rona Yu, Matthew Allison, Robert B Wallace, Qian Xiao, Longjian Liu, Philippe Gradidge, Su Yon Jung, Hilary A Tindle, Shawna Follis, Robert Brunner, Jack Tsai

Faculty, Staff and Student Publications

BACKGROUND: Cardiovascular disease (CVD) remains a leading cause of death for women in the United States, with veterans being at potentially higher risk than their nonveteran counterparts due to accelerated aging and distinct biopsychosocial mechanisms. We examined pathways between selected indicators of socioeconomic status (SES) such as education, occupation, household income, and neighborhood SES and major CVD events through lifestyle and health characteristics among veteran and nonveteran postmenopausal women.

METHODS AND RESULTS: A total of 121 286 study-eligible WHI (Women's Health Initiative) participants (3091 veterans and 118 195 nonveterans) were prospectively followed for an average of 17 years, during which …

Co-Inhibition Of Tgli1 And Gp130 Using Fda-Approved Ketoconazole And Bazedoxifene Is Synergistic Against The Growth And Metastasis Of Her2-Enriched And Triple-Negative Breast Cancers, Sara Manore, Chuling Zhuang, Mariana K Najjar, Grace L Wong, Shivani Bindal, Kounosuke Watabe, Jiayuh Lin, Hui-Wen Lo

Faculty, Staff and Student Publications

Breast cancer stem cells (CSCs) are resistant to most cancer therapeutics and contribute to tumor recurrence and metastasis. Two breast CSC-promoting transcription factors, truncated glioma-associated oncogene homolog 1 (tGLI1) and signal transducer and activator of transcription 3 (STAT3), have been reported to be frequently co-expressed in HER2-enriched breast cancer and triple-negative breast cancer (TNBC), undergo protein-protein interactions for gene regulation and activation, and functionally cooperate to promote breast CSCs. STAT3 can be activated by activated interleukin-6 receptor/glycoprotein-130 (IL-6R/GP130). Co-targeting of tGLI1 and IL-6R/GP130 has not been investigated in breast cancer or any tumor type. Here, we report that tGLI1 and …

Understanding Rare Genetic Variants Within The Terminal Pathway Of Complement System In Preeclampsia, A Inkeri Lokki, Michael Triebwasser, Emma Daly, Finnpec Core Investigator Group, Mitja I Kurki, Markus Perola, Kirsi Auro, Jane E Salmon, Java Anuja, Mark Daly, John P Atkinson, Hannele Laivuori, Seppo Meri

2020-Current year OA Pubs

Preeclampsia is a common multifactorial disease of pregnancy. Dysregulation of complement activation is among emerging candidates responsible for disease pathogenesis. In a targeted exomic sequencing study of 609 women with preeclampsia and 2092 non-preeclamptic controls, we identified 14 variants within nine genes coding for components of the membrane attack complex (MAC, C5b-9) that are associated with preeclampsia. We found two rare missense variants in the C5 gene that predispose to preeclampsia (rs200674959: I1296V, OR (CI95) = 24.13 (1.25-467.43), p value = 0.01 and rs147430470: I330T, OR (CI95) = 22.75 (1.17-440.78), p value = 0.01). In addition, one predisposing rare variant …

Clover (Clostridium Difficile Vaccine Efficacy Trial) Study: A Phase 3, Randomized Trial Investigating The Efficacy And Safety Of A Detoxified Toxin A/B Vaccine In Adults 50 Years And Older At Increased Risk Of Clostridioides Difficile Infection, Curtis J Donskey, Erik R Dubberke, Et Al.

2020-Current year OA Pubs

BACKGROUND: Clostridioides difficile infection (CDI) causes substantial mortality and healthcare burden. We assessed the detoxified toxin-A/B PF-06425090 vaccine for primary CDI prevention.

METHODS: This phase 3 observer-blinded study randomized (1:1) ≥50-year-olds at increased CDI risk (N = 17 535) to receive 3 PF-06425090 or placebo doses (0, 1, and 6 months). Primary end points were first CDI episode (≥3 unformed stools within 24 hours; central laboratory-confirmed toxin A/B positive) ≥14 days post-dose 3 (PD3; first primary) and post-dose 2 (PD2; second primary). CDI duration, need for CDI-related medical attention (secondary end points), and antibiotic use (post hoc analysis) PD3 were …

Large-Scale Crispr/Cas9 Deletions Within The Wfdc Gene Cluster Uncover Gene Functionality And Critical Roles In Mammalian Reproduction, Katarzyna Kent, Kaori Nozawa, Rachel Parkes, Laura Dean, Frey Daniel, Mei Leng, Antrix Jain, Anna Malovannaya, Martin M Matzuk, Thomas X Garcia

Faculty, Staff and Students Publications

Despite 96 million years of evolution separating humans and rodents, 11 closely related reproductive tract-specific genes in humans—SPINT3, WFDC6, EPPIN, WFDC8, WFDC9, WFDC10A, WFDC11, WFDC10B, WFDC13, SPINT4, and WFDC3—and the 13 reproductive tract-specific orthologous genes in mice, form highly conserved syntenic gene clusters indicative of conserved, combined critical functions. Further, despite significant progress toward a nonhormonal male contraceptive targeting the protein encoded by one of these genes, epididymal peptidase inhibitor (EPPIN), and associations found between mutations in EPPIN and an increased risk of male infertility, neither EPPIN nor …

Uba1 Inhibition Sensitizes Cancer Cells To Parp Inhibitors, Sharad Awasthi, Lacey E Dobrolecki, Christina Sallas, Xudong Zhang, Yang Li, Sima Khazaei, Sumanta Ghosh, Collene R Jeter, Jinsong Liu, Gordon B Mills, Shannon N Westin, Michael T Lewis, Weiyi Peng, Anil K Sood, Timothy A Yap, S Stephen Yi, Daniel J Mcgrail, Nidhi Sahni

Faculty, Staff and Students Publications

Therapeutic strategies targeting the DNA damage response, such as poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi), have revolutionized cancer treatment in tumors deficient in homologous recombination (HR). However, overcoming innate and acquired resistance to PARPi remains a significant challenge. Here, we employ a genome-wide CRISPR knockout screen and discover that the depletion of ubiquitin-activating enzyme E1 (UBA1) enhances sensitivity to PARPi in HR-proficient ovarian cancer cells. We show that silencing or pharmacological inhibition of UBA1 sensitizes multiple cell lines and organoid models to PARPi. Mechanistic studies uncover that UBA1 inhibition not only impedes HR repair to sensitize cells to PARP inhibition …

Development Of A Ripk1 Degrader To Enhance Antitumor Immunity, Xin Yu, Dong Lu, Xiaoli Qi, Rishi Ram Paudel, Hanfeng Lin, Bryan L Holloman, Feng Jin, Longyong Xu, Lang Ding, Weiyi Peng, Meng C Wang, Xi Chen, Jin Wang

Faculty, Staff and Students Publications

The scaffolding function of receptor interacting protein kinase 1 (RIPK1) confers intrinsic and extrinsic resistance to immune checkpoint blockades (ICBs) and emerges as a promising target for improving cancer immunotherapies. To address the challenge posed by a poorly defined binding pocket within the intermediate domain of RIPK1, here we harness proteolysis targeting chimera (PROTAC) technology to develop a RIPK1 degrader, LD4172. LD4172 exhibits potent and selective RIPK1 degradation both in vitro and in vivo. Degradation of RIPK1 by LD4172 triggers immunogenic cell death, enhances tumor-infiltrating lymphocyte responses, and sensitizes tumors to anti-PD1 therapy in female C57BL/6J mice. This work reports …

Whispers In The Wind: Face Mask Sampling For Mycobacterium Tuberculosis Detection In Children With Pulmonary Tuberculosis, Lennard Meiwes, Irina Kontsevaya, Dumitru Chesov, Stela Kulciţkaia, Viola Dreyer, Doris Hillemann, Qiniso Dlamini, Caroline Williams, Michael Barer, Folke Brinkmann, Renate Krüger, Stephanie Thee, Alexander Kay, Anna Maria Mandalakas, Christoph Lange

Faculty, Staff and Students Publications

Background: Recently, face mask sampling (FMS) confirmed detection of Mycobacterium tuberculosis DNA from exhaled breath in adults with tuberculosis. To date, no study has evaluated the use of FMS to detect pulmonary tuberculosis in children. We developed a method for FMS of M. tuberculosis-specific DNA in children and performed a clinical exploration to assess feasibility in children.

Methods: Face masks were spiked, analyzed on GeneXpert-Ultra, quantitative polymerase chain reaction, and targeted next-generation sequencing. Children with pulmonary tuberculosis were asked to wear 3 modified FFP2 masks for 30 minutes as part of an exploratory clinical study.

Results: Experiments with H37Ra M. …

Correlation Of Genogroup I, Genotype 1 (Gi.1) Norovirus Neutralizing Antibody Levels With Gi.1 Histo-Blood Group Antigen-Blocking Antibody Levels, Robert L Atmar, Khalil Ettayebi, Frederick H Neill, Ralph P Braun, James Sherwood, Sasirekha Ramani, Mary K Estes

Faculty, Staff and Students Publications

Background: The in vitro cultivation of human noroviruses allows a comparison of antibody levels measured in neutralization and histo-blood group antigen (HBGA)-blocking assays.

Methods: Serum samples collected during the evaluation of an investigational norovirus vaccine (HIL-214 [formerly TAK-214]) were assayed for neutralizing antibody levels against the vaccine's prototype Norwalk virus/genogroup I, genotype 1 (GI.1) (P1) virus strain. Results were compared with those previously determined using HBGA-blocking assays.

Results: Neutralizing antibody seroresponses were observed in 83% of 24 vaccinated adults, and antibody levels were highly correlated (r = 0.81; P < .001) with those measured by HBGA blocking.

Conclusions: Genogroup I, genotype 1 (GI.1)-specific HBGA-blocking antibodies are a surrogate …

Changes In Reproductive Health Information-Seeking Behaviors After The Dobbs Decision: Systematic Search Of The Wikimedia Database, Mackenzie Lemieux, Cyrus Zhou, Caroline Cary, Jeannie Kelly

2020-Current year OA Pubs

BACKGROUND: After the US Supreme Court overturned Roe v. Wade, confusion followed regarding the legality of abortion in different states across the country. Recent studies found increased Google searches for abortion-related terms in restricted states after the Dobbsv. Jackson Women's Health Organization decision was leaked. As patients and providers use Wikipedia (Wikimedia Foundation) as a predominant medical information source, we hypothesized that changes in reproductive health information-seeking behavior could be better understood by examining Wikipedia article traffic.

OBJECTIVE: This study aimed to examine trends in Wikipedia usage for abortion and contraception information before and after the Dobbs decision.

METHODS: Page …

First-In-Human Dose-Escalation Study Of Fianlimab, An Antilymphocyte Activation Gene-3 Antibody, With Cemiplimab In Patients With Advanced Malignancies, Nehal J Lakhani, Haeseong Park, Et Al.

2020-Current year OA Pubs

PURPOSE: Preclinical data indicate that fianlimab (antilymphocyte activation gene-3) plus cemiplimab (anti-PD-1) enhances antitumor activity. Here, we report prespecified final analyses of the dose-escalation part of a first-in-human, phase 1 study (NCT03005782) of fianlimab as monotherapy and in combination with cemiplimab in patients with advanced malignancies.

PATIENTS AND METHODS: Adult patients received 1 to 40 mg/kg of fianlimab plus 350 mg of cemiplimab every 3 weeks (Q3W) across various dose-escalation schedules. Primary objectives were the rate of dose-limiting toxicities, adverse events (including immune mediated), deaths, laboratory abnormalities, and pharmacokinetics. Secondary outcomes were objective response rate, best overall response, duration of …

Development, Progression, And Mortality Of Suspected Interstitial Lung Disease In Copdgene, Jonathan A Rose, Ann-Marcia C Tukpah, Claire Cutting, Noriaki Wada, Mizuki Nishino, Matthew Moll, Sean Kalra, Bina Choi, David A Lynch, Benjamin A Raby, Ivan O Rosas, Raúl San José Estépar, George R Washko, Edwin K Silverman, Michael H Cho, Hiroto Hatabu, Rachel K Putman, Gary M Hunninghake

Faculty, Staff and Students Publications

Rationale: Some with interstitial lung abnormalities (ILA) are suspected to have interstitial lung disease (ILD), a subgroup with adverse outcomes. Rates of development and progression of suspected ILD and their effect on mortality are unknown. Objectives: To determine rates of development, progression, and mortality in those with suspected ILD and assess effects of individual ILD and progression criteria.

Methods: Participants from COPDGene (Genetic Epidemiology of Chronic Obstructive Pulmonary Disease) with ILA characterization and FVC at enrollment and 5-year follow-up were included. ILD was defined as ILA and fibrosis and/or FVC < 80% predicted. Prevalent ILD was assessed at enrollment and incident ILD and progression were assessed at 5-year follow-up. Computed tomography (CT) progression was assessed visually and FVC decline as relative change. Multivariable Cox regression tested associations between mortality and prevalent ILD, incident ILD, and progression groups.

Measurements and Main Results: Of 9,588 participants at enrollment, 268 …

Global Impact Of Aging On The Hemodynamic Response Function In The Gray Matter Of Human Cerebral Cortex, Nooshin J Fesharaki, Amanda Taylor, Keisjon Mosby, Ruosha Li, Jung Hwan Kim, David Ress

Faculty, Staff and Students Publications

In functional magnetic resonance imaging, the hemodynamic response function (HRF) is a stereotypical response to local changes in cerebral hemodynamics and oxygen metabolism due to briefly (< 4 s) evoked neural activity. Accordingly, the HRF is often used as an impulse response with the assumption of linearity in data analysis. In cognitive aging studies, it has been very common to interpret differences in brain activation as age-related changes in neural activity. Contrary to this assumption, however, evidence has accrued that normal aging may also significantly affect the vasculature, thereby affecting cerebral hemodynamics and metabolism, confounding interpretation of fMRI cognitive aging studies. In this study, use was made of a multisensory task to evoke the HRF in ~87% of cerebral cortex in cognitively intact adults with ages ranging from 22 to 75 years. This widespread activation enabled us to investigate age trends in the spatial distributions of HRF characteristics within the majority of cortical gray matter, which we termed as global age trends. The task evoked both positive and negative HRFs, which were characterized using model-free parameters in native-space coordinates. We found significant global age trends in the distributions of HRF parameters in terms of both amplitudes (e.g., peak amplitude and contrast-to-noise ratio) and temporal dynamics (e.g., full-width-at-half-maximum). Our findings offer insight into how age-dependent changes affect neurovascular coupling and show promise for use of HRF parameters as non-invasive indicators for age-related pathology.

Impact Of Site-Specific Conjugation Strategies On The Pharmacokinetics Of Antibody Conjugated Radiotherapeutics, Ábel Nagy, David Ulmert, Wahed Zedan, Claire M Storey, Julie Park, Susanne Geres, Katharina Lückerath, Kjell Sjöström, Hadis Westin, Norbert Peekhaus, Daniel Lj Thorek, Amelie Eriksson Karlström, Mohamed Altai

2020-Current year OA Pubs

Antibody radionuclide conjugates are an emerging modality for targeted imaging and potent therapy of disseminated disease. Coupling of radionuclides to monoclonal antibodies (mAbs) is typically achieved by applying non-site-specific labelling techniques. With the ambition of reducing variability, increasing labelling efficacy and stability, several site-specific conjugation strategies have been developed in recent years for toxin- and fluorophore-mAb conjugates. In this study, we studied two site-specific labelling strategies for the conjugation of the macrocyclic chelating agent, DOTA, to the anti-Leucine Rich Repeat Containing 15 (LRRC15) mAb DUNP19. Specifically, one approach utilized a DOTA-bearing peptide (FcIII) with a strong affinity for the fragment …

Key Epigenetic And Signaling Factors In The Formation And Maintenance Of The Blood-Brain Barrier, Jayanarayanan Sadanandan, Sithara Thomas, Iny Elizabeth Mathew, Zhen Huang, Spiros L Blackburn, Nitin Tandon, Hrishikesh Lokhande, Pierre D Mccrea, Emery H Bresnick, Pramod K Dash, Devin W Mcbride, Arif Harmanci, Lalit K Ahirwar, Dania Jose, Ari C Dienel, Hussein A Zeineddine, Sungha Hong, Peeyush Kumar T

Faculty, Staff and Student Publications

The blood-brain barrier (BBB) controls the movement of molecules into and out of the central nervous system (CNS). Since a functional BBB forms by mouse embryonic day E15.5, we reasoned that gene cohorts expressed in CNS endothelial cells (EC) at E13.5 contribute to BBB formation. In contrast, adult gene signatures reflect BBB maintenance mechanisms. Supporting this hypothesis, transcriptomic analysis revealed distinct cohorts of EC genes involved in BBB formation and maintenance. Here, we demonstrate that epigenetic regulator's histone deacetylase 2 (HDAC2) and polycomb repressive complex 2 (PRC2) control EC gene expression for BBB development and prevent Wnt/β-catenin (Wnt) target genes …

Parent And Primary Care Clinician Perceptions About Pediatric Hypertension, Abbas H. Zaidi, Erica Sood, Sarah De Ferranti, Samuel Gidding, Varsha Zadokar, Jonathan Miller, Anne Kazak

Department of Pediatrics Faculty Papers

IMPORTANCE: Despite published guidelines and a prevalence of pediatric hypertension of approximately 3%, less than 25% of affected children are identified, with 60% not receiving any intervention despite detection. Understanding the knowledge and perceptions of parents or caregivers and health care teams is crucial to identify factors that may contribute to these unacceptably low detection rates.

OBJECTIVE: To examine the knowledge and perceptions of parents and health care teams regarding pediatric hypertension to identify common themes contributing to low hypertension detection.

DESIGN, SETTING, AND PARTICIPANTS: This qualitative study, interviewed parents of children diagnosed with hypertension who did not follow up …

Ire1Α Silences Dsrna To Prevent Taxane-Induced Pyroptosis In Triple-Negative Breast Cancer, Longyong Xu, Fanglue Peng, Qin Luo, Yao Ding, Fei Yuan, Liting Zheng, Wei He, Sophie S Zhang, Xin Fu, Jin Liu, Ayse Sena Mutlu, Shuyue Wang, Ralf Bernd Nehring, Xingyu Li, Qianzi Tang, Catherine Li, Xiangdong Lv, Lacey E Dobrolecki, Weijie Zhang, Dong Han, Na Zhao, Eric Jaehnig, Jingyi Wang, Weiche Wu, Davis A Graham, Yumei Li, Rui Chen, Weiyi Peng, Yiwen Chen, Andre Catic, Zhibin Zhang, Bing Zhang, Anthony M Mustoe, Albert C Koong, George Miles, Michael T Lewis, Meng C Wang, Susan M Rosenberg, Bert W O'Malley, Thomas F Westbrook, Han Xu, Xiang H-F Zhang, C Kent Osborne, Jin Billy Li, Matthew J Ellis, Mothaffar F Rimawi, Jeffrey M Rosen, Xi Chen

Faculty, Staff and Students Publications

Chemotherapy is often combined with immune checkpoint inhibitor (ICI) to enhance immunotherapy responses. Despite the approval of chemo-immunotherapy in multiple human cancers, many immunologically cold tumors remain unresponsive. The mechanisms determining the immunogenicity of chemotherapy are elusive. Here, we identify the ER stress sensor IRE1α as a critical checkpoint that restricts the immunostimulatory effects of taxane-chemotherapy and prevents the innate immune recognition of immunologically cold triple-negative breast cancer (TNBC). IRE1α RNase silences taxane-induced dsRNA through RIDD (Regulated IRE1-Dependent Decay) to prevent NLRP3 inflammasome–dependent pyroptosis. Inhibition of IRE1α in Trp53−/− TNBC allows taxane to induce extensive dsRNAs that are sensed …

Estimation Of Prevalence Of Autoimmune Diseases In The United States Using Electronic Health Record Data, Aaron H. Abend, Albert M. Lai, Et Al.

2020-Current year OA Pubs

BACKGROUNDPrevious epidemiologic studies of autoimmune diseases in the US have included a limited number of diseases or used metaanalyses that rely on different data collection methods and analyses for each disease.METHODSTo estimate the prevalence of autoimmune diseases in the US, we used electronic health record data from 6 large medical systems in the US. We developed a software program using common methodology to compute the estimated prevalence of autoimmune diseases alone and in aggregate that can be readily used by other investigators to replicate or modify the analysis over time.RESULTSOur findings indicate that over 15 million people, or 4.6% of …

Mexican Health And Aging Study Biomarker And Genetic Data Profile, Rafael Samper-Ternent, Jesús Daniel Zazueta-Borboa, Alejandra Michaels-Obregon, Dolly Reyes-Dumeyer, Sandra Barral, Giuseppe Tosto, Rebeca Wong

Faculty, Staff and Student Publications

The Mexican Health and Aging Study (MHAS) is one of the largest ongoing longitudinal studies of aging in Latin America, with six waves over 20 years. MHAS includes sociodemographic, economic, and health data from a nationally representative sample of adults 50 years and older in urban and rural Mexico. MHAS is designed to study the impact of diseases on adults' health, function, and mortality. As Mexico is experiencing rapid population aging, providing adequate information to study this phenomenon is vital for designing and implementing public policies. The availability of biomarker and genetic data and longitudinal survey data elevates opportunities for …

Diversity And Characteristics Of The Oral Microbiome Associated With Self-Reported Ancestral/Ethnic Groups, Qingguo Wang, Bing-Yan Wang, She'neka Williams, Hua Xie

Faculty, Staff and Student Publications

Periodontitis disproportionately affects genetic ancestral/ethnic groups. To characterize the oral microbiome from different genetic ancestral/ethnic groups, we collected 161 dental plaque samples from self-identified African Americans (AAs), Caucasian Americans (CAs), and Hispanic Americans (HAs) with clinical gingival health or biofilm-induced gingivitis on an intact periodontium. DNA was extracted from these samples, and then DNA libraries were prepared and sequenced using an Illumina NovaSeq high-throughput sequencer. We found significant differences in the diversity and abundance of microbial taxa among dental plaque samples of the AA, CA, and HA groups. We also identified unique microbial species in a self-reported ancestral/ethnic group. Moreover, …

Unraveling The Role Of Uils, A Urea-Induced Acyl-Homoserine Lactonase That Enhances Serratia Marcescens Fitness, Interbacterial Competition, And Urinary Tract Infection, Marisel R Tuttobene, Brayan S Arango Gil, Gisela Di Venanzio, Javier F Mariscotti, Rodrigo Sieira, Mario F Feldman, María Soledad Ramirez, Eleonora García Véscovi

2020-Current year OA Pubs

UNLABELLED:

IMPORTANCE: This work reveals the acyl-homoserine lactonase

A Trivalent Mucosal Vaccine Encoding Phylogenetically Inferred Ancestral Rbd Sequences Confers Pan-Sarbecovirus Protection In Mice, James Brett Case, Shilpa Sanapala, Suzanne M Scheaffer, Déborah Carolina Carvalho Dos Anjos, Lucas J Adams, Nadia Soudani, Chieh-Yu Liang, Baoling Ying, Adrianus C M Boon, Daved H Fremont, Sean P J Whelan, Michael S Diamond, Et Al.

2020-Current year OA Pubs

The continued emergence of SARS-CoV-2 variants and the threat of future Sarbecovirus zoonoses have spurred the design of vaccines that can induce broad immunity against multiple coronaviruses. Here, we use computational methods to infer ancestral phylogenetic reconstructions of receptor binding domain (RBD) sequences across multiple Sarbecovirus clades and incorporate them into a multivalent adenoviral-vectored vaccine. Mice immunized with this pan-Sarbecovirus vaccine are protected in the upper and lower respiratory tracts against infection by historical and contemporary SARS-CoV-2 variants, SARS-CoV, and pre-emergent SHC014 and Pangolin/GD coronavirus strains. Using genetic and immunological approaches, we demonstrate that vaccine-induced protection unexpectedly is conferred principally …

Defining Renal Recovery In Patients With Hepatorenal Syndrome-Acute Kidney Injury: Experience From North American Studies, Muhammad A. Mujtaba, Hussien Elsiesy, Sara Faiz, Syed A. Hussain, Ann Kathleen N. Gamilla-Crudo, Aftab Karim, Mohammad I. Khan, Muhammad W. Khattak, Zunaira Zafar, Michael Kueht, Khurram Jamil

Jefferson Health - Northeast Papers (formerly Aria Health Papers)

INTRODUCTION: The degree of improvement in serum creatinine (SCr) has previously been suggested as a sensitive indicator of treatment response in patients with hepatorenal syndrome-acute kidney injury (HRS-AKI), while HRS reversal remains the primary endpoint in clinical trials.

METHODS: A total of ≥ 30% SCr improvement was analyzed as an exploratory prespecified endpoint in the CONFIRM trial. In this post hoc analysis, intent-to-treat population data from three Phase 3 studies (OT-0401, REVERSE, and CONFIRM) conducted in North America in patients with HRS-AKI were pooled to assess the incidence of > 30% improvement in SCr and its association with clinical outcomes.

RESULTS: …