DR43 DataRelease
Release Date: 03/18/2022
| SDY1490: Immunosuppression Withdrawal for Stable Pediatric Liver Transplant Recipients (iWITH) | |||||||
| Status: | New | ||||||
| Description: | Our primary goal is to test the hypothesis that a defined subset of pediatric liver tx recipients can safely and durably withdraw from IS. A fundamental research question is whether 35% of selected pediatric liver transplant recipients can be withdrawn from IS and achieve operational tolerance. We will conduct a multi-center, longitudinal study to determine the safety and efficacy of ISW with concomitant translational studies to develop and validate a fingerprint which predicts operational tolerance. Pediatric recipients of deceased or living donor liver txs will be screened for eligibility and those eligible will begin ISW. Participants will undergo gradual ISW over no less than 36 weeks and no more than 52 weeks with frequent monitoring of liver tests. All participants will be followed for 48 months ensuring a minimum of 36 months of follow-up after successful ISW. | ||||||
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| DOI: | 10.21430/M3CJTCGUDP | ||||||
| Subjects: | 161 | ||||||
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| Clinical Assessments: | None | ||||||
| SDY1644: Urban Environmental Factors and Childhood Asthma (URECA) (ICAC-07) | |||||||||||||||||||||||
| Status: | New | ||||||||||||||||||||||
| Description: | The purpose of this study is to determine the way environmental factors (like the components of inner-city household dust) affect immune system development and symptoms of asthma in inner city children. The study is divided into three periods, as the subjects age from birth to 10 years old. Each age bracket will explore different objectives and endpoints. Study Objectives/Hypotheses: Subjects age 0 to 3 years old: Environmental factors in the inner city adversely influence the development of the immune system to promote cytokine dysregulation, allergy, and recurrent wheezing by age 3. Children who have had a viral lower respiratory infection and have developed cytokine dysregulation by age 3 are at increased risk for the development of asthma by age 6. Subjects age 4 to 7 years old: There is a unique pattern of immune development that is driven by specific urban exposures in early life, and this pattern of immune development is characterized by: 1) impairment of antiviral responses and 2) accentuation of Th2-like responses (e.g. cockroach-specific Interleukin-13(IL-13)). The clinical effects of these changes in immune development are frequent virus-induced wheezing and allergic sensitization by 3-4 years of age, and these characteristics synergistically increase the risk of asthma at age 7 years. Subjects age 7 to 10 years old: There are unique combinations of environmental exposures (cockroach allergens, indoor pollutants [Environmental Tobacco Smoke (ETS) and Nitrogen Dioxide (NO2)], lack of microbial exposure), and family characteristics (stress, genetic factors related to innate immunity) that synergistically promote asthma onset, persistence, and morbidity in urban neighborhoods. These exposures and characteristics influence immune expression and lung development during critical periods of growth, resulting in specific asthma phenotypes. Subjects age 10 to 16 years old: To determine the wheezing, asthma and atopy phenotypes in minority children growing up in poor urban neighborhoods as they develop from birth through adolescence. | ||||||||||||||||||||||
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| DOI: | 10.21430/M3H1YHLR5Z | ||||||||||||||||||||||
| Subjects: | 609 | ||||||||||||||||||||||
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| Assays: | None | ||||||||||||||||||||||
| Clinical Assessments: | None | ||||||||||||||||||||||
| SDY1720: A Retrospective Multicenter Study to Determine Clinical Outcomes in Subjects Previously Enrolled in the CTOTC-03 Study (CTOTC-14) | |||||||
| Status: | New | ||||||
| Description: | This study is a multicenter, non?randomized, retrospective study to collect long term (5 years post?transplant +/- 6 months) clinical outcome data on subjects previously enrolled in the CTOTC-03 study. | ||||||
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| DOI: | 10.21430/M3G3QHV9UG | ||||||
| Subjects: | 35 | ||||||
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| Assays: | None | ||||||
| Clinical Assessments: | None | ||||||
| SDY1781: Proinflammatory IgG Fc structures in patients with severe COVID-19 | |||||
| Status: | New | ||||
| Description: | Severe acute respiratory syndrome coronavirus 2 infections can cause coronavirus disease 2019 (COVID-19), which manifests with a range of severities from mild illness to life-threatening pneumonia and multi-organ failure. Severe COVID-19 is characterized by an inflammatory signature, including high levels of inflammatory cytokines, alveolar inflammatory infiltrates and vascular microthrombi. Here we show that patients with severe COVID-19 produced a unique serologic signature, including an increased likelihood of IgG1 with afucosylated Fc glycans. This Fc modification on severe acute respiratory syndrome coronavirus 2 IgGs enhanced interactions with the activating Fc? receptor Fc?RIIIa; when incorporated into immune complexes, Fc afucosylation enhanced production of inflammatory cytokines by monocytes, including interleukin-6 and tumor necrosis factor. These results show that disease severity in COVID-19 correlates with the presence of proinflammatory IgG Fc structures, including afucosylated IgG1. | ||||
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| DOI: | 10.21430/M33D4Y9RTM | ||||
| Subjects: | 0 | ||||
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| Assays: | None | ||||
| Clinical Assessments: | None | ||||
| SDY1789: Regimen verification phase: Sequential optimization of dose and schedule of PfSPZ Vaccine, verified by randomized, controlled, double-blind immunization and controlled human malaria infection in malaria-naive, healthy adult volunteers in Germany | |||||||
| Status: | New | ||||||
| Description: | The study is to take place at Institut fur Tropenmedizin, Eberhard Karls Universitat Tubingen, Tubingen Germany. The study has two phases: 1) dose optimization, and 2) regimen verification. In the first phase groups A, B1, B2, C1, C2 and C3 will be vaccinated sequentially in a pre-specified order, followed by homologous CHMI with 3,200 PfSPZ Challenge (NF54) three weeks after last vaccine injection. Dose optimization phase A: 9x10^5 PfSPZ on Days 0, 7 and 28 (n = 6) B1: 1.35x10^6 PfSPZ on Days 0 and 7 (n = 6) B2: 1.35x10^6 PfSPZ on Days 0, 7, and 28 (n = 6) C1: 2.7x10^6 PfSPZ on Day 0 (n = 6) C2: 2.7x10^6 PfSPZ on Day 0 and 7 (n = 6) C3: 2.7x10^6 PfSPZ on Days 0, 7 and 28 (n = 6) In parallel to CHMI with PfSPZ Challenge (NF54) during the optimization phase, a total of nine volunteers will receive either 800, 1,600 or 3,200 PfSPZ Challenge (7G8) (PfSPZ Challenge (7G8) dose finding) to assess safety, tolerability and infectivity of PfSPZ Challenge (7G8) in malaria-naive healthy adult volunteers. PfSPZ Challenge (7G8) dose finding/infection D1: 800 PfSPZ (n = 3) D2: 1,600 PfSPZ (n = 3) D3: 3,200 PfSPZ (n = 3) Subsequently, the shortest efficacious regimen (V1) and a three-dose regimen (Day 0, 7 and 28) of the highest safe dose (V2) will be selected and verified against placebo (normal saline (NS)). Groups V1 and V2 will be vaccinated at approximately the same time and undergo repeat CHMI three and eight weeks after the last immunization. Volunteers will either receive PfSPZ Vaccine or NS as placebo. Allocation will be random and double blind. Repeat CHMI will be done with PfSPZ Challenge (NF54) and PfSPZ Challenge (7G8), given in a randomized sequence. All immunizations are given by direct venous inoculation (DVI). Regimen verification phase V1: Shortest efficacious regimen (n = 12) against placebo (n = 6) V2: Maximum regimen (n = 12) against placebo (n = 6) P1: Placebo for V1 group (n=6) P2 Placebo for V2 group (n=6). | ||||||
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| DOI: | 10.21430/M3ABFZ7TY8 | ||||||
| Subjects: | 18 | ||||||
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| Publications: | None | ||||||
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| Assays: | None | ||||||
| Clinical Assessments: | None | ||||||
| SDY1798: Discovery and functional interrogation of SARS-CoV-2 RNA-host protein interactions | |||||||
| Status: | New | ||||||
| Description: | SARS-CoV-2 is the cause of a pandemic with growing global mortality. Using comprehensive identification of RNA-binding proteins by mass spectrometry (ChIRP-MS), we identified 309 host proteins that bind the SARS-CoV-2 RNA during active infection. Integration of this data with ChIRP-MS data from three other RNA viruses defined viral specificity of RNA-host protein interactions. Targeted CRISPR screens revealed that the majority of functional RNA-binding proteins protect the host from virus-induced cell death, and comparative CRISPR screens across seven RNA viruses revealed shared and SARS-specific antiviral factors. Finally, by combining the RNA-centric approach and functional CRISPR screens, we demonstrated a physical and functional connection between SARS-CoV-2 and mitochondria, highlighting this organelle as a general platform for antiviral activity. Altogether, these data provide a comprehensive catalog of functional SARS-CoV-2 RNA-host protein interactions, which may inform studies to understand the host-virus interface and nominate host pathways that could be targeted for therapeutic benefit. | ||||||
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| DOI: | 10.21430/M3NPEVXJWP | ||||||
| Subjects: | 0 | ||||||
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| Assays: | None | ||||||
| Clinical Assessments: | None | ||||||
| SDY1800: Durable SARS-CoV-2 B cell immunity after mild or severe disease | |||||||
| Status: | New | ||||||
| Description: | Multiple studies have shown loss of severe acute respiratory syndrome coronavirus 2-specific (SARS-CoV-2-specific) antibodies over time after infection, raising concern that humoral immunity against the virus is not durable. If immunity wanes quickly, millions of people may be at risk for reinfection after recovery from coronavirus disease 2019 (COVID-19). However, memory B cells (MBCs) could provide durable humoral immunity even if serum neutralizing antibody titers decline. We performed multidimensional flow cytometric analysis of S protein receptor binding domain-specific (S-RBD-specific) MBCs in cohorts of ambulatory patients with COVID-19 with mild disease (n = 7), and hospitalized patients with moderate to severe disease (n = 7), at a median of 54 days (range, 39-104 days) after symptom onset. We detected S-RBD-specific class-switched MBCs in 13 of 14 participants, failing only in the individual with the lowest plasma levels of anti-S-RBD IgG and neutralizing antibodies. Resting MBCs (rMBCs) made up the largest proportion of S-RBD-specific MBCs in both cohorts. FCRL5, a marker of functional memory on rMBCs, was more dramatically upregulated on S-RBD-specific rMBCs after mild infection than after severe infection. These data indicate that most SARS-CoV-2-infected individuals develop S-RBD-specific, class-switched rMBCs that resemble germinal center-derived B cells induced by effective vaccination against other pathogens, providing evidence for durable B cell-mediated immunity against SARS-CoV-2 after mild or severe disease. | ||||||
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| DOI: | 10.21430/M3YQ1SXVS6 | ||||||
| Subjects: | 14 | ||||||
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| Assays: | None | ||||||
| Clinical Assessments: | None | ||||||
| SDY1813: Comprehensive analysis of T cell immunodominance and immunoprevalence of SARS-CoV-2 epitopes in COVID-19 cases | |||||||||||||
| Status: | New | ||||||||||||
| Description: | T cells are involved in control of SARS-CoV-2 infection. To establish the patterns of immunodominance of different SARS-CoV-2 antigens and precisely measure virus-specific CD4+ and CD8+ T cells, we study epitope-specific T cell responses of 99 convalescent coronavirus disease 2019 (COVID-19) cases. The SARS-CoV-2 proteome is probed using 1,925 peptides spanning the entire genome, ensuring an unbiased coverage of human leukocyte antigen (HLA) alleles for class II responses. For HLA class I, we study an additional 5,600 predicted binding epitopes for 28 prominent HLA class I alleles, accounting for wide global coverage. We identify several hundred HLA-restricted SARS-CoV-2-derived epitopes. Distinct patterns of immunodominance are observed, which differ for CD4+ T cells, CD8+ T cells, and antibodies. The class I and class II epitopes are combined into epitope megapools to facilitate identification and quantification of SARS-CoV-2-specific CD4+ and CD8+ T cells. | ||||||||||||
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| DOI: | 10.21430/M3F1F8OJDN | ||||||||||||
| Subjects: | 0 | ||||||||||||
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| Assays: | None | ||||||||||||
| Clinical Assessments: | None | ||||||||||||
| SDY1829: Severely ill COVID-19 patients display impaired exhaustion features in SARS-CoV-2-reactive CD8+ T cells | |||||
| Status: | New | ||||
| Description: | The molecular properties of CD8+ T cells that respond to SARS-CoV-2 infection are not fully known. Here, we report on the single-cell transcriptomes of >80,000 virus-reactive CD8+ T cells, obtained using a modified Antigen-Reactive T cell Enrichment (ARTE) assay, from 39 COVID-19 patients and 10 healthy subjects. COVID-19 patients segregated into two groups based on whether the dominant CD8+ T cell response to SARS-CoV-2 was `exhausted? or not. SARS-CoV-2-reactive cells in the exhausted subset were increased in frequency and displayed lesser cytotoxicity and inflammatory features in COVID-19 patients with mild compared to severe illness. In contrast, SARS-CoV-2-reactive cells in the dominant non-exhausted subset from patients with severe disease showed enrichment of transcripts linked to co-stimulation, pro-survival NF-?B signaling, and anti-apoptotic pathways, suggesting the generation of robust CD8+ T cell memory responses in patients with severe COVID-19 illness. CD8+ T cells reactive to influenza and respiratory syncytial virus from healthy subjects displayed polyfunctional features and enhanced glycolysis. Cells with such features were largely absent in SARS-CoV-2-reactive cells from both COVID-19 patients and healthy controls non-exposed to SARS-CoV-2. Overall, our single-cell analysis revealed substantial diversity in the nature of CD8+ T cells responding to SARS-CoV-2. | ||||
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| DOI: | 10.21430/M3A57H738Q | ||||
| Subjects: | 0 | ||||
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| Assays: | None | ||||
| Clinical Assessments: | None | ||||
| SDY1831: Serological analysis reveals an imbalanced IgG subclass composition associated with COVID-19 disease severity | |||||
| Status: | New | ||||
| Description: | Coronavirus disease 2019 (COVID-19) is associated with a wide spectrum of disease presentation, ranging from asymptomatic infection to acute respiratory distress syndrome (ARDS). Paradoxically, a direct relationship has been suggested between COVID-19 disease severity and the levels of circulating severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific antibodies, including virus-neutralizing titers. A serological analysis of 536 convalescent healthcare workers reveals that SARS-CoV-2-specific and virus-neutralizing antibody levels are elevated in individuals that experience severe disease. The severity-associated increase in SARS-CoV-2-specific antibody is dominated by immunoglobulin G (IgG), with an IgG subclass ratio skewed toward elevated receptor binding domain (RBD)- and S1-specific IgG3. In addition, individuals that experience severe disease show elevated SARS-CoV-2-specific antibody binding to the inflammatory receptor Fc?RIIIa. Based on these correlational studies, we propose that spike-specific IgG subclass utilization may contribute to COVID-19 disease severity through potent Fc-mediated effector functions. These results may have significant implications for SARS-CoV-2 vaccine design and convalescent plasma therapy. | ||||
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| DOI: | 10.21430/M3B6163WG1 | ||||
| Subjects: | 0 | ||||
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| Assays: | None | ||||
| Clinical Assessments: | None | ||||
| SDY1832: Immunological imprinting of the antibody response in COVID-19 patients | |||||
| Status: | New | ||||
| Description: | In addition to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), humans are also susceptible to six other coronaviruses, for which consecutive exposures to antigenically related and divergent seasonal coronaviruses are frequent. Despite the prevalence of COVID-19 pandemic and ongoing research, the nature of the antibody response against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is unclear. Here we longitudinally profile the early humoral immune response against SARS-CoV-2 in hospitalized coronavirus disease 2019 (COVID-19) patients and quantify levels of pre-existing immunity to OC43, HKU1 and 229E seasonal coronaviruses, and find a strong back-boosting effect to conserved but not variable regions of OC43 and HKU1 betacoronaviruses spike protein. However, such antibody memory boost to human coronaviruses negatively correlates with the induction of IgG and IgM against SARS-CoV-2 spike and nucleocapsid protein. Our findings thus provide evidence of immunological imprinting by previous seasonal coronavirus infections that can potentially modulate the antibody profile to SARS-CoV-2 infection. | ||||
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| DOI: | 10.21430/M3EMGZH7G6 | ||||
| Subjects: | 0 | ||||
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| Assays: | None | ||||
| Clinical Assessments: | None | ||||
| SDY1877: Ethmoidal sinus scRNA from CRSwNP and CRSsNP | ||||||||
| Status: | New | |||||||
| Description: | scRNA-Seq data from ethmoidal sinus samples from adult human sbjects with chronic rhinosinusitis with nasal polypsosis (n=6) and chronic rhinosinusitis without nasal polyposis (n=6) | |||||||
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| DOI: | 10.21430/M392GKBPXD | |||||||
| Subjects: | 11 | |||||||
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| SDY1880: Multicenter Mayo Genomics Trial (GEN-04) | |||||||
| Status: | New | ||||||
| Description: | Gene expression profiling is used to study the activity of genes. Each gene has an "on/off" switch that controls how they are expressed in a cell, as well as a "volume control" that increases or decreases the level of expression of a particular gene as necessary. Researchers want to see if the presence and abundance of certain transcripts in a kidney biopsy at one year after transplant can predict which kidneys will have reduced function over time. | ||||||
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| DOI: | 10.21430/M31W8DCC1W | ||||||
| Subjects: | 494 | ||||||
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| Clinical Assessments: | None | ||||||
| SDY1886: Multiscale PHATE identifies multimodal signatures of COVID-19 | |||||||||||||
| Status: | New | ||||||||||||
| Description: | Multiscale PHATE is a machine learning novel tool for dimensionality reduction and data exploration that can be applied to biological data sets to learn and visualize | ||||||||||||
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| DOI: | 10.21430/M3D4FZNYFR | ||||||||||||
| Subjects: | 2170 | ||||||||||||
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| Clinical Assessments: | None | ||||||||||||
| SDY1912: Mouse blood gene expression after administration of 137 Cesium | |||||||
| Status: | New | ||||||
| Description: | In the current study, we investigated the gene expression response of blood cells of mice that were injected with variable amounts of 137Cs. We isolated total RNA from peripheral blood from mice with 0 (control), 158, 191, 215 and 259 uCi cesium source amount on days 2, 3, 5, 7 and 14 days after injection. Using Agilent Mouse Whole Genome microarrays, we identified x genes that were significantly differentially expressed across the 14-day time course of this study. We identified common biological functions affected that persisted across the 14-day study. | ||||||
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| DOI: | 10.21430/M37BKVG03K | ||||||
| Subjects: | 32 | ||||||
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| Clinical Assessments: | None | ||||||
| SDY1916: Inhibition of elastase enhances the adjuvanticity of alum and promotes anti-SARS-CoV-2 systemic and mucosal immunity | |||||
| Status: | New | ||||
| Description: | Alum, used as an adjuvant in injected vaccines, promotes T helper 2 (Th2) and serum antibody (Ab) responses. However, it fails to induce secretory immunoglobulin (Ig) A (SIgA) in mucosal tissues and is poor in inducing Th1 and cell-mediated immunity. Alum stimulates interleukin 1 (IL-1) and the recruitment of myeloid cells, including neutrophils. We investigated whether neutrophil elastase regulates the adjuvanticity of alum, and whether a strategy targeting neutrophil elastase could improve responses to injected vaccines. Mice coadministered a pharmacological inhibitor of elastase, or lacking elastase, developed high-affinity serum IgG and IgA antibodies after immunization with alum-adsorbed protein vaccines, including the spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2). These mice also developed broader antigen-specific CD4+ T cell responses, including high Th1 and T follicular helper (Tfh) responses. Interestingly, in the absence of elastase activity, mucosal SIgA responses were induced after systemic immunization with alum as adjuvant. Importantly, lack or suppression of elastase activity enhanced the magnitude of anti-SARS-CoV-2 spike subunit 1 (S1) antibodies, and these antibodies reacted with the same epitopes of spike 1 protein as sera from COVID-19 patients. Therefore, suppression of neutrophil elastase could represent an attractive strategy for improving the efficacy of alum-based injected vaccines for the induction of broad immunity, including mucosal immunity. | ||||
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| DOI: | 10.21430/M38FW5ZQHE | ||||
| Subjects: | 0 | ||||
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| Clinical Assessments: | None | ||||
| SDY1917: Impaired neutralizing antibody response to COVID-19 mRNA vaccines in cancer patients | |||||
| Status: | New | ||||
| Description: | There is currently a critical need to determine the efficacy of SARS-CoV-2 vaccination for immunocompromised patients. In this study, we determined the neutralizing antibody response in 160 cancer patients diagnosed with chronic lymphocytic leukemia (CLL), lung cancer, breast cancer, and various non-Hodgkin's lymphomas (NHL), after they received two doses of mRNA vaccines. Serum from 46 mRNA vaccinated health care workers (HCWs) served as healthy controls. We discovered that (1) cancer patients exhibited reduced neutralizing antibody titer (NT50) compared to HCWs; (2) CLL and NHL patients exhibited the lowest NT50 levels, with 50-60% of them below the detection limit; (3) mean NT50 levels in patients with CLL and NHL was ~2.6 fold lower than those with solid tumors; and (4) cancer patients who received anti-B cell therapy exhibited significantly reduced NT50 levels. Our results demonstrate an urgent need for novel immunization strategies for cancer patients against SARS-CoV-2, particularly those with hematological cancers and those on anti-B cell therapies. | ||||
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| DOI: | 10.21430/M383VCI57N | ||||
| Subjects: | 0 | ||||
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| Assays: | None | ||||
| Clinical Assessments: | None | ||||
| SDY1924: A multiomics study in a Japanese rheumatoid arthritis cohort | |||||
| Status: | New | ||||
| Description: | A multiomics study in a Japanese rheumatoid arthritis cohort | ||||
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| DOI: | 10.21430/M36KC4L9G2 | ||||
| Subjects: | 54 | ||||
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| Publications: | None | ||||
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| Clinical Assessments: | None | ||||
| SDY1927: Corticosteroid treatment in COVID-19 modulates host inflammatory responses and transcriptional signatures of immune dysregulation | |||||
| Status: | New | ||||
| Description: | Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of coronavirus disease-2019 (COVID-19), a respiratory disease that varies in severity from mild to severe/fatal. Several risk factors for severe disease have been identified, notably age, male sex, and pre-existing conditions such as diabetes, obesity, and hypertension. Several advancements in clinical care have been achieved over the past year, including the use of corticosteroids (e.g., corticosteroids) and other immune-modulatory treatments that have now become standard of care for patients with acute severe COVID-19. While the understanding of the mechanisms that underlie increased disease severity with age has improved over the past few months, it remains incomplete. Furthermore, the molecular impact of corticosteroid treatment on host response to acute SARS-CoV-2 infection has not been investigated. In this study, a cross-sectional and longitudinal analysis of Ab, soluble immune mediators, and transcriptional responses in young (< or = 65 years) and aged (> 65 years) diabetic males with obesity hospitalized with acute severe COVID-19 was conducted. Additionally, the transcriptional profiles in samples obtained before and after corticosteroids became standard of care were compared. The analysis indicates that severe COVID-19 is characterized by robust Ab responses, heightened systemic inflammation, increased expression of genes related to inflammatory and pro-apoptotic processes, and reduced expression of those important for adaptive immunity regardless of age. In contrast, COVID-19 patients receiving steroids did not show high levels of systemic immune mediators and lacked transcriptional indicators of heightened inflammatory and apoptotic responses. Overall, these data suggest that inflammation and cell death are key drivers of severe COVID-19 pathogenesis in the absence of corticosteroid therapy. | ||||
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| DOI: | 10.21430/M3WIUTT8OD | ||||
| Subjects: | 0 | ||||
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| Clinical Assessments: | None | ||||
| SDY1928: Microbial-driven preterm labour involves crosstalk between the innate and adaptive immune response | |||||||
| Status: | New | ||||||
| Description: | There has been a surge in studies implicating a role of vaginal microbiota in spontaneous preterm birth (sPTB), but most are associative without mechanistic insight. Here we show a comprehensive approach to understand the causative factors of preterm birth, based on the integration of longitudinal vaginal microbiota and cervicovaginal fluid (CVF) immunophenotype data collected from 133 women at high-risk of sPTB. We show that vaginal depletion of Lactobacillus species and high bacterial diversity leads to increased mannose binding lectin (MBL), IgM, IgG, C3b, C5, IL-8, IL-6 and IL-1? and to increased risk of sPTB. Cervical shortening, which often precedes preterm birth, is associated with Lactobacillus iners and elevated levels of IgM, C3b, C5, C5a and IL-6. These data demonstrate a role for the complement system in microbial-driven sPTB and provide a scientific rationale for the development of live biotherapeutics and complement therapeutics to prevent sPTB. | ||||||
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| DOI: | 10.21430/M31K1V0I9F | ||||||
| Subjects: | 133 | ||||||
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| SDY1930: The Metabolic Signature of the Placenta in SPTB | |||||||
| Status: | New | ||||||
| Description: | The placenta is metabolically active and supports the growth of the fetus. We hypothesize that deficits in the capacity of the placenta to maintain bioenergetic and metabolic stability during pregnancy may result in spontaneous preterm birth (SPTB). To explore this hypothesis, we performed a nested cased control study of metabolomic signatures in placentas from women with SPTB (<36 weeks gestation) compared to normal pregnancies (?38 weeks gestation). To control for the effects of gestational age on placenta metabolism, we also studied a subset of metabolites in non-laboring preterm and term Rhesus monkeys. Comprehensive quantification of metabolites demonstrated a significant elevation in the levels of amino acids, prostaglandins, sphingolipids, lysolipids, and acylcarnitines in SPTB placenta compared to term placenta. Additional quantification of placental acylcarnitines by tandem mass spectrometry confirmed the significant elevation in SPTB human, with no significant differences between midgestation and term placenta in Rhesus macaque. Fatty acid oxidation as measured by the flux of 3H-palmitate in SPTB placenta was lower than term. Collectively, significant and biologically relevant alterations in the placenta metabolome were identified in SPTB placenta. Altered acylcarnitine levels and fatty acid oxidation suggest that disruption in normal substrate metabolism is associated with SPTB. | ||||||
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| DOI: | 10.21430/M3HS37CJNW | ||||||
| Subjects: | 0 | ||||||
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| SDY1931: Common Cervicovaginal Microbial Supernatants Alter Cervical Epithelial Function | |||||||
| Status: | New | ||||||
| Description: | Cervicovaginal (CV) microbiota is associated with vaginal health and disease in non-pregnant women. Recent studies in pregnant women suggest that specific CV microbes are associated with preterm birth (PTB). While the associations between CV microbiota and adverse outcomes have been demonstrated, the mechanisms regulating the associations remain unclear. As the CV space contains an epithelial barrier, we postulate that CV microbiota can alter the epithelial barrier function. We investigated the biological, molecular, and epigenetic effects of Lactobacillus crispatus, Lactobacillus iners, and Gardnerella vaginalis on the cervical epithelial barrier function and determined whether L. crispatus mitigates the effects of lipopolysaccharide (LPS) and G. vaginalis on the cervical epithelial barrier as a possible mechanism by which CV microbiota mitigates disease risk. Ectocervical and endocervical cells treated with L. crispatus, L. iners, and G. vaginalis bacteria-free supernatants alone or combined were used to measure cell permeability, adherens junction proteins, inflammatory mediators, and miRNAs. Ectocervical and endocervical permeability increased after L. iners and G. vaginalis exposure. Soluble epithelial cadherin increased after exposure to L. iners but not G. vaginalis or L. crispatus. A Luminex cytokine/chemokine panel revealed increased proinflammatory mediators in all three bacteria-free supernatants with L. iners and G. vaginalis having more diverse inflammatory effects. L. iners and G. vaginalis altered the expression of cervical-, microbial-, and inflammatory-associated miRNAs. L. crispatus mitigated the LPS or G. vaginalis-induced disruption of the cervical epithelial barrier and reversed the G. vaginalis-mediated increase in miRNA expression. G. vaginalis colonization of the CV space of a pregnant C57/B6 mouse resulted in 100% PTB. These findings demonstrate that L. iners and G. vaginalis alter the cervical epithelial barrier by regulating adherens junction proteins, cervical immune responses, and miRNA expressions. These results provide evidence that L. crispatus confers protection to the cervical epithelial barrier by mitigating LPS- or G. vaginalis-induced miRNAs associated with cervical remodeling, inflammation, and PTB. This study provides further evidence that the CV microbiota plays a role in cervical function by altering the cervical epithelial barrier and initiating PTB. Thus, targeting the CV microbiota and/or its effects on the cervical epithelium may be a potential therapeutic strategy to prevent PTB. | ||||||
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| DOI: | 10.21430/M3WYLOVYKD | ||||||
| Subjects: | 0 | ||||||
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| Clinical Assessments: | None | ||||||
| SDY1932: Cross-Reactive Antibodies to SARS-CoV-2 and MERS-CoV in Pre-COVID-19 Blood Samples from Sierra Leoneans | |||||
| Status: | New | ||||
| Description: | Many countries in sub-Saharan Africa have experienced lower COVID-19 caseloads and fewer deaths than countries in other regions worldwide. Under-reporting of cases and a younger population could partly account for these differences, but pre-existing immunity to coronaviruses is another potential factor. Blood samples from Sierra Leonean Lassa fever and Ebola survivors and their contacts collected before the first reported COVID-19 cases were assessed using enzyme-linked immunosorbent assays for the presence of antibodies binding to proteins of coronaviruses that infect humans. Results were compared to COVID-19 subjects and healthy blood donors from the United States. Prior to the pandemic, Sierra Leoneans had more frequent exposures than Americans to coronaviruses with epitopes that cross-react with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), SARS-CoV, and Middle Eastern respiratory syndrome coronavirus (MERS-CoV). The percentage of Sierra Leoneans with antibodies reacting to seasonal coronaviruses was also higher than for American blood donors. Serological responses to coronaviruses by Sierra Leoneans did not differ by age or sex. Approximately a quarter of Sierra Leonian pre-pandemic blood samples had neutralizing antibodies against SARS-CoV-2 pseudovirus, while about a third neutralized MERS-CoV pseudovirus. Prior exposures to coronaviruses that induce cross-protective immunity may contribute to reduced COVID-19 cases and deaths in Sierra Leone. | ||||
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| DOI: | 10.21430/M3T4B7MGV4 | ||||
| Subjects: | 0 | ||||
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| SDY1600: Mapping Immune Responses to CMV in Renal Transplantation | ||||||||||||||||
| Status: | Updated | |||||||||||||||
| Description: | We propose to characterize in depth the relationship between CMV, the compromised host immune response and tissue injury using high-throughput technologies and novel statistical and computational approaches in the setting of solid organ transplant. This setting is unique as it provides the ability to understand viral infection and host tissue injury from the beginning, as the donor organ, when transplanted into a recipient, is generally pristine and without any substantive injury, and will experience exposure or reactivation of CMV only after engraftment. For the sake of homogeneity, we have elected to restrict these studies to kidney transplants, given that this is the most common organ transplanted, has a robust immune response profile that resembles most of the other organ transplants, and is the first organ system to be chosen for the conduct of all phase 1/2/3 pharmaceutical clinical trials. The primary goal of this proposal is to advance the field by creating a unique resource of highly annotated clinical phenotype and multidimensional omics data on the immune response to CMV during primary infection and reactivation. The secondary objective is to gain new insights into how CMV contributes to chronic allograft rejection and identify new approaches to patient management and therapy. These studies have broad applications to understanding the host:pathogen interactions in immunocompromised individuals and their downstream effects in other chronic disease states. | |||||||||||||||
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| DOI: | 10.21430/M30V1NQBF0 | |||||||||||||||
| Subjects: | 413 | |||||||||||||||
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