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  1. Article ; Online: PD-1 Limits IL-2 Production and Thymic Regulatory T Cell Development.

    Caruso, Breanna / Weeder, Benjamin R / Thompson, Reid F / Moran, Amy E

    ImmunoHorizons

    2024  Volume 8, Issue 3, Page(s) 281–294

    Abstract: Inhibitory proteins, such as programmed cell death protein 1 (PD-1), have been studied extensively in peripheral T cell responses to foreign Ags, self-Ags, and neoantigens. Notably, these proteins are first expressed during T cell development in the ... ...

    Abstract Inhibitory proteins, such as programmed cell death protein 1 (PD-1), have been studied extensively in peripheral T cell responses to foreign Ags, self-Ags, and neoantigens. Notably, these proteins are first expressed during T cell development in the thymus. Reports suggest that PD-1 limits regulatory T cell (Treg) development, but the mechanism by which PD-1 exerts this function remains unknown. The present study expands the evaluation of murine PD-1 and its ligands in the thymus, demonstrating that some of the highest expressers of PD-1 and programmed death-ligand 1 are agonist selected cells. Surprisingly, we reveal a selective role for PD-1 in regulating the developmental niche only for Tregs because other agonist selected cell populations, such as NK T cells, remain unchanged. We also ruled out PD-1 as a regulator of proliferation or cell death of agonist selected Tregs and further demonstrated that PD-1-deficient Tregs have reduced TCR signaling. Unexpectedly, the data suggest that PD-1-deficient thymocytes produce elevated levels of IL-2, a Treg niche-limiting cytokine. Collectively, these data suggest a novel role for PD-1 in regulating IL-2 production and the concurrent agonist selection of murine thymic Tregs. This observation has implications for the use of checkpoint blockade in the context of cancer and infection.
    MeSH term(s) Animals ; Mice ; Cytokines/metabolism ; Interleukin-2/metabolism ; Programmed Cell Death 1 Receptor/metabolism ; T-Lymphocytes, Regulatory/immunology ; Thymus Gland/cytology ; Thymus Gland/immunology
    Chemical Substances Cytokines ; Interleukin-2 ; Programmed Cell Death 1 Receptor ; Pdcd1 protein, mouse
    Language English
    Publishing date 2024-03-29
    Publishing country United States
    Document type Journal Article
    ISSN 2573-7732
    ISSN (online) 2573-7732
    DOI 10.4049/immunohorizons.2300079
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: pepsickle rapidly and accurately predicts proteasomal cleavage sites for improved neoantigen identification.

    Weeder, Benjamin R / Wood, Mary A / Li, Ellysia / Nellore, Abhinav / Thompson, Reid F

    Bioinformatics (Oxford, England)

    2021  Volume 37, Issue 21, Page(s) 3723–3733

    Abstract: Motivation: Proteasomal cleavage is a key component in protein turnover, as well as antigen processing and presentation. Although tools for proteasomal cleavage prediction are available, they vary widely in their performance, options and availability.!## ...

    Abstract Motivation: Proteasomal cleavage is a key component in protein turnover, as well as antigen processing and presentation. Although tools for proteasomal cleavage prediction are available, they vary widely in their performance, options and availability.
    Results: Herein, we present pepsickle, an open-source tool for proteasomal cleavage prediction with better in vivo prediction performance (area under the curve) and computational speed than current models available in the field and with the ability to predict sites based on both constitutive and immunoproteasome profiles. Post hoc filtering of predicted patient neoepitopes using pepsickle significantly enriches for immune-responsive epitopes and may improve current epitope prediction and vaccine development pipelines.
    Availability and implementation: pepsickle is open source and available at https://github.com/pdxgx/pepsickle.
    Supplementary information: Supplementary data are available at Bioinformatics online.
    MeSH term(s) Humans ; Proteasome Endopeptidase Complex/metabolism ; Antigens ; Epitopes ; Proteolysis
    Chemical Substances Proteasome Endopeptidase Complex (EC 3.4.25.1) ; Antigens ; Epitopes
    Language English
    Publishing date 2021-04-26
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 1422668-6
    ISSN 1367-4811 ; 1367-4803
    ISSN (online) 1367-4811
    ISSN 1367-4803
    DOI 10.1093/bioinformatics/btab628
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Putatively cancer-specific exon-exon junctions are shared across patients and present in developmental and other non-cancer cells.

    David, Julianne K / Maden, Sean K / Weeder, Benjamin R / Thompson, Reid F / Nellore, Abhinav

    NAR cancer

    2020  Volume 2, Issue 1, Page(s) zcaa001

    Abstract: This study probes the distribution of putatively cancer-specific junctions across a broad set of publicly available non-cancer human RNA sequencing (RNA-seq) datasets. We compared cancer and non-cancer RNA-seq data from The Cancer Genome Atlas (TCGA), ... ...

    Abstract This study probes the distribution of putatively cancer-specific junctions across a broad set of publicly available non-cancer human RNA sequencing (RNA-seq) datasets. We compared cancer and non-cancer RNA-seq data from The Cancer Genome Atlas (TCGA), the Genotype-Tissue Expression (GTEx) Project and the Sequence Read Archive. We found that (i) averaging across cancer types, 80.6% of exon-exon junctions thought to be cancer-specific based on comparison with tissue-matched samples (
    Language English
    Publishing date 2020-01-29
    Publishing country England
    Document type Journal Article
    ISSN 2632-8674
    ISSN (online) 2632-8674
    DOI 10.1093/narcan/zcaa001
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Burden of tumor mutations, neoepitopes, and other variants are weak predictors of cancer immunotherapy response and overall survival.

    Wood, Mary A / Weeder, Benjamin R / David, Julianne K / Nellore, Abhinav / Thompson, Reid F

    Genome medicine

    2020  Volume 12, Issue 1, Page(s) 33

    Abstract: Background: Tumor mutational burden (TMB; the quantity of aberrant nucleotide sequences a given tumor may harbor) has been associated with response to immune checkpoint inhibitor therapy and is gaining broad acceptance as a result. However, TMB harbors ... ...

    Abstract Background: Tumor mutational burden (TMB; the quantity of aberrant nucleotide sequences a given tumor may harbor) has been associated with response to immune checkpoint inhibitor therapy and is gaining broad acceptance as a result. However, TMB harbors intrinsic variability across cancer types, and its assessment and interpretation are poorly standardized.
    Methods: Using a standardized approach, we quantify the robustness of TMB as a metric and its potential as a predictor of immunotherapy response and survival among a diverse cohort of cancer patients. We also explore the additive predictive potential of RNA-derived variants and neoepitope burden, incorporating several novel metrics of immunogenic potential.
    Results: We find that TMB is a partial predictor of immunotherapy response in melanoma and non-small cell lung cancer, but not renal cell carcinoma. We find that TMB is predictive of overall survival in melanoma patients receiving immunotherapy, but not in an immunotherapy-naive population. We also find that it is an unstable metric with potentially problematic repercussions for clinical cohort classification. We finally note minimal additional predictive benefit to assessing neoepitope burden or its bulk derivatives, including RNA-derived sources of neoepitopes.
    Conclusions: We find sufficient cause to suggest that the predictive clinical value of TMB should not be overstated or oversimplified. While it is readily quantified, TMB is at best a limited surrogate biomarker of immunotherapy response. The data do not support isolated use of TMB in renal cell carcinoma.
    MeSH term(s) Antigens, Neoplasm/genetics ; Antigens, Neoplasm/immunology ; Biomarkers, Tumor/genetics ; Biomarkers, Tumor/immunology ; Carcinoma, Non-Small-Cell Lung/drug therapy ; Carcinoma, Non-Small-Cell Lung/genetics ; Epitopes/genetics ; Epitopes/immunology ; Humans ; Immune Checkpoint Inhibitors/therapeutic use ; Lung Neoplasms/drug therapy ; Lung Neoplasms/genetics ; Melanoma/drug therapy ; Melanoma/genetics ; Mutation Accumulation
    Chemical Substances Antigens, Neoplasm ; Biomarkers, Tumor ; Epitopes ; Immune Checkpoint Inhibitors
    Language English
    Publishing date 2020-03-30
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 2484394-5
    ISSN 1756-994X ; 1756-994X
    ISSN (online) 1756-994X
    ISSN 1756-994X
    DOI 10.1186/s13073-020-00729-2
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Predictors of thrombosis during VV ECMO: an analysis of 9809 patients from the ELSO registry.

    Kohs, Tia C L / Weeder, Benjamin R / Chobrutskiy, Boris I / Kartika, Thomas / Moore, Kerry K / McCarty, Owen J T / Zonies, David / Zakhary, Bishoy / Shatzel, Joseph J

    Journal of thrombosis and thrombolysis

    2023  Volume 57, Issue 3, Page(s) 345–351

    Abstract: Venovenous extracorporeal membrane oxygenation (VV-ECMO) is a life-saving therapy for critically ill patients, but it carries an increased risk of thrombosis due to blood interacting with non-physiological surfaces. While the relationship between ... ...

    Abstract Venovenous extracorporeal membrane oxygenation (VV-ECMO) is a life-saving therapy for critically ill patients, but it carries an increased risk of thrombosis due to blood interacting with non-physiological surfaces. While the relationship between clinical variables and thrombosis remains unclear, our study aimed to identify which factors are most predictive of thrombosis. The Extracorporeal Life Support Organization Registry was queried to obtain a cohort of VV-ECMO patients aged 18 years and older from 2015 to 2019. Patients who were over 80-years-old, at the extremes of weight, who received less than 24 h of ECMO, multiple rounds of ECMO, or had missing data were excluded. Multivariate logistic regression modeling was used to assess predictors of thrombosis and mortality. A total of 9809 patients were included in the analysis, with a mean age of 47.1 ± 15.1 years and an average ECMO run time of 305 ± 353 h. Thrombosis occurred in 19.9% of the cohort, with circuit thrombosis (8.6%) and membrane lung failure (6.1%) being the most common. Multivariate analysis showed that ECMO runs over 14 days (OR: 2.62, P < 0.001) and pregnancy-related complications (OR: 1.79, P = 0.004) were associated with an increased risk of thrombosis. Risk factors for circuit thrombosis included incremental unit increases in the pump flow rate at 24 h (OR: 1.07 [1.00-1.14], P = 0.044) and specific cannulation sites. Increased body weight (OR: 1.02 [1.00-1.04], P = 0.026) and increased duration on ECMO (OR: 3.82 [3.12-4.71], P < 0.001) were predictive of membrane lung failure. Additionally, patients with thrombosis were at increased likelihood of in-hospital mortality (OR: 1.52, P < 0.001). This study identified multiple thrombotic risk factors in VV-ECMO, suggesting that future studies investigating the impact of pregnancy associated complications and ECMO flow rate on hemostasis would be illuminating.
    MeSH term(s) Humans ; Adult ; Middle Aged ; Aged, 80 and over ; Extracorporeal Membrane Oxygenation/adverse effects ; Retrospective Studies ; Thrombosis/epidemiology ; Thrombosis/etiology ; Catheterization/adverse effects ; Registries ; Respiratory Insufficiency/etiology
    Language English
    Publishing date 2023-12-14
    Publishing country Netherlands
    Document type Journal Article
    ZDB-ID 1230645-9
    ISSN 1573-742X ; 0929-5305
    ISSN (online) 1573-742X
    ISSN 0929-5305
    DOI 10.1007/s11239-023-02909-4
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: Human Leukocyte Antigen Susceptibility Map for Severe Acute Respiratory Syndrome Coronavirus 2.

    Nguyen, Austin / David, Julianne K / Maden, Sean K / Wood, Mary A / Weeder, Benjamin R / Nellore, Abhinav / Thompson, Reid F

    Journal of virology

    2020  Volume 94, Issue 13

    Abstract: Genetic variability across the three major histocompatibility complex (MHC) class I genes (human leukocyte antigen A [HLA-A], -B, and -C genes) may affect susceptibility to and severity of the disease caused by severe acute respiratory syndrome ... ...

    Abstract Genetic variability across the three major histocompatibility complex (MHC) class I genes (human leukocyte antigen A [HLA-A], -B, and -C genes) may affect susceptibility to and severity of the disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for coronavirus disease 2019 (COVID-19). We performed a comprehensive
    MeSH term(s) Amino Acid Sequence ; Betacoronavirus/immunology ; COVID-19 ; COVID-19 Testing ; Clinical Laboratory Techniques ; Coronavirus Infections/diagnosis ; Coronavirus Infections/immunology ; Coronavirus Infections/virology ; Epitopes, T-Lymphocyte/immunology ; Genetic Variation ; Genotype ; Haplotypes ; Histocompatibility Antigens Class I/genetics ; Histocompatibility Antigens Class I/immunology ; Histocompatibility Testing/methods ; Humans ; Immunity, Innate/immunology ; Pandemics ; Pneumonia, Viral/immunology ; Pneumonia, Viral/virology ; SARS-CoV-2 ; T-Lymphocytes/immunology
    Chemical Substances Epitopes, T-Lymphocyte ; Histocompatibility Antigens Class I
    Keywords covid19
    Language English
    Publishing date 2020-06-16
    Publishing country United States
    Document type Journal Article ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 80174-4
    ISSN 1098-5514 ; 0022-538X
    ISSN (online) 1098-5514
    ISSN 0022-538X
    DOI 10.1128/JVI.00510-20
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article: Human Leukocyte Antigen Susceptibility Map for Severe Acute Respiratory Syndrome Coronavirus 2

    Nguyen, Austin / David, Julianne K / Maden, Sean K / Wood, Mary A / Weeder, Benjamin R / Nellore, Abhinav / Thompson, Reid F

    J. virol

    Abstract: Genetic variability across the three major histocompatibility complex (MHC) class I genes (human leukocyte antigen A [HLA-A], -B, and -C genes) may affect susceptibility to and severity of the disease caused by severe acute respiratory syndrome ... ...

    Abstract Genetic variability across the three major histocompatibility complex (MHC) class I genes (human leukocyte antigen A [HLA-A], -B, and -C genes) may affect susceptibility to and severity of the disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for coronavirus disease 2019 (COVID-19). We performed a comprehensive in silico analysis of viral peptide-MHC class I binding affinity across 145 HLA-A, -B, and -C genotypes for all SARS-CoV-2 peptides. We further explored the potential for cross-protective immunity conferred by prior exposure to four common human coronaviruses. The SARS-CoV-2 proteome was successfully sampled and was represented by a diversity of HLA alleles. However, we found that HLA-B*46:01 had the fewest predicted binding peptides for SARS-CoV-2, suggesting that individuals with this allele may be particularly vulnerable to COVID-19, as they were previously shown to be for SARS (M. Lin, H.-T. Tseng, J. A. Trejaut, H.-L. Lee, et al., BMC Med Genet 4:9, 2003, https://bmcmedgenet.biomedcentral.com/articles/10.1186/1471-2350-4-9). Conversely, we found that HLA-B*15:03 showed the greatest capacity to present highly conserved SARS-CoV-2 peptides that are shared among common human coronaviruses, suggesting that it could enable cross-protective T-cell-based immunity. Finally, we reported global distributions of HLA types with potential epidemiological ramifications in the setting of the current pandemic.IMPORTANCE Individual genetic variation may help to explain different immune responses to a virus across a population. In particular, understanding how variation in HLA may affect the course of COVID-19 could help identify individuals at higher risk from the disease. HLA typing can be fast and inexpensive. Pairing HLA typing with COVID-19 testing where feasible could improve assessment of severity of viral disease in the population. Following the development of a vaccine against SARS-CoV-2, the virus that causes COVID-19, individuals with high-risk HLA types could be prioritized for vaccination.
    Keywords covid19
    Publisher WHO
    Document type Article
    Note WHO #Covidence: #736047
    Database COVID19

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  8. Article ; Online: Human leukocyte antigen susceptibility map for SARS-CoV-2

    Nguyen, Austin / David, Julianne K / Maden, Sean K / Wood, Mary A / Weeder, Benjamin R / Nellore, Abhinav / Thompson, Reid F

    Abstract: We probe how genetic variability across the three major histocompatibility complex (MHC) class I genes (human leukocyte antigen [HLA] A, B, and C) may affect susceptibility to and severity of severe acute respiratory syndrome 2 (SARS-CoV-2), the virus ... ...

    Abstract We probe how genetic variability across the three major histocompatibility complex (MHC) class I genes (human leukocyte antigen [HLA] A, B, and C) may affect susceptibility to and severity of severe acute respiratory syndrome 2 (SARS-CoV-2), the virus responsible for coronavirus disease 2019 (COVID-19). We execute a comprehensive in silico analysis of viral peptide-MHC class I binding affinity across all known HLA -A, -B, and -C genotypes for all SARS-CoV-2 peptides. We further explore the potential for cross-protective immunity conferred by prior exposure to four common human coronaviruses. The SARS-CoV-2 proteome is successfully sampled and presented by a diversity of HLA alleles. However, we found that HLA-B*46:01 had the fewest predicted binding peptides for SARS-CoV-2, suggesting individuals with this allele may be particularly vulnerable to COVID-19, as they were previously shown to be for SARS (1). Conversely, we found that HLA-B*15:03 showed the greatest capacity to present highly conserved SARS-CoV-2 peptides that are shared among common human coronaviruses, suggesting it could enable cross-protective T-cell based immunity. Finally, we report global distributions of HLA types with potential epidemiological ramifications in the setting of the current pandemic.
    Keywords covid19
    Publisher MedRxiv; WHO
    Document type Article ; Online
    DOI 10.1101/2020.03.22.20040600
    Database COVID19

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  9. Article ; Online: Human leukocyte antigen susceptibility map for SARS-CoV-2

    Nguyen, Austin / David, Julianne K / Maden, Sean K / Wood, Mary A / Weeder, Benjamin R / Nellore, Abhinav / Thompson, Reid F

    medRxiv

    Abstract: We probe how genetic variability across the three major histocompatibility complex (MHC) class I genes (human leukocyte antigen [HLA] A, B, and C) may affect susceptibility to and severity of severe acute respiratory syndrome 2 (SARS-CoV-2), the virus ... ...

    Abstract We probe how genetic variability across the three major histocompatibility complex (MHC) class I genes (human leukocyte antigen [HLA] A, B, and C) may affect susceptibility to and severity of severe acute respiratory syndrome 2 (SARS-CoV-2), the virus responsible for coronavirus disease 2019 (COVID-19). We execute a comprehensive in silico analysis of viral peptide-MHC class I binding affinity across all known HLA -A, -B, and -C genotypes for all SARS-CoV-2 peptides. We further explore the potential for cross-protective immunity conferred by prior exposure to four common human coronaviruses. The SARS-CoV-2 proteome is successfully sampled and presented by a diversity of HLA alleles. However, we found that HLA-B*46:01 had the fewest predicted binding peptides for SARS-CoV-2, suggesting individuals with this allele may be particularly vulnerable to COVID-19, as they were previously shown to be for SARS (1). Conversely, we found that HLA-B*15:03 showed the greatest capacity to present highly conserved SARS-CoV-2 peptides that are shared among common human coronaviruses, suggesting it could enable cross-protective T-cell based immunity. Finally, we report global distributions of HLA types with potential epidemiological ramifications in the setting of the current pandemic.
    Keywords covid19
    Language English
    Publishing date 2020-03-26
    Publisher Cold Spring Harbor Laboratory Press
    Document type Article ; Online
    DOI 10.1101/2020.03.22.20040600
    Database COVID19

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  10. Article ; Online: Human Leukocyte Antigen Susceptibility Map for Severe Acute Respiratory Syndrome Coronavirus 2

    Nguyen, Austin / David, Julianne K. / Maden, Sean K. / Wood, Mary A. / Weeder, Benjamin R. / Nellore, Abhinav / Thompson, Reid F.

    Journal of Virology

    2020  Volume 94, Issue 13

    Abstract: ABSTRACT Genetic variability across the three major histocompatibility complex (MHC) class I genes (human leukocyte antigen A [HLA-A], -B, and -C genes) may affect susceptibility to and severity of the disease caused by severe acute respiratory syndrome ... ...

    Abstract ABSTRACT Genetic variability across the three major histocompatibility complex (MHC) class I genes (human leukocyte antigen A [HLA-A], -B, and -C genes) may affect susceptibility to and severity of the disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for coronavirus disease 2019 (COVID-19). We performed a comprehensive in silico analysis of viral peptide-MHC class I binding affinity across 145 HLA-A, -B, and -C genotypes for all SARS-CoV-2 peptides. We further explored the potential for cross-protective immunity conferred by prior exposure to four common human coronaviruses. The SARS-CoV-2 proteome was successfully sampled and was represented by a diversity of HLA alleles. However, we found that HLA-B*46:01 had the fewest predicted binding peptides for SARS-CoV-2, suggesting that individuals with this allele may be particularly vulnerable to COVID-19, as they were previously shown to be for SARS (M. Lin, H.-T. Tseng, J. A. Trejaut, H.-L. Lee, et al., BMC Med Genet 4:9, 2003, https://bmcmedgenet.biomedcentral.com/articles/10.1186/1471-2350-4-9 ). Conversely, we found that HLA-B*15:03 showed the greatest capacity to present highly conserved SARS-CoV-2 peptides that are shared among common human coronaviruses, suggesting that it could enable cross-protective T-cell-based immunity. Finally, we reported global distributions of HLA types with potential epidemiological ramifications in the setting of the current pandemic. IMPORTANCE Individual genetic variation may help to explain different immune responses to a virus across a population. In particular, understanding how variation in HLA may affect the course of COVID-19 could help identify individuals at higher risk from the disease. HLA typing can be fast and inexpensive. Pairing HLA typing with COVID-19 testing where feasible could improve assessment of severity of viral disease in the population. Following the development of a vaccine against SARS-CoV-2, the virus that causes COVID-19, individuals with high-risk HLA types could be prioritized for vaccination.
    Keywords Immunology ; Insect Science ; Microbiology ; Virology ; covid19
    Language English
    Publisher American Society for Microbiology
    Publishing country us
    Document type Article ; Online
    ZDB-ID 80174-4
    ISSN 1098-5514 ; 0022-538X
    ISSN (online) 1098-5514
    ISSN 0022-538X
    DOI 10.1128/jvi.00510-20
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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