ReactomeGSA - Efficient Multi-Omics Comparative Pathway Analysis

Griss, Johannes; Viteri, Guilherme; Sidiropoulos, Konstantinos; Nguyen, Vy Kim; Fabregat, Antonio; Hermjakob, Henning

doi:10.1101/2020.04.16.044958

Cited by 33 publications

(37 citation statements)

References 42 publications

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“…Thereby, any result is only a partial representation of the underlying biological changes. In addition these figures ignore any underlying quantitative information [ 29 ].…”

Section: Discussionmentioning

confidence: 99%

Distinct Pattern of Endoplasmic Reticulum Protein Processing and Extracellular Matrix Proteins in Functioning and Silent Corticotroph Pituitary Adenomas

Eieland

Normann

Sundaram

et al. 2020

Cancers

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Functioning (FCA) and silent corticotroph (SCA) pituitary adenomas act differently from a clinical perspective, despite both subtypes showing positive TBX19 (TPIT) and/or adrenocorticotropic hormone (ACTH) staining by immunohistochemistry. They are challenging to treat, the former due to functional ACTH production and consequently hypercortisolemia, and the latter due to invasive and recurrent behavior. Moreover, the molecular mechanisms behind their distinct behavior are not clear. We investigated global transcriptome and proteome changes in order to identify signaling pathways that can explain FCA and SCA differences (e.g., hormone production vs. aggressive growth). In the transcriptomic study, cluster analyses of differentially expressed genes revealed two distinct groups in accordance with clinical and histological classification. However, in the proteomic study, a greater degree of heterogeneity within the SCA group was found. Genes and proteins related to protein synthesis and vesicular transport were expressed by both adenoma groups, although different types and a distinct pattern of collagen/extracellular matrix proteins were presented by each group. Moreover, several genes related to endoplasmic reticulum protein processing were overexpressed in the FCA group. Together, our findings shed light on the different repertoires of activated signaling pathways in corticotroph adenomas, namely, the increased protein processing capacity of FCA and a specific pattern of adhesion molecules that may play a role in the aggressiveness of SCA.

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“…Thereby, any result is only a partial representation of the underlying biological changes. In addition these figures ignore any underlying quantitative information [ 29 ].…”

Section: Discussionmentioning

confidence: 99%

Distinct Pattern of Endoplasmic Reticulum Protein Processing and Extracellular Matrix Proteins in Functioning and Silent Corticotroph Pituitary Adenomas

Eieland

Normann

Sundaram

et al. 2020

Cancers

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“…RStudio: Integrated Development for R. RStudio, PBC, Boston, MA URL http://www.rstudio.com/.) Enrichment analysis was applied to the total gene counts using the reactome GSA package (52) in Rstudio. Enrichment analysis was applied to the total gene counts using the CAMERA algorithm (53).…”

Section: Rnaseq Data Analysismentioning

confidence: 99%

IL-13 is a driver of COVID-19 severity

Donlan¹,

Sutherland²,

Marie³

et al. 2021

JCI Insight

100

106

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Immune dysregulation is characteristic of the more severe stages of SARS-CoV-2 infection. Understanding the mechanisms by which the immune system contributes to COVID-19 severity may open new avenues to treatment. Here we report that elevated interleukin-13 (IL-13) was associated with the need for mechanical ventilation in two independent patient cohorts.In addition, patients who acquired COVID-19 while prescribed Dupilumab, a mAb that blocks IL-13 and IL-4 signaling, had less severe disease. In SARS-CoV-2 infected mice, IL-13 neutralization reduced death and disease severity without affecting viral load, demonstrating an immunopathogenic role for this cytokine. Following anti-IL-13 treatment in infected mice, hyaluronan synthase 1 (Has1) was the most downregulated gene and accumulation of the hyaluronan polysaccharide was decreased in the lung. In patients with COVID-19, hyaluronan was increased in the lungs and plasma. Blockade of the hyaluronan receptor, CD44, reduced mortality in infected mice, supporting the importance of hyaluronan as a pathogenic mediator.Finally, hyaluronan was directly induced in the lungs of mice by administration of IL-13, indicating a new role for IL-13 in lung disease. Understanding the role of IL-13 and hyaluronan has important implications for therapy of COVID-19 and potentially other pulmonary diseases.Summary: IL-13 levels were elevated in patients with severe COVID-19. In a mouse model of disease, IL-13 neutralization reduced disease and decreased lung hyaluronan deposition.Administration of IL-13 induced hyaluronan in the lung. Blockade of the hyaluronan receptor CD44 prevented mortality, highlighting a novel mechanism for IL-13-mediated hyaluronan synthesis in pulmonary pathology.

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“…Well-defined marker genes for each cluster were used to identify potential cell populations, such as T cells (CD3E, CD4, CD8A), B cells (CD19, CD20, SDC1), macrophages (CD14), and NK cells (NCAM1, FCRIII, Granzyme B). For gene sets representing specific cellular functions or pathways, we performed functional enrichment analysis with the online tool Reactome GSA (https://www.biorxiv.org/content/early/2020/04/18/2020.04.16.044958) [48].…”

Section: Single-cell Rna Sequencing and Analysismentioning

confidence: 99%

Expansion, persistence and efficacy of donor memory-like NK cells for the treatment of post-transplant relapse

Shapiro

Birch

Vergara

et al. 2021

Preprint

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Background. Responses to conventional donor lymphocyte infusion (DLI) for post-allogeneic hematopoietic cell transplantation (HCT) relapse are typically poor. Natural killer (NK) cell-based therapy is a promising modality to treat post-HCT relapse. Methods. We initiated this ongoing phase 1 trial of adoptively transferred cytokine induced memory-like (CIML) NK cells in patients with myeloid malignancies relapsed after haploidentical HCT. All patients received a donor-derived NK cell dose of 5-10 million cells/kg after lymphodepleting chemotherapy, followed by systemic IL-2 for 7 doses. High resolution profiling with mass cytometry and single cell RNA sequencing characterized the expanding and persistent NK cells subpopulations in a longitudinal manner after infusion. In vitro functional studies of infused CIML NK cells were complemented with in vivo evaluation of NK trafficking to disease sites using multiparameter immunofluorescence. Results. In the first 5 patients on the trial, infusion of CIML NK cells led to a rapid 10 to 50-fold in vivo expansion that was sustained over months. The infusion was well-tolerated, with fever and pancytopenia as the most common adverse events. Responses were attained in 4 of 5 patients at day +28. Immunophenotypic and transcriptional profiling revealed a dynamic evolution of the activated CIML NK cell phenotype, superimposed on the natural variation in donor NK cell repertoires. AML relapse after initial response to CIML NK cell therapy was associated with low transcript expression of CD2 ligands, including CD48/SLAMF2 and CD58/LFA3. Conclusion. Given their rapid expansion and long-term persistence, CIML NK cells serve as a promising platform for the treatment of post-transplant relapse of myeloid disease. Further characterization of their unique in vivo biology and interaction with both T-cells and tumor targets will lead to the development of novel cell-based immunotherapies.

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ReactomeGSA - Efficient Multi-Omics Comparative Pathway Analysis

Cited by 33 publications

References 42 publications

Distinct Pattern of Endoplasmic Reticulum Protein Processing and Extracellular Matrix Proteins in Functioning and Silent Corticotroph Pituitary Adenomas

Distinct Pattern of Endoplasmic Reticulum Protein Processing and Extracellular Matrix Proteins in Functioning and Silent Corticotroph Pituitary Adenomas

IL-13 is a driver of COVID-19 severity

Expansion, persistence and efficacy of donor memory-like NK cells for the treatment of post-transplant relapse

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