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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
agricultural and biological sciences
The relative resistance of children to sepsis mortality: from pathways to drug candidates
Molecular Systems Biology, Volume 14, No. 5, Article e7998, Year 2018
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Description
Attempts to develop drugs that address sepsis based on leads developed in animal models have failed. We sought to identify leads based on human data by exploiting a natural experiment: the relative resistance of children to mortality from severe infections and sepsis. Using public datasets, we identified key differences in pathway activity (Pathprint) in blood transcriptome profiles of septic adults and children. To find drugs that could promote beneficial (child) pathways or inhibit harmful (adult) ones, we built an in silico pathway drug network (PDN) using expression correlation between drug, disease, and pathway gene signatures across 58,475 microarrays. Specific pathway clusters from children or adults were assessed for correlation with drug-based signatures. Validation by literature curation and by direct testing in an endotoxemia model of murine sepsis of the most correlated drug candidates demonstrated that the Pathprint-PDN methodology is more effective at generating positive drug leads than gene-level methods (e.g., CMap). Pathway-centric Pathprint-PDN is a powerful new way to identify drug candidates for intervention against sepsis and provides direct insight into pathways that may determine survival. © 2018 The Authors. Published under the terms of the CC BY 4.0 license
Available Materials
https://efashare.b-cdn.net/share/pmc/articles/PMC5974511/bin/MSB-14-e7998-s001.pdf
https://efashare.b-cdn.net/share/pmc/articles/PMC5974511/bin/MSB-14-e7998-s002.pdf
https://efashare.b-cdn.net/share/pmc/articles/PMC5974511/bin/MSB-14-e7998-s003.zip
https://efashare.b-cdn.net/share/pmc/articles/PMC5974511/bin/MSB-14-e7998-s004.zip
https://efashare.b-cdn.net/share/pmc/articles/PMC5974511/bin/MSB-14-e7998-s005.zip
https://efashare.b-cdn.net/share/pmc/articles/PMC5974511/bin/MSB-14-e7998-s006.zip
https://efashare.b-cdn.net/share/pmc/articles/PMC5974511/bin/MSB-14-e7998-s007.zip
https://efashare.b-cdn.net/share/pmc/articles/PMC5974511/bin/MSB-14-e7998-s008.zip
https://efashare.b-cdn.net/share/pmc/articles/PMC5974511/bin/MSB-14-e7998-s009.zip
https://efashare.b-cdn.net/share/pmc/articles/PMC5974511/bin/MSB-14-e7998-s011.pdf
https://efashare.b-cdn.net/share/pmc/articles/PMC5974511/bin/MSB-14-e7998-s010.xlsx
Authors & Co-Authors
Altschuler, Gabriel M.
United Kingdom, Sheffield
The University of Sheffield
Wong, Hector R.
United States, Cincinnati
Cincinnati Children's Hospital Medical Center
Hide, Winston A.
United Kingdom, Sheffield
The University of Sheffield
United States, Boston
Harvard T.h. Chan School of Public Health
Statistics
Citations: 8
Authors: 3
Affiliations: 4
Identifiers
Doi:
10.15252/msb.20177998
ISSN:
17444292
Research Areas
Genetics And Genomics
Maternal And Child Health
Study Design
Randomised Control Trial
Study Approach
Quantitative