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Development and validation of a novel bioassay to determine glucocorticoid sensitivity

BACKGROUND: Glucocorticoids (GCs) remain the first line treatment for almost all non-infectious inflammatory diseases, ranging from acute asthma to rheumatoid arthritis. However, across all conditions, patients have a variable response to GCs with approximately 30% being non-responders. This group o...

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Autores principales: Williams, Emily L., Stimpson, Madeleine L., Collins, Peter L., Enki, Doyo G., Sinha, Ashish, Lee, Richard W., Dhanda, Ashwin D.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5157083/
https://www.ncbi.nlm.nih.gov/pubmed/27999674
http://dx.doi.org/10.1186/s40364-016-0079-y
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author Williams, Emily L.
Stimpson, Madeleine L.
Collins, Peter L.
Enki, Doyo G.
Sinha, Ashish
Lee, Richard W.
Dhanda, Ashwin D.
author_facet Williams, Emily L.
Stimpson, Madeleine L.
Collins, Peter L.
Enki, Doyo G.
Sinha, Ashish
Lee, Richard W.
Dhanda, Ashwin D.
author_sort Williams, Emily L.
collection PubMed
description BACKGROUND: Glucocorticoids (GCs) remain the first line treatment for almost all non-infectious inflammatory diseases, ranging from acute asthma to rheumatoid arthritis. However, across all conditions, patients have a variable response to GCs with approximately 30% being non-responders. This group of GC resistant patients is typically exposed to high-dose GCs and their side-effects before more appropriate immunotherapy is instituted. Hence, there is a pressing clinical need for a predictive biomarker of GC responsiveness. The availability of such a tool would also enable patient stratification for the conduct of smart clinical trials in GC resistance. Lymphocyte GC sensitivity has been shown to be closely associated with clinical GC sensitivity in a number of inflammatory diseases. However, the method for determining in vitro GC response is not standardized and requires the use of specialist equipment, including a radioisotope to quantify cellular proliferation, making it challenging to translate into clinical practice. RESULTS: Here we describe the optimization and validation of a novel non-radioactive in vitro bioassay based on measuring cellular proliferation by incorporation of bromodeoxyuridine (BrdU), termed the BrdU incorporation in lymphocyte steroid sensitivity assay (BLISS). In comparison to the current gold standard lymphocyte GC sensitivity assay in 101 healthy control samples, BLISS has an area under receiver operating characteristic of 0.82 and a sensitivity of 83% for correctly identifying GC resistant subjects. CONCLUSIONS: The performance of the novel BLISS bioassay makes it a strong candidate biomarker for clinical application. It now requires validation in a prospective patient cohort. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s40364-016-0079-y) contains supplementary material, which is available to authorized users.
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spelling pubmed-51570832016-12-20 Development and validation of a novel bioassay to determine glucocorticoid sensitivity Williams, Emily L. Stimpson, Madeleine L. Collins, Peter L. Enki, Doyo G. Sinha, Ashish Lee, Richard W. Dhanda, Ashwin D. Biomark Res Methodology BACKGROUND: Glucocorticoids (GCs) remain the first line treatment for almost all non-infectious inflammatory diseases, ranging from acute asthma to rheumatoid arthritis. However, across all conditions, patients have a variable response to GCs with approximately 30% being non-responders. This group of GC resistant patients is typically exposed to high-dose GCs and their side-effects before more appropriate immunotherapy is instituted. Hence, there is a pressing clinical need for a predictive biomarker of GC responsiveness. The availability of such a tool would also enable patient stratification for the conduct of smart clinical trials in GC resistance. Lymphocyte GC sensitivity has been shown to be closely associated with clinical GC sensitivity in a number of inflammatory diseases. However, the method for determining in vitro GC response is not standardized and requires the use of specialist equipment, including a radioisotope to quantify cellular proliferation, making it challenging to translate into clinical practice. RESULTS: Here we describe the optimization and validation of a novel non-radioactive in vitro bioassay based on measuring cellular proliferation by incorporation of bromodeoxyuridine (BrdU), termed the BrdU incorporation in lymphocyte steroid sensitivity assay (BLISS). In comparison to the current gold standard lymphocyte GC sensitivity assay in 101 healthy control samples, BLISS has an area under receiver operating characteristic of 0.82 and a sensitivity of 83% for correctly identifying GC resistant subjects. CONCLUSIONS: The performance of the novel BLISS bioassay makes it a strong candidate biomarker for clinical application. It now requires validation in a prospective patient cohort. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s40364-016-0079-y) contains supplementary material, which is available to authorized users. BioMed Central 2016-12-15 /pmc/articles/PMC5157083/ /pubmed/27999674 http://dx.doi.org/10.1186/s40364-016-0079-y Text en © The Author(s). 2016 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Methodology
Williams, Emily L.
Stimpson, Madeleine L.
Collins, Peter L.
Enki, Doyo G.
Sinha, Ashish
Lee, Richard W.
Dhanda, Ashwin D.
Development and validation of a novel bioassay to determine glucocorticoid sensitivity
title Development and validation of a novel bioassay to determine glucocorticoid sensitivity
title_full Development and validation of a novel bioassay to determine glucocorticoid sensitivity
title_fullStr Development and validation of a novel bioassay to determine glucocorticoid sensitivity
title_full_unstemmed Development and validation of a novel bioassay to determine glucocorticoid sensitivity
title_short Development and validation of a novel bioassay to determine glucocorticoid sensitivity
title_sort development and validation of a novel bioassay to determine glucocorticoid sensitivity
topic Methodology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5157083/
https://www.ncbi.nlm.nih.gov/pubmed/27999674
http://dx.doi.org/10.1186/s40364-016-0079-y
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