Lars Jørgen Østergaard

The histone deacetylase inhibitor panobinostat lowers biomarkers of cardiovascular risk and inflammation in HIV patients

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The histone deacetylase inhibitor panobinostat lowers biomarkers of cardiovascular risk and inflammation in HIV patients. / Høgh Kølbæk Kjær, Anne Sofie; Brinkmann, Christel Rothe; Dinarello, Charles A; Olesen, Rikke; Østergaard, Lars Jørgen; Søgaard, Ole Schmeltz; Tolstrup, Martin; Rasmussen, Thomas Aagaard.

In: AIDS, 13.04.2015.

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Høgh Kølbæk Kjær, Anne Sofie ; Brinkmann, Christel Rothe ; Dinarello, Charles A ; Olesen, Rikke ; Østergaard, Lars Jørgen ; Søgaard, Ole Schmeltz ; Tolstrup, Martin ; Rasmussen, Thomas Aagaard. / The histone deacetylase inhibitor panobinostat lowers biomarkers of cardiovascular risk and inflammation in HIV patients. In: AIDS. 2015.

Bibtex

@article{b730477797f74c8a9576d851925f7cc6,
title = "The histone deacetylase inhibitor panobinostat lowers biomarkers of cardiovascular risk and inflammation in HIV patients",
abstract = "OBJECTIVE: To investigate the effect of the histone deacetylase inhibitor panobinostat on HIV-associated inflammation.DESIGN: Sub-study of a single-arm, phase I/II clinical trial.METHODS: HIV-infected adults on suppressive antiretroviral therapy received oral panobinostat 20 mg three times per week, every other week, for 8 weeks, that is, four cycles of treatment. Plasma levels of high-sensitivity C-reactive protein, matrix metalloproteinase 9, soluble CD40 ligand and interleukin-6 were determined using human ELISA kits. Soluble endothelia selectin (E-selectin) was measured by a multiplex immunoassay. Total monocyte count, phenotype changes on monocytes and monocyte histone acetylation were analyzed using flow cytometry. Whole-genome expression in peripheral blood mononuclear cells was analyzed at baseline and on-panobinostat employing the Affymetrix Human Transcriptome Array 2.0 microarray assay. Changes from baseline were analyzed using Wilcoxon signed-rank test. For the gene-expression analyses, fold-changes, P values and false detection rate were computed using TAC software.RESULTS: Panobinostat treatment led to significant reductions in multiple established plasma markers of inflammation. Notably, high-sensitivity C-reactive protein decreased by a median of 58% during treatment and this change persisted for 4 weeks after treatment. Plasma levels of interleukin-6, matrix metalloproteinase 9, E-selectin and soluble CD40 ligand also significantly decreased on and/or postpanobinostat. Additionally, we observed a significant reduction in the proportions of intermediate monocytes and tissue factor-positive monocytes. This suppression of cardiovascular risk biomarkers was associated with a prominent reduction in the expression of genes related to inflammation and atherosclerosis.CONCLUSION: Collectively, these data indicate that panobinostat may have therapeutic potential to target excess inflammation in HIV patients with high cardiovascular risk.",
author = "{H{\o}gh K{\o}lb{\ae}k Kj{\ae}r}, {Anne Sofie} and Brinkmann, {Christel Rothe} and Dinarello, {Charles A} and Rikke Olesen and {\O}stergaard, {Lars J{\o}rgen} and S{\o}gaard, {Ole Schmeltz} and Martin Tolstrup and Rasmussen, {Thomas Aagaard}",
year = "2015",
month = apr,
day = "13",
doi = "10.1097/QAD.0000000000000678",
language = "English",
journal = "AIDS",
issn = "0269-9370",
publisher = "LIPPINCOTT WILLIAMS & WILKINS",

}

RIS

TY - JOUR

T1 - The histone deacetylase inhibitor panobinostat lowers biomarkers of cardiovascular risk and inflammation in HIV patients

AU - Høgh Kølbæk Kjær, Anne Sofie

AU - Brinkmann, Christel Rothe

AU - Dinarello, Charles A

AU - Olesen, Rikke

AU - Østergaard, Lars Jørgen

AU - Søgaard, Ole Schmeltz

AU - Tolstrup, Martin

AU - Rasmussen, Thomas Aagaard

PY - 2015/4/13

Y1 - 2015/4/13

N2 - OBJECTIVE: To investigate the effect of the histone deacetylase inhibitor panobinostat on HIV-associated inflammation.DESIGN: Sub-study of a single-arm, phase I/II clinical trial.METHODS: HIV-infected adults on suppressive antiretroviral therapy received oral panobinostat 20 mg three times per week, every other week, for 8 weeks, that is, four cycles of treatment. Plasma levels of high-sensitivity C-reactive protein, matrix metalloproteinase 9, soluble CD40 ligand and interleukin-6 were determined using human ELISA kits. Soluble endothelia selectin (E-selectin) was measured by a multiplex immunoassay. Total monocyte count, phenotype changes on monocytes and monocyte histone acetylation were analyzed using flow cytometry. Whole-genome expression in peripheral blood mononuclear cells was analyzed at baseline and on-panobinostat employing the Affymetrix Human Transcriptome Array 2.0 microarray assay. Changes from baseline were analyzed using Wilcoxon signed-rank test. For the gene-expression analyses, fold-changes, P values and false detection rate were computed using TAC software.RESULTS: Panobinostat treatment led to significant reductions in multiple established plasma markers of inflammation. Notably, high-sensitivity C-reactive protein decreased by a median of 58% during treatment and this change persisted for 4 weeks after treatment. Plasma levels of interleukin-6, matrix metalloproteinase 9, E-selectin and soluble CD40 ligand also significantly decreased on and/or postpanobinostat. Additionally, we observed a significant reduction in the proportions of intermediate monocytes and tissue factor-positive monocytes. This suppression of cardiovascular risk biomarkers was associated with a prominent reduction in the expression of genes related to inflammation and atherosclerosis.CONCLUSION: Collectively, these data indicate that panobinostat may have therapeutic potential to target excess inflammation in HIV patients with high cardiovascular risk.

AB - OBJECTIVE: To investigate the effect of the histone deacetylase inhibitor panobinostat on HIV-associated inflammation.DESIGN: Sub-study of a single-arm, phase I/II clinical trial.METHODS: HIV-infected adults on suppressive antiretroviral therapy received oral panobinostat 20 mg three times per week, every other week, for 8 weeks, that is, four cycles of treatment. Plasma levels of high-sensitivity C-reactive protein, matrix metalloproteinase 9, soluble CD40 ligand and interleukin-6 were determined using human ELISA kits. Soluble endothelia selectin (E-selectin) was measured by a multiplex immunoassay. Total monocyte count, phenotype changes on monocytes and monocyte histone acetylation were analyzed using flow cytometry. Whole-genome expression in peripheral blood mononuclear cells was analyzed at baseline and on-panobinostat employing the Affymetrix Human Transcriptome Array 2.0 microarray assay. Changes from baseline were analyzed using Wilcoxon signed-rank test. For the gene-expression analyses, fold-changes, P values and false detection rate were computed using TAC software.RESULTS: Panobinostat treatment led to significant reductions in multiple established plasma markers of inflammation. Notably, high-sensitivity C-reactive protein decreased by a median of 58% during treatment and this change persisted for 4 weeks after treatment. Plasma levels of interleukin-6, matrix metalloproteinase 9, E-selectin and soluble CD40 ligand also significantly decreased on and/or postpanobinostat. Additionally, we observed a significant reduction in the proportions of intermediate monocytes and tissue factor-positive monocytes. This suppression of cardiovascular risk biomarkers was associated with a prominent reduction in the expression of genes related to inflammation and atherosclerosis.CONCLUSION: Collectively, these data indicate that panobinostat may have therapeutic potential to target excess inflammation in HIV patients with high cardiovascular risk.

U2 - 10.1097/QAD.0000000000000678

DO - 10.1097/QAD.0000000000000678

M3 - Journal article

C2 - 25870990

JO - AIDS

JF - AIDS

SN - 0269-9370

ER -