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- Kindmark, Andreas, et al.
(författare)
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Genome-wide pharmacogenetic investigation of a hepatic adverse event without clinical signs of immunopathology suggests an underlying immune pathogenesis
- 2008
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Ingår i: The Pharmacogenomics Journal. - : Springer Science and Business Media LLC. - 1470-269X .- 1473-1150. ; 8:3, s. 186-195
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Tidskriftsartikel (refereegranskat)abstract
- One of the major goals of pharmacogenetics is to elucidate mechanisms and identify patients at increased risk of adverse events (AEs). To date, however, there have been only a few successful examples of this type of approach. In this paper, we describe a retrospective case–control pharmacogenetic study of an AE of unknown mechanism, characterized by elevated levels of serum alanine aminotransferase (ALAT) during long-term treatment with the oral direct thrombin inhibitor ximelagatran. The study was based on 74 cases and 130 treated controls and included both a genome-wide tag single nucleotide polymorphism and large-scale candidate gene analysis. A strong genetic association between elevated ALAT and the MHC alleles DRB1*07 and DQA1*02 was discovered and replicated, suggesting a possible immune pathogenesis. Consistent with this hypothesis, immunological studies suggest that ximelagatran may have the ability to act as a contact sensitizer, and hence be able to stimulate an adaptive immune response.
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- Nachat-Kappes, R., et al.
(författare)
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Effects of Enriched Environment on COX-2, Leptin and Eicosanoids in a Mouse Model of Breast Cancer
- 2012
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 7:12, s. e51525-
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Tidskriftsartikel (refereegranskat)abstract
- Cyclooxygenase-2 (COX-2) and adipokines have been implicated in breast cancer. This study investigated a possible link between COX-2 and adipokines in the development of mammary tumors. A model of environmental enrichment (EE), known to reduce tumor growth was used for a syngeneic murine model of mammary carcinoma. 3-week-old, female C57BL/6 mice were housed in standard environment (SE) or EE cages for 9 weeks and transplanted orthotopically with syngeneic EO771 adenocarcinoma cells into the right inguinal mammary fat pad. EE housing influenced mammary gland development with a decrease in COX-2 expressing cells and enhanced side-branching and advanced development of alveolar structures of the mammary gland. Tumor volume and weight were decreased in EE housed mice and were associated with a reduction in COX-2 and Ki67 levels, and an increase in caspase-3 levels. In tumors of SE mice, high COX-2 expression correlated with enhanced leptin detection. Non-tumor-bearing EE mice showed a significant increase in adiponectin levels but no change in those of leptin, F2-isoprostanes, PGF2α, IL-6, TNF-α, PAI-1, and MCP-1 levels. Both tumor-bearing groups (SE and EE housing) had increased resistin, IL-6, TNF-α, PAI-1 and MCP-1 levels irrespective of the different housing environment demonstrating higher inflammatory response due to the presence of the tumor. This study demonstrates that EE housing influenced normal mammary gland development and inhibited mammary tumor growth resulting in a marked decrease in intratumoral COX-2 activity and an increase in the plasma ratio of adiponectin/leptin levels.
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- Stevens, H. C., et al.
(författare)
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Regulation and function of miR-214 in pulmonary arterial hypertension
- 2016
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Ingår i: Pulmonary Circulation. - : Wiley. - 2045-8932 .- 2045-8940. ; 6:1, s. 109-117
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Tidskriftsartikel (refereegranskat)abstract
- Dysregulation of microRNAs (miRNAs) can contribute to the etiology of diseases, including pulmonary arterial hypertension (PAH). Here we investigated a potential role for the miR-214 stem loop miRNA and the closely linked miR-199a miRNAs in PAH. All 4 miRNAs were upregulated in the lung and right ventricle (RV) in mice and rats exposed to the Sugen (SU) 5416 hypoxia model of PAH. Further, expression of the miRNAs was increased in pulmonary artery smooth muscle cells exposed to transforming growth factor β 1 but not BMP4. We then examined miR-214-/- mice exposed to the SU 5416 hypoxia model of PAH or normoxic conditions and littermate controls. There were no changes in RV systolic pressure or remodeling observed between the miR-214-/- and wild-type hypoxic groups. However, we observed a significant increase in RV hypertrophy (RVH) in hypoxic miR-214-/- male mice compared with controls. Further, we identified that the validated miR-214 target phosphatase and tensin homolog was upregulated in miR-214-/- mice. Thus, miR-214 stem loop loss leads to elevated RVH and may contribute to the heart failure associated with PAH. © 2016 by the Pulmonary Vascular Research Institute. All rights reserved.
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