AROS Applied Biotechnology

Århus, Denmark

AROS Applied Biotechnology

Århus, Denmark
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Schou J.V.,Herlev University Hospital | Rossi S.,Swiss Institute of Bioinformatics | Jensen B.V.,Herlev University Hospital | Nielsen D.L.,Herlev University Hospital | And 8 more authors.
PLoS ONE | Year: 2014

Introduction: MicroRNAs (miRNAs) have important regulatory functions in cellular processes and have shown promising potential as prognostic markers for disease outcome in patients with cancer. The aim of the present study was to find miRNA expression profiles in whole blood that were prognostic for overall survival (OS) in patients with metastatic colorectal cancer (mCRC) treated with cetuximab and irinotecan. Methods: From 138 patients with mCRC in 3rd line therapy with cetuximab and irinotecan in a prospective phase II study, 738 pretreatment miRNAs were isolated and profiled from whole blood using the TaqMan MicroRNA Array v2.0. Mutation status of KRAS, BRAF, and PI3KCA was known. Results: After Bonferroni adjustment, 6 miRNAs: (miR-345, miR-143, miR-34a*, miR-628-5p, miR-886-3p and miR-324-3p), were found associated with short OS. miR-345 was the strongest prognostic miRNA, significant in the full cohort and in the non-KRAS mutant population. miR-345, as a continuous variable in the full cohort, resulted in a hazard ratio (HR) of 2.38 per IQR (CI 95%: 1.8-3.1, P-value = 2.86e 207, Bonferroni adjusted, univariable analysis) and a HR = 1.75 per IQR (CI 95%: 1.24-2.48, P-Wald = 1.45e-03) in the multivariable analysis adjusted for gender, age, KRAS, PI3KCA and performance status. miR-345 was prognostic in progression-free survival (PFS) with a HR = 1.63 per IQR (CI 95%: 1.25-2.114, P-Wald = 2.92e-4) in the multivariable analysis. In addition, high miR-345 expression was associated with lack of response to treatment with cetuximab and irinotecan. Conclusion: We identified miR-345 in whole blood as a potential biomarker for clinical outcome. MiR-345 was a single prognostic biomarker for both OS and PFS in all patients and also in the non-KRAS mutant population. © 2014 Schou et al.


Ammerpohl O.,University of Kiel | Pratschke J.,University of Innsbruck | Schafmayer C.,University of Kiel | Haake A.,University of Kiel | And 17 more authors.
International Journal of Cancer | Year: 2012

Abberrant DNA methylation is one of the hallmarks of cancerogenesis. Our study aims to delineate differential DNA methylation in cirrhosis and hepatic cancerogenesis. Patterns of methylation of 27,578 individual CpG loci in 12 hepatocellular carcinomas (HCCs), 15 cirrhotic controls and 12 normal liver samples were investigated using an array-based technology. A supervised principal component analysis (PCA) revealed 167 hypomethylated loci and 100 hypermethylated loci in cirrhosis and HCC as compared to normal controls. Thus, these loci show a "cirrhotic" methylation pattern that is maintained in HCC. In pairwise supervised PCAs between normal liver, cirrhosis and HCC, eight loci were significantly changed in all analyses differentiating the three groups (p < 0.0001). Of these, five loci showed highest methylation levels in HCC and lowest in control tissue (LOC55908, CELSR1, CRMP1, GNRH2, ALOX12 and ANGPTL7), whereas two loci showed the opposite direction of change (SPRR3 and TNFSF15). Genes hypermethylated between normal liver to cirrhosis, which maintain this methylation pattern during the development of HCC, are depleted for CpG islands, high CpG content promoters and polycomb repressive complex 2 (PRC2) targets in embryonic stem cells. In contrast, genes selectively hypermethylated in HCC as compared to nonmalignant samples showed an enrichment of CpG islands, high CpG content promoters and PRC2 target genes (p < 0.0001). Cirrhosis and HCC show distinct patterns of differential methylation with regards to promoter structure, PRC2 targets and CpG islands. Copyright © 2011 UICC.


PubMed | University Hospital Gasthuisberg, University of Southern Denmark, AROS Applied Biotechnology, University of Aalborg and 2 more.
Type: Clinical Trial, Phase II | Journal: PloS one | Year: 2014

MicroRNAs (miRNAs) have important regulatory functions in cellular processes and have shown promising potential as prognostic markers for disease outcome in patients with cancer. The aim of the present study was to find miRNA expression profiles in whole blood that were prognostic for overall survival (OS) in patients with metastatic colorectal cancer (mCRC) treated with cetuximab and irinotecan.From 138 patients with mCRC in 3rd line therapy with cetuximab and irinotecan in a prospective phase II study, 738 pretreatment miRNAs were isolated and profiled from whole blood using the TaqMan MicroRNA Array v2.0. Mutation status of KRAS, BRAF, and PI3KCA was known.After Bonferroni adjustment, 6 miRNAs: (miR-345, miR-143, miR-34a*, miR-628-5p, miR-886-3p and miR-324-3p), were found associated with short OS. miR-345 was the strongest prognostic miRNA, significant in the full cohort and in the non-KRAS mutant population. miR-345, as a continuous variable in the full cohort, resulted in a hazard ratio (HR) of 2.38 per IQR (CI 95%: 1.8-3.1, P-value=2.86e-07, Bonferroni adjusted, univariable analysis) and a HR=1.75 per IQR (CI 95%: 1.24-2.48, P-Wald=1.45e-03) in the multivariable analysis adjusted for gender, age, KRAS, PI3KCA and performance status. miR-345 was prognostic in progression-free survival (PFS) with a HR=1.63 per IQR (CI 95%: 1.25-2.114, P-Wald=2.92e-4) in the multivariable analysis. In addition, high miR-345 expression was associated with lack of response to treatment with cetuximab and irinotecan.We identified miR-345 in whole blood as a potential biomarker for clinical outcome. MiR-345 was a single prognostic biomarker for both OS and PFS in all patients and also in the non-KRAS mutant population.


Liaset B.,National Institute of Nutrition And Seafood Research | Hao Q.,Copenhagen University | Jorgensen H.,University of Aarhus | Hallenborg P.,University of Southern Denmark | And 17 more authors.
Journal of Biological Chemistry | Year: 2011

Bile acids (BAs) are powerful regulators of metabolism, and mice treated orally with cholic acid are protected from diet-induced obesity, hepatic lipid accumulation, and increased plasma triacylglycerol (TAG) and glucose levels. Here, we show that plasma BA concentration in rats was elevated by exchanging the dietary protein source from casein to salmon protein hydrolysate (SPH). Importantly, the SPH-treated rats were resistant to diet-induced obesity. SPH-treated rats had reduced fed state plasma glucose and TAG levels and lower TAG in liver. The elevated plasma BA concentration was associated with induction of genes involved in energy metabolism and uncoupling, Dio2, Pgc-1α, and Ucp1, in interscapular brown adipose tissue. Interestingly, the same transcriptional pattern was found in white adipose tissue depots of both abdominal and subcutaneous origin. Accordingly, rats fed SPH-based diet exhibited increased whole body energy expenditure and heat dissipation. In skeletal muscle, expressions of the peroxisome proliferator-activated receptor β/δ target genes (Cpt-1b, Angptl4, Adrp, and Ucp3) were induced. Pharmacological removal of BAs by inclusion of 0.5 weight % cholestyramine to the high fat SPH diet attenuated the reduction in abdominal obesity, the reduction in liver TAG, and the decrease in nonfasted plasma TAG and glucose levels. Induction of Ucp3 gene expression in muscle by SPH treatment was completely abolished by cholestyramine inclusion. Taken together, our data provide evidence that bile acid metabolism can be modulated by diet and that such modulation may prevent/ameliorate the characteristic features of the metabolic syndrome. © 2011 by The American Society for Biochemistry and Molecular Biology, Inc.


Knudsen A.R.,Aarhus University Hospital | Kannerup A.-S.,Aarhus University Hospital | Dich R.,Aarhus University Hospital | Funch-Jensen P.,Aarhus University Hospital | And 3 more authors.
American Journal of Physiology - Gastrointestinal and Liver Physiology | Year: 2012

Ischemic pre (IPC)-and postconditioning (IPO) protect the liver against ischemia/reperfusion injuries (IRI). Conditioning involves several different trigger factors, mediators, and effectors, many of which are affected during the early phase of reperfusion, ultimately resulting in decreased liver injuries. The aim of the present study was to investigate the genomic response induced by IPC and IPO in ischemia/reperfusion-damaged rat liver biopsies. Forty-eight male Wistar rats were divided into five groups: sham (n = 8), IRI (n = 10), IPC (n = 10), IPO (n = 10), and IPC + IPO (n = 10). The rat livers were subjected to 30 min of ischemia. Liver biopsies and blood samples were taken after 30 min of reperfusion. The biopsies were analyzed using cDNA microarrays with validation by quantitative RT-PCR. The significance analysis of microarray was used to identify genes with changed expression levels. A comparison analysis of the intervention groups showed a highly increased number of genes, with significantly different expression in the conditioned groups compared with the IRI group. A total of 172 genes were identified as the most highly affected, and these genes showed similar patterns with regard to the up-and downregulated expression levels within the conditioned groups. Pathway analysis of the 172 genes identified four networks that were involved in increased gene expression, cellular growth, and proliferation. In conclusion, the present study demonstrated that IPC, IPO, and IPC + IPO had pronounced effects on the expression levels of a large number of genes during early reperfusion. IPC, IPO, and IPC + IPO seem to mediate their protective effects by regulating the same genes and genetic networks. These identified networks are known to be involved in maintaining cellular homeostasis. © 2012 the American Physiological Society.

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