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Search Results: 1 - 10 of 194 matches for " Espen Thiis-Evensen "
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Fatty Acids in Habitual Diet, Plasma Phospholipids, and Tumour and Normal Colonic Biopsies in Young Colorectal Cancer Patients
Paula Berstad,Espen Thiis-Evensen,Morten H. Vatn,Kari Almendingen
Journal of Oncology , 2012, DOI: 10.1155/2012/254801
Fatty Acids in Habitual Diet, Plasma Phospholipids, and Tumour and Normal Colonic Biopsies in Young Colorectal Cancer Patients
Paula Berstad,Espen Thiis-Evensen,Morten H. Vatn,Kari Almendingen
Journal of Oncology , 2012, DOI: 10.1155/2012/254801
Abstract: Fatty acid metabolism is altered in colorectal cancer (CRC). We aimed to investigate incorporation of dietary -6 and -3 polyunsaturated fatty acids (PUFAs) into plasma phospholipids (PLs), tumour tissue, and normal mucosa in young CRC patients. We also aimed to study differences in PUFA composition between tumour and normal mucosa, and PUFA status associated with cancer stage. Sixty-five CRC patients younger than 55 years were included in a multicenter study. We assessed dietary fatty acid composition by food-frequency questionnaire. Fatty acid composition in plasma PL ( ) and tumour and normal colonic biopsies ( ) were analysed by gas chromatography. We observed a significant correlation for docosahexaenoic acid (DHA) between dietary intake and concentration in plasma PL (weight%) ( ; ), but not for any -6 PUFA. Tissue concentrations of arachidonic acid, eicosapentaenoic acid, and DHA (weight%) were 1.7–2.5 times higher in tumour than normal mucosa ( ). Concentrations of -3 and -6 PUFA in plasma PL and tissues were not related to Duke's stage, although patients with more severe cancer stage reported higher intake of -3 PUFA. In conclusion, we found accumulation of the long-chained -3 and -6 PUFA in tumour tissue in young CRC patients. 1. Introduction The association between dietary fat and risk of cancer has been extensively investigated, and the composition of polyunsaturated fatty acids (PUFA) in diet seems to be of particular importance [1]. However, the effects of single dietary -3 and -6 PUFA, and the ratio -3/ -6 PUFA are not completely clear. The majority of case-control studies seem to support a protective role of dietary -3 PUFA and -3/ -6 PUFA ratio [2–4], but these associations have been confirmed by only one cohort study [5], and have been contradicted or not found by several cohort studies [6–8]. Studies on serum and erythrocyte membrane fatty acid composition, regarded as biomarkers for fatty acid intake, mainly support a protective role for the very long-chained -3 PUFA docosahexaenoic acid (DHA) [8–11]. Abnormalities in plasma PUFA composition may also be interpreted as metabolic changes in CRC patients [12]. Dietary and biomarker studies have not established the role of -6 PUFA in CRC. Based on changes in -3 and -6 PUFA expression in colorectal tumours, compared to normal mucosal tissue [13, 14], also found at early stages of adenomas [13], it seems obvious that patients with CRC have an altered PUFA metabolism. Literature on CRC tumour PUFA pattern is sparse, and previous studies have not concluded on which particular PUFAs are
Phospholipase C Isozymes Are Deregulated in Colorectal Cancer – Insights Gained from Gene Set Enrichment Analysis of the Transcriptome
Stine A. Danielsen, Lina Cekaite, Trude H. ?gesen, Anita Sveen, Arild Nesbakken, Espen Thiis-Evensen, Rolf I. Skotheim, Guro E. Lind, Ragnhild A. Lothe
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0024419
Abstract: Colorectal cancer (CRC) is one of the most common cancer types in developed countries. To identify molecular networks and biological processes that are deregulated in CRC compared to normal colonic mucosa, we applied Gene Set Enrichment Analysis to two independent transcriptome datasets, including a total of 137 CRC and ten normal colonic mucosa samples. Eighty-two gene sets as described by the Kyoto Encyclopedia of Genes and Genomes database had significantly altered gene expression in both datasets. These included networks associated with cell division, DNA maintenance, and metabolism. Among signaling pathways with known changes in key genes, the “Phosphatidylinositol signaling network”, comprising part of the PI3K pathway, was found deregulated. The downregulated genes in this pathway included several members of the Phospholipase C protein family, and the reduced expression of two of these, PLCD1 and PLCE1, were successfully validated in CRC biopsies (n = 70) and cell lines (n = 19) by quantitative analyses. The repression of both genes was found associated with KRAS mutations (P = 0.005 and 0.006, respectively), and we observed that microsatellite stable carcinomas with reduced PLCD1 expression more frequently had TP53 mutations (P = 0.002). Promoter methylation analyses of PLCD1 and PLCE1 performed in cell lines and tumor biopsies revealed that methylation of PLCD1 can contribute to reduced expression in 40% of the microsatellite instable carcinomas. In conclusion, we have identified significantly deregulated pathways in CRC, and validated repression of PLCD1 and PLCE1 expression. This illustrates that the GSEA approach may guide discovery of novel biomarkers in cancer.
Plasma CCN2/connective tissue growth factor is associated with right ventricular dysfunction in patients with neuroendocrine tumors
Deidi Bergestuen, J?rgen Gravning, Kristina Haugaa, Laura G Sahakyan, Svend Aakhus, Espen Thiis-Evensen, Erik ?ie, P?l Aukrust, H?vard Attramadal, Thor Edvardsen
BMC Cancer , 2010, DOI: 10.1186/1471-2407-10-6
Abstract: Echocardiography was performed in 69 patients with neuroendocrine tumors. RV function was assessed using tissue Doppler analysis of myocardial systolic strain. Plasma CCN2 was analyzed using an enzyme-linked immunosorbent assay. Mann-Whitney U, Kruskal-Wallis, Chi-squared and Fisher's exact tests were used to compare groups where appropriate. Linear regression was used to evaluate correlation.Mean strain was -21% ± 5. Thirty-three patients had reduced RV function (strain > -20%, mean -16% ± 3). Of these, 8 had no or minimal tricuspid and/or pulmonary regurgitation (TR/PR). Thirty-six patients had normal or mildly reduced RV function (strain ≤ -20%, mean -25% ± 3). There was a significant inverse correlation between RV function and plasma CCN2 levels (r = 0.47, p < 0.001). Patients with reduced RV function had higher plasma CCN2 levels than those with normal or mildly reduced RV function (p < 0.001). Plasma CCN2 ≥ 77 μg/L was an independent predictor of reduced RV function (odds ratio 15.36 [95% CI 4.15;56.86]) and had 88% sensitivity and 69% specificity for its detection (p < 0.001). Plasma CCN2 was elevated in patients with mild or greater TR/PR compared to those with no or minimal TR/PR (p = 0.008), with the highest levels seen in moderate to severe TR/PR (p = 0.03).Elevated plasma CCN2 levels are associated with RV dysfunction and valvular regurgitation in NET patients. CCN2 may play a role in neuroendocrine tumor-related cardiac fibrosis and may serve as a marker of its earliest stages.Neuroendocrine tumors (NETs) are derived from the diffuse neuroendocrine cell system which is made up of cells that release hormones in response to signals from the nervous system. NETs most commonly arise from the gastrointestinal tract and the bronchopulmonary system. Carcinoid heart disease (CHD) is a known complication of these tumors, particularly of those arising from the small intestine, appendix and proximal colon (previously known as mid-gut carcinoids). CHD is characteri
Hypermethylated MAL gene – a silent marker of early colon tumorigenesis
Guro E Lind, Terje Ahlquist, Matthias Kolberg, Marianne Berg, Mette Ekn?s, Miguel A Alonso, Anne Kallioniemi, Gunn I Meling, Rolf I Skotheim, Torleiv O Rognum, Espen Thiis-Evensen, Ragnhild A Lothe
Journal of Translational Medicine , 2008, DOI: 10.1186/1479-5876-6-13
Abstract: Using methylation-specific polymerase chain reaction (MSP) the promoter methylation status of MAL was analyzed in 218 samples, including normal mucosa (n = 44), colorectal adenomas (n = 63), carcinomas (n = 65), and various cancer cell lines (n = 46). Direct bisulphite sequencing was performed to confirm the MSP results. MAL gene expression was investigated with real time quantitative analyses before and after epigenetic drug treatment. Immunohistochemical analysis of MAL was done using normal colon mucosa samples (n = 5) and a tissue microarray with 292 colorectal tumors.Bisulphite sequencing revealed that the methylation was unequally distributed within the MAL promoter and by MSP analysis a region close to the transcription start point was shown to be hypermethylated in the majority of colorectal carcinomas (49/61, 80%) as well as in adenomas (45/63, 71%). In contrast, only a minority of the normal mucosa samples displayed hypermethylation (1/23, 4%). The hypermethylation of MAL was significantly associated with reduced or lost gene expression in in vitro models. Furthermore, removal of the methylation re-induced gene expression in colon cancer cell lines. Finally, MAL protein was expressed in epithelial cells of normal colon mucosa, but not in the malignant cells of the same type.Promoter hypermethylation of MAL was present in the vast majority of benign and malignant colorectal tumors, and only rarely in normal mucosa, which makes it suitable as a diagnostic marker for early colorectal tumorigenesis.Epigenetic changes – non-sequence-based alterations that are inherited through cell division [1] – are frequently seen in human cancers, and likewise as genetic alterations they may lead to disruption of gene function. In colorectal cancer, several tumour suppressor genes have been identified to be epigenetically inactivated by CpG island promoter hypermethylation, including the DNA mismatch repair gene MLH1 [2-4], the gatekeeper APC [5], and the cell cycle inhibito
Identification of an epigenetic biomarker panel with high sensitivity and specificity for colorectal cancer and adenomas
Guro E Lind, Stine A Danielsen, Terje Ahlquist, Marianne A Merok, Kim Andresen, Rolf I Skotheim, Merete Hektoen, Torleiv O Rognum, Gunn I Meling, Geir Hoff, Michael Bretthauer, Espen Thiis-Evensen, Arild Nesbakken, Ragnhild A Lothe
Molecular Cancer , 2011, DOI: 10.1186/1476-4598-10-85
Abstract: Candidate biomarkers were subjected to quantitative methylation analysis in test sets of tissue samples from colorectal cancers, adenomas, and normal colonic mucosa. All findings were verified in independent clinical validation series. A total of 523 human samples were included in the study. Receiver operating characteristic (ROC) curve analysis was used to evaluate the performance of the biomarker panel.Promoter hypermethylation of the genes CNRIP1, FBN1, INA, MAL, SNCA, and SPG20 was frequent in both colorectal cancers (65-94%) and adenomas (35-91%), whereas normal mucosa samples were rarely (0-5%) methylated. The combined sensitivity of at least two positives among the six markers was 94% for colorectal cancers and 93% for adenoma samples, with a specificity of 98%. The resulting areas under the ROC curve were 0.984 for cancers and 0.968 for adenomas versus normal mucosa.The novel epigenetic marker panel shows very high sensitivity and specificity for both colorectal cancers and adenomas. Our findings suggest this biomarker panel to be highly suitable for early tumor detection.Colorectal cancer is the third most common cancer type in the US and is a major contributor to cancer-death [1]. Most cases of colorectal cancer develop from benign precursors (adenomas) during a long time interval. This provides a good opportunity for detection of colorectal cancer at an early curable stage and to screen for potentially pre-malignant adenomas [2]. Both flexible sigmoidoscopy and the Fecal Occult Blood Test (FOBT) have been tested in randomized trials and shown to reduce mortality from colorectal cancer [3]. By sigmoidoscopy adenomas may be detected and removed and thus the incidence of cancer will be reduced [4], however, this screening is invasive and cumbersome for the patient. FOBT on the other hand is non-invasive and currently the most commonly used screening test for colorectal cancer in Europe. Although the sensitivity and specificity measurements of FOBT have been
Distinct high resolution genome profiles of early onset and late onset colorectal cancer integrated with gene expression data identify candidate susceptibility loci
Marianne Berg, Trude H ?gesen, Espen Thiis-Evensen, [the INFAC-study group], Marianne A Merok, Manuel R Teixeira, Morten H Vatn, Arild Nesbakken, Rolf I Skotheim, Ragnhild A Lothe
Molecular Cancer , 2010, DOI: 10.1186/1476-4598-9-100
Abstract: The total fraction of the genome with aberrant copy number, the overall genomic profile and the TP53 mutation spectrum were similar between the two age groups. However, both the number of chromosomal aberrations and the number of breakpoints differed significantly between the groups. Gains of 2q35, 10q21.3-22.1, 10q22.3 and 19q13.2-13.31 and losses from 1p31.3, 1q21.1, 2q21.2, 4p16.1-q28.3, 10p11.1 and 19p12, positions that in total contain more than 500 genes, were found significantly more often in the early onset group as compared to the late onset group. Integration analysis revealed a covariation of DNA copy number at these sites and mRNA expression for 107 of the genes. Seven of these genes, CLC, EIF4E, LTBP4, PLA2G12A, PPAT, RG9MTD2, and ZNF574, had significantly different mRNA expression comparing median expression levels across the transcriptome between the two groups.Ten genomic loci, containing more than 500 protein coding genes, are identified as more often altered in tumors from early onset versus late onset CRC. Integration of genome and transcriptome data identifies seven novel candidate genes with the potential to identify an increased risk for CRC.Less than five percent of all patients diagnosed with colorectal cancers (CRC) carry known genetic germline alterations that predispose to the disease [1]. However, it has been estimated that up to 30% of all CRC patients may carry a genetic risk as suggested by young age at onset, multiple tumors in the same patient, and an excess of individuals with CRC within a family [2,3]. Many studies have tried to identify some of these genetic risk factors, and several recent genome-wide association studies (GWAS) have pinpointed SNP loci on chromosome arms 8q, 10p, 11q, 14q, 15q, 16q, 18q, 19q, and 20p to be associated with CRC [4-10]. Furthermore, a study by Mourra et al. [11] showed that microsatellite loci within chromosome arm 14q, known to be deleted in about 30% of all colorectal cancers, were more frequently
Gene methylation profiles of normal mucosa, and benign and malignant colorectal tumors identify early onset markers
Terje Ahlquist, Guro E Lind, Vera L Costa, Gunn I Meling, Morten Vatn, Geir S Hoff, Torleiv O Rognum, Rolf I Skotheim, Espen Thiis-Evensen, Ragnhild A Lothe
Molecular Cancer , 2008, DOI: 10.1186/1476-4598-7-94
Abstract: The methylation status of eleven genes (ADAMTS1, CDKN2A, CRABP1, HOXA9, MAL, MGMT, MLH1, NR3C1, PTEN, RUNX3, and SCGB3A1) was determined in 154 tissue samples including normal mucosa, adenomas, and carcinomas of the colorectum. The gene-specific and widespread methylation status among the carcinomas was related to patient gender and age, and microsatellite instability status. Possible CIMP tumors were identified by comparing the methylation profile with microsatellite instability (MSI), BRAF-, KRAS-, and TP53 mutation status.The mean number of methylated genes per sample was 0.4 in normal colon mucosa from tumor-free individuals, 1.2 in mucosa from cancerous bowels, 2.2 in adenomas, and 3.9 in carcinomas. Widespread methylation was found in both adenomas and carcinomas. The promoters of ADAMTS1, MAL, and MGMT were frequently methylated in benign samples as well as in malignant tumors, independent of microsatellite instability. In contrast, normal mucosa samples taken from bowels without tumor were rarely methylated for the same genes. Hypermethylated CRABP1, MLH1, NR3C1, RUNX3, and SCGB3A1 were shown to be identifiers of carcinomas with microsatellite instability. In agreement with the CIMP concept, MSI and mutated BRAF were associated with samples harboring hypermethylation of several target genes.Methylated ADAMTS1, MGMT, and MAL are suitable as markers for early tumor detection.Most cases of colorectal cancer (CRC) originate from adenomas. The malignant potential of adenomas increases with size, grade of dysplasia, and degree of villous components,[1] along with the number and order of genetic and epigenetic aberrations.[2] The majority (~85%) of the sporadic carcinomas are characterized by chromosomal aberrations, referred to as a chromosomal unstable (CIN) phenotype, whereas the smaller group (~15%) typically show microsatellite instability (MSI) caused by defect DNA mismatch repair.[2] Most CIN tumors are microsatellite stable (MSS). A third molecular phenotyp
DNA Sequence Profiles of the Colorectal Cancer Critical Gene Set KRAS-BRAF-PIK3CA-PTEN-TP53 Related to Age at Disease Onset
Marianne Berg,Stine A. Danielsen,Terje Ahlquist,Marianne A. Merok,Trude H. ?gesen,Morten H. Vatn,Tom Mala,Ole H. Sjo,Arne Bakka,Ingvild Moberg,Torunn Fetveit,?ystein Mathisen,Anders Husby,Oddvar Sandvik,Arild Nesbakken,Espen Thiis-Evensen,Ragnhild A. Lothe
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0013978
Abstract: The incidence of colorectal cancer (CRC) increases with age and early onset indicates an increased likelihood for genetic predisposition for this disease. The somatic genetics of tumor development in relation to patient age remains mostly unknown. We have examined the mutation status of five known cancer critical genes in relation to age at diagnosis, and compared the genomic complexity of tumors from young patients without known CRC syndromes with those from elderly patients. Among 181 CRC patients, stratified by microsatellite instability status, DNA sequence changes were identified in KRAS (32%), BRAF (16%), PIK3CA (4%), PTEN (14%) and TP53 (51%). In patients younger than 50 years (n = 45), PIK3CA mutations were not observed and TP53 mutations were more frequent than in the older age groups. The total gene mutation index was lowest in tumors from the youngest patients. In contrast, the genome complexity, assessed as copy number aberrations, was highest in tumors from the youngest patients. A comparable number of tumors from young (<50 years) and old patients (>70 years) was quadruple negative for the four predictive gene markers (KRAS-BRAF-PIK3CA-PTEN); however, 16% of young versus only 1% of the old patients had tumor mutations in PTEN/PIK3CA exclusively. This implies that mutation testing for prediction of EGFR treatment response may be restricted to KRAS and BRAF in elderly (>70 years) patients. Distinct genetic differences found in tumors from young and elderly patients, whom are comparable for known clinical and pathological variables, indicate that young patients have a different genetic risk profile for CRC development than older patients.
Immunohistochemical detection of piscine reovirus (PRV) in hearts of Atlantic salmon coincide with the course of heart and skeletal muscle inflammation (HSMI)
?ystein Finstad, Knut Falk, Marie L?voll, ?ystein Evensen, Espen Rimstad
Veterinary Research , 2012, DOI: 10.1186/1297-9716-43-27
Abstract: Aquaculture is the fastest growing food producing sector in the world, and fish farming will be a key contributor to meet the growing demand for animal proteins [1]. However, intensive production, including rearing fish in dense populations, has led to the emergence of several new infectious diseases. Heart and skeletal muscle inflammation (HSMI), first detected in 1999, is an increasingly important disease in farmed Atlantic salmon (Salmo salar L.) [2]. HSMI usually occurs 5-9 months after transfer of the fish to seawater, and is characterized by epi-, endo- and myocarditis, myocardial necrosis, myositis and necrosis of the red skeletal muscle [2,3]. The cumulative mortality may reach 20%, but the morbidity is higher as most fish in an affected sea cage show histopathological lesions in the heart [4]. Pathological changes in the heart are also seen in other diseases in Atlantic salmon, including pancreas disease (PD) and cardiomyopathy syndrome (CMS) [5-8].HSMI was recently found to be associated with a novel reovirus, piscine reovirus (PRV). The virus genome was identified using high throughput sequencing. Cultivation of PRV in commonly used fish cell lines has not been successful so far. The load of PRV, as measured by RT-qPCR, correlates with disease development in both naturally and experimentally infected salmon [9]. However, PRV is found to be ubiquitously distributed in healthy farmed Atlantic salmon, although at a much lower level than in diseased fish. PRV is also found in low quantities in wild Atlantic salmon [9].The PRV belongs to the family Reoviridae, but it has not yet been classified at genus level. Phylogenetic analysis of derived amino acid sequences of the open reading frames of each genome segment indicated that PRV branches off the common root of the orthoreovirus and aquareovirus genera [9]. Like the orthoreoviruses, PRV contains 10 dsRNA genome segments, while aquareoviruses have 11 segments [10]. Based on sequence homologies the annotation o
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