| 1. |
- Campbell, PJ, et al.
(författare)
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Pan-cancer analysis of whole genomes
- 2020
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 578:7793, s. 82-
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Tidskriftsartikel (refereegranskat)abstract
- Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale1–3. Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4–5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter4; identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation5,6; analyses timings and patterns of tumour evolution7; describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity8,9; and evaluates a range of more-specialized features of cancer genomes8,10–18.
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| 2. |
- Rotter Sopasakis, Victoria, 1972, et al.
(författare)
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High local concentrations and effects on differentiation implicate interleukin-6 as a paracrine regulator
- 2004
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Ingår i: Obes Res. - 1071-7323. ; 12:3, s. 454-60
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: To examine the possibility that interleukin-6 (IL-6) can act as a paracrine regulator in adipose tissue by examining effects on adipogenic genes and measuring interstitial IL-6 concentrations in situ. RESEARCH METHODS AND PROCEDURES: Circulating and interstitial IL-6 concentrations in abdominal and femoral adipose tissue were measured using the calibrated microdialysis technique in 20 healthy male subjects. The effects of adipose cell enlargement on gene expression and IL-6 secretion were examined, as well as the effect of IL-6 in vitro on gene expression of adiponectin and other markers of adipocyte differentiation. RESULTS: The IL-6 concentration in the interstitial fluid was approximately 100-fold higher than that in plasma, suggesting that IL-6 may be a paracrine regulator of adipose tissue. This was further supported by the finding that adding IL-6 in vitro at similar concentrations down-regulated the expression of adiponectin, aP2, and PPARgamma-2 in cultured human adipose tissue. In addition, gene expression and release of IL-6, both in vivo and in vitro, correlated with adipose cell size. DISCUSSION: These data suggest that IL-6 may be a paracrine regulator of adipose tissue. Furthermore, increased adipose tissue production of IL-6 after hypertrophic enlargement of the adipose cells may detrimentally affect systemic insulin action by inducing adipose tissue dysfunction with impaired differentiation of the pre-adipocytes and/or adipocytes and lower adiponectin.
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| 3. |
- Yang, Xiao Lin, 1955, et al.
(författare)
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Adipose tissue distribution and risk of metabolic disease: does thiazolidinedione-induced adipose tissue redistribution provide a clue to the answer?
- 2007
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Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 0012-186X .- 1432-0428. ; 50:6, s. 1127-39
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Tidskriftsartikel (refereegranskat)abstract
- The relative effect of visceral and subcutaneous obesity on the risk of chronic metabolic disease has been a matter of long-term dispute. While ample data support either of the fat depots being causative or associative, valid argument for one depot often automatically belittles the other. Paradigms such as the visceral/portal hypothesis and the acquired lipodystrophy/ectopic fat storage and endocrine hypothesis have been proposed. Nevertheless, neither hypothesis alone explains the entire pathophysiological setting. Treatment of diabetes with thiazolidinediones selectively increases fat partitioning to the subcutaneous adipose depot but does not change visceral fat accumulation. This is in contrast to the preferential visceral fat mobilisation by diet and exercise. Surgical removal of visceral or subcutaneous adipose tissue yields relatively long-lasting metabolic improvement only when combined with procedures that ameliorate adipose tissue cell composition. These studies illustrate that human adipose tissue in different anatomic locations does not work in isolation, and that there is a best-fit relationship in terms of volume and function among different fat depots that needs to be met to maintain the systemic energy balance and to prevent the complications related to obesity.
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| 4. |
- Yang, Xiao Lin, 1955, et al.
(författare)
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Effect of the interleukin-6 (-174) g/c promoter polymorphism on adiponectin and insulin sensitivity
- 2005
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Ingår i: Obes Res. - 1071-7323. ; 13:5, s. 813-7
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Tidskriftsartikel (refereegranskat)abstract
- We investigated the relation among the interleukin (IL)-6 (-174) G/C promoter polymorphism, adipose tissue gene expression of IL6, circulating adiponectin, and systemic insulin sensitivity. Eighty-five Swedish male subjects who had participated in our previous prediabetic phenotype characterization study were genotyped for the IL6 (-174) G/C polymorphism. Subcutaneous adipose tissue gene expression of IL6 and adiponectin was measured in 44 subjects. The IL6 (-174) G allele carriers had higher fasting plasma insulin levels (C/C, 7.8 +/- 1.1; G/C, 9.0 +/- 0.6; G/G, 10.5 +/- 1.0 mU/L) and higher homeostasis model assessment for insulin resistance (C/C, 1.6 +/- 0.2; G/C, 1.9 +/- 0.1; G/G, 2.2 +/- 0.2) compared with subjects with the C/C genotype. The circulating adiponectin levels were lower in the G allele carriers (C/C, 7.93 +/- 0.45; G/C, 7.05 +/- 0.44; G/G, 7.02 +/- 0.46 microg/mL), whereas the IL-6 levels did not differ among the three genotypes. Adipose tissue IL6 gene expression was significantly higher in the G allele carriers compared with the subjects homozygous for the C allele (C/C, 0.29 +/- 0.15; G/C, 0.84 +/- 0.29; G/G, 0.62 +/- 0.35). Our results suggest that IL6 (-174) G/C polymorphism is associated with insulin resistance and increased adipose tissue IL6 gene expression, which can impair adiponectin production.
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| 5. |
- Yang, Xiao Lin, 1955, et al.
(författare)
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Evidence of impaired adipogenesis in insulin resistance
- 2004
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Ingår i: Biochem Biophys Res Commun. - : Elsevier BV. - 0006-291X. ; 317:4, s. 1045-51
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Tidskriftsartikel (refereegranskat)abstract
- To elucidate the roles of adipose tissue and skeletal muscle in the early development of insulin resistance, we characterized gene expression profiles of isolated adipose cells and skeletal muscle of non-diabetic insulin-resistant first-degree relatives of type 2 diabetic patients using oligonucleotide microarrays. About 600 genes and expressed sequence tags, which displayed a gene expression pattern of cell proliferation, were differentially expressed in the adipose cells. The differentially expressed genes in the skeletal muscle were mostly related to the cellular signal transduction and transcriptional regulation. To verify the microarray findings, we studied expression of genes participating in adipogenesis. The expression of Wnt signaling genes, WNT1, FZD1, DVL1, GSK3beta, beta-catenin, and TCF1, and adipogenic transcription factors, C/EBPalpha and beta and delta, PPARgamma, and SREBP-1, was reduced in the adipose tissue. The expression of adipose-specific proteins related to terminal differentiation, such as adiponectin and aP2, was reduced both in the adipose tissue and in the adipose cells isolated from portions of the biopsies. The adipose cells were enlarged in the insulin-resistant relatives and the cell size inversely correlated with the expression of the Wnt signaling genes, adiponectin, and aP2. Our findings suggest that insulin resistance is associated with an impaired adipogenesis.
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