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Lin W.-R.,Chang Gung University | Lim S.-N.,Chang Gung University | McDonald S.A.C.,Cancer Research UK Research Institute | McDonald S.A.C.,Queen Mary, University of London | And 9 more authors.
Hepatology | Year: 2010

Here, we investigate the clonality and cells of origin of regenerative nodules in human liver cirrhosis using mitochondrial DNA (mtDNA) mutations as markers of clonal expansion. Mutated cells are identified phenotypically by deficiency in the entirely mtDNA encoded cytochrome c oxidase (CCO) enzyme by histochemical and immunohistochemical methods. Nodules were classified as either CCO-deficient or CCO-positive, and among 526 nodules from 10 cases, 18% were homogeneously CCO-deficient, whereas only 3% had a mixed phenotype. From frozen sections, hepatocytes were laser-capture microdissected from several sites within individual CCO-deficient nodules. Mutations were identified by polymerase chain reaction sequencing of the entire mtDNA genome. In all cases except for one, the nodules were monoclonal in nature, possessing up to four common mutations in all hepatocytes in a given nodule. Moreover, the identification of identical mutations in hepatic progenitor cells abutting CCO-deficient nodules proves that nodules can have their origins from such cells. Conclusion: These data support a novel pathway for the monoclonal derivation of human cirrhotic regenerative nodules from hepatic progenitor cells. Copyright © 2010 by the American Association for the Study of Liver Diseases.

Lederle W.,German Cancer Research Center | Lederle W.,RWTH Aachen | Depner S.,German Cancer Research Center | Schnur S.,German Cancer Research Center | And 5 more authors.
International Journal of Cancer | Year: 2011

Cytokines play a crucial role in tumor initiation and progression. Here, we demonstrate that interleukin (IL)-6 is a key factor by driving tumor progression from benign to malignant, invasive tumors in the HaCaT-model of human skin carcinoma. IL-6 activates STAT3 and directly stimulates proliferation and migration of the benign noninvasive HaCaT-ras A-5 cells in vitro. Furthermore, IL-6 induces a complex, reciprocally regulated cytokine network in the tumor cells that includes inflammatory and angiogenic factors such as IL-8, GM-CSF, VEGF and MCP-1. These IL-6 effects lead to tumor cell invasion in organotypic cultures in vitro and to the formation of malignant and invasive s.c. tumors in vivo. Tumor invasion is supported by the IL-6 induced overexpression of MMP-1 in vitro and in vivo. These data demonstrate a key function of IL-6 in the progression of skin SCCs by regulating a complex cytokine and protease network and suggest new therapeutic approaches to target this central player in skin carcinogenesis. © 2010 UICC.

De Graaff L.C.G.,Erasmus MC Sophia Childrens Hospital | Clark A.J.L.,John Vane Science Center | Tauber M.,Genetics | Tauber M.,French Institute of Health and Medical Research | And 11 more authors.
Hormone Research in Paediatrics | Year: 2014

Background: Fetal growth failure has been associated with an increased risk of hypertension, cardiovascular disease and diabetes in adulthood. Exploring the mechanisms underlying this association should improve our understanding of these common adult diseases. Patients and Methods: We investigated 225 SNPs in 10 genes involved in growth and glucose metabolism (GH1, GHR, IGF1, IGF1R, STAT5A, STAT5B, MAPK1, MAPK3, PPARγ and INS) in 1,437 children from the multinational NESTEGG consortium: 345 patients born small for gestational age who remained short (SGA-S), 288 who showed catch-up growth (SGA-Cu), 410 idiopathic short stature (ISS) and 394 controls. We related genotype to pre- and/or postnatal growth parameters, response to growth hormone (if applicable) and blood pressure. Results: We found several clinical associations for GH1, GHR, IGF1, IGF1R, PPARγ and MAPK1. One SNP remained significant after Bonferroni's correction: IGF1R SNP rs4966035's minor allele A was significantly more prevalent among SGA and associated with smaller birth length (p = 0.000378) and birth weight (weaker association), independent of gestational age. Conclusion:IGF1R SNP rs4966035 is significantly associated with birth length, independent of gestational age. This and other associations suggest that polymorphisms in these genes might partly explain the phenotype of short children born SGA and children with ISS. © 2013 S. Karger AG, Basel.

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