1,721,009 research outputs found
EXPRESSION OF 72 KD GELATINASE AND TYPE-IV COLLAGEN DURING CARBON TETRACHLORIDE-INDUCED RAT-LIVER FIBROSIS
No full textJak-STAT signaling in liver disease and repair : a way of living
Full text linkSignaling through the Jak-STAT pathway is initiated when an extracellular signaling protein binds to its corresponding transmembrane receptor. This leads to activation of the Jaks. The Jaks mediate phosphorylation at the specific receptor tyrosine residues, which then serve as docking sites for the STATs. Once recruited to the receptors, the STATs become phosphorylated by the Jaks. Activated STATs will dimerize, translocate to the nucleus and target gene promoters. STAT proteins display a wide range of functions in many biological aspects. Consequently they are involved in or mediating pathological processes. This thesis describes and discusses our research, performed to understand in more detail the role of Jak-STAT signaling in liver pathophysiology. Hepatitis C virus (HCV) is a major cause of chronic liver disease. It is believed that HCV proteins interfere with interferon alpha induced Jak-STAT signaling in order to escape the interferons induced antiviral state. We therefore analyzed interferon alpha induced Jak-STAT signaling in the presence of HCV viral proteins in in vivo and in vitro models to gain more insight in this interference, as well as to identify the viral protein(s) responsible for this interference. In chapterwe show inhibition of JakSTAT signaling in transgenic mice that express HCV proteins in their liver cells. The inhibition occurred in the nucleus and blocked binding of STATs to the promoters of interferon stimulated genes. This inhibition of interferon induced signaling resulted in an enhanced susceptibility of the HCV transgenic mice to LCMV infection and the development of severe hepatitis. The results described in chapter 3, show that the combined HCV structural proteins and the core protein alone partly inhibit interferon alpha induced Jak-STAT signaling, using a panel of tetracycline-regulated cell lines inducibly expressing individual HCV proteins or in different combinations. In cells expressing HCV nonstructural proteins, interferon alpha induced Jak-STAT signaling was not impaired. The last chapters of this thesis describe the generation of conditional active gainof-function models to study STAT signaling independent of natural ligands. Fusion proteins were constructed between STAT1, STAT3 or STAT5a and the modified ligand binding domain of the estrogen receptor (ER) and subsequently expressed in mouse embryonic fibroblasts. In addition several mutants of the fusion proteins were generated. The fusion protein between wild-type STAT3 and the ER (mSTAT3wt-ER) was shown to bind DNA and mimic STAT3 signaling upon activation by 4hydroxytamoxifen (synthetic steroid ligand) only (chapter 4). mSTAT3wt-ER and mSTAT5aR618K-rER (SH-2 domain mutant) fusion protein constructs were used to generate liver-specific conditional active gain-of-function mouse models. Chapterdescribes the multistep cloning approach to prepare the constructs for injection and the analysis of the transgenic mice designated albSTAT3wt-ER and albSTAT5R618K-rER. The transgenic mice were designed to express the fusion proteins under control of the albumin promoter allowing liver-specific expression. Transgenic founders have been identified, as well as a transgenic F1 offspring. The transgenic mice appeared to be healthy and show a normal phenotype. Further characterization has to be completed. In chapterpossibilities for future use of the in chapterdescribed transgenic mice are discussed. The mice could be used to study STAT3 and STAT5a signaling in processes as liver cell regeneration, cellular transformation, bacterial infection, gluconeogenesis and cell survival
E2F1 inhibits c-Myc-driven apoptosis via PIK3CA/Akt/mTOR and COX-2 in a mouse model of human liver cancer
No full textCytokeratin-19, a predictive marker and an early determinant of progenitor-derived hepatocellular carcinoma
No full textBackground: Human hepatocellular carcinoma (HCC) is a heterogeneous disease of distinct clinical subgroups. A principal source of tumor heterogeneity may be cell type of origin which in liver includes hepatocyte and/or adult stem/progenitor cells. Objective: To address this issue, we investigated the molecular mechanisms underlying the fate of the enzyme-altered preneoplastic lesions in the resistant hepatocyte (RH) model. Methods: Sixty samples classified as focal lesions, adenoma, early and advanced HCCs were micro-dissected after morphological and immunohistochemical evaluation and subjected to global gene expression profiling. Results: The analysis of progression of the persistent GSTP+ focal lesions to fully developed HCC showed that about 50% of persistent nodules and all HCCs expressed CK19 whereas 14% of remodeling nodules were CK19+. Unsupervised hierarchical clustering of the expression profiles also grouped the samples according to CK19 expression. Further, supervised analysis using the differentially expressed genes in each cluster combined with the gene connectivity tools identified 1308 unique genes and a predominance of the AP-1/JUN network in the CK19+ lesions. In contrast, the CK19-negative cluster exhibited only limited molecular changes (156 differentially expressed genes vs. normal liver) consistent with remodeling towards differentiated phenotype. Finally, comparative functional genomics revealed a stringent clustering of CK19+ early lesions and advanced HCCs with human HCCs characterized by poor prognosis. Furthermore, the CK19 associated gene expression signature accurately predicted the patient survival (P<0.009) and tumor recurrence (P<0.006). Conclusion: Our data establish CK19 as a prognostic marker of early neoplastic lesions and strongly suggest the progenitor derivation of HCC in the rat RH model. The capacity of the CK19 associated gene signature to stratify HCC patients according to clinical prognosis indicates the usefulness of the RH model for studies of stem/progenitor-derived HCC
Activation of the canonical Wnt/Beta-catenin pathway confers growth advantages in c-My/E2F1 transgenic mouse model of liver cancer
No full textCholangiocyte Biology and Pathobiology
No full textCholangiocytes are the epithelial cells that line the intrahepatic and extrahepatic biliary tree. The biliary system is a complex network of tubules coated by epithelial cells, or cholangiocytes, which starts from the canals of Hering in the liver lobules, continues outside the liver, and terminates into the ampulla of Vater. The extra- and intrahepatic branches of the biliary tree originate from different embryological areas, explaining their morphological and biological properties. A fundamental function of epithelial cells, including cholangiocytes, is to selectively control the diffusion of ions and molecules through the epithelial barrier. Biliary epithelial cells are usually quiescent, following a liver insult, cholangiocytes activate and/or proliferate as a part of the so-called "hepatic reparative complex". Proliferation of cholangiocytes is fundamental for the maintenance of the normal homeostasis of the biliary tree, and in response to liver damage. A major role in epithelial..
Classification and survival prediction of hepatocellular carcinoma by gene expression profiling
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Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
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