Hepatitis: Shackel NA

Shackel NA, McCaughan GW. · No affiliation provided · Hepatology. · Pubmed #17969041 No free full text.

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Bowen DG, Shackel NA, McCaughan GW. · No affiliation provided · J Gastroenterol Hepatol. · Pubmed #10847429 No free full text.

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McCaughan GW, Shackel NA, Bertolino P, Bowen DG. · AW Morrow Gastroenterology and Liver Centre, Centenary Institute, Royal Prince Alfred Hospital and Sydney University, Sydney, Australia. · Transplantation. · Pubmed #19384153 No free full text.

Abstract: Hepatitis C virus (HCV)-related liver disease postliver transplantation is associated with an accelerated course in comparison with that observed in the nonimmunosuppressed individual. Outcomes in transplantation for this indication have, therefore, been a major area of clinical interest in the field of liver transplantation. The factors underlying the rapid progression of HCV-related liver disease posttransplantation are complex and multifactorial. Nevertheless, recent data indicate a range of parameters assessable early posttransplantation that may be useful in the prediction of outcome of transplantation for this condition. This overview, therefore, concentrates on the early events occurring postliver transplantation in the HCV-infected patient, and the implications of these recent observations for the pathogenesis of the various forms of HCV-related allograft injury.

McCaughan GW, Gorrell MD, Bishop GA, Abbott CA, Shackel NA, McGuinness PH, Levy MT, Sharland AF, Bowen DG, Yu D, Slaitini L, Church WB, Napoli J. · Royal Prince Alfred Hospital, Centenary Institute of Cancer Medicine and Cell Biology and The University of Sydney, Australia. · Immunol Rev. · Pubmed #10807516 No free full text.

Abstract: The hallmarks of chronic liver diseases are chronic inflammation, cellular damage, regeneration and fibrosis. An appreciation of intrahepatic molecular expression patterns in normal and diseased liver provides clues for understanding pathogenic pathways whilst studies of the structure and function of molecules implicated in liver disease provide insights into their potential as therapeutic targets. We have examined the expression, function, molecular structure and structure-function relationships of type IV dipeptidyl aminopeptidases. In particular, the roles of CD26/DPPIV in T-cell proliferation and chemotaxis and of fibroblast activation protein in human cirrhosis are discussed. We have investigated the pathogenesis of liver disease by characterising patterns of cytokine and growth factor expression in experimental and human cirrhosis. We have quite recently expanded this approach to use differential gene expression analyses to elucidate overall pathways of gene activation and suppression in human cirrhosis. In addition, our detailed molecular and cellular studies of the mechanisms of spontaneous liver transplant tolerance have generated novel insights into this process. This review touches on these diverse aspects of liver function and disease.

Shackel NA, Jamias J, Rahman W, Prakoso E, Strasser SI, Koorey DJ, Crawford MD, Verran DJ, Gallagher J, McCaughan GW. · A.W. Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital, University of Sydney, Sydney, Australia. · Liver Transpl. · Pubmed #19562704 No free full text.

Abstract: The aim of this study was to examine the importance of the serum hepatitis C viral load within the first year post-liver transplant in determining posttransplant survival. A retrospective analysis of 118 consecutive hepatitis C virus-positive liver transplant recipients who received an allograft from January 1997 to September 2005 was undertaken with a median duration of follow-up of 32.4 months. Univariate and multivariate analyses were used to examine the effects of recipient, donor, surgical, and viral factors on posttransplant outcomes. A total of 620 viral load estimations were undertaken in the first 12 months following transplantation. Patient and graft survival rates at 1, 3, and 5 years were 87.8%, 79.9%, and 70.1% and 87.0%, 79.2%, and 68.2%, respectively. According to multivariate analysis, a peak viral load > or = 10(7) IU/mL (P = 0.004; hazard ratio, 8.68; 95% confidence interval, 2.04-37.02) and exposure to antirejection therapy (P = 0.05; hazard ratio, 2.26; 95% confidence interval, 1.01-5.38) were both independent predictors of diminished patient and graft survival and hepatitis C-related allograft failure. The only other independent predictor of hepatitis C virus-related outcome after transplant was azathioprine use, which was associated with improved outcomes (P = 0.04; hazard ratio, 0.25; 95% confidence interval, 0.07-0.91). A peak viral load in the first year after transplant of >10(8), 10(7) to 10(8), and <10(7) IU/mL was associated with a mean survival of 11.8, 70.6, and 89.1 months respectively (P < or = 0.03). The results emphasize the importance of high viral loads in the early posttransplant period as an independent predictor of recipient outcomes.

Huang XX, McCaughan GW, Shackel NA, Gorrell MD. · A W Morrow Gastroenterology and Liver Centre at Royal Prince Alfred Hospital, NSW, Australia. · Liver Int. · Pubmed #17696935 No free full text.

Abstract: BACKGROUND/AIMS: Cirrhosis can lead to hepatocellular carcinoma (HCC). Non-diseased liver and hepatitis C virus (HCV)-associated cirrhosis with or without HCC were compared. METHOD: Proliferation pathway genes, immune response genes and oncogenes were analysed by a quantitative real-time reverse transcriptase-polymerase chain reaction (RT-PCR) and immunostaining. RESULTS: Real-time RT-PCR showed up-regulation of genes in HCV cirrhosis including the proliferation-associated genes bone morphogenetic protein 3 (BMP3), placental growth factor 3 (PGF3), vascular endothelial growth factor receptor 1 (VEGFR1) and soluble VEGFR1, the oncogene FYN, and the immune response-associated genes toll-like receptor 9 (TLR9) and natural killer cell transcript 4 (NK4). Expressions of TLR2 and the oncogenes B-cell CLL/lymphoma 9 (BCL9) and PIM2 were decreased in HCV cirrhosis. In addition, PIM2 and TLR2 were increased in HCV cirrhosis with HCC compared with HCV cirrhosis. The ligand/receptor pair PGF and VEGFR1 was intensely expressed by the portal tract vascular endothelium. VEGFR1 was expressed in reactive biliary epithelial structures in fibrotic septum and in some stellate cells and macrophages. CONCLUSION: PGF and VEGFR1 may have an important role in the pathogenesis of the neovascular response in cirrhosis.

Shackel NA, McGuinness PH, Abbott CA, Gorrell MD, McCaughan GW. · A.W. Morrow Gastroenterology and Liver Centre, Centenary Institute of Cancer Medicine and Cell Biology, Royal Prince Alfred Hospital, Sydney, Australia. · Hepatology. · Pubmed #12939584 No free full text.

Abstract: Pathogenic molecular pathways in cirrhotic liver diseases such as hepatitis C virus (HCV), autoimmune hepatitis (AIH) and primary biliary cirrhosis (PBC) are poorly characterized. Differentially expressed genes are often important in disease pathogenesis. Suppression subtractive hybridization (SSH) is a genome-wide approach that enriches for differentially expressed mRNA transcripts. We aimed to make novel observations of differential gene expression in cirrhosis using SSH combined with quantitative real-time reverse transcriptase polymerase chain reaction (RT-PCR). Liver transcriptomes in HCV cirrhosis, AIH cirrhosis, PBC, and nondiseased liver tissue were examined by SSH. Resulting complementary DNA (cDNA) clones were rescreened for differential expression by dot-blot hybridization and then sequenced. Selected gene expression was quantified by real-time RT-PCR. Following SSH, 694 clones were rescreened for differential gene expression, of which 145 were sequenced and found to derive from 89 different genes. Seven clones were homologous only with expressed sequence tag (EST) sequences encoding genes having no known function. Up-regulated expression of four genes was confirmed by real-time RT-PCR: transmembrane 4 superfamily member 3 (tetraspanin CO-029) in all forms of cirrhosis, hedgehog interacting protein (HIP) in AIH cirrhosis and chitinase 3-like-1 (HC gp-39 or ykl-40) and arginine-glutamic acid repeat (RERE) in HCV cirrhosis. RERE gene polymorphisms and splice variants were observed in all tissues examined. Tetraspanin CO-029 up-regulation was primarily localized to bile ductular cells. In conclusion, novel observations of differential gene expression in human cirrhosis were made using SSH as the primary discovery tool. In particular, further studies of the RERE gene and its products in HCV associated liver disease are warranted.

Shackel NA, McGuinness PH, Abbott CA, Gorrell MD, McCaughan GW. · A. W. Morrow Gastroenterology and Liver Centre, Centenary Institute of Cancer Medicine and Cell Biology, Royal Prince Alfred Hospital, Sydney, Australia. · Am J Pathol. · Pubmed #11839585 links to  free full text

Abstract: The pathogenesis of hepatitis C virus (HCV)-associated liver injury involves many genes from multiple pathogenic pathways. cDNA array analysis, which examines the expression of many genes simultaneously, was used to achieve new insights into HCV liver injury. Membrane-based cDNA arrays of 874 genes compared HCV-associated cirrhosis with autoimmune hepatitis-associated cirrhosis as an inflammatory and cirrhotic control, and with nondiseased liver tissue. Array analysis identified many differentially expressed genes that are important in inflammation, fibrosis, proliferation, signaling, apoptosis, and oxidative stress. Genes up-regulated in HCV-associated cirrhosis were predominantly associated with a Th1 immune response, fibrosis, cellular proliferation, and apoptosis. Novel observations of differential gene expression included increased expression of secreted apoptosis-related protein 3, a Wnt pathway gene possibly involved in cellular apoptosis. EMMPRIN (CD147) and discoidin domain receptor 1 (CD167) were also shown to be increased and are likely to play a role in liver fibrosis. Real-time quantitative reverse transcriptase-polymerase chain reaction confirmed the increased expression of 15 genes. The comparison of HCV cirrhosis with autoimmune hepatitis cirrhosis showed a marked difference in the apoptosis-associated gene profile with HCV cirrhosis characterized by increased proapoptotic gene expression whereas autoimmune hepatitis was characterized by increased expression of both antiapoptotic and proapoptotic genes. Furthermore, expression of beta-catenin and the fibrosis-associated protein EMMPRIN were localized by immunohistochemistry to the plasma membranes of hepatocytes and biliary epithelium. In conclusion, HCV-associated cirrhosis was characterized by a proinflammatory, profibrotic, and proapoptotic gene expression profile.

McGaughan GW, Shackel NA, Gorrell MD. · No affiliation provided · Gastroenterology. · Pubmed #11706833 No free full text.

This publication has no abstract.