BackgroundActivation of hepatic CB1 receptors (CB1) is associated with steatosis and fibrosis in experimental forms of liver disease. However, CB1 expression has not been assessed in patients with chronic hepatitis C (CHC), a disease associated with insulin resistance, steatosis and metabolic disturbance. We aimed to determine the importance and explore the associations of CB1 expression in CHC.MethodsCB1 receptor mRNA was measured by real time quantitative PCR on extracted liver tissue from 88 patients with CHC (genotypes 1 and 3), 12 controls and 10 patients with chronic hepatitis B (CHB). The Huh7/JFH1 Hepatitis C virus (HCV) cell culture model was used to validate results.Principal FindingsCB1 was expressed in all patients with CHC and levels were 6-fold higher than in controls (P<0.001). CB1 expression increased with fibrosis stage, with cirrhotics having up to a 2 fold up-regulation compared to those with low fibrosis stage (p<0.05). Even in mild CHC with no steatosis (F0-1), CB1 levels remained substantially greater than in controls (p<0.001) and in those with mild CHB (F0-1; p<0.001). Huh7 cells infected with JFH-1 HCV showed an 8-fold upregulation of CB1, and CB1 expression directly correlated with the percentage of cells infected over time, suggesting that CB1 is an HCV inducible gene. While HCV structural proteins appear essential for CB1 induction, there was no core genotype specific difference in CB1 expression. CB1 significantly increased with steatosis grade, primarily driven by patients with genotype 3 CHC. In genotype 3 patients, CB1 correlated with SREBP-1c and its downstream target FASN (SREBP-1c; R = 0.37, FASN; R = 0.39, p<0.05 for both).Conclusions/SignificanceCB1 is up-regulated in CHC and is associated with increased steatosis in genotype 3. It is induced by the hepatitis C virus.
Immunohistochemistry of tumour samples is increasingly used in the triage of families where hereditary non-polyposis colorectal cancer (HNPCC) due to mismatch repair defects is suspected. Usually, this is undertaken in tumours that are a recognised part of the spectrum of HNPCC-related cancers e.g. colon or endometrial cancers. Although breast cancers are not classed as part of this spectrum, this study examined the extent to which some breast tumours do arise by the mismatch repair pathway in these families. This may have clinical utility in families where an individual with a 'classic HNPPC-related' tumour is not available for evaluation. Immunohistochemistry of a breast tumour may identify an individual in whom germline mutation testing is worthwhile.
Background: With the advent of screening mammography more breast cancer will be detected at an earlier stage, apparently confined to the breast with no nodal involvement. However, 30% of these will recur due to micrometastases present at the time of diagnosis. Chemotherapy and tamoxifen have been shown to improve disease‐free survival in axillary node‐negative patients but not overall survival. In the search for a useful predictor of breast cancer recurrence the relationship between c‐erbB‐2 expression and recurrence and survival was examined.
Methods: Eighty‐eight axillary node‐negative breast cancer patients were followed up for at least 5 years.
Results: There was a significant relationship between c‐erbB‐2 expression and both tumour recurrence (P < 0.001) and poorer survival (P = 0.003). In a Cox multiple regression analysis, c‐erbB‐2 staining remained the only significant prognostic variable for recurrence (P= 0.002) and survival (P = 0.032). Tumour recurrence in c‐erbB‐2‐positive cases tended to occur early in the course of follow up and was associated with poorer survival.
Conclusion: C‐erbB‐2 was found to be a useful prognostic indicator for early recurrence and poorer survival in axillary node‐negative breast cancer patients.
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