Carcinomas of the biliary tract have a poor prognosis. It is important to understand the molecular genetic characteristics of these tumours in order to employ newer effective treatments and to improve patient prognosis. There is increasing evidence that overexpression of tyrosine kinase growth factor receptors such as ErbB-2, epidermal growth factor receptor (EGFR), and Met may play important roles in the development of biliary tract carcinomas. The aim of this study was to assess the potential for novel chemotherapies targeting these receptors. Overexpression of the tyrosine kinase receptor proteins was examined by immunohistochemistry in 221 biliary tract carcinomas, of which 28 were from the intrahepatic bile duct, 78 from the extrahepatic bile duct, 89 from the gall bladder, and 26 from the ampulla of Vater. Positively stained tumours were further examined for gene amplification by fluorescence in situ hybridization. Overexpression of ErbB-2 was found in 15.7%, 11.5%, and 5.1% of carcinomas of the gall bladder, ampulla of Vater, and extrahepatic bile duct, respectively, and gene amplification was present in 79% of these. Overexpression of EGFR was found in 8.1% of tumours with no predominant location and was also associated with gene amplification with high frequency (77%). Met overexpression, most frequent in intrahepatic bile duct carcinomas (21.4%), was not associated with gene amplification. It is proposed that the new adjuvant chemotherapies could be directed to carcinomas of the biliary tract in which ErbB-2 and EGFR are overexpressed.
Overexpression of HER-2 and the epidermal growth factor receptor (EGFR) has been observed in many cancers, sometimes accompanied by gene amplification. To assess whether novel chemotherapies targeting these overexpressed proteins may be effective for the treatment of colorectal cancers, we examined the exact frequency of HER-2 and EGFR overexpression, the relationship between gene amplification and protein expression, and the heterogeneity of gene amplification within and between primary and metastatic tumors. We evaluated 244 colorectal cancers immunohistochemically. All tumors found to overexpress HER-2 or EGFR were further analyzed for gene amplification by fluorescent in situ DNA hybridization. Overexpression of HER-2 and EGFR was found in 8 (3%) and 19 (8%) of the 244 colorectal carcinomas, respectively. Gene amplification was observed in 100 and 58% of the tumors exhibiting HER-2 and EGFR overexpression, respectively. HER-2 amplification in cancer cells was characterized by clusters of hybridization signals, suggesting amplicons in homogeneously staining regions that were predominant in most primary and metastatic tumors. EGFR amplification, observed as scattered signals reminiscent of amplicons in double minute chromosomes, or coamplification of EGFR with the centromeric regions was observed as a minor population within primary tumors, and found in variety of populations in metastatic tumors. Overexpression of HER-2 and EGFR were observed in only a small fraction of colorectal carcinomas, but were frequently accompanied by gene amplification. The HER-2 gene is located on chromosomal region 17q11.2-q12 and the EGFR gene is located on 7p12. These encode 185 kDa (p185) and 170 kDa plasma membrane glycoproteins, respectively. They share approximately 50% overall homology and are composed of an N-terminus extracellular ligand-binding domain, a transmembrane lipophilic segment, and a C-terminus intracellular region containing a tyrosine kinase domain.
Objective. To clarify the role of interleukin-6 (IL-6) in the pathogenesis of collagen-induced arthritis Methods. CIA was induced by immunizing twice at a 3-week interval with bovine type I1 collagen (CII) emulsified with complete adjuvant. Rat anti-mouse IL-6 receptor (anti-IL-6R) monoclonal antibody MR16-1 or isotype-matched control antibody KH-5 was then injected once intraperitoneally. Symptoms of arthritis were evaluated with a visual scoring system, and serum anti-CII antibody and IL-6 levels were measured by enzyme-linked immunosorbent assay. In addition, the CII responsiveness of splenic lymphocytes from mice with CIA was examined.Results. In mice with CIA, excess production of IL-6 in sera was observed within 24 hours after the first CII immunization, and then rapidly decreased. Serum IL-6 increased again beginning 14 days after immunization, in conjunction with the onset of arthritis. When MR16-1 was injected immediately after immunization with CII, it inhibited the development of arthritis in a dose-dependent manner. Furthermore, MR16-1-treated mice exhibited lower serum levels of IgG anti-CII antibody and reduced responsiveness of lymphocytes to CII. This suppressive effect was observed when MR16-1 was injected on day 0 or 3, but not when injected on day 7 or 14.Conclusion. IL-6 produced after CII immunization appears to play an essential role in the immunity to (CIA).
Objective Little is known about whether economic crises widen health inequalities. Japan experienced more than 10 years of economic recession beginning in the 1990s. The question of whether socioeconomic-based inequality in self-rated health widened after the economic crisis was examined. Design, setting and participants Repeated cross-sectional survey design. Two pooled datasets from 1986 and 1989 and from 1998 and 2001 were analysed separately, and temporal change was examined. The study took place in Japan among the working-age population (20–60 years old). The two surveys consisted of 168 801 and 150 016 people, respectively, with about an 80% response rate. Results The absolute percentages of people reporting poor health declined across all socioeconomic statuses following the crisis. However, after controlling for confounding factors, the odds ratio (OR) for poor self-rated health (95% confidence intervals) among middle-class non-manual workers (clerical/sales/service workers) compared with the highest class workers (managers/administrators) was 1.02 (0.92 to 1.14) before the crisis but increased to 1.14 (1.02 to 1.29) after the crisis (p for temporal change = 0.02). The association was stronger among males. The adjusted ORs among professional workers and young female homemakers also marginally increased over time. Unemployed people were twice as likely to report poor health compared with the highest class workers throughout the period. Self-rated health of people with middle to higher incomes deteriorated in relative terms following the crisis compared with that of lower income people. Conclusions Self-rated health improved in absolute terms for all occupational groups even after the economic recession. However, the relative disparity increased between the top and middle occupational groups in men.
Relative deprivation has been hypothesized as one of the pathways accounting for the link between income inequality and health. We tested this hypothesis in a large national sample of men and women in Japan. Our survey included a probability sample of 22,871 men and 24,243 women aged 25-64, from whom information was gathered on demographic variables, household income, occupation or employment status, and self-rated health. Our measure of relative deprivation was the Yitzhaki Index, which calculates the deprivation suffered by each individual as a function of the aggregate income shortfall for each person relative to everyone else with higher incomes in that person's reference group. We modeled several alternative reference groups, including others with the same occupation, others of the same age group, and others living in the same geographic area (prefecture), as well as combinations of these. Generalized estimating equations demonstrated that higher relative deprivation was associated with worse self-rated health. Even after controlling for absolute income as well as other sociodemographic factors, the odds ratio and its 95% confidence intervals (CI) for poor health ranged from 1.09 (95% CI: 1.02-1.16) to 1.18 (95% CI: 1.11-1.26) for men and from 1.10 (95% CI: 1.04-1.16) to 1.16 (95% CI: 1.09-1.23) for women per 1 million increase in the Yitzhaki Index. As such, relative income deprivation is associated with poor self-rated health independently of absolute income, and relative deprivation may be a mechanism underlying the link between income inequality and population health.
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