Search

CD40 is expressed primarily on B cells and plays an important role in antigen presentation, B cell proliferation, and T cell activation. It has been reported that the CD40 signal modulates apoptosis and has an anti-viral effect in certain cells. Therefore, we investigated the expression and the function of CD40 in HCV-associated chronic liver disease. The expression of CD40 on liver tissues was determined through immunohistochemistry on 50 liver specimens obtained from HCV-positive patients. The effect of CD40 signaling on apoptosis of HepG2 cells was assessed using the MTT assay. The effect of CD40 stimulation on NF-kappaB activation was determined in NF-kappaB reporter gene-transfected HepG2 cells with the Luciferase assay. CD40 positive hepatocytes were observed in both periportal and lobular areas, accompanied by inflammation. In both areas, CD40 staining intensity became significantly stronger, correlating with the histological grading. Similarly, it became stronger with the progression of the histological staging in F1, F2 and F3 cases; however, the expression level decreased in F4 cases. CD40 ligation induced apoptosis in HepG2 cells in the presence of 500 ng/ml of actinomycin D, while CD40 ligation alone could not. Anti-CD40 monoclonal antibody caused NF-kappaB activation in HepG2 cells in a dose-dependent manner. These results suggest that hepatocyte over-expression of CD40 might play an important role in regulating hepatocyte survival and death in HCV-associated chronic liver diseases.

PPARgamma is known to induce apoptosis in malignant tumor cells, but the mechanism of this induction is not well understood. We investigated induction of apoptosis with 15-Deoxy-Delta12,14-prostaglandin J2 (15d-PGJ2), a PPARgamma ligand, in cholangio cell carcinoma (CCC) cells (RBE, ETK-1 or HuCCT-1). Apoptosis was induced in RBE and ETK-1 cells with 15d-PGJ2, but not in HuCCT-1 cells, although PPARgamma was expressed in all CCC cells. Apoptosis-related proteins were also expressed, including FLIP, bclx, Apaf-1 and XIAP, but expression levels differed among the three cell lines. RBE cells treated with 15d-PGJ2 showed caspase activation, and it appeared that PPARgamma-induced apoptosis was dependent on caspase activation. However, neither ETK-1 nor HuCCT-1 cells showed significant activation of caspase-8 or -3 with 15d-PGJ2 treatment, raising the possibility of a caspase-independent apoptosis induction pathway. XIAP was down-regulated by 15d-PGJ2 in all three CCC cell lines. Therefore, 15d-PGJ2 induces apoptosis in CCC cells via caspase-dependent or independent pathways. 15d-PGJ2 may also induce down-regulation of XIAP and may promote caspase cascade activation through TNF-family receptor signaling pathways.

Currently, pyogenic liver abscess is not frequent, but it is a severe infectious disease. However a strategy for the effective treatment of liver abscess is not established. We analyzed 75 cases of liver abscess over an eight year period and evaluated their prognosis, any associated underlying disease, or the effect of percutaneous transhepatic abscess drainage (PTAD). For all 75 cases, laboratory data were analyzed and imaging studies were performed. Next, PTAD and antibiotic administration were started on these cases as first choice treatments. These treatments were continued until the laboratory data of the patient were restored to within the normal range. Those cases that were PTAD non-effective or required operation for underlying diseases, underwent operations. Of the total 75 cases, 63 survived after treatment and 12 cases died. Bacteria were detected in 50 cases and Klebsiella pneumoniae was detected in 31 of these 50 cases, but 25 out of 75 cases were negative. The biliary system was the main route of infection. PTAD was effective, especially in cases that were complicated with disseminated intravascular coagulation (DIC) or acute renal failure (ARF). PTAD is an effective treatment for liver abscess, it is especially useful in the restoration of severe general conditions as indicated by this study.

Infection with Hepatitis B virus (HBV) genotype C predominates in Japan. We analyzed the efficacy of interferon (IFN) alpha or beta in the treatment of chronic hepatitis B patients with HBV genotype C and the clinical predictors for therapeutic response. Forty-three genotype C-infected, chronic hepatitis B e antigen (HBeAg)-positive patients (32 men and 11 women with a mean age of 35.6+/-10.1 years) who had been treated with IFN therapy were retrospectively studied. The patients were classified into two treatment groups. Short-term therapy group was administered a 5-6 MU dose three times weekly for 4 weeks, and the long-term therapy group for 24 weeks. At the end of the follow-up period, 4 (15%) of 27 short-term therapy group patients and 6 (38%) of 16 long-term therapy group patients had normalized serum ALT levels and seroconversion of HBeAg to anti-HBe (p=0.137). Multivariate analysis for parameters most important for the efficacy of IFN therapy was performed using Cox proportional hazard models in order to investigate the association between baseline characteristics of patients and the response to IFN treatment. As a result, the p-values of IFN treatment group and sex were

Infection with Hepatitis B virus (HBV) genotype C predominates in Japan. We analyzed the efficacy of interferon (IFN) alpha or beta in the treatment of chronic hepatitis B patients with HBV genotype C and the clinical predictors for therapeutic response. Forty-three genotype C-infected, chronic hepatitis B e antigen (HBeAg)-positive patients (32 men and 11 women with a mean age of 35.6+/-10.1 years) who had been treated with IFN therapy were retrospectively studied. The patients were classified into two treatment groups. Short-term therapy group was administered a 5-6 MU dose three times weekly for 4 weeks, and the long-term therapy group for 24 weeks. At the end of the follow-up period, 4 (15%) of 27 short-term therapy group patients and 6 (38%) of 16 long-term therapy group patients had normalized serum ALT levels and seroconversion of HBeAg to anti-HBe (p=0.137). Multivariate analysis for parameters most important for the efficacy of IFN therapy was performed using Cox proportional hazard models in order to investigate the association between baseline characteristics of patients and the response to IFN treatment. As a result, the p-values of IFN treatment group and sex were0.05, and both factors can be recognized as independent significant factors (relative risk, 2.93 and 2.53; p=0.027 and 0.040, respectively). Furthermore, the cumulative rates of seroconversion of HBeAg to anti-HBe analyzed by the Kaplan-Meier method was significantly higher in the female group (p=0.015) and in the long-term IFN therapy group (p=0.0046). In summary, long-term IFN therapy may be more effective than short-term IFN therapy for patients with chronic HBV genotype C infection.

Histone deacetylase inhibitor (HDAI) induces accumulation of highly acetylated histones by inhibiting the activity of histone deacetylase and inhibits cell proliferation, induces differentiation, and promotes apoptosis. TNF-related apoptosis inducing ligand (TRAIL) induces apoptosis in various human cancer cells, a promising observation because it raises the possibility of a death ligand selectively for tumor cells. However, resistance to TRAIL-induced apoptosis was seen in colonic adenocarcinoma cell lines. So we investigated whether human colonic adenocarcinoma cell lines can be sensitized to TRAIL-induced apoptosis by the addition of HDAI. We investigated sensitivity to histone deacetylase inhibitor in colonic adenocarcinoma cell lines using the MTT assay. Cell viability decreased with sodium butyrate (SB) and trichostatinA (TSA) in a dose-dependent manner in LS 180 and HT-29 cells. Nuclear condensation and fragmentation were observed by DAPI staining after 24 h stimulation with SB or TSA in LS 180 cells. We also investigated the combination of HDAI and TNF family members (TRAIL, anti-Fas antibody or TNFalpha) in colonic adenocarcinoma cell lines. HDAI augmented TNF family-related apoptosis in LS 180 cells and HT-29 cells. HDAI sensitizes human colonic adenocarcinoma cell lines to TRAIL-mediated apoptosis. HDAI may be useful as an adjuvant agent for TRAIL in the treatment of human colonic adenocarcinomas that are resistant to TRAIL.

Serum concentration levels of des-gamma-carboxy prothrombin (DCP), alpha-fetoprotein (AFP) and Lens culinaris agglutinin-reactive fraction (AFP-L3) are useful tumor markers for the diagnosis of hepatocellular carcinoma (HCC). Recently, a novel immunoassay using the electrochemiluminescence (ECLIA) was developed to enable measurement of low-concentration of DCP. This study investigated the usefulness of high-sensitive DCP for the early diagnosis of HCC. The subjects consisted of 90 patients with viral cirrhosis who could be followed for at least 24 months from 1992 to 1997. Fifty-six of these patients developed HCC and 34 patients had not by 1998. We measured the serum levels of high-sensitive DCP, AFP and %AFP-L3 every 3 months during 2 years before the detection of tumor in patients with HCC and during 2 years from 1995 to 97 in patients without HCC. Youden's index was calculated for evaluation of the ideal cut-off levels. The patterns of serial changes during 2 years were divided into two types: fluctuating type and non-fluctuating type. Cut-off levels of 40 mAU/ml for high-sensitive DCP (Youden's index = 0.435), 20 ng/ml for AFP (Youden's index = 0.442) and 10% for %AFP-L3 (Youden's index = 0.364) gave the highest index for each marker. When these markers were combined, the combination of high-sensitive DCP, AFP and %AFP-L3 gave the highest accuracy (sensitivity = 82.1%, specificity = 82.4%, accuracy = 82.2%). Fluctuating type of high-sensitive DCP, AFP and %AFP-L3 levels were found in 15 (17%), 29 (32%) and 11 (12%) patients, respectively. The rate of complication with HCC in the patients who showed the fluctuating type of high-sensitive DCP levels was significantly greater than that in the patients who showed non-fluctuating type (P

Serum concentration levels of des-gamma-carboxy prothrombin (DCP), alpha-fetoprotein (AFP) and Lens culinaris agglutinin-reactive fraction (AFP-L3) are useful tumor markers for the diagnosis of hepatocellular carcinoma (HCC). Recently, a novel immunoassay using the electrochemiluminescence (ECLIA) was developed to enable measurement of low-concentration of DCP. This study investigated the usefulness of high-sensitive DCP for the early diagnosis of HCC. The subjects consisted of 90 patients with viral cirrhosis who could be followed for at least 24 months from 1992 to 1997. Fifty-six of these patients developed HCC and 34 patients had not by 1998. We measured the serum levels of high-sensitive DCP, AFP and %AFP-L3 every 3 months during 2 years before the detection of tumor in patients with HCC and during 2 years from 1995 to 97 in patients without HCC. Youden's index was calculated for evaluation of the ideal cut-off levels. The patterns of serial changes during 2 years were divided into two types: fluctuating type and non-fluctuating type. Cut-off levels of 40 mAU/ml for high-sensitive DCP (Youden's index = 0.435), 20 ng/ml for AFP (Youden's index = 0.442) and 10% for %AFP-L3 (Youden's index = 0.364) gave the highest index for each marker. When these markers were combined, the combination of high-sensitive DCP, AFP and %AFP-L3 gave the highest accuracy (sensitivity = 82.1%, specificity = 82.4%, accuracy = 82.2%). Fluctuating type of high-sensitive DCP, AFP and %AFP-L3 levels were found in 15 (17%), 29 (32%) and 11 (12%) patients, respectively. The rate of complication with HCC in the patients who showed the fluctuating type of high-sensitive DCP levels was significantly greater than that in the patients who showed non-fluctuating type (P0.01). These results suggest that periodic measurement of serum DCP levels using ECLIA method is very useful for HCC screening and predicting the development of HCC.