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Biomedical subjects

Keisuke Hamasaki

Publications and source records attributed to Keisuke Hamasaki.

At least 19 recordsLinked to original sources
PubMed2006

Association between liver fibrosis and insulin sensitivity in chronic hepatitis C patients.

BACKGROUND: Several clinical studies have suggested a possible link between chronic hepatitis caused by hepatitis C virus (HCV) and the development of diabetes mellitus. We investigated the association between liver fibrosis and glucose intolerance in HCV-infected patients by measuring insulin sensitivity and beta-cell function. METHOD: A total of 83 chronic HCV-infected patients were recruited into this study. We evaluated insulin sensitivity and beta-cell function of all patients in a fasting state (homeostasis model assessment of insulin resistance [HOMA-R] and homeostasis model assessment of beta-cell function [HOMA-beta]) and after an oral load of 75 g glucose (whole-body insulin sensitivity index [WBISI] and Delta-insulin/Delta-glucose 30). RESULTS: In a multivariate analysis, severe fibrosis was the only independent factor associated with insulin resistance. There were significant differences in both HOMA-R (P= 0.0063) and WBISI (P= 0.0159) between patients with mild fibrosis (N = 34) and those with severe fibrosis (N = 49). Although HOMA-beta was increased significantly in the subjects with severe fibrosis compared with those with mild fibrosis (P= 0.0169), Delta-insulin/Delta-glucose 30 showed no significant difference in stage of liver fibrosis, suggesting an uncertain association between liver fibrosis and beta-cell function. CONCLUSION: Our findings suggest that the development of liver fibrosis is associated with insulin resistance in HCV-infected patients.

Blood Glucose↗
PubMed2006

The impact of newer treatment modalities on survival in patients with hepatocellular carcinoma.

BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide. However, although the therapeutic approaches for HCC have progressed rapidly, it remains unknown whether the current management of patients with HCC has reduced its mortality. We analyzed changes of survival rate in patients with HCC over a 20-year period. METHODS: Between 1982 and 2001, 463 patients were diagnosed with HCC at our hospital. Subjects were enrolled in the current cohort according to the following inclusion criteria: HCC lesion measuring less than 3 cm in diameter, no evidence of extrahepatic metastasis, and no evidence of main portal vein infiltration/thrombosis. A total of 257 patients with HCC were recruited for this study, and categorized into 5-year intervals. RESULTS: The survival rates improved significantly during the study period. When the patients were stratified according to Child-Pugh score, only patients with Child's B showed improved survival rates. Furthermore, patients with surgical resection or transarterial chemoembolization during the latter period had a better prognosis than those during the early period. CONCLUSIONS: Our findings suggest that the development of therapeutic interventions for HCC have led to improvements in the prognosis for HCC patients.

Aged↗
PubMed2006

Increasing hepatitis C virus-associated hepatocellular carcinoma mortality and aging: Long term trends in Japan.

BACKGROUND: The incidence of hepatocellular carcinoma (HCC) in Japan has been increasing. The aim of the study was to determine the epidemiological trends in HCC mortality in Japan. METHODS: We reviewed the medical records of all patients whose death was caused by liver disease between 1981 and 2000 at two hospitals. The courses of death were separated based on presence or absence of HCC when death ensued. Additionally, cohorts of patients with HCC were analyzed in 5-year time periods. RESULTS: The number of deaths from hepatitis C virus (HCV)-associated HCC steadily increased 2.6 times from 49 to 128 during observation period. The mean age at death from HCV-associated HCC from 1996 to 2000 was significantly higher than that in the period from 1981 to 1985 (p<0.0001). INTERPRETATION: Deaths from HCV-associated HCC increased from 1981 to 2000, consistent with the aging of the population in Japan.

Journal Article↗
PubMed2006

Different mechanisms for anti-tumor effects of low- and high-dose cyclophosphamide.

It is known that, besides its direct cytotoxic effect as an alkylating chemotherapeutic agent, cyclophosphamide also has immuno-modulatory effects, such as depletion of CD4+CD25+ regulatory T cells. However, its optimal concentration has not yet been fully elucidated. Therefore, we first compared the effects of different doses of cyclophosphamide on T cell subsets including CD4+CD25+ T cells in mice. Cyclophosphamide (20 mg/kg) decreased the numbers of splenocytes, CD4+ and CD8+ T cells by approximately 50%, while a decline in CD4+CD25+ T cell number was more profound, leading to the remarkably lower ratios of CD4+CD25+ T cells to CD4+ T cells. In contrast, 200 mg/kg cyclophosphamide severely decreased the numbers of all the T cell subsets by > 90% although the decreased ratios of CD4+CD25+ T cells to CD4+ T cells were still observed. Next, low-dose cyclophosphamide significantly inhibited in vivo growth of murine hepatoma MH129 tumor in immuno-competent but not immuno-deficient mice. This anti-tumor effect was abolished by CD4+CD25+ T cell repletion. In contrast, high-dose cyclophosphamide exhibited similar anti-tumor effects in both mice. In addition, contrary to antibody-mediated CD4+CD25+ T cell depletion, administration of low-dose cyclophosphamide after tumor inoculation was more efficacious than the prior administration. Our data show that low-dose cyclophosphamide selectively depletes CD4+CD25+ T cells, leading to enhanced anti-tumor effects against pre-existing tumors, while the anti-tumor effect of high-dose cyclophosphamide is solely attributed to its direct cytotoxicity. These findings appear to be highly crucial in a clinical setting of combined chemotherapy and immunotherapy for cancer treatment.

Animals↗
PubMed2006

Survivin downregulation by siRNA sensitizes human hepatoma cells to TRAIL-induced apoptosis.

Survivin, an anti-apoptotic protein, is abundantly expressed in a variety of cancer cells, including hepatoma cells, resulting in the resistance of these cells to various apoptotic stimuli. Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is known to induce cancer cell-specific apoptosis, but hepatoma cells are resistant to TRAIL-induced apoptosis. In the present study, we have examined whether the downregulation of survivin by short interfering RNA (siRNA) promotes spontaneous or TRAIL-induced apoptosis in Huh-7 human hepatoma cells. Survivin siRNA transfection downregulated the expression of survivin in Huh-7 cells and reduced cell viability by 20% through inducing spontaneous apoptosis. TRAIL (1 to 2 ng/ml) only slightly induced apoptosis in Huh-7 cells; however, survivin siRNA transfection apparently enhanced TRAIL-induced apoptosis. These results suggest that the level of survivin is linked to the susceptibility of Huh-7 cells to TRAIL. It is possible that survivin downregulation by siRNA combined with TRAIL administration may provide a new therapeutic strategy against hepatoma.

Apoptosis↗
PubMed2006

DHMEQ, a novel NF-kappaB inhibitor, induces apoptosis and cell-cycle arrest in human hepatoma cells.

Several reports have indicated that nuclear factor-kappaB (NF-kappaB) is constitutively activated in a variety of cancer cells including hepatoma cells and plays a key role in their growth and survival. Dehydroxymethylepoxyquinomicin (DHMEQ) derived from the structure of an antibiotic epoxyquinomicin C is a novel NF-kappaB inhibitor. In the present study, we evaluated the effect of DHMEQ on the NF-kappaB activity in human hepatoma cells, Huh-7, HepG2 and Hep3B, and the anti-tumor effect of DHMEQ on these cells in vitro and in vivo. DHMEQ inhibited the steady-state transcriptional activity of NF-kappaB in all hepatoma cells. DHMEQ blocked the constitutive DNA-binding activity and TNF-alpha-mediated nuclear translocation of NF-kappaB in Huh-7 cells. DHMEQ (5-20 microg/ml) dose-dependently reduced the viable cell number of all hepatoma cells. DHMEQ (20 microg/ml) induced apoptosis in all hepatoma cells, especially in Hep3B cells, and cell-cycle arrest in Huh-7 and HepG2 cells. These effects were accompanied by downregulation of proteins involved in anti-apoptosis (Bcl-xL, XIAP or c-IAP2) and cell-cycle progression (cyclin D1), and induction of proteins involved in pro-apoptosis (Bax) and cell-cycle retardation (p21Waf1/Cip1), although the degree of changes by DHMEQ was different in each hepatoma cell type. Moreover, intraperitoneal administration of DHMEQ (8 mg/kg) significantly repressed the growth of Huh-7 tumor subcutaneously transplanted into BALB/c nu/nu athymic mice. Our results suggest that DHMEQ could qualify as a candidate for a new chemotherapeutic agent against human hepatoma.

Animals↗
PubMed2006

Aging of patients with hepatitis C virus-associated hepatocellular carcinoma: long-term trends in Japan.

The incidence of hepatocellular carcinoma (HCC) in Japan has been increasing. The aim of the present study was to analyze epidemiological changes in Japanese HCC patients. A total of 463 patients with HCC diagnosed at our hospital between 1982 and 2001 were recruited for this study. Cohorts of patients with HCC were categorized into intervals of five years. The number of HBV- and HCV-associated HCC cases had decreased and increased in 1987-1991, respectively, and thereafter reached a plateau. The mean age of patients at diagnosis of HCV-associated HCC showed a steady significant increase from 60 to 68 years of age during the period, suggesting that these findings were associated with a shift toward an older-age group that had the highest rate of HCV infection. The mean age of patients with other types of HCC did not significantly change during the period. Since it is known that the prevalence of HCV infection in young Japanese persons is low and that the incidence of HCV infection is very low at present, our findings may indicate that the prevalence of HCC will decline in Japan, an advanced country with regard to HCV-associated HCC, in the near future.

Aged↗
PubMed2005

An autopsy case of acute pancreatitis with a high serum IgG4 complicated by amyloidosis and rheumatoid arthritis.

We report an autopsy case of acute pancreatitis with a high serum IgG4 concentration complicated by systemic amyloid A amyloidosis and rheumatoid arthritis (RA). The patient was a 42-year-old Japanese female with a 22-year history of rheumatoid arthritis. She was diagnosed with myasthenia gravis when she was 31-year old. At the onset of pancreatitis, the patient was anti-nuclear antibody-positive, and had high serum gamma globulin and IgG4 levels. Dexamethasone and conventional therapy induced clinical remission and significantly decreased the serum IgG4 and gamma globulin. However, despite the decreased disease parameters, the patient developed a bleeding pseudocyst and died of cardiac failure. In the autopsy examination, it was determined that pancreatitis was probably caused by ischemia due to vascular obstruction caused by amyloid deposition in the pancreas. Even though acute pancreatitis is a rare complication in RA patients, we speculate that an autoimmune pancreatitis-related mechanism and ischemia due to vascular obstruction by amyloid deposition might be attributable to a single source that leads to acute pancreatitis in our particular case.

Acute Disease↗
PubMed2005

Vaccination with dendritic cells pulsed with apoptotic cells elicits effective antitumor immunity in murine hepatoma models.

Dendritic cell (DC)-based vaccine is a developing strategy to treat cancer including hepatoma. We evaluated the antitumor efficacy of vaccination with DCs pulsed with apoptotic cells, as compared to vaccination with DCs pulsed with cell lysates, in murine hepatoma models. Murine hepatoma cells, Hepa1-6, MH134 and BNL1ME.A.7R.1, and their syngeneic mice, C57BL/6, C3H/HeN and BALB/c, respectively, were used in the study. Protective and therapeutic antitumor effects of vaccination with bone marrow-derived DCs pulsed with irradiation or sulindac-induced apoptotic cells or cell lysates were analyzed. Immature DCs efficiently phagocytosed apoptotic cells and increased expression of CD86, a cell surface maturation marker. Vaccination with apoptotic cell-pulsed, but not cell lysate-pulsed, DCs promoted significant protective immunity against parental hepatoma in vivo. Spleen cells from mice vaccinated with apoptotic cell-pulsed DCs showed higher cytolytic activity and contained higher number of IFN-gamma producing cells against parental hepatoma cells than those from mice vaccinated with cell lysate-pulsed DCs in vitro. Polyriboinosinic polyribocytidylic acid [poly (I:C)], double strand RNA, further enhanced CD86 expression and the therapeutic efficacy of vaccination with DCs pulsed with apoptotic cells for pre-established hepatoma. These results suggest that vaccination with DCs pulsed with apoptotic cells and treated with poly (I:C) appears to be a promising approach as a new therapeutic means for hepatoma.

Animals↗
PubMed2005

Clinical benefits of hepatocellular carcinoma surveillance: a single-center, hospital-based study.

Although there is no definitive evidence that hepatocellular carcinoma (HCC) screening in high-risk groups improves survival, many physicians screen high-risk populations with various tools such as alpha-fetoprotein (AFP) and ultrasonography (USG). The aim of this study was to clarify clinical differences between HCC patients diagnosed by surveillance and those with incidentally detected HCC. Two hundred and seventy-one Japanese patients with HCC diagnosed between January 1991 and December 2001 were recruited. They were categorized into two groups: 178 patients (group 1) had subclinical HCC diagnosed by surveillance and 93 patients (group 2) presented with incidentally detected HCC. The tumor size was significantly smaller in group 1 compared to that of group 2 (2.8 vs. 5.6 cm; P<0.0001). A significantly higher proportion of patients in group 2 had multiple HCC and portal vein infiltration when compared to group 1. Eighty-six (48.3%) group 1 patients and 16 (17.2%) group 2 patients underwent local ablation treatment, which is a curative treatment available for small HCCs (P<0.0001). The cumulative actuarial survival rate was significantly higher in group 1 than in group 2 (P=0.0091). Early detection of HCC by surveillance may contribute to a greater chance of receiving effective treatment and prolonged survival, although a further prospective, randomized study is needed.

Adult↗
PubMed2004

Cytokine gene polymorphisms in Japanese patients with hepatitis B virus infection--association between TGF-beta1 polymorphisms and hepatocellular carcinoma.

BACKGROUND/AIMS: In this study, we determined the frequencies of the genotypes associated with the polymorphism of the cytokines genes, and investigated their association with the risk of hepatocellular carcinoma (HCC) in hepatitis B virus (HBV) carriers. METHODS: Genetic polymorphism in the cytokines TNF-alpha, IFN-gamma, TGF-beta1, IL-6, and IL-10 were studied in 236 Japanese patients with HBV infection. The genetic polymorphisms of these cytokines were analyzed by polymerase chain reaction-sequence-specific primer (SSP). RESULTS: There was no statistically significant difference in the genetic polymorphisms of TNF-alpha, IFN-gamma, and IL-10 genes between HBV carriers with HCC and those without HCC. However, the TGF-beta1+29 (codon 10) C/C genotype was lower in HBV carriers with HCC than in those without HCC (HCC 14.6% vs non-HCC 31.9%). The association of HCC was significantly lower in HBV carriers with C/C genotype than in those with T/C or T/T genotype in position +29 of the TGF-beta1 gene. CONCLUSIONS: Our findings suggest that the genetic polymorphism in codon 10 of the TGF-beta1 gene may play a role in HCC development in patients with chronic HBV infection.

Adult↗
PubMed2004

Antiangiogenic property of pigment epithelium-derived factor in hepatocellular carcinoma.

Pigment epithelium-derived factor (PEDF) is one of the most powerful endogenous antiangiogenic reagents discovered to date. Its antiangiogenic potential in neoplastic disease remains unclear. In this study, we investigated antiangiogenic property of PEDF in hepatocellular carcinoma (HCC), a typical hypervascular tumor. In HCC cell lines, constitutive messenger RNA and protein expression of PEDF varied. Genomic DNA encoding the PEDF gene was the same in the cell lines examined by Southern blotting. In chemically induced hypoxic conditions, secreted PEDF protein was suppressed in contrast to elevation of vascular endothelial growth factor protein. When PEDF was overexpressed by gene transfer, proliferation and migration of endothelial cells were inhibited in conditioned media derived from all HCC cell lines. However, the serum concentration of PEDF, as measured by enzyme-linked immunosorbent assay, was decreased in patients with cirrhosis or HCC complicated by cirrhosis compared to healthy volunteers and patients with chronic hepatitis. According to the endothelial cell proliferation assay, the serum PEDF of patients with HCC had antiangiogenic activity. Moreover, intratumoral injection of a PEDF-expressing plasmid in athymic mouse models caused significant inhibition of preestablished tumor growth. In conclusion, PEDF plays a role in the angiogenic properties of HCC. Reduction of serum PEDF concentration associated with the development of chronic liver diseases may contribute to the progression of HCC. In addition, gene therapy using PEDF may provide an efficient treatment for HCC.

Animals↗
PubMed2004

High viral load is a risk factor for hepatocellular carcinoma in patients with chronic hepatitis B virus infection.

BACKGROUND AND AIMS: Hepatitis B virus (HBV) is considered a major risk factor for the progression to liver cirrhosis and hepatocellular carcinoma (HCC). The serum level of HBV-DNA is correlated with progression of the disease. The aim of the present study was to determine the relationship between the level of HBV-DNA and hepatocarcinogenesis in patients with chronic HBV infection. METHODS: The authors studied 73 patients who were diagnosed with chronic HBV infection at Nagasaki University Hospital (Nagasaki, Japan) between January 1980 and December 1999. The significance of age, sex, habitual drinking, serum alanine aminotransferase level, HBV viral load, interferon treatment, hepatic fibrosis and hepatic inflammation on the development of HCC were examined using univariate and multivariate analyses. RESULTS: The cumulative incidence rates of HCC were 14%, 29% and 48% at 5, 10 and 15 years after liver biopsy, respectively. Multivariate analysis identified high viral load, together with age and severe fibrosis, as independent and significant risk factors (P = 0.045, 0.047 and 0.013, respectively) for HCC. CONCLUSIONS: The present findings indicate that high viral load is a risk factor for HCC in patients with chronic HBV infection. Patients with a high HBV viral load should be carefully monitored for HCC.

Adolescent↗
PubMed2004

Nonalcoholic steatohepatitis with improved hepatic fibrosis after weight reduction.

A 65-year-old woman was admitted to our hospital for an investigation of liver dysfunction. She had mild obesity with hyperlipidemia, but no history of alcohol abuse. Other known causes of liver dysfunction, such as viruses, autoimmunity and drug effects, were excluded. The liver histology was consistent with nonalcoholic steatohepatitis (NASH). After diagnosis of NASH, the patient started diet and exercise therapy and, in parallel with weight reduction, her liver function improved. One year after the therapy, a liver biopsy showed that steatosis, necroinflammation and even fibrosis were improved. Hence, here we report a case of NASH in which weight reduction was effective in improving both biochemical and histological findings.

Aged↗
PubMed2004

Diverse efficacy of vaccination therapy using the alpha-fetoprotein gene against mouse hepatocellular carcinoma.

Antitumor vaccination therapy approaches using naked plasmid DNA or recombinant viruses encoding tumor-associated antigens are currently in development. In the present study, we examined the therapeutic efficacy of vaccination using the mouse alpha-fetoprotein (AFP) gene in mouse hepatocellular carcinoma (HCC) cells. C57L/J or C3H/HeN mice were primed with an injection of naked plasmid DNA expressing mouse AFP followed by a booster of replication-defective adenovirus expressing mouse AFP (plasmid-AFP prime/adenovirus-AFP booster vaccination). The mice were then challenged with high AFP-producing Hepa1-6 cells or low AFP-producing MH134 cells, respectively, and the tumor growth rate was monitored. Plasmid-AFP prime/adenovirus-AFP booster vaccination promoted protective immunity against Hepa1-6 cells, and significantly increased the number of interferon-gamma-producing splenic cells in C57L/J mice. In addition, this vaccination protocol repressed the growth of pre-established Hepa1-6 tumors in C57L/J mice. However, plasmid-AFP prime/adenovirus-AFP booster vaccination did not induce protective immunity against MH134 cells in C3H/HeN mice. These results suggest that vaccination with the AFP gene is a promising strategy to treat HCC, but its outcome may be affected by the level of AFP expression in HCC or by the immunological response of the host.

Adenoviridae↗
PubMed2003

Interferon alpha inhibits the nuclear factor kappa B activation triggered by X gene product of hepatitis B virus in human hepatoma cells.

X gene product of hepatitis B virus (HBV) (HBx) regulates many transcription factors including nuclear factor kappa B (NF-kappaB) and plays a key role in hepatocarcinogenesis. In this study, we demonstrated that the expression of full HBV genome and HBx gene similarly stimulated the transcriptional activity of NF-kappaB in HuH-7 human hepatoma cells, and that interferon (IFN)-alpha as well as dominant negative mutant of IkappaB kinase-alpha effectively inhibited the HBx-mediated NF-kappaB activation, but IFN-gamma did not. These results suggest that IFN-alpha may have a function to block the NF-kappaB activating pathway triggered by HBx in HBV hepatocytes.

Carcinoma, Hepatocellular↗
PubMed2003

Analysis of anti-HBs levels in healthcare workers over 10 years following booster vaccination for hepatitis B virus.

In this study, we analyzed anti-HBs levels in 104 Japanese healthcare workers who received three booster HBV surface antigen (HBsAg) vaccines because 80 became anti-HBs-negative at a mean of 2.4 years after the primary vaccination and 24 did not respond to primary vaccination. Of the re-vaccinees, 96% achieved a level of 10 mIU/ml or more of anti-HBs (i.e. seroprotected), 1 month after booster vaccination. Although anti-HBs levels of re-vaccinees decreased as rapidly as those of primary immunized vaccinees, at 10 years post-booster, 64% of re-vaccinees maintained anti-HBs levels at 10 mIU/ml or higher. Our results suggest that the additional three-dose protocol of booster HBsAg vaccination is beneficial in maintaining a seroprotective level of anti-HBs until new immunogenic vaccination protocols are established.

Adult↗