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Biomedical subjects

Norio Hayashi

Publications and source records attributed to Norio Hayashi.

At least 55 records · Page 3Linked to original sources
PubMed2004

Characteristics of patients with chronic hepatitis C who develop hepatocellular carcinoma after a sustained response to interferon therapy.

BACKGROUND: The objective of the current study was to determine the characteristic features of sustained responders who develop hepatocellular carcinoma after treatment with interferon for chronic hepatitis C. METHODS: This study included 3626 patients with chronic hepatitis C who had received interferon monotherapy. Cox proportional hazards analysis was used to compare sustained responders who did and did not develop hepatocellular carcinoma, and nonsustained responders who developed hepatocellular carcinoma in a multicenter, retrospective cohort study. RESULTS: Among 1197 sustained responders, 27 patients developed hepatocellular carcinoma (2.3%). Compared with sustained responders who did not develop hepatocellular carcinoma, patients who developed disease more often were male (P = 0.0212), were older (P = 0.0068), and had advanced-stage histologic disease before interferon therapy (P = 0.0345). Conversely, compared with patients with hepatocellular carcinoma who were not sustained responders, patients who were sustained responders tended to be older at the time of the initiation of interferon therapy (P = 0.0552) and at the time hepatocellular carcinoma was detected (P = 0.0593), and they also were predominantly male (P = 0.0507). The histologic staging and serum aminotransferase levels at the initiation of interferon therapy, the interval to the detection of tumor, and the tumor size showed no significant differences between the two groups. CONCLUSIONS: Sustained responders in the group at high risk for developing hepatocellular carcinoma after interferon therapy were older, more often were male, and had more advanced histologic disease stage. Such patients should be followed carefully periodically for > 10 years after they complete interferon therapy.

Age Factors↗
PubMed2004

Involvement of p38 signaling pathway in interferon-alpha-mediated antiviral activity toward hepatitis C virus.

We studied the involvement of the p38 signaling pathway in the interferon (IFN)-alpha-mediated antiviral activity toward hepatitis C virus (HCV) using HCV subgenomic replicon cells. When the cells were treated with IFN-alpha in the presence of p38 inhibitor, the suppressive effect of IFN-alpha on replicon RNA was reduced. Inhibition of p38 had almost no influence on phosphorylation of signal transducer and activator transcription factor 1 (STAT1) and interferon stimulatory response element-dependent gene expression after IFN-alpha treatment. This indicates that the anti-HCV activity through p38 may be independent of the Janus kinase-STAT pathway. Treatment with the inhibitor of the mitogen-activated protein kinase-activated protein kinase 2 (MK2) showed the same level of reduction in the IFN-alpha-mediated anti-HCV activity as that with the p38 inhibitor. Thus, MK2 may also be responsible for the anti-HCV activity through p38. In conclusion, the p38-MK2 signaling pathway may be substantially involved in the IFN-alpha-mediated anti-HCV activity.

Antiviral Agents↗
PubMed2004

Pseudotype hepatitis C virus enters immature myeloid dendritic cells through the interaction with lectin.

Dendritic cells (DC) are the most potent antigen-presenting cells that regulate immune responses. One of the mechanisms for hepatitis C virus (HCV) persistence is the ability of HCV to suppress DC function. Direct HCV infection to blood DC has been implicated for DC dysfunction. To clarify the susceptibility of each DC subset to HCV, we used pseudotype vesicular stomatitis virus (VSV) coated with chimeric HCV envelope glycoproteins (E1 and E2). We demonstrate that pseudotype VSV enters myeloid DC (MDC) but not plasmacytoid DC (PDC). The highest efficiency of pseudotype VSV entry to MDC was observed when MDC were cultured with GM-CSF. Such efficiency decreased when MDC are matured with the treatment of IL-4, CpG oligodeoxynucleotide, or CD40 ligand. Mannan inhibited pseudotype VSV entry to MDC, but Ca(2+) chelators failed to do so. These results show that pseudotype VSV possessing HCV-E1 and E2 enters immature MDC through the interaction with lectins in a Ca(2+)-independent manner.

Cells, Cultured↗
PubMed2004

Hepatitis C virus core functions as a suppressor of cyclin-dependent kinase-activating kinase and impairs cell cycle progression.

We investigated how the hepatitis C virus (HCV) core protein affects the cell cycle profile and cell cycle-related molecules by using the HCV core-expressing stable transfectant. Analysis of the cell cycle profile showed that HCV core impaired G(1) to S transition. The E2F-mediated transcription, phosphorylation of the retinoblastoma protein, and cyclin-dependent kinase (CDK) 4 and CDK2 activities were suppressed in HCV core-expressing cells. The expression levels of G(1) phase-related CDKs/cyclins and various CDK inhibitors were not substantially affected by expression of HCV core. When influences of HCV core on CDK-activating kinase (CAK) were examined, the expression levels of the CAK components, CDK7, cyclin H, and MAT1, were not affected. However, formation of the ternary CAK complex, CAK activity, and the CDK2 level with activating phosphorylation were inhibited by expression of the HCV core. The direct effect of HCV core on CAK was further assessed in the cell-free system by adding the in vitro translated HCV core protein to the anti-CDK7 immunoprecipitate from the cell. The results showed that HCV core led to dissociation of MAT1 from the CAK complex and suppressed the CAK activity. Furthermore, the binding assay revealed that the HCV core was directed against CDK7. Their interaction occurred mainly in the nucleus by the immunostaining. In conclusion, the HCV core protein interacts with CAK and functions as an extrinsic suppressor of CAK. This may be the molecular basis of HCV core-mediated suppression of cell cycle progression. Our findings suggest a novel mechanism concerning HCV core-mediated alteration in the cell cycle machinery.

Animals↗
PubMed2004

Concanavalin a injection activates intrahepatic innate immune cells to provoke an antitumor effect in murine liver.

Concanavalin A (ConA), directly injected into mice, induces T cell-mediated liver injury. However, it remains unclear whether ConA injection can activate innate immune cells, including natural killer (NK) cells and natural killer T (NKT) cells, both of which exist abundantly in the liver. Here we report that ConA injection stimulated interferon (IFN)-gamma production from liver NKT cells as early as 2 hours after injection and augmented YAC-1 cytotoxicity of liver NK cells. ConA-induced NK cell activation required other types of immune cells and critically depended on IFN-gamma. Because a nonhepatotoxic low dose of ConA was capable of fully activating both NKT cells and NK cells, we next addressed the possibility of ConA injection displaying an antitumor effect in the liver without liver injury. A nonhepatotoxic low-dose ConA injection augmented the cytotoxicity of liver NK cells against Colon-26 colon cancer cells and suppressed hepatic metastasis of Colon-26 cells in a NK cell- and IFN-gamma-dependent manner. In conclusion, a nonhepatotoxic low dose of ConA might serve as an immunomodulator that can preferentially activate the innate immune cells to induce an antitumor effect against metastatic liver tumor.

Animals↗
PubMed2004

Interferon therapy for aged patients with chronic hepatitis C: improved survival in patients exhibiting a biochemical response.

BACKGROUND: In Japan, generally, patients with chronic hepatitis C are aged. The aim of this study was to investigate the effect of interferon (IFN) therapy on the mortality of chronic hepatitis C patients over age 60. METHODS: Seven-hundred and seven patients with histologically proven chronic hepatitis C were enrolled in this study; 649 received IFN therapy (IFN group) and 58 did not (control group). The standardized mortality ratio (SMR) and Cox proportional hazard regression analysis were used to evaluate the effect of IFN on the survival of the patients. RESULTS: Mean follow-up periods in the IFN and control groups were 5.7 and 6.7 years, respectively. During follow-up, 13 patients in the control group died (7 of liver-related diseases) and 42 in the IFN group died (29 of liver-related diseases). The SMRs of the control and IFN groups were 1.40 (95% confidence interval [CI], 0.76-2.45) and 0.73 (95% CI, 0.52-0.98) for overall death, and 10.70 (95% CI, 4.29-22.05) and 5.05 (95% CI, 3.38-7.26) for liver-related death, respectively. Sustained and transient biochemical responders in the IFN group (SMR, 0.53; 95% CI, 0.01-2.97 and SMR, 3.25; 95% CI, 0.87-8.32, respectively) showed lower liver-related mortality compared with the control group. In patients with sustained virological response, liver-related mortality was also very low (SMR, 0.65; 95% CI, 0.01-3.61). The risk for liver-related death of sustained and transient biochemical responders was also low compared with that of the control group (adjusted risk ratios 0.10 [95% CI, 0.01-0.95] and 0.50 [95% CI, 0.11-2.21], respectively). CONCLUSIONS: These results suggest that IFN treatment could reduce liver-related mortality in chronic hepatitis C patients over age 60, notably in patients showing a biochemical response and in those showing a sustained virological response.

Aged↗
PubMed2004

Vogt-Koyanagi-Harada disease occurring during interferon alpha therapy for chronic hepatitis C.

Retinal abnormalities, including retinal hemorrhage and "cotton-wool" spots, often occur within the first 8 weeks in the course of interferon therapy in patients with chronic hepatitis C. Here, we describe a case of Vogt-Koyanagi-Harada disease occurring 4 months after the start of interferon alpha treatment, probably induced by the immunomodulatory effects of interferon. Therefore, we conclude that chronic hepatitis C patients, especially people with darkly pigmented skin, need to be closely monitored for ophthalmologic complications, by periodic check-up of the optic fundi, for a prolonged period, during interferon treatment.

Adult↗
PubMed2004

The significance of interferon and ribavirin combination therapy followed by interferon monotherapy for patients with chronic hepatitis C in Japan.

One hundred seventy-one patients with chronic hepatitis C were included in this study (genotype1 and high viral loads (1H), [Formula: see text]; non-1H, [Formula: see text]; N.D., [Formula: see text] ). The combination therapy of interferon and ribavirin for 24 weeks with an additional 24 weeks of interferon monotherapy (48-week treatment) was undergone by 42 1H patients and 5 non-1H patients. The combination therapy of interferon and ribavirin was administered for 24 weeks in 67 1H patients and 22 non-1H patients. Among the 1H patients, the HCV relapse rate was significantly higher in those receiving 24-week combination treatment than in those receiving 48-week treatment (78% versus 42%, [Formula: see text] ). Among the non-1H patients, no significant difference was found between them. Sustained virological response (SVR) rates were observed to decrease as the timing of HCV RNA disappearance was delayed. In spite of the small rate (16%), SVR was obtained from the patients who became negative for HCV RNA by week 24 (beyond week 12) only in those receiving 48-week treatment. In 1H patients, 24-week combination treatment followed by interferon monotherapy for 24 weeks was concluded to be the treatment offering the most hope among those that the medical insurance can be applied in Japan.

Journal Article↗
PubMed2004

Prediction of treatment outcome with daily high-dose IFN alpha-2b plus ribavirin in patients with chronic hepatitis C with genotype 1b and high HCV RNA levels: relationship of baseline viral levels and viral dynamics during and after therapy.

Data on 334 patients with HCV genotype 1b and high viral levels were extracted from two multicenter double-blind studies conducted in Japan comparing IFN alpha-2b plus ribavirin (n = 209) with IFN alpha-2b alone (n = 125) for 24 weeks. HCV RNA assay was conducted before and 4, 12, and 24 weeks after the start and 4, 12, and 24 weeks after the end of treatment. Both sustained viral response (SVR) rate and relapse rate after the end of treatment were analyzed in relation to baseline viral levels and the time of first disappearance of virus. In the combination treatment group, the percentage of patients who were HCV RNA-negative within 4 weeks decreased with increase in baseline viral levels (i.e. 42%, 15%, and 11% were HCV RNA-negative in the groups exhibiting <500, 500 to <850, and >/=850kcopies/mL, respectively). In the IFN monotherapy group, the response rates were lower at 13%, 15%, and 1%, respectively. Disappearance of virus within 12 weeks after the start of combination treatment was indicative of higher probability of SVR. The risk of relapse was more highly correlated with the timing of initial viral disappearance than with baseline HCV levels; it was 4.8 and 10.3 times higher in patients who became HCV-negative at 4-12 and 13-24 weeks compared with in those who were HCV-negative within 4 weeks.

Journal Article↗
PubMed2004

Ninjurin1 increases p21 expression and induces cellular senescence in human hepatoma cells.

BACKGROUND/AIMS: Ninjurin1 is a novel adhesion molecule that has a role in promoting nerve regeneration. Although ninjurin1 is ubiquitously expressed in various human tissues, including the liver, the biologic functions of ninjurin1 in tissues other than the nervous system remain unknown. The aim of this study was to investigate the function of ninjurin1 in hepatocytes. METHODS: The effect of ninjurin1 overexpression was examined in Huh-7 hepatoma cells. Ninjurin1 expression was examined by Western blot in human hepatocellular carcinoma tissues as well as their adjacent liver tissues. RESULTS: Ninjurin1-overexpressing clones exhibited strong growth inhibition due to G1 cell cycle arrest, which is associated with a posttranscriptional increase in p21WAF1/Cip1, a decrease of cyclin-dependent kinase 2 activity and the hypophosphorylation of Rb. The ninjurin1-overexpressing clones had increased senescence-associated beta-galactosidase activity and autofluorescent pigment, characteristic features of cellular senescence. The levels of ninjurin1 expression were higher in hepatocellular carcinoma tissues than those in adjacent liver tissues. CONCLUSIONS: The present study provides the first evidence that ninjurin1 is able to induce the senescence program. Ninjurin1 may be involved in the regulation of cellular senescence in the liver during carcinogenesis.

Carcinoma, Hepatocellular↗
PubMed2004

High prevalence of the hepatitis C virus infection among the inpatients of schizophrenia and psychoactive substance abuse in Japan.

Prevalence of anti-HCV antibody in 1193 hospitalized patients (848 males and 345 females) in psychiatric department was investigated. Overall prevalence ratio was 9.1%, indicating significantly higher than that of healthy blood donors. In the classification of ICD-10, the prevalence of the inpatients diagnosed in schizophrenia group and psychoactive substance use group accounted for 6.2% and 13.8%, respectively. However, adequate reasons such as sanitary issues were not found to account for the high prevalence. Only the age of the patients could account for the high prevalence in the schizophrenic group. In the psychoactive substance abuse group, the sanitary issues might be a major cause of the very high prevalence of anti-HCV antibody, while other factors such as dysfunction of the immune system might be considered to account for it.

Adult↗
PubMed2004

Hepatocyte-specific disruption of Bcl-xL leads to continuous hepatocyte apoptosis and liver fibrotic responses.

BACKGROUND & AIMS: Recent research has suggested that apoptosis could be involved in the development of fibrosis, although it is generally considered to be a mechanism of cell removal without consequences to the tissue. Bcl-xL , an antiapoptotic member of the Bcl-2 family, is expressed in hepatocytes and up-modulated during various pathologic conditions. The aim of this study was to explore the function of Bcl-xL in hepatocytes using the Cre-loxP system and to analyze the consequences of long-term apoptosis in hepatocytes. METHODS: Hepatocytes isolated from mice homozygous for a floxed bcl-x allele (bcl-x fl/fl) were infected with recombinant adenovirus expressing the Cre recombinase gene (AdexCre). Bcl-x fl/fl mice were crossed with Alb-Cre transgenic mice, which express Cre under regulation of the albumin gene promoter to generate hepatocyte-specific Bcl-xL-deficient mice. RESULTS: On AdexCre infection, primary cultured bcl-x fl/fl hepatocytes reduced their expression of Bcl-xL and rapidly underwent apoptosis associated with mitochondrial damage. In vivo hepatocyte-specific disruption of Bcl-xL resulted in spontaneous apoptosis of hepatocytes for more than 6 months. The Bcl-xL -deficient mice showed liver fibrosis with advanced age that was preceded by an increase in hepatic transforming growth factor beta production. In vitro, macrophages and hepatocytes produced transforming growth factor beta on exposure to apoptotic hepatocytes. CONCLUSIONS: The present study identified Bcl-xL as a critical apoptosis antagonist in hepatocytes. Furthermore, it offers proof that persistent apoptosis of parenchymal cells is sufficient to induce fibrotic responses and suggests a mechanistic link between apoptosis and fibrosis.

Animals↗
PubMed2004

Role of the heme regulatory motif in the heme-mediated inhibition of mitochondrial import of 5-aminolevulinate synthase.

5-Aminolevulinate synthase (ALAS) is a mitochondrial enzyme that catalyzes the first step of the heme biosynthetic pathway. The mitochondrial import, as well as the synthesis, of the nonspecific isoform of ALAS (ALAS1) is regulated by heme through a feedback mechanism. A short amino acid sequence, the heme regulatory motif (HRM), is known to be involved in the regulatory function of heme. To determine the role of the HRM in the heme-regulated transport of the nonspecific and erythroid forms of ALAS in vivo, we constructed a series of mutants of rat ALAS1, in which the cysteine residues in the three putative HRMs in the N-terminal region of the enzyme were converted to serine ones by site-directed mutagenesis. The wild-type and mutant enzymes were expressed in quail QT6 fibroblasts through transient transfection, and the mitochondrial import of these enzymes was examined in the presence of hemin. Hemin inhibited the mitochondrial import of wild-type ALAS1, but this inhibition was reversed on the mutation of all three HRMs in the enzyme, indicating that the HRMs are essential for the heme-mediated inhibition of ALAS1 transport in the cell. By contrast, exogenous hemin did not affect the mitochondrial import of the erythroid-specific ALAS isoform (ALAS2) under the same experimental conditions. These results may reflect the difference in the physiological functions of the two ALAS isoforms.

5-Aminolevulinate Synthetase↗
PubMed2004

Foods and beverages in relation to urothelial cancer: case-control study in Japan.

BACKGROUND: The roles of several foods and beverages in the development of bladder cancer remain unclear. METHODS: We undertook a hospital-based case-control study at Aichi Cancer Center Hospital, Japan. Subjects included 124 men and women (bladder cancer cases) with newly diagnosed cancers of the renal pelvis (n = 5), ureter (n = 6) or bladder (n = 113) and 620 age- and sex-matched, cancer-free outpatients (controls) presenting at the hospital in the period from 1994 to 2000. Smoking-adjusted odds ratios (OR) were estimated to assess the strength of associations between self-reported intake of foods or drinks and bladder cancer risk, using conditional logistic models. RESULTS: We found a decreased risk in relation to frequent intake of green-yellow vegetables; the OR for the highest intake score compared with the lowest was 0.54 (95% confidence interval [CI] 0.29-0.99). The OR for carrot intake of >/=5 times/week compared with </=1-3 times/month was 0.41 (95% CI 0.16-1.01) and a decreasing risk with increasing consumption of green vegetables was also detected (P for trend = 0.063). Inverse associations between black tea, eggs and meat and risk were also suggested, whereas moderate drinkers of green tea (5-9 cups/day) showed an elevated risk. Coffee and milk consumption did not appear to exert any influence. CONCLUSIONS: Those with an increased risk of bladder cancer, such as smokers, may benefit from increasing their consumption of green-yellow vegetables.

Adult↗
PubMed2004

[The effect of radiotherapy on patients with prostate specific antigen failure after radical prostatectomy].

We studied the effect of radiotherapy on patients with re-elevation of prostate specific antigen (PSA) after radical prostatectomy. Radiotherapy was performed on 8 patients with re-elevated PSA after radical prostatectomy without any previous treatment. Pathological stages were B in 2 patients, and C in 6 patients. Patients received three-dimensional dynamic conformal radiotherapy, and irradiation doses ranged from 44 to 70 Gy (median 60). The target area of irradiation included prostatic bed and seminal vesicles. PSA levels before radiotherapy were 0.31-1.9 ng/ml (median 0.40). In 7 patients, PSA levels decreased and no increase has been observed thereafter. In one patient, PSA level increased during radiotherapy; therefore, the treatment was discontinued at 44 Gy. Two patients suffered grade 1 to 2 acute toxicities, and no late toxicity has been observed so far. Radiotherapy is considered one of the effective treatments for re-elevation of PSA after radical prostatectomy.

Aged↗