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Y Shiratori

Publications and source records attributed to Y Shiratori.

At least 73 records · Page 4Linked to original sources
PubMed2000

A possible novel src-related tyrosine kinase in cancer cells of LEC rats that develop hepatocellular carcinoma.

BACKGROUNDS/AIMS: Src-related protein tyrosine kinase is known to be related to cell transformation. In this study, we report a possible novel src-related tyrosine kinase of 100 kDa specifically expressed in the nuclei of hepatocytes and/or cancer cells in Long-Evans Cinnamon rats, one of the experimental models of hepatocellular carcinoma. METHODS: Src-related protein tyrosine kinase in hepatocytes of Long-Evans Cinnamon rats was analyzed by using immunohistochemistry and Western blot and in vitro tyrosine kinase assay using a specific antibody (src antibody) against a synthetic peptide corresponding to the conserved autophosphorylation site of src family tyrosine kinases. RESULTS: Src-related protein was found to be expressed in the nuclei of hepatocytes and/or cancer cells in Long-Evans Cinnamon rat liver, exhibiting tyrosine kinase activity, and migrated to the position of 100 kDa. The protein quantity and activity of this 100-kDa src-related protein tyrosine kinase significantly increased with the progress of chronic hepatitis to hepatocellular carcinoma, especially in the tumorous portion of the liver. On the other hand, the 100-kDa src-protein tyrosine kinase was not observed in the nuclei of hepatocytes and/or cancer cells in normal age-matched control Wistar rats. CONCLUSIONS: Since the src-family tyrosine kinases have been observed at a molecular weight of 55 to 62 kDa and located in the hepatocellular membrane and/or cytoplasm, the 100-kDa src-related protein tyrosine kinase observed in the present study may be novel, and closely related to the pre-cancerous and cancerous process in Long-Evans Cinnamon rat liver.

Animals↗
PubMed2000

Different turnover rate of hepatitis C virus clearance by different treatment regimen using interferon-beta.

BACKGROUND/AIM: Since patients with high viral load and HCV subtype 1b are known to respond poorly to interferon (IFN) therapy, the viral dynamics of HCV RNA after initiation of interferon therapy were examined in the present study with respect to two different administration regimens, once vs. twice a day. METHODS: Twenty-two patients with chronic hepatitis C confirmed by liver biopsy and with >1 Meq/ml of HCV RNA and HCV subtype 1b were randomly assigned to two different IFN administration regimens (6 million units of IFN once a day or 3 million units of IFN twice a day), and the serum HCV RNA level was serially measured. RESULTS: Graphs of HCV RNA levels vs. treatment time showed an initial rapid fall, followed by a slower clearance phase. Fitting the data to a model for HCV decay proposed by Neumann et al. showed that the treatment efficacy was significantly higher with twice daily administration. Negativity for HCV RNA measured by Amplicor assay in the twice-a-day administration group was 18%, 73% and >89% at 1, 2 and 3 weeks, respectively, in contrast to 0%, 0%, and 18%, respectively, with once-a-day administration. However, a significant reduction of platelet count and albumin level, a marked increase in serum aspartate aminotransferase/alanine aminotransferase, and a high incidence of renal toxicity (proteinuria) were found in patients receiving IFN twice a day in comparison with those receiving it once a day. CONCLUSION: The twice-a-day administration of IFN accelerated the clearance of HCV RNA from serum, leading to a more efficient virological response for patients with chronic hepatitis C, but with a high rate of renal toxicity.

Adult↗
PubMed2000

Raman study on conformational equilibria of fluoroacetone in aqueous solutions.

The effects of water and heavy water on conformational equilibria of fluoroacetone have been investigated via Raman spectroscopy. Additional Raman bands have been observed in the C-F stretching and the C-C-C symmetric stretching regions for the aqueous solutions. Based on enthalpy and volume differences between the conformers, these bands are assigned to the syn conformer which has hydrogen bonds between the fluorine atom and water molecules (syn' conformer). The number of H2O molecules binding to the syn' conformer is estimated to be 2.4 from the concentration dependence of the spectrum. The enthalpy and the volume differences between the cis and syn conformers in the aqueous solutions show anomalous values in comparison with those in organic solvents. We discuss these thermodynamic behaviors from the viewpoint of the hydration structures of fluoroacetone.

Acetone↗
PubMed2000

Sustained viral response is rarely achieved in patients with high viral load of HCV RNA by excessive interferon therapy.

Adequate dosing of interferon (IFN) and its cost-effectiveness for sustained virological response were evaluated in relation to viral load and subtype. Prospective analysis of IFN therapy on 326 patients with chronic hepatitis C free from cirrhosis was performed using 9 or 6 million unit (MU) of IFN for six months daily and/or three times a week. Sustained virological response was achieved in 50-94% of patients with < or =2 x 10(4) copies/ml (competitive RT-PCR) or <100 x 10(3) copies/ml (Amplicor monitor) of HCV RNA by 468-1206 MU of IFN, but response was only 0-25% of the patients with > or =2 x 10(5.5) copies/ml (competitive RT-PCR) or >200 x 10(3) copies/ml (Amplicor monitor), even with 468-1206 MU of IFN. A high sustained rate was demonstrated in patients with 100-200 x 10(3) copies/ml of HCV RNA by 901-1206 MU of IFN, in comparison to that with < or =900 MU of IFN. Multivariate analysis showed that IFN dose had a significant value for the efficacy of IFN therapy in patients presenting 100-200 x 10(3) copies/ml of HCV RNA. Cost efficacy analysis indicated that it cost approximately $10,000, $26,000, and $50,000-227,000 for one person-viral eradication in the patients with <100, 100-200, and >200 x 10(3) copies/ml, respectively. High-dose IFN is only cost effective in patients with intermediate viral loads, and IFN therapy could be recommended in patients with <200 x 10(3) copies/ml of HCV RNA.

Adolescent↗
PubMed2000

High viral eradication with a daily 12-week natural interferon-beta treatment regimen in chronic hepatitis C patients with low viral load. IFN-beta Research Group.

Virological sustained response (SR) is achieved in 31-49% of patients with chronic hepatitis C with combination therapy using interferon (IFN)-alpha and ribavirin for 24-48 weeks. However, as a period of 24-48 weeks is a burden for patients, we investigated the effect of daily intravenous administration of natural IFN-beta for 12 weeks in this study. In all, 112 patients were enrolled and received a daily administration of 6 MU of natural IFN-beta intravenously for 12 weeks. Serum HCV-RNA before treatment was assessed by the competitive reverse-transcription polymerase chain reaction assay. The patients were divided into two groups according to pretreatment viral load: the low viral load group (N = 25, <6.3 x 10(5) copies/ml), and the high viral load group (N = 87, > or =6.3 x 10(5) copies/ml) who were additionally administered IFN-beta thrice weekly for subsequent 14 weeks at the patients' request. Virological SR was obtained in 37% (41/112) of all the patients; 88% of those with a low viral load, and 22% of patients with a high viral load. Virological SR was attained in 21% of patients with HCV subtype 1, and in 67% of those with subtype 2a. In patients with HCV subtype 1b, virological SR was obtained in patients with the mutant-type (> or =4 amino acid mutations in the NSSA2209-48) having a low viral load (4/4), but not in those having a high viral load (0/3). The results suggest that a daily intravenous administration of natural IFN-beta for 12 weeks showed high therapeutic efficacy in patients with a low viral load despite the shorter treatment period and that the therapeutic efficacy depends on viral load rather than on the number of NS5A2209-48 amino acid mutations.

Adolescent↗
PubMed2000

Poor association of TT virus viremia with hepatocellular carcinoma.

AIM: The aim of this study was to clarify the relationship between TT virus (TTV) infection and the development of hepatocellular carcinoma. METHODS: TTV from serum was examined in 224 patients with hepatocellular carcinoma (HCC) and 106 patients with chronic liver disease (CLD) but without HCC who were admitted to our hospital between 1995-1997. As controls, 48 patients without liver disease were also examined. TTV DNA was detected using nested PCR method after extraction of DNA from serum. RESULTS: TTV DNA was detected in 29/224 (13%) of patients with HCC; in 14% (4/28) of HCC patients negative for both hepatitis B virus surface antigen (HBsAg) and anti-hepatitis C virus antibody (anti-HCV), in 9% (2/22) of HCC patients positive for HBsAg, and in 12% (21/170) of HCC patients positive for anti-HCV. The prevalence of TTV DNA in HCC patients (13%) was not significantly higher than in CLD patients (22%). There were no significant differences in age, gender, liver function, tumor biology (size, TNM classification), other viral markers, or amount of alcohol intake between TTV-positive and -negative HCC patients. Only a history of blood transfusion was significantly more frequent in TTV-positive HCC patients than in TTV-negative cases (p= 0.02). Coinfection with TTV did not correlate with the severity of HCV-positive liver disease. There was no significant difference in prognosis between TTV-positive and -negative HCC patients. CONCLUSIONS: TTV does not seem to contribute to the development of HCC from chronic liver disease and is not correlated with severity of liver disease.

Aged↗
PubMed2000

A prospective study of interferon therapy modified by pre-treatment viral load in cirrhotic patients. Tokyo-Chiba Hepatitis Research Group.

BACKGROUND/AIMS: The relative role of hepatitis C virus (HCV) load and subtype as predictors of the efficacy of interferon therapy has been clarified in patients with chronic hepatitis C, but the effectiveness of interferon therapy in cirrhotic patients is still unclear. METHODS: To resolve this issue, we undertook a multicenter, randomized, and prospective study of 114 cirrhotic patients with hepatitis C virus infection. The patients were selected to undergo two different periods (6 or 12 months) of IFN therapy according to viral load. Patients with "low" viral load (< or = 10(5.8) copies/ml serum) were randomly divided into three groups, receiving 6 or 9 million units (MU) interferon three times a week for 6 months (total dose: 468 or 702 MU), or of a modified regimen using 6MU of IFN over 6 months (total dose 564 MU), while patients with "high" viral load (< or = 10(6.3) copies/ml serum) were also randomly divided into two groups of 6 or 9 MU of IFN three times a week for 12 months (total dose: 936 or 1,404 MU). RESULTS: HCV-RNA negativity rate at the completion of treatment with 6 or 9 MU IFN was 65% in patients with "low" viral load, in contrast to 14% in patients with "high" viral load. Sustained virological response was found in 40% of patients with "low" viral load irrespective of the three different regimens, in contrast to only 1 out of 35 patients (3%) with "high" viral load. Viral eradication was found in approximately 50% of patients having a low virus load (< or = 10(4.3) copies/ml) and with HCV subtype 2a. Univariate and multivariate analysis revealed that pretreatment viral load was a significant factor contributing to efficacy of IFN therapy. CONCLUSIONS: Sustained response was scarcely achieved in cirrhotic patients with high viral loads even after a 12-month course of intensive IFN therapy. This result indicates that there is a certain cut-off level of HCV RNA load which can not be eradicated.

Adult↗
PubMed2000

Determination of the optimal cut-off value for the [13C]-urea breath test based on a Helicobacter pylori-specific polymerase chain reaction assay.

BACKGROUND: This study was conducted to determine the optimal cut-off value and breath sample collection time for the [13C]-urea breath test based on the assessment of Helicobacter pylori status with a gastric juice-based polymerase chain reaction (PCR) assay. METHODS AND RESULTS: A total of 104 patients took 100 mg [13C]-urea orally and breath samples were collected at 5, 10, 20, 30 and 60 min. The increment of 13CO2:12CO, ratio from the baseline (delta13C) was measured using a laser spectroanalyser. The PCR assay was positive in 63 and negative in 41 patients. The optimal cut-off value of delta13C was calculated for each sample collection time so that the distance from the geometric mean value among Helicobacter pylori-positive patients and that from the arithmetic mean value among negative patients were simultaneously maximized. The cut-off value of 2.7% at 20 min had the longest distance, being separated by 3.16 SD from the two mean values. Using this cut-off value, the urea breath test showed 100% specificity and 98% sensitivity for the diagnosis of Helicobacter pylori infection.

Breath Tests↗
PubMed2000

Long-term effects of interferon therapy on histology and development of hepatocellular carcinoma in hepatitis C.

Chronic hepatitis C is a common disease that slowly progresses to cirrhosis and eventually to hepatocellular carcinoma (HCC). Histology offers an important insight into disease prognosis and treatment response. Biochemical and virological responses to interferon (IFN) therapy are associated with an improvement in liver histology during and shortly after treatment, but the impact of treatment on the history of a slowly progressive disease cannot be ascertained by evaluating results at the completion of treatment. Some recent studies showed that the severity of hepatic inflammation may be a major factor driving progression of chronic hepatitis C to cirrhosis, and that improving hepatic inflammation may be associated with regression or retardation of fibrosis, especially in patients with virological sustained response. Many recent studies have shown an inhibition of the development of decompensation and HCC after IFN therapy, but a randomized controlled study using a large number of subjects with a more than 5-year observation period will be required to elucidate the exact role of antiviral therapy for the delay of decompensation or suppression of HCC.

Antiviral Agents↗
PubMed2000

Predictors of the efficacy of interferon therapy for patients with chronic hepatitis C before and during therapy: how does this modify the treatment course?

Antiviral therapy for hepatitis C virus (HCV) infection should be based on the natural history of HCV infection; there is a sequential, but slow, progression from chronic hepatitis to cirrhosis, leading to death from either liver failure or hepatocellular carcinoma (HCC). The risk of HCC development increases in association with the advance of fibrosis, and antiviral therapy can reduce this risk. More than 30 indices have been proposed as 'predictors' of favourable response to IFN therapy: host factors (age, gender, duration of HCV-infection, alcohol intake, hepatic iron stores, platelet count, histological staging of the liver disease), viral factors (HCV RNA levels in serum, HCV subtype, diversity of the hypervariable region, mutation of non-structure 5A gene), and IFN factors (dose, duration of treatment, type, treatment regimens i.e. every day vs three times a week, escalating dose regimen). Before starting IFN therapy, HCV subtype and pretreatment HCV RNA load, as well as the fibrotic stage of the liver, should be determined. The response to IFN therapy should be monitored by the HCV RNA status in serum during therapy, and the treatment regimen modified, or discontinued as required. A sustained virological response should be checked at more than 3 months after the completion of therapy. Even though the risk of HCC is markedly reduced in sustained responders, it is possible to develop HCC several years after completion of IFN therapy.

Antiviral Agents↗
PubMed2000

H. pylori activates NF-kappaB through a signaling pathway involving IkappaB kinases, NF-kappaB-inducing kinase, TRAF2, and TRAF6 in gastric cancer cells.

BACKGROUND & AIMS: H. pylori infection on gastric epithelial cells has been shown to induce NF-kappaB activation, but the mechanism of intracellular signal conduction that leads to NF-kappaB activation is not clear. The aim of this study was to analyze the molecular mechanism responsible for H. pylori-mediated NF-kappaB activation on gastric cancer cells. METHODS: NF-kappaB activation by H. pylori was tested by using luciferase reporter assay. IkappaBalpha degradation by H. pylori infection was assessed by immunoblotting. IKKalpha and IKKbeta activation was analyzed by kinase assay. In transfection experiments, effects of dominant negative IkappaBalpha, IKKalpha, IKKbeta, NF-kappaB-inducing kinase (NIK), TRAF2, and TRAF6 mutants were investigated. The effects of an IKKbeta-specific inhibitor, aspirin, on NF-kappaB activation and IL-8 secretion were also analyzed. RESULTS: H. pylori promotes degradation of IkappaBalpha, a cytoplasmic inhibitor of NF-kappaB. In kinase assay, H. pylori induced IKKalpha and IKKbeta catalytic activity in gastric cancer cells. Transfection of kinase-deficient mutant of either IKK inhibited H. pylori-mediated NF-kappaB activation dose-dependently. Aspirin inhibited both NF-kappaB activation and IL-8 secretion induced by H. pylori. NF-kappaB activation was also inhibited by transfection of kinase-deficient NIK or a dominant negative mutant of upstream adapter protein TRAF2 or TRAF6. CONCLUSIONS: H. pylori induces NF-kappaB activation through an intracellular signaling pathway that involves IKKalpha, IKKbeta, NIK, TRAF2, and TRAF6.

Aspirin↗
PubMed2000

Hepatocellular carcinoma cell cycle: study of Long-Evans cinnamon rats.

Amplification found in a number of cyclin genes, especially in cyclin D and E, is an important event process that takes place in cancers, including hepatocellular carcinoma (HCC). The activities of a wide range of cell cycle-related kinases remain obscure in HCC. The purpose of the present study is to determine the cyclins and kinase activities of HCC in Long-Evans Cinnamon (LEC) rats. Cyclin D1, E, A, H, Cdk1(cyclin-dependent kinase; Cdc2), Cdk4, and Cdk6 protein levels were determined by Western blot analysis at different pathologic stages of liver tissues exhibiting HCC. Enzymatic activities of cyclin D1, E, A, Cdk4, Cdk6, Cdc2, Cdk7, and Wee1 kinase were measured by in-gel kinase assay. Protein levels and kinase activities of cyclin D1, E, Cdk4, cyclin A, and Wee1 increased proportionally with the development of HCC, especially in the transition process from chronic hepatitis to HCC. Although Cdc2 kinase activity was found to increase slightly from normal liver to chronic hepatitis, its activity remained unchanged in the process from chronic hepatitis to HCC. Cdk6 and Cdk7 activities remained unchanged in the process from normal liver to HCC. These data suggest that the increase in Cdc2 kinase may play a role in the process from normal liver to chronic hepatitis, whereas the predominant increase in cyclin D1, Cdk4, cyclin E, cyclin A, and Wee1 suggests involvement not only in the process from normal liver to chronic hepatitis, but also during transition into HCC.

Animals↗
PubMed2000

Risk factors for recurring hepatocellular carcinoma differ according to infected hepatitis virus-an analysis of 236 consecutive patients with a single lesion.

Patients with hepatocellular carcinoma (HCC) frequently experience intrahepatic HCC recurrence even after complete ablation of primary lesions. Because the oncogenic process may be different for hepatitis B viral (B-viral) and hepatitis C viral (C-viral) HCC, the present study was conducted to elucidate the factors contributing to HCC recurrence with respect to the infected hepatitis virus. Two hundred thirty-six patients with a single HCC lesion who underwent complete ablation of the tumor by PEIT and/or PMCT or surgical resection at Tokyo University and its affiliated hospitals from 1993 to 1997 were enrolled. The patients were classified into 3 groups: the B-viral group, C-viral group, and NBNC group. After complete removal of tumors, the patients were followed for a mean period of 39 months. The factors contributing to HCC recurrence were analyzed by univariate and multivariate analysis using the Cox proportional hazard model. The rate of intrahepatic recurrence in enrolled patients at 1, 3, and 5 years was 19%, 50%, and 64%, respectively. The intrahepatic recurrence rate in C-viral and B-viral HCC was higher than that in the NBNC-related HCC. Fibrosis staging, pathological grading of HCC, and serum AFP levels were significantly linked to intrahepatic recurrence by univariate analysis, and fibrosis staging was strongest in the multivariate analysis for C-viral HCC (P = .004). In contrast, fibrosis staging did not affect the recurrence in B-viral (P = .51) and NBNC-related (P = .77) HCC. Risk factors for HCC recurrence differed according to the infected viral state.

Aged↗
PubMed2000

Activation of intracellular signaling by hepatitis B and C viruses: C-viral core is the most potent signal inducer.

To clarify the effects of hepatitis C virus (HCV) infection on hepatocytes, we analyzed and compared the induction of intracellular signals by HCV and hepatitis B virus (HBV) proteins. We examined the influence of 7 HCV (core, NS2, NS3, NS4A, NS4B, NS5A, and NS5B) and 4 HBV (precore, core, polymerase, and X) proteins on 5 well-defined intracellular signaling pathways associated with cell proliferation, differentiation, and apoptosis by use of a reporter assay. Viral protein-expression vectors were cotransfected into mammalian cells with reporter vectors having a luciferase gene driven by the following inducible cis-enhancer elements: the cyclic adenosine monophosphate response element, the serum response element (SRE), and the binding sites for nuclear factor kappaB (NF-kappaB), activator protein 1 (AP-1), and serum response factor (SRF). In addition, the activation of signals by HCV proteins was examined in a reporter plasmid having a natural interleukin-8 (IL-8) promoter upstream of a luciferase gene. Of 11 HCV and HBV proteins, HCV core had the strongest influence on intracellular signals, especially NF-kappaB-, AP-1-, and SRE-associated pathways. HCV core's activation level exceeded that of HBV X protein, a well-characterized transactivator of these signals. Moreover, HCV core activated the IL-8 promoter through NF-kappaB and AP-1. For the other proteins, HCV NS4B showed signal activation, but signals were activated at a lesser extent. The luciferase reporter assay, a recently introduced technique, helped in the elucidation of molecular events underlying the inflammatory and proliferation process in the liver induced by HCV.

Blotting, Western↗
PubMed2000

Early detection of haemobilia associated with percutaneous ethanol injection for hepatocellular carcinoma.

OBJECTIVE: Haemobilia often results from iatrogenic injury caused by therapeutic procedures. The objective of this study was to evaluate the efficacy of early diagnosis of haemobilia based on ultrasonography in patients with hepatocellular carcinoma undergoing percutaneous ethanol injection. PATIENTS AND METHODS: A combination retrospective and prospective study on the early detection of haemobilia caused by percutaneous ethanol injection was conducted on 365 patients in 1995-1996. The retrospective study reviewed the clinical, laboratory and imaging data of 172 patients who had undergone ethanol injection therapy in 1995. The results showed that ultrasonographic changes in the gallbladder, namely the rapid appearance of echogenic material in the gallbladder lumen, are a useful early sign of haemobilia. Based on the results of the retrospective study, a prospective study on the early detection of haemobilia was carried out in 1996. In the prospective study, percutaneous ethanol injection was halted as soon as haemobilia was detected. RESULTS: The incidence of haemobilia in the prospective group (3.6%) was not different from that in the retrospective group (4.7%). However, the mean duration between percutaneous ethanol injection and diagnosis of haemobilia was only 0.3 +/- 0.2 days in the prospective group, compared with 2.8 +/- 2.1 days in the retrospective group (P < 0.001), and the mean duration of jaundice in the prospective group (4.3 days) was significantly shorter than in the retrospective group (40.0 days) (P< 0.05). CONCLUSION: Early diagnosis of haemobilia based on ultrasonographic findings of the gallbladder lumen effectively reduces the severity of haemobilia-related complications due to immediate interruption of the interventional procedure.

Administration, Cutaneous↗