Therapeutic benefit of sulfasalazine for patients with primary sclerosing cholangitis.
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Adolescent↗
Biomedical subjects
Shinichiro Tada
Publications and source records attributed to Shinichiro Tada.
Successful management of liver injury caused by imatinib mesylate in a patient with previously untreated chronic myelogenous leukemia in the chronic phase.
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Antineoplastic Agents↗
Role of erythrocytes as a reservoir for ribavirin and relationship with adverse reactions in the early phase of interferon combination therapy for chronic hepatitis C virus infections.
We investigated the relationship between serum ribavirin concentrations and clearance, as well as therapeutic efficacy and adverse reactions, in 97 Japanese patients with chronic hepatitis C virus infections treated with a 6-month course of high-dose alpha2b interferon (6 million units/day) plus ribavirin (600 to 800 mg/day) combination therapy. This randomized trial showed that the saturation of ribavirin uptake after taking ribavirin capsules does not occur within a dose range of 600 to 800 mg/day, which is a standard dosage used clinically in Japan. Serum ribavirin concentrations and clearance did not correlate with sustained virological response rates. Fourteen patients discontinued therapy because of adverse reactions, and sustained virological response rates were significantly reduced by discontinuation of therapy, while dose reduction of ribavirin did not alter the therapeutic effects. Ribavirin concentrations after 1 week and ribavirin clearance were significantly correlated with discontinuation of ribavirin; however, a multiple-regression analysis revealed that only hemoglobin concentration, but not ribavirin clearance, was a significant factor for discontinuation of therapy (odds ratio, 0.514; 95% confidence interval, 0.311 to 0.85; P = 0.0095). It appears that peripheral erythrocytes may act as a reservoir for ribavirin and regulate serum ribavirin levels in the very early phase of treatment.
Adult↗
Induction therapy with twice-daily interferon-beta does not improve the therapeutic efficacy of consensus interferon monotherapy for chronic hepatitis C.
We examined therapeutic superiority of induction therapy with twice-daily IFN-beta (3X2=6 million units/day) onto 6-months consensus interferon monotherapy for chronic hepatitis C. Patients were randomly assigned to monotherapy without (group I, n=16) and with induction therapy (group II, n=12). The mean age of group II was older than that of group I, and other baseline condition was not statistically significant. Sustained virological response (SVR) rates of group I and II were 81.3% (13/16) and 58.3% (7/12), respectively (p=0.365). SVR rates in patients with genotype 1b were 66.7% (4/6) and 0% (0/2, because of drop-out), and those with high viral load were 70% (7/10) and 75% (6/8) in group I and II, respectively (p=1.000). Drop-out rates during therapy were 6.3% (1/16) and 33.3% (4/12) in group I and II, respectively (p=0.176). Age less than 50 years was the only independent factor that was shown by multivariate logistic model analysis to be associated with a sustained virological response. Although randomization failed to produce and equal age distribution in the two groups in this study, our results suggest that induction therapy with twice-daily IFN-beta has no beneficial effect on the efficacy of monotherapy with consensus interferon, probably because of the higher drop-out rates and incidence of adverse reactions with induction therapy.
Female↗
Cyclooxygenase-2 inhibitor and interferon-beta synergistically induce apoptosis in human hepatoma cells in vitro and in vivo.
Recent clinical trials have shown that interferon (IFN) is effective for chemoprevention against hepatocellular carcinoma (HCC). However, it remains controversial as to whether IFN exerts direct cytotoxicity against HCC. Cyclooxygenase (COX)-2 also plays a role in hepatocarcinogenesis and may mediate resistance to apoptosis in HCC. Therefore, we aimed to elucidate the combined effect of COX-2 inhibitor, NS-398, and IFN on in vitro growth suppression of HCC using 3 hepatoma cell lines (HepG2, PLC/PRF/5, and Huh7) and in vivo nude mouse xenotransplantation model using Huh7 cells. Only minimal growth inhibition was observed after treatment with IFN-beta alone in the 3 hepatoma cell lines. In contrast, treatment with NS-398 and IFN-beta synergistically inhibited cell proliferation in dose- and time-dependent manner. Apoptosis was identified by 4',6-diamidino-2-phenylindole dihydrochloride and fluorescent staining. IFN-beta up-regulated the expression of TRAIL, while NS-398 increased the expression of TRAIL receptors (especially of death receptor 5). Subsequently, activation of caspase-8 and caspase-3 was observed following the treatment with NS-398 and IFN-beta. Blockade of TRAIL with a specific antibody attenuated this apoptosis. Furthermore, we found that IFN-beta up-regulated COX-2 expression in Huh7 cells, and NS-398 might suppress the up-regulated COX-2 activity downstream of IFN signaling. In vivo experiment showed the combined regimen with NS-398 and IFN-beta reduced the growth of xenotransplated HCCs in nude mice. In conclusion, NS-398 is sufficient to overcome IFN resistance in hepatoma cells through the TRAIL/TRAIL receptor pathway, therefore, the combination would appear to be a new therapeutic regimen for HCC.
Animals↗
Contribution of Irf-1 promoter polymorphisms to the Th1-type cell response and interferon-beta monotherapy for chronic hepatitis C.
We recently reported promoter polymorphisms in the IRF-1 gene, an interferon-inducible gene that plays an important role in host antiviral function. The promoter activity was shown to be different between different polymorphisms. In this study, we investigated the relationship between IRF-1 promoter polymorphisms and the response to interferon monotherapy for chronic hepatitis C. Eighteen patients with a low initial viral load or hepatitis C virus (HCV) genotype non-1b received 6-months course of interferon-beta monotherapy. IRF-1 gene mutations and the treatment response were investigated. The IRF-1 promoter type possessing a higher promoter activity (-415C/-410A/-300A) was found in only three patients, all of which had a lower viral load than those with other promoter types and were able to obtain a sustained viral response. Flow cytometric analysis of peripheral blood mononuclear cells showed that the patients with a higher promoter activity of the IRF-1 had a significantly higher proportion of T helper 1-type CD4(+) cells after interferon administration than those of other promoter types. These results suggest that IRF-1 promoter polymorphisms may contribute, at least partially, to host antiviral activity for chronic hepatitis C.
Journal Article↗
Value of computed tomography-derived estimated liver volume/standard liver volume ratio for predicting the prognosis of adult fulminant hepatic failure in Japan.
BACKGROUND AND AIMS: The prognosis of fulminant hepatic failure (FHF) has been improved but is still unsatisfactory, and liver atrophy has been reported as a poor prognostic factor for this disease. The aim of this study was to assess the clinical value of the estimated liver volume (ELV) compared to the standard liver volume (SLV) in patients with FHF. METHODS: Estimated liver volume of 24 adult patients with FHF receiving artificial liver support (ALS) was measured by using computed tomography. Actual liver weight (ALW) was measured if possible, and the calculated ELV/SLV ratio was compared to the ALW/SLV ratio and the ALW/BW (bodyweight) ratio. Sequential ELV/SLV ratios during the clinical course were analyzed in relation to the prognosis. RESULTS: The ELV/SLV ratio was significantly correlated with both the ALW/SLV and ALW/BW ratios. The mean ALW/SLV ratio of patients who underwent living donor liver transplantation (LDLT) was 0.59 +/- 0.17. The mean ELV/SLV ratio at the time of starting ALS (day 0) in the patients who survived (group 1) was 1.081 +/- 0.183, but that of cases who underwent LDLT or died without LDLT (group 2) was 0.764 +/- 0.255. The mean ELV/SLV ratios were 1.084 +/- 0.222 and 0.650 +/- 0.195 in groups 1 and 2, respectively, 5 days after starting ALS (day 5). Among the group 2 patients, those who had no liver atrophy on day 0 had a significantly decreased ELV/SLV ratio on day 5. CONCLUSIONS: These results suggest that the ELV/SLV ratio is a very useful objective marker to estimate liver atrophy and this marker reflects the prognosis of FHF patients very well.
Adult↗
Gene expression associated with the decrease in malignant phenotype of human liver cancer cells following stimulation with a histone deacetylase inhibitor.
Sodium butyrate is a short-chain fatty acid produced by fermentation in the gastrointestinal tract. It induces differentiation of several kinds of cancer by inhibiting histone deacetylase activity. We have reported that butyrate stimulates hepatocellular carcinoma cells into their normal phenotype. Since sodium butyrate affects both differentiation and apoptosis, we investigated expression of bcl-2-related genes in a human hepatocellular carcinoma cell line HCC-T. The expression of anti-apoptotic Bcl-2 and Mcl-1/EAT was up-regulated 4 h after the treatment, while pro-apoptotic Bax expression did not change. Gene expressions in the early stage of butyrate-stimulation were investigated by the differential display assay and the cDNA expression array. Laminin and keratin 18 were increased 6 h after the stimulation with sodium butyrate. The results of cDNA expression array revealed up-regulation of cell cycle inhibitory genes such as cyclin-dependent kinase 4 inhibitor, and interferon-related genes such as STAT2 and 3, while down-regulation of cyclin-dependent kinase 2 and cyclin E. Up-regulated production of p21WAF-1 and Mcl-1/EAT was also confirmed by Western blotting. The cytoskeletal change indicated by up-regulation of laminin and keratin 18 may be an important factor in the decrease in malignant phenotype of cancer cells. Up-regulation of interferon-related genes indicated that butyrate-treatment might induce a similar phenotypic change to that induced by type 1 interferons. This study suggests several target genes for the future gene therapy of cancer or genes preventing cancer development from pre-malignant tissues.
Antineoplastic Agents↗
[Primary sclerosing cholangitis].
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Adrenal Cortex Hormones↗
Efficacy of non-invasive elastometry on staging of hepatic fibrosis.
To assess the efficacy of elastmetry in the determination of fibrotic stage in the liver, we investigated correlation between liver histology and the elastometry using a device equipped with a vibrator and an ultrasound system (Echosens, Paris, France) in patients with chronic hepatitis C. Totally 75 patients, 24 in F1 stage, 17 in F2 stage, 18 in F3 stage, and 16 in F4 stage according to the new Inuyama classification without fatty change were investigated. Correlations between the staging of liver fibrosis and elastometry, serum fibrosis makers and platelet counts were investigated. The elastometry was absolutely non-invasive. Serum fibrosis markers did not well correlate with the stage of liver fibrosis. Platelet counts significantly ( [Formula: see text] ) correlated with the fibrotic stage. Median platelet counts in each stage was; F1, 191.5; F2, 172.0; F3, 132.0; F4, 77.5 (x10(3)microl(-1)). However, the deviation was comparatively broad. On the contrary, the elastometry correlated well to the stage of fibrosis and the deviation was small. Median elastometric levels in each stage were; F1, 6.25; F2, 7.80; F3, 13.85; F4, 34.00 (kPa). These results suggest that elastometry is significantly useful for evaluating fibrotic staging of the liver without any invasiveness.
Journal Article↗
Down-regulation of matrix-invasive potential of human liver cancer cells by type I interferon and a histone deacetylase inhibitor sodium butyrate.
We have demonstrated anti-proliferation and anti-metastasis effects of both interferon-alpha and a histone deacetylase inhibitor, sodium butyrate, on human liver cancer cell lines. In this study, invasive ability of human liver cancer cell lines through the matrix-coated membrane was examined and inhibitory effect of interferon-alpha and sodium butyrate was investigated. Among six human liver cancer cell lines, HLE and HLF showed high invasive ability using the Matrigel invasion assay. This invasion ability was significantly inhibited by pretreatment of the cells with 1000 IU/ml of interferon-alpha or 2 mM of sodium butyrate. Gelatin zymography and the matrix metalloproteinase-2 and -9 activity assay showed that these two cell lines produce active- and pro-matrix metalloproteinase-2 and -9, and their activity was significantly reduced by pretreatment with both agents. Real-time quantitative reverse transcription-polymerase chain reaction showed decrease in matrix metalloproteinase-1 mRNA levels by pretreatment with both agents, but mRNA levels of tissue inhibitor of matrix metalloproteinase-1 and -2 were differently modulated by interferon-alpha and sodium butyrate. These results suggest that interferon-alpha and sodium butyrate reduce a chance of invasion and metastasis of human liver cancer cells by inhibiting matrix metalloproteinase activity, although its inhibitor is differently regulated.
Antineoplastic Agents↗
A free radical scavenger, edaravone, attenuates steatosis and cell death via reducing inflammatory cytokine production in rat acute liver injury.
BACKGROUND/AIMS: Reactive oxygen radicals play an important role in various forms of liver injury. In this study, we evaluated the efficacy of edaravone, a newly synthesized free radical scavenger, in its clinical dosage on an experimental model of acute liver injury in rats. METHODS: The clinical dose of edaravone (3 mg/kg) was intravenously administered immediately and 3 h after intraperitoneal administration of carbon tetrachloride (CCl4) in rats. Histological evaluation including apoptosis and cytokine profiles were examined. RESULTS: Fatty degeneration and necrosis with marked elevation of serum alanine aminotransferase and lactate dehydrogenase levels developed after CCl4 administration were significantly reduced by edaravone. In addition, the apoptotic index assessed by TUNEL method was significantly lowered in the edaravone treated group. Serum and liver transcription levels of interleukin-6, tumor necrosis factor-alpha, interleukin-4, and interleukin-10 were increased following CCl4 administration, and they were attenuated by edaravone treatment. The formation of malondialdehyde, 4-hydroxynonenal adduct and one of the markers for oxidative DNA damage, 8-hydroxy-2'-deoxyguanosine, was also inhibited by edaravone treatment. CONCLUSION: Edaravone has a remarkable protective effect on acute liver injury caused by oxygen radicals through not only attenuating the membrane lipid peroxidation, but also inhibiting the production of inflammatory cytokines. We theorize that edaravone may have a clinical benefit in the treatment of various liver injuries.
8-Hydroxy-2'-Deoxyguanosine↗
Genomic mutations with amino acid substitutions of circulating hepatitis B virus found in non-B, non-C patients with hepatocellular carcinoma.
OBJECTIVE: Most hepatocellular carcinoma (HCC) in Japan is caused by chronic infection with hepatitis B virus (HBV) or hepatitis C virus (HCV). HBV DNA has been detected in the serum and liver tissue of some proportion of those patients who are HBs antigen-negative and HCV antibody-negative; i.e., non-B, non-C (NBNC) patients with HCC. We sought to detect HBV DNA in the serum from NBNC HCC cases and to investigate genomic mutations of HBV in seronegative cases. PATIENTS AND METHODS: The sera from 26 NBNC HCC patients were examined by polymerase chain reaction (PCR) followed by southern blotting for existence of HBV DNA. The precore/core and polymerase regions of the HBV genome in the sera from five seronegative cases were analyzed by direct sequence. RESULTS: HBV DNA was detected in 17 of 26 patients (65.4%). Demographic factors such as age, gender, anti-HBs positivity, anti-HBc positivity, complication with cirrhosis, and excessive alcohol intake did not affect circulating HBV positivity. Genomic mutations with amino acid substitutions were detected in the polymerase and the precore regions from one of the five cases, and in the core region from four of the five cases. CONCLUSIONS: PCR-based HBV screening is necessary in patients suffering from liver diseases of unknown etiology, although its etiological importance and benefit of viral elimination have not been established. Genomic mutations in the precore/core and the polymerase region detected in this study might be involved in the lack of HBsAg in NBNC HCC cases.
Amino Acid Substitution↗
ALL-1 is a histone methyltransferase that assembles a supercomplex of proteins involved in transcriptional regulation.
ALL-1 is a member of the human trithorax/Polycomb gene family and is also involved in acute leukemia. ALL-1 is present within a stable, very large multiprotein supercomplex composed of > or =29 proteins. The majority of the latter are components of the human transcription complexes TFIID (including TBP), SWI/SNF, NuRD, hSNF2H, and Sin3A. Other components are involved in RNA processing or in histone methylation. The complex remodels, acetylates, deacetylates, and methylates nucleosomes and/or free histones. The complex's H3-K4 methylation activity is conferred by the ALL-1 SET domain. Chromatin immunoprecipitations show that ALL-1 and other complex components examined are bound at the promoter of an active ALL-1-dependent Hox a9 gene. In parallel, H3-K4 is methylated, and histones H3 and H4 are acetylated at this promoter.
Blotting, Western↗
The detection of IRF-1 promoter polymorphisms and their possible contribution to T helper 1 response in chronic hepatitis C.
We described the interferon (IFN) regulatory factor-1 (IRF-1) promoter single nucleotide polymorphisms (SNPs), and the clinical and immunologic implications of these SNPs have been investigated. We successfully determined the mutation at -300 of the IRF-1 promoter by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP), and this mutation linked with other mutations in the promoter region. In our Japanese population, the frequency of the type -300*A/A was 11.9%, type A/G was 54.2%, and type G/G was 33.9%. We found no significant difference without IFN stimulation in the production levels of IFN-gamma and interleukin-10 (IL-10) from peripheral blood mononuclear cells (PBMC) between subjects with -300*A/A and those with other types. IFN-alpha stimulation, however, increased the levels of IFN-gamma significantly and decreased the IL-10 production level significantly only in the subject with -300*A/A type. Flow cytometric analysis showed that the Th1-type CD4(+) cell population was significantly increased by IFN-beta administration only in the patient with chronic hepatitis C with -300*A/A type. These results suggest that the IRF-1 promoter SNP types are positively involved in Th1-type response and, consequently, the -300*A/A type may be beneficial for viral elimination in chronic hepatitis C and IFN therapy.
Base Sequence↗
Influence of implant design and bone quality on stress/strain distribution in bone around implants: a 3-dimensional finite element analysis.
PURPOSE: A 3-dimensional finite element analysis was performed to evaluate the influence of implant type and length, as well as that of bone quality, on the stress/strain in bone and implant. MATERIALS AND METHODS: Two types (screw and cylinder) and 4 lengths (9.2, 10.8, 12.4, and 14.0 mm) of titanium implants were buried in 4 types of bone modeled by varying the elastic modulus for cancellous bone. Axial and buccolingual forces were applied to the occlusal node at the center of the abutment. RESULTS: Regardless of load direction, maximum equivalent stress/strain in bone increased with a decrease in cancellous bone density. Under axial load, especially in the low-density bone models, maximum equivalent strain in cancellous bone was lower with the screw-type implant than with the cylinder-type implant. It was also lower with the longer implants than with the shorter implants. Under buccolingual load, equivalent stress/strain was influenced mainly by bone density. DISCUSSION: This study confirms the importance of bone quality and its presurgical diagnosis for implant long-term prognosis. Implant length and type can also influence bone strain, especially in low-density bone. CONCLUSIONS: The results of this study suggest that cancellous bone of higher rather than lower density might ensure a better biomechanical environment for implants. Moreover, longer screw-type implants could be a better choice in a jaw with cancellous bone of low density.
Biomechanical Phenomena↗
Effect of long-term interferon therapy for refractory chronic hepatitis c: preventive effect on hepatocarcinogenesis.
BACKGROUND/AIMS: Effect of interferon (IFN) therapy for refractory chronic hepatitis C is not sufficient. For patients with persistent hepatitis C virus (HCV) infection, one of the clinical goals is prevention of progression to liver cirrhosis (LC) and hepatocellular carcinoma (HCC). In this study, we evaluated effect of long-term IFN administration for refractory chronic hepatitis C. METHODOLOGY: The patients who were positive for HCV of genotype lb in high viral load and failed in HCV elimination by standard IFN therapy were retrospectively analyzed. The patients were divided into three groups according to administration duration of IFN therapy. The patients in group 1, 2 and 3 received IFN therapy for 6 months, 6-24 months and more than 24 months, respectively. RESULTS: The normalization rate of alanine aminotransferase (ALT) levels less than twice that of the normal limit 6 months after the treatment was highest in group 3 (85%). The platelet counts in group 1 gradually decreased more than 3 x 10(4)/microL from the pretreatment levels at 100 months after the start of treatment. Cumulative hepatocarcinogenesis rate in groups 1, 2 and 3 were 34.7%, 5.9% and 0%, respectively. We found distinct improvement in both ALT levels and histopathological findings in the case that received the longest term of IFN therapy (91 months). CONCLUSIONS: Long-term IFN therapy is effective in preventing hepatocarcinogenesis through reduction of chronic necroinflammation and accumulation of fibrosis in the liver and may be a good indication even for refractory chronic hepatitis C.
Alanine Transaminase↗
Efficacy of natural BALL-1 interferon-alpha treatment for patients with chronic hepatitis C and a possible enhancing effect of a twice-daily starting regimen with interferon-beta.
BACKGROUND/AIMS: Two distinct natural interferon-alpha (BALL-1 and Namalwa) are available for patients with chronic hepatitis C in Japan, but the efficacy has not been well documented. We investigated two studies using a natural BALL-1 interferon-alpha treatment for chronic hepatitis C and assessed its efficacy. METHODOLOGY: In interferon-alpha monotherapy (Study I), 42 patients with chronic hepatitis C received 10 mega units of BALL-1 interferon-alpha intramuscularly consecutively for an initial 2 weeks followed by three times a week for 6 months totally. In a combination therapy of natural interferon-alpha and interferon-beta (Study II), 24 patients received intravenous 3 mega units of interferon-beta twice daily for the initial 2 weeks followed by 10 mega units of natural BALL-1 interferon-alpha consecutively for 2 weeks and three times a week for 6 months totally. Efficacy and predictive factors for sustained viral response was investigated. RESULTS: Study II included significant younger patients than study I. Sustained virological response was obtained in 31.0% in Study I and 56.5% in Study II by intention-to-treat analysis. Sustained viral response in the group of genotype 1b and viral load more than 100 KIU/mL was 3/23 (13.0%) and 8/18 (44.4%) in Study I and II, respectively. The response rate in Study II was higher than that of Study I especially among the patients with high pretreatment viral load or genotype 1b (p<0.05). Multivariate analysis showed that pre-treatment HCV-RNA levels, HCV-genotype, and histological staging before the interferon treatment were significant predictive factors of sustained viral response. CONCLUSIONS: These studies suggest that natural BALL-1 interferon-alpha is useful for inducing sustained viral response in patients with chronic hepatitis C, even in those possessing genotype 1b and high viral load. In addition, the combination therapy with a starting regimen with twice-daily interferon-beta administration for 2 weeks may be more effective than monotherapy.
Adult↗