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Kazumoto Murata,
Masaya Sugiyama,
Tatsuji Kimura,
Sachiyo Yoshio,
Tatsuya Kanto,
Ikue Kirikae,
Hiroaki Saito,
Yoshihiko Aoki,
Satoshi Hiramine,
Teppei Matsui,
Kiyoaki Ito,
Masaaki Korenaga,
Masatoshi Imamura,
Naohiko Masaki, Masashi Mizokami
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ABSTRACT: BACKGROUND: Genetic variation around interleukin-28B (IL28B), encoding IFN-λ3, predict non-responders to pegylated interferon-α/ribavirin (Peg-IFN/RBV) therapy in chronic hepatitis C (CHC). However, it remains unclear the expression and the role of IL28B itself. The aim of this study is to develop easy and useful methods for the prediction of treatment outcomes. METHODS: The mRNA and protein levels of IFN-λ3 induced by ex vivo stimulation of peripheral blood mononuclear cells (PBMC) or magnetically selected dendritic cells (DCs) with toll-like receptor agonists (TLR3; poly I:C, TLR7; R-837) were measured by the quantitative real-time polymerase chain reaction and our newly developed chemiluminescence enzyme immunoassays, respectively, and compared with the clinical data. RESULTS: We found that BDCA-4(+) plasmacytoid and BDCA-3(+) myeloid DCs were the main producers of IFN-λs when stimulated with R-837 and poly I:C, respectively. Detectable levels of IFN-λs were inducible even in a small amount of PBMC, and IFN-λ3 was more robustly up-regulated by R-837 in PBMC of CHC patients with favorable genotype for the response to Peg-IFN/RBV (TT in rs8099917) than those with TG/GG. Importantly, the protein levels of IFN-λ3 induced by R-837 clearly differentiated the response to Peg-IFN/RBV treatment (p = 1.0 × 10(-10)), including cases that IL28B genotyping failed to predict the treatment response. The measurement of IFN-λ3 protein more accurately predicted treatment efficacies (95.7 %) than that of IL28B genotyping (65.2 %). CONCLUSIONS: Genetic variations around IL28B basically affect IFN-λ3 production, but different amounts of IFN-λ3 protein determines the outcomes of Peg-IFN/RBV treatment. This study, for the first time, presents compelling evidence that IL28B confer a functional phenotype.
Journal of Gastroenterology 04/2013; · 4.16 Impact Factor
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Motokazu Mukaide,
Yasuhito Tanaka,
Tadasu Shin-I,
Man-Fung Yuen,
Fuat Kurbanov,
Osamu Yokosuka,
Michio Sata,
Yoshiyasu Karino,
Gotaro Yamada,
Kohsaku Sakaguchi,
Etsuro Orito,
Manami Inoue,
Sumbella Baqai,
Ching-Lung Lai, Masashi Mizokami
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ABSTRACT: The introduction of molecularly targeted drugs has increased the risk of reactivation of hepatitis B virus (HBV), which is a potentially fatal complication following anticancer chemotherapy even in patients who have previously resolved their HBV infection. CC chemokine receptor 4 (CCR4) has been identified as a novel molecular target in antibody therapy for patients with adult T-cell leukemia-lymphoma (ATL) and peripheral T-cell lymphoma, and the humanized anti-CCR4 monoclonal antibody mogamulizumab has been developed. We reported HBV reactivation of an ATL patient with previously resolved HBV infection after mogamulizumab treatment in a dose-finding study for this antibody. Our retrospective analysis using preserved samples also revealed the detailed kinetics of HBV DNA levels before and just after HBV reactivation.
Hepatology Research 03/2013; · 2.20 Impact Factor
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ABSTRACT: Background/Aims: Molecular epidemiology of hepatitis C virus (HCV) shows that HCV genotypes are unique with respect to their nucleotide sequence, geographical distribution and clinical relationship. Methods: In this study we enrolled 67 HCV-infected individuals with various stages of liver disease from four geographical regions of Turkey. A partial NS5B region of the HCV genome was sequenced and subjected to phylogenetic analysis to determine the circulating HCV genotypes and subtypes. Results: The results showed that HCV genotype 1 (subtype1b) is the main genetic variant of HCV in Turkey but did not reveal any Turkish indigenous phylogenetic cluster. Phylogenetic analysis showed that Turkish strains have their closest matches from both Asia (Japan) and Europe/USA. Conclusions: In view of Turkey's geographic position, HCV-1b transmission from Europe is not exceptional. This study could not establish a clear role of other HCV genotypes prevalent in neighboring Asian countries in Turkey's HCV transmission, which would need to be confirmed by further regional epidemiological studies.
Intervirology 03/2013; · 2.34 Impact Factor
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Masayuki Kurosaki,
Yasuhito Tanaka,
Nao Nishida,
Naoya Sakamoto,
Nobuyuki Enomoto,
Kentaro Matsuura,
Yasuhiro Asahina,
Mina Nakagawa,
Mamoru Watanabe,
Minoru Sakamoto,
Shinya Maekawa,
Katsushi Tokunaga, Masashi Mizokami,
Namiki Izumi
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ABSTRACT: This study aimed to develop a model for predicting anemia using the inosine triphosphatase (ITPA) genotype and to evaluate its relationship with treatment outcome. Patients with genotype 1b chronic hepatitis C (n = 446) treated with peg-interferon alpha and ribavirin (RBV) for 48 weeks were genotyped for the ITPA (rs1127354) and IL28B (rs8099917) genes. Data mining analysis generated a predictive model for anemia (hemoglobin (Hb) concentration <10 g/dl); the CC genotype of ITPA, baseline Hb <14.0 g/dl, and low creatinine clearance (CLcr) were predictors of anemia. The incidence of anemia was highest in patients with Hb <14.0 g/dl and CLcr <90 ml/min (76%), followed by Hb <14.0 g/dl and ITPA CC (57%). Patients with Hb ≥14.0 g/dl and ITPA AA/CA had the lowest incidence of anemia (17%). Patients with two predictors (high-risk) had a higher incidence of anemia than the others (64% vs. 28%, P < 0.0001). At baseline, the IL28B genotype was a predictor of a sustained virological response [adjusted odds ratio 9.88 (95% confidence interval 5.01-19.48), P < 0.0001]. In patients who achieved an early virological response, the IL28B genotype was not associated with a sustained virological response, while a high risk of anemia was a significant negative predictor of a sustained virological response [0.47 (0.24-0.91), P = 0.026]. For high-risk patients with an early virological response, giving >80% of the planned RBV dose increased sustained virological responses by 24%. In conclusion, a predictive model incorporating the ITPA genotype could identify patients with a high risk of anemia and reduced probability of sustained virological response. J. Med. Virol. © 2013 Wiley Periodicals, Inc.
Journal of Medical Virology 01/2013; · 2.82 Impact Factor
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Atsushi Kuno,
Yuzuru Ikehara,
Yasuhito Tanaka,
Kiyoaki Ito,
Atsushi Matsuda,
Satoru Sekiya,
Shuhei Hige,
Michiie Sakamoto,
Masayoshi Kage, Masashi Mizokami,
Hisashi Narimatsu
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ABSTRACT: Although liver fibrosis reflects disease severity in chronic hepatitis patients, there has been no simple and accurate system to evaluate the therapeutic effect based on fibrosis. We developed a glycan-based immunoassay, FastLec-Hepa, to fill this unmet need. FastLec-Hepa automatically detects unique fibrosis-related glyco-alteration in serum hyperglycosylated Mac-2 binding protein within 20 min. The serum FastLec-Hepa counts increased with advancing fibrosis and illustrated significant differences in medians between all fibrosis stages. FastLec-Hepa is sufficiently sensitive and quantitative to evaluate the effects of PEG-interferon-α/ribavirin therapy in a short post-therapeutic interval. The obtained fibrosis progression is equivalent to -0.30 stages/year in patients with sustained virological response, and 0.01 stages/year in relapse/nonresponders. Furthermore, long-term follow-up of the severely affected patients found hepatocellular carcinoma developed in patients after therapy whose FastLec-Hepa counts remained above a designated cutoff value. FastLec-Hepa is the only assay currently available for clinically beneficial therapy evaluation through quantitation of disease severity.
Scientific Reports 01/2013; 3:1065.
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ABSTRACT: The role of hepatitis B virus (HBV) genetics in the clinical manifestation of infection is increasingly recognized. Genotype D is one of eight currently recognized major HBV genotypes. The virus is ubiquitous worldwide, but shows different features in different regions. This study enrolled 198 patients with chronic HBV infection, 38 of whom were diagnosed with liver cirrhosis and/or hepatocellular carcinoma. HBV DNA was isolated from patients' blood samples and the entire genome and/or the basal core promoter/core promoter (BCP/CP) region was sequenced. Phylogenetic analysis of the complete genomes revealed that subgenotype D1 was the most prevalent subgenotype in Turkey, but there was no definite phylogenetic grouping according to geography for isolates from different regions within Turkey, or for isolates in Turkey relative to other parts of the world. Turkish isolates tended to be genetically similar to European and Central Asian isolates. Overall, HBV-infected patients in Turkey might be characterized by early HBeAg seroconversion, a high incidence of the A1896 core promoter mutation, and a low viral load. Genotype D characteristic mutations A1757 and T1764/G1766 were found in the BCP region. T1773 was associated with T1764/G1766 and a higher viral load. In conclusion, HBV genotype D in Turkey shares a similar clinical outcome described in Europe and Central Asia. Genotypic mutations in genotype D may be linked with disease prognosis in Turkey, but further studies with higher sample numbers and balanced clinical groups are needed.
Microbiology and Immunology 12/2012; · 1.30 Impact Factor
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Tsunamasa Watanabe,
Fuminaka Sugauchi,
Yasuhito Tanaka,
Kentaro Matsuura,
Hiroshi Yatsuhashi,
Shuko Murakami,
Sayuki Iijima,
Etsuko Iio,
Masaya Sugiyama,
Takashi Shimada,
Masakazu Kakuni,
Michinori Kohara, Masashi Mizokami
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ABSTRACT: OBJECTIVE: Recent studies have demonstrated that genetic polymorphisms near the IL28B gene are associated with the clinical outcome of pegylated interferon α (peg-IFN-α) plus ribavirin therapy for patients with chronic hepatitis C virus (HCV). However, it is unclear whether genetic variations near the IL28B gene influence hepatic interferon (IFN)-stimulated gene (ISG) induction or cellular immune responses, lead to the viral reduction during IFN treatment. DESIGN: Changes in HCV-RNA levels before therapy, at day 1 and weeks 1, 2, 4, 8 and 12 after administering peg-IFN-α plus ribavirin were measured in 54 patients infected with HCV genotype 1. Furthermore, we prepared four lines of chimeric mice having four different lots of human hepatocytes containing various single nucleotide polymorphisms (SNP) around the IL28B gene. HCV infecting chimeric mice were subcutaneously administered with peg-IFN-α for 2 weeks. RESULTS: There were significant differences in the reduction of HCV-RNA levels after peg-IFN-α plus ribavirin therapy based on the IL28B SNP rs8099917 between TT (favourable) and TG/GG (unfavourable) genotypes in patients; the first-phase viral decline slope per day and second-phase slope per week in TT genotype were significantly higher than in TG/GG genotype. On peg-IFN-α administration to chimeric mice, however, no significant difference in the median reduction of HCV-RNA levels and the induction of antiviral ISG was observed between favourable and unfavourable human hepatocyte genotypes. CONCLUSIONS: As chimeric mice have the characteristic of immunodeficiency, the response to peg-IFN-α associated with the variation in IL28B alleles in chronic HCV patients would be composed of the intact immune system.
Gut 11/2012; · 10.11 Impact Factor
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ABSTRACT: Hepatitis C virus (HCV) RNA values measured with two real-time PCR methods (Cobas Ampliprep/Cobas TaqMan, CAP/CTM, and the Abbott real-time PCR test, ART) vary among patients with genotype 1. We investigated HCV RNA values measured by two real-time PCR assays during pegylated interferon plus ribavirin (PEG-IFN/RBV) therapy. We evaluated 185 cases of chronic hepatitis C patients, among which 97 patients received the PEG-IFN/RBV therapy. HCV RNA values of CAP/CTM for genotype 1 were significantly higher than those of ART (p < 0.05) The difference in HCV RNA values (CAP/CTM minus ART) of genotype 1 was significantly higher than those in genotype 2 (p < 0.0001). The positive rate (>0) of the difference of HCV RNA values in genotype 1 was 100 % (55/55), which was significantly higher than the 78.6 % (33/42) of genotype 2 (p < 0.001). There was no difference between TT and TG/GG genotype groups in terms of difference of HCV RNA values (CAP/CTM minus ART). After PEG-IFN/RBV therapy was administered, reduction of HCV measurements was observed from day 1 for both assays regardless of genotype. The HCV value of CAP/CTM during PEG-IFN/RBV therapy was consistently higher than the value of ART, although the difference in these two values gradually became smaller during the course of therapy, and eventually no significant difference was observed near the detection level. No correlation was observed between the sustained virological response (SVR) rate and the difference between the CAP/CTM HCV values and the ART HCV value before treatment.
Journal of Infection and Chemotherapy 07/2012; · 1.80 Impact Factor
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Tomoko Date,
Takanobu Kato,
Junko Kato,
Hitoshi Takahashi,
Kenichi Morikawa,
Daisuke Akazawa,
Asako Murayama,
Keiko Tanaka-Kaneko,
Tetsutaro Sata,
Yasuhito Tanaka, Masashi Mizokami,
Takaji Wakita
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ABSTRACT: Although the recently developed infectious hepatitis C virus system that uses the JFH-1 clone enables the study of whole HCV viral life cycles, limited particular HCV strains have been available with the system. In this study, we isolated another genotype 2a HCV cDNA, the JFH-2 strain, from a patient with fulminant hepatitis. JFH-2 subgenomic replicons were constructed. HuH-7 cells transfected with in vitro transcribed replicon RNAs were cultured with G418, and selected colonies were isolated and expanded. From sequencing analysis of the replicon genome, several mutations were found. Some of the mutations enhanced JFH-2 replication; the 2217AS mutation in the NS5A interferon sensitivity-determining region exhibited the strongest adaptive effect. Interestingly, a full-length chimeric or wild-type JFH-2 genome with the adaptive mutation could replicate in Huh-7.5.1 cells and produce infectious virus after extensive passages of the virus genome-replicating cells. Virus infection efficiency was sufficient for autonomous virus propagation in cultured cells. Additional mutations were identified in the infectious virus genome. Interestingly, full-length viral RNA synthesized from the cDNA clone with these adaptive mutations was infectious for cultured cells. This approach may be applicable for the establishment of new infectious HCV clones.
Journal of Virology 07/2012; 86(19):10805-20. · 5.40 Impact Factor
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Hiromi Sawai,
Nao Nishida,
Hamdi Mbarek,
Koichi Matsuda,
Yoriko Mawatari,
Megumi Yamaoka,
Shuhei Hige,
Jong-Hon Kang,
Koichi Abe,
Satoshi Mochida, [......],
Kiyoaki Ito,
Masaya Sugiyama,
Sang Hoon Ahn,
Kwang-Hyub Han,
Jun Yong Park,
Man-Fung Yuen,
Yusuke Nakamura,
Yasuhito Tanaka, Masashi Mizokami,
Katsushi Tokunaga
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ABSTRACT: A recent genome-wide association study (GWAS) using chronic HBV (hepatitis B virus) carriers with and without hepatocellular carcinoma (HCC) in five independent Chinese populations found that one SNP (rs17401966) in KIF1B was associated with susceptibility to HCC. In the present study, a total of 580 HBV-derived HCC cases and 1351 individuals with chronic hepatitis B (CHB) or asymptomatic carrier (ASC) were used for replication studies in order to evaluate the reported association with HBV-derived HCC in other East Asian populations.
We did not detect any associations between rs17401966 and HCC in the Japanese cohorts (replication 1: OR = 1.09, 95 % CI = 0.82-1.43; replication 2: OR = 0.79, 95 % CI = 0.54-1.15), in the Korean cohort (replication 3: OR = 0.95, 95 % CI = 0.66-1.36), or in the Hong Kong Chinese cohort (replication 4: OR = 1.17, 95 % CI = 0.79-1.75). Meta-analysis using these cohorts also did not show any associations with P = 0.97.
None of the replication cohorts showed associations between rs17401966 and HBV-derived HCC. This may be due to differences in the genetic diversity among the Japanese, Korean and Chinese populations. Other reasons could be the high complexity of multivariate interactions between the genomic information and the phenotype that is manifesting. A much wider range of investigations is needed in order to elucidate the differences in HCC susceptibility among these Asian populations.
BMC Medical Genetics 06/2012; 13:47. · 2.33 Impact Factor
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ABSTRACT: The purpose of the present study was to develop a risk estimation model for the 10-year risk of hepatocellular carcinoma (HCC) that could be easily used in a general population to aid in the prevention of HCC.
Our prediction model was derived from data obtained on 17,654 Japanese aged 40 to 69 years who participated in health checkups (follow-up: 1993-2006). Cox proportional hazards regression was applied to obtain coefficients for each predictor.
During follow-up, a total of 104 cases of HCC were newly diagnosed. After checking the model fit, we incorporated age, sex, alcohol consumption, body mass index, diabetes, coffee consumption, and hepatitis B and C virus infection into the prediction model. The model showed satisfactory discrimination (Harrell's c-index=0.94) and was well calibrated (the overall observed/expected ratio=1.03, 95% confidence interval=0.83-1.29). We also developed a simple risk scoring system. Those subjects with total scores of 17 or more under this system (score range: -1 to 19) had an estimated 10-year HCC risk of over 90%; those with 4 points or less had an estimated risk of less than 0.1%.
We developed a simple 10-year risk prediction model for HCC in the Japanese general population as a public education tool.
Preventive Medicine 06/2012; 55(2):137-43. · 3.22 Impact Factor
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ABSTRACT: Hepatitis B virus (HBV) prevention program in Japan is considered one of the most successful and effective public anti-counter programs to HBV infection. However, almost all of population under twenty-five years is extremely susceptibility for HBV infection. HBV genotype A, which was not in Japan and has been from western countries, is increasing in chronic hepatitis B patients in Japan as a consequence of acute hepatitis B spreading in the younger generation through promiscuous sexual transmitted infection and the characteristics of HBV genotype A is a prolonged high HBVDNA viremia compared with other HBV genotypes. These data have strongly indicated that the main transmission route of HBV in Japan has been changed to a horizontal infection with sexual transmitted disease from perinatal transmission from HBsAg positive mothers. Although the HBV vaccine has tipped the balance in our favor, newly issues of HBV vaccine has been arisen such as vaccine escape mutant, efficacy and potency for the prevention of HBV infection, especially different HBV genotypes, HBV reactivation on the patients with HBsAg negative and anti-HBs antibody positive under systemic chemotherapy, and universal vaccination or selective vaccination and so on.
Uirusu 06/2012; 62(1):67-77.
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ABSTRACT: The inosine triphosphatase (ITPA) genotype is associated with ribavirin-induced anemia and pegylated interferon α (PEG IFN-α)-induced platelet reduction during PEG IFN-α plus ribavirin combination therapy. Natural IFN-β plus ribavirin therapy is associated with increases in platelet counts during treatment. We investigated decreases in platelet counts according to ITPA genotype during natural IFN-β/ribavirin therapy to determine if patients with low platelet counts were eligible for this combination therapy.
A total of 187 patients with chronic hepatitis C received PEG IFN-α/ribavirin or natural IFN-β/ribavirin therapy. Decreases in platelet counts based on ITPA genotype were investigated during treatment through 24 weeks.
Platelet counts decreased during week 1 of PEG IFN-α/ribavirin therapy, but increased during week 2, after which platelet counts decreased gradually. Platelet counts decreased until week 4 of natural IFN-β/ribavirin therapy, after which platelet counts increased. Platelet counts after week 8 were higher relative to pretreatment platelet counts. Patients with the ITPA-CC genotype showed a smaller decrease in platelet counts during natural IFN-β/ribavirin therapy than those with the ITPA-CA/AA genotype; platelet counts after week 8 of this therapy were higher than pretreatment platelet counts, regardless of pretreatment platelet counts. Multivariate logistic regression analyses showed that natural INF-β/ribavirin therapy was the only significant independent predictor for an increase in platelets through week 8.
Natural IFN-β/ribavirin therapy is safe for patients with the ITPA-CC genotype, even if their pretreatment platelet counts are low.
Journal of Gastroenterology and Hepatology 05/2012; 27(9):1461-6. · 2.87 Impact Factor
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ABSTRACT: IL28B polymorphism is associated with the response to pegylated interferon-α with ribavirin (PEG-IFN-α/RBV) treatment in chronic hepatitis C patients. As a genotyping assay for IL28B single nucleotide polymorphisms (SNPs) in clinical practice, the Invader Plus assay was developed. The accuracy, intra-assay, inter-assay precision, and the limit of detection of the Invader Plus assay were evaluated. Two SNPs (rs8099917 and rs12979860) associated with IL28B were genotyped by the Invader Plus and TaqMan assay in 512 Japanese patients. In comparison with direct sequencing, the Invader Plus assay showed 99% accuracy in rs8099917 and 100% accuracy in rs12979860. Intra-assay and inter-assay precision were sufficient to use in clinical practice and the detection limit was 1ngDNA/assay. Genotyping by rs8099917 showed that 361 (71%), 144 (28%) and seven (1%) of the patients were major homozygous, heterozygous and minor homozygous types, respectively. Five of the 512 cases (1%) had haplotype differences, but none showed differences between the two genotyping methods. For patients with HCV genotype 1, the prevalence of responders in the major homozygous type was 83.3%, and that of non-responders in the minor heterozygous/homozygous type was 72.5%. A convenient IL28B genotyping method using the Invader Plus assay could be useful to predict the treatment outcome in clinical practice.
Microbiology and Immunology 05/2012; 56(5):318-23. · 1.30 Impact Factor
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Kiyoaki Ito,
Atsushi Kuno,
Yuzuru Ikehara,
Masaya Sugiyama,
Hiroaki Saito,
Yoshihiko Aoki,
Teppei Matsui,
Masatoshi Imamura,
Masaaki Korenaga,
Kazumoto Murata,
Naohiko Masaki,
Yasuhito Tanaka,
Shuhei Hige,
Namiki Izumi,
Masayuki Kurosaki,
Shuhei Nishiguchi,
Michiie Sakamoto,
Masayoshi Kage,
Hisashi Narimatsu, Masashi Mizokami
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ABSTRACT: Assessment of liver fibrosis in patients with chronic hepatitis C (CHC) is critical for predicting disease progression and determining future antiviral therapy. LecT-Hepa, a new glyco-marker derived from fibrosis-related glyco-alteration of serum alpha 1-acid glycoprotein, was used to differentiate cirrhosis from chronic hepatitis in a single-center study. Herein, we aimed to validate this new glyco-marker for estimating liver fibrosis in a multicenter study. Overall, 183 CHC patients were recruited from 5 liver centers. The parameters Aspergillus oryzae lectin (AOL) / Dature stramonium lectin (DSA) and Maackia amurensis lectin (MAL)/DSA were measured using a bedside clinical chemistry analyzer in order to calculate LecT-Hepa levels. The data were compared with those of seven other noninvasive biochemical markers and tests (hyaluronic acid, tissue inhibitor of metalloproteases-1, platelet count, aspartate aminotransferase-to-platelet ratio index [APRI], Forns index, Fib-4 index, and Zeng's score) for assessing liver fibrosis using the receiver-operating characteristic curve. LecT-Hepa correlated well with the fibrosis stage as determined by liver biopsy. The area under the curve (AUC), sensitivity, and specificity of LecT-Hepa were 0.802, 59.6%, and 89.9%, respectively, for significant fibrosis; 0.882, 83.3%, and 80.0%, respectively, for severe fibrosis; and 0.929, 84.6%, and 88.5%, respectively, for cirrhosis. AUC scores of LecT-Hepa at each fibrosis stage were greater than those of the seven aforementioned noninvasive tests and markers. Conclusion: The efficacy of LecT-Hepa, a glyco-marker developed using glycoproteomics, for estimating liver fibrosis was demonstrated in a multicenter study. LecT-Hepa given by a combination of the two glyco-parameters is a reliable method for determining the fibrosis stage and is a potential substitute for liver biopsy. (HEPATOLOGY 2012).
Hepatology 04/2012; 56(4):1448-56. · 11.66 Impact Factor
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ABSTRACT: Aim: Single nucleotide polymorphisms (SNP) around interferon (IFN)-λ3 have been associated with the response to pegylated IFN-α treatment for chronic hepatitis C. Specific quantification methods for IFN-λ3 are required to facilitate clinical and basic study. Methods: Gene-specific primers and probes for IFN-λ1, 2 and 3 were designed for real-time detection PCR (RTD-PCR). Dynamic range and specificity were examined using specific cDNA clones. Total RNA from hematopoietic and hepatocellular carcinoma cell lines was prepared for RTD-PCR. Monoclonal antibodies were developed for the IFN-λ3-specific immunoassays. The immunoassays were assessed by measuring IFN-λ3 in serum and plasma. Results: The RTD-PCR had a broad detection range (10-10(7) copies/assay) with high specificity (∼10(7) -fold specificity). Distinct expression profiles were observed in several cell lines. Hematopoietic cell lines expressed high levels of IFN-λ compared with hepatocellular carcinoma cells, and Sendai virus infection induced strong expression of IFN-λ. The developed chemiluminescence enzyme immunoassays (CLEIA) detected 0.1 pg/mL of IFN-λ3 and showed a wide detection range of 0.1-10 000 pg/mL with little or no cross-reactivity to IFN-λ1 or IFN-λ2. IFN-λ3 could be detected in all the serum and plasma samples by CLEIA, with median concentrations of 0.92 and 0.86 pg/mL, respectively. Conclusion: Our newly developed RTD-PCR and CLEIA assays will be valuable tools for investigating the distribution and functions of IFN-λ3, which is predicted to be a marker for predicting outcome of therapy for hepatitis C or other virus diseases.
Hepatology Research 04/2012; 42(11):1089-99. · 2.20 Impact Factor
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ABSTRACT: ObjectiveThe association between metabolic factors and hepatocellular carcinoma (HCC) has not been well clarified. We prospectively
examined whether metabolic factors predicts the subsequent risk of HCC in the Japan Public Health Center-based Prospective
Study Cohort II, in consideration of hepatitis virus infection status.
MethodsA total of 17,590 subjects aged 40–69 participating in a questionnaire and health checkup survey during 1993–1994 were followed
for incidence of HCC through 2006. A total of 102 cases of HCC were newly documented. Hazard ratios (HRs) and 95% confidence
intervals (CIs) were calculated for metabolic factors controlling for potential confounding factors.
ResultsThe presence of metabolic factors in the aggregate was associated with a significantly increased risk of HCC, especially with
hepatitis virus infection. HCC was positively associated particularly with high glucose (HR=1.75, CI=1.11–2.74) and overweight
(HR=2.22, CI=1.42–3.48). Results were similar when analyses were limited to subjects with HCV infection.
ConclusionsAlthough metabolic factors in the aggregate may be associated with an increased risk of HCC, the main contributors to this
association under HCV infection appear to be overweight and high glucose. Improvement of these factors may be a crucial target
in preventing progression to HCC in those with HCV infection.
Cancer Causes and Control 04/2012; 20(5):741-750. · 2.88 Impact Factor
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Mostafa Ragheb,
Abeer Elkady,
Yasuhito Tanaka,
Shuko Murakami,
Fadia M Attia,
Adel A Hassan,
Mohamed F Hassan,
Mahmoud M Shedid,
Hassan B Abdel Reheem,
Anis Khan, Masashi Mizokami
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ABSTRACT: The transmission rate of intra-familial hepatitis B virus (HBV) and mode of transmission were investigated in north eastern Egypt. HBV infection was investigated serologically and confirmed by molecular evolutionary analysis in family members (N = 230) of 55 chronic hepatitis B carriers (index cases). Hepatitis B surface antigen (HBsAg) and hepatitis B core antibody (anti-HBc) prevalence was 12.2% and 23% among family members, respectively. HBsAg carriers were prevalent in the age groups; <10 (16.2%) and 21-30 years (23.3%). The prevalence of HBsAg was significantly higher in the family members of females (19.2%) than males (8.6%) index cases (P = 0.031). HBsAg and anti-HBc seropositive rates were higher significantly in the offspring of females (23%, 29.8%) than those of the males index cases (4.3%, 9.8%) (P = 0.001, 0.003), as well as higher in the offspring of an infected mother (26.5, 31.8%) than those of an infected father (4.7%, 10.5%) (P = 0.0006, 0.009). No significant difference was found in HBsAg seropositive rates between vaccinated (10.6%) and unvaccinated family members (14.8%). Phylogenetic analysis of the preS2 and S regions of HBV genome showed that the HBV isolates were of subgenotype D1 in nine index cases and 14 family members. HBV familial transmission was confirmed in five of six families with three transmission patterns; maternal, paternal, and sexual. It is concluded that multiple intra-familial transmission routes of HBV genotype D were determined; including maternal, paternal and horizontal. Universal HBV vaccination should be modified by including the first dose at birth with (HBIG) administration to the newborn of mothers infected with HBV.
Journal of Medical Virology 04/2012; 84(4):587-95. · 2.82 Impact Factor
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Hiroaki Saito,
Kiyoaki Ito,
Masaya Sugiyama,
Teppei Matsui,
Yoshihiko Aoki,
Masatoshi Imamura,
Kazumoto Murata,
Naohiko Masaki,
Hideyuki Nomura,
Hiroshi Adachi,
Shuhei Hige,
Nobuyuki Enomoto,
Naoya Sakamoto,
Masayuki Kurosaki, Masashi Mizokami,
Sumio Watanabe
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ABSTRACT: Aim: IL28B polymorphisms serve to predict response to pegylated interferon plus ribavirin therapy (PEG IFN/RBV) in Japanese patients with chronic hepatitis C (CHC) very reliably. However, the prediction by the IL28B polymorphism contradicted the virological response to PEG IFN/RBV in some patients. Here, we aimed to investigate the factors responsible for the discrepancy between the IL28B polymorphism prediction and virological responses. Methods: CHC patients with genotype 1b and high viral load were enrolled in this study. In a case-control study, clinical and virological factors were analyzed for 130 patients with rs8099917 TT genotype and 96 patients with rs8099917 TG or GG genotype who were matched according to sex, age, hemoglobin level and platelet count. Results: Higher low-density lipoprotein (LDL) cholesterol, lower γ-glutamyltransferase and the percentage of wild-type phenotype at amino acids 70 and 91 were significantly associated with the rs8099917 TT genotype. Multivariate analysis showed that rs8099917 TG or GG genotype, older age and lower LDL cholesterol were independently associated with the non-virological responder (NVR) phenotype. In patients with rs8099917 TT genotype (predicted as virological responder [VR]), multivariate analysis showed that older age was independently associated with NVR. In patients with rs8099917 TG or GG genotype (predicted as NVR), multivariate analysis showed that younger age was independently associated with VR. Conclusion: Patient age gave rise to the discrepancy between the prediction by IL28B polymorphism and the virological responses, suggesting that patients should be treated at a younger age.
Hepatology Research 03/2012; 42(10):958-965. · 2.20 Impact Factor
