担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Springer Science and Business Media LLC  

DOI： 10.1007/s12072-025-10784-9

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その他リンク： https://link.springer.com/article/10.1007/s12072-025-10784-9/fulltext.html

担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Baishideng Publishing Group Inc.  

Hepatitis B virus (HBV) infection causes acute and chronic hepatitis, compensated and decompensated cirrhosis, and hepatocellular carcinoma worldwide. The actual status of HBV infection and its treatment in certain regions of Asian and African countries, including Ethiopia, has not been well-documented thus far. Antiviral therapy for HBV infection can prevent the progression of HBV-related liver diseases and decrease the HBV-related symptoms, such as abdominal symptoms, fatigue, systemic symptoms and others. In Eastern Ethiopia, HBV-infected patients with cirrhosis were found to be positive for the HBV e antigen and to have a higher viral load than those without cirrhosis. Notably, 54.4% of patients practiced khat chewing and 18.1% consumed excessive amounts of alcohol. Tenofovir disoproxil fumarate effectively suppressed HBV DNA in those infected with HBV. It is important to elucidate the actual status of HBV infection in Eastern Ethiopia to eliminate HBV infection worldwide by 2030. HBV vaccination and the educational programs for Health Science students that provide practical strategies could help to reduce HBV infection in Eastern Ethiopia.

DOI： 10.4254/wjh.v17.i1.99209

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担当区分：筆頭著者,　最終著者,　責任著者   記述言語：日本語  

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Springer Science and Business Media LLC  

DOI： 10.1007/s12072-024-10707-0

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その他リンク： https://link.springer.com/article/10.1007/s12072-024-10707-0/fulltext.html

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Springer Science and Business Media LLC  

DOI： 10.1007/s12072-024-10702-5

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その他リンク： https://link.springer.com/article/10.1007/s12072-024-10702-5/fulltext.html

担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1111/hepr.14062

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.3390/ijms25105454

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.3892/mi.2024.162

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.3892/mi.2024.147

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Spandidos Publications  

DOI： 10.3892/mi.2024.146

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記述言語：日本語  

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担当区分：筆頭著者,　責任著者   記述言語：日本語  

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：MDPI AG  

Hepatitis E virus (HEV) genotypes 3 and 4 are zoonotic strains that are primarily transmitted through the consumption of undercooked pork or game meat. They also cause asymptomatic infections, acute hepatitis, acute-on-chronic liver failure, chronic hepatitis, and extrahepatic manifestations. Here, we report a man in his 80s who had chronic hepatitis B, took entecavir for it, and presented with higher levels of alanine aminotransferase (ALT) and jaundice. An abdominal computed tomography scan revealed choledocholithiasis with cholecystolithiasis. Although endoscopic papillary balloon dilatation was performed for the removal of a common bile duct stone, the abnormal liver function tests, including jaundice, were prolonged. After other viral hepatitis and other causes of the liver injury were ruled out, as his serum was positive for immunoglobulin A anti-HEV and HEV genotype 3b RNA, we diagnosed him as having acute hepatitis E. In this case, with chronic hepatitis B and a common bile duct stone, the prolonged abnormal results for the liver function tests seemed to be caused by HEV infection. In conclusion, in cases with high ALT levels after removing choledocholithiasis, other factors, including HEV infection, should be considered to determine the cause of abnormal liver function test results. The further examination of hepatitis D virus infection and high ALT levels may be needed in HBV-infected individuals.

DOI： 10.3390/reports6040055

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Wiley  

Abstract

In 2018, there was a hepatitis A outbreak in Japan, and HAV infection is considered a sexually transmitted disease. In general, patients with hepatitis A should be given attention, and this disease should be prevented more than ever. The Japan Agency for Medical Research and Development (AMED) Hepatitis A and E viruses (HAV and HEV) Study Group has worked on the project to create “Recent Advances in Hepatitis A Virus (HAV) Research and Clinical Practice Guidelines for HAV Infection in Japan”. The group consists of expert hepatologists and virologists who gathered at virtual meeting on 5 August 2023. Data about the pathogenesis, infection routes, diagnosis, complications, several factors for the severities, vaccination, and current and future treatments for hepatitis A were discussed and debated for a draft version. The participants assessed the quality of cited studies. The finalized recommendations are presented in this review. The recent advances in HAV research and clinical practice for HAV infection in Japan, have been reviewed by the AMED HAV and HEV Study Group.

DOI： 10.1111/hepr.13983

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掲載種別：研究論文（学術雑誌）  

We have reported that extent of proliferation of atypical hepatocytes (POAH) in non-cancerous liver in hepatocellular carcinoma and chromatin licensing and DNA replication factor 1 (CDT1) are associated with postoperative recurrence. Here, we investigated whether extent of POAH and expression of CDT1 in liver are also associated with chemically induced liver cancer in rats. Male Fisher strain rats were orally administered diethylnitrosamine (DEN) in their drinking water and sacrificed at 6, 8, 12, or 14 weeks after start of DEN administration. We serially monitored changes in extent of POAH, CDT1 expression by immunohistochemistry (IHC), and <i>CDT1</i> mRNA expression in liver by real-time quantitative PCR. The extent of POAH in liver progressed in a time-dependent manner after start of DEN administration. CDT1 expression was higher at 8 weeks than at 6 weeks by IHC, suggesting that CDT1 expression may be a marker of POAH severity. <i>CDT1</i> mRNA expression in liver was significantly higher at 12 weeks than at 6 weeks (<i>p</i><0.0001). We found that extent of POAH and the expression of CDT1 are also important factors in the development of chemical carcinogen-induced hepatocarcinogenesis. Furthermore, the association with POAH and CDT1 expression in carcinogenic process is important regardless of the cause of hepatocarcinogenesis.

DOI： 10.3164/jcbn.13-16

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：MDPI AG  

Background and Objectives: Muscle cramps are often observed in patients with liver diseases, especially advanced liver fibrosis. The exact prevalence of muscle cramps in outpatients with liver diseases in Japan is unknown. Patients and Methods: This study examined the prevalence of, and therapies for, muscle cramps in outpatients with liver diseases in Tokyo, Japan. A total of 238 outpatients with liver diseases were retrospectively examined. We investigated whether they had muscle cramps using a visual analog scale (VAS) (from 0, none, to 10, strongest), and also investigated their therapies. Results: Muscle cramps were observed in 34 outpatients with liver diseases (14.3%); their mean VAS score was 5.53. A multivariate analysis demonstrated that older age (equal to or older than 66 years) was the only significant factor as-sociated with muscle cramps. The prevalence of muscle cramps among patients with liver diseases seemed not to be higher. The problem was that only 11 (32.4%) of 34 outpatients received therapy for their muscle cramps. Conclusions: Only age is related to muscle cramps, which is rather weak, and it is possible that this common symptom may not be limited to liver disease patients.

DOI： 10.3390/medicina59091506

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担当区分：筆頭著者,　責任著者   記述言語：日本語  

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担当区分：最終著者,　責任著者   掲載種別：研究論文（学術雑誌）   出版者・発行元：MDPI AG  

The hepatitis A virus (HAV) infection causes acute hepatitis. HAV also induces acute liver failure or acute-on-chronic liver failure; however, no potent anti-HAV drugs are currently available in clinical situations. For anti-HAV drug screening, more convenient and useful models that mimic HAV replication are needed. In the present study, we established HuhT7-HAV/Luc cells, which are HuhT7 cells stably expressing the HAV HM175-18f genotype IB subgenomic replicon RNA harboring the firefly luciferase gene. This system was made by using a PiggyBac-based gene transfer system that introduces nonviral transposon DNA into mammalian cells. Then, we investigated whether 1134 US Food and Drug Administration (FDA)-approved drugs exhibited in vitro anti-HAV activity. We further demonstrated that treatment with tyrosine kinase inhibitor masitinib significantly reduced both HAV HM175-18f genotype IB replication and HAV HA11-1299 genotype IIIA replication. Masitinib also significantly inhibited HAV HM175 internal ribosomal entry-site (IRES) activity. In conclusion, HuhT7-HAV/Luc cells are adequate for anti-HAV drug screening, and masitinib may be useful for the treatment of severe HAV infection.

DOI： 10.3390/ijms24119708

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掲載種別：研究論文（学術雑誌）   出版者・発行元：MDPI AG  

In this Special Issue, “Molecular Mechanisms, Diagnosis and Treatments in Digestive Malignancy”, of the International Journal of Molecular Sciences, a total of 10 impactful articles have been published [...]

DOI： 10.3390/ijms24076471

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担当区分：筆頭著者,　最終著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Basel, Switzerland : MDPI  

DOI： 10.3390/ijms24076218

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Attiki, Greece : International Institute of Anticancer Research

DOI： 10.21873/anticanres.16249

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担当区分：最終著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Baltimore, American Society for Microbiology.  

Hepatitis A virus (HAV) infection often causes acute hepatitis, which results in a case fatality rate of 0.2% and fulminant hepatitis in 0.5% of cases. However, no specific potent anti-HAV drug is available on the market to date. In the present study, we focused on inhibition of HAV internal ribosomal entry site (IRES)-mediated translation and investigated novel therapeutic drugs through drug repurposing by screening for inhibitors of HAV IRES-mediated translation and cell viability using a reporter assay and cell viability assay, respectively. The initial screening of 1,158 drugs resulted in 77 candidate drugs. Among them, nicotinamide significantly inhibited HAV HA11-1299 genotype IIIA replication in Huh7 cells. This promising drug also inhibited HAV HM175 genotype IB subgenomic replicon and HAV HA11-1299 genotype IIIA replication in a dose-dependent manner. In the present study, we found that nicotinamide inhibited the activation of activator protein 1 (AP-1) and that knockdown of c-Jun, which is one of the components of AP-1, inhibited HAV HM175 genotype IB IRES-mediated translation and HAV HA11-1299 genotype IIIA and HAV HM175 genotype IB replication. Taken together, the results showed that nicotinamide inhibited c-Jun, resulting in the suppression of HAV IRES-mediated translation and HAV replication, and therefore, it could be useful for the treatment of HAV infection. <b>IMPORTANCE</b> Drug screening methods targeting HAV IRES-mediated translation with reporter assays are attractive and useful for drug repurposing. Nicotinamide (vitamin B3, niacin) has been shown to effectively inhibit HAV replication. Transcription complex activator protein 1 (AP-1) plays an important role in the transcriptional regulation of cellular immunity or viral replication. The results of this study provide evidence that AP-1 is involved in HAV replication and plays a role in the HAV life cycle. In addition, nicotinamide was shown to suppress HAV replication partly by inhibiting AP-1 activity and HAV IRES-mediated translation. Nicotinamide may be useful for the control of acute HAV infection by inhibiting cellular AP-1 activity during HAV infection processes.

DOI： 10.1128/jvi.01987-22

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Basel, Switzerland : MDPI  

Metabolic-dysfunction-associated fatty-liver disease (MAFLD) is the principal worldwide cause of liver disease. Individuals with nonalcoholic steatohepatitis (NASH) have a higher prevalence of small-intestinal bacterial overgrowth (SIBO). We examined gut-microbiota isolated from 12-week-old stroke-prone spontaneously hypertensive-5 rats (SHRSP5) fed on a normal diet (ND) or a high-fat- and high-cholesterol-containing diet (HFCD) and clarified the differences between their gut-microbiota. We observed that the <i>Firmicute/Bacteroidetes (F/B)</i> ratio in both the small intestines and the feces of the SHRSP5 rats fed HFCD increased compared to that of the SHRSP5 rats fed ND. Notably, the quantities of the 16S rRNA genes in small intestines of the SHRSP5 rats fed HFCD were significantly lower than those of the SHRSP5 rats fed ND. As in SIBO syndrome, the SHRSP5 rats fed HFCD presented with diarrhea and body-weight loss with abnormal types of bacteria in the small intestine, although the number of bacteria in the small intestine did not increase. The microbiota of the feces in the SHRSP5 rats fed HFCD was different from those in the SHRP5 rats fed ND. In conclusion, there is an association between MAFLD and gut-microbiota alteration. Gut-microbiota alteration may be a therapeutic target for MAFLD.

DOI： 10.3390/ijms24054603

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：New York, Academic Press.  

DOI： 10.1016/j.bbrc.2022.12.025

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Basel, Switzerland : MDPI  

DOI： 10.3390/v15010183

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

AIM: The prognosis of patients with acute liver failure has improved dramatically in the past three decades due to advances in medical critical care and use of liver transplantation (LT) in Western countries, where the etiology of acute liver failure is different from that in Japan. We analyzed patients with fulminant hepatitis (FH) and late-onset hepatic failure (LOHF) admitted to our unit over a 32-year period to clarify the nature of Japanese patients with FH and LOHF. METHODS: A total of 137 Japanese patients with FH and LOHF between 1986 and 2017 were analyzed for etiologies, disease types, treatment protocols, and outcome. RESULTS: Of 137 patients, 124 were FH (53 acute type and 71 subacute type) and 13 LOHF. The major etiology was due to viral infections in 48% of patients. A total of 23.4% of patients recovered without LT, 7.3% received LT, and 69.3% died without LT. The number of patients showed rise and fall without an evident decrease during the period. Patients with autoimmune hepatitis increased after the establishment of autoimmune hepatitis criteria in 1999 (p < 0.001), and that with indeterminate cause decreased (p < 0.01). The mean age was older in the last decade than in the first decade (p = 0.036). Spontaneous and overall survival rates were not different during the period. CONCLUSIONS: The prognosis of our patients with FH and LOHF has not improved, probably because of aging and the increasing proportion of etiologies with poor prognosis and difficult-to-treat patients without response to medications regardless of advancement of clinical management, including artificial liver support devices and LT.

DOI： 10.1111/hepr.13873

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：St. Louis, MO : Mosby  

DOI： 10.1016/j.surg.2022.11.001

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：MDPI  

<jats:p>Through living-donor liver transplantation (LDLT) from a human leukocyte antigen (HLA)-matched sibling donor, it may be possible to stop the use of immunosuppressants. It is possible that acute antibody-mediated rejection and chronic active antibody-mediated rejection through the positivity of donor-specific anti-HLA antibodies and/or T cell-mediated rejection may affect the prognosis of liver transplantation. The etiologies of liver diseases of the recipient may also affect the post-transplantation course. Herein, we report on the successful re-treatment with direct-acting antiviral (DAA) therapy against hepatitis C virus (HCV) infection in a patient who underwent a LDLT from HLA-matched sibling donor. After liver transplantation for HCV-related liver diseases, it is easy for HCV to re-infect the graft liver under a lack of immunosuppressants. DAA therapy against HCV re-infection immediately after transplantation should be commenced, and it is important to eradicate HCV for better prognosis of the recipients in LDLT for HCV-related liver diseases.</jats:p>

DOI： 10.3390/reports5040049

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Nature Publishing Group  

DOI： 10.1038/s41598-022-25201-6

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担当区分：最終著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Washington Dc : American Society For Microbiology  

Hepatitis A virus (HAV) infection is a major cause of acute viral hepatitis worldwide. Furthermore, HAV causes acute liver failure or acute-on-chronic liver failure. However, no potent anti-HAV drugs are currently available in the clinical situations. There have been some reports that amantadine, a broad-spectrum antiviral, suppresses HAV replication <i>in vitro</i>. Therefore, we examined the effects of amantadine and rimantadine, derivates of adamantane, on HAV replication, and investigated the mechanisms of these drugs. In the present study, we evaluated the effects of amantadine and rimantadine on HAV HM175 genotype IB subgenomic replicon replication and HAV HA11-1299 genotype IIIA replication in cell culture infection systems. Amantadine and rimantadine significantly inhibited HAV replication at the post-entry stage in Huh7 cells. HAV infection inhibited autophagy by suppressing the autophagy marker light chain 3 and reducing number of lysosomes. Proteomic analysis on HAV-infected Huh7 cells treated by amantadine and rimantadine revealed the changes of the expression levels in 42 of 373 immune response-related proteins. Amantadine and rimantadine inhibited HAV replication, partially through the enhancement of autophagy. Taken together, our results suggest a novel mechanism by which HAV replicates along with the inhibition of autophagy and that amantadine and rimantadine inhibit HAV replication by enhancing autophagy. <b>IMPORTANCE</b> Amantadine, a nonspecific antiviral medication, also effectively inhibits HAV replication. Autophagy is an important cellular mechanism in several virus-host cell interactions. The results of this study provide evidence indicating that autophagy is involved in HAV replication and plays a role in the HAV life cycle. In addition, amantadine and its derivative rimantadine suppress HAV replication partly by enhancing autophagy at the post-entry phase of HAV infection in human hepatocytes. Amantadine may be useful for the control of acute HAV infection by inhibiting cellular autophagy pathways during HAV infection processes.

DOI： 10.1128/jvi.00646-22

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：London : BioMed Central, 2006-  

DOI： 10.1186/s13027-022-00458-8

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記述言語：日本語   出版者・発行元：(NPO)日本がん検診・診断学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Tokyo : National Center for Global Health and Medicine  

DOI： 10.35772/ghm.2022.01026

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担当区分：最終著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Basel, Switzerland : MDPI, [2000-  

Alcohol is the one of the major causes of liver diseases and promotes liver cirrhosis and hepatocellular carcinoma (HCC). In hepatocytes, alcohol is converted to acetaldehyde, which causes hepatic steatosis, cellular apoptosis, endoplasmic reticulum stress, peroxidation, production of cytokines and reduces immune surveillance. Endotoxin and lipopolysaccharide produced from intestinal bacteria also enhance the production of cytokines. The development of hepatic fibrosis and the occurrence of HCC are induced by these alcohol metabolites. Several host genetic factors have recently been identified in this process. Here, we reviewed the molecular mechanism associated with HCC in alcoholic liver disease.

DOI： 10.3390/ijms23179679

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担当区分：筆頭著者,　責任著者   記述言語：英語  

Acute liver failure (ALF) and acute-on-chronic liver failure (ACLF), respectively, occur in patients with normal liver and patients with chronic liver diseases, including cirrhosis [...].

DOI： 10.3390/jcm11144249

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Previous RNA immunoprecipitation followed by proteomic approaches successfully demonstrated that Embryonic Lethal, Abnormal Vision, Drosophila-Like 1 (ELAVL1) interacts with hepatitis B virus (HBV)-derived RNAs. Although ELAVL family proteins stabilize AU-rich element (ARE)-containing mRNAs, their role in HBV transcription remains unclear. This study conducted loss-of-function assays of ELAVL1 for inducible HBV-replicating HepAD38 cells and HBx-overexpressed HepG2 cells. In addition, clinicopathological analyses in primary hepatocellular carcinoma (HCC) surgical samples were also conducted. Lentivirus-mediated short hairpin RNA knockdown of ELAVL1 resulted in a decrease in both viral RNA transcription and production of viral proteins, including HBs and HBx, probably due to RNA stabilization by ELAVL1. Cell growth of HepAD38 cells was more significantly impaired in ELAVL1-knockdown than those in the control group, with or without HBV replication, indicating that ELAVL1 is involved in proliferation by factors other than HBV-derived RNAs. Immunohistochemical analyses of 77 paired HCC surgical specimens demonstrated that diffuse ELAVL1 expression was detected more frequently in HCC tissues (61.0%) than in non-tumor tissues (27.3%). In addition, the abundant expression of ELAVL1 tended to affect postoperative recurrence in HBV-related HCC patients. In conclusion, ELAVL1 contributes not only to HBV replication but also to HCC cell growth. It may be a potent therapeutic target for HBV-related HCC treatment.

DOI： 10.3390/ijms23147878

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記述言語：日本語   出版者・発行元：医歯薬出版株式会社  

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：{MDPI} {AG}  

Hepatitis A virus (HAV) infection is a major cause of acute viral hepatitis globally, which can occasionally lead to acute liver failure (ALF) and acute-on-chronic liver failure (ACLF), which often result in death without liver transplantation [...].

DOI： 10.3390/ijms23137214

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担当区分：最終著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：{MDPI} {AG}  

Hepatitis A virus (HAV) infection is a major cause of acute hepatitis worldwide and occasionally causes acute liver failure and can lead to death in the absence of liver transplantation. Although HAV vaccination is available, the prevalence of HAV vaccination is not adequate in some countries. Additionally, the improvements in public health reduced our immunity to HAV infection. These situations motivated us to develop potentially new anti-HAV therapeutic options. We carried out the in silico screening of anti-HAV compounds targeting the 3C protease enzyme using the Schrodinger Modeling software from the antiviral library of 25,000 compounds to evaluate anti-HAV 3C protease inhibitors. Additionally, in vitro studies were introduced to examine the inhibitory effects of HAV subgenomic replicon replication and HAV HA11-1299 genotype IIIA replication in hepatoma cell lines using luciferase assays and real-time RT-PCR. In silico studies enabled us to identify five lead candidates with optimal binding interactions in the active site of the target HAV 3C protease using the Schrodinger Glide program. In vitro studies substantiated our hypothesis from in silico findings. One of our lead compounds, Z10325150, showed 47% inhibitory effects on HAV genotype IB subgenomic replicon replication and 36% inhibitory effects on HAV genotype IIIA HA11-1299 replication in human hepatoma cell lines, with no cytotoxic effects at concentrations of 100 μg/mL. The effects of the combination therapy of Z10325150 and RNA-dependent RNA polymerase inhibitor, favipiravir on HAV genotype IB HM175 subgenomic replicon replication and HAV genotype IIIA HA11-1299 replication showed 64% and 48% inhibitory effects of HAV subgenomic replicon and HAV replication, respectively. We identified the HAV 3C protease inhibitor Z10325150 through in silico screening and confirmed the HAV replication inhibitory activity in human hepatocytes. Z10325150 may offer the potential for a useful HAV inhibitor in severe hepatitis A.

DOI： 10.3390/ijms23116044

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Basel, Switzerland : MDPI  

DOI： 10.3390/cancers14102549

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Wyoming, N.S.W. : Ivyspring International Publisher  

DOI： 10.7150/jca.71494

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Tokyo, Japan : Springer Verlag  

DOI： 10.1007/s10396-022-01204-8

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担当区分：最終著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Basel, Switzerland : MDPI  

<jats:p>A 39-year-old male had a stomachache for 10 days before abnormal liver function tests were detected by a local doctor. Then, he was referred to us and admitted to our hospital for examination and treatment of elevated transaminases. He had taken benzbromarone to treat his hyperuricemia for seven months, and we diagnosed him with benzbromarone-induced liver injury. After the termination of benzbromarone, he finally recovered from his illness. There are several reports about benzbromarone-induced liver injury. In conclusion, as periodic liver function tests seem not to be completely performed, clinicians should regularly monitor liver function tests in patients taking benzbromarone.</jats:p>

DOI： 10.3390/reports5010008

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担当区分：最終著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：{MDPI} {AG}  

Hepatitis A virus (HAV) is a causative agent of acute hepatitis and can occasionally induce acute liver failure. However, specific potent anti-HAV drug is not available on the market currently. Thus, we investigated several novel therapeutic drugs through a drug repositioning approach, targeting ribonucleic acid (RNA)-dependent RNA polymerase and RNA-dependent deoxyribonucleic acid polymerase. In the present study, we examined the anti-HAV activity of 18 drugs by measuring the HAV subgenomic replicon and HAV HA11-1299 genotype IIIA replication in human hepatoma cell lines, using a reporter assay and real-time reverse transcription polymerase chain reaction, respectively. Mutagenesis of the HAV 5' untranslated region was also examined by next-generation sequencing. These specific parameters were explored because lethal mutagenesis has emerged as a novel potential therapeutic approach to treat RNA virus infections. Favipiravir inhibited HAV replication in both Huh7 and PLC/PRF/5 cells, although ribavirin inhibited HAV replication in only Huh7 cells. Next-generation sequencing demonstrated that favipiravir could introduce nucleotide mutations into the HAV genome more than ribavirin. In conclusion, favipiravir could introduce nucleotide mutations into the HAV genome and work as an antiviral against HAV infection. Provided that further in vivo experiments confirm its efficacy, favipiravir would be useful for the treatment of severe HAV infection.

DOI： 10.3390/ijms23052631

PubMed

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担当区分：筆頭著者,　責任著者   記述言語：日本語   出版者・発行元：日本メディカルセンター  

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記述言語：日本語   出版者・発行元：(一社)日本医療検査科学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Basel, Switzerland : MDPI  

DOI： 10.3390/medicina58020205

PubMed

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Athens : Dr. J.G. Delinassios  

DOI： 10.21873/invivo.12923

PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Athens, Greece : Hellenic Anticancer Institute  

DOI： 10.21873/anticanres.15442

PubMed

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Basel, Switzerland : MDPI AG  

DOI： 10.3390/jcm10235529

PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：London : Nature Pub. Group  

DOI： 10.1038/s41419-021-04371-7

PubMed

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Basel, Switzerland : MDPI  

DOI： 10.3390/v13112216

PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：London : Nature Publishing Group  

DOI： 10.1038/s41598-021-00889-0

PubMed

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記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

症例は70歳男性.X-12年に肝細胞癌(HCC)を合併し,局所治療と再発を繰り返していた.X-1年に腹部リンパ節転移および肺転移が出現したため,ソラフェニブによる全身化学療法を開始した.しかしその後も病勢は進行し,リンパ節転移巣からの浸潤による高度な十二指腸狭窄を来し,経口摂取不能となった.消化器外科医との緊密な協議と患者に対する十分なインフォームドコンセントを行った上で,腹腔鏡下に胃・小腸バイパス術を施行した.術後経過は良好で,経口摂取が可能となり,自宅退院となった.その後は在宅終末期医療を希望され,約6ヵ月後に原病の進行により死亡した.本症例のように進行期のHCCに起因する消化管閉塞であっても,外科的バイパス術により一定期間のQOLの向上が担保される症例が存在するものと考えられ,病状を十分に考慮した上で,適切な治療を行う必要があるものと考えられた.(著者抄録)

DOI： 10.2957/kanzo.62.656

CiNii Article

CiNii Books

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.jhep.2021.04.055

PubMed

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記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

症例は78歳女性.C型肝硬変を背景とする腫瘍径35mmと16mmの2個の肝細胞癌(HCC)の結節に対して,Emprintアブレーションシステムにて出力100W,計29分間のマイクロ波焼灼療法(MWA)を施行した.翌日のCTでは,腫瘍を含む広い焼灼範囲が得られていた.術後2日目,胸部症状の訴えがあり,十二誘導心電図においてV1-4でのT波の陰転化をみとめた.冠動脈造影検査では冠動脈に有意狭窄はなく,たこつぼ型心筋症と診断された.心不全に対してフロセミドによる心負荷軽減を行い,術後10日目に退院となった.たこつぼ型心筋症は,外科的手術など過剰な身体的ストレスも発症の一因となることが知られている.MWAは広い焼灼範囲が得られる優れたHCCの局所治療であるが,症例によっては身体的ストレスも大きいものと考えられ,たこつぼ型心筋症も合併症の一つとして念頭に置く必要がある.(著者抄録)

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その他リンク： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2021&ichushi_jid=J00263&link_issn=&doc_id=20210909130003&doc_link_id=10.2957%2Fkanzo.62.548&url=https%3A%2F%2Fdoi.org%2F10.2957%2Fkanzo.62.548&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.3390/medicina57080761

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：{MDPI} {AG}  

Zinc chloride is known to be effective in combatting hepatitis A virus (HAV) infection, and zinc ions seem to be especially involved in Toll-like receptor (TLR) signaling pathways. In the present study, we examined this involvement in human hepatoma cell lines using a human TLR signaling target RT-PCR array. We also observed that zinc chloride inhibited mitogen-activated protein kinase kinase 3 (MAP2K3) expression, which could downregulate HAV replication in human hepatocytes. It is possible that zinc chloride may inhibit HAV replication in association with its inhibition of MAP2K3. In that regard, this study set out to determine whether MAP2K3 could be considered a modulating factor in the development of the HAV pathogen-associated molecular pattern (PAMP) and its triggering of interferon-β production. Because MAP2K3 seems to play a role in antiviral immunity against HAV infection, it is a promising target for drug development. The inhibition of MAP2K3 may also prevent HAV patients from developing a severe hepatitis A infection.

DOI： 10.3390/ijms22147420

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担当区分：筆頭著者,　最終著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Springer Science and Business Media {LLC}  

DOI： 10.1007/s12072-021-10191-w

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Tokyo, Japan : Springer Verlag  

DOI： 10.1007/s10396-021-01107-0

PubMed

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担当区分：責任著者   記述言語：英語  

DOI： 10.1002/jgh3.12554

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Basel : S. Karger  

DOI： 10.1159/000515552

PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Tokyo, Japan : Springer Verlag, c2001-  

DOI： 10.1007/s10396-021-01094-2

PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：St. Louis, MO : Mosby  

DOI： 10.1016/j.surg.2021.02.027

PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Wyoming, N.S.W. : Ivyspring International Publisher, 2010-

DOI： 10.7150/jca.56436

PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：London : Nature Publishing Group  

DOI： 10.1038/s41598-021-84117-9

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Philadelphia, PA : W.B. Saunders  

DOI： 10.1053/j.gastro.2021.02.061

PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：San Diego, CA : Elsevier  

DOI： 10.1016/j.bbrc.2021.02.097

PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：London : Nature Publishing Group  

DOI： 10.1038/s41598-021-82986-8

PubMed

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Future Medicine Ltd  

London, UK : Future Medicine Ltd.

DOI： 10.2217/fvl-2020-0181

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Pleasanton, CA : Baishideng Publishing Group  

Pleasanton, CA : Baishideng Publishing Group

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Tokyo, Japan : Japanese Society of Internal Medicine  

Tokyo, Japan : Japanese Society of Internal Medicine

DOI： 10.2169/internalmedicine.6728-20.

PubMed

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Basel, Switzerland : MDPI  

Basel, Switzerland : MDPI

DOI： 10.3390/v13020207

PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Basel : S. Karger  

Basel : S. Karger

DOI： 10.1159/000512028

PubMed

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記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

症例は87歳男性。X年に肝S5の約20mm大の単発の肝細胞癌(Hepatocellular carcinoma:以下HCC)に対してラジオ波焼灼療法を施行した。術後6ヵ月の時点で再発がないことを確認し、インターフェロンフリー治療を行い、C型肝炎ウイルスを駆除した。X+2年に腫瘍マーカーの上昇を伴って右肺下葉に結節影が見つかった。肝内病変の再発はなかったことから、肺部分切除を行った結果HCCの肺転移の診断に至った。X+5年に、肺転移巣切除後に正常化していた腫瘍マーカーが再上昇し、第6胸椎に転移性骨腫瘍が見つかった。速やかに放射線照射を行うとともに経口マルチキナーゼ阻害剤による全身化学療法を開始した。昨今の抗ウイルス療法やHCCの治療法の進歩に伴い、しばしば肝内病変を伴わない遠隔転移のみの再発症例に遭遇することがある。治療経過や患者の病態を考慮した上で、適切な治療選択を行うことが予後延長に重要であると考えられた。(著者抄録)

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その他リンク： https://search-tp.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2021&ichushi_jid=J00263&link_issn=&doc_id=20210119050004&doc_link_id=10.2957%2Fkanzo.62.25&url=https%3A%2F%2Fdoi.org%2F10.2957%2Fkanzo.62.25&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

記述言語：日本語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Japan Society of Hepatology  

Case presentation: Tolvaptan has been administrated in a 61-year-old man with autosomal dominant polycystic kidney disease (ADPKD) for 11 weeks before the detection of liver dysfunction. At four weeks after the discontinuation of tolvaptan therapy, his liver dysfunction temporarily worsened. Abdominal imaging showed no sign of liver cirrhosis and biliary tract diseases. He received ursodeoxycholic acid (UDCA) with the discontinuation of the previous medication. His transaminase levels improved to levels within the normal range four months after the discontinuation of tolvaptan therapy. He was diagnosed with drug-induced liver injury associated with tolvaptan, based on the liver biopsy findings. Our case suggests that it is highly important to carefully monitor liver function in order to recognize early hepatic side effects in ADPKD patients under tolvaptan therapy. We also need to recognize the long-term effect of tolvaptan-induced liver disease after the discontinuation of tolvaptan therapy.

DOI： 10.2957/kanzo.62.72

Scopus

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記述言語：日本語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Japan Society of Hepatology  

A 78-year-old female patient underwent microwave ablation (MWA) for recurrent hepatocellular carcinoma (HCC) on segment 7 of the liver. On the day after treatment, contrast-enhanced computed tomography demonstrated a sufficient ablative area. On the second postoperative day, the patient complained of chest discomfort and shortness of breath on exertion, accompanied by a negative T wave in V1-4 on electrocardiography and an increase in serum myocardial troponin I. Coronary angiography and left ventriculography suggested Takotsubo cardiomyopathy, but not acute coronary syndrome. The patient’s symptoms gradually resolved in response to medication, and the patient was discharged 10 days after MWA. Although the pathogenesis of Takotsubo cardiomyopathy is unclear, excessive physical stress, such as surgical procedures, is associated with its development. Takotsubo cardiomyopathy should be considered a complication related to MWA for relatively large HCCs.

DOI： 10.2957/kanzo.62.548

Scopus

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記述言語：日本語   出版者・発行元：一般社団法人 日本肝臓学会  

症例は61歳男性。常染色体優性多発性嚢胞腎と診断され、トルバプタン60mg/日を開始した。11週後の血液検査で肝機能障害を認め、2日後トルバプタンの内服を中止した。しかし投与中止4週後の血液検査でトランスアミナーゼは更に上昇したために当科紹介となった。血液検査、腹部超音波検査、腹部造影CT検査で慢性肝障害、肝硬変を示唆する所見を認めなかった。ウイルス性肝炎や自己免疫性肝炎を示唆する検査所見もみられなかった。ウルソデオキシコール酸を内服開始したが、肝機能障害は遷延化したため約2ヵ月後に肝生検を施行し、トルバプタンによる薬物性肝障害と診断した。定期的に血液検査を施行したところ、トルバプタン中止約4ヵ月後にトランスアミナーゼは正常範囲内への改善がみられた。トルバプタン投与例では肝機能障害出現に注意するとともに、トルバプタン中止後も肝機能障害が遷延化する可能性に留意する必要があると考えられた。(著者抄録)

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Basel : S. Karger  

DOI： 10.1159/000519868

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担当区分：筆頭著者   記述言語：日本語   出版者・発行元：日本臨床社  

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：[Richmond, Victoria, Australia] : John Wiley & Sons Australia, Ltd.  

[Richmond, Victoria, Australia] : John Wiley & Sons Australia, Ltd.

DOI： 10.1002/jgh3.12483

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Athens : Dr. J.G. Delinassios  

Athens : Dr. J.G. Delinassios

DOI： 10.21873/invivo.12168

PubMed

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Athens : Dr. J.G. Delinassios  

Athens : Dr. J.G. Delinassios

DOI： 10.21873/invivo.12169

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVES:Quantitative image analysis is one of the methods to overcome the lack of objectivity of ultrasound (US). The aim of this study was to clarify the correlation between the features from a US image analysis and the histologic grade and microvascular invasion (MVI) of hepatocellular carcinoma (HCC) and differentiation of HCC smaller than 2 cm from borderline lesions. METHODS:We retrospectively analyzed grayscale US images with histopathologic evidence of HCC or a precancerous lesion using ImageJ version 1.47 software (National Institutes of Health, Bethesda, MD). RESULTS:A total of 148 nodules were included (borderline lesion, n = 31; early HCC [eHCC], n = 3; well-differentiated HCC [wHCC], n = 16; moderately differentiated HCC [mHCC], n = 79; and poorly differentiated HCC [pHCC], n = 19). A multivariate analysis selected lower minimum gray values (odds ratio [OR], 0.431; P = .003) and a higher standard deviation (OR, 1.880; P = .019) as predictors of HCC smaller than 2 cm. Median (range) minimum gray values of borderline lesions, eHCC, wHCC, mHCC, and pHCC were 29 (0-103), 7 (0-47), 6 (0-60), 10 (0-53), and 2 (0-38), respectively, and gradually decreased from borderline lesions to pHCC (P < 0.001). The multivariate analysis showed a higher aspect ratio (OR, 2.170; P = .001) and lower minimum gray value (OR, 0.475; P = .043) as predictors of MVI. An anechoic area diagnosed by a subjective evaluation was correlated with the minimum gray value (P < .0001). The proportion of the anechoic area gradually increased from eHCC to pHCC (P = .031). CONCLUSIONS:In a US image analysis, HCC smaller than 2 cm had features of greater heterogeneity and a lower minimum gray value than borderline lesions. Moderately differentiated HCC was smoother than borderline lesions, and the anechoic area correlated with histologic grading. Microvascular invasion was correlated with a slender shape and a lower minimum gray value.

DOI： 10.1002/jum.15439

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Attiki, Greece : International Institute of Anticancer Research  

Attiki, Greece : International Institute of Anticancer Research

DOI： 10.21873/anticanres.14449

PubMed

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Pleasanton, CA : Baishideng Publishing Group  

Pleasanton, CA : Baishideng Publishing Group

DOI： 10.35712/aig.v1.i1.5

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Tokyo : International Research and Cooperation Association for Bio & Socio-Sciences Advancement  

Tokyo : International Research and Cooperation Association for Bio & Socio-Sciences Advancement

DOI： 10.5582/bst.2020.03230

PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Basel : S. Karger  

Basel : S. Karger

DOI： 10.1159/000508809.

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: A prospective pilot study of tenofovir disoproxil fumarate (TDF) and pegylated interferon alpha 2a (P-IFN) add-on therapy was conducted to evaluate its efficacy in reducing viral antigen levels in Japanese patients with chronic hepatitis B (UMIN 000020179). METHODS: Patients with chronic hepatitis B receiving maintenance TDF therapy and exhibiting hepatitis B surface antigen (HBsAg) level > 800 IU/ml were divided into two arms. P-IFN was added for 48 weeks in the add-on arm (n = 32), while TDF monotherapy was maintained in the control arm (n = 51). Both groups were followed for 96 weeks after baseline measurements. RESULTS: Almost all patients in the control arm displayed a slow and constant reduction in HBsAg during follow-up. In contrast, roughly half of the add-on arm exhibited a sharp decline in HBsAg during P-IFN administration, which disappeared after halting P-IFN. At 96 weeks after baseline, 41% (13/32) of patients in the add-on arm had shown a rapid decrease in HBsAg, versus 2% (1/51) in the control arm (p < 0.001). Add-on therapy and increased cytotoxic T-cell response were significant factors associated with a rapid decrease in HBsAg according to multivariate analysis. In addition, higher HB core-related antigen (HBcrAg) level at baseline (p = 0.001) and add-on therapy (p = 0.036) were significant factors associated with a rapid reduction in HBcrAg. CONCLUSIONS: TDF and P-IFN add-on therapy in Japanese patients with chronic hepatitis B facilitated rapid decreases in HBsAg and HBcrAg. Further studies are needed to improve early HBsAg clearance rate.

DOI： 10.1007/s00535-020-01707-6

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Basel, Switzerland : MDPI  

Basel, Switzerland : MDPI

DOI： 10.3390/ijms21144906

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Future Medicine Ltd  

London, UK : Future Medicine Ltd.

DOI： 10.2217/fvl-2020-0104

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

Hepatitis B virus (HBV) infection is a leading cause of hepatocellular carcinoma (HCC) worldwide. The integration of HBV genomic DNA into the host genome occurs randomly, early after infection, and is associated with hepatocarcinogenesis in HBV-infected patients. Therefore, it is important to analyze HBV genome integration. We analyzed HBV genome integration in human hepatoma PLC/PRF/5 cells by HBV sequence capture-based next-generation sequencing (NGS) methods. We confirmed the results by using Sanger sequencing methods. We observed that HBV genotype A is integrated into the genome of PLC/PRF/5 cells. HBV sequence capture-based NGS is useful for the analysis of HBV genome integrants and their locations in the human genome. Among the HBV genome integrants, we performed functional analysis and demonstrated the automatic expression of some HBV proteins encoded by HBV integrants from chromosomes 3 and 11 in Huh7 cells transfected with these DNA sequences. HBV sequence capture-based NGS may be a useful tool for the assessment of HBV genome integration into the human genome in clinical samples and suggests new strategies for hepatocarcinogenesis in HBV infection.

DOI： 10.3390/genes11060661

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND:Confronting a once-in-a-century pandemic with COVID-19, tremendous stress has been placed in all walks of life worldwide. AIMS:In order to enhance scientific information interflow in the arena of liver diseases in Asia-Pacific region during this difficult time, Asian-Pacific Association for the Study of the Liver (APASL) has taken the initiative to form the APASL COVID-19 Taskforce to formulate a clinical practice guidance in Hepatology, liver-related oncology, transplantation and conduct of clinical trials. METHODS:A taskforce with 22 key opinion leaders in Hepatology from 16 countries or administration regions in Asia-Pacific regions was formed and through intense interaction via webinar, this guidance was formulated. Based on scientific data and experiences, recommendations were made in the management of liver injury, liver transplantation, autoimmune diseases, chronic liver diseases, delivery of elective and emergency services and conduct of clinical trials. CONCLUSIONS:This is the first consensus clinical guidance synthesized by APASL for our hepatologist and their allied medical personal.

DOI： 10.1007/s12072-020-10054-w

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Basel, Switzerland : MDPI  

Basel, Switzerland : MDPI

DOI： 10.3390/v12050533

PubMed

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Basel, Switzerland : MDPI  

Basel, Switzerland : MDPI

DOI： 10.3390/ijms21093349

PubMed

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

Nonalcoholic fatty liver disease (NAFLD), including nonalcoholic steatohepatitis (NASH), causes hepatic fibrosis, cirrhosis and hepatocellular carcinoma (HCC). The patatin-like phospholipase-3 (PNPLA3) I148M sequence variant is one of the strongest genetic determinants of NAFLD/NASH. PNPLA3 is an independent risk factor for HCC among patients with NASH. The obesity epidemic is closely associated with the rising prevalence and severity of NAFLD/NASH. Furthermore, metabolic syndrome exacerbates the course of NAFLD/NASH. These factors are able to induce apoptosis and activate immune and inflammatory pathways, resulting in the development of hepatic fibrosis and NASH, leading to progression toward HCC. Small intestinal bacterial overgrowth (SIBO), destruction of the intestinal mucosa barrier function and a high-fat diet all seem to exacerbate the development of hepatic fibrosis and NASH, leading to HCC in patients with NAFLD/NASH. Thus, the intestinal microbiota may play a role in the development of NAFLD/NASH. In this review, we describe recent advances in our knowledge of the molecular mechanisms contributing to the development of hepatic fibrosis and HCC in patients with NAFLD/NASH.

DOI： 10.3390/ijms21041525

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担当区分：筆頭著者,　責任著者   記述言語：日本語   出版者・発行元：じほう  

じほう

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記述言語：日本語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Life Science Publishing Co. Ltd  

Lusutrombopag has been covered by national health insurance in Japan, and now has been widely available for severe thrombocytopenia in the chronic liver disease patients. We experienced two cases of repeated treatment using lusutrombopag. Both of two patients had hepatocellular carcinoma with severe thrombocytopenia, and received repeated invasive treatments such as radiofrequency ablation and transcatheter arterial chemoembolization successfully, without severe bleeding, thrombosis or any serious adverse events. Repetitive administration of lusutrombopag was efficient and safe.

Scopus

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記述言語：日本語   出版者・発行元：株式会社日本小児医事出版社  

株式会社日本小児医事出版社

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担当区分：筆頭著者   記述言語：日本語  

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.3390/ijms21176384

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Basel : S. Karger  

Basel : S. Karger

DOI： 10.1159/000507022

PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Aim: Tolvaptan, an oral vasopressin-2 antagonist, sometimes improves hepatic edema including ascites in patients with decompensated cirrhosis. In this study, we examined the effectiveness and survival advantage in patients with the long-term administration of tolvaptan. Methods: A total of 115 patients with refractory ascites who were treated with tolvaptan were retrospectively analyzed based on their clinical records. Patients with a decrease in body weight of ≥1.5 kg from the baseline on day 7 were determined as responders. Re-exacerbation was defined as a return to the baseline BW, dose escalation of conventional diuretics, or abdominal drainage. Results: Of the 115 patients, 84 were included in this analysis. Response to tolvaptan treatment was observed in 55 out of the 84 patients (65.5%), with a mean weight reduction of 2.52 kg. Multivariate analyses demonstrated that body mass index (≥24) and urinary specific gravity (≥1.018) were significant predictors of the response to tolvaptan. However, cumulative re-exacerbation rates in responders at 6 and 12 months were 42.4 and 60.1%, respectively. Child-Pugh (classification C), HCC complication, and serum sodium levels (≥133 mEq/L) were determined as independent prognostic factors impacting overall survival (OS). Although there were no significant differences in OS between tolvaptan responders and non-responders, the responders without re-exacerbation within 3 months showed significantly longer OS than those with re-exacerbation within 3 months. Conclusion: A persistent therapeutic response, but not early response to tolvaptan, was associated with favorable survival of decompensated cirrhotic patients.

DOI： 10.7150/ijms.41454

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記述言語：日本語   掲載種別：研究論文（学術雑誌）   出版者・発行元：(一社)日本肝臓学会  

48歳、男性。C型肝炎ウイルス(hepatitis C virus、HCV)抗体陽性を指摘されていたが、抗ウイルス療法を受けていなかった。HCV-RNAは陽性で、HCV genotypeは2a型であった。切除不能肺扁平上皮癌に対して、ニボルマブ(3mg/kg)を2週ごとに3回投与した。3回目投与から2週間後に血中肝酵素の上昇を認めた。肝生検組織所見よりC型慢性肝炎の急性増悪(新犬山分類F1/A2)と診断し、ソホスブビル・リバビリン併用療法を12週間施行した。投与直後より肝機能改善がみられ、終了後24週での持続的ウイルス陰性化が得られた。その後肝機能異常は認めていない。抗PD-1抗体製剤をC型慢性肝炎患者に使用した際、肝炎の急性増悪をきたすことがあり、肝機能障害が起きた場合は速やかに肝生検の実施などを検討し、病態を鑑別することが重要であると考えられた。(著者抄録)

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その他リンク： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2019&ichushi_jid=J00263&link_issn=&doc_id=20191210020002&doc_link_id=10.2957%2Fkanzo.60.459&url=https%3A%2F%2Fdoi.org%2F10.2957%2Fkanzo.60.459&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1186/s12885-019-6322-9

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：New York, NY : Springer  

New York, NY : Springer

DOI： 10.1007/s12072-019-09988-7

PubMed

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Future Medicine Ltd  

DOI： 10.2217/fvl-2019-0089

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：日本大学医学会  

DOI： 10.4264/numa.78.5_295

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

<jats:p> Hepatitis B virus (HBV) genotypes affect the pathogenesis of disease progression during the course of HBV infection. In Japan, HBV genotype H is one of the rare HBV genotypes. We recovered HBV genotype H from a blood sample from a Japanese HIV-infected patient with acute exacerbation of chronic HBV infection. Due to the development of drugs for treating HBV and HIV, HBV genotype H and HIV coinfection has been well controlled by nucleos(t)ide analogs and highly active antiretroviral therapy, respectively, from 2002 to 2019. Further study is needed with regard to HBV genotype H and its pathogenesis. </jats:p>

DOI： 10.2217/fvl-2019-0089

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Springer Science and Business Media {LLC}  

New York, NY : Springer

DOI： 10.1007/s12072-019-09976-x

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：London : BioMed Central  

London : BioMed Central

DOI： 10.1186/s12876-019-1069-y

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Hong Kong : AME Publishing Company  

Hong Kong : AME Publishing Company

DOI： 10.21037/hbsn.2019.03.19

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Athens, Greece : Hellenic Anticancer Institute  

Athens, Greece : Hellenic Anticancer Institute

DOI： 10.21873/anticanres.13535

PubMed

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Future Medicine Ltd  

London, UK : Future Medicine Ltd.

DOI： 10.2217/fvl-2019-0031

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：New York : Springer  

New York : Springer

DOI： 10.1007/s10637-019-00801-8

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：[Australia] : Ivyspring International Publisher  

[Australia] : Ivyspring International Publisher

DOI： 10.7150/ijms.34245.

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Basel, Switzerland : MDPI  

Basel, Switzerland : MDPI

DOI： 10.3390/ijms20061406

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Basel, Switzerland : MDPI  

Almost all patients with hepatocellular carcinoma (HCC), a major type of primary liver cancer, also have liver cirrhosis, the severity of which hampers effective treatment for HCC despite recent progress in the efficacy of anticancer drugs for advanced stages of HCC. Here, we review recent knowledge concerning the molecular mechanisms of liver cirrhosis and its progression to HCC from genetic and epigenomic points of view. Because ~70% of patients with HCC have hepatitis B virus (HBV) and/or hepatitis C virus (HCV) infection, we focused on HBV- and HCV-associated HCC. The literature suggests that genetic and epigenetic factors, such as microRNAs, play a role in liver cirrhosis and its progression to HCC, and that HBV- and HCV-encoded proteins appear to be involved in hepatocarcinogenesis. Further studies are needed to elucidate the mechanisms, including immune checkpoints and molecular targets of kinase inhibitors, associated with liver cirrhosis and its progression to HCC.

DOI： 10.3390/ijms20061358

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担当区分：最終著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Wiley  

Wiley

DOI： 10.1002/jmv.25310

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1038/s41598-018-36490-1

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その他リンク： http://www.nature.com/articles/s41598-018-36490-1.pdf

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Springer  

Springer

DOI： 10.1007/s00535-018-1503-x

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記述言語：日本語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Japan Society of Hepatology  

A 48-year-old man was referred to our hospital for nivolumab administration for the treatment of unre- sectable squamous cell carcinoma of the lung. He had hepatitis C virus infection with virus genotype type 2a and was not treated with antiviral therapy with interferon or direct-acting antivirals. Nivolumab was administered three times every 2 weeks. The serum transaminase levels increased 2 weeks after the third administration. At first, drug-induced liver injury due to nivolumab was suspected
however, liver biopsy revealed acute exac¬erbation of chronic hepatitis C (new Inuyama classification, F1/A2). A 12-week combination therapy of sofosbu-vir and ribavirin was initiated. The serum transaminase levels improved, and a sustained virological response was obtained 24 weeks after the completion of antiviral therapy. No subsequent transaminase elevation has been observed.

DOI： 10.2957/kanzo.60.459

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：[Australia] : Ivyspring International Publisher  

[Australia] : Ivyspring International Publisher

DOI： 10.7150/ijms.32795

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.4254/wjh.v10.i12.898

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

Chronic hepatitis C virus (HCV) infection is common among patients with chronic kidney disease (CKD) and those on hemodialysis due to nosocomial infections and past blood transfusions. While a majority of HCV-infected patients with end-stage renal disease are asymptomatic, some may ultimately experience decompensated liver diseases and hepatocellular carcinoma. Administration of a combination of elbasvir/grazoprevir for 12 weeks leads to high sustained virologic response (SVR) rates in patients with HCV genotypes (GTs) 1a, 1b or 4 and stage 4 or 5 CKD. Furthermore, a combination of glecaprevir/pibrentasvir for 8-16 weeks also results in high SVR rates in patients with all HCV GTs and stage 4 or 5 CKD. However, these regimens are contraindicated in the presence of advanced decompensated cirrhosis. Although sofosbuvir and/or ribavirin are not generally recommended for HCV-infected patients with severe renal impairment, sofosbuvir-based regimens may be appropriate for those with mild renal impairment. To eliminate HCV worldwide, HCV-infected patients with renal impairment should be treated with interferon-free therapies.

DOI： 10.1007/s12072-018-9915-5

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Springer  

Springer

DOI： 10.1007/s12072-018-9915-5

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Carbohydrate-deficient transferrin is a biological marker of excessive drinking. The aim of this study was to evaluate the diagnostic value of a direct nephelometric immunoassay for the differential diagnosis of alcoholic and non-alcoholic liver diseases in comparison with gamma glutamyl transferase. METHODS: Serum samples were obtained from 305 subjects, including 122 patients with alcoholic and 102 cases with non-alcoholic liver diseases. Serum levels of carbohydrate-deficient transferrin were expressed as a percentage of total transferrin. RESULTS: Serum % carbohydrate-deficient transferrin levels were significantly higher in patients with alcoholic than with non-alcoholic liver diseases. Carbohydrate-deficient transferrin had better specificity than gamma glutamyl transferase to differentiate between alcoholic and non-alcoholic liver diseases.There were 8 alcoholic liver disease patients with normal gamma glutamyl transferase levels, and carbohydrate-deficient transferrin was significantly elevated in 6 of them. On the other hand, there were 25 non-alcoholic liver disease patients with elevated gamma glutamyl transferase levels; their carbohydrate-deficient transferrin levels were within the reference intervals in all cases. CONCLUSION: This simple carbohydrate-deficient transferrin immunoassay is useful to detect so-called gamma glutamyl transferase non-responding drinkers and also to exclude the possible role of excessive drinking in apparently non-alcoholic liver diseases. A large-scale prospective study is needed to further confirm the diagnostic utility of carbohydrate-deficient transferrin.

DOI： 10.1016/j.cca.2018.06.040

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掲載種別：研究論文（学術雑誌）  

BACKGROUND:Although direct-acting antiviral (DAA) developments make most of hepatitis C virus (HCV) infection curable, some HCV patients develop hepatocellular carcinoma (HCC) after curative treatment of HCV. There is much dispute whether the rapid clearance of the virus enhances the HCC development. In advance of the dispute, we should make clear the characteristics of the patients with very early occurrence and recurrence of HCC after DAA therapy because it was still unclear. METHODS:We prospectively followed consecutive patients with HCV who had received sofosbuvir (SOF)-based treatment at two hospitals. The baseline characteristics, laboratory data, and liver imaging findings were acquired. We evaluated the rate of HCC occurrence and recurrence within 1-year after DAA therapy and analyzed the associated factors of very early HCC occurrence and recurrence right after SOF therapy. RESULTS:Between July 2013 and October 2016, we studied two cohorts with HCV infection that received SOF therapy. 402 and 462 patients in Yamanashi Central Hospital and Chiba University Hospital were included in this analysis, respectively. The SVR12 rates of genotypes 1 and 2 were 98.9% (561/567) and 96.0% (285/297), respectively. 41 patients developed HCC within 1 year after SOF therapy. The cumulative HCC occurrence and recurrence rate after SOF therapy was 5.0%. The common associated factor of 1-year HCC occurrence and recurrence in all cohorts was the existence of imaging "dysplastic nodule". CONCLUSIONS:SOF regimens for HCV also have very high rates of SVR 12 in the post-market distribution. The appearance of imaging "dysplastic nodule" was an associated factor of 1-year HCC occurrence and recurrence. To investigate existence of "dysplastic nodule" by imaging surveillance before DAA treatment is useful to detect high-risk patients of very early HCC occurrence and recurrence and it should be performed.

DOI： 10.1007/s12072-018-9895-5

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Approximately 5-10% of individuals who are vaccinated with a hepatitis B (HB) vaccine designed based on the hepatitis B virus (HBV) genotype C fail to acquire protective levels of antibodies. Here, host genetic factors behind low immune response to this HB vaccine were investigated by a genome-wide association study (GWAS) and Human Leukocyte Antigen (HLA) association tests. The GWAS and HLA association tests were carried out using a total of 1,193 Japanese individuals including 107 low responders, 351 intermediate responders, and 735 high responders. Classical HLA class II alleles were statistically imputed using the genome-wide SNP typing data. The GWAS identified independent associations of HLA-DRB1-DQB1, HLA-DPB1 and BTNL2 genes with immune response to a HB vaccine designed based on the HBV genotype C. Five HLA-DRB1-DQB1 haplotypes and two DPB1 alleles showed significant associations with response to the HB vaccine in a comparison of three groups of 1,193 HB vaccinated individuals. When frequencies of DRB1-DQB1 haplotypes and DPB1 alleles were compared between low immune responders and HBV patients, significant associations were identified for three DRB1-DQB1 haplotypes, and no association was identified for any of the DPB1 alleles. In contrast, no association was identified for DRB1-DQB1 haplotypes and DPB1 alleles in a comparison between high immune responders and healthy individuals. Conclusion: The findings in this study clearly show the importance of HLA-DR-DQ (i.e., recognition of a vaccine related HB surface antigen (HBsAg) by specific DR-DQ haplotypes) and BTNL2 molecules (i.e., high immune response to HB vaccine) for response to a HB vaccine designed based on the HBV genotype C. (Hepatology 2018).

DOI： 10.1002/hep.29876

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1007/s12072-018-9883-9

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

The number of patients with nonalcoholic fatty liver diseases (NAFLD) including nonalcoholic steatohepatitis (NASH), has been increasing. NASH causes cirrhosis and hepatocellular carcinoma (HCC) and is one of the most serious health problems in the world. The mechanism through which NASH progresses is still largely unknown. Activation of caspases, Bcl-2 family proteins, and c-Jun N-terminal kinase-induced hepatocyte apoptosis plays a role in the activation of NAFLD/NASH. Apoptotic hepatocytes stimulate immune cells and hepatic stellate cells toward the progression of fibrosis in the liver through the production of inflammasomes and cytokines. Abnormalities in glucose and lipid metabolism as well as microbiota accelerate these processes. The production of reactive oxygen species, oxidative stress, and endoplasmic reticulum stress is also involved. Cell death, including apoptosis, seems very important in the progression of NAFLD and NASH. Recently, inhibitors of apoptosis have been developed as drugs for the treatment of NASH and may prevent cirrhosis and HCC. Increased hepatocyte apoptosis may distinguish NASH from NAFLD, and the improvement of apoptosis could play a role in controlling the development of NASH. In this review, the association between apoptosis and NAFLD/NASH are discussed. This review could provide their knowledge, which plays a role in seeing the patients with NAFLD/NASH in daily clinical practice.

DOI： 10.3748/wjg.v24.i25.2661

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

We have performed a genome-wide association study (GWAS) including 473 Japanese HBV (hepatitis B virus)-positive HCC (hepatocellular carcinoma) patients and 516 HBV carriers including chronic hepatitis and asymptomatic carrier individuals to identify new host genetic factors associated with HBV-derived HCC in Japanese and other East Asian populations. We identified 65 SNPs with P values < 10-4 located within the HLA class I region and three SNPs were genotyped in three independent population-based replication sets. Meta-analysis confirmed the association of the three SNPs (rs2523961: OR = 1.73, P = 7.50 × 10-12; rs1110446: OR = 1.79, P = 1.66 × 10-13; and rs3094137: OR = 1.73, P = 7.09 × 10-9). We then performed two-field HLA genotype imputation for six HLA loci using genotyping data to investigate the association between HLA alleles and HCC. HLA allele association testing revealed that HLA-A * 33:03 (OR = 1.97, P = 4.58 × 10-4) was significantly associated with disease progression to HCC. Conditioning analysis of each of the three SNPs on the HLA class I region abolished the association of HLA-A*33:03 with disease progression to HCC. However, conditioning the HLA allele could not eliminate the association of the three SNPs, suggesting that additional genetic factors may exist in the HLA class I region.

DOI： 10.1038/s41598-018-26217-7

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Blackwell Publishing  

Lipodystrophy is a rare condition that is often accompanied by one or more metabolic diseases. Here, we report a case of lipoatrophic diabetes induced by juvenile dermatomyositis. Although pioglitazone was not effective for lowering blood glucose levels, our observation suggested that it improved liver function slightly. The effectiveness of metreleptin for lowering blood glucose levels could not be determined, as we administered it in a short period. Liver biopsy showed burned-out non-alcoholic steatohepatitis. The present results show that the successful treatment of lipoatrophic diabetes induced by juvenile dermatomyositis requires an early diagnosis and therapeutic intervention.

DOI： 10.1111/jdi.12745

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Impact Journals LLC  

Background and Aim: Transarterial chemoembolization (TACE) is the standard procedure for treating Barcelona clinic liver cancer (BCLC) stage B hepatocellular carcinoma (HCC). However, it is often carried out in the treatment of BCLC stage 0/A HCC for various reasons. This study aimed to elucidate the prognosis for BCLC stage 0/A HCC patients treated with TACE or with radiofrequency ablation (RFA). Materials and Methods: The prognosis of 242 BCLC stage 0/A HCC patients within Milan criteria who underwent initially TACE or RFA were retrospectively analyzed using propensity score matching analysis. Results: The analyses of baseline patient characteristics revealed that the maximum tumor size and the proportion of BCLC stage A patients were significantly higher in patients treated with TACE than in those treated with RFA (P &lt
0.001 and 0.047, respectively). After adjusting these factors using propensity score matching (1:3 matching), patients treated with TACE (n=32) and those treated with RFA (n=96) were further analyzed. The local recurrence rate was significantly higher in the TACE group than in the RFA group (P &lt
0.001). However, the overall survival (OS) in HCC patients treated with TACE was comparable to that in HCC patients treated with RFA (1 year, 93.5 vs. 95.8%
3 years, 75.4 vs. 85.8%
5 years, 61.8 vs. 70.7%
P=0.196). Multivariate analyses followed by univariate analyses revealed that serum bilirubin level (P=0.032), serum albumin level (P=0.008), HBV-DNA (P=0.013), and tumor number (P=0.021) were independent predictors of OS. Conclusion: TACE can substitute RFA at least in some patients with BCLC 0/A HCC.

DOI： 10.18632/oncotarget.25108

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Springer New York LLC  

Background Regorafenib has been investigated for its efficacy and safety as a second-line treatment in patients with advanced hepatocellular carcinoma (HCC). We assessed the characteristics of patients with HCC treated with sorafenib who might be eligible for second-line treatment in general and regorafenib in particular. Methods Patients with HCC treated with sorafenib were retrospectively analyzed. We defined second-line candidate patients as maintaining Child–Pugh A and ECOG-PS ≤1 at the time of sorafenib failure. We also defined regorafenib candidate patients as follows: 1) continuing sorafenib at the time of radiological progression, 2) maintaining Child–Pugh A and ECOG-PS ≤ 1 at the time of sorafenib failure, and 3) continuing sorafenib 400 mg or more without intolerable adverse events at least 20 days of the last 28 days of treatment. Results Of 185 patients, 130 (70%) and 69 (37%) were candidates for second-line treatment and regorafenib. Child-Pugh score 6 and ECOG-PS 1 at the time of starting sorafenib were significantly lower in both second-line treatment and regorafenib candidate patients. Moreover, hand–foot skin reaction and liver failure during sorafenib treatment were associated with significantly low and high probabilities, respectively, of both Child–Pugh score &gt
6 and ECOG-PS &gt
1 at the time of sorafenib failure. Conclusion Regorafenib candidate patients after sorafenib failure are limited, and generally fewer than those who are candidates for second-line treatment. A lower Child–Pugh score and a better ECOG-PS were predictors of eligibility for second-line therapy and regorafenib treatment in sorafenib-treated patients with advanced HCC patients.

DOI： 10.1007/s10637-017-0507-3

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.4264/numa.77.2_123

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記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

症例は40歳、男性。慢性腎不全による腎移植後のため、近医で通院加療を受けていた。高アンモニア血症と意識消失発作を認め、同院のCT検査で腹部血行異常を疑われたため精査目的に紹介となった。超音波では、門脈から下大静脈へ連続する管腔構造が認められ、門脈側から下大静脈へ向かう血流が観察されたことから静脈管開存が疑われた。血管造影検査では下大静脈から短絡路部へバルンカテーテルが挿入され、静脈管開存の存在が確認された。バルンカテーテルによる短絡路の閉塞試験では、門脈ならびに脾静脈血流は停滞し肝内門脈血流も観察されなかった。以上より、先天性門脈欠損症I型と診断され、外科的な短絡路結紮切離による改善は期待できないと考えられた。なお肝生検組織から、原発性胆汁性胆管炎(Scheuer分類Stage 2、中沼分類Stage 3)と診断された。今後、肝移植の適応を含めた診療の展開が求められる。(著者抄録)

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その他リンク： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2018&ichushi_jid=J00263&link_issn=&doc_id=20180508070002&doc_link_id=10.2957%2Fkanzo.59.217&url=https%3A%2F%2Fdoi.org%2F10.2957%2Fkanzo.59.217&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Springer India  

DOI： 10.1007/s12072-018-9862-1

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Impact Journals LLC  

Background: Interferon-free treatment can achieve higher sustained virological response (SVR) rates, even in patients in whom hepatitis C virus (HCV) could not be eradicated in the interferon treatment era. Immune restoration in the liver is occasionally associated with HCV infection. We examined the safety and effects of interferon-free regimens on HCV patients with autoimmune liver diseases. Results: All 7 HCV patients with autoimmune hepatitis (AIH) completed treatment and achieved SVR. Three patients took prednisolone (PSL) at baseline, and 3 did not take PSL during interferon-free treatment. In one HCV patient with AIH and cirrhosis, PSL were not administered at baseline, but she needed to take 40 mg/day PSL at week 8 for liver dysfunction. She also complained back pain and was diagnosed with vasospastic angina by coronary angiography at week 11. However, she completed interferon-free treatment. All 5 HCV patients with primary biliary cholangitis (PBC) completed treatment and achieved SVR. Three of these HCV patients with PBC were treated with UDCA during interferon-free treatment. Conclusions: Interferon-free regimens could result in higher SVR rates in HCV patients with autoimmune liver diseases. As interferon-free treatment for HCV may have an effect on hepatic immunity and activity of the autoimmune liver diseases, careful attention should be paid to unexpected adverse events in their treatments. Methods: Total 12 patients with HCV and autoimmune liver diseases [7 AIH and PBC], who were treated with interferon-free regimens, were retrospectively analyzed.

DOI： 10.18632/oncotarget.24391

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: This prospective cohort study searched for factors associated with a response to nucleos(t)ide analogue/peg-interferon (NUC/peg-IFN) sequential therapy. METHODS: A total of 95 patients with chronic hepatitis B being treated with NUCs were enrolled. Immediately following NUC cessation, peg-IFN was administered at 180 µg/dose weekly for 48 weeks. RESULTS: Twenty-six patients (27%) were judged to be responders at 48 weeks after the completion of peg-IFN. Analysis of baseline factors revealed that hepatitis B surface antigen (HBsAg) <3.1 log IU/ml and HB core-related antigen (HBcrAg) <3.9 log U/ml were significant indicators of a treatment response. The levels of the markers decreased in both responders and non-responders during peg-IFN therapy but continued falling in responders only after halting peg-IFN. Lower HBsAg (<2.0 log IU/ml) and HBcrAg (<3.8 log U/ml) levels at the time of response judgment were also significantly associated with a favorable response. While lower HBcrAg at baseline was the sole predictor of decreased HBcrAg levels at judgment, lower HBsAg, lower HBcrAg, and the use of adefovir dipivoxil at baseline predicted decreased HBsAg levels at the study endpoint. The use of adefovir dipivoxil was also associated with higher serum IFN-λ3, which might have contributed to the reduction in patient HBsAg levels. CONCLUSIONS: The combinational use of HBsAg and HBcrAg levels at baseline and their changes throughout sequential therapy may be useful for predicting a response to NUC/peg-IFN sequential therapy.

DOI： 10.1007/s00535-017-1360-z

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.2169/internalmedicine.9670-17

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担当区分：筆頭著者,　責任著者   記述言語：日本語   出版者・発行元：文光堂  

文光堂

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担当区分：筆頭著者,　責任著者   記述言語：日本語  

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担当区分：筆頭著者,　責任著者   記述言語：日本語   出版者・発行元：科学評論社  

科学評論社

J-GLOBAL

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Impact Journals LLC  

Background: Interferon-free treatment results in higher sustained virologic response (SVR) rates, with no serious adverse events in hepatitis C virus (HCV)- infected patients. However, in some patients with treatment-failure in HCV NS5A inhibitor-including interferon-free regimens, the treatment-emergent HCV NS5A resistance-associated variants (RAVs), which are resistant to interferon-free retreatment including HCV NS5A inhibitors, are observed. In HCV-infected Japanese patients with daclatasvir and asunaprevir treatment failure, retreatment with sofosbuvir and ledipasvir could lead to only ~70% SVR rates. Case summary: Three HCV genotype (GT)-1b-infected cirrhotic patients who discontinued the combination of daclatasvir and asunaprevir due to adverse drug reactions within 4 weeks
retreatment with sofosbuvir and ledipasvir combination could result in SVR in these patients without RAVs. One HCV GT-1b-infected cirrhotic patient who discontinued the combination of daclatasvir and asunaprevir due to viral breakthrough at week 10
retreatment with sofosbuvir and ledipasvir combination for this patient with the treatment-emergent HCV NS5A RAV-Y93H resulted in viral relapse at week 4 after the end of the treatment. Conclusion: Retreatment with sofosbuvir and ledipasvir is effective for HCV GT- 1b patients who discontinue the combination of daclatasvir and asunaprevir within 4 weeks. The treatment response should be related to the existence of treatmentemergent HCV NS5A RAVs, but may not be related to the short duration of treatment.

DOI： 10.18632/oncotarget.23768

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.7150/ijms.23147

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.18632/oncotarget.24620

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.2169/internalmedicine.0247-17

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Impact Journals LLC  

Background: Excess iron is associated with non-alcoholic steatohepatitis (NASH). Results: mRNA expression of duodenal cytochrome b, divalent metal transporter 1, ferroportin 1, hepcidin, hephaestin and transferrin receptor 1 in liver were higher in high fat, high cholesterol-containing diet (HFCD) group than in normal diet (ND) group. mRNA levels of divalent metal transporter 1 and transferrin receptor 1, which stimulate iron absorption and excretion, were enhanced in small intestine. Epithelial mucosa of small intestine in HFCD group was characterized by plasma cell and eosinophil infiltration and increased vacuoles. Iron absorption was enhanced in this NASH model in the context of chronic inflammation of small intestinal epithelial cells, consequences of intestinal epithelial cell impairment caused by HFCD. Iron is transported to hepatocytes via portal blood, and abnormalities in iron absorption and excretion occur in small intestine from changes in iron transporter expression, which also occurs in NASH liver. Knockdown of hepcidin antimicrobial peptide led to enhanced heavy chain of ferritin expression in human hepatocytes, indicating association between hepcidin production and iron storage in hepatocytes. Conclusions: Iron-related transporters in liver and lower/upper portions of small intestine play critical roles in NASH development. Methods: Expression of iron metabolism-related genes in liver and small intestine was analyzed in stroke-prone spontaneously hypertensive rats (SHR-SP), which develop NASH. Five-week-old SHR-SP fed ND or HFCD were examined. mRNA and protein levels of iron metabolism-related genes in liver and small intestine from 12- and 19-week-old rats were evaluated by real-time RT-PCR and immunohistochemistry or Western blot.

DOI： 10.18632/oncotarget.25488

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

Hepatitis A virus (HAV) infection is one of the major causes of acute hepatitis and acute liver failure in developing and developed countries. Although effective vaccines for HAV infection are available, outbreaks of HAV infection still cause deaths, even in developed countries. One approach to control HAV infection is prevention through diet, which can inhibit HAV propagation and replication. Glucose-regulated protein 78 (GRP78) is a member of the heat shock protein 70 family of molecular chaperone required for endoplasmic reticulum stress and stress-induced autophagy. We previously showed that the elevation of GRP78 expression inhibits HAV replication. It has been reported that Japanese miso extracts, which was made from rice-koji, enhance GRP78 expression. In the present study, we used human hepatoma Huh7 cells and human hepatocyte PXB cells to examine the efficacy of Japanese miso extracts as antiviral agents against HAV. Japanese miso extracts enhanced GRP78 expression and inhibited HAV replication in human hepatocytes. Together, these results demonstrate that Japanese miso extracts may partly modulate GRP78 expression and additively or synergistically work as antivirals against HAV infection. Japanese miso extracts can be used as effective dietary supplements for severe hepatitis A.

DOI： 10.7150/ijms.27489

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：{MDPI} {AG}  

Myanmar is adjacent to India, Bangladesh, Thailand, Laos and China. In Myanmar, the prevalence of hepatitis B virus (HBV) infections is 6.5% and accounts for 60% of hepatocellular carcinoma. HBV has nine genotypes that have been identified by molecular genetic analysis. HBV genotypes are associated with several clinical features. We reviewed the prevalence of HBV genotypes in Myanmar and neighboring countries. We also reviewed HBV genotypes in refugees from Myanmar. HBV subgenotype C1 is predominant in Myanmar. As HBV genotype C is associated with hepatocellular carcinoma (HCC), it is important to screen for cirrhosis and HCC and to prevent their development in HBV-infected individuals of Myanmar.

DOI： 10.3390/diseases6010003

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記述言語：英語   出版者・発行元：BAISHIDENG PUBLISHING GROUP INC  

The recent development of direct-acting antiviral agents (DAAs) against hepatitis C virus (HCV) infection could lead to higher sustained virological response (SVR) rates, with shorter treatment durations and fewer adverse events compared with regimens that include interferon. However, a relatively small proportion of patients cannot achieve SVR in the first treatment, including DAAs with or without peginterferon and/or ribavirin. Although retreatment with a combination of DAAs should be conducted for these patients, it is more difficult to achieve SVR when retreating these patients because of resistance-associated substitutions (RASs) or treatment-emergent substitutions. In Japan, HCV genotype 1b (GT1b) is founded in 70% of HCV-infected individuals. In this minireview, we summarize the retreatment regimens and their SVR rates for HCV GT1b. It is important to avoid drugs that target the regions targeted by initial drugs, but next-generation combinations of DAAs, such as sofosbuvir/velpatasvir/voxilaprevir for 12 wk or glecaprevir/pibrentasvir for 12 wk, are proposed to be potential solution for the HCV GT1b-infected patients with treatment failure, mainly on a basis of targeting distinctive regions. Clinicians should follow the new information and resources for DAAs and select the proper combination of DAAs for the retreatment of HCV GT1b-infected patients with treatment failure.

DOI： 10.3748/wjg.v23.i46.8120

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.21926/obm.hg.1704005

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：PROUS SCIENCE, SAU-THOMSON REUTERS  

Hepatitis C virus (HCV) is a major cause of advanced liver diseases and hepatocellular carcinoma in the U.S. and Japan. In the era of direct-acting antiviral agents (DAAs) against HCV, interferon-free DAA combinations could achieve higher sustained virologic response rates in DAA-naive patients compared to interferon-including regimens. However, HCV nonstructural protein 5A (NS5A) resistance-associated variants (RAVs) could occur in treatment-failure patients treated with interferon-free regimens including first-generation HCV NS5A inhibitors. Odalasvir (ACH-3102), a second-generation HCV NS5A inhibitor, has improved potency against HCV genotype (GT)-1 (GT-1a/GT-1b), GT-2b and RAVs in vitro compared with first-generation HCV NS5A inhibitors. A phase IIa study showed that AL-335, odalasvir and simeprevir for 6 or 8 weeks were well tolerated and highly effective in HCV GT-1 patients. Odalasvir is a new HCV NS5A inhibitor with higher genetic barrier and picomolar potency than first-generation HCV NS5A inhibitors. Therefore, this agent may be useful for retreatment of DAA-failure patients treated with first-generation HCV NS5A inhibitors.

DOI： 10.1358/DOF.2017.042.09.2681978

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担当区分：筆頭著者,　責任著者   記述言語：英語   出版者・発行元：BAISHIDENG PUBLISHING GROUP INC  

Hepatitis C virus (HCV) infection induces steatosis and is accompanied by multiple metabolic alterations including hyperuricemia, reversible hypocholesterolemia and insulin resistance. Total cholesterol, low-density lipoprotein-cholesterol and triglyceride levels are increased by peginterferon and ribavirin combination therapy when a sustained virologic response (SVR) is achieved in patients with HCV. Steatosis is significantly more common in patients with HCV genotype 3 but interferon-free regimens are not always effective for treating HCV genotype 3 infections. HCV infection increases fatty acid synthase levels, resulting in the accumulation of fatty acids in hepatocytes. Of note, low-density lipoprotein receptor, scavenger receptor class B type. and Niemann-Pick C1-like 1 proteins are candidate receptors that may be involved in HCV. They are also required for the uptake of cholesterol from the external environment of hepatocytes. Among HCV-infected patients with or without human immunodeficiency virus infection, changes in serum lipid profiles are observed during interferon-free treatment and after the achievement of an SVR. It is evident that HCV affects cholesterol metabolism during interferon-free regimens. Although higher SVR rates were achieved with interferon-free treatment of HCV, special attention must also be paid to unexpected adverse events based on host metabolic changes including hyperlipidemia.

DOI： 10.3748/wjg.v23.i31.5645

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.21926/obm.hg.1703004

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：MDPI AG  

The aim of this study was to characterize the treatment response and tolerability of sofosbuvir plus ribavirin therapies in Japanese patients infected with hepatitis C virus (HCV) genotype (GT)-2. This retrospective study analyzed 114 Japanese HCV GT-2 patients treated for 12 weeks with 400 mg of sofosbuvir plus weight-based ribavirin daily. This treatment led to higher sustained virologic response at 12-weeks post-treatment (SVR12) rates in both treatment-naïve and treatment-experienced patients. The efficacy of this treatment in compensated cirrhotics was the same as that in patients with chronic hepatitis. HCV GT-2a infection and lower estimated glomerular filtration rates (eGFR) tended to be associated with SVR12. Of 114 patients, 113 completed the combination of sofosbuvir plus ribavirin for 12 weeks. Seven patients without SVR12 did not have HCV NS5B-S282 mutations. The overall SVR12 rate was 90.4% (103 of 114). More effective therapeutic options with less adverse events are desired to achieve higher SVR rates in HCV GT-2 Japanese patients.

DOI： 10.3390/biology6020030

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SPANDIDOS PUBL LTD  

Infection with hepatitis A virus (HAV) is a major cause of acute hepatitis globally and it is important to identify the mechanisms of HAV replication. Glucose-regulated protein 78 (GRP78) is an endoplasmic reticulum (ER) chaperone and serves a role in unfolded protein response pathways. Previous studies have demonstrated that GRP78 functions as an endogenous antiviral factor. In the present study, two loss-of-function studies using GRP78 were completed to elucidate the role of GRP78 in HAV infection. HAV replication was observed to be enhanced by deficient GRP78 although GRP78-deficiency also led to lower expression of ER stress molecules downstream of GRP78. Therefore, GRP78 appears to be a potential novel defensive molecule against HAV in hepatocytes.

DOI： 10.3892/etm.2017.4407

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SPANDIDOS PUBL LTD  

Hepatocellular carcinoma (HCC) is a predominantly male disease in which the androgen receptor (AR) serves an important pathogenic role in hepatocarcinogenesis. Fatty acid metabolism also contributes to hepatocarcinogenesis and is associated with the prognosis of cancer. The present study aimed to investigate the effects of the AR on fatty acid metabolism-associated gene expression in human hepatoma cell lines. AR-expression plasmids or control plasmids were transiently transfected into the human HCC cell lines Huh7 and HepG2. After 48 h, cellular protein and RNA were extracted and the expression of AR was confirmed by western blotting. Complementary DNA was synthesized and subjected to a quantitative polymerase chain reaction-based array to examine the expression of 84 fatty acid metabolism-associated genes. Overexpression of AR significantly downregulated the expression of 11 fatty acid metabolism-associated genes in Huh7 cells and 35 in HepG2 cells. The overexpression of AR also resulted in the upregulation of 6 fatty acid metabolism genes in HepG2 cells; however, it had no effect in Huh7 cells. Acyl-coenzyme A (CoA) thioesterase 7 and acyl-CoA oxidase 3 were downregulated in both cell lines. In conclusion, upregulation of AR via overexpression led to the disturbance of fatty acid metabolism-associated gene expression in human HCC cells. Therefore, the AR may serve a role in hepatocarcinogenesis via the regulation of hepatocellular fatty acid metabolism.

DOI： 10.3892/ol.2017.5973

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：PUBLIC LIBRARY SCIENCE  

Background
Noninvasive methods to accurately and conveniently evaluate liver fibrosis are desirable. MicroRNA (miR) is one of the candidates. MiRs are small RNAs consisting of 19-25 nucleotides that negatively regulate many target genes at transcriptional levels. Recently, many researchers have focused on circulating miRs in the blood stream as biomarkers. Hepatic miR-122 has been reported to have an association with viral replication and hepatic fibrosis in chronic hepatitis B virus (HBV) and hepatic C virus (HCV) infection.
Methods
We measured serum miR-122 levels in HBV- and HCV-infected patients confirmed with liver biopsy. We also investigated a novel liver fibrosis marker Wisteria floribunda agglutinin-positive Mac-2 binding protein [WFA(+)-M2BP]. We evaluated the diagnostic usefulness of these markers in hepatic fibrosis and inflammation of patients with chronic viral infection.
Results
The serum miR-122 levels of HBV-infected patients were higher than those of the control subjects. In HBV-infected patients, the serum miR-122 levels of patients with advanced liver fibrosis were significantly lower. Serum WFA(+)-M2BP was significantly higher dependent on both the staging of fibrosis and the grading of inflammatory activity in patients with both HBV and HCV infection. We also observed that higher serum WFA(+)-M2BP levels augmented the prediction of advanced liver fibrosis among HBV-infected patients with lower serum miR-122 levels.
Conclusions
A lower serum miR-122 level is a useful predictor of advanced liver fibrosis in HBV-infected patients. Serum WFA(+)-M2BP could predict liver fibrosis in both HBV and HCV infection. The combination of these markers may result in the more accurate evaluation of liver fibrosis in HBV infection.

DOI： 10.1371/journal.pone.0177302

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：MDPI AG  

Hepatocellular carcinoma (HCC) is a male-dominant disease with poor prognosis. Sorafenib is the only approved systemic chemotherapeutic drug for patients with advanced HCC. Previous studies have shown that androgen and androgen receptor (AR) are involved in human hepatocarcinogenesis and the development of HCC. Here, we discuss the recent data on AR and HCC, and the combination of sorafenib and inhibitors of AR for advanced-HCC patients. Androgen-dependent and androgen-independent AR activation exist in human hepatocarcinogenesis. AR could directly control hepatocarcinogenesis and regulate the innate immune system to influence HCC progression. Combination of sorafenib with AR inhibitors might represent a potential treatment for patients with advanced HCC.

DOI： 10.3390/cancers9050043

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：MDPI AG  

The aim of this study was to characterize the treatment response and serious adverse events of ledipasvir plus sofosbuvir therapies in Japanese patients infected with hepatitis C virus (HCV) genotype 1 (GT1). This retrospective study analyzed 240 Japanese HCV GT1 patients treated for 12 weeks with 90 mg of ledipasvir plus 400 mg of sofosbuvir daily. Sustained virological response at 12 weeks post-treatment (SVR12) was achieved in 236 of 240 (98.3%) patients. Among treatment-naive patients, SVR12 was achieved in 136 of 138 (98.6%) patients, and among treatment-experienced patients, SVR12 was achieved in 100 of 102 (98.0%) patients. In patients previously treated with peginterferon plus ribavirin with various HCV NS3/4A inhibitors, 100% SVR rates (25/25) were achieved. Two relapsers had HCV NS5A resistance-associated variants (RAVs), but no HCV NS5B-S282 was observed after they relapsed. We experienced two patients with cardiac events during treatment. In conclusion, combination of ledipasvir plus sofosbuvir for 12 weeks is a potential therapy for HCV GT1 patients. Caution is needed for HCV NS5A RAVs, which were selected by HCV NS5A inhibitors and cardiac adverse events.

DOI： 10.3390/ijms18050906

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ACADEMIC PRESS INC ELSEVIER SCIENCE  

Hepatitis B virus (HBV) surface antigen (HBsAg) loss is one of the treatment goals of chronic HBV infection. Bone marrow stromal cell antigen 2 (BST2) is one of the interferon (IFN)-stimulated genes (ISGs) and inhibits the release of various enveloped viruses. Here we examined the effects of antiviral treatment on HBsAg levels and its intracellular mechanism in HBsAg-producing hepatocytes. In PLC/PRF/ 5 and Huhl, IFNoc-2a treatment decreased HBsAg levels in their conditioned media. Upregulation of interleukin 8 (IL8), toll-like receptor 2 (TLR2) and interferon gamma -induced protein 10 (IP10) mRNAs was associated with the reduction of HBsAg in both PLC/PRF/5 and Huhl. The HBsAg level was upregulated by knockdown of IL8, TLR2 or IP10. Exogenous addition of IL8 enhanced BST2 promoter activity and BST2 mRNA expression. Additionally, knockdown of IL8 could lead to the downregulation of BST2 mRNA. Transfection of poly(I-C) enhanced IL8 and BST2 mRNA expression and inhibited HBsAg secretion from PLC/PRF/5 cells. In conclusion, IL8 might play an important role in the enhancement of BST2 and be involved in HBsAg eradication. (C) 2017 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.bbrc.2017.03.150

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：PUBLIC LIBRARY SCIENCE  

Background Despite recent advances in treatment strategies, it is still difficult to cure patients with hepatocellular carcinoma (HCC). Sorafenib is the only approved multiple kinase inhibitor for systemic chemotherapy in patients with advanced HCC. The majority of advanced HCC patients are resistant to sorafenib. The mechanisms of sorafenib resistance are still unknown.
Methods The expression of molecules involved in the mitogen-activated protein kinase (MAPK) signaling pathway in human hepatoma cell lines was examined in the presence or absence of sorafenib. Apoptosis of human hepatoma cells treated with sorafenib was investigated, and the expression of Jun proto-oncogene (c-Jun) was measured.
Results The expression and phosphorylation of c-Jun were enhanced in human hepatoma cell lines after treatment with sorafenib. Inhibiting c-Jun enhanced sorafenib-induced apoptosis. The overexpression of c-Jun impaired sorafenib-induced apoptosis. The expression of osteopontin, one of the established AP-1 target genes, was enhanced after treatment with sorafenib in human hepatoma cell lines.
Conclusions The protein c-Jun plays a role in sorafenib resistance in human hepatoma cell lines. The modulation and phosphorylation of c-Jun could be a new therapeutic option for enhancing responsiveness to sorafenib. Modulating c-Jun may be useful for certain HCC patients with sorafenib resistance.

DOI： 10.1371/journal.pone.0174153

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Springer Tokyo  

We describe a case of acute liver failure (ALF) without hepatic encephalopathy with marked elevation of aminotransferase due to hepatitis A, according to the revised Japanese criteria of ALF. This liver biopsy of the patient showed compatible to acute viral hepatitis and she immediately recovered without intensive care. She had no comorbid disorders. Of interest, phylogenetic tree analysis using almost complete genomes of hepatitis A virus (HAV) demonstrated that the HAV isolate from her belonged to the HAV subgenotype IA strain and was similar to the HAJFF-Kan12 strain (99% nucleotide identity) or FH1 strain (98% nucleotide identity), which is associated with severe or fulminant hepatitis A. Careful interpretation of the association between HAV genome variations and severity of hepatitis A is needed and the mechanism of the severe hepatitis should be explored.

DOI： 10.1007/s12328-016-0700-5

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：OXFORD UNIV PRESS  

A previous genome- wide association study (GWAS) performed in 963 Japanese individuals (487 primary biliary cholangitis [PBC] cases and 476 healthy controls) identified TNFSF15 (rs4979462) and POU2AF1 (rs4938534) as strong susceptibility loci for PBC. In this study, we performed GWAS in additional 1,923 Japanese individuals (894 PBC cases and 1,029 healthy controls),and combined the results with the previous data. This GWAS, together with a subsequent replication study in an independent set of 7,024 Japanese individuals (512 PBC cases and 6,512 healthy controls), identified PRKCB (rs7404928) as a novel susceptibility locus for PBC ( odds ratio [OR] = 1.26, P = 4.13 x 10(-9)). Furthermore, a primary functional variant of PRKCB (rs35015313) was identified by genotype imputation using a phased panel of 1,070 Japanese individuals from a prospective, general population cohort study and subsequent in vitro functional analyses. These results may lead to improved understanding of the disease pathways involved in PBC, forming a basis for prevention of PBC and development of novel therapeutics.

DOI： 10.1093/hmg/ddw406

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担当区分：筆頭著者,　責任著者   記述言語：英語  

DOI： 10.21926/obm.hg.1701002

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.21926/obm.hg.1701001

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Springer Tokyo  

Background: Hepatitis B e antigen (HBeAg)-negative inactive carriers, the majority of hepatitis B virus (HBV) carriers, are considered to have a good prognosis. The definition of the inactive HBV carrier state has been based on HBV DNA and alanine aminotransferase (ALT) levels. Here we conducted a prospective study involving 18 hospitals to clarify the prognosis of HBeAg-negative inactive carriers. Methods: Three hundred eighty-eight HBeAg-negative inactive carriers at the baseline were observed prospectively from January 2011 to November 2015. We evaluated the primary end point, defined as the development of cirrhosis, hepatocellular carcinoma (HCC), or liver-related death. Also, we analyzed the factors associated with inactive carrier dropout and markedly increased levels of ALT or HBV DNA or both during the follow-up period. Results: At the baseline, the mean age was 57.5 ± 13.1 years and 42 % of patients were male. No individual developed cirrhosis, HCC, or liver-related death during the follow-up period (1035 ± 252 days). Loss of inactive carrier status was seen in 75 patients (19.3 %). Factors associated with failure to meet the inactive carrier criteria in the multivariate analysis were the levels of ALT (hazard ratio 1.13, 95 % confidence interval 1.07–1.19, p &lt
 0.001), HBV DNA (hazard ratio 2.70, 95 % confidence interval 1.63–4.49, p &lt
 0.001), and γ-glutamyl transpeptidase (hazard ratio 1.01, 95 % confidence interval 1.00–1.02, p = 0.003) at the baseline. Conclusions: Most inactive carriers in Japan had a good prognosis. However, despite the short observation period, some patients had loss of IC status. The long-term prognosis of inactive carriers remains unclear
therefore, careful follow-up of inactive carriers is needed.

DOI： 10.1007/s00535-016-1229-6

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ACADEMIC PRESS INC ELSEVIER SCIENCE  

Although the interaction between host and hepatitis A virus (HAV) factors could lead to severe hepatitis A, the exact mechanism of acute liver failure caused by HAV infection is not yet fully understood. The effects of metabolic diseases such as dyslipidemia or diabetes mellitus on HAV replication are still unknown. Here, we examined the effects of free fatty acids or high-concentration glucose on HAV replication and the effects on mitogen-activated protein kinase signaling pathway-related genes in human hepatocytes. We discovered a novel effect of free fatty acids or high-concentration glucose on HAV replication in association with a reduction in the expression of glucose-regulated protein 78 (GRP78). We also observed that thapsigargin induced GRP78 expression and inhibited HAV replication. These findings may provide a new interpretation of the relationship between metabolic diseases and severity of hepatitis A and suggest a new understanding of the mechanism of severe HAV infection. (C)16 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.bbrc.2016.12.080

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担当区分：筆頭著者,　最終著者,　責任著者   記述言語：英語   出版者・発行元：SPRINGER  

Progress in interferon-free treatment against hepatitis C virus (HCV) has remained a challenge in patients with decompensated cirrhosis due to a paucity of information on efficacy and safety profiles. This review illustrates that interferon-free treatment could result in greater than 85 % sustained virological response (SVR) rates in patients with HCV genotype 1 and decompensated cirrhosis. The combination of pangenotypic HCV NS5A inhibitor velpatasvir and HCV NS5B inhibitor sofosbuvir has demonstrated high SVR rates in patients with HCV genotypes 1, 2, 3, 4 or 6 and decompensated cirrhosis. Certain patients discontinued treatment due to adverse events, death or having liver transplantation. Taken together, interferon-free treatment could produce higher SVR rates in decompensated hepatic cirrhosis. However, as adverse events were occasionally observed, liver transplantation should always be considered as well. Further improvements in treatment are called for in patients with decompensated cirrhosis.

DOI： 10.1007/s12072-016-9749-y

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：MDPI AG  

Determination of hepatitis C virus (HCV) genotypes plays an important role in the direct-acting agent era. Discrepancies between HCV genotyping and serotyping assays are occasionally observed. Eighteen samples with discrepant results between genotyping and serotyping methods were analyzed. HCV serotyping and genotyping were based on the HCV nonstructural 4 (NS4) region and 5'-untranslated region (5'-UTR), respectively. HCV core and NS4 regions were chosen to be sequenced and were compared with the genotyping and serotyping results. Deep sequencing was also performed for the corresponding HCV NS4 regions. Seventeen out of 18 discrepant samples could be sequenced by the Sanger method. Both HCV core and NS4 sequences were concordant with that of genotyping in the 5'-UTR in all 17 samples. In cloning analysis of the HCV NS4 region, there were several amino acid variations, but each sequence was much closer to the peptide with the same genotype. Deep sequencing revealed that minor clones with different subgenotypes existed in two of the 17 samples. Genotyping by genome amplification showed high consistency, while several false reactions were detected by serotyping. The deep sequencing method also provides accurate genotyping results and may be useful for analyzing discrepant cases. HCV genotyping should be correctly determined before antiviral treatment.

DOI： 10.3390/ijms18010172

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：IVYSPRING INT PUBL  

Background: Genetic variation near the interferon lambda 3 (IFNL3) is known to be associated with response to pegylated interferon (pegIFN) and ribavirin combination therapy in patients with chronic hepatitis C virus (HCV) infection which is often accompanied by hepatic steatosis.
Aims: We examined whether this genetic variation is associated with host lipids and treatment response.
Methods: A total of 101 Japanese patients who had underwent liver biopsy before treatment with pegIFN and ribavirin for HCV genotype 1b infection were retrospectively analyzed for association between IFNL3 genotypes (rs8099917) and clinical factors including histopathological features of the liver. The presence of &gt;5% steatosis in the liver specimen was defined as hepatic steatosis.
Results: Forty patients (40%) had liver steatosis before therapy. Patients with IFNL3 minor genotype (non-TT) showed lower low-density lipoprotein cholesterol level (p=0.0045), higher.-glutamyl transpeptidase level (p=0.0003) and higher prevalence of hepatic steatosis (p=0.0002). Advanced fibrosis [odds ratio (OR) 4.63, p=0.03] and IFNL3 major genotype (OR 0.13, p= 0.001) were 2 independent factors for determining the presence of hepatic steatosis. Among the factors associated with sustained virological response, IFNL3 genotype was the most significant predictor, as per multivariate analysis.
Conclusions: Our results confirmed that IFNL3 genotype is associated with hepatic steatosis as well as IFN response.

DOI： 10.7150/ijms.20171

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担当区分：筆頭著者,　責任著者   記述言語：日本語  

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.3390/diseases4040038

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY  

Background Corticosteroid (CS) has been introduced in most acute liver failure (ALF) patients for the purpose of suppressing pro-inflammatory cytokines in Japan where a shortage of donor livers exists, whereas CS use is evaluated to be no benefit in Western countries. In the present study, we aimed to clarify the association between infectious complications and CS use in ALF, and determine when to evaluate treatment response and consider the timing for switching to liver transplantation (LT).
Methods Corticosteroid was administered to patients in the early stage prospectively. Clinical and biochemical features of 110 adult patients were analyzed.
Results Corticosteroids were administered to 78 (71%) patients. The duration between start of CS and onset of infection was 17 +/- 10 days. Multivariate analysis revealed that infection was associated with age 50 years (P = 0.034) and T-BIL &gt; 15 mg/dl (P &lt; 0.001), and not with CS use (P = 0.10). Accumulative incidence of infection was not different between patients with and without CS (P = 0.18).
Conclusions Corticosteroid use did not significantly increase the incidence of infection. Two weeks after introduction of CS is a critical point for evaluating treatment response, avoiding infectious complications and switching to LT.

DOI： 10.1002/jhbp.399

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：S. Karger AG  

A 24-year-old man was admitted due to acute hepatitis with unknown etiology. After his condition and laboratory data gradually improved with conservative therapy, he was discharged 1 month later. Two months after his discharge, however, liver dysfunction reappeared. After his mother accidentally revealed that he took complementary and alternative medicine, discontinuation of the therapy caused his condition to improve. Finally, he was diagnosed with a recurrent drug-induced liver injury associated with Japanese complementary and alternative medicine. It is important to take the medical history in detail and consider complementary and alternative medicine as a cause of liver disease.

DOI： 10.1159/000452209

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SPRINGER  

The Asian-Pacific Association for the Study of the Liver (APASL) convened an international working party on the "APASL consensus statements and recommendation on management of hepatitis C" in March, 2015, in order to revise "APASL consensus statements and management algorithms for hepatitis C virus infection (Hepatol Int 6:409-435, 2012)". The working party consisted of expert hepatologists from the Asian-Pacific region gathered at Istanbul Congress Center, Istanbul, Turkey on 13 March 2015. New data were presented, discussed and debated to draft a revision. Participants of the consensus meeting assessed the quality of cited studies. Finalized recommendations on treatment of hepatitis C are presented in this review.

DOI： 10.1007/s12072-016-9717-6

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SPRINGER JAPAN KK  

BackgroundThe aim of the present study was to examine the diagnostic ability of two-dimensional shear wave elastography (2D-SWE) with propagation-based reliability for grading of hepatic fibrosis and portal hypertension.
MethodsThis prospective study (UMIN000022838) consisted of 135 subjects. Phase I (n=40) examined the effect of standard deviation (SD)/median as the reliability criterion of 2D-SWE, and phase II (n=95) compared the diagnostic ability of 2D-SWE under the best SD/median value and transient elastography (TE).
ResultsPhase I reported 0.49 as a best cut-off SD/median value. In phase II, the elasticity showed a correlation between the 2D-SWE and TE (r=0.88, P &lt;0.001). The area under the receiver operating characteristic curve (AUROC) was comparable between the 2D-SWE and TE (0.936 and 0.948 for chronic hepatitis, P=0.34; 0.939 and 0.956 for cirrhosis, P=0.25). The hepatic venous pressure gradient showed a positive correlation with the 2D-SWE (r=0.435, P=0.043) and TE (r=0.378, P=0.083) in 22 patients. The AUROC was comparable between the 2D-SWE (0.844 for 10mmHg, 0.838 for 12mmHg) and TE (0.781 for 10mmHg, P=0.484; 0.800 for 12mmHg, P=0.589).
Conclusions2D-SWE is promising for the assessment of the grade of hepatic fibrosis and portal hypertension, with the SD/median value as a reliability criterion.

DOI： 10.1002/jhbp.379

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SPRINGER  

The Asian Pacific Association for the Study of the Liver (APASL) convened an international working party on "APASL consensus statements and recommendations for management of hepatitis C" in March 2015 to revise the "APASL consensus statements and management algorithms for hepatitis C virus infection" (Hepatol Int 6:409-435, 2012). The working party consisted of expert hepatologists from the Asian-Pacific region gathered at the Istanbul Congress Center, Istanbul, Turkey on 13 March 2015. New data were presented, discussed, and debated during the course of drafting a revision. Participants of the consensus meeting assessed the quality of the cited studies. The finalized recommendations for hepatitis C prevention, epidemiology, and laboratory testing are presented in this review.

DOI： 10.1007/s12072-016-9736-3

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.3892/ijmm.2016.2643

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：BIOMED CENTRAL LTD  

Background: Ulcerative colitis is a lifelong, immunologically mediated disease. Direct-acting antivirals (DAAs) are now available for the treatment of chronic hepatitis C virus (HCV) infection. An interferon-free regimen appears useful, safe and effective for many patients for whom interferon-based treatment is contraindicated.
Case presentation: We studied a 56-year-old treatment-naive Japanese man with chronic HCV genotype 2b infection who had ulcerative colitis. This patient was treated with sofosbuvir and ribavirin for 12 weeks. During treatment, diarrhoea and bloody faeces were frequent. After ribavirin was reduced to 400 mg daily, these symptoms decreased. Finally, the patient achieved a sustained virologic response 12 weeks after the stoppage of the treatment.
Conclusion: Clinicians should pay careful attention to the ribavirin dose in the treatment of certain HCV patients with inflammatory bowel disease who are receiving sofosbuvir plus ribavirin.

DOI： 10.1186/s12876-016-0480-x

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担当区分：責任著者   記述言語：英語   出版者・発行元：BAISHIDENG PUBLISHING GROUP INC  

Myanmar is adjacent to India, Bangladesh, Thailand, Laos and China. In Myanmar, the prevalence of hepatitis C virus (HCV) infection is 2%, and HCV infection accounts for 25% of hepatocellular carcinoma. In this study, we reviewed the prevalence of HCV genotypes in Myanmar. HCV genotypes 1, 3 and 6 were observed in volunteer blood donors in and around the Myanmar city of Yangon. Although there are several reports of HCV genotype 6 and its variants in Myanmar, the distribution of the HCV genotypes has not been well documented in areas other than Yangon. Previous studies showed that treatment with peginterferon and a weight-based dose of ribavirin for 24 or 48 wk could lead to an 80%-100% sustained virological response (SVR) rates in Myanmar. Current interferon-free treatments could lead to higher SVR rates (90%-95%) in patients infected with almost all HCV genotypes other than HCV genotype 3. In an era of heavy reliance on direct-acting antivirals against HCV, there is an increasing need to measure HCV genotypes, and this need will also increase specifically in Myanmar. Current available information of HCV genotypes were mostly from Yangon and other countries than Myanmar. The prevalence of HCV genotypes in Myanmar should be determined.

DOI： 10.3748/wjg.v22.i27.6095

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担当区分：責任著者   記述言語：英語   出版者・発行元：SPRINGER  

Hepatitis B virus (HBV) is a major cause of acute and chronic hepatitis, cirrhosis and hepatocellular carcinoma, particularly in Asia-Pacific countries. The major complications in HBV carriers are hepatocellular carcinoma (HCC), liver failure and esophageal varices following the progression to cirrhosis, while some develop HCC without cirrhosis. The progression to liver fibrosis and these other complications could be prevented by treatment with nucleos(t)ide analogues (NUCs); however, NUCs must be continuously administered for a long time. Peginterferon could lead to HBV surface antigen loss. It is difficult to use peginterferon in HBV-infected patients with decompensated cirrhosis. Acute liver failure due to HBV infection and acute exacerbation of chronic hepatitis B could be treated by NUCs. Universal vaccination programs against HBV could prevent new HBV infections globally. Here, we review the currently available treatments for HBV infection.

DOI： 10.1007/s12072-016-9720-y

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1007/s00535-016-1229-6

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Ivyspring International Publisher  

Background. All-oral combination of direct-acting antivirals could lead to higher sustained virologic response (SVR) in hepatitis C virus (HCV)-infected patients. In the present study, we examined the efficacy and safety of the dual oral treatment with HCV nonstructural protein (NS) 5A inhibitor daclatasvir (DCV) plus HCV NS3/4A inhibitor asunaprevir (ASV) for 24 weeks in real-world HCV genotype 1-infected Japanese individuals. Methods. After screening for HCV NS5A resistance-associated variants (RAVs) by PCR invader assay, a total of 54 Japanese patients infected with HCV genotype 1 treated with DCV plus ASV were retrospectively analyzed. SVR12 was used for evaluation of the virologic response. Results. Of the total 54 patients, 46 patients (85.2%) were treated with DCV plus ASV for 24 weeks and achieved SVR12. The other 8 patients (14.8%) discontinued this treatment before 24 weeks due to adverse events. Of these 8 patients, 5 and 3 patients did and did not achieve SVR12, respectively. Finally, 51 of 54 (94.4%) patients achieved SVR12. Conclusion. Treatment with DCV and ASV after screening for HCV NS5A RAVs by PCR invader assay is effective and safe in the treatment of real-world HCV genotype 1-infected patients in Japan.

DOI： 10.7150/ijms.15519

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掲載種別：研究論文（学術雑誌）  

We describe a case of autoimmune hepatitis (AIH) that may have occurred following drug-induced liver injury with camostat mesilate and/or benzbromarone in an elderly patient. The patient's liver biopsy showed chronic active hepatitis and autoimmune hepatitis. Stopping the use of these drugs did not lead to complete remission, but the use of a low dose of corticosteroids completely cured his liver dysfunction. In the present case, liver dysfunction was caused by an autoimmune mechanism. Special attention should be paid to idiopathic AIH and drug-induced AIH in elderly patients.

DOI： 10.1007/s12328-016-0648-5

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SPRINGER JAPAN KK  

BackgroundAutoimmune hepatitis (AIH) is one of major etiologies of acute liver failure (ALF), and the survival rate without liver transplantation (LT) of patients with fulminant AIH is especially poor worldwide. We investigated the clinicopathological features of infectious complications in autoimmune ALF retrospectively and tried to determine when to continue corticosteroid (CS) treatment or abandon it for LT.
MethodsTwenty patients with autoimmune ALF, comprising five severe hepatitis, 13 fulminant hepatitis and two late onset hepatic failure, were analyzed.
ResultsCorticosteroids were administered to 19 patients. Seventeen infectious complications were observed in 12 patients. The median (range) duration between the introduction of CS and onset of infection was 15 (10-41) days. There were no significant differences in clinicobiochemical features between patients with and without infection. Of 20 patients, eight (40%) recovered without LT, four (20%) received LT and eight (40%) died without LT. Dead or transplanted patients had more advanced liver failure on admission than recovered ones (P&lt;0.01).
ConclusionsTwo-week after the introduction of CS is a critical point for avoiding infectious complications. Therefore, we should have evaluated efficacy of CS and performed LT by then at the latest in case of failure to improve.

DOI： 10.1002/jhbp.326

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：PUBLIC LIBRARY SCIENCE  

Background
The induction of apoptosis in hepatic stellate cells (HSCs) is a promising therapeutic strategy against hepatitis B virus (HBV)-related hepatic fibrosis. The underlying mechanisms of apoptosis in HSCs, however, are unknown under consideration of HBV infection. In this study, the effects of HBV on apoptosis and endoplasmic reticulum (ER) stress signaling in HSCs were examined.
Methods
The effects of conditioned media (CM) from HepG2.2.15 on apoptosis induced by the proteasome inhibitor MG132 in LX-2 and HHSteC were studied in regard to c-Jun. In combination with c-Fos, c-Jun forms the AP-1 early response transcription factor, leading to AP-1 activation, signal transduction, endoplasmic reticulum (ER) stress and apoptosis.
Results
In LX-2 cells, MG132 treatment was associated with the phosphorylation of c-Jun, activation of AP-1 and apoptosis. However, in the presence of CM from HepG2.2.15, these phenomena were attenuated. In HHSteC cells, similar results were observed. HBV genomic DNA is not involved in the process of HSC apoptosis. It is possible that HBeAg has an inhibitory effect on MG132-induced apoptosis in LX-2. We also observed the upregulation of several ER stress-associated genes, such as cAMP responsive element binding protein 3-like 3, inhibin-beta A and solute carrier family 17-member 2, in the presence of CM from HepG2.2.15, or CM from PXB cells infected with HBV.
Conclusions
HBV inhibits the activation of c-Jun/AP-1 in HSCs, contributing to the attenuation of apoptosis and resulting in hepatic fibrosis. HBV also up-regulated several ER stress genes associated with cell growth and fibrosis. These mechanistic insights might shed new light on a treatment strategy for HBV-associated hepatic fibrosis.

DOI： 10.1371/journal.pone.0146314

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：KARGER  

Objective: The utility of risk scores to predict the development of hepatocellular carcinoma (HCC) in chronic hepatitis B (CHB) patients treated with nucleos(t)ide analogue (NA) remains to be elucidated. Methods: CU-HCC (The Chinese University of Hong Kong-HCC) and GAG-HCC (Guide with Age, Gender, HBV DNA, Core promoter mutations and Cirrhosis) scores of 225 Japanese patients treated with NAs for at least 2 years were calculated before and 2 years after the NA treatment. According to the cutoff values, the patients were categorized into high-score or low-score groups. Results: Sixteen of 225 patients developed HCC. Patients with a high score before the NA treatment showed a significantly higher HCC incidence than those with a low score using both score models (p &lt; 0.001). Time-dependent receiver operating characteristic analyses based on scores before and 2 years after the NA treatment showed that both models exhibited moderate accuracy in predicting HCC development. The HCC incidence was significantly lower in the patients whose scores decreased below the cutoff values in response to the NA treatment than in those whose scores remained high using both models (p &lt; 0.01). Conclusions: The predictive performance of the CU-HCC and GAG-HCC scores in the CHB patients treated with NAs is comparable to that in the NA-naive patients. The patients with sustained high scores after the NA treatment showed a higher incidence of HCC development. (C) 2016 S. Karger AG, Basel

DOI： 10.1159/000444392

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1007/s12072-016-9736-3

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担当区分：責任著者   記述言語：英語   出版者・発行元：Baishideng Publishing Group Co  

Hepatitis C virus (HCV) infection is a serious problem worldwide. The use of interferon-based therapy has made HCV eradication challenging. The recent appearance of direct-acting antiviral agents (DAAs) has changed HCV therapy. Combining the use of DAAs with peginterferon and ribavirin has improved treatment efficacy. Furthermore, the combination of different orally administered DAAs has enabled interferon-free therapy with much higher efficacy and safety. In particular, sofosbuvir, a nucleotide-based NS5B inhibitor, prevents HCV RNA synthesis by acting as a "chain terminator". Treatment with sofosbuvir has attained an extremely high rate of sustained virologic response. The current review summarizes the efficacy and safety of sofosbuvir therapy.

DOI： 10.4254/wjh.v8.i3.183

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：IVYSPRING INT PUBL  

Background. Direct-acting antiviral agents against HCV with or without peginterferon plus ribavirin result in higher eradication rates of HCV and shorter treatment duration. We examined which is better for predicting persistent virologic response, the assessment of serum HCV RNA at 12 or 24 weeks after the end of treatment for predicting sustained virologic response (SVR12 or SVR24, respectively) in patients treated by HCV NS3/4A protease inhibitors with peginterferon plus ribavirin.
Methods. In all, 149 Japanese patients infected with HCV genotype 1b treated by peginterferon plus ribavirin with telaprevir or simeprevir were retrospectively analyzed: 59 and 90 patients were treated with telaprevir- and simeprevir-including regimens, respectively. HCV RNA was measured by TaqMan HCV Test, version 2.0, real-time PCR assay. SVR12 or SVR24, respectively, was defined as HCV RNA negativity at 12 or 24 weeks after ending treatment.
Results. Total SVR rates were 78.0% and 66.7% in the telaprevir and simeprevir groups, respectively. In the telaprevir group, all 46 patients with SVR12 finally achieved SVR24. In the simeprevir group, 60 (93.8%) of the total 64 patients with SVR12 achieved SVR24, with the other 4 patients all being previous-treatment relapsers.
Conclusions. SVR12 was suitable for predicting persistent virologic response in almost all cases. In simeprevir-including regimens, SVR12 could not always predict persistent virologic response. Clinicians should use SVR24 for predicting treatment outcome in the use of HCV NS3/4A protease inhibitors with peginterferon plus ribavirin for any group of real-world patients chronically infected with HCV.

DOI： 10.7150/ijms.14953

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：S. Karger AG  

On-line hemodiafiltration (OLHDF) is one of the treatment options in the management of acute liver failure (ALF) in Japan. It is essential to avoid infection in the management of ALF. In fact, infection is one of the prognostic factors in ALF. In this report, we present a middle-aged Japanese man with ALF associated with benzbromarone use. He was successfully managed without infection until liver transplantation by creating an arteriovenous fistula for OLHDF. Utilizing an arteriovenous fistula for OLHDF, rather than inserting a vascular access catheter, is a beneficial option to avoid infectious diseases in the management of ALF.

DOI： 10.1159/000445186

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：S. Karger AG  

Hepatitis C virus (HCV) infection leads to acute and chronic hepatitis, cirrhosis, and hepatocellular carcinoma. Following kidney transplantation, HCV increases the risk of graft loss and patient mortality compared with uninfected patients. The achievement of a sustained virological response with antiviral therapy improves survival and diminishes the risk of hepatic decompensation in HCV patients after a kidney transplant. It has been reported that direct-acting antivirals (DAAs) are relatively safe and highly effective for the eradication of HCV in patients who are liver transplant recipients. In the present study, we investigated HCV eradication via interferon-free therapies with DAAs in two HCV patients with advanced liver fibrosis following renal transplantation. In both cases, the interferon-free regimens with DAAs were effective in eradicating HCV in the patients after kidney transplantation. No adverse events caused by interferon were identified with the exception of anemia. Interferon-free regimens with DAAs for recurrent HCV in patients following kidney transplantation are relatively safe and effective. However, attention should be focused on anemia during these treatments.

DOI： 10.1159/000445374

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：S. Karger AG  

Direct-acting antivirals (DAAs) are relatively safe and highly effective for the eradication of hepatitis C virus (HCV) in liver transplant recipients. In this case study, we present a female with a graft reinfected with HCV genotype 2 who was treated with a combination of sofosbuvir and ribavirin after living donor liver transplantation (LDLT). Because the graft was from a hepatitis B core antibody-positive donor, passive immunization with hyperimmune hepatitis B immunoglobulin (HBIG) and entecavir were also provided to prevent hepatitis B virus (HBV) reactivation. It became clear that the combination of sofosbuvir and ribavirin promptly led to a sustained virologic response and that this combination was safe to treat graft reinfection with HCV genotype 2 after LDLT. Adverse events caused by DAAs were not observed, except for slight anemia. HBIG and entecavir were useful in the prevention of HBV reactivation. In conclusion, the present case indicated that DAA treatment for graft reinfection with HCV is safe and effective in LDLT from hepatitis B core antibody-positive donors.

DOI： 10.1159/000447423

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掲載種別：研究論文（学術雑誌）  

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掲載種別：研究論文（学術雑誌）  

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：PUBLIC LIBRARY SCIENCE  

MicroRNA-122 (miR-122) is one of the most abundant miRs in the liver. Previous studies have demonstrated that miR-122 plays a role in inflammation in the liver and functions in hepatic stellate cells (HSCs), which reside in the space of Disse. Here, we showed that the transient inhibition of PKR-activating protein (PACT) expression, by miR-122 or siRNA targeting of PACT, suppressed the production of proinflammatory cytokines, such as interleukin (IL)-6, monocyte chemoattractant protein-1 (MCP-1) and IL-1 beta, in human HSC LX-2. Sequence and functional analyses confirmed that miR-122 directly targeted the 30-untranslated region of PACT. Immunofluorescence analysis revealed that miR-122 blocked NF-kappa B-nuclear translocation in LX-2 cells. We also showed that conditioned medium from miR-122-transfected LX-2 cells suppressed human monocyte-derived THP-1 cell migration. Taken together, our study indicates that miR-122 may downregulate cytokine production in HSCs and macrophage chemotaxis and that the targeting of miR-122 may have therapeutic potential for preventing the progression of liver diseases.

DOI： 10.1371/journal.pone.0144295

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担当区分：責任著者   記述言語：英語   出版者・発行元：BAISHIDENG PUBLISHING GROUP INC  

Nonalcoholic fatty liver disease (NAFLD) including nonalcoholic steatohepatitis (NASH) is globally increasing and has become a world-wide health problem. Chronic infection with hepatitis B virus or hepatitis C virus (HCV) is associated with hepatic steatosis. Viral hepatitis-associated hepatic steatosis is often caused by metabolic syndrome including obesity, type 2 diabetes mellitus and/or dyslipidemia. It has been reported that HCV genotype 3 exerts direct metabolic effects that lead to hepatic steatosis. In this review, the differences between NAFLD/NASH and viral hepatitis-associated steatosis are discussed.

DOI： 10.3748/wjg.v21.i46.12989

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1111/hepr.12488

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ACADEMIC PRESS INC ELSEVIER SCIENCE  

Epigenetics plays a role in the regulation of gene expression. Epigenetic changes control gene expression at the transcriptional level. Our previous study suggested that the La protein, which is mainly localized in the nucleus, was associated with hepatitis A virus (HAV) internal ribosomal entry site (IRES)-mediated translation and HAV replication. The aim of this study was to investigate whether epigenetic compounds have effects on HAV IRES-mediated translation and HAV replication. Sirtinol, a sirtuin inhibitor, inhibited HAV IRES-mediated translation in COS7-HAV-IRES cells. Treatment with 10 mu M sirtinol resulted in a significant reduction in the intracellular RNA levels of HAV HA11-1299 genotype IIIA in Huh7 cells. Epigenetic treatment with a sirtuin inhibitor may represent a new treatment option for HAV infection. In conclusion, epigenetic control was involved in HAV IRES-dependent translation and HAV replication. Special attention should also be paid to underlying viral diseases in the clinical use of epigenetic treatments for malignancies. (C) 2015 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.bbrc.2015.09.083

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記述言語：日本語   出版者・発行元：(株)ニュー・サイエンス社  

ウイルス肝炎、特に慢性B型肝炎及び慢性C型肝炎に対する治療は変革期を迎えている。B型肝炎、C型肝炎双方の治療法の進歩において、核酸アナログ製剤の開発が重要な位置を占めている。慢性B型肝炎の分野では、本邦では2000年から核酸アナログ製剤が使用可能となり、B型肝炎ウイルス増殖・複製を効率的に抑制することが可能となった。また、慢性C型肝炎治療においては、ウイルス構成成分を直接の標的とした薬剤の開発が盛んであるが、その中でも核酸アナログ製剤としてRNAポリメラーゼ作用を阻害する薬剤が優れた治療成績を挙げている。本稿では、核酸アナログ製剤を中心に、慢性B型肝炎及び慢性C型肝炎の最新治療を中心に概説した。(著者抄録)

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記述言語：日本語   出版者・発行元：(株)アークメディア  

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-BLACKWELL  

AimThe outcome of acute liver failure (ALF) is influenced by its etiology, making etiological consideration of ALF important. However, specific etiology could not be identified in 30-40% of adult patients in a Japanese nationwide survey. We examined our patients with severe (SH) and fulminant hepatitis (FH) of indeterminate etiology for the better understanding of ALF.
MethodsWe investigated 106 adult patients with SH or FH including 24 of indeterminate etiology between 2000 and 2013, retrospectively.
ResultsOf 24 patients, 12 were men. Seventeen were SH and seven FH (three FH acute type and four FH subacute type). Eighty-three percent of patients were positive for antinuclear antibody. Seventeen recovered without liver transplantation (LT), two received LT and five died without LT. Histology of 15 patients showed a pattern of acute hepatitis (massive necrosis in four, submassive necrosis in one, severe acute hepatitis in two and acute hepatitis in eight). The involvement of immune-mediated liver injury was histologically suggested in some patients.
ConclusionThere was no large cluster of etiology in our patients with indeterminate cause. The causes of ALF of indeterminate etiology were the mixture of various minor or rare ones, if precise diagnosis of acute AIH was done. Outcome of our patients with indeterminate cause was not poor if they were treated as early as possible after the diagnosis of severe disease. Careful examination of unknown viral infection, drugs, toxins, undefined metabolic disorders and histology may help detect some of these etiologies.

DOI： 10.1111/hepr.12483

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SPRINGER  

Estimated hepatitis C virus (HCV) infection rates in the general populations were 1.3, 0.9, 0.4-1.0, 14.7, 0.1-0.3, 0.9-1.9, 1.0-2.0, 5, 4.4-8.6 and 0.5-1.3 % in Australia, Bangladesh, Mainland China, Egypt, Hong Kong, India, Japan, Pakistan, Taiwan and Turkey, respectively. The main HCV genotypes (Gs) are G1, G3, G1b, G4, G1b, G3, G1b, G3, G1b and G2, and G1 in Australia, Bangladesh, Mainland China, Egypt, Hong Kong, India, Japan, Pakistan, Taiwan and Turkey, respectively. Of IL28B genotypes, favorable alleles are similar to 50 % in Australia and Turkey, but 60-70 % in most of the other Asian countries. Peginterferon plus ribavirin is available in all ten Asian Pasific countries. In addition, HCV NS3/4A protease inhibitors with peginterferon plus ribavirin are currently available in several countries. Clinical trials of interferon-free regimens for HCV are ongoing in most of the ten Asian Pacific countries.

DOI： 10.1007/s12072-015-9630-4

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1111/jvh.12390

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-BLACKWELL  

DOI： 10.1002/hep.27693

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.14218/JCTH.2015.00016

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.3390/diseases3030213

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掲載種別：研究論文（学術雑誌）  

DOI： 10.2169/naika.104.1861

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：MDPI AG  

We examined whether hepatitis C virus (HCV) genotype 1b core- and NS5A-region mutations are associated with response to peginterferon -2b plus ribavirin combination therapy. A total of 103 patients with high HCV genotype 1b viral loads (100 KIU/mL) were treated with the combination therapy. Pretreatment mutations in the core region and interferon sensitivity determining region (ISDR) in the NS5A region were analyzed. In univariate analysis, arginine and leucine at positions 70 and 91 in the core region, defined as double wild (DW)-type, were associated with early virologic response (p = 0.002), sustained virologic response (SVR) (p = 0.004), and non-response (p = 0.005). Non-threonine at position 110 was associated with SVR (p = 0.004). Multivariate analysis showed the following pretreatment predictors of SVR: hemoglobin level 14 g/dL (odds ratio (OR) 6.2, p = 0.04); platelet count 14 x 10(4)/mm(3) (OR 5.2, p = 0.04); aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ratio &lt; 0.9 (OR 6.17, p = 0.009); DW-type (OR 6.8, p = 0.02); non-threonine at position 110 (OR 14.5, p = 0.03); and 2 mutations in the ISDR (OR 12.3, p = 0.02). Patients with non-DW-type, non-threonine at position 110, and &lt;2 ISDR mutations showed significantly lower SVR rates than others (11/45 (24.4%) vs. 27/37 (73.0%), respectively; p &lt; 0.001). SVR can be predicted through core and NS5A region mutations and host factors like hemoglobin, platelet count, and AST/ALT ratio in HCV genotype 1b-infected patients treated with peginterferon and ribavirin combination therapy.

DOI： 10.3390/ijms160921177

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ACADEMIC PRESS INC ELSEVIER SCIENCE  

Due to the lack of efficient hepatitis B virus (HBV) infection systems, progress in understanding the role of innate immunity in HBV infection has remained challenging. Here we used human hepatocytes from a humanized severe combined immunodeficiency albumin promoter/enhancer driven-urokinase-type plasminogen activator mouse model for HBV infection. HBV DNA levels in culture medium from these human hepatocytes were 4.8-5.7 log IU/mL between day 16 and day 66 post-infection by HBV genotype C inoculum. HBV surface antigen (HBsAg) was also detected by chemiluminescent immunoassay from day 7 to day 66 post-infection. Western blot analysis revealed that major histocompatibility complex class I-related chain A (MICA), which plays a role in the innate immune system, was induced in HBV-infected human hepatocytes 27 days after infection compared with the uninfected control. MICA was reduced at day 62 and undetectable at day 90. Of interest, MICA expression by human hepatocytes increased after HBV infection and decreased before HBsAg loss. Human hepatocytes derived from chimeric mice with hepatocyte-humanized liver could support HBV genome replication. Further studies of the association between HBV replication and MICA induction should be conducted. (C) 2015 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.bbrc.2015.07.102

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

In 2009, several groups reported that interleukin-28B (IL28B) genotypes are associated with the response to peginterferon plus ribavirin therapy for chronic hepatitis C virus (HCV) infection in a genome-wide association study, although the mechanism of this association is not yet well understood. However, in recent years, tremendous progress has been made in the treatment of HCV infection. In Japan, some patients infected with HCV have the IL28B major genotype, which may indicate a favorable response to interferon-including regimens; however, certain patients within this group are also interferon-intolerant or ineligible. In Japan, interferon-free 24-wk regimens of asunaprevir and daclatasvir are now available for HCV genotype 1b-infected patients who are interferon-intolerant or ineligible or previous treatment null-responders. The treatment response to interferon-free regimens appears better, regardless of IL28B genotype. Maybe other interferon-free regimens will widely be available soon. In conclusion, although some HCV-infected individuals have IL28B favorable alleles, importance of IL28B will be reduced with availability of oral interferon free regimen.

DOI： 10.5501/wjv.v4.i3.178

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-BLACKWELL  

AimOlder age has been widely believed to be associated with a poor prognosis of acute liver failure. We aimed to evaluate the impact of older age on outcomes of Japanese patients with severe and fulminant hepatitis in an era of a highly aging society.
MethodsWe investigated 105 consecutive adult patients with fulminant hepatitis (FH) or severe hepatitis (SH) admitted to our liver unit between 2000 and 2013, consisting of 14 elderly patients (65 years) and 91 younger ones (&lt;65 years).
ResultsIn elderly patients, the proportion of women was greater (P&lt;0.001), the levels of aspartate aminotransferase and lactate dehydrogenase on admission were lower (P=0.011 and P=0.010, respectively), and the survival rate without liver transplantation was lower (P=0.024) than younger ones. Two of seven SH and all seven FH elderly patients died, whereas all 45 SH and 16 of 46 FH younger patients recovered. Seventy-one percent of elderly patients had underlying diseases with medications, and 57% had additional complications after the start of treatment for acute liver failure. Patients aged 70 years or more showed even poorer prognoses than younger ones and those aged 65-69 years (P=0.0052 and P=0.036, respectively).
ConclusionOlder age was associated with a poor prognosis of patients with SH and FH. One of the reasons other than complications and loss of organ reserve by aging would be that elderly patients consulted us at a more advanced stage of illness than younger ones.

DOI： 10.1111/hepr.12426

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-BLACKWELL  

Background and AimWhether an antiviral interferon (IFN)-based therapy (IBT) after curative treatment of hepatocellular carcinoma (HCC) improves the prognosis in patients with hepatitis C virus (HCV)-related HCC remains to be elucidated.
MethodsA total of 178 patients within the Milan criteria underwent curative treatment for HCV-related HCC. Both the time to beyond the Milan criteria (TTBMC) and overall survival (OS) were compared between the sustained virologic response (SVR) (IFN with SVR, n=22), non-SVR (IFN without SVR, n=19), and non-IBT (control, n=82) groups using propensity score matching analysis. Prognostic factors to predict survival were also determined by the Cox proportional-hazards model.
ResultsTTBMC in the IFN with SVR group was significantly longer than those in the control and IFN without SVR groups (P&lt;0.001 and P=0.006, respectively), although no significant difference existed between the IFN without SVR and control groups. Similarly, OS of the IFN with SVR group was significantly longer than that of the control and IFN without SVR groups (P&lt;0.001 and P=0.029, respectively), although no significant difference existed between the IFN without SVR and control groups. The Cox proportional-hazards model identified SVR as an independent prognostic factor in these patients. The IFN with SVR group showed a 0.096-fold decrease in mortality risk compared with the control group (95% confidence intervals=0.023-0.405; P=0.001).
ConclusionElimination of HCV after curative treatment of patients with HCC within the Milan criteria inhibits recurrence and contributes to a preferential prognosis.

DOI： 10.1111/jgh.12925

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1371/journal.pone.0131973

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SPRINGER  

Recent advances in interferon-free treatment could lead to the eradication of hepatitis C virus (HCV) from patients infected with HCV. One of the direct-acting anti-viral agents, HCV NS5A inhibitor, is available for these combination therapies. However, naturally occurring resistance-associated variants (RAVs) to HCV NS5A inhibitors in treatment-na &lt; ve patients chronically infected with HCV genotype 1b are still unknown.
We performed ultra-deep sequencing and analysed previously reported RAVs in a total 132 HCV genotype 1b-infected Japanese patients who had never used HCV NS5A inhibitors. We also performed direct-sequencing by Sanger method in consecutively selected 50 of the total 132 samples, and the differences between the results of the two methods were compared.
In the comparison of the variant frequencies of ultra-deep sequencing with RAVs of direct-sequencing by Sanger method in 50 patients, we identified 32 RAVs by direct-sequencing with the Sanger method; minimum variant frequency was shown by ultra-deep sequencing to be 9 %. A total of 110 RAVs were identified only by ultra-deep sequencing. In the samples from all 132 patients, L31W (2.3 %), L31V (49.2 %), L31F (41.7 %), L31M (1.5 %), L31I (5.3 %), L31S (2.0 %), L31P (3.0 %) and L31R (0.8 %), and Y93N (2.3 %), Y93H (25 %), Y93C (0.8 %), Y93P (2.3 %) and Y93D (0.8 %) were identified.
We demonstrated naturally-occurring RAVs of HCV NS5A inhibitors by ultra-deep sequencing and that several mutations including Y93H are common in HCV NS5A inhibitor-treatment-na &lt; ve patients with chronic HCV genotype 1b. Careful attention should be paid to these RAVs, and further improvement of treatment options might be needed.

DOI： 10.1007/s12072-015-9624-2

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

Hepatocellular carcinoma (HCC) is one of the male-dominant liver diseases with poor prognosis, although treatments for HCC have been progressing in the past decades. Androgen receptor (AR) is a member of the nuclear receptor superfamily. Previous studies reported that AR was expressed in human HCC and non-HCC tissues. AR is activated both ligand-dependently and ligand-independently. The latter is associated with a mitogen-activated protein kinase-, v-akt murine thymoma viral oncogene homolog 1-, or signal-transducer and activator of transcription-signaling pathway, which has been implicated in the development of HCC. It has been reported that more than 200 RNA expression levels are altered by androgen treatment. In the liver, androgen-responsive genes are cytochrome P450s, transforming growth factor β, vascular endothelial growth factor, and glucose-regulated protein 78 kDa, which are also associated with human hepatocarcinogenesis. Recent studies also revealed that AR plays a role in cell migration and metastasis. It is possible that cross-talk among AR-signaling, endoplasmic reticulum stress, and innate immune response is important for human hepatocarcinogenesis and HCC development. This review shows that AR could play a potential role in human HCC and represent one of the important target molecules for the treatment of HCC.

DOI： 10.2147/jhc.s48956

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1159/000437138

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ACADEMIC PRESS INC ELSEVIER SCIENCE  

The JAK2 inhibitor AZD1480 has been reported to inhibit La protein expression. We previously demonstrated that the inhibition of La expression could inhibit hepatitis A virus (HAV) internal ribosomal entry-site (IRES)-mediated translation and HAV replication in vitro. In this study, we analyzed the effects of AZD1480 on HAV IRES-mediated translation and replication. HAV IRES-mediated translation in COS7-HAV-IRES cells was inhibited by 0.1-1 mu M AZD1480, a dosage that did not affect cell viability. Results showed a significant reduction in intracellular HAV HA11-1299 genotype IIIA RNA levels in Huh7 cells treated with AZD1480. Furthermore, AZD1480 inhibited the expression of phosphorylated-(Tyr-705)-signal transducer and activator of transcription 3 (STAT3) and La in Huh7 cells. Therefore, we propose that AZD1480 can inhibit HAV IRES activity and HAV replication through the inhibition of the La protein. (C) 2015 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.bbrc.2015.02.058

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担当区分：筆頭著者,　責任著者   記述言語：英語   出版者・発行元：MDPI AG  

The current treatments for chronic hepatitis C virus (HCV) genotype 1 infection are combinations of direct-acting antivirals, and faldaprevir is one of the new generation of HCV NS3/4A protease inhibitors. At the end of 2013, the US Food and Drug Administration (FDA) approved the HCV NS3/4A protease inhibitor simeprevir and the HCV NS5B polymerase inhibitor sofosbuvir. Simeprevir or sofosbuvir in combination with pegylated interferon and ribavirin are available for clinical use. Faldaprevir, another HCV NS3/4A protease inhibitor that also has fewer adverse events than telaprevir or boceprevir, is under development. Of interest, faldaprevir in combination with pegylated interferon and ribavirin, and interferon-free treatment with faldaprevir in combination with deleobuvir plus ribavirin provides high sustained virological response rates for HCV genotype 1 infection. The aim of this article is to review these data concerning faldaprevir. Faldaprevir in combination with pegylated interferon and ribavirin treatment appears to be associated with fewer adverse events than telaprevir or boceprevir in combination with pegylated interferon and ribavirin, and may be one of the therapeutic options for treatment-naive patients with HCV genotype 1. The interferon-free combination of faldaprevir and deleobuvir with ribavirin was effective for HCV genotype 1 infection and may hold promise for interferon-ineligible and interferon-intolerant patients.

DOI： 10.3390/ijms16034985

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：BIOMED CENTRAL LTD  

Background: Short interfering RNAs (siRNAs) can knockdown target genes and thus have an immense impact on biology and pharmacy research. The key question of which siRNAs have high knockdown ability in siRNA research remains challenging as current known results are still far from expectation.
Results: This work aims to develop a generic framework to enhance siRNA knockdown efficacy prediction. The key idea is first to enrich siRNA sequences by incorporating them with rules found for designing effective siRNAs and representing them as enriched matrices, then to employ the bilinear tensor regression to predict knockdown efficacy of those matrices. Experiments show that the proposed method achieves better results than existing models in most cases.
Conclusions: Our model not only provides a suitable siRNA representation but also can predict siRNA efficacy more accurate and stable than most of state-of-the-art models.

DOI： 10.1186/s12859-015-0495-2

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SPRINGER JAPAN KK  

BackgroundThere has existed important differences in the definition of acute liver failure (ALF) between Japanese criteria and those of other countries. The novel diagnostic criteria for ALF in Japanese patients were established by the Intractable Hepato-Biliary Diseases Study Group of Japan, in order to correspond to those for ALF in Europe and the USA. We prospectively diagnosed our ALF patients based on this novel criteria, and discussed the etiology by a fixed point observation.
MethodsWe investigated the etiology of 54 adult inpatients and outpatients with ALF between 2010 and 2012.
ResultsOf 54 patients, 36 were ALF without coma, 17 ALF with coma and one late onset hepatic failure. The etiology was due to viral infections in 38.9%, autoimmune hepatitis in 11.1%, drug-induced liver injury in 13.0%, etiologies without hepatitis in 29.6% (circulatory disturbance in 18.5%, infiltration of the liver by malignant cells in 7.4%, and metabolic diseases in 3.7%) and indeterminate causes in 7.4%.
ConclusionsCirculatory disturbance was the most frequent etiology according to the novel criteria. Indeterminate etiology was less observed in our study than the nation-wide survey with significance (P = 0.0014).

DOI： 10.1002/jhbp.178

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SPRINGER  

Mosapride citrate-a prokinetic agent-improves hemoglobin A1c levels in diabetic patients; however, the underlying mechanism is unclear. We aimed to clarify this mechanism.
Preprandial and postprandial (90 min after a meal) blood was obtained from 12 healthy men, and serum insulin and plasma active glucagon-like peptide-1 concentrations were measured. Measurements were also taken after the administration of 5 mg of mosapride citrate three times per day after every meal for 14 days. In addition, C57BL/6 mice were permitted free access to water containing 0.04 % domperidone (D group) or 0.02 % mosapride citrate (M group) for 2 weeks (four mice per group). T1r2 (taste receptor, type 1, member 2), T1r3, and Gnat3 (guanine nucleotide-binding protein, alpha transducing 3) mRNA expression levels of the stomach, duodenum, and proximal and mid-jejunum were evaluated.
In human subjects, postprandial plasma active glucagon-like peptide-1 and serum insulin concentrations after administration of mosapride citrate were significantly higher than those pre-administration (4.8 +/- A 2.2 pmol/L, 45.6 +/- A 41.6 mu IU/mL, and 3.7 +/- A 1.2 pmol/L, 34.1 +/- A 28.4 mu IU/mL, respectively). The mouse expression levels of T1r2 and Gnat3 in the proximal jejunum and mid-jejunum in the M group (4.1 +/- A 1.8-fold, 3.1 +/- A 1.6-fold, and 4.6 +/- A 0.8-fold, 3.1 +/- A 0.9-fold increases, respectively), were significantly higher than those of the control group.
The administration of mosapride citrate for 2 weeks enhanced postprandial plasma active glucagon-like peptide-1 and serum insulin concentration and increased the expression of sweet taste receptors in the upper intestine.

DOI： 10.1007/s10620-014-3271-7

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-BLACKWELL  

The short-term prognosis of patients with severe acute exacerbation of chronic hepatitis B (CHB) leading to acute liver failure is extremely poor. We have reported the efficacy of corticosteroid in combination with nucleoside analogue in the early stages, but virological efficacy has not been documented. Our aim was to elucidate the virological efficacy of this approach. Thirteen patients defined as severe acute exacerbation of CHB by our uniform criteria were prospectively examined for virological responses to treatment. Nucleoside analogue and sufficient dose of corticosteroids were introduced as soon as possible after the diagnosis of severe disease. Of the 13 patients, 7 (54%) survived, 5 (38%) died and 1 (8%) received liver transplantation. The decline of HBV DNA was significant between the first 2 weeks (P = 0.02) and 4 weeks (P &lt; 0.01). Mean reduction in HBV DNA during the first 2 weeks was 1.7 +/- 0.9 log copies per mL in overall patients, 2.1 +/- 0.8 in survived patients and 1.2 +/- 0.9 in dead/transplanted patients. The decline of HBV DNA was significant between the first 2 weeks (P = 0.03) and 4 weeks (P = 0.02) in survived patients, but not in dead/transplanted patients. Our study shows that corticosteroid treatment in combination with nucleotide analogue has sufficient virological effect against severe acute exacerbation of CHB, and a rapid decline of HBV DNA is conspicuous in survived patients.

DOI： 10.1111/jvh.12258

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：S. Karger AG  

Hepatitis E virus (HEV) infection is an emerging health concern in developing and developed countries, such as Japan. Five cases have recently been diagnosed as hepatitis E. Of interest, 3 of them had rheumatoid arthritis (RA), although a previous study demonstrated a lack of association between HEV and RA. One of the other patients developed autoimmune hepatitis and was successfully treated with corticosteroids approximately 150 days after the diagnosis of hepatitis E. In RA patients with liver dysfunction, the presence of HEV infection should be evaluated immediately because these patients are often relatively old. Further investigation of the association between HEV and autoimmune hepatitis is needed.

DOI： 10.1159/000441387

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Baishideng Publishing Group Co  

The current management therapies for hepatocellular carcinoma (HCC) patients are discussed in this review. Despite the development of new therapies, HCC remains a "difficult to treat" cancer because HCC typically occurs in advanced liver disease or hepatic cirrhosis. The progression of multistep and multicentric HCC hampers the prevention of the recurrence of HCC. Many HCC patients are treated with surgical resection and radiofrequency ablation (RFA), although these modalities should be considered in only selected cases with a certain HCC number and size. Although there is a shortage of grafts, liver transplantation has the highest survival rates for HCC. Several modalities are salvage treatments
however, intensive care in combination with other modalities or in combination with surgical resection or RFA might offer a better prognosis. Sorafenib is useful for patients with advanced HCC. In the near future, HCC treatment will include stronger molecular targeted drugs, which will have greater potency and fewer adverse events. Further studies will be ongoing.

DOI： 10.4254/wjh.v7.i15.1913

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担当区分：責任著者   記述言語：英語   出版者・発行元：Baishideng Publishing Group Co  

Hepatitis B virus (HBV) persistently infects approximately 350 million people, and approximately 600000 liverrelated deaths are observed per year worldwide. HBV infection is also one of the major risk factors for hepatocellular carcinoma (HCC). The persistence of serum hepatitis B e antigen (HBeAg) and high level of serum HBV DNA are thought to reflect a high HBV replication status in hepatocytes, causing cirrhosis, HCC and liver-related deaths. It has been reported that antiviral therapy, such as peginterferon and nucleos(t)ide analogues (NUCs), could suppress liver-related death by inhibiting the HBV DNA levels and inducing seroconversion from HBeAg to antibody to HBe antigen. Currently, peginterferon is widely used, but there are also several disadvantages in the use of peginterferon, such as various adverse events, the administration route and duration. It is difficult to predict the effects of treatment and interferon is contraindicated for the patients with advanced fibrosis of the liver and cirrhosis. With respect to NUCs, entecavir and tenofovir disoproxil fumarate are current the first-choice drugs. NUCs can be administered orally, and their anti-viral effects are stronger than that of peginterferon. However, because cessation of NUC administration leads to high levels of viral replication and causes severe hepatitis, they must be administered for a long time. On the other hand, the use of both interferon and NUCs cannot eliminate covalently closed circular DNA of HBV. In this review, we evaluate the natural course of chronic HBV infection and then provide an outline of these representative drugs, such as peginterferon, entecavir and tenofovir disoproxil fumarate.

DOI： 10.4254/wjh.v7.i11.1541

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担当区分：責任著者   記述言語：英語   出版者・発行元：Baishideng Publishing Group Co  

Patients who are infected with hepatitis C virus (HCV) and also have advanced fibrosis or cirrhosis have been recognized as "difficult-to-treat" patients during an era when peginterferon and ribavirin combination therapy is the standard of care. Recent guidelines have clearly stated that treatment should be prioritized in this population to prevent complications such as decompensation and hepatocellular carcinoma. Recent advances in the treatment of chronic hepatitis C have been achieved through the development of direct-acting antiviral agents (DAAs). Boceprevir and telaprevir are first-generation DAAs that inhibit the HCV NS3/4A protease. Boceprevir or telaprevir, in combination with peginterferon and ribavirin, improved the sustained virological response rates compared with peginterferon and ribavirin alone and were tolerated in patients with HCV genotype 1 infection without cirrhosis or compensated cirrhosis. However, the efficacy is lower especially in prior non-responders with or without cirrhosis. Furthermore, a high incidence of adverse events was observed in patients with advanced liver disease, including cirrhosis, in real-life settings. Current guidelines in the United States and in some European countries no longer recommend these regimens for the treatment of HCV. Next-generation DAAs include second-generation HCV NS3/4A protease inhibitors, HCV NS5A inhibitors and HCV NS5B inhibitors, which have a high efficacy and a lower toxicity. These drugs are used in interferon-free or in interferon-based regimens with or without ribavirin in combination with different classes of DAAs. Interferon-based regimens, such as simeprevir in combination with peginterferon and ribavirin, are well tolerated and are highly effective especially in treatment-naïve patients and in patients who received treatment but who relapsed. The efficacy is less pronounced in null-responders and in patients with cirrhosis. Interferon-free regimens in combination with ribavirin and/or two or more DAAs could be used for treatment-naïve, treatment-experienced and even for interferon-ineligible or interferon-intolerant patients. Some clinical trials have demonstrated promising results, and have shown that the efficacy and safety were not different between patients with and without cirrhosis. There are also promising regimens for genotypes other than genotype 1. Interferon is contraindicated in patients with decompensated cirrhosis, and further studies are needed to establish the optimal treatment regimen for this population. In the future, interferon-free and ribavirin-free regimens with high efficacy and improved safety are expected for HCV-infected patients with advanced liver diseases.

DOI： 10.4254/wjh.v7.i8.1133

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担当区分：責任著者   記述言語：英語   出版者・発行元：Baishideng Publishing Group Co  

Chronic hepatitis C virus (HCV) infection can cause liver cirrhosis and hepatocellular carcinoma (HCC). Several studies have demonstrated that the eradication of HCV reduces the occurrence of HCC. In Japan, as many people live to an advanced age, HCV-infected patients are also getting older, and the age at HCC diagnosis has also increased. Although older HCV-infected patients have a risk of developing HCC, the treatment response to peginterferon-alpha plus ribavirin therapy is relatively poor in these patients because of drop-out or discontinuation of this treatment due to adverse events. It is established that the mechanism of action between interferon-alpha and interferon-beta is slightly different. Short-term natural interferon-beta monotherapy is effective for patients with acute hepatitis C and patients infected with HCV genotype 2 and low viral loads. Natural interferon-beta plus ribavirin for 48 wk or for 24 wk are also effective for some patients with HCV genotype 1 or HCV genotype 2. Natural interferon-beta plus ribavirin has been used for certain "difficult-to-treat" HCV-infected patients. In the era of direct-acting anti-virals, natural interferon-beta plus ribavirin may be one of the therapeutic options for special groups of HCV-infected patients. In the near future, signal transduction pathways of interferon-beta will inform further directions.

DOI： 10.4254/wjh.v7.i8.1125

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Hindawi Limited  

Aim. Eradication of hepatitis C virus (HCV) is still challenging even if interferon- (IFN-) free regimens with direct-acting antiviral agents (DAAs) for HCV-infected individuals are available in clinical practice. IFNL4 is a newly described protein, associated with human antiviral defenses. We investigated whether IFNL4 ss469415590 variant has an effect on the prediction of treatment response in HCV-infected patients treated with IFN-including regimens.
Patients and Methods. In all, 185 patients infected with HCV genotype 1 treated with peg-IFN plus ribavirin, with or without telaprevir, were genotyped for IFNL4 ss469415590. We retrospectively investigated whether the role of IFNL4 ss469415590 variant and other factors could predict sustained virological response (SVR) in Japanese patients infected with HCV genotype 1.
Results. There were 65.7%, 31.5%, and 2.8% patients in the IFNL4 ss469415590 TT/TT, TT/-G, and -G/-G groups, respectively. SVR rates were 82.1% or 49.3% in patients treated with peg-IFN plus ribavirin with or without telaprevir, respectively. IFNL4 ss469415590 variant and HCV viral loads or IFNL4 ss469415590 variant and early virological response were better predictors of SVR in patients treated with peg-IFN plus ribavirin with or without telaprevir, respectively.
Conclusion. In the era of DAAs, measurement of IFNL4 ss469415590 variant could help the prediction of SVR in Japanese HCV genotype 1 infected individuals treated with IFN-including regimens.

DOI： 10.1155/2014/723868

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SPANDIDOS PUBL LTD  

The present study examined the expression of glucose-regulated protein 78 (GRP78/Bip) in human pancreatic cancer cell lines and the effect of knockdown of GRP78 on the cleavage of poly(ADP-ribose) polymerase (PARP). Human pancreatic cancer cell lines (KP-2, MIAPaCa-2, Panc-1 and SUIT-2), constitutively expressed GRP78. We also demonstrated that ER stress induced by thapsigargin upregulated protein levels of GRP78. In the presence of thapsigargin, knockdown of GRP78 enhanced the PARP cleavage in the human pancreatic cancer cells. These results provide evidence that GRP78 is a potential therapeutic target for 'difficult-to-treat' pancreatic cancer, in which ER stress signaling in part falls into disorder.

DOI： 10.3892/or.2014.3533

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：MDPI AG  

We retrospectively reviewed 413 recipients with hematologic malignancies who underwent hematopoietic stem cell transplantation (HSCT) between June 1986 and March 2013. Recipients with antibody to hepatitis B core antigen (anti-HBc) and/or to hepatitis B surface antigen (anti-HBs) were regarded as experiencing previous hepatitis B virus (HBV) infection. Clinical data of these recipients were reviewed from medical records. We defined &gt;= 1 log IU/mL increase in serum HBV DNA from nadir as HBV reactivation in hepatitis B surface antigen (HBsAg)-positive recipients, and also defined &gt;= 1 log IU/mL increase or re-appearance of HBV DNA and/or HBsAg as HBV reactivation in HBsAg-negative recipients. In 5 HBsAg-positive recipients, 2 recipients initially not administered with nucleos(t) ide analogues (NUCs) experienced HBV reactivation, but finally all 5 were successfully controlled with NUCs. HBV reactivation was observed in 11 (2.7%) of 408 HBsAg-negative recipients; 8 of these were treated with NUCs, and fortunately none developed acute liver failure. In 5 (6.0%) of 83 anti-HBc and/or anti-HBs-positive recipients, HBV reactivation occurred. None of 157 (0%) recipients without HBsAg, anti-HBs or anti-HBc experienced HBV reactivation. In HSCT recipients, HBV reactivation is a common event in HBsAg-positive recipients, or in HBsAg-negative recipients with anti-HBc and/or anti-HBs. Further attention should be paid to HSCT recipients with previous exposure to HBV.

DOI： 10.3390/ijms151121455

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：PUBLIC LIBRARY SCIENCE  

Background: We previously reported that the hepatitis C virus (HCV) nonstructural protein 5A (NS5A) down-regulates TLR4 signaling and lipopolysaccharide-induced apoptosis of hepatocytes. There have been several reports regarding the association between HCV infection and endoplasmic reticulum (ER) stress. Here, we examined the regulation of HCV NS5A on the apoptosis of hepatocytes induced by thapsigargin, an inducer of ER stress.
Methods: The apoptotic response to thapsigargin and the expression of molecules involved in human hepatocyte apoptotic pathways were examined in the presence or absence of HCV NS5A expression.
Results: HCV JFH1 infection induced ER stress in the Huh7 cell line. HCV NS5A protected HepG2 cells against thapsigargin-induced apoptosis, the effect of which was linked to the enhanced expression of the 78-kDa glucose-regulated protein/immunoglobulin heavy-chain binding protein (GRP78). Consistent with a conferred pro-survival advantage, HCV NS5A reduced poly(adenosine diphosphate-ribose) polymerase cleavage and activation of caspases-3, -7 and -9, and Bax expression, while increasing the expressions of the anti-apoptotic molecules XIAP and c-FLIP. HCV NS5A weakly interacts with GRP78 and enhances GRP78 expression in hepatocytes.
Conclusion: HCV NS5A enhances GRP78 expression, resulting in the inhibition of apoptotic properties, and inhibits thapsigargin-induced apoptotic pathways in human hepatocytes, suggesting that disruption of ER stress-mediated apoptosis may have a role in the pathogenesis of HCV infection. Thus, HCV NS5A might engender the survival of HCV-infected hepatocytes contributing to the establishment of persistent infection.

DOI： 10.1371/journal.pone.0113499

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掲載種別：研究論文（学術雑誌）  

There has existed important differences in the definition of acute liver failure (ALF) between Japanese criteria and those of other countries. The novel diagnostic criteria for ALF in Japanese patients were established by the Intractable Hepato-Biliary Diseases Study Group of Japan, in order to correspond to those for ALF in Europe and the USA. We prospectively diagnosed our ALF patients based on this novel criteria, and discussed the etiology by a fixed point observation.We investigated the etiology of 54 adult inpatients and outpatients with ALF between 2010 and 2012.Of 54 patients, 36 were ALF without coma, 17 ALF with coma and one late onset hepatic failure. The etiology was due to viral infections in 38.9%, autoimmune hepatitis in 11.1%, drug-induced liver injury in 13.0%, etiologies without hepatitis in 29.6% (circulatory disturbance in 18.5%, infiltration of the liver by malignant cells in 7.4%, and metabolic diseases in 3.7%) and indeterminate causes in 7.4%.Circulatory disturbance was the most frequent etiology according to the novel criteria. Indeterminate etiology was less observed in our study than the nation-wide survey with significance (P = 0.0014).

DOI： 10.1002/jhbp.178

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：PUBLIC LIBRARY SCIENCE  

Background: Despite the development and availability of hepatitis A virus (HAV) vaccine, HAV infection is still a major cause of acute hepatitis that occasionally leads to fatal liver disease. HAV internal ribosomal entry-site (IRES) is one of the attractive targets of antiviral agents against HAV. The aim of the present study is to evaluate the impact of La, one of the cellular proteins, on HAV IRES-mediated translation and HAV replication.
Methods and Findings: We investigated the therapeutic feasibility of siRNAs specific for cellular cofactors for HAV IRES-mediated translation in cell culture. It was revealed that siRNA against La could inhibit HAV IRES activities as well as HAV subgenomic replication. We also found that the Janus kinase (JAK) inhibitors SD-1029 and AG490, which reduce La expression, could inhibit HAV IRES activities as well as HAV replication.
Conclusions: Inhibition of La by siRNAs and chemical agents could lead to the efficient inhibition of HAV IRES-mediated translation and HAV replication in cell culture models. La might play important roles in HAV replication and is being exploited as one of the therapeutic targets of host-targeting antivirals.

DOI： 10.1371/journal.pone.0101993

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：BAISHIDENG PUBLISHING GROUP INC  

Hepatocellular carcinoma (HCC) and pancreatic cancer remain difficult to treat, and despite the ongoing development of new treatments, the overall survival rate has only modestly improved over the past decade. Liver and pancreatic progenitors commonly develop from endoderm cells in the embryonic foregut. A previous study showed that HCC and pancreatic cancer cell lines variably express androgen receptor (AR), and these cancers and the surrounding tissues also express AR. AR is a ligand-dependent transcription factor that belongs to the nuclear receptor superfamily. Androgen response element is present in regulatory elements on the AR-responsive target genes, such as transforming growth factor beta-1 (TGF beta-1) and vascular endothelial growth factor (VEGF). It is well known that the activation of AR is associated with human carcinogenesis in prostate cancer as well as HCC and pancreatic cancer and that GRP78, TGF beta, and VEGF all play important roles in carcinogenesis and cancer development in these cancers. HCC is a male-dominant cancer irrespective of its etiology. Previous work has reported that vertebrae forkhead box A 1/2 are involved in estrogen receptors and/or AR signaling pathways, which may contribute to the gender differences observed with HCC. Our recent work also showed that AR has a critical role in pancreatic cancer development, despite pancreatic cancer not being a male dominant cancer. Aryl hydrocarbon (or dioxin) receptor is also involved in both HCC and pancreatic cancer through the formation of complex with AR. It is possible that AR might be involved in their carcinogenesis through major histocompatibility complex class I chain-related gene A/B. This review article describes AR and its role in HCC and pancreatic cancer and suggests that more specific AR signaling-inhibitors may be useful in the treatment of these "difficult to treat" cancers. (C) 2014 Baishideng Publishing Group Inc. All rights reserved.

DOI： 10.3748/wjg.v20.i28.9229

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Dove Medical Press Ltd