Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

Abstract

Acute-on-chronic liver failure (ACLF) is a condition associated with high mortality in the absence of liver transplantation. There have been various definitions proposed worldwide. The first consensus report of the working party of the Asian Pacific Association for the Study of the Liver (APASL) set in 2004 on ACLF was published in 2009, and the “APASL ACLF Research Consortium (AARC)” was formed in 2012. The AARC database has prospectively collected nearly 10,500 cases of ACLF from various countries in the Asia–Pacific region. This database has been instrumental in developing the AARC score and grade of ACLF, the concept of the ‘Golden Therapeutic Window’, the ‘transplant window’, and plasmapheresis as a treatment modality. Also, the data has been key to identifying pediatric ACLF. The European Association for the Study of Liver-Chronic Liver Failure (EASL CLIF) and the North American Association for the Study of the End Stage Liver Disease (NACSELD) from the West added the concepts of organ failure and infection as precipitants for the development of ACLF and CLIF-Sequential Organ Failure Assessment (SOFA) and NACSELD scores for prognostication. The Chinese Group on the Study of Severe Hepatitis B (COSSH) added COSSH-ACLF criteria to manage hepatitis b virus-ACLF with and without cirrhosis. The literature supports these definitions to be equally effective in their respective cohorts in identifying patients with high mortality. To overcome the differences and to develop a global consensus, APASL took the initiative and invited the global stakeholders, including opinion leaders from Asia, EASL and AASLD, and other researchers in the field of ACLF to identify the key issues and develop an evidence-based consensus document. The consensus document was presented in a hybrid format at the APASL annual meeting in Kyoto in March 2024. The ‘Kyoto APASL Consensus’ presented below carries the final recommendations along with the relevant background information and areas requiring future studies.

DOI： 10.1007/s12072-024-10773-4

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

DOI： 10.1007/s12072-025-10784-9

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：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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Authorship：Lead author,　Last author,　Corresponding author   Language：Japanese  

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

DOI： 10.1007/s12072-024-10707-0

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

DOI： 10.1007/s12072-024-10702-5

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Other Link： https://link.springer.com/article/10.1007/s12072-024-10702-5/fulltext.html

Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1111/hepr.14062

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.3390/ijms25105454

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.3892/mi.2024.162

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Spandidos Publications  

DOI： 10.3892/mi.2024.147

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Spandidos Publications  

DOI： 10.3892/mi.2024.146

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Language：Japanese  

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Authorship：Lead author,　Corresponding author   Language：Japanese  

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：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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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：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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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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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：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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Authorship：Lead author,　Corresponding author   Language：Japanese  

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Authorship：Last author,　Corresponding author   Publishing type：Research paper (scientific journal)   Publisher：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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Publishing type：Research paper (scientific journal)   Publisher：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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Authorship：Lead author,　Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Basel, Switzerland : MDPI  

DOI： 10.3390/ijms24076218

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Language：English   Publishing type：Research paper (scientific journal)  

Attiki, Greece : International Institute of Anticancer Research

DOI： 10.21873/anticanres.16249

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Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：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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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：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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Language：English   Publishing type：Research paper (scientific journal)   Publisher：New York, Academic Press.  

Transforming growth factor (TGF)-β/Smad pathway is implicated in the pathogenesis of liver fibrosis, a condition characterized by excessive deposition of extracellular matrix (ECM) proteins such as collagen in response to chronic inflammation. It has been reported that ceramide regulates collagen production through TGF-β/Smad pathway activation. In this study, we examined whether miglustat, an inhibitor of glucosylceramide synthase, can suppress liver fibrosis by reducing TGF-β/Smad pathway activity. Human hepatic stellate cells (HHSteCs) were cultured with TGF-β and multiple miglustat concentrations to examine dose-dependent effects on the expression levels of ECM-related genes and Smad proteins. To evaluate the efficacy of miglustat for fibrosis mitigation, C57BL/6 mice were treated with carbon tetrachloride (CCl₄) for 4 weeks to induce liver fibrosis, followed by combined CCl₄ plus miglustat for a further 2 weeks. To examine if miglustat can also prevent fibrosis, mice were treated with CCl₄ for 2 weeks, followed by CCl₄ plus miglustat for 2 weeks. Miglustat dose-dependently downregulated expression of α-smooth muscle actin and ECM components in TGF-β-treated HHSteCs. Both phosphorylation and nuclear translocation of Smad2 and Smad3 were also suppressed by miglustat treatment. Sirius-Red staining and hydroxyproline assays of model mouse liver samples revealed that miglustat reduced fibrosis, an effect accompanied by decreased expression of ECM. Our findings suggest that miglustat can both prevent and reverse liver fibrosis by inhibiting TGF-β/Smad pathway.

DOI： 10.1016/j.bbrc.2022.12.025

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Basel, Switzerland : MDPI  

The hepatitis C virus (HCV) causes acute and chronic hepatitis, cirrhosis, and hepatocellular carcinoma, as well as extrahepatic manifestations such as malignant lymphoma. Currently, direct-acting antiviral agents (DAAs) against HCV infection can lead to a sustained virological response (SVR) in almost all HCV-infected patients. In this review article, we discuss acute exacerbation and alanine aminotransferase (ALT) flare in patients with chronic HCV infection. Although acute liver failure caused by HCV infection is rare, careful attention should be paid to the cases with ALT elevation during the natural course of chronic HCV infection. HCV genotype 2 infection, the use of rituximab, and a higher dose of corticosteroid are factors associated with HCV acute exacerbation and ALT flare. Treatment regimens for cancer have been interrupted or changed due to ALT flare due to HCV infection in some patients undergoing chemotherapy for cancer. The pathogenesis of HCV acute exacerbation and ALT flare could involve cellular as well as humoral immune responses. In the DAA era, the earlier introduction of DAAs may prevent chronic HCV-infected patients with acute exacerbation and ALT flare from developing into a more severe form, although DAAs may not be effective for all of them.

DOI： 10.3390/v15010183

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Language：English   Publishing type：Research paper (scientific journal)  

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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Language：English   Publishing type：Research paper (scientific journal)   Publisher：St. Louis, MO : Mosby  

BACKGROUND: Tumor stiffness measurement using magnetic resonance elastography can assess tumor mechanical properties and predict hepatocellular carcinoma recurrence. This study aimed to investigate preoperative tumor stiffness on magnetic resonance elastography as a predictor of overall survival and recurrence-free survival in patients with solitary nodular hepatocellular carcinoma who underwent curative resection. METHODS: Seventy-eight patients with solitary nodular hepatocellular carcinoma who underwent preoperative magnetic resonance elastography and curative resection were retrospectively analyzed. Potential associations of tumor stiffness and other clinicopathological variables with overall survival and recurrence-free survival were analyzed in both univariate and multivariate Cox proportional hazards analyses. The optimal tumor stiffness cutoff value was determined using the minimal P value approach. RESULTS: In multivariate analysis, tumor stiffness (hazard ratio 1.31; 95% confidence interval, 1.07-1.59; P = .008) and vascular invasion (hazard ratio 2.62; 95% confidence interval, 1.27-5.17; P = .010) were independent predictors of recurrence-free survival. For overall survival, tumor stiffness (hazard ratio, 1.33; 95% confidence interval, 1.02-1.76; P = .037) was the only independent predictor. The optimal tumor stiffness cutoff value was 5.81 kPa for both overall survival and recurrence-free survival. Patients with tumor stiffness ≥5.81 kPa had a significantly greater risk of death (hazard ratio 6.10; 95% confidence interval, 2.11-21.90; P < .001) than those with tumor stiffness <5.81 kPa. CONCLUSION: Preoperative tumor stiffness as measured by magnetic resonance elastography was a predictor of overall survival and recurrence-free survival in hepatocellular carcinoma patients who underwent curative resection. Higher tumor stiffness was associated with higher risk of recurrence and death.

DOI： 10.1016/j.surg.2022.11.001

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：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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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Nature Publishing Group  

Recently, we reported that extent of proliferation of atypical hepatocytes (atypical hepatocytes) was most important histological risk factor for development of hepatocellular carcinoma (HCC) from chronic hepatitis C or liver cirrhosis. Here, we aimed to clarify whether the atypical hepatocytes in noncancerous sections is also involved in postoperative recurrence. Furthermore, we investigated significant genes involved in the atypical hepatocytes. Association between the extent of atypical hepatocytes in noncancerous tissue and postoperative recurrence was validated in 356 patients with HCC. Next, we identified putative signature genes involved in extent of atypical hepatocytes. First, atypical hepatocytes or hepatocytes other than the atypical hepatocyte in noncancerous sections of 4 HCC patients were selectively collected by laser capture microdissection (LCM). Second, the gene expression profiles of the selected hepatocyte populations were compared using Ion AmpliSeq Transcriptome Human Gene Expression Kit (Thermo Fisher SCIENTIFIC, Waltham, MA, USA) analysis. Finally, we validated the mRNA expression of the extracted genes in noncancerous frozen liver tissue from 62 patients with HCC by RT-qPCR to identify the signature genes involved in both the extent of atypical hepatocytes and postoperative recurrence. Furthermore, the extent of atypical hepatocytes and CDT1 expression in noncancerous sections from 8 patients with HCC were also validated by selectively collecting samples using LCM. The extent of atypical hepatocytes was associated with postoperative recurrence. Of the genes that showed significant differences in expression levels between two populations, the expression of the chromatin licensing and DNA replication factor 1 (CDT1) gene was most strongly associated with the extent of atypical hepatocytes and was also associated with postoperative recurrence. Furthermore, CDT1-positive cells that exhibited stronger expression resembled those morphologically considered to be atypical hepatocytes. CDT1 and Ki-67 were colocalized in the nuclei of both hepatocytes and cancer cells. The hepatocytes in noncancerous livers were not uniform in each hepatocyte population, suggesting that the accumulation of genetic abnormalities was variable. We found that the strong degree of atypical hepatocytes and high CDT1 mRNA expression represent a high carcinogenic state of the liver. Thus, we consider the evaluation of degree of these could support the personalized medicine.

DOI： 10.1038/s41598-022-25201-6

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Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：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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Language：English   Publishing type：Research paper (scientific journal)   Publisher：London : BioMed Central, 2006-  

<h4>Background</h4>The most common type of cancer of the digestive system is hepatocellular carcinoma. In China, many patients harbour HBV. The lin28B/Let-7c/MYC axis is associated with the occurrence of many cancers. Therefore, we aimed to illuminate the function of the lin28B/Let-7c/MYC axis in hepatocellular carcinoma. We aimed to evaluate the critical involvement of lin28B and Let-7c in the carcinogenesis of human hepatocellular carcinoma (B-HCC).<h4>Methods</h4>Data from the GEO database were used to analyse differentially expressed genes and IRGs. A protein - protein interaction (PPI) network and Venn diagram were generated to analyse relationships. Real-time RT-PCR, Western blotting, and cell counting kit-8 assays were used to examine the association of lin28B, Let-7c, and MYC with cell proliferation.<h4>Results</h4>A total of 2552 functionally annotated differentially expressed RNAs were analysed in HBV patients from the GSE135860 database. In addition, 46 let-7c target genes were screened in HBV patients, and the interactions were analysed through PPI network analysis. The results confirmed that Let-7c and its target genes play a key role in HBV-related diseases. Next, we discovered a gradual decrease in Let-7c expression during the progression from HBV-associated chronic hepatitis (B-CH) and HBV-associated liver cirrhosis (B-LC) to B-HCC. We found evidence for a negative association between lin28B expression and Let-7c expression. The expression of MYC was obviously upregulated when Let-7c was inhibited.<h4>Conclusion</h4>Our results highlight that Let-7c and lin28B participate in the carcinogenesis of HBV-associated diseases through the lin28B/Let-7c/MYC axis.

DOI： 10.1186/s13027-022-00458-8

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Language：Japanese   Publisher：(NPO)日本がん検診・診断学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Tokyo : National Center for Global Health and Medicine  

It is well-known that sustained virological response (SVR) by interferon (IFN)-based therapy against hepatitis C virus (HCV) infection reduced the incidence of hepatocellular carcinoma (HCC). However, whether IFN-free direct-acting antivirals reduce the risk of HCC is controversial. Therefore, this study aims to compare the incidence of HCC after the achievement of SVR between sofosbuvir combined with ledipasvir (SOF/LDV) and simeprevir with pegylated interferon plus ribavirin (Sim+IFN). Japanese patients with HCV infection (genotype 1) who achieved SVR between January 2013 and December 2014 by SOF/LDV (NCT01975675, n = 320) or Sim+IFN (000015933, n = 289) therapy in two nationwide, multicenter, phase III studies were prospectively monitored for the development of HCC by ultrasonography for 5 years after the end of treatment (EOT). No HCC was detected before the treatment. HCC was detected in 9 and 7 patients in the SOF/LDV and the Sim+IFN group in 5 years, respectively. The cumulative incidences of HCC rates 1, 3, and 5 years after EOT were similar between the two groups (1.5%, 2.7%, and 3.2% for the SOF/LDV and 1.8%, 2.8%, and 3.0% for the Sim+IFN group, respectively). No HCC was developed 3.5 years after EOT. Interestingly, a retrospective careful review of imaging taken before therapy revealed hepatic nodules in 50% of HCC patients, suggesting HCC was pre-existed before therapy. In conclusion, we could not find any differences in the incidence of HCC after the HCV eradication between the two therapeutic regimens, suggesting no enhancement of HCC development by DAA.

DOI： 10.35772/ghm.2022.01026

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Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：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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Authorship：Lead author,　Corresponding author   Language：English  

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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Language：English   Publishing type：Research paper (scientific journal)  

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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Language：Japanese   Publisher：医歯薬出版株式会社  

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：{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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Authorship：Last author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：{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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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Basel, Switzerland : MDPI  

Cytokines are secreted soluble glycoproteins that regulate cellular growth, proliferation, and differentiation. Suppressors of cytokine signaling (SOCS) proteins negatively regulate cytokine signaling and form a classical negative feedback loop in the signaling pathways. There are eight members of the SOCS family. The SOCS proteins are all comprised of a loosely conserved N-terminal domain, a central Src homology 2 (SH2) domain, and a highly conserved SOCS box at the C-terminus. The role of SOCS proteins has been implicated in the regulation of cytokines and growth factors in liver diseases. The SOCS1 and SOCS3 proteins are involved in immune response and inhibit protective interferon signaling in viral hepatitis. A decreased expression of SOCS3 is associated with advanced stage and poor prognosis of patients with hepatocellular carcinoma (HCC). DNA methylations of SOCS1 and SOCS3 are found in HCC. Precise regulation of liver regeneration is influenced by stimulatory and inhibitory factors after partial hepatectomy (PH), in particular, SOCS2 and SOCS3 are induced at an early time point after PH. Evidence supporting the important role of SOCS signaling during liver regeneration also supports a role of SOCS signaling in HCC. Immuno-oncology drugs are now the first-line therapy for advanced HCC. The SOCS can be potential targets for HCC in terms of cell proliferation, cell differentiation, and immune response. In this literature review, we summarize recent findings of the SOCS family proteins related to HCC and liver diseases.

DOI： 10.3390/cancers14102549

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Wyoming, N.S.W. : Ivyspring International Publisher  

Atezolizumab plus bevacizumab (ATZ/BV) treatment is a combined immunotherapy consisting of immune checkpoint inhibitor (ICI) and anti-vascular endothelial growth factor monoclonal antibody, which has brought a major paradigm shift in the treatment of unresectable hepatocellular carcinoma (HCC). Gain-of-function mutation of CTNNB1 contributes to resistance of ICI monotherapy through the framework of non-T-cell-inflamed tumor microenvironment. However, whether CTNNB1 mutation renders resistance to ATZ/BV similar to ICI monotherapy remains to be elucidated. In this study, a liquid biopsy sample in plasma of 33 patients with HCC treated with ATZ/BV was subjected to droplet digital PCR for detecting hotspot mutations at the exon 3 of CTNNB1 locus. A total of eight patients (24.2%) exhibited at least one CTNNB1 mutation. The objective response rate (ORR) in patients with wild-type (WT) and mutant (MT) CTNNB1 was 8.0% and 12.5%, respectively, and the disease control rate (DCR) was 68.0% and 87.5%, respectively. No significant difference in both ORR and DCR has been observed between the two groups. The median progression-free survival in patients with WT and MT CTNNB1 was 6.6 and 7.6 months, respectively (not statistically significant). Similarly, no significant difference in overall survival has been observed between patients with WT and MT CTNNB1 (13.6 vs. 12.3 months). In conclusion, the treatment effect of ATZ/BV in patients with HCC with MT CTNNB1 was comparable to those patients with WT CTNNB1. These results implicate that BV added to ATZ might improve immunosuppressive tumor microenvironment caused by CTNNB1 mutation.

DOI： 10.7150/jca.71494

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Tokyo, Japan : Springer Verlag  

PURPOSE: Blood flow reduction after initiation of lenvatinib therapy may not always indicate tumor necrosis. This study aimed to compare the blood flow detectability of contrast-enhanced ultrasonography (CEUS), contrast-enhanced computed tomography (CT), and contrast-enhanced magnetic resonance imaging (MRI) in hepatocellular carcinoma (HCC) during lenvatinib therapy. METHODS: A total of 12 cases underwent CEUS and contrast-enhanced CT/MRI within 2 weeks during lenvatinib therapy. Vascularity on CEUS and CT/MRI was compared. RESULTS: At the time of CEUS examination, the median period from the start of lenvatinib was 227 ± 210 (31-570) days. CEUS showed hyperenhancement in eight cases (66.7%), hypoenhancement in two cases (16.7%), and no enhancement in one case (8.3%), while CT/MRI showed hyperenhancement in one case (8.3%), ring enhancement in three cases (25.0%), and hypoenhancement in eight cases (66.7%) (p = 0.007). Transarterial chemoembolization (n = 3), radiofrequency ablation (n = 2), and stereotactic body radiation therapy (n = 2) were performed after blood flow detection by CEUS. CONCLUSIONS: The viability of the HCC should be confirmed using CEUS when contrast-enhanced CT/MRI reveals lesion hypoenhancement during lenvatinib therapy.

DOI： 10.1007/s10396-022-01204-8

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Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：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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Authorship：Last author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：{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

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Authorship：Lead author,　Corresponding author   Language：Japanese   Publisher：日本メディカルセンター  

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Language：Japanese   Publisher：(一社)日本医療検査科学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Basel, Switzerland : MDPI  

Background and Objectives: Balloon-occluded retrograde transvenous obliteration (BRTO) could be currently one of the best therapies for patients with gastric varices. This study examined the exacerbation rates for esophageal varices following BRTO for gastric varices in patients with hepatic cirrhosis. Materials and Methods: We enrolled 91 cirrhotic patients who underwent BRTO for gastric varices. In total, 50 patients were examined for exacerbation rates of esophageal varices following BRTO. Esophageal varices and their associated exacerbation were evaluated by upper gastrointestinal endoscopy. Patients were allocated into two groups according to the main inflow tract for gastric varices: (1) 37 patients in the left gastric vein (LGV) group with an LGV width of more than 3.55 mm, and (2) 13 patients in the non-LGV group who had short gastric vein or posterior gastric vein. Moreover, treatment outcomes were retrospectively analyzed. Results: LGV width (p < 0.01) was the major risk factor for the deterioration of esophageal varices post BRTO. In addition, LGV was the most common inflow tract, and the LGV group contained 74% (37/50) of patients. The exacerbation rates of esophageal varices at 1, 2, 3, and 4 years post BRTO were 40%, 62%, 65%, and 68%, respectively. The comparison of the exacerbation rates for esophageal varices following BRTO according to inflow tract showed that the exacerbation rates were significantly higher in the LGV group than those of the non-LGV group (p = 0.03). In more than half of the subjects, LGV was the main inflow tract for gastric varices, and this group experienced more frequent exacerbations of esophageal varices following BRTO compared to patients with different inflow tract sources. Conclusion: Careful attention should be paid to the LGV width when BRTO is performed for gastric varices.

DOI： 10.3390/medicina58020205

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Athens : Dr. J.G. Delinassios  

BACKGROUND: Eradication of hepatitis C virus (HCV) from chronic HCV-infected patients could improve liver function and prevent hepatocarcinogenesis in the long term. Eradication of HCV by direct-acting antivirals (DAAs) also leads to dynamic immunological changes. We report a case of recurrent coronavirus disease 2019 (COVID-19) that developed immediately after combination treatment with DAAs for HCV infection and decompensated cirrhosis. CASE REPORT: A 55-year-old male was started on a 12-week treatment with combination of HCV NS5A inhibitor velpatasvir and HCV NS5B polymerase inhibitor sofosbuvir. HCV RNA became undetectable after six weeks of treatment and was undetectable at the end of the treatment (EOT). Twelve days after the EOT, we diagnosed the patient with COVID-19 pneumonia, admitted him to our hospital and he was discharged two weeks later. One week after his discharge, he visited our hospital again, was diagnosed with recurrent COVID-19 pneumonia readmitted for a second time. Four days after second admission, cardiac arrest occurred, however, he recovered from severe COVID-19 and achieved sustained virological response and his liver function improved. CONCLUSION: In the COVID-19 era, while attention should be paid to the occurrence or exacerbation of infection, including COVID-19, interferon-free DAA combination therapy should be performed for HCV-infected individuals.

DOI： 10.21873/invivo.12923

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Athens, Greece : Hellenic Anticancer Institute  

BACKGROUND: Hepatocellular carcinoma (HCC) occasionally presents with simultaneous or metachronous primary malignancies of other organs. Despite the limited scope of cytocidal anticancer drugs or molecular targeted agents, immune checkpoint inhibitors (ICIs) can still be used for various malignancies. Here, we present cases of double cancers including HCC treated with ICIs. CASE REPORT: Case 1: A 70-year-old man with lung cancer and 80-mm HCC underwent nivolumab therapy. The sizes of both cancers remained constant for nine months. Case 2: A 58-year-old man with pharyngeal cancer and HCC. Nivolumab was administered, but was withdrawn after one session because of progressive disease. Case 3: A 71-year-old man with a 5 cm HCC invading the inferior vena cava, and early esophageal cancer. HCC showed a significant volume reduction and esophageal cancer demonstrated slight improvement by atezolizumab and bevacizumab therapy. CONCLUSION: A combination therapy including ICI is a promising treatment option for HCC with concurrent malignancies.

DOI： 10.21873/anticanres.15442

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Basel, Switzerland : MDPI AG  

Hepatis virus C (HCV) infection causes liver cirrhosis and hepatocellular carcinoma (HCC) worldwide. The objective of our study was to examine the effects of the HCV nonstructural protein (NS) 3/4A inhibitor glecaprevir/NS5A inhibitor pibrentasvir on real-world HCV patients in the northern part of Tokyo, Japan. Although 106 patients were consecutively included, a total of 102 HCV-infected patients with chronic hepatitis or compensated cirrhosis, who received 8- or 12-week combination treatment with glecaprevir/pibrentasvir and were followed up to week 12 after the end of treatment were analyzed retrospectively. Only three patients discontinued treatment due to adverse events; however, they achieved a sustained virologic response at 12 weeks (SVR12). Finally, SVR rates were 99.0% (101/102). Only one patient without liver cirrhosis was a treatment relapser who received hepatic resection for HCC approximately two years after commencement of the 8-week combination treatment with glecaprevir/pibrentasvir. After the exclusion of patients with HCV genotype 1b and P32 deletion in the HCV NS5A region, a 12-week combination of glecaprevir/pibrentasvir led to SVR12 in all nine direct-acting antiviral-experienced patients. Glecaprevir/pibrentasvir had a high efficacy and an acceptable safety profile for real-world HCV patients in a single hospital in Japan.

DOI： 10.3390/jcm10235529

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：London : Nature Pub. Group  

Hepatocellular carcinoma (HCC) is one of the most common malignancy-related deaths. p53 mutation in HCC associates with worse clinicopathologic features including therapeutic limitation. A combination of targeted therapy may have some advantages. Akt/mTOR signaling contributes to the regulation of cell proliferation and cell death. Akt inhibitor (AZD5363) and mTORC1/2 dual inhibitor (AZD8055) are in a clinical trial for HCC and other cancers. In this study, we examined whether these inhibitors successfully induce antiproliferative activity in p53 mutant HCC cells, and the underlying mechanisms. We observed that a combination of AZD5363 and AZD8055 treatment synergizes antiproliferative activity on p53 mutated or wild-type HCC cell lines and induces apoptotic cell death. Mechanistic insights indicate that a combination of AZD5363 and AZD8055 activated FOXO3a to induce Bim-associated apoptosis in p53 mutated HCC cells, whereas cells retaining functional p53 enhanced Bax. siRNA-mediated knock-down of Bim or Bax prevented apoptosis in inhibitor-treated cells. We further observed a combination of treatment inhibits phosphorylation of FOXO3a and protects FOXO3a from MDM2 mediated degradation by preventing the phosphorylation of Akt and SGK1. FOXO3a accumulates in the nucleus under these conditions and induces Bim transcription in p53 mutant HCC cells. Combination treatment in the HCC cells expressing wild-type p53 causes interference of FOXO3a function for direct interaction with functional p53 and unable to induce Bim-associated cell death. On the other hand, Bim-associated cell death occurs in p53 mutant cells due to uninterrupted FOXO3a function. Overall, our findings suggested that a combined regimen of dual mTORC1/2 and Akt inhibitors may be an effective therapeutic strategy for HCC patients harboring p53 mutation.

DOI： 10.1038/s41419-021-04371-7

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Basel, Switzerland : MDPI  

Hepatitis B virus (HBV) infection is one of the serious health problems in the world as HBV causes severe liver diseases. Moreover, HBV reactivation has occasionally been observed in patients with resolved HBV infection and patients using immunosuppression and anticancer drugs. Large-scale hospital data focused on HBV infection and severe liver function were analyzed at our hospital, located in an urban area adjacent to Tokyo, the capital city of Japan. A total of 99,932 individuals whose blood samples were taken at 7,170,240 opportunities were analyzed. The HBV surface antigen (HBsAg)-positive group had a more frequent prevalence of patients with higher transaminase elevations than the HBsAg-negative group. However, among the HBsAg-negative group, patients who were positive for anti-HBV surface antibody and/or anti-HBV core antibody, had more severe liver conditions and fatal outcomes. More careful attention should be paid to alanine transaminase (ALT) elevations higher than 1000 IU/L in patients who had current and previous HBV infection.

DOI： 10.3390/v13112216

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：London : Nature Publishing Group  

Both EZH2 and its homolog EZH1 function as histone H3 Lysine 27 (H3K27) methyltransferases and repress the transcription of target genes. Dysregulation of H3K27 trimethylation (H3K27me3) plays an important role in the development and progression of cancers such as hepatocellular carcinoma (HCC). This study investigated the relationship between the expression of EZH1/2 and the level of H3K27me3 in HCC. Additionally, the role of EZH1/2 in cell growth, tumorigenicity, and resistance to sorafenib were also analyzed. Both the lentiviral knockdown and the pharmacological inhibition of EZH1/2 (UNC1999) diminished the level of H3K27me3 and suppressed cell growth in liver cancer cells, compared with EZH1 or EZH2 single knockdown. Although a significant association was observed between EZH2 expression and H3K27me3 levels in HCC samples, overexpression of EZH1 appeared to contribute to enhanced H3K27me3 levels in some EZH2lowH3K27me3high cases. Akt suppression following sorafenib treatment resulted in an increase of the H3K27me3 levels through a decrease in EZH2 phosphorylation at serine 21. The combined use of sorafenib and UNC1999 exhibited synergistic antitumor effects in vitro and in vivo. Combination treatment canceled the sorafenib-induced enhancement in H3K27me3 levels, indicating that activation of EZH2 function is one of the mechanisms of sorafenib-resistance in HCC. In conclusion, sorafenib plus EZH1/2 inhibitors may comprise a novel therapeutic approach in HCC.

DOI： 10.1038/s41598-021-00889-0

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Language：Japanese   Publisher：The Japan Society of Hepatology  

DOI： 10.2957/kanzo.62.656

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Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUNDS & AIMS: Primary biliary cholangitis (PBC) is a chronic liver disease in which autoimmune destruction of the small intrahepatic bile ducts eventually leads to cirrhosis. Many patients have inadequate response to licensed medications, motivating the search for novel therapies. Previous genome-wide association studies (GWAS) and meta-analyses (GWMA) of PBC have identified numerous risk loci for this condition, providing insight into its aetiology. We undertook the largest GWMA of PBC to date, aiming to identify additional risk loci and prioritise candidate genes for in silico drug efficacy screening. METHODS: We combined new and existing genotype data for 10,516 cases and 20,772 controls from 5 European and 2 East Asian cohorts. RESULTS: We identified 56 genome-wide significant loci (20 novel) including 46 in European, 13 in Asian, and 41 in combined cohorts; and a 57th genome-wide significant locus (also novel) in conditional analysis of the European cohorts. Candidate genes at newly identified loci include FCRL3, INAVA, PRDM1, IRF7, CCR6, CD226, and IL12RB1, which each play key roles in immunity. Pathway analysis reiterated the likely importance of pattern recognition receptor and TNF signalling, JAK-STAT signalling, and differentiation of T helper (TH)1 and TH17 cells in the pathogenesis of this disease. Drug efficacy screening identified several medications predicted to be therapeutic in PBC, some of which are well-established in the treatment of other autoimmune disorders. CONCLUSIONS: This study has identified additional risk loci for PBC, provided a hierarchy of agents that could be trialled in this condition, and emphasised the value of genetic and genomic approaches to drug discovery in complex disorders. LAY SUMMARY: Primary biliary cholangitis (PBC) is a chronic liver disease that eventually leads to cirrhosis. In this study, we analysed genetic information from 10,516 people with PBC and 20,772 healthy individuals recruited in Canada, China, Italy, Japan, the UK, or the USA. We identified several genetic regions associated with PBC. Each of these regions contains several genes. For each region, we used diverse sources of evidence to help us choose the gene most likely to be involved in causing PBC. We used these 'candidate genes' to help us identify medications that are currently used for treatment of other conditions, which might also be useful for treatment of PBC.

DOI： 10.1016/j.jhep.2021.04.055

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Other Link： 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

Language：English   Publishing type：Research paper (scientific journal)  

Background and Objectives: Direct-acting antiviral agents (DAAs) have improved sustained virologic response (SVR) rates in patients with chronic hepatitis C virus (HCV) infection. Our aim was to elucidate the occurrence of hepatocellular carcinoma (HCC) and to compare the outcomes of patients aged 75 years or older (older group) with those of patients younger than 75 years (younger group) after SVR. Materials and Methods: Among 441 patients treated with interferon-free DAA combinations, a total of 409 SVR patients were analyzed. We compared the two age groups in terms of HCC incidence and mortality rates. Results: Older and younger groups consisted of 68 and 341 patients, respectively. Occurrence of HCC after SVR did not differ between the two groups of patients with a history of HCC. Occurrence of HCC after SVR was observed more in younger patients without a history of HCC (p < 0.01). Although older patients without a history of HCC had a higher mortality rate (p < 0.01), their causes of death were not associated with liver diseases. Among younger patients without a history of HCC, none died. Conclusions: After SVR, liver disease may not be a prognostic factor in older HCV patients without a history of HCC.

DOI： 10.3390/medicina57080761

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：{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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Authorship：Lead author,　Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media {LLC}  

DOI： 10.1007/s12072-021-10191-w

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Tokyo, Japan : Springer Verlag  

<h4>Purpose</h4>Fibrosis is a predictor of mortality in patients with non-alcoholic fatty liver disease (NAFLD). In our institution, abdominal ultrasonography has been performed based on a unified method consisting of 25 images. We investigated ultrasonographic grayscale findings related to fibrosis in patients with NAFLD.<h4>Methods</h4>This retrospective study comprised 41 cases of pathologically proven fatty liver between January 2015 and September 2020. A total of 26 ultrasonographic findings were subjectively evaluated. These findings, transient elastography (TE) with M probe, and FIB-4 index were compared with fibrosis stage.<h4>Results</h4>The frequency of roughness of the dorsal side of the surface (p < 0.001), heterogenicity of the parenchyma (p = 0.003), narrowing of the hepatic vein (p = 0.004), and splenomegaly (p < 0.001) were strongly correlated with the fibrosis stage. Logistic regression analysis for stage ≥ 3 showed narrowing of the hepatic vein (odds ratio [OR] 5.860, p = 0.031) and splenomegaly (OR 6.290, p = 0.028). Logistic regression analysis for stage 4 showed roughness of the ventral side of the surface (OR 42.0, p = 0.019). The AUROC for stage 3 and stage 4 with the number of positive ultrasonographic findings was 0.856, and 0.940, respectively. The AUROC for F3 and F4 with TE was 0.831 and 0.861, respectively. The AUROC for stage 3 and stage 4 with FIB-4 index was 0.815 and 0.806, respectively.<h4>Conclusions</h4>Narrowing of the hepatic vein, roughness of the dorsal side of the surface, heterogenicity of the parenchyma, and splenomegaly and their combination could predict fibrosis in patients with NAFLD.

DOI： 10.1007/s10396-021-01107-0

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Authorship：Corresponding author   Language：English  

Recently, the use of immune checkpoint inhibitors (ICIs) with or without chemotherapeutic agents has been increasing in the treatment for advanced cancer. Here, we report the occurrence of liver failure after the use of pembrolizumab in an 82-year-old woman with metastatic liver disease derived from right advanced renal pelvis, ureteral cancer, and bladder cancer. She was successfully treated with 0.6 mg/kg daily prednisolone. In patients treated with ICIs, ICI-induced hepatitis is occasionally observed. Even if patients are older, it appears important to diagnose and treat ICI-induced hepatitis earlier by multidisciplinary therapies including steroid treatment. This is a first report of pembrolizumab-induced liver failure in elder patient with age over 80 years. Even if patients are older, it appears important to diagnose and treat ICI-induced hepatitis earlier by multidisciplinary therapies including steroid treatment.

DOI： 10.1002/jgh3.12554

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Basel : S. Karger  

BACKGROUND: There is no standard posttreatment for patients with advanced hepatocellular carcinoma (HCC) in whom lenvatinib therapy has failed. This study aimed to investigate rates of migration to posttreatment after lenvatinib and to explore candidates for second-line agents in the patients with failed lenvatinib therapy. METHODS: We retrospectively collected data on patients with advanced HCC who received lenvatinib as the first-line agent in 7 institutions. RESULTS: Overall survival and progression-free survival (PFS) of 178 patients who received lenvatinib as the first-line agent were 13.3 months (95% confidence interval [CI], 11.5-15.2) and 6.7 months (95% CI, 5.6-7.8), respectively. Sixty-nine of 151 patients (45.7%) who discontinued lenvatinib moved on to posttreatment. The migration rates from lenvatinib to the second-line agent and from the second-line agent to the third-line agent were 41.7 and 44.4%, respectively. Based on multivariate analysis, response to lenvatinib (complete or partial response according to modified RECIST) and discontinuation of lenvatinib due to radiological progression, as well as male were associated with a significantly higher probability of migration to posttreatment after lenvatinib. On the other hand, alpha-fetoprotein levels of 400 ng/mL or higher was correlated with a significantly lower probability of migration to posttreatment after lenvatinib. Of 63 patients who received second-line systemic therapy, 53 (84.2%) were administered sorafenib. PFS, objective response rate (ORR), and disease control rate (DCR) for sorafenib treatment were 1.8 months (95% CI, 0.6-3.0), 1.8%, and 20.8%, respectively. According to the Cox regression hazard model, Child-Pugh class B significantly contributed to shorter PFS. PFS, ORR, and DCR of 22 patients who received regorafenib after lenvatinib in any lines were 3.2 months (range, 1.5-4.9 months), 13.6%, and 36.3%, respectively. Similarly, PFS, ORR, and DCR of 17 patients who received regorafenib after lenvatinib in the third-line (after sorafenib) were 3.8 months (range, 1.1-6.5 months), 17.6%, and 41.2%, respectively. CONCLUSION: Sorafenib may not be a candidate for use as a posttreatment agent after lenvatinib, according to the results of the present study. Regorafenib has the potential to become an appropriate posttreatment agent after lenvatinib.

DOI： 10.1159/000515552

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Tokyo, Japan : Springer Verlag, c2001-  

<h4>Purpose</h4>Hemodynamic change after total paracentesis was investigated because it might lead to various complications. Although cell-free and concentrated ascites reinfusion therapy (CART) is safer and more effective than total paracentesis in theory, hemodynamic change after CART has been never reported. And previous studies did not mention hemodynamics of the venous system.<h4>Methods</h4>We investigated the hemodynamic change, including that of the venous system, before and after CART using color Doppler ultrasonography and fast Fourier transform analysis. Twenty-eight patients with tensive cirrhotic ascites underwent ultrasonography the day before and after total volume CART. The diameter and velocity of the main, right, and left portal vein; inferior vena cava (IVC); and right renal vein were measured using ultrasonography.<h4>Results</h4>A total of 11.8 ± 4.4 L of ascites (range 3.6-20.9 L) was filtered and concentrated to 0.85 ± 0.40 L (range 0.36-1.50 L). The diameter of the IVC increased from median 13.5 ± 5.4 mm (range 4-25 mm) to 18.5 ± 4.1 mm (range 7-29 mm) (p = 0.007). The diameter of the right segmental renal vein significantly increased after KM-CART [from 5.0 ± 1.0 (4-8) mm to 7.0 ± 2.0 (3-10) mm] (p = 0.011). Hemodynamic change of the portal venous system was not significant. The time to the next CART in patients with an IVC diameter ≥ 20 mm and < 20 mm was 86 days and 20.5 days (p = 0.035), respectively.<h4>Conclusion</h4>Tensive ascites results in venous congestion in patients with cirrhotic ascites. CART improved venous flow, but it did not change the hemodynamics of the portal venous system.

DOI： 10.1007/s10396-021-01094-2

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：St. Louis, MO : Mosby  

BACKGROUND: Liver stiffness measurement using magnetic resonance elastography can assess the severity of liver fibrosis, which is significantly associated with recurrence after curative resection for hepatocellular carcinoma. The aim of this prospective study was to investigate whether preoperative liver stiffness measurement by magnetic resonance elastograhy can predict recurrence after curative resection for hepatocellular carcinoma. METHODS: Patients who underwent preoperative liver stiffness measurement and curative resection for hepatocellular carcinoma were enrolled in this study. Potential associations between liver stiffness measurement, along with other clinical and pathologic variables, and intrahepatic hepatocellular carcinoma recurrence were analyzed. RESULTS: In total, 156 patients were included in this study. During a median follow-up period of 25.1 months (range, 6.0-60.5 months), 72 (46.1%) patients with hepatocellular carcinoma had an intrahepatic recurrence. The median disease-free period after resection was 17.9 months (range, 1.0-60.5 months). In the multivariate analysis, liver stiffness measurement (hazard ratio, 1.27; 95% confidence interval, 1.11-1.43; P <.001) and vascular invasion (hazard ratio, 1.96; 95% confidence interval, 1.15-3.25; P = .013) were identified as independent predictors of recurrence. When the optimal cutoff point was set at 4.53 kPa using the minimal P value approach, the disease-free period after curative resection in 71 patients with a liver stiffness measurement value ≥4.53 kPa (11.3 months [range, 2.0-60.5 months]) was significantly shorter than that of 85 patients with a liver stiffness measurement value <4.53 kPa (22.5 months [range, 1.1-60.5 months]; P <.001). CONCLUSION: Liver stiffness measurement using magnetic resonance elastography is a useful preoperative predictor of intrahepatic recurrence after curative resection for hepatocellular carcinoma.

DOI： 10.1016/j.surg.2021.02.027

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

DOI： 10.7150/jca.56436

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：London : Nature Publishing Group  

FGF19/FGFR4 autocrine signaling is one of the main targets for multi-kinase inhibitors (MKIs). However, the molecular mechanisms underlying FGF19/FGFR4 signaling in the antitumor effects to MKIs in hepatocellular carcinoma (HCC) remain unclear. In this study, the impact of FGFR4/ERK signaling inhibition on HCC following MKI treatment was analyzed in vitro and in vivo assays. Serum FGF19 in HCC patients treated using MKIs, such as sorafenib (n = 173) and lenvatinib (n = 40), was measured by enzyme-linked immunosorbent assay. Lenvatinib strongly inhibited the phosphorylation of FRS2 and ERK, the downstream signaling molecules of FGFR4, compared with sorafenib and regorafenib. Additional use of a selective FGFR4 inhibitor with sorafenib further suppressed FGFR4/ERK signaling and synergistically inhibited HCC cell growth in culture and xenograft subcutaneous tumors. Although serum FGF19high (n = 68) patients treated using sorafenib exhibited a significantly shorter progression-free survival and overall survival than FGF19low (n = 105) patients, there were no significant differences between FGF19high (n = 21) and FGF19low (n = 19) patients treated using lenvatinib. In conclusion, robust inhibition of FGF19/FGFR4 is of importance for the exertion of antitumor effects of MKIs. Serum FGF19 levels may function as a predictive marker for drug response and survival in HCC patients treated using sorafenib.

DOI： 10.1038/s41598-021-84117-9

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Philadelphia, PA : W.B. Saunders  

BACKGROUND & AIMS: Genome-wide association studies in primary biliary cholangitis (PBC) have failed to find X chromosome (chrX) variants associated with the disease. Here, we specifically explore the chrX contribution to PBC, a sexually dimorphic complex autoimmune disease. METHODS: We performed a chrX-wide association study, including genotype data from 5 genome-wide association studies (from Italy, United Kingdom, Canada, China, and Japan; 5244 case patients and 11,875 control individuals). RESULTS: Single-marker association analyses found approximately 100 loci displaying P < 5 × 10-4, with the most significant being a signal within the OTUD5 gene (rs3027490; P = 4.80 × 10-6; odds ratio [OR], 1.39; 95% confidence interval [CI], 1.028-1.88; Japanese cohort). Although the transethnic meta-analysis evidenced only a suggestive signal (rs2239452, mapping within the PIM2 gene; OR, 1.17; 95% CI, 1.09-1.26; P = 9.93 × 10-8), the population-specific meta-analysis showed a genome-wide significant locus in East Asian individuals pointing to the same region (rs7059064, mapping within the GRIPAP1 gene; P = 6.2 × 10-9; OR, 1.33; 95% CI, 1.21-1.46). Indeed, rs7059064 tags a unique linkage disequilibrium block including 7 genes: TIMM17B, PQBP1, PIM2, SLC35A2, OTUD5, KCND1, and GRIPAP1, as well as a superenhancer (GH0XJ048933 within OTUD5) targeting all these genes. GH0XJ048933 is also predicted to target FOXP3, the main T-regulatory cell lineage specification factor. Consistently, OTUD5 and FOXP3 RNA levels were up-regulated in PBC case patients (1.75- and 1.64-fold, respectively). CONCLUSIONS: This work represents the first comprehensive study, to our knowledge, of the chrX contribution to the genetics of an autoimmune liver disease and shows a novel PBC-related genome-wide significant locus.

DOI： 10.1053/j.gastro.2021.02.061

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：San Diego, CA : Elsevier  

Lenvatinib is one of the first-line drugs for patients with advanced hepatocellular carcinoma (HCC) and widely used around the world. However, the mechanisms underlying resistance to lenvatinib remain unclear. In this study, we conducted characteristic analyses of lenvatinib-resistant HCC cells. Lenvatinib-resistant HCC cell lines were established by exposure to serially escalated doses of lenvatinib over 2 months. The biological characteristics of these cells were examined by in vitro assays. To investigate the cytokine profile of lenvatinib-resistant HCC cells, the supernatant derived from lenvatinib-resistant Huh7 cells was subjected to nitrocellulose membrane-based sandwich immunoassay. Both activation of the MAPK/MEK/ERK signaling pathway and upregulation of epithelial mesenchymal transition markers were observed in lenvatinib-resistant cells. Concordant with these findings, proliferation and invasion abilities were enhanced in these cells compared with control cells. Screening of a cytokine array spotted with 105 different antibodies to human cytokines enabled us to identify 16 upregulated cytokines in lenvatinib-resistant cells. Among them, 3 angiogenic cytokines: vascular endothelial growth factor (VEGF), platelet-derived growth factor-AA (PDGF-AA), and angiogenin, were increased significantly. Conditioned medium from lenvatinib-resistant cells accelerated tube formation of human umbilical vein cells. In conclusion, lenvatinib-resistant HCC cells were characterized by enhanced proliferation and invasion abilities. These findings might contribute to the establishment of new combination therapies with lenvatinib.

DOI： 10.1016/j.bbrc.2021.02.097

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：London : Nature Publishing Group  

Hepatitis B (HB) vaccines (Heptavax-II and Bimmugen) designed based on HBV genotypes A and C are mainly used for vaccination against HB in Japan. To determine whether there are differences in the genetic background associated with vaccine responsiveness, genome-wide association studies were performed on 555 Heptavax-II and 1193 Bimmugen recipients. Further HLA imputation and detailed analysis of the association with HLA genes showed that two haplotypes, DRB1*13:02-DQB1*06:04 and DRB1*04:05-DQB1*04:01, were significantly associated in comparison with high-responders (HBsAb > 100 mIU/mL) for the two HB vaccines. In particular, HLA-DRB1*13:02-DQB1*06:04 haplotype is of great interest in the sense that it could only be detected by direct analysis of the high-responders in vaccination with Heptavax-II or Bimmugen. Compared with healthy controls, DRB1*13:02-DQB1*06:04 was significantly less frequent in high-responders when vaccinated with Heptavax-II, indicating that high antibody titers were less likely to be obtained with Heptavax-II. As Bimmugen and Heptavax-II tended to have high and low vaccine responses to DRB1*13:02, 15 residues were found in the Heptavax-II-derived antigenic peptide predicted to have the most unstable HLA-peptide binding. Further functional analysis of selected hepatitis B patients with HLA haplotypes identified in this study is expected to lead to an understanding of the mechanisms underlying liver disease.

DOI： 10.1038/s41598-021-82986-8

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Future Medicine Ltd  

London, UK : Future Medicine Ltd.

DOI： 10.2217/fvl-2020-0181

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Pleasanton, CA : Baishideng Publishing Group  

Pleasanton, CA : Baishideng Publishing Group

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Tokyo, Japan : Japanese Society of Internal Medicine  

Tokyo, Japan : Japanese Society of Internal Medicine

DOI： 10.2169/internalmedicine.6728-20.

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Basel, Switzerland : MDPI  

Basel, Switzerland : MDPI

DOI： 10.3390/v13020207

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Basel : S. Karger  

Basel : S. Karger

DOI： 10.1159/000512028

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Other Link： 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

Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：Japan Society of Hepatology  

DOI： 10.2957/kanzo.62.72

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：Japan Society of Hepatology  

DOI： 10.2957/kanzo.62.548

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Language：Japanese   Publisher：一般社団法人 日本肝臓学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Basel : S. Karger  

&lt;b&gt;&lt;i&gt;Background and Aims:&lt;/i&gt;&lt;/b&gt; The prognosis of patients with advanced hepatocellular carcinoma (HCC) is expected to improve as multiple molecular target agents (MTAs) are now available. However, the impact of the availability of sequential MTAs has not been fully verified yet. &lt;b&gt;&lt;i&gt;Approach and Results:&lt;/i&gt;&lt;/b&gt; We retrospectively collected the data on the whole clinical course of 877 patients who received any MTAs as first-line systemic therapy for advanced HCC between June 2009 and March 2019. The study population was divided into 3 groups according to the date of first-line MTA administration (period 1: 2009–2012, &lt;i&gt;n&lt;/i&gt; = 267; period 2: 2013–2016, &lt;i&gt;n&lt;/i&gt; = 352; period 3: 2017–2019, &lt;i&gt;n&lt;/i&gt; = 258). Then, we compared the number of MTAs used, overall survival (OS), and MTA treatment duration among the 3 groups. Analysis was also performed separately for advanced-stage and nonadvanced-stage HCC. The proportion of patients who received multiple MTAs was remarkably increased over time (1.1%, 10.2%, and 42.6% in periods 1, 2, and 3, respectively, &lt;i&gt;p&lt;/i&gt; &amp;#x3c; 0.001). The median OS times were prolonged to 10.4, 11.3, and 15.2 months in periods 1, 2, and 3, respectively (&lt;i&gt;p&lt;/i&gt; = 0.016). Similarly, the MTA treatment durations were extended (2.7, 3.2, and 6.6 months in periods 1, 2, and 3, respectively; &lt;i&gt;p&lt;/i&gt; &amp;#x3c; 0.001). We confirmed that the correlation between OS and MTA treatment duration was strengthened (period 1: 0.395, period 2: 0.505, and period 3: 0.667). All these trends were pronounced in the patients with advanced-stage HCC but limited in the patients with nonadvanced-stage HCC. &lt;b&gt;&lt;i&gt;Conclusions:&lt;/i&gt;&lt;/b&gt; The availability of multiple MTAs had steadily improved the prognosis of patients with advanced HCC patients, particularly advanced-stage HCC patients.

DOI： 10.1159/000519868

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Authorship：Lead author   Language：Japanese   Publisher：日本臨床社  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：[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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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Athens : Dr. J.G. Delinassios  

Athens : Dr. J.G. Delinassios

DOI： 10.21873/invivo.12168

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Athens : Dr. J.G. Delinassios  

Athens : Dr. J.G. Delinassios

DOI： 10.21873/invivo.12169

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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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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Attiki, Greece : International Institute of Anticancer Research  

Attiki, Greece : International Institute of Anticancer Research

DOI： 10.21873/anticanres.14449

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Pleasanton, CA : Baishideng Publishing Group  

Pleasanton, CA : Baishideng Publishing Group

DOI： 10.35712/aig.v1.i1.5

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：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

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Basel : S. Karger  

Basel : S. Karger

DOI： 10.1159/000508809.

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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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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Basel, Switzerland : MDPI  

Basel, Switzerland : MDPI

DOI： 10.3390/ijms21144906

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Future Medicine Ltd  

London, UK : Future Medicine Ltd.

DOI： 10.2217/fvl-2020-0104

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

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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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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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Basel, Switzerland : MDPI  

Basel, Switzerland : MDPI

DOI： 10.3390/v12050533

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Basel, Switzerland : MDPI  

Basel, Switzerland : MDPI

DOI： 10.3390/ijms21093349

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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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Authorship：Lead author,　Corresponding author   Language：Japanese   Publisher：じほう  

じほう

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：Life Science Publishing Co. Ltd  

Scopus

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Language：Japanese   Publisher：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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Authorship：Lead author   Language：Japanese  

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

Hepatitis A virus (HAV) infection occasionally leads to a critical condition in patients with or without chronic liver diseases. Acute-on-chronic liver disease includes acute-on-chronic liver failure (ACLF) and non-ACLF. In this review, we searched the literature concerning the association between HAV infection and chronic liver diseases in PubMed. Chronic liver diseases, such as metabolic associated fatty liver disease and alcoholic liver disease, coinfection with other viruses, and host genetic factors may be associated with severe hepatitis A. It is important to understand these conditions and mechanisms. There may be no etiological correlation between liver failure and HAV infection, but there is an association between the level of chronic liver damage and the severity of acute-on-chronic liver disease. While the application of an HAV vaccination is important for preventing HAV infection, the development of antivirals against HAV may be important for preventing the development of ACLF with HAV infection as an acute insult. The latter is all the more urgent given that the lives of patients with HAV infection and a chronic liver disease of another etiology may be at immediate risk.

DOI： 10.3390/ijms21176384

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Basel : S. Karger  

Basel : S. Karger

DOI： 10.1159/000507022

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Language：English   Publishing type：Research paper (scientific journal)  

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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Language：Japanese   Publishing type：Research paper (scientific journal)  

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Other Link： 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

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Abnormal autocrine fibroblast growth factor 19 (FGF19) production has been observed in several types of cancers, including hepatocellular carcinoma (HCC). In this study, we investigated the potential of serum FGF19 as a novel tumor marker of HCC based on a sandwich enzyme-linked immunosorbent assay (ELISA). METHODS: The serum FGF19 levels of 304 patients with HCC was measured by ELISA. The serum levels of existing markers, including alpha-fetoprotein (AFP) and des-gamma-carboxy prothrombin (DCP) were determined by chemiluminescence enzyme immunoassay. Both diagnostic value of FGF19 and its changes after curative ablation therapy was further examined. RESULTS: The median FGF19 levels in controls, chronic liver disease patients, and primary HCC patients, were 78.8 pg/mL, 100.1 pg/mL, and 214.5 pg/mL, respectively. The subsequent receiver operating characteristic curves (ROC) successfully determined an optimal cut-off value of 200.0 pg/mL. The area under the ROC curve (AUC) of FGF19 for HCC detection was comparable to those of AFP and DCP. Of importance, FGF19 showed higher sensitivity for the detection of small HCC (solitary cancer with diameter < 20 mm) than those of existing markers. In addition, 43 out of 79 cases (54.4%) with normal AFP and DCP (so-called "double negative HCC") exhibited serum FGF19 level ≥ 200 pg/mL. In 45 HCC patients treated with curative ablation therapy, serum FGF19 levels changed from 257.4 pg/mL to 112.0 pg/mL after the treatment. CONCLUSION: Our findings reveal that FGF19 can be a potential novel biomarker for HCC. Although FGF19 is not necessarily a substitute for existing markers, it may help improve the prognosis in HCC patients owing to its resourceful use in various aspects of HCC management and treatment.

DOI： 10.1186/s12885-019-6322-9

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：New York, NY : Springer  

New York, NY : Springer

DOI： 10.1007/s12072-019-09988-7

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Publishing type：Research paper (scientific journal)   Publisher：Future Medicine Ltd  

DOI： 10.2217/fvl-2019-0089

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：日本大学医学会  

DOI： 10.4264/numa.78.5_295

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Language：English   Publishing type：Research paper (scientific journal)  

<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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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media {LLC}  

New York, NY : Springer

DOI： 10.1007/s12072-019-09976-x

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：London : BioMed Central  

London : BioMed Central

DOI： 10.1186/s12876-019-1069-y

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Hong Kong : AME Publishing Company  

Hong Kong : AME Publishing Company

DOI： 10.21037/hbsn.2019.03.19

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Athens, Greece : Hellenic Anticancer Institute  

Athens, Greece : Hellenic Anticancer Institute

DOI： 10.21873/anticanres.13535

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Future Medicine Ltd  

London, UK : Future Medicine Ltd.

DOI： 10.2217/fvl-2019-0031

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：New York : Springer  

New York : Springer

DOI： 10.1007/s10637-019-00801-8

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：[Australia] : Ivyspring International Publisher  

[Australia] : Ivyspring International Publisher

DOI： 10.7150/ijms.34245.

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Basel, Switzerland : MDPI  

Basel, Switzerland : MDPI

DOI： 10.3390/ijms20061406

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：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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Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Wiley  

Wiley

DOI： 10.1002/jmv.25310

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

DOI： 10.1038/s41598-018-36490-1

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Other Link： http://www.nature.com/articles/s41598-018-36490-1.pdf

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer  

Springer

DOI： 10.1007/s00535-018-1503-x

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：Japan Society of Hepatology  

DOI： 10.2957/kanzo.60.459

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：[Australia] : Ivyspring International Publisher  

[Australia] : Ivyspring International Publisher

DOI： 10.7150/ijms.32795

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

The introduction of a direct-acting antiviral (DAA) for patients with hepatitis C virus (HCV) infection, could lead to higher sustained virologic response (SVR) rates with fewer adverse events, and it could shorten the treatment duration relative to the interferon era. Although most recent clinical studies have demonstrated that the occurrence rates of hepatocellular carcinoma (HCC) are decreased by SVR with both interferon-based and interferon-free-regimens, there are several reports about the unexpected observation of high rates of early tumor occurrence and recurrence in patients with HCV-related HCC undergoing interferon-free therapy despite SVR. Several mechanisms of HCC occurrence and rapid immunological changes, including cytokines and chemokines during and after DAA treatment, have also been reported. We focused on the possibilities that HCC occurs or recurs during and after DAA treatment, based on the reported clinical and basic studies. Further studies and observations will be needed to determine the short-term and long-term effects on hepatocarcinogenesis caused by the eradication of HCV with DAAs. New serum biomarkers and a follow-up system for HCV-patients with SVR should be established.

DOI： 10.4254/wjh.v10.i12.898

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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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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer  

Springer

DOI： 10.1007/s12072-018-9915-5

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Language：English   Publishing type：Research paper (scientific journal)  

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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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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Language：English   Publishing type：Research paper (scientific journal)  

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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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1007/s12072-018-9883-9

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

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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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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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Blackwell Publishing  

DOI： 10.1111/jdi.12745

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Impact Journals LLC  

DOI： 10.18632/oncotarget.25108

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer New York LLC  

DOI： 10.1007/s10637-017-0507-3

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Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.4264/numa.77.2_123

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Other Link： 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

Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer India  

DOI： 10.1007/s12072-018-9862-1

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Impact Journals LLC  

DOI： 10.18632/oncotarget.24391

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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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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Japanese Society of Internal Medicine  

DOI： 10.2169/internalmedicine.9670-17

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Authorship：Lead author,　Corresponding author   Language：Japanese   Publisher：文光堂  

文光堂

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Authorship：Lead author,　Corresponding author   Language：Japanese  

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Authorship：Lead author,　Corresponding author   Language：Japanese   Publisher：科学評論社  

科学評論社

J-GLOBAL

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Impact Journals LLC  

DOI： 10.18632/oncotarget.23768

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Ivyspring International Publisher  

DOI： 10.7150/ijms.23147

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Impact Journals LLC  

DOI： 10.18632/oncotarget.24620

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A 70-year-old woman with hepatitis C cirrhosis underwent balloon-occluded retrograde transvenous obliteration for hepatic encephalopathy due to spleno-renal shunt. Because the shunt was thick, long, and winding, we used a coaxial and double interruption system, which enables the effective occlusion of the drainage route, and shape-memory coils, which are more physically stable than conventional metallic coils because they form three-dimensional loops. The patient was successfully treated with the combined usage of these devices, resulting in a normal serum ammonia level. Thereafter, the patient was treated with direct-acting antivirals, and a sustained virological response was achieved.

DOI： 10.2169/internalmedicine.0247-17

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Impact Journals LLC  

DOI： 10.18632/oncotarget.25488

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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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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：{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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Language：English  

DOI： 10.3748/wjg.v23.i46.8120

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.21926/obm.hg.1704005

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1358/DOF.2017.042.09.2681978

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DOI： 10.3748/wjg.v23.i31.5645

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<jats:p>(1) Background: Infection with hepatitis B virus (HBV) infection during pregnancy occasionally raises concerns, including acute exacerbation and the potential for mother-to-child transmission.(2) Case Report: Here, we present a case of a female patient with a chronic HBV infection who was treated with tenofovir disoproxil fumarate (TDF) and had a normal pregnancy and delivery. Furthermore, the use of TDF, HBV vaccination and passive immunization of her child with hyperimmune hepatitis B immunoglobulin successfully prevented vertical transmission of HBV to her child.(3) Conclusions: Women with chronic active HBV infections who become pregnant may receive additional care and consideration such as the administration of TDF.</jats:p>

DOI： 10.21926/obm.hg.1703004

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：MDPI AG  

DOI： 10.3390/biology6020030

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DOI： 10.3892/etm.2017.4407

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.3892/ol.2017.5973

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DOI： 10.1371/journal.pone.0177302

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.3390/cancers9050043

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.3390/ijms18050906

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.bbrc.2017.03.150

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DOI： 10.1371/journal.pone.0174153

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Tokyo  

DOI： 10.1007/s12328-016-0700-5

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DOI： 10.1093/hmg/ddw406

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Authorship：Lead author,　Corresponding author   Language：English  

DOI： 10.21926/obm.hg.1701002

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<jats:p>(1) Background: Preventative treatment for Pneumocystis jirovecii pneumonia (PCP) has been recommended for patients receiving ≥20 mg/day prednisolone. We describe a patient who developed PCP while receiving a dose of 15 mg/day prednisolone, and consider criteria for the initiation of preventative therapy for PCP in patients with autoimmune hepatitis (AIH) treated with prednisolone.(2) Case Report: A 71-year-old woman initially possessed dark-colored urine, white stool, and decreased appetite, which indicated hepatic dysfunction. Further comprehensive investigation suggested a diagnosis of acute hepatitis with probable autoimmune etiology. Treatment was initiated at 60 mg/day prednisolone. Following a positive response by the patient, the dose was gradually reduced to 15 mg/day. Seventy days after the start of prednisolone treatment, respiratory symptoms appeared, and PCP was diagnosed following examination of bronchoalveolar lavage samples. The patient responded positively to treatment with sulfamethoxazole/trimethoprim combination therapy.(3) Conclusions: Preventative therapy for PCP may be indicated for AIH patients treated with steroids with (1) a dose of prednisolone of 12–15 mg/day or more, (2) a CD4+ lymphocyte count of 200–250/mm3 or less, or (3) a total lymphocyte count of 600/mm3 or less.</jats:p>

DOI： 10.21926/obm.hg.1701001

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Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1007/s00535-016-1229-6

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DOI： 10.1016/j.bbrc.2016.12.080

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Authorship：Lead author,　Last author,　Corresponding author   Language：English  

DOI： 10.1007/s12072-016-9749-y

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Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.3390/ijms18010172

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DOI： 10.7150/ijms.20171

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Authorship：Lead author,　Corresponding author   Language：Japanese  

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BACKGROUND: Wisteria floribunda agglutinin-positive human Mac-2-binding protein (WFA(+)-M2BP) is a novel non-invasive marker of liver fibrosis. The goal of the study was to investigate whether the novel serum biomarker WFA(+)-M2BP or other non-invasive markers are useful for the prediction of liver fibrosis in patients with nonalcoholic steatohepatitis (NASH), autoimmune hepatitis (AIH), and primary biliary cholangitis (PBC). METHODS: We examined a significant correlation between serum WFA(+)-M2BP levels and histological staging of fibrosis in several chronic liver diseases, such as NASH, AIH, and PBC. RESULTS: WFA(+)-M2BP could not predict hepatic fibrosis in these patients. We also showed that the level of platelet counts is a useful predictor of hepatic fibrosis progression in patients with NASH, AIH, and PBC. There was a significant correlation between staging of fibrosis and grading of activity in the liver in all groups except for AIH patients. CONCLUSION: Platelet counts can predict hepatic fibrosis in patients with NASH, AIH, or PBC. Clinicians should pay attention to the grading of liver activity in the use of WFA(+)-M2BP.

DOI： 10.3390/diseases4040038

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DOI： 10.1002/jhbp.399

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：S. Karger AG  

DOI： 10.1159/000452209

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DOI： 10.1007/s12072-016-9717-6

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DOI： 10.1002/jhbp.379

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DOI： 10.1007/s12072-016-9736-3

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.3892/ijmm.2016.2643

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DOI： 10.1186/s12876-016-0480-x

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DOI： 10.3748/wjg.v22.i27.6095

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DOI： 10.1007/s12072-016-9720-y

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Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1007/s00535-016-1229-6

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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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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.7150/ijms.15519

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DOI： 10.1002/jhbp.326

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DOI： 10.1371/journal.pone.0146314

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Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1159/000444392

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1007/s12072-016-9736-3

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Authorship：Corresponding author   Language：English   Publisher：Baishideng Publishing Group Co  

DOI： 10.4254/wjh.v8.i3.183

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.7150/ijms.14953

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：S. Karger AG  

DOI： 10.1159/000445186

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：S. Karger AG  

DOI： 10.1159/000445374

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：S. Karger AG  

DOI： 10.1159/000447423

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1371/journal.pone.0144295

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Authorship：Corresponding author   Language：English  

DOI： 10.3748/wjg.v21.i46.12989

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Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1111/hepr.12488

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.bbrc.2015.09.083

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Language：Japanese   Publisher：(株)ニュー・サイエンス社  

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Language：Japanese   Publisher：(株)アークメディア  

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Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1111/hepr.12483

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1007/s12072-015-9630-4

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Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1111/jvh.12390

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1002/hep.27693

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

Hepatitis A virus (HAV) infection is a major cause of acute hepatitis and occasionally leads to acute liver failure in both developing and developed countries. Although effective vaccines for HAV are available, the development of new antivirals against HAV may be important for the control of HAV infection in developed countries where no universal vaccination program against HAV exists, such as Japan. There are two forms of antiviral agents against HAV: direct-acting antivirals (DAAs) and host-targeting agents (HTAs). Studies using small interfering ribonucleic acid (siRNA) have suggested that the HAV internal ribosomal entry site (IRES) is an attractive target for the control of HAV replication and infection. Among the HTAs, amantadine and interferon-lambda 1 (IL-29) inhibit HAV IRES-mediated translation and HAV replication. Janus kinase (JAK) inhibitors inhibit La protein expression, HAV IRES activity, and HAV replication. Based on this review, both DAAs and HTAs may be needed to control effectively HAV infection, and their use should continue to be explored.

DOI： 10.14218/JCTH.2015.00016

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

Hepatitis B virus (HBV) infection, a cause of hepatocellular carcinoma (HCC), remains a serious global health concern. HCC development and human hepatocarcinogenesis are associated with hepatic inflammation caused by host interferons and cytokines. This article focused on the association between the HBV core protein, which is one of the HBV-encoding proteins, and cytokine production. The HBV core protein induced the production of interferons and cytokines in human hepatoma cells and in a mouse model. These factors may be responsible for persistent HBV infection and hepatocarcinogenesis. Inhibitors of programmed death (PD)-1 and HBV core and therapeutic vaccines including HBV core might be useful for the treatment of patients with chronic HBV infection. Inhibitors of HBV core, which is important for hepatic inflammation, could be helpful in preventing the progression of liver diseases in HBV-infected patients.

DOI： 10.3390/diseases3030213

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DOI： 10.2169/naika.104.1861

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Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.3390/ijms160921177

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.bbrc.2015.07.102

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

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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Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1111/hepr.12426

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DOI： 10.1111/jgh.12925

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1371/journal.pone.0131973

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1007/s12072-015-9624-2

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

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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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：S. Karger AG  

DOI： 10.1159/000437138

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.bbrc.2015.02.058

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Authorship：Lead author,　Corresponding author   Language：English  

DOI： 10.3390/ijms16034985

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Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1186/s12859-015-0495-2

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Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1002/jhbp.178

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Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1007/s10620-014-3271-7

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Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1111/jvh.12258

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：S. Karger AG  

DOI： 10.1159/000441387

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Authorship：Corresponding author   Language：English   Publisher：Baishideng Publishing Group Co  

DOI： 10.4254/wjh.v7.i8.1133

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Authorship：Corresponding author   Language：English   Publisher：Baishideng Publishing Group Co  

DOI： 10.4254/wjh.v7.i8.1125

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Authorship：Corresponding author   Language：English   Publisher：Baishideng Publishing Group Co  

DOI： 10.4254/wjh.v7.i11.1541

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Baishideng Publishing Group Co  

DOI： 10.4254/wjh.v7.i15.1913

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Hindawi Limited  

DOI： 10.1155/2014/723868

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.3892/or.2014.3533

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.3390/ijms151121455

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DOI： 10.1371/journal.pone.0113499

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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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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1371/journal.pone.0101993

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.3748/wjg.v20.i28.9229

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Dove Medical Press Ltd  

DOI： 10.2147/IMCRJ.S63296

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.3748/wjg.v20.i23.7197

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Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.3892/ijo.2014.2317