Publications by authors named "Mina Nakagawa"

74 Publications

A mixed methods study on the readiness of dental, medical, and nursing students for interprofessional learning.

PLoS One 2021 22;16(7):e0255086. Epub 2021 Jul 22.

Institute of Education, Tokyo Medical and Dental University, Tokyo, Japan.

Background: Interprofessional education (IPE) is crucial in dentistry, medicine, and nursing. However, scant mixed methods studies have compared the IPE outcomes across these disciplines to develop evidence-based IPE. This study explored the differences in the readiness of dental, medical, and nursing students for interprofessional learning before and after IPE workshops and elucidated reasons for this disparity.

Methods: Data were obtained from dental, medical, and nursing students who participated in IPE workshops conducted at Tokyo Medical and Dental University in Japan in 2019 and 2020. The participants filled the validated Japanese version of the Readiness for Interprofessional Learning Scale (RIPLS) before and after attending the workshops (n = 378). Paired t-tests were performed to assess differences between the pre- and post- workshop RIPLS scores. Welch's t-tests were deployed to evaluate interdisciplinary differences in their scores. Qualitative analyses were conducted using an explanatory sequential design with focus group discussions (FGDs) held with 17 dental students to explain the quantitative results.

Results: Total RIPLS scores increased significantly for every discipline after the workshops (p < 0.001). Dental students scored significantly lower pre- and post- workshop aggregates than medical and nursing students, respectively (p < 0.001). The FGDs yielded three principal themes in the explanations tendered by dental students on their lower scores: 1) dental students rarely felt the need for interprofessional collaborations, 2) dentists often worked without the need for interprofessional collaborations, and 3) dental students believed their contribution to the workshop was insufficient.

Conclusions: The results revealed divergences in the readiness of dental, medical, and nursing students for interprofessional learning, and the study illuminated possible reasons for these disparities. These outcomes will help develop evidence-based IPE by indicating approaches to place a higher value on interprofessional collaborations in educational environments, ameliorate the awareness of educators, and enhance the workshop facilitation style.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0255086PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8297869PMC
July 2021

Hepatocellular carcinoma recurrence after direct-acting antiviral therapy: an individual patient data meta-analysis.

Gut 2021 Mar 19. Epub 2021 Mar 19.

Liver and Transplant Unit, Policlinico Tor Vergata, Rome, Italy.

Objective: The benefit of direct-acting antivirals (DAAs) against HCV following successful treatment of hepatocellular carcinoma (HCC) remains controversial. This meta-analysis of individual patient data assessed HCC recurrence risk following DAA administration.

Design: We pooled the data of 977 consecutive patients from 21 studies of HCV-related cirrhosis and HCC, who achieved complete radiological response after surgical/locoregional treatments and received DAAs (DAA group). Recurrence or death risk was expressed as HCC recurrence or death per 100 person-years (100PY). Propensity score-matched patients from the ITA.LI.CA. cohort (n=328) served as DAA-unexposed controls (no-DAA group). Risk factors for HCC recurrence were identified using random-effects Poisson.

Results: Recurrence rate and death risk per 100PY in DAA-treated patients were 20 (95% CI 13.9 to 29.8, I=74.6%) and 5.7 (2.5 to 15.3, I=54.3), respectively. Predictive factors for recurrence were alpha-fetoprotein logarithm (relative risk (RR)=1.11, 95% CI 1.03 to 1.19; p=0.01, per 1 log of ng/mL), HCC recurrence history pre-DAA initiation (RR=1.11, 95% CI 1.07 to 1.16; p<0.001), performance status (2 vs 0, RR=4.35, 95% CI 1.54 to 11.11; 2 vs 1, RR=3.7, 95% CI 1.3 to 11.11; p=0.01) and tumour burden pre-HCC treatment (multifocal vs solitary nodule, RR=1.75, 95% CI 1.25 to 2.43; p<0.001). No significant difference was observed in RR between the DAA-exposed and DAA-unexposed groups in propensity score-matched patients (RR=0.64, 95% CI 0.37 to 1.1; p=0.1).

Conclusion: Effects of DAA exposure on HCC recurrence risk remain inconclusive. Active clinical and radiological follow-up of patients with HCC after HCV eradication with DAA is justified.
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http://dx.doi.org/10.1136/gutjnl-2020-323663DOI Listing
March 2021

Mac-2 binding protein glycosylation isomer as a novel predictive biomarker for patient survival after hepatitis C virus eradication by DAAs.

J Gastroenterol 2020 Oct 8;55(10):990-999. Epub 2020 Aug 8.

Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan.

Background: It is crucial to identify risk factors for life prognosis after hepatitis C virus (HCV) eradication among patients with or without a high risk of liver cancer or complications.

Methods: This is a prospective, multicenter and observational study using the database of 1031 patients after HCV eradication by direct-acting antiviral agents (DAAs) to evaluate the development of hepatocellular carcinoma (HCC) and patients' survival after a sustained virological response (SVR). The Cox proportional hazards regression model was used to estimate hazard ratios associated with HCC development and survival.

Results: AFP at SVR was significantly associated with HCC recurrence in the adjusted model. Liver fibrosis, Mac-2 binding protein glycosylation isomer (M2BPGi) at SVR and smoking status before treatment were positively associated with the development of HCC and M2BPGi was positively associated with HCC recurrence, although not reaching statistical significance. Among patients without a history of HCC, M2BPGi and estimated glomerular filtration rate (eGFR) at SVR were significantly associated with death after viral eradication [M2BPGi (HR 4.07, 95% CI 1.22, 13.57), eGFR (HR 0.97, 95% CI 0.94, 0.99)]. Strikingly, of 16 patients who died, among participants without a history of HCC, only two died of liver cancer associated with HCV, whereas 11 died of non-HCV- related cancer or cardiovascular diseases.

Conclusion: M2BPGi at SVR is a potential predictor for patients' survival and a candidate biomarker for detecting individuals who are at greater risk of death due to cancer-related and unrelated to HCV, as well as cardiovascular diseases, after viral eradication.
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http://dx.doi.org/10.1007/s00535-020-01715-6DOI Listing
October 2020

Associations between demographic factors and the academic trajectories of medical students in Japan.

PLoS One 2020 18;15(5):e0233371. Epub 2020 May 18.

Curricular Institutional Research Division, Institute of Education, Tokyo Medical and Dental University, Tokyo, Japan.

Background: Group-based trajectory modeling is a useful tool for categorizing students' academic trajectories and their determinants. Using insights gained from the analyses, we can identify students at risk for poor academic performance and monitor them to provide support. To date, studies investigating the associations between demographic factors and academic performance trajectories among medical students are scarce. The study objective was to examine the associations between demographic factors and academic performance trajectories in medical students using group-based trajectory modeling.

Methods: Participants included all medical students admitted to Tokyo Medical and Dental University in Japan in 2013 and 2014 (n = 202). Academic performance was evaluated by biannual grade point average (GPA) scores in preclinical years. We used group-based trajectory modeling to categorize students into GPA trajectories. Multinomial logistic regression was used to examine the association between the odds of being in a certain GPA trajectory group and demographic factors such as high school type, high school geographical area, admission test type, high school graduation year, whether the student was a biology major, and sex.

Results: Students' GPA trajectories were classified into four trajectory groups as well as another group that consisted of students who withdrew or repeated years. We found that students whose high school geographical area was outside the National Capital Region were 7.2 times more likely to withdraw or repeat years in comparison with students whose school was inside the National Capital Region (OR: 7.21, 95% CI: 1.87, 27.76). In addition, admission test type, high school graduation year, and sex were associated with GPA trajectories.

Conclusions: High school geographical area, admission test type, high school graduation year, and sex were associated with GPA trajectories. These findings provide important insights into identifying students at risk for poor academic performance and strategies for monitoring them to provide adequate and timely support.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0233371PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7233530PMC
August 2020

Differential effects of individual and school factors on the academic trajectories of Japanese dental students.

J Dent Educ 2020 Jul 26;84(7):792-798. Epub 2020 Mar 26.

Curricular Institutional Research Division, Institute of Education, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan.

Objective: Dental students follow different academic performance trajectories in response to increasing study load, based on individual and school factors. Group-based trajectory modeling is useful for clarifying the underlying trajectory patterns of students' academic performance and its determinants. To our knowledge, no studies have used group-based trajectory modeling to examine the effects of individual and school factors on academic performance trajectories in dental students. The objective of this study was to examine the effects of individual and school factors on academic performance trajectories in Japanese dental students using group-based trajectory modeling.

Methods: The analytical sample consists of 103 dental students admitted to Tokyo Medical and Dental University, Tokyo, Japan, in 2013 and 2014. Students' academic performance was assessed by biannual grade point average (GPA) score and GPA in the preclinical phase (second to fourth grade) was used for this study. We used group-based trajectory modeling to categorize students' GPA trajectories into different groups. A multinomial logistic regression model was fit to examine associations between students' individual and school factors, and odds of being assigned to certain GPA groups.

Results: GPA trajectories of dental students were classified into 4 different groups. Students' past academic performance in high school was associated with lower GPA trajectories and withdrawal or repeating years. Males were significantly associated with lower GPA trajectories and withdrawal or repeating years, even after adjusting for past academic performance.

Conclusions: Past lower academic performance and being male were positively associated with lower academic performance trajectories in Japanese dental students.
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http://dx.doi.org/10.1002/jdd.12150DOI Listing
July 2020

Vasoactive Intestinal Peptide Derived From Liver Mesenchymal Cells Mediates Tight Junction Assembly in Mouse Intrahepatic Bile Ducts.

Hepatol Commun 2020 Feb 24;4(2):235-254. Epub 2019 Dec 24.

Department of Gastroenterology and Hepatology Tokyo Medical and Dental University Tokyo Japan.

Formation of intrahepatic bile ducts (IHBDs) proceeds in accordance with their microenvironment. Particularly, mesenchymal cells around portal veins regulate the differentiation and ductular morphogenesis of cholangiocytes in the developing liver; however, further studies are needed to fully understand the arrangement of IHBDs into a continuous hierarchical network. This study aims to clarify the interaction between biliary and liver mesenchymal cells during IHBD formation. To identify candidate factors contributing to this cell-cell interaction, mesenchymal cells were isolated from embryonic day 16.5 matrix metalloproteinase 14 (MMP14)-deficient (knockout [KO]) mice livers, in which IHBD formation is retarded, and compared with those of the wild type (WT). WT mesenchymal cells significantly facilitated the formation of luminal structures comprised of hepatoblast-derived cholangiocytes (cholangiocytic cysts), whereas MMP14-KO mesenchymal cells failed to promote cyst formation. Comprehensive analysis revealed that expression of vasoactive intestinal peptide (VIP) was significantly suppressed in MMP14-KO mesenchymal cells. VIP and VIP receptor 1 (VIPR1) were mainly expressed in periportal mesenchymal cells and cholangiocytic progenitors during IHBD development, respectively, . VIP/VIPR1 signaling significantly encouraged cholangiocytic cyst formation and up-regulated tight junction protein 1, cystic fibrosis transmembrane conductance regulator, and aquaporin 1, . VIP antagonist significantly suppressed the tight junction assembly and the up-regulation of ion/water transporters during IHBD development . In a cholestatic injury model of adult mice, exogenous VIP administration promoted the restoration of damaged tight junctions in bile ducts and improved hyperbilirubinemia. VIP is produced by periportal mesenchymal cells during the perinatal stage. It supports bile duct development by establishing tight junctions and up-regulating ion/water transporters in cholangiocytes. VIP contributes to prompt recovery from cholestatic damage through the establishment of tight junctions in the bile ducts.
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http://dx.doi.org/10.1002/hep4.1459DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6996346PMC
February 2020

Time course alterations of virus sequences and immunoglobulin titers in a chronic hepatitis E patient.

Hepatol Res 2020 Apr 5;50(4):524-531. Epub 2020 Feb 5.

Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan.

Aim: Hepatitis E virus (HEV) can cause chronic infection in immunocompromised hosts. However, the dynamics of HEV during persistent infection is not well understood. To elucidate time course alterations in virus sequences and anti-HEV antibodies during persistent infection, we analyzed the HEV sequences and titers of anti-HEV antibodies from a chronic hepatitis E patient.

Methods: Serum samples were obtained from a chronic hepatitis E patient under corticosteroid therapy for neurological disease. The titers of anti-HEV antibodies (immunoglobulin A, immunoglobulin M, and immunoglobulin G) in serum samples were detected by enzyme immunoassay. The full or near-full nucleotide sequences of HEV isolated from consecutive serum samples were identified and compared. Phylogenetic analysis was also performed.

Results: Alterations of anti-HEV antibodies from a chronic hepatitis E patient were different from those previously reported in acute hepatitis E patients. The virus sequence was unchanged in the period without treatment, but nucleotide mutations were observed after ribavirin treatment was started. In addition, the sequence of this strain had extremely high identity to that isolated from swine liver in Japan.

Conclusions: Virus mutations in HEV emerged after ribavirin treatment was started. Sequence analysis may useful for deciding the treatment strategy for chronic hepatitis E patients who did not eliminate the virus with 3 months of RBV treatment and inferring the origin of the infection. This report provides insights into the chronicity of hepatitis E, and the impact of persistent infection and ribavirin treatment on the emergence of virus mutations.
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http://dx.doi.org/10.1111/hepr.13480DOI Listing
April 2020

Comprehensive genetic analysis of cholangiolocellular carcinoma with a coexistent hepatocellular carcinoma-like area and metachronous hepatocellular carcinoma.

Hepatol Res 2019 Dec 9;49(12):1466-1474. Epub 2019 Aug 9.

Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University (TMDU), Tokyo, Japan.

Aim: The genetic profile of cholangiolocellular carcinoma (CLC) and its origin in relation to hepatocellular carcinoma (HCC) remain unclear. To elucidate the genetic profile of CLC, a comprehensive analysis of genetic mutations was carried out in a case of CLC with an HCC-like focal area and metachronous HCC.

Method: Liver tissue was obtained from CLC, a co-existent HCC-like area, and metachronously developed HCC by laser capture microdissection of formalin-fixed paraffin-embedded specimens obtained by hepatectomy. Gene mutational profiles were analyzed comprehensively by next-generation sequencing and digital PCR. Relationships among gene profiles, immunohistochemistry, and clinicopathological findings were investigated.

Results: Mutations in EGFR, PTEN, RB1, TP53, and ERBB2 were found in CLC, whereas mutations in KIT, BRAF, PTEN, TP53, and SMAD4 were found in the coexistent HCC-like area. Only the mutation in PTEN has a common Catalogue of Somatic Mutations in Cancer ID in the CLC and coexistent HCC-like area, and is related to the kinase-RAS module. In contrast, no cancer-related mutations were found in the metachronous HCC. No TERT mutations were found in any of the regions by digital PCR. Immunohistochemical staining for p53 was negative in CLC, although ≤10% positive in the coexistent HCC-like area. Immunostaining of C-kit, HER2, PTEN, and SMAD4 were negative.

Conclusion: The genomic features of CLC and the focal area of an HCC-like region differ, but are related to the kinase-RAS module. The development of carcinogenesis in the CLC and HCC-like areas in this case might differ, following a common PTEN mutation, although alteration of the kinase-RAS module is the most common molecular event in CLC.
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http://dx.doi.org/10.1111/hepr.13403DOI Listing
December 2019

Impact of novel NS5A resistance-associated substitutions of hepatitis C virus detected in treatment-experienced patients.

Sci Rep 2019 04 5;9(1):5722. Epub 2019 Apr 5.

Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University (TMDU), Tokyo, Japan.

Resistance-associated substitutions (RASs) of hepatitis C virus (HCV) in the NS5A region impair the efficacy of NS5A inhibitors. In this study, we evaluated the characteristics of the novel RASs observed in treatment-failure patients, A92K and a deletion at P32 (P32del), and the susceptibility of viruses with these RASs to various anti-HCV reagents by using JFH-1 based recombinant HCV with NS5A from a genotype 1b Con1 strain (JFH1/5ACon1). We introduced A92K or P32del solely or in combination with Q24K, L28M, R30Q or L31F into the NS5A of JFH1/5ACon1. Viruses harboring R30Q/A92K showed high extracellular core antigens and infectivity titers, whereas the other viruses with RASs showed low replication levels and infectivity titers. All the viruses with A92K or P32del were markedly resistant to ledipasvir, velpatasvir and elbasvir. Interestingly, viruses with R30Q/A92K were more susceptible to grazoprevir than viruses without RAS. All the viruses had a similar susceptibility to ribavirin and sofosbuvir. In conclusion, combination RASs R30Q/A92K enhanced virus production whereas other RASs impaired virus replication. Both A92K and P32del conferred severe resistance even to second generation NS5A inhibitors. However, these viruses were susceptible to grazoprevir, ribavirin and sofosbuvir. Thus, combination regimens with these reagents may eradicate viruses harboring A92K or P32del.
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http://dx.doi.org/10.1038/s41598-019-42114-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6450881PMC
April 2019

Loss of fibrocystin promotes interleukin-8-dependent proliferation and CTGF production of biliary epithelium.

J Hepatol 2019 07 19;71(1):143-152. Epub 2019 Mar 19.

Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University (TMDU), Tokyo, Japan. Electronic address:

Background & Aims: Congenital hepatic fibrosis (CHF) is a genetic liver disease resulting in abnormal proliferation of cholangiocytes and progressive hepatic fibrosis. CHF is caused by mutations in the PKHD1 gene and the subsequent dysfunction of the protein it encodes, fibrocystin. However, the underlying molecular mechanism of CHF, which is quite different from liver cirrhosis, remains unclear. This study investigated the molecular mechanism of CHF pathophysiology using a genetically engineered human induced pluripotent stem (iPS) cell model to aid the discovery of novel therapeutic agents for CHF.

Methods: PKHD1-knockout (PKHD1-KO) and heterozygously mutated PKHD1 iPS clones were established by RNA-guided genome editing using the CRISPR/Cas9 system. The iPS clones were differentiated into cholangiocyte-like cells in cysts (cholangiocytic cysts [CCs]) in a 3D-culture system.

Results: The CCs were composed of a monolayer of cholangiocyte-like cells. The proliferation of PKHD1-KO CCs was significantly increased by interleukin-8 (IL-8) secreted in an autocrine manner. IL-8 production was significantly elevated in PKHD1-KO CCs due to mitogen-activated protein kinase pathway activation caused by fibrocystin deficiency. The production of connective tissue growth factor (CTGF) was also increased in PKHD1-KO CCs in an IL-8-dependent manner. Furthermore, validation analysis demonstrated that both the serum IL-8 level and the expression of IL-8 and CTGF in the liver samples were significantly increased in patients with CHF, consistent with our in vitro human iPS-disease model of CHF.

Conclusions: Loss of fibrocystin function promotes IL-8-dependent proliferation of, and CTGF production by, human cholangiocytes, suggesting that IL-8 and CTGF are essential for the pathogenesis of CHF. IL-8 and CTGF are candidate molecular targets for the treatment of CHF.

Lay Summary: Congenital hepatic fibrosis (CHF) is a genetic liver disease caused by mutations of the PKHD1 gene. Dysfunction of the protein it encodes, fibrocystin, is closely associated with CHF pathogenesis. Using an in vitro human induced pluripotent stem cell model and patient samples, we showed that the loss of fibrocystin function promotes proliferation of cholangiocytes and the production of connective tissue growth factor (CTGF) in an interleukin 8 (IL-8)-dependent manner. These results suggest that IL-8 and CTGF are essential for the pathogenesis of CHF.
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http://dx.doi.org/10.1016/j.jhep.2019.02.024DOI Listing
July 2019

LIM homeobox 2 promotes interaction between human iPS-derived hepatic progenitors and iPS-derived hepatic stellate-like cells.

Sci Rep 2019 02 14;9(1):2072. Epub 2019 Feb 14.

Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University (TMDU), Tokyo, Japan.

Human induced pluripotent stem (iPS) cells can differentiate into hepatocyte lineages, although the phenotype of the differentiated cells is immature compared to adult hepatocytes. Improvement of cell-cell interactions between epithelium and mesenchyme is a potential approach to address this phenotype issue. In this study, we developed a model system for improving interactions between human iPS-derived hepatic progenitor cells (iPS-HPCs) and human iPS-derived hepatic stellate cell-like cells (iPS-HSCs). The phenotype of iPS-HSCs, including gene and protein expression profiles and vitamin A storage, resembled that of hepatic stellate cells. Direct co-culture of iPS-HSCs with iPS-HPCs significantly improved hepatocytic maturation in iPS-HPCs, such as their capacity for albumin production. Next, we generated iPS cell lines overexpressing LIM homeobox 2 (LHX2), which suppresses myofibroblastic changes in HSCs in mice. Hepatocytic maturation in iPS-HPCs was significantly increased in direct co-culture with iPS-HSCs overexpressing LHX2, but not in co-culture with a human hepatic stellate cell line (LX-2) overexpressing LHX2. LHX2 regulated the expression of extracellular matrices, such as laminin and collagen, in iPS-HSCs. In conclusion, this study provides an evidence that LHX2 upregulation in iPS-HSCs promotes hepatocytic maturation of iPS-HPCs, and indicates that genetically modified iPS-HSCs will be of value for research into cell-cell interactions.
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http://dx.doi.org/10.1038/s41598-018-37430-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6376133PMC
February 2019

Diabetic Retinopathy as a Risk Factor Associated with the Development of Hepatocellular Carcinoma in Nonalcoholic Fatty Liver Disease.

Dig Dis 2019 9;37(3):247-254. Epub 2019 Jan 9.

Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan.

Background: The risk factors associated with the development of hepatocellular carcinoma (HCC) in nonalcoholic fatty liver disease (NAFLD) are still unclear. The aim of the present study was to identify such risk factors in NAFLD patients who developed HCC.

Methods: Between April 2000 and -December 2016, a total of 182 patients with NAFLD were enrolled in this study; of these, only 22 patients had HCC. To identify risk factors, univariate and multivariate analyses were performed. To identify risk factors other than the degree of fibrosis, propensity matched analysis adjusted by the NAFLD fibrosis score (NFS) was carried out on 44 patients. Multivariate and survival analyses were also performed in HCC patients.

Results: In 182 patients, multivariate analysis highlighted the NFS (OR 2.275; p < 0.001) and hypertension (OR 5.868; p = 0.037) as independent factors that were significantly associated with the development of HCC. After adjustment for the NFS, multivariate analysis identified diabetic retinopathy (OR 8.654; p = 0.017) as an independent factor that was significantly associated with the development of HCC. For predicting the development of HCC, the area under the receiver operating characteristic curve of diabetic retinopathy was significantly higher than that of diabetes (0.731 vs. 0.615; p < 0.001). In patients with HCC, multivariate analysis indicated that the NFS were significantly associated with diabetic retinopathy.

Conclusions: Diabetic retinopathy as well as liver fibrosis is a risk factor that associates with the development of HCC in NAFLD patients. Therefore, NAFLD patients with diabetic retinopathy should undergo careful screening for HCC.
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http://dx.doi.org/10.1159/000493580DOI Listing
March 2019

Association of serum interferon-λ3 levels with hepatocarcinogenesis in chronic hepatitis C patients treated with direct-acting antiviral agents.

Hepatol Res 2019 May 7;49(5):500-511. Epub 2019 Feb 7.

Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan.

Aim: Although the efficacy of hepatitis C virus (HCV) treatment is improved dramatically by direct-acting antiviral agents (DAAs), the assessment of hepatocellular carcinoma (HCC) remains important. Interferon lambda 3 (IFN-λ3) is associated with liver fibrosis and inflammation in chronic hepatitis C (CHC) patients, but its impact on carcinogenesis remains controversial and little is known about its effects after viral clearance. To determine the contribution of IFN-λ3 to hepatocarcinogenesis after HCV clearance, we analyzed IFNL3 genotypes and serial serum IFN-λ3 levels in CHC patients who achieved sustained virologic responses (SVR).

Methods: This study comprised 201 CHC patients treated with DAAs. Serum samples were collected sequentially and IFN-λ3 levels were quantified by chemiluminescence enzyme immunoassay. The IFNL3 polymorphism (rs8099917) was genotyped in 195 patients.

Results: One hundred and twenty-five patients were rs8099917 T/T and 70 were non-T/T. Serum IFN-λ3 levels did not differ significantly with IFNL3 genotype, dropped markedly by 1 week and remained low up to 24 weeks after the end of treatment. Interferon-λ3 levels were significantly higher after viral clearance in patients who developed HCC and were associated with a higher potential for hepatocarcinogenesis, such as a higher frequency of non-hypervascular hypointensive nodules (P = 0.046), higher stages of liver fibrosis (P < 0.001), and higher post-treatment levels of Wisteria floribunda agglutinin positive Mac-2 binding protein (P < 0.001) and alanine aminotransferase (P < 0.001).

Conclusions: Serum IFN-λ3 levels after HCV clearance are associated with the potential for HCC development. Interferon-λ3 could be helpful for elucidating the relationships among immunologic status, liver fibrosis, liver inflammation, and hepatocarcinogenesis, after achieving SVR.
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http://dx.doi.org/10.1111/hepr.13307DOI Listing
May 2019

Establishment of a quantitative and qualitative analysis and isolation method for tetracyclic iridoids from Morinda lucida Bentham leaves.

J Pharm Biomed Anal 2019 Feb 29;164:475-480. Epub 2018 Oct 29.

Department of Pharmacognosy, Faculty of Pharmaceutical Sciences, Nagasaki International University, Nagasaki 859-3298, Japan. Electronic address:

A new high performance liquid chromatography (HPLC) method has been established for quantitative and qualitative analysis of three tetracyclic iridoids: ML-2-3 (1), molucidin (2), and ML-F52 (3), which are responsible for anti-trypanosomal and anti-leishmanial activities of Morinda lucida Bentham leaves. Separation of 1-3 from dried 80% aqueous (aq.) ethanol extract was achieved on a reversed-phase cholester column packed with cholesteryl-bonded silica using an acetonitrile-0.1% aq. formic acid mobile phase system. Ultraviolet-visible (UV-VIS) spectroscopy was employed for detection of compounds, and their contents were determined by measuring absorbance at 254 nm. Depending on the above system, several factors potentially affecting the concentration of tetracyclic iridoids were evaluated resulting in several variation on plant organs, seasonality, variation between individual trees, and branch positions within the trees. Moreover, we developed a simple, quick, and effective method for tetracyclic iridoid isolation from M. lucida leaves that consisted of extraction by sonication into 80% aq. ethanol, basic hydrolysis, acid neutralization, liquid-liquid extraction into an organic solvent, and reverse phase open column chromatography. Employing this method, we have succeeded to obtain 1 as a colorless crystal yielding of 0.23%, which was 28 times higher than that of previous isolation method. Setting up methodology in this paper may be important for future in vitro and in vivo studies of tetracyclic iridoids and moreover for their applications in new drug design and development.
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http://dx.doi.org/10.1016/j.jpba.2018.10.044DOI Listing
February 2019

Association between alanine aminotransferase elevation and UGT1A1*6 polymorphisms in daclatasvir and asunaprevir combination therapy for chronic hepatitis C.

J Gastroenterol 2018 Jun 1;53(6):780-786. Epub 2017 Nov 1.

First Department of Internal Medicine, Faculty of Medicine, University of Yamanashi, 1110, Shimokato, Chuo, Yamanashi, 409-3898, Japan.

Background: Liver damage presented as alanine aminotransferase (ALT) elevation and high ALT-caused treatment discontinuation occurs with high frequency in Japanese patients receiving daclatasvir plus asunaprevir (DCV/ASV) therapy for hepatitis C virus (HCV) infection, and its mechanism is unknown.

Methods: A total of 247 Japanese patients consisting of two independent cohorts with genotype-1b HCV infection receiving DCV/ASV therapy were included. The association of ALT levels during therapy and single nucleotide polymorphisms (SNP) of five drug-metabolizing enzyme loci selected for their possible influence on NS3/4A and NS5A inhibitors was investigated.

Results: Among five SNPs, we found a significant correlation between the presence of the UGT1A1 rs4148323 A allele and ALT elevation (Grade 3 elevation in AA 57%, AG 18%, and GG 4%, P = 8.4E - 06) and drug discontinuation (AA 22%, AG 11%, and GG 2.5%, P = 8.7E - 04), while no association was observed with ALT values at baseline (Grade 3 elevation AA 0%, AG 4%, and GG 2%, P = 0.5). In contrast, patients with risk A allele for drug-induced ALT elevation had a tendency to respond more favorably to treatment (AA 100%, AG 93%, and GG 90%, P = 0.29).

Conclusions: Through the analysis we suggest that the A allele in UGT1A1 rs4148323 (UGT1A1*6), which is highly prevalent in the Japanese population, should be considered a risk for the development of DCV/ASV therapy-induced ALT elevation. Pretreatment SNP testing of UGT1A1*6 might be beneficial for the prediction of liver damage induced by DCV/ASV or even by DCV/ASV plus beclabuvir.
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http://dx.doi.org/10.1007/s00535-017-1405-3DOI Listing
June 2018

Reply to: "Imaging Basis of AFP and WFAM2BP as Indicators of the risk of HCC after SVR".

J Hepatol 2018 03 24;68(3):607-608. Epub 2017 Oct 24.

Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan; Department of Liver Disease Control, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan. Electronic address:

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http://dx.doi.org/10.1016/j.jhep.2017.10.012DOI Listing
March 2018

Effect of interferon-based and -free therapy on early occurrence and recurrence of hepatocellular carcinoma in chronic hepatitis C.

J Hepatol 2017 11 14;67(5):933-939. Epub 2017 Jun 14.

Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Japan.

Background And Aims: Although treatment for hepatitis C virus has been dramatically improved by the development of direct-acting antiviral agents (DAAs), whether interferon (IFN)-free therapy reduces hepatocarcinogenesis in an equivalent manner to IFN-based therapy remains controversial. The aims of this study were to evaluate the occurrence and recurrence of hepatocellular carcinoma (HCC) in chronic hepatitis C (CHC) patients treated with DAAs and to identify biomarkers of HCC development after antiviral treatment.

Methods: A restrospective review of a prospective database of 1,897 CHC patients who were treated with IFN-based (1,145) or IFN-free therapies (752) was carried out. Cumulative HCC occurrence and recurrence rates were compared using propensity score-matched analysis. Predictors of HCC development after viral eradication were identified by multivariate analysis.

Results: Propensity score-matched analysis showed no significant difference in HCC occurrence (p=0.49) and recurrence rates (p=0.54) between groups treated with IFN-based or IFN-free therapies. In multivariate analysis, higher levels of post-treatment α-fetoprotein (AFP) or Wisteria floribunda agglutinin positive Mac-2 binding protein (WFAM2BP) were independently associated with HCC occurrence and recurrence after viral eradication. Only post-treatment WFAM2BP level was significantly associated with HCC occurrence and recurrence among patients without severe fibrosis. The area under the receiver operating characteristic (ROC) curve for WFAM2BP levels was greater than that for AFP levels in ROC analysis.

Conclusion: The risks of early HCC occurrence and recurrence after viral eradication were similar between IFN-based and IFN-free therapies. Post-treatment levels of WFAM2BP may be helpful screening biomarkers for assessing the risk of HCC after IFN-free therapy. Patients with high WFAM2BP levels after antiviral treatment, even without severe fibrosis, must be followed up carefully for HCC development. Lay summary: The risks of early HCC occurrence and recurrence after viral eradication were similar between IFN-based and IFN-free therapies. Post-treatment levels of WFAM2BP may be helpful screening biomarkers for assessing the risk of HCC after IFN-free therapy.
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http://dx.doi.org/10.1016/j.jhep.2017.05.028DOI Listing
November 2017

Genome-Wide Association Study Identifies TLL1 Variant Associated With Development of Hepatocellular Carcinoma After Eradication of Hepatitis C Virus Infection.

Gastroenterology 2017 05 3;152(6):1383-1394. Epub 2017 Feb 3.

Department of Hepatology and Pancreatology, Kawasaki Medical School, Kurashiki, Japan.

Background & Aims: There is still a risk for hepatocellular carcinoma (HCC) development after eradication of hepatitis C virus (HCV) infection with antiviral agents. We investigated genetic factors associated with the development of HCC in patients with a sustained virologic response (SVR) to treatment for chronic HCV infection.

Methods: We obtained genomic DNA from 457 patients in Japan with a SVR to interferon-based treatment for chronic HCV infection from 2007 through 2015. We conducted a genome-wide association study (GWAS), followed by a replication analysis of 79 candidate single nucleotide polymorphisms (SNPs) in an independent set of 486 patients in Japan. The study end point was HCC diagnosis or confirmation of lack of HCC (at follow-up examinations until December 2014 in the GWAS cohort, and until January 2016 in the replication cohort). We collected clinical and laboratory data from all patients. We analyzed expression levels of candidate gene variants in human hepatic stellate cells, rats with steatohepatitis caused by a choline-deficient L-amino acid-defined diet, and a mouse model of liver injury caused by administration of carbon tetrachloride. We also analyzed expression levels in liver tissues of patients with chronic HCV infection with different stages of fibrosis or tumors vs patients without HCV infection (controls).

Results: We found a strong association between the SNP rs17047200, located within the intron of the tolloid like 1 gene (TLL1) on chromosome 4, and development of HCC; there was a genome-wide level of significance when the results of the GWAS and replication study were combined (odds ratio, 2.37; P = 2.66 × 10). Multivariate analysis showed rs17047200 AT/TT to be an independent risk factor for HCC (hazard ratio, 1.78; P = .008), along with male sex, older age, lower level of albumin, advanced stage of hepatic fibrosis, presence of diabetes, and higher post-treatment level of α-fetoprotein. Combining the rs17047200 genotype with other factors, we developed prediction models for HCC development in patients with mild or advanced hepatic fibrosis. Levels of TLL1 messenger RNA (mRNA) in human hepatic stellate cells increased with activation. Levels of Tll1 mRNA increased in liver tissues of rodents with hepatic fibrogenesis compared with controls. Levels of TLL1 mRNA increased in liver tissues of patients with progression of fibrosis. Gene expression levels of TLL1 short variants, including isoform 2, were higher in patients with rs17047200 AT/TT.

Conclusions: In a GWAS, we identified the association between the SNP rs17047200, within the intron of TLL1, and development of HCC in patients who achieved an SVR to treatment for chronic HCV infection. We found levels of Tll1/TLL1 mRNA to be increased in rodent models of liver injury and liver tissues of patients with fibrosis, compared with controls. We propose that this SNP might affect splicing of TLL1 mRNA, yielding short variants with high catalytic activity that accelerates hepatic fibrogenesis and carcinogenesis. Further studies are needed to determine how rs17047200 affects TLL1 mRNA levels, splicing, and translation, as well as the prevalence of this variant among other patients with HCC. Tests for the TLL1 SNP might be used to identify patients at risk for HCC after an SVR to treatment of HCV infection.
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http://dx.doi.org/10.1053/j.gastro.2017.01.041DOI Listing
May 2017

ITPA gene variation and ribavirin-induced anemia in patients with genotype 2 chronic hepatitis C treated with sofosbuvir plus ribavirin.

Hepatol Res 2017 Oct 7;47(11):1212-1218. Epub 2017 Mar 7.

Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan.

Aim: Sofosbuvir (SOF) and ribavirin (RBV) combination therapy produces a sustained response in many patients with genotype 2 chronic hepatitis C. However, RBV-induced anemia is a troublesome side-effect that may limit this treatment. Genetic variation leading to inosine triphosphatase (ITPA) deficiency is known to protect against RBV-induced hemolytic anemia. This study aimed to evaluate the relationships between the efficacy and safety of SOF/RBV treatment and ITPA gene variants.

Methods: Ninety patients with genotype 2 chronic hepatitis C treated with SOF/RBV were studied. The relationships among genetic polymorphisms of ITPA and the decline in hemoglobin levels from baseline, RBV dose reduction, and sustained virological response (SVR) rates were analyzed.

Results: Overall SVR at 12 weeks was 94.4% (85/90). Patients with the ITPA CA/AA genotypes had a lower degree of anemia throughout the therapy than those with the ITPA CC genotype. The percentage of patients requiring RBV dose reduction was significantly lower for those with the ITPA CA/AA variation, a difference even more apparent when the pretreatment hemoglobin level was <12 g/dL. The dose reduction of RBV and serum albumin level were significantly associated with SVR.

Conclusions: Patients with the ITPA CA/AA genotype were less likely to develop anemia than those with the ITPA CC genotype and were more likely to complete SOF/RBV therapy. These results may provide a valuable pharmacogenetic diagnostic tool to predict drug-induced adverse events, particularly in patients with pre-existing anemia.
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http://dx.doi.org/10.1111/hepr.12867DOI Listing
October 2017

Hepatic IFNL4 expression is associated with non-response to interferon-based therapy through the regulation of basal interferon-stimulated gene expression in chronic hepatitis C patients.

J Med Virol 2017 07 27;89(7):1241-1247. Epub 2017 Feb 27.

Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan.

Single nucleotide polymorphisms (SNPs) within or near interferon lambda 4 (IFNL4) gene located upstream of IFNL3 are associated with response to anti-HCV therapy both in interferon (IFN)-based and IFN-free regimens. IFNL4 encodes IFNλ4, a newly discovered type III IFN, and its expression is controlled by rs368234815-TT/ΔG, which is in strong linkage disequilibrium (LD) with other tag SNPs within or near IFNL4 such as rs12979860 and rs8099917. Intrahepatic expression levels of IFN-stimulated genes (ISGs) affect the responsiveness to IFNα and are also associated with IFNL4 genotype. However, IFNL4 expressions and its role in intrinsic antiviral innate immunity remain unclear. This study evaluated the effect of IFNL4 on intrahepatic ISG expression and investigated its relationship with treatment outcomes in liver samples obtained from 49 chronic hepatitis C patients treated with pegylated (PEG)-IFN/ribavirin therapy. IFNL4 mRNA was detected in 11 of 22 patients with IFNL4-unfavorable SNPs but not in patients with favorable genotypes. IFNL4 expression was associated with non-response to PEG-IFN/ribavirin therapy. Intrahepatic expression of antiviral ISGs (ISG15 and MX1) was significantly higher in IFNL4-unfavorable patients with detectable IFNL4 mRNA than in patients with undetectable IFNL4 mRNA, whereas the expression of suppressive ISGs (RNF125, SOCS1, SOCS3, and RNF11) was lower in patients with detectable IFNL4 mRNA. In summary, intrahepatic expression of IFNL4 was associated with increased antiviral ISG expression and decreased suppressive ISG expression at baseline, resulting in poor responsiveness to IFNα-based therapy in HCV infection.
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http://dx.doi.org/10.1002/jmv.24763DOI Listing
July 2017

Bone morphogenetic protein-4 modulates proliferation and terminal differentiation of fetal hepatic stem/progenitor cells.

Hepatol Res 2017 Aug 31;47(9):941-952. Epub 2016 Oct 31.

Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan.

Fetal hepatic stem/progenitor cells, called hepatoblasts, play central roles in liver organogenesis; however, molecular mechanisms regulating proliferation and terminal differentiation of such cells have not been completely elucidated. Bone morphogenetic protein-4 (BMP-4) is essential for the development of stem cells in various tissues, but its function in regulating the phenotype of hepatoblasts after the mid-gestational fetal stage remains unclear. The aim of this study is to clarify a functional role for BMP-4 in proliferation and terminal differentiation of murine hepatoblasts in mid-gestational fetal livers.

Methods: A functional role for BMP-4 in proliferation and terminal differentiation of murine hepatoblasts was validated by assay of colony formation, biliary luminal formation, and hepatic maturation using primary hepatoblasts in vitro. Molecular mechanisms regulating such effects of BMP-4 on primary hepatoblasts were also analyzed.

Results: Stimulation of BMP-4 upregulated phosphorylation of Smad1/5 in hepatoblasts. Bone morphogenetic protein-4 significantly suppressed colony formation of primary hepatoblasts in a dose-dependent manner, significantly suppressed cholangiocytic luminal formation of hepatoblasts, and promoted hepatic maturation of primary hepatoblasts. Stimulation of BMP-4 regulated the activation of several mitogen-activated protein kinases, such as extracellular signal-regulated kinase, Akt, p38 mitogen-activated protein kinase, and calcium/calmodulin-dependent protein kinase IIα in primary hepatoblasts. Moreover, Wnt5a, a molecule regulating cholangiocytic luminal formation, and BMP-4 coordinately suppressed proliferation and cholangiocytic luminal formation of hepatoblasts.

Conclusion: This study shows that BMP-4-mediated signaling controls proliferation and terminal differentiation of fetal hepatic stem/progenitor cells.
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http://dx.doi.org/10.1111/hepr.12823DOI Listing
August 2017

Serial measurement of Wisteria floribunda agglutinin positive Mac-2-binding protein is useful for predicting liver fibrosis and the development of hepatocellular carcinoma in chronic hepatitis C patients treated with IFN-based and IFN-free therapy.

Hepatol Int 2016 Nov 19;10(6):956-964. Epub 2016 Jul 19.

Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan.

Aim: Wisteria floribunda agglutinin positive (WFA) Mac-2-binding protein (M2BPGi) is a noninvasive glyco-marker for liver fibrosis. This study evaluated the utility of serial measurement of serum M2BPGi and total M2BP as a predictor of fibrosis and the development of hepatocellular carcinoma (HCC).

Methods: This study included 119 patients with chronic hepatitis C (CHC). Of these patients, 97 were treated with IFN-based therapy and 22 were treated with daclatasvir and asunaprevir. Serum M2BPGi values were measured prior to, at the end of, and at 24 weeks after the completion of treatment. As subanalysis, serum total M2BP levels were measured in patients treated with pegylated-interferon and ribavirin.

Results: In patients treated with IFN-based therapy, M2BPGi levels were elevated at the end of treatment but decreased afterwards. In contrast, M2BPGi levels in patients treated with IFN-free therapy decreased immediately after starting the treatment without transient elevation. Though pre-treatment M2BPGi levels significantly correlated with fibrosis in both patients with a sustained virological response (SVR) and non-SVR, post-treatment M2BPGi levels decreased regardless of the degree of fibrosis in patients with SVR. In multivariate analysis, non-SVR and HCC development were independent factors associated with M2BPGi level ≥2.2. In patients treated with pegylated-interferon and ribavirin, total M2BP levels were positively correlated with fibrosis and HCC development.

Conclusion: Real-time monitoring of the serum M2BPGi level after antiviral therapy for CHC patients could be a helpful screening tool for assessing the risk of HCC. M2BP and its glycan structure could be associated together with hepatocarcinogenesis.
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http://dx.doi.org/10.1007/s12072-016-9754-1DOI Listing
November 2016

Human induced pluripotent stem cell-derived hepatic cell lines as a new model for host interaction with hepatitis B virus.

Sci Rep 2016 07 8;6:29358. Epub 2016 Jul 8.

Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan.

Hepatitis B virus (HBV) is not eradicated by current antiviral therapies due to persistence of HBV covalently closed circular DNA (cccDNA) in host cells, and thus development of novel culture models for productive HBV infection is urgently needed, which will allow the study of HBV cccDNA eradication. To meet this need, we developed culture models of HBV infection using human induced pluripotent stem cell-derived hepatocyte lineages, including immature proliferating hepatic progenitor-like cell lines (iPS-HPCs) and differentiated hepatocyte-like cells (iPS-Heps). These cells were susceptible to HBV infection, produced HBV particles, and maintained innate immune responses. The infection efficiency of HBV in iPS-HPCs predominantly depended on the expression levels of sodium taurocholate cotransporting polypeptide (NTCP), and was low relative to iPS-Heps: however, long-term culture of iPS-Heps was difficult. To provide a model for HBV persistence, iPS-HPCs overexpressing NTCP were established. The long-term persistence of HBV cccDNA was detected in iPS-HPCs overexpressing NTCP, and depended on the inhibition of the Janus-kinase signaling pathway. In conclusion, this study provides evidence that iPS-derived hepatic cell lines can be utilized for novel HBV culture models with genetic variation to investigate the interactions between HBV and host cells and the development of anti-HBV strategies.
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http://dx.doi.org/10.1038/srep29358DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4937433PMC
July 2016

Evaluation of Interferon Resistance in Newly Established Genotype 1b Hepatitis C Virus Cell Culture System.

J Clin Transl Hepatol 2016 Mar 15;4(1):5-11. Epub 2016 Mar 15.

Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan.

Background And Aims: The hepatitis C virus (HCV) genotype 1b is known to exhibit treatment resistance with respect to interferon (IFN) therapy. Substitution of amino acids 70 and 91 in the core region of the 1b genotype is a significant predictor of liver carcinogenesis and poor response to pegylated-IFN-α and ribavirin therapy. However, the molecular mechanism has not yet been clearly elucidated because of limitations of the HCV genotype 1b infectious model. Recently, the TPF1-M170T HCV genotype 1b cell culture system was established, in which the clone successfully replicates and infects Huh-7-derived Huh7-ALS32.50 cells. Therefore, the purpose of this study was to compare IFN resistance in various HCV clones using this system.

Methods: HCV core amino acid substitutions R70Q and L91M were introduced to the TPF1-M170T clone and then transfected into Huh7-ALS32.50 cells. To evaluate the production of each virus, intracellular HCV core antigens were measured. RESULTS were confirmed with Western blot analysis using anti-NS5A antibodies, and IFN sensitivity was subsequently measured.

Results: Each clone was transfected successfully compared with JFH-1, with a significant difference in intracellular HCV core antigen (p < 0.05), an indicator of continuous HCV replication. Among all clones, L91M showed the highest increase in the HCV core antigen and HCV protein. There was no significant resistance against IFN treatment in core substitutions; however, IFN sensitivity was significantly different between the wildtype core and JFH-1 (p < 0.05).

Conclusions: A novel genotype 1b HCV cell culture was constructed with core amino acid substitutions, which demonstrated IFN resistance of genotype 1b. This system will be useful for future analyses into the mechanisms of HCV genotype 1b treatment.
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http://dx.doi.org/10.14218/JCTH.2015.00047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4807137PMC
March 2016

Matrix metalloproteinase-14 mediates formation of bile ducts and hepatic maturation of fetal hepatic progenitor cells.

Biochem Biophys Res Commun 2016 Jan 24;469(4):1062-8. Epub 2015 Dec 24.

Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan. Electronic address:

Fetal hepatic stem/progenitor cells, called hepatoblasts, play central roles in liver development; however, the molecular mechanisms regulating the phenotype of these cells have not been completely elucidated. Matrix metalloproteinase (MMP)-14 is a type I transmembrane proteinase regulating pericellular proteolysis of the extracellular matrix and is essential for the activation of several MMPs and cytokines. However, the physiological functions of MMP-14 in liver development are unknown. Here we describe a functional role for MMP-14 in hepatic and biliary differentiation of mouse hepatoblasts. MMP-14 was upregulated in cells around the portal vein in perinatal stage liver. Formation of bile duct-like structures in MMP-14-deficient livers was significantly delayed compared with wild-type livers in vivo. In vitro biliary differentiation assays showed that formation of cholangiocytic cysts derived from MMP-14-deficient hepatoblasts was completely impaired, and that overexpression of MMP-14 in hepatoblasts promoted the formation of bile duct-like cysts. In contrast, the expression of molecules associated with metabolic functions in hepatocytes, including hepatic nuclear factor 4α and tryptophan 2,3-dioxygenase, were significantly increased in MMP-14-deficient livers. Expression of the epidermal growth factor receptor and phosphorylation of mitogen-activated protein kinases were significantly upregulated in MMP-14-deficient livers. We demonstrate that MMP-14-mediated signaling in fetal hepatic progenitor cells promotes biliary luminal formation around the portal vein and negatively controls the maturation of hepatocytes.
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http://dx.doi.org/10.1016/j.bbrc.2015.12.105DOI Listing
January 2016

Comprehensive analyses of mutations and hepatitis B virus integration in hepatocellular carcinoma with clinicopathological features.

J Gastroenterol 2016 May 9;51(5):473-86. Epub 2015 Nov 9.

Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan.

Background And Aims: Genetic alterations in specific genes are critical events in carcinogenesis and hepatocellular carcinoma (HCC) progression. However, the genetic alterations responsible for HCC development, progression, and survival are unclear.

Methods: We investigated the essential difference in genetic alterations between HCC and adjacent non-HCC tissues using next-generation sequencing technology.

Results: We found recurrent mutations in several genes such as telomerase reverse transcriptase (TERT; 65% of the total 104 HCCs), TP53 (38%), CTNNB1 (30%), AXIN1 (2%), PTEN (2%), and CDKN2A (2%). TERT promoter mutations were associated with older age (p = 0.005), presence of hepatitis C virus (HCV) infection (p = 0.003), and absence of hepatitis B virus (HBV) infection (p < 0.0001). In hepatitis B surface antigen (HBs Ag)-positive HCC without TERT promoter mutations, HBV integration into TERT locus was found in 47% patients and was mutually exclusive to TERT promoter mutations. Most (89%) HBV integrants were in the HBx region. TP53 mutations were associated with HBV infection (p = 0.0001) and absence of HCV infection (p = 0.002). CTNNB1 mutations were associated with absence of HBV infection (p = 0.010). Moreover, TERT promoter mutation was significantly associated with shorter disease-free survival (p = 0.005) and poor overall survival (p = 0.024).

Conclusions: Gene alterations in TERT promoter, TP53, CTNNB1, and HBV integration were closely associated with HCC development, and mutations in TERT promoter are related to poor prognosis. These results are useful for understanding the underlying mechanism of hepatocarcinogenesis, diagnosis, and predicting outcomes of patients with HCC.
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http://dx.doi.org/10.1007/s00535-015-1126-4DOI Listing
May 2016

Efficacy of additional radiofrequency ablation after transcatheter arterial chemoembolization for intermediate hepatocellular carcinoma.

Hepatol Res 2016 Apr 15;46(4):312-9. Epub 2015 Sep 15.

Departments of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan.

Aim: For intermediate hepatocellular carcinoma (HCC), transcatheter arterial chemoembolization (TACE) therapy is recommended in the guidelines as a monotherapy, although TACE is a non-curative therapy. The aims of the present study were to evaluate the efficacy of adding radiofrequency ablation (RFA) to TACE in patients with intermediate HCC, and to identify the factors that were associated with favorable survival in these patients.

Methods: Fifty-nine patients with intermediate HCC were enrolled in this retrospective study. Thirty-nine patients were treated with TACE alone and 20 patients were treated with additional RFA after TACE.

Results: The recurrence-free survival rates at 0.5, 1 and 2 years for the additional RFA group were 32%, 19% and 13%, respectively, and these were significantly higher than those of the TACE group (8%, 3% and 0%, respectively; log-rank test, P = 0.001). The cumulative survival rates of the additional RFA group were significantly higher than those of the TACE group (log-rank test, P = 0.002), although this significant difference was not found in the subgroup of treatment naive patients because of small sample size. Multivariate analysis indicated male sex, lower total bilirubin, lower α-fetoprotein, lower des-γ-carboxyprothrombin, newly recurrent HCC nodules within the last 12 months and additional RFA as independent factors that were significantly associated with favorable overall survival.

Conclusion: Additional RFA of nodules insufficiently treated by TACE is effective therapy for obtaining favorable disease-free survival in patients with intermediate HCC, and leads to better overall survival particularly in recurrent patients.
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http://dx.doi.org/10.1111/hepr.12566DOI Listing
April 2016

Primary hepatic neuroendocrine carcinoma with a cholangiocellular carcinoma component in one nodule.

Clin J Gastroenterol 2014 Oct 13;7(5):449-54. Epub 2014 Aug 13.

Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 1138519, Japan.

Primary neuroendocrine carcinomas (NECs) in the liver are very rare; however, several reports have described cases of a primary hepatic NEC combined with a hepatocellular carcinoma (HCC). We present the first report of a primary hepatic NEC with a cholangiocellular carcinoma (CCC) component in one nodule in a patient with a metachronous liver HCC. A 73-year old man who had received partial hepatectomy surgery because of a primary HCC and a primary CCC two years prior was diagnosed with a primary hepatic NEC after surgical treatment. Histological analysis of the resected tumor revealed that the tumor consisted of a predominant NEC area with a partial CCC component in one nodule and that the NEC cells were negative for markers of pancreatic NEC. Neoplastic cells in both the NEC and CCC component focally expressed CD44, a representative marker for cancer-initiating cells, and the CD44-positive cells in the NEC component were seen in the vicinity of those in the CCC component of one nodule. This case report provides suggestive information for the origin of primary hepatic NECs.
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http://dx.doi.org/10.1007/s12328-014-0521-3DOI Listing
October 2014

Impaired induction of interleukin 28B and expression of interferon λ 4 associated with nonresponse to interferon-based therapy in chronic hepatitis C.

J Gastroenterol Hepatol 2015 Jun;30(6):1075-84

Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan.

Background And Aim: Interferon (IFN) λ plays an important role in innate immunity to protect against hepatitis C viral (HCV) infection. Single nucleotide polymorphisms (SNPs) near IL28B (IFNλ3) are strongly associated with treatment response to IFNα therapy in chronic hepatitis C (CHC) patients. Recently, IFNλ4 related to IL28B-unfavorable allele was discovered. However, the impact of IFNλs on CHC is unknown. We aimed to investigate the mechanism underlying responsiveness to IFN-based therapy in CHC associated with SNPs near IL28B.

Methods: We evaluated the basal mRNA levels and ex-vivo induction of IFNλ expression including IFNλ4 in peripheral blood mononuclear cells (PBMCs) from 50 CHC patients treated with pegylated-IFNα/RBV. Furthermore, we investigated the effect of IFNλ4 on induction of IL28B in vitro.

Results: When PBMCs were stimulated with IFNα and polyinosinic-polycytidylic acid, IL28B induction was significantly lower in patients with IL28B-unfavorable genotype (rs12979860 CT/TT) than those with IL28B-favorable genotype (rs12979860 CC; P=0.049). IL28B induction was lower in nonresponders than in relapsers (P = 0.04), and it was also lower in nonsustained virological responder patients for triple therapy including NS3 protease inhibitors. IFNλ4 mRNA was detected in 12 of 26 patients with IL28B-unfavorable SNP, and IFNλ4 expression was associated with lower IL28B induction in patients with IL28B-unfavorable genotype (P=0.04) and nonresponse to IFNα therapy (P=0.003). Overexpression of IFNλ4 suppressed IL28B induction and promoter activation.

Conclusions: Impaired induction of IL28B, related to IFNλ4 expression in PBMCs of IL28B-unfavorable patients, is associated with nonresponse to IFNα-based therapy for hepatitis C viral infection.
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http://dx.doi.org/10.1111/jgh.12902DOI Listing
June 2015
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