Publications by authors named "Shingo Nakamoto"

111 Publications

Serum Angiopoietin 2 acts as a diagnostic and prognostic biomarker in hepatocellular carcinoma.

J Cancer 2021 5;12(9):2694-2701. Epub 2021 Mar 5.

Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan.

Hepatocellular carcinoma (HCC) is typically accompanied by abundant arterial blood flow. Although angiogenic growth factors such as Angiopoietin 2 (Ang2) play a central role in tumor angiogenesis in HCC, the role of serum Ang2 as a biomarker in HCC remains unclear. In this study, we aimed to investigate the potential of Ang2 as a diagnostic and prognostic biomarker in HCC using a sandwich enzyme-linked immunosorbent assay (ELISA). The median Ang2 levels in controls (n=20), chronic liver disease patients (n=98), and HCC patients (n=275) were 1.58, 2.33, and 3.53 ng/mL, respectively. The optimal cut-off value of Ang2 was determined as 3.5 ng/mL by receiver operating curve analysis. The sensitivity, specificity, and accuracy of Ang2 for HCC detection were 50.9, 83.7, and 59.5%, respectively. Spearman's rank correlation coefficient analysis demonstrated only a weak correlation between Ang2 serum levels and alpha-fetoprotein (AFP) or des-gamma-carboxy prothrombin (DCP) serum levels. The diagnostic value of Ang2 was comparable to those of other existing markers. In addition, 24 out of 73 patients with normal AFP and DCP levels (32.9%) demonstrated abnormally high Ang2 levels (≥3.5 ng/mL). Although no significant difference in overall survival was found between Ang2 and Ang2 patients with curative ablation therapy, recurrence-free survival (RFS) in Ang2 patients was observed to be significantly shorter than those in Ang2 patients. Multivariate analysis demonstrated that high serum Ang2 levels (≥3.5 ng/mL) and the presence of multiple tumors were poor prognostic factors. In conclusion, our findings indicate that serum Ang2 is a potential novel biomarker for both diagnosis and prognosis in HCC.
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http://dx.doi.org/10.7150/jca.56436DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8040723PMC
March 2021

The impact of FGF19/FGFR4 signaling inhibition in antitumor activity of multi-kinase inhibitors in hepatocellular carcinoma.

Sci Rep 2021 Mar 5;11(1):5303. Epub 2021 Mar 5.

Division of Stem Cell and Molecular Medicine, Center for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo, 108-8639, Japan.

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 FGF19 (n = 68) patients treated using sorafenib exhibited a significantly shorter progression-free survival and overall survival than FGF19 (n = 105) patients, there were no significant differences between FGF19 (n = 21) and FGF19 (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.
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http://dx.doi.org/10.1038/s41598-021-84117-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7935880PMC
March 2021

Propofol midazolam for sedation during radiofrequency ablation in patients with hepatocellular carcinoma.

JGH Open 2021 Feb 22;5(2):273-279. Epub 2020 Dec 22.

Departmetn of Anesthesiology, Graduate School of Medicine Chiba University Chiba Japan.

Background And Aim: Standardization of the sedation protocol during radiofrequency ablation (RFA) in patients with hepatocellular carcinoma (HCC) is needed. This randomized, single-blind, investigator-initiated trial compared clinical outcomes during and after RFA using propofol and midazolam, respectively, in patients with HCC.

Methods: Few- and small-nodule HCC patients (≤3 nodules and ≤3 cm) were randomly assigned to either propofol or midazolam. Patient satisfaction was assessed using a 100-mm visual analog scale (VAS) (1 mm = not at all satisfied, 100 mm = completely satisfied). Sedation recovery rates 1, 2, 3, and 4 h after RFA were evaluated based on Modified Observer's Assessment of Alertness/Sedation (MOAA/S) scores; full recovery was defined as a MOAA/S score of 5.

Results: Between July 2013 and September 2017, 143 patients with HCC were enrolled, and 135 patients were randomly assigned to the treatment group. Compared with midazolam, propofol exhibited similar median procedural satisfaction (propofol: 73.1 mm, midazolam: 76.9 mm, = 0.574). Recovery rates 1 and 2 h after RFA were higher in the propofol group than in the midazolam group. Meanwhile, recovery rates observed 3 and 4 h after RFA were similar in the two groups. The safety profiles during and after RFA were almost identical in the two groups.

Conclusion: Patient satisfaction was almost identical in patients receiving propofol and midazolam sedation during RFA. Propofol sedation resulted in reduced recovery time compared with midazolam sedation in patients with HCC. The safety profiles of both propofol and midazolam sedation during and after RFA were acceptable.
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http://dx.doi.org/10.1002/jgh3.12483DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7857294PMC
February 2021

CCL113, a novel sulfonamide, induces selective mitotic arrest and apoptosis in HeLa and HepG2 cells.

Oncol Rep 2020 Dec 13;44(6):2770-2782. Epub 2020 Oct 13.

Department of Molecular Virology, Graduate School of Medicine, Chiba University, Chuo‑ku, Chiba 260‑8670, Japan.

Targeting cell‑cycle regulation to hinder cancer cell proliferation is a promising anticancer strategy. The present study investigated the effects of a novel sulfonamide, CCL113, on cell cycle progression in cancer cell lines (HeLa and HepG2), a noncancerous cell line (Vero) and a normal human fibroblast cell line (TIG‑1‑20). The present results showed that treatment with CCL113 significantly decreased the viability of the cancer cells. FACS analyses showed that CCL113 treatment increased the proportion of cancerous and noncancerous cells in the G2/M phase. Analyses of cell cycle regulatory proteins showed that CCL113 treatment inhibited the activity of CDK1 in HeLa cells, possibly due to the decrease in the level of Cdc25B/C proteins and arrest in the M phase. Using time‑lapse imaging‑assisted analyses of HeLa and Vero cells expressing fluorescent ubiquitination‑based cell cycle indicator (FUCCI), it was observed that CCL113 treatment led to a prolonged G2 phase at the G2/M checkpoint and arrest in the M phase in both cell lines. This possibly activated the DNA damage response in noncancerous cells, while inducing mitotic arrest leading to apoptosis in the cancer cells. The results of molecular docking studies suggested that CCL113 might have the potential to bind to the taxol‑binding site on β‑tubulin. In conclusion, CCL113 holds potential as a reliable anticancer drug due to its ability to induce mitotic arrest followed by apoptosis of cancer cells and to activate the DNA damage response in noncancerous cells, thereby facilitating exit from the cell cycle.
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http://dx.doi.org/10.3892/or.2020.7805DOI Listing
December 2020

Analyses of Intermediate-Stage Hepatocellular Carcinoma Patients Receiving Transarterial Chemoembolization prior to Designing Clinical Trials.

Liver Cancer 2020 Sep 22;9(5):596-612. Epub 2020 Jul 22.

Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan.

Background: Intermediate-stage hepatocellular carcinoma (HCC) has a high frequency of recurrence and progression to advanced stage after transarterial chemoembolization (TACE), particularly in patients with high tumor burden. Promising new results from immune checkpoint inhibitors (ICIs) and ICI-based therapies are expected to replace TACE, especially in HCC patients with high tumor burden.

Aims: The present study aimed to evaluate the effectiveness of TACE with a view to design clinical trials comparing TACE and ICIs.

Methods: We retrospectively identified intermediate-stage HCC patients undergoing TACE from our database and subdivided patients into low- and high-burden groups based on three subclassification models using the diameter of the maximum tumor and the number of tumors. Clinical outcomes were compared between low- and high-burden intermediate-stage HCC.

Results: Of 1,161 newly diagnosed HCC patients, 316 were diagnosed with intermediate-stage disease and underwent TACE. The median overall survival from high-burden intermediate-stage disease was not significantly different by clinical course, reaching high tumor burden in all subclassification models. The prognosis of high-burden patients after initial TACE was poor compared with low-burden patients for two models (except for the up-to-seven criteria). In all three models, high-burden patients showed a poor durable response rate (DRR) both ≥3 months and ≥6 months and poor prognosis after TACE. Moreover, patients with confirmed durable response ≥3 months and ≥6 months showed better survival outcomes for high-burden intermediate-stage HCC.

Conclusions: Our results demonstrate the basis for selecting a population that would not benefit from TACE and setting DRR ≥3 months or ≥6 months as alternative endpoints when designing clinical trials comparing TACE and ICIs.
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http://dx.doi.org/10.1159/000508809DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7548915PMC
September 2020

Potential of Lenvatinib for an Expanded Indication from the REFLECT Trial in Patients with Advanced Hepatocellular Carcinoma.

Liver Cancer 2020 Aug 5;9(4):382-396. Epub 2020 May 5.

Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan.

Background: The present study aimed to assess the efficacy and safety of lenvatinib and verify the possibility of lenvatinib for the expanded indication from the REFLECT trial in patients with advanced hepatocellular carcinoma (HCC) in real-world practice, primarily focusing on the population that was excluded in the REFLECT trial.

Methods: We retrospectively collected data on patients with advanced HCC who were administered lenvatinib in 7 institutions in Japan.

Results: Of 152 advanced HCC patients, 95 and 57 patients received lenvatinib in first-line and second- or later-line systemic therapies, respectively. The median progression-free survival in Child-Pugh class A patients was nearly equal between first- and second- or later-line therapies (5.2 months; 95% CI 3.7-6.9 for first line, 4.8 months; 95% CI 3.8-5.9 for second or later line, = 0.933). According to the modified Response Evaluation Criteria in Solid Tumors, the objective response rate of 27 patients (18%) who showed a high burden of intrahepatic lesions (i.e., main portal vein and/or bile duct invasion or 50% or higher liver occupation) at baseline radiological assessment was 41% and similar with that of other population. The present study included 20 patients (13%) with Child-Pugh class B. These patients observed high frequency rates of liver function-related adverse events due to lenvatinib. The 8-week dose intensity of lenvatinib had a strong correlation with liver function according to both the Child-Pugh and albumin - bilirubin scores.

Conclusion: Lenvatinib had potential benefits for patients with advanced HCC with second- or later-line therapies and a high burden of intrahepatic lesions. Dose modification should be paid increased attention among patients with poor liver function, such as Child-Pugh class B patients.
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http://dx.doi.org/10.1159/000507022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7506220PMC
August 2020

Interferon-γ induced PD-L1 expression and soluble PD-L1 production in gastric cancer.

Oncol Lett 2020 Sep 19;20(3):2161-2168. Epub 2020 Jun 19.

Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chuo-ku, Chiba 260-8670, Japan.

Programmed death-ligand 1 (PD-L1) plays an essential role in tumor cell escape from anti-tumor immunity in various types of cancer, including gastric cancer (GC). The present study investigated the intracellular and membrane-bound expression of PD-L1 in the GC cell lines MKN1, MKN74, KATO III and OCUM-1. Furthermore, soluble PD-L1 (sPD-L1) level in the supernatant of GC cells and the serum of patients with GC and healthy controls was determined by ELISA. Interferon (IFN)-γ treatment of cells resulted in increased cytoplasmic expression of PD-L1 in GC cells in a dose-dependent manner, except for MKN74 cells; however, there was no association between tumor necrosis factor-α treatment and enhanced PD-L1 expression. Concordant with these findings, results from flow cytometry analysis demonstrated that membrane-bound PD-L1 expression was also increased following GC cell treatment with IFN-γ in a dose-dependent manner. In addition, significant sPD-L1 overproduction was observed only in the culture supernatant of OCUM-1 cells. Serum level of sPD-L1 was significantly increased in patients with GC, in particular in stage IV patients, compared with healthy controls. In conclusion, the present study demonstrated that IFN-γ treatment increased the intracellular and membrane-bound PD-L1 expression in GC cells. In addition, sPD-L1 was detected not only in the supernatant of GC cells but also in the serum of patients with GC. Further investigation on the underlying mechanism of regulation of PD-L1 expression and sPD-L1 production is required.
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http://dx.doi.org/10.3892/ol.2020.11757DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7400993PMC
September 2020

Long-term administration of Tolvaptan to patients with decompensated cirrhosis.

Int J Med Sci 2020 15;17(7):874-880. Epub 2020 Mar 15.

Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan.

: 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. : 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. : 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. : A persistent therapeutic response, but not early response to tolvaptan, was associated with favorable survival of decompensated cirrhotic patients.
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http://dx.doi.org/10.7150/ijms.41454DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7163362PMC
February 2021

Switching to systemic therapy after locoregional treatment failure: Definition and best timing.

Clin Mol Hepatol 2020 04 15;26(2):155-162. Epub 2020 Jan 15.

Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan.

In patients with unresectable hepatocellular carcinoma (HCC) without both macrovascular invasion and extrahepatic metastasis, the initial treatment choice recommended is transarterial chemoembolization (TACE). Before sorafenib came into wide use, TACE had been pointlessly carried out repeatedly. It was in the early 2010s that the concept of TACE refractory was advocated. Two retrospective studies from Japan indicated that conversion from TACE to sorafenib the day after patients were deemed as TACE refractory improved overall survival compared with continued TACE, according to the definition by the Japan Society of Hepatology. Nowadays, phase 3 trials have shown clinical benefits of several novel molecular target agents. Compared with the era of sorafenib, sequential treatments with these molecular target agents have gradually prolonged patients' survival and have become major strategies in patients with HCC. Taking these together, conversion from TACE to systemic therapies at the time of TACE refractory, compared with before, may have a greater impact on survival and may be considered deeper in the decisions-making process in patients with unresectable HCC who are candidate for TACE. Up-to-date information on the concept of TACE refractory is summarized in this review. We believe that the survival of patients with unresectable HCC without both macrovascular invasion and extrahepatic metastasis may be dramatically improved by optimal timing of TACE refractory and switching to systemic therapies.
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http://dx.doi.org/10.3350/cmh.2019.0021nDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7160341PMC
April 2020

Serum fibroblast growth factor 19 serves as a potential novel biomarker for hepatocellular carcinoma.

BMC Cancer 2019 Nov 12;19(1):1088. Epub 2019 Nov 12.

Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan.

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.
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http://dx.doi.org/10.1186/s12885-019-6322-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6849282PMC
November 2019

Superinfection of hepatitis A virus in hepatocytes infected with hepatitis B virus.

Int J Med Sci 2019 20;16(10):1366-1370. Epub 2019 Sep 20.

Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, 30-1 Oyaguchi-Kamicho, Itabashi-ku, Tokyo 173-8610, Japan; (T.K.).

Hepatitis A virus (HAV) infection is a major cause of acute hepatitis including acute liver failure. Hepatitis B infection (HBV) occurs worldwide, with the highest rates in Asian and African countries, and there are several reports that HAV infection may have a more severe clinical course in patients with chronic HBV infection. We previously demonstrated that Japanese miso extracts have inhibitory effects on HAV replication. In the present study, we examined the replication of HAV and HBV in a hepatocyte superinfection model and the inhibitory effects of Japanese miso extracts on both viruses. According to the results, HAV infection inhibited HBV replication in superinfected hepatocytes, and Japanese rice-koji miso extracts had inhibitory effects on HAV replication. Our findings provide useful information for clinicians in managing HAV infection in patients with chronic HBV infection.
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http://dx.doi.org/10.7150/ijms.32795DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6818197PMC
April 2020

Sequential therapy with sorafenib and regorafenib for advanced hepatocellular carcinoma: a multicenter retrospective study in Japan.

Invest New Drugs 2020 02 6;38(1):172-180. Epub 2019 Jun 6.

Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan.

Background Conversion from sorafenib to regorafenib is primarily an evidence-based treatment strategy in patients with advanced hepatocellular carcinoma (HCC). This study aimed to assess the safety and efficacy of sequential therapy with sorafenib and regorafenib in patients with advanced HCC by analysis of outcomes in clinical practice with the aim to complement phase III findings. Methods The medical records of patients with advanced HCC receiving regorafenib were retrieved to collect data on sorafenib administration at seven Japanese institutions. Radiological responses and adverse events were evaluated using the Response Evaluation Criteria in Solid Tumors version 1.1 and the Common Terminology Criteria for Adverse Events version 4.0, respectively. Results Before March 2018, 44 patients were administered regorafenib for advanced HCC. The median sorafenib treatment duration was 8.4 months. The most common adverse events were similar to those reported by the RESORCE trial. The median overall survival (OS) was 17.3 months (95% confidence interval [CI] 11.4-22.9), and 17 of 37 patients (45.9%) discontinued regorafenib and received sequential systemic therapy after regorafenib. These patients had significantly longer OS than those who were treated by the best supportive care or sub-optimal therapy (not reached versus 8.7 months [95% CI 5.8-11.7]; P < 0.001). Conclusion The results based on Japanese clinical practices verified the tolerability of regorafenib in advanced HCC. Major regorafenib-associated adverse events were similar to those related to sorafenib. OS was significantly longer than expected, which might be associated with the sequential systemic therapies after regorafenib, mainly lenvatinib.
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http://dx.doi.org/10.1007/s10637-019-00801-8DOI Listing
February 2020

Inhibitory effect of Japanese rice-koji miso extracts on hepatitis A virus replication in association with the elevation of glucose-regulated protein 78 expression.

Int J Med Sci 2018 30;15(11):1153-1159. Epub 2018 Jul 30.

Department of Molecular Virology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan.

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.
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http://dx.doi.org/10.7150/ijms.27489DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6097272PMC
January 2019

Successful retreatment with grazoprevir and elbasvir for patients infected with hepatitis C virus genotype 1b, who discontinued prior treatment with NS5A inhibitor-including regimens due to adverse events.

Oncotarget 2018 Mar 23;9(22):16263-16270. Epub 2018 Mar 23.

Department of Gastroenterology, Chiba University, Graduate School of Medicine, Chuo-ku, Chiba 260-8670, Japan.

Background: Sustained virologic response (SVR) by interferon and interferon-free treatment can results in the reduction of advanced liver fibrosis and the occurrence of hepatocellular carcinoma in patients infected with hepatitis C virus (HCV). Recent interferon-free treatment for HCV shortens the duration of treatment and leads to higher SVR rates, without any serious adverse events. However, it is important to retreat patients who have had treatment-failure with HCV non-structural protein 5A (NS5A) inhibitor-including regimens. Combination of sofosbuvir and ledipasvir only leads to approximately 100% SVR rates in HCV genotype (GT1b), NS5A inhibitor-naïve patients in Japan. This combination is not an indication for severe renal disease or heart disease, and these patients should be treated or retreated with a different regimen.

Case Summary: Retreatment with HCV non-structural protein 3/4A inhibitor, grazoprevir, and HCV NS5A inhibitor, elbasvir, successfully eradicated HCV RNA in three patients with HCV genotype 1b infection who discontinued prior interferon-free treatments including HCV NS5A inhibitors due to adverse events within 2 weeks.

Conclusion: Retreatment with the 12-week combination regimen of grazoprevir and elbasvir is effective for HCV GT1b patients who discontinue the HCV NS5A inhibitor-including regimens within 2 weeks. The treatment response may be related to the short duration of initial treatment, which did not produce treatment-emergent RASs.
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http://dx.doi.org/10.18632/oncotarget.24620DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5882333PMC
March 2018

Interferon-free treatment for patients with chronic hepatitis C and autoimmune liver disease: higher SVR rates with special precautions for deterioration of autoimmune hepatitis.

Oncotarget 2018 Feb 3;9(14):11631-11637. Epub 2018 Feb 3.

Department of Gastroenterology, Chiba University, Graduate School of Medicine, Chiba 260-8670, Japan.

Background: Interferon-free treatment can achieve higher sustained virological response (SVR) rates, even in patients in whom hepatitis C virus (HCV) could not be eradicated in the interferon treatment era. Immune restoration in the liver is occasionally associated with HCV infection. We examined the safety and effects of interferon-free regimens on HCV patients with autoimmune liver diseases.

Results: All 7 HCV patients with autoimmune hepatitis (AIH) completed treatment and achieved SVR. Three patients took prednisolone (PSL) at baseline, and 3 did not take PSL during interferon-free treatment. In one HCV patient with AIH and cirrhosis, PSL were not administered at baseline, but she needed to take 40 mg/day PSL at week 8 for liver dysfunction. She also complained back pain and was diagnosed with vasospastic angina by coronary angiography at week 11. However, she completed interferon-free treatment. All 5 HCV patients with primary biliary cholangitis (PBC) completed treatment and achieved SVR. Three of these HCV patients with PBC were treated with UDCA during interferon-free treatment.

Conclusions: Interferon-free regimens could result in higher SVR rates in HCV patients with autoimmune liver diseases. As interferon-free treatment for HCV may have an effect on hepatic immunity and activity of the autoimmune liver diseases, careful attention should be paid to unexpected adverse events in their treatments.

Methods: Total 12 patients with HCV and autoimmune liver diseases [7 AIH and PBC], who were treated with interferon-free regimens, were retrospectively analyzed.
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http://dx.doi.org/10.18632/oncotarget.24391DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5837765PMC
February 2018

Successful retreatment with sofosbuvir plus ledipasvir for cirrhotic patients with hepatitis C virus genotype 1b, who discontinued the prior treatment with asunaprevir plus daclatasvir: A case series and review of the literature.

Oncotarget 2018 Jan 29;9(4):5509-5513. Epub 2017 Dec 29.

Department of Gastroenterology, Chiba University, Graduate School of Medicine, Inohana, Chuo-ku, Chiba, Japan.

Background: Interferon-free treatment results in higher sustained virologic response (SVR) rates, with no serious adverse events in hepatitis C virus (HCV)-infected patients. However, in some patients with treatment-failure in HCV NS5A inhibitor-including interferon-free regimens, the treatment-emergent HCV NS5A resistance-associated variants (RAVs), which are resistant to interferon-free retreatment including HCV NS5A inhibitors, are observed. In HCV-infected Japanese patients with daclatasvir and asunaprevir treatment failure, retreatment with sofosbuvir and ledipasvir could lead to only ∼70% SVR rates.

Case Summary: Three HCV genotype (GT)-1b-infected cirrhotic patients who discontinued the combination of daclatasvir and asunaprevir due to adverse drug reactions within 4 weeks; retreatment with sofosbuvir and ledipasvir combination could result in SVR in these patients without RAVs. One HCV GT-1b-infected cirrhotic patient who discontinued the combination of daclatasvir and asunaprevir due to viral breakthrough at week 10; retreatment with sofosbuvir and ledipasvir combination for this patient with the treatment-emergent HCV NS5A RAV-Y93H resulted in viral relapse at week 4 after the end of the treatment.

Conclusion: Retreatment with sofosbuvir and ledipasvir is effective for HCV GT-1b patients who discontinue the combination of daclatasvir and asunaprevir within 4 weeks. The treatment response should be related to the existence of treatment-emergent HCV NS5A RAVs, but may not be related to the short duration of treatment.
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http://dx.doi.org/10.18632/oncotarget.23768DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5797068PMC
January 2018

Hepatitis B Virus Genotype C is Predominant in Myanmar.

Diseases 2017 Dec 26;6(1). Epub 2017 Dec 26.

Department of Molecular Virology, Graduate School of Medicine, Chiba University, Inohana 1-8-1, Chuo-ku, Chiba 260-8677, Japan.

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.
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http://dx.doi.org/10.3390/diseases6010003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5871949PMC
December 2017

Association of Genotype with Hepatic Steatosis in Chronic Hepatitis C Patients Treated with Peginterferon and Ribavirin Combination Therapy.

Int J Med Sci 2017 4;14(11):1088-1093. Epub 2017 Sep 4.

Department of Molecular Virology, Graduate School of Medicine, Chiba University, Japan.

Background: Genetic variation near the interferon lambda 3 () is known to be associated with response to pegylated interferon (pegIFN) and ribavirin combination therapy in patients with chronic hepatitis C virus (HCV) infection which is often accompanied by hepatic steatosis.

Aims: We examined whether this genetic variation is associated with host lipids and treatment response.

Methods: A total of 101 Japanese patients who had underwent liver biopsy before treatment with pegIFN and ribavirin for HCV genotype 1b infection were retrospectively analyzed for association between genotypes (rs8099917) and clinical factors including histopathological features of the liver. The presence of >5% steatosis in the liver specimen was defined as hepatic steatosis.

Results: Forty patients (40%) had liver steatosis before therapy. Patients with minor genotype (non-TT) showed lower low-density lipoprotein cholesterol level (p=0.0045), higher γ-glutamyl transpeptidase level (p=0.0003) and higher prevalence of hepatic steatosis (p=0.0002). Advanced fibrosis [odds ratio (OR) 4.63, p=0.03] and major genotype (OR 0.13, p=0.001) were 2 independent factors for determining the presence of hepatic steatosis. Among the factors associated with sustained virological response, genotype was the most significant predictor, as per multivariate analysis.

Conclusions: Our results confirmed that genotype is associated with hepatic steatosis as well as IFN response.
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http://dx.doi.org/10.7150/ijms.20171DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5666539PMC
June 2018

Serum Wisteria Floribunda Agglutinin-Positive Mac-2 Binding Protein Could Not Always Predict Early Cirrhosis in Non-Viral Liver Diseases.

Diseases 2016 Dec 14;4(4). Epub 2016 Dec 14.

Department of Gastroenterology and Nephrology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8677, Japan.

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.
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http://dx.doi.org/10.3390/diseases4040038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5456321PMC
December 2016

Characteristics of patients with sorafenib-treated advanced hepatocellular carcinoma eligible for second-line treatment.

Invest New Drugs 2018 04 11;36(2):332-339. Epub 2017 Sep 11.

Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan.

Background Regorafenib has been investigated for its efficacy and safety as a second-line treatment in patients with advanced hepatocellular carcinoma (HCC). We assessed the characteristics of patients with HCC treated with sorafenib who might be eligible for second-line treatment in general and regorafenib in particular. Methods Patients with HCC treated with sorafenib were retrospectively analyzed. We defined second-line candidate patients as maintaining Child-Pugh A and ECOG-PS ≤1 at the time of sorafenib failure. We also defined regorafenib candidate patients as follows: 1) continuing sorafenib at the time of radiological progression, 2) maintaining Child-Pugh A and ECOG-PS ≤ 1 at the time of sorafenib failure, and 3) continuing sorafenib 400 mg or more without intolerable adverse events at least 20 days of the last 28 days of treatment. Results Of 185 patients, 130 (70%) and 69 (37%) were candidates for second-line treatment and regorafenib. Child-Pugh score 6 and ECOG-PS 1 at the time of starting sorafenib were significantly lower in both second-line treatment and regorafenib candidate patients. Moreover, hand-foot skin reaction and liver failure during sorafenib treatment were associated with significantly low and high probabilities, respectively, of both Child-Pugh score > 6 and ECOG-PS > 1 at the time of sorafenib failure. Conclusion Regorafenib candidate patients after sorafenib failure are limited, and generally fewer than those who are candidates for second-line treatment. A lower Child-Pugh score and a better ECOG-PS were predictors of eligibility for second-line therapy and regorafenib treatment in sorafenib-treated patients with advanced HCC patients.
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http://dx.doi.org/10.1007/s10637-017-0507-3DOI Listing
April 2018

Overexpression of the androgen receptor in human hepatoma cells and its effect on fatty acid metabolism.

Oncol Lett 2017 Jun 3;13(6):4481-4486. Epub 2017 Apr 3.

Department of Gastroenterology and Nephrology, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan.

Hepatocellular carcinoma (HCC) is a predominantly male disease in which the androgen receptor (AR) serves an important pathogenic role in hepatocarcinogenesis. Fatty acid metabolism also contributes to hepatocarcinogenesis and is associated with the prognosis of cancer. The present study aimed to investigate the effects of the AR on fatty acid metabolism-associated gene expression in human hepatoma cell lines. AR-expression plasmids or control plasmids were transiently transfected into the human HCC cell lines Huh7 and HepG2. After 48 h, cellular protein and RNA were extracted and the expression of AR was confirmed by western blotting. Complementary DNA was synthesized and subjected to a quantitative polymerase chain reaction-based array to examine the expression of 84 fatty acid metabolism-associated genes. Overexpression of AR significantly downregulated the expression of 11 fatty acid metabolism-associated genes in Huh7 cells and 35 in HepG2 cells. The overexpression of AR also resulted in the upregulation of 6 fatty acid metabolism genes in HepG2 cells; however, it had no effect in Huh7 cells. Acyl-coenzyme A (CoA) thioesterase 7 and acyl-CoA oxidase 3 were downregulated in both cell lines. In conclusion, upregulation of AR via overexpression led to the disturbance of fatty acid metabolism-associated gene expression in human HCC cells. Therefore, the AR may serve a role in hepatocarcinogenesis via the regulation of hepatocellular fatty acid metabolism.
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http://dx.doi.org/10.3892/ol.2017.5973DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5453011PMC
June 2017

Glucose-regulated protein 78 is an antiviral against hepatitis A virus replication.

Exp Ther Med 2017 Jun 28;13(6):3305-3308. Epub 2017 Apr 28.

Department of Gastroenterology and Nephrology, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan.

Infection with hepatitis A virus (HAV) is a major cause of acute hepatitis globally and it is important to identify the mechanisms of HAV replication. Glucose-regulated protein 78 (GRP78) is an endoplasmic reticulum (ER) chaperone and serves a role in unfolded protein response pathways. Previous studies have demonstrated that GRP78 functions as an endogenous antiviral factor. In the present study, two loss-of-function studies using GRP78 were completed to elucidate the role of GRP78 in HAV infection. HAV replication was observed to be enhanced by deficient GRP78 although GRP78-deficiency also led to lower expression of ER stress molecules downstream of GRP78. Therefore, GRP78 appears to be a potential novel defensive molecule against HAV in hepatocytes.
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http://dx.doi.org/10.3892/etm.2017.4407DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5450597PMC
June 2017

Treatment of Real-World HCV Genotype 2-Infected Japanese Patients with Sofosbuvir plus Ribavirin.

Biology (Basel) 2017 May 9;6(2). Epub 2017 May 9.

Department of Gastroenterology and Nephrology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan.

The aim of this study was to characterize the treatment response and tolerability of sofosbuvir plus ribavirin therapies in Japanese patients infected with hepatitis C virus (HCV) genotype (GT)-2. This retrospective study analyzed 114 Japanese HCV GT-2 patients treated for 12 weeks with 400 mg of sofosbuvir plus weight-based ribavirin daily. This treatment led to higher sustained virologic response at 12-weeks post-treatment (SVR12) rates in both treatment-naïve and treatment-experienced patients. The efficacy of this treatment in compensated cirrhotics was the same as that in patients with chronic hepatitis. HCV GT-2a infection and lower estimated glomerular filtration rates (eGFR) tended to be associated with SVR12. Of 114 patients, 113 completed the combination of sofosbuvir plus ribavirin for 12 weeks. Seven patients without SVR12 did not have HCV NS5B-S282 mutations. The overall SVR12 rate was 90.4% (103 of 114). More effective therapeutic options with less adverse events are desired to achieve higher SVR rates in HCV GT-2 Japanese patients.
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http://dx.doi.org/10.3390/biology6020030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5485477PMC
May 2017

Serum microRNA-122 and Wisteria floribunda agglutinin-positive Mac-2 binding protein are useful tools for liquid biopsy of the patients with hepatitis B virus and advanced liver fibrosis.

PLoS One 2017 5;12(5):e0177302. Epub 2017 May 5.

Department of Gastroenterology and Nephrology, Chiba University, Graduate School of Medicine, Chiba, Japan.

Background: Noninvasive methods to accurately and conveniently evaluate liver fibrosis are desirable. MicroRNA (miR) is one of the candidates. MiRs are small RNAs consisting of 19-25 nucleotides that negatively regulate many target genes at transcriptional levels. Recently, many researchers have focused on circulating miRs in the blood stream as biomarkers. Hepatic miR-122 has been reported to have an association with viral replication and hepatic fibrosis in chronic hepatitis B virus (HBV) and hepatic C virus (HCV) infection.

Methods: We measured serum miR-122 levels in HBV- and HCV-infected patients confirmed with liver biopsy. We also investigated a novel liver fibrosis marker Wisteria floribunda agglutinin-positive Mac-2 binding protein [WFA(+)-M2BP]. We evaluated the diagnostic usefulness of these markers in hepatic fibrosis and inflammation of patients with chronic viral infection.

Results: The serum miR-122 levels of HBV-infected patients were higher than those of the control subjects. In HBV-infected patients, the serum miR-122 levels of patients with advanced liver fibrosis were significantly lower. Serum WFA(+)-M2BP was significantly higher dependent on both the staging of fibrosis and the grading of inflammatory activity in patients with both HBV and HCV infection. We also observed that higher serum WFA(+)-M2BP levels augmented the prediction of advanced liver fibrosis among HBV-infected patients with lower serum miR-122 levels.

Conclusions: A lower serum miR-122 level is a useful predictor of advanced liver fibrosis in HBV-infected patients. Serum WFA(+)-M2BP could predict liver fibrosis in both HBV and HCV infection. The combination of these markers may result in the more accurate evaluation of liver fibrosis in HBV infection.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0177302PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5419651PMC
September 2017

Androgen Receptor Could Be a Potential Therapeutic Target in Patients with Advanced Hepatocellular Carcinoma.

Cancers (Basel) 2017 May 5;9(5). Epub 2017 May 5.

Department of Gastroenterology and Nephrology, Chiba University, Graduate School of Medicine, 1-8-1 Inohana, Chiba 260-8670, Japan.

Hepatocellular carcinoma (HCC) is a male-dominant disease with poor prognosis. Sorafenib is the only approved systemic chemotherapeutic drug for patients with advanced HCC. Previous studies have shown that androgen and androgen receptor (AR) are involved in human hepatocarcinogenesis and the development of HCC. Here, we discuss the recent data on AR and HCC, and the combination of sorafenib and inhibitors of AR for advanced-HCC patients. Androgen-dependent and androgen-independent AR activation exist in human hepatocarcinogenesis. AR could directly control hepatocarcinogenesis and regulate the innate immune system to influence HCC progression. Combination of sorafenib with AR inhibitors might represent a potential treatment for patients with advanced HCC.
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http://dx.doi.org/10.3390/cancers9050043DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5447953PMC
May 2017

Real-World Experiences with the Combination Treatment of Ledipasvir plus Sofosbuvir for 12 Weeks in HCV Genotype 1-Infected Japanese Patients: Achievement of a Sustained Virological Response in Previous Users of Peginterferon plus Ribavirin with HCV NS3/4A Inhibitors.

Int J Mol Sci 2017 Apr 25;18(5). Epub 2017 Apr 25.

Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan.

The aim of this study was to characterize the treatment response and serious adverse events of ledipasvir plus sofosbuvir therapies in Japanese patients infected with hepatitis C virus (HCV) genotype 1 (GT1). This retrospective study analyzed 240 Japanese HCV GT1 patients treated for 12 weeks with 90 mg of ledipasvir plus 400 mg of sofosbuvir daily. Sustained virological response at 12 weeks post-treatment (SVR12) was achieved in 236 of 240 (98.3%) patients. Among treatment-naïve patients, SVR12 was achieved in 136 of 138 (98.6%) patients, and among treatment-experienced patients, SVR12 was achieved in 100 of 102 (98.0%) patients. In patients previously treated with peginterferon plus ribavirin with various HCV NS3/4A inhibitors, 100% SVR rates (25/25) were achieved. Two relapsers had HCV NS5A resistance-associated variants (RAVs), but no HCV NS5B-S282 was observed after they relapsed. We experienced two patients with cardiac events during treatment. In conclusion, combination of ledipasvir plus sofosbuvir for 12 weeks is a potential therapy for HCV GT1 patients. Caution is needed for HCV NS5A RAVs, which were selected by HCV NS5A inhibitors and cardiac adverse events.
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http://dx.doi.org/10.3390/ijms18050906DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5454819PMC
April 2017

Interferon induces interleukin 8 and bone marrow stromal cell antigen 2 expression, inhibiting the production of hepatitis B virus surface antigen from human hepatocytes.

Biochem Biophys Res Commun 2017 05 28;486(3):858-863. Epub 2017 Mar 28.

Department of Gastroenterology and Nephrology, Chiba University, Graduate School of Medicine, Chiba 260-8670, Japan.

Hepatitis B virus (HBV) surface antigen (HBsAg) loss is one of the treatment goals of chronic HBV infection. Bone marrow stromal cell antigen 2 (BST2) is one of the interferon (IFN)-stimulated genes (ISGs) and inhibits the release of various enveloped viruses. Here we examined the effects of antiviral treatment on HBsAg levels and its intracellular mechanism in HBsAg-producing hepatocytes. In PLC/PRF/5 and Huh1, IFNα-2a treatment decreased HBsAg levels in their conditioned media. Upregulation of interleukin 8 (IL8), toll-like receptor 2 (TLR2) and interferon gamma-induced protein 10 (IP10) mRNAs was associated with the reduction of HBsAg in both PLC/PRF/5 and Huh1. The HBsAg level was upregulated by knockdown of IL8, TLR2 or IP10. Exogenous addition of IL8 enhanced BST2 promoter activity and BST2 mRNA expression. Additionally, knockdown of IL8 could lead to the downregulation of BST2 mRNA. Transfection of poly(I-C) enhanced IL8 and BST2 mRNA expression and inhibited HBsAg secretion from PLC/PRF/5 cells. In conclusion, IL8 might play an important role in the enhancement of BST2 and be involved in HBsAg eradication.
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http://dx.doi.org/10.1016/j.bbrc.2017.03.150DOI Listing
May 2017

Overexpression of c-Jun contributes to sorafenib resistance in human hepatoma cell lines.

PLoS One 2017 21;12(3):e0174153. Epub 2017 Mar 21.

Department of Gastroenterology and Nephrology, Chiba University, Graduate School of Medicine, Chiba, Japan.

Background: Despite recent advances in treatment strategies, it is still difficult to cure patients with hepatocellular carcinoma (HCC). Sorafenib is the only approved multiple kinase inhibitor for systemic chemotherapy in patients with advanced HCC. The majority of advanced HCC patients are resistant to sorafenib. The mechanisms of sorafenib resistance are still unknown.

Methods: The expression of molecules involved in the mitogen-activated protein kinase (MAPK) signaling pathway in human hepatoma cell lines was examined in the presence or absence of sorafenib. Apoptosis of human hepatoma cells treated with sorafenib was investigated, and the expression of Jun proto-oncogene (c-Jun) was measured.

Results: The expression and phosphorylation of c-Jun were enhanced in human hepatoma cell lines after treatment with sorafenib. Inhibiting c-Jun enhanced sorafenib-induced apoptosis. The overexpression of c-Jun impaired sorafenib-induced apoptosis. The expression of osteopontin, one of the established AP-1 target genes, was enhanced after treatment with sorafenib in human hepatoma cell lines.

Conclusions: The protein c-Jun plays a role in sorafenib resistance in human hepatoma cell lines. The modulation and phosphorylation of c-Jun could be a new therapeutic option for enhancing responsiveness to sorafenib. Modulating c-Jun may be useful for certain HCC patients with sorafenib resistance.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0174153PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5360329PMC
September 2017

Discrepancy between Hepatitis C Virus Genotypes and NS4-Based Serotypes: Association with Their Subgenomic Sequences.

Int J Mol Sci 2017 Jan 17;18(1). Epub 2017 Jan 17.

Department of Molecular Virology, Graduate School of Medicine, Chiba University, Chiba 260-8677, Japan.

Determination of hepatitis C virus (HCV) genotypes plays an important role in the direct-acting agent era. Discrepancies between HCV genotyping and serotyping assays are occasionally observed. Eighteen samples with discrepant results between genotyping and serotyping methods were analyzed. HCV serotyping and genotyping were based on the HCV nonstructural 4 (NS4) region and 5'-untranslated region (5'-UTR), respectively. HCV core and NS4 regions were chosen to be sequenced and were compared with the genotyping and serotyping results. Deep sequencing was also performed for the corresponding HCV NS4 regions. Seventeen out of 18 discrepant samples could be sequenced by the Sanger method. Both HCV core and NS4 sequences were concordant with that of genotyping in the 5'-UTR in all 17 samples. In cloning analysis of the HCV NS4 region, there were several amino acid variations, but each sequence was much closer to the peptide with the same genotype. Deep sequencing revealed that minor clones with different subgenotypes existed in two of the 17 samples. Genotyping by genome amplification showed high consistency, while several false reactions were detected by serotyping. The deep sequencing method also provides accurate genotyping results and may be useful for analyzing discrepant cases. HCV genotyping should be correctly determined before antiviral treatment.
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http://dx.doi.org/10.3390/ijms18010172DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5297804PMC
January 2017

Drug-Induced Liver Injury Associated with Complementary and Alternative Medicines.

Case Rep Gastroenterol 2016 Sep-Dec;10(3):706-713. Epub 2016 Nov 25.

Department of Gastroenterology and Nephrology, Chiba University, Graduate School of Medicine, Chiba, Japan.

A 24-year-old man was admitted due to acute hepatitis with unknown etiology. After his condition and laboratory data gradually improved with conservative therapy, he was discharged 1 month later. Two months after his discharge, however, liver dysfunction reappeared. After his mother accidentally revealed that he took complementary and alternative medicine, discontinuation of the therapy caused his condition to improve. Finally, he was diagnosed with a recurrent drug-induced liver injury associated with Japanese complementary and alternative medicine. It is important to take the medical history in detail and consider complementary and alternative medicine as a cause of liver disease.
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http://dx.doi.org/10.1159/000452209DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5216216PMC
November 2016