研究者業績

中村 昌人

ナカムラ マサト  (Masato Nakamura)

基本情報

所属
千葉大学 医学部附属病院消化器内科 助教
学位
医学博士(2015年3月 千葉大学)

J-GLOBAL ID
202101013597803050
researchmap会員ID
R000024824

論文

 152
  • Masato Nakamura, Tatsuo Kanda, Xia Jiang, Yuki Haga, Koji Takahashi, Shuang Wu, Shin Yasui, Shingo Nakamoto, Osamu Yokosuka
    PloS one 12(5) e0177302 2017年  
    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.
  • Yuki Haga, Tatsuo Kanda, Reina Sasaki, Masato Nakamura, Koji Takahashi, Shuang Wu, Shin Yasui, Makoto Arai, Shingo Nakamoto, Osamu Yokosuka
    Diseases (Basel, Switzerland) 4(4) 2016年12月14日  
    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.
  • Shin Yasui, Keiichi Fujiwara, Yuuki Haga, Masato Nakamura, Rintaro Mikata, Makoto Arai, Tatsuo Kanda, Shigeto Oda, Osamu Yokosuka
    Journal of hepato-biliary-pancreatic sciences 23(12) 756-762 2016年12月  
    BACKGROUND: Corticosteroid (CS) has been introduced in most acute liver failure (ALF) patients for the purpose of suppressing pro-inflammatory cytokines in Japan where a shortage of donor livers exists, whereas CS use is evaluated to be no benefit in Western countries. In the present study, we aimed to clarify the association between infectious complications and CS use in ALF, and determine when to evaluate treatment response and consider the timing for switching to liver transplantation (LT). METHODS: Corticosteroid was administered to patients in the early stage prospectively. Clinical and biochemical features of 110 adult patients were analyzed. RESULTS: Corticosteroids were administered to 78 (71%) patients. The duration between start of CS and onset of infection was 17 ± 10 days. Multivariate analysis revealed that infection was associated with age >50 years (P = 0.034) and T-BIL >15 mg/dl (P < 0.001), and not with CS use (P = 0.10). Accumulative incidence of infection was not different between patients with and without CS (P = 0.18). CONCLUSIONS: Corticosteroid use did not significantly increase the incidence of infection. Two weeks after introduction of CS is a critical point for evaluating treatment response, avoiding infectious complications and switching to LT.
  • Koji Takahashi, Tatsuo Kanda, Shin Yasui, Yuki Haga, Junichiro Kumagai, Reina Sasaki, Shuang Wu, Shingo Nakamoto, Masato Nakamura, Makoto Arai, Osamu Yokosuka
    Case Reports in Gastroenterology 10(3) 706-713 2016年11月25日  
    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.
  • Yuji Sakai, Toshio Tsuyuguchi, Harutoshi Sugiyama, Masahiro Hayashi, Jun-Ichi Senoo, Reina Sasaki, Yuko Kusakabe, Masato Nakamura, Shin Yasui, Rintaro Mikata, Masaru Miyazaki, Osamu Yokosuka
    World journal of clinical cases 4(8) 213-8 2016年8月16日  
    AIM: To examine whether it is possible to prevent the occurrence of post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis in patients experiencing difficulties with selective biliary duct cannulation by pancreatic duct stenting using a loop-tipped guidewire. METHODS: Procedure success rate, frequency of unintended insertion of the guidewire into side branches of the pancreatic duct, and incidence of procedural accidents were examined using a loop-tipped guidewire (Group A, 20 patients), and a conventional straight-type guidewire (Group B, 20 patients). RESULTS: The success rate of the procedure was 100% in both groups. Unintended insertion of the guidewire into a side branch of the pancreatic duct occurred 0.056 ± 0.23 (0-1) times in Group A and 2.3 ± 1.84 (0-5) times in Group B; thus, unintended insertion of the guidewire into a side branch of the pancreatic duct was seen significantly less frequently in Group A. There were no procedural accidents in Group A, whereas pancreatitis occurred in one Group B patient; however, the difference between the two groups was not statistically significant. The serum amylase level after ERCP was 257.15 ± 136.4 (88-628) IU/L in Group A, and 552.05 ± 534.57 (101-2389) IU/L in Group B, showing a significantly lower value in Group A. Hyperamylasemia was found in two patients (10%) in Group A, and nine (45%) in Group B, showing a significantly lower value in Group A. CONCLUSION: The results suggest that in patients who experience difficulties with biliary cannulation, the use of a loop-tipped guidewire for pancreatic duct stenting may assist with the prevention of post-ERCP pancreatitis, and thereby to a reduction of the risk of post-ERCP pancreatitis or hyperamylasemia.
  • Shuang Wu, Tatsuo Kanda, Shingo Nakamoto, Xia Jiang, Masato Nakamura, Reina Sasaki, Yuki Haga, Hiroshi Shirasawa, Osamu Yokosuka
    International journal of molecular medicine 38(2) 475-81 2016年8月  
    Elevated levels of inflammatory cytokines such as tumor necrosis factor-α (TNF-α) and interleukin (IL)-1β are often observed in the sera of hepatitis B virus (HBV)-infected patients. It is well known that these cytokines activate nuclear factor-κB (NF-κB)-signaling, and are associated with endoplasmic reticulum (ER) stress. We investigated whether HBV or HBV X protein (HBx) enhanced the activation of NF-κB in the presence of TNF and/or IL-1β, and their effects on the expression of metabolic pathway‑associated genes. We examined whether HBV or HBx enhanced cytokine-induced activation of NF-κB in hepatocytes, using a reporter assay, in the presence or absence of TNF and/or IL-1β. The expression of insulin-like growth factor binding protein 1 (IGFBP1), one of the NF-κB target genes was also examined. The expression of metabolic pathway-associated genes in HepG2 and HepG2.2.15 cells in the presence or absence of TNF was evaluated by RT-qPCR. Human hepatocytes expressed TNF receptors and IL-1 receptors. NF-κB was activated by cooperation between HBx and TNF in human hepatocytes. We observed IGFBP1 expression in HBV infection and that a number of metabolic pathway-associated genes were upregulated in HepG2.2.15 cells, compared with HepG2 cells with or without TNF treatment. We observed the cooperative effects of HBV and TNF which enhanced the activation of NF-κB as well as upregulated the expression of metabolic pathway-associated genes in hepatocytes. These effects may be important in the development of HBV-associated metabolic syndrome.
  • Yuki Ohta, Tatsuo Kanda, Tatsuro Katsuno, Shin Yasui, Yuki Haga, Reina Sasaki, Masato Nakamura, Shuang Wu, Shingo Nakamoto, Makoto Arai, Osamu Yokosuka
    BMC gastroenterology 16(1) 66-66 2016年7月11日  
    BACKGROUND: Ulcerative colitis is a lifelong, immunologically mediated disease. Direct-acting antivirals (DAAs) are now available for the treatment of chronic hepatitis C virus (HCV) infection. An interferon-free regimen appears useful, safe and effective for many patients for whom interferon-based treatment is contraindicated. CASE PRESENTATION: We studied a 56-year-old treatment-naïve Japanese man with chronic HCV genotype 2b infection who had ulcerative colitis. This patient was treated with sofosbuvir and ribavirin for 12 weeks. During treatment, diarrhoea and bloody faeces were frequent. After ribavirin was reduced to 400 mg daily, these symptoms decreased. Finally, the patient achieved a sustained virologic response 12 weeks after the stoppage of the treatment. CONCLUSION: Clinicians should pay careful attention to the ribavirin dose in the treatment of certain HCV patients with inflammatory bowel disease who are receiving sofosbuvir plus ribavirin.
  • Junichiro Kumagai, Tatsuo Kanda, Shin Yasui, Yuki Haga, Reina Sasaki, Masato Nakamura, Shuang Wu, Shingo Nakamoto, Makoto Arai, Yotaro Iino, Osamu Yokosuka
    Clinical journal of gastroenterology 9(3) 156-9 2016年6月  
    We describe a case of autoimmune hepatitis (AIH) that may have occurred following drug-induced liver injury with camostat mesilate and/or benzbromarone in an elderly patient. The patient's liver biopsy showed chronic active hepatitis and autoimmune hepatitis. Stopping the use of these drugs did not lead to complete remission, but the use of a low dose of corticosteroids completely cured his liver dysfunction. In the present case, liver dysfunction was caused by an autoimmune mechanism. Special attention should be paid to idiopathic AIH and drug-induced AIH in elderly patients.
  • Kanda T, Yasui S, Nakamura M, Suzuki E, Arai M, Haga Y, Sasaki R, Wu S, Nakamoto S, Imazeki F, Yokosuka O
    Int J Med Sci. 13(6) 418-423 2016年5月12日  査読有り
  • Masato Nakamura, Tatsuo Kanda, Yuki Haga, Reina Sasaki, Shuang Wu, Shingo Nakamoto, Shin Yasui, Makoto Arai, Fumio Imazeki, Osamu Yokosuka
    World journal of hepatology 8(3) 183-90 2016年1月28日  
    Hepatitis C virus (HCV) infection is a serious problem worldwide. The use of interferon-based therapy has made HCV eradication challenging. The recent appearance of direct-acting antiviral agents (DAAs) has changed HCV therapy. Combining the use of DAAs with peginterferon and ribavirin has improved treatment efficacy. Furthermore, the combination of different orally administered DAAs has enabled interferon-free therapy with much higher efficacy and safety. In particular, sofosbuvir, a nucleotide-based NS5B inhibitor, prevents HCV RNA synthesis by acting as a "chain terminator". Treatment with sofosbuvir has attained an extremely high rate of sustained virologic response. The current review summarizes the efficacy and safety of sofosbuvir therapy.
  • Kumagai J, Kanda T, Yasui S, Haga Y, Sasaki R, Nakamura M, Wu S, Nakamoto S, Arai M, Iino Y, Yokosuka O.
    Clin J Gastroenterol. 9(3) 156-159 2016年  査読有り
  • Reina Sasaki, Tatsuo Kanda, Shin Yasui, Yuki Haga, Masato Nakamura, Mutsumi Yamato, Shuang Wu, Shingo Nakamoto, Makoto Arai, Shigeru Mikami, Hideaki Miyauchi, Hisahiro Matsubara, Osamu Yokosuka
    Case Reports in Gastroenterology 10(2) 248-256 2016年  査読有り
    Hepatitis C virus (HCV) infection leads to acute and chronic hepatitis, cirrhosis, and hepatocellular carcinoma. Following kidney transplantation, HCV increases the risk of graft loss and patient mortality compared with uninfected patients. The achievement of a sustained virological response with antiviral therapy improves survival and diminishes the risk of hepatic decompensation in HCV patients after a kidney transplant. It has been reported that direct-acting antivirals (DAAs) are relatively safe and highly effective for the eradication of HCV in patients who are liver transplant recipients. In the present study, we investigated HCV eradication via interferon-free therapies with DAAs in two HCV patients with advanced liver fibrosis following renal transplantation. In both cases, the interferon-free regimens with DAAs were effective in eradicating HCV in the patients after kidney transplantation. No adverse events caused by interferon were identified with the exception of anemia. Interferon-free regimens with DAAs for recurrent HCV in patients following kidney transplantation are relatively safe and effective. However, attention should be focused on anemia during these treatments.
  • Reina Sasaki, Tatsuo Kanda, Masayuki Ohtsuka, Shin Yasui, Yuki Haga, Masato Nakamura, Masayuki Yokoyama, Shuang Wu, Shingo Nakamoto, Makoto Arai, Hitoshi Maruyama, Masaru Miyazaki, Osamu Yokosuka
    Case Reports in Gastroenterology 10(2) 366-372 2016年  査読有り
    Direct-acting antivirals (DAAs) are relatively safe and highly effective for the eradication of hepatitis C virus (HCV) in liver transplant recipients. In this case study, we present a female with a graft reinfected with HCV genotype 2 who was treated with a combination of sofosbuvir and ribavirin after living donor liver transplantation (LDLT). Because the graft was from a hepatitis B core antibody-positive donor, passive immunization with hyperimmune hepatitis B immunoglobulin (HBIG) and entecavir were also provided to prevent hepatitis B virus (HBV) reactivation. It became clear that the combination of sofosbuvir and ribavirin promptly led to a sustained virologic response and that this combination was safe to treat graft reinfection with HCV genotype 2 after LDLT. Adverse events caused by DAAs were not observed, except for slight anemia. HBIG and entecavir were useful in the prevention of HBV reactivation. In conclusion, the present case indicated that DAA treatment for graft reinfection with HCV is safe and effective in LDLT from hepatitis B core antibody-positive donors.
  • Yuki Haga, Shin Yasui, Tatsuo Kanda, Noriyuki Hattori, Toru Wakamatsu, Masato Nakamura, Reina Sasaki, Shuang Wu, Shingo Nakamoto, Makoto Arai, Hitoshi Maruyama, Masayuki Ohtsuka, Shigeto Oda, Masaru Miyazaki, Osamu Yokosuka
    Case Reports in Gastroenterology 10(1) 139-145 2016年  査読有り
    On-line hemodiafiltration (OLHDF) is one of the treatment options in the management of acute liver failure (ALF) in Japan. It is essential to avoid infection in the management of ALF. In fact, infection is one of the prognostic factors in ALF. In this report, we present a middle-aged Japanese man with ALF associated with benzbromarone use. He was successfully managed without infection until liver transplantation by creating an arteriovenous fistula for OLHDF. Utilizing an arteriovenous fistula for OLHDF, rather than inserting a vascular access catheter, is a beneficial option to avoid infectious diseases in the management of ALF.
  • Reina Sasaki, Tatsuo Kanda, Masato Nakamura, Shingo Nakamoto, Yuki Haga, Shuang Wu, Hiroshi Shirasawa, Osamu Yokosuka
    PloS one 11(1) e0146314 2016年  
    BACKGROUND: The induction of apoptosis in hepatic stellate cells (HSCs) is a promising therapeutic strategy against hepatitis B virus (HBV)-related hepatic fibrosis. The underlying mechanisms of apoptosis in HSCs, however, are unknown under consideration of HBV infection. In this study, the effects of HBV on apoptosis and endoplasmic reticulum (ER) stress signaling in HSCs were examined. METHODS: The effects of conditioned media (CM) from HepG2.2.15 on apoptosis induced by the proteasome inhibitor MG132 in LX-2 and HHSteC were studied in regard to c-Jun. In combination with c-Fos, c-Jun forms the AP-1 early response transcription factor, leading to AP-1 activation, signal transduction, endoplasmic reticulum (ER) stress and apoptosis. RESULTS: In LX-2 cells, MG132 treatment was associated with the phosphorylation of c-Jun, activation of AP-1 and apoptosis. However, in the presence of CM from HepG2.2.15, these phenomena were attenuated. In HHSteC cells, similar results were observed. HBV genomic DNA is not involved in the process of HSC apoptosis. It is possible that HBeAg has an inhibitory effect on MG132-induced apoptosis in LX-2. We also observed the upregulation of several ER stress-associated genes, such as cAMP responsive element binding protein 3-like 3, inhibin-beta A and solute carrier family 17-member 2, in the presence of CM from HepG2.2.15, or CM from PXB cells infected with HBV. CONCLUSIONS: HBV inhibits the activation of c-Jun/AP-1 in HSCs, contributing to the attenuation of apoptosis and resulting in hepatic fibrosis. HBV also up-regulated several ER stress genes associated with cell growth and fibrosis. These mechanistic insights might shed new light on a treatment strategy for HBV-associated hepatic fibrosis.
  • Tatsuo Kanda, Shingo Nakamoto, Reina Sasaki, Masato Nakamura, Shin Yasui, Yuki Haga, Sadahisa Ogasawara, Akinobu Tawada, Makoto Arai, Shigeru Mikami, Fumio Imazeki, Osamu Yokosuka
    International journal of medical sciences 13(4) 310-5 2016年  
    BACKGROUND: Direct-acting antiviral agents against HCV with or without peginterferon plus ribavirin result in higher eradication rates of HCV and shorter treatment duration. We examined which is better for predicting persistent virologic response, the assessment of serum HCV RNA at 12 or 24 weeks after the end of treatment for predicting sustained virologic response (SVR12 or SVR24, respectively) in patients treated by HCV NS3/4A protease inhibitors with peginterferon plus ribavirin. METHODS: In all, 149 Japanese patients infected with HCV genotype 1b treated by peginterferon plus ribavirin with telaprevir or simeprevir were retrospectively analyzed: 59 and 90 patients were treated with telaprevir- and simeprevir-including regimens, respectively. HCV RNA was measured by TaqMan HCV Test, version 2.0, real-time PCR assay. SVR12 or SVR24, respectively, was defined as HCV RNA negativity at 12 or 24 weeks after ending treatment. RESULTS: Total SVR rates were 78.0% and 66.7% in the telaprevir and simeprevir groups, respectively. In the telaprevir group, all 46 patients with SVR12 finally achieved SVR24. In the simeprevir group, 60 (93.8%) of the total 64 patients with SVR12 achieved SVR24, with the other 4 patients all being previous-treatment relapsers. CONCLUSIONS: SVR12 was suitable for predicting persistent virologic response in almost all cases. In simeprevir-including regimens, SVR12 could not always predict persistent virologic response. Clinicians should use SVR24 for predicting treatment outcome in the use of HCV NS3/4A protease inhibitors with peginterferon plus ribavirin for any group of real-world patients chronically infected with HCV.
  • Tatsuo Kanda, Shin Yasui, Masato Nakamura, Eiichiro Suzuki, Makoto Arai, Yuki Haga, Reina Sasaki, Shuang Wu, Shingo Nakamoto, Fumio Imazeki, Osamu Yokosuka
    International journal of medical sciences 13(6) 418-23 2016年  
    Background. All-oral combination of direct-acting antivirals could lead to higher sustained virologic response (SVR) in hepatitis C virus (HCV)-infected patients. In the present study, we examined the efficacy and safety of the dual oral treatment with HCV nonstructural protein (NS) 5A inhibitor daclatasvir (DCV) plus HCV NS3/4A inhibitor asunaprevir (ASV) for 24 weeks in real-world HCV genotype 1-infected Japanese individuals. Methods. After screening for HCV NS5A resistance-associated variants (RAVs) by PCR invader assay, a total of 54 Japanese patients infected with HCV genotype 1 treated with DCV plus ASV were retrospectively analyzed. SVR12 was used for evaluation of the virologic response. Results. Of the total 54 patients, 46 patients (85.2%) were treated with DCV plus ASV for 24 weeks and achieved SVR12. The other 8 patients (14.8%) discontinued this treatment before 24 weeks due to adverse events. Of these 8 patients, 5 and 3 patients did and did not achieve SVR12, respectively. Finally, 51 of 54 (94.4%) patients achieved SVR12. Conclusion. Treatment with DCV and ASV after screening for HCV NS5A RAVs by PCR invader assay is effective and safe in the treatment of real-world HCV genotype 1-infected patients in Japan.
  • Yuki Haga, Tatsuo Kanda, Reina Sasaki, Masato Nakamura, Shingo Nakamoto, Osamu Yokosuka
    World journal of gastroenterology 21(46) 12989-95 2015年12月14日  
    Nonalcoholic fatty liver disease (NAFLD) including nonalcoholic steatohepatitis (NASH) is globally increasing and has become a world-wide health problem. Chronic infection with hepatitis B virus or hepatitis C virus (HCV) is associated with hepatic steatosis. Viral hepatitis-associated hepatic steatosis is often caused by metabolic syndrome including obesity, type 2 diabetes mellitus and/or dyslipidemia. It has been reported that HCV genotype 3 exerts direct metabolic effects that lead to hepatic steatosis. In this review, the differences between NAFLD/NASH and viral hepatitis-associated steatosis are discussed.
  • Tatsuo Kanda, Reina Sasaki, Shingo Nakamoto, Yuki Haga, Masato Nakamura, Hiroshi Shirasawa, Hiroaki Okamoto, Osamu Yokosuka
    Biochemical and biophysical research communications 466(3) 567-71 2015年10月23日  
    Epigenetics plays a role in the regulation of gene expression. Epigenetic changes control gene expression at the transcriptional level. Our previous study suggested that the La protein, which is mainly localized in the nucleus, was associated with hepatitis A virus (HAV) internal ribosomal entry site (IRES)-mediated translation and HAV replication. The aim of this study was to investigate whether epigenetic compounds have effects on HAV IRES-mediated translation and HAV replication. Sirtinol, a sirtuin inhibitor, inhibited HAV IRES-mediated translation in COS7-HAV-IRES cells. Treatment with 10 μM sirtinol resulted in a significant reduction in the intracellular RNA levels of HAV HA11-1299 genotype IIIA in Huh7 cells. Epigenetic treatment with a sirtuin inhibitor may represent a new treatment option for HAV infection. In conclusion, epigenetic control was involved in HAV IRES-dependent translation and HAV replication. Special attention should also be paid to underlying viral diseases in the clinical use of epigenetic treatments for malignancies.
  • Yuji Sakai, Toshio Tsuyuguchi, Takao Nishikawa, Harutoshi Sugiyama, Reina Sasaki, Dai Sakamoto, Yuto Watanabe, Masato Nakamura, Shin Yasui, Rintaro Mikata, Osamu Yokosuka
    World journal of clinical cases 3(10) 887-93 2015年10月16日  
    AIM: To examine the usefulness of a new tapered metallic stent (MS) in patients with unresectable malignant hilar bile duct obstruction. METHODS: This new tapered MS was placed in 11 patients with Bismuth II or severer unresectable malignant hilar bile duct obstruction, as a prospective study. The subjects were six patients with bile duct carcinoma, three with gallbladder cancer, and two with metastatic bile duct obstruction. Stenosis morphology was Bismuth II: 7, IIIa: 3, and IV: 1. UMIN Clinical Trial Registry (UMIN000004758). RESULTS: MS placement was 100% (11/11) successful. There were no procedural accidents. The mean patency period was 208.401 d, the median survival period was 142.000 d, and the mean survival period was 193.273 d. Occlusion rate was 36.4% (4/11); the causes of occlusion were ingrowth and overgrowth in 2 patients each, 18.2%, respectively. Patients with occlusion underwent endoscopic treatment one more time and all were treatable. CONCLUSION: The tapered MS proved useful in patients with unresectable malignant hilar bile duct obstruction because it provided a long patency period, enabled re-treatment by re-intervention, and no procedural accidents occurred.
  • Masato Nakamura, Tatsuo Kanda, Shingo Nakamoto, Yuki Haga, Reina Sasaki, Xia Jiang, Shin Yasui, Makoto Arai, Osamu Yokosuka
    Hepatology (Baltimore, Md.) 62(4) 1329-1329 2015年10月  
  • Tatsuo Kanda, Shingo Nakamoto, Shuang Wu, Masato Nakamura, Xia Jiang, Yuki Haga, Reina Sasaki, Osamu Yokosuka
    Journal of clinical and translational hepatology 3(3) 205-10 2015年9月28日  
    Hepatitis A virus (HAV) infection is a major cause of acute hepatitis and occasionally leads to acute liver failure in both developing and developed countries. Although effective vaccines for HAV are available, the development of new antivirals against HAV may be important for the control of HAV infection in developed countries where no universal vaccination program against HAV exists, such as Japan. There are two forms of antiviral agents against HAV: direct-acting antivirals (DAAs) and host-targeting agents (HTAs). Studies using small interfering ribonucleic acid (siRNA) have suggested that the HAV internal ribosomal entry site (IRES) is an attractive target for the control of HAV replication and infection. Among the HTAs, amantadine and interferon-lambda 1 (IL-29) inhibit HAV IRES-mediated translation and HAV replication. Janus kinase (JAK) inhibitors inhibit La protein expression, HAV IRES activity, and HAV replication. Based on this review, both DAAs and HTAs may be needed to control effectively HAV infection, and their use should continue to be explored.
  • Tatsuo Kanda, Shuang Wu, Reina Sasaki, Masato Nakamura, Yuki Haga, Xia Jiang, Shingo Nakamoto, Osamu Yokosuka
    Diseases (Basel, Switzerland) 3(3) 213-220 2015年9月17日  
    Hepatitis B virus (HBV) infection, a cause of hepatocellular carcinoma (HCC), remains a serious global health concern. HCC development and human hepatocarcinogenesis are associated with hepatic inflammation caused by host interferons and cytokines. This article focused on the association between the HBV core protein, which is one of the HBV-encoding proteins, and cytokine production. The HBV core protein induced the production of interferons and cytokines in human hepatoma cells and in a mouse model. These factors may be responsible for persistent HBV infection and hepatocarcinogenesis. Inhibitors of programmed death (PD)-1 and HBV core and therapeutic vaccines including HBV core might be useful for the treatment of patients with chronic HBV infection. Inhibitors of HBV core, which is important for hepatic inflammation, could be helpful in preventing the progression of liver diseases in HBV-infected patients.
  • Shingo Nakamoto, Fumio Imazeki, Makoto Arai, Shin Yasui, Masato Nakamura, Yuki Haga, Reina Sasaki, Tatsuo Kanda, Hiroshi Shirasawa, Osamu Yokosuka
    International journal of molecular sciences 16(9) 21177-90 2015年9月7日  
    We examined whether hepatitis C virus (HCV) genotype 1b core- and NS5A-region mutations are associated with response to peginterferon α-2b plus ribavirin combination therapy. A total of 103 patients with high HCV genotype 1b viral loads (≥ 100 KIU/mL) were treated with the combination therapy. Pretreatment mutations in the core region and interferon sensitivity determining region (ISDR) in the NS5A region were analyzed. In univariate analysis, arginine and leucine at positions 70 and 91 in the core region, defined as double wild (DW)-type, were associated with early virologic response (p = 0.002), sustained virologic response (SVR) (p = 0.004), and non-response (p = 0.005). Non-threonine at position 110 was associated with SVR (p = 0.004). Multivariate analysis showed the following pretreatment predictors of SVR: hemoglobin level ≥ 14 g/dL (odds ratio (OR) 6.2, p = 0.04); platelet count ≥ 14 × 10⁴/mm³ (OR 5.2, p = 0.04); aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ratio < 0.9 (OR 6.17, p = 0.009); DW-type (OR 6.8, p = 0.02); non-threonine at position 110 (OR 14.5, p = 0.03); and ≥ 2 mutations in the ISDR (OR 12.3, p = 0.02). Patients with non-DW-type, non-threonine at position 110, and < 2 ISDR mutations showed significantly lower SVR rates than others (11/45 (24.4%) vs. 27/37 (73.0%), respectively; p < 0.001). SVR can be predicted through core and NS5A region mutations and host factors like hemoglobin, platelet count, and AST/ALT ratio in HCV genotype 1b-infected patients treated with peginterferon and ribavirin combination therapy.
  • Reina Sasaki, Tatsuo Kanda, Shuang Wu, Shingo Nakamoto, Yuki Haga, Xia Jiang, Masato Nakamura, Hiroshi Shirasawa, Osamu Yokosuka
    Biochemical and biophysical research communications 464(4) 1192-1195 2015年9月4日  
    Due to the lack of efficient hepatitis B virus (HBV) infection systems, progress in understanding the role of innate immunity in HBV infection has remained challenging. Here we used human hepatocytes from a humanized severe combined immunodeficiency albumin promoter/enhancer driven-urokinase-type plasminogen activator mouse model for HBV infection. HBV DNA levels in culture medium from these human hepatocytes were 4.8-5.7 log IU/mL between day 16 and day 66 post-infection by HBV genotype C inoculum. HBV surface antigen (HBsAg) was also detected by chemiluminescent immunoassay from day 7 to day 66 post-infection. Western blot analysis revealed that major histocompatibility complex class I-related chain A (MICA), which plays a role in the innate immune system, was induced in HBV-infected human hepatocytes 27 days after infection compared with the uninfected control. MICA was reduced at day 62 and undetectable at day 90. Of interest, MICA expression by human hepatocytes increased after HBV infection and decreased before HBsAg loss. Human hepatocytes derived from chimeric mice with hepatocyte-humanized liver could support HBV genome replication. Further studies of the association between HBV replication and MICA induction should be conducted.
  • Harutoshi Sugiyama, Toshio Tsuyuguchi, Yuji Sakai, Rintaro Mikata, Shin Yasui, Yuto Watanabe, Dai Sakamoto, Masato Nakamura, Reina Sasaki, Jun-Ichi Senoo, Yuko Kusakabe, Masahiro Hayashi, Osamu Yokosuka
    World journal of hepatology 7(18) 2171-6 2015年8月28日  
    Preoperative biliary drainage (PBD) was developed to improve obstructive jaundice, which affects a number of organs and physiological mechanisms in patients waiting for surgery. However, its role in patients who will undergo pancreaticoduodenectomy for biliary obstruction remains controversial. This article aims to review the current status of the use of preoperative drainage for distal biliary obstruction. Relevant articles published from 1980 to 2015 were identified by searching MEDLINE and PubMed using the keywords "PBD", "pancreaticoduodenectomy", and "obstructive jaundice". Additional papers were identified by a manual search of the references from key articles. Current studies have demonstrated that PBD should not be routinely performed because of the postoperative complications. PBD should only be considered in carefully selected patients, particularly in cases where surgery had to be delayed. PBD may be needed in patients with severe jaundice, concomitant cholangitis, or severe malnutrition. The optimal method of biliary drainage has yet to be confirmed. PBD should be performed by endoscopic routes rather than by percutaneous routes to avoid metastatic tumor seeding. Endoscopic stenting or nasobiliary drainage can be selected. Although more expensive, the use of metallic stents remains a viable option to achieve effective drainage without cholangitis and reintervention.
  • Reina Sasaki, Tatsuo Kanda, Shingo Nakamoto, Yuki Haga, Masato Nakamura, Shin Yasui, Xia Jiang, Shuang Wu, Makoto Arai, Osamu Yokosuka
    World journal of hepatology 7(8) 1125-32 2015年5月18日  
    Chronic hepatitis C virus (HCV) infection can cause liver cirrhosis and hepatocellular carcinoma (HCC). Several studies have demonstrated that the eradication of HCV reduces the occurrence of HCC. In Japan, as many people live to an advanced age, HCV-infected patients are also getting older, and the age at HCC diagnosis has also increased. Although older HCV-infected patients have a risk of developing HCC, the treatment response to peginterferon-alpha plus ribavirin therapy is relatively poor in these patients because of drop-out or discontinuation of this treatment due to adverse events. It is established that the mechanism of action between interferon-alpha and interferon-beta is slightly different. Short-term natural interferon-beta monotherapy is effective for patients with acute hepatitis C and patients infected with HCV genotype 2 and low viral loads. Natural interferon-beta plus ribavirin for 48 wk or for 24 wk are also effective for some patients with HCV genotype 1 or HCV genotype 2. Natural interferon-beta plus ribavirin has been used for certain "difficult-to-treat" HCV-infected patients. In the era of direct-acting anti-virals, natural interferon-beta plus ribavirin may be one of the therapeutic options for special groups of HCV-infected patients. In the near future, signal transduction pathways of interferon-beta will inform further directions.
  • Kanda T, Nakamura M, Sasaki R, Yasui S, Nakamoto S, Haga Y, Jiang X, Wu S, Tawada Akinobu, Arai M, Imazeki F, Yokosuka O
    Case reports in gastroenterology 9(2) 215-220 2015年5月1日  査読有り
  • Yuji Sakai, Toshio Tsuyuguchi, Harutoshi Sugiyama, Reina Sasaki, Dai Sakamoto, Masato Nakamura, Yuuto Watanabe, Takao Nishikawa, Shin Yasui, Rintaro Mikata, Osamu Yokosuka
    World journal of clinical cases 3(4) 353-9 2015年4月16日  
    AIM: To investigate whether endoscopic papillary large balloon dilation (EPLBD) can be safety and effectively performed in patients aged ≥ 80 years. METHODS: Lithotomy by EPLBD was conducted in 106 patients with bile duct stones ≥ 13 mm in size or with three or more bile duct stones ≥ 10 mm. The patients were divided into group A (< 80 years) and group B (≥ 80 years). Procedure success rate, number of endoscopic retrograde cholangiopancreatographies (ERCP), and incidence of complications were examined in both groups. RESULTS: Group B tended to include significantly more patients with peripapillary diverticulum, hypertension, hyperlipemia, cerebrovascular disease/dementia, respiratory disease/cardiac disease, and patients administered an anticoagulant or antiplatelet agent (P < 0.05). The success rate of the initial lithotomy was 88.7 (94/106)%. The final lithotomy rate was 100 (106/106)%. Complications due to treatment procedure occurred in 4.72 (5/106)% of the patients. There was no significant difference in procedure success rate, number of ERCP, or incidence of complications between group A and group B. CONCLUSION: EPLBD can be safely performed in elderly patients, the same as in younger patients.
  • Xia Jiang, Tatsuo Kanda, Shingo Nakamoto, Kengo Saito, Masato Nakamura, Shuang Wu, Yuki Haga, Reina Sasaki, Naoya Sakamoto, Hiroshi Shirasawa, Hiroaki Okamoto, Osamu Yokosuka
    Biochemical and biophysical research communications 458(4) 908-12 2015年3月20日  
    The JAK2 inhibitor AZD1480 has been reported to inhibit La protein expression. We previously demonstrated that the inhibition of La expression could inhibit hepatitis A virus (HAV) internal ribosomal entry-site (IRES)-mediated translation and HAV replication in vitro. In this study, we analyzed the effects of AZD1480 on HAV IRES-mediated translation and replication. HAV IRES-mediated translation in COS7-HAV-IRES cells was inhibited by 0.1-1 μM AZD1480, a dosage that did not affect cell viability. Results showed a significant reduction in intracellular HAV HA11-1299 genotype IIIA RNA levels in Huh7 cells treated with AZD1480. Furthermore, AZD1480 inhibited the expression of phosphorylated-(Tyr-705)-signal transducer and activator of transcription 3 (STAT3) and La in Huh7 cells. Therefore, we propose that AZD1480 can inhibit HAV IRES activity and HAV replication through the inhibition of the La protein.
  • Tatsuo Kanda, Shin Yasui, Masato Nakamura, Makoto Arai, Reina Sasaki, Yuki Haga, Shuang Wu, Shingo Nakamoto, Hiroaki Okamoto, Osamu Yokosuka
    Case Reports in Gastroenterology 9(3) 317-326 2015年  査読有り
    Hepatitis E virus (HEV) infection is an emerging health concern in developing and developed countries, such as Japan. Five cases have recently been diagnosed as hepatitis E. Of interest, 3 of them had rheumatoid arthritis (RA), although a previous study demonstrated a lack of association between HEV and RA. One of the other patients developed autoimmune hepatitis and was successfully treated with corticosteroids approximately 150 days after the diagnosis of hepatitis E. In RA patients with liver dysfunction, the presence of HEV infection should be evaluated immediately because these patients are often relatively old. Further investigation of the association between HEV and autoimmune hepatitis is needed.
  • Xia Jiang, Tatsuo Kanda, Shuang Wu, Shingo Nakamoto, Masato Nakamura, Reina Sasaki, Yuki Haga, Takaji Wakita, Hiroshi Shirasawa, Osamu Yokosuka
    PloS one 10(7) e0131973 2015年  
    BACKGROUND: Hepatitis C virus (HCV) infection is one of the major causes of cirrhosis and hepatocellular carcinoma. HCV nonstructural protein 5A (NS5A) is an attractive antiviral target and plays an important role in HCV replication as well as hepatocarcinogenesis. The aim of this study was to assess the effect of HCV NS5A protein in the abrogation of apoptotic cell death induced by the proteasome inhibitor MG132. METHODS: Apoptotic responses to MG132 and the expression of molecules involved in NF-κB signaling pathways in human hepatocytes were investigated with or without the expression of HCV NS5A. RESULTS: HCV NS5A protected HepG2 cells against MG132-induced apoptosis, in line with NF-κB-nuclear translocation. A similar NF-κB-nuclear translocation was observed in Huh7 cells infected with HCV JFH1. In agreement with this, after treatment with MG132, HCV NS5A could elevate the transcription of several NF-κB target genes such as BCL2 and BCLXL to inhibit MG132-induced apoptosis in hepatocytes. HCV HCV NS5A also enhanced phosphorylation of IκBα. Consistent with a conferred prosurvival advantage, HCV NS5A reduced MG132-induced poly(adenosine diphosphate-ribose) polymerase cleavage. CONCLUSIONS: HCV NS5A expression enhances phosphorylation of IκBα, liberates NF-κB for nuclear translocation and downregulates MG132-induced apoptotic pathways in human hepatocytes. It is possible that the disruption of proteasome-associated apoptosis plays a role in the pathogenesis of HCV infection.
  • Masato Nakamura, Tatsuo Kanda, Reina Sasaki, Yuki Haga, Xia Jiang, Shuang Wu, Shingo Nakamoto, Osamu Yokosuka
    PloS one 10(12) e0144295 2015年  
    MicroRNA-122 (miR-122) is one of the most abundant miRs in the liver. Previous studies have demonstrated that miR-122 plays a role in inflammation in the liver and functions in hepatic stellate cells (HSCs), which reside in the space of Disse. Here, we showed that the transient inhibition of PKR-activating protein (PACT) expression, by miR-122 or siRNA targeting of PACT, suppressed the production of proinflammatory cytokines, such as interleukin (IL)-6, monocyte chemoattractant protein-1 (MCP-1) and IL-1β, in human HSC LX-2. Sequence and functional analyses confirmed that miR-122 directly targeted the 3'-untranslated region of PACT. Immunofluorescence analysis revealed that miR-122 blocked NF-κB-nuclear translocation in LX-2 cells. We also showed that conditioned medium from miR-122-transfected LX-2 cells suppressed human monocyte-derived THP-1 cell migration. Taken together, our study indicates that miR-122 may downregulate cytokine production in HSCs and macrophage chemotaxis and that the targeting of miR-122 may have therapeutic potential for preventing the progression of liver diseases.
  • Yuji Sakai, Toshio Tsuyuguchi, Yoshiaki Kawaguchi, Nobuto Hirata, So Nakaji, Katsuya Kitamura, Shigeru Mikami, Tatsuya Fujimoto, Masashi Ijima, Eishin Kurihara, Shuhei Oana, Takayoshi Nishino, Ryo Tamura, Dai Sakamoto, Masato Nakamura, Takao Nishikawa, Harutoshi Sugiyama, Hitoshi Yoshida, Tetsuya Mine, Osamu Yokosuka
    World journal of gastroenterology 20(45) 17148-54 2014年12月7日  
    AIM: To investigate the efficacy and outcomes of endoscopic papillary large balloon dilation (EPLBD) for bile duct stones in a multicenter prospective study. METHODS: Lithotomy by EPLBD was conducted in 124 patients with bile duct stones ≥ 13 mm in size or with three or more bile duct stones ≥ 10 mm. After endoscopic sphincterotomy, the papilla was dilated using balloons 12-20 mm in diameter fitting the bile duct diameter. RESULTS: The success rate of first-time lithotomy was 86.3% (107/124) and the final lithotomy success rate was 100% (124/124). Lithotripsy was needed in 10 of the 124 (13.6%) patients. Adverse events due to the treatment procedure occurred in 6 (4.8%) patients, all of which were mild. Performing large balloon dilation after endoscopic sphincterotomy in patients with large stones or multiple stones in the bile duct is considered to ensure the safety of treatment and to reduce the need for lithotripsy. CONCLUSION: It is suggested that treatment by EPLBD for large bile duct stones may be safe and useful.
  • Xia Jiang, Tatsuo Kanda, Shingo Nakamoto, Yuki Haga, Reina Sasaki, Masato Nakamura, Shuang Wu, Rintaro Mikata, Osamu Yokosuka
    Oncology reports 32(6) 2343-8 2014年12月  
    The present study examined the expression of glucose‑regulated protein 78 (GRP78/Bip) in human pancreatic cancer cell lines and the effect of knockdown of GRP78 on the cleavage of poly(ADP-ribose) polymerase (PARP). Human pancreatic cancer cell lines (KP-2, MIAPaCa-2, Panc-1 and SUIT-2), constitutively expressed GRP78. We also demonstrated that ER stress induced by thapsigargin upregulated protein levels of GRP78. In the presence of thapsigargin, knockdown of GRP78 enhanced the PARP cleavage in the human pancreatic cancer cells. These results provide evidence that GRP78 is a potential therapeutic target for 'difficult-to-treat' pancreatic cancer, in which ER stress signaling in part falls into disorder.
  • Toshio Tsuyuguchi, Kaoru Miyakawa, Harutoshi Sugiyama, Yuji Sakai, Takao Nishikawa, Dai Sakamoto, Masato Nakamura, Shin Yasui, Rintaro Mikata, Osamu Yokosuka
    Journal of hepato-biliary-pancreatic sciences 21(11) 795-800 2014年11月  
    BACKGROUND: Long-term follow-up of non-surgical procedures for the management of hepatolithiasis has been reported, but risk factors for mortality have not been properly evaluated. METHODS: We conducted a retrospective study of the case records of 121 patients with hepatolithiasis who underwent endoscopic retrograde cholangiopancreatography (ERCP), peroral cholangioscopy (POCS), percutaneous transhepatic cholangioscopy (PTCS), or conservative treatment at the Department of Gastroenterology of Chiba University Hospital between January 1980 and July 2011. The primary outcome measure was mortality, defined as death due to hepatolithiasis (concomitant liver failure with cholangitis and cholangiocarcinoma). RESULTS: Complete clearance of intrahepatic stones was achieved in 22 (57.8%) of 38 patients by POCS, in 12 (66.7%) of 18 patients by ERCP, and in 10 (52.6%) of 18 patients by PTCS. The remaining 46 patients were treated conservatively. The mean follow-up period was 11.4 ± 7.1 years (range, 0.6-32.8). There were 14 hepatolithiasis-related deaths (11 with cholangiocarcinoma and three from liver failure with cholangitis) during the follow-up periods. Multivariate Cox proportional hazards analysis revealed liver atrophy (P = 0.015; HR = 3.98; 95% CI, 1.30-12.20) and congenital biliary dilatation after biliary-enteric anastomosis (P = 0.036; HR = 4.57; 95% CI, 1.11-18.87) as significant risk factors for mortality. CONCLUSIONS: Analysis of the 10-year long-term results after non-surgical management of hepatolithiasis identified liver atrophy and congenital biliary dilatation as risk factors for mortality. Patients with hepatic lobe atrophy should undergo a hepatectomy, if operable.
  • Takao Nishikawa, Toshio Tsuyuguchi, Hiroshi Ohyama, Yuto Watanabe, Hirotaka Koseki, Yuji Sakai, Harutoshi Sugiyama, Dai Sakamoto, Soichiro Kiyono, Masato Nakamura, Osamu Yokosuka
    Gastrointestinal endoscopy 80(4) 729-730 2014年10月  
  • Takao Nishikawa, Toshio Tsuyuguchi, Yuji Sakai, Harutoshi Sugiyama, Dai Sakamoto, Masato Nakamura, Osamu Yokosuka
    Digestive endoscopy : official journal of the Japan Gastroenterological Endoscopy Society 26(4) 569-76 2014年7月  
    BACKGROUND AND AIM: Various techniques are required in endoscopic biliary stone removal. Because the presence of biliary stones is a benign disease, it is essential to minimize procedure-related complications. Having a sound knowledge of the risk factors can help reduce the number and severity of complications. We determined the risk factors for complications in patients undergoing endoscopic biliary stone removal. METHODS: This was a retrospective observational cohort study. We analyzed 743 consecutive patients with biliary stones who were treated with endoscopic retrograde cholangiopancreatography and identified the independent risk factors for complications. RESULTS: Complications occurred in 66 patients (8.9%). Pancreatitis occurred in 26 patients (3.5%), cholangitis in 16 (2.2%), bleeding in 12 (1.6%) and other in 12 (1.6%). Independent risk factors for overall complications were multiple biliary stones (P = 0.0480) and anti-thrombotic drugs (P = 0.0186).Independent risk factors for moderate or severe complications were old age (P = 0.0201), multiple biliary stones (P = 0.0300), anti-thrombotic drugs (P = 0.0131), and cirrhosis of the liver (P = 0.0013). The respective risk factors for pancreatitis, cholangitis, and bleeding were precut technique (P = 0.0005), endoscopic mechanical lithotripsy (P = 0.0421), and both anti-thrombotic drugs (P = 0.0228) and cirrhosis of the liver (P = 0.0115). CONCLUSIONS: Old age was associated with a similar complication rate to younger age but increased the severity of complications following endoscopic biliary stone removal. Improved awareness of the severity of complications may be of benefit during periprocedural management. Further studies are warranted.
  • Xia Jiang, Tatsuo Kanda, Shuang Wu, Masato Nakamura, Tatsuo Miyamura, Shingo Nakamoto, Arup Banerjee, Osamu Yokosuka
    World journal of gastroenterology 20(23) 7197-206 2014年6月21日  
    Hepatitis B virus (HBV) chronically infects more than 350 million people worldwide. HBV causes acute and chronic hepatitis, and is one of the major causes of cirrhosis and hepatocellular carcinoma. There exist complex interactions between HBV and the immune system including adaptive and innate immunity. Toll-like receptors (TLRs) and TLR-signaling pathways are important parts of the innate immune response in HBV infections. It is well known that TLR-ligands could suppress HBV replication and that TLRs play important roles in anti-viral defense. Previous immunological studies demonstrated that HBV e antigen (HBeAg) is more efficient at eliciting T-cell tolerance, including production of specific cytokines IL-2 and interferon gamma, than HBV core antigen. HBeAg downregulates cytokine production in hepatocytes by the inhibition of MAPK or NF-κB activation through the interaction with receptor-interacting serine/threonine protein kinase. MicroRNAs (miRNAs) are also able to regulate various biological processes such as the innate immune response. When the expressions of approximately 1000 miRNAs were compared between human hepatoma cells HepG2 and HepG2.2.15, which could produce HBV virion that infects chimpanzees, using real-time RT-PCR, we observed several different expression levels in miRNAs related to TLRs. Although we and others have shown that HBV modulates the host immune response, several of the miRNAs seem to be involved in the TLR signaling pathways. The possibility that alteration of these miRNAs during HBV infection might play a critical role in innate immunity against HBV infection should be considered. This article is intended to comprehensively review the association between HBV and innate immunity, and to discuss the role of miRNAs in the innate immune response to HBV infection.
  • Tatsuo Kanda, Shingo Nakamoto, Shin Yasui, Masato Nakamura, Tatsuo Miyamura, Shuang Wu, Xia Jiang, Makoto Arai, Fumio Imazeki, Osamu Yokosuka
    Case reports in oncology 7(2) 288-96 2014年5月  
    The use of phlebotomy is relatively common for 'difficult-to-treat by antiviral therapies' hepatitis C virus (HCV)-infected patients and for certain patients having chronic liver diseases with an iron overload of the liver. In the present study, we retrospectively analyzed patients treated with phlebotomy and their adverse events. We observed the occurrence and recurrence of hepatocellular carcinoma, and the appearance of ascites in some patients infected with HCV as well as the reduction of serum ferritin and alanine aminotransferase levels. Severe adverse events necessitating a cessation of phlebotomy occurred independently of α-fetoprotein (>10 ng/ml) in patients infected with HCV according to multivariate logistic regression analysis. These findings may serve as a basis for phlebotomy especially in older patients with chronic hepatitis C.
  • Tatsuo Kanda, Shingo Nakamoto, Masato Nakamura, Xia Jiang, Tatsuo Miyamura, Shuang Wu, Osamu Yokosuka
    Journal of clinical and translational hepatology 2(1) 1-6 2014年3月  
    Hepatitis C virus (HCV) is a leading cause of cirrhosis and hepatocellular carcinoma (HCC) in the US and Japan. Therefore, eradication of HCV may reduce the occurrence of HCC in HCV-infected individuals. In 2011, the use of first-generation HCV NS3/4A protease inhibitors such as telaprevir and boceprevir was initiated for clinical treatment of HCV. Administration of telaprevir and boceprevir plus peginterferon and ribavirin increased rates of sustained virological response (SVR) in HCV genotype 1-infected patients. However, this treatment regimen also led to severe adverse events. Second-generation direct-acting antiviral agents (DAAs) for HCV, such as simeprevir plus peg-interferon and ribavirin also resulted in higher SVR rates, with similar adverse events to other peg-interferon and ribavirin treatments. Higher SVR rates in HCV genotype 1- and 2-infected patients were achieved with 12-16 weeks of sofosbuvir plus other class DAAs with/without ribavirin and 12 weeks of sofosbuvir plus ribavirin, respectively. For "difficult-to-treat" HCV-infected patients, more therapeutic options are needed. Further studies examining the efficacy and adverse effects of such therapies will be required for the development of additional treatments.
  • Mutsumi Yamato, Tatsuo Kanda, Shin Yasui, Masato Nakamura, Tatsuo Miyamura, Makoto Arai, Hitoshi Maruyama, Osamu Yokosuka
    Nihon Shokakibyo Gakkai zasshi = The Japanese journal of gastro-enterology 111(2) 318-25 2014年2月  
    Nocardia infection is a fatal complication in compromised hosts and is often associated with a poor prognosis. Here we report the case of a 42-year-old man with acute liver injury treated with steroids who developed pulmonary nocardiosis. Pulmonary computed tomography was performed followed by bronchoscopy, which confirmed the diagnosis of pulmonary nocardiosis. This facilitated expedient and successful treatment of the pulmonary infection. Computed tomography is a useful tool for screening respiratory tract infection in immunocompromised patients, such as those with acute liver injury.
  • 大和 睦実, 神田 達郎, 安井 伸, 中村 昌人, 宮村 達雄, 新井 誠人, 丸山 紀史, 横須賀 收
    日本消化機病學會雜誌. 乙 111(2) 318-325 2014年  
    42歳,男性.前医により原因不明の肝障害に対しステロイド加療が開始された.当科転入院後,胸部CTを含む諸検査から急性肝障害の治療にともなう肺ノカルジア症と診断した.肝機能低下およびステロイド投与による免疫抑制状態であったことが一因と考えられた.急性肝障害の加療中に肺ノカルジア症を合併した報告はまれであり,胸部CT検査によるスクリーニングの有用性を示す症例と考えられた.<br>
  • Shuang Wu, Shingo Nakamoto, Tatsuo Kanda, Xia Jiang, Masato Nakamura, Tatsuo Miyamura, Hiroshi Shirasawa, Nobuyuki Sugiura, Azusa Takahashi-Nakaguchi, Tohru Gonoi, Osamu Yokosuka
    International journal of medical sciences 11(1) 60-4 2014年  
    Hepatitis A virus (HAV) is a causative agent of acute viral hepatitis for which an effective vaccine has been developed. Here we describe ultra-deep pyrosequences (UDPSs) of HAV 5'-untranslated region (5'UTR) among cases of the same outbreak, which arose from a single source, associated with a revolving sushi bar. We determined the reference sequence from HAV-derived clone from an attendant by the Sanger method. Sixteen UDPSs from this outbreak and one from another sporadic case were compared with this reference. Nucleotide errors yielded a UDPS error rate of < 1%. This study confirmed that nucleotide substitutions of this region are transition mutations in outbreak cases, that insertion was observed only in non-severe cases, and that these nucleotide substitutions were different from those of the sporadic case. Analysis of UDPSs detected low-prevalence HAV variations in 5'UTR, but no specific mutations associated with severity in these outbreak cases. To our surprise, HAV strains in this outbreak conserved HAV IRES sequence even if we performed analysis of UDPSs. UDPS analysis of HAV 5'UTR gave us no association between the disease severity of hepatitis A and HAV 5'UTR substitutions. It might be more interesting to perform ultra-deep sequencing of full length HAV genome in order to reveal possible unknown genomic determinants associated with disease severity. Further studies will be needed.
  • Masahiro Hayashi, Tatsuo Kanda, Masato Nakamura, Tatsuo Miyamura, Shin Yasui, Shingo Nakamoto, Shuang Wu, Makoto Arai, Fumio Imazeki, Osamu Yokosuka
    Case reports in gastroenterology 8(1) 129-33 2014年1月  
    Some patients with alcohol dependence may initially present with atypical laboratory and histological features resembling autoimmune hepatitis (AIH) or drug-induced liver injury (DILI). Even with liver biopsy, it may be difficult to diagnose certain patients with alcohol dependence. However, careful follow-up of our patient and consultations with the attending psychiatrist were successful in diagnosing alcohol dependence and its liver injury. The immune mechanisms of alcoholic liver diseases, AIH and DILI may be overlapping. Certain patients are suffering from AIH with flares on a background of alcohol abuse. Certain patients with alcohol abuse may have a past history of DILI. This might be consistent with the fact that alcohol dependence initially presents with atypical laboratory features of AIH or DILI. With careful observation, the clinician should remind himself that alcohol dependence is not always required for developing liver disease, since many patients with liver disease do not meet the criteria for alcohol dependence.
  • Tatsuo Miyamura, Tatsuo Kanda, Shingo Nakamoto, Makoto Arai, Masato Nakamura, Shuang Wu, Xia Jiang, Reina Sasaki, Yuki Haga, Shin Yasui, Yoshihiko Ooka, Tetsuhiro Chiba, Fumio Imazeki, Shigeru Mikami, Osamu Yokosuka
    International journal of hepatology 2014 723868-723868 2014年  
    Aim. Eradication of hepatitis C virus (HCV) is still challenging even if interferon- (IFN-) free regimens with direct-acting antiviral agents (DAAs) for HCV-infected individuals are available in clinical practice. IFNL4 is a newly described protein, associated with human antiviral defenses. We investigated whether IFNL4 ss469415590 variant has an effect on the prediction of treatment response in HCV-infected patients treated with IFN-including regimens. Patients and Methods. In all, 185 patients infected with HCV genotype 1 treated with peg-IFN plus ribavirin, with or without telaprevir, were genotyped for IFNL4 ss469415590. We retrospectively investigated whether the role of IFNL4 ss469415590 variant and other factors could predict sustained virological response (SVR) in Japanese patients infected with HCV genotype 1. Results. There were 65.7%, 31.5%, and 2.8% patients in the IFNL4 ss469415590 TT/TT, TT/-G, and -G/-G groups, respectively. SVR rates were 82.1% or 49.3% in patients treated with peg-IFN plus ribavirin with or without telaprevir, respectively. IFNL4 ss469415590 variant and HCV viral loads or IFNL4 ss469415590 variant and early virological response were better predictors of SVR in patients treated with peg-IFN plus ribavirin with or without telaprevir, respectively. Conclusion. In the era of DAAs, measurement of IFNL4 ss469415590 variant could help the prediction of SVR in Japanese HCV genotype 1 infected individuals treated with IFN-including regimens.
  • Tatsuo Miyamura, Tatsuo Kanda, Masato Nakamura, Xia Jiang, Shuang Wu, Shingo Nakamoto, Shigeru Mikami, Nobuo Takada, Fumio Imazeki, Osamu Yokosuka
    World journal of hepatology 5(11) 635-41 2013年11月27日  
    AIM: To examine the association between the interleukin 28B (IL-28B) genotype and treatment response in hepatitis C virus (HCV)-infected patients with persistently normal alanine aminotransferase (PNALT). METHODS: We compared the treatment response of HCV-infected patients with PNALT to that of patients with non-PNALT. Between February 2010 and April 2013, 278 patients infected with HCV were enrolled in this study. All of the patients were treated with peginterferon-alpha 2a or 2b plus ribavirin. In addition, 180 μg of peginterferon alpha-2a or 1.5 μg/kg peginterferon alpha-2b per week plus weight-based ribavirin (600-1000 mg/d) were typically administered for 24 wk to HCV genotype 2-infected patients or for 48-72 wk to HCV genotype 1-infected patients. In all of the patients, the IL-28B rs8099917 genotype was determined using a TaqMan single-nucleotide polymorphism assay. HCV RNA was measured using the COBAS TaqMan HCV test. RESULTS: Female patients were dominant in the PNALT group (P < 0.0001). Among 72 HCV genotype 1-infected patients with PNALT, the early virologic response (EVR) rates (P < 0.01) and the sustained virologic response (SVR) rates (P < 0.01) were higher in patients with the IL-28B TT genotype than in those with the IL-28B TG/GG genotype. In HCV genotype 1-infected patients with PNALT, multivariate logistic-regression analysis showed that SVR was independently predicted by the IL-28B rs8099917 TT type (P < 0.05) and having an EVR (P < 0.01). The IL-28B rs8099917 TT genotype strongly correlated with treatment response in HCV genotype 1-infected Asian patients with PNALT. CONCLUSION: The IL-28B genotype may be useful for selecting HCV genotype 1-infected patients with PNALT who should receive interferon-based treatment.
  • Tatsuo Kanda, Xia Jiang, Shingo Nakamoto, Masato Nakamura, Tatsuo Miyamura, Shuang Wu, Osamu Yokosuka
    Cytokine 64(2) 577-83 2013年11月  
    IFNL1 (IL29), IFNL2 (IL28A) and IFNL3 (IL28B) might play important roles in anti-viral defense. IFNL3 genotypes have been shown to be associated with hepatitis C spontaneous and treatment-induced viral clearance. The effects of IFNL1, IFNL2 and IFNL3 on innate immunity including Toll-like receptor (TLR)-related pathway in human hepatocytes were examined. After G418 screening, we established the human hepatoma stable cell lines HepG2-IL28A, HepG2-IL28B, and HepG2-IL29, expressing IFNL2, IFNL3, and IFNL1 in conditioned medium, respectively, and a control cell line, HepG2-pcDNA3.1. We performed real-time RT-PCR to investigate 84 Toll-like receptor-related gene expressions in triplicate and, using ddCt methods, compared these gene expressions in each cell line. IFNL2, IFNL3 and IFNL1 were respectively detected by ELISA in HepG2-IL28A, HepG2-IL28B and HepG2-IL29. Compared to HepG2-pcDNA3.1 cells, 17 (20.2%), 11 (13.0%) and 16 genes (19.0%) were up-regulated 1.5-fold or more (p<0.05); 10 (11.9%), 2 (2.3%) and 10 genes (11.9%) were 1.5-fold or more down-regulated (p<0.05) in HepG2-IL28A, HepG2-IL28B and HepG2-IL29, respectively. EIF2AK2 and SARM1 were up-regulated among all cells. Of interest, TLR3, TLR4 and related molecules CXCL10 (IP10), IL6, EIF2K2, IFNB1, and IRF1, important genes in the progression of HCV-related pathogenesis and antiviral activities against HCV, in HepG2-IL28B, presented different profiles from those of HepG2-IL28A and HepG2-IL29. IFNL3 induces interferon-stimulated genes (ISGs) that are reportedly associated with the progression of HCV-related pathogenesis and antiviral activities against HCV. IFNL is a powerful modulator of innate immune response and it is supposed that the 3 IFNLs may play different roles in the antiviral activity against HBV and HCV.
  • Tatsuo Miyamura, Tatsuo Kanda, Shoko Minemura, Masato Nakamura, Shingo Nakamoto, Xia Jiang, Shuang Wu, Shin Yasui, Makoto Arai, Osamu Yokosuka
    Case reports in gastroenterology 7(2) 240-4 2013年5月  
    It seems appropriate to use propylthiouracil to treat maternal hyperthyroidism during the first trimester of pregnancy. We present the case of a 26-year-old woman with acute liver failure associated with propylthiouracil during the first trimester of pregnancy. She was successfully treated without liver transplantation. Attention should be paid to the possible occurrence of propylthiouracil-induced hepatotoxicity even during the first trimester of pregnancy.
  • Masato Nakamura, Tatsuo Kanda, Tatsuo Miyamura, Shuang Wu, Shingo Nakamoto, Osamu Yokosuka
    International journal of medical sciences 10(8) 1015-21 2013年  
    Alanine aminotransferase (ALT) elevation was occassionally observed during the treatment with combination peginterferon alpha plus ribavirin. Two forms of peginterferon are currently available as a standard of care with or without direct-acting antivirals against hepatitis C virus (HCV). Until the appearance of interferon-sparing regimen, peginterferon alpha plus ribavirin will play a central role in the eradication of HCV. In the present study, we compared ALT elevations in response to peginterferon alpha-2a plus ribavirin or peginterferon alpha-2b plus ribavirin in HCV genotype-1-infected patients. There were no significant differences in ALT elevations between treatments with the two peginterferons, but in a comparison of the proportions of patients with transient ALT elevation from baseline between the two groups, transient ALT elevation was observed more in sustained virological response (SVR) patients treated with peginterferon alpha-2a than with peginterferon alpha-2b. However, no patients discontinued treatment due to ALT elevation. Patients with transient ALT elevation from baseline during the treatment had less favorable IL28B rs8099917 genotype in the peginterferon alpha-2b group. Patients achieving SVR tended to have lower ALT levels, although some had persistent ALT elevation during treatment. In conclusion, clinicians should pay attention to possible ALT elevation during the treatment of chronic hepatitis C patients.

MISC

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共同研究・競争的資金等の研究課題

 2