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The envelope of hepatitis B virus (HBV), which is required for the entry to hepatocytes, consists of a lipid bilayer derived from hepatocyte and HBV envelope proteins, large/middle/small hepatitis B surface antigen (L/M/SHBs). The mechanisms and host factors for the envelope formation in the hepatocytes are being revealed. HBV-infected hepatocytes release a large amount of subviral particles (SVPs) containing L/M/SHBs that facilitate escape from the immune system. Recently, novel drugs inhibiting the functions of the viral envelope and those inhibiting the release of SVPs have been reported. LHBs that accumulate in ER is considered to promote carcinogenesis and, especially, deletion mutants in the preS1/S2 domain have been reported to be associated with the development of hepatocellular carcinoma (HCC). In this review, we summarize recent reports on the findings regarding the biological characteristics of HBV envelope proteins, their involvement in HCC development and new agents targeting the envelope.
Jun Inoue; Kosuke Sato; Masashi Ninomiya; Atsushi Masamune. Envelope Proteins of Hepatitis B Virus: Molecular Biology and Involvement in Carcinogenesis. Viruses 2021, 13, 1124 .
AMA StyleJun Inoue, Kosuke Sato, Masashi Ninomiya, Atsushi Masamune. Envelope Proteins of Hepatitis B Virus: Molecular Biology and Involvement in Carcinogenesis. Viruses. 2021; 13 (6):1124.
Chicago/Turabian StyleJun Inoue; Kosuke Sato; Masashi Ninomiya; Atsushi Masamune. 2021. "Envelope Proteins of Hepatitis B Virus: Molecular Biology and Involvement in Carcinogenesis." Viruses 13, no. 6: 1124.
Hepatitis C virus reactivation (HCVr) was defined previously as an increase in HCV RNA level of ≥ 1 log10 IU/mL from baseline HCV RNA level after chemotherapies or immunosuppressive therapies, but HCVr during a steroid monotherapy has rarely been reported. Here we report a 75-year-old Japanese female with chronic hepatitis C (genotype 2a) who developed HCVr after the administration of prednisolone for interstitial pneumonia. She experienced alanine aminotransferase (ALT) flare with icterus, but after the tapering of prednisolone and a liver supporting therapy, levels of HCV RNA and ALT were gradually decreased. Then, she received an anti-viral therapy with sofosbuvir/ledipasvir. Although HCV relapsed 4 weeks after the therapy, a second therapy with glecaprevir/pibrentasvir was successful. This case suggests that HCVr with hepatitis flare can occur even after a steroid monotherapy, and we should pay attention to HCVr when we administer prednisolone for patients with HCV chronic infection.
Kosuke Sato; Jun Inoue; Eiji Kakazu; Masashi Ninomiya; Tomoaki Iwata; Akitoshi Sano; Mio Tsuruoka; Atsushi Masamune. Reactivation of hepatitis C virus with severe hepatitis flare during steroid administration for interstitial pneumonia. Clinical Journal of Gastroenterology 2021, 1 -6.
AMA StyleKosuke Sato, Jun Inoue, Eiji Kakazu, Masashi Ninomiya, Tomoaki Iwata, Akitoshi Sano, Mio Tsuruoka, Atsushi Masamune. Reactivation of hepatitis C virus with severe hepatitis flare during steroid administration for interstitial pneumonia. Clinical Journal of Gastroenterology. 2021; ():1-6.
Chicago/Turabian StyleKosuke Sato; Jun Inoue; Eiji Kakazu; Masashi Ninomiya; Tomoaki Iwata; Akitoshi Sano; Mio Tsuruoka; Atsushi Masamune. 2021. "Reactivation of hepatitis C virus with severe hepatitis flare during steroid administration for interstitial pneumonia." Clinical Journal of Gastroenterology , no. : 1-6.
Currently, the hepatocellular trafficking pathways that are used by the hepatitis B virus (HBV) during viral infection and shedding are poorly defined. It is known that the HBV uses late endosomal and multivesicular body (MVB) compartments for assembly and release. The intraluminal vesicles (ILVs) generated within MVBs have also been implicated in the late synthesis stages of a variety of pathogenic viruses. We recently observed that the HBV within infected hepatocytes appears to associate with the tetraspanin protein CD63, known to be a prominent and essential component of ILVs. Immunofluorescence microscopy of HBV‐expressing cells showed that CD63 colocalized with HBV proteins (large hepatitis B surface antigens [LHBs] and hepatitis B core) and labeled an exceptionally large number of secreted extracellular vesicles of uniform size. Small interfering RNA (siRNA)–mediated depletion of CD63 induced a substantial accumulation of intracellular LHBs protein but did not alter the levels of either intracellular or extracellular HBV DNA, nor pregenomic RNA. Consistent with these findings, we found that markedly less LHBs protein was associated with the released HBV particles from CD63 siRNA‐treated cells. Importantly, the HBV viral particles that were shed from CD63‐depleted cells were substantially less infective than those collected from control cells with normal CD63 levels. Conclusion: These findings implicate the tetraspanin protein CD63 as a marker and an important component in the formation and release of infectious HBV particles.
Masashi Ninomiya; Jun Inoue; Eugene W. Krueger; Jing Chen; Hong Cao; Atsushi Masamune; Mark A. McNiven. The Exosome‐Associated Tetraspanin CD63 Contributes to the Efficient Assembly and Infectivity of the Hepatitis B Virus. Hepatology Communications 2021, 5, 1238 -1251.
AMA StyleMasashi Ninomiya, Jun Inoue, Eugene W. Krueger, Jing Chen, Hong Cao, Atsushi Masamune, Mark A. McNiven. The Exosome‐Associated Tetraspanin CD63 Contributes to the Efficient Assembly and Infectivity of the Hepatitis B Virus. Hepatology Communications. 2021; 5 (7):1238-1251.
Chicago/Turabian StyleMasashi Ninomiya; Jun Inoue; Eugene W. Krueger; Jing Chen; Hong Cao; Atsushi Masamune; Mark A. McNiven. 2021. "The Exosome‐Associated Tetraspanin CD63 Contributes to the Efficient Assembly and Infectivity of the Hepatitis B Virus." Hepatology Communications 5, no. 7: 1238-1251.
Hepatitis C virus (HCV) infection has an adverse impact on outcomes after allogeneic hematopoietic stem cell transplantation (HSCT). It is recommended that HSCT candidates infected with HCV receive the treatment prior to transplantation. Although the recent approval of direct-acting antivirals (DAAs) has led to great advances in the treatment of HCV infection, little information is available on the efficacy and safety of DAA therapy in patients receiving allogeneic HSCT. Herein, we report the clinical course of an umbilical cord blood (UCB) recipient treated with DAAs for HCV infection. The patient achieved HCV RNA negativity with glecaprevir and pibrentasvir after consolidation therapy for acute myeloid leukemia (AML), and underwent transplantation before confirming sustained virological response (SVR) at 12 weeks. The HCV viral load became detectable on day +28 after transplantation and second HCV treatment with sofosbuvir, velpatasvir, and ribavirin was required. It is important to confirm SVR prior to transplantation, but it is often difficult. If early transplantation is required, close monitoring of HCV RNA after transplantation is needed. Further investigation is required to clarify the optimal management of HCV infection for allogeneic HSCT recipients in the DAA era.
Koichi Onodera; Yasushi Onishi; Jun Inoue; Yuya Tanaka; Lee Yonha; Satoshi Ichikawa; Noriko Fukuhara; Hisayuki Yokoyama; Kazunori Murai; Atsushi Masamune; Hideo Harigae. Second direct-acting antiviral therapy for hepatitis C virus infection after umbilical cord blood transplantation: A case report. Journal of Infection and Chemotherapy 2021, 27, 1230 -1233.
AMA StyleKoichi Onodera, Yasushi Onishi, Jun Inoue, Yuya Tanaka, Lee Yonha, Satoshi Ichikawa, Noriko Fukuhara, Hisayuki Yokoyama, Kazunori Murai, Atsushi Masamune, Hideo Harigae. Second direct-acting antiviral therapy for hepatitis C virus infection after umbilical cord blood transplantation: A case report. Journal of Infection and Chemotherapy. 2021; 27 (8):1230-1233.
Chicago/Turabian StyleKoichi Onodera; Yasushi Onishi; Jun Inoue; Yuya Tanaka; Lee Yonha; Satoshi Ichikawa; Noriko Fukuhara; Hisayuki Yokoyama; Kazunori Murai; Atsushi Masamune; Hideo Harigae. 2021. "Second direct-acting antiviral therapy for hepatitis C virus infection after umbilical cord blood transplantation: A case report." Journal of Infection and Chemotherapy 27, no. 8: 1230-1233.
Reactivation of hepatitis B virus (HBV) is known to occur frequently after hematopoietic stem cell transplantation (HSCT). The reactivation can be prevented by nucleos(t)ide analogue (NA), but it is unclear how long NA should be continued. Here, we report 3 cases of HBV reactivation with discontinuation of NA following the discontinuation of immunosuppressive therapies after HSCT. Three male patients aged 34, 59, and 54 years received allogeneic HSCT (allo-HSCT) for chronic myeloid leukemia, mixed phenotype acute leukemia, and myelodysplastic syndrome, respectively. Before HSCT, 2 patients were positive for hepatitis B surface antigen (HBsAg) and 1 patient was negative for HBsAg and positive for antibodies to hepatitis B core antigen. NA (lamivudine or entecavir) was started at the same time as HSCT and stopped after the discontinuation of immunosuppressive therapies. In all patients, the serum HBV DNA levels were increased after the discontinuation of NAs. Two of the three patients developed severe hepatitis with high levels of HBV DNA (7.5 and 7.4 log IU/mL, respectively). A patient without hepatitis was re-administered NA soon after the HBV DNA started to increase (3.3 log IU/mL). Interestingly, the 2 patients who developed hepatitis cleared HBsAg promptly after the recovery from hepatitis and they could stop NAs without the reversion of HBsAg. It was speculated that transplanted immune cells, which were naïve for HBV, react strongly with HBV antigens that were increased after the NA discontinuation. The discontinuation of NA after allo-HSCT is not recommended generally because strong hepatitis might be induced even after several years.
Mio Tsuruoka; Jun Inoue; Yasushi Onishi; Masashi Ninomiya; Eiji Kakazu; Tomoaki Iwata; Akitoshi Sano; Kosuke Sato; Hideo Harigae; Atsushi Masamune. Hepatitis B Virus Reactivation with Discontinuation of Nucleoside Analogue in Patients Who Received Allogeneic Hematopoietic Stem Cell Transplantation. Case Reports in Gastroenterology 2021, 15, 178 -187.
AMA StyleMio Tsuruoka, Jun Inoue, Yasushi Onishi, Masashi Ninomiya, Eiji Kakazu, Tomoaki Iwata, Akitoshi Sano, Kosuke Sato, Hideo Harigae, Atsushi Masamune. Hepatitis B Virus Reactivation with Discontinuation of Nucleoside Analogue in Patients Who Received Allogeneic Hematopoietic Stem Cell Transplantation. Case Reports in Gastroenterology. 2021; 15 (1):178-187.
Chicago/Turabian StyleMio Tsuruoka; Jun Inoue; Yasushi Onishi; Masashi Ninomiya; Eiji Kakazu; Tomoaki Iwata; Akitoshi Sano; Kosuke Sato; Hideo Harigae; Atsushi Masamune. 2021. "Hepatitis B Virus Reactivation with Discontinuation of Nucleoside Analogue in Patients Who Received Allogeneic Hematopoietic Stem Cell Transplantation." Case Reports in Gastroenterology 15, no. 1: 178-187.
Although hepatitis B surface antigen (HBsAg) removal is considered the goal of chronic hepatitis B treatment, it can rarely be achieved with nucleos(t)ide analogues (NAs). It has been reported that tenofovir disoproxil fumarate (TDF) is superior in reducing HBsAg compared with entecavir (ETV) in treatment-naïve patients; however, the effect of TDF in patients who have received NAs is still unclear. The aim of the present study was to evaluate the efficacy of switching from ETV to TDF in patients who were already receiving ETV. A pilot randomized controlled study for 2 years in patients who had been treated with ETV for >1 year and did not exhibit drug resistance was performed (Clinical trial registration: UMIN000021948, UMIN-CTR, May 1, 2016). A total of 20 patients were enrolled and 19 patients were randomized into 2 groups, a TDF-switching group (n=12) or an ETV-continuing group (n=7). The mean change in HBsAg levels after 2 years was greater in the TDF group compared with the ETV group, but the difference was not significant (-0.25 vs. -0.06 log IU/ml). In the TDF group, hepatitis B e antigen (HBeAg)-positive patients at baseline showed significantly greater changes in HBsAg (-0.63 vs. -0.03 log IU/ml; P=0.030). In contrast, no difference between HBeAg-positive and HBeAg-negative patients was observed in the ETV group. No significant differences of estimated glomerular filtration rate and inorganic phosphorus changes were observed among the TDF and ETV groups. In conclusion, a significant HBsAg decrease was not achieved after switching from ETV to TDF in the overall analysis, but HBeAg-positive patients showed a larger HBsAg decrease after switching treatment.
Jun Inoue; Takehiro Akahane; Tomoo Kobayashi; Noriyuki Obara; Teruyuki Umetsu; Eiji Kakazu; Masashi Ninomiya; Tomoaki Iwata; Akitoshi Sano; Mio Tsuruoka; Kosuke Sato; Atsushi Masamune. Switching to tenofovir disoproxil fumarate in entecavir‑treated chronic hepatitis B patients: A pilot randomized controlled study. Biomedical Reports 2020, 14, 1 -1.
AMA StyleJun Inoue, Takehiro Akahane, Tomoo Kobayashi, Noriyuki Obara, Teruyuki Umetsu, Eiji Kakazu, Masashi Ninomiya, Tomoaki Iwata, Akitoshi Sano, Mio Tsuruoka, Kosuke Sato, Atsushi Masamune. Switching to tenofovir disoproxil fumarate in entecavir‑treated chronic hepatitis B patients: A pilot randomized controlled study. Biomedical Reports. 2020; 14 (2):1-1.
Chicago/Turabian StyleJun Inoue; Takehiro Akahane; Tomoo Kobayashi; Noriyuki Obara; Teruyuki Umetsu; Eiji Kakazu; Masashi Ninomiya; Tomoaki Iwata; Akitoshi Sano; Mio Tsuruoka; Kosuke Sato; Atsushi Masamune. 2020. "Switching to tenofovir disoproxil fumarate in entecavir‑treated chronic hepatitis B patients: A pilot randomized controlled study." Biomedical Reports 14, no. 2: 1-1.
Methotrexate-related lymphoproliferative disorder (MTX-LPD) is known to be a side effect of MTX, but its involvement in the liver has been rarely reported. We herein report a 70-year-old woman with autoimmune hepatitis and rheumatoid arthritis who developed multiple liver tumors. We initially considered that she had developed rapid-growing HCC in the cirrhotic liver based on imaging tests. A tumor biopsy and transcatheter arterial chemoembolization were thus performed. The tumors were then diagnosed as diffuse large B-cell lymphoma pathologically and considered to be MTX-LPD. This case indicates that MTX-LPD should be considered even in cirrhotic patients with liver tumors resembling HCC.
Mio Tsuruoka; Jun Inoue; Eiji Kakazu; Masashi Ninomiya; Tomoaki Iwata; Akitoshi Sano; Atsushi Masamune. Methotrexate-associated Lymphoproliferative Disorder in the Liver Resembling Hepatocellular Carcinoma Treated with Transarterial Chemoembolization. Internal Medicine 2020, 59, 2255 -2260.
AMA StyleMio Tsuruoka, Jun Inoue, Eiji Kakazu, Masashi Ninomiya, Tomoaki Iwata, Akitoshi Sano, Atsushi Masamune. Methotrexate-associated Lymphoproliferative Disorder in the Liver Resembling Hepatocellular Carcinoma Treated with Transarterial Chemoembolization. Internal Medicine. 2020; 59 (18):2255-2260.
Chicago/Turabian StyleMio Tsuruoka; Jun Inoue; Eiji Kakazu; Masashi Ninomiya; Tomoaki Iwata; Akitoshi Sano; Atsushi Masamune. 2020. "Methotrexate-associated Lymphoproliferative Disorder in the Liver Resembling Hepatocellular Carcinoma Treated with Transarterial Chemoembolization." Internal Medicine 59, no. 18: 2255-2260.
Sarcopenia worsens the prognosis of patients with hepatocellular carcinoma (HCC). The aim of this study was to elucidate the plasma free amino acids (PFAAs) associated with sarcopenia or myosteatosis in the course of HCC recurrence. In this cross-sectional study, 187 patients were enrolled retrospectively. All patients experienced more than one hospitalization (mean times, 2.65) owing to HCC recurrence. The skeletal muscle index (SMI) and muscle attenuation (MA) were measured by a transverse computed tomography (CT) scan image at the third lumbar vertebra (L3). The changes in the concentration of 24 PFAAs, SMI, and MA in the same patient between recurrences were defined as Δ. The associations between sarcopenia, myosteatosis, and PFAAs were evaluated by a logistic regression model. The ΔSMI and ΔMA were compared between the patients who received branched-chain amino acids (BCAAs) formulation and those who did not. Patients with sarcopenia showed lower survival rate; the 1-, 3-, and 5-y survival rates were 85%, 42%, and 9%, respectively. Multivariate analysis revealed that the level of total BCAAs was significantly associated with sarcopenia. The correlation coefficient value between the change of leucine (ΔLeu) and ΔSMI was highest (R = 0.256; P < 0.001) among the PFAAs. In the Child-Pugh grade B or C, the decrease of SMI was significantly more suppressed in the patients with the BCAAs formulation than in those without BCAAs formulation (ΔSMI: mean change –0.98 versus –3.45 cm²/m²; P = 0.038). Among the PFAAs, the level of BCAAs was associated with sarcopenia in the course of HCC recurrence.
Akitoshi Sano; Shunichi Tsuge; Eiji Kakazu; Tomoaki Iwata; Masashi Ninomiya; Mio Tsuruoka; Jun Inoue; Atsushi Masamune. Plasma free amino acids are associated with sarcopenia in the course of hepatocellular carcinoma recurrence. Nutrition 2020, 84, 111007 .
AMA StyleAkitoshi Sano, Shunichi Tsuge, Eiji Kakazu, Tomoaki Iwata, Masashi Ninomiya, Mio Tsuruoka, Jun Inoue, Atsushi Masamune. Plasma free amino acids are associated with sarcopenia in the course of hepatocellular carcinoma recurrence. Nutrition. 2020; 84 ():111007.
Chicago/Turabian StyleAkitoshi Sano; Shunichi Tsuge; Eiji Kakazu; Tomoaki Iwata; Masashi Ninomiya; Mio Tsuruoka; Jun Inoue; Atsushi Masamune. 2020. "Plasma free amino acids are associated with sarcopenia in the course of hepatocellular carcinoma recurrence." Nutrition 84, no. : 111007.
A hepatic cyst is usually asymptomatic but, in some cases, can be associated with various complications. Here we report a rare case with rapid enlargement of a hepatic hilar cyst that induced bile duct obstruction after an acute exacerbation of chronic hepatitis B. The case is a 60-year old female who discontinued entecavir by herself. Hyperbilirubinemia was prolonged along with bile duct obstruction due to an enlarged cyst. After the administration of entecavir and steroid pulse therapy, biliary drainage and punctuation of the cyst were performed. There was no evidence of malignancy in the cyst. The therapies were not effective enough, probably due to the prior liver damage, and she died of acute on chronic liver failure. This case suggests that a hepatic hilar cyst in a patient with acute hepatitis or an acute exacerbation of chronic hepatitis can become enlarged and may affect the clinical course of hepatitis. In such a case, the size of the cyst should be monitored frequently and bile duct obstruction should be treated early if it occurs.
Tomoaki Iwata; Jun Inoue; Eiji Kakazu; Masashi Ninomiya; Akitoshi Sano; Mio Tsuruoka; Kiyoshi Kume; Atsushi Masamune. Rapid enlargement of a hepatic hilar cyst leading to bile duct obstruction after acute exacerbation of chronic hepatitis B. Clinical Journal of Gastroenterology 2020, 13, 1247 -1251.
AMA StyleTomoaki Iwata, Jun Inoue, Eiji Kakazu, Masashi Ninomiya, Akitoshi Sano, Mio Tsuruoka, Kiyoshi Kume, Atsushi Masamune. Rapid enlargement of a hepatic hilar cyst leading to bile duct obstruction after acute exacerbation of chronic hepatitis B. Clinical Journal of Gastroenterology. 2020; 13 (6):1247-1251.
Chicago/Turabian StyleTomoaki Iwata; Jun Inoue; Eiji Kakazu; Masashi Ninomiya; Akitoshi Sano; Mio Tsuruoka; Kiyoshi Kume; Atsushi Masamune. 2020. "Rapid enlargement of a hepatic hilar cyst leading to bile duct obstruction after acute exacerbation of chronic hepatitis B." Clinical Journal of Gastroenterology 13, no. 6: 1247-1251.
Background & Aims We aimed to clarify the features of resistance-associated substitutions (RASs) after failure of multiple interferon (IFN)-free regimens in HCV genotype 1b infections. Methods A total of 1,193 patients with HCV for whom direct-acting antiviral (DAA) treatment had failed were enrolled from 67 institutions in Japan. The RASs in non-structural protein (NS)3, NS5A, and NS5B were determined by population sequencing. Results Failure of 1, 2, and 3 regimens was observed in 1,101; 80; and 12 patients, respectively. Among patients with failure of 1 regimen, Y56H and D168V in NS3 were more frequently detected after failure of paritaprevir, whereas D168E was more frequently detected after failure of regimens including asunaprevir. R30H and L31-RAS in NS5A were frequently detected after failure of regimens including daclatasvir. The prevalence of Y93-RAS was high irrespective of the regimen. S282T RAS in NS5B was detected in 3.9% of ledipasvir/sofosbuvir failures. The prevalence of D168-RAS increased significantly according to the number of failed regimens (p<0.01), which was similar to that seen with L31-RAS and Y93-RAS. The prevalence of patients with RASs in either NS3 or NS5A, or in both, increased significantly with increasing numbers of failed regimens. The P32del, which is unique to patients for whom DAA had failed, was linked to the absence of Y93H, the presence of L31F, and previous exposure to IFN plus protease inhibitor regimens. Conclusions Failure of multiple DAA regimens can lead to the generation of multiple RASs in the NS3 and NS5A regions of the HCV 1b genome. These mutations contribute to viral resistance to multiple treatment regimens and, therefore, should be considered during decision making for treatment of chronic HCV. Lay summary Resistance-associated substitutions (RAS) in the genome of the hepatitis C virus are 1 of the major causes for failed treatment. We investigated RASs after failure of various treatments for chronic hepatitis C, and found that more complicated RASs accumulated in the viral genome with successive failed treatments. The highly resistant P32del RAS at NS5A region was uniquely found in patients for whom DAA treatments had failed, and was linked to the presence and absence of specific RASs.
Jun Itakura; Masayuki Kurosaki; Satoru Kakizaki; Keisuke Amano; Nobuaki Nakayama; Jun Inoue; Tetsu Endo; Hiroyuki Marusawa; Chitomi Hasebe; Kouji Joko; Shuichi Wada; Takehiro Akahane; Youhei Koushima; Chikara Ogawa; Tatsuya Kanto; Masashi Mizokami; Namiki Izumi. Features of resistance-associated substitutions after failure of multiple direct-acting antiviral regimens for hepatitis C. JHEP Reports 2020, 2, 100138 .
AMA StyleJun Itakura, Masayuki Kurosaki, Satoru Kakizaki, Keisuke Amano, Nobuaki Nakayama, Jun Inoue, Tetsu Endo, Hiroyuki Marusawa, Chitomi Hasebe, Kouji Joko, Shuichi Wada, Takehiro Akahane, Youhei Koushima, Chikara Ogawa, Tatsuya Kanto, Masashi Mizokami, Namiki Izumi. Features of resistance-associated substitutions after failure of multiple direct-acting antiviral regimens for hepatitis C. JHEP Reports. 2020; 2 (5):100138.
Chicago/Turabian StyleJun Itakura; Masayuki Kurosaki; Satoru Kakizaki; Keisuke Amano; Nobuaki Nakayama; Jun Inoue; Tetsu Endo; Hiroyuki Marusawa; Chitomi Hasebe; Kouji Joko; Shuichi Wada; Takehiro Akahane; Youhei Koushima; Chikara Ogawa; Tatsuya Kanto; Masashi Mizokami; Namiki Izumi. 2020. "Features of resistance-associated substitutions after failure of multiple direct-acting antiviral regimens for hepatitis C." JHEP Reports 2, no. 5: 100138.
Generally, reactivation of hepatitis B virus (HBV) infection is induced by the administration of immunosuppressants or anticancer agents, but reactivation without such drugs has rarely been reported. Here we report an elder case with spontaneous reactivation of HBV replication accompanied by hepatitis B surface antigen (HBsAg) mutations. A 69-year-old man with a history of diabetes mellitus and chronic kidney disease (CKD) was found to be positive for HBsAg (0.072 IU/ml) in June 2018. In May 2019, marked hepatic dysfunction and increased HBsAg (2533.2 IU/ml) were observed when he visited the hospital due to diarrhea and worsening of CKD. At that time, hepatitis B surface antibody (HBsAb) was positive (268.9 mIU/ml) and HBV DNA was 6.0 log IU/ml. After treatment with entecavir, HBV DNA and HBsAg rapidly decreased. Full-genome HBV sequence analysis revealed that the patient was infected with HBV of subgenotype B1 and it had an “a” determinant mutation M133L in the S gene coding HBsAg. Notably, both HBsAg and HBsAb were positive at the time of HBV reactivation, suggesting that the HBV with these mutations escaped from neutralization by HBsAb. This case suggests that immune escape mutations could play an important role in spontaneous HBV reactivation.
Noriyuki Obara; Jun Inoue; Hiroyuki Endo; Eiji Kakazu; Masashi Ninomiya; Tomoaki Iwata; Akitoshi Sano; Mio Tsuruoka; Atsushi Masamune. Spontaneous reactivation of hepatitis B virus with S gene mutations in an elderly patient with diabetic nephropathy. Clinical Journal of Gastroenterology 2020, 13, 914 -919.
AMA StyleNoriyuki Obara, Jun Inoue, Hiroyuki Endo, Eiji Kakazu, Masashi Ninomiya, Tomoaki Iwata, Akitoshi Sano, Mio Tsuruoka, Atsushi Masamune. Spontaneous reactivation of hepatitis B virus with S gene mutations in an elderly patient with diabetic nephropathy. Clinical Journal of Gastroenterology. 2020; 13 (5):914-919.
Chicago/Turabian StyleNoriyuki Obara; Jun Inoue; Hiroyuki Endo; Eiji Kakazu; Masashi Ninomiya; Tomoaki Iwata; Akitoshi Sano; Mio Tsuruoka; Atsushi Masamune. 2020. "Spontaneous reactivation of hepatitis B virus with S gene mutations in an elderly patient with diabetic nephropathy." Clinical Journal of Gastroenterology 13, no. 5: 914-919.
The frequency of HBV genomic methylation in the liver was reported to vary among patients, but the detailed mechanism is still unknown. In this study, the effects of HBV genome methylation on HBV replication were investigated in vitro. A total of 6 plasmids containing 1.24-fold the HBV genome of different genotypes (subgenotypes A1, A2, B1, and C2) were purified after in vitro methylation with CpG methyltransferase (M.SssI) and transfected into HepG2 cells. In genotype B and C strains, methylation markedly decreased the amount of hepatitis B e antigen (HBeAg) in the culture supernatant. A reduction of hepatitis B surface antigen (HBsAg) was found in some HBV strains but the reduction was smaller than that of HBeAg. There was no significant difference in particle-associated HBV DNA in the culture supernatant. These findings suggest that HBV genomic methylation might be involved in the HBeAg decline in genotype B and C, in part, and that the reduction of HBsAg was less than that of HBeAg. In conclusion, this study showed that the effect of HBV genomic methylation differs among HBV genotypes, suggesting a potential explanation for the different clinical outcomes of genotypes A, B, and C.
Takuya Nakamura; Jun Inoue; Masashi Ninomiya; Eiji Kakazu; Tomoaki Iwata; Satoshi Takai; Akitoshi Sano; Takayuki Kogure; Tooru Shimosegawa; Atsushi Masamune. Effect of viral DNA methylation on expression of hepatitis B virus proteins depends on the virus genotype. Virus Genes 2020, 56, 439 -447.
AMA StyleTakuya Nakamura, Jun Inoue, Masashi Ninomiya, Eiji Kakazu, Tomoaki Iwata, Satoshi Takai, Akitoshi Sano, Takayuki Kogure, Tooru Shimosegawa, Atsushi Masamune. Effect of viral DNA methylation on expression of hepatitis B virus proteins depends on the virus genotype. Virus Genes. 2020; 56 (4):439-447.
Chicago/Turabian StyleTakuya Nakamura; Jun Inoue; Masashi Ninomiya; Eiji Kakazu; Tomoaki Iwata; Satoshi Takai; Akitoshi Sano; Takayuki Kogure; Tooru Shimosegawa; Atsushi Masamune. 2020. "Effect of viral DNA methylation on expression of hepatitis B virus proteins depends on the virus genotype." Virus Genes 56, no. 4: 439-447.
Selective immunoglobulin M deficiency (SIGMD) is an uncommon primary immunodeficiency disorder. We herein report an SIGMD patient with autoimmune hepatitis. A 21-year-old Japanese man was transferred to our hospital because of acute liver dysfunction. His serum IgM level was low, whereas those of IgG and IgA were normal, indicating that he had SIGMD. We diagnosed him with acute-onset autoimmune hepatitis, and his liver function test findings gradually recovered with corticosteroid administration. Although SIGMD with autoimmune diseases has been reported, the clinical features and pathogenesis have not yet been clarified. We have summarized previous reports on SIGMD patients with autoimmune diseases.
Akitoshi Sano; Jun Inoue; Eiji Kakazu; Masashi Ninomiya; Tomoaki Iwata; Tatsuki Morosawa; Satoshi Takai; Takuya Nakamura; Atsushi Masamune. Acute-onset Autoimmune Hepatitis in a Patient with Selective Immunoglobulin M Deficiency. Internal Medicine 2019, 58, 2185 -2190.
AMA StyleAkitoshi Sano, Jun Inoue, Eiji Kakazu, Masashi Ninomiya, Tomoaki Iwata, Tatsuki Morosawa, Satoshi Takai, Takuya Nakamura, Atsushi Masamune. Acute-onset Autoimmune Hepatitis in a Patient with Selective Immunoglobulin M Deficiency. Internal Medicine. 2019; 58 (15):2185-2190.
Chicago/Turabian StyleAkitoshi Sano; Jun Inoue; Eiji Kakazu; Masashi Ninomiya; Tomoaki Iwata; Tatsuki Morosawa; Satoshi Takai; Takuya Nakamura; Atsushi Masamune. 2019. "Acute-onset Autoimmune Hepatitis in a Patient with Selective Immunoglobulin M Deficiency." Internal Medicine 58, no. 15: 2185-2190.
HBV infection is a worldwide health problem, but the mechanisms of how HBV utilizes cellular machinery for its life cycle are poorly understood. In particular, it has been unclear how the viral components and virions are transported among the organelles. The HBV budding site has been reported to be the ER or MVB, but it has not been clearly determined. In this study, siRNA-based screening of Rab proteins using HBV-expressing cells showed that Rab5B, one of the Rab5 isoforms, has important roles in late steps of the HBV life cycle. Although Rab5 is known to work on early endosomes, this study showed that Rab5B plays a role in the transport of LHBs between the ER and MVB. Furthermore, it affects the transcription of LHBs. This is the first report on the mechanisms of HBV envelope protein transport among the organelles, and the results provide important insights into the therapeutic control of HBV infection.
Jun Inoue; Masashi Ninomiya; Teruyuki Umetsu; Takuya Nakamura; Takayuki Kogure; Eiji Kakazu; Tomoaki Iwata; Satoshi Takai; Akitoshi Sano; Mitsunori Fukuda; Koichi Watashi; Masanori Isogawa; Yasuhito Tanaka; Tooru Shimosegawa; Mark A. McNiven; Atsushi Masamune. Small Interfering RNA Screening for the Small GTPase Rab Proteins Identifies Rab5B as a Major Regulator of Hepatitis B Virus Production. Journal of Virology 2019, 93, 1 .
AMA StyleJun Inoue, Masashi Ninomiya, Teruyuki Umetsu, Takuya Nakamura, Takayuki Kogure, Eiji Kakazu, Tomoaki Iwata, Satoshi Takai, Akitoshi Sano, Mitsunori Fukuda, Koichi Watashi, Masanori Isogawa, Yasuhito Tanaka, Tooru Shimosegawa, Mark A. McNiven, Atsushi Masamune. Small Interfering RNA Screening for the Small GTPase Rab Proteins Identifies Rab5B as a Major Regulator of Hepatitis B Virus Production. Journal of Virology. 2019; 93 (15):1.
Chicago/Turabian StyleJun Inoue; Masashi Ninomiya; Teruyuki Umetsu; Takuya Nakamura; Takayuki Kogure; Eiji Kakazu; Tomoaki Iwata; Satoshi Takai; Akitoshi Sano; Mitsunori Fukuda; Koichi Watashi; Masanori Isogawa; Yasuhito Tanaka; Tooru Shimosegawa; Mark A. McNiven; Atsushi Masamune. 2019. "Small Interfering RNA Screening for the Small GTPase Rab Proteins Identifies Rab5B as a Major Regulator of Hepatitis B Virus Production." Journal of Virology 93, no. 15: 1.
Reactivation of hepatitis B virus (HBV) is a major problem in patients receiving chemotherapy for malignant diseases or immunosuppression therapies. It has been thought that a reduction in the immune responses might result in the reactivation of HBV replication from covalently closed circular DNA (cccDNA) residing in hepatocytes. However, not only the host's immune status, but also viral mutations have been reported to be associated with reactivation. Especially, several case reports about amino acid mutations in hepatitis B surface antigen (HBsAg) that escape from immune reactions have been reported, and recent reports showed that the frequencies of such mutations are higher than previously expected. In this review, we summarize the characteristics of viral mutations, including immune escape mutations in HBV-reactivated patients, and discuss their significance.
Jun Inoue; Takuya Nakamura; Atsushi Masamune. Roles of Hepatitis B Virus Mutations in the Viral Reactivation after Immunosuppression Therapies. Viruses 2019, 11, 457 .
AMA StyleJun Inoue, Takuya Nakamura, Atsushi Masamune. Roles of Hepatitis B Virus Mutations in the Viral Reactivation after Immunosuppression Therapies. Viruses. 2019; 11 (5):457.
Chicago/Turabian StyleJun Inoue; Takuya Nakamura; Atsushi Masamune. 2019. "Roles of Hepatitis B Virus Mutations in the Viral Reactivation after Immunosuppression Therapies." Viruses 11, no. 5: 457.
Aim Macrovesicular steatosis around the central vein (zone 3) is one of the pathological features of non‐alcoholic fatty liver disease, or steatohepatitis (NAFLD/NASH). The aim of this study is to elucidate precisely the association between the area of lipid droplets (LDs) and the plasma metabolic parameters in patients with NAFLD/NASH. Methods Eighty patients with NAFLD/NASH diagnosed by needle biopsy were enrolled. The LDs around zone 3 were counted automatically by image processing software, the total area of LDs (TLDs), the maximum area of LDs (MAXLDs), the average area of LDs (AVELDs) and the heterogeneity by the coefficient of variation (CV (%)) were quantified. The correlations between these values and plasma metabolic parameters were analyzed. We evaluated the association between branched chain amino acids (BCAAs) and the heterogeneity of LDs in hepatocytes, in vitro and in vivo. Results The MAXLDs was significantly correlated with more metabolic parameters than AVELDs and TLDs. The level of BCAAs was independently associated with the CV among the metabolic parameters. In early stage of NAFLD, aspartate and alanine aminotransferase were significantly higher in high CV group than that in low CV group. The high concentration of BCAAs increased the CV of LDs in hepatocytes accompanied by the expression of phosphor‐p70 S6 kinase and sterol regulatory element‐binding protein 1 (SREBP1) in vitro. A high BCAAs diet induced high heterogeneity of LDs around zone 3 in ob/ob mice. Conclusions The levels of BCAAs were associated with the LDs heterogeneity of hepatocytes around zone 3 in patients with NAFLD/NASH.
Eiji Kakazu; Akitoshi Sano; Tatsuki Morosawa; Jun Inoue; Masashi Ninomiya; Tomoaki Iwata; Takuya Nakamura; Satoshi Takai; Shojiro Sawada; Hideki Katagiri; Tooru Shimosegawa; Atsushi Masamune. Branched chain amino acids are associated with the heterogeneity of the area of lipid droplets in hepatocytes of patients with non‐alcoholic fatty liver disease. Hepatology Research 2019, 49, 860 -871.
AMA StyleEiji Kakazu, Akitoshi Sano, Tatsuki Morosawa, Jun Inoue, Masashi Ninomiya, Tomoaki Iwata, Takuya Nakamura, Satoshi Takai, Shojiro Sawada, Hideki Katagiri, Tooru Shimosegawa, Atsushi Masamune. Branched chain amino acids are associated with the heterogeneity of the area of lipid droplets in hepatocytes of patients with non‐alcoholic fatty liver disease. Hepatology Research. 2019; 49 (8):860-871.
Chicago/Turabian StyleEiji Kakazu; Akitoshi Sano; Tatsuki Morosawa; Jun Inoue; Masashi Ninomiya; Tomoaki Iwata; Takuya Nakamura; Satoshi Takai; Shojiro Sawada; Hideki Katagiri; Tooru Shimosegawa; Atsushi Masamune. 2019. "Branched chain amino acids are associated with the heterogeneity of the area of lipid droplets in hepatocytes of patients with non‐alcoholic fatty liver disease." Hepatology Research 49, no. 8: 860-871.
Until recently, interferon-free anti-hepatitis C virus (HCV) therapy for genotype 2 (GT2) HCV-infected hemodialysis patients was an unfulfilled medical need. Recent clinical trials of glecaprevir and pibrentasvir (G/P) for hemodialysis patients showed high efficacy and safety; however, the number of GT2 HCV-infected patients, especially Asian patients, was limited and most of them were treated with a 12-week regimen. In this prospective multicenter study, we aimed to investigate the efficacy and safety of G/P in Japanese hemodialysis patients with GT2 HCV infection. Twenty-seven Japanese hemodialysis patients with GT2 HCV infection who were started on with 8- or 12-week G/P regimen between November 2017 and June 2018 were included and followed up for around 12 weeks after treatment completion. Among the 27 included patients, 13 non-liver cirrhosis (LC) and direct-acting antivirals (DAAs)-naïve patients were treated with 8 weeks of G/P and 14 patients with LC (n = 13) or history of failure of DAAs (n = 1) were treated with a 12-week regimen. The overall sustained virological response at 12 weeks after treatment completion (SVR 12) was 96.3% (26/27). All patients with 8 weeks of treatment achieved SVR12. Two patients discontinued the therapy at 2 and 11 weeks after treatment initiation. The patient who discontinued at 2 weeks due to pruritus alone failed to respond to G/P. No patients experienced lethal adverse events during the therapy, and the most common adverse event was pruritus. An 8- or 12-week G/P regimen is highly effective and safe in GT2 HCV-infected hemodialysis patients.
Goki Suda; for the NORTE Study Group; Chitomi Hasebe; Masami Abe; Masayuki Kurosaki; Jun Itakura; Namiki Izumi; Yoshihito Uchida; Satoshi Mochida; Hiroaki Haga; Yoshiyuki Ueno; Kazumichi Abe; Atsushi Takahashi; Hiromasa Ohira; Yoko Tsukuda; Ken Furuya; Masaru Baba; Yoshiya Yamamoto; Tomoe Kobayashi; Jun Inoue; Katsumi Terasita; Masatsugu Ohara; Naoki Kawagishi; Takaaki Izumi; Masato Nakai; Takuya Sho; Mitsuteru Natsuizaka; Kenichi Morikawa; Koji Ogawa; Naoya Sakamoto. Safety and efficacy of glecaprevir and pibrentasvir in Japanese hemodialysis patients with genotype 2 hepatitis C virus infection. Journal of Gastroenterology 2019, 54, 641 -649.
AMA StyleGoki Suda, for the NORTE Study Group, Chitomi Hasebe, Masami Abe, Masayuki Kurosaki, Jun Itakura, Namiki Izumi, Yoshihito Uchida, Satoshi Mochida, Hiroaki Haga, Yoshiyuki Ueno, Kazumichi Abe, Atsushi Takahashi, Hiromasa Ohira, Yoko Tsukuda, Ken Furuya, Masaru Baba, Yoshiya Yamamoto, Tomoe Kobayashi, Jun Inoue, Katsumi Terasita, Masatsugu Ohara, Naoki Kawagishi, Takaaki Izumi, Masato Nakai, Takuya Sho, Mitsuteru Natsuizaka, Kenichi Morikawa, Koji Ogawa, Naoya Sakamoto. Safety and efficacy of glecaprevir and pibrentasvir in Japanese hemodialysis patients with genotype 2 hepatitis C virus infection. Journal of Gastroenterology. 2019; 54 (7):641-649.
Chicago/Turabian StyleGoki Suda; for the NORTE Study Group; Chitomi Hasebe; Masami Abe; Masayuki Kurosaki; Jun Itakura; Namiki Izumi; Yoshihito Uchida; Satoshi Mochida; Hiroaki Haga; Yoshiyuki Ueno; Kazumichi Abe; Atsushi Takahashi; Hiromasa Ohira; Yoko Tsukuda; Ken Furuya; Masaru Baba; Yoshiya Yamamoto; Tomoe Kobayashi; Jun Inoue; Katsumi Terasita; Masatsugu Ohara; Naoki Kawagishi; Takaaki Izumi; Masato Nakai; Takuya Sho; Mitsuteru Natsuizaka; Kenichi Morikawa; Koji Ogawa; Naoya Sakamoto. 2019. "Safety and efficacy of glecaprevir and pibrentasvir in Japanese hemodialysis patients with genotype 2 hepatitis C virus infection." Journal of Gastroenterology 54, no. 7: 641-649.
While the life cycles of hepatitis viruses (hepatitis A, B, C, D, and E viruses) have been modestly characterized, recent intensive studies have provided new insights. Because these viruses ‘hijack' the membrane trafficking of the host cell machinery during replicative propagation, it is essential to determine and understand these specific cellular pathways. Hepatitis B virus (HBV) and hepatitis C virus (HCV) are well known as a leading cause of liver cirrhosis and hepatocellular carcinoma. While substantial inroads toward treating HCV patients have recently been made, patients with HBV continue to require life-long treatment, which makes a thorough understanding of the HBV life cycle essential. Importantly, these viruses have been observed to “hijack” the secretory and endocytic membrane trafficking machineries of the hepatocyte. These can include the canonical clathrin-mediated endocytic process that internalizes virus through cell surface receptors. While these receptors are encoded by the host genome for normal hepatocellular functions, they also exhibit viral-specific recognition. Further, functions provided by the multivesicular body (MVB), that include endosomal sorting complexes required for transport (ESCRT), are now known to envelope a variety of different hepatitis viruses. In this review, we summarize the recent findings regarding the cellular membrane trafficking machineries utilized by HBV in the context of other hepatitis viruses. This article is protected by copyright. All rights reserved.
Jun Inoue; Masashi Ninomiya; Tooru Shimosegawa; Mark A. McNiven. Cellular Membrane Trafficking Machineries Used by the Hepatitis Viruses. Hepatology 2018, 68, 751 -762.
AMA StyleJun Inoue, Masashi Ninomiya, Tooru Shimosegawa, Mark A. McNiven. Cellular Membrane Trafficking Machineries Used by the Hepatitis Viruses. Hepatology. 2018; 68 (2):751-762.
Chicago/Turabian StyleJun Inoue; Masashi Ninomiya; Tooru Shimosegawa; Mark A. McNiven. 2018. "Cellular Membrane Trafficking Machineries Used by the Hepatitis Viruses." Hepatology 68, no. 2: 751-762.
Autoimmune hepatitis (AIH) and type 1 diabetes mellitus (T1DM) are thought to be induced by autoimmunity, but their coexistence has rarely been reported. We herein report a case in which a patient with T1DM developed acute-onset AIH. A 26-year-old woman, who had been diagnosed with T1DM in childhood, was transferred to our hospital because of acute liver failure of unknown etiology. The administration of corticosteroids including steroid pulse therapy was effective. Based on the histological finding of massive centrilobular necrosis and a good response to steroid therapy, we diagnosed the patient with acute-onset AIH. This case indicates that AIH can occur in young T1DM patients.
Satoshi Takai; Jun Inoue; Takayuki Kogure; Eiji Kakazu; Masashi Ninomiya; Tomoaki Iwata; Teruyuki Umetsu; Takuya Nakamura; Akitoshi Sano; Tooru Shimosegawa. Acute-onset Autoimmune Hepatitis in a Young Woman with Type 1 Diabetes Mellitus. Internal Medicine 2018, 57, 1591 -1596.
AMA StyleSatoshi Takai, Jun Inoue, Takayuki Kogure, Eiji Kakazu, Masashi Ninomiya, Tomoaki Iwata, Teruyuki Umetsu, Takuya Nakamura, Akitoshi Sano, Tooru Shimosegawa. Acute-onset Autoimmune Hepatitis in a Young Woman with Type 1 Diabetes Mellitus. Internal Medicine. 2018; 57 (11):1591-1596.
Chicago/Turabian StyleSatoshi Takai; Jun Inoue; Takayuki Kogure; Eiji Kakazu; Masashi Ninomiya; Tomoaki Iwata; Teruyuki Umetsu; Takuya Nakamura; Akitoshi Sano; Tooru Shimosegawa. 2018. "Acute-onset Autoimmune Hepatitis in a Young Woman with Type 1 Diabetes Mellitus." Internal Medicine 57, no. 11: 1591-1596.
Hepatitis B virus (HBV) infection is a worldwide health problem because of its potential to cause liver cirrhosis and hepatocellular carcinoma. Silibinin is a constituent of an extract of milk thistle, which is empirically used as a herbal medicine for the protection of liver, but its detailed effects on HBV are unknown. Because a previous study reported that silibinin hinders clathlin-mediated endocytosis (CME), we aimed to test whether silibinin inhibits the entry of HBV into hepatocytes. Using HepG2-NTCP-C4 cells, which overexpress sodium taurocholate cotransporting polypeptide (NTCP), it was shown that silibinin inhibited HBV infection dose-dependently. Similar effects were observed using human primary hepatocytes (PXB-cells). Additionally, a combination of silibinin and entecavir reduced HBV DNA in the culture supernatant more than either mono-treatment alone in HepG2-NTCP-C4 cells that had already been infected with HBV. Silibinin decreased transferrin uptake but did not affect the interaction between the HBV envelope and NTCP, suggesting that silibinin might inhibit HBV infection by hindering CME. In conclusion, this study showed that silibinin inhibits HBV entry in vitro.
Teruyuki Umetsu; Jun Inoue; Takayuki Kogure; Eiji Kakazu; Masashi Ninomiya; Tomoaki Iwata; Satoshi Takai; Takuya Nakamura; Akitoshi Sano; Tooru Shimosegawa. Inhibitory effect of silibinin on hepatitis B virus entry. Biochemistry and Biophysics Reports 2018, 14, 20 -25.
AMA StyleTeruyuki Umetsu, Jun Inoue, Takayuki Kogure, Eiji Kakazu, Masashi Ninomiya, Tomoaki Iwata, Satoshi Takai, Takuya Nakamura, Akitoshi Sano, Tooru Shimosegawa. Inhibitory effect of silibinin on hepatitis B virus entry. Biochemistry and Biophysics Reports. 2018; 14 ():20-25.
Chicago/Turabian StyleTeruyuki Umetsu; Jun Inoue; Takayuki Kogure; Eiji Kakazu; Masashi Ninomiya; Tomoaki Iwata; Satoshi Takai; Takuya Nakamura; Akitoshi Sano; Tooru Shimosegawa. 2018. "Inhibitory effect of silibinin on hepatitis B virus entry." Biochemistry and Biophysics Reports 14, no. : 20-25.