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Direct-acting antiviral agents against hepatitis C virus and lipid metabolism

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World Journal of Gastroenterology 2017年第31期23卷 5645-5649页

作者： tatsuo kanda mitsuhiko moriyama division of gastro-enterology and hepatology department of medicine nihon university school of medicine

Hepatitis C virus (HCV) infection induces steatosis and is accompanied by multiple metabolic alterations including hyperuricemia, reversible hypocholesterolemia and insulin resistance. Total cholesterol, low-density lipoprotein-cholesterol and triglyceride levels are increased by peginterferon and ribavirin combination therapy when a sustained virologic response (SVR) is achieved in patients with HCV. Steatosis is significantly more common in patients with HCV genotype 3 but interferon-free regimens are not always effective for treating HCV genotype 3 infections. HCV infection increases fatty acid synthase levels, resulting in the accumulation of fatty acids in hepatocytes. Of note, low-density lipoprotein receptor, scavenger receptor class B type I and Niemann-Pick C1-like 1 proteins are candidate receptors that may be involved in HCV. They are also required for the uptake of cholesterol from the external environment of hepatocytes. Among HCV-infected patients with or without human immunodeficiency virus infection, changes in serum lipid profiles are observed during interferon-free treatment and after the achievement of an SVR. It is evident that HCV affects cholesterol metabolism during interferon-free regimens. Although higher SVR rates were achieved with interferon-free treatment of HCV, special attention must also be paid to unexpected adverse events based on host metabolic changes including hyperlipidemia.

关键词： Cholesterol Hepatitis C virus Interferon-free Lipid metabolism

Androgen receptor signaling in hepatocellular carcinoma and pancreatic cancers

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World Journal of Gastroenterology 2014年第28期20卷 9229-9236页

作者： tatsuo kanda Xia Jiang Osamu Yokosuka Department of Gastroenterology and Nephrology Chiba UniversityGraduate School of Medicine

Hepatocellular carcinoma (HCC) and pancreatic cancer remain difficult to treat, and despite the ongoing development of new treatments, the overall survival rate has only modestly improved over the past decade. Liver and pancreatic progenitors commonly develop from endoderm cells in the embryonic foregut. A previous study showed that HCC and pancreatic cancer cell lines variably express androgen receptor (AR), and these cancers and the surrounding tissues also express AR. AR is a ligand-dependent transcription factor that belongs to the nuclear receptor superfamily. Androgen response element is present in regulatory elements on the AR-responsive target genes, such as transforming growth factor beta-1 (TGF beta-1) and vascular endothelial growth factor (VEGF). It is well known that the activation of AR is associated with human carcinogenesis in prostate cancer as well as HCC and pancreatic cancer and that GRP78, TGF beta, and VEGF all play important roles in carcinogenesis and cancer development in these cancers. HCC is a male-dominant cancer irrespective of its etiology. Previous work has reported that vertebrae forkhead box A 1/2 are involved in estrogen receptors and/or AR signaling pathways, which may contribute to the gender differences observed with HCC. Our recent work also showed that AR has a critical role in pancreatic cancer development, despite pancreatic cancer not being a male dominant cancer. Aryl hydrocarbon (or dioxin) receptor is also involved in both HCC and pancreatic cancer through the formation of complex with AR. It is possible that AR might be involved in their carcinogenesis through major histocompatibility complex class I chain-related gene A/B. This review article describes AR and its role in HCC and pancreatic cancer and suggests that more specific AR signaling-inhibitors may be useful in the treatment of these “difficult to treat” cancers.

关键词： Androgen receptor Gender difference Hepatocellular carcinoma Male-dominant Pancreas

Are direct-acting antivirals against hepatitis C virus infection not associated with the recurrence of hepatocellular carcinoma?

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Hepatobiliary Surgery and Nutrition 2019年第4期8卷 423-425页

作者： Masahiro Ogawa tatsuo kanda Mitsuhiko Moriyama Division of Gastroenterology and Hepatology Department of Medicine Nihon University School of Medicine Tokyo Japan

Hepatitis C virus (HCV) infection is one of the major causes of end-stage liver disease and hepatocellular carcinoma (HCC). Before the use of direct acting antivirals (DAAs) against HCV, liver transplantation was one of the best ways to achieve long-term survival and a better prognosis in patients with HCV infection and advanced liver fibrosis (1). In the interferon era, it is difficult for HCV infected patients with advanced liver fibrosis to achieve sustained virological response (SVR) because interferon therapy causes severe adverse events and these completely hamper this treatment in these patients.

关键词： interferon infection hepatocellular

Hepatitis C virus NS5A inhibitors and drug resistance mutations

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World Journal of Gastroenterology 2014年第11期20卷 2902-2912页

作者： Shingo Nakamoto tatsuo kanda Shuang Wu Hiroshi Shirasawa Osamu Yokosuka Department of Molecular Virology Graduate School of MedicineChiba UniversityChiba 260-8677Japan Department of Gastroenterology and Nephrology Graduate School of MedicineChiba UniversityChiba 260-8677Japan

Some direct-acting antiviral agents for hepatitis C virus (HCV), such as telaprevir and boceprevir have been available since 2011. It was reported that HCV NS5A is associated with interferon signaling related to HCV replication and hepatocarcinogenesis. HCV NS5A inhibitors efficiently inhibited HCV replication in vitro. Human studies showed that dual, triple and quad regimens with HCV NS5A inhibitors, such as daclatasvir and ledipasvir, in combination with other direct-acting antiviral agents against other regions of HCV with or without peginterferon/ribavirin, could efficiently inhibit HCV replication according to HCV genotypes. These combinations might be a powerful tool for “difficult-to-treat” HCV-infected patients. “First generation” HCV NS5A inhibitors such as daclatasvir, ledipasvir and ABT-267, which are now in phase III clinical trials, could result in resistance mutations. “Second generation” NS5A inhibitors such as GS-5816, ACH-3102, and MK-8742, have displayed improvements in the genetic barrier while maintaining potency. HCV NS5A inhibitors are safe at low concentrations, which make them attractive for use despite low genetic barriers, although, in fact, HCV NS5A inhibitors should be used with HCV NS3/4A inhibitors, HCV NS5B inhibitors or peginterferon plus ribavirin. This review article describes HCV NS5A inhibitor resistance mutations and recommends that HCV NS5A inhibitors be used in combination regimens potent enough to prevent the emergence of resistant variants.

关键词： ACH-3102 Direct-acting antiviral agents Daclatasvir Hepatitis C virus Ledipasvir

Current and future directions for treating hepatitis B virus infection

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World Journal of Hepatology 2015年第11期7卷 1541-1552页

作者： Akinobu Tawada tatsuo kanda Osamu Yokosuka Department of Gastroenterology and Nephrology Chiba Univer-sity Graduate School of Medicine

Hepatitis B virus(HBV) persistently infects approximately 350 million people, and approximately 600000 liverrelated deaths are observed per year worldwide. HBV infection is also one of the major risk factors for hepatocellular carcinoma(HCC). The persistence of serum hepatitis B e antigen(HBe Ag) and high level of serum HBV DNA are thought to reflect a high HBV replication status in hepatocytes, causing cirrhosis, HCC and liver-related deaths. It has been reported that antiviral therapy, such as peginterferon and nucleos(t)ide analogues(NUCs), could suppress liver-related death by inhibiting the HBV DNA levels and inducing seroconversion from HBe Ag to antibody to HBe antigen. Currently, peginterferon is widely used, but there are also several disadvantages in the use of peginterferon, such as various adverse events, the administration route and duration. It is difficult to predict the effects of treatment and interferon is contraindicated for the patients with advanced fibrosis of the liver and cirrhosis. With respect to NUCs, entecavir and tenofovir disoproxil fumarate are current the first-choice drugs. NUCs can be administered orally, and their anti-viral effects are stronger than that of peginterferon. However, because cessation of NUC administration leads to high levels of viral replication and causes severe hepatitis, they must be administered for a long time. On the other hand, the use of both interferon and NUCs cannot eliminate covalently closed circular DNA of HBV. In this review, we evaluate the natural course of chronic HBV infection and then provide an outline of these representative drugs, such as peginterferon, entecavir and tenofovir disoproxil fumarate.

关键词： Hepatocellular carcinoma Peginterferon Nucleotide analogue Chronic hepatitis B

Prolonged acute hepatitis A mimicking autoimmune hepatitis

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World Journal of Gastroenterology 2005年第24期11卷 3791-3793页

作者： Rintaro Mikata Osamu Yokosuka Fumio Imazeki Kenichi Fukai tatsuo kanda Hiromitsu Saisho Department of Medicine and Clinical Oncology

AIM: We report a case with a prolonged course of hepatitis A, with alanine aminotransferase (ALT) higher than 500 IU/L for more than 2 mo. METHODS: A middle-aged woman had an elevated IgG level of more than 2 000 mg/dL, positive anti-nudear antibodies (ANA) and anti-smooth muscle antibodies (ASMA), but no evidence of persistent hepatitis A virus (HAV) infection. Liver biopsy findings were compatible with prolonged acute hepatitis, although acute onset of autoimmune hepatitis could not be ruled out. RESULTS: It was assumed that she developed a course of hepatitis similar to autoimmune hepatitis triggered by HAV infection. Ursodeoxycholic acid (UDCA) treatment was initiated and a favorable outcome was obtained. CONCLUSION: We describe a case of a middle-aged woman who showed a prolonged course of acute hepatitis A mimicking autoimmune hepatitis. Treatment with UDCA proved to be effective.

关键词： Prolonged IgG Hepatitis A Autoimmune hepatitis

Hepatitis C virus protease inhibitor-resistance mutations: Our experience and review

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World Journal of Gastroenterology 2013年第47期19卷 8940-8948页

作者： Shuang Wu tatsuo kanda Shingo Nakamoto Fumio Imazeki Osamu Yokosuka Department of Gastroenterology and Nephrology Chiba UniversityGraduate School of MedicineChiba 260-8677Japan Postdoctoral Fellow Foreign Researcher of the Japan Society for Promotion of Science (JSPS)Tokyo 102-0083Japan Department of Molecular Virology Chiba UniversityGraduate School of MedicineChiba 260-8677Japan Safety and Health Organization Chiba UniversityChiba 263-8522Japan

Direct-acting antiviral agents(DAAs)for hepatitis C virus(HCV)infection are one of the major advances in its medical *** HCV protease inhibitors boceprevir and telaprevir were the first approved DAAs in the United States,Europe,and *** combined with peginterferon plus ribavirin,these agents increase sustained virologic response rates to70%-80%in treatment-na?ve patients and previoustreatment relapsers with chronic HCV genotype 1 *** peginterferon plus ribavirin,DAA monotherapies increased DAA-resistance *** new DAAs for HCV are now in clinical development and are likely to be approved in the near ***,it has been reported that the use of these drugs also led to the emergence of DAA-resistance mutations in certain ***,these mutations exhibit cross-resistance to multiple *** prevalence of DAA-resistance mutations in HCV-infected patients who were not treated with DAAs is unknown,and it is as yet uncertain whether such variants are sensitive to *** performed a population sequence analysis to assess the frequency of such variants in the sera of HCV genotype 1-infected patients not treated with HCV protease ***,we reviewed the literature on resistance variants of HCV protease inhibitors in treatment na?ve patients with chronic HCV genotype 1,as well as our experience.

关键词： Direct-acting antiviral agent Hepatitis C virus Protease inhibitor Resistance mutation Sequence analysis

Gastrojejunostomy followed by induction chemotherapy for incurable gastric cancer with outlet obstruction

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World Journal of Gastroenterology 2010年第34期16卷 4367-4370页

作者： Yasuhiro Okumura Manabu Ohashi Souya Nunobe Tomohiro Iwanaga tatsuo kanda Yoshiaki Iwasaki Department of Surgery Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital Department of Gastrointestinal Surgery Tokyo University Hospital Division of Digestive and General Surgery Niigata University Graduate School of Medical and Dental Sciences

A 72-year-old male gastric cancer patient with outlet obstruction underwent laparoscopic exploration. The examination disclosed intraperitoneal free cancer cells with no overt peritoneal, lymphatic, or hepatic metastasis. The patient underwent laparoscopy-assisted gastroje-junostomy (LAGJ) and started chemotherapy with S-1 plus cisplatin on postoperative day 13. Three course of the chemotherapy shrank the tumor markedly. Then, the patient underwent gastrectomy with a curative intent. Laparotomy revealed no intraperitoneal free cancer cells, and microscopically complete resection was achieved. The patient received S-1 chemotherapy as postoperative adjuvant treatment for 1 year, and is still alive with no evidence of peritoneal recurrence. LAGJ followed by S-1 plus cisplatin is one of the optional treatments that should be considered for patients with outlet obstruction as it may widen opportunities for potentially curative resection.

关键词： Gastric cancer Outlet obstruction CY1 Laparoscopy-assisted gastrojejunostomy S-1 plus cisplatin

Nonalcoholic fatty liver disease and hepatic cirrhosis: comparison with viral hepatitis-associated steatosis

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World Journal of Gastroenterology 2015年第46期21卷 12989-12995页

作者： Yuki Haga tatsuo kanda Reina Sasaki Masato Nakamura Shingo Nakamoto Osamu Yokosuka Department of Gastroenterology and Nephrology Chiba UniversityGraduate School of Medicine Department of Molecular Virology Chiba UniversityGraduate School of Medicine

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.

关键词： Hepatocellular carcinoma Hepatitis B virus Hepatit