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Keiko Arataki,
C Nelson Hayes,
Sakura Akamatsu,
Rie Akiyama,
Hiromi Abe,
Masataka Tsuge,
Daiki Miki,
Hidenori Ochi,
Nobuhiko Hiraga,
Michio Imamura,
Shoichi Takahashi,
Hiroshi Aikata,
Tomokazu Kawaoka,
Hiroiku Kawakami,
Waka Ohishi, Kazuaki Chayama
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ABSTRACT: Hepatitis B virus (HBV) infection is associated with increased expression of microRNA-122. Serum microRNA-122 and microRNA-22 levels were analyzed in 198 patients with chronic HBV who underwent liver biopsy and were compared with quantitative measurements of HBsAg, HBeAg, HBV DNA, and other clinical and histological findings. Levels of serum microRNA-122 and microRNA-22 were determined by reverse transcription-TaqMan PCR. Serum levels of microRNA-122 and microRNA-22 were correlated (R(2) = 0.576; P < 0.001), and both were elevated in chronic HBV patients. Significant linear correlations were found between microRNA-122 or microRNA-22 and HBsAg levels (R(2) = 0.824, P < 0.001 and R(2) = 0.394, P < 0.001, respectively) and ALT levels (R(2) = 0.498, P < 0.001 and R(2) = 0.528, P < 0.001, respectively). MicroRNA-122 levels were also correlated with HBV DNA titers (R(2) = 0.694, P < 0.001 and R(2) = 0.421, P < 0.001). Levels of these microRNAs were significantly higher in HBeAg-positive patients compared to HBeAg-negative patients (P < 0.001 and P < 0.001). MicroRNA-122 levels were also lower in patients with advanced liver fibrosis (P < 0.001) and lower inflammatory activity (P < 0.025). These results suggest that serum micro-RNA levels are significantly associated with multiple aspects of HBV infection. The biological meaning of the correlation between microRNA-122 and HBsAg and should be investigated further. J. Med. Virol. 85:789-798, 2013. © 2013 Wiley Periodicals, Inc.
Journal of Medical Virology 05/2013; 85(5):789-798. · 2.82 Impact Factor
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ABSTRACT: PURPOSE: Endoscopic submucosal dissection (ESD) for colorectal tumor is a minimally invasive treatment. Histologic information obtained from the entire ESD specimen is important for therapy selection in submucosal invasive colorectal carcinoma (SMca). This study aimed to identify risk factors for vertical incomplete resection (vertical margin-positive [VM+]) when ESD was performed as total excisional biopsy for SMca. METHODS: From June 2003 through December 2011, 78 SMca cases were resected by ESD at Hiroshima University Hospital. Patient and tumor characteristics, intraoperative variables, and histopathology were compared between the VM+ group and the vertical complete resection (vertical margin-negative) group. The ability of magnifying endoscopy (ME) and endoscopic ultrasonography (EUS) to predict VM+ was assessed. RESULTS: ESD resulted in VM+ in eight cases (10.3 %), with a greater percentage invading to a depth of ≥2,000 vs. <2,000 μm (P = 0.047). Severe submucosal fibrosis was found in five of the eight cases (62.5 %, P = 0.017). Poor differentiation was seen at the deepest invasive portion in six cases (75.0 %), and two of six cases had an invasion depth <2,000 μm. Of 39 EUS cases, 36 not showing deep invasion close to the muscularis propria were completely resected by ESD. CONCLUSIONS: Submucosal fibrosis and poor differentiation at the deepest invasive portion may be risk factors for VM+ in colorectal ESD for tumors with submucosal deep invasion. ME plus EUS is more likely to help determine whether ESD is indicated as complete total excisional biopsy for SMca.
International Journal of Colorectal Disease 04/2013; · 2.38 Impact Factor
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ABSTRACT: AIM: ME3738, a derivative of soyasapogenol B, enhances the anti-HCV effect of interferon in an in vitro replication system and an in vivo mouse model of HCV infection. ME3738 plus pegylated interferon alpha-2a(PEG-IFNα-2a) treatment for 12 weeks decreased HCV-RNA levels in enrolled late virus responder (LVR) patients with relapsed HCV. Half of the patients reached undetectable HCV-RNA level. The present clinical study of ME3738 was conducted in naïve chronic hepatitis C patients to investigate the sustained virologic response (SVR) and safety of 48-week treatment with ME3738 plus PEG-IFNα-2a. METHODS: Subjects (n=13(5) with genotype 1b chronic hepatitis C with high viral loads were divided into 3 groups (ME3738 50 mg bid, 200 mg bid, or 800 bid). ME3738 was orally and PEG-IFNα-2a (180 μg/week) was subcutaneously administered for 48 weeks, and SVR was assessed at 24 weeks of treatment-free follow-up. RESULTS: The viral disappearance rates at 12 and 48 weeks were 23.0% and 48.9%, respectively. SVR was seen in 5.9% of subjects. ME3738 did not worsen the adverse reactions generally seen with PEG-IFNα-2a treatment, and any adverse reactions specific to ME3738 were not observed. CONCLUSION: ME3738 plus PEG-IFNα-2a treatment to naïve chronic hepatitis C patients showed an antiviral effect and a good safety profile up to 48 weeks. However, HCV-RNA was again detected in many subjects after treatment termination. Even though ME3738 is not enough to suppress HCV reproduction in this treatment,. ME3738 was concurrently used with PEG-IFNα-2a treatment; however, a clear additional effect on SVR was not confirmed.
Hepatology Research 04/2013; · 2.20 Impact Factor
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ABSTRACT: BACKGROUND: Oxidative stress plays a pivotal role on the transition from simple steatosis to nonalcoholic steatohepatitis (NASH). Probucol is a lipid-lowering agent with strong antioxidant properties, and is reported to be effective for the treatment of NASH in several studies. The aim of the present study was to evaluate the efficacy of probucol for the treatment of NASH with dyslipidemia. METHODS: Twenty-six patients with biopsy-proven NASH accompanied by dyslipidemia were treated with 500 mg of probucol daily for 48 weeks. Body mass index (BMI), visceral fat area, liver function tests, serum lipids, fibrosis markers, ferritin, adiponectin, leptin, urinary 8-hydroxy-2'-deoxyguanosine (U-8OHdG), and elasticity (FibroScan502, echoSens, France) were measured periodically during the study. Follow-up liver biopsy was performed in 18 patients. RESULTS: Serum levels of aminotransferases, total cholesterol, and U-8OHdG significantly decreased (p<0.01). Levels of HbA1c, the homeostasis model assessment of insulin resistance index and serum levels of ferritin, type IV collagen 7S, hyaluronic acid significantly decreased (p<0.05). The serum levels of adiponectin tended to be increased. Liver stiffness significantly decreased from 8.8±6.8 to 6.6±4.0 kPa (p<0.01). NAFLD activity scores were significantly improved from 4.2±1.4 to 3.4±1.6 (p<0.05) and fibrosis stages tended to be improved from 1.6±0.8 to 1.3±1.1, respectively. No adverse effects of this treatment were noted. CONCLUSIONS: Probucol improved clinical and histological findings probably through its ability to reduce insulin resistance and oxidative stress. Probucol therapy was safe and effective for Japanese NASH patients with dyslipidemia.
Hepatology Research 04/2013; · 2.20 Impact Factor
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Shintaro Takaki,
Yoshiiku Kawakami,
Daisuke Miyaki,
Takashi Nakahara,
Noriaki Naeshiro,
Eisuke Murakami,
Mio Tanaka,
Yohji Honda,
Satoe Yokoyama,
Yuko Nagaoki,
Tomokazu Kawaoka,
Akira Hiramatsu,
Masataka Tsuge,
Nobuhiko Hiraga,
Michio Imamura,
Hideyuki Hyogo,
Hiroshi Aikata,
Shoichi Takahashi,
Koji Arihiro, Kazuaki Chayama
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ABSTRACT: AIMS: Acoustic radiation Force impulse (ARFI) technology, involving the shear wave velocity (SWV) with virtual touch tissue quantification (VTTQ), are currently available for the assessment of liver fibrosis, while there is no index derived from the combination of SWV and blood tests. The aim of this study was to develop a new index for assessment of liver fibrosis. METHODS: The subjects were 176 consecutive patients with hepatitis C [training set (n=120) and validation set (n=56)] who underwent liver biopsy in our institution. RESULTS: In the training set, SWV, international normalized ratio (INR), and alanine aminotransferase (ALT) correlated independently and significantly with fibrosis, According to this, we developed VIA index = -1.282 + 0.965 × SWV + 1.785 INR + 0.00185 ALT. The area under the receiver operating characteristic curve (AUROC) of the VIA index were 0.838 for the diagnosis of significant fibrosis (≧F2), 0.904 for the severe fibrosis (≧F3), and 0.958 for the cirrhosis (＝F4), in the training set. While in the validation set, AUROC of VIA index were 0.917 for ≧F2, 0.906 for ≧F3, and 1.000 for ＝F4, respectively. AUROC of VIA index was improved compared to SWV alone, equivalence for VIA for the diagnosis≧F2, and superior to that of FIB-4 index and APRI index for the diagnosis ≧F3 and =F4. CONCLUSION: The VIA index is potentially useful for assessment of liver fibrosis than SWV alone, and easily and accurately measures liver fibrosis stage.
Hepatology Research 04/2013; · 2.20 Impact Factor
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Journal of Gastroenterology 04/2013; · 4.16 Impact Factor
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Keiichi Masaki,
Shintaro Takaki,
Hideyuki Hyogo,
Tomoki Kobayashi,
Takayuki Fukuhara,
Noriaki Naeshiro,
Yoji Honda,
Takashi Nakahara,
Atsushi Ohno,
Daisuke Miyaki, [......],
Masataka Tsuge,
Nobuhiko Hiraga,
Akira Hiramatsu,
Michio Imamura,
Yoshiiku Kawakami,
Hiroshi Aikata,
Hidenori Ochi,
Shoichi Takahashi,
Koji Arihiro, Kazuaki Chayama
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ABSTRACT: AIM: Steatosis is a common histological feature of chronic liver disease, especially alcoholic and non-alcoholic fatty liver disease, as well as chronic hepatitis C. A recent study showed that evaluating the controlled attenuation parameter (CAP) with transient elastography was an efficient way of non-invasively determining the severity of hepatic steatosis. The objective of this study was to prospectively evaluate the utility of CAP for diagnosing steatosis in patients with chronic liver disease. METHODS: One hundred and fifty-five consecutive patients with suspected chronic liver disease underwent steatosis diagnosis using CAP, blood sample analyses, computed tomography for assessing the liver/spleen ratio and liver biopsy. Steatosis was graded according to the percentage of fat-containing hepatocytes: S0, less than 5%; S1, 5-33%; S2, 34-66%; and S3: more than 66%. RESULTS: The CAP was significantly correlated with steatosis grade, and there were significant differences between the CAP value of the S0 patients and those of the patients with other grades of steatosis. S0 and S1-3 hepatic steatosis were considered to represent mild and significant steatosis, respectively. The CAP values of the patients with mild and significant steatosis were significantly different (P < 0.0001). The area under the receiver-operator curve (AUROC) value of the CAP for diagnosing significant steatosis was 0.878 (95% confidence interval, 0.818-0.939), and the optimal CAP cut-off value for detecting significant steatosis was 232.5 db/m. In multivariate analysis, the CAP (P = 0.0002) and the liver to spleen ratio (P = 0.004) were found to be significantly associated with significant steatosis. CONCLUSION: The CAP is a promising tool for rapidly and non-invasively diagnosing steatosis.
Hepatology Research 04/2013; · 2.20 Impact Factor
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Yukiko Nakano, Kazuaki Chayama,
Hidenori Ochi,
Masaaki Toshishige,
Yasufumi Hayashida,
Daiki Miki,
C Nelson Hayes,
Hidekazu Suzuki,
Takehito Tokuyama,
Noboru Oda, [......],
Hiroshi Watanabe,
Naoto Endo,
Takeshi Aiba,
Wataru Shimizu,
Seiko Ohno,
Minoru Horie,
Koji Arihiro,
Satoshi Tashiro,
Naomasa Makita,
Yasuki Kihara
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ABSTRACT: Unexplained cardiac arrest (UCA) with documented ventricular fibrillation (VF) is a major cause of sudden cardiac death. Abnormal sympathetic innervations have been shown to be a trigger of ventricular fibrillation. Further, adequate expression of SEMA3A was reported to be critical for normal patterning of cardiac sympathetic innervation. We investigated the relevance of the semaphorin 3A (SEMA3A) gene located at chromosome 5 in the etiology of UCA. Eighty-three Japanese patients diagnosed with UCA and 2,958 healthy controls from two different geographic regions in Japan were enrolled. A nonsynonymous polymorphism (I334V, rs138694505A>G) in exon 10 of the SEMA3A gene identified through resequencing was significantly associated with UCA (combined P = 0.0004, OR 3.08, 95%CI 1.67-5.7). Overall, 15.7% of UCA patients carried the risk genotype G, whereas only 5.6% did in controls. In patients with SEMA3A (I334V), VF predominantly occurred at rest during the night. They showed sinus bradycardia, and their RR intervals on the 12-lead electrocardiography tended to be longer than those in patients without SEMA3A (I334V) (1031±111 ms versus 932±182 ms, P = 0.039). Immunofluorescence staining of cardiac biopsy specimens revealed that sympathetic nerves, which are absent in the subendocardial layer in normal hearts, extended to the subendocardial layer only in patients with SEMA3A (I334V). Functional analyses revealed that the axon-repelling and axon-collapsing activities of mutant SEMA3A (I334V) genes were significantly weaker than those of wild-type SEMA3A genes. A high incidence of SEMA3A (I334V) in UCA patients and inappropriate innervation patterning in their hearts implicate involvement of the SEMA3A gene in the pathogenesis of UCA.
PLoS Genetics 04/2013; 9(4):e1003364. · 8.69 Impact Factor
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Takuya Kitamoto,
Aya Kitamoto,
Masato Yoneda,
Hideyuki Hyogo,
Hidenori Ochi,
Takahiro Nakamura,
Hajime Teranishi,
Seiho Mizusawa,
Takato Ueno, Kazuaki Chayama,
Atsushi Nakajima,
Kazuwa Nakao,
Akihiro Sekine,
Kikuko Hotta
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ABSTRACT: We examined the genetic background of nonalcoholic fatty liver disease (NAFLD) in the Japanese population, by performing a genome-wide association study (GWAS). For GWAS, 392 Japanese NAFLD subjects and 934 control individuals were analyzed. For replication studies, 172 NAFLD and 1,012 control subjects were monitored. After quality control, 261,540 single-nucleotide polymorphisms (SNPs) in autosomal chromosomes were analyzed using a trend test. Association analysis was also performed using multiple logistic regression analysis using genotypes, age, gender and body mass index (BMI) as independent variables. Multiple linear regression analyses were performed to evaluate allelic effect of significant SNPs on biochemical traits and histological parameters adjusted by age, gender, and BMI. Rs738409 in the PNPLA3 gene was most strongly associated with NAFLD after adjustment (P = 6.8 × 10(-14), OR = 2.05). Rs2896019, and rs381062 in the PNPLA3 gene, rs738491, rs3761472, and rs2143571 in the SAMM50 gene, rs6006473, rs5764455, and rs6006611 in the PARVB gene had also significant P values (<2.0 × 10(-10)) and high odds ratios (1.84-2.02). These SNPs were found to be in the same linkage disequilibrium block and were associated with decreased serum triglycerides and increased aspartate aminotransferase (AST) and alanine aminotransferase (ALT) in NAFLD patients. These SNPs were associated with steatosis grade and NAFLD activity score (NAS). Rs738409, rs2896019, rs738491, rs6006473, rs5764455, and rs6006611 were associated with fibrosis. Polymorphisms in the SAMM50 and PARVB genes in addition to those in the PNPLA3 gene were observed to be associated with the development and progression of NAFLD.
Human Genetics 03/2013; · 5.07 Impact Factor
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Tatsuya Maruhashi,
Junko Soga,
Noritaka Fujimura,
Naomi Idei,
Shinsuke Mikami,
Yumiko Iwamoto,
Masato Kajikawa,
Takeshi Matsumoto,
Takayuki Hidaka,
Yasuki Kihara, Kazuaki Chayama,
Kensuke Noma,
Ayumu Nakashima,
Chikara Goto,
Yukihito Higashi
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ABSTRACT: OBJECTIVE: Nitroglycerine-induced vasodilation has been used as a control test for flow-mediated vasodilation (FMD) to differentiate endothelium-dependent from endothelium-independent response when evaluating endothelial function in humans. Recently, nitroglycerine-induced vasodilation has also been reported to be impaired in patients with atherosclerosis. The purpose of this study was to determine the relationships between nitroglycerine-induced vasodilation and cardiovascular risk factors.Approach and Results-We measured nitroglycerine-induced vasodilation and FMD in 436 subjects who underwent health examinations (mean age, 53±19 years; age range, 19-86 years), including patients with cardiovascular diseases. There was a significant relationship between nitroglycerine-induced vasodilation and FMD (r=0.42; P<0.001). Univariate regression analysis revealed that nitroglycerine-induced vasodilation correlated with age (r=-0.34; P<0.001), systolic blood pressure (r=-0.32; P<0.001), diastolic blood pressure (r=-0.24; P<0.001), heart rate (r=-0.21; P<0.001), glucose (r=-0.23; P<0.001), and smoking pack-year (r=-0.12; P=0.01), as well as Framingham risk score (r=-0.30; P<0.001). Nitroglycerine-induced vasodilation was significantly smaller in patients with cardiovascular disease than in both subjects with and without cardiovascular risk factors (10.5±5.6% versus 13.7±5.4% and 15.3±4.3%; P<0.001, respectively), whereas there was no significant difference in nitroglycerine-induced vasodilation between subjects with and without cardiovascular risk factors. Multivariate analysis revealed that male sex, body mass index, hypertension, diabetes mellitus, baseline brachial artery diameter, and FMD were independent predictors of nitroglycerine-induced vasodilation. CONCLUSIONS: These findings suggest that nitroglycerine-induced vasodilation may be a marker of the grade of atherosclerosis. FMD should be interpreted as an index of vascular function reflecting both endothelium-dependent vasodilation and endothelium-independent vasodilation in subjects with impaired nitroglycerine-induced vasodilation.
Arteriosclerosis Thrombosis and Vascular Biology 03/2013; · 6.37 Impact Factor
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Yoko Kominami,
Hiroshi Aikata,
Ken Hiramatsu,
Mio Tanaka,
Noriaki Naeshiro,
Takashi Nakahara,
Yoji Honda,
Yuko Nagaoki,
Eisuke Murakami,
Daisuke Miyaki, [......],
Shintaro Takaki,
Nobuhiko Hiraga,
Masaki Tsuge,
Masahiro Serikawa,
Michio Imamura,
Hideyuki Hyogo,
Yoshiiku Kawakami,
Shoichi Takahashi,
Tamito Sasaki, Kazuaki Chayama
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ABSTRACT: A 61-year-old man was admitted to our hospital for examination of the cause of rapid growth of a liver cyst. We found a slight dilatation of bile duct in the vicinity of the liver cyst. Then, we underwent ERCP and found a communication between the bile duct and liver cyst. Bile cytodiagnosis revealed a large quantity of clonorchis eggs. The patient like to do eat raw freshwater fish and we suspected that the acute expansion of the cyst was due to clonorchiasis. Following administration of 40mg/kg praziquantel, the blood clonorchis antibody disappeared and the liver cyst also disappeared after 6 months. We encountered a case of clonorchiasis complicated with growth of a liver cyst. Medical interviews should be conducted carefully along with meticulous examinations.
Nippon Shokakibyo Gakkai zasshi The Japanese journal of gastro-enterology 03/2013; 110(3):456-64.
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ABSTRACT: Among early colorectal carcinoma, endoscopic treatment is generally indicative for cases with intramucosal to submucosal (SM) superficial invasion, because cases with SM deep invasion should be treated surgically due to the risk of lymph node metastasis. It is important, therefore, to distinguish between superficial and deep SM invasion in early colorectal carcinoma prior to treatment. In this review we assessed the clinical usefulness and knack of pit pattern and narrow band imaging (NBI) diagnosis using magnifying observation. VN type pit pattern, type C3 in NBI Hiroshima classification and NBI type 3 in NBI international colorectal endoscopic (NICE) classification are useful predictors of SM deep invasion. In NBI magnifying observation evaluation of both the vascular pattern and surface pattern are important. We have to use pit pattern diagnosis and NBI magnifying diagnosis as the situation demands with the knowledge of both advantage and disadvantage in each diagnostic method.
Clinical endoscopy. 03/2013; 46(2):138-46.
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Rie Miyaki,
Shigeto Yoshida,
Shinji Tanaka,
Yoko Kominami,
Yoji Sanomura,
Taiji Matsuo,
Shiro Oka,
Bisser Raytchev,
Toru Tamaki,
Tetsushi Koide,
Kazufumi Kaneda,
Masaharu Yoshihara, Kazuaki Chayama
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ABSTRACT: BACKGROUND AND AIM: Magnifying endoscopy with flexible spectral imaging color enhancement (FICE) is clinically useful in diagnosing gastric cancer and determining treatment options. There is a learning curve, however. Accurate FICE-based diagnosis requires training and experience. In addition, objectivity is necessary. Thus, we developed a software program that can identify gastric cancer quantitatively. METHODS: We applied a bag-of-features framework with densely sampled scale-invariant feature transform (SIFT) descriptors to magnifying endoscopy images of 46 mucosal gastric cancers. We compared our computer-based findings to histologic findings. We calculated the probability of gastric cancer by means of logistic regression and determined sensitivity and specificity of our system. RESULTS: The average probability was 0.78±0.25 for the images of cancer and 0.31±0.25 for the images of noncancer tissue, with a significant difference between the two groups. An optimal cut-off point of 0.59 was determined on the basis of the ROC curves. The computer-aided diagnosis system yielded a detection accuracy of 85.9% (79/92), sensitivity for a diagnosis of cancer of 84.8% (39/46), and specificity of 87.0% (40/46). CONCLUSION: Further development of our system will allow for quantitative evaluation of mucosal gastric cancers on magnifying gastrointestinal endoscopy images obtained with FICE.
Journal of Gastroenterology and Hepatology 02/2013; · 2.87 Impact Factor
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Journal of Gastroenterology 02/2013; · 4.16 Impact Factor
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Masataka Tsuge,
Eisuke Murakami,
Michio Imamura,
Hiromi Abe,
Daiki Miki,
Nobuhiko Hiraga,
Shoichi Takahashi,
Hidenori Ochi,
C Nelson Hayes,
Hiroyuki Ginba,
Kazuhiro Matsuyama,
Hiroiku Kawakami, Kazuaki Chayama
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ABSTRACT: BACKGROUND: Treatment for chronic hepatitis B has improved drastically with the use of nucleot(s)ide analogues (NAs). However, NA therapy typically fails to eliminate Hepatitis B virus (HBV) completely, and it is difficult to discontinue these therapies. We previously demonstrated that NA therapy induced immature viral particles, including HBV RNA in sera of chronic hepatitis B patients. In the study reported here, we analyzed the association between HBV RNA titer and the recurrence rate of hepatitis after discontinuation of NA therapy. METHODS: The study cohort comprised 36 patients who had discontinued NA therapy. Serum HBV DNA or DNA plus RNA levels were measured by real time PCR and statistical analyses were performed using clinical data and HBV markers. RESULTS: At 24 weeks after discontinuation of NA therapy, HBV DNA rebound was observed in 19 of the 36 patients (52.8 %), and alanine aminotransferase (ALT) rebound was observed in 12 of 36 patients (33.3 %). Multivariate statistical analysis was used to identify factors predictive of HBV DNA rebound. The HBV DNA + RNA titer following 3 months of treatment was significantly associated with HBV DNA rebound [P = 0.043, odds ratio (OR) 9.474, 95 % confidence interval (CI) 1.069-83.957)]. Absence of hepatitis B e antigen (HBeAg) at the end of treatment was significantly associated with ALT rebound (P = 0.003, OR 13.500, 95 % CI 2.473-73.705). In HBeAg-positive patients, the HBV DNA + RNA titer after 3 months of treatment was marginally associated with ALT rebound (P = 0.050, OR 8.032, 95 % CI 0.997-64.683). CONCLUSIONS: Monitoring of serum HBV DNA + RNA levels may be a useful method for predicting re-activation of chronic hepatitis B after discontinuation of NA therapy.
Journal of Gastroenterology 02/2013; · 4.16 Impact Factor
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Niu Shi,
Nobuhiko Hiraga,
Michio Imamura,
C Nelson Hayes,
Yizhou Zhang,
Keiichi Kosaka,
Akihito Okazaki,
Eisuke Murakami,
Masataka Tsuge,
Hiromi Abe, [......],
Shoichi Takahashi,
Hidenori Ochi,
Chise Tateno-Mukaidani,
Katsutoshi Yoshizato,
Hirotaka Matsui,
Akinori Kanai,
Toshiya Inaba,
Fiona McPhee,
Min Gao, Kazuaki Chayama
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ABSTRACT: OBJECTIVE: We recently demonstrated that combination treatment with NS3 protease and NS5B polymerase inhibitors succeeded in eradicating the virus in genotype 1b hepatitis C virus (HCV)-infected mice. In this study, we investigated the effect of combining an NS5A replication complex inhibitor (RCI) with either NS3 protease or NS5B inhibitors on elimination of HCV genotypes 1b, 2a and 2b. DESIGN: The effects of Bristol-Myers Squibb (BMS)-605339 (NS3 protease inhibitor; PI), BMS-788329 (NS5A RCI) and BMS-821095 (NS5B non-nucleoside analogue inhibitor) on HCV genotypes 1b and 2a were examined using subgenomic HCV replicon cells. HCV genotype 1b, 2a or 2b-infected human hepatocyte chimeric mice were also treated with BMS-605339, BMS-788329 or BMS-821095 alone or in combination with two of the drugs for 4 weeks. Genotypic analysis of viral sequences was achieved by direct and ultra-deep sequencing. RESULTS: Anti-HCV effects of BMS-605339 and BMS-821095 were more potent against genotype 1b than against genotype 2a. In in-vivo experiments, viral breakthrough due to the development of a high prevalence of drug-resistant variants was observed in mice treated with BMS-605339, BMS-788329 and BMS-821095 in monotherapy. In contrast to monotherapy, 4 weeks of combination therapy with the NS5A RCI and either NS3 PI or NS5B inhibitor succeeded in completely eradicating the virus in genotype 1b HCV-infected mice. Conversely, these combination therapies failed to eradicate the virus in mice infected with HCV genotypes 2a or 2b. CONCLUSIONS: These oral combination therapies may serve as a Peg-alfa-free treatment for patients chronically infected with HCV genotype 1b.
Gut 01/2013; · 10.11 Impact Factor
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Yuji Urabe,
Hidenori Ochi,
Naoya Kato,
Vinod Kumar,
Atsushi Takahashi,
Ryosuke Muroyama,
Naoya Hosono,
Motoyuki Otsuka,
Ryosuke Tateishi,
Paulisally Hau Yi Lo, [......],
Kazuhiko Koike,
Daiki Miki,
Hiromi Abe,
Naoyuki Kamatani,
Joji Toyota,
Hiromitsu Kumada,
Michiaki Kubo, Kazuaki Chayama,
Yusuke Nakamura,
Koichi Matsuda
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ABSTRACT: BACKGROUND&AIM: We performed a genome-wide association study (GWAS) of hepatitis C virus (HCV)-induced liver cirrhosis (LC) to identify predictive biomarkers for the risk of LC in patients with chronic hepatitis C (CHC). METHOD: A total of 682 HCV-induced LC cases and 1,045 CHC patients of Japanese origin were genotyped by Illumina Human Hap 610-Quad bead Chip. RESULT: Eight SNPs which showed possible associations (P < 1.0 x 10(-5)) in the GWAS stage were further genotyped using 936 LC cases and 3,809 CHC patients. We found that two SNPs within the major histocompatibility complex (MHC) region on chromosome 6p21, rs910049 and rs3135363, were significantly associated with the progression from CHC to LC (P(combined) = 9.15 x 10(-11) and 1.45 x 10(-10), odds ratio (OR) = 1.46 and 1.37, respectively). We also found that HLA-DQA1∗0601 and HLA-DRB1∗0405 were associated with progression from CHC to LC (P = 4.53 x 10(-4) and 1.54 x 10(-4) with OR = 2.80 and 1.45, respectively). Multiple logistic regression analysis revealed that rs3135363, rs910049, and HLA-DQA1∗0601 were independently associated with the risk of HCV-induced LC. In addition, individuals with four or more risk alleles for these three loci have a 2.83-fold higher risk for LC than those with no risk allele, indicating the cumulative effects of these variations. CONCLUSION: Our findings elucidated the crucial roles of multiple genetic variations within the MHC region as prognostic/predictive biomarkers for CHC patients.
Journal of Hepatology 01/2013; · 9.26 Impact Factor
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Hisako Furusho,
Mutsumi Miyauchi,
Hideyuki Hyogo,
Toshihiro Inubushi,
Min Ao,
Kazuhisa Ouhara,
Junzou Hisatune,
Hidemi Kurihara,
Motoyuki Sugai,
C Nelson Hayes,
Takashi Nakahara,
Hiroshi Aikata,
Shoichi Takahashi, Kazuaki Chayama,
Takashi Takata
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ABSTRACT: BACKGROUND: We investigated the effects of dental infection with Porphyromonas gingivalis (P.g.), an important periodontal pathogen, on NASH progression, by feeding mice a high fat diet (HFD)and examining P.g. infection in the liver of NASH patients. METHODS: C57BL/6J mice were fed either chow-diet (CD) or HFD for 12 weeks, and then half of the mice in each group were infected with P.g. from the pulp chamber (HFD-P.g.(-), HFD-P.g.(+), CD-P.g.(-) and CD-P.g.(+)). Histological and immunohistochemical examinations, measurement of serum lipopolysaccharide (LPS) levels and ELISA for cytokines in the liver were performed. We then studied the effects of LPS from P.g. (P.g.-LPS) on palmitate-induced steatotic hepatocytes in vitro, and performed immunohistochemical detection of P.g. in liver biopsy specimens of NASH patients. RESULTS: Serum levels of LPS are upregulated in P.g.(+) groups. Steatosis of the liver developed in HFD groups, and foci of Mac2-positive macrophages were prominent in HFD-P.g.(+). P.g. was detected in Kupffer cells and hepatocytes. Interestingly, areas of fibrosis with proliferation of hepatic stellate cells and collagen formation were only observed in HFD-P.g.(+). In steatotic hepatocytes, expression of TLR2, one of the P.g.-LPS receptors, was upregulated. P.g.-LPS further increased mRNA levels of palmitate-induced inflammasome and proinflammatory cytokines in steatotic hepatocytes. We demonstrated for the first time that P.g. existed in the liver of NASH patients with advanced fibrosis. CONCLUSIONS: Dental infection of P.g. may play an important role in NASH progression through upregulation of the P.g.-LPS-TLR2 pathway and activation of inflammasomes. Therefore, preventing and/or eliminating P.g. infection by dental therapy may have a beneficial impact on management of NASH.
Journal of Gastroenterology 01/2013; · 4.16 Impact Factor
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ABSTRACT: Background/Aim: The aim of this study was to examine the relationship between narrow-band imaging (NBI) magnifying observation using the surface pattern as the main evaluation criterion and pit pattern diagnosis on the basis of magnifying observation using a dye in relation to the characteristics of colorectal tumors according to their morphologies. Methods: In this study, NBI observation and pit pattern diagnosis using a dye with magnifying observation were simultaneously performed in our hospital, and the consecutive 786 cases of colorectal lesions (hyperplasia, adenomata and early carcinomas) that had been endoscopically or surgically resected were retrospectively analyzed. NBI magnifying observation was in conformance with the Hiroshima classification and pit pattern diagnosis was in conformance with the Kudo and Tsuruta classification. The relationship between NBI magnifying observation and pit pattern diagnosis and that between NBI magnifying observation and the histological type/invasion depth were examined in relation to colorectal tumor morphology. Results: Type A corresponded to the type II pit pattern, type B corresponded to the type III(S), type III(L) and type IV regular pit patterns, type C1 corresponded to the type V(I) slightly irregular pit pattern, type C2 corresponded to the type V(I) highly irregular pit pattern and type C3 corresponded to the type V(N) pit pattern. In the protruded type, the irregularity of type C1 or C2 lesions agreed with the type V(I) slightly or highly irregular pit pattern, respectively, in 114 cases (64.0%). Moreover, the irregularity was higher with NBI magnifying observation than with pit pattern diagnosis in 58 cases (32.6%). In the superficial type, the irregularity of type C1 or C2 lesions agreed with the type V(I) slightly or highly irregular pit pattern, respectively, in 63 cases (71.6%). Moreover, the irregularity was higher with NBI magnifying observation than with pit pattern diagnosis in 19 cases (21.6%). In the case of type C1 or C2 lesions, the irregularity tended to be higher with NBI magnifying observation than with pit pattern diagnosis in the protruded type compared to the superficial type (p = 0.087). Conclusion: The surface pattern, which was visible in NBI magnifying observation, differed from the pit pattern findings obtained by magnifying endoscopic observation using a dye. Findings were more detailed in pit pattern diagnosis using a dye than in NBI magnifying observation.
Digestion 01/2013; 87(1):53-8. · 2.05 Impact Factor
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Paulisally Hau Yi Lo,
Yuji Urabe,
Vinod Kumar,
Chizu Tanikawa,
Kazuhiko Koike,
Naoya Kato,
Daiki Miki, Kazuaki Chayama,
Michiaki Kubo,
Yusuke Nakamura,
Koichi Matsuda
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ABSTRACT: Hepatitis C virus (HCV) infection is the major cause of hepatocellular carcinoma (HCC) in Japan. We previously identified the association of SNP rs2596542 in the 5' flanking region of the MHC class I polypeptide-related sequence A (MICA) gene with the risk of HCV-induced HCC. In the current study, we performed detailed functional analysis of 12 candidate SNPs in the promoter region and found that a SNP rs2596538 located at 2.8 kb upstream of the MICA gene affected the binding of a nuclear protein(s) to the genomic segment including this SNP. By electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP) assay, we identified that transcription factor Specificity Protein 1 (SP1) can bind to the protective G allele, but not to the risk A allele. In addition, reporter construct containing the G allele was found to exhibit higher transcriptional activity than that containing the A allele. Moreover, SNP rs2596538 showed stronger association with HCV-induced HCC (P = 1.82×10(-5) and OR = 1.34) than the previously identified SNP rs2596542. We also found significantly higher serum level of soluble MICA (sMICA) in HCV-induced HCC patients carrying the G allele than those carrying the A allele (P = 0.00616). In summary, we have identified a functional SNP that is associated with the expression of MICA and the risk for HCV-induced HCC.
PLoS ONE 01/2013; 8(4):e61279. · 4.09 Impact Factor
