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Background It is unclear whether hepatocyte function and/or portal hypertension improves if a sustained virologic response (SVR) is achieved with direct-acting antivirals in patients with decompensated hepatitis C-related cirrhosis. Methods We examined the safety and efficacy of a 12-week course of sofosbuvir/velpatasvir (SOF/VEL) in 20 patients with decompensated hepatitis C-related cirrhosis. We also investigated changes in the hepatocyte receptor index (LHL15) and blood clearance index (HH15) by Tc-99 m-galactosyl human serum albumin scintigraphy, liver stiffness measurement (LSM) by transient elastography, and hepatic venous pressure gradient (HVPG) in patients who achieved an SVR at 24 weeks after treatment (SVR24). Results One patient discontinued treatment because of rectal variceal hemorrhage, and 19 patients completed treatment. SVR24 was achieved in 17 patients (89%). Median LHL15 increased from 0.72 pre-treatment to 0.82 after SVR24 (p = 0.012), and median HH15 decreased from 0.82 pre-treatment to 0.76 after SVR24 (p = 0.010). The percentage of patients with LSM ≥ 20 kPa was 90% before treatment and remained at 90% after SVR24. However, the percentage with severe portal hypertension (defined as HVPG ≥ 12 mmHg) decreased from 92% pre-treatment to 58% after SVR24 (p = 0.046). Patients with a decreased HVPG from pre-treatment to after SVR24 had a smaller pre-treatment spleen volume than those with an increased HVPG (median, 252 vs. 537 mL, p = 0.028). Conclusion Achieving SVR24 with SOF/VEL treatment in patients with decompensated hepatitis C-related cirrhosis can be expected to improve hepatocyte function and portal hypertension on short-term follow-up.

A direct-acting antiviral (DAA)-induced sustained virological response (SVR) reduces the risk of mortality. However, the risk factors associated with liver-related and non-liver-related mortality following a SVR after DAA treatment are unclear. We assessed the incidence and risk factors of liver-related and non-liver-related mortality in 1,180 patients who achieved a SVR after DAA treatment. During the follow-up period after DAA treatment (median duration, 1,099 [range: 84-2,345] days), 53 (4.5%) patients died: 15 due to liver-related mortality, 25 due to non-liver-related mortality, and 13 due to unknown causes. The all-cause, liver-related, and non-liver-related mortality rates were 14.9, 4.2, and 7.0/1,000 person-years, respectively. In a multivariate analysis, the development of hepatocellular carcinoma (HCC) after DAA treatment (p = 0.009; hazard ratio [HR], 31.484), an estimated glomerular filtration rate (eGFR) at baseline ≤ 61.68 mL/min/1.73 m

研究グループは、C型肝炎ウイルスの感染がある初期の肝がん患者に対して、がんの治療後に経口治療薬(DAA)治療によりC型肝炎ウイルスを排除することで、肝がんの進行リスクを低下させることを初めて明らかにしました。さらに、肝がんの治療頻度、死亡リスクも低下させることを明らかにしました。本研究成果により、DAA治療が肝がん治療後の患者にも有益性が高いことが示されました。C型肝炎ウイルス感染症は肝がんの原因となる感染症で、DAA治療はC型肝炎ウイルスに直接作用して増殖を抑える飲み薬です。肝がんになったことのない患者にDAA治療を行うと、肝がんが発生しにくくなることが明らかとなっていますが、肝がん根治後の患者にもがんを抑える効果があるかどうかははっきりしていませんでした。今回、本研究グループは、初発で初期の肝がんを根治した患者165例を対象とし、がんの治療後にDAA治療でC型肝炎ウイルス感染症を治すことにより、肝がんの再発リスク、がんの進行リスク、がんの治療頻度、肝臓病による死亡リスクがどのように変化するか調査しました。その結果、DAA治療をした患者としなかった患者では、再発リスクはすでにいくつもの研究で報告されているのと同じく差が見られませんでした。しかし、がんの進行リスクは、DAA治療をした患者で72%も低下しました。さらに、肝臓病による死亡リスクは88%も低下し、治療頻度も1年で59%も低下しました。, Hepatocellular carcinoma (HCC) has high recurrence rates. HCC sometimes progresses from early-stage HCC (Barcelona Clinic Liver Cancer [BCLC] stage 0/A) to advanced-stage HCC after repeated recurrences and treatments. HCC progression deteriorates quality of life and prognosis. However, ......

Background and Aims: Tolvaptan, an orally active vasopressin V2-receptor antagonist, has been used for patients with difficult-to-treat ascites in Japan. In this study, we conducted a genome-wide association study (GWAS) in the Japanese population to identify genetic variants associated with tolvaptan’s efficacy for patients with hepatic ascites. Methods: From 2014 through 2018, genomic DNA samples were obtained from 550 patients who were treated with tolvaptan. Of those, 80 cases (non-responder; increase of body weight [BW]) and 333 controls (responder; > 1.5 kg decrease of BW) were included in the GWAS and replication study. Results: GWAS showed 5 candidate SNPs around the miR818, KIAA1109, and SVEP1 genes. After validation and performing a replication study, an SNP (rs2991364) located in the SVEP1 gene was found to have a significant genome-wide association (OR = 3.55, P = 2.01 x 10− 8). Univariate and multivariate analyses showed that blood urea nitrogen (BUN) and SVEP1 SNP were significantly associated with the response (OR = 1.03, p = 0.02 and OR = 4.24, p SVEP1 rs2991364 was identified as the specific SNP for the tolvaptan response. The prediction score can identify tolvaptan non-responders and help to avoid a lengthy period of futile treatment.

Background and Aim We assessed direct‐acting antiviral (DAA) treatment for patients with hepatitis C virus (HCV) and a history of injection drug use (IDU) in Japan. Method This retrospective observational study was based on clinical records. Overall, 804 DAA‐naïve HCV‐infected patients were enrolled, treated with a 12‐week regimen of DAAs, and had available information about a history of IDU. Anti‐HCV efficacy was defined as a sustained viral response 12 weeks post‐treatment (SVR12) only in patients who were assessed after 12 weeks [modified intention‐to‐treat (ITT) analyses]. We compared the antiviral effect between patients with (past‐IDU) and without a history of IDU (non‐IDU). We also evaluated the characteristics of each group, including the overall dropout rate and economic background. Results Overall, 78 (9.7%) patients had a history of IDU. Compared to the non‐IDU group at baseline, the past‐IDU group consisted of predominantly male and younger patients infected with HCV genotype 2. Overall, 3% (3/78) and 16% (116/726) of the patients had cirrhosis in the past‐IDU and non‐IDU group, respectively. There was a significantly higher rate of welfare recipients in the past‐IDU group. SVR rate was 97% (59/61) in the past‐IDU group and 99% (689/699) in the non‐IDU group. The cumulative rate of dropout from an aftercare program was high in the past‐IDU group (P, The cumulative dropout rates from the aftercare program of antihepatitis C therapy were significantly higher in the past‐IDU group compared to those in the non‐IDU group (P

It is not fully clear as to which dietary patterns are associated with the pathogenesis of nonalcoholic fatty liver disease (NAFLD) in Asia. We conducted a cross-sectional study of 136 consecutively recruited patients with NAFLD (49% female, median age 60 years). Severity of liver fibrosis was assessed using the Agile 3+ score, a recently proposed system based on vibration-controlled transient elastography. Dietary status was assessed using the 12-component modified Japanese diet pattern index (mJDI12). Skeletal muscle mass was assessed by bioelectrical impedance. Factors associated with intermediate–high-risk Agile 3+ scores and skeletal muscle mass (75th percentile or higher) were analyzed by multivariable logistic regression. After adjustment for confounders, such as age and sex, the mJDI12 (OR: 0.77; 95% CI: 0.61, 0.99) and skeletal muscle mass (75th percentile or higher) (OR: 0.23; 95% CI: 0.07, 0.77) were significantly associated with intermediate–high-risk Agile 3+ scores. Soybeans and soybean foods were significantly associated with skeletal muscle mass (75th percentile or higher) (OR: 1.02; 95% CI: 1.00, 1.04). In conclusion, the Japanese diet pattern was associated with the severity of liver fibrosis in Japanese patients with NAFLD. Skeletal muscle mass was also associated with the severity of liver fibrosis, and intake of soybeans and soybean foods.

It is unclear whether multiple nonstructural (NS) 5A resistance-associated substitutions (RASs) correlate with the outcome of sofosbuvir (SOF) and ledipasvir (LDV) therapy. We investigated the effects of multiple NS5A RASs in NS5A inhibitor-naive patients with chronic hepatitis C virus genotype 1b infection treated with SOF/LDV. In 313 patients treated with SOF/LDV, we assessed the effects of multiple NS5A RASs on the sustained virological response (SVR). RASs at L28, R30, L31, Q54, P58, Q62, A92, and Y93 in the NS5A region were examined by direct sequencing. The prevalence of RASs was as follows: 2.6% at L28, 8.7% at R30, 6.1% at L31, 48.7% at Q54, 9.9% at P58, 9.9% at Q62, 5.1% at A92, 13.8% at Y93, and 19.2% at L31 or Y93. A total of 133 patients had no RASs. SVR was achieved in 98.7% of the patients. SVR rates significantly differed between patients with and without the L31 or Y93 RAS (93.0% [53/57] vs 100% [250/250], P = .0011). In addition, among patients with the L31 or Y93 RAS, 29.8%, 45.6% and 24.6% had one, two and three or more NS5A RASs, respectively. The SVR rate was significantly lower in patients with the L31 or Y93 RAS with more than three NS5A RASs compared to those with fewer than three NS5A RASs (71.4% [10/14] vs 100% [43/43], P = .0025). Although the prevalence of multiple NS5A RASs at baseline was low in NS5A inhibitor-naive patients, the presence of multiple NS5A RASs was associated with the effectiveness of SOF/LDV therapy.

Background and Aim It is unclear whether polymorphism in the inosine triphosphatase (ITPA) gene correlates with the reduction in hemoglobin (Hb) concentrations during sofosbuvir (SOF) and ribavirin (RBV) therapy. We investigated the effects of the ITPA polymorphism in Japanese patients with chronic hepatitis C virus genotype 2 infection treated with SOF/RBV therapy. Methods In 106 patients treated with SOF/RBV therapy, we assessed the effects of the ITPA polymorphism (rs1127354) on anemia, RBV dose reduction, and sustained virological response (SVR). Results Of the 106 patients, 80 had the CC genotype, whereas 26 had a non-CC genotype in ITPA. Patients with the CC genotype had significantly larger reductions in Hb concentrations than those with a non-CC genotype throughout the treatment course. RBV dose reduction was required in 18/106 (17.0%) patients, with a significantly higher frequency in patients with the CC genotype than in those with a non-CC genotype (p = 0.010). In multivariate analysis, age ≥ 65 years (p = 0.011) and the ITPA CC genotype (p

Simeprevir (SMV) is a potent, macrocyclic hepatitis C virus (HCV) non-structural 3/4 A protease inhibitor. This prospective study compared the efficacy and safety of SMV in combination with peginterferon α2a + ribavirin (P2aR) and with peginterferon α2b + ribavirin (P2bR) in Japanese patients with HCV genotype 1b infection. Methods Hepatitis C virus genotype 1b patients were randomly assigned to receive SMV (100 mg QD) with P2aR for 12 weeks, then P2aR alone for 12 or 36 weeks; or SMV (100 mg QD) with P2bR for 12 weeks, then P2bR alone for 12 or 36 weeks. The primary endpoint was a sustained virologic response 24 weeks after completing treatment (SVR24). Results In total, 151 patients were randomly assigned to the P2aR (n = 76) or P2bR group (n = 75). Six patients dropped out. Sustained virologic response 24 weeks after completing treatment was achieved in 55 (75.3%) of 73 P2aR patients and 55 (76.4%) of 72 P2bR patients. There was no difference in the rate of SVR24 between the two groups (P = 0.88). No differences in the proportion of patients who became HCV RNA-negative were detected between the P2aR and P2bR groups. The two groups had comparable numbers of adverse events, which led to the discontinuation of treatment in 9.6% and 8.3% of participants in the P2aR and P2bR groups, respectively. Conclusion Peginterferon α2a or α2b in combination with SMV + ribavirin therapy showed identical antiviral effects in patients with chronic hepatitis C. Also, the incidence of adverse events was identical for both regimens.

In this study, we propose a sit-to-stand intention estimation method and verify its effectiveness. The proposed method uses the trunk forward inclination in sit-to-stand movements and the order of the associated activity of the lower limb muscles to estimate the sit-to-stand intention without learning data or recalibrating. The evaluation results of the proposed method on three subjects, who performed the sitto-stand movements, including three types of noisy movements, shows that the movement is predicted 211 ms before it commences with a 98.3% accuracy.

Recently, three tyrosine kinase inhibitors (TKIs) have become available for treatment of unresectable hepatocellular carcinoma (HCC). We herein report a case of a 59-year-old man with interstitial pneumonia that was suspected during regorafenib administration and was exacerbated by subsequent lenvatinib treatment for advanced HCC. After sorafenib was discontinued due to progressive HCC, regorafenib treatment was started. Progressive HCC was again noted and reticular shadows were suspected in both lower lung fields at 2 months after starting regorafenib administration. Subsequent treatment with lenvatinib obtained a partial response for HCC, but the reticular shadows became marked and dyspnea on effort emerged, followed by hypoxemia and an increased Krebs von den Lungen-6 (KL-6) value. Because we suspected acute interstitial pneumonia, due to these TKIs, intravenous pulse steroid therapy was started immediately after discontinuing lenvatinib. Within 1 week after starting steroid therapy, the patient’s respiratory condition and hypoxemia gradually began improving. No previous case of pulmonary interstitial changes that appeared in association with regorafenib administration for HCC and that were exacerbated by subsequent treatment with lenvatinib has been reported. This case emphasizes that it is necessary to observe the patient’s respiratory condition and to perform imaging examinations to monitor for adverse events during TKI treatment.

BACKGROUND AND AIMS It remains unclear whether there is an association between single-nucleotide polymorphisms (SNPs) and development of hepatocellular carcinoma (HCC) during entecavir (ETV) treatment in nucleos(t)ide analog-naive patients with chronic hepatitis B virus infection. We investigated the risk factors for HCC, especially host factors, during ETV treatment. METHODS A total of 127 Japanese patients undergoing ETV treatment were enrolled in this study. Univariate and multivariate analyses for clinical factors, hepatic fibrosis markers, and SNPs associated with HCC development were analyzed. RESULTS A total of 10 patients developed HCC during the follow-up period (median duration, 3.3 years). The 3-, 5-, and 7-year cumulative rates of HCC development were 4.8%, 10.6%, and 13.6%, respectively. Liver fibrosis (cirrhosis; P = 0.0005), age (≥ 49 years; P = 0.0048), platelet count (≤ 115 × 10/mm3 ; P = 0.0007), α-fetoprotein (≥ 8.0 ng/mL; P = 0.030), type IV collagen (≥ 200 ng/mL; P = 0.043), fibrosis-4 index (≥ 4.14; P = 0.0006), and human leukocyte antigen (HLA)-DQA1/DRB1-SNP (AA genotype; P = 0.0092) were significantly associated with HCC development according to the log-rank test. In multivariate analysis, AA genotype in the HLA-DQA1/DRB1 gene (P = 0.013; hazard ratio 4.907; 95% confidence interval 1.407-17.113) and cirrhosis (P = 0.019; hazard ratio 4.789; 95% confidence interval 1.296-17.689) were significantly associated with HCC development. CONCLUSIONS Our findings suggested that patients with AA genotype in the HLA-DQA1/DRB1 gene or cirrhosis should be carefully followed up as a population potentially at higher risk of HCC during ETV treatment.

【概要】C型慢性肝炎に対するDAA治療後の肝病理組織所見の検討は、これまで十分になされていませんでした。本研究ではDAA治療によってウイルス排除に成功し、かつ血液検査で異常が見られなかった51症例に対し肝生検を行い、炎症、線維化、鉄沈着、脂肪化などの項目について調べました。その結果、ほとんどの症例で肝組織の改善が見られました。また、同時に約2割程度の症例に有意な炎症が残存していることがわかりました。DAAによってC型肝炎ウイルスを排除することにより、血液検査のみならず肝生検結果の改善も見られたことから、治療によって将来的には肝硬変や肝臓がんへの進展が予防できることが期待されます。一方、炎症が残存していた症例の少なくとも一部は脂肪肝炎が原因であったことから、治療後もアルコール多飲や肥満などを避けて生活習慣に注意する必要があると考えられます。, Background: Interferon-free, direct-acting antiviral (DAA) treatments can result in a sustained virologic response (SVR) in nearly 100% of patients with chronic hepatitis C virus (HCV) infection. / Aims: To evaluate histological improvement after achieving an SVR to DAA treatments in patients with chronic hepatitis C. / Methods: Among 691 patients with chronic hepatitis C who achieved an SVR to DAAs, 51 underwent liver biopsy 41 ± 20 weeks after the end of treatment despite normal transaminase levels. In 20 patients, liver biopsy specimens obtained a median of 1.2 years before the start of treatment were available....

Background Hepatocellular carcinoma (HCC) develops in some patients who achieve sustained virological response (SVR) against hepatitis C virus (HCV) infection via anti-HCV therapy. To examine the pathogenesis of HCC development after HCV eradication, histopathological changes and clinical markers were evaluated in SVR patients. Methods Of 654 SVR patients treated with interferon (IFN)-based therapies, 34 patients who had undergone liver biopsy before initiating IFN therapy and after SVR achievement were enrolled: 11 patients with HCC and 23 patients without HCC (male/female, 9/2 and 8/15, respectively: age, 58 ± 5 and 54 ± 11 years, respectively). We compared the clinical and histopathological factors between the two groups. Immunohistochemistry for Cytoglobin (CYGB) and α smooth muscle actin (α-SMA) was also performed. Results At baseline, prior to initiating the IFN-based therapy, there were significant differences between the SVR-non-HCC and SVR-HCC groups in the male gender, HBc antibody positivity, prothrombin activity, and histological inflammatory grade. Histopathological evaluation, using the new Inuyama classification system, revealed an improvement in the inflammatory grade, from 2.1 ± 0.6 to 1.0 ± 0.6 (p < 0.0001), whereas the fibrosis stage remained unchanged, from 2.3 ± 0.9 to 2.0 ± 1.2 (p = 0.2749), during the 97 ± 72-month observation period in the SVR-HCC group. Both the grade and stage scores were significantly improved in the SVR-non-HCC group. The area of collagen deposition, evaluated using Sirius red staining, showed a marked decrease, from 18.6 ± 7.6% to 7.7 ± 4.6%, in the SVR-non-HCC group, with no change in the SVR-HCC group. CYGB- and α-SMA-positive hepatic stellate cells (HSCs), indicative of the HSC activated phenotype, remained in the fibrotic tissue of livers among patients in the SVR-HCC group. Conclusion Stagnation of fibrosis regression is associated with a high risk for HCC after SVR. HSC activation may inhibit improvement in fibrosis after SVR and potentially contribute to hepatocarcinogenesis.

This study was conducted to clarify the role of cytoglobin (Cygb), a globin expressed in hepatic stellate cells (HSCs), in the development of liver fibrosis and cancer in nonalcoholic steatohepatitis (NASH). Cygb expression was assessed in patients with NASH and hepatocellular carcinoma. Mouse NASH model was generated in Cygb-deficient (Cygb(-/-)) or wild-type (WT) mice by giving a choline-deficient amino acid-defined diet and, in some of them, macrophage deletion and N-acetyl cysteine treatment were used. Primary-cultured mouse HSCs isolated from WT (HSCs(Cygb-wild)) or Cygb(-/-) (HSCs(Cygb-null)) mice were characterized. As results, the expression of CYGB was reduced in patients with NASH and hepatocellular carcinoma. Choline-deficient amino acid treatment for 8 weeks induced prominent inflammation and fibrosis in Cygb(-/-) mice, which was inhibited by macrophage deletion. Surprisingly, at 32 weeks, despite no tumor formation in the WT mice, all Cygb(-/-) mice developed liver cancer, which was ameliorated by N-acetyl cysteine treatment. Altered expression of 31 genes involved in the metabolism of reactive oxygen species was notable in Cygb(-/-) mice. Both HSCs(Cygb-null) and Cygb siRNA-transfected-HSCs(Cygb-wild) exhibited the preactivation condition. Our findings provide important insights into the role that Cygb, expressed in HSCs during liver fibrosis, plays in cancer development with NASH.

We evaluated the transition of dominant resistance-associated substitutions (RASs) in hepatitis C virus during long-term follow-up after the failure of DAAs (direct acting antivirals)-based therapy. RASs in non-structure (NS)3/4A, NS5A, NS5B, and deletions in NS5A from 20 patients who failed simeprevir/pegylated-interferon/ribavirin (SMV/PEG-IFN/RBV) and 25 patients who failed daclatasvir/asunaprevir (DCV/ASV) treatment were examined by direct sequencing. With respect to SMV/PEG-IFN/RBV treatment, RAS was detected at D168 in NS3/4A but not detected in NS5A and NS5B at treatment failure in 16 of 20 patients. During the median follow-up period of 64 weeks, the RAS at D168 became less dominant in 9 of 16 patients. Among 25 DCV/ASV failures, RASs at D168, L31, and Y93 were found in 57.1%, 72.2%, and 76.9%, respectively. NS5A deletions were detected in 3 of 10 patients treated previously with SMV/PEG-IFN/RBV. The number of RASs in the breakthrough patients exceeded that in relapsers (mean 3.9 vs. 2.7, p < 0.05). RAS at D168 in NS3/4A became less dominant in 6 of 15 patients within 80 weeks. Y93H emerged at the time of relapse, then decreased gradually by 99% at 130 weeks post-treatment. Emerged RASs were associated with the clinical course of treatment and could not be detected during longer follow-up.

Cytoglobin (CYGB) is ubiquitously expressed in the cytoplasm of fibroblastic cells in many organs, including hepatic stellate cells. As yet, there is no specific marker with which to distinguish stellate cells from myofibroblasts in the human liver. To investigate whether CYGB can be utilized to distinguish hepatic stellate cells from myofibroblasts in normal and fibrotic human liver, human liver tissues damaged by infection with hepatitis C virus (HCV) and at different stages of fibrosis were obtained by liver biopsy. Immunohistochemistry was performed on histological sections of liver tissues using antibodies against CYGB, cellular retinol-binding protein-1 (CRBP-1), α-smooth muscle actin (α-SMA), thymocyte differentiation antigen 1 (Thy-1), and fibulin-2 (FBLN2). CYGB- and CRBP-1-positive cells were counted around fibrotic portal tracts in histological sections of the samples. The expression of several of the proteins listed above was examined in cultured mouse stellate cells. Quiescent stellate cells, but not portal myofibroblasts, expressed both CYGB and CRBP-1 in normal livers. In fibrotic and cirrhotic livers, stellate cells expressed both CYGB and α-SMA, whereas myofibroblasts around the portal vein expressed α-SMA, Thy-1, and FBLN2, but not CYGB. Development of the fibrotic stage was positively correlated with increases in Sirius red-stained, α-SMA-positive, and Thy-1-positive areas, whereas the number of CYGB- and CRBP-1-positive cells decreased with fibrosis development. Primary cultured mouse stellate cells expressed cytoplasmic CYGB at day 1, whereas they began to express α-SMA at the cellular margins at day 4. Thy-1 was undetectable throughout the culture period. In human liver tissues, quiescent stellate cells are CYGB positive. When activated, they also become α-SMA positive; however, they are negative for Thy-1 and FBLN2. Thus, CYGB is a useful marker with which to distinguish stellate cells from portal myofibroblasts in the damaged human liver.

UNLABELLED Concanavalin A (Con A) treatment induces severe hepatitis in mice in a manner dependent on T cells, interferon (IFN)-gamma, and tumor necrosis factor (TNF). Treatment with the anticoagulant heparin protects against hepatitis, despite healthy production of IFN-γ and TNF. Here, we investigated molecular and cellular mechanisms for hypercoagulation-mediated hepatitis. After Con A challenge, liver of wild-type (WT) mice showed prompt induction of Ifnγ and Tnf, followed by messenger RNA expression of tissue factor (TF) and plasminogen activator inhibitor-1 (PAI-1), which initiate blood coagulation and inhibit clot lysis, respectively. Mice developed dense intrahepatic fibrin deposition and massive liver necrosis. In contrast, Ifnγ(-/-) mice and Ifnγ(-/-) Tnf(-/-) mice neither induced Pai1 or Tf nor developed hepatitis. In WT mice TF blockade with an anti-TF monoclonal antibody protected against Con A-induced hepatitis, whereas Pai1(-/-) mice were not protected. Both hepatic macrophages and sinusoidal endothelial cells (ECs) expressed Tf after Con A challenge. Macrophage-depleted WT mice reconstituted with hematopoietic cells, including macrophages deficient in signal transducer and activator of transcription-1 (STAT1) essential for IFN-γ signaling, exhibited substantial reduction of hepatic Tf and of liver injuries. This was also true for macrophage-depleted Stat1(-/-) mice reconstituted with WT macrophages. Exogenous IFN-γ and TNF rendered T-cell-null, Con A-resistant mice deficient in recombination-activating gene 2, highly susceptible to Con A-induced liver injury involving TF. CONCLUSIONS Collectively, these results strongly suggest that proinflammatory signals elicited by IFN-γ, TNF, and Con A in both hepatic macrophages and sinusoidal ECs are necessary and sufficient for the development of hypercoagulation-mediated hepatitis.

It is unclear whether polymorphism in the inosine triphosphatase (ITPA) gene correlates to the reduction in hemoglobin (Hb) concentrations during sofosbuvir (SOF) and ribavirin (RBV) therapy. This study investigated the effects of the ITPA polymorphism on Japanese patients with chronic hepatitis C virus genotype 2 infection treated with SOF/RBV therapy.In 106 patients treated with SOF/RBV therapy, this study assessed the effects of the ITPA polymorphism (rs1127354) on anemia, RBV dose reduction, and sustained virological response.Of the 106 patients, 80 had the CC genotype, whereas 26 had a non-CC genotype in ITPA. Patients with the CC genotype had significantly larger reductions in Hb concentrations than those with a non-CC genotype throughout the treatment course. RBV dose reduction was required in 18/106 (17.0%) patients, with a significantly higher frequency in patients with the CC genotype than in those with a non-CC genotype (P = 0.010). In multivariate analysis, age ≥ 65 years (P = 0.011) and the ITPA CC genotype (P 0.0001) were factors significantly associated with anemia throughout the treatment course. Sustained virological response was achieved in 99.0% of all patients: 98.7% of patients with the CC genotype and 100% of patients with a non-CC genotype.Inosine triphosphatase polymorphism appeared to correlate with anemia incidence and RBV dose reduction during SOF/RBV therapy, but not the clinical outcome. Careful monitoring of Hb concentrations and prompt adjustment of RBV doses are required for successful treatment, particularly in patients harboring the ITPA CC genotype or age ≥ 65 years.

Since the development of wearable sensor, operating a device can be done by hand gesture based on EMG. However, some operations are not easily assigned by a single gesture, such as gradual volumes. To enable those operation types, we propose an estimation method that exploits the hysteresis loop between the joint angle and measured EMG. We confirm the effectiveness of the proposed method using EMG data recorded from five participants, during performing continuous wrist flexion and extention at constant speed. The results show averaged among the test subjects, was improved by 15.97% in average comparing with the conventional method.

Simeprevir (SMV) is a potent, macrocyclic hepatitis C virus (HCV) non-structural 3/4 A protease inhibitor. This prospective study compared the efficacy and safety of SMV in combination with peginterferon α2a + ribavirin (P2aR) and with peginterferon α2b + ribavirin (P2bR) in Japanese patients with HCV genotype 1b infection.Hepatitis C virus genotype 1b patients were randomly assigned to receive SMV (100 mg QD) with P2aR for 12 weeks, then P2aR alone for 12 or 36 weeks; or SMV (100 mg QD) with P2bR for 12 weeks, then P2bR alone for 12 or 36 weeks. The primary endpoint was a sustained virologic response 24 weeks after completing treatment (SVR24).In total, 151 patients were randomly assigned to the P2aR (n = 76) or P2bR group (n = 75). Six patients dropped out. Sustained virologic response 24 weeks after completing treatment was achieved in 55 (75.3%) of 73 P2aR patients and 55 (76.4%) of 72 P2bR patients. There was no difference in the rate of SVR24 between the two groups (P = 0.88). No differences in the proportion of patients who became HCV RNA-negative were detected between the P2aR and P2bR groups. The two groups had comparable numbers of adverse events, which led to the discontinuation of treatment in 9.6% and 8.3% of participants in the P2aR and P2bR groups, respectively.Peginterferon α2a or α2b in combination with SMV + ribavirin therapy showed identical antiviral effects in patients with chronic hepatitis C. Also, the incidence of adverse events was identical for both regimens.

Cytoglobin (Cygb) is a recently discovered vertebrate globin with molecular characteristics that are similar to myoglobin. To study the biological function of Cygb in vivo, we generated Cygb knockout mice and investigated their susceptibility to N,N-diethylnitrosamine (DEN)-induced tumorigenesis. Four-week-old male mice were administered DEN in drinking water at a dose of 25 ppm for 25 weeks or 0.05 ppm for 36 weeks. Cygb deficiency promoted the DEN-induced development of liver and lung tumors. All Cygb(+/-) and Cygb(-/-) mice treated with 25-ppm DEN exhibited liver tumors, compared with 44.4% of their wild-type counterparts. Lung tumors were present only in Cygb-deficient mice. More than 40% of Cygb(-/-) mice developed liver and lung tumors at the nontoxic dose of DEN (0.05 ppm), which did not induce tumors in wild-type mice. Cygb loss was associated with increased cancer cell proliferation, elevated extracellular signal-regulated kinase and Akt activation, overexpression of IL-1β, IL-6, Tnfα, and Tgfβ3 mRNAs, and hepatic collagen accumulation. Cygb-deficient mice also exhibited increased nitrotyrosine formation and dysregulated expression of cancer-related genes (cyclin D2, p53, Pak1, Src, Cdkn2a, and Cebpa). These results suggest that Cygb deficiency induces susceptibility to cancer development in the liver and lungs of mice exposed to DEN. Thus, globins such as Cygb will shed new light on the biological features of organ carcinogenesis.

e16116Background: The aim of this study was to assess the safety and efficacy of hepatic arterial infusion chemotherapy (HAIC) using cisplatin for patients with advanced hepatocellular carcinoma (H...

In this study, we discuss a layout of electrodes on a wrist for EMG measurements to recognize hand gestures. Experimental results show that the proposed layout uses only half of the electrodes, but suffers only about 3% drop in recognition rate compared with the conventional layout. Furthermore, we developed a television operating system based on hand gestures, using a wristband-type EMG device with the proposed electrode layout.

In the material testing, the displacement measurement system is indispensable. And usually such tests are done on a lot of test pieces and are continued for long time interval. Therefore, the simplified and automated displacement measurement system is required. In this paper, the authors propose a simple automatic displacement measurement system and give some experimental results. The proposed system utilizes a grating made by the photographic technology, a pair of optical pickups for CD, and the mouse interface for a personal computer. The movement of the grating that is detected by the CD optical pickups is processed by the mouse interface and is recorded as the mouse data with the personal computer. Simultaneously, the quantity of the displacement is automatically measured by the resolution of 1/4 of the grating interval by the mouse interface. Using the prototype equipment that utilizes a grating of which line interval is 100 µm, the 25 µm resolution has been obtained under the displacement speed of 0.5 mm/s. The maximum displacement speed of the system can be extended on the theory to 400 mm/s when using the grating of 100 µm line interval, but the investigation of the practical speed is left as a next problem. Because the mouse interface can detect the two-dimensional movement, the system is easily applied to measure the elongation between two points on the test piece. As the CD optical pickup and the mouse are very popular equipments, it is easy to obtain them. At the same time, as their structure and characteristics are well known, the applicability of these devices is excellent. Also, the proposed system is a very simple system. Therefore, this system will be able to be applied to various fields.

Experimental tests have been conducted on the mechanical behavior of a CFRP 1×7 strand cable with a central core subjected to torsional loading. The failure process of each helical string and the core has been probed independently by means of an electrical resistance method. Unloadingreloading torsion test has also been done to investigate the effects of cyclic loading. It has been found that the torsional failure of the CFRP strand cable has two stages. The first is a compressive failure of core, which does not immediately result in a loss of load-carrying capacity, but it later induces a tensile fracture of all spiral strings, i.e. the final failure of the cable. Although the tensile strength of the CFRP strand cable is almost the same as that of the steel strand cable of the same diameter, its torsional properties are far lower than those of the steel cable. Cyclic loading causes more damage to the core than to the spiral strings and it reduces the torsional strength significantly. The electrical resistance method, which requires no external sensor, works successfully for the sensitive detection of the fiber breakage in core and spiral strings and hence, the present CFRP strand cable can be regarded as a smart structural element with health-monitoring capability.