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The identification of patients with advanced fibrosis who do not need any further hepatocellular carcinoma (HCC) surveillance after the eradication of hepatitis C is pivotal. In this study, we developed a simple serum‐based risk model that could identify patients with low‐risk HCC. This was a nationwide multicenter study involving 16 Hospitals in Japan. Patients with advanced fibrosis (1,325 in a derivation cohort and 508 in a validation cohort) who achieved sustained virological responses at 24 weeks after treatment (SVR24) were enrolled. The HCC risk model at any point after SVR24 and its change were evaluated, and subsequent HCC development was analyzed. Based on the multivariable analysis, patients fulfilling all of the factors (GAF4 criteria: gamma‐glutamyl transferase

Abstract Background and Aim The pathogenic process underlying the development of hepatocellular carcinoma (HCC) is not yet clear in patients with hepatitis C virus (HCV) who have received direct‐acting antiviral (DAA) therapy and achieved sustained virological response (SVR). This study validated a composite predictive model for HCC in these patients. Methods This study included 3058 patients in whom HCV was eradicated with DAA therapy. After DAAs recommendation for surveillance (ADRES) score, which is based on sex, FIB‐4 index, and α‐fetoprotein, was used as a composite predictive model for HCC development. Results The 1‐, 3‐, and 5‐year cumulative incidence rates of HCC were 0.9, 4.5, and 15.2%, respectively. Multivariate analysis with Cox proportional hazards models showed that male sex (hazard ratio [HR], 2.646; 95% confidence interval [CI], 1.790–3.911), FIB‐4 index >3.25 (HR, 2.891; 95% CI, 1.947–4.293), and α‐fetoprotein >5 ng/mL (HR, 2.835; 95% CI, 1.914–4.200) are independently associated with HCC development. The incidence of HCC differed significantly by ADRES score (P

We aimed to clarify the characteristics of resistance-associated substitutions (RASs) after treatment failure with NS5A inhibitor, daclatasvir (DCV) in combination with NS3/4A inhibitor, asunaprevir (ASV), in patients with chronic hepatitis C virus genotype 1b infection.This is a nationwide multicenter study conducted by the Japanese Red Cross Liver Study Group. The sera were obtained from 68 patients with virological failure after 24 weeks of DCV/ASV treatment. RASs in NS5A and NS3 were determined by population sequencing.The frequency of signature RASs at position D168 of NS3 was 68%, and at positions L31 and Y93 of NS5A was 79 and 76%, respectively. The frequency of dual signature RASs in NS5A (L31-RAS and Y93-RAS) was 63%. RASs at L28, R30, P32, Q54, P58, and A92 in addition to dual signature RAS were detected in 5, 5, 1, 22, 2, and 0 patients, respectively. In total, triple, quadruple, and quintuple RASs in combination with dual signature RAS were detected in 35, 10, and 1.5% patients, respectively. These RASs were detected in patients without baseline RASs or who prematurely discontinued therapy. Co-existence of D168 RAS in NS3 and L31 and/or Y93 RAS in NS5A was observed in 62% of patients.Treatment-emergent RASs after failure with DCV/ASV combination therapy are highly complex in more than 50% of the patients. The identification of complex RAS patterns, which may indicate high levels of resistance to NS5A inhibitors, highlights the need for RAS sequencing when considering re-treatment with regimens including NS5A inhibitors.

Sixty-one chronic hepatitis C patients were randomly assigned to receive either 6x106 or 9x106 U of recombinant interferon-alpha-2a (IFNα-2a) six days a week for the first two weeks of treatment, followed in both cases by 6x106 U three days a week for the next 22 weeks. In the low dose group, 11 patients showed a complete response maintained for at least six months, 12 responded but then relapsed and nine did not respond; the corresponding figures in the high dose group were 10, 15 and five patients, respectively. The differences between groups are not statistically significant. Thus, this study provides no evidence of therapeutic benefit from increasing the initial dose of IFNα-2a. In both treatment groups, complete responders had significantly lower pretreatment viral titres than nonresponders and were significantly more likely to be infected by type 2a versus type 1b virus.

Gonadotropin-releasing hormone (GnRH) is a neuroendocrine peptide that plays a central role in the vertebrate hypothalamo-pituitary axis. The roles of GnRH in the control of vertebrate reproductive functions have been established, while its non-reproductive function has been suggested but less well understood. Here we show that the tunicate Ciona intestinalis has in its non-reproductive larval stage a prominent GnRH system spanning the entire length of the nervous system. Tunicate GnRH receptors are phylogenetically closest to vertebrate GnRH receptors, yet functional analysis of the receptors revealed that these simple chordates have evolved a unique GnRH system with multiple ligands and receptor heterodimerization enabling complex regulation. One of the gnrh genes is conspicuously expressed in the motor ganglion and nerve cord, which are homologous structures to the hindbrain and spinal cord of vertebrates. Correspondingly, GnRH receptor genes were found to be expressed in the tail muscle and notochord of embryos, both of which are phylotypic axial structures along the nerve cord. Our findings suggest a novel non-reproductive role of GnRH in tunicates. Furthermore, we present evidence that GnRH-producing cells are present in the hindbrain and spinal cord of the medaka, Oryzias latipes, thereby suggesting the deep evolutionary origin of a non-reproductive GnRH system in chordates.

The 2-unit size cubesat RAIKO is a nanosatellite developed by Tohoku University and Wakayama University. This paper shows the mission and system specifications. The satellite was released to space on October 4, 2012 from International Space Station, which was the 419-km alt. circular orbit. The techniques for 50-kg microsatellites by Tohoku University are transferred to this satellite, so a lot of functions are included although the power and mass budgets are strongly restricted. The primary missions are the photo storage by different 3 optical sensors, the de-orbit mechanism experiment by expandable thin films, and Ku-band downlink communication experiment. The satellite operation was finished by orbital decay on August 6, 2013. The telemetry data were successful received in total 123 passes, in which total 63 photo images were obtained and maximum 100 kbps (200 ksps) downlink was successful. Using color CMOS camera, gradually separating ISS could be confirmed. From analysis of house-keeping data, the solar generation power in sunshine was 3.38 W (no paddles) to 5.77 W (with paddles) in average, the temperature of onboard computer was in the range of 20.8 to 28.7 deg C, and the battery temperature was 4.2 deg C in average. The real flight data from the 10-month operation will be precious information for future nanosatellite projects. [ABSTRACT FROM AUTHOR]

PRIP‐1 was isolated as a novel inositol 1,4,5‐trisphosphate [Ins(1,4,5)P3] binding protein with a domain organization similar to phospholipase C‐δ1 (PLC‐δ1) but lacking the enzymatic activity. Further studies revealed that the pleckstrin homology (PH) domain of PRIP‐1 is the region responsible for binding Ins(1,4,5)P3. In this study we aimed to clarify the role of PRIP‐1 at the physiological concentration in Ins(1,4,5)P3‐mediated Ca2+ signaling, as we had previously used COS‐1 cells overexpressing PRIP‐1 (Takeuchi et al., 2000, Biochem J 349:357–368). For this purpose we employed PRIP‐1 knock out (PRIP‐1−/−) mice generated previously (Kanematsu et al., 2002, EMBO J 21:1004–1011). The increase in free Ca2+ concentration in response to purinergic receptor stimulation was lower in primary cultured cortical neurons prepared from PRIP‐1−/− mice than in those from wild type mice. The relative amounts of [3H]Ins(1,4,5)P3 measured in neurons labeled with [3H]inositol was also lower in cells from PRIP‐1−/− mice. In contrast, PLC activities in brain cortex samples from PRIP‐1−/− mice were not different from those in the wild type mice, indicating that the hydrolysis of Ins(1,4,5)P3 is enhanced in cells from PRIP‐1−/− mice. In vitro analyses revealed that type1 inositol polyphosphate 5‐phosphatase physically interacted with a PH domain of PRIP‐1 (PRIP‐1PH) and its enzyme activity was inhibited by PRIP‐1PH. However, physical interaction with these two proteins did not appear to be the reason for the inhibition of enzyme activity, indicating that binding of Ins(1,4,5)P3 to the PH domain prevented its hydrolyzation. Together, these results indicate that PRIP‐1 plays an important role in regulating the Ins(1,4,5)P3‐mediated Ca2+ signaling by modulating type1 inositol polyphosphate 5‐phosphatase activity through binding to Ins(1,4,5)P3. © 2004 Wiley‐Liss, Inc. [ABSTRACT FROM AUTHOR]