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CCG-1423 suppresses several pathological processes including cancer cell migration, tissue fibrosis, and the development of atherosclerotic lesions. These suppressions are caused by inhibition of myocardin-related transcription factor A (MRTF-A), which is a critical factor for epithelial-mesenchymal transition (EMT). CCG-1423 can therefore be a potent inhibitor for EMT. CCG-1423 and related compounds, CCG-100602 and CCG-203971 possess similar biological activities. Although these compounds are comprised of two stereoisomers, the differences in their biological activities remain to be assessed. To address this issue, we stereoselectively synthesized optically pure isomers of these compounds and validated their biological activities. The S-isomer of CCG-1423 rather than the R-isomer exhibited modestly but significantly higher inhibitory effects on the cellular events triggered by MRTF-A activation including serum response factor-mediated gene expression and cell migration of fibroblasts and B16F10 melanoma cells. Accordingly, the S-isomer of CCG- 1423 more potently blocked the serum-induced nuclear import of MRTF-A than the R-isomer. No such difference was observed in cells treated with each of two stereoisomers of CCG-100602 or CCG-203971. We previously reported that the N-terminal basic domain (NB), which functions as a nuclear localization signal of MRTF-A, is a binding site for CCG- 1423. Consistent with the biological activities of two stereoisomers of CCG-1423, docking simulation demonstrated that the S-isomer of CCG-1423 was more likely to bind to NB than the R-isomer. This is a first report demonstrating the stereospecific biological activities of CCG-1423.

The number of patients infected with H7N9 influenza virus has been increasing since 2013. We examined the efficacy of neuraminidase (NA) inhibitors and the efficacy of a vaccine against an H7N9 influenza virus, A/Anhui/1/2013 (H7N9), isolated from a patient in a cynomolgus macaque model. NA inhibitors (oseltamivir and peramivir) barely reduced the total virus amount because of the emergence of resistant variants with R289K or I219T in NA [residues 289 and 219 in N9 of A/Anhui/1/2013 (H7N9) correspond to 292 and 222 in N2, respectively] in three of the six treated macaques, whereas subcutaneous immunization of an inactivated vaccine derived from A/duck/Mongolia/119/2008 (H7N9) prevented propagation of A/Anhui/1/2013 (H7N9) in all vaccinated macaques. The percentage of macaques in which variant H7N9 viruses with low sensitivity to the NA inhibitors were detected was much higher than that of macaques in which variant H5N1 highly pathogenic influenza virus was detected after treatment with one of the NA inhibitors in our previous study. The virus with R289K in NA was reported in samples from human patients, whereas that with I219T in NA was identified for the first time in this study using macaques, though no variant H7N9 virus was reported in previous studies using mice. Therefore, the macaque model enables prediction of the frequency of emerging H7N9 virus resistant to NA inhibitors in vivo. Since H7N9 strains resistant to NA inhibitors might easily emerge compared to other influenza viruses, monitoring of the emergence of variants is required during treatment of H7N9 influenza virus infection with NA inhibitors.

The number of patients infected with H7N9 influenza virus has been increasing since 2013. We examined the efficacy of neuraminidase (NA) inhibitors and the efficacy of a vaccine against an H7N9 influenza virus, A/Anhui/1/2013 (H7N9), isolated from a patient in a cynomolgus macaque model. NA inhibitors (oseltamivir and peramivir) barely reduced the total virus amount because of the emergence of resistant variants with R289K or I219T in NA [residues 289 and 219 in N9 of A/Anhui/1/2013 (H7N9) correspond to 292 and 222 in N2, respectively] in three of the six treated macaques, whereas subcutaneous immunization of an inactivated vaccine derived from A/duck/Mongolia/119/2008 (H7N9) prevented propagation of A/Anhui/1/2013 (H7N9) in all vaccinated macaques. The percentage of macaques in which variant H7N9 viruses with low sensitivity to the NA inhibitors were detected was much higher than that of macaques in which variant H5N1 highly pathogenic influenza virus was detected after treatment with one of the NA inhibitors in our previous study. The virus with R289K in NA was reported in samples from human patients, whereas that with I219T in NA was identified for the first time in this study using macaques, though no variant H7N9 virus was reported in previous studies using mice. Therefore, the macaque model enables prediction of the frequency of emerging H7N9 virus resistant to NA inhibitors in vivo. Since H7N9 strains resistant to NA inhibitors might easily emerge compared to other influenza viruses, monitoring of the emergence of variants is required during treatment of H7N9 influenza virus infection with NA inhibitors.

Highly pathogenic avian influenza (HPAI) viruses of the H5N1 subtype often cause severe pneumonia and multiple organ failure in humans, with reported case fatality rates of more than 60%. To develop a clinical antibody therapy, we generated a human-mouse chimeric monoclonal antibody (MAb) ch61 that showed strong neutralizing activity against H5N1 HPAI viruses isolated from humans and evaluated its protective potential in mouse and nonhuman primate models of H5N1 HPAI virus infections. Passive immunization with MAb ch61 one day before or after challenge with a lethal dose of the virus completely protected mice, and partial protection was achieved when mice were treated 3 days after the challenge. In a cynomolgus macaque model, reduced viral loads and partial protection against lethal infection were observed in macaques treated with MAb ch61 intravenously one and three days after challenge. Protective effects were also noted in macaques under immunosuppression. Though mutant viruses escaping from neutralization by MAb ch61 were recovered from macaques treated with this MAb alone, combined treatment with MAb ch61 and peramivir reduced the emergence of escape mutants. Our results indicate that antibody therapy might be beneficial in reducing viral loads and delaying disease progression during H5N1 HPAI virus infection in clinical cases and combined treatment with other antiviral compounds should improve the protective effects of antibody therapy against H5N1 HPAI virus infection.

Highly pathogenic avian influenza (HPAI) viruses of the H5N1 subtype often cause severe pneumonia and multiple organ failure in humans, with reported case fatality rates of more than 60%. To develop a clinical antibody therapy, we generated a human-mouse chimeric monoclonal antibody (MAb) ch61 that showed strong neutralizing activity against H5N1 HPAI viruses isolated from humans and evaluated its protective potential in mouse and nonhuman primate models of H5N1 HPAI virus infections. Passive immunization with MAb ch61 one day before or after challenge with a lethal dose of the virus completely protected mice, and partial protection was achieved when mice were treated 3 days after the challenge. In a cynomolgus macaque model, reduced viral loads and partial protection against lethal infection were observed in macaques treated with MAb ch61 intravenously one and three days after challenge. Protective effects were also noted in macaques under immunosuppression. Though mutant viruses escaping from neutralization by MAb ch61 were recovered from macaques treated with this MAb alone, combined treatment with MAb ch61 and peramivir reduced the emergence of escape mutants. Our results indicate that antibody therapy might be beneficial in reducing viral loads and delaying disease progression during H5N1 HPAI virus infection in clinical cases and combined treatment with other antiviral compounds should improve the protective effects of antibody therapy against H5N1 HPAI virus infection.

地層処分研究開発部門東濃地科学ユニットでは、「地層処分技術に関する研究開発」のうち深地層の科学的研究(地層科学研究)の一環として、結晶質岩(花崗岩)を対象とした超深地層研究所計画を進めている。本計画は、「第1段階」,「第2段階」及び「第3段階」からなる約20年の計画であり、現在は、第2段階における調査研究を進めている。超深地層研究所計画は、「深部地質環境の調査・解析・評価技術の基盤の整備」及び「深地層における工学技術の基盤の整備」を第1段階から第3段階までを通した全体目標として定め、そのうち第2段階では、「研究坑道の掘削を伴う調査研究による地質環境モデルの構築及び研究坑道の掘削による深部地質環境の変化の把握」を段階目標の一つとして調査研究を進めている。本報告書は、第2段階目標に基づき、2008年度に実施した地質・地質構造に関する調査研究の成果を取りまとめたものである。, Tono Geoscientific Unit of Geological Isolation and Development Directoratte is performing Mizunami Underground Research Laboratory (MIU) Project, which is a broad scientific study of the deep geological environment as a basis of research and development for geological disposal of nuclear wastes, in order to establish comprehensive techniques for the investigation, analysis and assessment of the deep geological environment in fractured crystalline rock. The MIU Project has three overlapping 3 phases, with a total duration of 20 years. The project goals of the MIU Project from Phase I through to Phase III are: to establish techniques for investigation, analysis and assessment of the deep geological environment, and to develop a range of engineering for deep underground application. Currently, the project is under the Phase II. This document presents the overview of results of the research and development on "geology" performed in fiscal year 2008, with regard to the Phase II goal., 著者所属: 日本原子力研究開発機構(JAEA), JAEA-Research 2010-039

現在、瑞浪超深地層研究所において進めている研究坑道掘削工事では、坑道掘削に先立ちボーリング調査を行い、掘削範囲の地質や地下水状況を把握したうえで坑道を掘削している。調査の結果、深度200m付近の換気立坑側や深度300m研究アクセス坑道で大量湧水が発生する可能性が高いことがわかった。このため坑道掘削時の湧水を抑制する技術として、坑道掘削に先立ち掘削範囲周辺の割れ目にセメントを注入する工法(プレグラウチング)を行った。本報告書は、プレグラウチングの計画と実施過程で得られた技術的知見を取りまとめたものである。, The Mizunami Underground Research Laboratory (MIU), one of the main facilities in Japan for research and development of the technology for high-level radioactive waste disposal, is under construction in Mizunami City. In planning the construction, it was necessary to get reliable information on the bedrock conditions, specifically the rock mass stability and hydrogeology. Therefore, borehole investigations were conducted before excavations started. The results indicated that large water inflow could be expected during the excavation around the Ventilation Shaft at GL-200m and GL-300m Access/Research Gallery. In order to reduce water inflow, pre-excavation grouting was conducted before excavation of shafts and research tunnels. Grouting is the injection of material such as cement into a rock mass to stabilize and seal the rock. This report describes the knowledge and lessons learned during the planning and conducting of pre-excavation grouting., 著者所属: 日本原子力研究開発機構(JAEA), JAEA-Technology 2010-026