青色光は滑膜肉腫に対して活性酸素種によるミトコンドリア機能障害を起こし、アポトーシスとオートファジーを誘導する

Background: Synovial sarcoma (SS) has limited treatment options and there is an urgent need to develop a novel therapeutic strategy to treat SS. Blue light (BL) has been shown to inhibit the growth of several cancer cells. However, the efficacy of BL in soft tissue sarcomas such as SS has not been demonstrated, and the detailed mechanism underlying the antitumor activity of BL is not fully understood. In this study, we investigated the antitumor effect of BL on SS. Methods: Human SS cell lines were continuously irradiated with BL using light-emitting diodes (LEDs) in an incubator for in vitro analysis. The chicken chorioallantoic membrane (CAM) tumors and xenograft tumors in mice were subjected to daily BL irradiation with LEDs. Results: BL caused growth inhibition of SS cells and histological changes in CAM tumors. BL also suppressed the migration and invasion abilities of SS cells. The type of cell death in SS cells was revealed to be apoptosis. Furthermore, BL induced excessive production of reactive oxygen species (ROS) in mitochondria, resulting in oxidative stress and malfunctioned mitochondria. Reducing the production of ROS using N-acetylcysteine (NAC), a ROS scavenger, attenuated the inhibitory effect of BL on SS cells and mitochondrial dysfunction. In addition, BL induced autophagy, which was suppressed by the administration of NAC. The autophagy inhibitor of 3-methyladenine and small interfering RNA against the autophagy marker light chain 3B facilitated apoptotic cell death. Moreover, BL suppressed tumor growth in a mouse xenograft model. Conclusion: Taken together, our results revealed that BL induced apoptosis via the ROS-mitochondrial signaling pathway, and autophagy was activated in response to the production of ROS, which protected SS cells from apoptosis. Therefore, BL is a promising candidate for the development of an antitumor therapeutic strategy targeting SS

A Functional Polymorphism in B and T Lymphocyte Attenuator Is Associated with Susceptibility to Rheumatoid Arthritis

Inhibitory coreceptors are thought to play important roles in maintaining immunological homeostasis, and a defect in the negative signals from inhibitory coreceptors may lead to the development of autoimmune diseases. We have recently identified B and T lymphocyte attenuator (BTLA), a new inhibitory coreceptor expressed on immune cells, and we suggest that BTLA may be involved in the development of autoimmune diseases using BTLA-deficient mice. However, the role of BTLA in the pathogenesis of autoimmune diseases in humans remains unknown. We, therefore, examined the possible association between BTLA and rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and Sjögren's syndrome (SS) by conducting a case-control genetic association study. We found that 590C single-nucleotide polymorphism (SNP) of BTLA gene was significantly associated with susceptibility to RA, but not to SLE or SS. Furthermore, RA patients bearing this 590C SNP developed the disease significantly earlier than the patients without this allele. We also found that BTLA with 590C allele lacked the inhibitory activity on concanavalin A- and anti-CD3 Ab-induced IL-2 production in Jurkat T cells. These results suggest that BTLA is an RA-susceptibility gene and is involved in the protection from autoimmunity in humans

Association between discontinuation of benzodiazepine receptor agonists and post-operative delirium among inpatients with liaison intervention : A retrospective cohort study.

Background:Several studies have investigated the association between benzodiazepine receptor agonist (BZDRA) use during the perioperative period and an elevated incidence of delirium. However, no study has focused on the time course of BZDRA use, including continuation, discontinuation, initiation, and no use. This study aimed to examine the influence of the time course of BZDRA use on post-operative delirium.Methods:This retrospective cohort study was conducted by reviewing medical records. We included patients who were scheduled for surgery under general anesthesia and had been referred to a liaison psychiatrist for pre-operative psychiatric assessment. The patients were classified into four groups based on the pre- and post-operative time course of oral BZDRA use, as follows: continuation, discontinuation, initiation, and no use (never used). The primary outcome was the prevalence of post-operative delirium in non-intensive care unit settings. We also performed stratified analyses according to age, the presence of cognitive impairment, the presence of delirium history, and antipsychotic drug use on admission.Results:Among 250 patients, 78 (31%) developed post-operative delirium. The Discontinuation group had a higher rate of delirium (49%, 24/49) than the other groups (Continuation [14%, 4/29]; Initiation [38%, 3/8], Never used [29%, 47/164], p = 0.008).Conclusions:Abrupt discontinuation of BZDRAs during the perioperative period may be a risk factor for post-operative delirium and should therefore be avoided

BHLHA15-Positive Secretory Precursor Cells Can Give Rise to Tumors in Intestine and Colon in Mice

Background & Aims: The intestinal epithelium is maintained by long-lived intestinal stem cells (ISCs) that reside near the crypt base. Above the ISC zone, there are short-lived progenitors that normally give rise to lineage-specific differentiated cell types but can dedifferentiate into ISCs in certain circumstances. However, the role of epithelial dedifferentiation in cancer development has not been fully elucidated. Methods: We performed studies with Bhlha15-CreERT, Lgr5-DTR-GFP, Apc flox/flox , LSL-Notch (IC), and R26-reporter strains of mice. Some mice were given diphtheria toxin to ablate Lgr5-positive cells, were irradiated, or were given 5-fluorouracil, hydroxyurea, doxorubicin, or dextran sodium sulfate to induce intestinal or colonic tissue injury. In intestinal tissues, we analyzed the fate of progeny that expressed Bhlha15. We used microarrays and reverse-transcription PCR to analyze gene expression patterns in healthy and injured intestinal tissues and in tumors. We analyzed gene expression patterns in human colorectal tumors using The Cancer Genome Atlas data set. Results: Bhlha15 identified Paneth cells and short-lived secretory precursors (including pre-Paneth label-retaining cells) located just above the ISC zone in the intestinal epithelium. Bhlha15 + cells had no plasticity after loss of Lgr5-positive cells or irradiation. However, Bhlha15 + secretory precursors started to supply the enterocyte lineage after doxorubicin-induced epithelial injury in a Notch-dependent manner. Sustained activation of Notch converts Bhlha15 + secretory precursors to long-lived enterocyte progenitors. Administration of doxorubicin and expression of an activated form of Notch resulted in a gene expression pattern associated with enterocyte progenitors, whereas only sustained activation of Notch altered gene expression patterns in Bhlha15 + precursors toward those of ISCs. Bhlha15 + enterocyte progenitors with sustained activation of Notch formed intestinal tumors with serrated features in mice with disruption of Apc. In the colon, Bhlha15 marked secretory precursors that became stem-like, cancer-initiating cells after dextran sodium sulfate–induced injury, via activation of Src and YAP signaling. In analyses of human colorectal tumors, we associated activation of Notch with chromosome instability-type tumors with serrated features in the left colon. Conclusions: In mice, we found that short-lived precursors can undergo permanent reprogramming by activation of Notch and YAP signaling. These cells could mediate tumor formation in addition to traditional ISCs

Current Performance and On-Going Improvements of the 8.2 m Subaru Telescope

An overview of the current status of the 8.2 m Subaru Telescope constructed and operated at Mauna Kea, Hawaii, by the National Astronomical Observatory of Japan is presented. The basic design concept and the verified performance of the telescope system are described. Also given are the status of the instrument package offered to the astronomical community, the status of operation, and some of the future plans. The status of the telescope reported in a number of SPIE papers as of the summer of 2002 are incorporated with some updates included as of 2004 February. However, readers are encouraged to check the most updated status of the telescope through the home page, http://subarutelescope.org/index.html, and/or the direct contact with the observatory staff.Comment: 18 pages (17 pages in published version), 29 figures (GIF format), This is the version before the galley proo

焼却灰埋立海面処分場における重金属の移動性

廃棄物処分場内部における重金属の移動性, 緩衝作用はpH, Eh, 有機物, 微生物活動に大きく影響され, 埋立廃棄物の種類や時間経過によっても変化する。本研究では, 焼却灰海面埋立処分場の廃棄物層, 粘土層を模擬した大型カラム試験を長期に渡って実施し, 処分場内部での重金属の移動性を亜鉛をトレーサーとして用いることにより評価を行った。試験結果より, 重金属の移動性はpH, Ehによる影響がみられるが焼却灰層内部に固定化されること, ならびに微生物活動の影響は非常に小さいことが明らかになった。7ヶ月経過時点でpHとEhの値は安定しているが, 亜鉛の移動性が高くなると推測される値に近い値となっており, 今後も継続的な調査を実施する予定である。The natural attenuation process of heavy metals in landfill waste layer and clay liner depends on factors such as the pH, Eh, Total Organic Carbon (TOC), microbial activities, and certainly, on the waste material that generates the leachate. These factors can change in the long term affecting the containment and attenuation process of heavy metals within the landfill. This study investigates the mobility of heavy metals, in particular zinc, in the incinerator ash layer of a coastal landfill site by conducting a large-scale column test. Test results indicate that pH and Eh are the main factors that influence the solubility of Zn, and microorganisms only play a minor role. After 7 months, the values of pH and Eh stabilized at levels where soluble Zn were not detected; however those values are close to the limits where mobilization is expected.廃棄物処分場内部における重金属の移動性, 緩衝作用はpH, Eh, 有機物, 微生物活動に大きく影響され, 埋立廃棄物の種類や時間経過によっても変化する。本研究では, 焼却灰海面埋立処分場の廃棄物層, 粘土層を模擬した大型カラム試験を長期に渡って実施し, 処分場内部での重金属の移動性を亜鉛をトレーサーとして用いることにより評価を行った。試験結果より, 重金属の移動性はpH, Ehによる影響がみられるが焼却灰層内部に固定化されること, ならびに微生物活動の影響は非常に小さいことが明らかになった。7ヶ月経過時点でpHとEhの値は安定しているが, 亜鉛の移動性が高くなると推測される値に近い値となっており, 今後も継続的な調査を実施する予定である。The natural attenuation process of heavy metals in landfill waste layer and clay liner depends on factors such as the pH, Eh, Total Organic Carbon (TOC), microbial activities, and certainly, on the waste material that generates the leachate. These factors can change in the long term affecting the containment and attenuation process of heavy metals within the landfill. This study investigates the mobility of heavy metals, in particular zinc, in the incinerator ash layer of a coastal landfill site by conducting a large-scale column test. Test results indicate that pH and Eh are the main factors that influence the solubility of Zn, and microorganisms only play a minor role. After 7 months, the values of pH and Eh stabilized at levels where soluble Zn were not detected; however those values are close to the limits where mobilization is expected