KAG-308, a newly-identified EP4-selective agonist shows efficacy for treating ulcerative colitis and can bring about lower risk of colorectal carcinogenesis by oral administration

AbstractAgonists for EP4 receptor, a prostaglandin E2 receptor subtype, appear to be a promising therapeutic strategy for ulcerative colitis (UC) due to their anti-inflammatory and epithelial regeneration activities. However, the clinical development of orally-available EP4 agonists for mild to moderate UC has not yet been reported. Furthermore, the possibility of an increased risk of colitis-associated cancer (CAC) through direct proliferative effects on epithelial cells via EP4 signaling has not been ruled out. Recently, we identified KAG-308 as an orally-available EP4-selective agonist. Here, we investigated the pharmacological and pharmacokinetic profiles of KAG-308. Then, we compared KAG-308 and sulfasalazine (SASP) for their abilities to prevent colitis and promote mucosal healing in a mouse model of dextran sulfate sodium (DSS)-induced colitis. Finally, the effect of KAG-308 treatment on CAC was evaluated in an azoxymethane (AOM)/DSS-induced CAC mouse model. KAG-308 selectively activated EP4 and potently inhibited tumor necrosis factor-α production in peripheral whole blood and T cells. Oral administration of KAG-308, which showed relatively high bioavailability, suppressed the onset of DSS-induced colitis and promoted histological mucosal healing, while SASP did not. KAG-308 also prevented colorectal carcinogenesis by inhibiting colitis development and consequently decreasing mortality in a CAC model, whereas SASP had marginal effects. In contrast, MF-482, an EP4 antagonist, increased mortality. These results indicated that orally-administered KAG-308 suppressed colitis development and promoted mucosal healing. Moreover, it exhibited preventive effects on colorectal carcinogenesis, and thus may be a new therapeutic strategy for the management of UC that confers a reduced risk of colorectal carcinogenesis

卵巣明細胞腺癌における転写因子HNF-1βはDNA損傷チェックポイント機構の一つであるCHK1タンパクを制御し、抗癌剤耐性を獲得する

Objective Appropriate cell cycle checkpoints are essential for the maintenance of normal cells and chemosensitivity of cancer cells. Clear cell adenocarcinoma (CCA) of the ovary is highly resistant to chemotherapy. Hepatocyte nuclear factor-1β (HNF-1β) is known to be overexpressed in CCA, but its role and clinical significance is unclear. We investigated the role of HNF-1β in regulation of the cell cycle in CCA. Methods To clarify the effects of HNF-1β on cell cycle checkpoints, we compared the cell cycle distribution and the expression of key proteins involved in CCA cells in which HNF-1β had been stably knocked down and in vector-control cell lines after treatment with bleomycin. HNF-1β (+) cells were arrested in G2 phase because of DNA damage. Results HNF-1β (−) cells died because of a checkpoint mechanism. G2 arrest of HNF-1β (+) cells resulted from sustained CHK1 activation, a protein that plays a major role in the checkpoint mechanism. HNF-1β (+) cells were treated with a CHK1 inhibitor after bleomycin treatment. Flow cytometric analysis of the cell cycle demonstrated that DNA damage–induced G2-arrested cells were released from the checkpoint and killed by a CHK1 inhibitor. Conclusions The chemoresistance of CCA may be due to aberrant retention of the G2 checkpoint through overexpression of HNF-1β. This is the first study demonstrating cell cycle regulation and chemosensitization by a CHK1 inhibitor in CCA.博士（医学）・乙第1345号・平成26年12月3日© 2014 by the International Gynecologic Cancer Society and the European Society of Gynaecological Oncology

Isolation of cDNA Encoding 7H6-Reactive Polypeptide Defines a New Class of Protein with alpha-Helical Coiled-Coil Structure and DA-Box Similar to Yeast Chromosomal Segregation Proteins

7H6 monoclonal antibody was recently developed in our laboratory by im-munizing mice with a bile canaliculus-rich fraction of the rat liver. The anti-body reacted with a novel 155 Kd polypeptide designated 7H6 antigen that specifically localizes at tight junctions of various epithelia. Correlations of the paracellular barrier function of the tight junction with expression of the 7H6 antigen at the cell border have suggested important roles of this polypeptide for the maintenance of tight junctional functions. As the first step for the analysis of the antigen at the molecular level, we isolated a series of cDNA clones encod-ing 7H6-reactive polypeptides. Five clones were isolated by immunoscreening. Among them a clone designated RL5.3 which carries the largest 5.3Kb insert was characterized in this study. Both plaque screening and immunoblotting of the fusion protein produced by the RL5.3 clone with lysogen confirmed that the pro-tein specifically reacts with the 7H6 monoclonal antibody. Using DNA fragmentsof the RL5.3 clone, 21 clones were further identified. Studies with restriction enzymes and probe hybridization revealed that all the cDNA clones were derived from a single class of transcripts. A partial sequence identified one open reading frame with an α-helical coiled-coil structure and highly conserved aspartate (D)- alanine (A) residues with a helix-loop-helix structure corresponding to DA- box. Since this domain has been specifically found in yeast chromosomal segregation proteins (SMC1, CUT3 and CUT14), the polypeptide encoded by the RL5.3 clone provides the first rodent counterpart of these protein family. Yeast is known to be lethal when SMC and CUT proteins are deleted, suggesting essential roles of these proteins for cell cycle progression as a regulator for chromosomal segregation. Identification of a mammalian counterpart of this pro-tein family may give us some clues for a better understanding of fundamental regulatory mechanisms in the function of tigh junctions

Research Project on the Design for the Optimum Disclosure System Volume 2: Sustainable Growth of Japanese Companies and the Direction of Non-financial Information Disclosure (Japanese)

For quite some time there has been a debate surrounding the issue requiring companies to disclose not only financial information but also non-financial information, as shown in recent efforts for enhanced business reporting (EBR). This discussion paper explores non-financial information in three aspects: social and environmental information, intellectual capital information, and risk information, and it also examines the extent and reasons for the disclosure of non-financial information. In addition, the question about the media is also discussed with consideration to the trend for integrated reporting and XBRL. Ultimately, non-financial information should fuse with financial information and evolve to become integrated reporting. XBRL can only realize its potential if both non-financial information and financial information are integrated. However, there are many obstacles for realizing integrated reporting at one time. Therefore, to stimulate a change in investor behavior and company behavior, as argued by some international organizations such as IIFC, there is an urgent demand for extended reporting that integrates information on sustainability and information on intellectual capital as a source of company competitive advantage. For such non-financial information, there is a necessity to discuss questions related to an expansion in management's disclosure responsibility, as well as the corresponding judgment in auditing. There is also a necessity to discuss questions concerning how to reduce the cost of auditing and how to construct an assurance system that helps to improve the reliability of information and to limit the overextension of non-financial information.

Willingness to pay for municipality hospital services in rural Japan: a contingent valuation study

<p>Abstract</p> <p>Background</p> <p>The Japanese healthcare system has undergone reforms to address the struggles that municipality hospitals face. Reform guidelines clearly define criteria for administrative improvement. However, criteria to evaluate the demand for healthcare provisions in rural Japan, including the needs of rural residents for municipality hospitals in particular have not been specified. The purpose of this paper is to measure residents' willingness to pay (WTP) for municipality hospital services using the contingent valuation method, and to evaluate municipality hospital valuation on the basis of WTP. K town, located in the Hokkaido prefecture of Japan, was selected as the location for this study. Participants were recruited by a town hall healthcare administrator, hospital and clinic staff, and a local dentist. Participants were asked what amount they would be willing to pay as taxes to continue accessing the services of the municipality hospital for one year by using open-ended questions in face-to-face interviews.</p> <p>Findings</p> <p>Forty-eight residents were initially recruited, and 40 participants were selected for the study (response rate 83%). As compared to K town's population, this data slanted toward the elderly, although there was no significant difference in frequency among the characteristics. The median WTP was estimated at 39,484 yen ($438.71), with a 95$308.95-615.96). Logistic regression revealed no significant factors affecting WTP.</p> <p>Conclusions</p> <p>If the total amount of residents' WTP for the municipality hospital were to be estimated by this result, it would calculate with 129,586,000 yen ($1,439,844). This is approximately equal to the amount of money to be transferred from the general account of the government of K town, more than one-half of the town tax of K town, and about two-fold in comparison to Japan as a whole. This showed that K town's residents placed a high valuation on the municipality hospital, which nearly equalled the amount that the K town government provided to the municipality hospital to cover its annual deficit. K town residents had come to expect not only general clinical practice, but also emergency medical services and night practice provided by their own town's municipality hospital. WTP can be used as a measure of hospital evaluation because it reflects the importance of the hospital to the residents in its region.</p

The 3rd DBCLS BioHackathon: improving life science data integration with Semantic Web technologies.

BACKGROUND: BioHackathon 2010 was the third in a series of meetings hosted by the Database Center for Life Sciences (DBCLS) in Tokyo, Japan. The overall goal of the BioHackathon series is to improve the quality and accessibility of life science research data on the Web by bringing together representatives from public databases, analytical tool providers, and cyber-infrastructure researchers to jointly tackle important challenges in the area of in silico biological research. RESULTS: The theme of BioHackathon 2010 was the 'Semantic Web', and all attendees gathered with the shared goal of producing Semantic Web data from their respective resources, and/or consuming or interacting those data using their tools and interfaces. We discussed on topics including guidelines for designing semantic data and interoperability of resources. We consequently developed tools and clients for analysis and visualization. CONCLUSION: We provide a meeting report from BioHackathon 2010, in which we describe the discussions, decisions, and breakthroughs made as we moved towards compliance with Semantic Web technologies - from source provider, through middleware, to the end-consumer.RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are

Clear cell carcinoid tumor of the distal common bile duct

BACKGROUND: Carcinoid tumors rarely arise in the extrahepatic bile duct and can be difficult to distinguish from carcinoma. There are no reports of clear cell carcinoid (CCC) tumors in the distal bile duct (DBD) to the best of our knowledge. Herein, we report a CCC tumor in the DBD and review the literature concerning extrahepatic bile duct carcinoid tumors. CASE PRESENTATION: A 73-old man presented with fever and occult obstructive jaundice. Ultrasonography, computed tomography (CT) and magnetic resonance cholangiopancreaticography (MRCP) demonstrated a nodular tumor projection in the DBD without regional lymph node swelling. Under suspicion of carcinoma, we resected the head of the pancreas along with 2(nd )portion duodenectomy and a lymph node dissection. The surgical specimen showed a golden yellow polypoid tumor in the DBD (0.8 × 0.6 × 0.5 cm in size). The lesion was composed of clear polygonal cells arranged in nests and a trabecular pattern. The tumor invaded through the wall into the fibromuscular layer. Immunohistochemical stains showed that neoplastic cells were positive for neuron-specific enolase (NSE), chromogranin A, synaptophysin, and pancreatic polypeptide and negative for inhibin, keratin, CD56, serotonin, gastrin and somatostatin. The postoperative course was uneventful and he is living well without relapse 12 months after surgery. CONCLUSION: Given the preoperative difficulty in differentiating carcinoid from carcinoma, the pancreaticoduodenectomy is an appropriate treatment choice for carcinoid tumors located within the intra-pancreatic bile duct