ABSTRACT
Retinoid-related orphan receptor gamma (RORγ) directly controls the differentiation of Th17 cell and the production of interleukin-17, which plays an integral role in autoimmune diseases. To obtain insight into RORγ, we have determined the first crystal structure of a ternary complex containing RORγ ligand-binding domain (LBD) bound with a novel synthetic inhibitor and a repressor peptide, 22-mer peptide from silencing mediator of retinoic acid and thyroid hormone receptor (SMRT). Comparison of a binary complex of nonliganded (apo) RORγ-LBD with a nuclear receptor co-activator (NCoA-1) peptide has shown that our inhibitor displays a unique mechanism different from those caused by natural inhibitor, ursolic acid (UA). The compound unprecedentedly induces indirect disruption of a hydrogen bond between His479 on helix 11 (H11) and Tyr502 on H12, which is crucial for active conformation. This crystallographic study will allow us to develop novel synthetic compounds for autoimmune disease therapy.
Subject(s)
Nuclear Receptor Co-Repressor 2/metabolism , Nuclear Receptor Coactivator 1/metabolism , Nuclear Receptor Subfamily 1, Group F, Member 3/metabolism , Binding Sites , Humans , Hydrogen Bonding , Models, Molecular , Mutation , Nuclear Receptor Co-Repressor 2/agonists , Nuclear Receptor Co-Repressor 2/chemistry , Nuclear Receptor Co-Repressor 2/genetics , Nuclear Receptor Coactivator 1/chemistry , Nuclear Receptor Coactivator 1/genetics , Peptide Fragments , Protein Binding , Protein Conformation , Triterpenes/pharmacology , Ursolic AcidABSTRACT
An amendment concerning the enforcement of the law on the prevention of radiation hazards due to radioisotopes, etc., and the medical service law enforcement regulations were promulgated on June 1, 2005. This amendment concerned international basic safety standards and the sealing of radiation sources. Sealed radiation sources < or =3.7 MBq, which had been excluded from regulation, were newly included as an object of regulation. Investigation of the SPECT system instituted in hospitals indicated that almost all institutions adhere to the new amendment, and the calibration source, the checking source, etc., corresponding to this amendment were maintained appropriately. Any institutions planning to return sealed radioisotopes should refer to this report.
Subject(s)
Radioactive Hazard Release/prevention & control , Radioisotopes , Safety Management/legislation & jurisprudence , Calibration , Japan , Nuclear Medicine Department, Hospital , Safety Management/standards , Surveys and Questionnaires , Tomography, Emission-Computed, Single-PhotonABSTRACT
Although the prevention of habituation-related diseases has become an important topic in Japan, the early detection of cancers such as lung, gastric, and breast cancers is an important issue for X-ray-related imaging modalities. High cost-benefit and cost-effectiveness are necessary to perform mass screenings such as those for lung cancer. In order to assess cost-benefit and cost-effectiveness, a total of 100 institutions nationwide were investigated, with a 41% of recovery rate. There were at least one or two institutions in each prefecture. Cost-benefit analysis was based on factors including the price of the medical check-up vehicle, its service life, and income from the examinations. The mean price of medical check-up vehicles used for chest X-ray examinations was 4,445,000 yen. Cost-effectiveness analysis was based on the expense incurred to discover one lung cancer. According to our research, the cost-effectiveness involved in detecting one lung cancer by conventional chest X-ray examination was about 2,270,167 yen/person. Since this amount seems unduly high, it is necessary to improve cost-effectiveness.
