Thieno[2,3-d]pyrimidine-3-acetic acids. A new class of nonpeptide endothelin receptor antagonists

On the basis of structural information for the cyclic hexapeptide endothelin (ET) receptor antagonist, TAK-044, a series of thieno[2,3-d]pyrimidine-2,4-dione derivatives bearing a carboxyl group and aromatic rings that were important for receptor binding were designed, synthesized, and evaluated for ET receptor binding affinities and inhibitory activities against ET-induced vasoconstriction. Optimization of each substituent in the thieno[2,3-d]pyrimidine ring led to the discovery of a novel and potent nonpeptide ET receptor antagonist, 6-(4-methoxymethoxyphenyl)-5-methylsulfonylaminomethyl-1-(2- methylthiobenzyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]p yrimidine-3- acetic acid (32 g), which binded to human ETA and ETB receptor subtypes with affinities (IC50) of 7.6 and 100 nM, respectively. Compound 32 g effectively antagonized ET-induced vasoconstriction and the inhibitory effect mediated by the ETB receptor was more potent than that of bosentan, while the inhibitory effect mediated by the ETA receptor was slightly less potent than that of bosentan.     

Predicting length of stay in an acute psychiatric hospital

OBJECTIVE: Multivariate statistical methods were used to identify patient-related variables that predicted length of stay in a single psychiatric facility. The study investigated whether these variables remained stable over time and could be used to provide individual physicians with data on length of stay adjusted for differences in clinical caseloads and to detect trends in the physicians' practice patterns. METHODS: Data on all patients discharged over two six-month periods were collected at an acute psychiatric inpatient facility. Stepwise multiple regression analyses were conducted on the two datasets. RESULTS: The results from both analyses revealed that five variables significantly predicted length of stay and were stable over time. They were a primary diagnosis of schizophrenia, the number of previous admissions, a primary diagnosis of a mood disorder, age, and a secondary diagnosis of an alcohol- or other drug-related disorder. For some physicians, the mean length of stay of their patients differed significantly from the length predicted by the regression model--generally, it was shorter. CONCLUSIONS: The results demonstrate that patient-related predictors of length of stay in a single psychiatric hospital can be identified using relatively simple statistical procedures and can be consistent across a large dataset and over time.     

Depression in the quantity of intestinal secretory IgA and in the expression of the polymeric immunoglobulin receptor in caloric deficiency of the weanling mouse

Splenomegaly is uncommon in myelodysplasia (MDS) and, although cytopenias may be severe, therapeutic splenectomy is rarely performed. We report the histologic, histochemical, and immunophenotypic findings of nine cases of surgical splenectomy and four postmortem spleens from MDS patients. Four histologic patterns were identified: one dominated by erythrophagocytosis, one characterized by red pulp plasmacytosis, one with extramedullary hematopoiesis as the only salient finding, and one with marked red pulp expansion caused by a monocytic proliferation. Wright-Giemsa and histochemical stains were performed on touch preparations in three cases and played a critical role in the precise subclassification of one MDS patient's hematologic disorder, which ultimately proved to be chronic myelomonocytic leukemia. Splenectomy led to sustained improvement of cytopenias in three cases, but did not eliminate transfusion dependence for the remaining patients. Three splenectomy cases exhibited clustered Leder-negative mononuclear elements: two of these patients experienced disease progression to refractory anemia with excess blasts in transformation or acute myelogenous leukemia during post-splenectomy follow-up, whereas none of the three splenectomy patients without clustered mononuclear elements did. We conclude that splenomegaly in MDS usually reflects the sequelae of dyspoiesis rather than evidence of a proliferative phase, that clustering of Leder-negative large cells may correlate with either a substantial monocytic component or, possibly, increased risk of disease progression, and that the spleen can provide diagnostic as well as prognostic information in MDS patients with splenomegaly.     

Synthesis and comparative molecular field analysis (CoMFA) of antitumor 3-arylisoquinoline derivatives

In this study a series of 3-arylisoquinoline derivatives were synthesized and cytotoxicity against human melanoma tumor cell evaluated, and a three dimensional quantitative structure-activity relationship was investigated using the comparative molecular field analysis (CoMFA). The results suggested that the electrostatic, steric and hydrophobic factors of 3-arylisoquinolines were strongly correlated with the antitumor activity. Considerable predictive ability (cross-validated r2 as high as 0.721) was obtained through CoMFA.     

Extrinsic calibration of a camera and laser range finder using a new calibration structure of a plane with a triangular hole

Sensor fusion of a camera and laser range finder is important for the autonomous navigation of mobile robots. Finding the transformation between the camera and laser range finder is the first necessary step for the fusion of information. Many algorithms have been proposed, but these tend to require many different steps in order to achieve reliable and accurate results. A calibration structure that has triangular hole on its plane is proposed for the extrinsic calibration of a camera and laser range finder. Locations of laser scan data that are invisible on the calibration plane can be determined using property on the proposed calibration structure. First, we classify the laser scan data into two groups where one is on the plane and the other is off the plane. Then, we determine the absolute location of the laser scan data on the plane through a search of the parameters of the line. Finally, we can establish 3D-3D correspondences between the camera and laser range finder. Extrinsic calibration between a camera and laser range finder is found using a conventional 3D-3D transformation computing algorithm. Keywords: Calibration k]camera k]extrinsic calibration k]laser range finder     

A study on the dynamic characteristics of the Korean Yi-dynasty bell type structure

The dynamic characteristics of the Korean Yi-dynasty bell type structure, including the acoustic effects, are analyzed both theoretically and experimentally. The numerical solutions of natural frequencies and mode shape for membrane and flexural behavior are obtained by using the NASTRAN program for the finite element method with plate shell elements of triangular and quadrilateral types. Test bells, A and B types similar to the Kap-Sa bell in Kong-Ju chosen among typical Korean Yi-dynasty bells, are manufactured on different scales to the original bell. To consider the effects of the variation of the structural dimension on the dynamic response, these bells are analyzed with respect to the variation of the thickness of the wall and the bottom rim and the asymmetric Dang-Jwas. The impact method with the Fast Fourier Transform Analyzer is adopted to experimentally assess the dynamic response. Results are in good agreement with the numerical solutions.     

Design and Synthesis of a Novel PLK1 Inhibitor Scaffold Using a Hybridized 3D-QSAR Model

Polo-like kinase 1 (PLK1) plays an important role in cell cycle progression and proliferation in cancer cells. PLK1 also contributes to anticancer drug resistance and is a valuable target in anticancer therapeutics. To identify additional effective PLK1 inhibitors, we performed QSAR studies of two series of known PLK1 inhibitors and proposed a new structure based on a hybridized 3D-QSAR model. Given the hybridized 3D-QSAR models, we designed and synthesized 4-benzyloxy-1-(2-arylaminopyridin-4-yl)-1H-pyrazole-3-carboxamides, and we inspected its inhibitory activities to identify novel PLK1 inhibitors with decent potency and selectivity.     

Clinical Significance of Tumor Infiltrating Lymphocytes in Association with Hormone Receptor Expression Patterns in Epithelial Ovarian Cancer

Hormone receptor expression patterns often correlate with infiltration of specific lymphocytes in tumors. Specifically, the presence of specific tumor-infiltrating lymphocytes (TILs) with particular hormone receptor expression is reportedly associated with breast cancer, however, this has not been revealed in epithelial ovarian cancer (EOC). Therefore, we investigated the association between hormone receptor expression and TILs in EOC. Here we found that ERα, AR, and GR expression increased in EOC, while PR was significantly reduced and ERβ expression showed a reduced trend compared to normal epithelium. Cluster analysis indicated poor disease-free survival (DFS) in AR+/GR+/PR+ subgroup (triple dominant group); while the Cox proportional-hazards model highlighted the triple dominant group as an independent prognostic factor for DFS. In addition, significant upregulation of FoxP3+ TILs, PD-1, and PD-L1 was observed in the triple dominant group compared to other groups. NanoString analyses further suggested that tumor necrosis factor (TNF) and/or NF-κB signaling pathways were activated with significant upregulation of RELA, MAP3K5, TNFAIP3, BCL2L1, RIPK1, TRAF2, PARP1, and AKT1 in the triple dominant EOC group. The triple dominant subgroup correlates with poor prognosis in EOC. Moreover, the TNF and/or NF-κB signaling pathways may be responsible for hormone-mediated inhibition of the immune microenvironment.