Clinical Determinants of Response to Irinotecan-Based Therapy Derived from Cell Line Models

Purpose: In an attempt to identify genes that are involved in resistance to SN38, the active metabolite of irinotecan (also known as CPT-11), we carried out DNA microarray profiling of matched HCT116 human colon cancer parental cell lines and SN38-resistant cell lines following treatment with SN38 over time.

Determinants of human rights attitudes and behavior: A comparison and integration of psychological perspectives

Following several political-psychological approaches, the present research analyzed whether orientations toward human rights are a function of right-wing authoritarianism (RWA), social dominance orientation (SDO), basic human values in the sense of Schwartz (1992), and political ideology. Three dimensions of human rights attitudes (endorsement, restriction, and enforcement) were differentiated from human rights knowledge and behavior. In a time-lagged Internet survey (N = 479), using structural equation modeling, RWA, universalism and power values, and political ideology (measured at Time 1) differentially predicted dimensions of human rights attitudes (measured at Time 2 five months later). RWA and universalism values also predicted self-reported human rights behavior, with the effects mediated through human rights endorsement. Human rights knowledge also predicted behavior. The psychological roots of positive and negative orientations toward human rights, consequences for human rights education, and the particular role of military enforcement of human rights are discussed.

Integrating situational and dispositional determinants of job satisfaction: Findings from three samples of professionals

Job satisfaction can be conceptualized as a function of situational conditions, personal characteristics, and interactions between both groups of variables. The authors compared the relative predictive power of these determinants in 3 samples of professionals (total N = 1,065). Perceived job characteristics (qualification possibilities, social support, stress, autonomy, participatory leadership) uniquely explained 7-22% of the variance in job satisfaction, and dispositional factors (Big Five, occupational self-efficacy, work centrality, mastery goals) uniquely explained 8-12% of the variance. Dispositional influences were partially mediated by perceived job characteristics. Interactions between situational and dispositional factors were of little significance. The authors concluded that perceived job characteristics (especially autonomy and participatory leadership) are important determinants of job satisfaction, and neuroticism is an important determinant as well. Highly educated professionals job satisfaction also seems to be driven by qualification possibilities.

MMP expression and abnormal lung permeability are important determinants of outcome in IPF

Matrix metalloproteinases (MMPs) degrade all of the extracellular matrix components of the intersititium and may play a role in abnormal alveolar permeability, which is a feature of idiopathic pulmonary fibrosis (IPF). The aims of the present study were to evaluate MMP protein levels in patients with IPF and determine any relationship to treatment and markers of permeability.

Identification of Determinants of Glucose-Dependent Insulinotropic Polypeptide Receptor That Interact with N-Terminal Biologically Active Region of the Natural Ligand

Glucose-dependent insulinotropic polypeptide receptor (GIPR), a member of family B of the G-protein coupled receptors, is a potential therapeutic target for which discovery of nonpeptide ligands is highly desirable. Structure-activity relationship studies indicated that the N-terminal part of glucose-dependent insulinotropic polypeptide (GIP) is crucial for biological activity. Here, we aimed at identification of residues in the GIPR involved in functional interaction with N-terminal moiety of GIP. A homology model of the transmembrane core of GIPR was constructed, whereas a three-dimensional model of the complex formed between GIP and the N-terminal extracellular domain of GIPR was taken from the crystal structure. The latter complex was docked to the transmembrane domains of GIPR, allowing in silico identification of putative residues of the agonist binding/activation site. All mutants were expressed at the surface of human embryonic kidney 293 cells as indicated by flow cytometry and confocal microscopy analysis of fluorescent GIP binding. Mutation of residues Arg183, Arg190, Arg300, and Phe357 caused shifts of 76-, 71-, 42-, and 16-fold in the potency to induce cAMP formation, respectively. Further characterization of these mutants, including tests with alanine-substituted GIP analogs, were in agreement with interaction of Glu3 in GIP with Arg183 in GIPR. Furthermore, they strongly supported a binding mode of GIP to GIPR in which the N-terminal moiety of GIP was sited within transmembrane helices (TMH) 2, 3, 5, and 6 with biologically crucial Tyr1 interacting with Gln224 (TMH3), Arg300 (TMH5), and Phe357 (TMH6). These data represent an important step toward understanding activation of GIPR by GIP, which should facilitate the rational design of therapeutic agents.