Combination of molecular modeling, site-directed mutagenesis, and SAR studies to delineate the binding site of pyridopyrimidine antagonists on the human CCK1 receptor

A rational combination of site-directed mutagenesis studies, structure−activity relationships, and dynamic-based docking of pyridopyrimidine-derived CCK1R antagonists into a refined three-dimensional model of the CCK1R allowed us to identify the receptor residues and the ligand functional groups implicated in the molecular recognition process. Our results provided unambiguous evidence that the binding site of these antagonists is overlapping that of the C-terminal tetrapeptide of CCK. In particular, Asn333 and Arg336 residues of the CCK1R are essential for high-affinity binding of these ligands. Moreover, the 2-aryl group in the pyridopyrimidine derivatives shares the same binding pocket as the C-terminal Phe side chain of CCK. Our [pyridopyrimidine·CCK1R] complex model is consistent with previous suggestions concerning the molecular basis that governs functional activity and provides useful considerations about the high CCK1 versus CCK2 selectivity of our derivatives and could contribute to fine-tune the rational design of new molecules with optimized properties.This work has been supported by the Comisión Interministerial de Ciencia y Tecnología (SAF2003-07207-C02-01), by a CSIC/CNRS collaborative project and by ARC grants 4430 and 3882

Class III ß-Tubulin Isotope Predicts Response in Advanced Breast Cancer Patients Randomly Treated Either with Single-agent Doxorubicin or Docetaxel

Evaluate microtubule-associated variables as potential predictors of response and clinical outcome in patients with advanced breast cancer receiving single-agent docetaxel or doxorubicin chemotherapy. Expression of total alpha- or beta-tubulin, classes II to IV beta-tubulin isotypes, and tau protein was evaluated by immunohistochemistry on the primary breast cancer. Patients with "high" expression of class III beta-tubulin isotype had a higher probability of response to docetaxel than to doxorubicin treatment. This study suggests that the superiority of docetaxel over doxorubicin seems restricted to the subgroup of patients with "high" expression of class III beta-tubulin isotype.JRC.D.2-Reference material

Genotype of 88 Toxoplasma gondii Isolates Associated with Toxoplasmosis in Immunocompromised Patients and Correlation with Clinical Findings.

International audienceWe report the genotyping analysis of Toxoplasma gondii isolates in samples collected from 88 immunocompromised patients, along with clinical and epidemiological data. Most of these samples were collected in France during the current decade by the Toxoplasma Biological Resource Center. Lack of specific anti-Toxoplasma treatment, pulmonary toxoplasmosis, and involvement of multiple organs were the 3 main risk factors associated with death for this patient group. Genotyping results with 6 microsatellite markers showed that type II isolates were predominant among patients who acquired toxoplasmic infection in Europe. Non-type II isolates included 13 different genotypes and were mainly collected from patients who acquired toxoplasmosis outside Europe. Type III was the second most common genotype recovered from patients, whereas type I was rare in our population. Three nonarchetypal genotypes were repeatedly recovered from different patients who acquired the infection in sub-Saharan Africa (genotypes Africa 1 and Africa 2) and in the French West Indies (genotype Caribbean 1). The distribution of genotypes (type II vs. non-type II) was not significantly different when patients were stratified by underlying cause of immunosuppression, site of infection, or outcome. We conclude that in immunocompromised patients, host factors are much more involved than parasite factors in patients' resistance or susceptibility to toxoplasmosis

Adjuvant treatment of early breast cancer

SCOPUS: re.jinfo:eu-repo/semantics/publishe