GRK et arrestines : la piste thérapeutique ?

La phosphorylation d’un récepteur couplé aux protéines G (RCPG) par une kinase spécifique, nommée GRK (G protein-coupled receptor kinase), est une première étape qui participe, avec l’action des arrestines, à l’arrêt de la transmission du signal, au cours d’un processus appelé désensibilisation. Le dérèglement de ce mécanisme de protection cellulaire, mis en évidence dans différentes situations pathologiques, relève soit de mutations génétiques d’une GRK ou d’une arrestine, soit d’une variation de leur expression. Ce dérèglement a pour conséquence de modifier l’activité des RCPG qui interviennent dans de nombreuses fonctions vitales de l’organisme. Ainsi, dans la maladie d’Oguchi, la stimulation excessive de la rhodopsine par la lumière, due à la perte de fonction de la GRK1 ou de l’arrestine 1, conduit à des problèmes d’adaptation de la vision à l’obscurité. La mise au point d’un modèle de souris hypertendues, après transfection ciblée du gène de la GRK2 au niveau des vaisseaux, suggère fortement que l’augmentation de cette GRK participe, chez l’homme, au développement de l’hypertension associée à une baisse de l’effet vasodilatateur des récepteurs β-adrénergiques. L’idée de rétablir une activité RCPG normale en agissant sur ces mécanismes de désensibilisation a été couronnée de succès dans des modèles animaux de défaillance cardiaque chronique, et laisse supposer que la modulation de l’activité des GRK ou de la fonction des arrestines pourrait constituer une piste thérapeutique. Cependant, la réalisation d’essais chez l’homme devra encore attendre la découverte de molécules pharmacologiques efficaces et non toxiques.Phosphorylation of the agonist-activated form of G-protein-coupled receptors (GPCRs) by a protein kinase from the G-protein-coupled receptor kinase (GRK) family initiates, with arrestin proteins, a negative feedback process known as desensitization. Because these receptors are involved in so many vital functions, it seems likely that disorders affecting GRK- or arrestin-mediated regulation of GPCRs would contribute to, if not engender, disease. Traditionally, it is believed that the desensitization process protects the cell against an overstimulation; however, in certain situations, this process is maladjusted and participes in disease progression. For example, in Oguchi disease, excessive rhodopsin stimulation due to a functional loss of GRK1 or arrestin 1 leads to light sensitization and stationary night blindness. Also, transgenic mice with vascular smooth muscle-targeted overexpression of GRK2 showed an elevated resting blood pressure, suggesting that increase in GRK2 level in humans is involved in hypertension associated with a decreased effect of β-adrenergic receptor-mediated vasorelaxation. The restoration of normal GPCR function in modulating the desensitization process has been successfully demonstrated in animal models of heart failure, which indicates that targeting GRKs or arrestins may open a novel therapeutic strategy in human diseases with GPCR dysregulation. However, the few effective pharmacological compounds in this domain currently preclude human clinical tests

Measurement and comparison of individual external doses of high-school students living in Japan, France, Poland and Belarus -- the "D-shuttle" project --

Twelve high schools in Japan (of which six are in Fukushima Prefecture), four in France, eight in Poland and two in Belarus cooperated in the measurement and comparison of individual external doses in 2014. In total 216 high-school students and teachers participated in the study. Each participant wore an electronic personal dosimeter "D-shuttle" for two weeks, and kept a journal of his/her whereabouts and activities. The distributions of annual external doses estimated for each region overlap with each other, demonstrating that the personal external individual doses in locations where residence is currently allowed in Fukushima Prefecture and in Belarus are well within the range of estimated annual doses due to the background radiation level of other regions/countries

FDG PET uptake characterization through texture analysis: investigating the complementary nature of heterogeneity and functional tumor volume in a multi-cancer site patient cohort.: FDG-PET heterogeneity and volume

International audienceIntra-tumor uptake heterogeneity in 18F-FDG PET has been associated with patient treatment outcomes in several cancer types. Textural features (TF) analysis is a promising method for its quantification. An open issue associated with the use of TF for the quantification of intratumoral heterogeneity concerns its added contribution and dependence on the metabolically active tumor volume (MATV), which has already been shown as a significant predictive and prognostic parameter. Our objective was to address this question using a larger cohort of patients covering different cancer types.METHODS:A single database of 555 pre-treatment 18F-FDG PET images (breast, cervix, esophageal, head & neck and lung cancer tumors) was assembled. Four robust and reproducible TF-derived parameters were considered. The issues associated with the calculation of TF using co-occurrence matrices (such as the quantization and spatial directionality relationships) were also investigated. The relationship between these features and MATV, as well as among the features themselves was investigated using Spearman rank coefficients, for different volume ranges. The complementary prognostic value of MATV and TF was assessed through multivariate Cox analysis in the esophageal and NSCLC cohorts.RESULTS:A large range of MATVs was included in the population considered (3-415 cm3, mean = 35, median = 19, SD=50). The correlation between MATV and TF varied greatly depending on the MATVs, with reduced correlation for increasing volumes. These findings were reproducible across the different cancer types. The quantization and the calculation method both had an impact on the correlation. Volume and heterogeneity were independent prognostic factors (P = 0.0053 and 0.0093 respectively) along with stage (P = 0.002) in NSCLC, but in the esophageal tumors, volume and heterogeneity had less complementary value due to smaller overall volumes.CONCLUSION:Our results suggest that heterogeneity quantification and volume may provide valuable complementary information for volumes above 10cm3, although the complementary information increases substantially with larger volumes

Synthese, marquage et evaluation de vecteurs macromoleculaires et microcapsulaires utilisables en imagerie medicale

SIGLECNRS T Bordereau / INIST-CNRS - Institut de l'Information Scientifique et TechniqueFRFranc

Intérêt de la TEP [tomographie par émission de positons] au 18FDG et de la réalisation d'une acquisition dédiée à la sphère ORL dans le bilan pré-thérapeutique des carcinomes épidermoïdes de la tête et du cou

POITIERS-BU Médecine pharmacie (861942103) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Mesure de la clairance pulmonaire du DTPA-TC99m (Aspects méthodologiques.Intérêt dans le suivi thérapeutique en oncologie hématologique)

POITIERS-BU Médecine pharmacie (861942103) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Impact de la tomographie par émission de positons dans la définition des volumes cibles pour l'irradiation des cancers bronchiques non à petites cellules

POITIERS-BU Médecine pharmacie (861942103) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Apport de la TEP-TDM à la Fluorocholine dans la prise en charge des récidives d'adénocarcinomes prostatiques traités initialement par radiothérapie externe ou curiethérapie (étude prospective sur 11 patients)

POITIERS-BU Médecine pharmacie (861942103) / SudocSudocFranceF

Evaluation de la tomographie par émission de positons (TEP) au 18FDG double phase dans l'étude des tumeurs cérébrales

POITIERS-BU Médecine pharmacie (861942103) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF