Rôle de la petite GTPase Rhob dans la résistance des mélanomes aux thérapies ciblées

La prise en charge des mélanomes métastatiques a été récemment révolutionnée par la mise sur le marché du Vemurafenib, un inhibiteur de l'oncogène BRAFV600E. Cependant, l'efficacité de ce traitement est limitée par l'apparition rapide de résistances encore mal comprises. Ce travail doctoral a conduit à l'identification d'une nouvelle voie de résistance à cet inhibiteur ainsi qu'aux inhibiteurs de MEK, autre classe d'inhibiteurs nouvellement utilisée dans les mélanomes. En réponse à l'inhibition de la voie Ras/Raf/MEK/ERK (MAPK) par les inhibiteurs de B-Raf ou de MEK, c-Jun est surexprimé et activé, conduisant à la surexpression de la petite GTPase RhoB par activation transcriptionnelle dépendante de la boite iCCAAT de son promoteur. RhoB ainsi induite favorise la survie cellulaire en présence des inhibiteurs via l'activation de la voie AKT. L'inhibition de cette voie c-Jun/RhoB/AKT, par des ARNs interférents ou des inhibiteurs d'AKT potentialise l'efficacité des inhibiteurs de B-Raf et de MEK en induisant l'apoptose. En conclusion, nous avons mis en évidence l'implication de la voie c-Jun/RhoB/AKT dans la résistance au Vemurafenib et démontré l'activité synergique de l'association d'un inhibiteur d'AKT au Vemurafenib. Enfin, nos travaux amènent les arguments moléculaires soutenant le développement des associations d'inhibiteurs de B-RAF/MEK et d'AKT actuellement en cours d'essais cliniques.Melanoma treatment recently met a breakthrough with the approval of Vemurafenib, a BRAFV600E inhibitor. However, its efficiency is limited as patients rapidly develop resistances still misunderstood. This project reveals an original pathway involved in resistance to Vemurafenib and also to MEK inhibitors, another new therapeutic class approved in melanoma. In response to Ras/Raf/MEK/ERK pathway inhibition by B-Raf or MEK inhibitors, c-Jun is overexpressed and activated leading to RhoB overexpression by an iCCAAT box-dependent transcriptional activation. Induced RhoB favors cell survival in response to these inhibitors in an AKT-dependent manner. Inhibition of the c-Jun/RhoB/AKT pathway with siRNA or AKT inhibitors potently increases B-Raf and MEK inhibitors efficiency through apoptosis triggering. In conclusion, we identified for the first time the involvement of the c-Jun/RhoB/AKT pathway in Vemurafenib resistance and demonstrated the synergism of the Vemuranib/AKT inhibitor association. In fact, we demonstrated, at molecular level, the relevance of current clinical evaluation of B-Raf/MEK and AKT inhibitors association

Implication de la voie de signalisation c-Jun/RhoB/AKT dans la résistance des cellules de mélanome au Vemurafenib

TOULOUSE3-BU Santé-Centrale (315552105) / SudocSudocFranceF

Conséquences du mode d'effondrement sur les mécanismes de transfert de charge et sur le dimensionnement des géosynthétiques sur cavités potentielles

International audienceConsequence of the sinkhole mode on the load transfer mechanisms and on the design of geotextile-reinforced embankments overlying voids. The good geosynthetic sizing of the reinforcements on cavity requires a thorough knowledge of the mechanisms of load transfer of the zone of ground collapsed towards the stable zones. At present, the load acting on the geosynthetic sheet is estimated most of the time by using the mechanism of collapse proposed by Terzaghi and by supposing a uniform distribution of the stress on the sheet. To analyze more in detail these mechanisms of load transfer, full-scale experiments and DEM numerical simulations were performed. By testing two numerical processes, it was demonstrated that the cavity opening modes have a great influence on the shape of the load distribution transmitted to the geosynthetic sheet above the cavity and on the expansion mechanisms of the soil. An approximate conical load distribution seems well adapted when considering a progressive cavity diameter opening process, whereas an inverted load distribution seems more suitable for a gradual settlement process. In both cases and for the 20/40 mm used rolled gravel in the experimentation, the intensity of the load transfer mechanism can be approached by the Terzaghi's formulation using an appropriate value for the ratio between the horizontal and vertical stresses estimated at 1.3. The confrontation between the numerical and experimental results shows that all the complex mechanisms which are mobilized during the collapse of the ground on the geosynthetic is well enough taken into account in the numerical modelling (soil expansion, tension and displacement of the geosynthetic in the anchorage zones, distribution of load, etc.). An improvement of the design method is finally proposed from the results of this study with the consideration of a normative context including SLS and ULS calculations and with consideration of the safety factors.Le bon dimensionnement des renforts géosynthétiques sur cavité nécessite une connaissance approfondie des mécanismes de report de charge de la zone de sol effondrée vers les zones stables. Actuellement, la charge agissant sur la nappe géosynthétique est le plus souvent estimée en utilisant le mécanisme d'effondrement proposé par Terzaghi et en supposant une répartition uniforme des contraintes sur la nappe. Pour analyser plus en détail ces mécanismes de report de charge, des expérimentations en vraie grandeur et des simulations numériques mettant en oeuvre une modélisation éléments discrets ont été réalisées. En testant numériquement différents modes d'ouverture de la cavité (ouverture progressive du diamètre de la cavité et tassement progressif du sol situé sous la nappe au droit de la cavité), il a été démontré que le mécanisme d'ouverture de la cavité avait une influence importante sur le mode de distribution de la charge sur la nappe (répartition des charges tronconiques pour une ouverture progressive du diamètre de la cavité et parabolique inversée lors d'un tassement progressif du sol situé sous la nappe) et sur les mécanismes de foisonnement du sol. L'analyse des mécanismes de transfert de charge a montré que pour le matériau granulaire testé le coefficient K à considérer dans la formulation de Terzaghi utilisée pour évaluer l'intensité du report de charge est de 1,3. Globalement la confrontation entre les résultats numériques et expérimentaux montre que l'ensemble des mécanismes complexes qui sont mobilisés lors de l'effondrement du sol sur la nappe sont assez bien pris en compte dans la modélisation numérique (foisonnement du sol, mise en tension de la nappe dans les zones d'ancrages, transfert de charge, etc.). Enfin, une amélioration des méthodes de dimensionnement actuelles est proposée dans un contexte normatif incluant les calculs aux états limites et avec prise en compte des coefficients de sécurité. Mots clés : renforcement géosynthétique / effondrement localisé / expérimentation en vraie grandeur / modélisation numérique / dimensionnement analytiqu

Role of Biochemical Markers of Bone Turnover as Prognostic Indicator of Successful Osteoporosis Therapy

Most of the currently available anti-osteoporosis medications promptly and significantly influence the rate of bone turnover. Biochemical markers of bone turnover now provide a high sensitivity to change, allowing the detection of these bone turnover changes within a couple of weeks. Since the anti-fracture efficacy of inhibitors of bone resorption or stimulators of bone formation appears to be largely independent of baseline bone turnover, biochemical markers do not appear to play a significant role in the selection of one particular drug, for an individual patient. However, there are consistent data showing that short-term changes in biochemical markers of bone turnover may be significant predictors of future changes in bone mineral density or fracture reduction, hence suggesting that bone turnover markers play a significant role in the monitoring of anti-osteoporosis therapy

Influence of remodeling on the mineralization of bone tissue.

International audienceThe degree of mineralization of bone is a determinant of its mechanical strength and hardness. It is influenced by the level of activity of bone remodeling. Quantitative studies of bone mass, trabecular microarchitecture, bone organic matrix, and the degree of mineralization of bone are required to explain the anti-fracture effect of therapies at the tissue level and associated increases in lumbar bone density

A water soluble Cu-I-NHC for CuAAC ligation of unprotected peptides under open air conditions.

International audienceA reducing agent-free version of CuAAC able to operate under open air conditions is reported. A readily-synthesizable, hydrophilic and highly stable CuI-NHC allows the clean ligations of unprotected peptides comprising sensitive side chains, at millimolar concentrations

Simulation of a Potential CO2 Storage in the West Paris Basin: Site Characterization and Assessment of the Long-Term Hydrodynamical and Geochemical Impacts Induced by the CO2 Injection

This article presents the preliminary results of a study carried out as part of a demonstration project of CO2 storage in the Paris Basin. This project funded by ADEME (French Environment and Energy Management Agency) and several industrial partners (TOTAL, ENGIE, EDF, Lafarge, Air Liquide, Vallourec) aimed to study the possibility to set up an experimental infrastructure of CO2 transport and storage. Regarding the storage, the objectives were: (1) to characterize the selected site by optimizing the number of wells in a CO2 injection case of 200 Mt over 50 years in the Trias, (2) to simulate over time the CO2 migration and the induced pressure field, and (3) to analyze the geochemical behavior of the rock over the long term (1,000 years). The preliminary site characterization study revealed that only the southern area of Keuper succeeds to satisfy this injection criterion using only four injectors. However, a complementary study based on a refined fluid flow model with additional secondary faults concluded that this zone presents the highest potential of CO2 injection but without reaching the objective of 200 Mt with a reasonable number of wells. The simulation of the base scenario, carried out before the model refinement, showed that the overpressure above 0.1 MPa covers an area of 51,869 km2 in the Chaunoy formation, 1,000 years after the end of the injection, which corresponds to the whole West Paris Basin, whereas the CO2 plume extension remains small (524 km2). This overpressure causes brine flows at the domain boundaries and a local overpressure in the studied oil fields. Regarding the preliminary risk analysis of this project, the geochemical effects induced by the CO2 injection were studied by simulating the fluid-rock interactions with a coupled geochemical and fluid flow model in a domain limited to the storage complex. A one-way coupling of two models based on two domains fitting into each other was developed using dynamic boundary conditions. This approach succeeded to improve the simulation results of the pressure field and the CO2 plume as well as the geochemical behavior of the rock. These ones showed that the CO2 plume tends to stabilize thanks to the carbonation in calcite and dawsonite and no significant porosity change appears over 1,050 years. The CO2 mass balance per trapping type gives a CO2 carbonation rate of about 78% at 1,050 years that seemed to be excessive compared to the simulation study of other storage sites. Thus, an additional work dealing with both the kinetic data base and the textural models would be necessary in order to reduce the uncertainty of the injected CO2 mineralization

Simulation of a Potential CO

This article presents the preliminary results of a study carried out as part of a demonstration project of CO2 storage in the Paris Basin. This project funded by ADEME (French Environment and Energy Management Agency) and several industrial partners (TOTAL, ENGIE, EDF, Lafarge, Air Liquide, Vallourec) aimed to study the possibility to set up an experimental infrastructure of CO2 transport and storage. Regarding the storage, the objectives were: (1) to characterize the selected site by optimizing the number of wells in a CO2 injection case of 200 Mt over 50 years in the Trias, (2) to simulate over time the CO2 migration and the induced pressure field, and (3) to analyze the geochemical behavior of the rock over the long term (1,000 years). The preliminary site characterization study revealed that only the southern area of Keuper succeeds to satisfy this injection criterion using only four injectors. However, a complementary study based on a refined fluid flow model with additional secondary faults concluded that this zone presents the highest potential of CO2 injection but without reaching the objective of 200 Mt with a reasonable number of wells. The simulation of the base scenario, carried out before the model refinement, showed that the overpressure above 0.1 MPa covers an area of 51,869 km2 in the Chaunoy formation, 1,000 years after the end of the injection, which corresponds to the whole West Paris Basin, whereas the CO2 plume extension remains small (524 km2). This overpressure causes brine flows at the domain boundaries and a local overpressure in the studied oil fields. Regarding the preliminary risk analysis of this project, the geochemical effects induced by the CO2 injection were studied by simulating the fluid-rock interactions with a coupled geochemical and fluid flow model in a domain limited to the storage complex. A one-way coupling of two models based on two domains fitting into each other was developed using dynamic boundary conditions. This approach succeeded to improve the simulation results of the pressure field and the CO2 plume as well as the geochemical behavior of the rock. These ones showed that the CO2 plume tends to stabilize thanks to the carbonation in calcite and dawsonite and no significant porosity change appears over 1,050 years. The CO2 mass balance per trapping type gives a CO2 carbonation rate of about 78% at 1,050 years that seemed to be excessive compared to the simulation study of other storage sites. Thus, an additional work dealing with both the kinetic data base and the textural models would be necessary in order to reduce the uncertainty of the injected CO2 mineralization

Incidence of and risk factors for severe cardiovascular collapse after endotracheal intubation in the ICU: a multicenter observational study

International audienceIntroduction : Severe cardiovascular collapse (CVC) is a life-threatening complication after emergency endotrachealintubation (ETI) in the ICU. Many factors may interact with hemodynamic conditions during ETI, but no study todate has focused on factors associated with severe CVC occurrence. This study assessed the incidence of severeCVC after ETI in the ICU and analyzed the factors predictive of severe CVC.Methods : This was a secondary analysis of a prospective multicenter study of 1,400 consecutive intubations at 42ICUs. The incidence of severe CVC was assessed in patients who were hemodynamically stable (mean arterial bloodpressure >65 mmHg without vasoactive drugs) before intubation, and the factors predictive of severe CVC weredetermined by multivariate analysis based on patient and procedure characteristics.Results : Severe CVC occurred following 264 of 885 (29.8 %) intubation procedures. A two-step multivariate analysisshowed that independent risk factors for CVC included simple acute physiologic score II regardless of age (oddsratio (OR) 1.02,p75 years (OR 2.81,p70 % after intubation (OR 1.91,p= 0.001). Comatose patients who required ETI were less likely todevelop CVC during intubation (OR 0.48,p= 0.004).Conclusions : CVC is a frequent complication, especially in old and severely ill patients intubated for acuterespiratory failure in the ICU. Specific bundles to prevent CVC may reduce morbidity and mortality related tointubation of these high-risk, critically ill patients.Trial registration : clinicaltrials.gov NCT01532063; registered 8 February 201