Influence of MAGEA and effects of resveratrol on p53 biology

MAGEA1 and -A2 impair the stabilization and activation of p53 in presence of a genotoxic stress. MAGEA (Melanoma AntiGEn-A) genes are silenced in the vast majority of healthy human adult tissues. However, a re-expression is commonly observed in various types of cancer. Several studies demonstrated a correlation between MAGEA expression and advanced cancer stages as well as increased resistance to chemotherapy. However, the functions of MAGEA proteins in cancer cells remain largely unknown. Here, we present evidence that MAGEA1 and MAGEA2 (but not -A3, -A4, -A6 and -A12) diminish the sensitivity of breast cancer cells to the chemotherapeutic agent doxorubicin. We link this resistance to reduced DNA damage-induced apoptosis. Furthermore, we demonstrate that MAGEA1 and -A2 proteins directly interact with the tumor suppressor p53 and inhibit its stabilization and activation. We link the decreased activation and lowered half-life of stress-induced p53 to an impaired phosphorylation of its N-terminal region in presence of MAGEA1 or -A2. Resveratrol induces DNA damage in colon cancer cells by poisoning topoisomerase II and activates the ATM kinase to trigger p53-dependent apoptosis. Resveratrol (trans-3,4’,5-trihydroxystilbene) is a natural polyphenol synthesized by various plants such as grape vine. Resveratrol (RSV) is a widely studied molecule, largely for its chemopreventive effect in different mouse cancer models. We propose a mechanism underlying the cytotoxic activity of RSV on colon cancer cells. Our data show that resveratrol induces apoptosis. We show that the tumor suppressor p53 is activated and participates to the apoptotic process. RSV induces DNA damage including double strand breaks after a 24h treatment. The formation of DNA damage is the consequence of type II topoisomerase poisoning. Exposure of HCT-116 cells to RSV leads to activation of the Ataxia Telangiectasia Mutated (ATM) kinase, and ATM is required to activate p53.(SC - Sciences) -- UCL, 201

Multi-scale spray atomization model

International audienceThe purpose of the present article is to present a dynamic multi-scale approach for turbulent liquid jet atomization in dense flow (primary atomization), together with the possibility to recover Interface Capturing Method (ICM) / Direct Numerical Simulation (DNS) features for well resolved liquid-gas interface. A full ICM-DNS approach should give the best comparison with experimental data, but it is not industrially affordable for the time being, therefore models are mandatory. A numerical representation based on full ICM-DNS, for the initial destabilization of the complex turbulent liquid jet, going up to the spray formation, for which well established numerical models can be used, is appealing but has not yet been applied. Indeed such an approach requires the ICM-DNS to be applied up to the formation of each individual droplet. Hence, in many situation models have to be applied to the dense, unresolved and turbulent liquid-gas flow. To achieve this goal, the most important unresolved phenomena to address are, the sub-grid turbulent liquid flux and surface density, in which models based on the so-called Euler-Lagrange Spray Atomization (ELSA) concept, were developed and have been successfully applied to an Engine Combustion Network (ECN) database, in both RANS/LES (Reynolds-Averaged Navier-Stoke/Large Eddy Simulation) context. An innovative coupling between ICM and a complete ELSA approach was tested based on Interface Resolved Quality (IRQ) sensors to determine locally and dynamically whether or not the interface can be well captured. The ultimate aim is to conduct numerical simulations of fuel injection in an industrial scale, for which comprehensive database has been set up. The test case has been chosen for two reasons: (i) previous numerical studies showed, on the same test case, that RANS turbulence model requires a strong modification to get appropriate results, hence prompted the use of LES models. And (ii), liquid Reynolds and gas Weber numbers are relatively low, compared with ECN test cases, hence more flow regions are expected to be resolved. Results showed that using a fully resolved interface model in the whole domain, provides results in good agreement with the experiment in the primary atomization region only. Indeed, it effectively captured the surface instabilities and liquid structure detachments. In the far field, however, this model becomes rapidly unadapted downward in the dispersed spray region, and the ICM-ELSA model was able instead to treat low volume fractions of atomized liquid, where velocity fluctuations become important

Liquid transport in scale space

When a liquid stream is injected into a gaseous atmosphere, it destabilizes and continuously passes through different states characterized by different morphologies. Throughout this process, the flow dynamics may be different depending on the region of the flow and the scales of the involved liquid structures. Exploring this multi-scale, multi-dimensional phenomenon requires some new theoretical tools, some of which need yet to be elaborated. Here, a new analytical framework is proposed on the basis of two-point statistical equations of the liquid volume fraction. This tool, which originates from single phase turbulence, allows notably to decompose the fluxes of liquid in flow-position space and scale space. Direct Numerical Simulations of liquid-gas turbulence decaying in a triply periodic domain are then used to characterize the time and scale evolution of the liquid volume fraction. It is emphasized that two-point statistics of the liquid volume fraction depend explicitly on the geometrical properties of the liquid-gas interface and in particular its surface density. The stretch rate of the liquid-gas interface is further shown to be the equivalent for the liquid volume fraction (a non diffusive scalar) of the scalar dissipation rate. Finally, a decomposition of the transport of liquid in scale space highlights that non-local interactions between non adjacent scales play a significant role

Simulation numérique directe des écoulements liquide-gaz avec évaporation (application à l'atomisation)

Le but de cette thèse est d'étudier numériquement les écoulements diphasiques liquide-gaz à l'aide d'une méthode de suivi d'interface précise. Tout d'abord, nous mettons en place une configuration turbulence homogène isotrope diphasique. Cette configuration est utilisée pour étudier la turbulence liquide-gaz ainsi que le modèle ELSA. A l'aide de la simulation présentée il a été possible de déterminer les constantes de modélisation et de valider les termes sources utilisés dans la zone dense du spray. Ensuite, le phénomène d'évaporation est étudié en utilisant dans un premier temps un scalaire passif puis en utilisant un formalisme DNS d'évaporation. Les équations d'énergie et des espèces ont été ajoutées dans le code ARCHER. La validation de la DNS d'évaporation a été réalisée en comparant nos résultats aux solutions théoriques, tel que la loi du D2. Les limitations et les apports de cette approche sont finalement discutés et des perspectives d'améliorations sont proposées.The aim of this thesis is to study numerically two phase flow using accurate interface tracking method. First, a two phase flow homogeneous isotropic turbulence is performed. This numerical configuration is used to study two phase flows turbulence and the ELSA model used in primary atomization modelling. Based on these results, modelling constants and source terms have been determined and validated. Then the evaporation process is studied and modelized by using a passive scalar and then by using a DNS formalism. Energy and species equations are added in the ARCHER code. Validation of the DNS performed by comparing the DNS results with theorical solution, such as the D2 law. Finally, limitations and interests of this approach are discussed and further improvements are proposed.ROUEN-INSA Madrillet (765752301) / SudocSudocFranceF

Where does the drop size distribution come from?

[EN] This study employs DNS of two-phase flows to enhance primary atomization understanding and modelling to be used in numerical simulation in RANS or LES framework. In particular, the work has been aimed at improving the information on the liquid-gas interface evolution available inside the Eulerian-Lagrangian Spray Atomization (ELSA) framework. Even though this approach has been successful to describe the complete liquid atomization process from the primary region to the dilute spray, major improvements are expected on the establishment of the drop size distribution (DSD). Indeed, the DSD is easily defined once the spray is formed, but its appearance and even the mathematical framework to describe its creation during the initial breakup of the continuous liquid phase in a set of individual liquid parcels is missing. This is the main aim of the present work to review proposals to achieve a continuous description of the DSD formation during the atomization process. The attention is here focused on the extraction from DNS data of the behaviour of geometrical variable of the liquidgas interface, such as the mean and Gauss surface curvatures. A DNS database on curvature evolution has been generated. A Rayleigh-Plateau instability along a column of liquid is considered to analyse and to verify the capabilities of the code in correctly predicting the curvature distribution. A statistical analysis on the curvatures data, in terms of probability density function, was performed in order to determine the physical parameters that control the curvatures on this test case. Two different methods are presented to compute the curvature distribution and in addition, the probability to be at a given distance of the interface is studied. This approach finally links the new tools proposed to follow the formation of the spray with the pioneering work done on scale distribution analysis.Canu, R.; Dumouchel, C.; Duret, B.; Essadki, M.; Massot, M.; Ménard, T.; Puggelli, S.... (2017). Where does the drop size distribution come from?. En Ilass Europe. 28th european conference on Liquid Atomization and Spray Systems. Editorial Universitat Politècnica de València. 605-612. https://doi.org/10.4995/ILASS2017.2017.4706OCS60561

Internal Numerical Simulation of a Swirl Simplex Atomizer to Predict Atomization Outputs

International audienc

Overcoming Target Driven Fratricide for T Cell Therapy

Chimeric Antigen Receptor (CAR) T cells expressing the fusion of the NKG2D protein with CD3ζ (NKG2D-CAR T Cells) acquire a specificity for stress-induced ligands expressed on hematological and solid cancers. However, these stress ligands are also transiently expressed by activated T cells implying that NKG2D-based T cells may undergo self-killing (fratricide) during cell manufacturing or during the freeze thaw cycle prior to infusion in patients. To avoid target-driven fratricide and enable the production of NKG2D-CAR T cells for clinical application, two distinct approaches were investigated. The first focused upon the inclusion of a Phosphoinositol-3-Kinase inhibitor (LY294002) into the production process. A second strategy involved the inclusion of antibody blockade of NKG2D itself. Both processes impacted T cell fratricide, albeit at different levels with the antibody process being the most effective in terms of cell yield. While both approaches generated comparable NKG2D-CAR T cells, there were subtle differences, for example in differentiation status, that were fine-tuned through the phasing of the inhibitor and antibody during culture in order to generate a highly potent NKG2D-CAR T cell product. By means of targeted inhibition of NKG2D expression or generic inhibition of enzyme function, target-driven CAR T fratricide can be overcome. These strategies have been incorporated into on-going clinical trials to enable a highly efficient and reproducible manufacturing process for NKG2D-CAR T cells