BET Inhibition-Induced GSK3β Feedback Enhances Lymphoma Vulnerability to PI3K Inhibitors

The phosphatidylinositol 3 kinase (PI3K)-glycogen synthase kinase \u3b2 (GSK3\u3b2) axis plays a central role in MYC-driven lymphomagenesis, and MYC targeting with bromodomain and extraterminal protein family inhibitors (BETi) is a promising treatment strategy in lymphoma. In a high-throughput combinatorial drug screening experiment, BETi enhance the antiproliferative effects of PI3K inhibitors in a panel of diffuse large B cell lymphoma (DLBCL) and Burkitt lymphoma cell lines. BETi or MYC silencing upregulates several PI3K pathway genes and induces GSK3\u3b2 S9 inhibitory phosphorylation, resulting in increased \u3b2-catenin protein abundance. Furthermore, BETi or MYC silencing increases GSK3\u3b2 S9 phosphorylation levels and \u3b2-catenin protein abundance through downregulating the E2 ubiquitin conjugating enzymes UBE2C and UBE2T. In a mouse xenograft DLBCL model, BETi decrease MYC, UBE2C, and UBE2T and increase phospho-GSK3\u3b2 S9 levels, enhancing the anti-proliferative effect of PI3K inhibitors. Our study reveals prosurvival feedbacks induced by BETi involving GSK3\u3b2 regulation, providing a mechanistic rationale for combination strategies. In this study, Derenzini et al. demonstrate that BET inhibitors enhance lymphoma vulnerability to PI3K inhibitors by inducing GSK3\u3b2 feedback in a MYC-dependent manner and by downregulating E2-ubiquitin conjugating enzymes, which further enhance the feedback. These data provide the rationale for combining BET and PI3K inhibitors in lymphoma therapy

L’impact social des grands événements sportifs internationaux : processus, effets et enjeux. L’exemple de l’Euro 2016

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Impact social de l’euro 2016 : une étude co-construite avec les services de trois collectivités territoriales

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L’impact social de l’Euro 2016 : la puissance explicative des dynamiques locales

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A study of the phase transitions, electronic structures and thermodynamic properties of Mg2X (X = Ge, Si and Sn) under high pressure

In this work, we theoretically investigate phase transitions, electronic structures and thermodynamic properties of Mg2X (X = Ge, Si and Sn) under high pressures. To reach this goal, the total energy has been calculated by using the full-potential linearized augmented plane wave (FP-LAPW) method with generalized gradient approximation (GGA), local density approximation (LDA) and Engel–Vosko approximation (EV-GGA), which are based on the exchange-correlation energy optimization. The fully relaxed structure parameters of Mg2X compounds are in good agreement with the available experimental data. Our results demonstrate that the Mg2X compounds undergo two pressure-induced phase transitions. The first one is from the cubic antifluorite (Fm3¯m) structure to the orthorhombic anticotunnite (Pnma) structure in the pressure range of 3.77–8.78 GPa (GGA) and 4.88–8.16 GPa (LDA). The second transition is from the orthorhombic anticotunnite structure to the hexagonal Ni2In-type (P63m¯mc) structure in the pressure range of 10.41–29.77 GPa (GGA) and 8.89–63.45 GPa (LDA). All the structural parameters of the high pressure phases are analyzed in detail. Only a small difference in the structural parameters is observed at high pressures between the calculated and experimental results. The electronic and thermodynamic properties are also analyzed and discussed. The establishment of the metallic state of the Mg2X (X = Ge, Si and Sn) compounds at high pressure is confirmed