SMG1 and NIK regulate apoptosis induced by Smac mimetic compounds

Smac mimetic compounds (SMCs) are experimental small molecules that induce tumour necrosis factor alpha (TNFα)-dependent cancer cell death by targeting the inhibitor of apoptosis proteins. However, many cancer cell lines are resistant to SMC-mediated apoptosis despite the presence of TNFα. To add insight into the mechanism of SMC-resistance, we used functional siRNA-based kinomic and focused chemical screens and identified suppressor of morphogenesis in genitalia-1 (SMG1) and NF-κB-inducing kinase (NIK) as novel protective factors. Both SMG1 and NIK prevent SMC-mediated apoptosis likely by maintaining FLICE inhibitory protein (c-FLIP) levels to suppress caspase-8 activation. In SMC-resistant cells, the accumulation of NIK upon SMC treatment enhanced the activity of both the classical and alternative nuclear factor-κB pathways, and increased c-FLIP mRNA levels. In parallel, persistent SMG1 expression in SMC-resistant cells repressed SMC-mediated TNFα-induced JNK activation and c-FLIP levels were sustained. Importantly, SMC-resistance is overcome by depleting NIK and SMG1, which appear to facilitate the downregulation of c-FLIP in response to SMC and TNFα treatment, leading to caspase-8-dependent apoptosis. Collectively, these data show that SMG1 and NIK function as critical repressors of SMC-mediated apoptosis by potentially converging on the regulation of c-FLIP metabolism

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Genome-wide insertional mutagenesis of Arabidopsis thaliana

Over 225,000 independent Agrobacterium transferred DNA (T-DNA) insertion events in the genome of the reference plant Arabidopsis thaliana have been created that represent near saturation of the gene space. The precise locations were determined for more than 88,000 T-DNA insertions, which resulted in the identification of mutations in more than 21,700 of the approximately 29,454 predicted Arabidopsis genes. Genome-wide analysis of the distribution of integration events revealed the existence of a large integration site bias at both the chromosome and gene levels. Insertion mutations were identified in genes that are regulated in response to the plant hormone ethylene

De l'aspect du temps, représentation et expression du temps passé en anglais et en français (étude contrastive dans une perspective traductologique)

Cette étude est fondamentalement une approche linguistique des problèmes de traduction liés au prétérit et à l imparfait en contexte spécifique. Elle se compose de trois grandes parties. La première s intéresse à la distinction entre aspect lexical et aspect grammatical. Cette distinction se fonde essentiellement sur la définition que donne G. Guillaume de la lexigénèse. La deuxième partie analyse le signifé de puissance de l imparfait et du prétérit ainsi que leurs effets de sens respectifs. Dans la troisième et dernière partie sont introduits quatre concepts clefs visant à justifier la traduction du prétérit simple par l imparfait ou le passé simple, ceux de perfectivité verticale, horizontale, intégrale et transitive. Sont également répertoriés plusieurs critères favorisant l emploi de la forme perfective et imperfective du prétérit, tels que l image temporelle du verbe, le concept philosophique de esse est percipi / percipi est esse, le principe de la deixis ad occulos, etc. Cette étude peut être enfin globalement considérée comme une réflexion sur le principe d orthonymie dans le processus de traduction.This study is basically a linguistic approach to the translation of the English preterite and the French imparfait, primarily in a specific context. It falls into three major parts. The first one focuses on the distinction between lexical and grammatical aspect. This distinction is mainly based on G. Guillaume s definition of the concept of lexigenesis. The second part analyses the potential significate of the imparfait and of the preterit and their related sense effects. In the last and third part, four key concepts are introduced to account for the translation of the simple past into either the imparfait or the passé simple, those of vertical, horizontal, integral and transitive perfectivity. Various criteria are also listed favouring the use of the perfective or the imperfective form of the preterit, such as the temporal contour of the verb, the philosophical concept of esse est percipi / percipi est esse, the deixis ad occulos principle, etc. Lastly, this study can be considered as an overall reflection on the principle of orthonymy underlying the translating process at large.TOULON-BU Centrale (830622101) / SudocSudocFranceF