Üksikvastuste teooria rakendamine jõu mõistelise testi analüüsimisel

https://www.ester.ee/record=b5564736*es

Irinotecan induces steroid and xenobiotic receptor (SXR) signaling to detoxification pathway in colon cancer cells

<p>Abstract</p> <p>Background</p> <p>Resistance to chemotherapy remains one of the principle obstacles to the treatment of colon cancer. In order to identify the molecular mechanism of this resistance, we investigated the role of the steroid and xenobiotic receptor (SXR) in the induction of drug resistance. Indeed, this nuclear receptor plays an important role in response to xenobiotics through the upregulation of detoxification genes. Following drug treatments, SXR is activated and interacts with the retinoid X receptor (RXR) to induce expression of some genes involved in drug metabolism such as phase I enzyme (like CYP), phase II enzymes (like UGT) and transporters (e.g. MDR1).</p> <p>Results</p> <p>In this study, we have shown that endogenous SXR is activated in response to SN-38, the active metabolite of the anticancer drug irinotecan, in human colon cancer cell lines. We have found that endogenous SXR translocates into the nucleus and associates with RXR upon SN-38 treatment. Using ChIP, we have demonstrated that endogenous SXR, following its activation, binds to the native promoter of the CYP3A4 gene to induce its expression. RNA interference experiments confirmed SXR involvement in CYP3A4 overexpression and permitted us to identify CYP3A5 and MRP2 transporter as SXR target genes. As a consequence, cells overexpressing SXR were found to be less sensitive to irinotecan treatment.</p> <p>Conclusions</p> <p>Altogether, these results suggest that the SXR pathway is involved in colon cancer irinotecan resistance in colon cancer cell line via the upregulation of select detoxification genes.</p

Digital Technology To Support Organic Growers ? Mesclun: A Web App To Help Designing Complex Organic Vegetable Production

For organic vegetable growers, combining long rotations involving a high level of plant diversity with intercropping can bring economic and ecological benefits but often increase management complexity and workload. To support the decision making of farmers facing such challenges, the research-action objective of the MESCLUN programme is to develop a web application based on the innovative computer technologies of knowledge graphs and semantic web. In this French transdisciplinary project, we articulate methods and frameworks from different fields (agronomy, economy, design, knowledge and computer engineering) with expertise of agricultural practitioners (organic growers, advisors, teachers, organic farming students). Through an iterative and participatory approach based on co-innovation workshops in 4 contrasted regions of France, we design, develop and test web app prototypes to help farmers to appropriate systemic thinking, explore and assess their “own” solutions in the organisation of complex organic vegetables systems. We will present functionalities/interface of the first web app prototype. We will for example show how the web app can help growers to plan their crops in space and time considering contrasted fertility and plants health strategies as well as marketing requirements. We will also illustrate how different simulations can be assessed from a socio-economic perspective (workload and income). Based on those first results, we will examine the specificities, added value and blind spots of our web app compared to other decision making tools in the organic agricultural sector. To feed a more general debate, we will provide critical discussion points on the potentialities and limitations of innovative digital solutions to support decision making in complex organic farming systems

Essential omega-3 fatty acids tune microglial phagocytosis of synaptic elements in the mouse developing brain

AbstractOmega-3 fatty acids (n-3 PUFAs) are essential for the functional maturation of the brain. Westernization of dietary habits in both developed and developing countries is accompanied by a progressive reduction in dietary intake of n-3 PUFAs. Low maternal intake of n-3 PUFAs has been linked to neurodevelopmental diseases in Humans. However, the n-3 PUFAs deficiency-mediated mechanisms affecting the development of the central nervous system are poorly understood. Active microglial engulfment of synapses regulates brain development. Impaired synaptic pruning is associated with several neurodevelopmental disorders. Here, we identify a molecular mechanism for detrimental effects of low maternal n-3 PUFA intake on hippocampal development in mice. Our results show that maternal dietary n-3 PUFA deficiency increases microglia-mediated phagocytosis of synaptic elements in the rodent developing hippocampus, partly through the activation of 12/15-lipoxygenase (LOX)/12-HETE signaling, altering neuronal morphology and affecting cognitive performance of the offspring. These findings provide a mechanistic insight into neurodevelopmental defects caused by maternal n-3 PUFAs dietary deficiency.Infrastructure de Recherche Translationnelle pour les Biothérapies en NeurosciencesProgram Initiative d’Excellenc

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

Exploitation des gels d'électrophorèse bidimensionnelle

National audienc

Electrophorèse 2-D haute résolutionde polypeptides de la membrane plasmique de racine de maïs : identification de polypeptides dont l'expression est régulée par le nitrate

International audienc

Novel gels from wheat gluten proteins

International audienc

The stability investigation of variable viscosity control in the human‐robot interaction

International audienceBackground: For many co-manipulative applications, variable damping is a valuable feature provided by robots. One approach is implementing a high viscosity at low velocities and a low viscosity at high velocities. This, however, is proven to have the possibility to alter human natural motion performance.Methods: We show that the distortion is caused by the viscosity drop resulting in robot's resistance to motion. To address this, a method for stably achieving the desired behaviour is presented. It involves leveraging a first-order linear filter to slow the viscosity variation down.Results: The proposition is supported by a theoretical analysis using a robotic model. Meanwhile, the user performance in human-robot experiments gets significantly improved, showing the practical efficiency in real applications.Conclusions: This paper discusses the variable viscosity control in the context of co-manipulation. An instability problem and its solution were theoretically shown and experimentally evidenced through human-robot experiments