ICAR: endoscopic skull‐base surgery

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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

Multilateral Cooperation in International Labor Migration

What explains multilateral cooperation leading to the free movement of labor? I examine the ability of two theories of regime formation (structural and game-theoretic approaches) and of two theories of integration (supranationalism and intergovernmentalism) to account for such cooperation. Based on a review of attempts to promote cooperation at the regional and inter-regional levels, and on a more detailed analysis of two case studies (the EU and ECOWAS), I demonstrate that none of the four theories adequately explains how multilateral cooperation with regards to the free movement of labor emerges. I then offer an alternative model, which highlights bargaining between the countries of origin and those of destination. I assert that countries of origin are likely to support the free movement of labor, while countries of destination are likely to oppose it. Multilateral cooperation is achieved when the countries of destination agree to the free movement of labor, and in return, the countries of origin grant the former unrestricted entry into their markets, and/or accept their leadership status. This kind of cross-issue linkage mainly develops in regional integration schemes. I further explain the factors contributing to the durability of cooperation on the free movement of labor, and the paradoxical finding that the multilateral agreements most likely to emerge and survive are the ones that contribute the least to economic efficiency

Scintigraphic imaging of P-glycoprotein expression with a radiolabelled antibody.

Contains fulltext : 50164.pdf (publisher's version ) (Closed access)PURPOSE: P-glycoprotein (P-gp) is a membrane efflux pump protein that is involved in multidrug resistance (MDR). Tumour cells with high P-gp expression show poor response to cancer treatment with several chemotherapeutics. In vivo targeting and visualisation of P-gp expression would allow MDR to be evaluated non-invasively prior to treatment. The aim of this study was to investigate the feasibility of visualising P-gp expression in tumours using a monoclonal anti-P-gp antibody, 15D3. METHODS: Nude BALB/c mice with subcutaneously growing human uterine sarcoma cell tumours with either high (MES-SA/Dx5 1977) or low (MES-SA 1976) P-gp expression were used. When tumours were 0.2-0.4 g, mice received (131)I-15D3 or (111)In-DTPA-15D3 monoclonal anti-P-gp antibody intravenously. Images were acquired up to 3 days p.i. and radioactivity concentration in various tissues was determined after euthanisation of the animals. RESULTS: The images demonstrated that radioactivity accumulated to a higher concentration in high P-gp expressing tumours than in the low P-gp expressing MES-SA 1976 tumour. Furthermore, visualisation of the P-gp expressing tumours was superior with (111)In-DTPA-15D3 than with (131)I-15D3. After injection of (111)In-DTPA-15D3, the high P-gp expressing MES-SA/Dx5 1977 tumours were clearly visualised at 3 days p.i. The biodistribution data indicated that radioactivity concentration in the high P-gp expressing tumours was higher than in the tumours with low P-gp expression (20.78+/-1.42 %ID/g for MES-SA/Dx5 1977 tumours and 8.39+/-3.78 %ID/g for MES-SA 1976 tumours for (111)In-DTPA-15D3). CONCLUSION: The (111)In-labelled monoclonal anti-P-gp antibody clearly visualised P-gp expression in a human uterine sarcoma tumour in nude mice

Migraciones, Estado y una política del derecho humano a migrar ¿Hacia una nueva era en América Latina?

The objective of this article is to analyze whether the recent humanization of laws and migratory policies in Latin America allows us to speak of a new era of migrations in our region. In fact, the processes of integration, regional consultancies on migration, and domestic policies and legislation have all turned in recent years towards an understanding of these processes in terms of human rights. In the same way, the Inter-American Human Rights System has given greater visibility to migratory issues. I therefore discuss these mutual incorporations (of human rights into migrations and of the latter into human rights) from the perspective of the role of the state, both at the international and domestic level, and the effects of the legal determinations and their incompatibilities. The article concludes by showing that human rights were constructed precisely for movement and that their recent and mutual incorporation is due to the encounter of the emancipatory and regulatory logics of the paradigm of Modernity. Therefore, referring to migration with human rights neither changes nor challenges its starting points and so we should think in terms of a regional policy of the human right to migrate