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

Topos of the “Garden” as a Spatial Dominant in Anton Chekhov’s Works in the 1890s—1900s

Статья посвящена эволюции топоса «Сад» в творчестве А. П. Чехова 1890-1900-х гг. С помощью лексического анализа показывается, что в этом периоде исканий писателя происходит распад описанной В. Н. Топоровым и Н. Е. Разумовой топосной дуальности «море — степь». Формируется новая топосная доминанта — сад. Структура топоса складывается постепенно. В повести «Дуэль» Чеховым задается связка «сад — семья», но само пространство пока не выходит за границы придомовых палисадников. В рассказе «Страх» намечается вектор будущей символизации: во главу угла ставится субъективное восприятие. Страшными, радостными, грустными могут быть любые, самые простые детали садово-паркового пространства. В повести «Черный монах» Чехов, вступая в диалог с Ницше, использует для создания образа героев идеи дионисийского и аполлонического начал. Топос независим от жанрово-рядовых решений, Чехов продолжает формировать садовое пространство и в драме. В «Чайке» оформляется структура топоса: устанавливаются отношения между садом, парком и домом. Авторские наработки воплощаются в заключительном произведении — «Вишневом саде». Чехов выносит топос за пределы визуального действия. Пространство перестает быть местом совершения события, что усиливает эффект символизации. В чеховском подходе к оформлению крупных пространственных единиц выражается установка модернистов на расширение художественной впечатлительности. Мир больше не воспринимается как прекрасная и стабильная система, созданная богом, пространство прочитывается и преобразовывается через призму субъективного восприятия . This article studies the evolution of the topos of “garden” in Anton Chekhov’s works in the 1890s —1900s. The lexical analysis shows the decay of topos’s duality “Sea + steppe” described earlier by Toporov and Razumova. A new dominant toponym — a “garden” — is being formed. The structure of topos develops gradually. In Chekhov’s story “The Duel”, the garden becomes a reflection of the emotional state within the family. In the story “Fear”, the first elements of symbolization the come out. Subjectivity of perception of the world becomes the main purpose for the author. In the story “Black Monk”, Chekhov enters into a dialogue with Nietzsche and uses the idea of the Dionysian and Apollonian principles to create characters’ images. Topos is independent of the genre-ordinary decisions. Chekhov continues to shape a garden space in the drama as well. The topos “Garden” emerges in full in “Cherry Orchard”. Chekhov takes topos beyond visual action. Space is no longer the place of the event, which enhances the effect of symbolization. With the help of topos, Chekhov actualizes the installation of modernists to expand artistic impression. The world is no longer perceived as a beautiful and stable system created by God, space is transformed through the prism of subjective perception of heroes

On Structural Sensitivity of Young’s Modulus of Ni-Rich Ti-Ni Alloy

When developing bone implants, Young’s modulus is one of the primary characteristics of the material that should be considered. This study focuses on regulating the modulus of Ti-50.8 at.% Ni alloy by varying the grain/subgrain size as well as the initial structure using subsequent aging at 430 °C for 10 h. After post-deformation annealing (PDA), the temperature dependence of Young’s modulus exhibits a pronounced V-shaped character with a minimum at the onset temperature of the forward martensitic transformation, Ms, regardless of the structure. The grain/subgrain size of B2-austenite strongly affects the modulus magnitude. This effect is ambiguous for a material with a grain size range of 0.13–3 µm and depends on the test temperature. The effect of aging on the modulus reduction depends on the initial structure; it is most pronounced in an alloy with a relatively coarse grain size of 9 µm and brings a decrease of 3.8 times at a temperature of 37 °C. Aging of the initially recrystallized Ni-rich NiTi alloy makes it possible to obtain a вone-like elastic modulus of E = 12–13 GPa at an operating temperature of 37 °C. An ultrafine-grained substructure exhibits the same Young’s modulus values in the low temperature range from −100 to 25 °C