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

Die romanischen literaturen und sprachen, mit einschluss des keltischen,

Mode of access: Internet

Zeitschrift für ägyptische Sprache und Altertumskunde.

Published: Leipzig : J.C. Hinrichs'sche Buchhandlung, 1863-1936; Leipzig : J.C. Hinrichs Verlag, 1937-1943; Berlin : Akademie-Verlag in Arbeitsgemeinschaft mit J.C. Hinrichs Verlag, Leipzig, 1954-; Berlin : Akademie-Verlag, -2013; Berlin, Germany : De Gruyter, 2014-Editors: 1863-94, H. Brugsch (with R. Lepsius, 1864-84; A. Erman, 1881-84, 1889-94; L. Stern, 1881-88); 1894- G. Steindorff (with A. Erman, 1894-1907).None published 1944-1953.Mode of access: Internet.Issued by: Deutsche Morgenländische Gesellschaft, 1863-Vols. 1-23, 1863-85, 1886; Vols. 1-40, 1863-1903, in v. 40; Vols. 41-70, 1904-34, in v. 70; Vols. 1-88, 1863-1963, in v. 89.UPDATE

Short-term potentiation of mEPSCs requires N-, P/Q- and L-type Ca2+ channels and mitochondria in the supraoptic nucleus

The glutamatergic synapses of the supraoptic nucleus display a unique activity-dependent plasticity characterized by a barrage of tetrodotoxin-resistant miniature EPSCs (mEPSCs) persisting for 5–20 min, causing postsynaptic excitation. We investigated how this short-term synaptic potentiation (STP) induced by a brief high-frequency stimulation (HFS) of afferents was initiated and maintained without lingering presynaptic firing, using in vitro patch-clamp recording on rat brain slices. We found that following the immediate rise in mEPSC frequency, STP decayed with two-exponential functions indicative of two discrete phases. STP depends entirely on extracellular Ca2+ which enters the presynaptic terminals through voltage-gated Ca2+ channels but also, to a much lesser degree, through a pathway independent of these channels or reverse mode of the plasma membrane Na+–Ca2+ exchanger. Initiation of STP is largely mediated by any of the N-, P/Q- or L-type channels, and only a simultaneous application of specific blockers for all these channels attenuates STP. Furthermore, the second phase of STP is curtailed by the inhibition of mitochondrial Ca2+ uptake or mitochondrial Na+–Ca2+ exchanger. mEPSCs amplitude is also potentiated by HFS which requires extracellular Ca2+. In conclusion, induction of mEPSC-STP is redundantly mediated by presynaptic N-, P/Q- and L-type Ca2+ channels while the second phase depends on mitochondrial Ca2+ sequestration and release. Since glutamate influences unique firing patterns that optimize hormone release by supraoptic magnocellular neurons, a prolonged barrage of spontaneous excitatory transmission may aid in the induction of respective firing activities

Chemical abrasion applied to SHRIMP zircon geochronology: An example from the Variscan Karkonosze Granite (Sudetes, SW Poland)

International audienceThermal annealing followed by acid etching of zircon (chemical abrasion or CA) can be successfully utilised to minimize or eliminate the effects of major and cryptic Pb-loss for SIMS U-Pb zircon dating. The procedure is demonstrated by applying the U-Pb SIMS technique to both untreated and chemically abraded zircons from the Karkonosze Granite, Sudetes, SW Poland. Conventional U-Pb SIMS dating of untreated zircons yields an apparently coherent age population (n = 9) with a weighted mean 206Pb/238U age of 306 ± 4 Ma. Some untreated zircons display anomalously young 206Pb/238U ages (c. 225 and 238 Ma) and are likely to have suffered substantial Pb-loss. A sub-set of zircons from the same sample was chemically abraded. Physically, zircons treated in this manner display a range in the degree of etching and partial dissolution. Extreme examples developed a 3D network of sub-μm channels which follow high-U (dark CL) zones or linear defects, such as micro fractures or indistinct cleavage planes. U-Pb SIMS dating of treated zircons (n = 11) yields a mean 206Pb/238U age of 322 ± 3 Ma. Two analyses of treated zircons still display younger 206Pb/238U ages (c. 297 and 301 Ma) ascribed to the effects of Pb-loss. For the analysed sample, U-Pb ages determined from chemically abraded zircons are c. 5% older than those from untreated zircons. This is attributed to effective removal of metamict domains susceptible to Pb-loss. The CA technique also removes micro-inclusions thus lowering common Pb and reducing matrix effects. A cryptic Pb-loss in untreated zircons is only recognised when compared with chemically abraded counterparts or ages determined using other isotope techniques. This clearly demonstrates the utility of CA to high-spatial resolution methods and stresses that Pb-loss is detectable at a range of scales, regardless of the analytical technique used

Rudolf Ladenburg and the first quantum interpretation of optical dispersion

In 1921, the experimental physicist Rudolf Ladenburg put forward the first quantum interpretation of optical dispersion. Theoretical physicists had tried to explain dispersion from the point of view of quantum theory ever since 1913, when Niels Bohr proposed his quantum model of atom. Yet, their theories proved unsuccessful. It was Ladenburg who gave a breakthrough step toward our quantum understanding of dispersion. In order to understand Ladenburg’s step, I analyze Ladenburg’s experimental work on dispersion prior to 1913, the reasons why the first theories of dispersion after 1913 were not satisfactory, and Ladenburg’s 1921 proposal. I argue that Ladenburg’s early experimental work on dispersion is indispensable to understand his 1921 paper. The specific kind of experiments he performed before 1913, the related interpretative problems, and the way he tried to solve them, led him reapproach the dispersion problem in 1921 in a way that was completely different from the way theoretical physicists had done it before