43 research outputs found
Magnetic distortion of GDS transfer functions: An example from the Penninic Alps of Eastern Switzerland revealing a crustal conductor
Multi-scale imaging of a slow active fault zone: contribution for improved seismic hazard assessment in the Swiss Alpine foreland
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
Electron Impact Induced Loss of C-5/C-8 Substituents of 1,2,3,4-Tetrahydroisoquinolines, VI, Synthesis and Mass Spectrometric Fragmentation of Dihydroindole Derivatives
The syntheses of the C-4 substituted dihydroindoles 25, 31 (scheme 7), and
36 (scheme 8) are described. - The CID MIKE spectrum in the 2. field free
region (2. FFR) of m/z 146 from 25 is very similar to but not identical with
that of m/z 146 from the C-5 substituted tetrahydroisoquinolines 3,6, 7, and
8 (scheme 2), so supporting our hypothesis of a rearrangement in M+. of tetrahydroisoquinolines
prior to fragmentation, but not proving i t As the
CID MIKE spectra of the tetrahydroisoquinolines 3, 6,7, and 8 are not identical
among each other we assume that a 1.3-H-shift takes places in their M+. in competition to the rearrangement mentioned above.
Die Herstellung der C-4-substituierten Dihydroindole 25,31 (Schema 7) und
36 (Schema 8) wird beschrieben. - Das CID MIKE-Spektrum im 2. feldfreien
Raum (2. FFR) von m/z 146 aus 25 ist sehr ähnlich aber nicht identisch
mit den entspr. Spektren von m/z 146 aus den C-5-substituierten Tetrahydroisochinolinen
3,6,7 und 8 (Schema 2). Dies stĂĽtzt unsere Arbeitshypothese
einer Umlagerung in den M+. von Tetrahydroisochinolinen vor der
Fragmentierung, beweist sie aber nicht Da die CID MDCE-Spektren der Tetrahydroisochinoline
3,6,7 und 8 unter sich nicht identisch sind, nehmen wir
an, daß ein 1.3-H-shift in den M+. der Tetrahydroisochinoline zusätzlich zu
der o. a. Umlagerung stattfindet
Fragmentierungsreaktionen bei Naphtalin-Derivaten mit C4-Seitenketten
Von Naphthalin- bzw. 2,3-Dimethoxynaphthalin-Derivaten mit A2-Butenon(3)-, A2-Butenol-
(3)-, 3-Acetoxybuten(2)-, Butanol(3)-, 3-Acetoxybutan- und Butan-Seitenketten werden mit
einer Ausnahme C4-BruchstĂĽcke abgespalten.
With one exception, derivatives of naphthalene and 2,3-dimethoxynaphthalene having 3-hydroxy-
2-butenyl, 3-acetoxy-2-butenyl, 3-hydroxybutyl, 3-acetoxybutyl or butyl side-chains lose C 4
fragments during mass spectrometry