321 research outputs found
Ischemia Elicits a Coordinated Expression of Pro-Survival Proteins in Mouse Myocardium
Cardiomyocytes are post-mitotic, long-lived cells until disruptions to pro-survival factors occur after myocardial ischemia. To gain an understanding of the factors involved with ischemic injury, we examined expression changes in pro-survival and opposing pro-apoptotic signals at early and chronic periods of ischemia using an in vivo murine model. Alterations of pro-survival proteins such as the inhibitor of apoptosis protein on chromosome X (xIAP) and the apoptotic repressor protein (ARC) have not been evaluated in a murine model of cardiac ischemia. Early ischemia (1 day) resulted in a 50% reduction in ARC protein levels relative to sham-operated left ventricles, without significant changes in the expression of xIAP or other pro-survival factors. In contrast, a deficiency of xIAP expression was found in cardiac infarcts starting after 1 week, concomitant with significant evidence of apoptotic cell death and an up-regulation of pro-apoptotic signals including Bax, tumor necrosis factor-a, and caspase-8 activation. Chronic ischemia (after 2 weeks) was associated with elevated levels of other pro-survival factors such as Bcl-xL and the phosphorylated form of Akt, as part of the adaptive remodeling of the myocardium. Altogether, these findings suggest that strategies to increase IAP expression may promote myocyte survival after chronic ischemia
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
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Letter from Emmett L. Bennett, Jr. to Michael Ventris, December 12, 1950
Bennett replies to comments Ventris has sent him about a recent Bennett publication on Linear
A tablets. Bennett's publication discusses the fractions and mathematics on Linear A tablets;
Ventris wrote to him suggesting several other approaches and a close relationship between
Linear A and B. Bennett rejects Ventris's approaches and explains his own in this letter, while
lamenting the lack of Linear A evidence.Classic
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Letter from Emmett L. Bennett, Jr. to Michael Ventris, August 12, 1949
Bennett responds to a letter from Ventris discussing Ventris's suggested letter form. He clarifies
the difference between 'words' and 'sign-groups' and 'word groups' and discusses
disagreements in Ventris's interpretation of a few signs from Pylos tablets. Two future endeavors
are discussed: one, combining Ventris's suggest letter form table with Bennett's documentation
of multiple forms of one sign from multiple scribes; two, calculating frequency on signs with
position of sign within a 'word' or phrase considered.Classic
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Letter from Emmett L. Bennett, Jr. to Michael Ventris, June 27, 1950
Bennett thanks Ventris for sending him copies of his previous report to forward on to Cincinnati
and Yale. He praises a recent review by Alice Kober of Hrozny and Georgiev's recent article. He
concludes by letting Ventris know he will briefly be in London to collect materials to be collated
in Greece for the Scripta Minoa II.Classic
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Letter from Emmett L. Bennett, Jr. to Michael Ventris, May 20, 1950
Bennett thanks Ventris for his recent report and communications, and requests that Ventris send
two additional comments to deposit in Minoan archives at Yale and Cincinnati. He updates
Ventris on other Minoan scholars; he mentions an upcoming article from Georgiev and reports
the death of Alice Kober.Classic
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Letter from Emmett L. Bennett, Jr. to Michael Ventris, January 28, 1950
Bennett responds to a number of questions sent to him by Ventris. The first few address
similarities between Linear A, Linear B, and Cypriote fragments, which Bennett says are
superficial at best. The last few questions address Ventris's approach to his syllabary, praising it
but offering some of Bennett's own approach as feedback.Classic
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Letter from Emmett L. Bennett, Jr. to Michael Ventris, April 16, 1949
Bennett thanks Ventris for his proposal of a ‘transcript index’ and suggests changes, including
the inclusion of the symbols rather than just transcriptions. He speaks about frequency of
syllables and the likelihood of a large difference between Linear A and Linear B. Future plans,
including using Kober’s Knossos transcriptions, drawings, and photographs to study the
Knossos materials, are discussed in the conclusion.Classic
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Letter from Emmett L. Bennett, Jr. to Michael Ventris, October 25, 1952
Bennett encourages Ventris to publish his article including a grid of syllables of Linear B,
mentioning it is better than any previous attempts. Brief edits are offered, and the letter is
concluded by Bennett suggesting contacting Ktistopoulos or Blegen to try to apply Ventris's work
to the Knossos tablets.Classic
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