miR-210: fine-tuning the hypoxic response

Hypoxia is a central component of the tumor microenvironment and represents a major source of therapeutic failure in cancer therapy. Recent work has provided a wealth of evidence that noncoding RNAs and, in particular, microRNAs, are significant members of the adaptive response to low oxygen in tumors. All published studies agree that miR-210 specifically is a robust target of hypoxia-inducible factors, and the induction of miR-210 is a consistent characteristic of the hypoxic response in normal and transformed cells. Overexpression of miR-210 is detected in most solid tumors and has been linked to adverse prognosis in patients with soft-tissue sarcoma, breast, head and neck, and pancreatic cancer. A wide variety of miR-210 targets have been identified, pointing to roles in the cell cycle, mitochondrial oxidative metabolism, angiogenesis, DNA damage response, and cell survival. Additional microRNAs seem to be modulated by low oxygen in a more tissue-specific fashion, adding another layer of complexity to the vast array of protein-coding genes regulated by hypoxia

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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

Elective Thoracic Aortic Aneurysm Surgery: Better Outcomes from High-Volume Centers.

BACKGROUND: Although studies have demonstrated clinical advantages in high-volume (HV) centers performing esophageal and pancreatic resections, thoracic aortic aneurysm repair has not been studied in the same fashion. We sought to determine if HV centers have better outcomes after thoracic aortic aneurysm surgery relative to lower-volume (LV) centers. STUDY DESIGN: Retrospective review of prospectively collected data pooled from the 17 institutions participating in the Virginia Cardiac Surgery Quality Initiative (VCSQI) database was performed during a 3-year period. LV centers were those that performedperiod, and HV centers were those that performed \u3e80 operations. Preoperative risk factors and outcomes were compared between the 2 groups. Multivariate analysis was performed to evaluate the impact of center volume on mortality. Only elective operations were studied. RESULTS: HV centers performed 515 operations during the study period compared with 216 operations from LV centers. Perioperative mortality was significantly lower in HV centers (3.7%, n = 19) versus LV centers (8.3%, n = 18) (p = 0.02). Incidence of renal failure (HV: 4.5%; LV: 8.3%; p = 0.05) and prolonged ventilator course (HV: 16.7%; LV: 25.5%; p = 0.01) were also lower in the HV centers relative to LV centers. HV centers had higher stroke rates compared with LV centers (HV: 4.8%, LV: 1.4%; p \u3c 0.01). Total hospital cost was $42,736 in HV centers and$51,296 in LV centers (p = 0.04). On regression analysis, LV centers were significantly associated with increased complications and mortality (all p \u3c 0.05). CONCLUSIONS: Although LV centers had lower stroke rates, HV centers had overall better outcomes, lower mortality rates, and considerably lower cost compared with LV centers