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

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Abstract Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

Synergistic Modulation of Seed Metabolites and Enzymatic Antioxidants Tweaks Moisture Stress Tolerance in Non-Cultivated Traditional Rice Genotypes during Germination

Traditional rice landraces are treasures for novel genes to develop climate-resilient cultivars. Seed viability and germination determine rice productivity under moisture stress. The present study evaluated 100 rice genotypes, including 85 traditional landraces and 15 improved cultivars from various agro-ecological zones of Tamil Nadu, along with moisture-stress-susceptible (IR 64) and moisture-stress-tolerant (IR 64 Drt1) checks. The landraces were screened over a range of osmotic potentials, namely (&minus;) 1.0 MPa, (&minus;) 1.25 MPa and (&minus;) 1.5 MPa, for a period of 5 days in PEG-induced moisture stress. Physio-morphological traits, such as rate of germination, root and shoot length, vigor index, R/S ratio and relative water content (RWC), were assessed during early moisture stress at the maximum OP of (&minus;) 1.5 MPa. The seed macromolecules, phytohormones (giberellic acid, auxin (IAA), cytokinin and abscisic acid), osmolytes and enzymatic antioxidants (catalase and superoxide dismutase) varied significantly between moisture stress and control treatments. The genotype Kuliyadichan registered more IAA and giberellic acid (44% and 35%, respectively, over moisture-stress-tolerant check (IR 64 Drt1), whereas all the landraces showed an elevated catalase activity, thus indicating that the tolerant landraces effectively eliminate oxidative damages. High-performance liquid chromatography analysis showed a reduction in cytokinin and an increase in ABA level under induced moisture stress. Hence, the inherent moisture-stress tolerance of six traditional landraces, such as Kuliyadichan, Rajalakshmi, Sahbhagi Dhan, Nootripathu, Chandaikar and Mallikar, was associated with metabolic responses, such as activation of hydrolytic enzymes, hormonal crosstalk, ROS signaling and antioxidant enzymes (especially catalase), when compared to the susceptible check, IR 64. Hence, these traditional rice landraces can serve as potential donors for introgression or pyramiding moisture-stress-tolerance traits toward developing climate-resilient rice cultivars

Effects of Three Different Modes of Resistance Training on Appetite Hormones in Males With Obesity

International audiencePurpose: This study explored the effect of three different modes of resistance training on appetite hormones [leptin, ghrelin, cholecystokinin (CCK), glucagon-like peptide-1 (GLP-1), and peptide tyrosine-tyrosine (PYY)], cardiometabolic and anthropometric measures in males with obesity.Methods: Forty-four males with obesity (age: 27.5 +/- 9.4 yrs.; mean weight: 93.2 +/- 2.2 kg, body mass index: 32.9 +/- 1.2 kg/m(2)) were randomized to traditional resistance training (TRT, n = 11), circuit resistance training (CRT, n = 11), interval resistance training (IRT, n = 11) or control (C, n = 11) groups. All resistance training groups received 50 min of supervised training per session, three days per week, for 12 weeks. Measurements were taken at baseline and after 12 weeks of training.Results: Plasma levels of leptin, ghrelin, CCK, and PYY decreased significantly in all three different modalities of resistance training groups when compared to the control group (p &lt; 0.05). GLP-1 increased significantly in both CRT and IRT groups compared to TRT and C groups (p &lt; 0.05). Glucose-dependent insulinotropic polypeptide decreased significantly in CRT and IRT groups compared to the C group (p &lt; 0.05). Adiponectin levels increased significantly in all resistance training groups compared to the C group (p &lt; 0.05).Conclusion: Overall, CRT and IRT protocols had the greatest impact on appetite hormones compared to individuals who engaged in TRT or did not exercise (C)

Spatial transcriptomic analysis delineates epithelial and mesenchymal subpopulations and transition stages in childhood ependymoma

Background The diverse cellular constituents of childhood brain tumor ependymoma, recently revealed by single cell RNA-sequencing, may underly therapeutic resistance. Here we use spatial transcriptomics to further advance our understanding of the tumor microenvironment, mapping cellular subpopulations to the tumor architecture of ependymoma posterior fossa subgroup A (PFA), the commonest and most deadly childhood ependymoma variant. Methods Spatial transcriptomics data from intact PFA sections was deconvoluted to resolve the histological arrangement of neoplastic and non-neoplastic cell types. Key findings were validated using immunohistochemistry, in vitro functional assays and outcome analysis in clinically-annotated PFA bulk transcriptomic data. Results PFA are comprised of epithelial and mesenchymal histological zones containing a diversity of cellular states, each zone including co-existing and spatially distinct undifferentiated progenitor-like cells; a quiescent mesenchymal zone population, and a second highly mitotic progenitor population that is restricted to hypercellular epithelial zones and that is more abundant in progressive tumors. We show that myeloid cell interaction is the leading cause of mesenchymal transition in PFA, occurring in zones spatially distinct from hypoxia-induced mesenchymal transition, and these distinct EMT-initiating processes were replicated using in vitro models of PFA. Conclusions These insights demonstrate the utility of spatial transcriptomics to advance our understanding of ependymoma biology, revealing a clearer picture of the cellular constituents of PFA, their interactions and influence on tumor progression