Rapid 3D dynamic rupture modeling of the February 6, 2023, Kahramanmara\c{s}, Turkey, MWM_W7.8 and MWM_W7.7 earthquake doublet

The 2023 Turkey Earthquake sequence involved unexpected ruptures across numerous fault segments, challenging data interpretation efforts. We present rapid, 3D dynamic rupture simulations to illuminate the complexities of the $M_W$7.8 and $M_W$7.7 earthquake doublet. Constrained by observations available within days of the sequence, our models deliver timely, mechanically consistent explanations for the unforeseen rupture paths, diverse rupture speeds, multiple slip episodes, locally strong shaking, and fault system interactions. We reconcile regional seismo-tectonics, rupture dynamics, and ground motions of a fault system represented by ten curved dipping segments and a heterogeneous stress field. Our simulations link both events matching geodetic and seismic observations. The $M_W$7.8 earthquake features delayed backward branching from a steeply intersecting splay fault, not requiring supershear speeds. The asymmetrical dynamics of the distinct, bilateral $M_W$7.7 event is explained by heterogeneous fault strength, prestress orientation, fracture energy, and static stress changes from the previous event. Our models explain the northward deviation of its western rupture and the minimal slip observed on the S\"urg\"u fault. Rapidly developed 3D dynamic rupture scenarios can elucidate unexpected observations shortly after major earthquakes, providing timely insights for data-driven analysis and hazard assessment toward a comprehensive, physically consistent understanding of the mechanics of multi-fault systems

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