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A new design equation is proposed for the prediction of shear strength of reinforced concrete (RC) beams without stirrups using an innovative linear genetic programming methodology. The shear strength was formulated in terms of several effective parameters such as shear span to depth ratio, concrete cylinder strength at date of testing, amount of longitudinal reinforcement, lever arm, and maximum specified size of coarse aggregate. A comprehensive database containing 1938 experimental test results for the RC beams was gathered from the literature to develop the model. The performance and validity of the model were further tested using several criteria. An efficient strategy was considered to guarantee the generalization of the proposed design equation. For more verification, sensitivity and parametric analysis were conducted. The results indicate that the derived model is an effective tool for the estimation of the shear capacity of members without stirrups (R = 0.921). The prediction performance of the proposed model was found to be better than that of several existing buildings codes. © 2014 Elsevier B.V.

Recent preclinical evidence has suggested that Ewing Sarcoma (ES) bearing EWSR1-ETS fusions could be particularly sensitive to PARP inhibitors (PARPinh) in combination with DNA damage repair (DDR) agents. Trabectedin is an antitumoral agent that modulates EWSR1-FLI1 transcriptional functions, causing DNA damage. Interestingly, PARP1 is also a transcriptional regulator of EWSR1-FLI1, and PARPinh disrupts the DDR machinery. Thus, given the impact and apparent specificity of both agents with regard to the DNA damage/DDR system and EWSR1-FLI1 activity in ES, we decided to explore the activity of combining PARPinh and Trabectedin in in vitro and in vivo experiments. The combination of Olaparib and Trabectedin was found to be highly synergistic, inhibiting cell proliferation, inducing apoptosis, and the accumulation of G2/M. The drug combination also enhanced ?H2AX intranuclear accumulation as a result of DNA damage induction, DNA fragmentation and global DDR deregulation, while EWSR1-FLI1 target expression remained unaffected. The effect of the drug combination was corroborated in a mouse xenograft model of ES and, more importantly, in two ES patient-derived xenograft (PDX) models in which the tumors showed complete regression. In conclusion, the combination of the two agents leads to a biologically significant deregulation of the DDR machinery that elicits relevant antitumor activity in preclinical models and might represent a promising therapeutic tool that should be further explored for translation to the clinical setting.