High-content drug screening in zebrafish xenografts reveals high efficacy of dual MCL-1/BCL-XL inhibition against Ewing sarcoma

Ewing sarcoma is a pediatric bone and soft tissue cancer with an urgent need for new therapies to improve disease outcome. To identify effective drugs, phenotypic drug screening has proven to be a powerful method, but achievable throughput in mouse xenografts, the preclinical Ewing sarcoma standard model, is limited. Here, we explored the use of xenografts in zebrafish for high-throughput drug screening to discover new combination therapies for Ewing sarcoma. We subjected xenografts in zebrafish larvae to high-content imaging and subsequent automated tumor size analysis to screen single agents and compound combinations. We identified three drug combinations effective against Ewing sarcoma cells: Irinotecan combined with either an MCL-1 or an BCL-XL inhibitor and in particular dual inhibition of the anti-apoptotic proteins MCL-1 and BCL-XL, which efficiently eradicated tumor cells in zebrafish xenografts. We confirmed enhanced efficacy of dual MCL-1/BCL-XL inhibition compared to single agents in a mouse PDX model. In conclusion, high-content screening of small compounds on Ewing sarcoma zebrafish xenografts identified dual MCL-1/BCL-XL targeting as a specific vulnerability and promising therapeutic strategy for Ewing sarcoma, which warrants further investigation towards clinical application. Keywords: Anti-apoptotic protein inhibitors; Ewing sarcoma; High-content imaging; Phenotypic drug screening; Zebrafish xenograft

Transvesical endoscopic port in abdominal surgery: an updated perspective

Transvesical endoscopic port in abdominal surgery: an updated perspective.Natural orifice transluminal endoscopic surgery (NOTES) generated a huge hope among surgeons because it promised scarless surgery and eventually less pain and surgical stress. However, serious limitations regarding reliable visceral closing methods remain unsolved. This article provides an update in development and future applications of transvesical access in the field of surgery.(undefined