No abstract

Ewing sarcoma is characterized by pathognomonic translocations, most frequently fusing EWSR1 with FLI1. An estimated 30% of Ewing sarcoma tumors also display genetic alterations in STAG2, TP53, or CDKN2A (SPC). Numerous attempts to develop relevant Ewing sarcoma models from primary human cells have been unsuccessful in faithfully recapitulating the phenotypic, transcriptomic, and epigenetic features of Ewing sarcoma. In this study, by engineering the t(11;22)(q24;q12) translocation together with a combination of SPC mutations, we generated a wide collection of immortalized cells (EWIma cells) tolerating EWSR1-FLI1 expression from primary mesenchymal stem cells (MSC) derived from a patient with Ewing sarcoma. Within this model, SPC alterations strongly favored Ewing sarcoma oncogenicity. Xenograft experiments with independent EWIma cells induced tumors and metastases in mice, which displayed bona fide features of Ewing sarcoma. EWIma cells presented balanced but also more complex translocation profiles mimicking chromoplexy, which is frequently observed in Ewing sarcoma and other cancers. Collectively, these results demonstrate that bone marrow–derived MSCs are a source of origin for Ewing sarcoma and also provide original experimental models to investigate Ewing sarcomagenesis. Significance: These findings demonstrate that Ewing sarcoma can originate from human bone-marrow–derived mesenchymal stem cells and that recurrent mutations support EWSR1-FLI1 translocation-mediated transformation.

Introduction Arteriovenous fistula (AVF) is the gold standard for vascular access (VA) for end-stage chronic kidney disease (CKD) patients. Post-operative exercises may help to improve maturation. Nevertheless, scarce scientific evidence has been reported about their utility to date. Our objective was to assess the effect of a post-operative isometric exercise programme on native VA maturation in patients with stage 5–5D CKD. Methods We performed a 24-month prospective study. After surgery, patients were randomized to the isometric exercise group (EG) or control group (CG). An isometric exercise protocolled programme was performed in the EG. The CG received usual care. Demographic data, muscle strength using a hand-grip (HG) dynamometer, main Doppler ultrasound (DUS) measurements, clinical and DUS maturation and VA complications were assessed at 4 and 8 weeks post-operatively. Results For 60 sixty patients (30 in the EG), demographic data and HG and DUS measurements at baseline were similar. A significant increase in HG was observed only in the EG at the end of the study (20.7 ± 8.1 versus 25.1 ± 10.3 kg, P = 0.001). The EG obtained the highest clinical maturation at 4 (CG 33.3% versus EG 70%, P = 0.009) and 8 weeks (CG 33.3% versus EG 76.7%, P = 0.002). Similarly, DUS maturation was better in the EG at 4 (CG 40% versus EG 80%, P = 0.003) and 8 weeks (CG 43.3% versus EG 83.3%, P = 0.003) and remained so in the EG for both distal and proximal VA territories for all these periods. Conclusions The upper limb isometric exercise protocolled programme improved clinical and DUS maturation in our patients in both the distal and proximal VA territories. Further studies are required to support these results.