ABSTRACT
Purpose@#Osteosarcoma (OS) universally exhibits heterogeneity and cisplatin (CDDP) resistance. Although the Wee1/CDC2 and nuclear factor кB (NF-κB) pathways were reported to show abnormal activation in some tumor cells with CDDP resistance, whether there is any concrete connection is currently unclear. We explored it in human OS cells. @*Materials and Methods@#Multiple OS cell lines were exposed to a Wee1 inhibitor (AZD1775) and CDDP to assess the half-maximal inhibitory concentration values. Western blot, coimmunoprecipitation, confocal immunofluorescence, cell cycle, and Cell Counting Kit-8assays were performed to explore the connection between the Wee1/CDC2 and NF-κB pathways and their subsequent physiological contribution to CDDP resistance. Finally, CDDP-resistant PDX-OS xenograft models were established to confirm that AZD1775 restores the antitumor effects of CDDP. @*Results@#A sensitivity hierarchy of OS cells to CDDP and AZD1775 exists. In the highly CDDP-tolerant cell lines, Wee1 and RelA were physically crosslinked, which resulted in increased abundance of phosphorylated CDC2 (Y15) and RelA (S536) and consequent modulation of cell cycle progression, survival, and proliferation. Wee1 inhibition restored the effects of CDDP on these processes in CDDP-resistant OS cells. In addition, animal experiments with CDDP-resistant PDX-OS cells showed that AZD1775 combined with CDDP not only restored CDDP efficacy but also amplified AZD1775 in inhibiting tumor growth and prolonged the median survival of the mice. @*Conclusion@#Simultaneous enrichment of molecules in the Wee1/CDC2 and NF-κB pathways and their consequent coactivation is a new molecular mechanism of CDDP resistance in OS cells. OS with this molecular signature may respond well to Wee1 inhibition as an alternative treatment strategy.
ABSTRACT
Objective To investigate the design,incisional method and clinical experiences of using the mi cro-dissected polyfoliate anterolateral thigh perforator flap to repair of complex soft tissue defect in extremities.Methods From June,2017 to September,2018,12 cases of different kinds of complex soft tissue defect in extremities were repaired by micro-dissected free polyfoliate anterolateral thigh perforator flap.Each flap was divided into two cutaneous perforators to give two separate flap with a common vascular supply.The flaps were cut from the superficial layer of the deep cervical fesciae and without fascia lata.The donor sites were treated by subcutaneous cosmetic suture.Patients were followed-up by outpatient service,telephone and WeChat video to observe and record the flap's appearance,sensory recovery,extremities function and the scars of the donor site to evaluate its clinical efficacy.Results All flaps survived without vascular crisis happened except one-leaf necrosis occurred,which healed with local flap transferring.The donor sites remained linear scars.The mean flap thickness of this group after micro-dissection was (4.5±0.5) mm.All the patients were followed-up for 5-15 months.The 2 point discrimination ranged between 0.5-2.0 cm.Sensory restoration ranking was S3-S3+.The range of montion of wrist joint was 65°-90°,and that of ankle joint was 40°-60°.Conclusion The micro-dissected polyfoliate anterolateral thigh perforator flap is an ideal method for complex and irregular multiple sites soft tissue defect in extremities as it can keep good economic benefit and minimal damage to the donor site.