RESUMO
Insulin-like growth factor-1 receptor (IGF-1R) has been made an attractive anticancer target due to its overexpression in cancers. However, targeting it has often produced the disappointing results as the role played by cross talk with numerous downstream signalings. Here, we report a disobliging IGF-1R signaling which promotes growth of cancer through triggering the E3 ubiquitin ligase MEX3A-mediated degradation of RIG-I. The active β-arrestin-2 scaffolds this disobliging signaling to talk with MEX3A. In response to ligands, IGF-1Rβ activated the basal βarr2 into its active state by phosphorylating the interdomain domain on Tyr64 and Tyr250, opening the middle loop (Leu130‒Cys141) to the RING domain of MEX3A through the conformational changes of βarr2. The models of βarr2/IGF-1Rβ and βarr2/MEX3A could interpret the mechanism of the activated-IGF-1R in triggering degradation of RIG-I. The assay of the mutants βarr2Y64A and βarr2Y250A further confirmed the role of these two Tyr residues of the interlobe in mediating the talk between IGF-1Rβ and the RING domain of MEX3A. The truncated-βarr2 and the peptide ATQAIRIF, which mimicked the RING domain of MEX3A could prevent the formation of βarr2/IGF-1Rβ and βarr2/MEX3A complexes, thus blocking the IGF-1R-triggered RIG-I degradation. Degradation of RIG-I resulted in the suppression of the IFN-I-associated immune cells in the TME due to the blockade of the RIG-I-MAVS-IFN-I pathway. Poly(I:C) could reverse anti-PD-L1 insensitivity by recovery of RIG-I. In summary, we revealed a disobliging IGF-1R signaling by which IGF-1Rβ promoted cancer growth through triggering the MEX3A-mediated degradation of RIG-I.
RESUMO
Objective To observe the safety and efficacy of the SLIPA mask airway in the cesarean section operation under general anesthesia.Methods Fifty single birth pregnant women who underwent cesarean operation under general anesthesia were randomized into 2 groups.SLIPA mask group(group S,25 cases)and endotracheal intubation(ETT)group(group T,25 cases).Mean arterial pressure(MAP),heart rate(HR),partial pressure of carbon dioxide in end expired gas(P_(ET)CO_2),peak airway pressure(Paw)were measured before induction of anesthesia,just before intubation,2min after intubation,just before extubation,2 min after extubation.Bucking,style,reflow,vomiting,aspiration were observed at inmbation or SLIPA mask airway insertion,before and after extubation and intraoperative.Umbilical arteries and veins blood were collected at delivery for the blood gas analysis.All delivery times,operation time and Apgar scores at 1,5 min were recorded.Results The successful rate ofthe first time intubation was 100% in group S,there was 2 cases by the second time intubation in group T.There Was 3 cases with gently air leak,but no influence on respiratory management.After intubation and extubation,MAP and HR increased significantly in group T (P<0.05),while group S had no significant change.There was no occurrence of bucking,style,reflow,vomiting,aspiration intmoperative,but 17 cages occurred at extubation in group T.The incidence and degree of sore throat in group T(10 cases after 2 hours and 6 cases after 24 hours) were significantly higher than those in group S(P<0.05).The Apgar scores at 1,5 min and delivery times were not significant between the two groups(P>0.05).Conclusion There is less adverse effects of SLIPA mask airway than ETT under general anesthesia in the cesarean section operation,SLIPA mask airway is safe and efficacious.