Background Carbon dioxide （CO2） laser soldering is an alternative technique for tissue bonding.Basic fibroblast growth factor （bFGF） and transforming growth factor β1 （TGFβ1） are two key factors for wound heal...Background Carbon dioxide （CO2） laser soldering is an alternative technique for tissue bonding.Basic fibroblast growth factor （bFGF） and transforming growth factor β1 （TGFβ1） are two key factors for wound healing.This study was performed to demonstrate the efficacy of CO2 laser soldering for dural reconstruction and the effect of bFGF and TGFβ1 on healing.Methods In Part Ⅰ,10 minipigs were randomized into two equal groups.Dural defects were reconstructed by conventional fibrin glue bonding （group Ⅰa） or CO2 laser soldering （group Ⅰb）.The reconstructed dura was subjected to burst pressure （BP） measurement and immunohistochemical staining after 1 week.In Part Ⅱ,36 minipigs were randomized into three equal groups.Dural reconstruction was achieved by CO2 laser soldering.Exogenous bFGF （group Ⅱb） or TGFβ1 （group Ⅱc） was administered while group Ⅱa served as a control group.The specimens were subjected to BP measurement after 1,2,3,and 4 weeks,respectively.Results In Part Ⅰ,the dura specimens displayed positive staining of only bFGF in group la and of both bFGF and TGFβ1 in group lb.Group Ⅰb showed higher BP than group la （（98.00-±21.41） mmHg vs.（70.80±15.09） mmHg,respectively; P 〈0.05）.In Part Ⅱ,BP of group Ⅱc was significantly higher than that of group Ⅱla （P 〈0.01）.The BP of group Ⅱa trended toward stabilization after 3 weeks of growth,while that of groups lⅡb and Ⅱc trended toward stabilization after 2 weeks of growth.Conclusions CO2 laser soldering is a reliable technique for dural reconstruction.The superior healing of dural reconstruction by CO2 laser soldering may be related to higher expression of bFGF and TGFβ1,and CO2 lasers may stimulate their secretion.Exogenous bFGF or TGFβ1 may improve healing by shortening the wound healing time,and exogenous TGFβ1 may improve the tensile strength.展开更多
Genomic alterations are commonly found in the signaling pathways of fibroblast growth factor receptors(FGFRs). Although there is no selective FGFR inhibitors in market, several promising inhibitors have been investiga...Genomic alterations are commonly found in the signaling pathways of fibroblast growth factor receptors(FGFRs). Although there is no selective FGFR inhibitors in market, several promising inhibitors have been investigated in clinical trials, and showed encouraging efficacies in patients. By designing a hybrid between the FGFR-selectivity-enhancing motif dimethoxybenzene group and our previously identified novel scaffold, we discovered a new series of potent FGFR inhibitors, with the best one showing sub-nanomolar enzymatic activity. After several round of optimization and with the solved crystal structure, detailed structure–activity relationship was elaborated. Together with in vitro metabolic stability tests and in vivo pharmacokinetic profiling, a representative compound(35) was selected and tested in xenograft mouse model, and the result demonstrated that inhibitor 35 was effective against tumors with FGFR genetic alterations, exhibiting potential for further development.展开更多
基金This research project was supported by grants from the National Natural Science Foundation of China （No.30870752） and Beijing Natural Science Foundation （No.3092012）.
文摘Background Carbon dioxide （CO2） laser soldering is an alternative technique for tissue bonding.Basic fibroblast growth factor （bFGF） and transforming growth factor β1 （TGFβ1） are two key factors for wound healing.This study was performed to demonstrate the efficacy of CO2 laser soldering for dural reconstruction and the effect of bFGF and TGFβ1 on healing.Methods In Part Ⅰ,10 minipigs were randomized into two equal groups.Dural defects were reconstructed by conventional fibrin glue bonding （group Ⅰa） or CO2 laser soldering （group Ⅰb）.The reconstructed dura was subjected to burst pressure （BP） measurement and immunohistochemical staining after 1 week.In Part Ⅱ,36 minipigs were randomized into three equal groups.Dural reconstruction was achieved by CO2 laser soldering.Exogenous bFGF （group Ⅱb） or TGFβ1 （group Ⅱc） was administered while group Ⅱa served as a control group.The specimens were subjected to BP measurement after 1,2,3,and 4 weeks,respectively.Results In Part Ⅰ,the dura specimens displayed positive staining of only bFGF in group la and of both bFGF and TGFβ1 in group lb.Group Ⅰb showed higher BP than group la （（98.00-±21.41） mmHg vs.（70.80±15.09） mmHg,respectively; P 〈0.05）.In Part Ⅱ,BP of group Ⅱc was significantly higher than that of group Ⅱla （P 〈0.01）.The BP of group Ⅱa trended toward stabilization after 3 weeks of growth,while that of groups lⅡb and Ⅱc trended toward stabilization after 2 weeks of growth.Conclusions CO2 laser soldering is a reliable technique for dural reconstruction.The superior healing of dural reconstruction by CO2 laser soldering may be related to higher expression of bFGF and TGFβ1,and CO2 lasers may stimulate their secretion.Exogenous bFGF or TGFβ1 may improve healing by shortening the wound healing time,and exogenous TGFβ1 may improve the tensile strength.
基金financial support from the National Natural Science Foundation of China(Grants No.81661148046 and81773762,China)the "Personalized Medicines-Molecular Signature-based Drug Discovery and Development",Strategic Priority Research Program of the Chinese Academy of Sciences(Grants No.XDA12020317,China)+1 种基金the program for Innovative Research Team of the Ministry of Education(China)the program for Liaoning Innovative Research Team at Shenyang Pharmaceutical University(China)
文摘Genomic alterations are commonly found in the signaling pathways of fibroblast growth factor receptors(FGFRs). Although there is no selective FGFR inhibitors in market, several promising inhibitors have been investigated in clinical trials, and showed encouraging efficacies in patients. By designing a hybrid between the FGFR-selectivity-enhancing motif dimethoxybenzene group and our previously identified novel scaffold, we discovered a new series of potent FGFR inhibitors, with the best one showing sub-nanomolar enzymatic activity. After several round of optimization and with the solved crystal structure, detailed structure–activity relationship was elaborated. Together with in vitro metabolic stability tests and in vivo pharmacokinetic profiling, a representative compound(35) was selected and tested in xenograft mouse model, and the result demonstrated that inhibitor 35 was effective against tumors with FGFR genetic alterations, exhibiting potential for further development.
