Supported cell membrane coatings meet many requirements set to bioactive nanocarriers and materials,provided sidedness and fluidity of the natural membrane are maintained upon coating.However,the properties of a suppo...Supported cell membrane coatings meet many requirements set to bioactive nanocarriers and materials,provided sidedness and fluidity of the natural membrane are maintained upon coating.However,the properties of a support-surface responsible for maintaining correct sidedness and fluidity are unknown.Here,we briefly review the properties of natural membranes and membrane-isolation methods,with focus on the asymmetric distribution of functional groups in natural membranes(sidedness)and the ability of molecules to float across a membrane to form functional domains(fluidity).This review concludes that hydrophilic sugar-residues of glycoproteins in the outer-leaflet of cell membranes direct the more hydrophobic inner-leaflet towards a support-surface to create a correctly-sided membrane coating,regardless of electrostatic double-layer interactions.On positively-charged support-surfaces however,strong,electrostatic double-layer attraction of negatively-charged membranes can impede homogeneous coating.In correctly-sided membrane coatings,fluidity is maintained regardless of whether the surface carries a positive or negative charge.However,membranes are frozen on positively-charged,highly-curved,small nanoparticles and localized nanoscopic structures on a support-surface.This leaves an unsupported membrane coating in between nanostructures on planar support-surfaces that is in dual-sided contact with its aqueous environment,yielding enhanced fluidity in membrane coatings on nanostructured,planar support-surfaces as compared with smooth ones.展开更多
Background:Colorectal liver metastasis(CRLM)exhibits highly heterogeneity,with clinically and molecularly defined subgroups that differ in their prognosis.The aim of this study is to explore whether left-sided tumors ...Background:Colorectal liver metastasis(CRLM)exhibits highly heterogeneity,with clinically and molecularly defined subgroups that differ in their prognosis.The aim of this study is to explore whether left-sided tumors is clinically and gnomically distinct from right-sided tumors in CRLM.Methods:This retrospective study included 1,307 patients who underwent primary tumor and metastases resection at three academic centers in China from January 1,2012,to December 31,2020.Propensity score matching with 1:1 ratio matching was performed.The prognostic impact of tumor sidedness was determined after stratifying by the KRAS mutational status.Moreover,whole-exome sequencing(WES)of 200 liver tumor tissues were performed to describe the heterogeneity across the analysis of somatic and germline profiles.Results:The median follow-up was 68 months.Matching yielded 481 pairs of patients.Compared to right-sided CRLM,left-sided patients experienced with better 5-year overall survival(OS)in surgery responsiveness,with a 14.6 lower risk of death[hazard ratio(HR),1.36,95%confidence interval(CI),1.10-1.69,P=0.004].Interaction between tumor sidedness and KRAS status was statistically significant:left-sidedness was associated with better prognosis among KRAS wild-type patients(HR 1.71;95%CI:1.20-2.45;P=0.003),but not among KRAS mutated-type patients.Integrated molecular analyses showed that right-sided tumors more frequently harbored TP53,APC,KRAS,and BRAF alterations,and identified a critical role of KRAS mutation in correlation with their survival differences.Higher pathogenic germline variants were identified in the right-sided tumors compared with left-sided tumors(29.3%vs.15.5%,P=0.03).Conclusions:We demonstrated that the prognostic impacts of tumor sidedness in CRLM is restricted patients with KRAS wild-type tumors.Tumor sidedness displays considerable clinical and molecular heterogeneity that may associate with their therapy benefits and prognosis.展开更多
A recent subgroup analysis of the TRIBE trial suggested that FOLFOXIRI plus bevacizumab may be a preferred option for the first-line treatment of only right-sided metastatic colorectal cancer(mCRC), regardless of RAS ...A recent subgroup analysis of the TRIBE trial suggested that FOLFOXIRI plus bevacizumab may be a preferred option for the first-line treatment of only right-sided metastatic colorectal cancer(mCRC), regardless of RAS or BRAF status. Our subanalysis of a phase Ⅱ trial of the FOLFOXIRI triplet regimen plus bevacizumab in patients with mCRC who had RAS mutant tumors showed that tumor shrinkage was better and the duration of treatment was longer in patients with leftsided tumors than in those with right-sided tumors, leading to a higher rate of conversion to surgery in mCRC patients with left-sided tumors. The early and deep responses to the triplet-regimen in patients with left-sided tumors might facilitate conversion treatment resulting in favorable survival. Our data suggest that the FOLFOXIRI plus bevacizumab might be a promising treatment for left-sided mCRC involving RAS mutant tumors.展开更多
基金financially supported by the National Key Research and Development Program of China(2017YFE0131700)the National Natural Science Foundation of China(52293383)the Soochow University,the Nankai University,and UMCG,Groningen,The Netherlands.
文摘Supported cell membrane coatings meet many requirements set to bioactive nanocarriers and materials,provided sidedness and fluidity of the natural membrane are maintained upon coating.However,the properties of a support-surface responsible for maintaining correct sidedness and fluidity are unknown.Here,we briefly review the properties of natural membranes and membrane-isolation methods,with focus on the asymmetric distribution of functional groups in natural membranes(sidedness)and the ability of molecules to float across a membrane to form functional domains(fluidity).This review concludes that hydrophilic sugar-residues of glycoproteins in the outer-leaflet of cell membranes direct the more hydrophobic inner-leaflet towards a support-surface to create a correctly-sided membrane coating,regardless of electrostatic double-layer interactions.On positively-charged support-surfaces however,strong,electrostatic double-layer attraction of negatively-charged membranes can impede homogeneous coating.In correctly-sided membrane coatings,fluidity is maintained regardless of whether the surface carries a positive or negative charge.However,membranes are frozen on positively-charged,highly-curved,small nanoparticles and localized nanoscopic structures on a support-surface.This leaves an unsupported membrane coating in between nanostructures on planar support-surfaces that is in dual-sided contact with its aqueous environment,yielding enhanced fluidity in membrane coatings on nanostructured,planar support-surfaces as compared with smooth ones.
基金supported by National Natural Science Foundation of China(81874182,M-0334)Natural Science Foundation of Shanghai(22ZR1413300)+2 种基金National Science and Technology Major Project(2017ZX10203204-007-004)Shanghai Municipal Health Bureau(201940043)Shanghai Hospital Development Center(SHDC12019X19).
文摘Background:Colorectal liver metastasis(CRLM)exhibits highly heterogeneity,with clinically and molecularly defined subgroups that differ in their prognosis.The aim of this study is to explore whether left-sided tumors is clinically and gnomically distinct from right-sided tumors in CRLM.Methods:This retrospective study included 1,307 patients who underwent primary tumor and metastases resection at three academic centers in China from January 1,2012,to December 31,2020.Propensity score matching with 1:1 ratio matching was performed.The prognostic impact of tumor sidedness was determined after stratifying by the KRAS mutational status.Moreover,whole-exome sequencing(WES)of 200 liver tumor tissues were performed to describe the heterogeneity across the analysis of somatic and germline profiles.Results:The median follow-up was 68 months.Matching yielded 481 pairs of patients.Compared to right-sided CRLM,left-sided patients experienced with better 5-year overall survival(OS)in surgery responsiveness,with a 14.6 lower risk of death[hazard ratio(HR),1.36,95%confidence interval(CI),1.10-1.69,P=0.004].Interaction between tumor sidedness and KRAS status was statistically significant:left-sidedness was associated with better prognosis among KRAS wild-type patients(HR 1.71;95%CI:1.20-2.45;P=0.003),but not among KRAS mutated-type patients.Integrated molecular analyses showed that right-sided tumors more frequently harbored TP53,APC,KRAS,and BRAF alterations,and identified a critical role of KRAS mutation in correlation with their survival differences.Higher pathogenic germline variants were identified in the right-sided tumors compared with left-sided tumors(29.3%vs.15.5%,P=0.03).Conclusions:We demonstrated that the prognostic impacts of tumor sidedness in CRLM is restricted patients with KRAS wild-type tumors.Tumor sidedness displays considerable clinical and molecular heterogeneity that may associate with their therapy benefits and prognosis.
文摘A recent subgroup analysis of the TRIBE trial suggested that FOLFOXIRI plus bevacizumab may be a preferred option for the first-line treatment of only right-sided metastatic colorectal cancer(mCRC), regardless of RAS or BRAF status. Our subanalysis of a phase Ⅱ trial of the FOLFOXIRI triplet regimen plus bevacizumab in patients with mCRC who had RAS mutant tumors showed that tumor shrinkage was better and the duration of treatment was longer in patients with leftsided tumors than in those with right-sided tumors, leading to a higher rate of conversion to surgery in mCRC patients with left-sided tumors. The early and deep responses to the triplet-regimen in patients with left-sided tumors might facilitate conversion treatment resulting in favorable survival. Our data suggest that the FOLFOXIRI plus bevacizumab might be a promising treatment for left-sided mCRC involving RAS mutant tumors.
