Objective:The possible enhancing effect of anlotinib on programmed death receptor ligand(PD-L1)antibody and the efficacy-predicting power of PD-L1 in micro-conduit endothelium,including lymphatic endothelial cells(LEC...Objective:The possible enhancing effect of anlotinib on programmed death receptor ligand(PD-L1)antibody and the efficacy-predicting power of PD-L1 in micro-conduit endothelium,including lymphatic endothelial cells(LECs)and blood endothelial cells(BECs),were determined to identify patients who would benefit from this treatment.Methods:PD-L1 positivity in LECs,BECs,and tumor cells(TCs)was assessed using paraffin sections with multicolor immunofluorescence in an investigator’s brochure clinical trial of TQB2450(PD-L1 antibody)alone or in combination with anlotinib in patients with non-small cell lung cancer.Progression-free survival(PFS)with different levels of PD-L1 expression was compared between the two groups.Results:Among 75 patients,the median PFS(mPFS)was longer in patients who received TQB2450 with anlotinib[10 and 12 mg(161 and 194 days,respectively)]than patients receiving TQB2450 alone(61 days)[hazard ratio(HR)_(10 mg)=0.390(95%confidence interval{CI},0.201–0.756),P=0.005;HR_(12 mg)=0.397(0.208–0.756),P=0.005].The results were similar among 58 patients with high PD-L1 expression in LECs and TCs[159 and 209 vs.82 days,HR_(10 mg)=0.445(0.210–0.939),P=0.034;HR_(12 mg)=0.369(0.174–0.784),P=0.009],and 53 patients with high PD-L1 expression in BECs and TCs[161 and 209 vs.41 days,HR_(10 mg)=0.340(0.156–0.742),P=0.007;HR_(12 mg)=0.340(0.159–0.727),P=0.005].No differences were detected in the mPFS between the TQB2450 and combination therapy groups in 13 low/no LEC-expressing and 18 low/no BEC-expressing PD-L1 cases.Conclusions:Mono-immunotherapy is not effective in patients with high PD-L1 expression in LECs and/or BECs.Anlotinib may increase efficacy by downregulating PD-L1 expression in LECs and/or BECs,which is presumed to be a feasible marker for screening the optimal immune patient population undergoing anti-angiogenic therapy.展开更多
Objective:Bevacizumab is a recombinant humanized monoclonal antibody that blocks vascular endothelial growth factor(VEGF)with clear clinical benefits.However,overall survival of some cancer types remains low owing to ...Objective:Bevacizumab is a recombinant humanized monoclonal antibody that blocks vascular endothelial growth factor(VEGF)with clear clinical benefits.However,overall survival of some cancer types remains low owing to resistance to bevacizumab therapy.While resistance is commonly ascribed to tumor cell invasion induced by hypoxia-inducible factor(HIF),less attention has been paid to the potential involvement of endothelial cells(ECs)in vasculature activated by anti-angiogenic drugs.Methods:Human umbilical vein ECs(HUVECs),bEnd.3 cells,and mouse retinal microvascular ECs(MRMECs)were treated with bevacizumab under conditions of hypoxia and effects on biological behaviors,such as migration and tube formation,examined.Regulatory effects on TGFpi and CD 105(endoglin)were established via determination o f protein and mRNA levels.We further investigated whether the effects of bevacizumab could be reversed using the receptor tyrosine kinase inhibitor anlotinib.Results:Bevacizumab upregulated TGFpi as well as CD 105,a component o f the TGFP receptor complex and an angiogenesis promoter.Elevated CD 105 induced activation of Sm adl/5,the inflammatory pathway and endothelial-mesenchymal transition.The migration ability of HUVECs was enhanced by bevacizumab under hypoxia.Upregulation o f CD 105 was abrogated by anlotinib,which targets multiple receptor tyrosine kinases including VEGFR2/3,FGFR1-4,PD G FRα/β,C-Kit,and RET.Conclusions:Bevacizumab promotes migration and tube formation of HUVECs via activation of the TGFβi pathway and upregulation of CD105 expression.Anlotinib reverses the effects of bevacizumab by inhibiting the above signals.展开更多
Objective:In the phase II ALTER-1202(NCT03059797)trial,anlotinib significantly improved progression-free survival(PFS)and overall survival(OS)in patients with advanced small-cell lung cancer(SCLC)who underwent at leas...Objective:In the phase II ALTER-1202(NCT03059797)trial,anlotinib significantly improved progression-free survival(PFS)and overall survival(OS)in patients with advanced small-cell lung cancer(SCLC)who underwent at least 2 previous chemotherapy cycles,when compared with a placebo group.To identify potential factors for predicting efficacy and prognosis with anlotinib treatment,we analyzed hematological indices at baseline and adverse events(AEs)over the course of anlotinib treatment.Methods:Data were collected from March 2017 to April 2019 from a randomized,double-blind,placebo-controlled,multicenter,phase II trial of anlotinib.Eligible patients were randomly assigned 2:1 to receive anlotinib or placebo until disease progression,intolerable toxicity,or withdrawal of consent.The patients received anlotinib(12 mg)or an analogue capsule(placebo)orally once daily for 14 days every 3 weeks.The hematological indices at baseline and AEs that occurred in the initial 2 treatment cycles were recorded.The Kaplan-Meier test and Cox regression model were used to assess survival differences.Results:A total of 82 patients(81 patients with complete data)were randomly assigned to receive anlotinib,with 38 receiving a placebo as a control.Multivariate analysis indicated that an elevated neutrophil to lymphocyte ratio>7.75 and lactate dehydrogenase>254.65 U/L at baseline were independent risk factors for PFS;basal elevated aspartate aminotransferase>26.75 U/L,neuron specific enolase>18.64 ng/mL,and fibrinogen>4.645 g/L were independent risk factors for OS.During treatment,elevatedγglutamyltransferase and hypophosphatemia were independent predictors for a poor PFS,and elevatedγ-glutamyl transferase and hypercholesterolemia were independent factors for OS.Conclusions:Our study preliminarily defined potential factors that affected the PFS and OS at baseline and during anlotinib treatment in patients with advanced SCLC.Our findings provide a basis for screening the dominant population and for dynamic efficacy monitoring with anlotinib therapy.展开更多
目的:确定用于评估肺腺癌(lung adenocarcinoma,LUAD)患者糖酵解相关基因的风险评分模型。方法:使用公共数据库癌症基因组图谱(The Cancer Genome Atlas,TCGA)中LUAD患者转录组数据,通过基因富集分析(gene set enrichment analysis,GSEA...目的:确定用于评估肺腺癌(lung adenocarcinoma,LUAD)患者糖酵解相关基因的风险评分模型。方法:使用公共数据库癌症基因组图谱(The Cancer Genome Atlas,TCGA)中LUAD患者转录组数据,通过基因富集分析(gene set enrichment analysis,GSEA)、差异表达基因(differentially expressed genes,DEGs)分析和最小绝对收缩选择算子(least absolute shrinkage and selection operator,LASSO)回归分析构建风险预测模型。通过Kaplan-Meier分析、受试者工作特征(receiver operating characteristic,ROC)曲线、单因素及多因素Cox回归分析验证模型预测性能。使用CIBERSORT算法计算高、低风险两组免疫细胞浸润差异。构建用于临床预测患者预后的列线图。结果:识别出3个糖酵解相关基因集,筛选出6个糖酵解相关基因构建风险评分模型。高风险组总生存率显著低于低风险组,验证性结果显示该模型有良好的预测性能。高、低风险两组的免疫细胞浸润情况存在显著差异。列线图的构建开发了一种可以预测LUAD患者生存率的定量方法。结论:基于糖酵解相关基因构建的风险评分模型为早期LUAD患者预测预后提供了新型生物标志物。展开更多
Objective： The aim of this study was to compare effect of rh-endostatin on microvasculature in tumor and myocardium tissue. Methods： Nude mice were randomized into 4 groups, blank control group [did not burden tumor...Objective： The aim of this study was to compare effect of rh-endostatin on microvasculature in tumor and myocardium tissue. Methods： Nude mice were randomized into 4 groups, blank control group [did not burden tumor, normalsaline （NS） 100 μL/d], drug control group （did not burden tumor, rh-endostatin 400 μg/d）, model group （mice burdened tumor, NS 100 μL/d） and treatment group （mice burdened tumor, rh-endostatin 400 μg/d）, administration was given during d1-d28. The volume of tumor and the weight of mouse were measured before and after administration. The expression of CD34, MMP-2, MMP-9, HIF-la and VEGF in myocardium and tumor were detected by immunohistochemistry. The structure of vasculature was observed by immunoenzymatic double staining with CD34 and Masson. Results： The tumor volume increase of treatment group （48.18 mm3） was less than the model group （113.80 mm3）, the change of weight was not significant among the four groups. After treated with endotar, the expression of MMP-9 and VEGF in tumor were obviously down-regulated, but the same results was not found in MMP-2, HIF-la of tumor. MVD in tumor of treatment group decreased significantly compared with model group. Proportion of tumor vessels covered by collagen in treatment group increased compared with model group. However, MVD and microvasculature in myocardium did not change significantly. Conclusion： Rh-endostatin can decrease the expression of MMP-9, VEGF and MVD to inhibit growth of tumor and normalize micrangium in tumor but cannot weaken MMPs and MVD of mature micrangium in myocardium.展开更多
Whole-genome genotyping methods are important for breeding.However,it has been challenging to develop a robust method for simultaneous foreground and background genotyping that can easily be adapted to different genes...Whole-genome genotyping methods are important for breeding.However,it has been challenging to develop a robust method for simultaneous foreground and background genotyping that can easily be adapted to different genes and species.In our study,we accidently discovered that in adapter ligation-mediated PCR,the amplification by primertemplate mismatched annealing(PTMA)along the genome could generate thousands of stable PCR products.Based on this observation,we consequently developed a novel method for simultaneous foreground and background integrated genotyping by sequencing(FBI-seq)using one specific primer,in which foreground genotyping is performed by primer-template perfect annealing(PTPA),while background genotyping employs PTMA.Unlike DNA arrays,multiple PCR,or genome target enrichments,FBI-seq requires little preliminary work for primer design and synthesis,and it is easily adaptable to different foreground genes and species.FBI-seq therefore provides a prolific,robust,and accurate method for simultaneous foreground and background genotyping to facilitate breeding in the postgenomics era.展开更多
RuO_(x)是一种有潜力的析氢反应(HER)电催化剂,然而,其表面上*OH和*H中间体的竞争吸附以及过度H结合导致其析氢性能较差.FeOOH具有较强的亲氧性,有望与RuO_(x)耦合形成RuO_(x)/FeOOH复合材料来有效促进HER动力学.鉴于Ru^(3+)的强氧化性...RuO_(x)是一种有潜力的析氢反应(HER)电催化剂,然而,其表面上*OH和*H中间体的竞争吸附以及过度H结合导致其析氢性能较差.FeOOH具有较强的亲氧性,有望与RuO_(x)耦合形成RuO_(x)/FeOOH复合材料来有效促进HER动力学.鉴于Ru^(3+)的强氧化性,构建温和的反应环境是设计结构均匀、Ru位点可及的RuO_(x)/FeOOH复合材料的关键.本文提出一种乙醇调控铁腐蚀策略,在泡沫铁上原位生长了RuO_(x)/FeOOH电催化剂.醇羟基与Ru^(3+)配位降低了Ru^(3+)的氧化性,并减缓了其扩散,避免了剧烈的氧化还原反应.优化的纳米结构以及RuO_(x)和FeOOH之间的强电子相互作用,使所制备的催化剂在50和100 mA cm^(-2)电流密度下驱动HER和全解水,分别仅需67 mV过电位和1.56 V电压.基于羟基调控策略,乙二醇、正丙醇、异丙醇和甲醇同样可替代乙醇来增强RuO_(x)/FeOOH的HER活性.本工作提出了一种调节铁腐蚀行为的配位调控方法,为制备新型钌基复合催化剂提供了理论依据.展开更多
文摘Objective:The possible enhancing effect of anlotinib on programmed death receptor ligand(PD-L1)antibody and the efficacy-predicting power of PD-L1 in micro-conduit endothelium,including lymphatic endothelial cells(LECs)and blood endothelial cells(BECs),were determined to identify patients who would benefit from this treatment.Methods:PD-L1 positivity in LECs,BECs,and tumor cells(TCs)was assessed using paraffin sections with multicolor immunofluorescence in an investigator’s brochure clinical trial of TQB2450(PD-L1 antibody)alone or in combination with anlotinib in patients with non-small cell lung cancer.Progression-free survival(PFS)with different levels of PD-L1 expression was compared between the two groups.Results:Among 75 patients,the median PFS(mPFS)was longer in patients who received TQB2450 with anlotinib[10 and 12 mg(161 and 194 days,respectively)]than patients receiving TQB2450 alone(61 days)[hazard ratio(HR)_(10 mg)=0.390(95%confidence interval{CI},0.201–0.756),P=0.005;HR_(12 mg)=0.397(0.208–0.756),P=0.005].The results were similar among 58 patients with high PD-L1 expression in LECs and TCs[159 and 209 vs.82 days,HR_(10 mg)=0.445(0.210–0.939),P=0.034;HR_(12 mg)=0.369(0.174–0.784),P=0.009],and 53 patients with high PD-L1 expression in BECs and TCs[161 and 209 vs.41 days,HR_(10 mg)=0.340(0.156–0.742),P=0.007;HR_(12 mg)=0.340(0.159–0.727),P=0.005].No differences were detected in the mPFS between the TQB2450 and combination therapy groups in 13 low/no LEC-expressing and 18 low/no BEC-expressing PD-L1 cases.Conclusions:Mono-immunotherapy is not effective in patients with high PD-L1 expression in LECs and/or BECs.Anlotinib may increase efficacy by downregulating PD-L1 expression in LECs and/or BECs,which is presumed to be a feasible marker for screening the optimal immune patient population undergoing anti-angiogenic therapy.
文摘Objective:Bevacizumab is a recombinant humanized monoclonal antibody that blocks vascular endothelial growth factor(VEGF)with clear clinical benefits.However,overall survival of some cancer types remains low owing to resistance to bevacizumab therapy.While resistance is commonly ascribed to tumor cell invasion induced by hypoxia-inducible factor(HIF),less attention has been paid to the potential involvement of endothelial cells(ECs)in vasculature activated by anti-angiogenic drugs.Methods:Human umbilical vein ECs(HUVECs),bEnd.3 cells,and mouse retinal microvascular ECs(MRMECs)were treated with bevacizumab under conditions of hypoxia and effects on biological behaviors,such as migration and tube formation,examined.Regulatory effects on TGFpi and CD 105(endoglin)were established via determination o f protein and mRNA levels.We further investigated whether the effects of bevacizumab could be reversed using the receptor tyrosine kinase inhibitor anlotinib.Results:Bevacizumab upregulated TGFpi as well as CD 105,a component o f the TGFP receptor complex and an angiogenesis promoter.Elevated CD 105 induced activation of Sm adl/5,the inflammatory pathway and endothelial-mesenchymal transition.The migration ability of HUVECs was enhanced by bevacizumab under hypoxia.Upregulation o f CD 105 was abrogated by anlotinib,which targets multiple receptor tyrosine kinases including VEGFR2/3,FGFR1-4,PD G FRα/β,C-Kit,and RET.Conclusions:Bevacizumab promotes migration and tube formation of HUVECs via activation of the TGFβi pathway and upregulation of CD105 expression.Anlotinib reverses the effects of bevacizumab by inhibiting the above signals.
文摘Objective:In the phase II ALTER-1202(NCT03059797)trial,anlotinib significantly improved progression-free survival(PFS)and overall survival(OS)in patients with advanced small-cell lung cancer(SCLC)who underwent at least 2 previous chemotherapy cycles,when compared with a placebo group.To identify potential factors for predicting efficacy and prognosis with anlotinib treatment,we analyzed hematological indices at baseline and adverse events(AEs)over the course of anlotinib treatment.Methods:Data were collected from March 2017 to April 2019 from a randomized,double-blind,placebo-controlled,multicenter,phase II trial of anlotinib.Eligible patients were randomly assigned 2:1 to receive anlotinib or placebo until disease progression,intolerable toxicity,or withdrawal of consent.The patients received anlotinib(12 mg)or an analogue capsule(placebo)orally once daily for 14 days every 3 weeks.The hematological indices at baseline and AEs that occurred in the initial 2 treatment cycles were recorded.The Kaplan-Meier test and Cox regression model were used to assess survival differences.Results:A total of 82 patients(81 patients with complete data)were randomly assigned to receive anlotinib,with 38 receiving a placebo as a control.Multivariate analysis indicated that an elevated neutrophil to lymphocyte ratio>7.75 and lactate dehydrogenase>254.65 U/L at baseline were independent risk factors for PFS;basal elevated aspartate aminotransferase>26.75 U/L,neuron specific enolase>18.64 ng/mL,and fibrinogen>4.645 g/L were independent risk factors for OS.During treatment,elevatedγglutamyltransferase and hypophosphatemia were independent predictors for a poor PFS,and elevatedγ-glutamyl transferase and hypercholesterolemia were independent factors for OS.Conclusions:Our study preliminarily defined potential factors that affected the PFS and OS at baseline and during anlotinib treatment in patients with advanced SCLC.Our findings provide a basis for screening the dominant population and for dynamic efficacy monitoring with anlotinib therapy.
基金Supported by grants from the Tianjin Medical University Research Projects(2009KY37)CSCO Vascular Target Fund Research Projects of Roche(Y-X2011-001)
文摘Objective： The aim of this study was to compare effect of rh-endostatin on microvasculature in tumor and myocardium tissue. Methods： Nude mice were randomized into 4 groups, blank control group [did not burden tumor, normalsaline （NS） 100 μL/d], drug control group （did not burden tumor, rh-endostatin 400 μg/d）, model group （mice burdened tumor, NS 100 μL/d） and treatment group （mice burdened tumor, rh-endostatin 400 μg/d）, administration was given during d1-d28. The volume of tumor and the weight of mouse were measured before and after administration. The expression of CD34, MMP-2, MMP-9, HIF-la and VEGF in myocardium and tumor were detected by immunohistochemistry. The structure of vasculature was observed by immunoenzymatic double staining with CD34 and Masson. Results： The tumor volume increase of treatment group （48.18 mm3） was less than the model group （113.80 mm3）, the change of weight was not significant among the four groups. After treated with endotar, the expression of MMP-9 and VEGF in tumor were obviously down-regulated, but the same results was not found in MMP-2, HIF-la of tumor. MVD in tumor of treatment group decreased significantly compared with model group. Proportion of tumor vessels covered by collagen in treatment group increased compared with model group. However, MVD and microvasculature in myocardium did not change significantly. Conclusion： Rh-endostatin can decrease the expression of MMP-9, VEGF and MVD to inhibit growth of tumor and normalize micrangium in tumor but cannot weaken MMPs and MVD of mature micrangium in myocardium.
基金supported by the National Natural Science Foundation of China(31970379 and 32172086)the Jiangsu Collaborative Innovation Center for Modern Crop Production (JCIC-MCP)+3 种基金the National Key R&D Program of China (ZZ202001)the R&D program of Shenzhen (KCXFZ20211020164207012)the R&D program in key areas of Guangdong Province (2021B0707010006)the Science and Technology Planning Project of Guangdong Province (2022B0202060002)。
文摘Whole-genome genotyping methods are important for breeding.However,it has been challenging to develop a robust method for simultaneous foreground and background genotyping that can easily be adapted to different genes and species.In our study,we accidently discovered that in adapter ligation-mediated PCR,the amplification by primertemplate mismatched annealing(PTMA)along the genome could generate thousands of stable PCR products.Based on this observation,we consequently developed a novel method for simultaneous foreground and background integrated genotyping by sequencing(FBI-seq)using one specific primer,in which foreground genotyping is performed by primer-template perfect annealing(PTPA),while background genotyping employs PTMA.Unlike DNA arrays,multiple PCR,or genome target enrichments,FBI-seq requires little preliminary work for primer design and synthesis,and it is easily adaptable to different foreground genes and species.FBI-seq therefore provides a prolific,robust,and accurate method for simultaneous foreground and background genotyping to facilitate breeding in the postgenomics era.
基金supported by the National Natural Science Foundation of China(U1804255)the Key Research&Development and Promotion Projects of Henan Province(222102520038 and 212102210651)。
文摘RuO_(x)是一种有潜力的析氢反应(HER)电催化剂,然而,其表面上*OH和*H中间体的竞争吸附以及过度H结合导致其析氢性能较差.FeOOH具有较强的亲氧性,有望与RuO_(x)耦合形成RuO_(x)/FeOOH复合材料来有效促进HER动力学.鉴于Ru^(3+)的强氧化性,构建温和的反应环境是设计结构均匀、Ru位点可及的RuO_(x)/FeOOH复合材料的关键.本文提出一种乙醇调控铁腐蚀策略,在泡沫铁上原位生长了RuO_(x)/FeOOH电催化剂.醇羟基与Ru^(3+)配位降低了Ru^(3+)的氧化性,并减缓了其扩散,避免了剧烈的氧化还原反应.优化的纳米结构以及RuO_(x)和FeOOH之间的强电子相互作用,使所制备的催化剂在50和100 mA cm^(-2)电流密度下驱动HER和全解水,分别仅需67 mV过电位和1.56 V电压.基于羟基调控策略,乙二醇、正丙醇、异丙醇和甲醇同样可替代乙醇来增强RuO_(x)/FeOOH的HER活性.本工作提出了一种调节铁腐蚀行为的配位调控方法,为制备新型钌基复合催化剂提供了理论依据.
