Objective Isocitrate dehydrogenase gene(IDH)mutations are associated with tumor angiogenesis and therefore play an important role in glioma management.This study compared the performance of tumor blood vessels counted...Objective Isocitrate dehydrogenase gene(IDH)mutations are associated with tumor angiogenesis and therefore play an important role in glioma management.This study compared the performance of tumor blood vessels counted from contrast-enhanced 3D brain volume(3D-BRAVO)sequence and dynamic contrast-enhanced(DCE)MRI in differentiating IDH1 status in gliomas.Methods Forty-four glioma patients[16 with IDH1 mutant-type(IDH1-MT),28 with IDH1 wild-type(IDH1-WT)]were retrospectively analyzed.A blood vessel entering a tumor was defined as an intratumoral vessel;a blood vessel adjacent to the edge of a tumor was defined as a peritumoral vessel.Combined vessels were defined as the sum of the intratumoral and peritumoral vessels.DCE-derived metrics of tumor were normalized to the contralateral normal-appearing white matter.Results Intratumoral,peritumoral,and combined tumor blood vessels were all significantly different between IDH1-MT and IDH1-WT gliomas,and the range of area under curves(AUCs)was 0.816–0.855.For DCE-derived parameters,cerebral blood volume,cerebral blood flow,mean transit time,and volume transfer constant were significantly different between IDH1-MT and IDH1-WT gliomas,and the range of AUCs was 0.703–0.756.Combined vessels possessed the best performance for identifying IDH1 mutations in gliomas(AUC:0.855,sensitivity:0.857,specificity:0.812,P<0.001).Conclusion The number of tumor blood vessels has comparable diagnostic performance with DCE-derived parameters for differentiating IDH1 mutations and can serve as a potential imaging biomarker to reflect IDH1 mutations in gliomas.展开更多
BACKGROUND In traditional Chinese medicine(TCM),frankincense and myrrh are the main components of the antitumor drug Xihuang Pill.These compounds show anticancer activity in other biological systems.However,whether fr...BACKGROUND In traditional Chinese medicine(TCM),frankincense and myrrh are the main components of the antitumor drug Xihuang Pill.These compounds show anticancer activity in other biological systems.However,whether frankincense and/or myrrh can inhibit the occurrence of hepatocellular carcinoma(HCC)is unknown,and the potential molecular mechanism(s)has not yet been determined.AIM To predict and determine latent anti-HCC therapeutic targets and molecular mechanisms of frankincense and myrrh in vivo.METHODS In the present study,which was based on the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform(http://tcmspw.com/tcmsp.php),Universal Protein database(http://www.uniprot.org),GeneCards:The Human Gene Database(http://www.genecards.org/)and Comparative Toxicogenomics Database(http://www.ctdbase.org/),the efficacy of and mechanism by which frankincense and myrrh act as anti-HCC compounds were predicted.The core prediction targets were screened by molecular docking.In vivo,SMMC-7721 human liver cancer cells were transplanted as xenografts into nude mice to establish a subcutaneous tumor model,and two doses of frankincense plus myrrh or one dose of an EGFR inhibitor was administered to these mice continuously for 14 d.The tumors were collected and evaluated:the tumor volume and growth rate were gauged to evaluate tumor growth;hematoxylineosin staining was performed to estimate histopathological changes;immunofluorescence(IF)was performed to detect the expression of CD31,α-SMA and collagen IV;transmission electron microscopy(TEM)was conducted to observe the morphological structure of vascular cells;enzyme-linked immunosorbent assay(ELISA)was performed to measure the levels of secreted HIF-1αand TNF-α;reverse transcription-polymerase chain reaction(RT-qPCR)was performed to measure the mRNA expression of HIF-1α,TNF-α,VEGF and MMP-9;and Western blot(WB)was performed to determine the levels of proteins expressed in the EGFR-mediated PI3K/Akt and MAPK signaling pathways.RESULTS The results of the network pharmacology analysis showed that there were 35 active components in the frankincense and myrrh extracts targeting 151 key targets.The molecular docking analysis showed that both boswellic acid and stigmasterol showed strong affinity for the targets,with the greatest affinity for EGFR.Frankincense and myrrh treatment may play a role in the treatment of HCC by regulating hypoxia responses and vascular system-related pathological processes,such as cytokine-receptor binding,and pathways,such as those involving serine/threonine protein kinase complexes and MAPK,HIF-1 and ErbB signaling cascades.The animal experiment results were verified.First,we found that,through frankincense and/or myrrh treatment,the volume of subcutaneously transplanted HCC tumors was significantly reduced,and the pathological morphology was attenuated.Then,IF and TEM showed that frankincense and/or myrrh treatment reduced CD31 and collagen IV expression,increased the coverage of perivascular cells,tightened the connection between cells,and improved the shape of blood vessels.In addition,ELISA,RT-qPCR and WB analyses showed that frankincense and/or myrrh treatment inhibited the levels of hypoxia-inducible factors,inflammatory factors and angiogenesis-related factors,namely,HIF-1α,TNF-α,VEGF and MMP-9.Furthermore,mechanistic experiments illustrated that the effect of frankincense plus myrrh treatment was similar to that of an EGFR inhibitor with regard to controlling EGFR activation,thereby inhibiting the phosphorylation activity of its downstream targets:the PI3K/Akt and MAPK(ERK,p38 and JNK)pathways.CONCLUSION In summary,frankincense and myrrh treatment targets tumor blood vessels to exert anti-HCC effects via EGFR-activated PI3K/Akt and MAPK signaling pathways,highlighting the potential of this dual TCM compound as an anti-HCC candidate.展开更多
Epithelial glioma is the most common brain cancer,accounting for 35.26%-60.69%of intracranial tumors with an average of 44.69%,and it remains the greatest challenge in the field of neurosurgery.The median survival tim...Epithelial glioma is the most common brain cancer,accounting for 35.26%-60.69%of intracranial tumors with an average of 44.69%,and it remains the greatest challenge in the field of neurosurgery.The median survival time of patients with advanced glioma is only 12 to 18 months due to the characteristics of high aggression,and the therapeutic effect was poor though surgery,chemotherapy,and targeted drug therapy being treated.Because of the presence of heterogeneity and the differentiation disorder,only a small number of glioma cells are the source of tumor growth and metastasis,which are highly resistant to traditional treatments.They are deemed as the“seed”tumor cells as they could get rid of the effect of the treatment and reconstruct the organization of tumor.They are also termed as brain tumor stem cell(BTSC)or glioma stem cells(GSCs)since neural stem cells share similar features with them.Recent data reveal that they are directly related with invasion,angiogenesis,tolerance,chemotherapy,recurrence of glioma.Based on the research result by the team,the paper elaborates the characteristics of GSCs and the relationship with the tumor angiogenesis.展开更多
目的探讨动态对比增强MRI(dynamic contrast-enhancement MRI,DCE-MRI)瘤周血管特征结合瘤内血流动力学参数在乳腺影像报告和数据系统(breast imaging reporting and data system,BI-RADS)4类肿瘤中的鉴别诊断价值。材料与方法回顾性分...目的探讨动态对比增强MRI(dynamic contrast-enhancement MRI,DCE-MRI)瘤周血管特征结合瘤内血流动力学参数在乳腺影像报告和数据系统(breast imaging reporting and data system,BI-RADS)4类肿瘤中的鉴别诊断价值。材料与方法回顾性分析2018年8月至2023年3月于大连医科大学附属第一医院行乳腺MRI检查为BI-RADS 4类且病理结果明确肿瘤的女性病例102例,其中良性组43例,恶性组59例。记录患者年龄、病灶最大径(dmax)、乳腺DCE-MRI基本影像学特征、瘤周血管特征及瘤内血流动力学参数值。通过单因素和多因素logistic回归分析比较两组间多参数的差异,利用受试者工作特征(receiver operating characteristic,ROC)曲线以及曲线下面积(area under the curve,AUC)分析瘤周血管特征指标与瘤内参数值联合应用对BI-RADS 4类乳腺良恶性两组肿瘤鉴别的诊断效能。应用DeLong检验对AUC进行比较。结果乳腺良性组和恶性组病例在年龄、dmax、背景实质强化(background parenchymal enhancement,BPE)、纤维腺体组织量(fibroglandular tissue,FGT)、瘤周相邻血管征(adjacent vascular sign,AVS)数目、瘤周血管最大径、患侧瘤周与健侧同一象限血管直径差值(△d)、瘤周血管出现期相以及瘤内容积转移常数(volume transfer constant,K^(trans))、速率常数(flux rate constant,K_(ep))、最大增强斜率(maximum slope of increase,MSI)和时间-信号强度曲线(time-signal intensity curve,TIC)类型的差异均具有统计学意义(P<0.05),而病变位置、信号增强率(signal enhancement ratio,SER)和血管外细胞外间隙容积比(volume fraction of extravascular extra vascular space,V_(e))差异无统计学意义(P>0.05)。通过多因素logistic回归分析结果显示,△d、dmax、MSI和K^(trans)为区分两组间的独立影响因素,其中优势比最大的是MSI值(AUC为0.923)。将瘤周血管特征△d分别与dmax、MSI和K^(trans)进行两者联合模型比较,以△d与MSI联合模型的诊断效能最高(AUC为0.933,敏感度和特异度分别为93.2%和83.7%),且△d联合MSI与△d联合K^(trans)比较的差异具有统计学意义(P=0.001);其他联合指标在两两比较时差异无统计学意义(P>0.05),联合模型高于单独MSI模型的诊断效能。结论瘤周血管特征指标(△d)联合瘤内半定量(MSI)血流动力学参数对评价BI-RADS 4类乳腺肿瘤具有较好的鉴别诊断价值。展开更多
Angioarchitecture plays an important role in the malignant development of intracranial hemangiopericytoma. It remains poorly understood whether high frequency of hemorrhage during clinical surgery for intracranial hem...Angioarchitecture plays an important role in the malignant development of intracranial hemangiopericytoma. It remains poorly understood whether high frequency of hemorrhage during clinical surgery for intracranial hemangiopericytoma is associated with angioarchitecture. The present study utilized hematoxylin-eosin staining, and immunohistochemical staining with epithelial membrane antigen, vimentin, CD34, von Willebrand factor （vWF） and CD133 to observe characteristics of angioarchitecture. In addition, silver stains were used to demonstrate changes in reticular fibers in the wall of vessel channels in intracranial hemangiopericytoma and meningioma. Five patterns of angioarchitecture were identified in intracranial hemangiopericytoma, namely tumor cell islands, vasculogenic mimicry, mosaic blood vessels, sprouting angiogenesis, and intussusceptive angiogenesis. Several CD133＋ tumor cells were found to form tumor cell islands. A connection between vWF ^＋ and vWF channels was detected in the pattern of intussusceptive angiogenesis, and some vimentin^＋ tumor cells were embedded in the periodic acid-Schiff positive channel wall. Incomplete threads of reticular fibers formed the walls of larger pseudo-vascular channels and some tumor clumps or scattered tumor cells were detected ＂floating＂ in them. The angioarchitecture, specific markers and reticular fibers of intracranial hemangiopericytoma were significantly different from meningioma. Angioarchitecture provides a functional vascular network for vascular evolution in intracranial hemangiopericytoma and contributes to significant intra-operative bleeding.展开更多
Numerical simulation of hemodynamics under the combined effects of both the host blood vessel and the microvascular network, which is based on a 2-D tumor inside and outside vascular network generated from a discrete ...Numerical simulation of hemodynamics under the combined effects of both the host blood vessel and the microvascular network, which is based on a 2-D tumor inside and outside vascular network generated from a discrete mathematical model of tumor-induced angiogenesis, is performed systemically. And a ＂microvascular network-- transport across microvascular network--flow in interstitium＂ model is developed to study the flow in solid tumor. Simulations are carried out to examine the effects of the variations of the inlet Reynolds number in the host blood vessel, the hydraulic conductivity of the microvascular wall, and interstitial hydraulic conductivity coefficient on the fluid flow in tumor microcirculation. The results are consistent with data obtained in terms of physiology. These results may provide some theoretical references and the bases for further clinical experimental research.展开更多
基金the National Natural Science Foundation of China(No.81730049 and No.81801666)the Fundamental Research Funds for the Central Universities,HUST(No.2019JYCXJJ044).
文摘Objective Isocitrate dehydrogenase gene(IDH)mutations are associated with tumor angiogenesis and therefore play an important role in glioma management.This study compared the performance of tumor blood vessels counted from contrast-enhanced 3D brain volume(3D-BRAVO)sequence and dynamic contrast-enhanced(DCE)MRI in differentiating IDH1 status in gliomas.Methods Forty-four glioma patients[16 with IDH1 mutant-type(IDH1-MT),28 with IDH1 wild-type(IDH1-WT)]were retrospectively analyzed.A blood vessel entering a tumor was defined as an intratumoral vessel;a blood vessel adjacent to the edge of a tumor was defined as a peritumoral vessel.Combined vessels were defined as the sum of the intratumoral and peritumoral vessels.DCE-derived metrics of tumor were normalized to the contralateral normal-appearing white matter.Results Intratumoral,peritumoral,and combined tumor blood vessels were all significantly different between IDH1-MT and IDH1-WT gliomas,and the range of area under curves(AUCs)was 0.816–0.855.For DCE-derived parameters,cerebral blood volume,cerebral blood flow,mean transit time,and volume transfer constant were significantly different between IDH1-MT and IDH1-WT gliomas,and the range of AUCs was 0.703–0.756.Combined vessels possessed the best performance for identifying IDH1 mutations in gliomas(AUC:0.855,sensitivity:0.857,specificity:0.812,P<0.001).Conclusion The number of tumor blood vessels has comparable diagnostic performance with DCE-derived parameters for differentiating IDH1 mutations and can serve as a potential imaging biomarker to reflect IDH1 mutations in gliomas.
基金the National Natural Science Foundation of China,No.U20A20408(Major Program)and No.82074450(General Program)Natural Science Foundation of Hunan Province,No.2020JJ4066+2 种基金Hunan Province Research and innovation projects for Postgraduates,No.CX20190541Hunan Province"domestic firstclass cultivation discipline"Integrated Traditional Chinese and Western medicine open fund project,No.2018ZXYJH03Hunan University Undergraduate Research Learning and Innovative Experiment Project,No.201609030114.
文摘BACKGROUND In traditional Chinese medicine(TCM),frankincense and myrrh are the main components of the antitumor drug Xihuang Pill.These compounds show anticancer activity in other biological systems.However,whether frankincense and/or myrrh can inhibit the occurrence of hepatocellular carcinoma(HCC)is unknown,and the potential molecular mechanism(s)has not yet been determined.AIM To predict and determine latent anti-HCC therapeutic targets and molecular mechanisms of frankincense and myrrh in vivo.METHODS In the present study,which was based on the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform(http://tcmspw.com/tcmsp.php),Universal Protein database(http://www.uniprot.org),GeneCards:The Human Gene Database(http://www.genecards.org/)and Comparative Toxicogenomics Database(http://www.ctdbase.org/),the efficacy of and mechanism by which frankincense and myrrh act as anti-HCC compounds were predicted.The core prediction targets were screened by molecular docking.In vivo,SMMC-7721 human liver cancer cells were transplanted as xenografts into nude mice to establish a subcutaneous tumor model,and two doses of frankincense plus myrrh or one dose of an EGFR inhibitor was administered to these mice continuously for 14 d.The tumors were collected and evaluated:the tumor volume and growth rate were gauged to evaluate tumor growth;hematoxylineosin staining was performed to estimate histopathological changes;immunofluorescence(IF)was performed to detect the expression of CD31,α-SMA and collagen IV;transmission electron microscopy(TEM)was conducted to observe the morphological structure of vascular cells;enzyme-linked immunosorbent assay(ELISA)was performed to measure the levels of secreted HIF-1αand TNF-α;reverse transcription-polymerase chain reaction(RT-qPCR)was performed to measure the mRNA expression of HIF-1α,TNF-α,VEGF and MMP-9;and Western blot(WB)was performed to determine the levels of proteins expressed in the EGFR-mediated PI3K/Akt and MAPK signaling pathways.RESULTS The results of the network pharmacology analysis showed that there were 35 active components in the frankincense and myrrh extracts targeting 151 key targets.The molecular docking analysis showed that both boswellic acid and stigmasterol showed strong affinity for the targets,with the greatest affinity for EGFR.Frankincense and myrrh treatment may play a role in the treatment of HCC by regulating hypoxia responses and vascular system-related pathological processes,such as cytokine-receptor binding,and pathways,such as those involving serine/threonine protein kinase complexes and MAPK,HIF-1 and ErbB signaling cascades.The animal experiment results were verified.First,we found that,through frankincense and/or myrrh treatment,the volume of subcutaneously transplanted HCC tumors was significantly reduced,and the pathological morphology was attenuated.Then,IF and TEM showed that frankincense and/or myrrh treatment reduced CD31 and collagen IV expression,increased the coverage of perivascular cells,tightened the connection between cells,and improved the shape of blood vessels.In addition,ELISA,RT-qPCR and WB analyses showed that frankincense and/or myrrh treatment inhibited the levels of hypoxia-inducible factors,inflammatory factors and angiogenesis-related factors,namely,HIF-1α,TNF-α,VEGF and MMP-9.Furthermore,mechanistic experiments illustrated that the effect of frankincense plus myrrh treatment was similar to that of an EGFR inhibitor with regard to controlling EGFR activation,thereby inhibiting the phosphorylation activity of its downstream targets:the PI3K/Akt and MAPK(ERK,p38 and JNK)pathways.CONCLUSION In summary,frankincense and myrrh treatment targets tumor blood vessels to exert anti-HCC effects via EGFR-activated PI3K/Akt and MAPK signaling pathways,highlighting the potential of this dual TCM compound as an anti-HCC candidate.
文摘Epithelial glioma is the most common brain cancer,accounting for 35.26%-60.69%of intracranial tumors with an average of 44.69%,and it remains the greatest challenge in the field of neurosurgery.The median survival time of patients with advanced glioma is only 12 to 18 months due to the characteristics of high aggression,and the therapeutic effect was poor though surgery,chemotherapy,and targeted drug therapy being treated.Because of the presence of heterogeneity and the differentiation disorder,only a small number of glioma cells are the source of tumor growth and metastasis,which are highly resistant to traditional treatments.They are deemed as the“seed”tumor cells as they could get rid of the effect of the treatment and reconstruct the organization of tumor.They are also termed as brain tumor stem cell(BTSC)or glioma stem cells(GSCs)since neural stem cells share similar features with them.Recent data reveal that they are directly related with invasion,angiogenesis,tolerance,chemotherapy,recurrence of glioma.Based on the research result by the team,the paper elaborates the characteristics of GSCs and the relationship with the tumor angiogenesis.
文摘目的探讨动态对比增强MRI(dynamic contrast-enhancement MRI,DCE-MRI)瘤周血管特征结合瘤内血流动力学参数在乳腺影像报告和数据系统(breast imaging reporting and data system,BI-RADS)4类肿瘤中的鉴别诊断价值。材料与方法回顾性分析2018年8月至2023年3月于大连医科大学附属第一医院行乳腺MRI检查为BI-RADS 4类且病理结果明确肿瘤的女性病例102例,其中良性组43例,恶性组59例。记录患者年龄、病灶最大径(dmax)、乳腺DCE-MRI基本影像学特征、瘤周血管特征及瘤内血流动力学参数值。通过单因素和多因素logistic回归分析比较两组间多参数的差异,利用受试者工作特征(receiver operating characteristic,ROC)曲线以及曲线下面积(area under the curve,AUC)分析瘤周血管特征指标与瘤内参数值联合应用对BI-RADS 4类乳腺良恶性两组肿瘤鉴别的诊断效能。应用DeLong检验对AUC进行比较。结果乳腺良性组和恶性组病例在年龄、dmax、背景实质强化(background parenchymal enhancement,BPE)、纤维腺体组织量(fibroglandular tissue,FGT)、瘤周相邻血管征(adjacent vascular sign,AVS)数目、瘤周血管最大径、患侧瘤周与健侧同一象限血管直径差值(△d)、瘤周血管出现期相以及瘤内容积转移常数(volume transfer constant,K^(trans))、速率常数(flux rate constant,K_(ep))、最大增强斜率(maximum slope of increase,MSI)和时间-信号强度曲线(time-signal intensity curve,TIC)类型的差异均具有统计学意义(P<0.05),而病变位置、信号增强率(signal enhancement ratio,SER)和血管外细胞外间隙容积比(volume fraction of extravascular extra vascular space,V_(e))差异无统计学意义(P>0.05)。通过多因素logistic回归分析结果显示,△d、dmax、MSI和K^(trans)为区分两组间的独立影响因素,其中优势比最大的是MSI值(AUC为0.923)。将瘤周血管特征△d分别与dmax、MSI和K^(trans)进行两者联合模型比较,以△d与MSI联合模型的诊断效能最高(AUC为0.933,敏感度和特异度分别为93.2%和83.7%),且△d联合MSI与△d联合K^(trans)比较的差异具有统计学意义(P=0.001);其他联合指标在两两比较时差异无统计学意义(P>0.05),联合模型高于单独MSI模型的诊断效能。结论瘤周血管特征指标(△d)联合瘤内半定量(MSI)血流动力学参数对评价BI-RADS 4类乳腺肿瘤具有较好的鉴别诊断价值。
基金the Science and Technology Projects in Liaoning Province, No. 2010225036
文摘Angioarchitecture plays an important role in the malignant development of intracranial hemangiopericytoma. It remains poorly understood whether high frequency of hemorrhage during clinical surgery for intracranial hemangiopericytoma is associated with angioarchitecture. The present study utilized hematoxylin-eosin staining, and immunohistochemical staining with epithelial membrane antigen, vimentin, CD34, von Willebrand factor （vWF） and CD133 to observe characteristics of angioarchitecture. In addition, silver stains were used to demonstrate changes in reticular fibers in the wall of vessel channels in intracranial hemangiopericytoma and meningioma. Five patterns of angioarchitecture were identified in intracranial hemangiopericytoma, namely tumor cell islands, vasculogenic mimicry, mosaic blood vessels, sprouting angiogenesis, and intussusceptive angiogenesis. Several CD133＋ tumor cells were found to form tumor cell islands. A connection between vWF ^＋ and vWF channels was detected in the pattern of intussusceptive angiogenesis, and some vimentin^＋ tumor cells were embedded in the periodic acid-Schiff positive channel wall. Incomplete threads of reticular fibers formed the walls of larger pseudo-vascular channels and some tumor clumps or scattered tumor cells were detected ＂floating＂ in them. The angioarchitecture, specific markers and reticular fibers of intracranial hemangiopericytoma were significantly different from meningioma. Angioarchitecture provides a functional vascular network for vascular evolution in intracranial hemangiopericytoma and contributes to significant intra-operative bleeding.
基金Project supported by the National Natural Science Foundation of China (Grant No:10372026)
文摘Numerical simulation of hemodynamics under the combined effects of both the host blood vessel and the microvascular network, which is based on a 2-D tumor inside and outside vascular network generated from a discrete mathematical model of tumor-induced angiogenesis, is performed systemically. And a ＂microvascular network-- transport across microvascular network--flow in interstitium＂ model is developed to study the flow in solid tumor. Simulations are carried out to examine the effects of the variations of the inlet Reynolds number in the host blood vessel, the hydraulic conductivity of the microvascular wall, and interstitial hydraulic conductivity coefficient on the fluid flow in tumor microcirculation. The results are consistent with data obtained in terms of physiology. These results may provide some theoretical references and the bases for further clinical experimental research.
