目的探讨白介素2受体拮抗剂(IL-2Ra)对肝移植术后糖代谢异常患者预后的影响。方法选取儋州市人民医院与中山大学附属第一医院2015年6月—2018年6月收治的肝移植术后糖代谢异常患者80例,根据随机数字表法分成对照组(n=40)与观察组(n=40)...目的探讨白介素2受体拮抗剂(IL-2Ra)对肝移植术后糖代谢异常患者预后的影响。方法选取儋州市人民医院与中山大学附属第一医院2015年6月—2018年6月收治的肝移植术后糖代谢异常患者80例,根据随机数字表法分成对照组(n=40)与观察组(n=40)。对照组于肝移植术后给予常规治疗,观察组在此基础上加用IL-2Ra。分别在两组肝移植术后24 h、术后6个月检测糖代谢指标与胰岛素水平,包括空腹血糖(FPG)、糖化血红蛋白(HbA1c)、餐后2 h血糖(2 h PG)、空腹胰岛素(FINS)、餐后2 h胰岛素(2 h INS)、胰岛素抵抗指数(HOMA-IR)。比较两组肝移植术后6个月的新发糖尿病发生率,并记录治疗期间不良反应情况。结果两组术后6个月的FPG、HbA1c、2 h PG低于术后24 h,且观察组显著低于对照组(P<0.05)。两组术后6个月的FINS、2 h INS、HOMA-IR显著低于术后24 h,且观察组FINS、HOMA-IR显著低于对照组(P<0.05)。观察组新发糖尿病率为12.50%,显著低于对照组的32.50%(P<0.05)。观察组不良反应率为2.50%,对照组无不良反应病例,组间比较无显著差异(P>0.05)。结论IL-2Ra的应用能进一步纠正肝移植术后的糖代谢紊乱与胰岛素水平,降低新发糖尿病发生率,且未见严重不良反应。展开更多
Objective Gliomas are the most common malignant tumors in the central nervous system.Despite multiple therapies including surgery,chemotherapy,and radiotherapy,the prognosis of patients remains poor.Immunotherapy is a...Objective Gliomas are the most common malignant tumors in the central nervous system.Despite multiple therapies including surgery,chemotherapy,and radiotherapy,the prognosis of patients remains poor.Immunotherapy is an alternative method of treating glioma,and the use of dendritic cell vaccines is one of the promising treatment options.However,there is no specific tumor cell antigen that can trigger dendritic cells(DCs).IL-13Ra2 is a specific antigen expressed in glioma cells;in the current study,we have attempted to explore whether IL-13Ra2 could be the antigen that triggers DCs and to envisage its application as potential therapy for glioma.Methods The expression of IL-13Ra2 was detected in U251 glioma cell lines and primary glioma tissues using different methods.DCs from human blood were isolated and pulsed with recombinant IL-13Ra2,following which the cytotoxicity of these DCs on glioma cells was detected and analyzed.Results About 55.9% human glioma tissue cells expressed IL-13Ra2,while normal brain tissue cells did not show any expression.DC vaccines loaded with IL-13Ra2,glioma cell antigen,and brain tumor stem cell(BTSC) antigen could significantly stimulate the proliferation of T lymphocytes and induce cell death in the glioma tissue.Compared to other groups,DC vaccines loaded with BTSC antigen showed the strongest ability to activate cytotoxic T lymphocytes(CTLs),while the glioma cell antigen group showed no significant difference.Conclusion IL-13Ra2,which is expressed in gliomas and by glioma stem cells,as well as IL-13Ra2 could prove to be potential antigens for DC vaccine-based immunotherapy.展开更多
Objective： To investigate the expression of IL-13Ra2 gene in brain tumors. Methods： Seventy-nine human brain tumors were obtained from the department of Neurosurgery of China Medical University. Human IL-13Ra2 expre...Objective： To investigate the expression of IL-13Ra2 gene in brain tumors. Methods： Seventy-nine human brain tumors were obtained from the department of Neurosurgery of China Medical University. Human IL-13Ra2 expression was evaluated by reverse transcriptase polymerase chain reaction and immunohistochemical analysis. Results： IL-13Ra2 gene was highly expressed in glioblastoma, medulloblastoma, malignant meningioma and benign meningioma. Conclusion： Human IL-13Ra2 gene is expressed in brain tumors in addition to gliomas, and our result indicates that the IL-13Ra2 gene promoter based gene therapy method can be used to treat brain tumors in addition to gliomas. Further studies involving larger numbers of samples are necessary to fully understand the expression profile of IL-13Ra2 gene in the brain tumors.展开更多
Interleukin-2 （IL）-2 signaling plays a pivotal role in the activation of immune responses, and drugs that block this pathway have been shown to be effective for the immunosuppression in patients with organ transplan...Interleukin-2 （IL）-2 signaling plays a pivotal role in the activation of immune responses, and drugs that block this pathway have been shown to be effective for the immunosuppression in patients with organ transplantation to alleviate/eliminate allograft rejection. The first humanized monoclonal antibody （mAb） daclizumab falls into this category and shows high specificity and affinity against a key component of the IL-2 receptor complex, namely IL-2Ra. To reveal the molecular mechanism of the inhibition of the IL-2 signaling pathway by dacllzumab, we determined the crystal structures of the daclizumab Fab in free form and in complex with the IL-2Ra ectodomain at 2.6 and 2.8 A resolution, respectively. The daclizumab Fab adopts a similar conformation in the presence or absence of the IL- 2Ra ectodomain. The antigen-binding site of daclizumab is mainly composed of live complementarity determining regions （CDRs） that form a large positively charged surface depression and two flanking patches that are generally hydrophobic. The conformational epitope consists of several discontinuous segments of the IL-2Ru ectodomain, a large portion of which overlaps with the regions that interact with IL-2, suggesting that the binding of daclizumab to IL-2Ra would prevent the IL-2 binding to IL-2Ra and the subsequent formation of the IL-2fIL-2Ra[~/c complex, and therefore block the IL-2 signaling pathway. These results also have implications for the design and development of improved mAb drugs targeting IL-2Ra.展开更多
Cancer stem cells(CSCs)are considered tumor-initiating cells and the main drivers of disease progression.Targeting these rare cancer cells,however,remains challenging with respect to therapeutic benefit.Here,we report...Cancer stem cells(CSCs)are considered tumor-initiating cells and the main drivers of disease progression.Targeting these rare cancer cells,however,remains challenging with respect to therapeutic benefit.Here,we report the up-regulation of IL-13RA2 expression in colorectal cancer(CRC)tissues and spheroid cells.The expression of IL-13RA2 was positively correlated with canonical stemness markers in CRC.We further demonstrated that the level of IL-13 was up-regulated in the serum of CRC patients.Biologically,recombinant IL-13(rIL13)stimulation promoted the sphere formation,proliferation,and migration of CRC cells in vitro and enhanced tumorigenesis in vivo.This phenotype could be reversed by knocking down IL-13RA2.Mechanistically,IL-13 activated autophagy by inducing LC3I/LC3II transformation in CRC-CSCs,which was crucial for the biological functions of IL-13.We further demonstrated that IL-13RA2 acted as a modular link of the E3 ligase UBE3C and the substrate p53 protein,enhancing the interaction of UBE3C and p53,thereby inducing the K48-linked ubiquitination of p53.In conclusion,the IL-13/IL-13RA2 signaling cascade promotes CRC-CSC self-renewal and tumorigenesis by inducing p53 ubiquitination,adding an important layer to the connection between IL-13 and p53,which can be translated into novel targeted therapies.展开更多
Glioblastoma(GBM)is one of the most aggressive(grade IV)gliomas characterized by a high rate of recurrence,resistance to therapy and a grim survival prognosis.The long-awaited improvement in GBM patients'survival ...Glioblastoma(GBM)is one of the most aggressive(grade IV)gliomas characterized by a high rate of recurrence,resistance to therapy and a grim survival prognosis.The long-awaited improvement in GBM patients'survival rates essentially depends on advances in the development of new therapeutic approaches.Recent preclinical studies show that nanoscale materials could greatly contribute to the improvement of diagnosis and management of brain cancers.In the current review,we will discuss how specific features of glioma pathobiology can be employed for designing efficient targeting approaches.Moreover,we willsummarize the main evidence for the potential of the IL-13R alpha 2 receptor(IL13α2R)targeting in GBM early diagnosis and experimental therapy.展开更多
文摘目的探讨白介素2受体拮抗剂(IL-2Ra)对肝移植术后糖代谢异常患者预后的影响。方法选取儋州市人民医院与中山大学附属第一医院2015年6月—2018年6月收治的肝移植术后糖代谢异常患者80例,根据随机数字表法分成对照组(n=40)与观察组(n=40)。对照组于肝移植术后给予常规治疗,观察组在此基础上加用IL-2Ra。分别在两组肝移植术后24 h、术后6个月检测糖代谢指标与胰岛素水平,包括空腹血糖(FPG)、糖化血红蛋白(HbA1c)、餐后2 h血糖(2 h PG)、空腹胰岛素(FINS)、餐后2 h胰岛素(2 h INS)、胰岛素抵抗指数(HOMA-IR)。比较两组肝移植术后6个月的新发糖尿病发生率,并记录治疗期间不良反应情况。结果两组术后6个月的FPG、HbA1c、2 h PG低于术后24 h,且观察组显著低于对照组(P<0.05)。两组术后6个月的FINS、2 h INS、HOMA-IR显著低于术后24 h,且观察组FINS、HOMA-IR显著低于对照组(P<0.05)。观察组新发糖尿病率为12.50%,显著低于对照组的32.50%(P<0.05)。观察组不良反应率为2.50%,对照组无不良反应病例,组间比较无显著差异(P>0.05)。结论IL-2Ra的应用能进一步纠正肝移植术后的糖代谢紊乱与胰岛素水平,降低新发糖尿病发生率,且未见严重不良反应。
文摘Objective Gliomas are the most common malignant tumors in the central nervous system.Despite multiple therapies including surgery,chemotherapy,and radiotherapy,the prognosis of patients remains poor.Immunotherapy is an alternative method of treating glioma,and the use of dendritic cell vaccines is one of the promising treatment options.However,there is no specific tumor cell antigen that can trigger dendritic cells(DCs).IL-13Ra2 is a specific antigen expressed in glioma cells;in the current study,we have attempted to explore whether IL-13Ra2 could be the antigen that triggers DCs and to envisage its application as potential therapy for glioma.Methods The expression of IL-13Ra2 was detected in U251 glioma cell lines and primary glioma tissues using different methods.DCs from human blood were isolated and pulsed with recombinant IL-13Ra2,following which the cytotoxicity of these DCs on glioma cells was detected and analyzed.Results About 55.9% human glioma tissue cells expressed IL-13Ra2,while normal brain tissue cells did not show any expression.DC vaccines loaded with IL-13Ra2,glioma cell antigen,and brain tumor stem cell(BTSC) antigen could significantly stimulate the proliferation of T lymphocytes and induce cell death in the glioma tissue.Compared to other groups,DC vaccines loaded with BTSC antigen showed the strongest ability to activate cytotoxic T lymphocytes(CTLs),while the glioma cell antigen group showed no significant difference.Conclusion IL-13Ra2,which is expressed in gliomas and by glioma stem cells,as well as IL-13Ra2 could prove to be potential antigens for DC vaccine-based immunotherapy.
基金This work was supported by National Natural Science Foundation of China (No.303000100) and HYD Educational Foundation (No. 94018).
文摘Objective： To investigate the expression of IL-13Ra2 gene in brain tumors. Methods： Seventy-nine human brain tumors were obtained from the department of Neurosurgery of China Medical University. Human IL-13Ra2 expression was evaluated by reverse transcriptase polymerase chain reaction and immunohistochemical analysis. Results： IL-13Ra2 gene was highly expressed in glioblastoma, medulloblastoma, malignant meningioma and benign meningioma. Conclusion： Human IL-13Ra2 gene is expressed in brain tumors in addition to gliomas, and our result indicates that the IL-13Ra2 gene promoter based gene therapy method can be used to treat brain tumors in addition to gliomas. Further studies involving larger numbers of samples are necessary to fully understand the expression profile of IL-13Ra2 gene in the brain tumors.
基金Acknowledgments We are grateful to the staff members at Shanghai Synchrotron Radiation Facility for support in diffraction data collection and other members of our group for helpful discussion. This work was supported by grants from the Ministry of Science and Technology of China （2010CB833601, 2006AA02A313, and 2009ZX09503- 009）, the National Natural Science Foundation of China （30730028 and 90713046）, and the Chinese Academy of Sciences （KSCX2-YW-R- 107 and SIBS2008002）.
文摘Interleukin-2 （IL）-2 signaling plays a pivotal role in the activation of immune responses, and drugs that block this pathway have been shown to be effective for the immunosuppression in patients with organ transplantation to alleviate/eliminate allograft rejection. The first humanized monoclonal antibody （mAb） daclizumab falls into this category and shows high specificity and affinity against a key component of the IL-2 receptor complex, namely IL-2Ra. To reveal the molecular mechanism of the inhibition of the IL-2 signaling pathway by dacllzumab, we determined the crystal structures of the daclizumab Fab in free form and in complex with the IL-2Ra ectodomain at 2.6 and 2.8 A resolution, respectively. The daclizumab Fab adopts a similar conformation in the presence or absence of the IL- 2Ra ectodomain. The antigen-binding site of daclizumab is mainly composed of live complementarity determining regions （CDRs） that form a large positively charged surface depression and two flanking patches that are generally hydrophobic. The conformational epitope consists of several discontinuous segments of the IL-2Ru ectodomain, a large portion of which overlaps with the regions that interact with IL-2, suggesting that the binding of daclizumab to IL-2Ra would prevent the IL-2 binding to IL-2Ra and the subsequent formation of the IL-2fIL-2Ra[~/c complex, and therefore block the IL-2 signaling pathway. These results also have implications for the design and development of improved mAb drugs targeting IL-2Ra.
基金supported by the National Natural Science Foundation of China(No.82173371,82273447,82273069)the project funded by China Postdoctoral Science Foundation(No.2022M711320,2022M711322)+7 种基金Shandong Postdoctoral innovation project(China)(No.SDCX-ZG202201002)Tai Shan Young Scholar Foundation of Shandong Province,China(No.tsqn201909192)Shandong Provincial Natural Science Foundation(China)(No.ZR2020YQ59,ZR2021QH021,ZR202112020099)Youth Innovation Science and Technology Support Plan of Shandong Province’s colleges and universities(China)(No.2021KJ017)the Project of Medicine Health and Technology Development Plan of Shandong Province,China(No.202103030586 and 202103030411)the Miaopu Research of the Affiliated Hospital of Jining Medical University,Shandong,China(No.MP-ZD-2020-005 and MP-ZD-2021-001)Ph.D.Research Foundation of the Affiliated Hospital of Jining Medical University,Shandong,China(No.2022-BS003)Research Fund for Lin He’s Academician Workstation of New Medicine and Clinical Translation in Jining Medical University,Shandong,China(No.JYHL2022FZD04).
文摘Cancer stem cells(CSCs)are considered tumor-initiating cells and the main drivers of disease progression.Targeting these rare cancer cells,however,remains challenging with respect to therapeutic benefit.Here,we report the up-regulation of IL-13RA2 expression in colorectal cancer(CRC)tissues and spheroid cells.The expression of IL-13RA2 was positively correlated with canonical stemness markers in CRC.We further demonstrated that the level of IL-13 was up-regulated in the serum of CRC patients.Biologically,recombinant IL-13(rIL13)stimulation promoted the sphere formation,proliferation,and migration of CRC cells in vitro and enhanced tumorigenesis in vivo.This phenotype could be reversed by knocking down IL-13RA2.Mechanistically,IL-13 activated autophagy by inducing LC3I/LC3II transformation in CRC-CSCs,which was crucial for the biological functions of IL-13.We further demonstrated that IL-13RA2 acted as a modular link of the E3 ligase UBE3C and the substrate p53 protein,enhancing the interaction of UBE3C and p53,thereby inducing the K48-linked ubiquitination of p53.In conclusion,the IL-13/IL-13RA2 signaling cascade promotes CRC-CSC self-renewal and tumorigenesis by inducing p53 ubiquitination,adding an important layer to the connection between IL-13 and p53,which can be translated into novel targeted therapies.
基金This work was financed by the Ministry of Science and Higher Education of the Russian Federation within the framework of state support for the creation and development of World-Class Research Centers"Digital Biodesign and Personalized Healthcare"(No.075-15-2020-926).
文摘Glioblastoma(GBM)is one of the most aggressive(grade IV)gliomas characterized by a high rate of recurrence,resistance to therapy and a grim survival prognosis.The long-awaited improvement in GBM patients'survival rates essentially depends on advances in the development of new therapeutic approaches.Recent preclinical studies show that nanoscale materials could greatly contribute to the improvement of diagnosis and management of brain cancers.In the current review,we will discuss how specific features of glioma pathobiology can be employed for designing efficient targeting approaches.Moreover,we willsummarize the main evidence for the potential of the IL-13R alpha 2 receptor(IL13α2R)targeting in GBM early diagnosis and experimental therapy.
