目的:伴有肠母细胞分化的胃癌(gastric cancer with enteroblastic differentiation,GCED)是一种新的胃癌类型。该肿瘤表达胚胎干细胞标志物为SALL4以及癌胚蛋白(AFP和GPC3)等。本研究旨在探讨GCED的临床病理学特征及其分子表型。方法:...目的:伴有肠母细胞分化的胃癌(gastric cancer with enteroblastic differentiation,GCED)是一种新的胃癌类型。该肿瘤表达胚胎干细胞标志物为SALL4以及癌胚蛋白(AFP和GPC3)等。本研究旨在探讨GCED的临床病理学特征及其分子表型。方法:回顾性分析2013年3月至2017年3月浙江大学医学院附属第一医院就诊的胃部肠型腺癌337例,其中8例可诊断为GCED,患者均为老年人,其中男性6例,女性2例,年龄68～83岁,平均年龄为76.6岁。2例治疗前血清AFP≥200μg/L。收集相关临床资料,根据其组织病理学形态,采用免疫组织化学法分析免疫学表型,应用逆转录PCR(RT-PCR)方法检测SALL4基因。结果:显微镜下观察,所有病例均具有原始的肠样结构,由立方或柱状细胞组成,胞质透明、清晰,免疫组织化学法检测显示AFP和GPC3阳性,或SALL4阳性。RT-PCR检测结果显示SALL4基因mRNA的表达水平显著增高。随访1～5年,其中5例出现肝及其他脏器转移,2例死亡,1例无瘤生存。结论:GCED是一种罕见的侵袭性肠型腺癌,预后比普通肠型腺癌差,按照普通肠型腺癌的治疗方法效果甚微。其组织学上具有特征性的改变,熟悉其瘤谱及基因学特征有助于鉴别和诊断,有助于对原始标记物,制定如SALL4的靶向治疗方案。展开更多
Interferons(IFNs)play an important role in immunomodulatory and antiviral functions.IFN-induced necroptosis has been reported in cells deficient in receptor-interacting protein kinase 1(RIPK1),Fas-associated protein w...Interferons(IFNs)play an important role in immunomodulatory and antiviral functions.IFN-induced necroptosis has been reported in cells deficient in receptor-interacting protein kinase 1(RIPK1),Fas-associated protein with death domain(FADD),or caspase-8,but the mechanism is largely unknown.Here,we report that the DNA-dependent activator of IFN regulatory factors(ZBP1,also known as DAI)is required for both type Ⅰ(β)and type Ⅱ(γ)IFN-induced necroptosis.We show that L929 fibroblast cells became susceptible to IFN-induced necroptosis when RIPK1,FADD,or Caspase-8 was genetically deleted,confirming the antinecroptotic role of these proteins in IFN signaling.We found that the pronecroptotic signal from IFN stimulation depends on new protein synthesis and identified ZBP1,an IFN-stimulated gene(ISG)product,as the de novo synthesized protein that triggers necroptosis in IFN-stimulated cells.The N-terminal domain(ND)of ZBP1 is important for ZBP1–ZBP1 homointeraction,and its RHIM domain in the C-terminal region interacts with RIPK3 to initiate RIPK3-dependent necroptosis.The antinecroptotic function of RIPK1,FADD,and caspase-8 in IFN-treated cells is most likely executed by caspase-8-mediated cleavage of RIPK3,since the inhibitory effect on necroptosis was eliminated when the caspase-8 cleavage site in RIPK3 was mutated.ZBP1-mediated necroptosis in IFN-treated cells is likely physiologically relevant,as ZBP1 KO mice were significantly protected against acute systemic inflammatory response syndrome(SIRS)induced by TNF+IFN-γ.展开更多
Chemotherapy is one of the major approaches for the treatment of metastatic lung cancer.However,systemic chemotherapy is limited by poor therapeutic efficiency and severe toxic side effects,due to the extremely low de...Chemotherapy is one of the major approaches for the treatment of metastatic lung cancer.However,systemic chemotherapy is limited by poor therapeutic efficiency and severe toxic side effects,due to the extremely low delivery efficacy and non-specificity of anticancer drugs.Herein,we report a sericin microparticles enveloped with metal-organic networks as a pulmonary delivery system for treating lung metastasis of breast cancer in an animal model.The sericin microparticles(SMPs)were prepared using water in oil(w/o)emulsification method.After doxorubicin(DOX)loading,tannic acid(TA)/ferric irons(Fe3+)based metal organic networks(MON)were coated on the particles to obtain DOX-loaded microparticles(DOX@SMPs-MON).The SMPs-MON with good biocompatibility could effectively encapsulate DOX and sustainably unload cargos in a pH-dependent manner.The DOX-loaded microparticles could be uptaken by 4T1 cells,and effectively kill the cancer cells.In vivo,DOX@SMPs-MON was deposited in the lungs and remained for over 5 days after pulmonary administration.In contrast to conventional DOX treatment that did not show significantly inhibitory effects on lung metastatic tumor,DOX@SMPs-MON markedly decreased the number and size of metastatic nodules in lungs,and the lung weight and appearance were similar to those of healthy mice.In summary,the sericin microparticles with MON wrapping might be a promising pulmonary delivery system for treating lung metastatic cancer.展开更多
文摘目的:伴有肠母细胞分化的胃癌(gastric cancer with enteroblastic differentiation,GCED)是一种新的胃癌类型。该肿瘤表达胚胎干细胞标志物为SALL4以及癌胚蛋白(AFP和GPC3)等。本研究旨在探讨GCED的临床病理学特征及其分子表型。方法:回顾性分析2013年3月至2017年3月浙江大学医学院附属第一医院就诊的胃部肠型腺癌337例,其中8例可诊断为GCED,患者均为老年人,其中男性6例,女性2例,年龄68～83岁,平均年龄为76.6岁。2例治疗前血清AFP≥200μg/L。收集相关临床资料,根据其组织病理学形态,采用免疫组织化学法分析免疫学表型,应用逆转录PCR(RT-PCR)方法检测SALL4基因。结果:显微镜下观察,所有病例均具有原始的肠样结构,由立方或柱状细胞组成,胞质透明、清晰,免疫组织化学法检测显示AFP和GPC3阳性,或SALL4阳性。RT-PCR检测结果显示SALL4基因mRNA的表达水平显著增高。随访1～5年,其中5例出现肝及其他脏器转移,2例死亡,1例无瘤生存。结论:GCED是一种罕见的侵袭性肠型腺癌,预后比普通肠型腺癌差,按照普通肠型腺癌的治疗方法效果甚微。其组织学上具有特征性的改变,熟悉其瘤谱及基因学特征有助于鉴别和诊断,有助于对原始标记物,制定如SALL4的靶向治疗方案。
基金supported by the National Natural Science Foundation of China(81788101)the National Basic Research Program of China(973 Program 2015CB553800)+3 种基金the National Natural Science Foundation of China(31420103910,81630042,31500737,and 31601122)the China Postdoctoral Science Foundation(2018T110638,2017 M620267,and 2015T80680)the 111 Project(B12001)the National Science Foundation of China for Fostering Talents in Basic Research(J1310027).
文摘Interferons(IFNs)play an important role in immunomodulatory and antiviral functions.IFN-induced necroptosis has been reported in cells deficient in receptor-interacting protein kinase 1(RIPK1),Fas-associated protein with death domain(FADD),or caspase-8,but the mechanism is largely unknown.Here,we report that the DNA-dependent activator of IFN regulatory factors(ZBP1,also known as DAI)is required for both type Ⅰ(β)and type Ⅱ(γ)IFN-induced necroptosis.We show that L929 fibroblast cells became susceptible to IFN-induced necroptosis when RIPK1,FADD,or Caspase-8 was genetically deleted,confirming the antinecroptotic role of these proteins in IFN signaling.We found that the pronecroptotic signal from IFN stimulation depends on new protein synthesis and identified ZBP1,an IFN-stimulated gene(ISG)product,as the de novo synthesized protein that triggers necroptosis in IFN-stimulated cells.The N-terminal domain(ND)of ZBP1 is important for ZBP1–ZBP1 homointeraction,and its RHIM domain in the C-terminal region interacts with RIPK3 to initiate RIPK3-dependent necroptosis.The antinecroptotic function of RIPK1,FADD,and caspase-8 in IFN-treated cells is most likely executed by caspase-8-mediated cleavage of RIPK3,since the inhibitory effect on necroptosis was eliminated when the caspase-8 cleavage site in RIPK3 was mutated.ZBP1-mediated necroptosis in IFN-treated cells is likely physiologically relevant,as ZBP1 KO mice were significantly protected against acute systemic inflammatory response syndrome(SIRS)induced by TNF+IFN-γ.
基金the National Natural Science Foundation of China(81773104,81773263,81873931,81974382 and 21708008)the Natural Science Foundation Program of Hubei Province(2017CFB652 and 2018CFB474)+2 种基金the Fundamental Research Funds for the Central Universities(2017KFYXJJ241)the Integrated Innovative Team for Major Human Diseases Program of Tongji Medical College of HUST,and Health Commission of Hubei Province scientific research project(WJ2019M155)the Graduates'Innovation Fund of Huazhong University of Science and Technology(2019ygscxcy069).
文摘Chemotherapy is one of the major approaches for the treatment of metastatic lung cancer.However,systemic chemotherapy is limited by poor therapeutic efficiency and severe toxic side effects,due to the extremely low delivery efficacy and non-specificity of anticancer drugs.Herein,we report a sericin microparticles enveloped with metal-organic networks as a pulmonary delivery system for treating lung metastasis of breast cancer in an animal model.The sericin microparticles(SMPs)were prepared using water in oil(w/o)emulsification method.After doxorubicin(DOX)loading,tannic acid(TA)/ferric irons(Fe3+)based metal organic networks(MON)were coated on the particles to obtain DOX-loaded microparticles(DOX@SMPs-MON).The SMPs-MON with good biocompatibility could effectively encapsulate DOX and sustainably unload cargos in a pH-dependent manner.The DOX-loaded microparticles could be uptaken by 4T1 cells,and effectively kill the cancer cells.In vivo,DOX@SMPs-MON was deposited in the lungs and remained for over 5 days after pulmonary administration.In contrast to conventional DOX treatment that did not show significantly inhibitory effects on lung metastatic tumor,DOX@SMPs-MON markedly decreased the number and size of metastatic nodules in lungs,and the lung weight and appearance were similar to those of healthy mice.In summary,the sericin microparticles with MON wrapping might be a promising pulmonary delivery system for treating lung metastatic cancer.
