Receptor Tyrosine kinases (RTKs) play a crucial role in the signal transduction pathways at cellular levels. RTK plays a vital role in cellular communication and transmission of signals to the adjacent cells and regul...Receptor Tyrosine kinases (RTKs) play a crucial role in the signal transduction pathways at cellular levels. RTK plays a vital role in cellular communication and transmission of signals to the adjacent cells and regulates different functions of the cell, such as cellular growth, differentiation, metabolism and motility. RTK s triggers growth factor receptors such as epidermal growth factor, insulin growth factor-1 receptor, platelet derived growth factor receptor, and fibro blast growth factor receptor and vascular endothelial growth factor receptor, thereby initiating and regulating cell growth and proliferation. MAPK/RAS and PI3/AKT pathways are the major pathways of RTK’s function. Dysregulation of these RTK’s and pathways often leads to many diseases such as Noonan Syndrome, Logius Syndrome, CFC syndrome and different types of cancer. Point mutation and over expression of receptors and mutations in Ras leads to 30% of human cancers. Also over expression of different growth factor receptors by RTK too lead to several types of cancers as Glioblastoma, Thyroid cancer, Colon cancer and Non-small cell lung cancer. PTEN mutation in PI3/AKT pathway often leads to carcinoma relative to Thyroid, Skin, Large intestine, eye and Bone. Therefore, these RTK’s often used as targets for cancer therapies. The medical sector uses various types of small molecule tyrosine kinase inhibitors such as ATP competitive inhibitors, Allosteric inhibitors and covalent inhibitors which are known as Afatinib, Crizotinib, Eroltinib, Icotinib, Lepatinib and Lenvatinib in treatment and management of differential carcinomas.展开更多
BACKGROUND Therapy-related acute promyelocytic leukemia(t-APL)is a rare complication observed in solitary bone plasmacytoma(SBP),and SBP after radiotherapy evolving to APL harboring the FMS-like tyrosine kinase 3-inte...BACKGROUND Therapy-related acute promyelocytic leukemia(t-APL)is a rare complication observed in solitary bone plasmacytoma(SBP),and SBP after radiotherapy evolving to APL harboring the FMS-like tyrosine kinase 3-internal tandem duplication(FLT3-ITD)mutation has never been reported.Here,we present the first case reported until now.CASE SUMMARY We describe a 64-year-old woman who presented with lumbar pain and was initially diagnosed with SBP.However,after one year of radiotherapy treatment,this patient experienced a long-standing bone-marrow-suppressive period and finally developed APL harboring the FLT3-ITD mutation,as confirmed by analyses of clinical features,bone marrow morphology,flow cytometry,cytogenetic examination,and molecular biology.On admission,the patient had disseminated intravascular coagulation and intracranial hemorrhage,and the peripheral blood and bone marrow smear displayed abundant abnormal promyelocytes.Unfortunately,she died when the definite diagnosis was made.CONCLUSION The patient with t-APL harboring FLT3-ITD mutation evolving from SBP after radiotherapy had not been reported and had poor clinical outcomes.FLT3-ITD mutation in t-APL may be a potential pathogenesis of leukemogenesis.We should consider the potential risk of secondary neoplasms in SBP patients after radiotherapy.展开更多
Although VEGFR-3 deficiency disrupts blood vascular development during early embryogenesis, the underlying mechanism was not clear. To characterize its function in angiogenesis and lymphangiogenesis, we employed two g...Although VEGFR-3 deficiency disrupts blood vascular development during early embryogenesis, the underlying mechanism was not clear. To characterize its function in angiogenesis and lymphangiogenesis, we employed two genetically modified mouse models in this study, targeting the coding region for the ligand-binding domain （Vegfr△LBD） or the tyrosine kinase domain with an inactivation point mutation （Vegfr3^TKmat）. We show that lymphatic growth was disrupted in Vegfr3△LBD/△LBD and Vegfr3^TKmut3^TKmat mice, but blood vessels developed normally in both embryo and yolk sac. Interestingly, in Vegfr3△LBD/△LBD but not Vegfr3^TKmut3^TKmat mice, lymph sac was present but there was lack of iym- phangiogenic sprouting. We further demonstrate that both the wild-type and mutant forms of VEGFR-3 could form heterodimers with VEGFR-2, and decreased the level of phospho-VEGFR-2 and the downstream phospho-Erk1/2 in endothelial cells when they were treated with VEGF-A. These findings indicate that signaling mediated via VEGFR-3 activation by its cognate ligands （VEGF-C/-D） is not required for angiogenesis, and that VEGFR-3 may play a role in this process by modulating VEGFR-2-mediated signals.展开更多
目的:探讨鸢尾素调节Janus蛋白酪氨酸激酶2(Janus protein tyrosine kinase 2,JAK2)/信号转导和转录激活子3(Signal transduction and activator of transcription 3,STAT3)信号通路对牙周炎大鼠牙周组织损伤的影响。方法:通过结扎和接...目的:探讨鸢尾素调节Janus蛋白酪氨酸激酶2(Janus protein tyrosine kinase 2,JAK2)/信号转导和转录激活子3(Signal transduction and activator of transcription 3,STAT3)信号通路对牙周炎大鼠牙周组织损伤的影响。方法:通过结扎和接种牙龈卟啉单胞菌液建立牙周炎大鼠模型,将大鼠随机分为模型组、鸢尾素低(鸢尾素-L,50 mg/kg)、中(鸢尾素-M,100 mg/kg)、高剂量(鸢尾素-H,200 mg/kg)组、鸢尾素-H+激活剂(200 mg/kg鸢尾素+2 mg/kg香豆霉素)组,每组10只,并以注射等体积生理盐水的正常大鼠对照组。干预结束后,对大鼠牙龈出血指数、牙齿松动度评分;牙槽骨吸收、肿瘤坏死因子-α(Tumor necrosis factor-α,TNF-α)、白细胞介素(Interleukin,IL)-6、IL-1β以及丙二醛(Malondialdehyde,MDA)、超氧化物歧化酶(Superoxide dismutase,SOD)水平分别以Micro-CT试剂盒检测;HE检测牙周组织病理学变化;Western blot检测JAK2、STAT3、p-JAK2、p-STAT3蛋白表达。结果:与对照组相比,模型组大鼠牙周组织被破坏,炎性浸润严重,牙龈出血指数、牙齿松动度评分、牙槽骨吸收、TNF-α、IL-6、IL-1β、MDA水平、p-JAK2/JAK2、p-STAT3/STAT3表达显著增加,SOD水平显著降低(P<0.05);与模型组相比,不同剂量的鸢尾素组大鼠病理损伤得到改善,牙龈出血指数、牙齿松动度评分、牙槽骨吸收、TNF-α、IL-6、IL-1β、MDA水平、p-JAK2/JAK2、p-STAT3/STAT3表达显著降低,SOD水平显著增加,具有剂量依赖性(P<0.05);与鸢尾素-H组相比,鸢尾素-H组+激活剂组大鼠病理损伤加重,大鼠牙龈出血指数、牙齿松动度评分、牙槽骨吸收、TNF-α、IL-6、IL-1β、MDA水平、p-JAK2/JAK2、p-STAT3/STAT3表达显著增加,SOD水平显著降低(P<0.05)。结论:鸢尾素抑制牙周炎大鼠氧化应激、炎性反应,减轻大鼠牙周组织损伤,减少牙槽骨吸收,可能与抑制JAK2/STAT3信号通路有关。展开更多
文摘Receptor Tyrosine kinases (RTKs) play a crucial role in the signal transduction pathways at cellular levels. RTK plays a vital role in cellular communication and transmission of signals to the adjacent cells and regulates different functions of the cell, such as cellular growth, differentiation, metabolism and motility. RTK s triggers growth factor receptors such as epidermal growth factor, insulin growth factor-1 receptor, platelet derived growth factor receptor, and fibro blast growth factor receptor and vascular endothelial growth factor receptor, thereby initiating and regulating cell growth and proliferation. MAPK/RAS and PI3/AKT pathways are the major pathways of RTK’s function. Dysregulation of these RTK’s and pathways often leads to many diseases such as Noonan Syndrome, Logius Syndrome, CFC syndrome and different types of cancer. Point mutation and over expression of receptors and mutations in Ras leads to 30% of human cancers. Also over expression of different growth factor receptors by RTK too lead to several types of cancers as Glioblastoma, Thyroid cancer, Colon cancer and Non-small cell lung cancer. PTEN mutation in PI3/AKT pathway often leads to carcinoma relative to Thyroid, Skin, Large intestine, eye and Bone. Therefore, these RTK’s often used as targets for cancer therapies. The medical sector uses various types of small molecule tyrosine kinase inhibitors such as ATP competitive inhibitors, Allosteric inhibitors and covalent inhibitors which are known as Afatinib, Crizotinib, Eroltinib, Icotinib, Lepatinib and Lenvatinib in treatment and management of differential carcinomas.
基金Natural Science Foundation of Zhejiang Province,No.LY19H290003Zhejiang Provincial Medical and Health Science and Technology Project,No.2020KY196and Foundation of Zhejiang Province Chinese Medicine Science and Technology Planes,No.2017ZB030.
文摘BACKGROUND Therapy-related acute promyelocytic leukemia(t-APL)is a rare complication observed in solitary bone plasmacytoma(SBP),and SBP after radiotherapy evolving to APL harboring the FMS-like tyrosine kinase 3-internal tandem duplication(FLT3-ITD)mutation has never been reported.Here,we present the first case reported until now.CASE SUMMARY We describe a 64-year-old woman who presented with lumbar pain and was initially diagnosed with SBP.However,after one year of radiotherapy treatment,this patient experienced a long-standing bone-marrow-suppressive period and finally developed APL harboring the FLT3-ITD mutation,as confirmed by analyses of clinical features,bone marrow morphology,flow cytometry,cytogenetic examination,and molecular biology.On admission,the patient had disseminated intravascular coagulation and intracranial hemorrhage,and the peripheral blood and bone marrow smear displayed abundant abnormal promyelocytes.Unfortunately,she died when the definite diagnosis was made.CONCLUSION The patient with t-APL harboring FLT3-ITD mutation evolving from SBP after radiotherapy had not been reported and had poor clinical outcomes.FLT3-ITD mutation in t-APL may be a potential pathogenesis of leukemogenesis.We should consider the potential risk of secondary neoplasms in SBP patients after radiotherapy.
基金Acknowledgments We thank Dr Lena Claesson-Welsh （Uppsala University）, and PIs of Model Animal Research Center （MARC, Nanjing University） for the helpful discussion about the work, and Yanlan Cao, Wenting Shi and all the staff in the MARC Animal facility of Nanjing University for excellent technical assistance. This work wasfinancially supported by grants from the National Natural Science Foundation of China （30771069, 30671038, and 30930028）, the Ministry of Science and Technology of China （2006CB943500）, and the Ministry of Education of China （NCET： Program for New Century Excellent Talents in University）.
文摘Although VEGFR-3 deficiency disrupts blood vascular development during early embryogenesis, the underlying mechanism was not clear. To characterize its function in angiogenesis and lymphangiogenesis, we employed two genetically modified mouse models in this study, targeting the coding region for the ligand-binding domain （Vegfr△LBD） or the tyrosine kinase domain with an inactivation point mutation （Vegfr3^TKmat）. We show that lymphatic growth was disrupted in Vegfr3△LBD/△LBD and Vegfr3^TKmut3^TKmat mice, but blood vessels developed normally in both embryo and yolk sac. Interestingly, in Vegfr3△LBD/△LBD but not Vegfr3^TKmut3^TKmat mice, lymph sac was present but there was lack of iym- phangiogenic sprouting. We further demonstrate that both the wild-type and mutant forms of VEGFR-3 could form heterodimers with VEGFR-2, and decreased the level of phospho-VEGFR-2 and the downstream phospho-Erk1/2 in endothelial cells when they were treated with VEGF-A. These findings indicate that signaling mediated via VEGFR-3 activation by its cognate ligands （VEGF-C/-D） is not required for angiogenesis, and that VEGFR-3 may play a role in this process by modulating VEGFR-2-mediated signals.
