蛋白质酪氨酸激酶

摘要： 非小细胞肺癌(NSCLC)是世界上最常见的恶性肿瘤之一,已成为我国城市人口恶性肿瘤死亡原因的第一位.厄洛替尼是一种小分子选择性表皮生长因子受体酪氨酸激酶抑制剂.临床用于一线化疗失败的局部晚期或转移的非小细胞肺癌(NSCLC)的三线治疗.本文对厄洛替尼的药物制备、细胞活性、药理作用、药剂学性质以及临床研究等做一综述.%Non-small cell lung cancer (NSCLC) is one of the most common malignant tumors in the world, and has become the first cause of the death of the malignant tumor in urban China. Erlotini is a small molecule selective epidermal growth factor receptor tyrosine kinase inhibitor. It is usually clinical used of third-line treatment of non-small cell lung cancer (NSCLC) and applied for the failure of first-line chemotherapy. This paper made a roundup of the preparation, cell activity, pharmacologic action, pharmacological properties and clinical studies of erlotinib hydrochloride tablets.

摘要： 非小细胞肺癌（NSCLC）是世界上最常见的恶性肿瘤之一,已成为我国城市人口恶性肿瘤死亡原因的第一位。厄洛替尼是一种小分子选择性表皮生长因子受体酪氨酸激酶抑制剂。临床用于一线化疗失败的局部晚期或转移的非小细胞肺癌（NSCLC）的三线治疗。本文对厄洛替尼的药物制备、细胞活性、药理作用、药剂学性质以及临床研究等做一综述。

摘要： Thyroid cancer is the most common endocrine malignancy,and ninety percent is differentiated thyroid cancer.Surgery,radioactive iodine treatment,TSH suppressive therapy is one of the trilogies of differentiated thyroid cancer treatment.Although the diagnosis and treatment of differentiated thyroid cancer is very mature,there are some patients cannot benefit from the radioactive iodine treatment naming RAI-refractory DTC.For these patients showing dedifferentiated and a lower level of iodine uptake now use targeted drugs achieving curative effect.The studies of molecular pathology of thyroid provide a theoretical basis for the diagnosis and treatment of thyroid cancer.This review comprehensively discussing the progress of molecular targeted therapy about refractory thyroid cancer.%甲状腺癌是内分泌系统最常见的恶性肿瘤,其中90％为分化型甲状腺癌.外科手术、放射性碘治疗、TSH抑制是目前分化型甲状腺癌治疗的三步曲.虽然目前对分化型甲状腺癌的诊断和治疗手段非常成熟,但是仍有少量患者因病灶出现失分化摄碘能力下降,而无法获益于传统的131I治疗,称为碘难治性分化型甲状腺癌,对于这类患者使用分子靶向药物治疗是甲状腺癌治疗上的进步.甲状腺癌分子病理学的研究,为分子诊断和靶向治疗提供了可靠的理论基础.笔者就目前对于碘难治性分化型甲状腺癌的分子靶向治疗进展进行综述.

摘要： 目的 研究异丙酚对大鼠内毒素脑损伤中蛋白质酪氨酸激酶2(JAK2)和高迁移率族蛋白B1(HMGB1)表达的影响,探讨异丙酚在脑损伤中的保护作用及其机制.方法 SD大鼠72只,体质量220 ～ 250 g,随机分为3组(n=24):内毒素组(L组)和内毒素+异丙酚组(LP组)经颈内动脉注射内毒素200μg复制大鼠内毒素脑损伤模型,对照组(C组)经颈内动脉注射等量生理盐水,LP组颈内动脉注射内毒素后即予异丙酚100mg/kg剂量腹腔注射.3组分别于6、12、24和48h随机处死6只大鼠,取额叶皮质,检测脑组织含水量,免疫组织化学检测P-JAK2、HMGB1和核转录因子κB(NF-κB)表达水平的变化,免疫印迹(Western blot)检测大鼠内毒素脑损伤后P-JAK2蛋白表达水平的变化.结果 与C组相比,L组、LP组各时间点脑组织含水量、P-JAK2、HMGB1和NF-κB表达增加(P＜0.05);与L组比较,LP组各时间点脑含水量、P-JAK2、HMGB1和NF-κB表达明显减少(P＜o.05).结论 异丙酚可减轻大鼠内毒素性脑损伤,机制可能与抑制脑组织磷酸化JAK2、HMGB1和NF-κB表达水平上调,进而减轻炎症反应有关.

摘要： Objective To explore the possible role of proline-rich tyrosine kinase (Pyk2) in the pathogenesis of systemic lupus erythematosus (SLE).Methods The expression of Pyk2 in the peripheral blood mononuclear cells (PBMCs) of 50 patients with SLE and 36 healthy controls were tested with RT-PCR assay.The activation of Pyk2 was inhibited using specific inhibitor Pyk2 (TyrA9).Semi-quantitative PCR methodwas used to detect the Blys expression of PBMCs.One-way ANOVA and Pearson's correlation analysis were used for statistical analysis.Results The Pyk2 expression level (28.31 ±0.91) of SLE patients was significantly higher than that in healthy controls (33.69±0.04),the difference was statistically significant (P＜0.05).The activation of Pyk2 was stimulated and the expression levels of Blys in the PBMCs of patients with SLE was elevated.By inhibiting the activation of Pyk2,the BLyS expression levels decreased significantly.Conclusion Pyk2 may be involved in the abnormal activation of lymphocytes which lead to the pathogenesis of SLE.Pyk2 expression is associated with SLE disease activity,disease aggravation,and the Pyk2 expression levels is also increased significantly.In addition,the expression level of Pyk2 is higher in patients with renal involvement than those patients with other organ involvement.%目的 探讨富含脯氨酸的酪氨酸激酶2(Pyk2)在系统性红斑狼疮(SLE)发病过程中可能的作用机制.方法 采用反转录-聚合酶链反应(RT-PCR)法检测50例SLE患者和36名健康对照组成员外周血单个核细胞(PBMCs)中Pyk2的表达水平.用Pyk2特异性的抑制剂(TyrA9)抑制Pyk2的活化后,半定量PCR方法检测PBMCs中Blys的表达情况.采用单因素方差分析和Pearson相关分析进行统计学分析.结果 SLE患者Pyk2的表达水平(28.31±0.91)显著高于健康对照组(33.69±0.04),差异有统计学意义(P＜0.05)；促进Pyk2的活化后,SLE患者PBMCs中Blys的表达水平增高；而抑制Pyk2的活化后,Blys的表达水平明显下降.结论 Pyk2可能通过参与淋巴细胞的异常活化而导致SLE的发病.Pyk2的表达与SLE的疾病活动性相关,随着SLE病情的加重,Pyk2的表达水平亦明显增加.此外,合并有肾脏受累的患者Pyk2的表达水平明显高于其他脏器受累者.

摘要： 目的 研究在病毒性心肌炎小鼠模型上敲减Itk蛋白的表达对小鼠炎症反应的影响.方法 BALB/c小鼠尾静脉注射表达Itk-shRNA的质粒后感染CVB3,第4天后观察Itk基因的抑制情况、小鼠存活率,PBMC增殖率及部分炎症性细胞因子的分泌水平.结果 Itk-shRNA转染至小鼠体内后脾细胞中Itk基因的mRNA水平与空白对照组及转染shRNAnon的对照组相比,敲减率约40％(P＜0.05).与转染shRNAnon组相比,Itk-shRNA组中Itk基因表达的抑制导致小鼠PBMC增殖活性降低约41％,小鼠的存活率提高(P＜0.05).Itk-shRNA组血清中细胞因子水平降低.结论 抑制Itk表达能有效降低小鼠PBMC的增殖,同时减少炎症相关细胞因子的分泌,提高小鼠的存活率.%Objective To study the effect of Itk down regulation on PBMC cell proliferation and inflammatory cytokines production in a Coxsackievirus-induced myocarditis model.Methods BALB/c mice were injected via caudal vein with plasmid Itk-shRNA then infected with CVB3.The change of Itk protein expression,cell proliferation,cytokines production and mice survival rate of mice were observed in the fourth days after infected.Results Itk mRNA in groups of mice transfected with Itk-shRNA was reduced about 40％ in spleen cells,compared with that in control groups or shRNAnon groups (P＜0.05).PBMC proliferation and serum cytokines were significantly inhibited by transfected with Itk-shRNA.Conclusion Knocking down Itk expression can inhibit mice inflammatory reaction.

摘要： 目的 观察高糖对小鼠足细胞表型转化的诱导作用,并探讨其机制.方法 将传代培养后的小鼠足细胞随机分为A、B、C三组,A组常规培养,B组加入终浓度为30 mmol/L的葡萄糖、C组加入终浓度为30 mmol/L的葡萄糖及10 μmol/L的蛋白质酪氨酸激酶(JAK2)特异性阻断剂α-氰-(3,4-二羟基)-N-苄基肉桂酰胺(AG490)进行培养,48 h后收集细胞,采用Western blot法检测足细胞中自身标志物人肾病蛋白(Nephrin)、间充质细胞标志物α-平滑肌肌动蛋白(α-SMA)及磷酸化蛋白质酪氨酸激酶(p-JAK2)蛋白,采用RT-PCR检测足细胞中的Nephrin、α-SMA mRNA.结果 A组足细胞中Nephrin、α-SMA、p-JAK2蛋白积分光密度值分别为0.96 ±0.01、0.21 ±0.02、0.39±0.01,B组分别为0.58 ±0.01、0.66 ±0.07、0.71 ±0.02,C组分别为0.87±0.04、0.35 ±0.02、0.41±0.04;A组足细胞中Nephrin、α-SMA mRNA的相对表达量为1.53 ±0.04、0.57 ±0.01,B组分别为0.82 ±0.09、0.89±0.03,C组分别为1.30 ±0.04、0.78 ±0.03.B组与A组比较,P均＜0.05；C组与B组比较,P均＜0.05.结论 高糖可通过激活JAK/STAT信号途径诱导足细胞发生表型转化.%Objective To investigate the mechanism of high glucose-induced epithelial-mesenchymal transition in podocytes. Methods Cultured mouse podocytes were divided into three groups; group A ( cells cultured conventionally) , group B (cells cultured in 30 mmol/L glucose condition) and group C (3 cells cultured in 30 mmol/L glucose and 10 μmol/L AG490 conditions). Cells were collected after cultured 48 h. Western blotting analysis was used to determine the expression of nephrin, α-SMA and p-JAK2. RT-PCR analysis was used to detect the nephrin and α-SMA mRNA. Results The relative absorbance values of nephrin,α-SMA and p-JAK2 were 0.96 ±0.01 ,0.21 ±0.02,0.39 ±0.01 in group A, 0.58 ±0.01,0.66 ±0.07,0.71 ±0.02 in group B, 0.87 ±0.04,0.35 ±0.02,0.41 ±0.04 in group C. The relative absorbance values of nephrin,α-SMA mRNA were 1. 53 ± 0. 04,0. 57 ± 0. 01 in group A ,0. 82 ± 0. 09 ,0. 89 ± 0. 03 in group B,l. 30 ±0.04,0. 78 ±0.03 in group C. Compared with group B, these values in group A and C showed significant difference (all P<0. 05). Conclusion High glucose can induce the epithelial-mesenchymal transition in podocytes by activation of the JAK/STAT pathway.

摘要： 目的 明确常规树突状细胞(cDCs)靶向性的FMS样酪氨酸激酶3(FLT3)信号通路对急性肺损伤(ALI)早期炎症反应及肺损伤的调控效应及可能机制.方法 C57BL/6小鼠随机分为正常对照组、ALI组、FLT3-配体(ligand)( FLT3L)预处理组、来他替尼预处理组和二甲基亚砜(DMSO)对照组,分别给予FLT3L、来他替尼预处理5d后复制ALI模型,24 h后处死小鼠留取肺组织,采用流式细胞术检测评价肺cDCs的数量和成熟程度;比色法检测髓过氧化物酶(MPO)活性反映中性粒细胞浸润;多聚酶链反应(PCR)检测转录因子T-bet/GATA-3 mRNA比值反映Th1/Th2免疫反应平衡;计算肺湿重/体重比评价肺水肿程度;肺组织HE染色行组织病理学检查和肺损伤评分反映肺损伤程度.结果 与正常对照组相比,ALI组小鼠肺cDCs的数量[(1.71％±0.35％)比(0.68％±0.15％)]及其MHC Ⅱ表达[(21.5％±4.5％)比(6.7％±2.8％)]和CD80表达[(31.2％±5.3％)比(7.3％±1.7％)]均显著增高(均P＜0.05).与ALI组相比,FLT3L预处理进一步增加肺cDCs的数量[(2.81％±0.42％)比(1.71％±0.35％),P ＜0.05]及其MHC Ⅱ表达[(40.8％±6.7％)比(21.5％±4.5％),P＜0.05]和CD80表达[(59.9％±8.1％)比(31.2％±5.3％),P＜0.05],并上调肺组织MPO活性[(7.2±0.4) U/g比(5.3±0.6)U/g]及T-bet/GATA-3 mRNA比值(％)[(600±222)比(220±48)],加重肺水肿和肺损伤.与DMSO对照组相比,来他替尼预处理显著减少肺cDCs的数量[(0.90％±0.28％)比(1.65％±0.44％),P＜0.05]及其MHC Ⅱ表达[(23.1％±3.1％)比(35.6％±6.2％),P ＜0.05]和CD80表达[(22.9％±5.4％)比(43.3％±7.8％),P＜0.05],并下调肺组织MPO活性[(4.3±0.3) U/g比(6.5±0.5)U/g]及T-bet/GATA-3 mRNA比值[(190％±33％)比(400％±72％)],减轻肺水肿和肺损伤.结论 FLT3信号通路能有效调控肺cDCs的数量和成熟程度,通过拮抗FLT3信号通路可显著抑制ALI早期肺cDCs的聚集和分化成熟,进而减轻肺部炎症反应和肺损伤.%Objective To explore the effects of FLT3 signaling on the accumulation and maturation of pulmonary conventional dendritic cells (cDCs) and determine whether or not the inhibition of FLT3 signaling may attenuate acute lung inflammation/injury (ALI).Methods C57BL/6 mice were pretreated separately with FLT3-ligand (FLT3L) and lestaurtinib for 5 days.Murine model of ALI was subsequently induced by an intra-tracheal instillation of lipopolysaccharide (LPS) and lung specimens were harvested 24 hours later.The accumulation and maturation status of pulmonary cDCs were assessed by flow cytometry.Lung myeloperoxidase (MPO) activity was measured to evaluate the infiltration of neutrophils.The ratio between transcription factors T-bet and GATA-3 mRNA was determined to estimate the balance of Th1/Th2 response.Lung injury was estimated by lung wet weight/body weight ratio (LWW/BW) and histopathological assessment.Results LPS challenge resulted in rapid accumulation and maturation of pulmonary cDCs.FLT3L pretreatment further stimulated the accumulation and maturation of pulmonary cDCs,leading to a marked deterioration of LWW/BW and lung histopathological changes.Meanwhile,the lung MPO activity and T-bet/GATA-3 mRNA ratio were boosted by the administration of FLT3L.In contrast,the lestaurtinib pretreatment inhibited the accumulation and maturation of pulmonary cDCs,leading to a significant improvement of LWW/BW and lung histopathological changes.The administration of lestaurtinib also suppressed the lung MPO activity and T-bet/GATA-3 mRNA ratio in the lung.Conclusions FLT3 signaling attenuates ALI by regulating the accumulation and maturation of pulmonary cDCs,indicating a potential pharmacotherapy for ALI.

摘要： Objective To investigate the effect of Syk on the VEGF-C expression in breast cancer.Methods Immunohistochemical EnVision method was used to detect the protein expression of Syk,NFκBand VEGF-C in breast carcinoma; and the relationship between protein expression of Syk,NFκB,VEGF-C and lymph node metastasis was analysed.MDA-MB-231 cells were transfected with pcDNA3.1 ( - )-Syk,and the effect of Syk gene on the VEGF-C and NFκB expression was determined.Results In the lymph node metastatic group,a lower expression rate of Syk and higher expression rate of VEGF-C and NFκB were detected as compared to the non-metastatic group.The expression of Syk was negatively associated with NFκB (r=-0.448,P=0.002) and VEGF-C (r=-0.620,P=0.000) expression,and VEGF-C was associated with the nuclear expression of NFκB ( r =0.310,P =0.036).Compared with the non-transfected cells,the pcDNA3.1 ( -)-Syk transfected MDA-MB-231 cells showed significantly lower transcriptional level of VEGF-C mRNA,expression level of VEGF-C protein and NFκB activity ( P ＜ 0.05 ).Conclusions Syk may play an important role in the lymph node metastasis of breast cancer.It may down-regulate the expression of VEGF-C by inhibiting the activity of NFκB,which thus suppresses lymph node metastasis of breast cancer.%目的 研究Syk基因对乳腺癌血管内皮生长因子(VEGF)-C表达的调控机制.方法 采用免疫组织化学(EnVision法)检测乳腺癌组织中Syk、NFκB与VEGF-C的蛋白表达情况,分析三者的相关性及与淋巴转移的关系.转染pcDNA3.1(-)-Syk至乳腺癌MDA-MB-231细胞,检测对VEGF-C和NFκB表达的影响.结果 在淋巴转移组中,Syk蛋白阳性率低于非淋巴转移组,VEGF-C与NFκB阳性率在淋巴转移组高于非淋巴转移组.Syk蛋白表达与NFκB(r=-0.448,P=0.002)、VEGF-C(r=-0.620,P=0.000)蛋白表达呈负相关,VEGF-C与NFκB呈正相关(r =0.310,P=0.036).转染pcDNA3.1(-)-Syk重组质粒的乳腺癌细胞中VEGF-C的mRNA及蛋白表达水平均低于空白对照组,细胞核NFκB蛋白表达低于空白对照组(均P＜0.05).结论 Syk基因与乳腺癌转移相关,可能是通过抑制NFκB的活性而下调VEGF-C的表达,从而抑制乳腺癌的淋巴转移.

摘要： Objective To analyze the clinical and laboratory characteristics of hematological diseases associated with eosinophilia. Methods Karyotype analysis was performed by direct method and/or short-time culture of bone marrow cells for R-banding. Fluorescence in situ hybridization ( FISH ) was performed using PDGFRα, PDGFRβ and FGFR1 break-apart probes. Results The clinical and hematological findings of 44 patients were diagnosed as hematological diseases associated with eosinophilia. Abnormal karyotypes were detected in 6 cases ( 13.64% ) with karyotyping. The efficiency of the detection of abnormal clone was markedly increased to 29. 55% ( 13/44 ) with FISH techniques, including 7 cases with FIP1 L1-PDGFRα ( F/P,15.91% ), 3(6. 82% ) PDGFRα rearrangement, 2 (4. 55% ) aberrant PDGFRβ gene and 1 (2. 27% )FGFR1 rearrangement. Patients being PDGFRα, PDGFRβ or FGFR1 positive ( 13 cases) or negative (31 cases) showed predominant difference in clinical and laboratory features. The incidence of gut involvement, the absolute count of eosinophils in peripheral blood and the percentage of immature eosinophils in bone marrow were significantly increased in positive patients (P ＜ 0.05 ). Conclusions The hematological diseases associated with eosinophilia are characterized by unique clinical and laboratory features. Karyotyping should be a routine approach to detect the abnormal clone in these diseases. Screening for PDGFRα, PDGFRβ and FGFR1 gene with FISH can provide more genetic information.%目的 探讨伴有嗜酸粒细胞增多的血液病患者的临床和分子、细胞遗传学特征.方法 对44例伴有嗜酸粒细胞增多血液病患者的骨髓标本,经直接法和24 h短期培养后按常规方法制备染色体,采用R显带技术进行细胞遗传学分析;分别应用PDGFRα、PDGFRβ、FGFR1基因探针,进行荧光原位杂交(FISH)检测.结果 44例患者骨髓细胞经常规染色体核型分析,异常核型检出率为13.64%(44例中6例),而应用FISH技术分析,异常克隆检出率为29.55%(44例中13例),其中7例(15.91%)伴有FIP1L1-PDGFRα(简称F/P)融合基因,3例(6.82%)PDGFRα基因重排,2例(4.55%)PDGFRβ基因异常,1例(2.27%)FGFR1基因重排.将患者分为PDGFRα、PDGFRβ或FGFR1基因重排阳性(13例)与阴性(31例)组,阳性组患者的皮肤、心血管、脾脏、肺脏等器官受累程度以及WBC、PLT、HGB等血液学指标与阴性组患者无明显差异;与阴性组比较,阳性组患者胃肠道症状表现较为突出,且绝大多数患者外周血白细胞分类可见嗜酸粒细胞重度增高(绝对值＞5×109/L)以及骨髓中出现幼稚嗜酸粒细胞(P值均＜0.05).结论 伴有嗜酸粒细胞增多的血液病患者具有独特的临床和血液学特征.染色体核型分析与FISH方法结合具有较高的异常克隆(特别是PDGFRα基因异常)检出率,有助于鉴别疾病的良、恶性本质,判断预后及选择合理的治疗方案.

摘要： 蛋白质的磷酸化作用是细胞信号传导的初始步骤，也是最关键的步骤之一，从基础代谢到细胞生长、分化和变异的每一细胞过程都和磷酸化作用密切相关，它几乎调节着生命活动的所有过程。

摘要： 本发明涉及调节激酶级联的一个或多个组分的化合物和方法。本发明还涉及基本纯的化合物1和基本纯的化合物1盐(例如化合物1盐酸盐和化合物1苯磺酸盐)。本发明还涉及制备基本纯的化合物1和化合物1盐的方法。

摘要： 本发明提供以高亲和力特异性结合PTK7的分离的单克隆抗体，特别是人单克隆抗体。还提供了编码本发明的抗体的核酸分子、表达载体、宿主细胞和表达本发明的抗体的方法。还提供了包含本发明的抗体的免疫偶联物、双特异性分子和药物组合物。本发明还提供了检测PTK7的方法，以及使用抗PTK7抗体治疗包括癌症和感染性疾病在内的各种疾病的方法。

摘要： 本发明提供了式1化合物或其药学上可接受的盐，其中R1，G1，G2，R4，Z，X和n如文中定义，它可用作抗肿瘤剂和用于治疗多囊肾疾病。

摘要： 本发明提供了式1化合物或其药学上可接受的盐，其中R1，G1，G2，R4，Z，X和n如文中定义，它可用作抗肿瘤剂和用于治疗多囊肾疾病。

摘要： 本发明涉及用于选择性治疗以人表皮生长因子受体2型(HER2)的活性为特征的细胞生长和分化的方法。更具体地说，本发明涉及取代的或未取代的单-环或双-环芳基、杂芳基、环烷基或杂环烷基化合物在选择性地调节细胞生长中的用途。本发明也描述了用于选择性治疗细胞生长和分化的药物组合物。

摘要： 本发明涉及调节激酶级联的一个或多个组分的化合物和方法。本发明还涉及基本纯的化合物1和基本纯的化合物1盐(例如化合物1盐酸盐和化合物1苯磺酸盐)。本发明还涉及制备基本纯的化合物1和化合物1盐的方法。

摘要： 本发明涉及调节激酶级联的一个或多个组分的化合物和方法。本发明还涉及基本纯的化合物1和基本纯的化合物1盐(例如化合物1盐酸盐和化合物1苯磺酸盐)。本发明还涉及制备基本纯的化合物1和化合物1盐的方法。

摘要： 本发明提供了结合胰岛素样生长因子－I受体(IGF－IR)的新蛋白质，以及其它重要蛋白质。本发明还提供了药物制剂中的新蛋白质和此类蛋白质的衍生物，及其在诊断、研究和治疗应用中的用途。本发明进一步提供了包含此类蛋白质的细胞、编码此类蛋白质或其片段的多核苷酸、和包含编码该新蛋白质的多核苷酸的载体。

摘要： 本发明提供以高亲和力特异性结合PTK7的分离的单克隆抗体，特别是人单克隆抗体。还提供了编码本发明的抗体的核酸分子、表达载体、宿主细胞和表达本发明的抗体的方法。还提供了包含本发明的抗体的免疫偶联物、双特异性分子和药物组合物。本发明还提供了检测PTK7的方法，以及使用抗PTK7抗体治疗包括癌症和感染性疾病在内的各种疾病的方法。

摘要： 本发明公开了具有人酪氨酸激酶Hck结合活性的新型蛋白质。本发明蛋白质的代表例具有序列号1或12所示的氨基酸序列。本发明还公开了编码这些蛋白质的核酸。本发明的蛋白质具有结合人酪氨酸激酶Hck的性质，并具有促进肿瘤坏死因子刺激产生的细胞凋亡的功能。