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1.
目的 探索Janus Kinase 2V617F基因突变(JAK2V617F)在bcr-abl阴性骨髓增生性疾病(MPD)的发生率和临床意义.方法 基因组DNA从患者骨髓或外周血粒细胞中提取.采用等位基因特异性PCR(AS-PCR)、限制性内切酶消化和PCR产物测序的方法检测JAK2V617F突变.共检测患者110例,其中bcr-abl阴性MPD 41例、bcr-abl阳性慢性粒细胞白血病(CML)25例和急性白血病44例.结果 JAK2V617F阳性结果分别为真性红细胞增多症(PV)11例(91.7%)、原发性血小板增多症(ET)8例(53.3%)、特发性骨髓纤维化(IMF)4例(57.1%),而高嗜酸粒细胞增多症(HES)7例、bcr-abl阳性CML 25例和急性白血病44例[包括急性髓细胞白血病(AML)24例、急性淋巴细胞白血病(ALL)18例、急性混合细胞白血病2例1均未检测到JAK2V617F基因突变.在所有JAK2V617F阳性的标本和10份阴性标本中,AS-PCR和限制性内切酶消化方法的测定结果都可经测序进一步证实.结论 90%以上的PV、50%以上的ET和IMF可检测到JAK2V617F基因突变;JAK2V617F基因突变在PV、ET和IMF的诊断和鉴别诊断中有重要意义,可以作为诊断的分子标志,也可能是治疗的新靶点.  相似文献   

2.
目的:阐述康艾注射液(Kang’ai injection,KAI)治疗肝细胞癌(hepatocellular carcinoma,HCC)的物质基础与分子机制。方法:基于中药系统药理学数据库和分析平台(Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform,TCMSP),根据口服生物利用度(oral bioavailability,OB)≥30%、药物相似性(drug-likeness,DL)≥0.18筛选有效活性成分。GeneCard、OMIN、DrugBank及TTD数据库检索HCC相关靶基因。使用Cytoscape软件构建KAI-关键靶基因-HCC复合目标网络。利用String数据库构建蛋白质-蛋白质相互作用网络(protein-protein interaction,PPI)。对关键靶基因进行基于基因本体论(Gene Ontology,GO)生物功能分析及基因和基因组的京都百科全书(Kyoto Encyclopedia of Genes and Genomes,KEGG)通路富集分析。采用基因表达谱交互分析(gene expression profile interaction analysis,GEPIA)数据库对核心靶基因进行生存曲线分析。最后,对核心靶基因进行有效分子对接验证。结果:共获得52个有效活性成分调控166个关键靶基因。槲皮素、山柰酚及木犀草素是复合目标网络中主要有效活性成分。GO生物功能分析结果表明关键靶基因主要参与调节生物过程,如细胞代谢、凋亡和细胞增殖。KEGG通路富集分析显示的主要信号通路是P13K-Akt信号通路。拓扑分析示MYC、RELA、MAPK14、PPARA、CCND1、FOS、RXRA、MAPK1、AKT1、ESR1、CDKN1A、MR3C1、TP53、RB1、JUN、MAPK8是核心靶基因。RELA、MAPK1及JUN低表达的HCC患者总生存率更高(P<0.05),而ESR1高表达的HCC患者总生存率更低(P<0.05)。RELA、MAPK1、JUN及ESR1核心靶基因与KAI有效活性成分结合能均小于-5.0kcal/mol,KAI有效活性成分与核心靶基因具有较好亲和力。结论:KAI作用于多成分、多途径、多靶点协同干预治疗HCC的物质基础及分子机制,为药物开发和临床应用提供新策略。  相似文献   

3.
 目的 研究慢性髓系白血病(CML)细胞的胞外信号调节激酶(ERK)/丝裂原活化蛋白激酶(MAPK)的表达和法尼基转移酶抑制剂FTI-277抗细胞增生的作用机制。方法 以CML细胞系K562细胞、21例初治CML患者和15例正常供髓者骨髓细胞为研究对象,采用MTT法、AnnexinV-FITC法,观察FTI-277对细胞增生和凋亡的影响;应用流式细胞术、Western blot检测FTI-277对细胞周期、磷酸化ERK1/2(磷酸化P44/42MAPK)和ERK2(P42MAPK)表达的影响。结果 CML细胞与正常细胞相比,磷酸化ERK1/2和ERK2表达明显增高。 FTI-277对CML细胞的增生抑制及磷酸化ERK1/2的表达下调均呈剂量和时间依赖性,但对ERK2表达及正常细胞的增生无明显影响。FTI-277对CML细胞无明显诱导凋亡作用,但可使细胞阻滞于G2/M期时相。结论 CML细胞存在着ERK/MAPK信号途径的过度激活。FTI-277可通过阻断Ras下游ERK/MAPK信号途径、干预细胞周期调控蛋白的表达、使细胞阻滞于G2/M期等机制,抑制CML细胞的恶性增生。  相似文献   

4.
0引言 细胞因子受体-JAK-STAT通路是一条重要的细胞增殖信号转导通路,该通路的激活对促进细胞增殖、抑制细胞凋亡具有重要作用.上述信号通路中血小板生成素受体(MPL),JAK激酶突变的发现为真性红细胞增多症(PV)、原发性血小板增多症(ET)、原发性骨髓纤维化(IMF)等BCR/ABL融合基因阴性的骨髓增殖性疾病(MPD)的分子发病机制研究奠定了基础.研究发现JAK2V617F组成性激活活性需要Ⅰ型细胞因子受体的参与才能发挥作用.细胞冈子受体突变亦可引起某些MPD的发生,如MPLW515L.下面对细胞因子受体-JAK信号转导通路在MPD中的作用作一综述.  相似文献   

5.
目的 研究慢性粒细胞白血病(CML)中JAK2 V617F突变与BCR-ABL210易位的关系及其与临床特征及疗效的关系.方法 对1例新诊断的CML患者行血常规、染色体、融合基因及荧光原位杂交等检查,明确诊断后给予伊马替尼治疗.结果 患者发病时白细胞及血小板数目明显增多,同时存在JAK2 V617F突变与BCR-ABL210易位阳性,伊马替尼治疗1个月后患者达到血液学完全缓解,治疗3个月时达细胞遗传学完全缓解.结论 在典型CML患者中,可同时检测到JAK2 V617F突变与BCR-ABL210易位阳性,临床医师应提高对该现象的认识.  相似文献   

6.
简要回顾了近百余年人们对骨髓增殖性肿瘤(MPN)的认识过程,重点讨论这一类疾病的诊断与治疗.JAK2 V617F基因突变的发现将费城染色体阴性(Ph-)MPN带入分子生物学时代,为临床提供了重要的诊断手段和依据,指导、研发了芦可替尼(ruxolitinib)等一批靶向药物.但是,与慢性粒细胞白血病(CML)中的bcr-abl不同,JAK2 V617F突变不是MPN诊断的“金标准”,其他辅助检查和鉴别诊断仍不可少.目前,JAK抑制剂开始用于Ph-MPN患者,有一定的适应证,远期疗效正在观察,目前还不能替代有效的常规治疗,如羟基脲、阿司匹林等.  相似文献   

7.
李钰伟  于静萍 《癌症进展》2021,19(10):979-983,1057
聚腺苷酸二磷酸核糖转移酶(PARP)是一种广泛参与DNA损伤修复过程的酶.PARP抑制剂能通过抑制肿瘤细胞中PARP功能阻断细胞自身DNA损伤修复,促进肿瘤细胞的凋亡,以发挥抗肿瘤作用.PARP抑制剂单药利用合成致死作用,选择性地杀伤同源重组修复缺陷(尤其乳腺癌易感基因1/2突变)的肿瘤细胞.除此之外,与其他抗肿瘤治疗联合应用,在保证安全性的条件下,PARP抑制剂可以增强破坏肿瘤细胞DNA的抗癌药物(如烷化剂、拓扑异构酶抑制剂和铂类化疗药物)以及放疗的疗效.近年来更是与血管内皮生长因子(VEGF)抑制剂、程序性死亡受体1(PD-1)/程序性死亡受体配体1(PD-L1)抑制剂等一些新型靶向抗癌药进行联合治疗,扩大了临床适用范围.目前,PARP抑制剂奥拉帕利、鲁卡帕利、尼拉帕利和他拉唑帕利已经成功应用于卵巢癌、乳腺癌等一些肿瘤.本文将PARP抑制剂在恶性肿瘤中临床应用进展作一综述.  相似文献   

8.
目的 对国内外聚腺苷酸二磷酸核糖转移酶-1[Poly (ADP-ribose) polymerase-1,PARP1]抑制剂在三阴性乳腺癌中的应用现状进行综述分析.方法 应用PubMed及CNKI期刊全文数据库检索系统,以“聚腺苷酸二磷酸核糖转移酶-1、PARP1抑制剂、三阴性乳腺癌”等为关键词,检索2009-01-2014-02相关文献,共检索到英文文献322条,中文文献201条.纳入标准:1)PARP1分子的生物学功能;2)PARP1抑制剂在BRCA突变相关乳腺癌以及三阴性乳腺癌方面的基础与临床研究;剔除标准:1)PARP1抑制剂的药理学特性;2)PARP1与乳腺癌发生相关性研究.最后纳入分析33篇文献.结果 “合成致死”原理是PARP1抑制剂在BRCA突变相关乳腺癌中发挥抗肿瘤活性的理论基础,PARP1抑制剂治疗BRCA突变相关的乳腺癌的Ⅰ、Ⅱ临床试验取得良好的成果,但是在三阴性乳腺癌的治疗方面,Ⅲ期临床试验并未得到预期的试验结果,在应用PARP1抑制剂之前重组修复通路的功能状态以及PARP1的活性应该得到合理评估.结论 三阴性乳腺癌与BRCA突变相关乳腺癌存在表型的相似性,但是三阴性乳腺癌患者是否可以受益于PARP1抑制剂的治疗,还需要进一步深入研究,同时寻找可靠生物标记分子预测PARP1抑制剂治疗的敏感性,是目前PARP1抑制剂应用于临床所面临的挑战.  相似文献   

9.
MAPK在慢性髓细胞白血病K562细胞株信号转导中的作用   总被引:3,自引:0,他引:3  
Shang ZC  Sun BZ  Chen ZN  Wang W  Feng Q  Wang S  Zhang T 《癌症》2003,22(2):140-142
背景与目的:近年研究表明,ras-MAPK信号传导通路在慢性髓细胞白血病(CML)的发生和发展中起着重要作用。本研究拟探计丝裂原活化的蛋白激酶(mitogen-activated protein kinase,MAPK)在CML信号转导中的作用及其作用机理。方法:用脂质体转染法将MAPK的反义寡核苷酸(antisense oligodeoxynucleotide,ASO)导入CML细胞株K562细胞中,通过细胞增殖、DNA合成、MAPK含量和MAPK活性变化检测MAPK ASO对K562细胞的作用。结果:MAPK ASO可明显抑制细胞增殖、DNA合成、MAPK含量和MAPK活性,其抑制率分别为51.8%、57.1%、45.3%和61.6%,与对照组比较差异有统计学意义(P<0.05)。结论:MAPK在CML信号转导中起重要,极有可能成为治疗CML的新靶点。  相似文献   

10.
最近发现JAK2和/或MPL突变对真性红细胞增多症(PV)、原发性血小板增多症(ET)和原发性骨髓纤维化(PMF)的诊断和治疗产生着重大影响.例如,JAK2突变目前认为是诊断PV的必要条件,WHO分类系统最近修订的PV、ET和PMF诊断标准中包括JAK2和MPL(血小板生成素受体)突变作为克隆性标记.从治疗学的观点,JAK-STAT信号途径现已确定为研发骨髓增殖性新生物治疗新药的合理靶途径.本文简述ET、PV和PMF目前的处理,并复习抗JAK2小分子药物临床前和临床活性的有关资料.  相似文献   

11.
Li QF  Huang WR  Duan HF  Wang H  Wu CT  Wang LS 《Oncogene》2007,26(57):7904-7908
The signaling mechanisms responsible for BCR/ABL-induced regulation of Mcl-1 expression in chronic myelogenous leukemia (CML) cells remain unclear. In this study, we show that BCR/ABL could upregulate sphingosine kinase-1 (SPK1) expression via multiple signal pathways, including mitogen-activated protein kinase (MAPK), phosphoinositide 3-kinase (PI3K) and Janus kinase 2 (JAK2), leading to increase cellular SPK1 activity in CML cells. Retrovirus-mediated overexpression of bcr-abl gene in NIH-3T3, Ba/F3 and HL-60 cells results in upregulation and increased cellular activity of SPK1, whereas treatment of CML cells with specific inhibitors of the BCR/ABL, PI3K, MAPK and JAK2 pathways decreases BCR/ABL-induced SPK1 expression and cellular activity. BCR/ABL also induces upregulation of Mcl-1 expression in CML cells. Inhibition of SPK1 by adenovirus-mediated transfer of small interfering RNA or N,N-dimethylsphingosine reduced expression of Mcl-1 in CML cells. Our data indicated that BCR/ABL induces SPK1 expression and increases its cellular activity, leading to upregulation of Mcl-1 in CML cells. SPK1 silencing enhances the STI571-induced apoptosis of CML cell lines. It is suggested that SPK1 may be a potential therapeutic target in CML.  相似文献   

12.
In six patients with untreated, chronic myelocytic leukemia (CML), the dominating thymidine kinase (TK) activity was compared with the fetal form, TK 1, from mitogen stimulated and the adult form TK 2 from unstimulated normal human lymphocytes, and with TK-1-onc, TK-3-onc and TK-4-onc. This was done in human acute, myelocytic and monocytic leukemias, using the combined thymidine/dTTP enzyme kinetics for isoenzyme characterization. TK-1-onc was found in one, TK-2-onc in two and TK-3-onc in three CML patients. The suffix -onc indicates the difference in ATP kinetics and molecular weights between the normal and the leukemic thymidine kinases. A possible relation between the isoenzyme forms and the types of leukemias is discussed.  相似文献   

13.
Tetrandrine has a variety of anti-tumor effects including against or reversal of tumor chemoresistance, but its mechanism of against tumor chemoresistance is still unclear. Therefore, the analytical method of network pharmacology and molecular docking was used to investigate the mechanism by which tetrandrine acts in tumor chemoresistance. We used public databases (PubChem, SwissADEM, SwissTargetPrediction) to obtain the physicochemical information and targets of tetrandrine, and used gene databases (GeneCards and OMIM) to collected disease targets, respectively. The intersection targets of disease and drug were analyzed by RStudio. We built protein-protein interaction network through the STRING database, and used Cystoscope to screen out hub genes. GO and KEGG pathway enrichment analysis were analyzed by Metascape database and RStudio. “Component-target-pathway” network was erected by Cystoscope. Ultimately, the key targets were chosen to dock with tetrandrine via molecular docking to verify network analysis results. 29 common targets were screened out through intersection. AKT1, PIK3CA, PIK3CB, PIK3CG, JAK2, IGF1R, KDR, SRC and MTOR were the core targets. KEGG pathway enrichment mainly included PI3K-AKT signaling pathway, EGFR tyrosine kinase inhibitor resistance, and Rap1 signaling pathway. Molecular docking indicated that the configuration of protein binding of ligand is stable. In conclusion, the against tumor chemoresistance effect of tetrandrine has the characteristics of multiple targets and multiple pathways, and the prediction of network pharmacology and molecular docking indicated that MTOR, SRC, PIK3CA were the key targets of tetrandrine in tumor chemoresistance, which provides a scientific basis for subsequent research on its anti-tumor chemoresistance mechanism.  相似文献   

14.
Breast cancers that are negative for estrogen receptor (ER), progesterone receptors (PR) and HER2, using standard clinical assays, have been dubbed triple-negative (TN). Unlike other molecular subtypes of invasive breast cancer, validated targeted therapies are currently unavailable for patients with TN breast cancer. Preclinical studies however, have identified several potential targets such as epidermal growth factor receptor (EGFR), SRC, MET and poly ADP ribose polymerase 1/2 (PARP1/2). Because of tumor heterogeneity, it is unlikely that any single targeted therapy will be efficacious in all patients with TN breast cancer. The rational way forward for treating these patients is likely to be biomarker-driven, combination targeted therapies or combination of targeted therapy with cytotoxic chemotherapy.  相似文献   

15.
We report the emergence of chronic myelogenous leukemia (CML) in a patient with JAK2V617F-positive polycythemia vera after 15 years of phlebotomy. The polycythemia vera clinical and molecular findings were suppressed at the time of CML diagnosis, only to re-emerge after the leukemia was successfully treated with imatinib. We explored the potential association between myeloproliferative disorders and CML in the context of the current literature and found a higher-than-expected coincidence based on known epidemiologic data for each specific condition. We hypothesize that myeloproliferative disorder (JAK2V617F or molecular events that cause JAK2V617F) is a risk factor for CML (BCR-ABL translocation). Because of therapeutic implications, clinicians should be aware that the conditions co-occur more frequently than once thought.  相似文献   

16.
Objective: BCR/ABL oncoprotein-expression is associated with uncontrolled cell growth. Sphingosine kinase 1 (SPK1) regulates the production of sphingosine 1-phosphate (S1P), a key lipid signal molecular in cell proliferation and survival. The objective of this study was to elucidate the roles of S1P and its receptors in bcr/abl positive chronic myeloid leukemia (CML) cells.Methods: The expressions of S1P receptors: S1P1, S1P2 and S1P3 in CML cells were detected by RT-PCR. SPK1 expression, activity and extracellular S1P were determined in ECV304 and HL-60 cells which were transfected with bcr/abl gene. To elucidate the relationship between the BCR/ABL, ERK/MAPK (extracellular signal-regulated kinase/mitogen-activated protein kinase), SPK/S1P and S1P/S1P2 signal pathways, bcr/abl positive CML cell line K562 was treated with STI571, PD98059, N,N-dimethyl sphingosine (DMS) and JTE-013.Results: Retrovirus-mediated overexpression of bcr/abl gene in ECV304 and HL-60 cells resulted in upregulation of the expression, activity of SPK1 and increase of the secretion of S1P, whereas treatment of STI571 and PD98059 decreased the BCR/ABL-induced S1P secretion. Treatment of DMS reduced S1P secretion and P42/44MAPK phosphorylation. S1P2-selective antagonist JTE-013 could also decrease P42/44MAPK phosphorylation. Conclusion: These results suggest that BCR/ABL up-regulates extracellular sphingosine 1-phosphate through sphingosine kinase 1 and there is cross-talk between SPK1/S1P/S1P2 and P42/44MAPK in bcr/abl positive CML cells.  相似文献   

17.
R J Meyer  J Cuttner 《Cancer》1978,42(1):305-310
With the advent of more effective chemotherapy an increasing incidence of central nervous system involvement in acute lymphocyte (ALL) and myelocytic leukemias (AML) and chronic myelocytic leukemia (CML) in blast crisis has become evident. Meningeal involvement in the chronic phase of CML is rare. We report two children whose initial presentation of Ph1 CML was in the central nervous system as documented by cytocentrifugation. Aggressive combination chemotherapy and cranial irradiation has resulted in prolonged survival without blastic transformation or further meningeal disease. An approach to children with CML is suggested.  相似文献   

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