肿瘤
词汇介绍
拓展阅读
解析
Bruton
释 义 n. (Bruton)人名;(英)布鲁顿;(法)布吕东
例 句 That year, I was giving the traditional Irish greeting, cad mle filte, a hundred thousand welcomes, to a new Irish prime minister, John Bruton, who was continuing the peace policy of his predecessor. 那一年,我给新任爱尔兰首相约翰.布鲁顿发出了“十万声欢迎”的爱尔兰传统祝福语,他正继续执行着前任的和平政策。
Tyrosine 英 /'taɪrəsiːn/ 美 /'taɪrəsɪn/
释 义 n. [生化] 酪氨酸
例 句 Experts can not eat anything for depression, the problem was first set out the tyrosine content of foods and beverages, such as Chen cheese, canned meat, soy sauce, yeast extract, herring and salmon. 专家对于抑郁症不能吃什么这一问题首先罗列出了酪氨酸含量高的食物和饮料,如陈乳酪,罐头肉,酱油,酵母提取物,鲱鱼和鲑鱼等。
Kinase 英 /ˈkaɪneɪz/ 美 /ˈkɪnneɪz/
释 义 n. [生化] 激酶;致活酶
例 句 However, the involvement of tyrosine kinase either directly or through the prostaglandins and nitric oxide synthase in response to inflammation during diabetes is not completely understood.不过,酪氨酸激酶是直接参与还是通过前列腺素和一氧化氮合酶对糖尿病炎症产生反应的,我们目前还不清楚。
概述
概述
布鲁顿酪氨酸激酶(BTK),即非受体酪氨酸激酶Tec家族的一个成员,是在除了T淋巴细胞和自然杀伤细胞之外的所有造血细胞类型中表达的关键信号酶。BTK在将细胞表面B细胞受体(BCR)刺激连接到下游细胞内应答的B细胞信号途径中发挥至关重要的作用。BTK是B细胞发育、激活、信号传导和存活的关键调节剂;另外,BTK在众多其它造血细胞信号途径中起作用,例如,巨噬细胞中Toll样受体(TLR)和细胞因子受体介导的TNF-α产生,肥大细胞中IgE受体(FceRI)的信号传导,B系淋巴样细胞中Fas/ΑΡ0-1凋亡信号的抑制和受胶原刺激的血小板聚集。
结构
人BTK基因的染色体定位为Xq21.3~Xq22,基因全长37.5 kb,编码659个氨基酸。从N-末端开始,依次为PH结构域、TH结构域、SH3结构域、SH2结构域和SH1结构域5个主要结构域。PH结构域通过识别并结合磷脂肌醇三磷酸将BTK募集到细胞膜上,参与胞外刺激引发的信号转导。TH结构域由BTK motif 和富含脯氨酸区域两部分组成。SH3结构域能特异识别TH结构域中富含脯氨酸片段,诱发分子内折叠。SH1激酶区内有ATP,结合基序GTGQFG和自身磷酸化位点。这些结构域通过识别并结合多种信号分子,为BTK参与多种信号通路奠定基础。
功能
BTK激酶参与体内多数重要信号的传导,其活化对多个细胞过程具有重要影响。BTK参与B细胞的发育成熟。BTK障碍常导致严重的免疫缺陷,如X性连锁无丙种球蛋白血症,骨髓中祖B细胞增殖扩大,B细胞发育阻滞,外周成熟B细胞严重不足。BTK参与B细胞的增殖及凋亡。机体发生免疫应答时,BTK通过介导B细胞信号激活,诱导基因表达,调控B细胞的增殖;通过调控BAP-135/TFII-I转录因子核定位及转录活性,进而调控B细胞增殖凋亡相关蛋白表达;其他也可通过激活ARID家族转录因子,从而调控免疫球蛋白的表达。BTK参与过敏反应。机体受到抗原首次刺激,特异性B细胞产生IgE,通过其Fc段与高亲和受体FCεRI结合,当机体再次受到抗原刺激时,相邻IgE相互结合,使肥大细胞表面的FCεRI活化,进而激活Syk激酶,随后激活BTK激酶通路,最终使肥大细胞释放促炎介质,介导过敏反应的发生。
应用
布鲁顿酪氨酸激酶是B细胞受体信号通路的关键调节因子,在不同类型恶性血液病中广泛表达,参与B细胞的增殖、分化与凋亡,因此被作为治疗恶性血液肿瘤的重要靶点。依鲁替尼,是由Pharmacyclics公司和强生旗下子公司杨森制药共同研制,是第一个获FDA批准上市的口服布鲁顿酪氨酸激酶抑制剂。布鲁顿氏酪氨酸激酶抑制剂ibrutinib(拉铁尼伯)已经改变了慢性淋巴细胞性白血病(CLL)的治疗现况,许多患有以前无法治愈的慢性淋巴细胞性白血病的患者现在其病状能够得到持续的有效缓解。
选择性BTK抑制剂zanubrutinib治疗b细胞恶性肿瘤的1期研究及CLL的安全性和疗效评价
发表时间:2019-09-12
影响指数:16.6
作者: Constantine Tam
期刊:Blood
Zanubrutinib is a potent and highly selective inhibitor of Bruton tyrosine kinase (BTK). In this first-in-human, open-label, multicenter, phase 1 study, patients in part 1 (3 + 3 dose escalation) had relapsed/refractory B-cell malignancies and received zanubrutinib 40, 80, 160, or 320 mg once daily or 160 mg twice daily. Part 2 (expansion) consisted of disease-specific cohorts, including treatment-naive or relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). The primary end points were safety and tolerability, and definition of the maximum tolerated dose (part 1). Additional end points included pharmacokinetics/pharmacodynamics and preliminary efficacy. Reported herein are results from 144 patients enrolled in the dose-finding and CLL/SLL cohorts. No dose-limiting toxicities occurred in dose escalation. Median BTK occupancy in peripheral blood mononuclear cells was >95% at all doses. Sustained complete (>95%) BTK occupancy in lymph node biopsy specimens was more frequent with 160 mg twice daily than 320 mg once daily (89% vs 50%; P = .0342). Consequently, 160 mg twice daily was selected for further investigation. With median follow-up of 13.7 months (range, 0.4-30.5 months), 89 CLL/SLL patients (94.7%) remain on study. Most toxicities were grade 1/2; neutropenia was the only grade 3/4 toxicity observed in >2 patients.
译文