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Navigating the complex terrain of hepatitis B virus reactivation in the era of Bruton tyrosine kinase inhibitors
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作者 Wei-Nung Liu Ming-Shen Dai +1 位作者 Felicia Lin Gen-Min Lin 《World Journal of Gastroenterology》 SCIE CAS 2024年第21期2748-2750,共3页
In this editorial,we offer a summary of the risk associated with hepatitis B reactivation(HBVr)in the setting of both solid and hematologic malignancies treated with Bruton tyrosine kinase(BTK)inhibitors,with insights... In this editorial,we offer a summary of the risk associated with hepatitis B reactivation(HBVr)in the setting of both solid and hematologic malignancies treated with Bruton tyrosine kinase(BTK)inhibitors,with insights derived from current studies.Furthermore,we emphasize the critical need for a framework regarding robust risk evaluation in patients undergoing such treatments.This framework is essential for identifying those at increased risk of HBVr,enabling healthcare providers to implement proactive measures to prevent reactivation and ensure the safe administration of BTK inhibitor therapy. 展开更多
关键词 Hepatitis B virus reactivation bruton tyrosine kinase inhibitors Hematologic malignancies solid tumors Prophylaxis guidelines
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Bruton’s tyrosine kinase inhibitors in primary central nervous system lymphoma:New hopes on the horizon
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作者 Leonardo S Lino-Silva Sabrina B Martínez-Villavicencio Luisa Fernanda Rivera-Moncada 《World Journal of Clinical Oncology》 2024年第5期587-590,共4页
In this editorial,we comment on the article by Wang et al.This manuscript explores the potential synergistic effects of combining zanubrutinib,a novel oral inhibitor of Bruton’s tyrosine kinase,with high-dose methotr... In this editorial,we comment on the article by Wang et al.This manuscript explores the potential synergistic effects of combining zanubrutinib,a novel oral inhibitor of Bruton’s tyrosine kinase,with high-dose methotrexate(HD-MTX)as a therapeutic intervention for primary central nervous system lymphoma(PCNSL).The study involves a retrospective analysis of 19 PCNSL patients,highlighting clinicopathological characteristics,treatment outcomes,and genomic biomarkers.The results indicate the combination’s good tolerance and strong antitumor activity,with an 84.2%overall response rate.The authors emphasize the potential of zanubrutinib to modulate key genomic features of PCNSL,particularly mutations in myeloid differentiation primary response 88 and cluster of differentiation 79B.Furthermore,the study investigates the role of circulating tumor DNA in cerebrospinal fluid for disease surveillance and treatment response monitoring.In essence,the study provides valuable insights into the potential of combining zanubrutinib with HD-MTX as a frontline therapeutic regimen for PCNSL.The findings underscore the importance of exploring alternative treatment modalities and monitoring genomic and liquid biopsy markers to optimize patient outcomes.While the findings suggest promise,the study’s limitations should be considered,and further research is needed to establish the clinical relevance of this therapeutic approach for PCNSL. 展开更多
关键词 Primary central nervous system lymphoma Zanubrutinib brutons tyrosine kinase PROGNOsIs Myeloid differentiation primary response 88 gene Cluster of differentiation 79B gene
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Rituximab combined with Bruton tyrosine kinase inhibitor to treat elderly diffuse large B-cell lymphoma patients: Two case reports
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作者 Cang-Jian Zhang Min-Lei Zhao 《World Journal of Clinical Cases》 SCIE 2023年第29期7170-7178,共9页
BACKGROUND Diffuse large B-cell lymphoma(DLBCL)is a common aggressive non-Hodgkin's lymphoma(NHL),accounting for 30%-40%of adult NHLs.This report aims to explore the efficacy and safety of rituximab combined with ... BACKGROUND Diffuse large B-cell lymphoma(DLBCL)is a common aggressive non-Hodgkin's lymphoma(NHL),accounting for 30%-40%of adult NHLs.This report aims to explore the efficacy and safety of rituximab combined with Bruton tyrosine kinase inhibitors(BTKis)in the treatment of elderly patients with DLBCL.CASE SUMMARY The clinical data of two elderly patients with DLBCL who received rituximab combined with BTKi in our hospital were retrospectively analyzed,and the literature was reviewed.The patients were treated with chemotherapy using the R-miniCHOP regimen for two courses.Then,they received rituximab in combination with BTKi.CONCLUSION The treatment experience in these cases demonstrates the potential efficacy of rituximab combined with BTKi to treat elderly DLBCL patients,thus providing a new treatment strategy. 展开更多
关键词 Diffuse large B-cell lymphoma RITUXIMAB bruton tyrosine kinase inhibitors Elderly patients Case report
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Novel deletion mutation in Bruton’s tyrosine kinase results in X-linked agammaglobulinemia:A case report
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作者 Xiao-Mei Hu Ke Yuan +5 位作者 Hong Chen Chun Chen Yan-Lan Fang Jian-Fang Zhu Li Liang Chun-Lin Wang 《World Journal of Clinical Cases》 SCIE 2020年第17期3859-3866,共8页
BACKGROUND X-linked agammaglobulinemia is a primary immunodeficiency disease caused by gene mutations of Bruton’s tyrosine kinase(BTK).We found a new mutation point and summarized the correlation analysis and perform... BACKGROUND X-linked agammaglobulinemia is a primary immunodeficiency disease caused by gene mutations of Bruton’s tyrosine kinase(BTK).We found a new mutation point and summarized the correlation analysis and performed a literature review.CASE SUMMARY The proband was a 5-year-old boy.He was admitted to our hospital due to a recurrent cough and a fever that had persisted for a month.He had a history of multiple respiratory infections and sinusitis.There was no immunodeficiency or recurrent infection history among his family members.Agammaglobulinemia was characterized as follows:Immunoglobulin(Ig)A,90.0 mg/dL(90-450 mg/dL);IgG,20.0 mg/dL(800-1800 mg/dL);and IgM,18.0 mg/dL(60-280 mg/dL).Notably,the assessment of IgG subtypes revealed the following very low levels:Subtype 1,0.26 g/L(3.62-12.28 g/L);subtype 2,0.10 g/L(0.57-2.9 g/L);subtype 3,0.009 g/L(0.129-0.789 g/L);and subtype 4,0.003 g/L(0.013-1.446 g/L).Cellular immunological test results were as follows:CD3,74.6%(50%-84.0%);CD4,47.3%(27.0%-51.0%);and CD8,24.9%(15.0%-44.0%).A de novo hemizygous deletion in BTK was detected:c.902_c.904delAAG/p.E301del.Transcript levels of the mutant BTK were similar to those of the wild-type gene,though overexpression resulted in markedly reduced levels of mutant BTK(9.49%±1.58%),relative to the wildtype BTK(75.8%±2.98%,P<0.01).CONCLUSION This case of X-linked agammaglobulinemia was attributed to a de novo hemizygous deletion mutation in BTK(c.902_c.904delAAG/p.E301del).The mutation resulted in markedly reduced BTK protein stability in vitro. 展开更多
关键词 AGAMMAGLOBULINEMIA brutons tyrosine kinase MUTATION IMMUNODEFICIENCY Case report
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Ibrutinib and atrial fibrillation:An in-depth review of clinical implications and management strategies
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作者 Moiud Mohyeldin Shitij Shrivastava Sai Vishnu Vardhan Allu 《World Journal of Cardiology》 2024年第5期269-273,共5页
Ibrutinib,a targeted therapy for B-cell malignancies,has shown remarkable efficacy in treating various hematologic cancers.However,its clinical use has raised concerns regarding cardiovascular complications,notably at... Ibrutinib,a targeted therapy for B-cell malignancies,has shown remarkable efficacy in treating various hematologic cancers.However,its clinical use has raised concerns regarding cardiovascular complications,notably atrial fibrillation(AF).This comprehensive review critically evaluates the association between ibrutinib and AF by examining incidence,risk factors,mechanistic links,and management strategies.Through an extensive analysis of original research articles,this review elucidates the complex interplay between ibrutinib’s therapeutic benefits and cardiovascular risks.Moreover,it highlights the need for personalized treatment approaches,vigilant monitoring,and interdisciplinary collaboration to optimize patient outcomes and safety in the context of ibrutinib therapy.The review provides a valuable resource for healthcare professionals aiming to navigate the intricacies of ibrutinib’s therapeutic landscape while prioritizing patient well-being. 展开更多
关键词 Ibrutinib brutons tyrosine kinase inhibitor Atrial fibrillation Cardiovascular risk Management strategies
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Risk of hepatic decompensation from hepatitis B virus reactivation in hematological malignancy treatments
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作者 Michele Barone 《World Journal of Gastroenterology》 SCIE CAS 2024年第25期3147-3151,共5页
In this editorial,we discussed the apparent discrepancy between the findings described by Colapietro et al,in their case report and data found in the literature.Colapietro et al reported a case of hepatitis B virus(HB... In this editorial,we discussed the apparent discrepancy between the findings described by Colapietro et al,in their case report and data found in the literature.Colapietro et al reported a case of hepatitis B virus(HBV)-related hepatic decompensation in a patient with chronic myeloid leukemia and a previously resolved HBV infection who was receiving Bruton’s tyrosine kinase(BTK)inhibitor therapy.First of all,we recapitulated the main aspects of the immune system involved in the response to HBV infection in order to underline the role of the innate and adaptive response,focusing our attention on the protective role of anti-HBs.We then carefully analyzed literature data on the risk of HBV reactivation(HBVr)in patients with previous HBV infection who were treated with either tyrosine kinase inhibitors or BTK inhibitors for their hematologic malignancies.Based on literature data,we suggested that several factors may contribute to the different risks of HBVr:The type of hematologic malignancy;the type of therapy(BTK inhibitors,especially second-generation,seem to be at a higher risk of HBVr than those with tyrosine kinase inhibitors);previous exposure to an anti-CD20 as first-line therapy;and ethnicity and HBV genotype.Therefore,the warning regarding HBVr in the specific setting of patients with hematologic malignancies requires further investigation. 展开更多
关键词 Hematological malignancy HEPATITIs Hepatitis B virus-DNA brutons tyrosine kinase Previously resolved hepatitis B virus infection
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Repurposed anti-cancer epidermal growth factor receptor inhibitors: mechanisms of neuroprotective effects in Alzheimer’s disease 被引量:1
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作者 Heba M.Mansour Hala M.Fawzy +1 位作者 Aiman S.El-Khatib Mahmoud M.Khattab 《Neural Regeneration Research》 SCIE CAS CSCD 2022年第9期1913-1918,共6页
Numerous molecular mechanisms are being examined in an attempt to discover disease-modifying drugs to slow down the underlying neurodegeneration in Alzheimer’s disease.Recent studies have shown the beneficial effects... Numerous molecular mechanisms are being examined in an attempt to discover disease-modifying drugs to slow down the underlying neurodegeneration in Alzheimer’s disease.Recent studies have shown the beneficial effects of epidermal growth factor receptor inhibitors on the enhancement of behavioral and pathological sequelae in Alzheimer’s disease.Despite the promising effects of epidermal growth factor receptor inhibitors in Alzheimer’s disease,there is no irrefutable neuroprotective evidence in well-established animal models using epidermal growth factor receptor inhibitors due to many un-explored downstream signaling pathways.This caused controversy about the potential involvement of epidermal growth factor receptor inhibitors in any prospective clinical trial.In this review,the mystery beyond the under-investigation of epidermal growth factor receptor in Alzheimer’s disease will be discussed.Furthermore,their molecular mechanisms in neurodegeneration will be explained.Also,we will shed light on SARS-COVID-19 induced neurological manifestations mediated by epidermal growth factor modulation.Finally,we will discuss future perspectives and under-examined epidermal growth factor receptor downstream signaling pathways that warrant more exploration.We conclude that epidermal growth factor receptor inhibitors are novel effective therapeutic approaches that require further research in attempts to be repositioned in the delay of Alzheimer’s disease progression. 展开更多
关键词 Alzheimer’s disease AUTOPHAGY drug re-positioning epidermal growth factor receptor human epidermal growth factor receptor-2 neurodegenerative diseases NEUROINFLAMMATION oxidative stress tyrosine kinase inhibitors
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Prevention and management of hepatitis B virus reactivation in patients with hematological malignancies in the targeted therapy era 被引量:10
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作者 Joyce Wing Yan Mak Alvin Wing Hin Law +3 位作者 Kimmy Wan Tung Law Rita Ho Carmen Ka Man Cheung Man Fai Law 《World Journal of Gastroenterology》 SCIE CAS 2023年第33期4942-4961,共20页
Hepatitis due to hepatitis B virus(HBV)reactivation can be serious and potentially fatal,but is preventable.HBV reactivation is most commonly reported in patients receiving chemotherapy,especially rituximab-containing... Hepatitis due to hepatitis B virus(HBV)reactivation can be serious and potentially fatal,but is preventable.HBV reactivation is most commonly reported in patients receiving chemotherapy,especially rituximab-containing therapy for hematological malignancies and those receiving stem cell transplantation.Patients with inactive and even resolved HBV infection still have persistence of HBV genomes in the liver.The expression of these silent genomes is controlled by the immune system.Suppression or ablation of immune cells,most importantly B cells,may lead to reactivation of seemingly resolved HBV infection.Thus,all patients with hematological malignancies receiving anticancer therapy should be screened for active or resolved HBV infection by blood tests for hepatitis B surface antigen(HBsAg)and antibody to hepatitis B core antigen.Patients found to be positive for HBsAg should be given prophylactic antiviral therapy.For patients with resolved HBV infection,there are two approaches.The first is pre-emptive therapy guided by serial HBV DNA monitoring,and treatment with antiviral therapy as soon as HBV DNA becomes detectable.The second approach is prophy-lactic antiviral therapy,particularly for patients receiving high-risk therapy,especially anti-CD20 monoclonal antibody or hematopoietic stem cell transplantation.Entecavir and tenofovir are the preferred antiviral choices.Many new effective therapies for hematological malignancies have been introduced in the past decade,for example,chimeric antigen receptor(CAR)-T cell therapy,novel monoclonal antibodies,bispecific antibody drug conjugates,and small molecule inhibitors,which may be associated with HBV reactivation.Although there is limited evidence to guide the optimal preventive measures,we recommend antivi-ral prophylaxis in HBsAg-positive patients receiving novel treatments,including Bruton’s tyrosine kinase inhibitors,B-cell lymphoma 2 inhibitors,and CAR-T cell therapy.Further studies are needed to determine the risk of HBV reactivation with these agents and the best prophylactic strategy. 展开更多
关键词 Hepatitis B Hematologic neoplasms Chimeric antigen receptor-T cell therapy Monoclonal antibodies brutons tyrosine kinase inhibitors Antiviral agents
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依鲁替尼(Ibrutinib)合成路线图解
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作者 刘举 金凡琪 +4 位作者 车晋 高俊峰 李春艳 陈烨 周云鹏 《辽宁大学学报(自然科学版)》 CAS 2024年第2期97-102,共6页
依鲁替尼(Ibrutinib)是一款由Pharmacyclics和Janssen Biotech公司联合研发的布鲁顿酪氨酸激酶(Bruton′s tyrosine kinase,BTK)抑制剂,也是第一个BTK靶向治疗套细胞淋巴癌(MCL)的小分子药物.本文对依鲁替尼的合成工艺进行归纳总结,以... 依鲁替尼(Ibrutinib)是一款由Pharmacyclics和Janssen Biotech公司联合研发的布鲁顿酪氨酸激酶(Bruton′s tyrosine kinase,BTK)抑制剂,也是第一个BTK靶向治疗套细胞淋巴癌(MCL)的小分子药物.本文对依鲁替尼的合成工艺进行归纳总结,以期为依鲁替尼的合成路线设计提供新思路. 展开更多
关键词 依鲁替尼 合成路线 布鲁顿酪氨酸激酶(BTK)抑制剂 抗肿瘤药物
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原发性中枢神经系统淋巴瘤MRI图像参数与分子病理的关联性分析
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作者 张东阳 王树叶 +3 位作者 刘玥 杨昆鹏 于洪娟 王悦 《中国肿瘤临床》 CAS CSCD 北大核心 2024年第8期401-405,共5页
目的:研究原发性中枢神经系统淋巴瘤(primary central nervous system lymphoma,PCNSL)MRI图像参数与分子病理的关联性。方法:回顾性分析2020年1月至2023年6月就诊于哈尔滨医科大学附属第一医院26例PCNSL患者资料,根据细胞来源、BCL-2... 目的:研究原发性中枢神经系统淋巴瘤(primary central nervous system lymphoma,PCNSL)MRI图像参数与分子病理的关联性。方法:回顾性分析2020年1月至2023年6月就诊于哈尔滨医科大学附属第一医院26例PCNSL患者资料,根据细胞来源、BCL-2表达、Ki-67指数,MAP+布鲁顿酪氨酸激酶抑制剂(Bruton's tyrosine kinase inhibitor,BTKi)治疗反应性将患者归纳至非生发中心B细胞(non-germinal center B-cell,non-GCB)组和生发中心B细胞(germinal center B-cell,GCB)组、Ki-67≥75%组和Ki-67<75%组、BCL-2+组和BCL-2-组、对MAP+BTKi方案治疗有反应组和无反应组。提取患者基线期MRI图像一阶参数如平均值、标准差、方差、变异系数、偏度、峰度、熵,比较其在两组间的差异。结果:方差、峰度、偏度、变异系数等4个参数在组间差异无统计学意义;平均数、标准差、熵这3个参数在Ki-67表达、BCL-2表达组间的差异具有统计学意义;平均数、熵这两个参数在细胞来源、治疗是否有反应性两组间差异具有统计学意义(P<0.05);对于Ki-67指数,3个参数的曲线下面积(AUC)分别为0.731、0.831、0.913;对于BCL-2表达,平均数、标准差的曲线下面积(AUC)分别为0.889和0.938。多参数联合分析时其鉴识效果较利用单个纹理分析定量参数更高。结论:平均值、标准差、熵等3个MRI参数有助于预测PCNSL患者Ki-67、BCL-2的表达,对于治疗具有一定评估作用,有利于术前无创性评估肿瘤的恶性程度并为预后和治疗提供新的依据。 展开更多
关键词 原发中枢神经系统淋巴瘤 磁共振 图像参数 分子病理 布鲁顿酪氨酸激酶抑制剂
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布鲁顿氏酪氨酸激酶抑制剂治疗原发中枢神经系统淋巴瘤16例临床分析
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作者 戴紫港 周晓曦 +1 位作者 张义成 黄亮 《内科急危重症杂志》 2024年第2期117-121,共5页
目的:分析应用布鲁顿氏酪氨酸激酶(BTK)抑制剂治疗原发中枢神经系统淋巴瘤(PCNSL)患者的临床特征,探讨影响疗效的因素及疗效不佳患者的后续治疗经验。方法:回顾性分析初诊应用BTK抑制剂(包括奥布替尼、泽布替尼)联合传统化疗诱导治疗的P... 目的:分析应用布鲁顿氏酪氨酸激酶(BTK)抑制剂治疗原发中枢神经系统淋巴瘤(PCNSL)患者的临床特征,探讨影响疗效的因素及疗效不佳患者的后续治疗经验。方法:回顾性分析初诊应用BTK抑制剂(包括奥布替尼、泽布替尼)联合传统化疗诱导治疗的PCNSL患者的临床资料。结果:16例PCNSL患者中,男性13例,女性3例,中位年龄62.5岁。病灶数目以多发为主,占56%;病理分型以非生发中心B细胞(non-GCB)型为主,占62%;双表达型占38%;9例患者有初诊脑脊液生化数据,脑脊液蛋白升高者占78%;7例患者有基因测序结果,MYD88突变占57%,CD79B突变占43%;16例患者中9例(56%)接受奥布替尼联合传统化疗治疗,7例(44%)接受泽布替尼联合传统化疗治疗;16例患者的总体反应率(ORR)为69%。5例疗效不佳的患者中,4例为多发病灶,4例为双表达类型,3例具有MYD88突变;2例接受造血干细胞移植序贯嵌合抗原受体T细胞治疗(auto-HSCT+CAR-T),获得完全缓解。结论:BTK抑制剂联合传统化疗治疗PCNSL患者的ORR为69%,多发病灶、双表达、MYD88突变可能是疗效差的因素。auto-HSCT+CAR-T可能是BTK抑制剂联合传统化疗治疗PCNSL疗效不佳患者可行的后续治疗方案。 展开更多
关键词 原发中枢神经系统淋巴瘤 布鲁顿氏酪氨酸激酶抑制剂 临床特征
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复发/难治DLBCL患者继发CNS侵犯的临床特征及泽布替尼联合化疗方案的疗效 被引量:3
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作者 石磊 王亚丽 +5 位作者 孙恺 陆敏秋 高珊 褚彬 王宇彤 鲍立 《山东医药》 CAS 2022年第19期28-32,共5页
目的分析4例继发中枢神经系统(CNS)侵犯的复发/难治弥漫大B细胞淋巴瘤(DLBCL)患者的临床特征,并观察泽布替尼联合化疗方案的疗效。方法选择4例DLBCL继发CNS侵犯患者,分析其初诊及复发时的临床特征;并进行相应泽布替尼联合化疗方案治疗,... 目的分析4例继发中枢神经系统(CNS)侵犯的复发/难治弥漫大B细胞淋巴瘤(DLBCL)患者的临床特征,并观察泽布替尼联合化疗方案的疗效。方法选择4例DLBCL继发CNS侵犯患者,分析其初诊及复发时的临床特征;并进行相应泽布替尼联合化疗方案治疗,其中,2例采用泽布替尼+甲氨蝶呤(Z-MTX)方案治疗,1例采用泽布替尼+利妥昔单抗+吉西他滨+顺铂+地塞米松(Z-R-GDP)方案治疗,1例采用泽布替尼+利妥昔单抗+甲氨蝶呤(ZR-MTX)方案治疗,评价治疗方案的疗效及毒性反应。结果4例患者中,3例CNS复发仅侵犯脑实质,另1例同时侵犯脑、眼;3例具有淋巴瘤中枢侵袭的高危中枢神经系统国际预后指数(CNS-IPI)评分(4~6分),另1例CNS-IPI评分1分。3例患者为非生发中心(non-GCB)来源,其中MCD亚型2例、非MCD亚型1例;1例未进行相关分子生物学检查。化疗后完全缓解3例,部分缓解1例;随访4~5个月,至末次随访,3例完全缓解患者疗效持续缓解无复发,1例部分缓解患者复发。主要毒性反应为血液学毒性,未发生肿瘤溶解、心房颤动或高血压等其他3级及以上布鲁顿氏酪氨酸激酶选择性抑制剂相关的毒性反应。结论复发/难治DLBCL继发CNS侵犯多为non-GCB来源及MCD亚型,主要侵犯脑实质;泽布替尼联合化疗方案有显著、持续的疗效和生存优势,其主要毒性反应可控。 展开更多
关键词 复发/难治弥漫大B细胞淋巴瘤 中枢神经系统侵犯 泽布替尼 布鲁顿氏酪氨酸激酶选择性抑制剂
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Bruton酪氨酸激酶Btk的生物学特性研究进展 被引量:3
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作者 李庆伟 芦静 刘欣 《辽宁师范大学学报(自然科学版)》 CAS 2010年第1期90-95,共6页
酪氨酸激酶Btk是非受体酪氨酸家族的成员,它由PH结构域、TH结构域、SH3结构域、SH2结构域和催化结构域5部分组成.Btk参与多种信号通路,对细胞的增殖、分化和凋亡起着重要的调控作用.Btk的突变可导致X连锁无丙种球蛋白血症,一直以来都是... 酪氨酸激酶Btk是非受体酪氨酸家族的成员,它由PH结构域、TH结构域、SH3结构域、SH2结构域和催化结构域5部分组成.Btk参与多种信号通路,对细胞的增殖、分化和凋亡起着重要的调控作用.Btk的突变可导致X连锁无丙种球蛋白血症,一直以来都是研究热点.笔者将围绕Btk的结构、功能、X连锁无丙种球蛋白血症的临床表现等方面的内容加以综述,着重探讨Btk参与B细胞信号通路、TLR信号通路和肥大细胞脱颗粒等过程的具体机制. 展开更多
关键词 BTK 信号通路 B细胞 TOLL受体 肥大细胞脱颗粒
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慢性淋巴细胞白血病BTKi治疗后免疫功能重建研究
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作者 王远丽 唐培霞 +5 位作者 陈凯莉 郭光耀 龙金兰 邹杨清 梁鸿宇 许贞书 《中国实验血液学杂志》 CSCD 北大核心 2024年第1期1-5,共5页
目的:分析慢性淋巴细胞白血病(CLL)经布鲁顿酪氨酸激酶抑制剂(BTKi)治疗后的免疫功能重建情况。方法:收集2017年1月至2022年3月在福建医科大学附属协和医院血液科就诊的59例CLL患者的病历信息,对其诊断、治疗和实验室检查资料进行回顾... 目的:分析慢性淋巴细胞白血病(CLL)经布鲁顿酪氨酸激酶抑制剂(BTKi)治疗后的免疫功能重建情况。方法:收集2017年1月至2022年3月在福建医科大学附属协和医院血液科就诊的59例CLL患者的病历信息,对其诊断、治疗和实验室检查资料进行回顾性分析研究。结果:59例CLL患者中位年龄为60.5(36-78)岁;BTKi治疗1年后,51例(86.4%)的CLL肿瘤克隆(CD5+/CD19+)明显缩小,治疗前后分别为(46±6.1)×10^(9)/L和(2.3±0.4)×10^(9)/L(P=0.0013),而非肿瘤克隆(CD19+减去CD5+/CD19+)无明显变化;免疫球蛋白IgA明显升高,治疗前后分别为(0.75±0.09)g/L和(1.31±0.1)g/L(P<0.001),但IgG和IgM下降,分别为(8.1±0.2)g/L和(7.1±0.1)g/L(P<0.001)、(0.52±0.6)g/L和(0.47±0.1)g/L(P=0.002)。BTKi治疗前后CLL患者的T细胞亚群出现明显变化,表现为总T细胞数从(2.1±0.1)×10^(9)/L减少至(1.6±0.4)×10^(9)/L(P=0.042),CD4+细胞数从(0.15±6.1)×10^(9)/L增加至(0.19±0.4)×10^(9)/L(P<0.001),CD8+细胞数从(0.27±0.01)×10^(9)/L增加至(0.41±0.08)×10^(9)/L(P<0.001),NK/T细胞数从(0.11±0.1)×10^(9)/L下降至(0.07±0.01)×10^(9)/L(P=0.038);白细胞介素(IL)-2表达上调、IL-4和干扰素γ表达下降,但IL-6、IL-10、肿瘤坏死因子α表达变化不大;TCR和BCR组库多样性都得到恢复,完全缓解患者比部分缓解患者恢复更明显,完全缓解患者BTKi治疗前后TCR组库香农指数分别为0.02±0.008和0.14±0.01(P<0.001),部分缓解患者分别为0.01±0.03和0.05±0.02(P>0.05),而BCR组库香农指数分别是0.19±0.003和0.33±0.15(P<0.001)、0.15±0.009和0.23±0.18(P<0.05)。结论:BTKi治疗可以缩小CLL克隆,促进IgA表达,增加功能性T细胞数量,调节IL-2、IL-4、干扰素γ等分泌,改善肿瘤微环境的免疫调节状态;BTKi治疗还能促进TCR和BCR免疫组库多样性的恢复。BTKi治疗有助于CLL患者的免疫功能重建。 展开更多
关键词 慢性淋巴细胞白血病 布鲁顿酪氨酸激酶抑制剂 免疫功能重建 回顾性研究
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布鲁顿酪氨酸激酶抑制剂治疗套细胞淋巴瘤有效性及安全性的meta分析
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作者 尹硕 郑晓红 +3 位作者 张维春柏 郭汶慧 陈峰 李文斌 《北京医学》 CAS 2024年第2期87-96,共10页
目的 系统分析布鲁顿酪氨酸激酶抑制剂(Bruton’s tyrosine kinase inhibitor, BTKi)治疗套细胞淋巴瘤(mantle cell lymphoma, MCL)的有效性及安全性。方法 选取建库至2023年5月21日PubMed、Embase、The Cochrane Library、Clinical Tri... 目的 系统分析布鲁顿酪氨酸激酶抑制剂(Bruton’s tyrosine kinase inhibitor, BTKi)治疗套细胞淋巴瘤(mantle cell lymphoma, MCL)的有效性及安全性。方法 选取建库至2023年5月21日PubMed、Embase、The Cochrane Library、Clinical Trials.gov和Web of Science等数据库公开发表的BTKi治疗MCL的英文文献,由2位研究者独立筛选文献、提取资料并评价纳入研究的偏倚风险后,以总反应率(overall response rate, ORR)及治疗相关不良反应(adverse events, AEs)发生率作为结局指标,分析BTKi治疗MCL的有效性及安全性。结果 共检索文献4 818篇,最终纳入15篇,其中随机对照研究2篇,单臂研究13篇,共16项研究,涉及1 029例患者。Meta分析结果显示,BTKi治疗MCL的ORR为83.7%(95%CI:76.7%~89.8%)。亚组分析各因素合并反应率:低龄组(<65岁)为91.4%(95%CI:70.6%~100.0%),高龄组为(≥65岁)80.7%(95%CI:76.0%~85.0%);初治组为94.5%(95%CI:81.0%~100.0%),复发/难治组为79.0%(95%CI:75.3%~82.5%);BTKi联合治疗组为86.5%(95%CI:74.7%~95.3%),BTKi单药治疗组为79.0%(95%CI:74.4%~83.3%);第一代BTKi组为74.9%(95%CI:65.7%~83.2%),第二代BTKi组为81.7%(95%CI:77.4%~85.7%);IR方案(伊布替尼+利妥昔单抗)组为93.2%(95%CI:80.0%~99.9%),非IR方案组为77.4%(95%CI:69.6%~84.4%)。安全性方面共分析了8种不良反应,血液系统不良反应中血小板减少症(29.8%,95%CI:18.9%~42.0%)的发生率较高,非血液系统中疲劳(53.6%,95%CI:35.4%~71.4%)和腹泻(48.1%,95%CI:35.1%~61.2%)的发生率较高。结论 BTKi治疗MCL具有较好的有效性及安全性,年龄<65岁、疾病状态为初治、BTKi联合治疗、第二代BTKi单药治疗、联合治疗IR方案均有较高的反应率。 展开更多
关键词 布鲁顿酪氨酸激酶抑制剂 套细胞淋巴瘤 META分析 总反应率 不良反应
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新型BTK-PROTAC分子的设计、合成及生物活性评价
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作者 葛子豪 周卯 +2 位作者 查永骏 白海云 钟利 《合成化学》 CAS 2024年第6期534-541,共8页
蛋白降解靶向嵌合体(PROTAC)技术在新药研发领域越来越受到重视。基于NX-5948的靶蛋白配体(Warhead)结构,采用5-氟吲哚代替吡嗪胺的思路进行改造,成功合成化合物A。为研究不同连接子(Linker)和E3配体对蛋白降解活性的影响,成功设计合成... 蛋白降解靶向嵌合体(PROTAC)技术在新药研发领域越来越受到重视。基于NX-5948的靶蛋白配体(Warhead)结构,采用5-氟吲哚代替吡嗪胺的思路进行改造,成功合成化合物A。为研究不同连接子(Linker)和E3配体对蛋白降解活性的影响,成功设计合成了化合物B~F,化合物A~F结构均经^(1)H NMR和MS表征。通过蛋白质免疫印迹法(Western blot,WB)分别测定目标化合物布鲁顿酪氨酸激酶(BTK)的降解活性。结果表明:化合物A、C、D、E、F都有近似于NX-5948的蛋白降解活性,其半数降解浓度(DC_(50))小于1 nM;并且所有目标化合物24 h最大降解程度(D_(max))均略优于NX-5948,为进一步化合物改造提供结构依据。 展开更多
关键词 蛋白降解靶向嵌合体 布鲁顿酪氨酸激酶 蛋白降解 合成 分子设计
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Bruton酪氨酸激酶BTK及其抑制剂的研究进展 被引量:5
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作者 黄菲 朱海静 +3 位作者 周湘 陆涛 焦宇 唐伟方 《中国药科大学学报》 CAS CSCD 北大核心 2014年第6期617-624,共8页
Bruton酪氨酸激酶(BTK)是B细胞抗原受体(BCR)信号转导通路中的关键激酶,目前已成为治疗血液恶性肿瘤和自身免疫失调疾病的热门靶标。BTK有多个抑制剂已进入临床研究,表现出较好的开发前景,其代表性药物依鲁替尼(ibrutinib)在临床试验中... Bruton酪氨酸激酶(BTK)是B细胞抗原受体(BCR)信号转导通路中的关键激酶,目前已成为治疗血液恶性肿瘤和自身免疫失调疾病的热门靶标。BTK有多个抑制剂已进入临床研究,表现出较好的开发前景,其代表性药物依鲁替尼(ibrutinib)在临床试验中对于套细胞淋巴瘤和慢性淋巴细胞白血病显示出突出的治疗活性,已被批准上市。本文对BTK的结构功能以及在研的BTK抑制剂临床研究进展进行了综述。 展开更多
关键词 bruton酪氨酸激酶 小分子抑制剂 依鲁替尼 恶性肿瘤
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Bruton酪氨酸激酶泛素化调节的研究 被引量:1
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作者 房宜嘉 胡媛媛 +5 位作者 凌兰兰 陈月 史玉叶 张莉 王春玲 于亮 《中国实验血液学杂志》 CAS CSCD 北大核心 2017年第5期1559-1565,共7页
目的:探讨Bruton酪氨酸激酶(Bruton's Tyrosine Kinase,Btk)的代谢调节途径和可能的分子机制。方法:用蛋白酶体抑制剂和/或佛波酯(PMA)处理内源性表达Btk的B细胞系A20、Ramos细胞及转染了外源性Btk的293T、COS-7细胞,应用RT-PCR法... 目的:探讨Bruton酪氨酸激酶(Bruton's Tyrosine Kinase,Btk)的代谢调节途径和可能的分子机制。方法:用蛋白酶体抑制剂和/或佛波酯(PMA)处理内源性表达Btk的B细胞系A20、Ramos细胞及转染了外源性Btk的293T、COS-7细胞,应用RT-PCR法检测上述细胞Btk mRNA表达水平,Western blot法检测Btk蛋白表达水平;通过抗Ig M抗体交联BCR刺激A20细胞,检测细胞Btk泛素化水平;用Btk、泛素和Cbl共转染COS-7细胞,检测其泛素化Btk水平;用Btk和编码野生型或突变型泛素(K29R、K48R、K63R)即单泛素的质粒共转染293T细胞,经蛋白酶体抑制剂处理后用抗泛素抗体和抗Btk抗体检测泛素化Btk水平;稳定转染并表达Btk-GFP的293T细胞经氯喹处理后,应用Western blot检测其Btk蛋白表达水平。结果:蛋白酶体特异性抑制剂和/或佛波酯可减少Btk转录,从而引起Btk蛋白表达下降。Btk通过泛素化进行翻译后修饰,泛素化修饰程度与Btk的表达及活化水平有关。Cbl为Btk的E3泛素连接酶,它可导致Btk泛素化。Btk受多聚和/或单泛素化调节,Btk可在溶酶体内发生泛素化和降解,溶酶体抑制剂氯喹可上调Btk的表达。结论:Btk蛋白的表达水平受泛素化途径调节,该调节与Btk的表达水平有关。 展开更多
关键词 bruton酪氨酸激酶 泛素化 蛋白酶体抑制剂 B细胞
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新型布鲁顿酪氨酸激酶抑制剂奥布替尼研究进展 被引量:2
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作者 李宇浩 毛斐 李晓康 《中国医药导报》 CAS 2023年第7期37-41,共5页
奥布替尼是一种新型布鲁顿酪氨酸激酶(BTK)抑制剂,是我国自主研发的Ⅰ类创新药,为淋巴瘤患者尤其是复发/难治性套细胞淋巴瘤和复发/难治性慢性淋巴细胞白血病/小淋巴细胞淋巴瘤的治疗带来新的手段。BTK是B细胞抗原受体信号通路的关键激... 奥布替尼是一种新型布鲁顿酪氨酸激酶(BTK)抑制剂,是我国自主研发的Ⅰ类创新药,为淋巴瘤患者尤其是复发/难治性套细胞淋巴瘤和复发/难治性慢性淋巴细胞白血病/小淋巴细胞淋巴瘤的治疗带来新的手段。BTK是B细胞抗原受体信号通路的关键激酶,对恶性B细胞的增殖和生存至关重要,是治疗B细胞恶性淋巴瘤极具前景的药物靶标。因此,本文回顾了BTK抑制剂的作用机制与已上市BTK抑制剂的基本信息,整理了奥布替尼的药理学性质与临床数据,梳理了迄今为止最新的奥布替尼临床研究进展,提出了奥布替尼是目前具有潜力的BTK抑制剂并且是进行BTK抑制剂联合治疗时的最佳候选药物。 展开更多
关键词 奥布替尼 布鲁顿酪氨酸激酶抑制剂 临床研究 安全性
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泽布替尼在B细胞恶性肿瘤治疗中的研究进展 被引量:1
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作者 许新宁 邢晓静 《实用药物与临床》 CAS 2023年第8期760-764,共5页
泽布替尼是我国自主研发的一款口服布鲁顿酪氨酸激酶(BTK)选择性小分子抑制剂,通过与BTK结合抑制BTK磷酸化,从而阻断B细胞受体(BCR)信号通路和下游多条信号通路,发挥抗肿瘤作用。在慢性淋巴细胞白血病/小淋巴细胞淋巴瘤(CLL/SLL)、套细... 泽布替尼是我国自主研发的一款口服布鲁顿酪氨酸激酶(BTK)选择性小分子抑制剂,通过与BTK结合抑制BTK磷酸化,从而阻断B细胞受体(BCR)信号通路和下游多条信号通路,发挥抗肿瘤作用。在慢性淋巴细胞白血病/小淋巴细胞淋巴瘤(CLL/SLL)、套细胞淋巴瘤(MCL)及华氏巨球蛋白血症(WM)等获批适应证中显示出良好疗效,且耐受性较传统化疗或化学免疫方案更优。在其他类型的B细胞恶性肿瘤中,泽布替尼也逐步走进临床视野。本文结合近年来最新的临床数据,概述泽布替尼在B细胞恶性肿瘤治疗中的研究进展。 展开更多
关键词 B细胞恶性肿瘤 布鲁顿酪氨酸激酶 BTK抑制剂 华氏巨球蛋白血症 泽布替尼
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