肿瘤多药耐药机制的研究进展

肿瘤多药耐药是肿瘤治疗的难点,其产生机制错综复杂.经典的多药耐药机制涉及以下几个方面:多药耐药相关蛋白的高表达、酶系统的异常、细胞凋亡的抑制及基因修复异常.近年来发现肿瘤多药耐药还与肿瘤干细胞、肿瘤微环境及信号传导通路异常等关系密切.     

骨髓基质细胞对白血病细胞保护作用的研究进展

白血病骨髓基质细胞与其分泌的细胞因子、细胞外基质构成的骨髓微环境在机体造血发育、血液病发生、恶性血液病细胞凋亡等生理病理过程中发挥着重要作用.该文综述了白血病患者骨髓基质细胞与白血病细胞耐药、抗凋亡特性的关系及其机制的相关研究进展.     

骨髓基质细胞对白血病细胞保护作用的研究进展

白血病骨髓基质细胞与其分泌的细胞因子、细胞外基质构成的骨髓微环境在机体造血发育、血液病发生、恶性血液病细胞凋亡等生理病理过程中发挥着重要作用.该文综述了白血病患者骨髓基质细胞与白血病细胞耐药、抗凋亡特性的关系及其机制的相关研究进展.     

CD133分子在急性白血病干细胞鉴定中的研究进展

白血病干细胞是白血病患者耐药和复发的原因之一.CD133抗原是继CD34之后新发现的又一重要造血干、祖细胞表面标志.近年发现部分造血系统恶性疾病尤其是急性白血病存在CD133表达异常,其表达显著特点是随着细胞的分化迅速下调,成为分离和鉴定干细胞和祖细胞的独特分子标志.作为可能的肿瘤干细胞标志,CD133在多种实体肿瘤干细胞分选中起重要作用.实验证实CD133+细胞与肿瘤信号传导、肿瘤免疫逃逸、化疗药物耐药和放疗抵抗均相关,CD133+细胞有望成为白血病治疗的新靶点.     

血管内皮生长因子反义核酸对细胞株HL60及耐药细胞株HL60/VCR的抑制作用

目的 探讨反义血管内皮生长因子(AS-VEGF)对HL60、耐药细胞株HLb0/VCR的影响及其机制,包括基因水平的耐药相关基因(Bcl-2,Mcl-1,MDRl,MRP,GSTπ,TopoⅡα,TopoⅡβ)和蛋白水平的耐药相关蛋白P糖蛋白(P-gp)表达量变化.方法 分子生物学方法构建AS-VEGF表达真核载体,通过脂质体转染技术将其转染至细胞株HL60和耐药细胞株HL30/VCR内,观察并绘制细胞生长曲线,ELISA法检测细胞培养上清VEGF表达量变化,RT-PCR法从mRNA水平检测细胞内耐药相关基因表达,蛋白质印迹方法从蛋白水平检测细胞表面p-gp表达.结果 1.25 mmoL/L的AS-VEGF真核表达载体转染HL60和HL30/VCR细胞株后继续培养24和48 h与未转染组比较均可明显抑制细胞生长,细胞生长减慢;转染组细胞48与24 h相比较VEGF、MDRI、MRP、GSTπ和TopoⅡβ的表达量均明显减少,Bcl-2、Mcl-1和TopoⅡα表达量则无明显变化;转染组HL60/VCR细胞表面p-gP表达量48与24 h相比较也明显减少.结论 AS-VEGF可通过抑制白血病细胞生长,改变细胞内的微环境和细胞膜相关蛋白转运通道,降低细胞解毒能力和自我修复能力逆转白血病细胞多药耐药.     

糖皮质激素在急性淋巴细胞白血病中耐药机制的研究进展

糖皮质激素是儿童急性淋巴细胞白血病治疗中的核心药物,对其耐药会直接影响预后。目前就其耐药机制的研究主要是针对细胞凋亡通路的各个环节,包括受体前机制,糖皮质激素受体基因表达、自我诱导功能及受体相关蛋白的缺陷,糖皮质激素目标基因的缺陷及凋亡效应通路受抑制。此外还包括一些其他机制,如急性淋巴细胞白血病细胞基因的表达模式,细胞内氧化还原状态的调节剂──谷胱甘肽水平等。     

多重耐药鲍曼不动杆菌的耐药机制及治疗进展

近年来随着广谱抗生素的大量使用,多重耐药细菌、甚至是泛耐药及全耐药细菌不断产生.鲍曼不动杆菌是一种常见的条件致病菌,目前多重耐药鲍曼不动杆菌(multidrug-resistant acinetobacter baumannii,MDRAB)的院内感染已成为最为棘手的问题之一.MDRAB的耐药机制主要在于产生抗菌药物灭活酶、靶位或细胞功能改变、外膜屏障及药物主动外排泵作用.治疗MDRAB感染的药物包括舒巴坦制剂、碳青霉烯类、多黏菌素类、四环素类及其他药物.但是由于缺乏大规模的临床研究,目前对于MDRAB的治疗尚无统一的规范,儿科的临床经验更少.     

肺耐药相关蛋白与白血病多药耐药

肺耐药相关蛋白(LRP)的本质是人类主穹窿蛋白。LRP可以在正常细胞和包括白血病在内的多种肿瘤细胞中表达,并诱导非P-糖蛋白介导的多药耐药。本文对LRP的分子生物学特征、耐药机制、不同耐药蛋白质间的异同及IRP与白血病多药耐药的关系等问题进行综述,以便找出干预或克服LRP,引起多药耐药的对策。     

三氧化二砷对维甲酸耐药的神经母细胞瘤细胞SK-N-AS中HoxC9表达的影响

目的 本研究通过检测三氧化二砷(ATO)处理前后维甲酸(RA)耐药的SK-N-AS细胞中HoxC9以及EZH2的表达,初步探寻ATO促进RA耐药的NB细胞分化的具体机制.方法 用CCK-8试剂盒测定ATO对NB细胞SK-N-AS增殖抑制率,倒置相差显微镜下观察细胞生长情况,并测量神经突触总长度值.利用质谱技术和非标定量...     

细胞因子诱导的杀伤细胞的临床应用

细胞因子诱导的杀伤细胞是新一代过继性免疫T细胞,因其增殖速度快、杀瘤活性高、杀瘤谱广、对多重耐药肿瘤细胞敏感、不受环孢素A和FKS06等免疫抑制剂的影响及对正常骨髓造血前体细胞毒性很小等优点,已愈来愈得到血液肿瘤学界的关注,在儿科的临床应用也将越来越广泛,尤其在清除白血病微小残留病、根治病毒性肝炎等领域将发挥重要作用.     

Clinical relevance of in vitro drug resistance testing in childhood acute lymphoblastic leukemia: The state of the art

Nowadays about two-thirds of children with acute lymphoblastic leukemia (ALL) can be cured with chemotherapy, but one-third die from the disease. The clinical response of leukemic cells to chemotherapy is roughly due to two factors: the effective drug levels reaching the cells and the resistance of these cells to the drugs. The clinical value of cellular drug resistance in children with ALL is not known. We developed an in vitro assay to study drug resistance in these children. In this article, the main results obtained with this MTT assay on samples from 137 children with ALL are summarized: (1) patients whose cells are resistant to several drugs at initial diagnosis have a poor prognosis; (2) relapsed leukemias show a considerable drug resistance which might partly explain the poor prognosis. Relapsed cases differ in their type and degree of resistance; (3) the poor outcome of high risk groups as defined by age and immunophenotype can partly be explained by specific patterns of drug resistance; (4) P-glycoprotein-mediated multidrug resistance is not an important cause of resistance in childhood ALL; and (5) no relation exists between the activities of the purine enzymes HGPRT, 5′NT, ADA, and PNP and drug resistance in childhood ALL. The conclusion is that in vitro drug resistance data have clinical relevance and can be used to develop more effective and less toxic treatment strategies in childhood ALL. © 1994 Wiley-Liss, Inc.     

Role of chemotherapy in the treatment of brain tumors

Chemotherapy is a treatment of choice for children with brain tumors, since 20% are unresectable (hypothalamic and brainstem), or incompletely removed, and since radiation therapy often induces cognitive and endocrine sequellae. However, tumor cell heterogeneity and blood-brain barrier which play a role in restricting delivery of chemotherapy represent limiting factors to its efficiency. Neuroradiological procedures such as CT scan and magnetic resonance imaging may bring objective criteria in order to evaluate the efficacity of chemotherapy. Chemotherapy is tested in phase II trials to identify the most efficient drugs for each histological tumor type. This provides a rationale to elaborate phase III trials where polychemotherapy is combined to surgery and radiotherapy. Attempts to enhance drug penetration, such a high-dose chemotherapy and blood-brain barrier disruption, are under study. Primary and acquired drug resistance are being studied as well as the means of overcoming them.     

外泌体与白血病

外泌体是一种含有生物活性成分及信号分子的细胞外纳米级囊泡,能被体内细胞释放.白血病细胞来源的外泌体存在于白血病患者的血浆及白血病细胞培养上清液中,能把内部含有的白血病相关抗原及各种微小RNA呈递给靶细胞,不仅影响白血病的发生发展,也与白血病的治疗及预后密切相关.     

Neonatal transfusion malaria requiring exchange transfusion

Transfusion-acquired malaria in a neonate is uncommon and factors such as drug resistance and concomitant G6PD deficiency can cause treatment difficulties. We report a 26-day-old premature infant with chloroquine-resistant malaria who underwent exchange transfusion. The aim was to correct anaemia, decrease parasitaemia and remove G6PD-deficient cells to allow successful use of quinine.     

新乡市第一人民医院儿科1997年至2008年急性感染性疾病的耐药性变迁

目的 了解新乡市第一人民医院儿科1997年1月至2008年9月急性感染性疾病主要病原菌分布及耐药情况.方法 采用全自动微生物鉴定系统及纸片扩散法(K-B法)对2 733株菌株进行药敏试验.结果 在2 733株病原菌中革兰阴性菌占59.4%,革兰阳性菌占36.4%,真菌占4.2%.对大肠埃希菌、肺炎克雷白菌、铜绿假单胞菌高度敏感抗菌药物为亚胺培南、多粘菌素.革兰阳性菌中占前三位的为金黄色葡萄球菌、凝固酶阴性葡萄球菌和肺炎链球菌,是儿童急性感染的主要菌群.耐甲氧西林凝固酶阴性葡萄球菌的比例逐年升高,2005年至2006年、2007年至2008年与2001年至2002年相比均有显著性差异(P=0.003或P=0.024).耐药率较低的抗菌药物为万古霉素、亚胺培南等.金黄色葡萄球菌多对青霉素、红霉素和阿奇霉素产生耐药性,且耐药率近年有普遍增高趋势.凝固酶阴性葡萄球菌耐药率逐年增高趋势尤其明显.肺炎链球菌对青霉素、红霉素、阿奇霉素、诺氟沙星、罗红霉素等高度耐药.结论 对儿童急性感染性疾病在用药前应尽快做细菌培养及药敏试验以指导临床合理使用抗生素,从而有利于减少耐药菌株的产生.     

Cellular drug resistance in acute myeloid leukemia: literature review and preliminary analysis of an ongoing collaborative study.

Cellular drug resistance is one of the main causes of the frequent ultimate failure of chemotherapy in childhood acute myeloid leukemia (AML). We here summarize the results of a literature review on in vitro drug resistance in childhood AML, focusing on studies using so-called cell culture assays. We also briefly describe some results of an ongoing collaborative study between the Research Laboratory of Pediatric Oncology in Amsterdam (University Hospital Vrije Universiteit) and the German BFM-AML Group. In general, the literature and our preliminary data on in vitro cellular drug resistance in AML are promising in terms of clinical relevance. Cell biological features and clinical response to chemotherapy are related to in vitro drug resistance. However, a large study including multivariate analysis is required to more firmly establish the clinical value of cellular drug resistance testing in childhood AML, and the collaborative study will therefore be continued. Possible applications of cell culture assays include risk-group stratification, rational improvements of current treatment protocols for subgroups of patients based on specific drug resistance profiles, individualised tailored therapy, the study of cross-resistance patterns between drugs, the study of possibilities to modulate or circumvent drug resistance, the study of drug interactions, selection of patients for clinical phase II studies and drug screening.     

新乡市第一人民医院儿科1997年至2008年急性感染性疾病的耐药性变迁

目的 了解新乡市第一人民医院儿科1997年1月至2008年9月急性感染性疾病主要病原菌分布及耐药情况.方法 采用全自动微生物鉴定系统及纸片扩散法(K-B法)对2 733株菌株进行药敏试验.结果 在2 733株病原菌中革兰阴性菌占59.4%,革兰阳性菌占36.4%,真菌占4.2%.对大肠埃希菌、肺炎克雷白菌、铜绿假单胞菌高度敏感抗菌药物为亚胺培南、多粘菌素.革兰阳性菌中占前三位的为金黄色葡萄球菌、凝固酶阴性葡萄球菌和肺炎链球菌,是儿童急性感染的主要菌群.耐甲氧西林凝固酶阴性葡萄球菌的比例逐年升高,2005年至2006年、2007年至2008年与2001年至2002年相比均有显著性差异(P=0.003或P=0.024).耐药率较低的抗菌药物为万古霉素、亚胺培南等.金黄色葡萄球菌多对青霉素、红霉素和阿奇霉素产生耐药性,且耐药率近年有普遍增高趋势.凝固酶阴性葡萄球菌耐药率逐年增高趋势尤其明显.肺炎链球菌对青霉素、红霉素、阿奇霉素、诺氟沙星、罗红霉素等高度耐药.结论 对儿童急性感染性疾病在用药前应尽快做细菌培养及药敏试验以指导临床合理使用抗生素,从而有利于减少耐药菌株的产生.     

Differential chemosensitivity in a child with congenital relapsing acute lymphoblastic leukemia

Described is a case of a boy with congenital acute lymphoblastic leukemia (ALL) with pre-pre-B-ALL immunophenotype, presenting as diarrhea, organomegaly, hyperleucocytosis of 1434 G/L, and tumorlysis syndrome. The lymphoblasts showed low proliferative activity and high in vitro drug sensitivity measured by the MTT assay. An excellent response to therapy was observed, but relapse occurred 3 months later. On relapse, blasts showed extremely high drug resistance, high expression of P-glycoprotein, and high proliferative activity. The response to therapy was again positive, but a second relapse occurred in 1 month. The MTT assay indicated increasing drug resistance to all drugs. Cytogenetic analysis revealed deletion in 11q23 locus. This unfavorable case shows complex biology and differential drug resistance in congenital leukemia.     

学龄前儿童中耳感染病原菌分布及耐药性分析

目的 研究引起学龄前儿童中耳感染的病原菌分布及耐药特征。方法 选取2012年1月—2015年12月就诊的中耳感染患儿,进行耳分泌物常规病原菌分离培养及药物敏感性试验。结果 分离出病原菌200株,包括革兰阳性球菌156株,占78.0%,主要包括肺炎链球菌、金黄色葡萄球菌等;革兰阴性杆菌38株,占19.0%,主要为铜绿假单胞菌;念珠菌6株,占3%。肺炎链球菌对红霉素、四环素、克林霉素、复方新诺明的耐药率高,对青霉素的耐药率低,金黄色葡萄球菌对青霉素的耐药率高,未见对万古霉素、利奈唑胺、达托霉素耐药的金黄色葡萄球菌。在常规监测的12种抗菌药物中,铜绿假单胞菌总体耐药性低,各抗菌药物的耐药率均32%。结论 学龄前儿童中耳感染的常见病原菌为肺炎链球菌、金黄色葡萄球菌、铜绿假单胞菌,不同细菌对不同抗菌药物的耐药性不同,合理用药是控制感染的关键。     

Tuberculosis in children--what has changed in last 20 years?

Several changes have been observed in the epidemiology, clinical manifestations, diagnostic modalities and treatment of tuberculosis. Emergence of HIV epidemic and drug resistance have posed significant challenges. With increase in number of diseased adults and spread of HIV infection, the infection rates in children are likely to increase. It is estimated that in developing countries the annual risk of tuberculosis infection in children is 2.5%. Nearly 8-20% of the deaths caused by tuberculosis occur in children. Lymph node tuberculosis has increased over last two decades. HIV infected children are at an increased risk of tuberculosis, particularly disseminated disease. In last two decades drug resistant tuberculosis has increased gradually. The rates of drug resistance to any drug varied from 20% to 80% in different geographic regions. Various diagnostic techniques such as improved culture techniques, serodiagnosis, and nucleic acid amplification have been developed and evaluated to improve diagnosis of childhood tuberculosis. Serodiagnosis is an attractive investigation but till date none of the tests have desirable sensitivity and specificity. Tests based on nucleic acid amplification are a promising advance. Relatively less experience in children, need for technical expertise and high cost are limiting factors for their use in children with tuberculosis. Short-course chemotherapy for childhood tuberculosis is well established. Treatment with intermittent regimens is comparable to daily regimens. Directly observed treatment strategy have shown encouraging result.