Desferoxamine (DFO) – Mediated Iron Chelation: Rationale for a Novel Approach to Therapy for Brain Cancer

Iron homeostasis is crucial to normal cell metabolism, and its deficiency or excess is associated with numerous disease states. The association of increased iron load with cancer may be due to several factors including free radical production, reduction of the body's protective mechanism to combat oxidative stress, inhibition of immune systems, inhibition of essential nutrient functions, facilitation of cancer growth, suppression of antitumor actions of macrophages, and lowering of the ratio of T4-T8 positive lymphocytes. Antiproliferative effects of desferoxamine (DFO) both in vitro and in vivo are mediated by an intracellular pool of iron that is necessary for DNA synthesis rather than prevention of iron uptake from transferrin. Several clinical studies have shown it to have antitumor activity in the treatment of neuroblastoma, leukemia, bladder carcinoma, and hepatocellular carcinoma. Human neural tumor cells are susceptible to the effects of DFO. Continued study of DFO is necessary to further elucidate its antineoplastic profile and its use as an adjunct to current chemotherapy regimens. Given the lack of satisfactory treatment of central nervous system neoplasms, DFO could serve as an important tool in the management of such cancers.     

Reference distributions for serum iron and transferrin saturation: a comparison of a large cohort to the world's literature

The appropriate clinical use of serum iron and transferrin saturation (TSAT) requires satisfactory reference intervals from birth to old age, and for males and females. This study identified 54 publications from 1974 to 2001 that met the criteria used in three prior meta-analyses, and these were analyzed statistically. A summary of our review is presented along with our reference population data on these measurements. This analysis places previous publications in perspective and suggests possible reasons for the observed differences. Previous studies of the individual analytes, serum iron, transferrin, and TSAT values agree with the reference ranges presented in this study, although the entire experience over time and between sexes has not been available before. Our 95% reference ranges are somewhat broader than those of the smaller studies, but they agree well with those of the larger ones.     

Neural cell adhesion molecule is endocytosed via a clathrin-dependent pathway

Neural cell adhesion molecule (NCAM) constitutes a group of cell surface glycoproteins that regulate cell-cell interactions in the developing and adult brain. Endocytosis is a mechanism which dynamically controls the amount of cell surface NCAM expression and may involve the rapid changes occurring in NCAM expression under certain physiological or pathological conditions. However, the endocytic pathway of NCAM is presently unknown. Using astrocytes in culture and immunofluorescence we show that NCAM is internalized and that the immunolabelling presents a high degree of colocalization with clathrin, alpha-adaptin and transferrin, suggesting that NCAM is endocytosed by a clathrin-dependent pathway. Potassium depletion which disrupts clathrin-mediated endocytosis, inhibited internalization of NCAM. Electron microscopy and immunogold studies also demonstrate that the surface of clathrin-coated vesicles are also immunolabelled for both alpha-adaptin and PSA-NCAM, the highly sialylated isoform of NCAM. Furthermore, immunoprecipation studies demonstrate that NCAM is associated with both clathrin and alpha-adaptin, a component of adaptor complex AP-2, in brain, neurons and astrocytes. These findings indicate that NCAM is mainly endocytosed via clathrin-coated vesicles, suggesting a possible mechanism that may contribute to the rapid changes in NCAM expression at the cell surface.     

育龄妇女与儿童转铁蛋白受体的比较研究

目的比较健康儿童和育龄妇女血浆转铁蛋白受体(TfR)、铁蛋白(SF)浓度及TfRSF比值,研究血浆TfR与其它铁营养状况评价指标的相关性。方法以3组健康人群(3～6岁学龄前女童109名,11～12岁青春前期女孩133名,20～45岁育龄妇女115名)为研究对象,比较各组血浆TfR、铁蛋白(SF)浓度及TfRSF比值,研究TfR与SF、血红蛋白(Hb)、总铁结合力(TIBC)及年龄相关性。结果血浆TfR浓度在学龄前女童最高,青春前期女孩次之,育龄妇女最低,分别为(23.34±6.78)、(21.33±5.30)和(19.86±4.83)nmolL。青春前期女孩的血浆SF浓度高于育龄妇女,育龄妇女高于学龄前女童,分别为(60.37±33.39)、(57.17±29.81)和(47.83±24.49)μgL。TfRSF比值在学龄前女童最高,青春前期女孩次之,育龄期妇女最低,分别为(0.72±0.83)、(0.48±0.47)、(0.47±0.37)。多元线性回归分析表明,SF、Hb、年龄对TfR有影响。结论血浆SF、Hb(即使SF、Hb在正常值范围内)及年龄均对TfR有影响,储备铁含量越低SF对TfR的影响越强。儿童血浆TfR含量高于成年人,表明儿童生理性储备铁含量低于成年人。     

丙氨酰-谷氨酰胺营养支持联合参芪扶正注射液对恶性肿瘤恶液质患者白蛋白的影响

目的采用丙氨酰-谷氨酰胺营养支持,观察其对恶性肿瘤恶液质患者血清白蛋白(ALB)、转铁蛋白(TRF)、前白蛋白(PAB)的影响。方法恶性肿瘤恶液质患者52例随机分为治疗组和对照组,各26例。所有患者入院第1天常规营养支持,治疗组加丙氨酰-谷氨酰胺支持治疗14 d。对照组按传统方法进行营养支持。2组治疗前和治疗后的第15天检测ALB、TRF、PAB含量。结果 2组治疗后ALB、TRF、PAB有所上升;治疗后2组ALB,PAB水平比较,差异有统计学意义(P<0.01)。结论丙氨酰-谷氨酰胺在恶性肿瘤恶液质患者中应用能改善患者营养状态,相对缓和患者的恶液质状态。     

血清转铁蛋白受体在小儿缺铁性贫血诊断及分度中的研究

目的:探讨血清转铁蛋白受体(sTfR)在儿童缺铁性贫血(IDA)诊断及其分度中的意义。方法:6月-12岁IDA儿童50例及正常儿童20例均进行血红蛋白(Hb)、sTfR、血清铁蛋白(SF)、血清铁(SI)、总铁结合力(TIBC)测定,并将受测对象分为正常对照组(C组)、轻度IDA组(IDA1组)、中一重度IDA组(IDA2组),计算C组、IDA1组、IDA2组3组间sTfR均数并将其进行统计学分析比较。结果:C组、IDA1组、IDA2组sTfR浓度分别为27.6±9.3 nmol／L、44.3±8.5 nmol／L、63.4±12.6 nmol／L,将其3组间进行方差分析及两两比较,均有显著差异(P<0.01)。结论:sTfR在诊断IDA及判断IDA的严重程度中有着重要的意义。     

肿瘤坏死因子-α和转铁蛋白在肺结核感染中的检测及临床意义

目的通过对肺结核患者肿瘤坏死因子-α(TNF-α)和转铁蛋白(TRF)水平的联合测定,探讨它们在肺结核感染中的作用和临床意义。方法选择547例肺结核患者为病例组,72例健康体检者为对照组。病例组按照结核杆菌涂片结果、临床诊断分型、耐药性差异进行进一步分组,综合分析肺结核患者TNF-α和TRF水平的变化。结果 TNF-α和TRF浓度与痰结核分枝杆菌数量呈正相关;病例组TNF-α水平均高于对照组,差别有统计学意义(P<0.05,P<0.01);TRF水平均高于对照组,除抗酸杆菌阴性者,其余差别均有统计学意义(P<0.01)。抗酸杆菌阳性者TNF-α水平均高于抗酸杆菌阴性者,差别有统计学意义(P<0.01);TRF水平抗酸杆菌阳性者均高于抗酸杆菌阴性者,除抗酸杆菌弱阳性者,其余差别均有统计学意义(P<0.01)。继发性肺结核和结核性胸膜炎TNF-α水平明显高于原发性肺结核和血行播散性肺结核(P<0.01);血行播散性肺结核TRF水平明显高于原发性肺结核、继发性肺结核及结核性胸膜炎(P<0.01)。治疗前,TNF-α和TRF水平在不同耐药者之间差别无统计学意义(P>0.05);治疗后,不同耐药者TNF-α和TRF水平与治疗前比较均下降,除耐多药结核外,其余差别均有统计学意义(P<0.01)。结论 TNF-α和TRF的测定对研究结核杆菌致病机制、抗结核治疗疗效观察及耐药性的产生机制具有重要的研究价值。     

抗CD71抗体抑制移植物抗宿主反应的组织病理学研究

探讨抗CD71抗体在动物体内抗移植排斥反应的作用。采用D2C5 6细胞株表达并提纯抗CD71人 鼠嵌合抗体 ;将人外周血单个核细胞 (PBMC)注射到裸鼠体内建立移植排斥反应动物模型 ;将造模裸鼠分成 3组 :抗CD71抗体组、抗CD4抗体组和Hanks液模型组 ,分别注射抗体及Hanks液 ;2 0天后处死 ,取裸鼠肝、肺、脾组织 ,常规组织病理学处理并进行图像分析。实验发现 :Hanks液模型组动物的肝、肺组织有大量的淋巴细胞浸润、肝细胞坏死及脾脏巨噬细胞活化 ;抗CD71抗体组和抗CD4抗体组的炎症性病变轻于模型组 ,差异具有极显著的统计学意义 (P <0 0 1)。提示 :抗CD71抗体在动物模型体内具有抑制移植排斥反应的作用     

双配体修饰的阿霉素脂质体靶向于脑胶质瘤的体外研究

目的筛选和优化转铁蛋白、叶酸共同修饰的阿霉素脂质体的处方及制备工艺,以期得到具有良好的脑胶质瘤靶向治疗作用的给药系统。方法采用薄膜分散和硫酸铵梯度法制备阿霉素脂质体。将叶酸连接至二硬脂酸磷脂酰乙醇胺-聚乙二醇2000(DSPE-PEG2000-NH2)得到DSPE-PEG2000-Folic,考察不同磷脂种类、药脂比、水化介质和载药时间,对脂质体粒径、包封率和稳定性的影响,确定脂质体的处方工艺。以大鼠的脑毛细血管内皮细胞(bEnd3)和星形胶质细胞组成体外血脑屏障(blood-brain barrier,BBB),并结合大鼠胶质瘤C6细胞,构建体外模拟胶质瘤靶向治疗的复合BBB模型。考察阿霉素脂质体在bEnd3细胞中的摄取机制和透过BBB的转运速率及对C6细胞的毒性。结果确定了DSPC作为主要磷脂组分,并以120 mmol.L 1的硫酸铵作为水化介质,药脂比为1∶1 5,载药时间选择60 min,成功制备了高包封率和稳定性的双配体脂质体。其在bEnd3细胞中摄取远大于普通脂质体(P<0.05),摄取过程受网格蛋白和小窝内陷介导的细胞内吞作用,并受转铁蛋白和叶酸的影响;同时其在BBB模型中的药物透过速率、及其进一步透过BBB后对下层C6细胞的毒性,均显著高于其他脂质体组。结论转铁蛋白和叶酸共同修饰的阿霉素脂质体具有较好的体外脑胶质瘤靶向治疗作用。