Bispecific-armed, interferon gamma-primed macrophage-mediated phagocytosis of malignant non-Hodgkin's lymphoma

To show that macrophages can be effectively targeted against malignant B cells, bispecific antibodies (BsAb) were constructed from two antibodies having specificity for the high-affinity Fc receptor for IgG (Fc gamma RI/CD64) and the B-cell differentiation antigens CD19 and CD37. Using a flow cytometry-based assay and confocal imaging, we show that these constructs mediated significant phagocytosis of B lymphocytes by macrophages that could be enhanced with interferon gamma (IFN gamma) and IFN gamma in combination with macrophage colony- stimulating factor. BsAb-dependent phagocytosis was triggered through Fc gamma RI and could be blocked only by using F(ab')2 fragments from the parent molecule or by cross-linking Fc gamma RI. BsAb-dependent phagocytosis was not blocked by antibodies to the other Fc receptors, Fc gamma RII and Fc gamma RIII. Because these antibody constructs bind to an epitope outside the Fc gamma RI ligand binding site, we show that autologous serum, polyclonal IgG, and monomeric IgG1 did not block BsAb- dependent phagocytosis, whereas autologous serum and the IgG fractions blocked parent molecule monoclonal antibody-dependent phagocytosis due to the avid binding of monomeric IgG to Fc gamma RI. Finally, BsAb- mediated phagocytosis was effective against the malignant B cells of patients with mantle cell lymphoma, prolymphocytic leukemia, and chronic lymphocytic leukemia. Based on these studies, we propose that BsAbs may provide an effective means of immunomodulation for patients with B-cell malignancies.     

Relaxant effect and possible mechanism of 17-nor-subincanadine E in rabbit corpora cavernosa

Compounds with dual action on cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) may be a treatment option for erectile dysfunction, as they not only promote penile erection but also prevent the upregulation of phosphodiesterase-5. In this study, we examined the possible relaxant effect and mechanism of 17-nor-subincanadine E (SEC, 0.2–200 µmol l⁻¹), a plant-derived alkaloid, in rabbit corpus cavernosum (RbCC) strips that had been precontracted by exposure to phenylephrine (10 µmol l⁻¹) or a high concentration of K⁺ (60 mmol l⁻¹) in vitro. In addition to SEC''s effect on cAMP and cGMP levels, electrical field stimulation (EFS) in phenylephrine-precontracted RbCC and calcium chloride (1–100 mmol l⁻¹) evoked responses in depolarized RbCC were analysed. SEC relaxed the phenylephrine-precontracted RbCCs in a concentration-dependent manner. Atropine, guanethidine and N-ω-nitro-ℓ-arginine methyl ester (L-NAME) did not have any effect on the relaxation of RBCCs. When 1H-^{1, 2, 4}oxadiazole[4,3-a] quinoxalin-1-one (ODQ) was added, it effectively blocked the relaxant response of SEC. Although SEC enhanced the maximal relaxation produced by sodium nitroprusside (SNP) and forskolin in phenylephrine-precontracted cavernosal smooth muscle, it caused a decrease in the maximal contractile response induced by calcium chloride in depolarized RbCCs. The relaxant effect of SEC was paralleled by an increase in the tissue levels of the cyclic nucleotides cAMP and cGMP. We conclude that SEC promotes the relaxation of RbCC, possibly favouring cAMP and cGMP accumulation and calcium blockade. This novel mechanism could be useful for patients who do not benefit from phosphodiesterase inhibitors and for those with endothelial and nitrergic dysfunction, such as patients with diabetes, hypertension and dyslipidaemias.     

中国成人硒需要量研究

目的 探讨使人体血浆硒蛋白P(SEPPI)达到饱和的硒摄入量,以评估硒需要量,为膳食硒参考摄入量DRIB的修订提供参考.方法 时98名低硒健康受试者(体重平均58kg)进行为期40w的双盲补硒实验.随机分为七组,补硒(以硒蛋氨酸形式)剂量分别为0、21、35、55、79、102和125 μg/d.定期检测血浆中谷胱甘肽...     

纳米羟基磷灰石/硫酸庆大霉素缓释系统的制备及体内释放实验

目的:制备纳米羟基磷灰石/硫酸庆大霉素缓释系统(drug delivery system,DDS),观察其体内释药特性,为慢性骨髓炎的治疗寻找更好的方法。方法:实验于2004-05/2005-03在南方医科大学珠江医院中心实验室和华南理工大学生物工程与材料学院实验室完成。实验材料:纳米羟基磷灰石(nano-hydroxypatite,nano-HA)、聚羟基丁酸酯-羟基戊酸酯共聚物[poly(3-hydroxybutyrate-hydroxyvalerate),PHBV]、聚乙二醇(polyethylene glycol,PEG)、硫酸庆大霉素(gentamicin,GM)。新西兰大白兔24只。实验方法:①nano-HA/PHBV-PEG-GM-DDS的制备:以nano-HA为载药核心,外包裹生物相容性好且降解可调控的PHBV、PEG,承载GM制成。②采用SPSS10.0统计软件包绘制庆大霉素浓度与抑菌环直径的半对数标准曲线。③体内释放实验:在新西兰大白兔左股骨外上髁钻孔,刮除部分骨质和骨髓,将nano-HA-PHBV/PEG-GM微球自骨窗内植入,分别于术后1,3,5,7,10,14,21,28d8个时间点各选3只大白兔,麻醉后取干骺端松质骨及骨干皮质骨标本。用标准曲线计算出各标本药物浓度,用SPSS10.0统计软件包绘制nano-HA/PHBV-PEG-GM-DDS的释药浓度与时间关系曲线。实验评估:①扫描电镜下观察nano-HA/PHBV-PEG-GM-DDS的微球形态。②nano-HA/PHBV-PEG-GM-DDS的释药浓度与时间的关系。结果:纳入兔24只,均进入结果分析。①nano-HA/PHBV-PEG-GM-DDS微球形态:大小均匀规整,微球平均粒径为345μm,小微球粒径为78μm,微球表面形态一致,为多孔皱缩结构。②nano-HA/PHBV-PEG-GM-DDS释药浓度与时间的关系:术后第1天nano-HA/PHBV-PEG-GM-DDS周围皮质骨和松质骨中庆大霉素质量浓度分别为(110.10±11.70),(97.30±9.60)mg/L,其后逐渐下降,至术后第28天时皮质骨和松质骨中庆大霉素质量浓度仍可分别达(7.30±1.40),(6.80±1.10)mg/L,局部骨组织中庆大霉素质量浓度仍在金黄色葡萄球菌最小抑菌浓度(2mg/L)以上。结论:nano-HA/PHBV-PEG-GM-DDS具有较好的体内缓释作用。