Ex vivo cytotoxic drug evaluation by DiSC assay to expedite identification of clinical targets: results with 8-chloro-cAMP

There is a pressing need to reduce the time and cost of developing new cytotoxic agents and to accurately identify clinically active agents at an early stage. In this study, the differential staining cytotoxicity (DiSC) assay was used to assess the efficacy of the novel antitumour cAMP analogue, 8-chloro-cAMP (8-Cl-cAMP) (and its metabolite 8-Cl-adenosine) against 107 fresh specimens of human neoplastic and normal cells. Diagnoses included chronic and acute leukaemias, myeloma, non-Hodgkin's lymphoma (NHL) and miscellaneous solid tumours. The aim was to identify targets for subsequent phase I, II and III trials. 8-Cl-cAMP was tested at 4-985 microM, along with standard chemotherapeutic drugs. 8-Cl-cAMP and its metabolite caused no morphologically observable cell differentiation but induced dose-dependent cytotoxicity. Compared with untreated patients, previously treated chronic lymphocytic leukaemia (CLL) patients showed no increase in ex vivo resistance to 8-Cl-cAMP (P = 0.878); minimal cross-resistance with other cytotoxic drugs was detected. Compared with normal cells (mean LC90 = 1803 microM), 8-Cl-cAMP showed significant ex vivo activity against CLL (117.0 microM; P < 0.0001) and NHL (140.0 microM; P < 0.0001), of which eight were mantle cell NHL (84.7 microM), and greatest activity against cells from patients with acute myeloid leukaemia (AML; mean LC90 = 24.3 microM; in vitro therapeutic index 74-fold, P < 0.0001). Solid tumour specimens were comparatively resistant to 8-Cl-cAMP. The results highlight the clinical potential of 8-Cl-cAMP, point to several new phase I, II and III trial possibilities and provide a rationale for the inclusion of ex vivo cytotoxic drug evaluation in the drug development process.     

萌芽状态下的移动娱乐业

日本DoCoMoI-mode的成功,使人们感到移动娱乐业务将是移动通信的“杀手应用”。然而,WAP的挫折和失败、用户离网率的增加和ARPU值的下降,又让人们觉得依然是困难重重。目前的主要问题是,除了业务单调外,各个不同的角色还没有找准自己在价值链中的位置。虽然目前GPRS和其他2.5代技术正在快速发展,但只有等到3G设备大范围使用后,一些复杂的游戏才能推出。     

光通信无源器件的现状和展望

文章介绍了近年来光纤活动连接器,光分、合波器,光开关等光通信无源器件的现状及发展趋势,尤其介绍了光纤用户网系统光纤无源器件的开发情况。     

Chronic myelogenous leukemia

Chronic myelogenous leukemia is a clonal hematopoietic malignancy characterized by a balanced translocation between chromosomes 9 and 22 that results in the generation of an abnormal bcr/abl fusion protein with increased tyrosine kinase activity. This abnormal fusion protein has transforming activity for hematopoietic cells in vitro and causes chronic myelogenous leukemia-like myelopoiesis in mice. Chronic myelogenous leukemia progenitor cells display abnormalities in their interactions with bone marrow stroma, perhaps due to defective adhesion molecule function. Conventional therapies for chronic myelogenous leukemia include hydroxyurea, busulfan, or interferon. Treatment with interferon may prolong overall survival, especially in patients who achieve a cytogenetic response. Related donor marrow transplantation can result in long-term survival in more than 65% of patients treated early in the course of disease. For patients without an available matched sibling donor, unrelated donor marrow transplantation or autologous marrow transplantation are alternative therapeutic options.     

阿克库勒凸起奥陶系控油地质特征

阿克库勒凸起位于塔里木盆地沙雅隆起中段的南翼，奥陶系碳酸盐岩具有广阔的油气勘探前景，但受区域构造背景及储集体发育程度控制明显，油气分布不均，通过奥陶系油气藏类型及其分布，控油地质特征等方面分析，并预测了奥陶系油气藏有利成藏分布范围，认为阿克库勒凸起南部斜坡区的岩溶潜丘与强变形地带发育，并保留了有效的储集体和存在多期次的油气运聚成藏，封盖条件较好，是形成大型油气藏的有利部位。     

Differential effects on Xenopus development of interference with type IIA and type IIB activin receptors

One candidate for a mesoderm-inducing factor in early amphibian development is activin, a member of the TGF beta family. Overexpression of a truncated form of an activin receptor Type IIB abolishes activin responsiveness and mesoderm formation in vivo. The Xenopus Type IIA activin receptor XSTK9 differs from the Type IIB receptor by 43 and 25% in extracellular and intracellular domains respectively, suggesting the possibility of different functions in vivo. In this paper, we compare the Type IIA receptor with the Type IIB to test such a possibility. Simple overexpression of the wild-type receptors reveals minimal differences, but experiments with dominant negative mutants of each receptor show qualitatively distinct effects. We show that while truncated (kinase domain-deleted) Type IIB receptors cause axial defects as previously described, truncated type IIA receptors cause formation of secondary axes, similar to those seen by overexpression of truncated receptors for BMP-4, another TGF beta family member. Furthermore, in animal cap assays, truncated type IIB receptors inhibit induction of all mesodermal markers tested, while truncated type IIA receptors suppress induction only of ventral markers; the anterior/dorsal marker goosecoid is virtually unaffected. The suppression of ventral development by the type IIA truncated receptor suggests either that the truncated Type IIA receptor interferes with ventral BMP pathways, or that activin signaling through the Type IIA receptor is necessary for ventral patterning.     

A new silver sulfadiazine water soluble gel

Silver sulfadiazine is the most commonly used topical antibacterial agent for the treatment of burn wounds. It has many clinical advantages, including a broad spectrum of antimicrobial activity, low toxicity, and minimal pain on application. The current formulation of silver sulfadiazine contains a lipid soluble carrier, polypropylene glycol, that has certain disadvantages, including pseudo-eschar formation and the need for twice daily application. The purpose of this investigation was to describe a new formulation of silver sulfadiazine in a water soluble gel, poloxamer 188. The antibacterial activity of this new gel has been compared to that of the commercially available silver sulfadiazine cream by in vitro and in vivo testing. The results of the in vitro antibacterial testing of these two different agents demonstrated the superiority of the new gel formulation. In experimental wounds, the antibacterial activity of the gel and the commercially available silver sulfadiazine cream were not significantly different when applied once a day. The antibacterial activity of the gel when applied once a day was comparable to that encountered by twice daily applications of the silver sulfadiazine cream by experimental wounds. The major advantage of this gel was its ease of application and removal that is attributed to its water solubility.     

塔河油田钻井液体系优化

针对塔河油田的地层特征，研究适合塔河油田储集层的钻井液、完井液和防漏堵漏技术方案，有针对性地优选钻井液性能参数．使钻井液能有效地抑制泥页岩地层的水化膨胀和膏盐地层的污染、预防卡钻等其它井下复杂情况的发生，对提高该油田的钻井速度和储层的保护十分重要。通过对一开、二开、三开、四开井段的钻井液进行筛选试验，优选出密度小于1．20g／cm^2的低密度聚合醇防塌钻井液，密度大于1．20g／cm^3的聚合醇防塌钻井液和抗盐抗钙钻井液3套体系，以及相应的维护处理措施。一开井段，加入适量的包被剂和增粘降滤失剂，配合一定量的清洁剂，确保大井眼中携岩能力，井眼规则，提高固井质量；二开井段降低滤失量、粘度，提高絮凝能力，加强固相设备的使用；三开井段以聚合物抑制为主，加大抑制型聚合物用量，加入抗钙镁及抗温处理剂，补充防塌剂、降滤失剂、包被剂等，提高钻井液粘度，避免强紊流．减少对井壁的冲刷，控制好滤失量；四开井段防止井壁剥蚀掉块，井涌、井喷、漏失，要求钻井液有良好的抗温性能，增加抗盐处理剂。通过对塔河油田钻井液体系的优化，完善了钻井液性能，满足了钻井工程需要，减少了钻井事故，提高了钻井效率。     

Comparison of the roles of CD8 alpha alpha and CD8 alpha beta in interaction with MHC class I

The CD8 molecule is expressed either as an alpha/alpha homodimer or an alpha/beta heterodimer on thymocytes and cytotoxic T cells, and functions as a coreceptor in concert with TCR for binding the MHC class I/peptide complex. Although CD8alpha/beta heterodimers have been shown to be more effective coreceptors, the precise role of the beta-chain in TCR-mediated thymic maturation and T cell activation is not understood. To understand the role of CD8beta in mediating CD8/MHC class I interaction, we examined whether cell surface CD8alpha/beta heterodimer promotes better cell-cell adhesion with MHC class I than the CD8alpha/alpha homodimer. The abilities of different forms of CD8 to adhere to MHC class I were measured with a cell-cell binding assay. Using a wild-type CD8beta and -alpha, we found that CD8alphabeta heterodimers did not mediate greater cell-cell adhesion than CD8alphaalpha homodimers. Furthermore, we found that chimeric CD8beta-alpha homodimers afforded no detectable binding. These results do not support the idea that CD8alphabeta binding to MHC class I is greater than that of CD8alphaalpha. Rather, they point to an alternative explanation in which CD8beta may play an role in promoting CD8/TCR interaction and/or in signaling/regulatory pathways.