Hormone-induced refractoriness to mammary carcinogenesis in Wistar- Furth rats

One of the most consistent results in the epidemiology of human breast cancer is the inverse relationship of risk and early full-term parity. The goal of this study was to investigate the molecular mechanisms through which early full-term pregnancy protects the breast from cancer development. We used Wistar-Furth (WF) rats as our experimental system and mimicked pregnancy using estrogen and progesterone (E/P). Sexually mature female rats were treated with steroid hormones for 21 days and after 28 days of gland involution, the rats were administered MNU. Rats that received a high dose of 20 microg E and 20 mg P exhibited an 82% reduction in the incidence of mammary adenocarcinomas as compared to the rats receiving only blank pellets. Decreasing doses of E/P were partially protective suggesting that complete differentiation of the gland was not required for refractoriness. We measured the RNA expression levels of several target genes involved in the regulation of mammary cell proliferation and/or differentiation including estrogen receptor (ER) and progesterone receptor (PR), cyclins D1 and D2, the cell cycle inhibitors p16, p21 and p27, and the tumor suppressor p53. At the time of MNU treatment we found no significant differences in the expression of these genes, with the possible exception of p21, indicating that hormone treatment did not result in constitutive changes in expression levels. The numbers of apoptotic cells were low and comparable in the hormone exposed and age-matched virgin gland (AMV) at the time of carcinogen challenge and remained low for 8 days after MNU treatment. The number of BrdU-labeled cells at the time of carcinogen challenge were also low in both the AMV (1.8%) and hormone exposed (0.8%) animals. In contrast, cell proliferation in the AMV (5.7%) was significantly different from both the parous involuted (1.2%) and the E/P-treated involuted (1.5%) animals 8 days after MNU treatment. We interpret these data to indicate that hormone treatment results in mammary epithelial cells that have persistent alterations in intracellular pathways governing proliferation responses to carcinogens.      

Massive acroosteolysis in adult T-cell leukemia/lymphoma

Adult T-cell leukemia/lymphoma is a relatively uncommon disease, most often found in Japan, the Caribbean, the southeastern United States, and South America. To date there have been few reports of its skeletal manifestations. A case is reported in a 44-year-old man in which a short history of swelling of the hands and feet and painful motion in the fingers was followed by the rapid development of severe acroosteolysis.     

羟基磷灰石溶解度等温线的测定

目的：应用微量添加固体滴定和激光散射法测定HA(37℃)溶解度等温线。方法：滴定物为HA。半导体二极管激光为发射光源，散射光源探测器用于监测超过溶解平衡点出现的沉淀。微量添加固体滴定所引发的沉淀引起散射光源显著且恒定地高于基线，由此判断溶液已处于过饱和状态，该固体滴定总量用于代表溶解度等温线的数据点。结果：HA溶解度等温线(37℃)由6次滴定合共50个滴定终点构成。与传统方法所得结果比较，本实验所得HA的溶解度约为过往结果的百份之一。结论：微量添加固体滴定和激光散射法利于研究HA的溶解平衡且能得到准确的HA溶解度等温线。     

自体骨髓间充质干细胞治疗脊髓损伤疗效观察

目的:观察自体骨髓间充质干细胞移植治疗脊髓损伤患者的近期疗效及其安全性。方法:选择2005-04/2006-02在山东省残疾人康复中心住院的脊髓损伤患者24例,采用随机表法分为治疗组和对照组。患者知情同意并签署知情同意书。治疗组11例,对照组13例,均经CT或MRI确诊并行手术治疗。两组在年龄、病程、损伤程度(ASIA分级)等方面均具有可比性(P>0.05)。治疗组在综合康复治疗的基础上给予自体骨髓间充质干细胞治疗,经髂骨穿刺采集自体骨髓156～180mL,分离提取骨髓间充质干细胞后经静脉途径和/或蛛网膜下腔1次性或分次注射。对照组仅给予综合康复治疗。两组均于入院当天、治疗后7,15,30,60,90d进行运动与感觉、日常生活能力、膀胱功能评定。结果:24例患者均进入结果分析。①治疗组11例患者均有不同程度的感觉、运动和自主神经功能改善,与对照组比较,差异不显著。②治疗组ASIA分级A级8例,有2例在第60天、1例在第90天评估中恢复为B级。C级1例,在第30天评估中恢复为D级,第90天评估中恢复为E级,能独立行走,生活完全自理。D级2例,其中1例在第90天评估中恢复为E级。对照组A级9例,1例在第90天评估中恢复为B级。B级1例,治疗后无变化。C级2例,1例在第90天评估中恢复为D级。③骨髓间充质干细胞移植常见的不良反应包括低热(7/11例)、头痛(2/11例)、腹胀(1/11例),其中1例于蛛网膜下腔注射后出现双下肢麻木和脑膜刺激征,均于两三天内自行消失。结论:骨髓间充质干细胞移植治疗脊髓损伤近期有一定疗效而且安全,但远期疗效有待于进一步观察。     

Anti-cancer activity of withaferin A in B-cell lymphoma

Withaferin A (WA), a withanolide from the plant, Ashwagandha (Withania somnifera) used in Ayurvedic medicine, has been found to be valuable in the treatment of several medical ailments. WA has been found to have anticancer activity against various solid tumors, but its effects on hematological malignancies have not been studied in detail. WA strongly inhibited the survival of several human and murine B cell lymphoma cell lines. Additionally, in vivo studies with syngeneic-graft lymphoma cells suggest that WA inhibits the growth of tumor but does not affect other proliferative tissues. We demonstrate that WA inhibits the efficiency of NF-κB nuclear translocation in diffuse large B cell lymphomas and found that WA treatment resulted in a significant decrease in protein levels involved in B cell receptor signaling and cell cycle regulation. WA inhibited the activity of heat shock protein (Hsp) 90 as reflected by a sharp increase in Hsp70 expression levels. Hence, we propose that the anti-cancer effects of WA in lymphomas are likely due to its ability to inhibit Hsp90 function and subsequent reduction of critical kinases and cell cycle regulators that are clients of Hsp90.     

WAY-318068: a novel, potent and selective noradrenaline re-uptake inhibitor with activity in rodent models of pain and depression

Background and purpose:

Antidepressants, which raise the CNS concentrations of 5-HT and noradrenaline, are frequently used in the treatment of chronic pain; however, it is not known if increasing CNS noradrenaline levels alone is sufficient for efficacy, in part resulting from a lack of small molecules with sufficient selectivity.

Experimental approach:

In this report, we present the in vitro pharmacological and in vivo pharmacokinetic and pharmacological properties of the novel, orally available and CNS penetrant inhibitor of the noradrenaline transporter (NET), WAY-318068 (1-[(1S,2R)-1-(3,5-difluorophenyl)-2-hydroxy-3-(methylamino)propyl]-7-fluoro-3,3-dimethyl-1,3-dihydro-2H-indol-2-one).

Key results:

WAY-318068 is a potent and effective inhibitor of the NET with a K_i of 8.7 nM in a binding assay, and an IC₅₀ of 6.8 nM in an assay of transporter function, without significant binding to the dopamine transporter. Furthermore, the compound has only weak activity at the 5-HT transporter, leading to a functional selectivity of greater than 2500-fold. It is orally bioavailable with substantial quantities of the compound found in the CNS after oral dosing. As measured by microdialysis in rats, the compound causes a robust and significant increase in cortical noradrenaline levels without affecting 5-HT. WAY-318068 was effective in models of acute, visceral, inflammatory, osteoarthritic, neuropathic, diabetic and bone cancer pain, as well as in traditional models of depression at doses that do not cause motor deficits.

Conclusions and implications:

Collectively, the present results support the conclusion that selectively increasing CNS levels of noradrenaline is sufficient for efficacy in models of depression and pain.     

人工唾液对两种口腔充填材料承载能力的影响

目的:研究人工唾液对银汞合金和玻璃离子水门汀2种口腔充填材料承载能力的影响,比较不同材料受环境影响的特征.方法:制作10 mm直径、2 mm厚度的银汞合金和玻璃离子水门汀圆盘形试件各80个,各自随机分成8组,分别放入干燥容器和盛有人工唾液的容器内置于37℃恒温箱中保存1、7、30、90 d,置于30%玻璃纤维加强尼龙6,6基底上以20 mm直径不锈钢球加载进行赫兹压痕试验,记录初始断裂载荷值并进行统计分析.结果:在90 d观察期内,银汞合金的断裂载荷值在空气中从(641.09±121.16)N增加到(775.08±105.37)N(P＜0.05),在人工唾液中则从(680.09±115.90)N减少到(620.00±62.17)N,但无统计学差异(P＞0.05).玻璃离子水门汀的断裂载荷值在空气中波动于(391.18±83.10)～(456.25±74.14)N范围,无统计学差异(P＞0.05);在人工唾液中则从(388.70±66.78)N显著减少到(308.45±53.49)N(P＜0.05).经过不同的时间段后,2种材料最终均表现为在人工唾液中的断裂载荷值低于在空气中的值.结论:长期人工唾液浸泡对口腔充填材料的承载能力有明显负性影响;不同材料对储存介质的影响反应不同.