A trip through the signaling pathways of melanoma

Many cellular signaling pathways are involved in the development of cancer. Depending on the tumor entity, the nature as well as the mode of activation can differ. Some signaling pathways frequently show changes as all tumor cells have to fulfill some basic requirements such as independence from growth factors or insensitivity against apoptosis. In this review, the possibilities of a tumor to manipulate signaling pathways to reach these goals are exemplified based on an archetypical melanoma cell. In addition, new therapeutic options based on the knowledge of signaling pathways will be discussed.     

Morphine exposure prevents up-regulation of MR and GR binding sites in the brain of adult male and female rats due to prenatal stress

Our previous work demonstrated that the hormone response to stress and the negative feedback inhibition to these hormones are sex-dependently altered by prenatal morphine exposure in adult rats. An alteration in the glucocorticoid negative feedback inhibition is mediated by glucocorticoid receptors (GR) that are distributed throughout the brain, and mineralocorticoid receptors (MR) localized mainly in the hippocampus and involved in a tonic influence of brain functions. Therefore, the present study examined the binding characteristics of MR and GR in young adult male and female rats exposed prenatally (E11-E18) to morphine (10 mg/kg/2 x /day), saline or no treatment at all (controls). At 60-90 days of age, animals were adrenalectomized (ADX) 24 h prior to decapitation. The hippocampus and hypothalamus were dissected for saturation binding assays. The data demonstrate that prenatal stress due to maternal saline injections up-regulates MR and GR binding in the hippocampus of adult male rats and this effect is prevented by prenatal morphine exposure. There is no effect of prenatal morphine exposure on GR binding in the hypothalamus of males. In female rats, prenatal morphine exposure does not affect the binding of MR and GR in the hippocampus or GR in the hypothalamus relative to controls; however, they are affected by ovarian hormone fluctuation. Moreover, prenatal stress decreases MR binding in the hippocampus of diestrous females and GR binding in the hypothalamus of estrous females. Both decreases are prevented by prenatal morphine exposure. Thus, the present study demonstrates that: (1) prenatal stress due to maternal saline injections alters MR and GR binding of adult male and female rats and is prevented by prenatal morphine exposure; (2) the MR and GR binding in adult female rats are affected by ovarian hormone fluctuations.     

1,25(OH)2Vitamin D3 induces elevated expression of the cell cycle inhibitor p18 in a squamous cell carcinoma cell line of the head and neck

BACKGROUND: 1Alpha,25-dihydroxyvitamin D(3) [1,25(OH)(2) Vitamin D(3)] induces growth inhibition in squamous cell carcinoma (SCC) cell lines of the head and neck by arresting the cells in the G0/G1 phase of the cell cycle, probably due to an enhanced expression of p21, which could be demonstrated in other cell lines (JPPA, SCC9) before. In SCC25, a SCC cell line isolated from tongue, growth inhibition but no overexpression of p21 was detected. The retinoblastoma gene, as a direct target of G1 cyclin-CDK complexes, showed an obvious shift from the hyperphosphorylated to the hypophosphorylated form under 1,25(OH)(2)Vitamin D(3), which indicates that the growth inhibition takes place in the G0/G1 phase. To explore the possible pathway of growth inhibition in SCC25 we investigated other cell cycle inhibitors (p18, p19, p27). METHODS: Synchronized cells were treated with 1,25(OH)(2)Vitamin D(3) over 96 h. The cell cycle status and expression of cell cycle-regulating proteins was determined by fluorescence-activated cell sorting (FACS) and Western blotting. An overexpression of p18 in 1,25(OH)(2)Vitamin D(3) vs. ethanol-treated cells was determined until 30 h in SCC25. No influence was detectable on the expression of p27 and p19. CONCLUSION: One mechanism by which 1,25(OH)(2)Vitamin D(3) controls cell growth might be the upregulation of p21. As p21 was unsusceptible to 1,25(OH)(2)Vitamin D(3) in SCC25, other inhibiting proteins were necessary to be tested. The proven upregulation of p18 seems to be the responsible step for growth inhibition of 1,25(OH)(2)Vitamin D(3) in SCC25.     

Acoustic rhinometry in pre-school children

Acoustic rhinometry was performed in 35 normal nose-breathing children between 3 and 6 years. The average cross-sectional areas at the nasal valve, at the anterior end of the turbinates, and in the nasopharynx were 0.34±0.06 cm², 0.35±0.08 cm² and 1.37±0.48 cm² respectively. The average minimal cross-sectional area was 0.29±0.06 cm². The minimal cross-sectional area was located at the nasal valve in 14 and at the anterior end of nasal tubinates in 21 of the 35 children. As would be expected, the cross-sectional areas at different sites of the nasal cavity increased with increasing age of the children. But, whereas the minimal cross-sectional area increased by 0.024 cm² per year, the nasopharyngeal cross-sectional area increased by 0.20 cm² per year. No significant differences were found between boys and girls. Measurements of the posterior nasal and nasopharyngeal cross-sectional areas were unreliable, whenever the minimal cross-sectional area was less than 0.2 cm². Furthermore, assessment of the nasopharynx may be difficult because of involuntary movements of the soft palate.     

Motivated behavior and the estrous cycle in rats

(1) The estrous cycle in the rat may be used to study recurrent changes in motor behaviors and motivation which are strongly related to cyclic hormonal and CNS changes. (2) The peak in motivated behaviors occurs during a sharply defined period on the night between proestrus and estrus and is evident in facilitated wheel-running, lordosis, and intracranial self-stimulation. (3) Behaviors without a clearly motivated character do not show an estrous cyclicity. (4) The estrous cyclic variation in intracranial self-stimulation was observed at a specific locus — the pars campacta of the substantia nigra. (5) A neurochemical link between sexually motivated behavior, wheel running and intracranial self-stimulation is suggested. This link is in part dopaminergic but is probably also activated by many other systems.     

二甲基亚砜诱导人肝癌细胞BEL-7402凋亡的研究

目的 :研究二甲基亚砜 (DMSO)对人肝癌细胞凋亡的诱导作用。方法 :用不同浓度的DMSO处理体外培养的人肝癌细胞BEL 74 0 2 ,应用普通光镜、荧光显微镜、MTT分析方法和流式细胞技术 (FCM )检测肝癌细胞凋亡的形态学变化、细胞存活率、凋亡百分率和细胞周期分布的变化。结果 :DMSO诱导BEL 74 0 2细胞核DNA凝缩和核片段化 ,最后形成凋亡小体 ;随着DMSO浓度的增加和处理时间的延长 ,细胞存活率明显下降 ,其IC50 为 1.9% ;2 %的DMSO处理细胞 12h ,凋亡率达 17.2 1% ,同时S期细胞明显增加 ,G2 M期细胞明显下降。结论 :DMSO可诱导人肝癌细胞凋亡 ,并使细胞受阻于S期而进入凋亡程序。     

二乙酰二脱水卫矛醇对小鼠白血病L1210细胞增殖的影响

目的　研究二乙酰二脱水卫矛醇 (1 ,2 :5 ,6 dianhydro 3 ,4 diacetylgalactitol,DADAG)的抗脑白血病作用及机制。方法　用小鼠脑内移植瘤模型、MTT法、DNA掺入法、流式细胞仪和Westernblot法 ,观察DADAG对小鼠脑内移植瘤和体外白血病L1 2 1 0 细胞的作用 ,并探讨作用机制。结果　DADAG对DBA/ 2小鼠脑内移植白血病L1 2 1 0 有明显的抑制作用 ;对体外白血病L1 2 1 0 细胞同样有很强的抗增殖作用 ,其IC50 值为 2 4 6mg·L- 1 。DADAG不可逆地抑制L1 2 1 0 细胞内DNA的生物合成。DADAG 2 4mg·L- 1 处理L1 2 1 0 细胞 6h后 ,细胞发生G2 /M周期阻滞 ,2 4h后达最高峰。细胞周期素B1 蛋白水平在DADAG处理 2 4h后开始下降 ,而磷酸化的细胞周期依赖性激酶CDK1在DADAG处理 6h后开始上调 ,并呈时间依赖性。结论　DADAG的抗脑白血病作用与其抑制白血病细胞的增殖密切相关     

Reproductive Function in Epilepsy

Summary: : The hypothalamic-pituitary-gonadal axis is a complex system within which both positive and negative feedback occur among its elements and higher brain systems. The occurrence of seizures and changes in the secretion of pituitary hormones can affect the feedback loop. Both seizures and antiepileptic drugs can affect the hypothalamic-pituitary-gonadal axis of males and females and cause changes in hormones and sexuality. Reproductive dysfunction has a social impact because of reduced fertility. Once conception occurs, live birth rates are not diminished. Prospective studies of men and women with epilepsy are needed.     

REPERFUSION FOLLOWING MYOCARDIAL ISCHAEMIA ENHANCES INOSITOL PHOSPHATE RELEASE IN THE ISOLATED PERFUSED RAT HEART

1. Global myocariial ischaemia (MI) for periods greater tan 5 min caused an inhibition of phosphatidylinositol specific phospholipase C (PtdIns-PLC) activity. 2. Two min reperfusion following a 20 min MI period, a time point associated with reperfusion-induced arrhythmias, resulted in an activation of PtdIns-PLC activity, dependent on endogenous noradrenaline and mediated via al-adrenoceptors. 3. This 2 min reperfusion response, in contrast to healthy myocardium, resulted in: (i) enhanced PtdIns-PLC activity; (ii) increased sensitivity to endogenous noradrenaline; (iii) rapid increases in inositol(1,4,5)trisphosphate (Ins(1,4,5)P3); and (iv) PLC hydrolysis primarily of PtdIns(4,5)P₂, such that the majority of InsP isomers derive from Ins(1,4,5)P₃. 4. Together, these data suggest a functional role for Ins(1,4,5)P3 under postischaemic reperfusion conditions, and provide a possible link between al-adrenoceptor stimulation of the PtdIns turnover pathway and reperfusion injury.     

育龄妇女月经周期中心血管功能的变化

本研究采用先进的三维超声成像技术及多普勒技术对正常育龄妇女月经周期中心血管功能进行研究。结果：月经周期中ＨＲ、ＢＰ无变化；血清Ｅ２是周期性变化，排卵前达高峰。ＳＶ、ＣＯ、ＥＦ在排卵前期升高达峰值，显著高于月经期和黄体期；ＳＶＲ排卵前期最低，而Ｖｅｄ、Ｖｅｓ无变化。Ｖｍａｘ、Ａ、Ｅ在内源性Ｅ２高峰时明显加快，而Ｅ／Ａ比值无明显变化。结果提示：月经周期中随内源性Ｅ２的周期性变化，心脏功能也发生周期性变化。Ｅ２高峰时，心输出量、心搏量和射血分数达最高。外周阻力最低，心脏内血流速度加快。