Kinesin-5 Contributes to Spindle-length Scaling in the Evolution of Cancer toward Metastasis.

During natural evolution, the spindles often scale with cell sizes to orchestrate accurate chromosome segregation. Whether in cancer evolution, when the constraints on genome integrity are relaxed, cancer cells may evolve the spindle to confer other advantages has not been investigated. Using invasion as a selective pressure in vitro, we found that a highly metastatic cancer clone displays a lengthened metaphase spindle, with faster spindle elongation that correlates with transiently elevated speed of cell migration. We found that kinesin-5 is upregulated in this malignant clone, and weak inhibition of kinesin-5 activity could revert the spindle to a smaller aspect ratio, decrease the speed of spindle pole separation, and suppress post-mitotic cell migration. A correlation was found between high aspect ratio and strong metastatic potential in cancers that evolved and were selected in vivo, implicating that the spindle aspect ratio could serve as a promising cellular biomarker for metastatic cancer clones.

Fasting triglyceride is a major determinant of postprandial triglyceride response in postmenopausal women.

OBJECTIVE: The purpose of the study was to examine the relative influences of fasting lipids, insulin resistance, and waist circumference (WC) on postprandial lipemia in postmenopausal women. DESIGN: Forty-nine naturally postmenopausal women were recruited for the study. Each woman underwent a 75-g oral glucose tolerance test to measure insulin resistance and a 1,000-kcal high-fat mixed meal test for postprandial triglyceride (TG) response. RESULTS: The participants were divided into three groups by tertiles of incremental TG response in the mixed meal test. The three groups were comparable in weight, WC, and fasting high-density lipoprotein cholesterol (HDL-C) levels. There were significant differences in fasting TG and non-HDL-C concentrations among the three groups. The women in the high-tertile group were more insulin resistant than those in the low-tertile group, indicated by higher homeostasis model assessment for insulin resistance (HOMA-IR) values. The postprandial TG response was significantly correlated with Log(fasting TG), fasting non-HDL-C and Log(HOMA-IR), but not with WC, in univariate regression analyses. Log(fasting TG) was the only variable that remained significantly related to incremental TG response when all the above were entered into multiple regression models. Subsequently, we found that Log(HOMA-IR) and fasting non-HDL-C independently predicted the variance of Log(fasting TG) in stepwise multiple regression. CONCLUSIONS: Our data demonstrated that the fasting TG level is a major determinant of postprandial TG response in postmenopausal women. Insulin resistance and non-HDL-C may contribute independently to the fasting TG level. The influences of WC on postprandial lipemia seemed to be insignificant.

Nalbuphine is effective in decreasing the rewarding effect induced by morphine in rats.

Nalbuphine, a kappa-opioid agonist and mu-opioid partial agonist, has been widely used as an analgesic or an adjuvant with morphine in clinics. In rats, it attenuates tolerance and physical dependence caused by morphine, when co-administered. In this study, we investigated the effect of nalbuphine on morphine reward. Using the conditioned place preference (CPP) paradigm in rats, we demonstrated that co-administration of nalbuphine (1mg/kg, i.p.) with morphine (5mg/kg, i.p.) during conditioning could completely block the CPP induced by morphine. However, in experiments examining locomotor activity in rats, nalbuphine showed no effect on the development of behavioral sensitization induced by reported morphine administration. In microdialysis experiments, morphine induced a significant increase in the dopamine metabolites 3,4-dihydroxyphenylacetic acid and homovanillic acid in the shell region of the nucleus accumbens. Co-administration of nalbuphine blocked the increase in dopamine metabolites induced by morphine. These results may be due to the attenuating effect of nalbuphine on the dopaminergic activity of mesolimbic pathways. All of these results suggest nalbuphine could have a great potential as a pharmacotherapy for opiate abuse.