Tamoxifen inhibits phorbol ester stimulated osteoclastic bone resorption: an effect mediated by calmodulin.

Tamoxifen inhibits bone resorption by disrupting calmodulin-dependent processes. Since tamoxifen inhibits protein kinase C in other cells, we compared the effects of tamoxifen and the phorbol ester, phorbol myristate acetate, on osteoclast activity. Phorbol esters stimulate bone resorption and calmodulin levels four-fold (k0.5 = 0.1-0.3 microM). In contrast, tamoxifen inhibited osteoclast activity approximately 60% with an IC50 of 1.5 microM, had no apparent effect on protein kinase C activity in whole-cell lysates, and reduced protein kinase C alpha recovered by immunoprecipitation 75%. Phorbol esters stimulated resorption in a time-dependent manner that was closely correlated with a similar-fold increase in calmodulin. Protein kinase C alpha, beta, delta, epsilon, and zeta were all down-regulated in response to phorbol ester treatment. Tamoxifen and trifluoperazine inhibited PMA-dependent increases in bone resorption and calmodulin by 85 +/- 10%. Down-regulation of protein kinase C isoforms by phorbol esters suggests that the observed increases in bone resorption and calmodulin levels are most likely due to a mechanism independent of protein kinase C and dependent on calmodulin. In conclusion, the data suggest that protein kinase C negatively regulates calmodulin expression and support the hypothesis that the effects of both phorbol esters and tamoxifen on osteoclast activity is mediated by calmodulin.     

Bases and spaces: resources on the web for accessing the draft human genome - II - After publication of the draft

The volume of human genome sequence and the variety of web-based tools to access it continue to grow at an impressive rate, but a working knowledge of certain key resources can be sufficient to get the most from your genome. This article provides an update to Genome Biology 2000, 1(4):reviews2001.1-2001.5.     

How well is the probability of tumor cure after fractionated irradiation described by Poisson statistics?

The probability of tumor cure in a homogeneous population of tumors exposed to fractionated radiotherapy was modeled using numerical simulations and compared with the predictions of Poisson statistics, assuming exact knowledge of the relevant tumor parameters (clonogen number, radiosensitivity, and growth kinetics). The results show that although Poisson statistics (based on exact knowledge of all parameters) accurately describes the probability of tumor cure when no proliferation occurs during treatment, it underestimates the cure rate when proliferation does occur. In practice, however, the inaccuracy is not likely to be more than about 10%. When the tumor parameters are unknown and are estimated by fitting an empirical Poisson model to tumor-cure data from a homogeneous population of proliferative tumors, the resulting estimates of tumor growth rate and radiosensitivity accurately reflect the true values, but the estimate of initial clonogen number is biased downward. A new formula that is more accurate than Poisson statistics in predicting the probability of tumor cure when proliferation occurs during treatment is discussed.