CTP:phosphocholine cytidylyltransferase alpha (CCT␣) is a nuclear enzyme that catalyzes the rate-limiting step in the CDP-choline pathway, the primary route for synthesis of phosphatidylcholine (PtdCho) in eukaryotic cells. Induction of apoptosis by farnesol (FOH) and other cytotoxic drugs has been shown to alter PtdCho synthesis via the CDP-choline pathway. Here we report that FOH-induced apoptosis in CHO cells caused a dose-dependent activation of CCT␣ and inhibition of the final step in the pathway, resulting in a biphasic effect on PtdCho synthesis. Activation of CCT␣ was accompanied by enzyme translocation to the nuclear envelope within 30 min of FOH addition to cells. Following translocation to membranes, CCT␣ was exported from the nucleus and underwent caspase-mediated proteolysis that coincided with poly(ADP-ribose) polymerase cleavage. Site-directed mutagenesis and in vivo and in vitro expression studies mapped a caspase 6 and/or 8 cleavage site to TEED 282 G, the final residue in the CCT␣ nuclear localization signal. Nuclear export of CCT␣ appeared to be an active process in FOH-treated CHO cells that was independent of caspase removal of the nuclear localization signal. Caspase cleavage of CCT␣ occurred during UV or chelerythrine-induced apoptosis; however, nuclear membrane translocation and nuclear export were not evident under these conditions. Thus, caspase cleavage of CCT␣ was a late feature of several apoptotic programs that occurred in the nucleus or at the nuclear envelope. Activation and nuclear export of CCT␣ were early events in FOH-induced apoptosis that contributed to altered PtdCho synthesis and, in conjunction with caspase cleavage, excluded CCT␣ from the nucleus.Phosphatidylcholine (PtdCho), the major phospholipid in eukaryotic cells, serves vital roles in membrane function and bile and lipoprotein secretion and as a precursor for lipid second messengers (9, 21). With the exception of liver, the CDP-choline pathway (Fig.

Although external beam radiation is an essential component to the current standard treatment of primary brain tumors, its application is limited by toxicity at doses more than 80 Gy. Recent studies have suggested that brachytherapy with liposomally encapsulated radionuclides may be of benefit, and we have reported methods to markedly increase the specific activity of rhenium-186 ((186)Re)-liposomes. To better characterize the potential delivery, toxicity, and efficacy of the highly specific activity of (186)Re-liposomes, we evaluated their intracranial application by convection-enhanced delivery in an orthotopic U87 glioma rat model. After establishing an optimal volume of 25 µL, we observed focal activity confined to the site of injection over a 96-hour period. Doses of up to 1850 Gy were administered without overt clinical or microscopic evidence of toxicity. Animals treated with (186)Re-liposomes had a median survival of 126 days (95% confidence interval [CI], 78.4-173 days), compared with 49 days (95% CI, 44-53 days) for controls. Log-rank analysis between these 2 groups was highly significant (P = .0013) and was even higher when 100 Gy was used as a cutoff (P < .0001). Noninvasive luciferase imaging as a surrogate for tumor volume showed a statistically significant separation in bioluminescence by 11 days after 100 Gy or less treatment between the experimental group and the control animals (χ(2)[1, N= 19] = 4.8; P = .029). MRI also supported this difference in tumor size. Duplication of tumor volume differences and survival benefit was possible in a more invasive U251 orthotopic model, with clear separation in bioluminescence at 6 days after treatment (χ(2)[1, N= 9] = 4.7; P = .029); median survival in treated animals was not reached at 120 days because lack of mortality, and log-rank analysis of survival was highly significant (P = .0057). Analysis of tumors by histology revealed minimal areas of necrosis and gliosis. These results support the potential efficacy of the highly specific activity of brachytherapy by (186)Re-liposomes convection-enhanced delivery in glioma.

A potential difference between the guard and collecting electrodes was found to be the primary source of the voltage-dependent polarity effects demonstrated by microchambers. For a given potential difference between electrodes, the relative change in the collecting volume is smaller for larger-volume chambers, illustrating why these polarity effects are not seen in larger-volume chambers with similar guard and collecting electrode designs. Thus, for small-volume chambers, it is necessary to reduce the potential difference between the guard and collecting electrodes in order to reduce polarity effects for reference dosimetry measurements.

ObjectivesTo evaluate the effectiveness of a population-based, statewide public health intervention designed to improve women's awareness and knowledge of the link between alcohol and cancer.DesignCross-sectional tracking surveys conducted pre-intervention and post-intervention (waves I and III of campaign).SettingWestern Australia.ParticipantsCross-sectional samples of Western Australian women aged 25–54 years before the campaign (n=136) and immediately after wave I (n=206) and wave III (n=155) of the campaign.InterventionThe ‘Alcohol and Cancer’ mass media campaign ran from May 2010 to May 2011 and consisted of three waves of paid television advertising with supporting print advertisements.Main outcome measuresCampaign awareness; knowledge of drinking guidelines and the link between alcohol and cancer; intentions towards drinking.ResultsPrompted recognition of the campaign increased from 67% following wave I to 81% following wave III (adjusted OR (adj OR)=2.31, 95% CI 1.33 to 4.00, p=0.003). Improvements in women's knowledge that drinking alcohol on a regular basis increases cancer risk were found following wave I (adj OR=2.60, 95% CI 1.57 to 4.30, p<0.001) and wave III (adj OR=4.88, 95% CI 2.55 to 9.36, p<0.001) compared with baseline. Knowledge of the recommended number of standard drinks for low risk in the long term increased between baseline and wave I (adj OR=1.68, 95% CI 1.02 to 2.76, p=0.041), but not baseline and wave III (adj OR=1.42, 95% CI 0.84 to 2.39, p=0.191). Among women who drink alcohol, the proportion expressing intentions to reduce alcohol consumption increased significantly between baseline and wave III (adj OR=2.38, 95% CI 1.11 to 5.12, p=0.026). However, no significant reductions in recent drinking behaviour were found following the campaign.ConclusionsResults indicate a population-based mass media campaign can reach the target audience and raise awareness of links between alcohol and cancer, and knowledge of drinking guidelines. However, a single campaign may be insufficient to measurably curb drinking behaviour in a culture where pro-alcohol social norms and product marketing are pervasive.

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