Tumours with elevated levels of the Notch and Wnt pathways exhibit efficacy to PF-03084014, a γ-secretase inhibitor, in a preclinical colorectal explant model.

BACKGROUND: Dysregulation of the Notch pathway has been identified to play an important role in the development and progression of colorectal cancer (CRC). In this study, we used a patient-derived CRC explant model to investigate the efficacy of the clinical γ-secretase inhibitor (GSI) PF-03084014. METHODS: A total of 16 CRC explants were treated with PF-03084014. Knockdown of RBPjκ gene was used to determine the specificity of PF-03084014. Evaluation of the Notch and Wnt pathways in CRC explant tumours was performed by gene array and immunoblotting. RESULTS: We identified a subset of CRC tumours that exhibited elevations of the Notch and Wnt pathways sensitive to PF-03084014. Treatment with the GSI resulted in a significant reduction in cleaved Notch, Axin2 (Wnt-dependent gene) and active ß-catenin. In addition, knockdown of the RBPjκ gene showed that PF-03084014 has specificity for the Notch pathway in an HCT116 cell line xenograft model. Finally, an increase in apoptosis was observed in CRC001- and CRC021-sensitive tumours. CONCLUSION: This study provides evidence that inhibition of γ-secretase may be beneficial in a subset of patients with elevated levels of the Wnt and Notch pathways.

Women and the heterosexual transmission of HIV: risks and prevention strategies.

Heterosexual intercourse has become a significant means of HIV transmission, even in countries where this was previously not the case. Consequently the promotion of safer sexual practices for heterosexual women and men is of major public health importance. We examine the risks to women of contracting HIV through heterosexual sex, and critically discuss the most commonly recommended strategies for safer sex for heterosexuals. We conclude that all safer sex strategies have limitations, and therefore a wide range of options should be promoted.

PIP: Women are increasingly at risk of contracting HIV through heterosexual transmission, even in countries where this was initially not a major risk factor. Of the 30-40 million adult HIV cases expected to occur by the year 2000, more than 13 million will involve women. By 2000, 80% of HIV infections worldwide will result from heterosexual intercourse. Gender, race, and social class interact and overlap to render many women particularly vulnerable to HIV. Condom use has been presented as the primary HIV preventive strategy for heterosexuals, with varying degrees of success. Although the female condom offers women a method of protection under their control, it is not yet clear that this method will be markedly more acceptable than the male condom. Other safer sex strategies require changes in the nature of sexual relationships. These practices are limited, however, by their dependence on a certain level of interpersonal honesty and fidelity. Another strategy that deserves wider promotion among women is the practice of non-coital forms of sexual intimacy. Since no one safer sex strategy is likely to be acceptable to all heterosexual women, public health campaigns should emphasize as many choices as possible.