Active Notch1 confers a transformed phenotype to primary human melanocytes

The importance of mitogen-activated protein kinase signaling in melanoma is underscored by the prevalence of activating mutations in N-Ras and B-Raf, yet clinical development of inhibitors of this pathway has been largely ineffective, suggesting that alternative oncogenes may also promote melanoma. Notch is an interesting candidate that has only been correlated with melanoma development and progression; a thorough assessment of tumor-initiating effects of activated Notch on human melanocytes would clarify the mounting correlative evidence and perhaps identify a novel target for an otherwise untreatable disease. Analysis of a substantial panel of cell lines and patient lesions showed that Notch activity is significantly higher in melanomas than their nontransformed counterparts. The use of a constitutively active, truncated Notch transgene construct (N(IC)) was exploited to determine if Notch activation is a "driving" event in melanocytic transformation or instead a "passenger" event associated with melanoma progression. N(IC)-infected melanocytes displayed increased proliferative capacity and biological features more reminiscent of melanoma, such as dysregulated cell adhesion and migration. Gene expression analyses supported these observations and aided in the identification of MCAM, an adhesion molecule associated with acquisition of the malignant phenotype, as a direct target of Notch transactivation. N(IC)-positive melanocytes grew at clonal density, proliferated in limiting media conditions, and also exhibited anchorage-independent growth, suggesting that Notch alone is a transforming oncogene in human melanocytes, a phenomenon not previously described for any melanoma oncogene. This new information yields valuable insight into the basic epidemiology of melanoma and launches a realm of possibilities for drug intervention in this deadly disease.

Prospective association between physical activity and falls in community-dwelling older women

Abstract Objective: To explore associations between physical activity and risk of falls and broken or fractured bones in community-dwelling older women. Design, setting and participants: This was a prospective observational survey with 3- and 6-year follow-ups. The sample included 8562 healthy, community-dwelling women, aged 70-75 years in 1996, who completed surveys as participants in the Australian Longitudinal Study on Women’s Health. Outcomes were reports of a fall to the ground, injury from a fall, and broken or fractured bones in 1999 and 2002. The main predictor variable was physical activity level in 1996, categorized based on weekly frequency as none/very low, low, moderate, high, and very high. Covariates were demographic and health-related variables. Logistic regression models were computed separately for each outcome in 1999 and 2002. Main results: In multivariable models, very high physical activity was associated with decreased risk of a fall in 1999 (odds ratio 0.67, 95% CI 0.48 to 0.93) and in 2002 (odds ratio 0.62, 95% CI 0.42 to 0.92). High/very high physical activity was associated with decreased risk of broken or fractured bones in 2002 (odds ratio 0.64, 95% CI 0.42 to 0.96). No significant association was found between physical activity and injury from a fall. Conclusions: The results suggest that at least daily moderate to vigorous physical activity is required for the primary prevention of falls to the ground and broken or fractured bones in women aged 70-75 years.