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Rationale: Oxygen supplementation (e.g., hyperoxia) is used to support critically ill patients with noninfectious and infectious acute lung injury (ALI); however, hyperoxia exposure can potentially further contribute to and/or perpetuate preexisting ALI. Thus, developing novel therapeutic agents to minimize the side effects of hyperoxia is essential to improve the health of patients with severe ALI and respiratory dysfunction. We have previously shown that mice with a genetic disruption of the Nrf2 transcription factor, which squelches cellular stress by up-regulating the induction of several antioxidant enzymes and proteins, have greater susceptibility to hyperoxic lung injury. Moreover, we have recently demonstrated that Nrf2-deficiency impairs the resolution of lung injury and inflammation after nonlethal hyperoxia exposure.Objectives: To test the hypothesis that amplification of endogenous Nrf2 activity would prevent or dampen ALI induced by hyperoxia.Methods: Here, we tested our hypothesis using a synthetic triterpenoid compound CDDO-imidazole (CDDO-Im) (1-[2-cyano-3-,12-dioxooleana-1,9(11)-dien-28-oyl] imidazole) in Nrf2-sufficient and Nrf2-deficient mice subjected to hyperoxia-induced ALI.Measurements and Main Results: We demonstrate that oral administration of CDDO-Im at a dose of 30 micromol/kg body weight during the hyperoxic exposure is sufficient to markedly attenuate hyperoxia-induced ALI in Nrf2-sufficient but not Nrf2-deficient mice. This protection by the CDDO-Im against hyperoxic insult was accompanied by increased levels of Nrf2-regulated cytoprotective gene expression and reduced levels of DNA damage in the lung.Conclusions: These results suggest that up-regulation of Nrf2 signaling by CDDO-Im or its analogs may provide a novel therapeutic strategy to minimize the adverse effects of hyperoxia. [ABSTRACT FROM AUTHOR]

BACKGROUND: Raloxifene is a selective estrogen-receptor modulator (SERM) indicated for the prevention and treatment of osteoporosis in postmenopausal women. In the Multiple Outcomes of Raloxifene Evaluation (MORE) study, an osteoporosis treatment trial, raloxifene therapy was associated with a reduced incidence of invasive, estrogen receptor (ER)-positive breast cancer compared with placebo (relative risk, 0.16; 95% CI, 0.09-0.30). OBJECTIVE: This review summarizes available preclinical and clinical data pertaining to a potential role for raloxifene in the prevention of breast cancer, and examines the mechanisms of action by which raloxifene may exert an effect. METHODS: Relevant articles were identified through a search of MEDLINE for English-language studies published between 1966 and January 2003. Search terms included raloxifene, keoxifene, tamoxifen, SERM, estrogen, estrogen receptor, breast, mammary, growth factors, and apoptosis. The reference lists of identified articles were reviewed for additional publications. RESULTS: Both preclinical and clinical data suggest a role for raloxifene in the prevention of breast cancer. Like tamoxifen, raloxifene acts as an estrogen antagonist in breast tissue through competitive binding to the ER. Raloxifene may also inhibit breast tissue proliferation through mechanisms independent of the ER. CONCLUSIONS: Given raloxifene's mechanism of action and the preclinical evidence for its role in breast cancer prevention, a clinically favorable effect seems feasible. Results of ongoing clinical studies will provide evidence to support or refute the clinical findings of MORE and thus raloxifene's role in the breast cancer prevention. [ABSTRACT FROM AUTHOR]

25 years ago, then President Nixon "declared" War on Cancer. In this personal commentary, the war is reviewed. There have been obvious triumphs, for instance in cure of acute lymphocytic leukaemia and other childhood cancers, Hodgkin's disease, and testicular cancer. However, substantial advances in molecular oncology have yet to impinge on mortality statistics. Too many adults still die from common epithelial cancers. Failure to appreciate that local invasion and distant metastasis rather then cell proliferation itself are lethal, obsession with cure of advanced disease rather than prevention of early disease, and neglect of the need to arrest preneoplastic lesions may all have served to make victory elusive. [ABSTRACT FROM AUTHOR]