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The carcinogenicity of nickel compounds has been well documented both in vitro and in vivo; however, the molecular mechanisms by which nickel compounds cause cancers are far from understood. Because suppression of apoptosis is thought to contribute to carcinogenesis, we investigated the mechanisms implicated in nickel-induced anti-apoptotic effect in human bronchial epithelial (Beas-2B) cells. We found that exposure of Beas-2B cells to nickel compounds resulted in increased cyclooxygenase-2 (COX-2) expression and that small interfering RNA (siCOX-2) knockdown of COX-2 expression resulted in increased cell sensitivity to nickel-triggered cell apoptosis, demonstrating that COX-2 induction has an anti-apoptotic effect on Beas-2B cells. Overexpression of IKK␤-KM, a kinase inactive mutant of IKK␤, blocked NF-B activation and COX-2 induction by nickel compounds, indicating that activated NF-B may be a mediator for COX-2 induction. To further explore the contribution of the NF-B pathway in COX-2 induction and in protection from nickel exposure, mouse embryonic fibroblasts deficient in IKK␤, IKK␣, p65, and p50 were analyzed. Loss of IKK␤ impaired COX-2 induction by nickel exposure, whereas knockout of IKK␣ had a marginal effect. Moreover, the NF-B p65, and not the p50 subunit, was critical for nickel-induced COX-2 expression. In addition, a deficiency of IKK␤ or p65 rendered cells more sensitive to nickel-induced apoptosis as compared with those in wild type cells. Finally, it was shown that reactive oxygen species H 2 O 2 were involved in both NF-B activation and COX-2 expression. Collectively, our results demonstrate that COX-2 induction by nickel compounds occurs via an IKK␤/p65 NF-B-dependent but IKK␣-and p50-independent pathway and plays a crucial role in antagonizing nickel-induced cell apoptosis in Beas-2B cells.

Summary INTRODUCTION: Multi-domain intervention for Alzheimer’s disease (AD) risk reduction is an emerging therapeutic paradigm. METHODS: Patients were prescribed individually-tailored interventions (education/pharmacologic/non-pharmacologic) and rated on compliance. Normal cognition/subjective cognitive decline/preclinical-AD were classified as Prevention. Mild cognitive impairment due to AD/mild-AD were classified as Early Treatment. Change from baseline to 18-months on the modified-Alzheimer’s Prevention Cognitive Composite (primary outcome) was compared against matched historical control cohorts. Cognitive aging composite (CogAging), AD/cardiovascular risk-scales, and serum biomarkers were secondary outcomes. RESULTS: 174 were assigned interventions (age 25–86). Higher-compliance Prevention improved more than both historical cohorts (P=.0012,P<.0001). Lower-compliance Prevention also improved more than both historical cohorts (P=.0088,P<.0055). Higher-compliance Early Treatment improved more than lower-compliance (P=.0007). Higher-compliance Early Treatment improved more than historical cohorts (P<.0001,P=.0428). Lower-compliance Early Treatment did not differ (P=.9820,P=.1115). Similar effects occurred for CogAging. AD/cardiovascular risk-scales and serum biomarkers improved. DISCUSSION: Individualized multi-domain interventions may improve cognition and reduce AD/cardiovascular risk scores in patients at-risk for AD-dementia.

The terms “prevention” and “risk reduction” are often used interchangeably in medicine. There is considerable debate, however, over the use of these terms in describing interventions that aim to preserve cognitive health and/or delay disease progression of Alzheimer's disease (AD) for patients seeking clinical care. Furthermore, it is important to distinguish between Alzheimer's disease prevention and Alzheimer's dementia prevention when using these terms. While prior studies have codified research-based criteria for the progressive stages of AD, there are no clear clinical consensus criteria to guide the use of these terms for physicians in practice. A clear understanding of the implications of each term will help guide clinical practice and clinical research. The authors explore the semantics and appropriate use of the terms “prevention” and “risk reduction” as they relate to AD in clinical practice.

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