Fine-Scale Mapping of the 4q24 Locus Identifies Two Independent Loci Associated with Breast Cancer Risk

Background: A recent association study identified a common variant (rs9790517) at 4q24 to be associated with breast cancer risk. Independent association signals and potential functional variants in this locus have not been explored. Methods: We conducted a fine-mapping analysis in 55,540 breast cancer cases and 51,168 controls from the Breast Cancer Association Consortium. Results: Conditional analyses identified two independent association signals among women of European ancestry, represented by rs9790517 [conditional P = 2.51 × 10−4; OR, 1.04; 95% confidence interval (CI), 1.02–1.07] and rs77928427 (P = 1.86 × 10−4; OR, 1.04; 95% CI, 1.02–1.07). Functional annotation using data from the Encyclopedia of DNA Elements (ENCODE) project revealed two putative functional variants, rs62331150 and rs73838678 in linkage disequilibrium (LD) with rs9790517 (r2 ≥ 0.90) residing in the active promoter or enhancer, respectively, of the nearest gene, TET2. Both variants are located in DNase I hypersensitivity and transcription factor–binding sites. Using data from both The Cancer Genome Atlas (TCGA) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC), we showed that rs62331150 was associated with level of expression of TET2 in breast normal and tumor tissue. Conclusion: Our study identified two independent association signals at 4q24 in relation to breast cancer risk and suggested that observed association in this locus may be mediated through the regulation of TET2. Impact: Fine-mapping study with large sample size warranted for identification of independent loci for breast cancer risk

Efficacy and Safety of Modafinil for Improving Daytime Wakefulness in Patients Treated Previously With Psychostimulants

Objectives: To assess the efficacy and safety of modafinil for improving wakefulness in narcolepsy patients treated previously with psychostimulants. Background: Modafinil has become a standard therapy for improving daytime wakefulness in narcolepsy patients and may be a useful therapeutic alternative to psychostimulants used to improve waking function in other medical conditions. Modafinil is chemically dissimilar to and has a pharmacological profile that differs from the psychostimulants. Modafinil has a low abuse potential and is well tolerated. Methods: Patients (N = 151) with narcolepsy who had been unsatisfactorily treated with dextroamphetamine (N = 48), methylphenidate (N = 66), or pemoline (N = 37) were enrolled in this 6-week, open-label, multicenter study. Following a 2-week washout period, patients received modafinil once daily (Week 1, 200 mg; Weeks 2-6, 200 or 400 mg). Efficacy was evaluated at Weeks 1, 2, and 6 using the Epworth Sleepiness Scale and the Clinical Global Impression of Change. Adverse events were monitored throughout the study. Results: Treatment with modafinil improved daytime wakefulness versus baseline regardless of which psychostimulant was taken previously. Mean ESS scores were improved after 1 week of treatment with modafinil. Improvements were maintained throughout the 6 weeks of treatment (all P \u3c 0.001 versus baseline after washout). At Week 6, 79% of all patients were considered to be clinically improved relative to post-washout baseline. The most frequent adverse events were headache, nausea, and insomnia; the majority of adverse events were mild or moderate in nature. Approximately 70% of patients were receiving 400 mg of modafinil once daily at the end of the study. Conclusion: During this 6-week, open-label study, modafinil was an effective and well-tolerated treatment for improving daytime wakefulness in narcolepsy patients previously treated with psychostimulants. (C) 2002 Elsevier Science B.V. All rights reserved

Emprego de uma lama com caráter refratário para o processo de fundição odontológica Use of a refractory slurry characteristic in mold casting

A utilização de novos materiais, especialmente aqueles metálicos, tem sido uma constante na odontologia. Graças às necessidades da indústria no desenvolvimento de produtos cada vez com maior resistência, principalmente à corrosão, a prótese tem-se beneficiado com um número elevado de ligas metálicas excelentes. Para atender a necessidade de conformar as ligas em restaurações ou aparelhos próprios à nossa profissão, devem ser desenvolvidos refratários para estas ligas. Este é o caso da proposta de usar uma lama refratária como molde para confecção da fundição. A lama proposta, além de servir aos propósitos, tem-se mostrado capaz de oferecer melhor acabamento da liga.<br>The use of new materials, particularly metal alloys, has been a constant trend in Dentistry. The industrial need to develop products with greater resistance to corrosion has benefited prosthodontics with a large number of excellent metallic alloys. In order to adapt such alloys to dental restorations or devices, refractory materials ought to be developed. That is the aim of using slurry as a mold in the casting process, which also makes it possible to obtain surfaces with improved finish