Boron-Templated Dimerization of Allylic Alcohols To Form Protected 1,3-Diols via Acid Catalysis.

We report an unprecedented boron-templated dimerization of allylic alcohols that generates a 1,3-diol product with two stereogenic centers in high yield and diastereoselectivity. This acid-catalyzed reaction is achieved via in situ formation of a boronic ester intermediate that facilitates selective cyclization and formation of a cyclic boronic ester product. High yields are observed with a variety of allylic alcohols, and mechanistic studies confirm the role of boron as a template for the reaction.

Relation of successful dietary restriction to change in bulimic symptoms: a prospective study of adolescent girls.

Recent experimental evidence that dietary restriction results in decreased bulimic and depressive symptoms seems inconsistent with findings from prospective studies and etiologic theory. However, because the dieting manipulated in these experiments may be unrepresentative of real-world weight loss dieting, the authors tested whether successful dietary restriction was associated with decreases in these outcomes by using longitudinal data from a school-based study of 496 adolescent girls. Moderately overweight participants who evidenced successful dietary restriction showed significantly greater decreases in bulimic symptoms than weight-matched participants who did not show successful dietary restriction; however, there were no effects for depressive symptoms. In conjunction with past experimental findings, results seem to imply that successful dietary restriction curbs bulimic symptoms, suggesting that current etiologic models may need revision.

A functional variant in NKX3.1 associated with prostate cancer risk in the Selenium and Vitamin E Cancer Prevention Trial (SELECT).

NKX3.1 is an androgen-regulated prostate tumor suppressor protein. We previously found that antioxidant administration (N-acetylcysteine) in the Nkx3.1 knockout mouse model promoted prostate epithelial proliferation, suggesting that NKX3.1 activity modifies the effect of antioxidant administration on prostate carcinogenesis. Interestingly, administration of the antioxidant vitamin E significantly increased prostate cancer risk in the Selenium and Vitamin E Cancer Prevention Trial (SELECT), suggesting that our animal experiments may be relevant to humans. To determine whether NKX3.1 played a role in increased human prostate cancer risk associated with antioxidant administration in SELECT, we investigated the joint risk of antioxidant administration and NKX3.1 genotypes previously found to be associated with decreased NKX3.1 mRNA expression (rs11781886) or DNA-binding activity in vitro (rs2228013) in the SELECT biomarker case-cohort substudy (1,866 cases; 3,135 non-cases). Multivariable COX regression models were developed to determine the joint association of NKX3.1 genotypes with administration of vitamin E, selenium, or the combination, compared with placebo. The CC genotype at rs11781886 combined with selenium administration was associated with increased overall prostate cancer risk [HR, 1.676; 95% confidence interval (CI), 1.011-2.777; P = 0.045] and low-grade prostate cancer risk (HR, 1.811; 95% CI, 1.016-3.228; P = 0.0441). Similarly, the rs11781886 minor allele (CC+CT) combined with vitamin E administration was significantly associated with increased prostate cancer risk (HR, 1.450; 95% CI, 1.117-1.882; P = 0.0052). Our results indicate that variation in NKX3.1 expression combined with selenium or vitamin E treatment modifies the risk of prostate cancer. Genetic background may modulate the effects of antioxidant supplementation thought to act as chemoprevention agents.

Antioxidant treatment promotes prostate epithelial proliferation in Nkx3.1 mutant mice.

Discordant results in preclinical and clinical trials have raised questions over the effectiveness of antioxidants in prostate cancer chemoprevention. Results from the large-scale Selenium and Vitamin E Cancer Prevention Trial (SELECT) showed that antioxidants failed to prevent, and in some cases promoted, prostate cancer formation in men without a history of the disease. One possible explanation for these alarming results is the notion that the effects of antioxidant treatment on the prostate are modified by specific, intrinsic genetic risk factors, causing some men to respond negatively to antioxidant treatment. Loss of expression of the homeobox transcription factor NKX3.1 in the prostate is frequently associated with human prostate cancer. Nkx3.1 mutant mice display prostatic hyperplasia and dysplasia and are used as a model of the early stages of prostate cancer initiation. While the mechanisms by which Nkx3.1 loss promotes prostate tumorigenicity are not completely understood, published data have suggested that elevated reactive oxygen species (ROS) associated with Nkx3.1 loss may be a causative factor. Here we have tested this hypothesis by treating Nkx3.1 mutant mice with the antioxidant N-acetylcysteine (NAC) for 13 weeks post-weaning. Surprisingly, while NAC treatment decreased ROS levels in Nkx3.1 mutant mouse prostates, it failed to reduce prostatic epithelial hyperplasia/dysplasia. Rather, NAC treatment increased epithelial cell proliferation and promoted the expression of a pro-proliferative gene signature. These results show that ROS do not promote proliferation in the Nkx3.1-null prostate, but instead inhibit proliferation, suggesting that antioxidant treatment may encourage prostate epithelial cell proliferation early in prostate tumorigenesis. Our findings provide new insight that may help explain the increased prostate cancer risk observed with vitamin E treatment in the SELECT trial and emphasize the need for preclinical studies using accurate models of cancer.

Cigarette smoking prospectively predicts retarded physical growth among female adolescents.

PURPOSE: This study tested the hypothesis that cigarette smoking retards physical development during early adolescence among girls. METHODS: A school-recruited sample of adolescent girls (N = 496) completed surveys assessing smoking behaviors and related variables as well as direct measures of height and weight annually over 3-years. Analyses tested whether smoking trajectories and initial smoking correlated with changes in physical growth over time. RESULTS: Relative to persistent nonsmoking, persistent smoking was associated with reduced growth in height, weight, and body mass index (BMI). Initiation of smoking, relative to persistent nonsmoking, was associated with reduced growth in weight and BMI but not height. Smoking cessation, relative to persistent smoking, was associated with increased gains in weight and BMI but not height. Results also documented a prospective dose-response relation of initial smoking quantity and frequency to subsequent growth retardation in height, weight, and BMI. CONCLUSIONS: Findings are generally consistent with the assertion that smoking in early adolescence retards physical development among adolescent girls.