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BACKGROUND - Coffee consumption has been reported to be inversely associated with hepatocellular carcinoma (HCC), the most common type of liver cancer. Caffeine has chemopreventive properties, but whether caffeine is responsible for the coffee-HCC association is not well studied. In addition, few studies have examined the relationship by sex, and no studies have examined whether there is an association between coffee and intrahepatic cholangiocarcinoma (ICC), the second most common type of liver cancer.
METHODS - In the Liver Cancer Pooling Project, a consortium of U.S.-based cohort studies, data from 1,212,893 individuals (HCC, n = 860; ICC, n = 260) in nine cohorts were pooled. Multivariable-adjusted hazard ratios (HR) and 95% confidence intervals (CI) were estimated using proportional hazards regression.
RESULTS - Higher coffee consumption was associated with lower risk of HCC (HR>3 cups/day vs. non-drinker, 0.73; 95% CI, 0.53-0.99; Ptrend cups/day = <0.0001). More notable reduced risk was seen among women than men (Pinteraction = 0.07). Women who consumed more than three cups of coffee per day were at a 54% lower risk of HCC (HR, 0.46; 95% CI, 0.26-0.81), whereas men had more modest reduced risk of HCC (HR, 0.93; 95% CI, 0.63-1.37). The associations were stronger for caffeinated coffee (HR>3 cups/day vs. non-drinker, 0.71; 95% CI, 0.50-1.01) than decaffeinated coffee (HR, 0.92; 95% CI, 0.55-1.54). There was no association between coffee consumption and ICC.
CONCLUSIONS - These findings suggest that, in a U.S. population, coffee consumption is associated with reduced risk of HCC.
IMPACT - Further research into specific coffee compounds and mechanisms that may account for these associations is needed.
©2015 American Association for Cancer Research.
Flecainide blocks ryanodine receptor type 2 (RyR2) channels in the open state, suppresses arrhythmogenic Ca2+ waves and prevents catecholaminergic polymorphic ventricular tachycardia (CPVT) in mice and humans. We hypothesized that differences in RyR2 activity induced by CPVT mutations determines the potency of open-state RyR2 blockers like flecainide (FLEC) and R-propafenone (RPROP) against Ca2+ waves in cardiomyocytes. Using confocal microscopy, we studied Ca2+ sparks and waves in isolated saponin-permeabilized ventricular myocytes from two CPVT mouse models (Casq2-/-, RyR2-R4496C+/-), wild-type (c57bl/6, WT) mice, and WT rabbits (New Zealand white rabbits). Consistent with increased RyR2 activity, Ca2+ spark and wave frequencies were significantly higher in CPVT compared to WT mouse myocytes. We next obtained concentration-response curves of Ca2+ wave inhibition for FLEC, RPROP (another open-state RyR2 blocker), and tetracaine (TET) (a state-independent RyR2 blocker). Both FLEC and RPROP inhibited Ca2+ waves with significantly higher potency (lower IC50) and efficacy in CPVT compared to WT. In contrast, TET had similar potency in all groups studied. Increasing RyR2 activity of permeabilized WT myocytes by exposure to caffeine (150 µM) increased the potency of FLEC and RPROP but not of TET. RPROP and FLEC were also significantly more potent in rabbit ventricular myocytes that intrinsically exhibit higher Ca2+ spark rates than WT mouse ventricular myocytes. In conclusion, RyR2 activity determines the potency of open-state blockers FLEC and RPROP for suppressing arrhythmogenic Ca2+ waves in cardiomyocytes, a mechanism likely relevant to antiarrhythmic drug efficacy in CPVT.
OBJECTIVE - To determine the association of coffee, decaffeinated coffee, caffeine, and tea consumption in young adulthood with the presence and progression of coronary artery calcified (CAC) plaque and carotid intima-media thickness later in life.
METHODS AND RESULTS - The Coronary Artery Risk Development in Young Adults (CARDIA) Study is a cohort of 5115 white and black adults who were aged 18 to 30 years when they completed a baseline clinic examination from 1985 to 1986. Subsequent examinations were conducted 2, 5, 7, 10, 15, and 20 years later. After multivariable adjustment, no association was observed between average coffee, decaffeinated coffee, or caffeine consumption (years 0 and 7) and presence of CAC (score, >0 Agatston units at year 15 or 20), CAC progression (incident CAC at year 20 or increase in CAC score by ≥20 Agatston units), or high carotid intima-media thickness (>80th percentile, year 20). However, tea consumption displayed a nonsignificant trend for an inverse association with CAC (P=0.08 for trend) and an inverse association with CAC progression (P=0.04 for trend) but no association with high carotid intima-media thickness (P>0.20 for trend). Stratification of the coffee analyses by sex, race, or smoking yielded similar nonsignificant patterns.
CONCLUSIONS - We observed no substantial association between coffee or caffeine intake and coronary and carotid atherosclerosis. However, our results suggested an inverse association between tea and CAC but not carotid atherosclerosis.
Topical therapies for nail diseases are limited by keratinized cells in the human nail plate. An optimal permeation enhancer would not only improve drug delivery through the nail plate, but would also open new possibilities for treating neighboring target sites if systemic circulation is reached. The aim of the present work was to identify permeation enhancers and to improve the understanding of physicochemical parameters that influence drug permeation. Caffeine served as the model drug, and formulations were prepared in water and 20% (v/v) ethanol/water solutions. Tested enhancers were urea, dimethyl sulfoxide (DMSO), methanol, N-acetyl-L-cysteine (NAC), docusate sodium salt (DSS), boric acid, and fungal proteins, such as hydrophobins. Permeability studies employed cadaver nails in modified Franz-type diffusion cells. The permeability coefficient of caffeine in ethanol/water was determined to be 1.56 E-08 cm/s and was improved to 2.27 E-08 cm/s by the addition of NAC. Formulations containing either methanol or DMSO showed the highest permeability coefficients in the range of 5-7.5 E-08 cm/s. Enhancers could be classified according to their permeation enhancement: methanol>class II hydrophobins>DMSO>followed by class I hydrophobins and urea. Ethanol at a concentration of 20% (v/v) in water did not influence swelling of nail samples. Hydrophobins are suggested to be efficient in drug delivery through the nail plate.
Copyright 2009 Elsevier B.V. All rights reserved.
Histone deacetylases (HDACs) are enzymes that modify key residues in histones to regulate chromatin architecture, and they play a vital role in cell survival, cell-cycle progression, and tumorigenesis. To understand the function of Hdac3, a critical component of the N-CoR/SMRT repression complex, a conditional allele of Hdac3 was engineered. Cre-recombinase-mediated inactivation of Hdac3 led to a delay in cell-cycle progression, cell-cycle-dependent DNA damage, and apoptosis in mouse embryonic fibroblasts (MEFs). While no overt defects in mitosis were observed in Hdac3-/- MEFs, including normal H3Ser10 phosphorylation, DNA damage was observed in Hdac3-/- interphase cells, which appears to be associated with defective DNA double-strand break repair. Moreover, we noted that Hdac3-/- MEFs were protected from DNA damage when quiescent, which may provide a mechanistic basis for the action of HDAC inhibitors on cycling tumor cells.
BACKGROUND - Coffee and caffeine have been inconsistently found to be associated with increased risk of clinical miscarriage-a potentially important association given the high prevalence of exposure.
METHODS - Women were recruited before or early in pregnancy and interviewed regarding sources of caffeine, including assessment of changes over the perinatal period. We identified 2407 clinically-recognized pregnancies resulting in 258 pregnancy losses. We examined the relationship of coffee and caffeine intake with clinically-recognized pregnancy loss prior to 20 weeks' completed gestation, using a discrete-time continuation ratio logistic survival model.
RESULTS - Coffee and caffeine consumption at all 3 time points were unrelated to total miscarriage risk and the risk of loss after the interview. Reported exposure at the time of the interview was associated with increased risk among those with losses before the interview.
CONCLUSIONS - There is little indication of possible harmful effects of caffeine on miscarriage risk within the range of coffee and caffeine consumption reported, with a suggested reporting bias among women with losses before the interview. The results may reflect exposure misclassification and unmeasured heterogeneity of pregnancy losses.
BACKGROUND - Consumption of soft drinks has been linked to obesity in children and adolescents, but it is unclear whether it increases metabolic risk in middle-aged individuals.
METHODS AND RESULTS - We related the incidence of metabolic syndrome and its components to soft drink consumption in participants in the Framingham Heart Study (6039 person-observations, 3470 in women; mean age 52.9 years) who were free of baseline metabolic syndrome. Metabolic syndrome was defined as the presence of > or = 3 of the following: waist circumference > or = 35 inches (women) or > or = 40 inches (men); fasting blood glucose > or = 100 mg/dL; serum triglycerides > or = 150 mg/dL; blood pressure > or = 135/85 mm Hg; and high-density lipoprotein cholesterol < 40 mg/dL (men) or < 50 mg/dL (women). Multivariable models included adjustments for age, sex, physical activity, smoking, dietary intake of saturated fat, trans fat, fiber, magnesium, total calories, and glycemic index. Cross-sectionally, individuals consuming > or = 1 soft drink per day had a higher prevalence of metabolic syndrome (odds ratio [OR], 1.48; 95% CI, 1.30 to 1.69) than those consuming < 1 drink per day. On follow-up (mean of 4 years), new-onset metabolic syndrome developed in 717 of 4033 participants (17.8%) consuming < 1 drink/day and in 433 of 2006 persons (21.6%) [corrected] consuming > or = 1 soft drink/day [corrected] Consumption of > or = 1 soft drink per day was associated with increased odds of developing metabolic syndrome (OR, 1.44; 95% CI, 1.20 to 1.74), obesity (OR, 1.31; 95% CI, 1.02 to 1.68), increased waist circumference (OR, 1.30; 95% CI, 1.09 to 1.56), impaired fasting glucose (OR, 1.25; 95% CI, 1.05 to 1.48), higher blood pressure (OR, 1.18; 95% CI, 0.96 to 1.44), hypertriglyceridemia (OR, 1.25; 95% CI, 1.04 to 1.51), and low high-density lipoprotein cholesterol (OR, 1.32; 95% CI 1.06 to 1.64).
CONCLUSIONS - In middle-aged adults, soft drink consumption is associated with a higher prevalence and incidence of multiple metabolic risk factors.
BACKGROUND - Cardiovascular disease, including myocardial infarction (MI), is increasing in developing countries. Knowledge of risk factors and their impact on the population could offer insights into primary prevention.
METHODS AND RESULTS - We estimated the population-attributable risk (PAR) for major MI risk factors among Costa Ricans without a history of diabetes, hypertension, or regular use of medication (889 MI cases, 1167 population-based controls). Lifestyle and dietary variables were measured with validated questionnaires. In multivariate analyses, abdominal obesity (PAR, 29.3%), smoking (PAR, 25.6%), nonuse of alcohol (PAR, 14.8%), caffeine intake (PAR, 12.8%), physical inactivity (PAR, 9.6%), and poor diet (PAR, 6.0%) were the most important MI risk factors. Subjects in the favorable categories of the above 6 risk factors showed a lower risk of MI (odds ratio, 0.09; 95% CI, 0.03 to 0.33) than those in the unfavorable categories. Compared with women, men were more likely to smoke (31% versus 10%) but less likely to have waist circumferences greater than Adult Treatment Panel III cutoffs (9% versus 35%). Many subjects did not meet the American Heart Association or World Health Organization/Food and Agriculture Organization dietary guidelines. For instance, 95% obtained > or = 7% of energy from saturated fat, 25% had < or = 5% of energy from polyunsaturated fat, 63% had > or = 1% energy from trans fat, and 53% had low fiber intake (< 25 g/d).
CONCLUSIONS - These findings confirm the benefit of a healthy diet, physical activity, moderate alcohol, and cessation of smoking as approaches for the primary prevention of MI. Obesity and smoking were the 2 most important risk factors for nonfatal MI in Costa Rica.
BACKGROUND - The effects of coffee on myocardial infarction are uncertain. We hypothesize that coffee in the presence of predisposing factors can induce a cascade of events that, through sympathetic nervous activation, can induce the onset of myocardial infarction.
METHODS - We recruited 503 incident cases of nonfatal myocardial infarction between 1994 and 1998 in Costa Rica. We used a case-crossover design to calculate relative risks (RRs) and 95% confidence intervals (95% CIs).
RESULTS - The RR of myocardial infarction in the hour after coffee intake was 1.49 (95% CI = 1.17-1.89). Occasional coffee drinkers (< or =1 cup/day, n = 103) had a RR of myocardial infarction of 4.14 (2.03-8.42), moderate coffee drinkers (2-3 cups/day, n = 280) had a RR of 1.60 (1.16-2.21), and heavy coffee drinkers (> or =4 cups/d, n = 120) had a RR of 1.06 (0.69-1.63; P = 0.006, test of homogeneity). Patients with 3 or more risk factors (n = 101) had a RR of myocardial infarction of 2.10 (1.30-3.39), whereas patients with fewer than 3 risk factors (n = 396) had a RR of 1.39 (1.04-1.82; P = 0.15, test of homogeneity); and RR was 1.72 (1.30-2.30) among sedentary patients compared with 1.07 (0.66-1.72) among nonsedentary (P = 0.10, test of homogeneity).
CONCLUSIONS - The findings indicate that coffee intake may trigger myocardial infarction. The association is particularly strong among people with light/occasional intake of coffee (< or =1 cup/day), with sedentary lifestyle, or with 3 or more risk factors for coronary heart disease.
To examine whether caffeine, the most widely used xenobiotic compound, would induce insect cytochrome P450 or CYP gene expression, upstream DNA fragments of Cyp6a2 (0.12, 0.26, 0.52 and 0.98-kb) and Cyp6a8 (0.06, 0.1, 0.2, 0.5 and 0.8-kb) genes of Drosophila melanogaster were individually fused to the firefly luciferase (luc) reporter gene. Promoter activities of these constructs were examined in Drosophila SL-2 cells using luciferase assays. Activity of 0.2- and 0.8-kb upstream DNA of Cyp6a8 was also measured in transgenic female flies. When these flies were treated with 2 mM pure caffeine or Vivarin caffeine, both DNA fragments showed a 4-5-fold induction of promoter activity. Endogenous Cyp6a8 and Cyp6a2 genes in these flies also showed caffeine-induced expression. In addition, both 0.2- and 0.8-kb DNAs showed differential basal and caffeine-induced activity in head, ovaries, gut, cuticle plus fat body and malpighian tubules. However, in all tissues 0.8-kb DNA always showed higher basal and caffeine-induced activities compared to the 0.2-kb DNA, suggesting that the additional DNA present in the 0.8-kb fragment has sequences that enhance both activities. In SL-2 cells, all reporter constructs of each Cyp6 gene showed significantly higher basal activity than the empty vector. Sequences that boost basal activity are located in -265/-129 and -983/-522 DNA of Cyp6a2, and -199/-109 and -491/-199 DNA of Cyp6a8 genes. While the 0.12- and 0.1-kb upstream DNAs of Cyp6a2 and Cyp6a8 genes respectively did not show caffeine-inducibility in SL-2 cells, the longest upstream DNA of each gene gave the highest level of induction. Caffeine-responsive sequences are not clustered at one place; they appear to be dispersed in -983/-126 and -761/-109 regions of Cyp6a2 and Cyp6a8 genes which also contain many binding sites for activator protein 1 (AP1) and cyclic AMP response element binding protein (CRE-BP). Significance of these binding sites in caffeine-inducibility has been discussed.