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Many anticipate that application of findings in molecular genetics will help to achieve greater precision in defining high-risk populations that may benefit from chemopreventive interventions. We must recognize, however, that genetic susceptibility, environmental factors, and complex gene-environment interactions are all likely to be risk determinants for most cancers. Cohort studies of twins and cancer indicate that having "identical" genes is generally not a very accurate predictor of cancer incidence. Data from twin studies support the suggestion that environmental factors such as tobacco use significantly influence cancer risk. The complexities of the genetic contribution to disease risk are exemplified by the development of Duchenne muscular dystrophy in only one of monozygotic twin girls, hypothesized to be the result of X chromosome inactivation, with the distribution patterns of the X chromosome being skewed to the female X in the manifesting twin and to the male X in the normal twin. Evidence from transgenic and genetic-environmental studies in animals support the possibility of genetic-environmental interactions. Calorie restriction modifies tumor expression in p53 knockout mice; a high-fat, low-calcium, low-vitamin D diet increases prepolyp hyperplasia formation in Apc-mutated mice; and calorie restriction early in life influences development of obesity in the genetically obese Zucker rat (fafa). Such environmental modulation of gene expression suggests that chemoprevention has the potential to reduce risk for both environmentally and genetically determined cancers. In view of the growing research efforts in chemoprevention, the NCI has developed a Prevention Trials Decision Network (PTDN) to formalize the evaluation and approval process for large-scale chemoprevention trials. The PTDN addresses large trial prioritization and the associated issues of minority recruitment and retention; identification and validation of biomarkers as intermediate endpoints for cancer; and chemopreventive agent selection and development. A comprehensive database is being established to support the PTDN's decision-making process and will help to determine which agents investigated in preclinical and early phase clinical trials should move to large-scale testing. Cohorts for large-scale chemoprevention trials include individuals who are determined to be at high risk as a result of genetic predisposition, carcinogenic exposure, or the presence of biomarkers indicative of increased risk. Current large-scale trials in well-defined, high-risk populations include the Breast Cancer Prevention Trial (tamoxifen), the Prostate Cancer Prevention Trial (finasteride), and the N-(4-hydroxyphenyl) retinamide (4-HPR) breast cancer prevention study being conducted in Milan. Biomarker studies will provide valuable information for refining the design and facilitating the implementation of future large-scale trials. For example, potential biomarkers are being assessed at biopsy in women with ductal carcinoma in situ (DCIS). The women are then randomized to either placebo, tamoxifen, 4-HPR, or tamoxifen plus 4-HPR for 2-4 weeks, at which time surgery is performed and the biomarkers reassessed to determine biomarker modulation by the interventions. For prostate cancer, modulation of prostatic intraepithelial neoplasia (PIN) by 4-HPR and difluoromethylornithine is being investigated; similar studies are being planned for oltipraz, dehydroepiandrosterone, and vitamin E plus selenomethionine. The validation of biomarkers as surrogate endpoints for cancer incidence in high-risk cohorts will allow more agents to be evaluated in shorter studies that use fewer subjects to achieve the desired statistical power.
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PMID:Cancer risk factors for selecting cohorts for large-scale chemoprevention trials. 902 95

This cross-sectional study was conducted to determine the association of high body fat per cent measured by bioelectric impedance analysis with known risk factors of obesity as well as with serum levels of vitamins, trace elements and magnesium and oxidative stress in an urban population in India. There were 850 men aged 25-64 years, randomly selected from the city of Moradabad. Subjects were divided into high body fat per cent (n = 357), over fat per cent (n = 230), desirable fat (n = 200) and low fat (n = 63) based on criteria of body fat per cent analysis. The prevalence of central obesity, sedentary lifestyle, family history and higher visible fat intake showed significant association with higher over fat per cent. Postprandial plasma insulin and glucose and serum iron and oxidative stress were significantly higher and plasma levels of vitamin C and E and serum zinc/insulin ratio as well as serum magnesium/insulin ratio showed inverse association with high body fat per cent. Multivariate logistic regression analysis after adjustment of age showed a significant positive association of body mass index (odds ratio 0.97), sedentary lifestyle (odds ratio 1.12) and serum iron (OR 1.00) with higher body fat per cent. Zinc (OR 1.03), magnesium (OR 1.02), vitamins C (OR 1.08 and E (OR 1.09) deficiency were risk factors of higher body per cent and central obesity. It is possible that some Indian men can benefit by increased intake of zinc, magnesium, vitamin C and vitamin E in conjunction with lifestyle changes.
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PMID:Association of low plasma concentrations of antioxidant vitamins, magnesium and zinc with high body fat per cent measured by bioelectrical impedance analysis in Indian men. 959 44

The resistance to insulin (insulin resistance, IR) is a common feature and a possible link between such frequent disorders as non-insulin dependent diabetes mellitus (NIDDM), hypertension and obesity. Pharmacological amelioration of IR and understanding its pathophysiology are therefore essential for successful management of these disorders. In this review, we will discuss the mechanisms of action of thiazolidinediones (TDs), a new family of insulin-sensitizing agents. Experimental studies of various models of IR and an increasing number of clinical studies have shown that TDs normalize a wide range of metabolic abnormalities associated with IR. By improving insulin sensitivity in skeletal muscles, the adipose tissue and hepatocytes, TDs reduce fasting hyperglycaemia and insulinaemia. Furthermore, TDs markedly influence lipid metabolism--they decrease plasma triglyceride, free fatty acid and LDL-cholesterol levels, and increase plasma HDL-cholesterol concentrations. Although TDs do not stimulate insulin secretion, they improve the secretory response of beta cells to insulin secretagogues. TDs act at various levels of glucose and lipid metabolism--ameliorate some defects in the signalling cascade distal to the insulin receptor and improve glucose uptake in insulin-resistant tissues via increased expression of glucose transporters GLUT1 and GLUT4. TDs also activate glycolysis in hepatocytes, oppose intracellular actions of cyclic AMP, and increase intracellular magnesium levels. TDs bind to peroxisome proliferator activating receptors gamma (PPAR gamma), members of the steroid/thyroid hormone nuclear receptor superfamily of transcription factors involved in adipocyte differentiation and glucose and lipid homeostasis. Activation of PPAR gamma results in the expression of adipocyte-specific genes and differentiation of various cell types in mature adipocytes capable of active glucose uptake and energy storage in the form of lipids. Furthermore, TDs inhibit the pathophysiological effects exerted by tumour-necrosis factor (TNF alpha), a cytokine involved in the pathogenesis of IR. These effects are most likely also mediated by stimulation of PPAR gamma. In mature adipocytes, PPAR gamma stimulation inhibits stearoyl-CoA desaturase 1 (SCD1) enzyme activity resulting in a change of cell membrane fatty acid composition. Apart from their metabolic actions, TDs modulate cardiovascular function and morphology independently of the insulin-sensitizing effects. TDs decrease blood pressure in various models of hypertension as well as in hypertensive insulin-resistant patients, and inhibit proliferation, hypertrophy and migration of vascular smooth muscle cells (VSMC) induced by growth factors. These processes are considered to be crucial in the development of vascular remodelling, atherosclerosis and diabetic organ complications. TDs induce vasodilation by blockade of Ca2+ mobilisation from intracellular stores and by inhibition of extracellular calcium uptake via L-channels. Furthermore, TDs interfere with pressor systems (catecholamines, renin-angiotensin system) and enhance endothelium-dependent vasodilation. A key role of TDs effects in vascular remodelling is played by inhibition of the mitogen-activated protein (MAP) kinase pathway. This signalling pathway is important for VSMC growth and migration in response to stimulation with tyrosine-kinase dependent growth factors. In addition to the vasoprotective mechanisms mentioned above, troglitazone, the latest representative of this pharmacological group, possesses antioxidant actions comparable to vitamin E. In summary, TDs have the unique ability to attack mechanisms responsible for metabolic alterations as well as for vascular abnormalities characteristic for IR. Therefore, TDs represent a powerful research tool in attempts to find a common denominator underlying the pathophysiology of the metabolic syndrome X. A recently reported link between MAP kinase signalling pathway and PPAR gamma
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PMID:Thiazolidinediones--tools for the research of metabolic syndrome X. 980 67

Twenty-nine obese female Zucker rats (fa/fa) were fed with a laboratory chow supplemented or not with a selenium-rich yeast (Selenion), or Selenion + vitamin E, or vitamin E alone. Twelve lean female Zucker rats (Fa/Fa) of the same littermates fed with the same diet were used as control. After 32 wk of diet, obesity induced a large increase in plasma insulin and lipid levels. A significant decrease in the plasma vitamin E/triglycerides ratio (p<0.005) and an increase in plasma thiobarbituric reactive substances (TBARS) (p<0.005) were also observed. Plasma selenium and vitamin E increased in all supplemented rats. The plasma insulin level was decreased by selenion supplementation and the vitamin E/triglycerides ratio was completely corrected by double supplementation with Selenion + vitamin E. TBARS were also efficiently decreased in two obese groups receiving vitamin E. In plasma, adipose tissue and aorta, obesity induced an increase in palmitic acid (C16:0), a very large increase in monounsaturated fatty acids (palmitoleic acid C16:1, stearic acid C18:1) associated with a decrease in polyunsaturated n-6 fatty acids (linoleic acid C18:2 n-6, arachidonic C20:4 n-6). These alterations in fatty acid distribution were only partly modulated by Se and vitamin E supplements. However, in the aorta, antioxidant treatment in obese rats significantly reduced the increase in C16:0 and C16:1 (p<0.05 and p<0.01, respectively) and the decrease in arachidonic acid (p<0.05). These changes could be beneficial in the reduction of insulin resistance and help to protect the vascular endothelium.
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PMID:Effect of selenium and vitamin E supplementation on lipid abnormalities in plasma, aorta, and adipose tissue of Zucker rats. 989 95

Approximately 80% of all patients with diabetes die of cardiovascular disease. The traditional management of type 2 diabetes has been ineffective in altering this dismal prognosis. Insulin resistance is the fundamental defect of type 2 diabetes. Insulin resistance often leads to hyperinsulinemia, which is associated with hypertension, atherogenic dyslipidemia, left ventricular hypertrophy, impaired fibrinolysis, visceral obesity, and sedentary lifestyle. Although all these conditions are associated with atherosclerosis and adverse cardiovascular events, the therapeutic efforts in patients with diabetes have focused predominantly on normalizing glucose levels. Improved insulin sensitivity through lifestyle modifications or pharmacologic therapy (troglitazone and metformin) will lower both insulin and glucose levels as well as diminish dyslipidemia and hypertension. In contrast, sulfonylurea agents lower glucose by increasing insulin levels and may increase the risk of cardiovascular events. Therapy including aspirin, lipid agents (for example, statins), angiotensin-converting enzyme inhibitors, beta-adrenergic blockers, postmenopausal estrogen replacement, and vitamin E should be considered for patients with type 2 diabetes. In most patients with diabetes who have multivessel coronary artery disease, coronary artery bypass grafting is superior to coronary angioplasty for improving long-term cardiovascular prognosis. This superiority is mediated in part by the use of a left internal mammary graft to the left anterior descending coronary artery. Urgent coronary angioplasty or thrombolytic therapy should be considered for all patients with diabetes who have acute myocardial infarction.
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PMID:Improving the adverse cardiovascular prognosis of type 2 diabetes. 1006 57

As in many other countries, the New Zealand Cancer Society produces guidelines for cancer prevention. These recommend avoiding asbestos, smoking, sunlight, alcohol, fatty food and obesity. Women are advised to have a regular cervical smear test. Additional 'probably helpful' suggestions include eating plenty of fresh fruit and vegetables and dietary fibre. However, considerable data from animal studies and more slowly accumulating data from human intervention studies suggest additional and more specific advice may be appropriate. Fruit and vegetable servings should total a minimum of five each day. Some specific fruits and vegetables (e.g., tomato, broccoli, onions) may have particular benefits against individual cancer types. Positive human evidence on potential benefits of increasing dietary fibre comes from studies where wheat bran was added to the diet. This is not a dietary fibre per se, but merely a good fibre source. Indeed, our own studies suggest that it could be various phytochemicals in the bran, rather than dietary fibre, which is beneficial. An increase either in whole wheat or wheat bran, rather than fibre, would be a sounder recommendation. Although there is some evidence that multivitamin supplementation can protect against cancer, this may be only in the special situation where the population is already significantly vitamin-deficient. For example, a combination of beta-carotene, vitamin E and selenium significantly reduced cancer mortality in a Chinese population, whereas lung cancer risks (in already high risk groups) were increased in Finnish and American trials with high dose beta-carotene. Various other chemopreventive drugs are being actively developed and at various stages in clinical trials. The enhanced cancer incidence in the beta-carotene trial illustrates the potential benefit of utilising surrogate endpoints of malignant disease rather than incident cancer as a trial endpoint.
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PMID:Prospects for cancer prevention. 1051 4

This review presents current knowledge of diet and breast cancer. In the first part it reviews current knowledge of nutritional risk factors. Obesity, total energy intake, intake of saturated fatty acids and alcohol were considered as high risk factors for breast cancer in the past. In addition to these factors intake of n-6 and n-3 polyunsaturated fatty acids has been discussed. Possible differences between their carcinogenic activity are summarized. The mechanisms of promotion and inhibition are described in the present review. In the second part there protective nutritional factors are reviewed: fiber, antioxidant micronutrients (vitamin C, vitamin b-A, carotene and other carotenoids, vitamin E, antioxidant trace elements), n-3 polyunsaturated fatty acids, olive oil and oestrogen compounds of plant origin. Influence of several diet components can not be considered individually. Nutrition has to be taken into account as a whole complex of protective and risk components. It is necessary to increase the intake of probably protective nutrients and minimize all cancer risk factors including nutrition. (Tab. 2, Fig. 3, Ref. 181.)
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PMID:[Nutrition and female breast tumors]. 1064 42

The Women's Health Study (WHS) is a randomized, double-blind, placebo-controlled trial designed to evaluate the balance of benefits and risks of low-dose aspirin and vitamin E in the primary prevention of cardiovascular disease and cancer in women. A total of 39,876 female health professionals, age 45 years or older and without a history of cardiovascular disease or cancer (other than nonmelanoma skin cancer), were randomized in a 2x2 factorial design to one of four treatment groups: active aspirin and vitamin E placebo, aspirin placebo and active vitamin E, both active agents, or both placebos. The process of randomization was successful, as evidenced by the equal distribution of a large number of baseline demographic, lifestyle, and health history characteristics among the four treatment groups. Similar distribution of known potential confounders, as well as the large sample size, provides reassuring evidence that unmeasured or unknown potential confounders are also equally distributed. As expected in a clinical trial, the women in the study are healthier in some respects than the general population, but they have very comparable rates of obesity, hypertension, and elevated cholesterol. With adequate duration of treatment and follow-up, this trial will provide important and relevant information on the balance of benefits and risks of aspirin and vitamin E supplementation in the primary prevention of cardiovascular disease and cancer in women.
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PMID:Baseline characteristics of participants in the Women's Health Study. 1071 1

For the first time in history, populations in affluent countries may concomitantly indulge in rich food and physical idleness. Various combinations of obesity, diabetes, and hypertriglyceridemia, with insulin resistance as the common feature, cause hepatic steatosis, which can trigger necroinflammation and fibrosis. Patients with "primary" steatohepatitis exhibit ultrastructural mitochondrial lesions, decreased activity of respiratory chain complexes, and have impaired ability to resynthesize ATP after a fructose challenge. Mitochondria play a major role in fat oxidation and energy production but also leak reactive oxygen species (ROS) and are the main cellular source of ROS. In patients with steatosis, mitochondrial ROS may oxidize hepatic fat deposits, as suggested in animal models. Lipid peroxidation products impair the flow of electrons along the respiratory chain, which may cause overreduction of respiratory chain components, further increasing mitochondrial ROS formation and lipid peroxidation. Another vicious circle could involve ROS-induced depletion of antioxidants, impairing ROS inactivation. Blood vitamin E is decreased in some obese children with steatohepatitis, and serum transaminases improve after vitamin E supplementation. Steatohepatitis is also caused by alcohol abuse, drugs, and other causes. In "secondary" steatohepatitis, mitochondrial ROS formation is further increased as the causative disease itself directly increases ROS or first impairs respiration, which secondarily increases mitochondrial ROS formation. This "second hit" could cause more lipid peroxidation, cytokine induction, Fas ligand induction, and fibrogenesis than in primary steatohepatitis.
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PMID:Mitochondria in steatohepatitis. 1129 97

The study aim at revealing the associations between the intake of dietary antioxidant vitamins and personal characteristics on age, sex, education, working status and household gross income etc. The intake of antioxidant vitamins in a population of Guangdong Province was studied. A total of 418 males and 503 females, aged 25-84 year were interviewed, and questionnaires on socio-demography and on a 12-month food intake frequency (FFQ) were completed in 1995. The daily average intake of antioxidant vitamins and energy was higher in male than in female. Older subjects consumed lesser antioxidant vitamins. The vitamin E intake of higher education persons as well as high family income females (> 15001RMB) was higher. Individual business owners and farmers consumed lesser antioxidant vitamins than the other counterparts. The highest vitamin E intake was found in the currently unemployed men and retired women. BMI was positively associated with the intake of antioxidant vitamins excepted for the obesity group. The result suggests that the consumption of antioxidant vitamins varies with characteristics of socio-demographic status. Health promotion programs, such as suggestions on eating more fruits and vegetables should be targeted at the elderly, the less educated, lower income families and rural community.
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PMID:[Dietary intake of antioxidant vitamins and personal demographic characteristics of Guangdong residents]. 1132 43


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