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PubMed2026

Functional characterization of the 9q34.13 locus identifies RAPGEF1 as modulating risk for melanoma and nevi via RAS activation.

Genome-wide association studies identified a melanoma- and nevus count-associated locus on chromosome band 9q34.13. Fine-mapping and melanocyte expression data collectively suggest two potential causal genes with opposite association with risk: higher levels of Rap guanine nucleotide exchange factor 1 (RAPGEF1) and lower levels of uridine-cytidine kinase 1 (UCK1). Colocalization analyses and conditional TWAS suggest multiple causal cis-regulatory sequence variants in partial linkage disequilibrium (LD) to each other. Melanocyte capture-HiC and CRISPR-inhibition demonstrated regulatory interactions between fine-mapped variants and the RAPGEF1 and UCK1 promoters. Focusing on RAPGEF1, we demonstrate RAPGEF1 expression promotes melanocyte growth and drives malignant transformation of human immortalized melanocytes. Following treatment with human EGF, RAPGEF1 overexpression activated both RAP1 and RAS. Further, we show RAPGEF1 expression is significantly enriched in melanomas lacking strongly activating RAS-MAPK mutations, suggesting that RAPGEF1 may promote oncogenic RAS-MAPK signaling in melanomas. Furthermore, in these tumors, we provide preliminary evidence to support the prognostic relevance of RAPGEF1 expression in patients lacking RAS or BRAF mutations. Together with other recent studies, these data suggest that germline variation influencing RAS activation may play a key role in nevus development and melanoma risk.

Journal Article↗
PubMed1992

[Evaluation of acquired data on long-term risk of hypolipidemic treatments].

At present, it is very difficult, if not impossible, to draw reliable conclusions about the long-term risks of lipid lowering therapy. Many so-called "long-term" trials only cover a few years of treatment, comparative studies versus placebo are very rare and the notification of acute events in the context of pharmacovigilance does not provide information about the long-term risk. However, analysis of large scale primary or secondary prevention trials, the Lipid Research Clinics study with cholestyramine, the Helsinki cardiological study with gemfibrozil, the Coronary Drug Project with clofibrate and nicotinic acid, has not shown any significant differences between the treatment and control groups, in particular with regards to the prevalence of malignant disease. These reassuring observations contradict those of the WHO study with clofibrate: a significant increase in the incidence of cancer, especially gastrointestinal, is observed in the treatment group. Therefore, despite the absence of confirmed long-term clinical or biological adverse effects of lipid lowering drugs (apart from the WHO clofibrate study), the physician must remain vigilant, especially as the long-term risks are difficult to assess.

Clofibrate↗
PubMed1992

[Hypolipidemic treatment after myocardial infarction].

Treatment of hyperlipidaemia is even more important after than before myocardial infarction. Currently available data should be confirmed by larger studies including women and lasting over 10 years. Analysis of the results would be facilitated by studying comparable groups with respect to left ventricular function and severity of the coronary disease. The total serum cholesterol should optimally be under 2 g/l and the LDL-cholesterol under 1.30 g/l. However, coronary artery disease is a multifactorial condition and the correction of only one predisposing factor, albeit a major one, is not sufficient for effective prevention.

Aged↗
PubMed1992

[Evaluation of trials on regression of atheromatous lesions with hypolipemic drugs].

Experimental studies have demonstrated regression of atheromatous lesions with diet and lipid lowering drugs. In order to confirm these results clinically, reliable angiographic methods of analysis must be developed along two lines: quantitative by consensus between independent "blinded" experts, qualitative by digitalizing radiological images. Given the reproducibility of these methods, a variation of 17 to 20% in the size of the atheromatous plaques should be required to affirm a change. Five studies have been performed in patients with atherosclerosis associated with variable degrees of hyperlipidaemia and compared with a control group. NHLBI type II: 59 out of 146 patients with type II hyperlipoproteinaemia were treated with cholestyramine for 5 years with reduction of the progression of > 50% stenosis but no evidence of regression (6%). CLAS: 80 out of 160 coronary patients were treated with cholestipol and nicotinic acid for 2 years and a reduction of progression and a regression of lesions were observed in 16% of cases. Nikkila: 28 coronary patients with hyperlipidaemia were given clofibrate or nicotinic acid for a 7 year period, stabilising the evolution but with no signs of regression. FATS: 74 of 120 coronary patients with apolipoprotein B concentrations of over 1.25 g/l were given lovastatine-cholestipol or nicotinic acid-cholestipol for 2.5 years: regression of coronary lesions was observed in 32 to 39% of cases depending on the treatment administered. Olsson: reported the same results for femoral atheroma with treatments associating fenofibrate and nicotinic acid: 20% regression and reduction of progression.(ABSTRACT TRUNCATED AT 250 WORDS)

Arteriosclerosis↗
PubMed1992

[Blood cholesterol and mortality].

Mortality rates vary with serum cholesterol levels: the causal nature of this relationship is studied by prospective studies (analysis of associations) and unifactorial primary prevention trials (experimentation to determine causality). In prospective studies all cause mortality is often increased at low and high cholesterol levels because of the inverse relationships of this factor with cardiovascular mortality (positive) and non-cardiovascular mortality (negative). Coronary death increases proportionally to serum cholesterol levels in all populations, including those with low cholesterol levels, in both sexes and at all ages. The relationship with cerebrovascular mortality seems to depend on the clinical feature: increased mortality rate due to cerebral haemorrhage in patients with low serum cholesterol and a positive correlation with cerebral thrombosis. Mortality due to cancers is generally negatively correlated to serum cholesterol levels with a significant increase in mortality in patients with a low serum cholesterol. This relationship often becomes less significant as the time between measurement and death increases. Mortality due to violent causes is not usually related to serum cholesterol. The multitude of possible causes of confusion makes any causal interpretation of data illusory. Experimentation by unifactorial primary prevention trials is essential for any etiological research but none of the trials performed to date was designed to analyse the effect of lowering serum cholesterol on global or coronary mortality.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1992

[Relations between HDL-cholesterol and cardiovascular diseases].

Many retrospective and prospective epidemiological studies have demonstrated an inverse relationship between HDL-cholesterol and coronary risk. The predictive value of HDL-cholesterol is observed both in asymptomatic subjects and those with a primary vascular event. Several genetic abnormalities may be responsible for low HDL cholesterol (under 100 mg/dl or 0.26 mmol/l) or for a less severe hypoalphalipoproteinaemia. Despite some very low values, these rare causes of HDL deficiency are not all atherogenic and serve to emphasize the complexity of HDL metabolism. The protective role of HDL is explained by a number of mechanisms such as their role in the reverse transport from the peripheral tissues to the liver, their anti-oxidant effect and the increase in prostacyclin levels. The correction of isolated hypoalphalipoproteinaemia by drugs is controversial, but associated hyperlipidaemic states would be an indication to use drugs which increase the HDl-cholesterol the most.

Apolipoprotein A-I↗
PubMed1992

[Serum cholesterol and cancer. Is there a causal relationship?].

Several studies have reported an inverse relationship between serum cholesterol levels and the risk of cancer, especially of the colon (Seven Countries, Framingham, Chicago studies, London Whitehall Study, Paris prospective study, New Zealand Maori, Honolulu Heart Study, Hypertension Detection and Follow-Up Program, ...). For example, in the Multiple Risk Factor Intervention Trial (361 662 men), the global mortality graph was J-shaped, higher at either side of the 4.6-5.1 mmol/l value of serum cholesterol. This increased mortality with lower serum cholesterol levels was due to increased numbers of death from cancer. However, when the relationship is studied with respect to the time elapsed between the cholesterol measurement and death from cancer, the relative risk of death in the lowest decile with respect to the average of the following deciles, decreases with the period between measurement of the serum cholesterol and time of death. The negative relationship between serum cholesterol and death by cancer, very significant for deaths occurring within the first 5 years, disappeared almost completely for deaths occurring after 5 years. Other trials designed mainly to examine cardiovascular risk, and concerning smaller numbers, have not demonstrated this inverse relationship between serum cholesterol and cancer. This negative relationship between serum cholesterol and cancer must be acknowledged. It is weak and concerns mainly colonic cancer, especially in men in the elderly age groups. Several explanations have been put forward: influence of the combination of factors, competition of risk of death by other causes, chance, alteration of normal biological function of the cell membrane.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1992

[Is regression of atherosclerosis possible?].

Experimental studies have shown the regression of atherosclerosis in animals given a cholesterol-rich diet and then given a normal diet or hypolipidemic therapy. Despite favourable results of clinical trials of primary prevention modifying the lipid profile, the concept of atherosclerosis regression in man remains very controversial. The methodological approach is difficult: this is based on angiographic data and requires strict standardisation of angiographic views and reliable quantitative techniques of analysis which are available with image processing. Several methodologically acceptable clinical coronary studies have shown not only stabilisation but also regression of atherosclerotic lesions with reductions of about 25% in total cholesterol levels and of about 40% in LDL cholesterol levels. These reductions were obtained either by drugs as in CLAS (Cholesterol Lowering Atherosclerosis Study), FATS (Familial Atherosclerosis Treatment Study) and SCOR (Specialized Center of Research Intervention Trial), by profound modifications in dietary habits as in the Lifestyle Heart Trial, or by surgery (ileo-caecal bypass) as in POSCH (Program On the Surgical Control of the Hyperlipidemias). On the other hand, trials with non-lipid lowering drugs such as the calcium antagonists (INTACT, MHIS) have not shown significant regression of existing atherosclerotic lesions but only a decrease on the number of new lesions. The clinical benefits of these regression studies are difficult to demonstrate given the limited period of observation, relatively small population numbers and the fact that in some cases the subjects were asymptomatic. The decrease in the number of cardiovascular events therefore seems relatively modest and concerns essentially subjects who were symptomatic initially. The clinical repercussion of studies of prevention involving a single lipid factor is probably partially due to the reduction in progression and anatomical regression of the atherosclerotic plaque.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1992

[Optimal serum cholesterol and efficacy of methods for lowering cholesterolemia].

Analysis of epidemiological studies enables definition of the optimal serum cholesterol level between 2 and 2.2 g/l (5.2 and 5.7 mmol/l). Higher levels are associated with an exponential risk of coronary artery disease: lower levels should be interpreted with caution because of the J-shaped curve of global mortality reported in several trials. In primary prevention, therapeutic trials have clearly shown that a significant reduction in the number of coronary event may be obtained by lowering the serum cholesterol (15 for every 1,000 patients treated). In trials performed to date this benefit has not resulted in any gain in global mortality. In secondary prevention, the benefits of lowering serum cholesterol on the incidence of coronary disease seems identical in terms of relative risk to that observed in primary prevention. Nevertheless, the benefits in terms of absolute risk are much higher because of the high incidence of coronary mortality in a patient population with a previous coronary event. Thus, for 1,000 patients treated, there are 50 less cardiac events and this is reflected in a reduction of global mortality of about 20 for every 1,000 patients treated.

Cholesterol↗
PubMed1992

[Should men aged 20 to 30 years with hypercholesterolemia be managed in the same way as older men?].

Serum cholesterol intervention studies have been mainly performed in middle-aged men. Is the extrapolation of these results to men aged 20 to 30 years justified? Atherosclerosis is a process which continues throughout life. It is clear that increased serum cholesterol levels are associated with a higher coronary risk. In addition, serum cholesterol levels increase with age up to 60 years old. Do young men obtain the same benefits from medical intervention as older men? Therapeutic trials have been performed in middle-aged men. The increase in life expectancy associated with a 6.7% lowering of the serum cholesterol by life-long dietary restrictions would only be 4 months in 20 year old subjects at high risk (hypertension, smokers, low HDL cholesterol). With a 20% reduction in serum cholesterol, the gain would be 12 months. There is no reason for not extrapolating acquired data in the over 30s to 20 to 30 year old subjects. Due to the fact that young subjects are exposed to the risk for longer periods, it is advisable to treat their hypercholesterolaemia even more seriously than that of older patients.

Adult↗
PubMed1992

[Should hypercholesterolemic women be treated?].

There have been few studies designed to evaluate the problem of hypercholesterolaemia in women despite the fact that, like men, cardiovascular disease is their main cause of death. Serum cholesterol is a risk factor in women, but the increased risk appears at much higher values of serum cholesterol than observed in men. In women, low HDL-cholesterol seems to be the best predictive factor for the occurrence of a coronary event, especially if the triglycerides are raised. The absence of therapeutic data on the treatment of hypercholesterolaemia in women underlines the need for a specific trial to assess the effects of lipid-lowering drugs in this population. The cardiovascular benefits of hormone substitute therapy at the menopause have been reported in several studies and a large scale randomised trial is under way to confirm these results. The benefit of hypercholesterolaemic therapy in women with mild hypercholesterolaemia has not been proved. When the serum cholesterol level is over 3 g/l (7.77 mmol/l), early treatment is advisable.

Adult↗
PubMed1992

Reversibility of left ventricular hypertrophy.

Left ventricular hypertrophy (LVH) is a powerful independent risk factor for coronary artery disease. This overview of 104 studies examines the ability of various types of antihypertensive therapies to reverse LVH as assessed by echocardiography. Combination therapy, angiotensin converting enzyme (ACE) inhibitors, and methyldopa were the most effective in reversing LV mass; vasodilators such as minoxidil and hydralazine had no effect on LVH. These differences were independent of the degree of fall in blood pressure and duration of therapy. beta-blockers were as effective as ACE inhibitors in decreasing LV wall thickness. Possible reasons for drug differences in reversing LVH are discussed. Preliminary evidence suggests that reversing LVH by antihypertensive drug therapy is associated with a reduction in cardiovascular complications.

Antihypertensive Agents↗
PubMed1992

Cholesterol reduction in single and multifactor randomized trials: relationship to CHD incidence and total mortality as found by meta analysis of twenty-two trials.

This paper reports on a meta analysis in twenty-two randomized both single and multifactor trials regarding the effect of designed cholesterol reduction on total mortality and CHD incidence. Per cent reduction in CHD incidence was 2.5 for every per cent associated net reduction in total cholesterol, but was only 0.74% for total mortality. Since total net reduction in cholesterol was about 5% in all trials combined, the number of participants was far too small to demonstrate a significant expected reduction of 4% in total mortality. However, the 4% reduction lies just outside the observed 95% confidence limits of the overall estimate of effect on total mortality (OR = 1.02; CL 0.97, 1.07). It is concluded that cholesterol reduction must be much larger than 5% to be able to reduce the relative risk of CHD substantially and total mortality moderately.

Cholesterol↗
PubMed1992

Efficacy of tianeptine in comparative trials versus reference antidepressants. An overview.

The clinical properties of tianeptine have been assessed in double-blind controlled studies, which involved depressed patients fulfilling DSM-III criteria for either major depression--single episode or recurrent (without melancholia and psychotic features)--or dysthymic disorder--with or without an additional diagnosis of alcohol abuse or dependence. Five studies have compared tianeptine with reference antidepressants: its efficacy has been found to be similar to that of amitriptyline in depressed out-patients. However, these data need to be confirmed by other controlled trials v. reference drugs and by at least two placebo-controlled studies. Tianeptine does not induce sleep disorders, anticholinergic effects, or modifications of cardiovascular variables or biological parameters (renal, haematological, or hepatic). After the end of treatment, the only signs of withdrawal have been some disturbances of sleep.

Amitriptyline↗
PubMed1992

A quantitative assessment of oral contraceptive use and risk of ovarian cancer.

OBJECTIVE: To provide a quantitative assessment of the association between oral contraceptive (OC) use and ovarian cancer using results from the published literature. DATA SOURCES: We conducted a MEDLINE literature search for all epidemiologic studies of OC and ovarian cancer published in English between 1970-1991. The reference list for each article was reviewed to locate additional published articles. METHODS OF STUDY SELECTION: We included 20 studies in which a relative risk and either a standard error, confidence interval, or P value was reported, or sufficient data were presented to allow us to calculate these measures. DATA EXTRACTION AND SYNTHESIS: We summarized the findings using weighted averages and regression analyses. We found a summary relative risk of 0.64 (95% confidence interval 0.57-0.73) associated with ever-use of OC, indicating a 36% reduction in ovarian cancer risk. The risk of ovarian cancer decreased with increasing duration of OC use; we noted a 10-12% decrease in risk with 1 year of use and approximately a 50% decrease after 5 years of use. The reduced risk was present among both nulliparous and parous women and it appeared to last for at least 10 years after cessation of use. Although most studies assessed the use of cessation of use. Although most studies assessed the use of OC formulations from the 1960s and 1970s, data from the Cancer and Steroid Hormone Study indicate that the decreased ovarian cancer risk may also be present with current lower-dose formulations. CONCLUSION: The protective effect of OC against ovarian cancer risk should be considered in a woman's decision to use OC.

Contraceptives, Oral↗