Hypoxia regulates global membrane protein endocytosis through caveolin-1 in cancer cells.

Hypoxia promotes tumour aggressiveness and resistance of cancers to oncological treatment. The identification of cancer cell internalizing antigens for drug targeting to the hypoxic tumour niche remains a challenge of high clinical relevance. Here we show that hypoxia down-regulates the surface proteome at the global level and, more specifically, membrane proteome internalization. We find that hypoxic down-regulation of constitutive endocytosis is HIF-independent, and involves caveolin-1-mediated inhibition of dynamin-dependent, membrane raft endocytosis. Caveolin-1 overexpression inhibits protein internalization, suggesting a general negative regulatory role of caveolin-1 in endocytosis. In contrast to this global inhibitory effect, we identify several proteins that can override caveolin-1 negative regulation, exhibiting increased internalization at hypoxia. We demonstrate antibody-mediated cytotoxin delivery and killing specifically of hypoxic cells through one of these proteins, carbonic anhydrase IX. Our data reveal that caveolin-1 modulates cell-surface proteome turnover at hypoxia with potential implications for specific targeting of the hypoxic tumour microenvironment.

Symptoms in peri- and postmenopausal women in relation to testosterone concentrations: data from The Women's Health in the Lund Area (WHILA) study.

OBJECTIVES: The aim of this study was to investigate possible associations between androgen concentrations in perimenopausal women and symptoms that may be associated with low androgen concentrations in the blood. METHODS: All women born in the period 1935-1945 and living in a defined geographic area in Sweden (n = 10 766) were invited to a screening program that included physical and laboratory examinations and a questionnaire. Three groups were identified: premenopausal women, women on hormone replacement therapy (HRT) and postmenopausal women without HRT. Concentrations of testosterone, androstendione, sex hormone binding globulin and estradiol were measured. Waist-hip ratio, body mass index and free testosterone index (FTI) were calculated. RESULTS: A total of 6908 women participated. The women on HRT had lower testosterone and FTI and were less satisfied with mood and energy (p < 0.05). Women with hot flushes had higher testosterone and FTI and women reporting coldness had lower concentrations (p < 0.05). Sexual well-being was not correlated to testosterone or FTI (p > 0.05). CONCLUSIONS: Lower testosterone concentrations were associated with lower quality of life in perimenopausal women but not to sexual well-being. There must be factors other than decrements in sex hormones that contribute to the emergence of some perimenopausal symptoms.

Could androgens protect middle-aged women from cardiovascular events? A population-based study of Swedish women: The Women's Health in the Lund Area (WHILA) Study.

OBJECTIVE: The aim of this analysis was to delineate perceived associations between androgens and cardiovascular events in perimenopausal women. DESIGN: A cross-sectional, population-based study of 6440 perimenopausal women aged 50-59 years, living in Southern Sweden. In all, 461 (7.1%) women were premenopausal (PM), 3328 (51.7%) postmenopausal without hormone therapy (HT) (PM0) and 2651 (41.2%) postmenopausal with HT (PMT). For further comparisons, 104 women (1.6%) who reported cardiovascular disease (CVD) were studied in detail; 49 had had a myocardial infarction, 49 a stroke and six women both events. For each woman with CVD, two matched controls were selected (n=208). RESULTS: In the matched controlled series, androstenedione levels were lower (p<0.005) in cases. Cases with hormone therapy had also lower testosterone levels than matched controls (p=0.05). In the total cohort, by using multiple logistic regression analyses, testosterone was positively associated with low density lipoprotein cholesterol (p<0.001) and high density lipoprotein cholesterol (HDL-C) (p<0.001) in all women, but negatively associated with levels of triglycerides in both the PM0 (p<0.001) and PMT (p<0.001) groups. Androstenedione levels were positively associated with HDL-C (p<0.05) and negatively with triglycerides (p<0.05) in the PM group. CONCLUSION: Women with cardiovascular disease had lower serum androgen levels, particularly women using hormone replacement therapy, even when controlled for lipids and other potential risk factors.

Cardiovascular risk factors in middle-aged women and the association with use of hormone therapy: results from a population-based study of Swedish women. The Women's Health in the Lund Area (WHILA) Study.

OBJECTIVE: Cardiovascular diseases in women are multifactorial. Women carry different risk factors compared to men and these specific risk factors need to be delineated, particularly in relation to the hormonal situation, and effects of diet and lifestyle. METHODS: Out of the total cohort of 10,766 women born 1935-1945 living in the Lund area of southern Sweden, 6917 women completed a generic questionnaire and underwent a physical and laboratory assessment. According to hormonal status, 492 women were premenopausal (PM), 3600 were postmenopausal without hormone therapy (HT) (PM0) and 2816 were postmenopausal with ever-use of HT (PMT). Major cardiovascular risk factors as well as level of education, diet, and degree of physical activity were assessed in relation to hormonal status. RESULTS: Compared to the PM0 group, the women in the PMT group had a higher level of education, more often worked full time, more often had sedentary work and lived a more regular life. They also had a lower rate of cigarette consumption, lower waist-to-hip ratio and lower body mass index than women in the PM0 group. The PMT group had lower levels of serum total cholesterol, low density lipoprotein cholesterol, high density lipoprotein cholesterol and triglycerides than the PM0 group and also had lower systolic and diastolic blood pressures, a lower prevalence of type II diabetes mellitus, of deep venous thrombosis and of coronary artery disease. Low-risk factors for cardiovascular disease and high level of education were still associated with HT, after adjustment by multiple logistic regression. Major risk factors for coronary heart disease were similar between the PM and the PMT groups. CONCLUSION: Use of HT is accompanied by a lower risk profile for cardiovascular disease and also by several factors indicating a healthier lifestyle.

Socio-demographic and psychosocial factors are associated with features of the metabolic syndrome. The Women's Health in the Lund Area (WHILA) study.

AIM: The aim was to analyse any associations between socio-demographic and psychosocial factors and different features of the metabolic syndrome in a geographically well-defined population of middle-aged women. METHODS: A population of 10 766 Caucasian women aged 50-59 years was investigated regarding biological and socio-demographic conditions, physical activity, dietary habits, aspects of quality of life, and subjective physical and mental symptoms. The screening instrument was used to discriminate subjects as positive or negative on one or more of a total of eight variables considered to be linked to the metabolic syndrome. The cut-off values for positive screening were non-fasting capillary blood glucose >/= 8.0 mmol/l and serum triglycerides >/= 2.3 mmo/l, BMI >/= 30 kg/m2, WHR >/= 0.90, blood pressure >/= 160 and/or 95 mmHg, a family history of diabetes, and pharmacological treatment for hypertension or hyperlipidaemia. RESULTS: Altogether 6805 women (63.2%) participated: 3535 with positive and 3270 with negative screening. Multiple logistic regression analyses showed that comprehensive (OR 1.62, 95% CI 1.41-1.87) and upper secondary (1.40, 1.24-1.57) school, low physical quality of life (1.41, 1.23-1.61) and high sum of subjective physical symptoms (1.06, 1.04-1.08) were positively associated with one or more features of the metabolic syndrome, while high leisure-time exercise and healthy diet (0.84, 0.71-0.99), and low (

A screening procedure detecting high-yield candidates for OGTT. The Women's Health in the Lund Area (WHILA) study: a population based study of middle-aged Swedish women.

The objective was to evaluate a screening procedure for detecting high-yield candidates for an OGTT, in a population of middle-aged Swedish women. A two-step screening procedure was performed in 6917 subjects. Women with a positive screening outcome, i.e. increased non-fasting capillary blood glucose, serum triglycerides, BMI, WHR, blood pressure or a family history of diabetes, pharmacological treatment of hypertension or hyperlipidaemia at the primary screening underwent a 75-g OGTT. A control group of women with negative screening outcome (n = 221) also underwent an OGTT. In 2923 women with positive screening outcome, 517 (17.7%) had NFG/IGT (normal fasting venous blood glucose <5.6 mmol/l and 2h-glucose 6.7-9.9 mmol/l), 109 (3.7%) IFG/IGT (fasting 5.6-6.0 and 2h 6.7-9.9 mmol/l) and 223 (7.6%) diabetes (fasting > or = 6.1 or 2h > or = 10.0 mmol/l). These figures were three, five and four times higher, respectively, than in the control group with negative screening outcome (p < 0.001 for all); no differences were found for IFG/NGT (fasting 5.6-6.0 and normal 2h < 6.7 mmol/l) (4.6% vs. 7.2%). For predicting impaired glucose metabolism (IFG/NGT, NFG/IGT, IFG/IGT, diabetes), the screening instrument showed an estimated sensitivity of 70%, specificity of 55%, positive predictive value of 34% and negative predictive value of 85%, based on findings in the control sample. The odds ratio for NFG/IGT increased with the numbers of risk factors from 2.8 to 7.7, for IFG/ IGT from 5.7 to 55.0 and for diabetes from 2.5 to 18.1. High B-glucose, WHR and BMI were the three most important factors associated with an increased risk for NFG/IGT, IFG/IGT and diabetes. In subjects with IFG/NGT, none of the screening variables was associated with an increased risk. In summary, the results show a population screening method focused on features of the metabolic syndrome that discloses high-yield candidates for OGTT. A high prevalence of unknown impaired glucose metabolism was found in middle-aged women with a positive screening profile.

Dyslipidaemia and impaired well-being in middle-aged women reporting low Sense of Coherence. The Women's Health in the Lund Area (WHLA) Study.

OBJECTIVE: A low Sense of Coherence (SOC) is a concept related to a feeling of ill health. Not much is known about possible relationships between SOC and biological factors. SETTING: Population-based study of middle-aged women. SUBJECTS AND METHODS: Four-hundred-and-fifty women participated as a subgroup of a larger study of cardiovascular risk factor screening. A self-administered questionnaire with 29 questions related to SOC was completed in addition to questions on social background factors and medical history. RESULTS: The mean score of SOC was 150.9 (SD 23.4). HDL cholesterol was lower (p < 0.05) and triglyceride levels higher (p < 0.05) in women with low SOC (1.5 and 2.1 mmol/L) compared to women with medium (1.8 and 1.4 mmol/L) or high SOC (1.7 and 1.5 mmol/L). In multiple regression analysis, a low HDL cholesterol level was still significantly associated with low SOC (p < 0.05) after adjustment for possible confounders. Women reporting low SOC were further characterised by a higher proportion of subjects with regular clinical visits for health care (49% vs 35% and 29%). CONCLUSIONS: Middle-aged women reporting low SOC showed lower HDL cholesterol and higher triglyceride levels, and reported more clinical visits and medical symptoms than women with higher SOC.

Urogenital symptoms in women aged 50-59 years. Women's Health in Lund Area (WHILSA) Study Group.

Problems related to the urogenital tract are common in elderly women. Control of micturition is often impeded and questionnaire-based studies have reported a prevalence of poor control of micturition in about 30% of postmenopausal women. In an ongoing cohort comprising women born between 1935 and 1945, an interim analysis was performed in 1800 women based on an interview and questionnaire. The prevalence of urinary incontinence was found to be 33%, which is in accordance with previous reports. The main difference between the interview and the questionnaire was that the interview could take into account intensity as well as intermittence of symptoms. There were no differences between premenopausal women and postmenopausal women using or not using hormone replacement therapy. In agreement with earlier studies, we found poorer control of micturition in parous women. A higher percentage of incontinence was also found in women who had lost more than 5 kg in body weight during the preceding 5 years. In addition, women with a family history of diabetes were more prone to complaints of incontinence. Of the 155 women who had a family history of diabetes, 66 were incontinent (p < 0.01). It was also found that women who were incontinent were more often on regular surveillance for various diseases, using more medications regularly and had been hospitalized during the last 5 years more often than women who were continent. There were no differences in smoking habits. The present results imply that urinary incontinence in women is of a complicated origin and that the hormonal situation plays a minor role for this socially handicapping symptom.

Old patients with hypertension. A 25-year observational study of a geographically defined population (Dalby), aged 67 years at entry.

OBJECTIVES: To evaluate the impact of hypertension and other risk factors on mortality, in particular cardiovascular mortality, in a geographically defined population of elderly subjects. DESIGN: An observational 25-year study of a total population. SETTING: The local health centre in the village of Dalby in southern Sweden. SUBJECTS: All men and women born in 1902 or 1903, living in Dalby, were, at the age of 67, invited for medical and psychological examinations. The population comprised 188 subjects (109 men and 79 women); 156 (83%) of them took part in the first medical examination. Blood pressure, heart rate, weight and height were measured and laboratory tests performed at entry. Blood pressures were thereafter recorded six times, and this report is based on a 25-year follow-up period ending in October 1994. MAIN OUTCOME MEASURES: Survival analyses were performed, based on definition of underlying causes of death, divided into all-cause and cardiovascular. RESULTS: At entry, females had higher blood pressure than males, both at baseline and during the first 16 years of the study, regardless of whether they were hypertensives or not. Most men smoked but only a few women. At the end of the follow-up of the present study in 1994, 138 out of 156 (88%) subjects had died and only 18 (12%) remained alive; 78 (57%) had died of a cardiovascular disease. In men, a diagnosis of hypertension as well as increased blood pressure at entry was associated with increased mortality. In women this was the case for blood pressure and risk of cardiovascular mortality. In men, both systolic and diastolic blood pressures during the study were significant risk factors for death, whereas in women this was not the case. CONCLUSIONS: Elderly male hypertensives ran an increased mortality risk even though they were treated according to the then current guidelines; female hypertensives seemed to run the same risk of dying as normotensive females.

Blood pressure in relation to medical, psychological and social variables in a population of 80-year-olds. Survival during 6 years.

OBJECTIVES: To relate elevated blood pressure in 80-year-olds to symptoms, life satisfaction and survival. DESIGN: Examinations of medical, psychological and social factors every year between 80 and 86 years of age. SETTING: Primary health care in the city of Lund in southern Sweden. SUBJECTS: Three-hundred and thirty-three persons living in the city of Lund and born in 1908. Participation rate was 67%. INTERVENTION: Abnormal findings were further examined and treated. MAIN OUTCOME MEASURES: Symptoms, blood pressure, laboratory values, psychological factors, cognition, living conditions, and survival. RESULTS: Hypertension according to the definition used was found in 70%. Women were over-represented (P < 0.05). Amongst persons with alleged hypertension, diuretics (P < 0.001) and 'other cardiovascular drugs' (P < 0.001) were more often used. Analgesics were more often used amongst assessed hypertensives (P < 0.05). Those with assessed hypertension scored better in testing of cognition compared to nonhypertensives (P < 0.05), and less often lived in institutions (P < 0.001). Assessed hypertensives had a better survival than alleged hypertensives during the following 7 years (P < 0.01). CONCLUSIONS: Eighty-year-olds with assessed hypertension in the consulting room showed fewer symptoms and had a better cognition and survival than alleged hypertensives (those with a history of hypertension).