Sortilin‐related receptor is a druggable therapeutic target in breast cancer

In breast cancer, the currently approved anti‐receptor tyrosine‐protein kinase erbB‐2 (HER2) therapies do not fully meet the expected clinical goals due to therapy resistance. Identifying alternative HER2‐related therapeutic targets could offer a means to overcome these resistance mechanisms. We have previously demonstrated that an endosomal sorting protein, sortilin‐related receptor (SorLA), regulates the traffic and signaling of HER2 and HER3, thus promoting resistance to HER2‐targeted therapy in breast cancer. This study aims to assess the feasibility of targeting SorLA using a monoclonal antibody. Our results demonstrate that anti‐SorLA antibody (SorLA ab) alters the resistance of breast cancer cells to HER2 monoclonal antibody trastuzumab in vitro and in ovo. We found that SorLA ab and trastuzumab combination therapy also inhibits tumor cell proliferation and tumor cell density in a mouse xenograft model of HER2‐positive breast cancer. In addition, SorLA ab inhibits the proliferation of breast cancer patient‐derived explant three‐dimensional cultures. These results provide, for the first time, proof of principle that SorLA is a druggable target in breast cancer.     

Reproductive history and carotid intima-media thickness

BACKGROUND: Intima-media thickness (IMT) of the carotid arteries is a valid measure of preclinical atherosclerosis which may predict cardiovascular outcomes. Metabolic and hormonal changes associated with the reproductive history of women may contribute to the development of cardiovascular disease (CVD). METHODS: In a population-based cross-sectional study comprising 746 Finnish women, aged 45-74 years, associations of reproductive history (assessed by questionnaire) and measures of subclinical atherosclerosis (by ultrasonographic detection) were studied. Statistical methods included linear and logistic regression models. RESULTS: Mean carotid IMT was positively associated with parity, but after adjustment for age its statistical significance disappeared. Women with a history of stillbirth tended to have higher IMT than other women. History of hysterectomy was an independent determinant of carotid plaque in models with age, blood pressure, fasting blood glucose and cholesterol, body mass index (BMI), education and smoking (odds ratio (OR): 0.32; 95% confidence interval (CI): 0.11-0.96). But when oophorectomy (yes/no) was included in the model, this association lost its statistical significance (adjusted OR: 0.36; 95% CI: 0.11-1.22). A history of stillbirth was associated with an increased age-adjusted risk of plaque (OR=3.43; 95% CI: 1.07-11.05), but in the fully adjusted model it lost its statistical significance (OR=3.61; 95% CI: 0.86-15.23). CONCLUSION: Stillbirth was associated with increased risk of atherosclerotic plaque. Atherosclerosis is a lifelong process to which stillbirth is related. However, due to the cross-sectional design of this study, the causality of this association remains unclear.     

Diagnosis and treatment of menorrhagia

One-third of all women experience heavy menstrual bleeding at some point in their life. In western countries, about 5% of women of reproductive age will seek help for menorrhagia annually. Half of all women who consult for hypermenorrhea have some uterine abnormality, most often fibroids (among patients under 40 years of age) and endometrial polyps (above 40 years of age). Appropriate treatment considerably improves the quality of life of these patients, and it is important to make a rigorous assessment of the patient to provide the best treatment options. This guideline provides instructions on how to examine and treat women of fertile age who have menorrhagia. The subject's own assessment of the amount of menstrual blood loss does not generally reflect the true amount. All patients should undergo a pelvic examination and, if the menstrual pattern has changed substantially or if anaemia is present, a vaginal sonography should be carried out as the most important supplemental examination. Vaginal sonography combined with an endometrial biopsy is a reliable method for diagnosing endometrial hyperplasia or carcinoma, but it is insufficient for diagnosing endometrial polyps and fibroids; these can be diagnosed more reliably by sonohysterography or hysteroscopy. Non-steroidal anti-inflammatory drugs and tranexamic acid reduce menstrual blood loss by 20-60%, and the effectiveness of a hormonal intrauterine system (IUS) is comparable with that of endometrial ablation or hysterectomy. Cyclic progestogens do not significantly reduce menstrual bleeding of women who ovulate. Treatment should be started with one of the drug therapies, i.e. the IUS, tranexamic acid, anti-inflammatory drugs, or oral contraceptive. Drug treatment should be used and evaluated before surgical interventions are considered. With an effective training and feedback system, it is possible to organise the diagnostics, medical treatment and follow-up of heavy menstrual bleeding in the primary health care setting or in outpatient clinics, which reduces the burden on specialist health care.     

Infertility and the use of infertility treatments in Finland: prevalence and socio-demographic determinants 1992-2004

OBJECTIVE: To examine changes in the use of infertility treatments by time, the causes of infertility, lifetime prevalence of subfertility, and the use of infertility treatments by socio-demographic factors. STUDY DESIGN: Aggregate IVF statistics (1992-2004) and two nationally representative cross-sectional surveys (1997 and 2002). RESULTS: Total number of IVF, ICSI and FET treatments initiated more than tripled between 1992 and 2004. The proportion of tubal injury as a cause of infertility treatment decreased over time while other female factors, male factor and multiple causes became more common. Self-reported lifetime subfertility was 16.0% in 2002 among women aged 25-64 years. Subfertility differed notably by age and education: young less educated women and older more educated women more frequently reported subfertility. Use of hormone therapy to treat subfertility (1997 and 2002) and participation in infertility treatments or medical examinations (2002) was more common among urban, highly educated and affluent women. CONCLUSIONS: The use of infertility treatments increased and the proportions of causes of infertility have changed over time. Self-reported subfertility differed by age and education. There are socio-demographic differences in the use of infertility treatments.     

Cardiovascular risks and socioeconomic status: differences between men and women in Finland.

STUDY OBJECTIVE--The study aimed to assess the association of different indicators of socioeconomic status with levels of cardiovascular disease risk factors in men and women aged 25-64 years. DESIGN--This was a cross sectional survey, using a community based random sample. SETTING--The provinces of North Karelia and Kuopio in eastern Finland and the cities of Turku and Loimaa and surrounding communities in southwestern Finland in 1987. PARTICIPANTS--Altogether 2164 men and 2182 women aged 25-64 years took part. MEASUREMENTS AND MAIN RESULTS--Data were collected using self administered questionnaires and the measurement of height, body weight, and blood pressure and blood sampling for lipid determinations were done at the survey site. The risk of cardiovascular disease was determined by calculating a simple risk factor score based on the observed values of HDL and total cholesterol, leisure time, physical activity, blood pressure, medication for hypertension, body mass index, and smoking. Indicators of socioeconomic position used were years of education, family income, marital status, and the person's occupation. Lower levels of education, occupation, and income were all significantly associated with an unfavorable risk factor profile in men and women. Education and occupation showed the strongest associations with the risk factor score in both men and women. The results changed little when adjusting for income and marital status. Family income was more strongly associated with the risk factor score in women than men. When adjusting for occupation and education, income was no longer significantly associated with the risk factor score in men. Marital status was not significantly associated with the risk factor score in either sex. CONCLUSIONS--Using the strength of the association with the cardiovascular risk factor score as the criterion for a good socioeconomic indicator, the present study suggests that education and occupation may be equally good indicators in both men and women. Family income may have some additional importance, especially in women.     

Blood pressure and menopausal transition: the Atherosclerosis Risk in Communities study (1987-95)

OBJECTIVE: Blood pressure changes during menopausal transition have not been studied previously using a biracial sample. We investigated whether menopausal transition was associated with change in blood pressure in African-American or white women. DESIGN, SETTING AND PARTICIPANTS: The prospective multicenter study, the Atherosclerosis Risk In Communities (ARIC) Study (1987-95) was utilized. Included were never-users of hormone replacement therapy (3,800 women, 44% of the original sample). MAIN OUTCOME MEASURE: Changes in blood pressure were adjusted for baseline age and body mass index, baseline blood pressure, antihypertensive use, ARIC field center and weight change. The menopausal transition group was compared to the non-transition group, separately, by ethnicity. RESULTS: Women undergoing the menopausal transition did not differ significantly in regard to systolic blood pressure change [5.2, 95% confidence interval (CI) 4.0-6.4] from non-transitional women (4.6, 95% CI 4.0-5.2); adjustment for age, baseline systolic blood pressure and other factors did not alter this finding. Transitional women had significantly less diastolic blood pressure change (-0.5, 95% CI -1.1 to 0.2) than non-transitional women (-2.0, 95% CI -2.4 to -1.7, P= 0.000) but, after adjustment for other covariates, the result was not significant African-American women had significantly (P= 0.003) higher systolic blood pressure change compared to white women, but this difference became non-significant (P= 0.21) after restricting the sample to women younger than 55 years of age. Interactions between menopausal transition and ethnicity were not significant, either in systolic blood pressure or diastolic blood pressure change. CONCLUSION: Menopausal transition is not associated with significant blood pressure change in African-American or white women.     

The effect of adjunctive low-dose doxycycline therapy on clinical parameters and gingival crevicular fluid matrix metalloproteinase-8 levels in chronic periodontitis

BACKGROUND: Low-dose doxycycline (LDD) is recognized to have non-antimicrobial properties that can therapeutically modulate the host response. The aim of the present randomized, double-blind, placebo-controlled, parallel-arm study was to examine the effectiveness of LDD in combination with non-surgical periodontal therapy, compared to non-surgical periodontal therapy alone, on gingival crevicular fluid (GCF) matrix metalloproteinase-8 (MMP-8) levels and clinical parameters over a 12-month period in patients with chronic periodontitis. METHODS: GCF samples were collected, and clinical parameters including probing depth (PD), clinical attachment level, gingival index (GI), and plaque index were recorded. Thirty chronic periodontitis patients were randomized either to a low-dose doxycycline (LDD) or placebo group. The LDD group received low-dose doxycycline (20 mg) b.i.d. for 3 months plus scaling and root planing (SRP), while the placebo group was given placebo capsules b.i.d. for 3 months plus SRP. The patients were evaluated every 3 months during the 12-month study period. At each visit, all clinical measurements and GCF sampling were repeated. GCF MMP-8 levels were determined by a time-resolved immunofluorescence assay. Intragroup comparisons were tested by the Friedman test followed by Wilcoxon signed-rank test to analyze significance of changes over time. The Mann-Whitney test was used to determine differences between the LDD and placebo groups. RESULTS: Significant improvements were observed in all clinical parameters in both groups over the 12-month period (P < 0.0125). The LDD group showed a significantly greater reduction in mean PD scores at 9 and 12 months and in mean GI scores at all time points than the placebo group (P < 0.05). From baseline to 12 months, GCF MMP-8 levels were significantly reduced in both groups (P < 0.0125). The GCF MMP-8 level in the LDD group was significantly lower than that of the placebo group at 6 months (P < 0.05). CONCLUSIONS: The present results indicate that low-dose doxycycline therapy in combination with scaling and root planing can reduce GCF MMP-8 levels and improve clinical periodontal parameters in patients with chronic periodontitis. These results provide additional information about the usefulness of low-dose doxycycline therapy as an adjunct to non-surgical periodontal therapy in the long-term management of periodontal disease. The effectiveness and course of low-dose doxycycline therapy can be monitored conveniently by assessing GCF MMP-8 levels.     

Reducing the health consequences of smoking--a progress report.

Smoking has been identified as one of the health priority areas to be addressed by the Public Health Service''s Objectives for the Nation initiative. Several gains in moving toward the 1990 goals for smoking and health have been recorded. Only 32.6 percent of the U.S. population over 16 years old were smokers in 1980, compared with 41.7 percent in 1965. The proportion of high school seniors who were daily smokers fell from nearly 30 percent in 1977 to 20 percent in 1981. Changes in smoking prevalence were related to critical events, such as the Surgeon General''s reports on smoking. A variety of information and education programs aimed at specific groups are being carried out by Federal, State, and local governmental agencies and voluntary health organizations.