Stability of domain structures in multi-domain proteins

Multi-domain proteins have many advantages with respect to stability and folding inside cells. Here we attempt to understand the intricate relationship between the domain-domain interactions and the stability of domains in isolation. We provide quantitative treatment and proof for prevailing intuitive ideas on the strategies employed by nature to stabilize otherwise unstable domains. We find that domains incapable of independent stability are stabilized by favourable interactions with tethered domains in the multi-domain context. Stability of such folds to exist independently is optimized by evolution. Specific residue mutations in the sites equivalent to inter-domain interface enhance the overall solvation, thereby stabilizing these domain folds independently. A few naturally occurring variants at these sites alter communication between domains and affect stability leading to disease manifestation. Our analysis provides safe guidelines for mutagenesis which have attractive applications in obtaining stable fragments and domain constructs essential for structural studies by crystallography and NMR

Menopausal hormone use and ovarian cancer risk: individual participant meta-analysis of 52 epidemiological studies

Background Half the epidemiological studies with information about menopausal hormone therapy and ovarian cancer risk remain unpublished, and some retrospective studies could have been biased by selective participation or recall. We aimed to assess with minimal bias the effects of hormone therapy on ovarian cancer risk. Methods Individual participant datasets from 52 epidemiological studies were analysed centrally. The principal analyses involved the prospective studies (with last hormone therapy use extrapolated forwards for up to 4 years). Sensitivity analyses included the retrospective studies. Adjusted Poisson regressions yielded relative risks (RRs) versus never-use. Findings During prospective follow-up, 12 110 postmenopausal women, 55% (6601) of whom had used hormone therapy, developed ovarian cancer. Among women last recorded as current users, risk was increased even with <5 years of use (RR 1·43, 95% CI 1·31–1·56; p<0·0001). Combining current-or-recent use (any duration, but stopped <5 years before diagnosis) resulted in an RR of 1·37 (95% CI 1·29–1·46; p<0·0001); this risk was similar in European and American prospective studies and for oestrogen-only and oestrogen-progestagen preparations, but differed across the four main tumour types (heterogeneity p<0·0001), being definitely increased only for the two most common types, serous (RR 1·53, 95% CI 1·40–1·66; p<0·0001) and endometrioid (1·42, 1·20–1·67; p<0·0001). Risk declined the longer ago use had ceased, although about 10 years after stopping long-duration hormone therapy use there was still an excess of serous or endometrioid tumours (RR 1·25, 95% CI 1·07–1·46, p=0·005). Interpretation The increased risk may well be largely or wholly causal; if it is, women who use hormone therapy for 5 years from around age 50 years have about one extra ovarian cancer per 1000 users and, if its prognosis is typical, about one extra ovarian cancer death per 1700 users

Assisted Reproductive Technologies in Europe. Usage and Regulation in the Context of Cross-Boarder Reproductive Care

This chapter reviews assisted reproductive technologies (ART) usage and policies across European countries, and scrutinizes emerging issues related to cross-border reproductive care (or “reproductive tourism”). Although Europe is currently the largest market for ART, the extent of usage varies widely across countries, largely because of differences in the laws, the affordability, the types of reimbursement, and the norms surrounding childbearing and conception. Since 2009, the regulation of ART has been expanding in Europe, and all countries now have some form of ART legislation. Countries where the treatments are completely covered by national health plans have the highest level of ART utilization. Being in a legal marriage or a stable union is often a prerequisite for access to ART. Currently, only half of European countries allow single women to use ART, and even fewer grant access to lesbian women. Surrogate motherhood is strictly prohibited in many countries in Europe, and where it is allowed, strong restrictions against commercial surrogacy are in place. While restrictive national legislation can be easily circumvented by crossing national boundaries for ART treatments, questions of equity of access have been raised, as not all prospective parents can afford to travel for treatment

Incidence of arterial disease among oral contraceptive users. Royal College of General Practitioners' Oral Contraception Study.

During 1968-69, 23,000 women taking oral contraceptives (OCs) and an equal number of controls were recruited by 1400 general practitioners (GPs) throughout the UK. Every 6 months the GPs report on the health and OC use of women in the continuing study. To determine the incidence of arterial disease the number of reports of initial vascular illnesses in each OC-usage group is divided by the calendar months of observation for women in that group. The standardized incidence rate (number of cases) of ischemic heart disease was 0.77 for current OC users, 0.63 for former users, and 0.54 for controls and of cerebrovascular disease for OC users was 0.62 for current users, 0.50 for former users, and 0.20 for controls. The only subcategory for which current users had a significantly increased relative risk was acute myocardial infarction (2.0). Current users also had increased risk of cerebral thrombosis, cerebral embolism, and transient ischemic attacks. Women aged 35 years and over had higher rates of arterial disease than did younger women and cigarette smoking increased the risk for older women in each OC usage group, having little effect on women under 35 years of age. Women over 35 who smoked had a 3.1 times greater risk of developing arterial disease than did nonsmokers. Neither ischemic heart disease nor peripheral vascular disease was shown to be associated with duration of OC use. It was also found that women who smoked and had used OCs had case-fatality rates 2-3 times greater than women in other groups. General conclusions are: 1) the relative risks of OC use are lower for the incidence of 1st events of arterial disease than for deaths, and 2) for cerebrovascular disease there is an increased risk in former users which remains high for over 6 years after stopping OCs

Age-specific differences in the relationship between oral contraceptive use and breast cancer.

Nearly all studies have suggested that the use of oral contraceptives (OC) is not associated with the aggregate risk of breast cancer diagnosed in women aged 20-54. Because of age-specific differences in the breast cancer-parity relationship and because of age-specific differences in other breast cancer risk factors, the Centers for Disease Control reexamined data from the Cancer and Steroid Hormone Study to assess whether OC use has different effects on the risk of breast cancer at different ages of diagnosis. This was a population-based case-control study conducted in eight geographic areas in the United States during 1980-1982. In these data, the relationship between the risk of breast cancer and OC use appeared to vary by age at diagnosis. Among women aged 20-34 years at diagnosis or interview, those who had ever used OC had a slightly increased risk of breast cancer (odds ratio 1.4, 95% confidence interval 1.0-2.1) when compared with women of the same ages who had never used OC. Among these women, there were no trends of increasing or decreasing risk with any measure of OC use. Among women aged 35-44 years, there was no association between OC use and breast cancer. Among women aged 45-54 years, those who used OC had a slightly decreased risk of breast cancer (odds ratio 0.9, 95% confidence interval 0.8-1.0). Among these women, the risk estimates decreased significantly with increasing time since first and last use. Although the slightly increased risk estimates for the youngest women are compatible with findings by other investigators, the decreased risk estimates for the oldest women have not been described in as many studies. Available data provide no reasons for changes in prescribing practices or in the use of OC as related to breast cancer risk

Age-specific differences in the relationship between oral contraceptive use and breast cancer.

BACKGROUND: Nearly all studies have suggested that the use of oral contraceptives (OC) is not associated with the aggregate risk of breast cancer diagnosed in women aged 20-54 years. Because of age-specific differences in the breast cancer-parity relationship and because of age-specific differences in other breast cancer risk factors, the Centers for Disease Control reexamined data from the Cancer and Steroid Hormone Study (CASH) to assess whether OC use has different effects on the risk of breast cancer at different ages of diagnosis. METHODS: This population-based case-control study was designed to examine the relationship between the use of OC and the risk of breast, ovarian, and endometrial cancer. CASH was conducted in eight geographic areas in the United States during 1980-1982. All participants were interviewed at home with a pretested standardized questionnaire including a calendar of life events and a photograph book of all pills marketed in the United States. RESULTS: We found that the relationship between the risk of breast cancer and OC use appeared to vary by the age at diagnosis. Among women aged 20-34 years at diagnosis or interview, those who had ever used OC had a slightly increased risk of breast cancer (odds ratio [OR], 1.4; 95% confidence interval [CI], 1.0-2.1) compared with women of the same ages who had never used OC. Among these women, there were no trends of increasing or decreasing risk with any measure of OC use. Among women aged 35-44 years, there was no association between OC use and breast cancer. Among women aged 45-54 years, those who used OC had a slightly decreased risk of breast cancer (OR, 0.9; 95% CI, 0.8-1.0). Among these women, risk estimates decreased significantly with increasing time since first and last use. CONCLUSIONS: Although the slightly increased risk estimates for the youngest women were compatible with findings by other investigators, the decreased risk estimates for the oldest women have not been described in as many studies. Available data provide no reasons to change prescribing practices or the use of OC that are related to the breast cancer risk