Directed differentiation of pluripotent cells to neural lineages: homogeneous formation and differentiation of a neurectoderm population

During embryogenesis the central and peripheral nervous systems arise from a neural precursor population, neurectoderm, formed during gastrulation. We demonstrate the differentiation of mouse embryonic stem cells to neurectoderm in culture, in a manner which recapitulates embryogenesis, with the sequential and homogeneous formation of primitive ectoderm, neural plate and neural tube. Formation of neurectoderm occurs in the absence of extraembryonic endoderm or mesoderm and results in a stratified epithelium of cells with morphology, gene expression and differentiation potential consistent with positionally unspecified neural tube. Differentiation of this population to homogeneous populations of neural crest or glia was also achieved. Neurectoderm formation in culture allows elucidation of signals involved in neural specification and generation of implantable cell populations for therapeutic use

Accuracy of Risk Estimates from the iPrevent Breast Cancer Risk Assessment and Management Tool.

BACKGROUND: iPrevent is an online breast cancer (BC) risk management decision support tool. It uses an internal switching algorithm, based on a woman's risk factor data, to estimate her absolute BC risk using either the International Breast Cancer Intervention Study (IBIS) version 7.02, or Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm version 3 models, and then provides tailored risk management information. This study assessed the accuracy of the 10-year risk estimates using prospective data. METHODS: iPrevent-assigned 10-year invasive BC risk was calculated for 15 732 women aged 20-70 years and without BC at recruitment to the Prospective Family Study Cohort. Calibration, the ratio of the expected (E) number of BCs to the observed (O) number and discriminatory accuracy were assessed. RESULTS: During the 10 years of follow-up, 619 women (3.9%) developed BC compared with 702 expected (E/O = 1.13; 95% confidence interval [CI] =1.05 to 1.23). For women younger than 50 years, 50 years and older, and BRCA1/2-mutation carriers and noncarriers, E/O was 1.04 (95% CI = 0.93 to 1.16), 1.24 (95% CI = 1.11 to 1.39), 1.13 (95% CI = 0.96 to 1.34), and 1.13 (95% CI = 1.04 to 1.24), respectively. The C-statistic was 0.70 (95% CI = 0.68 to 0.73) overall and 0.74 (95% CI = 0.71 to 0.77), 0.63 (95% CI = 0.59 to 0.66), 0.59 (95% CI = 0.53 to 0.64), and 0.65 (95% CI = 0.63 to 0.68), respectively, for the subgroups above. Applying the newer IBIS version 8.0b in the iPrevent switching algorithm improved calibration overall (E/O = 1.06, 95% CI = 0.98 to 1.15) and in all subgroups, without changing discriminatory accuracy. CONCLUSIONS: For 10-year BC risk, iPrevent had good discriminatory accuracy overall and was well calibrated for women aged younger than 50 years. Calibration may be improved in the future by incorporating IBIS version 8.0b

Mitochondrial physiology

As the knowledge base and importance of mitochondrial physiology to evolution, health and disease expands, the necessity for harmonizing the terminology concerning mitochondrial respiratory states and rates has become increasingly apparent. The chemiosmotic theory establishes the mechanism of energy transformation and coupling in oxidative phosphorylation. The unifying concept of the protonmotive force provides the framework for developing a consistent theoretical foundation of mitochondrial physiology and bioenergetics. We follow the latest SI guidelines and those of the International Union of Pure and Applied Chemistry (IUPAC) on terminology in physical chemistry, extended by considerations of open systems and thermodynamics of irreversible processes. The concept-driven constructive terminology incorporates the meaning of each quantity and aligns concepts and symbols with the nomenclature of classical bioenergetics. We endeavour to provide a balanced view of mitochondrial respiratory control and a critical discussion on reporting data of mitochondrial respiration in terms of metabolic flows and fluxes. Uniform standards for evaluation of respiratory states and rates will ultimately contribute to reproducibility between laboratories and thus support the development of data repositories of mitochondrial respiratory function in species, tissues, and cells. Clarity of concept and consistency of nomenclature facilitate effective transdisciplinary communication, education, and ultimately further discovery

Mitochondrial physiology

As the knowledge base and importance of mitochondrial physiology to evolution, health and disease expands, the necessity for harmonizing the terminology concerning mitochondrial respiratory states and rates has become increasingly apparent. The chemiosmotic theory establishes the mechanism of energy transformation and coupling in oxidative phosphorylation. The unifying concept of the protonmotive force provides the framework for developing a consistent theoretical foundation of mitochondrial physiology and bioenergetics. We follow the latest SI guidelines and those of the International Union of Pure and Applied Chemistry (IUPAC) on terminology in physical chemistry, extended by considerations of open systems and thermodynamics of irreversible processes. The concept-driven constructive terminology incorporates the meaning of each quantity and aligns concepts and symbols with the nomenclature of classical bioenergetics. We endeavour to provide a balanced view of mitochondrial respiratory control and a critical discussion on reporting data of mitochondrial respiration in terms of metabolic flows and fluxes. Uniform standards for evaluation of respiratory states and rates will ultimately contribute to reproducibility between laboratories and thus support the development of data repositories of mitochondrial respiratory function in species, tissues, and cells. Clarity of concept and consistency of nomenclature facilitate effective transdisciplinary communication, education, and ultimately further discovery

Breast cancer chemoprevention : Use and views of Australian women and their clinicians

Guidelines endorse the use of chemoprevention for breast cancer risk reduction. This study examined the barriers and facilitators to chemoprevention use for Australian women at increased risk of breast cancer, and their clinicians. Surveys, based on the Theoretical Domains Framework, were mailed to 1,113 women at ≥16% lifetime risk of breast cancer who were enrolled in the Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer cohort study (kConFab), and their 524 treating clinicians. Seven hundred twenty-five women (65%) and 221 (42%) clinicians responded. Only 10 (1.4%) kConFab women had ever taken chemoprevention. Three hundred seventy-eight (52%) kConFab women, two (3%) breast surgeons, and 51 (35%) family physicians were not aware of chemoprevention. For women, the strongest barriers to chemoprevention were side effects (31%) and inadequate information (23%), which operate in the Theoretical Domains Framework domains of “beliefs about consequences” and “knowledge,” respectively. Strongest facilitators related to tamoxifen's long-term efficacy (35%, “knowledge,” “beliefs about consequences,” and “goals” domains), staying healthy for family (13%, “social role” and “goals” domains), and abnormal breast biopsy (13%, “environmental context” domain). The strongest barrier for family physicians was insufficient knowledge (45%, “knowledge” domain) and for breast surgeons was medication side effects (40%, “beliefs about consequences” domain). The strongest facilitators for both clinician groups related to clear guidelines, strong family history, and better tools to select patients (“environmental context and resources” domain). Clinician knowledge and resources, and beliefs about the side-effect consequences of chemoprevention, are key domains that could be targeted to potentially enhance uptake

Motivators of inappropriate ovarian cancer screening : A survey of women and their clinicians

Background This study examined why women and doctors screen for ovarian cancer (OC) contrary to guidelines. Methods Surveys, based on the Theoretical Domains Framework, were sent to women in the Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer and family physicians and gynecologists who organized their screening. Results Of 1264 Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer women, 832 (65.8%) responded. In the past 2 years, 126 (15.1%) had screened. Most of these (n = 101, 80.2%) would continue even if their doctor told them it is ineffective. For women, key OC screening motivators operated in the domains of social role and goals (staying healthy for family, 93.9%), emotion and reinforcement (peace of mind, 93.1%), and beliefs about capabilities (tests are easy to have, 91.9%). Of 531 clinicians 252 (47.5%) responded; a minority (family physicians 45.8%, gynecologists 16.7%) thought OC screening was useful. For gynecologists, the main motivators of OC screening operated in the domains of environmental context (lack of other screening options, 27.6%), and emotion (patient peace of mind, 17.2%; difficulty discontinuing screening, 13.8%). For family physicians,, the strongest motivators were in the domains of social influence (women ask for these tests, 20.7%), goals (a chance these tests will detect cancer early, 16.4%), emotion (patient peace of mind, 13.8%), and environmental context (no other OC screening options, 11.2%). Conclusion Reasons for OC screening are mostly patient driven. Clinician knowledge and practice are discordant. Motivators of OC screening encompass several domains, which could be targeted in interventions to reduce inappropriate OC screening

Alcohol consumption, cigarette smoking, and familial breast cancer risk: findings from the Prospective Family Study Cohort (ProF-SC)

Abstract Background Alcohol consumption and cigarette smoking are associated with an increased risk of breast cancer (BC), but it is unclear whether these associations vary by a woman’s familial BC risk. Methods Using the Prospective Family Study Cohort, we evaluated associations between alcohol consumption, cigarette smoking, and BC risk. We used multivariable Cox proportional hazard models to estimate hazard ratios (HR) and 95% confidence intervals (CI). We examined whether associations were modified by familial risk profile (FRP), defined as the 1-year incidence of BC predicted by Breast Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA), a pedigree-based algorithm. Results We observed 1009 incident BC cases in 17,435 women during a median follow-up of 10.4 years. We found no overall association of smoking or alcohol consumption with BC risk (current smokers compared with never smokers HR 1.02, 95% CI 0.85–1.23; consuming ≥ 7 drinks/week compared with non-regular drinkers HR 1.10, 95% CI 0.92–1.32), but we did observe differences in associations based on FRP and by estrogen receptor (ER) status. Women with lower FRP had an increased risk of ER-positive BC associated with consuming ≥ 7 drinks/week (compared to non-regular drinkers), whereas there was no association for women with higher FRP. For example, women at the 10th percentile of FRP (5-year BOADICEA = 0.15%) had an estimated HR of 1.46 (95% CI 1.07–1.99), whereas there was no association for women at the 90th percentile (5-year BOADICEA = 4.2%) (HR 1.07, 95% CI 0.80–1.44). While the associations with smoking were not modified by FRP, we observed a positive multiplicative interaction by FRP (pinteraction = 0.01) for smoking status in women who also consumed alcohol, but not in women who were non-regular drinkers. Conclusions Moderate alcohol intake was associated with increased BC risk, particularly for women with ER-positive BC, but only for those at lower predicted familial BC risk (5-year BOADICEA < 1.25). For women with a high FRP (5-year BOADICEA ≥ 6.5%) who also consumed alcohol, being a current smoker was associated with increased BC risk

Alcohol consumption, cigarette smoking, and familial breast cancer risk: findings from the Prospective Family Study Cohort (ProF-SC)

Background Alcohol consumption and cigarette smoking are associated with an increased risk of breast cancer (BC), but it is unclear whether these associations vary by a woman’s familial BC risk. Methods Using the Prospective Family Study Cohort, we evaluated associations between alcohol consumption, cigarette smoking, and BC risk. We used multivariable Cox proportional hazard models to estimate hazard ratios (HR) and 95% confidence intervals (CI). We examined whether associations were modified by familial risk profile (FRP), defined as the 1-year incidence of BC predicted by Breast Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA), a pedigree-based algorithm. Results We observed 1009 incident BC cases in 17,435 women during a median follow-up of 10.4 years. We found no overall association of smoking or alcohol consumption with BC risk (current smokers compared with never smokers HR 1.02, 95% CI 0.85–1.23; consuming ≥ 7 drinks/week compared with non-regular drinkers HR 1.10, 95% CI 0.92–1.32), but we did observe differences in associations based on FRP and by estrogen receptor (ER) status. Women with lower FRP had an increased risk of ER-positive BC associated with consuming ≥ 7 drinks/week (compared to non-regular drinkers), whereas there was no association for women with higher FRP. For example, women at the 10th percentile of FRP (5-year BOADICEA = 0.15%) had an estimated HR of 1.46 (95% CI 1.07–1.99), whereas there was no association for women at the 90th percentile (5-year BOADICEA = 4.2%) (HR 1.07, 95% CI 0.80–1.44). While the associations with smoking were not modified by FRP, we observed a positive multiplicative interaction by FRP (pinteraction = 0.01) for smoking status in women who also consumed alcohol, but not in women who were non-regular drinkers. Conclusions Moderate alcohol intake was associated with increased BC risk, particularly for women with ER-positive BC, but only for those at lower predicted familial BC risk (5-year BOADICEA < 1.25). For women with a high FRP (5-year BOADICEA ≥ 6.5%) who also consumed alcohol, being a current smoker was associated with increased BC risk

Age-specific breast cancer risk by body mass index and familial risk: prospective family study cohort (ProF-SC)

Abstract Background The association between body mass index (BMI) and risk of breast cancer depends on time of life, but it is unknown whether this association depends on a woman’s familial risk. Methods We conducted a prospective study of a cohort enriched for familial risk consisting of 16,035 women from 6701 families in the Breast Cancer Family Registry and the Kathleen Cunningham Foundation Consortium for Research into Familial Breast Cancer followed for up to 20 years (mean 10.5 years). There were 896 incident breast cancers (mean age at diagnosis 55.7 years). We used Cox regression to model BMI risk associations as a function of menopausal status, age, and underlying familial risk based on pedigree data using the Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA), all measured at baseline. Results The strength and direction of the BMI risk association depended on baseline menopausal status (P < 0.001); after adjusting for menopausal status, the association did not depend on age at baseline (P = 0.6). In terms of absolute risk, the negative association with BMI for premenopausal women has a much smaller influence than the positive association with BMI for postmenopausal women. Women at higher familial risk have a much larger difference in absolute risk depending on their BMI than women at lower familial risk. Conclusions The greater a woman’s familial risk, the greater the influence of BMI on her absolute postmenopausal breast cancer risk. Given that age-adjusted BMI is correlated across adulthood, maintaining a healthy weight throughout adult life is particularly important for women with a family history of breast cancer