Background The precise involvement of the PI3K/mTOR and RAS/MEK pathways in carcinoid tumors is not well defined. Therefore, the purpose of our study was to evaluate the role these pathways play in carcinoid cell proliferation, apoptosis, and secretion and to determine the effects of combined treatment on carcinoid tumor inhibition. Methods The human neuroendocrine cell lines BON (pancreatic carcinoid), NCI-H727 (lung carcinoid), and QGP-1 (somatostatinoma) were treated with either the pan-PI3K inhibitor, BKM120, or the dual PI3K-mTOR inhibitor, BEZ235, alone or in combination with the MEK inhibitor, PD0325901; proliferation, apoptosis, and protein expression were assessed. Peptide secretion was evaluated in BON and QGP-1 cells. The anti-proliferative effect of BEZ235, alone or combined with PD0325901, was then tested in vivo. Results Both BKM120 and BEZ235 decreased proliferation and increased apoptosis; combination with PD0325901 significantly enhanced the antineoplastic effects of either treatment alone. In contrast, neurotensin (NT) peptide secretion was markedly stimulated with BKM120 treatment, but not BEZ235. The combination of BEZ235 + PD0325901 significantly inhibited the growth of BON xenografts without systemic toxicity. Conclusions Both BKM120 and BEZ235 effectively inhibited NET cell proliferation and stimulated apoptosis. However, inhibition of the PI3K pathway alone with BKM120 significantly stimulated NT peptide secretion; this did not occur with the dual inhibition of both PI3K and mTOR using BEZ235 suggesting that this would be a more effective treatment regimen for NETs. Moreover, the combination of BEZ235 and the MEK inhibitor PD0325901 was a safe and more effective therapy in vivo compared with single agents alone.

Although there were differences found between negative mood and depressive symptom scores in relation to categories of reproductive aging, age was found to be the driving influence to their association.

Alzheimer's disease neuropathology (amyloid, tauopathies) and brain atrophy are present decades prior to manifestation of clinical symptoms. With the failure of treatment trials it is becoming clearer that the window for prevention and therapeutic intervention is before significant neuronal loss and clinical deterioration of cognition has occurred. Early identification of those at risk of disease and optimizing their management to prevent disease in later life are crucial to delaying disease onset and improving people's quality of life. The Women's Healthy Aging Project (WHAP) is a longitudinal study of over 400 Australian-born women, epidemiologically randomly sampled in 1990. The WHAP aims to identify modifiable mid-life risk factors for the development of late-life cognitive decline, improve the understanding of the pathogenesis of dementia, and target early disease identification utilizing clinical, biomarker and health risk profiles. These aims are fortified by the ability to leverage the considerable database on health, lifestyle and socio-demographics collected prospectively from 1990 to date. This is the first study with a comprehensive neuropsychological battery, over a decade of cognitive follow-up, with all participants being offered amyloid imaging from 2012, and prospective longitudinal data including clinical and physical measures and bio-bank samples from over 20 years prior.

Significantly more Japanese women scored within the mild and moderate ranges on the GDS compared with their Australian peers, even when controlling for possible confounding factors. Of the lifestyle and health factors assessed in this analysis no single variable was a common risk factor for higher depressive scores for both countries. The presence of cultural influences that may impact the risk of experiencing depressive symptoms, and culture specific patterns of item endorsement on depressive symptom measures, needs to be explored in more detail.

Background: Data available from longitudinal studies of adequate duration to explore midlife risk factors for late life higher depressive symptom scores in women is lacking. This study examines midlife (mean ages 50 years and 60 years) predictors of late life (mean age 70 years) depressive symptom scores to enrich our understanding of the role of changing risk factors across the lifespan. Methods: This investigation was an assessment of the long-term impact of lifestyle and health variables on depressive symptoms. Data were drawn from an epidemiological prospective study of women's healthy ageing spanning two decades. Variables included assessment of mood, demographics, physical health, smoking status, attitudes towards ageing and menopause, alcohol consumption and employment. Analysis was conducted to determine the set of strongest predictors assessed in 1992 (mean age 50 years) and in 2002 (mean age 60 years) in relation to higher CESD-SF scores measured in 2012 (mean aged 70 years (n = 249)). A cross-sectional analysis determining concurrent associations at mean age 70 years was also conducted.Results: An increase in positive mood at 50 and 60 years was associated with a 0.3 (95% CI 0.1-0.5) and 0.4 (95%CI 0.1-0.8) point reduction in CESD score at 70 years respectively. An increase in Hassles score at age 50 was associated with a 0.18-point increase in CESD (95% CI 0.01-0.05) 20 years later. However, no relationship was observed between Hassles score at 60 and CESD 10 years later. Analysis of concurrent risk factors demonstrated that bothersome symptom frequency and higher anxiety were associated with higher depressive symptom scores when women were 70 years.Conclusion: Low levels of positive mood were consistently associated with depressive symptoms scores 10 and 20 years later, suggesting clinical interventions aimed at improving positive affect may be particularly useful across the midlife.