Enhanced sensitivity to rapamycin following long-term oestrogen deprivation in MCF-7, T-47-D and ZR-75-1 human breast cancer cells

Human breast cancer cells (MCF-7, T-47-D and ZR-75-1) can adapt to circumvent any reduced growth rate during long-term oestrogen deprivation, and this provides three model systems to investigate mechanisms of endocrine resistance in breast cancer. In this paper we report consistent differences in the effects of three growth inhibitors following long-term oestrogen deprivation in all three cell models. Long-term oestrogen deprivation of MCF-7, T-47-D and ZR-75-1 cells resulted in reduced growth inhibition by PD98059 (2–10 µg/ml), implying a loss of dependence on mitogen-activated protein kinase pathways for growth. The growth inhibitor LY294002 (2–10 µM) inhibited growth of both oestrogen-maintained and oestrogen-deprived cells with similar dose–responses, implying continued similar dependence on phosphoinositide 3-kinase (PI3K) pathways with no alteration after adaptation to oestrogen independent growth. However, by contrast, long-term oestrogen deprivation resulted in an increased sensitivity to growth inhibition by rapamycin, which was not reduced by readdition of oestradiol. The enhanced inhibition of long-term oestrogen-deprived MCF-7-ED, T-47-D-ED and ZR-75-1-ED cell growth by combining rapamycin with LY294002 at concentrations where each alone had little effect, offers preclinical support to the development of therapeutic combinations of rapamycin analogues with other PI3K inhibitors in endocrine-resistant breast cancer.

Effect of long-term olive oil dietary intervention on postprandial triacylglycerol and factor VII metabolism

Although the beneficial effects of Mediterranean-type diets, which are rich in olive oil, a good source of monounsaturated fatty acids (MUFAs), are generally accepted, little is known about the effects of long-term dietary MUFA intake on postprandial lipoprotein metabolism and hemostasis. This study used a single-blind, randomized, crossover design to investigate the relative effects of a long-term dietary olive oil intervention and a control [saturated fatty acid (SFA)-enriched] diet on postprandial triacylglycerol metabolism and factor VII activity. The postprandial response to a standard test meal was investigated in 23 healthy men who adhered to both diets for 8 wk. cis-MUFAs were successfully substituted for SFAs in the MUFA diet without affecting total dietary fat or energy intakes. The long-term dietary MUFA intervention significantly reduced plasma and LDL-cholesterol concentrations (P = 0.01). Postprandial triacylglycerol concentrations were significantly greater in the early postprandial period after the MUFA diet (P = 0.003). Postprandial factor VII activation and the concentration of the factor VII antigen were significantly lower after the MUFA diet (P = 0.04 and P = 0 006, respectively). This study showed that isoenergetic substitution of MUFAs for SFAs reduces plasma cholesterol and reduces the degree of postprandial factor VII activation. The alterations in the postprandial triacylglycerol response suggest a greater rate of dietary fat absorption and postprandial triacylglycerol metabolism after a diet rich in MUFAs. This study presents new insights into the biochemical basis of the beneficial effects associated with long-term dietary MUFA consumption, which may explain the lower rates of coronary mortality in Mediterranean regions.

Crosstalk with insulin and dependence on PI3K/Akt/mTOR rather than MAPK pathways in upregulation of basal growth following long-term oestrogen deprivation in three human breast cancer cell lines

Background: MCF-7, T-47-D, ZR-75-1 human breast cancer cell lines are dependent on oestrogen for growth but can adapt to grow during long-term oestrogen deprivation. This serves as a model for identification of therapeutic targets in endocrine-resistant breast cancer. Methods: An overlooked complication of this model is that it involves more than non-addition of oestrogen, and inadequate attention has been given to separating molecular events associated with each of the culture manipulations. Results: Insulin and oestradiol were shown to protect MCF-7 cells against upregulation of basal growth, demonstrating a crosstalk in the growth adaptation process. Increased phosphorylation of p44/42MAPK and c-Raf reflected removal of insulin from the medium and proliferation of all three cell lines was inhibited to a lesser extent by PD98059 and U0126 following long-term oestrogen/insulin withdrawal, demonstrating a reduced dependence on the MAPK pathway. By contrast, long-term oestrogen/insulin deprivation did not alter levels of phosphorylated Akt and did not alter the dose-response of growth inhibition with LY294002 in any of the three cell lines. The IGF1R inhibitor picropodophyllin inhibited growth of all MCF-7 cells but only in the long-term oestrogen/insulin-deprived cells was this paralleled by reduction in phosphorylated p70S6K, a downstream target of mTOR. Long-term oestrogen/insulin-deprived MCF-7 cells had higher levels of phosphorylated p70S6K and developed increased sensitivity to growth inhibition by rapamycin. Conclusions: The greater sensitivity to growth inhibition by rapamycin in all three cell lines following long-term oestrogen/insulin deprivation suggests rapamycin-based therapies might be more effective in breast cancers with acquired oestrogen resistance. Keywords Akt, breast cancer cells, endocrine resistance, insulin, MAPK, MCF-7 cells, mTOR, oestrogen, oestrogen-deprived, PI3K, picropodophyllin, rapamycin, T-47-D cells, ZR-75-1 cells

The long-term price-earnings ratio

price-earnings ratio;value premium;arbitrage trading rule;UK stock returns;contrarian investment Abstract:  The price-earnings effect has been thoroughly documented and is the subject of numerous academic studies. However, in existing research it has almost exclusively been calculated on the basis of the previous year's earnings. We show that the power of the effect has until now been seriously underestimated due to taking too short-term a view of earnings. Looking at all UK companies since 1975, using the traditional P/E ratio we find the difference in average annual returns between the value and glamour deciles to be 6%. This is similar to other authors' findings. We are able to almost double the value premium by calculating the P/E ratio using earnings averaged over the previous eight years.

Long-term acclimation of leaf production, development, longevity and quality following 3 yr exposure to free-air CO2 enrichment during canopy closure in Populus

The effects of elevated CO2 on leaf development in three genotypes of Populus were investigated during canopy closure, following exposure to elevated CO2 over 3 yr using free-air enrichment.• Leaf quality was altered such that nitrogen concentration per unit d. wt (Nmass) declined on average by 22 and 13% for sun and shade leaves, respectively, in elevated CO2. There was little evidence that this was the result of ‘dilution’ following accumulation of nonstructural carbohydrates. Most likely, this was the result of increased leaf thickness. Specific leaf area declined in elevated CO2 on average by 29 and 5% for sun and shade leaves, respectively.• Autumnal senescence was delayed in elevated CO2 with a 10% increase in the number of days at which 50% leaf loss occurred in elevated as compared with ambient CO2.• These data suggest that changes in leaf quality may be predicted following long-term acclimation of fast-growing forest trees to elevated CO2, and that canopy longevity may increase, with important implications for forest productivity.

Solar cycle 24: implications for energetic particles and long-term space climate change

The recent solar minimum was the longest and deepest of the space age, with the lowest average sunspot numbers for nearly a century. The Sun appears to be exiting a grand solar maximum (GSM) of activity which has persisted throughout the space age, and is headed into a significantly quieter period. Indeed, initial observations of solar cycle 24 (SC24) continue to show a relatively low heliospheric magnetic field strength and sunspot number (R), despite the average latitude of sunspots and the inclination of the heliospheric current sheet showing the rise to solar maximum is well underway. We extrapolate the available SC24 observations forward in time by assuming R will continue to follow a similar form to previous cycles, despite the end of the GSM, and predict a very weak cycle 24, with R peaking at ∼65–75 around the middle/end of 2012. Similarly, we estimate the heliospheric magnetic field strength will peak around 6nT. We estimate that average galactic cosmic ray fluxes above 1GV rigidity will be ∼10% higher in SC24 than SC23 and that the probability of a large SEP event during this cycle is 0.8, compared to 0.5 for SC23. Comparison of the SC24 R estimates with previous ends of GSMs inferred from 9300 years of cosmogenic isotope data places the current evolution of the Sun and heliosphere in the lowest 5% of cases, suggesting Maunder Minimum conditions are likely within the next 40 years.

Validation of the GRAPE single view aerosol retrieval for ATSR-2 and insights into the long term global AOD trend over the ocean

The Global Retrieval of ATSR Cloud Parameters and Evaluation (GRAPE) project has produced a global data-set of cloud and aerosol properties from the Along Track Scanning Radiometer-2 (ATSR-2) instrument, covering the time period 1995�2001. This paper presents the validation of aerosol optical depths (AODs) over the ocean from this product against AERONET sun-photometer measurements, as well as a comparison to the Advanced Very High Resolution Radiometer (AVHRR) optical depth product produced by the Global Aerosol Climatology Project (GACP). The GRAPE AOD over ocean is found to be in good agreement with AERONET measurements, with a Pearson's correlation coefficient of 0.79 and a best-fit slope of 1.0±0.1, but with a positive bias of 0.08±0.04. Although the GRAPE and GACP datasets show reasonable agreement, there are significant differences. These discrepancies are explored, and suggest that the downward trend in AOD reported by GACP may arise from changes in sampling due to the orbital drift of the AVHRR instruments.

The effects of landscape modifications on the long-term persistence of animal populations

Background: The effects of landscape modifications on the long-term persistence of wild animal populations is of crucial importance to wildlife managers and conservation biologists, but obtaining experimental evidence using real landscapes is usually impossible. To circumvent this problem we used individual-based models (IBMs) of interacting animals in experimental modifications of a real Danish landscape. The models incorporate as much as possible of the behaviour and ecology of four species with contrasting life-history characteristics: skylark (Alauda arvensis), vole (Microtus agrestis), a ground beetle (Bembidion lampros) and a linyphiid spider (Erigone atra). This allows us to quantify the population implications of experimental modifications of landscape configuration and composition. Methodology/Principal Findings: Starting with a real agricultural landscape, we progressively reduced landscape complexity by (i) homogenizing habitat patch shapes, (ii) randomizing the locations of the patches, and (iii) randomizing the size of the patches. The first two steps increased landscape fragmentation. We assessed the effects of these manipulations on the long-term persistence of animal populations by measuring equilibrium population sizes and time to recovery after disturbance. Patch rearrangement and the presence of corridors had a large effect on the population dynamics of species whose local success depends on the surrounding terrain. Landscape modifications that reduced population sizes increased recovery times in the short-dispersing species, making small populations vulnerable to increasing disturbance. The species that were most strongly affected by large disturbances fluctuated little in population sizes in years when no perturbations took place. Significance: Traditional approaches to the management and conservation of populations use either classical methods of population analysis, which fail to adequately account for the spatial configurations of landscapes, or landscape ecology, which accounts for landscape structure but has difficulty predicting the dynamics of populations living in them. Here we show how realistic and replicable individual-based models can bridge the gap between non-spatial population theory and non-dynamic landscape ecology. A major strength of the approach is its ability to identify population vulnerabilities not detected by standard population viability analyses.