166 research outputs found

    The predictability of the extratropical stratosphere on monthly time-scales and its impact on the skill of tropospheric forecasts

    Get PDF
    This is the final version of the article. Available from Wiley via the DOI in this record.Extreme variability of the winter- and spring-time stratospheric polar vortex has been shown to affect extratropical tropospheric weather. Therefore, reducing stratospheric forecast error may be one way to improve the skill of tropospheric weather forecasts. In this review, the basis for this idea is examined. A range of studies of different stratospheric extreme vortex events shows that they can be skilfully forecasted beyond 5 days and into the sub-seasonal range (0–30 days) in some cases. Separate studies show that typical errors in forecasting a stratospheric extreme vortex event can alter tropospheric forecast skill by 5–7% in the extratropics on sub-seasonal time-scales. Thus understanding what limits stratospheric predictability is of significant interest to operational forecasting centres. Both limitations in forecasting tropospheric planetary waves and stratospheric model biases have been shown to be important in this context.This work is supported by the Natural Environmental Research Council (NERC) funded project Stratospheric Network for the Assessment of Predictability (SNAP) (Grant H5147600) and partially supported by the SPARC. ACP and RGH acknowledge funding through the EU ARISE project (Grant 284387) (EU-FP7). We also acknowledge Steven Pawson and Lawrence Coy from NASA for providing Figure 1. We wish to thank Lorenzo Polvani from Columbia University for providing Figure 4 and Amy Butler from NOAA for her contribution to Figure 5. We thank Adrian Simmons of ECMWF for his insightful review and two anonymous reviewers for their comments and suggestions that improved the quality of the manuscript

    In vitro synergistic cytotoxicity of gemcitabine and pemetrexed and pharmacogenetic evaluation of response to gemcitabine in bladder cancer patients

    Get PDF
    The present study was performed to investigate the capability of gemcitabine and pemetrexed to synergistically interact with respect to cytotoxicity and apoptosis in T24 and J82 bladder cancer cells, and to establish a correlation between drug activity and gene expression of selected genes in tumour samples. The interaction between gemcitabine and pemetrexed was synergistic; indeed, pemetrexed favoured gemcitabine cytotoxicity by increasing cellular population in S-phase, reducing Akt phosphorylation as well as by inducing the expression of a major gemcitabine uptake system, the human equilibrative nucleoside transporter-1 (hENT1), and the key activating enzyme deoxycytidine kinase (dCK) in both cell lines. Bladder tumour specimens showed an heterogeneous gene expression pattern and patients with higher levels of dCK and hENT1 had better response. Moreover, human nucleoside concentrative transporter-1 was detectable only in 3/12 patients, two of whom presented a complete response to gemcitabine. These data provide evidence that the chemotherapeutic activity of the combination of gemcitabine and pemetrexed is synergistic against bladder cancer cells in vitro and that the assessment of the expression of genes involved in gemcitabine uptake and activation might be a possible determinant of bladder cancer response and may represent a new tool for treatment optimization

    Molecular pathways involved in the synergistic interaction of the PKCβ inhibitor enzastaurin with the antifolate pemetrexed in non-small cell lung cancer cells

    Get PDF
    Conventional regimens have limited impact against non-small cell lung cancer (NSCLC). Current research is focusing on multiple pathways as potential targets, and this study investigated molecular mechanisms underlying the combination of the PKCβ inhibitor enzastaurin with the multitargeted antifolate pemetrexed in the NSCLC cells SW1573 and A549. Pharmacologic interaction was studied using the combination-index method, while cell cycle, apoptosis induction, VEGF secretion and ERK1/2 and Akt phosphorylation were studied by flow cytometry and ELISAs. Reverse transcription–PCR, western blot and activity assays were performed to assess whether enzastaurin influenced thymidylate synthase (TS) and the expression of multiple targets involved in cancer signaling and cell cycle distribution. Enzastaurin-pemetrexed combination was highly synergistic and significantly increased apoptosis. Enzastaurin reduced both phosphoCdc25C, resulting in G2/M checkpoint abrogation and apoptosis induction in pemetrexed-damaged cells, and GSK3β and Akt phosphorylation, which was additionally reduced by drug combination (−58% in A549). Enzastaurin also significantly reduced pemetrexed-induced upregulation of TS expression, possibly through E2F-1 reduction, whereas the combination decreased TS in situ activity (>50% in both cell lines) and VEGF secretion. The effects of enzastaurin on signaling pathways involved in cell cycle control, apoptosis and angiogenesis, as well as on the expression of genes involved in pemetrexed activity provide a strong experimental basis to their evaluation as pharmacodynamic markers in clinical trials of enzastaurin-pemetrexed combination in NSCLC patients
    • …
    corecore