Potential use of COX-2–aromatase inhibitor combinations in breast cancer

Cyclooxygenase-2 (COX-2) is overexpressed in several epithelial tumours, including breast cancer. Cyclooxygenase-2-positive tumours tend to be larger, higher grade, node-positive and HER-2/neu-positive. High COX-2 expression is associated with poor prognosis. Cyclooxygenase-2 inhibition reduces the incidence of tumours in animal models, inhibits the development of invasive cancer in colorectal cancer and reduces the frequency of polyps in familial adenomatous polyposis (FAP). These effects may be as a result of increased apoptosis, reduced angiogenesis and/or proliferation. Studies of COX-2 inhibitors in breast cancer are underway both alone and in combination with other agents. There is evidence to suggest that combining COX-2 inhibitors with aromatase inhibitors, growth factor receptor blockers, or chemo- or radiotherapy may be particularly effective. Preliminary results from combination therapy with celecoxib and exemestane in postmenopausal women with advanced breast cancer showed that the combination increased the time to recurrence. Up to 80% of ductal carcinomas in situ (DCISs) express COX-2, therefore COX-2 inhibition may be of particular use in this situation. Cyclooxygenase-2 expression correlates strongly with expression of HER-2/neu. As aromatase inhibitors appear particularly effective in patients with HER-2/neu-positive tumours, the combination of aromatase inhibitors and COX-2 inhibitors may be particularly useful in both DCIS and invasive cancer

Seriously personal:The reasons that motivate entrepreneurs to address climate change

This is the author accepted manuscript. The final version is freely available from Springer Verlag via the DOI in this record.Scholars increasingly argue that entrepreneurs and their small- and medium-sized enterprises should play a central role in reducing the rate and magnitude of climate change. However, evidence suggests that while some entrepreneurs recognize their crucial role in addressing climate change, most do not. Why some entrepreneurs nevertheless concern themselves with climate change has largely been overlooked. Some initial work in this area tentatively suggests that these entrepreneurs may engage with climate change because of their personal values, which either focus on financial or socio-ecological reasons, or a combination of both. Yet, it is unclear if all for-profit entrepreneurs engage with climate change for the same reasons, or if indeed their motivations vary across business types. Over a period of four years, we examined entrepreneurs’ motivations to engage with climate change through a variety of qualitative research methods. Our findings illustrate how entrepreneurs who address climate change have motivations specific to their business activity/industry and level of maturity. In each instance, we link these motivations to distinct conceptualizations of time and place. We contend that, through a more differentiated understanding of entrepreneurial motivations, policy-makers can draft climate change-related policies tailored to entrepreneurial needs. Policies could both increase the number of entrepreneurs who already engage in climate change mitigation and leverage the impact of those entrepreneurs already mitigating climate change.This study was funded by the European Social Fund (09099NCO5). We acknowledge with thanks the participation of the entrepreneurs and the support of Business Leaders for Low Carbon, Cornwall Council, and Cornwall Sustainable Tourism Project. The authors wish to thank Professor John Amis, Professor Kenneth Amaeshi and the anonymous reviewers who provided useful feedback on earlier versions of the article

Simulating the midlatitude atmospheric circulation: what might we gain from high-resolution modeling of air-sea interactions?

Purpose of Review. To provide a snapshot of the current research on the oceanic forcing of the atmospheric circulation in midlatitudes and a concise update on previous review papers. Recent findings. Atmospheric models used for seasonal and longer timescales predictions are starting to resolve motions so far only studied in conjunction with weather forecasts. These phenomena have horizontal scales of ~ 10–100 km which coincide with energetic scales in the ocean circulation. Evidence has been presented that, as a result of this matching of scale, oceanic forcing of the atmosphere was enhanced in models with 10–100 km grid size, especially at upper tropospheric levels. The robustness of these results and their underlying mechanisms are however unclear. Summary. Despite indications that higher resolution atmospheric models respond more strongly to sea surface temperature anomalies, their responses are still generally weaker than those estimated empirically from observations. Coarse atmospheric models (grid size greater than 100 km) will miss important signals arising from future changes in ocean circulation unless new parameterizations are developed

Pan-cancer analysis of whole genomes

Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale(1-3). Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4-5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter(4); identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation(5,6); analyses timings and patterns of tumour evolution(7); describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity(8,9); and evaluates a range of more-specialized features of cancer genomes(8,10-18).Peer reviewe

The relationship between manual coordination and mental health

Motor coordination impairments frequently co-occur with other developmental disorders and mental health problems in clinically referred populations. But does this reflect a broader dimensional relationship within the general population? A clearer understanding of this relationship might inform improvements in mental health service provision. However, ascertainment and referral bias means that there is limited value in conducting further research with clinically referred samples. We, therefore, conducted a cross-sectional population-based study investigating children’s manual coordination using an objective computerised test. These measures were related to teacher-completed responses on a behavioural screening questionnaire [the Strength and Difficulties Questionnaire (SDQ)]. We sampled 298 children (4–11 years old; 136 males) recruited from the general population. Hierarchical (logistic and linear) regression modelling indicated significant categorical and continuous relationships between manual coordination and overall SDQ score (a dimensional measure of psychopathology). Even after controlling for gender and age, manual coordination explained 15 % of the variance in total SDQ score. This dropped to 9 % after exclusion of participants whose SDQ responses indicated potential mental health problems. These results: (1) indicate that there is a clear relationship between children’s motor and mental health development in community-based samples; (2) demonstrate the relationship’s dimensional nature; and (3) have implications for service provision