ATR-dependent radiation-induced gammaH2AX foci in bystander primary human astrocytes and glioma cells.

Radiotherapy is an important treatment for patients suffering from high-grade malignant gliomas. Non-targeted (bystander) effects may influence these cells' response to radiation and the investigation of these effects may therefore provide new insights into mechanisms of radiosensitivity and responses to radiotherapy as well as define new targets for therapeutic approaches. Normal primary human astrocytes (NHA) and T98G glioma cells were irradiated with helium ions using the Gray Cancer Institute microbeam facility targeting individual cells. Irradiated NHA and T98G glioma cells generated signals that induced gammaH2AX foci in neighbouring non-targeted bystander cells up to 48 h after irradiation. gammaH2AX bystander foci were also observed in co-cultures targeting either NHA or T98G cells and in medium transfer experiments. Dimethyl sulphoxide, Filipin and anti-transforming growth factor (TGF)-beta 1 could suppress gammaH2AX foci in bystander cells, confirming that reactive oxygen species (ROS) and membrane-mediated signals are involved in the bystander signalling pathways. Also, TGF-beta 1 induced gammaH2AX in an ROS-dependent manner similar to bystander foci. ROS and membrane signalling-dependent differences in bystander foci induction between T98G glioma cells and normal human astrocytes have been observed. Inhibition of ataxia telangiectasia mutated (ATM) protein and DNA-PK could not suppress the induction of bystander gammaH2AX foci whereas the mutation of ATM- and rad3-related (ATR) abrogated bystander foci induction. Furthermore, ATR-dependent bystander foci induction was restricted to S-phase cells. These observations may provide additional therapeutic targets for the exploitation of the bystander effect.

Reflexive learning in pre-service training of primary school teachers: from experience to assimilation of contents

This article presents an educational experiment carried out in the Primary School Teaching Degree at the University of Barcelona. Specifically, the article analyses the application of the “Work Corners” approach in a core subject. In a three-year action research process, trainers put into practice an innovation which enabled them to boost cooperative work and reflexive learning among trainees. Firstly, the theoretical model underpinning the project and guiding many of the actions carried out by the training team is presented. After providing detailed information on the practical development of the experiment, the data-gathering process and its results are shown. Various information-gathering strategies were used in assessing the project, such as a questionnaire, participant observation, and teachers’ diaries. The results demonstrate, amongst other things, that “work corners” offer viable and appropriate educational conditions for the articulation of theoretical and practical knowledge, for building professional knowledge, and therefore, the beginnings of a reflexive teaching practice.

Validity of the Perceived Health Competence Scale in a UK primary care setting.

The Perceived Health Competence Scale (PHCS) is a measure of self-efficacy regarding general healthrelated behaviour. This brief paper examines the psychometric properties of the PHCS in a UK context. Questionnaires containing the PHCS, the SF-36 and questions about perceived health needs were posted to 486 patients randomly selected from a GP practice list. Complete questionnaires were returned by 320 patients. Analyses of these responses provide strong evidence for the validity of the PHCS in this setting. Consequently, we conclude that the PHCS is a useful addition to measures of global self-efficacy and measures of self-efficacy regarding specific behaviours in the toolkit of health psychologists. This range of self-efficacy assessment tools will ensure that psychologists can match the level of specificity of the measure of expectancy beliefs to the level of specificity of the outcome of interest.

Effects of the aurora kinase inhibitors AZD1152-HQPA and ZM447439 on growth arrest and polyploidy in acute myeloid leukemia cell lines and primary blasts.

BACKGROUND:
Aurora kinases play an essential role in the orchestration of chromosome separation and cytokinesis during mitosis. Small-molecule inhibition of the aurora kinases has been shown to result in inhibition of cell division, phosphorylation of histone H3 and the induction of apoptosis in a number of cell systems. These characteristics have led aurora kinase inhibitors to be considered as potential therapeutic agents.
DESIGN AND METHODS:
Aurora kinase gene expression profiles were assessed in 101 samples from patients with acute myeloid leukemia. Subsequently, aurora kinase inhibitors were investigated for their in vitro effects on cell viability, histone H3 phosphorylation, cell cycle and morphology in acute myeloid leukemia cell lines and primary acute myeloid leukemia samples.
RESULTS:
The aurora kinase inhibitors AZD1152-HQPA and ZM447439 induced growth arrest and the accumulation of hyperploid cells in acute myeloid leukemia cell lines and primary acute myeloid leukemia cultures. Furthermore, both agents inhibited histone H3 phosphorylation and this preceded perturbations in cell cycle and the induction of apoptosis. Single cell cloning assays were performed on diploid and polyploid cells to investigate their colony-forming capacities. Although the polyploid cells showed a reduced capacity for colony formation when compared with their diploid counterparts, they were consistently able to form colonies.
CONCLUSIONS:
AZD1152-HQPA- and ZM447439 are effective apoptosis-inducing agents in acute myeloid leukemia cell lines and primary acute myeloid leukemia cultures. However, their propensity to induce polyploidy does not inevitably result in apoptosis.

A phase Ib trial of Docetaxel, Carboplatin and Erlotinib in ovarian, fallopian tube and primary peritoneal cancers.

The safety and maximum tolerated dose (MTD) of erlotinib with docetaxel/carboplatin were assessed in patients with ovarian cancer. Chemonaive patients received intravenous docetaxel (75 mg m(-2)) and carboplatin (area under the curve 5) on day 1 of a 3-week cycle, and oral erlotinib at 50 (cohort 1), 100 (cohort 2a) or 75 mg day(-1) (cohort 2b) for up to six cycles. Dose-limiting toxicities were determined in cycle 1. Forty-five patients (median age 59 years) received treatment. Dose-limiting toxicities occurred in 1/5/5 patients (cohorts 1/2a/2b). The MTD of erlotinib in this regimen was determined to be 75 mg day(-1) (cohort 2b; the erlotinib dose was escalated to 100 mg day(-1) in 11 out of 19 patients from cycle 2 onwards). Neutropaenia was the predominant grade 3/4 haematological toxicity (85/100/95% respectively). Common non-haematological toxicities were diarrhoea, fatigue, nausea and rash. There were five complete and seven partial responses in 23 evaluable patients (52% response rate). Docetaxel/carboplatin had no measurable effect on erlotinib pharmacokinetics. In subsequent single-agent maintenance, erlotinib was given at 100-150 mg day(-1), with manageable toxicity, until tumour progression. Further investigation of erlotinib in epithelial ovarian carcinoma may be warranted, particularly as maintenance therapy

The journey to concordance for patients with hypertension: a qualitative study in primary care

Objective: We aimed to explore, using qualitative methods, the perspectives of patients with hypertension on issues relating to concordance in prescribing.

Method: This study took place in NHS general practices in Northern Ireland. A purposeful sample of patients who had been prescribed anti-hypertensive medication for at least one year were invited to participate in focus groups or semi-structured interviews; data were analysed using constant comparison.

Main outcome measures: The perspectives of patients with hypertension on issues relating to concordance in prescribing.

Results: Twenty-five individuals participated in five focus groups; two participated in semi-structured interviews. Participants felt they could make valuable contributions to consultations regarding their management. They were prepared to negotiate with GPs regarding their medication, but most deferred to their doctor’s advice, perceiving doctors’ attitudes and time constraints as barriers to their greater involvement in concordant decision-making. They had concerns about taking anti-hypertensive drugs, were aware of lifestyle influences on hypertension and reported using personal strategies to facilitate adherence and reduce the need to take medication.

Conclusions: Participants indicated a willingness to be?involved in concordance in prescribing anti- hypertensive medication but needed health professionals to address their concerns and confusion about the nature of hypertension. These findings suggest that there is a need for doctors and other healthcare professionals with responsibility for prescribing to develop skills specifically to explore the beliefs and views underlying an individual’s medication use. Such skills may need to be developed through specific training programmes at both undergraduate and postgraduate level.