DNA methylation changes associated with acquired platinum resistance in ovarian cancer

Despite high responses to initial chemotherapy most patients with ovarian cancer (OC) relapse and inevitably die from their disease. Aberrant DNA methylation is frequently seen in ovarian tumours and may provide biomarkers of clinical outcome or insight into mechanisms of chemoresistance. We firstly performed Differential Methylation Hybridisation (DMH) to identify loci that gained methylation between 34 matched cisplatin sensitive and resistant OC tumour cell lines. Differentially methylated loci identified were further validated by Methylation Specific PCR (MSP) and bisulphite pyrosequencing. Selected loci were further investigated for association with clinical outcome in primary OC tumour samples and matched tumour samples from patients' pre- and post-chemotherapy. Frequent increased methylation of a CpG island at the NR2E1 gene was identified in this experiment. Increased methylation correlated with decreased gene expression and could be reversed following treatment with a demethylating agent. Increased methylation at NR2E1 was observed between matched pre- and post-treatment tumour pairs. A novel biostatistical method, methylation linear discrimination analysis (MLDA), was next used to identify differentially methylated loci in sensitive and resistant A2780 human ovarian cell lines. Eight of nine loci identified were validated by MSP. A locus at the SP5 gene was further investigated by pyrosequencing and found to show a very high level methylation in most cell lines and ovarian tumours. Increased methylation correlated with decreased gene expression and this could be reversed using decitabine treatment. Knockdown of SP5 expression caused increased apoptosis. DMH was next used to identify loci that gained methylation between 3 in vivo derived matched sensitive and resistant cell lines. KIAA1383, a gene of unknown function, was identified and methylation shown to correlate with response to chemotherapy and progression-free survival (PFS) in patients with OC. Over-expression was found to attenuate the response to cisplatin, in the PEA2 cell line, as measured by cell cycle analysis

An exploration of African-Caribbean boys’ underachievement and their stories of schooling

This thesis was submitted for the degree of Doctor of Education and awarded by Brunel University.This study investigates why African-Caribbean boys continue to underachieve in schools. It is based on an extensive study of one Inner London school and has also involved a thorough review of the existing literature about why this particular group of students do not fulfil their potential. The inspiration for this study has been the work of Bernard Coard (1971) who wrote influentially about how the first generation of West Indian children was branded as ‘Educationally Subnormal’ by the British school system. Over thirty years later, the failure of African-Caribbean boys continues to be an alarming phenomenon, despite years of multi-culturalism and education for ‘diversity’. One of the arguments of my study is that African-Caribbean boys can even become ‘hidden’ amongst much larger groups of students who have English as an Additional Language (EAL) and who as a result, often receive extensive additional support. British schools have changed since the time that Coard (1971) was writing, but as my study demonstrates African-Caribbean boys are still likely to be over represented in the various Behaviour or Learning Support Units. I have also discovered that, far fewer African-Caribbean boys in the school investigated are likely to go on to the sixth form in comparison to students from other backgrounds. Even though there have been many studies about race and education, far fewer researchers have tried to ‘hear it from the boys’. I have carried out extensive research at school level amongst the boys and their teachers. As well as conducting an Institutional Focus Study of the school in question. I have argued that, whilst other groups such as white working class boys have been hostile to school, on the contrary, most of the boys in my study wanted to learn or saw the importance of obtaining qualifications in order to improve their chances in life. African-Caribbean boys are not ‘their own worst enemies’, but the reasons for their underachievement are complex, being the result of a range of factors. As I am a practitioner, I have concluded my study with some practical proposals for change which I hope will make a difference to the lives of these boys

A pilot study of subjective well-being in colorectal cancer patients and their caregivers

Background: Traditional endpoints in oncology are based on measuring the tumor size and combining this with a time factor. Current studies with immunotherapy show that even when median survival is unaltered, a significant proportion of patients can achieve prolonged survival. Objective tumor response does not always mean “overall” improvement, especially if toxicity is harsh. Novel agents are significantly expensive, and it is therefore crucial to measure the impact on “quality” of life, in addition to “quantity”. Materials and methods: We studied the preferences and experiences of cancer patients and their caregivers, measuring subjective well-being (SWB) ratings, EQ5D descriptions and time trade-off preferences. Results: We studied 99 patients and 88 caregivers. Life satisfaction ratings were similar between the two groups, but daily mood was significantly lower in caregivers (P<0.1). Anxiety/depression affected SWB, while pain and mobility did not. Positive thoughts about health were associated with better daily moods in both groups, and stage IV cancer was associated with lower life satisfaction. Cancer in remission was associated with better daily moods, but, interestingly, not with patient life satisfaction. Patients with better daily mood and positive thoughts about family were less willing to “trade-off” life years. Conclusion: Caregivers are as anxious or depressed as patients, and report similar levels of life satisfaction but lower daily mood. A focus on SWB could provide a valid assessment of treatment benefit. Given the interesting results of this pilot study, we suggest a larger study should be conducted, measuring SWB over time

"New" and distributed leadership in quality and safety in healthcare, or "old" and hierarchical? : An interview study with strategic stakeholders

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The friends and family test : a qualitative study of concerns that influence the willingness of English National Health Service staff to recommend their organisation

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Kentucky Law Survey: Domestic Relations

In the decade since Kentucky\u27s adoption of the Uniform Marriage and Divorce Act (UMDA), appellate domestic relations opinions have focused primarily upon property division and child custody. Recent decisions continue this emphasis but also address problems regarding the marital relationship, spousal maintenance, and child support. This article provides a survey of Kentucky law in the field of domestic relations

The European Bioinformatics Institute's data resources: towards systems biology

Genomic and post-genomic biological research has provided fine-grain insights into the molecular processes of life, but also threatens to drown biomedical researchers in data. Moreover, as new high-throughput technologies are developed, the types of data that are gathered en masse are diversifying. The need to collect, store and curate all this information in ways that allow its efficient retrieval and exploitation is greater than ever. The European Bioinformatics Institute's (EBI's) databases and tools have evolved to meet the changing needs of molecular biologists: since we last wrote about our services in the 2003 issue of Nucleic Acids Research, we have launched new databases covering protein–protein interactions (IntAct), pathways (Reactome) and small molecules (ChEBI). Our existing core databases have continued to evolve to meet the changing needs of biomedical researchers, and we have developed new data-access tools that help biologists to move intuitively through the different data types, thereby helping them to put the parts together to understand biology at the systems level. The EBI's data resources are all available on our website at http://www.ebi.ac.uk

Wildlife Damage Management in the Digital Age: Collaborating With Others

Three seemingly disparate Communities of Practice (CoPs)—Urban Integrated Pest Management (Urban IPM), Wildlife Damage Management (WDM), and Imported Fire Ants—came together to promote IPM and WDM by sharing information on websites and through webinars. Originally, each CoP on the eXtension web site was set up to be a unique information source. It became clear very early in eXtension’s development that many of these unique, single-topic sites had information that could be used by others. These 3 CoPs had the foresight to work together and link information, rather than creating new material

Communities of practice: acknowledging vulnerability to improve resilience in healthcare teams.

The majority of healthcare professionals regularly witness fragility, suffering, pain and death in their professional lives. Such experiences may increase the risk of burnout and compassion fatigue, especially if they are without self-awareness and a healthy work environment. Acquiring a deeper understanding of vulnerability inherent to their professional work will be of crucial importance to face these risks. From a relational ethics perspective, the role of the team is critical in the development of professional values which can help to cope with the inherent vulnerability of healthcare professionals. The focus of this paper is the role of Communities of Practice as a source of resilience, since they can create a reflective space for recognising and sharing their experiences of vulnerability that arises as part of their work. This shared knowledge can be a source of strength while simultaneously increasing the confidence and resilience of the healthcare team