The role of the ETS factor ELF3 in the normal and malignant prostate

The ETS transcription factor family members are involved in multiple cancers, including prostate cancer. Whilst extensive literature exists on the highly prevalent TMPRSS2-ERG gene fusion, the role of other ETS factors in prostate cancer is less well understood. ELF3 has been ascribed both oncogenic and tumour suppressive roles in prostate cancer and has been highlighted as a regulator of epithelial cell differentiation in other tissues. The overarching aim of this project was to elucidate the role of ELF3 in the context of both normal prostate development and prostate cancer. This study details an extensive expression profile of ELF3 in prostate epithelial cell lines, primary prostate cell subpopulations and prostate tissue. ELF3 expression was restricted to the basal compartment of epithelial glands, specifically to the committed basal cell subpopulation of the basal epithelial hierarchy. Appropriate cell models were used to investigate the role of ELF3 in the prostate. By silencing ELF3 in BPH-1 and PC3 cells, ELF3 was established as a regulator of the cell cycle. This manifested as a decrease in colony forming ability, migration and cell viability caused by G2 cell cycle arrest. Furthermore, manipulating ELF3 expression altered the differentiation status of cell lines and primary cells, highlighting that a balance of ELF3 expression is required to maintain proper differentiation of the epithelial hierarchy. Finally, a possible link of ELF3 to more advanced prostate tumours using tissue microarray analysis, a potential association with neuroendocrine differentiation and putative survival advantage of ELF3 expression in cancer vs normal cells, was identified. These results suggest that ELF3 acts as an oncogene in the prostate cancer setting. However, its importance in normal prostate epithelial cell growth and differentiation has also been demonstrated. Work should now focus on identifying appropriate downstream effectors that could be targeted to exploit these properties for prostate cancer treatment

Student perceptions of adverse health events during ambulance clinical placements

This pilot study intended to augment current literature in the clinical placement field by investigating the frequency and nature of adverse health events experiences by paramedic students undertaking ambulance clinical placements. Supports accessed post event were also reviewed. A purposive sample of fifty-six paramedic students completed the questionnaire. The results indicate that a number of students experience adverse health events while on clinical placement, with fourteen cases of verbal abuse, one case of physical abuse, nine cases of sexualised behavior and seven cases of psychological distress reported. While some case related incidents were flagged by ambulance services and followed up by peer support, students did not initiate any formal support processes themselves. Moreover, no student filed a formal report regarding any of the incidents raised. The results of this pilot study require further investigation. In the interim, the benefits of clinical placements must be weighed against their risks, and processes put in place to minimize the risk to students undertaking clinical placements

Succession of physiological stages hallmarks the transcriptomic response of the fungus Aspergillus niger to lignocellulose.

BackgroundUnderstanding how fungi degrade lignocellulose is a cornerstone of improving renewables-based biotechnology, in particular for the production of hydrolytic enzymes. Considerable progress has been made in investigating fungal degradation during time-points where CAZyme expression peaks. However, a robust understanding of the fungal survival strategies over its life time on lignocellulose is thereby missed. Here we aimed to uncover the physiological responses of the biotechnological workhorse and enzyme producer Aspergillus niger over its life time to six substrates important for biofuel production.ResultsWe analysed the response of A. niger to the feedstock Miscanthus and compared it with our previous study on wheat straw, alone or in combination with hydrothermal or ionic liquid feedstock pretreatments. Conserved (substrate-independent) metabolic responses as well as those affected by pretreatment and feedstock were identified via multivariate analysis of genome-wide transcriptomics combined with targeted transcript and protein analyses and mapping to a metabolic model. Initial exposure to all substrates increased fatty acid beta-oxidation and lipid metabolism transcripts. In a strain carrying a deletion of the ortholog of the Aspergillus nidulans fatty acid beta-oxidation transcriptional regulator farA, there was a reduction in expression of selected lignocellulose degradative CAZyme-encoding genes suggesting that beta-oxidation contributes to adaptation to lignocellulose. Mannan degradation expression was wheat straw feedstock-dependent and pectin degradation was higher on the untreated substrates. In the later life stages, known and novel secondary metabolite gene clusters were activated, which are of high interest due to their potential to synthesize bioactive compounds.ConclusionIn this study, which includes the first transcriptional response of Aspergilli to Miscanthus, we highlighted that life time as well as substrate composition and structure (via variations in pretreatment and feedstock) influence the fungal responses to lignocellulose. We also demonstrated that the fungal response contains physiological stages that are conserved across substrates and are typically found outside of the conditions with high CAZyme expression, as exemplified by the stages that are dominated by lipid and secondary metabolism

Resolution of Cellular Heterogeneity in Human Prostate Cancers : Implications for Diagnosis and Treatment

Prostate cancers have a justified reputation as one of the most heterogeneous human tumours. Indeed, there are some who consider that advanced and castration-resistant prostate cancers are incurable, as a direct result of this heterogeneity. However, tumour heterogeneity can be defined in different ways. To a clinician, prostate cancer is a number of different diseases, the treatments for which remain equally heterogeneous and uncertain. To the pathologist, the histopathological appearances of the tumours are notoriously heterogeneous. Indeed, the genius of Donald Gleason in the 1960s was to devise a classification system designed to take into account the heterogeneity of the tumours both individually and in the whole prostate context. To the cell biologist, a prostate tumour consists of multiple epithelial cell types, inter-mingled with various fibroblasts, neuroendocrine cells, endothelial cells, macrophages and lymphocytes, all of which interact to influence treatment responses in a patient-specific manner. Finally, genetic analyses of prostate cancers have been compromised by the variable gene rearrangements and paucity of activating mutations observed, even in large numbers of patient tumours with consistent clinical diagnoses and/or outcomes. Research into familial susceptibility has even generated the least tractable outcome of such studies: the genetic loci are of low penetrance and are of course heterogeneous. By fractionating the tumour (and patient-matched non-malignant tissues) heterogeneity can be resolved, revealing homogeneous markers of patient outcomes

INCITE: A randomised trial comparing constraint induced movement therapy and bimanual training in children with congenital hemiplegia

Background: Congenital hemiplegia is the most common form of cerebral palsy (CP) accounting for 1 in 1300 live births. These children have limitations in capacity to use the impaired upper limb and bimanual coordination deficits which impact on daily activities and participation in home, school and community life. There are currently two diverse intensive therapy approaches. Traditional therapy has adopted a bimanual approach (BIM training) and recently, constraint induced movement therapy (CIMT) has emerged as a promising unimanual approach. Uncertainty remains about the efficacy of these interventions and characteristics of best responders. This study aims to compare the efficacy of CIMT to BIM training to improve outcomes across the ICF for school children with congenital hemiplegia