In this study, we have used the human BV173 and the mouse BaF3/Bcr-Abl-expressing cell lines as model systems to investigate the molecular mechanisms whereby STI571 and FoxO3a regulate Bim expression and apoptosis. FoxO3a lies downstream of Bcr-Abl signalling and is constitutively phosphorylated in the Bcr-Ablpositive BV173 and BaF3/Bcr-Abl cells. Inhibition of Bcr-Abl kinase by STI571 results in FoxO3a activation, induction of Bim expression and apoptosis. Using reporter gene assays, we demonstrate that STI571 and FoxO3a activate Bim transcription through a FoxO-binding site (FHRE) located within the promoter. This was verified by DNA pull-down and chromatin immunoprecipitation analyses. We find that conditional activation of FoxO3a leads to induction of Bim expression and apoptosis. Conversely, silencing of FoxO3a in Bcr-Abl-expressing cells abolishes STI571-mediated Bim induction and apoptosis. Together, the results presented clearly confirm FoxO3a as a key regulator of apoptosis induced by STI571, and show that Bim is a direct transcriptional target of FoxO3a that mediates the STI571-induced apoptosis. Thus, STI571 induces an accumulation of FoxO3a activity which in turn binds directly to an FHRE in the promoter to activate Bim expression and apoptosis.
The Rapid Diagnostic Clinic (RDC) was introduced to comply with NICE recommendations for improving head and neck cancer services (National Institute of Clinical Excellence 2004 Improving outcomes in head and neck cancer: the manual. NICE, London). It provides multi-modality specialist assessment for new referrals, with on-site sonography and cytology. We have critically appraised the efficacy of our RDC, with respect to its impact on patients' timelines and outcomes. A retrospective audit of new referrals to the head and neck clinic during a 6-month period was conducted (pre-RDC period); areas in delay in patients reaching a definitive outcome were identified. Following implementation of the RDC, a second cycle, prospective audit was performed and its impact on timelines for patients' journey and outcomes determined. One hundred and ninety-seven patients were seen during the pre-RDC period. The average time from referral to being seen was 11 days for 2-week wait (2WW) referrals and 34 days for other sources. During the RDC period, 299 patients were seen in total. The average waiting time was reduced to 9 days for 2WW referrals and 23 days for other referrals. During the RDC period, over one-third of patients utilised the provision of ultrasound ± FNAC, and consequently, the majority reached a definitive outcome (discharged or scheduled for surgery) following their first consultation. This was a significant improvement compared to the pre-RDC period, where the main outcome was referral for an investigation, with consequently longer waiting time for surgery. We report the first study to consider the effect of a 'one-stop' clinic on patients' journey timelines and outcomes. Our study has shown that the RDC provides an efficient and effective system, which facilitates the patients' pathway to a definitive management plan.
International consensus was achieved for a number of factors across process-related and structural themes that may influence safety in the postoperative environment. These should be championed and prioritized for future improvements in patient safety at the ward-level.
This study demonstrates that there are a number of factors that may contribute to safety on the surgical ward spanning multiple processes, organizational, and environmental factors. Safety indicators identified across all these categories presents an opportunity to develop broader and more effectual safety improvement measures focusing on multiple areas simultaneously.
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