BACKGROUND: Imatinib is a direct and potent inhibitor of the constitutively active tyrosine kinase, breakpoint cluster region-Abelson (Bcr-Abl), which is central to the pathogenesis of chronic myeloid leukaemia (CML) patients. As such, imatinib has become the frontline treatment for CML patients. However, the recent emergence of imatinib resistance, commonly associated with point mutations within the kinase domain, has led to the search for alternative drug treatments and combination therapies for CML. METHODS: In this report, we analyse the effects of representative members of the novel pro-apoptotic microtubule depolymerising pyrrolo-1,5-benzoxazepines or PBOX compounds on chemotherapy-refractory CML cells using a series of Bcr-Abl mutant cell lines, clinical ex vivo patient samples and an in vivo mouse model. RESULTS: The PBOX compounds potently reduce cell viability in cells expressing the E225K and H396P mutants as well as the highly resistant T315I mutant. The PBOX compounds also induce apoptosis in primary CML samples including those resistant to imatinib. We also show for the first time, the in vivo efficacy of the pro-apoptotic PBOX compound, PBOX-6, in a CML mouse model of the T315I Bcr-Abl mutant. CONCLUSION: Results from this study highlight the potential of these novel series of PBOX compounds as an effective therapy against CML.

This paper presents an analysis of primary schoolchildren's attitudes to the Irish language, Gaeilge, in the context of national policy in the Republic of Ireland. In particular, the study examines the factors (social, cultural, cognitive and organisational) that may be related to a pronounced excess in disengagement with Irish over and above general engagement with schooling. The data derives from the 9 year old child cohort of the national longitudinal study of children, the Growing Up in Ireland (GUI) survey. Unlike previous findings in relation to general engagement with school, excess disengagement with Irish is not found to be related to socioeconomic or ethnic factors, factors related to teacher profile, training, self-efficacy or style or school ethos. As expected, children with less exposure to spoken Irish in school or at home are more likely to show excess disengagement with the language. Literacy activity, special education needs and school patronage are also found to be related to excess disengagement. Significant random effects indicate the importance of the individual teacher and school in the development of pupil engagement with Irish. The current study presents a timely perspective on attitudes to Irish among the younger population and possible implications for policy.