Telomerase inhibition abolishes the tumorigenicity of pediatric ependymoma tumor-initiating cells

Pediatric ependymomas are highly recurrent tumors resistant to conventional chemotherapy. Telomerase, a ribonucleoprotein critical in permitting limitless replication, has been found to be critically important for the maintenance of tumor-initiating cells (TICs). These TICs are chemoresistant, repopulate the tumor from which they are identified, and are drivers of recurrence in numerous cancers. In this study, telomerase enzymatic activity was directly measured and inhibited to assess the therapeutic potential of targeting telomerase. Telomerase repeat amplification protocol (TRAP) (n = 36) and C-circle assay/telomere FISH/ATRX staining (n = 76) were performed on primary ependymomas to determine the prevalence and prognostic potential of telomerase activity or alternative lengthening of telomeres (ALT) as telomere maintenance mechanisms, respectively. Imetelstat, a phase 2 telomerase inhibitor, was used to elucidate the effect of telomerase inhibition on proliferation and tumorigenicity in established cell lines (BXD-1425EPN, R254), a primary TIC line (E520) and xenograft models of pediatric ependymoma. Over 60 % of pediatric ependymomas were found to rely on telomerase activity to maintain telomeres, while no ependymomas showed evidence of ALT. Children with telomerase-active tumors had reduced 5-year progression-free survival (29 +/- A 11 vs 64 +/- A 18 %; p = 0.03) and overall survival (58 +/- A 12 vs 83 +/- A 15 %; p = 0.05) rates compared to those with tumors lacking telomerase activity. Imetelstat inhibited proliferation and self-renewal by shortening telomeres and inducing senescence in vitro. In vivo, Imetelstat significantly reduced subcutaneous xenograft growth by 40 % (p = 0.03) and completely abolished the tumorigenicity of pediatric ependymoma TICs in an orthotopic xenograft model. Telomerase inhibition represents a promising therapeutic approach for telomerase-active pediatric ependymomas found to characterize high-risk ependymomas.Canadian Institutes of Health Research [MOP 82727]info:eu-repo/semantics/publishedVersio

A qualitative investigation into the characteristics and effects of music accompanying exercise

The purpose of the present study was to identify the characteristics of music used to accompany physical exercise and investigate the effects of such music using a qualitative approach. This work underpins the further development of a theoretical structure that is still relatively new. Semi-structured interviews were conducted with a sample of exercise participants (N = 13), seven males and six females, all with at least two years’ experience of exercising to music. An inductive content analysis of the interview data was undertaken and results contrasted with the conceptual model developed by Karageorghis et al. (1999) which describes the effects of musical and cultural factors with reference to psychophysical outcomes. The findings demonstrated the importance of musical (e.g. rhythm, lyrics, bass), contextual (e.g. time of day) and individual factors (e.g. background, personality) in determining both shortterm (e.g. mood, imagery) and long-term outcomes (e.g. heightened work-rate, endurance). The findings point towards a more expansive conceptual framework. In particular, facets of the response to music such as flow state, cognitive responses, rhythm response and anticipation are discussed. Music perceived to be motivating could lead to increases in exercise intensity and endurance during performance of self-regulated tasks. These findings have implications for the use of music in physical education settings