Services for children with central auditory processing disorder in the Republic of Ireland: current and future service provision

Purpose: An interdisciplinary research group was established to investigate current and future service provision for children with central auditory processing disorder ([C]APD) in the Republic of Ireland. The aim of Phase 1 was to identify current awareness and knowledge of (C) APD among the relevant professionals in Ireland, including level of service provision, if any, available for children with (C) APD. The aim of Phase 2 was to explore the initial steps required to develop an integrated service for children presenting with (C) APD.Method: A quantitative design was used in Phase 1, and 520 surveys were distributed to speech and language therapists, audiologic scientists, and educational psychologists. A qualitative participative design was used in Phase 2.Results: There was a 53% response rate to the survey. The main findings from Phase 1 were that all professional groups considered themselves to be inadequately informed and lacking in skills for (C) APD assessment or intervention. In Phase 2, 98 participants with backgrounds in speech and language therapy, audiologic science, educational psychology, and occupational therapy engaged in interdisciplinary discussions to identify the first steps required to develop a (C) APD service.Conclusion: All professional groups considered that they were inadequately informed about (C) APD, and the first steps required to develop services in Ireland include the promotion and development of interdisciplinary teamwork and education, a need for additional resources, a clearer understanding of the definition of (C) APD, and evidence-based assessment and management of this condition.HS

The novel pyrrolo-1,5-benzoxazepine, PBOX-6, synergistically enhances the apoptotic effects of carboplatin in drug sensitive and multidrug resistant neuroblastoma cells

Neuroblastoma, a malignancy of neuroectoderrmal origin, accounts for 15% of childhood cancer deaths. Despite advances in understanding the biology, it remains one of the most difficult paediatric cancers to treat. A major obstacle in the effective treatment of neuroblastoma is the development of multidrug resistance (MDR). There is thus a compelling demand for new treatment strategies for this cancer that can bypass such resistance mechanisms. The pyrrolo-1,5-benzoxazepine (PBOX) compounds are a series of novel microtubule-targeting agents that potently induce apoptosis in various cancer cell lines, ex vivo patient samples and in vivo cancer models. In this study we examined the ability of two members, PBOX-6 and -15, to exhibit anti-cancer effects in a panel of drug sensitive and MDR neuroblastoma cell lines. The PBOX compounds potently reduced the viability of all neuroblastoma cells examined and exhibited a lower fold resistance in MDR cells when compared to standard chemotherapeutics. In addition, the PBOX compounds synergistically enhanced apoptosis induced by etoposide, carboplatin and doxorubicin. Exposure of drug sensitive and resistant cell lines to PBOX-6/carboplatin induced cleavage of Bcl-2, a downregulation of Mcl-1 and a concomitant increase in Bak. Furthermore, activation of caspase-3, -8 and -9 was demonstrated. Finally, gene silencing of Mcl-1 by siRNA was shown to sensitise both drug sensitive and multidrug resistant cells to carboplatin-induced apoptosis demonstrating the importance of Mcl-1 downregulation in the apoptotic pathway mediated by the PBOX compounds in neuroblastoma. In conclusion, our findings indicate the potential of the PBOX compounds in enhancing chemosensitivity in neuroblastoma.</p

The Fanconi Anemia DNA Repair Pathway Is Regulated by an Interaction between Ubiquitin and the E2-like Fold Domain of FANCL.

The Fanconi Anemia (FA) DNA repair pathway is essential for the recognition and repair of DNA interstrand crosslinks (ICL). Inefficient repair of these ICL can lead to leukemia and bone marrow failure. A critical step in the pathway is the monoubiquitination of FANCD2 by the RING E3 ligase FANCL. FANCL comprises 3 domains, a RING domain that interacts with E2 conjugating enzymes, a central domain required for substrate interaction, and an N-terminal E2-like fold (ELF) domain. The ELF domain is found in all FANCL homologues, yet the function of the domain remains unknown. We report here that the ELF domain of FANCL is required to mediate a non-covalent interaction between FANCL and ubiquitin. The interaction involves the canonical Ile44 patch on ubiquitin, and a functionally conserved patch on FANCL. We show that the interaction is not necessary for the recognition of the core complex, it does not enhance the interaction between FANCL and Ube2T, and is not required for FANCD2 monoubiquitination in vitro. However, we demonstrate that the ELF domain is required to promote efficient DNA damage-induced FANCD2 monoubiquitination in vertebrate cells, suggesting an important function of ubiquitin binding by FANCL in vivo