The small GTPase ADP-Ribosylation Factor 1 mediates the sensitivity of triple negative breast cancer cells to EGFR tyrosine kinase inhibitors

The clinical use of EGFR-targeted therapy, in triple negative breast cancer patients, has been limited by the development of resistance to these drugs. Although activated signaling molecules contribute to this process, the molecular mechanisms remain relatively unknown. We have previously reported that the small GTPase ADP-Ribosylation Factor 1 (ARF1) is highly expressed in invasive breast cancer cells and acts as a molecular switch to activate EGF-mediated responses. In this study, we aimed at defining whether the high expression of ARF1 limits sensitivity of these tumor cells to EGFR inhibitors, such as gefitinib. Here, we show that the knock down of ARF1 expression or activity decreased the dose and latency time required by tyrosine kinase inhibitors to induce cell death. This may be explained by the observation that the depletion of ARF1 suppressed gefitinib-mediated activation of key mediators of survival such as ERK1/2, AKT and Src, while enhancing cascades leading to apoptosis such as the p38MAPK and JNK pathways, modifying the Bax/Bcl2 ratio and cytochrome c release. In addition, inhibiting ARF1 expression and activation also results in an increase in gefitinib-mediated EGFR internalization and degradation further limiting the ability of this receptor to promote its effects. Interestingly, we observed that gefitinib treatment resulted in the enhanced activation of ARF1 by promoting its recruitment to the receptor AXL, an important mediator of EGFR inhibition suggesting that ARF1 may promote its pro-survival effects by coupling to alternative mitogenic receptors in conditions where the EGFR is inhibited. Together our results uncover a new role for ARF1 in mediating the sensitivity to EGFR inhibition and thus suggest that limiting the activation of this GTPase could improve the therapeutic efficacy of EGFR inhibitors.     

‘More effort and more time.’ Considerations in the establishment of interprofessional education programs in the workplace

The argument for integrating interprofessional education (IPE) activities into the workplace has been made concurrently with the call for collaborative clinical practice. An exploratory case study investigation of existing activities in a large metropolitan health care network was undertaken to inform the development of future IPE initiatives. Purposive sampling invited clinicians involved in the design or delivery of workplace IPE activities to participate in a semi-structured interview to discuss their existing programs and the opportunities and challenges facing future work. Interviews were audiotaped, transcribed and thematically analysed. In total, 15 clinicians were interviewed representing medicine, nursing, occupational therapy, pharmacy, physiotherapy, psychology, social work and speech pathology. The IPE programs identified included one medical and midwifery student workshop, several dedicated new graduate or intern programs combining the professions and multiple continuing professional development programs. Three dominant themes were identified to inform the development of future work: clinician factors, organisational factors and IPE considerations. In addition to the cultural, physical and logistical challenges associated with education that integrates professions in the workplace, the time required for the design and delivery of integrated team training should be accounted for when establishing such programs. Considerations for sustainability include ongoing investment in education skills for clinicians, establishment of dedicated education roles and expansion of existing education activities.     

Catheter ablation therapy for atrial fibrillation

The past several years have witnessed a significant growth in the number of institutions offering catheter ablation for atrial fibrillation (AF). This growth has been a result of a better understanding of pathophysiology of AF and use of instruments and approaches that made catheter ablation of AF a safe and an effective alternative to the drug therapy. The procedure increasingly is becoming a therapy of choice for a select group of symptomatic, drug-refractory patients without structural heart disease, and it is being offered to a rapidly widening patient pool. This article reviews the procedural aspects and clinical evidence supporting this wider use of AF ablation. In addition, new techniques and technologies for AF ablation and new avenues of research in this area are explored.     

Improving the prevention and management of chronic disease in low-income and middle-income countries: a priority for primary health care

The burden of chronic diseases, such as heart disease, cancer, diabetes, and mental disorders is high in low-income and middle-income countries and is predicted to increase with the ageing of populations, urbanisation, and globalisation of risk factors. Furthermore, HIV/AIDS is increasingly becoming a chronic disorder. An integrated approach to the management of chronic diseases, irrespective of cause, is needed in primary health care. Management of chronic diseases is fundamentally different from acute care, relying on several features: opportunistic case finding for assessment of risk factors, detection of early disease, and identification of high risk status; a combination of pharmacological and psychosocial interventions, often in a stepped-care fashion; and long-term follow-up with regular monitoring and promotion of adherence to treatment. To meet the challenge of chronic diseases, primary health care will have to be strengthened substantially. In the many countries with shortages of primary-care doctors, non-physician clinicians will have a leading role in preventing and managing chronic diseases, and these personnel need appropriate training and continuous quality assurance mechanisms. More evidence is needed about the cost-effectiveness of prevention and treatment strategies in primary health care. Research on scaling-up should be embedded in large-scale delivery programmes for chronic diseases with a strong emphasis on assessment.