Expression of a protease-resistant insulin-like growth factor-binding protein-4 inhibits tumour growth in a murine model of breast cancer

BACKGROUND: Insulin-like growth factor 1 (IGF1) promotes breast cancer and disease progression. Bioavailability of IGF1 is modulated by IGF-binding proteins (IGFBPs). IGFBP4 inhibits IGF1 activity but cleavage by pregnancy-associated plasma protein-A (PAPP-A) protease releases active IGF1. METHODS: Expression of IGF pathway components and PAPP-A was assessed by western blot or RT-PCR. IGFBP4 (dBP4) resistant to PAPP-A cleavage, but retaining IGF-binding capacity, was used to block IGF activity in vivo. 4T1.2 mouse mammary adenocarcinoma cells transfected with empty vector, vector expressing wild-type IGFBP4 or vector expressing dBP4 were implanted in the mammary fat pad of BALB/c mice and tumour growth was assessed. Tumour angiogenesis and endothelial cell apoptosis were assessed by immunohistochemistry. RESULTS: 4T1.2 cells expressed the IGF1R receptor and IGFBP4. PAPP-A was expressed within mammary tumours but not by 4T1.2 cells. Proliferation and vascular endothelial growth factor (VEGF) production by 4T1.2 cells was increased by IGF1(E3R) (recombinant IGF1 resistant to binding by IGFBPs) but not by wild-type IGF1. IGF1-stimulated microvascular endothelial cell proliferation was blocked by recombinant IGFBP4. 4T1.2 tumours expressing dBP4 grew significantly more slowly than controls or tumours expressing wild-type IGFBP4. Inhibition of tumour growth by dBP4 was accompanied by the increased endothelial cell apoptosis. CONCLUSION: Protease-resistant IGFBP4 blocks IGF activity, tumour growth and angiogenesis

Implementation of Mindfulness Training for Mental Health Staff: Organizational Context and Stakeholder Perspectives

Occupational stress and burnout adversely impacts mental health care staff well-being and patient outcomes. Mindfulness training reduces staff stress and may improve patient care. However, few studies explore mental health setting implementation. This qualitative study used focus groups to evaluate stakeholders’ perceptions of organizational factors affecting implementation of an adapted version of Mindfulness-Based Stress Reduction (MBSR) for staff on adolescent mental health units. Common facilitators included leadership securing buy-in with staff, allocating staff time to participate, and quiet space for training and practice. Other facilitators were past staff knowledge of mindfulness, local champions, and acculturating staff with mindfulness through a non-mandatory training attendance policy. Common barriers were limited staff time to attend training sessions and insufficient training coverage for some staff. Staff also reported improved focus when interacting with adolescents and improved social cohesion on the units. We conclude that a mindfulness-based program for reducing occupational stress can be successfully implemented on adolescent mental health units. Implementation appeared to change the social context of the units, including staff and patient interactions. More broadly, our findings highlight the importance of environmental factors in shaping attitudes, diffusion of innovation, and acculturation of wellness program implementations