Dasatinib prevents skeletal metastasis of osteotropic MDA-MB-231 cells in a xenograft mouse model.

PURPOSE: Bone metastasis in breast cancer has been linked to activity of c-Src kinase, one of the extensively explored tyrosine kinases in cell biology. The impact of TNF-related apoptosis inducing ligand (TRAIL) and TRAIL receptors has just recently been integrated into this conception. METHODS: An osteotropic clone of MDA-MB-231 cells simulated a model for bone metastasis of triple-negative breast cancer (TNBC). The effects of Dasatinib, a clinically established inhibitor of Src kinases family and Abl were evaluated in vitro and in vivo. In vivo effects of Dasatinib treatment on the occurrence of skeletal metastases were tested in a xenograft mouse model after intra-cardiac injection of osteotropic MDA-MB-231-cells. Ex vivo analyses of the bone sections confirmed intraosseous growth of metastases and allowed determination of osteoclastic activity. RESULTS: Treatment of osteotropic MDA-MB-231 cells with Dasatinib inhibited proliferation rates in vitro. A shift in TRAIL-receptor expression towards an induction of oncogenic TRAIL-R2 was observed. In vivo, 15 of 30 mice received an intra-peritoneal treatment with Dasatinib. These mice showed significantly less skeletal metastases in bioluminescence scans. Moreover, a pronounced increase in bone volume was observed in the treatment group, as detected by µ-Computed Tomography. Dasatinib treatment also led to a greater increase in bone density in tibiae without metastatic affection, which was accompanied by reduced recruitment of osteoclasts. CONCLUSION: Our observations support the concept of utilizing Dasatinib in targeting early-stage bone metastatic TNBC and sustaining bone health.

Ethik First - extracurricular support for medical students and young physicians facing moral dilemmas in hospital routine.

Introduction: Moral value conflicts play an increasingly central role in everyday hospital life. Clinical ethics, however, is only marginally represented in the compulsory curriculum for human medicine and the additional education regulations. The aim of the Ethik First project at the University Medical Center Schleswig-Holstein, Campus Kiel is to close this gap with an extracurricular offer and to support medical students from the fifth clinical semester onward and during their practical year as well as assistant doctors in dealing with moral dilemmas in everyday hospital life. The project has taken the concomitant learning objectives from the national competency-based learning objective catalog for medicine. According to the target group, the address in particular, showed higher taxonomy levels. Project description: The multimodal concept is based on three pillars: In monthly principle-based case conferences, participants practice ethical reflection and moral judgment primarily on the basis of concrete cases introduced by them using the methods of problem-based learning and consideration-based deliberation. If participants do not bring forth a case, they discuss ethical aspects of current political relevance. Moreover, there is an annual public speaker event. Results: Since the project began in 2017, ~20 students and interns have taken part in Ethik First one or more times. In a web-based interim evaluation (N=13), all respondents fully agreed that they considered the format helpful for dealing with ethical questions at the clinic. They rated the relevance for their later profession as high. There is evidence for support in moral dilemma situations. Discussion: The first evaluation results of the voluntary extracurricular offer show the acceptance of the selected format, which goes beyond pure teaching in its conception in that it addresses moral stress as well and strengthens the participants' individual resilience. Conclusion: Ethik First reinforces the role of ethical aspects in the training of (prospective) doctors and focuses on reflecting on cases they have experienced firsthand. We formulate a desideratum for appropriate advanced training concepts both in medical studies and in advanced medical training such that the training and development of comparable projects at medical faculties and at medical associations with student participation can be discussed.