Characterization of Cyclin E Expression in Multiple Myeloma and Its Functional Role in Seliciclib-Induced Apoptotic Cell Death

Multiple Myeloma (MM) is a lymphatic neoplasm characterized by clonal proliferation of malignant plasma cell that eventually develops resistance to chemotherapy. Drug resistance, differentiation block and increased survival of the MM tumor cells result from high genomic instability. Chromosomal translocations, the most common genomic alterations in MM, lead to dysregulation of cyclin D, a regulatory protein that governs the activation of key cell cycle regulator – cyclin dependent kinase (CDK). Genomic instability was reported to be affected by over expression of another CDK regulator - cyclin E (CCNE). This occurs early in tumorigenesis in various lymphatic malignancies including CLL, NHL and HL. We therefore sought to investigate the role of cyclin E in MM. CCNE1 expression was found to be heterogeneous in various MM cell lines (hMMCLs). Incubation of hMMCLs with seliciclib, a selective CDK-inhibitor, results in apoptosis which is accompanied by down regulation of MCL1 and p27. Ectopic over expression of CCNE1 resulted in reduced sensitivity of the MM tumor cells in comparison to the paternal cell line, whereas CCNE1 silencing with siRNA increased the cell sensitivity to seliciclib. Adhesion to FN of hMMCLs was prevented by seliciclib, eliminating adhesion–mediated drug resistance of MM cells. Combination of seliciclib with flavopiridol effectively reduced CCNE1 and CCND1 protein levels, increased subG1 apoptotic fraction and promoted MM cell death in BMSCs co-culture conditions, therefore over-coming stroma-mediated protection. We suggest that seliciclib may be considered as essential component of modern anti MM drug combination therapy

Migrant-friendly hospitals: a paediatric perspective--improving hospital care for migrant children.

BACKGROUND: The European Union (EU) Migrant-Friendly Hospital (MFH) Initiative, introduced in 2002, promotes the adoption of care approaches adapted to meet the service needs of migrants. However, for paediatric hospitals, no specific recommendations have been offered for MFH care for children. Using the Swiss MFH project as a case study, this paper aims to identify hospital-based care needs of paediatric migrants (PMs) and good service approaches. METHODS: Semi-structured interviews were conducted with principal project leaders of five paediatric hospitals participating in the Swiss MFH project. A review of the international literature on non-clinical hospital service needs and service responses of paediatric MFHs was conducted. RESULTS: Paediatric care can be complex, usually involving both the patient and the patient's family. Key challenges include differing levels of acculturation between parents and children; language barriers; cultural differences between patient and provider; and time constraints. Current service and infrastructural responses include interpretation services for PMs and parents, translated information material, and special adaptations to ensure privacy, e.g., during breastfeeding. Clear standards for paediatric migrant-friendly hospitals (P-MFH) are lacking. CONCLUSIONS: International research on hospital care for migrant children is scarce. The needs of paediatric migrants and their families may differ from guidance for adults. Paediatric migrant needs should be systematically identified and used to inform paediatric hospital care approaches. Hospital processes from admission to discharge should be revised to ensure implementation of migrant-sensitive approaches suitable for children. Staff should receive adequate support, such as training, easily available interpreters and sufficient consultation time, to be able to provide migrant-friendly paediatric services. The involvement of migrant groups may be helpful. Improving the quality of care for PMs at both policy and service levels is an investment in the future that will benefit native and migrant families

Lenalidomide enhances MOR202-dependent macrophage -mediated effector functions via the vitamin D pathway

Macrophages are key mediators of the therapeutic effects exerted by monoclonal antibodies, such as the anti-CD38 antibody MOR202, currently introduced in multiple myeloma (MM) therapy. Therefore, it is important to understand how antibody mediated effector functions of myeloma-associated macrophages (MAMs) are regulated. Here, we focused on the effects of vitamin D, a known regulator of macrophage effector functions. Consequently, it was the aim of this study to assess whether modulation of the vitamin D pathway alters the tumoricidal activity of MAMs. Here, we demonstrate that MAMs display a defective vitamin D pathway with reduced expression level of CYP27B1 and limited tumoricidal activity which can be restored by the IMiD lenalidomide in vitro. Furthermore, our data indicate that the vitamin D pathway of MAMs from MM patients does recover during an IMiD-containing therapy shown by an improved MOR202-mediated cytotoxic activity of these MAMs against primary MM cells ex vivo. Here, the ex vivo cytotoxic activity could be further enhanced by vitamin D supplementation. These data suggest that vitamin D holds a key role for the effector functions of MAMs and that vitamin D supplementation in IMiD combination trials could further increase the therapeutic efficacy of anti-CD38 antibodies such as MOR202, which remains to be investigated in clinical studies