We propose a conceptual framework which may guide research on fostering diagnostic competences in simulations in higher education. We first review and link research perspectives on the components and the development of diagnostic competences, taken from medical and teacher education. Applying conceptual knowledge in diagnostic activities is considered necessary for developing diagnostic competences in both fields. Simulations are considered promising in providing opportunities for knowledge application when real experience is overwhelming or not feasible for ethical, organizational or economic reasons. To help learners benefit from simulations, we then propose a systematic investigation of different types of instructional support in such simulations. We particularly focus on different forms of scaffolding during problemsolving and on the possibly complementary roles of the direct presentation of information in these kinds of environments. Two sets of possibly moderating factors, individual learning prerequisites (such as executive functions) or epistemic emotions and contextual factors (such as the nature of the diagnostic situation or the domain) are viewed as groups of potential moderators of the instructional effects. Finally, we outline an interdisciplinary research agenda concerning the instructional design of simulations for advancing diagnostic competences in medical and teacher education.

Up-to-date osteoporosis and post-fracture management of older persons should aim at both, bone and muscle.

Primary drug resistance is a major problem in multiple myeloma, an incurable disease of the bone marrow. Cell adhesion-mediated drug resistance (CAM-DR) causes strong primary resistance. By coculturing multiple myeloma cells with bone marrow stromal cells (BMSCs), we observed a CAM-DR of about 50% to melphalan, treosulfan, doxorubicin, dexamethasone, and bortezomib, which was not reversed by secreted soluble factors. Targeting the adhesion molecules lymphocyte function-associated antigen 1 (LFA-1) and very late antigen 4 (VLA-4) by monoclonal antibodies or by the LFA-1 inhibitor LFA703 reduced CAM-DR significantly. Only statins such as simvastatin and lovastatin, however, were able to completely restore chemosensitivity. All these effects were not mediated by deadhesion or reduced secretion of interleukin 6. Targeting

Multiple myeloma is still an incurable disease; therefore, new therapeutics are urgently needed. A771726 is the active metabolite of the immunosuppressive drug leflunomide, which is currently applied in the treatment of rheumatoid arthritis, BK virus nephropathy, and cytomegaly viremia. Here, we show that dihydroorotate dehydrogenase (DHODH) is commonly expressed in multiple myeloma cell lines and primary multiple myeloma cells. The DHODH inhibitor A771726 inhibits cell growth in common myeloma cell lines at clinically achievable concentrations in a time-and dose-dependent manner. Annexin V-FITC/ propidium iodide staining revealed induction of apoptosis of multiple myeloma cell lines and primary multiple myeloma cells. The 5-bromo-2 ¶-deoxyuridine cell proliferation assay showed that inhibition of cell growth was partly due to inhibition of multiple myeloma cell proliferation. A771726 induced G 1 cell cycle arrest via modulation of cyclin D2 and pRb expression. A771726 decreased phosphorylation of protein kinase B (Akt), p70S6K, and eukaryotic translation initiation factor 4E-binding protein-1 as shown by Western blotting experiments. Furthermore, we show that the stimulatory effect of conditioned medium of HS-5 bone marrow stromal cells on multiple myeloma cell growth is completely abrogated by A771726. In addition, synergism studies revealed synergistic and additive activity of A771726 together with the genotoxic agents melphalan, treosulfan, and doxorubicin as well as with dexamethasone and bortezomib. Taken together, we show that inhibition of DHODH by A771726/leflunomide is effective in multiple myeloma. Considering the favorable toxicity profile and the great clinical experience with leflunomide in rheumatoid arthritis, this drug represents a potential new candidate for targeted therapy in multiple myeloma. [Mol Cancer Ther 2009;8(2):366 -75]

No abstract

Adhesion is a hallmark of haematological and solid cancer cells. All five classes of cell adhesion molecules (CAM) - integrins, cadherins, immunoglobulin-like CAMs, selectins and CD44s - are characteristically dysregulated in human cancer. Adhesion enables and promotes cancer-defining biological processes like growth, survival, migration, extravasation, homing, and metastasis. Furthermore, cell adhesion mediates drug resistance (CAM-DR) in multiple myeloma, malignant lymphoma, acute and chronic leukaemias, as well as in pancreatic cancer, neuroblastoma, small cell and non-small cell lung cancer, mesothelioma, colorectal carcinoma, and breast cancer. Cell adhesion protects from death by radiation, genotoxic chemotherapy, or targeted pathway inhibitors. Adhesion molecules are overexpressed on drug resistant cells (e.g. multiple myeloma or prostate cancer). Very recently, several cell adhesion mediated survival pathways have been elucidated, with key mediators being LFA-1, VLA-4, FAK, ILK, Src, PI3K, Akt, Ras, MEK, Erk, HMG-CoA reductase, Rho, Rho kinase, PKC, and NFkB. Because the surface and the intracellular targets are now known and because specific compounds are becoming increasingly available, first clinical trials regarding ANTI-ADHESION therapies are ongoing. However, in comparison to the comprehensive preclinical and clinical knowledge about CAMs, the number of drugs developed thusfar is quite low. ANTI-ADHESION strategies include targeting of surface antigens, inhibition of cell adhesion associated pathways, inhibition of CAM-DR, and targeted drug delivery. As ANTI-ADHESION is based on general characteristics of cancer cells independent of specific disease entities or treatment modalities, it may become a successful, low-toxic and broadly applicable concept in cancer treatment.

Professional knowledge is highlighted as an important prerequisite of both medical doctors and teachers. Based on recent conceptions of professional knowledge in these fields, knowledge can be differentiated within several aspects. However, these knowledge aspects are currently conceptualized differently across different domains and projects. Thus, this paper describes recent frameworks for professional knowledge in medical and educational sciences, which are then integrated into an interdisciplinary two-dimensional model of professional knowledge that can help to align terminology in both domains and compare research results. The models’ two dimensions differentiate between cognitive types of knowledge and content-related knowledge facets and introduces a terminology for all emerging knowledge aspects. The models’ applicability for medical and educational sciences is demonstrated in the context of diagnosis by describing prototypical diagnostic settings for medical doctors as well as for teachers, which illustrate how the framework can be applied and operationalized in these areas. Subsequently, the role of the different knowledge aspects for acting and the possibility of transfer between different content areas are discussed. In conclusion, a possible extension of the model along a “third dimension” that focuses on the effects of growing expertise on professional knowledge over time is proposed and issues for further research are outlined.

Bendamustine induces ATM-Chk2-Cdc2-mediated G2 arrest and p53 mediated apoptosis. Inhibition of p38 MAPK augments apoptosis and abrogates G2 arrest and can be considered as a new therapeutic strategy in combination with bendamustine.