Four proteins governing overangiogenic endothelial cell phenotype in patients with multiple myeloma are plausible therapeutic targets.

Bone marrow (BM) angiogenesis has an important role in the initiation and progression of multiple myeloma (MM). We looked at novel mechanisms of vessel formation in patients with MM through a comparative proteomic analysis between BM endothelial cells (ECs) of patients with active MM (MMECs) and ECs of patients with monoclonal gammopathy of undetermined significance (MGECs) and of subjects with benign anemia (normal ECs). Four proteins were found overexpressed in MMECs: filamin A, vimentin, α-crystallin B and 14-3-3ζ/δ protein, not yet linked to overangiogenic phenotype. These proteins gave a typical distribution in the BM of MM patients and in MMECs versus MGECs, plausibly according to a different functional state. Their expression was enhanced by vascular endothelial growth factor, fibroblast growth factor 2, hepatocyte growth factor and MM plasma cell conditioned medium in step with enhancement of MMEC angiogenesis. Their silencing RNA knockdown affected critical MMEC angiogenesis-related functions, such as spreading, migration and tubular morphogenesis. A gradual stabilization of 14-3-3ζ/δ protein was observed, with transition from normal ECs to MGECs and MMECs that may be a critical step for the angiogenic switch in MMECs and maintenance of the cell overangiogenic phenotype. These proteins were substantially impacted by anti-MM drugs, such as bortezomib, lenalidomide and panobinostat. Results suggest that these four proteins could be new targets for the antiangiogenic management of MM patients.

Immune effects of polychlorinated biphenyls, smoking and alcohol.

Polychlorinated biphenyls (PCB) have been shown to exert some immune effects. Here we analysed their effects also on immune parameters not previously studied such as TCR alpha-beta, TCR gamma-delta and regulatory T cells (Treg), taking into account the specific and cumulative interference of smoking and alcohol. The study subjects consisted of 26 male workers in a steel works factory, employed in the electrical maintenance sector, with previous exposure to a mixture of PCB (exposed subjects), and 30 male workers with no occupational exposure to PCB (controls). All subjects were given a questionnaire and peripheral venous blood samples were taken to determine serum PCB (33 congeners), total cholesterol and triglycerides, leukocytes, total lymphocytes and the T lymphocyte subpopulations (TCR alpha-beta, TCRgamma-delta, CD4+ and Treg lymphocytes). PCB, even though at a very low concentration, were significantly higher in exposed subjects than controls, and were significantly correlated with age. Monocytes% and CD4+ were significantly reduced in the exposed subjects as compared to the controls. The serum concentration of PCB positively correlated with TCR alpha-beta, and negatively with TCRgamma-delta. Treg lymphocytes showed a positive dependence on tobacco smoking, while the monocytes percentage and CD4+ showed a negative and positive dependence, respectively, on alcohol intake. Our results seem to show some effects of slight exposure to PCB in particular reducing the relative concentration of TCRgamma-delta. This effect can favour indirectly the increase in Treg induced by smoking, the anti-inflammatory or proinflammatory/fibrogenetic/angiogenetic effect of which, exerted by produced cytokines, particularly TGF-beta, deserves further clarification.