Das Manifest zur Brechung der Zinsknechtschaft des Geldes

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Multiple mechanisms underlie defective recognition of melanoma cells cultured in three-dimensional architectures by antigen-specific cytotoxic T lymphocytes

Cancer cells` growth in three-dimensional (3D) architectures promotes resistance to drugs, cytokines, or irradiation. We investigated effects of 3D culture as compared to monolayers (2D) on melanoma cells` recognition by tumour-associated antigen (TAA)-specific HLA-A*0201-restricted cytotoxic T-lymphocytes (CTL). Culture of HBL, D10 (both HLA-A*0201+, TAA+) and NA8 (HLA-A* 0201+, TAA-) melanoma cells on polyHEMA-coated plates, resulted in generation of 3D multicellular tumour spheroids (MCTS). Interferon-gamma (IFN-gamma) production by HLA-A*0201-restricted Melan-A/MART-1(27-35) or gp100(280-288)-specific CTL clones served as immunorecognition marker. Co-culture with melanoma MCTS, resulted in defective TAA recognition by CTL as compared to 2D as witnessed by decreased IFN-gamma production and decreased Fas Ligand, perforin and granzyme B gene expression. A multiplicity of mechanisms were potentially involved. First, MCTS per se limit CTL capacity of recognising HLA class I restricted antigens by reducing exposed cell surfaces. Second, expression of melanoma differentiation antigens is downregulated in MCTS. Third, expression of HLA class I molecules can be downregulated in melanoma MCTS, possibly due to decreased interferonregulating factor-1 gene expression. Fourth, lactic acid production is increased in MCTS, as compared to 2D. These data suggest that melanoma cells growing in 3D, even in the absence of immune selection, feature characteristics capable of dramatically inhibiting TAA recognition by specific CTL

From Empirics to Empiricists

Although the notion of empiricism looms large in many histories of early modern philosophy, its origins are not well understood. This paper aims to shed light on them. It examines the notions of empirical philosopher, physician, and politician that are employed in a range of seventeenth- and eighteenth-century texts, alongside related notions (e.g. "experimental philosophy") and methodological stances. It concludes that the notion of empiricism used in many histories of early modern thought does not have pre-Kantian origins. It first appeared and became widely used in late eighteenth-century Germany, in the course of the early debates on Kant's Critical philosophy