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  • 1
    Keywords: EXPRESSION ; SURVIVAL ; NETWORK ; NETWORKS ; GENE ; LINKAGE ; SUSCEPTIBILITY ; LYMPHOMA ; MALIGNANCIES ; genetics ; molecular ; FEATURES ; MALIGNANCY ; REGRESSION ; review ; FAMILIES ; CANDIDATE GENES ; CLL ; PREDISPOSITION ; leukaemia ; USA ; ENGLAND ; EXPANSION ; chronic lymphocytic leukaemia ; B-CELL LYMPHOCYTOSIS ; CHALLENGES ; family studies ; genetic association
    Abstract: Although the familial aspect of chronic lymphocytic leukaemia (CLL) has been appreciated for decades, it is only with the recent confluence of improved molecular and gene technologies and world-wide collaborative networks that accelerated progress has become apparent. In this summary we highlight selected themes in the genetics of CLL emphasizing the opportunities and challenges of this malignancy
    Type of Publication: Journal article published
    PubMed ID: 18021078
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  • 2
    Keywords: EXPRESSION ; ACTIVATION ; mechanisms ; CELL-DEATH ; PROSTATE-CANCER ; MUTATIONS ; PET ; PHASE-II TRIAL ; IMATINIB MESYLATE ; 2-DEOXY-D-GLUCOSE
    Abstract: Positron emission tomography (PET) with 18F-fluorodeoxyglucose (FDG) is frequently used for visualizing gastrointestinal stromal tumors (GIST), which are highly glucose-avid tumors. Dramatic metabolic responses following imatinib treatment indicate a high, KIT-dependent glucose turnover which has been particularly helpful for predicting tumor response to imatinib. The glucose analogue 2-deoxyglucose (2DG) inhibits glucose metabolism in cancer cells that depend on aerobic glycolysis for ATP production. We show that 2DG inhibits proliferation in both imatinib-sensitive and imatinib-resistant GIST cell lines at levels that can be achieved clinically. KIT-negative GIST48B have 3-14-fold higher IC50 levels than KIT-positive GIST cells indicating that oncogenic KIT may sensitize cells to 2DG. GIST sensitivity to 2DG is increased in low-glucose media (110mg/dl). 2DG leads to dose- and glucose dependent inhibition of KIT glycosylation with resultant reduction of membrane-bound KIT, inhibition of KIT-phosphorylation and inactivation of KIT-dependent signaling intermediates. In contrast to imatinib, 2DG caused ER-stress and elicited the unfolded protein response (UPR). Mannose but not pyruvate rescued GIST cells from 2DG-induced growth arrest, suggesting that loss of KIT integrity is the predominant effect of 2DG in GIST. Additive anti-tumoral effects were seen with imatinib and BH3-mimetics. Our data provide the first evidence that modulation of the glucose-metabolism by 2DG may have a disease-specific effect and may be therapeutically useful in GIST.
    Type of Publication: Journal article published
    PubMed ID: 25781619
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  • 3
    Keywords: RECEPTOR ; CELLS ; EXPRESSION ; IN-VITRO ; CELL ; Germany ; IN-VIVO ; VITRO ; VIVO ; DISEASE ; MICE ; ACTIVATION ; DNA ; INFECTION ; kidney ; MECHANISM ; murine ; SERA ; renal ; CONTRAST ; DENDRITIC CELLS ; mechanisms ; INJECTION ; antibodies ; PROGRESSION ; ESCHERICHIA-COLI ; EPITHELIAL-CELLS ; VIRAL-INFECTION ; AUTOIMMUNITY ; BACTERIAL CPG-DNA ; CHEMOKINE RECEPTOR ; chemokines,autoimmune diseases,kidney,lupus,immunity ; IMMUNE-COMPLEX GLOMERULONEPHRITIS ; IMMUNIZATION ; NZB/NZW MICE ; SYSTEMIC-LUPUS-ERYTHEMATOSUS
    Abstract: How bacterial or viral infections trigger flares of autoimmunity is poorly understood. As toll-like receptor (TLR)-9 activation by exogenous or endogenous CpG-DNA may contribute to disease activity of systemic lupus erythematosus, we examined the effects of CpG-oligodeoxynucleotides (ODN) or DNA derived from Escherichia coli (E. coli) on the course of nephritis in MRL1pr/1pr mice. In kidneys of these mice, TLR9 localized to glomerular, tubulointerstitial, and perivascular infiltrates. After intraperitoneal injection labeled CpG-ODN localized to glomerular and interstitial macrophages and dendritic cells in nephritic kidneys of MRL1pr/1pr mice but not in healthy MRL controls. Furthermore, murine J774 macrophages and splenocytes from MRL1pr/1pr mice, but not tubular epithelial cells, renal fibroblasts, or mesangial cells, expressed TLR9 and up-regulated CCL5/RANTES mRNA upon stimulation with CpG-ODN in vitro. In vivo both E. coli DNA and CpG-ODN increased serum DNA autoantibodies of the IgG(2a) isotype in MRL1pr/1pr mice. This was associated with progression of mild to crescentic glomerulonephritis, interstitial fibrosis, and heavy proteinuria. CpG-ODN increased renal CCL2/MCP-1 and CCL5/RANTES expression associated with increased glomerular and interstitial leukocyte recruitment. In contrast control GpC-ODN had no effect. We conclude that TLR9 activation triggers disease activity of systemic autoimmunity, for example, lupus nephritis, and that adaptive and innate immune mechanisms contribute to the CpG-DNA-induced progression of lupus nephritis
    Type of Publication: Journal article published
    PubMed ID: 14734643
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