Blood
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The antiphospholipid syndrome is characterized by the presence of antiphospholipid antibodies in plasma of patients with thromboembolic complications. A major problem in defining the syndrome is that serologic assays to detect antiphospholipid antibodies have a low specificity. We recently published a method that specifically detects lupus anticoagulant (LAC) caused by anti-beta(2)-glycoprotein I antibodies. ⋯ An increased frequency of thrombosis was not found in 33 patients with LAC independent of anti-beta(2)-glycoprotein I antibodies (odds ratio, 1.6; 95% confidence interval, 3.9-0.8). The use of an LAC assay with cardiolipin as confirming agent strongly improves the detection of patients at risk of thrombosis. Our findings suggest that anti-beta(2)-glycoprotein I antibodies with LAC activity are antibodies that are responsible for the thromboembolic complications in the antiphospholipid syndrome.
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Expression of the activating CD94/NKG2C killer lectin-like receptor (KLR) specific for HLA-E was analyzed in peripheral blood lymphocytes (PBLs) from healthy adult blood donors; the expression of other natural killer (NK) cell receptors (ie, CD94/NKG2A, KIR, CD85j, CD161, NKp46, NKp30, and NKG2D) was also studied. Human cytomegalovirus (HCMV) infection as well as the HLA-E and killer immunoglobulin-like receptor (KIR) genotypes were considered as potentially relevant variables associated with CD94/NKG2C expression. The proportion of NKG2C(+) lymphocytes varied within a wide range (<0.1% to 22.1%), and a significant correlation (r = 0.83; P < .001) between NKG2C(+) NK and T cells was noticed. ⋯ By contrast, a positive serology for HCMV, but not for other herpesviruses (ie, Epstein-Barr and herpes simplex), turned out to be strongly associated (P < .001) with increased proportions of NKG2C(+) NK and T cells. Remarkably, the CD94/NKG2C(+) population expressed lower levels of natural cytotoxicity receptors (NCRs) (ie, NKp30, NKp46) and included higher proportions of KIR(+) and CD85j(+) cells than CD94/NKG2A(+) cells. Altogether, these data support that HCMV infection selectively shapes the natural killer cell receptor (NKR) repertoire of NK and T cells from healthy carrier individuals.
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The deregulated, oncogenic tyrosine kinase Bcr-Abl causes chronic myeloid leukemia (CML). Imatinib mesylate (Gleevec, STI571), a Bcr-Abl kinase inhibitor, selectively inhibits proliferation and promotes apoptosis of CML cells. Despite the success of imatinib mesylate in the treatment of CML, resistance is observed, particularly in advanced disease. ⋯ Importantly, the low nanomolar cellular and biochemical inhibitory properties of AP23464 extend to frequently observed imatinib mesylate-resistant Bcr-Abl mutants, including nucleotide binding P-loop mutants Q252H, Y253F, E255K, C-terminal loop mutant M351T, and activation loop mutant H396P. AP23464 was ineffective against mutant T315I, an imatinib mesylate contact residue. The potency of AP23464 against imatinib mesylate-refractory Bcr-Abl and its distinct binding mode relative to imatinib mesylate warrant further investigation of AP23464 for the treatment of CML.