Mastocytosis is associated with an activating mutation in the KIT oncoprotein (KIT D816V ) that results in autophosphorylation of the KIT receptor in a ligandindependent manner. This mutation is inherently resistant to imatinib and, to date, there remains no effective curative therapy for systemic mastocytosis associated with KIT D816V . Dasatinib (BMS-354825) is a novel orally bioavailable SRC/ ABL inhibitor that has activity against multiple imatinib-resistant BCR-ABL isoforms in vitro that is presently showing considerable promise in early-phase clinical trials of chronic myeloid leukemia (CML). Pharmacokinetic analysis suggests that high nanomolar concentrations of dasatinib can be achieved safely in humans. In this study, we demonstrate significant inhibitory activity of dasatinib against both wild-type KIT and the KIT D816V mutation in the nanomolar range in in vitro and cell-based kinase assays. Additionally, dasatinib leads to growth inhibition of a KIT D816V -harboring human mastocytosis cell line. Significantly, dasatinib selectively kills primary neoplastic bone marrow mast cells from patients with systemic mastocytosis while sparing other hematopoietic cells. Computer modeling suggests that the KIT D816V mutation destabilizes the inactive conformation of the KIT activation loop to which imatinib binds, but it is not predicted to impair binding of KIT IntroductionSystemic mastocytosis and mast-cell leukemia are relatively rare conditions that are characterized by a pathologic accumulation of mast cells in various tissues. 1 Previous work has demonstrated the clonal nature of the disorder as evidenced by an activating point mutation in the KIT receptor tyrosine kinase. 2,3 This mutation, KIT D816V , occurs near the activation loop of the kinase and can be identified in more than 80% of systemic mastocytosis cases and thus represents an attractive target for this disorder, for which few effective therapeutic options exist. 1 Although a small molecule tyrosine kinase inhibitor of KIT, imatinib mesylate, has been available to patients recently, both preclinical and clinical studies have demonstrated convincingly that the KIT D816V mutation is inherently resistant to imatinib. [4][5][6] The crystal structure of the wild-type KIT kinase domain has been solved in an autoinhibited state, with the activation loop of the kinase in a closed conformation, 7 similar to the cocrystal structure of imatinib bound to the ABL kinase domain. 7,8 These structural studies suggest that substitution of valine for aspartic acid at position 816 in KIT may alter the conformation of the activation loop and thus prevent imatinib from efficiently binding to KIT D816V .Inhibition of KIT D816V has thus become the focus of recent studies aiming to find a curative therapy for mast-cell disease, and several potential drug candidates with an ability to inhibit KIT D816V have been identified. [9][10][11][12][13][14][15] Dasatinib (BMS-354825) is a novel, potent, oral, multitargeted kinase inhibitor that targets ABL, SRC, KIT, PDGFR, ...

BackgroundRecent guidelines on iron deficiency anaemia (IDA) have confirmed the aetiological role of Helicobacter pylori (H pylori), but the relationship still remains controversial.MethodsStarting in May 2009, searches of the following databases were undertaken: Medline (1966 to April 2009), Embase (1980 to April 2009), the Cochrane library (1800 to June 2008), Cochrane Central Register of Controlled Trials, Premedline, Healthstar, CBMdisc and the Chinese National Knowledge Infrastructure Database (January 1970 to April 2009). Changes in haemoglobin (Hb) concentrations and serum ferritin (SF) concentrations were recorded for intervention and control groups. The meta-analysis used random effect models and subgroup analyses were performed to explain heterogeneity.ResultsEight studies met the inclusion criteria. All studies were performed in Asia, an area with a high incidence of IDA and H pylori. The pooled analysis of eight studies showed that H pylori eradication therapy can improve IDA, since changes in Hb and SF concentrations in the intervention groups were higher than in controls. The weighted mean difference (WMD) of Hb was 12.88 g/l (95% CI 6.03 to 19.74 g/l, p<0.00001); the WMD of SF was 10.05 μg/l (95% CI 5.48 to 14.63 μg/l, p<0.00001).ConclusionsH pylori eradication therapy combined with iron administration is more effective than iron administration alone for the treatment of IDA. Eradication therapy has different effects on adults and children. Bismuth based triple therapy has a better response in terms of increased Hb and SF concentrations than proton pump inhibitor (PPI) based triple therapy.