Citations

Abstract Gain-of-function mutations of the receptor tyrosine kinase KIT play a key role in the pathogenesis of systemic mastocytosis (SM), gastrointestinal stromal tumors (GISTs), and some cases of acute myeloid leukemia (AML). Whereas KIT juxtamembrane domain mutations seen in most patients with GIST are highly sensitive to imatinib, the kinase activation loop mutant D816V, frequently encountered in SM, hampers the binding ability of imatinib. We investigated the inhibitory activity of the novel tyrosine kinase inhibitor EXEL-0862 against 2 subclones of human mast cell line-1 (HMC-1)—HMC-1.1, harboring the juxtamembrane domain mutation V560G, and HMC-1.2, carrying V560G and the activation loop mutation D816V, found in more than 80% of patients with SM. EXEL-0862 inhibited the phosphorylation of KIT in a dose-dependent manner and decreased cell proliferation in both mast cell lines with higher activity against HMC-1.2 cells. The phosphorylation of KIT-dependent signal transducer and activator of transcription-3 (STAT3) and STAT5 was abrogated upon exposure to nanomolar concentrations of EXEL-0862. In addition, EXEL-0862 induced a time- and dose-dependent proapoptotic effect in both mast cell lines and caused a significant reduction in mast-cell content in bone marrow samples from patients with SM harboring D816V and from those without the D816V mutation. We conclude that EXEL-0862 is active against KIT activation loop mutants and is a promising candidate for the treatment of patients with SM and other KIT-driven malignancies harboring active site mutations.

Objective— We assessed the clinical significance of intima (IT), media (MT), and intima–media (IMT) thickness of the common carotid artery using B-mode ultrasonographic image processing. Methods and Results— One hundred seventy consecutive patients underwent common carotid artery scanning using high-resolution ultrasonography. A total of 150 patients could be analyzed off-line using ultrasonographic image processing, devised for individual measurement of IT, MT, and IMT. By univariate analysis, IT (range, 0.27 to 0.41 mm) was associated with age, whereas MT (range, 0.27 to 0.74 mm) and IMT (range, 0.49 to 1.12 mm) were associated with age, fibrinogen, and creatinine. Among atherosclerosis risk factors, hypertension was associated with thickness of all 3 layers, whereas smoking was associated with IT only. By multivariate analysis, IT was associated with age, hypertension, and smoking, whereas MT and IMT were associated with age, hypertension, and blood urea nitrogen level. Conclusions— Carotid IT is associated with smoking, whereas age and hypertension are associated with thickness of all 3 arterial layers. Our results suggest a differential response of the vasculature to systemic risk factors.

Objective— We evaluated the role of lipoprotein-associated phospholipase A 2 (Lp-PLA 2 ), an inflammatory biomarker, in defining risk after myocardial infarction (MI). Methods and Results— Olmsted County, Minn, residents who experienced an MI meeting standardized criteria between 2003 and 2005 (n=271) were prospectively identified and followed. Lp-PLA 2 levels were measured at baseline and evaluated along with traditional risk indicators. Lp-PLA 2 was modestly associated with total and low-density lipoprotein cholesterol, smoking, and age (inversely) but not with MI characteristics or severity, comorbidities, C-reactive protein, or the time from symptom onset to blood sampling. During the first year of follow-up, 42 deaths occurred. The survival estimates (95% confidence intervals [CI]) at 1 year were 92% (86% to 98%), 85% (78% to 93%), and 74% (65% to 84%) in the lowest, middle, and upper Lp-PLA 2 tertiles, respectively ( P =0.007). After adjustment for age and sex, the hazard ratios for death in the middle and upper Lp-PLA 2 tertiles were 2.20 (95% CI: 0.88 to 5.54) and 4.93 (95% CI: 2.10 to 11.60), compared with the lowest tertile, respectively ( P trend <0.001). Further adjustment for other risk indicators resulted in even stronger associations. Lp-PLA 2 also contributed to risk discrimination as indicated by the increases in the area under the receiver operating characteristic curves obtained in each of the models examined (all P ≤0.05). Conclusions— Among community subjects presenting with MI, increased Lp-PLA 2 levels measured early after MI are strongly and independently associated with mortality and provide incremental value in risk discrimination over traditional predictors.