Key Points• Imatinib-resistant/-intolerant patients with chronic myeloid leukemia in chronic phase can experience long-term benefit with dasatinib.• Early (3-and 6-month) molecular and cytogenetic responses were associated with improved progression-free survival and overall survival.We present long-term follow-up of a dasatinib phase 3 study of patients with imatinibresistant/-intolerant chronic myeloid leukemia (CML). In the CA180-034 study, 670 patients with imatinib-resistant/-intolerant CML in chronic phase (CML-CP) received dasatinib 100 mg once daily, 50 mg twice daily, 140 mg once daily, or 70 mg twice daily. At 6 years, 188 (28%) of 670 patients remained on study treatment. Estimated 6-year protocol-defined progression-free survival (PFS) rates were 49%, 51%, 40%, and 47%, respectively, and estimated 6-year overall survival (OS) rates were 71%, 74%, 77%, and 70%, respectively (intent-to-treat population, including protocol-defined progression or death after discontinuation). Estimated 6-year rates of survival without transformation on study treatment were 76%, 80%, 83%, and 74%, respectively. Major molecular response was achieved in 43% (100 mg once daily) and 40% (all other arms) of patients by 6 years. Molecular and cytogenetic responses at 3 and 6 months were highly predictive of PFS and OS. Notably, estimated 6-year PFS rates based on £1%, >1% to 10%, and >10% BCR-ABL transcripts at 3 months were 68%, 58%, and 26%, respectively. Most adverse events occurred by 2 years. Imatinib-resistant/-intolerant patients with CML-CP can experience long-term benefit with dasatinib therapy, particularly if achieving BCR-ABL £10% at 3 months. This study was registered at ClinicalTrials.gov: NCT00123474. (Blood. 2014;123(15):2317-2324

Endothelin-1 and endothelin-4 may activate leukocytes after shock or gut ischemia, resulting in further injury to reperfused tissues and distant injury to lungs and other organs.

Agonist-generated inside-out signals enable the platelet integrin ␣ IIb ␤ 3 to bind soluble ligands such as fibrinogen. We found that inhibiting actin polymerization in unstimulated platelets with cytochalasin D or latrunculin A mimics the effects of platelet agonists by inducing fibrinogen binding to ␣ IIb ␤ 3 . By contrast, stabilizing actin filaments with jasplakinolide prevented cytochalasin D-, latrunculin A-, and ADP-induced fibrinogen binding. Cytochalasin D-and latrunculin A-induced fibrinogen was inhibited by ADP scavengers, suggesting that subthreshold concentrations of ADP provided the stimulus for the actin filament turnover required to see cytochalasin D and latrunculin A effects. Gelsolin, which severs actin filaments, is activated by calcium, whereas the actin disassembly factor cofilin is inhibited by serine phosphorylation. Consistent with a role for these factors in regulating ␣ IIb ␤ 3 function, cytochalasin D-and latrunculin A-induced fibrinogen binding was inhibited by the intracellular calcium chelators 1,2-bis(2-aminophenoxy)ethane-N,N,N,N-tetraacetic acid acetoxymethyl ester and EGTA acetoxymethyl ester and the Ser/Thr phosphatase inhibitors okadaic acid and calyculin A. Our results suggest that the actin cytoskeleton in unstimulated platelets constrains ␣ IIb ␤ 3 in a low affinity state. We propose that agonist-stimulated increases in platelet cytosolic calcium initiate actin filament turnover. Increased actin filament turnover then relieves cytoskeletal constraints on ␣ IIb ␤ 3 , allowing it to assume the high affinity conformation required for soluble ligand binding.The function of integrins in circulating blood cells is regulated by limiting their access to ligands. The prototypical example of this form of regulation is the platelet integrin ␣ IIb ␤ 3 since agonist-generated "inside-out" signals are required to enable ␣ IIb ␤ 3 to bind soluble ligands such as fibrinogen (1). Because the binding of soluble fibrinogen to ␣ IIb ␤ 3 is a prerequisite for platelet aggregation (2), regulating the affinity of ␣ IIb ␤ 3 for fibrinogen in this way assures that only stimulated platelets aggregate. It is likely that intracellular molecules regulate the function of ␣ IIb ␤ 3 by interacting with its cytoplasmic domains (3), but the identity of these molecules and how they interact with ␣ IIb ␤ 3 are not known.The actin cytoskeleton appears to play a role in regulating ␣ IIb ␤ 3 function. Thus, micromolar concentrations of cytochalasins, fungal metabolites that impair actin polymerization by binding to the barbed end of actin filaments (4), inhibit agonistinduced fibrinogen binding to ␣ IIb ␤ 3 on platelets (5-7), whereas nanomolar concentrations induce fibrinogen binding to recombinant ␣ IIb ␤ 3 expressed on the surface of B lymphocytes (8). In the work described in this paper, we used cytochalasin D (Cyto-D), 1 latrunculin A (Lat-A; another inhibitor of actin polymerization (9)), and jasplakinolide (a compound that stabilizes actin filaments (10)) to examine the role of actin filament turnover in...

Two classes of 5-substituted benzimidazoles were identified as potent antagonists of the NR2B subtype of the N-methyl-d-aspartate (NMDA) receptor. Selected compounds show very good selectivity versus the NR2A, NR2C, and NR2D subtypes of the NMDA receptor as well as versus hERG-channel activity and alpha(1)-adrenergic binding. Benzimidazole 37a shows excellent activity in the carrageenan-induced mechanical hyperalgesia assay in rats as well as good pharmacokinetic behavior in dogs.