19 research outputs found
Dasatinib impairs long-term expansion of leukemic progenitors in a subset of acute myeloid leukemia cases
A number of signaling pathways might be frequently disrupted in acute myeloid leukemia (AML). We questioned whether the dual SRC/ABL kinase inhibitor dasatinib can affect AML cells and whether differences can be observed with normal CD34+ cells. First, we demonstrated that normal cord blood (CB) CD34+ cells were unaffected by dasatinib at a low concentration (0.5Â nM) in the long-term culture on MS5 stromal cells. No changes were observed in proliferation, differentiation, and colony formation. In a subset of AML cases (3/15), a distinct reduction in cell proliferation was observed, ranging from 48% to 91% inhibition at 0.5Â nM of dasatinib, in particular, those characterized by BCRâABL or KIT mutations. Moreover, the inhibitory effects of dasatinib were cytokine specific. Stem cell factor-mediated proliferation was significantly impaired, associated with a reduced phosphorylation of ERK1/2 and STAT5, whereas no effect was observed on interleukin-3 and thrombopoietin-mediated signaling despite SRC activation. In conclusion, this study demonstrates that dasatinib is a potential inhibitor in a subgroup of AML, especially those that express BCRâABL or KIT mutations
Transverse-momentum and pseudorapidity distributions of charged hadrons in pp collisions at âs=7 TeV
This is the pre-print version of the Published Article which can be accessed from the link below.Charged-hadron transverse-momentum and pseudorapidity distributions in proton-proton collisions at âs=7ââTeV are measured with the inner tracking system of the CMS detector at the LHC. The charged-hadron yield is obtained by counting the number of reconstructed hits, hit pairs, and fully reconstructed charged-particle tracks. The combination of the three methods gives a charged-particle multiplicity per unit of pseudorapidity dNch/dΡ||Ρ|<0.5=5.78Âą0.01(stat)Âą0.23(syst) for non-single-diffractive events, higher than predicted by commonly used models. The relative increase in charged-particle multiplicity from âs=0.9 to 7 TeV is [66.1Âą1.0(stat)Âą4.2(syst)]%. The mean transverse momentum is measured to be 0.545Âą0.005(stat)Âą0.015(syst)ââGeV/c. The results are compared with similar measurements at lower energies
Identified hidden genomic changes in mantle cell lymphoma using high-resolution single nucleotide polymorphism genomic array
OBJECTIVE:
Mantle cell lymphoma (MCL) is a lymphoma characterized by aberrant activation of CCND1/cyclin D1 followed by sequential genetic abnormalities. Genomic abnormalities in MCL have been extensively examined by classical cytogenetics and microarray-based comparative genomic hybridization techniques, pointing out a number of alterations in genomic regions that correlate with the neoplastic phenotype and survival. Recently, single nucleotide polymorphism genomic microarrays (SNP-chip) have been developed and used for analysis of cancer genomics. This technique allows detection of genomic changes with higher resolution, including loss of heterozygosity without changes of gene dosage, so-called acquired uniparental disomy (aUPD).
MATERIALS AND METHODS:
We have examined 33 samples of MCL (28 primary MCL and 5 cell lines) using the 250,000 SNP-chip from Affymetrix.
RESULTS:
Known alterations were confirmed by SNP arrays, including deletion of INK4A/ARF, duplication/amplification of MYC, deletion of ATM, and deletion of TP53. We also identified a duplication/amplification that occurred at 13q involving oncogenic microRNA, miR17-92. We found other genomic abnormalities, including duplication/amplification of cyclin D1, del(1p), del(6q), dup(3q) and dup(18q). Our SNP-chip analysis detected these abnormalities at high resolution, allowing us to narrow the size of the commonly deleted regions, including 1p and 6q. Our SNP-chip analysis detected a number of aUPD sites, including whole chromosome 9 aUPD and 9p aUPD. We also found an MCL case with 19p, leading to homozygous deletion of TNFSF genes.
CONCLUSION:
SNP-chip analysis detected in MCL very small genomic gains/losses, as well as aUPDs, which could not be detected by more conventional methods
Total Synthesis, Stereochemical Assignment, and Biological Activity of All Known (â)-Trigonoliimines
A full account of our concise and enantioselective total syntheses of all known (â)-trigonoliimine alkaloids is described. Our retrobiosynthetic analysis of these natural products enabled identification of a single bistryptamine precursor as a precursor to all known trigonoliimines through a sequence of transformations involving asymmetric oxidation and reorganization. Our enantioselective syntheses of these alkaloids enabled the revision of the absolute stereochemistry of (â)-trigonoliimines A, B, and C. We report that trigonoliimines A, B, C and structurally related compounds showed weak anticancer activities against HeLa and U-937 cells.National Institute of General Medical Sciences (U.S.) (GM074825)EMD Serono, Inc. (Graduate Fellowship)Kenneth Gordon Summer Fellowshi