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 (0.5 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 0.5 nM of dasatinib, in particular, those characterized by BCR–ABL 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 BCR–ABL or KIT mutations

Transverse-momentum and pseudorapidity distributions of charged hadrons in pp collisions at √s=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 √s=7  TeV 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/dη||η|<0.5=5.78±0.01(stat)±0.23(syst) for non-single-diffractive events, higher than predicted by commonly used models. The relative increase in charged-particle multiplicity from √s=0.9 to 7 TeV is [66.1±1.0(stat)±4.2(syst)]%. The mean transverse momentum is measured to be 0.545±0.005(stat)±0.015(syst)  GeV/c. The results are compared with similar measurements at lower energies

Adaptor protein Lnk binds to PDGF receptor and inhibits PDGF-dependent signaling

10.1016/j.exphem.2011.02.001Experimental Hematology395591-600EXHE

Molecular investigation of lymph nodes in patients with colon cancer: a new road to better staging

Objective: Small nodal tumor infiltrates are identified by applying multilevel sectioning and immunohistochemistry (IHC) in addition to H&amp;E (hematoxylin and eosin) stains of resected lymph nodes. However, the use of multilevel sectioning and IHC is very time-consuming and costly. The current standard analysis of lymph nodes in colon cancer patients is based on one slide per lymph node stained by H&amp;E. A new molecular diagnostic system called ''One tep Nucleic Acid Amplification'' (OSNA) was designed for a more accurate detection of lymph node metastases. The objective of the present investigation was to compare the performance ofOSNAto current standard histology (H&amp;E). We hypothesize that OSNA provides a better staging than the routine use of one slide H&amp;E per lymph node.Methods: From 22 colon cancer patients 307 frozen lymph nodes were used to compare OSNA with H&amp;E. The lymph nodes were cut into halves. One half of the lymph node was analyzed by OSNA. The semi-automated OSNA uses amplification of reverse-transcribed cytokeratin19 (CK19) mRNA directly from the homogenate. The remaining tissue was dedicated to histology, with 5 levels of H&amp;E and IHC staining (CK19).Results: On routine evaluation of oneH&amp;Eslide 7 patients were nodal positive (macro-metastases). All these patients were recognized by OSNA analysis as being positive (sensitivity 100%). Two of the remaining 15 patients had lymph node micro-metastases and 9 isolated tumor cells. For the patients with micrometastases both H&amp;E and OSNA were positive in 1 of the 2 patients. For patients with isolated tumor cells, H&amp;E was positive in 1/9 cases whereas OSNA was positive in 3/9 patients (IHC as a reference). There was only one case to be described as IHC negative/OSNA positive. On the basis of single lymph nodes the sensitivity of OSNA and the 5 levels of H&amp;E and IHC was 94・5%.Conclusion: OSNA is a novel molecular tool for the detection of lymph node metastases in colon cancer patients which provides better staging compared to the current standard evaluation of one slide H&amp;E stain. Since the use of OSNA allows the analysis of the whole lymph node, sampling bias and undetected tumor deposits due to uninvestigated material will be overcome. OSNA improves staging in colon cancer patients and may replace the current standard of H&amp;E staining in the future

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

Adaptor protein Lnk inhibits c-Fms-mediated macrophage function

Lnk physically interacts with c-Fms and blunts its activity in-cluding proliferation of macrophage progenitor cells, M-CSF stimulated migration, and generaton of ROS