26 research outputs found

    The inhibition of FGF receptor 1 activity mediates sorafenib-induced antiproliferative effects in human mesothelioma tumor-initiating cells

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    Tumor-initiating cells (TICs), the subset of cells within tumors endowed with stem-like features, being highly resistant to conventional cytotoxic drugs, are the major cause of tumor relapse. The identification of molecules able to target TICs remains a significant challenge in cancer therapy. Using TIC-enriched cultures (MM1, MM3 and MM4), from 3 human malignant pleural mesotheliomas (MPM), we tested the effects of sorafenib on cell survival and the intracellular mechanisms involved. Sorafenib inhibited cell-cycle progression in all the TIC cultures, but only in MM3 and MM4 cells this effect was associated with induction of apoptosis via the down-regulation of Mcl-1. Although sorafenib inhibits the activity of several tyrosine kinases, its effects are mainly ascribed to Raf inhibition. To investigate the mechanisms of sorafenib-mediated antiproliferative activity, TICs were treated with EGF or bFGF causing, in MM3 and MM4 cells, MEK, ERK1/2, Akt and STAT3 phosphorylation. These effects were significantly reduced by sorafenib in bFGF-treated cells, while a slight inhibition occurred after EGF stimulation, suggesting that sorafenib effects are mainly due to FGFR inhibition. Indeed, FGFR1 phosphorylation was inhibited by sorafenib. A different picture was observed in MM1 cells, which, releasing high levels of bFGF, showed an autocrine activation of FGFR1 and a constitutive phosphorylation/activation of MEK-ERK1/2. A powerful inhibitory response to sorafenib was observed in these cells, indirectly confirming the central role of sorafenib as FGFR inhibitor. These results suggest that bFGF signaling may impact antiproliferative response to sorafenib of MPM TICs, which is mainly mediated by a direct FGFR targeting

    A Study of Parton Fragmentation in Hadronic Z0 Decays Using Lambda-Lambdabar Correlations

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    The correlated production of Lambda and Lambdabar baryons has been studied using 4.3 million multihadronic Zo decays recorded with the OPAL detector at LEP. Di-lambda pairs were investigated in the full data sample and for the first time also in 2-jet and 3-jet events selected with the k_t algorithm. The distributions of rapidity differences from correlated Lambda-Lambdabar pairs exhibit short-range, local correlations and prove to be a sensitive tool to test models, particularly for 2-jet events. The JETSET model describes the data best but some extra parameter tuning is needed to improve agreement with the experimental results in the rates and the rapidity spectra simultaneously. The recently developed modification of JETSET, the MOdified Popcorn Scenarium (MOPS), and also HERWIG do not give satisfactory results. This study of di-lambda production in 2- and 3-jet events supports the short-range compensation of quantum numbers.Comment: 23 pages, LaTeX, 6 figures included plus 1 in colour, submitted to Physics Letters

    Baylisascaris procyonis Roundworm Seroprevalence among Wildlife Rehabilitators, United States and Canada, 2012–2015

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    Baylisascaris procyonis roundworms can cause potentially fatal neural larva migrans in many species, including humans. However, the clinical spectrum of baylisascariasis is not completely understood. We tested 347 asymptomatic adult wildlife rehabilitators for B. procyonis antibodies; 24 were positive, suggesting that subclinical baylisascariasis is occurring among this population
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