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101.
Drumo R Widmer G Morrison LJ Tait A Grelloni V D'Avino N Pozio E Cacciò SM 《Applied and environmental microbiology》2012,78(10):3523-3529
Recent studies have revealed extensive genetic variation among isolates of Cryptosporidium parvum, an Apicomplexan parasite that causes gastroenteritis in both humans and animals worldwide. The parasite's population structure is influenced by the intensity of transmission, the host-parasite interaction, and husbandry practices. As a result, C. parvum populations can be panmictic, clonal, or even epidemic on both a local scale and a larger geographical scale. To extend the study of C. parvum populations to an unexplored region, 173 isolates of C. parvum collected in Italy from humans and livestock (calf, sheep, and goat) over a 10-year period were genotyped using a multilocus scheme based on 7 mini- and microsatellite loci. In agreement with other studies, extensive polymorphism was observed, with 102 distinct multilocus genotypes (MLGs) identified among 173 isolates. The presence of linkage disequilibrium, the confinement of MLGs to individual farms, and the relationship of many MLGs inferred using network analysis (eBURST) suggest a predominantly clonal population structure, but there is also evidence that part of the diversity can be explained by genetic exchange. MLGs from goats were found to differ from bovine and sheep MLGs, supporting the existence of C. parvum subpopulations. Finally, MLGs from isolates collected between 1997 and 1999 were also identified as a distinct subgroup in principal-component analysis and eBURST analysis, suggesting a continuous introduction of novel genotypes in the parasite population. 相似文献
102.
Sanchez RM Erhard K Hardwicke MA Lin H McSurdy-Freed J Plant R Raha K Rominger CM Schaber MD Spengler MD Moore ML Yu H Luengo JI Tedesco R Rivero RA 《Bioorganic & medicinal chemistry letters》2012,22(9):3198-3202
A series of 1,2,4-triazolo[1,5-a]pyrimidin-7(3H)-ones with excellent enzyme inhibition, improved isoform selectivity, and excellent inhibition of downstream phosphorylation of AKT has been identified. Several compounds in the series demonstrated potent (~ 0.100 μM IC(50)) growth inhibition in a PTEN deficient cancer cell line. 相似文献
103.
Colombo F Tintori C Furlan A Borrelli S Christodoulou MS Dono R Maina F Botta M Amat M Bosch J Passarella D 《Bioorganic & medicinal chemistry letters》2012,22(14):4693-4696
The use of Cu(I)-catalyzed azide-alkyne 1,3-dipolar cycloaddition permitted the synthesis of a new compound that is able to inhibit the HGF-induced scattering of MDCK (epithelial cells) and in vitro tumorigenesis of H1437 (non-small-cell lung cancer) and GTL-16 (human gastric carcinoma). In agreement with biochemical and biological results, docking studies within the ATP binding site of Met suggested for the new synthesized compound a binding mode similar to that of the active compound Triflorcas previously reported. 相似文献
104.
105.
AW Solomon D Engels RL Bailey IM Blake S Brooker JX Chen JH Chen TS Churcher CJ Drakeley T Edwards A Fenwick M French AF Gabrielli NC Grassly EM Harding-Esch MJ Holland A Koukounari PJ Lammie J Leslie DC Mabey M Rhajaoui WE Secor JR Stothard H Wei AL Willingham XN Zhou RW Peeling 《PLoS neglected tropical diseases》2012,6(7):e1746
106.
Benicchi T Iozzi S Svahn A Axelsson H Mori E Bernocco S Cappelli F Caramelli C Fanti P Genesio E Maccari L Markova N Micco I Porcari V Schultz J Fecke W 《Journal of biomolecular screening》2012,17(7):933-945
The TWEAK-Fn14 pathway is upregulated in models of inflammation, autoimmune diseases, and cancer. Both TWEAK and Fn14 show increased expression also in the CNS in response to different stimuli, particularly astrocytes, microglia, and neurons, leading to activation of NF-κB and release of proinflammatory cytokines. Although neutralizing antibodies against these proteins have been shown to have therapeutic efficacy in animal models of inflammation, no small-molecule therapeutics are yet available. Here, we describe the development of a novel homogeneous time-resolved fluorescence (HTRF)-based screening assay together with several counterassays for the identification of small-molecule inhibitors of this protein-protein interaction. Recombinant HIS-TWEAK and Fn14-Fc proteins as well as FLAG-TWEAK and Fn14-FLAG proteins and an anti-Fn14 antibody were used to establish and validate these assays and to screen a library of 60 000 compounds. Two HTRF counterassays with unrelated proteins in the same assay format, an antiaggregation assay and a redox assay, were applied to filter out potential false-positive compounds. The novel assay and associated screening cascade should be useful for the discovery of small-molecule inhibitors of the TWEAK-Fn14 protein interaction. 相似文献
107.
Vaschetto R Kroumova V Olivieri C Bergamaschi V Cancelliere L Borrè S Fortina G Navalesi P Della Corte F 《The new microbiologica》2012,35(1):77-82
A 22-year-old insulin-dependent diabetic male was admitted for diabetic ketoacidosis. He developed hospital-acquired pneumonia (HAP) for which empirical antibiotic and antifungal therapy was started on the ward. On day 6, clinical and laboratory findings worsened, and bronchoalveolar lavage (BAL) was performed. Serum real time-polymerase chain reaction (RT-PCR) indicated invasive pulmonary aspergillosis (IPA) and led to antifungal therapy being initiated 48 hours before the results of the BAL culture were available. Despite early appropriate antifungal therapy, however, the patient died on day 22 while being supported by venovenous extracorporeal membrane oxygenation. 相似文献
108.
Alessandro Furlan Benjamin Roux Fabienne Lamballe Filippo Conti Nathalie Issaly Fabrice Daian Jean-Fran?ois Guillemot Sylvie Richelme Magali Contensin Joan Bosch Daniele Passarella Oreste Piccolo Rosanna Dono Flavio Maina 《PloS one》2012,7(10)
The development of targeted molecular therapies has provided remarkable advances into the treatment of human cancers. However, in most tumors the selective pressure triggered by anticancer agents encourages cancer cells to acquire resistance mechanisms. The generation of new rationally designed targeting agents acting on the oncogenic path(s) at multiple levels is a promising approach for molecular therapies. 2-phenylimidazo[2,1-b]benzothiazole derivatives have been highlighted for their properties of targeting oncogenic Met receptor tyrosine kinase (RTK) signaling. In this study, we evaluated the mechanism of action of one of the most active imidazo[2,1-b]benzothiazol-2-ylphenyl moiety-based agents, Triflorcas, on a panel of cancer cells with distinct features. We show that Triflorcas impairs in vitro and in vivo tumorigenesis of cancer cells carrying Met mutations. Moreover, Triflorcas hampers survival and anchorage-independent growth of cancer cells characterized by “RTK swapping” by interfering with PDGFRβ phosphorylation. A restrained effect of Triflorcas on metabolic genes correlates with the absence of major side effects in vivo. Mechanistically, in addition to targeting Met, Triflorcas alters phosphorylation levels of the PI3K-Akt pathway, mediating oncogenic dependency to Met, in addition to Retinoblastoma and nucleophosmin/B23, resulting in altered cell cycle progression and mitotic failure. Our findings show how the unusual binding plasticity of the Met active site towards structurally different inhibitors can be exploited to generate drugs able to target Met oncogenic dependency at distinct levels. Moreover, the disease-oriented NCI Anticancer Drug Screen revealed that Triflorcas elicits a unique profile of growth inhibitory-responses on cancer cell lines, indicating a novel mechanism of drug action. The anti-tumor activity elicited by 2-phenylimidazo[2,1-b]benzothiazole derivatives through combined inhibition of distinct effectors in cancer cells reveal them to be promising anticancer agents for further investigation. 相似文献
109.
110.
Akselsen OW Odlo K Cheng JJ Maccari G Botta M Hansen TV 《Bioorganic & medicinal chemistry》2012,20(1):234-242
The synthesis, cytotoxicity, inhibition of tubulin polymerization data and anti-angiogenetic effects of seven 1,5-disubstituted 1,2,3-triazole analogs and two 1,4-disubstituted 1,2,3-triazole analogs of combretastatin A-1 (1) are reported herein. The biological studies revealed that the 1,5-disubstituted 1,2,3-triazoles 3-methoxy-6-(1-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)benzene-1,2-diol (6), 3-methoxy-6-(1-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)benzene-1,2-diamine (8) and 5-(2,3-difluoro-4-methoxyphenyl)-1-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazole (9) were the three most active compounds regarding inhibition of both tubulin polymerization and angiogenesis. Molecular modeling studies revealed that combretastatins 1 and 2 and analogs 5-11 could be successfully docked into the colchicine binding site of α,β-tubulin. 相似文献