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101.
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
102.
103.
When someone is choosing one piece from a bowl full of fruit, many pieces are within reach and visible. Although the desired piece seems to govern the particular pattern and direction of that person's reaching movement, the selection process is not impervious to the presence of task-irrelevant information (i.e. the other fruits). Evidence suggests that the kinematics of reach-to-grasp actions for a desired object integrates the motor features of all the objects which might become potential targets. Transcranial magnetic stimulation (TMS) and motor-evoked potentials (MEPs) were used by us to establish if that motor integration process can be transferred to an onlooker. Our results indicate that observation of hybrid reach-to-grasp movement kinematics is reflected in the observer's pattern of MEP amplitudes. This effect can be defined as a form of motor resonance which operates by 'reading' the kinematics of an observed action. The brain's ability to mirror motor integration processes while observing someone else's action helps an onlooker to understand what the other person is doing and to predict his/her motor alternatives. 相似文献
104.
Donato Traversa Annunziata Giangaspero Umberto Molini Raffaella Iorio Barbara Paoletti Domenico Otranto Carla Giansante 《Applied microbiology》2004,70(7):4367-4370
Chamelea gallina clams collected from the mouths of rivers along the Adriatic Sea (central Italy) were found to harbor Cryptosporidium parvum (genotype 2), which is the lineage involved in zoonotic transmission. The clams were collected from the mouths of rivers near whose banks ruminants are brought to graze. This paper reports the environmental spread of C. parvum in Italy and highlights the fact that genotyping of seaborne Cryptosporidium isolates is a powerful tool with which to investigate the transmission patterns and epidemiology of this microorganism. 相似文献
105.
Muscatello U 《Biochemical and biophysical research communications》2008,369(1):52-56
The object of this paper is to trace the growth of a fundamental problem that for a decade hindered the development of several lines of muscle research: the molecular mechanism that allows and controls contraction and relaxation of muscle fiber. Emphasis is placed on the difficulties to be overcome; thus the paper records not only the achievements and successes, but also the unavoidable failure and disappointments. The account highlights the essential contribution of Setsuro Ebashi to find the solution of the problem. 相似文献
106.
Peng Y Feng Q Wilk D Adjei AA Salavaggione OE Weinshilboum RM Yee VC 《Biochemistry》2008,47(23):6216-6225
Thiopurine S-methyltransferase (TPMT) modulates the cytotoxic effects of thiopurine prodrugs such as 6-mercaptopurine by methylating them in a reaction using S-adenosyl- l-methionine as the donor. Patients with TPMT variant allozymes exhibit diminished levels of protein and/or enzyme activity and are at risk for thiopurine drug-induced toxicity. We have determined two crystal structures of murine TPMT, as a binary complex with the product S-adenosyl- l-homocysteine and as a ternary complex with S-adenosyl- l-homocysteine and the substrate 6-mercaptopurine, to 1.8 and 2.0 A resolution, respectively. Comparison of the structures reveals that an active site loop becomes ordered upon 6-mercaptopurine binding. The positions of the two ligands are consistent with the expected S N2 reaction mechanism. Arg147 and Arg221, the only polar amino acids near 6-mercaptopurine, are highlighted as possible participants in substrate deprotonation. To probe whether these residues are important for catalysis, point mutants were prepared in the human enzyme. Substitution of Arg152 (Arg147 in murine TPMT) with glutamic acid decreases V max and increases K m for 6-mercaptopurine but not K m for S-adenosyl- l-methionine. Substitution at this position with alanine or histidine and similar substitutions of Arg226 (Arg221 in murine TPMT) result in no effect on enzyme activity. The double mutant Arg152Ala/Arg226Ala exhibits a decreased V max and increased K m for 6-mercaptopurine. These observations suggest that either Arg152 or Arg226 may participate in some fashion in the TPMT reaction, with one residue compensating when the other is altered, and that Arg152 may interact with substrate more directly than Arg226, consistent with observations in the murine TPMT crystal structure. 相似文献
107.
Molecular characteristics of small intestinal and renal brush border thiamin transporters in rats. 总被引:1,自引:0,他引:1
Anna Verri Umberto Laforenza Giulia Gastaldi Marisa Tosco Gianguido Rindi 《Biochimica et biophysica acta》2002,1558(2):187-197
The molecular characteristics of thiamin (T) transport were studied in the small intestinal and renal brush border membrane vesicles of rats, using [(3)H]T at high specific activity. The effects of various chemical modifiers (amino acid blockers) on T uptake were examined and their specificity assessed. Treatment with the carboxylic specific blockers 1-cyclohexyl-3-(2-morpholinoethyl) carbodiimide metho-p-toluene sulfonate, (1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride and N-ethyl-5-phenylisoaxolium-3'-sulfonate (Woodward's Reagent K) and with the sulfhydryl specific blocker p-chloromercuribenzene sulfonate inhibited T transport in both types of vesicles. Phenylglyoxal, but not ninhydrin, both reagents for arginine residues, and diethylpyrocarbonate, a reagent for histidine residues, specifically decreased T transport only in renal and small intestinal vesicles respectively. Similarly 7-chloro-4-nitrobenzo-2-oxa-1,3-diazole reacted, but not N-acetylimidazole, both of which are reagents for tyrosine residues. However, 7-chloro-4-nitrobenzo-2-oxa-1,3-diazole inhibition was aspecific. Acetylsalicylic acid, a reagent for lysine and serine residues, decreased T transport, but the lysine effect was aspecific. Acetylsalicylic acid serine blockage also eliminated T/H(+) exchange in small intestinal vesicles. Taken together, these results suggest that for T transport carboxylic and sulfhydryl groups and serine residues are essential in both renal and small intestinal brush border membrane vesicles. In addition, arginine and histidine residues are also essential respectively for renal and small intestinal transporters. Serine was essential for the T/H(+) antiport mechanism. 相似文献
108.
109.
The self-organization of fluorescent dyes and receptors on a proper template to form an organized assembly is a new strategy for the realization of fluorescence chemosensors. In the assembly, the two subunits do not interact directly and the communication between the bound substrate and the dye is only determined by their spatial closeness ensured by the template. The method is simple and the main advantages are related to the minimization of the synthetic work, the ease of modification and optimization of the sensor, the possibility to tune its properties by the simple adjustment of the components ratio. Self-organizing methodologies can open new perspectives to fluorescence chemosensors, both by allowing a simplified preparation and by opening the way to new and more complex functions. This article deals with this new approach and discusses its evolution, applications, and limitations. 相似文献
110.
P. Pellegrini Anna Maria Berghella T. Del Beato Sergio Cicia Domenico Adorno Carlo Umberto Casciani 《Cancer immunology, immunotherapy : CII》1996,42(1):1-8
Recent theories have established that, during an ongoing immune response, the lymphokines produced by TH1 and TH2 subsets
of CD4+ T cells are critical to the effectiveness of that response. In vivo and in vitro studies have demonstrated that the type
of environmental cytokines plays a determinant role in directing the development of naive T cells into TH1 or TH2 effector
cells. Disregulated expansion of one or other subset may contribute to the development of certain diseases. To establish whether
a similar situation might exist in the cells of the peripheral blood (PBMC) of colorectal cancer patients, we have performed
immunological studies on a group of patients and a group of healthy subjects. We examined the interleukin-2 (IL-2), interferon
γ (IFNγ), IL-4, IL-6 and tumour necrosis factor α levels in serum; the production of IL-4 and IL-2, with and without activating
agents, by PBMC, tumour-draining lymph node lymphocytes and tumour cells; and the proliferative response of PBMC to IL-2,
IL-4 and anti-CD3 monoclonal antibody (anti-CD3), which were variously combined. The data of the present study lead us to
hypothesize that, because of suppressive effects probably due to environmental IL-4, in the peripheral blood of patients there
seems to be a disregulation in the functionality of TH1 and TH2 subsets of CD4+ T cells, with an expansion in TH2 and a malfunction in TH1 cells. Moreover it seems that this disregulation increases with
as the disease progresses through the stages, suggesting that it can be directly implicated in the mechanisms that allow the
tumour to locate and progress in the host.
Received: 27 June 1995 / Accepted: 13 November 1995 相似文献