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Alessandra Monaco Vincent Zoete Gian Carlo Alghisi Curzio Rüegg Olivier Michelin John Prior Leonardo Scapozza Yann Seimbille 《Bioorganic & medicinal chemistry letters》2013,23(22):6068-6072
The development of RGD-based antagonist of αvβ3 integrin receptor has enhanced the interest in PET probes to image this receptor for the early detection of cancer, to monitor the disease progression and the response to therapy. In this work, a novel prosthetic group (N-(4-fluorophenyl)pent-4-ynamide or FPPA) for the 18F-labeling of an αvβ3 selective RGD-peptide was successfully prepared. [18F]FPPA was obtained in three steps with a radiochemical yield of 44% (decay corrected). Conjugation to c(RGDfK(N3)) by the Cu(II) catalyzed Huisgen azido alkyne cycloaddition provided the [18F]FPPA-c(RGDfK) with a radiochemical yield of 29% (decay corrected), in an overall synthesis time of 140 min. 相似文献
74.
Inês Sofia Vala Leila R. Martins Natsuko Imaizumi Raquel J. Nunes José Rino Fran?ois Kuonen Lara M. Carvalho Curzio Rüegg Isabel Monteiro Grillo Jo?o Taborda Barata Marc Mareel Susana Constantino Rosa Santos 《PloS one》2010,5(6)
Radiotherapy is a widely used treatment option in cancer. However, recent evidence suggests that doses of ionizing radiation (IR) delivered inside the tumor target volume, during fractionated radiotherapy, can promote tumor invasion and metastasis. Furthermore, the tissues that surround the tumor area are also exposed to low doses of IR that are lower than those delivered inside the tumor mass, because external radiotherapy is delivered to the tumor through multiple radiation beams, in order to prevent damage of organs at risk. The biological effects of these low doses of IR on the healthy tissue surrounding the tumor area, and in particular on the vasculature remain largely to be determined. We found that doses of IR lower or equal to 0.8 Gy enhance endothelial cell migration without impinging on cell proliferation or survival. Moreover, we show that low-dose IR induces a rapid phosphorylation of several endothelial cell proteins, including the Vascular Endothelial Growth Factor (VEGF) Receptor-2 and induces VEGF production in hypoxia mimicking conditions. By activating the VEGF Receptor-2, low-dose IR enhances endothelial cell migration and prevents endothelial cell death promoted by an anti-angiogenic drug, bevacizumab. In addition, we observed that low-dose IR accelerates embryonic angiogenic sprouting during zebrafish development and promotes adult angiogenesis during zebrafish fin regeneration and in the murine Matrigel assay. Using murine experimental models of leukemia and orthotopic breast cancer, we show that low-dose IR promotes tumor growth and metastasis and that these effects were prevented by the administration of a VEGF receptor-tyrosine kinase inhibitor immediately before IR exposure. These findings demonstrate a new mechanism to the understanding of the potential pro-metastatic effect of IR and may provide a new rationale basis to the improvement of current radiotherapy protocols. 相似文献
75.
Joseph B. Mascarenhas Markus A. Rüegg Takako Sasaki Johannes A. Eble Jürgen Engel Jrg Stetefeld 《Matrix biology》2005,23(8):507-513
Agrin is a key organizer for postsynaptic differentiation at the neuromuscular junction (NMJ). This activity requires the binding of agrin to the synaptic basal lamina via its N-terminal (NtA) domain. It has been suggested that this binding is mediated by conserved amino acids in the gamma 1 chain of laminin. Here, we report the crystal structure of chicken NtA expressed in eukaryotic HEK293 cells. In contrast to the previously published structure [Stetefeld, J., Jenny, M., Schulthess, T., Landwehr, R., Schumacher, B., Frank, S., Ruegg, M.A., Engel, J., Kammerer, R.A., 2001. The laminin-binding domain of agrin is structurally related to N-TIMP-1. Nat. Struct. Biol., 8, 705-709.], which was derived from the NtA domain expressed in E. coli, the new data show that the N-terminal tail region (amino acid residues Asn1-Arg5) is highly structured. Moreover, the disulfide bridge between Cys2 and Cys74 was also present. In addition, we show that the binding of NtA requires the gamma 1 chain of laminin and is not greatly affected by the composition of beta chains. These results confirm a model of the NtA-laminin complex where conserved amino acids in the gamma 1 chain are prerequisite for the binding to agrin and they further emphasize that the source of protein can be critical in structure determination. 相似文献
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The thermal properties of the beta-lactoglobulin-water system were investigated by differential scanning calorimetry in the temperature range from -50 to 130 degrees C. Determination of the heat and temperature of fusion of the absorbed water allowed resolution of the water into four different states. The amounts of water in these states were different for samples before and after heat denaturation. In the case of denatured beta-lactoglobulin, a smaller amount of water with thermal properties different from ordinary water was observed and its total water binding capacity was lower. The thermal stability of beta-lactoglobulin in the water content range from 0 to 0.75 g/g showed a strong dependence on the degree of hydration. A correlation was observed between the changes in the thermal stability of the protein and the changes in the state of the absorbed water. The results are compared with those obtained from similar measurements of other globular proteins and of fibrillar proteins. 相似文献
78.
Infrared spectra of as-, beta- and micellar casein were studied at relative water vapor pressures (p/po) ranging from 0 to 0.98. The samples were prepared as self-supporting films by evaporating concentrated aqueous suspensions of the caseins under study. An infrared cell and a vacuum apparatus were constructed which allowed exposure of the casein films either to vacuum or to sorbate vapor. Following the increase in intensities of the OH and O2H absorption bands during hydration, a sigmoid-shaped curve was observed, similar to the type II isotherm usually obtained by gravimetric sorption measurements. The pronounced frequency and intensity changes in the amide I, II and III bands in the p/po range from 0 to about 0.10 lead to the conclusion that water molecules are already attached to the peptide repeat unit at very low humidities. Based on calculations of the amount of polar groups per casein molecule it was shown that much less than one water molecule per polar group is needed to cause these significant spectral changes. 相似文献
79.
80.
Caroline Huzé Pascale Richard Evelyne Goillot Asma Ben Ammar Annie Chaboud Heba-Aude Lecuyer Andrée Rouche Thierry Kuntzer Emmanuel Fournier Markus A. Rüegg Bruno Eymard Laurent Schaeffer 《American journal of human genetics》2009,85(2):155-167
We report the case of a congenital myasthenic syndrome due to a mutation in AGRN, the gene encoding agrin, an extracellular matrix molecule released by the nerve and critical for formation of the neuromuscular junction. Gene analysis identified a homozygous missense mutation, c.5125G>C, leading to the p.Gly1709Arg variant. The muscle-biopsy specimen showed a major disorganization of the neuromuscular junction, including changes in the nerve-terminal cytoskeleton and fragmentation of the synaptic gutters. Experiments performed in nonmuscle cells or in cultured C2C12 myotubes and using recombinant mini-agrin for the mutated and the wild-type forms showed that the mutated form did not impair the activation of MuSK or change the total number of induced acetylcholine receptor aggregates. A solid-phase assay using the dystrophin glycoprotein complex showed that the mutation did not affect the binding of agrin to α-dystroglycan. Injection of wild-type or mutated agrin into rat soleus muscle induced the formation of nonsynaptic acetylcholine receptor clusters, but the mutant protein specifically destabilized the endogenous neuromuscular junctions. Importantly, the changes observed in rat muscle injected with mutant agrin recapitulated the pre- and post-synaptic modifications observed in the patient. These results indicate that the mutation does not interfere with the ability of agrin to induce postsynaptic structures but that it dramatically perturbs the maintenance of the neuromuscular junction. 相似文献