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1.
Jean-Emmanuel Bibault Sylvain Dewas Claire Vautravers-Dewas Antoine Hollebecque Hajer Jarraya Thomas Lacornerie Eric Lartigau Xavier Mirabel 《PloS one》2013,8(10)
Purpose
Stereotactic body radiation therapy (SBRT) for hepatocellular carcinoma (HCC) has been evaluated in several recent studies. The CyberKnife® is an SBRT system that allows for real-time tracking of the tumor. The purpose of this study was to evaluate the prognostic factors for local control and overall survival following this treatment.Patients and Methods
75 patients with 96 liver-confined HCC were treated with SBRT at the Oscar Lambret Comprehensive Cancer Center. Fiducials were implanted in the liver before treatment and were used as markers to track the lesion’s movement. Treatment response was scored according to RECIST v1.1. Local control and overall survival were calculated using the Kaplan and Meier method. A stepwise multivariate analysis (Cox regression) of prognostic factors was performed for local control and overall survival.Results
There were 67 patients with Child-Turcotte-Pugh (CTP) Class A and eight patients with CTP Class B. Treatment was administered in three sessions. A total dose of 40–45 Gy to the 80% isodose line was delivered. The median follow-up was 10 months (range, 3–49 months). The local control rate was 89.8% at 1 and 2 years. Overall survival was 78.5% and 50.4% at 1 and 2 years, respectively. Toxicity mainly consisted of grade 1 and grade 2 events. Higher alpha-fetoprotein (aFP) levels were associated with less favorable local control (HR=1.001; 95% CI [1.000, 1.002]; p=0.0063). A higher dose was associated with better local control (HR=0.866; 95% CI [0.753, 0.996]; p=0.0441). A Child-Pugh score higher than 5 was associated with worse overall survival (HR= 3.413; 95% CI [1.235, 9.435]; p=0.018).Conclusion
SBRT affords good local tumor control and higher overall survival rates than other historical controls (best supportive care or sorafenib). High aFP levels were associated with lesser local control, but a higher treatment dose improved local control. 相似文献2.
3.
Fertilization in Arabidopsis thaliana wild type: developmental stages and time course 总被引:1,自引:0,他引:1
Faure JE Rotman N Fortuné P Dumas C 《The Plant journal : for cell and molecular biology》2002,30(4):481-488
We describe some previously uncharacterised stages of fertilization in Arabidopsis thaliana and provide for the first time a precise time course of the fertilization process. We hand-pollinated wild type pistils with wild type pollen (Columbia ecotype), fixed them at various times after pollination, and analysed 600 embryo sacs using Confocal Laser Scanning Microscopy. Degeneration of one of the synergid cells starts at 5 Hours After Pollination (HAP). Polarity of the egg changes rapidly after this synergid degeneration. Karyogamy is then detected by the presence of two nucleoli of different diameters in both the egg and central cell nuclei, 7-8 HAP. Within the next hour, first nuclear division takes place in the fertilized central cell and two nucleoli can then be seen transiently in each nucleus produced. In a second set of experiments, we hand-pollinated wild type pistils with pollen from a transgenic promLAT52::EGFP line that expresses EGFP in its pollen vegetative cell. Release of the pollen tube contents into the synergid cell could be detected in living material. We show that the timing of synergid degeneration and pollen tube release correlate well, suggesting that either the synergid cell degenerates at the time of pollen tube discharge or very shortly before it. These observations and protocols constitute an important basis for the further phenotypic analysis of mutants affected in fertilization. 相似文献
4.
ObjectiveThe purpose of the study was to find the potential impact of the sunitinib on the captation of a tracer of the hypoxia, 18F-FMISO, on non tumoral tissues.Population and methodsIt was about a multicentric prospective study on 43 patients with advanced or metastatic renal cancer, treated with Sunitinib. 18F-FMISO PET/CT scan was performed before treatment, followed with a second PET/CT scan after 4 weeks of treatment with sunitinib.ResultsWe have shown a significant increase of FMISO captation under sunitinib in the lungs (p < 0.02) and the liver (p < 0.001). We have also found a significant increase of FMISO captation under antiangiogenic (p < 0.02) of the arterial wall partially calcified among 23/37 patients reached of atherosclerosis, without notable cardiovascular events in the follow-up of these patients. On the other hand, we highlighted a significant reduction of FMISO captation in arthrosic lesions (p < 0.05).Conclusion18F-FMISO PET/CT scan could be a good indicator of the potential toxicities of sunitinib, in particular the pulmonary, hepatic and cardiovascular side effects. It also shows the potential interest of antiangiogenic in inflammatory rheumatic diseases. 相似文献
5.
Mainardi JL Hugonnet JE Rusconi F Fourgeaud M Dubost L Moumi AN Delfosse V Mayer C Gutmann L Rice LB Arthur M 《The Journal of biological chemistry》2007,282(42):30414-30422
The beta-lactam antibiotics mimic the D-alanyl(4)-D-alanine(5) extremity of peptidoglycan precursors and act as "suicide" substrates of the DD-transpeptidases that catalyze the last cross-linking step of peptidoglycan synthesis. We have previously shown that bypass of the dd-transpeptidases by the LD-transpeptidase of Enterococcus faecium (Ldt(fm)) leads to high level resistance to ampicillin. Ldt(fm) is specific for the L-lysyl(3)-D-alanine(4) bond of peptidoglycan precursors containing a tetrapeptide stem lacking D-alanine(5). This specificity was proposed to account for resistance, because the substrate of Ldt(fm) does not mimic beta-lactams in contrast to the D-alanyl(4)-D-alanine(5) extremity of pentapeptide stems used by the DD-transpeptidases. Here, we unexpectedly show that imipenem, a beta-lactam of the carbapenem class, totally inhibited Ldt(fm) at a low drug concentration that was sufficient to inhibit growth of the bacteria. Peptidoglycan cross-linking was also inhibited, indicating that Ldt(fm) is the in vivo target of imipenem. Stoichiometric and covalent modification of Ldt(fm) by imipenem was detected by mass spectrometry. The modification was mapped into the trypsin fragment of Ldt(fm) containing the catalytic Cys residue, and the Cys to Ala substitution prevented imipenem binding. The mass increment matched the mass of imipenem, indicating that inactivation of Ldt(fm) is likely to involve rupture of the beta-lactam ring and acylation of the catalytic Cys residue. Thus, the spectrum of activity of beta-lactams is not restricted to transpeptidases of the DD-specificity, as previously thought. Combination therapy with imipenem and ampicillin could therefore be active against E. faecium strains having the dual capacity to manufacture peptidoglycan with transpeptidases of the LD- and DD-specificities. 相似文献
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7.
Role of class A penicillin-binding proteins in PBP5-mediated beta-lactam resistance in Enterococcus faecalis
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Arbeloa A Segal H Hugonnet JE Josseaume N Dubost L Brouard JP Gutmann L Mengin-Lecreulx D Arthur M 《Journal of bacteriology》2004,186(5):1221-1228
Peptidoglycan polymerization complexes contain multimodular penicillin-binding proteins (PBP) of classes A and B that associate a conserved C-terminal transpeptidase module to an N-terminal glycosyltransferase or morphogenesis module, respectively. In Enterococcus faecalis, class B PBP5 mediates intrinsic resistance to the cephalosporin class of beta-lactam antibiotics, such as ceftriaxone. To identify the glycosyltransferase partner(s) of PBP5, combinations of deletions were introduced in all three class A PBP genes of E. faecalis JH2-2 (ponA, pbpF, and pbpZ). Among mutants with single or double deletions, only JH2-2 DeltaponA DeltapbpF was susceptible to ceftriaxone. Ceftriaxone resistance was restored by heterologous expression of pbpF from Enterococcus faecium but not by mgt encoding the monofunctional glycosyltransferase of Staphylococcus aureus. Thus, PBP5 partners essential for peptidoglycan polymerization in the presence of beta-lactams formed a subset of the class A PBPs of E. faecalis, and heterospecific complementation was observed with an ortholog from E. faecium. Site-directed mutagenesis of pbpF confirmed that the catalytic serine residue of the transpeptidase module was not required for resistance. None of the three class A PBP genes was essential for viability, although deletion of the three genes led to an increase in the generation time and to a decrease in peptidoglycan cross-linking. As the E. faecalis chromosome does not contain any additional glycosyltransferase-related genes, these observations indicate that glycan chain polymerization in the triple mutant is performed by a novel type of glycosyltransferase. The latter enzyme was not inhibited by moenomycin, since deletion of the three class A PBP genes led to high-level resistance to this glycosyltransferase inhibitor. 相似文献
8.
Lecoq L Bougault C Hugonnet JE Veckerlé C Pessey O Arthur M Simorre JP 《Structure (London, England : 1993)》2012,20(5):850-861
β-lactams inhibit peptidoglycan polymerization by acting as suicide substrates of essential d,d-transpeptidases. Bypass of these enzymes by unrelated l,d-transpeptidases results in β-lactam resistance, although carbapenems remain unexpectedly active. To gain insight into carbapenem specificity of l,d-transpeptidases (Ldts), we solved the nuclear magnetic resonance (NMR) structures of apo and imipenem-acylated Bacillus subtilis Ldt and show that the cysteine nucleophile is present as a neutral imidazole-sulfhydryl pair in the substrate-free enzyme. NMR relaxation dispersion does not reveal any preexisting conformational exchange in the apoenzyme, and change in flexibility is not observed upon noncovalent binding of β-lactams (K(D) > 37.5 mM). In contrast, covalent modification of active cysteine by both carbapenems and 2-nitro-5-thiobenzoate induces backbone flexibility that does not result from disruption of the imidazole-sulfhydryl proton interaction or steric hindrance. The chemical step of the reaction determines enzyme specificity since no differences in drug affinity were observed. 相似文献
9.
The intrinsic resistance of Mycobacterium tuberculosis to the beta-lactam class of antibiotics arises from a chromosomally encoded, extended spectrum, class A beta-lactamase, BlaC. Herein, we report the X-ray crystallographic structure of BlaC inhibited with clavulanate at a resolution of 1.7 A with an R-factor value of 0.180 and R-free value of 0.212 for the m/ z +154 clavulanate-derived fragment observed in the active site. Structural evidence reveals the presence of hydrogen bonds to the C1 carbonyl along with a coplanar arrangement of C1, C2, C3, and N4, which favors enolization to generate a trans-alpha,beta-eneamine, stabilizing the +154 adduct from hydrolysis. The irreversible inhibition of BlaC suggests that treatment of M. tuberculosis with a combination of a beta-lactam antibiotic and clavulanate may lead to rapid bactericidal activity. 相似文献
10.
Pierre Soubeyran Carine Bellera Jean Goyard Damien Heitz Hervé Curé Hubert Rousselot Gilles Albrand Véronique Servent Olivier Saint Jean Isabelle van Praagh Jean-Emmanuel Kurtz Stéphane Périn Jean-Luc Verhaeghe Catherine Terret Christophe Desauw Véronique Girre Cécile Mertens Simone Mathoulin-Pélissier Muriel Rainfray 《PloS one》2014,9(12)