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991.
992.
Da Violante G Zerrouk N Richard I Frendo JL Zhiri A Li-Khuan R Tricottet V Provot G Chaumeil JC Arnaud P 《Biological & pharmaceutical bulletin》2004,27(12):1986-1992
The Caco-2 cell model is a valuable tool for studying intestinal biotransformation of xenobiotics and to evaluate the potential of human intestinal absorption of new compounds. These properties were evaluated with Caco-2/TC7 cells in accelerated conditions to reduce maturation lag time from 21-d to 3-d in order to increase time and labor efficiency. Transmission electron and fluorescent microscopy were used for morphological characterization. Alkaline phosphatase and lactate dehydrogenase activities were assessed within time. Cytochrome P450 expression was studied by RT-PCR. Apparent permeabilities of a set of passively absorbed molecules across Caco-2/TC7 cell monolayers were determined to evaluate potential of both systems for prediction of human intestinal absorption. Microscopic images revealed that cells under both conditions differentiated as enterocyte-like cells but did so heterogeneously in the 3-d model. TEER values have shown that the 3-d model is a leakier cell system with higher mannitol Papp (cm/s). Biochemical characterization (hydrolase activities, CYP450 expression) suggested that the 3-d model was at a lower maturation level than the 21-d model. Carrier-mediated uptake of L-Phe was lower in the 3-d model suggesting that this model has limited application for mechanistic studies. Reasonable correlation was obtained between the two models (r2=0.88, p>0.01) for 11 passively absorbed compounds with high potential of rank ordering of compounds. Although results suggested that the 3-d cells are under-differentiated, they could be usable to estimate the oral absorption of passively absorbed compounds. 相似文献
993.
Chau N Gauchard GC Siegfried C Benamghar L Dangelzer JL Français M Jacquin R Sourdot A Perrin PP Mur JM 《International archives of occupational and environmental health》2004,77(1):60-66
Objectives To assess the relationships of job, age, and life conditions with the causes and severity of occupational injuries in male construction labourers.Methods The sample included 880 male construction workers having had at least one occupational injury with subsequent sick leave. The survey used a standardised questionnaire, filled in by the occupational physician in the presence of the subject: socio-demographic data, job, safety training, smoking habit, alcohol consumption, sporting activities, physical disabilities, hearing, vision, and sleep disorders. Statistical analysis was via the logistic regression method.Results Logistic models showed that falls and injuries from the handling of objects or hand tools was similar for all jobs, while masons, plumbers and electricians had a higher risk of injury from moving objects, and carpenters, roofers and civil-engineering workers were more exposed to injury from construction machinery and devices. Age <30 was related to injury from hand tools [adjusted OR (95%CI) 2.20 (1.28–3.79)]; sleep disorders and hearing disorders to those from moving objects [ORs 2.29 (1.27–4.12) and 1.85 (1.01–3.41) respectively]; no sporting activity to those from the handling of objects [OR 1.54 (1.09–2.17)]; and being overweight to falls on the same level [OR 2.04 (1.30–3.21)] and falls to a lower level [OR 1.55 (1.13–2.13)]. Injuries from the handling of objects were less frequent in overweight workers [OR 0.62 (0.46–0.84)]. Injuries with hospitalisation or sick leave 60 days were associated with age 30 and hearing disorders.Conclusions The causes of injuries were related to jobs. Prevention through working conditions could be made against the revealed risks. The risks for each worker depended on age, body mass index, hearing disorders, sleep disorders, and sporting activities. The occupational physician could inform the workers of these risks and encourage them to practise sporting activities and reduce their hearing disorders and sleep disorders. 相似文献
994.
Rivail L Giner M Gastineau M Berthouze M Soulier JL Fischmeister R Lezoualc'h F Maigret B Sicsic S Berque-Bestel I 《British journal of pharmacology》2004,143(3):361-370
A body of evidences suggests that a hydrophobic pocket of the human 5-HT(4) receptor contributes to the high affinity of some bulky 5-HT(4) ligands. A thorough study of this pocket was performed using mutagenesis and molecular modeling. Ligand binding or competition studies with selected bulky ligands (RS39604, RS100235, [(3)H]GR113808 and ML11411) and small ligands (5-HT and ML10375) were carried out on wild-type and mutant receptors (W7.40A/F, Y7.43F, R3.28L) transiently transfected in COS-7 cells. The functional activity of the mutated receptors was evaluated by measuring the ability of 5-HT to stimulate adenylyl cyclase. For W7.40F mutation, no changes in the affinity of studied ligands and in the functional activity of the mutant receptor were observed, in contrary to W7.40A mutation, which abolished both binding of ligands and 5-HT-induced cAMP production. Mutation R3.28L revealed a totally silent receptor with a basal level of cAMP production similar to the mock control despite its ability to product cAMP in the presence of 5-HT. Moreover, a one order loss of affinity of RS39604 and a 45-fold increase of ML11411 affinity were observed. Mutation Y7.43F modified the affinity of GR113808, which displays a 13-fold lower affinity for the mutant than for the wild-type receptor. In conclusion, in the hydrophobic pocket, two polar amino acids are able to interact through hydrogen bonds with bulky ligands depending on their chemical properties. Moreover, these experimental data may validate the proposed new three-dimensional model of the human 5-HT(4) receptor. 相似文献
995.
Julémont F de Leval X Michaux C Renard JF Winum JY Montero JL Damas J Dogné JM Pirotte B 《Journal of medicinal chemistry》2004,47(27):6749-6759
In this study, we report the synthesis and pharmacological evaluation of original pyridinic sulfonamides related to nimesulide, a cyclooxygenase-2 (COX-2) preferential inhibitor widely used as an anti-inflammatory agent. These original pyridinic derivatives were synthesized in three steps starting from the condensation of 3-bromo-4-nitropyridine N-oxide with appropriately substituted phenols, thiophenols, or anilines followed by a reduction of the nitro moiety into the corresponding aminopyridine, which was finally condensed with alkane- or trifluoromethanesulfonyl chloride to obtain the corresponding sulfonamides. The pK(a) determinations demonstrated that the major ionic form present in solution at physiological pH depends on the nature of the sulfonamide moiety subsituent. Indeed, alkanesulfonamides were mainly present as zwitterionic molecules while trifluoromethanesulfonamides, more acidic derivatives, were mainly present as anionic molecules. The in vitro pharmacological evaluation of the synthesized compounds against COX-1 and COX-2 was performed in a human whole blood model. Results obtained demonstrated that most of alkanesulfonamide derivatives displayed a COX-2 preferential inhibition with selectivity ratio values (IC(50)(COX-1)/IC(50)(COX-2)) up to 7.92 (celecoxib displaying a ratio value of 7.46 in the same test). On the other hand, trifluoromethanesulfonamide derivatives displayed weaker selectivity ratios although they exhibited IC(50) values against COX-2 up to 0.09 microM (celecoxib IC(50) against COX-2: 0.35 microM). Finally, in vivo evaluation of selected compounds showed that they exhibited anti-inflammatory properties similar to that of nimesulide when tested in a carrageenan-induced rat paw oedema model. 相似文献
996.
997.
STRAP is a strong predictive marker of adjuvant chemotherapy benefit in colorectal cancer 总被引:1,自引:0,他引:1
Buess M Terracciano L Reuter J Ballabeni P Boulay JL Laffer U Metzger U Herrmann R Rochlitz C 《Neoplasia (New York, N.Y.)》2004,6(6):813-820
BACKGROUND: Molecular predictors for the effectiveness of adjuvant chemotherapy in colorectal cancer are of considerable clinical interest. To this aim, we analyzed the serine threonine receptor-associated protein (STRAP), an inhibitor of TGF-beta signaling, with regard to prognosis and prediction of adjuvant 5-FU chemotherapy benefit. METHODS: The gene copy status of STRAP was determined using quantitative real-time polymerase chain reaction in 166 colorectal tumor biopsies, which had been collected from a randomized multicenter trial of 5-fluorouracil (5-FU)/mitomycin C (MMC) adjuvant chemotherapy of the Swiss Group for Clinical Cancer Research (SAKK). RESULTS: Amplification of STRAP was found in 22.8% of the tumors. When left without adjuvant chemotherapy, patients bearing tumors with a STRAP amplification had a significantly better prognosis (hazard ratio for death: 0.26; P=.004). Interestingly, these patients, when receiving adjuvant treatment, had a worse survival (hazard ratio for death: 3.48; P=.019) than without chemotherapy, whereas patients carrying tumors with diploidy or deletion of STRAP benefited from the treatment (hazard ratio for death: 0.44; P=.052). This suggests the amplification of STRAP as a strong predictor of an unfavorable effect of 5-FU-based adjuvant chemotherapy. CONCLUSION: If confirmed, the STRAP gene copy status might provide a parameter to decide about the use of 5-FU-based adjuvant chemotherapy. 相似文献
998.
999.
Guéant-Rodriguez RM Juilliére Y Candito M Adjalla CE Gibelin P Herbeth B Van Obberghen E Gueánt JL 《Thrombosis and haemostasis》2005,94(3):510-515
Methylenetetrahydrofolate reductase polymorphism (MTHFR C677T) is an established determinant of homocysteine plasma level (t-Hcys) while its association with coronary artery disease (CAD) seems to be more limited. In contrast, the association of the substitutions A2756G of methionine synthase (MTR), A66G of methionine synthase reductase (MTRR) and C776G of transcobalamin (TCN) to both t-Hcys and CAD needs to be evaluated further. The objective was to evaluate the association of these polymorphisms with t-Hcys and CAD in a French population. We investigated the individual and combined effects of these polymorphisms and of vitamin B12 and folates with t-Hcys in 530 CAD patients and 248 matched healthy controls. t-Hcys was higher in the CAD group than in controls (11.8 vs 10.4 microM, P < 0.0001) and in carriers of MTRRAA and MTHFR 677TT than in those carrying the most frequent allele of both polymorphisms (13.8 vs 11.4 microM, P = 0.0102 and 12.5 vs 11.0 mM, P = 0.0065 respectively).The frequency of MTRR A allele was higher in CAD patients than in controls (0.48 [95% CI: 0.44-0.52] vs 0.38 [95% CI: 0.32-0.44], P = 0.0081) while no difference was observed for MTHFR 677T frequency. In multivariate analysis, t-Hcys > median and MTRRAA genotype were two significant independent predictors of CAD with respective odds ratios of 3.1 (95 % CI: 1.8-5.1, P < 0.0001) and 4.5 (95% CI: 1.5-13.1, P = 0.0051). In conclusion, in contrast to North Europe studies, MTRRAA genotype is a genetic determinant of moderate hyperhomocysteinemia associated with CAD in a French population without vitamin fortification. 相似文献
1000.