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101.
Certal V Halley F Virone-Oddos A Delorme C Karlsson A Rak A Thompson F Filoche-Rommé B El-Ahmad Y Carry JC Abecassis PY Lejeune P Vincent L Bonnevaux H Nicolas JP Bertrand T Marquette JP Michot N Benard T Below P Vade I Chatreaux F Lebourg G Pilorge F Angouillant-Boniface O Louboutin A Lengauer C Schio L 《Journal of medicinal chemistry》2012,55(10):4788-4805
Most of the phosphoinositide-3 kinase (PI3K) kinase inhibitors currently in clinical trials for cancer treatment exhibit pan PI3K isoform profiles. Single PI3K isoforms differentially control tumorigenesis, and PI3Kβ has emerged as the isoform involved in the tumorigenicity of PTEN-deficient tumors. Herein we describe the discovery and optimization of a new series of benzimidazole- and benzoxazole-pyrimidones as small molecular mass PI3Kβ-selective inhibitors. Starting with compound 5 obtained from a one-pot reaction via a novel intermediate 1, medicinal chemistry optimization led to the discovery of compound 8, which showed a significant activity and selectivity for PI3Kβ and adequate in vitro pharmacokinetic properties. The X-ray costructure of compound 8 in PI3Kδ showed key interactions and structural features supporting the observed PI3Kβ isoform selectivity. Compound 8 achieved sustained target modulation and tumor growth delay at well tolerated doses when administered orally to SCID mice implanted with PTEN-deficient human tumor xenografts. 相似文献
102.
Jousse-Joulin S Breton S Cangemi C Fenoll B Bressolette L de Parscau L Saraux A Devauchelle-Pensec V 《Arthritis care & research》2011,63(6):849-855
Objective
Enthesitis is a major feature of juvenile idiopathic arthritis (JIA) but is difficult to diagnose clinically. Our objective was to compare the accuracy of ultrasonography with power Doppler (US‐PD) versus clinical examination for diagnosing enthesitis in patients with JIA and healthy controls.Methods
Twenty‐six consecutive patients with JIA and 41 healthy volunteers underwent standardized clinical and US‐PD examinations of 5 entheseal sites (proximal and distal quadricepital tendon insertions, Achilles tendon, and plantar fascia). US‐PD reproducibility was evaluated. US‐PD enthesitis was defined as a PD signal at the enthesis insertion. Bursitis, erosions, and cartilage vascularization were recorded.Results
In the JIA group, 27 (12.5%) of the entheseal sites exhibited clinical enthesitis (distal patellar ligament in 45% of cases) and 20 (9.4%) exhibited US‐PD enthesitis (distal patellar tendon in 30%), including 10 clinically normal sites (50%). US‐PD enthesitis was found in several patients with oligoarthritis or polyarthritis. Clinical enthesitis (P < 0.0001) and HLA–B27–positive (P = 0.05) status were significantly associated with US‐PD enthesitis. Erosion and bursitis, but not tendon thickening, were associated with US‐PD enthesitis. US‐PD enthesitis was not found at any of the 410 entheseal sites in controls; grade 1 cartilage vascularization was noted at 6% of the control sites.Conclusion
Enthesitis is a rare phenomenon in JIA. Clinically silent enthesitis is detected by US‐PD and can be found in JIA categories other than enthesitis‐related arthritis. Tendon thickening and cartilage vascularization can be detected in healthy controls. These findings may have implications for patient classification of the use of US‐PD. 相似文献103.
Cicek MS Lindor NM Gallinger S Bapat B Hopper JL Jenkins MA Young J Buchanan D Walsh MD Le Marchand L Burnett T Newcomb PA Grady WM Haile RW Casey G Plummer SJ Krumroy LA Baron JA Thibodeau SN 《The Journal of molecular diagnostics : JMD》2011,13(3):271-281
The detection of defective mismatch repair (MMR), as assessed by the presence of tumor microsatellite instability (MSI) and/or loss of MMR protein expression by IHC, has been useful for risk assessment, prognosis, and prediction of treatment in patients with colorectal cancer. We analyzed tumors for the presence of defective MMR from 5927 Colorectal Cancer Family Registry patients recruited at six international consortium sites. We evaluated the appropriate percentage instability cutoff used to distinguish the three MSI phenotypes [ie, stable (MSS), low instability (MSI-L), and high instability (MSI-H)]; the sensitivity, specificity, and performance characteristics of individual markers; and the concordance between MSI and IHC phenotypes. Guided by the results of the IHC testing, our findings indicate that the distinction between an MSI-H phenotype from a low-instability or MSS phenotype can best be accomplished by using a cutoff of 30% or greater of the markers showing instability. The sensitivity and specificity of the mononucleotide markers were higher than those of the dinucleotide markers. Specifically, BAT26 and BAT25 had the highest sensitivity (94%) and specificity (98%), and the use of mononucleotide markers alone identified 97% of the MSI-H cases correctly. As expected, the presence of MSI-H correlated with an older age of diagnosis, the presence of tumor in the proximal colon, and female sex. 相似文献
104.
105.
Loic Belle MD Magali Fourny MSc Thomas Reynaud MD Laure Hammer MD Gérald Vanzetto MD PhD José Labarère MD 《Catheterization and cardiovascular interventions》2011,78(3):376-384
Objective : To compare clinical outcomes between glycoprotein IIb/IIIa receptor antagonist recipients and nonrecipients who underwent percutaneous coronary intervention (PCI) within 12 hr of fibrinolysis. Background : Despite limited evidence, glycoprotein IIb/IIIa receptor antagonists are widely used in ST‐elevation myocardial infarction (STEMI) patients undergoing routine early or rescue PCI after fibrinolysis. Methods: We evaluated 87 and 556 glycoprotein IIb/IIIa receptor antagonist recipients and nonrecipients enrolled in a regional registry of STEMI between October 2002 and December 2005. The primary efficacy endpoint was a composite of death from any cause, reinfarction, and stroke at 1 year of follow‐up. The primary safety endpoint was the rate of in‐hospital major bleeding that was not related to coronary artery bypass grafting. Results : The primary efficacy endpoint occurred in 12% (10 of 81) and 13% (72 of 525) of glycoprotein IIb/IIIa receptor antagonist recipients and nonrecipients, respectively (P = 0.74). The corresponding rates of major bleeding during index hospitalization were 4.8% (4 of 84) and 5.1% (28 of 544) (P = 0.88), respectively. Two glycoprotein IIb/IIIa receptor antagonist recipients and five nonrecipients experienced intracranial hemorrhage. After adjusting for propensity score, the odds of primary efficacy (odds ratio, 0.79; 95% confidence interval, 0.34–1.83) and safety (odds ratio, 0.75; 95% confidence interval, 0.22–2.62) endpoints did not differ according to the use of glycoprotein IIb/IIIa receptor antagonists. Conclusion : In this observational cohort study of unselected patients with STEMI, the administration of glycoprotein IIb/IIIa receptor antagonists provided no additional benefit to PCI performed within 12 hr of fibrinolysis, nor did it compromise patient safety. © 2011 Wiley‐Liss, Inc. 相似文献
106.
107.
Jean Bahebeck Eugene Sobgui Loic Fonfoe Bernadette Ngo Nonga Jean Claude Mbanya Maurice Sosso 《The Journal of foot and ankle surgery》2010,49(1):43-46
Limb- and life-threatening hand and foot infections in diabetic patients account for a large proportion of amputations and a substantial number of deaths. Between August 2006 and the end of July 2008, we conducted a prospective cohort study of consecutive diabetic patients with serious hand or foot infections, in an effort to identify clinical patterns and outcomes related to the treatment of these infections. Infections were categorized as dry, gas, and wet gangrene; necrotizing fasciitis or cellulitis; acute extensive osteomyelitis; and any of these infections involving the hand. All of the patients underwent a standard examination and treatment protocol, although none of the patients received vascular surgical care. End points included healing following debridement or minor amputation, major (transtibial or more proximal) amputation, or death. A total of 56 patients were included in the final analyses, and their mean age was 70 (range 51 to 86) years. Of the patients, 17 (30.36%) had necrotizing cellulitis, 12 (21.43%) had wet gangrene, 9 (16.07%) had acute extensive osteomyelitis, 5 (8.93%) had dry gangrene, 5 (8.93%) had gas gangrene, 4 (7.14%) had necrotizing fasciitis, and 4 (7.14) had diffuse hand infections. Five (8.93%) patients died (2 after prior amputation), 26 (46.43%) underwent debridement and/or minor amputation, and 27 (48.21%) required major amputations. Based on our findings, we concluded that 7 patterns of serious limb- or life-threatening infection were identified and, in the absence of vascular surgical intervention, mortality can be reduced at the expense of more amputations. 相似文献
108.
Rosenberger A Bickeböller H McCormack V Brenner DR Duell EJ Tjønneland A Friis S Muscat JE Yang P Wichmann HE Heinrich J Szeszenia-Dabrowska N Lissowska J Zaridze D Rudnai P Fabianova E Janout V Bencko V Brennan P Mates D Schwartz AG Cote ML Zhang ZF Morgenstern H Oh SS Field JK Raji O McLaughlin JR Wiencke J LeMarchand L Neri M Bonassi S Andrew AS Lan Q Hu W Orlow I Park BJ Boffetta P Hung RJ 《Carcinogenesis》2012,33(3):587-597
Asthma has been hypothesized to be associated with lung cancer (LC) risk. We conducted a pooled analysis of 16 studies in the International Lung Cancer Consortium (ILCCO) to quantitatively assess this association and compared the results with 36 previously published studies. In total, information from 585?444 individuals was used. Study-specific measures were combined using random effects models. A meta-regression and subgroup meta-analyses were performed to identify sources of heterogeneity. The overall LC relative risk (RR) associated with asthma was 1.28 [95% confidence intervals (CIs) = 1.16-1.41] but with large heterogeneity (I(2) = 73%, P < 0.001) between studies. Among ILCCO studies, an increased risk was found for squamous cell (RR = 1.69, 95%, CI = 1.26-2.26) and for small-cell carcinoma (RR = 1.71, 95% CI = 0.99-2.95) but was weaker for adenocarcinoma (RR = 1.09, 95% CI = 0.88-1.36). The increased LC risk was strongest in the 2 years after asthma diagnosis (RR = 2.13, 95% CI = 1.09-4.17) but subjects diagnosed with asthma over 10 years prior had no or little increased LC risk (RR = 1.10, 95% CI = 0.94-1.30). Because the increased incidence of LC was chiefly observed in small cell and squamous cell lung carcinomas, primarily within 2 years of asthma diagnosis and because the association was weak among never smokers, we conclude that the association may not reflect a causal effect of asthma on the risk of LC. 相似文献
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110.