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991.
992.
Huang Z Dias R Jones T Liu S Styhler A Claveau D Otu F Ng K Laliberte F Zhang L Goetghebeur P Abraham WM Macdonald D Dubé D Gallant M Lacombe P Girard Y Young RN Turner MJ Nicholson DW Mancini JA 《Biochemical pharmacology》2007,73(12):1971-1981
Type 4 phosphodiesterases (PDE4) inhibitors are emerging therapeutics in the treatment of a number of chronic disorders including asthma, chronic obstructive pulmonary disease (COPD) and cognitive disorders. This study delineates the preclinical profile of L-454,560, which is a potent, competitive and preferential inhibitor of PDE4A, 4B, and 4D with IC50 values of 1.6, 0.5 and 1.2 nM, respectively. In contrast to the exclusive binding of cilomilast and the preferential binding of roflumilast to the PDE4 holoenzyme state (Mg2+-bound form), L-454,560 binds to both the apo-(Mg2+-free) and holoenzyme states of PDE4. The intrinsic enzyme potency for PDE4 inhibition by L-454,560 also results in an effective blockade of LPS-induced TNFalpha formation in whole blood (IC50 = 161 nM) and is comparable to the human whole blood potency of roflumilast. The cytokine profile of inhibition of L-454,560 is mainly a Th1 profile with significant inhibition of IFNgamma and no detectable inhibition of IL-13 formation up to 1 microM. L-454,560 was also found to be efficacious in two models of airway hyper-reactivity, the ovalbumin (OVA) sensitized and challenged guinea pig and the ascaris sensitized sheep model. Furthermore, L-454560 was also effective in improving performance in the delayed matching to position (DMTP) version of the Morris watermaze, at a dose removed from that associated with potential emesis. Therefore, L-454,560 is a novel PDE4 inhibitor with an overall in vivo efficacy profile at least comparable to roflumilast and clearly superior to cilomilast. 相似文献
993.
Zhelmy Martín-Quintal Rosa Moo-Puc Francisco González-Salazar Manuel J. Chan-Bacab Luis W. Torres-Tapia Sergio R. Peraza-Sánchez 《Journal of ethnopharmacology》2009
Ethnopharmacological relevance
Tridax procumbens is an active herb against leishmaniasis.Aim of the study
Leishmaniasis is a group of diseases caused by Leishmania protozoa. We investigated the antileishmanial activity of Tridax procumbens extracts and a pure compound against promastigotes of Leishmania mexicana, the causative agent of cutaneous leishmaniasis in the New World.Materials and methods
Extracts and (3S)-16,17-didehydrofalcarinol (1) were obtained by chromatographic methods from Tridax procumbens, and the latter identified by spectroscopic analysis. The effect of these extracts and 1 on the growth inhibition of promastigotes of Leishmania mexicana was evaluated. In order to test the safety of extracts and 1, mammalian cells were treated with them, and cell viability was assessed using trypan blue and MTT.Results
We demonstrated that extracts of Tridax procumbens and 1 showed a pronounced activity against Leishmania mexicana. The methanol extract inhibited promastigotes growth of Leishmania mexicana with a 50% inhibitory concentration (IC50) of 3 μg/ml, while oxylipin 1 exhibited the highest inhibition at IC50 = 0.478 μg/ml.Conclusions
In this study we report the biological activity of extracts and (3S)-16,17-didehydrofalcarinol (1), obtained from Tridax procumbens, on the promastigote form of Leishmania mexicana, with no effect upon mammalian cells. 相似文献994.
995.
New syngeneic inflammatory‐related lung cancer metastatic model harboring double KRAS/WWOX alterations
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Anne‐Marie Bleau Javier Freire María José Pajares Isabel Zudaire Iker Anton Estanislao Nistal‐Villán Miriam Redrado Caroli na Zandueta Irati Garmendia Daniel Ajona David Blanco Ruben Pio Fernando Lecanda Alfonso Calvo Luis M. Montuenga 《International journal of cancer. Journal international du cancer》2014,135(11)
New mouse models with specific drivers of genetic alterations are needed for preclinical studies. Herein, we created and characterized at the genetic level a new syngeneic model for lung cancer and metastasis in Balb‐c mice. Tumor cell lines were obtained from a silica‐mediated airway chronic inflammation that promotes tumorigenesis when combined with low doses of N‐nitrosodimethylamine, a tobacco smoke carcinogen. Orthotopic transplantation of these cells induced lung adenocarcinomas, and their intracardiac injection led to prominent colonization of various organs (bone, lung, liver and brain). Driver gene alterations included a mutation in the codon 12 of KRAS (G–A transition), accompanied by a homozygous deletion of the WW domain‐containing oxidoreductase (WWOX) gene. The mutant form of WWOX lacked exons 5–8 and displayed reduced protein expression level and activity. WWOX gene restoration decreased the in vitro and in vivo tumorigenicity, confirming the tumor suppressor function of this gene in this particular model. Interestingly, we found that cells displayed remarkable sphere formation ability with expression of specific lung cancer stem cell markers. Study of non‐small‐cell lung cancer patient cohorts demonstrated a deletion of WWOX in 30% of cases, with significant reduction in protein levels as compared to normal tissues. Overall, our new syngeneic mouse model provides a most valuable tool to study lung cancer metastasis in balb‐c mice background and highlights the importance of WWOX deletion in lung carcinogenesis. 相似文献
996.
Prada Diddier Baccarelli Andrea A. Terry Mary Beth Valdéz Leonora Cabrera Paula Just Allan Kloog Itai Caro Haydee García-Cuellar Claudia Sánchez-Pérez Yesennia Cruz Rodrigo Diaz-Chávez Jose Cortés Carlo Pérez Delia Meneses-García Abelardo Cantú-de-León David Herrera Luis A. Bargalló Enrique 《Breast cancer research and treatment》2021,187(2):525-533
Breast Cancer Research and Treatment - Many patients seek breast reconstruction following mastectomy. Debate exists regarding the best reconstructive option. The authors evaluate outcomes comparing... 相似文献
997.
Good performance of p16/ki‐67 dual‐stained cytology for surveillance of women treated for high‐grade CIN
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![点击此处可从《International journal of cancer. Journal international du cancer》网站下载免费的PDF全文](/ch/ext_images/free.gif)
Nicole J. Polman Margot H. Uijterwaal Birgit I. Witte Johannes Berkhof Folkert J. van Kemenade Johan W.M. Spruijt W. Marchien van Baal Peppino G.C.M. Graziosi Dorenda K.E. van Dijken René H.M. Verheijen Theo J.M. Helmerhorst Renske D.M. Steenbergen Daniëlle A.M. Heideman Ruediger Ridder Peter J.F. Snijders Chris J.L.M. Meijer 《International journal of cancer. Journal international du cancer》2017,140(2):423-430
Women treated for high‐grade cervical intraepithelial neoplasia (CIN) are at risk of recurrent CIN Grade 2 or worse (rCIN2+). Currently, posttreatment monitoring is performed using cytology or cytology/high‐risk (hr)HPV cotesting. This study aimed to evaluate the performance of p16/Ki‐67 dual‐stained cytology (p16/Ki‐67) for posttreatment monitoring. Three hundred and twenty‐three women treated for high‐grade CIN in the SIMONATH study underwent close surveillance by cytology, hrHPV and DNA methylation marker testing up to 12 months posttreatment. Histological endpoints were ascertained by colposcopy with biopsy at 6 and/or 12 months. p16/Ki‐67 dual‐staining was performed on residual liquid‐based cytology samples obtained at, or shortly before biopsy collection. Clinical performance estimates of cytology, hrHPV, p16/Ki‐67 testing and combinations thereof for the detection of rCIN2+ were determined and compared to each other. Sensitivity of p16/Ki‐67 for rCIN2+ (69.2%) was nonsignificantly lower than that of cytology (82.1%; ratio 0.84, 95% CI: 0.71–1.01), but significantly lower than that of hrHPV testing (84.6%; ratio 0.82, 95% CI: 0.68–0.99). Specificity of p16/Ki‐67 for rCIN2+ (90.4%) was significantly higher compared to both cytology (70.8%; ratio 1.28, 95% CI: 1.19–1.37) and hrHPV testing (76.2%; ratio 1.19, 95% CI: 1.12–1.26). Overall, hrHPV testing showed very high sensitivity, along with a good specificity. When considering cotesting, combined p16/Ki‐67/hrHPV testing showed rCIN2+ sensitivity comparable to cytology/hrHPV cotesting (87.2% vs. 89.7%; ratio 0.97, 95% CI: 0.92–1.03), but with significantly increased specificity (74.2% vs. 58.1%; ratio 1.28, 95% CI: 1.19–1.38). Thus, when considered in combination with hrHPV, p16/Ki‐67 might be an attractive approach for surveillance of women treated for high‐grade CIN. 相似文献
998.
José?Rodrigues?PereiraEmail author Sandro?J?Martins Sueli?M?Nikaedo Flora?K?Ikari 《BMC cancer》2004,4(1):69
Background
Although modest improvements in the survival of patients with non-small cell lung cancer (NSCLC) can be achieved with cisplatin-based chemotherapy (CT), its value is disputed in the geriatric setting. In this study, we evaluate the feasibility of vinorelbine/cisplatin CT for elderly NSCLC patients. 相似文献999.
Natalie M. G. M. Appels Maria J. Bolijn Maria A. J. van Eijndhoven Trevor C. Stephens Jos H. Beijnen Jan H. M. Schellens 《Cancer chemotherapy and pharmacology》2011,67(1):137-145
Purpose
AZD3409 is a novel DPTI that has potent activity against both FTase and GGTase-1. The in vitro inhibition profile of AZD3409 was characterized using three different cell lines: mouse embryogenic fibroblasts, transfected with H-RasV12 (MEF), A549 cells (Ki4B-Ras mutation) and MCF-7 cells (no Ras mutation).Methods
Both cytotoxicity and levels of inhibition of farnesylation and geranylgeranylation were determined in different assays in relation to the concentration of AZD3409. Results were compared with those obtained with the first-generation FTase inhibitor lonafarnib or the GGTase-1 inhibitor GGTI-2147.Results
The mean IC50 for cytotoxicity of AZD3409 and lonafarnib was 510 and 15,200?nM in MEF cells, 10,600 and 2,740?nM in A549 cells and 6,170 and 9,490?nM in MCF7 cells, respectively. In these cells, the IC50 for FTase activity of AZD3409 ranged from 3.0 to 14.2?nM and of lonafarnib from 0.26 to 31.3?nM. The inhibiting activity of AZD3409 and lonafarnib on general protein farnesylation was comparable with the specific farnesylation levels of HDJ-2. In vitro geranylgeranylation of Rap1a could be inhibited by GGTI-2147 in all three cell lines, but only in MCF-7 cells by AZD3409. These results are in agreement with the IC50 values for GGTase-1 activity as the lowest IC50 for AZD3409 was found in the MCF-7 cell line.Conclusions
AZD3409 inhibits farnesylation to a higher extent than geranylgeranylation. Both inhibition of farnesylation and geranylgeranylation could not be correlated to the antiproliferative activity of the drug. 相似文献1000.