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Ly-Thuy-Tram Le Morgane Couvet Bertrand Favier Jean-Luc Coll Chi-Hung Nguyen Annie Molla 《Oncotarget》2015,6(26):22152-22166
Aurora kinases play an essential role in mitotic progression and are attractive targets in cancer therapy. The first generation of benzo[e]pyridoindole exhibited powerful aurora kinase inhibition but their low solubility limited further development. Grafting a pyperidine-ethoxy group gives rise to a hydrosoluble inhibitor: compound C5M.C5M could efficiently inhibit the proliferation of cells from different origins. C5M prevented cell cycling, induced a strong mitotic arrest then, cells became polyploid and finally died. C5M did not impair the spindle checkpoint, the separation of the sister chromatids and the transfer of aurora B on the mid-zone. C5M prevented histone H3 phosphorylation at mitotic entry and erased AMPK-Thr172 phosphorylation in late mitosis. With this unique profile of inhibition, C5M could be useful for understanding the role of phospho-Thr172-AMPK, in abscission and the relationship between the chromosomal complex and the energy sensing machinery.C5M is a multikinase inhibitor with interesting preclinical characteristics: high hydro-solubility and a good stability in plasma. A single dose prevents the expansion of multicellular spheroids. C5M can safely be injected to mice and reduces significantly the development of xenograft. The next step will be to define the protocol of treatment and the cancer therapeutic field of this new anti-proliferative drug. 相似文献
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Amélie Huynh Le Maux Bernadette Pignol Delphine Behr-Roussel Jean-Luc Blachon Pierre-Etienne Chabrier Sandrine Compagnie Philippe Picaut Jacques Bernabé Fran?ois Giuliano Pierre Denys 《Toxins》2015,7(12):5462-5471
Intradetrusor injections of Botulinum toxin A—currently onabotulinumtoxinA—is registered as a second-line treatment to treat neurogenic detrusor overactivity (NDO). The common clinical practice is 30 × 1 mL injections in the detrusor; however, protocols remain variable and standardization is warranted. The effect of reducing the number of injection sites of Dysport® abobotulinumtoxinA (aboBoNTA) was assessed in the spinal cord-injured rat (SCI). Nineteen days post-spinalization, female rats received intradetrusor injections of saline or aboBoNTA 22.5 U distributed among four or eight sites. Two days after injection, continuous cystometry was performed in conscious rats. Efficacy of aboBoNTA 22.5 U was assessed versus aggregated saline groups on clinically-relevant parameters: maximal pressure, bladder capacity, compliance, voiding efficiency, as well as amplitude, frequency, and volume threshold for nonvoiding contractions (NVC). AboBoNTA 22.5 U significantly decreased maximal pressure, without affecting voiding efficiency. Injected in four sites, aboBoNTA significantly increased bladder capacity and compliance while only the latter when in eight sites. AboBoNTA significantly reduced NVC frequency and amplitude. This preclinical investigation showed similar inhibiting effects of aboBoNTA despite the number of sites reduction. Further studies are warranted to optimize dosing schemes to improve the risk-benefit ratio of BoNTA-based treatment modalities for NDO and further idiopathic overactive bladder. 相似文献
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Sandrine Lemoine René Rouet Alain Manrique Jean‐Luc Hanouz 《Fundamental & clinical pharmacology》2014,28(5):481-488
Lipid emulsions are used in the reversal of local anesthetic toxicity. The aim of this study was to investigate the cellular electrophysiological effects of long‐chain triglyceride lipid emulsion (LCTE) on cardiac action potential characteristics and conduction disturbances induced by bupivacaine. Purkinje fibers were dissected from the left ventricle of New Zealand white rabbit hearts and superfused with either Tyrode's solution during 30 min (control group), with bupivacaine 10?6 m , 10?5 m , and 5.10?5 m alone, or in the presence of LCTE 0.5%, in addition, LCTE at 0.1%, 0.5%, and 1% was perfused alone. Electrophysiological parameters were recorded using the conventional microelectrode technique (37 °C, 1 Hz frequency). Bupivacaine 5.10?5 m ‐induced conduction blocks (8/8 preparations): LCTE 0.5% suppressed the bupivacaine 5.10?5 m ‐induced conduction blocks (1/8 preparations). Exposure to bupivacaine 10?6 m , 10?5 m , and 5.10?5 m resulted in a significant decrease in the maximal rate of depolarization (Vmax) (respectively, 25%, 55%, 75%; P < 0.002 vs. control group). In the presence of LCTE 0.5%, bupivacaine 10?6 m did not significantly decreased Vmax (13%; P = 0.10 vs. control group). The decrease in Vmax resulting from bupivacaine 10?5 m alone was significantly less in the presence of LCTE 0.5% (P < 0.01 vs. bupivacaine 10?5 m alone). Exposure to bupivacaine 10?6 m , 10?5 m , and 5.10?5 m alone or in the presence of LCTE 0.5% resulted in a significant decrease in action potential duration measured at 50% and 90% repolarization (APD50 and APD90; P < 0.01 vs. control group). LCTE inhibited the Purkinje fibers conduction blocks induced by bupivacaine. Moreover, LCTE 0.5% attenuates the decrease in Vmax induced by bupivacaine 10?6 m and 10?5 m . 相似文献
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Martinus Richter Per-Henrik Agren Jean-Luc Besse Maria Coester Hakon Kofoed Nicola Maffulli Martijn Steultjens Amir Reza Vosoughi Milad Bahari 《Foot and Ankle Surgery》2021,27(5):496-500
BackgroundThe Score Committee of the European Foot and Ankle Society (EFAS) developed, validated, and published the EFAS Score in nine European languages (English, German, French, Italian, Polish, Dutch, Swedish, Finnish, Turkish). From other languages under validation, the Persian version finished data acquisition and underwent further validation.MethodsThe Persian version of the EFAS Score was developed and validated in three stages: 1) item (question) identification (completed during initial validation study), 2) item reduction and scale exploration (completed during initial validation study), 3) confirmatory analyses and responsiveness of Persian version (completed during initial validation study in nine other languages). The data were collected pre-operatively and post-operatively at a minimum follow-up of 3 months and mean follow-up of 6 months. Item reduction, scale exploration, confirmatory analyses and responsiveness were executed using classical test theory and item response theory.ResultsThe internal consistency was confirmed in the Persian version (Cronbach’s Alpha 0.82). The Standard Error of Measurement (SEM) was 0.38 and is similar to other language versions. Between baseline and follow-up, 97% of patients showed an improvement on their EFAS score, with excellent responsiveness (effect size 1.93).ConclusionsThe Persian EFAS Score version was successfully validated in patients with a wide variety of foot and ankle pathologies. All score versions are freely available at www.efas.co. 相似文献