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排序方式: 共有3586条查询结果,搜索用时 93 毫秒
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Dr. Hui Qiu Richard Caldwell Dr. Lesley Liu-Bujalski Dr. Andreas Goutopoulos Reinaldo Jones Justin Potnick Dr. Brian Sherer Dr. Andrew Bender Dr. Roland Grenningloh Dr. Daigen Xu Dr. Anna Gardberg Dr. Igor Mochalkin Dr. Theresa Johnson Dr. Ariele Viacava Follis Jared Head Dr. Federica Morandi 《ChemMedChem》2019,14(2):217-223
Bruton's tyrosine kinase (Btk) is an attractive target for the treatment of a wide array of B-cell malignancies and autoimmune diseases. Small-molecule covalent irreversible Btk inhibitors targeting Cys481 have been developed for the treatment of such diseases. In clinical trials, probe molecules are required in occupancy studies to measure the level of engagement of the protein by these covalent irreversible inhibitors. The result of this pharmacodynamic (PD) activity provides guidance for appropriate dosage selection to optimize inhibition of the drug target and correlation of target inhibition with disease treatment efficacy. This information is crucial for successful evaluation of drug candidates in clinical trials. Based on the pyridine carboxamide scaffold of a novel solvent-accessible pocket (SAP) series of covalent irreversible Btk inhibitors, we successfully developed a potent and selective affinity-based biotinylated probe 12 (2-[(4-{4-[5-(1-{5-[(3aS,4S,6aR)-2-oxo-hexahydro-1H-thieno[3,4-d]imidazol-4-yl]pentanamido}-3,6,9,12-tetraoxapentadecan-15-amido)pentanoyl]piperazine-1-carbonyl}phenyl)amino]-6-[1-(prop-2-enoyl)piperidin-4-yl]pyridine-3-carboxamide). Compound 12 has been used in Btk occupancy assays for preclinical studies to determine the therapeutic efficacy of Btk inhibition in two mouse lupus models driven by TLR7 activation and type I interferon. 相似文献
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IH Bjerkli R Myklebust S R?is?nen S Telimaa LE Stenfors 《Canadian Metallurgical Quarterly》1996,36(3):205-213
Dopaminergic agents and carbidopa/levodopa have become the preferred treatment for both the restless legs (RL) syndrome and for periodic limb movements in sleep (PLMS). For once-nightly treatments with carbidopa/ levodopa, a problem with morning end-of-dose rebound increases in leg movements has been reported to occur in the about one-fourth of the patients. In our clinical studies a previously unreported but far more significant problem of markedly augmented RL symptoms occurred in the afternoon and the evening prior to taking the next nightly dose. A systematic prospective evaluation of this augmentation in 46 consecutive patients treated with carbidopa/ levodopa for RL syndrome or PLMS disorder found this augmentation to be the major adverse effect of treatment. Augmentation occurred for 31% of PLMS patients and 82% of all RL patients. It was greater for subjects with more severe RL symptoms and for patients on higher doses (> or = 50/200 mg carbidopa/levodopa) but was unrelated to gender, age or baseline severity of PLMS. This augmentation was severe enough to require medication change for 50% of the RL patients and 13% of PLMS patients. Augmentation resolved with cessation of the medication and could be minimized by keeping the dose low. 相似文献
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Recurrent erosion of the corneal epithelium has been treated successfully by phototherapeutic keratectomy when convention therapy has failed. We present a case of recurrent corneal erosion occurring 1 year after photorefractive keratectomy in a 55-year-old myopic woman. No corneal abnormalities were previously identified in either the affected or the fellow eye. This case demonstrates the potential for ineffective healing of the corneal epithelial basement membrane complex after excimer laser photorefractive keratectomy. 相似文献
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LE Lindner 《Canadian Metallurgical Quarterly》1993,41(3):439-445
The silver-staining technique for nucleolar organizer regions (AgNOR) of Ploton et al., as popularized by Crocker, is being widely used for evaluation of nucleolar function, especially in neoplasia. It suffers from limited reliability, background staining, precipitates, and fading of the sections. Factors were identified that affect these problems. The oxidation-reduction level and gelatin used are particularly important. An improved procedure is presented which incorporates pre-reduction of the sections, selection of an optimal gelatin, and post-treatment of the sections to produce a permanent preparation. It is compatible with many fixatives and with other stains used before or after the silver stain. 相似文献
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D Averill D Blockus B Brabson J Brom C Jung H Ogren DR Rust M Derrick P Kooijman JS Loos B Musgrave LE Price J Repond K Sugano B Cork C Akerlof J Chapman D Errede MT Ken DI Meyer H Neal D Nitz R Thun R Tschirhart S Abachi P Baringer BG Bylsma R DeBonte D Koltick EH Low RL McIlwain DH Miller CR Ng EI Shibata 《Canadian Metallurgical Quarterly》1989,39(1):123-137
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The technique of immunocytochemistry was used to identify myoglobin in kidney, confirming a diagnosis of neuroleptic malignant syndrome following an otherwise obscure autopsy in a decomposed body. The features of neuroleptic malignant syndrome are reviewed with a differential diagnosis of myoglobin renal casts. The report emphasizes a thorough and detailed assessment of deaths which occur during treatment with neuroleptic drugs. 相似文献
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We developed a new in vitro model of neuronal injury using NT2-N cells to examine the effects of hydrodynamic loading rate on intraneuronal calcium dynamics and lactate dehydrogenase (LDH) release. Our apparatus consisted of a parallel disk viscometer which induced fluid shear stress with well-defined magnitudes and loading rates to cultured cells. We found that the deformation response of the cells was dependent on the severity of the insult, with increased cellular strains generated for higher shear stresses at a constant loading rate. Peak intracellular free calcium concentration correlated with strain, suggesting that mechanical deformation may regulate calcium response. Slowly applied fluid shear stress elicited no response, whereas high loading rates resulted in peak calcium increases 2.9 to 3.6 times baseline values as injury severity was increased. LDH release measured within 5 min after the insult correlated with loading rate. In addition, LDH release continued to increase out to 24 h following high loading rate conditions, demonstrating that the application of fluid shear stress led to prolonged cell damage. The acute response in NT2-N cells subjected to an insult with the CSID is dependent on the loading rate, and these results suggest that initial membrane deformation may trigger subsequent events. 相似文献