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排序方式: 共有671条查询结果,搜索用时 15 毫秒
1.
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
2.
Guangyan Li W. Ian Hamilton Ged Morrisroe Theresa Clarke 《Cognition, Technology & Work》2006,8(1):30-40
A study was carried out using simulation to investigate driver responses to lineside signals and signs at various approach
speeds. The objectives of the study were: (1) to find out whether train speed would significantly affect signal/sign reading;
(2) to examine at which point certain types of signs or signals could be detected or recognised, and (3) to determine a speed
cut-off level above which certain types of signs or signals are no longer recognisable or detectable. Fifty-seven train drivers
from 12 Train Operating Companies in the UK participated in the trials. Twenty different types of lineside signs and ten types
of signals were tested under six different approach speeds ranging from 100 to 350 km/h (62–218 mph). Driver performance measures
were ‘time remaining to the signal/sign’ at the point of detection or recognition, and reading error rate. The results showed
a significant influence of train speed on driver responses to lineside signals/signs and demonstrated a non-linear relationship
between driver responses to signals/signs and approach speed. This has been used to estimate a maximum approach speed limit
within which a specific signal or sign can be correctly detected or recognised. The findings and implications of the study
are discussed in the paper. 相似文献
3.
JJ Callaghan GS Tooma JP Olejniczak DD Goetz RC Johnston 《Canadian Metallurgical Quarterly》1996,(333):118-125
The senior authors' initial experience with primary hybrid hip replacement in patients with osteoarthritis was studied to evaluate the efficacy of the procedure. Hybrid total hip arthroplasty (uncemented Harris-Galante acetabular component and cemented Iowa precoated femoral component) was performed in 131 consecutive, nonselected hips in 118 patients with the diagnosis of primary osteoarthritis. Followup was performed at 8 to 9 years after the procedure. The average age at the time of the procedure was 68 years (range, 45-87 years). There were 50 men (55 hips) and 68 women (76 hips). At final followup 19 patients (22 hips) had died. The femoral component had been revised for aseptic loosening in 8 hips (6.1%). One additional hip showed definite radiographic loosening. Hence, the prevalence of radiographic femoral failure was 6.9% (9 hips). No acetabular component had been revised for aseptic loosening and no acetabular component had migrated. The senior author continues to perform hybrid total hip arthroplasty in all patients with primary osteoarthritis. However, design modifications have been made in the femoral component that is used. 相似文献
4.
Various indexes have been proposed to mark when a child is on the verge of acquiring new knowledge. This article described a new method for indexing this point of transition, which is based on the specificity of children's verbal explanations. The degree to which children were specific in their verbal explanations was related to whether they benefited from instruction. In particular, children who were vague in their explanations (i.e., less specific) benefited from instruction more than children who were explicit in their explanations (i.e., more specific). This index provides insights into the child's mental state prior to acquiring new knowledge. (PsycINFO Database Record (c) 2010 APA, all rights reserved) 相似文献
5.
6.
Comments on S. Harvey's (see record 1994-43015-001) article on using the Canadian Psychological Association's (CPA's) Code of Ethics for psychologists in an organizational case. T. J. Kline disputes the necessity of developing specific standards for particular areas of practice because she contends that the CPA code is meant to serve as a guide and a conceptual device, not a body of law. (PsycINFO Database Record (c) 2010 APA, all rights reserved) 相似文献
7.
Heriberto Cabezas Christopher W. Pawlowski Audrey L. Mayer N. Theresa Hoagland 《Clean Technologies and Environmental Policy》2003,5(3-4):167-180
Sustainability is generally associated with a definition by the World Commission on Environment and Development, 1987: "... development that meets the needs of the present without compromising the ability of future generations to meet their own needs ..." However, there is no mathematical theory embodying these concepts, although one would be immensely valuable in humanity's efforts to manage the environment. The concept of sustainability applies to integrated systems comprising humans and the rest of nature; the structures and operation of the human component (society, economy, law, etc.) must be such that they reinforce the persistence of the structures and operation of the natural component (ecosystem trophic linkages, biodiversity, biogeochemical cycles, etc.). One of the challenges of sustainability research lies in linking measures of ecosystem functioning to the structure and operation of the associated social system. We review the nature of this complex system including its ecological, social, economic, and technological aspects, and propose an approach to assessing sustainability based on Information Theory that bridges the natural and human systems. These principles are then illustrated using a model system with an ecological food web linked to a rudimentary social system. This work is part of the efforts of a larger multidisciplinary group at the U.S. Environmental Protection Agency's National Risk Management Research Laboratory. 相似文献
8.
D Becker Y Razskazovskii MU Callaghan MD Sevilla 《Canadian Metallurgical Quarterly》1996,146(4):361-368
A major problem in the intensive care unit nowadays is the development of multiple organ dysfunction syndrome (MODS), a cumulative sequence of progressive deterioration of organ functions. While the pathogenic pathways of MODS remain to be elucidated, it is assumed that cells of the host defence system, especially the macrophages, are altered in their function. During the development of MODS it is assumed that macrophages are overactivated and that an exaggerated inflammatory response may contribute to its pathogenesis. In order to gain insight into the alterations of the functional status of the macrophage during the development of MODS, a series of macrophage functions was measured in the subsequent phases of zymosan induced generalized inflammation in mice. Male C57BL/6 mice received a single dose of zymosan intraperitoneally and groups of animals were killed after 2, 5, 8, and 12 days. Peritoneal macrophages were collected for in vitro assessment of the ADCC, the production of superoxide (O2-) and nitric oxide (NO), and complement mediated phagocytosis and intracellular killing of Staphylococcus aureus. A single intraperitoneal injection with zymosan resulted in a three-phase illness. During the third phase the animals developed MODS-like symptoms. Peritoneal cells from control animals produced very low to non-detectable amounts of O2- and NO, and the cytotoxic activity was also low. During the development of MODS, from day 7 onwards, the ability to produce O2- and NO2- became strongly elevated, as did the cytotoxic activity. These findings are in parallel with the development of MODS whereas the phagocytic and killing capacity remained essentially unaltered. The changes found could be detrimental for the organism, thus possibly contributing to the onset and development of MODS. 相似文献
9.
Little is known of the current smoking cessation activities of practice nurses and their attitudes toward giving smoking cessation advice. This study aimed to (a) compare practice nurses' reports of giving smoking cessation advice as part of cervical screening with their reports of giving such advice in cardiovascular disease screening and diabetes care, (b) compare their beliefs about providing such advice in these three contexts, and (c) determine the strongest predictors of their reports of giving smoking cessation advice. A survey was completed by 152 practice nurses in the United Kingdom. The frequency with which they reported giving smoking cessation advice and their beliefs about giving such advice in three contexts are reported. Nurses reported being more likely to give smoking cessation advice and had more positive beliefs about giving it in the more traditional contexts of cardiovascular screening and diabetes care compared with cervical screening. Beliefs about the appropriateness and practicality of giving such advice in the latter context were the strongest predictors of nurses' reports of doing so. This study provides guidance on the potential barriers that need to be overcome to increase the frequency with which nurses give smoking cessation advice in the context of cervical screening. 相似文献
10.
JJ Callaghan EE Forest JP Olejniczak DD Goetz RC Johnston 《Canadian Metallurgical Quarterly》1998,80(5):704-714
We evaluated the results twenty to twenty-five years after ninety-three consecutive, nonselected Charnley total hip arthroplasties performed with cement by the senior one of us in sixty-nine patients who were less than fifty years old at the time of the procedure. Seventy of the seventy-two hips in the living patients were followed radiographically for at least twenty years. Twenty-seven hips (29 per cent) had a revision or a resection of the prosthesis during the follow-up period. The revision or the resection was performed because of aseptic loosening in twenty-one hips (23 per cent), infection in four (4 per cent), dislocation in one (1 per cent), and fracture of the femur in one. Eighteen acetabular components (19 per cent) and five femoral components (5 per cent) were revised because of aseptic loosening, and an additional fourteen acetabular components (15 per cent) and seven femoral components (8 per cent) demonstrated definite or probable radiographic loosening. The present study demonstrates the long-term durability of total hip arthroplasty performed with cement in an active population of patients. The fixation of the femoral component was found to perform better than that of the acetabular component at twenty to twenty-five years after the procedure. 相似文献