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排序方式: 共有195条查询结果,搜索用时 15 毫秒
1.
Freshly isolated decidual large granular lymphocytes (LGL) show natural killer (NK) activity against K562 cells but not against normal human trophoblast. We now show that these decidual LGL proliferate in vitro in response to recombinant interleukin-2 (rIL-2) and that these rIL-2-stimulated cells acquire a broad cytolytic potential that is characteristic of lymphokine-activated killer (LAK) cells. Both fetal fibroblasts and JEG-3 choriocarcinoma cells are resistant to lysis by freshly isolated decidual effectors but are readily killed by IL-2-stimulated decidual LGL. The ability to kill these target cells is acquired after only 18 hr exposure to rIL-2. rIL-2-activated decidual LGL also kill cultured normal trophoblast cells but much lower levels of cytolysis were seen even after the effectors had been stimulated with rIL-2 for 4-6 days. The preferential killing of malignant over normal human trophoblast cells raises questions about the potential role of IL-2-activated decidual LGL in the control of unduly invasive or malignant trophoblast populations in vivo. 相似文献
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Absolute Quantification of E1, Ubiquitin-Like Proteins and Nedd8–MLN4924 Adduct by Mass Spectrometry
Xiaofeng Yang James E. Brownell Qing Xu Fengying Zhu Jingya Ma Huay-Keng Loke Neil Rollins Teresa A. Soucy James J. Minissale Michael P. Thomas William D. Mallender Lawrence R. Dick Ping Li Hua Liao 《Cell biochemistry and biophysics》2013,67(1):139-147
Ubiquitin (Ub) and ubiquitin-like (Ubl) proteins regulate a variety of important cellular processes by forming covalent conjugates with target proteins or lipids. Ubl conjugation is catalyzed by a cascade of proteins including activating enzymes (E1), conjugating enzymes (E2), and in many cases ligation enzymes (E3). The discovery of MLN4924 (Brownell et al., Mol Cell 37: 102–111, 1), an investigational small molecule that is a mechanism-based inhibitor of NEDD8-activating enzyme (NAE), reveals a promising strategy of targeting E1/Ubl pathway for therapeutic purposes. In order to better understand, the biochemical dynamics of Ubl conjugation in cells and tissues, we have developed a mass spectrometry-based method to quantify E1 and Ubls using isotope-labeled proteins as internal standards. Furthermore, we have used the described method to quantify levels of the covalent Nedd8-inhibitor adduct formed in MLN4924 treated cells and tissues. The Nedd8–MLN4924 adduct is a tight-binding inhibitor of NAE, and its cellular concentration represents an indirect pharmacodynamic readout of NAE/Nedd8 pathway inhibition. 相似文献
4.
David Martino Yuk Jin Loke Lavinia Gordon Miina Ollikainen Mark N Cruickshank Richard Saffery Jeffrey M Craig 《Genome biology》2013,14(5):R42
Background
The extent to which development- and age-associated epigenetic changes are influenced by genetic, environmental and stochastic factors remains to be discovered. Twins provide an ideal model with which to investigate these influences but previous cross-sectional twin studies provide contradictory evidence of within-pair epigenetic drift over time. Longitudinal twin studies can potentially address this discrepancy.Results
In a pilot, genome-scale study of DNA from buccal epithelium, a relatively homogeneous tissue, we show that one-third of the CpGs assayed show dynamic methylation between birth and 18 months. Although all classes of annotated genomic regions assessed show an increase in DNA methylation over time, probes located in intragenic regions, enhancers and low-density CpG promoters are significantly over-represented, while CpG islands and high-CpG density promoters are depleted among the most dynamic probes. Comparison of co-twins demonstrated that within-pair drift in DNA methylation in our cohort is specific to a subset of pairs, who show more differences at 18 months. The rest of the pairs show either minimal change in methylation discordance, or more similar, converging methylation profiles at 18 months. As with age-associated regions, sites that change in their level of within-pair discordance between birth and 18 months are enriched in genes involved in development, but the average magnitude of change is smaller than for longitudinal change.Conclusions
Our findings suggest that DNA methylation in buccal epithelium is influenced by non-shared stochastic and environmental factors that could reflect a degree of epigenetic plasticity within an otherwise constrained developmental program. 相似文献5.
Barbara A. Jennings Yoon K. Loke Jane Skinner Melanie Keane Gavin S. Chu Richard Turner Daniel Epurescu Ann Barrett Gavin Willis 《PloS one》2013,8(10)
The potential clinical utility of genetic markers associated with response to fluoropyrimidine treatment in colorectal cancer patients remains controversial despite extensive study. Our aim was to test the clinical validity of both novel and previously identified markers of adverse events in a broad clinical setting. We have conducted an observational pharmacogenetic study of early adverse events in a cohort study of 254 colorectal cancer patients treated with 5-fluorouracil or capecitabine. Sixteen variants of nine key folate (pharmacodynamic) and drug metabolising (pharmacokinetic) enzymes have been analysed as individual markers and/or signatures of markers. We found a significant association between TYMP S471L (rs11479) and early dose modifications and/or severe adverse events (adjusted OR = 2.02 [1.03; 4.00], p = 0.042, adjusted OR = 2.70 [1.23; 5.92], p = 0.01 respectively). There was also a significant association between these phenotypes and a signature of DPYD mutations (Adjusted OR = 3.96 [1.17; 13.33], p = 0.03, adjusted OR = 6.76 [1.99; 22.96], p = 0.002 respectively). We did not identify any significant associations between the individual candidate pharmacodynamic markers and toxicity. If a predictive test for early adverse events analysed the TYMP and DPYD variants as a signature, the sensitivity would be 45.5 %, with a positive predictive value of just 33.9 % and thus poor clinical validity. Most studies to date have been under-powered to consider multiple pharmacokinetic and pharmacodynamic variants simultaneously but this and similar individualised data sets could be pooled in meta-analyses to resolve uncertainties about the potential clinical utility of these markers. 相似文献
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BackgroundWe performed a systematic review to assess whether we can quantify the underreporting of adverse events (AEs) in the published medical literature documenting the results of clinical trials as compared with other nonpublished sources, and whether we can measure the impact this underreporting has on systematic reviews of adverse events.ConclusionsThere is strong evidence that much of the information on adverse events remains unpublished and that the number and range of adverse events is higher in unpublished than in published versions of the same study. The inclusion of unpublished data can also reduce the imprecision of pooled effect estimates during meta-analysis of adverse events. 相似文献
7.
Gunasekaran Suwarnalata Ai Huey Tan Hidayah Isa Ranganath Gudimella Arif Anwar Mun Fai Loke Sanjiv Mahadeva Shen-Yang Lim Jamuna Vadivelu 《PloS one》2016,11(4)
Parkinson''s disease (PD) is the second most common chronic and progressive neurodegenerative disorder. Its etiology remains elusive and at present only symptomatic treatments exists. Helicobacter pylori chronically colonizes the gastric mucosa of more than half of the global human population. Interestingly, H. pylori positivity has been found to be associated with greater of PD motor severity. In order to investigate the underlying cause of this association, the Sengenics Immunome protein array, which enables simultaneous screening for autoantibodies against 1636 human proteins, was used to screen the serum of 30 H. pylori-seropositive PD patients (case) and 30 age- and gender-matched H. pylori-seronegative PD patients (control) in this study. In total, 13 significant autoantibodies were identified and ranked, with 8 up-regulated and 5 down-regulated in the case group. Among autoantibodies found to be elevated in H. pylori-seropositive PD were included antibodies that recognize Nuclear factor I subtype A (NFIA), Platelet-derived growth factor B (PDGFB) and Eukaryotic translation initiation factor 4A3 (eIFA3). The presence of elevated autoantibodies against proteins essential for normal neurological functions suggest that immunomodulatory properties of H. pylori may explain the association between H. pylori positivity and greater PD motor severity. 相似文献
8.
Peter A. Todd Eliza C. Heery Lynette H. L. Loke Ruth H. Thurstan D. Johan Kotze Christopher Swan 《Oikos》2019,128(9):1215-1242
Human population density within 100 km of the sea is approximately three times higher than the global average. People in this zone are concentrated in coastal cities that are hubs for transport and trade – which transform the marine environment. Here, we review the impacts of three interacting drivers of marine urbanization (resource exploitation, pollution pathways and ocean sprawl) and discuss key characteristics that are symptomatic of urban marine ecosystems. Current evidence suggests these systems comprise spatially heterogeneous mosaics with respect to artificial structures, pollutants and community composition, while also undergoing biotic homogenization over time. Urban marine ecosystem dynamics are often influenced by several commonly observed patterns and processes, including the loss of foundation species, changes in biodiversity and productivity, and the establishment of ruderal species, synanthropes and novel assemblages. We discuss potential urban acclimatization and adaptation among marine taxa, interactive effects of climate change and marine urbanization, and ecological engineering strategies for enhancing urban marine ecosystems. By assimilating research findings across disparate disciplines, we aim to build the groundwork for urban marine ecology – a nascent field; we also discuss research challenges and future directions for this new field as it advances and matures. Ultimately, all sides of coastal city design: architecture, urban planning and civil and municipal engineering, will need to prioritize the marine environment if negative effects of urbanization are to be minimized. In particular, planning strategies that account for the interactive effects of urban drivers and accommodate complex system dynamics could enhance the ecological and human functions of future urban marine ecosystems. 相似文献
9.
F H Falcone P Loke X Zang A S MacDonald R M Maizels J E Allen 《Journal of immunology (Baltimore, Md. : 1950)》2001,167(9):5348-5354
10.
There has been considerable attention focused recently on the risk of deep venous thrombosis (DVT) associated with air travel. Despite the lack of evidence among air travelers, a single dose of aspirin has been widely recommended as a means of preventing such thrombosis. We have calculated the potential benefit of aspirin by applying the data for aspirin in preventing DVT in hip fracture patients to the estimated rates of travel-related DVT. If the rate of travel-related DVT is 20 per 100,000 travelers, then we will have to treat 17,000 people with aspirin to prevent 1 additional DVT. 相似文献