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排序方式: 共有81条查询结果,搜索用时 15 毫秒
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Kathryn Davidson Paul Grevitt Maria F. Contreras-Gerenas Katherine S. Bridge Miguel Hermida Kunal M. Shah Faraz K. Mardakheh Mark Stubbs Rosemary Burke Pedro Casado Pedro R. Cutillas Sarah A. Martin Tyson V. Sharp 《Cell death & disease》2021,12(11)
An early event in lung oncogenesis is loss of the tumour suppressor gene LIMD1 (LIM domains containing 1); this encodes a scaffold protein, which suppresses tumorigenesis via a number of different mechanisms. Approximately 45% of non-small cell lung cancers (NSCLC) are deficient in LIMD1, yet this subtype of NSCLC has been overlooked in preclinical and clinical investigations. Defining therapeutic targets in these LIMD1 loss-of-function patients is difficult due to a lack of ‘druggable’ targets, thus alternative approaches are required. To this end, we performed the first drug repurposing screen to identify compounds that confer synthetic lethality with LIMD1 loss in NSCLC cells. PF-477736 was shown to selectively target LIMD1-deficient cells in vitro through inhibition of multiple kinases, inducing cell death via apoptosis. Furthermore, PF-477736 was effective in treating LIMD1−/− tumours in subcutaneous xenograft models, with no significant effect in LIMD1+/+ cells. We have identified a novel drug tool with significant preclinical characterisation that serves as an excellent candidate to explore and define LIMD1-deficient cancers as a new therapeutic subgroup of critical unmet need.Subject terms: Targeted therapies, Non-small-cell lung cancer 相似文献
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The striatum of rats was lesioned by unilateral administration of MPP+. Two weeks later, a suspension of fetal mesencephalic cells (FMC), obtained from 14-day rat embryos, was injected into the lesioned striatum. Two weeks after grafting, the success of implantation and recovery of dopamine function were assessed by tyrosine hydroxylase immunocytochemistry (TH) and the measurement of striatal dopamine content. In addition, the extracellular concentrations of dopamine and dopamine metabolites were studied by microdialysis in vivo before and after perfusion of MPP+ to induce dopamine release from vesicular stores. TH+ cell bodies were seen in the lesioned grafted striata, indicating that fetal cells survived in these striata. In addition, there was a marked increase in TH-immunoreactivity in the neuronal fibers and terminals in the area surrounding the cell implant, suggesting a compensatory response of the host tissue which may involve fiber sprouting. Grafting induced a recovery in indices of dopamine function, including recovery in dopamine content, and basal and MPP+-induced dopamine release. Thus, grafts of FMC may provide a significant recovery of dopamine function in MPP+-lesioned striata. 相似文献
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MS (mass spectrometry) techniques are rapidly evolving to high levels of performance and robustness. This is allowing the application of these methods to the interrogation of signalling networks with unprecedented depth and accuracy. In the present review we discuss how MS-based multiplex quantification of kinase activities and phosphoproteomics provide complementary means to assess biological signalling activity. In addition, we discuss how a wider application of these analytical concepts to quantify kinase signalling will result in a more comprehensive understanding of normal and disease biology at the system level. 相似文献
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PR Marcelino MS Aoki AFS Arruda CG Freitas A Mendez-Villanueva A Moreira 《Biology of sport / Institute of Sport》2016,33(1):37-42
The purpose of this study was to investigate the effect of court size on physiological responses and physical performance of young elite basketball players. Twelve male basketball players (18.6 ± 0.5 years; 88.8 ± 14.5 kg; 192.6 ± 6.5 cm) from an under-19 team performed two small-sided games (matches) with different court areas (28x15 m and 28x9 m; 28x15 and 28x9 protocols). The number of players (3x3) was kept the same in each protocol. The players performed a repeated-sprint ability (RSA) test before and after each match. Blood lactate concentration was collected before (pre) and after (post) the matches, and the session rating of perceived exertion (session-RPE) was determined 30 minutes after the match. Best and mean time in the RSA test were not different between the 28x15 and the 28x9 match protocols (p > 0.05). A significant difference was observed for lactate concentration from pre- to post-match (p < 0.05) in both protocols (28x15 and 28x9); however, there was no significant interaction between protocols. A similar session-RPE mean score (28x15: 7.2 ± 1.4 and 28x9: 6.6 ± 1.4) was detected for both protocols (p > 0.05, ES=0.41). In summary, the results of the current study suggest that the different court areas induced similar responses. Although there was no significant difference in effort perception, players tended to perceive a greater effort in the larger court size. 相似文献
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Phosphoproteomics is increasingly used to address a wide range of biological questions. However, despite some success, techniques for phosphoproteomics are not without challenges. Phosphoproteins are present in cells in low abundance relative to their unphosphorylated counterparts; therefore phosphorylated proteins (or phosphopeptides after protein digestion) are rarely detected in standard shotgun proteomics experiments. Thus, extraction of phosphorylated polypeptides from complex mixtures is a critical step in the success of phosphoproteomics experiments. Intense research over the last decade has resulted in the development of powerful techniques for phosphopeptide enrichment prior to analysis by mass spectrometry. Here, we review how the development of IMAC, MOAC, chemical derivatization and antibody affinity purification and chromatography is contributing to the evolution of phosphoproteomics techniques. Although further developments are needed for the technology to reach maturity, current state-of-the-art techniques can already be used as powerful tools for biological research. 相似文献
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Pedro Casado Maria P Alcolea Francesco Iorio Juan-Carlos Rodríguez-Prados Bart Vanhaesebroeck Julio Saez-Rodriguez Simon Joel Pedro R Cutillas 《Genome biology》2013,14(4):R37
Background
Tumor classification based on their predicted responses to kinase inhibitors is a major goal for advancing targeted personalized therapies. Here, we used a phosphoproteomic approach to investigate biological heterogeneity across hematological cancer cell lines including acute myeloid leukemia, lymphoma, and multiple myeloma.Results
Mass spectrometry was used to quantify 2,000 phosphorylation sites across three acute myeloid leukemia, three lymphoma, and three multiple myeloma cell lines in six biological replicates. The intensities of the phosphorylation sites grouped these cancer cell lines according to their tumor type. In addition, a phosphoproteomic analysis of seven acute myeloid leukemia cell lines revealed a battery of phosphorylation sites whose combined intensities correlated with the growth-inhibitory responses to three kinase inhibitors with remarkable correlation coefficients and fold changes (> 100 between the most resistant and sensitive cells). Modeling based on regression analysis indicated that a subset of phosphorylation sites could be used to predict response to the tested drugs. Quantitative analysis of phosphorylation motifs indicated that resistant and sensitive cells differed in their patterns of kinase activities, but, interestingly, phosphorylations correlating with responses were not on members of the pathway being targeted; instead, these mainly were on parallel kinase pathways.Conclusion
This study reveals that the information on kinase activation encoded in phosphoproteomics data correlates remarkably well with the phenotypic responses of cancer cells to compounds that target kinase signaling and could be useful for the identification of novel markers of resistance or sensitivity to drugs that target the signaling network. 相似文献9.
Populations of Trichuris spp. isolated from six species of sigmodontine rodents from Argentina were analyzed based on morphological characteristics and ITS2 (rDNA) region sequences. Molecular data provided an opportunity to discuss the phylogenetic relationships among the Trichuris spp. from Noth and South America (mainly from Argentina). Trichuris specimens were identified morphologically as Trichuris pardinasi, T. navonae, Trichuris sp. and Trichuris new species, described in this paper. Sequences analyzed by Maximum Parsimony, Maximum Likelihood and Bayesian inference methods showed four main clades corresponding with the four different species regardless of geographical origin and host species. These four species from sigmodontine rodents clustered together and separated from Trichuris species isolated from murine and arvicoline rodents (outgroup). Different genetic lineages observed among Trichuris species from sigmodontine rodents which supported the proposal of a new species. Moreover, host distribution showed correspondence with the different tribes within the subfamily Sigmodontinae. 相似文献
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波长514nm的激光照射可用于研究激光导致有丝分裂染色体畸变的效应。本文提供了一种新的辐照系统,能用于研究突变的感应现象,并与从γ-线辐射源获得的结果进行了比较。Abstract:Laser irradiation at wavelength 514 nm was used to study the effect of lasers in inducing chromosomal aberrations at mitosis.This study offers a new radiation system which could be used for the induction of mutations.Results are compared with those obtained from studies using γ-rays as irradiation source. 相似文献