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181.
Purpose
Dendritic cell (DC) vaccines have recently emerged as an innovative therapeutic option for glioblastoma patients. To identify novel surrogates of anti-tumor immune responsiveness, we studied the dynamic expression of activation and inhibitory markers on peripheral blood lymphocyte (PBL) subsets in glioblastoma patients treated with DC vaccination at UCLA.Experimental Design
Pre-treatment and post-treatment PBL from 24 patients enrolled in two Phase I clinical trials of dendritic cell immunotherapy were stained and analyzed using flow cytometry. A univariate Cox proportional hazards model was utilized to investigate the association between continuous immune monitoring variables and survival. Finally, the immune monitoring variables were dichotomized and a recursive partitioning survival tree was built to obtain cut-off values predictive of survival.Results
The change in regulatory T cell (CD3+CD4+CD25+CD127low) frequency in PBL was significantly associated with survival (p = 0.0228; hazard ratio = 3.623) after DC vaccination. Furthermore, the dynamic expression of the negative co-stimulatory molecule, CTLA-4, was also significantly associated with survival on CD3+CD4+ T cells (p = 0.0191; hazard ratio = 2.840) and CD3+CD8+ T cells (p = 0.0273; hazard ratio = 2.690), while that of activation markers (CD25, CD69) was not. Finally, a recursive partitioning tree algorithm was utilized to dichotomize the post/pre fold change immune monitoring variables. The resultant cut-off values from these immune monitoring variables could effectively segregate these patients into groups with significantly different overall survival curves.Conclusions
Our results suggest that monitoring the change in regulatory T cell frequencies and dynamic expression of the negative co-stimulatory molecules on peripheral blood T cells, before and after DC vaccination, may predict survival. The cut-off point generated from these data can be utilized in future prospective immunotherapy trials to further evaluate its predictive validity. 相似文献182.
Durrant C Swertz MA Alberts R Arends D Möller S Mott R Prins P van der Velde KJ Jansen RC Schughart K 《Briefings in bioinformatics》2012,13(2):135-142
During a meeting of the SYSGENET working group 'Bioinformatics', currently available software tools and databases for systems genetics in mice were reviewed and the needs for future developments discussed. The group evaluated interoperability and performed initial feasibility studies. To aid future compatibility of software and exchange of already developed software modules, a strong recommendation was made by the group to integrate HAPPY and R/qtl analysis toolboxes, GeneNetwork and XGAP database platforms, and TIQS and xQTL processing platforms. R should be used as the principal computer language for QTL data analysis in all platforms and a 'cloud' should be used for software dissemination to the community. Furthermore, the working group recommended that all data models and software source code should be made visible in public repositories to allow a coordinated effort on the use of common data structures and file formats. 相似文献
183.
Webber SE Marakovits JT Dragovich PS Prins TJ Zhou R Fuhrman SA Patick AK Matthews DA Lee CA Srinivasan B Moran T Ford CE Brothers MA Harr JE Meador JW Ferre RA Worland ST 《Bioorganic & medicinal chemistry letters》2001,11(20):2683-2686
Novel tripeptidyl C-terminal Michael acceptors with an ester replacement of the P(2)-P(3) amide bond were investigated as irreversible inhibitors of the human rhinovirus (HRV) 3C protease (3CP). When screened against HRV serotype-14 the best compound was shown to have very good 3CP inhibition (k(obs)/[I]=270,000M(-1)s(-1)) and potent in vitro antiviral activity (EC(50)=7.0nM). 相似文献
184.
Depolarization of Cell Membrane Potential during Trans-Plasma Membrane Electron Transfer to Extracellular Electron Acceptors in Iron-Deficient Roots of Phaseolus vulgaris L 总被引:1,自引:8,他引:1
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Transfer of electrons from the cytosol of bean (Phaseolus vulgaris L.) root cells to extracellular acceptors such as ferricyanide and FeIIIEDTA causes a rapid depolarization of the membrane potential. This effect is most pronounced (30-40 millivolts) with root cells of Fe-deficient plants, which have an increased capacity to reduce extracellular ferric salts. Ferrocyanide has no effect. In the state of ferricyanide reduction, H+ (1H+/2 electrons) and K+ ions are excreted. The reduction of extracellular ferric salts by roots of Fe-deficient bean plants is driven by cellular NADPH (Sijmons, van den Briel, Bienfait 1984 Plant Physiol 75: 219-221). From this and from the membrane potential depolarization, we conclude that trans-plasma membrane electron transfer from NADPH is the primary process in the reduction of extracellular ferric salts. 相似文献
185.
Prins A van Heerden PD Olmos E Kunert KJ Foyer CH 《Journal of experimental botany》2008,59(7):1935-1950
The roles of cysteine proteinases (CP) in leaf protein accumulation and composition were investigated in transgenic tobacco (Nicotiana tabacum L.) plants expressing the rice cystatin, OC-1. The OC-1 protein was present in the cytosol, chloroplasts, and vacuole of the leaves of OC-1 expressing (OCE) plants. Changes in leaf protein composition and turnover caused by OC-1-dependent inhibition of CP activity were assessed in 8-week-old plants using proteomic analysis. Seven hundred and sixty-five soluble proteins were detected in the controls compared to 860 proteins in the OCE leaves. A cyclophilin, a histone, a peptidyl-prolyl cis-trans isomerase, and two ribulose-1,5-bisphosphate carboxylase/oxygenase (Rubisco) activase isoforms were markedly altered in abundance in the OCE leaves. The senescence-related decline in photosynthesis and Rubisco activity was delayed in the OCE leaves. Similarly, OCE leaves maintained higher leaf Rubisco activities and protein than controls following dark chilling. Immunogold labelling studies with specific antibodies showed that Rubisco was present in Rubisco vesicular bodies (RVB) as well as in the chloroplasts of leaves from 8-week-old control and OCE plants. Western blot analysis of plants at 14 weeks after both genotypes had flowered revealed large increases in the amount of Rubisco protein in the OCE leaves compared to controls. These results demonstrate that CPs are involved in Rubisco turnover in leaves under optimal and stress conditions and that extra-plastidic RVB bodies are present even in young source leaves. Furthermore, these data form the basis for a new model of Rubisco protein turnover involving CPs and RVBs. 相似文献
186.
187.
Aim Anthropogenic fires are a major component of the ecology of rangelands throughout the world. To assess the effects of these fires on the diversity patterns of herbivores, we related gradients in fire occurrence, climate and soil fertility to patterns in alpha and beta diversity of African ungulates. Location West Africa. Methods We used a survey‐based approach for ungulates in 37 protected areas in desert, savanna and rain forest habitats throughout West Africa, combined with satellite images of fire occurrence and digital maps of actual evapotranspiration and soil fertility. Alpha diversity was related to the environmental variables using conventional and spatial regression models. We investigated beta diversity using partial Mantel tests and ordination techniques, and by partitioning the variance in assemblage composition into environmental and spatial components. Results The species richness of grazers showed a quadratic relationship with actual evapotranspiration, whereas that of browsers and frugivores showed a linear relationship. However, in the multiple regression models fire occurrence was the only variable that significantly correlated with the species richness of grazers. Soil fertility was weakly related to overall beta diversity and the species richness of browsers, but was non‐significant in the multiple regression models. Fire occurrence was the most important variable explaining species composition of the overall species set and of grazers, whereas the assemblage composition of browsers and frugivores was explained mostly by actual evapotranspiration. Main conclusions In contrast to previous studies, our analyses show that moisture and nutrients alone fail to adequately predict the diversity patterns of grazing ungulates. Rather, the species richness and assemblage composition of grazers are largely governed by anthropogenic fires that modify the quality and structure of the grass sward. Diversity patterns of browsers and frugivores are markedly different from grazers and depend mainly on the availability of moisture, which is positively correlated with the availability of foliage and fruits. Our study highlights the importance of incorporating major human‐induced disturbances or habitat alterations into analyses of diversity patterns. 相似文献
188.
189.
Recently, cover of large trees in African savannas has rapidly declined due to elephant pressure, frequent fires and charcoal
production. The reduction in large trees could have consequences for large herbivores through a change in forage quality.
In Tarangire National Park, in Northern Tanzania, we studied the impact of large savanna trees on forage quality for wildebeest
by collecting samples of dominant grass species in open grassland and under and around large Acacia tortilis trees. Grasses growing under trees had a much higher forage quality than grasses from the open field indicated by a more
favourable leaf/stem ratio and higher protein and lower fibre concentrations. Analysing the grass leaf data with a linear
programming model indicated that large savanna trees could be essential for the survival of wildebeest, the dominant herbivore
in Tarangire. Due to the high fibre content and low nutrient and protein concentrations of grasses from the open field, maximum
fibre intake is reached before nutrient requirements are satisfied. All requirements can only be satisfied by combining forage
from open grassland with either forage from under or around tree canopies. Forage quality was also higher around dead trees
than in the open field. So forage quality does not reduce immediately after trees die which explains why negative effects
of reduced tree numbers probably go initially unnoticed. In conclusion our results suggest that continued destruction of large
trees could affect future numbers of large herbivores in African savannas and better protection of large trees is probably
necessary to sustain high animal densities in these ecosystems. 相似文献
190.
We previously documented a ten-fold increase in gamma(cyto)-actin expression in dystrophin-deficient skeletal muscle and hypothesized that increased gamma(cyto)-actin expression may participate in an adaptive cytoskeletal remodeling response. To explore whether increased gamma(cyto)-actin fortifies the cortical cytoskeleton in dystrophic skeletal muscle, we generated double knockout mice lacking both dystrophin and gamma(cyto)-actin specifically in skeletal muscle (ms-DKO). Surprisingly, dystrophin-deficient mdx and ms-DKO mice presented with comparable levels of myofiber necrosis, membrane instability, and deficits in muscle function. The lack of an exacerbated phenotype in ms-DKO mice suggests gamma(cyto)-actin and dystrophin function in a common pathway. Finally, because both mdx and ms-DKO skeletal muscle showed similar levels of utrophin expression and presented with identical dystrophies, we conclude utrophin can partially compensate for the loss of dystrophin independent of a gamma(cyto)-actin-utrophin interaction. 相似文献