Growing evidence is showing that acetylation plays an essential role in cancer, but studies on the impact of KDAC inhibition (KDACi) on the metabolic profile are still in their infancy. Here, we analyzed, by using an iTRAQ-based quantitative proteomics approach, the changes in the proteome of KRAS-mutated non-small cell lung cancer (NSCLC) A549 cells in response to trichostatin-A (TSA) and nicotinamide (NAM) under normoxia and hypoxia. Part of this response was further validated by molecular and biochemical analyses and correlated with the proliferation rates, apoptotic cell death, and activation of ROS scavenging mechanisms in opposition to the ROS production. Despite the differences among the KDAC inhibitors, up-regulation of glycolysis, TCA cycle, oxidative phosphorylation and fatty acid synthesis emerged as a common metabolic response underlying KDACi. We also observed that some of the KDACi effects at metabolic levels are enhanced under hypoxia. Furthermore, we used a drug repositioning machine learning approach to list candidate metabolic therapeutic agents for KRAS mutated NSCLC. Together, these results allow us to better understand the metabolic regulations underlying KDACi in NSCLC, taking into account the microenvironment of tumors related to hypoxia, and bring new insights for the future rational design of new therapies. 相似文献
Maximum intensity projections (MIPs) are an important visualization technique for angiographic data sets. Efficient data inspection requires frame rates of at least five frames per second at preserved image quality. Despite the advances in computer technology, this task remains a challenge. On the one hand, the sizes of computed tomography and magnetic resonance images are increasing rapidly. On the other hand, rendering algorithms do not automatically benefit from the advances in processor technology, especially for large data sets. This is due to the faster evolving processing power and the slower evolving memory access speed, which is bridged by hierarchical cache memory architectures. In this paper, we investigate memory access optimization methods and use them for generating MIPs on general-purpose central processing units (CPUs) and graphics processing units (GPUs), respectively. These methods can work on any level of the memory hierarchy, and we show that properly combined methods can optimize memory access on multiple levels of the hierarchy at the same time. We present performance measurements to compare different algorithm variants and illustrate the influence of the respective techniques. On current hardware, the efficient handling of the memory hierarchy for CPUs improves the rendering performance by a factor of 3 to 4. On GPUs, we observed that the effect is even larger, especially for large data sets. The methods can easily be adjusted to different hardware specifics, although their impact can vary considerably. They can also be used for other rendering techniques than MIPs, and their use for more general image processing task could be investigated in the future. 相似文献
Hepatocyte growth factor/scatter factor (HGF/SF) treatment of the Madin-Darby canine kidney epithelial cell line causes scattering of cells grown in monolayer culture and the formation of branching tubules by cells grown in collagen gels. HGF/SF causes prolonged activation of both the mitogen-activated protein (MAP) kinase extracellular signal-regulated kinase 2 (ERK2) and the phosphoinositide 3-OH kinase (PI 3-kinase) target protein kinase B (PKB)/Akt; inhibition of either the MAP kinase pathway by the MAP kinase/ERK kinase inhibitor PD98059 or the PI 3-kinase pathway by LY294002 blocks HGF/SF induction of scattering, although in morphologically distinct ways. Expression of constitutively activated PI 3-kinase, Ras, or R-Ras will cause scattering, but activated Raf will not, indicating that activation of the MAP kinase pathway is not sufficient for this response. Downstream of PI 3-kinase, activated PKB/Akt and Rac are both unable to induce scattering, implicating a novel pathway. Scattering induced by Ras or PI 3-kinase is sensitive to PD98059, as well as to LY294002, suggesting that basal MAP kinase activity is required, but not sufficient, for the scattering response. Induction of MDCK cell tubulogenesis in collagen gels by HGF/SF is inhibited by PD98059; expression of activated Ras and Raf causes disorganized growth in this system, but activated PI 3-kinase or R-Ras causes branching tubule formation similar to that seen with HGF/SF treatment. These data indicate that multiple signaling pathways acting downstream of Met and Ras are needed for these morphological effects; scattering is induced primarily by the PI 3-kinase pathway, which acts through effectors other than PKB/Akt or Rac and requires at least basal MAP kinase function. Elevated PI 3-kinase activity induces tubulogenesis, but total inhibition and excess activation of the MAP kinase pathway both oppose this effect. 相似文献
A CEC-funded project has been performed to tackle the problem of producing an advanced Life Monitoring System (LMS) which would calculate the creep and fatigue damage experienced by high temperature pipework components. Four areas were identified where existing Life Monitoring System technology could be improved:
1. 1. the inclusion of creep relaxation
2. 2. the inclusion of external loads on components
3. 3. a more accurate method of calculating thermal stresses due to temperature transients
4. 4. the inclusion of high cycle fatigue terms.
The creep relaxation problem was solved using stress reduction factors in an analytical in-elastic stress calculation. The stress reduction factors were produced for a number of common geometries and materials by means of non-linear finite element analysis. External loads were catered for by producing influence coefficients from in-elastic analysis of the particular piping system and using them to calculate bending moments at critical positions on the pipework from load and displacement measurements made at the convenient points at the pipework. The thermal stress problem was solved by producing a completely new solution based on Green's Function and Fast Fourier transforms. This allowed the thermal stress in a complex component to be calculated from simple non-intrusive thermocouple measurements made on the outside of the component. The high-cycle fatigue problem was dealt with precalculating the fatigue damage associated with standard transients and adding this damage to cumulative total when a transient occurred.
The site testing provided good practical experience and showed up problems which would not otherwise have been detected. 相似文献
Skeletal development of transgenic mice with a type II collagen mutation was analyzed and compared with wild-type littermates. The single base substitution in Col2a1 resulted in a glycine to serine mutation within the helical domain and corresponded to one previously identified in a patient with the lethal human chondrodysplasia, hypochondrogenesis (Horton et al. [1992] Proc. Natl. Acad. Sci. U.S.A. 89:4583-4587). Skeletal staining of embryos from 14.5 through 18.5 days of gestation demonstrated a dwarf phenotype in the transgenic embryos, most notably short limb bones and vertebral column that was first detected at 15.5 days post-coitus. In addition to the reduced length, the extent of ossification was less in the transgenic mice. The architecture of the long bone growth plate was abnormal in the transgenic tissue, in particular there was no discernible proliferative zone. There were few stacks of characteristically flattened cells and the overall length of the growth plate in the mutant embryos was reduced. At the ultrastructural level, there were fewer collagen fibrils present in the transgenic mouse cartilage compared to that of wild-type littermates. Ultrastructural localization of collagen types II, IX and XI revealed a similar pattern between the transgenic and wild-type pups, suggesting that the collagen fibrils present in the matrix of littermates with both phenotypes had a similar composition. Skeletal analysis and cartilage histochemistry indicated that effect of the type II collagen mutation was to reduce the density of the collagen fibrils within the cartilage matrix which was associated with delayed bone formation and resulted in a short-limbed phenotype. 相似文献
A neurostimulator application-specific integrated circuit (ASIC) with scalable circuitry that can stimulate 14 channels, has been developed for an epi-retinal vision prosthesis. This ASIC was designed to allow seven identical units to be connected to control up to 98 channels, with the ability to stimulate 14 electrodes simultaneously. The neurostimulator forms part of a vision prosthesis, designed to restore vision to patients who have lost their sight due to retinal diseases such as retinitis pigmentosa and macular degeneration. For charge balance, the neurostimulator was designed to stimulate with current sources and sinks operating together, and with the ability to drive a hexagonal mosaic of electrodes to reduce the electrical crosstalk that occurs when multiple bipolar stimulation sites are active simultaneously. A hexagonal mosaic of electrodes surrounds each stimulation site and has been shown to effectively isolate each site, increasing the ability to inject localized independent charge into multiple regions simultaneously. 相似文献
The microstructure of polycrystalline alumina deformed under hydrostatic pressure and at low temperature is investigated by transmission electron microscopy. Deformation occurs mainly by prism plane slip and rhombohedral twinning. Introduction of hydrogen leads to a significant decrease in the yield stress. In large grain size alumina deformed with hydrogen, accommodation of twinning involves dislocation reactions in the twin boundary and in the grains rather than by cracking. Prism plane dislocations decompose into basal dislocations by cross slip probably due to a decrease of Peierls stress for basal slip in the presence of hydrogen. 相似文献