Autophagy is a critical process in acquiring drug resistance in solid tumors. However, the mechanisms by which autophagy modulate resistance to chemotherapy in bladder cancer remains poorly ...understood.
We have established cisplatin resistant patient derived primary cultured cells as well as T24 bladder cancer cells. The autophagy flux as well as the effect of chemotherapeutic agents, gemcitabine (GC) and mitomycin (MM) were evaluated in these cells. Side population analysis, tumorisphere assay and expression of stemness genes were also studied to evaluate the role of autophagy during chemoresistance. The role of cytokines in autophagy induced chemoresistance was demonstrated.
Our results show that resistant cells have higher basal autophagic flux. GC and MM led to increase in autophagy and combination of autophagy inhibitors synergistically inhibited bladder cancer cell growth. When autophagy was inhibited, only IFN-γ level was decreased in cytokine array. Blocking IFN-γ decreased JAK2 expression and reduced the autophagy. Inhibition of JAK2 decreased the proportion of cancer stem cell enriched side population, tumor sphere forming ability and led to decrease in expression of stemness genes. Combined treatment with inhibitors of JAK2 and autophagy led to inhibition in cell growth, reduced the levels of inflammatory cytokines and decreased the resistance gene expression.
GC and MM treatment increased autophagy process via IFN-γ mediated JAK2 and STAT3 pathway.
These findings support a key role of the autophagy in drug resistance. Thus, autophagy-based, “customized” combinatorial approaches may effectively manage resistance and relapse in bladder cancer.
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•Cisplatin resistant bladder cancer cells have higher basal autophagic flux.•Gemcitabine and mitomycin led to increase in IFN-γ level, autophagy and proportion of cancer stem cells (CSCs).•Blocking IFN-γ decreased JAK2/STAT3 expression and autophagy.•Inhibition of JAK2 decreased the proportion of CSCs, tumorisphere forming ability and increased cancer cell death.
Nanocrystalline GaN films with different crystallite sizes were deposited onto quartz and NaCl substrates by magnetron sputtering of a GaN target in argon plasma. All the films showed predominant ...hexagonal phase. The band gap values were always found to be higher than that of the bulk. This blue shift in band gap could be attributed to the quantum confinement effect. The optical absorption in these films could be explained by the combined effects of phonon and inhomogeneity broadening along with optical loss due to light scattering at the nanocrystallites. Band edge luminescence is absent in these GaN nanocrystalline films. The line shapes of the photoluminescence (PL) spectra are asymmetric and broad. The film deposited at lower substrate temperature showed broader PL peak. It may be observed that no significant energy shift in the peak positions was observed with reduction in crystallite size but the intensity of the peak decreased for films with the reduction in crystallite size. Below band gap emission observed in this study may also originate due to the presence of polarization-induced electric field present in wurtzite GaN deposited here.
Current trends in high performance and embedded computing include design of increasingly complex hardware architectures with high parallelism, heterogeneous processing elements, and nonuniform ...communication resources. In order to take hardware and software design decisions, early evaluations of the system nonfunctional properties are needed. These evaluations of system efficiency require electronic system-level information on both algorithms and architecture. Contrary to algorithm models for which a major body of work has been conducted on defining formal models of computation (MoCs), architecture models from the literature are mostly empirical models from which reproducible experimentation requires the accompanying software. In this paper, a precise definition of a model of architecture (MoA) is proposed that focuses on reproducibility and abstraction and removes the overlap previously existing between the notions of MoA and MoC. A first MoA, called the linear system-level architecture model (LSLA), is presented. To demonstrate the generic nature of the proposed new architecture modeling concepts, we show that the LSLA model can be integrated flexibly with different MoCs. LSLA is then used to model the energy consumption of a state-of-the-art multiprocessor system-on-chip (MPSoC) when running an application described using the synchronous dataflow MoC. A method to automatically learn LSLA model parameters from platform measurements is introduced. Despite the high complexity of the underlying hardware and software, a simple LSLA model is demonstrated to estimate the energy consumption of the MPSoC with a fidelity of 86%.
► Large bore superferric magnet with approx. 22tons of cold mass. ► Coupled Thermal, magnetic and structural analysis for magnet iron, coil, helium vessel and support links. ► Design of outer vacuum ...chamber for self weight, external pressure, magnet handling and transportation. ► Thermal design. ► Quench and loss of vacuum analysis.
The quadrupole magnets for FAIR Super FRS energy buncher have large usable aperture, high magnetic pole-tip field and high gradient field quality. The iron-dominated magnets with superconducting coils have to be used in this application. The NbTi coil, laminated iron, and support structure of about 22tons is immersed in liquid helium. The 4.5K helium chamber is completely covered with a thermal shield cooled by helium at 50–80K on its outer and inner surface. The helium chamber and thermal shield is enclosed in a vacuum shell.
The paper presents design details of the long quadrupole. Coupled thermal, magnetic and structural analysis was carried out to design the magnet iron, magnet coil, helium vessel and support links and ensure the required gradient field quality is achieved. The paper also presents the design of support links and outer vacuum chamber.
Introduction Neuropsychological and neuroimaging studies of response inhibition in cannabis users have reported inconsistent results. The age of onset of cannabis use and individual genetic ...differences may play a critical role in the regulation of inhibition in cannabis users. Aims We examine the influence of COMT Val158Met functional polymorphism on the response inhibition brain network in a group of early-onset chronic cannabis users compared with healthy controls. Methods fMRI data was acquired from 27 chronic cannabis users who began use cannabis before 16 years of age, and 29 non-using control subjects matched in terms of age, educational level and intelligence quotient while undergoing the Multi-Source Interference Task (MSIT). Participants were male, Caucasians aged between 18 and 30 years. All were assessed by a structured psychiatric interview (PRISM) to exclude any lifetime Axis-I disorder (DSM-IV). COMT genotyping was performed and resonance imaging data was analysed by voxel-based morphometry (VBM). Results Both groups did not differ on their behavioural performance and brain responses during the MSIT task. A significant group-by-genotype interaction was observed on task-related brain activation (and on MSIT reaction times), in which met carrier load was associated with increased activation in cannabis users and val carrier load with increased activation in controls. The interaction pattern included the medial frontal cortex, ACC, inferior frontal gyrus, ventral striatum, anterior mesencephalon, inferior parietal and superior temporal cortices and the PCC. Conclusion Chronic cannabis exposure interacts with the genetically driven dopamine function in the modulation of the neural mechanisms related to response inhibition. Grants:PNSD/2011/050, PNSD2006/101, SGR2009/1435.
Si-doped GaN films in polycrystalline form were deposited on quartz substrates at deposition temperatures ranging from 300–623 K using r.f. sputtering technique. Electrical, optical and ...microstructural properties were studied for these films. It was observed that films deposited at room temperature contained mainly hexagonal gallium nitride (
h
-GaN) while films deposited at 623 K were predominantly cubic (
c
-GaN) in nature. The films deposited at intermediate temperatures were found to contain both the hexagonal and cubic phases of GaN. Studies on the variation of conductivity with temperature indicated Mott’s hopping for films containing
c
-GaN while Efros and Shklovskii (E-S) hopping within the Coulomb gap was found to dominate the carrier transport mechanism in the films containing
h
-GaN. A crossover from Mott’s hopping to E-S hopping in the ‘soft’ Coulomb gap was noticed with lowering of temperature for films containing mixed phases of GaN. The relative intensity of the PL peak at ∼2·73 eV to that for peak at ∼3·11 eV appearing due to transitions from deep donor to valence band or shallow acceptors decreased significantly at higher temperature. Variation of band gap showed a bowing behaviour with the amount of cubic phase present in the films.
Magnesium–aluminium spinel has been synthesized by citrate–nitrate route using hydrated nitrates of Mg and Al as the precursors with a citrate–nitrate ratio of 1:1. Self-ignition of the gel-like mass ...yielded a black mass, which crystallized to Mag–Al spinel on calcination at 650 °C for 9 h. The crystallized mass was a mixture of ordered and disordered phases of Mag–Al spinel. Phase pure-ordered spinel could be obtained for powders calcined at 1100 °C and above. The green compacts of the spinel powders could be sintered to near theoretical density at 1150 °C for 30 min. The activation energy for densification was calculated (16.4 kcal/mol) assuming Arrhenius type behaviour. The densification mechanism could be assigned to the ordering of the disordered spinel involving vacancy diffusion through the surface.
The reason for dominance of fluorescence over autoionization decay of 2p3d(1P0) state of highly stripped He-like Cl, S and Si ions have been discussed.
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