A hypoxic microenvironment induces resistance to alkylating agents by activating targets in the mammalian target of rapamycin (mTOR) pathway. The molecular mechanisms involved in this mTOR-mediated ...hypoxia-induced chemoresistance, however, are unclear. Here we identify the mTOR target N -myc downstream regulated gene 1 (NDRG1) as a key determinant of resistance toward alkylating chemotherapy, driven by hypoxia but also by therapeutic measures such as irradiation, corticosteroids, and chronic exposure to alkylating agents via distinct molecular routes involving hypoxia-inducible factor (HIF)-1alpha, p53, and the mTOR complex 2 (mTORC2)/serum glucocorticoid-induced protein kinase 1 (SGK1) pathway. Resistance toward alkylating chemotherapy but not radiotherapy was dependent on NDRG1 expression and activity. In posttreatment tumor tissue of patients with malignant gliomas, NDRG1 was induced and predictive of poor response to alkylating chemotherapy. On a molecular level, NDRG1 bound and stabilized methyltransferases, chiefly O ⁶-methylguanine-DNA methyltransferase (MGMT), a key enzyme for resistance to alkylating agents in glioblastoma patients. In patients with glioblastoma, MGMT promoter methylation in tumor tissue was not more predictive for response to alkylating chemotherapy in patients who received concomitant corticosteroids.
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•Comparative study of relaxation and diffusion of CO2 and CH4 in nanopores.•Adsorbed phase T1 and T2 in ZIF-8 exceed bulk gas phase data.•Surface relaxivities in ZIF-8 are smaller ...than in ZSM-58.•8-Ring windows of ZSM-58 reduce CH4 self-diffusion stronger than 6-ring windows of ZIF-8.
The 1H and 13C relaxation times of methane and carbon dioxide adsorbed in nanoporous ZIF-8 increase with loading and exceed the values of the bulk gases at the corresponding equilibrium pressure. The surface relaxation for the adsorbed molecules was determined by plotting the relaxation rates as function of inverse density. Longitudinal surface relaxivities of (3.1±0.7)×10-10m·s-1 for CH4 at 125MHz and of (1.22±0.07)×10-10m·s-1 for 13CO2 at 100.6MHz were obtained in ZIF-8. This approach applied to zeolite ZSM-58 yields much higher, density dependent surface relaxivities of 0.7-5.4×10-8m·s-1 for methane. In ZIF-8, the self-diffusion coefficients of both gases are in the range of 10-10m2·s-1 and do not depend significantly on density. In ZSM-58, there is a two orders of magnitude difference in the diffusivities of both gases, which is caused by the small 8-ring windows of this zeolite.
Gain and plasmon dynamics in active negative-index metamaterials Wuestner, Sebastian; Pusch, Andreas; Tsakmakidis, Kosmas L. ...
Philosophical transactions of the Royal Society of London. Series A: Mathematical, physical, and engineering sciences,
09/2011, Volume:
369, Issue:
1950
Journal Article
Peer reviewed
Open access
Photonic metamaterials allow for a range of exciting applications unattainable with ordinary dielectrics. However, the metallic nature of their meta-atoms may result in increased optical losses. ...Gain-enhanced metamaterials are a potential solution to this problem, but the conception of realistic, three-dimensional designs is a challenging task. Starting from fundamental electrodynamic and quantum mechanical equations, we establish and deploy a rigorous theoretical model for the spatial and temporal interaction of lightwaves with free and bound electrons inside and around metallic (nano-) structures and gain media. The derived numerical framework allows us to self-consistently study the dynamics and impact of the coherent plasmon-gain interaction, nonlinear saturation, field enhancement, radiative damping and spatial dispersion. Using numerical pump-probe experiments on a double-fishnet metamaterial structure with dye molecule inclusions, we investigate the build-up of the inversion profile and the formation of the plasmonic modes in a low-Q cavity. We find that full loss compensation occurs in a regime where the real part of the effective refractive index of the metamaterial becomes more negative compared to the passive case. Our results provide a deep insight into how internal processes affect the overall optical properties of active photonic metamaterials fostering new approaches to the design of practical, loss-compensated plasmonic nanostructures.
The application of plasmonics to thermal emitters is generally assisted by absorptive losses in the metal because Kirchhoff's law prescribes that only good absorbers make good thermal emitters. Based ...on a designed plasmonic crystal and exploiting a slow-wave lattice resonance and spontaneous thermal plasmon emission, we engineer a tungsten-based thermal emitter, fabricated in an industrial CMOS process, and demonstrate its markedly improved practical use in a prototype non-dispersive infrared (NDIR) gas-sensing device. We show that the emission intensity of the thermal emitter at the CO(2) absorption wavelength is enhanced almost 4-fold compared to a standard non-plasmonic emitter, which enables a proportionate increase in the signal-to-noise ratio of the CO(2) gas sensor.
Human astrocytomas and oligodendrogliomas are defined by mutations of the metabolic enzymes isocitrate dehydrogenase (IDH) 1 or 2, resulting in the production of the abnormal metabolite D-2 ...hydroxyglutarate. Here, we studied the effect of mutant IDH on cell proliferation and apoptosis in a glioma mouse model. Tumors were generated by inactivating
and
in forebrain progenitors and compared with tumors additionally expressing the Idh1 R132H mutation. Idh-mutant cells proliferated less
and mice with Idh-mutant tumors survived significantly longer compared with Idh-wildtype mice. Comparison of miRNA and RNA expression profiles of Idh-wildtype and Idh-mutant cells and tumors revealed miR-183 was significantly upregulated in IDH-mutant cells. Idh-mutant cells were more sensitive to endoplasmic reticulum (ER) stress, resulting in increased apoptosis and thus reduced cell proliferation and survival. This was mediated by the interaction of miR-183 with the 5' untranslated region of semaphorin 3E, downregulating its function as an apoptosis suppressor. In conclusion, we show that mutant Idh1 delays tumorigenesis and sensitizes tumor cells to ER stress and apoptosis. This may open opportunities for drug treatments targeting the miR-183-semaphorin axis. SIGNIFICANCE: The pathologic metabolite 2-hydroxyglutarate, generated by IDH-mutant astrocytomas, sensitizes tumor cells to ER stress and delays tumorigenesis. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/79/19/4994/F1.large.jpg.
Recognizing and categorizing visual stimuli are cognitive functions vital for survival, and an important feature of visual systems in primates as well as in birds. Visual stimuli are processed along ...the ventral visual pathway. At every stage in the hierarchy, neurons respond selectively to more complex features, transforming the population representation of the stimuli. It is therefore easier to read-out category information in higher visual areas. While explicit category representations have been observed in the primate brain, less is known on equivalent processes in the avian brain. Even though their brain anatomies are radically different, it has been hypothesized that visual object representations are comparable across mammals and birds. In the present study, we investigated category representations in the pigeon visual forebrain using recordings from single cells responding to photographs of real-world objects. Using a linear classifier, we found that the population activity in the visual associative area mesopallium ventrolaterale (MVL) distinguishes between animate and inanimate objects, although this distinction is not required by the task. By contrast, a population of cells in the entopallium, a region that is lower in the hierarchy of visual areas and that is related to the primate extrastriate cortex, lacked this information. A model that pools responses of simple cells, which function as edge detectors, can account for the animate vs. inanimate categorization in the MVL, but performance in the model is based on different features than in MVL. Therefore, processing in MVL cells is very likely more abstract than simple computations on the output of edge detectors.
Papillary glioneuronal tumor (PGNT) is a WHO-defined brain tumor entity that poses a major diagnostic challenge. Recently,
SLC44A1
–
PRKCA
fusions have been described in PGNT. We subjected 28 brain ...tumors from different institutions histologically diagnosed as PGNT to molecular and morphological analysis. Array-based methylation analysis revealed that 17/28 tumors exhibited methylation profiles typical for other tumor entities, mostly dysembryoplastic neuroepithelial tumor and hemispheric pilocytic astrocytoma. Conversely, 11/28 tumors exhibited a unique profile, thus constituting a distinct methylation class PGNT. By screening the extended Heidelberg cohort containing over 25,000 CNS tumors, we identified three additional tumors belonging to this methylation cluster but originally histologically diagnosed otherwise. RNA sequencing for the detection of
SLC44A1
–
PRKCA
fusions could be performed on 19 of the tumors, 10 of them belonging to the methylation class PGNT. In two additional cases,
SLC44A1
–
PRKCA
fusions were confirmed by FISH. We detected fusions involving
PRKCA
in all cases of this methylation class with material available for analyses: the canonical
SLC44A1
–
PRKCA
fusion was observed in 11/12 tumors, while the remaining case exhibited a
NOTCH1
-
PRKCA
fusion. Neither of the fusions was found in the tumors belonging to other methylation classes. Our results point towards a high misclassification rate of the morphological diagnosis PGNT and clearly demonstrate the necessity of molecular analyses.
PRKCA
fusions are highly diagnostic for PGNT, and detection by RNA sequencing enables the identification of rare fusion partners. Methylation analysis recognizes a unique methylation class PGNT irrespective of the nature of the
PRKCA
fusion.
Multiple studies have shown that patients with IDH mutant gliomas survive longer than those with IDH wild type gliomas. However, how the IDH mutation confers a better prognosis, is still largely ...unclear. To study the role of IDH mutation during glioma initiation and growth, we used a mouse model, which can express mutant Idh1 R132H upon Cre mediated recombination. In vitro, murine Idh1 R132H neural stem cells showed significantly lower proliferation but increased apoptosis rate when compared with normal SVZ derived stem/progenitor cells. We found that Idh1 R132H alone did not generate gliomas in neonatal or adult mice, and only upon crossing Idh1 R132H mice with PtenloxP/loxP;p53loxP/loxP mice, we observed formation of gliomas. In this context, the additional presence of the Idh mutation slowed down tumour growth and increased the rate of apoptosis. We performed RNA and miRNA sequencing on double (Pten/p53) and triple (Idh1/Pten/p53) mutant glioma initiating cells. Gene expression analysis shows a significant enrichment of genes involved in apoptosis and endoplasmic reticulum (ER) stress response in IDH mutant cells. Treatment of the cells with tunicamycin and tharpsigargin, two ER stress inducers, caused significant apoptosis in Idh1 mutant cells but not in Idh1 wt cells. Furthermore, the upregulation of Chop, Atf4 and Gadd34, constituents of the PERK branch (apoptosis), was increased after tunicamycin and tharpsigargin treatment. MiRNA sequencing data showed upregulation of miR-183-5p in Idh1 mutant cells. Subsequent overexpression of miR-183-5p promoted Idh1 wt cells to apoptosis under ER stress. In conclusion, we show here a pathway involved in triggering apoptosis in IDH mutant tumours. Triggering apoptosis with ER-Stress-inducing drugs may in the future provide an option for therapeutic intervention in IDH mutant tumours.
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