SFRP2 induces a mesenchymal subtype transition by suppression of SOX2 in glioblastoma.

Intratumoral heterogeneity is a characteristic of glioblastomas that contain an intermixture of cell populations displaying different glioblastoma subtype gene expression signatures. Proportions of these populations change during tumor evolution, but the occurrence and regulation of glioblastoma subtype transition is not well described. To identify regulators of glioblastoma subtypes we utilized a combination of in vitro experiments and in silico analyses, using experimentally generated as well as publicly available data. Through this combined approach SOX2 was identified to confer a proneural glioblastoma subtype gene expression signature. SFRP2 was subsequently identified as a SOX2-antagonist, able to induce a mesenchymal glioblastoma subtype signature. A subset of patient glioblastoma samples with high SFRP2 and low SOX2 expression was particularly enriched with mesenchymal subtype samples. Phenotypically, SFRP2 decreased tumor sphere formation, stemness as assessed by limiting dilution assay, and overall cell proliferation but increased cell motility, whereas SOX2 induced the opposite effects. Furthermore, an SFRP2/non-canonical-WNT/KLF4/PDGFR/phospho-AKT/SOX2 signaling axis was found to be involved in the mesenchymal transition. Analysis of human tumor tissue spatial gene expression patterns showed distinct expression of SFRP2- and SOX2-correlated genes in vascular and cellular areas, respectively. Finally, conditioned media from SFRP2 overexpressing cells increased CD206 on macrophages. Together, these findings present SFRP2 as a SOX2-antagonist with the capacity to induce a mesenchymal subtype transition in glioma cells located in vascular tumor areas, highlighting its role in glioblastoma tumor evolution and intratumoral heterogeneity.

Reduced Expression of PROX1 Transitions Glioblastoma Cells into a Mesenchymal Gene Expression Subtype.

The homeodomain transcription factor PROX1 has been linked to several cancer types, including gliomas, but its functions remain to be further elucidated. Here we describe a functional role and the prognostic value of PROX1 in glioblastoma. Low expression of PROX1 correlated with poor overall survival and the mesenchymal glioblastoma subtype signature. The latter finding was recapitulated in vitro, where suppression or overexpression of PROX1 in glioma cell cultures transitioned cells to a mesenchymal or to a nonmesenchymal glioblastoma gene expression signature, respectively. PROX1 modulation affected proliferation rates that coincided with changes in protein levels of CCNA1 and CCNE1 as well as the cyclin inhibitors CDKN1A, CDKN1B, and CDKN1C. Overexpression of SOX2 increased PROX1 expression, but treatment with a CDK2 inhibitor subsequently decreased PROX1 expression, which was paralleled by decreased SOX2 levels. The THRAP3 protein was a novel binding partner for PROX1, and suppression of THRAP3 increased both transcript and protein levels of PROX1. Together, these findings highlight the prognostic value of PROX1 and its role as a regulator of glioblastoma gene expression subtypes, intratumoral heterogeneity, proliferation, and cell-cycle control.Significance: These findings demonstrate the role and prognostic value of PROX1 in glioblastomas; low PROX1 levels correlate with a mesenchymal gene expression subtype and shorter survival in glioblastoma tumors. Cancer Res; 78(20); 5901-16. ©2018 AACR.

The Effect of Allium cepa Extract on Lung Oxidant, Antioxidant, and Immunological Biomarkers in Ovalbumin-Sensitized Rats.

OBJECTIVES: To evaluate the effects of Allium cepa (A. cepa) on levels of oxidants, antioxidants, and immunological markers in bronchoalveolar lavage fluids (BALF) of sensitized rats. MATERIALS AND METHODS: Oxidant/antioxidant markers and cytokines in BALF of control rats treated with saline (group C), ovalbumin-sensitized rats (group S), rats treated with 1.25 µg/mL dexamethasone and 3 doses of A. cepa extract (35, 70, and 140 mg/kg body weight [BW]/day) (S + AC) were investigated. Comparison of the results between groups was performed using analysis of variance with the Tukey-Kramer post hoc test. RESULTS: The oxidant markers nitrogen dioxide (NO2), nitrate (NO3-), and malondialdehyde (MDA), and immunological markers interleukin (IL)-4 and immunoglobulin E (IgE) were significantly higher, but the antioxidant markers superoxide dismutase (SOD), catalase (CAT), thiol, and interferon (IFN)-γ, and the IFN-γ/IL-4 ratio were lower in sensitized rats compared to control rats (p < 0.001 to p < 0.01). Compared to group S, the levels of the following markers were significantly lower: NO2, NO3-, and IgE in groups treated with the A. cepa extract, MDA and IL-4 levels in groups treated with 70 and 140 mg/kg BW/day of the A. cepa extract, and all these markers as well as IFN-γ in rats treated with dexamethasone (p < 0.001 to p < 0.05). However, there were significantly higher levels of SOD and CAT and an increased IFN-γ/IL-4 ratio (groups treated with 70 and 140 mg/kg BW/day of the A. cepa extract), and levels of thiol and IFN-γ (group treated with 140 mg/kg BW/day of the A. cepa extract) as well as SOD, CAT, and thiol (dexamethasone-treated group) versus group S (p < 0.00 to p < 0.05). CONCLUSION: A. cepa showed antioxidant and immunomodulatory properties in sensitized rats.

Controlling the exciton emission of gold coated GaAs-AlGaAs core-shell nanowires with an organic spacer layer.

Excitons are the most prominent optical excitations and controlling their emission is an important step towards new optical devices. We have investigated the exciton emission from uncoated and gold/aluminum quinoline (Alq3) coated GaAs-AlGaAs-GaAs core-shell nanowires (NWs) using temperature-, intensity- and polarization dependent photoluminescence (PL). Plasmonic GaAs-AlGaAs-GaAs NWs with a ∼10 nm thick Au coating but without an Alq3 spacer layer reveal a significant reduction of the PL intensity of the exciton emission compared with the uncoated NW sample. Plasmonic NW samples with the same nominal Au coverage and an additional Alq3 interlayer of 3 or 6 nm thickness show a clearly stronger PL intensity which increases with rising Alq3 spacer thickness. Time-resolved (TR) PL measurements reveal an increase of the exciton decay rate by a factor of up to two with decreasing Alq3 spacer thickness suggesting the presence of Förster energy transfer from NW excitons to plasmon oscillations in the gold film. The weak change of the decay time, however, indicates that Förster energy-transfer is only partially responsible for the PL quenching in the gold coated NWs. The main reason for the reduction of the PL emission is attributed to a gold induced band-bending in the GaAs NW core which causes exciton dissociation. With increasing Alq3 spacer thickness the band-bending decreases leading to a reduction of the exciton dissociation and PL quenching. Our interpretation is supported by electron energy loss spectroscopy measurements which show a signal reduction and blue shift of defect (possibly EL2) transitions when gold particles are deposited on NWs compared with bare or Alq3 coated NWs.

Landfill site selection using combination of GIS and fuzzy AHP, a case study: Iranshahr, Iran.

One of the most important recent challenges in solid waste management throughout the world is site selection of sanitary landfill. Commonly, because of simultaneous effects of social, environmental, and technical parameters on suitability of a landfill site, landfill site selection is a complex process and depends on several criteria and regulations. This study develops a multi-criteria decision analysis (MCDA) process, which combines geographic information system (GIS) analysis with a fuzzy analytical hierarchy process (FAHP), to determine suitable sites for landfill construction in Iranshahr County, Iran. The GIS was used to calculate and classify selected criteria and FAHP was used to assess the criteria weights based on their effectiveness on selection of potential landfill sites. Finally, a suitability map was prepared by overlay analyses and suitable areas were identified. Four suitability classes within the study area were separated, including high, medium, low, and very low suitability areas, which represented 18%, 15%, 55%, and 12% of the study area, respectively.

Role of ribosomal protein mutations in tumor development (Review).

Ribosomes are cellular machines essential for protein synthesis. The biogenesis of ribosomes is a highly complex and energy consuming process that initiates in the nucleolus. Recently, a series of studies applying whole-exome or whole-genome sequencing techniques have led to the discovery of ribosomal protein gene mutations in different cancer types. Mutations in ribosomal protein genes have for example been found in endometrial cancer (RPL22), T-cell acute lymphoblastic leukemia (RPL10, RPL5 and RPL11), chronic lymphocytic leukemia (RPS15), colorectal cancer (RPS20), and glioma (RPL5). Moreover, patients suffering from Diamond-Blackfan anemia, a bone marrow failure syndrome caused by mutant ribosomal proteins are also at higher risk for developing leukemia, or solid tumors. Different experimental models indicate potential mechanisms whereby ribosomal proteins may initiate cancer development. In particular, deregulation of the p53 tumor suppressor network and altered mRNA translation are mechanisms likely to be involved. We envisage that changes in expression and the occurrence of ribosomal protein gene mutations play important roles in cancer development. Ribosome biology constitutes a re-emerging vital area of basic and translational cancer research.

Colonization Rate and Risk Factors of Vancomycin-Resistant Enterococci among Patients Received Hematopoietic Stem Cell Transplantation in Shiraz, Southern Iran.

BACKGROUND: Infections caused by antimicrobial-resistant bacteria are associated with increased mortality and health care costs. Enterococci have been recognized as a clinically important pathogen in hospitalized patients. Vancomycin-resistant enterococci (VRE) infections cause significant morbidity and mortality among patients undergoing transplantation. OBJECTIVE: To identify epidemiology of VRE colonization and related risk factors among patients with hematological malignancies after hematopoietic stem cell transplantation (HSCT). METHODS: This cross-sectional study was performed on 42 patients who underwent bone-marrow transplantation between July 2013 and March 2014. A stool sample was taken from each patient 3-5 days after transplantation and cultured on appropriate media. Suspected colonies of enterococci were detected to species level by their culture characteristics, biochemical reactions and molecular features. VRE were confirmed via phenotypic and genotypic methods. RESULTS: VRE were detected in 14 (33%) of studied samples. 10 (71%) of the detected VRE isolates were identified as high level vancomycin-resistant E. faecium with minimum inhibitory concentration (MIC) of ≥256 µg/mL of vancomycin; 3 isolates were E. galinarum and 1 was E. casseliflavus with an MIC of 8-16 µg/mL. VanA was dominant phenotype and all VRE isolates with high-level of vancomycin resistance had vanA gene. VRE isolation was mostly observed in patients with acute lymphoblastic leukemia (ALL) than other diseases. Moreover, antibiotic prophylaxis and hospitalization were independent risk factors for acquisition of VRE after transplantation. CONCLUSION: We found high level of vancomycin-resistance in E. faecium isolates obtained from HSCT patients. The vancomycin-resistant isolates of E.faecium had vanA and/or simultaneously vanB genes.

Electrically tunable coherent optical absorption in graphene with ion gel.

We demonstrate electrical control over coherent optical absorption in a graphene-based Salisbury screen consisting of a single layer of graphene placed in close proximity to a gold back reflector. The screen was designed to enhance light absorption at a target wavelength of 3.2 µm by using a 600 nm-thick, nonabsorbing silica spacer layer. An ionic gel layer placed on top of the screen was used to electrically gate the charge density in the graphene layer. Spectroscopic reflectance measurements were performed in situ as a function of gate bias. The changes in the reflectance spectra were analyzed using a Fresnel based transfer matrix model in which graphene was treated as an infinitesimally thin sheet with a conductivity given by the Kubo formula. The analysis reveals that a careful choice of the ionic gel layer thickness can lead to optical absorption enhancements of up to 5.5 times for the Salisbury screen compared to a suspended sheet of graphene. In addition to these absorption enhancements, we demonstrate very large electrically induced changes in the optical absorption of graphene of ∼3.3% per volt, the highest attained so far in a device that features an atomically thick active layer. This is attributable in part to the more effective gating achieved with the ion gel over the conventional dielectric back gates and partially by achieving a desirable coherent absorption effect linked to the presence of the thin ion gel that boosts the absorption by 40%.

mTOR inhibitors blunt the p53 response to nucleolar stress by regulating RPL11 and MDM2 levels.

Mechanistic target of rapamycin (mTOR) is a master regulator of cell growth through its ability to stimulate ribosome biogenesis and mRNA translation. In contrast, the p53 tumor suppressor negatively controls cell growth and is activated by a wide range of insults to the cell. The mTOR and p53 signaling pathways are connected by a number of different mechanisms. Chemotherapeutics that inhibit ribosome biogenesis often induce nucleolar stress and activation of p53. Here we have investigated how the p53 response to nucleolar stress is affected by simultaneous mTOR inhibition in osteosarcoma and glioma cell lines. We found that inhibitors of the mTOR pathway including rapamycin, wortmannin, and caffeine blunted the p53 response to nucleolar stress induced by actinomycin D. Synthetic inhibitors of mTOR (temsirolimus, LY294.002 and PP242) also impaired actinomycin D triggered p53 stabilization and induction of p21. Ribosomal protein (RPL11) is known to be required for p53 protein stabilization following nucleolar stress. Treatment of cells with mTOR inhibitors may lead to reduced synthesis of RPL11 and thereby destabilize p53. We found that rapamycin mimicked the effect of RPL11 depletion in terms of blunting the p53 response to nucleolar stress. However, the extent to which the levels of p53 and RPL11 were reduced by rapamycin varied between cell lines. Additional mechanisms whereby rapamycin blunts the p53 response to nucleolar stress are likely to be involved. Indeed, rapamycin increased the levels of endogenous MDM2 despite inhibition of its phosphorylation at Ser-166. Our findings may have implications for the design of combinatorial cancer treatments with mTOR pathway inhibitors.

Transparent metallic fractal electrodes for semiconductor devices.

Nanostructured metallic films have the potential to replace metal oxide films as transparent electrodes in optoelectronic devices. An ideal transparent electrode should possess a high, broadband, and polarization-independent transmittance. Conventional metallic gratings and grids with wavelength-scale periodicities, however, do not have all of these qualities. Furthermore, the transmission properties of a nanostructured electrode need to be assessed in the actual dielectric environment provided by a device, where a high-index semiconductor layer can reflect a substantial fraction of the incident light. Here we propose nanostructured aluminum electrodes with space-filling fractal geometries as alternatives to gratings and grids and experimentally demonstrate their superior optoelectronic performance through integration with Si photodetectors. As shown by polarization and spectrally resolved photocurrent measurements, devices with fractal electrodes exhibit both a broadband transmission and a flat polarization response that outperforms both square grids and linear gratings. Finally, we show the benefits of adding a thin silicon nitride film to the nanostructured electrodes to further reduce reflection.

Mass fabrication and delivery of 3D multilayer µTags into living cells.

Continuous monitoring of in vivo biological processes and their evolution at the cellular level would enable major advances in our understanding of biology and disease. As a stepping stone towards chronic cellular monitoring, we demonstrate massively parallel fabrication and delivery of 3D multilayer micro-Tags (µTags) into living cells. Both 10 µm × 10 µm × 1.5 µm and 18 µm × 7 µm × 1.5 µm devices containing inductive and capacitive structures were designed and fabricated as potential passive radio-frequency identification tags. We show cellular internalization and persistence of µTags over a 5-day period. Our results represent a promising advance in technologies for studying biology and disease at the cellular level.

Characteristics of care and caregivers of Alzheimer's patients in elderly care homes: a qualitative research.

BACKGROUND: Due to the increase in the number of Alzheimer's patients in Iran and also the limitation of cultural knowledge about caring of these patients, this study was designed to explore the perceptions of Iranian caregivers about caring Alzheimer patients in the elderly care homes. METHODS: A qualitative content analysis method was conducted on two elderly care homes of Shiraz/Iran, during 2009-2011. Fourteen key informants (10 women and 4 men, between 25-35 years of age), who had been working in elderly care homes caring for the elderly with Alzheimer disease for about 1-11 years (Mean=30 months) were selected by purposive sampling method. The caring experience and ability of transferring their experience to others were the main criteria for selection of the participants. They were participated in 2 focus groups and 4 interviews. RESULTS: Nearly, 800 initial codes were extracted and categorized into 3 groups of "multidimensional care", "going along with the patients" and "need to be professional" and 12 subcategories. Although several aspects of care were mentioned by the participants but the main aspect was physical care. Infantilizing the patients was the main feature of care and caring personality was an important characteristic of caregivers. CONCLUSION: An appropriate schedule of care considering main categories and subcategories of this research based on cultural context should be prepared. Moreover, consistent promotion of the schedule, employment of trained staff and plans for continued education for them can improve the quality of care and patient's life in elderly care homes.

Near field detector for integrated surface plasmon resonance biosensor applications.

Integrated surface plasmon resonance biosensors promise to enable compact and portable biosensing at high sensitivities. To replace the far field detector traditionally used to detect surface plasmons we integrate a near field detector below a functionalized gold film. The evanescent field of a surface plasmon at the aqueous-gold interface is converted into photocurrent by a thin film organic heterojunction diode. We demonstrate that use of the near field detector is equivalent to the traditional far field measurement of reflectivity. The sensor is stable and reversible in an aqueous environment for periods of 6 hrs. For specific binding of neutravidin, the detection limit is 4 microg/cm(2). The sensitivity can be improved by reducing surface roughness of the gold layers and optimization of the device design. From simulations, we predict a maximum sensitivity that is two times lower than a comparable conventional SPR biosensor.

Oral methylphenidate fails to elicit significant changes in extracellular putaminal dopamine levels in Parkinson's disease patients: positron emission tomographic studies.

In this study, we assessed the changes of endogenous dopamine (DA) levels in response to methylphenidate in 5 patients with idiopathic Parkinson's disease (PD) and 6 healthy controls. Three-dimensional positron emission tomography was performed with the D2 receptor antagonist [11C]raclopride (RAC) at baseline and 1 hour following the administration of oral methylphenidate (0.8 mg/kg) to assess changes in dopamine levels indirectly. Oral methylphenidate produced no significant change in extracellular DA levels in the putamen, as estimated by comparing changes in RAC binding at baseline and 1 hour following its administration in PD subjects and healthy controls. However, there were small changes in RAC binding of opposite direction in caudate and ventral striatal regions compared between the two groups. Although there was no consistent improvement in motor function in the PD group, some patients did experience a subjective high in response to methylphenidate (MP). Failure of oral MP to alter extracellular DA levels in putamen could result from degeneration of presynaptic dopaminergic terminals, with consequent severe reductions in the levels of endogenous DA and dopamine transporter in PD subjects. Our data provide in vivo neurochemical support for the lack of clinical efficacy following MP in PD patients and are also in keeping with reduced DA release following amphetamine in PD subjects.

Minocycline as a neuroprotective agent.

Several studies have shown that minocycline, a semisynthetic, second-generation tetracycline derivative, is neuroprotective in animal models of central nervous system trauma and several neurodegenerative diseases. Common to all these reports are the beneficial effects of minocycline in reducing neural inflammation and preventing cell death. Here, the authors review the proposed mechanisms of action of minocycline and suggest that minocycline may inhibit several aspects of the inflammatory response and prevent cell death through the inhibition of the p38 mitogen-activated protein kinase pathway, an important regulator of immune cell function and cell death.

Fourth-order partial differential equations for noise removal.

A class of fourth-order partial differential equations (PDEs) are proposed to optimize the trade-off between noise removal and edge preservation. The time evolution of these PDEs seeks to minimize a cost functional which is an increasing function of the absolute value of the Laplacian of the image intensity function. Since the Laplacian of an image at a pixel is zero if the image is planar in its neighborhood, these PDEs attempt to remove noise and preserve edges by approximating an observed image with a piecewise planar image. Piecewise planar images look more natural than step images which anisotropic diffusion (second order PDEs) uses to approximate an observed image. So the proposed PDEs are able to avoid the blocky effects widely seen in images processed by anisotropic diffusion, while achieving the degree of noise removal and edge preservation comparable to anisotropic diffusion. Although both approaches seem to be comparable in removing speckles in the observed images, speckles are more visible in images processed by the proposed PDEs, because piecewise planar images are less likely to mask speckles than step images and anisotropic diffusion tends to generate multiple false edges. Speckles can be easily removed by simple algorithms such as the one presented in this paper.

Blind image restoration by anisotropic regularization.

This paper presents anisotropic regularization techniques to exploit the piecewise smoothness of the image and the point spread function (PSF) in order to mitigate the severe lack of information encountered in blind restoration of shift-invariantly and shift-variantly blurred images. The new techniques, which are derived from anisotropic diffusion, adapt both the degree and direction of regularization to the spatial activities and orientations of the image and the PSF. This matches the piecewise smoothness of the image and the PSF which may be characterized by sharp transitions in magnitude and by the anisotropic nature of these transitions. For shift-variantly blurred images whose underlying PSFs may differ from one pixel to another, we parameterize the PSF and then apply the anisotropic regularization techniques. This is demonstrated for linear motion blur and out-of-focus blur. Alternating minimization is used to reduce the computational load and algorithmic complexity.