Glioma cells on the run – the migratory transcriptome of 10 human glioma cell lines

<p>Abstract</p> <p>Background</p> <p>Glioblastoma multiforme (GBM) is the most common primary intracranial tumor and despite recent advances in treatment regimens, prognosis for affected patients remains poor. Active cell migration and invasion of GBM cells ultimately lead to ubiquitous tumor recurrence and patient death.</p> <p>To further understand the genetic mechanisms underlying the ability of glioma cells to migrate, we compared the matched transcriptional profiles of migratory and stationary populations of human glioma cells. Using a monolayer radial migration assay, motile and stationary cell populations from seven human long term glioma cell lines and three primary GBM cultures were isolated and prepared for expression analysis.</p> <p>Results</p> <p>Gene expression signatures of stationary and migratory populations across all cell lines were identified using a pattern recognition approach that integrates <it>a priori </it>knowledge with expression data. Principal component analysis (PCA) revealed two discriminating patterns between migrating and stationary glioma cells: i) global down-regulation and ii) global up-regulation profiles that were used in a proband-based rule function implemented in GABRIEL to find subsets of genes having similar expression patterns. Genes with up-regulation pattern in migrating glioma cells were found to be overexpressed in 75% of human GBM biopsy specimens compared to normal brain. A 22 gene signature capable of classifying glioma cultures based on their migration rate was developed. Fidelity of this discovery algorithm was assessed by validation of the invasion candidate gene, connective tissue growth factor (CTGF). siRNA mediated knockdown yielded reduced <it>in vitro </it>migration and <it>ex vivo </it>invasion; immunohistochemistry on glioma invasion tissue microarray confirmed up-regulation of CTGF in invasive glioma cells.</p> <p>Conclusion</p> <p>Gene expression profiling of migratory glioma cells induced to disperse <it>in vitro </it>affords discovery of genomic signatures; selected candidates were validated clinically at the transcriptional and translational levels as well as through functional assays thereby underscoring the fidelity of the discovery algorithm.</p

Electronic and Lattice Dynamics in The Photoinduced Ionic-to-Neutral Phase Transition in a One-Dimensional Extended Peierls-Hubbard Model

Real-time dynamics of charge density and lattice displacements is studied during photoinduced ionic-to-neutral phase transitions by using a one-dimensional extended Peierls-Hubbard model with alternating potentials for the one-dimensional mixed-stack charge-transfer complex, TTF-CA. The time-dependent Schr\"odinger equation and the classical equation of motion are solved for the electronic and lattice parts, respectively. We show how neutral domains grow in the ionic background. As the photoexcitation becomes intense, more neutral domains are created. Above threshold intensity, the neutral phase is finally achieved. After the photoexcitation, ionic domains with wrong polarization also appear. They quickly reduce the averaged staggered lattice displacement, compared with the averaged ionicity. As the degree of initial lattice disorder increases, more solitons appear between these ionic domains with different polarizations, which obstruct the growth of neutral domains and slow down the transition.Comment: 9 pages, 10 figures, submitted to J. Phys. Soc. Jp

Polymorphisms in Plasmodium falciparum chloroquine resistance transporter and multidrug resistance 1 genes: parasite risk factors that affect treatment outcomes for P. falciparum malaria after artemether-lumefantrine and artesunate-amodiaquine.

Adequate clinical and parasitologic cure by artemisinin combination therapies relies on the artemisinin component and the partner drug. Polymorphisms in the Plasmodium falciparum chloroquine resistance transporter (pfcrt) and P. falciparum multidrug resistance 1 (pfmdr1) genes are associated with decreased sensitivity to amodiaquine and lumefantrine, but effects of these polymorphisms on therapeutic responses to artesunate-amodiaquine (ASAQ) and artemether-lumefantrine (AL) have not been clearly defined. Individual patient data from 31 clinical trials were harmonized and pooled by using standardized methods from the WorldWide Antimalarial Resistance Network. Data for more than 7,000 patients were analyzed to assess relationships between parasite polymorphisms in pfcrt and pfmdr1 and clinically relevant outcomes after treatment with AL or ASAQ. Presence of the pfmdr1 gene N86 (adjusted hazards ratio = 4.74, 95% confidence interval = 2.29 - 9.78, P < 0.001) and increased pfmdr1 copy number (adjusted hazards ratio = 6.52, 95% confidence interval = 2.36-17.97, P < 0.001 : were significant independent risk factors for recrudescence in patients treated with AL. AL and ASAQ exerted opposing selective effects on single-nucleotide polymorphisms in pfcrt and pfmdr1. Monitoring selection and responding to emerging signs of drug resistance are critical tools for preserving efficacy of artemisinin combination therapies; determination of the prevalence of at least pfcrt K76T and pfmdr1 N86Y should now be routine

General models in min-max continous location

In this paper, a class of min-max continuous location problems is discussed. After giving a complete characterization of th stationary points, we propose a simple central and deep-cut ellipsoid algorithm to solve these problems for the quasiconvex case. Moreover, an elementary convergence proof of this algorithm and some computational results are presented

Community-based benchmarking improves spike rate inference from two-photon calcium imaging data

In recent years, two-photon calcium imaging has become a standard tool to probe the function of neural circuits and to study computations in neuronal populations. However, the acquired signal is only an indirect measurement of neural activity due to the comparatively slow dynamics of fluorescent calcium indicators. Different algorithms for estimating spike rates from noisy calcium measurements have been proposed in the past, but it is an open question how far performance can be improved. Here, we report the results of the spikefinder challenge, launched to catalyze the development of new spike rate inference algorithms through crowd-sourcing. We present ten of the submitted algorithms which show improved performance compared to previously evaluated methods. Interestingly, the top-performing algorithms are based on a wide range of principles from deep neural networks to generative models, yet provide highly correlated estimates of the neural activity. The competition shows that benchmark challenges can drive algorithmic developments in neuroscience

miRNA Expression Profiling in Migrating Glioblastoma Cells: Regulation of Cell Migration and Invasion by miR-23b via Targeting of Pyk2

Glioblastoma (GB) is the most common and lethal type of primary brain tumor. Clinical outcome remains poor and is essentially palliative due to the highly invasive nature of the disease. A more thorough understanding of the molecular mechanisms that drive glioma invasion is required to limit dispersion of malignant glioma cells.We investigated the potential role of differential expression of microRNAs (miRNA) in glioma invasion by comparing the matched large-scale, genome-wide miRNA expression profiles of migrating and migration-restricted human glioma cells. Migratory and migration-restricted cell populations from seven glioma cell lines were isolated and profiled for miRNA expression. Statistical analyses revealed a set of miRNAs common to all seven glioma cell lines that were significantly down regulated in the migrating cell population relative to cells in the migration-restricted population. Among the down-regulated miRNAs, miR-23b has been reported to target potential drivers of cell migration and invasion in other cell types. Over-expression of miR-23b significantly inhibited glioma cell migration and invasion. A bioinformatics search revealed a conserved target site within the 3' untranslated region (UTR) of Pyk2, a non-receptor tyrosine kinase previously implicated in the regulation of glioma cell migration and invasion. Increased expression of miR-23b reduced the protein expression level of Pyk2 in glioma cells but did not significantly alter the protein expression level of the related focal adhesion kinase FAK. Expression of Pyk2 via a transcript variant missing the 3'UTR in miR-23b-expressing cells partially rescued cell migration, whereas expression of Pyk2 via a transcript containing an intact 3'UTR failed to rescue cell migration.Reduced expression of miR-23b enhances glioma cell migration in vitro and invasion ex vivo via modulation of Pyk2 protein expression. The data suggest that specific miRNAs may regulate glioma migration and invasion to influence the progression of this disease

The lectin concanavalin-A signals MT1-MMP catalytic independent induction of COX-2 through an IKKγ/NF-κB-dependent pathway

The lectin from Canavalia ensiformis (Concanavalin-A, ConA), one of the most abundant lectins known, enables one to mimic biological lectin/carbohydrate interactions that regulate extracellular matrix protein recognition. As such, ConA is known to induce membrane type-1 matrix metalloproteinase (MT1-MMP) which expression is increased in brain cancer. Given that MT1-MMP correlated to high expression of cyclooxygenase (COX)-2 in gliomas with increasing histological grade, we specifically assessed the early proinflammatory cellular signaling processes triggered by ConA in the regulation of COX-2. We found that treatment with ConA or direct overexpression of a recombinant MT1-MMP resulted in the induction of COX-2 expression. This increase in COX-2 was correlated with a concomitant decrease in phosphorylated AKT suggestive of cell death induction, and was independent of MT1-MMP’s catalytic function. ConA- and MT1-MMP-mediated intracellular signaling of COX-2 was also confirmed in wild-type and in Nuclear Factor-kappaB (NF-κB) p65−/− mutant mouse embryonic fibroblasts (MEF), but was abrogated in NF-κB1 (p50)−/− and in I kappaB kinase (IKK) γ−/− mutant MEF cells. Collectively, our results highlight an IKK/NF-κB-dependent pathway linking MT1-MMP-mediated intracellular signaling to the induction of COX-2. That signaling pathway could account for the inflammatory balance responsible for the therapy resistance phenotype of glioblastoma cells, and prompts for the design of new therapeutic strategies that target cell surface carbohydrate structures and MT1-MMP-mediated signaling. Concise summary Concanavalin-A (ConA) mimics biological lectin/carbohydrate interactions that regulate the proinflammatory phenotype of cancer cells through yet undefined signaling. Here we highlight an IKK/NF-κB-dependent pathway linking MT1-MMP-mediated intracellular signaling to the induction of cyclooxygenase-2, and that could be responsible for the therapy resistance phenotype of glioblastoma cells

Different Origins of Gamma Rhythm and High-Gamma Activity in Macaque Visual Cortex

High-gamma (80–200 Hz) activity can be dissociated from gamma rhythms in the monkey cortex, and appears largely to reflect spiking activity in the vicinity of the electrode