Neutralizing the EGF receptor in glioblastoma cells stimulates cell migration by activating uPAR-initiated cell signaling.

In glioblastoma (GBM), the EGF receptor (EGFR) and Src family kinases (SFKs) contribute to an aggressive phenotype. EGFR may be targeted therapeutically; however, resistance to EGFR-targeting drugs such as Erlotinib and Gefitinib develops quickly. In many GBMs, a truncated form of the EGFR (EGFRvIII) is expressed. Although EGFRvIII is constitutively active and promotes cancer progression, its activity is attenuated compared with EGF-ligated wild-type EGFR, suggesting that EGFRvIII may function together with other signaling receptors in cancer cells to induce an aggressive phenotype. In this study, we demonstrate that in EGFRvIII-expressing GBM cells, the urokinase receptor (uPAR) functions as a major activator of SFKs, controlling phosphorylation of downstream targets, such as p130Cas and Tyr-845 in the EGFR in vitro and in vivo. When EGFRvIII expression in GBM cells was neutralized, either genetically or by treating the cells with Gefitinib, paradoxically, the cells demonstrated increased cell migration. The increase in cell migration was explained by a compensatory increase in expression of urokinase-type plasminogen activator, which activates uPAR-dependent cell signaling. GBM cells that were selected for their ability to grow in vivo in the absence of EGFRvIII also demonstrated increased cell migration, due to activation of the uPAR signaling system. The increase in GBM cell migration, induced by genetic or pharmacologic targeting of the EGFR, was blocked by Dasatinib, highlighting the central role of SFKs in uPAR-promoted cell migration. These results suggest that compensatory activation of uPAR-dependent cell signaling, in GBM cells treated with targeted therapeutics, may adversely affect the course of the disease by promoting cell migration, which may be associated with tumor progression

Application of the health assessment questionnaire disability index to various rheumatic diseases

Purpose\ud \ud To investigate whether the Stanford Health Assessment Questionnaire Disability Index (HAQ-DI) can serve as a generic instrument for measuring disability across different rheumatic diseases and to propose a scoring method based on item response theory (IRT) modeling to support this goal.\ud \ud Methods\ud \ud The HAQ-DI was administered to a cross-sectional sample of patients with confirmed rheumatoid arthritis (n = 619), osteoarthritis (n = 125), or gout (n = 102). The results were analyzed using the generalized partial credit model as an IRT model.\ud \ud Results\ud \ud It was found that 4 out of 8 item categories of the HAQ-DI displayed substantial differential item functioning (DIF) over the three diseases. Further, it was shown that this DIF could be modeled using an IRT model with disease-specific item parameters, which produces measures that are comparable for the three diseases.\ud \ud Conclusion\ud \ud Although the HAQ-DI partially functioned differently in the three disease groups, the measurement regarding the disability level of the patients can be made comparable using IRT methods\u

Can we rate public support for democracy in a comparable way? Cross-national equivalence of democratic attitudes in the World Value Survey

In this study we examine the cross-cultural equivalence of two scales that measure attitudes toward democracy across 36 countries in the World Value Survey (WVS) 2000. We examine the equivalence of these scales in order to explore if we can meaningfully compare democratic attitudes across countries. Multiple group confirmatory factor analyses (MGCFA) is applied to answer this question. The analyses indicate that the scales may be compared but only to a certain extent and not across all the countries. We close this article by discussing the implications of the findings

Cytokine preconditioning of engineered cartilage provides protection against interleukin-1 insult

Research reported in this publication was supported in part by the National Institute of Arthritis and Musculoskeletal and Skin Diseases and National Institute of Biomedical Imaging and Bioengineering of the National Institutes of Health under Award Number R01AR60361, R01AR061988, P41EB002520). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. ART was supported by a National Science Foundation Graduate Fellowship

Effects of adult exposure to bisphenol A on genes involved in the physiopathology of rat prefrontal cortex

Several neurological and behavioral dysfunctions have been reported in animals exposed to bisphenol A (BPA). However, little is known about the impact of adult exposure to BPA on brain physiopathology. Here, we focused on prefrontal cortex (PFC) of rats, because it is an important area for cognitive control, complex behaviors and is altered in many psychopathologies. Gamma-aminobutyric acid (GABA) and serotonin (5-HT) systems are essential for PFC function. Therefore, we examined the effects of adult exposure to BPA on 5α-Reductase (5α-R) and cytochrome P450 aromatase (P450arom), enzymes that synthesize GABAA receptor modulators, and tryptophan hydroxylase (Tph), the rate-limiting enzyme in 5-HT biosynthesis. To gain better understanding of BPA’s action in the adult PFC, 84 genes involved in neurotoxicity were also analysed. Adult male and female rats were subcutaneously injected for 4 days with 50 µg/kg/day, the current reference safe dose for BPA. mRNA and protein levels of 5α-R, P450arom and Tph were quantified by real-time RT-PCR and Western blot. Genes linked to neurotoxicity were analyzed by PCR-Array technology. Adult exposure to BPA increased both P450arom and Tph2 expression in PFC of male and female, but decreased 5α-R1 expression in female. Moreover, we identified 17 genes related to PFC functions such as synaptic plasticity and memory, as potential targets of BPA. Our results provided new insights on the molecular mechanisms underlying BPA action in the physiopathology of PFC, but also raise the question about the safety of short-term exposure to it in the adulthood.This research was supported by grants from Ministerio de Ciencia e Innovación (BFU2008-05340) and by the Junta de Andalucía (CTS202-Endocronología y Metabolismo)

Dendritic Spikes Amplify the Synaptic Signal to Enhance Detection of Motion in a Simulation of the Direction-Selective Ganglion Cell

The On-Off direction-selective ganglion cell (DSGC) in mammalian retinas responds most strongly to a stimulus moving in a specific direction. The DSGC initiates spikes in its dendritic tree, which are thought to propagate to the soma with high probability. Both dendritic and somatic spikes in the DSGC display strong directional tuning, whereas somatic PSPs (postsynaptic potentials) are only weakly directional, indicating that spike generation includes marked enhancement of the directional signal. We used a realistic computational model based on anatomical and physiological measurements to determine the source of the enhancement. Our results indicate that the DSGC dendritic tree is partitioned into separate electrotonic regions, each summing its local excitatory and inhibitory synaptic inputs to initiate spikes. Within each local region the local spike threshold nonlinearly amplifies the preferred response over the null response on the basis of PSP amplitude. Using inhibitory conductances previously measured in DSGCs, the simulation results showed that inhibition is only sufficient to prevent spike initiation and cannot affect spike propagation. Therefore, inhibition will only act locally within the dendritic arbor. We identified the role of three mechanisms that generate directional selectivity (DS) in the local dendritic regions. First, a mechanism for DS intrinsic to the dendritic structure of the DSGC enhances DS on the null side of the cell's dendritic tree and weakens it on the preferred side. Second, spatially offset postsynaptic inhibition generates robust DS in the isolated dendritic tips but weak DS near the soma. Third, presynaptic DS is apparently necessary because it is more robust across the dendritic tree. The pre- and postsynaptic mechanisms together can overcome the local intrinsic DS. These local dendritic mechanisms can perform independent nonlinear computations to make a decision, and there could be analogous mechanisms within cortical circuitry

Impacts of food contact chemicals on human health: a consensus statement

Food Packaging Forum Foundation (FPF) and the Plastics Solution Fund (PSF

Prenatal testosterone does not explain sex differences in spatial ability

The most consistent sex differences in cognition are found for spatial ability, in which males, on average, outperform females. Utilizing a twin design, two studies have shown that females with male co-twins perform better than females with female co-twins on a mental rotation task. According to the Twin Testosterone Transfer hypothesis (TTT) this advantage is due to in-uterine transmission of testosterone from males to females. The present study tested the TTT across 14 different spatial ability measures, including mental rotation tasks, in a large sample of 19–21-year-old twins. Males performed significantly better than females on all spatial tasks, with effect sizes ranging from η2 = 0.02 to η2 = 0.16. Females with a male co-twin outperformed females with a female co-twin in two of the tasks. The effect sizes for both differences were negligible (η2 < 0.02). Contrary to the previous studies, our results gave no indication that prenatally transferred testosterone, from a male to a female twin, influences sex differences in spatial ability