Epidermal growth factor receptor: a re-emerging target in glioblastoma.

PURPOSE OF REVIEW: Amplification and overexpression of the epidermal growth factor receptor (EGFR) gene are a hallmark of primary glioblastoma (45%), making it a prime target for therapy. In addition, these amplifications are frequently associated with oncogenic mutations in the extracellular domain. However, efforts at targeting the EGFR tyrosine kinase using small molecule inhibitors or antibodies have shown disappointing efficacy in clinical trials for newly diagnosed or recurrent glioblastoma. Here, we review recent insights into molecular mechanisms relevant for effective targeting of the EGFR pathway. RECENT FINDINGS: Molecular workup of glioblastoma tissue of patients under treatment with small molecule inhibitors has established drug concentrations in the tumor tissue, and has shed light on the effectiveness of target inhibition and respective effects on pathway signaling. Further, functional analyses of interaction of small molecule inhibitors with distinct properties to bind to the active or inactive form of EGFR have provided new insights that will impact the choice of drugs. Finally, vaccination approaches targeting the EGFRvIII mutant featuring a tumor-specific antigen have shown promising results that warrant larger controlled clinical trials. SUMMARY: A combination of preclinical and clinical studies at the molecular level has provided new insights that will allow refining strategies for targeting the EGFR pathway in glioblastoma.

Trapping of naive lymphocytes triggers rapid growth and remodeling of the fibroblast network in reactive murine lymph nodes.

Adaptive immunity is initiated in T-cell zones of secondary lymphoid organs. These zones are organized in a rigid 3D network of fibroblastic reticular cells (FRCs) that are a rich cytokine source. In response to lymph-borne antigens, draining lymph nodes (LNs) expand several folds in size, but the fate and role of the FRC network during immune response is not fully understood. Here we show that T-cell responses are accompanied by the rapid activation and growth of FRCs, leading to an expanded but similarly organized network of T-zone FRCs that maintains its vital function for lymphocyte trafficking and survival. In addition, new FRC-rich environments were observed in the expanded medullary cords. FRCs are activated within hours after the onset of inflammation in the periphery. Surprisingly, FRC expansion depends mainly on trapping of naïve lymphocytes that is induced by both migratory and resident dendritic cells. Inflammatory signals are not required as homeostatic T-cell proliferation was sufficient to trigger FRC expansion. Activated lymphocytes are also dispensable for this process, but can enhance the later growth phase. Thus, this study documents the surprising plasticity as well as the complex regulation of FRC networks allowing the rapid LN hyperplasia that is critical for mounting efficient adaptive immunity.

The Azadirachtins: potent insect growth inhibitors

In the course of their coevolution with insects, plants have learnt to protect themselves by chemical means. Semiochemical act as antifeedants or deterrents, others by disrupting growth and development. By use of the Epilachna varivestis bioassay we isolated from Azadirachta indica seed a group of triterpenoids which interfee with larval growth and development in ppm range. Main components are the azadirachtins A and B with identical biological activity. Various other azadirachtins were obtained, either as minor seed components or by chemical modification of the naturally occuring compounds. Structure vs. activity relation studies enabled us to postulate a basic structural element that should still be biologically active and with much simpler chemical structure than natural compounds. What underlies the biological activity of these insect growth inhibitors? Their interference with the hormonal regulation of development and reproduction has been studied in Locusta migratoria and Rhodnius prolixus. In addition, tritiated dihydroazadirachtin A was used. With this approach, a precise correlation between administered dose, resulting effects, and retention of the compound was established. The azadirachtins either interrupt, delay, or deviate whole developmental programs. Results from these studies provide another chemical probe for studies in insect endocrinology and physiology.

Estudo da ação do moluscocida (Bayluscide-SRB) da Dynatech R/D Company em lagos do nordeste brasileiro - Sergipe, Brasil

To study the action of molluscicide nine ponds were selected: 3 of them lying in Maruim municipality, 29 km far from north Aracaju, the State capital, and 6 ponds in Itabaianinha municipality, 118 km far from south Aracaju. This study was carried out for 16 months. Environmental parameters observed were those thought to have any influence on the planorbids and/or the molluscicide: water temperature, transparence, salinity, pH, dissolved oxygen, CO2, and the nutrients-phosphorus, nitrogen, potassium and calcium. Plancton microorganisms were also considered to observe Bayluscide action on them. SRB was used in a concentration of 6.25 kg per 1.000 [cubic metres] water, to achieve 1.0 ppm Bayluscide concentration according to the producer's instruction in Massachussett-USA.

On the growth rate of minor-closed classes of graphs

"Vegeu el resum a l'inici del document del fitxer adjunt."

Immigration and Firm Growth: Evidence from Spanish cities

This article analyses the effect of immigration flows on the growth and efficiency of manufacturing firms in Spanish cities. To date, most studies have tended to focus on the effect immigrants have on labour markets at an aggregate level. Here, however, we undertake an exhaustive analysis at the firm level and report conclusive empirical findings. Ten years ago, Spain began to register massive immigration flows, concentrated above all on its most dynamic and advanced regions. Here, therefore, rather than focusing on the impact this has had on Spain’s labour market (changes to the skill structure of the workforce, increase in labour supply, the displacement of native workers, etc.), we examine the arrival of immigrants in terms of the changes this has meant to the structure of the country’s cities and their amenities. Thus, we argue that the impact of immigration on firm performance should not only be considered in terms of the labour market, but also in terms of how a city’s amenities can affect the performance of firms. Employing a panel data methodology, we show that the increasing pressure brought to bear by immigrants has a positive effect on the evolution of labour productivity and wages and a negative effect on the job evolution of these manufacturing firms. In addition, both small and new firms are more sensitive to the pressures of such immigrant inflows, while foreign market oriented firms report higher productivity levels and a less marked impact of immigration than their counterparts. In this paper, we also present a set of instruments to correct the endogeneity bias, which confirms the effect of local immigration flows on the performance of manufacturing firms.

Explaining High Economic Growth in Small Tourism Countries with a Dynamic General Equilibrium Model

This paper shows that tourism specialisation can help to explain the observed high growth rates of small countries. For this purpose, two models of growth and trade are constructed to represent the trade relations between two countries. One of the countries is large, rich, has an own source of sustained growth and produces a tradable capital good. The other is a small poor economy, which does not have an own engine of growth and produces tradable tourism services. The poor country exports tourism services to and imports capital goods from the rich economy. In one model tourism is a luxury good, while in the other the expenditure elasticity of tourism imports is unitary. Two main results are obtained. In the long run, the tourism country overcomes decreasing returns and permanently grows because its terms of trade continuously improve. Since the tourism sector is relatively less productive than the capital good sector, tourism services become relatively scarcer and hence more expensive than the capital good. Moreover, along the transition the growth rate of the tourism economy holds well above the one of the rich country for a long time. The growth rate differential between countries is particularly high when tourism is a luxury good. In this case, there is a faster increase in the tourism demand. As a result, investment of the small economy is boosted and its terms of trade highly improve.

Productivity growth and competition in Spanish manufacturing firms: What has happened in recent years?

This paper addresses the issue of the relationship between productivity and market competition. In comparison to the economies of other European countries, the Spanish economy has been growing, while productivity growth has stagnated. Here we provide empirical evidence about the relationship between productivity and market competition from Spanish manufacturing firms at firm level between 1994 and 2004. Correcting for selection bias, our study pays special attention to the patterns of productivity growth between openness and non-openness firms. When market competition increases the effect on firms operating in domestic markets is positive but when the level of competition is high incentives to invest in innovation and productivity gains disappear. The empirical relationship between competition and productivity is an inverted U-shape, where productivity growth is highest at intermediate levels of competition. The productivity growth of firms operating in international markets is higher than that of non-openness firms, but when market competition rises they moderate their productivity growth. Our empirical results suggest that the correct competition policy in the Spanish economy should remove the barriers to competition in internal markets in order to increase the incentives for manufacturing firms to invest in innovation and productivity growth.

Garnet growth in the Nufenen Pass area (Swiss Alps)

Abstract : Textural division of a mineral in pyramids, with their apices located at the centre of the mineral and their bases corresponding to the mineral faces is called textural sector zoning. Textural sector zoning is observed in many metamorphic minerals like andalousite and garnet. Garnets found in the graphite rich black shales of the Mesozoic cover of the Gotthard Massif display textural sector zoning. The morphology of this sector zoning is not the same in different types of black shales observed in the Nufenen pass area. Garnets in foliated black shales display a well developed sector zoning while garnets found in cm-scale layered black shales display well developed sectors in the direction of the schistosity plane. This sector zoning is always associated with up to 30μm sized birefringent lamellae emanating radial from the sector boundaries. They alternate with isotrope lamellae. The garnet forming reaction was determined using singular value decomposition approach and results compared to thermodynamic calculations. It is of the form chl + mu + cc + cld = bt + fds + ank + gt + czo and is similar in both layered and foliated black shales. The calculated X(O) is close to 0.36 and does not significantly vary during the metamorphic history of the rock. This corresponds to X CO2, X CH4, and X H2O BSE imaging of garnets on oriented-cuts revealed that the orientation of the lamellae found within the sectors is controlled by crystallography. BSE imaging and electron microprobe analysis revealed that these lamellae are calcium rich compared to the isotropic lamellae. The addition of Ca to an almandine rich garnet causes a small distortion of the X site and potentially, ordering. Ordered and disordered garnet might have very similar free energies for this composition. Hence, two garnets with different composition can be precipitated with minor overstepping of the reaction. It is enough that continued nucleation of a new garnet layer slightly prefers the same structure to assure a fiber-like growth of both garnet compositions side by side. This hypothesis is in agreement with the thermodynamic properties of the garnet solid solution described in the literature and could explain the textures observed in garnets with these compositions. To understand the differences in sector zoning morphology, and crystal growth kinetics, crystal size distribution were determined in several samples using 2D spatial analysis of slab surfaces. The same nucleation rate law was chosen for all cases. Different growth rate law for non-layered black shales and layered black shales were used. Garnet in layered black shales grew according to a growth rate law of the form R=kt ½. The transport of nutrient is the limiting factor. Transport will occur preferentially on the schistosity planes. The shapes of the garnets in such rocks are therefore ovoid with the longest axis parallel to the schistosity planes. Sector zoning is less developed with sectors present only parallel to the schistosity planes. Garnet in non-layered blackshales grew according to a growth rate law of the form R=kt. The limiting factor is the attachment at the surface of the garnet. Garnets in these rocks will display a well developed sector zoning in all directions. The growth rate law is thus influenced by the texture of the rock. It favours or hinders the transport of nutrient to the mineral surface. Résumé : La zonation sectorielle texturale consiste en la division d'un cristal en pyramides dont les sommets sont localisés au centre du minéral. La base de ces pyramides correspond aux faces du minéral. Ce type de zonation est fréquemment observé dans les minéraux métamorphiques tels que l'andalousite ou le grenat. Les grenats présents dans les marnes riches en graphites de la couverture Mésozoïque du Massif du Gotthard présent une zonation sectorielle texturale. La morphologie de cette zonation n'est pas la même dans les marnes litées et dans les marnes foliées. Les grenats des marnes foliées montrent des secteurs bien développés dans 3 directions. Les grenats des marnes litées montrent des secteurs développés uniquement dans la direction des plans de schistosité. Cette zonation sectorielle est toujours associée à des lamelles biréfringentes de quelques microns de large qui partent de la limite des secteurs et qui sont perpendiculaires aux faces du grenat. Ces lamelles alternent avec des lamelles isotropes. La réaction de formation du grenat a été déterminée par calcul matriciel et thermodynamique. La réaction est de la forme chl + mu + cc + cld= bt + fds + ank + gt + czo. Elle est similaire dans les roches litées et dans les roches foliées. L'évaluation des conditions fluides montrent que le X(O) est proche de 0.36 et ne change pas de façon significative durant l'histoire métamorphique de la roche. Des images BSE sur des coupes orientées ont révélé que l'orientation de lamelles biréfringentes est contrôlée parla crystallographie. La comparaison des analyses à la microsonde électronique et des images BSE révèle également que les lamelles biréfringentes sont plus riches en calcium que les lamelles isotropes. L'addition de calcium va déformer légèrement le site X et ainsi créer un ordre sur ce site. L'énergie interne d'un grenat ordré et d'un grenat désordonné sont suffisamment proches pour qu'un léger dépassement de l'énergie de la réaction de formation permette la coexistence des 2 types de grenat dans le même minéral. La formation de lamelles est expliquée par le fait qu'un grenat préférera la même structure. Ces observations sont en accord avec la thermodynamique des solutions solides du grenat et permet d'expliquer les structures similaires observées dans des grenats provenant de lithologies différentes. Une étude de la distribution des tailles des grenats et une modélisation de la croissance a permis de mettre en évidence 2 mécanismes de croissance différents suivant la texture de la roche. Dans les 2 cas, la loi de nucléation est la même. Dans les roches litées, la loi de croissance est de forme R=kt½. Le transport des nutriments est le facteur limitant. Ce transport a lieu préférentiellement dans la direction des niveaux de schistosité. Les grenats ont une forme légèrement allongée car la croissance des secteurs est facilitée sur les niveaux de schistosité. La croissance des grenats dans les roches foliées suit une loi de croissance de la forme R=kt. Les seuls facteurs limitant la croissance sont les processus d'attachement à la surface du grenat. La loi de croissance de ces grenats est donc contrainte par la texture de la roche. Cela se marque par des différences dans la morphologie de la zonation sectorielle.

PHYTOCHROME KINASE SUBSTRATE4 modulates phytochrome-mediated control of hypocotyl growth orientation

Gravity and light are major factors shaping plant growth. Light perceived by phytochromes leads to seedling deetiolation, which includes the deviation from vertical hypocotyl growth and promotes hypocotyl phototropism. These light responses enhance survival of young seedlings during their emergence from the soil. The PHYTOCHROME KINASE SUBSTRATE (PKS) family is composed of four members in Arabidopsis (Arabidopsis thaliana): PKS1 to PKS4. Here we show that PKS4 is a negative regulator of both phytochrome A- and B-mediated inhibition of hypocotyl growth and promotion of cotyledon unfolding. Most prominently, pks4 mutants show abnormal phytochrome-modulated hypocotyl growth orientation. In dark-grown seedlings hypocotyls change from the original orientation defined by seed position to the upright orientation defined by gravity and light reduces the magnitude of this shift. In older seedlings with the hypocotyls already oriented by gravity, light promotes the deviation from vertical orientation. Based on the characterization of pks4 mutants we propose that PKS4 inhibits changes in growth orientation under red or far-red light. Our data suggest that in these light conditions PKS4 acts as an inhibitor of asymmetric growth. This hypothesis is supported by the phenotype of PKS4 overexpressers. Together with previous findings, these results indicate that the PKS family plays important functions during light-regulated tropic growth responses

Tax Structure, Growth and Welfare in the UK

This paper studies the quantitative implications of changes in the composition of taxes for long-run growth and expected lifetime utility in the UK economy over 1970-2005. Our setup is a dynamic stochastic general equilibrium model incorporating a detailed scal policy struc- ture, and where the engine of endogenous growth is human capital accumulation. The government s spending instruments include pub- lic consumption, investment and education spending. On the revenue side, labour, capital and consumption taxes are employed. Our results suggest that if the goal of tax policy is to promote long-run growth by altering relative tax rates, then it should reduce labour taxes while simultaneously increasing capital or consumption taxes to make up for the loss in labour tax revenue. In contrast, a welfare promoting policy would be to cut capital taxes, while concurrently increasing labour or consumption taxes to make up for the loss in capital tax revenue.

Firms in Scottish High Technology Clusters: software, life sciences, microelectronics, optoelectronics and digital media – preliminary evidence and analysis on firm size, growth and optimality

This paper reports on: (a) new primary source evidence on; and (b) statistical and econometric analysis of high technology clusters in Scotland. It focuses on the following sectors: software, life sciences, microelectronics, optoelectronics, and digital media. Evidence on a postal and e-mailed questionnaire is presented and discussed under the headings of: performance, resources, collaboration & cooperation, embeddedness, and innovation. The sampled firms are characterised as being small (viz. micro-firms and SMEs), knowledge intensive (largely graduate staff), research intensive (mean spend on R&D GBP 842k), and internationalised (mainly selling to markets beyond Europe). Preliminary statistical evidence is presented on Gibrat’s Law (independence of growth and size) and the Schumpeterian Hypothesis (scale economies in R&D). Estimates suggest a short-run equilibrium size of just 100 employees, but a long-run equilibrium size of 1000 employees. Further, to achieve the Schumpeterian effect (of marked scale economies in R&D), estimates suggest that firms have to grow to very much larger sizes of beyond 3,000 employees. We argue that the principal way of achieving the latter scale may need to be by takeovers and mergers, rather than by internally driven growth.

Solovian and New Growth Theory from the Perspective of Allyn Young on Macroeconomic Increasing Returns

This paper evaluates, from an Allyn Youngian perspective, the neoclassical Solow model of growth and the associated empirical estimates of the sources of growth based on it. It attempts to clarify Young’s particular concept of generalised or macroeconomic “increasing returns” to show the limitations of a model of growth based on an assumption that the aggregate production function is characterised by constant returns to scale but “augmented” by exogenous technical progress. Young’s concept of endogenous, self-sustaining growth is also shown to differ in important respects (including in its policy implications) from modern endogenous growth theory.