Dual activation of pathways regulated by steroid receptors and peptide growth factors in primary prostate cancer revealed by Factor Analysis of microarray data

Background: We use an approach based on Factor Analysis to analyze datasets generated for transcriptional profiling. The method groups samples into biologically relevant categories, and enables the identification of genes and pathways most significantly associated to each phenotypic group, while allowing for the participation of a given gene in more than one cluster. Genes assigned to each cluster are used for the detection of pathways predominantly activated in that cluster by finding statistically significant associated GO terms. We tested the approach with a published dataset of microarray experiments in yeast. Upon validation with the yeast dataset, we applied the technique to a prostate cancer dataset. Results: Two major pathways are shown to be activated in organ-confined, non-metastatic prostate cancer: those regulated by the androgen receptor and by receptor tyrosine kinases. A number of gene markers (HER3, IQGAP2 and POR1) highlighted by the software and related to the later pathway have been validated experimentally a posteriori on independent samples. Conclusion: Using a new microarray analysis tool followed by a posteriori experimental validation of the results, we have confirmed several putative markers of malignancy associated with peptide growth factor signalling in prostate cancer and revealed others, most notably ERRB3 (HER3). Our study suggest that, in primary prostate cancer, HER3, together or not with HER4, rather than in receptor complexes involving HER2, could play an important role in the biology of these tumors. These results provide new evidence for the role of receptor tyrosine kinases in the establishment and progression of prostate cancer.

Development of an epidermal growth factor derivative with EGFR blocking activity.

The members of the epidermal growth factor (EGF)/ErbB family are prime targets for cancer therapy. However, the therapeutic efficiency of the existing anti-ErbB agents is limited. Thus, identifying new molecules that inactivate the ErbB receptors through novel strategies is an important goal on cancer research. In this study we have developed a shorter form of human EGF (EGFt) with a truncated C-terminal as a novel EGFR inhibitor. EGFt was designed based on the superimposition of the three-dimensional structures of EGF and the Potato Carboxypeptidase Inhibitor (PCI), an EGFR blocker previously described by our group. The peptide was produced in E. coli with a high yield of the correctly folded peptide. EGFt showed specificity and high affinity for EGFR but induced poor EGFR homodimerization and phosphorylation. Interestingly, EGFt promoted EGFR internalization and translocation to the cell nucleus although it did not stimulate the cell growth. In addition, EGFt competed with EGFR native ligands, inhibiting the proliferation of cancer cells. These data indicate that EGFt may be a potential EGFR blocker for cancer therapy. In addition, the lack of EGFR-mediated growth-stimulatory activity makes EGFt an excellent delivery agent to target toxins to tumours over-expressing EGFR.

Dual Action of BPC194: A Membrane Active Peptide Killing Bacterial Cells

Membrane active peptides can perturb the lipid bilayer in several ways, such as poration and fusion of the target cell membrane, and thereby efficiently kill bacterial cells. We probe here the mechanistic basis of membrane poration and fusion caused by membrane-active, antimicrobial peptides. We show that the cyclic antimicrobial peptide, BPC194, inhibits growth of Gram-negative bacteria and ruptures the outer and inner membrane at the onset of killing, suggesting that not just poration is taking place at the cell envelope. To simplify the system and to better understand the mechanism of action, we performed Förster resonance energy transfer and cryogenic transmission electron microscopy studies in model membranes and show that the BPC194 causes fusion of vesicles. The fusogenic action is accompanied by leakage as probed by dual-color fluorescence burst analysis at a single liposome level. Atomistic molecular dynamics simulations reveal how the peptides are able to simultaneously perturb the membrane towards porated and fused states. We show that the cyclic antimicrobial peptides trigger both fusion and pore formation and that such large membrane perturbations have a similar mechanistic basis

Financial development, labor and market regulations and growth

This paper investigates the importance that market regulation and financial imperfections have on firm growth. We analyse institutions af- fecting labor market as Employment Protection Laws (EP) and Product Market Regulation (PM). We show that together with the beneficial effects of financial development, a firm will get less financing, and thus investless, in a weak financial market (finance effect), the strictness of product and labor market regulations also affect firm growth (labor effect). In particular, we show that the stricter the rules the more detrimental the influence on growth in sectoral value added for a large number of countries. We also show that the labor effect overcomes the positive finance effect.

Environment conditions and biological innovations in the european agrarian growth, 1819-1939

The circumstances that were the driving forces behind Europe's economic growth beginning in the 19th century are diverse, and not easily prioritized. Until the 1970's, specifically, in Economy and Economic History, attention was focused on different institutional and technological variables, and various regularities were proposed. Nevertheless, new studies also underlined that the evolution of economic activity could not be understood considering only the new production possibilities offered by market economies. As a result, today it is also accepted that those processes can not be explained without considering two additional circumstances: the energy flows that sustained them, and the changes undergone in their transformation In this context, a question arises that takes on special importance. Which was the influence of the biological change in the economic growth?. A part of the flows of energy must be made into food, and this transformation can only happen with the participation.

Growth of positive words and lower bounds of the growth rate for Thompson's group (F)p

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

Capitalism, unemployment and the transition to the contemporary pattern of growth

A new model of unemployment based on an idea of Marx is presented and used to interpret the development of the British economy from the beginning of capitalism to the present. It is shown that unemployment may be created purposely by capitalists in order to weaken the bargaining position of the workers. This mechanism leads to complex temporal pattern of unemployment and can explain why wages took almost a century and a half to react to the growing capital to labour ratio that characterised early British capitalism.

Human capital as a factor of growth and employment at the regional level. The case of Spain

We use statistical techniques to quantify the effects of school attainment on individual wages, participation rates and employment probabilities in Spain, and to measure the contribution of education to labour productivity at the regional level. These estimates are then combined with data on private and public expenditure on education and with information on taxes and social benefits to construct measures of the private and social returns to schooling, to explore the effects of public policies on private incentives to invest in human capital, and to analyse the long-term effects of schooling on public finances. The results are used, together with estimates of the returns to alternative assets, to draw some tentative conclusions regarding the adequacy of the aggregate investment patterns observed in the regions of Spain, and to identify changes in the design of national and EU cohesion and growth policies that may help enhance their effectiveness.

Spillovers and growth in a local interaction model

In this paper we aim at studying to what extent spillovers between firms may foster economic growth. The attention is addressed to the spillovers connected with the R&D activity that improves the quality of the goods firms supply. Our model develops a growth theory framework and we assume that firms spread around a circle. Our study assesses that spillovers between neighbors affect the probability of successful research for each of them. In particular, spillovers are the forces fuelling growth when, on the whole, firms turn out to be net receivers with respect to their neighbors.

Human capital in growth regressions: how much difference does data quality make? An update and further results

We construct estimates of educational attainment for a sample of OECD countries using previously unexploited sources. We follow a heuristic approach to obtain plausible time profiles for attainment levels by removing sharp breaks in the data that seem to reflect changes in classification criteria. We then construct indicators of the information content of our series and a number of previously available data sets and examine their performance in several growth specifications. We find a clear positive correlation between data quality and the size and significance of human capital coefficients in growth regressions. Using an extension of the classical errors in variables model, we construct a set of meta-estimates of the coefficient of years of schooling in an aggregate Cobb-Douglas production function. Our results suggest that, after correcting for measurement error bias, the value of this parameter is well above 0.50.

The possibility for continuous growth with exhaustible resources: unknowingly an agreement has been reached, but it may not be correct

It is the size of the elasticity of substitution that has been the central issue in the long debate over the possibility of continuous growth in the presence of exhaustible resources. This paper reviews the debate and comes to the surprising conclusion that , unnoticed by the pessimists, the optimist position has gradually evolved so that it now approximates that of the pessimists. The paper also summarises some preliminary work by the author that indicates that this common position may not be correct

Unemployment and wage formation in a growth model with public capital

We study the relation between public capital, employment and growth under different assumptions concerning wage formation. We show that public capital increases economic growth, and that, if there is wage inertia, employment positively depends on both economic growth and public capital.

Growth, habit formation, and catching-up\ with the Joneses

When habits are introduced multiplicatively in a capital accumulation model, the consumers' objective function might fail to be concave. In this paper we provide conditions aimed at guaranteeing the existence of interior solutions to the consumers' problem. We also characterize the equilibrium path of two growth models with multiplicative habits: the internal habit formation model, where individual habits coincide with own past consumption, and the external habit formation (or catching-up with the Joneses) model, where habits arise from the average past consumption in the economy. We show that the introduction of external habits makes the equilibrium path inefficient during the transition towards the balanced growth path. We characterize in this context the optimal tax policy.