Networking of differentially expressed genes in human cancer cells resistant to methotrexate

BACKGROUND: The need for an integrated view of data obtained from high-throughput technologies gave rise to network analyses. These are especially useful to rationalize how external perturbations propagate through the expression of genes. To address this issue in the case of drug resistance, we constructed biological association networks of genes differentially expressed in cell lines resistant to methotrexate (MTX). METHODS: Seven cell lines representative of different types of cancer, including colon cancer (HT29 and Caco2), breast cancer (MCF-7 and MDA-MB-468), pancreatic cancer (MIA PaCa-2), erythroblastic leukemia (K562) and osteosarcoma (Saos-2), were used. The differential expression pattern between sensitive and MTX-resistant cells was determined by whole human genome microarrays and analyzed with the GeneSpring GX software package. Genes deregulated in common between the different cancer cell lines served to generate biological association networks using the Pathway Architect software. RESULTS: Dikkopf homolog-1 (DKK1) is a highly interconnected node in the network generated with genes in common between the two colon cancer cell lines, and functional validations of this target using small interfering RNAs (siRNAs) showed a chemosensitization toward MTX. Members of the UDP-glucuronosyltransferase 1A (UGT1A) family formed a network of genes differentially expressed in the two breast cancer cell lines. siRNA treatment against UGT1A also showed an increase in MTX sensitivity. Eukaryotic translation elongation factor 1 alpha 1 (EEF1A1) was overexpressed among the pancreatic cancer, leukemia and osteosarcoma cell lines, and siRNA treatment against EEF1A1 produced a chemosensitization toward MTX. CONCLUSIONS: Biological association networks identified DKK1, UGT1As and EEF1A1 as important gene nodes in MTX-resistance. Treatments using siRNA technology against these three genes showed chemosensitization toward MTX.

Measurement of a Structured Backflow in an Open Small Channel Induced by Surface-Tension Gradients

We present experiments in which the laterally confined flow of a surfactant film driven by controlled surface tension gradients causes the subtended liquid layer to self-organize into an inner upstream microduct surrounded by the downstream flow. The anomalous interfacial flow profiles and the concomitant backflow are a result of the feedback between two-dimensional and three-dimensional microfluidics realized during flow in open microchannels. Bulk and surface particle image velocimetry data combined with an interfacial hydrodynamics model explain the dependence of the observed phenomena on channel geometry.

EURECCA colorectal: multidisciplinary mission statement on better care for patients with colon and rectal cancer in Europe

Background: Care for patients with colon and rectal cancer has improved in the last twenty years however still considerable variation exists in cancer management and outcome between European countries. Therefore, EURECCA, which is the acronym of European Registration of cancer care, is aiming at defining core treatment strategies and developing a European audit structure in order to improve the quality of care for all patients with colon and rectal cancer. In December 2012 the first multidisciplinary consensus conference about colon and rectum was held looking for multidisciplinary consensus. The expert panel consisted of representatives of European scientific organisations involved in cancer care of patients with colon and rectal cancer and representatives of national colorectal registries. Methods: The expert panel had delegates of the European Society of Surgical Oncology (ESSO), European Society for Radiotherapy & Oncology (ESTRO), European Society of Pathology (ESP), European Society for Medical Oncology (ESMO), European Society of Radiology (ESR), European Society of Coloproctology (ESCP), European CanCer Organisation (ECCO), European Oncology Nursing Society (EONS) and the European Colorectal Cancer Patient Organisation (EuropaColon), as well as delegates from national registries or audits. Experts commented and voted on the two web-based online voting rounds before the meeting (between 4th and 25th October and between the 20th November and 3rd December 2012) as well as one online round after the meeting (4th-20th March 2013) and were invited to lecture on the subjects during the meeting (13th-15th December 2012). The sentences in the consensus document were available during the meeting and a televoting round during the conference by all participants was performed. All sentences that were voted on are available on the EURECCA website www.canceraudit.eu. The consensus document was divided in sections describing evidence based algorithms of diagnostics, pathology, surgery, medical oncology, radiotherapy, and follow-up where applicable for treatment of colon cancer, rectal cancer and stage IV separately. Consensus was achieved using the Delphi method. Results: The total number of the voted sentences was 465. All chapters were voted on by at least 75% of the experts. Of the 465 sentences, 84% achieved large consensus, 6% achieved moderate consensus, and 7% resulted in minimum consensus. Only 3% was disagreed by more than 50% of the members. Conclusions: It is feasible to achieve European Consensus on key diagnostic and treatment issues using the Delphi method. This consensus embodies the expertise of professionals from all disciplines involved in the care for patients with colon and rectal cancer. Diagnostic and treatment algorithms were developed to implement the current evidence and to define core treatment guidance for multidisciplinary team management of colon and rectal cancer throughout Europe.

A highly expressed miR-101 isomiR is a functional silencing small RNA

Background MicroRNAs (miRNAs) are short non-coding regulatory RNAs that control gene expression usually producing translational repression and gene silencing. High-throughput sequencing technologies have revealed heterogeneity at length and sequence level for the majority of mature miRNAs (IsomiRs). Most isomiRs can be explained by variability in either Dicer1 or Drosha cleavage during miRNA biogenesis at 5" or 3" of the miRNA (trimming variants). Although isomiRs have been described in different tissues and organisms, their functional validation as modulators of gene expression remains elusive. Here we have characterized the expression and function of a highly abundant miR-101 5"-trimming variant (5"-isomiR-101). Results The analysis of small RNA sequencing data in several human tissues and cell lines indicates that 5"-isomiR-101 is ubiquitously detected and a highly abundant, especially in the brain. 5"- isomiR-101 was found in Ago-2 immunocomplexes and complementary approaches showed that 5"-isomiR-101 interacted with different members of the silencing (RISC) complex. In addition, 5"-isomiR-101 decreased the expression of five validated miR-101 targets, suggesting that it is a functional variant. Both the binding to RISC members and the degree of silencing were less efficient for 5"-isomiR-101 compared with miR-101. For some targets, both miR-101 and 5"-isomiR-101 significantly decreased protein expression with no changes in the respective mRNA levels. Although a high number of overlapping predicted targets suggest similar targeted biological pathways, a correlation analysis of the expression profiles of miR-101 variants and predicted mRNA targets in human brains at different ages, suggest specific functions for miR-101- and 5"-isomiR-101. Conclusions These results suggest that isomiRs are functional variants and further indicate that for a given miRNA, the different isomiRs may contribute to the overall effect as quantitative and qualitative fine-tuners of gene expression.

Topological phases in small quantum Hall samples

Topological order has proven a useful concept to describe quantum phase transitions which are not captured by the Ginzburg-Landau type of symmetry-breaking order. However, lacking a local order parameter, topological order is hard to detect. One way to detect it is via direct observation of anyonic properties of excitations which are usually discussed in the thermodynamic limit, but so far has not been realized in macroscopic quantum Hall samples. Here we consider a system of few interacting bosons subjected to the lowest Landau level by a gauge potential, and theoretically investigate vortex excitations in order to identify topological properties of different ground states. Our investigation demonstrates that even in surprisingly small systems anyonic properties are able to characterize the topological order. In addition, focusing on a system in the Laughlin state, we study the robustness of its anyonic behavior in the presence of tunable finite-range interactions acting as a perturbation. A clear signal of a transition to a different state is reflected by the system's anyonic properties.

Privatization, cooperation and costs of solid waste services in small towns

This paper analyzes the cost implications of privatization and cooperation in the provision of solid waste services for a sample of small municipalities. In conducting this empirical analysis, a survey is first designed and administered to municipalities in the Spanish region of Aragon, and then an estimation of the determinants of service costs is undertaken, considering the possible endogeneity of delivery choices. Our findings indicate that cooperation is more effective than privatization in saving costs. Both production forms can enable small municipalities to cut costs by exploiting scale economies. However, the fact that inter-municipal cooperation involves lower transaction costs and is less likely to be affected by competition problems would seem to account for the fact that it is a more effective way of reducing costs.

The situation of rural women in Spain: the case of small-scale artisan food producers

La discriminación de las mujeres rurales y la falta de una aplicación efectiva de la legislación sobre la igualdad de género es un fenómeno extendido alrededor del mundo. Las mujeres han sido tradicionalmente las responsables del cuidado y alimentación familiar, en consecuencia han desarrollado tareas productivas que facilitan la combinación de actividades productivas y reproductivas en la explotación agraria. La transformación alimentaria es una de esas actividades que permite a las mujeres tener un trabajo remunerado o complementar la renta agraria en un contexto dónde la mayoría de los trabajos agrícolas están vetados para ellas. Sin embargo, las mujeres suelen estar vinculadas a proyectos que priorizan la producción local y de calidad, y la expansión de la producción industrial de alimentos ha empeorado la situación de las mujeres artesanas alimentarias. En el presente estudio se pretende, mediante el uso de metodologías cualitativas, abordar un diagnóstico de la situación de las mujeres que llevan a cabo proyectos de transformación alimentaria a pequeña escala en España mostrando sus principales dificultades, necesidades y propuestas.

Social differences in avoidable mortality between small areas of 15 European cities: an ecological study

Health and inequalities in health among inhabitants of European cities are of major importance for European public health and there is great interest in how different health care systems in Europe perform in the reduction of health inequalities. However, evidence on the spatial distribution of cause-specific mortality across neighbourhoods of European cities is scarce. This study presents maps of avoidable mortality in European cities and analyses differences in avoidable mortality between neighbourhoods with different levels of deprivation. Methods: We determined the level of mortality from 14 avoidable causes of death for each neighbourhood of 15 large cities in different European regions. To address the problems associated with Standardised Mortality Ratios for small areas we smooth them using the Bayesian model proposed by Besag, York and Mollié. Ecological regression analysis was used to assess the association between social deprivation and mortality. Results: Mortality from avoidable causes of death is higher in deprived neighbourhoods and mortality rate ratios between areas with different levels of deprivation differ between gender and cities. In most cases rate ratios are lower among women. While Eastern and Southern European cities show higher levels of avoidable mortality, the association of mortality with social deprivation tends to be higher in Northern and lower in Southern Europe. Conclusions: There are marked differences in the level of avoidable mortality between neighbourhoods of European cities and the level of avoidable mortality is associated with social deprivation. There is no systematic difference in the magnitude of this association between European cities or regions. Spatial patterns of avoidable mortality across small city areas can point to possible local problems and specific strategies to reduce health inequality which is important for the development of urban areas and the well-being of their inhabitants

Cancer mortality inequalities in urban areas: a Bayesian small area analysis in Spanish cities [correcció]

After publication of this work in 'International Journal of Health Geographics' on 13 january 2011 was wrong. The map of Barcelona in Figure two (figure 1 here) was reversed. The final correct Figure is presented here

Importance of the embedding environment on the strain within small rings in siliceous materials

The effect of the local environment on the energetic strain within small (SiO)N rings (with N=2,3) in silica materials is investigated via periodic model systems employing density functional calculations. Through comparison of the energies of various nonterminated systems containing small rings in strained and relatively unstrained environments, with alpha quartz, we demonstrate how small ring strain is affected by the nature of the embedding environment. We compare our findings with numerous previously reported calculations, often predicting significantly different small-ring strain energies, leading to a critical assessment of methods of calculating accurate localized ring energies. The results have relevance for estimates of the strain-induced response (e.g., chemical, photo, and radio) of small silica rings, and the propensity for them to form in bulk glasses, thin films, and nanoclusters.

Driver costs in small firms: Empirical analysis for farms

The agricultural sector has always been characterized by a predominance of small firms. International competition and the consequent need for restraining costs are permanent challenges for farms. This paper performs an empirical investigation of cost behavior in agriculture using panel data analysis. Our results show that transactions caused by complexity influence farm costs with opposite effects for specific and indirect costs. While transactions allow economies of scale in specific costs, they significantly increase indirect costs. However, the main driver for farm costs is volume. In addition, important differences exist for small and big farms, since transactional variables significantly influence the former but not the latter. While sophisticated management tools, such ABC, could provide only limited complementary useful information but no essential allocation bases for farms, they seem inappropriate for small farms

Driver costs in small firms: Empirical analysis for farms

The agricultural sector has always been characterized by a predominance of small firms. International competition and the consequent need for restraining costs are permanent challenges for farms. This paper performs an empirical investigation of cost behavior in agriculture using panel data analysis. Our results show that transactions caused by complexity influence farm costs with opposite effects for specific and indirect costs. While transactions allow economies of scale in specific costs, they significantly increase indirect costs. However, the main driver for farm costs is volume. In addition, important differences exist for small and big farms, since transactional variables significantly influence the former but not the latter. While sophisticated management tools, such ABC, could provide only limited complementary useful information but no essential allocation bases for farms, they seem inappropriate for small farms

Investigating the impact of small versus large firms on economic performance of countries and industries

Following earlier work by Audretsch et al. (2002), we assume that an optimal size-class structure exists, in terms of achieving maximal economic growth rates. Such an optimal structure is likely to exist as economies need a balance between the core competences of large firms (such as exploitation of economies of scale) and those of smaller firms (such as flexibility and exploration of new ideas). Accordingly, changes in size-class structure (i.e., changes in the relative shares in economic activity accounted for by micro, small, medium-sized and large firms) may affect macro-economic growth. Using a unique data base of the EU-27 countries for the period 2002-2008 for five broad sectors of economic activity and four size-classes, we find empirical support which suggests that, on average for these countries over this period, the share of micro and large firms may have been ‘above optimum’ (particularly in lower income EU countries) whereas the share of medium-sized firms may have been ‘below optimum’ (particularly in higher income EU countries). This evidence suggests that the transition from a ‘managed’ to an ‘entrepreneurial’ economy (Audretsch and Thurik, 2001) has not been completed yet in all countries of the EU-27. Keywords: small firms, large firms, size-classes, macro-economic performance

Small but powerful: Top predator local extinction affects ecosystem structure and function in an intermittent stream.

Top predator loss is a major global problem, with a current trend in biodiversity loss towards high trophic levels that modifies most ecosystems worldwide. Most research in this area is focused on large-bodied predators, despite the high extinction risk of small-bodied freshwater fish that often act as apex consumers. Consequently, it remains unknown if intermittent streams are affected by the consequences of top-predators' extirpations. The aim of our research was to determine how this global problem affects intermittent streams and, in particular, if the loss of a small-bodied top predator (1) leads to a 'mesopredator release', affects primary consumers and changes whole community structures, and (2) triggers a cascade effect modifying the ecosystem function. To address these questions, we studied the topdown effects of a small endangered fish species, Barbus meridionalis (the Mediterranean barbel), conducting an enclosure/exclosure mesocosm experiment in an intermittent stream where B. meridionalis became locally extinct following a wildfire.We found that top predator absence led to 'mesopredator release', and also to 'prey release' despite intraguild predation, which contrasts with traditional food web theory. In addition, B. meridionalis extirpation changed whole macroinvertebrate community composition and increased total macroinvertebrate density. Regarding ecosystem function, periphyton primary production decreased in apex consumer absence. In this study, the apex consumer was functionally irreplaceable; its local extinction led to the loss of an important functional role that resulted in major changes to the ecosystem's structure and function. This study evidences that intermittent streams can be affected by the consequences of apex consumers' extinctions, and that the loss of small-bodied top predators can lead to large ecosystem changes. We recommend the reintroduction of small-bodied apex consumers to systems where they have been extirpated, to restore ecosystem structure and function.

Intermunicipal cooperation and privatization of solid waste services among small municipalities in Spain

The aim of this paper is to analyze the effects of intermunicipal cooperation and privatization on the delivery costs of urban solid waste services. The results of our empirical analysis, which we conducted among a sample of very small municipalities, indicate that small towns that cooperate incur lower costs for their waste collection service. Cooperation also raises collection frequency and improves the quality of the service in small towns. By contrast, the form of production, whether it is public or private, does not result in systematic differences in costs. Interestingly, the degree of population dispersion has a significant positive relation with service costs. No evidence of scale economies is found because, it would seem, small municipalities exploit them by means of intermunicipal cooperation.