Writers, readers and erasers of RNA modifications in cancer

Although cancer was originally considered a disease driven only by genetic mutations, it has now been proven that it is also an epigenetic disease driven by DNA hypermethylation-associated silencing of tumor suppressor genes and aberrant histone modifications. Very recently, a third component has emerged: the so-called epitranscriptome understood as the chemical modifications of RNA that regulate and alter the activity of RNA molecules. In this regard, the study of genetic and epigenetic disruption of the RNA-modifying proteins is gaining momentum in advancing our understanding of cancer biology. Furthermore, the development of epitranscriptomic anticancer drugs could lead to new promising and unexpected therapeutic strategies for oncology in the coming years

Aplicación de la Topología Molecular en la búsqueda de nuevos agentes activos frente a Leishmania

A topological-mathematical model has been arranged to search for new derivatives of 3,5-dinitrobenzene sulphonamide and/or benzamide, active against L. donovani. By using linear discriminant analysis as well as multilinear regression, a model capable to identify the activity of 90% of the analyzed compounds has been achieved. After carrying out a virtual screening based upon such a model, new structures potentially active against the parasite are proposed.Key Words: Leishmania, Linear discriminant analysis, Multilinear regression analysis, topological descriptors.Se ha desarrollado un modelo topológico-matemático encaminado a buscar nuevos compuestos derivados del 3,5 dinitrobenceno sulfonamida y/o benzamida activos frente a Leishmania. Utilizando el análisis lineal discriminante y el análisis de regresión multilineal se ha obtenido un modelo capaz de identificar la actividad del 90% de los compuestos estudiados. Tras realizar un barrido virtual se proponen nuevas estructuras potencialmente activas frente a L. donovani.Palabras clave: Leishmania, Análisis lineal discriminante, Análisis de regresión multilineal, índices topológicos

Estimation of age- and stage-specific Catalan breast cancer survival functions using US and Catalan survival data

<p>Abstract</p> <p>Background</p> <p>During the last part of the 1990s the chance of surviving breast cancer increased. Changes in survival functions reflect a mixture of effects. Both, the introduction of adjuvant treatments and early screening with mammography played a role in the decline in mortality. Evaluating the contribution of these interventions using mathematical models requires survival functions before and after their introduction. Furthermore, required survival functions may be different by age groups and are related to disease stage at diagnosis. Sometimes detailed information is not available, as was the case for the region of Catalonia (Spain). Then one may derive the functions using information from other geographical areas. This work presents the methodology used to estimate age- and stage-specific Catalan breast cancer survival functions from scarce Catalan survival data by adapting the age- and stage-specific US functions.</p> <p>Methods</p> <p>Cubic splines were used to smooth data and obtain continuous hazard rate functions. After, we fitted a Poisson model to derive hazard ratios. The model included time as a covariate. Then the hazard ratios were applied to US survival functions detailed by age and stage to obtain Catalan estimations.</p> <p>Results</p> <p>We started estimating the hazard ratios for Catalonia versus the USA before and after the introduction of screening. The hazard ratios were then multiplied by the age- and stage-specific breast cancer hazard rates from the USA to obtain the Catalan hazard rates. We also compared breast cancer survival in Catalonia and the USA in two time periods, before cancer control interventions (USA 1975–79, Catalonia 1980–89) and after (USA and Catalonia 1990–2001). Survival in Catalonia in the 1980–89 period was worse than in the USA during 1975–79, but the differences disappeared in 1990–2001.</p> <p>Conclusion</p> <p>Our results suggest that access to better treatments and quality of care contributed to large improvements in survival in Catalonia. On the other hand, we obtained detailed breast cancer survival functions that will be used for modeling the effect of screening and adjuvant treatments in Catalonia.</p

Activation of β-Catenin by Oncogenic PIK3CA and EGFR Promotes Resistance to Glucose Deprivation by Inducing a Strong Antioxidant Response

Glucose is an essential fuel for cell survival and its availability limits aberrant cellular proliferation. We have hypothesized that specific cancer mutations regulate metabolic response(s) to glucose deprivation (GD). By means of somatic knock-in cellular models, we have analyzed the response to glucose deprivation in cells carrying the frequent delE746-A750EGFR, G13DKRAS or E545KPIK3CA cancer alleles. We demonstrate that, in mammary epithelial cells, glucose has an essential antioxidant function and that these cells are very sensitive to GD. Conversely, isogenic cells carrying the delE746-A750EGFR or the E545KPIK3CA, but not the G13DKRAS allele, display high tolerance to GD by stimulating the expression of anti-oxidant genes (MnSOD and catalase). This adaptive transcriptional response is mediated by the activation of WNT/β-catenin and FOXO4 signalling. Our data highlights a new functional synergism between oncogenic EGFR and PIK3CA with WNT/β-catenin conferring high tolerance to oxidative stress generated by nutrient deprivation

Fixed income strategies based on the prediction of parameters in the NS model for the Spanish public debt market

Using different econometric models, Diebold and Li (J Econom 130:337-364, 2006) addressed the practical problem of forecasting the yield curve by predicting the factors level, slope and curvature in the Nelson-Siegel framework. This paper has two main aims: on the one hand, to investigate the predictive possibilities of the yield curve for the Spanish public debt market, using the methodology proposed by Diebold and Li (J Econom 130:337-364, 2006); and on the other hand, to study the capability of generating profits by transforming these yield curve predictions into technical trading strategies. The Sharpe ratios of our strategies outperform the hedging strategy benchmarks for long (1 year) horizons in our prediction period (2000 - 2010) and also for the current crisis period (2008 - 2010).Nevertheless, these strategies do not outperform their benchmarks for short (1 month) horizons. The introduction of nonparametric models improves the profitability of the strategies in terms of the Sharpe ratio, especially in the 1-year-ahead predictions. This finding is in line with Diebold and Li (J Econom 130:337-364, 2006), whose forecasts for long horizons are much more accurate than those of several standard benchmark models

Writers, readers and erasers of RNA modifications in cancer

Although cancer was originally considered a disease driven only by genetic mutations, it has now been proven that it is also an epigenetic disease driven by DNA hypermethylation-associated silencing of tumor suppressor genes and aberrant histone modifications. Very recently, a third component has emerged: the so-called epitranscriptome understood as the chemical modifications of RNA that regulate and alter the activity of RNA molecules. In this regard, the study of genetic and epigenetic disruption of the RNA-modifying proteins is gaining momentum in advancing our understanding of cancer biology. Furthermore, the development of epitranscriptomic anticancer drugs could lead to new promising and unexpected therapeutic strategies for oncology in the coming years

Assessment of prenatal exposure to tobacco smoke by cotinine in cord blood for the evaluation of smoking control policies in Spain

Background: Over the last few years a decreasing trend in smoking has occurred not only in the general population but also during pregnancy. Several countries have implemented laws requiring all enclosed workplace and public places to be free of second hand smoke (SHS). In Spain, legislation to reduce SHS was implemented in 2005. The present study examines the possible effect of this legislation on prenatal SHS exposure. Methods: Mothers and newborns were recruited from 3 independent studies performed in Hospital del Mar (Barcelona) and approved by the local Ethics Committee: 415 participated in a study in 1996-1998, 283 in 20022004 and 207 in 2008. A standard questionnaire, including neonatal and sociodemographic variables, tobacco use and exposure during pregnancy, was completed at delivery for all the participants in the three study groups. Fetal exposure to tobacco was studied by measuring cotinine in cord blood by radioimmunoassay (RIA). Results: 32.8% of the pregnant women reported to smoke during pregnancy in 1996-1998, 25.9% in 2002-2004 and 34.1% in 2008. In the most recent group, the percentage of no prenatal SHS exposure (cord blood cotinine 0.2-1 ng/mL) showed an increase compared to the previous groups while the percentages of both: low (1.1-14 ng/mL) and very high (> 100 ng/mL) prenatal SHS exposure showed a decrease. Discussion: The results of the three study periods (1996-2008) demonstrated a significant increase in the percentage of newborns free from SHS exposure and a decrease in the percentage of newborns exposed to SHS during pregnancy, especially at the very high levels of exposure. A significant maternal smoking habit was noted in this geographical area with particular emphasis on immigrant pregnant smoking women. Conclusions: Our study indicates that there is a significant maternal smoking habit in this geographical area. Our recommendation is that campaigns against smoking should be directed more specifically towards pregnant women with particular emphasis on non-native pregnant smokers due to the highest prevalence of tobacco consumption in the immigrant women