Influencia del tipo de directivo sobre la creación de valor: una aplicación a las empresas diversificadas españolas

El objetivo básico de este trabajo es analizar la relación existente entre el tipo de directivo que adopta la decisión de diversificar y la riqueza generada tras acometer dicho proceso de desarrollo. Para ello, tras revisar la literatura correspondiente, se distinguen dos grupos de directivos, agentes y servidores, en función de sus características psicológicas y situacionales. Seguidamente se contrasta una hipótesis que defiende que las empresas diversificadas gobernadas por directivos tipo servidor obtienen niveles de rentabilidad financiera significativamente superiores que aquellas a cargo de directivos tipo agente. Los resultados obtenidos a partir de una muestra de 118 empresas diversificadas españolas permiten verificar tal hipótesis e indican la conveniencia de contratar servidores para salvaguardar el valor de los accionistas.The main purpose of this paper is to analyse the existing relationship among the type of manager that chooses to diversify and the wealth effect of diversification. For that, after revising the corresponding literature, we cluster the managers en two different groups according to their psychological and situational characteristics. After that, we have tested one hypotheses related to the diversified firms managed by stewards reach bigger profitability than those controlled by agents. Results support that hypotheses on a sample of 118 Spanish diversified firms and affirm the convenience of contracting stewards to safeguard the shareholders´ value

Efecto de la política nacional de subsidios a la innovación según la localización de la empresa

Este trabajo se fundamenta en la reciente visión de que la actividad innovadora es un fenómeno territorial estimulado por la cooperación entre actores e infraestructuras locales. El objetivo del trabajo es determinar sí la localización de una empresa influye sobre el efecto que la política nacional de innovación tiene sobre su intensidad en I+D. El análisis está dirigido a comparar el efecto de esta política entre empresas ubicadas en Madrid, Cataluña y el País Vasco, regiones que concentran cerca del 70% de la actividad innovadora en España. El tipo de análisis empleado permite llegar a una situación próxima que soluciona importantes problemas metodológicos en la práctica de la evaluación de la política. Los resultados permiten concluir que la región ejerce un importante efecto diferenciador en el resultado final de esta política. Por lo tanto, este estudio recomienda incluir la localización de la empresa en futuras prácticas de evaluación.Este trabajo se fundamenta en la reciente visión de que la actividad innovadora es un fenómeno territorial estimulado por la cooperación entre actores e infraestructuras locales. El objetivo del trabajo es determinar sí la localización de una empresa influye sobre el efecto que la política nacional de innovación tiene sobre su intensidad en I+D. El análisis está dirigido a comparar el efecto de esta política entre empresas ubicadas en Madrid, Cataluña y el País Vasco, regiones que concentran cerca del 70% de la actividad innovadora en España. El tipo de análisis empleado permite llegar a una situación próxima que soluciona importantes problemas metodológicos en la práctica de la evaluación de la política. Los resultados permiten concluir que la región ejerce un importante efecto diferenciador en el resultado final de esta política. Por lo tanto, este estudio recomienda incluir la localización de la empresa en futuras prácticas de evaluación

Transcriptional epigenetic regulation of Fkbp1/Pax9 genes is associated with impaired sensitivity to platinum treatment in ovarian cancer

Background: In an effort to contribute to overcoming the platinum resistance exhibited by most solid tumors, we performed an array of epigenetic approaches, integrating next-generation methodologies and public clinical data to identify new potential epi-biomarkers in ovarian cancer, which is considered the most devastating of gynecological malignancies. Methods: We cross-analyzed data from methylome assessments and restoration of gene expression through microarray expression in a panel of four paired cisplatin-sensitive/cisplatin-resistant ovarian cancer cell lines, along with publicly available clinical data from selected individuals representing the state of chemoresistance. We validated the methylation state and expression levels of candidate genes in each cellular phenotype through Sanger sequencing and reverse transcription polymerase chain reaction, respectively. We tested the biological role of selected targets using an ectopic expression plasmid assay in the sensitive/resistant tumor cell lines, assessing the cell viability in the transfected groups. Epigenetic features were also assessed in 189 primary samples obtained from ovarian tumors and controls. Results: We identified PAX9 and FKBP1B as potential candidate genes, which exhibited epigenetic patterns of expression regulation in the experimental approach. Re-establishment of FKBP1B expression in the resistant OVCAR3 phenotype in which this gene is hypermethylated and inhibited allowed it to achieve a degree of platinum sensitivity similar to the sensitive phenotype. The evaluation of these genes at a translational level revealed that PAX9 hypermethylation leads to a poorer prognosis in terms of overall survival. We also set a precedent for establishing a common epigenetic signature in which the validation of a single candidate, MEST, proved the accuracy of our computational pipelines. Conclusions: Epigenetic regulation of PAX9 and FKBP1B genes shows that methylation in non-promoter areas has the potential to control gene expression and thus biological consequences, such as the loss of platinum sensitivity. At the translational level, PAX9 behaves as a predictor of chemotherapy response to platinum in patients with ovarian cancer. This study revealed the importance of the transcript-specific study of each gene under potential epigenetic regulation, which would favor the identification of new markers capable of predicting each patient’s progression and therapeutic response.The study was financially supported by FIS (ISCIII) and ERDF/FSE funds (PI15/00186, PI18/0050, and ERDF/FSE, A way to make Europe). The authors gratefully acknowledge the Colombian Ministry for Science, Technology and Innovation (MINCIENCIAS), Code 568-2012, for providing J.S. with partial funding for this study

Caracterización de las reacciones adversas reportadas en la Atención Primaria de Salud de la provincia de Las Tunas en el primer semestre del año 2019

Introducción: una parte sustancial del uso de los medicamentos se lleva a cabo en atención primaria, de ahí la necesidad del estudio y control de las reacciones adversas en este nivel de atención.Objetivo: caracterizar las reacciones adversas medicamentosas reportadas en la atención primaria de salud en la provincia Las Tunas, en el primer semestre de 2019.Método: estudio de farmacovigilancia, observacional, descriptivo y transversal. El universo estuvo constituido por los 1061 reportes realizados en el periodo y la muestra por los 212 pacientes que reportaron reacciones adversas en la atención primaria y que fueron registrados en la unidad coordinadora provincial de farmacovigilancia en el primer semestre de 2019. Se utilizó un muestreo probabilístico intencionado. Se utilizó estadística descriptiva.Resultados: predominó el grupo etario de 61 años y más (29,71 %), el sexo femenino (69,3 %) y el sistema de órgano piel (35,4 %). En el caso de la frecuencia, causalidad y severidad, correspondió a frecuentes (66,5 %), moderadas (58,9 %) y probables (67 %). El motivo de prescripción más común fue la hipertensión arterial (21,6 %), el medicamento más reportado el captopril (10,84 %), el grupo farmacológico más común fue el de los antibacterianos (63 %) y la reacción adversa más frecuente fue tos (10,8 %).Conclusiones: se caracterizaron las reacciones adversas en la atención primaria de salud en la provincia de Las Tunas en el primer semestre de 2019

A novel role for the tumor suppressor gene itf2 in tumorigenesis and chemotherapy response

Despite often leading to platinum resistance, platinum-based chemotherapy continues to be the standard treatment for many epithelial tumors. In this study we analyzed and validated the cytogenetic alterations that arise after treatment in four lung and ovarian paired cisplatin-sensitive/resistant cell lines by 1-million microarray-based comparative genomic hybridization (array-CGH) and qRT-PCR methodologies. RNA-sequencing, functional transfection assays, and gene-pathway activity analysis were used to identify genes with a potential role in the development of this malignancy. The results were further explored in 55 lung and ovarian primary tumors and control samples, and in two extensive in silico databases. Long-term cell exposure to platinum induces the frequent deletion of ITF2 gene. Its expression re-sensitized tumor cells to platinum and recovered the levels of Wnt/β-catenin transcriptional activity. ITF2 expression was also frequently downregulated in epithelial tumors, predicting a worse overall survival. We also identified an inverse correlation between ITF2 and HOXD9 expression, revealing that Non-small cell lung cancer (NSCLC) patients with lower expression of HOXD9 had a better overall survival rate. We defined the implication of ITF2 as a molecular mechanism behind the development of cisplatin resistance probably through the activation of the Wnt-signaling pathway. This data highlights the possible role of ITF2 and HOXD9 as novel therapeutic targets for platinum resistant tumors.This research was funded by the Fondo de Investigación Sanitaria-Instituto de Salud Carlos III, PI15/00186 and PI18/00050, CP19/00063, and CM19/00100 for HR and by MINECO, RTC-2016-5314-1 to I.I.C; by the MINECO, SAF2016-75531-R, by the CAM B2017/BMD-3724 and by the AECC GCB14142311CRES to P.S; and the European Regional Development Fund/European Social Fund FIS (FEDER/FSE, Una Manera de Hacer Europa)

MAFG is a potential therapeutic target to restore chemosensitivity in cisplatin-resistant cancer cells by increasing reactive oxygen species

Adjuvant chemotherapy for solid tumors based on platinum-derived compounds such as cisplatin is the treatment of choice in most cases. Cisplatin triggers signaling pathways that lead to cell death, but it also induces changes in tumor cells that modify the therapeutic response, thereby leading to cisplatin resistance. We have recently reported that microRNA-7 is silenced by DNA methylation and is involved in the resistance to platinum in cancer cells through the action of the musculoaponeurotic fibrosarcoma oncogene family, protein G (MAFG). In the present study, we first confirm the miR-7 epigenetic regulation of MAFG in 44 normal- and/or tumor-paired samples in non–small-cell lung cancer (NSCLC). We also provide translational evidence of the role of MAFG and the clinical outcome in NSCLC by the interrogation of two extensive in silico databases of 2019 patients. Moreover, we propose that MAFG-mediated resistance could be conferred due to lower reactive oxygen species production after cisplatin exposure. We developed specifically selected aptamers against MAFG, with high sensitivity to detect the protein at a nuclear level probed by aptacytochemistry and histochemistry analyses. The inhibition of MAFG activity through the action of the specific aptamer apMAFG6F increased the levels of reactive oxygen species production and the sensitivity to cisplatin. We report first the specific nuclear identification of MAFG as a novel detection method for diagnosis in NSCLC, and then we report that MAFG modulates the redox response and confers cell protection against free radicals generated after platinum administration, thus also being a promising therapeutic target.This study was supported by the “Fondo de Investigación Sanitaria-Instituto de Salud Carlos III” [PI15/00186 and CP 08/000689 to I.I.C. ] ; and the European Regional Development Fund/European Social Fund FIS [FEDER/FSE, Una Manera de Hacer Europa] . MINECO funds support O.V., C.R.A. and O.P.contracts through RTC-2015-4362-1 and RTC-2016-5314-1 projects

Structural Basis for the Limited Response to Oxidative and Thiol-Conjugating Agents by Triosephosphate Isomerase From the Photosynthetic Bacteria Synechocystis

In plants, the ancestral cyanobacterial triosephosphate isomerase (TPI) was replaced by a duplicated version of the cytosolic TPI. This isoform acquired a transit peptide for chloroplast localization and functions in the Calvin-Benson cycle. To gain insight into the reasons for this gene replacement in plants, we characterized the TPI from the photosynthetic bacteria Synechocystis (SyTPI). SyTPI presents typical TPI enzyme kinetics profiles and assembles as a homodimer composed of two subunits that arrange in a (β-α)8 fold. We found that oxidizing agents diamide (DA) and H2O2, as well as thiol-conjugating agents such as oxidized glutathione (GSSG) and methyl methanethiosulfonate (MMTS), do not inhibit the catalytic activity of SyTPI at concentrations required to inactivate plastidic and cytosolic TPIs from the plant model Arabidopsis thaliana (AtpdTPI and AtcTPI, respectively). The crystal structure of SyTPI revealed that each monomer contains three cysteines, C47, C127, and C176; however only the thiol group of C176 is solvent exposed. While AtcTPI and AtpdTPI are redox-regulated by chemical modifications of their accessible and reactive cysteines, we found that C176 of SyTPI is not sensitive to redox modification in vitro. Our data let us postulate that SyTPI was replaced by a eukaryotic TPI, because the latter contains redox-sensitive cysteines that may be subject to post-translational modifications required for modulating TPI's enzymatic activity

High efficacy of Sofosbuvir plus Simeprevir in a large cohort of Spanish cirrhotic patients infected with genotypes 1 and 4

[Abstract] Background and Aims. Hepatitis C (HCV) therapy with Sofosbuvir (SOF)/Simeprevir (SMV) in clinical trials and real‐world clinical practice, showed high rates of sustained virological response (SVR) in non‐cirrhotic genotype (GT)‐1 and GT‐4 patients. These results were slightly lower in cirrhotic patients. We investigated real‐life effectiveness and safety of SOF/SMV with or without ribavirin (RBV) in a large cohort of cirrhotic patients. Methods. This collaborative multicentre study included data from 968 patients with cirrhosis infected with HCV‐GT1 or 4, treated with SOF/SMV±RBV in 30 centres across Spain between January‐2014 and December‐2015. Demographic, clinical, virological and safety data were analysed. Results. Overall SVR was 92.3%; the majority of patients were treated with RBV (62%) for 12 weeks (92.4%). No significant differences in SVR were observed between genotypes (GT1a:94.3%; GT1b:91.7%; GT4:91.1%). Those patients with more advanced liver disease (Child B/C, MELD≥10) or portal hypertension (platelet count≤100×109/L, transient elastography≥21 Kpa) showed significantly lower SVR rates (84.4%‐91.9%) than patients with less advanced liver disease (93.8%‐95.9%, P<.01 in all cases). In the multivariate analysis, the use of RBV, female gender, baseline albumin≥35 g/L, MELD<10 and lack of exposure to a triple therapy regimen were independent predictors of SVR (P<.05). Serious adverse events (SAEs) and SAE‐associated discontinuation events occurred in 5.9% and 2.6%. Conclusions. In this large cohort of cirrhotic patients managed in the real‐world setting in Spain, SOF/SMV±RBV yielded to excellent SVR rates, especially in patients with compensated liver cirrhosis. In addition, this combination showed to be safe, with low rates of SAEs and early discontinuations.Instituto de Salud Carlos III; PI15/0015

Deep-sequencing reveals broad subtype-specific HCV resistance mutations associated with treatment failure

A percentage of hepatitis C virus (HCV)-infected patients fail direct acting antiviral (DAA)-based treatment regimens, often because of drug resistance-associated substitutions (RAS). The aim of this study was to characterize the resistance profile of a large cohort of patients failing DAA-based treatments, and investigate the relationship between HCV subtype and failure, as an aid to optimizing management of these patients. A new, standardized HCV-RAS testing protocol based on deep sequencing was designed and applied to 220 previously subtyped samples from patients failing DAA treatment, collected in 39 Spanish hospitals. The majority had received DAA-based interferon (IFN) a-free regimens; 79% had failed sofosbuvir-containing therapy. Genomic regions encoding the nonstructural protein (NS) 3, NS5A, and NS5B (DAA target regions) were analyzed using subtype-specific primers. Viral subtype distribution was as follows: genotype (G) 1, 62.7%; G3a, 21.4%; G4d, 12.3%; G2, 1.8%; and mixed infections 1.8%. Overall, 88.6% of patients carried at least 1 RAS, and 19% carried RAS at frequencies below 20% in the mutant spectrum. There were no differences in RAS selection between treatments with and without ribavirin. Regardless of the treatment received, each HCV subtype showed specific types of RAS. Of note, no RAS were detected in the target proteins of 18.6% of patients failing treatment, and 30.4% of patients had RAS in proteins that were not targets of the inhibitors they received. HCV patients failing DAA therapy showed a high diversity of RAS. Ribavirin use did not influence the type or number of RAS at failure. The subtype-specific pattern of RAS emergence underscores the importance of accurate HCV subtyping. The frequency of “extra-target” RAS suggests the need for RAS screening in all three DAA target regions

La Revolución de 1868 y la Guinea Española

La Revolución de 1868 tuvo una notable repercusión en las posesiones del Golfo de Guinea, pues dió la oportunidad para establecer una administración más sencilla y barata. La asunción de los principios liberales en la economía y religión supusieron aceptar la realidad económico-social de la Colonia, así como poner de manifiesto la incapacidad española para llevar a cabo la colonización, lo que provocaría dudas acerca del mantenimiento de la Colonia