Crecimiento longitudinal fetal en el tercer trimestre como predictor de la aparición de eventos perinatales y hallazgos placentarios significativos

Tesis doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Medicina, Departamento de Obstetricia y Ginecología. Fecha de lectura: 26-09-2017Esta tesis tiene embargado el acceso al texto completo hasta el 26-03-201

Inhibition of COX-2 Impairs Colon Cancer Liver Metastasis through Reduced Stromal Cell Reaction

Liver colonization is initiated through the interplay between tumor cells and adhesion molecules present in liver sinusoidal endothelial cells (LSECs). This crosstalk stimulates tumor COX-2 upregulation and PGE 2 secretion. To elucidate the role of the LSEC intercellular adhesion molecule-1 (ICAM-1) in the prometastatic response exerted by tumor and stromal COX-2, we utilized celecoxib (CLX) as a COX-2 inhibitory agent. We analyzed the in vitro proliferative and secretory responses of murine C26 colorectal cancer (CRC) cells to soluble ICAM-1 (sICAM-1), cultured alone or with LSECs, and their effect on LSEC and hepatic stellate cell (HSC) migration and in vivo liver metastasis. CLX reduced sICAM-1-stimulated COX-2 activation and PGE 2 secretion in C26 cells cultured alone or cocultured with LSECs. Moreover, CLX abrogated sICAM-1-induced C26 cell proliferation and C26 secretion of promigratory factors for LSECs and HSCs. Interestingly, CLX reduced the protumoral response of HSC, reducing their migratory potential when stimulated with C26 secretomes and impairing their secretion of chemotactic factors for LSECs and C26 cells and proliferative factors for C26 cells. In vivo, CLX abrogated the prometastatic ability of sICAM-1-activated C26 cells while reducing liver metastasis. COX-2 inhibition blocked the creation of a favorable tumor microenvironment (TME) by hindering the intratumoral recruitment of activated HSCs and macrophages in addition to the accumulation of fibrillar collagen. These results point to COX-2 being a key modulator of processes initiated by host ICAM-1 during tumor cell/LSEC/HSC crosstalk, leading to the creation of a prometastatic TME in the liver.This work was supported by the Department of Industry and Research of the Basque Government SAIOTEK SPE12UN075 and S-PE11UN043 to B.A., IT-487-09 to E.O., and by the Spanish Science and Technology Ministry MINECOR18/P32

Liver sinusoidal endothelial cell ICAM-1 mediated tumor/endothelial crosstalk drives the development of liver metastasis by initiating inflammatory and angiogenic responses

The prometastatic stroma generated through tumor cells/host cells interaction is critical for metastatic growth. To elucidate the role of ICAM-1 on the crosstalk between tumor and primary liver sinusoidal endothelial cells (LSECs) and hepatic stellate cells (HSCs), implicated in tumor adhesion and angiogenesis, we performed in vitro cocultures and an in vivo model of liver metastasis of colorectal cancer (CRC). ICAM-1 blockade in the LSECs decreased the adhesion and transmigration of tumor cells through an LSEC in vitro and vivo. Cocultures of C26 cells and LSECs contained higher amounts of IL-1 beta, IL-6, PGE-2, TNF-alpha and ICAM-1 than monocultures. C26 cells incubated with sICAM-1 secreted higher amounts of PGE-2, IL-6, VEGF, and MMPs, while enhanced the migration of LSECs and HSCs. HSCs cultures activated by media from C26 cells pretreated with sICAM-1 contained the largest amounts of VEGF and MMPs. C26 cell activation with sICAM-1 enhanced their metastasizing potential in vivo, while tumor LFA-1 blockade reduced tumor burden and LSECs and HSC-derived myofibroblasts recruitment. In vivo ICAM-1 silencing produced similar results. These findings uncover LSEC ICAM-1 as a mediator of the CRC metastatic cascade in the liver and identifies it as target for the inhibition of liver colonization and metastatic progression.This work has been supported by a predoctoral grant from the University of the Basque Country to the principal author and from the Department of Industry and Research of the Basque Government SAIOTEK S-PE12UN075 and S-PE11UN043 to BA, and IT-487-09 to EO

Silencing of Sinusoidal DDR1 Reduces Murine Liver Metastasis by Colon Carcinoma

Liver metastasis depends on the collagenous microenvironment generated by hepatic sinusoidal cells (SCs). DDR1 is an atypical collagen receptor linked to tumor progression, but whether SCs express DDR1 and its implication in liver metastasis remain unknown. Freshly isolated hepatic stellate cells (HSCs), Kupffer cells (KCs), and liver sinusoidal endothelial cells (LSECs), that conform the SCs, expressed functional DDR1. HSCs expressed the largest amounts. C26 colon carcinoma secretomes increased DDR1 phosphorylation in HSCs and KCs by collagen I. Inhibition of kinase activity by DDR1-IN-1 or mRNA silencing of DDR1 reduced HSCs secretion of MMP2/9 and chemoattractant and proliferative factors for LSECs and C26 cells. DDR1-IN-1 did not modify MMP2/9 in KCs or LSECs secretomes, but decreased the enhancement of C26 migration and proliferation induced by their secretomes. Gene array showed that DDR1 silencing downregulated HSCs genes for collagens, MMPs, interleukins and chemokines. Silencing of DDR1 before tumor inoculation reduced hepatic C26 metastasis in mice. Silenced livers bore less tumor foci than controls. Metastatic foci in DDR1 silenced mice were smaller and contained an altered stroma with fewer SCs, proliferating cells, collagen and MMPs than foci in control mice. In conclusion, hepatic DDR1 promotes C26 liver metastasis and favors the pro-metastatic response of SCs to the tumor.We would like to acknowledge the following core facilities and individuals for their support: CIC bioGUNE Center for Cooperative Research in Biosciences, University of the Basque Country Animal Core Facility and SGIker Advanced Light Microscopy Core Facility. We thank Iratxe Basaldua for the in situ MMPs assay

El Caso Watergate en la prensa española: ¿escándalo o conspiración?

Nuestra investigación nace con el objetivo de analizar el seguimiento, el tratamiento y la valoración que hizo la prensa española del Caso Watergate y de su máximo protagonista, el presidente Richard Nixon. El estudio se contextualiza en la situación política española y en la coyuntura internacional del periodo comprendido entre los años 1972-1974. Finalmente, hemos analizado las noticias referidas al Caso Watergate con motivo de la muerte de Richard Nixon en el año 1994, en los diarios nacionales de mayor tirada en esa fecha —ABC, Ya, El Mundo y El País—, con el objetivo de examinar las valoraciones e interpretaciones del suceso y de su principal protagonista dos décadas después

Are the existing levels of training and access to finance enough to encourage entrepreneurial intention?

RESUMEN. En un entorno de recesión económica como el actual, en el que la tasa de empleo supera el 25%, el emprendimiento se presenta como una salida a considerar, especialmente si se tiene en cuenta que más del 99% de las empresas españolas son PYMES. Dada la relevancia del emprendimiento como medio para potenciar el desarrollo económico y social de las regiones, resulta especialmente interesante analizar cuáles son los factores que influyen en la intención emprendedora de los individuos. Con la Teoría de Comportamiento Planificado como marco de referencia este trabajo analiza la influencia del entorno sobre la intención emprendedora de los universitarios. Las principales conclusiones obtenidas, sobre una muestra de 302 estudiantes, ponen de manifiesto que los alumnos perciben que la formación existente es aceptable pero que el acceso a la financiación es limitado.ABSTRACT. In times of recession such as the present, when the unemployment rate exceeds 25%, entrepreneurship could be considered as a potential solution. This could be especially useful in the Spanish case where more than 99% of companies are SMEs. Given the importance of entrepreneurship as a means to promote regional economic and social development, it is particularly interesting to analyse the factors that influence entrepreneurial intention of people. This paper analyses the influence the environment has on the entrepreneurial intention of university students using the ‘Theory of Planned Behavior’ as a framework. The main conclusions obtained from a sample of 302 students show that the existing level of training seems acceptable but access to finance is still limited

Auto-atribuciones Académicas: Diferencias de Género y Curso en Estudiantes de Educación Secundaria

El análisis de las autoatribuciones académicas constituyeun aspecto esencial del componente afectivo y emocionalde la motivación escolar en estudiantes de educaciónsecundaria obligatoria (ESO). El objetivo de este estudiofue analizar, mediante un diseño transversal, las diferenciasde género y curso y el papel predictivo de estas variables enlas atribuciones causales académicas de los alumnos medidasa través de las escalas generales de la Sydney AttributionScale (SAS). El cuestionario fue administrado a 2.022estudiantes (51.08% chicos) de 1º a 4º de ESO. El rangode edad fue de 12 a 16 años (M = 13.81; DT = 1.35).Los resultados derivados de los análisis de varianza y de los tamaños del efecto (índice d) revelaron que los chicosatribuyeron sus éxitos significativamente más a su capacidad,mientras las chicas los atribuyeron significativamente másal esfuerzo. Respecto a las atribuciones de fracaso escolar,los resultados indicaron que los chicos los atribuyeronsignificativamente más a la falta de esfuerzo que las chicas.Asimismo, se hallaron diferencias de curso académico en lamayoría de las atribuciones causales analizadas. Los análisisde regresión logística indicaron que el género y el cursofueron predictores significativos de las atribuciones causalesacadémicas, aunque los resultados variaron para cada unade las escalas de la SAS. Los resultados son discutidos enrelación a la necesidad de diseñar programas de intervenciónque tengan en cuenta las variables sexo y curso académico

LDR brachytherapy offers superior tumor control to single-fraction HDR prostate brachytherapy: A prospective study

[Purpose]: To compare the clinical outcomes of single-fraction high-dose-rate (HDR) brachytherapy and single-fraction low-dose-rate (LDR) brachytherapy as the sole treatment for primary prostate cancer. [Material and Methods]: A quasi-randomized study that allocated, from March 2008 to February 2012, 129 low and intermediate risk prostate cancer patients to one single-fraction HDR of 19 Gy (61 patients) or to a 145 Gy 125I LDR permanent implant (68 patients. Biochemical relapse-free survival (bRFS) and overall survival (OS) were compared using the Kaplan–Meier method and Cox regression analysis. [Results]: After a median follow-up of 72 months in the HDR group, 26 patients relapsed, and after a median follow-up of 84 months in the LDR group, 7 patients relapsed (p < 0.0001). The 5-year bRFS was significantly better for the LDR group than for the HDR group (93.7% and 61.1%, respectively) (p < 0.0001). The 5-year OS also was significantly better in the LDR group (95.5% vs. 89.9%) (p = 0.0436). [Conclusions]: Permanent LDR prostate implant brachytherapy offers better clinical outcomes than single-fraction HDR for prostate cancer.Peer reviewe

Predictive modeling of therapeutic response to chondroitin sulfate/glucosamine hydrochloride in knee osteoarthritis

[Abstract] Background: In the present study, we explored potential protein biomarkers useful to predict the therapeutic response of knee osteoarthritis (KOA) patients treated with pharmaceutical grade Chondroitin sulfate/Glucosamine hydrochloride (CS+GH; Droglican, Bioiberica), in order to optimize therapeutic outcomes. Methods: A shotgun proteomic analysis by iTRAQ labelling and liquid chromatography–mass spectrometry (LC-MS/MS) was performed using sera from 40 patients enrolled in the Multicentre Osteoarthritis interVEntion trial with Sysadoa (MOVES). The panel of proteins potentially useful to predict KOA patient’s response was clinically validated in the whole MOVES cohort at baseline (n = 506) using commercially available enzyme-linked immunosorbent assays kits. Logistic regression models and receiver-operating-characteristics (ROC) curves were used to analyze the contribution of these proteins to our prediction models of symptomatic drug response in KOA. Results: In the discovery phase of the study, a panel of six putative predictive biomarkers of response to CS+GH (APOA2, APOA4, APOH, ITIH1, C4BPa and ORM2) were identified by shotgun proteomics. Data are available via ProteomeXchange with identifier PXD012444. In the verification phase, the panel was verified in a larger set of KOA patients (n = 262). Finally, ITIH1 and ORM2 were qualified by a blind test in the whole MOVES cohort at baseline. The combination of these biomarkers with clinical variables predict the patients’ response to CS+GH with a specificity of 79.5% and a sensitivity of 77.1%. Conclusions: Combining clinical and analytical parameters, we identified one biomarker that could accurately predict KOA patients’ response to CS+GH treatment. Its use would allow an increase in response rates and safety for the patients suffering KOA.Insituto de Salud Carlos III; PI14/01707Instituto de Salud Carlos III; PI16/02124Insituto de Salud Carlos III; PI17/00404Instituto de Salud Carlos III; DTS17/00200Instituto de Salud Carlos III; CIBER-CB06/01/0040Insituto de Salud Carlos III; RETIC-RIER-RD16/0012/000

Descomposición de la capa de hojarasca de diferentes especies perennifolias y caducifolias

Las hojarascas de las especies caducifolias y perennifolias presentan procesos diferenciales de descomposición, debidos, en gran parte, a las diferencias en su composición químic