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Abstract Background ETV4 is one of the ETS proteins overexpressed in prostate cancer (PC) as a result of recurrent chromosomal translocations. In human prostate cell lines, ETV4 promotes migration, invasion, and proliferation; however, its role in PC has been unclear. In this study, we have explored the effects of ETV4 expression in the prostate in a novel transgenic mouse model. Methods We have created a mouse model with prostate-specific expression of ETV4 (ETV4 mice). By histochemical and molecular analysis, we have investigated in these engineered mice the expression of p21, p27, and p53. The implications of our in vivo findings have been further investigated in human cells lines by chromatin-immunoprecipitation (ChIP) and luciferase assays. Results ETV4 mice, from two independent transgenic lines, have increased cell proliferation in their prostate and two-thirds of them, by the age of 10 months, developed mouse prostatic intraepithelial neoplasia (mPIN). In these mice, cdkn1a and its p21 protein product were reduced compared to controls; p27 protein was also reduced. By ChIP assay in human prostate cell lines, we show that ETV4 binds to a specific site (-704/-696 bp upstream of the transcription start) in the CDKN1A promoter that was proven, by luciferase assay, to be functionally competent. ETV4 further controls CDKN1A expression by downregulating p53 protein: this reduction of p53 was confirmed in vivo in ETV4 mice. Conclusions ETV4 overexpression results in the development of mPIN but not in progression to cancer. ETV4 increases prostate cell proliferation through multiple mechanisms, including downregulation of CDKN1A and its p21 protein product: this in turn is mediated through direct binding of ETV4 to the CDKN1A promoter and through the ETV4-mediated decrease of p53. This multi-faceted role of ETV4 in prostate cancer makes it a potential target for novel therapeutic approaches that could be explored in this ETV4 transgenic model.

Cancer progression is supported by the cross-talk between tumor cells and the surrounding stroma. In this context, senescent cells in the tumor microenvironment contribute to the development of a pro-inflammatory milieu and the acquisition of aggressive traits by cancer cells. Anticancer treatments induce cellular senescence (therapy-induced senescence, TIS) in both tumor and non-cancerous cells, contributing to many detrimental side effects of therapies. Thus, we focused on the effects of chemotherapy on the stromal compartment of prostate and ovarian cancer. We demonstrated that anticancer chemotherapeutics, regardless of their specific mechanism of action, promote a senescent phenotype in stromal fibroblasts, resulting in metabolic alterations and secretion of paracrine factors, sustaining the invasive and clonogenic potential of both prostate and ovarian cancer cells. The clearance of senescent stromal cells, through senolytic drug treatment, reverts the malignant phenotype of tumor cells. The clinical relevance of TIS was validated in ovarian and prostate cancer patients, highlighting increased accumulation of lipofuscin aggregates, a marker of the senescent phenotype, in the stromal compartment of tissues from chemotherapy-treated patients. These data provide new insights into the potential efficacy of combining traditional anticancer strategies with innovative senotherapy to potentiate anticancer treatments and overcome the adverse effects of chemotherapy.

Screened fiction stirs people’s psyches through emotions, which refer to a virtual world and therefore have the potential to help the individual grow in self-awareness while feeling relatively “safe”. An innovative method to work on movies for education and training purposes was developed by Eugenio Torre, and is proposed here for the film 12 Angry Men. This movie may be used in training settings focused on helping relationships to reflect upon the meaning of being an individual in a group, being a group, responsibility and choice. A key to the reading of the movie is proposed at two different but complementary levels. From an “extra-psychical” standpoint, movie characters may represent a working group of 12 very different people sharing a task, while from an “intra-psychical” one, each character may represent an embodiment or symbol of an individual’s part and/or complex. According to the movie suggestion, we describe a path from objectiveness to subjectiveness and the final accomplishment of an ethical choice.

We have previously shown that endothelial cell matrix metalloprotease 12 (MMP12) and pentraxin 3 (PTX3) overproduction is the main alteration accounting for reduced proneness to angiogenesis in systemic sclerosis (SSc). On this basis, we stably transfected MMP12 and PTX3 in two breast cancer cell lines expressing very low amounts of the target molecules when compared with normal breast epithelial cells, relying on the hypothesis that antiangiogenic molecules released by cancer cells could confer an SSc-like antiangiogenic pattern on target endothelial cells. In Matrigel Boyden chamber invasion and capillary morphogenesis studies, transfected clones reduced endothelial cell invasion and capillary tube formation, which were abolished by tumor cell populations expressing both molecules. The Matrigel sponge assay, performed in vivo in C57/BL6 mice by injecting aliquots of lyophilized culture medium of transfected clones, indicated a similar reduction in angiogenesis. Functional studies have shown that endothelial cells treated with a culture medium of MMP12-expressing clones underwent cleavage of urokinase-type plasminogen activator receptor domain 1 which is indispensable to angiogenesis. We did not observe angiostatin production from plasminogen under the same experimental conditions. PTX3-overexpressing clones showed a powerful anti-fibroblast growth factor 2 (FGF2) activity in FGF2-dependent capillary morphogenesis. We have injected control and transfected clones into nude nu/nu (CD-1) BR mice to study the differential tumor growth pattern. We observed a reduction of tumor growth in transfected clones, which was basically complete when clones expressing both molecules were simultaneously injected. The extent of tumor necrosis suggested an antiangiogenesis-dependent inhibition of tumor development.

BackgroundTGFß overproduction in cancer cells is one of the main characteristics of late tumor progression being implicated in metastasis, tumor growth, angiogenesis and immune response. We investigated the therapeutic efficacy of anti-TGFß peptides in the control of angiogenesis elicited by conditional over-expression of TGFß.MethodsWe have inserted in human MCF7 mammary-cancer cells a mutated TGFß gene in a tetracycline-repressible vector to obtain conditional expression of mature TGFß upon transient transfection, evaluated the signaling pathways involved in TGFß-dependent endothelial cells activation and the efficacy of anti-TGFß peptides in the control of MCF7-TGFß-dependent angiogenesis.ResultsTGFß over-expression induced in MCF7 several markers of the epithelial-to-mesenchymal transition. Conditioned-medium of TGFß-transfected MCF7 stimulated angiogenesis in vivo and in vitro by subsequent activation of SMAD2/3 and SMAD1/5 signaling in endothelial cells, as well as SMAD4 nuclear translocation, resulting in over-expression of the pro-angiogenic growth and differentiation factor-5 (GDF5). Inhibition or silencing of GDF5 in TGFß-stimulated EC resulted in impairment of GDF5 expression and of TGFß-dependent urokinase-plasminogen activator receptor (uPAR) overproduction, leading to angiogenesis impairment. Two different TGFß antagonist peptides inhibited all the angiogenesis-related properties elicited in EC by exogenous and conditionally-expressed TGFß in vivo and in vitro, including SMAD1/5 phosphorylation, SMAD4 nuclear translocation, GDF5 and uPAR overexpression. Antagonist peptides and anti-GDF5 antibodies efficiently inhibited in vitro and in vivo angiogenesis.ConclusionsTGFß produced by breast cancer cells induces in endothelial cells expression of GDF5, which in turn stimulates angiogenesis both in vitro and in vivo. Angiogenesis activation is rapid and the involved mechanism is totally opposed to the old and controversial dogma about the AKL5/ALK1 balance. The GDF-dependent pro-angiogenic effects of TGFß are controlled by anti-TGFß peptides and anti-GDF5 antibodies, providing a basis to develop targeted clinical studies.

El propósito de este artículo es estudiar el desarrollo histórico de las devociones populares del beato Gonzalo de Amarante y su trasplante, a partir del siglo XVI, desde Portugal a Brasil, México y Colombia. Asimismo, identificar sus diferentes manifestaciones, sobre todo sus patronazgos, exvotos y danzas, que con la piedad ilustrada de finales del siglo XVIII fueron cuestionados por algunos obispos, presbíteros y frailes, sin que ello influyera en el deterioro de la devoción que, en México, si fue afectada por la demolición o cierre de iglesias, a mediados del siglo XIX.

La introducción del grupo ciclopropilo en la estructura de curcuminoides constituye un retopor la disminución en la reactividad en el grupo metileno, debido a la existencia del equilibrio ceto-enólico en estos compuestos. El desarrollo de esta reacción es afectado por la inestabilidad de los curcuminoides en medio básico. Teniendo en cuenta la posibilidad de desarrollar reacciones de alquilación en medio acuoso, en este trabajo se obtuvieron cinco ciclopropil derivados de curcuminoides a partir de la reacción de sus correspondientes 3,5-pentatrienonas con 1,2-dibromoetano, en relación molar 1:1, en presencia de carbonato de potasio como base y bromuro de tetrabutilamonio como catalizador de transferencia de fases. La mezcla de reacción se calentó a 40 °C durante 12 h para obtener los productos deseados, con rendimientos que oscilaron entre un 22 y un32 %. Todos los compuestos obtenidos son sólidos coloreados, los cuales se caracterizaron mediante espectroscopia de RMN, análisis elemental cuantitativo y espectrometría de masas. El procedimiento empleado se presenta como un novedoso método de ciclopropanación de curcuminoides que emplea agua como disolvente, facilitando además la separación del producto debido a su insolubilidad en el medio de reacción, lo que le confiere valor medioambiental y económico.

In this work a novel procedure of synthesis of compounds analogues to curcumin with halogens atoms in its structure is described, which can increase its solubility and biological activity. Four halogenated curcuminoids were obtained with great pharmacological interest, none of them reported in literature before. Synthesis was carried out by means of the aldol condensation assisted by microwaves of halogenated aromatic aldehydes and acetylacetona, using morpholine as basic catalyst, in absence of solvent, and the reaction just needed 1 min. The products were purified by treatment of the reaction mixture with methanol under ultrasound irradiation, followed by chromatographic column. All obtained compounds were characterized by infrared spectroscopy, nuclear magnetic resonance, quantitative elementary analysis and high resolution mass spectrometry. The RMN-1H data demonstrate in all structures of synthesized curcuminoids the enol form is the most favored.

Los curcuminoides son heptatrienonas naturales o sintéticas de gran interés biológico por su potencial empleo como anticancerígenos, anti VIH y antioxidantes. En el laboratorio, estos compuestos se obtienen mediante la condensación de aldehídos aromáticos y acetilacetona. En este trabajo, se describe un estudio comparativo de la síntesis de cuatro nuevos curcuminoides, mediante condensación de aldehídos aromáticos halogenados y acetilacetona por dos métodos diferentes. En el método A, la mezcla de reacción se agita en dimetilformamida durante 4 h, a 85 ºC, con rendimientos entre 9 y 14 %. Cuando la reacción es asistida por microondas (método B), no se emplea disolvente, el tiempo de reacción es solo de un minuto, al tratar la mezcla de reacción con ultrasonido se facilita considerablemente el aislamiento del producto por ruptura del complejo-boro-curcuminoide a temperatura ambiente sin necesidad de emplear condiciones ácidas y se logran rendimientos entre 36 y 48 %. El método B, resultó operacionalmente más simple, presenta ventajas económicas y ecológicas, que lo hacen un procedimiento atractivo para la síntesis de curcuminoides. Todos los compuestos sintetizados fueron caracterizados inequívocamente mediante espectroscopia de Resonancia Magnética Nuclear (RMN1-H), análisis elemental cuantitativo y Espectrometría de Masas de Alta Resolución. En el espectro RMN-1H de cada uno de los compuestos aparece un singuleto sobre 16 ppm correspondiente al protón hidróxílico del grupo OH enólico, lo que demuestra que en estas estructuras la forma enólica es la más favorecida

En este trabajo se describe un novedoso procedimiento de síntesis de compuestos análogos a la curcumina con átomos de halógenos en su estructura que pudieran incrementar su solubilidad y actividad biológica. Fueron obtenidos cuatro curcuminoides halogenados con gran interés farmacológico, no reportados en la literatura. La síntesis se realizó mediante la condensación aldólica asistida por microondas de aldehídos aromáticos halogenados y acetilacetona, empleando morfolina como catalizador básico, en ausencia de disolventes y necesitando solo 1 min. de reacción. Los productos fueron purificados por tratamiento de la mezcla de reacción con metanol bajo la acción de ultrasonido, seguido por cromatografía de columna. Todos los compuestos obtenidos fueron caracterizados por espectroscopía infrarroja, resonancia magnética nuclear, análisis elemental cuantitativo y espectrometría de masas de alta resolución. Los datos de RMN-1H demuestran que en todas las estructuras de los curcuminoides sintetizados la forma enólica es la más favorecida.

El 153Sm-hm es una nueva opción para realizar sinovectomía por radiación, que actualmente se encuentra en valoración. Este trabajo tiene como objetivo calcular la dosis absorbida en tejidos articulares proporcionada por la administración de 153Sm-hm intraarticular, utilizando la simulación de Monte Carlo, en una propuesta de un modelo simplificado anatómico geométrico de la articulación de la rodilla. Esto con el propósito de aportar datos que apoyen la administración segura y eficaz del radiofármaco en estudio a pacientes con enfermedad reumática de la articulación de la rodilla. Se concluye que la actividad administrada de 153Sm-hm por vía intra-articular es de 370 MBq para conseguir una dosis absorbida en membrana sinovial de 110 Gy, considerada como la dosis de ablación de la mencionada membrana.

En este artículo se examina la trayectoria histórica del grupo Urquijo, uno de los grupos empresariales más importantes de España en el siglo XX. Se trata de un ejemplo representativo del modelo de grupos empresariales creados por algunos bancos mixtos en España entre finales del siglo XIX y principios del XX. El trabajo enfatiza la importancia de este tipo de organización económica en el desarrollo industrial del país, al promover la creación de empresas y garantizar su crecimiento a largo plazo mediante el aporte de tres recursos esenciales: financiación permanente, capacidad tecnológica procedente del exterior y capital humano cualificado (técnicosy directivos).

Al hilo de la reciente publicación de un libro con los perfiles biográficos de 100 destacados empresarios españoles del siglo XX, en este artículo se repasan algunas de las características más relevantes del empresariado de este periodo con la intención de dibujar un retrato aproximado del mismo. En él se tienen en cuenta aspectos como: el origen de los empresarios, su educación/formación, su actitud ante la innovación, las estrategias de mercado, los estilos de gestión, la actitud ante las relaciones laborales y las relaciones con la política.

Background: The prevalence of essential tremor (ET) is still not well understood and the various studies performed to date have generated highly variable results. Few epidemiologic studies on the prevalence of ET have been reported from Spain.Methods: A one‐stage door‐to‐door survey was conducted on Arosa Island, northwestern Spain, to determine the prevalence of ET in the population aged 65 years and older. The diagnostic criteria for ET were the presence of non‐dystonic head tremor or moderate‐ to severe‐amplitude tremor on at least four tests of the revised Washington Heights‐Inwood Genetic Study of Essential Tremor (WHIGET) Scale.Results: A total of 65 individuals with ET (28 males, 37 females) were identified, resulting in a crude prevalence of 8.63% (adjusted rate 8.42%). Prevalence increased with advancing age. There were no significant differences in prevalence between sexes in any of the age groups. Among the prevalent cases, 12.3% (n = 8) had been previously diagnosed. Only 29.2% (n = 19) reported functional disability caused by tremor. A family history of tremor was reported in 35.4% (n = 23).Discussion: The prevalence of ET was higher than that seen in similar populations in Spain and other countries. A high proportion of those with ET were previously undiagnosed. Since Arosa Island has been a relatively isolated area, these results might indicate a predominant role, at least in the elderly, for genetic factors in the development of ET.

Sin resumen

El objeto de esta comunicación es dar a conocer de forma breve algunas de las principales conclusiones de mi tesis doctoral titulada Ramón de la Sota: Historia económica de un empresario (1857-1936), que defendí el pasado mes de mayo en el departamento que figura al comienzo de este escrito, y para cuya realización conté con la ayuda material del Banco de España y con la dirección del catedrático don Pedro Tedde de Lorca. Dado el contenido y los fines del coloquio, dividiré la exposición en tres partes. Situaré en la primera a Ramón de la Sota en el contexto histórico en el que desenvolvió su actividad, para sintetizar después lo que puede considerarse como su aportación a la modernización económica (parte segunda) y política (parte tercera) de la España de la Restauración.