Córdoba en el siglo XX (1929-2002): poder económico y humanismo ético: comunión y controversia

El objetivo esencial de esta tesis es la interpretación de las claves que configuran un periodo capital de la historia de Córdoba, teniendo como eje la biografía de Miguel Castillejo, presidente de CajaSur, quien puede considerarse uno de sus principales artífices. El trabajo se inicia en las postrimerías de la dictadura de Primo de Rivera y nos acerca hasta el tiempo presente, principiado ya el tercer milenio. Consta de tres partes diferenciadas pero implicadas cualitativamente. El método de la prosopografía -sobre la apoyatura de cuatro clases de documentos: orales, hemerográficos, privados y archivísticos- signa las dos primeras partes de carácter biográfico, en las que se reflejan tres aspectos esenciales: el dintorno biográfico, la trama prosopográfica y la sociología del poder. En el primer apartado se relata la biografía lineal, desde el nacimiento en 1929 a la obtención de la canonjía de penitenciario en 1973. En un segundo momento, se establecen tres vectores esenciales: el de sacerdote renacentista, el del intelectual mecenas y el del hombre de empresa. La tercera parte está orientada a la exégesis de la obra escrita de Castillejo, vertebrada en cuatro espacios: el teológico filosófico, el espiritual antropológico, el ético social y el oratorio didáctico. Éste es el primer acercamiento científico que se lleva a cabo acerca de Miguel Castillejo, sobre el que ha pesado uno de los cometidos cardinales de este siglo: El desarrollo sociocultural y económico de Córdoba y, por extensión, de Andalucía. La coherencia ha marcado una andadura fértil, sobre tres coordenadas claves: La misión ministerial, la actitud intelectual y de mecenazgo y la responsabilidad empresarial de servicio. He pretendido reflejar una situación histórica desde la perspectiva biográfica, analizando el excepcional protagonismo de un hombre que ha marcado capitalmente el último cuarto del siglo XX en Córdoba; interpretando las claves que lo han conducido a ser lo que es; y descubriendo en esta prospección sociología muchas de las coordenadas que determinan el cáracter del pueblo cordobés y algunas de las circunstancias que han motivado y modificado sus planteamientos y actuacione

Somatostatin, cortistatin, ghrelin and their receptors: From an endocrine system to a pleiotropic system of pathophysiologic relevance

Somatostatina (SST)/cortistatina (CST) y ghrelina son los más conocidos miembros de dos sistemas complejos formados por un gran número de péptidos y receptores (ssts y GHS-Rs, respectivamente), que, aunque exhiben claras diferencias desde el punto de vista estructural, evolutivo y funcional, presentan importantes similitudes y coincidencias. De hecho, además de los bien conocidos efectos opuestos de los sistemas SST/CST y ghrelina en la regulación de varios tipos celulares en la adenohipófisis, actuando directamente a nivel hipofisario o indirectamente a través del hipotálamo, ambos sistemas ejercen además un gran número de funciones biológicas diversas. Sin embargo, numerosas pruebas apuntan a que los sistemas de la SST/CST y de la ghrelina no son sistemas de neuro-péptidos y receptores aislados con funciones diversas y separadas, sino que componen un red de componentes interrelacionados fisiológicamente capaces de interaccionar funcionalmente a nivel molecular, celular y orgánico para regular multitud de funciones. Teniendo en cuenta estos antecedentes, el reto consiste en identificar, caracterizar y colocar en un contexto fisiológico y en una posición de posible aplicación terapéutica los elementos que componen el supra-sistema SST/CST/ghrelina y receptores, sus interacciones y los nuevos elementos. En este sentido, el objetivo general de la Tesis consiste en ampliar nuestros conocimientos acerca del papel de los sistemas de la SST/CST y la ghrelina en condiciones pato-fisiológicas, extendiendo las acciones más clásicas a nivel hipotálamo-hipofisario, e incorporando nuevas funciones e interacciones en la interfase del cáncer, el metabolismo y los desórdenes neurodegenerativos. Los resultados obtenidos en el presente estudio se resumen en los siguientes: 1)Los sistemas de la SST y la ghrelina están regulados diferencialmente y de manera tejido-dependiente en respuesta a insultos metabólicos en el eje hipotálamo-hipófisis-estómago, donde parece que estos sistemas se regulan de manera cruzada. De hecho, el ayuno altera, en ratones, la expresión de SST y ghrelina en dicho eje, así como los niveles de ghrelina plasmáticos. Interesantemente, los ratones deficientes en SST presentan elevados niveles de ghrelina en plasma y en estómago, lo que sugiere que los niveles basales de SST son importantes en la regulación de la ghrelina. Además, la regulación de la expresión de la enzima responsable de la acilación de la ghrelina, así como su actividad enzimática y la disponibilidad de sustrato, podrían actuar sinérgicamente para regular los niveles plasmáticos de ghrelina acilada bajo condiciones de estrés metabólico en ratones. 2)Los sistemas de la SST/CST y de la ghrelina están desregulados en cáncer de mama en mujeres, donde algunos de los nuevos componentes de estos sistemas (sst5TMD4, In2-ghrelina, GHS-R1b, GOAT) pueden tener una contribución especial en esta patología. Así, el receptor truncado sst5TMD4 está presente en cánceres de mama agresivos, donde se asocia con marcadores de mal pronóstico. Además, en líneas celulares derivadas de cáncer de mama, su expresión incrementa su malignidad, posiblemente a través de la disrupción de sistema "protector"compuesto por SST y sst2. Por otro lado, una nueva variante de la ghrelina, la In2-ghrelina, así como la GOAT o el GHS-R1b, están altamente expresados en muestras humanas de cáncer de mama y su sobreexpresión en líneas celulares de cáncer de mama provoca un incremento en su tasa de proliferación. 3)Los sistemas de la SST/CST y de la ghrelina, en pacientes con la enfermedad de Alzheimer, están profundamente alterados en el giro temporal, una de las regiones corticales más importantes en procesos cognitivos. Puesto que los estos sistemas parecen ejercer acciones protectoras influyendo directamente en los procesos relacionados con la memoria, la desregulación de estos sistemas en el lóbulo temporal de los pacientes con enfermedad de Alzheimer puede contribuir a las alteraciones de los procesos cognitivos observadas en esta patología. En conclusión, los sistemas de la SST/CST y de la ghrelina están presentes y regulados diferencialmente en ejes y en condiciones patológicas claramente diferentes y distantes de sus originales funciones neuroendocrinas a nivel hipotálamo-hipofisario. Por lo tanto, parece razonable proponer que la SST/CST, la ghrelina, los péptidos relacionados y sus receptores conforman dos sistemas pleiotrópicos profundamente interrelacionados, los cuales podrían ser considerados como nuevas dianas para la intervención terapéutica

Molecular and Clinical Implications of Somatostatin Receptor Profile and Somatostatin Analogues Treatment in Oral Cavity Squamous Cell Carcinoma

Oral squamous cell carcinoma (OSCC) incidence has increased by 50% over the last decade. Unfortunately, surgery and adjuvant radiotherapy and chemotherapy are still the mainstream modality of treatment, underscoring the need for alternative therapies. Somatostatin-analogues (SSA) are efficacious and safe treatments for a variety of tumors, but the presence of somatostatin-receptors (SSTs) and pharmacological effects of SSA on OSCC are poorly known. In this study, we demonstrated that SST2 and SST3 levels were significantly higher in OSCC, compared to adjacent healthy control tissues. SST2 expression was associated with less regional metastasis and a lower recurrence rate. Moreover, SST2 was elevated in OSCC and associated with histopathological good prognosis factors, such as high peritumoral inflammation, smaller depth of invasion, and expansive vs. infiltrative front of tumor invasion. Importantly, treatment with different SSA (octreotide, lanreotide, and pasireotide) significantly reduced cell-proliferation in OSCC primary cell cultures. Altogether, this study demonstrated that SST2 is overexpressed in OSCC vs. healthy tissues and could represent a novel prognostic biomarker, since its expression is associated with tumors that show better prognostic factors and less recurrent rate. Moreover, our data unveil clear antitumoral effects of SSAs on OSCC, opening new avenues to explore their potential as targeting therapy to OSCC

A Novel Human Ghrelin Variant (In1-Ghrelin) and Ghrelin-O-Acyltransferase Are Overexpressed in Breast Cancer: Potential Pathophysiological Relevance

The human ghrelin gene, which encodes the ghrelin and obestatin peptides, contains 5 exons (Ex), with Ex1-Ex4 encoding a 117 amino-acid (aa) preproprotein that is known to be processed to yield a 28-aa (ghrelin) and/or a 23-aa (obestatin) mature peptides, which possess biological activities in multiple tissues. However, the ghrelin gene also encodes additional peptides through alternative splicing or post-translational modifications. Indeed, we previously identified a spliced mRNA ghrelin variant in mouse (In2-ghrelin-variant), which is regulated in a tissue-dependent manner by metabolic status and may thus be of biological relevance. Here, we have characterized a new human ghrelin variant that contains Ex0-1, intron (In) 1, and Ex2 and lacks Ex3-4. This human In1-ghrelin variant would encode a new prepropeptide that conserves the first 12aa of native-ghrelin (including the Ser3-potential octanoylation site) but has a different C-terminal tail. Expression of In1-variant was detected in 22 human tissues and its levels were positively correlated with those of ghrelin-O-acyltransferase (GOAT; p = 0.0001) but not with native-ghrelin expression, suggesting that In1-ghrelin could be a primary substrate for GOAT in human tissues. Interestingly, levels of In1-ghrelin variant expression in breast cancer samples were 8-times higher than those of normal mammary tissue, and showed a strong correlation in breast tumors with GOAT (p = 0.0001), ghrelin receptor-type 1b (GHSR1b; p = 0.049) and cyclin-D3 (a cell-cycle inducer/proliferation marker; p = 0.009), but not with nativeghrelin or GHSR1a expression. Interestingly, In1-ghrelin variant overexpression increased basal proliferation of MDA-MB-231 breast cancer cells. Taken together, our results provide evidence that In1-ghrelin is a novel element of the ghrelin family with a potential pathophysiological role in breast cance

Ghrelin-O-Acyltransferase (GOAT) Enzyme as a Novel Potential Biomarker in Gastroenteropancreatic Neuroendocrine Tumors

Objectives: The association between the presence and alterations of the components of the ghrelin system and the development and progression of neuroendocrine tumors (NETs) is still controversial and remains unclear. Methods: Here, we systematically evaluated the expression levels (by quantitative-PCR) of key ghrelin system components of in gastroenteropancreatic (GEP)-NETs, as compared to non-tumor adjacent (NTA; n = 42) and normal tissues (NT; n = 14). Then, we analyzed their putative associations with clinical-histological characteristics. Results: The results indicate that ghrelin and its receptor GHSR1a are present in a high proportion of normal tissues, while the enzyme ghrelin-O-acyltransferase (GOAT) and the splicing variants In1-ghrelin and GHSR1b were present in a lower proportion of normal tissues. In contrast, all ghrelin system components were present in a high proportion of tumor and NTA tissues. GOAT was significantly overexpressed (by quantitative-PCR (qPCR)) in tumor samples compared to NTA, while a trend was found for ghrelin, In1-ghrelin and GHSR1a. In addition, expression of these components displayed significant correlations with key clinical parameters. The marked overexpression of GOAT in tumor samples compared to NTA regions was confirmed by IHC, revealing that this enzyme is particularly overexpressed in gastrointestinal NETs, where it is directly correlated with tumor diameter. Conclusions: These results provide novel information on the presence and potential pathophysiological implications of the ghrelin system components in GEP-NETs, wherein GOAT might represent a novel diagnostic biomarker

Somatostatin Receptor Splicing Variant sst5TMD4 Overexpression in Glioblastoma Is Associated with Poor Survival, Increased Aggressiveness Features and Somatostatin Analogs Resistance

Glioblastoma (GBM) is the most malignant and lethal brain tumor. Current standard treatment consists of surgery followed by radiotherapy/chemotherapy; however, this is only a palliative approach with a mean post-operative survival of scarcely ~12–15 months. Thus, the identification of novel therapeutic targets to treat this devastating pathology is urgently needed. In this context, the truncated splicing variant of the somatostatin receptor subtype 5 (sst5TMD4), which is produced by aberrant alternative splicing, has been demonstrated to be overexpressed and associated with increased aggressiveness features in several tumors. However, the presence, functional role, and associated molecular mechanisms of sst5TMD4 in GBM have not been yet explored. Therefore, we performed a comprehensive analysis to characterize the expression and pathophysiological role of sst5TMD4 in human GBM. sst5TMD4 was significantly overexpressed (at mRNA and protein levels) in human GBM tissue compared to non-tumor (control) brain tissue. Remarkably, sst5TMD4 expression was significantly associated with poor overall survival and recurrent tumors in GBM patients. Moreover, in vitro sst5TMD4 overexpression (by specific plasmid) increased, whereas sst5TMD4 silencing (by specific siRNA) decreased, key malignant features (i.e., proliferation and migration capacity) of GBM cells (U-87 MG/U-118 MG models). Furthermore, sst5TMD4 overexpression in GBM cells altered the activity of multiple key signaling pathways associated with tumor aggressiveness/progression (AKT/JAK-STAT/NF-κB/TGF-β), and its silencing sensitized GBM cells to the antitumor effect of pasireotide (a somatostatin analog). Altogether, these results demonstrate that sst5TMD4 is overexpressed and associated with enhanced malignancy features in human GBMs and reveal its potential utility as a novel diagnostic/prognostic biomarker and putative therapeutic target in GBMs

LRP10, PGK1 and RPLP0: best reference genes in periprostatic adipose tissue under obesity and prostate cancer conditions

Obesity (OB) is a metabolic disorder characterized by adipose tissue dysfunction that has emerged as a health problem of epidemic proportions in recent decades. OB is associated with multiple comorbidities, including some types of cancers. Specifically, prostate cancer (PCa) has been postulated as one of the tumors that could have a causal relationship with OB. Particularly, a specialized adipose tissue (AT) depot known as periprostatic adipose tissue (PPAT) has gained increasing attention over the last few years as it could be a key player in the pathophysiological interaction between PCa and OB. However, to date, no studies have defined the most appropriate internal reference genes (IRGs) to be used in gene expression studies in this AT depot. In this work, two independent cohorts of PPAT samples (n = 20/n = 48) were used to assess the validity of a battery of 15 literature-selected IRGs using two widely used techniques (reverse transcription quantitative PCR [RT-qPCR] and microfluidic-based qPCR array). For this purpose, ΔCt method, GeNorm (v3.5), BestKeeper (v1.0), NormFinder (v.20.0), and RefFinder software were employed to assess the overall trends of our analyses. LRP10, PGK1, and RPLP0 were identified as the best IRGs to be used for gene expression studies in human PPATs, specifically when considering PCa and OB conditions

Experiences in flipped learning

El presente trabajo describe unas experiencias de innovación docente, de igual perfil y metodología, desarrolladas por un conjunto de profesores noveles participantes bajo la tutela experta de profesorado senior. El tipo de experiencia seleccionada ha sido el diseño y ejecución de una flipped classroom, o clase invertida. Además, se incluye la correspondiente evaluación de la acción con una valoración académica o impacto en los aprendizajes, y una valoración de la experiencia por parte del alumnado y profesorado responsable. Los resultados de cinco experiencias con impacto a mas de 270 alumnos de distinto perfil académico (tres asignaturas de titulo de Grado y dos de Máster) y las evaluaciones cuantificadas indican una valoracion muy positiva de esta metodología flipped learning (FL) por los alumnos y su deseo de aplicabilidad. Por su parte, el profesorado constata que las experiencias FL han incrementado satisfactoriamente el aprendizaje de sus alumnos y declaran una alta valoración de la experiencia para la mejora de sus competencia docentes.The present work describes experiences of teaching innovation, of the same profile and methodology, developed by a group of participating junior teachers under the expert guidance of senior teaching staff. The type of experience selected has been the design and execution of a flipped classroom, or inverted class. In addition, the corresponding evaluation of the action is included with an academic assessment or impact on learning, and an assessment of the experience by the students and teaching staff responsible. The results of five experiences with impact to more than 270 students of different academic profiles (three degrees and two Masters) and the quantified evaluations indicate a very positive assessment of this flipped learning methodology by the students and their desire for applicability. On the other hand, the teachers note that the FL experiences have successfully increased the learning of their students and declare a high evaluation of the experience for the improvement of their teaching competences

Comparative Cytotoxic Activity of Hydroxytyrosol and Its Semisynthetic Lipophilic Derivatives in Prostate Cancer Cells

A high adherence to a Mediterranean diet has been related to numerous beneficial effects in human health, including a lower incidence and mortality of prostate cancer (PCa). Olive oil is an important source of phenolic bioactive compounds, mainly hydroxytyrosol (HT), of this diet. Because of the growing interest of this compound and its derivatives as a cancer chemopreventive agent, we aimed to compare the in vitro effect of HT isolated from olive mill wastewaters and five semisynthetic alkyl ether, ester, and nitro-derivatives against prostate cancer (PCa) cell lines. The effect in cell proliferation was determined in RWPE-1, LNCaP, 22Rv1, and PC-3 cells by resazurin assay, the effect in cell migration by wound healing assay, and tumorsphere and colony formation were evaluated. The changes in key signaling pathways involved in carcinogenesis were assessed by using a phosphorylation pathway profiling array and by Western blotting. Antiproliferative effects of HT and two lipophilic derivatives [hydroxytyrosyl acetate (HT-Ac)/ethyl hydroxytyrosyl ether (HT-Et)] were significantly higher in cancerous PC-3 and 22Rv1 cells than in non-malignant RWPE-1 cells. HT/HT-Ac/HT-Et significantly reduced migration capacity in RWPE-1 and PC-3 and prostatosphere size and colony formation in 22Rv1, whereas only HT-Ac and HT-Et reduced these functional parameters in PC-3. The cytotoxic effect in 22Rv1 cells was correlated with modifications in the phosphorylation pattern of key proteins, including ERK1/2 and AKT. Consistently, HT-Ac and HT-Et decreased p-AKT levels in PC-3. In sum, our results suggest that HT and its lipophilic derivatives could be considered as potential therapeutic tools in PCa

Dietary Intervention Modulates the Expression of Splicing Machinery in Cardiovascular Patients at High Risk of Type 2 Diabetes Development: From the CORDIOPREV Study

Type-2 diabetes mellitus (T2DM) has become a major health problem worldwide. T2DM risk can be reduced with healthy dietary interventions, but the precise molecular underpinnings behind this association are still incompletely understood. We recently discovered that the expression profile of the splicing machinery is associated with the risk of T2DM development. Thus, the aim of this work was to evaluate the influence of 3-year dietary intervention in the expression pattern of the splicing machinery components in peripheral blood mononuclear cells (PBMCs) from patients within the CORDIOPREV study. Expression of splicing machinery components was determined in PBMCs, at baseline and after 3 years of follow-up, from all patients who developed T2DM (Incident-T2DM, n = 107) and 108 randomly selected non-T2DM subjects, who were randomly enrolled in two healthy dietary patterns (Mediterranean or low-fat diets). Dietary intervention modulated the expression of key splicing machinery components (i.e., up-regulation of SPFQ/RMB45/RNU6, etc., down-regulation of RNU2/SRSF6) after three years, independently of the type of healthy diet. Some of these changes (SPFQ/RMB45/SRSF6) were associated with key clinical features and were differentially induced in Incident-T2DM patients and non-T2DM subjects. This study reveals that splicing machinery can be modulated by long-term dietary intervention, and could become a valuable tool to screen the progression of T2DM