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

In1-ghrelin splicing variant is associated with reduced disease-free survival of breast cancer patients and increases malignancy of breast cancer cells lines

OXFORD UNIVERSITY: This is a pre-copyedited, author-produced version of an article accepted for publication in Carcinogenesis following peer review. The version of record David Rincón-Fernández, Michael D Culler, Natia Tsomaia, Gema Moreno-Bueno, Raúl M Luque, Manuel D Gahete, Justo P Castaño; In1-ghrelin splicing variant is associated with reduced disease-free survival of breast cancer patients and increases malignancy of breast cancer cells lines, Carcinogenesis, Volume 39, Issue 3, 8 March 2018, Pages 447–457, https://doi.org/10.1093/carcin/bgx146Ghrelin gene generates several variants that regulate multiple pathophysiological functions, including tumor-related processes. In1-ghrelin is a splicing variant that was previously shown to be overexpressed in breast cancer (BCa), where it correlated with proliferation markers; however, its possible association with clinical outcome of BCa patients and underlying mechanisms are still unknown. To address this issue, expression levels and clinical associations of In1-ghrelin were analyzed in a cohort of 117 BCa samples. Additionally, a battery of cellular and molecular assays was implemented using two BCa cell lines (MCF-7 and MDA-MB-231), wherein the role of In1-ghrelin on proliferation, migration, dedifferentiation and signaling pathways was explored. The results generated revealed that high expression of In1-ghrelin in BCa samples was associated with lymph node metastasis and reduced disease-free survival. Indeed, In1-ghrelin overexpression stimulated proliferation and migration in MCF-7 and MDA-MB-231 cells. Similar results were found by treating MDA-MB-231 and MCF-7 with In1- ghrelin-derived peptides. Conversely, In1-ghrelin silencing decreased proliferation and migration capacities of MDA-MB-231. Furthermore, In1-ghrelin (but not ghrelin) overexpression increased the capacity to form mammospheres in both cell lines. These effects could be associated with activation of MAPK-ERK, Jag1/Notch, Wnt/β-catenin and/or TGF-β1 pathways. Altogether, our data indicate that In1-ghrelin could play relevant functional roles in the regulation of BCa development and progression and may provide insights to identify novel biomarkers and new therapeutic approaches for this pathology.BIO-0139, CTS-1406, PI-639-2012, PI-0541-2013 (Junta de Andalucia), BFU2013-43282-R, BFU2016-80360-R (MINECO), PI13-00651, PI16/00264 (Proyectos de Investigación en Salud FIS, funded by Instituto de Salud Carlos III), GETNE Grant 2014, Merck Serono Grant 2013 and CIBERobn (to RML and JPC); PI13/00132, RETICC RD12/0036/0007, CIBERonc and S2010/BMD-2303 (to GMB

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

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

Role of metformin and other metabolic drugs in the prevention and therapy of endocrine-related cancers

Metabolic syndrome is associated with chronic diseases, including type 2 diabetes, cardiovascular diseases, and cancer. This review summarizes the current evidence on the antitumor effects of some relevant drugs currently used to manage metabolic-related pathologies (i.e. insulin and its analogs, metformin, statins, etc.) in endocrine-related cancers including breast cancer, prostate cancer, pituitary cancer, ovarian cancer, and neuroendocrine neoplasms. Although current evidence does not provide a clear antitumor role of several of these drugs, metformin seems to be a promising chemopreventive and adjuvant agent in cancer management, modulating tumor cell metabolism and microenvironment, through both AMP-activated protein kinase-dependent and -independent mechanisms. Moreover, its combination with statins might represent a promising therapeutic strategy to tackle the progression of endocrine-related tumors. However, further studies are needed to endorse the clinical relevance of these drugs as adjuvants for cancer chemotherapy.Ministerio de Ciencia e Innovación de España. PID2019- 105564RB-I00/FPU16-05059Fondo Europeo de Desarrollo Regional (FEDER) y Fondo Social Europeo (FSE). PI20/01301Instituto de Salud Carlos III de España. SCIII-AES-2019/002525Junta de Andalucía. PI-0152-2019, PI-0094-2020, PI-0038/2019, RH-0084-2020 y BIO-013

Multidisciplinary Prehabilitation and Postoperative Rehabilitation for Avoiding Complications in Patients Undergoing Resection of Colon Cancer: Rationale, Design, and Methodology of the ONCOFIT Study

ONCOFIT is a randomized clinical trial with a two-arm parallel design aimed at determining the influence of a multidisciplinary Prehabilitation and Postoperative Program (PPP) on post-surgery complications in patients undergoing resection of colon cancer. This intervention will include supervised physical exercise, dietary behavior change, and psychological support comparing its influence to the standard care. Primary and secondary endpoints will be assessed at baseline, at preoperative conditions, at the end of the PPP intervention (after 12 weeks) and 1-year post-surgery, and will include: post-surgery complications (primary endpoint); prolonged hospital length of stay; readmissions and emergency department call within 1-year after surgery; functional capacity; patient reported outcome measures targeted; anthropometry and body composition; clinical/tumor parameters; physical activity levels and sedentariness; dietary habits; other unhealthy habits; sleep quality; and fecal microbiota diversity and composition. Considering the feasibility of the present intervention in a real-life scenario, ONCOFIT will contribute to the standardization of a cost-effective strategy for preventing and improving health-related consequences in patients undergoing resection of colon cancer with an important clinical and economic impact, not only in the scientific community, but also in clinical practice.This study was funded by the University of Granada, Plan Propio de Investigación 2016-Excellence actions: Unit of Excellence on Exercise and Health (UCEES). P.C. was supported by the Margarita Salas postdoctoral grant, convened by de University of the Basque Country (UPV/EHU), funded by the Ministry of Universities of Spain and the European Union-Next Generation EU

Obesity- and gender-dependent role of endogenous somatostatin and cortistatin in the regulation of endocrine and metabolic homeostasis in mice

Somatostatin (SST) and cortistatin (CORT) regulate numerous endocrine secretions and their absence [knockout (KO)-models] causes important endocrine-metabolic alterations, including pituitary dysregulations. We have demonstrated that the metabolic phenotype of single or combined SST/CORT KO-models is not drastically altered under normal conditions. However, the biological actions of SST/CORT are conditioned by the metabolic-status (e.g. obesity). Therefore, we used male/female SST- and CORT-KO mice fed low-fat (LF) or high-fat (HF) diet to explore the interplay between SST/CORT and obesity in the control of relevant pituitary-axes and whole-body metabolism. Our results showed that the SST/CORT role in the control of GH/prolactin secretions is maintained under LF- and HF-diet conditions as SST-KOs presented higher GH/prolactin-levels, while CORT-KOs displayed higher GH- and lower prolactin-levels than controls under both diets. Moreover, the impact of lack of SST/CORT on the metabolic-function was gender- and diet-dependent. Particularly, SST-KOs were more sensitive to HF-diet, exhibiting altered growth and body-composition (fat/lean percentage) and impaired glucose/insulin-metabolism, especially in males. Conversely, only males CORT-KO under LF-diet conditions exhibited significant alterations, displaying higher glucose-levels and insulin-resistance. Altogether, these data demonstrate a tight interplay between SST/CORT-axis and the metabolic status in the control of endocrine/metabolic functions and unveil a clear dissociation of SST/CORT rolesThis work was supported by the following grants: Junta de Andalucía (CTS-1406, BIO-0139), ISCIII-FIS [PI13/00651 and PIE14/00005 (co-funded by European Regional Development Fund/European Social Fund “Investing in your future”)], MINECO (BFU2013–43282-R), “Miguel Servet” Program, CIBERobn and Ayuda Merck Serono 2013S

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