In1-ghrelin splicing variant is overexpressed in pituitary adenomas and increases their aggressive features

Pituitary adenomas comprise a heterogeneous subset of pathologies causing serious comorbidities, which would benefit from identification of novel, common molecular/cellular biomarkers and therapeutic targets. The ghrelin system has been linked to development of certain endocrine-related cancers. Systematic analysis of the presence and functional implications of some components of the ghrelin system, including native ghrelin, receptors and the recently discovered splicing variant In1-ghrelin, in human normal pituitaries (n 5 11) and pituitary adenomas (n 5 169) revealed that expression pattern of ghrelin system suffers a clear alteration in pituitary adenomasas comparedwith normal pituitary, where In1-ghrelin is markedly overexpressed. Interestingly, in cultured pituitary adenoma cells In1-ghrelin treatment (acylated peptides at 100 nM; 24–72 h) increasedGHandACTHsecretion, Ca21 and ERK1/2 signaling and cell viability, whereas In1-ghrelin silencing (using a specific siRNA; 100 nM) reduced cell viability. These results indicate that an alteration of the ghrelin system, specially its In1-ghrelin variant, could contribute to pathogenesis of different pituitary adenomas types, and suggest that this variant and its related ghrelin system could provide new tools to identify novel, more general diagnostic, prognostic and potential therapeutic targets in pituitary tumors

Splicing Machinery is Dysregulated in Pituitary Neuroendocrine Tumors and is Associated with Aggressiveness Features

Pituitary neuroendocrine tumors (PitNETs) constitute approximately 15% of all brain tumors, and most have a sporadic origin. Recent studies suggest that altered alternative splicing and, consequently, appearance of aberrant splicing variants, is a common feature of most tumor pathologies. Moreover, spliceosome is considered an attractive therapeutic target in tumor pathologies, and the inhibition of SF3B1 (e.g., using pladienolide-B) has been shown to exert antitumor effects. Therefore, we aimed to analyze the expression levels of selected splicing-machinery components in 261 PitNETs (somatotropinomas/non-functioning PitNETS/corticotropinomas/prolactinomas) and evaluated the direct effects of pladienolide-B in cell proliferation/viability/hormone secretion in human PitNETs cell cultures and pituitary cell lines (AtT-20/GH3). Results revealed a severe dysregulation of splicing-machinery components in all the PitNET subtypes compared to normal pituitaries and a unique fingerprint of splicing-machinery components that accurately discriminate between normal and tumor tissue in each PitNET subtype. Moreover, expression of specific components was associated with key clinical parameters. Interestingly, certain components were commonly dysregulated throughout all PitNET subtypes. Finally, pladienolide-B reduced cell proliferation/viability/hormone secretion in PitNET cell cultures and cell lines. Altogether, our data demonstrate a drastic dysregulation of the splicing-machinery in PitNETs that might be associated to their tumorigenesis, paving the way to explore the use of specific splicing-machinery components as novel diagnostic/prognostic and therapeutic targets in PitNETs

Correction : Chaparro et al. Incidence, Clinical Characteristics and Management of Inflammatory Bowel Disease in Spain: Large-Scale Epidemiological Study. J. Clin. Med. 2021, 10, 2885

The authors wish to make the following corrections to this paper [...]

Incidence, Clinical Characteristics and Management of Inflammatory Bowel Disease in Spain : Large-Scale Epidemiological Study

(1) Aims: To assess the incidence of inflammatory bowel disease (IBD) in Spain, to describe the main epidemiological and clinical characteristics at diagnosis and the evolution of the disease, and to explore the use of drug treatments. (2) Methods: Prospective, population-based nationwide registry. Adult patients diagnosed with IBD-Crohn's disease (CD), ulcerative colitis (UC) or IBD unclassified (IBD-U)-during 2017 in Spain were included and were followed-up for 1 year. (3) Results: We identified 3611 incident cases of IBD diagnosed during 2017 in 108 hospitals covering over 22 million inhabitants. The overall incidence (cases/100,000 person-years) was 16 for IBD, 7.5 for CD, 8 for UC, and 0.5 for IBD-U; 53% of patients were male and median age was 43 years (interquartile range = 31-56 years). During a median 12-month follow-up, 34% of patients were treated with systemic steroids, 25% with immunomodulators, 15% with biologics and 5.6% underwent surgery. The percentage of patients under these treatments was significantly higher in CD than UC and IBD-U. Use of systemic steroids and biologics was significantly higher in hospitals with high resources. In total, 28% of patients were hospitalized (35% CD and 22% UC patients, p < 0.01). (4) Conclusion: The incidence of IBD in Spain is rather high and similar to that reported in Northern Europe. IBD patients require substantial therapeutic resources, which are greater in CD and in hospitals with high resources, and much higher than previously reported. One third of patients are hospitalized in the first year after diagnosis and a relevant proportion undergo surgery

Innovación, desarrollo tecnológico y gestión : una construcción desde la investigación

Libro que compila investigaciones de carácter aplicadas y descriptivas en materia de innovación y desarrollo tecnológico, gestión organizacional y empresarial orientada a productividad, rentabilidad, competitividad y sostenibilidadBook that compiles researches of applied and descriptive character in the matter of innovation and technological development, organizational and business management oriented to productivity, profitability, competitiveness and sustainabilityCapítulo 1. Material compuesto para la construcción a partir de la celulosa del papel y cartón reciclado / Carlos Arturo Tamayo S; Nicolás Montero Camacho; Fredy Antonio Herrera -- Capítulo 2. Tecnologías de conservación para base de sopa de frijol rojo (phaseolus vulgaris) y vegetales / Yaceris Castro Escorcia; Teresa Altamar Pérez; Enedys Florez Cortés; Ángela Ortiz Ruiz. Capítulo 3. Utilización de harina compuesta de frijol caupi (vigna unguiculata) en masas para alimentos congelados / Marcela Villalba Cadavid; Matilde Rodríguez Muñoz; Beatriz Fernández; Juan Mendoza Combatt -- Capítulo 4. Elaboración de biorrecubrimiento comestible para carne de hamburguesa como alternativa de conservación y condimento natural / Camila Andrea Ubaque Beltrán. CAPÍTULO 5. Identificación de alternativas de industrialización de productos y subproductos agroindustriales en nuevos materiales bio poliméricos / Luz Henao Díaz; Deya Pérez Zúñiga; Herold Arango Gómez. Capítulo 6. SCADA inalámbrico para monitoreo de sistemas de energía solar / Nelson Giovanni Agudelo Cristancho; Juan Carlos Amezquita Tovar; Ángela María Montoya Castro. -- Capítulo 7. Evaluación de la calidad del agua para consumo humano del corregimiento de Jaraquiel, Montería, Córdoba / Carlos Burgos Galeano; Álvaro Aleán Vásquez; Paula Estrada Palencia -- Capítulo 8. Optimización del sistema de abastecimiento de agua en la comunidad de Jaraquel, Montería Colombia / Carlos Burgos Galeano; Pedro Ramos Tejada; Paula Estrada Palencia; Jhon Sánchez Correa. -- Capítulo 9. Ejecución y sostenibilidad de proyectos productivos en la microrregión cafetera del municipio de Ciénaga, Magdalena / Sugey Issa Fontalvo; Eduardo Robles Panetta; Freddy González Castillo. -- Capítulo 10. Aplicación del método cualitativo por puntos para determinar aspirante favorito a cargos directivos en IES / Zamir Martelo Ballesteros; Raúl Martelo Gómez; Luis Tovar Garrido; Natividad Villabona Gómez; David Franco Borré. -- Capítulo 11 Responsabilidad social en comunidades indígenas orientada al diseño de automatización de válvulas del gasoducto Riohacha-Maicao / Gelvis Melo Freile; César Rivera Romero; Jesús García Guiliany. -- Capítulo 12 Fortalecimiento de la gestión económica de las Mipymes a través de la consultoría / Gloria Amparo Acosta Romero; Mónica Andrade Ríos; Karen Roxana Sánchez. -- Capítulo 13. El compromiso como valor en la responsabilidad social universitaria / Maura Quintero Gutiérrez, Dubys Villarreal Torres; Jesús García Guiliany; Annherys Paz Marcano; Marieth Orcasitas Peñaloza. -- Capítulo 14. Educación financiera como alternativa de desarrollo económico y social para el distrito de Riohacha / Henitzo Martínez Pinedo; Darcy Luz Mendoza; Martha Jaramillo Acosta; Edwin Salas Solano. -- Capítulo 15. Tecnologías de información y comunicación en proceso contable y financiero en pymes del sector turístico / Martha Josefina Castrillón Rois; Edilberto Rafael Santos Moreno; Lorena Esther Gómez Bermúdez; Génesis Barros González. -- Capítulo 16. Aplicación de brainstorming y problem trees para determinar factores que inciden en enseñanza del inglés / Jesús Llerena; Raúl J. Martelo; Jhon Cuesta; Javier Pinedo; David Franco.-- Capítulo 17. Incidencia del marketing en las microempresas del sector comercio en Rionegro Antioquia: conceptualización / Santiago Álzate Carmona; María Yamile Mazo Gil; Leidy García Jaramillo. -- Capítulo 18. Turismo en el Cabo de la Vela: un acercamiento entre los imaginarios turísticos de los visitantes y la creencia de Jepirra, territorio sagrado / María Laura Aponte Aarón; Esmerlis Camargo Torres. -- Capítulo 19. Caracterización de la actividad turística en buenaventura y su integración con las comunidades locales / Víctor Cándelo Aragón; Henry Orobio García; Luis Montaño Aguilar. -- Capítulo 20. Plataforma de comercialización electrónica de un centro de abastos / Karen Ávila Suarez; Mauro Reyes Ortiz. -- Capítulo 21. El teletrabajo en la gestión administrativa / Estefanía Sandoval Cruz; René Alexander Guerrero Vergel. -- Capítulo 22. Gestión del conocimiento y alianzas estratégicas en los procesos de innovación tecnológica / Elder Rivero Gutiérrez; Fátima Bolaño Mendoza. -- Capítulo 23. Competitividad e innovación en el aprendiz SENA: perspectivas de formación / Elizabeth Tuberquia Vanegas; René Alexander Guerrero Vergel. -- Capítulo 24. Bomba de riego por goteo solar, una alternativa para aumentar la eficiencia energética en las unidades acuícolas / Sergio Gabriel Brito Brito; Daldo Ricardo Araujo Vidal; Nicolás Annicharico Jiménez. -- Capítulo 25. Herramienta digital de consultas contables y tributarias para unidades productivas creadas en el fondo emprender / Elkin Fuentes Jiménez; Alda Pérez Campuzano; Marieth Orcasitas Peñaloza; Olga Elena Guerra ArmentaPrimera ediciónna347 página

Association between dopamine and somatostatin receptor expression and pharmacological response to somatostatin analogues in acromegaly.

Acromegaly is a hormonal disorder resulting from excessive growth hormone (GH) secretion frequently produced by pituitary adenomas and consequent increase in insulin-like growth factor 1 (IGF-I). Elevated GH and IGF-I levels result in a wide range of somatic, cardiovascular, endocrine, metabolic and gastrointestinal morbidities. Somatostatin analogues (SSAs) form the basis of medical therapy for acromegaly and are currently used as first-line treatment or as second-line therapy in patients undergoing unsuccessful surgery. However, a considerable percentage of patients do not respond to SSAs treatment. Somatostatin receptors (SSTR1-5) and dopamine receptors (DRD1-5) subtypes play critical roles in the regulation of hormone secretion. These receptors are considered important pharmacological targets to inhibit hormone oversecretion. It has been proposed that decreased expression of SSTRs may be associated with poor response to SSAs. Here, we systematically examine SSTRs and DRDs expression in human somatotroph adenomas by quantitative PCR. We observed an association between the response to SSAs treatment and DRD4, DRD5, SSTR1 and SSTR2 expression. We also examined SSTR expression by immunohistochemistry and found that the immunohistochemical detection of SSTR2 in particular might be a good predictor of response to SSAs

Association between radiological parameters and clinical and molecular characteristics in human somatotropinomas

Abstract Acromegaly is a rare but severe disease, originated in 95% of cases by a growth hormone-secreting adenoma (somatotropinoma) in the pituitary. Magnetic resonance imaging (MRI) is a non-invasive technique used for the diagnosis and prognosis of pituitary tumours. The aim of this study was to determine whether the use of T2-weighted signal intensity at MRI could help to improve the characterisation of somatotropinomas, by analysing its relationship with clinical/molecular features. An observational study was implemented in a cohort of 22 patients (mean age = 42.1 ± 17.2 years; 59% women; 95% size>10 mm). Suprasellar-extended somatotropinomas presented larger diameters vs. non-extended tumours. T2-imaging revealed that 59% of tumours were hyperintense and 41% isointense adenomas, wherein hyperintense were more invasive (according to Knosp-score) than isointense adenomas. A higher proportion of hyperintense somatotropinomas presented extrasellar-growth, suprasellar-growth and invasion of the cavernous sinus compared to isointense adenomas. Interestingly, somatostatin receptor-3 and dopamine receptor-5 (DRD5) expression levels were associated with extrasellar and/or suprasellar extension. Additionally, DRD5 was also higher in hyperintense adenomas and its expression was directly correlated with Knosp-score and with tumour diameter. Hence, T2-weighted MRI on somatotropinomas represents a potential tool to refine their diagnosis and prognosis, and could support the election of preoperative treatment, when required

The oncogenic role of the In1-ghrelin splicing variant in prostate cancer aggressiveness

Abstract Background The Ghrelin-system is a complex, pleiotropic family composed of several peptides, including native-ghrelin and its In1-ghrelin splicing variant, and receptors (GHSR 1a/b), which are dysregulated in various endocrine-related tumors, where they associate to pathophysiological features, but the presence, functional role, and mechanisms of actions of In1-ghrelin splicing variant in prostate-cancer (PCa), is completely unexplored. Herein, we aimed to determine the presence of key ghrelin-system components (native-ghrelin, In1-ghrelin, GHSR1a/1b) and their potential pathophysiological role in prostate cancer (PCa). Methods In1-ghrelin and native-ghrelin expression was evaluated by qPCR in prostate tissues from patients with high PCa-risk (n = 52; fresh-tumoral biopsies), and healthy-prostates (n = 12; from cystoprostatectomies) and correlated with clinical parameters using Spearman-test. In addition, In1-ghrelin and native-ghrelin was measured in plasma from an additional cohort of PCa-patients with different risk levels (n = 30) and control-healthy patients (n = 20). In vivo functional (proliferation/migration) and mechanistic (gene expression/signaling-pathways) assays were performed in PCa-cell lines in response to In1-ghrelin and native-ghrelin treatment, overexpression and/or silencing. Finally, tumor progression was monitored in nude-mice injected with PCa-cells overexpressing In1-ghrelin, native-ghrelin and empty vector (control). Results In1-ghrelin, but not native-ghrelin, was overexpressed in high-risk PCa-samples compared to normal-prostate (NP), and this expression correlated with that of PSA. Conversely, GHSR1a/1b expression was virtually absent. Remarkably, plasmatic In1-ghrelin, but not native-ghrelin, levels were also higher in PCa-patients compared to healthy-controls. Furthermore, In1-ghrelin treatment/overexpression, and to a much lesser extent native-ghrelin, increased aggressiveness features (cell-proliferation, migration and PSA secretion) of NP and PCa cells. Consistently, nude-mice injected with PC-3-cells stably-transfected with In1-ghrelin, but not native-ghrelin, presented larger tumors. These effects were likely mediated by ERK1/2-signaling activation and involved altered expression of key oncogenes/tumor suppressor genes. Finally, In1-ghrelin silencing reduced cell-proliferation and PSA secretion from PCa cells. Conclusions Altogether, our results indicate that In1-ghrelin levels (in tissue) and circulating levels (in plasma) are increased in PCa where it can regulate key pathophysiological processes, thus suggesting that In1-ghrelin may represent a novel biomarker and a new therapeutic target in PCa

Cultura en Castilla-La Mancha en el siglo XX

Resumen tomado de la publicaciónSe analizan, por bloques, las principales manifestaciones en el terreno de las artes plásticas, la arquitectura, la conservación del patrimonio histórico-artístico, la edición, la prensa, el cine, el teatro, la música, y dos últimos apartados sobre la producción intelectual en filosofía y en etnología. Y concluye con una amplia cronología de los principales acontecimientos del ámbito de la cultura en Castilla-La Mancha en el siglo XX. Se parte de la constatación de la inexistencia de una cultura que pueda calificarse como regional, aunque eso no significa que no haya habido muchas, y a veces importantes, manifestaciones culturales particulares en las cinco provincias que conforman Castilla-La Mancha, así como grandísimos creadores, en todas las disciplinas, que han sumado sus obras a la cultura española en general. El libro quiere ser un punto de partida para estudios más detallados en cada uno de estos territorios, y ofrece una primera mirada de conjunto a un rico, aunque desigual, panorama cultural, a lo largo de toda una centuria.Castilla La ManchaConsejería de Educación, Ciencia y Cultura. Viceconsejería de Educación y Cultura. Servicio de Documentación; Bulevar del Río Alberche, s. n. - 1 Planta; 45071 Toledo; +34925286045; +34925247410; [email protected]

BIM-23A760 influences key functional endpoints in pituitary adenomas and normal pituitaries: molecular mechanisms underlying the differential response in adenomas

Chimeric somatostatin/dopamine compounds such as BIM-23A760, an sst2/sst5/D2 receptors-agonist, have emerged as promising new approaches to treat pituitary adenomas. However, information on direct in vitro effects of BIM-23A760 in normal and tumoral pituitaries remains incomplete. The objective of this study was to analyze BIM-23A760 effects on functional parameters (Ca2+ signaling, hormone expression/secretion, cell viability and apoptosis) in pituitary adenomas (n = 74), and to compare with the responses of normal primate and human pituitaries (n = 3–5). Primate and human normal pituitaries exhibited similar sst2/sst5/D2 expression patterns, wherein BIM-23A760 inhibited the expression/secretion of several pituitary hormones (specially GH/PRL), which was accompanied by increased sst2/sst5/D2 expression in primates and decreased Ca2+ concentration in human cells. In tumoral pituitaries, BIM-23A760 also inhibited Ca2+ concentration, hormone secretion/expression and proliferation. However, BIM-23A760 elicited stimulatory effects in a subset of GHomas, ACTHomas and NFPAs in terms of Ca2+ signaling and/or hormone secretion, which was associated with the relative somatostatin/dopamine-receptors levels, especially sst5 and sst5TMD4. The chimeric sst2/sst5/D2 compound BIM-23A760 affects multiple, clinically relevant parameters on pituitary adenomas and may represent a valuable therapeutic tool. The relative ssts/D2 expression profile, particularly sst5 and/or sst5TMD4 levels, might represent useful molecular markers to predict the ultimate response of pituitary adenomas to BIM-23A760.This work has been funded by the following grants: Junta de Andalucía (BIO-0139, CTS-1406, PI-639-2012); Ministerio de Economía y Competitividad, Gobierno de España (BFU2013-43282) ; Proyectos de Investigación en Salud FIS, funded by Instituto de Salud Carlos III (PI13-00651, co-funded by ERDF/ESF, “Investing in your future”); Instituto de Salud Carlos III, Ministerio de Sanidad, Servicios Sociales e Igualdad ‘CIBERobn’; and Ayuda Merck Serono 2013 (to RML and JPC). Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development Merit Award and the National Institutes of Health: R21AG031465 and R01DK088133 (to RDK).Peer reviewe