Análisis de los patrones de expresión génica en el carcinoma colorrectal: desarrollo de biomarcadores predictivos de respuesta a la quimioterapia en pacientes con enfermedad avanzada

La quimioterapia basada en fluoropirimidinas ha sido la base del tratamiento del cáncer colorrectal metastásico (CCRm) durante años. Sin embargo, tan sólo aproximadamente la mitad de los pacientes tratados alcanzan respuestas tumorales objetivas y, hasta la fecha, no disponemos de herramientas fiables que permitan identificar de forma prospectiva a aquellos pacientes que presentan mayor probabilidad de beneficiarse del tratamiento. El objetivo de este estudio fue la identificación de un perfil de expresión génica predictivo de respuesta a la quimioterapia en CCRm. Con este fin, se realizó la hibridación en microarrays (Affymetrix GeneChip® HGU133 Plus 2.0) del genoma completo de muestras tumorales congeladas en fresco de una cohorte inicial de 37 pacientes con CCRm. Los perfiles de expresión génica en las dos condiciones del estudio (respondedores a la quimioterapia de primera línea versus no respondedores) se compararon mediante análisis bioinformático supervisado, identificándose un panel de 161 genes diferencialmente expresados en pacientes respondedores (23 pacientes; 62%) con respecto a los no respondedores (14 pacientes; 38%). Estos genes fueron seleccionados para su evaluación mediante qRT-PCR TaqMan®Low Density Arrays (TLDA) 7900 HT Micro Fluidic Cards) en una cohorte independiente multicéntrica que incluyó muestras de 53 pacientes. Siete de estos genes fueron validados como predictores de respuesta a quimioterapia en CCRm. Los pacientes con un perfil de expresión favorable presentaron tasas de respuesta (58% vs 13%, p=0.024), supervivencia libre de progresión (61% vs 13% a 1 año, HR=0.32, p=0.009) y supervivencia global (32 vs 16 meses, HR=0.21, p=0.003) significativamente mayores que los pacientes con un perfil de expresión no favorable. Este ha sido el primer estudio en validar un perfil de expresión génica predictivo de respuesta a la quimioterapia en pacientes con CCRm. Sin embargo, serán necesarios estudios prospectivos y con mayor número de pacientes para confirmar estos hallazgos y poder trasladar a la clínica herramientas útiles que permitan optimizar la selección del tratamiento más adecuado para cada paciente.Premio Extraordinario de Doctorado U

Gene expression profile predictive of response to chemotherapy in metastatic colorectal cancer

Estévez-García, Purificación et al.Fluoropyrimidine-based chemotherapy (CT) has been the mainstay of care of metastatic colorectal cancer (mCRC) for years. Response rates are only observed, however, in about half of treated patients, and there are no reliable tools to prospectively identify patients more likely to benefit from therapy. The purpose of our study was to identify a gene expression profile predictive of CT response in mCRC. Whole genome expression analyses (Affymetrix GeneChip® HG-U133 Plus 2.0) were performed in fresh frozen tumor samples of 37 mCRC patients (training cohort). Differential gene expression profiles among the two study conditions (responders versus non-responders) were assessed using supervised class prediction algorithms. A set of 161 differentially expressed genes in responders (23 patients; 62%) versus non-responders (14 patients; 38%) was selected for further assessment and validation by RT-qPCR (TaqMan®Low Density Arrays (TLDA) 7900 HT Micro Fluidic Cards) in an independent multi-institutional cohort (53 mCRC patients). Seven of these genes were confirmed as significant predictors of response. Patients with a favorable predictive signature had significantly greater response rate (58% vs 13%, p = 0.024), progression-free survival (61% vs 13% at 1 year, HR = 0.32, p = 0.009) and overall survival (32 vs 16 months, HR = 0.21, p = 0.003) than patients with an unfavorable gene signature. This is the first study to validate a gene-expression profile predictive of response to CT in mCRC patients. Larger and prospective confirmatory studies are required, however, in order to successfully provide oncologists with adequate tools to optimize treatment selection in routine clinical practice.This work was supported by a grant of the Fundacion Mutua Madrileña (FMM) (P0497/2006) and from the Fondo de Investigación Sanitaria/Instituto de Salud Carlos III Spanish Cancer Networks RTICC (R12/0036/0008 and R12/0036/0028). RGC is funded by Fondo de Investigación Sanitaria (PI10/02164, PI13/02295), Servicio Andaluz de Salud (PI-0259/2007) and RTICC (R12/0036/0028). PEG is funded by a Rio Hortega grant (09/00207) from the Instituto de Salud Carlos III (ISCiii), Ministerio de Sanidad, Spain and Consejeria de Salud of the Junta de Andalucia (PI-0135–2010). SMP is funded by Fondo de Investigación Sanitaria (CD1100153) and Fundación Científica de la Asociación Española Contra el Cáncer. MDP is funded by Fondo de Investigación Sanitaria (CD0900148). LPA is funded by the ISCiii (PI081156, PI1102688, RTICC R12/0036/0008), Consejería de Innovacion, Ciencia y Empresa – Junta de Andalucia (P08-CVI-04090) and the 75th Anniversary Roche Spain Fellowship. AC is funded by the Spanish Ministry of Science and Innovation (SAF2009–08605), FIS (PI12/00137), Consejeria de Ciencia e Innovacion and Consejeria de Salud of the Junta de Andalucia (CTS-6844 and PI-0142), and by Fundacion Oncologica FERO, supported by Fundació Josep Botet.Peer Reviewe

MiR-107 and miR-99a-3p predict chemotherapy response in patients with advanced colorectal cancer

Molina-Pinelo, Sonia et al.[Background] MicroRNAs (miRNAs) are involved in numerous biological and pathological processes including colorectal cancer (CRC). The aim of our study was to evaluate the ability of miRNA expression patterns to predict chemotherapy response in a cohort of 78 patients with metastatic CRC (mCRC).[Methods] We examined expression levels of 667 miRNAs in the training cohort and evaluated their potential association with relevant clinical endpoints. We identified a miRNA profile that was analysed by RT-qPCR in an independent cohort. For a set of selected miRNAs, bioinformatic target predictions and pathway analysis were also performed.[Results] Eight miRNAs (let-7 g*, miR-107, miR-299-5p, miR-337-5p, miR-370, miR-505*, miR-889 and miR-99a-3p) were significant predictors of response to chemotherapy in the training cohort. In addition, overexpression of miR-107, miR-337-5p and miR-99a-3p, and underexpression of miR-889, were also significantly associated with improved progression-free and/or overall survival. MicroRNA-107 and miR-99a-3p were further validated in an independent cohort as predictive markers for chemotherapy response. In addition, an inverse correlation was confirmed in our study population between miR-107 levels and mRNA expression of several potential target genes (CCND1, DICER1, DROSHA and NFKB1).[Conclusions] MiR-107 and miR-99a-3p were validated as predictors of response to standard fluoropyrimidine-based chemotherapy in patients with mCRC. © 2014 Molina-Pinelo et al.; licensee BioMed Central Ltd.RGC is funded by Fondo de Investigación Sanitaria (PI10/02164), Servicio Andaluz de Salud (PI-0259/2007) and RTICC (R12/0036/0028). SM-P is funded by Fondo de Investigación Sanitaria (CD1100153) and Fundación Científica de la Asociación Española Contra el Cáncer. MDP is funded by Fondo de Investigación Sanitaria (CD0900148). AC lab was supported by grants to from the Spanish Ministry of Economy and Competitivity, ISCIII (Fis: PI12/00137, RTICC: RD12/0036/0028), Consejeria de Ciencia e Innovacion (CTS-6844) and Consejeria de Salud of the Junta de Andalucia (PI-0135-2010 and PI-0306-2012).Peer Reviewe

Entrevista de apego para niños (EAN): Estudio exploratorio de un nuevo instrumento de evaluación del apego en población infantil de 3 a 7 años

This study analizes the psychometric properties of a new instrument about the working model of children´s attachment. The sample was composed of 60 subjects (30 from normal  population and 30 from a social risk population). The age of children ranges from 3 to 7 years old. This instrument is an interview based on the completion story task, however it includes new contents as well as a new procedure in regarding to previous attachment measures. The findings show good validity and reliability. The found results are going to be the beginning of future studies.ResumenEl presente artículo analiza las propiedades psicométricas de un nuevo instrumento de evaluación de los modelos de representación deapego en niños. La muestra está constituida por un total de 60 sujetos de entre 3 y 7 años, 30 procedentes de población normativa y 30 de una población de riesgo psicosocial. El instrumento se administra con un formato de entrevista basado en la técnica del completamiento de historias pero incluye, respecto a instrumentos previos, elementos novedosos tanto en los contenidos que evalúa como en su metodología. Los resultados preliminares de esta medida indican índices adecuados de validez y fiabilidad, lo que supone un punto de partida prometedor y relevante para futuras investigaciones. Abstract This study analizes the psychometric properties of a new instrument about the working model of children´s attachment. The sample was composed of 60 subjects (30 from normal  population and 30 from a social risk population). The age of children ranges from 3 to 7 years old. This instrument is an interview based on the completion story task, however it includes new contents as well as a new procedure in regarding to previous attachment measures. The findings show good validity and reliability. The found results are going to be the beginning of future studies

Spinophilin loss correlates with poor patient prognosis in advanced stages of colon carcinoma

[Purpose+ The genomic region 17q21 is frequently associated with microsatellite instability and LOH in cancer, including gastric and colorectal carcinomas. This region contains several putative tumor suppressor genes, including Brca1, NM23, prohibitin, and spinophilin (Spn, PPP1R9B, neurabin II). The scaffold protein Spn is one of the regulatory subunits of phosphatase-1 (PP1) that targets PP1 to distinct subcellular locations and couples PP1 to its target. Thus, Spn may alter cell-cycle progression via the regulation of the phosphorylation status of the retinoblastoma protein, a direct target of PP1. Therefore, we analyzed whether Spn levels were reduced in colorectal carcinomas and whether Spn levels correlated with prognosis or response to therapy.[Experimental Design] By means of immunohistochemistry or quantitative PCR, we studied the levels of Spn in stages II, III, and IV colorectal carcinoma tumors and correlated to other clinicopathologic features as well as prognosis or response to therapy.[Results] Spn was lost in a percentage of human gastric, small intestine, and colorectal carcinomas. In patients with colorectal carcinoma, tumoral Spn downregulation correlated with a more aggressive histologic phenotype (poorer tumor differentiation and higher proliferative Ki67 index). Consistent with this observation, lower Spn protein expression levels were associated with faster relapse and poorer survival in patients with stage III colorectal carcinoma, particularly among those receiving adjuvant fluoropyrimidine therapy. We validated this result in an independent cohort of patients with metastatic colorectal carcinoma treated with standard chemotherapy. Although patients that achieved an objective tumor response exhibited Spn levels similar to nontumoral tissue, nonresponding patients showed a significant reduction in Spn mRNA levels.[Conclusions] Our data suggest that Spn downregulation contributes to a more aggressive biologic behavior, induces chemoresistance, and is associated with a poorer survival in patients with advanced stages of colorectal carcinoma. © 2013 American Association for Cancer Research.This work was supported by grants from the Spanish Ministry of Science and Innovation (SAF2009-08605), Fondo de Investigacion Sanitaria (PI12/00137), Consejeria de Ciencia e Innovacion, and Consejeria de Salud of the Junta de Andalucia (CTS-6844 and PI-0142). A. Carnero's laboratory is also funded by a fellowship from Fundacion Oncologica FERO. P. Estevez-Garcia and I. Lopez-Calderero are supported by Rio Ortega Fellowships and S. Molina-Pinelo is supported by a Sara Borrell fellowship. R. Garcia-Carbonero is funded by the Instituto de Salud Carlos III, Ministerio de Sanidad, Spain (PI 10.02164).Peer Reviewe

Conclusiones finales del 1er Congreso Internacional sobre Desarrollo Personal en la Formación Inicial del Docente

El estudio que presentamos forma parte del proyecto de investigación “La formación ética docente de los futuros profesionales de los grados de Educación Infantil y Educación Primaria como elemento de selección: diagnóstico y análisis, (PID2021-129018NB-I00)”, financiado por MCIN/AEI/10.13039/501100011033/FEDER Una manera de hacer Europa. El estudio también forma parte del proyecto titulado “El desarrollo personal en la formación inicial del docente: la empatía del estudiantado y del profesorado”, que ha sido financiado con cargo a la ayuda P20-00698 concedida por la Consejería de Universidad, Investigación e Innovación de la Junta de Andalucía y por FEDER, Una manera de Hacer Europa.Ser docente en el siglo XXI requiere desempeñar funciones, algunas similares y otras diferentes, a las de los siglos que nos han precedido, para las que hemos de formarnos y formar. El papel del nuevo docente ya no es únicamente ser “transmisor de conocimientos”, sino que le toca ser “una persona comprometida y transformadora”, capaz de enseñar de forma crítica, así como conseguir que su alumnado aprenda a convivir y a ser un ciudadano responsable en la sociedad. Este documento recoge las conclusiones finales en torno a cuatro interrogantes: ¿Qué perfil docente exige la sociedad del siglo XXI?; ¿Son las habilidades blandas una necesidad formativa global?; ¿Deberíamos poner el foco en la entrada o en la salida de la formación inicial?; ¿Con el diseño de los planes de estudios de los grados actuales, podemos afrontar los retos que exige la Agenda 2030?P20_00698PID2021-129018NB-100 financiado por MCIN/AEI/10.13039/501100011033/FEDE

Mirvetuximab Soravtansine in FRα-Positive, Platinum-Resistant Ovarian Cancer

[BACKGROUND] Mirvetuximab soravtansine-gynx (MIRV), a first-in-class antibody–drug conjugate targeting folate receptor α (FRα), is approved for the treatment of platinum-resistant ovarian cancer in the United States.[METHODS] We conducted a phase 3, global, confirmatory, open-label, randomized, controlled trial to compare the efficacy and safety of MIRV with the investigator’s choice of chemotherapy in the treatment of platinum-resistant, high-grade serous ovarian cancer. Participants who had previously received one to three lines of therapy and had high FRα tumor expression (≥75% of cells with ≥2+ staining intensity) were randomly assigned in a 1:1 ratio to receive MIRV (6 mg per kilogram of adjusted ideal body weight every 3 weeks) or chemotherapy (paclitaxel, pegylated liposomal doxorubicin, or topotecan). The primary end point was investigator-assessed progression-free survival; key secondary analytic end points included objective response, overall survival, and participant-reported outcomes.[RESULTS] A total of 453 participants underwent randomization; 227 were assigned to the MIRV group and 226 to the chemotherapy group. The median progression-free survival was 5.62 months (95% confidence interval [CI], 4.34 to 5.95) with MIRV and 3.98 months (95% CI, 2.86 to 4.47) with chemotherapy (P<0.001). An objective response occurred in 42.3% of the participants in the MIRV group and in 15.9% of those in the chemotherapy group (odds ratio, 3.81; 95% CI, 2.44 to 5.94; P<0.001). Overall survival was significantly longer with MIRV than with chemotherapy (median, 16.46 months vs. 12.75 months; hazard ratio for death, 0.67; 95% CI, 0.50 to 0.89; P=0.005). During the treatment period, fewer adverse events of grade 3 or higher occurred with MIRV than with chemotherapy (41.7% vs. 54.1%), as did serious adverse events of any grade (23.9% vs. 32.9%) and events leading to discontinuation (9.2% vs. 15.9%).[CONCLUSIONS] Among participants with platinum-resistant, FRα-positive ovarian cancer, treatment with MIRV showed a significant benefit over chemotherapy with respect to progression-free and overall survival and objective response. (Funded by ImmunoGen; MIRASOL ClinicalTrials.gov number, NCT04209855.)Peer reviewe

Method for predicting the response to chemotherapy treatment in patients suffering from colorectal cancer

Método de obtención de datos útiles para predecir la respuesta al tratamiento con quimioterapia en pacientes con cáncer colorrectal, kit, dispositivo y microarray para llevar a cabo dicho método.Peer reviewedServicio Andaluz de Salud, Consejo Superior de Investigaciones Científicas, Fundación Pública Andaluza para la Gestión de la Investigación de la Salud en Sevilla, Universidad de SevillaA1 Solicitud de patente con informe sobre el estado de la técnic

Método para predecir la respuesta al tratamiento con quimioterapia en pacientes de cáncer colorrectal

The invention relates to a method for obtaining useful data for predicting the response to chemotherapy treatment in patients suffering from colorectal cancer, which allows a specific individual quantitative identification model to be established, based on the analysis of the expression profile of certain marker genes.Peer reviewedServicio Andaluz de Salud, Consejo Superior de Investigaciones Científicas, Fundación Pública Andaluza para la Gestión de la Investigación de la Salud en Sevilla, Universidad de SevillaA1 Solicitud de patente con informe sobre el estado de la técnic

Tendencias pedagógicas

Resumen tomado de la publicaciónEl apego seguro al cuidador principal es un promotor del desarrollo. El objetivo del estudio fue explorar el papel moderador y/o mediador del apego dentro de un modelo de relaciones entre el contexto psicosocial de los niños y su ajuste psicológico. La muestra estaba compuesta por dos grupos equivalentes: uno de riesgo psicosocial procedente de un centro tutelado de menores de la Comunidad de Madrid (n=30; 60% varones) y otro grupo de niños provenientes de un entorno familiar normativo (n=30; 58% varones). La edad media en ambos grupos fue de 5.45 años. Nuestros resultados sugieren el papel del apego como un potencial mecanismo explicativo de las relaciones entre riesgo psicosocial y problemas de ajuste en los niños. Se discuten las implicaciones teóricas y prácticas de estos resultados.ES