Interaction of Mitogen-activated Protein Kinases with the Kinase Interaction Motif of the Tyrosine Phosphatase PTP-SL Provides Substrate Specificity and Retains ERK2 in the Cytoplasm

ERK1 and ERK2 associate with the tyrosine phosphatase PTP-SL through a kinase interaction motif (KIM) located in the juxtamembrane region of PTP-SL. A glutathioneS-transferase (GST)-PTP-SL fusion protein containing the KIM associated with ERK1 and ERK2 as well as with p38/HOG, but not with the related JNK1 kinase or with protein kinase A or C. Accordingly, ERK2 showed in vitro substrate specificity to phosphorylate GST-PTP-SL in comparison with GST-c-Jun. Furthermore, tyrosine dephosphorylation of ERK2 by the PTP-SLΔKIM mutant was impaired. Thein vitro association of ERK1/2 with GST-PTP-SL was highly stable; however, low concentrations of nucleotides partially dissociated the ERK1/2·PTP-SL complex. Partial deletions of the KIM abrogated the association of PTP-SL with ERK1/2, indicating that KIM integrity is required for interaction. Amino acid substitution analysis revealed that Arg and Leu residues within the KIM are essential for the interaction and suggested a regulatory role for Ser231. Finally, coexpression of PTP-SL and ERK2 in COS-7 cells resulted in the retention of ERK2 in the cytoplasm in a KIM-dependent manner. Our results demonstrate that the noncatalytic region of PTP-SL associates with mitogen-activated protein kinases with high affinity and specificity, providing a mechanism for substrate specificity, and suggest a role for PTP-SL in the regulation of mitogen-activated protein kinase translocation to the nucleus upon activation

Imaginería medieval mariana en Navarra. Santa María de Ujué.

El trabajo se centra en el estudio de la imaginería mariana medieval en el marco geográfico del territorio navarro, perteneciente a los siglos del románico y el gótico, poniendo de relieve las características estilísticas de las tallas y el uso y función de las mismas. Dada la amplitud del tema, demasiado extenso para ser abordado en el presente trabajo de investigación, hemos decidido delimitarlo, con objeto de analizar con mayor profundidad la tipología de la estatuaria mariana sedente, además de abordar de forma individualizada una de las imágenes más sobresalientes de la comunidad foral, tanto desde el punto de vista artístico como devocional, a saber, la Virgen de Santa María de Ujué.<br /

Interaction of sedentary behaviour and educational level in breast cancer risk

Objective This cross-sectional study aims to analyse the relationship between sedentary behaviour and breast cancer (BC) risk from a social perspective. Methods Women aged 45–70 who participated in the Valencia Region Breast Cancer Screening Programme (2018–2019) were included, with a total of 121,359 women analysed, including 506 with cancer and 120,853 without cancer. The response variable was BC (screen-detected) and the main explanatory variable was sedentary behaviour (≤2 / >2-≤3 / >3-≤5 / >5 hours/day, h/d). Nested logistic regression models (M) were estimated: M1: sedentary behaviour adjusted for age and family history of BC; M2: M1 + hormonal/reproductive variables (menopausal status, number of pregnancies, hormone replacement therapy; in addition, months of breastfeeding was added for a subsample of women with one or more live births); M3: M2 + lifestyle variables (body mass index, smoking habits); M4: M3 + socioeconomic variables (educational level, occupation); Final model: M4 + gender variables (childcare responsibilities, family size). Interaction between sedentary behaviour and educational level was analysed in the Final model. Moreover, for the whole sample, postmenopausal women and HR+ BC, the Final model was stratified by educational level. Results Sedentary behaviour was associated with an increased risk of BC with a nearly statistically significant effect in the Final model (>2-≤3 h/d: OR = 1.22 (0.93–1.61); >3-≤5 h/d: OR = 1.14 (0.86–1.52); >5: OR = 1.19 (0.89–1.60)). For women with a low educational level, sitting more than 2 h/d was associated with an increased risk of BC in the whole sample (>2-≤3 h/d OR = 1.93 (1.19–3.21); in postmenopausal women (>2-≤3 h/d, OR = 2.12 (1.18–2.96), >5h/d OR = 1.75 (1.01–3.11)) and in HR+ BC (>2-≤3h/d, OR = 2.15 (1.22–3.99)). Similar results were observed for women with one or more live births. Conclusions Sitting >2 h/d is associated with BC risk in women with low educational level, especially in postmenopausal women and those with live births.M.P-C: This work was supported by the Generalitat Valenciana and the European Social Fund [grant number ACIF/2019/085]

Tumor phenotype and breast density in distinct categories of interval cancer: results of population-based mammography screening in Spain

Introduction: Interval cancers are tumors arising after a negative screening episode and before the next screening invitation. They can be classified into true interval cancers, false-negatives, minimal-sign cancers, and occult tumors based on mammographic findings in screening and diagnostic mammograms. This study aimed to describe tumor-related characteristics and the association of breast density and tumor phenotype within four interval cancer categories. Methods: We included 2,245 invasive tumors (1,297 screening-detected and 948 interval cancers) diagnosed from 2000 to 2009 among 645,764 women aged 45 to 69 who underwent biennial screening in Spain. Interval cancers were classified by a semi-informed retrospective review into true interval cancers (n = 455), false-negatives (n = 224), minimal-sign (n = 166), and occult tumors (n = 103). Breast density was evaluated using Boyd’s scale and was conflated into: 75%. Tumor-related information was obtained from cancer registries and clinical records. Tumor phenotype was defined as follows: luminal A: ER+/HER2- or PR+/HER2-; luminal B: ER +/HER2+ or PR+/HER2+; HER2: ER-/PR-/HER2+; triple-negative: ER-/PR-/HER2-. The association of tumor phenotype and breast density was assessed using a multinomial logistic regression model. Adjusted odds ratios (OR) and 95% confidence intervals (95% CI) were calculated. All statistical tests were two-sided. Results: Forty-eight percent of interval cancers were true interval cancers and 23.6% false-negatives. True interval cancers were associated with HER2 and triple-negative phenotypes (OR = 1.91 (95% CI:1.22-2.96), OR = 2.07 (95% CI:1.42-3.01), respectively) and extremely dense breasts (>75%) (OR = 1.67 (95% CI:1.08-2.56)). However, among true interval cancers a higher proportion of triple-negative tumors was observed in predominantly fatty breasts (<25%) than in denser breasts (28.7%, 21.4%, 11.3% and 14.3%, respectively; <0.001). False-negatives and occult tumors had similar phenotypic characteristics to screening-detected cancers, extreme breast density being strongly associated with occult tumors (OR = 6.23 (95% CI:2.65-14.66)). Minimal-sign cancers were biologically close to true interval cancers but showed no association with breast density. Conclusions: Our findings revealed that both the distribution of tumor phenotype and breast density play specific and independent roles in each category of interval cancer. Further research is needed to understand the biological basis of the overrepresentation of triple-negative phenotype among predominantly fatty breasts in true interval cancers

Factors influencing participation in colorectal cancer screening programs in Spain

To analyze the sociodemographic and organizational factors influencing participation in population-based colorectal cancer screening programs (CRCSP) in Spain, a retrospective study was conducted in a cohort of people invited to participate in the first 3 screening rounds of 6 CRCSP from 2000 to 2012. Mixed logistic regression models were used to analyze the relationship between sociodemographic and organizational factors, such as the type of fecal occult blood test (FOBT) used and the FOBT delivery type. The analysis was performed separately in groups (Initial screening-first invitation, Subsequent invitation for previous never-responders, Subsequent invitation-regular, Subsequent invitation-irregular intervals). The results showed that, in the Initial screening-first invitation group, participation was higher in women than in men in all age groups (OR 1.05 in persons aged 50–59 years and OR 1.12 in those aged 60–69 years). Participation was also higher when no action was required to receive the FOBT kit, independently of the type of screening (Initial screening-first invitation [OR 2.24], Subsequent invitation for previous never-responders [OR 2.14], Subsequent invitation-regular [OR 2.03], Subsequent invitation-irregular intervals [OR 9.38]) and when quantitative rather than qualitative immunological FOBT (FIT) was offered (Initial screening-first invitation [OR 0.70], Subsequent invitation for previous never-responders [OR 0.12], Subsequent invitation-regular [OR 0.20]) or guaiac testing (Initial screening-first invitation [OR 0.81], Subsequent invitation for previous never-responders [OR 0.88], Subsequent invitation-regular [OR 0.73]). In conclusion, the results of this study show that screening participation could be enhanced by inclusion of the FOBT kit with the screening invitation and the use of the quantitative FIT.This Project was funded by the Fondo de Investigación Sanitario with cofunding from FEDER [PI12/00944

DNA sequences within glioma-derived extracellular vesicles can cross the intact blood-brain barrier and be detected in peripheral blood of patients

Tumor-cell-secreted extracellular vesicles (EVs) can cross the disrupted bloodbrain barrier (BBB) into the bloodstream. However, in certain gliomas, the BBB remains intact, which might limit EVs release. To evaluate the ability of tumor-derived EVs to cross the BBB, we used an orthotopic xenotransplant mouse model of human glioma-cancer stem cells featuring an intact BBB. We demonstrated that all types of tumor cells-derived EVs−apoptotic bodies, shedding microvesicles and exosomes− cross the intact BBB and can be detected in the peripheral blood, which provides a minimally invasive method for their detection compared to liquid biopsies obtained from cerebrospinal fluid (CSF). Furthermore, these EVs can be readily distinguished from total murine EVs, since they carry human-specific DNA sequences relevant for GBM biology. In a small cohort of glioma patients, we finally demonstrated that peripheral blood EVs cargo can be successfully used to detect the presence of IDH1G395A, an essential biomarker in the current management of human gliomaWe are grateful for the financial support from the ‘Fondo de Investigaciones Sanitarias’ (FIS) (PI10/01069 and PI14/00077) and the ‘Miguel Servet Program’ (CP11/00147) from the ‘Instituto de Salud Carlos III’ (AAS), RTC-2015-3846-1 from Ministerio de Economía y Competitividad and FEDER fund

Impacto de la educación en la cultura del emprendimiento: estudio cualitativo

Entrepreneurship is a reality that is optimistic about the possibilities of development, progress and well-being. The economic policies of the most advanced countries encourage and promote actions for their citizens to implement their business ideas and generate their own jobs. In this research we will focus on the educational aspect that has traditionally been positively linked to formal entrepreneurship. The figure of the entrepreneur is key when generating social transformations and it is worth approaching not only his personal vision but also the perception that these promoters have different age groups.In this sense, the University of Burgos through the Interuniversity Program of Experience and in the framework of training for older people, launches concrete actions to meet the needs, experiences and expectations of university majors in relation to entrepreneurship. We consider it of great importance that the University, as a long-standing institution in the field of knowledge, supports the processes of entrepreneurship with all the resources at its disposal, among them, the great human capital that is not only among its faculty or staff, but also in their classrooms, mainly those of the elderly.We show in the present investigation the initial results of the qualitative study implemented through a discussion group in which the elders have discussed the concept of entrepreneurship, motives, aid, training and skills. The results will serve as a basis for future proposals and interventions.El emprendimiento es una realidad que se nos presenta optimista en cuanto a posibilidades de desarrollo, progreso y bienestar. Las políticas económicas de los países más avanzados animan y promueven acciones para que sus ciudadanos pongan en marcha sus ideas de negocio y generen sus propios puestos de trabajo. En la presente investigación nos centraremos en el aspecto educativo que tradicionalmente se ha vinculado positivamente con el emprendimiento formal. La figura del emprendedor es clave a la hora de generar transformaciones de tipo social y merece la pena acercarse no solo a su visión personal sino también a la percepción que de estos promotores tienen los diferentes grupos de edad.En este sentido, la Universidad de Burgos a través del Programa Interuniversitario de la Experiencia y en el marco de la formación para personas mayores, pone en marcha acciones concretas para conocer las necesidades, experiencias y expectativas de los mayores universitarios en relación con el emprendimiento. Consideramos de gran importancia que la Universidad, como institución de larga trayectoria en el campo del saber, apoye los procesos de emprendimiento con todos los recursos a su alcance, entre ellos, el gran capital humano que no solo se encuentra entre su profesorado o personal, sino también en sus aulas, principalmente en las de las personas mayores.Mostramos en la presente investigación los resultados iniciales del estudio cualitativo implementado a través de un grupo de discusión en el que los mayores han dialogado sobre el concepto de emprendimiento, motivos, ayudas, formación y competencias. Los resultados nos servirán de base para futuras propuestas e intervenciones

SOX2(+) Cell Population from Normal Human Brain White Matter Is Able to Generate Mature Oligodendrocytes

Peer reviewe

Flipped classroom en el aprendizaje multidisciplinar colaborativo en diferentes Grados Universitarios

La implementación de nuevas metodologías que nos permita valorar si el estudiante ha alcanzado los conocimientos necesarios así como una serie de competencias y habilidades, es una de las prioridades docentes del proceso de convergencia en el espacio europeo de educación superior. El empleo de la clase inversa (flipped classroom) con el cambio en los roles aula/casa y profesor/estudiante consigue que el estudiante adquiera un papel protagonista en el proceso de la enseñanza, alcanzando destrezas en el aprendizaje autónomo, trabajo en equipo y empleo de las nuevas tecnologías. Al mismo tiempo, esta metodología hace posible la participación de estudiantes de distintos grados que trabajen en grupos temas relacionados con su titulación, así como la consecución de competencias básicas (que los estudiantes puedan transmitir información, ideas, problemas y soluciones a un público tanto especializado como no especializado), generales (capacidad para las relaciones interpersonales y el trabajo en equipo) y específicas. Esta experiencia piloto tiene como objetivo mejorar el proceso enseñanza-aprendizaje de los estudiantes del grado en farmacia, grado en ingeniería agroalimentaria y medio rural y grado en biotecnología, mediante la implementación de la metodología flipped classroom para potenciar el aprendizaje autónomo, desarrollo de competencias cognitivas y habilidades interpersonales de comunicación

Prevención, diagnóstico y tratamiento de la sepsis neonatal: Guía de práctica clínica basada en evidencias del Instituto Nacional Materno Perinatal del Perú

Introduction. Neonatal sepsis is a set of clinical signs and symptoms caused by a systemic infection, associated with maternal, neonatal or&nbsp;hospital risk factors. Objective. Provide informed recommendations for the best available evidence for the prevention, diagnosis and treatment&nbsp;of neonatal sepsis. Methods an Evidence-based Clinical Practice Guide (CPG) was developed through an adaptation process, in charge of&nbsp;a team of methodologists and neonatologists who are experts in the clinical management of neonatal sepsis. The search and pre-selection&nbsp;of CPGs that respond to the scope and objectives set were carried out, using the AGREE-II instrument, the methodological quality of the&nbsp;guides was evaluated and their adaptation decided. To identify the evidence that answers the questions in the guideline, a systematic&nbsp;search was carried out in multiple databases: Medline / PubMed, Embase / Ovid, Cochrane Library and LILACS. These were selected and&nbsp;critically analyzed by clinical and methodological peers, the recommendations were elaborated using the GRADE approach. Results. 16&nbsp;clinical questions and recommendations based on evidence were formulated, which were reached, through a deliberative dialogue of clinical&nbsp;experts from different reference hospitals for the management of neonatal sepsis in Peru. The recommendations address the identification&nbsp;of risk factors, the use of confirmatory methods and antibiotic treatment as prophylaxis and during disease management. Conclusions. The&nbsp;CPG allows standardizing the clinical management of neonatal sepsis, as well as the identification of research needs to be carried out in the&nbsp;Peruvian context.Introducción. La sepsis neonatal es un conjunto de signos y síntomas clínicos causados por una infección sistémica, asociada a&nbsp;factores de riesgo de tipo materno, neonatal u hospitalario. Objetivo. Brindar recomendaciones informadas por la mejor evidencia&nbsp;disponible para la prevención, diagnóstico y tratamiento de la sepsis neonatal. Métodos. Se desarrolló una guía de práctica clínica&nbsp;(GPC) basada en evidencias, mediante un proceso de adaptación, a cargo de un equipo de metodólogos y médicos neonatólogos&nbsp;expertos en el manejo clínico de la sepsis neonatal. Se realizó la búsqueda y preselección de GPC que respondan al alcance y&nbsp;objetivos planteados, utilizando el instrumento AGREE-II se evalúo la calidad metodológica de las guías para decidir su adaptación.&nbsp;Se realizó una búsqueda sistemática en múltiples bases de datos: Medline/PubMed, Embase/Ovid, Cochrane Library y LILACS,&nbsp;para identificar la evidencia que responda a las preguntas de la guía. Estas fueron seleccionadas y analizadas críticamente por&nbsp;pares clínicos y metodológicos, las recomendaciones fueron elaboradas usando el enfoque GRADE. Resultados. Se formularon 16&nbsp;preguntas clínicas y recomendaciones basadas en evidencia a las que se llegó, mediante un diálogo deliberativo de expertos clínicos&nbsp;de diferentes hospitales de referencia para el manejo de la sepsis neonatal en el Perú. Las recomendaciones abordan la identificación&nbsp;de factores de riesgo, el uso de métodos confirmatorios y el tratamiento antibiótico como profilaxis y durante manejo de la enfermedad.&nbsp;Conclusiones: La GPC permite estandarizar el manejo clínico de la sepsis neonatal, así como la identificación de necesidades de&nbsp;investigación a realizarse en el contexto peruano