Stratification of Colorectal Patients Based on Survival Analysis Shows the Value of Consensus Molecular Subtypes and Reveals the CBLL1 Gene as a Biomarker of CMS2 Tumours.

The consensus molecular subtypes (CMSs) classification of colorectal cancer (CRC) is a system for patient stratification that can be potentially applied to therapeutic decisions. Hakai (CBLL1) is an E3 ubiquitin-ligase that induces the ubiquitination and degradation of E-cadherin, inducing epithelial-to-mesenchymal transition (EMT), tumour progression and metastasis. Using bioinformatic methods, we have analysed CBLL1 expression on a large integrated cohort of primary tumour samples from CRC patients. The cohort included survival data and was divided into consensus molecular subtypes. Colon cancer tumourspheres were used to analyse the expression of stem cancer cells markers via RT-PCR and Western blotting. We show that CBLL1 gene expression is specifically associated with canonical subtype CMS2. WNT target genes LGR5 and c-MYC show a similar association with CMS2 as CBLL1. These mRNA levels are highly upregulated in cancer tumourspheres, while CBLL1 silencing shows a clear reduction in tumoursphere size and in stem cell biomarkers. Importantly, CMS2 patients with high CBLL1 expression displayed worse overall survival (OS), which is similar to that associated with CMS4 tumours. Our findings reveal CBLL1 as a specific biomarker for CMS2 and the potential of using CMS2 with high CBLL1 expression to stratify patients with poor OS.

Role of the Abcg2 Transporter in Secretion into Milk of the Anthelmintic Clorsulon: Interaction with Ivermectin.

Clorsulon is a benzenesulfonamide drug that is effective in treating helminthic zoonoses such as fascioliasis. When used in combination with the macrocyclic lactone ivermectin, it provides high broad-spectrum antiparasitic efficacy. The safety and efficacy of clorsulon should be studied by considering several factors such as drug-drug interactions mediated by ATP-binding cassette (ABC) transporters due to their potential effects on the pharmacokinetics and drug secretion into milk. The aim of this work was to determine the role of ABC transporter G2 (ABCG2) in clorsulon secretion into milk and the effect of ivermectin, a known ABCG2 inhibitor, on this process. Using in vitro transepithelial assays with cells transduced with murine Abcg2 and human ABCG2, we report that clorsulon was transported in vitro by both transporter variants and that ivermectin inhibited its transport mediated by murine Abcg2 and human ABCG2. Wild-type and Abcg2-/- lactating female mice were used to carry out in vivo assays. The milk concentration and the milk-to-plasma ratio were higher in wild-type mice than in Abcg2-/- mice after clorsulon administration, showing that clorsulon is actively secreted into milk by Abcg2. The interaction of ivermectin in this process was shown after the coadministration of clorsulon and ivermectin to wild-type and Abcg2-/- lactating female mice. Treatment with ivermectin had no effect on the plasma concentrations of clorsulon, but the milk concentrations and milk-to-plasma ratios of clorsulon decreased in comparison to those with treatment without ivermectin, only in wild-type animals. Consequently, the coadministration of clorsulon and ivermectin reduces clorsulon secretion into milk due to drug-drug interactions mediated by ABCG2.

The ethics of nursing care for transgender people / A ética do cuidado de enfermagem às pessoas transgênero / La ética de la atención de enfermería a las personas transgénero

ABSTRACT Objectives: to discuss ethical aspects in nursing care for transgender people. Methods: reflective study based on the dilemmas that emerges in nursing care for transgender people. The report was structured around the four bioethical principles. Results: health care for trans people is complex, transversal to many devices and specialties and longitudinal in time, that is why it requires coordinated action. There is an ethical framework in which the nursing care must be observed in the care of this group. Final Considerations: the nurse as a health worker can assume several general lines in the care of transgender patients. So, complementary training should be provided not only to professionals, but also to students of nursing and other health sciences.

RESUMO Objetivos: discutir aspectos éticos na assistência de enfermagem às pessoas transgênero. Métodos: estudo reflexivo a partir dos dilemas que surgem no cuidado de enfermagem às pessoas transgênero. O relato foi estruturado em torno dos quatro princípios bioéticos. Resultados: a atenção à saúde de pessoas trans é complexa, transversal a muitos dispositivos e especialidades e longitudinal no tempo, por isso requer ação coordenada. Existe um referencial ético no qual se enquadram os cuidados de enfermagem que devem ser observados no atendimento a esse grupo. Considerações Finais: o enfermeiro como agente de saúde pode assumir diversas linhas gerais no atendimento a pacientes transgênero. Para tal, deve ser proporcionada formação complementar não só aos profissionais, mas também aos estudantes de enfermagem e outras ciências da saúde.

RESUMEN Objetivos: debatir sobre aspectos éticos en la atención de enfermería a personas transgénero. Métodos: estudio reflexivo fundamentado sobre los dilemas que se plantean en los cuidados de enfermería a personas transgénero. El relato se ha estructurado en torno a los cuatro principios bioéticos. Resultados: la atención sanitaria a las personas trans es compleja, transversal a muchos dispositivos y especialidades y longitudinal en el tiempo por lo que precisa de la actuación coordinada. Existe un marco ético en el que se encuadran los cuidados de enfermería que se precisan en la atención a este colectivo. Consideraciones Finales: la enfermera como agente de salud puede asumir diversas líneas generales en la atención a pacientes transgénero. Para ello, se debe brindar formación adicional no solo a los profesionales, también a los estudiantes de enfermería y de las demás ciencias de la salud.

Role of the E3 ubiquitin-ligase Hakai in intestinal inflammation and cancer bowel disease.

The E3 ubiquitin-ligases are important for cellular protein homeostasis and their deregulation is implicated in cancer. The E3 ubiquitin-ligase Hakai is involved in tumour progression and metastasis, through the regulation of the tumour suppressor E-cadherin. Hakai is overexpressed in colon cancer, however, the implication in colitis-associated cancer is unknown. Here, we investigated the potential role of Hakai in intestinal inflammation and cancer bowel disease. Several mouse models of colitis and associated cancer were used to analyse Hakai expression by immunohistochemistry. We also analysed Hakai expression in patients with inflamed colon biopsies from ulcerative colitis and Crohn's disease. By Hakai interactome analysis, it was identified Fatty Acid Synthase (FASN) as a novel Hakai-interacting protein. Moreover, we show that Hakai induces FASN ubiquitination and degradation via lysosome, thus regulating FASN-mediated lipid accumulation. An inverse expression of FASN and Hakai was detected in inflammatory AOM/DSS mouse model. In conclusion, Hakai regulates FASN ubiquitination and degradation, resulting in the regulation of FASN-mediated lipid accumulation, which is associated to the development of inflammatory bowel disease. The interaction between Hakai and FASN may be an important mechanism for the homeostasis of intestinal barrier function and in the pathogenesis of this disease.

Protein Degradation by E3 Ubiquitin Ligases in Cancer Stem Cells.

Cancer stem cells are a small subpopulation within the tumor with high capacity for self-renewal, differentiation and reconstitution of tumor heterogeneity. Cancer stem cells are major contributors of tumor initiation, metastasis and therapy resistance in cancer. Emerging evidence indicates that ubiquitination-mediated post-translational modification plays a fundamental role in the maintenance of cancer stem cell characteristics. In this review, we will discuss how protein degradation controlled by the E3 ubiquitin ligases plays a fundamental role in the self-renewal, maintenance and differentiation of cancer stem cells, highlighting the possibility to develop novel therapeutic strategies against E3 ubiquitin ligases targeting CSCs to fight cancer.

Regulation of Epithelial-Mesenchymal Plasticity by the E3 Ubiquitin-Ligases in Cancer.

The epithelial-mesenchymal plasticity (EMP) is a process by which epithelial cells acquire the ability to dynamically switch between epithelial and mesenchymal phenotypic cellular states. Epithelial cell plasticity in the context of an epithelial-to-mesenchymal transition (EMT) confers increased cell motility, invasiveness and the ability to disseminate to distant sites and form metastasis. The modulation of molecularly defined targets involved in this process has become an attractive therapeutic strategy against cancer. Protein degradation carried out by ubiquitination has gained attention as it can selectively degrade proteins of interest. In the ubiquitination reaction, the E3 ubiquitin-ligases are responsible for the specific binding of ubiquitin to a small subset of target proteins, and are considered promising anticancer drug targets. In this review, we summarize the role of the E3 ubiquitin-ligases that control targeted protein degradation in cancer-EMT, and we highlight the potential use of the E3 ubiquitin-ligases as drug targets for the development of small-molecule drugs against cancer.

Características clínicas, complicaciones secundarias y apoyos en personas con lesión medular traumática en Asturias / Traumatic spinal cord injury in Asturias: clinical features, complications and patient support

INTRODUCCIÓN: La lesión medular traumática es un acontecimiento sobrevenido y frecuentemente devastador debido a la pérdida funcional, a las complicaciones secundarias y a la inexistencia de tratamiento curativo. Se plantea como un reto personal, sanitario y social. El objetivo del estudio es describir las características epidemiológicas, clínicas y los apoyos utilizados de las personas con lesión medular traumática del Principado de Asturias. MATERIALES Y MÉTODO: Estudio observacional, descriptivo y transversal. La población estuvo conformada por personas con lesión medular traumática ingresadas por cualquier causa en el Hospital Universitario Central de Asturias del 1 de enero de 2005 al 31 de enero de 2015. RESULTADOS: El número de casos fue 92. Un 76,9% eran hombres. La edad media fue 48,5 años y la edad media cuando se produjo la lesión 40,2 años. Las causas más frecuentes fueron los accidentes: de tráfico, laborales y fortuitos. El tipo de lesión más frecuente: según afectación de miembros, la paraplejia con un 38,5%; según la extensión, la lesión incompleta con un 52,6%; según el nivel neurológico, la lesión dorsal con un 45,4% y según la escala de clasificación de la American Spinal Injury Association (ASIA), la lesión ASIA A con un 50,7%. Como complicaciones secundarias más frecuentes: el 68,7% presenta vejiga neurógena, el 60,2% intestino neurógeno, el 46,5 úlceras por presión, 46,4% espasticidad y el 30,1% dolor neuropático. CONCLUSIONES: Existe una alta prevalencia de complicaciones secundarias en la lesión medular, siendo necesario aunar esfuerzos en la prevención y tratamiento de las mismas

BACKGROUND AND OBJECTIVE: Traumatic spinal cord injury is a supervening and often devastating event due to functional loss, secondary complications and lack of curative treatment. It is posed as a personal, health and social challenge. The objective of the study is to describe the epidemiological, clinical and support characteristics of people with traumatic spinal cord injury in the Principality of Asturias. MATERIALS AND METHOD: Observational, descriptive and cross-sectional study. The population comprised people with traumatic spinal cord injury admitted for any reason at the Central University Hospital of Asturias from January 1, 2005 to January 31, 2015. RESULTS: The number of cases was 92. 76.9% were men. The average age was 48.5 years old and the average age when the injury occurred was 40.2 years old. The most frequent causes were accidents: traffic, labor and fortuitous. The most frequent type of injury: according to limb involvement, paraplegia with 38.5%; according to the extension, the incomplete lesion with 52.6%; according to the neurological level, the dorsal lesion with 45.4% and according to the classification scale of the American Spinal Injury Association (ASIA), the ASIA A lesion with 50.7%. As most frequent secondary complications: 68.7% have neurogenic bladder, 60.2% neurogenic bowel, 46.5% pressure ulcers, 46.4% spasticity and 30.1% neuropathic pain. CONCLUSIONS: There is a high prevalence of secondary complications in spinal cord injury, being necessary to join efforts in the prevention and treatment of them

La formación especializada en enfermería familiar y comunitaria: oscuro objeto de deseo / Specialised training in the field of community and family nursing: dark object of desire

La formación especializada en Enfermería Familiar y Comunitaria viene desarrollándose desde que en 2010 se publicó su Programa Oficial. Se ha integrado en las Unidades Docentes Multiprofesionales de Atención Familiar y Comunitaria, lo cual ha supuesto ciertas ventajas pero también inconvenientes. La especialidad tiene unas amplias competencias que abarcan integralmente a las personas, las familias y las comunidades en el entorno en el que desarrollan su vida. Algunas competencias vienen a cubrir áreas actualmente no atendidas por el sistema sanitario e implican una cierta complejidad para su adquisición. La oferta formativa se ve incrementada paulatinamente desde los inicios de la especialidad. Está pendiente de que se dé el paso para que las especialistas formadas desarrollen sus competencias en el sistema sanitario; las Comunidades Autónomas avanzan en ese sentido

Specialised training in the field of community and family nursing has been developed since 2010, when its Official Programme was published. It has been integrated in the Multiprofessional Training Units of Family and Community Care, which implies certain advantages, but also some drawbacks. This specialised training covers a wide range of competences that involve people, family and communities in their living environment. Some of these competences cover areas that are currently not taken into account by the medical system and they imply certain complexity in their acquisition. The training programme has been gradually increased since the beginning of this specialised training. The acquisitions of these competences by the professionals working in this field are still pending and the regions of Spain are making progress in this direction

Estudio de la satisfacción laboral en los equipos de atención primaria en un área sanitaria de Asturias / Study of job satisfaction in primary healthcare in an area of Asturias

Objetivo: valorar nivel de satisfacción laboral de los profesionales que trabajan en Atención Primaria en un Área de Asturias y los factores asociados. Metodología: estudio descriptivo transversal. Población de estudio: profesionales de cualquier categoría que trabajen en Centros de Salud del Área V (Asturias). Muestra: toda la población. Utilizamos el cuestionario validado Font-Roja AP y recogemos variables sociodemográficas y laborales. Las variables cuantitativas se describen con media y desviación estándar, las cualitativas con distribución porcentual de frecuencias. Se buscan posibles relaciones entre satisfacción laboral y resto de variables usando Chi-Cuadrado, t-Student y ANOVA. Resultados: tasa de respuesta: 57.22% (329 de 575). 72.3% mujeres. Edad media: 50,8 años (DE: 10.09). El 83.9% se autodeclaran como satisfechos (IC95%:83.5-91.2). Sólo el 62.6% (IC 95%: 57.4-68.2) están satisfechos calculando la Satisfacción Media Global (SMG) derivada de Font-Roja. Dimensiones del Font-Roja con mayor satisfacción "relación con los compañeros" y "competencia profesional". Menor satisfacción: "promoción profesional" y "tensión relacionada con trabajo". Todas las categorías otorgan baja puntuación al sueldo, siendo las peores administrativos y celadores (p< 0,001). En el análisis bivariante entre SMG y variables sociodemográficas, hay asociación estadísticamente significativa con la docencia, 68.8% satisfechos en centros docentes (p 0,039) y con categoría profesional, siendo los más satisfechos los MIR/EIR 88,9% y los menos los médicos 46,1% (p: 0.009). Conclusiones: la mayoría de los profesionales se encuentran satisfechos laboralmente. Presentan una mayor satisfacción autodeclarada que la que se deduce de la medición SMG en Font-Roja. Áreas de mejora: sueldo, promoción profesional y tensión en el trabajo

Objective: evaluate the level of job satisfaction of professionals working in Primary healthcare in Asturias and associated factors. Methodology: cross-sectional descriptive study.Study Population: professionals of any category working at Health Centers in the province of V (Asturias). Sample: Whole population. We used the validated Red Font AP "Roja Font" questionnaire and gathered it up with variables socio-demographic and work variables. The quantitative variables are described with average and standard deviation, the qualitative with frequency distribution percentage. Possible relationships are sought between job satisfaction and the remaining variables using chi-square, t-Student and ANOVA. Results: response rate: 57.22% (329 out of 575). 72.3% women. Average age: 50.8 years (From: 10.09). 83.9% self-reported as satisfied (95% CI: 83.5-91.2). Only 62.6% (95% CI: 57.4-68.2) were satisfied by calculating the Global Average Satisfaction (GAS) derived from "Font-Roja". Dimensions of the "Font-Roja" with greater satisfaction: "relationship with coworkers" and "professional competence". Lower satisfaction: "professional promotion" and "work-related tension". All the categories gave low score to the salary, being the worse administrative and hospital attendant (p <0,001). In the bivariate analysis between GAS and socio-demographic variables, there was a statistically significant association with teaching, 68.8% satisfied in the educational centers (p .039) and with professional category, remaining the most satisfied being MIR / EIR 88.9% and the least were doctors with 46.1% (w: 0.009). Conclusions: the majority of professionals are satisfied occupationally. They present a higher self-reported satisfaction than that derived from the GAS measurement in Font-Roja.Areas of improvement: wages, professional promotion and development and tension at work