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.