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.

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.

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.

Estudio de caso de narrativas infantiles en videollamadas: Aportes al análisis de interacciones mediadas por tecnología / Case study of children's narratives in videochats: contributions to the analysis of technology-mediated interactions

Resumen El aislamiento social preventivo y obligatorio por la pandemia del SARS-CoV-2 condujo a las familias a buscar alternativas para mantener el vínculo con sus parientes no convivientes. Una de ellas fue la videollamada, cuyo carácter audiovisual habilita nuevas maneras de comunicación (Ames et al., 2010; Ballagas et al., 2009; McClure y Barr, 2017) que podrían modificar las interacciones en las que adultos/as y niños/as participan y colaboran en la construcción de distintos tipos de discursos. La narración constituye una de las primeras y más relevantes formas de discurso en la infancia que permite reconstruir y comunicar la propia experiencia. En este trabajo se realizó un análisis de caso de 31 narrativas que tuvieron lugar en cinco videollamadas en las que participaban una misma niña residente de la Ciudad de Buenos Aires y sus familiares, pertenecientes al corpus "Contextos naturales de interacción en los hogares en los que los/as niños/as usan tempranamente tecnología"[1], a fin de caracterizar las interacciones que contribuyen a la configuración de las narrativas infantiles en contextos mediados por tecnología. Los resultados mostraron una mayor presencia de narrativas personales y de futuro, frente a pocas de ficción; mientras que estas últimas fueron en su totalidad autorreguladas, la cantidad de narrativas hetero y autorreguladas fue similar para los otros dos tipos de narrativas. Se identificaron distintas estrategias a las que, en el marco de videollamadas, la niña recurrió para participar en la construcción de narrativas.

Abstract The preventive and compulsory social isolation established in Argentina due to the SARS-CoV-2 pandemic led families to look for alternatives to maintain the bond and communicate with their non-cohabitant relatives. One of these alternatives was the use of videochat. Videochat enables new ways of audiovisual communication (Ames et al., 2010; Ballagas et al., 2009; McClure & Barr, 2017) that could affect the interactions in which adults and children collaborate in the construction of different types of discourses. Narratives are one of the first and most relevant forms of discourse, it allows for the reconstruction and communication of one's experience and is one of the ways in which thought is configured. In this work, a case study was conducted of the narratives produced during videochat conversations of a four-year-old girl with non-cohabiting relatives. The aim was to characterize the interactions that help in the configuration of children's narratives during technology-mediated situations. The research question were: (a) how do technology-mediated interactions allow the child to narrate about past and future events and to create fictional narratives?; (b) how does the child participate in the construction of those narrative in the context of these technology-mediated situations? Five videos of videochat interaction belonging to a single four year old girl were selected from the corpus "Contextos naturales de interacción en los hogares en los que los/as niños/as usan tempranamente tecnología". This corpus gathers different technology-mediated interactions collected during daily activities in the home of children aged 0 to 6 years. First, 31 narratives in which the girl participated were identified. Subsequently, used the constant comparative method was used (Strauss & Corbin, 1998) as well as analysis tools developed within the framework of interactive sociolinguistics (Gumperz, 1982, 1984); also, concepts developed in previous research (Arrúe et al., 2014; Labov, 1972; Rosemberg et al., 2010; Stein et al., 2020) were heuristically recovered to answer the research questions. Of the 31 narratives produced in the interactions, 14 were related to personal experience, 13 were of future events, and 4 were fiction narratives. Regarding the posed questions, results showed that children do in fact create personal, future and fictional narratives in technology-mediated interactions with adults. Technology also enables children to decide how much they want to participate in interactions: they can lead the narrative, or they can back off to a yes-or-no answer kind of participation. The child relies on the possibility to share visual information, beyond audio, to provide both events and context information. This interactive and multimodal aspect of videochats was also found to enable the girl to turn to present adults both to scaffold her narrative production and to resolve doubts about unknown words. Even though there are methodological limitations to this study, this first approach to narratives in technology-mediated interactions shows the richness that this type of interaction can have for the development of children's language.