Fibroblasts activation and abnormal extracellular matrix remodelling as common hallmarks in three cancer-prone genodermatoses

Background. Recessive dystrophic epidermolysis bullosa (RDEB), Kindler syndrome (KS) and xeroderma pigmentosum complementation group C (XPC) are three cancer-prone genodermatoses whose causal genetic mutations cannot fully explain, on their own, the array of associated phenotypic manifestations. Recent evidence highlights the role of the stromal microenvironment in the pathology of these disorders. Objectives. To investigate, by means of comparative gene expression analysis, the role played by dermal fibroblasts in the pathogenesis of RDEB, KS and XPC. Methods. We conducted RNA-Seq analysis, which included a thorough examination of the differentially expressed genes, a functional enrichment analysis and a description of affected signalling circuits. Transcriptomic data were validated at the protein level in cell cultures, serum samples and skin biopsies. Results. Interdisease comparisons against control fibroblasts revealed a unifying signature of 186 differentially expressed genes and four signalling pathways in the three genodermatoses. Remarkably, some of the uncovered expression changes suggest a synthetic fibroblast phenotype characterized by the aberrant expression of extracellular matrix (ECM) proteins. Western blot and immunofluorescence in situ analyses validated the RNA-Seq data. In addition, enzyme-linked immunosorbent assay revealed increased circulating levels of periostin in patients with RDEB. Conclusions. Our results suggest that the different causal genetic defects converge into common changes in gene expression, possibly due to injury-sensitive events. These, in turn, trigger a cascade of reactions involving abnormal ECM deposition and underexpression of antioxidant enzymes. The elucidated expression signature provides new potential biomarkers and common therapeutic targets in RDEB, XPC and KS.This study was supported by grants from the Spanish Ministry of Economy and Competitiveness (SAF2013-43475R, SAF2017-88908-R and SAF2017-86810-R); from Instituto de Salud Carlos III and CIBERER, cofunded with European Regional Development Funds (ERDF) (PT13/0001/0007, PI14/00931, PI15/00716, PI15/00956, PT17/0009/0006 and PI17/01747); and from the European Union (HEALTH-F2-2011-261392 and H2020-INFRADEV-1-2015-1/ELIXIR-EXCELERATEref. 676559). Additional funding from Comunidad de Madrid (AvanCell-CM S2017/BMD-3692); Catalan Government (AGAUR 2014_SGR_603); ‘Fundacio' La Marató de TV3, 01331-30’; CERCA Programme/Generalitat de Catalunya; and ‘Fundación Científica de la Asociación Española Contra el Cáncer’, Spain

Fostering Professional Ethical Competence During Teacher Training Practice

Professionals who have undergone their training at university should possess not only the knowledge-base necessary to practice in their chosen profession, but also the ethical principles that ensure responsible professional practice and the corresponding benefits for society. The research project addressed in the present article aimed to contribute to fostering ethical competence and commitment amongst future teachers. During the experience the participants had the opportunity to design tasks that stimulated reflection, critique and ethical awareness.Specialistai, įgiję universitetinį išsilavinimą, turi būti sukaupę ne tik žinių, kurios būtinos profesinėje veikloje, bet ir gebėti vadovautis etikos principais, kurie užtikrintų atsakingą ir visuomenės gerovei reikalingą profesinę veiklą. Tyrime, pristatomame šiame straipsnyje, analizuojamos būsimųjų mokytojų etinės kompetencijos plėtros ir atsidavimo darbui problemos. Tyrimo dalyviai turėjo galimybę kurti užduotis, kurios skatino refleksiją, kritiką ir etinį sąmoningumą.Les professionnels ayant reçu leur formation auprès des Universités disposeront, non seulement des connaissances de base nécessaires à l'exercice de leur métier, mais aussi les principes éthiques garantissant un exercice professionnel responsable portant bénéfice sur la société. Le projet de recherche présenté sous ce titre a comme objectif la contribution à la favorisation de la compétence éthique et de l'engagement parmi les futurs enseignants. Lors de cette expérience, les participants ont eu l'occasion d'élaborer des tâches favorisant la réflexion, la critique et la pensée critique.Профессионалы, получившие университетское образование, не только получают основные знания для работы по своей профессии, но и моральные принципы, которые обеспечивают ответственную профессиональную работу и соответствующую выгоду для общества. Целью исследовательского проекта,представленного под этим именем, является участие в стимуляции профессиональной этики и компромисса среди будущих преподавателей. Во время проведения эксперимента, участники получили возможность разработать задания, стимулирующие размышление, критику и критичиское сознание.Los profesionales que han recibido su formación en la Universidad, poseerán no solo el conocimiento base necesario para la práctica en su profesión, sino también los principios éticos que aseguran la práctica profesional responsable y el correspondiente beneficio para la sociedad. El proyecto de investigación presentado con este título tiene como objetivo contribuir a estimular la competencia ética y el compromiso entre los futuros docentes. Durante la experiencia, los participantes tuvieron la oportunidad de diseñar tareas que estimularan la reflexión, la crítica y la conciencia crítica

The regenerative potential of fibroblasts in a new diabetes-induced delayed humanised wound healing model

Cutaneous diabetic wounds greatly affect the quality of life of patients, causing a substantial economic impact on the healthcare system. The limited clinical success of conventional treatments is mainly attributed to the lack of knowledge of the pathogenic mechanisms related to chronic ulceration. Therefore, management of diabetic ulcers remains a challenging clinical issue. Within this context, reliable animal models that recapitulate situations of impaired wound healing have become essential. In this study, we established a new in vivo humanised model of delayed wound healing in a diabetic context that reproduces the main features of the human disease. Diabetes was induced by multiple low doses of streptozotocin in bioengineered human-skin-engrafted immunodeficient mice. The significant delay in wound closure exhibited in diabetic wounds was mainly attributed to alterations in the granulation tissue formation and resolution, involving defects in wound bed maturation, vascularisation, inflammatory response and collagen deposition. In the new model, a cell-based wound therapy consisting of the application of plasma-derived fibrin dermal scaffolds containing fibroblasts consistently improved the healing response by triggering granulation tissue maturation and further providing a suitable matrix for migrating keratinocytes during wound re-epithelialisation. The present preclinical wound healing model was able to shed light on the biological processes responsible for the improvement achieved, and these findings can be extended for designing new therapeutic approaches with clinical relevance.This work was supported by grants from the Science and Innovation Ministry of Spain (SAF2010-16976), from the European VI Framework Programme (LSHB-CT-512102), from Comunidad de Madrid (S2010/BMD-2420; CELLCAM) and from Fundacion Ramon Areces (CIVP16A1864)

A crowdsourcing database for the copy-number variation of the spanish population

Background: Despite being a very common type of genetic variation, the distribution of copy-number variations (CNVs) in the population is still poorly understood. The knowledge of the genetic variability, especially at the level of the local population, is a critical factor for distinguishing pathogenic from non-pathogenic variation in the discovery of new disease variants. Results: Here, we present the SPAnish Copy Number Alterations Collaborative Server (SPACNACS), which currently contains copy number variation profiles obtained from more than 400 genomes and exomes of unrelated Spanish individuals. By means of a collaborative crowdsourcing effort whole genome and whole exome sequencing data, produced by local genomic projects and for other purposes, is continuously collected. Once checked both, the Spanish ancestry and the lack of kinship with other individuals in the SPACNACS, the CNVs are inferred for these sequences and they are used to populate the database. A web interface allows querying the database with different filters that include ICD10 upper categories. This allows discarding samples from the disease under study and obtaining pseudo-control CNV profiles from the local population. We also show here additional studies on the local impact of CNVs in some phenotypes and on pharmacogenomic variants. SPACNACS can be accessed at: http://csvs.clinbioinfosspa.es/spacnacs/. Conclusion: SPACNACS facilitates disease gene discovery by providing detailed information of the local variability of the population and exemplifies how to reuse genomic data produced for other purposes to build a local reference database.This work is supported by Grants PID2020-117979RB-I00 from the Spanish Ministry of Science and Innovation; by the Institute of Health Carlos III (project IMPaCT-Data, exp. IMP/00019, IMP/00009 and PI20/01305), co-funded by the European Union, European Regional Development Fund (ERDF, “A way to make Europe”)

Physical Fitness Enhancement Through Education, EDUFIT Study: Background, Design, Methodology and Dropout Analysis

El nivel de forma física es un potente indicador del estado de salud cardiovascular ya desde edades tempranas. Mejorar el nivel de condición física es una necesidad educativa ya que contribuye a aumentar la salud pública y el bienestar presente y futuro. El objeto del presente artículo es describir la metodología y diseño de un pro­ yecto educativo diseñado con esta finalidad, denominado EDUFIT (EDUcación para el FITness). EDUFIT se llevó a cabo en 2007 y participaron 67 escolares de 13±1 años, pertenecientes a tres clases de Enseñanza Secundaria. Las clases fueron aleatoriamente asigna­ das a grupo control (GC), grupo experimental 1 (GE1) o grupo expe­ rimental 2 (GE2). El GC recibió 2 sesiones de educación física por semana, el GE1 recibió 4 sesiones (incremento del volumen) y el GE2 recibió 4 sesiones de alta intensidad (incremento del volu­ men+intensidad). Al inicio y tras 16 semanas de intervención se valoró: condición física, composición corporal, perfil lipídico­ metabólico, parámetros ventilatorios, tensión arterial, y rendimiento cognitivo y escolar. La intervención fue viable y tuvo buena acepta­ ción entre el alumnado, padres y centro educativo. Se observaron altas tasas de participación (96%, n=67) y de adhesión al programa (84%, n=56). El análisis de adhesión/abandono mostró que, aunque no llega a ser una diferencia significativa (0,1>P>0,05), los adoles­ centes que completaron el programa mostraron mejores valores en capacidad cognitiva y rendimiento académico, y peores en adiposi­ dad, tensión diastólica, fuerza de prensión manual y presión espira­ toria máxima. La hipótesis del estudio EDUFIT es que duplicar el número de clases de educación física por semana mejorará la condi­ ción física de los adolescentes. Si dicha hipótesis se constata, las implicaciones desde el punto de vista de salud pública podrían ser importantes.Physical fitness is a powerful marker of cardiovascular health already at early stages in life. To promote physical fitness enhancement from the school is therefore needed. The present study describes a school intervention program specifically designed for these purposes, called EDUFIT (EDUcation for FITness). The study was carried out in 2007 and comprised 67 adolescents aged 13+/-1 years from a secondary school who belonged to three different classes. The classes were randomly allocated to control group (CG), experimental group 1 (EG1) and experimental group 2 (EG2). The CG was involved in 2 physical education sessions/week, the EG1 was involved in 4 physical education sessions/week (volume increased) and the EG2 was involved in 4 physical education sessions/week of high intensity (volume+intensity increased). Several health parameters were assessed before and after a 16-weeks intervention: physical fitness, body composition, lipid-metabolic profile, ventilatory parameters, blood pressure, and cognitive and academic performance. The intervention was feasible and well-tolerated. There were high participation and adherence rates, i.e. 96% (n=67) and 84% (n=56) respectively. Yet not always significant (0,1>P>0,05), we observed that the adolescents who satisfactory complete the program showed better cognitive and academic performance, and worse levels of adiposity, diastolic tension, handgrip strength and maximal expiratory pressure. The hypothesis of the EDUFIT study is that to double the number of physical education classes will improve physical fitness in adolescents. The confirmation of the hypothesis could have important public health implications.El presente estudio tiene lugar gracias a recursos materiales y humanos procedentes de dos proyectos europeos financiados por la Comisión Europea: el estudio HELENA (Contract FOOD-CT-2005-007034) y el estudio ALPHA (Ref: 2006120). También gracias a fondos FEDER del Ministerio de Educación y Ciencia (Acciones Complementarias DEP2007-29933-E) y del Grupo de Trabajo 0123/07 del Centro de Profesores y Recursos Murcia II de la Consejería de Educación, Formación y Empleo de la Región de Murcia. Algunos de los investigadores involucrados en este estudio están financiados por becas pre-doctorales y post-doctorales del Ministerio de Educación y Ciencia (AP-2005-3827, AP2005-4358, EX-2007-1124, EX-2008-0641)

Keratinocyte Growth Factor Induces Gene Expression Signature Associated with Suppression of Malignant Phenotype of Cutaneous Squamous Carcinoma Cells

Keratinocyte growth factor (KGF, fibroblast growth factor-7) is a fibroblast-derived mitogen, which stimulates proliferation of epithelial cells. The expression of KGF by dermal fibroblasts is induced following injury and it promotes wound repair. However, the role of KGF in cutaneous carcinogenesis and cancer progression is not known. We have examined the role of KGF in progression of squamous cell carcinoma (SCC) of the skin. The expression of KGF receptor (KGFR) mRNA was lower in cutaneous SCCs (n = 6) than in normal skin samples (n = 6). Expression of KGFR mRNA was detected in 6 out of 8 cutaneous SCC cell lines and the levels were downregulated by 24-h treatment with KGF. KGF did not stimulate SCC cell proliferation, but it reduced invasion of SCC cells through collagen. Gene expression profiling of three cutaneous SCC cell lines treated with KGF for 24 h revealed a specific gene expression signature characterized by upregulation of a set of genes specifically downregulated in SCC cells compared to normal epidermal keratinocytes, including genes with tumor suppressing properties (SPRY4, DUSP4, DUSP6, LRIG1, PHLDA1). KGF also induced downregulation of a set of genes specifically upregulated in SCC cells compared to normal keratinocytes, including genes associated with tumor progression (MMP13, MATN2, CXCL10, and IGFBP3). Downregulation of MMP-13 and KGFR expression in SCC cells and HaCaT cells was mediated via ERK1/2. Activation of ERK1/2 in HaCaT cells and tumorigenic Ha-ras-transformed HaCaT cells resulted in downregulation of MMP-13 and KGFR expression. These results provide evidence, that KGF does not promote progression of cutaneous SCC, but rather suppresses the malignant phenotype of cutaneous SCC cells by regulating the expression of several genes differentially expressed in SCC cells, as compared to normal keratinocytes

CIBERER : Spanish national network for research on rare diseases: A highly productive collaborative initiative

Altres ajuts: Instituto de Salud Carlos III (ISCIII); Ministerio de Ciencia e Innovación.CIBER (Center for Biomedical Network Research; Centro de Investigación Biomédica En Red) is a public national consortium created in 2006 under the umbrella of the Spanish National Institute of Health Carlos III (ISCIII). This innovative research structure comprises 11 different specific areas dedicated to the main public health priorities in the National Health System. CIBERER, the thematic area of CIBER focused on rare diseases (RDs) currently consists of 75 research groups belonging to universities, research centers, and hospitals of the entire country. CIBERER's mission is to be a center prioritizing and favoring collaboration and cooperation between biomedical and clinical research groups, with special emphasis on the aspects of genetic, molecular, biochemical, and cellular research of RDs. This research is the basis for providing new tools for the diagnosis and therapy of low-prevalence diseases, in line with the International Rare Diseases Research Consortium (IRDiRC) objectives, thus favoring translational research between the scientific environment of the laboratory and the clinical setting of health centers. In this article, we intend to review CIBERER's 15-year journey and summarize the main results obtained in terms of internationalization, scientific production, contributions toward the discovery of new therapies and novel genes associated to diseases, cooperation with patients' associations and many other topics related to RD research