Aurora Kinase A expression is associated with lung cancer histological-subtypes and with tumor de-differentiation

<p>Abstract</p> <p>Background</p> <p>Aurora kinase A (<it>AURKA</it>) is a member of serine/threonine kinase family. Several kinases belonging to this family are activated in the G2/M phase of the cell cycle being involved in mitotic chromosomal segregation. <it>AURKA </it>overexpression is significantly associated with neoplastic transformation in several tumors and deregulated <it>Aurora Kinases </it>expression leads to chromosome instability, thus contributing to cancer progression. The purpose of the present study was to investigate the expression of <it>AURKA </it>in non small cell lung cancer (NSCLC) specimens and to correlate its mRNA or protein expression with patients' clinico-pathological features.</p> <p>Materials and methods</p> <p>Quantitative real-time PCR and immunohistochemistry analysis on matched cancer and corresponding normal tissues from surgically resected non-small cell lung cancers (NSCLC) have been performed aiming to explore the expression levels of <it>AURKA </it>gene.</p> <p>Results</p> <p><it>AURKA </it>expression was significantly up-modulated in tumor samples compared to matched lung tissue (p < 0.01, mean log2(FC) = 1.5). Moreover, <it>AURKA </it>was principally up-modulated in moderately and poorly differentiated lung cancers (p < 0.01), as well as in squamous and adenocarcinomas compared to the non-invasive bronchioloalveolar histotype (p = 0.029). No correlation with survival was observed.</p> <p>Conclusion</p> <p>These results indicate that in NSCLC <it>AURKA </it>over-expression is restricted to specific subtypes and poorly differentiated tumors.</p

Targeting epigenetic alterations in cancer stem cells

Oncogenes or tumor suppressor genes are rarely mutated in several pediatric tumors and some early stage adult cancers. This suggests that an aberrant epigenetic reprogramming may crucially affect the tumorigenesis of these tumors. Compelling evidence support the hypothesis that cancer stem cells (CSCs), a cell subpopulation within the tumor bulk characterized by selfrenewal capacity, metastatic potential and chemo-resistance, may derive from normal stem cells (NSCs) upon an epigenetic deregulation. Thus, a better understanding of the specific epigenetic alterations driving the transformation from NSCs into CSCs may help to identify efficacious treatments to target this aggressive subpopulation. Moreover, deepening the knowledge about these alterations may represent the framework to design novel therapeutic approaches also in the field of regenerative medicine in which bioengineering of NSCs has been evaluated. Here, we provide a broad overview about: 1) the role of aberrant epigenetic modifications contributing to CSC initiation, formation and maintenance, 2) the epigenetic inhibitors in clinical trial able to specifically target the CSC subpopulation, and 3) epigenetic drugs and stem cells used in regenerative medicine for cancer and diseases

Homeobox gene Dlx3 is regulated by p63 during ectoderm development : relevance in the pathogenesis of ectodermal dysplasias

Ectodermal dysplasias (EDs) are a group of human pathological conditions characterized by anomalies in organs derived from epithelial-mesenchymal interactions during development. Dlx3 and p63 act as part of the transcriptional regulatory pathways relevant in ectoderm derivatives, and autosomal mutations in either of these genes are associated with human EDs. However, the functional relationship between both proteins is unknown. Here, we demonstrate that Dlx3 is a downstream target of p63. Moreover, we show that transcription of Dlx3 is abrogated by mutations in the sterile alpha-motif (SAM) domain of p63 that are associated with ankyloblepharon-ectodermal dysplasia-clefting (AEC) dysplasias, but not by mutations found in ectrodactylyectodermal dysplasia-cleft lip/palate (EEC), Limb-mammary syndrome (LMS) and split hand-foot malformation (SHFM) dysplasias. Our results unravel aspects of the transcriptional cascade of events that contribute to ectoderm development and pathogenesis associated with p63 mutations

Impaired autophagic flux is associated with increased endoplasmic reticulum stress during the development of NAFLD

This work is licensed under a Creative Commons Attribution-NonCommercialNoDerivs 3.0 Unported License.-- et al.The pathogenic mechanisms underlying the progression of non-alcoholic fatty liver disease (NAFLD) are not fully understood. In this study, we aimed to assess the relationship between endoplasmic reticulum (ER) stress and autophagy in human and mouse hepatocytes during NAFLD. ER stress and autophagy markers were analyzed in livers from patients with biopsy-proven non-alcoholic steatosis (NAS) or non-alcoholic steatohepatitis (NASH) compared with livers from subjects with histologically normal liver, in livers from mice fed with chow diet (CHD) compared with mice fed with high fat diet (HFD) or methionine-choline-deficient (MCD) diet and in primary and Huh7 human hepatocytes loaded with palmitic acid (PA). In NASH patients, significant increases in hepatic messenger RNA levels of markers of ER stress (activating transcription factor 4 (ATF4), glucose-regulated protein 78 (GRP78) and C/EBP homologous protein (CHOP)) and autophagy (BCN1) were found compared with NAS patients. Likewise, protein levels of GRP78, CHOP and p62/SQSTM1 (p62) autophagic substrate were significantly elevated in NASH compared with NAS patients. In livers from mice fed with HFD or MCD, ER stress-mediated signaling was parallel to the blockade of the autophagic flux assessed by increases in p62, microtubule-associated protein 2 light chain 3 (LC3-II)/LC3-I ratio and accumulation of autophagosomes compared with CHD fed mice. In Huh7 hepatic cells, treatment with PA for 8 h triggered activation of both unfolding protein response and the autophagic flux. Conversely, prolonged treatment with PA (24 h) induced ER stress and cell death together with a blockade of the autophagic flux. Under these conditions, cotreatment with rapamycin or CHOP silencing ameliorated these effects and decreased apoptosis. Our results demonstrated that the autophagic flux is impaired in the liver from both NAFLD patients and murine models of NAFLD, as well as in lipid-overloaded human hepatocytes, and it could be due to elevated ER stress leading to apoptosis. Consequently, therapies aimed to restore the autophagic flux might attenuate or prevent the progression of NAFLD.We acknowledge the following grant support: SAF2012-33283 (MINECO, Spain), Comunidad de Madrid S2010/BMD-2423, EFSD and Amylin Paul Langerhans Grant and Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM, ISCIII, Barcelona, Spain) to AMV.; SAF2010-16037, SAF2013-43713-R (MINECO) and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD, ISCIII) to PMS. RD12/0042/0019 (ISCIII) and S2010/BMD-2478 (Comunidad de Madrid) to LB, PI 13/01299 and Fundación Mutua Madrileña 2012 to C G-M and AIRC IG-2012 to GMF.Peer Reviewe

Evaluación del grado de conocimiento interdisciplinar y del grado de interés en participar en grupos multidisciplinares de los estudiantes de Proyectos del Grado de Ingeniería Industrial e Ingeniería Química y los estudiantes de SIG avanzado del Grado en Ingeniería Geomática y Topografía

[ES] El actual contexto socio económico y laboral plantea el reto de formar a los estudiantes en competencias que les ayuden en un futuro a trabajar cooperativamente en equipos multidisciplinares. Las posibilidades de encontrar soluciones a problemas se incrementan cuando los miembros del equipo conocen el potencial que puede aportar cada uno de ellos. En este trabajo se ha evaluado la percepción del estudiantado respecto a la interdisciplinariedad y su grado de interés, con el objetivo de conocer la base sobre la cual poder aplicar innovaciones docentes que mejoren esta percepción entre los grados de Ingeniería Industrial e Ingeniería Química y el grado en Ingeniería Geomática y Topografía de la UPV. Tras diseñar y realizar una encuesta a los estudiantes, se concluye que existe una falta de conocimiento sobre las posibilidades y potencialidades de la colaboración interdisciplinar, aunque los estudiantes sí están interesados en trabajar en equipos multidisciplinares, por lo que se debería tratar de incorporar esta multidisciplinariedad en la docencia para el beneficio de los futuros egresados.[EN] The current socio-economic and labor context poses the challenge of training students in competencies that will help them in the future to work cooperatively in multidisciplinary teams. The possibilities of finding solutions to problems increase when the members of the team know the potential that each of them can contribute. In this work we have evaluated the students' perception of interdisciplinarity and their degree of interest, with the aim of knowing the basis on which to apply teaching innovations to improve this perception between the degrees of Industrial Engineering and Chemical Engineering and the degree in Geomatics Engineering and Surveying of the UPV. After designing and conducting a survey to students, it is concluded that there is a lack of knowledge about the possibilities and potential of interdisciplinary collaboration, although students are interested in working in multidisciplinary teams, so we should try to incorporate this multidisciplinarity in teaching for the benefit of future graduates.Esta innovación se ha realizado gracias a los proyectos de innovación docente PIME/22-23/354 y al PIME/21-22/268.Lerma-Arce, V.; Coll Aliaga, E.; Pastor-Ferrando, JP.; Fuentes-Bargues, JL.; Lo-Iacono Ferreira, VG.; Lorenzo-Sáez, E. (2023). Evaluación del grado de conocimiento interdisciplinar y del grado de interés en participar en grupos multidisciplinares de los estudiantes de Proyectos del Grado de Ingeniería Industrial e Ingeniería Química y los estudiantes de SIG avanzado del Grado en Ingeniería Geomática y Topografía. Editorial Universitat Politècnica de València. 978-990. https://doi.org/10.4995/INRED2023.2023.1664197899

Claudin-1 Is a p63 Target Gene with a Crucial Role in Epithelial Development

The epidermis of the skin is a self-renewing, stratified epithelium that functions as the interface between the human body and the outer environment, and acts as a barrier to water loss. Components of intercellular junctions, such as Claudins, are critical to maintain tissue integrity and water retention. p63 is a transcription factor essential for proliferation of stem cells and for stratification in epithelia, mutated in human hereditary syndromes characterized by ectodermal dysplasia. Both p63 and Claudin-1 null mice die within few hours from birth due to dehydration from severe skin abnormalities. These observations suggested the possibility that these two genes might be linked in one regulatory pathway with p63 possibly regulating Claudin-1 expression. Here we show that silencing of ΔNp63 in primary mouse keratinocytes results in a marked down-regulation of Claudin-1 expression (−80%). ΔNp63α binds in vivo to the Claudin-1 promoter and activates both the endogenous Claudin-1 gene and a reporter vector containing a –1.4 Kb promoter fragment of the Claudin-1 gene. Accordingly, Claudin-1 expression was absent in the skin of E15.5 p63 null mice and natural p63 mutant proteins, specifically those found in Ankyloblepharon–Ectodermal dysplasia–Clefting (AEC) patients, were indeed altered in their capacity to regulate Claudin-1 transcription. This correlates with deficient Claudin-1 expression in the epidermis of an AEC patient carrying the I537T p63 mutation. Notably, AEC patients display skin fragility similar to what observed in the epidermis of Claudin-1 and p63 null mice. These findings reinforce the hypothesis that these two genes might be linked in a common regulatory pathway and that Claudin-1 may is an important p63 target gene involved in the pathogenesis of ectodermal dysplasias

Challenges in developing methods for quantifying the effects of weather and climate on water-associated diseases: A systematic review

Infectious diseases attributable to unsafe water supply, sanitation and hygiene (e.g. Cholera, Leptospirosis, Giardiasis) remain an important cause of morbidity and mortality, especially in low-income countries. Climate and weather factors are known to affect the transmission and distribution of infectious diseases and statistical and mathematical modelling are continuously developing to investigate the impact of weather and climate on water-associated diseases. There have been little critical analyses of the methodological approaches. Our objective is to review and summarize statistical and modelling methods used to investigate the effects of weather and climate on infectious diseases associated with water, in order to identify limitations and knowledge gaps in developing of new methods. We conducted a systematic review of English-language papers published from 2000 to 2015. Search terms included concepts related to water-associated diseases, weather and climate, statistical, epidemiological and modelling methods. We found 102 full text papers that met our criteria and were included in the analysis. The most commonly used methods were grouped in two clusters: process-based models (PBM) and time series and spatial epidemiology (TS-SE). In general, PBM methods were employed when the bio-physical mechanism of the pathogen under study was relatively well known (e.g. Vibrio cholerae); TS-SE tended to be used when the specific environmental mechanisms were unclear (e.g. Campylobacter). Important data and methodological challenges emerged, with implications for surveillance and control of water-associated infections. The most common limitations comprised: non-inclusion of key factors (e.g. biological mechanism, demographic heterogeneity, human behavior), reporting bias, poor data quality, and collinearity in exposures. Furthermore, the methods often did not distinguish among the multiple sources of time-lags (e.g. patient physiology, reporting bias, healthcare access) between environmental drivers/exposures and disease detection. Key areas of future research include: disentangling the complex effects of weather/climate on each exposure-health outcome pathway (e.g. person-to-person vs environment-to-person), and linking weather data to individual cases longitudinally

Isotope correlations as a probe for freeze-out characterization: central 124Sn+64Ni, 112Sn+58Ni collisions

124Sn+64Ni and 112Sn+58Ni reactions at 35 AMeV incident energy were studied with the forward part of CHIMERA multi-detector. The most central collisions were selected by means of a multidimensional analysis. The characteristics of the source formed in the central collisions, as size, temperature and volume, were inspected. The measured isotopes of light fragments (3 <= Z <=8) were used to examine isotope yield ratios that provide information on the free neutron to proton densities.Comment: 4 pages, Contribution to 8th International Conference on Nucleus-Nucleus Collisions, Moscow 200

Mass and charge identification of fragments detected with the Chimera Silicon-CsI(Tl) telescopes

Mass and charge identification of charged products detected with Silicon-CsI(Tl) telescopes of the Chimera apparatus is presented. An identification function, based on the Bethe-Bloch formula, is used to fit empirical correlation between Delta E and E ADC readings, in order to determine, event by event, the atomic and mass numbers of the detected charged reaction products prior to energy calibration.Comment: 24 pages, 7 .jpg figures, submitted to Nucl.Instr.