Gallblader carcinomas from risk factors to targeted therapy

To revise the epidemiology, pathogenesis, diagnosis, treatment and prognosis in gallbladder carcinomas. To revise the role of molecular pathology in this entity and its importance in therapeutic perspectives. Methods: A revision of all the articles published between 2006-2016 and indexed in PubMed containing the keywords “gallbladder”, “cancer”, “carcinoma”, “diagnosis”, “treatment”, “perspectives” and/or “targeted therapy ” was carried out. Results: The incidence of gallbladder carcinoma varies greatly depending on the geographical area [considered]. Its natural history is related to chronic inflammation and cholelithiasis is its main risk factor. The diagnosis is usually made at a late stage and, despite the treatment, it shows/has a poor prognosis. Changes in p53 and K-Ras are common. Modulation of inflammation is postulated as a therapeutic alternative. Conclusions: Gallbladder carcinoma is a neoplasm with an aggressive course. The improvement in its prognosis needs of the control of risk factors and early diagnosis supported by imaging tests. New surgical techniques and the description of new therapeutic targets also offer promising prospects

Lights and shadows of the scientific innovation and technology policies during the Kirchner administration (2003-2015)

El objetivo de este artículo de investigación es analizar las capacidades de gestión y producción de Ciencia y Tecnología creadas y puesta en marcha durante la gestión kirchnerista(2003-2015). El trabajo se inicia con una revisión de la literatura académica sobre la definición y operacionalización del concepto de capacidades en esta área de la política pública; para luego identificar, a través de un mapeo del desarrollo histórico, cuáles son las líneas de continuidad y ruptura de las distintas gestiones hasta los años 2016. Este trabajo se realiza a través de la evidencia recogida de entrevistas a protagonistas tanto del ámbito público, como universitario y empresarial. La idea que se desprende del análisis de campoes que se trató de una gestión que marcó una continuidad con la gestiones anteriores, en lo que hace a la idea y concepción de un sistema basado en tres vectores fundamentales; pero al mismo tiempo, marcó una ruptura, que no sólo se manifiesta en el aumento de presupuesto y construcción de un ministerio, sinoprincipalmente en una práctica creciente de articulación y programación estratégica, que avanzó en la definición de líneas al interior de muchos ministerios; pero no pudo trascender el tiempo ni el espacio.The aim of this paper is to analyze management and production capacities of Science and Technology created and implemented during Kirchner`s government (2003-2015). First, the work begins with an academic literature revision about the definition and operationalization of the capabilities concept in this area of public policy. After that, we identify, through a mapping of historical development, which are the lines of continuity and rupture of the different administration until 2016. This work was done on the evidence collected from interviews with protagonists from public, university and business area. The idea that emerges was that the administration in the period of time analyzed marked a continuity with previous administrations, in terms of the idea and conception of a system based on three essential vectors; but at the same time, it marked a rupture, which is not only manifested in the budget increasing and ministry construction, but mainly in a rising practice of articulation and strategic programming, which advanced on the definition of lines within many ministries; but it could not go beyond time or space.Fil: Botto, Mercedes Isabel. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Quilmes; ArgentinaFil: Betancor, Leticia V.. Facultad Latinoamericana de Ciencias Sociales; Argentin

Classical and atypical scrapie in sheep and goats: Review on the etiology, genetic factors, pathogenesis, diagnosis, and control measures of both diseases

Prion diseases, such as scrapie, are neurodegenerative diseases with a fatal outcome, caused by a conformational change of the cellular prion protein (PrPC), originating with the pathogenic form (PrPSc). Classical scrapie in small ruminants is the paradigm of prion diseases, as it was the first transmissible spongiform encephalopathy (TSE) described and is the most studied. It is necessary to understand the etiological properties, the relevance of the transmission pathways, the infectivity of the tissues, and how we can improve the detection of the prion protein to encourage detection of the disease. The aim of this review is to perform an overview of classical and atypical scrapie disease in sheep and goats, detailing those special issues of the disease, such as genetic fac-tors, diagnostic procedures, and surveillance approaches carried out in the European Union with the objective of controlling the dissemination of scrapie disease

ARID2 deficiency promotes tumor progression and is associated with higher sensitivity to chemotherapy in lung cancer

The survival rate in lung cancer remains stubbornly low and there is an urgent need for the identification of new therapeutic targets. In the last decade, several members of the SWI/SNF chromatin remodeling complexes have been described altered in different tumor types. Nevertheless, the precise mechanisms of their impact on cancer progression, as well as the application of this knowledge to cancer patient management are largely unknown. In this study, we performed targeted sequencing of a cohort of lung cancer patients on genes involved in chromatin structure. In addition, we studied at the protein level the expression of these genes in cancer samples and performed functional experiments to identify the molecular mechanisms linking alterations of chromatin remodeling genes and tumor development. Remarkably, we found that 20% of lung cancer patients show ARID2 protein loss, partially explained by the presence of ARID2 mutations. In addition, we showed that ARID2 deficiency provokes profound chromatin structural changes altering cell transcriptional programs, which bolsters the proliferative and metastatic potential of the cells both in vitro and in vivo. Moreover, we demonstrated that ARID2 deficiency impairs DNA repair, enhancing the sensitivity of the cells to DNA-damaging agents. Our findings support that ARID2 is a bona fide tumor suppressor gene in lung cancer that may be exploited therapeutically.Financial Support: I. V. is supported by SAF2012-31627 and SAF2016-76758-R grants from the Spanish Ministerio de Economía y Competitividad (MINECO), by a Fundación Ramón Areces grant and by ERC2014-StG637904 grant from the European Research Council. I. V has been awardee of the Programa Ramón y Cajal (MINECO, Spain). T. M has been awardee of the Ayudas para la contratación de investigadores predoctorales (MINECO, Spain). B. M is awardee of the Ayudas para la formación de profesorado universitario (FPU, Ministerio de Educación y Formación Profesional, Spain). PC laboratory is supported by grant SAF-2015-63638R (MINECO/FEDER, UE); by Centro de Investigación Biomédica en Red de Cáncer (CIBERONC) and by Asociación Española Contra el Cáncer (AECC), grant GCB141423113. BC has been supported by a Retos Jóvenes Investigadores grant SAF2015-73364-JIN (AEI/FEDER, UE) and a grant from Fundación Francisco Cobos. P. S. is supported by the Francis Crick Institute, which receives its core funding from Cancer Research UK (FC001152), the UK Medical Research Council (FC001152). HUCA/IUOPA which is jointly financed by Servicio de Salud del Principado de Asturias, Instituto de Salud Carlos III and Fundación Bancaria Cajastur. This research was funded in part by the Wellcome Trust [FC001152]

Peripheral T-cell lymphoma: Molecular profiling recognizes subclasses and identifies prognostic markers

Peripheral T-cell lymphoma (PTCL) is a clinically aggressive disease, with a poor response to therapy and a low overall survival rate of approximately 30% after 5 years. We have analyzed a series of 105 cases with a diagnosis of PTCL using a customized NanoString platform (NanoString Technologies, Seattle, WA) that includes 208 genes associated with T-cell differentiation, oncogenes and tumor suppressor genes, deregulated pathways, and stromal cell subpopulations. A comparative analysis of the various histological types of PTCL (angioimmunoblastic T-cell lymphoma [AITL]; PTCL with T follicular helper [TFH] phenotype; PTCL not otherwise specified [NOS]) showed that specific sets of genes were associated with each of the diagnoses. These included TFH markers, cytotoxic markers, and genes whose expression was a surrogate for specific cellular subpopulations, including follicular dendritic cells, mast cells, and genes belonging to precise survival (NF-κB) and other pathways. Furthermore, the mutational profile was analyzed using a custom panel that targeted 62 genes in 76 cases distributed in AITL, PTCL-TFH, and PTCL-NOS. The main differences among the 3 nodal PTCL classes involved the RHOAG17V mutations (P < .0001), which were approximately twice as frequent in AITL (34.09%) as in PTCL-TFH (16.66%) cases but were not detected in PTCL-NOS. A multivariate analysis identified gene sets that allowed the series of cases to be stratified into different risk groups. This study supports and validates the current division of PTCL into these 3 categories, identifies sets of markers that can be used for a more precise diagnosis, and recognizes the expression of B-cell genes as an IPI-independent prognostic factor for AITL

CRISPR/Cas9-mediated glycolate oxidase disruption is an efficacious and safe treatment for primary hyperoxaluria type I

CRISPR/Cas9 technology offers novel approaches for the development of new therapies for many unmet clinical needs, including a significant number of inherited monogenic diseases. However, in vivo correction of disease-causing genes is still inefficient, especially for those diseases without selective advantage for corrected cells. We reasoned that substrate reduction therapies (SRT) targeting non-essential enzymes could provide an attractive alternative. Here we evaluate the therapeutic efficacy of an in vivo CRISPR/Cas9-mediated SRT to treat primary hyperoxaluria type I (PH1), a rare inborn dysfunction in glyoxylate metabolism that results in excessive hepatic oxalate production causing end-stage renal disease. A single systemic administration of an AAV8-CRISPR/Cas9 vector targeting glycolate oxidase, prevents oxalate overproduction and kidney damage, with no signs of toxicity in Agxt1(-/-) mice. Our results reveal that CRISPR/Cas9-mediated SRT represents a promising therapeutic option for PH1 that can be potentially applied to other metabolic diseases caused by the accumulation of toxic metabolites

BRCAness and breast cancer: BRCAness y cáncer de mama

Breast cancer constitutes the neoplasm of highest incidence, prevalence and mortality among women in western countries. Around 25-30% of these tumors are estrogen receptor (ER), progesterone receptor (PR) and HER2 negative. These tumors are called triple negative breast cancer (TNBC). TNBCs frequently appear in young patients. Familial aggregation is common. They show a high histological grade and larger lymph node loco-regional affectation when diagnosed. In addition, they recur and progress prematurely after the standard combined treatment. A part of these TNBCs -up to 50% according to some authors- show specific phenotypical and molecular features that allow them to be considered BRCAness positive. BRCAness encompasses a combination of changes, of varied nature. These changes point towards a deficit in homology-directed repair (HDR). These TNBC types are generated and ensure their survival through the accumulation of unrepaired damage that increases genome instability. Recently it has been demonstrated that these tumors could be susceptible to specific treatments (alkylating agents, PARP inhibitors) with better response and survival rates. This leads to a greater accumulation of unrepaired damage that directs tumor cells towards apoptosis. Several techniques have been proposed to study BRCAness. Among them: conventional immunohistochemistry techniques with specific markers; pyrosequencing to determine the methylation degree of the BRCA1 promoter; multiplex ligationdependant probe amplification (MLPA), comparative genome hybridization, quantitative real-time PCR and, more recently, miRNAs and tumor circulating DNA study through digital droplet PCR (ddPCR)

A predictive model of academic performance based on High School grade point average and University Access Test results

Numerosas investigaciones educativas muestran que el rendimiento académico en el primer año de universidad incide en el éxito con el que se cursan los años subsiguientes, lo que justifica el interés de analizar el rendimiento, durante el primer curso, del alumnado de nuevo ingreso e identificar los factores que influyen en él. En el presente trabajo se ha definido un nuevo indicador de este rendimiento y se han determinado, para cada uno de los grados en Ciencias de la ULL, aquellos indicadores de rendimiento previo con los que se encuentra más correlacionado el indicador introducido. Se han obtenido así sendos modelos de regresión lineal multivariante que permiten predecir el rendimiento de un estudiante de nuevo ingreso en el primer cuatrimestre del primer curso de cada grado en función de su rendimiento en Bachillerato y PAU. En todos los grados de Ciencias, la variable predictora dominante ha resultado ser la nota media de Bachillerato. La bondad de ajuste de los modelos que utilizan el nuevo indicador supera ampliamente la de otros modelos preexistentes en la literatura. El método es extensible a cualquier grado y universidad. Su aplicación sistemática permitiría definir y detectar perfiles de riesgo académico con el propósito de contribuir, por una parte, a que cada estudiante adopte una actitud proactiva hacia la subsanación de sus posibles deficiencias formativas y, por otra, a que el gestor universitario optimice los recursos humanos y materiales necesarios para mejorar el aprovechamiento académico de los estudiantes en situación de riesgo.Several educational investigations have shown that the academic performance in the first year of university affects the success in subsequent years, which justifies the interest of analyzing the performance, during the first year, of new students in order to identify the factors that influence it. In the present work, a new indicator of this performance has been defined and those indicators of previous performance which are best correlated with the indicator introduced have been determined for each one of the degrees in Science of the ULL. We have thus obtained multivariate linear regression models that allow us to predict the performance of new students in the first semester of the first year of each degree, based on their performance in High School and the University Access Test. In all of Science degrees, the dominant predictor variable has turned out to be the High School grade point average. The goodness of fit of the models that use the new indicator far exceeds that of other pre-existing models in the literature. Our method is extensible to any degree and university. Its systematic application would allow defining and detecting academic risk profiles so that, on the one hand, affected students may be encouraged to adopt a proactive attitude towards the correction of their training deficiencies and, on the other hand, university managers can optimize the human and material resources necessary to improve the academic performance of those students at risk