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Dermatologic adverse events (DAEs) are associated with a better outcome in patients with hepatocellular carcinoma (HCC) irrespective of the therapeutic agent received. The exact mechanisms associated with the development of DAEs are unknown although several studies point to direct toxicity of tyrosine kinase inhibitors (TKIs) to the skin or an immune-mediated reaction triggered by the oncologic treatment. As is the case in other conditions, individual genetic variants may partially explain a higher risk of DAEs.To evaluate the contribution of several gene variants to the risk of developing DAEs in HCC patients treated with TKIs.We first analyzed 27 single-nucleotide polymorphisms (SNPs) from 12 genes selected as potential predictors of adverse event (AE) development in HCC patients treated with sorafenib [Barcelona Clinic Liver Cancer 1 (BCLC1) cohort]. Three additional cohorts were analyzed forThe BCLC1 cohort showed that patients with arterial hypertension (AHT) (HR = 1.61;DAE development in HCC patients receiving TKIs could be explained by the

Zeb1 hemizygosity doesn't prevent long term development of PDAC in 30-weeks old KPC;Z+/

Antibodies used for immunohistochemistry and immunofluorescence (Table 1), and for western blot (Table 2)

The transcription factor Zeb1 has been identified as a crucial player in Kras-dependent oncogenesis. In pancreatic ductal adenocarcinoma (PDAC), Zeb1 is highly expressed in myofibroblasts and correlates with poor prognosis. As Kras mutations are key drivers in PDAC, we aimed here to assess the necessity of Zeb1 for Kras-driven PDAC and to define the role of Zeb1-expressing myofibroblasts in PDAC development. Genetically engineered mice with conditional pancreatic KrasG12D and Trp53 mutations (KPC) were crossed with Zeb1 haploinsufficient mice (Z+/−). Extensive PDAC was prominent in all 20-week-old KPC;Z+/+ mice, whereas only low-grade precursor lesions were detected in age-matched KPC;Z+/− littermates, with PDAC developing eventually in KPC;Z+/− aged animals. Zeb1 expression in myofibroblasts occurred early in tumorigenesis and Zeb1 haploinsufficiency retarded native expansion of stromal myofibroblasts during precursor-to-cancer progression. Zeb1 downregulation in mPSC repressed their activated gene profile, impaired their migratory and proliferative activity, and attenuated their tumor-supporting features. Conditioned media from Z+/+ mouse-activated (myofibroblast-like) pancreatic stellate cells (mPSC) boosted Ras activity in pancreatic cancer cells carrying mutant Kras; this effect was not observed when using conditioned media from Z+/− mPSC, revealing a paracrinal cooperative axis between Zeb1-expressing PSC and oncogenic Kras-bearing tumor cells. We conclude that Zeb1-expressing stromal myofibroblasts enable a heterotypic collaboration with the Kras-fated epithelial compartment, thus supporting pancreatic malignancy.Significance: Zeb1 expression in stromal myofibroblasts supports PDAC development via collaboration with the epithelial compartment bearing oncogenic Kras mutations. Cancer Res; 78(10); 2624–37. ©2018 AACR.

El presente ensayo es producto de una revisión documental que tuvo por analizar los derechos humanos de la comunidad wayuu desde la perspectiva de la educación superior. El trabajo tiene una naturaleza descriptiva y pretende impulsar más investigaciones sobre el tema. Se encuentra que la comunidad wayuu vive en extrema pobreza y la población infantil padece de desnutrición. Se concluye que es urgente la intervención de organismos internacionales que restauren las garantías de los derechos humanos de la comunidad wayuu.

Background & aims Sorafenib and lenvatinib are the first-line treatments approved in hepatocellular carcinoma (HCC), but information is lacking about the relationships between their pharmacokinetics, patients pharmacogenetic profiles, adverse events (AE) and overall survival. We aimed to elucidate these relationships of tyrosine Kinase Inhibitors, such as sorafenib, in order to improve the design of trials testing it in combination with checkpoint inhibitors. Methods We assessed the pharmacokinetics of sorafenib and its N-oxide metabolite at day-0, day-7, day-30, day-60, day-90, day-120, day-150 and day-180 and nine single-nucleotide polymorphisms (SNP) in five genes related to sorafenib metabolism/transport to identify the best point for starting the combination between tyrosine kinases and checkpoint inhibitors. Results We prospectively included 49 patients (96% cirrhotic, 37% hepatitis-C, 82% Child-Pugh-A and 59% BCLC-C). Pharmacokinetic values peaked at day-7 and progressively declined until day-60. In the 16 patients without further dose modifications after day-60, pharmacokinetic values remained stable through day-180 (sorafenib P = .90; N-oxide P = .93). Pharmacokinetic values were higher in patients with early dermatological adverse events and lower in patients with early diarrhoea. Sorafenib and N-oxide pharmacokinetic values varied linearly with different alleles of MRP2*3972. Conclusions Sorafenib's pharmacokinetics is heterogeneous across HCC patients. This heterogeneity affects adverse events development and must be taken into account in setting the dose and timing of its combination with checkpoint inhibitors.

This article is the product of the advance of the doctoral thesis on human rights subject and the insertion of immigrants in Colombia affected by the political crisis in their country. Hence, the need arises for a social reflection that is carried out in a documentary or empirical way, the documentary is carried out with the bibliographic inquiry, magazine, documentaries. Empirical research is carried out through direct or indirect observation; as well as the application of surveys to experts, the universe of this research are migrants. The population was represented by 200 Venezuelan. The sample is 136 Venezuelans. The population's own parameters are Venezuelan migrants who do not have a foreign certificate, permanence visa, or entry and permanence permit (PIP) or a special permanence permit (PEP). The method applied for this research is the qualitative one from which a delimited and concrete study problem arises, interpretative practice predominates that makes the world visible and transforms it into representations of reality, as well as practical methods by Emilio Durkheim, French sociologist (1864-1917), who uses the comparative historical method. Key words: Colombia, Human rights, Migration, Venezuela. How to reference this article: Samper Ibanez, J., E. (2019). Los derechos humanos en el siglo xxi una verdadera realidad de colombia. Revista Ciencia Juridica y Politica, 71-81. Recuperado de: https://portalderevistas.upoli.edu.ni/index.php/5-revciencasjuridicasypoliticas/article/view/377

Este artículo es producto de varias investigaciones en materia de competencias ciudadanas y resolución de postconflicto y la necesidad de una comunicación asertiva en torno al proceso de Reconciliación frente a los nuevos retos que se esbozan, ya que se están cambiando las perspectivas hacia una cultura de paz, fundamentales dentro de los métodos de la comunicación asertiva desde la educación. La calidad y alcance de analizar la comunicación asertiva, dentro sus características y de formación. Cuál es el rol del docente en la educación Universitaria inherente después de muchos años de conflictos. También pone de relieve el papel que han desempeñado el gobierno Nacional no sólo en la propagación de cultura de paz del ciudadano, sino también un nuevo modelo de comunicación asertivo en la construcción del ciudadano

Objetivo: Analizar las redes sociales como modelo estratégico en la competencia comunicativa de la lengua inglesa. Metodología: El diseño metodológico se enmarcó en una investigación sistemática, empírica y cualitativa. Se tomó como muestra a los estudiantes de la asignatura de lengua inglesa. Para lo cual se identifican las dificultades que se presenta con esta asignatura en los estudiantes que muestran dificultad en el manejo de la producción oral y escrita de la lengua inglés, por lo que se hace necesario diseñar estrategias llamativas e innovadoras y que sean de su agrado. Resultados: Se pretende que en el aprendizaje de la lengua francesa haya mayor fluidez en la producción oral y escrita, en los dicentes de dicha institución. Para esta investigación se hace necesaria la revisión analítica de las diferentes estrategias de redes sociales que se hayan implementado en diferentes universidades nacionales e internacionales, para así intervenir en los estudiantes de la educación superior. Conclusiones: Los hallazgos encontrados a través Pruebas y entrevistas, evidenciaron las falencias existentes en la producción oral y escrita de la lengua debido al empleo de estrategias tradicionales. Esta investigación se espera que sea pertinente y que arroje buenos resultados, porque se tiene la oportunidad de aplicar las TIC`s y las redes sociales que ya están inmersas en la sociedad (especialmente en los jóvenes), oportunidad que no se puede desaprovechar para ponerla a jugar a favor del mejoramiento del desarrollo de las competencias lectoras y escritoras.

Background/aim Dermatological adverse events (DAE) in hepatocellular carcinoma (HCC) patients treated with sorafenib predicts better outcome. Some turn into skin lesions (SL) requiring pathology examination. We describe incidence, characteristics and molecular profile of SL in HCC patients treated with sorafenib. Materials and methods SL were prospectively collected in 311 HCC patients who started sorafenib. SL from sorafenib cohort were compared to those from a control patient group selected to match SL type and demographics. HRAS, KRAS and BRAF mutations were analyzed by CAST-PCR, mutated p53 and MAPK pathway activation by immunohistochemistry and immune infiltration by hematoxylin-eosin staining. Results Eighty-eight out of 311 patients developed DAE and 7.4% SL required histological assessment. Most frequent lesions were keratoacanthomas (n = 4), squamous-cell carcinomas (SCC)(n = 5), basal-cell carcinomas (BCC)(n = 3) and seborrheic keratosis (n = 5). HRAS and KRAS mutations were detected in 4 SL, while no mutations showed in control SL. Nuclear pERK immunostaining was identified in 33.3% of cases versus 5.3% of controls. Most SL (90%) from patients with DAE were proliferative with intense immune infiltration (73%). Conclusions The onset of SL and their molecular profile did not impact negatively on patient's prognosis, but intense proliferation of SL may reflect compensatory activation of MAPK pathway and warrants their close monitoring.

Altres ajuts: Asociación Española Contra el Cáncer PI044031 Hepatocellular carcinoma is the second cause of cancer-related death worldwide. Of those advanced-stage patients who are treated with sorafenib, those who develop early dermatologic adverse events have a better prognosis. These events are possibly immune-related. Therefore, we analyzed the phenotype of 52 sorafenib-treated patients' circulating lymphocytes throughout treatment. We found that different co-stimulatory and immune exhaustion markers, such as Programmed cell death protein 1 (PD-1) and DNAX accessory molecule 1 (DNAM-1) amongst others, correlate with the probability of developing these adverse events, both before and during the treatment. We also compared the phenotype of those lymphocytes expressing DNAM-1 with those that do not, and while NK DNAM-1-expressing cells have a co-stimulatory phenotype, T DNAM-1-expressing cells are immune-suppressors. Overall, we set a rationale for the combination of sorafenib and immune-targeted therapies; and for the use of immune markers (such as DNAM-1) for patients' prognosis evaluation. Advanced hepatocellular carcinoma patients treated with sorafenib who develop early dermatologic adverse events (eDAEs) have a better prognosis. This may be linked to immune mechanisms, and thus, it is relevant to assess the association between peripheral immunity and the probability of developing eDAEs. Peripheral blood mononuclear cells of 52 HCC patients treated with sorafenib were analyzed at baseline and throughout the first eight weeks of therapy. T, B, Natural Killer cells, and their immune checkpoints expression data were characterized by flow cytometry. Cytokine release and immune-suppression assays were carried out ex vivo. Cox baseline and time-dependent regression models were applied to evaluate the probability of increased risk of eDAEs. DNAM-1, PD-1, CD69, and LAG-3 in T cells, plus CD16 and LAG-3 in NK cells, are significantly associated with the probability of developing eDAEs. While NK DNAM-1 + cells express activation markers, T DNAM-1 + cells induce immune suppression and show immune exhaustion. This is the first study to report an association between immune checkpoints expression in circulating immune cells and the increased incidence of eDAEs. Our results support the hypothesis for an off-target role of sorafenib in immune modulation. We also describe a novel association between DNAM-1 and immune exhaustion in T cells.

Tissue engineering utilizes an interdisciplinary approach to generate constructs for the treatment and repair of diseased organs. Generation of small vessels as vascular grafts or as envisioned central vessel for vascularized constructs is still a challenge. Here, the decellularization of porcine vessels by a non-detergent based protocol was developed and investigated. Perfusion-decellularization with sodium hydroxide solution resulted in removal of cellular material throughout the whole length of the vessel while preserving structural and mechanical integrity. A re-endothelialization of the retrieved matrix with human umbilical vein endothelial cells and cardiac endothelial cells was achieved through rotation-based seeding employing a custom-made bioreactor. A confluent monolayer was detected on the entire luminal surface. Thus, a non-detergent-based decellularization method allowing the re-endothelialization of the luminal surface was developed in this study, thereby paving the way for future implementation of the resulting construct as vascular graft or as central vessel for tissue engineered constructs in need of a perfusion system with readily available anastomosis sites.

In natural tissues, the nutrition of cells and removal of waste products is facilitated by a dense capillary network which is generated during development. This perfusion system is also indispensable for tissue formation in vitro. Nutrition depending solely on diffusion is not sufficient to generate tissues of clinically relevant dimensions, which is a core aim in tissue engineering research. In this study, the establishment of a vascular network was investigated in a self-assembling approach employing endothelial and mural cells. The process of vascularization was analyzed in constructs based on a carrier matrix of decellularized porcine small intestinal submucosa (SIS). A three-dimensional hydrogel containing Matrigel™, collagen, and respective cells was casted on top of the SIS. Various types of human endothelial cells (hECs), e.g. HUVECs, cardiac tissue ECs (hCECs), pulmonary artery ECs (hPAECs), and iPSC-derived ECs, were co-cultured with human adipose tissue-derived stromal cells (hASCs) within the hydrogel. Analyzed hECs were able to self-assemble and form three-dimensional networks harboring small caliber lumens within the hydrogel constructs in the presence of hASCs as supporting cells. Additionally, microvessel assembling required exogenous growth factor supplementation. This study demonstrates the development of stable vascularized hydrogels applying hASCs as mural cells in combination with various types of hECs, paving the way for the generation of clinically applicable tissue engineered constructs.

The transcription factor Zeb1 has been identified as a crucial player in Kras-dependent oncogenesis. In pancreatic ductal adenocarcinoma (PDAC), Zeb1 is highly expressed in myofibroblasts and correlates with poor prognosis. As Kras mutations are key drivers in PDAC, we aimed here to assess the necessity of Zeb1 for Kras-driven PDAC and to define the role of Zeb1-expressing myofibroblasts in PDAC development. Genetically engineered mice with conditional pancreatic KrasG12D and Trp53 mutations (KPC) were crossed with Zeb1 haploinsufficient mice (Z+/−). Extensive PDAC was prominent in all 20-week-old KPC;Z+/+ mice, whereas only low-grade precursor lesions were detected in age-matched KPC;Z+/− littermates, with PDAC developing eventually in KPC;Z+/− aged animals. Zeb1 expression in myofibroblasts occurred early in tumorigenesis and Zeb1 haploinsufficiency retarded native expansion of stromal myofibroblasts during precursor-to-cancer progression. Zeb1 downregulation in mPSC repressed their activated gene profile, impaired their migratory and proliferative activity, and attenuated their tumor-supporting features. Conditioned media from Z+/+ mouse-activated (myofibroblast-like) pancreatic stellate cells (mPSC) boosted Ras activity in pancreatic cancer cells carrying mutant Kras; this effect was not observed when using conditioned media from Z+/− mPSC, revealing a paracrinal cooperative axis between Zeb1-expressing PSC and oncogenic Kras-bearing tumor cells. We conclude that Zeb1-expressing stromal myofibroblasts enable a heterotypic collaboration with the Kras-fated epithelial compartment, thus supporting pancreatic malignancy. Significance: Zeb1 expression in stromal myofibroblasts supports PDAC development via collaboration with the epithelial compartment bearing oncogenic Kras mutations. Cancer Res; 78(10); 2624–37. ©2018 AACR.

EPICOLON consortium: et al., Colorectal cancer (CRC) is one of the most common neoplasms and an important cause of mortality worldwide (http://globocan.iarc.fr/). Approximately 35% of the variation in CRC susceptibility is likely due to heritable factors (Lichtenstein et al., 2000). Genetic variations in the human genome include single nucleotide variants (SNVs), short insertions and deletions, and larger structural variants resulting in gain or loss of genomic DNA larger than 1 kb, such as copy number variants (CNVs). Leaving aside the importance of CNVs in sporadic tumor development, these variants can also be present in the germline DNA of healthy individuals from the general population and be considered polymorphic. Common germline CNVs can confer a small increase in the risk of predisposition to disease, whereas rare CNVs have been linked to hereditary cancer predisposition including CRC. Recent examples include alterations involving EPCAM, PTPRJ, CDH18, GREM1 and FOCAD (Ligtenberg et al., 2009; Venkatachalam et al., 2011; Jaeger et al., 2012; Weren et al., 2015)., This work was supported by CIBEREHD (to SFE, CEJ and JM), CIBERER, Fondo de Investigación Sanitaria/FEDER (14/00173, 14/00230 and 17/00878), Ministerio de Economía y Competitividad (SAF2014-54453-R), Fundación Científica de la Asociación Española contra el Cáncer (GCB13131592CAST), PERIS (SLT002/16/00398, Generalitat de Catalunya), COST Action BM1206, Beca Grupo de Trabajo “Oncología” AEG (Asociación Española de Gastroenterología), CERCA Programme (Generalitat de Catalunya) and Agència de Gestió d'Ajuts Universitaris i de Recerca (Generalitat de Catalunya, FI 2017 B00619 to MDG, 2014SGR255, 2014SGR135).

The transcription factor Zeb1 has been identified as a crucial player in Kras-dependent oncogenesis. In pancreatic ductal adenocarcinoma (PDAC), Zeb1 is highly expressed in myofibroblasts and correlates with poor prognosis. As Kras mutations are key drivers in PDAC, we aimed here to assess the necessity of Zeb1 for Kras-driven PDAC and to define the role of Zeb1-expressing myofibroblasts in PDAC development. Genetically engineered mice with conditional pancreatic

Acute myocardial infarction is a major problem of world public health and available treatments have limited efficacy. Cardiac cell therapy is a new therapeutic strategy focused on regeneration and repair of the injured cardiac muscle. Among different cell types used, mesenchymal stem cells (MSC) have been widely tested in preclinical studies and several clinical trials have evaluated their clinical efficacy in myocardial infarction. However, the beneficial effects of MSC in humans are limited due to poor engraftment and survival of these cells, therefore ways to overcome these obstacles should improve efficacy. Different strategies have been used, such as genetically modifying MSC, or preconditioning the cells with factors that potentiate their survival and therapeutic mechanisms. In this review we compile the most relevant approaches used to improve MSC therapeutic capacity and to understand the molecular mechanisms involved in MSC mediated cardiac repair.

This document presents a monitoring and remote control system for mobile robotics platforms, with the possibility of communication via RS232 or a wireless Bluetooth connection. Three accessible and user friendly GUIs (graphical user interfaces) have been designed so that any person can interact, remotely and in real time, with the different types of mobile robots that can be controlled. For this purpose, a USB steering wheel with pedals for acceleration and breaking which can be used for complete control of the mobility parameters of the robot is made available to the user. For the development of the software, the JAVA programming language has been used, primarily for its multiplatform compatibility. This system is a tool to bring the world of robotics closer to people with varied levels of understanding, that allows for the simple explanation of the different elements that make up a robot as well as its function and its interaction with the environment. The system can also be used as a didactic tool in laboratory courses that study Embedded Systems, Java and Basic Robotics