Optimal MHC-II-restricted tumor antigen presentation to CD4+ T helper cells: the key issue for development of anti-tumor vaccines

Present immunoprevention and immunotherapeutic approaches against cancer suffer from the limitation of being not “sterilizing” procedures, as very poor protection against the tumor is obtained. Thus newly conceived anti-tumor vaccination strategies are urgently needed. In this review we will focus on ways to provide optimal MHC class II-restricted tumor antigen presentation to CD4+ T helper cells as a crucial parameter to get optimal and protective adaptive immune response against tumor. Through the description of successful preventive or therapeutic experimental approaches to vaccinate the host against the tumor we will show that optimal activation of MHC class II-restricted tumor specific CD4+ T helper cells can be achieved in various ways. Interestingly, the success in tumor eradication and/or growth arrest generated by classical therapies such as radiotherapy and chemotherapy in some instances can be re-interpreted on the basis of an adaptive immune response induced by providing suitable access of tumor-associated antigens to MHC class II molecules. Therefore, focussing on strategies to generate better and suitable MHC class II–restricted activation of tumor specific CD4+ T helper cells may have an important impact on fighting and defeating cancer

Particular distribution and expression pattern of endoglin (CD105) in the liver of patients with hepatocellular carcinoma

<p>Abstract</p> <p>Background</p> <p>Endoglin (CD105) has been considered a prognostic marker for hepatocellular carcinoma (HCC), and widely used as an appropriate targeting for antiangenesis therapy in some cancers. Our aim was to evaluate the distribution and expression of CD105 in the liver of patients with HCC, and to discuss whether CD105 may be used as an appropriate targeting for antiangenesis therapy in HCC.</p> <p>Methods</p> <p>Three parts of liver tissues from each of 64 patients with HCC were collected: tumor tissues (TT), adjacent non-tumor (AT) liver tissues within 2 cm, and tumor free tissues (TF) 5 cm far from the tumor edge. Liver samples from 8 patients without liver diseases served as healthy controls (HC). The distribution and expression of CD105 in tissues were evaluated by immunohistochemistry, Western blotting analysis, and real-time PCR. HIF-1alpha and VEGF₁₆₅protein levels in tissues were analyzed by Immunohistochemistry and Western blotting analysis or ELISA.</p> <p>Results</p> <p>CD105 was positively stained mostly in a subset of microvessels 'endothelial sprouts' in TT of all patients while CD105 showed diffuse positive staining, predominantly on hepatic sinus endothelial cells in the surrounding of draining veins in TF and AT. The mean score of MVD-CD105 (mean ± SD/0.74 mm²) was 19.00 ± 9.08 in HC, 153.12 ± 53.26 in TF, 191.12 ± 59.17 in AT, and 85.43 ± 44.71 in TT, respectively. Using a paired <it>t </it>test, the expression of CD105 in AT and TF was higher than in TT at protein (MVD, <it>p </it>= 0.012 and <it>p </it>= 0.007, respectively) and mRNA levels (<it>p </it>< 0.001 and <it>p </it>= 0.009, respectively). Moreover, distribution and expression of CD105 protein were consistent with those of HIF-1alpha and VEGF₁₆₅protein in liver of patients with HCC. The level of <it>CD105 </it>mRNA correlated with VEGF₁₆₅level in TF (r = 0.790, <it>p </it>= 0.002), AT (r = 0.723, <it>p </it>< 0.001), and TT (r = 0.473, <it>p </it>= 0.048), respectively.</p> <p>Conclusion</p> <p>It is demonstrated that CD105 was not only present in neovessels in tumor tissues, but also more abundant in hepatic sinus endothelium in non-tumor tissues with cirrhosis. Therefore, CD105 may not be an appropriate targeting for antiangenesis therapy in HCC, especially with cirrhosis.</p

The Cardiac Transcription Network Modulated by Gata4, Mef2a, Nkx2.5, Srf, Histone Modifications, and MicroRNAs

The transcriptome, as the pool of all transcribed elements in a given cell, is regulated by the interaction between different molecular levels, involving epigenetic, transcriptional, and post-transcriptional mechanisms. However, many previous studies investigated each of these levels individually, and little is known about their interdependency. We present a systems biology study integrating mRNA profiles with DNA–binding events of key cardiac transcription factors (Gata4, Mef2a, Nkx2.5, and Srf), activating histone modifications (H3ac, H4ac, H3K4me2, and H3K4me3), and microRNA profiles obtained in wild-type and RNAi–mediated knockdown. Finally, we confirmed conclusions primarily obtained in cardiomyocyte cell culture in a time-course of cardiac maturation in mouse around birth. We provide insights into the combinatorial regulation by cardiac transcription factors and show that they can partially compensate each other's function. Genes regulated by multiple transcription factors are less likely differentially expressed in RNAi knockdown of one respective factor. In addition to the analysis of the individual transcription factors, we found that histone 3 acetylation correlates with Srf- and Gata4-dependent gene expression and is complementarily reduced in cardiac Srf knockdown. Further, we found that altered microRNA expression in Srf knockdown potentially explains up to 45% of indirect mRNA targets. Considering all three levels of regulation, we present an Srf-centered transcription network providing on a single-gene level insights into the regulatory circuits establishing respective mRNA profiles. In summary, we show the combinatorial contribution of four DNA–binding transcription factors in regulating the cardiac transcriptome and provide evidence that histone modifications and microRNAs modulate their functional consequence. This opens a new perspective to understand heart development and the complexity cardiovascular disorders

Z-disc protein CHAPb induces cardiomyopathy and contractile dysfunction in the postnatal heart

The Z-disc is a crucial structure of the sarcomere and is implicated in mechanosensation/transduction. Dysregulation of Z-disc proteins often result in cardiomyopathy. We have previously shown that the Z-disc protein Cytoskeletal Heart-enriched Actin-associated Protein (CHAP) is essential for cardiac and skeletal muscle development. Furthermore, the CHAP gene has been associated with atrial fibrillation in humans. Here, we studied the misregulated expression of CHAP isoforms in heart disease. Mice that underwent transverse aortic constriction and calcineurin transgenic (Tg) mice, both models of experimental heart failure, displayed a significant increase in cardiac expression of fetal isoform CHAPb. To investigate whether increased expression of CHAPb postnatally is sufficient to induce cardiomyopathy, we generated CHAPb Tg mice under the control of the cardiac-specific αMHC promoter. CHAPb Tg mice displayed cardiac hypertrophy, interstitial fibrosis and enlargement of the left atrium at three months, which was more pronounced at the age of six months. Hypertrophy and fibrosis were confirmed by evidence of activation of the hypertrophic gene program (Nppa, Nppb, Myh7) and increased collagen expression, respectively. Connexin40 and 43 were downregulated in the left atrium, which was associated with delayed atrioventricular conduction. Tg hearts displayed both systolic and diastolic dysfunction partly caused by impaired sarcomere function evident from a reduced force generating capacity of single cardiomyocytes. This co-incided with activation of the actin signalling pathway leading to the formation of stress fibers. This study demonstrated that the fetal isoform CHAPb initiates progression towards cardiac hypertrophy, which is accompanied by delayed atrioventricular conduction and diastolic dysfunction. Moreover, CHAP may be a novel therapeutic target or candidate gene for screening in cardiomyopathies and atrial fibrillatio

Conceptos sobre espacio público, gestión de proyectos y lógica social: reflexiones sobre la experiencia chilena

Este documento trata de una serie de definiciones de espacio abierto urbano público, proponiendo el uso de la expresión espacios urbanos colectivamente usados, entendido como la red de espacios de dominio público y privado y edificaciones utilizado por la población para su recreación y circulación, sea de manera permanente o regular, estando ligados específicamente uno al otro en el plano peatonal. Según el autor, este concepto une el enfoque particular de varias disciplinas, particularmente, arquitectura, ingeniería, diseño paisajístico y ecología paisajística, así como las reglas que rigen el producto de esas profesiones, abriendo un amplio rango de posibilidades de acción para planificadores y administradores urbanos. El artículo se refiere a la necesidad de entender los proyectos de espacios abiertos como oportunidades de renovación urbana que proveen nuevo financiamiento y otros recursos a la gestión de la ciudad, e ilustra algunos de los beneficios que entraña el incorporar la administración y mantención de espacios urbanos abiertos como parte esencial del proceso de materialización de distintas iniciativas, donde la participación de actores urbanos y la evitación de un enfoque excesivamente tecnocrático son factores esencialesThe present document deals with a series of definitions of urban open space, proposing the use of the term collectively used urban spaces, understood as the network of publicly and privately owned spaces and edifications used by the population for its recreation and circulation, either on a permanent or regular basis, being explicitly linked with one another at the scale of the pedestrian. According to the author this concept brings together the particular approach of several disciplines, particularly architecture, engineering, landscape design and landscape ecology, as well as the regulations that norm the products of these professions, opening an ample range of action possibilities for urban planners and managers. The article discusses the necessity of understanding urban open space projects as urban renewal opportunities that provide fresh financial and other resources to city management, and illustrates some of the benefits of incorporating the administration and maintenance of urban open spaces as an essential part of the process of materialisation of different initiatives, where the participation of urban actors and the avoidance of an excessively technocratic approach are essential element

Transport and mobility : perspectives in the planning of the city of Mérida, Venezuela

El surgimiento y proliferación, en América Latina, de ciudades intermedias y grandes metrópolis, ha generado una compleja e intensa movilidad que genera mayores efectos sobre los espacios. La Corporación Andina de Fomento (CAF), a través del Observatorio de Movilidad Urbana, se ha abocado al estudio de este tema y ha avanzado en los escritos sobre la movilidad en las principales ciudades de América Latina. Ahora, la movilidad constituye un elemento fundamental dentro del proceso de planificación, pues es un factor que cohesiona y comunica los espacios urbanos a través de los medios de circulación (transporte), transformando las ciudades en entornos cada vez más dinámicos. En consonancia, la finalidad de este trabajo es presentar algunas consideraciones sobre la movilidad urbana en la ciudad de Mérida - Venezuela, bajo un enfoque reflexivo acerca de la relación entre la morfología de la ciudad y los medios de transporte masivo que, recientemente, han tenido impacto en la dinámica central de la ciudad y que aún, pese a las deficiencias y problemas, todavía no han sido incorporados en el proceso de planificación de la ciudad.The appearance and proliferation in Latin America, of medium cities and big metropolis, has generated an intense and complex mobility that create greater effects over the spaces. The Corporación Andina de Fomento CAF, through the observatory of urban movement, has dedicated itself to studying this subject and has advanced in the writtens about mobility into the principal cities of Latin America. Now, mobility it´s a fundamental element into the planning process, because it is a factor that cohesive and communicate the urban spaces through the circulation mediums (transport), transforming the cities in a more dynamic environments each time. Accordingly, the purpose of this work is to present some considerations about the urban mobility in Mérida city in Venezuela, under a reflexive approach on the relationship between the morphology of the city and mass transportation mediums, that have recently had impact on the central dynamic of the city and still, in spite of deficiencies and problems, they have been not incorporated yet in the planning process of the city.Fil: Balza-Moreno, Luis F.