The match between molecular subtypes, histology and microenvironment of pancreatic cancer and its relevance for chemoresistance

In the last decade, several studies based on whole transcriptomic and genomic analyses of pancreatic tumors and their stroma have come to light to supplement histopathological stratification of pancreatic cancers with a molecular point-of-view. Three main molecular studies: Collisson et al. 2011, Moffitt et al. 2015 and Bailey et al. 2016 have found specific gene signatures, which identify different molecular subtypes of pancreatic cancer and provide a comprehensive stratification for both a personalized treatment or to identify potential druggable targets. However, the routine clinical management of pancreatic cancer does not consider a broad molecular analysis of each patient, due probably to the lack of target therapies for this tumor. Therefore, the current treatment decision is taken based on patients’ clinicopathological features and performance status. Histopathological evaluation of tumor samples could reveal many other attributes not only from tumor cells but also from their microenvironment specially about the presence of pancreatic stellate cells, regulatory T cells, tumor-associated macrophages, myeloid derived suppressor cells and extracellular matrix structure. In the present article, we revise the four molecular subtypes proposed by Bailey et al. and associate each subtype with other reported molecular subtypes. Moreover, we provide for each subtype a potential description of the tumor microenvironment that may influence treatment response according to the gene expression profile, the mutational landscape and their associated histolog

Towards a Functional Explanation of the Connectivity LGN - V1

The principles behind the connectivity between LGN and V1 are not well understood. Models have to explain two basic experimental trends: (i) the combination of thalamic responses is local and it gives rise to a variety of oriented Gabor-like receptive felds in V1 [1], and (ii) these filters are spatially organized in orientation maps [2]. Competing explanations of orientation maps use purely geometrical arguments such as optimal wiring or packing from LGN [3-5], but they make no explicit reference to visual function. On the other hand, explanations based on func- tional arguments such as maximum information transference (infomax) [6,7] usually neglect a potential contribution from LGN local circuitry. In this work we explore the abil- ity of the conventional functional arguments (infomax and variants), to derive both trends simultaneously assuming a plausible sampling model linking the retina to the LGN [8], as opposed to previous attempts operating from the retina. Consistently with other aspects of human vi- sion [14-16], additional constraints should be added to plain infomax to understand the second trend of the LGN-V1 con- nectivity. Possibilities include energy budget [11], wiring constraints [8], or error minimization in noisy systems, ei- ther linear [16] or nonlinear [14, 15]. In particular, consideration of high noise (neglected here) would favor the redundancy in the prediction (which would be required to match the relations between spatially neighbor neurons in the same orientation domain)

Pacto fiscal y autonomía concejil

UIDB/00749/2020 UIDP/00749/2020El objetivo de este trabajo es describir la relación entre la estabilización del sistema fiscal castellano y la lucha por las rentas señoriales a través de los pleitos y las concordias que se dieron en una etapa de clara expansión de la economía en la corona de Castilla (c.a 1450-1550). El recurso a la justicia regia y la concordia fiscal es, en nuestra opinión, un excelente índice para mostrar la funcionalidad del sistema en esa época y la integración de la nobleza en el estado, frente a las resistencias de los vasallos señoriales. PDFpublishersversionpublishe

Derivatives and Inverse of a Linear-Nonlinear Multi-Layer Spatial Vision Model

Analyzing the mathematical properties of perceptually meaningful linear-nonlinear transforms is interesting because this computation is at the core of many vision models. Here we make such analysis in detail using a specific model [Malo & Simoncelli, SPIE Human Vision Electr. Imag. 2015] which is illustrative because it consists of a cascade of standard linear-nonlinear modules. The interest of the analytic results and the numerical methods involved transcend the particular model because of the ubiquity of the linear-nonlinear structure. Here we extend [Malo&Simoncelli 15] by considering 4 layers: (1) linear spectral integration and nonlinear brightness response, (2) definition of local contrast by using linear filters and divisive normalization, (3) linear CSF filter and nonlinear local con- trast masking, and (4) linear wavelet-like decomposition and nonlinear divisive normalization to account for orientation and scale-dependent masking. The extra layers were measured using Maximum Differentiation [Malo et al. VSS 2016]. First, we describe the general architecture using a unified notation in which every module is composed by isomorphic linear and nonlinear transforms. The chain-rule is interesting to simplify the analysis of systems with this modular architecture, and invertibility is related to the non-singularity of the Jacobian matrices. Second, we consider the details of the four layers in our particular model, and how they improve the original version of the model. Third, we explicitly list the derivatives of every module, which are relevant for the definition of perceptual distances, perceptual gradient descent, and characterization of the deformation of space. Fourth, we address the inverse, and we find different analytical and numerical problems in each specific module. Solutions are proposed for all of them. Finally, we describe through examples how to use the toolbox to apply and check the above theory. In summary, the formulation and toolbox are ready to explore the geometric and perceptual issues addressed in the introductory section (giving all the technical information that was missing in [Malo&Simoncelli 15])

The UNIVERSIA/UPM OPEN COURSEWARE iniciative to share the knowledge

This paper shows the most innovative aspects of the Universia/UPM OpenCourseWare (OCW) project referred to globalization of higher education in a Latin-American environment and the sharing of knowledge. The MIT idea of offering, through Internet, the available educational resources in an open way has been spread all over the world and many Universities and Institutions have joint this initiative. Universia, Institution which gathers one of the biggest world universities net, has launched an OCW site, with the technical collaboration of the Technical University of Madrid (UPM) who is working as the main university project promoter. The OCW-Universia site has one of the greatest growth rates at present and is facing new challenges and developments which will allow its expansion as a reference within an international context

Objetivos, evolución y perspectivas del OPEN COURSEWARE de la UPM

En esta comunicación se presentan los principales objetivos, la situación actual y los retos futuros, del sitio OCW de la Universidad Politécnica de Madrid, enmarcados en el entorno de la iniciativa OCW Universia y del Consocio Mundial OCW. Durante los dos últimos cursos la UPM ha realizado un importante esfuerzo que la ha permitido situarse como la Universidad Iberoamericana con mayor cantidad de contenidos educativos en abierto y con el mayor número de accesos y descargas de este tipo de recursos. Para poder afianzar esta posición privilegiada, e impulsar y desarrollar nuevas ideas del sitio OCW-UPM son necesarios una serie de requisitos, que son detallados y analizados en esta ponenci

Association of Candidate Gene Polymorphisms With Chronic Kidney Disease: Results of a Case-Control Analysis in the Nefrona Cohort

Chronic kidney disease (CKD) is a major risk factor for end-stage renal disease, cardiovascular disease and premature death. Despite classical clinical risk factors for CKD and some genetic risk factors have been identified, the residual risk observed in prediction models is still high. Therefore, new risk factors need to be identified in order to better predict the risk of CKD in the population. Here, we analyzed the genetic association of 79 SNPs of proteins associated with mineral metabolism disturbances with CKD in a cohort that includes 2, 445 CKD cases and 559 controls. Genotyping was performed with matrix assisted laser desorption ionizationtime of flight mass spectrometry. We used logistic regression models considering different genetic inheritance models to assess the association of the SNPs with the prevalence of CKD, adjusting for known risk factors. Eight SNPs (rs1126616, rs35068180, rs2238135, rs1800247, rs385564, rs4236, rs2248359, and rs1564858) were associated with CKD even after adjusting by sex, age and race. A model containing five of these SNPs (rs1126616, rs35068180, rs1800247, rs4236, and rs2248359), diabetes and hypertension showed better performance than models considering only clinical risk factors, significantly increasing the area under the curve of the model without polymorphisms. Furthermore, one of the SNPs (the rs2248359) showed an interaction with hypertension, being the risk genotype affecting only hypertensive patients. We conclude that 5 SNPs related to proteins implicated in mineral metabolism disturbances (Osteopontin, osteocalcin, matrix gla protein, matrix metalloprotease 3 and 24 hydroxylase) are associated to an increased risk of suffering CKD

TORTURA Y PROTOCOLO DE ESTABMBÚL: Perspectivas, alternativas y contextos

La obra presenta el tema central de la tortura que esta presente en la sociedad mexicana. Sus perspectivas, alternativas y contextos.El libro consta de 23 capítulos en los cuales los autores presentan de forma analítica y crítica el contexto de la tortura en México; sus efectos, alcances y perspectivas

The Susceptibility of Trypanosomatid Pathogens to PI3/mTOR Kinase Inhibitors Affords a New Opportunity for Drug Repurposing

In our study we describe the potency of established phosphoinositide-3-kinase (PI3K) and mammalian Target of Rapamycin (mTOR) kinase inhibitors against three trypanosomatid parasites: Trypanosoma brucei, T. cruzi, and Leishmania sp., which are the causative agents for African sleeping sickness, Chagas disease, and leishmaniases, respectively. We noted that these parasites and humans express similar kinase enzymes. Since these similar human targets have been pursued by the drug industry for many years in the discovery of cellular growth and proliferation inhibitors, compounds developed as human anti-cancer agents should also have effect on inhibiting growth and proliferation of the parasites. With that in mind, we selected eight established PI3K and mTOR inhibitors for profiling against these pathogens. Among these inhibitors is an advanced clinical candidate against cancer, NVP-BEZ235, which we demonstrate to be a highly potent trypanocide in parasite cultures, and in a mouse model of T. brucei infection. Additionally, we describe observations of these inhibitors' effects on parasite growth and other cellular characteristics

Familial hypercholesterolaemia in children and adolescents from 48 countries: a cross-sectional study

Background: Approximately 450 000 children are born with familial hypercholesterolaemia worldwide every year, yet only 2·1% of adults with familial hypercholesterolaemia were diagnosed before age 18 years via current diagnostic approaches, which are derived from observations in adults. We aimed to characterise children and adolescents with heterozygous familial hypercholesterolaemia (HeFH) and understand current approaches to the identification and management of familial hypercholesterolaemia to inform future public health strategies. Methods: For this cross-sectional study, we assessed children and adolescents younger than 18 years with a clinical or genetic diagnosis of HeFH at the time of entry into the Familial Hypercholesterolaemia Studies Collaboration (FHSC) registry between Oct 1, 2015, and Jan 31, 2021. Data in the registry were collected from 55 regional or national registries in 48 countries. Diagnoses relying on self-reported history of familial hypercholesterolaemia and suspected secondary hypercholesterolaemia were excluded from the registry; people with untreated LDL cholesterol (LDL-C) of at least 13·0 mmol/L were excluded from this study. Data were assessed overall and by WHO region, World Bank country income status, age, diagnostic criteria, and index-case status. The main outcome of this study was to assess current identification and management of children and adolescents with familial hypercholesterolaemia. Findings: Of 63 093 individuals in the FHSC registry, 11 848 (18·8%) were children or adolescents younger than 18 years with HeFH and were included in this study; 5756 (50·2%) of 11 476 included individuals were female and 5720 (49·8%) were male. Sex data were missing for 372 (3·1%) of 11 848 individuals. Median age at registry entry was 9·6 years (IQR 5·8-13·2). 10 099 (89·9%) of 11 235 included individuals had a final genetically confirmed diagnosis of familial hypercholesterolaemia and 1136 (10·1%) had a clinical diagnosis. Genetically confirmed diagnosis data or clinical diagnosis data were missing for 613 (5·2%) of 11 848 individuals. Genetic diagnosis was more common in children and adolescents from high-income countries (9427 [92·4%] of 10 202) than in children and adolescents from non-high-income countries (199 [48·0%] of 415). 3414 (31·6%) of 10 804 children or adolescents were index cases. Familial-hypercholesterolaemia-related physical signs, cardiovascular risk factors, and cardiovascular disease were uncommon, but were more common in non-high-income countries. 7557 (72·4%) of 10 428 included children or adolescents were not taking lipid-lowering medication (LLM) and had a median LDL-C of 5·00 mmol/L (IQR 4·05-6·08). Compared with genetic diagnosis, the use of unadapted clinical criteria intended for use in adults and reliant on more extreme phenotypes could result in 50-75% of children and adolescents with familial hypercholesterolaemia not being identified. Interpretation: Clinical characteristics observed in adults with familial hypercholesterolaemia are uncommon in children and adolescents with familial hypercholesterolaemia, hence detection in this age group relies on measurement of LDL-C and genetic confirmation. Where genetic testing is unavailable, increased availability and use of LDL-C measurements in the first few years of life could help reduce the current gap between prevalence and detection, enabling increased use of combination LLM to reach recommended LDL-C targets early in life