Search

Not available.

Abstract MALAT1 long non-coding RNA has oncogenic roles but has been poorly studied in indolent B-cell neoplasms. Here, MALAT1 expression was analyzed using RNA-seq, microarrays or qRT-PCR in primary samples from clinico-biological subtypes of chronic lymphocytic leukemia (CLL, n = 266), paired Richter transformation (RT, n = 6) and follicular lymphoma (FL, n = 61). In peripheral blood (PB) CLL samples, high MALAT1 expression was associated with a significantly shorter time to treatment independently from other known prognostic factors. Coding genes expressed in association with MALAT1 in CLL were predominantly related to oncogenic pathways stimulated in the lymph node (LN) microenvironment. In RT paired samples, MALAT1 levels were lower, concordant with their acquired increased independency of external signals. Moreover, MALAT1 levels in paired PB/LN CLLs were similar, suggesting that the prognostic value of MALAT1 expression in PB is mirroring expression differences already present in LN. Similarly, high MALAT1 expression in FL predicted for a shorter progression-free survival, in association with expression pathways promoting FL pathogenesis. In summary, MALAT1 expression is related to pathophysiology and more aggressive clinical behavior of indolent B-cell neoplasms. Particularly in CLL, its levels could be a surrogate marker of the microenvironment stimulation and may contribute to refine the clinical management of these patients.

Metabolic plasticity is the ability of a biological system to adapt its metabolic phenotype to different environmental stressors. We used a whole-body and tissue-specific phenotypic, functional, proteomic, metabolomic and transcriptomic approach to systematically assess metabolic plasticity in diet-induced obese mice after a combined nutritional and exercise intervention. Although most obesity and overnutrition-related pathological features were successfully reverted, we observed a high degree of metabolic dysfunction in visceral white adipose tissue, characterized by abnormal mitochondrial morphology and functionality. Despite two sequential therapeutic interventions and an apparent global healthy phenotype, obesity triggered a cascade of events in visceral adipose tissue progressing from mitochondrial metabolic and proteostatic alterations to widespread cellular stress, which compromises its biosynthetic and recycling capacity. In humans, weight loss after bariatric surgery showed a transcriptional signature in visceral adipose tissue similar to our mouse model of obesity reversion. Overall, our data indicate that obesity prompts a lasting metabolic fingerprint that leads to a progressive breakdown of metabolic plasticity in visceral adipose tissue.

Abstract Robust protocols and automation now enable large-scale single-cell RNA and ATAC sequencing experiments and their application on biobank and clinical cohorts. However, technical biases introduced during sample acquisition can hinder solid, reproducible results, and a systematic benchmarking is required before entering large-scale data production. Here, we report the existence and extent of gene expression and chromatin accessibility artifacts introduced during sampling and identify experimental and computational solutions for their prevention.

Extramedullary multiple myeloma (EMM) has an overall survival of 6 months and occurs in 20% of multiple myeloma (MM) patients. Genetic and epigenetic mechanisms involved in EMM and the therapeutic role of new agents for MM are not well established. Besides, well-characterized preclinical models for EMM are not available. Herein, a patient-derived orthotopic xenograft (PDOX) was generated from a patient with an aggressive EMM to study in-depth genetic and epigenetic events, and drug responses related to extramedullary disease. A fresh punch of an extramedullary cutaneous lesion was orthotopically implanted in NOD.Cg-PrkdcscidIl2rgtm1Wjl/SzJ(NSG) mouse. The PDOX mimicked histologic and phenotypic features of the tumor of the patient. Cytogenetic studies revealed a hyperploid genome with multiple genetic poor-prognosis alterations. Copy number alterations (CNAs) were detected in all chromosomes. The IGH translocation t(14;16)(q32;q23)IGH/MAF was already observed at the medullary stage and a new one, t(10;14)(p?11-12;q32), was observed only with extramedullary disease and could be eventually related to EMM progression in this case. Exome sequencing showed 24 high impact single nucleotide variants and 180 indels. From the genes involved, only TP53 was previously described as a driver in MM. A rather balanced proportion of hyper/hypomethylated sites different to previously reported widespread hypomethylation in MM was also observed. Treatment with lenalidomide, dexamethasone and carfilzomib showed a tumor weight reduction of 90% versus non-treated tumors, whereas treatment with the anti-CD38 antibody daratumumab showed a reduction of 46%. The generation of PDOX from a small EMM biopsy allowed us to investigate in depth the molecular events associated with extramedullary disease in combination with drug testing.

O método de Montessori foi aplicado inicialmente às crianças, mas atualmente aplica-se a pessoas com demência. O objetivo deste trabalho é fazer uma revisão sistemática da investigação sobre a eficácia desse método, utilizando a Medical Literature Analysis and Retrieval System Online (Medline) com as palavras-chave demência e método de Montessori. Foram selecionados 10 estudos, onde se verificam melhorias significativas na participação e no envolvimento construtivo e diminuição dos afectos negativos e do envolvimento passivo. Não obstante, as revisões da literatura acerca desta intervenção não farmacológica em demência classificam esse método como fraco, em termos de eficácia. Essa aparente discrepância pode explicar-se porque o método de Montessori pode ter, de fato, uma influência pouco significativa em dimensões como a dos problemas comportamentais ou porque não existe investigação acerca desse método com elevados níveis de controle como são a presença de vários grupos de controle ou o duplo-cego.El método Montessori se aplicó inicialmente a los niños, pero ahora se aplica a las personas con demencia. El propósito de este estudio es revisar de forma sistemática la investigación sobre la eficacia de este método, utilizando Medical Literature Analysis and Retrieval System Online (Medline) con las palabras clave demencia y método Montessori. Se seleccionaron 10 estudios, que tienen mejoras significativas en la participación y en el compromiso constructivo, y la reducción de efectos negativos y de la participación pasiva. Sin embargo, la revisión de la literatura sobre esta intervención no farmacológica en la demencia clasifica este método como débil en términos de eficacia. Esta aparente discrepancia puede explicarse porque el método Montessori puede tener una influencia poco significativa en los problemas de conducta, o porque no hay investigación sobre este método con altos niveles de control como son la presencia de varios grupos de control o el estudio doble ciego.The Montessori method was initially applied to children, but now it has also been applied to people with dementia. The purpose of this study is to systematically review the research on the effectiveness of this method, using Medical Literature Analysis and Retrieval System Online (Medline) with the keywords dementia and Montessori method. We selected 10 studies, in which there were significant improvements in participation and constructive engagement, and reduction of negative affects and passive engagement. Nevertheless, systematic reviews about this non-pharmacological intervention in dementia rate this method as weak in terms of effectiveness. This apparent discrepancy can be explained because the Montessori method may have, in fact, a small influence on dimensions such as behavioral problems, or because there is no research about this method with high levels of control, such as the presence of several control groups or a double-blind study.

Aim: Employment and work-related disability were investigated in a cohort of colorectal cancer patients to describe a possible discrimination and other work issues. Patients and Methods: The study included consecutively 73 colorectal cancer patients who were employed at diagnosis. The questionnaire included cancer-related symptoms and work-related factors. Clinical details were obtained from the medical record. Patients were interviewed face to face. The study was approved by the Ethical Committee of La Paz Hospital. All patients gave consent to participate. Results: Eighty six per cent of patients were unable to work after diagnosis, but 55% returned to work at the end of treatment. The age, having a metastatic illness and the sequelae of the disease or its treatment were independently associated with the ability to work after the end of treatment. Almost all patients told their employers and co-workers about their disease. Conclusions: This is the fi rst exploratory study in Spain about labour reintegration in colorectal cancer. Further studies are necessary.

Most DNA methylation studies in classic Philadelphia-negative myeloproliferative neoplasms have been performed on a gene-by-gene basis. Therefore, a more comprehensive methylation profiling is needed to study the implications of this epigenetic marker in myeloproliferative neoplasms. Here, we have analyzed 71 chronic (24 polycythemia vera, 23 essential thrombocythemia and 24 primary myelofibrosis) and 13 transformed myeloproliferative neoplasms using genome-wide DNA methylation arrays. The three types of chronic Philadelphia-negative myeloproliferative neoplasms showed a similar aberrant DNA methylation pattern when compared to control samples. Differentially methylated regions were enriched in a gene network centered on the NF-κB pathway, indicating that they may be involved in the pathogenesis of these diseases. In the case of transformed myeloproliferative neoplasms, we detected an increased number of differentially methylated regions with respect to chronic myeloproliferative neoplasms. Interestingly, these genes were enriched in a list of differentially methylated regions in primary acute myeloid leukemia and in a gene network centered around the IFN pathway. Our results suggest that alterations in the DNA methylation landscape play an important role in the pathogenesis and leukemic transformation of myeloproliferative neoplasms. The therapeutic modulation of epigenetically-deregulated pathways may allow us to design targeted therapies for these patients.

Chronic myelomonocytic leukemia (CMML) has recently been associated with a high incidence of diverse mutations in genes such as TET2 or EZH2 that are implicated in epigenetic mechanisms. We have performed genome-wide DNA methylation arrays and mutational analysis of TET2, IDH1, IDH2, EZH2 and JAK2 in a group of 24 patients with CMML. 249 genes were differentially methylated between CMML patients and controls. Using Ingenuity pathway analysis, we identified enrichment in a gene network centered around PLC, JNK and ERK suggesting that these pathways, whose deregulation has been recently described in CMML, are affected by epigenetic mechanisms. Mutations of TET2, JAK2 and EZH2 were found in 15 patients (65%), 4 patients (17%) and 1 patient (4%) respectively while no mutations in the IDH1 and IDH2 genes were identified. Interestingly, patients with wild type TET2 clustered separately from patients with TET2 mutations, showed a higher degree of hypermethylation and were associated with higher risk karyotypes. Our results demonstrate the presence of aberrant DNA methylation in CMML and identifies TET2 mutant CMML as a biologically distinct disease subtype with a different epigenetic profile.

Aberrant DNA methylation is one of the most frequent alterations in patients with Acute Lymphoblastic Leukemia (ALL). Using methylation bead arrays we analyzed the methylation status of 807 genes implicated in cancer in a group of ALL samples at diagnosis (n = 48). We found that 154 genes were methylated in more than 10% of ALL samples. Interestingly, the expression of 13 genes implicated in the TP53 pathway was downregulated by hypermethylation. Direct or indirect activation of TP53 pathway with 5-aza-2'-deoxycitidine, Curcumin or Nutlin-3 induced an increase in apoptosis of ALL cells. The results obtained with the initial group of 48 patients was validated retrospectively in a second cohort of 200 newly diagnosed ALL patients. Methylation of at least 1 of the 13 genes implicated in the TP53 pathway was observed in 78% of the patients, which significantly correlated with a higher relapse (p = 0.001) and mortality (p

Aberrant promoter DNA methylation has been shown to play a role in acute myeloid leukemia (AML) pathophysiology. However, further studies to discuss the prognostic value and the relationship of the epigenetic signatures with defined genomic rearrangements in acute myeloid leukemia are required.We carried out high-throughput methylation profiling on 116 de novo AML cases and we validated the significant biomarkers in an independent cohort of 244 AML cases. Methylation signatures were associated with the presence of a specific cytogenetic status. In normal karyotype cases, aberrant methylation of the promoter of DBC1 was validated as a predictor of the disease-free and overall survival. Furthermore, DBC1 expression was significantly silenced in the aberrantly methylated samples. Patients with chromosome rearrangements showed distinct methylation signatures. To establish the role of fusion proteins in the epigenetic profiles, 20 additional samples of human hematopoietic stem/progenitor cells (HSPC) transduced with common fusion genes were studied and compared with patient samples carrying the same rearrangements. The presence of MLL rearrangements in HSPC induced the methylation profile observed in the MLL-positive primary samples. In contrast, fusion genes such as AML1/ETO or CBFB/MYH11 failed to reproduce the epigenetic signature observed in the patients.Our study provides a comprehensive epigenetic profiling of AML, identifies new clinical markers for cases with a normal karyotype, and reveals relevant biological information related to the role of fusion proteins on the methylation signature.

RESUMEN: La rivalidad banderil de los últimos años del siglo XV y los primeros del XVI que enfrentó en Ciudad Rodrigo a los principales linajes de la ciudad, se extendió también al estamento eclesiástico. Los conflictos derivaron muchas veces en asaltos y encastillamientos, esto es, una de las partes se hacía fuerte con armas y gente en el interior de un edificio para resistir la presión del bando contrario. En el fondo lo que estaba en juego era la lucha por el poder civil y militar de la ciudad, así como por la permanencia de encomiendas en determinados monasterios. A ello no eran ajenas tampoco las discrepancias por la jurisdicción eclesiástica, así como por la posesión de beneficios. Águilas y Pachecos, Obispo y Cabildo, así como otros intereses ligados a miembros de la nobleza y del clero protagonizaron dichos sucesos.ABSTRACT: In the late 15th century and the early 16th century, the rivalry among the main noble families in Ciudad Rodrigo also included the clergy. Conflicts often resulted in assaults and encastillamientos, i.e., one of the sides took over a castle and kept arms and people in it to resist pressure from the opposite side. Civil and military powers in town were at stake, as well as life annuities in some monasteries. There was also conflict over the jurisdiction of the church and the possession of endowments. These conflicts were led by Águilas and Pachecos (two noble families), Chapters and Bishops, and other members of the aristocracy and the clergy.

El conjunto arqueológico que aquí presentamos fue hallado por nosotros en el verano de 1982, dentro de una sistemática campaña de prospecciones que desde hace varios años venimos realizando en el valle del río Águeda, con el fin de poder conocer y establecer una secuencia de las industrias achelenses que nos permita tener un apoyo de base en el estudio de otros complejos similarmente culturales de otras áreas o regiones de la cuenca del Duero, y contribuir, de esta manera, a un mayor conocimiento del Paleolítico Inferior en la meseta duriense.

RESUMEN: La Fosa de Ciudad Rodrigo constituye un espacio geomorfológico rico en industrias achelenses. Como sucede en otras regiones del Paleolítico Inferior de la Península Ibérica, los hendidores son aquí útiles con escasa representatividad dentro de la estructura interna de las industrias. Por lo demás, el hendidor es una pieza que, generalmente, presenta una escasa evolución en cuanto a tipos y técnicas, manteniéndose a lo largo de la secuencia los tipos menos complejos. No obstante, no faltan ejemplares que llevan asociados determinados logros técnicos representados, a su vez, en el conjunto de la industria en la que se incluyen y que delatan, por tanto, un mayor grado de desarrollo tecnológico frente a las industrias donde estos logros son inusuales.RÉSUMÉ: La Fosse de Ciudad Rodrigo constitue un espace géomorphologique riche en industries acheuléennes. Ainsi que dans d'autres régions du' Paléolithique Inférieur de la Péninsule Ibérique, les hacheraux sont ici des outils rarement représentés dans la structure interne des industries. D'ailleurs, le hacherau c'est une pièce qui, généralement, présente une évolution pauvre quant aux types et techniques. Cependant, il ne manque pas d'exemplaires qui portent associés certains avancements techniques représentés, à leur tour, dans l'ensemble de l'industrie où ils sont inclus et qui montrent, par conséquent, un plus haut degré de développement par rapport aux industries dans lesquelles ces avancements son inhabituels.

BackgroundThe therapeutic use of multipotent stem cells depends on their differentiation potential, which has been shown to be variable for different populations. These differences are likely to be the result of key changes in their epigenetic profiles.Methodology/principal findingsto address this issue, we have investigated the levels of epigenetic regulation in well characterized populations of pluripotent embryonic stem cells (ESC) and multipotent adult stem cells (ASC) at the trancriptome, methylome, histone modification and microRNA levels. Differences in gene expression profiles allowed classification of stem cells into three separate populations including ESC, multipotent adult progenitor cells (MAPC) and mesenchymal stromal cells (MSC). The analysis of the PcG repressive marks, histone modifications and gene promoter methylation of differentiation and pluripotency genes demonstrated that stem cell populations with a wider differentiation potential (ESC and MAPC) showed stronger representation of epigenetic repressive marks in differentiation genes and that this epigenetic signature was progressively lost with restriction of stem cell potential. Our analysis of microRNA established specific microRNA signatures suggesting specific microRNAs involved in regulation of pluripotent and differentiation genes.Conclusions/significanceOur study leads us to propose a model where the level of epigenetic regulation, as a combination of DNA methylation and histone modification marks, at differentiation genes defines degrees of differentiation potential from progenitor and multipotent stem cells to pluripotent stem cells.

RESUMEN: Se realiza aquí una aproximación general sobre las industrias achelenses del occidente de la Meseta norte española, atendiendo a aspectos puramente tecnológicos, tanto por lo que se refiere a su estructura interna como a las características de su evolución. Se observará, asimismo, que las convergencias tecnológicas de las industrias reflejan una cierta unidad en el Achelense de la cuenca del Duero.SUMMARY: This paper a general approach to the Acheulean industry of the Western Meseta, taking into account purely technological aspects as to the internal structures and the characteristics of its evolution. It is also observed that the technological convergencies of these industries reflect a certain similarity with the Acheulean of the Duero basin.

Manifestaciones de industrias inferopaleolíticas en el valle del Tormes son conocidas ya desde las primeras décadas de este siglo, gracias a las noticias y trabajos de M. Gómez Moreno1 y C. Moran. Las investigaciones que se han venido llevando a cabo desde la década de los setenta —centradas, sobre todo, en el curso medio— han permitido sistematizar o diseñar el desarrollo evolutivo de la secuencia Achelense en este colector meridional del Duero.

El útil objeto de nuestro estudio fue encontrado de manera casual durante el transcurso de las obras de construcción, a comienzos de los años ochenta, de un camino que enlaza la población de La Hoya con el sitio denominado «La Cobatilla» en plena Sierra de Béjar. El hacha fue encontrada por uno de los operarios aproximadamente a medio camino entre ambos lugares, durante los trabajos de terraplenado llevados a cabo por una máquina excavador

Son prácticamente desconocidas en la Meseta española cualquier tipo de estructuras constructivas en contextos de «campos de hoyos» de la Edad del Bronce. El fin de este artículo es dar a conocer una de estas estructuras, localizada en el yacimiento del «Teso del Cuerno», en el término municipal de Forfoleda (Salamanca).

Abstract Background The gut microbiome has been reported to induce epigenetic modifications in the host, which may be involved in the pathophysiology of metabolic diseases. Objective To evaluate the potential interactions between the gut microbiome and DNA methylome in subjects with different metabolic characteristics. Methods Sixty-four participants with different metabolic characteristics (i.e., participants without obesity -healthy controls-, and participants with obesity and normal insulin sensitivity/insulin resistance/ type 2 diabetes-T2DM-) were included in this study. A machine learning approach was performed in order to identify distinctive patterns in three omics (gut microbiome, blood DNA methylome, and visceral adipose tissue-VAT- DNA methylome) according to the different study groups. Results Robust distinctive distribution patterns of the three different omics were found between healthy controls and patients with obesity; participants with and without T2DM, and patients with obesity with and without insulin resistance. Importantly, strong correlations between the gut microbiome (including Odoribacteriaceae and Christensenllaceae families) and both blood and VAT DNA methylome were found. Moreover, in the entire study population, three main bacterial genera (Sutterella, Collinsella and Eubacterium) were related to the epigenetic regulation of different genes involved in distinct processes related to cellular metabolism and metabolic diseases, including small ubiquitin-related modifier (SUMO) transferase activity or lipid binding. Conclusion We show that distinctive interactions between the gut microbiome and DNA methylome may occur in subjects with different metabolic characteristics. Further research is needed to elucidate the potential role of these interactions in the pathophysiology of obesity and related comorbidities.