More than 90% of patients with myelodysplastic/myeloproliferative neoplasms (MDSs/MPNs) harbor somatic mutations in myeloid-related genes, but still, current diagnostic criteria do not include ...molecular data. We performed genome-wide sequencing techniques to characterize the mutational landscape of a large and clinically well-characterized cohort including 367 adults with MDS/MPN subtypes, including chronic myelomonocytic leukemia (CMML; n = 119), atypical chronic myeloid leukemia (aCML; n = 71), MDS/MPN with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T; n = 71), and MDS/MPN unclassifiable (MDS/MPN-U; n = 106). A total of 30 genes were recurrently mutated in ≥3% of the cohort. Distribution of recurrently mutated genes and clonal architecture differed among MDS/MPN subtypes. Statistical analysis revealed significant correlations between recurrently mutated genes, as well as genotype-phenotype associations. We identified specific gene combinations that were associated with distinct MDS/MPN subtypes and that were mutually exclusive with most of the other MDSs/MPNs (eg, TET2-SRSF2 in CMML, ASXL1-SETBP1 in aCML, and SF3B1-JAK2 in MDS/MPN-RS-T). Patients with MDS/MPN-U were the most heterogeneous and displayed different molecular profiles that mimicked the ones observed in other MDS/MPN subtypes and that had an impact on the outcome of the patients. Specific gene mutations also had an impact on the outcome of the different MDS/MPN subtypes, which may be relevant for clinical decision-making. Overall, the results of this study help to elucidate the heterogeneity found in these neoplasms, which can be of use in the clinical setting of MDS/MPN.
•Specific gene mutation combinations correlate with morphologic MDS/MPN subtypes and help elucidate the heterogeneity in these neoplasms.•Patients with MDS/MPN-U display different molecular profiles that mimic the ones observed in other MDS/MPN subtypes.
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Myelodysplastic/myeloproliferative neoplasms (MDS/MPN) are myeloid neoplasms characterized by the presentation of overlapping features from both myelodysplastic syndromes and myeloproliferative ...neoplasms. Although the classification of MDS/MPN relies largely on clinical features and peripheral blood and bone marrow morphology, studies have demonstrated that a large proportion of patients (~90%) with this disease harbor somatic mutations in a group of genes that are common across myeloid neoplasms. These mutations play a role in the clinical heterogeneity of these diseases and their clinical evolution. Nevertheless, none of them is specific to MDS/MPN and current diagnostic criteria do not include molecular data. Even when such alterations can be helpful for differential diagnosis, they should not be used alone as proof of neoplasia because some of these mutations may also occur in healthy older people. Here, we intend to review the main genetic findings across all MDS/MPN overlap syndromes and discuss their relevance in the management of the patients.
Hepatocytes release extracellular vesicles (EVs) loaded with signaling molecules and enzymes into the bloodstream. Although the importance of EVs in the intercellular communication is already ...recognized, the metabolic impact of the enzymes carried by these vesicles is still unclear. We evaluated the global effect of the enzymatic activities of EVs by performing untargeted metabolomic profiling of serum samples after their exposure to EVs. This approach revealed a significant change in the abundance of 94 serum metabolic signals. Our study shows that these vesicles modify the concentration of metabolites of different chemical nature including metabolites related to arginine metabolism, which regulates vascular function. To assess the functional relevance of this finding, we examined the levels of arginase-1 protein and its activity in the hepatic EVs carrying the exosomal markers CD81 and CD63. Remarkably, the arginase activity was also detected in EVs isolated from the serum in vivo, and this vesicular activity significantly increased under liver-damaging conditions. Finally, we demonstrated that EVs secreted by hepatocytes inhibited the acetylcholine-induced relaxation in isolated pulmonary arteries, via an arginase-dependent mechanism. In summary, our study demonstrates that the hepatocyte-released EVs are metabolically active, affecting a number of serum metabolites involved in oxidative stress metabolism and the endothelial function.
En el siguiente artículo se analiza la evolución genética que sufre el capítulo “III. Riegos. Borsipa. Babilonia”, inserto en el bloque “Magos” de una obra inédita, fragmentaria y casi desconocida de ...Gabriel Miró: Figuras de Bethlem. Para ello, estudiamos las tres disposiciones manuscritas que se conservan de este apartado, teniendo en cuenta su organización textual, el uso de las fuentes empleadas para configurarlo y su contenido.
A new magnetic functionalized material based on graphene oxide magnetic nanoparticles named by us, M@GO-TS, was designed and characterized in order to develop a magnetic solid-phase extraction method ...(MSPE) to enrich inorganic and organic species of lead, mercury, and vanadium. A flow injection (FI) system was used to preconcentrate the metallic and organometallic species simultaneously, while the ultra-trace separation and determination of the selected species were achieved by high-performance liquid chromatography coupled to inductively coupled plasma mass spectrometry (HPLC-ICP MS). Therefore, preconcentration and separation/determination processes were automated and conducted separately. To the best of our knowledge, this is the first method combining an online MSPE and HPLC-ICP MS for multielemental speciation. Under the optimized conditions, the enrichment factor obtained for Pb
II
, trimethyllead (TML), Hg
II
, methylmercury (MetHg), and V
V
was 27. The calculated LOD for all studied species were as follows: 5 ng L
−1
, 20 ng L
−1
, 2 ng L
−1
, 10 ng L
−1
, and 0.4 ng L
−1
, respectively. The RSD values calculated with a solution containing 0.5 μg L
−1
of all species were between 2.5 and 4.5%. The developed method was validated by analyzing Certified Reference Materials TMDA 64.3 for total concentration and also by recovery analysis of the species in human urine from volunteers and a seawater sample collected in Málaga. The t statistical test showed no significant differences between the certified and found values for TMDA 64.3. All the recoveries obtained from spiked human urine and seawater samples were close to 100%. All samples were analyzed using external calibration. The developed method is sensitive and promising for routine monitoring of the selected species in environmental waters and biological samples.
Graphical abstract
En el siguiente artículo se describe cómo llevamos a cabo el análisis del proceso de génesis de Figuras de Bethlem, una obra inédita de Gabriel Miró. Para ello, explicamos cuáles fueron los tres ...aspectos relacionados con su desarrollo en los que decidimos centrarnos, teniendo en cuenta que el material que se conserva de este libro se limita a un grupo de manuscritos y unos artículos publicados en la prensa periódica: la transcripción y ordenación de los documentos y el estudio de aquellas fuentes que tuvieron una especial relevancia en su gestación. Finalmente, apuntamos algunas de las conclusiones a las que nos ha llevado nuestro trabajo.
L'article analyse les contributions que l'écrivaine espagnole Rosa Chacel publia dans la revue Hora de España (1937-1938). Pour ce faire, ses apports sont contextualisés, mis en relation avec les ...courants de pensée dominants dans le panorama européen et espagnol du début du XXe siècle et reliés à la question de l'interpénétration de concepts comme l'histoire, la culture, l'identité et l'idéologie.
Alzheimer's disease (AD) constitutes the most prominent form of dementia among elderly individuals worldwide. Disease modeling using murine transgenic mice was first initiated thanks to the discovery ...of heritable mutations in amyloid precursor protein (APP) and presenilins (PS) genes. However, due to the repeated failure of translational applications from animal models to human patients, along with the recent advances in genetic susceptibility and our current understanding on disease biology, these models have evolved over time in an attempt to better reproduce the complexity of this devastating disease and improve their applicability. In this review, we provide a comprehensive overview about the major pathological elements of human AD (plaques, tauopathy, synaptic damage, neuronal death, neuroinflammation and glial dysfunction), discussing the knowledge that available mouse models have provided about the mechanisms underlying human disease. Moreover, we highlight the pros and cons of current models, and the revolution offered by the concomitant use of transgenic mice and omics technologies that may lead to a more rapid improvement of the present modeling battery.
Bone marrow mesenchymal stem/stromal cells (BM-MSCs) are key components of the hematopoietic niche thought to have a direct role in leukemia pathogenesis. BM-MSCs from patients with acute myeloid ...leukemia (AML) have been poorly characterized due to disease heterogeneity. We report a functional, genetic, and immunological characterization of BM-MSC cultures from 46 AML patients, stratified by molecular/cytogenetics into low-risk (LR), intermediate-risk (IR), and high-risk (HR) subgroups. Stable MSC cultures were successfully established and characterized from 40 of 46 AML patients irrespective of the risk subgroup. AML-derived BM-MSCs never harbored tumor-specific cytogenetic/molecular alterations present in blasts, but displayed higher clonogenic potential than healthy donor (HD)-derived BM-MSCs. Although HD- and AML-derived BM-MSCs equally provided chemoprotection to AML cells in vitro, AML-derived BM-MSCs were more immunosuppressive/anti-inflammatory, enhanced suppression of lymphocyte proliferation, and diminished secretion of pro-inflammatory cytokines. Multivariate analysis revealed that the level of interleukin-10 produced by AML-derived BM-MSCs as an independent prognostic factor negatively affected overall survival. Collectively our data show that AML-derived BM-MSCs are not tumor related, but display functional differences contributing to therapy resistance and disease evolution.
•Functional, genetic, and immunological characterization of BM-MSCs from 46 AML patients•BM-MSCs never harbored tumor-specific cytogenetic/molecular alterations as in blasts•HD- and AML-BM-MSCs equally provided chemoprotection to AML cells in vitro•IL-10 produced by AML-BM-MSCs is a prognostic factor with negative impact on OS
In this article, Díaz de la Guardia and colleagues report a functional, genetic, and immunological characterization of BM-MSC cultures from 46 AML patients, stratified by molecular/cytogenetics into low-risk (LR), intermediate-risk (IR), and high-risk (HR) subgroups. BM-MSCs never harbored tumor-specific cytogenetic/molecular alterations present in blasts, and IL-10 produced by AML-derived BM-MSCs is an independent prognostic factor negatively impacting on overall survival.
El artículo analiza el contenido filosófico, ético e ideológico que late en «Herodes», el tercer bloque de contenidos de Figuras de Bethlem, una obra en su mayor parte inédita y, por ello poco ...conocida, de Gabriel Miró, en la que el soberano israelita encarna la negación de los valores planteados en las dos partes anteriores, la tierra y la humanidad, mediante su comportamiento egoísta, violento y manipulador.
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