The DNA methylation landscape of hematological malignancies : an update

Altres ajuts: the Cellex Foundation; and la Caixa Banking Foundation (LCF/PR/GN18/51140001).The rapid advances in high-throughput sequencing technologies have made it more evident that epigenetic modifications orchestrate a plethora of complex biological processes. During the last decade, we have gained significant knowledge about a wide range of epigenetic changes that crucially contribute to some of the most aggressive forms of leukemia, lymphoma, and myelodysplastic syndromes. DNA methylation is a key epigenetic player in the abnormal initiation, development, and progression of these malignancies, often acting in synergy with other epigenetic alterations. It also contributes to the acquisition of drug resistance. In this review, we summarize the role of DNA methylation in hematological malignancies described in the current literature. We discuss in detail the dual role of DNA methylation in normal and aberrant hematopoiesis, as well as the involvement of this type of epigenetic change in other aspects of the disease. Finally, we present a comprehensive overview of the main clinical implications, including a discussion of the therapeutic strategies that regulate or reverse aberrant DNA methylation patterns in hematological malignancies, including their combination with (chemo)immunotherapy

Acid/base flow battery environmental and economic performance based on its potential service to renewables support

An innovative technology, called Acid Base Flow Battery (AB-FB), has been developed to overcome the intermittent supply of wind and solar electricity generation. It stores electrical energy using pH and salinity differences in the water and compared with other battery technologies, such as Vanadium Redox Flow Battery (VRFB), the new system is expected to be safer, more sustainable and to become a cost competitive option. To provide a deeper knowledge of the new system potentials, in this research, Life Cycle studies under cradle to grave approach have been carried out to assess the environmental and economic performance of 1 MW/6 MWh AB-FB system. Furthermore, 1 MW/6 MWh VRFB has been considered as the reference case. According to the comparative analysis, the AB-FB system exhibited the best environmental and economic performance, placing the AB-FB system as the most sustainable technology. In terms of environmental impacts related to the three process stages, the AB-FB system operation stage yielded the most relevant environmental burden, mostly attributed to energy losses due to the system efficiency. Manufacturing of the AB-FB system was the second stage with the more significant quote to the total environmental burden. Particularly, impacts were related to the power subsystem components being steel, copper, polyethylene and polyvinylchloride identified as the key materials responsible of this tendency. In contrast, the VRFB manufacturing was the most relevant process stage in terms of environmental implications. The energy subsystem was responsible for this tendency due to the vanadium-based electrolyte production related impacts. This component of the VRFB system was also its main constrains in terms of costs. The VRFB investment cost (339 €/kWh) was almost twice the AB-FB one (184 €/kWh), mostly affected by the VRFB electrolyte cost production

Refinement of computational identification of somatic copy number alterations using DNA methylation microarrays illustrated in cancers of unknown primary

High-throughput genomic technologies are increasingly used in personalized cancer medicine. However, computational tools to maximize the use of scarce tissues combining distinct molecular layers are needed. Here we present a refined strategy, based on the R-package 'conumee', to better predict somatic copy number alterations (SCNA) from deoxyribonucleic acid (DNA) methylation arrays. Our approach, termed hereafter as 'conumee-KCN', improves SCNA prediction by incorporating tumor purity and dynamic thresholding. We trained our algorithm using paired DNA methylation and SNP Array 6.0 data from The Cancer Genome Atlas samples and confirmed its performance in cancer cell lines. Most importantly, the application of our approach in cancers of unknown primary identified amplified potentially actionable targets that were experimentally validated by Fluorescence in situ hybridization and immunostaining, reaching 100% specificity and 93.3% sensitivity

The DNA methylation landscape of hematological malignancies : an update

Altres ajuts: the Cellex Foundation; and la Caixa Banking Foundation (LCF/PR/GN18/51140001).The rapid advances in high-throughput sequencing technologies have made it more evident that epigenetic modifications orchestrate a plethora of complex biological processes. During the last decade, we have gained significant knowledge about a wide range of epigenetic changes that crucially contribute to some of the most aggressive forms of leukemia, lymphoma, and myelodysplastic syndromes. DNA methylation is a key epigenetic player in the abnormal initiation, development, and progression of these malignancies, often acting in synergy with other epigenetic alterations. It also contributes to the acquisition of drug resistance. In this review, we summarize the role of DNA methylation in hematological malignancies described in the current literature. We discuss in detail the dual role of DNA methylation in normal and aberrant hematopoiesis, as well as the involvement of this type of epigenetic change in other aspects of the disease. Finally, we present a comprehensive overview of the main clinical implications, including a discussion of the therapeutic strategies that regulate or reverse aberrant DNA methylation patterns in hematological malignancies, including their combination with (chemo)immunotherapy

Antitumor Activity of the Novel BTK Inhibitor TG-1701 Is Associated with Disruption of Ikaros Signaling in Patients with B-cell Non-Hodgkin Lymphoma

Despite the remarkable activity of BTK inhibitors (BTKi) in relapsed B-cell non-Hodgkin lymphoma (B-NHL), no clinically-relevant biomarker has been associated to these agents so far. The relevance of phosphoproteomic profiling for the early identification of BTKi responders remains underexplored. A set of six clinical samples from an ongoing phase I trial dosing patients with chronic lymphocytic leukemia (CLL) with TG-1701, a novel irreversible and highly specific BTKi, were characterized by phosphoproteomic and RNA sequencing (RNA-seq) analysis. The activity of TG-1701 was evaluated in a panel of 11 B-NHL cell lines and mouse xenografts, including two NF-κB- and BTK C481S -driven BTKi-resistant models. Biomarker validation and signal transduction analysis were conducted through real-time PCR, Western blot analysis, immunostaining, and gene knockout (KO) experiments. A nonsupervised, phosphoproteomic-based clustering did match the early clinical outcomes of patients with CLL and separated a group of "early-responders" from a group of "late-responders." This clustering was based on a selected list of 96 phosphosites with Ikaros-pSer442/445 as a potential biomarker for TG-1701 efficacy. TG-1701 treatment was further shown to blunt Ikaros gene signature, including YES1 and MYC, in early-responder patients as well as in BTKi-sensitive B-NHL cell lines and xenografts. In contrast, Ikaros nuclear activity and signaling remained unaffected by the drug in vitro and in vivo in late-responder patients and in BTK C481S, BTK KO, and noncanonical NF-κB models. These data validate phosphoproteomic as a valuable tool for the early detection of response to BTK inhibition in the clinic, and for the determination of drug mechanism of action

Loss-of-function mutations in ATP6AP1 and ATP6AP2 in granular cell tumors

Granular cell tumors (GCTs) are rare tumors that arise in multiple anatomical locations. Here, the authors investigate the genomics of GCTs, finding inactivating somatic mutations in ATP6AP1 or ATP6AP2 in 72% of the 82 GCTs analyzed. In vitro manipulation of these genes recapitulated GCT phenotypes in cellular models

Hommage à Robert Jammes

Né en 1927, Robert Jammes a été élève de l'École Normale Supérieure de la rue d'Ulm. Après quelques années passées dans les universités de Montpellier et de Grenoble, il s'est fixé à l'université de Toulouse-Le Mirail, où il a enseigné entre 1965 et 1987. Créateur et directeur d'une équipe de recherche associée au CNRS (LESO : Littérature Espagnole du Siècle d'Or), il a fondé en 1978 la revue Criticón, dont il continue d'assurer la direction, et a été, en 1985, à l'origine de l'Association internationale « Siècle d'Or ». Parmi les travaux de ce spécialiste de la poésie du Siècle d'Or, on retiendra : - ses Études sur l'œuvre poétique de don Luis de Góngora y Argote (1967), traduites en espagnol en 1987, sous le titre de La obra poética de Góngora ; - ses éditions des oeuvres de Luis de Góngora : Letrillas (édition critique française de 1963 ; édition espagnole de 1980) ; Las firmezas de Isabela (1984) ; Soledades (1994) ; - son anthologie pionnière de poèmes érotiques du Siècle d'Or, Floresta de poesías eróticas del Siglo de Oro, avec la collaboration de Pierre Alzieu et d'Yvan Lissorgues (édition française de 1975 ; édition espagnole de 1984, sous le titre de Poesía erótica del Siglo de Oro) ; - son élaboration d'outils destinés aux chercheurs et aux étudiants : glossaire, manuel de traduction, notes pour l'édition de textes du Siècle d'Or..

Homologous recombination DNA repair defects in PALB2-associated breast cancers

Abstract Mono-allelic germline pathogenic variants in the Partner And Localizer of BRCA2 (PALB2) gene predispose to a high-risk of breast cancer development, consistent with the role of PALB2 in homologous recombination (HR) DNA repair. Here, we sought to define the repertoire of somatic genetic alterations in PALB2-associated breast cancers (BCs), and whether PALB2-associated BCs display bi-allelic inactivation of PALB2 and/or genomic features of HR-deficiency (HRD). Twenty-four breast cancer patients with pathogenic PALB2 germline mutations were analyzed by whole-exome sequencing (WES, n = 16) or targeted capture massively parallel sequencing (410 cancer genes, n = 8). Somatic genetic alterations, loss of heterozygosity (LOH) of the PALB2 wild-type allele, large-scale state transitions (LSTs) and mutational signatures were defined. PALB2-associated BCs were found to be heterogeneous at the genetic level, with PIK3CA (29%), PALB2 (21%), TP53 (21%), and NOTCH3 (17%) being the genes most frequently affected by somatic mutations. Bi-allelic PALB2 inactivation was found in 16 of the 24 cases (67%), either through LOH (n = 11) or second somatic mutations (n = 5) of the wild-type allele. High LST scores were found in all 12 PALB2-associated BCs with bi-allelic PALB2 inactivation sequenced by WES, of which eight displayed the HRD-related mutational signature 3. In addition, bi-allelic inactivation of PALB2 was significantly associated with high LST scores. Our findings suggest that the identification of bi-allelic PALB2 inactivation in PALB2-associated BCs is required for the personalization of HR-directed therapies, such as platinum salts and/or PARP inhibitors, as the vast majority of PALB2-associated BCs without PALB2 bi-allelic inactivation lack genomic features of HRD