Serum Homocysteine Levels in Patients with Retinal Vein Occlusion in a Spanish Population

Purpose Our aim was a) to compare serum Hcy levels in patients with RVO and population-based controls, and b) to evaluate whether hyperhomocysteinemia is a risk factor for RVO. Patients and methods Prospective case-control study of all patients diagnosed with RVO at a tertiary-care hospital, and age-and sex-matched controls taking part in a population-based prospective cohort in the same geographic area. Differences in serum Hcy between both groups were analyzed by a general linear model adjusted for age, body mass index (BMI), glomerular filtration rate (GFR), hypertension, dyslipidemia, diabetes, tobacco use and alcohol intake. Besides, we tested the relationship between hyperhomocysteinemia (> 15 µmol/L) and RVO, by a stepwise logistic regression analysis. Results RVO patients (n = 85) had a higher prevalence of hypertension (p = 0.002), diabetes (p = 0.008), and dyslipidemia (p = 0.04) than controls (n = 82). Adjusted median Hcy levels were higher in RVO patients (p < 0.0001). Adjusted OR for hyperhomocysteinemia were 4.4 (95% CI, 2.0-9.3; p < 0.0001) in the overall sample, and 2.6 (95% CI, 1.04-6.6; p = 0.04) and 6.1 (95% CI, 1.7-21.6; p = 0.005) for men and women, respectively. Conclusion Patients with RVO have higher serum Hcy levels than age- and sex-matched population-based controls. Hyperhomocysteinemia seems to be a risk factor for RVO, independent of age, BMI, GFR and classical vascular risk factors

Vitamin C enhances NF-κB-driven epigenomic reprogramming and boosts the immunogenic properties of dendritic cells

Dendritic cells (DCs), the most potent antigen-presenting cells, are necessary for effective activation of naïve T cells. DCs' immunological properties are modulated in response to various stimuli. Active DNA demethylation is crucial for DC differentiation and function. Vitamin C, a known cofactor of ten-eleven translocation (TET) enzymes, drives active demethylation. Vitamin C has recently emerged as a promising adjuvant for several types of cancer; however, its effects on human immune cells are poorly understood. In this study, we investigate the epigenomic and transcriptomic reprogramming orchestrated by vitamin C in monocyte-derived DC differentiation and maturation. Vitamin C triggers extensive demethylation at NF-κB/p65 binding sites, together with concordant upregulation of antigen-presentation and immune response-related genes during DC maturation. p65 interacts with TET2 and mediates the aforementioned vitamin C-mediated changes, as demonstrated by pharmacological inhibition. Moreover, vitamin C increases TNFβ production in DCs through NF-κB, in concordance with the upregulation of its coding gene and the demethylation of adjacent CpGs. Finally, vitamin C enhances DC's ability to stimulate the proliferation of autologous antigen-specific T cells. We propose that vitamin C could potentially improve monocyte-derived DC-based cell therapies

The HDAC7-TET2 epigenetic axis is essential during early B lymphocyte development

Correct B cell identity at each stage of cellular differentiation during B lymphocyte development is critically dependent on a tightly controlled epigenomic landscape. We previously identified HDAC7 as an essential regulator of early B cell development and its absence leads to a drastic block at the pro-B to pre-B cell transition. More recently, we demonstrated that HDAC7 loss in pro-B-ALL in infants associates with a worse prognosis. Here we delineate the molecular mechanisms by which HDAC7 modulates early B cell development. We find that HDAC7 deficiency drives global chromatin de-condensation, histone marks deposition and deregulates other epigenetic regulators and mobile elements. Specifically, the absence of HDAC7 induces TET2 expression, which promotes DNA 5-hydroxymethylation and chromatin de-condensation. HDAC7 deficiency also results in the aberrant expression of microRNAs and LINE-1 transposable elements. These findings shed light on the mechanisms by which HDAC7 loss or misregulation may lead to B cell-based hematological malignancies.FUNDING: Spanish Ministry of Economy and Competitiveness (MINECO) [SAF2017-87990-R]; Spanish Ministry of Science and Innovation (MICINN) [EUR2019-103835]; Josep Carreras Leukaemia Research Institute (IJC, Badalona, Barcelona); IDIBELL Research Institute (L’Hospitalet de Llobregat, Barcelona); A.M. is funded by the Spanish Ministry of Science, Innovation and Universities, which is part of the Agencia Estatal de Investigacion (AEI) [PRE2018-083183] (cofunded by the European Social Fund]; OdB. was funded by a Juan de la Cierva Formacion Fellowship from the Spanish Ministry of Science, Innovation and Universities [FJCI-2017-32430]; Postdoctoral Fellowship from the Asociacion Española Contra el Cáncer (AECC) ´ Foundation [POSTD20024DEBA]; B.M. is awardee of the Ayudas para la formacion del profesorado universitario [FPU18/00755, Ministerio de Universidades]; B.M.J. is funded by La Caixa Banking Foundation Junior Leader project [LCF/BQ/PI19/11690001]; FEDER/Spanish Ministry of Science and Innovation [RTI2018-094788-A-I00]; L.T.-D. is funded by the FPI Fellowship [PRE2019- 088005]; L.R. is funded by an AGAUR FI fellowship [2019FI-B00017]; J.L.S. is funded by ISCIII [CP19/00176], co-funded by ESF, ‘Investing in your future’ and the Spanish Ministry of Science, Innovation and Universities [PID2019-111243RA-I00]. CRG acknowledge the support of the Spanish Ministry of Science and Innovation through the Centro de Excelencia Severo Ochoa (CEX2020-001049- S, MCIN/AEI /10.13039/501100011033). Funding for open access charge: Spanish Ministry of Science, Innovation and Universities (MICIU) [SAF2017-87990-R, EUR2019-103835].ACKNOWLEDGEMENTS: We thank CERCA Programme/Generalitat de Catalunya and the Josep Carreras Foundation for institutional support. We thank Dr Eric Olson (UT Southwestern Medical Center, Dallas, TX, USA) and Dr Michael Reth (Max Planck Institute of Immunology and Epigenetics, Freiburg, Germany) for kindly providing the Hdac7loxp/- and mb1- Cre mice, respectively. We thank Luc´ıa Fanlo for her assistance in technical issues and bioinformatics analysis of ChIP-seq and ATAC-seq experiments. We thank Alberto Bueno for deep analysis of our RNA-seq and hMeDIP-seq data, in order to assess the presence of differentially expressed dsRNA species. We also thank Drs Pura Munoz ˜ Canoves and Tokameh Mahmoudi for helpful comments on ´ the manuscript

Dissecting TET2 Regulatory Networks in Blood Differentiation and Cancer

Cytosine methylation (5mC) of CpG is the major epigenetic modification of mammalian DNA, playing essential roles during development and cancer. Although DNA methylation is generally associated with transcriptional repression, its role in gene regulation during cell fate decisions remains poorly understood. DNA demethylation can be either passive or active when initiated by TET dioxygenases. During active demethylation, transcription factors (TFs) recruit TET enzymes (TET1, 2, and 3) to specific gene regulatory regions to first catalyze the oxidation of 5mC to 5-hydroxymethylcytosine (5hmC) and subsequently to higher oxidized cytosine derivatives. Only TET2 is frequently mutated in the hematopoietic system from the three TET family members. These mutations initially lead to the hematopoietic stem cells (HSCs) compartment expansion, eventually evolving to give rise to a wide range of blood malignancies. This review focuses on recent advances in characterizing the main TET2-mediated molecular mechanisms that activate aberrant transcriptional programs in blood cancer onset and development. In addition, we discuss some of the key outstanding questions in the field

Supports used for face-mount photographs and digital prints. Analytical and structural characterization

There is a new tendency among photographic and digital artists to exhibit their works without frames, using a new photographic support system which is known as face-mounting. It presents a complex assembly process, and the supports are usually multilayer. In addition, materials of dif-ferent composition and thickness are used that can affect to the image properties in the long-term behavior. For that, it is necessary to characterize these new supports to identify the exact nature of its componentsDepto. de Pintura y Conservación-RestauraciónFac. de Bellas ArtesTRUEpu

NOX2 control over energy metabolism plays a role in acute myeloid leukaemia prognosis and survival

Carla Ijurko and Marta Romo-González were recipient of pre-doctoral fellowships from the Regional Government of Castile and Leon, Spain and ERDF funds. Angel Hernández-Hernández lab is supported by Spanish Government (PID2020-117692RB-I00), Regional Government of Castile & Leon (SA077P20) and Ramón Areces Foundation (CIV17A2822). Jose Luis Sardina lab is supported by Instituto de Salud Carlos III (CP19/00176). NMR analyses were carried out by the GEMELI platform, supported by the program IRICE from the Auvergne-Rhône-Alpes region and MSDAvenir funds (project ERiCAN). We thank Dr. I. García-Tuñón for his help with the CRISPR-CAS9 technique.Carla Ijurko and Marta Romo-González were recipient of pre-doctoral fellowships from the Regional Government of Castile and Leon, Spain and ERDF funds. Angel Hernández-Hernández lab is supported by Spanish Government (PID2020-117692RB-I00), Regional Government of Castile & Leon (SA077P20) and Ramón Areces Foundation (CIV17A2822). Jose Luis Sardina lab is supported by Instituto de Salud Carlos III (CP19/00176). NMR analyses were carried out by the GEMELI platform, supported by the program IRICE from the Auvergne-Rhône-Alpes region and MSDAvenir funds (project ERiCAN).Acute myeloid leukaemia (AML) is a highly heterogeneous disease, however the therapeutic approaches have hardly changed in the last decades. Metabolism rewiring and the enhanced production of reactive oxygen species (ROS) are hallmarks of cancer. A deeper understanding of these features could be instrumental for the development of specific AML-subtypes treatments. NADPH oxidases (NOX), the only cellular system specialised in ROS production, are also involved in leukemic metabolism control. NOX2 shows a variable expression in AML patients, so patients can be classified based on such difference. Here we have analysed whether NOX2 levels are important for AML metabolism control. The lack of NOX2 in AML cells slowdowns basal glycolysis and oxidative phosphorylation (OXPHOS), along with the accumulation of metabolites that feed such routes, and a sharp decrease of glutathione. In addition, we found changes in the expression of 725 genes. Among them, we have discovered a panel of 30 differentially expressed metabolic genes, whose relevance was validated in patients. This panel can segregate AML patients according to CYBB expression, and it can predict patient prognosis and survival. In summary, our data strongly support the relevance of NOX2 for AML metabolism, and highlights the potential of our discoveries in AML prognosis

The HDAC7-TET2 epigenetic axis is essential during early B lymphocyte development

Spanish Ministry of Economy and Competitiveness (MINECO) [SAF2017-87990-R]; Spanish Ministry of Science and Innovation (MICINN) [EUR2019-103835]; Josep Carreras Leukaemia Research Institute (IJC, Badalona, Barcelona); IDIBELL Research Institute (L'Hospitalet de Llobregat, Barcelona); A.M. is funded by the SpanishMinistry of Science, Innovation and Universities, which is part of the Agencia Estatal de Investigación (AEI) [PRE2018- 083183] (cofunded by the European Social Fund]; OdB. was funded by a Juan de la Cierva Formación Fellowship from the Spanish Ministry of Science, Innovation and Universities [FJCI-2017-32430]; Postdoctoral Fellowship from the Asociación Española Contra el Cáncer (AECC) Foundation [POSTD20024DEBA]; B.M. is awardee of the Ayudas para la formación del profesorado universitario [FPU18/00755, Ministerio de Universidades]; B.M.J. is funded by La Caixa Banking Foundation Junior Leader project [LCF/BQ/PI19/11690001]; FEDER/SpanishMinistry of Science and Innovation [RTI2018-094788-A-I00]; L.T.-D. is funded by the FPI Fellowship [PRE2019- 088005]; L.R. is funded by an AGAUR FI fellowship [2019FI-B00017]; J.L.S. is funded by ISCIII [CP19/00176], co-funded by ESF, 'Investing in your future' and the Spanish Ministry of Science, Innovation and Universities [PID2019-111243RA-I00]. CRG acknowledge the support of the SpanishMinistry of Science and Innovation through the Centro de Excelencia Severo Ochoa (CEX2020-001049- S, MCIN/AEI /10.13039/501100011033). Funding for open access charge: Spanish Ministry of Science, Innovation and Universities (MICIU) [SAF2017-87990-R, EUR2019-103835].Correct B cell identity at each stage of cellular differentiation during B lymphocyte development is critically dependent on a tightly controlled epigenomic landscape. We previously identified HDAC7 as an essential regulator of early B cell development and its absence leads to a drastic block at the pro-B to pre-B cell transition. More recently, we demonstrated that HDAC7 loss in pro-B-ALL in infants associates with a worse prognosis. Here we delineate the molecular mechanisms by which HDAC7 modulates early B cell development. We find that HDAC7 deficiency drives global chromatin de-condensation, histone marks deposition and deregulates other epigenetic regulators and mobile elements. Specifically, the absence of HDAC7 induces TET2 expression, which promotes DNA 5-hydroxymethylation and chromatin de-condensation. HDAC7 deficiency also results in the aberrant expression of microRNAs and LINE-1 transposable elements. These findings shed light on the mechanisms by which HDAC7 loss or misregulation may lead to B cell-based hematological malignancies

NOX2 control over energy metabolism plays a role in acute myeloid leukaemia prognosis and survival

International audienceAcute myeloid leukaemia (AML) is a highly heterogeneous disease, however the therapeutic approaches have hardly changed in the last decades. Metabolism rewiring and the enhanced production of reactive oxygen species (ROS) are hallmarks of cancer. A deeper understanding of these features could be instrumental for the development of specific AML-subtypes treatments. NADPH oxidases (NOX), the only cellular system specialised in ROS production, are also involved in leukemic metabolism control. NOX2 shows a variable expression in AML patients, so patients can be classified based on such difference. Here we have analysed whether NOX2 levels are important for AML metabolism control. The lack of NOX2 in AML cells slowdowns basal glycolysis and oxidative phosphorylation (OXPHOS), along with the accumulation of metabolites that feed such routes, and a sharp decrease of glutathione. In addition, we found changes in the expression of 725 genes. Among them, we have discovered a panel of 30 differentially expressed metabolic genes, whose relevance was validated in patients. This panel can segregate AML patients according to CYBB expression, and it can predict patient prognosis and survival. In summary, our data strongly support the relevance of NOX2 for AML metabolism, and highlights the potential of our discoveries in AML prognosis