Publicaciones científicas

Se han encontrado 1572 publicaciones con los criterios indicados.
Chen-Jen Hsu, Oliver Meers, Marcus Buschbeck, Florian H. Heidel

The Role of MacroH2A Histone Variants in Cancer

Cancers 2021, 13(12), 3003 15 Jun 2021, . Epub 15 Jun 2021
The epigenome regulates gene expression and provides a molecular memory of cellular events. A growing body of evidence has highlighted the importance of epigenetic regulation in physiological tissue homeostasis and malignant transformation. Among epigenetic mechanisms, the replacement of replication-coupled histones with histone variants is the least understood. Due to differences in protein sequence and genomic distribution, histone variants contribute to the plasticity of the epigenome. Here, we focus on the family of macroH2A histone variants that are particular in having a tripartite structure consisting of a histone fold, an intrinsically disordered linker and a globular macrodomain. We discuss how these domains mediate different molecular functions related to chromatin architecture, transcription and DNA repair. Dysregulated expression of macroH2A histone variants has been observed in different subtypes of cancer and has variable prognostic impact, depending on cellular context and molecular background. We aim to provide a concise review regarding the context- and isoform-dependent contributions of macroH2A histone variants to cancer development and progression.
Rossi M, Meggendorfer M, Zampini M, Tettamanti M, Riva E, Travaglino E, Bersanelli M, Mandelli S, Galbussera AA, Mosca E, Saba E, Chiereghin C, Manes N, Milanesi C, Ubezio M, Morabito L, Peano C, Soldà G, Asselta R, Duga S, Selmi C, De Santis M, Malik K, Maggioni G, Bicchieri ME, Campagna A, Tentori CA, Russo A, Civilini E, Allavena P, Piazza R, Corrao G, Sala C, Termanini A, Giordano L, Detoma P, Malabaila A, Sala L, Rosso S, Zanetti R, Saitta C, Riva E, Condorelli G, Passamonti F, Santoro A, Sole F, Platzbecker U, Fenaux P, Bolli N, Castellani G, Kern W, Vassiliou G, Haferlach T, Lucca U, Della Porta MG

Clinical relevance of clonal hematopoiesis in the oldest-old population.

Blood 14 Jun 2021, . Epub 14 Jun 2021
Clonal hematopoiesis of indeterminate potential (CHIP) is associated with increased risk of cancers and inflammation-related diseases. This phenomenon becomes very common in oldest-old individuals, in whom the implications of CHIP are not well defined. We performed a mutational screening in 1794 oldest-old individuals enrolled in two population-based studies and investigate the relationships between CHIP and associated pathologies. Clonal mutations were observed in one third of oldest-old individuals and were associated with reduced survival. Mutations in JAK2 and splicing genes, multiple mutations (DNMT3A, TET2, ASXL1 with additional genetic lesions) and variant allele frequency ≥0.096 had positive predictive value for myeloid neoplasms. Combining mutation profiles with abnormalities in red blood cell indices improved the ability of myeloid neoplasm prediction. On this basis, we defined a predictive model that identifies 3 risk groups with different probabilities of developing myeloid neoplasms. Mutations in DNMT3A, TET2, ASXL1 or JAK2 (most occurring as single lesion) were associated with coronary heart disease and rheumatoid arthritis. Cytopenia was a common finding in oldest-old population, the underlying cause remaining unexplained in 30% of cases. Among individuals with unexplained cytopenia, the presence of highly-specific mutation patterns was associated with myelodysplastic-like phenotype and a probability of survival comparable to that of myeloid neoplasms. Accordingly, 7.5% of oldest-old subjects with cytopenia had presumptive evidence of myeloid neoplasm. In conclusion, specific mutational patterns define different risk of developing myeloid neoplasms vs. inflammatory-associated diseases in oldest-old population. In individuals with unexplained cytopenia, mutational status may identify those subjects with presumptive evidence of myeloid neoplasms.
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Palomo L, Santiago-Vacas E, Pascual-Figal D, Fuster JJ, Solé F, Bayés-Genís A

Prevalence and characteristics of clonal hematopoiesis in heart failure.

Rev Esp Cardiol (Engl Ed) 9 Jun 2021, . Epub 9 Jun 2021
No abstract available.
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Genescà E, Morgades M, González-Gil C, Fuster-Tormo F, Haferlach C, Meggendorfer M, Montesinos P, Barba P, Gil C, Coll R, Moreno MJ, Martínez-Carballeira D, García-Cadenas I, Vives S, Ribera J, González-Campos J, Díaz-Beya M, Mercadal S, Artola MT, Cladera A, Tormo M, Bermúdez A, Vall-Llovera F, Martínez-Sánchez P, Amigo ML, Monsalvo S, Novo A, Cervera M, García-Guiñon A, Ciudad J, Cervera J, Hernández-Rivas JM, Granada I, Haferlach T, Orfao A, Solé F, Ribera JM

Adverse prognostic impact of complex karyotype (≥3 cytogenetic alterations) in adult T-cell acute lymphoblastic leukemia (T-ALL).

Leuk Res 8 Jun 2021, 109 106612. Epub 8 Jun 2021
The potential prognostic value of conventional karyotyping in adult T-cell acute lymphoblastic leukemia (T-ALL) remains an open question. We hypothesized that a modified cytogenetic classification, based on the number and type of cytogenetic abnormalities, would allow the identification of high-risk adult T-ALL patients. Complex karyotype defined by the presence of ≥3 cytogenetic alterations identified T-ALL patients with poor prognosis in this study. Karyotypes with ≥3 abnormalities accounted for 16 % (22/139) of all evaluable karyotypes, corresponding to the largest poor prognosis cytogenetic subgroup of T-ALL identified so far. Patients carrying karyotypes with ≥3 cytogenetic alterations showed a significantly inferior response to therapy, and a poor outcome in terms of event-free survival (EFS), overall survival (OS) and cumulative incidence of relapse (CIR), independently of other baseline characteristics and the end-induction minimal residual disease (MRD) level. Additional molecular analyses of patients carrying ≥3 cytogenetic alterations showed a unique molecular profile that could contribute to understand the underlying molecular mechanisms of resistance and to evaluate novel targeted therapies (e.g. IL7R directed) with potential impact on outcome of adult T-ALL patients.
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Castro P, Palomo M, Moreno-Castaño AB, Fernández S, Torramadé-Moix S, Pascual G, Martinez-Sanchez J, Richardson E, Téllez A, Nicolas JM, Carreras E, Richardson PG, Badimon JJ, Escolar G, Diaz-Ricart M

Is the Endothelium the Missing Link in the Pathophysiology and Treatment of COVID-19 Complications?

Cardiovasc Drugs Ther 7 Jun 2021, . Epub 7 Jun 2021
Patients with COVID-19 present a wide spectrum of disease severity, from asymptomatic cases in the majority to serious disease leading to critical care and even death. Clinically, four different scenarios occur within the typical disease timeline: first, an incubation and asymptomatic period; second, a stage with mild symptoms due mainly to the virus itself; third, in up to 20% of the patients, a stage with severe symptoms where a hyperinflammatory response with a cytokine storm driven by host immunity induces acute respiratory distress syndrome; and finally, a post-acute sequelae (PASC) phase, which present symptoms that can range from mild or annoying to actually quite incapacitating. Although the most common manifestation is acute respiratory failure of the lungs, other organs are also frequently involved. The clinical manifestations of the COVID-19 infection support a key role for endothelial dysfunction in the pathobiology of this condition. The virus enters into the organism via its interaction with angiotensin-converting enzyme 2-receptor that is present prominently in the alveoli, but also in endothelial cells, which can be directly infected by the virus. Cytokine release syndrome can also drive endothelial damage independently. Consequently, a distinctive feature of SARS-CoV-2 infection is vascular harm, with severe endothelial injury, widespread thrombosis, microangiopathy, and neo-angiogenesis in response to endothelial damage. Therefore, endothelial dysfunction seems to be the pathophysiological substrate for severe COVID-19 complications. Biomarkers of endothelial injury could constitute strong indicators of disease progression and severity. In addition, the endothelium could represent a very attractive target to both prevent and treat these complications. To establish an adequate therapy, the underlying pathophysiology and corresponding clinical stage should be clearly identified. In this review, the clinical features of COVID-19, the central role of the endothelium in COVID-19 and in other pathologies, and the potential of specific therapies aimed at protecting the endothelium in COVID-19 patients are addressed.
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Claudia Vivori, Panagiotis Papasaikas, Ralph Stadhouders, Bruno Di Stefano, Anna Ribó Rubio, Clara Berenguer Balaguer, Serena Generoso, Anna Mallol, José Luis Sardina, Bernhard Payer, Thomas Graf, Juan Valcárcel

Dynamics of alternative splicing during somatic cell reprogramming reveals functions for RNA-binding proteins CPSF3, hnRNP UL1, and TIA1

Genome Biol 22, 171 (2021) 3 Jun 2021, .
BACKGROUND Somatic cell reprogramming is the process that allows differentiated cells to revert to a pluripotent state. In contrast to the extensively studied rewiring of epigenetic and transcriptional programs required for reprogramming, the dynamics of post-transcriptional changes and their associated regulatory mechanisms remain poorly understood. Here we study the dynamics of alternative splicing changes occurring during efficient reprogramming of mouse B cells into induced pluripotent stem (iPS) cells and compare them to those occurring during reprogramming of mouse embryonic fibroblasts. RESULTS We observe a significant overlap between alternative splicing changes detected in the two reprogramming systems, which are generally uncoupled from changes in transcriptional levels. Correlation between gene expression of potential regulators and specific clusters of alternative splicing changes enables the identification and subsequent validation of CPSF3 and hnRNP UL1 as facilitators, and TIA1 as repressor of mouse embryonic fibroblasts reprogramming. We further find that these RNA-binding proteins control partially overlapping programs of splicing regulation, involving genes relevant for developmental and morphogenetic processes. CONCLUSIONS Our results reveal common programs of splicing regulation during reprogramming of different cell types and identify three novel regulators of this process and their targets.
Antonio Gómez, Miguel L. Pato, Luis Bujanda, Núria Sala, Osmel Companioni, Ángel Cosme, Martina Tufano, David J. Hanly, Nadia García, José Miguel Sanz-Anquela, Javier P. Gisbert, Consuelo López, José Ignacio Elizalde, Miriam Cuatrecasas, Victoria Andreu, María José Paules, María Dolores Martín-Arranz, Luis Ortega, Elvira Poves, Jesús Barrio, María Ángeles Torres, Guillermo Muñoz, Ángel Ferrández, María José Ramírez-Lázaro, Sergio Lario, Carlos A González, Manel Esteller, María Berdasco

Follow-Up Study Confirms the Presence of Gastric Cancer DNA Methylation Hallmarks in High-Risk Precursor Lesions

Cancers 2021, 13(11), 2760; 2 Jun 2021, .
To adopt prevention strategies in gastric cancer, it is imperative to develop robust biomarkers with acceptable costs and feasibility in clinical practice to stratified populations according to risk scores. With this aim, we applied an unbiased genome-wide CpG methylation approach to a discovery cohort composed of gastric cancer (n = 24), and non-malignant precursor lesions (n = 64). Then, candidate-methylation approaches were performed in a validation cohort of precursor lesions obtained from an observational longitudinal study (n = 264), with a 12-year follow-up to identify repression or progression cases. H. pylori stratification and histology were considered to determine their influence on the methylation dynamics. As a result, we ascertained that intestinal metaplasia partially recapitulates patterns of aberrant methylation of intestinal type of gastric cancer, independently of the H. pylori status. Two epigenetically regulated genes in cancer, RPRM and ZNF793, consistently showed increased methylation in intestinal metaplasia with respect to earlier precursor lesions. In summary, our result supports the need to investigate the practical utilities of the quantification of DNA methylation in candidate genes as a marker for disease progression. In addition, the H. pylori-dependent methylation in intestinal metaplasia suggests that pharmacological treatments aimed at H. pylori eradication in the late stages of precursor lesions do not prevent epigenome reprogramming toward a cancer signature.
Mhibik M, Gaglione EM, Eik D, Kendall EK, Blackburn A, Keyvanfar K, Baptista MJ, Ahn IE, Sun C, Qi J, Rader C, Wiestner A

BTK Inhibitors, Irrespective of ITK Inhibition, Increase Efficacy of a CD19/CD3 Bispecific Antibody in CLL.

Blood 27 May 2021, . Epub 27 May 2021
Bruton Tyrosine Kinase inhibitors (BTKis) are a preferred treatment for patients with chronic lymphocytic leukemia (CLL). Indefinite therapy with BTKis, while effective, presents clinical challenges. Combination therapy can deepen responses, shorten treatment duration, and possibly prevent or overcome drug resistance. We previously reported on a CD19/CD3 bispecific antibody (bsAb) that recruits autologous T cell cytotoxicity against CLL cells in vitro. Compared to observations with samples from treatment-naïve patients, T cells from patients being treated with ibrutinib expanded more rapidly and exerted superior cytotoxic activity in response to the bsAb. In addition to BTK, ibrutinib also inhibits IL2 inducible T cell Kinase (ITK). In contrast, acalabrutinib, does not inhibit ITK. Whether ITK inhibition contributes to the observed immune effects is unknown. To better understand how BTKis modulate T-cell function and cytotoxic activity, we cultured peripheral blood mononuclear cells (PBMCs) from BTKi-naive, and ibrutinib- or acalabrutinib-treated CLL patients with CD19/CD3 bsAb in vitro. T-cell expansion, activation, differentiation, and cytotoxicity were increased in PBMCs from patients on treatment with either BTKi compared to that observed for BKTi-naïve patients. BTKi therapy transcriptionally downregulated immunosuppressive effectors expressed by CLL cells, including CTLA-4 and CD200. CTLA-4 blockade with ipilimumab in vitro increased the cytotoxic activity of the bsAb in BTKi-naïve but not BTKi-treated PBMCS. Taken together, BTKis enhance bsAb induced cytotoxicity by relieving T cells of immunosuppressive restraints imposed by CLL cells. The benefit of combining bsAb immunotherapy with BTKis needs to be confirmed in clinical trials.
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Maximilian Lassi, Archana Tomar, Gemma Comas-Armangué, Rebekka Vogtmann
Dorieke J. Dijkstra, David Corujo, Raffaele Gerlini, Jonatan Darr, Fabienne Scheid, Jan Rozman, Antonio Aguilar-Pimentel, Omry Koren, Marcus Buschbeck, Helmut Fuchs, Susan Marschall, Valerie Gailus-Durner, Martin Hrabe de Angelis, Torsten Plösch, Alexandra Gellhaus and 
Raffaele Teperino

Disruption of paternal circadian rhythm affects metabolic health in male offspring via nongerm cell factors

Science Advances 26 May 2021: Vol. 7, no. 22, eabg6424 26 May 2021, .
Circadian rhythm synchronizes each body function with the environment and regulates physiology. Disruption of normal circadian rhythm alters organismal physiology and increases disease risk. Recent epidemiological data and studies in model organisms have shown that maternal circadian disruption is important for offspring health and adult phenotypes. Less is known about the role of paternal circadian rhythm for offspring health. Here, we disrupted circadian rhythm in male mice by night-restricted feeding and showed that paternal circadian disruption at conception is important for offspring feeding behavior, metabolic health, and oscillatory transcription. Mechanistically, our data suggest that the effect of paternal circadian disruption is not transferred to the offspring via the germ cells but initiated by corticosterone-based parental communication at conception and programmed during in utero development through a state of fetal growth restriction. These findings indicate paternal circadian health at conception as a newly identified determinant of offspring phenotypes.
Tian TV, Sardina JL

Uncovering Sequence-Specific Transcription Factors Interacting with TET2.

Methods Mol Biol 20 May 2021, 2272 239-250.
Ten-eleven Translocation (TET) enzymes are methylcytosine dioxygenases that are involved in multiple cellular processes, including cellular differentiation and forced cell fate conversions. However, deciphering the molecular mechanisms underlying epigenetic control exerted by these proteins has been hampered by technical limitations, which prevent the identification of essential partners that work in concert with these enzymes to modulate gene expression. In this chapter, we provide a comprehensive description of cutting-edge methods designed to assess physical interactions between sequence-specific transcription factors and the TET2 enzyme.
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