Publicació científica

S'han trobat 1577 publicacions amb els criteris indicats.
Patricia Garcia, Rita Fernandez-Hernandez, Ana Cuadrado, Ignacio Coca, Antonio Gomez, Maria Maqueda, Ana Latorre-Pellicer, Beatriz Puisac, Feliciano J. Ramos, Juan Sandoval, Esteller, Manel, Jose Luis Mosquera, Jairo Rodriguez, J. Pié, Ana Losada and Ethel Queralt

Disruption of NIPBL/Scc2 in Cornelia de Lange Syndrome provokes cohesin genome-wide redistribution with an impact in the transcriptome

Nature Communications 27 Jul 2021, 12, 4551 . Epub 27 Jul 2021
Cornelia de Lange syndrome (CdLS) is a rare disease affecting multiple organs and systems during development. Mutations in the cohesin loader, NIPBL/Scc2, were first described and are the most frequent in clinically diagnosed CdLS patients. The molecular mechanisms driving CdLS phenotypes are not understood. In addition to its canonical role in sister chromatid cohesion, cohesin is implicated in the spatial organization of the genome. Here, we investigate the transcriptome of CdLS patient-derived primary fibroblasts and observe the downregulation of genes involved in development and system skeletal organization, providing a link to the developmental alterations and limb abnormalities characteristic of CdLS patients. Genome-wide distribution studies demonstrate a global reduction of NIPBL at the NIPBL-associated high GC content regions in CdLS-derived cells. In addition, cohesin accumulates at NIPBL-occupied sites at CpG islands potentially due to reduced cohesin translocation along chromosomes, and fewer cohesin peaks colocalize with CTCF.
Més informació
Xavier Solanich, Gardenia Vargas-Parra, Caspar I. van der Made, Annet Simons, Janneke Schuurs-Hoeijmakers, Arnau Antolí, Jesús del Valle, Gemma Rocamora-Blanch, Fernando Setién, Esteller, Manel, Simon V. van Reijmersdal, Antoni Riera-Mestre, Joan Sabater-Riera, Gabriel Capellá, Frank L. van de Veerdonk, Ben van der Hoven, Xavier Corbella, Alexander Hoischen and Conxi Lázaro

Genetic Screening for TLR7 Variants in Young and Previously Healthy Men With Severe COVID-19

Front. Immunol 23 Jul 2021, 12 . Epub 23 Jul 2021
Introduction: Loss-of-function TLR7 variants have been recently reported in a small number of males to underlie strong predisposition to severe COVID-19. We aimed to determine the presence of these rare variants in young men with severe COVID-19. Methods: We prospectively studied males between 18 and 50 years-old without predisposing comorbidities that required at least high-flow nasal oxygen to treat COVID-19. The coding region of TLR7 was sequenced to assess the presence of potentially deleterious variants. Results: TLR7 missense variants were identified in two out of 14 patients (14.3%). Overall, the median age was 38 (IQR 30-45) years. Both variants were not previously reported in population control databases and were predicted to be damaging by in silico predictors. In a 30-year-old patient a maternally inherited variant [c.644A>G; p.(Asn215Ser)] was identified, co-segregating in his 27-year-old brother who also contracted severe COVID-19. A second variant [c.2797T>C; p.(Trp933Arg)] was found in a 28-year-old patient, co-segregating in his 24-year-old brother who developed mild COVID-19. Functional testing of this variant revealed decreased type I and II interferon responses in peripheral mononuclear blood cells upon stimulation with the TLR7 agonist imiquimod, confirming a loss-of-function effect. Conclusions: This study supports a rationale for the genetic screening for TLR7 variants in young men with severe COVID-19 in the absence of other relevant risk factors. A diagnosis of TLR7 deficiency could not only inform on treatment options for the patient, but also enables pre-symptomatic testing of at-risk male relatives with the possibility of instituting early preventive and therapeutic interventions.
Octavio A. Romero, Andrea Vilarrubi, Juan J. Alburquerque-Bejar, Antonio Gomez, Alvaro Andrades, Deborah Trastulli, Eva Pros, Fernando Setien, Sara Verdura, Lourdes Farré, Juan F. Martín-Tejera, Paula Llabata, Ana Oaknin, Maria Saigi, Josep M. Piulats, Xavier Matias-Guiu, Pedro P. Medina, August Vidal, Alberto Villanueva, Sanchez-Céspedes Montse

SMARCA4 deficient tumours are vulnerable to KDM6A/UTX and KDM6B/JMJD3 blockade

Nat Commun 14 Jul 2021, 12(1):4319 . Epub 14 Jul 2021
Despite the genetic inactivation of SMARCA4, a core component of the SWI/SNF-complex commonly found in cancer, there are no therapies that effectively target SMARCA4-deficient tumours. Here, we show that, unlike the cells with activated MYC oncogene, cells with SMARCA4 inactivation are refractory to the histone deacetylase inhibitor, SAHA, leading to the aberrant accumulation of H3K27me3. SMARCA4-mutant cells also show an impaired transactivation and significantly reduced levels of the histone demethylases KDM6A/UTX and KDM6B/JMJD3, and a strong dependency on these histone demethylases, so that its inhibition compromises cell viability. Administering the KDM6 inhibitor GSK-J4 to mice orthotopically implanted with SMARCA4-mutant lung cancer cells or primary small cell carcinoma of the ovary, hypercalcaemic type (SCCOHT), had strong anti-tumour effects. In this work we highlight the vulnerability of KDM6 inhibitors as a characteristic that could be exploited for treating SMARCA4-mutant cancer patients.
Més informació
Berdasco M, Esteller M

Towards a "druggable" epitranscriptome: Compounds that target RNA modifications in cancer.

Br J Pharmacol 29 Jun 2021, . Epub 29 Jun 2021
Epitranscriptomics is an exciting emerging area that studies biochemical modifications of RNA. The field is boosted by the technical efforts of the last decade to characterize and quantify RNA modifications which have led to a map of post-transcripcional RNA marks in normal cell fate and develoment. However, the scientific interest has been fueled by the discovery of aberrant epitranscriptomes associated with human diseases, mainly cancer. The challenge is now to see whether epitrancriptomics offers a tunable mechanims to be targeted by small- molecule intervention. In this review, we will describe the principal RNA modifications (with a focus on mRNA), summarize the latest scientific evidences of their dysregulation in cancer and provide an overview of the state-of-the-art drug discovery to target the epitranscriptome. Finally, we will discuss the principal challenges in the field of chemical biology and drug development to increase the potential of targeted-RNA for clinical benefit.
Més informació
Mallo M, Solé F

Beyond morphology: to be or not to be an MDS.

Br J Haematol 28 Jun 2021, . Epub 28 Jun 2021
No abstract available
Més informació
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.
Més informació
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.
Més informació
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.
Més informació
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.
Més informació