Publicació científica

S'han trobat 1149 publicacions amb els criteris indicats.
Marjanović MP, Hurtado-Bagès S, Lassi M, Valero V, Malinverni R, Delage H, Navarro M, Corujo D, Guberovic I, Douet J, Gama-Perez P, Garcia-Roves PM, Ahel I, Ladurner AG, Yanes O, Bouvet P, Suelves M, Teperino R, Pospisilik JA, Buschbeck M

MacroH2A1.1 regulates mitochondrial respiration by limiting nuclear NAD(+) consumption.

Nat. Struct. Mol. Biol. 9 Oct 2017, . Epub 9 Oct 2017
Histone variants are structural components of eukaryotic chromatin that can replace replication-coupled histones in the nucleosome. The histone variant macroH2A1.1 contains a macrodomain capable of binding NAD(+)-derived metabolites. Here we report that macroH2A1.1 is rapidly induced during myogenic differentiation through a switch in alternative splicing, and that myotubes that lack macroH2A1.1 have a defect in mitochondrial respiratory capacity. We found that the metabolite-binding macrodomain was essential for sustained optimal mitochondrial function but dispensable for gene regulation. Through direct binding, macroH2A1.1 inhibits basal poly-ADP ribose polymerase 1 (PARP-1) activity and thus reduces nuclear NAD(+) consumption. The resultant accumulation of the NAD(+) precursor NMN allows for maintenance of mitochondrial NAD(+) pools that are critical for respiration. Our data indicate that macroH2A1.1-containing chromatin regulates mitochondrial respiration by limiting nuclear NAD(+) consumption and establishing a buffer of NAD(+) precursors in differentiated cells.
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Torres-Ruiz R, Martinez-Lage M, Martin MC, Garcia A, Bueno C, Castaño J, Ramirez JC, Menendez P, Cigudosa JC, Rodriguez-Perales S

Efficient Recreation of t(11;22) EWSR1-FLI1(+) in Human Stem Cells Using CRISPR/Cas9.

Stem Cell Reports 9 Mai 2017, 8 (5) 1408-1420.
Efficient methodologies for recreating cancer-associated chromosome translocations are in high demand as tools for investigating how such events initiate cancer. The CRISPR/Cas9 system has been used to reconstruct the genetics of these complex rearrangements at native loci while maintaining the architecture and regulatory elements. However, the CRISPR system remains inefficient in human stem cells. Here, we compared three strategies aimed at enhancing the efficiency of the CRISPR-mediated t(11;22) translocation in human stem cells, including mesenchymal and induced pluripotent stem cells: (1) using end-joining DNA processing factors involved in repair mechanisms, or (2) ssODNs to guide the ligation of the double-strand break ends generated by CRISPR/Cas9; and (3) all-in-one plasmid or ribonucleoprotein complex-based approaches. We report that the generation of targeted t(11;22) is significantly increased by using a combination of ribonucleoprotein complexes and ssODNs. The CRISPR/Cas9-mediated generation of targeted t(11;22) in human stem cells opens up new avenues in modeling Ewing sarcoma.
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Romero-Moya D, Santos-Ocaña C, Castaño J, Garrabou G, Rodríguez-Gómez JA, Ruiz-Bonilla V, Bueno C, González-Rodriguez P, Giorgetti A, Perdiguero E, Prieto C, Moren-Nuñez C, Fernández-Ayala DJ, Cascajo MV, Velasco I, Canals JM, Montero R, Yubero D, Jou C, López-Barneo J, Cardellach F, Muñoz-Cánoves P, Artuch R, Navas P, Menéndez P

Genetic rescue of Mitochondrial and Skeletal Muscle Impairment in an IPSCs Model of Coenzyme Q10 Deficiency.

Stem Cells 4 Mai 2017, . Epub 4 Mai 2017
Coenzyme Q10 (CoQ10 ) plays a crucial role in mitochondria as an electron carrier within the mitochondrial respiratory chain (MRC), and is an essential antioxidant. Mutations in genes responsible for CoQ10 biosynthesis (COQ genes) cause primary CoQ10 deficiency, a rare and heterogeneous mitochondrial disorder with no clear genotype-phenotype association, mainly affecting tissues with high-energy demand including brain and skeletal muscle (SkM). Here, we report a 4-year old girl diagnosed with minor mental retardation and lethal rhabdomyolysis harboring a heterozygous mutation (c.483G>C (E161D)) in COQ4. The patient's fibroblasts showed a decrease in [CoQ10 ], CoQ10 biosynthesis, MRC activity affecting complexes I/II+III, and respiration defects. Bona fide induced pluripotent stem cell (iPSCs) lines carrying the COQ4 mutation (CQ4-iPSCs) were generated, characterized and genetically edited using the CRISPR-Cas9 system (CQ4(ed) -iPSCs). Extensive differentiation and metabolic assays of control-iPSCs, CQ4-iPSCs and CQ4(ed) -iPSCs demonstrated a genotype association, reproducing the disease phenotype. The COQ4 mutation in iPSC was associated with CoQ10 deficiency, metabolic dysfunction, and respiration defects. iPSC differentiation into SkM was compromised, and the resulting SkM also displayed respiration defects. Remarkably, iPSC differentiation in dopaminergic or motor neurons was unaffected. This study offers an unprecedented iPSC model recapitulating CoQ10 deficiency-associated functional and metabolic phenotypes caused by COQ4 mutation. This article is protected by copyright. All rights reserved.
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Pesarrodona M, Crosas E, Cubarsi R, Sánchez-Chardi A, Saccardo P, Unzueta U, Rueda F, Sanchez-García L, Serna N, Mangues R, Ferrer-Miralles N, Vázquez E, Villaverde A

Intrinsic functional and architectonic heterogeneity of tumor-targeted protein nanoparticles.

Nanoscale 2 Mai 2017, . Epub 2 Mai 2017
Self-assembling proteins are gaining attention as building blocks for application-tailored nanoscale materials. This is mostly due to the biocompatibility, biodegradability, and functional versatility of peptide chains. Such a potential for adaptability is particularly high in the case of recombinant proteins, which are produced in living cells and are suitable for genetic engineering. However, how the cell factory itself and the particular protein folding machinery influence the architecture and function of the final material is still poorly explored. In this study we have used diverse analytical approaches, including small-angle X-ray scattering (SAXS) and field emission scanning electron microscopy (FESEM) to determine the fine architecture and geometry of recombinant, tumor-targeted protein nanoparticles of interest as drug carriers, constructed on a GFP-based modular scheme. A set of related oligomers were produced in alternative Escherichia coli strains with variant protein folding networks. This resulted in highly regular populations of morphometric types, ranging from 2.4 to 28 nm and from spherical- to rod-shaped materials. These differential geometric species, whose relative proportions were determined by the features of the producing strain, were found associated with particular fluorescence emission, cell penetrability and receptor specificity profiles. Then, nanoparticles with optimal properties could be analytically identified and further isolated from producing cells for use. The cell's protein folding machinery greatly modulates the final geometry reached by the constructs, which in turn defines the key parameters and biological performance of the material.
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Sanchez R, Ayala R, Alonso RA, Martínez MP, Ribera J, García O, Sanchez-Pina J, Mercadal S, Montesinos P, Martino R, Barba P, González-Campos J, Barrios M, Lavilla E, Gil C, Bernal T, Escoda L, Abella E, Amigo ML, Moreno MJ, Bravo P, Guàrdia R, Hernández-Rivas JM, García-Guiñón A, Piernas S, Ribera JM, Martínez-López J

Clinical characteristics of patients with central nervous system relapse in BCR-ABL1-positive acute lymphoblastic leukemia: the importance of characterizing ABL1 mutations in cerebrospinal fluid.

Ann. Hematol. 27 Abr 2017, . Epub 27 Abr 2017
We investigated the frequency, predictors, and evolution of acute lymphoblastic leukemia (ALL) in patients with CNS relapse and introduced a novel method for studying BCR-ABL1 protein variants in cDNA from bone marrow (BM) and cerebrospinal fluid (CSF) blast cells. A total of 128 patients were analyzed in two PETHEMA clinical trials. All achieved complete remission after imatinib treatment. Of these, 30 (23%) experienced a relapse after achieving complete remission, and 13 (10%) had an isolated CNS relapse or combined CNS and BM relapses. We compared the characteristics of patients with and without CNS relapse and further analyzed CSF and BM samples from two of the 13 patients with CNS relapse. In both patients, classical sequencing analysis of the kinase domain of BCR-ABL1 from the cDNA of CSF blasts revealed the pathogenic variant p.L387M. We also performed ultra-deep next-generation sequencing (NGS) in three samples from one of the relapsed patients. We did not find the mutation in the BM sample, but we did find it in CSF blasts with 45% of reads at the time of relapse. These data demonstrate the feasibility of detecting BCR-ABL1 mutations in CSF blasts by NGS and highlight the importance of monitoring clonal evolution over time.
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Sorigue M, Juncà J, Orna E, Romanic N, Sarrate E, Castellvi J, Soler M, Rodríguez-Hernandez I, Feliu E, Ruiz S

Retinal vein occlusion and paroxysmal nocturnal hemoglobinuria.

J. Thromb. Thrombolysis 26 Abr 2017, . Epub 26 Abr 2017
Paroxysmal nocturnal hemoglobinuria (PNH) is a rare disorder associated with increased risk for thrombosis and reduced life expectancy. Retinal vein occlusion (RVO) is a frequent cause of vision loss but its relationship with PNH has not been studied systematically. Patients followed up for RVO in our ophthalmology department were screened for the presence of a PNH clone in peripheral blood by means of flow cytometry. The presence of other well-documented risk factors for RVO was also analyzed. In a series of 110 patients (54 males, median age of 67) we found no evidence of PNH. Most patients (97/110) had cardiovascular risk factors and/or hyperhomocysteinemia (67/110). Inherited thrombophilias were rare (three confirmed cases). Therefore, PNH does not appear to play a role in the development of RVO. However, this finding does not necessarily apply to young patients and/or those with no conventional risk factors for RVO, due to the low number of patients in these subgroups in our population.
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Ribera JM, Vives S

Acute lymphoblastic leukemia in adults: Steps ahead.

Med Clin (Barc) 26 Abr 2017, . Epub 26 Abr 2017Més informació
Dimopoulos MA, Stewart AK, Masszi T, Špička I, Oriol A, Hájek R, Rosiñol L, Siegel D, Mihaylov GG, Goranova-Marinova V, Rajnics P, Suvorov A, Niesvizky R, Jakubowiak A, San-Miguel J, Ludwig H, Ro S, Aggarwal S, Moreau P, Palumbo A

Carfilzomib-lenalidomide-dexamethasone vs lenalidomide-dexamethasone in relapsed multiple myeloma by previous treatment.

Blood Cancer J 21 Abr 2017, 7 (4) e554. Epub 21 Abr 2017
Carfilzomib, a proteasome inhibitor, is approved as monotherapy and in combination with dexamethasone or lenalidomide-dexamethasone (Rd) for relapsed or refractory multiple myeloma. The approval of carfilzomib-lenalidomide-dexamethasone (KRd) was based on results from the randomized, phase 3 study ASPIRE (NCT01080391), which showed KRd significantly improved progression-free survival (PFS) vs Rd (median 26.3 vs 17.6 months; hazard ratio (HR)=0.690; P=0.0001). This subgroup analysis of ASPIRE evaluated KRd vs Rd by number of previous lines of therapy and previous exposure to bortezomib, thalidomide or lenalidomide. Treatment with KRd led to a 12-month improvement in median PFS vs Rd after first relapse (HR 0.713) and a 9-month improvement after ⩾2 previous lines of therapy (HR 0.720). Treatment with KRd led to an approximate 8-month improvement vs Rd in median PFS in bortezomib-exposed patients (HR 0.699), a 15-month improvement in thalidomide-exposed patients (HR 0.587) and a 5-month improvement in lenalidomide-exposed patients (HR 0.796). Objective response and complete response or better rates were higher with KRd vs Rd, irrespective of previous treatment. KRd had a favorable benefit-risk profile and should be considered an appropriate treatment option for patients with 1 or ⩾2 previous lines of therapy and those previously exposed to bortezomib, thalidomide or lenalidomide.
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Klosin A, Casas E, Hidalgo-Carcedo C, Vavouri T, Lehner B

Transgenerational transmission of environmental information in C. elegans.

Science 21 Abr 2017, 356 (6335) 320-323.
The environment experienced by an animal can sometimes influence gene expression for one or a few subsequent generations. Here, we report the observation that a temperature-induced change in expression from a Caenorhabditis elegans heterochromatic gene array can endure for at least 14 generations. Inheritance is primarily in cis with the locus, occurs through both oocytes and sperm, and is associated with altered trimethylation of histone H3 lysine 9 (H3K9me3) before the onset of zygotic transcription. Expression profiling reveals that temperature-induced expression from endogenous repressed repeats can also be inherited for multiple generations. Long-lasting epigenetic memory of environmental change is therefore possible in this animal.
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Hernández-Boluda JC, Correa JG, Alvarez-Larrán A, Ferrer-Marín F, Raya JM, Martínez-López J, Velez P, Pérez-Encinas M, Estrada N, García-Gutiérrez V, Fox ML, Luño E, Kerguelen A, Cuevas B, Durán MA, Ramírez MJ, Gómez-Casares M, Mata-Vázquez MI, Regadera A, Pereira A, Cervantes F

Clinical characteristics, prognosis and treatment of myelofibrosis patients with severe thrombocytopenia.

Br. J. Haematol. 17 Abr 2017, . Epub 17 Abr 2017Més informació