Mosaicism in Fanconi anemia : concise review and evaluation of published cases with focus on clinical course of blood count normalization

Fanconi anemia (FA) is a DNA repair disorder resulting from mutations in genes encoding for FA DNA repair complex components and is characterized by variable congenital abnormalities, bone marrow failure (BMF), and high incidences of malignancies. FA mosaicism arises from reversion or other compensatory mutations in hematopoietic cells and may be associated with BMF reversal and decreased blood cell sensitivity to DNA-damaging agents (clastogens); this sensitivity is a phenotypic and diagnostic hallmark of FA. Uncertainty regarding the clinical significance of FA mosaicism persists; in some cases, patients have survived multiple decades without BMF or hematologic malignancy, and in others hematologic failure occurred despite the presence of clastogen-resistant cell populations. Assessment of mosaicism is further complicated because clinical evaluation is frequently based on clastogen resistance in lymphocytes, which may arise from reversion events both in lymphoid-specific lineages and in more pluripotent hematopoietic stem/progenitor cells (HSPCs). In this review, we describe diagnostic methods and outcomes in published mosaicism series, including the substantial intervals (1-6 years) over which blood counts normalized, and the relatively favorable clinical course in cases where clastogen resistance was demonstrated in bone marrow progenitors. We also analyzed published FA mosaic cases with emphasis on long-term clinical outcomes when blood count normalization was identified. Blood count normalization in FA mosaicism likely arises from reversion events in long-term primitive HSPCs and is associated with low incidences of BMF or hematologic malignancy. These observations have ramifications for current investigational therapeutic programs in FA intended to enable gene correction in long-term repopulating HSPCs. The online version of this article (10.1007/s00277-020-03954-2) contains supplementary material, which is available to authorized users

Targeted gene therapy and cell reprogramming in Fanconi anemia

Altres ajuts: European Regional Development FEDER Funds, Italian Ministry of Health, Fondo de Investigaciones Sanitarias, Dirección General de Investigación de la Comunidad de Madrid S2010/BMD-2420, La Fundació Privada La Marató de TV3 121430/31/32, Marató de TV3 464/C/2012Gene targeting is progressively becoming a realistic therapeutic alternative in clinics. It is unknown, however, whether this technology will be suitable for the treatment of DNA repair deficiency syndromes such as Fanconi anemia (FA), with defects in homology-directed DNA repair. In this study, we used zinc finger nucleases and integrase-defective lentiviral vectors to demonstrate for the first time that FANCA can be efficiently and specifically targeted into the AAVS1 safe harbor locus in fibroblasts from FA-A patients. Strikingly, up to 40% of FA fibroblasts showed gene targeting 42 days after gene editing. Given the low number of hematopoietic precursors in the bone marrow of FA patients, gene-edited FA fibroblasts were then reprogrammed and re-differentiated toward the hematopoietic lineage. Analyses of gene-edited FA-iPSCs confirmed the specific integration of FANCA in the AAVS1 locus in all tested clones. Moreover, the hematopoietic differentiation of these iPSCs efficiently generated disease-free hematopoietic progenitors. Taken together, our results demonstrate for the first time the feasibility of correcting the phenotype of a DNA repair deficiency syndrome using gene-targeting and cell reprogramming strategies

Adelante / Endavant

Séptimo desafío por la erradicación de la violencia contra las mujeres del Institut Universitari d’Estudis Feministes i de Gènere "Purificación Escribano" de la Universitat Jaume

Gestión del conocimiento. Perspectiva multidisciplinaria. Volumen 17

El libro “Gestión del Conocimiento. Perspectiva Multidisciplinaria”, Volumen 17 de la Colección Unión Global, es resultado de investigaciones. Los capítulos del libro, son resultados de investigaciones desarrolladas por sus autores. El libro es una publicación internacional, seriada, continua, arbitrada, de acceso abierto a todas las áreas del conocimiento, orientada a contribuir con procesos de gestión del conocimiento científico, tecnológico y humanístico. Con esta colección, se aspira contribuir con el cultivo, la comprensión, la recopilación y la apropiación social del conocimiento en cuanto a patrimonio intangible de la humanidad, con el propósito de hacer aportes con la transformación de las relaciones socioculturales que sustentan la construcción social de los saberes y su reconocimiento como bien público

Mosaicism in Fanconi anemia : concise review and evaluation of published cases with focus on clinical course of blood count normalization

Fanconi anemia (FA) is a DNA repair disorder resulting from mutations in genes encoding for FA DNA repair complex components and is characterized by variable congenital abnormalities, bone marrow failure (BMF), and high incidences of malignancies. FA mosaicism arises from reversion or other compensatory mutations in hematopoietic cells and may be associated with BMF reversal and decreased blood cell sensitivity to DNA-damaging agents (clastogens); this sensitivity is a phenotypic and diagnostic hallmark of FA. Uncertainty regarding the clinical significance of FA mosaicism persists; in some cases, patients have survived multiple decades without BMF or hematologic malignancy, and in others hematologic failure occurred despite the presence of clastogen-resistant cell populations. Assessment of mosaicism is further complicated because clinical evaluation is frequently based on clastogen resistance in lymphocytes, which may arise from reversion events both in lymphoid-specific lineages and in more pluripotent hematopoietic stem/progenitor cells (HSPCs). In this review, we describe diagnostic methods and outcomes in published mosaicism series, including the substantial intervals (1-6 years) over which blood counts normalized, and the relatively favorable clinical course in cases where clastogen resistance was demonstrated in bone marrow progenitors. We also analyzed published FA mosaic cases with emphasis on long-term clinical outcomes when blood count normalization was identified. Blood count normalization in FA mosaicism likely arises from reversion events in long-term primitive HSPCs and is associated with low incidences of BMF or hematologic malignancy. These observations have ramifications for current investigational therapeutic programs in FA intended to enable gene correction in long-term repopulating HSPCs. The online version of this article (10.1007/s00277-020-03954-2) contains supplementary material, which is available to authorized users

Paisajes comerciales y turismo II: Virtualización de casos de estudio para el aprendizaje autónomo del estudiante (191)

El proyecto tiene como objetivo realizar casos de estudio de paisajes comerciales derivados/ generados por el turismo. Los ejemplos serán virtualizados y servirán de modelo para facilitar al profesorado y alumnado su utilización y consultaDepto. de GeografíaFac. de Geografía e HistoriaFALSEsubmitte

Disease-corrected haematopoietic progenitors from Fanconi anemia induced pluripotent stem cells

Premi a l'excel·lència investigadora. Àmbit de les Ciències de la Salut. 2010The generation of induced pluripotent stem (iPS) cells by ectopic expression of a defined set of factors1-5 has enabled the derivation of patient-specific pluripotent cells and provided valuable experimental platforms to model human disease6-8. Patientspecific iPS cells are also thought to hold great therapeutic potential, although direct evidence for this is still lacking. Here we show that somatic cells from Fanconi anemia (FA) patients, upon correction of the genetic defect, can be reprogrammed to pluripotency to generate patient-specific iPS cells. These cell lines appear indistinguishable from human embryonic stem cells and iPS cells from healthy individuals in colony morphology, growth properties, expression of pluripotencyassociated transcription factors and surface markers, and differentiation potential in vitro and in vivo. Most importantly, we show that corrected FA-specific iPS cells can give rise to hematopoietic progenitors of the myeloid and erythroid lineages that are phenotypically normal, i.e. disease-free. These data offer proof-f-concept that iPS cell technology can be used for the generation of disease-corrected, patient-specific cells with potential value for cell therapy applications

Guía de Terapéutica Antimicrobiana del Área Aljarafe, 3ª edición

Coordinadora: Rocío Fernández Urrusuno. Co-coordinadora: Carmen Serrano Martino.YesEstas guías son un recurso indispensable en los Programas de Optimización de Antibióticos (PROA). No sólo constituyen una herramienta de ayuda para la toma de decisiones en los principales síndromes infecciosos, proporcionando recomendaciones para el abordaje empírico de dichos procesos, sino que son el patrón/estándar de referencia que permitirá determinar la calidad o adecuación de los tratamientos realizados. Las guías pueden ser utilizadas, además, como herramienta de base para la formación y actualización en antibioterapia, ya que permiten mantener actualizados los conocimientos sobre las nuevas evidencias en el abordaje de las infecciones. Por último, deberían incorporar herramientas que faciliten el proceso de toma de decisiones compartidas con el paciente. El objetivo de esta guía es proporcionar recomendaciones para el abordaje de las enfermedades infecciosas más prevalentes en la comunidad, basadas en las últimas evidencias disponibles y los datos de resistencias de los principales patógenos que contribuyan a mejorar la calidad de la prescripción de antimicrobianos