Search results for "Embryon"
showing 10 items of 988 documents
Bis(1H-indol-2-yl)methanones are effective inhibitors of FLT3-ITD tyrosine kinase and partially overcome resistance to PKC412A in vitro.
2009
Inhibition of the mutated fms-like tyrosine kinase 3 (FLT3) receptor tyrosine kinase is a promising therapeutic strategy in acute myeloid leukaemia (AML). However, development of resistance to FLT3 tyrosine kinase inhibitors (TKI), such as PKC412A, has been described recently. This observation may have an increasing impact on the duration of response and relapse rates in upcoming clinical trials employing FLT3-TKI. Herein we investigated two representatives of a novel class of FLT3-TKI: Bis(1H-indol-2-yl)methanones. Both compounds effectively induced apoptosis in FLT3-internal tandem duplicate (ITD)-transfected murine myeloid cells and in primary FLT3-ITD positive blasts. Combination of bot…
Centrioles Shape ERK Signaling Outcomes to Support Lung Branching
2021
Centrioles comprise the heart of centrosomes, where they organize microtubules. To study the function of centrioles in development, we genetically disrupted centrioles throughout the mouse endoderm. Surprisingly, removing centrioles from endoderm did not disrupt intestinal growth or development. In contrast, in the lung, loss of centrioles blocked branching. In lung, loss of centrioles led to apoptosis specifically of SOX2-expressing airway epithelial cells. Loss of centrioles also activated p53. Deleting p53 in mice with acentriolar endoderm rescued SOX2+ cell survival, lung branching and viability. To investigate why endoderm-wide p53 activation specifically disrupted SOX2+ cell survival,…
Toxicity of ligand-dependent Cre recombinases and generation of a conditional Cre deleter mouse allowing mosaic recombination in peripheral tissues.
2007
Ligand-activated Cre recombinases are widely used for studying gene function in vitro and in conditional mouse models. To compare ligand-dependent Cre recombinases, different Cre estrogen receptor fusions were introduced into the ROSA26 locus of embryonic stem (ES) cells and assayed for genotoxicity and recombination efficiency. Of the tested recombinases, the CreERT2 variant showed no toxicity and was highly responsive to ligand induction. To constitutively express CreERT2 in mice and also to clarify whether the CreERT2 system displays background activity, we generated a knock-in mouse line harboring the CreERT2 coding region under the control of the ROSA26 locus. Analysis of this ROSA26-…
Clinical risk factors for invasive aspergillosis in lung transplant recipients: Results of an international cohort study
2018
BACKGROUND: Invasive aspergillosis (IA) is a frequent complication in lung transplant recipients (LTRs). Clinical risk factors for IA have not been fully characterized, especially in the era of extensive anti-fungal prophylaxis. The primary objective of this study was to evaluate the clinical risk factors associated with IA in LTRs. The secondary objective was to assess the mortality in LTRs who had at least 1 episode of IA compared with LTRs who never had experienced IA.METHODS: We conducted an international, multicenter, retrospective cohort study of 900 consecutive adults who received lung transplants between 2005 and 2008 with 4years of follow-up. Risk factors associated with IA were id…
Wnt3a Neutralization Enhances T-cell Responses through Indirect Mechanisms and Restrains Tumor Growth
2018
Abstract The Wnt/β-catenin pathway regulates T-cell functions, including the repression of effector functions to the advantage of memory development via Tcf1. In a companion study, we demonstrate that, in human cancers, Wnt3a/β-catenin signaling maintains tumor-infiltrating T cells in a partially exhausted status. Here, we have investigated the effects of Wnt3a neutralization in vivo in a mouse tumor model. Abundant Wnt3a was released, mostly by stromal cells, in the tumor microenvironment. We tested whether Wnt3a neutralization in vivo could rescue the effector capacity of tumor-infiltrating T cells, by administering an antibody to Wnt3a to tumor-bearing mice. This therapy restrained tumor…
WNT Signaling Perturbations Underlie the Genetic Heterogeneity of Robinow Syndrome
2018
International audience; Locus heterogeneity characterizes a variety of skeletal dysplasias often due to interacting or overlapping signaling pathways. Robinow syndrome is a skeletal disorder historically refractory to molecular diagnosis, potentially stemming from substantial genetic heterogeneity. All current known pathogenic variants reside in genes within the noncanonical Wnt signaling pathway including ROR2, WNT5A, and more recently, DVL1 and DVL3. However, ∼70% of autosomal-dominant Robinow syndrome cases remain molecularly unsolved. To investigate this missing heritability, we recruited 21 families with at least one family member clinically diagnosed with Robinow or Robinow-like pheno…
Generation of an iPSC line (UNINAi001-A) from a girl with neonatal-onset epilepsy and non-syndromic intellectual disability carrying the homozygous K…
2021
Abstract Heterozygous variants in the KCNQ3 gene cause epileptic and/or developmental disorders of varying severity. Here we describe the generation of induced pluripotent stem cells (iPSCs) from a 9-year-old girl with pharmacodependent neonatal-onset epilepsy and intellectual disability who carry a homozygous single-base duplication in exon 12 of KCNQ3 (NM_004519.3: KCNQ3 c.1599dup; KCNQ3 p.PHE534ILEfs*15), and from a non-carrier brother of the proband. For iPSC generation, non-integrating episomal plasmid vectors were used to transfect fibroblasts isolated from skin biopsies. The obtained iPSC lines had a normal karyotype, showed embryonic stem cell-like morphology, expressed pluripotency…
WNT2b activates epithelial-mesenchymal transition through FZD4: relevance in penetrating Crohns disease.
2020
Abstract Background and Aims Epithelial-mesenchymal transition [EMT] has been related to fibrosis and fistula formation, common complications associated with Crohn´s disease [CD]. The WNT signalling pathway mediates EMT, and specific WNT/FZD interactions have been related to the activation of this process in several diseases. We aim to analyse the relevance of EMT and WNT ligands and receptors in the penetrating behaviour of CD. Methods Intestinal surgical resections were obtained from control and CD patients with a stenotic or penetrating behaviour. Fibrosis was determined by the histological analysis of collagen deposition and EMT by confocal microscopy. The expression of WNT ligands, inh…
New neurons use Slit-Robo signaling to migrate through the glial meshwork and approach a lesion for functional regeneration
2018
Appropriate positioning of new neurons in the brain promotes post-stroke functional recovery.
Dynamic Changes in Ultrastructure of the Primary Cilium in Migrating Neuroblasts in the Postnatal Brain
2019
New neurons, referred to as neuroblasts, are continuously generated in the ventricular-subventricular zone of the brain throughout an animal's life. These neuroblasts are characterized by their unique potential for proliferation, formation of chain-like cell aggregates, and long-distance and high-speed migration through the rostral migratory stream (RMS) toward the olfactory bulb (OB), where they decelerate and differentiate into mature interneurons. The dynamic changes of ultrastructural features in postnatal-born neuroblasts during migration are not yet fully understood. Here we report the presence of a primary cilium, and its ultrastructural morphology and spatiotemporal dynamics, in mig…