Search results for " Abnormal"
showing 10 items of 597 documents
Abstract LB-085: A new role for LKB1 to regulate Heat Shock Protein 90 activity
2018
Abstract Approximately 30% of human non-small cell lung cancer (NSCLC) patients harbor a somatic KRAS mutation resulting, in aberrant activation of downstream signaling pathways that control cell proliferation, cell growth, and cell survival. Importantly, alleles of LKB1, a serine/threonine kinase that functions as a tumor suppressor, are somatically inactivated in ~30% of NSCLCs within KRAS-mutant NSCLC. The loss of LKB1 gives rise to aggressive, highly metastatic, and highly drug resistant tumors. We have previously demonstrated that the inactivation of the tumor suppressor lkb1 rendered mutant kras murine NSCLC resistant to targeted agents including BET bromodomain and kinase inhibitors.…
G6PD protects from oxidative damage and improves healthspan in mice
2016
S.N.-P. and P.J.F.-M. have been funded by the Spanish Association Against Cancer(aecc). Work in the laboratory of M.S. is funded by the CNIO and by grants from the Spanish Ministry of Economy co-funded by the European Regional Development Fund(SAF project), the European Research Council (ERC Advanced Grant), the Regional Government of Madrid co-funded by the European Social Fund (ReCaRe project), the European Union (RISK-IR project), the Botin Foundation and Banco Santander(Santander Universities Global Division), the Ramon Areces Foundation, and the AXA Foundation. Work in the laboratory of J.V. was supported by grants SAF2013-44663-R,from the Spanish Ministry of Education and Science (MEC…
A Typical Immune T/B Subset Profile Characterizes Bicuspid Aortic Valve: In an Old Status?
2018
Bicuspid valve disease is associated with the development of thoracic aortic aneurysm. The molecular mechanisms underlying this association still need to be clarified. Here, we evaluated the circulating levels of T and B lymphocyte subsets associated with the development of vascular diseases in patients with bicuspid aortic valve or tricuspid aortic valve with and without thoracic aortic aneurysm. We unveiled that the circulating levels of the MAIT, CD4+IL−17A+, and NKT T cell subsets were significantly reduced in bicuspid valve disease cases, when compared to tricuspid aortic valve cases in either the presence or the absence of thoracic aortic aneurysm. Among patients with tricuspid aortic…
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…
Mutation spectrum of NF1 gene in Italian patients with neurofibromatosis type 1 using Ion Torrent PGM™ platform
2017
Neurofibromatosis type 1 (NF1) is caused by mutations of the NF1 gene and is one of the most common human autosomal dominant disorders. The patient shows different signs on the skin and other organs from early childhood. The best known are six or more café au lait spots, axillary or inguinal freckling, increased risk of developing benign nerve sheath tumours and plexiform neurofibromas. Mutation detection is complex, due to the large gene size, the large variety of mutations and the presence of pseudogenes. Using Ion Torrent PGM⢠Platform, 73 mutations were identified in 79 NF1 Italian patients, 51% of which turned out to be novel mutations. Pathogenic status of each variant was classifi…
Early-infantile onset epilepsy and developmental delay caused by bi-allelic GAD1 variants
2020
Mice lacking GAD1 show neonatal mortality, but the human phenotype associated with GAD1 disruption is poorly characterized. Neuray et al. describe six patients with biallelic GAD1 mutations, presenting with early-infantile onset epilepsy, neurodevelopmental delay, muscle weakness and non-CNS manifestations.
Inhibition of histone deacetylation rescues phenotype in a mouse model of Birk-Barel intellectual disability syndrome
2020
Mutations in the actively expressed, maternal allele of the imprinted KCNK9 gene cause Birk-Barel intellectual disability syndrome (BBIDS). Using a BBIDS mouse model, we identify here a partial rescue of the BBIDS-like behavioral and neuronal phenotypes mediated via residual expression from the paternal Kcnk9 (Kcnk9pat) allele. We further demonstrate that the second-generation HDAC inhibitor CI-994 induces enhanced expression from the paternally silenced Kcnk9 allele and leads to a full rescue of the behavioral phenotype suggesting CI-994 as a promising molecule for BBIDS therapy. Thus, these findings suggest a potential approach to improve cognitive dysfunction in a mouse model of an impri…
Expanding the β-III Spectrin-Associated Phenotypes toward Non-Progressive Congenital Ataxias with Neurodegeneration
2021
(1) Background: A non-progressive congenital ataxia (NPCA) phenotype caused by b-III spectrin (SPTBN2) mutations has emerged, mimicking spinocerebellar ataxia, autosomal recessive type 14 (SCAR14). The pattern of inheritance, however, resembles that of autosomal dominant classical spinocerebellar ataxia type 5 (SCA5). (2) Methods: In-depth phenotyping of two boys studied by a customized gene panel. Candidate variants were sought by structural modeling and protein expression. An extensive review of the literature was conducted in order to better characterize the SPTBN2-associated NPCA. (3) Results: Patients exhibited an NPCA with hypotonia, developmental delay, cerebellar syndrome, and cogni…
N-Acetylcysteine Amide Exerts Possible Neuroprotective Effects in Newborn Pigs after Perinatal Asphyxia
2016
<b><i>Background:</i></b> Perinatal asphyxia and ensuing reoxygenation change the antioxidant capacity of cells and organs. <b><i>Objectives:</i></b> To analyze the neuroprotective effect of the antioxidant N-acetylcysteine amide (NACA) after perinatal hypoxia-reoxygenation with an emphasis on proinflammatory cytokines and the transcription factor NF-&#x03BA;B in the prefrontal cortex of neonatal pigs. <b><i>Methods:</i></b> Twenty-nine newborn pigs, aged 12-36 h, were subjected to global hypoxia and hypercapnia. One sham-operated group (n = 5) and 2 experimental groups (n = 12) were exposed to 8% oxygen, until the …
Reversing behavioural abnormalities in mice exposed to maternal inflammation
2016
Viral infection during pregnancy is correlated with increased frequency of neurodevelopmental disorders, and this is studied in mice prenatally subjected to maternal immune activation (MIA). We previously showed that maternal T helper 17 cells promote the development of cortical and behavioural abnormalities in MIA-affected offspring. Here we show that cortical abnormalities are preferentially localized to a region encompassing the dysgranular zone of the primary somatosensory cortex (S1DZ). Moreover, activation of pyramidal neurons in this cortical region was sufficient to induce MIA-associated behavioural phenotypes in wild-type animals, whereas reduction in neural activity rescued the be…