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Sci Rep ; 9(1): 11983, 2019 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-31427717


Rett syndrome (RTT) is a severe neurological disorder usually caused by mutations in the MECP2 gene. Since the MECP2 gene is located on the X chromosome, X chromosome inactivation (XCI) could play a role in the wide range of phenotypic variation of RTT patients; however, classical methylation-based protocols to evaluate XCI could not determine whether the preferentially inactivated X chromosome carried the mutant or the wild-type allele. Therefore, we developed an allele-specific methylation-based assay to evaluate methylation at the loci of several recurrent MECP2 mutations. We analyzed the XCI patterns in the blood of 174 RTT patients, but we did not find a clear correlation between XCI and the clinical presentation. We also compared XCI in blood and brain cortex samples of two patients and found differences between XCI patterns in these tissues. However, RTT mainly being a neurological disease complicates the establishment of a correlation between the XCI in blood and the clinical presentation of the patients. Furthermore, we analyzed MECP2 transcript levels and found differences from the expected levels according to XCI. Many factors other than XCI could affect the RTT phenotype, which in combination could influence the clinical presentation of RTT patients to a greater extent than slight variations in the XCI pattern.

Clin Immunol ; 195: 49-58, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30063981


Monoallelic loss-of-function mutations in NFKB1 were recently recognized as the most common monogenic cause of common variable immunodeficiency (CVID). The prototypic clinical phenotype of NFKB1-deficient patients includes common CVID features, such as hypogammaglobulinaemia and sinopulmonary infections, plus other highly variable individual manifestations. Here, we describe a patient with a profound CVID phenotype and severe gastrointestinal manifestations, including chronic and recurrent diarrhoea. Using an NGS customized panel of 323 genes related to primary immunodeficiencies, we identified a novel monoallelic loss-of-function mutation in NFKB1 leading to a truncated protein (c.1149delT/p.Gly384Glu ∗ 48). Interestingly, we also found a rare variant in NOD2 previously associated with Crohn's disease (p.His352Arg). Our patient had hypogammaglobulinaemia with a small number of B cells, most of which were naïve. The most noteworthy findings included marked skewing towards a Th1 phenotype in peripheral blood T cells and excessive production of proinflammatory cytokines (IL-1ß, TNFα). The patient's 6-year-old daughter, a carrier of the NFKB1 mutation, is clinically asymptomatic, but has started to show cellular and molecular changes. This case of NFKB1 deficiency appears to be a combination of immunodeficiency and a hyperinflammatory state. The current situation of the patient's daughter provides a glimpse of the preclinical phase of the condition.

Linfócitos B/fisiologia , Imunodeficiência de Variável Comum/imunologia , Gastroenteropatias/imunologia , NF-kappa B/genética , Deleção de Sequência/genética , Células Th1/fisiologia , Adolescente , Adulto , Agamaglobulinemia , Células Cultivadas , Imunodeficiência de Variável Comum/genética , Citocinas/metabolismo , Feminino , Gastroenteropatias/genética , Humanos , Mediadores da Inflamação/metabolismo , Masculino , Proteína Adaptadora de Sinalização NOD2/genética , Infecções Respiratórias , Adulto Jovem
Oncotarget ; 9(24): 16701-16717, 2018 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-29682179


Sorafenib, systemic treatment for advanced hepatocellular carcinoma (HCC), and regorafenib, novel second line treatment after sorafenib failure, have efficacy limited by evasive mechanisms of acquired-drug resistance. BCL-2 proteins participate in the response to tyrosine kinase inhibitors; however, their role in HCC therapy with sorafenib/regorafenib remains uncertain. BH3-mimetic ABT-263 (navitoclax) enhanced sorafenib activity, inducing cell death via a mitochondrial caspase-dependent mechanism, after BCL-xL/BCL-2 inhibition. Sorafenib-resistant hepatoma cells (HepG2R and Hep3BR) exhibited altered mRNA expression of BCL-2 and other anti-apoptotic family members, such as MCL-1, priming drug-resistant cancer cells to death by BH3-mimetics. ABT-263 restored sorafenib efficacy in sorafenib-resistant cell lines and HCC mouse models. Moreover, in mice xenografts from patient-derived BCLC9 cells, better tumor response to sorafenib was associated to higher changes in the BCL-2 mRNA pattern. HCC non-treated patients displayed altered BCL-2, MCL-1 and BCL-xL mRNA levels respect to adjacent non-tumoral biopsies and an increased BCL-2/MCL-1 ratio, predictive of navitoclax efficacy. Moreover, regorafenib administration also modified the BCL-2/MCL-1 ratio and navitoclax sensitized hepatoma cells to regorafenib by a mitochondrial caspase-dependent mechanism. In conclusion, sorafenib/regorafenib response is determined by BCL-2 proteins, while increased BCL-2/MCL-1 ratio in HCC sensitizes drug resistant-tumors against ABT-263 co-administration. Thus, changes in the BCL-2 profile, altered in HCC patients, could help to follow-up sorafenib efficacy, allowing patient selection for combined therapy with BH3-mimetics or early switch them to second line therapy.

J Phys Chem B ; 121(43): 10166-10179, 2017 11 02.
Artigo em Inglês | MEDLINE | ID: mdl-29016133


Polyethylenes with halogens placed on each and every 21st, 15th, or ninth backbone carbon display crystallization patterns enabled by the size of the halogen and by changing crystallization kinetics. The different structures have been identified from X-ray patterns combined with a detailed analysis of the infrared spectra of series containing F, Cl, or Br atoms that were either fast or isothermally crystallized from the melt. Under both crystallization modes, all specimens develop layered crystallites that accommodate 5-9 repeating units along the chain's axis. The size of the halogen and intermolecular staggering to maximize packing symmetry are responsible for striking structural differences observed between the series and between the two modes of crystallization. While the small size of the F atom causes a small perturbation to the crystal lattice and the orthorhombic structure is maintained for all members of the series either fast or isothermally crystallized, each Cl or Br-containing system presents dimorphism. Under fast crystallization, Cl and Br containing samples adopt the all-trans conformation (planar Form I), while in slowly crystallized samples gauche conformers set for bonds of the backbone carbons adjacent to the carbon with the halogen due to a close intermolecular staggering of halogens (herringbone Form II). In both forms the methylene sequence between halogens maintains the all-trans conformation. The structural details are extracted from the analysis of the C-halogen stretching region of the IR spectra, and from adherence to the n-alkane behavior of CH2 rocking, CH2 wagging, and C-C stretching progression modes.

Sci Rep ; 7(1): 12288, 2017 09 25.
Artigo em Inglês | MEDLINE | ID: mdl-28947817


Rett syndrome (RTT) is an early-onset neurodevelopmental disorder that almost exclusively affects girls and is totally disabling. Three genes have been identified that cause RTT: MECP2, CDKL5 and FOXG1. However, the etiology of some of RTT patients still remains unknown. Recently, next generation sequencing (NGS) has promoted genetic diagnoses because of the quickness and affordability of the method. To evaluate the usefulness of NGS in genetic diagnosis, we present the genetic study of RTT-like patients using different techniques based on this technology. We studied 1577 patients with RTT-like clinical diagnoses and reviewed patients who were previously studied and thought to have RTT genes by Sanger sequencing. Genetically, 477 of 1577 patients with a RTT-like suspicion have been diagnosed. Positive results were found in 30% by Sanger sequencing, 23% with a custom panel, 24% with a commercial panel and 32% with whole exome sequencing. A genetic study using NGS allows the study of a larger number of genes associated with RTT-like symptoms simultaneously, providing genetic study of a wider group of patients as well as significantly reducing the response time and cost of the study.

Testes Genéticos/métodos , Sequenciamento de Nucleotídeos em Larga Escala , Síndrome de Rett/diagnóstico , Estudos de Coortes , Variações do Número de Cópias de DNA/genética , Fatores de Transcrição Forkhead/genética , Humanos , Proteína 2 de Ligação a Metil-CpG/genética , Mutação , Proteínas do Tecido Nervoso/genética , Polimorfismo de Nucleotídeo Único , Proteínas Serina-Treonina Quinases/genética , Síndrome de Rett/genética , Sequenciamento Completo do Exoma
Rev. chil. cir ; 68(5): 373-375, oct. 2016. ilus
Artigo em Espanhol | LILACS | ID: lil-797347


Objetivo: Enfatizar la importancia de sospechar esta etiología en la patogenia de la apendicitis aguda, especialmente en pacientes procedentes de países endémicos. Casos clínicos: Presentamos dos casos, con cursos clínicos divergentes.

Aim: We would like to emphasize the importance of having a high grade of suspect about the parasitic etiology of appendicitis acute, especially in patients from endemic countries. Case report: We present two cases with divergent clinical evolution.

Humanos , Feminino , Adolescente , Adulto , Doenças Parasitárias/complicações , Apendicite/parasitologia , Doenças Parasitárias/tratamento farmacológico , Apendicite/cirurgia , Ascaris lumbricoides/isolamento & purificação , Enterobius/isolamento & purificação , Mebendazol/uso terapêutico , Antinematódeos/uso terapêutico