RESUMEN
Breast cancer is a prevalent neoplastic disease among women worldwide which treatments still present several side effects and resistance. Considering that cancer cells present derangements in their energetic homeostasis, and that peroxisome proliferator-activated receptor- gamma coactivator 1 (PGC-1) is crucial for cellular metabolism and redox signaling, the main objective of this study was to investigate whether there is a relationship between PGC-1 expression, the proliferation of breast cancer cells and the mechanisms involved. We initially assessed PGC-1ß expression in complementary DNA (cDNA) from breast tumor of patients bearing luminal A, luminal B, and HER2-overexpressed and triple negative tumors. Our data showed that PGC-1ß expression is increased in patients bearing HER2-overexpressing tumors as compared to others subtypes. Using quantitative PCR and immunoblotting, we showed that breast cancer cells with HER2-amplification (SKBR-3) have greater expression of PGC-1ß as compared to a non-tumorous breast cell (MCF-10A) and higher proliferation rate. PGC-1ß expression was knocked down with short interfering RNA in HER2-overexpressing cells, and cells decreased proliferation. In these PGC-1ß-inhibited cells, we found increased citrate synthase activity and no marked changes in mitochondrial respiration. Glycolytic pathway was decreased, characterized by lower intracellular lactate levels. In addition, after PGC-1ß knockdown, SKBR-3 cells showed increased reactive oxygen species production, no changes in antioxidant activity, and decreased expression of ERRα, a modulator of metabolism. In conclusion, we show an association of HER2-overexpression and PGC-1ß. PGC-1ß knockdown impairs HER2-overexpressing cells proliferation acting on ERRα signaling, metabolism, and redox balance.
Asunto(s)
Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Proteínas Portadoras/metabolismo , Regulación Neoplásica de la Expresión Génica , Genes erbB-2 , Redes y Vías Metabólicas , Oxidación-Reducción , Anciano , Neoplasias de la Mama/patología , Línea Celular Tumoral , Proliferación Celular , Supervivencia Celular/genética , Femenino , Técnicas de Silenciamiento del Gen , Silenciador del Gen , Humanos , Persona de Mediana Edad , Clasificación del Tumor , Estadificación de Neoplasias , ARN Interferente Pequeño/genética , Proteínas de Unión al ARN , Especies Reactivas de Oxígeno , Receptores de Estrógenos/genética , Receptores de Estrógenos/metabolismo , Neoplasias de la Mama Triple Negativas/genética , Neoplasias de la Mama Triple Negativas/metabolismo , Neoplasias de la Mama Triple Negativas/patología , Carga Tumoral , Receptor Relacionado con Estrógeno ERRalfaRESUMEN
BACKGROUND: Botulinum toxin A (BTA) is commonly used to treat children with cerebral palsy (CP). However, the variables measured before BTA application and associated with motor function and independent mobility, known as predictors of functional outcomes, have not been well defined. OBJECTIVE: To identify clinical predictors of gains in functional motor skills and independence of mobility among children with CP, three and six months after BTA application. METHODS: This was a convenience sample of children with spastic CP (n=35). Measurements of quantitative gains in motor skills and independence of mobility were taken three and six months after BTA application. These outcomes were observed through repeated applications of two functional tests: GMFM (Gross Motor Function Measure) and PEDI (Pediatric Evaluation of Disability Inventory). These tests evaluated gross motor function while sitting or standing and during transitions between these postures, and also during dynamic activities such as walking, running and jumping, along with the children's independence in mobility tasks. The independent variables included the children's characteristics such as age, severity, topographic diagnosis, neuromuscular-skeletal parameters (range of motion and spasticity), gait quality and performance in the functional tests before BTA. RESULTS: Four predictive models were developed (R² between 0.58 and 0.83; p<0.05) through the use of CART analysis: two at three months and two at six months after BTA application. The results indicated that children with better gait quality, smaller repertoire of functional motor skills, less independence of locomotion and age below four years and six months before BTA presented greater gains in motor skills and independence in mobility. CONCLUSION: The results identified significant clinical parameters that can predict functional outcomes of BTA applications among children with CP.
CONTEXTUALIZAÇÃO: A toxina botulínica A (TBA) é comumente utilizada em crianças com paralisia cerebral (PC), entretanto preditores de desfechos funcionais, ou seja, variáveis mensuradas pré-aplicação da TBA e associadas a ganho na função motora e independência na mobilidade não são bem definidos. OBJETIVO: Identificar preditores clínicos de ganho em habilidades motoras funcionais e independência em mobilidade em crianças com PC, aos três e seis meses pós-aplicação de TBA. MÉTODOS: Amostra de conveniência de crianças com PC espástica (n=35). As medidas incluíram: melhora quantitativa nas habilidades motoras e na independência em mobilidade aos três e seis meses após a aplicação da TBA. Esses desfechos foram observados por meio de aplicações repetidas dos testes funcionais GMFM (Gross Motor Function Measure) e PEDI (Pediatric Evaluation of Disability Inventory). Esses testes avaliaram a função motora grossa durante a manutenção e transições entre as posturas sentada e de pé, além de atividades dinâmicas como andar, correr e pular, e a independência da criança em tarefas de mobilidade. As variáveis independentes incluíram características das crianças como idade, severidade e diagnóstico topográfico, parâmetros neuromusculoesquelético (amplitude de movimento, espasticidade), qualidade da marcha e desempenho nos testes funcionais antes da TBA. RESULTADOS: Foram gerados quatro modelos preditivos (R² entre 0,58 e 0,83; p<0,05), dois aos três e dois aos seis meses após a aplicação da TBA, a partir da análise CART. Os resultados indicaram que crianças com melhor qualidade da marcha, menor repertório de habilidades da função motora, menor independência na locomoção e idade menor que quatro anos e seis meses pré TBA apresentaram maior ganho de habilidades motoras e de independência em mobilidade. CONCLUSÃO: Os resultados identificaram parâmetros clínicos importantes de serem documentados em crianças com PC submetidas à aplicação da TBA para predizer...
RESUMEN
Comparar o desempenho de criancas com paralisia cerebral (PC) em duas condicoes: com ortese e sem ortese. Metodos: vinte criancas PC foram avaliadas utilizando-se o teste Gross Motor Function Measure (GMFM), a versao modificada da avaliacao da marcha Physicians Rating Scale (PRS) e entrevista com os pais para avalair o uso de oreteses na rotina diaria. Resultados: o teste ANOVA que foi utilizado para avaliar o efeito do uso ortese na mobilidade das criancas revelou medias significativamente superiores na condicao com ortese durante o desempenho motor grosso e na marcha. entrevistas informaram que o uso de orteses estava inserido na rotina diaria e os pais demonstraram percepcao positiva com relacao ao uso desse dispositivo. Conclusao: as orteses promoveram o desempenho de tarefas motoras da rotina diaria de criancas com PC, podendo orientar os processos de avaliacao e de intervencao dos profissionais que trbalaham com essa clientela
Asunto(s)
Humanos , Niño , Parálisis Cerebral , Niño , Marcha , Locomoción , Actividad MotoraRESUMEN
Haim-Munk syndrome (HMS) is a rare autosomal recessive disorder characterized clinically by abnormal palmoplantar hyperkeratosis and destruction of the periodontium, with hallmarks of onychogryphosis and arachnodactyly. Germline mutations in the lysosomal protease cathepsin C gene (CTSC) have been described in a single patient with HMS and in several individuals with the clinically related disorder Papillon-Lefevre syndrome (PLS). We describe a patient with HMS. We have analysed the cathepsin C gene in the proband and her mother. Sequence analysis of CTSC in the proband revealed a homozygous mutation at codon 196 (587T-->C) within exon 4 that altered the conserved leucine to proline (Leu196Pro), whereas the patient's mother was heterozygous for that mutation. The same mutation has previously been described in an unrelated Brazilian family with PLS. An identical single missense mutation in the cathepsin C gene may underlie both PLS and HMS. These findings confirm that HMS and PLS are allelic variants of cathepsin C gene mutations and suggest that other factors (environmental or genetic) may be important determinants of the clinical phenotype of HMS and PLS.
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Catepsina C/genética , Queratodermia Palmoplantar/genética , Mutación , Adulto , Femenino , Homocigoto , Humanos , Queratodermia Palmoplantar/patología , Enfermedad de Papillon-Lefevre/genética , Linaje , Análisis de Secuencia de ADN , SíndromeRESUMEN
Periapical lesions, as well as periodontal disease, seems to have cyclic patterns of evolution. Periods of burst may be intercalated with periods of quiescence. Because keratinocyte division must occur during cyst growth, it is presumed that epithelium status could indicate the biological activity of radicular cysts (RCs). Th1 and Th2 are important heterogeneous stages of lymphocyte differentiation. Delayed-type hypersensitivity immune reactions are mediated by Th1 lymphocytes, whereas Th2 populations mediate some types of humoral immune response. Th2 lymphocytes are characterized by high expression of CD30 glycoprotein. Th1 and Th2 lymphocytes have not been evaluated in periapical inflammatory lesions. The purpose of this study was to evaluate CD30+ cells in RCs with atrophic and hyperplastic epithelium. A biotin-streptavidin amplified system was used for identification of CD30 receptor. Results demonstrate increased proportions of Th2 cells in cysts with hyperplastic epithelium. Our results suggest that Th2 cells could be associated with RC growth.