6 resultados para Muscat of Alexandria
em Deakin Research Online - Australia
Resumo:
SMARCB1 is deleted in rhabdoid tumor, an aggressive paediatric malignancy affecting the kidney and CNS. We hypothesized that the oncogenic pathway in rhabdoid tumors involved epigenetic silencing of key cell cycle regulators as a consequence of altered chromatin-remodelling, attributable to loss of SMARCB1, and that this hypothesis if proven could provide a biological rationale for testing epigenetic therapies in this disease. We used an inducible expression system to show that the imprinted cell cycle inhibitor CDKN1C is a downstream target for SMARCB1 and is transcriptionally activated by increased histone H3 and H4 acetylation at the promoter. We also show that CDKN1C expression induces cell cycle arrest, CDKN1C knockdown with siRNA is associated with increased proliferation, and is able to compete against the anti-proliferative effect of restored SMARCB1 expression. The histone deacetylase inhibitor (HDACi), Romidepsin, specifically restored CDKN1C expression in rhabdoid tumor cells through promoter histone H3 and H4 acetylation, recapitulating the effect of SMARCB1 on CDKNIC allelic expression, and induced cell cycle arrest in G401 and STM91-01 rhabdoid tumor cell lines. CDKN1C expression was also shown to be generally absent in clinical specimens of rhabdoid tumor, however CDKN1A and CDKN1B expression persisted. Our observations suggest that maintenance of CDKN1C expression plays a critical role in preventing rhabdoid tumor growth. Significantly, we report for the first time, parallels between the molecular pathways of SMARCB1 restoration and Romidepsin treatment, and demonstrate a biological basis for the further exploration of histone deacetylase inhibitors as relevant therapeutic reagents in the treatment of rhabdoid tumor.
Resumo:
LBH589 is one of the many histone deacetylase inhibitors (HDACi) that are currently in clinical trial. Despite their wide-spread use, there is little literature available describing the typical levels of histone acetylation in untreated peripheral blood, the treatment and storage of samples to retain optimal measurement of histone acetylation nor methods by which histone acetylation analysis may be monitored and measured during the course of a patient’s treatment. In this study, we have used cord or peripheral blood as a source of human leukocytes, performed a comparative analysis of sample processing methods and developed a flow cytometric method suitable for monitoring histone acetylation in isolated lymphocytes and liquid tumors. Western blotting and immunohistochemistry techniques have also been addressed. We have tested these methods on blood samples collected from four patients treated with LBH589 as part of an Australian Children’s Cancer Clinical Trial (CLBH589AAU03T) and show comparable results when comparing in vitro and in vivo data. This paper does not seek to correlate histone acetylation levels in peripheral blood with clinical outcome but describes methods of analysis that will be of interest to clinicians and scientists monitoring the effects of HDACi on histone acetylation in blood samples in clinical trials or in related research studies.
Resumo:
ABSTRACT
The consumption of sweetened beverages is a known common risk factor for the development of obesity and dental caries in children and children consume sweet drinks frequently and in large volumes from an early age. The aim of this study was to examine factors that influence mothers when choosing drinks for their children.
Method
Semi-structured interviews (n = 32) were conducted with a purposive sample of mothers of young children from Victoria’s Barwon South Western Region (selected from a larger cohort study to include families consuming different types of water, and different socioeconomic status and size). Inductive thematic analysis was conducted on transcribed interviews.
Results
Several themes emerged as influencing child drink choice. Child age: Water was the main beverage for the youngest child however it was seen as more acceptable to give older children sweetened beverages. Child preference and temperament: influencing when and if sweet drinks were given; Family influences such as grandparents increased children’s consumption of sweet drinks, often providing children drinks such as fruit juice and soft drinks regardless of maternal disapproval. The Setting: children were more likely to be offered sweetened drinks either as a reward or treat for good behaviour or when out shopping, out for dinner or at parties.
Conclusions
Limiting intake of sweet drinks is considered an important step for child general and oral health. However, the choice of drinks for children has influences from social, environmental and behavioural domains, indicating that a multi-strategy approach is required to bring about this change.
