ABSTRACT
The prognosis for people with the high-grade brain tumor glioblastoma is very poor, due largely to low cell death in response to genotoxic therapy. The transcription factor BCL6, a protein that normally suppresses the DNA damage response during immune cell maturation, and a known driver of B-cell lymphoma, was shown to mediate the survival of glioblastoma cells. Expression was observed in glioblastoma tumor specimens and cell lines. When BCL6 expression or activity was reduced in these lines, increased apoptosis and a profound loss of proliferation was observed, consistent with gene expression signatures suggestive of anti-apoptotic and pro-survival signaling role for BCL6 in glioblastoma. Further, treatment with the standard therapies for glioblastoma-ionizing radiation and temozolomide-both induced BCL6 expression in vitro, and an in vivo orthotopic animal model of glioblastoma. Importantly, inhibition of BCL6 in combination with genotoxic therapies enhanced the therapeutic effect. Together these data demonstrate that BCL6 is an active transcription factor in glioblastoma, that it drives survival of cells, and that it increased with DNA damage, which increased the survival rate of therapy-treated cells. This makes BCL6 an excellent therapeutic target in glioblastoma-by increasing sensitivity to standard DNA damaging therapy, BCL6 inhibitors have real potential to improve the outcome for people with this disease.
Subject(s)
Brain Neoplasms/genetics , DNA Damage/genetics , Glioblastoma/genetics , Oncogenes/genetics , Proto-Oncogene Proteins c-bcl-6/genetics , Up-Regulation/genetics , Animals , Cell Line, Tumor , Gene Expression Regulation, Neoplastic/genetics , Humans , Male , Mice , Mice, Inbred C57BL , Signal Transduction/genetics , Transcriptional Activation/genetics , Xenograft Model Antitumor Assays/methodsABSTRACT
BACKGROUND: Cost is a barrier to use of emergency contraception (EC). Since 2008, EC has been available free of charge without restriction in pharmacies throughout Scotland. A survey of EC use among women requesting abortion in 2010 allows comparison of use reported in earlier surveys, when EC was only available on prescription and when EC was available from the pharmacy but at a cost. STUDY DESIGN: A questionnaire survey about knowledge of the availability of free EC from pharmacies, and its use to prevent the index pregnancy, was performed among 204 women requesting abortion in Edinburgh, Scotland. RESULTS: Seventy percent of 204 respondents (n=143) knew that EC was available free from pharmacies; 22 (11%) had used it in the cycle in which conception occurred. EC use was not influenced by knowledge of its availability free of charge. Women from affluent areas were significantly more likely to have used EC to try to prevent the pregnancy than counterparts from less affluent areas (p=.041). CONCLUSIONS: Neither availability from the pharmacy nor removal of a charge for EC has increased its use among women having an abortion in Scotland.
