Molecular genetics of radiographically defined de novo glioblastoma multiforme.

Glioblastoma multiforme (GBM) represents the final endpoint of anaplastic progression in astrocytomas. GBM which arise without clinical evidence of a prior low-grade astrocytoma (LGA) have been designated de novo GBM, and are thought to develop rapidly from initial tumour formation. However, a purely clinical definition of de novo GBM does not exclude a long-standing, asymptomatic low-grade tumour. This study therefore sought to determine the genetic features of a unique group of cases in which GBMs were documented to have arisen radiographically in defined period of time (radiographically defined de novo GBM). Clinical and genetic features were examined in a group of 11 patients with a histological diagnosis of high-grade astrocytoma at first biopsy and radiographically defined de novo GBM. The mean age of the patients at tumour diagnosis was 62 years (range 32-87). Six of 11 tumours arose in the temporal lobes. Eight of 11 tumours had epidermal growth factor receptor (EGFR) overexpression, and EGFR gene amplification was found in five of the six analysed cases. Overexpression of p53 was observed in only one tumour, and a TP53 mutation was present in this case. p16 immunostaining was undetectable in 10 cases, and homozygous deletion of CDKN2A was observed in four of the six studied tumours. pRb expression was lost in four tumours. Mutations in the PTEN gene were detected in two of six cases. The results in this unique group of cases confirms the prior hypothesis that the profile of genetic alterations in de novo GBM is distinct from that of GBM arising from a known LGA, and that these specific genetic pathways promote the rapid development of GBM.

Lead induced alterations in nitrite and nitrate levels in different regions of the rat brain.

Nitric oxide (NO) is a free radical synthesized by nitric oxide synthase (NOS) during the conversion of L-arginine to citrulline. Lead (Pb) affects neuronal functioning in the rat brain. Nitric oxide, a neuronal messenger has a short half life and converts immediately into nitrite and nitrate. The present study is designed to determine lead-induced alterations in NO production by measuring nitrite and nitrate in the cerebellum, the hippocampus, the frontal cortex and the brain stem of the rat brain. Male Sprague-Dawley rats were treated with lead acetate (5 and 15 mg/kg body wt.) by intraperitoneal injection. The control and experimental rats were sacrificed at the end of 7 and 14 days after treatment and different regions of the brain were isolated. Nitrite and nitrate (NOx) levels were estimated by the chemiluminescent method using the NOA 280 (Sievers). The data suggested dose-dependent and region-specific responses to lead. Both treatments of lead reduced NOx levels in the cerebellum and the hippocampus. However, the frontal cortex and the brain stem responded differently to Pb exposure. NOx levels in the frontal cortex were significantly increased in rats treated with low and high doses of Pb for 7 days but not in rats treated for 14 days, whereas in the brain stem, NOx levels were increased in a dose- and time-dependent manner. Although, the response was time-dependent, the variation between 7- and 14-day treatment was not clearly delineated. These results provide additional evidence that Pb exposure alters NO-production in rat brain leading to neuronal dysfunction.