Effects of ethanol and various alcoholic beverages on the formation of O6-methyldeoxyguanosine from concurrently administered N-nitrosomethylbenzylamine in rats: a dose-response study

Consumption of alcoholic beverages has been identified as a major cause of oesophageal cancer in industrialized countries, with an exceptionally high risk associated with apple-based liquors (calvados). En the present study, we have determined the dose-activity relationship of the effects of coincident ethanol on the formation of O6-methyldeoxyguanosine (O6-MEdG) by the oesophageal carcinogen N-nitrosomethylbenzylamine (NMBzA). Male Fischer 344 rats received a single intragastric dose of NMBzA (2.5 mg/kg body wt; 7.4 ml/kg body wt) in tap water containing 0-20% ethanol (v/v). Survival time was 3 h. In controls, concentrations of O6-MEdG were similar in oesophagus, lung and liver (11-14.9 μmol/mol dG). In oesophagus, coincident ethanol increased levels of O6-MEdG from 15.2 μmol/mol (0.1% ethanol) to 46.0 μmol/mol (20%). This increase was dose dependent for 1-20% ethanol; however, low doses produced a larger effect per gram of ethanol than higher doses. In lung, concentrations of O6-MEdG increased from 11 μmol/mol (0.1%) to a plateau value of 24 μmol/mol (≥5%). In nasal mucosa, an increase in O6-MEdG from 3.9 μmol/mol (controls) to 30.7 μmol/mol was observed with 4% ethanol. Effects of ethanol on hepatic DNA methylation were statistically non-significant. Modulation of NMBzA bioactivation by various alcoholic beverages (adjusted to 4% ethanol) was also investigated. Increases in oesophageal O6-MEdG were similar (+50% to + 116%) with pear brandy, rice wine (sake), farm-made calvados, gin, Scotch whisky, white wine, Pilsner beer and aqueous ethanol. Significantly higher increases were elicited by commercially distilled calvados (+125%) and red burgundy (+162%). In contrast to its effects at an ethanol content of 4%, farm-made calvados diluted to 20% ethanol produced significantly higher (+200%) increases in oesophageal DNA methylation than aqueous ethanol (+148%). Our results show that ethanol is an effective modulator of nitrosamine bioactivation in vivo at intake levels equivalent to moderate social drinking, and that some alcoholic beverages contain congeners that amplify the effects of ethanol, suggesting that modulation of nitrosamine metabolism by acute ethanol may play a role in the etiology of human cance

MGMT gene silencing and benefit from temozolomide in glioblastoma.

BACKGROUND: Epigenetic silencing of the MGMT (O6-methylguanine-DNA methyltransferase) DNA-repair gene by promoter methylation compromises DNA repair and has been associated with longer survival in patients with glioblastoma who receive alkylating agents. METHODS: We tested the relationship between MGMT silencing in the tumor and the survival of patients who were enrolled in a randomized trial comparing radiotherapy alone with radiotherapy combined with concomitant and adjuvant treatment with temozolomide. The methylation status of the MGMT promoter was determined by methylation-specific polymerase-chain-reaction analysis. RESULTS: The MGMT promoter was methylated in 45 percent of 206 assessable cases. Irrespective of treatment, MGMT promoter methylation was an independent favorable prognostic factor (P<0.001 by the log-rank test; hazard ratio, 0.45; 95 percent confidence interval, 0.32 to 0.61). Among patients whose tumor contained a methylated MGMT promoter, a survival benefit was observed in patients treated with temozolomide and radiotherapy; their median survival was 21.7 months (95 percent confidence interval, 17.4 to 30.4), as compared with 15.3 months (95 percent confidence interval, 13.0 to 20.9) among those who were assigned to only radiotherapy (P=0.007 by the log-rank test). In the absence of methylation of the MGMT promoter, there was a smaller and statistically insignificant difference in survival between the treatment groups. CONCLUSIONS: Patients with glioblastoma containing a methylated MGMT promoter benefited from temozolomide, whereas those who did not have a methylated MGMT promoter did not have such a benefit

Dependence of the 12^{12}C(γ⃗\vec{\gamma},pd) reaction on photon linear polarisation

The sensitivity of the $^{12}$C$(\vec{\gamma},pd)$ reaction to photon linear polarisation has been determined at MAMI, giving the first measurement of the reaction for a nucleus heavier than $^{3}$He. Photon asymmetries and cross sections were measured for $E_{\gamma}$=170 to 350 MeV. For $E_{\gamma}$ below the $\Delta$ resonance, reactions leaving the residual $^{9}$Be near its ground state show a positive asymmetry of up to 0.3, similar to that observed for $^{3}$He suggesting a similar reaction mechanism for the two nuclei.Comment: 4 pages, 2 figure

Comment [In Primary CNS lymphoma in immunocompetent patients from 1989 to 2001: a retrospective analysis of 164 cases uniformly diagnosed by stereotactic biopsy p.838]

Background. We present outcome data of a cohort of 164 immunocompetent PCNSL patients uniformly diagnosed at a single center for stereotactic neurosurgery, and evaluate the acceptance and impact of combination radiotherapy (RT) and chemotherapy (CHT) with high-dose methotrexate (HD-MTX) over time.Method. We assessed choice of treatment and patient survival in a series of 164 PCNSL cases diagnosed from 1989 to 2001, and performed a re-evaluation of histopathology and pre-operative clinical data. Findings. From 1989 to 1993, RT was the predominant therapy, and additional CHT did not improve survival. After 1994, the use of combination CHT=RT increased continuously, consistently contained MTX, and was associated with longer survival than RT only: median survival was 14 months after CHT=RT (2-year survival 35.7%) and 10 months (2-year survival 26.2%) after RT only (not significant). Overall median survival remained poor, increasing from six (1989–1993) to nine months (1994–2001) (p=0.008). Survival was variable, with a few patients surviving>4 years after diagnosis in the CHT=RT as well as in the RT only group.Conclusions. Despite considerable improvement of PCNSL therapy, the overall benefit of combined CHT=RT versus RT only was lower than that expected from previous phase II clinical trials. The striking variability of survival in either treatment group may suggest a yet undefined biological heterogeneity of PCNSL, which may also include a more aggressive PCNSL subtype in the group of patients with rapidly progressive disease and not eligible for standard therapy

Cerebral amyloid angiopathy: pathogenesis and effects on the ageing and Alzheimer brain

Cerebral amyloid angiopathy (CAA) is a feature of ageing and Alzheimer's disease (AD); it is also associated with intracerebral hemorrhage and stroke. Here, the pathogenesis of CAA and its effects on the brain are reviewed and the possible effects of CAA on therapies for Alzheimer's disease are evaluated. Tracer experiments in animals and observations on human brains suggest that peptides such as A? are eliminated along the peri-arterial interstitial fluid drainage pathways that are effectively the lymphatics of the brain. In CAA, A? becomes entrapped in drainage pathways in the walls of cerebral arteries, reflecting a failure of elimination of A? from the ageing brain. One consequence of failure in clearance of A? is accumulation of soluble and insoluble A? associated with cognitive decline in AD. Replacement of vascular smooth muscle cells by A? occurs in severe CAA with weakening of artery walls and increased risk of vessel rupture and intracerebral hemorrhage. Risk factors for CAA include mutations of the amyloid precursor protein (APP) gene and possession of the epsi4 allele of apolipoprotein E. There is also evidence that cerebrovascular disease may be a factor in the failure of elimination of Abeta along perivascular pathways in sporadic AD; this would link ageing in cerebral arteries with the pathogenesis of Alzheimer's disease. If therapeutic agents, including anti-Abeta antibodies, are to be used to eliminate A? in the treatment of Alzheimer's disease, the effects of CAA on the treatment and the effects of the treatment on the CAA need to be considered