We have developed a high-throughput method for analyzing the methylation status of hundreds of preselected genes simultaneously and have applied it to the discovery of methylation signatures that distinguish normal from cancer tissue samples. Through an adaptation of the GoldenGate genotyping assay implemented on a BeadArray platform, the methylation state of 1536 specific CpG sites in 371 genes (one to nine CpG sites per gene) was measured in a single reaction by multiplexed genotyping of 200 ng of bisulfite-treated genomic DNA. The assay was used to obtain a quantitative measure of the methylation level at each CpG site. After validating the assay in cell lines and normal tissues, we analyzed a panel of lung cancer biopsy samples (N = 22) and identified a panel of methylation markers that distinguished lung adenocarcinomas from normal lung tissues with high specificity. These markers were validated in a second sample set (N = 24). These results demonstrate the effectiveness of the method for reliably profiling many CpG sites in parallel for the discovery of informative methylation markers. The technology should prove useful for DNA methylation analyses in large populations, with potential application to the classification and diagnosis of a broad range of cancers and other diseases.

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Previous electrophysiological studies had found an early anterior negativity often with a maximum over the left hemisphere to correlate with the early detection of an error in the syntactic structure of a sentence. In this paper, the cortical structures involved in such early syntactic parsing processes were localized using MEG. Subjects were presented with acoustic sentences and asked to judge their syntactic correctness. The subjects' brain responses to syntactic violations were recorded with a 148-channel whole-head magnetometer. Dipole source localization was performed using a realistically shaped standard volume conductor model with fMRI constraints. The results show that the early syntactic parsing processes are supported by temporal regions, possibly the planum polare, as well as by frontolateral regions. As indicated by the resultant dipole strengths, these regions are activated bilaterally with a dominance in the left hemisphere for four out of the five subjects. The contribution of the left temporal regions to the early syntactic processes seems to be larger than that of the left fronto-lateral regions. Hum.

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