Zebularine is a stable DNA demethylating agent and the first drug in its class able to reactivate an epigenetically silenced gene by oral administration.

Almost 1-2% of the human genome is located within 500 bp of either side of a transcription initiation site, whereas a far larger proportion (Ϸ25%) is potentially transcribable by elongating RNA polymerases. This observation raises the question of how the genome is packaged into chromatin to allow start sites to be recognized by the regulatory machinery at the same time as transcription initiation, but not elongation, is blocked in the 25% of intragenic DNA. We developed a chromatin scanning technique called ChAP, coupling the chromatin immunoprecipitation assay with arbitrarily primed PCR, which allows for the rapid and unbiased comparison of histone modification patterns within the eukaryotic nucleus. Methylated lysine 4 (K4) and acetylated K9͞14 of histone H3 were both highly localized to the 5 regions of transcriptionally active human genes but were greatly decreased downstream of the start sites. Our results suggest that the large transcribed regions of human genes are maintained in a deacetylated conformation in regions read by elongating polymerase. Common models depicting widespread histone acetylation and K4 methylation throughout the transcribed unit do not therefore apply to the majority of human genes.

Meniscal T1(rho) and T2 values correlate with clinical findings of OA and can be used to differentiate healthy subjects from patients with mild or severe OA.

The frequent silencing of tumor suppressor genes by altered cytosine methylation and chromatin structural changes makes this process an attractive target for epigenetic therapy. Here we show that zebularine, a stable DNA cytosine methylation inhibitor, is preferentially incorporated into DNA and exhibits greater cell growth inhibition and gene expression in cancer cell lines compared to normal fibroblasts. In addition, zebularine preferentially depleted DNA methyltransferase 1 (DNMT1) and induced expression of cancer-related antigen genes in cancer cells relative to normal fibroblasts. Our results demonstrate that zebularine can be selective toward cancer cells and may hold clinical promise as an anticancer therapy.

Purpose-A direct correlation between T 1ρ , T 2 and quantified proteoglycan and collagen contents in human osteoarthritic cartilage has yet to be documented. We aimed to investigate the orientation effect on T 1ρ and T 2 values in human osteoarthritic cartilage; and to quantify the correlation between T 1ρ , T 2 , versus biochemical composition and histology in human osteoarthritic cartilage.Materials and Methods-Thirty-three cartilage specimens were collected from patients who underwent total knee arthroplasty due to severe osteoarthritis, and scanned with a 3T MR scanner for T 1ρ and T 2 quantification. Nine specimens were scanned at three different orientations with respect to the B 0 : 0°, 90°, and 54.7°. Core punches were taken after MRI. Collagen and proteoglycan contents were quantified using biochemical assays. Histology sections were graded using Mankin scores. The correlation between imaging parameters, biochemical contents and histological scores were studied.Results-Both mean T 1ρ and T 2 at 54.7° were significantly higher than those measured at 90°a nd 0°, with T 1ρ showing a less increase compared to T 2 . R 1ρ (1/T 1ρ ) values had a significant, but moderate correlation with proteoglycan contents (R = 0.45, P = 0.002), while R 2 (1/T 2 ) was not correlated with proteoglycan. No significant correlation was found between relaxation times (T 1ρ or T 2 ) and collagen contents. The T 1ρ values of specimen sections with high Mankin scores were significantly higher than those with low Mankin scores (P < 0.05) © 2010 Elsevier Inc. All rights reserved.Corresponding author: Xiaojuan Li, PhD, Department of Radiology and Biomedical Imaging, University of California, San Francisco, 185 Berry Street, Suite 350, San Francisco, CA 94107, xiaojuan.li@radiology.ucsf.edu,. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Competing InterestThe authors declare that they have no competing interests. Conclusions-Quantitative MRI has a great potential to provide non-invasive imaging biomarkers for cartilage degeneration in OA. NIH Public Access