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Quantitative Determination of Decitabine Incorporation Into DNA and Its Effect on Mutation Rates in Human Cancer Cells
Abstract: Decitabine (5-aza-2′-deoxycytidine) is a DNA methyltransferase inhibitor and an archetypal epigenetic drug for the therapy of myeloid leukemias. The mode of action of decitabine strictly depends on the incorporation of the drug into DNA. However, DNA incorporation and ensuing genotoxic effects of decitabine have not yet been investigated in human cancer cell lines or in models related to the approved indication of the drug. Here we describe a robust assay for the quantitative determination of decitabine incorporation rates into DNA from human cancer cells. Using a panel of human myeloid leukemia cell lines we show appreciable amounts of decitabine incorporation that closely corre...
In Vivo Kinetics of Early, Non-random Methylome and Transcriptome Changes Induced by DNA-hypomethylating Treatment in Primary AML Blasts
Abstract: Despite routine use of DNA-hypomethylating agents (HMAs) in AML/MDS therapy, their mechanisms of action are not yet unraveled. Pleiotropic effects of HMAs include global methylome and transcriptome changes. We asked whether in blasts and T-cells from AML patients HMA-induced in vivo demethylation and remethylation occur randomly or non-randomly, and whether gene demethylation is associated with gene induction. Peripheral blood AML blasts from patients receiving decitabine (20 mg/m2 day 1-5) were serially isolated for methylome analyses (days 0, 8 and 15, n = 28) and methylome-plus-transcriptome analyses (days 0 and 8, n = 23), respectively. T-cells were isolated for methylome analy...
Integrative Study of EZH2 Mutational Status, Copy Number, Protein Expression and H3K27 Trimethylation in AML/MDS Patients
Abstract: Background Mutations in the EZH2 gene are recurrently found in patients with myeloid neoplasms and are associated with a poor prognosis. We aimed to characterize genetic and epigenetic alterations of EZH2 in 58 patients (51 with acute myeloid leukemia and 7 with myelodysplastic or myeloproliferative neoplasms) by integrating data on EZH2 mutational status, co-occurring mutations, and EZH2 copy number status with EZH2 protein expression, histone H3K27 trimethylation, and EZH2 promoter methylation. Results EZH2 was mutated in 6/51 acute myeloid leukemia patients (12%) and 7/7 patients with other myeloid neoplasms. EZH2 mutations were not overrepresented in patients with chromosome 7q...
Small Molecules in Oncology
Extensive research into the molecular mechanisms of cancer disease has heralded a new age of targeted therapy. In malignant cells, key proteins that are crucial to tumor growth and survival are now being targeted directly with rationally designed inhibitors. Apart from monoclonal antibodies, small molecule therapeutics such as oncogenic protein kinase inhibitors are attracting a vast amount of investigational attention. This textbook, written by acknowledged experts, provides a broad overview of the small molecules currently used for the treatment of malignant diseases and discusses interesting novel compounds that are in the process of clinical development to combat cancer.
Henry Adams
This book, first published in 1933, examines the life and achievements of Henry Adams, the American historian and political journalist. It looks at his youth and early development of his ideas, and goes on to look at his time as a diplomat, historian and journalist – and his impact upon American political and intellectual life.
The Discourse of Peer Review
This book examines reports that are written by reviewers of submissions to a peer-reviewed journal. This includes a thorough study of the reports from the perspectives of context, content and genre, as well as from the point of view of pragmatics and politeness. The author examines the use of evaluative language, and the roles reviewers assume as they make their evaluations. He also explores how reviewers learn to write these reports. He then discusses the results of these analyses from the point of view of reviewer training, making suggestions for further research in the area of editorial peer review. The demystification of this occluded genre will be of benefit to doctoral students and early career academics not yet familiar with the peer review process, as well as those working in the broader areas of English for Specific Purposes and English for Academic Purposes, discourse analysis and writing for publication.
