Early epigenetic changes and DNA damage do not predict clinical response in an overlapping schedule of 5-azacytidine and entinostat in patients with myeloid malignancies.

Sequential administration of DNA methyltransferase (DNMT) inhibitors and histone deacetylase (HDAC) inhibitors has demonstrated clinical efficacy in patients with hematologic malignancies. However, the mechanism behind their clinical efficacy remains controversial. In this study, the methylation dynamics of 4 TSGs (p15(INK4B), CDH-1, DAPK-1, and SOCS-1) were studied in sequential bone marrow samples from 30 patients with myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) who completed a minimum of 4 cycles of therapy with 5-azacytidine and entinostat. Reversal of promoter methylation after therapy was observed in both clinical responders and nonresponders across all genes. There was no association between clinical response and either baseline methylation or methylation reversal in the bone marrow or purified CD34(+) population, nor was there an association with change in gene expression. Transient global hypomethylation was observed in samples after treatment but was not associated with clinical response. Induction of histone H3/H4 acetylation and the DNA damage-associated variant histone gamma-H2AX was observed in peripheral blood samples across all dose cohorts. In conclusion, methylation reversal of candidate TSGs during cycle 1 of therapy was not predictive of clinical response to combination "epigenetic" therapy. This trial is registered with http://www.clinicaltrials.gov under NCT00101179.

Improved field-portable system to measure Cs-137 in wildlife.

We have developed an improved system to measure Cs-137 in wildlife at the Savannah River Site. This field-portable system consists of a shielded 5 cm by 10 cm by 40 cm NaI detector controlled by an Ametek Ortec Digibase. Measurement of an animal's radioactivity is made by placing the animal at a predefined location on the detector system for a one minute count-time. The counts, animal type, and animal weight are then used as inputs to an algorithm which calculates the amount of Cs-137 within the whole animal and within the edible meat portion of the animal. The results from these calculations are used to estimate the received dose from eating this animal and is included in the Savannah River Site's Hunter Dose Tracking System. This system has a detection limit of 0.60 pCi/g (22.20 Bq/kg) with a typical measurement uncertainty of less than 0.32 pCi/g (11.84 Bq/kg).