Histone deacetylase inhibitors: potential targets responsible for their anti-cancer effect

The histone deacetylase inhibitors (HDACi) have demonstrated anticancer efficacy across a range of malignancies, most impressively in the hematological cancers. It is uncertain whether this clinical efficacy is attributable predominantly to their ability to induce apoptosis and differentiation in the cancer cell, or to their ability to prime the cell to other pro-death stimuli such as those from the immune system. HDACi-induced apoptosis occurs through altered expression of genes encoding proteins in both intrinsic and extrinsic apoptotic pathways; through effects on the proteasome/aggresome systems; through the production of reactive oxygen species, possibly by directly inducing DNA damage; and through alterations in the tumor microenvironment. In addition HDACi increase the immunogenicity of tumor cells and modulate cytokine signaling and potentially T-cell polarization in ways that may contribute the anti-cancer effect in vivo. Here, we provide an overview of current thinking on the mechanisms of HDACi activity, with attention given to the hematological malignancies as well as scientific observations arising from the clinical trials. We also focus on the immune effects of these agents

Dust mobilization and transport in the northern Sahara during SAMUM 2006 � a meteorological overview

The SAMUM field campaign in southern Morocco in May/June 2006 provides valuable data to study the emission, and the horizontal and vertical transports of mineral dust in the Northern Sahara. Radiosonde and lidar observations show differential advection of air masses with different characteristics during stable nighttime conditions and up to 5-km deep vertical mixing in the strongly convective boundary layer during the day. Lagrangian and synoptic analyses of selected dust periods point to a topographic channel from western Tunisia to central Algeria as a dust source region. Significant emission events are related to cold surges from the Mediterranean in association with eastward passing upper-level waves and lee cyclogeneses south of the Atlas Mountains. Other relevant events are local emissions under a distinct cut-off low over northwestern Africa and gust fronts associated with dry thunderstorms over the Malian and Algerian Sahara. The latter are badly represented in analyses from the European Centre for Medium�Range Weather Forecasts and in a regional dust model, most likely due to problems with moist convective dynamics and a lack of observations in this region. This aspect needs further study. The meteorological source identification is consistent with estimates of optical and mineralogical properties of dust samples

Metabolomics of prostate cancer gleason score in tumor tissue and serum

Gleason score, a measure of prostate tumor differentiation, is the strongest predictor of lethal prostate cancer at the time of diagnosis. Metabolomic profiling of tumor and of patient serum could identify biomarkers of aggressive disease and lead to the development of a less-invasive assay to perform active surveillance monitoring. Metabolomic profiling of prostate tissue and serum samples was performed. Metabolite levels and metabolite sets were compared across Gleason scores. Machine learning algorithms were trained and tuned to predict transformation or differentiation status from metabolite data. A total of 135 metabolites were significantly different (Padjusted < 0.05) in tumor versus normal tissue, and pathway analysis identified one sugar metabolism pathway (Padjusted ¼ 0.03). Machine learning identified profiles that predicted tumor versus normal tissue (AUC of 0.82 ± 0.08). In tumor tissue, 25 metabolites were associated with Gleason score (unadjusted P < 0.05), 4 increased in high grade while the remainder were enriched in low grade. While pyroglutamine and 1,5-anhydroglu-citol were correlated (0.73 and 0.72, respectively) between tissue and serum from the same patient, no metabolites were consistently associated with Gleason score in serum. Previously reported as well as novel metabolites with differing abundance were identified across tumor tissue. However, a “metabolite signature” for Gleason score was not obtained. This may be due to study design and analytic challenges that future studies should consider