Histone deacetylase inhibitors: clinical implications for hematological malignancies

Histone modifications have widely been implicated in cancer development and progression and are potentially reversible by drug treatments. The N-terminal tails of each histone extend outward through the DNA strand containing amino acid residues modified by posttranslational acetylation, methylation, and phosphorylation. These modifications change the secondary structure of the histone protein tails in relation to the DNA strands, increasing the distance between DNA and histones, and thus allowing accessibility of transcription factors to gene promoter regions. A large number of HDAC inhibitors have been synthesized in the last few years, most being effective in vitro, inducing cancer cells differentiation or cell death. The majority of the inhibitors are in clinical trials, unlike the suberoylanilide hydroxamic acid, a pan-HDACi, and Romidepsin (FK 228), a class I-selective HDACi, which are only approved in the second line treatment of refractory, persistent or relapsed cutaneous T-cell lymphoma, and active in approximately 150 clinical trials, in monotherapy or in association. Preclinical studies investigated the use of these drugs in clinical practice, as single agents and in combination with chemotherapy, hypomethylating agents, proteasome inhibitors, and MTOR inhibitors, showing a significant effect mostly in hematological malignancies. The aim of this review is to focus on the biological features of these drugs, analyzing the possible mechanism(s) of action and outline an overview on the current use in the clinical practice

Minor psychiatric disorder in NHS Trust staff::Occupational and gender differences

BACKGROUND It is widely suggested that many National Health Service (NHS) workers experience high levels of minor psychiatric disorder. However, inadequacies of sampling and measurement in studies to date have not allowed this suggestion to be properly evaluated. METHOD The present study was designed to overcome these methodological weaknesses by using a sample of over 11,000 employees from 19 NHS trusts and a well-established measure of minor psychiatric disorder for which there are comparative data. RESULTS The findings show that 26.8% of the health service workers reported significant levels of minor psychiatric disorder, compared with 17.8% of people in the general population. Psychiatric morbidity was highest among managers, doctors, nurses and professions allied to medicine, with each of these groups recording higher rates than their professional counterparts outside the health service. It was lower among those in support occupations, such as administrative and ancillary staff. A feature of the findings was that female doctors and managers showed a much higher prevalence of minor psychiatric disorder than their male colleagues. CONCLUSION Studies are required to establish the organisational, occupational and individual determinants of minor psychiatric disorder among NHS employees