Hydroxyl Radical-induced Strand Break Formation of Poly(U) in Anoxic Solution. Effect of Dithiothreitol and Tetranitromethane

Summary

The role of dithiothreitol (DTT) and tetranitromethane (TNM) on the yields of radiation-induced strand break formation in polyuridylic acid (poly(U)) was studied in anoxic aqueous solutions at neutral pH by low-angle laser light-scattering. From G (single-strand breaks) as a function of DTT concentration it follows that two different processes lead to OH radical-induced single-strand break (ssb) formation. Only one of the two processes, which accounts for 80 per cent of the ssb formation, is inhibited by DTT, the other one, 20 per cent, is not inhibited. The ‘repair’ process is attributed to H-donation to the C-6-yl radical of the uracil moiety. The C-6-yl radical is produced by OH addition to the C-5 position of the uracil moiety. It follows that the sugar radicals, in contrast to earlier suggestions, do not seem to be repaired by DTT at the low concentrations used. The strand break formation not inhibited by DTT is induced by radicals other than the uracil-6-yl radical, e.g. the uracil-5-yl or the OH radicals reacting with the sugar moiety. The strong reduction of G(ssb) from 2·3 to 0·2 on addition of TNM is also discussed.     

A new instrument for assessing the quality of studies on prevalence

There are numerous scientific articles of studies on the prevalence of disorders with non-standardised examination and diagnostic protocols. Because their quality is heterogeneous, a new instrument has been developed for the assessment of such studies. The new instrument is based mainly on statistical criteria. The points assigned for each of the main criteria according to the information gained from each paper are summed up to form a Total Quality Score (TQS). The interrater reliability of the instrument was tested by employing Kappa and Interrater Correlation Coefficient (ICC) statistics. The latter was assessed on the results of three independent investigators. The new quality instrument appeared to be easy to use, and the instructions were comprehensible. The ICC_(2,1) for the TQS ranged between 0.94 and 1.00 indicating almost perfect agreement between the investigators. The reliability of the new instrument enables its use for scientific review purposes. In this way, its validity will also be tested. The instrument could be adopted for assessment of scientific articles of studies on the prevalence of disorders in many, similar, scientific areas.     

Gender differences in anxiety and depressive symptoms in patients with primary hyperaldosteronism: A cross-sectional study

Objective. The renin-angiotensin-aldosterone-system (RAAS) has gained increasing attention in the investigation of the pathogenesis of depression. Primary hyperaldosteronism (PA) is associated with a marked aldosterone excess. Prior studies on PA describe an increased prevalence of anxiety and sub-threshold depressive symptoms in these patients. Methods. In a cross-sectional exploratory study we investigated 132 patients with PA. Twenty-seven patients were studied before initiation of specific treatment (U = untreated), 56 were studied 5.4 years after initiation of mineralocorticoid antagonist treatment (MRA) and 49 patients were studied 4.3 years after unilateral adrenalectomy (ADX). GAD-7 and PHQD self-rating questionnaires were used to assess symptoms for anxiety and depression. Results. No significant difference was found between the three investigated groups. A higher prevalence for depression and anxiety compared to the normal population was found. Women of all groups had higher mean values compared to men, for depression in untreated patients this difference was found to be significant. Correlations between the psychopathology and hormones were only found for renin. Plasma renin concentration correlated significantly with anxious symptoms of untreated females. Conclusions. This study supports the RAAS to be involved in the pathogenesis of depression as patients with PA seem to be more depressive and anxious compared to the normal population. Gender differences in the regulation of the RAAS seem to be apparent, as females were more affected by the dysregulation than males.     

Limited efficacy of specific HDAC6 inhibition in urothelial cancer cells

Epigenetic modifiers such as histone deacetylases (HDACs) have come into focus as novel drug targets for cancer therapy due to their functional role in tumor progression. Since common pan-HDAC inhibitors have adverse side effects and minor anti-cancer activity against solid tumors, enzyme-specific inhibitors were developed. HDAC6 is especially well-suited for specific inhibition due to its unique domain structure and mode of action and has been suggested to provide an exceptionally suitable target for cancer therapy. However, expression and function of HDACs have been insufficiently studied in urothelial cancers (UC), a disease urgently requiring new therapeutic approaches. The present study sought to evaluate HDAC6 as a target for treatment of urothelial cancers with enzyme-specific inhibitors. We observed moderate HDAC6 overexpression in urothelial cancer tissues and a broad range of expression in urothelial cancer cell lines. In the cell lines Tubacin was the most potent inhibitor, compared with Tubastatin and ST-80, but still active only at high micromolar concentrations. HDAC6 expression levels correlated poorly with sensitivity to enzyme inhibition. Combined treatments with heat shock, HSP90 inhibition by 17-AAG, proteasome inhibition by bortezomib, or DNA-damaging agents did not result in significant synergistic effects. Experiments with siRNA-mediated knockdown further underlined that urothelial cancer cells do not critically depend on HDAC6 expression for survival.