Bleomycin‐induced chromosomal damage and shortening of telomeres in peripheral blood lymphocytes of incident cancer patients

Disruption of genomic integrity due to deficient DNA repair capacity and telomere shortening constitute hallmarks of malignant diseases. Incomplete or deficient repair of DNA double‐strand breaks (DSB) is manifested by chromosomal aberrations and their frequency reflects inter‐individual differences of response to exposure to mutagenic compounds. In this study, we investigated chromosomal integrity in peripheral blood lymphocytes (PBL) from newly diagnosed cancer patients, including 47 breast (BC) and 44 colorectal cancer (CRC) patients and 90 matched healthy controls. Mutagen sensitivity was evaluated by measuring chromatid breaks (CTAs) induced by bleomycin and supplemented by the chemiluminescent measurement of γ‐H2AX phosphorylation in 19 cancer patients (11 BC, 8 CRC). Relative telomere length (RTL) was determined in 22 BC, 32 CRC, and 64 controls. We observed statistically significant increased level of CTAs (P = .03) and increased percentage of aberrant cells (ACs) with CTAs (P = .05) in CRC patients compared with controls after bleomycin treatment. No differences were observed between BC cases and corresponding controls. CRC and BC patients with shorter RTL (below median) exhibited significantly higher amount of ACs (P = .02), CTAs (P = .02), and cells with high frequency of CTAs (≥12 CTAs/PBL; P = .03) after bleomycin treatment. No such associations were observed in healthy controls. γ‐H2AX phosphorylation after bleomycin treatment in PBL did not differ between CRC and BC patients. Our results suggest that altered DSB repair measured by sensitivity towards mutagen in PBL occurs particularly in CRC carcinogenesis. Irrespective of cancer type, telomere shortening may be associated with a decreased capacity to repair DSB.     

ADHD and cannabis use in young adults examined using fMRI of a Go/NoGo task

Children diagnosed with attention-deficit/hyperactivity disorder (ADHD) are at increased risk for substance abuse. Response inhibition is a hallmark of ADHD, yet the combined effects of ADHD and regular substance use on neural networks associated with response inhibition are unknown. Task-based functional Magnetic Resonance Imaging (fMRI) data from young adults with childhood ADHD with (n?=?25) and without (n?=?25) cannabis use ≥ monthly in the past year were compared with a local normative comparison group (LNCG) with (n?=?11) and without (n?=?12) cannabis use. Go/NoGo behavioral and fMRI data were evaluated for main and interaction effects of ADHD diagnosis and cannabis use. ADHD participants made significantly more commission errors on NoGo trials than controls. ADHD participants also had less frontoparietal and frontostriatal activity, independent of cannabis use. No main effects of cannabis use on response inhibition or functional brain activation were observed. An interaction of ADHD diagnosis and cannabis use was found in the right hippocampus and cerebellar vermis, with increased recruitment of these regions in cannabis-using controls during correct response inhibition. ADHD participants had impaired response inhibition combined with less fronto-parietal/striatal activity, regardless of cannabis use history. Cannabis use did not impact behavioral response inhibition. Cannabis use was associated with hippocampal and cerebellar activation, areas rich in cannabinoid receptors, in LNCG but not ADHD participants. This may reflect recruitment of compensatory circuitry in cannabis using controls but not ADHD participants. Future studies targeting hippocampal and cerebellar-dependent function in these groups may provide further insight into how this circuitry is altered by ADHD and cannabis use.     

Gender Specificities in Risk Stratification After Myocardial Infarction

Objective: Although gender specificities of various risk factors have been well documented, risk stratification after myocardial infarction has never been compared in women and men. Methods: The power of left ventricular ejection fraction, heart rate variability, and mean RR interval computed from 24-hour Holter recordings, was compared in women and men for the prediction of cardiac mortality after an acute myocardial infarction. The study population consisted of 456 patients (108 women, 348 men) aged 50–75 years. Results: During a follow-up of 3 years, there were 41 cardiac deaths (13 women vs 28 men, P = NS). The positive predictive accuracy of left ventricular ejection fraction, heart rate variability, and mean RR interval at all sensitivity levels was higher in women than in men. For a 40% sensitivity, positive predictive accuracy of left ventricular ejection fraction was 46% in women and 16% in men (P < 0.05), positive predictive accuracy of mean RR interval was 90% in women and 28% in men (P < 0.05), and positive predictive accuracy of heart rate variability was 61% in women and 43% in men (P = NS). Mean RR interval had the highest positive predictive accuracy for cardiac mortality in women, but its superiority over heart rate variability was not statistically significant. In men, heart rate variability was the strongest predictor of mortality that was significantly more powerful than mean RR interval and left ventricular ejection fraction (P < 0.05). Conclusion: Increased 24-hour mean heart rate is the strongest predictor of cardiac mortality in women in whom it performs significantly better than in men. While in men, heart rate variability is a significantly better predictor of postinfarction cardiac mortality than 24-hour mean heart rate, this is not the case in women.     

Endogenous estrogen levels are associated with endothelial function in males independently of lipid levels

Estrogens and androgens may play an important role in vascular health in both sexes. The aim of this study was to examine the relation of endogenous sex hormone levels with early markers of atherosclerosis in a cohort of apparently healthy males. 124 males (age 46.25 ± 9.56) attending a preventive medicine program were examined for unrecognised features of the metabolic syndrome. Flow-mediated dilatation (FMD) and intima-media thickness (IMT) of the common carotid artery were evaluated. Obesity parameters were recorded; estradiol, testosterone, SHBG, free testosterone, insulin, as well as glucose and lipid levels were measured. FMD was positively correlated with estradiol (r = 0.201, P = 0.041) and negatively with total cholesterol (r = -0.205, P = 0.022), low density lipoproteins (r = -0.232, P = 0.009), and triglyceride levels (r = -0.179, P = 0.046). In multivariate analysis, the association of FMD with estrogen was independent of BMI and lipid levels. No significant association between FMD and testosterone levels was found. Subjects with an increased mean IMT (> 0.73 mm, i.e., > 3rd tertile) had lower levels of free (P = 0.021) and bioavailable (P = 0.016) testosterone. In multivariate logistic regression analysis, this association was no longer significant when age or cholesterol levels were considered. Endogenous estrogen levels are associated with FMD, independently of age and lipid levels, showing a protective effect in middle-age male subjects. Circulating androgens are associated, although not independently, with structural changes such as the IMT of carotid artery; this effect is possibly influenced by lipid levels and age.     

Prognosis of children with mixed phenotype acute leukemia treated on the basis of consistent immunophenotypic criteria

Background

Mixed phenotype acute leukemia (MPAL) represents a diagnostic and therapeutic dilemma. The European Group for the Immunological Classification of Leukemias (EGIL) scoring system unambiguously defines MPAL expressing aberrant lineage markers. Discussions surrounding it have focused on scoring details, and information is limited regarding its biological, clinical and prognostic significance. The recent World Health Organization classification is simpler and could replace the EGIL scoring system after transformation into unambiguous guidelines.

Design and Methods

Simple immunophenotypic criteria were used to classify all cases of childhood acute leukemia in order to provide therapy directed against acute lymphoblastic leukemia or acute myeloid leukemia. Prognosis, genotype and immunoglobulin/T-cell receptor gene rearrangement status were analyzed.

Results

The incidences of MPAL were 28/582 and 4/107 for children treated with acute lymphoblastic leukemia and acute myeloid leukemia regimens, respectively. In immunophenotypic principal component analysis, MPAL treated as T-cell acute lymphoblastic leukemia clustered between cases of non-mixed T-cell acute lymphoblastic leukemia and acute myeloid leukemia, while other MPAL cases were included in the respective non-mixed B-cell progenitor acute lymphoblastic leukemia or acute myeloid leukemia clusters. Analogously, immunoglobulin/T-cell receptor gene rearrangements followed the expected pattern in patients treated as having acute myeloid leukemia (non-rearranged, 4/4) or as having B-cell progenitor acute lymphoblastic leukemia (rearranged, 20/20), but were missing in 3/5 analyzed cases of MPAL treated as having T-cell acute lymphobastic leukemia. In patients who received acute lymphoblastic leukemia treatment, the 5-year event-free survival of the MPAL cases was worse than that of the non-mixed cases (53±10% and 76±2% at 5 years, respectively, P=0.0075), with a more pronounced difference among B lineage cases. The small numbers of MPAL cases treated as T-cell acute lymphoblastic leukemia or as acute myeloid leukemia hampered separate statistics. We compared prognosis of all subsets with the prognosis of previously published cohorts.

Conclusions

Simple immunophenotypic criteria are useful for therapy decisions in MPAL. In B lineage leukemia, MPAL confers poorer prognosis. However, our data do not justify a preferential use of current acute myeloid leukemia-based therapy in MPAL.     

Anti-ageing and rejuvenating effects of quercetin

Homeostasis is a key feature of the cellular lifespan. Its maintenance influences the rate of ageing and it is determined by several factors, including efficient proteolysis. The proteasome is the major cellular proteolytic machinery responsible for the degradation of both normal and damaged proteins. Alterations of proteasome function have been recorded in various biological phenomena including ageing and replicative senescence. Proteasome activities and function are decreased upon replicative senescence, whereas proteasome activation confers enhanced survival against oxidative stress, lifespan extension and maintenance of the young morphology longer in human primary fibroblasts. Several natural compounds possess anti-ageing/anti-oxidant properties. In this study, we have identified quercetin (QUER) and its derivative, namely quercetin caprylate (QU-CAP) as a proteasome activator with anti-oxidant properties that consequently influence cellular lifespan, survival and viability of HFL-1 primary human fibroblasts. Moreover, when these compounds are supplemented to already senescent fibroblasts, a rejuvenating effect is observed. Finally, we show that these compounds promote physiological alterations when applied to cells (i.e. whitening effect). In summary, these data demonstrate the existence of naturally occurring anti-ageing products that can be effectively used through topical application.     

Abnormal overexpression of mastocytes in skin biopsies of fibromyalgia patients

Formalin-fixed, paraffin-embedded skin tissue sections were collected from a matched cohort of 63 fibromyalgia syndrome (FMS) patients and 49 volunteers from the general population with both alpha1-antitrypsin (AAT) normal and deficiency variants. These tissues were examined for the expression of the broad-spectrum inhibitor AAT, the serine proteinases elastase and tryptase, the proinflammatory cytokines MCP-1 and TNFα, the endothelium biomarker VEGF, and the inflammation/nociception-related receptor PAR₂. The most relevant finding of the study was a significantly increased number of mast cells (MCs) in the papillary dermis of all FMS patients (greater than or equal to five to 14 per microscopic high power field) compared to zero to one in controls (p < 0.001). MCs strongly stained with tryptase, AAT and PAR₂ antibodies, exhibited a spindle-like shape and were uniformly distributed around blood vessels and appendages. MCP-1 and VEGF expressed weak/moderate positivity in most samples, with a higher expression in controls than in FMS patients (p < 0.001 and 0.051, respectively). No differences in elastase and TNFα were found between both groups. Moreover, no histological differences were found between samples from AAT deficiency and normal AAT phenotypes. Our results indicate that FMS is a MC-associated condition. MCs are present in skin and mucosal surfaces throughout the human body, and are easily stimulated by a number of physical, psychological, and chemical triggers to degranulate, releasing several proinflammatory products which are able to generate nervous peripheral stimuli causing CNS hypersensitivity, local, and systemic symptoms. Our findings open new avenues of research on FMS mechanisms and will benefit the diagnosis of patients and the development of therapeutics.     

Fatigue and depressive symptoms associated with chronic viral hepatitis patients. health-related quality of life (HRQOL)

Background and rationale. It is well established that chronic viral hepatitis (CVH) negatively affects patients’ health-related quality of life (HRQOL). The aim of the present study was to assess the extent to which fatigue and depressive symptoms are associated with CVH patients’ HRQOL.Methods. Eighty-four adult CVH outpatients [45 with hepatitis B virus (HBV) and 39 with hepatitis C virus (HCV) infection] participated in the study. The Short Form-36 Health Survey (SF-36), the Beck Depression Inventory-II (BDI-II) and the Fatigue subscale of the Functional Assessment of Cancer Therapy-Anemia Scale (FACT-F) were used to assess HRQOL, depression and fatigue, respectively.Results. All aspects of HRQOL perceived by CVH patients were significantly impaired compared to the general population, as a comparison with Greek population-based normative data revealed. HBV patients presented similar HRQOL with HCV patients. Clinical parameters including infection activity, fibrosis stage or inflammation grade, as well as depressive symptoms and fatigue were found to be significantly associated with HRQOL. Multivariate analyses showed that older age (p <0.001) and higher fatigue scores (p <0.001) were the variables most closely associated with the physical HRQOL, whereas higher rates on depressive symptoms (p <0.0005) and fatigue (p <0.020) scales were the variables most closely associated with the mental HRQOL.Conclusions. In conclusion, CVH is associated with impaired HRQOL. Fatigue and impaired psychological functioning is associated with diminished HRQOL in CHV, independent of the disease etiology. Consequently, management of fatigue and depressive symptoms should be considered a priority, in order to improve HRQOL in CVH patients.