Telomere Length, Mitochondrial DNA, and Micronucleus Yield in Response to Oxidative Stress in Peripheral Blood Mononuclear Cells.

Telomere shortening, chromosomal damage, and mitochondrial dysfunction are major initiators of cell aging and biomarkers of many diseases. However, the underlying correlations between nuclear and mitochondrial DNA alterations remain unclear. We investigated the relationship between telomere length (TL) and micronucleus (MN) and their association with mitochondrial DNA copy number (mtDNAcn) in peripheral blood mononuclear cells (PBMCs) in response to 100 µM and 200 µM of hydrogen peroxide (H2O2) at 44, 72, and 96 h. Significant TL shortening was observed after both doses of H2O2 and at all times (all p < 0.05). A concomitant increase in MN was found at 72 h (p < 0.01) and persisted at 96 h (p < 0.01). An increase in mtDNAcn (p = 0.04) at 200 µM of H2O2 was also found. In PBMCs treated with 200 µM H2O2, a significant inverse correlation was found between TL and MN (r = -0.76, p = 0.03), and mtDNA content was directly correlated with TL (r = 0.6, p = 0.04) and inversely related to MN (r = -0.78, p = 0.02). Telomere shortening is the main triggering mechanism of chromosomal damage in stimulated T lymphocytes under oxidative stress. The significant correlations between nuclear DNA damage and mtDNAcn support the notion of a telomere-mitochondria axis that might influence age-associated pathologies and be a target for the development of relevant anti-aging drugs.

FLASH Radiotherapy: Expectations, Challenges, and Current Knowledge.

Major strides have been made in the development of FLASH radiotherapy (FLASH RT) in the last ten years, but there are still many obstacles to overcome for transfer to the clinic to become a reality. Although preclinical and first-in-human clinical evidence suggests that ultra-high dose rates (UHDRs) induce a sparing effect in normal tissue without modifying the therapeutic effect on the tumor, successful clinical translation of FLASH-RT depends on a better understanding of the biological mechanisms underpinning the sparing effect. Suitable in vitro studies are required to fully understand the radiobiological mechanisms associated with UHDRs. From a technical point of view, it is also crucial to develop optimal technologies in terms of beam irradiation parameters for producing FLASH conditions. This review provides an overview of the research progress of FLASH RT and discusses the potential challenges to be faced before its clinical application. We critically summarize the preclinical evidence and in vitro studies on DNA damage following UHDR irradiation. We also highlight the ongoing developments of technologies for delivering FLASH-compliant beams, with a focus on laser-driven plasma accelerators suitable for performing basic radiobiological research on the UHDR effects.

Clinical and Biological Predictors of Cancer Incidence and Mortality in Patients with Stable Coronary Artery Disease.

Clinical and epidemiological evidence has recently revealed a link between coronary artery disease (CAD) and cancer. Shared risk factors and common biological pathways are probably involved in both pathological conditions. The aim of this paper was to evaluate whether and which conventional risk factors and novel circulating biomarkers could predict cancer incidence and death in patients with CAD. The study included 750 CAD patients, who underwent blood sampling for the evaluation of systemic inflammatory indexes (NLR and SII) and specific biomarkers of oxidative damage (leukocyte telomere length (LTL), mitochondrial DNA copy number (mtDNAcn)). Study participants were followed up for a mean of 5.4 ± 1.2 years. Sixty-seven patients (8.9%) developed cancer during the follow-up time, and nineteen (2.5%) died of cancer. Cox multivariable analysis revealed that age (HR = 1.071; 95% CI: 1.034-1.109; p < 0.001), smoking habit (HR = 1.994; 95% CI: 1.140-3.488; p = 0.016), obesity (HR = 1.708; 95% CI: 1.022-2.854; p = 0.041) and SII (HR = 1.002; 95% CI: 1.001-1.003; p = 0.045) were associated with cancer incidence, while only age (HR = 1.132; 95% CI: 1.052-1.219; p = 0.001) was a predictor of cancer death. Patients with lung and gastrointestinal cancers had significantly higher median mtDNAcn levels than those without cancer. Our study suggests that aggressive risk factor modification and suppression of chronic inflammation may be essential to preventing cancer in CAD patients.

A Longitudinal Study of Individual Radiation Responses in Pediatric Patients Treated with Proton and Photon Radiotherapy, and Interventional Cardiology: Rationale and Research Protocol of the HARMONIC Project.

The Health Effects of Cardiac Fluoroscopy and Modern Radiotherapy (photon and proton) in Pediatrics (HARMONIC) is a five-year project funded by the European Commission that aimed to improve the understanding of the long-term ionizing radiation (IR) risks for pediatric patients. In this paper, we provide a detailed overview of the rationale, design, and methods for the biological aspect of the project with objectives to provide a mechanistic understanding of the molecular pathways involved in the IR response and to identify potential predictive biomarkers of individual response involved in long-term health risks. Biological samples will be collected at three time points: before the first exposure, at the end of the exposure, and one year after the exposure. The average whole-body dose, the dose to the target organ, and the dose to some important out-of-field organs will be estimated. State-of-the-art analytical methods will be used to assess the levels of a set of known biomarkers and also explore high-resolution approaches of proteomics and miRNA transcriptomes to provide an integrated assessment. By using bioinformatics and systems biology, biological pathways and novel pathways involved in the response to IR exposure will be deciphered.

Advanced glycation end products, leukocyte telomere length, and mitochondrial DNA copy number in patients with coronary artery disease and alterations of glucose homeostasis: From the GENOCOR study.

BACKGROUND AND AIM: Alterations of glucose homeostasis can increase advanced glycation end products (AGEs) that exacerbate vascular inflammatory disease and may increase vascular senescence and aging. This study examined the relationships between carboxymethyl-lysine (CML) and soluble receptor for AGEs (sRAGE) with leukocyte telomere length (LTL) and mitochondrial DNA copy number (mtDNAcn), as cell aging biomarkers, in patients with established coronary artery disease (CAD). METHODS AND RESULTS: We studied 459 patients with CAD further categorized as having normal glucose homeostasis (NG, n = 253), pre-diabetes (preT2D, n = 85), or diabetes (T2D, n = 121). All patients were followed up for the occurrence of major adverse cardiovascular events (MACEs). Plasma concentrations of sRAGE and CML were measured by ELISA. mtDNAcn and LTL were measured by qRT-PCR. CML levels were significantly higher in patients with preT2D (p < 0.007) or T2D (p < 0.003) compared with those with NG. mtDNAcn resulted lower in T2D vs preT2D (p = 0.04). At multivariate Cox proportional hazard analysis, short LTL (HR: 2.89; 95% CI: 1.11-10.1; p = 0.04) and high levels of sRAGE (HR: 2.20; 95% CI: 1.01-5.14; p = 0.04) were associated with an increased risk for MACEs in patients with preT2D and T2D, respectively. T2D patients with both short LTL and high sRAGE levels had the highest risk of MACEs (HR: 3.11; 95% CI: 1.11-9.92; p = 0.04). CONCLUSIONS: High levels of sRAGE and short LTL were associated with an increased risk of MACEs, especially in patients with diabetes, supporting the usefulness of both biomarkers of glycemic impairment and aging in predicting cardiovascular outcomes in patients with CAD.

Individual and joint effects of genetic polymorphisms in microRNA-machinery genes on congenital heart disease susceptibility.

Single-nucleotide polymorphisms in miRNA-machinery genes may alter the biogenesis of miRNAs affecting disease susceptibility. In this case-control study, we aimed to evaluate the impact of three single-nucleotide polymorphisms (DICER rs1057035, DROSHA rs10719, and XPO5 rs11077) and their combined effect in a genetic risk score model on congenital heart disease (CHD) risk. A total of 639 participants was recruited, including 125 patients with CHD (65 males; age 9.2 ± 10 years) and 514 healthy controls (289 males; age 15.8 ± 18 years). Genotyping of polymorphisms in miRNA-machinery genes was performed using a TaqMan®SNP genotyping assay. A genetic risk score was calculated by summing the number of risk alleles of selected single-nucleotide polymorphisms. There was a significantly increased risk of CHD in patients with XPO5 rs11077 CC genotype as compared to AC heterozygote and AA homozygote patients (ORadjusted = 1.7; 95% CI: 1.1-2.8; p = 0.018). A clear tendency to significance was also found for DROSHA rs10719 AA genotype and CHD risk for both codominant and recessive models (ORadjusted = 1.8; 95% CI: 0.91-3.8; p = 0.09 and ORadjusted = 1.9; 95% CI: 0.92-4; p = 0.08, respectively). The resulting genetic risk score predicted a 1.73 risk for CHD per risk allele (95% CI: 1.2-2.5; p = 0.002). Subjects in the top tertile of genetic risk score were estimated to have more than three-fold increased risk of CHD compared with those in the bottom tertile (ORadjusted = 3.52; 95% CI: 1.4-9; p = 0.009). Our findings show that the genetic variants in miRNA-machinery genes might participate in the development of CHD.

Biomarkers of Genotoxicity in Medical Workers Exposed to Low-Dose Ionizing Radiation: Systematic Review and Meta-Analyses.

Medical staff represent the largest group of workers occupationally exposed to ionizing radiation (IR). Chronic exposure to low-dose IR may result in DNA damage and genotoxicity associated with increased risk of cancer. This review aims to identify the genotoxicity biomarkers that are the most elevated in IR-exposed vs. unexposed health workers. A systematic review of the literature was performed to retrieve relevant studies with various biomarkers of genotoxicity. Subsequent meta-analyses produced a pooled effect size for several endpoints. The search procedure yielded 65 studies. Chromosome aberrations (CA) and micronuclei (MN) frequencies were significantly different between IR-exposed and unexposed workers (θpooled = 3.19, 95% CI 1.46-4.93; and θpooled = 1.41, 95% CI 0.97-1.86, for total aberrant cells and MN frequencies, respectively), which was not the case for ring chromosomes and nucleoplasmic bridges. Although less frequently used, stable translocations, sister chromatid exchanges (SCE) and comet assay endpoints were also statistically different between IR-exposed and unexposed workers. This review confirms the relevance of CA and MN as genotoxicity biomarkers that are consistently elevated in IR-exposed vs. unexposed workers. Other endpoints are strong candidates but require further studies to validate their usefulness. The integration of the identified biomarkers in future prospective epidemiological studies is encouraged.

Functional characterization and circulating expression profile of dysregulated microRNAs in BAV-associated aortopathy.

Compelling evidence has shown that microRNAs (miRs) are involved in the pathophysiology of BAV-associated aortopathy. The purpose of this study was to assess the biological role as well as the circulating expression of two miRs (miR-424-3p and miR-3688-3p) that have been previously identified as significantly dysregulated in thoracic aortic aneurysm specimens of BAV patients. Bioinformatic tools were used to predict miR gene targets followed by functional validation transfecting synthetic miR mimics and negative controls into human aortic smooth muscle cells (HASMCs). Levels of miRs and target genes were evaluated by qRT-PCR. The circulating miR expression profile analysis was assessed on plasma samples collected from a cohort of 72 patients with aortopathy including 39 BAV (33 males; 58 ± 13 years) and 33 TAV patients (26 males; 67 ± 9 years). Computational analysis revealed that SMAD7 and YAP1 were potential targets of miR-424-3p and miR-3688-3p, respectively. Transfection with mimics confirmed a significantly decreased gene expression of SMAD7 and YAP1 compared to mimic negative control (p = 0.04 and p = 0.0005, respectively) or blank control (p = 0.01 and p = 0.0007, respectively). Overexpression of miR-3688-3p also significantly upregulated pro-apoptotic caspase-3 gene expression compared to mimic negative control (p = 0.02) or blank control (p = 0.01). Furthermore, a significant down-regulation of the circulating miR-424-3p was observed in BAV compared to TAV patients (p = 0.001). In multiple linear regression analysis, the aortic valve morphology (ß = - 0.29, p = 0.04) and the presence of aortic stenosis (ß = - 0.28, p = 0.03) had a significant effect on the miR-424-3p expression. In conclusion, our study demonstrated that miR-424-3p and miR-3688-3p directly targeted SMAD7 and YAP1 in HASMCs, pivotal genes of the TGF-ß and Hippo-signaling pathways. Circulating miR-424-3p was also found to be significantly decreased in BAV patients when compared to TAV patients, especially in patients with aortic stenosis. Further large studies of well-characterized BAV patient cohorts are needed to define the clinical significance of the miR-424-3p.

The HARMONIC project: study design for the assessment of radiation doses and associated cancer risks following cardiac fluoroscopy in childhood.

The HARMONIC project (Health Effects of Cardiac Fluoroscopy and Modern Radiotherapy in Paediatrics) is a European study aiming to improve our understanding of the long-term health risks from radiation exposures in childhood and early adulthood. Here, we present the study design for the cardiac fluoroscopy component of HARMONIC. A pooled cohort of approximately 100 000 patients who underwent cardiac fluoroscopy procedures in Belgium, France, Germany, Italy, Norway, Spain or the UK, while aged under 22 years, will be established from hospital records and/or insurance claims data. Doses to individual organs will be estimated from dose indicators recorded at the time of examination, using a lookup-table-based dosimetry system produced using Monte Carlo radiation transport simulations and anatomically realistic computational phantom models. Information on beam geometry and x-ray energy spectra will be obtained from a representative sample of radiation dose structured reports. Uncertainties in dose estimates will be modelled using 2D Monte Carlo methods. The cohort will be followed up using national registries and insurance records to determine vital status and cancer incidence. Information on organ transplantation (a major risk factor for cancer development in this patient group) and/or other conditions predisposing to cancer will be obtained from national or local registries and health insurance data, depending on country. The relationship between estimated radiation dose and cancer risk will be investigated using regression modelling. Results will improve information for patients and parents and aid clinicians in managing and implementing changes to reduce radiation risks without compromising medical benefits.

Independent and Combined Effects of Telomere Shortening and mtDNA4977 Deletion on Long-term Outcomes of Patients with Coronary Artery Disease.

Aging is one of the main risk factors for cardiovascular disease, resulting in a progressive organ and cell decline. This study evaluated a possible joint impact of two emerging hallmarks of aging, leucocyte telomere length (LTL) and common mitochondrial DNA deletion (mtDNA4977), on major adverse cardiovascular events (MACEs) and all-cause mortality in patients with coronary artery disease (CAD). We studied 770 patients (673 males, 64.8 ± 8.3 years) with known or suspected stable CAD. LTL and mtDNA4977 deletion were assessed in peripheral blood using qRT-PCR. During a median follow-up of 5.4 ± 1.2 years, MACEs were 140 while 86 deaths were recorded. After adjustments for confounding risk factors, short LTLs and high mtDNA4977 deletion levels acted independently as predictors of MACEs (HR: 2.2, 95% CI: 1.2-3.9, p = 0.01 and HR: 1.7, 95% CI: 1.1-2.9, p = 0.04; respectively) and all-cause mortality events (HR: 2.1, 95% CI: 1.1-4.6, p = 0.04 and HR: 2.3, 95% CI: 1.1-4.9, p = 0.02; respectively). Patients with both short LTLs and high mtDNA4977 deletion levels had an increased risk for MACEs (HR: 4.3; 95% CI: 1.9-9.6; p = 0.0006) and all-cause mortality (HR: 6.0; 95% CI: 2.0-18.4; p = 0.001). The addition of mtDNA4977 deletion to a clinical reference model was associated with a significant net reclassification improvement (NRI = 0.18, p = 0.01). Short LTL and high mtDNA4977 deletion showed independent and joint predictive value on adverse cardiovascular outcomes and all-cause mortality in patients with CAD. These findings strongly support the importance of evaluating biomarkers of physiological/biological age, which can predict disease risk and mortality more accurately than chronological age.

Targeted Next-Generation Sequencing in Patients with Non-syndromic Congenital Heart Disease.

Congenital heart disease (CHD) is a genetically heterogeneous disease. Targeted next-generation sequencing (NGS) offers a unique opportunity to sequence multiple genes at lower cost and effort compared to Sanger sequencing. We tested a targeted NGS of a specific gene panel in a relatively large population of non-syndromic CHD patients. The patient cohort comprised 68 CHD patients (45 males; 8.3 ± 1.7 years). Amplicon libraries for 16 CHD-strictly related genes were generated using a TruSeq® Custom Amplicon kit (Illumina, CA) and sequenced using the Illumina MiSeq platform. Sequence data were processed through the MiSeq Reporter and wANNOVAR softwares. After applying stringent filtering criteria, 20 missense variants in 9 genes were predicted to be damaging and were validated by Sanger sequencing with 100% concordance. Fourteen variants were present in public databases with very rare allele frequency, of which four variants (p.Arg25Cys in NKX2-5, p.Val763Ile in ZFPM2, p.Arg1398Gln and Gly1826Asp in MYH6) have been previously linked to CHD or cardiomyopathy. The remaining six variants in four genes (GATA4, NKX2-5, NOTCH1, TBX1) were novel mutations, currently not found in public databases, and absent in 200 control alleles of healthy subjects. Four patients (5.8%) carried two missense variants (1 compound heterozygote in the same gene and 3 double heterozygotes in different genes), with possibly synergistic deleterious effects. Targeted NGS is a powerful and efficient tool to detect DNA sequence variants in multiple genes, providing the opportunity for discovery of the co-occurrence of two or more missense rare variants.

Repair activity of oxidatively damaged DNA and telomere length in human lung epithelial cells after exposure to multi-walled carbon nanotubes.

One type of carbon nanotubes (CNTs) (MWCNT-7, from Mitsui) has been classified as probably carcinogenic to humans, however insufficient data does not warrant the same classification for other types of CNTs. Experimental data indicate that CNT exposure can result in oxidative stress and DNA damage in cultured cells, whereas these materials appear to induce low or no mutagenicity. Therefore, the present study aimed to investigate whether in vitro exposure of cultured airway epithelial cells (A549) to multi-walled CNTs (MWCNTs) could increase the DNA repair activity of oxidatively damaged DNA and drive the cells toward replicative senescence, assessed by attrition of telomeres. To investigate this, H2O2 and KBrO3 were used to induce DNA damage in the cells and the effect of pre-exposure to MWCNT tested for a change in repair activity inside the cells or in the extract of treated cells. The effect of MWCNT exposure on telomere length was investigated for concentration and time response. We report a significantly increased repair activity in A549 cells exposed to MWCNTs compared to non-exposed cells, suggesting that DNA repair activity may be influenced by exposure to MWCNTs. The telomere length was decreased at times longer than 24h, but this decrease was not concentration dependent. The results suggest that the seemingly low mutagenicity of CNTs in cultured cells may be associated with an increased DNA repair activity and a replicative senescence, which may counteract the manifestation of DNA lesions to mutations.

Stress echo 2020: the international stress echo study in ischemic and non-ischemic heart disease.

BACKGROUND: Stress echocardiography (SE) has an established role in evidence-based guidelines, but recently its breadth and variety of applications have extended well beyond coronary artery disease (CAD). We lack a prospective research study of SE applications, in and beyond CAD, also considering a variety of signs in addition to regional wall motion abnormalities. METHODS: In a prospective, multicenter, international, observational study design, > 100 certified high-volume SE labs (initially from Italy, Brazil, Hungary, and Serbia) will be networked with an organized system of clinical, laboratory and imaging data collection at the time of physical or pharmacological SE, with structured follow-up information. The study is endorsed by the Italian Society of Cardiovascular Echography and organized in 10 subprojects focusing on: contractile reserve for prediction of cardiac resynchronization or medical therapy response; stress B-lines in heart failure; hypertrophic cardiomyopathy; heart failure with preserved ejection fraction; mitral regurgitation after either transcatheter or surgical aortic valve replacement; outdoor SE in extreme physiology; right ventricular contractile reserve in repaired Tetralogy of Fallot; suspected or initial pulmonary arterial hypertension; coronary flow velocity, left ventricular elastance reserve and B-lines in known or suspected CAD; identification of subclinical familial disease in genotype-positive, phenotype- negative healthy relatives of inherited disease (such as hypertrophic cardiomyopathy). RESULTS: We expect to recruit about 10,000 patients over a 5-year period (2016-2020), with sample sizes ranging from 5,000 for coronary flow velocity/ left ventricular elastance/ B-lines in CAD to around 250 for hypertrophic cardiomyopathy or repaired Tetralogy of Fallot. This data-base will allow to investigate technical questions such as feasibility and reproducibility of various SE parameters and to assess their prognostic value in different clinical scenarios. CONCLUSIONS: The study will create the cultural, informatic and scientific infrastructure connecting high-volume, accredited SE labs, sharing common criteria of indication, execution, reporting and image storage of SE to obtain original safety, feasibility, and outcome data in evidence-poor diagnostic fields, also outside the established core application of SE in CAD based on regional wall motion abnormalities. The study will standardize procedures, validate emerging signs, and integrate the new information with established knowledge, helping to build a next-generation SE lab without inner walls.

miRNome Profiling in Bicuspid Aortic Valve-Associated Aortopathy by Next-Generation Sequencing.

The molecular mechanisms underlying thoracic aortic aneurysm (TAA) in patients with bicuspid aortic valve (BAV) are incompletely characterized. MicroRNAs (miRNAs) may play a major role in the different pathogenesis of aortopathy. We sought to employ next-generation sequencing to analyze the entire miRNome in TAA tissue from patients with BAV and tricuspid aortic valve (TAV). In the discovery stage, small RNA sequencing was performed using the Illumina MiSeq platform in 13 TAA tissue samples (seven patients with BAV and six with TAV). Gene ontology (GO) and KEGG pathway analysis were used to identify key pathways and biological functions. Validation analysis was performed by qRT-PCR in an independent cohort of 30 patients with BAV (26 males; 59.5 ± 12 years) and 30 patients with TAV (16 males; 68.5 ± 9.5 years). Bioinformatic analysis identified a total of 489 known mature miRNAs and five novel miRNAs. Compared to TAV samples, 12 known miRNAs were found to be differentially expressed in BAV, including two up-regulated and 10 down-regulated (FDR-adjusted p-value ≤ 0.05 and fold change ≥ 1.5). GO and KEGG pathway enrichment analysis (FDR-adjusted p-value < 0.05) identified different target genes and pathways linked to BAV and aneurysm formation, including Hippo signaling pathway, ErbB signaling, TGF-beta signaling and focal adhesion. Validation analysis of selected miRNAs confirmed the significant down-regulation of miR-424-3p (p = 0.01) and miR-3688-3p (p = 0.03) in BAV patients as compared to TAV patients. Our study provided the first in-depth screening of the whole miRNome in TAA specimens and identified specific dysregulated miRNAs in BAV patients.

Effects of Highly Polluted Environment on Sperm Telomere Length: A Pilot Study.

High environmental pressure may impair male fertility by affecting sperm quality, but the real effect remains controversial. Herein, we assessed the influence of environmental exposure on telomere length (TL) in both leukocytes (LTL) and sperm cells (STL). A pilot biomonitoring study was conducted in 112 clinically healthy, normospermic men living in various areas of Campania region (South of Italy) with high (n = 57, High Group) or low (n = 55, Low Group) environmental pressure. TL analysis was assessed by quantitative real time-PCR. STL was not significantly correlated with either age (p = 0.6) or LTL (p = 0.7), but was significantly longer in the High Group compared with the Low Group (p = 0.04). No significant difference was observed between leukocyte TL in the High or Low Group. Our results showed that male residents in areas with high environment exposure had a significant increase in STL. This finding supports the view that the human semen is a sentinel biomarker of environmental exposure.

Arsenic exposure, genetic susceptibility and leukocyte telomere length in an Italian young adult population.

Arsenic-induced health effects may be associated with critically shortened telomeres. However, few data are available on the effects of arsenic exposure on telomere length. The aim of this study was to investigate the effects of chronic arsenic exposure on leukocyte telomere length (LTL) as well as the contribution of common polymorphisms in genes implicated in arsenic metabolism (GSTT1 and GSTM1) and DNA repair (hOGG1 and XRCC1). A group of 241 healthy subjects was enrolled from four areas of Italy known to be affected by natural or anthropogenic arsenic pollution. Urine samples were tested for inorganic As (iAs), monomethylarsinic (MMA) and dimethylarsinic acid (DMA). LTL was evaluated by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR). Genotyping was carried out by PCR-RFLP on leukocyte DNA. In multiple linear regression analysis, LTL was significantly and inversely correlated with age (ß = -0.231, P = 0.006) and showed a certain trend toward significance with iAs urinary concentration (log10 iAs, ß = -0.106, P = 0.08). The genotype distribution showed significant associations between GSTT1 and the As concentration (log10 iAs, P = 0.01) and metabolite patterns (log10 DMA, P = 0.05) in the urine. However, GST genes did not interact with arsenic exposure in the modulation of LTL. Conversely, the combined presence of a higher level of iAs + MMA + DMA ≥ 19.3 µg/l (F = 6.0, P interaction = 0.01), Asi ≥ 3.86 (F = 3.9, P interaction = 0.04) µg/l, iAs + MMA + DMA ≥ 15 µg/l (F = 4.2, P interaction = 0.04) and hOGG1 Cys allele was associated with a significantly lower LTL. An interaction between XRCC1 Arg399Gln and arsenic exposure was also observed (all P interaction = 0.04). These findings suggest that telomere shortening may represent a mechanism that contributes to arsenic-related disease. The interaction of hOGG1 and XRCC1 DNA repair polymorphisms and exposure enhances telomeric DNA damage. Future studies are warranted to understand better the epidemiologic impact of arsenic on telomere function as well as to identify the subgroups of exposed subjects who need better health surveillance.

The Potential Role of Lung Ultrasound B-Lines for Detection of Lung Radio-Induced Toxicity in Breast Cancer Patients after Radiation Therapy.

BACKGROUND AND PURPOSE: Breast cancer patients exposed to doses of radiation after radiotherapy could develop toxicity to lung. Lung ultrasound (LUS) is able to detect interstitial lung disease by the evaluation of B-lines. The aim of our study was to assess the number of B-lines to diagnose lung involvement after chest radiotherapy. MATERIALS AND METHODS: We measured LUS B-lines in the treated and contralateral lung of 20 breast cancer patients, 1-3 months after the end of radiotherapy and 1 year after previous LUS. The sum of the B-lines number in the 72 sites on anterior and posterior chest yielded a global B-lines score. RESULTS: B-lines were more numerous in treated (median: 21; 1st-3rd quartiles: 11-31) versus untreated hemithorax (median: 3; 1st-3rd quartiles: 1-5) in both examination at T1-3 months (Kolmogorov-Smirnov test P < 0.001) and T1 year (median: 21; 1st-3rd quartiles: 12-28 vs. median: 4; 1st-3rd quartiles: 1-10; Kolmogorov-Smirnov test P < 0.01). Within the treated hemithorax, B-lines were more frequent in the anterior than in the posterior chest in both examination at T1-3 months (Kolmogorov-Smirnov test: P < 0.0001) and T1 year (Kolmogorov-Smirnov test: P < 0.01). Abnormal scores (B-lines>5) were present in 17/20 treated versus 7/20 untreated hemithoraxes (85.0 vs. 35.0%, P < 0.01) in the first LUS and likewise in 16/17 treated versus 7/17 in untreated hemithorax (94.1% vs. 41.2%, P < 0.01) after 1-year follow-up. CONCLUSION: Among women receiving radiotherapy after breast cancer, B-lines are present predominantly in the irradiated lung. These data suggest that B-lines by LUS could provide, at a subclinical stage, a radiation-free biomarker of radiotherapy-induced lung damage.

Chronic and acute effects of endurance training on telomere length.

Telomere shortening is considered a cellular marker of health status and biological ageing. Exercise may influence the health and lifespan of an individual by affecting telomere length (TL). However, it is unclear whether different endurance exercise levels may have beneficial or detrimental effects on biological aging. The aims of the study were to assess both chronic and acute effects of endurance training on TL after an exceptional and extreme trail race. TL was assessed in 20 endurance athletes (17 males; age = 45.4 ± 9.2 years) and 42 age- and gender-matched sedentary controls (32 males; age = 45.9 ± 9.5 years) with quantitative real-time PCR at baseline conditions. Of the 20 runners enrolled in the 'Tor des Géants ®' ultra-distance trail race, 15 athletes (12 males; age = 47.2 ± 8.5 years) were re-evaluated at the intermediate point and 14 athletes (11 males; age = 47.1 ± 8.8 years) completed the competition and were analysed at the final point. Comparison between the two groups (endurance athletes vs. sedentary controls) revealed a significant difference in TL (1.28 ± 0.4 vs. 1.02 ± 0.3, P = 0.005). TL was better preserved in elder endurance runners compared with the same age control group (1.3 ± 0.27 vs. 0.91 ± 0.21, P = 0.003). TL was significantly reduced at the intermediate (0.88 ± 0.36 vs. 1.11 ± 0.34, P = 0.002) and final point compared with baseline measurements (0.86 ± 0.4 vs. 1.11 ± 0.34, P = 0.0006) for athletes engaged in the ultra-marathon race. Our data suggest that chronic endurance training may provide protective effects on TL attenuating biological aging. Conversely, acute exposure to an ultra-distance endurance trail race implies telomere shortening probably caused by oxidative DNA damage.

Neuropsychological Testing in Interventional Cardiology Staff after Long-Term Exposure to Ionizing Radiation.

This study aimed at comparing neuropsychological test scores in 83 cardiologists and nurses (exposed group, EG) working in the cardiac catheterization laboratory, and 83 control participants (non exposed group, nEG), to explore possible cognitive impairments. The neuropsychological assessment was carried out by means of a battery called "Esame Neuropsicologico Breve." EG participants showed significantly lower scores on the delayed recall, visual short-term memory, and semantic lexical access ability than the nEG ones. No dose response could be detected. EG participants showed lower memory and verbal fluency performances, as compared with nEG. These reduced skills suggest alterations of some left hemisphere structures that are more exposed to IR in interventional cardiology staff. On the basis of these findings, therefore, head protection would be a mandatory good practice to reduce effects of head exposure to ionizing radiation among invasive cardiology personnel (and among other exposed professionals).