No abstract

Laser-driven electron accelerators are capable of producing high-energy electron bunches in shorter distances than conventional radiofrequency accelerators. To date, our knowledge of the radiobiological effects in cells exposed to electrons using a laser-plasma accelerator is still very limited. In this study, we compared the dose-response curves for micronucleus (MN) frequency and telomere length in peripheral blood lymphocytes exposed to laser-driven electron pulse and X-ray radiations. Additionally, we evaluated the effects on cell survival of in vitro tumor cells after exposure to laser-driven electron pulse compared to electron beams produced by a conventional radiofrequency accelerator used for intraoperative radiation therapy. Blood samples from two different donors were exposed to six radiation doses ranging from 0 to 2 Gy. Relative biological effectiveness (RBE) for micronucleus induction was calculated from the alpha coefficients for electrons compared to X rays (RBE = alpha laser/alpha X rays). Cell viability was monitored in the OVCAR-3 ovarian cancer cell line using trypan blue exclusion assay at day 3, 5 and 7 postirradiation (2, 4, 6, 8 and 10 Gy). The RBE values obtained by comparing the alpha values were 1.3 and 1.2 for the two donors. Mean telomere length was also found to be reduced in a significant dose-dependent manner after irradiation with both electrons and X rays in both donors studied. Our findings showed a radiobiological response as mirrored by the induction of micronuclei and shortening of telomere as well as by the reduction of cell survival in blood samples and cancer cells exposed in vitro to laser-generated electron bunches. Additional studies are needed to improve preclinical validation of the radiobiological characteristics and efficacy of laser-driven electron accelerators in the future.

Holt-Oram syndrome (HOS) is a rare autosomal dominant disorder characterized by upper limb defects and congenital heart defects (CHD), which are often simple septal and conduction defects, less frequently complex CHDs. We report on a 9 year-old boy with clinical and radiologic features of HOS consisting of bilateral asymmetric hypoplastic thumbs, generalized brachydactyly, limited supination due to radioulnar synostosis, and sloping shoulders, and intermediate atrioventricular canal defect (AVCD) with aortic coarctation. A de novo, previously described mutation, (Arg279ter) was identified in the TBX5 gene. Molecular characterization of this mutation was carried out due to the atypical CHD. In order to investigate whether the mutated transcript of TBX5 was able to escape the post-transcriptional surveillance mechanism and to produce a truncated TBX5 protein, we analyzed the TBX5 transcript, and protein pattern in HOS, and WT cardiac tissues. Our results demonstrate that the mutant TBX5 transcript is cleared by the cellular mechanism of surveillance. This data provides some support for the hypothesis that a dominant negative mutation, which strongly impairs the WT allele, might be too hazardous to be maintained. The literature suggests that HOS is relatively common among syndromes associated with AVCD.

No abstract

Cigarette smoking is a powerful human germ cell mutagen and teratogen. Congenital heart defects (CHD) is the most prevalent of all birth defects and leading cause of death in the first year of life. The purpose of this article is to review the epidemiology of the impact of cigarette smoking on CHD risk as well as to discuss the potential biological mechanisms of smoking-mediated abnormal cardiac development. Although epidemiological studies of association between parental smoking and CHD are limited, biological evidence support the concept that cigarette smoking may substantially contribute to the aetiology of CHD through induction of either male and female germ-cell mutation or interference with epigenetic pathways. Further research is needed to better define the relationship between parental smoking and the risk of heart defects as well as to assess parental-fetal gene-smoking interactions.

The GSTP1 gene, highly expressed early in fetal life, is the most abundant phase 2 xenobiotic metabolism enzyme in a human placenta. Fetal inherited GSTP1 Ile105Val polymorphism may modify the metabolism and excretion of xenobiotics from fetal tissue and increase the risk of congenital heart disease (CHD). This study aimed to analyze the joint effects of GSTP1 genetic polymorphism (Ile105Val) and maternal environmental exposure on CHD risk. Within a case-control design, a total of 190 children with CHD (104 boys age 4 ± 5.6 years) and 190 healthy children (114 newborn boys) were genotyped for the GSTP1 Ile105Val polymorphism. Mothers completed a structured questionnaire on the demographics as well as the preconceptional and lifestyle exposures. A higher frequency of mothers of children with CHD (38 %) reported a positive history of exposure to toxicants (occupational and environmental) than mothers of healthy children (23 %) (p = 0.0013). Logistic regression analysis showed that maternal occupational and environmental exposures increased the risk of CHD (odds ratio, 2.6; 95 % confidence interval, 1.6-4.2; p < 0.0001). No significant differences in Ile105Val genotype frequencies were observed between the children with CHD and the healthy children (p = 0.9). Furthermore, case-control analysis showed no evidence of significant interaction between the maternal exposures and GSTP1 polymorphism. Maternal exposure to toxicants increased the risk of children with CHD. However, fetal GSTP1 Ile105Val polymorphism did not increase the risk of CHD.

Cardiac diagnostic or therapeutic testing is an essential tool for diagnosis and treatment of cardiovascular disease, but it also involves considerable exposure to ionizing radiation. Every exposure produces a corresponding increase in cancer risk, and risks are highest for radiation exposure during infancy and adolescence. Recent studies on chromosomal biomarkers corroborate the current radioprotection assumption showing that even modest radiation load due to cardiac catheter-based fluoroscopic procedures can damage the DNA of the cell. In this article, we review the biological and clinical risks of cardiac imaging employing ionizing radiation. We also discuss the perspectives offered by the use of molecular biomarkers in order to better assess the long-term development of health effects.

Congenital heart defects (CHDs) are the most prevalent of all birth defects and the leading cause of death in the first year of life. The molecular causes of most CHDs remain largely unknown. The LIM homeodomain transcriptor factor ISL1 is a marker for undifferentiated cardiac progenitor cells that give rise to both the right ventricle and the inflow and outflow tracts, which are affected by several cardiovascular malformations. Contradictory findings about the role of the ISL1 rs1017 single-nucleotide polymorphism in increasing the risk of CHD have been reported. In this study, we aimed to investigate whether the ISL1 rs1017 genetic polymorphism conferred susceptibility to CHD in the white population. In a case-control study design, 309 patients with CHD (197 men [age 21.3 ± 25.2]) and 500 healthy controls (272 men [age 15.7 ± 21.3]) were genotyped for the ISL1 rs1017 polymorphism. No significant difference in the genotype and variant allele distributions was found between patients and controls. In addition, the ISL1 rs1017 polymorphism was not associated with the risk of CHD neither overall (p = 0.7) nor stratifying the population by sex and CHD classification. In conclusion, ISL1 common variant rs1017 is not associated with increased genetic risk of CHD in the white population.