Nanotechnology is a fast growing emerging field, the benefits of which are widely publicized. Our current knowledge of the health effects of metal nanoparticles such as nano-sized cobalt (Nano-Co) and titanium dioxide (Nano-TiO2) is limited but suggests that metal nanoparticles may exert more adverse pulmonary effects as compared with standard-sized particles. To investigate metal nanoparticle-induced genotoxic effects and the potential underlying mechanisms, human lung epithelial cell lines A549 cells were exposed to Nano-Co and Nano-TiO2. Our results showed that exposure of A549 cells to Nano-Co caused reactive oxygen species (ROS) generation that was abolished by pretreatment of cells with ROS inhibitors or scavengers, such as catalase and N-acetyl-L(+)-cysteine (NAC). However, exposure of A549 cells to Nano-TiO2 did not cause ROS generation. Nano-Co caused DNA damage in A549 cells which was reflected by an increase in length, width, and DNA content of the comet tail by Comet assay. Exposure of A549 cells to Nano-Co also caused a dose-and a time- response increased expression of phosphorylated histone H2AX (γ-H2AX), Rad51 and phosphorylated p53. These effects were significantly attenuated when A549 cells were pre-treated with catalase or NAC. Nano-TiO2 did not show these effects. These results suggest that oxidative stress may be involved in Nano-Co-induced DNA damage. To further investigate the pathways involved in the Nano-Co-induced DNA damage, we measured the phosphorylation of ataxia telangiectasia mutant (ATM). Our results showed that phosphorylation of ATM was increased when A549 cells were exposed to Nano-Co, and this effect was attenuated when cells were pretreated with catalase or NAC. Pre-treatment of A549 cells with an ATM specific inhibitor, KU55933, significantly abolished Nano-Co-induced DNA damage. Furthermore, pre-treatment of A549 cells with ROS scavengers, such as catalase and NAC, significantly abolished Nano-Co-induced increased expression of phosphorylated ATM. Taken together, oxidative stress and ATM activation are involved in Nano-Co-induced DNA damage. These findings have important implications for understanding the potential health effects of metal nanoparticle exposure.

The diagnostic value of the concentration of circulating cell-free DNA (cfDNA) for breast cancer has generated inconsistent results. The aim of this study was to evaluate the first diagnostic value of the concentration of cfDNA for breast cancer by meta-analysis. Studies were retrieved by searching PubMed, Cochrane Library, and Web of Science before June 2018. Sensitivity, specificity, diagnostic odds ratio (DOR), the summary receiver operating characteristic (SROC) curve, and the area under curve (AUC) were used to summarize overall diagnostic performance. The random-effects model was used to calculate the pooled statistics. Subgroup analysis and meta-regression analysis were carried out to detect the source of heterogeneity. A total of 13 studies were identified with 1,087 breast cancer patients and 720 healthy controls. Overall, the pooled sensitivity and specificity of concentration of cfDNA for breast cancer were 87% (95% CI, 73–94%) and 87% (95% CI, 79–93%), respectively. The pooled DOR was 32.93 (95% CI, 13.52–80.19) and the SROC curve revealed an AUC of 0.93 (95% CI, 0.91–0.95). Meta-regression analysis showed that no covariate had a significant correlation with relative DOR (RDOR). Publication bias was not detected in this meta-analysis. This meta-analysis indicates that the concentration of cfDNA has potential first diagnostic value for breast cancer and plasma may be a better source of cfDNA for detection of breast cancer.

Previous studies have shown that ambient ultrafine particles with diameters less than 100 nm (UFPs) can pass from the lungs to the circulation because of their very small diameter, and induce lung oxidative stress with a resultant dysfunction of lung endothelial cells. However, no studies have addressed the potential combined effects of UFPs and cigarette smoke on vascular endothelial cells. We hypothesized that co-exposure to UFPs and cigarette smoke extract (CSE) may cause combined effects on activation of endothelial cells and dysfunction of endothelium by oxidative stress through activation of NADPH oxidase. We determined the effects of UFPs with or without CSE on mouse pulmonary microvascular endothelial cells (MPMVEC) obtained from C57BL/6J (wild-type) and gp91phox knock-out mice (gp91phox is one of the key components of NADPH oxidase, one of ROS generators). Our results showed that exposure of MPMVEC from wild-type mice to UFPs or CSE, at a non-toxic dose, induced reactive oxygen species (ROS) generation, increased phosphorylation of p38 and Erk1/2, and up-regulated early growth response -1 (Egr-1) and IL-6 genes. These effects were significantly enhanced when cells were co-exposed to both UFPs and CSE. However, exposure of MPMVEC from gp91phox knock-out mice did not induce the above effects. Furthermore, UFPs- and/or CSE-induced Egr-1 mRNA upregulation was attenuated significantly when cells were pre-treated with p38 specific inhibitor, SB 203580, or MEK1/2 inhibitor, PD98059, and Egr-1 siRNA treatment abolished UFPs- and/or CSE- induced overexpression of IL-6. Our results suggest that UFPs and/or CSE caused activation of NADPH oxidase, resulting in ROS generation that led to activation of MAPKs through induced phosphorylation of p38 and ERK1/2 MAPKs and upregulation of Egr-1. Those effects may further result in endothelial dysfunction through production of cytokines such as IL-6. Our results suggest that co-exposure to UFPs and CSE causes enhanced injury to endothelial cells.

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