Personalized neoantigen vaccine enhances the therapeutic efficacy of bevacizumab and anti-PD-1 antibody in advanced non-small cell lung cancer.

Clinically, a considerable number of non-small cell lung cancer (NSCLC) patients are unable to receive or resist chemotherapy, and the efficacy of non-chemotherapy treatment strategies based on anti-angiogenic agents combined with immune checkpoint blockade is still unsatisfactory. Neoantigen vaccine, based on personalized tumor DNA mutations, could elicit tumor specific T cell infiltration into the tumor site, exerting potent anti-tumor efficacy. Here, we evaluated the feasibility and safety of a new antitumor strategy by adding neoantigen vaccine to the regimen of bevacizumab and anti-PD-1 antibody. Firstly, 7 novel immunogenic neoantigen peptides were identified and developed for neoantigen vaccine (LLCvac), which can elicit strong antitumor immune response in vivo. Then, in orthotopic lung cancer model, LLCvac further combining with bevacizumab and anti-PD-1 antibody exerted a stronger antitumor effect, exhibiting significant decrease of tumor volume without obvious toxicity. Furthermore, tumor immune microenvironment assessment also showed that the proportion of neoantigen-specific T cells in blood could be induced dramatically by the combined therapy. And a large amount of neoantigen-specific Ki67-positive CD8+ T cells were found in tumor tissues, which infiltrated tumor tissues effectively to kill tumor cells expressing identified neoantigens. Overall, these results suggested that this combined therapy could safely induce robust antitumor efficacy, serving as an effective chemotherapy-free strategy for NSCLC treatment.

Impact of Hepatic Pedicle Clamping on Long-Term Survival Following Hepatectomy for Hepatocellular Carcinoma: Stratified Analysis Based on Intraoperative Blood Transfusion Status.

BACKGROUND: Hepatic pedicle clamping (HPC) is frequently utilized during hepatectomy to reduce intraoperative bleeding and diminish the need for intraoperative blood transfusion (IBT). The long-term prognostic implications of HPC following hepatectomy for hepatocellular carcinoma (HCC) remain under debate. This study aims to elucidate the association between HPC and oncologic outcomes after HCC resection, stratified by whether IBT was administered. PATIENTS AND METHODS: Prospectively collected data on patients with HCC who underwent curative resection from a multicenter database was studied. Patients were stratified into two cohorts on the basis of whether IBT was administered. The impact of HPC on long-term overall survival (OS) and recurrence-free survival (RFS) between the two cohorts was assessed by univariable and multivariable Cox regression analyses. RESULTS: Of 3362 patients, 535 received IBT. In the IBT cohort, using or not using HPC showed no significant difference in OS and RFS outcomes (5-year OS and RFS rates 27.9% vs. 24.6% and 13.8% vs. 12.0%, P = 0.810 and 0.530). However, in the non-IBT cohort of 2827 patients, the HPC subgroup demonstrated significantly decreased OS (5-year 45.9% vs. 56.5%, P < 0.001) and RFS (5-year 24.7% vs. 33.3%, P < 0.001) when compared with the subgroup without HPC. Multivariable Cox regression analysis identified HPC as an independent risk factor of OS and RFS [hazard ratios (HR) 1.16 and 1.12, P = 0.024 and 0.044, respectively] among patients who did not receive IBT. CONCLUSIONS: The impact of HPC on the oncological outcomes following hepatectomy for patients with HCC differed significantly whether IBT was administered, and HPC adversely impacted on long-term survival for patients without receiving IBT during hepatectomy.

Association of Concurrent Metabolic Syndrome with Long-term Oncological Prognosis Following Liver Resection for Hepatocellular Carcinoma Among Patients with Chronic Hepatitis B Virus Infection: A Multicenter Study of 1753 Patients.

BACKGROUND: Although hepatitis B virus (HBV) infection remains the main cause of hepatocellular carcinoma (HCC) worldwide, metabolic syndrome, with its increase in prevalence, has become an important and significant risk factor for HCC. This study was designed to investigate the association of concurrent metabolic syndrome with long-term prognosis following liver resection for patients with HBV-related HCC. METHODS: From a Chinese, multicenter database, HBV-infected patients who underwent curative resection for HCC between 2010 and 2020 were identified. Long-term oncological prognosis, including overall survival (OS), recurrence-free survival (RFS), and early (≤2 years of surgery) and late (>2 years) recurrences were compared between patients with versus those without concurrent metabolic syndrome. RESULTS: Of 1753 patients, 163 (9.3%) patients had concurrent metabolic syndrome. Compared with patients without metabolic syndrome, patients with metabolic syndrome had poorer 5-year OS (47.5% vs. 61.0%; P = 0.010) and RFS (28.3% vs. 44.2%; P = 0.003) rates and a higher 5-year overall recurrence rate (67.3% vs. 53.3%; P = 0.024). Multivariate analysis revealed that concurrent metabolic syndrome was independently associated with poorer OS (hazard ratio: 1.300; 95% confidence interval: 1.018-1.660; P = 0.036) and RFS (1.314; 1.062-1.627; P = 0.012) rates, and increased rates of late recurrence (hazard ratio: 1.470; 95% confidence interval: 1.004-2.151; P = 0.047). CONCLUSIONS: In HBV-infected patients with HCC, concurrent metabolic syndrome was associated with poorer postoperative long-term oncologic survival outcomes. These results suggested that patients with metabolic syndrome should undergo enhanced surveillance for tumor recurrence even after 2 years of surgery to early detect late HCC recurrence. Whether improving metabolic syndrome can reduce postoperative recurrence of HCC deserves further exploration.

Prognostic implications of alpha-fetoprotein and C-reactive protein elevation in hepatocellular carcinoma following resection (PACE): a large cohort study of 2770 patients.

BACKGROUND: Routine clinical staging for hepatocellular carcinoma (HCC) incorporates liver function, general health, and tumor morphology. Further refinement of prognostic assessments and treatment decisions may benefit from the inclusion of tumor biological marker alpha-fetoprotein (AFP) and systemic inflammation indicator C-reactive protein (CRP). METHODS: Data from a multicenter cohort of 2770 HCC patients undergoing hepatectomy were analyzed. We developed the PACE risk score (Prognostic implications of AFP and CRP Elevation) after initially assessing preoperative AFP and CRP's prognostic value. Subgroup analyzes were performed in BCLC cohorts A and B using multivariable Cox analysis to evaluate the prognostic stratification ability of the PACE risk score and its complementary utility for BCLC staging. RESULTS: Preoperative AFP ≥ 400ng/mL and CRP ≥ 10 mg/L emerged as independent predictors of poorer prognosis in HCC patients who underwent hepatectomy, leading to the creation of the PACE risk score. PACE risk score stratified patients into low, intermediate, and high-risk groups with cumulative 5-year overall (OS) and recurrence-free survival (RFS) rates of 59.6%/44.9%, 43.9%/38.4%, and 20.6%/18.0% respectively (all P < 0.001). Increased PACE risk scores correlated significantly with early recurrence and extrahepatic metastases frequency (all P < 0.001). The multivariable analysis identified intermediate and high-risk PACE scores as independently correlating with poor postoperative OS and RFS. Furthermore, the PACE risk score proficiently stratified the prognosis of BCLC stages A and B patients, with multivariable analyses demonstrating it as an independent prognostic determinant for both stages. CONCLUSION: The PACE risk score serves as an effective tool for postoperative risk stratification, potentially supplementing the BCLC staging system.

Analysis of conditional survival in primary hepatocellular carcinoma after narrow-margin hepatectomy: a large-sample, dual-centre, retrospective study.

BACKGROUND: Overall survival (OS) reflects the constant hazard and survival probabilities calculated from the initial follow-up. Conditional survival (CS) dynamically estimates prognosis based on survival time after treatment. This study aimed to estimate CS in patients who had undergone narrow-margin hepatectomy for primary hepatocellular carcinoma. METHODS: The clinical data of 1010 eligible patients between 2012 and 2017 were retrospectively analysed. The equation CS1=OS(x+1)/OS(x) was used to calculate the probability of an additional 1-year survival in patients who had survived for x years. RESULTS: Tumour differentiation, microvascular invasion, and tumour emboli were independent risk factors for OS. Actuarial survival decreased from 91.53% at 1 year after hepatectomy to 48.92% at 4 years, whereas CS1 increased from 69.45% at 1 year to 94.62% at 4 years. The difference was more obvious in the tumour-emboli subgroup, with an OS of 26.38% at 5 years versus a CS1 of 88.91% at 4 years following narrow-margin hepatectomy (Δ62.53%). CONCLUSION: CS is potentially useful in providing a dynamic evaluation of survival, predicting prognosis more accurately than OS during follow-up, and formulating more appropriate treatment measures based on disease progression.

Cholinesterase homozygous genotype as susceptible biomarker of hypertriglyceridaemia for pesticide-exposed agricultural workers.

PURPOSE: Dyslipidemia is an emerging metabolic disorder among pesticide-exposed agricultural workers, and this study was aimed to explore biomarkers of hypertriglyceridaemia susceptibility. METHODS: This cross-sectional study recruited 72 pesticide-exposed subjects and 78 non-exposed controls. Lipid profile, cholinesterase activity, and thyroid hormones were analysed with routine assays. Six loci, including rs11206244 and rs2235544 for deiodinase 1, rs12885300 and rs225014 for deiodinase 2, rs1803274 for butyrylcholinesterase, and rs3757869 for acetylcholinesterase were genotyped using an improved multiplex ligation detection reaction technique. RESULTS: Pesticide-exposed subjects showed higher levels of triglyceride than controls (p = 0.009), although there were comparable cholinesterase activity and genotype frequencies of all six loci between pesticide-exposed subjects and controls. Pesticide-exposed subjects with homozygous genotype of cholinesterase had increased triglyceride levels than controls (p < 0.05). The percentage of hypertriglyceridaemia was 28.6% and 8.8% for pesticide-exposed subjects and controls with homozygous butyrylcholinesterase genotype (p = 0.007) and 20.8% and 14.3% with homozygous acetylcholinesterase genotype (p = 0.792), respectively. Multivariate logistic regression analyses found that odds ratio of hypertriglyceridaemia is 21.92 and 4.56 for pesticide-exposed subjects with homozygous genotype of butyrylcholinesterase (p = 0.001) and acetylcholinesterase (p = 0.036), respectively. CONCLUSIONS: Cholinesterase homozygous genotype might be a potential susceptible biomarker in screening pesticide-exposed agricultural workers vulnerable to hypertriglyceridaemia.

Characteristics of iron status, oxidation response, and DNA methylation profile in response to occupational iron oxide nanoparticles exposure.

Although the growing development and application of iron oxide nanoparticles (IONPs) may pose exposure risk and adverse health outcomes, biological changes due to occupational exposure remain unexplored. This cross-sectional study recruited 23 workers at a plant that manufactures IONPs and 23 age- and sex-matched controls without metal-rich occupational hazards exposure. Exposure metrics at worksites were monitored, and iron status, oxidation markers, and methylation profiles of genomic DNA in peripheral blood were measured using corresponding enzyme-linked immunosorbent assays and methylation-specific polymerase chain reaction (PCR), respectively. The mass concentration, number counting, and surface area concentration of airborne particles at the worksite significantly increased during the work process of manufacturing/handling IONPs. Overall, compared to controls, workers exhibited increased 5-hydroxymethylcytosine (5hmC) levels without changes in 5-methylcytosine (5mC), hepcidin methylation, iron, soluble transferrin receptor (sTfR), ferritin, hepcidin, 8-hydroxydeoxyguanosine, and glutathione. A positive correlation was found between 5hmC and IONP exposure year with adjustment for age, sex, and cotinine using partial correlation analyses (r = 0.521, p < 0.001). After stratification of INOPs exposure and 5hmC levels, the univariate general linear model with adjustment for age, sex, and cotinine found that the estimated mean levels of 5mC and sTfR in subjects with low and high 5hmC levels among controls were 11% and 14.4% (p ≤ 0.01) and 80.9 nM and 70.3 nM (p < 0.05), respectively. The estimated mean levels of sTfR in workers and controls with low 5hmC levels were 88.3 nM and 68.7 nM (p ≤ 0.01). Multivariate linear regression analyses suggested an association between sTfR and 5hmC (standardized ß = -0.420, p = 0.014) and female sex (standardized ß = 0.672, p < 0.001) for subjects with low 5hmC levels. These findings suggest that increased 5hmC could be differentially employed to monitor an epigenetic signature with steady iron homeostasis for occupational IONP-exposed individuals who are likely to experience early but specific decreased sTfR, especially for females concurrent with the onset of increment in 5hmC at low level.

Threshold Effects of Serum Uric Acid on Chronic Kidney Disease in US Women without Hypertension and Diabetes: A Cross-Sectional Study.

BACKGROUND: Serum uric acid (SUA) has been associated with increased risk of chronic kidney disease (CKD) in observational studies; however, data in women without hypertension and diabetes are sparse. PURPOSE: To examine the association between SUA and CKD among women without hypertension and diabetes. METHODS: In this cross-sectional study of 6,776 US women without hypertension and diabetes from the National Health and Nutrition Examination Survey (1999-2006), we investigated the relationship between SUA and CKD using multivariable logistic regression models. Moreover, a generalized additive model and smooth curve fitting (penalized spline method) and a 2 piecewise logistic regression models were conducted to address for nonlinearity. RESULTS: The prevalence of CKD was 8.3%. Multiple logistic analyses showed that per 1 mg/dL increase in SUA was associated with 39% increased prevalence of CKD. Analyses using restricted cubic spline confirmed that the association between SUA and CKD was nonlinear. Further, threshold and saturation effect analysis showed that the inflection point of SUA was 4.5 mg/dL. The ORs (95% CIs) were 0.84 (0.66-1.08) on the left side of inflection point and 1.87 (1.56-2.24) on the right side of inflection point, respectively. Subgroup analysis showed that the stronger association between SUA and CKD was observed in elder women with never/former smoking and higher fasting blood glucose levels (all p values for interaction <0.05). CONCLUSION: Our study suggested threshold effects of SUA on the prevalence of CKD among US women without hypertension and diabetes. SUA levels >4.5 mg/dL were positively and independently associated with CKD.

Association of low-level blood lead with serum uric acid in U.S. adolescents: a cross-sectional study.

BACKGROUND: Uncertainty remains regarding the association between blood lead levels (BLL) and serum uric acid (SUA) with relatively low BLL exposure because of limited data in the adolescent population. We examined the association between BLL and SUA in U.S. adolescents. METHODS: In this cross-sectional study, 8303 adolescents aged 12-19 years from NHANES 1999-2006 were analyzed. BLL was Ln-transformed for analysis for the skewed distribution. Elevated SUA was defined as ≥5.5 mg/dL. Multivariate linear and multiple logistic regression analyses were performed to evaluate the association of BLL with SUA and elevated SUA. Moreover, a generalized additive model (GAM) and a fitted smoothing curve (penalized spline method) were conducted. RESULTS: The overall mean BLL was 1.3 µg/dL. Multivariate linear regression analyses showed that LnBLL was independently and positively correlated with SUA level (ß = 0.13, 95%CI: 0.09-0.17). Multiple logistic analyses showed that LnBLL was associated with a 24% increased prevalence of elevated SUA (OR = 1.24; 95% CI, 1.11-1.38). Analyses using restricted cubic spline confirmed that the associations of LnBLL with SUA and elevated SUA were linear. Subgroup analyses showed that stronger associations between LnBLL and SUA were detected in adolescents with lower levels of education and estimated glomerular filtration rate (eGFR) (all P for interaction < 0.05). CONCLUSIONS: BLL was independently and positively correlated with SUA level and elevated SUA among U.S. adolescents, particularly with lower levels of education and eGFR. The data suggest that there is no "safe" threshold level of exposure to lead.

Comparative mouse lung injury by nickel nanoparticles with differential surface modification.

BACKGROUND: Previous studies have demonstrated that exposure to nickel nanoparticles (Nano-Ni) causes oxidative stress and severe, persistent lung inflammation, which are strongly associated with pulmonary toxicity. However, few studies have investigated whether surface modification of Nano-Ni could alter Nano-Ni-induced lung injury, inflammation, and fibrosis in vivo. Here, we propose that alteration of physicochemical properties of Nano-Ni through modification of Nano-Ni surface may change Nano-Ni-induced lung injury, inflammation, and fibrosis. METHODS: At first, dose-response and time-response studies were performed to observe lung inflammation and injury caused by Nano-Ni. In the dose-response studies, mice were intratracheally instilled with 0, 10, 20, 50, and 100 µg per mouse of Nano-Ni and sacrificed at day 3 post-exposure. In the time-response studies, mice were intratracheally instilled with 50 µg per mouse of Nano-Ni and sacrificed at days 1, 3, 7, 14, 28, and 42 post-instillation. At the end of the experiment, mice were bronchoalveolar lavaged (BAL) and the neutrophil count, CXCL1/KC level, LDH activity, and concentration of total protein in the BAL fluid (BALF) were determined. In the comparative studies, mice were intratracheally instilled with 50 µg per mouse of Nano-Ni or with the same molar concentration of Ni as Nano-Ni of either partially [O]-passivated Nano-Ni (Nano-Ni-P) or carbon-coated Nano-Ni (Nano-Ni-C). At day 3 post-exposure, BAL was performed and the above cellular and biochemical parameters in the BALF were analyzed. The MMP-2/9 protein levels and activities in the BALF and mouse lung tissues were also determined. Mouse lung tissues were also collected for H&E staining, and measurement of thiobarbituric acid reactive substances (TBARS) and 8-hydroxy-2'-deoxyguanosine (8-OHdG) in the genomic DNA. At day 42 post-exposure, mouse right lung tissues were collected for H&E and Trichrome stainings, and left lung tissues were collected to determine the hydroxyproline content. RESULTS: Exposure of mice to Nano-Ni resulted in a dose-response increase in acute lung inflammation and injury reflected by increased neutrophil count, CXCL1/KC level, LDH activity, and concentration of total protein in the BALF. The time-response study showed that Nano-Ni-induced acute lung inflammation and injury appeared as early as day 1, peaked at day 3, and attenuated at day 7 post-instillation. Although the neutrophil count, CXCL1/KC level, LDH activity, and concentration of total protein in the BALF dramatically decreased over the time, their levels were still higher than those of the controls even at day 42 post-exposure. Based on the results of the dose- and time-response studies, we chose a dose of 50 µg per mouse of Nano-Ni, and day 3 post-exposure as short-term and day 42 post-exposure as long-term to compare the effects of Nano-Ni, Nano-Ni-P, and Nano-Ni-C on mouse lungs. At day 3 post-exposure, 50 µg per mouse of Nano-Ni caused acute lung inflammation and injury that were reflected by increased neutrophil count, CXCL1/KC level, LDH activity, concentration of total protein, and MMP-2/9 protein levels and activities in the BALF. Nano-Ni exposure also caused increased MMP-2/9 activities in the mouse lung tissues. Histologically, infiltration of large numbers of neutrophils and macrophages in the alveolar space and interstitial tissues was observed in mouse lungs exposed to Nano-Ni. Nano-Ni-P exposure caused similar acute lung inflammation and injury as Nano-Ni. However, exposure to Nano-Ni-C only caused mild acute lung inflammation and injury. At day 42 post-exposure, Nano-Ni caused extensive interstitial fibrosis and proliferation of interstitial cells with inflammatory cells infiltrating the alveolar septa and alveolar space. Lung fibrosis was also observed in Nano-Ni-P-exposed lungs, but to a much lesser degree. Only slight or no lung fibrosis was observed in Nano-Ni-C-exposed lungs. Nano-Ni and Nano-Ni-P, but not Nano-Ni-C, caused significantly elevated levels of TBARS in mouse lung tissues and 8-OHdG in mouse lung tissue genomic DNA, suggesting that Nano-Ni and Nano-Ni-P induce lipid peroxidation and oxidative DNA damage in mouse lung tissues, while Nano-Ni-C does not. CONCLUSION: Our results demonstrate that short-term Nano-Ni exposure causes acute lung inflammation and injury, while long-term Nano-Ni exposure causes chronic lung inflammation and fibrosis. Surface modification of Nano-Ni alleviates Nano-Ni-induced pulmonary effects; partially passivated Nano-Ni causes similar effects as Nano-Ni, but the chronic inflammation and fibrosis were at a much lesser degree. Carbon coating significantly alleviates Nano-Ni-induced acute and chronic lung inflammation and injury.

Role of Autophagy in Zinc Oxide Nanoparticles-Induced Apoptosis of Mouse LEYDIG Cells.

Zinc oxide nanoparticles (ZnO NPs) have shown adverse health impact on the human male reproductive system, with evidence of inducing apoptosis. However, whether or not ZnO NPs could promote autophagy, and the possible role of autophagy in the progress of apoptosis, remain unclear. In the current study, in vitro and in vivo toxicological responses of ZnO NPs were explored by using a mouse model and mouse Leydig cell line. It was found that intragastrical exposure of ZnO NPs to mice for 28 days at the concentrations of 100, 200, and 400 mg/kg/day disrupted the seminiferous epithelium of the testis and decreased the sperm density in the epididymis. Furthermore, serum testosterone levels were markedly reduced. The induction of apoptosis and autophagy in the testis tissues was disclosed by up-regulating the protein levels of cleaved Caspase-8, cleaved Caspase-3, Bax, LC3-II, Atg 5, and Beclin 1, accompanied by down-regulation of Bcl 2. In vitro tests showed that ZnO NPs could induce apoptosis and autophagy with the generation of oxidative stress. Specific inhibition of autophagy pathway significantly decreased the cell viability and up-regulated the apoptosis level in mouse Leydig TM3 cells. In summary, ZnO NPs can induce apoptosis and autophagy via oxidative stress, and autophagy might play a protective role in ZnO NPs-induced apoptosis of mouse Leydig cells.

Effect of titanium dioxide nanoparticles on glucose homeostasis after oral administration.

As food additives, titanium dioxide nanoparticles (TiO2 NPs) have been widely used in various products that are usually simultaneously consumed with a high content of sugar, thus necessitating research on the effect of TiO2 NPs on glucose homeostasis. We conducted an animal study to explore the effect of orally administrated TiO2 NPs on glucose absorption and metabolism in rats at 0, 2, 10 and 50 mg kg-1 body weight day-1 for 30 and 90 days. The results showed that oral exposure to TiO2 NPs caused a slight and temporary hypoglycemic effect in rats at 30 days post-exposure but recovered at 90 days post-exposure. Decreased levels of intestinal glucose absorption and increased levels of hepatic glucose metabolism may be responsible for the hypoglycemic effect. Remodeling of the villi in the small intestine that decreased the surface area available for glucose absorption and increased levels of hepatic glucose uptake, utilization and storage related to hepatocellular injury are supposed to be the mechanisms. Our results demonstrated that dietary intake of TiO2 NPs as food additives could affect the absorption and metabolism of glucose.

Cobalt nanoparticles induce lung injury, DNA damage and mutations in mice.

BACKGROUND: We and other groups have demonstrated that exposure to cobalt nanoparticles (Nano-Co) caused oxidative stress and inflammation, which have been shown to be strongly associated with genotoxic and carcinogenic effects. However, few studies have reported Nano-Co-induced genotoxic effects in vivo. Here, we propose that Nano-Co may have high genotoxic effects due to their small size and high surface area, which have high capacity for causing oxidative stress and inflammation. METHODS: gpt delta transgenic mice were used as our in vivo study model. They were intratracheally instilled with 50 µg per mouse of Nano-Co. At day 1, 3, 7 and 28 after exposure, bronchoalveolar lavage (BAL) was performed and the number of neutrophils, CXCL1/KC level, LDH activity and concentration of total protein in the BAL fluid (BALF) were determined. Mouse lung tissues were collected for H&E staining, and Ki-67, PCNA and γ-H2AX immunohistochemical staining. 8-OHdG level in the genomic DNA of mouse lungs was determined by an OxiSelect™ Oxidative DNA Damage ELISA Kit, and mutant frequency and mutation spectrum in the gpt gene were also determined in mouse lungs at four months after Nano-Co exposure by 6-TG selection, colony PCR, and DNA sequencing. RESULTS: Exposure of mice to Nano-Co (50 µg per mouse) resulted in extensive acute lung inflammation and lung injury which were reflected by increased number of neutrophils, CXCL1/KC level, LDH activity and concentration of total protein in the BALF, and infiltration of large amount of neutrophils and macrophages in the alveolar space and interstitial tissues. Increased immunostaining of cell proliferation markers, Ki-67 and PCNA, and the DNA damage marker, γ-H2AX, was also observed in bronchiolar epithelial cells and hyperplastic type II pneumocytes in mouse lungs at day 7 after Nano-Co exposure. At four months after exposure, extensive interstitial fibrosis and proliferation of interstitial cells with inflammatory cells infiltrating the alveolar septa were observed. Moreover, Nano-Co caused increased level of 8-OHdG in genomic DNA of mouse lung tissues. Nano-Co also induced a much higher mutant frequency as compared to controls, and the most common mutation was G:C to T:A transversion, which may be explained by Nano-Co-induced increased formation of 8-OHdG. CONCLUSION: Our study demonstrated that exposure to Nano-Co caused oxidative stress, lung inflammation and injury, and cell proliferation, which further resulted in DNA damage and DNA mutation. These findings have important implications for understanding the potential health effects of nanoparticle exposure.

Vibration characteristics of golf club heads in their handheld grinding process and potential approaches for reducing the vibration exposure.

To control vibration-induced white finger among workers performing the fine grinding of golf club heads, the aims of this study are to clarify the major vibration sources in the grinding process, to identify and understand the basic characteristics of the club head vibration, and to propose potential approaches for reducing the vibration exposure. The vibrations on two typical club heads and two belt grinding machines were measured at a workplace. A simulated test station was also constructed and used to help examine some influencing factors of the club head vibration. This study found that the club head vibration was the combination of the vibration transmitted from the grinding machines and that generated in the grinding process. As a result, any factor that affects the machine vibration, the grinding vibration, and/or the dynamic response of the club head can influence the vibration exposure of the fingers or hands holding the club head in the grinding process. The significant influencing factors identified in the study include testing subject, grinding machine, machine operation speed, drive wheel condition, club head model, mechanical constraints imposed on the club head during the grinding, and machine foot pad. These findings suggest that the vibration exposure can be controlled by reducing the grinding machine vibration, changing the workpiece dynamic properties, and mitigating the vibration transmission in its pathway. Many potential methods for the control are proposed and discussed. RELEVANCE TO INDUSTRY: Vibrations on handheld workpieces can be effectively transmitted to the hands, especially the fingers. As a result, a major component of the hand-arm vibration syndrome - vibration-induced white finger - has been observed among some workers performing the grinding and/or polishing tasks of the handheld workpieces such as golf club heads. The results of this study can be used to develop more effective methods and technologies to control the vibration exposure of these workers. This may help effectively control this occupational disease.

Rapid Detection of Atrazine at Workplace with Near-Infrared Spectroscopy.

As a wildly used herbicide, Atrazine is mainly produced in China. In order to strengthen the routine detection of Atrazine exposure concentration and protect the health of occupational contact workers, it's of great importance to develop on-site rapid detection method. A self-assembled near infrared spectrometer was used to record spectra of laboratory prepared atrazine solutions with concentration range from 10 to 1 000 mg·L-1. The influences of different pretreatment methods, such as multiplicative scatter correction, standard normal variate, first order derivative (D1), second order derivative and their combinations, different variable selection methods, such as competitive adaptive reweighted sampling (CARS) and genetic algorithm (GA), different regression methods, such as partial least square (PLS) and support vector regression(nu-SVR), on the model prediction accuracy were investigated. Results show that D1 is the best pretreatment method; GA obtain better results than CARS on selecting highly related spectral variables; nu-SVR model perform better than PLS model. The nu-SVR model constructed with 16 spectral variables selected by GA obtained the best results, whose coefficient of determination for calibration, the coefficient of determination for validation, root mean square error of calibration, root mean square error of validation (RMSEV) and residual validation deviation (defined as SD/RMSEV where SD denotes standard deviation) are 1, 0.99, 17.54 mg·L-1, 25.42 mg·L-1 and 11.43, respectively. These results indicate near infrared spectroscopy combined with chemometrics has great potential to quantify Atrazine concentration at workplace. This research explores the feasibility of quantification Atrazine at workplace with near infrared spectroscopy for the first time, which has great reference value for similar work in the future.

MWCNTs Induce ROS Generation, ERK Phosphorylation, and SOD-2 Expression in Human Mesothelial Cells.

Biological oxidative responses are involved in the toxicity of multiwall carbon nanotubes (MWCNTs), which may cause asbestos-like pathogenicity. Superoxide dismutase 2 (SOD-2) has been proposed as a biomarker of early responses to mesothelioma-inducing fibers. This study was conducted to investigate the alteration of SOD-2 expression in the human mesothelial cell lines Met-5A after exposure to nontoxic doses of MWCNTs and the potential signaling pathway. The parameters measured included the viability, morphological change, superoxide formation, extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation, and messenger RNA (mRNA)/protein levels of SOD-2. Our results showed that MWCNTs upregulated SOD-2 expression at both mRNA and protein level. Coincidently, both superoxide formation and ERK1/2 phosphorylation were observed in Met-5A cells exposed to MWCNTs and were diminished by pretreatment with the reactive oxidative species (ROS) scavenger, N-acetyl-l-(+)-cysteine (NAC). To further investigate the role of ROS/ERK1/2 in MWCNTs-induced SOD-2 overexpression, prior to MWCNTs exposure, cells were pretreated with the Mitogen-activated protein kinase kinase 1/2 (MEK 1/2) inhibitor (U0126) or with NAC. Both pretreatments decreased the MWCNTs-induced overexpression of SOD-2. These results suggest that upregulation of SOD-2 in Met-5A cells exposed to MWCNTs is mediated by ROS formation and ERK1/2 activation.

Exposure characteristics of ferric oxide nanoparticles released during activities for manufacturing ferric oxide nanomaterials.

The exposure characteristics of Fe2O3 nanoparticles (NPs) released in a factory were investigated, as exposure data on this type of NP is absent. The nature of the particles was identified in terms of their concentrations [i.e. number concentration (NC(20-1000 nm)), mass concentration (MC(100-1000 nm)), surface area concentration (SAC(10-1000 nm))], size distribution, morphology and elemental composition. The relationships between different exposure metrics were determined through analyses of exposure ranking (ER), concentration ratios (CR), correlation coefficients and shapes of the particle concentration curves. Work activities such as powder screening, material feeding and packaging generated higher levels of NPs as compared to those of background particles (p < 0.01). The airborne Fe2O3 NPs exhibited a unimodal size distribution and a spindle-like morphology and consisted predominantly of the elements O and Fe. Periodic and activity-related characteristics were noticed in the temporal variations in NC(20-1000 nm) and SAC(10-1000 nm). The modal size of the Fe2O3 NPs remained relatively constant (ranging from 10 to 15 nm) during the working periods. The ER, CR values and the shapes of NC(20-1000 nm) and SAC(10-1000 nm) curves were similar; however, these were significantly different from those for MC(100-1000 nm). There was a high correlation between NC(20-1000 nm) and SAC(10-1000 nm), and relatively lower correlations between the two and MC(100-1000 nm). These findings suggest that the work activities during the manufacturing processes generated high levels of primary Fe2O3 NPs. The particle concentrations exhibited periodicity and were activity dependent. The number and SACs were found to be much more relevant metrics for characterizing NPs than was the mass concentration.

[An analysis of characteristics of exposure to nanoparticles in a workplace manufacturing iron oxide nanoparticles].

OBJECTIVE: To investigate the characteristics of exposure to iron oxide nanoparticles in workplace. METHODS: The real-time particle number (NC), surface area (SAC), and mass (MC) concentrations of nanoparticles were measured in various locations of a selected workplace manufacturing iron oxide nanoparticles. The collected particles were analyzed for morphology and elemental composition. RESULTS: The average NCs and SACs in milling site (16,566 pt/cm3, 106.082 µm2/cm3), packaging site (12,386 pt/cm3, 89.861 µm2/cm3), shipping site (13,808 pt/cm3, 102.071 µm2/cm3), and product storage room (17,192 pt/cm, 115.044 µm2/cm3) of the yellow powder (α-Fe2O3 . nH2O) were all significantly higher than the workplace background concentrations (11,420 pt/cm3, 85.026 µm2/cm3) (all P<0.05). The NC was highly correlated with the SAC (r= 0.784), while both NC and SAC were loosely correlated with the MC (r1=0.323, r2=0.331). Scanning electron microscopy revealed a spindle-like shape of the iron oxide nanoparticle; the chemical composition of the collected particles contained 19.33 weight percent iron (Fe). CONCLUSION: The milling site and product storage room of the yellow powder are exposed to a higher concentration of nanoparticles, which are mainly composed of iron oxide nanoparticles. The NC is highly correlated with the SAC.