Comparing the lung cancer burden of ambient particulate matter using scenarios of air quality standards versus acceptable risk levels.
- 作者列表："Castro A","Götschi T","Achermann B","Baltensperger U","Buchmann B","Felber Dietrich D","Flückiger A","Geiser M","Gälli Purghart B","Gygax H","Kutlar Joss M","Lüthi LM","Probst-Hensch N","Strähl P","Künzli N
OBJECTIVES:Ambient particulate matter (PM) is regulated with science-based air quality standards, whereas carcinogens are regulated with a number of "acceptable" cases. Given that PM is also carcinogenic, we identify differences between approaches. METHODS:We assessed the lung cancer deaths for Switzerland attributable to exposure to PM up to 10 µm (PM10) and to five particle-bound carcinogens. For PM10, we used an epidemiological approach based on relative risks with four exposure scenarios compared to two counterfactual concentrations. For carcinogens, we used a toxicological approach based on unit risks with four exposure scenarios. RESULTS:The lung cancer burden using concentrations from 2010 was 10-14 times larger for PM10 than for the five carcinogens. However, the burden depends on the underlying exposure scenarios, counterfactual concentrations and number of carcinogens. All scenarios of the toxicological approach for five carcinogens result in a lower burden than the epidemiological approach for PM10. CONCLUSIONS:Air quality standards-promoted so far by the WHO Air Quality Guidelines-provide a more appealing framework to guide health risk-oriented clean air policymaking than frameworks based on a number of "acceptable" cases.
目的: 环境颗粒物 (PM) 受到基于科学的空气质量标准的监管，而致癌物受到许多 “可接受” 情况的监管。鉴于PM也是致癌的，我们确定了方法之间的差异。 方法: 我们评估了瑞士肺癌死亡归因于暴露于PM高达 10 µ m (PM10) 和 5 种颗粒结合致癌物。对于PM10，我们使用了基于相对风险的流行病学方法，与两种反事实浓度相比，使用了四种暴露情景。对于致癌物，我们使用了基于四种暴露场景的单位风险的毒理学方法。 结果: 使用 2010 年的浓度的肺癌负担为PM10 比 5 种致癌物的 10-14 倍。然而，负担取决于潜在的暴露情景、反事实浓度和致癌物的数量。五种致癌物的毒理学方法的所有情况导致比pm10 的流行病学方法更低的负担。 结论: 迄今为止，世卫组织空气质量指南所推广的空气质量标准提供了一个更具吸引力的框架，以指导面向健康风险的清洁空气决策，而不是基于一些 “可接受的” 案例的框架。
METHODS::Pulmonary artery sling is a rare congenital anomaly of the origin and course of the left pulmonary artery. Patients with this condition typically present with respiratory failure in young infancy, and asymptomatic cases are uncommon. We describe the case of an adult patient with a lung adenocarcinoma of the right upper lobe, extending into the hilum and superior mediastinum, and with a previously unknown pulmonary artery sling anomaly. The local invasiveness of the tumor and the peculiar vascular anatomy contributed to a unique surgical scenario, wherein multiple reconstructive procedures were required.
METHODS::Patients with idiopathic pulmonary fibrosis (IPF) have higher risk of developing lung cancer, for example, squamous cell carcinoma (SCC), and show poor prognosis, while the molecular basis has not been fully investigated. Here we conducted DNA methylome analysis of lung SCC using 20 SCC samples with/without IPF, and noncancerous lung tissue samples from smokers/nonsmokers, using Infinium HumanMethylation 450K array. SCC was clustered into low- and high-methylation epigenotypes by hierarchical clustering analysis. Genes hypermethylated in SCC significantly included genes targeted by polycomb repressive complex in embryonic stem cells, and genes associated with Gene Ontology terms, for example, "transcription" and "cell adhesion," while genes hypermethylated specifically in high-methylation subgroup significantly included genes associated with "negative regulation of growth." Low-methylation subgroup significantly correlated with IPF (78%, vs. 17% in high-methylation subgroup, p = 0.04), and the correlation was validated by additional Infinium analysis of SCC samples (n = 44 in total), and data from The Cancer Genome Atlas (n = 390). The correlation between low-methylation subgroup and IPF was further validated by quantitative methylation analysis of marker genes commonly hypermethylated in SCC (HOXA2, HOXA9 and PCDHGB6), and markers specifically hypermethylated in high-methylation subgroup (DLEC1, CFTR, MT1M, CRIP3 and ALDH7A1) in 77 SCC cases using pyrosequencing (p = 0.003). Furthermore, low-methylation epigenotype significantly correlated with poorer prognosis among all SCC patients, or among patients without IPF. Multivariate analysis showed that low-methylation epigenotype is an independent predictor of poor prognosis. These may suggest that lung SCC could be stratified into molecular subtypes with distinct prognosis, and low-methylation lung SCC that significantly correlates with IPF shows unfavorable outcome.
METHODS::The role of Fyn-related kinase (FRK) in malignant tumors remains controversial. Our study investigated the function of FRK in lung cancer. Immunohistochemistry staining and generating a knockout of FRK by CRISPR/Cas9 in H1299 (FRK-KO-H1299) cells were strategies used to explore the role of FRK. Immunohistochemistry staining indicated that FRK expression was elevated in 223 lung cancer tissues compared to 26 distant normal lung tissues. FRK contributed to poor survival status in lung cancer patients and acted as a predictor for poor prognosis of lung cancer. Knockout of FRK by CRISPR/Cas9 markedly inhibited proliferation, invasion, colony formation and epithelial-mesenchymal transition (EMT) process in the lung cancer cell line H1299. Further exploration indicated that FRK-KO damaged the stemness phenotype of H1299 by inhibiting CD44 and CD133 expression. Seahorse detection and a U-13 C flux assay revealed that FRK-KO induced metabolism reprogramming by inhibiting the Warburg effect and changing the energy type in H1299 cells. Epidermal growth factor stimulation recovered the expression of FRK and biological functions, metabolic reprogramming and stemness phenotype of H1299 cells. FRK plays an oncogenic role in lung cancer cells via a novel regulation mechanism of enhancing the stemness of H1299 cells by inducing metabolism reprogramming, which finally promotes EMT and metastasis. Our study also indicates that FRK could be used as a potential therapeutic target for drug development.