Cisplatin in the era of PARP inhibitors and immunotherapy.

Platinum compounds such as cisplatin, carboplatin and oxaliplatin are widely used in chemotherapy. Cisplatin induces cytotoxic DNA damage that blocks DNA replication and gene transcription, leading to arrest of cell proliferation. Although platinum therapy alone is effective against many tumors, cancer cells can adapt to the treatment and gain resistance. The mechanisms for cisplatin resistance are complex, including low DNA damage formation, high DNA repair capacity, changes in apoptosis signaling pathways, rewired cell metabolisms, and others. Drug resistance compromises the clinical efficacy and calls for new strategies by combining cisplatin with other therapies. Exciting progress in cancer treatment, particularly development of poly (ADP-ribose) polymerase (PARP) inhibitors and immune checkpoint inhibitors, opened a new chapter to combine cisplatin with these new cancer therapies. In this Review, we discuss how platinum synergizes with PARP inhibitors and immunotherapy to bring new hope to cancer patients.

Pan-cancer mutational signature surveys correlated mutational signature with geospatial environmental exposures and viral infections.

Background: Cancer has been disproportionally affecting minorities. Genomic-based cancer disparity analyses have been less common than conventional epidemiological studies. In the past decade, mutational signatures have been established as characteristic footprints of endogenous or exogenous carcinogens. Methods: Integrating datasets of diverse cancer types from The Cancer Genome Atlas and geospatial environmental risks of the registry hospitals from the United States Environmental Protection Agency, we explored mutational signatures from the aspect of racial disparity concerning pollutant exposures. The raw geospatial environmental exposure data were refined to 449 air pollutants archived and modeled from 2007 to 2017 and aggregated to the census county level. Additionally, hepatitis B and C viruses and human papillomavirus infection statuses were incorporated into analyses for skin cancer, cervical cancer, and liver cancer. Results: Mutation frequencies of key oncogenic genes varied substantially between different races. These differences were further translated into differences in mutational signatures. Survival analysis revealed that the increased pollution level is associated with worse survival. The analysis of the oncogenic virus revealed that aflatoxin, an affirmed carcinogen for liver cancer, was higher in Asian liver cancer patients than in White patients. The aflatoxin mutational signature was exacerbated by hepatitis infection for Asian patients but not for White patients, suggesting a predisposed genetic or genomic disadvantage for Asians concerning aflatoxin. Conclusions: Environmental pollutant exposures increase a mutational signature level and worsen cancer prognosis, presenting a definite adverse risk factor for cancer patients.

Alterations to biomarkers related to long-term exposure to diesel exhaust at concentrations below occupational exposure limits in the European Union and the USA.

BACKGROUND: We previously found that occupational exposure to diesel engine exhaust (DEE) was associated with alterations to 19 biomarkers that potentially reflect the mechanisms of carcinogenesis. Whether DEE is associated with biological alterations at concentrations under existing or recommended occupational exposure limits (OELs) is unclear. METHODS: In a cross-sectional study of 54 factory workers exposed long-term to DEE and 55 unexposed controls, we reanalysed the 19 previously identified biomarkers. Multivariable linear regression was used to compare biomarker levels between DEE-exposed versus unexposed subjects and to assess elemental carbon (EC) exposure-response relationships, adjusted for age and smoking status. We analysed each biomarker at EC concentrations below the US Mine Safety and Health Administration (MSHA) OEL (<106 µg/m3), below the European Union (EU) OEL (<50 µg/m3) and below the American Conference of Governmental Industrial Hygienists (ACGIH) recommendation (<20 µg/m3). RESULTS: Below the MSHA OEL, 17 biomarkers were altered between DEE-exposed workers and unexposed controls. Below the EU OEL, DEE-exposed workers had elevated lymphocytes (p=9E-03, false discovery rate (FDR)=0.04), CD4+ count (p=0.02, FDR=0.05), CD8+ count (p=5E-03, FDR=0.03) and miR-92a-3p (p=0.02, FDR=0.05), and nasal turbinate gene expression (first principal component: p=1E-06, FDR=2E-05), as well as decreased C-reactive protein (p=0.02, FDR=0.05), macrophage inflammatory protein-1ß (p=0.04, FDR=0.09), miR-423-3p (p=0.04, FDR=0.09) and miR-122-5p (p=2E-03, FDR=0.02). Even at EC concentrations under the ACGIH recommendation, we found some evidence of exposure-response relationships for miR-423-3p (ptrend=0.01, FDR=0.19) and gene expression (ptrend=0.02, FDR=0.19). CONCLUSIONS: DEE exposure under existing or recommended OELs may be associated with biomarkers reflective of cancer-related processes, including inflammatory/immune response.

Association between diesel exhaust exposure and mitochondrial DNA methylation.

OBJECTIVES: Diesel exhaust is an established human carcinogen, however the mechanisms by which it leads to cancer development are not fully understood. Mitochondrial dysfunction is an established contributor to carcinogenesis. Recent studies have improved our understanding of the role played by epigenetic modifications in the mitochondrial genome on tumorigenesis. In this study, we aim to evaluate the association between diesel engine exhaust (DEE) exposure with mitochondrial DNA (mtDNA) methylation levels in workers exposed to DEE. METHODS: The study population consisted of 53 male workers employed at a diesel engine manufacturing facility in Northern China who were routinely exposed to diesel exhaust in their occupational setting, as well as 55 unexposed male control workers from other unrelated factories in the same geographic area. Exposure to DEE, elemental carbon, organic carbon, and particulate matter (PM2.5) were assessed. mtDNA methylation for CpG sites (CpGs) from seven mitochondrial genes (D-Loop, MT-RNR1, MT-CO2, MT-CO3, MT-ATP6, MT-ATP8, MT-ND5) was measured in blood samples. Linear regression models were used to estimate the associations between DEE, elemental carbon, organic carbon and PM2.5 exposures with mtDNA methylation levels, adjusting for potential confounders. RESULTS: DEE exposure was associated with decreased MT-ATP6 (difference = -35.6%, P-value = 0.019) and MT-ATP8 methylation (difference = -30%, P-value = 0.029) compared to unexposed controls. Exposures to elemental carbon, organic carbon, and PM2.5 were also significantly and inversely associated with methylation in MT-ATP6 and MT-ATP8 genes (all P-values < 0.05). CONCLUSIONS: Our findings suggest that DEE exposure perturbs mtDNA methylation, which may be of importance for tumorigenesis.

Exposure to diesel engine exhaust and alterations to the Cys34/Lys525 adductome of human serum albumin.

We investigated whether exposure to carcinogenic diesel engine exhaust (DEE) was associated with altered adduct levels in human serum albumin (HSA) residues. Nano-liquid chromatography-high resolution mass spectrometry (nLC-HRMS) was used to measure adducts of Cys34 and Lys525 residues in plasma samples from 54 diesel engine factory workers and 55 unexposed controls. An untargeted adductomics and bioinformatics pipeline was used to find signatures of Cys34/Lys525 adductome modifications. To identify adducts that were altered between DEE-exposed and unexposed participants, we used an ensemble feature selection approach that ranks and combines findings from linear regression and penalized logistic regression, then aggregates the important findings with those determined by random forest. We detected 40 Cys34 and 9 Lys525 adducts. Among these findings, we found evidence that 6 Cys34 adducts were altered between DEE-exposed and unexposed participants (i.e., 841.75, 851.76, 856.10, 860.77, 870.43, and 913.45). These adducts were biologically related to antioxidant activity.

Wood smoke exposure affects lung aging, quality of life, and all-cause mortality in New Mexican smokers.

BACKGROUND: The role of wood smoke (WS) exposure in the etiology of chronic obstructive pulmonary disease (COPD), lung cancer (LC), and mortality remains elusive in adults from countries with low ambient levels of combustion-emitted particulate matter. This study aims to delineate the impact of WS exposure on lung health and mortality in adults age 40 and older who ever smoked. METHODS: We assessed health impact of self-reported "ever WS exposure for over a year" in the Lovelace Smokers Cohort using both objective measures (i.e., lung function decline, LC incidence, and deaths) and two health related quality-of-life questionnaires (i.e., lung disease-specific St. George's Respiratory Questionnaire [SGRQ] and the generic 36-item short-form health survey). RESULTS: Compared to subjects without WS exposure, subjects with WS exposure had a more rapid decline of FEV1 (- 4.3 ml/s, P = 0.025) and FEV1/FVC ratio (- 0.093%, P = 0.015), but not of FVC (- 2.4 ml, P = 0.30). Age modified the impacts of WS exposure on lung function decline. WS exposure impaired all health domains with the increase in SGRQ scores exceeding the minimal clinically important difference. WS exposure increased hazard for incidence of LC and death of all-cause, cardiopulmonary diseases, and cancers by > 50% and shortened the lifespan by 3.5 year. We found no evidence for differential misclassification or confounding from socioeconomic status for the health effects of WS exposure. CONCLUSIONS: We identified epidemiological evidence supporting WS exposure as an independent etiological factor for the development of COPD through accelerating lung function decline in an obstructive pattern. Time-to-event analyses of LC incidence and cancer-specific mortality provide human evidence supporting the carcinogenicity of WS exposure.

Lung Effects of Household Air Pollution.

Biomass fuel smoke, secondhand smoke, and oxides of nitrogen are common causes of household air pollution (HAP). Almost 2.4 billion people worldwide use solid fuels for cooking and heating, mostly in low- and middle-income countries. Wood combustion for household heating is also common in many areas of high-income countries, and minorities are particularly vulnerable. HAP in low- and middle-income countries is associated with asthma, acute respiratory tract infections in adults and children, chronic obstructive pulmonary disease, lung cancer, tuberculosis, and respiratory mortality. Although wood smoke exposure levels in high-income countries are typically lower than in lower-income countries, it is similarly associated with accelerated lung function decline, higher prevalence of airflow obstruction and chronic bronchitis, and higher all-cause and respiratory cause-specific mortality. Household air cleaners with high-efficiency particle filters have mixed effects on asthma and chronic obstructive pulmonary disease outcomes. Biomass fuel interventions in low-income countries include adding chimneys to cookstoves, improving biomass fuel combustion stoves, and switching fuel to liquid petroleum gas. Still, the impact on health outcomes is inconsistent. In high-income countries, strategies for reducing biomass fuel-related HAP are centered on community-level woodstove changeout programs, although the results are again inconsistent. In addition, initiatives to encourage home smoking bans have mixed success in households with children. Environmental solutions to reduce HAP have varying success in reducing pollutants and health problems. Improved understanding of indoor air quality factors and actions that prevent degradation or improve polluted indoor air may lead to enhanced environmental health policies, but health outcomes must be rigorously examined.

Early natural menopause is associated with poor lung health and increased mortality among female smokers.

BACKGROUND: Early natural menopause has been regarded as a biomarker of reproductive and somatic aging. Cigarette smoking is the most harmful factor for lung health and also an established risk factor for early menopause. Understanding the effect of early menopause on health outcomes in middle-aged and older female smokers is important to develop preventive strategies. OBJECTIVE: This study aimed to examine the associations of early menopause with multiple lung health and aging biomarkers, lung cancer risk, and all-cause and cause-specific mortality in postmenopausal women who were moderate or heavy smokers. STUDY DESIGN: This study was conducted on postmenopausal women with natural (n=1038) or surgical (n=628) menopause from the Pittsburgh Lung Screening Study. The Pittsburgh Lung Screening Study is a community-based research cohort of current and former smokers, screened with low-dose computed tomography and followed up for lung cancer. Early menopause was defined as occurring before 45 years of age. The analyses were stratified by menopause types because of the different biological and medical causes of natural and surgical menopause. Statistical methods included linear model, generalized linear model, linear mixed-effects model, and time-to-event analysis. RESULTS: The average age of the 1666 female smokers was 59.4±6.7 years, with 1519 (91.2%) of the population as non-Hispanic Whites and 1064 (63.9%) of the population as current smokers at baseline. Overall, 646 (39%) women reported early menopause, including 198 (19.1%) women with natural menopause and 448 (71.3%) women with surgical menopause (P<.001). Demographic variables did not differ between early and nonearly menopause groups, regardless of menopause type. Significant associations were identified between early natural menopause and higher risk of wheezing (odds ratio, 1.65; P<.01), chronic bronchitis (odds ratio, 1.73; P<.01), and radiographic emphysema (odds ratio, 1.70; P<.001) and lower baseline lung spirometry in an obstructive pattern (-104.8 mL/s for forced expiratory volume in the first second with P<.01, -78.6 mL for forced vital capacity with P=.04, and -2.1% for forced expiratory volume in the first second-to-forced vital capacity ratio with P=.01). In addition, early natural menopause was associated with a more rapid decline of forced expiratory volume in the first second-to-forced vital capacity ratio (-0.16% per year; P=.01) and incident airway obstruction (odds ratio, 2.02; P=.04). Furthermore, women early natural menopause had a 40% increased risk of death (P=.023), which was mainly driven by respiratory diseases (hazard ratio, 2.32; P<.001). Mediation analyses further identified that more than 33.3% of the magnitude of the associations between early natural menopause and all-cause and respiratory mortality were explained by baseline forced expiratory volume in the first second. Additional analyses in women with natural menopause identified that the associations between continuous smoking and subsequent lung cancer risk and cancer mortality were moderated by early menopause status, and females with early natural menopause who continued smoking had the worst outcomes (hazard ratio, >4.6; P<.001). This study did not find associations reported above in female smokers with surgical menopause. CONCLUSION: Early natural menopause was found to be a risk factor for malignant and nonmalignant lung diseases and mortality in middle-aged and older female smokers. These findings have strong public health relevance as preventive strategies, including smoking cessation and chest computed tomography screening, should target this population (ie, female smokers with early natural menopause) to improve their postmenopausal health and well-being.

Genetic Associations and Architecture of Asthma-COPD Overlap.

BACKGROUND: Some people have characteristics of both asthma and COPD (asthma-COPD overlap), and evidence suggests they experience worse outcomes than those with either condition alone. RESEARCH QUESTION: What is the genetic architecture of asthma-COPD overlap, and do the determinants of risk for asthma-COPD overlap differ from those for COPD or asthma? STUDY DESIGN AND METHODS: We conducted a genome-wide association study in 8,068 asthma-COPD overlap case subjects and 40,360 control subjects without asthma or COPD of European ancestry in UK Biobank (stage 1). We followed up promising signals (P < 5 × 10-6) that remained associated in analyses comparing (1) asthma-COPD overlap vs asthma-only control subjects, and (2) asthma-COPD overlap vs COPD-only control subjects. These variants were analyzed in 12 independent cohorts (stage 2). RESULTS: We selected 31 independent variants for further investigation in stage 2, and discovered eight novel signals (P < 5 × 10-8) for asthma-COPD overlap (meta-analysis of stage 1 and 2 studies). These signals suggest a spectrum of shared genetic influences, some predominantly influencing asthma (FAM105A, GLB1, PHB, TSLP), others predominantly influencing fixed airflow obstruction (IL17RD, C5orf56, HLA-DQB1). One intergenic signal on chromosome 5 had not been previously associated with asthma, COPD, or lung function. Subgroup analyses suggested that associations at these eight signals were not driven by smoking or age at asthma diagnosis, and in phenome-wide scans, eosinophil counts, atopy, and asthma traits were prominent. INTERPRETATION: We identified eight signals for asthma-COPD overlap, which may represent loci that predispose to type 2 inflammation, and serious long-term consequences of asthma.

Risk of Acute Lung Injury after Esophagectomy.

To develop a new approach for identifying acute lung injury (ALI) in surgical ward setting and to assess incidence rate, clinical outcomes, and risk factors for ALI cases after esophagectomy. We also compare the degree of lung injury between operative and non-operative sides. Consecutive esophageal cancer patients (n=1022) who underwent esophagectomy from Dec 2012 to Nov 2018 in our hospital were studied. An approach for identifying ALI was proposed that integrated radiographic assessment of lung edema (RALE) score to quantify degree of lung edema. Stepwise logistic regression identified risk factors for postoperative ALI incidence. The degree of bilateral lung injury was compared using the RALE score. The approach for identifying ALI in surgical ward setting was defined as acute onset, PaO2/FiO2≤300 mmHg, bilateral opacities on bedside chest radiograph with a RALE score≥16, and exclusion of cardiogenic pulmonary edema. Incidence rate of ALI was estimated to be 9.7%. ALI diagnosis was associated with multiple clinical complications, prolonged hospital stay, higher medical bills, and higher perioperative mortality. Nine risk factors including BMI, ASA class, DLCO%, duration of surgery, neutrophil percentage, high-density lipoprotein, and electrolyte disorders were identified. The RALE score of the lung lobes of the operative side was higher than the non-operative side. A new approach for identifying ALI in esophageal cancer patients receiving esophagectomy was proposed and several risk factors were identified. ALI is common and has severe outcomes. The lung lobes on the operative side are more likely to be affected than the non-operative side.

VCAM-1 Is Upregulated in Uranium Miners Compared to Other Miners.

The United States has a rich history of mining including uranium (U)-mining, coal mining, and other metal mining. Cardiovascular diseases (CVD) are largely understudied in miners and recent literature suggests that when compared to non-U miners, U-miners are more likely to report CVD. However, the molecular basis for this phenomenon is currently unknown. In this pilot study, a New Mexico (NM)-based occupational cohort of current and former miners (n = 44) were recruited via a mobile screening clinic for miners. Serum- and endothelial-based endpoints were used to assess circulating inflammatory potential relevant to CVD. Non-U miners reported significantly fewer pack years of smoking than U-miners. Circulating biomarkers of interest revealed that U-miners had significantly greater serum amyloid A (SAA), soluble intercellular adhesion molecule 1 (ICAM-1, ng/mL), soluble vascular cell adhesion molecule 1 (VCAM-1, ng/mL), and VCAM-1 mRNA expression, as determined by the serum cumulative inflammatory potential (SCIP) assay, an endothelial-based assay. Even after adjusting for various covariates, including age, multivariable analysis determined that U-miners had significantly upregulated VCAM-1 mRNA. In conclusion, VCAM-1 may be an important biomarker and possible contributor of CVD in U-miners. Further research to explore this mechanism may be warranted.

Blood leukocyte count as a systemic inflammatory biomarker associated with a more rapid spirometric decline in a large cohort of iron and steel industry workers.

OBJECTIVE: Iron and steel industry workers are exposed to high levels of inhalable dust particles that contain various elements, including metals, and cause occupational lung diseases. We aim to assess the relationship between occupational dust exposure, systemic inflammation, and spirometric decline in a cohort of Chinese iron and steel workers. METHODS: We studied 7513 workers who participated in a Health Surveillance program at Wugang Institute for Occupational Health between 2008 and 2017. Time-weighted exposure intensity (TWEI) of dust was quantified based on self-reported dust exposure history, the experience of occupational hygienists, and historical data of dust exposure for workers with certain job titles. A linear mixed-effects model was used for association analyses. RESULTS: The average annual change of lung function was - 50.78 ml/year in forced expiratory volume in 1 s (FEV1) and - 34.36 ml/year in forced vital capacity (FVC) in males, and - 39.06 ml/year in FEV1 and - 26.66 ml/year in FVC in females. Higher TWEI prior to baseline was associated with lower longitudinal measurements of FEV1 and FVC but not with their decline rates. Higher WBC and its differential at baseline were associated with lower longitudinal measurements and a more rapid decline of FEV1 and FVC in a dose-dependent monotonically increasing manner. Moreover, the increase of WBC and its differential post-baseline was also associated with a more rapid decline of FEV1 and FVC. CONCLUSIONS: Our findings support the important role of systemic inflammation in affecting the temporal change of lung function in iron and steel industry workers.

Elevated Alu retroelement copy number among workers exposed to diesel engine exhaust.

BACKGROUND: Millions of workers worldwide are exposed to diesel engine exhaust (DEE), a known genotoxic carcinogen. Alu retroelements are repetitive DNA sequences that can multiply and compromise genomic stability. There is some evidence linking altered Alu repeats to cancer and elevated mortality risks. However, whether Alu repeats are influenced by environmental pollutants is unexplored. In an occupational setting with high DEE exposure levels, we investigated associations with Alu repeat copy number. METHODS: A cross-sectional study of 54 male DEE-exposed workers from an engine testing facility and a comparison group of 55 male unexposed controls was conducted in China. Personal air samples were assessed for elemental carbon, a DEE surrogate, using NIOSH Method 5040. Quantitative PCR (qPCR) was used to measure Alu repeat copy number relative to albumin (Alb) single-gene copy number in leucocyte DNA. The unitless Alu/Alb ratio reflects the average quantity of Alu repeats per cell. Linear regression models adjusted for age and smoking status were used to estimate relations between DEE-exposed workers versus unexposed controls, DEE tertiles (6.1-39.0, 39.1-54.5 and 54.6-107.7 µg/m3) and Alu/Alb ratio. RESULTS: DEE-exposed workers had a higher average Alu/Alb ratio than the unexposed controls (p=0.03). Further, we found a positive exposure-response relationship (p=0.02). The Alu/Alb ratio was highest among workers exposed to the top tertile of DEE versus the unexposed controls (1.12±0.08 SD vs 1.06±0.07 SD, p=0.01). CONCLUSION: Our findings suggest that DEE exposure may contribute to genomic instability. Further investigations of environmental pollutants, Alu copy number and carcinogenesis are warranted.

Chronic exposure to diesel exhaust may cause small airway wall thickening without lumen narrowing: a quantitative computerized tomography study in Chinese diesel engine testers.

BACKGROUND: Diesel exhaust (DE) is a major source of ultrafine particulate matters (PM) in ambient air and contaminates many occupational settings. Airway remodeling assessed using computerized tomography (CT) correlates well with spirometry in patients with obstructive lung diseases. Structural changes of small airways caused by chronic DE exposure is unknown. Wall and lumen areas of 6th and 9th generations of four candidate airways were quantified using end-inhalation CT scans in 78 diesel engine testers (DET) and 76 non-DETs. Carbon content in airway macrophage (CCAM) in sputum was quantified to assess the dose-response relationship. RESULTS: Environmental monitoring and CCAM showed a much higher PM exposure in DETs, which was associated with higher wall area and wall area percent for 6th generation of airways. However, no reduction in lumen area was identified. No study subjects met spirometry diagnosis of airway obstruction. This suggested that small airway wall thickening without lumen narrowing may be an early feature of airway remodeling in DETs. The effect of DE exposure status on wall area percent did not differ by lobes or smoking status. Although the trend test was of borderline significance between categorized CCAM and wall area percent, subjects in the highest CCAM category has a 14% increase in wall area percent for the 6th generation of airways compared to subjects in the lowest category. The impact of DE exposure on FEV1 can be partially explained by the wall area percent with mediation effect size equal to 20%, Pperm = 0.028). CONCLUSIONS: Small airway wall thickening without lumen narrowing may be an early image feature detected by CT and underlie the pathology of lung injury in DETs. The pattern of changes in small airway dimensions, i.e., thicker airway wall without lumen narrowing caused by occupational DE exposure was different to that (i.e., thicker airway wall with lumen narrowing) seen in our previous study of workers exposed to nano-scale carbon black aerosol, suggesting constituents other than carbon cores may contribute to such differences. Our study provides some imaging indications of the understanding of the pulmonary toxicity of combustion derived airborne particulate matters in humans.

Smoke Chemistry, In Vitro Cytotoxicity, and Genotoxicity Demonstrates Enhanced Toxicity of Cigarillos Compared With Cigarettes.

There has been limited toxicity testing of cigarillos, including comparison to cigarettes. This study compared the smoke chemistry and the cytotoxic and genotoxic potential of 10 conventional cigarettes and 10 cigarillos based on the greatest market share. Whole smoke and total particulate matter (TPM) were generated using the Canadian Intense and International Organization for Standardization puffing protocols. Tobacco-specific nitrosamines, carbonyls, and polycyclic aromatic hydrocarbons were measured using gas chromatography-mass spectrometry. TPM smoke extracts were used for the in vitro assays. Cytotoxicity was assessed in human bronchial epithelial continuously cultured cell line cells using the neutral red uptake assay. Genotoxic potential was assessed using the micronucleus (human lung adenocarcinoma continuously cultured cell line cells), Ames, and thymidine kinase assays. TPM from all cigarillos tested was more cytotoxic than cigarettes. Micronucleus formation was significantly greater for cigarillos compared with cigarettes at the highest dose of TPM, with or without rat liver S9 fraction. In the Ames test +S9, both tobacco products exhibited significant dose-dependent increases in mutation frequency, indicating metabolic activation is required for genotoxicity. In the thymidine kinase assay +S9, cigarillos showed a significantly enhanced mutation frequency although both tobacco products were positive. The levels of all measured polycyclic aromatic hydrocarbons, tobacco-specific nitrosamines, and carbonyls (except acrolein) were significantly greater in cigarillos than cigarettes. The Canadian Intense puffing protocol demonstrated increased smoke constituent levels compared with International Organization for Standardization. Even though the gas vapor phase was not tested, the results of this study showed that under the tested conditions the investigated cigarillos showed greater toxicity than comparator cigarettes. This study found that there is significantly greater toxicity in the tested U.S. marketed cigarillos than cigarettes for tobacco constituent levels, cytotoxicity, and genotoxicity. These findings are important for understanding the human health toxicity from the use of cigarillos relative to cigarettes and for building upon knowledge regarding harm from cigarillos to inform risk mitigation strategies.

Occupational exposure to carbon black nanoparticles increases inflammatory vascular disease risk: an implication of an ex vivo biosensor assay.

BACKGROUND: Among manufactured or engineered nanoparticles, carbon black (CB) has largest production worldwide and is also an occupational respiratory hazard commonly seen in rubber industry. Few studies have assessed the risk for cardiovascular disease in carbon black exposed populations. An endothelial biosensor assay was used to quantify the capacity of sera from 82 carbon black packers (CBP) and 106 non-CBPs to induce endothelial cell activation ex vivo. The mediation effect of circulatory proinflammatory factors on the association between carbon black exposure and endothelial cell activation was assessed and further validated using in vitro intervention experiments. RESULTS: The average elemental carbon level inside carbon black bagging facilities was 657.0 µg/m3, which was 164-fold higher than that seen in reference areas (4.0 µg/m3). A global index was extracted from mRNA expression of seven candidate biosensor genes using principal component analysis and used to quantify the magnitude of endothelial cell activation. This global index was found to be significantly altered in CBPs compared to non-CBPs (P < 0.0001), however this difference did not vary by smoking status (P = 0.74). Individual gene analyses identified that de novo expression of key adhesion molecules (e.g., ICAM and VCAM) and chemotactic factors (e.g., CCL2, CCL5, and CXCL8) responsible for the recruitment of leukocytes was dramatically induced in CBPs with CXCL8 showing the highest fold of induction (relative quantification = 9.1, P < 0.0001). The combination of mediation analyses and in vitro functional validation confirmed TNF-α, IL-1ß, and IL-6 as important circulatory factors mediating the effects of carbon black exposure on endothelial cell activation responses. CONCLUSIONS: Inflammatory mediators in sera from CBPs may bridge carbon black exposure and endothelial cell activation response assessed ex vivo. CBPs may have elevated risk for cardiovascular diseases when comorbidity exists. Our study may serve as a benchmark for understanding health effects of engineered carbon based nanoparticles with environmental and occupational health relevance.

Small Airway Wall Thickening Assessed by Computerized Tomography Is Associated With Low Lung Function in Chinese Carbon Black Packers.

Nanoscale carbon black as virtually pure elemental carbon can deposit deep in the lungs and cause pulmonary injury. Airway remodeling assessed using computed tomography (CT) correlates well with spirometry in patients with obstructive lung diseases. Structural airway changes caused by carbon black exposure remain unknown. Wall and lumen areas of sixth and ninth generations of airways in 4 lobes were quantified using end-inhalation CT scans in 58 current carbon black packers (CBPs) and 95 non-CBPs. Carbon content in airway macrophage (CCAM) in sputum was quantified to assess the dose-response. Environmental monitoring and CCAM showed a much higher level of elemental carbon exposure in CBPs, which was associated with higher wall area and lower lumen area with no change in total airway area for either airway generation. This suggested small airway wall thickening is a major feature of airway remodeling in CBPs. When compared with wall or lumen areas, wall area percent (WA%) was not affected by subject characteristics or lobar location and had greater measurement reproducibility. The effect of carbon black exposure status on WA% did not differ by lobes. CCAM was associated with WA% in a dose-dependent manner. CBPs had lower FEV1 (forced expiratory volume in 1 s) than non-CBPs and mediation analysis identified that a large portion (41-72%) of the FEV1 reduction associated with carbon black exposure could be explained by WA%. Small airway wall thickening as a major imaging change detected by CT may underlie the pathology of lung function impairment caused by carbon black exposure.

Association between air pollution and lung development in schoolchildren in China.

BACKGROUND: China has been facing nationwide air pollution at unprecedented high levels primarily from fossil-fuel combustion in the past decade. However, few studies have been conducted on the adverse effect of severe air pollution on lung development in school-age children. METHODS: Using wellness check and air pollution data from 2014 to 2017, we conducted a retrospective analysis of lung development in 21 616 school-age children from Shijiazhuang and Qingdao from North China with severe vs mild air pollution. Linear mixed effects model was performed to assess the effect of air pollution on forced vital capacity (FVC) growth. RESULTS: Exposure to severe air pollution was associated with a dramatic reduction in annual FVC growth rate (-71.3 mL,  p< 0.001). In addition, every 10 µg/m3 increase in annual PM2.5 level was associated with a reduction of annual FVC growth by 12.2 mL ( p< 0.001). Sex discrepancy (boys vs girls) in FVC growth was greater in Qingdao (35.4 mL/year, 95% CI: 26.0 to 44.7) than in Shijiazhuang (19.8 mL/year, 95% CI: 9.3 to 30.3) (p for interaction=0.063). Exposure to indoor coal- or wood-burning stove heating (-79.4 mL,  p< 0.001) and secondhand smoke at home (-59.3 mL,  p= 0.003) were inversely associated with FVC growth. CONCLUSION: Our study raised serious alarm over the threat of severe air pollution to lung development in school-age children. Sex discrepancy in lung development was reduced dramatically in heavily polluted area.

Carbon content in airway macrophages and genomic instability in Chinese carbon black packers.

Carbon black (CB) particulates as virtually pure elemental carbon can deposit deep in the lungs of humans. International Agency for Research on Cancer classified CB as a Group 2B carcinogen due to inconclusive human evidence. A molecular epidemiological study was conducted in an established cohort of CB packers (CBP) to assess associations between CB exposure and genomic instability in peripheral lymphocytes using cytokinesis-block micronucleus assay (CBMN). Carbon content in airway macrophages (CCAM) was quantified as a bio-effective dosimeter for chronic CB exposure. Dose-response observed in CBPs was compared to that seen in workers exposed to diesel exhaust. The association between CB exposure status and CBMN endpoints was identified in 85 CBPs and 106 non-CBPs from a 2012 visit and replicated in 127 CBPs and 105 non-CBPs from a 2018 visit. The proportion of cytoplasm area occupied by carbon particles in airway macrophages was over fivefold higher in current CBPs compared to non-CBPs and was associated with CBMN endpoints in a dose-dependent manner. CB aerosol and diesel exhaust shared the same potency of inducing genomic instability in workers. Circulatory pro-inflammatory factors especially TNF-α was found to mediate associations between CB exposure and CBMN endpoints. In vitro functional validation supported the role of TNF-α in inducing genomic instability. An estimated range of lower limits of benchmark dose of 4.19-7.28% of CCAM was recommended for risk assessment. Chronic CB exposure increased genomic instability in human circulation and this provided novel evidence supporting its reclassification as a human carcinogen.

Vasorin/ATIA Promotes Cigarette Smoke-Induced Transformation of Human Bronchial Epithelial Cells by Suppressing Autophagy-Mediated Apoptosis.

BACKGROUND: Escaping cell death pathways is an important event during carcinogenesis. We previously identified anti-TNFα-induced apoptosis (ATIA, also known as vasorin) as an antiapoptotic factor that suppresses reactive oxygen species (ROS) production. However, the role of vasorin in lung carcinogenesis has not been investigated. METHODS: Vasorin expression was examined in human lung cancer tissues with immunohistochemistry and database analysis. Genetic and pharmacological approaches were used to manipulate protein expression and autophagy activity in human bronchial epithelial cells (HBECs). ROS generation was measured with fluorescent indicator, apoptosis with release of lactate dehydrogenase, and cell transformation was assessed with colony formation in soft agar. RESULTS: Vasorin expression was increased in human lung cancer tissues and cell lines, which was inversely associated with lung cancer patient survival. Cigarette smoke extract (CSE) and benzo[a]pyrene diol epoxide (BPDE)-induced vasorin expression in HBECs. Vasorin knockdown in HBECs significantly suppressed CSE-induced transformation in association with enhanced ROS accumulation and autophagy. Scavenging ROS attenuated autophagy and cytotoxicity in vasorin knockdown cells, suggesting that vasorin potentiates transformation by impeding ROS-mediated CSE cytotoxicity and improving survival of the premalignant cells. Suppression of autophagy effectively inhibited CSE-induced apoptosis, suggesting that autophagy was pro-apoptotic in CSE-treated cells. Importantly, blocking autophagy strongly potentiated CSE-induced transformation. CONCLUSION: These results suggest that vasorin is a potential lung cancer-promoting factor that facilitates cigarette smoke-induced bronchial epithelial cell transformation by suppressing autophagy-mediated apoptosis, which could be exploited for lung cancer prevention.