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1.
Environ Sci Technol ; 2020 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-32384243

RESUMO

Evidence of long-term effects of high exposure to ambient fine particulate matter (PM2.5) on coronary heart disease (CHD) remains limited. We incorporated the high-resolution satellite-based PM2.5 estimates with a large-scale, population-based Chinese cohort comprising 118 229 individuals, to assess the CHD risk of long-term exposure to high PM2.5. During the follow-up of 908 376 person-years, 1586 incident CHD cases were identified. The long-term average PM2.5 concentration for study population was 64.96 µg/m3, ranging from 31.17 to 96.96 µg/m3. For an increment of 10 µg/m3 in PM2.5, the multivariate-adjusted hazard ratios (HRs) were 1.43 (95% confidence interval [CI]: 1.35-1.51) for total CHD, 1.45 (95% CI: 1.36-1.56) for nonfatal CHD, and 1.38 (95% CI: 1.25-1.53) for fatal CHD, respectively. The effects were different across specific CHD outcomes, with greater effects for unstable angina (HR, 1.71 [95% CI, 1.56-1.88]), and weaker effects for acute myocardial infarction (HR, 1.28 [95% CI, 1.19-1.39]) and other CHD (HR, 1.27 [95% CI, 1.10-1.48]). The exposure-response curve suggested that HRs increased with elevated PM2.5 concentration over the entire exposure range. Elderly and hypertensive individuals were more susceptible to PM2.5-induced CHD. Our findings demonstrate the adverse health effects of severe air pollution and highlight the potential health benefits of air quality improvement.

2.
Environ Int ; 141: 105776, 2020 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-32402983

RESUMO

To improve air quality, China has been implementing strict clean air policies since 2013. These policies not only substantially improved air quality but may also modify the spatial distribution of air pollution, since urban emission sources were under stricter control and some were moved to rural regions with lower air quality improvement targets and lacking of monitoring. Here, we predicted satellite-based monthly PM2.5 concentrations during 2000-2018 at a 1-km resolution with complete spatial-temporal coverage to analyze changes in the spatial pattern of PM2.5 pollution in China. We found that the PM2.5 concentration in urban regions was higher than that in rural regions of the same city by an average of 3.3 µg/m3 during 2000-2018. This urban-rural disparity in PM2.5 concentration significantly increased from 2.5 µg/m3 in 2000 and peaked in 2007 of 3.8 µg/m3, then it sharply declined by 49% during 2013-2018 with the implementation of clean air policies. This shrinkage in the urban-rural PM2.5 gap was partly due to the 1.3 µg/m3 greater average decrease in the PM2.5 level in the urban region than in the rural region of the same town during 2013-2018 on average. We also observed that cities that started monitoring earlier experienced greater decreases in the urban-rural PM2.5 difference, and regions surrounding monitor showed significantly greater PM2.5 decrease than regions far away from monitor during 2013-2018. Additionally, clean air policies modified the relationship between PM2.5 concentrations and per capita gross domestic product (GDP), leading to a lower PM2.5 level with the same per capita GDP after 2013. Emissions in rural and suburban regions should be considered to further improve air quality in China.

3.
Hum Genet ; 139(5): 623-646, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32206879

RESUMO

ATP-binding cassette (ABC) transporters constitute a superfamily of 48 structurally similar membrane transporters that mediate the ATP-dependent cellular export of a plethora of endogenous and xenobiotic substances. Importantly, genetic variants in ABC genes that affect gene function have clinically important effects on drug disposition and can be predictors of the risk of adverse drug reactions and efficacy of chemotherapeutics, calcium channel blockers, and protease inhibitors. Furthermore, loss-of-function of ABC transporters is associated with a variety of congenital disorders. Despite their clinical importance, information about the frequencies and global distribution of functionally relevant ABC variants is limited and little is known about the overall genetic complexity of this important gene family. Here, we systematically mapped the genetic landscape of the entire human ABC superfamily using Next-Generation Sequencing data from 138,632 individuals across seven major populations. Overall, we identified 62,793 exonic variants, 98.5% of which were rare. By integrating five computational prediction algorithms with structural mapping approaches using experimentally determined crystal structures, we found that the functional ABC variability is extensive and highly population-specific. Every individual harbored between 9.3 and 13.9 deleterious ABC variants, 76% of which were found only in a single population. Carrier rates of pathogenic variants in ABC transporter genes associated with autosomal recessive congenital diseases, such as cystic fibrosis or pseudoxanthoma elasticum, closely mirrored the corresponding population-specific disease prevalence, thus providing a novel resource for rare disease epidemiology. Combined, we provide the most comprehensive, systematic, and consolidated overview of ethnogeographic ABC transporter variability with important implications for personalized medicine, clinical genetics, and precision public health.


Assuntos
Transportadores de Cassetes de Ligação de ATP/genética , Grupos Étnicos/genética , Evolução Molecular , Família Multigênica , Pneumonia Aspirativa/etiologia , Polimorfismo Genético , Geografia , Humanos , Pneumonia Aspirativa/patologia
4.
Environ Int ; 138: 105589, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32146266

RESUMO

BACKGROUND: The concentration-response relationship between mortality and long-term exposure to fine particulate matter (PM2.5) has not been fully elucidated, especially at high levels of PM2.5 concentrations. OBJECTIVE: We aimed to evaluate chronic effects of ambient PM2.5 exposure on deaths among Chinese adults in high-exposure settings. METHODS: Participants of the Prediction for Atherosclerotic cardiovascular disease Risk in China (China-PAR) project were included from four prospective cohorts among Chinese adults aged ≥18 years old. The overall follow-up rate of the four cohorts was 93.4% until the recent follow-up survey that ended in 2015. The average of satellite-based PM2.5 concentrations during 2000-2015 at 1-km spatial resolution was assigned to each participant according to individual residence addresses. Based on the pooled analysis of individual data from the four cohorts, a Cox proportional hazards model was used to estimate the hazard ratio (HR) and corresponding 95% confidence intervals (95% CIs) for the association of PM2.5 exposure with mortality after multivariate adjustment. RESULTS: A total of 116,821 participants were eligible in the final analysis. During a mean of 7.7 years of follow-up, 6,395 non-accidental deaths and 2,507 cardio-metabolic deaths occurred. The mean of PM2.5 concentration was 64.9 µg/m3 ranging from 31.2 µg/m3 to 97.0 µg/m3. For each 10 µg/m3 increment in PM2.5, the HR was 1.11 (95% CI: 1.08-1.14) for non-accidental mortality and 1.22 (95% CI: 1.16-1.27) for cardio-metabolic mortality. In addition, a weak exponential curve for the concentration-response association between mortality and PM2.5 was observed among Chinese adults. CONCLUSIONS: Our study provided important evidence of the long-term effects of PM2.5 exposure on deaths among Chinese adults. The findings expand our knowledge on concentration-response relationship in high-exposure environments, which is essential to address the urgent challenge of reducing the disease burden attributable to PM2.5 exposure in rapidly industrializing countries such as China.

5.
Int J Cancer ; 146(9): 2475-2487, 2020 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-32010961

RESUMO

Multidrug resistance due to facilitated drug efflux mediated by ATP-binding cassette (ABC) transporters is a main cause for failure of cancer therapy. Genetic polymorphisms in ABC genes affect the disposition of chemotherapeutics and constitute important biomarkers for therapeutic response and toxicity. Here we correlated germline variability in ABC transporters with disease-specific survival (DSS) in 960 breast cancer (BRCA), 314 clear cell renal cell carcinoma and 325 hepatocellular carcinoma patients. We find that variant burden in ABCC1 is a strong predictor of DSS in BRCA patients, whereas candidate polymorphisms are not associated with DSS. This association is highly drug-specific for subgroups treated with the MRP1 substrates cyclophosphamide (log-rank p = 0.0011) and doxorubicin (log-rank p = 0.0088) independent of age and tumor stage, whereas no association was found in individuals treated with tamoxifen (log-rank p = 0.13). Structural mapping of significant variants revealed multiple variants at residues involved in protein stability, cofactor stabilization or substrate binding. Our results demonstrate that BRCA patients with high variant burden in ABCC1 are less prone to respond appropriately to pharmacological therapy with MRP1 substrates, thus incentivizing the consideration of genomic germline data for precision cancer medicine.

6.
J Am Coll Cardiol ; 75(7): 707-717, 2020 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-32081278

RESUMO

BACKGROUND: Evidence of the effects of long-term fine particulate matter (PM2.5) exposure on cardiovascular diseases (CVDs) is rare for populations exposed to high levels of PM2.5 in China and in other countries with similarly high levels. OBJECTIVES: The aim of this study was to assess the CVD risks associated with long-term exposure to PM2.5 in China. METHODS: A nationwide cohort study, China-PAR (Prediction for Atherosclerotic Cardiovascular Disease Risk in China), was used, with 116,972 adults without CVD in 2000 being included. Participants were followed until 2015. Satellite-based PM2.5 concentrations at 1-km spatial resolution during the study period were used for exposure assessment. A Cox proportional hazards model with time-varying exposures was used to estimate the CVD risks associated with PM2.5 exposure, adjusting for individual risk factors. RESULTS: Annual mean concentrations of PM2.5 at the China-PAR sites ranged from 25.5 to 114.0 µg/m3. For each 10 µg/m3 increase in PM2.5 exposures, the multivariate-adjusted hazard ratio was 1.251 (95% confidence interval: 1.220 to 1.283) for CVD incidence and 1.164 (95% confidence interval: 1.117 to 1.213) for CVD mortality. The slopes of concentration-response functions of PM2.5 exposure and CVD risks were steeper at high PM2.5 levels. In addition, older residents, rural residents, and never smokers were more prone to adverse effects of PM2.5 exposure. CONCLUSIONS: This study provides evidence that elevated long-term PM2.5 exposures lead to increased CVD risk in China. The effects are more pronounced at higher PM2.5 levels. These findings expand the current knowledge on adverse health effects of severe air pollution and highlight the potential cardiovascular benefits of air quality improvement in China and other low- and middle-income countries.

7.
Chemosphere ; 239: 124678, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31494323

RESUMO

In the developing countries such as China, most well-developed areas have suffered severe haze pollution, which was associated with increased premature morbidity and mortality and attracted widespread public concerns. Since ground-based PM2.5 monitoring has limited temporal and spatial coverage, satellite aerosol remote sensing data has been increasingly applied to map large-scale PM2.5 characteristics through advanced spatial statistical models. Although most existing research has taken advantage of the polar orbiting satellite instruments, a major limitation of the polar orbiting platform is its limited sampling frequency (e.g., 1-2 times/day), which is insufficient for capturing the PM2.5 variability during short but intense heavy haze episodes. As the first attempt, we quantitatively investigated the feasibility of using the aerosol optical depth (AOD) data retrieved by the Geostationary Ocean Color Imager (GOCI) to estimate hourly PM2.5 concentrations during winter haze episodes in the Yangtze River Delta (YRD). We developed a three-stage spatial statistical model, using GOCI AOD and fine mode fraction, as well as corresponding monitoring PM2.5 concentrations, meteorological and land use data on a 6-km modeling grid with complete coverage in time and space. The 10-fold cross-validation R2 was 0.72 with a regression slope of 1.01 between observed and predicted hourly PM2.5 concentrations. After gap filling, the R2 value for the three-stage model was 0.68. We further analyzed two representative large regional episodes, i.e., a "multi-process diffusion episode" during December 21-26, 2015 and a "Chinese New Year episode" during February 7-8, 2016. We concluded that AOD retrieved by geostationary satellites could serve as a new valuable data source for analyzing the heavy air pollution episodes.


Assuntos
Poluentes Atmosféricos/análise , Poluição do Ar/análise , Monitoramento Ambiental/métodos , Material Particulado/análise , Tecnologia de Sensoriamento Remoto/métodos , Aerossóis/análise , China , Meteorologia , Modelos Estatísticos , Rios , Estações do Ano , Astronave
8.
BMC Bioinformatics ; 20(Suppl 15): 489, 2019 Dec 24.
Artigo em Inglês | MEDLINE | ID: mdl-31874600

RESUMO

BACKGROUND: The biological network is highly dynamic. Functional relations between genes can be activated or deactivated depending on the biological conditions. On the genome-scale network, subnetworks that gain or lose local expression consistency may shed light on the regulatory mechanisms related to the changing biological conditions, such as disease status or tissue developmental stages. RESULTS: In this study, we develop a new method to select genes and modules on the existing biological network, in which local expression consistency changes significantly between clinical conditions. The method is called DNLC: Differential Network Local Consistency. In simulations, our algorithm detected artificially created local consistency changes effectively. We applied the method on two publicly available datasets, and the method detected novel genes and network modules that were biologically plausible. CONCLUSIONS: The new method is effective in finding modules in which the gene expression consistency change between clinical conditions. It is a useful tool that complements traditional differential expression analyses to make discoveries from gene expression data. The R package is available at https://cran.r-project.org/web/packages/DNLC.


Assuntos
Redes Reguladoras de Genes , Algoritmos , Perfilação da Expressão Gênica/métodos , Humanos , Software
9.
Remote Sens (Basel) ; 11(6)2019 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-31372305

RESUMO

It is well recognized that exposure to fine particulate matter (PM2.5) affects health adversely, yet few studies from South America have documented such associations due to the sparsity of PM2.5 measurements. Lima's topography and aging vehicular fleet results in severe air pollution with limited amounts of monitors to effectively quantify PM2.5 levels for epidemiologic studies. We developed an advanced machine learning model to estimate daily PM2.5 concentrations at a 1 km2 spatial resolution in Lima, Peru from 2010 to 2016. We combined aerosol optical depth (AOD), meteorological fields from the European Centre for Medium-Range Weather Forecasts (ECMWF), parameters from the Weather Research and Forecasting model coupled with Chemistry (WRF-Chem), and land use variables to fit a random forest model against ground measurements from 16 monitoring stations. Overall cross-validation R2 (and root mean square prediction error, RMSE) for the random forest model was 0.70 (5.97 µg/m3). Mean PM2.5 for ground measurements was 24.7 µg/m3 while mean estimated PM2.5 was 24.9 µg/m3 in the cross-validation dataset. The mean difference between ground and predicted measurements was -0.09 µg/m3 (Std.Dev. = 5.97 µg/m3), with 94.5% of observations falling within 2 standard deviations of the difference indicating good agreement between ground measurements and predicted estimates. Surface downwards solar radiation, temperature, relative humidity, and AOD were the most important predictors, while percent urbanization, albedo, and cloud fraction were the least important predictors. Comparison of monthly mean measurements between ground and predicted PM2.5 shows good precision and accuracy from our model. Furthermore, mean annual maps of PM2.5 show consistent lower concentrations in the coast and higher concentrations in the mountains, resulting from prevailing coastal winds blown from the Pacific Ocean in the west. Our model allows for construction of long-term historical daily PM2.5 measurements at 1 km2 spatial resolution to support future epidemiological studies.

10.
Hypertension ; 73(6): 1195-1201, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31067193

RESUMO

The risk of incident hypertension associated with long-term exposure to fine particulate matter (PM2.5) was still unclear by studies conducted in North America and Europe, and this relationship has rarely been quantified at higher ambient concentrations typically found in developing countries. We aimed to investigate the association between PM2.5 and incident hypertension using the large-scale prospective cohorts in China. We included 59 456 participants without hypertension aged ≥18 years from the China-PAR (Prediction for Atherosclerotic Cardiovascular Disease Risk in China) project. Data on ambient PM2.5 at participants' residential address were obtained during 2004 to 2015 using a satellite-based spatial-temporal model. Hazard ratios and 95% CIs were calculated for incident hypertension using stratified Cox proportional hazards models with adjustment of potential confounders. The findings indicated that average PM2.5 concentration from 2004 to 2015 at study participants' address was 77.7 µg/m3. During the follow-up of 364 947 person-years, we identified 13 981 incident hypertension cases. Compared with the lowest quartile exposure of PM2.5, participants in the highest quartile had an increased risk of incident hypertension with a hazard ratio (95% CI) of 1.77 (1.56-2.00). Each 10 µg/m3 increment of PM2.5 concentration could increase 11% risk of hypertension (hazard ratio, 1.11; 95% CI, 1.05-1.17). This cohort study provided the first evidence from China that long-term exposure to PM2.5 was independently associated with incident hypertension at relatively high ambient concentrations. Stringent strategies on PM2.5 pollution control are warranted to improve the air quality and contribute to the reduction of disease burden of hypertension in China.


Assuntos
Exposição Ambiental/efeitos adversos , Previsões , Hipertensão/epidemiologia , Material Particulado/efeitos adversos , China/epidemiologia , Feminino , Seguimentos , Humanos , Hipertensão/etiologia , Incidência , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Fatores de Risco
11.
Environ Int ; 126: 568-575, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30852444

RESUMO

BACKGROUND: Diabetes caused substantial economic and health burden worldwide. However, the associations between air pollution and diabetes incidence were rarely reported in the developing countries, especially in China with relatively high PM2.5 concentrations. OBJECTIVES: A cohort-based study was conducted to assess the diabetes incidence associated with long-term exposure to ambient PM2.5. METHODS: We collected individual health data and risk factors from the project of Prediction for Atherosclerotic Cardiovascular Disease Risk in China (China-PAR Project) from 15 provinces over China. Diabetes was defined as fasting glucose levels ≥7.0 mmol/L at the follow-ups and/or the use of insulin or oral hypoglycemic agents and/or diagnosed medical history of diabetes during 2004 to 2015. Individual-level PM2.5 exposures were estimated from satellite-based PM2.5 concentrations (10 km spatial resolution) during the study period. Cox proportional hazards models with random intercepts of each cohort and region were employed to estimate the diabetes incidence attributable to PM2.5, after the adjustment for age, gender, body mass index, smoking status, education, work-related physical activity level, hypertension, urbanicity, county-level averaged years of education, and long-term levels of temperature and relative humidity. RESULTS: A total of 88,397 subjects were analyzed with 580,928 person-years of follow-up after 2004, among which 6439 new cases of diabetes were observed. The mean age of the subjects was 51.7 years at baseline. For an increase of 10 µg/m3 in long-term PM2.5 exposure, the multivariable-adjusted percent increase in the diabetes incidence was estimated to be 15.66% (95% confidence interval: 6.42%, 25.70%). The adverse effects of PM2.5 were larger among females, rural subjects, non-smokers, normotensives, subjects younger than 65 years and subjects with body mass index <25 kg/m2. CONCLUSIONS: Our findings provided evidence for the association of long-term exposure to PM2.5 with diabetes incidence in China. A sustained improvement of air quality will benefit the reduction for diabetes epidemic in China.


Assuntos
Poluentes Atmosféricos/análise , Diabetes Mellitus/epidemiologia , Exposição Ambiental/análise , Material Particulado/análise , Adulto , China/epidemiologia , Estudos de Coortes , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Fatores de Risco
12.
BMJ ; 367: l6720, 2019 12 30.
Artigo em Inglês | MEDLINE | ID: mdl-31888885

RESUMO

OBJECTIVE: To study the effect of long term exposure to ambient fine particulate matter of diameter ≤2.5 µm (PM2.5) on the incidence of total, ischemic, and hemorrhagic stroke among Chinese adults. DESIGN: Population based prospective cohort study. SETTING: Prediction for Atherosclerotic Cardiovascular Disease Risk in China (China-PAR) project carried out in 15 provinces across China. PARTICIPANTS: 117 575 Chinese men and women without stroke at baseline in the China-PAR project. MAIN OUTCOME MEASURES: Incidence of total, ischemic, and hemorrhagic stroke. RESULTS: The long term average PM2.5 level from 2000 to 2015 at participants' residential addresses was 64.9 µg/m3, ranging from 31.2 µg/m3 to 97.0 µg/m3. During 900 214 person years of follow-up, 3540 cases of incident stroke were identified, of which 63.0% (n=2230) were ischemic and 27.5% (n=973) were hemorrhagic. Compared with the first quarter of exposure to PM2.5 (<54.5 µg/m3), participants in the highest quarter (>78.2 µg/m3) had an increased risk of incident stroke (hazard ratio 1.53, 95% confidence interval 1.34 to 1.74), ischemic stroke (1.82, 1.55 to 2.14), and hemorrhagic stroke (1.50, 1.16 to 1.93). For each increase of 10 µg/m3 in PM2.5 concentration, the increased risks of incident stroke, ischemic stroke, and hemorrhagic stroke were 13% (1.13, 1.09 to 1.17), 20% (1.20, 1.15 to 1.25), and 12% (1.12, 1.05 to 1.20), respectively. Almost linear exposure-response relations between long term exposure to PM2.5 and incident stroke, overall and by its subtypes, were observed. CONCLUSIONS: This study provides evidence from China that long term exposure to ambient PM2.5 at relatively high concentrations is positively associated with incident stroke and its major subtypes. These findings are meaningful for both environmental and health policy development related to air pollution and stroke prevention, not only in China, but also in other low and middle income countries.


Assuntos
Monitoramento Ambiental/métodos , Material Particulado/análise , Acidente Vascular Cerebral/epidemiologia , Adulto , China/epidemiologia , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Material Particulado/efeitos adversos , Estudos Prospectivos , Comunicações Via Satélite , Acidente Vascular Cerebral/induzido quimicamente
13.
Environ Sci Technol ; 52(22): 13260-13269, 2018 11 20.
Artigo em Inglês | MEDLINE | ID: mdl-30354085

RESUMO

The long satellite aerosol data record enables assessments of historical PM2.5 level in regions where routine PM2.5 monitoring began only recently. However, most previous models reported decreased prediction accuracy when predicting PM2.5 levels outside the model-training period. In this study, we proposed an ensemble machine learning approach that provided reliable PM2.5 hindcast capabilities. The missing satellite data were first filled by multiple imputation. Then the modeling domain, China, was divided into seven regions using a spatial clustering method to control for unobserved spatial heterogeneity. A set of machine learning models including random forest, generalized additive model, and extreme gradient boosting were trained in each region separately. Finally, a generalized additive ensemble model was developed to combine predictions from different algorithms. The ensemble prediction characterized the spatiotemporal distribution of daily PM2.5 well with the cross-validation (CV) R2 (RMSE) of 0.79 (21 µg/m3). The cluster-based subregion models outperformed national models and improved the CV R2 by ∼0.05. Compared with previous studies, our model provided more accurate out-of-range predictions at the daily level ( R2 = 0.58, RMSE = 29 µg/m3) and monthly level ( R2 = 0.76, RMSE = 16 µg/m3). Our hindcast modeling system allows for the construction of unbiased historical PM2.5 levels.


Assuntos
Poluentes Atmosféricos , Material Particulado , China , Monitoramento Ambiental , Aprendizado de Máquina
14.
Lancet Respir Med ; 6(10): 771-781, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30100403

RESUMO

BACKGROUND: Anti-programmed death-1 (PD-1) treatment for advanced non-small-cell lung cancer (NSCLC) has improved the survival of patients. However, a substantial percentage of patients do not respond to this treatment. We examined the use of DNA methylation profiles to determine the efficacy of anti-PD-1 treatment in patients recruited with current stage IV NSCLC. METHODS: In this multicentre study, we recruited adult patients from 15 hospitals in France, Spain, and Italy who had histologically proven stage IV NSCLC and had been exposed to PD-1 blockade during the course of the disease. The study structure comprised a discovery cohort to assess the correlation between epigenetic features and clinical benefit with PD-1 blockade and two validation cohorts to assess the validity of our assumptions. We first established an epigenomic profile based on a microarray DNA methylation signature (EPIMMUNE) in a discovery set of tumour samples from patients treated with nivolumab or pembrolizumab. The EPIMMUNE signature was validated in an independent set of patients. A derived DNA methylation marker was validated by a single-methylation assay in a validation cohort of patients. The main study outcomes were progression-free survival and overall survival. We used the Kaplan-Meier method to estimate progression-free and overall survival, and calculated the differences between the groups with the log-rank test. We constructed a multivariate Cox model to identify the variables independently associated with progression-free and overall survival. FINDINGS: Between June 23, 2014, and May 18, 2017, we obtained samples from 142 patients: 34 in the discovery cohort, 47 in the EPIMMUNE validation cohort, and 61 in the derived methylation marker cohort (the T-cell differentiation factor forkhead box P1 [FOXP1]). The EPIMMUNE signature in patients with stage IV NSCLC treated with anti-PD-1 agents was associated with improved progression-free survival (hazard ratio [HR] 0·010, 95% CI 3·29 × 10-4-0·0282; p=0·0067) and overall survival (0·080, 0·017-0·373; p=0·0012). The EPIMMUNE-positive signature was not associated with PD-L1 expression, the presence of CD8+ cells, or mutational load. EPIMMUNE-negative tumours were enriched in tumour-associated macrophages and neutrophils, cancer-associated fibroblasts, and senescent endothelial cells. The EPIMMUNE-positive signature was associated with improved progression-free survival in the EPIMMUNE validation cohort (0·330, 0·149-0·727; p=0·0064). The unmethylated status of FOXP1 was associated with improved progression-free survival (0·415, 0·209-0·802; p=0·0063) and overall survival (0·409, 0·220-0·780; p=0·0094) in the FOXP1 validation cohort. The EPIMMUNE signature and unmethylated FOXP1 were not associated with clinical benefit in lung tumours that did not receive immunotherapy. INTERPRETATION: Our study shows that the epigenetic milieu of NSCLC tumours indicates which patients are most likely to benefit from nivolumab or pembrolizumab treatments. The methylation status of FOXP1 could be associated with validated predictive biomarkers such as PD-L1 staining and mutational load to better select patients who will experience clinical benefit with PD-1 blockade, and its predictive value should be evaluated in prospective studies. FUNDING: "Obra Social" La Caixa, Cellex Foundation, and the Health and Science Departments of the Generalitat de Catalunya.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/genética , Metilação de DNA/genética , Neoplasias Pulmonares/genética , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/uso terapêutico , Biomarcadores Tumorais/genética , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Epigenômica , Feminino , Fatores de Transcrição Forkhead/genética , Humanos , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Nivolumabe/uso terapêutico , Valor Preditivo dos Testes , Intervalo Livre de Progressão , Modelos de Riscos Proporcionais , Proteínas Repressoras/genética , Estudos Retrospectivos , Resultado do Tratamento
15.
Environ Pollut ; 242(Pt A): 675-683, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30025341

RESUMO

Exposure to fine particulate matter (PM2.5) remains a worldwide public health issue. However, epidemiological studies on the chronic health impacts of PM2.5 in the developing countries are hindered by the lack of monitoring data. Despite the recent development of using satellite remote sensing to predict ground-level PM2.5 concentrations in China, methods for generating reliable historical PM2.5 exposure, especially prior to the construction of PM2.5 monitoring network in 2013, are still very rare. In this study, a high-performance machine-learning model was developed directly at monthly level to estimate PM2.5 levels in North China Plain. We developed a random forest model using the latest Multi-angle implementation of atmospheric correction (MAIAC) aerosol optical depth (AOD), meteorological parameters, land cover and ground PM2.5 measurements from 2013 to 2015. A multiple imputation method was applied to fill the missing values of AOD. We used 10-fold cross-validation (CV) to evaluate model performance and a separate time period, January 2016 to December 2016, was used to validate our model's capability of predicting historical PM2.5 concentrations. The overall model CV R2 and relative prediction error (RPE) were 0.88 and 18.7%, respectively. Validation results beyond the modeling period (2013-2015) shown that this model can accurately predict historical PM2.5 concentrations at the monthly (R2 = 0.74, RPE = 27.6%), seasonal (R2 = 0.78, RPE = 21.2%) and annual (R2 = 0.76, RPE = 16.9%) level. The annual mean predicted PM2.5 concentration from 2013 to 2016 in our study domain was 67.7 µg/m3 and Southern Hebei, Western Shandong and Northern Henan were the most polluted areas. Using this computationally efficient, monthly and high-resolution model, we can provide reliable historical PM2.5 concentrations for epidemiological studies on PM2.5 health effects in China.


Assuntos
Poluentes Atmosféricos/análise , Poluição do Ar/estatística & dados numéricos , Monitoramento Ambiental/métodos , Material Particulado/análise , Aerossóis/análise , Poluição do Ar/análise , China , Poluição Ambiental , Humanos , Aprendizado de Máquina , Meteorologia
16.
Environ Pollut ; 242(Pt A): 492-499, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30005261

RESUMO

Severe and persistent haze accompanied by high concentrations of fine particulate matter (PM2.5) has become a great public health concern in urban China. However, research on the health effects of PM2.5 in China has been hindered by the lack of high-quality exposure estimates. In this study, we assessed the excess mortality associated with both short- and long-term exposure to ambient PM2.5 simultaneously using satellite-derived exposure data at a high spatiotemporal resolution. Adult registries of non-accidental, respiratory and cardiovascular deaths in urban Beijing in 2013 were collected. Exposure levels were estimated from daily satellite-based PM2.5 concentrations at 1 km spatial resolution from 2004 to 2013. Mixed Poisson regression models were fitted to estimate the cause-specific mortality in association with PM2.5 exposures. With the mutual adjustment of short- and long-term exposure of PM2.5, the percent increases associated with every 10 µg/m3 increase in short-term PM2.5 exposure were 0.09% (95% CI: -0.14%, 0.33%; lag 01), 1.02% (95% CI: 0.08%, 1.97%; lag 04) and 0.09% (95% CI: -0.23%, 0.42%; lag 01) for non-accidental, respiratory and cardiovascular mortality, respectively; those attributable to every 10 µg/m3 increase in long-term PM2.5 exposure (9-year moving average) were 16.78% (95% CI: 10.58%, 23.33%), 44.14% (95% CI: 20.73%, 72.10%) and 3.72% (95% CI: -3.75%, 11.77%), respectively. Both associations of short- and long-term exposure with the cause-specific mortality decreased after they were mutually adjusted. Associations between short-term exposure to satellite-based PM2.5 and cause-specific mortality were larger than those estimated using fixed measurements. Satellite-based PM2.5 predictions help to improve the spatiotemporal resolution of exposure assessments and the mutual adjustment model provide better estimation of PM2.5 associated health effects. Effects attributable to long-term exposure of PM2.5 were larger than those of short-term exposure, which should be more concerned for public health.


Assuntos
Poluentes Atmosféricos/análise , Poluição do Ar/estatística & dados numéricos , Exposição Ambiental/estatística & dados numéricos , Mortalidade/tendências , Material Particulado/análise , Imagens de Satélites , Adulto , Pequim/epidemiologia , China , Humanos , Saúde Pública
17.
Environ Int ; 117: 226-236, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29763818

RESUMO

BACKGROUND: Few studies have estimated effects of maternal PM2.5 exposure on birth outcomes in China due to the lack of historical air pollution data. OBJECTIVES: We estimated the associations between maternal PM2.5 exposure and birth outcomes using gap-filled satellite estimates in Shanghai, China. METHODS: We obtained birth registration records of 132,783 singleton live births during 2011-2014 in Shanghai. PM2.5 exposures were assessed from satellite-derived estimates or central-site measurements. Linear and logistic regressions were used to estimate associations with term birth weight and term low birth weight (LBW), respectively. Logistic and discrete-time survival models were used to estimate associations with preterm birth. Effect modification by maternal age and parental education levels was investigated. RESULTS: A 10 µg/m3 increase in gap-filled satellite-based whole-pregnancy PM2.5 exposure was associated with a -12.85 g (95% CI: -18.44, -7.27) change in term birth weight, increased risk of preterm birth (OR 1.27, 95% CI: 1.20, 1.36), and increased risk of term LBW (OR 1.22, 95% CI: 1.06, 1.41). Sensitivity analyses during 2013-2014, when ground PM2.5 measurements were available, showed that the health associations using gap-filled satellite PM2.5 concentrations were higher than those obtained using satellite PM2.5 concentrations without accounting for missingness. The health associations using gap-filled satellite PM2.5 had similar magnitudes to those using central-site measurements, but with narrower confidence intervals. CONCLUSIONS: The magnitude of associations between maternal PM2.5 exposure and adverse birth outcomes in Shanghai was higher than previous findings. One reason could be reduced exposure error of the gap-filled high-resolution satellite PM2.5 estimates.


Assuntos
Poluentes Atmosféricos , Exposição Materna/estatística & dados numéricos , Material Particulado , Resultado da Gravidez/epidemiologia , Poluentes Atmosféricos/análise , Poluentes Atmosféricos/toxicidade , China/epidemiologia , Feminino , Humanos , Material Particulado/análise , Material Particulado/toxicidade , Gravidez
18.
Sci Total Environ ; 616-617: 1589-1598, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29055576

RESUMO

Satellite-driven statistical models have been proven to be able to provide spatially resolved PM2.5 estimates worldwide. The North China Plain has been suffering from severe PM2.5 pollution in recent years. An accurate assessment of the spatiotemporal characteristics of PM2.5 levels in this region is crucial to design effective air pollution control policy. Our objective is to estimate daily PM2.5 concentrations at 1km spatial resolution from 2004 to 2014 in Beijing and its surrounding areas using the Multi-angle implementation of atmospheric correction (MAIAC) aerosol optical depth (AOD). A high-performance three-stage model was developed with AOD, meteorological, demographic and land use variables as predictors, which includes a custom-designed PM2.5 gap-filling method. The 11-year average annual coverage increased from 177days to 279days and annual PM2.5 prediction error decreased from 14.1µg/m3 to 8.3µg/m3 after gap-filling techniques were applied. Results show that the 11-year overall mean of predicted PM2.5 was 67.1µg/m3 in our study domain. The cross-validation R2 value of our model is 0.82 in 2013 and 0.79 in 2014. In addition, the models predicted historical PM2.5 concentrations with relatively high accuracy at the seasonal and annual levels (R2 ranged from 0.78 to 0.86). Our long-term PM2.5 prediction filled the gaps left by ground monitors, which would be beneficial to PM2.5 related epidemiological studies in Beijing.


Assuntos
Poluentes Atmosféricos/análise , Poluição do Ar/estatística & dados numéricos , Monitoramento Ambiental , Material Particulado/análise , Pequim , China , Meteorologia , Modelos Estatísticos
19.
Braz J Cardiovasc Surg ; 32(5): 401-407, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29211221

RESUMO

OBJECTIVE: To evaluate the safety and feasibility of a novel stent-graft for thoracic endovascular aortic repair (TEVAR) in a canine model, 9 adult hybrid dogs were used for the experiment. METHODS: All animals were implanted with a novel thoracic aortic stent-graft via femoral artery. Blood sample was collected at pre-operation and 1, 2, 4, 8 and 12 weeks after implantation for hematological examination. Moreover, tissues from randomly selected 4 dogs were subjected to histopathological analysis with the optical microscope after stent-grafts were implanted for 3, 6, 9, and 12 months respectively. The experimental period lasted for more than 2 years. RESULTS: A total of 9 stent-grafts were successfully implanted in the canine thoracic aortas and no migration or deformation occurred. Related indicators of blood routine, inflammatory factors, and immunology changes were not significantly (P>0.05), except the white blood cell (WBC) counts in the first week. Moreover, abnormal morphology was not found in all thoracic aortas via histopathological examination. Additionally, all stent-grafts were patent and did not migrate, and there was no thrombus in the lumens of stent-grafts. CONCLUSION: The novel thoracic aortic stent-graft made in China was safe and feasible for thoracic endovascular aortic repair in a canine model.


Assuntos
Aorta Torácica/cirurgia , Implante de Prótese Vascular , Procedimentos Endovasculares/instrumentação , Stents , Animais , Cães , Estudos de Viabilidade , Teste de Materiais , Modelos Animais , Desenho de Prótese , Fatores de Tempo
20.
Rev. bras. cir. cardiovasc ; 32(5): 401-407, Sept.-Oct. 2017. tab, graf
Artigo em Inglês | LILACS-Express | ID: biblio-897950

RESUMO

Abstract Objective: To evaluate the safety and feasibility of a novel stent-graft for thoracic endovascular aortic repair (TEVAR) in a canine model, 9 adult hybrid dogs were used for the experiment. Methods: All animals were implanted with a novel thoracic aortic stent-graft via femoral artery. Blood sample was collected at pre-operation and 1, 2, 4, 8 and 12 weeks after implantation for hematological examination. Moreover, tissues from randomly selected 4 dogs were subjected to histopathological analysis with the optical microscope after stent-grafts were implanted for 3, 6, 9, and 12 months respectively. The experimental period lasted for more than 2 years. Results: A total of 9 stent-grafts were successfully implanted in the canine thoracic aortas and no migration or deformation occurred. Related indicators of blood routine, inflammatory factors, and immunology changes were not significantly (P>0.05), except the white blood cell (WBC) counts in the first week. Moreover, abnormal morphology was not found in all thoracic aortas via histopathological examination. Additionally, all stent-grafts were patent and did not migrate, and there was no thrombus in the lumens of stent-grafts. Conclusion: The novel thoracic aortic stent-graft made in China was safe and feasible for thoracic endovascular aortic repair in a canine model.

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