Genetic Determinants of Somatic Selection of Mutational Processes in 3,566 Human Cancers.

The somatic landscape of the cancer genome results from different mutational processes represented by distinct "mutational signatures." Although several mutagenic mechanisms are known to cause specific mutational signatures in cell lines, the variation of somatic mutational activities in patients, which is mostly attributed to somatic selection, is still poorly explained. Here, we introduce a quantitative trait, mutational propensity (MP), and describe an integrated method to infer genetic determinants of variations in the mutational processes in 3,566 cancers with specific underlying mechanisms. As a result, we report 2,314 candidate determinants with both significant germline and somatic effects on somatic selection of mutational processes, of which, 485 act via cancer gene expression and 1,427 act through the tumor-immune microenvironment. These data demonstrate that the genetic determinants of MPs provide complementary information to known cancer driver genes, clonal evolution, and clinical biomarkers. SIGNIFICANCE: The genetic determinants of the somatic mutational processes in cancer elucidate the biology underlying somatic selection and evolution of cancers and demonstrate complementary predictive power across cancer types.

Exonic variants undergoing allele-specific selection in cancers.

BACKGROUND: Allelic imbalance (AI) in tumors is caused by chromosomal and sub-chromosomal gains and losses. RESULTS: We evaluated AI at 109,086 germline exonic SNP loci in four cancer types, and identified a set of SNPs that demonstrate strong tumor allele specificity in AI events. Further analyses demonstrated that these alleles show consistently different frequencies in the cancer population compared to the healthy population and are significantly enriched for predicted protein-damaging variants. Moreover, genes harboring SNPs that demonstrate allele specificity are enriched for cancer-related biological processes and are more likely to be essential in cancer cells. CONCLUSIONS: In summary, our study provides a unique and complementary method to identify genes and variants that are relevant to carcinogenesis.

IRF4 and STAT3 activities are associated with the imbalanced differentiation of T-cells in responses to inhalable particulate matters.

BACKGROUND: Particulate Matter (PM) is known to cause inflammatory responses in human. Although prior studies verified the immunogenicity of PM in cell lines and animal models, the effectors of PM exposure in the respiratory system and the regulators of the immunogenicity of PM is not fully elucidated. METHODS: To identify the potential effector of PM exposure in human respiratory system and to better understand the biology of the immunogenicity of PM, We performed gene-expression profiling of peripheral blood mononuclear cells from 171 heathy subjects in northern China to identify co-expressed gene modules associated with PM exposure. We inferred transcription factors regulating the co-expression and validated the association to T-cell differentiation in both primary T-cells and mice treated with PM. RESULTS: We report two transcription factors, IRF4 and STAT3, as regulators of the gene expression in response to PM exposure in human. We confirmed that the activation of IRF4 and STAT3 by PM is strongly associated with imbalanced differentiation of T-cells in the respiratory tracts in a time-sensitive manner in mouse. We also verified the consequential inflammatory responses of the PM exposure. Moreover, we show that the protein levels of phosphorylated IRF4 and STAT3 increase with PM exposure. CONCLUSIONS: Our study suggests the regulatory activities of IRF4 and STAT3 are associated with the Th17-mediated inflammatory responses to PM exposure in the respiratory tracts, which informs the biological background of the immunogenicity of particulate matters.

Multi-Factor Analysis of Single-Center Asthma Control in Xiamen, China.

We evaluated the effects of air pollutants, age, allergic history, family allergic history, treatment, treatment steps, and compliance on uncontrolled childhood asthma in Xiamen, China. The clinical data of children with asthma in the pediatric outpatient department of the First Affiliated Hospital of Xiamen University from January 2016 to June 2018 were analyzed retrospectively. According to the assessment of the patients' outcome including well-controlled, partly-controlled and uncontrolled, 7,211 cases of 3,268 patients were selected. Rank sum test and ordered multi-class logistic regression analysis were used. In the rank sum test, age, allergic history, family allergic history, season, treatment, treatment steps and compliance were found associated with uncontrolled rate (all P < 0.001). Logistic regression analysis showed that PM10, NO2, and SO2 raised uncontrolled-asthma rate (aOR 1.311, aOR 1.281, aOR 1.252, respectively). Older children had lower uncontrolled rate (OR = 0.849, 95% CI: 0.758-0.950), children with higher treatment steps had higher uncontrolled rate (OR = 1.227, 95%CI: 1.040-1.448), and children with better treatment compliance have lower uncontrolled rate (OR = 0.374 95% CI: 0.331-0.424). The order of the uncontrolled rate of asthma from high to low was winter, spring, autumn, and summer. PM10, NO2, SO2, age, season, treatment steps, and treatment compliance have significance for predicting the control rate of childhood asthma in Xiamen, China.

Effects of particulate matter (PM) on childhood asthma exacerbation and control in Xiamen, China.

BACKGROUND: The short-term effects of particulate matter (PM) exposure on childhood asthma exacerbation and disease control rate is not thoroughly assessed in Chinese population yet. The previous toxic effects of PM exposure are either based on long-term survey or experimental data from cell lines or mouse models, which also needs to be validated by real-world evidences. METHODS: We evaluated the short-term effects of PM exposure on asthma exacerbation in a Chinese population of 3106 pediatric outpatientsand disease control rate (DCR) in a population of 3344 children using case-crossover design. All the subjects enrolled are non-hospitalized outpatients. All data for this study were collected from the electronic health record (EHR) in the period between January 1, 2016 and June 30, 2018 in Xiamen, China. RESULTS: We found that exposure to PM2.5 and PM10 within the past two weeks was significantly associated with elevated risk of exacerbation (OR = 1.049, p < 0.001 for PM2.5and OR = 1.027, p < 0.001 for PM10). In addition, exposure to PM10 was associated with decreased DCR (OR = 0.976 for PM10, p < 0.001). CONCLUSIONS: Our results suggest that exposure to both PM10 and PM2.5 has significant short-term effects on childhood asthma exacerbation and DCR, which serves as useful epidemiological parameters for clinical management of asthma risk in the sensitive population.

Ambient air pollution, weather changes, and outpatient visits for allergic conjunctivitis: A retrospective registry study.

Allergic conjunctivitis is a common problem that significantly impairs patients' quality of life. Whether air pollution serves as a risk factor for the development of allergic conjunctivitis remains elusive. In this paper, we assess the relationship between air pollutants and weather conditions with outpatient visits for allergic conjunctivitis. By using a time-series analysis based on the largest dataset ever assembled to date, we found that the number of outpatient visits for allergic conjunctivitis was significantly correlated with the levels of NO2, O3, and temperature, while its association with humidity was statistically marginal. No associations between PM10, PM2.5, SO2, or wind velocity and outpatient visits were seen. Subgroup analyses showed that sex seemed to modify the effects of humidity on outpatient visits for allergic conjunctivitis, but not for NO2, O3, or temperature. People younger than 40 were found to be susceptible to changes of all four parameters, while those older than 40 were only consistently affected by NO2 levels. Our findings revealed that higher levels of ambient NO2, O3, and temperature increase the chances of outpatient visits for allergic conjunctivitis. Ambient air pollution and weather changes may contribute to the worsening of allergic conjunctivitis.

[Development and assessment of a dry eye questionnaire applicable to the Chinese population].

OBJECTIVE: To develop and assess a new dry eye questionnaire applicable to the Chinese population. METHODS: Based on literature review and clinical practice, a dry eye questionnaire was developed and optimized to apply to Chinese dry eye patients in the language expression and culture background. Participants (78 patients with dry eye and 82 controls) completed the dry eye questionnaire and the ocular surface disease index (OSDI) questionnaire, and ophthalmic examinations were performed, including slit lamp examination, tear breakup time, fluorescein staining, Schirmer I test and meibomian gland assessment. The original questionnaire was optimized with factor analysis according to the answers from respondents and clinical evaluations. The Cronbach α and intraclass correlation coefficient (ICC) were used to evaluate the internal consistency reliability and test-retest reliability. Factor analysis was used to assess the construct validity, concurrent validity was obtained by Spearman correlation analysis, and discriminant validity was obtained by ANOVA and Wilcoxon rank sum test. Receiver operator characteristics curves were generated to identify the sensitivity and specificity of each questionnaire for diagnosis of dry eye. RESULTS: The questionnaire was optimized to 12 items by factor analysis. The response rate from respondents to the dry eye questionnaire and the OSDI was 100% and 91.25%, respectively. The Cronbachαof the dry eye questionnaire and the OSDI was 0.794 and 0.925, respectively, whilst the ICC of both questionnaires was 0.99, indicating good to excellent reliability. The factor analysis suggested that these two questionnaires had good construct validity. The Spearman correlation analysis indicated that the dry eye questionnaire score correlated positively with the OSDI score (r = 0.812, P < 0.01) and had a greater correlation relationship with the clinical evaluations compared with the OSDI score (r for each was 0.613 and 0.605, P < 0.01). The discriminant validity analysis suggested that there was significant difference in the dry eye questionnaire score between the dry eye group and non-dry eye group (P < 0.01). When the dry eye questionnaire score of 7 was used as the diagnostic threshold, the sensitivity and specificity were 83.33% and 70.73%, respectively, and the area under roc curve was 0.814, which was higher than 0.772 of the OSDI (P < 0.01). CONCLUSION: The dry eye questionnaire we developed is applicable to the Chinese population with Chinese culture characteristics, high reliability, validity, specificity, and sensitivity, and holds a better diagnostic value than the OSDI for Chinese patients with dry eye.