Determinants of personal exposure to fine particulate matter (PM2.5) adult subjects in Hong Kong

Personal monitoring for fine particulate matter (PM2.5) was conducted for adults (48 subjects, 18-63 years of age) in Hong Kong during the summer and winter of 2014-2015. All filters were analyzed for PM2.5 mass and constituents (including carbonaceous aerosols, water-soluble ions, and elements). We found that season (p = 0.02) and occupation (p < 0.001) were significant factors affecting the strength of the personal-ambient PM2.5 associations. We applied mixed-effects models to investigate the determinants of personal exposure to PM2.5 mass and constituents, along with within- and between-individual variance components. Ambient PM2.5 was the dominant predictor of (R-2 = 0.12-0.59, p < 0.01) and the largest contributor (>37.3%) to personal exposures for PM2.5 mass and most components. For all subjects, a one-unit (2.72 mu g/m(3)) increase in ambient PM2.5 was associated with a 0.75 mu g/m(3) (95% CI: 0.59-0.94 mu g/m(3)) increase in personal PM2.5 exposure. The adjusted mixed-effects models included information extracted from individual's activity diaries as covariates. The results showed that season, occupation, time indoors at home, in transit, and cleaning were significant determinants for PM2.5 components in personal exposure (R-beta(2) = 0.06-0.63, p < 0.05), contributing to 3.0-70.4% of the variability. For onehour extra time spent at home, in transit; and cleaning an average increase of 1.7-3.6% (ammonium, sulfate, nitrate, sulfur), 2.7-12.3% (elemental carbon, ammonium, titanium, iron), and 8.7-19.4% (ammonium, magnesium ions, vanadium) in components of personal PM2.5 were observed, respectively. In this research, the within-individual variance component dominated the total variability for all investigated exposure data except PM2.5 and EC. Results from this study indicate that performing long-term personal monitoring is needed for examining the associations of mass and constituents of personal PM2.5 with health outcomes in epidemiological studies by describing the impacts of individual-specific data on personal exposures. (C) 2018 Elsevier B.V. All rights reserved

Association of BANK1 and TNFSF4 with systemic lupus erythematosus in Hong Kong Chinese

Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease with complex genetic inheritance. Recently, single nucleotide polymorphisms (SNPs) in BANK1 and TNFSF4 have been shown to be associated with SLE in Caucasian populations, but it is not known whether they are also involved in the disease in other ethnic groups. Recent data from our genome-wide association study (GWAS) for 314 SLE cases and 920 controls collected in Hong Kong identified SNPs in and around BANK1 and TNFSF4 to be associated with SLE risk. On the basis of the results of the reported studies and our GWAS, SNPs were selected for further genotyping in 949 SLE patients (overlapping with the 314 cases in our GWAS) and non-overlapping 1042 healthy controls. We confirmed the associations of BANK1 and TNFSF4 with SLE in Chinese (BANK1, rs3733197, odds ratio (OR)=0.84, P=0.021; BANK1, rs17266594, OR=0.61, P=4.67 × 10−9; TNFSF4, rs844648, OR=1.22, P=2.47 × 10−3; TNFSF4, rs2205960, OR=1.30, P=2.41 × 10−4). Another SNP located in intron 1 of BANK1, rs4522865, was separately replicated by Sequenom in 360 cases and 360 controls and was also confirmed to be associated with SLE (OR=0.725, P=2.93 × 10−3). Logistic regression analysis showed that rs3733197 (A383T in ankyrin domain) and rs17266594 (a branch point-site SNP) from BANK1 had independent contributions towards the disease association (P=0.037 and 6.63 × 10−8, respectively). In TNFSF4, rs2205960 was associated with SLE independently from the effect of rs844648 (P=6.26 × 10−3), but not vice versa (P=0.55). These findings suggest that multiple independent genetic variants may be present within the gene locus, which exert their effects on SLE pathogenesis through different mechanisms

Disease Detection by Ultrasensitive Quantification of Microdosed Synthetic Urinary Biomarkers

The delivery of exogenous agents can enable noninvasive disease monitoring, but existing low-dose approaches require complex infrastructure. In this paper, we describe a microdose-scale injectable formulation of nanoparticles that interrogate the activity of thrombin, a key regulator of clotting, and produce urinary reporters of disease state. We establish a customized single molecule detection assay that enables urinary discrimination of thromboembolic disease in mice using doses of the nanoparticulate diagnostic agents that fall under regulatory guidelines for “microdosing.”National Science Foundation (U.S.). Graduate Research FellowshipNational Institutes of Health (U.S.) (Ruth L. Kirschstein National Research Service Award F32CA159496-02)Burroughs Wellcome Fund (Career Award at the Scientific Interface)National Cancer Institute (U.S.) (Koch Institute Support (Core) Grant P30-CA14051)David H. Koch Institute for Integrative Cancer Research at MIT (Frontier Research Program

Impact of prevalent and incident vertebral fractures on utility: results from a patient-based and a population-based sample

Data are scarce on the impact of vertebral fractures (VFX) on utility. The objective of this study was to assess the impact of prevalent and incident VFX on utility in both a patient-based and population-based sample. Data from the Multiple Outcomes of Raloxifene Evaluation (MORE) study (n = 550 for prevalent VFX and n = 174 for incident VFX) and the European Prospective Osteoporosis Study (EPOS) (n = 236) were used. Utility was assessed by the index score of the EQ-5D. In the MORE study, highly statistically significant associations were found between utility and the presence of prevalent VFX (p < 0.001), number of prevalent VFX (p < 0.001), severity of prevalent VFX (p < 0.001), the combination of number and severity of prevalent VFX (p = 0.001) and location of prevalent VFX (p = 0.019). The mean utility was significantly lower among women who suffered an incident VFX (utility = 0.67) than among women who did not (utility = 0.77) (p = 0.005), although utility loss was not significantly different between the two groups (p = 0.142). In EPOS, the combination of number and severity of incident VFX was significantly related to utility (p = 0.030). In conclusion, utility is lower among persons with prevalent and incident VFX, especially in a patient-based sample. Utility loss was not significantly different between women without and with incident VFX

An Integrated TCGA Pan-Cancer Clinical Data Resource to Drive High-Quality Survival Outcome Analytics

For a decade, The Cancer Genome Atlas (TCGA) program collected clinicopathologic annotation data along with multi-platform molecular profiles of more than 11,000 human tumors across 33 different cancer types. TCGA clinical data contain key features representing the democratized nature of the data collection process. To ensure proper use of this large clinical dataset associated with genomic features, we developed a standardized dataset named the TCGA Pan-Cancer Clinical Data Resource (TCGA-CDR), which includes four major clinical outcome endpoints. In addition to detailing major challenges and statistical limitations encountered during the effort of integrating the acquired clinical data, we present a summary that includes endpoint usage recommendations for each cancer type. These TCGA-CDR findings appear to be consistent with cancer genomics studies independent of the TCGA effort and provide opportunities for investigating cancer biology using clinical correlates at an unprecedented scale. Analysis of clinicopathologic annotations for over 11,000 cancer patients in the TCGA program leads to the generation of TCGA Clinical Data Resource, which provides recommendations of clinical outcome endpoint usage for 33 cancer types

Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas

Although theMYConcogene has been implicated incancer, a systematic assessment of alterations ofMYC, related transcription factors, and co-regulatoryproteins, forming the proximal MYC network (PMN),across human cancers is lacking. Using computa-tional approaches, we define genomic and proteo-mic features associated with MYC and the PMNacross the 33 cancers of The Cancer Genome Atlas.Pan-cancer, 28% of all samples had at least one ofthe MYC paralogs amplified. In contrast, the MYCantagonists MGA and MNT were the most frequentlymutated or deleted members, proposing a roleas tumor suppressors.MYCalterations were mutu-ally exclusive withPIK3CA,PTEN,APC,orBRAFalterations, suggesting that MYC is a distinct onco-genic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such asimmune response and growth factor signaling; chro-matin, translation, and DNA replication/repair wereconserved pan-cancer. This analysis reveals insightsinto MYC biology and is a reference for biomarkersand therapeutics for cancers with alterations ofMYC or the PMN

Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smokin

Spatial Organization and Molecular Correlation of Tumor-Infiltrating Lymphocytes Using Deep Learning on Pathology Images

Beyond sample curation and basic pathologic characterization, the digitized H&E-stained images of TCGA samples remain underutilized. To highlight this resource, we present mappings of tumorinfiltrating lymphocytes (TILs) based on H&E images from 13 TCGA tumor types. These TIL maps are derived through computational staining using a convolutional neural network trained to classify patches of images. Affinity propagation revealed local spatial structure in TIL patterns and correlation with overall survival. TIL map structural patterns were grouped using standard histopathological parameters. These patterns are enriched in particular T cell subpopulations derived from molecular measures. TIL densities and spatial structure were differentially enriched among tumor types, immune subtypes, and tumor molecular subtypes, implying that spatial infiltrate state could reflect particular tumor cell aberration states. Obtaining spatial lymphocytic patterns linked to the rich genomic characterization of TCGA samples demonstrates one use for the TCGA image archives with insights into the tumor-immune microenvironment