Human leukocyte antigen and tumor immunotherapy (Review).

Malignant tumors seriously endanger human health and life, and restrict economic development. Human leukocyte antigen (HLA) is the expression product of the human major histocompatibility complex, which, at present, is the most complex known polymorphic system. The polymorphism and expression of HLA molecules have been demonstrated to be associated with the occurrence and development of tumors. HLA molecules can regulate the proliferation of tumor cells and inhibit antitumor immunity. In the present review, the structure and function of HLA molecules, the polymorphism and expression of HLA in tumor tissue, the roles of HLA in tumor cells and tumor immunity, and the potential clinical application of HLA in tumor immunotherapy are summarized. The overall aim of the present review is to provide relevant information for the development of antitumor immunotherapies involving HLA in the clinic.

Evidence-based assessment on environmental mixture using a concentration-dependent transcriptomics approach.

Development of new approach methodologies is urgently needed to characterize the likelihood that complex mixtures of chemicals affect water quality. Omics advances in ecotoxicology allow assessment on a broadest coverage of disrupted biological pathway by mixtures. Here the usefulness of transcriptomic analyses for evaluation of combined effects and identification of main effect components are explored. Two artificial mixtures (Mix 1 and Mix 2) were tested by a concentration-dependent reduced zebrafish transcriptome (CRZT) approach and toxicity bioassays using zebrafish embryos. Then, the toxicities and transcriptomic effects of 12 component chemicals on embryos were incorporated into additivity models to characterize the combined effects of chemicals in mixtures and to identify the main bioactive compounds. Mix 1 and Mix 2 displayed similar embryo toxicities (LD50: 6.6 µM and 8.7 µM, respectively), however, Mix 2 elicited broader biological process perturbations and 5-fold higher transcriptome potency (point of departure eliciting a 20% pathway response, PODpath20) than Mix 1. The predicted mixture toxicities derived from additivity expectations deviated by 2-fold or less from the measured embryo toxicities except for the Jaw defect endpoint; most biological processes deviated by 3-fold or less. Finally, diclofenac (DFC) and propiconazole (PCZ) were identified as the main contributing components (≥80% explanation) to the embryo toxicity and biological process perturbations by Mix 1. While DFC and chlorophene (CLP) explained up to 80% of the embryo toxicities and biological effects of Mix 2 associated with development and Metabolism processes. The CRZT approach provides a powerful tool for assessment of biological pathways perturbed by chemicals in mixtures and for identification of main bioactive compounds.

A Tiered Approach for Screening and Assessment of Environmental Mixtures by Omics and In Vitro Assays.

New methodology approaches with a broad coverage of the biological effects are urgently needed to evaluate the safety of the universe of environmentally relevant chemicals. Here, we propose a tiered approach incorporating transcriptomics and in vitro bioassays to assess environmental mixtures. The mixture samples and the perturbed biological pathways are prioritized by concentration-dependent transcriptome (CDT) and then used to guide the selection of in vitro bioassays for toxicant identification. To evaluate omics' screening capability, we first applied a CDT technique to test mixture samples by HepG2 and MCF7 cells. The effect recoveries of large-volume solid-phase extraction on the overall bioactivity of the mixture were 48.9% in HepG2 and 58.3% in MCF7. The overall bioactivity potencies obtained by transcriptomics were positively correlated with the panel of 8 bioassays among 14 mixture samples combined with the previous data. Transcriptomics could predict their activation status (AUC = 0.783) and the relative potency (p < 0.05) of bioassays for four of the eight receptors (AhR, ER, AR, and Nrf2). Furthermore, the CDT identified other biological pathways perturbated by mixture samples, such as the pathway related to TP53, CAR, FXR, HIF, THRA, etc. Overall, this study demonstrates the potential of concentration-dependent omics for effect-based water quality assessment.

Toxicogenomic Assessment of Complex Chemical Signatures in Double-Crested Cormorant Embryos from Variably Contaminated Great Lakes Sites.

Using omics approaches to monitor complex environmental mixtures is challenging. Previously, we evaluated in vitro transcriptomic effects of complex organic extracts derived from avian eggs. However, there is a lack of studies using wild species that are naturally exposed to contaminant mixtures. Here, we examined polychlorinated biphenyl (PCB) and polybrominated diphenyl ether (PBDE) residues and gene expression in embryonic liver tissue of double-crested cormorants (Phalacrocorax auritus) collected from six variably contaminated colonies. Colonies near industrialized areas were distinguished from less contaminated sites based on their PCB and PBDE concentrations. The most variably expressed genes between sites were involved in pathways including, xenobiotic metabolism (e.g., Cyp1a4), lipid/bile acid homeostasis (e.g., Lbfabp), and oxidative stress (e.g., Mt4). Hierarchical clustering, based on relative gene expression, revealed a grouping pattern similar to chemical residue concentrations. Further, partial least squares regression analysis was used to estimate chemical concentrations from transcriptomics data. PCB 155 and BDE 47 showed the highest slopes (0.77 and 0.69, respectively) fitted by linear regression of measured and estimated chemical concentrations. The application of transcriptomics to a wild avian species, naturally exposed to complex chemical mixtures and other stressors, represents a promising means to distinguish and prioritize variably contaminated sites.

Pathway-based assessment of single chemicals and mixtures by a high-throughput transcriptomics approach.

The ever-increasing number of chemicals and complex mixtures demands a high-throughput and cost-effective approach for chemical safety assessment. High-throughput transcriptomics (HTT) is promising in investigating genome-scale perturbation of chemical exposure in concentration-dependent manner. However, the application of HTT has been limited due to lack of methodology for single chemicals and mixture assessment. This study aimed to evaluate the ability of a newly-developed human reduced transcriptomics (RHT) approach to assess pathway-based profiles of single chemicals, and to develop a biological pathway-based approach for benchmarking mixture potency using single chemical-based prediction model. First, concentration-dependent RHT were used to qualitatively and quantitatively differentiate pathway-based patterns of different chemicals, using three model toxicants, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), triclosan (TCS) and 5-Chloro-6-hydroxy-2,2',4,4'-tetrabromodiphenyl ether (5-Cl-6-OH-BDE-47). AHR-regulated genes and pathways were most sensitively induced by TCDD, while TCS and 5-Cl-6-OH-BDE-47 were much less potent in AHR-associated activation, which was concordant with known MoA of each single chemical. Second, two artificial mixtures and their components of twelve individual chemicals were performed with concentration-dependent RHT. Concentration addition (CA) and independent action (IA) models were used to predict transcriptional potency of mixtures from transcriptomics of individual chemicals. For overall bioactivity, CA and IA models can both predict potency of observed responses within 95% confidence interval. For specific biological processes, multiple biological processes such as hormone signaling and DNA damage can be predicted using CA models for mixtures. The concentration-dependent RHT can provide a powerful approach for qualitative and quantitative assessment of biological pathway perturbated by environment chemical and mixtures.

Concentration-dependent transcriptome of zebrafish embryo for environmental chemical assessment.

Mechanistic information is essential to screen and predict the adverse effects of a large number of chemicals during early-life exposure. Concentration-dependent omics can capture the extent of perturbations of biological pathways or processes and provide information on the mechanism of toxicity. However, the application of concentration-dependent transcriptome to assess the developmental toxicity of environmental chemicals is still limited. Here, twelve chemicals representing five different modes of action (MOAs) were tested by the concentration-dependent reduced zebrafish transcriptome approach (CRZT) in combination with a phenotype-based high content screen (PHCS). The responsiveness, sensitivity and mechanistic differentiation of CRZT were validated in comparison with PHCS. First, PHCS identified 10 chemicals with obvious embryotoxicity (LD50 range: 2.11-70.68 µM), while the potencies of the biological pathways perturbed by 12 chemicals (PODpath20 range: 0.002-2.1 µM) were demonstrated by CRZT. Second, although the potency of the transcriptome perturbations was positively correlated with lethality (LD50) (R2 = 0.64, P-value < 0.05) for most tested chemicals, BbF was non-embryotoxic but was the most potent on the perturbance of biological pathways. Finally, the profiles of the perturbed biological processes and the transcriptome potency (PODpath20) captured by CRZT could effectively classify most chemicals corresponding to their known MOAs. In summary, CRZT could significantly improve testing the developmental toxicity of environmental chemicals.

Environmental risk assessment of polycyclic musks HHCB and AHTN in consumer product chemicals in China.

An environmental risk assessment (ERA) framework was recently developed for consumer product chemicals in China using a tiered approach, applying an existing Chinese regulatory qualitative method in Tier Zero and, then, utilizing deterministic and probabilistic methods for Tiers One and Two. The exposure assessment methodology in the framework applied conditions specific to China including physical setting, infrastructure, and consumers' habits and practices. Furthermore, two scenarios were identified for quantitatively assessing environmental exposure: (1) Urban with wastewater treatment, and; (2) Rural without wastewater treatment (i.e., direct-discharge of wastewater). Upon a brief discussion on the framework methodology, this paper primarily presented a case study conducted using this new approach for assessing two fragrance chemicals, the polycyclic musks HHCB (Galaxolide, 1,3,4,6,7,8-hexahydro-4,6,6,7,8,8-hexamethylcyclopenta-[gamma]-2-benzopyran) and AHTN (Tonalide, 7-acetyl-1,1,3,4,4,6-hexamethyl-1,2,3,4-tetrahydronaphthalene). Both HHCB and AHTN are widely used as fragrances in a variety of consumer products in China, and occurrences of both compounds have been reported in wastewater influents, effluents, and sludge, in addition to surface water and sediments across several major metropolitan regions throughout China. This case study illustrated the very conservative nature of Tier Zero, which indicated a high risk potential of the fragrances to receiving water aquatic communities due to the fragrance's non-ready biodegradability and eco-toxicity profiles. However, the higher-tiered assessments (including deterministic and site-specific probabilistic) demonstrated greater environmental realism with the conclusion of HHCB and AHTN posing minimal risk, consistent with local monitoring data as well as a recent similar study conducted in the United States.

Toxicogenomic Assessment of 6-OH-BDE47-Induced Developmental Toxicity in Chicken Embryos.

Hydroxylated polybrominated diphenyl ethers (OH-PBDEs) are analogs of PBDEs with hundreds of possible structures and are frequently detected in the environment. However, the in vivo evidence on the toxicity of OH-PBDEs is still very limited. Here, the developmental toxicity of 6-OH-BDE47, a predominant congener of OH-PBDEs detected in the environment, in chicken embryos was assessed using a toxicogenomic approach. Fertilized chicken eggs were dosed via in ovo administration of 0.006 to 0.474 nmol 6-OH-BDE47/g egg followed by 18 days of incubation. Significant embryo lethality (LD50 = 1.940 nmol/g egg) and increased hepatic somatic index (HSI) were caused by 6-OH-BDE47 exposure. The functional enrichment of differentially expressed genes (DEGs) was associated with oxidative phosphorylation, generation of precursor metabolites and energy, and electron transport chains, which suggest that 6-OH-BDE47 exposure may disrupt the embryo development by altering the function of energy production in mitochondria. Moreover, aryl hydrocarbon receptor (AhR)-mediated responses including up-regulation of CYP1A4 were observed in the livers of embryos exposed to 6-OH-BDE47. Overall, this study confirmed the embryo lethality by 6-OH-BDE47 and further improved the mechanistic understanding of OH-PBDEs-caused toxicity. Ecological risk assessment via application of both no-observed-effect level (NOEL) and the sensitive NOTEL (transcriptional NOEL) suggested that OH-PBDEs might cause ecological risk to wild birds.

Functional Toxicogenomic Assessment of Triclosan in Human HepG2 Cells Using Genome-Wide CRISPR-Cas9 Screening.

There are thousands of chemicals used by humans and detected in the environment for which limited or no toxicological data are available. Rapid and cost-effective approaches for assessing the toxicological properties of chemicals are needed. We used CRISPR-Cas9 functional genomic screening to identify the potential molecular mechanism of a widely used antimicrobial triclosan (TCS) in HepG2 cells. Resistant genes at IC50 (the concentration causing a 50% reduction in cell viability) were significantly enriched in the adherens junction pathway, MAPK signaling pathway, and PPAR signaling pathway, suggesting a potential role in the molecular mechanism of TCS-induced cytotoxicity. Evaluation of the top-ranked resistant genes, FTO (encoding an mRNA demethylase) and MAP2K3 (a MAP kinase kinase family gene), revealed that their loss conferred resistance to TCS. In contrast, sensitive genes at IC10 and IC20 were specifically enriched in pathways involved with immune responses, which was concordant with transcriptomic profiling of TCS at concentrations of

Assessment of liver fat content using quantitative ultrasonography to evaluate risks for metabolic diseases.

OBJECTIVE: The ultrasound quantitative method for liver fat content (LFC) is a recent established method for non-invasive assessment of liver steatosis. Its use in clinical practice is further explored by investigating the quantitative relationships between LFC measured by quantitative ultrasonography and metabolic diseases in a middle-aged and elderly Chinese population. METHODS: Liver fat content was measured by the quantitative ultrasound method in 4,916 participants from the Shanghai Changfeng Community Study. The anthropometric and serum biochemical parameters related to glucose and lipid metabolism were detected for each participant. The carotid artery intima-media thickness (CIMT) was measured by ultrasonography. RESULTS: The LFC displayed a non-Gaussian and positively skewed distribution in the community population and was significantly correlated with body weight, serum glucose, lipid profile, and CIMT. The 95th percentile of LFC in the subgroup of participants without any metabolic disease was 10.8%, and a LFC ≥ 10% was correlated with remarkable increases in the risks for glucose and lipid metabolic diseases. CONCLUSIONS: The quantitative ultrasound method that was developed for measuring LFC was useful in a population study. A LFC ≥ 10% might help to identify the subjects with an increased risk for metabolic diseases.