DNA methylation regulator-based molecular subtyping and tumor microenvironment characterization in hepatocellular carcinoma.

Backgroud: Although recent studies have reported the regulation of the immune response in hepatocellular carcinoma (HCC) through DNA methylation, the comprehensive impact methylation modifications on tumor microenvironment characteristics and immunotherapy efficacy has not been fully elucidated. Methods: In this research, we conducted a comprehensive assessment of the patterns of DNA methylation regulators and the profiles of the tumor microenvironment (TME) in HCC, focusing on 21 specific DNA methylation regulators. We subsequently developed a unique scoring system, a DNA methylation score (DMscore), to assess the individual DNA methylation modifications among the three distinct methylation patterns for differentially expressed genes (DEGs). Results: Three distinct methylation modification patterns were identified with distinct TME infiltration characteristics. We demonstrated that the DMscore could predict patient subtype, TME infiltration, and patient prognosis. A low DMscore, characterized by an elevated tumor mutation burden (TMB), hepatitis B virus (HBV)/hepatitis C virus (HCV) infection, and immune activation, indicates an inflamed tumor microenvironment phenotype with a 5-year survival rate of 7.8%. Moreover, a low DMscore appeared to increase the efficacy of immunotherapy in the anti-CTLA-4/PD-1/PD-L1 cohort. Conclusions: In brief, this research has enhanced our understanding of the correlation between modifications in DNA methylation patterns and the profile of the tumor microenvironment in individuals diagnosed with HCC. The DMscore may serve as an alternative biomarker for survival and efficacy of immunotherapy in patients with HCC.

Multi-omics network analysis on samples from sequential biopsies reveals vital role of proliferation arrest for Macrosteatosis related graft failure in rats after liver transplantation.

To investigate the molecular impact of graft MaS on post-transplant prognosis, based on multi-omics integrative analysis. Rats were fed by methionine-choline deficient diet (MCD) for MaS grafts. Samples were collected from grafts by sequential biopsies. Transcriptomic and metabolomic profilings were assayed. Post-transplant MaS status showed a close association with graft failure. Differentially expressed genes (DEGs) for in-vivo MaS were mainly enriched on pathways of cell cycle and DNA replication. Post-transplant MaS caused arrests of graft regeneration via inhibiting the E2F1 centered network, which was confirmed by an in vitro experiment. Data from metabolomics assays found insufficient serine/creatine which is located on one­carbon metabolism was responsible for MaS-related GF. Pre-transplant MaS caused severe fibrosis in long-term survivors. DEGs for grafts from long-term survivors with pre-transplant MaS were mainly enriched in pathways of ECM-receptor interaction and focal adhesion. Transcriptional regulatory network analysis confirmed SOX9 as a key transcription factor (TF) for MaS-related fibrosis. Metabolomic assays found elevation of aromatic amino acid (AAA) was a major feature of fibrosis in long-term survivors. Graft MaS in vivo increased post-transplant GF via negative regulations on graft regeneration. Pre-transplant MaS induced severe fibrosis in long-term survivors via activations on ECM-receptor interaction and AAA metabolism.

Evolution hydrothermal aging mechanism for Ag/CeO2 catalysts in regeneration of catalytic diesel particulate filter with DFT calculation.

In order to avoid the high cost of existing precious metal catalyst like Pt, Ag/CeO2 was the most promising catalysts for mobile source soot emission control technologies, but there was a clear trade-off between hydrothermal aging resistance and catalytic oxidation performance hindered the application of this catalyst. In order to reveal the hydrothermal aging mechanism of Ag/CeO2 catalysts, the TGA (thermogravimetric analysis) experiments were investigated to reveal the mechanism of Ag modification on catalytic activity of CeO2 catalyst between fresh and hydrothermal aging and were also characterized with the related characterization experiments to in-depth research the lattice morphology and valence changes. The degradation mechanism of Ag/CeO2 catalysts in vapor with high-temperature was also explained and demonstrated based on density functional and molecular thermodynamics theories. The experimental and simulation data showed that the catalytic activity of soot combustion within Ag/CeO2 decreased more significantly after hydrothermal aging than CeO2 due to the less agglomerated, which caused by the decreased in OII/OI and Ce3+/Ce4+ compared with CeO2. As shown in density function theory (DFT) calculation, the decreased surface energy and the increased oxygen vacancy formation energy of the low Mille index surface after Ag modification led to the instability structure and the high catalytic activity. Ag modification also increased the adsorption energy and Gibbs free energy of H2O on the low Miller index surface compared to CeO2, indicating that the desorption temperature of H2O molecules in (1 1 0) and (1 0 0) was higher than (1 1 1) in CeO2 and Ag/CeO2, which led to the migration of (1 1 1) crystal surfaces to (1 1 0) and (1 0 0) in the vapor environment. These conclusions can provide a valuable addition to the regenerative application of Ce-based catalysts in diesel exhaust aftertreatment system the aerial pollution.

Human health ambient water quality criteria and risk assessment of pentachlorophenol in Poyang Lake Basin, China.

Pentachlorophenol (PCP) has been widely used as an insecticide for killing oncomelania (the intermediate host of schistosome) in China and leads to severe environmental contamination. Poyang Lake, as the largest freshwater lake and bird habitat in China, was once a schistosomiasis epidemic area. In this study, the concentrations of PCP in water and aquatic products from Poyang Lake were determined and analyzed, and then the human health ambient water quality criteria (AWQC) was derived based on native parameters of Poyang Lake basin. Finally, a comprehensive analysis of the health risks of drinking water and different types of aquatic products consumption was carried out. The results showed that PCP concentrations were ranged from 0.01 to 0.43 µg/L in surface water and 3.90 to 85.95 µg/kg in aquatic products. Due to the carcinogenicity of PCP, the human health AWQC for PCP are 0.02 µg/L for consumption of water and organisms and 0.03 µg/L for consumption of organisms only. Deterministic and probabilistic risk analysis indicated that the non-carcinogenic risk of PCP were acceptable in Poyang Lake, while the carcinogenic risk cannot be ignored. The health risks of PCP caused by aquatic products consumption were higher than that by drinking water. The percentages of acceptable risk for the population in Poyang Lake Basin were 99.95% at acceptable level of 10-4. Based on the sensitivity analysis, the impact of PCP concentrations on health risk values ranged from 53 to 82%. The study provided valuable information for regional water quality criteria development and water quality assessment.

Recent Progress and Future Direction for the Application of Multiomics Data in Clinical Liver Transplantation.

Omics data address key issues in liver transplantation (LT) as the most effective therapeutic means for end-stage liver disease. The purpose of this study was to review the current application and future direction for omics in LT. We reviewed the use of multiomics to elucidate the pathogenesis leading to LT and prognostication. Future directions with respect to the use of omics in LT are also described based on perspectives of surgeons with experience in omics. Significant molecules were identified and summarized based on omics, with a focus on post-transplant liver fibrosis, early allograft dysfunction, tumor recurrence, and graft failure. We emphasized the importance omics for clinicians who perform LTs and prioritized the directions that should be established. We also outlined the ideal workflow for omics in LT. In step with advances in technology, the quality of omics data can be guaranteed using an improved algorithm at a lower price. Concerns should be addressed on the translational value of omics for better therapeutic effects in patients undergoing LT.

Graft-to-recipient weight ratio exerts nonlinear effects on prognosis by interacting with donor liver macrosteatosis.

Aim: To investigate the interactions between the graft-to-recipient weight ratio (GWRWR) and other risk factors responsible for inferior allograft outcomes. Methods: A total of 362 patients who received liver transplantation (LT) were enrolled. Indicators such as graft/recipient weight and other prognostic factors were collected. Comparisons of indicators and survival analysis were performed in groups categorized by the GWRWR. Interactions of large-for-size grafts (LFSGs) with graft macrosteatosis (MaS) were evaluated in terms of relative excess risk caused by interaction (RERI) and attributable proportion (AP). Cytoscape visualized the role of LFSGs in the risk profile for poor prognosis. Results: Based on the GWRWR, LT cases can be categorized into three subgroups, standard (1%-2.5%), optimal (2.5%-3.0%), and inferior prognosis (>3.0%). Survival analysis confirmed clear separations in cases categorized by the above-defined limits on the GWRWR (P < 0.05). LFSGs caused inferior prognosis by initiating positive interactions with MaS severity. Conclusion: The GWRWR exerted nonlinear effects on prognosis in deceased donor LT cases. LFSGs (GWRWR > 3.0%) caused inferior outcomes, while grafts sized within (2.5%-3.0%) had optimal post-transplant prognosis. MaS increased the risk of poor prognosis by exerting positive synergistic effects on LFSGs.

Prognostic Model and Nomogram Construction Based on a Novel Ferroptosis-Related Gene Signature in Lower-Grade Glioma.

Background: Low-grade glioma (LGG) is considered a fatal disease for young adults, with overall survival widely ranging from 1 to 15 years depending on histopathologic and molecular subtypes. As a novel type of programmed cell death, ferroptosis was reported to be involved in tumorigenesis and development, which has been intensively studied in recent years. Methods: For the discovery cohort, data from The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) were used to identify the differentially expressed and prognostic ferroptosis-related genes (FRGs). The least absolute shrinkage and selection operator (LASSO) and multivariate Cox were used to establish a prognostic signature with the above-selected FRGs. Then, the signature was developed and validated in TCGA and Chinese Glioma Genome Atlas (CGGA) databases. By combining clinicopathological features and the FRG signature, a nomogram was established to predict individuals' one-, three-, and five-year survival probability, and its predictive performance was evaluated by Harrell's concordance index (C-index) and calibration curves. Enrichment analysis was performed to explore the signaling pathways regulated by the signature. Results: A novel risk signature contains seven FRGs that were constructed and were used to divide patients into two groups. Kaplan-Meier (K-M) survival curve and receiver-operating characteristic (ROC) curve analyses confirmed the prognostic performance of the risk model, followed by external validation based on data from the CGGA. The nomogram based on the risk signature and clinical traits was validated to perform well for predicting the survival rate of LGG. Finally, functional analysis revealed that the immune statuses were different between the two risk groups, which might help explain the underlying mechanisms of ferroptosis in LGG. Conclusion: In conclusion, this study constructed a novel and robust seven-FRG signature and established a prognostic nomogram for LGG survival prediction.

Integrative Network Analysis Revealed Genetic Impact of Pyruvate Kinase L/R on Hepatocyte Proliferation and Graft Survival after Liver Transplantation.

BACKGROUND: Pyruvate kinase L/R (PKLR) has been suggested to affect the proliferation of hepatocytes via regulation of the cell cycle and lipid metabolism. However, its impact on the global metabolome and its clinical implications remain unclear. AIMS: We aimed to clarify the genetic impact of PKLR on the metabolomic profiles of hepatoma cells and its potential effects on grafts for liver transplantation (LT). METHODS: Nontargeted and targeted metabolomic assays were performed in human hepatoma cells transfected with lentiviral vectors causing PKLR overexpression and silencing, respectively. We then constructed a molecular network based on integrative analysis of transcriptomic and metabolomic data. We also assessed the biological functions of PKLR in the global metabolome in LT grafts in patients via a weighted correlation network model. RESULTS: Multiomic analysis revealed that PKLR perturbations significantly affected the pyruvate, citrate, and glycerophospholipid metabolism pathways, as crucial steps in de novo lipogenesis (DNL). We also confirmed the importance of phosphatidylcholines (PC) and its derivative lyso-PC supply on improved survival of LT grafts in patients. Coexpression analysis revealed beneficial effects of PKLR overexpression on posttransplant prognosis by alleviating arachidonic acid metabolism of the grafts, independent of operational risk factors. CONCLUSION: This systems-level analysis indicated that PKLR affected hepatoma cell viability via impacts on the whole process of DNL, from glycolysis to final PC synthesis. PKLR also improved prognosis after LT, possibly via its impact on the increased genesis of beneficial glycerophospholipids.

A rare case of retroperitoneal paraganglioma located in the neck of the pancreas: a case report and literature review.

Paraganglioma (PGL) is an uncommon tumor located in the head, neck and abdomen. The majority of the tumor is benign and the patient has no obvious clinical symptoms. However, PGL located in the pancreas is rather rare and tends to mimic Castleman's disease, pancreatic neuroendocrine tumors and pancreatic primary tumor. Herein, we reported a patient with PGL that occurred in the neck of the pancreas. A 75-year-old Chinese female presented to our hospital with a complaint of upper abdomen pain for two weeks and she had good past health. The laboratory findings and physical examination were all normal. Preoperative computed tomography (CT) and magnetic resonance imaging revealed a tumor located in the neck of the pancreas and a tentative diagnosis of Castleman's disease or PGL was made. We resected the tumor by laparoscopic surgery. Postoperative pathology and immunohistochemistry confirmed that the tumor was a PGL. The patient was recovered well after a postoperative follow-up of 6 months. PGL located in the neck of the pancreas is difficult to be diagnosed accurately and clinicians have difficulties in distinguishing PGL from Castleman's disease, pancreatic neuroendocrine tumors and pancreatic primary tumor. Fifteen cases were listed to show the characters of PGL located in the pancreas and we also presented the difference among PGL, Castleman's disease and pancreatic neuroendocrine tumor. We showed our experience of treating such a rare tumor hoping to help clinicians correctly diagnose and treat PGL.

Aquatic life criteria & human health ambient water quality criteria derivations and probabilistic risk assessments of 7 benzenes in China.

The benzenes have attracted worldwide attention due to their high biological toxicity in the environment. In this study, using species sensitivity distribution method to derive the aquatic life criteria of 7 benzenes (carbazole, 1,3-Dichlorobenzene, 1,4-Dichlorobenzene, 1,2,4-Trichlorobenzene, phenol, 2,4-Dichlorophenol and nitrobenzene), then risk quotient method (RQ), potentially affected fraction (PAF) method and joint probability curve (JPC) method were applied for multilevel ecological risk assessment for 7 benzenes in Tai Lake Basin. In addition, the human health ambient water quality criteria (AWQC) of 7 benzenes were derived according to USEPA guidelines, and the probability distributions of human health AWQC for 7 benzenes in China were simulated by Monte Carlo simulation combined with crystal ball software. Finally, the health risks of 7 benzenes in Tai Lake were assessed by RQ method assisted by Monte Carlo simulation. The results showed that nitrobenzene had the maximum aquatic life criteria value, followed by phenol, chlorobenzenes, 2,4-Dichlorophenol and carbazole. All recommended human health AWQC values of 7 benzenes were found at a position of 27th-55th percentiles in the output criteria distributions, indicating that recommended national human health AWQC values could provide effective protection for most of the population in China. Furthermore, the consumption of aquatic products was found to be the most influential parameter of human health AWQC for benzenes with higher Kow values. The risk assessments showed that noncarcinogenic 2,4-Dichlorophenol had potential ecological risk, carcinogenic carbazole and 1,2,4-Trichlorobenzene had significant human health risk in Tai Lake.

Water quality criteria for the protection of human health of 15 toxic metals and their human risk in surface water, China.

In the absence of water quality criteria (WQC) support for the current water quality standard (WQS), systematic WQC studies have been carried out in recent years in China. WQC for the protection of human health is established to reflect long-term consumption safety of aquatic products and water. Human health WQC for 15 toxic metals and metalloids based on exposure factors of the Chinese population and 40 field bioaccumulation factors (BAFs) were developed and analyzed in this study. Moreover, age-specific (age 2-5, 6-8, 9-11, 12-14, 15-17, and adult) and region-specific (east, central and west China) WQC were analyzed to better understanding of the impact of specific parameter values on WQC. Human health WQC with consumption of fishes and water, consumption of fishes only, and consumption of water only were derived separately. WQC with consumption of water and organism for Hg, Cd, As, Sb, Se, Zn, Co, Cu, Ni, Pb, Mn, Sn, Ba, and Sr were 0.0264, 0.710, 0.827, 3.48, 22.1, 25.7, 32.2, 32.9, 35.5, 41.8, 72.1, 97.1, 206 and 2.20 × 103 µg/L, and were 13.3 and 6.67 × 103 µg/L for Cr(VI) and Cr(III) with consumption of water only. Comparison of age-specific and region-specific WQC showed that the protection for a specific population should be considered in the development of WQC and WQS, as well as cancer effect for carcinogenic metals. Health risk analysis showed that Cd, Cu, Zn, As, Hg and Mn average concentrations in 7, 5, 9, 22, 11 and 5 provinces exceeded the WQC values with consumption of water and aquatic product, showing potential long-term health risk (HQ ≥ 1) to the local population. Therefore, health risks posed by these metals from dietary intake related to surface water should be paying more attention.

Experience With Anti-PD-1 Antibody, Camrelizumab, Monotherapy for Biliary Tract Cancer Patients and Literature Review.

BACKGROUND: Novel immunotherapy is one of the options for advanced biliary tract cancer (BTC) patients who are traditionally intolerant to chemotherapy. However, clinical evidence for single immunotherapy with pembrolizumab or nivolumab is limited. The present study assessed the safety and efficiency of the anti-PD-1 antibody, camrelizumab, as monotherapy in patients with unresectable or recurrent BTC. METHODS: A retrospective evaluation was conducted among 4 patients with BTC, including 2 with intrahepatic cholangiocellular carcinoma (ICC), one with extrahepatic bile duct cancer, and one with gallbladder cancer. The patients with unresectable or recurrent BTC were refractory or intolerant to gemcitabine plus cisplatin treatment regimens and received at least one intravenous dose (3 mg/kg) of camrelizumab monotherapy every 3 weeks. Gene sequencing analysis was also performed for biomarker screening. Patient reaction was evaluated according to modified response evaluation criteria in solid tumor (RECIST) version 1.1, progression-free survival (PFS), and toxicity. RESULTS: In this cohort, 1 patient with recurrent ICC had a positive response to treatment, with a substantial tumor size reduction in liver and lung metastases verified using a radiological test after receiving 3 cycles of camrelizumab. The PFS was 4.9 months. The remaining 3 patients showed no response to treatment and experienced disease progression. RNA sequence analysis didn't found high expression on genes that related to PD-L1, microsatellite instability, tumor mutation burden, and DNA mismatch repair in these patients. Grade 3 treatment-related adverse event was observed in 1 patient. CONCLUSIONS: Anti-PD-1 antibody camrelizumab had a manageable safety profile in patients with advanced BTC. This initial assessment of camrelizumab monotherapy provides effective evidence for patients with refractory BTC in biomarker-unselected patients.

Clear mortality gap caused by graft macrosteatosis in Chinese patients after cadaveric liver transplantation.

BACKGROUND: Liver transplantation (LT) is one of the most effective surgical treatment for patients with end-stage liver disease. Steatosis is a contributor for inferior graft quality. But its impact and safety on transplantation was less assessed in Chinese patients. METHODS: Graft steatosis and related information involved in recipients, donors and surgical procedures were retrospectively collected from 239 patients. RESULTS: Donor macrosteatosis (MaS) caused about 2.14 and 2.80 folds of increment on patient and graft mortality. Dose-response analysis revealed prominent risk of grafts on overall patient/organ mortality when MaS content exceeded 10% (P<0.05). Noteworthy, deaths were only observed in MaS group when concurrent with extremely higher post-transplant alanine aminotransferase (ALT, 64%). However, microsteatosis (MiS) grafts didn't affect outcomes after LT. In a cohort of Chinese patients, MaS had comprehensive effects on post-transplant outcomes with relatively lower safety threshold at 10%. Mortality gap caused by MaS grafts was observed in patients with severer ischemia reperfusion injury. CONCLUSIONS: Our study revealled the graft MaS affected the post-transplant outcomes in lower risk cutoff in Chinese patients. Further study is worthy to validate these results and investigate inner mechanism under the phenomenon.

Development of human health ambient water quality criteria of 12 polycyclic aromatic hydrocarbons (PAH) and risk assessment in China.

Polycyclic aromatic hydrocarbons (PAHs) are widely distributed in various environmental media and have thus attracted extensive attention worldwide. To prevent and control PAH pollution in China, the study of ambient water quality criteria (AWQC), human health risks, and aquatic ecological risk is critical. There are no reports to date on the human health AWQC of PAHs in China. Therefore, this study first derived the human health AWQC values of 12 PAHs based on exposure data and bioaccumulation factor in China. We found that local exposure parameters and other relevant factors were key during the development of AWQC in different countries and regions, which led to differences with the reference value recommended by USEPA. Based on the incremental life time cancer risk (ILCR), hazard quotients (HQ) and potentially affected fraction (PAF) methods, the health and ecological risks of 16 PAHs were assessed subsequently. And the results are as follows: the non-carcinogenic PAHs' health risks ranged from 1.01 × 10-10 to 1.60 × 10-9, and carcinogenic PAH health risks ranged from 5.03 × 10-7 to 4.74 × 10-5. The toxic effects of 8 PAHs on aquatic organisms exhibited the following order: benzo (a) pyrene (BaP) > anthracene (Ant) > pyrene (Pye) > phenanthrene (Phe) > fluoranthene (Flua) > acenaphthene (Ace) > fluorene (Flu) > naphthalene (Nap). Among these, the ecological risks posed by Ant and BaP were the highest, according to the HQ and PAF methods.

Establishment of a prognostic model for predicting short-term disease-free survival in cases of hepatitis B-related hepatocellular carcinoma with the TP53 249Ser mutation in southern China.

BACKGROUND: Hepatitis B virus (HBV) infection and dietary aflatoxin exposure are two major and synergistic carcinogenic factors of hepatocellular carcinoma (HCC) in southern China. Mutation of the TP53 gene at codon 249 (TP53 249Ser) is recognized as a fingerprint of aflatoxin B1 (AFB1) exposure. METHODS: A total of 485 HCC patients positive for serum hepatitis B surface antigen were enrolled. The clinicopathological information and survival time were collected. TP53 249Ser mutations in HCC were detected by Sanger DNA sequencing after PCR amplification. Immunohistochemical staining was used to evaluate TP53 expression. Propensity score matching (PSM) and Cox proportional hazards regression (CPHR) were conducted to identify independent risk factors for prognosis that were incorporated into the nomogram. Univariate logistic regression analysis was used to compare differences in clinical factors between the TP53 249Ser mutation group and the non-mutation group. A Kaplan-Meier plot, univariate and multivariate Cox proportional hazards models were used to assess the association between clinicopathological characteristics and survival outcomes. RESULTS: After PSM, a total of 322 cases were included in the analysis of clinical prognosis. Results of CPHR showed that the mutation group had a relatively higher risk of tumor recurrence within 2 years after undergoing hepatectomy (P=0.039, HR =1.47, 95% CI: 1.02-2.18). The prognostic model performed better in terms of 2-year DFS prediction than BCLC stage. Patients who had a nomogram score of more than 160 were considered to have a higher risk of recurrence within 2 years. CONCLUSIONS: Our study found that the TP53 249Ser mutation may be a high risk factor of HBV-related HCC recurrence in the short term. And we initially established a nomogram scoring system for predicting 2-year recurrence in HBV-related HCC patients in southern China.

Genome-wide association study of the TP53 R249S mutation in hepatocellular carcinoma with aflatoxin B1 exposure and infection with hepatitis B virus.

BACKGROUND: Exposure to dietary aflatoxin B1 (AFB1) induces DNA damage and mutation in the TP53 gene at codon 249, known as the TP53 R249S mutation, and is a major risk factor for hepatocellular carcinoma (HCC). AFB1 and the hepatitis B virus (HBV) together exert synergistic effects that promote carcinogenesis and TP53 R249S mutation in HCC. METHODS: A genome-wide association study (GWAS) of whole genome exons was conducted using 485 HCC patients with chronic HBV infection. This was followed by an independent replication study conducted using 270 patients with chronic HBV infection. Immunohistochemistry was used to evaluate TP53 expression in all samples. This showed a correlation between codon 249 mutations and TP53 expression. Susceptibility variants for the TP53 R249S mutation in HCC were identified based on both the GWAS and replication study. The associations between identified variants and the expression levels of their located genes were analyzed in 20 paired independent samples. RESULTS: The likelihood of positive TP53 expression was found to be higher in HCC patients with the R249S mutation both in the GWAS (P<0.001) and the replication study (P=0.006). The combined analyses showed that the TP53 R249S mutation was significantly associated with three single nucleotide polymorphisms (SNPs): ADAMTS18 rs9930984 (adjusted P=4.84×10-6), WDR49 rs75218075 (adjusted P=7.36×10-5), and SLC8A3 rs8022091 (adjusted P=0.042). The TP53 R249S mutation was found to be highly associated with the TT genotypes of rs9930984 (additive model, P=0.01; dominant model, P=6.43×10-5) and rs75218075 (additive model, P=0.002; dominant model, P=2.16×10-4). Additionally, ADAMTS18 mRNA expression was significantly higher in HCC tissue compared with its expression in paired non-tumor tissue (P=0.041), and patients carrying the TT genotype at rs9930984 showed lower ADAMTS18 expression in non-tumor tissue compared with patients carrying the GT genotype (P=0.0028). WDR49 expression was markedly lower in HCC tissue compared with paired non-tumor tissue (P=0.0011). CONCLUSIONS: TP53 expression is significantly associated with the R249S mutation in HCC. Our collective results suggest that rs9930984, rs75218075, and rs8022091 are associated with R249S mutation susceptibility in HCC patients exposed to AFB1 and HBV infection.

Comprehensive investigation of key biomarkers and pathways in hepatitis B virus-related hepatocellular carcinoma.

Objective: Our study is aim to explore potential key biomarkers and pathways in hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) using genome-wide expression profile dataset and methods. Methods: Dataset from the GSE14520 is used as the training cohort and The Cancer Genome Atlas dataset as the validation cohort. Differentially expressed genes (DEGs) screening were performed by the limma package. Gene set enrichment analysis (GSEA), weighted gene co-expression network analysis (WGCNA), gene ontology, the Kyoto Encyclopedia of Genes and Genomes, and risk score model were used for pathway and genes identification. Results: GSEA revealed that several pathways and biological processes are associated with hepatocarcinogenesis, such as the cell cycle, DNA repair, and p53 pathway. A total of 160 DEGs were identified. The enriched functions and pathways of the DEGs included toxic substance decomposition and metabolism processes, and the P450 and p53 pathways. Eleven of the DEGs were identified as hub DEGs in the WGCNA. In survival analysis of hub DEGs, high expression of PRC1 and TOP2A were significantly associated with poor clinical outcome of HBV-related HCC, and shown a good performance in HBV-related HCC diagnosis. The prognostic signature consisting of PRC1 and TOP2A also doing well in the prediction of HBV-related HCC prognosis. The diagnostic and prognostic values of PRC1 and TOP2A was confirmed in TCGA HCC patients. Conclusions: Key biomarkers and pathways identified in the present study may enhance the comprehend of the molecular mechanisms underlying hepatocarcinogenesis. Additionally, mRNA expression of PRC1 and TOP2A may serve as potential diagnostic and prognostic biomarkers for HBV-related HCC.

Integrated analysis of competing endogenous RNA network revealing potential prognostic biomarkers of hepatocellular carcinoma.

Objective: The goal of our study is to identify a competing endogenous RNA (ceRNA) network using dysregulated RNAs between HCC tumors and the adjacent normal liver tissues from The Cancer Genome Atlas (TCGA) datasets, and to investigate underlying prognostic indicators in hepatocellular carcinoma (HCC) patients. Methods: All of the RNA- and miRNA-sequencing datasets of HCC were obtained from TCGA, and dysregulated RNAs between HCC tumors and the adjacent normal liver tissues were investigated by DESeq and edgeR algorithm. Survival analysis was used to confirm underlying prognostic indicators. Results: In the present study, we constructed a ceRNA network based on 16 differentially expressed genes (DEGs), 7 differentially expressed microRNAs and 34 differentially expressed long non-coding RNAs (DELs). Among these dysregulated RNAs, three DELs (AP002478.1, HTR2A-AS1, and ERVMER61-1) and six DEGs (enhancer of zeste homolog 2 [EZH2], kinesin family member 23 [KIF23], chromobox 2 [CBX2], centrosomal protein 55 [CEP55], cell division cycle 25A [CDC25A], and claspin [CLSPN]) were used for construct a prognostic signature for HCC overall survival (OS), and performed well in HCC OS (adjusted P<0.0001, adjusted hazard ratio = 2.761, 95% confidence interval = 1.838-4.147). Comprehensive survival analysis demonstrated that this prognostic signature may be act as an independent prognostic indicator of HCC OS. Functional assessment of these dysregulated DEGs in the ceRNA network and gene set enrichment of this prognostic signature suggest that both were enriched in the biological processes and pathways of the cell cycle, cell division and cell proliferation. Conclusions: Our current study constructed a ceRNA network for HCC, and developed a prognostic signature that may act as an independent indicator for HCC OS.

[Distribution and Risk Assessment of Polycyclic Aromatic Hydrocarbons in Water Bodies in Seven Basins of China].

The concentrations and spatial distribution characteristics of 16 US EPA priority Polycyclic Aromatic Hydrocarbons (PAHs) in water bodies in seven basins in China were systematically analyzed and summarized. The acute ecological risks of 8 PAHs to aquatic organisms were evaluated by means of species sensitivity distribution (SSD). The joint acute ecological risks of ΣPAH8 to aquatic organisms were evaluated by concentration addition model and response addition model. The health risks of PAHs ingestion were estimated by hazard quotients. The results showed that the 2-, 3-, and 4 ringed-PAHs had higher-than-average concentrations in the water bodies from the seven basins, and the mean concentration of ΣPAH16 was 2596.25 ng·L-1, which is higher than in most foreign water bodies. The composition characteristics and sources of PAHs in water bodies of China and other countries were similar. The pollution of ΣPAH16 in northern water bodies was more serious compared with that of southern water bodies. The potentially affected fraction (PAF) values of naphthalene, acenaphthene, fluorene, phenanthrene, fluoranthene, pyrene, and anthracene to aquatic organisms in the seven basins were less than 4%. Except for the Haihe River and Yangtze River basins, the PAF values of benzo (a) pyrene to aquatic organisms exceeded 5%, which indicates that benzo (a) pyrene had high acute ecological risks to aquatic organisms. The concentration addition model was not suitable for water ecological risk assessments of PAHs. The results of risk assessments based on response addition model showed that except for the Haihe River, the multisubstance PAF (msPAF) values of ΣPAH8 to aquatic organisms in other basins exceeded 5%, which indicates that ΣPAH8 constitutes high joint acute ecological risks to aquatic organisms. The health risks through ingestion of carcinogenic PAHs from water bodies of the seven basins were at 10-5 level, which is higher than the baseline value of acceptable risk (10-6) from the US EPA. The health risks through the ingestion of non-carcinogenic PAHs were at 10-9 level, which is far lower than the baseline value of acceptable risk. The results indicate that there are potential carcinogenic risks to human health through ingestion of PAHs from seven basins in China.

Genetic variants and Expression of Cytochrome p450 Oxidoreductase Predict Postoperative Survival in Patients with Hepatitis B Virus-Related Hepatocellular Carcinoma.

Our current study investigates the prognostic values of genetic variants and mRNA expression of cytochrome p450 oxidoreductase (POR) in hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). A total of 19 candidate single nucleotide polymorphisms (SNPs) located in the exons of POR were genotyped using Sanger sequencing from 476 HBV-related HCC patients who underwent hepatectomy between 2003 and 2013. The mRNA expression of POR in 212 patients with HBV-related HCC was obtained from GSE14520 dataset. Survival analysis was performed to investigate the association of POR variants and mRNA expression with overall survival (OS) and recurrence-free survival (RFS). Nomograms were used to predict the prognosis of HBV-related HCC patients. Gene set enrichment analysis (GSEA) was used to investigate the mechanism of POR in HBV-related HCC prognosis. The polymorphism POR-rs1057868 was significantly associated with HBV-related HCC OS (CT/TT vs. CC, hazard ratio [HR] = 0.69, 95% confidence interval [CI] = [0.54, 0.88], P = 0.003), but not significantly associated with RFS (CT/TT vs. CC, P = 0.378). POR mRNA expression was also significantly associated with HBV-related HCC OS (high vs. low, HR = 0.61, 95% CI = [0.38, 0.97], P = 0.036), but not significantly associated with the RFS (high vs. low, P = 0.201). Two nomograms were developed to predict the HBV-related HCC OS. Furthermore, GSEA suggests that multiple gene sets were significantly enriched in liver cancer survival and recurrence, as well as POR-related target therapy in the liver. In conclusion, our study suggests that POR-rs1057868 and mRNA expression may serve as a potential postoperative prognosis biomarker in HBV-related HCC.