Deciphering ACE2-RBD binding affinity through peptide scanning: A molecular dynamics simulation approach.

Rapid discovery of target information for protein-protein interactions (PPIs) is significant in drug design, diagnostics, vaccine development, antibody therapy, etc. Peptide microarray is an ideal tool for revealing epitope information of PPIs. In this work, the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) spike receptor-binding domain (RBD) and the host cell receptor angiotensin-converting enzyme 2 (ACE2) were introduced as a model to study the epitope information of RBD-specific binding to ACE2 via a combination of theoretical calculations and experimental validation. Through dock and molecular dynamics simulations, it was found that among the 22 peptide fragments that consist of RBD, #14 (YNYLYRLFRKSNLKP) has the highest binding strength. Subsequently, the experiments of peptide microarray constructed based on plasmonic materials chip also confirmed the theoretical calculation data. Compared to other methods, such as phage display technology and surface plasmon resonance (SPR), this method is rapid and cost-effective, providing insights into the investigation of pathogen invasion processes and the timely development of peptide drugs and other fields.

In Vivo Evaluation of Corneal Biomechanics Following Cross-Linking Surgeries Using Optical Coherence Elastography in a Rabbit Model of Keratoconus.

Purpose: Validation of the feasibility of novel acoustic radiation force optical coherence elastography (ARF-OCE) for the evaluation of biomechanical enhancement of the in vivo model of keratoconus by clinical cross-linking (CXL) surgery. Methods: Twelve in vivo rabbit corneas were randomly divided into two groups. Both groups were treated with collagenase type II, and a keratoconus model was obtained. Then, the two groups were treated with CXL procedures with different irradiation energy of 15 J and 30 J (CXL-15 J and CXL-30 J, respectively). An ARF-OCE probe with an ultrasmall ultrasound transducer was used to detect the biomechanical properties of cornea. An antisymmetric Lamb wave model was combined with the frequency dispersion relationship to achieve depth-resolved elastography. Results: Compared with the phase velocity of the Lamb wave in healthy corneas (approximately 3.96 ± 0.27 m/s), the phase velocity of the Lamb wave was lower in the keratoconus region (P < 0.05), with an average value of 3.12 ± 0.12 m/s. Moreover, the corneal stiffness increased after CXL treatment (P < 0.05), and the average phase velocity of the Lamb wave was 4.3 ± 0.19 m/s and 4.54 ± 0.13 m/s after CXL-15 J and CXL-30 J treatment. Conclusions: The Young's moduli of the keratoconus regions were significantly lower than the healthy corneas. Moreover, the Young's modulus of the keratoconus regions was significantly higher after CXL-30 J treatment than after CXL-15 J treatment. We demonstrated that the ARF-OCE technique has great potential in screening keratoconus and guiding clinical CXL treatment. Translational Relevance: This work accelerates the clinical translation of OCE systems using ultrasmall ultrasound transducers and is used to guide CXL procedures.

An Antioxidative and Active Shrinkage Hydrogel Integratedly Promotes Re-Epithelization and Skin Constriction for Enhancing Wound Closure.

Delayed re-epithelization and weakened skin contractions are the two primary factors that hinder wound closure in large-scale acute or chronic wounds. However, effective strategies for targeting these two aspects concurrently are still lacking. Herein, an antioxidative active-shrinkage hydrogel (AHF@AS Gel) is constructed that can integratedly promote re-epithelization and skin constriction to accelerate large-scale acute and diabetic chronic wound closure. The AHF@AS Gel is encapsulated by antioxidative amino- and hydroxyl-modified C70 fullerene (AHF) and a thermosensitive active shrinkage hydrogel (AS Gel). Specifically, AHF relieves overactivated inflammation, prevents cellular apoptosis, and promotes fibroblast migration in vitro by reducing excessive reactive oxygen species (ROS). Notably, the AHF@AS Gel achieved ≈2.7-fold and ≈1.7-fold better re-epithelization in acute wounds and chronic diabetic wounds, respectively, significantly contributing to the promotion of wound closure. Using proteomic profiling and mechanistic studies, it is identified that the AHF@AS Gel efficiently promoted the transition of the inflammatory and proliferative phases to the remodeling phase. Notably, it is demonstrated that AS Gel alone activates the mechanosensitive epidermal growth factor receptor/Akt (EGFR/Akt) pathway and promotes cell proliferation. The antioxidative active shrinkage hydrogel offers a comprehensive strategy for acute wound and diabetic chronic wound closure via biochemistry regulation integrating with mechanical forces stimulation.

Duration-dependent impact of cardiometabolic diseases and multimorbidity on all-cause and cause-specific mortality: a prospective cohort study of 0.5 million participants.

BACKGROUND: The association of incident cardiometabolic multimorbidity (CMM) with mortality risk is rarely studied, and neither are the durations of cardiometabolic diseases (CMDs). Whether the association patterns of CMD durations with mortality change as individuals progress from one CMD to CMM is unclear. METHODS: Data from China Kadoorie Biobank of 512,720 participants aged 30-79 was used. CMM was defined as the simultaneous presence of two or more CMDs of interest, including diabetes, ischemic heart disease, and stroke. Cox regression was used to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs) for the duration-dependent associations of CMDs and CMM with all-cause and cause-specific mortality. All information on exposures of interest was updated during follow-up. RESULTS: During a median follow-up of 12.1 years, 99,770 participants experienced at least one incident CMD, and 56,549 deaths were documented. Among 463,178 participants free of three CMDs at baseline, compared with no CMD during follow-up, the adjusted HRs (95% CIs) between CMM and all-cause mortality, mortality from circulatory system diseases, respiratory system diseases, cancer, and other causes were 2.93 (2.80-3.07), 5.05 (4.74-5.37), 2.72 (2.35-3.14), 1.30 (1.16-1.45), and 2.30 (2.02-2.61), respectively. All CMDs exhibited a high mortality risk in the first year of diagnosis. Subsequently, with prolonged disease duration, mortality risk increased for diabetes, decreased for IHD, and sustained at a high level for stroke. With the presence of CMM, the above association estimates inflated, but the pattern of which remained. CONCLUSION: Among Chinese adults, mortality risk increased with the number of the CMDs and changed with prolonged disease duration, the patterns of which varied among the three CMDs.

The screening of compounds regulating PD-L1 transcriptional activity in a cell functional high-throughput manner.

Immune checkpoints are protein molecules expressed on the immune cell membrane, which regulate the immune system to kill tumor cells. As an essential immune checkpoint, overexpressed PD-1 on tumor cells could inhibit T-cell activation after being bonded to PD-1. Due to this inhibitory effect, T-cell proliferation and cytokine secretion are suppressed, leading to immune escape of tumor cells. Here, we established a high-throughput method based on cell function screening technology to screen drugs regulating PD-L1 expression in tumor cells at the transcriptional level. After two screening rounds, 12 compounds that enhanced PD-L1 transcription while seven weakened were sorted out among 1018 FDA-approved drugs. Finally, a tumor cell line was used to verify the upregulation of endogenous PD-L1 expression for a drug named "vorinostat," a histone deacetylation inhibitor, after the two rounds of optional selection. Therefore, our research provides another perspective for using "vorinostat" in treating tumors and offers a convenient method to detect the transcriptional expression of other intracellular proteins besides PD-L1.

Construction and validation of N6-methyladenosine long non-coding RNAs signature of prognostic value for early biochemical recurrence of prostate cancer.

PURPOSE: Early biochemical recurrence (eBCR) indicated a high risk for potential recurrence and metastasis in prostate cancer. The N6-methyladenosine (m6A) methylation modification played an important role in prostate cancer progression. This study aimed to develop a m6A lncRNA signature to accurately predict eBCR in prostate cancer. METHODS: Pearson correlation analysis was first conducted to explore m6A lncRNAs and univariate Cox regression analysis was further performed to identify m6A lncRNAs of prognostic roles for predicting eBCR in prostate cancer. The m6A lncRNA signature was constructed by least absolute shrinkage and selection operator analysis (LASSO) in training cohort and further validated in test cohort. Furthermore, half maximal inhibitory concentration (IC50) values were utilized to explore potential effective drugs for high-risk group in this study. RESULTS: Five hundred and thirty-eighth m6A lncRNAs were searched out through Pearson correlation analysis and 25 out of 538 m6A lncRNAs were identified to pose prediction roles for eBCR in prostate cancers. An m6A lncRNA signature including 5 lncRNAs was successfully built in training cohort. The high-risk group derived from m6A lncRNA signature could efficiently predict eBCR occurrence in both training (p < 0.001) and test cohort (p = 0.002). ROC analysis also confirmed that lncRNA signature in this study posed more accurate prediction roles for eBCR occurrence when compared with PSA, TNM stages and Gleason scores. Drug sensitivity analysis further discovered that various drugs could be potentially utilized to treat high-risk samples in this study. CONCLUSIONS: The m6A lncRNA signature in this study could be utilized to efficiently predict eBCR occurrence, various clinical characteristic and immune microenvironment for prostate cancer.

Retention of trace elements in coal-fired flue gas by a novel heterogeneous agglomeration technology.

Heterogeneous agglomeration (HA) is a very potential technology for coal-fired flue gas treatment. In this paper, the distribution and migration mechanisms of trace elements (TEs) such as Se, As and Pb in CFPPs were studied on a 30,000 m3/hr pilot-scale experimental platform. The influences of HA on the removal efficiency of gaseous and particulate TEs were well analyzed. The results showed that Se, As and Pb were enriched in fly ash, and their sensitivity to particle size is quite different. The content of Se was the highest in PM1, reaching 193.04 mg/kg at the electrostatic precipitator (ESP) outlet. The average particle size of the total dust before ESP increased significantly from 21.686 to 62.612 µm after injecting the heterogeneous agglomeration adsorbent, conducive to its further removal by ESP. In addition, the concentrations of gaseous Se, As and Pb in the flue gas decreased after adsorbent spray, and accordingly, their contents in the hierarchical particles increased, indicating that the adsorbent could effectively promote the adsorption of gaseous trace elements in fly ash and reduce the possibility of their escape to the atmosphere. Total concentrations of Se, As and Pb emitted by wet flue gas desulfurization (WFGD) are 0.223, 0.668 and 0.076 µg/m3, which decreased by 59.98%, 47.69% and 90.71%, respectively. Finally, a possible HA mechanism model was proposed, where chemical adsorption, physical condensation and collision agglomeration of gaseous TEs and fine particles with adsorbent droplets occurred to form larger agglomerates.

N6-methyladenosine long non-coding RNAs reveal novel tool to implicate overall survival and immune microenvironment in renal clear cell carcinoma.

PURPOSE: This study aimed to investigate whether N6-methyladenosine (m6A)-related long non-coding RNAs (m6ARelncRNAs) could provide novel tools to predict overall survival of renal clear cell carcinoma. METHODS: The transcriptomic data and clinical information of patients with renal clear cell carcinoma from The Cancer Genome Atlas (TCGA) were analysed. Distinct m6A modification patterns were systemically analysed via consensus clustering analysis. An m6ARelncRNA signature was constructed in the training cohort using the least absolute shrinkage and selection operator (LASSO) analysis and validated in the test cohort. Potential predictive accuracy of the signature was further assessed via Kaplan-Meier survival, univariate and multivariate Cox regression and subgroup analyses. The Tumour Immune Dysfunction and Exclusion (TIDE) algorithm was used to investigate the role of m6ARelncRNAs in guiding immunotherapy for patients with renal carcinoma. RESULTS: An m6ARelncRNA signature based on only six lncRNAs was successfully constructed. The high-risk group derived from this signature had significantly poorer overall survival in both training and test cohorts (p < 0.001). Independent prognostic analysis further revealed that m6ARelncRNA risk (p < 0.01) was an independent risk factor for survival outcomes of renal carcinoma. TIDE algorithm revealed that immunotherapy response was poorer in the high-risk group than in the low-risk group. Drug sensitivity analysis based on IC50 revealed that high-risk patients were potentially sensitive to various anti-tumour drugs, including bortezomib, cisplatin, docetaxel, etoposide and sunitinib. CONCLUSION: m6ARelncRNAs provide novel tools that can be used to predict overall survival and examine the immune microenvironment of renal clear cell carcinoma.

Ferroptosis-Related Long Noncoding RNAs Have Excellent Predictive Ability for Multiomic Characteristics of Bladder Cancer.

Background: The role of ferroptosis-related long non-coding RNAs (lncRNAs) in bladder cancer remains elusive. This study is aimed at examining the prognostic role of ferroptosis-related lncRNAs in bladder cancer. Materials and Methods: The transcriptomic matrix and clinical information of patients with bladder cancer were obtained from The Cancer Genome Atlas (TCGA) database. A ferroptosis-related lncRNA signature was developed via the least absolute shrinkage and selection operator (LASSO) analysis using data from the training cohort, and the signature was further validated using data from the test cohort. The role of AC006160.1, the most significant lncRNA in the risk signature, was examined in various cell lines including SV-HUC-1, BIU-87, HT-1376, T24, RT4, RT-112, 5637, and UMUC3. The pcDNA3.1-AC006160.1 plasmid was constructed and transfected into the bladder cancer cell lines T24 and BIU-87. In addition, cell proliferation, colony formation, transwell, and wound healing assays were performed to examine the biological function of AC006160.1 in T24 and BIU-87 cell lines. Results: Two clusters were identified through consensus clustering based on prognostic ferroptosis-related lncRNAs. A 5-lncRNA risk signature was successfully constructed using data from the training cohort and validated using data from the test cohort. The risk signature had excellent ability to predict survival outcomes, clinical stages, pathological grades, expression of immune checkpoints, and immunotherapeutic responses in bladder cancer samples. Furthermore, AC006160.1 expression was found to be lower in the cancer cell lines BIU-87, T24, RT4, RT-112, and 5637 than in the normal control cell line SV-HUC-1. Cell proliferation, colony formation, transwell migration, and wound healing assays validated that overexpression of AC006160.1 significantly inhibited the proliferation and invasion abilities of both T24 and BIU-87 cells. Drug sensitivity analysis revealed that patients with high expression of AC006160.1 were sensitive to metformin and methotrexate, and the results were further validated via in vitro drug experiments. Conclusions: Ferroptosis-related lncRNAs play a vital role in predicting the multiomic characteristics of bladder cancer. The lncRNA AC006160.1 serves as a protective factor for the development of bladder cancer.

Novel MDM2 Inhibitor XR-2 Exerts Potent Anti-Tumor Efficacy and Overcomes Enzalutamide Resistance in Prostate Cancer.

Background: The inactivation of tumor-suppressor p53 plays an important role in second generation anti-androgens (SGAs) drug resistance and neuroendocrine differentiation in castration-resistant prostate cancer (CRPC). The reactivation of p53 by blocking the MDM2-p53 interaction represents an attractive therapeutic remedy in cancers with wild-type or functional p53. Whether MDM2-p53 inhibitor could overcome SGAs drug resistance in CRPC is still needed further research. Here, we investigated the anti-tumor efficacy and mechanisms of a novel MDM2-p53 inhibitor XR-2 in CRPC. Methods: To investigate the functions and mechanisms of XR-2 in prostate cancer, in vitro and in vivo biofunctional assays were performed. Western blot and qRT-PCR assay were performed to detect the protein and mRNA expression levels of indicated genes. CCK8, colony formation, flow cytometry and senescence assays were performed for cell function identifications. RNA-sequencing and bioinformatics analysis were mainly used to identify the influence of XR-2 on prostate cancer cells transcriptome. Subcutaneous 22Rv1 derived xenografts mice model was used to investigate the in vivo anti-tumor activity of XR-2. In addition, the broad-spectrum anti-tumor activities in vivo of XR-2 were evaluated by different xenografts mice models. Results: XR-2 could directly bind to MDM2, potently reactivate the p53 pathway and thus induce cell cycle arrest and apoptosis in wild-type p53 CRPC cell lines. XR-2 also suppresses the AR pathway as p53 regulates AR transcription inhibition and MDM2 participates in AR degradation. As a result, XR-2 efficiently inhibited CRPC cell viability, showed a synergistic effect with enzalutamide and overcame enzalutamide resistance both in vitro and in vivo. Moreover, results illustrated that XR-2 possesses broad-spectrum anti-tumor activities in vivo with favourable safety. Conclusion: MDM2-p53 inhibitor (XR-2) possesses potently prostate cancer progresses inhibition activity both in vitro and in vivo. XR-2 shows a synergistic effect with enzalutamide and overcomes enzalutamide resistance.

Predictive role of ferroptosis-related long non-coding RNAs in bladder cancer and their association with immune microenvironment and immunotherapy response.

BACKGROUND: We have previously reported that ferroptosis has an important role in bladder cancer development. In this study, we aimed to further explore the possible predictive ability of ferroptosis-related long non-coding RNAs (lncRNAs) in bladder cancer and their relation with immune microenvironment and immunotherapy response. MATERIALS AND METHODS: The ferroptosis-related lncRNAs were identified by Pearson's correlation analysis. The predictive lncRNA signature was developed by univariate and multivariate regression analyses. Only the main effects of independent variables in multivariate analysis were included in this signature. The TCGA dataset was defined as the training cohort and GEO was the validation cohort in this study. All samples were grouped into a high- or low-risk group depending on risk signature. The prognostic role of lncRNA signature was explored through survival analysis and receiver operating characteristic curve (ROC) analysis in both TCGA and GEO cohorts. Additionally, the independent prognostic ability of the lncRNA signature was confirmed by multivariate independent analysis. Furthermore, the relationship between lncRNAs and immune microenvironment as well as immunotherapy response in bladder cancers was studied. RESULTS: The Kaplan-Meier curves identified significantly poorer overall survival outcomes for high-risk groups in both TCGA (p < 0.001) and GEO (p < 0.001) cohorts. The area under the curve (AUC) during ROC analysis of 1, 3, and 5 years was 0.781 ± 0.046, 0.784 ± 0.027, and 0.817 ± 0.025, respectively, in the TCGA cohort and 0.665 ± 0.177, 0.719 ± 0.068, and 0.791 ± 0.055, respectively, in the GEO cohort. The multivariate independent analysis in TCGA cohort identified age (p = 0.003), stage (p < 0.001), and signature risk score (p < 0.001) as independent risk factors for overall survival. Furthermore, this study demonstrated a significant difference in infiltration levels of various immune cells between high- and low-risk groups. The high risk group tended to have a lower expression of proteins including PD1 (p < 0.01), PD-L1 (p < 0.01), CTLA-4 (p < 0.05), etc. corresponding to various immune checkpoints. Additionally, the immunotherapy trial confirmed that the high-risk group tended to have a poorer treatment response than the low-risk group (p < 0.001). CONCLUSIONS: The ferroptosis-related lncRNAs exhibited a good predictive capacity for overall survival in bladder cancer. Additionally, they could be utilized to reveal tumour-immune microenvironment and immunotherapy responses.

Ferroptosis Mediation Patterns Reveal Novel Tool to Implicate Immunotherapy and Multi-Omics Characteristics in Bladder Cancer.

Background: The regulatory role of ferroptosis in malignant tumours has been recently demonstrated. However, the potential roles of ferroptosis mediation patterns in bladder cancer remain elusive. Materials and Methods: The ferroptosis mediation patterns of 889 bladder cancer samples were comprehensively evaluated based on ferroptosis-related genes. The underlying correlations between these mediation patterns and multi-omic characteristics of bladder cancer were systematically analysed. The ferroptosis mediation patterns of individual samples were quantified by ferropscore using the principal component analysis algorithm. The typical ferroptosis-related genes with prognostic roles were further randomly validated using immunohistochemical staining, real-time polymerase chain reaction and western blotting. Results: Three different ferroptosis mediation patterns were identified. The abundance of infiltration of 23 immune cells was different among the three mediation patterns. The quantification of ferroptosis mediation patterns in individual samples served as a promising tool for predicting patient survival outcomes; immune cell infiltration abundance; tumour mutation burden; oncogenic mutation status and tumour grade, stage and molecular subtypes. Low ferropscore combined with high tumour mutation burden was associated with the best survival prognosis. Expressions of PD-L1 (p < 0.001), PD-1 (p = 0.002) and CTLA-4 (p = 0.003) were all significantly upregulated in the high ferropscore group. Low ferropscores also predicted good immunotherapy response for anti-CTLA4 strategy. The mRNA and protein levels of FADS2, a typical ferroptosis-related gene used in the study, were higher in bladder cancer cell lines than in controlled SV-HUC-1 cells. In addition, immunohistochemical staining revealed significantly higher expression levels of FADS2 in human bladder cancer tumour tissues than in normal tissues. Conclusion: This study identified three distinct ferroptosis mediation patterns in bladder cancer. Quantification of ferroptosis mediation patterns in individual samples may help to improve the understanding of multiomic characteristics and guide future immunotherapy responses to bladder cancer.

Alcohol metabolism genes and risks of site-specific cancers in Chinese adults: An 11-year prospective study.

Two genetic variants that alter alcohol metabolism, ALDH2-rs671 and ADH1B-rs1229984, can modify oesophageal cancer risk associated with alcohol consumption in East Asians, but their associations with other cancers remain uncertain. ALDH2-rs671 G>A and ADH1B-rs1229984 G>A were genotyped in 150 722 adults, enrolled from 10 areas in China during 2004 to 2008. After 11 years' follow-up, 9339 individuals developed cancer. Cox regression was used to estimate hazard ratios (HRs) for site-specific cancers associated with these genotypes, and their potential interactions with alcohol consumption. Overall, the A-allele frequency was 0.21 for ALDH2-rs671 and 0.69 for ADH1B-rs1229984, with A-alleles strongly associated with lower alcohol consumption. Among men, ALDH2-rs671 AA genotype was associated with HR of 0.69 (95% confidence interval: 0.53-0.90) for IARC alcohol-related cancers (n = 1900), compared to GG genotype. For ADH1B-rs1229984, the HRs of AG and AA vs GG genotype were 0.80 (0.69-0.93) and 0.75 (0.64-0.87) for IARC alcohol-related cancers, 0.61 (0.39-0.96) and 0.61 (0.39-0.94) for head and neck cancer (n = 196) and 0.68 (0.53-0.88) and 0.60 (0.46-0.78) for oesophageal cancer (n = 546). There were no significant associations of these genotypes with risks of liver (n = 651), colorectal (n = 556), stomach (n = 725) or lung (n = 1135) cancers. Among male drinkers, the risks associated with higher alcohol consumption were greater among ALDH2-rs671 AG than GG carriers for head and neck, oesophageal and lung cancers (Pinteraction < .02). Among women, only 2% drank alcohol regularly, with no comparable associations observed between genotype and cancer. These findings support the causal effects of alcohol consumption on upper aerodigestive tract cancers, with ALDH2-rs671 AG genotype further exacerbating the risks.

In-situ constructing nanostructured magnesium ferrite on steel slag for Cr(VI) photoreduction.

An innovative method is created for transforming iron-rich RO phase (MgO0.239FeO0.761) on steel slag surface into nanostructured Mg0.04Fe2.96O4 layer. The phase change process is investigated, and it is found that salicylic acid modification and alkaline roasting procedures remarkably increase the specific surface area from 0.46 m2/g (raw steel slag) to 69.5 m2/g (Mg0.04Fe2.96O4), and the generation of Mg0.04Fe2.96O4 enhances the absorption of visible light and Cr(VI) conversion with 2-times increasement than raw steel slag. Surface complexation between H2C2O4 ligands and Fe metal moiety on Mg0.04Fe2.96O4 induces the intramolecular electron transfer under visible light irradiation based on a ligand-to-metal charge transfer mechanism, thus resulting in Cr(VI) photoreduction, and the catalytic efficiency is above 90% for Cr(VI) (40 mg/L) under inherent pH= 5.5 conditions. Moreover, recyclability tests based on magnetic separation show that the photoreactivity is closely related to Mg content of Mg0.04Fe2.96O4 layer where Mg leaching occurs and finally generates cubic spinel configuration Fe3O4. This work highlights the importance of surface functionalization in post-use phases of steel slag in which surface reactivity and application potential can be greatly altered by chemical exposure history and surface transformations. It also provides valuable references for studying the metastable state mechanism of magnesium ferrite photocatalysts.

Identification of a Hypoxia-Related Gene Signature for Predicting Systemic Metastasis in Prostate Cancer.

Background: Systemic metastasis is the main cause of death in patients with prostate cancer. It is necessary to establish a more accurate model to distinguish and predict patients with a high risk of metastasis to optimize individualized treatment. Methods: In this study, it was determined that hypoxia could affect the metastasis-free survival of patients with prostate cancer, and a hypoxia-related gene signature composed of seven genes for predicting metastasis was established and verified in different cohorts. The study further evaluated the effects of ALDOB expression on the proliferation and invasion of the LNCaP and DU145 cell lines under hypoxia and finally constructed a nomogram containing specific clinical characteristics of prostate cancer combined with the hypoxia gene signature to quantify the metastasis risk of individual patients. Results: The hypoxia-related gene signature was identified as an independent risk factor for metastasis-free survival in patients with prostate cancer. The expression of ALDOB increased under hypoxia and promoted the proliferation and invasion of LNCaP and DU145 cells. In addition, patients with a high risk score showed therapeutic resistance and immunosuppression. Compared with other parameters, the nomogram had the strongest predictive power and net clinical benefit. Conclusion: The study established a hypoxia-related gene signature and a nomogram to distinguish and predict patients with a high risk of prostate cancer metastasis, which may help to optimize individualized treatment and explore possible therapeutic targets.

Epigenome-wide analysis of DNA methylation and coronary heart disease: a nested case-control study.

Background: Identifying environmentally responsive genetic loci where DNA methylation is associated with coronary heart disease (CHD) may reveal novel pathways or therapeutic targets for CHD. We conducted the first prospective epigenome-wide analysis of DNA methylation in relation to incident CHD in the Asian population. Methods: We did a nested case-control study comprising incident CHD cases and 1:1 matched controls who were identified from the 10 year follow-up of the China Kadoorie Biobank. Methylation level of baseline blood leukocyte DNA was measured by Infinium Methylation EPIC BeadChip. We performed the single cytosine-phosphate-guanine (CpG) site association analysis and network approach to identify CHD-associated CpG sites and co-methylation gene module. Results: After quality control, 982 participants (mean age 50.1 years) were retained. Methylation level at 25 CpG sites across the genome was associated with incident CHD (genome-wide false discovery rate [FDR] < 0.05 or module-specific FDR < 0.01). One SD increase in methylation level of identified CpGs was associated with differences in CHD risk, ranging from a 47 % decrease to a 118 % increase. Mediation analyses revealed 28.5 % of the excessed CHD risk associated with smoking was mediated by methylation level at the promoter region of ANKS1A gene (P for mediation effect = 0.036). Methylation level at the promoter region of SNX30 was associated with blood pressure and subsequent risk of CHD, with the mediating proportion to be 7.7 % (P = 0.003) via systolic blood pressure and 6.4 % (P = 0.006) via diastolic blood pressure. Network analysis revealed a co-methylation module associated with CHD. Conclusions: We identified novel blood methylation alterations associated with incident CHD in the Asian population and provided evidence of the possible role of epigenetic regulations in the smoking- and blood pressure-related pathways to CHD risk. Funding: This work was supported by National Natural Science Foundation of China (81390544 and 91846303). The CKB baseline survey and the first re-survey were supported by a grant from the Kadoorie Charitable Foundation in Hong Kong. The long-term follow-up is supported by grants from the UK Wellcome Trust (202922/Z/16/Z, 088158/Z/09/Z, 104085/Z/14/Z), grant (2016YFC0900500, 2016YFC0900501, 2016YFC0900504, 2016YFC1303904) from the National Key R&D Program of China, and Chinese Ministry of Science and Technology (2011BAI09B01).

Sorption of organochlorine pesticides on polyethylene microplastics in soil suspension.

As a new type of environmental pollutant, microplastics (MPs) can adsorb residual organochlorine pesticides (OCPs) in the soil and pose a severe threat to the soil ecosystems. To understand the interaction between soil MPs and OCPs, the sorption of two kinds of OCPs, including hexachlorocyclohexanes (HCHs) and dichlorodiphenyltrichloroethanes (DDTs), on polyethylene (PE) microplastics in soil suspension was studied through sorption kinetics and isotherm models. The effects of solution/soil ratio and MPs diameter on sorption were examined. The kinetic experiment results show that the sorption equilibrium was 12 h， and the sorption process of OCPs on MPs can be well described by a pseudo-second-order model. The Freundlich model (R2 = 0.942-0.997) provides a better fit to the sorption isotherm data than the Langmuir model (R2 = 0.062-0.634), indicating that the sorption process takes place on the nonuniform surface of MPs. The MPs had a good sorption effect on OCPs when the solution/soil ratio was from 75:1 to 100:1. As the diameter of MPs increases, the sorption capacity decreases. These results provide support for further research on microplastic pollution in soil.

Construction and External Validation of a Ferroptosis-Related Gene Signature of Predictive Value for the Overall Survival in Bladder Cancer.

Purpose: To identify whether ferroptosis-related genes play predictive roles in bladder cancer patients and to develop a ferroptosis-related gene signature to predict overall survival outcomes. Materials and Methods: We downloaded the mRNA expression files and clinical data of 256 bladder samples (188 bladder tumour and 68 nontumour samples) from the GEO database and 430 bladder samples (411 bladder tumour and 19 nontumour samples) from the TCGA database. A multigene signature based on prognostic ferroptosis-related genes was constructed by least absolute shrinkage and selection operator Cox regression analysis in the GEO cohort. The TCGA cohort was used to validate the ferroptosis-related gene signature. Next, functional enrichment analysis, including both Kyoto Encyclopedia of Genes and Genomes and Gene Ontology analyses, was performed to elucidate the mechanism underlying the signature. The ssGSEA scores of 16 immune cells and 13 immune-related pathway activities between the high-risk and low-risk groups were also analysed in our study. Results: Thirty-three (67.3%) ferroptosis-related genes were differentially expressed between bladder tumour samples and nontumour samples in the GEO cohort. The intersection of prognostic ferroptosis-related genes and differentially expressed genes identified four prognostic targets, including ALOX5, FANCD2, HMGCR and FADS2. The least absolute shrinkage and selection operator Cox regression successfully built a 4-gene signature: risk score value = esum (each gene's normalized expression * each gene's coefficient). Univariate and multivariate Cox regression analyses were performed in both the GEO and TCGA cohorts to test the independent prognostic value of the 4-gene risk signature. Multivariate Cox regression analysis in the GEO cohort identified age (p < 0.001), grade (p = 0.129) and risk score (p = 0.016) as independent prognostic predictors for overall survival. Multivariate Cox regression analysis in the TCGA cohort also identified age (p = 0.002), stage (p < 0.001) and risk score (p = 0.006) as independent prognostic predictors for overall survival. The type II IFN response was determined to be significantly weakened in the high-risk group in both the GEO and TCGA cohorts. Conclusion: We successfully built a ferroptosis-related gene signature of significant predictive value for bladder cancer. These results suggest a novel research direction for targeted therapy of bladder cancer in the future.

Identification of a prognostic signature based on immune-related genes in bladder cancer.

Bladder cancer (BLCA) has a high incidence and recurrence rate, and the effect of immunotherapy varies from person to person. Immune-related genes (IRGs) have been shown to be associated with immunotherapy and prognosis in many other cancers, but their role in immunogenic BLCA is less well defined. In this study, we constructed an eight-IRG risk model, which demonstrated strong prognostic and immunotherapeutic predictive power. The signature was significantly related to tumor clinicopathological characteristics, tumor class, immune cell infiltration and mutation status. Additionally, a nomogram containing the risk score and other potential risk factors could effectively predict the long-term overall survival probability of BLCA patients. The enriched mechanisms identified by gene set enrichment analysis suggested that the reason why this signature can accurately distinguish high- and low-risk populations may be closely related to the different degrees of innate immune response and T cell activation in different patients.

Comprehensive Analysis of N6-methyladenosine Modification Patterns Associated With Multiomic Characteristics of Bladder Cancer.

Purpose: To comprehensively analyze N6-methyladenosine modification patterns in bladder tumors and to further systematically explore the inherent relationships between these modification patterns and multiomic tumor characteristics. Materials and Methods: A total of 901 bladder tumor samples, including 405 samples from TCGA database, 188 samples from GSE13507 and 308 samples from GSE32894, were included in this systematic analysis. The N6-methyladenosine modification patterns were identified utilizing unsupervised clustering analysis. To quantify N6-methyladenosine modification patterns, the m6Ascore of individual sample was developed using principal component analysis algorithms. Relationships among immune infiltration, tumor mutation burden, various clinical characteristics, molecular subtypes, and the m6Ascore were systematically analyzed. The guiding value of m6Ascore in immunotherapy was further validated in an external trial cohort. Genomics of Drug Sensitivity in Cancer expression references were also utilized to perform drug sensitivity analysis for patients with distinct m6A modification patterns. Results: We determined three different N6-methyladenosine modification patterns for 901 bladder tumors. The quantitative m6Ascore of individual sample derived from N6-methyladenosine modification patterns could play a significant role in predicting overall survival, immune cell infiltration, and classic oncogene mutations. A low m6Ascore combined with high tumor mutation burden indicated better survival outcomes (p < 0.001). A higher m6Ascore also indicated a higher grade, higher T and N stage, elder ages, higher death rate, and higher PD1/PDL1/CTLA4 expressions (p < 0.01). The Basal type tended to exhibit significantly higher m6Ascores than the Luminal and Neuronal subtypes. External immunotherapy cohorts demonstrated that no difference in therapeutic effects was noted between the high and low m6Ascore groups when anti-PD1 immunotherapy was exclusively administered. When anti-PD1 and anti-CTLA4 immunotherapy were simultaneously administered, the high m6Ascore group had a significantly better prognosis than the low m6Ascore group (p < 0.001). High m6A groups were potentially sensitive to various medical treatments including Bleomycin, Bortezomib, Cisplatin, Cyclopamine, Dasatinib, Docetaxe, Rapamycin, and Vinblastine in this study. Conclusions: This study systematically revealed the important roles of m6A methylation modification patterns in bladder tumors. Detailed quantification of m6A modification patterns could improve our understanding of the bladder tumor microenvironments and could provide guidance for future immunotherapy strategies.