Adsorption behavior of triazine pesticides on polystyrene microplastics aging with different processes in natural environment.

The presence of microplastics in the ecological environment, serving as carriers for other organic pollutants, has garnered widespread attention. These microplastics exposed in the environment may undergo various aging processes. However, there is still a lack of information regarding how these aged microplastics impact the environmental behavior and ecological toxicity of pollutants. In this study, we modified polystyrene microplastics by simulating the aging behavior that may occur under environmental exposure, and then explored the adsorption behavior and adsorption mechanism of microplastics before and after aging for typical triazine herbicides. It was shown that all aging treatments of polystyrene increased the adsorption of herbicides, the composite aged microplastics had the strongest adsorption capacity and the fastest adsorption rate, and of the three herbicides, metribuzin was adsorbed the most by microplastics. The interactions between microplastics and herbicides involved mechanisms such as hydrophobic interactions, surface adsorption, the effect of π-π interactions, and the formation of hydrogen bonds. Further studies confirmed that microplastics adsorbed with herbicides cause greater biotoxicity to E. coli. These findings elucidate the interactions between microplastics before and after aging and triazine herbicides. Acting as carriers, they alter the environmental behavior and ecological toxicity of organic pollutants, providing theoretical support for assessing the ecological risk of microplastics in water environments.

Comparison of the toxic effects of polystyrene and sulfonated polystyrene on wheat under cadmium stress.

With advances in plastic resource utilization technologies, polystyrene (PS) and sulfonated polystyrene (SPS) microplastics continue to be produced and retained in environmental media, potentially posing greater environmental risks. These plastics, due to their different physicochemical properties, may have different environmental impacts when compounded with other pollutants. The objective of this study was to investigate the combined toxic effects of PS and SPS on wheat using cadmium (Cd) as a background contaminant. The results demonstrated that Cd significantly impeded the normal growth of wheat by disrupting root development. Both PS and SPS exhibited hormesis at low concentrations and promoted wheat growth. Under combined toxicity, PS reduced oxidative stress and promoted the uptake of essential metal elements in wheat. Additionally, KEGG pathway analysis revealed that PS facilitated the repair of Cd-induced blockage of the TCA cycle and glutathione metabolism. However, high concentrations of SPS in combined toxicity not only enhanced oxidative stress and interfered with the uptake of essential metal elements, but also exacerbated the blocked TCA cycle and interfered with pyrimidine metabolism. These differences are related to the different stability (Zeta potential, Hydrodynamic particle size) of the two microplastics in the aquatic environment and their ability to carry heavy metal ions, especially Cd. The results of this study provide important insights into understanding the effects of microplastics on crops in the context of Cd contamination and their environmental and food safety implications.

The influence of digestive tract protein on cytotoxicity of polyvinyl chloride microplastics.

Microplastics in food and drinking water can enter the human body through oral exposure, posing potential health risks to the human health. Most studies on the toxic effects of microplastics have focused on aquatic organisms, but the effects of the human digestive environment on the physicochemical properties of microplastics and their potential toxicity during gastrointestinal digestion are often limited. In this study, we first studied the influence of interactions between digestive tract protein (α-amylase, pepsin, and trypsin) and microplastics on the activity and conformation of digestive enzymes, and the physicochemical properties of polyvinyl chloride microplastics (PVC-MPs). Subsequently, a simulated digestion assay was performed to determine the biotransformation of PVC-MPs in the digestive tract and the intestinal toxicity of PVC-MPs. The in vitro experiments showed that the protein structure and activity of digestive enzymes were changed after adsorption by microplastics. After digestion, the static contact angle of PVC-MPs was decreased, indicating that the hydrophilicity of the PVC-MPs increased, which will increase its mobility in organisms. Cell experiment showed that the altered physicochemical property of PVC-MPs after digestion process also affect its cytotoxicity, including cellular uptake, cell viability, cell membrane integrity, reactive oxygen species levels, and mitochondrial membrane potential. Transcriptome analyses further confirmed the enhanced biotoxic effect of PVC-MPs after digestion treatment. Therefore, the ecological risk of microplastics may be underestimated owing to the interactions of microplastics and digestive tract protein during biological ingestion.

CAPN5 attenuates cigarette smoke extract-induced apoptosis and inflammation in BEAS-2B cells.

INTRODUCTION: Apoptosis and chronic inflammation are the main phenotypes in chronic obstructive pulmonary disease (COPD) pathogenesis. Cigarette smoke exposure is the leading risk factor for COPD, which causes aberrant airway epithelial structure and function. As a non-classical calpain, the molecular function of calpain5 (CAPN5) in COPD remains unclear. This study investigated the role of CAPN5 in mediating cigarette smoke extract (CSE)-induced apoptosis and inflammation. METHODS: Immunohistochemistry (IHC) and Western blotting (WB) were performed to detect the location and expression of CAPN5. In vitro, BEAS-2B cells were transfected with CAPN5 siRNA or CAPN5 plasmid, followed by phosphate-buffered saline (PBS) or cigarette smoke extract (CSE) treatment. The protein expression levels of CAPN5, NF-κB p65, p-p65, IκBα, p-IκBα and apoptosis proteins (BCL-2, BAX) were measured by WB. Flow cytometry (FCM) was performed to analyze the cell apoptosis index. RESULTS: CAPN5 was mainly expressed in the airway epithelium and significantly decreased in the COPD-smoker and emphysema-mouse groups. Silencing CAPN5 significantly decreased the protein expression of BCL-2, IκBα, and increased p-p65 and BAX protein expression. Additionally, an increased apoptosis index was detected after silencing CAPN5. Moreover, overexpression of CAPN5 partly inhibited IκBα degradation and p65 activation, and reduced CSE-induced inflammation and apoptosis. CONCLUSIONS: These combined results indicate that CAPN5 could protect against CSE-induced apoptosis and inflammation, which may provide a potential therapeutic target for smoking-related COPD.

TET2 stabilized by deubiquitinase USP21 ameliorates cigarette smoke-induced apoptosis in airway epithelial cells.

DNA demethylase TET2 was related with lung function. However, the precise role of TET2 in cigarette smoke (CS)-induced apoptosis of airway epithelium cells, and the mechanisms involved, have yet to be elucidated. Here, we showed that CS decreased TET2 protein levels but had no significant effect on its mRNA levels in lung tissues of chronic obstructive pulmonary disease (COPD) patients and CS-induced COPD mice model and even in airway epithelial cell lines. TET2 could inhibit CS-induced apoptosis of airway epithelial cell in vivo and in vitro. Moreover, we identified ubiquitin-specific protease 21 (USP21) as a deubiquitinase of TET2 in airway epithelial cells. USP21 interacted with TET2 and inhibited CSE-induced TET2 degradation. USP21 downregulated decreased TET2 abundance and further reduced the anti-apoptosis effect of TET2. Thus, we draw a conclusion that the USP21/TET2 axis is involved in CS-induced apoptosis of airway epithelial cells.

PU.1 alleviates the inhibitory effects of cigarette smoke on endothelial progenitor cell function and lung-homing through Wnt/ß-catenin and CXCL12/CXCR4 pathways.

INTRODUCTION: Endothelial progenitor cells (EPCs) dysfunction is involved in the pathogenesis of chronic obstructive pulmonary disease (COPD). The transcription factor PU.1 is essential for the maintenance of stem/progenitor cell homeostasis. However, the role of PU.1 in COPD and its effects on EPC function and lung-homing, remain unclear. This study aimed to explore the protective activity of PU.1 and the underlying mechanisms in a cigarette smoke extract (CSE)-induced emphysema mouse model. METHODS: C57BL/6 mice were treated with CSE to establish a murine emphysema model and injected with overexpressed PU.1 or negative control adeno-associated virus. Morphometry of lung slides, lung function, and apoptosis of lung tissues were evaluated. Immunofluorescence co-localization was used to analyze EPCs homing into the lung. Flow cytometry was performed to detect EPC count in lung tissues and bone marrow (BM). The angiogenic ability of BM-derived EPCs cultured in vitro was examined by tube formation assay. We determined the expression levels of PU.1, ß-catenin, C-X-C motif ligand 12 (CXCL12), C-X-C motif receptor 4 (CXCR4), stem cell antigen-1 (Sca-1), and stemness genes. RESULTS: CSE exposure significantly reduced the expression of PU.1 in mouse lung tissues, BM, and BM-derived EPCs. PU.1 overexpression attenuated CSE-induced emphysematous changes, lung function decline, and apoptosis. In emphysematous mice, PU.1 overexpression markedly reversed the decreased proportion of EPCs in BM and promoted the lung-homing of EPCs. The impaired angiogenic ability of BM-derived EPCs induced by CSE could be restored by the overexpression of PU.1. In addition, PU.1 upregulation evidently reversed the decreased expression of ß-catenin, CXCL12, CXCR4, Scal-1, and stemness genes in mouse lung tissues, BM, and BM-derived EPCs after CSE exposure. CONCLUSIONS: PU.1 alleviates the inhibitory effects of CSE on EPC function and lung-homing via activating the canonical Wnt/ß-catenin pathway and CXCL12/CXCR4 axis. While further research is needed, our research may indicate a potential therapeutic target for COPD patients.

Enhanced management and antifouling performance of a novel NiFe-LDH@MnO2/PVDF hybrid membrane for efficient oily wastewater treatment.

Layered double hydroxides (LDHs) have gained significant recognition for their facile synthesis and super-hydrophilic two-dimensional (2D) structure to fabricate antifouling membranes for oily wastewater separation. However, conventional PVDF membranes, due to their hydrophobic nature and inert matrix, often exhibit insufficient permeance and compatibility. In this study, a novel NiFe-LDH@MnO2/PVDF membrane was synthesized using ultrasonic, redox, and microwave-hydrothermal processes. This innovative approach cultivated grass-like NiFe-LDH@MnO2 nanoparticles within an inert PVDF matrix, promoting the growth of highly hydrophilic composites. The presence of NiFe-LDH@MnO2 resulted in pronounced enhancements in surface morphology, interfacial wettability, and oil rejection for the fabricated membrane. The optimal NiFe-LDH@MnO2/PVDF-2 membrane exhibited an extremely high pure water flux (1364 L m-2•h-1), and increased oil rejection (from 81.2% to 93.5%) without sacrificing water permeation compared to the original PVDF membrane. Additionally, the NiFe-LDH@MnO2/PVDF membrane demonstrated remarkable antifouling properties, evident by an exceptional fouling resistance ratio of 96.8% following slight water rinsing. Mechanistic insights into the enhanced antifouling performance were elucidated through a comparative "semi-immersion" investigation. The facile synthesis method, coupled with the improved membrane performance, highlights the potential application prospects of this hybrid membrane in emulsified oily wastewater treatment and environmental remediation.

DNA dioxygenases TET2 deficiency promotes cigarette smoke induced chronic obstructive pulmonary disease by inducing ferroptosis of lung epithelial cell.

Chronic obstructive pulmonary disease (COPD) is a significant global cause of morbidity and mortality currently. Long-term exposure of cigarette smoke (CS) inducing persistent inflammation, small airway remodeling and emphysematous lung are the distinguishing features of COPD. Ferroptosis, occurred in lung epithelial cells has recently been reported to be associated with COPD pathogenesis. DNA dioxygenase ten-eleven translocation 2 (TET2) is an important demethylase and its genetic mutation is associated with low forced expiratory volume in 1 s (FEV1) of lung function. However, its role in COPD remains elusive. Here, we found that TET2 regulates CS induced lipid peroxidation through demethylating glutathione peroxidase 4 (GPx4), thus alleviating airway epithelial cell ferroptosis in COPD. TET2 protein levels were mainly reduced in the airway epithelia of COPD patients, mouse models, and CS extract-treated bronchial epithelial cells. The deletion of TET2 triggered ferroptosis and further exaggerated CS-induced airway remodeling, inflammation, and emphysema in vivo. Moreover, we demonstrated that TET2 silencing intensified ferroptosis, while TET2 overexpression inhibited ferroptosis in airway epithelial cell treated with CSE. Mechanically, TET2 protected airway epithelial cells from CS-induced lipid peroxidation and ferroptosis through demethylating the promoter of glutathione peroxidase 4 (GPx4). Finally, co-administration of methylation inhibitor 5'-aza-2'-deoxycytidine (5-AZA) and the antioxidant N-acetyl-cysteine (NAC) have more protective effects on CS-induced COPD than either administration alone. Overall, our study reveals that TET2 is an essential modulator in the lipid peroxidation and ferroptosis of airway epithelial cell, and could act as a potential therapeutic target for CS-induced COPD.

CSE reduces OTUD4 triggering lung epithelial cell apoptosis via PAI-1 degradation.

Ovarian tumor family deubiquitinase 4 (OTUD4), a member of the OTU deubiquitinating enzyme, is implicated to decrease in cancer to regulate cell apoptosis. However, the role of OTUD4 in cigarette smoke induced epithelial cell apoptosis and its mechanism have not been elucidated. In this study, we showed that OTUD4 protein reduced in CSE treated mice and airway epithelial cells. OTUD4 silence aggravated cell apoptosis and emphysematous change in the lung tissue of cigarette smoke extract (CSE) treated mice. Additionally, restoration of OTUD4 in the lung of mice alleviated CSE induced apoptosis and emphysematous morphology change. The effect of OTUD4 on cell apoptosis was also confirmed in vitro. Through protein profile screening, we identified that OTUD4 may interact with plasminogen activator inhibitor 1(PAI-1). We further confirmed that OTUD4 interacted with PAI-1 for de-ubiquitination and inhibiting CSE induced PAI-1 degradation. Furthermore, the protective role of OTUD4 in airway epithelial cells apoptosis was blocked by PAI-1 deactivation. Taken together, our data suggest that OTUD4 regulates cigarette smoke (CS)-triggered airway epithelial cell apoptosis via modulating PAI-1 degradation. Targeting OUTD4/PAI-1 signaling might potentially provide a therapeutic target against the lung cell apoptosis in cigarette smoke (CS)-induced emphysema.

An event-driven Spike-DBN model for fault diagnosis using reward-STDP.

Deep neural networks (DNNs) have shown high accuracy in fault diagnosis, but they struggle to effectively capture changes over time in multivariate time-series data and suffer from resource consumption issues. Spike deep belief networks (spike-DBNs) address these limitations by capturing the change in time-varying signals and reducing resource consumption, but they sacrifice accuracy. To overcome these limitations, we propose integrating an event-driven approach into spike-DBNs through the Latency-Rate coding method and the reward-STDP learning rule. The encoding method enhances the event representation capability, while the learning rule focuses on the global behavior of spiking neurons triggered by events. Our proposed method not only maintains low resource consumption but also improves the fault diagnosis ability of spike-DBNs. We conducted a series of experiments to verify our model's performance, and the results demonstrate that our proposed method improves the accuracy of fault classification of manipulators and reduces learning time by nearly 76% compared to spike-CNN under the same conditions.

Integrated analysis reveals common DNA methylation patterns of alcohol-associated cancers: A pan-cancer analysis.

Background: The role of alcohol in carcinogenesis has received increasing attention in recent years. Evidence shows its impacts on various aspects, including epigenetics alteration. The DNA methylation patterns underlying alcohol-associated cancers are not fully understood. Methods: We investigated the aberrant DNA methylation patterns in four alcohol-associated cancers based on the Illumina HumanMethylation450 BeadChip. Pearson coefficient correlations were identified between differential methylated CpG probes and annotated genes. Transcriptional factor motifs were enriched and clustered using MEME Suite, and a regulatory network was constructed. Results: In each cancer, differential methylated probes (DMPs) were identified, and 172 hypermethylated and 21 hypomethylated pan-cancer DMPs (PDMPs) were examined further. Annotated genes significantly regulated by PDMPs were investigated and enriched in transcriptional misregulation in cancers. The CpG island chr19:58220189-58220517 was hypermethylated in all four cancers and silenced in the transcription factor ZNF154. Various biological effects were exerted by 33 hypermethylated and seven hypomethylated transcriptional factor motifs grouped into five clusters. Eleven pan-cancer DMPs were identified to be associated with clinical outcomes in the four alcohol-associated cancers, which might provide a potential point of view for clinical outcome prediction. Conclusion: This study provides an integrated insight into DNA methylation patterns in alcohol-associated cancers and reveals the corresponding features, influences, and potential mechanisms.

Assessing Healthy Aging Score and Its Association With All-Cause Mortality: Findings From the China Health and Retirement Longitudinal Study.

Background and Objectives: To construct a comprehensive healthy aging score (HAS) and explore its association with all-cause mortality and its potential interactions with other demographics on mortality. Research Design and Methods: This study included 5,409 participants aged ≥60 years from the China Health and Retirement Longitudinal Study. An HAS was constructed based on three dimensions of healthy aging including intrinsic capacity (IC), environmental support (ES), and chronic disease (CD), which were assessed at baseline, and categorized by tertiles (poor, moderate, and high). Participants were followed up biennially for all-cause mortality through the death registration or family interview from 2011 to 2018. Data were analyzed using Cox regression, Laplace regression, and receiver-operating characteristic analysis. Results: During 7 years of follow-up, 877 (16.21%) participants died. An HAS was constructed based on the cognition, mobility, and instrumental activity of daily living in the IC dimension; housing in the ES dimension; and hypertension, diabetes, chronic lung disease, stroke, and cancer in the CD dimension, which was associated with death. HAS seems a good predictor of all-cause mortality, with an area under the curve of 0.749. The hazard ratios and 95% confidence intervals for all-cause mortality related to moderate and poor HAS (vs high HAS) were 1.26 (1.01-1.56) and 2.38 (1.94-2.91), respectively. The median survival time was 2.46 years shorter in participants with poor HAS than those with high HAS. There were significant additive interactions of HAS with age, sex, and marital status on death. Discussion and Implications: Poor HAS may increase mortality and shorten survival, especially among older, male, and single adults.

Transition metal-doped germanium oxide nanozyme with enhanced enzyme-like activity for rapid detection of pesticide residues in water samples.

Designing highly active nanozymes for bioanalysis and environmental sensing remains a challenge. In this study, transition metal, palladium (Pd) and iron (Fe), doped germanium oxide (GeO2) nanozyme was designed and optimized. Compared with the pristine GeO2 nanozyme, the transition metal doped GeO2 nanozyme have lower Michaelis-Menten constants and higher catalytic activity, indicating that the Pd and Fe doped GeO2 nanozyme not only enhance their affinity for the substrate but also improve its catalytic activity. In addition, a colorimetric sensor based on the GeO2@Pd-H2O2-TMB system was constructed for the visual detection of simazine in water samples due to the good affinity between TMB and simazine. This sensor has good selectivity and sensitivity with a detection limit of 6.21 µM because of the highest catalytic performance of GeO2@Pd nanozyme. This study broadens the application of nanozymes in environmental field and other nanozymes can also be enhanced in activity by simple transition metal doping.

MFG-E8 stabilized by deubiquitinase USP14 suppresses cigarette smoke-induced ferroptosis in bronchial epithelial cells.

Milk fat globule epidermal growth factor 8 (MFG-E8) participates in a range of cellular processes, including reducing apoptosis and oxidative stress. However, its protective activity against cigarette smoke-induced ferroptosis in the pathogenesis of the chronic obstructive pulmonary disease (COPD) and the modulation of MFG-E8 remain unclear. Here, we showed that cigarette smoke diminished MFG-E8 protein levels but had no significant effect on its mRNA levels in lung tissues of humans and mice and in two human bronchial epithelial cell lines. MFG-E8 could attenuate ferroptosis induced by cigarette smoke extract (CSE) in vivo and in vitro. We identified ubiquitin-specific protease 14 (USP14) as a deubiquitinase of MFG-E8 in human bronchial epithelial cells. USP14 interacted with, deubiquitinated and stabilized MFG-E8. Furthermore, USP14 inhibited CSE-induced MFG-E8 proteasomal degradation. USP14 expression downregulated by CSE decreased MFG-E8 abundance and further reduced the antiferroptotic effect of MFG-E8. These findings suggest that USP14 is an essential regulator of MFG-E8 through the proteasomal pathway and that the USP14/MFG-E8 axis plays a critical role in regulating CSE-induced ferroptosis of bronchial epithelial cells.

Taxifolin ameliorates cigarette smoke-induced chronic obstructive pulmonary disease via inhibiting inflammation and apoptosis.

Chronic obstructive pulmonary disease (COPD) is a significant cause of morbidity and mortality worldwide and is characterized by chronic airway inflammation and lung parenchymal cell apoptosis. Cigarette smoke is the major risk factor for the occurrence and development of COPD. Taxifolin (TAX) showed promising pharmacological effects in the management of inflammation, oxidative stress, and apoptosis. In the present study, our results demonstrated that TAX significantly alleviated cigarette smoke-induced inflammation and apoptosis both in vivo and in vitro. TAX notably lowered the elevated total cell count in mouse BALF compared with that in the COPD group. The cigarette smoke-induced emphysematous changes were remarkably reversed by TAX. In addition, treatment with TAX suppressed the elevated mRNA and protein levels of IL-1ß, IL-6 and TNF-α in COPD mouse lung tissue and cigarette smoke extract (CSE)-treated human bronchial epithelial cells (HBECs). Additionally, TAX significantly decreased the ratios of p-iκB to iκB and p-p65 to p65 compared with the COPD group and CSE-treated HBECs. Moreover, the results of the TUNEL assay and flow cytometry also demonstrated the anti-apoptotic effect of TAX in mouse lung tissue and HBECs. Furthermore, the elevated Bax and CCP3 levels and decreased Bcl-2 levels induced by cigarette smoke were significantly reversed by TAX treatment in vivo and in vitro. Our results highlight the ameliorating effects of TAX against cigarette smoke-induced inflammation and apoptosis in the pathogenesis of COPD.

Efficient and recyclable degradation of organic dye pollutants by CeO2@ZIF-8 nanozyme-based non-photocatalytic system.

Advanced oxidation processes-based catalysis system as the most typical pollutant degradation technology always suffer from poor durability and photo-dependent. Inspired by the fact that some nanomaterials exhibit catalytic properties closer to natural enzymes, a high peroxidase-like activity and stability CeO2@ZIF-8 nanozyme was synthesized in this study for non-photodegradation of dyes pollution. Multiple characterization techniques were applied to prove the successful synthesis of the nanozyme. The influence of different parameters on the catalytic degradation of organic dye by nanozyme was investigated. This nanozyme achieved a maximum degradation efficiency of 99.81% for methyl orange and maintained its catalytic performance in repeated experiments. Possible degradation intermediates and pathways for methyl orange were then proposed. In addition, the CeO2@ZIF-8 loaded starch/agarose films were prepared for the portable and recyclable remediation of real dye wastewater, which maintained more than 80% degradation efficiency after 5 successive cycles. These results suggested that nanozyme based non-photocatalytic system is a potential catalyst for dye degradation and it opens a new avenue to develop high-performance and recyclable catalysts for pollutant remediation.

Genomic profiling of relapsed small cell lung cancer reveals potential pathways of therapeutic targets.

Background: Almost all patients with small cell lung cancer (SCLC) relapse. The therapeutic options of relapsed SCLC are limited, and the clinical outcomes are poor. Thus, genomic profiling of relapsed SCLC patients may help to develop more effective therapeutic options. Methods: We collected blood specimens and follow-up information from a consecutive cohort of 31 patients diagnosed with relapsed SCLC in Zhongnan Hospital, Wuhan University, between 2018 and 2019, to analyze the comprehensive genomic profiling, and to investigate the impact of genomic alterations on therapeutic options and survival. Results: In our cohort of relapsed SCLC, the median number of genomic alterations was 5 (range, 1-11) per sample. The majority of patients were defined as low tumor mutation burden (TMB; 83.9%) and microsatellite stability (MSS; 87.1%). Immune checkpoint inhibitors (ICIs)-based treatment still brought considerable progression-free survival (PFS; 4.93-20.27 months) for patients with low TMB and MSS. Additionally, the most frequent genetic alterations observed in relapsed SCLC were TP53 (77%) and RB1 (52%). Other genomic alterations of high frequency were breast cancer 2 (BRCA2) (32%), ataxia telangiectasia mutated (ATM) (13%), epidermal growth factor receptor (EGFR) (10%), Notch receptor 1 (NOTCH1) (10%), and Fanconi anemia complementation group A (FANCA) (10%), in turn. Finally, based on the survival of therapeutic strategies targeting potential mutation genes, the role of genotyping in relapsed SCLC was confirmed. Conclusions: Our studies first exhibited comprehensive genomic profiling of relapsed SCLC, identifying several candidate genes, and briefly analyzed the association of survival and genomic alterations. Our data from a small cohort of relapsed SCLC will benefit further exploration the potential targets or biomarkers.

Prediction of radiosensitivity and radiocurability using a novel supervised artificial neural network.

BACKGROUND: Radiotherapy has been widely used to treat various cancers, but its efficacy depends on the individual involved. Traditional gene-based machine-learning models have been widely used to predict radiosensitivity. However, there is still a lack of emerging powerful models, artificial neural networks (ANN), in the practice of gene-based radiosensitivity prediction. In addition, ANN may overfit and learn biologically irrelevant features. METHODS: We developed a novel ANN with Selective Connection based on Gene Patterns (namely ANN-SCGP) to predict radiosensitivity and radiocurability. We creatively used gene patterns (gene similarity or gene interaction information) to control the "on-off" of the first layer of weights, enabling the low-dimensional features to learn the gene pattern information. ANN-SCGP was trained and tested in 82 cell lines and 1,101 patients from the 11 pan-cancer cohorts. RESULTS: For survival fraction at 2 Gy, the root mean squared errors (RMSE) of prediction in ANN-SCGP was the smallest among all algorithms (mean RMSE: 0.1587-0.1654). For radiocurability, ANN-SCGP achieved the first and second largest C-index in the 12/20 and 4/20 tests, respectively. The low dimensional output of ANN-SCGP reproduced the patterns of gene similarity. Moreover, the pan-cancer analysis indicated that immune signals and DNA damage responses were associated with radiocurability. CONCLUSIONS: As a model including gene pattern information, ANN-SCGP had superior prediction abilities than traditional models. Our work provided novel insights into radiosensitivity and radiocurability.

An integrative analysis of DNA methylation and gene expression to predict lung adenocarcinoma prognosis.

Background: Abnormal DNA methylation of gene promoters is an important feature in lung adenocarcinoma (LUAD). However, the prognostic value of DNA methylation remains to be further explored. Objectives. We sought to explore DNA methylation characteristics and develop a quantifiable criterion related to DNA methylation to improve survival prediction for LUAD patients. Methods: Illumina Human Methylation450K array data, level 3 RNA-seq data and corresponding clinical information were obtained from TCGA. Cox regression analysis and the Akaike information criterion were used to construct the best-prognosis methylation signature. Receiver operating characteristic curve analysis was used to validate the prognostic ability of the DNA methylation-related feature score. qPCR was used to measure the transcription levels of the identified genes upon methylation. Results: We identified a set of DNA methylation features composed of 11 genes (MYEOV, KCNU1, SLC27A6, NEUROD4, HMGB4, TACR3, GABRA5, TRPM8, NLRP13, EDN3 and SLC34A1). The feature score, calculated based on DNA methylation features, was independent of tumor recurrence and TNM stage in predicting overall survival. Of note, the combination of this feature score and TNM stage provided a better overall survival prediction than either of them individually. The transcription levels of all the hypermethylated genes were significantly increased after demethylation, and the expression levels of 3 hypomethylated proteins were significantly higher in tumor tissues than in normal tissues, as indicated by immunohistochemistry data from the Human Protein Atlas. Our results suggested that these identified genes with prognostic features were regulated by DNA methylation of their promoters. Conclusion: Our studies demonstrated the potential application of DNA methylation markers in the prognosis of LUAD.