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Background: Esophageal squamous cell carcinoma (ESCC) is a deadly type of esophageal cancer. Programmed cell death (PCD) is an important pathway of cellular self-extermination and is closely involved in cancer progression. A detailed study of its mechanism may contribute to ESCC treatment. Methods: We obtained expression profiling data of ESCC patients from public databases and genes related to 12 types of PCD from previous studies. Hub genes in ESCC were screened from PCD-related genes applying differential expression analysis, machine learning analysis, linear support vector machine (SVM), random forest and Least Absolute Shrinkage and Selection Operator (LASSO) regression analysis. In addition, based on the HTFtarget and TargetScan databases, transcription factors (TFs) and miRNAs interacting with the hub genes were selected. The relationship between hub genes and immune cells were analyzed using the CIBERSORT algorithm. Finally, to verify the potential impact of the screened hub genes on ESCC occurrence and development, a series of in vitro cell experiments were conducted. Results: We screened 149 PCD-related DEGs, of which five DEGs (INHBA, LRRK2, HSP90AA1, HSPB8, and EIF2AK2) were identified as the hub genes of ESCC. The area under the curve (AUC) of receiver operating characteristic (ROC) curve of the integrated model developed using the hub genes reached 0.997, showing a noticeably high diagnostic accuracy. The number of TFs and miRNAs regulating hub genes was 105 and 22, respectively. INHBA, HSP90AA1 and EIF2AK2 were overexpressed in cancer tissues and cells of ESCC. Notably, INHBA knockdown suppressed ECSS cell migration and invasion and altered the expression of important apoptotic and survival proteins. Conclusion: This study identified significant molecules with promising accuracy for the diagnosis of ESCC, which may provide a new perspective and experimental basis for ESCC research.
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Apoptose , Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Regulação Neoplásica da Expressão Gênica , MicroRNAs , Humanos , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas do Esôfago/genética , Carcinoma de Células Escamosas do Esôfago/patologia , Carcinoma de Células Escamosas do Esôfago/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Apoptose/genética , Perfilação da Expressão Gênica , Proteínas de Choque Térmico HSP90/genética , Proteínas de Choque Térmico HSP90/metabolismo , Linhagem Celular Tumoral , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Movimento Celular/genética , Proliferação de Células/genéticaRESUMO
OBJECTIVES: To screen programmed cell death (PCD)-related genes in esophageal squamous cell carcinoma (ESCC) based on transcriptomic data and to explore its clinical value. METHODS: Differentially expressed PCD genes (DEPCDGs) were screened from ESCC transcriptome and clinical data in TCGA database. Univariate COX and LASSO COX were performed on prognostically DEPCDGs in ESCC to develop prognostic model. Differences in immune cell infiltration in different RiskScore groups were determined by ssGSEA and CIBERSORT. The role of RiskScore in immunotherapy response was explored using Tumor Immune Dysfunction and Exclusion (TIDE) and IMvigor210 cohorts. RESULTS: Fourteen DEPCDGs associated with prognosis were tapped in ESCC. These DEPCDGs form a RiskScore with good predictive performance for prognosis. RiskScore demonstrated excellent prediction accuracy in three data sets. The abundance of M2 macrophages and Tregs was higher in the high RiskScore group, and the abundance of M1 macrophages was higher in the low RiskScore group. The RiskScore also showed good immunotherapy sensitivity. RT-qPCR analysis showed that AUP1, BCAP31, DYRK2, TAF9 and UBQLN2 were higher expression in KYSE-150 cells. Knockdown BCAP31 inhibited migration and invasion. CONCLUSION: A prognostic risk model can predict prognosis of ESCC and may be a useful biomarker for risk stratification and immunotherapy assessment.
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Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Regulação Neoplásica da Expressão Gênica , Transcriptoma , Humanos , Prognóstico , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas do Esôfago/genética , Carcinoma de Células Escamosas do Esôfago/patologia , Perfilação da Expressão Gênica , Imunoterapia/métodos , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Apoptose , Bases de Dados Genéticas , Linhagem Celular TumoralRESUMO
BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is a highly fatal malignancy with increasing incidence, and programmed cell death (PCD) plays an important role in homeostasis. AIMS: This study aimed to explore the ESCC of heterogeneity based on the PCD signatures for the diagnosis and treatment of patients. METHODS: The clinical information and RNA-seq data of patients with ESCC and the PCD-related genes set were used to identify PCD signatures.The "limma" package was used to identify the differentially expressed genes (DEGs). "Clusterprofiler" package was used for function enrichment analysis, and the "ConsensusClusterPlus" package was performed for consensus clustering. Finally, the "GSVA" package and the Cibersort algorithm were used for the immune infiltration analysis. RESULTS: We performed differential expression analysis between ESCC and normal samples and identified 1659 DEGs, of which 124 DEGs were PCD genes. Then, the patients were divided into cluster1 and cluster2 based on the expression of 124 PCD genes. There was a significant difference in immune infiltration between the two clusters. The patients in cluster 1 had a higher immune score and more CD56dim natural killer cells, monocytes, activated CD4 T cells, eosinophil, and activated B cells infiltration, while cluster2 had a higher stromal score, more immune regulation, and immune checkpoint genes expression. CONCLUSION: We identified two clusters based on PCD gene expression and characterized their tumor microenvironment and immune checkpoint difference. Our findings may provide some new insight into the treatment of ESCC.
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Micro/nano photonic barcoding has emerged as a promising technology for information security and anti-counterfeiting applications owing to its high security and robust tamper resistance. However, the practical application of conventional micro/nano photonic barcodes is constrained by limitations in encoding capacity and identification verification (e.g., broad emission bandwidth and the expense of pulsed lasers). Herein, we propose high-capacity photonic barcode labels by leveraging continuous-wave (CW) pumped monolayer tungsten disulfide (WS2) lasing. Large-area, high-quality monolayer WS2 films were grown via a vapor deposition method and coupled with external cavities to construct optically pumped microlasers, thus achieving an excellent CW-pumped lasing with a narrow linewidth (~0.39 nm) and a low threshold (~400 W cm-2) at room temperature. Each pixel within the photonic barcode labels consists of closely packed WS2 microlasers of varying sizes, demonstrating high-density and nonuniform multiple-mode lasing signals that facilitate barcode encoding. Notably, CW operation and narrow-linewidth lasing emission could significantly simplify detection. As proof of concept, a 20-pixel label exhibits a high encoding capacity (2.35 × 10108). This work may promote the advancement of two-dimensional materials micro/nanolasers and offer a promising platform for information encoding and security applications.
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As p-type phase-change degenerate semiconductors, crystalline and amorphous germanium telluride (GeTe) exhibit metallic and semiconducting properties, respectively. However, the massive structural defects and strong interface scattering in amorphous GeTe films significantly reduce their performance. In this work, two-dimensional (2D) p-type GeTe nanosheets are synthesized via a specially designed space-confined chemical vapor deposition (CVD) method, with the thickness of the GeTe nanosheets reduced to 1.9 nm. The space-confined CVD method improves the crystallinity of ultrathin GeTe by lowering the partial pressure of the reactant gas, resulting in GeTe nanosheets with excellent p-type semiconductor properties, such as a satisfactory on/off ratio of 105. Temperature-dependent electrical measurements demonstrate that variable-range hopping and optical-phonon-assisted hopping mechanisms dominate transport behavior at low and high temperatures, respectively. GeTe devices exhibit significantly high responsivity (6589 and 2.2 A W-1 at 633 and 980 nm, respectively) and detectivity (1.67 × 1011 and 1.3 × 108 Jones at 633 and 980 nm, respectively), making them feasible for broadband photodetectors in the visible to near-infrared range. Furthermore, the fabricated GeTe/WS2 diode exhibits a rectification ratio of 103 at zero gate voltage. These satisfactory p-type semiconductor properties demonstrate that ultrathin GeTe exhibits enormous potential for applications in optoelectronic interconnection circuits.
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Developing multi-functional electrocatalysts is of great practical significance for fuel cells and water splitting. Herein, Rh-Rh2O3 nanoclusters are prepared and the surface oxygen vacancy content is regulated elaborately by post-treatment. The optimized Rh-Rh2O3/C-400 exhibits superior trifunctional catalytic activity for hydrogen oxidation reaction (HOR), hydrogen evolution reaction (HER) and hydrazine oxidation reaction (HzOR), i.e., the mass activity for HOR is 2.29 mA µgRh-1, and the overpotential for HER and HzOR at 10 mA cm-2 is as low as 12 mV and 31 mV, respectively, superior to the benchmark Pt/C. Rh-Rh2O3/C-400 also displays promising performance in practical devices, with the H2-O2 anion-exchange-membrane fuel cell delivering a peak power density of 0.66 W cm-2, and the hydrazine-assisted water splitting electrolyzer requiring a low electrolysis voltage of 0.161 V at 0.1 A cm-2. The experimental and theoretical investigations discover that the hydrogen binding energy (HBE) is linearly depended on surface oxygen vacancy contents, and the HBE directly determines the catalytic activity for HOR, HER and HzOR. This work not only innovates an efficient Rh-based nanocluster tri-functional electrocatalyst, but also eludicates the intrinsic relationship of surface structure-intermediate adsorption-catalytic activity.
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The ataxia telangiectasia mutated and rad3-related (ATR) kinase regulates the DNA damage response (DDR), which plays a critical role in the ATR-Chk1 signaling pathway. ATR inhibition can induce synthetic lethality (SL) with several DDR deficiencies, making it an attractive drug target for cancers with DDR defects. In this study, we developed a series of selective and potent ATR inhibitors with a thieno[3,2-d]pyrimidine scaffold using a hybrid design. We identified compound 34 as a representative molecule that inhibited ATR kinase with an IC50 value of 1.5 nM and showed reduced potency against other kinases tested. Compound 34 also exhibited potent antiproliferative effects against LoVo cells and SL effects against HT-29 cells. Moreover, compound 34 demonstrated good pharmacokinetic properties, in vivo antitumor efficacy, and no obvious toxicity in the LoVo xenograft tumor model. Therefore, compound 34 is a promising lead compound for drug development to combat specific DDR deficiencies in cancer patients.
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Ataxia Telangiectasia , Neoplasias , Humanos , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Transdução de Sinais , Dano ao DNARESUMO
Targeting ataxia telangiectasia mutated and Rad3-related (ATR) kinase is being pursued as a new therapeutic strategy for the treatment of advanced solid tumor with specific DNA damage response deficiency. Herein, we report a series of pyrido[3,2-d]pyrimidine derivatives with potent ATR inhibitory activity through structure-based drug design. Among them, the representative compound 10q exhibited excellent potency against ATR in both biochemical and cellular assays. More importantly, 10q exhibited good liver microsomes stability in different species and also showed moderate inhibitory activity against HT-29 cells in combination treatment with the ATM inhibitor AZD1390. Thus, this work provides a promising lead compound against ATR for further study.
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Desenho de Fármacos , Inibidores de Proteínas Quinases , Proteínas Mutadas de Ataxia Telangiectasia , Pirimidinas/farmacologiaRESUMO
Insufficient evidence exists regarding the effects of microplastics (MPs) on the neuronal toxicity of heavy metals in the early stages of organisms. Herein, the effects of micro-polystyrene (µ-PS; 157 µm) and nano-polystyrene (n-PS; 100 nm) particles on the neurodevelopmental toxicity of mercury (Hg) in zebrafish embryos were compared. Zebrafish embryos exposed to Hg at the concentration of 0.1 mg L-1 revealed blood disorders, delayed hatching, and malformations such as pericardial oedema and tail deformity. The length of the larval head was significantly reduced (P < 0.01) and in vivo expression of atoh1a in the cerebellum of neuron-specific transgenic zebrafish Tg(atoh1a:dTomato) larvae was inhibited by 29.46% under the Hg treatment. Most of the toxic effects were inhibited by the combined exposure to µ-PS or n-PS with Hg, and n-PS decreased the neurodevelopmental toxicity of Hg more significantly than µ-PS. Metabolomic analysis revealed that in addition to inhibiting the amino acid metabolism pathway as in the µ-PS+Hg treatment, the n-PS+Hg treatment inhibited unsaturated fatty acid metabolism in zebrafish larvae, likely because of a greater reduction in Hg bioavailability, thus reducing the oxidative damage caused by Hg in the larvae. The combined effects of MPs and heavy metals differ greatly among different species and their targeted effects. We conclude that the combined toxicity mechanisms of MPs and heavy metals require further clarification.
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Mercúrio , Metais Pesados , Poluentes Químicos da Água , Animais , Microplásticos , Peixe-Zebra/metabolismo , Poliestirenos/toxicidade , Plásticos/metabolismo , Larva , Mercúrio/toxicidade , Mercúrio/metabolismo , Poluentes Químicos da Água/metabolismo , Metais Pesados/metabolismo , Ácidos Graxos Insaturados/metabolismo , Aminoácidos/metabolismoRESUMO
Microplastics (MPs) have become a hot issue of environmental pollution. However, insufficient evidence exists regarding the distributions and fates of MPs in terrestrial environment, especially in farmlands. The distributions of MPs in paddy fields were investigated in Xiangtan City, a typical rice production area in China. The abundance of MPs in paddy seedling raising fields was 3805 ± 511 n·kg-1, which increased by approximately 9 times than that in common paddy fields. Transparent films became the dominant forms due to the huge usage of mulching films, corresponding to that the proportion of polyvinyl chloride (PVC) increased to 17% there. Moreover, an industrial plant nearby also contributed considerably to the MP pollution; the proportion of PVC (33%) in the paddy fields nearby increased to approximately 4 times of common paddy fields, while polyvinyl alcohol (PVA; 13%) used as an important chemical raw material to synthesis in various applications was uniquely detected there. These results highlight the input of MPs from agricultural and industrial activities in farmlands. Their contributions to the MP pollution in farmlands should be continuously investigated.
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Microplásticos , Poluentes Químicos da Água , Plásticos , Cloreto de Polivinila , Álcool de Polivinil , Monitoramento Ambiental , Poluentes Químicos da Água/análise , Poluição Ambiental , ChinaRESUMO
Vanadium flow battery (VFB) is one of the most promising candidates for large-scale energy storage. A modified polyacrylonitrile (PAN) porous membrane is successfully applied in VFB. Herein, a simple solvent post-processing method is presented to modify PAN porous membranes prepared by the traditional nonsolvent induced phase separation (NIPS) method. In the design, polymer PAN is chosen as the membrane material owing to its low cost and high stability. The large-size pores from NIPS method are well optimized by the solvent swelling and shrinking during the solvent post-processing. Meanwhile, the interconnectivity of pores is maintained well. As a result, the ion selectivity of PAN porous membranes is dramatically improved, and the CE of a VFB with PAN porous membranes rises from 68% to 93% after the solvent post-processing process. A VFB with the modified PAN porous membranes is capable of delivering a limiting current density of 900 mA cm-2, and a high peak power density of 650 mW cm-2, which is very competitive among the various flow batteries.
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The ingestion of petroleum-based microplastics (MPs) by aquatic animals and their toxicological effects are of wide concern. However, the ecological risks of bio-based MPs to aquatic animals remain largely unknown. In the present study, zebrafish (Danio rerio) were exposed to MPs of polylactic acid (PLA), the most widely used bio-based plastic, and polyethylene terephthalate (PET), a high-production volume petroleum-based plastic. PLA MPs were more actively ingested by fish than PET MPs. The abundance of PLA MPs in fish intestines was approximately 170 times greater than that of PET MPs after one day of exposure. The ingestion of PLA MPs caused gastrointestinal damage in zebrafish. In addition, the ingestion of PLA MPs induced specific changes in the diversity of intestinal microbiota and promoted species closely linked with energy metabolism, cellular processes, and fish diseases. This might have been related to the depolymerization of PLA in the digestive tract, which decreased the intestinal pH and changed the carbon source structure. Overall, bio-based MPs may have different ecological effects on aquatic animals than traditional petroleum-based MPs.
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Microbiota , Poluentes Químicos da Água , Animais , Dieta , Disbiose/induzido quimicamente , Intestinos/química , Microplásticos/toxicidade , Plásticos/toxicidade , Poliésteres/toxicidade , Poluentes Químicos da Água/análise , Poluentes Químicos da Água/toxicidade , Peixe-ZebraRESUMO
Nanoplastics in aquatic environments may induce adverse immunotoxicity effects in fish. However, there is insufficient evidence on the visible immunotoxicity endpoints in the larval stages of fish. The liver plays an important role in systemic and local innate immunity in the fish. In this study, the hepatic inflammatory effects of polystyrene (PS) nanoplastic particles (NPs: 100 and 50 nm) and micron PS particles on transgenic zebrafish (Danio rerio) larvae were estimated using fluorescent-labeled neutrophils, macrophages, and liver-type inflammatory binding protein (fabp10a). Particles with smaller size induced higher aggregations of neutrophils and apoptosis of macrophages in the abdomen of the larvae, corresponding to greater hepatic inflammation in the larvae. NPs increased the expression of fabp10a in the larval livers in a dose- and size-dependent manner. PS particles of 50 nm at a concentration of 0.1 mg·L-1 increased the expression of fabp10a in the larval liver by 21.90% (P < 0.05). The plausible mechanisms of these effects depend on their distribution and the generation of reactive oxygen species in the larvae. Metabonomic analysis revealed that the metabolic pathways of catabolic processes, amino acids, and purines were highly promoted by NPs, compared to micron PS particles. NPs also activate steroid hormone biosynthesis in zebrafish larvae, which may lead to the occurrence of immune-related diseases. For the first time, the liver was identified as the target organ for the immunotoxicity effects of NPs in the larval stage of fish.
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Poluentes Químicos da Água , Peixe-Zebra , Abdome , Animais , Larva , Fígado , Microplásticos/toxicidade , Poliestirenos/metabolismo , Poliestirenos/toxicidade , Poluentes Químicos da Água/metabolismo , Peixe-Zebra/metabolismoRESUMO
Insufficient evidence exists regarding the visible physiological toxic endpoints of MPs exposures on zebrafish larvae due to their small sizes. Herein, the impacts of micro-polystyrene particles (µ-PS) and 100 nm polystyrene particles (n-PS) on the toxicity of cadmium (Cd) through altering neutrophil expressions were identified and quantified in the transgenic zebrafish (Danio rerio) larvae Tg(lyz:DsRed2), and the effects were size-dependent. When exposed together with µ-PS, the amount of neutrophils in Cd treated zebrafish larvae decreased by 25.56% through reducing Cd content in the larvae. By contrast, although n-PS exposure caused lower Cd content in the larvae, the expression of neutrophils under their combined exposure remained high. The mechanism of immune toxicity was analyzed based on the results of metabonomics. n-PS induced high oxidative stress in the larvae, which promoted taurine metabolism and unsaturated fatty biosynthesis in n-PS + Cd treatment. This observation was accordance with the significant inhibition of the activities of superoxide dismutase and catalase enzymes detected in their combined treatment. Moreover, n-PS promoted the metabolic pathways of catabolic processes, amino acid metabolism, purine metabolism, and steroid hormone biosynthesis in Cd treated zebrafish larvae. Nanoplasctis widely coexist with other pollutants in the environment at relatively low concentrations. We conclude that more bio-markers of immune impact should be explored to identify their toxicological mechanisms and mitigate the effects on the environment.
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Microplásticos , Poluentes Químicos da Água , Animais , Cádmio/toxicidade , Larva , Neutrófilos , Plásticos , Poliestirenos/toxicidade , Poluentes Químicos da Água/toxicidade , Peixe-ZebraRESUMO
Toxicity of microplastics (MPs) in granular form to aquatic animals has been frequently tested, whereas the effects of fibrous MPs remain further explored. In this study, the effects of polyethylene terephthalate granular particles (p-PET, approximately 150 µm in diameter) and fibers (f-PET, approximately 3-5 mm in length and 20 µm in diameter) on the development of zebrafish embryos and their joint effects with cadmium (Cd) were compared. p-PET and f-PET accelerated the velocities of blood flow and heart rate and inhibited hatching in zebrafish embryos because of their barrier effects on the channels in the embryonic chorion and enhanced the mechanical strength of the chorion. The Cd content in the chorion increased by p-PET due to the adsorption of p-PET on the chorion. By contrast, more f-PET dissociated in culture medium and resulted in low Cd content in the chorion. Given that chorion can effectively block p-PET and f-PET, the Cd accumulation in eggs significantly decreased (p < 0.05) under p-PET/f-PET and Cd combined treatment because of the reduction in the bioavailability of Cd. Therefore, p-PET and f-PET decreased the toxicities of Cd on all the target endpoints in this study, and the detoxification effect of f-PET at 72 hpf was more significant than that of p-PET. These results suggest that the toxicity induced by MPs might be form-related.
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Microplásticos , Poluentes Químicos da Água , Animais , Cádmio/toxicidade , Córion , Embrião não Mamífero , Plásticos/toxicidade , Poluentes Químicos da Água/toxicidade , Peixe-ZebraRESUMO
Micro-plastics (MPs) pollution has been a hotspot in soil environment. To explore the correlation of the vegetation cover and the distribution of MPs in Yellow River Delta wetland, the characters of MPs in the soil sampled at 16 sites where reed (Phragmites communis, a low-salt dominant species) and Suaeda salsa (a high-salt dominant species) covered were investigated. The abundance of MPs here ranged to 80-4640 n·kg-1, and the particle size ranged to 13 µm-5 mm. The main components of MPs with large size were polyethylene (PE), polyethylene terephthalate (PET) and polystyrene (PS), and the content of PET ranged to 0.22-1.16 µg·kg-1. The barrier effect of reed on MPs was higher than that of Suaeda salsa. The average abundance of MPs and PET contents at the sites where reed covered were 1423 n·kg-1 and 0.62 µg·kg-1, and they mainly consisted of small particles with a size less than 50 µm. The average abundance of MPs and PET contents at the site Suaeda salsa covered were 584 n·kg-1 and 0.33 µg·kg-1, and they mainly consisted of fragments and fibers with a size ranged to 100-1000 µm. The abundance of MPs in the soil was significantly correlated with the growth statues of the vegetations (P=0.001). Therefore, the distribution of MPs in the soil in the same area covered by different vegetation might be spatial different.