DNMT3A promotes glioma growth and malignancy via TNF-α/NF-κB signaling pathway.

Background: DNMT3A is the main molecule responsible for DNA methylation in cells. DNMT3A affects the progression of inflammation, degenerative diseases, and malignant tumors, and exhibits significant aberrantly expression in tumor tissues. Methods: Transcriptome data and relevant clinical information were downloaded from The Cancer Genome Atlas (TCGA), Chinese Glioma Genome Atlas (CGGA), and Gene Expression Omnibus (GEO) datasets. Differential expression analysis and prognostic analysis were conducted based on above statistics. We constructed a clinical prognostic model and identified DNMT3A as an independent prognostic factor to accurately predict patient prognosis. Differential gene enrichment analysis revealed that DNMT3A affects the progression of glioma through multiple pathways, among which the tumor necrosis factor-α (TNF-α)/nuclear factor-kappa B (NF-κB) pathway shows a strong correlation. Immunological analysis also revealed a certain correlation between DNMT3A and tumor immunity. We demonstrated through gene editing that DNMT3A can affect the release of TNF-α in cells, thereby affecting the progression of glioma. Functional experiments have also demonstrated that DNMT3A plays a crucial role in tumors. Results: RNA-sequencing and survival analyses of lower-grade glioma (LGG) patients in TCGA, CGGA, and GEO cohorts showed that high DNMT3A expression correlated with poor prognosis of LGG patients. Univariate and multivariate Cox regression analyses showed that DNMT3A expression was an independent prognostic indicator in LGG. The prognosis prediction nomogram with age, World Health Organization (WHO) grading, and DNMT3A expression showed reliable performance in predicting the 1-, 3-, and 5-year overall survival (OS) of LGG patients. Functional enrichment analysis, gene set enrichment analysis (GSEA), and ESTIMATE algorithm analyses showed that DNMT3A expression was associated with the tumor infiltration of immune cells and predicted response to immunotherapy in two immunotherapy cohorts of pan-cancer patients. Furthermore, short hairpin RNA (shRNA)-mediated knockdown of DNMT3A in the LGG cell lines suppressed proliferation, migration, and invasion of LGG cells by downregulating the TNF-α/NF-κB signaling pathway. Conclusions: Our data showed that DNMT3A was a potential prognostic biomarker in glioma. DNMT3A promoted proliferation and malignancy of LGG cells through the TNF-α/NF-κB signaling pathway. DNMT3A is a promising therapeutic target for treating patients with LGG.

Comprehensive analyses of m1A regulator-mediated modification patterns determining prognosis in lower-grade glioma (running title: m1A in LGG).

N1-methyladenosine (m1A) modification is a crucial post-transcriptional regulatory mechanism of messenger RNA (mRNA) in living organisms. Few studies have focused on analysis of m1A regulators in lower-grade gliomas (LGG). We employed the Nonnegative Matrix Factorization (NMF) technique on The Cancer Genome Atlas (TCGA) dataset to categorize LGG patients into 2 groups. These groups exhibited substantial disparities in terms of both overall survival (OS) and levels of infiltrating immune cells. We collected the significantly differentially expressed immune-related genes between the 2 clusters, and performed LASSO regression analysis to obtain m1AScores, and established an m1A-related immune-related gene signature (m1A-RIGS). Next, we categorized all patients with LGG into high- and low-risk subgroups, predictive significance of m1AScore was confirmed by conducting univariate/multivariate Cox regression analyses. Additionally, we confirmed variations in immune-related cells and ssGSEA and among the high-/low-risk subcategories in the TCGA dataset. Finally, our study characterized the effects of MSR1 and BIRC5 on LGG cells utilizing Edu assay and flow cytometry to explore the effects of modulation of these genes on glioma. The results of this study suggested that m1A-RIGS may be an excellent prognostic indicator for patients with LGG, and could also promote development of novel immune-based treatment strategies for LGG. Additionally, BIRC5 and MSR1 may be potential therapeutic targets for LGG.

Identifying the prognosis implication, immunotherapy response prediction value, and potential targeted compound inhibitors of integrin subunit α3 (ITGA3) in human cancers.

The integrin subunit α3 (ITGA3) is a member of the integrin alpha chain protein family, which could promote progression, metastasis, and invasion in some cancers. Still, its function in the tumor microenvironment (TME), cancer prognosis, and immunotherapy remains unclear. A multifaceted analysis of ITGA3 in pan-cancer utilizing various databases and online web tools revealed ITGA3 was aberrantly expressed in tumor tissues and upregulated in most cancers, which may be related to ITGA3 genomic alterations and methylation modification. In addition, ITGA3 was significantly correlated with the poor or better prognosis of cancer patients, immune-related pathways in hallmark, immune infiltration, and immune checkpoints, revealing a biological function of ITGA3 in the tumor progression, tumor microenvironment, and tumor immunity. We also found that ITGA3 could predict the response to tumor immunotherapy based on cytokine-treated samples and immunotherapy cohorts. ITGA3 may participate in shaping and regulating the tumor microenvironment to affect the tumor immune response, which was a promising immunotherapy response predictive biomarker and potential therapeutic target to work synergistically with cancer immunotherapy to boost the response and efficacy. Finally, potential targeted compound inhibitors and sensitive drugs were screened using databases ConnectivityMap (CMap) and CellMiner, and AutoDock Tools was used for molecular docking.

The link between neutrophils, neutrophil extracellular traps, and NLRP3 inflammasomes: The dual effect of CD177 and its therapeutic potential in acute respiratory distress syndrome/acute lung injury.

Neutrophils are important inflammatory effector cells that protect against foreign invasion but also cause self-harm. Numerous neutrophils infiltrate the lungs in acute respiratory distress syndrome/acute lung injury (ARDS/ALI) patients. However, the exact impact of neutrophil infiltration on ARDS's onset and progression remains unclear. To investigate this, we analyzed two ARDS-related datasets from the Gene Expression Omnibus public database and discovered an association between CD177, a neutrophil-specific surface protein, and ARDS progression. We used quantitative flow cytometry to assess CD177+ neutrophils in the peripheral blood of clinical ARDS patients versus healthy controls, finding a significant increase in CD177+ neutrophils percentage among total neutrophils in ARDS patients. This finding was further confirmed in ALI mouse models. Subsequent animal experiments showed that anti-CD177 effectively reduces pulmonary edema, neutrophil infiltration, and inflammatory cytokine release, along with a decrease in reactive oxygen species (ROS) and myeloperoxidase (MPO) levels. We also established an in vitro co-culture system to mimic neutrophil and lung epithelial cell interactions. In the anti-CD177 group, we observed decreased expression of NLRP3, caspase 1, PAD4, MPO, and ROS, along with a reduction in certain inflammatory cytokines. These results indicate a crucial role for the CD177 gene in ARDS's development and progression. Inhibiting CD177 may help mitigate excessive activation of NLRP3 inflammasomes, ROS, and neutrophil extracellular traps (NETs), thus alleviating ARDS.

Influence of A/B Element Substitution on Negative Thermal Expansion in AB(CN)6 (A = Al, Ga, In; B = Co, Fe, Mn, Cr, V, Ti): A Density Functional Theory Study.

Negative thermal expansion as an abnormal physical behavior of materials has promising applications in a high sophisticated equipment field, but the materials are rare. Here, we use the first-principles calculations based on density functional theory combined with the recently developed average atomic volume (AAV = V/N, where V is unit cell volume and N is the number of atoms in the unit) rule to predict the large isotropic negative thermal expansion materials of Prussian blue analogues AB(CN)6 (A = Al, Ga, In; B = Co, Fe, Mn, Cr, V, Ti) in a wide temperature range. Our results clearly show that the coefficient of negative thermal expansion has a near-linear relationship with the average atomic volume of the systems and is also influenced by the element substitution at the A or B site. Lattice dynamic simulations indicate that the main contribution to the negative thermal expansion comes from the low-frequency transverse vibration of the (B)-C≡N-(A) groups, especially the transverse vibration of the N atoms. Thus, the element substitution at the A site (binding to N) can tune the negative thermal expansion behavior of the systems more effectively than that at the B site (binding to C), indicating the different roles of bonds on the negative thermal expansion. Our present work not only expands the kinds of isotropic materials but also gives some insights into the relationship between the average atomic volume and negative thermal expansion.

Cost-effective, high-performance Ni3Sn4 electrocatalysts for methanol oxidation reaction in acidic environments.

Methanol (CH3OH) oxidation offers a promising avenue for transitioning to clean energy, particularly in the field of direct methanol fuel cells (DMFCs). However, the development of efficient and cost-effective catalysts for the methanol oxidation reaction (MOR) remains a critical challenge. Herein, we report the exceptional electrocatalytic activity and stability of Ni3Sn4 toward MOR in acidic media, achieving a performance comparable to that of commercial Pt/C catalysts. Our catalyst design incorporates Earth-abundant Ni and Sn elements, resulting in a material that is 1800 times more cost-effective than Pt/C. Density functional theory (DFT) modeling substantiates our experimental findings, shedding light on the favorable reaction mechanisms and kinetics on the Ni3Sn4 surface. Additionally, the as-synthesized Ni3Sn4 electrocatalyst demonstrates commendable durability, maintaining its electrocatalytic activity even after prolonged exposure to harsh acidic conditions.

Introducing non-bridging ligand in metal-organic framework-based electrocatalyst enabling reinforced oxygen evolution in seawater.

Using seawater as the replacement of freshwater for electrolysis, with the integration of renewable energy, is deemed as an attractive manner to harvest green hydrogen. However, the complexity of seawater puts forward stricter requirement to the electrocatalyst to alleviate the chlorine electrochemistry and corrosion. Herein, a nanosheet array of NiFe-MOF@Ni2P/Ni(OH)2 is devised by partially substituting terephthalic acid (H2BDC) ligand by ferrocenecarboxylic acid (FcCA). Tailoring the active site into an under-coordinated fashion affords NiFe-MOF@Ni2P/Ni(OH)2 excellent performance towards oxygen evolution reaction (OER), only requiring the overpotentials of 302 mV and 394 mV in alkaline seawater to drive the current densities of 100 and 1000 mA cm-2, respectively. Moreover, the as-obtained electrocatalyst showed robust durability for operating more than 120 h at 500 mA cm-2 under harsh condition (6 M KOH + 1.5 M NaCl, 60 ℃). Density functional theory (DFT) calculations confirmed that tuning the coordination environment of Ni in NiFe-MOF by incorporating the non-bridging FcCA ligands could boost the formation of more active catalytic sites, which can simultaneously enhance the electronic conductivity and accelerate OER kinetics. This work provides beneficial enlightenment of combining MOF-based electrocatalyst with direct electrolysis of seawater.

Identification of a robust scoring system based on metabolic genes followed by in-depth validation of ATP1A3 in glioma.

AIMS: In the past few decades, the prognosis of glioma patients has not significantly improved. Therefore, to provide more precise medical services for glioma patients, it is urgent to identify more clinically meaningful subtypes, establish more robust clinical prediction models, and find more effective therapeutic targets. MATERIALS AND METHODS: Four distinct metabolic-associated subtypes were identified by the NMF algorithm based on metabolic genes (MEGs). A robust scoring system was constructed based on the differentially expressed genes (DEGs) screened from the four metabolic-associated subtypes with the LASSO regression algorithm and multivariate Cox regression analysis. Further analysis of scoring systems was done by different R packages. In addition, the ATP1A3 gene was screened and bioinformatics analysis of it was conducted on several public websites. GSEA software was utilized to search hallmark signaling pathways closely related to ATP1A3. Cytological experiments were used to investigate the role of ATP1A3 in the malignant progression of glioblastoma (GBM) cells. KEY FINDINGS: Four metabolic-associated subtypes with significantly different clinicopathological characteristics were identified, and a robust scoring system with outstanding clinical application value was established. In addition, a tumor suppressor gene ATP1A3 was found, which is expected to be a potential therapeutic target for glioma. SIGNIFICANCE: This study is of great significance in the diagnosis, prognosis, and prediction of the response to immune checkpoint blockers (ICBs) for glioma patients. More importantly, this study found a potential therapeutic target for glioma.

Ferroptosis in tumor immunity and therapy.

Ferroptosis is a type of regulated cell death (RCD), and it plays an important role in the occurrence of diseases, especially the development of tumors. Ferroptosis of tumor cells affects the antitumor immunity and the immune response to treatment to varying degrees. Ferroptosis also plays a key role in immune cells. This review outlines the mechanism of the immune-related effects of ferroptosis pathways in tumor progression and treatment, and it discusses potential methods for improving antitumor immunity and enhancing the efficacy of current cancer treatments by targeting ferroptosis.

Comprehensive analysis of the prognostic implications and functional exploration of PAK gene family in human cancer.

BACKGROUND: The p21-activated kinase (PAK) family (PAKs) plays a key role in the formation and development of human tumors. However, a systematic analysis of PAKs in human cancers is lacking and the potential role of PAKs in cancer immunity has not been explored. METHODS: We used datasets from in The Cancer Genome Atlas (TCGA) database and Genotype-Tissue Expression database (GTEx). RESULTS: Based on TCGA datasets most PAKs show noteworthy differences in expression between tumors and corresponding normal tissues or across different tumor tissues. Patients with high expression of PAKs often show a worse prognosis. However, copy number variation, mutation, and DNA methylation of PAKs have limited impact on tumor development. Further analysis showed that the impact of PAKs on immunity varies with the type of tumor and the respective tumor microenvironment. PAK1 and PAK4 may be stronger predictors of immune characteristics, and are more suitable as drugs and molecular therapeutic targets. Furthermore, Cox regression analysis revealed that a PAK gene signature could be used as an independent prognostic factor for lower grade glioma (LGG) and glioblastoma (GBM). Gene set enrichment analysis (GSEA) analysis indicated that PAK genes may affect the occurrence and development of GBM through the PI3K signaling pathway. Further experiments verified that PAK1 and AKT1 have a significant interaction in GBM cells, and inhibiting the overactivation of PAK1 can significantly inhibit the proliferation of GBM cells. CONCLUSIONS: Our study provides a rationale for further research on the prognostic and therapeutic potential of PAKs in human tumors.

Immune Characteristics and Prognosis Analysis of the Proteasome 20S Subunit Beta 9 in Lower-Grade Gliomas.

Glioma is a common intracranial malignancy in adults and has a high mortality due to its poor prognosis and high recurrence rate. Dysregulation of protein degradation is one of the main promoting factors in glioma development. As an indispensable unit of the proteasome, Proteasome 20S Subunit Beta 9 (PSMB9) is one of the major enzymes in ubiquitin-dependent protein degradation in cells. In addition, proteasomes also participate in a series of cellular processing, like immune regulation, nerve signal transduction, material transport through channels, cell adhesion, and various signaling pathways. However, the relationship between the PSMB9 expression and the occurrence of lower-grade glioma (LGG) is still unknown. First, we collected the RNA-seq and clinical information about LGG clinical samples from The Cancer Genome Atlas (TCGA) cohort, Chinese Glioma Genome Atlas (CGGA; including CGGAseq1 and CGGAseq2) cohort, and Gene Expression Omnibus (GEO; GSE16011, GSE61374, and Rembrandt) cohort. Then, these data were used for differential analysis, survival analysis, enrichment analysis, clinical model construction, etc. In addition, we combine immune-related data for immune-related analysis, including immune infiltration and immunotherapy. Through the above research, we have provided a new biomarker for LGG prognosis prediction and more comprehensively explained the role of PSMB9 in the development of LGG. This study determined that PSMB9 can be used as an immunotherapy target through the analysis of immune data, providing new ideas for the clinical treatment of LGG.

Analysis of Carbonation Behavior of Cracked Concrete.

The crack and carbonation of concrete pose a great challenge to its durability. Therefore, this paper studies the effect of cracks on the carbonation depth of cement paste under different factors. The relationship between carbonation and cracks was determined, and the carbonation mechanism of cement paste with cracks was clarified. The results show that a small water-binder ratio can effectively inhibit the carbonation process. The bidirectional carbonation enlarged the carbonation area around the crack. Within 21 days of the carbonation, the carbonation depth increased with carbonation time, and the Ca(OH)2 on the surface of the specimen was sufficient, allowing for a convenient chemical reaction with CO2. The influence of crack width on the carbonation process at the crack was greater than the influence of the crack depth. Carbonation influenced the hydration of cement-based materials, altering the types and quantities of hydration products. In conclusion, accurately predicting the regularity of carbonation in cracked structures is critical for improving the durability of concrete.

DNAJC10 correlates with tumor immune characteristics and predicts the prognosis of glioma patients.

BACKGROUND: The role of DnaJ heat shock protein family (Hsp40) member C10 (DNAJC10) in cancers has been reported but its function in glioma is not clear. We reveal the prognostic role and underlying functions of DNAJC10 in glioma in the present study. METHODS: Reverse Transcription and Quantitative Polymerase Chain Reaction (RT-qPCR) was used to quantify the relative DNAJC10 messenger RNA (mRNA) expression of clinical samples. Protein expressions of clinical samples were tested by Western blot. The overall survival (OS) of glioma patients with different DNAJC10 expression was compared by Kaplan-Meier method (two-sided log-rank test). Single-sample gene set enrichment analysis (ssGSEA) was used to estimate the immune cell infiltrations and immune-related function levels. The independent prognostic role of DNAJC10 was determined by univariate and multivariate Cox regression analyses. The DNAJC10-based nomogram model was established using multivariate Cox regression by R package 'rms'. RESULTS: Higher DNAJC10 is observed in gliomas and it is up-regulated in higher grade, isocitrate dehydrogenase (IDH)-wild, 1p/19q non-codeletion, O(6)-methylguanine-DNA methyltransferase (MGMT) unmethylated gliomas. Gliomas with higher DNAJC10 expression present poorer prognosis compared with low-DNAJC10 gliomas. The predictive accuracy of 1/3/5-OS of DNAJC10 is found to be stable and robust using time-dependent ROC model. Enrichment analysis recognized that T-cell activation and T-cell receptor signaling were enriched in higher DNAJC10 gliomas. Immune/stromal cell infiltrations, tumor mutation burden (TMB), copy number alteration (CNA) burden and immune checkpoint genes (ICPGs) were also positively correlated with DNAJC10 expression in gliomas. DNAJ10-based nomogram model was established and showed strong prognosis-predictive ability. CONCLUSION: Higher DNAJC10 expression correlates with poor prognosis of glioma and it was a potential prognostic biomarker for glioma.

Pan-cancer analysis of N4-acetylcytidine adaptor THUMPD1 as a predictor for prognosis and immunotherapy.

BACKGROUND: THUMPD1 is a specific RNA adaptor that assists acetylation of mRNA and production of N4-acetylcytidine (ac4C). However, it remains unclear whether THUMPD1 plays a part in tumorigenesis and therapeutic efficacy. Here, we analyzed the expression profiles and prognostic value of THUMPD1 in pan-cancer and gained insights into the correlation between THUMPD1 expression level and immunotherapy efficacy. METHODS: Gene expression pattern and its correlation with prognosis, immune cell infiltration in pan-cancer were obtained from Genotype-Tissue Expression (GTEx), Cancer Cell Line Encyclopedia (CCLE) and The Cancer Genome Atlas (TCGA) databases, with Kaplan-Meier method and Spearman correlation analysis used. Western blotting and immunofluorescence on clinical samples were performed to validate our database-derived results. Correlation between THUMPD1 expression level and immunotherapy responses was also explored, based on clinical cohorts receiving programmed cell death protein 1 ligand (PD-L1) antibody therapy. Finally, gene set enrichment analysis (GSEA) was performed to show the possible tumorigenic mechanism. RESULTS: THUMPD1 was highly expressed in most cancer types, and this elevated expression indicated poor or improved prognosis for different cancers. In kidney renal clear cell carcinoma (KIRC) and rectum adenocarcinoma (READ), patients with higher THUMPD1 expression exhibited a better prognosis, while liver hepatocellular carcinoma (LIHC) patients had worse prognosis. Besides, THUMPD1 was significantly associated with immune cell infiltration, tumor mutational burden (TMB), microsatellite instability (MSI), immune checkpoints and neoantigen in many cancer types. Further, more clinical advantages and therapeutic responses were observed in patients with high THUMPD1 expression. CONCLUSIONS: THUMPD1 may serve as a novel predictor to evaluate cancer prognosis and immune therapy efficacy in diverse cancer types.

Effect of bond on negative thermal expansion of Prussian blue analogues MCo(CN)6 (M = Fe, Ti and Sc): a first-principles study.

Negative thermal expansion (NTE) is an abnormal physical behavior that has promising applications for high precision thermal control. Since Prussian blue analogues have the two central linking atoms of -C≡N-, they have large structure flexibility and are suitable to explore new NTE materials. However, understanding the nature of structure flexibility from the point of view of chemical bonding is important and urgent. Here, we adopt for the first time first-principles calculations to predict that the cubic TiCo(CN)6 and ScCo(CN)6 have NTE behavior. The calculated results for M in MCo(CN)6 (M = Fe, Ti and Co) indicated that the Sc-N bond is the strongest, but with the weakest direction dependence among the M-N bonds in the three systems. The lattice dynamics calculations results revealed that the low-frequency phonon vibration modes for NTE in MCo(CN)6 have much stronger relationship with the M-N bond feature. The present work reveals the important role of the related bond in the NTE open-framework materials.

Appending triphenyltriazine to 1,10-phenanthroline: a robust electron-transport material for stable organic light-emitting diodes.

There has been an increasing demand for high-performance and cost-effective organic electron-transport materials for organic light-emitting diodes (OLEDs). In this contribution, we present a simple compound 3-(3-(4,6-diphenyl-1,3,5-triazin-2-yl)phenyl)-1,10-phenanthroline through the facile Pd-catalyzed coupling of a triphenyltriazine boronic ester with 3-bromo-1,10-phenanthroline. It shows a high Tg of 112 °C. The ultraviolet photoelectron spectroscopy measurements reveal a deep HOMO level of -6.5 eV. The LUMO level is derived as -3.0 eV, based on the optical bandgap. The low-temperature solid-state phosphorescent spectrum gives a triplet energy of ∼2.36 eV. n-Doping with 8-hydroxyquinolatolithium (Liq, 1:1) leads to considerably improved electron mobility of 5.2 × 10-6-5.8 × 10-5 cm2 V-1 s-1 at E = (2-5) × 105 V cm-1, in contrast with the triarylphosphine oxide-phenantroline molecular conjugate we reported previously. It has been shown that through optimizing the device structure and hence suppressing polaron-exciton annihilation, introducing this single Liq-doped electron-transport layer could offer high-efficiency and stable phosphorescent OLEDs.