Constructing regulable supports via non-stoichiometric engineering to stabilize ruthenium nanoparticles for enhanced pH-universal water splitting.

Establishing appropriate metal-support interactions is imperative for acquiring efficient and corrosion-resistant catalysts for water splitting. Herein, the interaction mechanism between Ru nanoparticles and a series of titanium oxides, including TiO, Ti4O7 and TiO2, designed via facile non-stoichiometric engineering is systematically studied. Ti4O7, with the unique band structure, high conductivity and chemical stability, endows with ingenious metal-support interaction through interfacial Ti-O-Ru units, which stabilizes Ru species during OER and triggers hydrogen spillover to accelerate HER kinetics. As expected, Ru/Ti4O7 displays ultralow overpotentials of 8 mV and 150 mV for HER and OER with a long operation of 500 h at 10 mA cm-2 in acidic media, which is expanded in pH-universal environments. Benefitting from the excellent bifunctional performance, the proton exchange membrane and anion exchange membrane electrolyzer assembled with Ru/Ti4O7 achieves superior performance and robust operation. The work paves the way for efficient energy conversion devices.

Switching the Oxygen Evolution Mechanism on Atomically Dispersed Ru for Enhanced Acidic Reaction Kinetics.

Designing stable single-atom electrocatalysts with lower energy barriers is urgent for the acidic oxygen evolution reaction. In particular, the atomic catalysts are highly dependent on the kinetically sluggish acid-base mechanism, limiting the reaction paths of intermediates. Herein, we successfully manipulate the steric localization of Ru single atoms at the Co3O4 surface to improve acidic oxygen evolution by precise control of the anchor sites. The delicate structure design can switch the reaction mechanism from the lattice oxygen mechanism (LOM) to the optimized adsorbate evolution mechanism (AEM). In particular, Ru atoms embedded into cation vacancies reveal an optimized mechanism that activates the proton donor-acceptor function (PDAM), demonstrating a new single-atom catalytic pathway to circumvent the classic scaling relationship. Steric interactions with intermediates at the anchored Ru-O-Co interface played a primary role in optimizing the intermediates' conformation and reducing the energy barrier. As a comparison, Ru atoms confined to the surface sites exhibit a lattice oxygen mechanism for the oxygen evolution process. As a result, the delicate atom control of the spatial position presents a 100-fold increase in mass activity from 36.96 A gRu(ads)-1 to 4012.11 A gRu(anc)-1 at 1.50 V. These findings offer new insights into the precise control of single-atom catalytic behavior.

Boosting the Ultrastable High-Na-Content P2-type Layered Cathode Materials with Zero-Strain Cation Storage via a Lithium Dual-Site Substitution Approach.

P2-type layered transition-metal (TM) oxides, NaxTMO2, are highly promising as cathode materials for sodium-ion batteries (SIBs) due to their excellent rate capability and affordability. However, P2-type NaxTMO2 is afflicted by issues such as Na+/vacancy ordering and multiple phase transitions during Na-extraction/insertion, leading to staircase-like voltage profiles. In this study, we employ a combination of high Na content and Li dual-site substitution strategies to enhance the structural stability of a P2-type layered oxide (Na0.80Li0.024[Li0.065Ni0.22Mn0.66]O2). The experimental results reveal that these approaches facilitate the oxidation of Mn ions to a higher valence state, thereby affecting the local environment of both TM and Na ions. The resulting modification in the local structure significantly improves the Na-ion storage capabilities as required for cathode materials in SIBs. Furthermore, it induces a solid-solution reaction and enables nearly zero-strain operation (ΔV = 0.7%) in the Na0.80Li0.024[Li0.065Ni0.22Mn0.66]O2 cathode during cycling. The assembled full cells demonstrate an exceptional rate performance, with a retention rate of 87% at 10 C compared to that of 0.1 C, as well as an ultrastable cycling capability, maintaining a capacity retention of 73% at 2 C after 1000 cycles. These findings offer valuable insights into the electronic and structural chemistry of ultrastable cathode materials with "zero-strain" Na-ion storage.

Cardioprotective effect of epigallocatechin gallate in myocardial ischemia/reperfusion injury and myocardial infarction: a meta-analysis in preclinical animal studies.

This meta-analysis aims to determine the efficacy of Epigallocatechin gallate (EGCG) in the treatment of myocardial ischemia-reperfusion injury (MIRI) and summarize the mechanisms involved. Literature from six databases including Web of Science, PubMed, Embase, China National Knowledge Infrastructure (CNKI), Wan-Fang database, and VIP database (VIP) were systematically searched. All the analysis were conducted by R. Twenty-five eligible studies involving 443 animals were included in this meta-analysis. The results indicated that compared to controls, EGCG exerts a cardioprotective effect by reducing myocardial infarct size (SMD = -4.06; 95% CI: -5.17, -2.94; P < 0.01; I2 = 77%). The funnel plot revealed publication bias. Moreover, EGCG significantly improves cardiac function, serum myocardial injury enzyme, and oxidative stress levels in MIRI animal models. This meta-analysis demonstrates that EGCG exhibits therapeutic promise in animal models of MIRI. However, further validation is still needed in large animal models and large clinical studies.

Cardioprotective effect of curcumin on myocardial ischemia/reperfusion injury: a meta-analysis of preclinical animal studies.

Objective: This meta-analysis aimed to determine the efficacy of curcumin in preventing myocardial ischemia/reperfusion (I/R) injury in animal models. Methods: Studies published from inception to January 2023 were systematically searched in databases including PubMed, Web of Science, Embase, China's National Knowledge Infrastructure (CNKI), Wan-Fang database, and VIP database (VIP). The SYRCLE's RoB tool was used to determine methodological quality. Sensitivity analysis and subgroup analysis were performed when there was high heterogeneity. Publication bias was assessed using a funnel plot. Results: Thirty-seven studies involving 771 animals were included in this meta-analysis with methodology quality scores ranging from 4 to 7. The results indicated that curcumin treatment significantly improved myocardial infarction size standard mean difference (SMD) = -5.65; 95% confidence interval (CI): 6.94, -4.36; p < 0.01; I2 = 90%). The sensitivity analysis for infarct size showed that the results were stable and reliable. However, the funnel plot was asymmetric. The subgroup analysis included species, animal model, dose, administration, and duration. The results showed that the subgroup dose was statistically significant between subgroups. In addition, curcumin treatment improved cardiac function, myocardial injury enzymes, and oxidative stress levels in animal models of myocardial I/R injury. The funnel plot revealed that there is publication bias for creatine kinase and lactate dehydrogenase. Finally, we performed a meta-analysis of inflammatory cytokines and apoptosis index. The results showed that curcumin treatment downregulated serum inflammatory cytokine levels and myocardial apoptosis index. Conclusion: This meta-analysis suggests that curcumin has excellent potential for the treatment of myocardial I/R injury in animal models. However, this conclusion needs to be further discussed and verified in large animal models and human clinical trials. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42022383901.

In-situ spectroscopic probe of the intrinsic structure feature of single-atom center in electrochemical CO/CO2 reduction to methanol.

While exploring the process of CO/CO2 electroreduction (COxRR) is of great significance to achieve carbon recycling, deciphering reaction mechanisms so as to further design catalytic systems able to overcome sluggish kinetics remains challenging. In this work, a model single-Co-atom catalyst with well-defined coordination structure is developed and employed as a platform to unravel the underlying reaction mechanism of COxRR. The as-prepared single-Co-atom catalyst exhibits a maximum methanol Faradaic efficiency as high as 65% at 30 mA/cm2 in a membrane electrode assembly electrolyzer, while on the contrary, the reduction pathway of CO2 to methanol is strongly decreased in CO2RR. In-situ X-ray absorption and Fourier-transform infrared spectroscopies point to a different adsorption configuration of *CO intermediate in CORR as compared to that in CO2RR, with a weaker stretching vibration of the C-O bond in the former case. Theoretical calculations further evidence the low energy barrier for the formation of a H-CoPc-CO- species, which is a critical factor in promoting the electrochemical reduction of CO to methanol.

The efficacy and safety of anti-PD-1/PD-L1 in treatment of glioma: a single-arm meta-analysis.

Objective: This meta-analysis aimed to evaluate the efficacy and safety of PD-1/PD-L1 inhibitors in patients with glioma. Methods: PubMed, EMBASE, Web of Science, and the Cochrane library were searched from inception to January 2023 without language restriction. Primary outcomes included overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and adverse events (AEs). The risk of bias was assessed by subgroup analysis, sensitivity analysis, and publication bias, including funnel plot, Egger's test, and Begg's test. Results: A total of 20 studies involving 2,321 patients were included in this meta-analysis. In the analysis of the included phase III clinical trials, the forest plot showed that PD-1/PD-L1 inhibitors did not improve the OS (HR=1.15, 95% CI: 1.03-1.29, P=0.02, I2 = 14%) and PFS (HR=1.43, 95% CI: 1.03-1.99, P=0.03, I2 = 87%). In the single-arm analysis, the forest plot demonstrated that the 6-month OS was 71% (95% CI: 57%-83%, I2 = 92%), 1-year OS was 43% (95% CI: 33%-54%, I2 = 93%), and the 2-year OS was 27% (95% CI: 13%-44%, I2 = 97%). The pooled estimate of the median OS was 8.85 months (95% CI: 7.33-10.36, I2 = 91%). Furthermore, the result indicated that the 6-month PFS was 28% (95% CI: 18%-40%, I2 = 95%), 1-year PFS was 15% (95% CI: 8%-23%, I2 = 92%), and the 18-month PFS was 10% (95% CI: 3%-20%, I2 = 93%). The pooled estimate of the median PFS was 3.72 months (95% CI: 2.44-5.00, I2 = 99%). For ORR, the pooled estimate of ORR was 10% (95% CI: 2%-20%, I2 = 88%). We further analyzed the incidence of PD-1/PD-L1 inhibitor-related AEs, and the pooled incidence of AEs was 70% (95% CI: 58%-81%, I2 = 94%). The incidence of AEs ≥ grade 3 was 19% (95% CI: 11%-30%, I2 = 94%). The funnel plot for the median PFS and median OS was symmetric with no significant differences in Egger's test and Begg's test. The sensitivity analysis revealed that our results were stable and reliable. Conclusion: The results of this meta-analysis suggest that anti-PD-1/PD-L1 therapy is relatively safe but could not prolong survival in glioma. More randomized controlled trials are needed to confirm our results. Systematic review registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42023396057.

Operando Spectroscopic Analysis of Axial Oxygen-Coordinated Single-Sn-Atom Sites for Electrochemical CO2 Reduction.

Sn-based materials have been demonstrated as promising catalysts for the selective electrochemical CO2 reduction reaction (CO2RR). However, the detailed structures of catalytic intermediates and the key surface species remain to be identified. In this work, a series of single-Sn-atom catalysts with well-defined structures is developed as model systems to explore their electrochemical reactivity toward CO2RR. The selectivity and activity of CO2 reduction to formic acid on Sn-single-atom sites are shown to be correlated with Sn(IV)-N4 moieties axially coordinated with oxygen (O-Sn-N4), reaching an optimal HCOOH Faradaic efficiency of 89.4% with a partial current density (jHCOOH) of 74.8 mA·cm-2 at -1.0 V vs reversible hydrogen electrode (RHE). Employing a combination of operando X-ray absorption spectroscopy, attenuated total reflectance surface-enhanced infrared absorption spectroscopy, Raman spectroscopy, and 119Sn Mössbauer spectroscopy, surface-bound bidentate tin carbonate species are captured during CO2RR. Moreover, the electronic and coordination structures of the single-Sn-atom species under reaction conditions are determined. Density functional theory (DFT) calculations further support the preferred formation of Sn-O-CO2 species over the O-Sn-N4 sites, which effectively modulates the adsorption configuration of the reactive intermediates and lowers the energy barrier for the hydrogenation of *OCHO species, as compared to the preferred formation of *COOH species over the Sn-N4 sites, thereby greatly facilitating CO2-to-HCOOH conversion.

A novel inflammation-related lncRNAs prognostic signature identifies LINC00346 in promoting proliferation, migration, and immune infiltration of glioma.

In this study, a total of 13 inflammation-related lncRNAs with a high prognostic value were identified with univariate, multivariate Cox regression analysis, and LASSO analysis. LINC00346, which is one of the 13 lncRNAs identified, was positively associated with type 2 macrophage activation and the malignant degree of glioma. Fluorescence in situ hybridization (FISH) and immunohistochemical staining showed that LINC00346 was highly expressed in high-grade glioma, while type 2 macrophages key transcription factor STAT3 and surface marker CD204 were also highly expressed simultaneously. LINC00346 high-expression gliomas were more sensitive to the anti-PD-1 and anti-CTLA-4 therapy. LINC00346 was also associated with tumor proliferation and tumor migration validated by EdU, cell colony, formation CCK8, and transwell assays. These findings reveal novel biomarkers for predicting glioma prognosis and outline relationships between lncRNAs inflammation, and glioma, as well as possible immune checkpoint targets for glioma.

A Pan-Cancer Analysis Reveals CLEC5A as a Biomarker for Cancer Immunity and Prognosis.

Background: CLEC5A is a member of the C-type lectin superfamily. It can activate macrophages and lead to a series of immune-inflammation reactions. Previous studies reveal the role of CLEC5A in infection and inflammation diseases. Method: We acquire and analyze data from The Cancer Genome Atlas (TCGA) database, Genotype-Tissue Expression (GTEx) database, and other comprehensive databases via GSCALite, cBioPortal, and TIMER 2.0 platforms or software. Single-cell sequencing analysis was performed for quantifying the tumor microenvironment of several types of cancers. Results: CLEC5A is differentially expressed in a few cancer types, of which overexpression accompanies low overall survival of patients. DNA methylation mainly negatively correlates with CLEC5A expression. Moreover, CLEC5A is positively related to immune infiltration, including macrophages, cancer-associated fibroblasts (CAFs), and regulatory T cells (Tregs). Immune checkpoint genes are significantly associated with CLEC5A expression in diverse cancers. In addition, CLEC5A expression correlates with mismatch repair (MMR) in several cancers. Tumor mutation burden (TMB), microsatellite instability (MSI), and neoantigens show a positive association with CLEC5A expression in several cancers. Furthermore, CLEC5A in cancer correlates with signal transduction, the immune system, EMT, and apoptosis process. The drug sensitivity analysis screens out potential therapeutic agents associated with CLEC5A expression, including FR-180204, Tivozanib, OSI-930, Linifanib, AC220, VNLG/124, Bexarotene, omacetaxine mepesuccinate, narciclasine, leptomycin B, PHA-793887, LRRK2-IN-1, and CR-1-31B. Conclusion: CLEC5A overexpresses in multiple cancers in contrast to normal tissues, and high CLEC5A expression predicts poor prognosis of patients and immune infiltration. CLEC5A is a potential prognostic biomarker of diverse cancers and a target for anti-tumor therapy.

A Novel Thrombosis-Related Signature for Predicting Survival and Drug Compounds in Glioblastoma.

Glioblastoma is the most common primary tumor in the central nervous system, and thrombosis-associated genes are related to its occurrence and progression. Univariate Cox and LASSO regression analysis were utilized to develop a new prognostic signature based on thrombosis-associated genes. Gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and HALLMARK were used for functional annotation of risk signature. ESTIMATE, MCP-counter, xCell, and TIMER algorithms were used to quantify immune infiltration in the tumor microenvironment. Genomics of Drug Sensitivity in Cancer (GDSC) was used for selecting potential drug compounds. Risk signature based on thrombosis-associated genes shows moderate performance in prognosis prediction. The functional annotation of the risk signature indicates that the signaling pathways related to the cell cycle, apoptosis, tumorigenesis, and immune suppression are rich in the high-risk group. Somatic mutation analysis shows that tumor-suppressive gene TP53 and oncogene PTEN have higher expression in low-risk and high-risk groups, respectively. Potential drug compounds are explored in risk score groups and show higher AUC values in the low-risk score group. A nomogram with valuable prognostic factors exhibits high sensitivity in predicting the survival outcome of GBM patients. Our research screens out multiple thromboses-associated genes with remarkable clinical significance in GBM and further develops a meaningful prognostic risk signature predicting drug sensitivity and survival outcome.

Regulatory mechanisms of immune checkpoints PD-L1 and CTLA-4 in cancer.

The cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4)/B7 and programmed death 1 (PD-1)/ programmed cell death-ligand 1 (PD-L1) are two most representative immune checkpoint pathways, which negatively regulate T cell immune function during different phases of T-cell activation. Inhibitors targeting CTLA-4/B7 and PD1/PD-L1 pathways have revolutionized immunotherapies for numerous cancer types. Although the combined anti-CTLA-4/B7 and anti-PD1/PD-L1 therapy has demonstrated promising clinical efficacy, only a small percentage of patients receiving anti-CTLA-4/B7 or anti-PD1/PD-L1 therapy experienced prolonged survival. Regulation of the expression of PD-L1 and CTLA-4 significantly impacts the treatment effect. Understanding the in-depth mechanisms and interplays of PD-L1 and CTLA-4 could help identify patients with better immunotherapy responses and promote their clinical care. In this review, regulation of PD-L1 and CTLA-4 is discussed at the levels of DNA, RNA, and proteins, as well as indirect regulation of biomarkers, localization within the cell, and drugs. Specifically, some potential drugs have been developed to regulate PD-L1 and CTLA-4 expressions with high efficiency.

Identified lung adenocarcinoma metabolic phenotypes and their association with tumor immune microenvironment.

BACKGROUND: Lung adenocarcinoma (LUAD), a subtype of non-small cell lung cancer (NSCLC), causes high mortality around the world. Previous studies have suggested that the metabolic pattern of tumor is associated with tumor response to immunotherapy and patient's survival outcome. Yet, this relationship in LUAD is still unknown. METHODS: Therefore, in this study, we identified the immune landscape in different tumor subtypes classified by metabolism-related genes expression with a large-scale dataset (tumor samples, n = 2181; normal samples, n = 419). We comprehensively correlated metabolism-related phenotypes with diverse clinicopathologic characteristics, genomic features, and immunotherapeutic efficacy in LUAD patients. RESULTS: And we confirmed tumors with activated lipid metabolism tend to have higher immunocytes infiltration and better response to checkpoint immunotherapy. This work highlights the connection between the metabolic pattern of tumor and tumor immune infiltration in LUAD. A scoring system based on metabolism-related gene expression is not only able to predict prognosis of patient with LUAD but also applied to pan-cancer. LUAD response to checkpoint immunotherapy can also be predicted by this scoring system. CONCLUSIONS: This work revealed the significant connection between metabolic pattern of tumor and tumor immune infiltration, regulating LUAD patients' response to immunotherapy.

Aberrant ASPM expression mediated by transcriptional regulation of FoxM1 promotes the progression of gliomas.

Gliomas are the most common form of malignant tumour in the central nervous system. However, the molecular mechanism of the tumorigenesis and progression of gliomas remains unclear. In this study, we used the GEO database to identify genes differentially expressed in gliomas and predict the prognosis of glioma. We observed that ASPM mRNA was increased obviously in glioma tissue, and higher ASPM mRNA expression predicted worse disease prognosis. ASPM was highly expressed in glioma cell lines U87-MG and U251, and knockdown of ASPM expression in these cells significantly repressed the proliferation, migration and invasion ability and induced G0/G1 phase arrest. In addition, down-regulation of ASPM suppressed the growth of glioma in nude mice. Five potential binding sites for transcription factor FoxM1 were predicted in the ASPM promoter. FoxM1 overexpression significantly increased the expression of ASPM and promoted the proliferation and migration of glioma cells, which was abolished by ASPM ablation. ChIP and dual-luciferase reporter analysis confirmed that FoxM1 bound to the ASPM promoter at -236 to -230 bp and -1354 to -1348 bp and activated the transcription of ASPM directly. Collectively, our results demonstrated for the first time that aberrant ASPM expression mediated by transcriptional regulation of FoxM1 promotes the malignant properties of glioma cells.

Identification of gene expression and DNA methylation of SERPINA5 and TIMP1 as novel prognostic markers in lower-grade gliomas.

BACKGROUND: Lower-grade gliomas (LGGs) is characteristic with great difference in prognosis. Due to limited prognostic biomarkers, it is urgent to identify more molecular markers to provide a more objective and accurate tumor classification system for LGGs. METHODS: In the current study, we performed an integrated analysis of gene expression data and genome-wide methylation data to determine novel prognostic genes and methylation sites in LGGs. RESULTS: To determine genes that differentially expressed between 44 short-term survivors (<2 years) and 48 long-term survivors (≥2 years), we searched LGGs TCGA RNA-seq dataset and identified 106 differentially expressed genes. SERPINA5 and TIMP1 were selected for further study. Kaplan-Meier plots showed that SERPINA5 and TIMP1 expression were significantly correlated with overall survival (OS) and relapse-free survival (RFS) in TCGA LGGs patients. We next validated the correlation between the candidate genes expression and clinical outcome in CGGA LGGs patients. Multivariate analysis showed that TIMP1 mRNA expression had a significant prognostic value independent of other variables (HR = 4.825, 95% CI = 1.370-17.000, P = 0.014). Then, differential methylation sites were identified from differentially candidate gene expression groups, and all four methylation sites were significantly negatively correlated with gene expression (spearman r <  - 0.5, P < 0.0001). Moreover, hyper-methylation of four methylation sites indicated better OS (P < 0.05), and three of them also shown statistical significantly association with better RFS, except for SERPINA5 cg15509705 (P = 0.0762). CONCLUSION: Taken together, these findings indicated that the gene expression and methylation of SERPINA5 and TIMP1 may serve as prognostic predictors in LGGs and may help to precise the current histology-based tumors classification system and to provide better stratification for future clinical trials.

Downregulation of iASPP Expression Suppresses Proliferation, Invasion and Increases Chemosensitivity to Paclitaxel of Head and Neck Squamous Cell Carcinoma In Vitro.

Objective Our previous study has revealed that iASPP is elevated in human head and neck squamous cell carcinoma (HNSCC) and iASPP overexpression signifcantly correlates with tumor malignant progression and poor survival of HNSCC. This study investigated the function of iASPP playing in proliferation and invasion of HNSCC in vitro. Methods HNSCC cell line Tu686 transfected with Lentiviral vector-mediated iASPP-specific shRNA and control shRNA were named the shRNA-iASPP group and shRNA-NC group, respectively. The non-infected Tu686 cells were named the CON group. CCK-8 assay, flow cytometry, transwell invasion assay were performed to detect the effects of iASPP inhibition in vitro. Results Our results demonstrated that the proliferation of shRNA-iASPP cells at the time of 72 h (F=32.459, P=0.000), 96 h (F=51.407, P=0.000), 120 h (F=35.125, P=0.000) post-transfection, was significantly lower than that of shRNA-NC cells and CON cells. The apoptosis ratio of shRNA-iASPP cells was 9.42% ± 0.39% (F=299.490, P=0.000), which was significantly higher than that of CON cells (2.80% ± 0.42%) and shRNA-NC cells (3.18% ± 0.28%). The percentage of shRNA-iASPP cells in G0/G1 phase was 74.65% ± 1.09% (F=388.901, P=0.000), which was strikingly increased, compared with that of CON cells (55.19% ± 1.02%) and shRNA-NC cells (54.62% ± 0.88%). The number of invading cells was 56 ± 4 in the shRNA-iASPP group (F=84.965, P=0.000), which decreased significantly, compared with the CON group (111 ± 3) and the shRNA-NC group (105 ± 8). The survival rate of shRNA-iASPP cells administrated with paclitaxel was highly decreased, compared with CON cells and shRNA-NC cells (F=634.841, P=0.000). Conclusion These results suggest iASPP may play an important role in progression and aggressive behavior of HNSCC and may be an efficient chemotherapeutic target for the treatment of HNSCC.

Influence of DNMT3A R882 mutations on AML prognosis determined by the allele ratio in Chinese patients.

BACKGROUND: The influence of DNMT3A R882 mutations on adult acute myeloid leukemia (AML) prognosis is still controversial presently. The influence of R882 allele ratio on drug response and prognosis of AML is unknown yet. Besides, it is obscure whether anthracyclines are involved in chemoresistance resulted from R882 mutations. METHODS: DNMT3A R882 mutations in 870 adult AML patients receiving standard induction therapy were detected by pyrosequencing. Associations of the mutants with responses to induction therapy and disease prognosis were analyzed. RESULTS: DNMT3A R882 mutations were detected in 74 (8.51%) patients and allele ratio of the mutations ranged from 6 to 50% in the cohort. After the first and second courses of induction therapy including aclarubicin, complete remission rates were significantly lower in carriers of the DNMT3A R882 mutants as compared with R882 wildtype patients (P = 0.022 and P = 0.038, respectively). Compared with R882 wild-type patients, those with the R882 mutations showed significantly shorter overall survival (OS) and disease-free survival (DFS) (P = 1.92 × 10-4 and P = 0.004, respectively). Patients with higher allele ratio of R882 mutations showed a significantly shorter OS as compared with the lower allele ratio group (P = 0.035). CONCLUSION: Our results indicate that the impact of DNMT3A R882 mutations on AML prognosis was determined by the mutant-allele ratio and higher allele ratio could predict a worse prognosis, which might improve AML risk stratification. In addition, DNMT3A R882 mutations were associated with an inferior response to induction therapy with aclarubicin in Chinese AML patients.

Knockdown ATG4C inhibits gliomas progression and promotes temozolomide chemosensitivity by suppressing autophagic flux.

BACKGROUND: Gliomas are the most common primary tumors in central nervous system. Despite advances in diagnosis and therapy, the prognosis of glioma remains gloomy. Autophagy is a cellular catabolic process that degrades proteins and damaged organelles, which is implicated in tumorigenesis and tumor progression. Autophagy related 4C cysteine peptidase (ATG4C) is an autophagy regulator responsible for cleaving of pro-LC3 and delipidation of LC3 II. This study was designed to investigate the role of ATG4C in glioma progression and temozolomide (TMZ) chemosensitivity. METHODS: The association between ATG4C mRNA expression and prognosis of gliomas patients was analyzed using the TCGA datasets. The role of ATG4C in proliferation, apoptosis, autophagy, and TMZ chemosensitivity were investigated by silencing ATG4C in vivo. Ectopic xenograft nude mice model was established to investigate the effects of ATG4C on glioma growth in vivo. RESULTS: The median overall survival (OS) time of patients with higher ATG4C expression was significantly reduced (HR: 1.48, p = 9.91 × 10- 7). ATG4C mRNA expression was evidently increased with the rising of glioma grade (p = 2.97 × 10- 8). Knockdown ATG4C suppressed glioma cells proliferation by inducing cell cycle arrest at G1 phase. ATG4C depletion suppressed autophagy and triggered apoptosis through ROS accumulation. Depletion of ATG4C suppressed TMZ-activated autophagy and promoted sensitivity of glioma cells to TMZ. Additionally, ATG4C knockdown suppressed the growth of glioma remarkably in nude mice. CONCLUSION: ATG4C is a potential prognostic predictor for glioma patient. Targeting ATG4C may provide promising therapy strategies for gliomas treatment.

Under explored epigenetic modulators: role in glioma chemotherapy.

Patients with somatic mutations of epigenetic regulators are characterized by aberrant chromatin modification patterns. Recent mechanistic studies pairing chemical tool compounds and deep-sequencing technology have greatly broadened our understanding of epigenetic regulation in glioma progression and underpinned alternative treatment of epigenetic inhibitors. However, the effect of most inhibitors is condition-dependent, and the overall results of clinical trials still have not been applied to patients. There is an intense need to develop more potent and specific compounds as well as identify the population who may achieve clinical benefits. Besides, combination therapy with conventional therapeutics is another alternative strategy. In this review, we summarize well-characterized chemical probes in glioma research and clinical translation. We also discuss the target population and combination of therapy regimens of various agents. In a holistic sense, we try to provide guidance for selecting targeted chemical probes and pave the way for personalized rational therapy.