High B7-H3 expression with low PD-L1 expression identifies armored-cold tumors in triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is generally regarded as the most aggressive subtype among breast cancers, but exhibits higher chemotherapeutic and immunotherapeutic responses due to its unique immunogenicity. Thus, appropriate discrimination of subtypes is critical for guiding therapeutic options in clinical practice. In this research, using multiple in-house and public cohorts, we investigated the expression features and immuno-correlations of B7-H3 in breast cancer and checked the anti-tumor effect of the B7-H3 monoclonal antibody in a mouse model. We also developed a novel classifier combining B7-H3 and PD-L1 expression in TNBC. B7-H3 was revealed to be related to immuno-cold features and accumulated collagen in TNBC. In addition, targeting B7-H3 using the monoclonal antibody significantly suppressed mouse TNBC growth, reversed the armored-cold phenotype, and also boosted anti-PD-1 immunotherapy. In addition, patients with B7-H3 high and PD-L1 low expression showed the lowest anti-tumor immune infiltration, the highest collagen level, and the lowest therapeutic responses to multiple therapies, which mostly belong to armored-cold tumors. Overall, this research provides a novel subtyping strategy based on the combination of B7-H3/PD-L1 expression, which leads to a novel approach for the management of TNBC.

Altered functional connectivity in language and non-language brain networks in patients diagnosed with acute post-stroke aphasia.

OBJECTIVE: A resting-state functional magnetic resonance imaging (rs-fMRI) approach was used to explore functional connectivity (FC) in language and non-language brain networks in acute post-stroke aphasia (PSA) patients, with a specific focus on the relationship between these fMRI results and patient clinical presentation. METHODS: In total, 20 acute PSA patients and 30 age-, sex-, and education level-matched healthy control (HC) participants were recruited and subjected to rs-fMRI imaging. In addition, western aphasia battery analyses（WAB） were used to compute aphasia quotient (AQ) values for PSA patients. Granger causality was employed to examine connections among cognition-associated resting-state brain networks, and the right middle frontal gyrus (RMFG),the mirror brain regions of Broca's area and the Wernicke's area, the right superior temporal gyrus were selected as regions of interest (ROIs). The REST plus software was then used to perform FC analyses of these regions to analyze changes in FC related to PSA pathogenesis. RESULTS: Relative to HC individuals, PSA patients exhibited significantly higher levels of intra-network FC between the right middle frontal gyrus (RMFG) and the left middle occipital gyrus (LMOG), with such FC being positively correlated with the AQ scores (P = 0.018). Moreover, reduced FC was detected between the Broca's area homolog and the left middle frontal gyrus (LMFG), while FC was enhanced between the Wernicke's area homolog and cerebellar vermis, and this FC was similarly positively correlated with patient AQ scores (P = 0.0297). CONCLUSION: These results suggest that FC between the bilateral hemispheres of the brain is significantly disrupted in acute PSA patients, interfering with the normal non-specific language network. Aphasia severity was further found to correlate with FC among many of the analyzed regions of the brain.

DOCK8 inhibits the immune function of neutrophils in sepsis by regulating aerobic glycolysis.

INTRODUCTION: This study endeavored to investigate the role of DOCK8 in modulating the immune function triggered by sepsis. METHODS: Expression of DOCK8 in the whole blood of sepsis patients and its enrichment pathways were assayed by bioinformatics. Pearson analysis was used to predict the relationship between glycolytic signaling pathway and its relevance to neutrophil function in sepsis. A sepsis mouse model was then built by performing cecal ligation and puncture treatment on male mice. Neutrophils were isolated, and their purity was tested by flow cytometry. Neutrophils were then stimulated by lipopolysaccharide to build a sepsis cell model. Next, quantitative reverse transcription polymerase chain reaction and CCK-8 were applied to test the expression of DOCK8 and cell viability, western blot to assay the expression of HK-2, PKM2, and LDHA proteins, ELISA to measure the concentrations of TNF-α, IL-1ß, and IL-6, Transwell to detect the chemotaxis of neutrophils and flow cytometry to detect the phagocytic activity of neutrophils. Finally, in different treatment groups, we used Seahorse XF 96 to analyze the extracellular acidification rate (ECAR) of sepsis cells and used enzyme-linked immunosorbent assay to detect the contents of pyruvic acid, lactic acid, and ATP in sepsis cells. RESULTS: DOCK8 was downregulated in sepsis blood and activated neutrophils. Aerobic glycolysis was positively correlated with sepsis. Activated neutrophils promoted the expression of inflammatory factors TNF-α, IL-1ß, and IL-6. Low expression of DOCK8 facilitated the proliferation, chemotaxis, and phagocytic activity of sepsis cells and promoted the expression of inflammatory factors. Bioinformatics analysis revealed that DOCK8 was enriched in the glycolytic signaling pathway. Low expression of DOCK8 induced ECAR, promoted the protein expression of HK-2, PKM2 and LDHA, and favored the increase of pyruvate, lactate, and ATP contents. While 2-DG treatment could restore these effects. CONCLUSION: DOCK8 may inhibit sepsis-induced neutrophil immune function by regulating aerobic glycolysis and causing excessive inflammation, which helps to explore potential therapeutic targets.

Self-Assembled BODIPY Nanoparticles for Near-Infrared Fluorescence Bioimaging.

In vivo optical imaging is an important application value in disease diagnosis. However, near-infrared nanoprobes with excellent luminescent properties are still scarce. Herein, two boron-dipyrromethene (BODIPY) molecules (BDP-A and BDP-B) were designed and synthesized. The BODIPY emission was tuned to the near-infrared (NIR) region by regulating the electron-donating ability of the substituents on its core structure. In addition, the introduction of polyethylene glycol (PEG) chains on BODIPY enabled the formation of self-assembled nanoparticles (NPs) to form optical nanoprobes. The self-assembled BODIPY NPs present several advantages, including NIR emission, large Stokes shifts, and high fluorescence quantum efficiency, which can increase water dispersibility and signal-to-noise ratio to decrease the interference by the biological background fluorescence. The in vitro studies revealed that these NPs can enter tumor cells and illuminate the cytoplasm through fluorescence imaging. Then, BDP-B NPs were selected for use in vivo imaging due to their unique NIR emission. BDP-B was enriched in the tumor and effectively illuminated it via an enhanced penetrability and retention effect (EPR) after being injected into the tail vein of mice. The organic nanoparticles were metabolized through the liver and kidney. Thus, the BODIPY-based nanomicelles with NIR fluorescence emission provide an effective research basis for the development of optical nanoprobes in vivo.

A systematic review and meta-analysis of sacubitril-valsartan in the treatment of ventricular remodeling in patients with heart failure after acute myocardial infarction.

Objective: To systematically review the efficacy and safety of sacubitril and valsartan in treating acute myocardial infarction complicated with heart failure and to observe whether it can further improve patients' cardiac function, delay left ventricular remodeling, and reduce major adverse cardiovascular events (MACEs). Methods: Electronic databases including Pubmed, Embase, the Web of Science, Cochrane Library, Scopus, CNKI, Wanfang Data, and VIP were searched. The search period was from the establishment of the database to March 2022 to search for relevant controlled trials. Two investigators independently screened the literature, extracted data, and assessed the risk of bias. Revman5.3 and Stata14 software were used for statistical analysis. Results: A total of 13 studies, with 6,968 patients were included. Meta-analysis results showed that sacubitril-valsartan increased left ventricular ejection fraction (LVEF) and decreased NT-proBNP level was better at 6 months and within 3 months of follow-up compared with the control group (P < 0.00001), but there was no significant difference at the 12-month follow-up (P > 0.05). Sacubitril-valsartan reducing LVEDD [MD = -2.55, 95%CI(-3.21, -1.88), P < 0.00001], LVEDVI [MD = -3.61, 95%CI(-6.82, -0.39), P = 0.03], LVESVI [MD = -3.77, 95%CI(-6.05, -1.49), P = 0.001], and increasing the distance of the 6-min walk test [MD = 48.20, 95%CI(40.31, 56.09), P < 0.00001] were more effective. Compared with ACEI/ARB, the use of ARNI can further reduce the total incidence of adverse cardiovascular events [RR = 0.72, 95%CI(0.62, 0.84), P<0.0001] and the rate of HF rehospitalization [RR = 0.73, 95%CI(0.61, 0.86), P = 0.0002] in patients with acute myocardial infarction and heart failure; there was no significant difference in the incidence of cardiac death, recurrence of myocardial infarction, and malignant arrhythmia between the experimental group and the control group (P > 0.05). In terms of the incidence of adverse reactions, the incidence of cough in ARNI was lower than that in ACEI/ARB group [RR = 0.69, 95%CI(0.60, 0.80), P < 0.00001], but the incidence of hypotension was higher [RR = 1.29, 95%CI(1.18, 1.41), P < 0.00001], and the adverse reactions of hyperkalemia, angioedema and renal insufficiency were not increased (P > 0.05). Conclusion: The use of sacubitril-valsartan sodium in patients with acute myocardial infarction complicated with heart failure can significantly improve cardiac function and reverse ventricular remodeling, reducing the risk of re-hospitalization for heart failure. There is no apparent adverse reaction except easy cause hypotension. Systematic trial registration: [www.ClinicalTrials.gov], identifier [CRD42022322901].

GATA binding protein 5 (GATA5) induces Rho GTPase activating protein 9 (ARHGAP9) to inhibit the malignant process of lung adenocarcinoma cells.

Lung adenocarcinoma is the main cause of the excessive mortality for patients who lives with lung cancers. According to the GEPIA database analysis, GATA5 and ARHGAP9 were found to be low expressed in lung adenocarcinoma, and they were positively correlated, and in addition ARHGAP9 low expression was associated with poor prognosis in lung adenocarcinoma. Therefore, the present study focused on the effect of promoting GATA5 to induce ARHGAP9 on the malignant process of lung adenocarcinoma cells. The expressions of GATA5 and ARHGAP9 were measured with Western blot and RT-qPCR. With the adoption of CCK-8, EDU staining, transwell and colony formation, the cell viability, proliferation, invasion and tumorigenesis ability were detected, respectively. In addition, the wound healing and Western blot were employed to evaluate migration and metastasis-related proteins individually. Moreover, the luciferase activity as well as the binding of GATA5 and ARHGAP9 promoters were detected by luciferase report and ChIP. After further comprehensive assessments, the results confirmed that GATA5 could successfully activate ARHGAP9. Moreover, ARHGAP9 upregulation remarkably inhibited lung adenocarcinoma cell proliferation, invasion and migration as compared to the control group. More importantly, GATA5 silencing reversed the inhibitory effect of ARHGAP9 upregulation on the malignant progression of lung adenocarcinoma cells. To conclude, the present study successfully demonstrated for the first time that GATA5-induced ARHGAP9 upregulation has a protective effect on lung adenocarcinoma cells.

Comprehensive study of a novel immune-related lncRNA for prognosis and drug treatment of cervical squamous cell carcinoma.

A comprehensive study focusing on immune-related long non-coding RNAs (lncRNAs) in cervical cancer (CC) was performed. Through the integration of TCGA data, a total of 266 immune-related lncRNAs were obtained. We defined all samples as an entire set, and randomly divided them into train set and test set at a ratio of 1:1. Univariate, LASSO and multivariate Cox regression analyses were carried out based on train set for key lncRNAs (UBL7-AS1, AC083809.1, LIPE-AS1, PCED1B-AS1, ELFN1-AS1 and NCK1-DT) to construct a prognostic model, while the others were used for validation. The overall survival (OS) suggested that we may have longer survival expectations for patients classified into the low-risk group. The P values of risk score in univariate analysis and multivariate analysis were all less than 0.05, indicating the ability of risk score to independently assess the prognosis of patients. For clinical application, a nomogram with a high degree of agreement between the predicted curve and the actual curve was constructed. Subsequently, immune status and chemotherapy response were investigated in two prognostic subtypes. The associations between risk score and immune cell were estimated, in which CD8+ T cells showed the highest positive correlation and activated mast cell showed the highest negative correlation. In addition, checkpoint proteins (CTLA4, LAG3, PD-1, and TIGIT) showing negative correlation with risk score were found to be upregulated in low-risk group. A total of 3 chemotherapy drugs including paclitaxel, vinorelbine and methotrexate were considered effective in patients of high-risk group. Using 6 key immune-related lncRNAs, we identified two prognostic subtypes and provided new insights for CC immunotherapy.

Identification of the Prognostic Signature Associated With Tumor Immune Microenvironment of Uterine Corpus Endometrial Carcinoma Based on Ferroptosis-Related Genes.

Background: Uterine corpus endometrial carcinoma (UCEC) is the sixth most common cancer worldwide. Ferroptosis plays an important role in malignant tumors. However, the study of ferroptosis in the endometrial carcinoma remains blank. Methods: First, we constructed a ferroptosis-related signature based on the expression profiles from The Cancer Genome Atlas database. Then, patients were divided into the high-risk and low-risk groups based on this signature. The signature was evaluated by Kaplan-Meier analysis and receiver operating characteristic (ROC) analysis. We further investigated the relationship between this signature and immune microenvironment via CIBERSORT algorithm, ImmuCellAI, MAF, MSI sensor algorithm, GSEA, and GDSC. Results: This signature could be an independent prognostic factor based on multivariate Cox regression analysis. GSEA revealed that this signature was associated with immune-related phenotype. In addition, we indicated the different status of immune infiltration and response to the immune checkpoint between low-risk and high-risk groups. Patients in the low-risk group were more likely to present with a higher expression of immune checkpoint molecules and tumor mutation burden. Meanwhile, the low-risk patients showed sensitive responses to chemotherapy drugs. Conclusion: In summary, the six ferroptosis-related genes signature could be used in molecular subgrouping and accurately predict the prognosis of UCEC.

Establishment and evaluation of a nomogram prediction model for recurrence risk of atrial fibrillation patients after radiofrequency ablation.

OBJECTIVE: To explore the risk factors for recurrence of atrial fibrillation (AF) in patients after radiofrequency ablation and construction of a targeted nomogram prediction model. METHODS: A prospective cohort study design was used to select 312 patients who were separated into two groups; a recurrence group (n = 79) and a non-recurrence group (n = 233) with or without AF, who underwent radiofrequency ablation for the first time between January 2017 and December 2017, with a completed a 12-month follow-up after surgery. The recurrence of AF within 12 months after follow-up was recorded. The nomogram prediction model was established. The original data were resampled using the Bootstrap method. The recurrence risk after resampling was predicted using a nomogram model. The calibration curve and ROC curve of the nomogram model were established. The predicted calibration degree and discrimination degree of the nomogram model were evaluated with the Hosmer-Lemeshow deviation test and area under the curve. RESULTS: The 12-month follow-up showed that a total of 79 patients (25.32%) had recurrence of AF. The type of AF, sex, gender, disease course, left atrial anteroposterior diameter, left atrial volume, and cardiac function classification were independent risk factors for the recurrence of AF (P < 0.05). After the nomogram prediction model passed the Bootstrap self-sampling 1000 times, Hosmer-Lemeshow deviation test: χ2 = 8.070, P = 0.427; the area under ROC curve was 0.852 (95% CI: 0.806-0.898), the sensitivity was 78.48%, and the specificity was 81.12%, suggesting that the nomogram model has better predictive calibration and discrimination. CONCLUSION: The recurrence rate in patients with AF after radiofrequency ablation is high. The nomogram model based on the risk factors of AF recurrence has high prediction accuracy and can be used to predict the recurrence risk of AF in patients after radiofrequency ablation.

Interferon-Induced Transmembrane Protein 3 Shapes an Inflamed Tumor Microenvironment and Identifies Immuno-Hot Tumors.

Interferon-induced transmembrane protein 3 (IFITM3) is an interferon-induced membrane protein, which has been identified as a functional gene in multiple human cancers. The role of IFITM3 in cancer has been preliminarily summarized, but its relationship to antitumor immunity is still unclear. A pancancer analysis was conducted to investigate the expression pattern and immunological role of IFITM3 based on transcriptomic data downloaded from The Cancer Genome Atlas (TCGA) database. Next, correlations between IFITM3 and immunological features in the bladder cancer (BLCA) tumor microenvironment (TME) were assessed. In addition, the role of IFITM3 in estimating the clinical characteristics and the response to various therapies in BLCA was also evaluated. These results were next confirmed in the IMvigor210 cohort and a recruited cohort. In addition, correlations between IFITM3 and emerging immunobiomarkers, such as microbiota and N6-methyladenosine (m6A) genes, were assessed. IFITM3 was enhanced in most tumor tissues in comparison with adjacent tissues. IFITM3 was positively correlated with immunomodulators, tumor-infiltrating immune cells (TIICs), cancer immunity cycles, and inhibitory immune checkpoints. In addition, IFITM3 was associated with an inflamed phenotype and several established molecular subtypes. IFITM3 expression also predicted a notably higher response to chemotherapy, anti-EGFR therapy, and immunotherapy but a low response to anti-ERBB2, anti-ERBB4, and antiangiogenic therapy. In addition, IFITM3 was correlated with immune-related microbiota and m6A genes. In addition to BLCA, IFITM3 is expected to be a marker of high immunogenicity in most human cancers. In conclusion, IFITM3 expression can be used to identify immuno-hot tumors in most cancers, and IFITM3 may be a promising pancancer biomarker to estimate the immunological features of tumors.

Identification of methylation-driven genes prognosis signature and immune microenvironment in uterus corpus endometrial cancer.

BACKGROUND: Uterus corpus endometrial cancer (UCEC) is the main malignant tumor in gynecology, with a high degree of heterogeneity, especially in terms of prognosis and immunotherapy efficacy. DNA methylation is one of the most important epigenetic modifications. Studying DNA methylation can help predict the prognosis of cancer patients and provide help for clinical treatment. Our research aims to discover whether abnormal DNA methylation can predict the prognosis of UCEC and reflect the patient's tumor immune microenvironment. PATIENTS AND METHODS: The clinical data, DNA methylation data, gene expression data and somatic mutation data of UCEC patients were all downloaded from the TCGA database. The MethylMix algorithm was used to integrate DNA methylation data and mRNA expression data. Univariate Cox regression analysis, Multivariate Cox regression analysis, and Lasso Cox regression analysis were used to determine prognostic DNA methylation-driven genes and to construct an independent prognostic index (MDS). ROC curve analysis and Kaplan-Meier survival curve analysis were used to evaluate the predictive ability of MDS. GSEA analysis was used to explore possible mechanisms that contribute to the heterogeneity of the prognosis of UCEC patients. RESULTS: 3 differential methylation-driven genes (DMDGs) (PARVG, SYNE4 and CDO1) were considered as predictors of poor prognosis in UCEC. An independent prognostic index was finally established based on 3 DMDGs. From the results of ROC curve analysis and survival curve analysis, MDS showed excellent prognostic ability in TCGA-UCEC. A new nomogram based on MDS and other prognostic clinical indicators has also been successfully established. The C-index of the nomogram for OS prediction was 0.764 (95% CI = 0.702-0.826). GSEA analysis suggests that there were differences in immune-related pathways among patients with different prognosis. The abundance of M2 macrophages and M0 macrophages were significantly enhanced in the high-risk group while T cells CD8, Eosinophils and Neutrophils were markedly elevated in the low-risk group. Meanwhile, patients in the low-risk group had higher levels of immunosuppressant expression, higher tumor mutational burden and immunophenoscore (IPS) scores. Joint survival analysis revealed that 7 methylation-driven genes could be independent prognostic factors for overall survival for UCEC. CONCLUSION: We have successfully established a risk model based on 3 DMDGs, which could accurately predict the prognosis of patients with UCEC and reflect the tumor immune microenvironment.

Alginate-azo/chitosan nanocapsules in vitro drug delivery for hepatic carcinoma cells: UV-stimulated decomposition and drug release based on trans-to-cis isomerization.

In this study, a nanocapsule (AL-azo/CH) was prepared with the anionic alginate-azo (AL-azo) and cationic chitosan (CH) via layer-by-layer method. Doxorubicin hydrochloride (DOX), an anticancer drug, was entrapped inside the AL-azo nanocapsules to form the DOX-loaded nanocapsules (DOX/AL-azo/CH). When the DOX/AL-azo/CH nanocapsules were irradiated with 365-nm light, the electrostatic attraction between the layers would be weakened as the trans-to-cis isomerization of AL-azo, which would lead to the UV-responsive decomposition and drug-release. Furthermore, cellular experiments showed that DOX/AL-azo/CH nanocapsules could be endocytosed by the HepG2 cells, and the confocal laser scanning microscope images showed that the DOX fluorescence intensity became stronger with the prolonging of irradiation time, indicating that the intracellular DOX-release could be controlled by UV irradiation. The AL-azo/CH nanocarriers were UV-triggered decomposition and drug-release, which stepped further towards the next-generation of nano-therapeutics with spatial and temporal external control in the field of polysaccharide.

Azo modified hyaluronic acid based nanocapsules: CD44 targeted, UV-responsive decomposition and drug release in liver cancer cells.

Herein, we demonstrate a novel UV-induced decomposable nanocapsule of natural polysaccharide (HA-azo/PDADMAC). The nanocapsules are fabricated based on layer-by-layer co-assembly of anionic azobenzene functionalized hyaluronic acid (HA-azo) and cationic poly diallyl dimethylammonium chloride (PDADMAC). When the nanocapsules are exposed to 365 nm light, ultraviolet photons can trigger the photo-isomerization of azobenzene groups in the framework. The nanocapsules could decompose from large-sized nanocapsules to small fragments. Due to their optimized original size (~180 nm), the nanocapsules can effectively avoid biological barriers, provide a long blood circulation and achieve high tumor accumulation. It can fast eliminate nanocapsules from tumor and release the loaded drugs for chemotherapy after UV-induced dissociation. Besides, HA is an endogenous polysaccharide that shows intrinsic targetability to CD44 receptors on surface of cancer cells. The intracellular experiment shows that the HA-azo/PDADMAC nanocapsules with CD44 targeting ability and UV-controlled intracellular drug release are promising for cancer chemotherapy.

Low Expression of RILPL2 Predicts Poor Prognosis and Correlates With Immune Infiltration in Endometrial Carcinoma.

Increasing numbers of biomarkers have been identified in various cancers. However, biomarkers associated with endometrial carcinoma (EC) remain largely to be explored. In the current research, we downloaded the RNA-seq data and corresponding clinicopathological features from the Cancer Genome Atlas (TCGA) database. We conducted an expression analysis, which resulted in RILPL2 as a novel diagnostic biomarker in EC. The dysregulation of RILPL2 in EC was also validated in multiple datasets. The correlations between clinical features and RILPL2 expression were assessed by logistic regression analysis. Then, Kaplan-Meier analysis, univariate and multivariate Cox regression analysis were performed to estimate prognostic values of RILPL2 in the TCGA cohort, which revealed that increased level of RILPL2 was remarkably associated with better prognosis and could act as an independent prognostic biomarker in patients with EC. Moreover, correlation analysis of RILPL2 and tumor-infiltrating immune cells (TIICs) indicated that RILPL2 might play a critical role in regulating immune cell infiltration in EC and is related to immune response. Besides, high methylation level was a significant cause of low RILPL2 expression in EC. Subsequently, weighted gene co-expression network analysis (WGCNA) and enrichment analysis were conducted to explore the RILPL2-involved underlying oncogenic mechanisms, and the results indicated that RILPL2 mainly regulated cell cycle. In conclusion, our findings provided evidence that downregulation of RILPL2 in EC is an indicator of adverse prognosis and RILPL2 may act as a promising target for the therapeutics of EC.

A fluorescence turn-on probe for hydrogen sulfide and biothiols based on PET & TICT and its imaging in HeLa cells.

In this paper, a photoinduced electron transfer (PET)& twisted intramolecular charge transfer (TICT)-based fluorescent probe (1) for detecting biothiols (GSH/Cys/Hcy) and hydrogen sulfide with fluorescence turn on was developed. The probe could recognize hydrogen sulfide over primary ions and selectively detect GSH/Cys/Hcy over other amino acids with fluorescence turn-on (an ESIPT process). H2S can be distinguished from GSH/Cys/Hcy with wavelength shift by UV-Vis spectra. In addition, detection limits for H2S/GSH/Cys/Hcy of probe 1 were 1.42 µM (0-100 µM), 0.13 µM (0-40 µM), 0.27 (0-30 µM), 0.22 µM (0-40 µM), respectively. The proposed thiolysis of the 2,4-dinitrochlorophenyl ether reaction in identification process was verified by the characteristic peak in 1H NMR and HRMS spectra. Finally, the biological imaging experiments and low cytotoxicity investigations in HeLa cells demonstrated that probe 1 could provide a promising method for the determination of H2S and biothiols in aqueous solution and living cells.

Establishing a Prognostic Signature Based on Epithelial-Mesenchymal Transition-Related Genes for Endometrial Cancer Patients.

Backgrounds: Epithelial-mesenchymal transition (EMT) is a sequential process where tumor cells develop from the epithelial state to the mesenchymal state. EMT contributes to various tumor functions including initiation, propagating potential, and resistance to therapy, thus affecting the survival time of patients. The aim of this research is to set up an EMT-related prognostic signature for endometrial cancer (EC). Methods: EMT-related gene (ERG) expression and clinical data were acquired from The Cancer Genome Atlas (TCGA). The entire set was randomly divided into two sets, one for contributing the risk model (risk score) and the other for validating. Univariate and multivariate Cox proportional hazards regression analyses were applied to the training set to select the prognostic ERGs. The expression of 10 ERGs was confirmed by qRT-PCR in clinical samples. Then, we developed a nomogram predicting 1-/3-/5-year survival possibility combining the risk score and clinical factors. The entire set was stratified into the high- and low-risk groups, which was used to analyze the immune infiltrating, tumorigenesis pathways, and response to drugs. Results: A total of 220 genes were screened out from 1,316 ERGs for their differential expression in tumor versus normal. Next, 10 genes were found to be associated with overall survival (OS) in EC, and the expression was validated by qRT-PCR using clinical samples, so we constructed a 10-ERG-based risk score to distinguish high-/low-risk patients and a nomogram to predict survival rate. The calibration plots proved the predictive value of our model. Gene Set Enrichment Analysis (GSEA) discovered that in the low-risk group, immune-related pathways were enriched; in the high-risk group, tumorigenesis pathways were enriched. The low-risk group showed more immune activities, higher tumor mutational burden (TMB), and higher CTAL4/PD1 expression, which was in line with a better response to immune checkpoint inhibitors. Nevertheless, response to chemotherapeutic drugs turned out better in the high-risk group. The high-risk group had higher N6-methyladenosine (m6A) RNA expression, microsatellite instability level, and stemness indices. Conclusion: We constructed the ERG-related signature model to predict the prognosis of EC patients. What is more, it might offer a reference for predicting individualized response to immune checkpoint inhibitors and chemotherapeutic drugs.

Overexpression of TPX2 predicts poor clinical outcome and is associated with immune infiltration in hepatic cell cancer.

Targeting protein for Xenopus kinesin-like protein 2 (TPX2) has been identified as an oncogene in multiple cancers. However, the associations among TPX2 expression, prognosis, and tumor immunity in hepatic cell cancer (HCC) have not been explored. We analyzed TPX2 expression by multiple gene expression databases, including Oncomine, TIMER, and UALCAN. The prognosis effect of TPX2 was analyzed by Kaplan--Meier plotter. The coexpressed genes with TPX2 were analyzed using Linked Omics. The association among TPX2 and immune infiltrates and immune checkpoints was determined by TIMER. It was found that TPX2 expression was notably upregulated in multiple HCC tissues. Overexpression of TPX2 has associations with race, age, weight, clinical stage and tumor grade, as well as poor prognosis in overall survival (OS), progression-free survival (PFS), disease-free survival (DFS), and disease-specific survival (DSS). In addition, TPX2 expression has a positive association with the infiltration of immune cells and the expression of immune checkpoint molecules. Coexpressed genes and functional network analysis suggested several potential mechanisms of TPX2 affecting HCC progression. The findings reveal that TPX2 has associations with prognosis and infiltration of immune cells in HCC patients, which has laid a basis for in-depth study of TPX2 role in HCC.

lncRNA TPTEP1 competitively sponges miR­328­5p to inhibit the proliferation of non­small cell lung cancer cells.

Accumulating evidence suggests that lncRNAs are involved in almost all normal physiological processes and that aberrant expression of lncRNAs may be involved in the development of diseases, including non­small cell lung cancer (NSCLC). However, the roles of lncRNA­TPTE pseudogene 1 (TPTEP1) in lung cancer and the underlying molecular mechanisms have remained elusive. In the present study, significant downregulation of TPTEP1 in tumors compared with normal tissues from patients with NSCLC was observed. Overexpression of TPTEP1 inhibited cell proliferation and induced apoptosis in NSCLC cells. A bioinformatics analysis based on miRDB predicted microRNA (miR)­328­5p as a potential binding miRNA for TPTEP1. Using a dual­luciferase reporter assay and western blot analysis, it was further validated that TPTEP1 sponged miR­328­5p to upregulate Src kinase signaling inhibitor 1 (SRCIN1) in NSCLC cells. Through regulation of SRCIN1, TPTEP1 was indicated to inactivate the Src and STAT3 pathways in NSCLC cells. Notably, silencing of SRCIN1 reversed the TPTEP1 overexpression­induced inhibition of cell proliferation and increase of the apoptotic rate in NSCLC cells. Pearson correlation analysis revealed a significant positive correlation between TPTEP1 and SRCIN1 mRNA levels in NSCLC tumors. The present results provided insight into the roles of TPTEP1 in NSCLC and the underlying mechanisms.

The preparation of hollow AgPt@Pt core-shell nanoparticles loaded on polypyrrole nanosheet modified electrode and its application in immunosensor.

The designed synthesis of efficient materials can significantly enhance the performance of electrochemical immunoassay in the detection of diseases, pesticide residues and environmental pollutants. The hollow AgPt@Pt core-shell nanoparticles (AgPt@Pt HNs) have exhibited high catalytic efficiency to the hydrogen peroxide (H2O2) reduction for its high mass activity from their hollow structure. Their limitation of instability can be overcome by loading on polypyrrole nanosheet (PPy NS). Besides, PPy NS exhibits good conductivity, and there exists environmentally-friendly method for its synthetic. Thus, AgPt@Pt HNs loaded on PPy NS (AgPt@Pt HNs/PPy NS) exhibits high catalytic efficiency to the reduction of H2O2 and good stability. Furthermore, the quick electron transfer of AgPt@Pt HNs/PPy NS modified glassy carbon electrode has been evidenced by the finding that the large constant of apparent electron transfer rate has also enlarged the current signal when the amount of electron is invariant. The modified electrode has fabricated a label-free amperometric immunosensor to detect sensitively prostate-specific antigen (PSA) with H2O2 as the electroactive material. The immunosensor in hollow core-shell nanosheet structure exhibiting good detection performance of PSA shows its promising applications in the clinical diagnosis.

Curcumin-induced promoter hypermethylation of the mammalian target of rapamycin gene in multiple myeloma cells.

Curcumin, a polyphenol derived from the rhizome of Curcuma, is a potential tumor inhibitor through affecting signaling pathways and epigenetic regulation. The mammalian target of rapamycin (mTOR) gene serves a crucial role in the carcinogenesis of multiple myeloma. The curcumin-induced epigenetic regulation of mTOR, including promoter DNA methylation in multiple myeloma, has not yet been fully elucidated. In the present study, antitumor effects of curcumin were investigated in RPMI-8226 and NCI-H929 cells using an MTT assay and flow cytometry. The expression of mTOR and DNA methyltransferase proteins were determined by western blot analysis, and the methylation status of the mTOR promoter were detected by sequencing following bisulfite conversion. The results of the present study revealed that the half-maximal inhibitory concentration of curcumin was 10 µM in myeloma cells. Following curcumin treatment, the mRNA and protein expression levels of mTOR were decreased by 43.31 and 39.34% in NCI-H929 cells, respectively. The promoter of mTOR, located in chromosome 1 (chromosome position, 11262153-11263153), contains a CpG island that was hypermethylated in myeloma cells following curcumin treatment. The expression levels of DNA methyltransferase (DNMT)3a and DNMT3b were increased in curcumin-treated cells. Collectively, these results indicate that curcumin serves a role in the epigenetic regulation of mTOR expression, and that mTOR downregulation is due to promoter hypermethylation, which may be associated with DNMT3a and DNMT3b upregulation. The results of the present study contribute towards improving the understanding of curcumin treatment in multiple myeloma and provide novel insights into the molecular mechanisms underlying the epigenetic regulation of mTOR.