Unlocking reproducible transcriptomic signatures for acute myeloid leukaemia: Integration, classification and drug repurposing.

Acute myeloid leukaemia (AML) is a highly heterogeneous disease, which lead to various findings in transcriptomic research. This study addresses these challenges by integrating 34 datasets, including 26 control groups, 6 prognostic datasets and 2 single-cell RNA sequencing (scRNA-seq) datasets to identify 10,000 AML-related genes (ARGs). We focused on genes with low variability and high consistency and successfully discovered 191 AML signatures (ASs). Leveraging machine learning techniques, specifically the XGBoost model and our custom framework, we classified AML subtypes with both scRNA-seq and bulk RNA-seq data, complementing the ELN2022 classification approach. Our research also identified promising treatments for AML through drug repurposing, with solasonine showing potential efficacy for high-risk AML patients, supported by molecular docking and transcriptomic analyses. To enhance reproducibility and customizability, we developed CSAMLdb, a user-friendly database platform. It facilitates the reuse and personalized analysis of nearly all results obtained in this research, including single-gene prognostics, multi-gene scoring, enrichment analysis, machine learning risk assessment, drug repositioning analysis and literature abstract named entity recognition. CSAMLdb is available at http://www.csamldb.com.

Gut microbiota regulation of T lymphocyte subsets during systemic lupus erythematosus.

BACKGROUND: Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by disturbance of pro-inflammatory and anti-inflammatory lymphocytes. Growing evidence shown that gut microbiota participated in the occurrence and development of SLE by affecting the differentiation and function of intestinal immune cells. The purpose of this study was to investigate the changes of gut microbiota in SLE and judge its associations with peripheral T lymphocytes. METHODS: A total of 19 SLE patients and 16 HCs were enrolled in this study. Flow cytometry was used to detect the number of peripheral T lymphocyte subsets, and 16 s rRNA was used to detect the relative abundance of gut microbiota. Analyzed the correlation between gut microbiota with SLEDAI, ESR, ds-DNA and complement. SPSS26.0 software was used to analyze the experimental data. Mann-Whitney U test was applied to compare T lymphocyte subsets. Spearman analysis was used for calculating correlation. RESULTS: Compared with HCs, the proportions of Tregs (P = 0.001), Tfh cells (P = 0.018) and Naïve CD4 + T cells (P = 0.004) significantly decreased in SLE patients, and proportions of Th17 cells (P = 0.020) and γδT cells (P = 0.018) increased in SLE. The diversity of SLE patients were significantly decreased. Addition, there were 11 species of flora were discovered to be distinctly different in SLE group (P < 0.05). In the correlation analysis of SLE, Tregs were positively correlated with Ruminococcus2 (P = 0.042), Th17 cells were positively correlated with Megamonas (P = 0.009), γδT cells were positively correlated with Megamonas (P = 0.003) and Streptococcus (P = 0.004), Tfh cells were positively correlated with Bacteroides (P = 0.040), and Th1 cells were negatively correlated with Bifidobacterium (P = 0.005). As for clinical indicators, the level of Tregs was negatively correlated with ESR (P = 0.031), but not with C3 and C4, and the remaining cells were not significantly correlated with ESR, C3 and C4. CONCLUSION: Gut microbiota and T lymphocyte subsets of SLE changed and related to each other, which may break the immune balance and affect the occurrence and development of SLE. Therefore, it is necessary to pay attention to the changes of gut microbiota and provide new ideas for the treatment of SLE.

Efficacy and safety of current therapies for difficult-to-treat rheumatoid arthritis: a systematic review and network meta-analysis.

BACKGROUND: Difficult-to-treat Rheumatoid arthritis (D2T RA) is primarily characterised by failure of at least two different mechanism of action biologic/targeted synthetic disease-modifying antirheumatic drug (DMARDs) with evidence of active/progressive disease. While a variety of drugs have been used in previous studies to treat D2T RA, there has been no systematic summary of these drugs. This study conducted a systematic review of randomized controlled trials aimed at analyzing the efficacy and safety of individual therapeutic agents for the treatment of D2T RA and recommending the optimal therapeutic dose. METHODS: The English databases were searched for studies on the treatment of D2T RA published between the date of the database's establishment and March, 2024. This study uses R 3.1.2 for data analysis, and the rjags package runs JAGS 3.4.0.20. The study fitted a stochastic effects Bayesian network meta-analysis for each outcome measure. RESULT: A total of 42 studies were included in this study. Compared with placebo, the improvement of Disease Activity Score of 28 Joints (DAS28) score is ranked from high to low as tocilizumab, baricitinib and opinercept. The improvement of American College of Rheumatology 50 response (ACR50) score in patients with drug use was ranked from good to poor as follows: olokizumab, tocilizumab, adalimumab, baricitinib, and upadacitinib, and 8 mg/4w tocilizumab demonstrated the best efficacy. Notably, rituximab is generally the safest drug. Janus kinase (JAK) inhibitors and T cell costimulation modulators are effective in D2T RA refractory to biologic DMARDs, while JAK inhibitors and interleukin-6 (IL-6) inhibitors show effectiveness in D2T RA refractory to csDMARDs. CONCLUSION: Tocilizumab and rituximab have better efficacy and safety in the treatment of D2T RA, and the 8 mg/4w dose of tocilizumab may be the first choice for achieving disease remission.

Nitrogen-Doped Biochar for Enhanced Peroxymonosulfate Activation to Degrade Phenol through Both Free Radical and Direct Oxidation Based on Electron Transfer Pathways.

Nowadays, super nitrogen-doped biochar (SNBC) material has become one of the most promising metal-free catalysts for activating peroxymonosulfate (PMS) to degrade organic pollutants. To understand the evolution of SNBC properties with fabrication conditions, a variety of SNBC materials were prepared and characterized by elemental analysis, N2 adsorption-desorption, scanning electron microscopy, Fourier transform infrared spectroscopy, Raman spectroscopy, X-ray photoelectron spectroscopy, and X-ray diffraction. We systematically investigated the activation potential of these SNBC materials for PMS to degrade phenol. SN1BC-800 with the best catalytic performance was obtained by changing the activation temperatures and the ratio of biochar to melamine. The effects of catalyst dosage, the PMS concentration, pH, and reaction temperature on phenol degradation were studied in detail. In the presence of 0.3 g/L SN1BC-800 and 1 g/L PMS, the removal rate of 20 mg/L phenol could reach 100% within 5 min. According to electron paramagnetic resonance spectra and free radical quenching experiments, a nonfree radical pathway of phenol degradation dominated by 1O2 and electron transfer was proposed. More interestingly, the excellent catalytic performance of the SN1BC-800/PMS system is universally applicable in the degradation of other typical organic pollutants. In addition, the degradation rate of phenol is still over 80% after five reuses, which shows that the SN1BC-800 catalyst has high stability and good application prospects in environmental remediation.

Mendelian randomization analysis suggests no associations of herpes simplex virus infections with systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) characterized by immune dysfunction is possibly more vulnerable to herpes simplex virus (HSV) infection. The infection has been intensively considered a common onset and exacerbation of SLE. This study is aimed at elucidating the causal association between SLE and HSV. A bidirectional two-sample Mendelian Randomization (TSMR) analysis was systematically conducted to explore the causal effect of SLE and HSV on each other. The causality was estimated by inverse variance weighted (IVW), MR-Egger and weighted median methods based on the summary-level genome-wide association studies (GWAS) data from a publicly available database. Genetically proxied HSV infection exhibited no causal association with SLE in the forward MR analysis using IVW method (odds ratio [OR] = 0.987; 95% confidence interval [CI]: 0.891-1.093; p = 0.798), nor did HSV-1 IgG (OR = 1.241; 95% CI: 0.874-1.762; p = 0.227) and HSV-2 IgG (OR = 0.934; 95% CI: 0.821-1.062; p = 0.297). Similar null results with HSV infection (OR = 1.021; 95% CI: 0.986-1.057; p = 0.245), HSV-1 IgG (OR = 1.003; 95% CI: 0.982-1.024; p = 0.788) and HSV-2 IgG (OR = 1.034; 95% CI: 0.991-1.080; p = 0.121) were observed in the reverse MR where SLE served as the exposure. Our study demonstrated no causal association between the genetically predicted HSV and SLE.

Deep stratification by transcriptome molecular characters for precision treatment of patients with systemic lupus erythematosus.

OBJECTIVES: To leverage the high clinical heterogeneity of systemic lupus erythematosus (SLE), we developed and validated a new stratification scheme by integrating genome-scale transcriptomic profiles to identify patient subtypes sharing similar transcriptomic markers and drug targets. METHODS: A normalized compendium of transcription profiles was created from peripheral blood mononuclear cells (PBMCs) of 1046 SLE patients and 86 healthy controls (HCs), covering an intersection of 13 689 genes from six microarray datasets. Upregulated differentially expressed genes were subjected to functional and network analysis in which samples were grouped using unsupervised clustering to identify patient subtypes. Then, clustering stability was evaluated by the stratification of six integrated RNA-sequencing datasets using the same method. Finally, the Xgboost classifier was applied to the independent datasets to identify factors associated with treatment outcomes. RESULTS: Based on 278 upregulated DEGs of the transcript profiles, SLE patients were classified into three subtypes (subtype A-C) each with distinct molecular and cellular signatures. Neutrophil activation-related pathways were markedly activated in subtype A (named NE-driving), whereas lymphocyte and IFN-related pathways were more enriched in subtype B (IFN-driving). As the most severe subtype, subtype C [NE-IFN-dual-driving (Dual-driving)] shared functional mechanisms with both NE-driving and IFN-driving, which was closely associated with clinical features and could be used to predict the responses of treatment. CONCLUSION: We developed the largest cohesive SLE transcriptomic compendium for deep stratification using the most comprehensive microarray and RNA sequencing datasets to date. This result could guide future design of molecular diagnosis and the development of stratified therapy for SLE patients.

Specific enterotype of gut microbiota predicted clinical effect of methotrexate in patients with rheumatoid arthritis.

OBJECTIVE: The most used drug for the treatment of rheumatoid arthritis (RA) remains methotrexate (MTX). Unfortunately, up to 50% of patients do not achieve a clinically adequate outcome. Here we study whether the gut microbiota patterns can aid in the prediction of MTX efficacy for RA. METHOD: To dissect gut microbiome profiles of RA patients (n = 145), 16S rRNA gene sequencing was performed. Dirichlet multinomial mixture (DMM) clustering was used to identify enterotypes at genus level. The relationships between enterotypes and clinical measures (such as lymphocyte subsets and cytokines detected by flow cytometry) were explored. Then, enterotype stability was evaluated by the stratification of the RA patient cohort (n = 66) in Shanghai, China, using the same method. Finally, the enterotype-based gut microbial human index classifier was applied to another independent RA patient cohort (n = 27) to identify the factors associated with MTX clinical response. RESULTS: Our analysis revealed that the RA patients always displayed two different dysbiotic microbiota patterns: RA E1 comprised predominantly Prevotella and RA E2 comprised predominantly Bacteroides. Among all of the lymphocyte subsets and cytokines, only the number of CD8+ T cells showed a significant difference between RA E1 and RA E2. These results were validated in the RA patient cohort in Shanghai, China. Significant associations of RA E1 with clinical response to subsequent MTX treatment were confirmed by another independent RA patient cohort. CONCLUSION: Together, the enterotype-based gut microbial human index (EGMI) classifier was useful to precisely and effectively identify enterotypes of individual RA patients, which could effectively evaluate MTX clinical responses.

Risk factors analysis and risk assessment model construction of systemic lupus erythematosus patients with infection.

OBJECTIVE: To analyze the characteristics of peripheral blood lymphocyte subsets in systemic lupus erythematosus (SLE) patients with infection and non-infection group. Explore the risk factors of infection in SLE patients and establish a risk matrix model to predict the occurrence of co-infection. METHODS: total of 333 SLE patients without infection, 163 patients suffering from infection, and 132 healthy controls (HCs) were recruited. General clinical data and disease activity indicators were collected. The levels of total T, B, CD4+T, CD8+T, NK, Th1, Th2, Th17, and Treg cells in peripheral blood of HCs, SLE patients (including infected and non-infected group) were analyzed by flow cytometry. The risk assessment model was constructed, and the receiver operating characteristic curve was drawn. 39 SLE patients with infection and 20 patients without infection were randomly selected to evaluate the predictive power of the regression model. RESULTS: The levels of T, B, CD4+T, CD8+T, and NK cells in the infected patients were significantly decreased when compared with that of both non-infected patients and HCs (p < .05). The non-infected patients had a higher level of Th17 than that of HCs (p < . 05), but the absolute numbers of Th17 in infected patients was the lowest among the three groups (p < .001). The number of Treg cells in SLE patients was significantly lower than that of HCs (p < .01), and the infected patients had the fewest Treg cells among all these groups (p < . 05). A risk assessment model for SLE with infection was established, p = 1/(1-e-y), Y = 1.763-0.004 × Absolute number of CD4 + T cells-0.005 × Absolute number of NK cells -0.005 × Platelet count(×1012/L) + 1.033 × Absolute number of lymphocytes (×109/L) + 0.023 × C-reactive protein (mg/dL), whose predictive sensitivity is 77.5%, and specificity is 78.3%. CONCLUSION: The new risk assessment model exhibits good predictive ability to assess co-infection risk in SLE patients. T cells, NK cells, and CD4 + T cells along with other parameters help in differentiating Lupus with infection from Lupus alone.

Reduced circulating Tregs and positive pANCA were robustly associated with the occurrence of antiphospholipid syndrome in patients with systemic lupus erythematosus.

BACKGROUND: Systemic lupus erythematosus (SLE) is a typical chronic immune disorder with clinical heterogeneity. The systemic abnormal immune response not only challenges the diagnosis and treatment of the disease itself but also the secondary antiphospholipid syndrome (APS), characterized by recurrent arterial or venous thrombosis, recurrent spontaneous abortion, or stillbirth. Clinical interest has primarily focused on primary APS's pathological and clinical features. However, differences in clinical features and laboratory indicators between SLE with or without APS are still lacking, especially differences between circulating lymphocytes, which are critical in the pathogenesis of SLE and its complications. METHODS: In this retrospective study, we collected and analyzed clinical characteristics, general laboratory indicators, immunological indicators, and circulating lymphocyte subsets of SLE with or without APS. RESULTS: Systemic lupus erythematosus with APS (SLE-APS) had elevated SLEDAI scores, hospitalization costs and time, and frequencies of central nervous system symptoms and spontaneous abortion compared with those without APS. SLE-APS had higher positive anti-Cardiolipin antibodies, anti-ß2 Glycoprotein 1 antibodies, and perinuclear antineutrophil cytoplasmic antibody (pANCA) than none-APS patients. Compared with healthy controls (HCs), the circulating lymphocyte subsets were altered to some extent in all patients, especially in patients with SLE-APS. Reduced Tregs and positive pANCA were independent risk factors for SLE secondary APS. CONCLUSION: The present study revealed a robust association between APS secondary to SLE and reduced Tregs and positive pANCA, which provides essential information regarding the diagnosis and therapeutic possibilities of APS secondary to SLE.

Genetically predicted cardiovascular diseases could increase the risk of erectile dysfunction: a bidirectional Mendelian randomization.

PURPOSE: Erectile dysfunction (ED) often appears concomitantly with cardiovascular diseases (CVDs). However, the causal relationship between ED and CVDs is still unclear. This study aimed to investigate the causal effects between CVDs and ED using bidirectional Mendelian randomization (MR). METHODS: ED data (6175 cases and 217,630 controls) were obtained from the IEU OpenGWAS project. Seven types of CVDs were acquired in our study, including stroke (Sample size = 440,328), myocardial infection (Sample size = 184,305), coronary heart disease (Sample size = 86,995), hypertension (Sample size = 36,683), heart failure (Sample size = 208,178), atrial fibrillation (Sample size = 1,030,836), and coronary artery disease (Sample size = 141,217). Inverse variance weighted (IVW) was selected as the primary method for MR analysis. RESULTS: IVW results indicated that stroke (OR = 1.14, 95% CI = 1.02-1.29, P = 0.025), coronary artery disease (OR = 1.09, 95% CI = 1.02-1.16, P = 0.013), coronary heart disease (OR = 1.07, 95% CI = 1.01-1.13, P = 0.017), myocardial infection (OR = 1.09, 95% CI = 1.02-1.17, P = 0.011), and atrial fibrillation (OR = 1.06, 95% CI = 1.00-1.12, P = 0.04) were causally associated with ED. The reverse MR analysis suggested that ED did not influence the prevalence of CVDs. CONCLUSION: These findings highlighted CVDs as causal risk factors for ED, but ED did not directly result in the development of CVDs. Regular monitoring of the erectile function of individuals with CVDs, along with implementing appropriate preventive measures, might help reduce the incidence of ED and enhance the sexual well-being of patients with CVDs.

Genetic evidence supporting a causal role of Janus kinase 2 in prostate cancer: a Mendelian randomization study.

BACKGROUND: Janus kinase-2 (JAK2) inhibitors are now being tried in basic research and clinical practice in prostate cancer (PCa). However, the causal relationship between JAK2 and PCa has not been uniformly described. Here, we examined the cause-effect relation between JAK2 and PCa. METHODS: Two-sample Mendelian randomization (MR) analysis of genetic variation data of JAK2, PCa from IEU OpenGWAS Project was performed by inverse variance weighted, MR-Egger, and weighted median. Cochran's Q heterogeneity test and MR-Egger multiplicity analysis were performed to normalize the MR analysis results to reduce the effect of bias on the results. RESULTS: Five instrumental variables were identified for further MR analysis. Specifically, combining the inverse variance-weighted (OR: 1.0009, 95% CI: 1.0001-1.0015, p = 0.02) and weighted median (OR: 1.0009, 95% CI: 1.0000-1.0017, p = 0.03). Sensitivity analysis showed that there was no heterogeneity (p = 0.448) and horizontal multiplicity (p = 0.770) among the instrumental variables. CONCLUSIONS: We found JAK2 was associated with the development of PCa and was a risk factor for PCa, which might be instructive for the use of JAK2 inhibitors in PCa patients.

Identifying cellular senescence associated genes involved in the progression of end-stage renal disease as new biomarkers.

BACKGROUND: Cellular senescence plays an essential role in the development and progression of end-stage renal disease (ESRD). However, the detailed mechanisms phenomenon remains unclear. METHODS: The mRNA expression profiling dataset GSE37171 was taken from the Gene Expression Omnibus (GEO) database. The cell senescence-associated hub genes were selected by applying protein-protein interaction (PPI), followed by correlation analysis, gene interaction analysis, Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. We next explored the relationships of hub genes with miRNAs, TFs, and diseases. The absolute abundance of eight immune cells and two stromal cells were calculated by MCPcount and the correlation of hub genes with these ten cells was analyzed. Lasso was used to selecting for trait genes. ROC curves and DCA decision curves were used to assess the accuracy and predictive power of the trait genes. RESULTS: A total of 65 cellular senescence signature genes were identified among patients and controls. The PPI network screened out ten hub genes. GO and KEGG indicated that ten hub genes were associated with ESRD progression. Transcription factor gene interactions and common regulatory networks of miRNAs were also identified in the datasets. The hub genes were significantly correlated with immune cells and stromal cells. Then the lasso model was constructed to screen out the five most relevant signature genes (FOS, FOXO3, SIRT1, TP53, SMARCA4). The area under the ROC curve (AUC) showed that these five characteristic genes have good resolving power for the diagnostic model. CONCLUSIONS: Our findings suggested that cellular senescence-associated genes played an important role in the development of ESRD and immune regulation.

A random forest algorithm-based prediction model for moderate to severe acute postoperative pain after orthopedic surgery under general anesthesia.

BACKGROUND: Postoperative pain is one of the most common complications after surgery. In order to detect early and intervene in time for moderate to severe postoperative pain, it is necessary to identify risk factors and construct clinical prediction models. This study aimed to identify significant risk factors and establish a better-performing model to predict moderate to severe acute postoperative pain after orthopedic surgery under general anesthesia. METHODS: Patients who underwent orthopedic surgery under general anesthesia were divided into patients with moderate to severe pain group (group P) and patients without moderate to severe pain group (group N) based on VAS scores. The features selected by Lasso regression were processed by the random forest and multivariate logistic regression models to predict pain outcomes. The classification performance of the two models was evaluated through the testing set. The area under the curves (AUC), the accuracy of the classifiers, and the classification error rate for both classifiers were calculated, the better-performing model was used to predict moderate to severe acute postoperative pain after orthopedic surgery under general anesthesia. RESULTS: A total of 327 patients were enrolled in this study (228 in the training set and 99 in the testing set). The incidence of moderate to severe postoperative pain was 41.3%. The random forest model revealed a classification error rate of 25.2% and an AUC of 0.810 in the testing set. The multivariate logistic regression model revealed a classification error rate of 31.3% and an AUC of 0.764 in the testing set. The random forest model was chosen for predicting clinical outcomes in this study. The risk factors with the greatest and second contribution were immobilization and duration of surgery, respectively. CONCLUSIONS: The random forest model can be used to predict moderate to severe acute postoperative pain after orthopedic surgery under general anesthesia, which is of potential clinical application value.

Sulfurized nano zero-valent iron prepared via different methods: Effect of stability and types of surface corrosion products on removal of 2,4,6-trichlorophenol.

Sulfurization improves the stability and activity of nano zero-valent iron (nZVI). The sulfurized nZVI (S-nZVI) were prepared with ball milling, vacuum chemical vapor deposition (CVD) and liquid-phase reduction techniques and the corresponding products were the mixture of FeS2 and nZVI (nZVI/FeS2), well-defined core-shell structure (FeSx@Fe) or seriously oxidized (S-nZVI(aq)), respectively. All these materials were applied to eliminate 2,4,6-trichlorophenol (TCP) from water. The removal of TCP was irrelevant with the structure of S-nZVI. Both nZVI/FeS2 and FeSx@Fe showed remarkable performance for the degradation of TCP. S-nZVI(aq) possessed poor mineralization efficiency to TCP due to its bad crystallinity degree and severe leaching of Fe ions, which retarded the affinity of TCP. Desorption and quenching experiments suggested that TCP removal by nZVI and S-nZVI was based on surface adsorption and subsequent direct reduction by Fe0, oxidation by in-situ produced ROS and polymerization on the surface of these materials. In the reaction process, the corrosion products of these materials transformed into crystalline Fe3O4 and α/ß-FeOOH, which enhanced the stability of nZVI and S-nZVI materials and was conductive to the electron transferring from Fe0 to TCP and strong affinity of TCP onto Fe or FeSx phases. All these were contributed to high performance of nZVI and sulfurized nZVI in removal and minerazilation of TCP in continuous recycle test.

Efficient activation of persulfate by Nickel-supported cherry core biochar composite for removal of bisphenol A.

In this study, low-cost and easily obtained biochar was chosen to prepare nickel-modified biochar materials (Ni/BC) through a one-step activation pyrolysis method. Characterization with X-ray diffraction, X-ray photoelectron spectroscopy and high-resolution transmission electron microscopy proved the existence of Ni0 and NiO nanocrystals in Ni/BC catalyst. The optimal Ni0.5/BC exhibited excellent peroxymonosulfate (PMS) and peroxydisulfate (PDS) activation efficiency toward bisphenol A (BPA) degradation. The Ni0.5/BC (0.03 g) reacted with 1.0 g L-1 PMS or PDS could completely remove 20 mg L-1 BPA in 10 min with the first-order kinetic constants (k1) of 0.322 min-1 (PMS) and 0.336 min-1 (PDS). More importantly, the composite has better structural and functional attributes for the BPA degradation with universal applicability at wide pH and temperature range, proving as a better degradation mediator with high adaptation for numerous organic pollutants. Catalytic activity decreased slightly even after 4 cycles. Based on the quenching experiment and electron paramagnetic resonance, it was found that SO4•-, •OH and 1O2 were the dominant active species in BPA degradation process. Therefore, this work not only supplies a promising catalyst for the removal of organic contaminants, but also is beneficial for the further development of alternative catalysts for sulfate radical based advanced oxidation processes.

Potential new therapeutic target for Alzheimer's disease: Glucagon-like peptide-1.

Increasing evidence shows a close relationship between Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM). Recently, glucagon-like peptide-1 (GLP-1), a gut incretin hormone, has become a well-established treatment for T2DM and is likely to be involved in treating cognitive impairment. In this mini review, the similarities between AD and T2DM are summarised with the main focus on GLP-1-based therapeutics in AD.

Identification of novel hub genes associated with gastric cancer using integrated bioinformatics analysis.

BACKGROUND: Gastric cancer (GC) is one of the most common solid malignant tumors worldwide with a high-recurrence-rate. Identifying the molecular signatures and specific biomarkers of GC might provide novel clues for GC prognosis and targeted therapy. METHODS: Gene expression profiles were obtained from the ArrayExpress and Gene Expression Omnibus database. Differentially expressed genes (DEGs) were picked out by R software. The hub genes were screened by cytohubba plugin. Their prognostic values were assessed by Kaplan-Meier survival analyses and the gene expression profiling interactive analysis (GEPIA). Finally, qRT-PCR in GC tissue samples was established to validate these DEGs. RESULTS: Total of 295 DEGs were identified between GC and their corresponding normal adjacent tissue samples in E-MTAB-1440, GSE79973, GSE19826, GSE13911, GSE27342, GSE33335 and GSE56807 datasets, including 117 up-regulated and 178 down-regulated genes. Among them, 7 vital upregulated genes (HMMR, SPP1, FN1, CCNB1, CXCL8, MAD2L1 and CCNA2) were selected. Most of them had a significantly worse prognosis except SPP1. Using qRT-PCR, we validated that their transcriptions in our GC tumor tissue were upregulated except SPP1 and FN1, which correlated with tumor relapse and predicts poorer prognosis in GC patients. CONCLUSIONS: We have identified 5 upregulated DEGs (HMMR, CCNB1, CXCL8, MAD2L1, and CCNA2) in GC patients with poor prognosis using integrated bioinformatical methods, which could be potential biomarkers and therapeutic targets for GC treatment.

Absolute reduction of peripheral regulatory T cell in patients with relapsing polychondritis.

OBJECTIVES: Although relapsing polychondritis (RP) is considered as an immune-mediated systemic disease, the levels of peripheral lymphocyte subpopulations are rarely studied in patients with RP. In this study, we focused on changes of peripheral CD4+T cell subsets in patients with RP. METHODS: Absolute numbers and percentages of CD4+T cell subsets including helper T(Th)1, Th2, Th17 cells and regulatory T (Treg) cells in peripheral blood (PB) from 19 RP patients, healthy controls and RA patients respectively were assessed by flow cytometry combined a microbead-based single-platform method. We compared the CD4+T cell levels in all RP patients and healthy controls. In addition, we analysed the difference of the absolute number and percentage of Treg cells between RP and RA patients. RESULTS: Compared with healthy controls, all RP patients had significantly both lower absolute number and proportion of Treg cells (absolute number, 45.10/µl vs. 22.48/µl, p<0.001; proportion, 5.19% vs. 3.78%, p<0.001) no matter whether they had received treatment or not. Similarly, the absolute number of Th2 cells in all RP patients was decreased (10.19/µl vs. 7.44/µl, p=0.030). However, there were no significant differences in percentages and absolute numbers of Th1 and Th17 cells between RP patients and healthy controls. The above results led to increased ratios of Th1/Treg (3.68 vs. 2.06, p=0.020), Th2/Treg (0.29 vs. 0.21, p=0.037) and Th17/Treg (0.25 vs. 0.14, p<0.001) in RP patients, and untreated RP patients were mainly characterised by the imbalance of Th17/Treg (0.25 vs. 0.14, p<0.01). There was no significant difference in Treg cells between RP and RA patients (p>0.05). CONCLUSIONS: Our data suggest that the reduction of Treg cells and its imbalance with Th cells play an important role in the pathogenesis of RP.

Long non-coding RNA MEG3 inhibits M2 macrophage polarization by activating TRAF6 via microRNA-223 down-regulation in viral myocarditis.

Viral myocarditis (VMC) commonly triggers heart failure, for which no specific treatments are available. This study aims to explore the specific role of long non-coding RNA (lncRNA) maternally expressed 3 (MEG3) in VMC. A VMC mouse model was induced by Coxsackievirus B3 (CVB3). Then, MEG3 and TNF receptor-associated factor 6 (TRAF6) were silenced and microRNA-223 (miR-223) was over-expressed in the VMC mice, followed by determination of ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS). Dual-luciferase reporter assay was introduced to test the interaction among MEG3, TRAF6 and miR-223. Macrophages were isolated from cardiac tissues and bone marrow, and polarization of M1 or M2 macrophages was induced. Then, the expressions of components of NLRP3 inflammatory body (NLRP3, ASC, Caspase-1), M1 markers (CD86, iNOS and TNF-α) and M2 markers (CD206, Arginase-1 and Fizz-1) were measured following MEG3 silencing. In the VMC mouse model, MEG3 and TRAF6 levels were obviously increased, while miR-223 expression was significantly reduced. Down-regulation of MEG3 resulted in the inhibition of TRAF6 by promoting miR-223. TRAF6 was negatively correlated with miR-223, but positively correlated with MEG3 expression. Down-regulations of MEG3 or TRAF6 or up-regulation of miR-223 was observed to increase mouse weight, survival rate, LVEF and LVFS, while inhibiting myocarditis and inflammation via the NF-κB pathway inactivation in VMC mice. Down-regulation of MEG3 decreased M1 macrophage polarization and elevated M2 macrophage polarization by up-regulating miR-223. Collectively, down-regulation of MEG3 leads to the inhibition of inflammation and induces M2 macrophage polarization via miR-223/TRAF6/NF-κB axis, thus alleviating VMC.

Methylsiloxanes and Their Brominated Products in One e-Waste Recycling Area in China: Emission, Environmental Distribution, and Elimination.

The present study investigated the sources and fates of methylsiloxanes and their brominated products in one e-waste recycling area of China. During thermal (30-1000 °C) recycling experiments for printed wiring boards (PWBs), besides volatile methylsiloxanes (D4, D5, and D6), their monobrominated products, that is, D3D(CH2Br), D4D(CH2Br), and D5D(CH2Br), were also found by quadrupole time-of-flight gas chromatography-mass spectrometry to have 2-3 orders of magnitude lower emissions (0.31-1.3 µg/g) than those (18.1-866 µg/g) of parent methylsiloxanes. Overall, the fastest emissions of methylsiloxanes and bromo-methylsiloxanes occurred at 300-400 and 400-500 °C, respectively, accounting for 35.3-51.0 and 39.4-82.1% of their total emission. In the e-waste recycling area, concentrations of D4-D6 were 1.1-75.0 µg/g dw [detection frequency (df) = 100%] in 31 dusts from PWB treatment workshops, while limits of detection (LOD) < 683 ng/g dw (df = 69-100%) in 48 surrounding soils were up to 3 orders of magnitudes higher than those in reference areas. Meanwhile, D3D(CH2Br)-D5D(CH2Br) were detected in both dusts (