Identification of genes related to low-grade glioma progression and prognosis based on integrated transcriptome analysis.

Glioma is one of the most common types of human brain tumor, with high mortality in high-grade gliomas (HGG). Low-grade gliomas (LGG) can progress into HGG, leading to poor prognosis. However, it is unclear what factors affect the progression of LGG to HGG. This study aims to explore the function of the crosstalk genes on the progression and prognosis of LGG using bioinformatics analysis. Integrated transcriptome analysis was used to screen differentially expressed genes (DEGs). Then, gene ontology (GO) function enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were performed to investigate the association between DEGs and gene functions and pathways by ClusterProfiler package and ClueGO plug-in. Protein-protein interaction (PPI) network analysis was applied to explore the connection between genes and biological processes. Subsequently, the gene clusters were analyzed using the Centiscape and molecular complex detection (MCODE) plug-in in Cytoscape software, where the crosstalk genes were identified for further study. Ultimately, the UALCAN website and Gene Expression Profiling Interactive Analysis (GEPIA) website were performed to visualize the expression levels and survival curves of genes, respectively. There were 74 DEGs identified in glioma, including 55 upregulated genes and 19 downregulated genes, which mainly were enriched in extracellular matrix (ECM)-receptor interaction, focal adhesion, PI3K-Akt signaling pathway, and so on. Then, six crosstalk genes were selected, including COL1A1, COL1A2, COL3A1, COL4A1, COL4A2, and COL5A2 genes. Overall survival (OS) analysis of crosstalk genes was conducted on the GEPIA website. High expression levels of crosstalk genes were closely related to the low survival rate of patients with LGG. The overexpressed crosstalk genes, such as COL1A1, COL1A2, COL3A1, COL4A1, COL4A2, and COL5A2 may participate in the progression and poor prognosis of LGG through the ECM-receptor interaction pathway.

Microglia in Ischemic Stroke: Pathogenesis Insights and Therapeutic Challenges.

Ischemic stroke is the most common type of stroke, which is the main cause of death and disability on a global scale. As the primary immune cells in the brain that are crucial for preserving homeostasis of the central nervous system microenvironment, microglia have been found to exhibit dual or even multiple effects at different stages of ischemic stroke. The anti-inflammatory polarization of microglia and release of neurotrophic factors may provide benefits by promoting neurological recovery at the lesion in the early phase after ischemic stroke. However, the pro-inflammatory polarization of microglia and secretion of inflammatory factors in the later phase of injury may exacerbate the ischemic lesion, suggesting the therapeutic potential of modulating the balance of microglial polarization to predispose them to anti-inflammatory transformation in ischemic stroke. Microglia-mediated signaling crosstalk with other cells may also be key to improving functional outcomes following ischemic stroke. Thus, this review provides an overview of microglial functions and responses under physiological and ischemic stroke conditions, including microglial activation, polarization, and interactions with other cells. We focus on approaches that promote anti-inflammatory polarization of microglia, inhibit microglial activation, and enhance beneficial cell-to-cell interactions. These targets may hold promise for the creation of innovative therapeutic strategies.

Risk Factors, Outcomes, and Predictions of Extensively Drug-Resistant Acinetobacter baumannii Nosocomial Infections in Patients with Nervous System Diseases.

Purpose: Acinetobacter baumannii has evolved to become a major pathogen of nosocomial infections, resulting in increased morbidity and mortality. This study aimed to investigate the risk factors, outcomes, and predictions of extensively drug-resistant (XDR)-A. baumannii nosocomial infections in patients with nervous system diseases (NSDs). Methods: A retrospective study of patients infected with XDR-A. baumannii admitted to the Affiliated Hospital of Southwest Medical University (Luzhou, China) from January 2021 to December 2022 was conducted. Three multivariate regression models were used to assess the risk factors and predictive value for specific diagnostic and prognostic subgroups. Results: A total of 190 patients were included, of which 84 were diagnosed with NSDs and 80% of those were due to stroke. The overall rates of all-cause mortality for XDR-A. baumannii nosocomial infections and those in NSDs were 38.9% and 40.5%, respectively. Firstly, hypertension, indwelling gastric tube, tracheotomy, deep puncture, bladder irrigation, and pulmonary infections were independent risk factors for XDR-A. baumannii nosocomial infections in patients with NSDs. Moreover, pulmonary infections, the aspartate aminotransferase (AST) to alanine aminotransferase (ALT) ratio, and the neutrophil-to-lymphocyte ratio (NLR) were significantly associated with increased mortality rates in patients with nosocomial infections caused by XDR-A. baumannii. Thirdly, NLR and cardiovascular diseases accounted for a high risk of mortality for XDR-A. baumannii nosocomial infections in patients with NSDs. The area under the curves of results from each multivariate regression model were 0.827, 0.811, and 0.853, respectively. Conclusion: This study reveals the risk factors of XDR-A. baumannii nosocomial infections in patients with NSDs, and proves their reliable predictive value. Early recognition of patients at high risk, sterilizing medical tools, and regular blood monitoring are all critical aspects for minimizing the nosocomial spread and mortality of A. baumannii infections.

Application of surface-enhanced laser desorption/ionization time-of-flight mass spectrometry coupled with an artificial neural network model for the diagnosis of hepatocellular carcinoma.

BACKGROUND/AIMS: There are no satisfactory biomarkers for hepatocellular carcinoma (HCC). The surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF-MS) technique has been used to identify biomarkers for cancer. METHODOLOGY: Four hundred thirty five serum samples were tested by SELDI-TOF-MS matching on a gold chip. Samples were assigned to a training set and a testing set according to collection order. The training set was used to identify statistically significant peaks and to develop the artificial neural network (ANN) model for diagnosing HCC. The testing set was used in a blind test to validate the diagnostic efficiency of the ANN model. RESULTS: A total of 75 proteins that differed between patients and controls were identified (p<0.05). Seven of these proteins (p<0.01; m/z at 4207Da, 6604Da, 7734Da, 8106Da, 8545Da, 8599Da, 8894Da) were chosen to develop the ANN model. The model was subjected to a blind test using the testing set for HCC diagnosis. Sensitivity and specificity were 84.00% and 81.25%, respectively, and the accuracy was 81.90%. CONCLUSIONS: These results suggest that patients with HCC may have serum proteins that differ from healthy controls. The ANN is a new method for diagnosing and identifying HCC.

Target invasion-triggered signal amplification based on duplex-specific nuclease for selective and sensitive detection of miRNAs.

Dysregulation of MicroRNAs (miRNAs) cause various diseases in humans, and developing reliable methods to detect miRNAs is critical for molecular diagnostics and personalized medicine. This study developed a toehold-mediated target invasion combined with duplex-specificity nuclease (DSN)-assisted cyclic signal amplification fluorescent sensor. Herein, we take advantage of toehold-mediated target invasion process to ensure the high selectivity of miRNA determination, coupled with the unique cleavage properties of DSN to improve the sensitivity of the strategy significantly. Throughout the assay, the whole procedure of detection the target let-7a has a limit of detection (LOD) as low as 9.00 fM and an excellent linear range from 1 pM to 100 nM for no more than 60 min. The assay shows reasonable specificity in detecting mismatched miRNAs and can realize single-base discrimination in the let-7 families. Finally, the developed method was applied to detect the miRNAs extracted from human serum. The results were consistent with those based on the quantitative reverse transcription-polymerase chain reaction(qRT-PCR) method, which shows great potential application value in clinical molecular diagnostics and biological research.

Ethanol promoting the upregulation of C-X-C Motif Chemokine Ligand 1（CXCL1） and C-X-C Motif Chemokine Ligand 6（CXCL6） in models of early alcoholic liver disease.

Alcoholic liver disease (ALD) denotes a series of liver diseases caused by ethanol. Recently, immune-related genes (IRGs) play increasingly crucial role in diseases. However, it's unclear the role of IRGs in ALD. Bioinformatic analysis was used to discern the core immune-related differential genes (IRDGs) in the present study. Subsequently, Cell Counting Kit-8 say, oil red O staining, and triglyceride detection were employed to explore optimal experimental conditions of establishing hepatocellular models of early ALD. Ultimately, real-time reverse transcription-PCR and immunohistochemistry/immunocytochemistry methods were adopted to verify the expressions of mRNA and proteins of core IRDGs, respectively. C-X-C Motif Chemokine Ligand 1 (Cxcl1) and Cxcl6 were regarded as core IRDGs via integrated bioinformatics analysis. Besides, Lieber Decarli Ethanol feeding and 200 mM and 300 mM ethanol stimulating L02 cells for 36 h can both successfully hepatocellular model. In ethanol groups, the levels of CXCL1 and CXCL6 mRNA were significantly upregulated than pair-fed groups (P < 0.0001). Also, immunohistochemistry revealed that positive particles of CXCL1 and CXCL6 in mice model of early ALD were obviously more than control groups (P < 0.0001). Besides, in L02 hepatocytes stimulated by ethanol, CXCL1 and CXCL6 mRNA were over-expressed, compared with normal L02 cells (P < 0.0001). Meanwhile, immunocytochemistry indicated that CXCL1 and CXCL6 proteins in hepatocellular model of early ALD were higher than normal L02 hepatocytes stimulus (P < 0.0001). Ethanol promoted the upregulation of Cxcl1 and Cxcl6 mRNA and proteins in models of early ALD, denoting their potentiality of acting as biomarkers of ALD.

Long noncoding RNAs as biomarkers for the diagnosis of hepatocellular carcinoma: A meta-analysis.

BACKGROUND: Long non-coding RNAs (lncRNAs) are often aberrantly expressed in hepatocellular carcinoma (HCC). The role of lncRNAs in the diagnosis of HCC has attracted increasing attention. Hence, we performed a meta-analysis based on current studies to assess the diagnostic value of lncRNAs for HCC. METHODS: A systematic search was performed using PubMed, Web of Science, and Embase databases for relevant studies. The quality of the studies was assessed with the Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2). A fixed-effect model was used if the value of I2 statistics < 50%; otherwise, a bivariate random effects model was applied (I2 ≥ 50%). In addition, subgroup analysis and meta-regression analysis were conducted to explore the sources of heterogeneity. Statistical analyses were based on Meta-Disc statistical software (Version 1.4) and STATA software (Version 15.1). RESULTS: A total of 52 studies in 20 related articles were selected for this meta-analysis, including 4930 patients and 4614 controls. The pooled sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR), and area under the curve (AUC) were 0.85 [95% confidence interval (CI) 0.82-0.88], 0.76 (95% CI 0.73-0.80), 3.6 (95% CI 3.1-4.2), 0.19 (95% CI 0.16-0.24), 19 (95% CI 14-26), and 0.88 (95% CI 0.85-0.91), respectively. The publication bias was evaluated by the Deek's funnel plot in our meta-analysis. CONCLUSIONS: LncRNAs can serve as feasible HCC diagnostic biomarkers. However, further studies are necessary to confirm its diagnostic and clinical value.

Exploration of a Robust and Prognostic Immune Related Gene Signature for Cervical Squamous Cell Carcinoma.

Background: Cervical squamous cell carcinoma (CESC) is one of the most frequent malignancies in women worldwide. The level of immune cell infiltration and immune-related genes (IRGs) can significantly affect the prognosis and immunotherapy of CESC patients. Thus, this study aimed to identify an immune-related prognostic signature for CESC. Methods: TCGA-CESC cohorts, obtained from TCGA database, were divided into the training group and testing group; while GSE44001 dataset from GEO database was viewed as external validation group. ESTIMATE algorithm was applied to evaluate the infiltration levels of immune cells of CESC patients. IRGs were screened out through weighted gene co-expression network analysis (WGCNA). A multi-gene prognostic signature based on IRGs was constructed using LASSO penalized Cox proportional hazards regression, which was validated through Kaplan-Meier, Cox, and receiver operating characteristic curve (ROC) analyses. The abundance of immune cells was calculated using ssGSEA algorithm in the ImmuCellAI database, and the response to immunotherapy was evaluated using immunophenoscore (IPS) analysis and the TIDE algorithm. Results: In TCGA-CESC cohorts, higher levels of immune cell infiltration were closely associated with better prognoses. Moreover, a prognostic signature was constructed using three IRGs. Based on this given signature, Kaplan-Meier analysis suggested the significant differences in overall survival (OS) and the ROC analysis demonstrated its robust predictive potential for CESC prognosis, further confirmed by internal and external validation. Additionally, multivariate Cox analysis revealed that the three IRGs signature served as an independent prognostic factor for CESC. In the three-IRGs signature low-risk group, the infiltrating immune cells (B cells, CD4/8 + T cells, cytotoxic T cells, macrophages and so on) were much more abundant than that in high-risk group. Ultimately, IPS and TIDE analyses showed that low-risk CESC patients appeared to present with a better response to immunotherapy and a better prognosis than high-risk patients. Conclusion: The present prognostic signature based on three IRGs (CD3E, CD3D, LCK) was not only reliable for survival prediction but efficient to predict the clinical response to immunotherapy for CESC patients, which might assist in guiding more precise individual treatment in the future.

Integrated Analyses Identify Key Molecules and Reveal the Potential Mechanism of miR-182-5p/FOXO1 Axis in Alcoholic Liver Disease.

Background: Alcoholic liver disease (ALD) is one of the most common chronic liver diseases worldwide. However, the potential molecular mechanism in ALD development remains unclear. The objective of this work was to identify key molecules and demonstrate the underlying regulatory mechanisms. Methods: RNA-seq datasets were obtained from Gene Expression Omnibus (GEO), and key molecules in ALD development were identified with bioinformatics analysis. Alcoholic liver disease mouse and cell models were constructed using Lieber-DeCarli diets and alcohol medium, respectively. Quantitative real-time PCR and Western blotting were conducted to confirm the differential expression level. Dual-luciferase reporter assays were performed to explore the targeting regulatory relationship. Overexpression and knockdown experiments were applied to reveal the potential molecular mechanism in ALD development. Results: Between ALD patients and healthy controls, a total of 416 genes and 21 microRNAs (miRNAs) with significantly differential expression were screened. A comprehensive miRNA-mRNA network was established; within this network, the miR-182-5p/FOXO1 axis was considered a significant pathway in ALD lipid metabolism. Mouse and cell experiments validated that miR-182-5p was substantially higher in ALD than in normal livers, whereas the expression of FOXO1 was dramatically decreased by alcohol consumption (P < 0.05). Next, dual-luciferase reporter assays demonstrated that miR-182-5p directly targets the binding site of the FOXO1 3'UTR and inhibits its mRNA and protein expression. In addition, miR-182-5p was found to promote hepatic lipid accumulation via targeting the FOXO1 signaling pathway, and inhibition of the miR-182-5p/FOXO1 axis improved hepatic triglyceride (TG) deposition in ALD by regulating downstream genes involved in lipid metabolism. Conclusion: In summary, key molecules were identified in ALD development and a comprehensive miRNA-mRNA network was established. Meanwhile, our results suggested that miR-182-5p significantly increases lipid accumulation in ALD by targeting FOXO1, thereby providing novel scientific insights and potential therapeutic targets for ALD.

The value of microRNAs as the novel biomarkers for colorectal cancer diagnosis: A meta-analysis.

BACKGROUND: Numerous studies have reported that microRNAs (miRNAs) hold great potential as the biomarkers for colorectal cancer (CRC). However, inconsistent results have made it challenging to evaluate their diagnostic performance. Thus, the aim of this meta-analysis was to systematically assess the pooled efficacy of miRNAs for CRC diagnosis. METHODS: A search for eligible studies up to October 30, 2019 was conducted using PubMed, Web of Science and EMBASE databases. A random-effects model was used to evaluate the pooled sensitivity and specificity. The summary receiver operator characteristic (SROC) curve and area under the curve (AUC) were calculated to assess the overall diagnostic efficacy. RESULTS: A total of 3258 CRC patients and 2683 healthy controls were identified in 35 included studies. The overall diagnostic accuracy was as follows: sensitivity, 0.80 [95 % confidence interval (CI) 0.75-0.83]; specificity, 0.80 (95 % CI, 0.75-0.84); positive likelihood ratio (PLR), 4.0 (95 % CI, 3.2-5.0); negative likelihood ratio (NLR), 0.26 (95 % CI, 0.21-0.31); diagnostic odds ratio (DOR), 16 (95 % CI, 11-23); and AUC, 0.87 (95 % CI, 0.83-0.89). CONCLUSION: The results indicated that miRNAs, particularly serum-derived miRNAs, can serve as the powerful and promising biomarkers for early CRC screening.

Pathogenesis and management of heparin-induced thrombocytopenia and thrombosis.

Heparin-induced thrombocytopenia and thrombosis is a severe immune-mediated adverse drug effect caused by the IgG antibodies to platelet factor4/heparin complexes. Activated platelets, vascular endothelium, and monocytes generate the life-threatening thrombocytopenia and thrombosis. In this review, we will update the reader on recent findings on the pathogenesis and clinical management of heparin-induced thrombocytopenia and thrombosis. Firstly, PF4/heparin complexes make IgM mediate complement activation by classical pathway. Secondly, Marginal zoneB cells play a crucial role in producing anti-PF4/heparin complex IgG antibody. Thirdly, two activation signals of platelets (protease-activated receptor 1/Fc gamma IIA receptor) were confirmed. Based on these findings, we present a potential laboratory test of HITT (receptor glycoprotein Ⅳ) and two possible treatments by using receptor inhibitors (vorapaxar/atopaxar) and IgG-degrading enzyme (streptococcus pyogenes/glutamyl endopeptidase V8/matrix metalloproteinases).

Identification of Circulating MicroRNAs as a Promising Diagnostic Biomarker for Cervical Intraepithelial Neoplasia and Early Cancer: A Meta-Analysis.

BACKGROUND: Cervical cancer (CC) is one of the most common female malignant tumors. And cervical intraepithelial neoplasia (CIN) is the precancerous lesion of CC, which can progress to invasive CC. MicroRNAs (miRNAs) have been found to be potential diagnostic biomarkers for CIN or CC. However, recently, the lack of sufficient studies about the diagnostic value of miRNAs for CIN made it challenging to separately investigate the diagnostic efficacy of miRNAs for CIN. Likewise, the conclusions among those studies were discordant. Therefore, we conducted this meta-analysis, aimed at evaluating the diagnostic efficacy of miRNAs for CIN and CC patients. METHODS: Literature search was performed in PubMed, Embase, and Web of Science databases. Pooled sensitivity, specificity, and other diagnostic parameters were calculated through Stata 14.0 software. Furthermore, subgroup analyses and metaregression analysis were conducted to explore the main sources of heterogeneity. RESULTS: Ten articles covering 50 studies were eligible, which included 5,908 patients and 4,819 healthy individuals. The pooled sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR), and area under the curve (AUC) were 0.81 (95% CI, 0.77-0.85), 0.86 (95% CI, 0.83-0.89), 5.9 (95% CI, 4.5-7.7), 0.22 (95% CI, 0.17-0.28), 27 (95% CI, 17-44), and 0.91 (95% CI, 0.88-0.93), respectively. Additionally, the ethnicity and internal reference were the main sources of heterogeneity. CONCLUSIONS: Circulating miRNAs can be a promising noninvasive diagnostic biomarker for CIN and early CC, especially miR-9 and miR-205, which need to be verified by large-scale studies.

The Diagnostic Value of MicroRNAs as a Biomarker for Hepatocellular Carcinoma: A Meta-Analysis.

BACKGROUND: Recently, the role of microRNAs (miRNAs) in diagnosing cancer has been attracted increasing attention. However, few miRNAs have been applied in clinical practice. The purpose of this study was to evaluate the diagnostic efficacy of miRNAs for hepatocellular carcinoma (HCC) at early stages clinically. METHODS: A literature search was carried out using PubMed, Web of Science, and EMBASE databases. We explored the diagnostic value of miRNAs in distinguishing HCC from healthy individuals. The quality assessment was performed in Review Manager 5.3 software. The overall sensitivity and specificity and 95% confidence intervals (CIs) were obtained with random-effects models through Stata 14.0 software. And heterogeneity was assessed using Q test and I 2 statistics. Meta-regression and subgroup analyses were conducted based on the sample, nation, quality of studies, and miRNA profiling. The publication bias was evaluated through Deeks' funnel plot. RESULTS: A total of 34 studies, involving in 2747 HCC patients and 2053 healthy individuals, met the inclusion criteria in the 33 included literature studies. In the summary receiver operating characteristic (sROC) curve, AUC was 0.92 (95% CI, 0.90-0.94), with 0.84 (95% CI, 0.79-0.88) sensitivity and 0.87 (95% CI, 0.83-0.90) specificity. There was no publication bias (P=0.48). CONCLUSION: miRNAs in vivo can be acted as a potential diagnostic biomarker for HCC, which can facilitate the early diagnosis of HCC in clinical practice.

Diagnostic and prognostic serum marker of cholangiocarcinoma (Review).

Cholangiocarcinoma (CCA) is a fatal disease that is typically diagnosed late and treated ineffectively. As the morbidity and mortality rates for CCA rise markedly, patietns with CCA currently have a poor prognosis. However, if it were possible to diagnose CCA early while effective treat methods are available, CCA patients would achieve a better quality of life. Therefore, preventing the process of CCA in the early stages is an urgent problem to solve. An accurate, quick and safe method to diagnose early-stage CCA is required. The present review discusses the risk factors, status of research and certain serum markers of CCA. The sensitivity and specificity of these markers differ from each other. To explore the more accurate serum markers may be a novel direction and method for the diagnosis of CCA in laboratory medicine in the future.