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Identification of disulfidptosis-related genes and immune infiltration in lower-grade glioma

  • Xiao-min Li , Shan-peng Liu , Dan-man Liu , Yu Li , Xiao-ming Cai , Yun Su EMAIL logo and Ze-feng Xie EMAIL logo
Published/Copyright: October 25, 2023
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Open Medicine
From the journal Open Medicine Volume 18 Issue 1

Abstract

Lower-grade glioma (LGG), a prevalent malignant tumor in the central nervous system, requires accurate prediction and treatment to prevent aggressive progression. We aimed to explore the role of disulfidptosis-related genes (DRGs) in LGG, a recently discovered form of programmed cell death characterized by abnormal disulfide accumulation. Leveraging public databases, we analyzed 532 LGG tumor tissues (The Cancer Genome Atlas), 1,157 normal samples (Genotype-Tissue Expression), and 21 LGG tumor samples with 8 paired normal samples (GSE16011). Our research uncovered intricate relationships between DRGs and crucial aspects of LGG, including gene expression, immune response, mutation, drug sensitivity, and functional enrichment. Notably, we identified significant heterogeneity among disulfidptosis sub-clusters and elucidated specific differential gene expression in LGG, with myeloid cell leukemia-1 (MCL1) as a key candidate. Machine learning techniques validated the relevance of MCL1, considering its expression patterns, prognostic value, diagnostic potential, and impact on immune infiltration. Our study offers opportunities and challenges to unravel potential mechanisms underlying LGG prognosis, paving the way for personalized cancer care and innovative immunotherapeutic strategies. By shedding light on DRGs, particularly MCL1, we enhance understanding and management of LGG.

Keywords: disulfidptosis; lower-grade glioma; immune infiltration; machine learning; MCL1

1 Introduction

Gliomas are the most common primary intracranial malignant tumors of the central system, with approximately 50% of patients exhibiting aggressiveness [1]. Gliomas are mainly classified as lower-grade glioma (LGG) and glioblastoma multiforme (GBM). LGG is considered a worldwide health problem, accounting for approximately 20% of gliomas diagnosed in the United States [2]. Although LGG is less aggressive than GBM, there is a higher incidence in young people and a tendency to progress to high grade in later stages [3]. Therefore, efficient and sensitive diagnostic novel markers are needed to predict prognosis and stop progression.

Research is now proposing a novel mode of cell death, disulfidptosis, independent of the currently existing programmed cell death such as apoptosis, ferroptosis, necroptosis, and cuproptosis. It is a rapid form of death caused by disulfide stress resulting from the accumulation of excess intracellular cystine [4]. Earlier studies found that under glucose starvation conditions, NADPH was heavily depleted in SLC7A11 overexpressing cells and disulfides such as cystine accumulated abnormally, inducing disulfide stress and rapid cell death [5]. The endoplasmic reticulum of eukaryotic cells and the periplasmic space of prokaryotic cells are capable of forming and transferring protein disulfide bonds. The formation of structural disulfide bonds is a catalytic process involving many proteins and small molecules [6]. The formation of disulfide bonds has now been identified in cancer-related proteins and it is time to consider how this allosteric bond can be used as a target for new therapies [7]. In addition, a variety of disulfide isomerases have been shown to be associated with tumorigenicity in a variety of tumors [8,9]. Notably, protein disulfide isomerase may play a role in the malignant progression of gliomas and predict the clinical prognostic value of gliomas [10]. Furthermore, RAC1, a component of the WAVE regulatory complex, plays a significant role in actin polymerization and the formation of thin-walled cells, processes that are implicated in disulfidptosis. The RAC1 signaling pathway has been linked to epileptogenic mechanisms in glioma-associated epilepsy [11]. However, the precise impact of disulfidptosis on the prognosis and immune infiltration of LGG is still unclear and requires further investigation.

To explore possible pathogenic mechanisms, we analyzed genes differentially expressed between LGG samples and normal tissue using Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Disulfidptosis-related gene (DRGs) were interrogated and explored for expression, immunity, mutation, and drug sensitivity in LGG. Sub-clusters of DRGs were then constructed based on clinical features and gene expression and the associated mechanisms explored. Differential genes and DRGs were then extracted for crossover to find the differentially expressed DRGs. In addition, machine learning algorithms were applied to find key differential genes. Finally, the strongest trait gene was identified and the relationship with prognosis and immune infiltration was further considered in LGG. This provides a new perspective to better understand the underlying molecular mechanisms of LGG pathogenesis.

2 Materials and methods

2.1 Identification of DRGs

We identified nine DRGs from the previous literature [12]. This study identified and selected DRG genes based on their consistent and notable association with disulfidptosis, a cellular process of interest. Each gene encodes specific proteins that play crucial roles in biochemical pathways and cellular structures involved in disulfidptosis. Among these genes, SLC7A11 was emphasized due to its central role as a cystine transporter in this process. Additionally, the selection criteria included genes that interact with the WAVE regulatory complex (NCKAP1, WASF2, CYFIP1, ABI2, BRK1, and RAC1), which is known to be involved in actin polymerization and the formation of lamellipodia, both relevant to disulfidptosis. Moreover, BAK1 and ACSL4 were chosen for their significant roles in regulating programmed cell death and their close association with disulfidptosis. GeneMANIA Prediction Server is a biological network integration for gene prioritization and prediction of gene function [13]. We used the GeneMANIA website (http://www.genemania.org) to identify functionally similar genes and create 29 DRGs.

2.2 LGG datasets

LGGs are a group of primary brain tumors that originate from glial cells. Currently, LGGs include WHO grade II and III gliomas, and their classification is based on molecular features rather than histopathological characteristics [14]. The RNA-sequencing (RNA-seq) data and relevant clinical data of 532 LGG tumor tissues were downloaded from TCGA (http://cancergenome.nih.gov) and Genotype-Tissue Expression (GTEx) database (https://www.gtexportal.org/home/-index.html) of LGG normal was extracted (n = 1,157). The above datasets were selected to meet the criteria at the time of the last data freeze in spring 2023. In addition, the GSE16011 dataset [15] was derived from GEO (https://www.ncbi.nlm.nih.gov/geo/.), which contains 21 LGG cancer samples and 8 paired normal samples. Two datasets are used to explore DRGs’ expression levels, differential gene analysis, machine learning, prognosis, and immune infiltration, among others. Data were extracted in TPM format and further log2(x + 1) transformations were performed for each expression value. All data analyses was carried out using R (version 4.2.1) and the relevant bioinformatics analysis website.

2.3 Gene set and differentially expressed gene (DEG) functional enrichment analysis

For gene set functional enrichment, we used the kyoto encyclopedia of genes and genomes (KEGG) rest API (https://www.kegg.jp/kegg/rest/keggapi.html) to obtain the latest KEGG pathway gene annotations as background, mapped the genes to the background set, and used the R package ClusterProfiler (version 3.14.3) [16] to perform the enrichment analysis to obtain the results of gene set enrichment. Similarly, we used the Gene Ontology (GO) annotations of genes from the R package org.Hs.eg.db (version 3.1.0) as a background, mapped the genes to the background set, and used the R package ClusterProfiler (version 3.14.3) to perform enrichment analysis to obtain the gene set enrichment results. p values < 0.05 and false discovery rate (FDR) < 0.1 were considered statistically significant.

For DEGs’ functional enrichment, KEGG enrichment analysis is practical for analyzing gene function and associated high-level genomic functional information. GO is a widely used tool for the annotation of genes with functions, in particular molecular function, biological pathway, and cellular component. To better understand the oncogenic and immune infiltration of target genes, we obtained enrichment results for differentially up/down-regulated genes KEGG pathway and enrichment results for differentially up/down-regulated genes GO term. The functional enrichment results were obtained from the R package ClusterProfiler (version:3.18.0). p values <0.05 were considered statistically significant.

2.4 Gene set cancer analysis (GSCA)

GSCA is an integrated platform for genomic, pharmacogenomic, and immunogenomic cancer analysis [17]. Within this enhanced GSCA, a range of services are provided to perform gene set genomic including expression, single-nucleotide variation (SNV), copy number variation (CNV), methylation, and immunogenomic (24 immune cells) analysis. In addition, the combination of clinical information and small molecule drugs allows the mining of candidate biomarkers and valuable small drugs to inform further clinical trials.

2.5 Subgroup analysis

Consistency analysis was performed using the ConsensusClusterPlus R package (v1.54 4.0) [18] with a maximum number of clusters of 6 and 80% of the total sample drawn 100 times, clusterAlg = “hc,” innerLinkage = “ward.D2.” Cluster heatmaps were performed using the R package pheatmap (v1.0.12). Gene expression heatmaps retained genes with an SD of >0.1.

2.6 Differential genetic screening

Limma (linear models for microarray data) is a differential expression screening method that utilizes a generalized linear model [19]. In the TCGA database, DEGs were screened in subgroup C1 and C2 data sets. Differentially expressed mRNA was studied using the limma package (version 3.40.6). Threshold for differential mRNA expression between two clusters was set at “Adjusted p < 0.05 and |log2 FC| > 1.” In GSE16011, p < 0.05 and |log2 FC| > 1.5 was selected as the cut-off standard.

2.7 Machine learning

To identify trait genes, two machine learnings were used to screen for DRGs. The least absolute shrinkage and selection operator (LASSO) is a regression method used for regularization to improve prediction accuracy and model comprehensibility by select variables [20]. Random Forest is a learning method that constructs a large number of decision trees and outputs classes of individual trees. This method has a high degree of accuracy, sensitivity, and specificity [21]. Log rank was used to test survival analysis comparing survival differences between two groups, and timeROC analysis was performed to discriminate the accuracy of the predictive model.

2.8 Statistical analysis

All statistical tests were performed using the R package (version 4.2.1) and visualizations were performed using the ggplot2 package (version 3.3.6). Expression correlation network of the DRGs analysis and visualization using igraph package (version 1.3.4) and ggraph package (version 2.1.0). With the xCell package (version 1.1.0), the integrated level of 64 cell types was estimated, including 14 stromal cell types. LASSO regression and Random Forest analyses were carried out using the R packages “glmnet” [22] and “randomForest” [23]. Kaplan–Meier survival analyses were performed with the “survival R” and “survminer R” packages (version 3.3.1). ROC analysis was performed with the qROC package (version 1.18.0). Construction and visualization of Nomogram models were carried out using the rms package (version 6.4.0). Spearman correlation analysis was used to understand the relationship between myeloid cell leukemia-1 (MCL1) expression levels and immune infiltration. The immune infiltration algorithm (ssGSVA) in the GSVA package (version 1.46.0) was used to calculate immune scores [24]. Wilcoxon rank-sum test was used to compare differences between groups. p < 0.05 was considered to indicate statistical significance (ns, p ≥ 0.05; ∗p < 0.05; ∗∗p < 0.01; ∗∗∗p < 0.001).

3 Results

3.1 Assessing differential expression of DRGs in LGG

As previously described, nine genes (BAK1, NCKAP1, ACSL4, SLC7A11, CYFIP1, WASF2, ABI2, BRK1, and RAC1) were shown to be associated with disulfidptosis [12]. To confirm the expression of these related genes in LGG, we downloaded expression data from the TCGA and GTEx databases for cancer and normal tissues, which showed differences in the expression of DRGs. All relevant genes were upregulated and significant in tumor expression. Consistent results were also obtained in the GEO database (Figure 1(a) and (b)). We used GeneMANIA on predicting functionally similar genes in hub genes. We obtained 20 similar gene hub genes, comprising WASF1, CYFIP2, MFN1, NCKAP1L, SLC25A25, MCL1, DPYSL2, BAAT, SLC3A2, ABI1, POTEI, TRIO, PLCB2, BID, TRIM32, RAP1GDS1, MFN2, BCL2L1, BOK, and PREX1. The hub gene was located in the inner circle, while the predicted genes were in the outer circle. The relationships between genes were specifically based on five types, including Predicted, Physical Interactions, Pathway Co-expression, and Genetic Interactions (Figure 1(c)). Combined with the network diagram of correlation analysis, most of the related gene expressions were positively correlated with each other (Figure 1(d)). Enrichment analysis of DRGs in the KEGG dataset identified some apoptosis and disease-related pathways such as pathogenic Escherichia coli infection, regulation of actin cytoskeleton, apoptosis-multiple species, ferroptosis, amyotrophic lateral sclerosis, apoptosis, and so on (Figure 1(e)). Further enrichment analysis of these genes on the GO dataset indicated that certain related actin nucleation items, such as organelle outer membrane, outer membrane, positive regulation of Arp2/3 complex-mediated actin nucleation, vascular endothelial growth factor (VEGF) receptor signaling pathway, actin polymerization or depolymerization, regulation of Arp2/3 complex-mediated actin nucleation, positive regulation of actin nucleation, actin cytoskeleton organization, and so on (Figure 1(f)). The above analysis shows that DRGs are confirmed with some reliability in LGG.

Figure 1 Expression distributions, Spearman correlation, and enrichment analysis of DRGs in LGG. Expression distributions of nine DRGs between cancer and normal tissues in the (a) TCGA and (b) GEO datasets. (c) GeneMANIA website for identifying functionally similar genes and establishing 29 DRGs. Twenty similar genes are located in the outer circle, while nine hub genes are located in the inner circle. Five colors of the lines represent the type of gene interactions. (d) Expression correlation network of the DRGs. Positive correlations are shown by the red line and negative correlations are shown by the blue line. The thickness of the line indicates the strength of the correlation. (e) KEGG and (f) GO concentrated circle diagram. *p < 0.05, **p < 0.01, ***p < 0.001 and ****p < 0.0001.
Figure 1

Expression distributions, Spearman correlation, and enrichment analysis of DRGs in LGG. Expression distributions of nine DRGs between cancer and normal tissues in the (a) TCGA and (b) GEO datasets. (c) GeneMANIA website for identifying functionally similar genes and establishing 29 DRGs. Twenty similar genes are located in the outer circle, while nine hub genes are located in the inner circle. Five colors of the lines represent the type of gene interactions. (d) Expression correlation network of the DRGs. Positive correlations are shown by the red line and negative correlations are shown by the blue line. The thickness of the line indicates the strength of the correlation. (e) KEGG and (f) GO concentrated circle diagram. *p < 0.05, **p < 0.01, ***p < 0.001 and ****p < 0.0001.

3.2 Exploring the expression, immunity, mutations, and drug sensitivity of 29 DRGs in LGG

To gain a comprehensive understanding of the role and relevance of DRGs in cancer diagnosis, we used GSCA to further correlate the analysis of four modules, including expression, immunity, mutations, and drug sensitivity. In the expression module, summarize the percentage of LGG for which specific gene mRNA expression has a potential impact on pathway activity (Figure 2(a)). Specific pathways include: Apoptosis, Cellcycle, DNA damage, EMT, Hormone AR, Hormone ER, PI3KAKT, RASMAPK, RTK, and TSCmTOR. Specifically, gene sets were most meaningfully and positively correlated with Hormone ER (p < 0.05, #FDR < 0.05) and most negatively correlated with DNA Damage pathways (p < 0.05, #FDR < 0.05) (Figure 2(b)). Moreover, the gene set has an impact on patient survival outcomes, with overall survival (OS) and disease-specific survival close but less significant (p > 0.05) (Figure 2(c)). In the immunity module, gene sets were most meaningfully and positively correlated with macrophage (p < 0.05, #FDR < 0.05) and most negatively correlated with Gamma delta (p < 0.05, #FDR < 0.05) (Figure 2(d)). Interestingly, Figure 2(e) summarizes the difference of immune infiltration between gene set CNV groups. CD8 native, Gamma delta, and Tr1 are meaningfully highly expressed in CNV, as opposed to Exhausted, Macrophage, and InfiltrationScore. In the mutation module, we can see that the waterfall plot is dominated by Missense mutation, with PREX1 and TRIO reaching the highest 29.1% (Figure 2(f)). NCKAP1L and ACSL4 were the most frequent mutants (Figure 2(g)). CNV induced the extensive upregulation of its mRNA expression (Figure 2(i)) and survival (Figure 2(k)). Methylation, however, affected extensive downregulation of their mRNA expression (Figure 2(h)) and survival (Figure 2(j)). Furthermore, the correlation of gene expression with the genomics of drug sensitivity in cancer (GDSC) drug sensitivity (top 30) (Figure 2(l)) and Cancer Therapeutics Response Portal (CTRP) drug sensitivity (top 30) (Figure 2(m)) in pan-cancer demonstrates consistency and reliability of results. In conclusion, analysis of the multiple modules described above showed strong associations in terms of expression, immune infiltration, mutations, and drug sensitivity of DRGs in LGG.

Figure 2 Expression, immunity, mutations, and drug sensitivity of 29 DRGs in LGG. (a) Percentage of LGG in which mRNA expression of specific genes has a potential effect on pathway activity. (b) The association between GSVA score and activity of cancer-related pathways in LGG. (c) The results of survival difference between GSVA score groups in LGG. (d) The association between GSVA score and activity of cancer-related pathways in LGG. (e) the difference of immune infiltration between gene set CNV groups. (f) Waterfall plot showing the mutational landscape of DRGs in LGG. (g) The profile of SNV of the DRGs set in LGG. (h) The profile of correlations between methylation and mRNA expression of DRGs in LGG. (i) The correlations between CNV and mRNA expression in LGG. (j) The OS difference between higher and lower methylation groups in LGG. (k) The difference of survival between CNV and wide type in LGG. Correlation of gene expression with (l) GDSC drug sensitivity (top 30) and (m) CTRP drug sensitivity (top 30) in pan-cancer. DFI: disease-free interval; DSS: disease-specific survival; OS: overall survival; PFS: progression-free survival; GSVA score: gene set expression score; CNV: copy number variation; SNV: single-nucleotide variation; Amp: amplification; Dele: deletion; WT: wild type; CTRP: The Cancer Therapeutics Response Portal. *p < 0.05, #FDR <0.05.
Figure 2

Expression, immunity, mutations, and drug sensitivity of 29 DRGs in LGG. (a) Percentage of LGG in which mRNA expression of specific genes has a potential effect on pathway activity. (b) The association between GSVA score and activity of cancer-related pathways in LGG. (c) The results of survival difference between GSVA score groups in LGG. (d) The association between GSVA score and activity of cancer-related pathways in LGG. (e) the difference of immune infiltration between gene set CNV groups. (f) Waterfall plot showing the mutational landscape of DRGs in LGG. (g) The profile of SNV of the DRGs set in LGG. (h) The profile of correlations between methylation and mRNA expression of DRGs in LGG. (i) The correlations between CNV and mRNA expression in LGG. (j) The OS difference between higher and lower methylation groups in LGG. (k) The difference of survival between CNV and wide type in LGG. Correlation of gene expression with (l) GDSC drug sensitivity (top 30) and (m) CTRP drug sensitivity (top 30) in pan-cancer. DFI: disease-free interval; DSS: disease-specific survival; OS: overall survival; PFS: progression-free survival; GSVA score: gene set expression score; CNV: copy number variation; SNV: single-nucleotide variation; Amp: amplification; Dele: deletion; WT: wild type; CTRP: The Cancer Therapeutics Response Portal. *p < 0.05, #FDR <0.05.

3.3 Two disulfidptosis sub-clusters and analysis of associated differential genes

We performed consensus unsupervised clustering on a sample of 512 patients in LGG from TCGA databases, with 2 clusters (Cluster 1 [n = 317], Cluster 2 [n = 195]) selected for relative stability under the distribution (Figure 3(a) and (b)). In contrast to the C1 subgroup, DRGs were highly expressed in the C2 subgroup (Figure 3(c)) and had a poorer prognosis on the survival curve (Figure 3(d)). To further explore the differences between the two subgroups, Limma analysis of the volcano map (Figure 3(e)) and heat map (Figure 3(f)) was used to demonstrate the differential genes between the two subgroups. 115 upregulated genes such as SNCB, CHGA, LICAM, CPLX2, TRIM67 and 473 downregulated genes were identified in DRGs-high group such as CYBB, SCIN, C3, FPR1, ALOX5AP were identified in the DRGs-low group (C1) compared to DRGs-high group (C2) (Figure 3(e)). Enrichment analysis of the upregulated genes in the KEGG dataset is shown in the neuroactive ligand−receptor interaction pathway (Figure 3(g)), compared to the downregulated genes in the tuberculosis, Staphylococcus aureus infection, and phagosome pathways (Figure 3(i)). The further enrichment analysis of the upregulated genes in the GO dataset is shown in the regulation of trans-synaptic signaling, modulation of chemical synaptic transmission, and vesicle-mediated transport in synapse (Figure 3(h)), compared to the downregulated genes in T-cell activation, neutrophil activation involved in immune response, and neutrophil degranulation, which were involved in immune response (Figure 3(j)). In addition, the xCell algorithms were used to analyze the immunological characteristics of subgroups (Figure 4(a)). Compared to C1 subgroup, C2 subgroup showed a meaningful positive correlation with immune cells. The proportions of all immune cell types are shown in Figure 4(b). To predict the effect of immune checkpoint blockade therapy, we also explored the expression of key immune checkpoint genes in the groups (Figure 4(c)). The results showed that the expressions of CD274, CTLA4, HAVCR2, LAG3, PDCD1, PDCD1LG2, and SIGLEC15 were elevated in C2 subgroup (Figure 4(c)), which suggested an immunosuppressive status.

Figure 3 Two disulfidptosis sub-clusters were shown. (a) Cumulative distribution function (CDF) curve of K (2–6). The relative change in area under the CDF curve of K (2–6). (b) Appropriate unsupervised clustering analysis (k = 2). (c) Heat map showing the relationship between DRGs’ expression in subgroups. (d) Survival curve analysis revealed differences in OS between 2 subgroups. Two groups were tested by log rank, with 95% CL representing the HR confidence interval; median time represents the time in years corresponding to survival in the different groups at 50%. (e) Differential analysis of subgroups. (f) Heatmap showing DEGs. (g–j) KEGG pathway and GO air bubble diagram. In the enrichment result, p values <0.05 are considered to be a meaningful pathway (enrichment score with −log10 (P) of more than 1.3).
Figure 3

Two disulfidptosis sub-clusters were shown. (a) Cumulative distribution function (CDF) curve of K (2–6). The relative change in area under the CDF curve of K (2–6). (b) Appropriate unsupervised clustering analysis (k = 2). (c) Heat map showing the relationship between DRGs’ expression in subgroups. (d) Survival curve analysis revealed differences in OS between 2 subgroups. Two groups were tested by log rank, with 95% CL representing the HR confidence interval; median time represents the time in years corresponding to survival in the different groups at 50%. (e) Differential analysis of subgroups. (f) Heatmap showing DEGs. (g–j) KEGG pathway and GO air bubble diagram. In the enrichment result, p values <0.05 are considered to be a meaningful pathway (enrichment score with −log10 (P) of more than 1.3).

Figure 4 Immune cells’ infiltration between subgroups. (a) Immune cells’ infiltration between different groups by xCell algorithms. (b) The proportion structure of all Immune cell types. (c) The expression of eight key immune checkpoint genes in two subgroups. *p < 0.05, **p < 0.01 and ***p < 0.001.
Figure 4

Immune cells’ infiltration between subgroups. (a) Immune cells’ infiltration between different groups by xCell algorithms. (b) The proportion structure of all Immune cell types. (c) The expression of eight key immune checkpoint genes in two subgroups. *p < 0.05, **p < 0.01 and ***p < 0.001.

3.4 Construction of prognosis risk model based on DRGs in TCGA dataset

To identify new prognostic markers for LGG, we performed a LASSO regression analysis of LGG patients in the TCGA database based on 29 DRGs. The LASSO regression algorithm used 10-fold cross-validation for feature selection, and all genes except POTEI showed consistency (Figure 5(a)). Finally, 14 genes were identified with disulfidptosis-signature, including BAK1, SLC7A11, CYFIP1, WASF2, ABI2, BCL2L1, BID, TRIO, ABI1, SLC3A2, DPYSL2, MCL1, SLC25A25, and CYFIP2 (Figure 4(b) and (c)). We also confirmed that OS was significantly longer in the low-risk group than in the high-risk group (hazard ratio [HR] = 4.266, 95% confidence interval [CI] = 1.78–2.89, P < 0.001), comparing median times of 11.3–4.3 years, respectively (Figure 5(d)). Meanwhile, ROC time-dependent curves demonstrated that the accuracy of 14 gene signatures was greater than 0.70 for 1-, 3-, and 5-year survival rates (area under curve > 0.7 indicates a high degree of accuracy) (Figure 5(e)).

Figure 5 Evaluation of disulfidptosis signature by the performance of the 14-gene signature in the TCGA dataset. (a) Construction of disulfidptosis signatures using LASSO regression. (b) Determining the appropriate number of genes by confidence intervals of lambda. (c) Risk score, survival time, and expression of the 14-gene signature in LGG. (d) Kaplan–Meier survival analysis of OS was compared between low- and high-risk score groups in LGG. (e) ROC curves over time at 1, 3, and 5 years, respectively.
Figure 5

Evaluation of disulfidptosis signature by the performance of the 14-gene signature in the TCGA dataset. (a) Construction of disulfidptosis signatures using LASSO regression. (b) Determining the appropriate number of genes by confidence intervals of lambda. (c) Risk score, survival time, and expression of the 14-gene signature in LGG. (d) Kaplan–Meier survival analysis of OS was compared between low- and high-risk score groups in LGG. (e) ROC curves over time at 1, 3, and 5 years, respectively.

3.5 Application of machine learning to the identification of trait genes via the GEO dataset

To verify the reliability of the above analysis based on TCGA data, we also performed further machine learning analysis of LGG patients based on the GEO database. First, we used Limma analysis of heat map (showed top 50 up/downregulated genes respectively) (Figure 6(a)) and volcano map (Figure 6(b)) to demonstrate differential genes in LGG patients in GSE16011. A total of 1,533 upregulated genes and 1,818 downregulated genes were identified, 7 of which were associated with DRGs (Figure 6(c)). Second, LASSO regression was used to select the most relevant trait genes. When λ = 0.17, MCL1 and RAP1GDS1 were selected (Figure 6(d) and (e)). Meanwhile, we used RandomForest algorithm to screen DRGs and construct potential genes based on the GSE16011 dataset. We show the top 10 genes in order, including MCL1, RAP1GDS1, MFN2, SLC3A2, WASF1, CYFIP2, CYFIP1, DPYSL2, WASF2, and BOK (Figure 6(f)). Ultimately, MCL1 was selected as the only candidate gene (Figure 6(g)).

Figure 6 Machine learning to identify trait genes in the GEO dataset. Differential genes in GSE16011 showing (a) heat map and (b) volcano map. (c) Trait genes shared by DRGs and differential genes of GSE16011. (d and e) Selection of the most relevant trait genes using LASSO regression. (f) Selection of the most relevant DRGs based on GSE16011 using RandomForest (top 10). (g) The Venn diagram shows the overlap of candidate genes between the two databases.
Figure 6

Machine learning to identify trait genes in the GEO dataset. Differential genes in GSE16011 showing (a) heat map and (b) volcano map. (c) Trait genes shared by DRGs and differential genes of GSE16011. (d and e) Selection of the most relevant trait genes using LASSO regression. (f) Selection of the most relevant DRGs based on GSE16011 using RandomForest (top 10). (g) The Venn diagram shows the overlap of candidate genes between the two databases.

3.6 Clinical diagnosis and prognostic value analysis of MCL1-related gene marker

In the present study, we found that MCL1 expression was upregulated in LGG patients compared to normal tissue by analyzing data from the TCGA and GTEx databases (Figure 7(b)). This finding was validated on the GEO database (Figure 7(c)). Kaplan–Meier survival analysis of LGG patients suggests the reliability of MCL1 as a bad prognostic factor (HR = 1.66, 95% CI = 1.15–2.41, P < 0.01). MCL1 combined with four other markers to construct a new nomogram to predict the probability of survival at 1, 3, and 5 years of clinical diagnosis in patients with LGG based on patient’s WHO grade, gender, age and histological type (Figure 7(d)). Nomogram calibration curves validate the agreement between predicted and actual survival probabilities for LGG at 1, 3, and 5 years (Figure 7(e)).

Figure 7 Construction of nomogram for OS prediction based on TCGA. (a) Kaplan–Meier survival analysis of LGG patients in the high-risk and low-risk groups. Expression distributions of MLC1 between cancer and normal tissues in the (b) TCGA and (c) GEO datasets. (d) A nomogram combining MLC1 and clinicopathological features from TCGA LGG data. (e) Nomogram calibration curve for predicting OS in TCGA LGG data.
Figure 7

Construction of nomogram for OS prediction based on TCGA. (a) Kaplan–Meier survival analysis of LGG patients in the high-risk and low-risk groups. Expression distributions of MLC1 between cancer and normal tissues in the (b) TCGA and (c) GEO datasets. (d) A nomogram combining MLC1 and clinicopathological features from TCGA LGG data. (e) Nomogram calibration curve for predicting OS in TCGA LGG data.

3.7 Immune infiltration analysis of MCL1 in LGG

By performing the ssGSEA algorithm on 24 immune cells, we analyzed the results of the correlation between MCL1 and immune infiltration and presented them in the form of a lollipop plot (Figure 8(a)). Specifically, MCL1 was positively correlated with most immune cells such as T helper cells, neutrophils, and eosinophils and negatively correlated with NK CD56bright, TReg, and Mast cells. Among these immune cells, we specifically show a statistically significant correlation between T helper cells and NK CD56bright cells’ infiltration in the MCL1 differential expression analysis (Figure 8(b)). MCL1 expression levels were significantly positively and negatively correlated with the enrichment scores of T helper cells (Figure 8(c)) and NK CD56bright cells (Figure 8(d)), respectively. At the overall level of infiltration, we explore three immune infiltration scores that correlate with MCL1, including ESTIMATEScore (r = 0.37), ImnuneScore (r = 0.37), and StromaScore (r = 0.34). Results showed a meaningful positive correlation (all p < 0.001) (Figure 8(e)–(g)).

Figure 8 MLC1 expression is linked with immune infiltration in LGG based on TCGA. (a) Correlation between MLC1 and multiple immune cells. (b) MLC1 was associated with T helper cells and NK CD56bright cells. Correlation between enrichment scores and (c) MLC1 in T helper cells and (d) NK CD56bright cells. (e–g) Correlation between the expression level of MCL1 and three infiltration score. **p < 0.01, ***p < 0.001.
Figure 8

MLC1 expression is linked with immune infiltration in LGG based on TCGA. (a) Correlation between MLC1 and multiple immune cells. (b) MLC1 was associated with T helper cells and NK CD56bright cells. Correlation between enrichment scores and (c) MLC1 in T helper cells and (d) NK CD56bright cells. (e–g) Correlation between the expression level of MCL1 and three infiltration score. **p < 0.01, ***p < 0.001.

4 Discussion

The identification and characterization of cell death mechanisms not only promotes a fundamental understanding of cellular homeostasis but also provides important ideas for the treatment of many diseases such as cancer. Recent studies have identified a new form of disulfide-induced cell death in human cells, called disulfidptosis. This study suggests that GLUT inhibitor-induced disulfidptosis may be an effective strategy for treating tumors [12].

There has long been a search for better treatments for gliomas, particularly LGG, which has a relatively low stage and malignancy, can be stopped with aggressive treatment in some young people with the disease, and is the more promising of the glioma tumors to be cured [3,25]. However, traditional surgical resection combined with chemotherapy and radiotherapy is difficult to avoid tumor resistance and progression. Therefore, it becomes crucial to evaluate LGG prediagnosis and to investigate new drugs targeting specific functional pathways. Our study links disulfidptosis to the pathogenesis of LGG, identifies possible key genes through bioinformatics analysis, and explores potential therapeutic approaches.

In this study, we compared the expression of related genes in LGG tumors and normal tissues from the TCGA and GEO databases, and the data showed significant upregulation in tumor expression. We used GeneMANIA to predict functionally similar genes in hub genes to obtain 29 similar DRGs, most of which were positively correlated with each other. This defined gene set has scientific validity and reliability. The gene set KEGG enrichment analysis revealed enrichment of some apoptosis and disease-related pathways such as pathogenic E. coli infection, regulation of actin cytoskeleton, apoptosis-multiple species, ferroptosis, apoptosis, and so on.

This confirms the intrinsic pathway correlation between disulfidptosis and various cell deaths such as ferroptosis and apoptosis. Ferroptosis is a unique form of cell death that is driven by iron-dependent lipid peroxidation. Ferroptosis is closely associated with a variety of biological scenarios, including development, aging, immunity, and cancer [26]. In GO terms studies, we found that DRGs are involved not only in organelle outer membrane components and actin cytoskeleton organization but also in the VEGF receptor signaling pathway. The proven role of VEGF in promoting tumor angiogenesis and human cancer pathogenesis has led to the rational design and development of drugs that selectively target this pathway [27]. This partly explains the oncogenic role of disulfidptosis in LGG cells.

At the overall level, we perform a preliminary exploration of DRGs, which are strongly correlated with expression, immune infiltration, mutation, and drug sensitivity in LGG. Taking MCL1 for example, it ranked high in the list of methylation difference and was a significant prognostic risk factor for LGG.

MCL1 is a member of the BCL2 family and its high expression is closely associated with drug resistance in tumor [28]. MCL1 of expression also links to the pathway of Apoptosis, Cellcycle, DNA Damage, and other pathways, which is consistent with previous article studies [29]. For example, DNA damage induces apoptosis, which occurs in part through p53-responsive genes encoding pro-apoptotic BCL2 family proteins that bind to and inhibit anti-apoptotic Bcl-2 family members such as MCL1.

Based on consensus clustering, we identified two LGG subtypes (C1 and C2) by DRGs’ expression and found that the C2 subtype was associated with poor prognosis. On further analysis, C2 subgroup was more significant in relation to immune scores and immune checkpoints. The subgroups were then further explored for differential genes and finally found that enrichment analysis of the downregulated genes in the GO dataset is shown in T-cell activation, neutrophil activation involved in immune response, and neutrophil degranulation. This is further evidence of the importance of immunity and disulfidptosis in the development of LGG.

To identify new prognostic markers for LGG, we performed the LASSO regression analysis based on 29 DRGs for LGG patients in the TCGA database. We identified 14 genes with a disulfidptosis signature, including BAK1, SLC7A11, CYFIP1, WASF2, ABI2, BCL2L1, BID, TRIO, ABI1, SLC3A2, DPYSL2, MCL1, SLC25A25, and CYFIP2. We also confirmed that OS was significantly longer in the low-risk group than in the high-risk group. Meanwhile, the ROC time-dependent curves showed an accuracy of >0.70 for 1-, 3-, and 5-year survival rates. To verify the reliability of the above analysis based on TCGA data, further machine learning analysis was performed on LGG patients based on the GEO database. First, we used Limma analysis to identify a total of 1,533 upregulated genes and 1,818 downregulated genes, of which 7 were associated with DRGs, including MCL1, RAP1GDS1, WASF1, MFN2, CYFIP2, SLC3A2, and BOK. LASSO regression was then used to screen out the most relevant trait genes, MCL1 and RAP1GDS1. Meanwhile, we screened DRGs using RandomForest algorithm, showing the top 10 genes, including MCL1, RAP1GDS1, MFN2, SLC3A2, WASF1, CYFIP2, CYFIP1, DPYSL2, WASF2, and BOK. MCL1 was finally selected as the only candidate gene, a result that further demonstrates the role of MCL1 in LGG carcinogenesis. Previous studies have confirmed that MCL1 can promote cell migration and invasion in some types of cancers, including renal cell carcinoma [30], acute myeloid leukemia [31], and pancreatic ductal adenocarcinoma [32]. We further found that MCL1 expression was upregulated in LGG patients by analyzing data from TCGA and GTEx databases. This finding was validated on the GEO database. The reliability of MCL1 as a poor prognostic factor ultimately establishes nomogram as an aid to clinicians in the early clinical diagnosis of LGG.

Accelerated progression of tumors is not only associated with malignant cells but is also influenced by tumor microenvironment [33]. As researchers continue to learn more about the tumor microenvironment, there is great potential for further understanding of the relevant immune cell components and roles in the tumor microenvironment to guide immunotherapy [34]. We analyzed the results of the correlation between MCL1 and immune infiltration. MCL1 showed the most positive correlation with T helper cells and the most negative correlation with NK CD56 bright cells. T helper cells (CD4+ T cells) are essential for host defense but are also a major driver of immune-mediated disease [35]. For instance, multiple sclerosis is confirmed to be an autoimmune inflammatory disease caused by the recruitment of self-reactive lymphocytes (mainly CD4+ T cells) in the central nervous system [36,37]. Previous studies have revealed that immunity based on T helper cell characteristics of tumor subtypes affects prognosis and treatment response in breast cancer [38]. In addition, compared to the NK CD56 dim cells, NK CD56 bright cells are capable of producing large amounts of cytokines when monocytes are activated but have a lower natural cytotoxicity [39]. Therefore, studies focusing on one or more unique immune cells may help to identify potential mechanisms of action of MCL1 and demonstrate that MCL1 is a promising diagnostic LGG biomarker involved in immune regulation. Ultimately, MCL1-related studies and new targeted immunotherapies may help to improve the poor prognosis of patients and give physicians one more possibility to treat LGG.

Understanding the mechanisms and consequences of disulfidptosis may provide insights into novel therapeutic targets and strategies for cancer treatment. Currently, disulfidptosis has been shown to correlate with bladder cancer [40], hepatocellular carcinoma [12], and renal cell carcinoma [41], but an association with LGG has not yet been reported. MCL1 plays an important role in cancer development and has been associated with drug resistance in a variety of cancers. MCL1-selective inhibitors may represent a new class of anticancer agents that could provide clinical benefit to patients with a variety of hematological malignancies and solid tumors [42]. Furthermore, the literature suggests that exploring ubiquitination and deubiquitination of MCL1 is advancing therapeutic approaches and future directions [43]. This groundbreaking study provides novel insights and innovative findings by proposing, for the first time in the existing literature, a potential link between disulfidoptosis and LGG. The study further explores the significance of MCL1 expression of DRGs as a crucial prognostic factor in LGG.

This study has some limitations. We first explored DRGs using public databases such as GEO, TCGA, and GTEx but lacked clinical data of our own. This article lacks human tissue validation and further precise validation through biological experiments is needed. To address the heterogeneity of tumor samples, further techniques such as single-cell analysis or spatial transcriptomics allow for a more detailed characterization of the heterogeneity of cells within a tumor and their impact on gene expression patterns and immune infiltration

5 Conclusion

Our study reveals significant associations between DRGs and expression, immune response, mutations, and drug sensitivity in patients with LGG. We observed substantial heterogeneity among LGG patients, particularly within distinct disulfidptosis subclusters and DEGs. Importantly, we found that MCL1 may serve as a prognostic biomarker in LGG, predicting poor prognosis and correlating with levels of immune infiltration. These findings provide valuable insights into the potential use of MCL1 as a novel prognostic indicator and highlight its relevance for the development of new immunotherapeutic strategies. Our study represents a scientific and bold endeavor. Moving forward, further research should aim to explore and investigate the mechanistic aspects of MCL1’s role in LGG and explore potential therapeutic interventions based on these findings.

Acknowledgments

The authors thank TCGA and GEO databases for making the data available.

  1. Funding information: This work was supported by the National Natural Science Foundation of China (No. 81001340), the Medical Scientific Research Foundation of Guangdong Province, China (A2021474), Medical and Health Science and Technology Project of Shantou, Guangdong, China (210526156491330), Medical and Health Science and Technology Project of Shantou, Guangdong, China (211123176491711), Medical and Health Science and Technology Project of Shantou, Guangdong, China (221117126497682), 2021 Guangdong Clinical Teaching Base Teaching Reform Research Project (2021JD065), and 2022 Teaching Reform and Research Project of Shantou Medical College (2022-19).

  2. Author contributions: ZX and XL conceptualized and designed the study. SL, XC, and YL collected data. XL and DL performed the data analysis. ZX and YS designed and revised the manuscript. All authors contributed to the article and approved the submitted version.

  3. Conflict of interest: The authors declare that they have no conflict of interest to disclose.

  4. Data availability statement: All data are available through TCGA and GEO databases. More detailed data are available from the corresponding author on reasonable request.

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Received: 2023-06-23
Revised: 2023-09-20
Accepted: 2023-10-03
Published Online: 2023-10-25

© 2023 the author(s), published by De Gruyter

This work is licensed under the Creative Commons Attribution 4.0 International License.

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  88. PTPN12 down-regulated by miR-146b-3p gene affects the malignant progression of laryngeal squamous cell carcinoma
  89. miR-141-3p accelerates ovarian cancer progression and promotes M2-like macrophage polarization by targeting the Keap1-Nrf2 pathway
  90. lncRNA OIP5-AS1 attenuates the osteoarthritis progression in IL-1β-stimulated chondrocytes
  91. Overexpression of LINC00607 inhibits cell growth and aggressiveness by regulating the miR-1289/EFNA5 axis in non-small-cell lung cancer
  92. Subjective well-being in informal caregivers during the COVID-19 pandemic
  93. Nrf2 protects against myocardial ischemia-reperfusion injury in diabetic rats by inhibiting Drp1-mediated mitochondrial fission
  94. Unfolded protein response inhibits KAT2B/MLKL-mediated necroptosis of hepatocytes by promoting BMI1 level to ubiquitinate KAT2B
  95. Bladder cancer screening: The new selection and prediction model
  96. circNFATC3 facilitated the progression of oral squamous cell carcinoma via the miR-520h/LDHA axis
  97. Prone position effect in intensive care patients with SARS-COV-2 pneumonia
  98. Clinical observation on the efficacy of Tongdu Tuina manipulation in the treatment of primary enuresis in children
  99. Dihydroartemisinin ameliorates cerebral I/R injury in rats via regulating VWF and autophagy-mediated SIRT1/FOXO1 pathway
  100. Knockdown of circ_0113656 assuages oxidized low-density lipoprotein-induced vascular smooth muscle cell injury through the miR-188-3p/IGF2 pathway
  101. Low Ang-(1–7) and high des-Arg9 bradykinin serum levels are correlated with cardiovascular risk factors in patients with COVID-19
  102. Effect of maternal age and body mass index on induction of labor with oral misoprostol for premature rupture of membrane at term: A retrospective cross-sectional study
  103. Potential protective effects of Huanglian Jiedu Decoction against COVID-19-associated acute kidney injury: A network-based pharmacological and molecular docking study
  104. Clinical significance of serum MBD3 detection in girls with central precocious puberty
  105. Clinical features of varicella-zoster virus caused neurological diseases detected by metagenomic next-generation sequencing
  106. Collagen treatment of complex anorectal fistula: 3 years follow-up
  107. LncRNA CASC15 inhibition relieves renal fibrosis in diabetic nephropathy through down-regulating SP-A by sponging to miR-424
  108. Efficacy analysis of empirical bismuth quadruple therapy, high-dose dual therapy, and resistance gene-based triple therapy as a first-line Helicobacter pylori eradication regimen – An open-label, randomized trial
  109. SMOC2 plays a role in heart failure via regulating TGF-β1/Smad3 pathway-mediated autophagy
  110. A prospective cohort study of the impact of chronic disease on fall injuries in middle-aged and older adults
  111. circRNA THBS1 silencing inhibits the malignant biological behavior of cervical cancer cells via the regulation of miR-543/HMGB2 axis
  112. hsa_circ_0000285 sponging miR-582-3p promotes neuroblastoma progression by regulating the Wnt/β-catenin signaling pathway
  113. Long non-coding RNA GNAS-AS1 knockdown inhibits proliferation and epithelial–mesenchymal transition of lung adenocarcinoma cells via the microRNA-433-3p/Rab3A axis
  114. lncRNA UCA1 regulates miR-132/Lrrfip1 axis to promote vascular smooth muscle cell proliferation
  115. Twenty-four-color full spectrum flow cytometry panel for minimal residual disease detection in acute myeloid leukemia
  116. Hsa-miR-223-3p participates in the process of anthracycline-induced cardiomyocyte damage by regulating NFIA gene
  117. Anti-inflammatory effect of ApoE23 on Salmonella typhimurium-induced sepsis in mice
  118. Analysis of somatic mutations and key driving factors of cervical cancer progression
  119. Hsa_circ_0028007 regulates the progression of nasopharyngeal carcinoma through the miR-1179/SQLE axis
  120. Variations in sexual function after laparoendoscopic single-site hysterectomy in women with benign gynecologic diseases
  121. Effects of pharmacological delay with roxadustat on multi-territory perforator flap survival in rats
  122. Analysis of heroin effects on calcium channels in rat cardiomyocytes based on transcriptomics and metabolomics
  123. Risk factors of recurrent bacterial vaginosis among women of reproductive age: A cross-sectional study
  124. Alkbh5 plays indispensable roles in maintaining self-renewal of hematopoietic stem cells
  125. Study to compare the effect of casirivimab and imdevimab, remdesivir, and favipiravir on progression and multi-organ function of hospitalized COVID-19 patients
  126. Correlation between microvessel maturity and ISUP grades assessed using contrast-enhanced transrectal ultrasonography in prostate cancer
  127. The protective effect of caffeic acid phenethyl ester in the nephrotoxicity induced by α-cypermethrin
  128. Norepinephrine alleviates cyclosporin A-induced nephrotoxicity by enhancing the expression of SFRP1
  129. Effect of RUNX1/FOXP3 axis on apoptosis of T and B lymphocytes and immunosuppression in sepsis
  130. The function of Foxp1 represses β-adrenergic receptor transcription in the occurrence and development of bladder cancer through STAT3 activity
  131. Risk model and validation of carbapenem-resistant Klebsiella pneumoniae infection in patients with cerebrovascular disease in the ICU
  132. Calycosin protects against chronic prostatitis in rats via inhibition of the p38MAPK/NF-κB pathway
  133. Pan-cancer analysis of the PDE4DIP gene with potential prognostic and immunotherapeutic values in multiple cancers including acute myeloid leukemia
  134. The safety and immunogenicity to inactivated COVID-19 vaccine in patients with hyperlipemia
  135. Circ-UBR4 regulates the proliferation, migration, inflammation, and apoptosis in ox-LDL-induced vascular smooth muscle cells via miR-515-5p/IGF2 axis
  136. Clinical characteristics of current COVID-19 rehabilitation outpatients in China
  137. Luteolin alleviates ulcerative colitis in rats via regulating immune response, oxidative stress, and metabolic profiling
  138. miR-199a-5p inhibits aortic valve calcification by targeting ATF6 and GRP78 in valve interstitial cells
  139. The application of iliac fascia space block combined with esketamine intravenous general anesthesia in PFNA surgery of the elderly: A prospective, single-center, controlled trial
  140. Elevated blood acetoacetate levels reduce major adverse cardiac and cerebrovascular events risk in acute myocardial infarction
  141. The effects of progesterone on the healing of obstetric anal sphincter damage in female rats
  142. Identification of cuproptosis-related genes for predicting the development of prostate cancer
  143. Lumican silencing ameliorates β-glycerophosphate-mediated vascular smooth muscle cell calcification by attenuating the inhibition of APOB on KIF2C activity
  144. Targeting PTBP1 blocks glutamine metabolism to improve the cisplatin sensitivity of hepatocarcinoma cells through modulating the mRNA stability of glutaminase
  145. A single center prospective study: Influences of different hip flexion angles on the measurement of lumbar spine bone mineral density by dual energy X-ray absorptiometry
  146. Clinical analysis of AN69ST membrane continuous venous hemofiltration in the treatment of severe sepsis
  147. Antibiotics therapy combined with probiotics administered intravaginally for the treatment of bacterial vaginosis: A systematic review and meta-analysis
  148. Construction of a ceRNA network to reveal a vascular invasion associated prognostic model in hepatocellular carcinoma
  149. A pan-cancer analysis of STAT3 expression and genetic alterations in human tumors
  150. A prognostic signature based on seven T-cell-related cell clustering genes in bladder urothelial carcinoma
  151. Pepsin concentration in oral lavage fluid of rabbit reflux model constructed by dilating the lower esophageal sphincter
  152. The antihypertensive felodipine shows synergistic activity with immune checkpoint blockade and inhibits tumor growth via NFAT1 in LUSC
  153. Tanshinone IIA attenuates valvular interstitial cells’ calcification induced by oxidized low density lipoprotein via reducing endoplasmic reticulum stress
  154. AS-IV enhances the antitumor effects of propofol in NSCLC cells by inhibiting autophagy
  155. Establishment of two oxaliplatin-resistant gallbladder cancer cell lines and comprehensive analysis of dysregulated genes
  156. Trial protocol: Feasibility of neuromodulation with connectivity-guided intermittent theta-burst stimulation for improving cognition in multiple sclerosis
  157. LncRNA LINC00592 mediates the promoter methylation of WIF1 to promote the development of bladder cancer
  158. Factors associated with gastrointestinal dysmotility in critically ill patients
  159. Mechanisms by which spinal cord stimulation intervenes in atrial fibrillation: The involvement of the endothelin-1 and nerve growth factor/p75NTR pathways
  160. Analysis of two-gene signatures and related drugs in small-cell lung cancer by bioinformatics
  161. Silencing USP19 alleviates cigarette smoke extract-induced mitochondrial dysfunction in BEAS-2B cells by targeting FUNDC1
  162. Menstrual irregularities associated with COVID-19 vaccines among women in Saudi Arabia: A survey during 2022
  163. Ferroptosis involves in Schwann cell death in diabetic peripheral neuropathy
  164. The effect of AQP4 on tau protein aggregation in neurodegeneration and persistent neuroinflammation after cerebral microinfarcts
  165. Activation of UBEC2 by transcription factor MYBL2 affects DNA damage and promotes gastric cancer progression and cisplatin resistance
  166. Analysis of clinical characteristics in proximal and distal reflux monitoring among patients with gastroesophageal reflux disease
  167. Exosomal circ-0020887 and circ-0009590 as novel biomarkers for the diagnosis and prediction of short-term adverse cardiovascular outcomes in STEMI patients
  168. Upregulated microRNA-429 confers endometrial stromal cell dysfunction by targeting HIF1AN and regulating the HIF1A/VEGF pathway
  169. Bibliometrics and knowledge map analysis of ultrasound-guided regional anesthesia
  170. Knockdown of NUPR1 inhibits angiogenesis in lung cancer through IRE1/XBP1 and PERK/eIF2α/ATF4 signaling pathways
  171. D-dimer trends predict COVID-19 patient’s prognosis: A retrospective chart review study
  172. WTAP affects intracranial aneurysm progression by regulating m6A methylation modification
  173. Using of endoscopic polypectomy in patients with diagnosed malignant colorectal polyp – The cross-sectional clinical study
  174. Anti-S100A4 antibody administration alleviates bronchial epithelial–mesenchymal transition in asthmatic mice
  175. Prognostic evaluation of system immune-inflammatory index and prognostic nutritional index in double expressor diffuse large B-cell lymphoma
  176. Prevalence and antibiogram of bacteria causing urinary tract infection among patients with chronic kidney disease
  177. Reactive oxygen species within the vaginal space: An additional promoter of cervical intraepithelial neoplasia and uterine cervical cancer development?
  178. Identification of disulfidptosis-related genes and immune infiltration in lower-grade glioma
  179. A new technique for uterine-preserving pelvic organ prolapse surgery: Laparoscopic rectus abdominis hysteropexy for uterine prolapse by comparing with traditional techniques
  180. Self-isolation of an Italian long-term care facility during COVID-19 pandemic: A comparison study on care-related infectious episodes
  181. A comparative study on the overlapping effects of clinically applicable therapeutic interventions in patients with central nervous system damage
  182. Low intensity extracorporeal shockwave therapy for chronic pelvic pain syndrome: Long-term follow-up
  183. The diagnostic accuracy of touch imprint cytology for sentinel lymph node metastases of breast cancer: An up-to-date meta-analysis of 4,073 patients
  184. Mortality associated with Sjögren’s syndrome in the United States in the 1999–2020 period: A multiple cause-of-death study
  185. CircMMP11 as a prognostic biomarker mediates miR-361-3p/HMGB1 axis to accelerate malignant progression of hepatocellular carcinoma
  186. Analysis of the clinical characteristics and prognosis of adult de novo acute myeloid leukemia (none APL) with PTPN11 mutations
  187. KMT2A maintains stemness of gastric cancer cells through regulating Wnt/β-catenin signaling-activated transcriptional factor KLF11
  188. Evaluation of placental oxygenation by near-infrared spectroscopy in relation to ultrasound maturation grade in physiological term pregnancies
  189. The role of ultrasonographic findings for PIK3CA-mutated, hormone receptor-positive, human epidermal growth factor receptor-2-negative breast cancer
  190. Construction of immunogenic cell death-related molecular subtypes and prognostic signature in colorectal cancer
  191. Long-term prognostic value of high-sensitivity cardiac troponin-I in patients with idiopathic dilated cardiomyopathy
  192. Establishing a novel Fanconi anemia signaling pathway-associated prognostic model and tumor clustering for pediatric acute myeloid leukemia patients
  193. Integrative bioinformatics analysis reveals STAT2 as a novel biomarker of inflammation-related cardiac dysfunction in atrial fibrillation
  194. Adipose-derived stem cells repair radiation-induced chronic lung injury via inhibiting TGF-β1/Smad 3 signaling pathway
  195. Real-world practice of idiopathic pulmonary fibrosis: Results from a 2000–2016 cohort
  196. lncRNA LENGA sponges miR-378 to promote myocardial fibrosis in atrial fibrillation
  197. Diagnostic value of urinary Tamm-Horsfall protein and 24 h urine osmolality for recurrent calcium oxalate stones of the upper urinary tract: Cross-sectional study
  198. The value of color Doppler ultrasonography combined with serum tumor markers in differential diagnosis of gastric stromal tumor and gastric cancer
  199. The spike protein of SARS-CoV-2 induces inflammation and EMT of lung epithelial cells and fibroblasts through the upregulation of GADD45A
  200. Mycophenolate mofetil versus cyclophosphamide plus in patients with connective tissue disease-associated interstitial lung disease: Efficacy and safety analysis
  201. MiR-1278 targets CALD1 and suppresses the progression of gastric cancer via the MAPK pathway
  202. Metabolomic analysis of serum short-chain fatty acid concentrations in a mouse of MPTP-induced Parkinson’s disease after dietary supplementation with branched-chain amino acids
  203. Cimifugin inhibits adipogenesis and TNF-α-induced insulin resistance in 3T3-L1 cells
  204. Predictors of gastrointestinal complaints in patients on metformin therapy
  205. Prescribing patterns in patients with chronic obstructive pulmonary disease and atrial fibrillation
  206. A retrospective analysis of the effect of latent tuberculosis infection on clinical pregnancy outcomes of in vitro fertilization–fresh embryo transferred in infertile women
  207. Appropriateness and clinical outcomes of short sustained low-efficiency dialysis: A national experience
  208. miR-29 regulates metabolism by inhibiting JNK-1 expression in non-obese patients with type 2 diabetes mellitus and NAFLD
  209. Clinical features and management of lymphoepithelial cyst
  210. Serum VEGF, high-sensitivity CRP, and cystatin-C assist in the diagnosis of type 2 diabetic retinopathy complicated with hyperuricemia
  211. ENPP1 ameliorates vascular calcification via inhibiting the osteogenic transformation of VSMCs and generating PPi
  212. Significance of monitoring the levels of thyroid hormone antibodies and glucose and lipid metabolism antibodies in patients suffer from type 2 diabetes
  213. The causal relationship between immune cells and different kidney diseases: A Mendelian randomization study
  214. Interleukin 33, soluble suppression of tumorigenicity 2, interleukin 27, and galectin 3 as predictors for outcome in patients admitted to intensive care units
  215. Identification of diagnostic immune-related gene biomarkers for predicting heart failure after acute myocardial infarction
  216. Long-term administration of probiotics prevents gastrointestinal mucosal barrier dysfunction in septic mice partly by upregulating the 5-HT degradation pathway
  217. miR-192 inhibits the activation of hepatic stellate cells by targeting Rictor
  218. Diagnostic and prognostic value of MR-pro ADM, procalcitonin, and copeptin in sepsis
  219. Review Articles
  220. Prenatal diagnosis of fetal defects and its implications on the delivery mode
  221. Electromagnetic fields exposure on fetal and childhood abnormalities: Systematic review and meta-analysis
  222. Characteristics of antibiotic resistance mechanisms and genes of Klebsiella pneumoniae
  223. Saddle pulmonary embolism in the setting of COVID-19 infection: A systematic review of case reports and case series
  224. Vitamin C and epigenetics: A short physiological overview
  225. Ebselen: A promising therapy protecting cardiomyocytes from excess iron in iron-overloaded thalassemia patients
  226. Aspirin versus LMWH for VTE prophylaxis after orthopedic surgery
  227. Mechanism of rhubarb in the treatment of hyperlipidemia: A recent review
  228. Surgical management and outcomes of traumatic global brachial plexus injury: A concise review and our center approach
  229. The progress of autoimmune hepatitis research and future challenges
  230. METTL16 in human diseases: What should we do next?
  231. New insights into the prevention of ureteral stents encrustation
  232. VISTA as a prospective immune checkpoint in gynecological malignant tumors: A review of the literature
  233. Case Reports
  234. Mycobacterium xenopi infection of the kidney and lymph nodes: A case report
  235. Genetic mutation of SLC6A20 (c.1072T > C) in a family with nephrolithiasis: A case report
  236. Chronic hepatitis B complicated with secondary hemochromatosis was cured clinically: A case report
  237. Liver abscess complicated with multiple organ invasive infection caused by hematogenous disseminated hypervirulent Klebsiella pneumoniae: A case report
  238. Urokinase-based lock solutions for catheter salvage: A case of an upcoming kidney transplant recipient
  239. Two case reports of maturity-onset diabetes of the young type 3 caused by the hepatocyte nuclear factor 1α gene mutation
  240. Immune checkpoint inhibitor-related pancreatitis: What is known and what is not
  241. Does total hip arthroplasty result in intercostal nerve injury? A case report and literature review
  242. Clinicopathological characteristics and diagnosis of hepatic sinusoidal obstruction syndrome caused by Tusanqi – Case report and literature review
  243. Synchronous triple primary gastrointestinal malignant tumors treated with laparoscopic surgery: A case report
  244. CT-guided percutaneous microwave ablation combined with bone cement injection for the treatment of transverse metastases: A case report
  245. Malignant hyperthermia: Report on a successful rescue of a case with the highest temperature of 44.2°C
  246. Anesthetic management of fetal pulmonary valvuloplasty: A case report
  247. Rapid Communication
  248. Impact of COVID-19 lockdown on glycemic levels during pregnancy: A retrospective analysis
  249. Erratum
  250. Erratum to “Inhibition of miR-21 improves pulmonary vascular responses in bronchopulmonary dysplasia by targeting the DDAH1/ADMA/NO pathway”
  251. Erratum to: “Fer exacerbates renal fibrosis and can be targeted by miR-29c-3p”
  252. Retraction
  253. Retraction of “Study to compare the effect of casirivimab and imdevimab, remdesivir, and favipiravir on progression and multi-organ function of hospitalized COVID-19 patients”
  254. Retraction of “circ_0062491 alleviates periodontitis via the miR-142-5p/IGF1 axis”
  255. Retraction of “miR-223-3p alleviates TGF-β-induced epithelial-mesenchymal transition and extracellular matrix deposition by targeting SP3 in endometrial epithelial cells”
  256. Retraction of “SLCO4A1-AS1 mediates pancreatic cancer development via miR-4673/KIF21B axis”
  257. Retraction of “circRNA_0001679/miR-338-3p/DUSP16 axis aggravates acute lung injury”
  258. Retraction of “lncRNA ACTA2-AS1 inhibits malignant phenotypes of gastric cancer cells”
  259. Special issue Linking Pathobiological Mechanisms to Clinical Application for cardiovascular diseases
  260. Effect of cardiac rehabilitation therapy on depressed patients with cardiac insufficiency after cardiac surgery
  261. Special issue The evolving saga of RNAs from bench to bedside - Part I
  262. FBLIM1 mRNA is a novel prognostic biomarker and is associated with immune infiltrates in glioma
  263. Special Issue Computational Intelligence Methodologies Meets Recurrent Cancers - Part III
  264. Development of a machine learning-based signature utilizing inflammatory response genes for predicting prognosis and immune microenvironment in ovarian cancer
https://doi.org/10.1515/med-2023-0825
Keywords for this article
disulfidptosis; lower-grade glioma; immune infiltration; machine learning; MCL1
Creative Commons
BY 4.0

Articles in the same Issue

  1. Research Articles
  2. Exosomes derived from mesenchymal stem cells overexpressing miR-210 inhibits neuronal inflammation and contribute to neurite outgrowth through modulating microglia polarization
  3. Current situation of acute ST-segment elevation myocardial infarction in a county hospital chest pain center during an epidemic of novel coronavirus pneumonia
  4. circ-IARS depletion inhibits the progression of non-small-cell lung cancer by circ-IARS/miR-1252-5p/HDGF ceRNA pathway
  5. circRNA ITGA7 restrains growth and enhances radiosensitivity by up-regulating SMAD4 in colorectal carcinoma
  6. WDR79 promotes aerobic glycolysis of pancreatic ductal adenocarcinoma (PDAC) by the suppression of SIRT4
  7. Up-regulation of collagen type V alpha 2 (COL5A2) promotes malignant phenotypes in gastric cancer cell via inducing epithelial–mesenchymal transition (EMT)
  8. Inhibition of TERC inhibits neural apoptosis and inflammation in spinal cord injury through Akt activation and p-38 inhibition via the miR-34a-5p/XBP-1 axis
  9. 3D-printed polyether-ether-ketone/n-TiO2 composite enhances the cytocompatibility and osteogenic differentiation of MC3T3-E1 cells by downregulating miR-154-5p
  10. Propofol-mediated circ_0000735 downregulation restrains tumor growth by decreasing integrin-β1 expression in non-small cell lung cancer
  11. PVT1/miR-16/CCND1 axis regulates gastric cancer progression
  12. Silencing of circ_002136 sensitizes gastric cancer to paclitaxel by targeting the miR-16-5p/HMGA1 axis
  13. Short-term outcomes after simultaneous gastrectomy plus cholecystectomy in gastric cancer: A pooling up analysis
  14. SCARA5 inhibits oral squamous cell carcinoma via inactivating the STAT3 and PI3K/AKT signaling pathways
  15. Molecular mechanism by which the Notch signaling pathway regulates autophagy in a rat model of pulmonary fibrosis in pigeon breeder’s lung
  16. lncRNA TPT1-AS1 promotes cell migration and invasion in esophageal squamous-cell carcinomas by regulating the miR-26a/HMGA1 axis
  17. SIRT1/APE1 promotes the viability of gastric cancer cells by inhibiting p53 to suppress ferroptosis
  18. Glycoprotein non-metastatic melanoma B interacts with epidermal growth factor receptor to regulate neural stem cell survival and differentiation
  19. Treatments for brain metastases from EGFR/ALK-negative/unselected NSCLC: A network meta-analysis
  20. Association of osteoporosis and skeletal muscle loss with serum type I collagen carboxyl-terminal peptide β glypeptide: A cross-sectional study in elder Chinese population
  21. circ_0000376 knockdown suppresses non-small cell lung cancer cell tumor properties by the miR-545-3p/PDPK1 pathway
  22. Delivery in a vertical birth chair supported by freedom of movement during labor: A randomized control trial
  23. UBE2J1 knockdown promotes cell apoptosis in endometrial cancer via regulating PI3K/AKT and MDM2/p53 signaling
  24. Metabolic resuscitation therapy in critically ill patients with sepsis and septic shock: A pilot prospective randomized controlled trial
  25. Lycopene ameliorates locomotor activity and urinary frequency induced by pelvic venous congestion in rats
  26. UHRF1-induced connexin26 methylation is involved in hearing damage triggered by intermittent hypoxia in neonatal rats
  27. LINC00511 promotes melanoma progression by targeting miR-610/NUCB2
  28. Ultra-high-performance liquid chromatography-tandem mass spectrometry analysis of serum metabolomic characteristics in people with different vitamin D levels
  29. Role of Jumonji domain-containing protein D3 and its inhibitor GSK-J4 in Hashimoto’s thyroiditis
  30. circ_0014736 induces GPR4 to regulate the biological behaviors of human placental trophoblast cells through miR-942-5p in preeclampsia
  31. Monitoring of sirolimus in the whole blood samples from pediatric patients with lymphatic anomalies
  32. Effects of osteogenic growth peptide C-terminal pentapeptide and its analogue on bone remodeling in an osteoporosis rat model
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  34. WGCNA-based identification of potential targets and pathways in response to treatment in locally advanced breast cancer patients
  35. Radiomics model using preoperative computed tomography angiography images to differentiate new from old emboli of acute lower limb arterial embolism
  36. Dysregulated lncRNAs are involved in the progress of myocardial infarction by constructing regulatory networks
  37. Single-arm trial to evaluate the efficacy and safety of baclofen in treatment of intractable hiccup caused by malignant tumor chemotherapy
  38. Genetic polymorphisms of MRPS30-DT and NINJ2 may influence lung cancer risk
  39. Efficacy of immune checkpoint inhibitors in patients with KRAS-mutant advanced non-small cell lung cancer: A retrospective analysis
  40. Pyroptosis-based risk score predicts prognosis and drug sensitivity in lung adenocarcinoma
  41. Upregulation of lncRNA LANCL1-AS1 inhibits the progression of non-small-cell lung cancer via the miR-3680-3p/GMFG axis
  42. CircRANBP17 modulated KDM1A to regulate neuroblastoma progression by sponging miR-27b-3p
  43. Exosomal miR-93-5p regulated the progression of osteoarthritis by targeting ADAMTS9
  44. Downregulation of RBM17 enhances cisplatin sensitivity and inhibits cell invasion in human hypopharyngeal cancer cells
  45. HDAC5-mediated PRAME regulates the proliferation, migration, invasion, and EMT of laryngeal squamous cell carcinoma via the PI3K/AKT/mTOR signaling pathway
  46. The association between sleep duration, quality, and nonalcoholic fatty liver disease: A cross-sectional study
  47. Myostatin silencing inhibits podocyte apoptosis in membranous nephropathy through Smad3/PKA/NOX4 signaling pathway
  48. A novel long noncoding RNA AC125257.1 facilitates colorectal cancer progression by targeting miR-133a-3p/CASC5 axis
  49. Impact of omicron wave and associated control measures in Shanghai on health management and psychosocial well-being of patients with chronic conditions
  50. Clinicopathological characteristics and prognosis of young patients aged ≤45 years old with non-small cell lung cancer
  51. TMT-based comprehensive proteomic profiling identifies serum prognostic signatures of acute myeloid leukemia
  52. The dose limits of teeth protection for patients with nasopharyngeal carcinoma undergoing radiotherapy based on the early oral health-related quality of life
  53. miR-30b-5p targeting GRIN2A inhibits hippocampal damage in epilepsy
  54. Long non-coding RNA AL137789.1 promoted malignant biological behaviors and immune escape of pancreatic carcinoma cells
  55. IRF6 and FGF1 polymorphisms in non-syndromic cleft lip with or without cleft palate in the Polish population
  56. Comprehensive analysis of the role of SFXN family in breast cancer
  57. Efficacy of bronchoscopic intratumoral injection of endostar and cisplatin in lung squamous cell carcinoma patients underwent conventional chemoradiotherapy
  58. Silencing of long noncoding RNA MIAT inhibits the viability and proliferation of breast cancer cells by promoting miR-378a-5p expression
  59. AG1024, an IGF-1 receptor inhibitor, ameliorates renal injury in rats with diabetic nephropathy via the SOCS/JAK2/STAT pathway
  60. Downregulation of KIAA1199 alleviated the activation, proliferation, and migration of hepatic stellate cells by the inhibition of epithelial–mesenchymal transition
  61. Exendin-4 regulates the MAPK and WNT signaling pathways to alleviate the osteogenic inhibition of periodontal ligament stem cells in a high glucose environment
  62. Inhibition of glycolysis represses the growth and alleviates the endoplasmic reticulum stress of breast cancer cells by regulating TMTC3
  63. The function of lncRNA EMX2OS/miR-653-5p and its regulatory mechanism in lung adenocarcinoma
  64. Tectorigenin alleviates the apoptosis and inflammation in spinal cord injury cell model through inhibiting insulin-like growth factor-binding protein 6
  65. Ultrasound examination supporting CT or MRI in the evaluation of cervical lymphadenopathy in patients with irradiation-treated head and neck cancer
  66. F-box and WD repeat domain containing 7 inhibits the activation of hepatic stellate cells by degrading delta-like ligand 1 to block Notch signaling pathway
  67. Knockdown of circ_0005615 enhances the radiosensitivity of colorectal cancer by regulating the miR-665/NOTCH1 axis
  68. Long noncoding RNA Mhrt alleviates angiotensin II-induced cardiac hypertrophy phenotypes by mediating the miR-765/Wnt family member 7B pathway
  69. Effect of miR-499-5p/SOX6 axis on atrial fibrosis in rats with atrial fibrillation
  70. Cholesterol induces inflammation and reduces glucose utilization
  71. circ_0004904 regulates the trophoblast cell in preeclampsia via miR-19b-3p/ARRDC3 axis
  72. NECAB3 promotes the migration and invasion of liver cancer cells through HIF-1α/RIT1 signaling pathway
  73. The poor performance of cardiovascular risk scores in identifying patients with idiopathic inflammatory myopathies at high cardiovascular risk
  74. miR-2053 inhibits the growth of ovarian cancer cells by downregulating SOX4
  75. Nucleophosmin 1 associating with engulfment and cell motility protein 1 regulates hepatocellular carcinoma cell chemotaxis and metastasis
  76. α-Hederin regulates macrophage polarization to relieve sepsis-induced lung and liver injuries in mice
  77. Changes of microbiota level in urinary tract infections: A meta-analysis
  78. Identification of key enzalutamide-resistance-related genes in castration-resistant prostate cancer and verification of RAD51 functions
  79. Falls during oxaliplatin-based chemotherapy for gastrointestinal malignancies – (lessons learned from) a prospective study
  80. Outcomes of low-risk birth care during the Covid-19 pandemic: A cohort study from a tertiary care center in Lithuania
  81. Vitamin D protects intestines from liver cirrhosis-induced inflammation and oxidative stress by inhibiting the TLR4/MyD88/NF-κB signaling pathway
  82. Integrated transcriptome analysis identifies APPL1/RPS6KB2/GALK1 as immune-related metastasis factors in breast cancer
  83. Genomic analysis of immunogenic cell death-related subtypes for predicting prognosis and immunotherapy outcomes in glioblastoma multiforme
  84. Circular RNA Circ_0038467 promotes the maturation of miRNA-203 to increase lipopolysaccharide-induced apoptosis of chondrocytes
  85. An economic evaluation of fine-needle cytology as the primary diagnostic tool in the diagnosis of lymphadenopathy
  86. Midazolam impedes lung carcinoma cell proliferation and migration via EGFR/MEK/ERK signaling pathway
  87. Network pharmacology combined with molecular docking and experimental validation to reveal the pharmacological mechanism of naringin against renal fibrosis
  88. PTPN12 down-regulated by miR-146b-3p gene affects the malignant progression of laryngeal squamous cell carcinoma
  89. miR-141-3p accelerates ovarian cancer progression and promotes M2-like macrophage polarization by targeting the Keap1-Nrf2 pathway
  90. lncRNA OIP5-AS1 attenuates the osteoarthritis progression in IL-1β-stimulated chondrocytes
  91. Overexpression of LINC00607 inhibits cell growth and aggressiveness by regulating the miR-1289/EFNA5 axis in non-small-cell lung cancer
  92. Subjective well-being in informal caregivers during the COVID-19 pandemic
  93. Nrf2 protects against myocardial ischemia-reperfusion injury in diabetic rats by inhibiting Drp1-mediated mitochondrial fission
  94. Unfolded protein response inhibits KAT2B/MLKL-mediated necroptosis of hepatocytes by promoting BMI1 level to ubiquitinate KAT2B
  95. Bladder cancer screening: The new selection and prediction model
  96. circNFATC3 facilitated the progression of oral squamous cell carcinoma via the miR-520h/LDHA axis
  97. Prone position effect in intensive care patients with SARS-COV-2 pneumonia
  98. Clinical observation on the efficacy of Tongdu Tuina manipulation in the treatment of primary enuresis in children
  99. Dihydroartemisinin ameliorates cerebral I/R injury in rats via regulating VWF and autophagy-mediated SIRT1/FOXO1 pathway
  100. Knockdown of circ_0113656 assuages oxidized low-density lipoprotein-induced vascular smooth muscle cell injury through the miR-188-3p/IGF2 pathway
  101. Low Ang-(1–7) and high des-Arg9 bradykinin serum levels are correlated with cardiovascular risk factors in patients with COVID-19
  102. Effect of maternal age and body mass index on induction of labor with oral misoprostol for premature rupture of membrane at term: A retrospective cross-sectional study
  103. Potential protective effects of Huanglian Jiedu Decoction against COVID-19-associated acute kidney injury: A network-based pharmacological and molecular docking study
  104. Clinical significance of serum MBD3 detection in girls with central precocious puberty
  105. Clinical features of varicella-zoster virus caused neurological diseases detected by metagenomic next-generation sequencing
  106. Collagen treatment of complex anorectal fistula: 3 years follow-up
  107. LncRNA CASC15 inhibition relieves renal fibrosis in diabetic nephropathy through down-regulating SP-A by sponging to miR-424
  108. Efficacy analysis of empirical bismuth quadruple therapy, high-dose dual therapy, and resistance gene-based triple therapy as a first-line Helicobacter pylori eradication regimen – An open-label, randomized trial
  109. SMOC2 plays a role in heart failure via regulating TGF-β1/Smad3 pathway-mediated autophagy
  110. A prospective cohort study of the impact of chronic disease on fall injuries in middle-aged and older adults
  111. circRNA THBS1 silencing inhibits the malignant biological behavior of cervical cancer cells via the regulation of miR-543/HMGB2 axis
  112. hsa_circ_0000285 sponging miR-582-3p promotes neuroblastoma progression by regulating the Wnt/β-catenin signaling pathway
  113. Long non-coding RNA GNAS-AS1 knockdown inhibits proliferation and epithelial–mesenchymal transition of lung adenocarcinoma cells via the microRNA-433-3p/Rab3A axis
  114. lncRNA UCA1 regulates miR-132/Lrrfip1 axis to promote vascular smooth muscle cell proliferation
  115. Twenty-four-color full spectrum flow cytometry panel for minimal residual disease detection in acute myeloid leukemia
  116. Hsa-miR-223-3p participates in the process of anthracycline-induced cardiomyocyte damage by regulating NFIA gene
  117. Anti-inflammatory effect of ApoE23 on Salmonella typhimurium-induced sepsis in mice
  118. Analysis of somatic mutations and key driving factors of cervical cancer progression
  119. Hsa_circ_0028007 regulates the progression of nasopharyngeal carcinoma through the miR-1179/SQLE axis
  120. Variations in sexual function after laparoendoscopic single-site hysterectomy in women with benign gynecologic diseases
  121. Effects of pharmacological delay with roxadustat on multi-territory perforator flap survival in rats
  122. Analysis of heroin effects on calcium channels in rat cardiomyocytes based on transcriptomics and metabolomics
  123. Risk factors of recurrent bacterial vaginosis among women of reproductive age: A cross-sectional study
  124. Alkbh5 plays indispensable roles in maintaining self-renewal of hematopoietic stem cells
  125. Study to compare the effect of casirivimab and imdevimab, remdesivir, and favipiravir on progression and multi-organ function of hospitalized COVID-19 patients
  126. Correlation between microvessel maturity and ISUP grades assessed using contrast-enhanced transrectal ultrasonography in prostate cancer
  127. The protective effect of caffeic acid phenethyl ester in the nephrotoxicity induced by α-cypermethrin
  128. Norepinephrine alleviates cyclosporin A-induced nephrotoxicity by enhancing the expression of SFRP1
  129. Effect of RUNX1/FOXP3 axis on apoptosis of T and B lymphocytes and immunosuppression in sepsis
  130. The function of Foxp1 represses β-adrenergic receptor transcription in the occurrence and development of bladder cancer through STAT3 activity
  131. Risk model and validation of carbapenem-resistant Klebsiella pneumoniae infection in patients with cerebrovascular disease in the ICU
  132. Calycosin protects against chronic prostatitis in rats via inhibition of the p38MAPK/NF-κB pathway
  133. Pan-cancer analysis of the PDE4DIP gene with potential prognostic and immunotherapeutic values in multiple cancers including acute myeloid leukemia
  134. The safety and immunogenicity to inactivated COVID-19 vaccine in patients with hyperlipemia
  135. Circ-UBR4 regulates the proliferation, migration, inflammation, and apoptosis in ox-LDL-induced vascular smooth muscle cells via miR-515-5p/IGF2 axis
  136. Clinical characteristics of current COVID-19 rehabilitation outpatients in China
  137. Luteolin alleviates ulcerative colitis in rats via regulating immune response, oxidative stress, and metabolic profiling
  138. miR-199a-5p inhibits aortic valve calcification by targeting ATF6 and GRP78 in valve interstitial cells
  139. The application of iliac fascia space block combined with esketamine intravenous general anesthesia in PFNA surgery of the elderly: A prospective, single-center, controlled trial
  140. Elevated blood acetoacetate levels reduce major adverse cardiac and cerebrovascular events risk in acute myocardial infarction
  141. The effects of progesterone on the healing of obstetric anal sphincter damage in female rats
  142. Identification of cuproptosis-related genes for predicting the development of prostate cancer
  143. Lumican silencing ameliorates β-glycerophosphate-mediated vascular smooth muscle cell calcification by attenuating the inhibition of APOB on KIF2C activity
  144. Targeting PTBP1 blocks glutamine metabolism to improve the cisplatin sensitivity of hepatocarcinoma cells through modulating the mRNA stability of glutaminase
  145. A single center prospective study: Influences of different hip flexion angles on the measurement of lumbar spine bone mineral density by dual energy X-ray absorptiometry
  146. Clinical analysis of AN69ST membrane continuous venous hemofiltration in the treatment of severe sepsis
  147. Antibiotics therapy combined with probiotics administered intravaginally for the treatment of bacterial vaginosis: A systematic review and meta-analysis
  148. Construction of a ceRNA network to reveal a vascular invasion associated prognostic model in hepatocellular carcinoma
  149. A pan-cancer analysis of STAT3 expression and genetic alterations in human tumors
  150. A prognostic signature based on seven T-cell-related cell clustering genes in bladder urothelial carcinoma
  151. Pepsin concentration in oral lavage fluid of rabbit reflux model constructed by dilating the lower esophageal sphincter
  152. The antihypertensive felodipine shows synergistic activity with immune checkpoint blockade and inhibits tumor growth via NFAT1 in LUSC
  153. Tanshinone IIA attenuates valvular interstitial cells’ calcification induced by oxidized low density lipoprotein via reducing endoplasmic reticulum stress
  154. AS-IV enhances the antitumor effects of propofol in NSCLC cells by inhibiting autophagy
  155. Establishment of two oxaliplatin-resistant gallbladder cancer cell lines and comprehensive analysis of dysregulated genes
  156. Trial protocol: Feasibility of neuromodulation with connectivity-guided intermittent theta-burst stimulation for improving cognition in multiple sclerosis
  157. LncRNA LINC00592 mediates the promoter methylation of WIF1 to promote the development of bladder cancer
  158. Factors associated with gastrointestinal dysmotility in critically ill patients
  159. Mechanisms by which spinal cord stimulation intervenes in atrial fibrillation: The involvement of the endothelin-1 and nerve growth factor/p75NTR pathways
  160. Analysis of two-gene signatures and related drugs in small-cell lung cancer by bioinformatics
  161. Silencing USP19 alleviates cigarette smoke extract-induced mitochondrial dysfunction in BEAS-2B cells by targeting FUNDC1
  162. Menstrual irregularities associated with COVID-19 vaccines among women in Saudi Arabia: A survey during 2022
  163. Ferroptosis involves in Schwann cell death in diabetic peripheral neuropathy
  164. The effect of AQP4 on tau protein aggregation in neurodegeneration and persistent neuroinflammation after cerebral microinfarcts
  165. Activation of UBEC2 by transcription factor MYBL2 affects DNA damage and promotes gastric cancer progression and cisplatin resistance
  166. Analysis of clinical characteristics in proximal and distal reflux monitoring among patients with gastroesophageal reflux disease
  167. Exosomal circ-0020887 and circ-0009590 as novel biomarkers for the diagnosis and prediction of short-term adverse cardiovascular outcomes in STEMI patients
  168. Upregulated microRNA-429 confers endometrial stromal cell dysfunction by targeting HIF1AN and regulating the HIF1A/VEGF pathway
  169. Bibliometrics and knowledge map analysis of ultrasound-guided regional anesthesia
  170. Knockdown of NUPR1 inhibits angiogenesis in lung cancer through IRE1/XBP1 and PERK/eIF2α/ATF4 signaling pathways
  171. D-dimer trends predict COVID-19 patient’s prognosis: A retrospective chart review study
  172. WTAP affects intracranial aneurysm progression by regulating m6A methylation modification
  173. Using of endoscopic polypectomy in patients with diagnosed malignant colorectal polyp – The cross-sectional clinical study
  174. Anti-S100A4 antibody administration alleviates bronchial epithelial–mesenchymal transition in asthmatic mice
  175. Prognostic evaluation of system immune-inflammatory index and prognostic nutritional index in double expressor diffuse large B-cell lymphoma
  176. Prevalence and antibiogram of bacteria causing urinary tract infection among patients with chronic kidney disease
  177. Reactive oxygen species within the vaginal space: An additional promoter of cervical intraepithelial neoplasia and uterine cervical cancer development?
  178. Identification of disulfidptosis-related genes and immune infiltration in lower-grade glioma
  179. A new technique for uterine-preserving pelvic organ prolapse surgery: Laparoscopic rectus abdominis hysteropexy for uterine prolapse by comparing with traditional techniques
  180. Self-isolation of an Italian long-term care facility during COVID-19 pandemic: A comparison study on care-related infectious episodes
  181. A comparative study on the overlapping effects of clinically applicable therapeutic interventions in patients with central nervous system damage
  182. Low intensity extracorporeal shockwave therapy for chronic pelvic pain syndrome: Long-term follow-up
  183. The diagnostic accuracy of touch imprint cytology for sentinel lymph node metastases of breast cancer: An up-to-date meta-analysis of 4,073 patients
  184. Mortality associated with Sjögren’s syndrome in the United States in the 1999–2020 period: A multiple cause-of-death study
  185. CircMMP11 as a prognostic biomarker mediates miR-361-3p/HMGB1 axis to accelerate malignant progression of hepatocellular carcinoma
  186. Analysis of the clinical characteristics and prognosis of adult de novo acute myeloid leukemia (none APL) with PTPN11 mutations
  187. KMT2A maintains stemness of gastric cancer cells through regulating Wnt/β-catenin signaling-activated transcriptional factor KLF11
  188. Evaluation of placental oxygenation by near-infrared spectroscopy in relation to ultrasound maturation grade in physiological term pregnancies
  189. The role of ultrasonographic findings for PIK3CA-mutated, hormone receptor-positive, human epidermal growth factor receptor-2-negative breast cancer
  190. Construction of immunogenic cell death-related molecular subtypes and prognostic signature in colorectal cancer
  191. Long-term prognostic value of high-sensitivity cardiac troponin-I in patients with idiopathic dilated cardiomyopathy
  192. Establishing a novel Fanconi anemia signaling pathway-associated prognostic model and tumor clustering for pediatric acute myeloid leukemia patients
  193. Integrative bioinformatics analysis reveals STAT2 as a novel biomarker of inflammation-related cardiac dysfunction in atrial fibrillation
  194. Adipose-derived stem cells repair radiation-induced chronic lung injury via inhibiting TGF-β1/Smad 3 signaling pathway
  195. Real-world practice of idiopathic pulmonary fibrosis: Results from a 2000–2016 cohort
  196. lncRNA LENGA sponges miR-378 to promote myocardial fibrosis in atrial fibrillation
  197. Diagnostic value of urinary Tamm-Horsfall protein and 24 h urine osmolality for recurrent calcium oxalate stones of the upper urinary tract: Cross-sectional study
  198. The value of color Doppler ultrasonography combined with serum tumor markers in differential diagnosis of gastric stromal tumor and gastric cancer
  199. The spike protein of SARS-CoV-2 induces inflammation and EMT of lung epithelial cells and fibroblasts through the upregulation of GADD45A
  200. Mycophenolate mofetil versus cyclophosphamide plus in patients with connective tissue disease-associated interstitial lung disease: Efficacy and safety analysis
  201. MiR-1278 targets CALD1 and suppresses the progression of gastric cancer via the MAPK pathway
  202. Metabolomic analysis of serum short-chain fatty acid concentrations in a mouse of MPTP-induced Parkinson’s disease after dietary supplementation with branched-chain amino acids
  203. Cimifugin inhibits adipogenesis and TNF-α-induced insulin resistance in 3T3-L1 cells
  204. Predictors of gastrointestinal complaints in patients on metformin therapy
  205. Prescribing patterns in patients with chronic obstructive pulmonary disease and atrial fibrillation
  206. A retrospective analysis of the effect of latent tuberculosis infection on clinical pregnancy outcomes of in vitro fertilization–fresh embryo transferred in infertile women
  207. Appropriateness and clinical outcomes of short sustained low-efficiency dialysis: A national experience
  208. miR-29 regulates metabolism by inhibiting JNK-1 expression in non-obese patients with type 2 diabetes mellitus and NAFLD
  209. Clinical features and management of lymphoepithelial cyst
  210. Serum VEGF, high-sensitivity CRP, and cystatin-C assist in the diagnosis of type 2 diabetic retinopathy complicated with hyperuricemia
  211. ENPP1 ameliorates vascular calcification via inhibiting the osteogenic transformation of VSMCs and generating PPi
  212. Significance of monitoring the levels of thyroid hormone antibodies and glucose and lipid metabolism antibodies in patients suffer from type 2 diabetes
  213. The causal relationship between immune cells and different kidney diseases: A Mendelian randomization study
  214. Interleukin 33, soluble suppression of tumorigenicity 2, interleukin 27, and galectin 3 as predictors for outcome in patients admitted to intensive care units
  215. Identification of diagnostic immune-related gene biomarkers for predicting heart failure after acute myocardial infarction
  216. Long-term administration of probiotics prevents gastrointestinal mucosal barrier dysfunction in septic mice partly by upregulating the 5-HT degradation pathway
  217. miR-192 inhibits the activation of hepatic stellate cells by targeting Rictor
  218. Diagnostic and prognostic value of MR-pro ADM, procalcitonin, and copeptin in sepsis
  219. Review Articles
  220. Prenatal diagnosis of fetal defects and its implications on the delivery mode
  221. Electromagnetic fields exposure on fetal and childhood abnormalities: Systematic review and meta-analysis
  222. Characteristics of antibiotic resistance mechanisms and genes of Klebsiella pneumoniae
  223. Saddle pulmonary embolism in the setting of COVID-19 infection: A systematic review of case reports and case series
  224. Vitamin C and epigenetics: A short physiological overview
  225. Ebselen: A promising therapy protecting cardiomyocytes from excess iron in iron-overloaded thalassemia patients
  226. Aspirin versus LMWH for VTE prophylaxis after orthopedic surgery
  227. Mechanism of rhubarb in the treatment of hyperlipidemia: A recent review
  228. Surgical management and outcomes of traumatic global brachial plexus injury: A concise review and our center approach
  229. The progress of autoimmune hepatitis research and future challenges
  230. METTL16 in human diseases: What should we do next?
  231. New insights into the prevention of ureteral stents encrustation
  232. VISTA as a prospective immune checkpoint in gynecological malignant tumors: A review of the literature
  233. Case Reports
  234. Mycobacterium xenopi infection of the kidney and lymph nodes: A case report
  235. Genetic mutation of SLC6A20 (c.1072T > C) in a family with nephrolithiasis: A case report
  236. Chronic hepatitis B complicated with secondary hemochromatosis was cured clinically: A case report
  237. Liver abscess complicated with multiple organ invasive infection caused by hematogenous disseminated hypervirulent Klebsiella pneumoniae: A case report
  238. Urokinase-based lock solutions for catheter salvage: A case of an upcoming kidney transplant recipient
  239. Two case reports of maturity-onset diabetes of the young type 3 caused by the hepatocyte nuclear factor 1α gene mutation
  240. Immune checkpoint inhibitor-related pancreatitis: What is known and what is not
  241. Does total hip arthroplasty result in intercostal nerve injury? A case report and literature review
  242. Clinicopathological characteristics and diagnosis of hepatic sinusoidal obstruction syndrome caused by Tusanqi – Case report and literature review
  243. Synchronous triple primary gastrointestinal malignant tumors treated with laparoscopic surgery: A case report
  244. CT-guided percutaneous microwave ablation combined with bone cement injection for the treatment of transverse metastases: A case report
  245. Malignant hyperthermia: Report on a successful rescue of a case with the highest temperature of 44.2°C
  246. Anesthetic management of fetal pulmonary valvuloplasty: A case report
  247. Rapid Communication
  248. Impact of COVID-19 lockdown on glycemic levels during pregnancy: A retrospective analysis
  249. Erratum
  250. Erratum to “Inhibition of miR-21 improves pulmonary vascular responses in bronchopulmonary dysplasia by targeting the DDAH1/ADMA/NO pathway”
  251. Erratum to: “Fer exacerbates renal fibrosis and can be targeted by miR-29c-3p”
  252. Retraction
  253. Retraction of “Study to compare the effect of casirivimab and imdevimab, remdesivir, and favipiravir on progression and multi-organ function of hospitalized COVID-19 patients”
  254. Retraction of “circ_0062491 alleviates periodontitis via the miR-142-5p/IGF1 axis”
  255. Retraction of “miR-223-3p alleviates TGF-β-induced epithelial-mesenchymal transition and extracellular matrix deposition by targeting SP3 in endometrial epithelial cells”
  256. Retraction of “SLCO4A1-AS1 mediates pancreatic cancer development via miR-4673/KIF21B axis”
  257. Retraction of “circRNA_0001679/miR-338-3p/DUSP16 axis aggravates acute lung injury”
  258. Retraction of “lncRNA ACTA2-AS1 inhibits malignant phenotypes of gastric cancer cells”
  259. Special issue Linking Pathobiological Mechanisms to Clinical Application for cardiovascular diseases
  260. Effect of cardiac rehabilitation therapy on depressed patients with cardiac insufficiency after cardiac surgery
  261. Special issue The evolving saga of RNAs from bench to bedside - Part I
  262. FBLIM1 mRNA is a novel prognostic biomarker and is associated with immune infiltrates in glioma
  263. Special Issue Computational Intelligence Methodologies Meets Recurrent Cancers - Part III
  264. Development of a machine learning-based signature utilizing inflammatory response genes for predicting prognosis and immune microenvironment in ovarian cancer
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