Startseite Development of a machine learning-based signature utilizing inflammatory response genes for predicting prognosis and immune microenvironment in ovarian cancer
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Development of a machine learning-based signature utilizing inflammatory response genes for predicting prognosis and immune microenvironment in ovarian cancer

  • Li Dong , Ya-ping Qian , Shu-xiu Li und Hao Pan EMAIL logo
Veröffentlicht/Copyright: 2. Juni 2023
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Open Medicine
Aus der Zeitschrift Open Medicine Band 18 Heft 1

Abstract

Ovarian cancer (OC) represents a significant health challenge, characterized by a particularly unfavorable prognosis for affected women. Accumulating evidence supports the notion that inflammation-related factors impacting the normal ovarian epithelium may contribute to the development of OC. However, the precise role of inflammatory response-related genes (IRRGs) in OC remains largely unknown. To address this gap, we performed an integration of mRNA expression profiles from 7 cohorts and conducted univariate Cox regression analysis to screen 26 IRRGs. By utilizing these IRRGs, we categorized patients into subtypes exhibiting diverse inflammatory responses, with subtype B displaying the most prominent immune infiltration. Notably, the elevated abundance of Treg cells within subtype B contributed to immune suppression, resulting in an unfavorable prognosis for these patients. Furthermore, we validated the distribution ratios of stromal cells, inflammatory cells, and tumor cells using whole-slide digitized histological slides. We also elucidated differences in the activation of biological pathways among subtypes. In addition, machine learning algorithms were employed to predict the likelihood of survival in OC patients based on the expression of prognostic IRRGs. Through rigorous testing of over 100 combinations, we identified CXCL10 as a crucial IRRG. Single-cell analysis and vitro experiments further confirmed the potential secretion of CXCL10 by macrophages and its involvement in lymphangiogenesis within the tumor microenvironment. Overall, the study provides new insights into the role of IRRGs in OC and may have important implications for the development of novel therapeutic approaches.

Keywords: ovarian cancer; inflammatory response; machine learning; prognosis; CXCL10

1 Introduction

Ovarian cancer (OC) is a prevalent malignancy among women, characterized by a poor prognosis with the lowest survival rate among gynecologic cancers. In 2020 alone, around 320,000 women worldwide were diagnosed with OC [1]. However, the asymptomatic nature of most OC cases leads to distant metastases at the time of diagnosis [2]. While postoperative chemotherapy and maintenance therapy have shown improved therapeutic outcomes, common side effects such as nausea and vomiting pose a significant challenge [3]. Thus, developing a robust model for predicting OC prognosis is crucial for personalized treatment.

The association between inflammation and cancer has two pathways: an extrinsic path that increases cancer risk due to inflammatory conditions and an intrinsic path that causes inflammation and tumor formation due to genetic alterations [4]. Inflammatory cells and mediators in the tumor microenvironment (TME) orchestrate pro-inflammatory responses that act in an autocrine and paracrine manner on malignant and non-malignant cells [5,6]. Furthermore, recent studies have established a connection between inflammation of the normal ovarian epithelium and an increased risk of OC, such as ovulation, endometriosis, and pelvic inflammatory disease [7]. Inflammatory mediators and cytokines, such as TNF-α, IL-1β, and IL-6, have been implicated in promoting OC growth, progression, and development [8,9] While previous studies have investigated mRNA-level prognostic signatures in OC patients [10,11,12], genetic signatures associated with inflammatory response, TME, and drug sensitivity have not been studied in the field of OC to date.

This study aimed to comprehensively investigate the molecular alterations and clinical relevance of inflammatory response-related genes (IRRGs) in OC. To achieve this, we constructed molecular subtypes, screened hub IRRGs, and established prognostic models. The results of this study provide novel insights into the prognosis of OC and offer new opportunities for personalized treatment strategies.

2 Materials and methods

2.1 Datasets and data preprocessing

We selected 200 IRRGs from previously published references [13–15]. We then obtained gene expression profile data from the Cancer Genome Atlas (TCGA) [16] and the Gene Expression Omnibus (GEO) [17] databases, including GSE19829, GSE18520, GSE9891, GSE26193, GSE30161, and GSE63885 based on microarray, and the TCGA-OV cohort based on RNA-seq, using the same inclusion criteria. For more detailed description, see Table A1. Only samples with both sequencing data, clinical information, prognostic data, and no duplicate sequencing were included, resulting in 597 patients in the GPL570 platform cohort and 372 patients in the TCGA-OV cohort. To remove batch effects between RNA-seq and microarray data, we utilized the “sva” package. We also retrieved mutation data from the TCGA-OV cohort, which included 274 samples, and used the “maftools” package to present the top 10 gene mutations. In addition, we downloaded whole-slide digitized histological slides that corresponded to RNA-seq data from the TCGA database.

2.2 Cell culture

The HO-8910 and A2780 cell lines as well as human lymphatic tube endothelial cells (HLECs) were obtained from Dr. Feng at Southeast University. HO-8910 and A2780 cells were cultured in RPMI-1640 supplemented with 10% fetal bovine serum (FBS), while HLECs were cultured in Endothelial Cell Medium (ScienCell Research Laboratories, Inc.) with 10% FBS. The cultures were maintained at 37°C in a humidified incubator with 5% CO2. To stimulate CXCL10 in vitro, we purchased recombinant human CXCL10 from Peprotech and incubated cells with 100 and 200 ng/ml hCXCL10 for 48 h.

2.3 Lymphangiogenesis and cell adhesion assay

A precooled 96-well plate was first filled with 50 μL of precooled PBS, followed by the addition of 50 μL Matrigel Basement Membrane (BD Biosciences). HLECs were diluted with conditioned medium, and 60,000 cells were introduced into each well. Lymphangion formation was observed to begin at 6 h and reach completion around 10 h. HO-8910 and A2780 cells were then seeded onto the HLECs in a separate 96-well plate for 30 min, washed twice with PBS to remove free cells, and lysed by the addition of red blood cell lysate for 10 min. The absorbance at 690 nm was measured, and the NC group was normalized to 1.

2.4 Single-cell analysis

The Tumor Immune Single-cell Hub (TISCH) is a scRNA-seq database that characterizes the TME at the single-cell level [18]. To explore cell interactions in GSE154600, we used this database. The single-cell level expression matrix was standardized by scaling the raw counts (UMI) in each cell to 10,000 using Seurat’s “NormalizeData” function. The data were then log-transformed. More detailed pre-processing steps are available in the TISCH database documentation function. We focused on CXCL10-related data from the cell–cell interaction module.

2.5 Construction and functional verification of molecular subtypes

In the meta-cohort (GPL570 platform and TCGA-OV), univariate cox regression analysis was used to determine the prognostic value of IRRGs, followed by unsupervised consensus clustering to determine the optimal number of clusters (k value) using “consensusClusterPlus” package and principal component analysis (PCA) to determine subtype heterogeneity. Importantly, we performed consensus clustering with a range of k values (from 2 to 10), and found that k = 3 gave the most stable and significant clustering results based on the consensus heatmap and consensus cumulative distribution function plots. Kaplan–Meier analysis and log-rank test were used to assess the different for overall survival (OS). For functional analysis, differential expression genes (DEGs) between subtypes were analyzed using the limma package (adj. p < 0.05, |logFC| > 1), and Kyoto Gene and Genome Encyclopedia (KEGG) enrichment analysis was performed using the “clusterProfiler” package. Moreover, gene set variation analysis (GSVA) was used to assess differences in biological pathways between different subtypes. p-value <0.05 and q-value <0.05 were considered significant enrichment pathways.

2.6 Immune cell analysis

Following the pipeline developed in previous studies [12], we used eight algorithms (TIMER, CIBERSORT, QUANTISEQ, MCP-counter, XCELL, EPIC, ESTIMATE, and ssGSEA) to estimate the abundances of immune cells in different risk groups and molecular subtypes.

2.7 Construction and validation of machine learning-derived risk score

To create a consensus prognostic model for EC patients, we employed our prior approach [19,20,21]. First, we created a combination of 101 machine learning algorithms based on the traits of ten models, including LASSO, RSF, GBM, Survival-SVM, SuperPC, ridge regression, plsRcox, CoxBoost, StepCox, and Enet. We chose antecedent models with variable filtering capabilities (RSF, CoxBoost, StepCox, and LASSO). Subsequently, we generated signatures in an expression file using predictive IRRGs in the TCGA-OV training cohort. Finally, we calculated risk scores using the obtained signatures in the training cohort and validated the scores in other testing cohorts (GSE19829, GSE18520, GSE9891, GSE26193, GSE30161, and GSE63885) to identify the best consensus prognostic model based on the mean C-index of the seven cohorts. We plotted ROC curves to evaluate the predictive accuracy of the risk score and used Cox regression analysis to determine the independent prognostic value of the risk score.

As the cell cycle, PI3K/mTOR pathway, and Wnt pathway have been implicated in AML progression, we used the “pRRophetic” package to calculate the half maximal inhibitory concentration (IC50) of various targeted and chemotherapy drugs, such as CGP.60474 (cell cycle), JW.7.52.1 (PI3K/mTOR), CHIR.99021 (Wnt), cisplatin, bleomycin, and paclitaxel. Relevant references support the role of these pathways in AML progression.

2.8 Statistical analysis

Statistical analyses of the genome were conducted using R software (v.4.1.2). Further elaboration on the statistical methods is provided in statistical section in the previous reference [11]. Briefly, to compare categorical variables, we applied the chi-squared or Fisher exact test, while the Wilcoxon rank-sum test or T-test was used to compare continuous variables. Statistical significance was defined as p < 0.05.

3 Results

3.1 Identification of inflammatory response-derived subtypes

In the meta-cohort, we conducted univariate Cox analysis on all IRRGs to identify their prognostic significance. Among them, only 26 IRRGs demonstrated a strong association with survival (Figure 1a). Based on the expression profile of these 26 IRRGs in the meta-cohort, we performed consistent clustering to classify all patients into three molecular subtypes. The clustering results were more stable when k = 3 (Figure 1b and c). The three molecular subtypes identified were subtype A, subtype B, and subtype C, with subtype C being the most prevalent (415 patients), and subtypes A and B having similar numbers of patients (268 and 288, respectively). Notably, subtype B had the poorest prognosis, whereas subtype A had the best prognosis (Figure 1d). PCA confirmed the genomic heterogeneity of the different subtypes, with significant dispersion among the three subtypes (Figure 1e). Intriguingly, heatmap analysis of clinical information and IRRGs expression in the meta-cohort revealed that most IRRGs were significantly down-regulated in subtype C (Figure 1f).

Figure 1 Identification of molecular subtypes associated with inflammatory response. (a) Univariate Cox analysis of IRRGs in the meta cohort. (b and c) Selection of the optimal k value based on conensusClusterPlus package. (d) Kaplan-Meier analysis of different molecular subtypes. (e) PCA in three molecular subtypes. (e) A heatmap combined clinical characteristics with gene expression in different molecular subtypes.
Figure 1

Identification of molecular subtypes associated with inflammatory response. (a) Univariate Cox analysis of IRRGs in the meta cohort. (b and c) Selection of the optimal k value based on conensusClusterPlus package. (d) Kaplan-Meier analysis of different molecular subtypes. (e) PCA in three molecular subtypes. (e) A heatmap combined clinical characteristics with gene expression in different molecular subtypes.

3.2 Difference in immune microenvironment in different subtypes

The immune microenvironment of different molecular subtypes was analyzed using ssGSEA. Although there was no significant difference in the number of activated T cells between subtype A, which had a better prognosis, and subtype B, which had the worst prognosis, the number of Treg cells was significantly higher in subtype B compared to the other subtypes. These results suggest that subtype C has a greater infiltration of immune cells, but its immune cell function is suppressed, which may be the main reason for its poorer prognosis (Figure 2a). In addition, a comparison of HLA and ICI mRNA expression in different molecular subtypes revealed higher expression in subtype A (Figure 2b and c). The ESTIMATE algorithm was used to re-evaluate the overall TME landscape of different subtypes, and subtype B had the highest stromal score (Figure 2d). To investigate the sensitivity of different subtypes to commonly used chemotherapy regimens (cisplatin, bleomycin, and paclitaxel), we found that subtype B, with more immune-infiltrating cells, had better sensitivity to the three chemotherapeutic agents (Figure 2e). Notably, subtype B was also more sensitive to CHIR.99021, JW.7.52.1, and CGP.60474 (Figure A1). Furthermore, the combination of corresponding HE sections of the molecular subtypes in the TCGA database revealed more lymphoid follicle-like structures in subtype B (Figure 2f).

Figure 2 Immune landscape in molecular subtypes associated with inflammatory response. (a) Abundance of 24 immune cells based on ssGSEA algorithm. (b and c) Differences in mRNA associated with ICIs and HLA. (d) Overall TME status based on ESTIMATE algorithm. (e) Differences in the sensitivity of three commonly used chemotherapy regimens (cisplatin, bleomycin, and paclitaxel). (f) HE sections of the different molecular subtypes in the TCGA database. **p < 0.01, ***p < 0.001.
Figure 2

Immune landscape in molecular subtypes associated with inflammatory response. (a) Abundance of 24 immune cells based on ssGSEA algorithm. (b and c) Differences in mRNA associated with ICIs and HLA. (d) Overall TME status based on ESTIMATE algorithm. (e) Differences in the sensitivity of three commonly used chemotherapy regimens (cisplatin, bleomycin, and paclitaxel). (f) HE sections of the different molecular subtypes in the TCGA database. **p < 0.01, ***p < 0.001.

3.3 Difference in functional analysis in different subtypes

We performed a comparative analysis of the mutation differences among different molecular subtypes. Remarkably, MUC16 and CSMD3 had significantly higher mutation frequencies in subtype C than in subtypes A and B, which were among the top 10 mutations in the TCGA-OV cohort (Figure 3a). We further identified 60 DEGs between subtypes, with the volcano map highlighting significant changes in the collagen and chemokine families, such as CXCL10, CXCL11, COL11A1, COL5A2, and COL5A1 (Figure 3b–e). KEGG analysis revealed that cytokine–cytokine receptor interaction was a major enrichment pathway of the 60 DEGs (Figure 4a). Based on KEGG and Hallmark gene sets, GSVA showed that compared to subtype A, subtype B was significantly enriched in p53, KRAS signaling, and IL2-STAT5 signaling pathways (Figure 4b). Subtype C was significantly enriched in wnt-beta and hedgehog signaling pathways, while subtype B was enriched in interferon gamma response, complement pathway, and inflammatory response, compared to subtype A (Figure 4c and d). Furthermore, subtype B was enriched in TGF beta signaling pathway, glycosaminoglycan biosynthesis chondroitin sulfate, and melanoma compared to subtype A (Figure 4e), whereas subtype A was significantly enriched in cell adhesion molecules cams, leishmania infection, and toll-like receptor signaling pathway compared to subtype C (Figure 4f). Finally, compared to subtype C, subtype B was enriched in ECM receptor interaction, focal adhesion, and leukocyte transendothelial migration (Figure 4g).

Figure 3 Genetic variants in different molecular subtypes. (a) The top 10 mutated genes in the different molecular subtypes. (b) Common differential expression genes in molecular subtypes. (c) Volcano map of DEGs for subtypes A and B. (d) Volcano map of DEGs for subtypes C and A. (e) Volcano map of DEGs for subtypes C and B.
Figure 3

Genetic variants in different molecular subtypes. (a) The top 10 mutated genes in the different molecular subtypes. (b) Common differential expression genes in molecular subtypes. (c) Volcano map of DEGs for subtypes A and B. (d) Volcano map of DEGs for subtypes C and A. (e) Volcano map of DEGs for subtypes C and B.

Figure 4 Biological function in molecular subtypes associated with inflammatory response. (a) KEGG enrichment analysis of DEGs. (b) Heatmap of matrix of Hallmark enrichment scores using GSVA algorithm in subtypes A and B. (c) Heatmap of matrix of Hallmark enrichment scores using GSVA algorithm in subtypes A and C. (d) Heatmap of matrix of Hallmark enrichment scores using GSVA algorithm in subtypes B and C. (e) Heatmap of matrix of KEGG enrichment scores using GSVA algorithm in subtypes A and B. (f) Heatmap of matrix of KEGG enrichment scores using GSVA algorithm in subtypes A and C. (g) Heatmap of matrix of KEGG enrichment scores using GSVA algorithm in subtypes B and C.
Figure 4

Biological function in molecular subtypes associated with inflammatory response. (a) KEGG enrichment analysis of DEGs. (b) Heatmap of matrix of Hallmark enrichment scores using GSVA algorithm in subtypes A and B. (c) Heatmap of matrix of Hallmark enrichment scores using GSVA algorithm in subtypes A and C. (d) Heatmap of matrix of Hallmark enrichment scores using GSVA algorithm in subtypes B and C. (e) Heatmap of matrix of KEGG enrichment scores using GSVA algorithm in subtypes A and B. (f) Heatmap of matrix of KEGG enrichment scores using GSVA algorithm in subtypes A and C. (g) Heatmap of matrix of KEGG enrichment scores using GSVA algorithm in subtypes B and C.

3.4 Construction and validation of a machine learning-based signature

We conducted an analysis to determine the effectiveness of different algorithms in predicting the risk of OC. Our results showed that the RSF algorithm had the highest average C-index (0.615) across all cohorts (Figure 5a and b). The top 5 IRRGs identified by the RSF model were CXCL11, ITGB8, CLEC5A, MMP14, and CXCL10 (Figure 5c). We then established an optimal cut-off value of 45.71 based on risk scores in the TCGA-OV cohort (Figure 5d). Notably, the AUC values for the ROC curve at each time point in the training set exceeded 0.9 (Figure A2a). Additionally, the Kaplan–Meier survival curve revealed that high-risk patients, of the 374 in the training set, had significantly reduced OS (Figure A2b). The AUC values for the 1-, 2-, and 3-year OS were 0.960, 0.998, and 0.993 in the training cohort (Figure A2c). Finally, the risk survival distribution showed that OC patients with a higher risk score had a worse prognosis (Figure A2d).

Figure 5 Construction of machine learning-derived signature. (a) The C-indexes of 101 machine-learning algorithm combinations. (b) Error rate curve of random forest tree model. (c) Importance of each variable in random forest tree model. (d) Risk score distribution map and optimal cut-off value selection.
Figure 5

Construction of machine learning-derived signature. (a) The C-indexes of 101 machine-learning algorithm combinations. (b) Error rate curve of random forest tree model. (c) Importance of each variable in random forest tree model. (d) Risk score distribution map and optimal cut-off value selection.

3.5 Evaluating clinical significance of machine learning-derived risk score

The distribution of FIGO stage was markedly distinct between the high- and low-risk groups (Figure 6a). Notably, our findings indicated a significant association between risk score and advanced age, higher FIGO stage, and higher grade (Figure 6b). Furthermore, we observed that patients with larger postoperative residual size had higher risk scores, suggesting that our risk score could serve as a useful tool for preoperative guidance. Cox regression analyses were performed in both the TCGA-OV (Figure 6c) and all GEO-OV cohorts (Figure 6d), confirming the independent prognostic value of the risk score.

Figure 6 Clinical significance of risk score. (a) The differences in risk scores across clinical subgroups, including age, grade, FIGO stage, and pathologic types. (b) Kaplan–Meier analysis of different age subgroups. (c) Cox regression analyses in TCGA-OV cohorts. (d) Cox regression analyses in GEO-OV cohorts. *p < 0.05, **p < 0.01.
Figure 6

Clinical significance of risk score. (a) The differences in risk scores across clinical subgroups, including age, grade, FIGO stage, and pathologic types. (b) Kaplan–Meier analysis of different age subgroups. (c) Cox regression analyses in TCGA-OV cohorts. (d) Cox regression analyses in GEO-OV cohorts. *p < 0.05, **p < 0.01.

3.6 Macrophage-derived CXCL10 is the hub indicator of signature

In our analysis of immune cell infiltration, we employed multiple algorithms to estimate immune cell activity across various samples. The resulting heatmap indicated that the low-risk group had a more active TME (Figure A3a). Although patients in both the high- and low-risk groups did not exhibit significant differences in top mutated genes based on whole-exome sequencing data, the overall mutation frequency was higher in the low-risk group (Figure A3b and c). To explore the molecular importance of immune-related risk genes (IRRGs) involved in the RSF model, we constructed a protein–protein interaction (PPI) network in the STRING database and ranked the IRRGs by maximum matching coefficient (MMC) (Figure A3d). CCL17, CCR7, CXCL10, CXCL9, and CCL5 were the top 5 genes in the PPI network, with CXCL10 being the most important. Using single-cell data, we confirmed that CXCL10 is mainly located in macrophages (C5) (Figure 7a). Cell communication analysis indicated a significant association of CXCL10 between macrophages and endothelial cells (C15) (Figure 7b–c). LYVE1, the lymph endothelial cell marker, was significantly overexpressed in the C15 subgroup (data not shown). We, therefore, hypothesize that CXCL10 secreted by macrophages promotes lymphangiogenesis and cell adhesion. As anticipated, with increasing hCXCL10 concentrations, lymphatic tube growth was observed (Figure 7d), along with increased adhesion to tumor cells (Figure 7e and f).

Figure 7 Macrophage-derived CXCL10 in ovarian cancer. (a) Clusters of single-cell dataset. (b) Localization of CXCL10. (c) Cell communication analysis between different cell types. (d) Relative length of tube in different concentration of CXCL10. (e) The ability of adhesion of A2780 to HLECs in different concentration of CXCL10. (f) The ability of adhesion of HO-8910 to HLECs in different concentration of CXCL10.
Figure 7

Macrophage-derived CXCL10 in ovarian cancer. (a) Clusters of single-cell dataset. (b) Localization of CXCL10. (c) Cell communication analysis between different cell types. (d) Relative length of tube in different concentration of CXCL10. (e) The ability of adhesion of A2780 to HLECs in different concentration of CXCL10. (f) The ability of adhesion of HO-8910 to HLECs in different concentration of CXCL10.

4 Discussion

Chronic inflammation plays a critical role in cancer, and OC’s TME exhibits elevated levels of inflammatory proteins [22]. TCGA has described an immune-responsive subtype of high-grade plasmacytosis characterized by the expression of T-cell chemokine ligands CXCL11 and CXCL10 and the receptor CXCR3 and observed overexpression of inflammatory lipoxygenase pathway receptors [23]. A recent study found that minor alleles ALOX5 in rs17561 and rs4848300 and rs1864414 in IL-1A were consistently and negatively associated with the risk of OC [24]. However, no study has investigated genetic signatures associated with inflammatory response, TME, and drug sensitivity in OC. Therefore, in our study, we performed consistent clustering to classify all patients based on IRRGs. We identified three molecular subtypes, with subtype C accounting for the majority of all patients, and subtype B exhibiting the worst prognosis.

We observed that while the number of activated T cells did not differ significantly between subtype A, which had a favorable prognosis, and subtype B, which had the worst prognosis, the number of Treg cells was significantly higher in subtype B than in other subtypes. Our findings suggest that subtype C has a higher infiltration of immune cells, but the function of its immune cells is suppressed, which may contribute to its poorer prognosis. Regulatory T cells, which are tumor immunosuppressors, have emerged as a critical area of research to identify the underlying biological mechanisms associated with OC development and progression [25]. Although Treg cells are known to inhibit CD4+ and CD8+ T cells [26,27], evidence also suggests that they suppress natural killer cells and specialized antigen-presenting cells, such as dendritic cells [28]. Furthermore, in an intentional epidemiological survey, the average frequency of Treg cells was significantly higher in newly diagnosed OC patients than in women with benign ovarian disease and cancer-free controls [27].

Our study has revealed that the B subtype, characterized by more immune-infiltrating cells, displayed better sensitivity to the three chemotherapeutic agents. Further analysis of the corresponding HE sections of the molecular subtypes revealed more lymphoid follicle-like structures in the B subtype. The known effects of chemotherapy on the TME of OC include enhanced T-cell activation, increased density of T cells, B cells, and NK cells and decreased density of Treg cells [29,30,31]. Our findings suggest that our inflammatory response-related subtypes may be associated with chemotherapy sensitivity and underscore the critical role of the TME.

We computed the average C-index for all cohorts to evaluate the machine learning-based signature. The RSF algorithm yielded the highest C-index. The top 5 IRRGs of importance in the RSF model were CXCL11, ITGB8, CLEC5A, MMP14, and CXCL10. Notably, the AUC value at each time point in the training set was above 0.9. Previous studies have constructed prognostic signatures for OC based on cancer-associated fibroblasts [11] or ferroptosis-related long non-coding RNA [32], using only the LASSO-Cox modeling scheme. To avoid personal preferences and inappropriate modeling approaches, we combined 101 machine learning algorithms and selected the best-performing model. We examined the molecular significance of the IRRGs identified by the RSF model by constructing a PPI network in the STRING database. The top 5 genes in the PPI network were CCL17, CCR7, CXCL10, CXCL9, and CCL5, with CXCL10 being the most critical. Notably, our study is the first to investigate the correlation of CXCL10 with human lymphatic endothelial cells. An earlier study highlights the clinical relevance of the CXCL10 + IRF1 + STAT1 + macrophage subset as a biomarker for intratumoral T-cell activation [33]. A combined bioinformatics in vitro assay suggested that CXCL10 could impact OC progression by increasing the expression of cytotoxic T cells and inhibiting angiogenesis [34].

However, our study has some limitations that need to be acknowledged. First, further experiments are required to unravel the mechanism underlying CXCL10’s impact on human lymphatic endothelial cells. Second, although we validated our findings on six external cohorts, prospective clinical trials involving larger local cohorts are necessary. In conclusion, our machine learning-based signature for the inflammatory response can distinguish the TME and predict prognosis in patients with OC.

5 Conclusion

The study aimed to investigate the role of IRRGs in OC and develop a machine learning-based inflammatory response-related signature to identify distinct TME and predict patient prognosis. The study integrated mRNA expression profiles from seven cohorts and identified CXCL10 as a critical factor in distinguishing patient prognosis based on the expression of prognostic IRRGs. The study also confirmed the distribution ratios of stromal cells, inflammatory cells, and tumor cells using whole-slide digitized histological slides and elucidated differences in biological pathway activation among subtypes using KEGG-related gene sets. Single-cell and in vitro experiments confirmed that macrophage-derived CXCL10 promotes lymphangiogenesis and cell adhesion. Overall, the study provides new insights into the role of IRRGs in OC and may have important implications for the development of novel therapeutic approaches.

  1. Funding information: The authors received no funding for this work.

  2. Author contributions: Li Dong conceived and designed the study. Shu-xiu Li was responsible for materials. Ya-ping Qian drafted the article. Hao Pan revised the article critically. All authors had final approval of the submitted versions.

  3. Conflict of interest: There are no conflicts of interest regarding the publication of this article.

  4. Data availability statement: The analyzed data sets generated during the study are available from the corresponding author on reasonable request.

Appendix

Figure A1 Differences in the sensitivity of three targeted drugs.
Figure A1

Differences in the sensitivity of three targeted drugs.

Figure A2 Validation of prognostic signature. (a) The distribution between risk groups and clinical features. (b) The differences in risk scores across clinical subgroups. (c) AUC for the 1-year, 2-year, and 3-year OS in the TCGA-OV cohort. (d) Risk score distribution map.
Figure A2

Validation of prognostic signature. (a) The distribution between risk groups and clinical features. (b) The differences in risk scores across clinical subgroups. (c) AUC for the 1-year, 2-year, and 3-year OS in the TCGA-OV cohort. (d) Risk score distribution map.

Figure A3 Identification of hub IRRGs in PPI network. (a) Difference of abundance of immune cells based on six algorithms in different risk groups. (b and c) The top 10 mutated genes in the high-risk and low-risk group. (c) PPI network of IRRGs in prognostic model.
Figure A3

Identification of hub IRRGs in PPI network. (a) Difference of abundance of immune cells based on six algorithms in different risk groups. (b and c) The top 10 mutated genes in the high-risk and low-risk group. (c) PPI network of IRRGs in prognostic model.

Table A1

Detailed description for different datasets

Dataset Platform Samples Type
GSE19829 Affymetrix Human Genome U133 Plus 2.0 Array 28 Microarray
GSE30161 Affymetrix Human Genome U133 Plus 2.0 Array 58 Microarray
GSE63885 Affymetrix Human Genome U133 Plus 2.0 Array 75 Microarray
GSE26193 Affymetrix Human Genome U133 Plus 2.0 Array 107 Microarray
GSE9891 Affymetrix Human Genome U133 Plus 2.0 Array 276 Microarray
GSE18520 Affymetrix Human Genome U133 Plus 2.0 Array 53 Microarray
TCGA_OV Illumina HiSeq 2000 374 RNA-seq

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Received: 2022-11-28
Revised: 2023-05-16
Accepted: 2023-05-17
Published Online: 2023-06-02

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

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

Artikel in diesem Heft

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  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-2023-0734
Schlagwörter für diesen Artikel
ovarian cancer; inflammatory response; machine learning; prognosis; CXCL10
Creative Commons
BY 4.0

Artikel in diesem Heft

  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
  33. A novel autophagy-related long non-coding RNAs signature predicting progression-free interval and I-131 therapy benefits in papillary thyroid carcinoma
  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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Heruntergeladen am 3.10.2025 von https://www.degruyterbrill.com/document/doi/10.1515/med-2023-0734/html
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