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The G protein-coupled receptor-related gene signatures for predicting prognosis and immunotherapy response in bladder urothelial carcinoma

  • Zhengqiang Wan , Yinglei Wang EMAIL logo , Cheng Li and Dongbing Zheng
Published/Copyright: August 10, 2023
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Open Life Sciences
From the journal Open Life Sciences Volume 18 Issue 1

Abstract

Bladder urothelial carcinoma (BLCA) is the most common malignant tumor of the urinary tract with a high lethality rate, and its immunotherapy resistance and tumor recurrence have become a major challenge in its clinical treatment. G Protein-Coupled Receptors (GPRs) are the largest family of receptors on the cell membrane surface, involved in multiple signaling pathways, and are excellent targets for oncology drug action. The transcriptome profile, single cell transcriptome profile, and clinical data of BLCA were extracted and integrated from TCGA and GEO databases, respectively. The GPR-related genes were obtained from GSEA-MSigDB database. The GPR-related gene signatures of 15 genes were constructed by using the methods of least absolute shrinkage and selection operator regression, multifactor Cox model. At the same time, tumor microenvironment (TME)-score signatures were constructed based on the immune microenvironment of BLCA, and GPR-TME-score signature was further constructed. The stability of this model was verified by using the external dataset GSE160693. We constructed risk groups by combining BLCA patient prognostic information, and with the help of BLCA scRNA transcriptome profiling, we explored differences in prognosis, immune scores, cell–cell interactions, tumor mutational burden, immune checkpoints, and response to immunotherapy in each risk group. We found that the GPR-TME-score signature was an independent prognostic factor for BLCA patients. the TME-score was a protective factor for the prognosis of BLCA patients. Among BLCA patients, GPR-high + TME-low risk group had the worst prognosis, while GPR-high + TME-high risk group had the best prognosis, and the latter had better immune score and immunotherapy response. The above differences in immune response among the subgroups may be related to the higher immune cell infiltration in the GPR-high + TME-high group. GPR-related gene signatures and TME are closely related to BLCA prognosis and immunotherapy, and GPR-related gene signature can be a useful tool to assess BLCA prognosis and immunotherapy response.

Keywords: bladder urothelial carcinoma; G protein-coupled receptors; tumor microenvironment; immune checkpoint; cellular communication; scRNA; immunotherapy

1 Introduction

Bladder cancer is one of the most common malignant tumors of the urinary system. 20–30% of patients with bladder cancer have developed muscle-invasive bladder cancer (MIBC) at the time of diagnosis, and 20–25% of non-muscle-invasive bladder cancer can progress to MIBC [1,2]. Nearly 50% of patients with MIBC treated only with radical cystectomy develop metastases to other sites and have a very poor prognosis [3]. The methotrexate, vincristine, gemcitabine, and cisplatin regimen is currently the first-line chemotherapy regimen for bladder cancer, and although patients can be effectively remitted or even cured after conventional postoperative bladder infusion chemotherapy, the recurrence rate is as high as 60% [4]. The malignancy of recurrent bladder tumors will gradually increase and eventually develop into muscle-infiltrating bladder tumors. With the recurrence of tumor, many patients are no longer sensitive to new rounds of chemotherapy, which seriously affects the prognosis of patients [5]. Immunotherapy is based on tumor immunology, which involves several physiopathological processes: (i) Tumor specific antigens must be recognized, presented, and expressed by major histocompatibility complex molecules on the surface of antigen-presenting cells (APCs), which must receive accurate second messenger activation signals (such as B7-1 or B7-2) to achieve an immune phenotype; (ii) Once activated, APCs move to lymphoid tissues, where they interact with T lymphocytes; (iii) If APCs are fully immunocompetent, they induce the generation of CD8 + cytotoxic T lymphocytes (CTL) and natural killer (NK) effector cells that move to the TME and generate anti-tumor immune responses [6]. These effector cells move to the TME and generate an anti-tumor immune response. The discovery of immune checkpoint inhibitors (ICIs) such as programmed cell death factor 1 (PD-1) antibodies, programmed cell death molecule ligand 1 (PD-L1) antibodies, CTL-associated protein 4 (CTLA-4) antibodies, co-stimulatory receptor agonists, photoimmunotherapy, cytokine therapies, and chimeric antigen receptor therapies, has led to the development of a number of new technologies [7]. Therapy, chimeric antigen receptor T (CAR-T) cell therapy, and other therapeutic modalities have provided new directions for the treatment of locally progressive and metastatic bladder cancer [8]. Foreign studies have concluded that upregulation of PD-L1 expression is closely associated with immune evasion in early bladder cancer, and high PD-L1 expression has been shown to be associated with high-grade bladder cancer and worse clinical prognosis [9]. In a single-arm phase II KEYNOTE-052 clinical trial, pembrolizumab was shown to have a durable clinical response in cisplatin-intolerant patients with advanced bladder cancer and was associated with prolonged overall survival, particularly in patients with high PD-L1 expression [10].

G Protein-Coupled Receptor (GPR) is the largest family of membrane receptors linked to G proteins and can be activated by different ligands such as hormones and peptides. Its binding to ligands can activate intracellular G proteins and regulate different physiopathological responses through different signaling pathways. The human genome contains several GPR genes, accounting for about 3% of the total human genome, and GPR has become one of the most important drug targets for drug development [11]. The related research has found that GPR is also closely related to the development of many tumors, and it is involved in the occurrence and development of many tumors such as gastric cancer, colorectal cancer, lung cancer, bladder cancer, and breast cancer, and has the role of promoting tumor growth [12,13]. In addition, GPR is closely related to a variety of malignant biological behaviors such as proliferation, invasion, and metastasis of tumor cells, involving multiple signaling pathways [14]. Zhan et al. [15] found that the GPR signaling pathway promotes the acquisition of drug resistance by tumor cells through the activation of transcription factor Gli downstream of the Hedgehog signaling pathway. However, it is not clear how GPR-related genes affect the prognosis of bladder cancer patients and whether they can predict the response to immunotherapy in bladder cancer patients.

In this study, we used TCGA and GEO databases to screen and identify GPR related gene signatures closely related to the prognosis of bladder cancer, explore their interaction with bladder urothelial carcinoma (BLCA) immune microenvironment, and use this gene signatures to predict the response of BLCA to immunotherapy. In conclusion, our study is the first to explore the impact of GPR related gene signatures on the diagnosis, prediction, and immunotherapy of BLCA, providing reference for personalized immunotherapy of BLCA patients.

2 Materials and methods

2.1 Data collection and processing

We obtained the original transcriptome data and standardized RNA seq data of 430 BLCA patients and 8 normal bladder tissues from the University of California, Santa Cruz database. The clinical pathological characteristics, follow-up data, and copy number variation (CNV) data of BLCA patients are downloaded from the TCGA-GDC portal. BLCA scRNA transcriptome data (ID: GSM5329919 and GSM5751919) were obtained from the GEO database. Repetitive samples and samples with total survival time of less than 30 days were excluded. In the risk grouping of GPR-score and tumor microenvironment (TME) score, we only used the data of BLCA tumor patients, including transcriptome data and survival data. All data analysis in this study was completed by R language (version 4.0.3). GPR-related genes were obtained from GSEA-MSigDB database. The transcriptome data of 22 immune cells were obtained from CIBERSORT database. The validation dataset is obtained from the GEO database, and its ID is GSE160693.

  1. Informed consent: Informed consent has been obtained from all individuals included in this study.

  2. Ethical approval: The research related to human use has been complied with all the relevant national regulations, institutional policies, and in accordance with the tenets of the Helsinki Declaration, and has been approved by Ethics Committee of Binzhou Medical University.

2.2 Identification of GPR-related genes differentially expressed in BLCA

Differentially expressed genes (DEG) between tumor and normal samples were screened using the R studio “Limma” software package. |Log2FC| > 1, P < 0.05, and false discovery rate (FDR) <0.05 were set as cut-off values for DEG in the TCGA cohort. Univariate Cox regression was used to identify prognostic GPR-related genes. Genes with P values <0.05 in the Cox regression were identified as prognostic genes for further least absolute shrinkage and selection operator (LASSO) regression analysis.

2.3 Tumor immune microenvironment analysis

We downloaded TCGA-BLCA cohort gene expression data and LM22 gene signatures. With the help of the online platform CIBERSORT database, we analyzed the level of BLCA immune microenvironment infiltration, combined with survival data of BLCA patients, and classified them into different risk groups.

2.4 Construction and validation of the diagnostic signature

Univariate Cox regression was utilized to evaluate whether the DEGs had an impact on the survival status of TCGA-BLCA cohort based on the DEGs obtained previously, and the lasso Cox regression method (R package “glmnet”) was further used to shrink the candidates to construct the most suitable gene signature, and finally bootstrap model was utilized to further optimize the gene signature model to obtain the GPR-score model. Based on the results of CIBERSORT of TCGA-BLCA cohort, combined with the survival files, we screened the immune cells with good prognosis using the optimal cutoff analysis and constructed a TME-score model using bootstrap. The receiver operating characteristic (ROC) curves were utilized to verify the reliability of the above models.

2.5 Constructing risk subgroups

We divided the GPR-score into low- and high-risk groups according to the BLCA patient survival median time and similarly divided the TME score into low and high risk groups. In the combined analysis of GPR score and TME score on the prognosis and immunotherapy of BLCA patients, to remove the influence of confounding factors on the outcome, we divided them into three risk groups: GPR-low + TME-high, GPR-high + TME-low, and mixed (GPR-low + TME-low and GPR-high + TME-high). Prognostic differences between the various risk groups were investigated by Kaplan–Meier (KM) analysis (R package “survival”). In addition, “survminer,” “RMS” and “timeROC” R packages were used to complete ROC analysis.

2.6 Independent prognostic analysis of the risk score

We collected the clinical characteristics (Age, T stage, and N stage) of BLCA patients in TCGA cohort and analyzed them together with GPR-TME-score by univariate and multivariate Cox regression to screen independent risk factors for BLCA prognosis.

2.7 Calculation of GPR-TME-score for different risk groups tumor mutation load

We downloaded the CNV data of BLCA from TCGA database, and the tumor mutational burden (TMB) was calculated by the formula: TMB (mut/mb) = total number of mutations (including synonymous, non-synonymous point mutations, substitution, insertion, and deletion mutations)/size of target region coding area. With the help of the “oncoplot” software package, the waterfall plot shows the different characteristics of the different risk groups of the GPR-TME-score.

2.8 Differences in expression levels of immune checkpoint-related genes among each risk groups

The list of immune checkpoint-associated genes is given in Table S1, and we calculated the expression levels of immune checkpoint-associated genes in each risk group using BLCA transcriptomic data, and the results are presented in box plots, and P < 0.05 was considered statistically significant.

2.9 Single-cell data analysis of interactions between cells in each risk group

In this study, the BLCA scRNA-Seq datasets were GSM5329919 and GSM5751919, and the R package “Seurat” was used for cell quality control, filtering low-abundance genes (genes expressed in less than three cells) and low-quality cells (number of genes ≤200 or ≥5,000, percentage of mitochondrial genes ≥10%, and percentage of hemoglobin genes ≥5%). The filtered data were normalized for subsequent analysis, and the QC data were subjected to Principal Components Analysis (PCA), t-distributed stochastic neighbor embedding, and uniform manifold approximation and projection (UMAP) for dimensional clustering and cell type annotation using cytomolecular markers, which are given in Table S2. Finally, we used the R package “cellchat” to analyze the interactions between major cell types in each risk group.

2.10 Immunotherapy forecast

The half maximal inhibitory concentration (IC50) of chemotherapeutic drugs in clusters was calculated using the prophetic algorithm, while we applied the cancer immunome Atlas database to observe the response to immunotherapy in patients with different risk groups and the signaling pathways that were shared by the risk group and ICIs response group were also analyzed using the proteomaps database.

2.11 Statistical analysis

All statistical analyses were performed by R4.1.0. Wilcoxon test was used to evaluate the differences in expression levels between BLCA samples and normal tissues as well as each risk group. The relationship between each risk group and neoadjuvant treatment response was assessed by the chi square test.

3 Results

3.1 Construction and validation of PGR-score model

First, we screened prognosis-related GPR-related genes using univariate regression analysis, and a total of 29 prognosis-related genes were obtained, and their results were presented in heat maps (Figure S1). Further, we optimized the variables using LASSO regression and multifactor Cox regression analysis, and screened a total of 15 variables, combined with the median survival of patients, divided the GPR-score into low- and high-risk groups, and constructed the PGR-score model using Bootstrap model (Figure 1a–d). In the multifactorial Cox regression analysis, we found that genes SIGMAR1 (HR = 1.52, P < 0.001), OR2B6 (HR = 0.79, P = 0.017) and PTGER4 (HR = 0.86, P = 0.023) were independent risk factors for the prognosis of BLCA patients, OR2B6 and PTGER4 were protective factors for BLCA patients, while the opposite was true for SIGMAR1 (Figure 1c). Using KM curves to verify the survival difference between GPR-score low and high groups, we found that high GPR-score means a worse prognosis (N = 406, P = 3.853 × 10−9) (Figure 1d).

Figure 1 (a) LASSO coefficient pathway plots of GPR gene signatures associated with BLCA prognosis. (b) Cross-validation curves of LASSO regression. (c) Forest plot of multifactor regression analysis of GPR-score gene signatures. (d) Effect of GPR-score high and low risk groups on the prognosis of BLCA patients. P < 0.05 was considered statistically significant.
Figure 1 (a) LASSO coefficient pathway plots of GPR gene signatures associated with BLCA prognosis. (b) Cross-validation curves of LASSO regression. (c) Forest plot of multifactor regression analysis of GPR-score gene signatures. (d) Effect of GPR-score high and low risk groups on the prognosis of BLCA patients. P < 0.05 was considered statistically significant.
Figure 1

(a) LASSO coefficient pathway plots of GPR gene signatures associated with BLCA prognosis. (b) Cross-validation curves of LASSO regression. (c) Forest plot of multifactor regression analysis of GPR-score gene signatures. (d) Effect of GPR-score high and low risk groups on the prognosis of BLCA patients. P < 0.05 was considered statistically significant.

3.2 Construction and validation of the TME-score model

We used TCGA-BLCA transcriptome data, and with the help of CIBERSORT database, we analyzed the level of immune infiltration in BLCA. The most abundant immune cell type in the sample was T cells, and CD8 T cells were the most abundant immune cell subtype (Figure 2a and b). KM curves were used to screen immune cell types relevant to the prognosis of BLCA patients, and the TME-score model was further constructed using Bootstrap. We found that a total of 12 immune cell subtypes were associated with the prognosis of BLCA patients (Figure 2c). Current tumor immunology studies suggest that CD8+ T cells, CD4 memory activated, and Dendritic cells activated play a protective role in tumors, and the higher their infiltration levels, the better the patient prognosis. Therefore, based on these views, we selected the above three immune cells to construct the TME-score model. Based on the survival data of patients, we divided TME score into TME score low and high risk groups. KM curve indicates that the prognosis of patients in the high TME-score group is better than that in the low group, indicating that TME-score is a protective factor for the prognosis of patients with BLCA (Figure 2d). Finally, to analyze the effects of GPR gene signature and TME on the prognosis of BLCA patients, we further constructed a GPR-TME risk set and validated its diagnostic efficacy with KM curves. we found that patients in the GPR-low + TME-high group had the best prognosis and those in the GPR-high + TME-low group had the worst prognosis (Figure 2e).

Figure 2 (a) Immune landscape map of BLCA based on CIBSORT database. (b) Box plot of the number of immune cells based on CIBSORT database. (c) The effect of 22 immune cell subtypes in high-risk and low-risk groups on the prognosis of patients with BLCA based on CIBSORT database. (d) Effect of TME-score high and low risk groups on the prognosis of BLCA patients. P < 0.05 was considered statistically significant. (e) Effect of different risk groups of GPR-TME-score on the prognosis of BLCA patients.
Figure 2 (a) Immune landscape map of BLCA based on CIBSORT database. (b) Box plot of the number of immune cells based on CIBSORT database. (c) The effect of 22 immune cell subtypes in high-risk and low-risk groups on the prognosis of patients with BLCA based on CIBSORT database. (d) Effect of TME-score high and low risk groups on the prognosis of BLCA patients. P < 0.05 was considered statistically significant. (e) Effect of different risk groups of GPR-TME-score on the prognosis of BLCA patients.
Figure 2

(a) Immune landscape map of BLCA based on CIBSORT database. (b) Box plot of the number of immune cells based on CIBSORT database. (c) The effect of 22 immune cell subtypes in high-risk and low-risk groups on the prognosis of patients with BLCA based on CIBSORT database. (d) Effect of TME-score high and low risk groups on the prognosis of BLCA patients. P < 0.05 was considered statistically significant. (e) Effect of different risk groups of GPR-TME-score on the prognosis of BLCA patients.

3.3 Identification of independent risk factors for prognosis of BLCA patients

Using transcriptomic data from the TCGA-BLCA cohort, we combined patient clinicopathological data (age, gender, differentiation grade, clinical stage, T-stage, N-stage, and M-stage), prognostic information, and GPR-TME-score to identify independent risk factors for prognosis of BLCA patients. From the KM curves of each clinical subgroup, we found that three risk groups were associated with the prognosis of BLCA patients in different clinical subgroups, including age, gender, differentiation grade, clinical stage, T stage, N stage, and M stage (P < 0.05), but not statistically significant in differentiated grade clinical subgroups (P > 0.05). Among the clinical subgroups, BLCA survival had the best overall prognosis in the GPR-low + TME-high group and the worst prognosis in the GPR-high + TME-low group (Figure 3a). In multifactorial Cox regression analysis, we found that gender (HR = 1.777, P-value = 0.037), clinical stage (HR = 1.771, P-value = 0.001), T stage (HR = 1.593, P-value = 0.019), N stage (HR = 1.570, P-value < 0.001), M stage (HR = 2.594, P-value = 0.043) and GPR-TME-score (HR = 1.968, P-value < 0.01) as independent risk factors for the prognosis of BLCA patients (Figure 3b).

Figure 3 (a) The impact of clinicopathological characteristics of each risk group of GPR-TME-score on the prognosis of BLCA patients. (b) Forest plot of independent risk factors for prognosis in BLCA patients. P < 0.05 was considered statistically significant.
Figure 3

(a) The impact of clinicopathological characteristics of each risk group of GPR-TME-score on the prognosis of BLCA patients. (b) Forest plot of independent risk factors for prognosis in BLCA patients. P < 0.05 was considered statistically significant.

3.4 Single-cell transcriptome reveals interactions among risk group cells

Two BLCA samples with transcriptome data from GEO data with sample numbers GSM5329919 and GSM5751919 were used in this study. First, we used the R package “Seurat” to QC the BLCA single cell transcriptome data, filtered out null cells, mitochondrial genes, ribosomal genes, and hemoglobin genes (Figure S2), removed sample differences using PCA, and normalized the data for subsequent analysis. We used the FindVariableSignature function of the R package “Seurat” to find the high-variable genes in the samples (Figure S3), and then performed UMAP downscaling clustering of the high-variable genes to obtain a total of 18 cell clusters by UMAP clustering (Figure 4a and b). The 18 cell clusters were annotated using cell markers (Figure 4c), and the detailed list of cell type markers is shown in Table S2. 13 cell types were obtained, of which 2 cell types could not be clearly classified as a certain cell type, and the largest number of cells were epithelial cells (Figure 4d). Among the 13 cell types, GPR-score is highly expressed in CD8 + T cells of immune cells and in endothelial cells of non-immune cells, suggesting that GPR-score acts in BLCA mainly by affecting endothelial cells and CD8+ T cells (Figure 4e and f). Next we further explored the intercellular interactions between CD8+ T cells and endothelial cells according to the GPR-score risk score, which was divided into three risk groups: high, median, and low. We found that endothelial cells were not active in intercellular interactions, interacting mainly with NK cells, macrophages, and monocytes, with the greatest intensity of action with macrophages. The CD8+ T cells were extremely active in intercellular interactions, both in terms of the number and intensity of cells interacting, with the greatest intensity of action being displayed by epithelial cells (Figure 4g). Given that the CD8+ T cells are extremely active in BLCA cell communication, suggesting an important role in intercellular interactions, we further explored the ligand receptors in cell communication of CD8+ T cells according to the GPR risk score, and we found that CD8+ T cells in both GPR-high and GPR-low risk groups interacting with MIF-(CD74 + CXCR4) ligand–receptor relationships were extremely correlated (Figure 4h and i). Since MIF-(CD74 + CXCR4) ligand–receptors were extremely associated with both GPR-high and GPR-low risk groups, we further explored the MIF-signaling-pathway-network and found that the interaction between CD8 + T cells of different risk groups of GPR-score and other cell types is related to MIF signaling pathway (Figure 4j).

Figure 4 (a) Scatter plot of PCA of BLCA single-cell transcriptome data. (b) Scatter plot of UMAP downscaling clustering of BLCA single cell transcriptome data. (c) Scatter plot of cellular annotation of 18 cell clusters of BLCA. (d) Cellular annotation of BLCA based on UMAP downscaling clustering. (e and f) GPR-score expression levels in each cell type of BLCA. (g) Number and intensity of interactions between endothelial cells and CD8+ T cells with other cells in each risk group of GPR-score. (h) Ligand–receptor pair bubble plots of CD8+ T cell–cell interactions in GPR-score high-risk groups. (i) Ligand–receptor pair bubble plots of CD8+ T-cell interactions in the GPR-score low risk group. (j) Interactions between GPR-score risk groups and other cell types via MIF-signaling-pathway. P < 0.05 was considered statistically significant.
Figure 4 (a) Scatter plot of PCA of BLCA single-cell transcriptome data. (b) Scatter plot of UMAP downscaling clustering of BLCA single cell transcriptome data. (c) Scatter plot of cellular annotation of 18 cell clusters of BLCA. (d) Cellular annotation of BLCA based on UMAP downscaling clustering. (e and f) GPR-score expression levels in each cell type of BLCA. (g) Number and intensity of interactions between endothelial cells and CD8+ T cells with other cells in each risk group of GPR-score. (h) Ligand–receptor pair bubble plots of CD8+ T cell–cell interactions in GPR-score high-risk groups. (i) Ligand–receptor pair bubble plots of CD8+ T-cell interactions in the GPR-score low risk group. (j) Interactions between GPR-score risk groups and other cell types via MIF-signaling-pathway. P < 0.05 was considered statistically significant.
Figure 4 (a) Scatter plot of PCA of BLCA single-cell transcriptome data. (b) Scatter plot of UMAP downscaling clustering of BLCA single cell transcriptome data. (c) Scatter plot of cellular annotation of 18 cell clusters of BLCA. (d) Cellular annotation of BLCA based on UMAP downscaling clustering. (e and f) GPR-score expression levels in each cell type of BLCA. (g) Number and intensity of interactions between endothelial cells and CD8+ T cells with other cells in each risk group of GPR-score. (h) Ligand–receptor pair bubble plots of CD8+ T cell–cell interactions in GPR-score high-risk groups. (i) Ligand–receptor pair bubble plots of CD8+ T-cell interactions in the GPR-score low risk group. (j) Interactions between GPR-score risk groups and other cell types via MIF-signaling-pathway. P < 0.05 was considered statistically significant.
Figure 4 (a) Scatter plot of PCA of BLCA single-cell transcriptome data. (b) Scatter plot of UMAP downscaling clustering of BLCA single cell transcriptome data. (c) Scatter plot of cellular annotation of 18 cell clusters of BLCA. (d) Cellular annotation of BLCA based on UMAP downscaling clustering. (e and f) GPR-score expression levels in each cell type of BLCA. (g) Number and intensity of interactions between endothelial cells and CD8+ T cells with other cells in each risk group of GPR-score. (h) Ligand–receptor pair bubble plots of CD8+ T cell–cell interactions in GPR-score high-risk groups. (i) Ligand–receptor pair bubble plots of CD8+ T-cell interactions in the GPR-score low risk group. (j) Interactions between GPR-score risk groups and other cell types via MIF-signaling-pathway. P < 0.05 was considered statistically significant.
Figure 4

(a) Scatter plot of PCA of BLCA single-cell transcriptome data. (b) Scatter plot of UMAP downscaling clustering of BLCA single cell transcriptome data. (c) Scatter plot of cellular annotation of 18 cell clusters of BLCA. (d) Cellular annotation of BLCA based on UMAP downscaling clustering. (e and f) GPR-score expression levels in each cell type of BLCA. (g) Number and intensity of interactions between endothelial cells and CD8+ T cells with other cells in each risk group of GPR-score. (h) Ligand–receptor pair bubble plots of CD8+ T cell–cell interactions in GPR-score high-risk groups. (i) Ligand–receptor pair bubble plots of CD8+ T-cell interactions in the GPR-score low risk group. (j) Interactions between GPR-score risk groups and other cell types via MIF-signaling-pathway. P < 0.05 was considered statistically significant.

3.5 TMB of different risk groups of GPR-TME-score and its ability to predict immunotherapy response

To investigate whether there is a difference in TMB among different risk groups of GPR-TME-score, we explored the level of tumor mutation load in each of their risk groups with the help of CNV data from the TCGA-BLCA cohort to predict the response of different risk groups to immunotherapy. We first depicted the mutational landscape of each risk group and further calculated its TMB. We found that missense mutations were the most frequent mutation type in BLCA, with a lower mutation rate in the GPR-high + TME-low group (93.04%) than in the GPR-low + TME-high group (95.61%), and further calculated the TMB of each risk group and found that the GPR-high + TME-low group had a lower TMB than the GPR-low + TME-high group (95.61%). GPR-high + TME-low group having lower TMB than the GPR-low + TME-high group (N = 394, P = 2.5 × 10−4) suggested that the GPR-low + TME-high group had a better response to immunotherapy (Figure 5a and b). We also calculated the effect of TMB on the prognosis of BLCA patients in each risk group, and found that the GPR-low + TME-high group had the best prognosis and the GPR-high + TME-low group had the worst prognosis (P < 0.001) (Figure 5c). To investigate whether there were differences in immune checkpoint expression levels among risk groups, we calculated the expression levels of immune checkpoint-associated genes in the three risk groups. We found that the immune checkpoint-related genes CD209, CD276, CD86, and PDCD1LG2 differed among the risk groups (P < 0.05), and we also found that the expression levels of immune checkpoint-related genes in the GPR-low + TME-high group were generally higher than those in the remaining two risk groups, suggesting that the GPR-low + TME-high group had a better response to ICIs (Figure 5d). Human leukocyte antigen (HLA), an independent factor in tumor-associated antigen presentation, plays an important role in antitumor immune response and de novo tumor progression. Here we explored the expression levels of HLA-related genes in each risk group, and found that HLA-related genes HLA-B, HLA-C, and HLA-DOB were differentially expressed in different risk groups (P < 0.05), and we also found that the expression levels of HLA-related genes in the GPR-low + TME-high group were generally higher than those in other risk groups (Figure 5e). We then investigated the correlation between GPR-score gene expression levels and chemotherapy drug sensitivity with the GDSC database and CTRP database, and found that their expression levels were very closely related to MEK1/2 locus-targeting drug selumetinib and CTRP drug Cerulenin (Figure 5f and g). Finally, we explored the responsiveness of each risk group to immunotherapy using the TCGA-BLCA cohort with the help of the Tumor Immune Dysfunction and Exclusion Database (TIDE). We found that 17% of the 160 patients in the GPR-high + TME-low group responded to immunotherapy and 83% did not (P = 1.71 × 10−12), and the immune response in the remaining two risk groups was not statistically significant (Figure 5h). We further analyzed the difference in response levels to immune checkpoint blockade (ICIs) between patients with GPR-score and TME-score, and found that patients with GPR-score (P = 7.7 × 10−9) and TME-score (P = 0.013) responded to ICIS and there was a difference (Figure 5i). Finally, we used transcriptomic data from ICIs-responding patients to screen for differential genes with the help of the R package “Limma,” and used the proteomap database to explore the signaling pathways common to patients in the GPR-high + TME-low risk group responding to immunotherapy and their ICIs-responding counterparts. We found many signaling pathways common to both, such as the P13-AKT-signaling-pathway and MAPK-signal-pathway, suggesting that the GPR-TME-score may influence the response to immunotherapy in BLCA patients through the above pathways (Figure 5j). In conclusion, the GPR-TME-score model can better predict the response to immunotherapy in BLCA patients.

Figure 5 (a) Mutation waterfall plots of high and low GPR-TME-score risk groups. (b) Differences in TMB levels in different risk groups of GPR-TME-score. (c) Effect of TMB in different risk groups of GPR-TME-score on the overall survival rate of BLCA patients. (d) Immune checkpoint-associated gene signatures were differentially expressed in the GPR-TME-score across risk groups. (e) HLA-related gene signatures were differentially expressed in the GPR-TME-score across risk groups. (f) Bubble plot of the correlation between GPR-score gene and targeted drugs based on GDSC database. (g) Bubble plot of the correlation between GPR-score gene signatures and targeted drugs based on CTRP database. (h) Differences in response to immunotherapy among risk groups of GPR-TME-score based on the TIDE database. (i) Box line plot of differential response to ICIs in patients with GPR-score and TME-score. (j) Fragmentation plots of signaling pathways for immunotherapy responders in the GPR-TME-score and their ICI responders acting together based on the proteomap database. P < 0.05 was considered statistically significant.
Figure 5 (a) Mutation waterfall plots of high and low GPR-TME-score risk groups. (b) Differences in TMB levels in different risk groups of GPR-TME-score. (c) Effect of TMB in different risk groups of GPR-TME-score on the overall survival rate of BLCA patients. (d) Immune checkpoint-associated gene signatures were differentially expressed in the GPR-TME-score across risk groups. (e) HLA-related gene signatures were differentially expressed in the GPR-TME-score across risk groups. (f) Bubble plot of the correlation between GPR-score gene and targeted drugs based on GDSC database. (g) Bubble plot of the correlation between GPR-score gene signatures and targeted drugs based on CTRP database. (h) Differences in response to immunotherapy among risk groups of GPR-TME-score based on the TIDE database. (i) Box line plot of differential response to ICIs in patients with GPR-score and TME-score. (j) Fragmentation plots of signaling pathways for immunotherapy responders in the GPR-TME-score and their ICI responders acting together based on the proteomap database. P < 0.05 was considered statistically significant.
Figure 5 (a) Mutation waterfall plots of high and low GPR-TME-score risk groups. (b) Differences in TMB levels in different risk groups of GPR-TME-score. (c) Effect of TMB in different risk groups of GPR-TME-score on the overall survival rate of BLCA patients. (d) Immune checkpoint-associated gene signatures were differentially expressed in the GPR-TME-score across risk groups. (e) HLA-related gene signatures were differentially expressed in the GPR-TME-score across risk groups. (f) Bubble plot of the correlation between GPR-score gene and targeted drugs based on GDSC database. (g) Bubble plot of the correlation between GPR-score gene signatures and targeted drugs based on CTRP database. (h) Differences in response to immunotherapy among risk groups of GPR-TME-score based on the TIDE database. (i) Box line plot of differential response to ICIs in patients with GPR-score and TME-score. (j) Fragmentation plots of signaling pathways for immunotherapy responders in the GPR-TME-score and their ICI responders acting together based on the proteomap database. P < 0.05 was considered statistically significant.
Figure 5 (a) Mutation waterfall plots of high and low GPR-TME-score risk groups. (b) Differences in TMB levels in different risk groups of GPR-TME-score. (c) Effect of TMB in different risk groups of GPR-TME-score on the overall survival rate of BLCA patients. (d) Immune checkpoint-associated gene signatures were differentially expressed in the GPR-TME-score across risk groups. (e) HLA-related gene signatures were differentially expressed in the GPR-TME-score across risk groups. (f) Bubble plot of the correlation between GPR-score gene and targeted drugs based on GDSC database. (g) Bubble plot of the correlation between GPR-score gene signatures and targeted drugs based on CTRP database. (h) Differences in response to immunotherapy among risk groups of GPR-TME-score based on the TIDE database. (i) Box line plot of differential response to ICIs in patients with GPR-score and TME-score. (j) Fragmentation plots of signaling pathways for immunotherapy responders in the GPR-TME-score and their ICI responders acting together based on the proteomap database. P < 0.05 was considered statistically significant.
Figure 5

(a) Mutation waterfall plots of high and low GPR-TME-score risk groups. (b) Differences in TMB levels in different risk groups of GPR-TME-score. (c) Effect of TMB in different risk groups of GPR-TME-score on the overall survival rate of BLCA patients. (d) Immune checkpoint-associated gene signatures were differentially expressed in the GPR-TME-score across risk groups. (e) HLA-related gene signatures were differentially expressed in the GPR-TME-score across risk groups. (f) Bubble plot of the correlation between GPR-score gene and targeted drugs based on GDSC database. (g) Bubble plot of the correlation between GPR-score gene signatures and targeted drugs based on CTRP database. (h) Differences in response to immunotherapy among risk groups of GPR-TME-score based on the TIDE database. (i) Box line plot of differential response to ICIs in patients with GPR-score and TME-score. (j) Fragmentation plots of signaling pathways for immunotherapy responders in the GPR-TME-score and their ICI responders acting together based on the proteomap database. P < 0.05 was considered statistically significant.

4 Discussion

BLCA, one of the most common malignancies of the urological tract, is highly susceptible to drug resistance, and there is a lack of effective therapeutic targets and accurate efficacy prediction models. In this study, we constructed a 15-gene risk signatures in the TCGA-BLCA cohort by univariate Cox analysis and LASSO regression analysis, and a TME signature based on the TCGA-BLCA immune microenvironment, and because the immune microenvironment affects the tumor response to immunotherapy, we combined the above two risk profiles to construct a GPR-TME signatures, and explored the value of this model in BLCA overall survival and immunotherapy. We found that the GPR gene signatures was a risk factor for overall survival in BLCA, while the TME risk signatures was a protective factor for overall survival in BLCA, and the GPR-TME signature was an independent risk factor for overall survival in BLCA. In exploring the level of immune infiltration in BLCA, we found that T cells were the predominant immune cell type in BLCA, and that the level of immune infiltration differed among risk groups, with lower GPR signatures or higher TME signatures implying higher levels of immune infiltration. In BLCA, higher levels of immune infiltration represent a better response to immunotherapy. In exploring the independent risk factors for overall survival in BLCA, we found that gender, clinical stage, T stage, N stage, M stage, and GPR-TME signatures were independent risk factors for their overall survival. In exploring the single cell transcriptome data of BLCA, we found that epithelial cells were the cell type with the highest cell number in BLCA and CD8+ T cells were the immune cells with the highest cell number in it. Based on these two cell types, we further explored their intercellular interactions and found that CD8+ T cells were extremely active in intercellular interactions, while epithelial cells were far less active than CD8+ T cells. Furthermore, the MIF-(CD74 + CXCR4) ligand–receptor is extremely important for CD8+ T cells to play intercellular roles. Finally, we investigated whether the GPR-TME signatures could predict the response to immunotherapy in BLCA patients, and the response to immunotherapy differed among risk groups in this model, with lower GPR signatures or higher TME signatures implying better levels of immune response. We applied the model to the ICIs treatment cohort and found that the model could be used to predict the efficacy of ICIs treatment in BLCA patients.

The mechanisms of tumor drug resistance are complex, but most of them are related to epigenetic modifications and mutations in oncogenes, and drug resistance in bladder cancer can be considered as a result of relevant genetic variants [16]. In addition, abnormal non-coding RNA function, generation of bladder cancer stem cells, increased drug efflux, and autophagy are also important causes of drug resistance in bladder cancer [17,18]. Gene expression and regulation play an important role in tumor cell growth and differentiation, invasion, metastasis, and drug resistance. The epithelial-mesenchymal transition (EMT) plays an important role in tumor invasion, metastasis, formation of cancer initiating cells (CICs), and drug resistance. The CXCL5 gene may induce bladder cancer recurrence by activating NF-kB pathway-regulated EMT that causes chemoresistance in bladder cancer cells [19,20]. Li et al. found that FAT10 was highly expressed in bladder cancer cell lines and promoted the formation of EMT and CICs in bladder cancer UMUC-3 cells, leading to cisplatin resistance [21]. Tumor stem cells (CSCs) are defined as a subpopulation of self-renewing and self-protective cancer cells that can differentiate into morphologically and functionally diverse cancer cells with a limited lifespan and are a major factor in tumor drug-resistant recurrence [22]. The production of BCSCs and bladder cancer resistance and recurrence may involve alterations in multiple signaling pathways, such as the KMT1A-GATA3-STAT3 pathway, Hedgehog pathway, Notch pathway, Wnt pathway, JAK-STAT pathway, COX2/PGE2 pathway, YAP1 pathway, and miR34a/GOLPH3 pathway, and may play a key role in maintaining the properties of BCSCs, thus promoting bladder cancer drug resistance and recurrence [23,24,25]. In the gene enrichment analysis of the most relevant signature module genes obtained from WGCNA analysis for each risk group and differential genes in ICIs-responding patients, we found that they were enriched in signaling pathways such as NF-KB signaling pathway, JAK-STAT pathway, and Wnt pathway, which suggested that the above signaling pathways might be related to bladder cancer drug resistance and recurrence.

GPR is a class of transmembrane protein receptors with seven transmembrane helices, which can recognize and bind to various extracellular signaling molecules and undergo structural changes, activating a series of intracellular signaling pathways and ultimately causing changes in cellular state [26]. It is an important target for drug development. In the treatment of tumors, 21 anti-cancer drugs targeting GPR have been approved for marketing [27]. These include the gonadotropin-releasing hormone receptor antagonist Degarelix for advanced prostate cancer and the SMO receptor inhibitors Sonidegib and Vemurafenib for basal cell carcinoma [28]. There are also 23 GPR drugs under development for the treatment of cancer, seven of which target novel targets, including chemokine receptors and proteins in the Wnt signaling pathway [29]. Numerous studies have confirmed that members of the GPR family are closely associated with the development of tumors.

The results of a study suggest that CD97 overexpression increases migration and induces early tumor growth in colon cancer cells [30]. In a mouse model of gastric cancer, CD97 was also shown to promote local tumor growth and metastatic spread [31]. It has been shown that BAI1 can inhibit glioblastoma angiogenesis [32]. In addition, BAI1 has been found to inhibit neovascularization in colon cancer, breast cancer, gastric cancer, and renal cell carcinoma [33]. A study that included 37 patients with pancreatic cancer showed that CD97 was associated with aggressiveness and overall survival of pancreatic cancer [34]. In two independent cohort studies that included 187 and 539 patients with glioblastoma, respectively, CD97 expression was upregulated in stage IV glioblastoma and correlated with overall survival [35]. In univariate Cox analysis of GPR-related genes, we also found that GPR family members were associated with overall survival in BLCA patients, and GPR family-related genes SIGMAR1, OR2B6, and PTGER4 were independent risk factors for overall survival in BLCA patients. In predicting ICIs response, GPR gene signatures could predict the response to ICIs in BLCA patients.

TME is mainly composed of tumor cells, immune cells, stromal cells, endothelial cells and tumor-associated fibroblasts [36]. Several studies have shown that [37,38,39] tumor-associated macrophages (TAMs) and tumor-infiltrating lymphocytes (TILs) are important components of immune cells in TME and are strongly associated with bladder cancer progression, overall clinical survival, and response to immunotherapy. TAMs are important components of immune cells in bladder cancer TME and are characterized by M1-type macrophages and M2-type macrophages. M1-macrophages exert anti-tumor effects by promoting increased expression and release of cytokines such as IL-1β, TNF-α, IL-6, and IL-12 and elevating the helper T cell 1 (Th1)-mediated immune response. M2-macrophages exert immunosuppressive functions by promoting the expression and secretion of immunosuppressive cytokines such as TGF-β 1 and IL-10, thereby promoting tumor progression and metastasis [40]. The study showed that M2-macrophage cells have a strong immunosuppressive function by promoting the expression and secretion of immunosuppressive cytokines such as TGF-1 and IL-10. Related studies have shown that an increased proportion of M2-macrophage infiltration is associated with poorer overall survival in bladder cancer patients [41]. Pfannstiel et al. [42] conducted a study showing that high levels of TIL in bladder cancer were associated with increased expression of immune checkpoints such as PD-1 and PD-L1, tumor antigens, and mutational load, suggesting that bladder cancer patients with high infiltrating lymphocytes would benefit more from ICIs. Initial CD8+ T cells are activated by specific antigen stimulation and subsequently differentiate into cytotoxic T cells (CTL) with the assistance of effector Th cells, which can exert cytotoxic killing effects in direct contact with target cells. B lymphocytes have a dual effect of promoting or inhibiting tumor growth in the TME [43]. In an early study carried out by De Visser et al. [44] using transgenic mouse models showed that B cells can promote chronic inflammation and thus promote tumorigenesis and progression. However, some reports [45,46] show that B cells can inhibit the development of other types of tumors and that the higher the number of tumor-infiltrating B cells, the better the overall survival rate. This is because they may exert their antitumor effects through synergistic effects with T lymphocytes or by their own action. Although B cells in the TME may play an important role in inhibiting tumor progression [47,48,49], their effects on bladder cancer are unknown. Although PD-L1 and TMB have been used clinically as biomarkers for immunotherapy selection in many patients, there are still many patients who cannot benefit based on these two markers [50]. By analyzing the tumor immune microenvironment, the response of bladder cancer patients to immunotherapy can be effectively predicted, and how to further modulate TME and improve the anti-tumor capacity of T cells in bladder cancer is a potential direction for future bladder cancer immunotherapy. In this study, with the help of the CIBERSORT database, we explored the infiltration levels of 22 immune cell types in BLCA, TAMs and TILs were its main immune cell types, 12 of which were immune cell subtypes associated with overall survival of BLCA patients, M2-macrophages were risk factors for overall survival of BLCA patients, and CD8+ T cells were the protective factors, which is consistent with numerous researchers. Further analyzing the level of immune cell infiltration in each risk group, we found differences in the levels of TAM and TIL infiltration. In the analysis of BLCA single-cell data, we found that CD8+ T cells were its main immune cell type, and its transcriptome data also indicated that CD8+ T cells were the main immune cell type, and CD8+ T cells tended to imply better overall survival, and the KM curves of BLCA confirmed this view. In conclusion, the TME signatures we constructed were able to predict the overall survival and immunotherapy response of patients. A high TME signature implies better overall survival and immune response.

The GPR-TME risk model constructed in this study performed well in predicting the overall survival and immunotherapy response in BLCA patients, but had some shortcomings. First, the GPR gene signature was a risk factor for overall survival of BLCA patients and negatively correlated with the immune response of BLCA patients, while the TME signatures was a protective factor for overall survival of BLCA patients and positively correlated with the immune response of BLCA patients, and the interaction between the two signatures within each other needs to be further investigated. Second, when univariate Cox analysis was performed on immune cells to explore their effects with overall survival, we found that 12 immune cells were associated with overall survival of BLCA patients, but according to the current view of tumor immunology, the effects of some immune cells on overall tumor survival are not exact, and some immune cells have both pro-tumor and tumor suppressive effects, such as macrophages, and it is difficult for us to screen immune cells with protective effects according to KM curve and then conduct risk modeling. To ensure the reliability of this model, we followed the mainstream view of tumor immunology for modeling, but as tumor immunology continues to be studied in depth, this model may not be appropriate, and we are happy to adjust this model to make it more scientific and applicable. Finally, this gene signature lacks validation from large-scale perspective trials. In addition, the TCGA cohort consists of gene sequencing data, whereas GSE160693 is gene chip data, and data from external cohorts may not fully reveal the actual overall survival effect of this model in BLCA. Also, the detailed mechanism of action of this gene signature in BLCA has not been explored at the cellular and molecular level.

In conclusion, we propose a new GPR-related gene signature as a practical tool for BLCA patients, which better predicts the overall survival of BLCA patients and their response to immunotherapy.

Acknowledgements

We thank the authors of GSM5329919, GSM5751919 and GSE160693 for providing data, and the CIBERSORT database and the TIP database for providing the platform for data analysis.

  1. Funding information: Authors state no funding involved.

  2. Author contributions: W.Z.Q. designed and conducted the whole research. L.C. used R language to analyze BLCA data from GEO database and TCGA database. W.Z.Q. completed thedata analysis and drafted the manuscript. W.Y.L. revised and finalized the manuscript. All authors contributed equally to this work and approved the submitted version.

  3. Conflict of interest: Authors state no conflict of interest.

  4. Data availability statement: The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Received: 2023-01-26
Revised: 2023-06-28
Accepted: 2023-07-18
Published Online: 2023-08-10

© 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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  5. Effects of phytoestrogens combined with cold stress on sperm parameters and testicular proteomics in rats
  6. A case of pulmonary embolism with bad warfarin anticoagulant effects caused by E. coli infection
  7. Neutrophilia with subclinical Cushing’s disease: A case report and literature review
  8. Isoimperatorin alleviates lipopolysaccharide-induced periodontitis by downregulating ERK1/2 and NF-κB pathways
  9. Immunoregulation of synovial macrophages for the treatment of osteoarthritis
  10. Novel CPLANE1 c.8948dupT (p.P2984Tfs*7) variant in a child patient with Joubert syndrome
  11. Antiphospholipid antibodies and the risk of thrombosis in myeloproliferative neoplasms
  12. Immunological responses of septic rats to combination therapy with thymosin α1 and vitamin C
  13. High glucose and high lipid induced mitochondrial dysfunction in JEG-3 cells through oxidative stress
  14. Pharmacological inhibition of the ubiquitin-specific protease 8 effectively suppresses glioblastoma cell growth
  15. Levocarnitine regulates the growth of angiotensin II-induced myocardial fibrosis cells via TIMP-1
  16. Age-related changes in peripheral T-cell subpopulations in elderly individuals: An observational study
  17. Single-cell transcription analysis reveals the tumor origin and heterogeneity of human bilateral renal clear cell carcinoma
  18. Identification of iron metabolism-related genes as diagnostic signatures in sepsis by blood transcriptomic analysis
  19. Long noncoding RNA ACART knockdown decreases 3T3-L1 preadipocyte proliferation and differentiation
  20. Surgery, adjuvant immunotherapy plus chemotherapy and radiotherapy for primary malignant melanoma of the parotid gland (PGMM): A case report
  21. Dosimetry comparison with helical tomotherapy, volumetric modulated arc therapy, and intensity-modulated radiotherapy for grade II gliomas: A single‑institution case series
  22. Soy isoflavone reduces LPS-induced acute lung injury via increasing aquaporin 1 and aquaporin 5 in rats
  23. Refractory hypokalemia with sexual dysplasia and infertility caused by 17α-hydroxylase deficiency and triple X syndrome: A case report
  24. Meta-analysis of cancer risk among end stage renal disease undergoing maintenance dialysis
  25. 6-Phosphogluconate dehydrogenase inhibition arrests growth and induces apoptosis in gastric cancer via AMPK activation and oxidative stress
  26. Experimental study on the optimization of ANM33 release in foam cells
  27. Primary retroperitoneal angiosarcoma: A case report
  28. Metabolomic analysis-identified 2-hydroxybutyric acid might be a key metabolite of severe preeclampsia
  29. Malignant pleural effusion diagnosis and therapy
  30. Effect of spaceflight on the phenotype and proteome of Escherichia coli
  31. Comparison of immunotherapy combined with stereotactic radiotherapy and targeted therapy for patients with brain metastases: A systemic review and meta-analysis
  32. Activation of hypermethylated P2RY1 mitigates gastric cancer by promoting apoptosis and inhibiting proliferation
  33. Association between the VEGFR-2 -604T/C polymorphism (rs2071559) and type 2 diabetic retinopathy
  34. The role of IL-31 and IL-34 in the diagnosis and treatment of chronic periodontitis
  35. Triple-negative mouse breast cancer initiating cells show high expression of beta1 integrin and increased malignant features
  36. mNGS facilitates the accurate diagnosis and antibiotic treatment of suspicious critical CNS infection in real practice: A retrospective study
  37. The apatinib and pemetrexed combination has antitumor and antiangiogenic effects against NSCLC
  38. Radiotherapy for primary thyroid adenoid cystic carcinoma
  39. Design and functional preliminary investigation of recombinant antigen EgG1Y162–EgG1Y162 against Echinococcus granulosus
  40. Effects of losartan in patients with NAFLD: A meta-analysis of randomized controlled trial
  41. Bibliometric analysis of METTL3: Current perspectives, highlights, and trending topics
  42. Performance comparison of three scaling algorithms in NMR-based metabolomics analysis
  43. PI3K/AKT/mTOR pathway and its related molecules participate in PROK1 silence-induced anti-tumor effects on pancreatic cancer
  44. The altered expression of cytoskeletal and synaptic remodeling proteins during epilepsy
  45. Effects of pegylated recombinant human granulocyte colony-stimulating factor on lymphocytes and white blood cells of patients with malignant tumor
  46. Prostatitis as initial manifestation of Chlamydia psittaci pneumonia diagnosed by metagenome next-generation sequencing: A case report
  47. NUDT21 relieves sevoflurane-induced neurological damage in rats by down-regulating LIMK2
  48. Association of interleukin-10 rs1800896, rs1800872, and interleukin-6 rs1800795 polymorphisms with squamous cell carcinoma risk: A meta-analysis
  49. Exosomal HBV-DNA for diagnosis and treatment monitoring of chronic hepatitis B
  50. Shear stress leads to the dysfunction of endothelial cells through the Cav-1-mediated KLF2/eNOS/ERK signaling pathway under physiological conditions
  51. Interaction between the PI3K/AKT pathway and mitochondrial autophagy in macrophages and the leukocyte count in rats with LPS-induced pulmonary infection
  52. Meta-analysis of the rs231775 locus polymorphism in the CTLA-4 gene and the susceptibility to Graves’ disease in children
  53. Cloning, subcellular localization and expression of phosphate transporter gene HvPT6 of hulless barley
  54. Coptisine mitigates diabetic nephropathy via repressing the NRLP3 inflammasome
  55. Significant elevated CXCL14 and decreased IL-39 levels in patients with tuberculosis
  56. Whole-exome sequencing applications in prenatal diagnosis of fetal bowel dilatation
  57. Gemella morbillorum infective endocarditis: A case report and literature review
  58. An unusual ectopic thymoma clonal evolution analysis: A case report
  59. Severe cumulative skin toxicity during toripalimab combined with vemurafenib following toripalimab alone
  60. Detection of V. vulnificus septic shock with ARDS using mNGS
  61. Novel rare genetic variants of familial and sporadic pulmonary atresia identified by whole-exome sequencing
  62. The influence and mechanistic action of sperm DNA fragmentation index on the outcomes of assisted reproduction technology
  63. Novel compound heterozygous mutations in TELO2 in an infant with You-Hoover-Fong syndrome: A case report and literature review
  64. ctDNA as a prognostic biomarker in resectable CLM: Systematic review and meta-analysis
  65. Diagnosis of primary amoebic meningoencephalitis by metagenomic next-generation sequencing: A case report
  66. Phylogenetic analysis of promoter regions of human Dolichol kinase (DOLK) and orthologous genes using bioinformatics tools
  67. Collagen changes in rabbit conjunctiva after conjunctival crosslinking
  68. Effects of NM23 transfection of human gastric carcinoma cells in mice
  69. Oral nifedipine and phytosterol, intravenous nicardipine, and oral nifedipine only: Three-arm, retrospective, cohort study for management of severe preeclampsia
  70. Case report of hepatic retiform hemangioendothelioma: A rare tumor treated with ultrasound-guided microwave ablation
  71. Curcumin induces apoptosis in human hepatocellular carcinoma cells by decreasing the expression of STAT3/VEGF/HIF-1α signaling
  72. Rare presentation of double-clonal Waldenström macroglobulinemia with pulmonary embolism: A case report
  73. Giant duplication of the transverse colon in an adult: A case report and literature review
  74. Ectopic thyroid tissue in the breast: A case report
  75. SDR16C5 promotes proliferation and migration and inhibits apoptosis in pancreatic cancer
  76. Vaginal metastasis from breast cancer: A case report
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  90. Genetic alterations of KRAS and TP53 in intrahepatic cholangiocarcinoma associated with poor prognosis
  91. Granulomatous polyangiitis involving the fourth ventricle: Report of a rare case and a literature review
  92. Studying infant mortality: A demographic analysis based on data mining models
  93. Metaplastic breast carcinoma with osseous differentiation: A report of a rare case and literature review
  94. Protein Z modulates the metastasis of lung adenocarcinoma cells
  95. Inhibition of pyroptosis and apoptosis by capsaicin protects against LPS-induced acute kidney injury through TRPV1/UCP2 axis in vitro
  96. TAK-242, a toll-like receptor 4 antagonist, against brain injury by alleviates autophagy and inflammation in rats
  97. Primary mediastinum Ewing’s sarcoma with pleural effusion: A case report and literature review
  98. Association of ADRB2 gene polymorphisms and intestinal microbiota in Chinese Han adolescents
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  100. Study on the cytokines related to SARS-Cov-2 in testicular cells and the interaction network between cells based on scRNA-seq data
  101. Effect of periostin on bone metabolic and autophagy factors during tooth eruption in mice
  102. HP1 induces ferroptosis of renal tubular epithelial cells through NRF2 pathway in diabetic nephropathy
  103. Intravaginal estrogen management in postmenopausal patients with vaginal squamous intraepithelial lesions along with CO2 laser ablation: A retrospective study
  104. Hepatocellular carcinoma cell differentiation trajectory predicts immunotherapy, potential therapeutic drugs, and prognosis of patients
  105. Effects of physical exercise on biomarkers of oxidative stress in healthy subjects: A meta-analysis of randomized controlled trials
  106. Identification of lysosome-related genes in connection with prognosis and immune cell infiltration for drug candidates in head and neck cancer
  107. Development of an instrument-free and low-cost ELISA dot-blot test to detect antibodies against SARS-CoV-2
  108. Research progress on gas signal molecular therapy for Parkinson’s disease
  109. Adiponectin inhibits TGF-β1-induced skin fibroblast proliferation and phenotype transformation via the p38 MAPK signaling pathway
  110. The G protein-coupled receptor-related gene signatures for predicting prognosis and immunotherapy response in bladder urothelial carcinoma
  111. α-Fetoprotein contributes to the malignant biological properties of AFP-producing gastric cancer
  112. CXCL12/CXCR4/CXCR7 axis in placenta tissues of patients with placenta previa
  113. Association between thyroid stimulating hormone levels and papillary thyroid cancer risk: A meta-analysis
  114. Significance of sTREM-1 and sST2 combined diagnosis for sepsis detection and prognosis prediction
  115. Diagnostic value of serum neuroactive substances in the acute exacerbation of chronic obstructive pulmonary disease complicated with depression
  116. Research progress of AMP-activated protein kinase and cardiac aging
  117. TRIM29 knockdown prevented the colon cancer progression through decreasing the ubiquitination levels of KRT5
  118. Cross-talk between gut microbiota and liver steatosis: Complications and therapeutic target
  119. Metastasis from small cell lung cancer to ovary: A case report
  120. The early diagnosis and pathogenic mechanisms of sepsis-related acute kidney injury
  121. The effect of NK cell therapy on sepsis secondary to lung cancer: A case report
  122. Erianin alleviates collagen-induced arthritis in mice by inhibiting Th17 cell differentiation
  123. Loss of ACOX1 in clear cell renal cell carcinoma and its correlation with clinical features
  124. Signalling pathways in the osteogenic differentiation of periodontal ligament stem cells
  125. Crosstalk between lactic acid and immune regulation and its value in the diagnosis and treatment of liver failure
  126. Clinicopathological features and differential diagnosis of gastric pleomorphic giant cell carcinoma
  127. Traumatic brain injury and rTMS-ERPs: Case report and literature review
  128. Extracellular fibrin promotes non-small cell lung cancer progression through integrin β1/PTEN/AKT signaling
  129. Knockdown of DLK4 inhibits non-small cell lung cancer tumor growth by downregulating CKS2
  130. The co-expression pattern of VEGFR-2 with indicators related to proliferation, apoptosis, and differentiation of anagen hair follicles
  131. Inflammation-related signaling pathways in tendinopathy
  132. CD4+ T cell count in HIV/TB co-infection and co-occurrence with HL: Case report and literature review
  133. Clinical analysis of severe Chlamydia psittaci pneumonia: Case series study
  134. Bioinformatics analysis to identify potential biomarkers for the pulmonary artery hypertension associated with the basement membrane
  135. Influence of MTHFR polymorphism, alone or in combination with smoking and alcohol consumption, on cancer susceptibility
  136. Catharanthus roseus (L.) G. Don counteracts the ampicillin resistance in multiple antibiotic-resistant Staphylococcus aureus by downregulation of PBP2a synthesis
  137. Combination of a bronchogenic cyst in the thoracic spinal canal with chronic myelocytic leukemia
  138. Bacterial lipoprotein plays an important role in the macrophage autophagy and apoptosis induced by Salmonella typhimurium and Staphylococcus aureus
  139. TCL1A+ B cells predict prognosis in triple-negative breast cancer through integrative analysis of single-cell and bulk transcriptomic data
  140. Ezrin promotes esophageal squamous cell carcinoma progression via the Hippo signaling pathway
  141. Ferroptosis: A potential target of macrophages in plaque vulnerability
  142. Predicting pediatric Crohn's disease based on six mRNA-constructed risk signature using comprehensive bioinformatic approaches
  143. Applications of genetic code expansion and photosensitive UAAs in studying membrane proteins
  144. HK2 contributes to the proliferation, migration, and invasion of diffuse large B-cell lymphoma cells by enhancing the ERK1/2 signaling pathway
  145. IL-17 in osteoarthritis: A narrative review
  146. Circadian cycle and neuroinflammation
  147. Probiotic management and inflammatory factors as a novel treatment in cirrhosis: A systematic review and meta-analysis
  148. Hemorrhagic meningioma with pulmonary metastasis: Case report and literature review
  149. SPOP regulates the expression profiles and alternative splicing events in human hepatocytes
  150. Knockdown of SETD5 inhibited glycolysis and tumor growth in gastric cancer cells by down-regulating Akt signaling pathway
  151. PTX3 promotes IVIG resistance-induced endothelial injury in Kawasaki disease by regulating the NF-κB pathway
  152. Pancreatic ectopic thyroid tissue: A case report and analysis of literature
  153. The prognostic impact of body mass index on female breast cancer patients in underdeveloped regions of northern China differs by menopause status and tumor molecular subtype
  154. Report on a case of liver-originating malignant melanoma of unknown primary
  155. Case report: Herbal treatment of neutropenic enterocolitis after chemotherapy for breast cancer
  156. The fibroblast growth factor–Klotho axis at molecular level
  157. Characterization of amiodarone action on currents in hERG-T618 gain-of-function mutations
  158. A case report of diagnosis and dynamic monitoring of Listeria monocytogenes meningitis with NGS
  159. Effect of autologous platelet-rich plasma on new bone formation and viability of a Marburg bone graft
  160. Small breast epithelial mucin as a useful prognostic marker for breast cancer patients
  161. Continuous non-adherent culture promotes transdifferentiation of human adipose-derived stem cells into retinal lineage
  162. Nrf3 alleviates oxidative stress and promotes the survival of colon cancer cells by activating AKT/BCL-2 signal pathway
  163. Favorable response to surufatinib in a patient with necrolytic migratory erythema: A case report
  164. Case report of atypical undernutrition of hypoproteinemia type
  165. Down-regulation of COL1A1 inhibits tumor-associated fibroblast activation and mediates matrix remodeling in the tumor microenvironment of breast cancer
  166. Sarcoma protein kinase inhibition alleviates liver fibrosis by promoting hepatic stellate cells ferroptosis
  167. Research progress of serum eosinophil in chronic obstructive pulmonary disease and asthma
  168. Clinicopathological characteristics of co-existing or mixed colorectal cancer and neuroendocrine tumor: Report of five cases
  169. Role of menopausal hormone therapy in the prevention of postmenopausal osteoporosis
  170. Precisional detection of lymph node metastasis using tFCM in colorectal cancer
  171. Advances in diagnosis and treatment of perimenopausal syndrome
  172. A study of forensic genetics: ITO index distribution and kinship judgment between two individuals
  173. Acute lupus pneumonitis resembling miliary tuberculosis: A case-based review
  174. Plasma levels of CD36 and glutathione as biomarkers for ruptured intracranial aneurysm
  175. Fractalkine modulates pulmonary angiogenesis and tube formation by modulating CX3CR1 and growth factors in PVECs
  176. Novel risk prediction models for deep vein thrombosis after thoracotomy and thoracoscopic lung cancer resections, involving coagulation and immune function
  177. Exploring the diagnostic markers of essential tremor: A study based on machine learning algorithms
  178. Evaluation of effects of small-incision approach treatment on proximal tibia fracture by deep learning algorithm-based magnetic resonance imaging
  179. An online diagnosis method for cancer lesions based on intelligent imaging analysis
  180. Medical imaging in rheumatoid arthritis: A review on deep learning approach
  181. Predictive analytics in smart healthcare for child mortality prediction using a machine learning approach
  182. Utility of neutrophil–lymphocyte ratio and platelet–lymphocyte ratio in predicting acute-on-chronic liver failure survival
  183. A biomedical decision support system for meta-analysis of bilateral upper-limb training in stroke patients with hemiplegia
  184. TNF-α and IL-8 levels are positively correlated with hypobaric hypoxic pulmonary hypertension and pulmonary vascular remodeling in rats
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  186. Comparison of the prognostic value of four different critical illness scores in patients with sepsis-induced coagulopathy
  187. Application and teaching of computer molecular simulation embedded technology and artificial intelligence in drug research and development
  188. Hepatobiliary surgery based on intelligent image segmentation technology
  189. Value of brain injury-related indicators based on neural network in the diagnosis of neonatal hypoxic-ischemic encephalopathy
  190. Analysis of early diagnosis methods for asymmetric dementia in brain MR images based on genetic medical technology
  191. Early diagnosis for the onset of peri-implantitis based on artificial neural network
  192. Clinical significance of the detection of serum IgG4 and IgG4/IgG ratio in patients with thyroid-associated ophthalmopathy
  193. Forecast of pain degree of lumbar disc herniation based on back propagation neural network
  194. SPA-UNet: A liver tumor segmentation network based on fused multi-scale features
  195. Systematic evaluation of clinical efficacy of CYP1B1 gene polymorphism in EGFR mutant non-small cell lung cancer observed by medical image
  196. Rehabilitation effect of intelligent rehabilitation training system on hemiplegic limb spasms after stroke
  197. A novel approach for minimising anti-aliasing effects in EEG data acquisition
  198. ErbB4 promotes M2 activation of macrophages in idiopathic pulmonary fibrosis
  199. Clinical role of CYP1B1 gene polymorphism in prediction of postoperative chemotherapy efficacy in NSCLC based on individualized health model
  200. Lung nodule segmentation via semi-residual multi-resolution neural networks
  201. Evaluation of brain nerve function in ICU patients with Delirium by deep learning algorithm-based resting state MRI
  202. A data mining technique for detecting malignant mesothelioma cancer using multiple regression analysis
  203. Markov model combined with MR diffusion tensor imaging for predicting the onset of Alzheimer’s disease
  204. Effectiveness of the treatment of depression associated with cancer and neuroimaging changes in depression-related brain regions in patients treated with the mediator-deuterium acupuncture method
  205. Molecular mechanism of colorectal cancer and screening of molecular markers based on bioinformatics analysis
  206. Monitoring and evaluation of anesthesia depth status data based on neuroscience
  207. Exploring the conformational dynamics and thermodynamics of EGFR S768I and G719X + S768I mutations in non-small cell lung cancer: An in silico approaches
  208. Optimised feature selection-driven convolutional neural network using gray level co-occurrence matrix for detection of cervical cancer
  209. Incidence of different pressure patterns of spinal cerebellar ataxia and analysis of imaging and genetic diagnosis
  210. Pathogenic bacteria and treatment resistance in older cardiovascular disease patients with lung infection and risk prediction model
  211. Adoption value of support vector machine algorithm-based computed tomography imaging in the diagnosis of secondary pulmonary fungal infections in patients with malignant hematological disorders
  212. From slides to insights: Harnessing deep learning for prognostic survival prediction in human colorectal cancer histology
  213. Ecology and Environmental Science
  214. Monitoring of hourly carbon dioxide concentration under different land use types in arid ecosystem
  215. Comparing the differences of prokaryotic microbial community between pit walls and bottom from Chinese liquor revealed by 16S rRNA gene sequencing
  216. Effects of cadmium stress on fruits germination and growth of two herbage species
  217. Bamboo charcoal affects soil properties and bacterial community in tea plantations
  218. Optimization of biogas potential using kinetic models, response surface methodology, and instrumental evidence for biodegradation of tannery fleshings during anaerobic digestion
  219. Understory vegetation diversity patterns of Platycladus orientalis and Pinus elliottii communities in Central and Southern China
  220. Studies on macrofungi diversity and discovery of new species of Abortiporus from Baotianman World Biosphere Reserve
  221. Food Science
  222. Effect of berrycactus fruit (Myrtillocactus geometrizans) on glutamate, glutamine, and GABA levels in the frontal cortex of rats fed with a high-fat diet
  223. Guesstimate of thymoquinone diversity in Nigella sativa L. genotypes and elite varieties collected from Indian states using HPTLC technique
  224. Analysis of bacterial community structure of Fuzhuan tea with different processing techniques
  225. Untargeted metabolomics reveals sour jujube kernel benefiting the nutritional value and flavor of Morchella esculenta
  226. Mycobiota in Slovak wine grapes: A case study from the small Carpathians wine region
  227. Elemental analysis of Fadogia ancylantha leaves used as a nutraceutical in Mashonaland West Province, Zimbabwe
  228. Microbiological transglutaminase: Biotechnological application in the food industry
  229. Influence of solvent-free extraction of fish oil from catfish (Clarias magur) heads using a Taguchi orthogonal array design: A qualitative and quantitative approach
  230. Chromatographic analysis of the chemical composition and anticancer activities of Curcuma longa extract cultivated in Palestine
  231. The potential for the use of leghemoglobin and plant ferritin as sources of iron
  232. Investigating the association between dietary patterns and glycemic control among children and adolescents with T1DM
  233. Bioengineering and Biotechnology
  234. Biocompatibility and osteointegration capability of β-TCP manufactured by stereolithography 3D printing: In vitro study
  235. Clinical characteristics and the prognosis of diabetic foot in Tibet: A single center, retrospective study
  236. Agriculture
  237. Biofertilizer and NPSB fertilizer application effects on nodulation and productivity of common bean (Phaseolus vulgaris L.) at Sodo Zuria, Southern Ethiopia
  238. On correlation between canopy vegetation and growth indexes of maize varieties with different nitrogen efficiencies
  239. Exopolysaccharides from Pseudomonas tolaasii inhibit the growth of Pleurotus ostreatus mycelia
  240. A transcriptomic evaluation of the mechanism of programmed cell death of the replaceable bud in Chinese chestnut
  241. Melatonin enhances salt tolerance in sorghum by modulating photosynthetic performance, osmoregulation, antioxidant defense, and ion homeostasis
  242. Effects of plant density on alfalfa (Medicago sativa L.) seed yield in western Heilongjiang areas
  243. Identification of rice leaf diseases and deficiency disorders using a novel DeepBatch technique
  244. Artificial intelligence and internet of things oriented sustainable precision farming: Towards modern agriculture
  245. Animal Sciences
  246. Effect of ketogenic diet on exercise tolerance and transcriptome of gastrocnemius in mice
  247. Combined analysis of mRNA–miRNA from testis tissue in Tibetan sheep with different FecB genotypes
  248. Isolation, identification, and drug resistance of a partially isolated bacterium from the gill of Siniperca chuatsi
  249. Tracking behavioral changes of confined sows from the first mating to the third parity
  250. The sequencing of the key genes and end products in the TLR4 signaling pathway from the kidney of Rana dybowskii exposed to Aeromonas hydrophila
  251. Development of a new candidate vaccine against piglet diarrhea caused by Escherichia coli
  252. Plant Sciences
  253. Crown and diameter structure of pure Pinus massoniana Lamb. forest in Hunan province, China
  254. Genetic evaluation and germplasm identification analysis on ITS2, trnL-F, and psbA-trnH of alfalfa varieties germplasm resources
  255. Tissue culture and rapid propagation technology for Gentiana rhodantha
  256. Effects of cadmium on the synthesis of active ingredients in Salvia miltiorrhiza
  257. Cloning and expression analysis of VrNAC13 gene in mung bean
  258. Chlorate-induced molecular floral transition revealed by transcriptomes
  259. Effects of warming and drought on growth and development of soybean in Hailun region
  260. Effects of different light conditions on transient expression and biomass in Nicotiana benthamiana leaves
  261. Comparative analysis of the rhizosphere microbiome and medicinally active ingredients of Atractylodes lancea from different geographical origins
  262. Distinguish Dianthus species or varieties based on chloroplast genomes
  263. Comparative transcriptomes reveal molecular mechanisms of apple blossoms of different tolerance genotypes to chilling injury
  264. Study on fresh processing key technology and quality influence of Cut Ophiopogonis Radix based on multi-index evaluation
  265. An advanced approach for fig leaf disease detection and classification: Leveraging image processing and enhanced support vector machine methodology
  266. Erratum
  267. Erratum to “Protein Z modulates the metastasis of lung adenocarcinoma cells”
  268. Erratum to “BRCA1 subcellular localization regulated by PI3K signaling pathway in triple-negative breast cancer MDA-MB-231 cells and hormone-sensitive T47D cells”
  269. Retraction
  270. Retraction to “Protocatechuic acid attenuates cerebral aneurysm formation and progression by inhibiting TNF-alpha/Nrf-2/NF-kB-mediated inflammatory mechanisms in experimental rats”
https://doi.org/10.1515/biol-2022-0682
Keywords for this article
bladder urothelial carcinoma; G protein-coupled receptors; tumor microenvironment; immune checkpoint; cellular communication; scRNA; immunotherapy
Creative Commons
BY 4.0

Articles in the same Issue

  1. Biomedical Sciences
  2. Systemic investigation of inetetamab in combination with small molecules to treat HER2-overexpressing breast and gastric cancers
  3. Immunosuppressive treatment for idiopathic membranous nephropathy: An updated network meta-analysis
  4. Identifying two pathogenic variants in a patient with pigmented paravenous retinochoroidal atrophy
  5. Effects of phytoestrogens combined with cold stress on sperm parameters and testicular proteomics in rats
  6. A case of pulmonary embolism with bad warfarin anticoagulant effects caused by E. coli infection
  7. Neutrophilia with subclinical Cushing’s disease: A case report and literature review
  8. Isoimperatorin alleviates lipopolysaccharide-induced periodontitis by downregulating ERK1/2 and NF-κB pathways
  9. Immunoregulation of synovial macrophages for the treatment of osteoarthritis
  10. Novel CPLANE1 c.8948dupT (p.P2984Tfs*7) variant in a child patient with Joubert syndrome
  11. Antiphospholipid antibodies and the risk of thrombosis in myeloproliferative neoplasms
  12. Immunological responses of septic rats to combination therapy with thymosin α1 and vitamin C
  13. High glucose and high lipid induced mitochondrial dysfunction in JEG-3 cells through oxidative stress
  14. Pharmacological inhibition of the ubiquitin-specific protease 8 effectively suppresses glioblastoma cell growth
  15. Levocarnitine regulates the growth of angiotensin II-induced myocardial fibrosis cells via TIMP-1
  16. Age-related changes in peripheral T-cell subpopulations in elderly individuals: An observational study
  17. Single-cell transcription analysis reveals the tumor origin and heterogeneity of human bilateral renal clear cell carcinoma
  18. Identification of iron metabolism-related genes as diagnostic signatures in sepsis by blood transcriptomic analysis
  19. Long noncoding RNA ACART knockdown decreases 3T3-L1 preadipocyte proliferation and differentiation
  20. Surgery, adjuvant immunotherapy plus chemotherapy and radiotherapy for primary malignant melanoma of the parotid gland (PGMM): A case report
  21. Dosimetry comparison with helical tomotherapy, volumetric modulated arc therapy, and intensity-modulated radiotherapy for grade II gliomas: A single‑institution case series
  22. Soy isoflavone reduces LPS-induced acute lung injury via increasing aquaporin 1 and aquaporin 5 in rats
  23. Refractory hypokalemia with sexual dysplasia and infertility caused by 17α-hydroxylase deficiency and triple X syndrome: A case report
  24. Meta-analysis of cancer risk among end stage renal disease undergoing maintenance dialysis
  25. 6-Phosphogluconate dehydrogenase inhibition arrests growth and induces apoptosis in gastric cancer via AMPK activation and oxidative stress
  26. Experimental study on the optimization of ANM33 release in foam cells
  27. Primary retroperitoneal angiosarcoma: A case report
  28. Metabolomic analysis-identified 2-hydroxybutyric acid might be a key metabolite of severe preeclampsia
  29. Malignant pleural effusion diagnosis and therapy
  30. Effect of spaceflight on the phenotype and proteome of Escherichia coli
  31. Comparison of immunotherapy combined with stereotactic radiotherapy and targeted therapy for patients with brain metastases: A systemic review and meta-analysis
  32. Activation of hypermethylated P2RY1 mitigates gastric cancer by promoting apoptosis and inhibiting proliferation
  33. Association between the VEGFR-2 -604T/C polymorphism (rs2071559) and type 2 diabetic retinopathy
  34. The role of IL-31 and IL-34 in the diagnosis and treatment of chronic periodontitis
  35. Triple-negative mouse breast cancer initiating cells show high expression of beta1 integrin and increased malignant features
  36. mNGS facilitates the accurate diagnosis and antibiotic treatment of suspicious critical CNS infection in real practice: A retrospective study
  37. The apatinib and pemetrexed combination has antitumor and antiangiogenic effects against NSCLC
  38. Radiotherapy for primary thyroid adenoid cystic carcinoma
  39. Design and functional preliminary investigation of recombinant antigen EgG1Y162–EgG1Y162 against Echinococcus granulosus
  40. Effects of losartan in patients with NAFLD: A meta-analysis of randomized controlled trial
  41. Bibliometric analysis of METTL3: Current perspectives, highlights, and trending topics
  42. Performance comparison of three scaling algorithms in NMR-based metabolomics analysis
  43. PI3K/AKT/mTOR pathway and its related molecules participate in PROK1 silence-induced anti-tumor effects on pancreatic cancer
  44. The altered expression of cytoskeletal and synaptic remodeling proteins during epilepsy
  45. Effects of pegylated recombinant human granulocyte colony-stimulating factor on lymphocytes and white blood cells of patients with malignant tumor
  46. Prostatitis as initial manifestation of Chlamydia psittaci pneumonia diagnosed by metagenome next-generation sequencing: A case report
  47. NUDT21 relieves sevoflurane-induced neurological damage in rats by down-regulating LIMK2
  48. Association of interleukin-10 rs1800896, rs1800872, and interleukin-6 rs1800795 polymorphisms with squamous cell carcinoma risk: A meta-analysis
  49. Exosomal HBV-DNA for diagnosis and treatment monitoring of chronic hepatitis B
  50. Shear stress leads to the dysfunction of endothelial cells through the Cav-1-mediated KLF2/eNOS/ERK signaling pathway under physiological conditions
  51. Interaction between the PI3K/AKT pathway and mitochondrial autophagy in macrophages and the leukocyte count in rats with LPS-induced pulmonary infection
  52. Meta-analysis of the rs231775 locus polymorphism in the CTLA-4 gene and the susceptibility to Graves’ disease in children
  53. Cloning, subcellular localization and expression of phosphate transporter gene HvPT6 of hulless barley
  54. Coptisine mitigates diabetic nephropathy via repressing the NRLP3 inflammasome
  55. Significant elevated CXCL14 and decreased IL-39 levels in patients with tuberculosis
  56. Whole-exome sequencing applications in prenatal diagnosis of fetal bowel dilatation
  57. Gemella morbillorum infective endocarditis: A case report and literature review
  58. An unusual ectopic thymoma clonal evolution analysis: A case report
  59. Severe cumulative skin toxicity during toripalimab combined with vemurafenib following toripalimab alone
  60. Detection of V. vulnificus septic shock with ARDS using mNGS
  61. Novel rare genetic variants of familial and sporadic pulmonary atresia identified by whole-exome sequencing
  62. The influence and mechanistic action of sperm DNA fragmentation index on the outcomes of assisted reproduction technology
  63. Novel compound heterozygous mutations in TELO2 in an infant with You-Hoover-Fong syndrome: A case report and literature review
  64. ctDNA as a prognostic biomarker in resectable CLM: Systematic review and meta-analysis
  65. Diagnosis of primary amoebic meningoencephalitis by metagenomic next-generation sequencing: A case report
  66. Phylogenetic analysis of promoter regions of human Dolichol kinase (DOLK) and orthologous genes using bioinformatics tools
  67. Collagen changes in rabbit conjunctiva after conjunctival crosslinking
  68. Effects of NM23 transfection of human gastric carcinoma cells in mice
  69. Oral nifedipine and phytosterol, intravenous nicardipine, and oral nifedipine only: Three-arm, retrospective, cohort study for management of severe preeclampsia
  70. Case report of hepatic retiform hemangioendothelioma: A rare tumor treated with ultrasound-guided microwave ablation
  71. Curcumin induces apoptosis in human hepatocellular carcinoma cells by decreasing the expression of STAT3/VEGF/HIF-1α signaling
  72. Rare presentation of double-clonal Waldenström macroglobulinemia with pulmonary embolism: A case report
  73. Giant duplication of the transverse colon in an adult: A case report and literature review
  74. Ectopic thyroid tissue in the breast: A case report
  75. SDR16C5 promotes proliferation and migration and inhibits apoptosis in pancreatic cancer
  76. Vaginal metastasis from breast cancer: A case report
  77. Screening of the best time window for MSC transplantation to treat acute myocardial infarction with SDF-1α antibody-loaded targeted ultrasonic microbubbles: An in vivo study in miniswine
  78. Inhibition of TAZ impairs the migration ability of melanoma cells
  79. Molecular complexity analysis of the diagnosis of Gitelman syndrome in China
  80. Effects of maternal calcium and protein intake on the development and bone metabolism of offspring mice
  81. Identification of winter wheat pests and diseases based on improved convolutional neural network
  82. Ultra-multiplex PCR technique to guide treatment of Aspergillus-infected aortic valve prostheses
  83. Virtual high-throughput screening: Potential inhibitors targeting aminopeptidase N (CD13) and PIKfyve for SARS-CoV-2
  84. Immune checkpoint inhibitors in cancer patients with COVID-19
  85. Utility of methylene blue mixed with autologous blood in preoperative localization of pulmonary nodules and masses
  86. Integrated analysis of the microbiome and transcriptome in stomach adenocarcinoma
  87. Berberine suppressed sarcopenia insulin resistance through SIRT1-mediated mitophagy
  88. DUSP2 inhibits the progression of lupus nephritis in mice by regulating the STAT3 pathway
  89. Lung abscess by Fusobacterium nucleatum and Streptococcus spp. co-infection by mNGS: A case series
  90. Genetic alterations of KRAS and TP53 in intrahepatic cholangiocarcinoma associated with poor prognosis
  91. Granulomatous polyangiitis involving the fourth ventricle: Report of a rare case and a literature review
  92. Studying infant mortality: A demographic analysis based on data mining models
  93. Metaplastic breast carcinoma with osseous differentiation: A report of a rare case and literature review
  94. Protein Z modulates the metastasis of lung adenocarcinoma cells
  95. Inhibition of pyroptosis and apoptosis by capsaicin protects against LPS-induced acute kidney injury through TRPV1/UCP2 axis in vitro
  96. TAK-242, a toll-like receptor 4 antagonist, against brain injury by alleviates autophagy and inflammation in rats
  97. Primary mediastinum Ewing’s sarcoma with pleural effusion: A case report and literature review
  98. Association of ADRB2 gene polymorphisms and intestinal microbiota in Chinese Han adolescents
  99. Tanshinone IIA alleviates chondrocyte apoptosis and extracellular matrix degeneration by inhibiting ferroptosis
  100. Study on the cytokines related to SARS-Cov-2 in testicular cells and the interaction network between cells based on scRNA-seq data
  101. Effect of periostin on bone metabolic and autophagy factors during tooth eruption in mice
  102. HP1 induces ferroptosis of renal tubular epithelial cells through NRF2 pathway in diabetic nephropathy
  103. Intravaginal estrogen management in postmenopausal patients with vaginal squamous intraepithelial lesions along with CO2 laser ablation: A retrospective study
  104. Hepatocellular carcinoma cell differentiation trajectory predicts immunotherapy, potential therapeutic drugs, and prognosis of patients
  105. Effects of physical exercise on biomarkers of oxidative stress in healthy subjects: A meta-analysis of randomized controlled trials
  106. Identification of lysosome-related genes in connection with prognosis and immune cell infiltration for drug candidates in head and neck cancer
  107. Development of an instrument-free and low-cost ELISA dot-blot test to detect antibodies against SARS-CoV-2
  108. Research progress on gas signal molecular therapy for Parkinson’s disease
  109. Adiponectin inhibits TGF-β1-induced skin fibroblast proliferation and phenotype transformation via the p38 MAPK signaling pathway
  110. The G protein-coupled receptor-related gene signatures for predicting prognosis and immunotherapy response in bladder urothelial carcinoma
  111. α-Fetoprotein contributes to the malignant biological properties of AFP-producing gastric cancer
  112. CXCL12/CXCR4/CXCR7 axis in placenta tissues of patients with placenta previa
  113. Association between thyroid stimulating hormone levels and papillary thyroid cancer risk: A meta-analysis
  114. Significance of sTREM-1 and sST2 combined diagnosis for sepsis detection and prognosis prediction
  115. Diagnostic value of serum neuroactive substances in the acute exacerbation of chronic obstructive pulmonary disease complicated with depression
  116. Research progress of AMP-activated protein kinase and cardiac aging
  117. TRIM29 knockdown prevented the colon cancer progression through decreasing the ubiquitination levels of KRT5
  118. Cross-talk between gut microbiota and liver steatosis: Complications and therapeutic target
  119. Metastasis from small cell lung cancer to ovary: A case report
  120. The early diagnosis and pathogenic mechanisms of sepsis-related acute kidney injury
  121. The effect of NK cell therapy on sepsis secondary to lung cancer: A case report
  122. Erianin alleviates collagen-induced arthritis in mice by inhibiting Th17 cell differentiation
  123. Loss of ACOX1 in clear cell renal cell carcinoma and its correlation with clinical features
  124. Signalling pathways in the osteogenic differentiation of periodontal ligament stem cells
  125. Crosstalk between lactic acid and immune regulation and its value in the diagnosis and treatment of liver failure
  126. Clinicopathological features and differential diagnosis of gastric pleomorphic giant cell carcinoma
  127. Traumatic brain injury and rTMS-ERPs: Case report and literature review
  128. Extracellular fibrin promotes non-small cell lung cancer progression through integrin β1/PTEN/AKT signaling
  129. Knockdown of DLK4 inhibits non-small cell lung cancer tumor growth by downregulating CKS2
  130. The co-expression pattern of VEGFR-2 with indicators related to proliferation, apoptosis, and differentiation of anagen hair follicles
  131. Inflammation-related signaling pathways in tendinopathy
  132. CD4+ T cell count in HIV/TB co-infection and co-occurrence with HL: Case report and literature review
  133. Clinical analysis of severe Chlamydia psittaci pneumonia: Case series study
  134. Bioinformatics analysis to identify potential biomarkers for the pulmonary artery hypertension associated with the basement membrane
  135. Influence of MTHFR polymorphism, alone or in combination with smoking and alcohol consumption, on cancer susceptibility
  136. Catharanthus roseus (L.) G. Don counteracts the ampicillin resistance in multiple antibiotic-resistant Staphylococcus aureus by downregulation of PBP2a synthesis
  137. Combination of a bronchogenic cyst in the thoracic spinal canal with chronic myelocytic leukemia
  138. Bacterial lipoprotein plays an important role in the macrophage autophagy and apoptosis induced by Salmonella typhimurium and Staphylococcus aureus
  139. TCL1A+ B cells predict prognosis in triple-negative breast cancer through integrative analysis of single-cell and bulk transcriptomic data
  140. Ezrin promotes esophageal squamous cell carcinoma progression via the Hippo signaling pathway
  141. Ferroptosis: A potential target of macrophages in plaque vulnerability
  142. Predicting pediatric Crohn's disease based on six mRNA-constructed risk signature using comprehensive bioinformatic approaches
  143. Applications of genetic code expansion and photosensitive UAAs in studying membrane proteins
  144. HK2 contributes to the proliferation, migration, and invasion of diffuse large B-cell lymphoma cells by enhancing the ERK1/2 signaling pathway
  145. IL-17 in osteoarthritis: A narrative review
  146. Circadian cycle and neuroinflammation
  147. Probiotic management and inflammatory factors as a novel treatment in cirrhosis: A systematic review and meta-analysis
  148. Hemorrhagic meningioma with pulmonary metastasis: Case report and literature review
  149. SPOP regulates the expression profiles and alternative splicing events in human hepatocytes
  150. Knockdown of SETD5 inhibited glycolysis and tumor growth in gastric cancer cells by down-regulating Akt signaling pathway
  151. PTX3 promotes IVIG resistance-induced endothelial injury in Kawasaki disease by regulating the NF-κB pathway
  152. Pancreatic ectopic thyroid tissue: A case report and analysis of literature
  153. The prognostic impact of body mass index on female breast cancer patients in underdeveloped regions of northern China differs by menopause status and tumor molecular subtype
  154. Report on a case of liver-originating malignant melanoma of unknown primary
  155. Case report: Herbal treatment of neutropenic enterocolitis after chemotherapy for breast cancer
  156. The fibroblast growth factor–Klotho axis at molecular level
  157. Characterization of amiodarone action on currents in hERG-T618 gain-of-function mutations
  158. A case report of diagnosis and dynamic monitoring of Listeria monocytogenes meningitis with NGS
  159. Effect of autologous platelet-rich plasma on new bone formation and viability of a Marburg bone graft
  160. Small breast epithelial mucin as a useful prognostic marker for breast cancer patients
  161. Continuous non-adherent culture promotes transdifferentiation of human adipose-derived stem cells into retinal lineage
  162. Nrf3 alleviates oxidative stress and promotes the survival of colon cancer cells by activating AKT/BCL-2 signal pathway
  163. Favorable response to surufatinib in a patient with necrolytic migratory erythema: A case report
  164. Case report of atypical undernutrition of hypoproteinemia type
  165. Down-regulation of COL1A1 inhibits tumor-associated fibroblast activation and mediates matrix remodeling in the tumor microenvironment of breast cancer
  166. Sarcoma protein kinase inhibition alleviates liver fibrosis by promoting hepatic stellate cells ferroptosis
  167. Research progress of serum eosinophil in chronic obstructive pulmonary disease and asthma
  168. Clinicopathological characteristics of co-existing or mixed colorectal cancer and neuroendocrine tumor: Report of five cases
  169. Role of menopausal hormone therapy in the prevention of postmenopausal osteoporosis
  170. Precisional detection of lymph node metastasis using tFCM in colorectal cancer
  171. Advances in diagnosis and treatment of perimenopausal syndrome
  172. A study of forensic genetics: ITO index distribution and kinship judgment between two individuals
  173. Acute lupus pneumonitis resembling miliary tuberculosis: A case-based review
  174. Plasma levels of CD36 and glutathione as biomarkers for ruptured intracranial aneurysm
  175. Fractalkine modulates pulmonary angiogenesis and tube formation by modulating CX3CR1 and growth factors in PVECs
  176. Novel risk prediction models for deep vein thrombosis after thoracotomy and thoracoscopic lung cancer resections, involving coagulation and immune function
  177. Exploring the diagnostic markers of essential tremor: A study based on machine learning algorithms
  178. Evaluation of effects of small-incision approach treatment on proximal tibia fracture by deep learning algorithm-based magnetic resonance imaging
  179. An online diagnosis method for cancer lesions based on intelligent imaging analysis
  180. Medical imaging in rheumatoid arthritis: A review on deep learning approach
  181. Predictive analytics in smart healthcare for child mortality prediction using a machine learning approach
  182. Utility of neutrophil–lymphocyte ratio and platelet–lymphocyte ratio in predicting acute-on-chronic liver failure survival
  183. A biomedical decision support system for meta-analysis of bilateral upper-limb training in stroke patients with hemiplegia
  184. TNF-α and IL-8 levels are positively correlated with hypobaric hypoxic pulmonary hypertension and pulmonary vascular remodeling in rats
  185. Stochastic gradient descent optimisation for convolutional neural network for medical image segmentation
  186. Comparison of the prognostic value of four different critical illness scores in patients with sepsis-induced coagulopathy
  187. Application and teaching of computer molecular simulation embedded technology and artificial intelligence in drug research and development
  188. Hepatobiliary surgery based on intelligent image segmentation technology
  189. Value of brain injury-related indicators based on neural network in the diagnosis of neonatal hypoxic-ischemic encephalopathy
  190. Analysis of early diagnosis methods for asymmetric dementia in brain MR images based on genetic medical technology
  191. Early diagnosis for the onset of peri-implantitis based on artificial neural network
  192. Clinical significance of the detection of serum IgG4 and IgG4/IgG ratio in patients with thyroid-associated ophthalmopathy
  193. Forecast of pain degree of lumbar disc herniation based on back propagation neural network
  194. SPA-UNet: A liver tumor segmentation network based on fused multi-scale features
  195. Systematic evaluation of clinical efficacy of CYP1B1 gene polymorphism in EGFR mutant non-small cell lung cancer observed by medical image
  196. Rehabilitation effect of intelligent rehabilitation training system on hemiplegic limb spasms after stroke
  197. A novel approach for minimising anti-aliasing effects in EEG data acquisition
  198. ErbB4 promotes M2 activation of macrophages in idiopathic pulmonary fibrosis
  199. Clinical role of CYP1B1 gene polymorphism in prediction of postoperative chemotherapy efficacy in NSCLC based on individualized health model
  200. Lung nodule segmentation via semi-residual multi-resolution neural networks
  201. Evaluation of brain nerve function in ICU patients with Delirium by deep learning algorithm-based resting state MRI
  202. A data mining technique for detecting malignant mesothelioma cancer using multiple regression analysis
  203. Markov model combined with MR diffusion tensor imaging for predicting the onset of Alzheimer’s disease
  204. Effectiveness of the treatment of depression associated with cancer and neuroimaging changes in depression-related brain regions in patients treated with the mediator-deuterium acupuncture method
  205. Molecular mechanism of colorectal cancer and screening of molecular markers based on bioinformatics analysis
  206. Monitoring and evaluation of anesthesia depth status data based on neuroscience
  207. Exploring the conformational dynamics and thermodynamics of EGFR S768I and G719X + S768I mutations in non-small cell lung cancer: An in silico approaches
  208. Optimised feature selection-driven convolutional neural network using gray level co-occurrence matrix for detection of cervical cancer
  209. Incidence of different pressure patterns of spinal cerebellar ataxia and analysis of imaging and genetic diagnosis
  210. Pathogenic bacteria and treatment resistance in older cardiovascular disease patients with lung infection and risk prediction model
  211. Adoption value of support vector machine algorithm-based computed tomography imaging in the diagnosis of secondary pulmonary fungal infections in patients with malignant hematological disorders
  212. From slides to insights: Harnessing deep learning for prognostic survival prediction in human colorectal cancer histology
  213. Ecology and Environmental Science
  214. Monitoring of hourly carbon dioxide concentration under different land use types in arid ecosystem
  215. Comparing the differences of prokaryotic microbial community between pit walls and bottom from Chinese liquor revealed by 16S rRNA gene sequencing
  216. Effects of cadmium stress on fruits germination and growth of two herbage species
  217. Bamboo charcoal affects soil properties and bacterial community in tea plantations
  218. Optimization of biogas potential using kinetic models, response surface methodology, and instrumental evidence for biodegradation of tannery fleshings during anaerobic digestion
  219. Understory vegetation diversity patterns of Platycladus orientalis and Pinus elliottii communities in Central and Southern China
  220. Studies on macrofungi diversity and discovery of new species of Abortiporus from Baotianman World Biosphere Reserve
  221. Food Science
  222. Effect of berrycactus fruit (Myrtillocactus geometrizans) on glutamate, glutamine, and GABA levels in the frontal cortex of rats fed with a high-fat diet
  223. Guesstimate of thymoquinone diversity in Nigella sativa L. genotypes and elite varieties collected from Indian states using HPTLC technique
  224. Analysis of bacterial community structure of Fuzhuan tea with different processing techniques
  225. Untargeted metabolomics reveals sour jujube kernel benefiting the nutritional value and flavor of Morchella esculenta
  226. Mycobiota in Slovak wine grapes: A case study from the small Carpathians wine region
  227. Elemental analysis of Fadogia ancylantha leaves used as a nutraceutical in Mashonaland West Province, Zimbabwe
  228. Microbiological transglutaminase: Biotechnological application in the food industry
  229. Influence of solvent-free extraction of fish oil from catfish (Clarias magur) heads using a Taguchi orthogonal array design: A qualitative and quantitative approach
  230. Chromatographic analysis of the chemical composition and anticancer activities of Curcuma longa extract cultivated in Palestine
  231. The potential for the use of leghemoglobin and plant ferritin as sources of iron
  232. Investigating the association between dietary patterns and glycemic control among children and adolescents with T1DM
  233. Bioengineering and Biotechnology
  234. Biocompatibility and osteointegration capability of β-TCP manufactured by stereolithography 3D printing: In vitro study
  235. Clinical characteristics and the prognosis of diabetic foot in Tibet: A single center, retrospective study
  236. Agriculture
  237. Biofertilizer and NPSB fertilizer application effects on nodulation and productivity of common bean (Phaseolus vulgaris L.) at Sodo Zuria, Southern Ethiopia
  238. On correlation between canopy vegetation and growth indexes of maize varieties with different nitrogen efficiencies
  239. Exopolysaccharides from Pseudomonas tolaasii inhibit the growth of Pleurotus ostreatus mycelia
  240. A transcriptomic evaluation of the mechanism of programmed cell death of the replaceable bud in Chinese chestnut
  241. Melatonin enhances salt tolerance in sorghum by modulating photosynthetic performance, osmoregulation, antioxidant defense, and ion homeostasis
  242. Effects of plant density on alfalfa (Medicago sativa L.) seed yield in western Heilongjiang areas
  243. Identification of rice leaf diseases and deficiency disorders using a novel DeepBatch technique
  244. Artificial intelligence and internet of things oriented sustainable precision farming: Towards modern agriculture
  245. Animal Sciences
  246. Effect of ketogenic diet on exercise tolerance and transcriptome of gastrocnemius in mice
  247. Combined analysis of mRNA–miRNA from testis tissue in Tibetan sheep with different FecB genotypes
  248. Isolation, identification, and drug resistance of a partially isolated bacterium from the gill of Siniperca chuatsi
  249. Tracking behavioral changes of confined sows from the first mating to the third parity
  250. The sequencing of the key genes and end products in the TLR4 signaling pathway from the kidney of Rana dybowskii exposed to Aeromonas hydrophila
  251. Development of a new candidate vaccine against piglet diarrhea caused by Escherichia coli
  252. Plant Sciences
  253. Crown and diameter structure of pure Pinus massoniana Lamb. forest in Hunan province, China
  254. Genetic evaluation and germplasm identification analysis on ITS2, trnL-F, and psbA-trnH of alfalfa varieties germplasm resources
  255. Tissue culture and rapid propagation technology for Gentiana rhodantha
  256. Effects of cadmium on the synthesis of active ingredients in Salvia miltiorrhiza
  257. Cloning and expression analysis of VrNAC13 gene in mung bean
  258. Chlorate-induced molecular floral transition revealed by transcriptomes
  259. Effects of warming and drought on growth and development of soybean in Hailun region
  260. Effects of different light conditions on transient expression and biomass in Nicotiana benthamiana leaves
  261. Comparative analysis of the rhizosphere microbiome and medicinally active ingredients of Atractylodes lancea from different geographical origins
  262. Distinguish Dianthus species or varieties based on chloroplast genomes
  263. Comparative transcriptomes reveal molecular mechanisms of apple blossoms of different tolerance genotypes to chilling injury
  264. Study on fresh processing key technology and quality influence of Cut Ophiopogonis Radix based on multi-index evaluation
  265. An advanced approach for fig leaf disease detection and classification: Leveraging image processing and enhanced support vector machine methodology
  266. Erratum
  267. Erratum to “Protein Z modulates the metastasis of lung adenocarcinoma cells”
  268. Erratum to “BRCA1 subcellular localization regulated by PI3K signaling pathway in triple-negative breast cancer MDA-MB-231 cells and hormone-sensitive T47D cells”
  269. Retraction
  270. Retraction to “Protocatechuic acid attenuates cerebral aneurysm formation and progression by inhibiting TNF-alpha/Nrf-2/NF-kB-mediated inflammatory mechanisms in experimental rats”
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