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Pyroptosis-based risk score predicts prognosis and drug sensitivity in lung adenocarcinoma

  • Zhengsong Jiang , Xiang Wang , Jinghan Huang , Guoyin Li EMAIL logo and Shangfu Li EMAIL logo
Published/Copyright: March 13, 2023
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Open Medicine
From the journal Open Medicine Volume 18 Issue 1

Abstract

Pyroptosis is a recently identified form of programmed cell death; however, its role in lung adenocarcinoma (LUAD) remains unclear. Therefore, we set out to explore the prognostic potential of pyroptosis-related genes in LUAD. The pyroptosis-related risk score (PRRS) was developed by least absolute shrinkage and selection operator Cox regression and multivariate Cox regression. We found that PRRS was an independent prognostic factor for LUAD. LUAD patients in the high-PRRS group showed a significantly shorter overall survival (OS) and enriched in cell proliferation-related pathways. Then pathway enrichment analyses, mutation profile, tumor microenvironment, and drug sensitivity analysis were further studied in PRRS stratified LUAD patients. Tumor purity (TP) analyses revealed that L-PRRS LUAD patients had a lower TP, and patients in L-TP + L-PRRS subgroup had the most prolonged OS. Mutation analyses suggested that the L-PRRS LUAD patients had a lower tumor mutation burden (TMB), and patients in H-TMB + L-PRRS subgroup had the most prolonged OS. Drug sensitivity analyses showed that PRRS was significantly negatively correlated with the sensitivity of cisplatin, besarotene, etc., while it was significantly positively correlated with the sensitivity of kin001-135. Eventually, a nomogram was constructed based on PRRS and clinical characters of LUAD. Overall, the pyroptosis-related signature is helpful for prognostic prediction and in guiding treatment for LUAD patients.

Keywords: pyroptosis; lung adenocarcinoma; tumor microenvironment; tumor mutation burden; drug sensitivity

1 Introduction

Lung cancer (LC) is the leading cause of death among all cancer types, with an estimated 1.8 million deaths annually, which means one in five cancer-related deaths results from it. It is the most common cancer in males and is primarily distributed in Eastern Europe, Eastern Asia, and Southern Europe [1]. LC can be classified into two types: small cell lung carcinoma (SCLC) and non-small-cell lung carcinoma (NSCLC), with a percentage of 15 and 85%, respectively [2]. NSCLC can be further subtyped as squamous-cell carcinoma, adenocarcinoma, and large-cell carcinoma, among which lung adenocarcinoma (LUAD) is the most common, comprising about 40% of all LC [3]. In addition to surgical resection and radiotherapy, systemic treatments for NSCLC include traditional chemotherapy (cytotoxic agents), targeted therapies (tyrosine-kinase inhibitors or TKIs) and immunotherapy (immune checkpoint inhibitors or ICIs) [4,5]. Although great success has been achieved in the clinical application of TKIs and CTLA-4/PD-1/PD-L1 blockers, resistance remains the major challenge. Studies have shown that only 14–45% of patients exhibited significant pathological response when ICI therapy is applied [2,6]. Therefore, indicators that can predict responses to immunotherapy would greatly benefit the effective treatment of NSCLC. Nowadays, the incoming new concept precision medicine has also called for the need to subtype cancer according to molecular features. However, current biomarkers showing the response to ICIs are PD-L1 expression in tumor tissues and tumor mutational burden (TMB), which have inherent shortcomings [7]. Not all patients with a PD-L1 expression proportion higher than the 50% cutoff showed a response to anti-PD-1/PD-L1 antibodies, and some patients below that cutoff expression responded to the treatment [8–10]. Besides, differential expressions within a single lesion also contribute to the discordance between PD-L1 expression and treatment response [11]. Despite NSCLC patients with high TMB being associated with better response to ICIs [12], TMB cannot well predict the overall survival (OS) after ICIs treatment [7]. Hence, new biomarkers that indicate response to ICI treatment and predict prognosis are urgently needed.

Pyroptosis, defined as gasdermin-mediated pro-inflammatory programmed death [13,14], is emerging as a hot topic and has drawn researchers’ interest worldwide. Different from apoptosis or necrosis, pyroptosis has its unique mechanism and characteristics. In the canonical pathway, it begins with the assembly of inflammasome, which takes place after pattern recognition receptors recognize signals from bacteria, viruses, etc. [15]. Subsequently, gasdermins are cleaved by caspases or granzymes. The N-terminal poreforming domain is separated from the C-terminal repressor domain and functions by forming pores in the cell membrane, leading to the release of inflammation mediators, including IL-1β and IL-18, and cell death [16]. Accumulating studies have recognized the two-sided role of pyroptosis in tumorigenesis and cancer progression. Gasdermin D (GSDMD) was found to be up-regulated in NSCLC and promote tumor growth [17]. Besides, both paclitaxel and cisplatin can induce pyroptosis [18], and cisplatin-sensitive NSCLC cells had higher expression of inflammasome components than cisplatin-resistant cells [19]. Moreover, pyroptosis is closely linked with anti-cancer immunity and immunotherapy response [20,21]. Synergistic effects were observed when giving ICIs and gasdermin treatment simultaneously [22].

Given the above facts, it is reasonable to speculate that pyroptosis-related genes (PRGs) might have prognostic values and indicate drug resistance. Over the years, there is a growing body of literature that investigated the application potential of PRGs and constructed different forms of pyroptosis-related risk score (PRRS) in various types of cancer [23–29]. Thanks to high-throughput sequencing, microarray, and establishment of public datasets, it is possible to make a thorough bioinformatics analysis based on the combination of previous data. Therefore, our study aims to utilize data from TCGA and GEO to screen PRGs that are associated with the prognosis of LUAD patients and construct a risk score based on the expression of those genes. Then we analyze the association of the risk score with prognosis, tumor microenvironment (TME), TMB, and drug sensitivity, attempting to broaden the clinical application of the risk score. Eventually, we established a nomogram based on PRRS and clinical characters that can effectively predict the prognosis of LUAD patients.

2 Materials and methods

2.1 Data acquisition and processing

The LUAD projects of the TCGA (TCGA_LUAD), GSE31210, GSE41271, GSE42127, GSE68465, and GSE72094 datasets were obtained from public databases and were processed as described in our previous study [30]. Briefly, normalized RNA-seq data (HTSeq-FPKM) of the TCGA-LUAD cohort were used for analyses with no further transformation and normalization. The gene expression data (series matrix file) downloaded from the GEO database were normalized (if required) by the normalizeBetweenArrays function of the “limma” package in R. The mutation data of the TCGA_LUAD cohort were downloaded, processed, and visualized as reported in Song’s study [31]. All datasets used in this work were downloaded from public databases, and an extra ethical approval was not necessary.

2.2 Development of PRRS

The COX regression analysis was used to identify the PRGs that were significantly related to the prognosis of patients, and patients were divided into C1 and C2 clusters by the consistent cluster analysis according to their expression levels. Patients from the TCGA_LUAD cohort were divided into two clusters, and the “limma” package in R software was used for differential expression analysis between them (log FC ≥ 1, FDR ≤ 0.05). Univariate Cox regression analysis was performed for these differentially expressed genes to generate genes associated with prognosis (p < 0.01). The above generated genes were input into the least absolute contraction and selection operator (LASSO) regression mode, which generated 14 key genes, and their corresponding coefficients were obtained by multi-variate cox analysis. A new score for each patient was calculated by the formula as follows: score = ∑ i Coefficient(Gene i) Expression(Gene i). To facilitate comparison across different LUAD cohorts, the PRRS was calculated with the formula as follows: PRRS = (score-Min)/absolute (Max) [32,33]. The TCGA_LUAD cohort was used as the training set, and GSE31210, GSE41271, GSE42127, GSE68465, and GSE72094 cohorts were used as the validation sets.

2.3 Enrichment analysis

In the TCGA_LUAD cohort, a total of 128 differentially expressed genes were identified between high-PRRS (H-PRRS) and low-PRRS (L-PRRS) subgroups. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis of the 128 genes in the TCGA_LUAD cohort were performed by the “clusterProfiler,” “org.Hs.eg.db,” “DOSE,” and “enrichplot” packages in R software [34]. Gene Set Enrichment Analysis (GSEA) of PRRS-based classification of LUAD patients was performed by “c2.cp.kegg.symbols.gmt” package in R software [32].

2.4 Immune profile and mutation profile analysis

TME score of patients from the TCGA_LUAD cohort was calculated using the “estimate” package in R software. The infiltration ratio of 22 types of immune cells in TME was calculated by the CIBERSORT algorithm in R software [35]. The TMB and the mutant-allele tumor heterogeneity score were calculated by the package “maftools” in R software [36].

2.5 Drug sensitivity analysis

Immunotherapy data of patients in the TCGA_LUAD cohort were downloaded from The Cancer Immunome Atlas (https://tcia.at/). Drug sensitivity analysis was performed by the “prrophetic” package in R software.

2.6 Development and evaluation of the nomogram

Univariate and multivariate Cox regression analyses were performed using the “survival” package in R. The nomogram was performed using the “rsm” package in R. Calibration curve was used to evaluate the accuracy of the nomogram.

2.7 Statistical analysis

The data were analyzed by R software (version 4.1.0). The “limma” package was used for differential expression analysis between the two clusters. The “limma,” “survival,” and “ConsensusClusterPlus” packages were used for the consistent cluster analysis. The univariate Cox regression analysis was performed by the “survival” package. The LASSO regression model was developed by “glmnet” and “survival” packages. Survival analysis was executed by “survival” and “survminer” packages. ROC curves were drawn by “survival,” “survminer,” “timeROC,” and “rms” packages. The C-index value was calculated by “dplyr,” “survival” “rms,” and “pec” packages. The nomogram was drawn by “survival,” “regplot,” “survminer,” “timeROC,” and “rms” packages. A value of p < 0.05 was considered to be statistically significant (*, p < 0.05; **, p < 0.01; ***, p < 0.001).

3 Results

3.1 The construction and predictive analysis of pyroptosis-related LUAD subtypes

According to Hu’s study [37], we screened 52 PRGs in the TCGA_LUAD dataset (Figure S1; Table S1) and found that 17 genes were down-regulated and 26 genes were up-regulated in tumor tissues compared to normal tissues (Figure S1; Table S2; p < 0.05). This result revealed that the expression of PRGs was dysregulated in LUAD. Subsequently, we performed a consistent cluster analysis using 52 PRGs on patients from the TCGA_LUAD cohort. To confirm that PRG can effectively distinguish patients, we increased the clustering variable (k) from 2 to 10. The results showed that at k = 2, the intragroup correlations were low, indicating that cases could be well split into two categories (Figure 1a–c). According to the PRGs, patients from TCGA_LUAD, GSE31210, and GSE41271 cohorts were divided into two clusters, respectively. Kaplan–Meier (KM) analysis suggested that patients in the C2 cluster had a more prolonged OS time in all three cohorts (Figure 1d and f). These results suggested that the expression level of PRGs was closely related to the prognosis of LUAD patients.

Figure 1 Classification and prognosis of LUAD according to the PRGs. (a) Two clusters were generated by unsupervised consensus clustering. (b and c) Consensus clustering cumulative distribution function (CDF) and relative change in area under the CDF curve (k from 2 to 10). (d–f) KM analysis showed that patients in the C2 cluster had a longer OS in the TCGA_LUAD (d), GSE31210 (e), and GSE41271 (f) cohorts.
Figure 1

Classification and prognosis of LUAD according to the PRGs. (a) Two clusters were generated by unsupervised consensus clustering. (b and c) Consensus clustering cumulative distribution function (CDF) and relative change in area under the CDF curve (k from 2 to 10). (d–f) KM analysis showed that patients in the C2 cluster had a longer OS in the TCGA_LUAD (d), GSE31210 (e), and GSE41271 (f) cohorts.

3.2 Construction and validation of PRRS

Patients from the TCGA_LUAD cohort were used as the training set to develop the pyroptosis-related risk models. First, patients were classified into C1 and C2 clusters according to PRGs. Second, we performed differential gene analysis on the two clusters and generated 567 differentially expressed genes (log FC > 1; FDR < 0.05). Third, we carried out a univariate Cox regression analysis on the 567 genes and identified 125 genes with significant prognostic correlation (p < 0.01). Finally, the 125 genes were put into a LASSO regression model and obtained 14 crucial genes and their corresponding coefficients (Figure 2a and b). The score of each patient in a cohort was calculated by the following formula: score = 0.0247 * SLC16A1 + 0.0355 * ARL14 − 0.0081 * CFTR + 0.0251 * CDKN3 − 0.0026 * SERPIND1 + 0.052 * IGFBP1 − 0.0351 * CA4 − 0.0443 * P2RY13 − 0.0708 * C6 − 0.0462 * ZNF493 + 0.0753 * PKP2 + 0.0982 * DKK1 − 0.0466 * MS4A1 + 0.0319 * KYNU. The PRRS of patients was calculated as reported in Section 2.

Figure 2 Construction of PRRS using TCGA_LUAD dataset. (a and b) LASSO Cox regression model was constructed from 125 prognosis-related genes. The 14 crucial genes were generated by the best-fit profile. (c) Distribution and cutoff value of the PRRS. (d) OS and survival status of patients in H-PRRS and L-PRRS groups. (e) Expression heatmap of the 14 crucial genes in the TCGA_LUAD dataset.
Figure 2

Construction of PRRS using TCGA_LUAD dataset. (a and b) LASSO Cox regression model was constructed from 125 prognosis-related genes. The 14 crucial genes were generated by the best-fit profile. (c) Distribution and cutoff value of the PRRS. (d) OS and survival status of patients in H-PRRS and L-PRRS groups. (e) Expression heatmap of the 14 crucial genes in the TCGA_LUAD dataset.

Patients were equally assigned to H-PRRS and L-PRRS groups (Figure 2c and d). KM analysis showed that patients from the L-PRRS had significantly longer OS (Figure 3a). The AUC values of PRRS in the TCGA_LUAD dataset were 0.769 for 1 year, 0.741 for 2 years, and 0.706 for 3 years (Figure 3g). In the five external validation datasets (GSE31210, GSE41271, GSE42127, GSE68465, and GSE72094 cohorts), patients were equally divided into H-PRRS and L-PRRS groups based on the value of PRRS in each cohort. In all of the five validation cohorts, patients from the L-PRRS groups had significantly longer OS than that in the H-PRRS groups, which was highly consistent with the training cohort (Figure 3b–f). The area under curve (AUC) values of PRRS in the GSE31210 cohort were 0.699 for 1 year, 0.695 for 2 years, and 0.592 for 3 years; were 0.671 for 1 year, 0.674 for 2 years, and 0.64 for 3 years in the GSE41271 cohort; were 0.747 for 1 year, 0.731 for 2 years, and 0.662 for 3 years in the GSE42127 cohort; were 0.682 for 1 year, 0.662 for 2 years, and 0.653 for 3 years in the GSE68465 cohort, and were 0.769 for 1 year, 0.741 for 2 years, and 0.706 for 3 years in the GSE72094 cohort (Figure 3h–l). The calibration curves confirmed that the PRRS could reasonably predict the prognosis of patients in both the training and validation cohorts (Figure 3m–r). The principal component analysis (PCA) results showed that PRRS could effectively distinguish H-PRRS and lL-PRRS patients in both the training and validation datasets (Figure 3s–x). The aforementioned results confirmed that PRRS was an excellent prognostic indicator of LUAD.

Figure 3 Evaluation of the effectiveness of PRRS in the training and verification datasets. (a–f) KM survival curves of OS in training (a) and validation (b–f) datasets. (g–l) ROC curves evaluate the effectiveness of PRRS in training (g) and validation (h–l) datasets. (m–r) Calibration curves for evaluating the accuracy of PRRS in training (m) and validation (n–r) datasets. (s–x) PCA results of patients from the training (s) and validation (t–x) datasets according to PRRS.
Figure 3

Evaluation of the effectiveness of PRRS in the training and verification datasets. (a–f) KM survival curves of OS in training (a) and validation (b–f) datasets. (g–l) ROC curves evaluate the effectiveness of PRRS in training (g) and validation (h–l) datasets. (m–r) Calibration curves for evaluating the accuracy of PRRS in training (m) and validation (n–r) datasets. (s–x) PCA results of patients from the training (s) and validation (t–x) datasets according to PRRS.

To investigate the potential molecular mechanism of prognosis difference between H-PRRS and L-PRRS subgroups, we performed GSEA using the TCGA_LUAD dataset. The results suggested that the H-PRRS subgroup was enriched in cell cycle, DNA replication, proteasome, spliceosome, and steroid hormone biosynthesis pathways. In contrast the L-PRRS subgroup was enriched in allograft rejection, asthma, intestinal immune network for IgA production, systemic lupus erythematosus, and viral myocarditis pathways (Figure 4a and b). We obtained 128 differentially expressed genes (log FC > 1; FDR < 0.05) from H-PRRS and L-PRRS groups using the “limma” package, and performed GO and KEGG analysis. GO and KEGG analysis results suggested that the above differentially expressed genes were mainly enriched in humoral immune response-related pathways, and regulated humoral response (Figure 4c and d).

Figure 4 Enrichment analysis of PRRS-based LUAD groups. (a and b) GSEA of the H-PRRS and L-PRRS groups in the TCGA_LUAD cohort. (c and d) GO and KEGG enrichment analysis of 128 differentially expressed genes between the H-PRRS and L-PRRS groups in the TCGA_LUAD cohort.
Figure 4

Enrichment analysis of PRRS-based LUAD groups. (a and b) GSEA of the H-PRRS and L-PRRS groups in the TCGA_LUAD cohort. (c and d) GO and KEGG enrichment analysis of 128 differentially expressed genes between the H-PRRS and L-PRRS groups in the TCGA_LUAD cohort.

3.3 TME landscape of PRRS-based classification

TME provides a favorable environment for tumor progression and is closely related to the treatment and prognosis of various tumors [38]. Tumor purity can act as a powerful prognostic indicator for various carcinomas [39–41]. In the TCGA_LUAD cohort, we found that the stromal score or the immune score of patients in the H-PRRS subgroup was significantly lower than that in the L-PRRS subgroup, while the tumor purity was the opposite (Figure 5a and b). We noticed that in the TCGA_LUAD, GSE41271, GSE42127, and GSE72094 cohorts, the infiltration ratios of immune cells such as aDCs, B cells, iDCs, mast cells, neutrophils, T helper cells, and TIL significantly reduced in the H-PRRS subgroup (Figure S1a–d). In addition, correlation analysis confirmed that T cells CD4 memory resting/activated, macrophages M0/M1, dendritic cells resting/activated, and B cells memory were significantly co-expressed with most of the 14 crucial genes (Figure S2).

Figure 5 Tumor purity combined with PRRS to evaluate the prognosis of LUAD patients. (a) The immune, stromal, and ESTIMATE scores of the L-PRRS group were higher than the H-PRRS group (p < 0.01). (b) The tumor purity of the L-PRRS group was lower than the H-PRRS group (p < 0.001). (c, e, g, i) In the TCGA_LUAD (c), GSE41271 (e), GSE42127 (g), and GSE72094 (i) cohorts, patients in the L-TP groups had a longer OS than the H-TP group (p ≤ 0.01). (d, f, h, j) In the TCGA_LUAD (d), GSE41271 (f), GSE42127 (h), and GSE72094 (j) cohorts, patients in the L-TP + L-PRRS groups had the best prognosis, while the H-TP + H-PRRS had the worst prognosis. **, p < 0.01; ***, p < 0.001; L-TP: low tumor purity; H-TP: high tumor purity; L-PRRS: low PRRS; H-PRRS: high PRRS.
Figure 5

Tumor purity combined with PRRS to evaluate the prognosis of LUAD patients. (a) The immune, stromal, and ESTIMATE scores of the L-PRRS group were higher than the H-PRRS group (p < 0.01). (b) The tumor purity of the L-PRRS group was lower than the H-PRRS group (p < 0.001). (c, e, g, i) In the TCGA_LUAD (c), GSE41271 (e), GSE42127 (g), and GSE72094 (i) cohorts, patients in the L-TP groups had a longer OS than the H-TP group (p ≤ 0.01). (d, f, h, j) In the TCGA_LUAD (d), GSE41271 (f), GSE42127 (h), and GSE72094 (j) cohorts, patients in the L-TP + L-PRRS groups had the best prognosis, while the H-TP + H-PRRS had the worst prognosis. **, p < 0.01; ***, p < 0.001; L-TP: low tumor purity; H-TP: high tumor purity; L-PRRS: low PRRS; H-PRRS: high PRRS.

In the above four datasets, we also identified that the function of HLA and type II IFN response was significantly down-regulated in the HPRRS subgroup (Figure S3a–d). In the four datasets, KM analysis showed that the OS of patients in the low tumor purity (L-TP) group was significantly longer than that in the high tumor purity (H-TP) group (Figure 5c, e, g, and i). In the four cohorts, we comprehensively analyzed PRRS and tumor purity and found that patients in L-TP + L-PRRS group had the best prognosis, and patients in H-TP + H-PRRS group had the worst prognosis (Figure 5d, f, h, and j). The above results suggested that PRRS was closely related to tumor purity and patient prognosis.

3.4 Tumor mutation burden (TMB) of PRRS-based classification

Previous studies have shown that TMB can be used as a predictor of immunotherapy response in NSCLC [42–44]. We further studied the mutation profile of PRRS-stratified LUAD patients. In the TCGA_LUAD cohort, we observed that the L-PRRS group had a lower TMB, and patients exhibited different mutation signatures between the two subgroups (Figure 6a–c). The top five genes with the highest mutant frequency in the L-PRRS group were TP53 (40%), TTN (39%), MUC16 (39%), CSMD3 (32%), and RYR2 (32%); whereas, those in the H-PRRS group were TP53 (56%), TTN (51%), MUC16 (42%), CSMD3 (47%), and RYR2 (39%) (Figure 6a and b). KM analysis showed that the OS of patients in H-TMB group was longer than that of patients in the L-TMB group, and patients in the H-TMB + L-PRRS group had the best prognosis (Figure 6d and e).

Figure 6 Mutation signatures of PRRS-based LUAD patients. (a and b) Waterfall plots of mutation genes in L-PRRS (a) and H-PRRS (b) subgroups from the TCGA_LUAD cohort. (c) TMB of the H-PRRS group was significantly higher than the L-PRRS group. (d) In the TCGA_LUAD cohorts, patients in the H-TMB groups had a longer OS than the L-TMB group. (e) In the TCGA_LUAD cohorts, patients in the H-TMB + L-PRRS group had the best prognosis. L-TMB: low TMB; H-TMB: high TMB; L-PRRS: low PRRS; H-PRRS: high PRRS.
Figure 6

Mutation signatures of PRRS-based LUAD patients. (a and b) Waterfall plots of mutation genes in L-PRRS (a) and H-PRRS (b) subgroups from the TCGA_LUAD cohort. (c) TMB of the H-PRRS group was significantly higher than the L-PRRS group. (d) In the TCGA_LUAD cohorts, patients in the H-TMB groups had a longer OS than the L-TMB group. (e) In the TCGA_LUAD cohorts, patients in the H-TMB + L-PRRS group had the best prognosis. L-TMB: low TMB; H-TMB: high TMB; L-PRRS: low PRRS; H-PRRS: high PRRS.

3.5 Guidance of PRRS in LUAD therapy

As negative regulators of T cell immunity, CTLA-4 and PD-1 have become immunotherapeutic targets for NSCLC. CTLA-4 and PD-1 negatively regulate T cell activity at different stages of immune response, respectively [45]. We obtained the clinical data of LUAD patients treated with CTLA-4 or/and PD-1 from The Cancer Immunome Atlas (TCIA) database. We found patients in the L-PRRS subgroup could benefit more from immunotherapy (Figure 7a–d). In addition, we also analyzed the correlation between the sensitivity of 23 drugs and PRRS. As shown in Figure 8, the sensitivity of 22 drugs was negatively correlated with PPRS, such as cisplatin, bexarotene, and methotrexate, while the sensitivity of KIN001-135 was positively correlated with PRRS (|R| ≥ 0.4; p < 0.001). The statistical results suggested that patients in the L-PRRS subgroup had higher sensitivity to 22 drugs, such as cisplatin, bexarotene, and methotrexate, and lower sensitivity to KIN001-135 (p < 0.001; Figure S4).

Figure 7 Guidance of PRRS in LUAD immunotherapy. (a–d) LUAD patients in the L-PRRS will benefit more from CTLA4 and, or PD1 inhibitor treatment.
Figure 7

Guidance of PRRS in LUAD immunotherapy. (a–d) LUAD patients in the L-PRRS will benefit more from CTLA4 and, or PD1 inhibitor treatment.

Figure 8 Screening of potential drugs for LUAD patients. Correlation analysis between the sensitivity of 23 drugs and PRRS.
Figure 8

Screening of potential drugs for LUAD patients. Correlation analysis between the sensitivity of 23 drugs and PRRS.

3.6 Establishment of a nomogram based on PRRS and clinical characters

Univariate and multivariate Cox regression analyses were presented on the TCGA_LUAD dataset, and PRRS, stage, and tumor purity were recognized as independent risk factors for LUAD (Figure 9a and b). We plotted the C-index curves of the above characters, and the found PRRS had the most immense value, indicating that it had the highest prognostic accuracy for LUAD prognosis (Figure 9c). We also drew 1-, 2-, and 3-year ROC curves using PRRS and clinical features, and found that the PRRS + clinical group always had the biggest AUC (Figure 9d and f). Finally, we plotted the nomogram using the above features for LUAD to develop a nomogram to quantitatively establish the 1-, 2- and 3-year survival rates (Figure 9g). TheAUC values of PRRS in the TCGA_LUAD cohort were 0.785 for 1 year, 0.753 for 2 years, and 0.738 for 3 years (Figure 9h). In addition, the calibration curves of patients at 1, 2, and 3 years confirmed the accurateness of the nomogram (Figure 9i). Thus, nomogram was the best model to predict the prognosis of LUAD compared with single risk factor.

Figure 9 Development and verification of nomogram. (a and b) Univariate and multivariate regression analyses of the correlation between PRRS and clinical characteristics regarding OS in the TCGA-LUAD cohort. (c) C-index curves of PRRS and clinical features. (d–f) Time-dependent ROC analyses of PRRS and, or clinical features regarding the OS and survival status in the TCGA_LUAD cohort. (g) Nomogram is based on gender, age, tumor purity, TMB, PRRS, and stage. (h) Time-dependent ROC analyses of the nomogram regarding the OS and survival status in the TCGA_LUAD cohort. (i) Calibration curves of the nomogram between predicted and observed 3-, 5- and 10-year OS in the TCGA_LUAD cohort.
Figure 9

Development and verification of nomogram. (a and b) Univariate and multivariate regression analyses of the correlation between PRRS and clinical characteristics regarding OS in the TCGA-LUAD cohort. (c) C-index curves of PRRS and clinical features. (d–f) Time-dependent ROC analyses of PRRS and, or clinical features regarding the OS and survival status in the TCGA_LUAD cohort. (g) Nomogram is based on gender, age, tumor purity, TMB, PRRS, and stage. (h) Time-dependent ROC analyses of the nomogram regarding the OS and survival status in the TCGA_LUAD cohort. (i) Calibration curves of the nomogram between predicted and observed 3-, 5- and 10-year OS in the TCGA_LUAD cohort.

4 Discussion

Pyroptosis, a novel type of programmed cell death, was first discovered in 1992 [46] but did not catch researchers’ attention until recent years. Pyroptosis is characterized by gasdermin cleavage, pore formation, cell swelling, and subsequent release of inflammatory mediators [20]. There is a growing body of literature that recognizes the two-sided role of pyroptosis in tumorigenesis and cancer progression [47]. On the one hand, pyroptosis is accompanied by IL-1β and IL-18 release, which could mediate tumor-promoting inflammation [48,49]. Gao et al. found that GSDMD was significantly up-regulated in NSCLC and that knockdown of GSDMD mitigated cell proliferation and tumor growth in xenograft mouse models [17]. On the other hand, pyroptosis inhibits tumor progression and stimulates anti-cancer immunity [50]. Previous research studies show that GSDMD is required for CD8+ T cell cytotoxicity toward LC cells [51], and GSDME represses tumor growth in vivo [52]. Considering the pivotal role that pyroptosis plays in cancer progression, we suppose that PRGs might have predictive value and be associated with drug resistance in LUAD. Nevertheless, relevant research studies are relatively scarce. Hence, we set out to investigate the predictive potential of PRGs and construct a PRRS for clinical application.

First, we performed cluster analysis using the expression profile of 52 PRGs and split the patients from TCGA_LUAD, GSE31210, and GSE41271 cohorts into two clusters, respectively. In all cohorts, patients in C2 had a better prognosis than those in C1, confirming the predictive potential of PRGs. Then we tried to construct a PRRS more stable than cluster analysis. A total of 567 differentially expressed genes were discovered after comparing the two clusters of the TCGA_LUAD cohort. Further, univariate Cox regression analysis and LASSO regression model extracted 14 crucial genes, and incorporated into the formula to obtain the PRRS.

Among the 14 genes, some have been shown to participate in LC progression or have prognostic potential. ARL14, an ADP ribosylation factor family member, was up-regulated in NSCLC tissue samples, indicating poor survival [53]. ARL14 could promote LUAD cell proliferation, and knockdown of ARL14 induced a dormant state in cancer cells [54]. The cystic fibrosis transmembrane conductance regulator (CFTR) was down-regulated in NSCLC tissues compared with paired normal tissues [55]. High CFTR was correlated with better survival in NSCLC patients, and knockdown of CFTR enhanced cell migration, invasion in vitro, and metastasis in vivo [56]. High expression of cyclin-dependent kinase inhibitor 3 (CDKN3) was observed in LC cell lines and was associated with poor survival of LUAD patients [57]. Combretastain A4 (CA4) was a tumor suppressor which inhibited NSCLC cell proliferation and tumor growth in xenograft mouse models [58]. Plakophilin 2 (PKP2) was up-regulated in LUAD tissues and LC cells, and its high expression indicated worse prognosis for LUAD patients. Mechanistically, PKP2 promoted LC cell proliferation and invasion via enhancing epithelial–mesenchymal transition (EMT) and focal adhesion [59]. Moreover, PKP2 contributed to LC radioresistance and its high expression was associated with worse survival in LC patients after radiotherapy [60]. The dickkopf WNT signaling pathway inhibitor 1 (DKK1) also exhibited tumor-promoting phenotype in LC. It was up-regulated in NSCLC tissues compared with normal lung tissues and could promote migration, invasion, and EMT in LC cells. Patients with DKK1-positive tumors had shorter disease-free survival than those with negative tumors [61,62]. Notably, the knockdown of DKK1 sensitized NSCLC cell lines to cisplatin treatment, indicating that DKK1 partly contributed to the intrinsic cisplatin resistance [63]. A study revealed that kynureninase (KYNU) expression was positively correlated with CD8+ tumor infiltrating lymphocytes and PD-L1 cell positivity. Higher expression of KYNU was associated with worse OS in LUAD patients [64]. Therefore, our PRRS seems reliable since many of the 14 genes play an active role in LC progression and have prognostic value alone.

Afterward, we investigated the association of PRRS with patient survival, TME, TMB, and drug sensitivity. In both the training and validation cohorts, patients in the L-PRRS groups had significantly longer OS than those in the H-PRRS groups, confirming the predictive value of PRRS in LUAD. Tumor purity reflects the tumor cell content in the tissue and is a prognostic indicator in various cancers [39–41]. Our result revealed that tumor purity of patients in the H-PRRS group was significantly higher than that in the L-PRRS group. Tumor purity can predict prognosis of LUAD patients alone or combined with PRRS. Besides, the infiltration ratios of immune cells such as aDCs, B cells, iDCs, mast cells, neutrophils, T helper cells, and TIL were significantly reduced in the H-PRRS group, suggesting that PRRS is associated with TME in LUAD. TMB is a biomarker for predicting the clinical benefit from immunotherapy response, and higher TMB was associated with prolonged OS after immunotherapy [7,42,44,65]. Our results showed that patients in the H-PRRS group had a higher TMB, suggesting that this group is likely to have survival better after immunotherapy. After analyzing the IPS score acquired from TCIA database, we found that patients in the L-PRRS group had higher IPS than those in the H-PRRS group, suggesting that the L-PRRS group might exhibit a better response to immune checkpoint blockers [66]. Previous research showed that applying gasdermin could sensitize breast cancer cells to anti-PD1 therapy, which supports our results [22].

The underlying mechanism behind the association between pyroptosis and immunotherapy can be rather complex. On the one hand, pyroptosis can secrete IL-1β and IL-18 to trigger inflammatory responses and recruiting immune cells, which might enhance the anti-tumor effects of immunotherapy [67]. In addition, pyroptosis also plays a role in the activation and functioning of immune cells. For instance, the expression of GSDMD is higher in activated CD8+ T cells than in naïve T cells, and GSDMD is essential in the cytolytic ability of CD8+ T cells [68]. On the other hand, pyroptosis is accompanied by the release of inflammatory mediators, such as IL-1 and IL-18, which might facilitate cancer development and progression [48,49]. Moreover, chimeric antigen receptor (CAR) T cell therapy can induce pyroptosis in target cells, and subsequent cytokine release can induce severe adverse reactions after CART therapy [21,69].

Interestingly, PRRS was also associated with the sensitivity of 23 drugs, including cisplatin and other targeted therapies. This is not surprising since chemotherapy drugs like cisplatin can induce pyroptosis in GSDME-high cancer cells and GSDME-deficient mice showed fewer adverse effects induced by chemotherapy [70]. Taken together, PRRS is a powerful predictor of prognosis, immunotherapy response, and drug sensitivity, which might be suitable for clinical application. Eventually, we built a nomogram based on gender, age, tumor purity, TMB, PRRS, and stage, which was accurate for predicting LUAD prognosis.

Pyroptosis-related prognostic signatures have been constructed in various tumors, including glioma, breast cancer, gastric cancer, LC, hepatocellular carcinoma, cervical cancer, etc. [23,25,29,71–78]. However, the PRRS seems more reliable since we included more PRGs (52 genes) as the input than the other studies. Besides, we used a combination of univariate Cox regression analysis and LASSO regression model to obtain the PRRS, which can solve the problem of multicollinearity among the PRGs and simplify the risk score. In addition, we found that many of the PRGs included in the PRRS play an active role in LC progression and have their prognostic value through literature search, which has been stated earlier. Moreover, the PRRS can not only predict prognosis, but also guide therapeutic options in LUAD management.

5 Conclusion

In summary, this study constructed a PRRS which incorporated the expression of 14 PRGs and validated the predictive value of the risk score. Further investigation demonstrated the association between PRRS and TME, immunotherapy response and drug sensitivity, suggesting its potential for clinical application. Finally, a nomogram was constructed based on gender, age, tumor purity, TMB, PRRS, and stage, which achieved good accuracy in predicting prognosis.

# These authors contributed equally to this work.

  1. Funding information: This work was supported by the National Natural Science Foundation of China (81903031), China Postdoctoral Science Foundation (2020M682334), and Henan Postdoctoral Foundation (202003002).

  2. Author contributions: Shangfu Li and Guoyin Li designed the project. Zhengsong Jiang and Xiang Wang analyzed the data, prepared figures, and tables. Shangfu Li, Guoyin Li and Jinghan Huang wrote the manuscript.

  3. Conflict of interest: The authors declare that they have no conflicts of interest.

  4. Data availability statement: The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found in the manuscript.

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Received: 2022-09-27
Revised: 2023-01-06
Accepted: 2023-01-19
Published Online: 2023-03-13

© 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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  14. SCARA5 inhibits oral squamous cell carcinoma via inactivating the STAT3 and PI3K/AKT signaling pathways
  15. Molecular mechanism by which the Notch signaling pathway regulates autophagy in a rat model of pulmonary fibrosis in pigeon breeder’s lung
  16. lncRNA TPT1-AS1 promotes cell migration and invasion in esophageal squamous-cell carcinomas by regulating the miR-26a/HMGA1 axis
  17. SIRT1/APE1 promotes the viability of gastric cancer cells by inhibiting p53 to suppress ferroptosis
  18. Glycoprotein non-metastatic melanoma B interacts with epidermal growth factor receptor to regulate neural stem cell survival and differentiation
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  21. circ_0000376 knockdown suppresses non-small cell lung cancer cell tumor properties by the miR-545-3p/PDPK1 pathway
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  23. UBE2J1 knockdown promotes cell apoptosis in endometrial cancer via regulating PI3K/AKT and MDM2/p53 signaling
  24. Metabolic resuscitation therapy in critically ill patients with sepsis and septic shock: A pilot prospective randomized controlled trial
  25. Lycopene ameliorates locomotor activity and urinary frequency induced by pelvic venous congestion in rats
  26. UHRF1-induced connexin26 methylation is involved in hearing damage triggered by intermittent hypoxia in neonatal rats
  27. LINC00511 promotes melanoma progression by targeting miR-610/NUCB2
  28. Ultra-high-performance liquid chromatography-tandem mass spectrometry analysis of serum metabolomic characteristics in people with different vitamin D levels
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  30. circ_0014736 induces GPR4 to regulate the biological behaviors of human placental trophoblast cells through miR-942-5p in preeclampsia
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  33. A novel autophagy-related long non-coding RNAs signature predicting progression-free interval and I-131 therapy benefits in papillary thyroid carcinoma
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  36. Dysregulated lncRNAs are involved in the progress of myocardial infarction by constructing regulatory networks
  37. Single-arm trial to evaluate the efficacy and safety of baclofen in treatment of intractable hiccup caused by malignant tumor chemotherapy
  38. Genetic polymorphisms of MRPS30-DT and NINJ2 may influence lung cancer risk
  39. Efficacy of immune checkpoint inhibitors in patients with KRAS-mutant advanced non-small cell lung cancer: A retrospective analysis
  40. Pyroptosis-based risk score predicts prognosis and drug sensitivity in lung adenocarcinoma
  41. Upregulation of lncRNA LANCL1-AS1 inhibits the progression of non-small-cell lung cancer via the miR-3680-3p/GMFG axis
  42. CircRANBP17 modulated KDM1A to regulate neuroblastoma progression by sponging miR-27b-3p
  43. Exosomal miR-93-5p regulated the progression of osteoarthritis by targeting ADAMTS9
  44. Downregulation of RBM17 enhances cisplatin sensitivity and inhibits cell invasion in human hypopharyngeal cancer cells
  45. HDAC5-mediated PRAME regulates the proliferation, migration, invasion, and EMT of laryngeal squamous cell carcinoma via the PI3K/AKT/mTOR signaling pathway
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  48. A novel long noncoding RNA AC125257.1 facilitates colorectal cancer progression by targeting miR-133a-3p/CASC5 axis
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  50. Clinicopathological characteristics and prognosis of young patients aged ≤45 years old with non-small cell lung cancer
  51. TMT-based comprehensive proteomic profiling identifies serum prognostic signatures of acute myeloid leukemia
  52. The dose limits of teeth protection for patients with nasopharyngeal carcinoma undergoing radiotherapy based on the early oral health-related quality of life
  53. miR-30b-5p targeting GRIN2A inhibits hippocampal damage in epilepsy
  54. Long non-coding RNA AL137789.1 promoted malignant biological behaviors and immune escape of pancreatic carcinoma cells
  55. IRF6 and FGF1 polymorphisms in non-syndromic cleft lip with or without cleft palate in the Polish population
  56. Comprehensive analysis of the role of SFXN family in breast cancer
  57. Efficacy of bronchoscopic intratumoral injection of endostar and cisplatin in lung squamous cell carcinoma patients underwent conventional chemoradiotherapy
  58. Silencing of long noncoding RNA MIAT inhibits the viability and proliferation of breast cancer cells by promoting miR-378a-5p expression
  59. AG1024, an IGF-1 receptor inhibitor, ameliorates renal injury in rats with diabetic nephropathy via the SOCS/JAK2/STAT pathway
  60. Downregulation of KIAA1199 alleviated the activation, proliferation, and migration of hepatic stellate cells by the inhibition of epithelial–mesenchymal transition
  61. Exendin-4 regulates the MAPK and WNT signaling pathways to alleviate the osteogenic inhibition of periodontal ligament stem cells in a high glucose environment
  62. Inhibition of glycolysis represses the growth and alleviates the endoplasmic reticulum stress of breast cancer cells by regulating TMTC3
  63. The function of lncRNA EMX2OS/miR-653-5p and its regulatory mechanism in lung adenocarcinoma
  64. Tectorigenin alleviates the apoptosis and inflammation in spinal cord injury cell model through inhibiting insulin-like growth factor-binding protein 6
  65. Ultrasound examination supporting CT or MRI in the evaluation of cervical lymphadenopathy in patients with irradiation-treated head and neck cancer
  66. F-box and WD repeat domain containing 7 inhibits the activation of hepatic stellate cells by degrading delta-like ligand 1 to block Notch signaling pathway
  67. Knockdown of circ_0005615 enhances the radiosensitivity of colorectal cancer by regulating the miR-665/NOTCH1 axis
  68. Long noncoding RNA Mhrt alleviates angiotensin II-induced cardiac hypertrophy phenotypes by mediating the miR-765/Wnt family member 7B pathway
  69. Effect of miR-499-5p/SOX6 axis on atrial fibrosis in rats with atrial fibrillation
  70. Cholesterol induces inflammation and reduces glucose utilization
  71. circ_0004904 regulates the trophoblast cell in preeclampsia via miR-19b-3p/ARRDC3 axis
  72. NECAB3 promotes the migration and invasion of liver cancer cells through HIF-1α/RIT1 signaling pathway
  73. The poor performance of cardiovascular risk scores in identifying patients with idiopathic inflammatory myopathies at high cardiovascular risk
  74. miR-2053 inhibits the growth of ovarian cancer cells by downregulating SOX4
  75. Nucleophosmin 1 associating with engulfment and cell motility protein 1 regulates hepatocellular carcinoma cell chemotaxis and metastasis
  76. α-Hederin regulates macrophage polarization to relieve sepsis-induced lung and liver injuries in mice
  77. Changes of microbiota level in urinary tract infections: A meta-analysis
  78. Identification of key enzalutamide-resistance-related genes in castration-resistant prostate cancer and verification of RAD51 functions
  79. Falls during oxaliplatin-based chemotherapy for gastrointestinal malignancies – (lessons learned from) a prospective study
  80. Outcomes of low-risk birth care during the Covid-19 pandemic: A cohort study from a tertiary care center in Lithuania
  81. Vitamin D protects intestines from liver cirrhosis-induced inflammation and oxidative stress by inhibiting the TLR4/MyD88/NF-κB signaling pathway
  82. Integrated transcriptome analysis identifies APPL1/RPS6KB2/GALK1 as immune-related metastasis factors in breast cancer
  83. Genomic analysis of immunogenic cell death-related subtypes for predicting prognosis and immunotherapy outcomes in glioblastoma multiforme
  84. Circular RNA Circ_0038467 promotes the maturation of miRNA-203 to increase lipopolysaccharide-induced apoptosis of chondrocytes
  85. An economic evaluation of fine-needle cytology as the primary diagnostic tool in the diagnosis of lymphadenopathy
  86. Midazolam impedes lung carcinoma cell proliferation and migration via EGFR/MEK/ERK signaling pathway
  87. Network pharmacology combined with molecular docking and experimental validation to reveal the pharmacological mechanism of naringin against renal fibrosis
  88. PTPN12 down-regulated by miR-146b-3p gene affects the malignant progression of laryngeal squamous cell carcinoma
  89. miR-141-3p accelerates ovarian cancer progression and promotes M2-like macrophage polarization by targeting the Keap1-Nrf2 pathway
  90. lncRNA OIP5-AS1 attenuates the osteoarthritis progression in IL-1β-stimulated chondrocytes
  91. Overexpression of LINC00607 inhibits cell growth and aggressiveness by regulating the miR-1289/EFNA5 axis in non-small-cell lung cancer
  92. Subjective well-being in informal caregivers during the COVID-19 pandemic
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  94. Unfolded protein response inhibits KAT2B/MLKL-mediated necroptosis of hepatocytes by promoting BMI1 level to ubiquitinate KAT2B
  95. Bladder cancer screening: The new selection and prediction model
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  110. A prospective cohort study of the impact of chronic disease on fall injuries in middle-aged and older adults
  111. circRNA THBS1 silencing inhibits the malignant biological behavior of cervical cancer cells via the regulation of miR-543/HMGB2 axis
  112. hsa_circ_0000285 sponging miR-582-3p promotes neuroblastoma progression by regulating the Wnt/β-catenin signaling pathway
  113. Long non-coding RNA GNAS-AS1 knockdown inhibits proliferation and epithelial–mesenchymal transition of lung adenocarcinoma cells via the microRNA-433-3p/Rab3A axis
  114. lncRNA UCA1 regulates miR-132/Lrrfip1 axis to promote vascular smooth muscle cell proliferation
  115. Twenty-four-color full spectrum flow cytometry panel for minimal residual disease detection in acute myeloid leukemia
  116. Hsa-miR-223-3p participates in the process of anthracycline-induced cardiomyocyte damage by regulating NFIA gene
  117. Anti-inflammatory effect of ApoE23 on Salmonella typhimurium-induced sepsis in mice
  118. Analysis of somatic mutations and key driving factors of cervical cancer progression
  119. Hsa_circ_0028007 regulates the progression of nasopharyngeal carcinoma through the miR-1179/SQLE axis
  120. Variations in sexual function after laparoendoscopic single-site hysterectomy in women with benign gynecologic diseases
  121. Effects of pharmacological delay with roxadustat on multi-territory perforator flap survival in rats
  122. Analysis of heroin effects on calcium channels in rat cardiomyocytes based on transcriptomics and metabolomics
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  124. Alkbh5 plays indispensable roles in maintaining self-renewal of hematopoietic stem cells
  125. Study to compare the effect of casirivimab and imdevimab, remdesivir, and favipiravir on progression and multi-organ function of hospitalized COVID-19 patients
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  127. The protective effect of caffeic acid phenethyl ester in the nephrotoxicity induced by α-cypermethrin
  128. Norepinephrine alleviates cyclosporin A-induced nephrotoxicity by enhancing the expression of SFRP1
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  130. The function of Foxp1 represses β-adrenergic receptor transcription in the occurrence and development of bladder cancer through STAT3 activity
  131. Risk model and validation of carbapenem-resistant Klebsiella pneumoniae infection in patients with cerebrovascular disease in the ICU
  132. Calycosin protects against chronic prostatitis in rats via inhibition of the p38MAPK/NF-κB pathway
  133. Pan-cancer analysis of the PDE4DIP gene with potential prognostic and immunotherapeutic values in multiple cancers including acute myeloid leukemia
  134. The safety and immunogenicity to inactivated COVID-19 vaccine in patients with hyperlipemia
  135. Circ-UBR4 regulates the proliferation, migration, inflammation, and apoptosis in ox-LDL-induced vascular smooth muscle cells via miR-515-5p/IGF2 axis
  136. Clinical characteristics of current COVID-19 rehabilitation outpatients in China
  137. Luteolin alleviates ulcerative colitis in rats via regulating immune response, oxidative stress, and metabolic profiling
  138. miR-199a-5p inhibits aortic valve calcification by targeting ATF6 and GRP78 in valve interstitial cells
  139. The application of iliac fascia space block combined with esketamine intravenous general anesthesia in PFNA surgery of the elderly: A prospective, single-center, controlled trial
  140. Elevated blood acetoacetate levels reduce major adverse cardiac and cerebrovascular events risk in acute myocardial infarction
  141. The effects of progesterone on the healing of obstetric anal sphincter damage in female rats
  142. Identification of cuproptosis-related genes for predicting the development of prostate cancer
  143. Lumican silencing ameliorates β-glycerophosphate-mediated vascular smooth muscle cell calcification by attenuating the inhibition of APOB on KIF2C activity
  144. Targeting PTBP1 blocks glutamine metabolism to improve the cisplatin sensitivity of hepatocarcinoma cells through modulating the mRNA stability of glutaminase
  145. A single center prospective study: Influences of different hip flexion angles on the measurement of lumbar spine bone mineral density by dual energy X-ray absorptiometry
  146. Clinical analysis of AN69ST membrane continuous venous hemofiltration in the treatment of severe sepsis
  147. Antibiotics therapy combined with probiotics administered intravaginally for the treatment of bacterial vaginosis: A systematic review and meta-analysis
  148. Construction of a ceRNA network to reveal a vascular invasion associated prognostic model in hepatocellular carcinoma
  149. A pan-cancer analysis of STAT3 expression and genetic alterations in human tumors
  150. A prognostic signature based on seven T-cell-related cell clustering genes in bladder urothelial carcinoma
  151. Pepsin concentration in oral lavage fluid of rabbit reflux model constructed by dilating the lower esophageal sphincter
  152. The antihypertensive felodipine shows synergistic activity with immune checkpoint blockade and inhibits tumor growth via NFAT1 in LUSC
  153. Tanshinone IIA attenuates valvular interstitial cells’ calcification induced by oxidized low density lipoprotein via reducing endoplasmic reticulum stress
  154. AS-IV enhances the antitumor effects of propofol in NSCLC cells by inhibiting autophagy
  155. Establishment of two oxaliplatin-resistant gallbladder cancer cell lines and comprehensive analysis of dysregulated genes
  156. Trial protocol: Feasibility of neuromodulation with connectivity-guided intermittent theta-burst stimulation for improving cognition in multiple sclerosis
  157. LncRNA LINC00592 mediates the promoter methylation of WIF1 to promote the development of bladder cancer
  158. Factors associated with gastrointestinal dysmotility in critically ill patients
  159. Mechanisms by which spinal cord stimulation intervenes in atrial fibrillation: The involvement of the endothelin-1 and nerve growth factor/p75NTR pathways
  160. Analysis of two-gene signatures and related drugs in small-cell lung cancer by bioinformatics
  161. Silencing USP19 alleviates cigarette smoke extract-induced mitochondrial dysfunction in BEAS-2B cells by targeting FUNDC1
  162. Menstrual irregularities associated with COVID-19 vaccines among women in Saudi Arabia: A survey during 2022
  163. Ferroptosis involves in Schwann cell death in diabetic peripheral neuropathy
  164. The effect of AQP4 on tau protein aggregation in neurodegeneration and persistent neuroinflammation after cerebral microinfarcts
  165. Activation of UBEC2 by transcription factor MYBL2 affects DNA damage and promotes gastric cancer progression and cisplatin resistance
  166. Analysis of clinical characteristics in proximal and distal reflux monitoring among patients with gastroesophageal reflux disease
  167. Exosomal circ-0020887 and circ-0009590 as novel biomarkers for the diagnosis and prediction of short-term adverse cardiovascular outcomes in STEMI patients
  168. Upregulated microRNA-429 confers endometrial stromal cell dysfunction by targeting HIF1AN and regulating the HIF1A/VEGF pathway
  169. Bibliometrics and knowledge map analysis of ultrasound-guided regional anesthesia
  170. Knockdown of NUPR1 inhibits angiogenesis in lung cancer through IRE1/XBP1 and PERK/eIF2α/ATF4 signaling pathways
  171. D-dimer trends predict COVID-19 patient’s prognosis: A retrospective chart review study
  172. WTAP affects intracranial aneurysm progression by regulating m6A methylation modification
  173. Using of endoscopic polypectomy in patients with diagnosed malignant colorectal polyp – The cross-sectional clinical study
  174. Anti-S100A4 antibody administration alleviates bronchial epithelial–mesenchymal transition in asthmatic mice
  175. Prognostic evaluation of system immune-inflammatory index and prognostic nutritional index in double expressor diffuse large B-cell lymphoma
  176. Prevalence and antibiogram of bacteria causing urinary tract infection among patients with chronic kidney disease
  177. Reactive oxygen species within the vaginal space: An additional promoter of cervical intraepithelial neoplasia and uterine cervical cancer development?
  178. Identification of disulfidptosis-related genes and immune infiltration in lower-grade glioma
  179. A new technique for uterine-preserving pelvic organ prolapse surgery: Laparoscopic rectus abdominis hysteropexy for uterine prolapse by comparing with traditional techniques
  180. Self-isolation of an Italian long-term care facility during COVID-19 pandemic: A comparison study on care-related infectious episodes
  181. A comparative study on the overlapping effects of clinically applicable therapeutic interventions in patients with central nervous system damage
  182. Low intensity extracorporeal shockwave therapy for chronic pelvic pain syndrome: Long-term follow-up
  183. The diagnostic accuracy of touch imprint cytology for sentinel lymph node metastases of breast cancer: An up-to-date meta-analysis of 4,073 patients
  184. Mortality associated with Sjögren’s syndrome in the United States in the 1999–2020 period: A multiple cause-of-death study
  185. CircMMP11 as a prognostic biomarker mediates miR-361-3p/HMGB1 axis to accelerate malignant progression of hepatocellular carcinoma
  186. Analysis of the clinical characteristics and prognosis of adult de novo acute myeloid leukemia (none APL) with PTPN11 mutations
  187. KMT2A maintains stemness of gastric cancer cells through regulating Wnt/β-catenin signaling-activated transcriptional factor KLF11
  188. Evaluation of placental oxygenation by near-infrared spectroscopy in relation to ultrasound maturation grade in physiological term pregnancies
  189. The role of ultrasonographic findings for PIK3CA-mutated, hormone receptor-positive, human epidermal growth factor receptor-2-negative breast cancer
  190. Construction of immunogenic cell death-related molecular subtypes and prognostic signature in colorectal cancer
  191. Long-term prognostic value of high-sensitivity cardiac troponin-I in patients with idiopathic dilated cardiomyopathy
  192. Establishing a novel Fanconi anemia signaling pathway-associated prognostic model and tumor clustering for pediatric acute myeloid leukemia patients
  193. Integrative bioinformatics analysis reveals STAT2 as a novel biomarker of inflammation-related cardiac dysfunction in atrial fibrillation
  194. Adipose-derived stem cells repair radiation-induced chronic lung injury via inhibiting TGF-β1/Smad 3 signaling pathway
  195. Real-world practice of idiopathic pulmonary fibrosis: Results from a 2000–2016 cohort
  196. lncRNA LENGA sponges miR-378 to promote myocardial fibrosis in atrial fibrillation
  197. Diagnostic value of urinary Tamm-Horsfall protein and 24 h urine osmolality for recurrent calcium oxalate stones of the upper urinary tract: Cross-sectional study
  198. The value of color Doppler ultrasonography combined with serum tumor markers in differential diagnosis of gastric stromal tumor and gastric cancer
  199. The spike protein of SARS-CoV-2 induces inflammation and EMT of lung epithelial cells and fibroblasts through the upregulation of GADD45A
  200. Mycophenolate mofetil versus cyclophosphamide plus in patients with connective tissue disease-associated interstitial lung disease: Efficacy and safety analysis
  201. MiR-1278 targets CALD1 and suppresses the progression of gastric cancer via the MAPK pathway
  202. Metabolomic analysis of serum short-chain fatty acid concentrations in a mouse of MPTP-induced Parkinson’s disease after dietary supplementation with branched-chain amino acids
  203. Cimifugin inhibits adipogenesis and TNF-α-induced insulin resistance in 3T3-L1 cells
  204. Predictors of gastrointestinal complaints in patients on metformin therapy
  205. Prescribing patterns in patients with chronic obstructive pulmonary disease and atrial fibrillation
  206. A retrospective analysis of the effect of latent tuberculosis infection on clinical pregnancy outcomes of in vitro fertilization–fresh embryo transferred in infertile women
  207. Appropriateness and clinical outcomes of short sustained low-efficiency dialysis: A national experience
  208. miR-29 regulates metabolism by inhibiting JNK-1 expression in non-obese patients with type 2 diabetes mellitus and NAFLD
  209. Clinical features and management of lymphoepithelial cyst
  210. Serum VEGF, high-sensitivity CRP, and cystatin-C assist in the diagnosis of type 2 diabetic retinopathy complicated with hyperuricemia
  211. ENPP1 ameliorates vascular calcification via inhibiting the osteogenic transformation of VSMCs and generating PPi
  212. Significance of monitoring the levels of thyroid hormone antibodies and glucose and lipid metabolism antibodies in patients suffer from type 2 diabetes
  213. The causal relationship between immune cells and different kidney diseases: A Mendelian randomization study
  214. Interleukin 33, soluble suppression of tumorigenicity 2, interleukin 27, and galectin 3 as predictors for outcome in patients admitted to intensive care units
  215. Identification of diagnostic immune-related gene biomarkers for predicting heart failure after acute myocardial infarction
  216. Long-term administration of probiotics prevents gastrointestinal mucosal barrier dysfunction in septic mice partly by upregulating the 5-HT degradation pathway
  217. miR-192 inhibits the activation of hepatic stellate cells by targeting Rictor
  218. Diagnostic and prognostic value of MR-pro ADM, procalcitonin, and copeptin in sepsis
  219. Review Articles
  220. Prenatal diagnosis of fetal defects and its implications on the delivery mode
  221. Electromagnetic fields exposure on fetal and childhood abnormalities: Systematic review and meta-analysis
  222. Characteristics of antibiotic resistance mechanisms and genes of Klebsiella pneumoniae
  223. Saddle pulmonary embolism in the setting of COVID-19 infection: A systematic review of case reports and case series
  224. Vitamin C and epigenetics: A short physiological overview
  225. Ebselen: A promising therapy protecting cardiomyocytes from excess iron in iron-overloaded thalassemia patients
  226. Aspirin versus LMWH for VTE prophylaxis after orthopedic surgery
  227. Mechanism of rhubarb in the treatment of hyperlipidemia: A recent review
  228. Surgical management and outcomes of traumatic global brachial plexus injury: A concise review and our center approach
  229. The progress of autoimmune hepatitis research and future challenges
  230. METTL16 in human diseases: What should we do next?
  231. New insights into the prevention of ureteral stents encrustation
  232. VISTA as a prospective immune checkpoint in gynecological malignant tumors: A review of the literature
  233. Case Reports
  234. Mycobacterium xenopi infection of the kidney and lymph nodes: A case report
  235. Genetic mutation of SLC6A20 (c.1072T > C) in a family with nephrolithiasis: A case report
  236. Chronic hepatitis B complicated with secondary hemochromatosis was cured clinically: A case report
  237. Liver abscess complicated with multiple organ invasive infection caused by hematogenous disseminated hypervirulent Klebsiella pneumoniae: A case report
  238. Urokinase-based lock solutions for catheter salvage: A case of an upcoming kidney transplant recipient
  239. Two case reports of maturity-onset diabetes of the young type 3 caused by the hepatocyte nuclear factor 1α gene mutation
  240. Immune checkpoint inhibitor-related pancreatitis: What is known and what is not
  241. Does total hip arthroplasty result in intercostal nerve injury? A case report and literature review
  242. Clinicopathological characteristics and diagnosis of hepatic sinusoidal obstruction syndrome caused by Tusanqi – Case report and literature review
  243. Synchronous triple primary gastrointestinal malignant tumors treated with laparoscopic surgery: A case report
  244. CT-guided percutaneous microwave ablation combined with bone cement injection for the treatment of transverse metastases: A case report
  245. Malignant hyperthermia: Report on a successful rescue of a case with the highest temperature of 44.2°C
  246. Anesthetic management of fetal pulmonary valvuloplasty: A case report
  247. Rapid Communication
  248. Impact of COVID-19 lockdown on glycemic levels during pregnancy: A retrospective analysis
  249. Erratum
  250. Erratum to “Inhibition of miR-21 improves pulmonary vascular responses in bronchopulmonary dysplasia by targeting the DDAH1/ADMA/NO pathway”
  251. Erratum to: “Fer exacerbates renal fibrosis and can be targeted by miR-29c-3p”
  252. Retraction
  253. Retraction of “Study to compare the effect of casirivimab and imdevimab, remdesivir, and favipiravir on progression and multi-organ function of hospitalized COVID-19 patients”
  254. Retraction of “circ_0062491 alleviates periodontitis via the miR-142-5p/IGF1 axis”
  255. Retraction of “miR-223-3p alleviates TGF-β-induced epithelial-mesenchymal transition and extracellular matrix deposition by targeting SP3 in endometrial epithelial cells”
  256. Retraction of “SLCO4A1-AS1 mediates pancreatic cancer development via miR-4673/KIF21B axis”
  257. Retraction of “circRNA_0001679/miR-338-3p/DUSP16 axis aggravates acute lung injury”
  258. Retraction of “lncRNA ACTA2-AS1 inhibits malignant phenotypes of gastric cancer cells”
  259. Special issue Linking Pathobiological Mechanisms to Clinical Application for cardiovascular diseases
  260. Effect of cardiac rehabilitation therapy on depressed patients with cardiac insufficiency after cardiac surgery
  261. Special issue The evolving saga of RNAs from bench to bedside - Part I
  262. FBLIM1 mRNA is a novel prognostic biomarker and is associated with immune infiltrates in glioma
  263. Special Issue Computational Intelligence Methodologies Meets Recurrent Cancers - Part III
  264. Development of a machine learning-based signature utilizing inflammatory response genes for predicting prognosis and immune microenvironment in ovarian cancer
https://doi.org/10.1515/med-2023-0663
Keywords for this article
pyroptosis; lung adenocarcinoma; tumor microenvironment; tumor mutation burden; drug sensitivity
Creative Commons
BY 4.0

Articles in the same Issue

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