Identification of differentially expressed ER stress-related genes and their association with pulmonary arterial hypertension.

BACKGROUND: Pulmonary arterial hypertension (PAH) is a complex and progressive illness that has a multifaceted origin, significant fatality rates, and profound effects on health. The pathogenesis of PAH is poorly defined due to the insufficient understanding of the combined impact of endoplasmic reticulum (ER) stress and immune infiltration, both of which play vital roles in PAH development. This study aims to identify potential ER stress-related biomarkers in PAH and investigate their involvement in immune infiltration. METHODS: The GEO database was used to download gene expression profiles. Genes associated with ER stress were obtained from the MSigDB database. Weighted gene co-expression network analysis (WGCNA), GO, KEGG, and protein-protein interaction (PPI) were utilized to conduct screening of hub genes and explore potential molecular mechanisms. Furthermore, the investigation also delved into the presence of immune cells in PAH tissues and the correlation between hub genes and the immune system. Finally, we validated the diagnostic value and expression levels of the hub genes in PAH using subject-workup characterization curves and real-time quantitative PCR. RESULTS: In the PAH and control groups, a total of 31 genes related to ER stress were found to be differentially expressed. The enrichment analysis revealed that these genes were primarily enriched in reacting to stress in the endoplasmic reticulum, dealing with unfolded proteins, transporting proteins, and processing proteins within the endoplasmic reticulum. EIF2S1, NPLOC4, SEC61B, SYVN1, and DERL1 were identified as the top 5 hub genes in the PPI network. Immune infiltration analysis revealed that these hub genes were closely related to immune cells. The receiver operating characteristic (ROC) curves revealed that the hub genes exhibited excellent diagnostic efficacy for PAH. The levels of SEC61B, NPLOC4, and EIF2S1 expression were in agreement with the findings of bioinformatics analysis in the PAH group. CONCLUSIONS: Potential biomarkers that could be utilized are SEC61B, NPLOC4, and EIF2S1, as identified in this study. The infiltration of immune cells was crucial to the development and advancement of PAH. This study provided new potential therapeutic targets for PAH.

Identification and verification of atrial fibrillation hub genes caused by primary mitral regurgitation.

In the clinic, atrial fibrillation (AF) is a common arrhythmia. Despite constant innovation in treatments for AF, they remain limited by a lack of knowledge of the underlying mechanism responsible for AF. In this study, we examined the molecular mechanisms associated with primary mitral regurgitation (MR) in AF using several bioinformatics techniques. Limma was used to identify differentially expressed genes (DEGs) associated with AF using microarray data from the GSE115574 dataset. WGCNA was used to identify significant module genes. A functional enrichment analysis for overlapping genes between the DEGs and module genes was done and several AF hub genes were identified from a protein-protein interaction (PPI) network. Receiver operating characteristic (ROC) curves were generated to evaluate the validity of the hub genes. We examined 306 DEGs and 147 were upregulated and 159 were downregulated. WGCNA analysis revealed black and ivory modules that contained genes associated with AF. Functional enrichment analysis revealed various biological process terms related to AF. The AUCs for the 8 hub genes screened by the PPI network analysis were > 0.7, indicating satisfactory diagnostic accuracy. The 8 AF-related hub genes included SYT13, VSNL1, GNAO1, RGS4, RALYL, CPLX1, CHGB, and CPLX3. Our findings provide novel insight into the molecular mechanisms of AF and may lead to the development of new treatments.

lncRNA-TCONS_00008552 expression in patients with pulmonary arterial hypertension due to congenital heart disease.

Long noncoding RNAs (lncRNAs) are potential regulators of a variety of cardiovascular diseases. Therefore, there is a series of differentially expressed lncRNAs in pulmonary arterial hypertension (PAH) that may be used as markers to diagnose PAH and even predict the prognosis. However, their specific mechanisms remain largely unknown. Therefore, we investigated the biological role of lncRNAs in patients with PAH. First, we screened patients with PAH secondary to ventricular septal defect (VSD) and those with VSD without PAH to assess differences in lncRNA and mRNA expression between the two groups. Our results revealed the significant upregulation of 813 lncRNAs and 527 mRNAs and significant downregulation of 541 lncRNAs and 268 mRNAs in patients with PAH. Then, we identified 10 hub genes in a constructed protein-protein interaction network. Next, we performed bioinformatics analyses, including Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analysis and subsequently constructed coding-noncoding co-expression networks. We screened lncRNA-TCONS_00008552 and lncRNA-ENST00000433673 as candidate genes and verified the expression levels of the lncRNAs using quantitative reverse-transcription PCR. Although expression levels of lncRNA-TCONS_00008552 in the plasma from the PAH groups were significantly increased compared with the control groups, there was no significant difference in the expression of lncRNA-ENST00000433673 between the two groups. This study bolsters our understanding of the role of lncRNA in PAH occurrence and development and indicates that lncRNA-TCONS_00008552 is a novel potential molecular marker for PAH.

Upregulation of TMCO3 Promoting Tumor Progression and Contributing to the Poor Prognosis of Hepatocellular Carcinoma.

Background and Aims: TMCO3, a member of the monovalent cation:proton antiporter-2 family, has been annotated as a Na+/H+ antiporter, but its pathophysiological role is still unclear. We aimed to investigate the expression profile, prognostic significance, and oncogenic role of TMCO3 in hepatocellular carcinoma (HCC). Methods: Bioinformatic analyses were conducted using transcriptome data from public databases to determine the expression, prognosis, and functional enrichment of TMCO3 in HCC. TMCO3 expression was further validated in an independent HCC cohort from our institution. The oncogenic role of TMCO3 in HCC was evaluated using in vitro and in vivo experiments. Results: The upregulated expression of TMCO3 was identified and verified in multiple HCC cohorts, and worse overall survival and recurrence-free survival were observed in patients with high TMCO3 expression. The overexpression and knockdown of TMCO3 could affect the proliferation and metastasis of HCC cells, which might be associated with the p53-induced cell cycle regulation and epithelial-mesenchymal transition, respectively. Notably, significant correlations were found between dysregulated TMCO3 and various antitumor agents. Its role in sorafenib sensitivity was further identified by in vitro experiments and the potential mechanism might be related to the regulation of apoptosis. Positive correlations were also identified between upregulation of TMCO3 and the increased infiltration of various immune cells and the elevated expression of multiple immune checkpoint genes in HCC. Conclusions: Upregulated TMCO3 could act as an oncogenic mediator and promote sorafenib resistance in HCC, providing a potential therapeutic target for HCC treatment.

Prognostic Role and Potential Mechanisms of N6-methyladenosine-related Long Noncoding RNAs in Hepatocellular Carcinoma.

Background and Aims: Numerous studies have explored the important role of N6-methyladenosine (m6A) in cancer. Nonetheless, the interaction between m6A and long noncoding RNAs (lncRNAs) is poorly investigated. Herein, we systematically analyzed the role and prognostic value of m6A-related lncRNAs in hepatocellular carcinoma (HCC). Methods: The m6A-related lncRNAs were identified based on the correlation coefficients with m6A-related genes in HCC from The Cancer Genome Atlas. Subsequently, a novel risk score model was determined using the least absolute shrinkage and selection operator Cox regression analyses. Univariate and multivariate Cox analyses were used to identify independent prognostic factors for overall survival (OS) of HCC; thereafter, a prognostic nomogram was constructed. Results: A total of 259 lncRNAs showed significant correlations with m6A in HCC, while 29 lncRNAs had prognostic significance. Further, six critical m6A-related lncRNAs (NRAV, SNHG3, KDM4A-AS1, AC074117.1, AC025176.1, and AL031985.3) were screened out to construct a novel risk score model which classified HCC patients into high- and low-risk groups. Survival analyses revealed that patients in the high-risk group exhibited worse OS, both in the training and validation groups. The risk score was also identified as an independent prognostic factor of OS, and a nomogram was established and verified with superior prediction capacity. Besides, the risk score significantly correlated with the expression of immune checkpoint genes and immune subtypes. Conclusions: These findings indicated the significant role of m6A-related lncRNAs in HCC and the potential application of the novel risk score model for prognostic prediction.

Regulation Network and Prognostic Significance of Aldo-Keto Reductase (AKR) Superfamily Genes in Hepatocellular Carcinoma.

PURPOSE: The aldo-keto reductase (AKR) superfamily members have been proposed with multiple roles in various tumors. Here, a comprehensive analysis on the integral role of AKR genes was conducted to evaluate the expression profile, regulation network, and prognostic significance in hepatocellular carcinoma (HCC). MATERIALS AND METHODS: Transcriptome datasets of HCC were obtained from the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus. Univariate and multivariate Cox regression analyses were used to build a novel risk score model, and then were further used to identify independent prognostic factors for overall survival (OS) of HCC. A prognostic nomogram was developed and validated. The expression of these critical AKR members was also evaluated by quantitative real-time polymerase chain reaction and immunohistochemistry in HCC specimens. RESULTS: Eight differentially expressed AKR genes were identified in HCC. The dysregulation of most AKR genes was negatively correlated with DNA methylation, and a regulation network with transcription factors (TFs) was also established. Then, three critical AKR genes (AKR1B10, AKR1D1, and AKR7A3) were screened out to build a novel risk score model. Worse OS was observed in high-risk patients. Besides, a prognostic nomogram based on the model was further established and validated in both the TCGA and GSE14520 cohorts, which showed superior performance in predicting the OS of HCC patients. Notably, close correlations were identified between the risk score and tumor immune microenvironment, somatic mutation profiles, and drug susceptibilities of HCC. Finally, the upregulated AKR1B10 and downregulated AKR1D1 and AKR7A3 were further verified in HCC tumor and adjacent tissues from our institution. CONCLUSION: The dysregulated AKR genes could be mediated by DNA methylation and TFs in HCC. The risk model established with superior prognostic performance further suggested the significant role of AKR genes involved in the progression of HCC.

Small-molecule inhibitor LF3 restrains the development of pulmonary hypertension through the Wnt/ß-catenin pathway.

Pulmonary hypertension (PH) associated with congenital heart disease is a progressive hemodynamic disease that can lead to increased pulmonary vascular resistance, vascular remodeling, and even right heart failure and death. LF3 is a novel inhibitor of the reporter gene activity of ß-catenin/TCF4 interaction in the Wnt/ß-catenin signal pathway. However, whether this action of LF3 can prevent PH development remains unclear. In this study, we investigated the therapeutic effect of LF3 in rat primary pulmonary artery smooth muscle cells (PASMCs) of the PH model. We found that LF3 inhibited the decrease in pulmonary artery acceleration time and ejection time by ultra-high-resolution ultrasound imaging and blocked the increase of pulmonary artery systolic pressure by using the BL420 biological function experimental system and right ventricular hypertrophy index by the electronic scales. Simultaneously, it prevented the increase of α-smooth muscle actin and fibronectin and the decrease of elastin in pulmonary arteries of rats in the PH group, as revealed by an immunohistochemical analysis. Moreover, cell proliferation and migration assays showed that LF3 significantly reduced the proliferation and migration of PASMCs. Western blotting and quantitative real-time polymerase chain reaction analyses revealed that LF3 suppressed the expression of proliferating cell nuclear antigens and Bcl-2 and increased the expression of Bax but did not alter the expressions of ß-catenin and TCF4. Taken together, LF3 can reduce the migration and proliferation of PASMCs and induce their apoptosis to prevent the development of PH. It would be worthwhile to explore the potential use of LF3 in the treatment of PH.

Prognostic Role and Potential Mechanisms of the Ferroptosis-Related Metabolic Gene Signature in Hepatocellular Carcinoma.

PURPOSE: Ferroptosis, as a novel regulated cell death form, has a close interaction with metabolism, which is largely unknown in cancer. In the present study, we conducted a comprehensive analysis of ferroptosis-related metabolic genes to delineate the metabolic signatures induced by ferroptosis and evaluate its prognostic significance in hepatocellular carcinoma (HCC). METHODS: The ferroptosis-related metabolic genes (Fer-MRGs) were identified by correlation analyses with transcriptome data from The Cancer Genome Atlas and Gene Expression Omnibus. Then, univariate and the least absolute shrinkage and selection operator Cox regression analysis was used to establish a novel risk score model. Univariate and multivariate COX analyses were used to identify independent prognostic factors for overall survival (OS) of HCC, and a nomogram was developed. The Fer-MRGs' expression was further evaluated by quantitative real-time polymerase chain reaction in HCC. RESULTS: A total of 77 metabolic genes were identified as Fer-MRGs, and 26 were found with prognostic values for OS of HCC. Then, a novel nine-gene (AKR1C3, ATIC, G6PD, GMPS, GNPDA1, IMPDH1, PRIM1, RRM2, and TXNRD1) risk score model was constructed. Survival analyses showed worse OS in high-risk patients both in the training and validation groups. The model was also identified as an independent prognostic factor for HCC, and a prognostic nomogram for OS was further established with superior discriminative capacity and prediction accuracy. Notably, close correlations were also identified between the risk score and the expression of immune checkpoint genes, immune subtypes of tumor, and susceptibility of HCC to chemotherapeutic agents. Finally, elevated expression of eight Fer-MRGs (except for IMPDH1) was further verified in 16 pairs of HCC tumor and adjacent tissues. CONCLUSION: These results indicated the intense interaction between ferroptosis and metabolism, the significant role of ferroptosis-related MRGs, and the great potential of the novel risk score model for prognosis prediction in HCC.

Nomograms based on clinicopathological factors and inflammatory indicators for prediction of early and late recurrence of hepatocellular carcinoma after surgical resection for patients with chronic hepatitis B.

BACKGROUND: Few studies have focused on the prognostic values of inflammation-related factors for different phases of recurrence in hepatocellular carcinoma (HCC). We aimed to identify the different risk factors for overall, early, and late recurrence, and to establish nomograms based on inflammation-related parameters for predicting the risks of recurrence in a group of HCC patients undergoing hepatectomy. METHODS: We retrospectively enrolled 383 HCC patients with chronic hepatitis B (CHB) who underwent hepatectomy. Univariate and multivariate Cox analyses were conducted to identify independent risk factors for recurrence. Nomograms for overall, early, and late recurrence-free survival (RFS) were established. The discrimination and calibration abilities of the nomograms were evaluated by concordance indexes (C-index), calibration plots, and Kaplan-Meier curves. Finally, receiver operating characteristic (ROC) curves were used to compare the derived nomograms with other existing models. RESULTS: Fibrinogen, lymphocyte-to-monocyte ratio, and S-index inflammation-related factors were independently related to overall and early RFS, but only the S-index correlated with late recurrence. Nomograms with tumor number, diameter, and pathological differentiation for overall and early RFS were established, while nomogram for late recurrence was constructed with tumor number and Child-Pugh grade. The C-indexes for overall, early, and late RFS were 0.679, 0.677, and 0.728, respectively. The calibration plots fit well. The nomograms showed superior discrimination capacities and better performance prediction with larger areas under the curve for recurrence. CONCLUSIONS: The developed nomograms that integrated inflammation-related factors showed high predictive accuracy for overall, early, and late recurrence in HCC patients with CHB after hepatectomy.

Association between hepatitis B virus infection and colorectal liver metastasis: a meta-analysis.

The paper aims to assess the association between Hepatitis B Virus infection and colorectal liver metastasis by conducting a meta-analysis. The relevant studies were searched until 24 July 2020, Studies that assessed the correlation between HBV infection and CRLM were recruited. A random effects model was applied to calculate the odds ratio (OR) with 95% confidence interval (CI). All data analyses were performed by STATA 12.0 software. Ten studies involving 17529 participants were included in the study. The results shown that there was obvious association between HBV infection and CRLM (OR: 0.51, 95% CI: 0.28-0.91). The study type and case-control rate may be the main causes of heterogeneity. In addition, HBV infection had no association with extrahepatic metastasis or prognosis of patients with CRLM. Sensitivity analyses confirmed that the results were stable, and Egg's test indicated that there was no publication bias. Patients with HBV infection have the reduced risk of CRLM.

Prognostic value of combined pretreatment fibrinogen and neutrophil-lymphocyte ratio in digestive system cancers: a meta-analysis of 17 retrospective studies.

BACKGROUND: Several epidemiological studies have reported the relationship between the combined pretreatment fibrinogen and neutrophil-lymphocyte ratio (F-NLR) and prognosis of digestive system cancers (DSCs). However, the results are controversial. We aimed to assess the prognostic value of F-NLR in patients with DSCs. METHODS: A comprehensive search for relevant studies was conducted until June, 2020. Studies that evaluated the association of the F-NLR score with survival outcome in patients with any DSCs were included. The hazard ratio (HR) and 95% confidence interval (CI) were calculated using a fixed-effects model. All data analyses were performed using the STATA 12.0 software. RESULTS: A total of 17 studies involving 5,767 participants were included in the meta-analysis. We found that high F-NLR score was significantly associated with poor overall survival (OS) in patients with DSCs (HR =2.0; 95% CI, 1.78-2.24). In addition, patients with high F-NLR score had poor disease-free survival/progression-free survival/recurrence-free survival (DFS/PFS/RFS) (HR =2.01; 95% CI, 1.47-2.74) and DFS (HR =1.97; 95% CI, 1.35-2.87). Sensitivity analyses for OS confirmed that the results were stable. CONCLUSIONS: High F-NLR score is significantly associated with poor prognostic outcomes in patients with DSCs and can serve as an effective prognostic indicator for the Asian population.

Giant aneurysmal of the left sinus of Valsalva in adults.

OBJECTIVE: To investigate the aneurysmal of the left sinus of Valsalva, and to improve the understanding of the disease and the level of diagnosis and treatment. METHOD: This article mainly reports a case of a huge aneurysmal of the left sinus of Valsalva patients treated with surgical treatment. RESULT: After surgery, the prognosis of the case was good. CONCLUSION: Aneurysmal of the left sinus of Valsalva has a low incidence, which is rare in clinical with no clinical specific symptoms leading to difficulty in early detection. The appropriate surgical method should be considered to the patient's condition, to prevent the tumor rupture and the death of patients.

Prognostic value of combined preoperative gamma-glutamyl transpeptidase to platelet ratio and fibrinogen in patients with HBV-related hepatocellular carcinoma after hepatectomy.

The gamma-glutamyl transpeptidase to platelet ratio (GPR) has been reported as a non-invasive parameter for evaluating hepatic fibrosis and cirrhosis. However, only a few of studies investigated the relationship between GPR and liver cancer. Here, we sought to clarify the prognostic value of GPR as well as its combination with fibrinogen in patients with HBV-related hepatocellular carcinoma (HCC). We performed a retrospective study using data collected from 302 HCC patients, and evaluated the association between GPR, fibrinogen and clinicopathological characteristics using the chi-square test. Additionally, we assessed disease-free survival (DFS) and overall survival (OS) using the Kaplan-Meier method and log-rank test, then performed univariate and multivariate COX analyses to identify the prognostic factors. The prognostic performance of combined GPR and fibrinogen was evaluated by the receiver operating characteristic curve analysis. Results showed that GPR was associated with gender, history of smoking and drinking, cirrhosis, antiviral treatments, tumor number, and Child-Pugh grade. Univariate analysis revealed a significant correlation between tumor diameter, vascular invasion, BCLC stage, alpha-fetal protein, GPR, fibrinogen, and NLR with both DFS and OS in HCC patients. Only GPR and fibrinogen were found to be independently associated with both DFS and OS according to multivariate analysis. Furthermore, predictive capacity was enhanced by combining GPR with fibrinogen owing to a larger area under the curve than other indexes or models. Overall, preoperative GPR could be an effective non-invasive predictor for prognosis of HBV-related HCC patients, and a combination of GPR and fibrinogen improved the prognostic performance.

The prognostic significance of neutrophil-to-lymphocyte ratio at different time points in patients with hepatocellular carcinoma receiving liver resection.

BACKGROUND: Neutrophil-to-lymphocyte ratio (NLR) has been demonstrated a significant association with the prognosis of hepatocellular carcinoma (HCC). The current study aimed to evaluate the prognostic value of NLR at different time points in HCC patients receiving liver resection. METHODS: Data were retrospectively collected from 195 HCC patients receiving liver resection. The preoperative NLR (pre-NLR), postoperative NLR (post-NLR) and corresponding changes of NLR (NLRc) at different time points were calculated. The disease-free survival (DFS) and overall survival (OS) was calculated by the Kaplan-Meier method and compared by the log-rank test. Both univariate and multivariate analyses were performed to evaluate their prognostic values for DFS and OS. And the prognostic significance of pre-NLR, post-NLRs, and NLRcs were further evaluated with subgroup analysis and with early and late recurrence of HCC. RESULTS: Pre-NLR was not significantly correlated with DFS or OS (both P>0.05), whereas higher post-NLR at 4-8 weeks [NLR (4-8 w)] and 3-6 months [(NLR (3-6 m)] predicted worse DFS (P=0.023 and P<0.001, respectively) and OS (P=0.012 and P=0.001, respectively). The value of area under the curve (AUC) of NLR (3-6 m) were higher than NLR (4-8 w) for DFS (0.656 vs. 0.572) and OS (0.650 vs. 0.621). Multivariate analyses showed that NLRc (4-8 w) was not a significant predictor of DFS (P=0.369) or OS (P=0.173), while the NLRc (3-6 m) with 25% increase was found to be an independent factor for adverse DFS in patients with HCC (P=0.041). The AUC of NLRc (3-6 m) for DFS was 0.600. Subgroup analysis showed NLR (3-6 m) was significantly corrected to DFS (P<0.001) and OS (P=0.001) in patients with cirrhosis. And NLR (3-6 m) also showed with significant correlation with early recurrence (P<0.001), while NLR (4-8 w) was found with significant association both with early and late recurrence (P=0.037 and P=0.027, respectively). CONCLUSIONS: The post-NLRs are significant predictors of clinical outcome in HCC patients receiving liver resection, and post-NLR and NLRc with a relatively long-term interval after operation have better prognostic values.

Efficacy and safety of dacron patch in surgical treatment of congenital disease by echocardiography.

To evaluate the efficacy and safety of a new domestic dacron patch in the surgical treatment of congenital heart disease (CHD) with infective endocarditis (IE), a clinical controlled trial is conducted. 48 patients with CHD complicated with IE are selected and randomly divided into two groups. 26 patients in the experimental group are treated with a new domestic dacron patch, while 22 patients in the control group are treated with an imported cardiac polyester patch. By echocardiography, collecting chest X-ray, echocardiography and laboratory examination before and after operation, the residual shunt, cardiac function, liver function, renal function, coagulation function and other related indicators are observed after operation in the two groups, and the therapeutic effect and safety of the new dacron patch are evaluated. The results showed that there is no significant difference in C/T (cardiothoracic ratio), LAD (Left atrial diameter), LVSD (left ventricular end systolic diameter) and LVDD (left ventricular end diastolic diameter) between the two groups before operation, before discharge and 1, 3 and 6 months after discharge (P>0.05). The C/T, LAD and LVDD of the two groups decrease 6 months after operation, and the size of atrioventricle decreases significantly. There is a decreasing trend in the experimental group compared with the control group, but there is no significant difference (P>0.05). There are no significant differences in cardiac function classification, echocardiography, electrocardiogram, patch performance evaluation and blood compatibility between the two groups before operation and 6 months after discharge. CONCLUSION: The new domestic dacron patch has good clinical efficacy and safety.