Association of hepatic steatosis and liver fibrosis with chronic obstructive pulmonary disease among adults.

With high prevalence and substantial mortality, metabolic dysfunction-associated steatotic liver disease and chronic obstructive pulmonary disease (COPD) are significant public health concerns. Utilizing a large, population-based dataset from the National Health and Nutrition Examination Survey, our study probes the relationship between COPD prevalence and hepatic steatosis and fibrosis, as measured by Vibration-Controlled Transient Elastography. We analyzed data from 693 individuals with COPD and 7229 without. Through weighted multivariate logistic regression analysis, a restricted cubic spline curve, and threshold effect analysis, we investigated the correlation between the severity of hepatic steatosis and fibrosis and the presence of COPD. Our findings revealed a positive correlation between the controlled attenuation parameter (CAP) and COPD prevalence [OR = 1.03 (95% CI 1.01, 1.05)], even after multivariate adjustment. Furthermore, we observed a U-shaped association between CAP and COPD, where the inflection point, CAP value of 264.85 dB/m, corresponded to the lowest COPD prevalence. Our study emphasizes a substantial and complex link between hepatic steatosis and COPD. These findings urge healthcare professionals to factor liver health into COPD management and prompt further exploration into the underlying mechanisms. This could pave the way for the development of improved prevention and treatment strategies.

TFAP2A upregulates SKA3 to promote glycolysis and reduce the sensitivity of lung adenocarcinoma cells to cisplatin.

INTRODUCTION: This work was designed to delve into the effects of SKA3 on glycolysis and cisplatin (CDDP) resistance in LUAD cells and to find new possibilities for individualized treatment of LUAD. METHODS: LUAD mRNA expression data from the TCGA database were procured to scrutinize the differential expression patterns of SKA3 in both tumor and normal tissues. GSEA and Pearson correlation analyses were employed to elucidate the impact of SKA3 on signaling pathways within the context of LUAD. In order to discern the upstream regulatory mechanisms, the ChEA and JASPAR databases were utilized to predict the transcription factors and binding sites associated with SKA3. qRT-PCR and Western blot were implemented to assay the mRNA and protein expression levels of SKA3 and TFAP2A. Chromatin immunoprecipitation (ChIP) and dual luciferase assays were performed to solidify the binding relationship between the two. Extracellular acidification rate, glucose consumption, lactate production, and glycolysis-related proteins (HK2, GLUT1, and LDHA) were used to evaluate the level of glycolysis. Cell viability under CDDP treatment was determined utilizing the CCK-8, allowing for the calculation of IC50. The expression levels of SKA3 and TFAP2A proteins were detected by immunohistochemistry (IHC). RESULTS: SKA3 exhibited upregulation in LUAD tissues and cell lines, establishing a direct linkage with glycolysis pathway. Overexpression of SKA3 fostered glycolysis in LUAD, resulting in reduced sensitivity towards CDDP treatment. The upstream transcription factor of SKA3, TFAP2A, was also upregulated in LUAD and could promote SKA3 transcription. Overexpression of TFAP2A also fostered the glycolysis of LUAD. Rescue assays showed that TFAP2A promoted glycolysis in LUAD cells by activating SKA3, reducing the sensitivity of LUAD cells to CDDP. The IHC analysis revealed a positive correlation between high expression of SKA3 and TFAP2A and CDDP resistance. CONCLUSION: In summary, TFAP2A can transcriptionally activate SKA3, promote glycolysis in LUAD, and protect LUAD cells from CDDP treatment, indicating that targeting the TFAP2A/SKA3 axis may become a plausible and pragmatic therapeutic strategy for the clinical governance of LUAD.

Construction of a prognostic model for lung adenocarcinoma based on heat shock protein-related genes and immune analysis.

Lung adenocarcinoma (LUAD) represents a prevalent form of cancer, with low early diagnosis rates and high mortality rates, posing a global health challenge. Heat shock proteins (HSPs) assume a crucial role within the tumor immune microenvironment (TME) of LUAD. Here, a collection of 97 HSP-related genes (HSPGs) was assembled based on prior literature reports, of which 36 HSPGs were differentially expressed in LUAD. In The Cancer Genome Atlas (TCGA) cohort, we constructed a prognostic model for risk stratification and prognosis prediction by integrating 13 HSPGs. In addition, the prognostic significance and predictive efficacy of the HSP-related riskscore were examined and validated in the Gene Expression Omnibus (GEO) cohort. To facilitate the clinical use of this riskscore, we also established a nomogram scale by verifying its effectiveness through different methods. In light of these outcomes, we concluded a significant correlation between HSPs and TME in LUAD, and the riskscore can be a reliable prognostic indicator. Furthermore, this study evaluated the differences in immunophenoscore, tumor immune dysfunction and exclusion score, and sensitivity to several common chemotherapy drugs among LUAD individuals in different risk groups, which may aid in clinical decision-making for immune therapy and chemotherapy in LUAD individuals.

Identification of EGFR-Related LINC00460/mir-338-3p/MCM4 Regulatory Axis as Diagnostic and Prognostic Biomarker of Lung Adenocarcinoma Based on Comprehensive Bioinformatics Analysis and Experimental Validation.

Background: Lung adenocarcinoma (LUAD) is one of the most aggressive and lethal tumor types and requires effective diagnostic and therapeutic targets. Though the epidermal growth factor receptor (EGFR) is an important target for LUAD therapy, acquired resistance is still inevitable. In recent years, the regulation of the EGFR by competing endogenous RNAs (ceRNAs) has been extensively studied and significant progress has been made. Therefore, we aim to find new targets for the diagnosis and treatment of LUAD by analyzing the EGFR-related ceRNA network in LUAD and expect to address the problem of EGFR resistance. Methods: We identified differentially expressed lncRNAs, miRNAs and mRNAs closely associated with the EGFR by analyzing transcriptome data from LUAD samples. Comprehensive bioinformatics analysis strongly suggests that the LINC00460-mir-338-3p-MCM4 ceRNA network plays an important role in the diagnosis and prognosis of LUAD. The effects of different patterns of the LINC00460/MCM4 axis on the overall survival of patients with LUAD were analyzed by a polygene regulation model. We also verified the expression of these genes in LUAD cell lines and tumor tissues by RT-PCR and immunohistochemistry. The functional enrichment analysis and targeted drug prediction of the MCM4 gene were performed. Results: Survival analysis indicated that high expressions of LINC00460 and MCM4 predict a shorter survival period for patients. Univariate and multivariate regression analyses demonstrated that higher expressions of LINC00460 and MCM4 were significantly associated with tumor size, lymph node metastasis, distant metastasis and TNM stage. A multi-gene regulation model analysis revealed that the LINC00460 (downregulation)-mir-338-3p (upregulation)-MCM4 (downregulation) pattern significantly improved the overall survival of LUAD patients (p = 0.0093). RT-PCR and immunohistochemical experiments confirmed our analytical results. In addition, the functional enrichment analysis indicated that MCM4-related genes were mainly enriched in the cell cycle and cell division. A functional association network analysis showed that MCM4 was closely related to the EGFR. Finally, the possible targeted drugs of MCM4 were queried through the drug database platform, hoping to solve its drug resistance problem by targeting EGFR-related genes. Conclusions: In summary, the LINC00460/MCM4 axis can be used as a potential new perspective for targeting EGFR genes in precision medicine and is expected to serve as a diagnostic, prognostic and drug target for LUAD.

Clinical significance of securin expression in solid cancers: A PRISMA-compliant meta-analysis of published studies and bioinformatics analysis based on TCGA dataset.

BACKGROUND: Numerous studies have investigated the clinical significance of securin expression in solid cancers; however, the results have been inconsistent. Hence, we performed a meta-analysis of published studies to assess the clinical value of securin expression in patients with solid cancers. METHODS: The Chinese National Knowledge Infrastructure, Web of Science, PubMed, and EMDASE databases were searched for eligible studies (from inception up to April 2021). Bioinformatics analysis based on The Cancer Genome Atlas dataset was also performed to evaluate the prognostic value of securin expression. RESULTS: A total of 25 articles with 26 studies were included in the meta-analysis. The results of the meta-analysis implied that high securin expression was positively correlated with unfavorable overall survival (OS) (hazard ratio = 1.52, 95% CI, 1.33-1.73; P < .001) and lymph node metastasis (odd ratio = 2.96, 95% CI, 2.26-3.86; P < .001). Consistently, our bioinformatics analysis showed that increased securin expression was associated with worse OS and shorter disease-free survival in cancer patients. CONCLUSION: Our study indicated that securin overexpression was positively associated with metastasis and inversely related to the prognosis of patients with solid cancers. However, additional high-quality studies should be conducted to validate these findings.

Let-7c-5p Restrains Cell Growth and Induces Apoptosis of Lung Adenocarcinoma Cells via Targeting ESPL1.

Lung adenocarcinoma (LUAD) is a predominant malignancy, and its high mortality prompts us to incessantly probe the relevant targeted treatment. This work intended to study the molecular mechanism of ESPL1 in LUAD. Bioinformatics analysis was performed for pan-cancer and prognosis analysis as well as target gene prediction. Expression of ESPL1 mRNA and let-7c-5p was determined via qRT-PCR, and western blot was employed to detect protein level of ESPL1. Dual-luciferase reporter gene method verified the interaction between ESPL1 and let-7c-5p. Thereafter, CCK-8, wound healing, Transwell, and flow cytometry assays were utilized to investigate proliferation, migration, and apoptosis of LUAD cells. The results revealed that ESPL1 was upregulated in LUAD, which was associated with poor prognosis. Overexpressed ESPL1 promoted LUAD cells to invade, proliferate, and migrate. Furthermore, ESPL1 was a target gene of let-7c-5p. Let-7c-5p was downregulated in LUAD cells, and played a suppressive role in LUAD malignant development, while reversed by ESPL1. Taken together, it was posited that let-7c-5p/ESPL1 may be underlying therapeutic targets of LUAD.

Comprehensive Analysis of CDK1-Associated ceRNA Network Revealing the Key Pathways LINC00460/LINC00525-Hsa-Mir-338-FAM111/ZWINT as Prognostic Biomarkers in Lung Adenocarcinoma Combined with Experiments.

Lung adenocarcinoma (LUAD) is the leading cause of cancer deaths worldwide, and effective biomarkers are still lacking for early detection and prognosis prediction. Here, based on gene expression profiles of LUAD patients from The Cancer Genome Atlas (TCGA), 806 long non-coding RNAs (lncRNAs), 122 microRNAs (miRNAs) and 1269 mRNAs associated with CDK1 were identified. The regulatory axis of LINC00460/LINC00525-hsa-mir-338-FAM111B/ZWINT was determined according to the correlation between gene expression and patient prognosis. The abnormal up-regulation of FAM111B/ZWINT in LUAD was related to hypomethylation. Furthermore, immune infiltration analysis suggested FAM111B/ZWINT could affect the development and prognosis of cancer by regulating the LUAD immune microenvironment. EMT feature analysis suggested that FAM111B/ZWINT promoted tumor spread through the EMT process. Functional analysis showed FAM111B/ZWINT was involved in cell cycle events such as DNA replication and chromosome separation. We analyzed the HERB and GSCALite databases to identify potential target medicines that may play a role in the treatment of LUAD. Finally, the expression of LINC00460/LINC00525-hsa-mir-338-FAM111B/ZWINT axis was verified in LUAD cells by RT-qPCR, and these results were consistent with bioinformatics analysis. Overall, we constructed a CDK1-related ceRNA network and revealed the LINC00460/LINC00525-hsa-mir-338-FAM111/ZWINT pathways as potential diagnostic biomarkers or therapeutic targets of LUAD.

Co-Occurring Alterations of ERBB2 Exon 20 Insertion in Non-Small Cell Lung Cancer (NSCLC) and the Potential Indicator of Response to Afatinib.

Background: Human epidermal growth factor receptor 2 (ERBB2, HER-2) exon 20 insertion (ERBB2ex20ins) remains a refractory oncogenic driver in lung cancer. So far there is limited data showing the co-occurring mutation background of ERBB2ex20ins in Chinese lung cancer and its relationship with response to afatinib. Patients and Methods: A total of 112 Chinese patients with ERBB2ex20ins identified by next-generation sequencing from 17 hospitals were enrolled. The clinical outcomes of 18 patients receiving afatinib treatment were collected. Results: Among the 112 patients, insertion-site subtypes comprised of A775ins (71%; 79/112), G776indel (17%; 19/112), and P780ins (12%; 14/112). There were 66.1% (74/112) of patients carrying TP53 co-mutation and FOXA1 was the most prevalent co-amplified gene (5.5%, 3/55). The co-occurring genomic feature was similar among three insertional-site subtypes and had an overall strong concordance with the western population from the MSKCC cohort (R 2 = 0.74, P < 0.01). For the prognosis, patients with co-occurring mutation in cell-cycle pathway especially TP53 showed shorter OS than patients without [median OS: 14.5 m (95% CI:12.7-16.3 m) vs. 30.3 m (95% CI: not reached), p = 0.04], while the OS was comparable among three subtypes. For the response to afatinib, ERBB2ex20ins as a subclonal variant was an independent factor relating to shorter PFS [median PFS: 1.2 m (95% CI: 0.8-1.6 m) vs. 4.3 m (95% CI: 3.3-5.3 m), p < 0.05]. Conclusion: Our data revealed co-occurring TP53 represent an unfavorable prognosis of patients with ERBB2ex20ins, emphasizing the more valuable role of the co-mutation patterns than insertion-site subtypes in predicting prognosis of this group of patients. Moreover, the clonality status of ERBB2ex20ins was identified as a potential indicator for response to afatinib.

Prognostic predictors of remission in ocular myasthenia after thymectomy.

BACKGROUND: Identifying prognostic predictors can assist in making clinical decisions. This study aimed to identify the potential predictors of remission in patients with ocular myasthenia gravis (OMG) after thymectomy. METHODS: OMG patients who had thymectomy between 2011 and 2017 were reviewed retrospectively. Clinical outcomes were assessed according to the Myasthenia Gravis Foundation of America Post-Intervention Status (MGFA-PIS). Kaplan-Meier analysis was used to estimate the cumulative probability of complete stable remission (CSR). Univariate and multivariable analyses with Cox proportional hazards regression were used to identify predictors of CSR. RESULTS: Fifty-one patients (23 male, 28 female) with a median age at OMG onset of 40 (range, 5-79) years were eligible for inclusion. Patients with thymomatous OMG (n=9) had a statistically older median age at disease onset [61 (range, 32-78) vs. 33.5 (range, 5-79) years, P=0.001], shorter duration from disease onset to thymectomy [3 (range, 2-24) vs. 10 (range, 1-132) months, P=0.004], and a higher rate of postoperative complication (44.4% vs. 9.5%, P=0.025), compared with non-thymomatous OMG (n=42). The estimated cumulative probability of CSR in the whole cohort was 41.8% (95% CI, 28.6-58.2%) 5 years after surgery. Age at onset of 40 years or younger (P=0.00016), female sex (P=0.069), and thymic hyperplasia (P=0.0061) were potential predictors under univariate analysis. However, only age at onset of 40 years or younger (HR: 4.117, 95% CI, 1.177-14.399, P=0.027) remained significant after multivariable analysis. CONCLUSIONS: CSR could be achieved in about 40% of OMG patients 5 years after thymectomy and is likely to be predicted by age at onset of 40 years or younger.