Genetic association of circulating C-reactive protein levels with idiopathic pulmonary fibrosis: a two-sample Mendelian randomization study.

BACKGROUND: Several observational studies have found that idiopathic pulmonary fibrosis (IPF) is often accompanied by elevated circulating C-reactive protein (CRP) levels. However, the causal relationship between them remains to be determined. Therefore, our study aimed to explore the causal effect of circulating CRP levels on IPF risk by the two-sample Mendelian randomization (MR) analysis. METHODS: We analyzed the data from two genome-wide association studies (GWAS) of European ancestry, including circulating CRP levels (204,402 individuals) and IPF (1028 cases and 196,986 controls). We primarily used inverse variance weighted (IVW) to assess the causal effect of circulating CRP levels on IPF risk. MR-Egger regression and MR-PRESSO global test were used to determine pleiotropy. Heterogeneity was examined with Cochran's Q test. The leave-one-out analysis tested the robustness of the results. RESULTS: We obtained 54 SNPs as instrumental variables (IVs) for circulating CRP levels, and these IVs had no significant horizontal pleiotropy, heterogeneity, or bias. MR analysis revealed a causal effect between elevated circulating CRP levels and increased risk of IPF (ORIVW = 1.446, 95% CI 1.128-1.854, P = 0.004). CONCLUSIONS: The present study indicated that elevated circulating CRP levels could increase the risk of developing IPF in people of European ancestry.

GABA receptors differentially regulate life span and health span in C. elegans through distinct downstream mechanisms.

GABA, a prominent inhibitory neurotransmitter, is best known to regulate neuronal functions in the nervous system. However, much less is known about the role of GABA signaling in other physiological processes. Interestingly, recent work showed that GABA signaling can regulate life span via a metabotropic GABAB receptor in Caenorhabditis elegans. However, the role of other types of GABA receptors in life span has not been clearly defined. It is also unclear whether GABA signaling regulates health span. Here, using C. elegans as a model, we systematically interrogated the role of various GABA receptors in both life span and health span. We find that mutations in four different GABA receptors extend health span by promoting resistance to stress and pathogen infection and that two such receptor mutants also show extended life span. Different GABA receptors engage distinct transcriptional factors to regulate life span and health span, and even the same receptor regulates life span and health span via different transcription factors. Our results uncover a novel, profound role of GABA signaling in aging in C. elegans, which is mediated by different GABA receptors coupled to distinct downstream effectors.

Identification and validation of a glycosyltransferase gene signature as a novel prognostic model for lung adenocarcinoma.

Background: The role of glycosyltransferase (GT) genes in lung adenocarcinoma (LUAD) needs further elucidation. Thus, our study aims to identify the prognostic gene signature of LUAD and explore its molecular functions. Methods: We initially extracted GT gene sets from the database, and obtained mRNA expression levels and clinical data from The Cancer Genome Atlas (TCGA) database. For constructing a prognostic model for GT genes, we utilized univariate, least absolute shrinkage and selection operator (LASSO), and multivariate Cox regression analyses. Using the model, patients were categorized into high- and low-risk groups. Additionally, we evaluated differences in tumor immune infiltration between these groups and identified potential therapeutic drugs. Finally, we experimentally validated the expression levels of these crucial prognostic genes. Results: We developed a risk score comprising nine GT genes (C1GALT1, FUT1, GALNT2, PLOD2, POMK, PYGB, ST3GAL6, UGT2B11, UGT3A1). Patients were then categorized into low- and high-risk groups based on this score. The low-risk group showed superior overall survival (OS) compared to the high-risk group. There were significantly distinct tumor immune microenvironment statuses observed between the two groups. We identified potential therapeutic drugs, including the MEK inhibitor (PD-184352). Finally, we verified the expression of these nine GT genes through immunohistochemistry (IHC) staining and quantitative real-time PCR (qPCR). Conclusion: We identified a distinct LUAD GT gene signature, and these differentially expressed mRNAs could serve as valuable prognostic biomarkers and therapeutic targets. Furthermore, we experimentally validated their expression levels and identified potential therapeutic agents.

Causal relationships between lung cancer and sepsis: a genetic correlation and multivariate mendelian randomization analysis.

Background: Former research has emphasized a correlation between lung cancer (LC) and sepsis, but the causative link remains unclear. Method: This study used univariate Mendelian Randomization (MR) to explore the causal relationship between LC, its subtypes, and sepsis. Linkage Disequilibrium Score (LDSC) regression was used to calculate genetic correlations. Multivariate MR was applied to investigate the role of seven confounding factors. The primary method utilized was inverse-variance-weighted (IVW), supplemented by sensitivity analyses to assess directionality, heterogeneity, and result robustness. Results: LDSC analysis revealed a significant genetic correlation between LC and sepsis (genetic correlation = 0.325, p = 0.014). Following false discovery rate (FDR) correction, strong evidence suggested that genetically predicted LC (OR = 1.172, 95% CI 1.083-1.269, p = 8.29 × 10-5, P fdr = 2.49 × 10-4), squamous cell lung carcinoma (OR = 1.098, 95% CI 1.021-1.181, p = 0.012, P fdr = 0.012), and lung adenocarcinoma (OR = 1.098, 95% CI 1.024-1.178, p = 0.009, P fdr = 0.012) are linked to an increased incidence of sepsis. Suggestive evidence was also found for small cell lung carcinoma (Wald ratio: OR = 1.156, 95% CI 1.047-1.277, p = 0.004) in relation to sepsis. The multivariate MR suggested that the partial impact of all LC subtypes on sepsis might be mediated through body mass index. Reverse analysis did not find a causal relationship (p > 0.05 and P fdr > 0.05). Conclusion: The study suggests a causative link between LC and increased sepsis risk, underscoring the need for integrated sepsis management in LC patients.

MECOM: a bioinformatics and experimentally identified marker for the diagnosis and prognosis of lung adenocarcinoma.

Objective: We aimed to explore the clinical value of MDS1 and EVI1 complex locus (MECOM) in lung adenocarcinoma (LUAD). Methods: Bioinformatics and experimental validation confirmed MECOM expression levels in LUAD. The value of MECOM was analyzed by receiver operating characteristic (ROC) curve and Cox regression analysis. Results: Serum MECOM levels were lower in LUAD and correlated with gender, TNM stage, tumor size, lymph node metastasis and distant metastasis. The ROC curve showed that the area under the curve of MECOM was 0.804 for LUAD and, of note, could reach 0.889 for advanced LUAD; specificity was up to 90%. Conclusion: MECOM may contribute to independently identifying LUAD patients, particularly in advanced stages.

Lung adenocarcinoma is a common type of lung cancer with a high incidence and death rate. However, clinical indicators that effectively identify lung adenocarcinoma patients are still lacking. The protein encoded by the MECOM gene is a DNA-binding protein regulating gene expression, which has been found to play a cancer-promoting role in many cancers, but we found that it may play a cancer-suppressing role in lung adenocarcinoma. This study aimed to confirm whether MECOM can be a predictor for lung adenocarcinoma. Our results showed that lung adenocarcinoma patients had lower serum MECOM levels than healthy people, and patients with lower MECOM levels had a shorter survival rate. That is, patients with lower serum MECOM levels may indicate a high risk of developing lung adenocarcinoma and death. Thus, the MECOM gene is expected to be a predictor associated with the risk of developing lung adenocarcinoma and death.

Bioinformatics and experimental approach identify lipocalin 2 as a diagnostic and prognostic indicator for lung adenocarcinoma.

BACKGROUND: lipocalin 2 (LCN2) is a secreted glycoprotein that plays key roles in tumorigenesis and progression. Interestingly, LCN2 appears to have a contradictory function in developing lung adenocarcinoma (LUAD). Thus, we intend to explore the role of LCN2 in LUAD through bioinformatics and experimental validation. METHODS: LCN2 expression of LUAD was investigated in the TCGA, TIMER and HPA databases. The relationship between LCN2 and prognosis was investigated by KM plotter, TCGA and GEO databases. GO, KEGG and protein-protein interactions network analysis were conducted to investigate the potential mechanism of LCN2. The relevance of LCN2 to cancer-immune infiltrates was investigated in the TCGA and TIMER databases. Quantitative reverse transcription PCR, western blot and enzyme-linked immunosorbent assay were performed to identify the expression level of LCN2 in cells and serum samples. The CCK-8, wound healing and transwell assay were used to confirm the effect of LCN2 on cell proliferation, migration and invasion in LUAD. The receiver operating characteristic curve was utilized to assess the diagnostic efficiency of LCN2 further. RESULTS: LCN2 expression was significantly upregulated in LUAD (P < 0.05), and was correlated with the clinical stage, tumor size, lymph node metastasis and distant metastasis (P < 0.05). There was a high correlation between high LCN2 and worse prognosis in LUAD. Functional network analysis suggested that LCN2 was associated with multiple signal pathways in cancers, such as JAK-STAT, TNF, NF-κB, HIF-1 and PI3K-Akt signal pathways. In addition, the knockdown of LCN2 significantly inhibited the ability of cell proliferation, migration and invasion. Immune infiltration analysis indicated that LCN2 is associated with multiple immune cell infiltration. Notably, LCN2 demonstrated high diagnostic efficiency for LUAD (AUC = 0.818, P < 0.05), especially for stage III-IV patients could reach 0.895. CONCLUSIONS: LCN2 as an oncogenic glycoprotein promotes the cancer progression related to immune infiltrates, which might be a potential diagnostic and prognostic marker in LUAD.

Mendelian randomization study reveals the effect of idiopathic pulmonary fibrosis on the risk of erectile dysfunction.

Background: Several studies have found that erectile dysfunction (ED) is associated with interstitial lung disease. However, the causal relationship between idiopathic pulmonary fibrosis (IPF) and ED risk remains unclear. The present two-sample Mendelian randomization (MR) study aimed to reveal the causal effect of IPF on ED risk. Methods: This study included two GWAS summary statistics of IPF (1,028 cases and 196,986 controls) and ED (6,175 cases and 217,630 controls) of European ancestry. The inverse-variance weighted (IVW) was applied as the primary method, and MR-Egger, weighted median, weighted mode, and simple mode were applied as complementary methods to estimate the causal impact of IPF on ED risk. The MR-PRESSO global test and MR-Egger regression were applied to evaluate the pleiotropy. The Cochran's Q test was applied to examine heterogeneity. The leave-one-out analysis ensured the robustness and reliability of the results. Results: Twenty-one genetic variants were obtained as IPF instrumental variables without pleiotropy and heterogeneity. MR analysis using the IVW showed a potential causal relationship between IPF and increased ED risk (ORIVW = 1.046, 95% CI: 1.020-1.073, p = 0.001), and consistent results were obtained with MR-Egger, weighted median, and weighted mode. The leave-one-out analysis showed that no instrumental variables unduly influenced the results. Conclusion: This study suggested that IPF may increase the ED risk of the European population.

Clinicopathological characteristics correlated with programmed cell death-ligand 1 expression in advanced lung adenocarcinoma.

Background: Recent studies have shown that immune checkpoint inhibitors (ICIs) targeting programmed cell death-ligand 1 (PD-L1) have potential benefits in patients with non-small cell lung cancer (NSCLC) subgroups, while the clinicopathological characteristics associated with PD-L1 expression have not been well established. The purpose of this study was to detect the expression level of PD-L1 in tumor tissues of patients with advanced lung adenocarcinoma (ADC) and analyze its possible relationship with clinicopathological characteristics, so as to identify the predictors of PD-L1 expression. Methods: This retrospective study was conducted by analyzing the clinicopathological and imaging characteristics of hospitalized advanced lung ADC patients with PD-L1 available data and admitted to the respiratory department of our hospital. The expression level of PD-L1 in fresh-frozen tumor tissue samples of 136 advanced ADC patients was analyzed by immunohistochemistry. The patients were divided into positive and negative groups based on a cut-off of 1% PD-L1 expression level. Subsequently, the significant correlation between PD-L1 levels and clinicopathological features were evaluated. The predictive performance of clinicopathological characteristics on PD-L1 expression was evaluated and the optimal cut-off values were identified by plotting the receiver operating characteristic (ROC) curve. Results: The expression level of PD-L1 was related to sex, clinical stage, serum carcinoembryonic antigen (CEA), neuron specific enolase (NSE), white blood cell (WBC), and tumor (T) and metastasis (M) stage. Multivariate logistic regression analysis showed the CEA, NSE, T stage, and WBC were independent predictors of PD-L1 positive expression in lung ADC patients. The ROC curve suggested the model combining CEA with NSE [area under the curve (AUC) =0.815] could better predict the expression levels of PD-L1. The optimal cut-off values for identifying advanced lung ADC patients with PD-L1 positive were CEA ≤13.38 ng/mL and NSE ≤42.35 ng/mL, with sensitivity and specificity of 85.4% and 55.6%, and 92.7% and 32.1%, respectively. Conclusions: Some commonly used clinicopathological features are related to the histological expression of PD-L1. The serum CEA, NSE, T stage, and WBC values can be used as indicators to predict the expression level of PD-L1 in advanced lung ADC, and are used as predictors to evaluate the efficacy of ICIs before treatment.

A C. elegans neuron both promotes and suppresses motor behavior to fine tune motor output.

How neural circuits drive behavior is a central question in neuroscience. Proper execution of motor behavior requires precise coordination of many neurons. Within a motor circuit, individual neurons tend to play discrete roles by promoting or suppressing motor output. How exactly neurons function in specific roles to fine tune motor output is not well understood. In C. elegans, the interneuron RIM plays important yet complex roles in locomotion behavior. Here, we show that RIM both promotes and suppresses distinct features of locomotion behavior to fine tune motor output. This dual function is achieved via the excitation and inhibition of the same motor circuit by electrical and chemical neurotransmission, respectively. Additionally, this bi-directional regulation contributes to motor adaptation in animals placed in novel environments. Our findings reveal that individual neurons within a neural circuit may act in opposing ways to regulate circuit dynamics to fine tune behavioral output.

High blood urea nitrogen to creatinine ratio is associated with increased risk of sarcopenia in patients with chronic obstructive pulmonary disease.

BACKGROUND AND AIMS: Sarcopenia has been reported to be a prognostic factor for chronic obstructive pulmonary disease (COPD). However, the relationship between the ratio of blood urea nitrogen to creatinine (BUN/Cr) and sarcopenia in patients with COPD remain unclear. Therefore, the purpose of this study is to explore whether the ratio can be used as a predictor of sarcopenia in hospitalized COPD patients. METHODS: The skeletal muscle area index (SMI) at the level of the 12th thoracic vertebra (T12) was used to assess the risk of sarcopenia in patients. This single center cross-sectional study was conducted by analyzing the clinical parameters and identifying the T12 skeletal muscle area (SMA) and density (SMD) on chest CT images of COPD hospitalized patients admitted to the respiratory department of our hospital from March 2018 to August 2021. The study enrolled 265 hospitalized patients. Based on the different statistical properties of the above variables, differences between groups were measured by independent sample Student t-tests, Mann-Whitney U tests, or Chi-Square tests. Multivariable linear regression analysis was used to evaluate the relationship between the value of BUN/Cr and the risk of sarcopenia. RESULTS: The serum BUN/Cr ratio was negatively correlated with SMI (r = -0.201, p = 0.001) in COPD patients, and multivariate linear regression analysis showed that this ratio was associated with the risk of sarcopenia (ß = -0.109, p = 0.041). The optimal cut-off value of BUN/Cr ratio for identifying COPD patients with sarcopenia was 97.893. There was also a significant negative correlation between serum BUN/Cr ratio and forced vital capacity (FVC; r = -0.235, p < 0.001) and forced expiratory volume in the first second (FEV1; r = -0.219, p < 0.001). CONCLUSION: The BUN/Cr ratio can be used to predict sarcopenia and evaluate pulmonary function in hospitalized COPD patients.

Cytoplasmic and mitochondrial aminoacyl-tRNA synthetases differentially regulate lifespan in Caenorhabditis elegans.

Reducing the rate of translation promotes longevity in multiple organisms, representing a conserved mechanism for lifespan extension. Aminoacyl-tRNA synthetases (ARSs) catalyze the loading of amino acids to their cognate tRNAs, thereby playing an essential role in translation. Mutations in ARS genes are associated with various human diseases. However, little is known about the role of ARSs in aging, particularly whether and how these genes regulate lifespan. Here, using Caenorhabditis elegans as a model, we systematically characterized the role of all three types of ARS genes in lifespan regulation, including mitochondrial, cytoplasmic, and cyto-mito bifunctional ARS genes. We found that, as expected, RNAi knockdown of mitochondrial ARS genes extended lifespan. Surprisingly, knocking down cytoplasmic or cyto-mito bifunctional ARS genes shortened lifespan, though such treatment reduced the rate of translation. These results reveal opposing roles of mitochondrial and cytoplasmic ARSs in lifespan regulation, demonstrating that inhibiting translation may not always extend lifespan.

Ferroptosis-Related Genes in Bronchoalveolar Lavage Fluid Serves as Prognostic Biomarkers for Idiopathic Pulmonary Fibrosis.

Background: Idiopathic pulmonary fibrosis (IPF) is a chronic progressive disease with unknown etiology and unfavorable prognosis. Ferroptosis is a form of regulated cell death with an iron-dependent way that is involved in the development of various diseases. Whereas the prognostic value of ferroptosis-related genes (FRGs) in IPF remains uncertain and needs to be further elucidated. Methods: The FerrDb database and the previous studies were screened to explore the FRGs. The data of patients with IPF were obtained from the GSE70866 dataset. Wilcoxon's test and univariate Cox regression analysis were applied to identify the FRGs that are differentially expressed between normal and patients with IPF and associated with prognosis. Next, a multigene signature was constructed by the least absolute shrinkage and selection operator (LASSO)-penalized Cox model in the training cohort and evaluated by using calibration and receiver operating characteristic (ROC) curves. Then, 30% of the dataset samples were randomly selected for internal validation. Finally, the potential function and pathways that might be affected by the risk score-related differently expressed genes (DEGs) were further explored. Results: A total of 183 FRGs were identified by the FerrDb database and the previous studies, and 19 of them were differentially expressed in bronchoalveolar lavage fluid (BALF) between IPF and healthy controls and associated with prognosis (p < 0.05). There were five FRGs (aconitase 1 [ACO1], neuroblastoma RAS viral (v-ras) oncogene homolog [NRAS], Ectonucleotide pyrophosphatase/phosphodiesterase 2 [ENPP2], Mucin 1 [MUC1], and ZFP36 ring finger protein [ZFP36]) identified as risk signatures and stratified patients with IPF into the two risk groups. The overall survival rate in patients with high risk was significantly lower than that in patients with low risk (p < 0.001). The calibration and ROC curve analysis confirmed the predictive capacity of this signature, and the results were further verified in the validation group. Risk score-related DEGs were found enriched in ECM-receptor interaction and focal adhesion pathways. Conclusion: The five FRGs in BALF can be used for prognostic prediction in IPF, which may contribute to improving the management strategies of IPF.

A Comprehensive Understanding of Dietary Effects on C. elegans Physiology.

Diet has been shown to play an important role in human physiology. It is a predominant exogenous factor regulating the composition of gut microbiota, and dietary intervention holds promise for treatment of diseases such as obesity, type 2 diabetes, and malnutrition. Furthermore, it was reported that diet has significant effects on physiological processes of C. elegans, including reproduction, fat storage, and aging. To reveal novel signaling pathways responsive to different diets, C. elegans and its bacterial diet were used as an interspecies model system to mimic the interaction between host and gut microbiota. Most signaling pathways identified in C. elegans are highly conserved across different species, including humans. A better understanding of these pathways can, therefore, help to develop interventions for human diseases. In this article, we summarize recent achievements on molecular mechanisms underlying the response of C. elegans to different diets and discuss their relevance to human health.