Targeted inhibition of m6A demethylase FTO by FB23 attenuates allergic inflammation in the airway epithelium.

Epithelial cells play a crucial role in asthma, contributing to chronic inflammation and airway hyperresponsiveness. m6A modification, which involves key proteins such as the demethylase fat mass and obesity-associated protein (FTO), is crucial in the regulation of various diseases, including asthma. However, the role of FTO in epithelial cells and the development of asthma remains unclear. In this study, we investigated the demethylase activity of FTO using a small-molecule inhibitor FB23 in epithelial cells and allergic inflammation in vivo and in vitro. We examined the FTO-regulated transcriptome-wide m6A profiling by methylated RNA immunoprecipitation sequencing (MeRIP-seq) and RNA-seq under FB23 treatment and allergic inflammation conditions. Immunofluorescence staining was performed to assess the tissue-specific expression of FTO in asthmatic bronchial mucosa. We demonstrated that FB23 alleviated allergic inflammation in IL-4/IL-13-treated epithelial cells and house dust mite (HDM)-induced allergic airway inflammation mouse model. The demethylase activity of FTO contributed to the regulation of TNF-α signaling via NF-κB and epithelial-mesenchymal transition-related pathways under allergic inflammation conditions in epithelial cells. FTO was expressed in epithelial, submucosal gland, and smooth muscle cells in human bronchial mucosa. In conclusion, FB23-induced inhibition of FTO alleviates allergic inflammation in epithelial cells and HDM-induced mice, potentially through diverse cellular processes and epithelial-mesenchymal transition signaling pathways, suggesting that FTO is a potential therapeutic target in asthma management.

Alteration of the airway microbiota is associated with the progression of post-COVID-19 chronic cough in adults: a prospective study.

Cough is one of the most common symptoms observed in patients presenting with COVID-19, persisting for an extended duration following SARS-CoV-2 infection. We aim to describe the distribution of airway microbiota and explore its role in patients with post-COVID-19 chronic cough. A total of 57 patients experiencing persistent cough after infection were recruited during the Omicron wave of SARS-CoV-2 in China. Airway microbiota profiling is assessed in nasopharyngeal swab, nasal lavage, and induced sputum samples at 4 and 8 weeks after SARS-CoV-2 infection. Our findings reveal that bacterial families Staphylococcaceae, Corynebacteriaceae, and Enterobacteriaceae are the most prevalent in the upper airway, while Streptococcaceae, Lachnospiraceae, and Prevotellaceae emerge as the most prevalent bacterial families in the lower airway. An increase in the abundance of Staphylococcus in nasopharyngeal swab samples and of Streptococcus in induced sputum samples is observed after one month. Furthermore, the abundance of Staphylococcus identified in nasopharyngeal swab samples at the baseline period emerges as an insightful predictor for improvement in cough severity. In conclusion, dynamic alterations in the airway microbial composition may contribute to the post-COVID-19 chronic cough progression, while the compositional signatures of nasopharyngeal microbiota could reflect the improvement of this disease.

Sex differences in the correlation between white matter hyperintensity and 3-month outcome in acute stroke patients.

Background: The severity of white matter hyperintensities (WMH) has been shown to be an independent predictor of poor stroke outcome, but the effect of sex on this correlation has not been investigated further. Therefore, the purpose of our study was to assess whether there was a sex difference between the severity of WMH and poor stroke outcome. Methods: This retrospective study included 449 patients with acute ischemic stroke (AIS) who received intravenous thrombolysis. WMH severity was graded based on the Fazekas scale. The association between WMH severity and stroke outcome was explored through multivariable regression analyses in men and women. Results: Among women, when dividing WMH severity into tertiles, T3 (Fazekas scale >3) had a 5.334 times higher risk for unfavorable outcomes than T1 (Fazekas scale <2) (p-trend = 0.026) in the adjusted model. In addition, moderate-severe WMH (Fazekas scale 3-6) had a 3.391 (1.151-9.991) times higher risk than none-mild WMH (Fazekas scale 0-2) (p = 0.027). Conclusions: The risk of unfavorable outcomes increased proportionally with the enlargement of the WMH severity in females, suggesting the sex-specific value of the WMH severity in optimizing the risk stratification of stroke.

Predictive value of neutrophil to apolipoprotein A1 ratio in patients with acute ischaemic stroke.

The neutrophil to apolipoprotein A1 ratio has emerged as a possible prognostic biomarker in different medical conditions. Nonetheless, the predictive potential of neutrophil to apolipoprotein A1 ratio in determining the 3-month prognosis of acute ischaemic stroke patients who undergo intravenous thrombolysis has yet to be fully acknowledged. In this study, 196 acute ischaemic stroke patients with recombinant tissue plasminogen activator and 133 healthy controls were included. Meanwhile, we incorporated a total of 386 non-thrombolytic acute ischaemic stroke patients. The acute ischaemic stroke patients with recombinant tissue plasminogen activator were divided into four groups based on quartiles of neutrophil to apolipoprotein A1 ratio. The association between neutrophil to apolipoprotein A1 ratio and the 3-month prognosis was evaluated through univariate and multivariate regression analyses. Additionally, subgroup analyses were conducted to investigate the predictive value of neutrophil to apolipoprotein A1 ratio in different patient populations. Adverse outcomes were defined as a modified Rankin Scale score of 3-6. The study findings revealed a significant association between elevated neutrophil to apolipoprotein A1 ratio levels and poor prognosis in acute ischaemic stroke patients. In the highest quartile of neutrophil to apolipoprotein A1 ratio levels (Q4), after controlling for age, gender, admission National Institutes of Health Stroke Scale score, blood urea nitrogen and stroke subtypes, the odds ratio for adverse outcomes at 3 months was 13.314 (95% confidence interval: 2.878-61.596, P = 0.001). An elevated neutrophil to apolipoprotein A1 ratio value was found to be associated with a poor prognosis in acute ischaemic stroke patients, regardless of whether they received recombinant tissue plasminogen activator treatment or not. The new model, which incorporating neutrophil to apolipoprotein A1 ratio into the conventional model, demonstrated a statistically significant improvement in discriminatory power and risk reclassification for 3-month poor outcomes in acute ischaemic stroke patients treated with recombinant tissue plasminogen activator. The new model exhibited a categorical net reclassification index (P = 0.035) of 12.9% and an integrated discrimination improvement (P = 0.013) of 5.2%. Subgroup analyses indicated that the predictive value of neutrophil to apolipoprotein A1 ratio differed across stroke subtypes. Neutrophil to apolipoprotein A1 ratio is a potential biomarker for predicting the prognosis of acute ischaemic stroke patients. The clinical implications of our findings are significant, as early identification and intervention in high-risk patients can improve their outcomes. However, further studies are required to validate our results and elucidate the underlying mechanisms of the association between neutrophil to apolipoprotein A1 ratio and poor prognosis in acute ischaemic stroke patients.

The white blood cell count to mean platelet volume ratio for ischemic stroke patients after intravenous thrombolysis.

Background and Purpose: White blood cell count to mean platelet volume ratio (WMR) is increasingly recognized as a promising biomarker. However, its predictive capability for acute ischemic stroke (AIS) patients is relatively less researched. The primary aim of this study is to explore its prognostic value in AIS patients after reperfusion regarding 3-month poor functional outcome. Methods: A total of 549 AIS patients who had undergone vascular reperfusion procedure with complete 3-month follow-up were retrospectively recruited in this study. White blood cell count, mean platelet volume at 24 h of admission were recorded. Stroke severity had been estimated using the National Institutes of Health Stroke Scale (NIHSS) and poor outcome was defined as modified Rankin Scale (mRS) 3-6 at 3 months. Results: AIS patients with poor functional outcome at 3 months displayed higher WMR. A positive correlation between WMR and NIHSS score was found (r = 0.334, p < 0.001). After adjusting potential confounders, WMR was still an independent risk factor for poor prognosis at 3 months (OR = 2.257, 95% CI [1.117-4.564], p = 0.023) in multivariate logistic regression model. Subgroup analyses further suggested a significant association between WMR and poor outcome in high baseline NIHSS (per 0.1-point increase: OR = 1.153, 95% CI [1.014-1.312], p = 0.030) group. Receiver operating characteristic (ROC) curves analysis was utilized to assess the predictive ability of WMR, indicating a cut-off value of 0.86. A nomogram that includes age, sex, NIHSS on admission, high WMR for predicting 1-year all-cause survival was also developed (C-index = 0.628). Conclusions: WMR is significantly correlated with stroke severity on admission and is proved to be an important prognostic indicator for AIS outcomes, especially in high NIHSS on admission group. Additionally, the developed nomogram that includes high WMR for predicting 1-year survival provides us with an effective visualization tool.

Human lung adenocarcinoma CD47 is upregulated by interferon-γ and promotes tumor metastasis.

Tumor cells can evade attack by phagocytes by upregulating the self-marker CD47. The mechanisms underlying tumor CD47 upregulation, however, remain unclear. Here, we report that human lung adenocarcinoma CD47 is upregulated by interferon-γ (IFN-γ), the level in the tumor microenvironment of which is markedly increased after tumor metastasis and chemotherapy. The IFN-γ receptor is expressed in various human lung adenocarcinoma tissues regardless of the CD47 protein expression, and lung adenocarcinoma CD47 expression is significantly enhanced following tumor metastasis or chemotherapy treatment. In line with this, CD47 expression in various lung cancer cells is markedly increased by IFN-γ treatment. Mechanistically, IFN-γ promotes CD47 expression by activating interferon regulatory factor-1 (IRF-1), which binds to an IRF-1-binding domain within the CD47 promoter region and increases CD47 transcription. Functionally, IFN-γ-enhanced CD47 expression facilitates human lung cancer cell invasion both in vitro and in vivo, whereas IFN-γ-induced CD47 upregulation and cancer metastasis are blocked by mutating the IRF-1-binding site within the CD47 promoter. Our results reveal IFN-γ-enhanced CD47 expression as a novel mechanism promoting human lung adenocarcinoma progression.

PD-L1 lncRNA splice isoform promotes lung adenocarcinoma progression via enhancing c-Myc activity.

BACKGROUND: Although using a blockade of programmed death-ligand 1 (PD-L1) to enhance T cell immune responses shows great promise in tumor immunotherapy, the immune-checkpoint inhibition strategy is limited for patients with solid tumors. The mechanism and efficacy of such immune-checkpoint inhibition strategies in solid tumors remains unclear. RESULTS: Employing qRT-PCR, Sanger sequencing, and RNA BaseScope analysis, we show that human lung adenocarcinoma (LUAD) all produce a long non-coding RNA isoform of PD-L1 (PD-L1-lnc) by alternative splicing, regardless if the tumor is positive or negative for the protein PD-L1. Similar to PD-L1 mRNA, PD-L1-lnc in various lung adenocarcinoma cells is significantly upregulated by IFNγ. Both in vitro and in vivo studies demonstrate that PD-L1-lnc increases proliferation and invasion but decreases apoptosis of lung adenocarcinoma cells. Mechanistically, PD-L1-lnc promotes lung adenocarcinoma progression through directly binding to c-Myc and enhancing c-Myc transcriptional activity. CONCLUSIONS: In summary, the PD-L1 gene can generate a long non-coding RNA through alternative splicing to promote lung adenocarcinoma progression by enhancing c-Myc activity. Our results argue in favor of investigating PD-L1-lnc depletion in combination with PD-L1 blockade in lung cancer therapy.

MEX3A promotes development and progression of breast cancer through regulation of PIK3CA.

Breast cancer has been identified as the most common malignant tumors among women and the morbidity of breast cancer is still increasing rapidly. MEX3A possesses important functions in the regulation of mRNAs and may be involved in a variety of human diseases including cancer, whose relationship with breast cancer is still not clear. In this study, MEX3A was identified as a potential promotor in breast cancer, whose expression was strongly higher in breast cancer tissues than normal tissues. The in vitro experiments showed that MEX3A is capable of promoting the development of breast cancer through stimulating cell proliferation, inhibiting cell apoptosis, arresting cell cycle and promoting cell migration. The functions of MEX3A were also verified in vivo. Furthermore, a combination of genechip analysis and Ingenuity pathway analysis (IPA) identified PIK3CA as a potential downstream target of MEX3A, knockdown of which executes similar inhibitory effects on breast cancer and could alleviate MEX3A-induced progression of breast cancer. In conclusion, our study unveiled, as the first time, MEX3A as a tumor promotor for breast cancer, whose function was carried out probably through the regulation of PIK3CA.

Integrated analysis of long noncoding RNA interactions reveals the potential role in progression of human papillary thyroid cancer.

Recent scientific evidence has suggested that long noncoding RNAs (lncRNAs) play an important part in tumorigenesis as an important member of competing endogenous RNAs (ceRNAs). Hundreds of RNA sequence data and relevant clinic information are freely accessible in The Cancer Genome Atlas (TCGA) datasets. However, the role of cancer-related lncRNAs in papillary thyroid cancer (PTC) is not fully understood yet. In this study, we identified 461 RNA sequencing data from TCGA. Subsequently, 45 lncRNAs, 21 miRNAs, and 78 mRNAs were chosen to construct a ceRNA network of PTC. Then, we analyzed the correlation between these 45 PTC-specific lncRNAs and clinic features and patient outcome. Thirty-seven of these lncRNAs were found to be closely related to age, race, gender, lymph node metastasis, TNM staging system, and patient outcome. Additionally, three of them were linked to PTC patient overall survival. Eventually, we selected eight lncRNAs randomly and performed quantificational real-time polymerase chain reaction (qRT-PCR) in 28 newly diagnosed patients with PTC to verify the reliability of the above results. The results of qRT-PCR are totally in agreement with the bioinformatics analysis. Additionally, it was found that HAND2-AS1 was negatively related to tumor size (P < 0.05). The results were consistent with the bioinformatics analysis in TCGA. Taken together, we identified the differentially expressed lncRNAs and constructed a PTC ceRNA network. The study provides a new perspective and supplement for our understanding of lncRNAs in PTC development and reveals potential diagnostic and prognostic markers in PTC.