Pyrite-activated persulfate to degrade 3,5,6-trichloro-2-pyridyl in water: Degradation and Fe release mechanism.

TCP (3,5,6-trichloro-2-pyridinol), the main recalcitrant degradation product of chlorpyrifos, poses a high risk to human health and ecological systems. This study provided a comprehensive exploration of the pyrite-activated persulfate (PS) system for the removal of TCP in water and placed particular emphasis on the pyrite oxidation process that releases Fe. The results showed that the pyrite-activated PS system can completely degrade TCP within 300 min at 5.0 mmol/L PS and 1000 mg/L pyrite at 25 °C, wherein small amounts of PS (1 mmol/L) can effectively facilitate TCP removal and the oxidation of pyrite elements, while excessive PS (>20 mmol/L) can lead to competitive inhibitory effects, especially in the Fe release process. Aimed at the dual effects, the evident positive correlation (R2 > 0.90) between TCP degradation (kTCP) and Fe element release (kFe), but the value of k (0.00237) in the pyrite addition variable experiment was less than that in the PS experiment (k = 0.00729), further indicating that the inhibition effect of excessive addition consists of PS but not notably pyrite. Moreover, the predominant free radicals and non-free radicals produced in the pyrite/PS system were tested, with the order of significance being •OH < Fe (Ⅳ) < SO4•- < â€¢O2- < 1O2, wherein 1O2 emerged as the principal player in both TCP degradation and Fe release from the pyrite oxidation process. Additionally, CO32- can finitely activate PS but generally slows TCP degradation and inhibit pyrite oxidation releasing Fe process. This study provides a theoretical basis for the degradation of TCP using pyrite-activated PS.

Emerging role of N6-methyladenosine RNA modification in regulation of SARS-CoV-2 infection and virus-host interactions.

Since December 2019, the infection caused by Severe Acute Respiratory Syndrome Coronavirus Type 2 (SARS-CoV-2) has posed an enormous threat to human health security worldwide. Constant mutation of viral genome and varying therapeutic responses of patients infected with this virus prompted efforts to uncover more novel regulators in the pathogenesis. The involvement of N6-methyladenosine, a modified form of RNA, plays a crucial role in viral replication, viral pathogenicity, and intricate signaling pathways connected with immune responses. This review discusses research advances revealing the regulation of the life cycle of SARS-CoV-2 and antiviral responses of host cells by RNA m6A modification, highlights the biological functions of N6-methyladenosine components in SARS-CoV-2 infection and virus-host interactions, and outlines current challenges and future directions for exploring the potential clinical value of m6A modification in COVID-19.

Airway epithelial overexpressed cathepsin K induces airway remodelling through epithelial-mesenchymal trophic unit activation in asthma.

BACKGROUND AND PURPOSE: Airway epithelial cells (AECs) regulate the activation of epithelial-mesenchymal trophic units (EMTUs) during airway remodelling through secretion of signalling mediators. However, the major trigger and the intrinsic pathogenesis of airway remodelling is still obscure. EXPERIMENTAL APPROACH: The differing expressed genes in airway epithelia related to airway remodelling were screened and verified by RNA-sequencing and signalling pathway analysis. Then, the effects of increased cathepsin K (CTSK) in airway epithelia on airway remodelling and EMTU activation were identified both in vitro and in vivo, and the molecular mechanism was elucidated in the EMTU model. The potential of CTSK as an an effective biomarker of airway remodelling was analysed in an asthma cohort of differing severity. Finally, an inhibitor of CTSK was administered for potential therapeutic intervention for airway remodelling in asthma. KEY RESULTS: The expression of CTSK in airway epithelia increased significantly along with the development of airway remodelling in a house dust mite (HDM)-stressed asthma model. Increased secretion of CTSK from airway epithelia induced the activation of EMTUs by activation of the PAR2-mediated pathway. Blockade of CTSK inhibited EMTU activation and alleviated airway remodelling as an effective intervention target of airway remodelling. CONCLUSION AND IMPLICATIONS: Increased expression of CTSK in airway epithelia is involved in the development of airway remodelling in asthma through EMTU activation, mediated partly through the PAR2-mediated signalling pathway. CTSK is a potential biomarker for airway remodelling, and may also be a useful intervention target for airway remodelling in asthma patients.

Transformation of chronic disease management: Before and after the COVID-19 outbreak.

Adults with chronic diseases often experience a decline in their quality of life along with frequent exacerbations. These diseases can cause anxiety and impose a significant economic burden. Self-management is a crucial aspect of treatment outside of the hospital and can improve quality of life and reduce the financial burden resulting from unexpected hospitalizations. With the COVID-19 pandemic, telehealth has become a vital tool for both medical professionals and patients; many in-person appointments have been canceled due to the pandemic, leading to increased reliance on online resources. This article aimed to discuss various methods of chronic disease management, both traditional self-management and modern telehealth strategies, comparing before and after the COVID-19 outbreak and highlighting challenges that have emerged.

N6-methyladenosine (m6A) regulator expression pattern correlates with the immune landscape in lung adenocarcinoma.

Lung adenocarcinoma is the leading cause of tumor-related death. The tumor microenvironment (TME) may determine anti-tumor treatment responses. We focused on 23 m6A regulators, and analyzed m6A regulator expression patterns in 995 lung adenocarcinoma samples collected from 7 publicly available datasets. Two m6A clusters were identified, wherein gene clusters and m6A score were generated using unsupervised clustering and principal component analysis based on differentially expressed genes with prognostic significance. Further, three independent datasets from TCGA-LUAD and GEO were employed to validate the impact of m6A signatures and score. We found that m6A cluster 1 with high m6A score was associated with an inflamed TME, higher neoantigen and tumor mutation burden and improved response to immunotherapy. However, anti-tumor immunity cells were exhausted in high m6A score patients; thus, the prognosis of these patients was poor. Elucidation of m6A regulator expression pattern may facilitate the development of effective treatment strategies for lung adenocarcinoma.

Exposure to second-hand smoke is an independent risk factor of small airway dysfunction in non-smokers with chronic cough: A retrospective case-control study.

Objectives: This study aimed to identify the potential risk factors for small airway dysfunction (SAD) in non-smokers with chronic cough. Methods: Non-smokers with chronic cough who underwent lung function tests at Xiangya Hospital from May 2019 to May 2020 were enrolled, and divided into the derivation and validation cohorts based on their hospital admission time. SAD was determined based on the presence of at least two of the following three indicators of lung function being less than 65% of predicted: maximal mid-expiratory flow, forced expiratory flow at 50% of forced vital capacity (FVC), and forced expiratory flow at 75% of FVC. Clinical data of these patients were collected. Risk factors for SAD were identified by logistic regression analysis in the derivation cohort and further confirmed in the validation cohort. Results: In total, 316 patients (152 in the non-SAD group and 164 in the SAD group) were included in the derivation cohort. Compared with the non-SAD group, the SAD group had a higher proportion of female patients (82.3 vs. 59.2%, P < 0.001), was more commonly exposed to second-hand smoke (SHS) (61.6 vs. 27.6%, P < 0.001), and tended to be older (median age, 45.5 vs. 40.0 years old, P = 0.004). The median FVC, forced expiratory volume in one second (FEV1) % pred, FEV1/FVC ratio, and peak expiratory flow (PEF) % pred were slightly lower in the SAD group. Multivariable logistic analysis showed that exposure to SHS was an independent risk factor (OR 4.166 [95% CI 2.090-8.302], P < 0.001) for SAD in non-smokers with chronic cough after adjusting for related variables. In the validation cohort (n = 146), patients with SHS exposure had a relative risk of 1.976 (95% CI 1.246-3.135, P = 0.004) for SAD compared to those without SHS exposure. Multivariable logistic analysis consistently confirmed that exposure to SHS was an independent risk factor (OR 3.041 [95% CI 1.458-6.344], P = 0.003) for SAD in non-smokers. Conclusions: Exposure to SHS is independently associated with a higher risk of SAD in non-smokers with chronic cough. Reduction in SHS exposure may ameliorate lung function, thus lowering the risk of irreversible airway obstruction.

Clinical application of oscillometry in respiratory diseases: an impulse oscillometry registry.

Background: Respiratory oscillometry is a promising complement to the traditional pulmonary function tests for its simplicity. The usefulness of oscillometry in adult clinical practice has not been clarified. This study aimed to analyse the characteristics and diagnostic performance of oscillometry in respiratory diseases, and explore the cut-offs of oscillometric parameters for severity grading. Methods: In this multicentre registry of impulse oscillometry (IOS), IOS and spirometric data of healthy individuals and patients with respiratory diseases were collected and analysed. Linear mixed model analysis was performed to explore the effects of disease and forced expiratory volume in 1 s (FEV1) on oscillometric parameters. Results: The study included 567 healthy subjects, 781 asthmatic patients, 688 patients with chronic obstructive pulmonary disease (COPD), 109 patients with bronchiectasis, 40 patients with upper airway obstruction (UAO) and 274 patients with interstitial lung disease (ILD) in the analysis. Compared at the same FEV1 level, asthma, COPD, bronchiectasis, UAO and ILD displayed different oscillometric characteristics. The z-score of resistance at 5 Hz (R 5) was the best variable to identify respiratory diseases with a sensitivity of 62.4-66.7% and a specificity of 81.5-90.3%. With reference to the severity grading cut-offs of FEV1, R 5 z-scores of 2.5 and 4 were defined as the cut-off values of moderately and severely increased R 5. Conclusion: Respiratory oscillometry is more appropriate to be a tool of evaluating, rather than of diagnosing, respiratory diseases. A severity grading system of oscillometric parameters was developed to help the interpretation of oscillometry in clinical practice.

Early-like differentiation status of systemic PD-1+CD8+ T cells predicts PD-1 blockade outcome in non-small cell lung cancer.

Objectives: Despite remarkable advances in the treatment of non-small cell lung cancer (NSCLC) with anti-programmed death (PD)-1 therapy; only a fraction of patients derives durable clinical benefit. In this study, we investigated whether the differentiation status of systemic CD8+ T cells predicts the outcome of PD-1 blockade in NSCLC. Methods: We carried out a prospective study on a total of 77 NSCLC patients receiving anti-PD-1 blockers, among which 47 patients were assigned as a discovery cohort and 30 patients as a validation cohort. Peripheral blood samples were obtained at baseline and upon multiple therapy cycles and analyzed by multi-parameter flow cytometry. Results: We found that a higher baseline ratio of PD-1+ early effector memory CD8+ T cells (CD28+CD27-CD45RO+, TEEM) to PD-1+ effector CD8+ T cells (CD28-CD27-CD45RO-, TE) delineated responders to PD-1 blockade from progressors and was associated with prolonged progression-free survival (PFS) and durable clinical benefit. Moreover, PD-1+CD8 TEEM cells exhibited early responses after anti-PD-1 therapy and was the major fraction of cycling PD-1+Ki67+CD8+ T cells to expand specifically with positive impact on PFS. Conclusion: These findings provide insights into how the baseline differentiation status of the peripheral immune system determines responses to PD-1-targeted therapies.

Discovery of tumor immune infiltration-related snoRNAs for predicting tumor immune microenvironment status and prognosis in lung adenocarcinoma.

Lung adenocarcinoma (LUAD) has a high mortality rate and is difficult to diagnose and treat in its early stage. Previous studies have demonstrated that small nucleolar RNAs (snoRNAs) play a critical role in tumor immune infiltration and the development of a variety of solid tumors. However, there have been no studies on the correlation between tumor-infiltrating immune-related snoRNAs (TIISRs) and LUAD. In this study, we filtered six immune-related snoRNAs based on the tissue specificity index (TSI) and expression profile of all snoRNAs between all LUAD cell lines from the Cancer Cell Line Encyclopedia and 21 types of immune cells from the Gene Expression Omnibus database. Further, we performed real-time quantitative polymerase chain reaction (RT-qPCR) to validate the expression status of these snoRNAs on peripheral blood mononuclear cells (PBMCs) and lung cancer cell lines. Next, we developed a TIISR signature based on the expression profiles of snoRNAs from 479 LUAD patients filtered by the random survival forest algorithm. We then analyzed the value of this TIISR signature (TIISR risk score) for assessing tumor immune infiltration, immune checkpoint inhibitor (ICI) treatment response, and the prognosis of LUAD between groups with high and low TIISR risk score. Further, we found that the TIISR risk score groups showed significant differences in biological characteristics and that the risk score could be used to assess the level of tumor immune cell infiltration, thereby predicting prognosis and responsiveness to immunotherapy in LUAD patients.

Reference values of respiratory impedance with impulse oscillometry in healthy Chinese adults.

BACKGROUND: Impulse oscillometry (IO) is a non-invasive pulmonary function test for measuring respiratory impedance. Available reference equations of IO indices for adults are limited. The aim of this study was to develop reference equations of IO indices for Chinese adults. METHODS: In a multicentral, cross-sessional study of IO in Chinese adults, IO data from healthy subjects were collected from 19 general hospitals across China between 2016 and 2018. Oscillometry measurements were conducted in accordance with recommendations of the European Respiratory Society (ERS). Multiple linear regression was performed to develop sex-specific reference equations of IO indices. RESULTS: IO measurements were performed in 1,318 subjects, of which 567 subjects were defined as healthy individuals with acceptable IO data and were included in the final analysis. Reference equations and limits of normal [lower limit of normal (LLN)/upper limit of normal (ULN)] of IO indices were developed separately for males and females. Height but not age was shown to be the most influential contributor to IO indices. The reference equations currently used in lung function laboratories predicted higher R5 and X5. Normal ranges of R5 and X5 recommended by the equipment manufacturer were clearly different from the ULN/LLN derived from the reference equations. CONCLUSIONS: Reference equations of IO indices for Chinese adults from a wide region were provided in this study. It is necessary to update new IO reference equations and adopt ULN/LLN as normal ranges of IO indices. TRIAL REGISTRATION: This study was registered at www.clinicaltrials.gov as part of a larger study NCT03467880.

Neutrophil extracellular traps amplify neutrophil recruitment and inflammation in neutrophilic asthma by stimulating the airway epithelial cells to activate the TLR4/ NF-κB pathway and secrete chemokines.

Neutrophilic asthma (NA) is a distinct airway inflammation disease with prominent neutrophil infiltration. The role played by neutrophil extracellular traps (NETs) in NA, however, is quite unclear. This study was based on the hypothesis that NETs are responsible for the second neutrophil wave and therefore contribute significantly to inflammation. The proinflammatory effects of NETs were evaluated in vitro and in vivo. Formation of NETs and neutrophil swarming was seen in a mouse model of NA. Additionally, NETs were found to stimulate airway cells to express CXCL1, CXCL2, and CXCL8 via the TLR4/NF-κB pathway, which recruits neutrophils to the inflammation site. Furthermore, prevention of NET formation decreased the recruitment of lung neutrophils and hence reduce neutrophilic inflammation. Additionally, the structural integrity of NETs had no effect on the recruitment of lung neutrophils and neutrophilic inflammation. In NA mice, NETs could trigger airway and alveolar epithelial cells to express chemokines which recruit more neutrophils via activation of the TLR4/NF-κB pathway.

Mutational landscape and clonal diversity of pulmonary adenoid cystic carcinoma.

Pulmonary adenoid cystic carcinoma is a rare and indolent lung malignancy, characterized by a protracted but unpredictable growth behavior. Currently, the treatment of PACC relies on surgery and local radiotherapy. However, treatment options for advanced PACC patients are limited. A larger number of studies demonstrated that advanced PACC patients obtained limited benefit from chemotherapy. Moreover, only a few case reports revealed PACC patients were candidates for target therapy. Therefore, there is an urgent need to develop novel therapies. Due to its rareness, its mutational landscape remains largely elusive. In this study, we performed capture-based ultra-deep sequencing on multiregional surgical specimens obtained from 8 PACC patients using a panel consisting of 295 cancer-related genes. Our data revealed distinctive mutational spectrum of PACC, which differed from non-small cell lung cancer and adenoid cystic carcinomas originated from other anatomical sites. PACC, lacking mutations in a majority of non-small cell lung cancer driver genes, has frequent mutations in genes participating in chromatin remodeling and NOTCH signaling pathway. We also elucidated spatial intra-tumoral heterogeneity, which varied among cases. Most mutations in chromatin remodelers were subclonal. Collectively, our findings elucidated molecular signature associated with PACC and highlighted the potential for epigenetic therapy in this disease.

Inhibition of SERPINE2/protease nexin-1 by a monoclonal antibody attenuates airway remodeling in a murine model of asthma.

SERPINE2, also known as protease nexin-1 (PN-1), is a serine protease inhibitor produced by many cell types and has pleiotropic biological functions. It has been reported that SERPINE2/PN-1 is involved in tissue remodeling of fibrotic diseases including idiopathic pulmonary fibrosis and cardiac fibrosis. However, the potential role of SERPINE2/PN-1 in asthmatic airway remodeling has remained barely investigated so far. In this study, BALB/c male mice were sensitized and challenged by ovalbumin to generate murine models of airway remodeling. Anti-SERPINE2 monoclonal antibody was intraperitoneally injected into these mice during the ovalbumin challenge while IgG antibody was used as a vehicle control. The results revealed that the expression of SERPINE2/PN-1 was significantly upregulated in the lung extracts of ovalbumin-challenged mice, and this upregulation was inhibited by dexamethasone. Sustained ovalbumin stimulation increased the thickness of airway wall and α-SMA positive areas in lung, which was attenuated by the treatment with SERPINE2 antibody. In addition, SERPINE2 antibody partially blocked the phosphorylation of ERK, and reduced the upregulation of MMP-9 and TIMP-1 expressions in asthmatic mice. These findings suggest that SERPINE2/PN-1 may play a role in the pathologic development of airway remodeling. Monoclonal antibody against SERPINE2 may have the potential as an effective pharmacotherapy for asthmatic airway remodeling.

MicroRNA-33b inhibits lung adenocarcinoma cell growth, invasion, and epithelial-mesenchymal transition by suppressing Wnt/ß-catenin/ZEB1 signaling.

Altered expression of microRNA (miRNA) is associated with lung carcinogenesis and metastasis. Our previous study of lung cancer miRNAs using the gene chip assay demonstrated altered miR-33b expression in lung adenocarcinoma. The present study further investigated miR-33b expression, function, and gene regulation in lung cancer cells in vitro and in nude mouse xenografts. Our data showed that the level of miR-33b expression was dramatically decreased in lung adenocarcinoma cell lines and tissues and that the reduced miR-33b expression was associated with tumor lymph node metastasis. Furthermore, restoration of miR-33b expression inhibited lung adenocarcinoma cell proliferation, migration, and invasion and tumor cell epithelial-mesenchymal transition (EMT) in vitro. Luciferase assay revealed that miR-33b bound to ZEB1 3'-UTR region and inhibited ZEB1 expression, while expression of ZEB1 mRNA and miR-33b was inversely associated with lung adenocarcinoma cell lines and tissues. Subsequently, we found that miR-33b suppressed the activity of WNT/ß-catenin signaling in lung adenocarcinoma cells and in turn suppressed tumor cell growth and EMT in vitro and in vivo nude mouse xenografts. In conclusion, the present study provided novel insight into the molecular mechanism of lung adenocarcinoma progression. MicroRNA-33b should be further investigated as a potential therapeutic target in human lung adenocarcinoma.