Comparison of extrafine beclomethasone dipropionate/formoterol fumarate dry powder inhaler and pressurized metered-dose inhaler in Chinese patients with asthma: the FORTUNE study.

OBJECTIVE: When selecting inhaled therapies, it is important to consider both the active molecules and the device. Extrafine formulation beclomethasone dipropionate plus formoterol fumarate (BDP/FF) has been available for some years delivered via pressurized metered-dose inhaler (pMDI). More recently, a breath-activated, multi-dose dry-powder inhaler (DPI), the NEXThaler, has been approved. The current study aimed to demonstrate the non-inferiority of BDP/FF delivered via the DPI vs. via the pMDI, in Chinese adults with asthma. METHODS: After a four-week run-in period, when all patients received BDP/FF pMDI 100/6 µg, two inhalations twice daily (BID), patients were randomized equally to BDP/FF pMDI or DPI, both 100/6 µg, two inhalations BID for 12 weeks. The primary objective was to demonstrate non-inferiority of BDP/FF DPI vs. BDP/FF pMDI in terms of average pre-dose morning peak expiratory flow (PEF) over the entire treatment period. RESULTS: Of 252 and 242 patients in the DPI and pMDI groups, respectively, 88.5% and 88.8% completed the study. The primary objective was met, with no statistically significant difference between the treatments in average pre-dose morning PEF, and with the lower limit of the 95% CI above the -15 L/min non-inferiority margin (adjusted mean difference: 5.25 L/min [95% CI: -0.56, 11.06]). Adverse events were reported by 48.4% and 49.6% patients in the DPI and pMDI groups, respectively, most mild or moderate. CONCLUSIONS: The NEXThaler DPI is a similarly effective device to the pMDI for the administration of BDP/FF in adults, so extending the options available for the management of asthma.

Unravelling the enigma of the human microbiome: Evolution and selection of sequencing technologies.

The human microbiome plays a crucial role in maintaining health, with advances in high-throughput sequencing technology and reduced sequencing costs triggering a surge in microbiome research. Microbiome studies generally incorporate five key phases: design, sampling, sequencing, analysis, and reporting, with sequencing strategy being a crucial step offering numerous options. Present mainstream sequencing strategies include Amplicon sequencing, Metagenomic Next-Generation Sequencing (mNGS), and Targeted Next-Generation Sequencing (tNGS). Two innovative technologies recently emerged, namely MobiMicrobe high-throughput microbial single-cell genome sequencing technology and 2bRAD-M simplified metagenomic sequencing technology, compensate for the limitations of mainstream technologies, each boasting unique core strengths. This paper reviews the basic principles and processes of these three mainstream and two novel microbiological technologies, aiding readers in understanding the benefits and drawbacks of different technologies, thereby guiding the selection of the most suitable method for their research endeavours.

PIF1 Promotes Autophagy to Inhibit Chronic Hypoxia Induced Apoptosis of Pulmonary Artery Endothelial Cells.

Purpose: Pulmonary artery hypertension (PAH) is a common complication of chronic obstructive pulmonary disease and obstructive sleep apnea/hypopnea syndrome worldwide. Pulmonary vascular alterations associated with PAH have multifactorial causes, in which endothelial cells play an important role. Autophagy is closely related to endothelial cell injury and the development of PAH. PIF1 is a multifunctional helicase crucial for cell survival. The present study investigated the effect of PIF1 on autophagy and apoptosis in human pulmonary artery endothelial cells (HPAECs) under chronic hypoxia stress. Methods: Chronic hypoxia Gene expression profiling chip-assays identified the PIF1 gene as differentially expressed, which was verified by RT-qPCR analysis. Electron microscopy, immunofluorescence, and Western blotting were used to analyze autophagy and the expression of LC3 and P62. Apoptosis was analyzed using flow cytometry. Results: Our study found that chronic hypoxia induces autophagy in HPAECs, and apoptosis was exacerbated by inhibiting autophagy. Levels of the DNA helicase PIF1 were increased in HPAECs after chronic hypoxia. PIF1 knockdown inhibited autophagy and promoted the apoptosis of HPAECs under chronic hypoxia stress. Conclusion: Based on these findings, we conclude that PIF1 inhibits the apoptosis of HPAECs by accelerating the autophagy pathway. Therefore, PIF1 plays a crucial role in HPAEC dysfunction in chronic hypoxia-induced PAH and may be a potential target for the treatment of PAH.

Efficient clinical data analysis for prediction of coal workers' pneumoconiosis using machine learning algorithms.

PURPOSE: The purpose of this study is to propose an efficient coal workers' pneumoconiosis (CWP) clinical prediction system and put it into clinical use for clinical diagnosis of pneumoconiosis. METHODS: Patients with CWP and dust-exposed workers who were enrolled from August 2021 to December 2021 were included in this study. Firstly, we chose the embedded method through using three feature selection approaches to perform the prediction analysis. Then, we performed the machine learning algorithms as the model backbone and combined them with three feature selection methods, respectively, to determine the optimal predictive model for CWP. RESULTS: Through applying three feature selection approaches based on machine learning algorithms, it was found that AaDO2 and some pulmonary function indicators played an important role in prediction for identifying CWP of early stage. The support vector machine (SVM) algorithm was proved as the optimal machine learning model for predicting CWP, with the ROC curves obtained from three feature selection methods using SVM algorithm whose AUC values of 97.78%, 93.7%, and 95.56%, respectively. CONCLUSION: We developed the optimal model (SVM algorithm) through comparisons and analyses among the performances of different models for the prediction of CWP as a clinical application.

Advances in Exosome Research in the Management of Lung Cancer.

Lung cancer is one of the most common malignant tumors, and its death rate is much higher than that of colon, kidney, breast, and prostate cancers, and its 5-year survival rate is only 18%. Lung cancer has no specific clinical symptoms in its early stages and lacks effective detection, making early detection difficult. The survival rate for advanced lung cancer is meager, with a median survival of only 12 months for stage IIIB/IV non-small cell lung cancer treated with platinumbased chemotherapy. Exosomes could provide vital information for the early diagnosis of lung cancer and have the potential to become a tumor marker for lung cancer. In addition, scientists have proposed encouraging ways to treat lung cancer by loading drugs, proteins, microRNAs, and siRNAs into exosomes. Therefore, studying lung cancer exosomes and exosomal nano drugs will provide new ideas and approaches for the diagnosis and treatment of lung cancer. This paper reviews the progress of research on the biological functions of exosomes and exosomal nanomedicines and their applications in clinical practice.

Incidence and influencing factors of occupational pneumoconiosis: a systematic review and meta-analysis.

OBJECTIVES: To determine the incidence of pneumoconiosis worldwide and its influencing factors. DESIGN: Systematic review and meta-analysis. SETTING: Cohort studies on occupational pneumoconiosis. PARTICIPANTS: PubMed, Embase, the Cochrane Library and Web of Science were searched until November 2021. Studies were selected for meta-analysis if they involved at least one variable investigated as an influencing factor for the incidence of pneumoconiosis and reported either the parameters and 95% CIs of the risk fit to the data, or sufficient information to allow for the calculation of those values. PRIMARY OUTCOME MEASURES: The pooled incidence of pneumoconiosis and risk ratio (RR) and 95% CIs of influencing factors. RESULTS: Our meta-analysis included 19 studies with a total of 335 424 participants, of whom 29 972 developed pneumoconiosis. The pooled incidence of pneumoconiosis was 0.093 (95% CI 0.085 to 0.135). We identified the following influencing factors: (1) male (RR 3.74; 95% CI 1.31 to 10.64; p=0.01), (2) smoking (RR 1.80; 95% CI 1.34 to 2.43; p=0.0001), (3) tunnelling category (RR 4.75; 95% CI 1.96 to 11.53; p<0.0001), (4) helping category (RR 0.07; 95% CI 0.13 to 0.16; p<0.0001), (5) age (the highest incidence occurs between the ages of 50 and 60), (6) duration of dust exposure (RR 4.59, 95% CI 2.41 to 8.74, p<0.01) and (7) cumulative total dust exposure (CTD) (RR 34.14, 95% CI 17.50 to 66.63, p<0.01). A dose-response analysis revealed a significant positive linear dose-response association between the risk of pneumoconiosis and duration of exposure and CTD (P-non-linearity=0.10, P-non-linearity=0.16; respectively). The Pearson correlation analysis revealed that silicosis incidence was highly correlated with cumulative silica exposure (r=0.794, p<0.001). CONCLUSION: The incidence of pneumoconiosis in occupational workers was 0.093 and seven factors were found to be associated with the incidence, providing some insight into the prevention of pneumoconiosis. PROSPERO REGISTRATION NUMBER: CRD42022323233.

Cyclovirobuxine D inhibits growth and progression of non­small cell lung cancer cells by suppressing the KIF11­CDC25C­CDK1­CyclinB1 G2/M phase transition regulatory network and the NFκB/JNK signaling pathway.

Lung cancer is the leading cause of cancer­related mortality worldwide. Non­small cell lung cancer (NSCLC) is the most common pathological subtype of lung cancer and is associated with low 5­year overall survival rates. Therefore, novel and effective chemotherapeutic drugs are urgently required for improving the survival outcomes of patients with lung cancer. Cyclovirobuxine D (CVB­D) is a natural steroidal alkaloid, used for the treatment of cardiovascular diseases in Traditional Chinese Medicine. Several studies have also demonstrated the antitumor effects of CVB­D. Therefore, in the present study, the therapeutic effects of CVB­D in lung cancer and the underlying mechanisms were investigated using the in vivo xenograft model of NSCLC in nude mice and in vitro experiments with the NSCLC cell lines. Bioinformatics analyses of RNA­sequencing data, and cell­based functional assays demonstrated that CVB­D treatment significantly inhibited in vitro and in vivo NSCLC cell proliferation, survival, invasion, migration, angiogenesis, epithelial­to­mesenchymal transition and G2/M phase cell cycle. CVB­D exerted its antitumor effects by inhibiting the KIF11­CDK1­CDC25C­cyclinB1 G2/M phase transition regulatory oncogenic network and the NF­κB/JNK signaling pathway. CVB­D treatment significantly reduced the sizes and weights and malignancy of xenograft NSCLC tumors in the nude mice. In conclusion, the present study demonstrated that CVB­D inhibited the growth and progression of NSCLC cells by inhibiting the KIF11­CDK1­CDC25C­CyclinB1 G2/M phase transition regulatory network and the NF­κB/JNK signaling pathway. Therefore, CVB­D is a promising drug for the treatment of NSCLC patients.

Adenovirus-mediated Overexpression of FcγRIIB Attenuates Pulmonary Inflammation and Fibrosis.

Progressive fibrosing interstitial lung diseases (PF-ILDs) result in high mortality and lack effective therapies. The pathogenesis of PF-ILDs involves macrophages driving inflammation and irreversible fibrosis. Fc-γ receptors (FcγRs) regulate macrophages and inflammation, but their roles in PF-ILDs remain unclear. We characterized the expression of FcγRs and found upregulated FcγRIIB in human and mouse lungs after exposure to silica. FcγRIIB deficiency aggravated lung dysfunction, inflammation, and fibrosis in silica-exposed mice. Using single-cell transcriptomics and in vitro experiments, FcγRIIB was found in alveolar macrophages, where it regulated the expression of fibrosis-related genes Spp1 and Ctss. In mice with macrophage-specific overexpression of FcγRIIB and in mice treated with adenovirus by intratracheal instillation to upregulate FcγRIIB, silica-induced functional and histological changes were ameliorated. Our data from three genetic models and a therapeutic model suggest that FcγRIIB plays a protective role that can be enhanced by adenoviral overexpression, representing a potential therapeutic strategy for PF-ILDs.

Cold spells linked with respiratory disease hospitalization, length of hospital stay, and hospital expenses: Exploring cumulative and harvesting effects.

BACKGROUND: Previous studies have revealed the relationship between cold spells and morbidity and mortality due to respiratory diseases, while the detrimental effects of cold spells on the length of hospital stay and hospitalization expenses remain largely unknown. METHODS: We collected hospitalization data for respiratory diseases in 11 cities of Shanxi, China during 2017-2019. In each case, exposure to meteorological variables and air pollution was estimated by the bilinear interpolation approach and inverse distance weighting method, respectively, and then averaged at the city level. Cold spells were defined as the daily mean temperature below the 10th, 7.5th, or 5th percentiles for at least 2 to 5 consecutive days. We applied distributed lag non-linear models combined with generalized additive models to assess cumulative effects and harvesting effects. RESULTS: There were significant associations between cold spells and hospital admissions, length of hospital stay, and hospital expenses for respiratory diseases. Compared with the non-cold spell period, the overall (lag 0-21) cumulative risk of hospitalization for total respiratory diseases was 1.232 (95 % CI: 1.090, 1.394) on cold spell days, and the increased length of hospital stay and hospitalization expenses were 112.793 (95 % CI: 10.755, 214.830) days and 127.568 (95 % CI: 40.513, 214.624) thousand Chinese yuan. The overall cumulative risks of cold spells on total respiratory diseases and pneumonia were statistically significant. We further observed harvesting effects in the associations between cold spells and hospital admission, length of hospital stay, and hospitalization expenses for respiratory diseases. CONCLUSIONS: Cumulative cold-spell exposure for up to three weeks is associated with hospitalization, length of hospital stay, and hospital expenses for respiratory diseases. The observed harmful effects of cold spells on respiratory diseases can be partly attributable to harvesting effects.

Exosomal miRNAs contribute to coal dust particle-induced pulmonary fibrosis in rats.

Coal workers' pneumoconiosis (CWP) is a fatal occupational disease caused by inhalation of coal dust particles, which leads to progressive pulmonary fibrosis. Recently, as new signal carriers for intercellular communication, exosomal miRNAs have been validated in the pathogenesis of multiple diseases. However, the research on exosomal miRNAs in CWP is still in the preliminary stage. Here, using miRNA sequencing, exosomal miRNA profiles in bronchoalveolar lavage fluid (BALF) from rats with pulmonary fibrosis induced by coal dust particles were analyzed, and the underlying biological function of putative target genes was explored by GO term analysis and KEGG pathway enrichment analysis. According to the results, intratracheal instillation of coal dust particles can alter the exosomal miRNAs expression in the BALF of rats. Further bioinformatics analysis provided some clues to reveal their function in pathological process of pneumoconiosis. More importantly, we identified 4 differentially expressed exosomal miRNAs (miRNA-21-5p, miRNA-29a-3p, miRNA-26a-5p, and miRNA-34a-5p) by qRT­PCR and further verified the temporal changes in the expression of these exosomal miRNAs in animal models from 2 weeks to 16 weeks postexposure. In addition, we conducted a preliminary study on Smad7 as a potential target of miRNA-21-5p and found that exosomal miRNA 21-5p/Smad7 may contribute to the pulmonary fibrosis induced by coal dust particles. Our study confirmed the contribution of exosomal miRNAs to coal dust particle-induced pulmonary fibrosis and provided new insights into the pathogenesis of CWP.

Associations of Ambient NO2 with Daily Hospitalization, Hospitalization Expenditure and Length of Hospital Stay of Cause-Specific Respiratory Diseases - Shanxi, China, 2017-2019.

What is already known about this topic?: Numerous epidemiological studies have documented the association between ambient nitrogen dioxide (NO2) and mortality and morbidity of respiratory diseases, however, research on the effect of NO2 on the length of hospital stay (LOS) and hospitalization expenditure is limited. What is added by this report?: This study collected the respiratory hospitalization, hospital expenditure, and LOS for respiratory diseases from 2017-2019 in Shanxi, China, and comprehensively evaluated the association between ambient NO2 exposure and respiratory hospitalization, expenditure, and LOS. What are the implications for public health practice?: This study provides evidence on the association between ambient NO2 and respiratory burden, suggesting that continuously reducing the NO2 concentrations could prevent respiratory disease-associated hospital admissions and decrease the relative burden in Shanxi Province and other similar regions.

Use data augmentation for a deep learning classification model with chest X-ray clinical imaging featuring coal workers' pneumoconiosis.

PURPOSE: This paper aims to develop a successful deep learning model with data augmentation technique to discover the clinical uniqueness of chest X-ray imaging features of coal workers' pneumoconiosis (CWP). PATIENTS AND METHODS: We enrolled 149 CWP patients and 68 dust-exposure workers for a prospective cohort observational study between August 2021 and December 2021 at First Hospital of Shanxi Medical University. Two hundred seventeen chest X-ray images were collected for this study, obtaining reliable diagnostic results through the radiologists' team, and confirming clinical imaging features. We segmented regions of interest with diagnosis reports, then classified them into three categories. To identify these clinical features, we developed a deep learning model (ShuffleNet V2-ECA Net) with data augmentation through performances of different deep learning models by assessment with Receiver Operation Characteristics (ROC) curve and area under the curve (AUC), accuracy (ACC), and Loss curves. RESULTS: We selected the ShuffleNet V2-ECA Net as the optimal model. The average AUC of this model was 0.98, and all classifications of clinical imaging features had an AUC above 0.95. CONCLUSION: We performed a study on a small dataset to classify the chest X-ray clinical imaging features of pneumoconiosis using a deep learning technique. A deep learning model of ShuffleNet V2 and ECA-Net was successfully constructed using data augmentation, which achieved an average accuracy of 98%. This method uncovered the uniqueness of the chest X-ray imaging features of CWP, thus supplying additional reference material for clinical application.

Efficacy and Safety of Limertinib (ASK120067) in Patients With Locally Advanced or Metastatic EGFR Thr790Met-Mutated NSCLC: A Multicenter, Single-Arm, Phase 2b Study.

INTRODUCTION: Limertinib (ASK120067) is a newly developed third-generation EGFR tyrosine kinase inhibitor targeting both sensitizing EGFR and EGFR Thr790Met (T790M) mutations. This study aimed to evaluate the efficacy and safety of limertinib in patients with locally advanced or metastatic EGFR T790M-mutated NSCLC. METHODS: This is a single-arm, open-label, phase 2b study conducted at 62 hospitals across the People's Republic of China. Patients with locally advanced or metastatic NSCLC with centrally confirmed EGFR T790M mutations in tumor tissue or blood plasma who progressed after first- or second-generation EGFR tyrosine kinase inhibitors or with primary EGFR T790M mutations were enrolled. Patients received limertinib 160 mg orally twice daily until disease progression or unacceptable toxicity. The primary end point was objective response rate (ORR) assessed by independent review committee per the Response Evaluation Criteria in Solid Tumors version 1.1. Secondary end points included disease control rate, progression-free survival (PFS), duration of response (DoR), overall survival, and safety. Safety was assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03. RESULTS: From July 16, 2019, to March 10, 2021, a total of 301 patients were enrolled and started the treatment of limertinib. All patients entered the full analysis set and safety set. By the data cutoff date on September 9, 2021, 76 (25.2%) remained on treatment. The median follow-up time was 10.4 months (range: 0.3-26.3). On the basis of full analysis set, the independent review committee-assessed ORR was 68.8% (95% confidence interval [CI]: 63.2%-74.0%) and disease control rate was 92.4% (95% CI: 88.8%-95.1%). The median PFS was 11.0 months (95% CI: 9.7-12.4), median DoR was 11.1 months (95% CI: 9.6-13.8), and median OS was not reached (95% CI 19.7 months-not evaluable). Objective responses were achieved across all prespecified subgroups. For 99 patients (32.9%) with central nervous system (CNS) metastases, the ORR was 64.6% (95% CI: 54.4%-74.0%), median PFS was 9.7 months (95% CI: 5.9-11.6), and median DoR was 9.6 months (95% CI: 8.1-15.2). For 41 patients who had assessable CNS lesion, the confirmed CNS-ORR was 56.1% (95% CI: 39.7%-71.5%) and median CNS-PFS was 10.6 months (95% CI: 5.6-not evaluable). In safety set, 289 patients (96.0%) experienced at least one treatment-related adverse event (TRAE), with the most common being diarrhea (81.7%), anemia (32.6%), rash (29.9%), and anorexia (28.2%). Grade ≥3 TRAEs occurred in 104 patients (34.6%), with the most common including diarrhea (13.0%), hypokalemia (4.3%), anemia (4.0%), and rash (3.3%). TRAEs leading to dose interruption and dose discontinuation occurred in 24.6% and 2% of patients, respectively. No TRAE leading to death occurred. CONCLUSIONS: Limertinib (ASK120067) was found to have promising efficacy and an acceptable safety profile for the treatment of patients with locally advanced or metastatic EGFR T790M-mutated NSCLC. CLINICAL TRIAL INFORMATION: NCT03502850.

Inhibition of gasdermin D-dependent pyroptosis attenuates the progression of silica-induced pulmonary inflammation and fibrosis.

Silicosis is a leading cause of occupational disease-related morbidity and mortality worldwide, but the molecular basis underlying its development remains unclear. An accumulating body of evidence supports gasdermin D (GSDMD)-mediated pyroptosis as a key component in the development of various pulmonary diseases. However, there is little experimental evidence connecting silicosis and GSDMD-driven pyroptosis. In this work, we investigated the role of GSDMD-mediated pyroptosis in silicosis. Single-cell RNA sequencing of healthy and silicosis human and murine lung tissues indicated that GSDMD-induced pyroptosis in macrophages was relevant to silicosis progression. Through microscopy we then observed morphological alterations of pyroptosis in macrophages treated with silica. Measurement of interleukin-1ß release, lactic dehydrogenase activity, and real-time propidium iodide staining further revealed that silica induced pyroptosis of macrophages. Additionally, we verified that both canonical (caspase-1-mediated) and non-canonical (caspase-4/5/11-mediated) signaling pathways mediated silica-induced pyroptosis activation, in vivo and in vitro. Notably, Gsdmd knockout mice exhibited dramatically alleviated silicosis phenotypes, which highlighted the pivotal role of pyroptosis in this disease. Taken together, our results demonstrated that macrophages underwent GSDMD-dependent pyroptosis in silicosis and inhibition of this process could serve as a viable clinical strategy for mitigating silicosis.

Genetic Polymorphisms of Pneumocystis jirovecii in HIV-Positive and HIV-Negative Patients in Northern China.

Pneumocystis jirovecii is an opportunistic fungus that can cause severe and potentially fatal Pneumocystis pneumonia (PCP) in immunodeficient patients. In this study, we investigated the genetic polymorphisms of P. jirovecii at eight different loci, including six nuclear genes (ITS, 26S rRNA, sod, dhps, dhfr and ß-Tub) and two mitochondrial genes (mtLSU-rRNA and cyb) in three PCP cases, including two patients with HIV infection and one without HIV infection in Shanxi Province, P.R. China. The gene targets were amplified by PCR followed by sequencing of plasmid clones. The HIV-negative patient showed a coinfection with two genotypes of P. jirovecii at six of the eight loci sequenced. Of the two HIV-positive patients, one showed a coinfection with two genotypes of P. jirovecii at the same two of the six loci as in the HIV-negative patient, while the other showed a single infection at all eight loci sequenced. None of the three drug target genes (dhfr, dhps and cyb) showed mutations known to be potentially associated with drug resistance. This is the first report of genetic polymorphisms of P. jirovecii in PCP patients in Shanxi Province, China. Our findings expand our understanding of the genetic diversity of P. jirovecii in China.

A Retrospectively Study: Diagnosis of Pathological Types of Malignant Lung Tumors by Dual-layer Detector Spectral Computed Tomography.

Object: By retrospectively analyzing the energy spectrum of squamous cell carcinoma, adenocarcinoma, small cell lung cancer (SCLC), and pulmonary metastases that underwent dual-layer detector spectral computed tomography (DLCT) 3-phase scan of the chest, we explored the value of a multiparameter energy spectrum in the assessment of pathological types of lung tumors. Methods: Cases of squamous cell carcinoma (n = 20), adenocarcinoma (n = 24), SCLC (n = 26), and metastases (n = 14) were collected. Then the largest cross-sectional area (LCA) of the lesion, computed tomography (CT) values in the plain scan phase, arterial and venous phases (HU, HUa, and HUv), iodine concentration, and effective atomic number in the arterial and venous phases (ICa, ICv, Zeff[a], and Zeff[v]) were measured and compared among the nonsmall cell lung cancer (NSCLC), SCLC and metastases, and other 3 groups of SCLC, squamous cell carcinoma, and adenocarcinoma. Results: Only the LCA is statistically different among SCLC, NSCLC, and metastases (P < .05). And the treated subgroup analysis did not show significant differences among the groups. However, the untreated subgroup analysis showed that there was a significant difference between NSCLC and metastases in LCA, SCLC and metastases in ICa, NSCLC and SCLC in HUv, NSCLC and SCLC in Zeff(v) (P < .05). Conclusion: The energy spectrum parameters of DLCT have a certain clinical value in distinguishing NSCLC from SCLC in the Zeff(v) and distinguishing SCLC from metastases in the ICa.

Tetrandrine alleviates silicosis by inhibiting canonical and non-canonical NLRP3 inflammasome activation in lung macrophages.

Silicosis caused by inhalation of silica particles leads to more than ten thousand new occupational exposure-related deaths yearly. Exacerbating this issue, there are currently few drugs reported to effectively treat silicosis. Tetrandrine is the only drug approved for silicosis treatment in China, and despite more than decades of use, its efficacy and mechanisms of action remain largely unknown. Here, in this study, we established silicosis mouse models to investigate the effectiveness of tetrandrine of early and late therapeutic administration. To this end, we used multiple cardiopulmonary function test, as well as markers for inflammation and fibrosis. Moreover, using single cell RNA sequencing and transcriptomics of lung tissue and quantitative microarray analysis of serum from silicosis and control mice, our results provide a novel description of the target pathways for tetrandrine. Specifically, we found that tetrandrine attenuated silicosis by inhibiting both the canonical and non-canonical NLRP3 inflammasome pathways in lung macrophages. Taken together, our work showed that tetrandrine yielded promising results against silicosis-associated inflammation and fibrosis and further lied the groundwork for understanding its molecular targets. Our results also facilitated the wider adoption and development of tetrandirne, potentially accelerating a globally accepted therapeutic strategy for silicosis.

Pirfenidone ameliorates silica-induced lung inflammation and fibrosis in mice by inhibiting the secretion of interleukin-17A.

Silicosis is a global occupational disease characterized by lung dysfunction, pulmonary inflammation, and fibrosis, for which there is a lack of effective drugs. Pirfenidone has been shown to exert anti-inflammatory and anti-fibrotic properties in the lung. However, whether and how pirfenidone is effective against silicosis remains unknown. Here, we evaluated the efficacy of pirfenidone in the treatment of early and advanced silicosis in an experimental mouse model and explored its potential pharmacological mechanisms. We found that pirfenidone alleviated silica-induced lung dysfunction, secretion of inflammatory cytokines (TNF-α, IL-1ß, IL-6) and deposition of fibrotic proteins (collagen I and fibronectin) in both early and advanced silicosis models. Moreover, we observed that both 100 and 200 mg/kg pirfenidone can effectively treat early-stage silicosis, while 400 mg/kg was recommended for advanced silicosis. Mechanistically, antibody array and bioinformatic analysis showed that the pathways related to IL-17 secretion, including JAK-STAT pathway, Th17 differentiation, and IL-17 pathway, might be involved in the treatment of silicosis by pirfenidone. Further in vivo experiments confirmed that pirfenidone reduced the production of IL-17A induced by silica exposure via inhibiting STAT3 phosphorylation. Neutralizing IL-17A by anti-IL-17A antibody improved lung function and reduced pulmonary inflammation and fibrosis in silicosis animals. Collectively, our study has demonstrated that pirfenidone effectively ameliorated silica-induced lung dysfunction, pulmonary inflammation and fibrosis in mouse models by inhibiting the secretion of IL-17A.

Ambient sulfur dioxide and hospital expenditures and length of hospital stay for respiratory diseases: A multicity study in China.

BACKGROUND: Ambient sulfur dioxide (SO2) has been associated with morbidity and mortality of respiratory diseases, however, its effect on length of hospital stays (LOS) and cost for these diagnoses remain unclear. METHODS: We collected hospital admission information for respiratory diseases from all 11 cities in the Shanxi Province of China during 2017-2019. We assessed individual-level exposure by using an inverse distance weighting approach based on geocoded residential addresses. A generalized additive model was built to delineate city-specific effects of SO2 on hospitalization, hospital expenditure, and length of hospital stay for respiratory diseases. The overall effects were obtained by random-effects meta-analysis. We further estimated the respiratory burden attributable to SO2 by comparing different reference concentrations. RESULTS: We observed significant effects of SO2 exposure on respiratory diseases. At the provincial level, each 10 µg/m3 increase in SO2 on lag03 was associated with a 0.63% (95% CI: 0.14-0.11) increase in hospital admission, an increase of 4.56 days (95% CI: 1.16-7.95) of hospital stay, and 3647.97 renminbi (RMB, Chinese money) (95% CI: 1091.05-6204.90) in hospital cost. We estimated about 6.13 (95% CI: 1.33-11.10) thousand hospital admissions, 65.77 million RMB (95% CI: 19.67-111.87) in hospital expenditure, and 82.13 (95% CI: 20.87-143.40) thousand days of hospital stay could have potentially been avoided had the daily SO2 concentrations been reduced to WHO's reference concentration (40 µg/m3). Variable values in correspondence with this reference concentration could reduce the hospital cost and LOS of each case by 52.67 RMB (95% CI: 15.75-89.59) and 0.07 days (95% CI: 0.02-0.117). CONCLUSION: This study provides evidence that short-term ambient SO2 exposure is an important risk factor of respiratory diseases, indicating that continually tightening policies to reduce SO2 levels could effectively reduce respiratory disease burden in Shanxi Province.

Palbociclib Enhances Migration and Invasion of Cancer Cells via Senescence-Associated Secretory Phenotype-Related CCL5 in Non-Small-Cell Lung Cancer.

Palbociclib is the first CDK4/6 inhibitor approved by FDA and has been studied in many types of cancer. However, some studies showed that it could induce epithelial-mesenchymal transition (EMT) of cancer cells. To test the effect of palbociclib on non-small-cell lung cancer (NSCLC) cells, we treated NSCLC cells with different concentrations of palbociclib and detected its effects via MTT, migration and invasion assays, and apoptosis test. Further RNA sequencing was performed in the cells treated with 2 µM palbociclib or control. And Gene Ontology, Kyoto Encyclopedia of Genes and Genomes (KEGG), Gene Set Enrichment Analysis (GSEA), and protein-protein interaction network (PPI) were analyzed to explore the mechanism of palbociclib. The results showed that palbociclib significantly inhibited the growth of NSCLC cells and promoted apoptosis of cells, however, enhanced the migration and invasion abilities of cancer cells. RNA sequencing showed that cell cycle, inflammation-/immunity-related signaling, cytokine-cytokine receptor interaction, and cell senescence pathways were involved in the process, and CCL5 was one of the significantly differential genes affected by palbociclib. Further experiments showed that blocking CCL5-related pathways could reverse the malignant phenotype induced by palbociclib. Our results revealed that palbociclib-induced invasion and migration might be due to senescence-associated secretory phenotype (SASP) rather than EMT and suggested that SASP could act as a potential target to potentiate the antitumor effects of palbociclib in cancer treatment.