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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.
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Antiasmáticos , Asma , Adulto , Humanos , Administração por Inalação , Antiasmáticos/uso terapêutico , Asma/tratamento farmacológico , Beclometasona/uso terapêutico , China , Método Duplo-Cego , Combinação de Medicamentos , Inaladores de Pó Seco , Fumarato de Formoterol/uso terapêutico , Inaladores Dosimetrados , Resultado do TratamentoRESUMO
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.
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Doenças Pulmonares Intersticiais , Pneumonia , Humanos , Animais , Camundongos , Adenoviridae/genética , Adenoviridae/metabolismo , Pneumonia/genética , Inflamação/genética , Inflamação/metabolismo , Receptores de IgG/genética , Receptores de IgG/metabolismo , Fibrose , Dióxido de SilícioRESUMO
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.
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Antracose , Minas de Carvão , MicroRNAs , Pneumoconiose , Fibrose Pulmonar , Ratos , Animais , Fibrose Pulmonar/induzido quimicamente , MicroRNAs/metabolismo , Carvão Mineral/toxicidade , Poeira , Antracose/genética , MineraisRESUMO
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.
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Inflamassomos , Silicose , Animais , Benzilisoquinolinas , Fibrose , Inflamassomos/metabolismo , Inflamação/metabolismo , Pulmão/patologia , Macrófagos/metabolismo , Camundongos , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Silicose/tratamento farmacológico , Silicose/metabolismoRESUMO
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.
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Interleucina-17 , Pneumonia , Animais , Modelos Animais de Doenças , Fibrose , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Interleucina-17/metabolismo , Janus Quinases/metabolismo , Janus Quinases/uso terapêutico , Pulmão/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Pneumonia/induzido quimicamente , Pneumonia/tratamento farmacológico , Pneumonia/metabolismo , Piridonas , Fatores de Transcrição STAT/metabolismo , Fatores de Transcrição STAT/uso terapêutico , Transdução de Sinais , Dióxido de Silício/toxicidadeRESUMO
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.
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Antracose , Minas de Carvão , Aprendizado Profundo , Pneumoconiose , Antracose/diagnóstico por imagem , Carvão Mineral , Humanos , Pneumoconiose/diagnóstico por imagem , Estudos Prospectivos , Raios XRESUMO
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.
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Poluentes Atmosféricos , Poluição do Ar , Poluentes Atmosféricos/análise , Poluição do Ar/análise , China/epidemiologia , Exposição Ambiental/análise , Gastos em Saúde , Hospitais , Humanos , Tempo de Internação , Dióxido de Nitrogênio/análise , Material Particulado/análise , Dióxido de Enxofre/análiseRESUMO
BACKGROUND: Few studies have examined the effects of ambient particulate matter with an aerodynamic diameter less than or equal to 2.5 µm (PM2.5) on hospital cost and length of hospital stay for respiratory diseases in China. METHODS: We estimated ambient air pollution exposure for respiratory cases through inverse distance-weighted averages of air monitoring stations based on their residential address and averaged at the city level. We used generalised additive models to quantify city-specific associations in 11 cities in Shanxi and a meta-analysis to estimate the overall effects. We further estimated respiratory burden attributable to PM2.5 using the standards of WHO (25 µg/m3) and China (75 µg/m3) as reference. RESULTS: Each 10 µg/m3 increase in lag03 PM2.5 corresponded to 0.53% (95% CI: 0.33% to 0.73%) increase in respiratory hospitalisation, an increment of 3.75 thousand RMB (95% CI: 1.84 to 5.670) in hospital cost and 4.13 days (95% CI: 2.51 to 5.75) in length of hospital stay. About 9.7 thousand respiratory hospitalisations, 132 million RMB in hospital cost and 145 thousand days of hospital stay could be attributable to PM2.5 exposures using WHO's guideline as reference. We estimated that 193 RMB (95% CI: 95 to 292) in hospital cost and 0.21 days (95% CI: 0.13 to 0.30) in hospital stay could be potentially avoidable for an average respiratory case. CONCLUSION: Significant respiratory burden could be attributable to PM2.5 exposures in Shanxi Province, China. The results need to be factored into impact assessment of air pollution policies to provide a more complete indication of the burden addressed by the policies.
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Glucose-regulating protein 78 (GRP78) is a molecular chaperone in the endoplasmic reticulum (ER) that promotes folding and assembly of proteins, controls the quality of proteins, and regulates ER stress signaling through Ca2+ binding to the ER. In tumors, GRP78 is often upregulated, acting as a central stress sensor that senses and adapts to changes in the tumor microenvironment, mediating ER stress of cancer cells under various stimulations of the microenvironment to trigger the folding protein response. Increasing evidence has shown that GRP78 is closely associated with the progression and poor prognosis of lung cancer, and plays an important role in the treatment of lung cancer. Herein, we reviewed for the first time the functions and mechanisms of GRP78 in the pathological processes of lung cancer, including tumorigenesis, apoptosis, autophagy, progression, and drug resistance, giving a comprehensive understanding of the function of GRP78 in lung cancer. In addition, we also discussed the potential role of GRP78 as a prognostic biomarker and therapeutic target for lung cancer, which is conducive to improving the assessment of lung cancer and the development of new therapeutic interventions.
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Proteínas de Choque Térmico , Neoplasias Pulmonares , Apoptose , Retículo Endoplasmático/metabolismo , Chaperona BiP do Retículo Endoplasmático , Estresse do Retículo Endoplasmático , Proteínas de Choque Térmico/metabolismo , Humanos , Neoplasias Pulmonares/metabolismo , Chaperonas Moleculares/metabolismo , Microambiente Tumoral , Resposta a Proteínas não DobradasRESUMO
Accumulating evidence indicates that Clara cell protein-16 (CC16) has anti-inflammatory functions, although the involved molecular pathways have not been completely elucidated. Here, we evaluated the effect of recombinant rat CC16 (rCC16) on the expression of tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), and IL-8 in lipopolysaccharide (LPS)-stimulated mouse macrophages (RAW264.7 cells) and explored the underlying molecular mechanisms. It was found that rCC16 inhibited LPS-induced TNF-α, IL-6, and IL-8 expression at both the messenger ribonucleicacid (mRNA) level and protein level in a concentration-dependent manner, as demonstrated by real-time reverse transcriptase-polymerase chain reaction and enzyme-linked immunosorbent assay. Such suppressive effects were accompanied by the inhibition of transcriptional activity and the deoxyribonucleic acid binding activity of nuclear factor (NF)-κB but not activator protein (AP)-1. Western blot analysis further revealed that rCC16 inhibited the increase of nuclear NF-κB and the reduction of cytosolic NF-κB, the phosphorylation and reduction of NF-κB inhibitory protein IκBα, and the p38 mitogen-activated protein kinase (MAPK)-dependent NF-κB activation by phosphorylation at Ser276 of its p65 subunit. Furthermore, rCC16 was found to have no effect on the phosphorylation of c-Jun N-terminal kinase, c-Jun, or the nuclear translocation of c-Jun. In addition, reduction of TNF-α, IL-6, and IL-8 were reversed when the level of endogenous uteroglobin-binding protein was reduced by RNA interference in rCC16- and LPS-treated RAW264.7 cells. Our data suggest that rCC16 suppresses LPS-mediated inflammatory mediator TNF-α, IL-6, and IL-8 production by inactivating NF-κB and p38 MAPK but not AP-1 in RAW264.7 cells.
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Citocinas/imunologia , Mediadores da Inflamação/imunologia , Inflamação/imunologia , NF-kappa B/imunologia , Uteroglobina/administração & dosagem , Uteroglobina/imunologia , Proteínas Quinases p38 Ativadas por Mitógeno/imunologia , Animais , Relação Dose-Resposta a Droga , Regulação para Baixo/efeitos dos fármacos , Regulação para Baixo/imunologia , Inflamação/prevenção & controle , Lipopolissacarídeos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/imunologia , Camundongos , Células RAW 264.7 , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/genética , Uteroglobina/genéticaRESUMO
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.
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Microbiota , Humanos , Metagenoma , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Metagenômica , TecnologiaRESUMO
OBJECTIVES: To investigate the mediating role of the activation degree of arginine-proline metabolism in the association of coal dust and decreased lung function. METHODS: CDE represented coal dust exposure, while the Hyp/Arg in BALF gauged arginine-proline metabolism activation. Pulmonary function indicators, including FVC%pred, FEV1/FVC%, and FEV1%pred, DLCO%pred, P(A-a) O2 and 6MWT, were assessed. RESULTS: Findings revealed a significant association between elevated CDE and increased Hyp/Arg, increased P(A-a) O2, decreased 6MWT, DLCO%pred, and decreased FVC%pred. However, no statistically significant association was found between CDE and FEV1%pred or FEV1/FVC%. The mediating effect of Hyp/Arg was significant for CDE's impact on P(A-a) O2 and DLCO%pred but not on 6MWT and FVC%pred. CONCLUSIONS: These results highlight the role of Hyp/Arg in mediating the association between CDE and lung function parameters, shedding light on potential therapeutic avenues for mitigating coal dust-induced lung function impairment.
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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.
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Carcinoma Pulmonar de Células não Pequenas , Exossomos , Neoplasias Pulmonares , MicroRNAs , Masculino , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Carcinoma Pulmonar de Células não Pequenas/metabolismo , MicroRNAs/metabolismo , Biomarcadores Tumorais/metabolismoRESUMO
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.
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Pneumoconiose , Masculino , Humanos , Pessoa de Meia-Idade , Incidência , Poeira , Razão de Chances , PubMedRESUMO
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.
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Antracose , Minas de Carvão , Pneumoconiose , Humanos , Poeira/análise , Carvão MineralRESUMO
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.
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Carcinoma Pulmonar de Células não Pequenas , Pontos de Checagem do Ciclo Celular , Medicamentos de Ervas Chinesas , Neoplasias Pulmonares , Animais , Humanos , Camundongos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Fosfatases cdc25/metabolismo , Divisão Celular , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Cinesinas/metabolismo , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos Nus , NF-kappa B/metabolismo , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/genética , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêuticoRESUMO
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.
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Hipertensão Arterial Pulmonar , Doença Pulmonar Obstrutiva Crônica , Humanos , Apoptose , Autofagia , Hipóxia Celular , Proliferação de Células , DNA Helicases/genética , DNA Helicases/metabolismo , Células Endoteliais/metabolismo , Hipóxia/complicações , Hipóxia/genética , Hipóxia/metabolismo , Artéria Pulmonar , Doença Pulmonar Obstrutiva Crônica/metabolismoRESUMO
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.
Assuntos
Poluição do Ar , Transtornos Respiratórios , Doenças Respiratórias , Humanos , Tempo de Internação , Temperatura Baixa , Hospitalização , Doenças Respiratórias/epidemiologia , China/epidemiologia , HospitaisRESUMO
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.
Assuntos
Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/patologia , Tomografia Computadorizada por Raios X/métodos , Idoso , Tomada de Decisão Clínica , Diagnóstico Diferencial , Gerenciamento Clínico , Feminino , Humanos , Processamento de Imagem Assistida por Computador , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Estudos Retrospectivos , Tomografia Computadorizada por Raios X/normasRESUMO
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.