MicroRNA-377-3p exacerbates chronic obstructive pulmonary disease through suppressing ZFP36L1 expression and inducing lung fibroblast senescence.

Chronic obstructive pulmonary disease (COPD) is a leading aging related cause of global mortality. Small airway narrowing is recognized as an early and significant factor for COPD development. Senescent fibroblasts were observed to accumulate in lung of COPD patients and promote COPD progression through aberrant extracellular matrix (ECM) deposition and senescence-associated secretory phenotype (SASP). On the basis of our previous study, we further investigated the the causes for the increased levels of miR-377-3p in the blood of COPD patients, as well as its regulatory function in the pathological progression of COPD. We found that the majority of up-regulated miR-377-3p was localized in lung fibroblasts. Inhibition of miR-377-3p improved chronic smoking-induced COPD in mice. Mechanistically, miR-377-3p promoted senescence of lung fibroblasts, while knockdown of miR-377-3p attenuated bleomycin-induced senescence in lung fibroblasts. We also identified ZFP36L1 as a direct target for miR-377-3p that likely mediated its pro senescence activity in lung fibroblasts. Our data reveal that miR-377-3p is crucial for COPD pathogenesis, and may serve as a potential target for COPD therapy.

Metformin alleviates benzo[a]pyrene-induced alveolar injury by inhibiting necroptosis and protecting AT2 cells.

Exposure to benzo[a]pyrene (B[a]P) has been linked to lung injury and carcinogenesis. Airway epithelial cells express the B[a]P receptor AHR, so B[a]P is considered to mainly target airway epithelial cells, whereas its potential impact on alveolar cells remains inadequately explored. Metformin, a first-line drug for diabetes, has been shown to exert anti-inflammatory and tissue repair-promoting effects under various injurious conditions. Here, we explored the effect of chronic B[a]P exposure on alveolar cells and the impact of metformin on B[a]P-induced lung injury by examining the various parameters including lung histopathology, inflammation, fibrosis, and related signal pathway activation. MLKL knockout (Mlkl-/-) and AT2-lineage tracing mice (SftpcCre-ERT2;LSL-tdTomatoflox+/-) were used to delineate the role of necroptosis in B[a]P-induced alveolar epithelial injury and repair. Mice receiving weekly administration of B[a]P for 6 weeks developed a significant alveolar damaging phenotype associated with pulmonary inflammation, fibrosis, and activation of the necroptotic cell death pathway. These effects were significantly relieved in MLKL null mice. Furthermore, metformin treatment, which were found to promote AMPK phosphorylation and inhibit RIPK3, as well as MLKL phosphorylation, also significantly alleviated B[a]P-induced necroptosis and lung injury phenotype. However, the protective efficacy of metformin was rendered much less effective in Mlkl null mice or by blocking the necroptotic pathway with RIPK3 inhibitor. Our findings unravel a potential protective efficacy of metformin in mitigating the detrimental effects of B[a]P exposure on lung health by inhibiting necroptosis and protecting AT2 cells.

Using Vision Transformer for high robustness and generalization in predicting EGFR mutation status in lung adenocarcinoma.

BACKGROUND: Lung adenocarcinoma is a common cause of cancer-related deaths worldwide, and accurate EGFR genotyping is crucial for optimal treatment outcomes. Conventional methods for identifying the EGFR genotype have several limitations. Therefore, we proposed a deep learning model using non-invasive CT images to predict EGFR mutation status with robustness and generalizability. METHODS: A total of 525 patients were enrolled at the local hospital to serve as the internal data set for model training and validation. In addition, a cohort of 30 patients from the publicly available Cancer Imaging Archive Data Set was selected for external testing. All patients underwent plain chest CT, and their EGFR mutation status labels were categorized as either mutant or wild type. The CT images were analyzed using a self-attention-based ViT-B/16 model to predict the EGFR mutation status, and the model's performance was evaluated. To produce an attention map indicating the suspicious locations of EGFR mutations, Grad-CAM was utilized. RESULTS: The ViT deep learning model achieved impressive results, with an accuracy of 0.848, an AUC of 0.868, a sensitivity of 0.924, and a specificity of 0.718 on the validation cohort. Furthermore, in the external test cohort, the model achieved comparable performances, with an accuracy of 0.833, an AUC of 0.885, a sensitivity of 0.900, and a specificity of 0.800. CONCLUSIONS: The ViT model demonstrates a high level of accuracy in predicting the EGFR mutation status of lung adenocarcinoma patients. Moreover, with the aid of attention maps, the model can assist clinicians in making informed clinical decisions.

Antioxidant diet/lifestyle could mitigate the adverse impacts of urinary polycyclic aromatic hydrocarbons on lung function.

BACKGROUND: Extant research has demonstrated a correlation between exposure to polycyclic aromatic hydrocarbons (PAHs) and impaired lung function. The maintenance of an antioxidant-rich diet/lifestyle positively benefits pulmonary health. However, the potential ameliorative impact of an antioxidant-based diet/lifestyle on PAH-induced detrimental effects remains unclear. METHODS: The study drew upon cross-sectional data encompassing 1615 participants derived from the National Health and Nutrition Examination Survey 2007 to 2012. To gauge the maintenance of an antioxidant-rich diet/lifestyle, we employed Oxidative Balance Score (OBS) that incorporates sixteen nutrients and four lifestyle factors. Lung function was evaluated using percent-predicted Forced Vital Capacity (FVC), Forced Expiratory Volume 1st Second (FEV1), FEV1/FVC, and fractional exhaled nitric oxide (FENO). Our analytical approach entailed the utilization of weighted linear models. RESULTS: Our analysis unveiled interaction effects between urinary monohydroxy polycyclic aromatic hydrocarbons (OH-PAHs) and OBS concerning lung function. A one-unit increase in ∑OH-PAH (sum of eight OH-PAHs) was linked to a -0.75% reduction (95% CI: -1.28, -0.22) in FEV1/FVC. Individuals exhibiting low OBS displayed a marked decrease in FEV1/FVC (mean difference = -1.10%; 95% CI: -1.82, -0.39) for each unit increase in ∑OH-PAH, whereas no significant associations were discerned for those with medium or high OBS. Further stratification by gender yielded consistent results. The correlation between ∑OH-PAH and FENO proved statistically significant among participants with low OBS (P = 0.002) and medium OBS (P = 0.001), but non-significant for those with high OBS. Parallel findings emerged when examining percent-predicted FEV1 and FVC. CONCLUSIONS: In conclusion, our study underscores the existence of statistically significant interactions between OH-PAHs and the maintenance of an antioxidant-rich diet and lifestyle concerning lung function. These findings underscore the pivotal role of maintaining an antioxidant-based diet and lifestyle in mitigating the adverse impacts of PAH exposure on lung function.

Associations of blood cadmium and lead concentrations with all-cause mortality in US adults with chronic obstructive pulmonary disease.

BACKGROUND: Some literature indicates an association between exposure to cadmium and lead and the presence of emphysema and chronic bronchitis, which are the two primary components of COPD. Understanding whether there is a potential association between cadmium and lead exposure and higher mortality rates in individuals with COPD could provide profound insights into the long-term effects of these two metal exposures on human health. METHODS: This study included 2024 patients with COPD in the US from the NHANES from 1999 through 2016 who were followed up to 2019. Multivariable Cox regression models were used to calculate HRs and 95 % CIs for all-cause mortality in relation to blood cadmium and lead concentrations. Plotting Kaplan-Meier curves and Restricted cubic spline curves to visualize results. Furthermore, stratified and sensitivity analyses were conducted. RESULTS: After multivariate adjustment, blood cadmium and blood lead concentrations were independently associated with an increased risk of all-cause mortality. Compared with the first tertile, the HRs of all-cause mortality associated with the blood cadmium concentration were 1.74 (95 % CI, 1.22-2.49) in the second tertile and 1.89 (95 % CI, 1.31-2.72) in the third tertile. The HRs of all-cause mortality associated with the blood lead concentration were 1.13 (95 % CI, 0.84-1.51) in the second tertile and 1.43 (95 % CI, 1.05-1.93) in the third tertile. CONCLUSION: This study found that increased blood cadmium and blood lead concentrations were associated with increased all-cause mortality in COPD patients. Reducing cadmium and lead exposure could potentially mitigate mortality risk in these individuals. More prospective studies are needed in the future to demonstrate our findings.

An investigation of the risk factors of chronic obstructive pulmonary disease in natural population-based cohorts in China - a nested case-control study.

Background: Chronic obstructive pulmonary disease (COPD) has become one of the most significant chronic diseases in China. According to conventional wisdom, smoking is the pathogenic factor. However, current research indicates that the pathophysiology of COPD may be associated with prior respiratory system events (e.g., childhood hospitalization for pneumonia, chronic bronchitis) and environmental exposure (e.g., dust from workplace, indoor combustion particles). Dyspnea, persistent wheezing, and other respiratory symptoms further point to the need for pulmonary function tests in this population. Reducing the burden of chronic diseases in China requires a thorough understanding of the various factors that influence the occurrence of COPD. Methods: Using a cohort from the natural population, this study used nested case-control analysis. We carried out a number of researches, including questionnaire surveys and pulmonary function testing, in the Northwest and Southeast cohorts of China between 2014 and 2021. After removing any variations in the baseline data between patients and control subjects using propensity score matching analysis, the risk factors were examined using univariate or multivariate regression. Result: It was discovered that prior history of chronic bronchitis, long-term wheezing symptoms, and environmental exposure-including smoking and biofuel combustion-were risk factors for COPD. Dyspnea, symptoms of mobility limitation, organic matter, and a history of hospitalization for pneumonia at an early age were not significant in the clinical model but their incidence in COPD group is higher than that in healthy population. Discussion: COPD screening effectiveness can be increased by looking for individuals with chronic respiratory symptoms. Smokers should give up as soon as they can, and families that have been exposed to biofuels for a long time should convert to clean energy or upgrade their ventilation. Individuals who have previously been diagnosed with emphysema and chronic bronchitis ought to be extra mindful of the prevention or advancement of COPD.

Epithelial-mesenchymal transition is associated with osteopontin-induced EGFR­TKI resistance in EGFR mutant non-small cell lung cancer.

Background: Resistance restricts the long-term therapeutic efficacy of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) in the treatment of non-small cell lung cancer (NSCLC) with positive EGFR mutations. The present study sought to identify the potential protein osteopontin (OPN) involved in EGFR-TKI resistance and examine its therapeutic mechanism in NSCLC. Methods: The expression of OPN in NSCLC tissues was evaluated by immunohistochemistry (IHC). Western blot (WB), quantitative real­time polymerase chain reaction (qRT-PCR), and immunofluorescence staining were used to analyze OPN and epithelial-mesenchymal transition (EMT)-related protein expression in the PC9 and PC9 gefitinib resistance (PC9GR) cells. Enzyme-linked immunosorbent assays (ELISAs) were used to detect the secreted OPN. Cell Counting Kit-8 (CCK-8) assays and flow cytometry were used to examine the effect of OPN on the gefitinib-induced growth and death of PC9 or PC9GR cells. Results: OPN was upregulated in the human NSCLC tissues and cells resistant to EGFR-TKIs. The overexpression of OPN inhibited EGFR-TKI-induced apoptosis and was associated with the formation of EMT. By activating the phosphatidylinositol-3 kinase (PI3K)/protein kinase B (AKT)-EMT pathway, OPN contributed to the development of EGFR-TKI resistance. Reducing OPN expression and inhibiting PI3K/AKT signaling improved EGFR-TKI sensitivity significantly more than the use of either agent alone. Conclusions: This study showed that OPN increased EGFR-TKI resistance in NSCLC through the OPN-PI3K/AKT-EMT pathway. Our findings may provide a possible therapeutic target for overcoming EGFR-TKI resistance in this pathway.

Role of GSDM family members in airway epithelial cells of lung diseases: a systematic and comprehensive transcriptomic analysis.

Gasdermin (GSDM) family, the key executioners of pyroptosis, play crucial roles in anti-pathogen and anti-tumor immunities, although little is known about the expression of GSDM in lung diseases at single-cell resolution, especially in lung epithelial cells. We comprehensively investigated the transcriptomic profiles of GSDM members in various lung tissues from healthy subjects or patients with different lung diseases at single cell level, e.g., chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), lung adenocarcinoma (LUAD), or systemic sclerosis (SSC). The expression of GSDM members varied among pulmonary cell types (immune cells, structural cells, and especially epithelial cells) and even across lung diseases. Regarding disease-associated specificities, we found that GSDMC or GSDMD altered significantly in ciliated epithelia of COPD or LUAD, GSDMD in mucous, club, and basal cells of LUAD and GSDMC in mucous epithelia of para-tumor tissue, as compared with the corresponding epithelia of other diseases. The phenomic specificity of GSDM in lung cancer subtypes was noticed by comparing with 15 non-pulmonary cancers and para-cancer samples. GSDM family gene expression changes were also observed in different lung epithelial cell lines (e.g., HBE, A549, H1299, SPC-1, or H460) in responses to external challenges, including lipopolysaccharide (LPS), lysophosphatidylcholine (lysoPC), cigarette smoking extract (CSE), cholesterol, and AR2 inhibitor at various doses or durations. GSDMA is rarely expressed in those cell lines, while GSDMB and GSDMC are significantly upregulated in human lung epithelia. Our data indicated that the heterogeneity of GSDM member expression exists at different cells, pathologic conditions, challenges, probably dependent upon cell biological phenomes, functions, and behaviors, upon cellular responses to external changes, and the nature and severity of lung disease. Thus, the deep exploration of GSDM phenomes may provide new insights into understanding the single-cell roles in the tissue, regulatory roles of the GSDM family in the pathogenesis, and potential values of biomarker identification and development.

Acetalized starch-based nanoparticles stabilized acid-sensitive Pickering emulsion as a potential antitumor drug carrier.

Pickering emulsions are attracting increased attention owing to their therapeutic applications. However, the slow-release property of Pickering emulsions and the in vivo solid particle accumulation caused by the solid particle stabilizer film limit their applications in therapeutic delivery. In this study, drug-loaded, acid-sensitive Pickering emulsions were prepared using acetal-modified starch-based nanoparticles as stabilizers. The acetalized starch-based nanoparticles (Ace-SNPs) not only act as a solid-particle emulsifier to stabilize Pickering emulsions but also exhibit acid sensitivity and degradability, conducive to the destabilization of Pickering emulsions to release the drug and reduce the effect of particle accumulation in an acidic therapeutic environment. In vitro drug release profiles show that 50 % of curcumin was released in 12 h in an acidic medium (pH 5.4), whereas only 14 % of curcumin was released in 12 h at higher pH (7.4), indicating that the Ace-SNP stabilized Pickering emulsion possess good acid-responsive release characteristics in acidic environments. Moreover, acetalized starch-based nanoparticles and their degradation products showed good biocompatibility, and the resulting curcumin-loaded Pickering emulsions exhibited significant anticancer activity. These features suggest that the acetalized starch-based nanoparticle-stabilized Pickering emulsion has the potential for application as an antitumor drug carrier to enhance therapeutic effects.

Glycyrrhizin protects against particulate matter-induced lung injury via regulation of endoplasmic reticulum stress and NLRP3 inflammasome-mediated pyroptosis through Nrf2/HO-1/NQO1 signaling pathway.

Particulate matter (PM) is a major environmental pollutant that contributes considerably to deaths worldwide. The pathogenesis of PM-induced lung injury (PILI) is far from elucidated and warrants effective intervention. An effective component of licorice, glycyrrhizin (GL), has been the subject of much research due to its anti-inflammatory and anti-oxidative capabilities. Although preventive properties of GL are well-known, the precise mechanism of GL in PILI has not yet been investigated. A mouse model of PILI was used to examine the protective effects of GL in vivo, and a human bronchial epithelial cells (HBECs) model was used in vitro. In order to determine whether GL mitigates PILI, its effects on endoplasmic reticulum (ER) stress, NLRP3 inflammasome-mediated pyroptosis and the oxidative response were examined. According to the findings, GL reduced PILI and activate anti-oxidative Nrf2/HO-1/NQO1 signaling in mice. Notably, the effect of GL on PM-induced ER stress and NLRP3 inflammasome-mediated pyroptosis was significantly attenuated by the Nrf2 inhibitor ML385. The data suggest that via the anti-oxidative Nrf2 signaling, GL may reduce oxidative stress-mediated ER stress and NLRP3 inflammasome-mediated pyroptosis. Therefore, GL may serve as a promising treatment for PILI.

FGF1 ameliorates obesity-associated hepatic steatosis by reversing IGFBP2 hypermethylation.

Obesity is a major contributing factor for metabolic-associated fatty liver disease (MAFLD). Fibroblast growth factor (FGF) 1 is the first paracrine FGF family member identified to exhibit promising metabolic regulatory properties capable of conferring glucose-lowering and insulin-sensitizing effect. This study explores the role and molecular underpinnings of FGF1 in obesity-associated hepatic steatosis. In a mouse high-fat diet (HFD)-induced MAFLD model, chronic treatment with recombinant FGF1(rFGF1) was found to effectively reduce the severity of insulin resistance, hyperlipidemia, and inflammation. FGF1 treatment decreased lipid accumulation in the mouse liver and palmitic acid-treated AML12 cells. These effects were associated with decreased mature form SREBF1 expression and its target genes FASN and SCD1. Interestingly, we uncovered that rFGF1 significantly induced IGFBP2 expression at both mRNA and protein levels in HFD-fed mouse livers and cultured hepatocytes treated with palmitic acid. Adeno-associated virus-mediated IGFBP2 suppression significantly diminished the therapeutic benefit of rFGF1 on MAFLD-associated phenotypes, indicating that IGFBP2 plays a crucial role in the FGF1-mediated reduction of hepatic steatosis. Further analysis revealed that rFGF1 treatment reduces the recruitment of DNA methyltransferase 3 alpha to the IGFBP2 genomic locus, leading to decreased IGFBP2 gene methylation and increased mRNA and protein expression. Collectively, our findings reveal FGF1 modulation of lipid metabolism via epigenetic regulation of IGFBP2 expression, and unravel the therapeutic potential of the FGF1-IGFBP2 axis in metabolic diseases associated with obesity.

ESE1/AGR2 axis antagonizes TGF-ß-induced epithelial-mesenchymal transition in low-grade pancreatic cancer.

Epithelium-specific ETS transcription factor 1 (ESE1) has been implicated in epithelial homeostasis, inflammation, as well as tumorigenesis, and cancer progression. However, numerous studies have reported contradictory roles-as an oncogene or a tumor suppressor of ESE1 in different cancers, and its function in the development and progression of pancreatic ductal adenocarcinoma (PDAC) has remained largely unexplored. Herein, we report that ESE1 was found upregulated in primary PDAC compared to normal pancreatic tissue, but high expression of ESE1 correlated to better relapse-free survival in patients with PDAC. Interestingly, ESE1 was found to exhibit dual roles in regulation of malignant properties of PDAC cells in that its overexpression promoted cell proliferation, whereas its downregulation enhanced epithelial-mesenchymal transition (EMT) phenotype. In the context of TGF-ß-induced EMT, ESE1 is markedly downregulated at post-transcriptional level, and reconstituted ESE1 expression partially reversed TGF-ß-induced EMT marker expression. Furthermore, we identify AGR2 as a novel transcriptional target of ESE1 that participates in TGF-ß-induced EMT in PDAC. Collectively, our findings reveal an ESE1/AGR2 axis that interacts with TGF-ß signaling to modulate EMT phenotype in PDAC.

Regulatory roles of NAT10 in airway epithelial cell function and metabolism in pathological conditions.

N-acetyltransferase 10 (NAT10), a nuclear acetyltransferase and a member of the GNAT family, plays critical roles in RNA stability and translation processes as well as cell proliferation. Little is known about regulatory effects of NAT10 in lung epithelial cell proliferation. We firstly investigated NTA10 mRNA expression in alveolar epithelial types I and II, basal, ciliated, club, and goblet/mucous epithelia from heathy and patients with chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, lung adenocarcinoma, para-tumor tissue, and systemic sclerosis, respectively. We selected A549 cells for representative of alveolar epithelia or H1299 and H460 cells as airway epithelia with different genetic backgrounds and studied dynamic responses of NAT10-down-regulated epithelia to high temperature, lipopolysaccharide, cigarette smoking extract (CSE), drugs, radiation, and phosphoinositide 3-kinase (PI3K) inhibitors at various doses. We also compared transcriptomic profiles between alveolar and airway epithelia, between cells with or without NAT10 down-regulation, between early and late stages, and between challenges. The present study demonstrated that NAT10 expression increased in human lung epithelia and varied among epithelial types, challenges, and diseases. Knockdown of NAT10 altered epithelial mitochondrial functions, dynamic responses to LPS, CSE, or PI3K inhibitors, and transcriptomic phenomes. NAT10 regulates biological phenomes, and behaviors are more complex and are dependent upon multiple signal pathways. Thus, NAT10-associated signal pathways can be a new alternative for understanding the disease and developing new biomarkers and targets.

Fibroblast growth factor 10 protects against particulate matter-induced lung injury by inhibiting oxidative stress-mediated pyroptosis via the PI3K/Akt/Nrf2 signaling pathway.

Particulate matter (PM) is a major environmental contaminant that causes and worsens respiratory diseases. Fibroblast growth factor 10 (FGF10), a paracrine fibroblast growth factor that specifically stimulates repair and regeneration after injury, has been shown to protect against PM-induced lung injury. However, the underlying mechanisms are still unclear. In this study, the protective effects of FGF10 were investigated using a PM-induced lung injury mouse model in vivo and BEAS-2B cells in vitro. According to the findings, FGF10 treatment alleviated PM-induced oxidative damage and pyroptosis in vivo and in vitro. Mechanistically, FGF10 activated antioxidative Nrf2 signaling. Inhibition of PI3K signaling with LY294002 or Nrf2 signaling with ML385 revealed that FGF10-mediated lung protection was mediated by the PI3K/Akt/Nrf2 pathway. These results collectively indicate that FGF10 inhibits oxidative stress-mediated pyroptosis via the PI3K/Akt/Nrf2 pathway, suggesting a possible therapy for PM-induced lung injury.

Whole exome sequencing identified a novel POT1 variant as a candidate pathogenic allele underlying a Li-Fraumeni-like family.

Background: Li-Fraumeni syndrome (LFS) and Li-Fraumeni-like (LFL) syndrome are rare hereditary diseases characterized by predisposition to a diverse spectrum of cancer types, primarily sarcoma. The pathogenic variants underlying the majority of LFL cases remain to be explored. Methods: We performed whole-exome sequencing (WES) on 13 core members of a large LFL family with highly aggregated incidences of cancers, including cases with sarcoma, non-small cell lung cancer and cardiac angiosarcoma, and conducted a comprehensive literature review of candidate gene associations in LFS/LFL syndromes or sarcoma to identify potential pathogenic germline variants. Results: No germline variants in the best-known LFL/LFS-associated gene TP53 were detected. Of all the genes associated with LFS/LFL or sarcoma that we have surveyed, we identified a novel p.P35L germline variant in POT1 (protection of telomeres 1). Germline and somatic alterations in POT1 have been implicated in a series of familial cancers, including angiosarcoma, glioma, melanoma and colorectal cancer. This particular variant is located in the telomere-binding OB1 domain, which is important in maintaining the proper telomere length, and showed high conservation across different POT1 orthologues. No record of the variant was found in any of the 1000 genomes, ExAC, gnomAD, dpSNP and COSMIC databases. Prediction algorithms and in silico structural analysis suggested completely disrupted protein structure and function of POT1 in the presence of this mutation. Conclusions: Leveraging WES, we identified a novel germline risk allele, p.P35L in POT1, that likely predisposes to LFL syndrome. Our results support the routine testing of POT1 and other LFL/LFS-associated genes in the risk populations to enable early cancer diagnosis, prevention and intervention.

Supplementary benefits of CT-guided transthoracic lung aspiration biopsy for core needle biopsy.

Objective: This study aimed to investigate the diagnostic efficacy of computed tomography (CT)-guided transthoracic lung core needle biopsy combined with aspiration biopsy and the clinical value of this combined routine microbial detection. Materials and methods: We retrospectively collected the electronic medical records, CT images, pathology, and other data of 1085 patients with sequential core needle biopsy and aspiration biopsy of the same lung lesion under CT guidance in the First Affiliated Hospital of Wenzhou Medical University from January 2016 to January 2021. GenXpert MTB/RIF detection and BD BACTEC™ Mycobacterium/fungus culture were applied to identifying the microbiological results of these patients. We then compared the positive diagnostic rate, false negative rate, and diagnostic sensitivity rate of three methods including core needle biopsy alone, aspiration biopsy alone, and both core needle biopsy and aspiration biopsy. Results: The pathological results of cutting histopathology and aspiration of cell wax were examined for 1085 patients. The diagnostic rates of cutting and aspiration pathology were 90.1% (978/1085) and 86.3% (937/1085), respectively, with no significant difference (P > 0.05). Considering both cutting and aspiration pathologies, the diagnostic rate was significantly improved, up to 98% (1063/1085) (P < 0.001). A total of 803 malignant lesions were finally diagnosed (803/1085, 74.0%). The false negative rate by cutting pathology was 11.8% (95/803), which was significantly lower than that by aspiration biopsy [31.1% (250/803), P < 0.001]. Compared with core needle biopsy alone, the false negative rate of malignant lesions decreased to 5.6% (45/803) (P < 0.05). Next, the aspirates of the malignant lesions highly suspected of corresponding infection were cultured. The results showed that 16 cases (3.1%, 16/511) were infected with Mycobacterium tuberculosis complex, Aspergillus niger, and Acinetobacter baumannii, which required clinical treatment. 803 malignant tumors were excluded and 282 cases of benign lesions were diagnosed, including 232 cases of infectious lesions (82.3%, 232/282). The diagnostic rate of Mycobacterium/fungus culture for infectious lesions by aspiration biopsy (47.4%) was significantly higher than that by lung core needle biopsy (22.8%; P < 0.001). The diagnostic rate of aspiration biopsy combined with core needle biopsy was 56% (130/232). The parallel diagnostic rate of aspirated biopsy for GenXpert detection and Mycobacterium/fungal culture combined with core needle biopsy was 64.7% (150/232), which was significantly higher than that of lung core needle biopsy alone (P < 0.001). Finally, pulmonary tuberculosis was diagnosed in 90 cases (38.8%) of infectious lesions. Compared with the sensitivity of core needle biopsy to detect tuberculosis (27.8%, 25/90), the sensitivity of aspirating biopsy for GenXpert detection and Mycobacterium/fungal culture was significantly higher, at 70% (63/90) and 56.7% (51/90), respectively. Although there was no significant difference in the sensitivity of aspirated biopsy for GenXpert and Mycobacterium/fungal culture to detect pulmonary tuberculosis, the sensitivity was significantly increased to 83.3% (P < 0.05) when the two tests were combined. Moreover, when aspirated biopsies were combined with GenXpert detection, Mycobacterium/fungus culture, and core needle biopsy, the sensitivity was as high as 90% (81/90). Conclusion: CT-guided lung aspiration biopsy has a significant supplementary effect on core needle biopsies, which is indispensable in clinical application. Additionally, the combination of aspiration biopsy and core needle biopsy can significantly improve the diagnostic rate of benign and malignant lesions. Aspiration biopsy showed that pulmonary malignant lesions are complicated with pulmonary tuberculosis, aspergillus, and other infections. Finally, the diagnostic ability of lung puncture core needle biopsy and aspiration biopsy combined with routine microbial detection under CT positioning in the diagnosis of pulmonary infectious diseases was significantly improved.

Comparison of operation time, efficacy and safety between through-the-scope stent and over-the-while stent in malignant central airway obstruction: a multi-center randomized control trial.

Background: Self-expandable metallic (SEM) airway stents are an important approach to treating malignant central airway obstruction (CAO). Standard over-the-while (OTW) stent needs the guidance of a guide-wire. It should be implanted under flouroscopy or the guidance of bronchoscope visualization. In this study, we evaluated the operation time and safety between OTW stent and a novel through-the-scope (TTS) SEM airway stent. Methods: In this multi-center, randomized, parallel-group superiority study, malignant CAO patients were enrolled randomly assigned (2:1) to the TTS stent implantation group (TTS group) or the standard OTW stent group (OTW group) in six sites across China. The entire process of all surgical procedures was recorded by video. Primary endpoint was the operation time of the airway stent implantation and secondary endpoint was the success rate of the stent implantation as well as its efficacy and safety. Results: From May 15, 2017, to December 30, 2018, 148 patients were enrolled from the six sites. We analyzed 134 patients (including 91 patients from the TTS group and 43 patients from the OTW group) according to the per-protocol set. There were no significant differences in the ages, genders, underlying diseases, and stenosis sites between the two groups. The operation time in the TTS group was significantly shorter than that in the OTW group (104±68 vs. 252±111 seconds, P<0.001). Compared to the OTW group, the efficacy of stent implantation (97.80% vs. 90.70%, P=0.093) and rate of first-time successful stent implantation (78.02% vs. 74.42%, P=0.668) were higher in the TTS group, but did not reach statistically significance. The rates of granulation (28.57% vs. 41.86%, P=0.128) and restenosis (15.38% vs. 30.23%, P=0.064) in the TTS group were slightly lower as compared with the OTW group without achieving statistical significance. Conclusions: The TTS stent implantation procedure time was significantly shorter than that of the OTW airway stent with similar efficacy and complications, which might reduce the risk and flexibility of stent implantation. Trial Registration: Chinese Clinical Trial Registry ChiCTR-IOR-17011431.

Establishing a novel model of malignant airway stenosis in rabbit.

Background: Malignant central airway stenosis is a life-threatening condition. However, treatment of malignant airway stenosis remains challenging. There is currently a severe lack of an excellent animal model of malignant airway stenosis to facilitate treatment approaches. This is the first study to establish a rabbit model of malignant airway stenosis for bronchoscopic interventional studies. Materials and methods: New Zealand White rabbits were used in this study, randomly divided into group A (18 rabbits) and group B (6 rabbits). A VX2 fragment suspension was injected into the submucosal layer of rabbits' airway by bronchoscopy. Bronchoscopic examinations were performed once a week after VX2 tumor implantation to observe tumor growth and the degree of airway stenosis. Randomly, three rabbits were generally dissected after a weekly bronchoscopic examination in group A. The rabbits that reached grade III airway stenosis underwent stent implantation in group B. Results: A total of 24 rabbits were successfully implanted with the VX2 fragment suspension in the airway without significant adverse events, and the success rate of the tumor growth was 100%. The degree of airway stenosis reaching grade III took 2 to 3 weeks after implantation of the VX2 tumor. The median survival time of rabbit models without stent implantation and rabbits with stent implantation was 32.5 and 32.0 days, respectively. Conclusions: The implanting method is safe and effective for the establishment of a rabbit model of malignant airway stenosis. When the tumor grows to 2 to 3 weeks, the rabbit model is available for stent implantation. We recommend the models for more preclinical animal studies on bronchoscopic interventional treatments.

Efficacy and Safety of Befotertinib (D-0316) in Patients With EGFR T790M-Mutated NSCLC That Had Progressed After Prior EGFR Tyrosine Kinase Inhibitor Therapy: A Phase 2, Multicenter, Single-Arm, Open-Label Study.

INTRODUCTION: Befotertinib (D-0316) is a novel, third-generation EGFR tyrosine kinase inhibitor (TKI). This study evaluated befotertinib in patients with locally advanced or metastatic NSCLC who developed an EGFR T790M mutation after progression on first- or second-generation EGFR TKI therapy. METHODS: This was a single-arm, open-label, phase 2 study at 49 hospitals across mainland China. Patients with locally advanced or metastatic NSCLC harboring EGFR T790M mutations with disease progression after prior first- or second-generation EGFR TKI therapy received oral befotertinib of 50 mg (cohort A) or 75 to 100 mg (cohort B) once daily. The primary end point was objective response rate (ORR) assessed by an independent review committee in intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT03861156. RESULTS: A total of 176 patients and 290 patients were included in cohorts A (50 mg) and B (75-100 mg), respectively. At data cutoff (August 15, 2021), independent review committee-assessed ORR was 67.6% (95% confidence interval [CI]: 61.9%-72.9%) in cohort B. The investigator-assessed ORR was 54.0% (95% CI: 46.3%-61.5%) in cohort A and 65.9% (95% CI: 60.1%-71.3%) in cohort B. The median investigator-assessed progression-free survival was 11.0 (95% CI: 9.6-12.5) months in cohort A and 12.5 (95% CI: 11.1-13.8) months in cohort B. The median independent review committee-assessed progression-free survival in cohort B was 16.6 (95% CI: 15.0-not evaluable [NE]) months. The intracranial ORR was 26.7% (95% CI: 7.8%-55.1%) in cohort A by investigator assessment, while 57.1% (95% CI: 34.0%-78.2%) and 55.9% (95% CI: 37.9%-72.8%) in cohort B by investigator and independent review committee assessment, respectively. The median investigator-assessed intracranial progression-free survival was 16.5 (95% CI: 8.6-NE) months in cohort A, while the median intracranial progression-free survival was not evaluable in cohort B due to immature data regardless of investigator or independent review committee assessment. and NE (95% CI: 13.8-NE) in cohort B. The overall survival was immature. Grade 3 or higher treatment-related adverse events and treatment-related serious adverse events occurred in 20.5% and 11.4% of patients in cohort A and in 29.3% and 10.0% of patients in cohort B, respectively. CONCLUSIONS: Befotertinib of 75 to 100 mg has satisfying efficacy and manageable toxicity in patients with locally advanced or metastatic NSCLC harboring T790M mutation with resistance to first- or second-generation EGFR TKIs. A phase 3 randomized trial is underway (NCT04206072).

Macrophage Cell Membrane-Cloaked Nanoplatforms for Biomedical Applications.

Biomimetic approaches utilize natural cell membrane-derived nanovesicles to camouflage nanoparticles to circumvent some limitations of nanoscale materials. This emergent cell membrane-coating technology is inspired by naturally occurring intercellular interactions, to efficiently guide nanostructures to the desired locations, thereby increasing both therapeutic efficacy and safety. In addition, the intrinsic biocompatibility of cell membranes allows the crossing of biological barriers and avoids elimination by the immune system. This results in enhanced blood circulation time and lower toxicity in vivo. Macrophages are the major phagocytic cells of the innate immune system. They are equipped with a complex repertoire of surface receptors, enabling them to respond to biological signals, and to exhibit a natural tropism to inflammatory sites and tumorous tissues. Macrophage cell membrane-functionalized nanosystems are designed to combine the advantages of both macrophages and nanomaterials, improving the ability of those nanosystems to reach target sites. Recent studies have demonstrated the potential of these biomimetic nanosystems for targeted delivery of drugs and imaging agents to tumors, inflammatory, and infected sites. The present review covers the preparation and biomedical applications of macrophage cell membrane-coated nanosystems. Challenges and future perspectives in the development of these membrane-coated nanosystems are addressed.