CD36 inhibition reduces non-small-cell lung cancer development through AKT-mTOR pathway.

Lung cancer is the most common cause of cancer-related deaths worldwide and is caused by multiple factors, including high-fat diet (HFD). CD36, a fatty acid receptor, is closely associated with metabolism-related diseases, including cardiovascular disease and cancer. However, the role of CD36 in HFD-accelerated non-small-cell lung cancer (NSCLC) is unclear. In vivo, we fed C57BL/6J wild-type (WT) and CD36 knockout (CD36-/-) mice normal chow or HFD in the presence or absence of pitavastatin 2 weeks before subcutaneous injection of LLC1 cells. In vitro, A549 and NCI-H520 cells were treated with free fatty acids (FFAs) to mimic HFD situation for exploration the underlying mechanisms. We found that HFD promoted LLC1 tumor growth in vivo and that FFAs increased cell proliferation and migration in A549 and NCI-H520 cells. The enhanced cell or tumor growth was inhibited by the lipid-lowering agent pitavastatin, which reduced lipid accumulation. More importantly, we found that plasma soluble CD36 (sCD36) levels were higher in NSCLC patients than those in healthy ones. Compared to that in WT mice, the proliferation of LLC1 cells in CD36-/- mice was largely suppressed, which was further repressed by pitavastatin in HFD group. At the molecular level, we found that CD36 inhibition, either with pitavastatin or plasmid, reduced proliferation- and migration-related protein expression through the AKT/mTOR pathway. Taken together, we demonstrate that inhibition of CD36 expression by pitavastatin or other inhibitors may be a viable strategy for NSCLC treatment.

The importance and feasibility of hospital interventions to prevent and manage patient aggression and violence against physicians in China: a Delphi study.

BACKGROUND: Aggression and violence by patient (and their relatives/friends) is widely acknowledged as a serious occupational hazard, with physicians being particularly susceptible to witnessing and experiencing such incidents within hospitals. Research has shown that the negative consequences of such aggression and violence are not only felt at the individual level, but also at the team and organizational levels. Understanding how to prevent and manage this behavior towards physicians in hospitals is urgent and not fully researched. While there are many potentially effective interventions, it is unclear which ones would be valuable and feasible for Chinese hospitals. Because patient aggression and violence may occur more frequently in Chinese hospitals than in other countries, this suggests that cultural differences play a role and that tailored interventions may be needed. METHOD: We conducted a Delphi study to reach a consensus on the importance and feasibility of hospital interventions to prevent and manage patient (and their relatives/friends) aggression and violence against physicians in Chinese hospitals. Seventeen experts in China were invited to complete online questionnaires over three rounds. RESULTS: After three rounds, consensus was achieved concerning 44 interventions, five other interventions were rejected, and no consensus was reached on another two. These interventions were clustered into eight categories: environment design, access and entrance, staffing and working practices, leadership and culture, training and education, support, during/after-the-event actions, and hospital policy. Each category is considered important in preventing and managing patient (and their relatives/friends) aggression and violence towards physicians in Chinese hospitals. This study also investigated the feasibility of the suggested interventions and found that 36 of the 44 interventions were considered not only relevant, but also feasible for implementation in Chinese hospitals. CONCLUSIONS: This study provides an overview of interventions that can be implemented in Chinese hospitals to prevent and manage patient (and their relatives/friends) aggression and violence before, during, and after a violent incident occurs.

A novel CDK8 inhibitor with poly-substituted pyridine core: Discovery and anti-inflammatory activity evaluation in vivo.

As an ideal anti-inflammatory target, cyclin-dependent kinase 8 (CDK8) has gradually attracted the attention of researchers. CDK8 inhibition up-regulates Interleukin-10 (IL-10) expression by enhancing the transcriptional activity of activator protein-1 (AP-1), and augmenting IL-10 abundance is a viable strategy for the treatment of inflammatory bowel disease (IBD). In this research, through structure-based drug design and dominant fragment hybridization, a series of poly-substituted pyridine derivatives were designed and synthesized as CDK8 inhibitors. Ultimately, compound CR16 was identified as the best one, which exhibited good inhibitory activity against CDK8 (IC50 = 74.4 nM). In vitro and in vivo studies indicated that CR16 could enhance the transcriptional activity of AP-1, augment the abundance of IL-10, and affect CDK8-related signaling pathways including TLR7/NF-κB/MAPK and IL-10-JAK1-STAT3 pathways. In addition, CR16 showed potent therapeutic effect in an animal model of IBD.

Comprehensive identification of RNA transcripts and construction of RNA network in chronic obstructive pulmonary disease.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is one of the world's leading causes of death and a major chronic disease, highly prevalent in the aging population exposed to tobacco smoke and airborne pollutants, which calls for early and useful biomolecular predictors. Roles of noncoding RNAs in COPD have been proposed, however, not many studies have systematically investigated the crosstalk among various transcripts in this context. The construction of RNA functional networks such as lncRNA-mRNA, and circRNA-miRNA-mRNA interaction networks could therefore facilitate our understanding of RNA interactions in COPD. Here, we identified the expression of RNA transcripts in RNA sequencing from COPD patients, and the potential RNA networks were further constructed. METHODS: All fresh peripheral blood samples of three patients with COPD and three non-COPD patients were collected and examined for mRNA, miRNA, lncRNA, and circRNA expression followed by qRT-PCR validation. We also examined mRNA expression to enrich relevant biological pathways. lncRNA-mRNA coexpression network and circRNA-miRNA-mRNA network in COPD were constructed. RESULTS: In this study, we have comprehensively identified and analyzed the differentially expressed mRNAs, lncRNAs, miRNAs, and circRNAs in peripheral blood of COPD patients with high-throughput RNA sequencing. 282 mRNAs, 146 lncRNAs, 85 miRNAs, and 81 circRNAs were differentially expressed. GSEA analysis showed that these differentially expressed RNAs correlate with several critical biological processes such as "ncRNA metabolic process", "ncRNA processing", "ribosome biogenesis", "rRNAs metabolic process", "tRNA metabolic process" and "tRNA processing", which might be participating in the progression of COPD. RT-qPCR with more clinical COPD samples was used for the validation of some differentially expressed RNAs, and the results were in high accordance with the RNA sequencing. Given the putative regulatory function of lncRNAs and circRNAs, we have constructed the co-expression network between lncRNA and mRNA. To demonstrate the potential interactions between circRNAs and miRNAs, we have also constructed a competing endogenous RNA (ceRNA) network of differential expression circRNA-miRNA-mRNA in COPD. CONCLUSIONS: In this study, we have identified and analyzed the differentially expressed mRNAs, lncRNAs, miRNAs, and circRNAs, providing a systematic view of the differentially expressed RNA in the context of COPD. We have also constructed the lncRNA-mRNA co-expression network, and for the first time constructed the circRNA-miRNA-mRNA in COPD. This study reveals the RNA involvement and potential regulatory roles in COPD, and further uncovers the interactions among those RNAs, which will assist the pathological investigations of COPD and shed light on therapeutic targets exploration for COPD.

Abnormal expression and clinical significance of surface receptors on natural killer cells in the peripheral blood of patients with non-small cell lung cancer.

Natural killer (NK) cells typically function as frontline lymphocytes against cancer although little is known about their engagement in non-small cell lung cancer (NSCLC). This study compared the performance and activity of NK cells and their subsets in the peripheral blood of NSCLC sufferers and healthy participants. In total, 67 healthy controls (40 males; 59.7%) and 56 patients with NSCLC (35 males; 62.5%) were included (mean age, 66.6 years). Flow cytometry identified NK cells and their subpopulations in external blood, and the total number, proportion, activity, surface activating, and inhibitory receptor expression levels were determined. Results showed that NK cell surface receptors CD107a, IFN-γ, and TNF-α activity were markedly reduced in lung cancer patients compared to healthy controls. The number and ratio of NK cells within the lymphocyte population were decreased in patients. The concentration of the inhibitory receptors TIGIT, TIM-3, CD96, PD-1, and Siglec-7 were increased in patients, whereas the expression level of the activating receptor NKP30 was decreased. Moreover, the expression levels of IFN-γ, TIGIT, CD96, PD-1, and TIM-3 were correlated with the clinical phase of NSCLC. These findings suggest that surface receptors from NK cells are likely to be involved in the evolution of NSCLC.

Biomarkers of connective tissue disease-associated interstitial lung disease in bronchoalveolar lavage fluid: A label-free mass spectrometry-based relative quantification study.

BACKGROUND: The pathogenesis of connective tissue disease-associated interstitial lung disease (CTD-ILD) is unclear. This study aims to identify differentially expressed proteins (DEPs) in CTD-ILD to determine the potential role of these DEPs that may play in the pathogenesis of CTD-ILD and to offer potential therapeutic targets. METHODS: Bronchoalveolar lavage fluid (BALF) samples were collected from four patients with CTD-ILD and four patients without CTD-ILD. Label-free mass spectrometry-based relative quantification was used to identify the DEPs. Bioinformatics were used to determine the potential biological processes and signaling pathways associated with these DEPs. RESULTS: We found 65 upregulated DEPs including SFTPD, CADM1, ACSL4, TSTD1, CD163, LUM, SIGLEC1, CPB2, TGFBI and HGD, and 67 downregulated DEPs including SGSH, WIPF1, SIL1, RAB20, OAS3, GMPR2, PLBD1, DNAJC3, RNASET2 and OAS2. The results of GO functional annotation for the DEPs showed that the DEPS were mainly enriched in the binding, cellular anatomical entity, cellular processes, and biological regulation GO terms. The results of KEGG analyses showed that the pathways most annotated with the DEPs were complement and coagulation cascades, metabolic pathways, pathways in cancer, and PPAR signaling pathway. COG analyses further informed the functions associated with these DEPs, with most focused on signal transduction mechanisms; posttranslational modification, protein turnover, chaperones; intracellular trafficking, secretion, and vesicular transport; amino acid transport and metabolism; and lipid transport and metabolism. CONCLUSIONS: DEPs identified between patients with vs. without CTD-ILD may play important roles in the development of CTD-ILD and are potential new biomarkers for early diagnosis of CTD-ILD.

Resveratrol Ameliorates Fibrosis in Rheumatoid Arthritis-Associated Interstitial Lung Disease via the Autophagy-Lysosome Pathway.

Interstitial lung disease associated with rheumatoid arthritis (RA-ILD) can lead to interstitial fibrosis and even lung failure as a complication of rheumatoid arthritis (RA), and there is currently no effective treatment and related basic research. Studies have found that resveratrol (Res) can improve the progression of RA by regulating autophagy, and increasing evidence supports the connection between autophagy and common interstitial lung disease (ILD). We explored changes in autophagy levels in fibrotic lungs in RA-ILD and found that the level of autophagy is enhanced in the early stage but inhibited in the late stage. However, resveratrol treatment improved the level of autophagy and reversed the inhibition of autophagy, and attenuated fibrosis. We created corresponding cell models that exhibited the same phenotypic changes as animal models; under the effect of resveratrol, the level of fibrosis changed accordingly, and the fusion process of lysosomes and autophagosomes in autophagy was liberated from the inhibition state. Resveratrol effects were reversed by the addition of the late autophagy inhibitor chloroquine. These results suggest that resveratrol attenuates pulmonary fibrosis, increases autophagic flux, and modulates the autophagy-lysosome pathway, and particularly it may work by improving the formation of autophagic lysosomes, which may be an effective treatment for induced RA-ILD.

Prediction model for malignant pulmonary nodules based on cfMeDIP-seq and machine learning.

Cell-free methylated DNA immunoprecipitation and high-throughput sequencing (cfMeDIP-seq) is a new bisulfite-free technique, which can detect the whole-genome methylation of blood cell-free DNA (cfDNA). Using this technique, we identified differentially methylated regions (DMR) of cfDNA between lung tumors and normal controls. Based on the top 300 DMR, we built a random forest prediction model, which was able to distinguish malignant lung tumors from normal controls with high sensitivity and specificity of 91.0% and 93.3% (AUROC curve of 0.963). In summary, we reported a non-invasive prediction model that had good ability to distinguish malignant pulmonary nodules.

Patient satisfaction with outpatient care in China: a comparison of public secondary and tertiary hospitals.

OBJECTIVE: The aims of this study were to investigate and compare patient satisfaction with outpatient care in public secondary and tertiary hospitals in China and to explore the factors affecting patient satisfaction for improving the quality of outpatient care in public hospitals. METHODS: This cross-sectional study comprised a sample survey of 11 097 adults in 31 provincial cities in China from February to April 2018. A pretested structured questionnaire was used to collect outpatient experience data through a computer-assisted telephone interviewing system. Patient satisfaction was assessed using nine questions answered on a 4-point Likert scale. Multivariate regression models were employed to examine the relationships of patient satisfaction with outpatient services and healthcare provider level and to identify the factors associated with satisfaction. RESULTS: Patient's overall satisfaction score with outpatient care was 27.3 (SD = 3.8), with lower scores observed in tertiary hospitals than in secondary hospitals (27.3 vs. 27.6, P < 0.05). The domain with the highest satisfaction was 'consulting environment', and the domain with the lowest satisfaction was 'patient waiting time in the hospital'. Patients who went to tertiary hospitals reported lower satisfaction in 'patient waiting time in the hospital', 'medical expenses', 'patient length of treatment time' and 'attitudes of other health workers' than patients who went to secondary hospitals (P < 0.05). In secondary hospitals, no significant difference in patient satisfaction was observed between different sociodemographic categories (P > 0.05). In tertiary hospitals, female and single respondents were more likely to have higher satisfaction (P < 0.05), whereas respondents with high school or junior college degrees were more likely to have lower satisfaction (P < 0.05). CONCLUSION: The aforementioned results suggested that tertiary hospitals face larger challenges in patient satisfaction with outpatient care than secondary hospitals. Measures must be adopted to improve patient satisfaction with outpatient care in future healthcare reforms. Patient waiting time, medical expenses and treatment duration especially require improvements in tertiary hospitals.

A Comparative Study on the Clinical Features of Coronavirus 2019 (COVID-19) Pneumonia With Other Pneumonias.

BACKGROUND: A novel coronavirus (COVID-19) has raised world concern since it emerged in Wuhan, China in December 2019. The infection may result in severe pneumonia with clusters of illness onsets. Its impacts on public health make it paramount to clarify the clinical features with other pneumonias. METHODS: Nineteen COVID-19 and 15 other patients with pneumonia (non-COVID-19) in areas outside of Hubei were involved in this study. Both COVID-19 and non-COVID-19 patients were confirmed to be infected using throat swabs and/or sputa with/without COVID-2019 by real-time RT-PCR. We analyzed the demographic, epidemiological, clinical, and radiological features from those patients, and compared the differences between COVID-19 and non-COVID-19. RESULTS: All patients had a history of exposure to confirmed cases of COVID-19 or travel to Hubei before illness. The median (IQR) duration was 8 (6-11) and 5 (4-11) days from exposure to onset in COVID-19 and non-COVID-19 cases, respectively. The clinical symptoms were similar between COVID-19 and non-COVID-19. The most common symptoms were fever and cough. Fifteen (78.95%) COVID-19 but 4 (26.67%) non-COVID-19 patients had bilateral involvement while 17 COVID-19 patients (89.47%) but 1 non-COVID-19 patient (6.67%) had multiple mottling and ground-glass opacity on chest CT images. Compared with non-COVID-19, COVID-19 presents remarkably more abnormal laboratory tests, including AST, ALT, γ-GT, LDH, and α-HBDH. CONCLUSIONS: The COVID-19 infection has onsets similar to other pneumonias. CT scan may be a reliable test for screening COVID-19 cases. Liver function damage is more frequent in COVID-19 than non-COVID-19 patients. LDH and α-HBDH may be considerable markers for evaluation of COVID-19.

Pleural translocation and lesions by pulmonary exposed multi-walled carbon nanotubes.

Carbon nanotubes (CNTs) are recently developed tubular nanomaterials, with diameters ranging from a few nanometers to tens of nanometers, and the length reaching up to several micrometers. They can be either single-walled carbon nanotubes (SWCNTs) or multi-walled carbon nanotubes (MWCNTs). Due to their nano-scaled structure, CNTs have a unique set of mechanical, electrical, and chemical properties that make them useful in information technologies, optoelectronics, energy technologies, material sciences, medical technologies, and other fields. However, with the wide application and increasing production of CNTs, their potential risks have led to concerns regarding their impact on environment and health. The shape of some types of CNTs is similar to asbestos fibers, which suggests that these CNTs may cause characteristic pleural diseases similar to those found in asbestos-exposed humans, such as pleural plaques and malignant mesothelioma. Experimental data indicate that CNTs can induce lung and pleural lesions, inflammation, pleural fibrosis, lung tumors, and malignant mesothelioma upon inhalation in the experimental animals. In this review, we focus on the potential of MWCNTs to induce diseases similar to those by asbestos, molecular and cellular mechanisms associated with these diseases, and we discuss a method for evaluating the pleural toxicity of MWCNTs.

International variations in trust in health care systems.

Public trust in health care systems has been measured in many countries, but there have been few studies of the intercountry variability in trust, or the degree to which such variability is because of population or structural characteristics. We used data from the health care survey conducted by the International Social Survey Program from 2011 to 2013 in 31 countries to assess whether intercountry variability was significantly greater than intracountry variability using general linear models in which country was treated as a fixed factor. We also assessed the extent to which intercountry variability was because of respondent and economic circumstances (gross national income per capita). Public trust in the health care system varied significantly across countries (P < .001), even after adjustment for 8 within-country predictors and gross national income per capita. One of the strongest predictors of trust was the respondents' most recent health care experience. Higher respondent education, urban residence, and a lower country's gross national income predicted less trust in the health care system. After countries with the 10% highest health expenditures per capita (United States) and the 10% lowest health care expenditures per capita (China and the Philippines) were removed, public trust in the health care system was positively associated with the remaining countries' health care expenditures per capita (Pearson correlation coefficient, 0.490; P = .008) and gross national income per capita (Pearson correlation coefficient, 0.495; P = .007). There is significant variation in public trust in health care across the countries studied. The intercountry differences are due, in part to economic circumstances.

Development and validation of a nomogram to predict the depressive symptoms among older adults: A national survey in China.

BACKGROUND: Depressive symptoms (DS) have become a global public health problem. However, a risk prediction model for DS in the elderly population has not been established. The purpose of this study was to develop and validate a predictive nomogram to screen for DS in the elderly population. METHODS: A cross-sectional data of 3396 participants aged 60 and over were obtained from the China Health and Retirement Longitudinal Study 2018 (CHARLS). Participants were divided into the development and validation set. Predictive factors were selected through a single-factor analysis, and then a predictive model nomogram was established. The discrimination, calibration, and clinical validity were evaluated using the receiver operating characteristic (ROC) curves, Hosmer-Lemeshow tests, and decision curve analyses (DCA). RESULTS: A total of 2379 and 1017 participants were included in the development and validation set, respectively. The analysis found that gender, residence, dyslipidemia, self-rated health, and ADL disability were risk factors for DS in older adults, and were included in the final model. This nomogram showed an acceptable predictive performance as evaluated by the area under the ROC curve with values of 0.684 (95 % confidence interval (CI): 0.663-0.706) and 0.687 (95 % CI: 0.655-0.719) in the development and validation set, respectively. The calibration curve indicated that the model was accurate, and DCA demonstrated a good clinical application value. CONCLUSION: Five factors were selected to establish a nomogram for predicting DS in older adults. The nomogram has a good evaluation performance and can be used as a reliable tool to predict DS among older adults.

Research trends on airway remodeling: A bibliometrics analysis.

Background: Airway remodeling is an essential pathological basis of respiratory diseases such as asthma and COPD, which is significantly related to pulmonary function and clinical symptoms. And pulmonary disease can be improved by regulating airway remodeling. This study aimed to establish a knowledge map of airway remodeling to clarify current research hotspots and future research trends. Methods: A comprehensive search was performed to analyze all relevant articles on airway remodeling using the Web of Science Core Collection Database from January 01, 2004 to June 03, 2023.2 reviewers screened the retrieved literature. Besides, the CiteSpace (6.2. R3) and VOSviewer (1.6.19) were utilized to visualize the research focus and trend regarding the effect of airway remodeling. Results: A total of 4077 articles about airway remodeling were retrieved. The United States is the country with the most published literature, underscoring the country's role in airway remodeling. In recent years, China has been the country with the fastest growth in the number of published literature, suggesting that China will play a more critical role in airway remodeling in the future. From the perspective of co-operation among countries, European co-operation was closer than Asian co-operation. The co-citation analysis showed that 98,313 citations were recorded in 3594 articles, and 25 clusters could be realized. In recent years, Burst detection shows that oxidative stress and epithelial-mesenchymal transition are hot words. Conclusions: Based on the bibliometric analysis of airway remodeling studies in the past 20 years, a multi-level knowledge structure map was drawn, it mainly includes countries, institutions, research fields, authors, journals, keywords and so on. The research directions represented by obstructive airway disease, PDGF-BB treatment of airway smooth muscle, allergen-induced airway remodeling, extracellular matrix, and non-coding RNA are the research hotspots in the field of airway remodeling. While the risk factors for airway remodeling, the application of new noninvasively assessing tools, biomarkers as well as The molecular mechanism represented by EMT and autophagy had been frontiers in recent years.

Trajectory of COVID-19 response and management strategy in China: scientific rationale driven strategy adjustments.

The pneumonia caused by novel coronavirus SARS-CoV-2 infection in early December 2019, which was later named coronavirus disease 2019 (COVID-19) by the World Health Organization (WHO), rapidly spread across the world. China has made extraordinary efforts to this unprecedented pandemic, put its response and control at a very high level of infectious disease management (Category B but with measures for Category A), given top priority to the people and their lives, and balanced the pandemic control and socio-economic development. After more than three years' fighting against this disease, China downgraded the management of COVID-19 to Category B infectious disease on January 8, 2023 and the WHO declared the end of public health emergency on May 5, 2023. However, the ending of pandemic does not mean that the disease is no longer a health threat. Experiences against COVID-19 from China and the whole world should be learned to prepare well for the future public health emergencies. This article gives a systematic review of the trajectory of COVID-19 development in China, summarizes the critical policy arrangements and provides evidence for the adjustment during policy making process, so as to share experiences with international community and contribute to the global health for all humanity.

Using Apnea-Hypopnea Duration per Hour to Predict Hypoxemia Among Patients with Obstructive Sleep Apnea.

Purpose: To explore the role of the mean apnea-hypopnea duration (MAD) and apnea-hypopnea duration per hour (HAD) in hypoxemia and evaluate whether they can effectively predict the occurrence of hypoxemia among adults with OSA. Patients and Methods: A total of 144 participants underwent basic information gathering and polysomnography (PSG). Logistic regression models were conducted to evaluate the best index in terms of hypoxemia. To construct the prediction model for hypoxemia, we randomly divided the participants into the training set (70%) and the validation set (30%). Results: The participants with hypoxemia tend to have higher levels of obesity, diabetes, AHI, MAD, and HAD compared with non-hypoxemia. The most relevant indicator of blood oxygen concentration is HAD (r = 0.73) among HAD, MAD, and apnea-hypopnea index (AHI). The fitness of HAD on hypoxemia showed the best. In the stage of establishing the prediction model, the area under the curve (AUC) values of both the training set and the validation set are 0.95. The increased HAD would elevate the risk of hypoxemia [odds ratio (OR): 1.30, 95% confidence interval (CI): 1.13-1.49]. Conclusion: The potential role of HAD in predicting hypoxemia underscores the significance of leveraging comprehensive measures of respiratory disturbances during sleep to enhance the clinical management and prognostication of individuals with sleep-related breathing disorders.

Sunvozertinib for patients in China with platinum-pretreated locally advanced or metastatic non-small-cell lung cancer and EGFR exon 20 insertion mutation (WU-KONG6): single-arm, open-label, multicentre, phase 2 trial.

BACKGROUND: Sunvozertinib is an oral, irreversible, and selective tyrosine kinase inhibitor that has a favourable safety profile and encouraging antitumour activity, as shown in phase 1 studies of patients with heavily pretreated non-small cell lung cancer (NSCLC) with EGFR exon 20 insertion mutation (exon20ins). We aimed to assess the antitumour efficacy of sunvozertinib in patients with platinum-pretreated locally advanced or metastatic NSCLC with EGFR exon20ins. METHODS: WU-KONG6 is a single-group, open-label, multicentre phase 2 trial of sunvozertinib monotherapy, conducted across 37 medical centres in China. We enrolled adult patients with pathologically or cytologically confirmed locally advanced or metastatic NSCLC whose tumour tissue carried an EGFR exon20ins mutation. All patients had received at least one line of previous systemic therapy, with at least one line containing platinum-based chemotherapy. The primary endpoint was objective response rate (ORR), as assessed by the independent review committee. The ORR was defined as the percentage of patients who achieved complete or partial response, confirmed by two separate assessments with at least 4-week time interval, until disease progression or initiation of any new anti-cancer therapy. Enrolled patients received sunvozertinib 300 mg once daily until meeting discontinuation criteria per the protocol. Patients who received at least one dose of treatment and were evaluable for efficacy analysis were included in the primary analysis, and all patients who received at least one dose of treatment were included in the safety analysis. This study is registered with ChinaDrugTrials.org, CTR20211009, and ClinicalTrials.gov, NCT05712902, and efficacy and safety follow-up are ongoing. FINDINGS: Between July 19, 2021, and May 6, 2022, 104 patients were enrolled. At data cutoff (Oct 17, 2022), the last enrolled patient had been followed up for about 6 months. Among 97 patients evaluable for efficacy analysis, 59 (61%) patients achieved tumour response, with a confirmed ORR of 61% (95% CI 50-71). All tumour responses were partial responses. Tumour responses were observed irrespective of age, sex, smoking history, EGFR exon20ins subtypes, brain metastasis at baseline, previous lines of therapy, and history of onco-immunotherapy. In total, 19 death events occurred over a median follow-up period of 7·6 months (IQR 6·1-9·4). Sunvozertinib was well tolerated at 300 mg once daily. The most common grade 3 or worse treatment-related adverse events were blood creatine phosphokinase increased (18 [17%] of 104), diarrhoea (eight [8%]), and anaemia (six [6%]). The most common serious treatment-related adverse events were interstitial lung disease (five [5%] of 104), anaemia (three [3%]), vomiting (two [2%]), nausea (two [2%]) and pneumonia (two [2%]). INTERPRETATION: In this phase 2 study, sunvozertinib demonstrated antitumour efficacy in patients with platinum-based chemotherapy pretreated NSCLC with EGFR exon20ins, with a manageable safety profile. A multinational randomised, phase 3 study of sunvozertinib versus platinum-doublet chemotherapy in EGFR exon20ins NSCLC is ongoing (NCT05668988). FUNDING: Dizal Pharmaceutical.

Corrigendum: Advanced NSCLC patients with EGFR T790M harbouring TP53 R273C or KRAS G12V cannot benefit from osimertinib based on a clinical multicentre study by tissue and liquid biopsy.

[This corrects the article DOI: 10.3389/fonc.2021.621992.].

Osimertinib versus comparator first-generation epidermal growth factor receptor tyrosine kinase inhibitors as first-line treatment in patients with advanced EGFR-mutated non-small cell lung cancer: a Chinese, multicenter, real-world cohort study.

Background: In the phase 3 FLAURA trial, osimertinib was compared with first-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) as a first-line treatment for EGFR-mutant non-small cell lung cancer (NSCLC). Osimertinib showed longer progression-free survival (PFS), overall survival (OS), and a similar safety profile. However, more studies demonstrating the effectiveness and safety of osimertinib as a first-line strategy are needed in real-world populations. Methods: We enrolled 1,556 patients with EGFR-mutated stage IIIc-IV NSCLC from the CAPTRA-Lung database. All patients received either osimertinib (n=202) or a first-generation EGFR-TKI (n=1,354) as their initial treatment. To adjust for differences in baseline characteristics between two groups, 1:2 propensity score matching (PSM) was performed. Propensity scores included gender, age, Eastern Cooperative Oncology Group performance status score, smoking history, family history of tumor, pathology, EGFR mutations, and central nervous system (CNS) metastases. The standardized mean differences (SMD) before and after PSM were calculated to examine the balance of covariate distributions between two groups. Results: After PSM, 202 patients receiving osimertinib and 404 patients receiving first-generation EGFR-TKIs were finally identified. SMD of each matched variable is less than 0.10. The median PFS was 19.4 months [95% confidence interval (CI): 14.3-24.4] in the osimertinib arm and 10.9 months (95% CI: 9.3-12.5) in the comparator arm [hazard ratio (HR) for progression, 0.47; 95% CI: 0.38-0.59; P<0.001). The median OS was 40.5 months (95% CI: 27.1-54.0) vs. 34.3 months (95% CI: 30.6-38.0) in two groups, respectively (HR for death, 0.76; 95% CI: 0.58-1.00; P=0.045). The incidence of grade 3 adverse events (AEs) between the two groups was 1% and 4.2%, respectively. No grade 4 AEs and treatment-related deaths were reported in both groups. Conclusions: In real-world settings, osimertinib demonstrates longer PFS and OS, with a similar safety profile to that of comparator EGFR-TKIs when used as a first-line strategy in NSCLC patients.

ASIC1a induces mitochondrial apoptotic responses in acute lung injury.

AIM: This study aimed to investigate the promoting effect of acid-sensing ion channel 1a (ASIC1a) on lipopolysaccharide (LPS)-induced acute lung injury (ALI) and its mechanisms. METHODS: In this experiment, the ALI rat model was induced by intratracheal injection of LPS, and the ASIC1a specific blocker psalmotoxin-1 (PcTx-1) was injected into the tail vein before LPS administration once. Western blot, immunofluorescence, immunohistochemistry and real-time PCR methods were used to detect ASIC1a and apoptosis-related proteins expressions in lung tissue and RLE-6TN rat type II alveolar epithelial cells. Confocal Laser Scanning Microscopy was used to detect Ca2+ fluorescence intensity in RLE-6TN cells. RESULTS: PcTx-1 pretreatment not only inhibited the pathological changes of LPS-induced ALI in lung tissue, but also inhibited lung dysfunction. PcTx-1 also reduced the increased levels of the apoptosis-related proteins B-cell lymphoma-2-associated X (Bax) and cleaved cysteinyl aspartate specific proteinase 3 (Cleaved caspase-3) and increased the decreased level of B-cell lymphoma-2 (Bcl-2) in the lung tissue of the model group. LPS-induced changes in mitochondrial membrane potential and calcium influx in alveolar epithelial cells were also reversed by PcTx-1. CONCLUSION: ASIC1a induces an apoptotic response in ALI through mitochondrial apoptosis.