Using time-series chest radiographs and laboratory data by machine learning for identifying pulmonary infection and colonization of Acinetobacter baumannii.

BACKGROUND: Accurately distinguishing between pulmonary infection and colonization in patients with Acinetobacter baumannii is of utmost importance to optimize treatment and prevent antibiotic abuse or inadequate therapy. An efficient automated sorting tool could prompt individualized interventions and enhance overall patient outcomes. This study aims to develop a robust machine learning classification model using a combination of time-series chest radiographs and laboratory data to accurately classify pulmonary status caused by Acinetobacter baumannii. METHODS: We proposed nested logistic regression models based on different time-series data to automatically classify the pulmonary status of patients with Acinetobacter baumannii. Advanced features were extracted from the time-series data of hospitalized patients, encompassing dynamic pneumonia indicators observed on chest radiographs and laboratory indicator values recorded at three specific time points. RESULTS: Data of 152 patients with Acinetobacter baumannii cultured from sputum or alveolar lavage fluid were retrospectively analyzed. Our model with multiple time-series data demonstrated a higher performance of AUC (0.850, with a 95% confidence interval of [0.638-0.873]), an accuracy of 0.761, a sensitivity of 0.833. The model, which only incorporated a single time point feature, achieved an AUC of 0.741. The influential model variables included difference in the chest radiograph pneumonia score. CONCLUSION: Dynamic assessment of time-series chest radiographs and laboratory data using machine learning allowed for accurate classification of colonization and infection with Acinetobacter baumannii. This demonstrates the potential to help clinicians provide individualized treatment through early detection.

The development of a novel zeolite-based assay for efficient and deep plasma proteomic profiling.

Plasma proteins are considered the most informative source of biomarkers for disease diagnosis and monitoring. Mass spectrometry (MS)-based proteomics has been applied to identify biomarkers in plasma, but the complexity of the plasma proteome and the extremely large dynamic range of protein abundances in plasma make the clinical application of plasma proteomics highly challenging. We designed and synthesized zeolite-based nanoparticles to deplete high-abundance plasma proteins. The resulting novel plasma proteomic assay can measure approximately 3000 plasma proteins in a 45 min chromatographic gradient. Compared to those in neat and depleted plasma, the plasma proteins identified by our assay exhibited distinct biological profiles, as validated in several public datasets. A pilot investigation of the proteomic profile of a hepatocellular carcinoma (HCC) cohort identified 15 promising protein features, highlighting the diagnostic value of the plasma proteome in distinguishing individuals with and without HCC. Furthermore, this assay can be easily integrated with all current downstream protein profiling methods and potentially extended to other biofluids. In conclusion, we established a robust and efficient plasma proteomic assay with unprecedented identification depth, paving the way for the translation of plasma proteomics into clinical applications.

COMMD10 inhibits HIF1α/CP loop to enhance ferroptosis and radiosensitivity by disrupting Cu-Fe balance in hepatocellular carcinoma.

BACKGROUND & AIMS: Copper (Cu) is an essential trace element whose serum levels have been reported to act as an effective indicator of the efficacy of radiotherapy. However, little is known about the role of Cu in radiotherapy. In this study we aimed to determine this role and investigate the precise mechanism by which Cu or Cu-related proteins regulate the radiosensitivity of hepatocellular carcinoma (HCC). METHODS: The expression and function of Cu and copper metabolism MURR1 domain 10 (COMMD10) were assessed via a Cu detection assay, immunostaining, real-time PCR, western blot, a radiation clonogenic assay and a 5-ethynyl-2'-deoxyuridine assay. Ferroptosis was determined by detecting glutathione, lipid peroxidation, malondialdehyde and ferrous ion (Fe) levels. The in vivo effects of Cu and COMMD10 were examined with Cu/Cu chelator treatment or lentivirus modification of COMMD10 expression in radiated mouse models. RESULTS: We identified a novel role of Cu in promoting the radioresistance of HCC cells. Ionizing radiation (IR) induced a reduction of COMMD10, which increased intracellular Cu and led to radioresistance of HCC. COMMD10 enhanced ferroptosis and radiosensitivity in vitro and in vivo. Mechanistically, low expression of COMMD10 induced by IR inhibited the ubiquitin degradation of HIF1α (by inducing Cu accumulation) and simultaneously impaired its combination with HIF1α, promoting HIF1α nuclear translocation and the transcription of ceruloplasmin (CP) and SLC7A11, which jointly inhibited ferroptosis in HCC cells. In addition, elevated CP promoted HIF1α expression by reducing Fe, forming a positive feedback loop. CONCLUSIONS: COMMD10 inhibits the HIF1α/CP loop to enhance ferroptosis and radiosensitivity by disrupting Cu-Fe homeostasis in HCC. This work provides new targets and treatment strategies for overcoming radioresistance in HCC. LAY SUMMARY: Radiotherapy benefits patients with unresectable or advanced hepatocellular carcinoma (HCC), but its effectiveness is hampered by radioresistance. Herein, we uncovered a novel role for copper in promoting the radioresistance of HCCs. This work has revealed new targets and potential treatment strategies that could be used to sensitize HCC to radiotherapy.

SFTPA1 is a potential prognostic biomarker correlated with immune cell infiltration and response to immunotherapy in lung adenocarcinoma.

Pulmonary surfactant protein A1 (SFTPA1) is a member of the C-type lectin subfamily that plays a critical role in maintaining lung tissue homeostasis and the innate immune response. SFTPA1 disruption can cause several acute or chronic lung diseases, including lung cancer. However, little research has been performed to associate SFTPA1 with immune cell infiltration and the response to immunotherapy in lung cancer. The findings of our study describe the SFTPA1 expression profile in multiple databases and was validated in BALB/c mice, human tumor tissues, and paired normal tissues using an immunohistochemistry assay. High SFTPA1 mRNA expression was associated with a favorable prognosis through a survival analysis in lung adenocarcinoma (LUAD) samples from TCGA. Further GeneOntology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses showed that SFTPA1 was involved in the toll-like receptor signaling pathway. An immune infiltration analysis clarified that high SFTPA1 expression was associated with an increased number of M1 macrophages, CD8+ T cells, memory activated CD4+ T cells, regulatory T cells, as well as a reduced number of M2 macrophages. Our clinical data suggest that SFTPA1 may serve as a biomarker for predicting a favorable response to immunotherapy for patients with LUAD. Collectively, our study extends the expression profile and potential regulatory pathways of SFTPA1 and may provide a potential biomarker for establishing novel preventive and therapeutic strategies for lung adenocarcinoma.

Short isoform thymic stromal lymphopoietin reduces inflammation and aerobic glycolysis of asthmatic airway epithelium by antagonizing long isoform thymic stromal lymphopoietin.

BACKGROUND: Up-regulation of aerobic glycolysis has been reported as a characterization of asthma and facilitates airway inflammation. We has been previously reported that short isoform thymic stromal lymphopoietin (sTSLP) could reduce inflammation in asthmatic airway epithelial cells. Here we wanted to investigate whether the inhibition of sTSLP on asthma is related to aerobic glycolysis. METHODS: Asthmatic model was established in challenging Male BALB/c mice and 16-HBE (human bronchial epithelial) cell line with house dust mite (HDM). Indicators of glycolysis were assessed to measure whether involve in sTSLP regulating airway epithelial cells inflammation in asthmatic model in vivo and in vitro. RESULTS: sTSLP decreased inflammation of asthmatic airway and aerobic glycolysis in mice. HDM or long isoform thymic stromal lymphopoietin (lTSLP) promoted HIF-1α expression and aerobic glycolysis by miR-223 to target and inhibit VHL (von Hippel-Lindau) expression 16-HBE. Inhibition of aerobic glycolysis restrained HDM- and lTSLP-induced inflammatory cytokines production. sTSLP along had almost no potential to alter aerobic glycolysis of 16-HBE. But sTSLP decreased LDHA (lactate dehydrogenase A) and LD (Lactic acid) levels in BALF, and HIF-1α and LDHA protein levels in airway epithelial cells of asthma mice model. lTSLP and sTSLP both induced formation of TSLPR and IL-7R receptor complex, and lTSLP obviously facilitated phosphorylation of JAK1, JAK2 and STAT5, while sTSLP induced a little phosphorylation of JAK1 and STAT5. CONCLUSION: We identified a novel mechanism that lTSLP could promote inflammatory cytokines production by miR-223/VHL/HIF-1α pathway to upregulate aerobic glycolysis in airway epithelial cells in asthma. This pathway is suppressed by sTSLP through occupying binding site of lTSLP in TSLPR and IL-7R receptor complex.

RAGE mediates airway inflammation via the HDAC1 pathway in a toluene diisocyanate-induced murine asthma model.

BACKGROUND: Exposure to toluene diisocyanate (TDI) is a significant pathogenic factor for asthma. We previously reported that the receptor for advanced glycation end products (RAGE) plays a key role in TDI-induced asthma. Histone deacetylase (HDAC) has been reported to be important in asthmatic pathogenesis. However, its effect on TDI-induced asthma is not known. The aim of this study was to determine the role of RAGE and HDAC in regulating airway inflammation using a TDI-induced murine asthma model. METHODS: BALB/c mice were sensitized and challenged with TDI to establish an asthma model. FPS-ZM1 (RAGE inhibitor), JNJ-26482585 and romidepsin (HDAC inhibitors) were administered intraperitoneally before each challenge. In vitro, the human bronchial epithelial cell line 16HBE was stimulated with TDI-human serum albumin (TDI-HSA). RAGE knockdown cells were constructed and evaluated, and MK2006 (AKT inhibitor) was also used in the experiments. RESULTS: In TDI-induced asthmatic mice, the expression of RAGE, HDAC1, and p-AKT/t-AKT was upregulated, and these expressions were attenuated by FPS-ZM1. Airway reactivity, Th2 cytokine levels in lymph supernatant, IgE, airway inflammation, and goblet cell metaplasia were significantly increased in the TDI-induced asthmatic mice. These increases were suppressed by JNJ-26482585 and romidepsin. In addition, JNJ-26482585 and romidepsin ameliorated the redistribution of E-cadherin and ß-catenin in TDI-induced asthma. In TDI-HSA-stimulated 16HBE cells, knockdown of RAGE attenuated the upregulation of HDAC1 and phospho-AKT (p-AKT). Treatment with the AKT inhibitor MK2006 suppressed TDI-induced HDAC1 expression. CONCLUSIONS: These findings indicate that RAGE modulates HDAC1 expression via the PI3K/AKT pathway, and that inhibition of HDAC prevents TDI-induced airway inflammation.

A multicenter analysis of genomic profiles and PD-L1 expression of primary lymphoepithelioma-like carcinoma of the lung.

To understand the molecular mechanism of tumorigenesis of pulmonary lymphoepithelioma-like carcinoma and explore potential therapeutic strategies, we investigated the genomic profiles and PD-L1 expression of 29 Chinese pulmonary lymphoepithelioma-like carcinoma patients at various stages. We performed capture-based targeted sequencing on tissue samples collected from 27 patients with sufficient samples using a panel consisting of 520 cancer-related genes, spanning 1.64 Mb of the human genome. We identified 184 somatic mutations in 109 genes from 26 patients. One patient had no mutations detected by this panel. Copy number variations were detected in 52% (14/27) of the patients, with a majority having advanced-stage disease (10/14). Except for the detection of ERBB2 amplification and KRAS mutation in two patients, no other classic lung cancer driver mutations were detected. Interestingly, 78% (21/27) of the patients had mutations in epigenetic regulators. Of the 184 mutations identified, 51 occurred in 29 epigenetics-related genes. Furthermore, we performed PD-L1 immunohistochemistry staining using the Dako 22C3 assay and demonstrated that 69% (20/29) of the cohort had positive PD-L1 expression, of which three patients received and benefited from a PD-1 inhibitor. In conclusion, we elucidated a distinct genomic landscape associated with pulmonary lymphoepithelioma-like carcinoma with no classic lung cancer driver mutation but an enrichment of mutations in epigenetic regulators. The detection of high PD-L1 expression and lack of any canonical druggable driver mutations raises the potential of checkpoint immunotherapy for pulmonary lymphoepithelioma-like carcinoma.

TSLP signaling blocking alleviates E-cadherin dysfunction of airway epithelium in a HDM-induced asthma model.

Recent studies have indicated that Thymic stromal lymphopoietin (TSLP) plays an important role in the prevention and treatment of asthma. However the role of TSLP in dysfunction of airway epithelial adherens junctions E-cadherin in house dust mite (HDM)-induced asthma has not been addressed. We hypothesized that TSLP contributed to HDM-induced E-cadherin dysfunction in asthmatic BALB/c mice and 16HBE cells. In vivo, a HDM-induced asthma mouse model was set up for 8weeks. Mice inhaled an anti-TSLP monoclonal antibody (mAb) before HDM. The mice treated with the anti-TSLP mAb ameliorated airway inflammation, the decreasing and aberrant distribution of E-cadherin and ß-catenin as well as phosphorylation(p)-AKT induced by HDM. In vitro, HDM increased the expression of TSLP and E-cadherin dysfunction by PI3K/Akt signaling pathway. The exposure of 16HBE to TSLP resulted in redistribution of E-cadherin. These results indicate that TSLP may be an important contributor in E-cadherin dysfunction of HDM-induced asthma. TSLP signaling blocking shows a protective effect in mice and that the PI3K/Akt pathway may play a role in this process.

Bevacizumab reduced auto-phosphorylation of VEGFR2 to protect HDM-induced asthma mice.

Vascular endothelial growth factor (VEFG) is a major angiogenic factor involved in both normal physiological processes, such as embryonic development and wound healing, and in diseases, like cancer. Recent studies have revealed the functions of VEGF in inflammation and immunoregulation. Asthma is a chronic inflammation of the airways characterized by airway epithelial barrier dysfunction and imbalance in T-helper (Th) 1/Th2 during immunoregulation. We hypothesized that VEGF plays an important role in asthma. Utilizing a house dust mite extract (HDM)-induced murine model of asthma, we investigated whether bevacizumab, a humanized anti-VEGF monoclonal antibody, could protect the epithelial barrier in murine airways. We found that bevacizumab reduced airway hyper-responsiveness (AHR) and airway inflammation induced by HDM. In addition, HDM exposure promoted expression of VEGF, and caused AHR, disruptions of the epithelial barrier, and airway inflammation. Bevacizumab ameliorated AHR and the release of Th2 cytokines, thereby protecting the epithelial barrier. Our data suggest that bevacizumab may be a new therapeutic strategy for asthma.

VLDL and LDL Subfractions Enhance the Risk Stratification of Individuals Who Underwent Epstein-Barr Virus-Based Screening for Nasopharyngeal Carcinoma: A Multicenter Cohort Study.

Serological tests for Epstein-Barr virus (EBV) antibodies have been widely conducted for the screening of nasopharyngeal carcinoma (NPC) in endemic areas. Further risk stratification of NPC can be achieved through plasma lipoprotein and metabolic profiles. A total of 297 NPC patients and 149 EBV-positive participants are enrolled from the NCT03919552 and NCT05682703 cohorts for plasma nuclear magnetic resonance (NMR) metabolomic analysis. Small, dense very low density lipoprotein particles (VLDL-5) and large, buoyant low density lipoprotein particles (LDL-1) are found to be closely associated with nasopharyngeal carcinogenesis. Herein, an NMR-based risk score (NRS), which combines lipoprotein subfractions and metabolic biomarkers relevant to NPC, is developed and well validated within a multicenter cohort. Combining the median cutoff value of the NRS (N50) with that of the serological test for EBV antibodies, the risk stratification model achieves a satisfactory performance in which the area under the curve (AUC) is 0.841 (95% confidence interval: 0.811-0.871), and the positive predictive value (PPV) reaches 70.08% in the combined cohort. These findings not only suggest that VLDL-5 and LDL-1 particles can serve as novel risk factors for NPC but also indicate that the NRS has significant potential in personalized risk prediction for NPC.

The value of bronchodilator response in FEV1 and FeNO for differentiating between chronic respiratory diseases: an observational study.

BACKGROUND: There is no uniform standard for a strongly positive bronchodilation test (BDT) result. In addition, the role of bronchodilator response in differentiating between asthma, chronic obstructive pulmonary disease (COPD), and asthma-COPD overlap (ACO) in patients with a positive BDT result is unclear. We explored a simplified standard of a strongly positive BDT result and whether bronchodilator response combined with fractional exhaled nitric oxide (FeNO) can differentiate between asthma, COPD, and ACO in patients with a positive BDT result. METHODS: Three standards of a strongly positive BDT result, which were, respectively, defined as post-bronchodilator forced expiratory volume in 1-s responses (ΔFEV1) increasing by at least 400 mL + 15% (standard I), 400 mL (standard II), or 15% (standard III), were analyzed in asthma, COPD, and ACO patients with a positive BDT result. Receiver operating characteristic curves were used to determine the optimal values of ΔFEV1 and FeNO. Finally, the accuracy of prediction was verified by a validation study. RESULTS: The rates of a strongly positive BDT result and the characteristics between standards I and II were consistent; however, those for standard III was different. ΔFEV1 ≥ 345 mL could predict ACO diagnosis in COPD patients with a positive BDT result (area under the curve [AUC]: 0.881; 95% confidence interval [CI] 0.83-0.94), with a sensitivity and specificity of 90.0% and 91.2%, respectively, in the validation study. When ΔFEV1 was < 315 mL combined with FeNO < 28.5 parts per billion, patients with a positive BDT result were more likely to have pure COPD (AUC: 0.774; 95% CI 0.72-0.83). CONCLUSION: The simplified standard II can replace standard I. ΔFEV1 and FeNO are helpful in differentiating between asthma, COPD, and ACO in patients with a positive BDT result.

Tiam1 is associated with hepatocellular carcinoma metastasis.

We have previously demonstrated that overexpression of T lymphoma invasion and metastasis 1 (Tiam1) is correlated with poor prognosis in patients with hepatocellular carcinoma (HCC). In this study, we tried to further investigate the potential roles of Tiam1 in the progression of HCC in a larger set of samples. By detecting Tiam1 expression in 213 HCC patients, we observed that Tiam1 had a higher probability of being overexpressed in HCC patients with metastasis than those without metastasis (68.3% vs. 52.7%, p = 0.036). In addition, the cell line with high metastatic potential expressed more Tiam1 than did the cell line with low metastatic potential. Overexpression of Tiam1 was suggested to be significantly correlated with HCC metastasis. We stably upregulated Tiam1 expression in MHCC97L as well as knocked down Tiam1 expression in HCCLM6. We also investigated the effects of Tiam1 overexpression and knockdown on HCC cells proliferation, migration and invasion in vitro and on tumorigenicity and metastasis in vivo. Overexpression of Tiam1 increased proliferation, migration and invasion of MHCC97L cells, while knockdown of Tiam1 in HCCLM6 cells resulted in the reverse. In vivo functional studies showed upregulation of Tiam1 expression led to an enhancement of tumorigenicity and metastatic potential in mice. However, knockdown of Tiam1 expression exhibited nearly 2.2-fold retardation in tumor growth and great inhibition on tumor metastases. Our results indicate that Tiam1, as a metastasis-related gene, may contribute to HCC invasion and metastasis, and consequently, it may be a useful biomarker for therapeutic strategy and control in HCC treatment.

Cbx4 governs HIF-1α to involve in Th9 cell differentiation promoting asthma by its SUMO E3 ligase activity.

The potential role of polycomb chromobox 4 (Cbx4), as a small ubiquitin-like ligase (SUMO) E3 ligase, in the development and exacerbation of asthma remains unclear. Hypoxia inducible factor-1 (HIF-1) is a key transcription factor in the cellular response to hypoxia and contributes to the pathogenesis and progression of a range of diseases, including asthma. Here, we aimed to investigate the interaction of Cbx4 with Hypoxia inducible factor-1α (HIF-1α) and the potent mechanism of action in asthma progression. In present study, in vitro and ex vivo results demonstrated that Cbx4 interacts with HIF-1α protein through its SUMO E3 ligase activity and enhances the sumoylation, which increases HIF-1 transactivation through Cbx4 and promotes the differentiation of Th9 cells, then in turn promotes the process of asthma. Treatment of inhibitors targeting SUMO E3 ligase activity of Cbx4 or HIF-1α can effectively reduce HIF-1α activation and differentiation of Th9 cells, which further attenuates the asthma in mouse model. Current results collectively demonstrated Cbx4 can govern HIF-1α to involve in Th9 cell differentiation promoting asthma by its SUMO E3 ligase activity, providing a new direction for clinical treatment of asthma.

Expression Profile and Gene Regulation Network of NUSAP1 in Pan Cancers Based on Integrated Bioinformatics Analysis.

Background: Nucleolar and spindle-associated protein 1 (NUSAP1) plays key roles in microtubules and chromosomes in normal cells both structurally and functionally. In malignancies, NUSAP1 is frequently dysregulated and mutated. However, the expression profiles and biological functions of NUSAP1 in tumors remain unclear. Methods: NUSAP1 expression in BALB/c mice and human normal or tumor tissues was examined using immunohistochemistry. Kaplan-Meier survival analysis was utilized to assess the prognostic significance of NUSAP1 in tumors, and principal component analysis and co-expression analysis were performed to explore the unique roles of NUSAP1. Gene ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses were performed with DAVID. The relevance between NUSAP1 and tumor-infiltrating immune cells was investigated using TIMER. A transcriptional regulation network was constructed using data from The Cancer Genome Atlas. Results: NUSAP1 expression levels in various mice tissues were different. Compared with normal tissues, NUSAP1 was strongly expressed in several human tumor tissues. We believe that NUSAP1 distinctly impacts the prognosis of several cancers and plays various roles in thymoma and testicular germ cell tumors. Further, NUSAP1 expression levels were significantly positively associated with diverse infiltrating levels of immune cells, including B cells, CD4+ and CD8+ T cells, dendritic cells, and macrophages, in thymoma. The expression level of NUSAP1 demonstrated strong relevance with various immune markers in thymoma. Finally, the miR-1236-5p-NUSAP1 and TCF3-NUSAP1 network revealed the tumor-promoting role of NUSAP1 and pertinent underlying mechanisms in human liver hepatocellular carcinoma. Conclusion: NUSAP1 may be regarded as a therapeutic target or potential prognostic biomarker for various cancer types.

Variations in pleural microbiota and metabolic phenotype associated with malignant pleural effusion in human lung adenocarcinoma.

BACKGROUND: Lung cancer is the most common cancer-related death worldwide. In 2022, the number of daily deaths of lung cancer was estimated to reach around 350 in the United States. Lung adenocarcinoma is the main subtype of lung cancer and patients with malignant pleural effusion (MPE) suffer from poor prognosis. Microbiota and its metabolites are associated with cancer progression. However, the effect of pleural microbiota on pleural metabolic profile of MPE in lung adenocarcinoma patients remains largely unknown. METHODS: Pleural effusion samples collected from lung adenocarcinoma patients with MPE (n = 14) and tuberculosis pleurisy patients with benign pleural effusion (BPE group, n = 10) were subjected to microbiome (16S rRNA gene sequencing) and metabolome (liquid chromatography tandem mass spectrometry [LC-MS/MS]) analyses. The datasets were analyzed individually and integrated for combined analysis using various bioinformatic approaches. RESULTS: The metabolic profile of MPE in lung adenocarcinoma patients were clearly distinguished from BPE with 121 differential metabolites across six significantly enriched pathways identified. Glycerophospholipids, fatty and carboxylic acids, and derivatives were the most common differential metabolites. Sequencing of microbial data revealed nine significantly enriched genera (i.e., Staphylococcus, Streptococcus, Lactobacillus) and 26 enriched ASVs (i.e., species Lactobacillus_delbrueckii) in MPE. Integrated analysis correlated MPE-associated microbes with metabolites, such as phosphatidylcholine and metabolites involved in the citrate cycle pathway. CONCLUSION: Our results provide substantial evidence of a novel interplay between the pleural microbiota and metabolome, which was drastically perturbed in MPE in lung adenocarcinoma patients. Microbe-associated metabolites can be used for further therapeutic explorations.

Befotertinib (D-0316) versus icotinib as first-line therapy for patients with EGFR-mutated locally advanced or metastatic non-small-cell lung cancer: a multicentre, open-label, randomised phase 3 study.

BACKGROUND: Befotertinib (D-0316) is a novel, selective oral third-generation epidermal growth factor receptor (EGFR) tyrosine-kinase inhibitor. This phase 3 trial compared the efficacy and safety of befotertinib with icotinib as a first-line treatment for patients with EGFR mutation-positive locally advanced or metastatic non-small-cell lung cancer (NSCLC). METHODS: This study was a multicentre, open-label, randomised, controlled phase 3 study at 39 hospitals in China. Eligible patients were 18 years of age or older, had histologically confirmed locally advanced or metastatic stage IIIB, IIIC, or IV unresectable NSCLC, and had confirmed exon 19 deletions or exon 21 Leu858Arg mutation. Patients were randomly assigned (1:1) via an interactive web response system to receive either oral befotertinib (75-100 mg once daily) or oral icotinib (125 mg three times per day) in 21-day cycles until disease progression or withdrawal criteria were met. Randomisation was stratified by type of EGFR mutation, CNS metastasis status, and gender, and participants, investigators, and data analysts were not masked to treatment allocation. The primary endpoint was independent review committee (IRC)-assessed progression-free survival in the full analysis set, which comprised all randomly assigned patients. All patients who received at least one dose of the study drug were included in safety analyses. This study was registered with ClinicalTrials.gov, NCT04206072, and the overall survival follow-up is still in progress. FINDINGS: Between Dec 24, 2019, and Dec 18, 2020, 568 patients were screened, of whom 362 were randomly assigned to the befotertinib (n=182) or icotinib (n=180) group; all 362 patients were included in the full analysis set. Median follow-up was 20·7 months (IQR 10·2-23·5) in the befotertinib group and 19·4 months (10·3-23·5) in the icotinib group. Median IRC-assessed progression-free survival was 22·1 months (95% CI 17·9-not estimable) in the befotertinib group and 13·8 months (12·4-15·2) in the icotinib group (hazard ratio 0·49 [95% CI 0·36-0·68], p<0·0001). Grade 3 or higher treatment-related adverse events occurred in 55 (30%) of 182 patients in the befotertinib group and in 14 (8%) of 180 patients in the icotinib group. Treatment-related serious adverse events were reported in 37 (20%) patients in the befotertinib group and in five (3%) patients in the icotinib group. Two (1%) patients in the befotertinib group and one (1%) patient in the icotinib group died due to treatment-related adverse events. INTERPRETATION: Befotertinib demonstrated superior efficacy compared with icotinib in first-line treatment for patients with EGFR mutation-positive NSCLC. Although serious adverse events were more common in the befotertinib than the icotinib arm, the safety profile of befotertinib was manageable overall. FUNDING: Betta Pharmaceuticals (China). TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

A mobile phone short message service improves perceived control of asthma: a randomized controlled trial.

OBJECTIVE: Mobile phone short message service (SMS) has been suggested as a potentially powerful tool to improve asthma outcomes, and it can overcome external barriers such as time and distance to participate education programs. We wanted to know whether SMS can help to overcome intrinsic barriers such as perceived control of asthma (PCA). SUBJECTS AND METHODS: One hundred fifty outpatients with asthma were randomly assigned to the control, traditional, and SMS groups. Patients in all groups received verbal education based on the Global Initiative for Asthma, and patients in the traditional group received additional individualized asthma action plan for self-management with peak expiratory flow monitoring and recording asthma diary, while patients in the SMS group received additional daily SMS reminders on their mobile phone. The six-item PCA Questionnaire (PCAQ-6), Standard Asthma-Specific Quality of Life [AQLQ(S)], spirometry, blood and induced sputum cell count, follow-up compliance rate, medicine compliance rate, and emergency department (ED) visits data were collected at the initial visit and at 12 weeks. RESULTS: In total, 71 participants completed the trial for analysis. Patients' PCAQ-6 score was significantly increased in the SMS and traditional groups (p<0.001) after 12 weeks, and the change of patients' PCAQ-6 score in the SMS group was higher than in the traditional group (p=0.018). Patients in the SMS group had the highest AQLQ(S) score and follow-up rate after 12 weeks. The change in PCAQ-6 score was associated with change in AQLQ(S) score (r=0.442). Patients in all groups had better forced expiratory volume in 1 s (FEV1%) and fewer ED visits after 12 weeks, but no significant differences were found among the three groups in the changes of FEV1% and blood and induced sputum eosinophil counts and neutrophil counts. CONCLUSIONS: SMS can improve PCA, and it has a greater advantage in improving follow-up rate and asthma-specific quality of life than traditional programs.

[Post-therapeutic change of cathelicidin LL-37 in asthmatics of different inflammatory phenotypes].

OBJECTIVE: To explore the post-therapeutic change of cathelicidin LL-37 in asthmatics of different inflammatory phenotypes. METHODS: Thirty-four patients with initially diagnosed asthma (asthma group) and 14 normal subjects (control group) were recruited at Nanfang Hospital from August 2009 to August 2010 for this prospective study. Sputum and venous blood samples were collected and analyzed for cell differential. Eosinophilic asthma was defined as the count of sputum eosinophils ≥ 3%. The LL-37 concentrations in plasma and sputum supernatant were measured by enzyme-linked immunosorbent assay (ELISA) kit. The subjects were treated with budesonide/formoterol (160/4.5 µg) one inhalation twice daily and re-examined after 1 month. RESULTS: Prior to treatment, there were no differences between the asthma and control groups in the levels of LL-37 in plasma and sputum supernatant (P = 0.427,0.427). The plasma concentrations of LL-37 in asthma group were negatively correlated with baseline forced expiratory volume in one second (FEV(1), r = -0.470, P = 0.005), percent predicted of FEV(1) (FEV(1)%pred, r = -0.421, P = 0.013) and forced vital capacity (FVC, r = -0.367, P = 0.033). After treatment, the plasma and sputum supernatant concentrations of LL-37 (M (Q(R))) in the asthma group (5.6 (16.2), 65.6 (184.0) µg/L) were significantly higher than those baseline concentrations (5.03 (9.21), 28.40(109.76) µg/L, P = 0.005, 0.015). In the eosinophilic asthma subgroup, the plasma and sputum supernatant concentrations of LL-37 (M (Q(R))) after treatment (5.3 (19.3), 65.6 (185.2) µg/L) were significantly higher than those baseline concentrations (6.7 (8.9) L, 35.3 (102.0) µg/L, P = 0.021,0.014). And in the non-eosinophilic asthma subgroup, the changes of plasma and sputum supernatant concentrations of LL-37 showed no significant differences (P = 0.139, 0.386). In the asthma group, the correlations between plasma concentrations of LL-37 and FEV(1), FEV(1)%pred, FVC were not statistically significant (P = 0.283, 0.706,0.272) after treatment. CONCLUSIONS: LL-37 may participate in the aggravation of asthma. The elevated concentrations of LL-37 in eosinophilic asthma is probably due to the resolved suppression of LL-37 expression by eosinophilic inflammation. But its mechanism needs further researches.

LATPS, a novel prognostic signature based on tumor microenvironment of lung adenocarcinoma to better predict survival and immunotherapy response.

Background: Clinically, only a minority of patients benefit from immunotherapy and few efficient biomarkers have been identified to distinguish patients who would respond to immunotherapy. The tumor microenvironment (TME) is reported to contribute to immunotherapy response, but details remain unknown. We aimed to construct a prognostic model based on the TME of lung adenocarcinoma (LUAD) to predict the prognosis and immunotherapy efficacy. Methods: We integrated computational algorithms to describe the immune infiltrative landscape of LUAD patients. With the least absolute shrinkage and selection operator (LASSO) and Cox regression analyses, we developed a LUAD tumor microenvironment prognostic signature (LATPS). Subsequently, the immune characteristics and the benefit of immunotherapy in LATPS-defined subgroups were analyzed. RNA sequencing of tumor samples from 28 lung cancer patients treated with anti-PD-1 therapy was conducted to verify the predictive value of the LATPS. Results: We constructed the LATPS grounded on four genes, including UBE2T, KRT6A, IRX2, and CD3D. The LATPS-low subgroup had a better overall survival (OS) and tended to have a hot immune phenotype, which was characterized by an elevated abundance of immune cell infiltration and increased activity of immune-related pathways. Additionally, tumor immune dysfunction and exclusion (TIDE) score was markedly decreased in the LATPS-low subgroup, indicating an enhanced opportunity to benefit from immunotherapy. Survival analysis in 28 advanced lung cancer patients treated with an anti-PD-1 regimen at Nanfang hospital revealed that the LATPS-low subgroup had better immunotherapy benefit. Conclusion: LATPS is an effective predictor to distinguish survival, immune characteristics, and immunotherapy benefit in LUAD patients.

High mobility group protein B1 (HMGB1) in Asthma: comparison of patients with chronic obstructive pulmonary disease and healthy controls.

High mobility group protein B1 (HMGB1) has been implicated as an important mediator in the pathogenesis of asthma and chronic obstructive pulmonary disease (COPD). However, the expression of HMGB1 in plasma and sputum of patients with asthma and COPD across disease severity needs to be defined. The objective of the study was to examine the induced sputum and plasma concentrations of HMGB1 in COPD and asthmatic patients to determine differences in HMGB1 levels between these diseases and their relationship with airway obstruction and inflammatory patterns. A total of 147 participants were enrolled in this study. The participants included 34 control subjects, 61 patients with persistent asthma (according to the Global Initiative for Asthma [GINA] guidelines) and 47 patients with stable COPD (stratified by Global Initiative for Chronic Obstructive Lung Disease [GOLD] status). Spirometry was performed before sputum induction. HMGB1 levels in induced sputum and plasma were determined by enzyme-linked immunosorbent assay. Sputum and plasma concentrations of HMGB1 in patients with asthma and COPD were significantly higher than concentrations in control subjects and were significantly negatively correlated with forced expiratory volume in 1 s (FEV(1)), FEV(1) (% predicted) in all 147 participants. The levels of HMGB1 in induced sputum of COPD patients were significantly higher than those of asthma patients and healthy controls (P < 0.001). This difference was present even after adjusting for sex, age, smoking status, daily dose of inhaled corticosteroids and disease severity. There were no significant differences in HMGB1 levels between patients with eosinophilic and noneosinophilic asthma. HMGB1 levels in asthmatic and COPD patients were positively correlated with neutrophil counts and percentage of neutrophils. In multivariate analysis, the two diseases (asthma and COPD) and disease severity were independent predictors of sputum HMGB1, but not smoking, age or use of inhaled corticosteroids. In conclusion, these data support a potential role for HMGB1 as a biomarker and diagnostic tool for the differential diagnosis of asthma and COPD. The importance of this observation on asthma and COPD mechanisms and outcomes should be further investigated in large prospective studies.