Development of an Intelligent Reactive Oxygen Species-Responsive Dual-Drug Delivery Nanoplatform for Enhanced Precise Therapy of Acute Lung Injury.

Introduction: Acute lung injury (ALI) and its most severe form acute respiratory distress syndrome (ARDS) are commonly occurring devastating conditions that seriously threaten the respiratory system in critically ill patients. The current treatments improve oxygenation in patients with ALI/ARDS in the short term, but do not relieve the clinical mortality of patients with ARDS. Purpose: To develop the novel drug delivery systems that can enhance the therapeutic efficacy of ALI/ARDS and impede adverse effects of drugs. Methods: Based on the key pathophysiological process of ARDS that is the disruption of the pulmonary endothelial barrier, bilirubin (Br) and atorvastatin (As) were encapsulated into an intelligent reactive oxygen species (ROS)-responsive nanocarrier DSPE-TK-PEG (DPTP) to form nanoparticles (BA@DPTP) in which the thioketal bonds could be triggered by high ROS levels in the ALI tissues. Results: BA@DPTP could accumulate in inflammatory pulmonary sites through passive targeting strategy and intelligently release Br and As only in the inflammatory tissue via ROS-responsive bond, thereby enhancing the drugs effectiveness and markedly reducing side effects. BA@DPTP effectively inhibited NF-κB signaling and NLRP3/caspase-1/GSDMD-dependent pyroptosis in mouse pulmonary microvascular endothelial cells. BA@DPTP not only protected mice with lipopolysaccharide-induced ALI and retained the integrity of the pulmonary structure, but also reduced ALI-related mortality. Conclusion: This study combined existing drugs with nano-targeting strategies to develop a novel drug-targeting platform for the efficient treatment of ALI/ARDS.

Profiles of Cough and Associated Risk Factors in Nonhospitalized Individuals With SARS-CoV-2 Omicron Variant Infection: Cross-Sectional Online Survey in China.

BACKGROUND: Cough is a common symptom during and after COVID-19 infection; however, few studies have described the cough profiles of COVID-19. OBJECTIVE: The aim of this study was to investigate the prevalence, severity, and associated risk factors of severe and persistent cough in individuals with COVID-19 during the latest wave of the Omicron variant in China. METHODS: In this nationwide cross-sectional study, we collected information of the characteristics of cough from individuals with infection of the SARS-CoV-2 Omicron variant using an online questionnaire sent between December 31, 2022, and January 11, 2023. RESULTS: There were 11,718 (n=7978, 68.1% female) nonhospitalized responders, with a median age of 37 (IQR 30-47) years who responded at a median of 16 (IQR 12-20) days from infection onset to the time of the survey. Cough was the most common symptom, occurring in 91.7% of participants, followed by fever, fatigue, and nasal congestion (68.8%-87.4%). The median cough visual analog scale (VAS) score was 70 (IQR 50-80) mm. Being female (odds ratio [OR] 1.31, 95% CI 1.20-1.43), having a COVID-19 vaccination history (OR 1.71, 95% CI 1.37-2.12), current smoking (OR 0.48, 95% CI 0.41-0.58), chronic cough (OR 2.04, 95% CI 1.69-2.45), coronary heart disease (OR 1.71, 95% CI 1.17-2.52), asthma (OR 1.22, 95% CI 1.02-1.46), and gastroesophageal reflux disease (GERD) (OR 1.21, 95% CI 1.01-1.45) were independent factors for severe cough (VAS>70, 37.4%). Among all respondents, 35.0% indicated having a productive cough, which was associated with risk factors of being female (OR 1.44, 95% CI 1.31-1.57), having asthma (OR 1.84, 95% CI 1.52-2.22), chronic cough (OR 1.44, 95% CI 1.19-1.74), and GERD (OR 1.22, 95% CI 1.01-1.47). Persistent cough (>3 weeks) occurred in 13.0% of individuals, which was associated with the risk factors of having diabetes (OR 2.24, 95% CI 1.30-3.85), asthma (OR 1.70, 95% CI 1.11-2.62), and chronic cough (OR 1.97, 95% CI 1.32-2.94). CONCLUSIONS: Cough is the most common symptom in nonhospitalized individuals with Omicron SARS-CoV-2 variant infection. Being female, having asthma, chronic cough, GERD, coronary heart disease, diabetes, and a COVID-19 vaccination history emerged as independent factors associated with severe cough, productive cough, and persistent cough.

Time-course transcriptome analysis of lungs from mice infected with inhaled aerosolized Stenotrophomonas maltophilia.

Background: Stenotrophomonas maltophilia (SMA) has emerged as an important pathogen capable of causing an opportunistic and nosocomial infection. We performed RNA sequencing (RNA-seq) of lung tissues from mice with pulmonary SMA infection over time via aerosolized intratracheal inhalation to investigate transcription profile changes in SMA-infected lungs. Methods: A mouse model of acute lethal SMA pneumonia was established in this study using aerosolized intratracheal inhalation, laying the groundwork for future SMA research. RNA-seq was then used to create a transcriptional profile of the lungs of the model mice at 0, 4, 12, 24, 48, and 72 hours post-infection (hpi). Mfuzz time clustering, weighted gene coexpression network analysis (WGCNA), and Immune Cell Abundance Identifier for mouse (ImmuCellAI-mouse) were used to analyze RNA-seq data. Results: A gradual change in the lung transcriptional profile was observed, which was consistent with the expected disease progression. At 4 hpi, the expression of genes related to the acute phase inflammatory response increased, as predicted abundance of innate immune cells. At this stage, an increased demand for energy was also observed, including an increase in the expression of genes involved in circulation, muscle function and mitochondrial respiratory chain function. The expression of genes associated with endoplasmic reticulum stress (ERS) and autophagy increased at 24 hpi. Unlike the number of natural killer (NK) cells following most bacterial lung infections, the abundance of NK cells decreased following infection with SMA. The expression levels of Cxcl10, Cd14, Gbp5, Cxcr2, Tnip1, Zc3h12a, Egr1, Sell and Gbp2 were high and previously unreported in SMA pneumonia, and they may be important targets for future studies. Conclusions: To our knowledge, this is the first study to investigate the pulmonary transcriptional response to SMA infection. The findings shed light on the molecular mechanisms underlying the pathogenesis of SMA pneumonia, which may aid in the development of therapies to reduce the occurrence of SMA pulmonary infection.

Clinical analysis of prolonged viral clearance time in patients with lymphoma combined with novel coronavirus infection.

Objective: To compare the period of viral clearance and its influencing factors after severe acute respiratory syndrome coronavirus (SARS-CoV-2) infection between patients with lymphoma and lung cancer. Methods: We retrospectively collected the clinical data of patients with lymphoma and lung cancer (118 cases) diagnosed with SARS-CoV-2 infection and hospitalized in the First Affiliated Hospital of Anhui Medical University between 1 December 2022, and 15 March 2023. Finally, 87 patients with prolonged virus clearance times were included and divided into lymphoma (40 cases) and lung cancer (47 cases) groups. We used the Kaplan-Meier method to draw a negative turn curve. We performed a univariate analysis of the prolongation of virus clearance time and a Cox regression model for multivariate analysis. Results: The median times for viral clearance in the lung cancer and lymphoma groups were 18 (95% confidence interval [CI] 15.112-20.888) and 32 (95%CI 27.429-36.571) days, respectively. Log-rank analysis showed a statistically significant difference (p = 0.048), and the lymphocyte count in the lymphoma group was lower than that in the lung cancer group (p = 0.044). We used the Cox regression model to conduct a multivariate analysis, which revealed that in lymphoma patients, the interval between the time of diagnosis and the time of SARS-CoV-2 infection <24 months (hazard ratio [HR]: 0.182, 95%CI: 0.062-0.535, p = 0.02), an interval between the last anti-CD20 monoclonal antibody treatment and the time of SARS-CoV-2 infection of <2 months (HR: 0.101, 95%CI: 0.029-0.358, p < 0.001), and a decrease in peripheral blood lymphocyte levels (HR: 0.380, 95%CI: 0.179-0.808, p = 0.012) were independent risk factors for prolonged viral clearance time. Conclusion: Patients with lymphoma combined with SARS-CoV-2 infection had a longer virus clearance time than did patients with lung cancer. Moreover, the lymphocyte count in the lymphoma group was lower than that in the lung cancer group; therefore, the immune status of patients with lymphoma is lower than that of patients with lung cancer. An interval between lymphoma diagnosis and SARS-CoV-2 infection of <2 years, anti-CD20 monoclonal antibody treatment within the past 2 months, and a decrease in lymphocyte levels in the peripheral blood prolonged the virus clearance time in the patients in this study.

Biomimetic Nanophotosensitizer Amplifies Immunogenic Pyroptosis and Triggers Synergistic Cancer Therapy.

Immunotherapy is considered to be an effective treatment for cancer and has drawn extensive interest. Nevertheless, the insufficient antigenicity and immunosuppressive tumor microenvironment often cause unsatisfactory therapeutic efficacy. Herein, a photo-activated reactive oxygen species (ROS) amplifying system (defined as "M-Cu-T") is developed to induce antitumor immune response by triggering a tumor-specific immunogenic pyroptosis. In M-Cu-T, M1 macrophage membrane-based vesicles are used for drug loading and tumor targeting, photosensitizers (meso-tetra(4-aminophenyl) porphyrin, TAPP) are used as a pyroptosis inducer, copper ions (Cu2+ ) can enhance ROS-induced pyroptosis by consuming antioxidant systems in cells. As expected, the prepared M-Cu-T targets enrichment into tumor cells and cascades the generation of ROS, which further induces pyroptosis through caspase 3-mediated gasdermin E (GSDME) cleavage under laser activation. The pyroptotic cancer cells accompanying secrete related pattern molecules, induce immunogenic cell death, and activate antitumor immunity for immunotherapy. An effective tumor ablation is observed in LLC and CT26 cancer mouse models. This study provides inspiration for boosting the immunogenicity and achieving satisfactory therapeutic effects in cancer therapy.

Efficacy and safety of durvalumab + chemotherapy vs. atezolizumab + chemotherapy in the treatment of small­cell lung cancer: a retrospective comparative cohort study.

Background: Durvalumab and atezolizumab have recently been approved in extensive small cell lung cancer (SCLC) with moderate median overall survival (OS) improvements. However, only limited data exist regarding the impact of immunotherapy in real-world SCLC patients. This study sought to assess the efficacy and safety of atezolizumab plus chemotherapy and durvalumab plus chemotherapy in the treatment of SCLC in a real-world setting. Methods: A retrospective cohort study of all patients treated for SCLC with chemotherapy with PD-L1 inhibitor, at 3 centers in China between February 1, 2020 and April 30, 2022. Patient characteristics, adverse-events and survival analyses were conducted. Results: A total of 143 patients were enrolled in this study, 100 were treated with durvalumab and the remainder with atezolizumab. The baseline characteristics of the two groups were fundamentally balanced before using PD-L1 inhibitors (P>0.05). The median OS (mOS) of the patients who received durvalumab or atezolizumab as the first-line treatment were 22.0 and 10.0 months, respectively (P=0.03). Survival analysis of patients with brain metastasis (BM) revealed that the median progression-free survival (mPFS) of patients without BM treated with durvalumab plus chemotherapy (5.5 months) was longer than that of those with BM (4.0 months) (P=0.03). In contrast, in the atezolizumab plus chemotherapy regimen, BM did not affect survival. In addition, the addition of radiotherapy to treatment with PD-L1 inhibitors in combination with chemotherapy has a tendency to improve long-term survival. As for safety analysis, there was no significant difference in the incidence of immune-related adverse events (IRAEs) during PD-L1 inhibitor therapy between the 2 groups (P>0.05). And during treatment with immunochemotherapy, radiotherapy was not associated with the development of IRAE (P=0.42) but increased the risk of immune-related pneumonitis (P=0.026). Conclusions: The implication of this study for clinical practice is a preference for durvalumab in first-line immunotherapy for SCLC. In addition, appropriate radiotherapy during treatment with PD-L1 inhibitors in combination with chemotherapy may prolong long-term survival, but the occurrence of immune-related pneumonitis should be vigilant. Data from this study are limited and the baseline characteristics of the two populations still need to be more finely classified.

A retrospective real-world experience of immunotherapy in patients with extensive stage small-cell lung cancer.

BACKGROUND: The treatment of extensive stage small-cell lung cancer (ES-SCLC) has only made modest progress in the past decade, with two immune checkpoint inhibitors (ICIs), atezolizumab and durvalumab, approved for the treatment of SCLC by January 2022. However, currently, there is limited real-world data on ES-SCLC patients received immunotherapy. METHODS: We retrospectively collected and analyzed the demographic and treatment data of ES-SCLC patients at the First Affiliated Hospital of Guangzhou Medical University from January 2017 to January 2022. Survival and prognosis information was obtained through follow-up. RESULTS: A total of 353 ES-SCLC patients were included, of which 165 received immunotherapy combined with chemotherapy as the first-line (FL) treatment (chemo-immune group), and 188 received chemotherapy (chemotherapy group). The objective response rate (ORR) and disease control rate (DCR) of patients receiving immunotherapy as the FL treatment were better than the chemotherapy group (76.97% vs. 48.40%, p < 0.001, and 83.03% vs. 68.09%, p < 0.001). Moreover, the progression-free survival (PFS) and overall survival (OS) of ES-SCLC patients receiving immunotherapy as the FL treatment were better than the chemotherapy group (6.7 months vs. 5.1 months, p < 0.001, and 12.5 months vs. 11.2 months, p < 0.001). Furthermore, the OS of ES-SCLC patients who received immunotherapy as second-line treatment was better than that in the chemotherapy group (15.9 months vs. 12.9 months, p = 0.036). CONCLUSION: ICIs combined with chemotherapy as the FL treatment could be beneficial to the ORR, DCR, PFS, and OS of ES-SCLC patients. Furthermore, ES-SCLC patients can benefit from ICIs in the second-line treatment, even if they had not received ICIs in the FL treatment.

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.

Real-world data on severe lung cancer: a multicenter retrospective study.

Background: Severe lung cancer is a novel concept that describes a patient with poor performance status (PS; 2-4) but with a high probability of receiving survival benefit and improvement in the PS score. However, there is currently no relevant research or real-world data on those with severe lung cancer, such as incidence, cause, clinical features, and risk factors. Methods: The data from patients with advanced lung cancer attending multiple centers from January 1, 2022, to June 30, 2022, were collected for a cross-sectional study. In addition, data from fatal cases from January 1, 2019, to June 30, 2022, were retrospectively collected as another cohort. And we developed a questionnaire to assess clinicians' mastery of severe lung cancer. Results: Three participating institutes enrolled the data set of 1,725 patients, and the dataset of 269 fatal cases were included in another cohort; the incidence of severe lung cancer was 13.10% and 37.55%, respectively. Severe lung cancer patients were mainly stage IV elderly male patients without gene mutation and a history of resection. And the proportion of smoking and comorbidities in severe lung cancer patients is more than in non-severe lung cancer patients (50.4% vs. 40.8%, P=0.006; 46.9% vs. 36.4%, P=0.002). Treatment-related adverse events (AEs) (46.0%) accounted for the largest proportion of the primary causes of severe lung cancer in the cross-sectional study, while cancer-related symptoms (54.5%) accounted for the largest proportion of the primary causes of sever lung cancer in the 101 fatal cases. For the fatal cases, the overall survival of severe lung cancer patients caused by cancer-related symptoms was longer than that caused by treatment-related AEs (8 vs. 3 months; P=0.019). A total of 616 clinicians completed the questionnaire; 90.26% of clinicians agreed with the concept of severe lung cancer. Conclusions: The incidence of severe lung cancer cannot be ignored based on real-world data. Treatment-related AEs are gradually account for more of the causes of severe lung cancer, surpassing cancer-related symptoms and comorbidities. Furthermore, the prognosis of patients with advanced lung cancer who develop severe lung cancer due to treatment-related AEs is worse than cancer-related symptoms.

Biomimetic gene editing system for precise tumor cell reprogramming and augmented tumor therapy.

The abnormal level of hypoxia-inducible factor-1 alpha (HIF-1α) is closely related to cancer metastasis and treatment resistance. CRISPR-Cas9-based gene editing technology has sparked profound hope to solve this issue by precise gene disruption, although the in vivo application remains hindered by the lack of a safe and efficient delivery strategy. Herein, we developed a cell membrane biomimetic core-shell system for light-controllable, precise gene editing. The inner core of the system comprises protamine for CRISPR-Cas9/sgRNA plasmid (pCas9) loading and calcium ions for efficient pCas9 transfection. The shell of the system is camouflaged by a cell membrane and modified with AS1411 aptamers for tumor targeting and photosensitizers to induce lysosomal escape and pCas9 release through reactive oxygen species production, thereby producing light-controllable enhanced gene editing. Neoplastic H1299 cells were reprogrammed using the biomimetic gene editing system upon laser irradiation with reduced VEGF and Vimentin expression, leading to enhanced antimetastatic effects. Genetic disruption of HIF-1α augmented the in vivo chemotherapeutic efficacy of paclitaxel. Our approach of using a membrane-camouflaged system combined with light augmentation provides a potential solution for the in vivo delivery of CRISPR-Cas9 as well as a feasible strategy for cancer therapy.

The impact of aspirin exposure prior to intensive care unit admission on the outcomes for patients with sepsis-associated acute respiratory failure.

Objectives: This present study aimed to infer the association between aspirin exposure prior to ICU admission and the clinical outcomes of patients with Sepsis-associated acute respiratory failure (S-ARF). Methods: We obtained data from the Medical Information Mart for Intensive Care IV 2.0. Patients were divided into pre-ICU aspirin exposure group and Non-aspirin exposure group based on whether they took aspirin before ICU admission. The primary outcome is 28-day mortality. Augmented inverse propensity weighted was used to explore the average treatment effect (ATE) of the pre-ICU aspirin exposure. A generalized additive mixed model was used to analyze the longitudinal data of neutrophil to lymphocyte ratio (NLR), red cell distribution width (RDW), oxygenation index (P/F), dynamic lung compliance (Cdyn), mechanical power (MP), and mechanical power normalized to predicted body weight (WMP) in the two groups. A multiple mediation model was constructed to explore the possible mediators between pre-ICU aspirin exposure and outcomes of patients with S-ARF. Results: A total of 2090 S-ARF patients were included in this study. Pre-ICU aspirin exposure decreased 28-day mortality (ATE, -0.1945, 95% confidence interval [CI], -0.2786 to -0.1103, p < 0.001), 60-day mortality (ATE, -0.1781, 95% Cl, -0.2647 to -0.0915, p < 0.001), and hospital mortality (ATE, -0.1502, 95%CI, -0.2340 to -0.0664, p < 0.001). In subgroup analysis, the ATE for 28-day mortality, 60-day mortality, and hospital mortality were not statistically significant in the coronary care unit group, high-dose group (over 100 mg/d), and no invasive mechanical ventilation (IMV) group. After excluding these non-beneficiaries, Cdyn and P/F ratio of the pre-ICU aspirin exposure group increased by 0.31mL/cmH2O (SE, 0.21, p = 0.016), and 0.43 mmHg (SE, 0.24, p = 0.041) every hour compared to that of non-aspirin exposure group after initialing IMV. The time-weighted average of NLR, Cdyn, WMP played a mediating role of 8.6%, 24.7%, and 13% of the total effects of pre-ICU aspirin exposure and 28-day mortality, respectively. Conclusion: Pre-ICU aspirin exposure was associated with decreased 28-day mortality, 60-day mortality, and hospital mortality in S-ARF patients except those admitted to CCU, and those took a high-dose aspirin or did not receive IMV. The protective effect of aspirin may be mediated by a low dynamic level of NLR and a high dynamic level of Cdyn and WMP. The findings should be interpreted cautiously, given the sample size and potential for residual confounding.

MiRNA and Potential Prognostic Value in Non-Smoking Females with Lung Adenocarcinoma by High-Throughput Sequencing.

Background: Non-smoking females with lung adenocarcinoma (LUAD) account for a unique disease entity and miRNA play critical roles in cancer development and progression. The purpose of this study is to explore prognosis-related differentially expressed miRNA (DEmiRNA) and establish a prognostic model for non-smoking females with LUAD. Methods: Eight specimens were collected from thoracic surgery of non-smoking females with LUAD and implemented the miRNA sequencing. The intersection of our miRNA sequencing data and TCGA database were identified as common DEmiRNA. Then, we predicted the target genes of the common DEmiRNAs (DETGs) and explored the functional enrichment and prognosis of DETGs. A risk model by overall survival (OS)-related DEmiRNA was constructed based on multivariate Cox regression analyses. Results: A total of 34 overlapping DEmiRNA were obtained. The DETGs were enriched in pathways including "Cell cycle" and "miRNAs in cancer". The DETGs (KPNA2, CEP55, TRIP13, MYBL2) were risk factors, significantly related to OS, progression-free survival (PFS), and were also hub genes. ScRNA-seq data also validated the expression of the four DETGs. Hsa-mir-200a, hsa-mir-21, and hsa-mir-584 were significantly associated with OS. The prognostic prediction model constructed by the 3 DEmiRNA could effectively predict OS and can be used as an independent prognostic factor of non-smoking females with LUAD. Conclusion: Hsa-mir-200a, hsa-mir-21, and hsa-mir-584 can serve as potential prognostic predictors in non-smoking females with LUAD. A novel prognostic model based on the three DEmiRNAs was also constructed to predict the survival of non-smoking females with LUAD and showed good performance. The result of our paper can be helpful for treatment and prognosis prediction for non-smoking females with LUAD.

Blood heparin-binding protein and neutrophil-to-lymphocyte ratio as indicators of the severity and prognosis of community-acquired pneumonia.

BACKGROUND: Community-acquired pneumonia (CAP) is particularly prevalent and has high mortality in severely ill patients, but the role of current biomarkers is limited. This study aimed to evaluate the importance of blood heparin-binding protein (HBP) and neutrophil-to-lymphocyte ratio (NLR) in assessing the severity and prognosis of CAP in adults. METHODS: The clinical information of 206 CAP patients was retrospectively analyzed. Receiver operating characteristic (ROC) curves were created, and the accuracy of the diagnosis of severe pneumonia was evaluated by the area under the curve (AUC). Univariate and multivariate Cox regression analysis was used to examine independent factors affecting the 30-day prognosis. The Kruskal-Wallis test was utilized to contrast the variations among etiology. RESULTS: Patients with severe pneumonia showed greater HBP and NLR compared to those with common pneumonia. The AUC of HBP was 0.723 (95% CI: 0.655-0.790) for the diagnosis of severe pneumonia, while NLR and HBP exhibited superior sensitivity (80.00%) and specificity (76.19%), respectively. Their combination boosted the diagnostic specificity (84.13%) while increasing the diagnostic sensitivity (86.25%) when combined with white blood cell (WBC) count. The 30-day mortality in CAP patients was independently predicted by HBP and NLR. However, there were no appreciable differences in HBP amongst patients with various etiologies. CONCLUSION: HBP and NLR were also independent predictors of 30-day death in CAP patients and grew with increasing severity in these patients. Their combination opened up new possibilities. Furthermore, there is no connection between HBP and the etiology of CAP.

The Biological Processes of Ferroptosis Involved in Pathogenesis of COVID-19 and Core Ferroptoic Genes Related With the Occurrence and Severity of This Disease.

Background: A worldwide outbreak of coronavirus disease 2019 (COVID-19) has resulted in millions of deaths. Ferroptosis is a form of iron-dependent cell death which is characterized by accumulation of lipid peroxides on cellular membranes, and is related with many physiological and pathophysiological processes of diseases such as cancer, inflammation and infection. However, the role of ferroptosis in COVID-19 has few been studied. Material and Method: Based on the RNA-seq data of 100 COVID-19 cases and 26 Non-COVID-19 cases from GSE157103, we identified ferroptosis related differentially expressed genes (FRDEGs, adj.P-value < .05) using the "Deseq2" R package. By using the "clusterProfiler" R package, we performed Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment. Next, a protein-protein interaction (PPI) network of FRDEGs was constructed and top 30 hub genes were selected by cytoHubba in Cytoscape. Subsequently, we established a prediction model for COVID-19 by utilizing univariate logistic regression and the least absolute shrinkage and selection operator (LASSO) regression. Based on core FRDEGs, COVID-19 patients were identified as two clusters using the "ConsenesusClusterPlus" R package. Finally, the miRNA-mRNA network was built by Targetscan online database and visualized by Cytoscape software. Results: A total of 119 FRDEGs were identified and the GO and KEGG enrichment analyses showed the most important biologic processes are oxidative stress response, MAPK and PI3K-AKT signaling pathway. The top 30 hub genes were selected, and finally, 7 core FRDEGs (JUN, MAPK8, VEGFA, CAV1, XBP1, HMOX1, and HSPB1) were found to be associated with the occurrence of COVID-19. Next, the two patterns of COVID-19 patients had constructed and the cluster A patients were likely to be more severe. Conclusion: Our study suggested that ferroptosis was involved in the pathogenesis of COVID-19 disease and the functions of core FRDEGs may become a new research aspect of this disease.

The dipeptidyl peptidase-4 inhibitor linagliptin ameliorates LPS-induced acute lung injury by maintenance of pulmonary microvascular barrier via activating the Epac1/AKT pathway.

Pulmonary microvascular endothelial cells (PMVECs) barrier dysfunction is a main pathophysiological feature of sepsis-related acute lung injury (ALI). This study aimed to investigate whether the dipeptidyl peptidase (DPP)-4 inhibitor linagliptin could protect against LPS-induced PMVECs barrier disruption and its underlying molecular mechanisms. A classical ALI animal model and LPS-treated PMVECs were applied and all were treated with or without linagliptin. Cellular experiments demonstrated that linagliptin could mitigate LPS-induced PMVECs hyperpermeability and intercellular junction (VE-cadherin, ß-catenin, and ZO-1) disruption in a dose-dependent manner. Correspondingly, it was observed that linagliptin pretreatment distinctly relieved LPS-induced lung injury, oxidative stress, and pulmonary edema in vivo. Furthermore, we found that the inhibition of oxidative stress by linagliptin may be achieved by reversing impaired mitochondrial function. Mechanistically, linagliptin administration promoted the activation of the Epac1 pathway and its downstream AKT pathway, while inhibition of the Epac1/Akt signaling pathway significantly alleviated the above-mentioned protective effect of linagliptin on the PMVECs barrier. Taken together, these data suggest that linagliptin can effectively reserve PMVECs barrier dysfunction and inhibit oxidative stress to protect against ALI via activating the Epac1/AKT signaling pathway, and thus may become a potential clinical therapeutic strategy for ALI.

Cell Membrane-Anchoring Nano-Photosensitizer for Light-Controlled Calcium-Overload and Tumor-Specific Synergistic Therapy.

Poor selectivity and unintended toxicity to normal organs are major challenges in calcium ion (Ca2+ ) overload tumor therapy. To address this issue, a cell membrane-anchoring nano-photosensitizer (CMA-nPS) is constructed for inducing tumor-specific Ca2+ overload through multistage endogenous Ca2+ homeostasis disruption under light guidance, i.e., the extracellular Ca2+ influx caused by cell membrane damage, followed by the intracellular Ca2+ imbalance caused by mitochondrial dysfunction. CMA-nPS is decorated by two types of functionalized cell membranes, the azide-modified macrophage cell membrane is used to conjugate the dibenzocyclooctyne-decorated photosensitizer, and the vesicular stomatitis virus glycoprotein (VSV-G)-modified NIH3T3 cell membrane is used to guide the anchoring of photosensitizer to the lung cancer cell membrane. The in vitro study shows that CMA-nPS mainly anchors on the cell membrane, and further causes membrane damage, mitochondrial dysfunction, as well as intracellular Ca2+ overload upon light irradiation. Synergistically enhanced antitumor efficiency is observed in vitro and in vivo. This study provides a new synergistic strategy for Ca2+ -overload-based cancer therapy, as well as a strategy for anchoring photosensitizer on the cell membrane, offering broad application prospects for the treatment of lung cancer.

The effect of N6-methyladenosine (m6A) factors on the development of acute respiratory distress syndrome in the mouse model.

Acute respiratory distress syndrome (ARDS) can cause loss of alveolar-capillary membrane integrity and life-threatening immune responses. The underlying molecular mechanisms of ARDS remain unclear. N6-methyladenosine (m6A)-RNA modification plays an important part in many biological processes. However, it is not clear whether ARDS alters RNA methylation in lung tissue. We tried to investigate the changes of m6A-RNA methylation in lung tissues of lipopolysaccharide (LPS)-induced ARDS mice. Lung tissue samples were collected to detect the expression of m6A factors through hematoxylin and eosin (HE) staining, quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR), immunohistochemical analysis and western blot. The overall m6A levels in lung tissue of ARDS in mouse were detected by UPLC-UV-MS. HE staining showed that the degree of the inflammatory response was more severe in the LPS-3 h group. The mRNA expression of YTHDF1, YTHDC1 and IGFBP3 was remarkably up-regulated at, respectively, 6, 6 and 12 h after LPS treatment. The mRNA expression of METTL16, FTO, METTL3, KIAA1429, RBM15, ALKBH5, YTHDF2, YTHDF3, YTHDC2 and IGFBP2 was significantly down-regulated at 24 h after LPS treatment. The protein expression of METTL16 and FTO increased, YTHDC1, IGFBP3 YTHDF1 and YTHDF3 showed a down-regulation trend after LPS induction. Overall m6A-RNA methylation levels were significantly increased at 6 h after LPS induction. In ARDS mice, LPS-induced m6A methylation may be involved in the expression regulation of inflammatory factors and may play important roles in the occurrence and development of lung tissue. It is suggested that m6A modification may be a promising therapeutic target for ARDS.

Diagnostic value of periostin in lung cancer-related malignant pleural effusion.

BACKGROUND: Periostin (POSTN) is an extracellular matrix protein that is overexpressed in lung cancer and is considered an effective diagnostic and prognostic biomarker for lung cancer. The purpose of this study was to investigate the diagnostic performance of POSTN and to further evaluate the diagnostic value of POSTN combined with carcinoembryonic antigen (CEA) and cancer ratio [CR: serum lactate dehydrogenase (LDH)/pleural effusion adenosine deaminase (PE ADA)] in lung cancer-related malignant PE (MPE). METHODS: A total of 108 patients with PE, including 54 with lung cancer and 54 with benign lung disease, were enrolled in this study. The POSTN levels of PE and serum were detected using an enzyme-linked immunosorbent assay. Information on the expression of PE and serum CEA, serum LDH, and PE ADA was collected from medical records. RESULTS: The levels of PE POSTN in MPE of patients with lung cancer were significantly higher than those in patients with benign PE (p < 0.0001). The receiver operating characteristic (ROC) curve indicated that the diagnostic sensitivity and specificity of PE POSTN for lung cancer-related MPE were respectively 77.78% and 68.52% when the cutoff value was determined to be 53.45 ng/ml. The ROC curve analysis demonstrated that PE POSTN has a high diagnostic value in MPE associated with lung cancer [area under the curve (AUC) = 0.764], and the combination of PE POSTN, PE CEA, and CR can improve the diagnostic accuracy of lung cancer-related MPE (AUC = 0.948). CONCLUSION: POSTN can be used as a potential marker for lung cancer-related MPE diagnosis.

LPS induces pulmonary microvascular endothelial cell barrier dysfunction by upregulating ceramide production.

The specific role of ceramides in pulmonary microvascular endothelial cell (PMVEC) barrier dysfunction remains unclear. In the present study, pretreatment with pan-caspase inhibitors significantly reduced LPS-induced PMVEC apoptosis and helped to stimulate PMVEC barrier reconstruction after 12 h but had no effect on PMVEC barrier dysfunction in the first 8 h. Further studies showed that imipramine, an acid sphingomyelinase (ASMase) inhibitor, significantly inhibited LPS-induced barrier dysfunction, while an siRNA targeting serine palmityl transferase subunit 1 (SPTLC1) and the pharmacological inhibitor myriocin did not inhibit early acute barrier dysfunction but significantly inhibited PMVEC apoptosis and apoptosis-dependent delayed barrier dysfunction. In addition, LPS was shown to activate RhoA by inducing transient receptor potential channel 6 (TRPC6) overexpression and calcium influx through the ASMase/ceramide pathway, and activation of RhoA further induced the cytoskeletal rearrangement of PMVECs and destruction of intercellular junctions, ultimately leading to early acute PMVEC barrier dysfunction. However, regarding apoptosis-dependent delayed barrier dysfunction, the ceramide-induced de novo synthesis pathway in paracellular cells induced the apoptosis of PMVECs, in which Txnip overexpression inhibited Trx activity and subsequently activated ASK1 in the context of LPS-induced PMVEC apoptosis, acting upstream of the ceramide-induced activation of p38 MAPK and JNK. At the same time, in rats with LPS- or exogenous C8 ceramide-induced ALI, ceramide was demonstrated to play an important role in lung injury by inducing the Txnip/TRX/ASK1/P38 and JNK pathways. Thus, the Txnip/TRX/ASK1/p38 and JNK pathways might be involved in ceramide-mediated PMVEC apoptosis in LPS-induced ALI.