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Long non-coding RNAs play a key role in silicosis, a fatal fibrotic lung disease, and there is an urgent need to develop new treatment targets. Long intergenic non-protein-coding RNA 3047 (LINC03047) is associated with cancer, but its role and mechanism in the progression of silicosis require further elucidation. This study investigated the function of LINC03047 in the epithelial-mesenchymal transition (EMT) during silicosis progression. LINC03047 expression was upregulated in SiO2-treated BEAS-2B and A549 cells, promoting SiO2-induced ferroptosis and subsequent EMT. Moreover, knockdown of LINC03047 significantly decreased the expression of solute carrier family 39 member 14 (SLC39A14), a ferrous iron transporter, and inhibition of SLC39A14 alleviated the ferroptosis and EMT caused by LINC03047 overexpression. We further investigated that NF-κB p65 (RELA) was critical for LINC03047 transcription in SiO2-treated BEAS-2B and A549 cells. In vivo experiments showed that SLC39A14 deficiency improved SiO2-induced lipid peroxidation and EMT. Collectively, our study reveals the function of the RELA/LINC03047/SLC39A14 axis in SiO2-induced ferroptosis and EMT, thereby contributing to the identification of novel drug targets for silicosis therapy.
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Background: Type 2 diabetes (T2D) frequently co-occurs with respiratory system diseases such as chronic obstructive pulmonary disease (COPD), bronchial asthma, lung cancer, interstitial lung disease, and pulmonary tuberculosis. Although a potential association is noted between these conditions, the available research is limited. Objective: To investigate the causal relationship between patients with T2D and respiratory system diseases using two-sample Mendelian randomization analysis. Methods: Causal relationships were inferred using a two-sample Mendelian randomization (MR) analysis based on publicly available genome-wide association studies. We employed the variance inverse-weighted method as the primary analytical approach based on three key assumptions underlying MR analysis. To bolster the robustness and reliability of our results, we utilized MR Egger's intercept test to detect potential pleiotropy, Cochran's Q test to assess heterogeneity, funnel plots to visualize potential bias, and "leave-one-out" sensitivity analysis to ensure that our findings were not unduly influenced by any single genetic variant. Result: The inverse variance weighted (IVW) analysis indicated a causal relationship between T2D and COPD [Odds Ratio (OR) = 0.87; 95% Confidence Interval (CI) = 0.82-0.96; p < 0.05]. No significant heterogeneity or pleiotropy were observed through their respective tests (p > 0.05), and the statistical power calculations indicated that the results were reliable. The IVW analysis showed a negative causal relationship between T2D and bronchial asthma [OR = 0.85; 95% CI = 0.81-0.89; p < 0.05]. However, the IVW under the random-effects model indicated heterogeneity (p < 0.05), suggesting instability in the results and requiring cautious interpretation. The study found a positive causal relationship between T2D and pulmonary tuberculosis (OR = 1.24, 95% CI = 1.05-1.45, p < 0.05). However, they exhibited pleiotropy (p < 0.05), indicating their instability. No correlation between T2D and interstitial lung disease or lung cancer was observed. Conclusion: T2D is negatively associated with COPD, suggesting that T2D may reduce the risk of developing COPD. A negative causal relationship between T2D and bronchial asthma has been observed, but the results exhibit heterogeneity. There is a positive causal relationship between T2D and pulmonary tuberculosis, yet the findings suggest the presence of pleiotropy. No significant causal relationship between T2D and lung cancer or interstitial lung disease was observed.
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Background: Asthma is associated with persistent airway inflammation, and numerous studies have investigated inflammatory markers causing asthma. However, the systemic immune-inflammation index (SII) is a novel inflammatory marker, with scarce research reporting on the correlation between SII and asthma and asthma-related events. Objective: The purpose of this study was to assess the relationship between SII and asthma and asthma-related events (including whether asthma is still present, asthma flare-ups in the past year, and asthma duration) using data from the National Health and Nutrition Examination Survey (NHANES). Methods: The study utilized data from NHANES 2009-2018 with asthma and asthma-related events as dependent variables and SII as an independent variable. Multifactor logistic regression was employed to assess the correlation between the independent and dependent variables. Smoothed curve-fitting and threshold effect analyses were also carried out to determine the presence of non-linear relationships. Subgroup analyses were then performed to identify sensitive populations. Results: In this study, we analyzed data from 40,664 participants to elucidate the association between SII and asthma and its related events. The study findings indicated a positive correlation between SII and asthma, with a relative risk increase of 0.03% for asthma incidence per one percentage point increase in SII (OR = 1.0003, 95% CI: 1.0002, 1.0004). For individuals still suffering from asthma, higher SII also indicated a positive correlation with ongoing asthma (OR = 1.0004, 95% CI: 1.0001, 1.0006). However, no statistically significant association was observed between SII and asthma exacerbations within the following year (OR = 1.0001, p > 0.05). When considering the duration of asthma, we observed a slight positive correlation with SII (ß = 0.0017, 95% CI: 0.0005, 0.0029). Additionally, a significant non-linear relationship between SII and asthma duration emerged at the threshold of 504.3 (ß = 0.0031, 95% CI: 0.0014-0.0048, p = 0.0003). Subgroup analysis revealed a stronger correlation between SII and asthma in male patients (OR = 1.0004, 95% CI: 1.0002-1.0006) and individuals aged 60 and above (OR = 1.0005, 95% CI: 1.0003-1.0007). No gender differences were observed for individuals still suffering from asthma. However, the positive correlation between SII and asthma was more pronounced in participants under 20 years old (OR = 1.0004 in Model 3, 95% CI: 1.0002-1.0006). Specific sensitive subgroups for asthma exacerbation recurrence within the past year were not identified. When considering asthma duration, we observed this association to be significant in male individuals (ß = 0.0031 in Model 3, 95% CI: 0.0014-0.0049) as well as individuals aged 20 to 39 (ß = 0.0023 in Model 3, 95% CI: 0.0005-0.0040). Conclusion: Our study concludes that SII is positively correlated with the persistence of asthma yet has limited predictive power for asthma recurrence. This highlights SII's potential as a tool for assessing asthma risk and formulating targeted management strategies.
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Noninflammatory apoptosis is transformed into inflammatory pyroptosis by activating caspase-3 to lyse gasdermin E (GSDME), and this process can be used as an effective therapeutic strategy. Thus, a selective and powerful inducer of activated caspase-3 plays a vital role in pyroptosis-based cancer therapy. Herein, a human cell membrane vesicle-based nanoplatform (HCNP) is designed for photodynamic therapy (PDT). HCNP is modified with vesicular stomatitis virus G-protein (VSVG) to anchor nano-photosensitizers on the tumor cell membrane. Photosensitizers are bonded to HCNP by clicking chemical reaction as pyroptosis inducers. The results show that HCNP effectively disrupts the mitochondrial function of cells by generating reactive oxygen species (ROS) upon laser irradiation; concomitantly, GSDME is cleaved by activated caspase-3 and promotes pyroptosis of lung cancer cells. Here an effective intervention strategy is proposed to induce pyroptosis based on light-activated PDT.
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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.
Subject(s)
Acute Lung Injury , Respiratory Distress Syndrome , Humans , Animals , Mice , Reactive Oxygen Species , Endothelial Cells , Acute Lung Injury/chemically induced , Lung , Respiratory Distress Syndrome/therapy , LipopolysaccharidesABSTRACT
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.
Subject(s)
Asthma , COVID-19 , Coronary Disease , Diabetes Mellitus , Gastroesophageal Reflux , Female , Humans , Infant , Male , SARS-CoV-2 , Cross-Sectional Studies , COVID-19 Vaccines , COVID-19/complications , COVID-19/epidemiology , Cough/epidemiology , Risk Factors , Chronic Cough , China/epidemiology , Asthma/complications , Asthma/epidemiologyABSTRACT
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.
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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.
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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.
Subject(s)
Neoplasms , Pyroptosis , Animals , Mice , Biomimetics , Copper , Reactive Oxygen Species , Immunotherapy , Neoplasms/drug therapyABSTRACT
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.
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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.
Subject(s)
Lung Neoplasms , Small Cell Lung Carcinoma , Humans , Retrospective Studies , Immunotherapy , Hospitals , Immune Checkpoint Inhibitors/therapeutic use , Small Cell Lung Carcinoma/drug therapy , Lung Neoplasms/drug therapyABSTRACT
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.
Subject(s)
Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Adolescent , Adult , Humans , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/pathology , Disease-Free Survival , ErbB Receptors/genetics , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Protein Kinase InhibitorsABSTRACT
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.
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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.
Subject(s)
Gene Editing , Neoplasms , Humans , CRISPR-Cas Systems/genetics , Biomimetics , Cellular Reprogramming , Neoplasms/genetics , Neoplasms/therapy , Neoplasms/metabolismABSTRACT
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.
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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.
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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.
ABSTRACT
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.
Subject(s)
Community-Acquired Infections , Pneumonia , Adult , Humans , Neutrophils , Retrospective Studies , Lymphocytes , Prognosis , ROC CurveABSTRACT
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.
Subject(s)
Lung Neoplasms , Photochemotherapy , Mice , Animals , Humans , Photosensitizing Agents/pharmacology , Photosensitizing Agents/therapeutic use , Calcium/metabolism , NIH 3T3 Cells , Cell Membrane/metabolism , Lung Neoplasms/drug therapy , Cell Line, TumorABSTRACT
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.