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Abstract Background To investigate the associations of different combinations of moderate to vigorous physical activity (MVPA) and muscle strengthening activity (MSA) with all-cause and cancer mortality among lung cancer survivors. Methods This nationwide prospective cohort study used data from the US National Health Interview Survey 2009–2018. A total of 785 lung cancer survivors were included in the study. Participants were linked to the National Death Index through December 31, 2019. Self-reported MVPA and MSA frequency data were used to obtain 4 mutually exclusive exposure categories. Multivariate Cox proportional hazard models were applied to explore the association between exposure categories and outcomes. Results The mean (standard deviation [SD]) age of the study population was 69.1 (11.3) years and 429 (54.6%) were female. Among them, 641 (81.7%) were White and 102 (13.0%) were Black. The median follow-up time was 3 years (2526 person-years), and 349 (44.5%) all-cause deaths and 232 (29.6%) cancer deaths occurred. Compared to the MVPA

Abstract Background Acute lung injury (ALI) and its more severe form, acute respiratory distress syndrome (ARDS) as common life-threatening lung diseases with high mortality rates are mostly associated with acute and severe inflammation in lungs. Recently, increasing evidence supports activated inflammation and gasdermin D (GSDMD)-mediated pyroptosis in macrophage are closely associated with ALI. Basic helix-loop-helix family member e40 (Bhlhe40) is a transcription factor that is comprehensively involved in inflammation. However, there is little experimental evidence connecting Bhlhe40 and GSDMD-driven pyroptosis. The study sought to verify the hypothesis that Bhlhe40 is required for GSDMD-mediated pyroptosis in lipopolysaccharide (LPS)-induced inflammatory injury. Method We performed studies using Bhlhe40-knockout (Bhlhe40 −/−) mice, small interfering RNA (siRNA) targeting Bhlhe40 and pyroptosis inhibitor disulfiram to investigate the potential roles of Bhlhe40 on LPS-induced ALI and the underlying mechanisms. Results Bhlhe40 was highly expressed in total lung tissues and macrophages of LPS-induced mice. Bhlhe40 −/− mice showed alleviative lung pathological injury and inflammatory response upon LPS stimulation. Meanwhile, we found that Bhlhe40 deficiency significantly suppressed GSDMD-mediated pyroptosis in macrophage in vivo and in vitro. By further mechanistic analysis, we demonstrated that Bhlhe40 deficiency inhibited GSDMD-mediated pyroptosis and subsequent ALI by repressing canonical (caspase-1-mediated) and non-canonical (caspase-11-mediated) signaling pathways in vivo and in vitro. Conclusion These results indicate Bhlhe40 is required for LPS-induced ALI. Bhlhe40 deficiency can inhibit GSDMD-mediated pyroptosis and therefore alleviate ALI. Targeting Bhlhe40 may be a potential therapeutic strategy for LPS-induced ALI.

BackgroundEndobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is a minimally invasive technique for biopsy of lung, peri-pulmonary tissue and lymph nodes under real-time ultrasound-guided biopsy. It is used in the diagnosis and/or staging of benign and malignant pulmonary and non-pulmonary diseases. Our study is based on a large sample size, in a diversified population which provides a representative real-world cohort for analysis.MethodsPatients who underwent EBUS-TBNA procedure between September 2019 and August 2022 were included in this retrospective study. For cases diagnosed as benign and unclassified lesions by EBUS-TBNA, the final diagnosis was determined by further invasive surgery or a combination of therapy and clinical follow-up for at least 6 months.ResultsA total of 618 patients were included in the study, including 182 females (29.4%) and 436 males (70.6%). The mean age of all patients was 61.9 ± 10.5 years. These patients were successfully punctured by EBUS-TBNA to obtain pathological results. The pathological diagnosis results of EBUS-TBNA were compared with the final clinical diagnosis results as follows: 133 cases (21.5%) of benign lesions and 485 cases (78.5%) of malignant lesions were finally diagnosed. Among them, the pathological diagnosis was obtained by EBUS-TBNA in 546 patients (88.3%) (464 malignant lesions and 82 benign conditions), while EBUS-TBNA was unable to define diagnosis in 72 patients (11.6%). 20/72 non-diagnostic EBUS-TBNA were true negative. The overall diagnostic sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of EBUS-TBNA were 91.3%, 100%, 100%, 27.8%, and 91.6% [95% confidence interval (CI): 89.1–93.6%], respectively. In this study, only one case had active bleeding without serious complications during the EBUS-TBNA procedure.ConclusionGiven its low invasiveness, high diagnostic accuracy, and safety, EBUS-TBNA is worth promoting in thoracic lesions.

Abstract Objectives To explore the diagnostic value of radiomics in differentiating between lung adenocarcinomas appearing as ground‐glass opacity nodules (GGO) with high‐ and low Ki‐67 expression levels. Materials and Methods From January 2018 to January 2021, patients with pulmonary GGO who received lung resection were evaluated for potential enrollment. The included GGOs were then randomly divided into a training cohort and a validation cohort with a ratio of 7:3. Logistic regression (LR), decision tree (DT), support vector machines (SVM), and adaboost (AB) were applied for radiomic model construction. Area under the curve (AUC) of the receiver operating characteristic (ROC) curve was used to evaluate the diagnostic efficacy of the established models. Results Seven hundred and sixty‐nine patients with 769 GGOs were included in this study. Two hundred and forty‐five GGOs were confirmed to be of high Ki‐67 labeling index (LI). In the training cohort, gender, age, spiculation sign, pleural indentation sign, bubble sign, and maximum 2D diameter of the nodule were found to be significantly different between high‐ and low Ki‐67 LI groups (p

Pollution from fine particulate matter (PM2.5) has become a major threat to public health and has been related to lung toxicity. One of the key regulators of the Hippo signaling system, Yes-associated protein 1 (YAP1), is speculated to play a role in ferroptosis development. Here, we focused on investigating the function of YAP1 in pyroptosis and ferroptosis, aiming to explore its therapeutic potential in PM2.5-induced lung toxicity. PM2.5-induced lung toxicity was induced in Wild-type WT and conditional YAP1-knockout mice, and lung epithelial cells were stimulatd by PM2.5 in vitro. We used western blot, transmission electron microscopy, and fluorescence microscopy to investigate pyroptosis- and ferroptosis-related characteristics. We found that PM2.5 leads to lung toxicity using mechanisms involving pyroptosis and ferroptosis. YAP1 knockdown impeded pyroptosis, ferroptosis, and PM2.5-induced lung damage, as shown by increased histopathology, higher levels of proinflammatory cytokines, GSDMD protein, lipid peroxidation, and iron accumulation, as well as increased NLRP3 inflammasome activation and decreased SLC7A11 expression. YAP1 silencing consistently promoted NLRP3 inflammasome activation and reduced SLC7A11 levels, aggravating PM2.5-induced cellular damage. In contrast, YAP1-overexpressing cells inhibited NLRP3 inflammasome activation and increased SLC7A11 levels, preventing pyroptosis and ferroptosis. Overall, our data suggest that YAP1 ameliorates PM2.5-induced lung injury by inhibiting NLRP3-mediated pyroptosis and SL7A11-dependent ferroptosis.

Abstract Background High-flow nasal cannula (HFNC) can improve ventilatory function in patients with acute COPD exacerbation. However, its effect on clinical outcomes remains uncertain. Methods This randomized controlled trial was conducted from July 2017 to December 2020 in 16 tertiary hospitals in China. Patients with acute COPD exacerbation with mild hypercapnia (pH ≥ 7.35 and arterial partial pressure of carbon dioxide > 45 mmHg) were randomly assigned to either HFNC or conventional oxygen therapy. The primary outcome was the proportion of patients who met the criteria for intubation during hospitalization. Secondary outcomes included treatment failure (intolerance and need for non-invasive or invasive ventilation), length of hospital stay, hospital cost, mortality, and readmission at day 90. Results Among 337 randomized patients (median age, 70.0 years; 280 men [83.1%]; median pH 7.399; arterial partial pressure of carbon dioxide 51 mmHg), 330 completed the trial. 4/158 patients on HFNC and 1/172 patient on conventional oxygen therapy met the criteria for intubation (P = 0.198). Patients progressed to NPPV in both groups were comparable (15 [9.5%] in the HFNC group vs. 22 [12.8%] in the conventional oxygen therapy group; P = 0.343). Compared with conventional oxygen therapy, HFNC yielded a significantly longer median length of hospital stay (9.0 [interquartile range, 7.0–13.0] vs. 8.0 [interquartile range, 7.0–11.0] days) and a higher median hospital cost (approximately $2298 [interquartile range, $1613–$3782] vs. $2005 [interquartile range, $1439–$2968]). There were no significant differences in other secondary outcomes between groups. Conclusions In this multi-center randomized controlled study, HFNC compared to conventional oxygen therapy did not reduce need for intubation among acute COPD exacerbation patients with mild hypercapnia. The future studies should focus on patients with acute COPD exacerbation with respiratory acidosis (pH

Objectives: This study aimed to assess the current incidence and risk factors for polymyxin B-associated acute kidney injury (AKI) in Chinese hospitals for a more effective clinical use for polymyxin B. Methods: This multicenter, retrospective cohort study included patients from 14 Chinese teaching hospitals who received polymyxin B therapy. Univariate and multivariate logistic regression models were used to determine the factors associated with polymyxin B-associated incident AKI. Furthermore, a multivariate logistic regression model was used to identify the independent risk factors for AKI. Results: A total of 251 patients were included in the analysis. The overall incidence of AKI was 33.5%. A multivariate logistic regression model identified the loading dose (hazard ratio (HR), 1.84; 95% confidence interval (CI), 1.01–3.38; P = 0.0491) and the use of two or more nephrotoxic drugs (HR, 3.56; 95% CI, 1.55–8.18; P = 0.0029) as independent risk factors for the occurrence of AKI. Meanwhile, the estimated glomerular filtration rate had a protective effect (HR, 0.99; 95% CI, 0.98–0.99; P = 0.0006) on the occurrence of AKI. The daily dose, cumulative dose, and treatment duration of polymyxin B did not affect the occurrence of AKI. Conclusions: The use of polymyxin B loading doses and the combined use of multiple nephrotoxic drugs are independent risk factors for polymyxin B-associated AKI. The severity of AKI may be higher in patients with elevated baseline creatinine levels.

Background: Epstein-Barr virus (EBV) usually leads to latent infection and is reported mostly in infectious mononucleosis, lymphoma, and cancer in adolescents and adults, but pneumonitis due to EBV infection in adults is rare. Case presentation: We hereby reported a case of a 52-year-old woman with breast cancer who developed acute pneumonia during neoadjuvant chemotherapy. Her serologic workup revealed a low CD4+ count and positive anti-EBV antibodies. Chest computed tomography (CT) shows multiple patchy ground-glass shadows in the bilateral lung. Microscopic examination of stained sputum and bronchoalveolar lavage fluid (BALF) smear specimens did not find any pathogens. Metagenomic next-generation sequencing (mNGS) of BALF indicated a large number of EBV reads, allowing to confirm the diagnosis of EBV induced pneumonitis. The patient was then treated with ganciclovir with subsequent dramatic clinical and radiological improvement. Conclusions: This case highlights the combined application of mNGS and traditional tests in the clinical diagnosis of invasive pulmonary infection. In the meanwhile, clinicians should be aware neoadjuvant chemotherapy for breast cancer carries a risk of EBV induced pneumonitis, so that EBV induced pneumonitis could be considered in differential diagnosis while similar patients present, to orchestrate improvements in diagnosis, treatment, and prognosis.

Abstract Azvudine (FNC) is a nucleoside analog that inhibits HIV-1 RNA-dependent RNA polymerase (RdRp). Recently, we discovered FNC an agent against SARS-CoV-2, and have taken it into Phase III trial for COVID-19 patients. FNC monophosphate analog inhibited SARS-CoV-2 and HCoV-OC43 coronavirus with an EC50 between 1.2 and 4.3 μM, depending on viruses or cells, and selective index (SI) in 15–83 range. Oral administration of FNC in rats revealed a substantial thymus-homing feature, with FNC triphosphate (the active form) concentrated in the thymus and peripheral blood mononuclear cells (PBMC). Treating SARS-CoV-2 infected rhesus macaques with FNC (0.07 mg/kg, qd, orally) reduced viral load, recuperated the thymus, improved lymphocyte profiles, alleviated inflammation and organ damage, and lessened ground-glass opacities in chest X-ray. Single-cell sequencing suggested the promotion of thymus function by FNC. A randomized, single-arm clinical trial of FNC on compassionate use (n = 31) showed that oral FNC (5 mg, qd) cured all COVID-19 patients, with 100% viral ribonucleic acid negative conversion in 3.29 ± 2.22 days (range: 1–9 days) and 100% hospital discharge rate in 9.00 ± 4.93 days (range: 2–25 days). The side-effect of FNC is minor and transient dizziness and nausea in 16.12% (5/31) patients. Thus, FNC might cure COVID-19 through its anti-SARS-CoV-2 activity concentrated in the thymus, followed by promoted immunity.

IntroductionIt is not clear whether polymyxin B/tigecycline (PMB/TGC) combination is better than PMB or TGC alone in the treatment of hospital-acquired pneumonia (HAP) caused by carbapenem-resistant organisms (CROs).MethodsWe conducted a multicenter, retrospective cohort study in patients with HAP caused by CROs. The primary outcome was 28-day mortality, and the secondary outcomes included clinical success and the incidence of acute kidney injury (AKI). Multivariate Cox regression analysis was performed to examine the relationship between antimicrobial treatments and 28-day mortality by adjusting other potential confounding factors.ResultsA total of 364 eligible patients were included in the final analysis, i.e., 99 in the PMB group, 173 in the TGC group, and 92 in the PMB/TGC combination group. The 28-day mortality rate was 28.3% (28/99) in the PMB group, 39.3% (68/173) in the TGC group, and 48.9% (45/92) in the PMB/TGC combination group (p = 0.014). The multivariate Cox regression model showed that there was a statistically significant lower risk of 28-day mortality among participants in the PMB group when compared with the PMB/TGC combination group [hazard ratio (HR) 0.50, 95% confidence interval (CI) 0.31–0.81, p = 0.004] and that participants in the TGC group had a lower risk of 28-day mortality than in the PMB/TGC combination group but without statistical significance. The incidence of AKI in the PMB group (52.5%) and the PMB/TGC combination group (53.3%) was significantly higher than that in the TGC group (33.5%, p = 0.001).ConclusionThe appropriate PMB/TGC combination was not superior to appropriate PMB therapy in the treatment of HAP caused by carbapenem-resistant Enterobacteriaceae/carbapenem-resistant Acinetobacter baumannii (CRE/CRAB) in terms of 28-day mortality.

Tissue remodeling/fibrosis is a main feature of idiopathic pulmonary fibrosis (IPF), which results in the replacement of normal lung parenchyma with a collagen-rich extracellular matrix produced by fibroblasts and myofibroblasts. Epithelial-mesenchymal transition (EMT) in type 2 lung epithelial cells is a key process in IPF, which leads to fibroblasts and myofibroblasts accumulation and excessive collagen deposition. DEC1, a structurally distinct class of basic helix-loop-helix proteins, is associated with EMT in cancer. However, the functional role of DEC1 in pulmonary fibrosis (PF) remains elusive. Herein, we aimed to explore DEC1 expression in IPF and bleomycin (BLM)-induced PF in mice and the mechanisms underlying the fibrogenic effect of DEC1 in PF in vivo and in vitro by Dec1-knockout (Dec1−/−) mice, knockdown and overexpression of DEC1 in alveolar epithelial cells (A549 cells). We found that the expression of DEC1 was increased in IPF and BLM-injured mice. More importantly, Dec1−/− mice had reduced PF after BLM challenge. Additionally, DEC1 deficiency relieved EMT development and repressed the PI3K/AKT/GSK-3β/β-catenin integrated signaling pathway in mice and in A549 cells, whereas DEC1 overexpression in vitro had converse effects. Moreover, the PI3K/AKT and Wnt/β-catenin signaling inhibitors, LY294002 and XAV-939, ameliorated BLM-meditated PF in vivo and relieved EMT in vivo and in vitro. These pathways are interconnected by the GSK-3β phosphorylation status. Our findings indicated that during PF progression, DEC1 played a key role in EMT via the PI3K/AKT/GSK-3β/β-catenin integrated signaling pathway. Consequently, targeting DEC1 may be a potential novel therapeutic approach for IPF.

Despite past extensive studies, the mechanisms underlying pulmonary fibrosis (PF) still remain poorly understood. The aberrantly activated lung myofibroblasts, predominantly emerging through fibroblast-to-myofibroblast differentiation, are considered to be the key cells in PF, resulting in excessive accumulation of extracellular matrix (ECM). Latent transforming growth factor-β (TGFβ) binding protein-2 (LTBP2) has been suggested as playing a critical role in modulating the structural integrity of the ECM. However, its function in PF remains unclear. Here, we demonstrated that lungs originating from different types of patients with PF, including idiopathic PF and rheumatoid arthritis-associated interstitial lung disease, and from mice following bleomycin (BLM)-induced PF were characterized by increased LTBP2 expression in activated lung fibroblasts/myofibroblasts. Moreover, serum LTBP2 was also elevated in patients with COVID-19-related PF. LTBP2 silencing by lentiviral shRNA transfection protected against BLM-induced PF and suppressed fibroblast-to-myofibroblast differentiation in vivo and in vitro. More importantly, LTBP2 overexpression was able to induce differentiation of lung fibroblasts to myofibroblasts in vitro, even in the absence of TGFβ1. By further mechanistic analysis, we demonstrated that LTBP2 silencing prevented fibroblast-to-myofibroblast differentiation and subsequent PF by suppressing the phosphorylation and nuclear translocation of NF-κB signaling. LTBP2 overexpression-induced fibroblast-to-myofibroblast differentiation depended on the activation of NF-κB signaling in vitro. Therefore, our data indicate that intervention to silence LTBP2 may represent a promising therapy for PF.

The balance between M1 and M2 macrophage polarization is involved in the regulation of pulmonary inflammation. Nuclear factor erythroid-derived 2-like 2 (Nfe2l2, also known as Nrf2), a nuclear transcription factor, is reported to play protective roles in acute lung injury (ALI) and inflammation, and increasing evidence indicates that the protective effects of Nrf2 are closely related to autophagy. This study aimed to explore whether Nrf2 is involved in sepsis-induced acute pulmonary injury and inflammation and in the role of macrophage polarization in the process. In the present study, sepsis patients, an Nrf2 knockout mouse that underwent cecal ligation and puncture (CLP), and lipopolysaccharide (LPS)-treated macrophage cell lines were employed to investigate the potential functions of Nrf2 in sepsis-induced lung injury and the underlying mechanisms. Clinical studies showed that the NRF2 mRNA level was inversely correlated with pulmonary inflammation and disease severity in patients with sepsis. Analyses in a CLP-treated Nrf2 knockout mouse model indicated that an Nrf2 deficiency promoted a CLP-induced increase in M1 macrophage polarization and apoptosis and inhibited CLP-induced upregulation of the autophagy level in lung tissues. Experiments in RAW264.7 cells revealed that Nrf2 overexpression inhibited M1 macrophage polarization but promoted M2 macrophage polarization by improving the autophagy, and Nrf2 overexpression promoted PPARγ but inhibited NF-κB nuclear translocation. In conclusion, these results indicate that Nrf2 plays a protective role in sepsis-induced pulmonary injury and inflammation through the regulation of autophagy- and NF-κB/PPARγ-mediated macrophage polarization.