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Abstract Cone‐beam computed tomography (CBCT) system can provide real‐time 3D images and fluoroscopy images of the region of interest during the operation. Some systems can even offer augmented fluoroscopy and puncture guidance. The use of CBCT for interventional pulmonary procedures has grown significantly in recent years, and numerous clinical studies have confirmed the technology's efficacy and safety in the diagnosis, localization, and treatment of pulmonary nodules. In order to optimize and standardize the technical specifications of CBCT and guide its application in clinical practice, the consensus statement has been organized and written in a collaborative effort by the Professional Committee on Interventional Pulmonology of China Association for Promotion of Health Science and Technology.

Cinnamides are common core structures that exist in a great number of pharmaceuticals and natural products. The development of efficient methods for preparing cinnamides is in great need. We report herein an efficient polyphosphoric acid (PPA)-promoted direct aldol condensation of an amide for the convenient and straightforward preparation of cinnamides. A variety of cinnamides were obtained in moderate-to-excellent yields (65–89%). This strategy features the use of equivalent amides and a short reaction time.

Abstract Background Macrophage migration inhibitory factor (MIF) and GTPase dynamin-related protein 1 (Drp1)-dependent aberrant mitochondrial fission are closely linked to the pathogenesis of asthma. However, it is unclear whether Drp1-mediated mitochondrial fission and its downstream targets mediate MIF-induced proliferation of airway smooth muscle cells (ASMCs) in vitro and airway remodeling in chronic asthma models. The present study aims to clarify these issues. Methods In this study, primary cultured ASMCs and ovalbumin (OVA)-induced asthmatic rats were applied. Cell proliferation was detected by CCK-8 and EdU assays. Western blotting was used to detect extracellular signal-regulated kinase (ERK) 1/2, Drp1, autophagy-related markers and E-cadherin protein phosphorylation and expression. Inflammatory cytokines production, airway reactivity test, histological staining and immunohistochemical staining were conducted to evaluate the development of asthma. Transmission electron microscopy was used to observe the mitochondrial ultrastructure. Results In primary cultured ASMCs, MIF increased the phosphorylation level of Drp1 at the Ser616 site through activation of the ERK1/2 signaling pathway, which further activated autophagy and reduced E-cadherin expression, ultimately leading to ASMCs proliferation. In OVA-induced asthmatic rats, MIF inhibitor 4-iodo-6-phenylpyrimidine (4-IPP) treatment, suppression of mitochondrial fission by Mdivi-1 or inhibiting autophagy with chloroquine phosphate (CQ) all attenuated the development of airway remodeling. Conclusions The present study provides novel insights that MIF promotes airway remodeling in asthma by activating autophagy and degradation of E-cadherin via ERK/Drp1 signaling pathway, suggesting that targeting MIF/ERK/Drp1 might have potential therapeutic value for the prevention and treatment of asthma.

Abstract Anaplastic lymphoma kinase (ALK) rearrangements are present in about 5–6% of non-small cell lung cancer (NSCLC) cases and associated with increased risks of central nervous system (CNS) involvement. Envonalkib, a novel ALK inhibitor, demonstrated promising anti-tumor activity and safety in advanced ALK-positive NSCLC in the first-in-human phase I study. This phase III trial (ClinicalTrials.gov NCT04009317) investigated the efficacy and safety of first-line envonalkib in advanced ALK-positive NSCLC cases. Totally 264 participants were randomized 1:1 to receive envonalkib (n = 131) or crizotinib (n = 133). Median independent review committee (IRC)-assessed progression-free survival (PFS) times were 24.87 (95% confidence interval [CI]: 15.64–30.36) and 11.60 (95% CI: 8.28–13.73) months in the envonalkib and crizotinib groups, respectively (hazard ratio [HR] = 0.47, 95% CI: 0.34–0.64, p

Background: Ischemic heart disease (IHD) is the leading cause of death worldwide. High fasting plasma glucose (FPG) is an increasing risk factor for IHD. We aimed to explore the long-term trends of high FPG-attributed IHD mortality during 1990–2019. Methods: Data were obtained from the Global Burden of Disease Study 2019 database. Deaths, disability-adjusted life-years (DALYs), the age-standardized mortality rate (ASMR) and age-standardized DALY rate (ASDR) of IHD attributable to high FPG were estimated by sex, socio-demographic index (SDI), regions and age. Estimated annual percentage changes (EAPCs) were calculated to assess the trends of ASMR and ASDR of IHD attributable to high FPG. Results: IHD attributable to high FPG deaths increased from 1.04 million (0.62–1.63) in 1990 to 2.35 million (1.4–3.7) in 2019, and the corresponding DALYs rose from 19.82 million (12.68–29.4) to 43.3 million (27.8–64.2). In 2019, ASMR and ASDR of IHD burden attributable to high FPG were 30.45 (17.09–49.03) and 534.8 (340.7–792.2), respectively. The highest ASMR and ASDR of IHD attributable to high FPG occurred in low-middle SDI quintiles, with 39.28 (22.40–62.76) and 742.3 (461.5–1117.5), respectively, followed by low SDI quintiles and middle SDI quintiles. Males had higher ASMR and ASDR compared to females across the past 30 years. In addition, ASRs of DALYs and deaths were highest in those over 95 years old. Conclusion: High FPG-attributed IHD mortality and DALYs have increased dramatically and globally, particularly in low, low-middle SDI quintiles and among the elderly. High FPG remains a great concern on the global burden of IHD and effective prevention and interventions are urgently needed to curb the ranking IHD burden, especially in lower SDI regions.

Abstract Background HMGB1 and ER stress have been considered to participate in the progression of pulmonary artery hypertension (PAH). However, the molecular mechanism underlying HMGB1 and ER stress in PAH remains unclear. This study aims to explore whether HMGB1 induces pulmonary artery smooth muscle cells (PASMCs) functions and pulmonary artery remodeling through ER stress activation. Methods Primary cultured PASMCs and monocrotaline (MCT)-induced PAH rats were applied in this study. Cell proliferation and migration were determined by CCK-8, EdU and transwell assay. Western blotting was conducted to detect the protein levels of protein kinase RNA-like endoplasmic reticulum kinase (PERK), activating transcription factor-4 (ATF4), seven in absentia homolog 2 (SIAH2) and homeodomain interacting protein kinase 2 (HIPK2). Hemodynamic measurements, immunohistochemistry staining, hematoxylin and eosin staining were used to evaluate the development of PAH. The ultrastructure of ER was observed by transmission electron microscopy. Results In primary cultured PASMCs, HMGB1 reduced HIPK2 expression through upregulation of ER stress-related proteins (PERK and ATF4) and subsequently increased SIAH2 expression, which ultimately led to PASMC proliferation and migration. In MCT-induced PAH rats, interfering with HMGB1 by glycyrrhizin, suppression of ER stress by 4-phenylbutyric acid or targeting SIAH2 by vitamin K3 attenuated the development of PAH. Additionally, tetramethylpyrazine (TMP), as a component of traditional Chinese herbal medicine, reversed hemodynamic deterioration and vascular remodeling by targeting PERK/ATF4/SIAH2/HIPK2 axis. Conclusions The present study provides a novel insight to understand the pathogenesis of PAH and suggests that targeting HMGB1/PERK/ATF4/SIAH2/HIPK2 cascade might have potential therapeutic value for the prevention and treatment of PAH.

Objective This study aimed to analyse the burden and temporal trends of tuberculosis (TB) incidence and mortality globally, as well as the association between mortality-to-incidence ratio (MIR) and Socio-Demographic Index (SDI).Design A retrospective analysis of TB data from 1990 to 2019 was conducted using the Global Burden of Disease Study database.Results Between 1990 and 2019, there was a declining trend in the global incidence and mortality of TB. High SDI regions experienced a higher declining rate than in low SDI regions during the same period. Nearly half of the new patients occurred in South Asia. In addition, there is a sex–age imbalance in the overall burden of TB, with young males having higher incidence and mortality than females. In terms of the three subtypes of TB, drug-sensitive (DS)-TB accounted for more than 90% of the incidents and deaths and experienced a decline over the past 30 years. However, drug-resistant TB (multidrug-resistant (MDR)-TB and extensively drug-resistant (XDR)-TB) showed an overall increasing trend in age-standardised incidence rates and age-standardised mortality rates, with an inflection point after the year 2000. At the regional level, South Asia and Eastern Europe remained a high burden of drug-resistant TB incidence and mortality. Interestingly, a negative correlation was found between the MIR and SDI for TB, including DS-TB, MDR-TB and XDR-TB. Notably, central sub-Saharan Africa had the highest MIR, which indicated a higher-than-expected burden given its level of sociodemographic development.Conclusion This study provides comprehensive insights into the global burden and temporal trends of TB incidence and mortality, as well as the relationship between MIR and SDI. These findings contribute to our understanding of TB epidemiology and can inform public health strategies for prevention and management.

Background Staphylococcus aureus is one of the most important foodborne pathogens in the world and the main cause of dairy cow mastitis. Few studies have investigated the epidemic pedigree of S. aureus of bovine origin in Hunan, China. Therefore, we aimed to analyze the capsular polysaccharides (CP), molecular typing, and antibiotic resistance characteristics of S. aureus isolated from raw milk of dairy farms in Hunan Province. Methods Between 2018 and 2022, 681 raw milk samples were collected from dairy cows from farms in Changsha, Changde, Shaoyang, Yongzhou, and Chenzhou in Hunan Province. S. aureus was isolated from these samples, and the isolates were subjected to molecular typing, CP typing, and determination of antibiotic resistance through broth dilution and polymerase chain reaction (PCR). Results From 681 raw milk samples, 76 strains of S. aureus were isolated. The pathogenicity of 76 isolates was determined preliminarily by detecting cp5 and cp8 CP genes. Eighteen types of antimicrobial resistance phenotypes of 76 S. aureus strains were detected by the broth dilution method, and 11 kinds of related resistance genes were amplified by PCR. The S. aureus isolates had CP5 (42.10%) and CP8 (57.89%). S. aureus had a multiple antimicrobial resistance rate of 26.75%. The isolated strains had the highest resistance rate to penicillin (82.89%) and showed varying degrees of resistance to other drugs, but no isolate showed resistance to doxycycline. The 76 isolates all carried two or more antibiotic resistance genes, with a maximum of eight antibiotics resistance genes. FemB was detected in all isolates, but none of isolates carried vanA, ermA, or glrA. The 76 isolates were divided into 22 sequence types (ST) and 20 spa types by MLST and spa typing, and the number of t796-ST7 (n = 15) isolates was the highest, which may be the major epidemic strain of multidrug-resistant S. aureus. Conclusion The present findings indicate the need to increase production of the CP8 S. aureus vaccine in Hunan Province and strengthen resistance monitoring of t796-ST7 isolates with the prevalent molecular type of multi-drug resistant strains. The use of β-lactam, macrolides, and lincosamides should be reduced; doxycycline, sulfonamides, and glycopeptides could be appropriately added to veterinary antibiotics to treat infectious diseases in dairy cows.

Abstract Background Constipation has been hypothesized to be associated with the increased risk of wheezing or asthma. However, the relation remains a subject of debate. We conducted this meta-analysis to assess whether constipation influences the risk of wheezing/asthma. Methods PubMed, Embase, and Web of Science were systematically searched for studies published between 1955 and January 2022. Two reviewers independently extracted data and assessed the quality of each study. Results were pooled using fixed-effects models or random-effects models as appropriate. Results In total, 3 original articles with 178,661 participants, which met the criteria, were included in this meta-analysis. Constipation was associated with an increased risk of wheezing/asthma in later life (RR = 2.02, 95% CI = 1.24–3.29, P

Background: It has been demonstrated that elevated telomerase reverse transcriptase (TERT) expression or activity is implicated in pulmonary hypertension (PH). In addition, activation of peroxisome-proliferator-activated receptor γ (PPAR-γ) has been found to prevent PH progression. However, the molecular mechanism responsible for the protective effect of PPAR-γ activation on TERT expression in the pathogenesis of PH remains unknown. This study was performed to address these issues. Methods: Intraperitoneal injection of monocrotaline (MCT) was used to establish PH. BIBR1532 was applied to inhibit the activity of telomerase. The right ventricular systolic pressure (RVSP) and histological analysis were used to detect the development of PH. The protein levels of p-Akt, t-Akt, c-Myc and TERT were determined by western blotting. Pharmacological inhibition of TERT by BIBR1532 effectively suppressed RVSP, RVHI and the WT% in MCT-induced PH rats. Results: Pharmacological inhibition of Akt/c-Myc pathway by LY294002 diminished TERT upregulation, RVSP, RVHI and WT% in MCT-PH rats. Activation of PPAR-γ by pioglitazone inhibited p-Akt and c-Myc expressions and further downregulated TERT, thus to reduced RVSP, RVHI and WT% in MCT-treated PH rats. Conclusions: In conclusion, TERT upregulation contributes to PH development in MCT-treated rats. Activation of PPAR-γ prevents pulmonary arterial remodeling through Akt/c-Myc/TERT axis suppression.

ObjectiveThis study aimed to analyze the correlation between quantitative computed tomography (CT) parameters and airflow obstruction in patients with COPD.MethodsPubMed, Embase, Cochrane and Web of Knowledge were searched by two investigators from inception to July 2022, using a combination of pertinent items to discover articles that investigated the relationship between CT measurements and lung function parameters in patients with COPD. Five reviewers independently extracted data, and evaluated it for quality and bias. The correlation coefficient was calculated, and heterogeneity was explored. The following CT measurements were extracted: percentage of lung attenuation area

Pulmonary arterial hypertension is a devastating pulmonary vascular disease, in which the pathogenesis is complicated and unclear. Pulmonary arterial smooth muscle cells (PASMCs) proliferation is a key pathological feature of pulmonary arterial hypertension. It has been shown that ubiquitin‐specific protease 7 (USP7) is involved in cancer cell proliferation via deubiquitinating and stabilizing E3 ubiquitin ligase mouse double minute 2 (MDM2). However, the effect of USP7 and MDM2 on platelet‐derived growth factor (PDGF)‐induced PASMCs proliferation is uncertain. This study aims to explore this issue. Our results indicated that PDGF up‐regulated USP7 protein expression and stimulated PASMCs proliferation; this was accompanied with the increase of MDM2, forkhead box O4 (FoxO4) reduction and elevation of CyclinD1. While prior transfection of USP7 siRNA blocked PDGF‐induced MDM2 up‐regulation, FoxO4 down‐regulation, increase of CyclinD1 and cell proliferation. Pre‐depletion of MDM2 by siRNA transfection reversed PDGF‐induced reduction of FoxO4, up‐regulation of CyclinD1 and PASMCs proliferation. Furthermore, pre‐treatment of cells with proteasome inhibitor MG‐132 also abolished PDGF‐induced FoxO4 reduction, CyclinD1 elevation and cell proliferation. Our study suggests that USP7 up‐regulates MDM2, which facilitates FoxO4 ubiquitinated degradation, and subsequently increases the expression of CyclinD1 to mediate PDGF‐induced PASMCs proliferation.

Abstract Background Previous studies have demonstrated the preclinical pharmacological and toxicological consistency, and clinical pharmacokinetic equivalence of bevacizumab biosimilar LY01008 with reference bevacizumab (Avastin). This randomized controlled trial aimed to compare the efficacy and safety of LY01008 with Avastin in first‐line treatment of Chinese patients with advanced or recurrent non‐squamous non‐small cell lung cancer (NSCLC). Methods Stage IIIB‐IV NSCLC patients with evaluable lesions, good physical status, and adequate organ functions from 67 centers across China were randomized in a ratio of 1:1 to receive LY01008 or Avastin 15 mg/kg intravenously in combination with paclitaxel/carboplatin (combined treatment) for 4‐6 cycles, followed by maintenance monotherapy with LY01008 until disease progression, intolerable toxicity, or death. The primary endpoint was objective response rate (ORR) in accordance with Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 confirmed by independent radiological review committees (IRRC). Secondary endpoints included disease control rate (DCR), duration of response (DoR), progression‐free survival (PFS), overall survival (OS), and safety. This study was registered in ClinicalTrials.gov (NCT03533127). Results Between December 15th, 2017, and May 15th, 2019, a total of 649 patients were randomized to the LY01008 (n = 324) or Avastin (n = 325) group. As of September 25th, 2019 for primary endpoint analysis, 589 patients received ORR evaluation, with a median number of combined treatment cycles of 5 (range 1‐6) and median duration of treatment of 3.0 (range 0.0‐5.1) months. ORR of response‐evaluable patients in the LY01008 and Avastin groups were 48.5% and 53.0%, respectively. The stratified ORR ratio was 0.91 (90% CI 0.80‐1.04, within the prespecified equivalence margin of 0.75‐1.33). Up to May 15th, 2020, with a median follow‐up of 13.6 (range 0.8‐28.4) months, no notable differences in DCR, median DoR, median PFS, median OS, and 1‐year OS rate were observed between the LY01008 and Avastin groups. There were no clinically meaningful differences in safety and immunogenicity across treatment groups. Conclusions LY01008 demonstrated similarity to Avastin in terms of efficacy and safety in Chinese patients with advanced or recurrent non‐squamous NSCLC. LY01008 combined with paclitaxel/carboplatin is expected to become a new treatment option for unresectable, metastatic, or recurrent non‐squamous NSCLC patients in the first‐line setting.

BackgroundDurvalumab, as a PD-L1 inhibitor, is commonly used for the treatment of various cancers. Adverse events associated with the therapy include hepatitis, nephritis, dermatitis, and myocarditis. Especially, myocarditis as an adverse event after PD-L1 inhibitor therapy is characterized for its low incidence and high mortality.Case SummaryHere we present a rare case of a 67-year-old male with lung squamous cell carcinoma complicated with empyema who experienced myocarditis after only PD-L1 inhibitor durvalumab monotherapy. He presented with markedly decrease left ventricular ejection fraction, elevated Natriuretic peptide BNP, Troponin T, Troponin I, ESR, CRP and interleukin-6. The electrocardiogram showed sinus tachycardia, low voltage of limb leads, T wave inversion in anterior waves and V1-V3 QS type. Myocardial injury occurred in a short period and quickly returned to normal after glucocorticoids therapy.ConclusionThis case report is of clinical value for the treatment of PD-L1 related myocarditis.

BackgroundImmune checkpoint inhibitors (ICIs) induce durable responses, but only a minority of patients achieve clinical benefits. The development of gene expression profiling of tumor transcriptomes has enabled identifying prognostic gene expression signatures and patient selection with targeted therapies.MethodsImmune exclusion score (IES) was built by elastic net-penalized Cox proportional hazards (PHs) model in the discovery cohort and validated via four independent cohorts. The survival differences between the two groups were compared using Kaplan-Meier analysis. Both GO and KEGG analyses were performed for functional annotation. CIBERSORTx was also performed to estimate the relative proportion of immune-cell types.ResultsA fifteen-genes immune exclusion score (IES) was developed in the discovery cohort of 65 patients treated with anti-PD-(L)1 therapy. The ROC efficiencies of 1- and 3- year prognosis were 0.842 and 0.82, respectively. Patients with low IES showed a longer PFS (p=0.003) and better response rate (ORR: 43.8% vs 18.2%, p=0.03). We found that patients with low IES enriched with high expression of immune eliminated cell genes, such as CD8+ T cells, CD4+ T cells, NK cells and B cells. IES was positively correlated with other immune exclusion signatures. Furthermore, IES was successfully validated in four independent cohorts (Riaz’s SKCM, Liu’s SKCM, Nathanson’s SKCM and Braun’s ccRCC, n = 367). IES was also negatively correlated with T cell–inflamed signature and independent of TMB.ConclusionsThis novel IES model encompassing immune-related biomarkers might serve as a promising tool for the prognostic prediction of immunotherapy.

Abstract Background In recent years, many studies have discovered that cystatin C (Cys C) may play an important role in respiratory diseases, especially in chronic obstructive pulmonary disease (COPD). However, the findings of these studies were inconsistent. This systematic review and meta-analysis aimed to assess the relationship between serum Cys C and COPD. Methods We conducted a systematic literature search in PubMed, Embase, Web of Science, Wanfang databases, and the China National Knowledge Infrastructure. The standardized mean difference (SMD), Fisher’s Z-value and 95% confidence interval (CI) were calculated to investigate the effect sizes. Subgroup analyses were performed on disease status, ethnicity, assay method, and study design. Sensitivity was performed, and publication bias was assessed. Results A total of 15 studies, including 4079 COPD patients and 5949 controls, were included in this meta-analysis. The results showed that serum Cys C levels in patients with COPD were significantly higher than those in controls (SMD = 0.99, 95% CI =0.62–1.37, P

Background. Chronic obstructive pulmonary disease (COPD) is a common chronic disease. Progression is further exacerbated by the coexistence of cardiovascular disease (CVD). We aim to construct a diagnostic nomogram for predicting the risk of coexisting CVD and a prognostic nomogram for predicting long-term survival in COPD. Methods. The 540 eligible participants selected from the NHANES 2005–2010 were included in this study. Logistic regression analysis was used to construct a diagnostic nomogram for the diagnosis of coexisting CVD in COPD. Cox regression analyses were used to construct a prognostic nomogram for COPD. A risk stratification system was developed based on the total score generated from the prognostic nomogram. We used C-index and ROC curves to evaluate the discriminant ability of the newly built nomograms. The models were also validated utilizing calibration curves. Survival curves were made using the Kaplan–Meier method and compared by the Log-rank test. Results. Logistic regression analysis showed that gender, age, neutrophil, RDW, LDH, and HbA1c were independent predictors of coexisting CVD and were included in the diagnostic model. Cox regression analysis indicated that CVD, gender, age, BMI, RDW, albumin, LDH, creatinine, and NLR were independent predictors of COPD prognosis and were incorporated into the prognostic model. The C-index and ROC curves revealed the good discrimination abilities of the models. And the calibration curves implied that the predicted values by the nomograms were in good agreement with the actual observed values. In addition, we found that coexisting with CVD had a worse prognosis compared to those without CVD, and the prognosis of the low-risk group was better than that of the high-risk group in COPD. Conclusions. The nomograms we developed can help clinicians and patients to identify COPD coexisting CVD early and predict the 5-year and 10-year survival rates of COPD patients, which has some clinical practical values.

Objective The long intergenic non-coding RNA 01296 (LINC01296) has been reported to be overexpressed in multiple tumours. However, the role of LINC01296 in clinicopathologic and prognostic value in cancers remains completely unknown. The aim of the present meta-analysis was to comprehensively elucidate the correlation between LINC01296 with clinicopathological features and survival outcomes in tumours.Methods Electronic databases of PubMed, Web of Science, Chinese National Knowledge Infrastructure (CNKI), and Wanfang Database were used to search relevant studies. The role of LINC01296 in cancers was evaluated by pooled hazard ratios (HRs), odds ratios (ORs) and 95% confidence intervals (CIs).Results In total, nine studies compromising 720 participants were enrolled in this analysis. The pooled results showed increased LINC01296 expression could predict unfavourable overall survival (OS) (HR = 1.89, 95%CI = 1.47–2.43, p

Objective Early life bronchiolitis has been hypothesised to be associated with the subsequent risk of persistent wheezing or asthma. However, the link remains controversial. The objective of our study was to evaluate the association between bronchiolitis before 2 years of age and the late-onset wheezing/asthma.Design Systematic review and meta-analysis.Methods PubMed, Embase and Web of Science databases were systematically searched for studies published between 1955 and January 2020. Meanwhile, we also checked through the reference lists of relevant articles to see whether these references included reports of other studies that might be eligible for the review. Cohort and case–control studies assessing the association between early-life bronchiolitis and late-onset wheezing/asthma were included in this meta-analysis. Data were extracted by two independent reviewers. Results were pooled using a random-effects model or fixed-effects model according to the heterogeneity among studies.Results 32 original articles with 292 844 participants, which met the criteria, were included in this meta-analysis. Bronchiolitis before 2 years of age was associated with an increased risk of subsequent wheezing/asthma (relative risk=2.46, 95% CI 2.14 to 2.82, p

BackgroundMetagenomic next-generation sequencing (mNGS) is a powerful method for pathogen detection. In this study, we assessed the value of mNGS for bronchoalveolar lavage (BAL) samples in the diagnosis of pulmonary infections.MethodsFrom February 2018 to April 2019, BAL samples were collected from 235 patients with suspected pulmonary infections. mNGS and microbial culture were performed to evaluate the effectiveness of mNGS in pulmonary infection diagnosis.ResultsWe employed mNGS to evaluate the alpha diversity, results suggesting that patients with confirmed pathogens had a lower microbial diversity index compared to that of patients with uncertain pathogens. For the patients admitted to the respiratory intensive care unit (RICU) or on a ventilator, they experienced a lower diversity index than that of the patients in the general ward or not on a ventilator. In addition, mNGS of BAL had a diagnostic sensitivity of 88.89% and a specificity of 14.86% in pulmonary infection, with 21.16% positive predictive value (PPV) and 83.87% negative predictive value (NPV). When rare pathogens were excluded, the sensitivity of mNGS decreased to 73.33%, and the specificity increased to 41.71%. For patients in the simple pulmonary infection group and the immunocompromised group, the main infection types were bacterial infection (58.33%) and mixed-infection (43.18%). Furthermore, mNGS had an advantage over culture in describing polymicrobial ecosystem, demonstrating the microbial distribution and the dominant strains of the respiratory tract in patients with different underlying diseases.ConclusionsThe study indicated that mNGS of BAL samples could provide more accurate diagnostic information in pulmonary infections and demonstrate the changes of respiratory microbiome in different underlying diseases. This method might play an important role in the clinical use of antimicrobial agents in the future.

Background/Aims: The underlying molecular mechanisms involved in sphingosine kinase 1 (SphK1)/sphingosine 1-phosphate (S1P) mediation of platelet-derived growth factor (PDGF)-induced pulmonary arterial smooth muscle cell (PASMC) proliferation are still unclear, and the present study aims to address this issue. Methods: Small interfering RNA (siRNA) and microRNA inhibitor transfection was performed to block the expression of SphK1, bone morphogenetic protein receptor II (BMPRII) and microRNA-21 (miR-21). Gene expression levels of SphK1, BMPRII and inhibitor of DNA binding 1 (Id1) were detected by immunoblotting, miR-21 expression level was examined with qRT-PCR, and S1P production was measured by ELISA. Additionally, PASMC proliferation was determined by BrdU incorporation assay. Results: Our results indicated that PDGF increased the expression of SphK1 protein and S1P production, up-regulated miR-21 expression, reduced BMPRII and Id1 expression, and promoted PASMCs proliferation. Pre-silencing of SphK1 with siRNA reversed PDGF-induced S1P production, miR-21 up-regulation, BMPRII and Id1 down-regulation, as well as PASMC proliferation. Pre-inhibition of miR-21 also blocked BMPRII and Id1 down-regulation as well as PASMC proliferation caused by PDGF. Knockdown of BMPRII down-regulated Id1 expression in PASMCs. We further found that inhibition of PI3K/Akt and ERK signaling pathways, particularly ERK cascade, suppressed PDGF-induced above changes. Conclusion: Our study indicates that SphK1/S1P pathway plays an important role in PDGF-induced PASMC proliferation via miR-21/BMPRII/Id1 axis and targeting against SphK1/S1P axis might be a novel strategy in the prevention and treatment of pulmonary arterial hypertension (PAH).

Abstract Background Previous studies have indicated that chitinase 3-like 1 (CHI3L1) gene rs4950928 polymorphism and acidic mammalian chitinase (AMCase or CHIA) gene rs10494132 polymorphism are associated with the risk of asthma. However, the results are inconsistent because of small sample size and varied ethnicity and age in studies. Therefore, a systematic meta-analysis was important to clarify the effect of CHI3L1 rs4950928 polymorphism and CHIA rs10494132 variant on asthma risk. Methods An electronic literature search was conducted to identify all the eligible studies. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated and sensitivity analysis as well as publication bias were assessed to investigate the associations. All statistical analyses were performed using STATA 12.0. Results Eight published articles with 10 case-control studies were included, 5 studies were of CHI3L1 rs4950928 polymorphism and another 5 studies involved CHIA rs10494132 polymorphism. Overall, no significant association was found between CHI3L1 polymorphism and asthma susceptibility. After stratified according to ethnicity, CHI3L1 rs4950928 variant was associated with decreased asthma risk in Caucasians (GG + GC vs. CC: OR = 0.621, 95% CI = 0.484–0.797, P = 0.000; GC vs. CC: OR = 0.612, 95% CI = 0.470–0.796, P = 0.000; G vs. C: OR = 0.696, 95% CI = 0.567–0.856, P = 0.001). When stratified population by age, there was no association in children under all genetic models. As for CHIA rs10494132 polymorphism, no evidence of association between CHIA rs10494132 polymorphism and asthma risk was identified. Furthermore, subgroup analysis by ethnicity revealed a positive correlation between CHIA rs10494132 polymorphism and asthma risk among Asians (TT vs. TC + CC: OR = 1.476, 95% CI = 1.071–2.032, P = 0.017; T vs. C: OR = 1.326, 95% CI = 1.024–1.717, P = 0.032). Additionally, in the subgroup analysis conducted according to age, CHIA rs10494132 variant was also found to be associated with the increased risk of asthma in children (TT vs. TC + CC: OR = 1.472, 95% CI = 1.067–2.030, P = 0.019; T vs. C: OR = 1.320, 95% CI = 1.016–1.713, P = 0.037). Conclusions The G allele of CHI3L1 rs4950928 might be a protective factor against the development of asthma. However, the rs10494132 polymorphism of CHIA might be a risk factor for asthma.

Abstract The up-regulation of transient receptor potential channel 6 (TRPC6) has been found to contribute to the proliferation of pulmonary artery smooth muscle cells (PASMCs), and inhibition of phosphodiesterase-5 (PDE5) has been shown to suppress TRPC6 expression in PASMCs. However, the molecular mechanisms underlying the up-regulation of TRPC6 expression and PDE5 modulation of TRPC6 expression in PASMCs remain largely unclear. The aim of this study is to address these issues. Endothelin-1 (ET-1) dose and time-dependently up-regulated TRPC6 expression in primary cultured rat PASMCs, and this was accompanied with the activation of calcineurin and subsequent translocation of NFATc4 to the nucleus. Further study indicated that inhibition of calcineurin by cyclosporine A or knockdown of NFATc4 using small interfering RNA suppressed ET-1-induced TRPC6 up-regulation. In addition, luciferase reporter assay showed that NFATc4 directly regulated the expression of TRPC6 in PASMCs. Inhibition of PDE5 by sildenafil suppressed ET-1-induced activation of calcineurin/NFATc4 signaling pathway and consequent TRPC6 up-regulation in PASMCs, while these inhibitory effects of sildenafil were abolished by PKG inhibitor Rp-8Br-cGMPs. Taken together, our study indicates that ET-1 stimulates TRPC6 expression by activation of calcineurin/NFATc4 signaling pathway, and inhibition of PDE5 suppresses calcineurin/NFATc4- mediated TRPC6 expression in PASMCs in a cGMP-PKG-dependent manner.

Ventilator-associated pneumonia (VAP) is one of the most prevalent and serious complications of mechanical ventilation, which is considered a common nosocomial infection in critically ill patients. There are some great options for the prevention of VAP: (i) minimize ventilator exposure; (ii) intensive oral care; (iii) aspiration of subglottic secretions; (iv) maintain optimal positioning and encourage mobility; and (v) prophylactic probiotics. Furthermore, clinical management of VAP depends on appropriate antimicrobial therapy, which needs to be selected based on individual patient factors, such as previous antibacterial therapy, history of hospitalization or mechanical ventilation, and bacterial pathogens and antibiotic resistance patterns. In fact, antibiotic resistance has exponentially increased over the last decade, and the isolation of a multidrug-resistant (MDR) pathogen has been identified as an independent predictor of inadequate initial antibiotic therapy and which is significantly associated with increased mortality. Multiple attempts were used in the treatment of VAP, such as novel antibacterial agents, inhaled antibiotics and monoclonal antibodies. In this review, we summarize the current therapeutic options for the prevention and treatment of VAP, aiming to better management of VAP in clinical practice.

Objective. The purpose of this study was to compare matrix metalloproteinase-12 (MMP-12), neutrophil elastase (NE), and tissue inhibitor of metalloproteinase-4 (TIMP-4) in peripheral blood of patients with chronic obstructive pulmonary disease (COPD) and controls. At the same time, MMP-12, NE, and TIMP-4 in exhaled breath condensate (EBC) were also evaluated. Methods. Peripheral blood and EBC samples from COPD patients and healthy controls were collected. In serum and EBC, MMP-12, NE, and TIMP-4 proteins were detected by enzyme-linked immunoassays. The mRNA expression levels of MMP-12, NE, and TIMP-4 in peripheral blood mononuclear cells (PBMCs) were analyzed by quantitative real-time polymerase chain reaction (qRT-PCR). Results. The concentration of TIMP-4 protein in EBC was lower in patients with COPD (P

The upregulation of Sphingosine kinase 1 (SphK1) expression and accompanied sphingosine-1-phosphate (S1P) production have been reported to contribute to the proliferation of pulmonary artery smooth muscle cells (PASMC) and pulmonary arterial remodeling. However, the molecular mechanisms of SphK1/S1P upregulation in PASMC and the specific mechanisms of how SphK1/S1P pathway promotes PASMC proliferation remain largely unclear. This study aims to address these issues. Here, we demonstrated that TGF-β1 significantly upregulated SphK1 expression and S1P production by promoting the phosphorylation of Smad2/3 in PASMC. Further study indicated that SphK1/S1P pathway mediated TGF-β1-induced Notch3 activation in PASMC. In addition, we showed that TGF-β1 significantly induced proliferation of PASMC, while pre-inhibition of Smad2/3 phosphorylation with SB431542 or silencing SphK1 using small interfering RNA in advance, or pre-blocking Notch3 pathway with N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (DAPT), attenuated TGF-β1-induced PASMC proliferation. Taken together, our study indicates that Smad2/3/SphK1/S1P/Notch3 pathway mediates TGF-β1-induced PASMC proliferation and suggests this pathway as a potential therapeutic target in the prevention and treatment of pulmonary hypertension.

Activation of the Notch3 cascade is involved in the development of pulmonary arterial hypertension by stimulating the proliferation of vascular smooth muscle cells. However, the detailed molecular mechanisms underlying this effect are still unclear. The present study aims to address this issue. We demonstrated that over‐expression of intracellular domain of the Notch3 receptor (NICD3) by adenovirus transfection dramatically induced proliferation of primary cultured pulmonary artery smooth muscle cells. This was accompanied with up‐regulation of Hes1 protein and down‐regulation of p27Kip1 protein. More importantly, we observed that prior silencing of Hes1 with siRNA blocked NICD3 over‐expression‐induced p27Kip1 reduction and cell proliferation. The present study suggests that Hes1 lies downstream of NICD3 and particularly mediates Notch3 signaling‐induced proliferation of pulmonary arterial smooth muscle cells by down‐regulation of p27Kip1 expression.

Chronic obstructive pulmonary disease (COPD) is characterized by intense lung infiltrations of immune cells (macrophages and monocytes). Lipopolysaccharide (LPS) activates macrophages/monocytes, leading to production of tumor necrosis factor α (TNFα) and other cytokines, which cause subsequent lung damages. In the current study, our results demonstrated that AS-703026, a novel MEK/ERK inhibitor, suppressed LPS-induced TNFα mRNA expression and protein secretion in RAW 264.7 murine macrophages, and in murine bone marrow-derived macrophages (BMDMs). Meanwhile, TNFα production in LPS-stimulated COPD patents' peripheral blood mononuclear cells (PBMCs) was also repressed by AS-703026. At the molecular level, we showed that AS-703026 blocked LPS-induced MEK/ERK activation in above macrophages/monocytes. However, restoring ERK activation in AS-703026-treated RAW 264.7 cells by introducing a constitutive-actively (CA)-ERK1 only partially reinstated LPS-mediated TNFα production. Meanwhile, AS-703026 could still inhibit TNFα response in ERK1/2-depleted (by shRNA) RAW 264.7 cells. Significantly, we found that AS-703026 inhibited LPS-induced nuclear factor κB (NFκB) activation in above macrophages and COPD patients' PBMCs. In vivo, oral administration of AS-703026 inhibited LPS-induced TNFα production and endotoxin shock in BALB/c mice. Together, we show that AS-703026 in vitro inhibits LPS-induced TNFα production in macrophages/monocytes, and in vivo protects mice from LPS-induced endotoxin shock. Thus, it could be further studied as a useful anti-inflammatory therapy for COPD patients.