Publications by authors named "Chunxue Bai"

223 Publications

Association of fine particulate matter air pollution and its constituents with lung function: The China Pulmonary Health study.

Environ Int 2021 Jun 26;156:106707. Epub 2021 Jun 26.

Department of Respiratory and Critical Care Medicine, Beijing Hospital, Beijing, China; National Center of Gerontology, Beijing, China.

The associations of long-term exposure to various constituents of fine particulate matter (≤2.5 μm in aerodynamic diameter, PM) air pollution with lung function were not clearly elucidated in developing countries. The aim was to evaluate the associations of long-term exposure to main constituents of PM with lung function in China. This is a nationwide, cross-sectional analysis among 50,991 study participants from the China Pulmonary Health study. Multivariable linear regression models were used to obtain differences of forced expiratory volume in 1 s (FEV), forced vital capacity (FVC), FEV/FVC, peak expiratory flow (PEF), and forced expiratory flow at 25-75% of exhaled FVC (FEF) associated with an interquartile range (IQR) change of PM or its constituents. Residential annual PM levels varied from 26 μg/m to 92 μg/m (average: 53 μg/m). An IQR increase of PM concentrations was associated with lower FEV (19.82 mL, 95% CI: 11.30-28.33), FVC (17.45 mL, 95% CI: 7.16-27.74), PEF (86.64 mL/s, 95% CI: 59.77-113.52), and FEF (31.93 mL/s, 95% CI: 16.64-47.22). Black carbon, organic matter, ammonium, sulfate, and nitrate were negatively associated with most lung function indicators, with organic matter and nitrate showing consistently larger magnitude of associations than PM mass. This large-scale study provides first-hand epidemiological evidence that long-term exposure to ambient PM and some constituents, especially organic matter and nitrate, were associated with lower large- and small- airway function.
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http://dx.doi.org/10.1016/j.envint.2021.106707DOI Listing
June 2021

Announcing the Editorial Board Fellowship Program of the .

Am J Physiol Lung Cell Mol Physiol 2021 Jul 9;321(1):L116-L118. Epub 2021 Jun 9.

Department of Translational Pulmonology and Translational Lung Research Center Heidelberg, University Hospital Heidelberg, member of the German Center for Lung Research (DZL), Heidelberg, Germany.

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http://dx.doi.org/10.1152/ajplung.00239.2021DOI Listing
July 2021

[Clinical Recommendations for Perioperative Immunotherapy-induced Adverse Events in Patients with Non-small Cell Lung Cancer].

Zhongguo Fei Ai Za Zhi 2021 Mar;24(3):141-160

Department of Thoracic Surgery, Peking University Cancer Hospital, Beijing 100142, China.

Background: Perioperative treatment has become an increasingly important aspect of the management of patients with non-small cell lung cancer (NSCLC). Small-scale clinical studies performed in recent years have shown improvements in the major pathological remission rate after neoadjuvant therapy, suggesting that it will soon become an important part of NSCLC treatment. Nevertheless, neoadjuvant immunotherapy may be accompanied by serious adverse reactions that lead to delay or cancelation of surgery, additional illness, and even death, and have therefore attracted much attention. The purpose of the clinical recommendations is to form a diagnosis and treatment plan suitable for the current domestic medical situation for the immune-related adverse event (irAE).

Methods: This recommendation is composed of experts in thoracic surgery, oncologists, thoracic medicine and irAE related departments (gastroenterology, respirology, cardiology, infectious medicine, hematology, endocrinology, rheumatology, neurology, dermatology, emergency section) to jointly complete the formulation. Experts make full reference to the irAE guidelines, large-scale clinical research data published by thoracic surgery, and the clinical experience of domestic doctors and publicly published cases, and repeated discussions in multiple disciplines to form this recommendation for perioperative irAE.

Results: This clinical recommendation covers the whole process of prevention, evaluation, examination, treatment and monitoring related to irAE, so as to guide the clinical work comprehensively and effectively.

Conclusions: Perioperative irAE management is an important part of immune perioperative treatment of lung cancer. With the continuous development of immune perioperative treatment, more research is needed in the future to optimize the diagnosis and treatment of perioperative irAE.
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http://dx.doi.org/10.3779/j.issn.1009-3419.2021.101.06DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8143963PMC
March 2021

Circulating Genetically Abnormal Cells Add Non-Invasive Diagnosis Value to Discriminate Lung Cancer in Patients With Pulmonary Nodules ≤10 mm.

Front Oncol 2021 11;11:638223. Epub 2021 Mar 11.

Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, Shanghai, China.

Background: Lung cancer screening using low-dose computed tomography (LDCT) often leads to unnecessary biopsy because of the low specificity among patients with pulmonary nodules ≤10 mm. Circulating genetically abnormal cells (CACs) can be used to discriminate lung cancer from benign lung disease. To examine the diagnostic value of CACs in detecting lung cancer for patients with malignant pulmonary nodules ≤10 mm.

Methods: In this prospective study, patients with pulmonary nodules ≤10 mm who were detected at four hospitals in China from January 2019 to January 2020 were included. CACs were detected using fluorescence hybridization. All patients were confirmed as lung cancer or benign disease by further histopathological examination. Multivariable logistic regression models were established to detect the presence of lung cancer using CACs and other associated characteristics. Receiver operating characteristic analysis was used to evaluate the performance of CACs for lung cancer diagnosis.

Results: Overall, 125 patients were included and analyzed. When the cutoff value of CACs was >2, the sensitivity and specificity for lung cancer were 70.5 and 86.4%. Male (OR = 0.330, P = 0.005), maximum solid nodule (OR = 2.362, P = 0.089), maximum nodule located in upper lobe (OR = 3.867, P = 0.001), and CACs >2 (OR = 18.525, P < 0.001) met the P < 0.10 criterion for inclusion in the multivariable models. The multivariable logistic regression model that included the dichotomized CACs (>2 ≤2) and other clinical factors (AUC = 0.907, 95% CI = 0.842-0.951) was superior to the models that only considered dichotomized CACs or other clinical factors and similar to the model with numerical CACs and other clinical factors (AUC = 0.913, 95% CI = 0.850-0.956).

Conclusion: CACs presented a significant diagnostic value in detecting lung cancer for patients with pulmonary nodules ≤10 mm.
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http://dx.doi.org/10.3389/fonc.2021.638223DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7991838PMC
March 2021

Detection of circulating genetically abnormal cells using 4-color fluorescence in situ hybridization for the early detection of lung cancer.

J Cancer Res Clin Oncol 2021 Aug 6;147(8):2397-2405. Epub 2021 Feb 6.

Division of Thoracic Surgery, Zhongshan Hospital, Fudan University, Shanghai, China.

Purpose: Available biomarkers lack sensitivity for an early lung cancer. Circulating genetically abnormal cells (CACs) occur early in tumorigenesis. To determine the diagnostic value of CACs in blood detected by 4-color fluorescence in situ hybridization (FISH) for lung cancer.

Methods: This was a prospective study of patients with pulmonary nodules ≤ 30 mm detected between 10/2019 and 01/2020 at four tertiary hospitals in China. All patients underwent a pathological examination of lung nodules found by imaging and were grouped as malignant and benign. CACs were detected by 4-color FISH. Patients were divided into the training and validation cohorts. Receiver operating characteristics analysis was used to analyze the diagnosis value of CACs.

Results: A total of 205 participants were enrolled. Using a cut-off value of ≥ 3, blood CACs achieved areas under the curve (AUCs) of 0.887, 0.823, and 0.823 for lung cancer in the training and validation cohorts, and all patients, respectively. CACs had high diagnostic values across all tumor sizes and imaging lesion types. CACs were decreased after surgery (median, 4 vs. 1, P < 0.001) in the validation set. The CAC status between blood and tissues was highly consistent (kappa = 0.909, P < 0.001). The AUC of CAC (0.823) was higher than that of CEA (0.478), SCC (0.516), NSE (0.506), ProGRP (0.519), and CYFRA21-1 (0.535) (all P < 0.001).

Conclusion: CACs might have a high value for the early diagnosis of lung cancer. These findings might need to be validated in future studies. Evidence suggested homology in genetic aberrations between the CACs and the tumor cells.
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http://dx.doi.org/10.1007/s00432-021-03517-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8236478PMC
August 2021

A pharmacogenetics study of platinum-based chemotherapy in lung cancer: polymorphism and its genetic interaction with are associated with response and survival.

J Cancer 2021 1;12(5):1270-1283. Epub 2021 Jan 1.

Center for Medical Research and Innovation, Shanghai Pudong Hospital and Pudong Medical Center, Shanghai Medical College, Fudan University, Shanghai, China.

The expression and function of platinum transporters affect drug tissue concentration and therapeutic effects. We had previously characterized functional variant of platinum intake transporter gene. We aimed to investigate the association of platinum efflux transporter gene polymorphism and combined and polymorphisms with clinical outcomes of NSCLC patients receiving platinum-based chemotherapy. We genotyped thirteen tagging and functional SNPs of in 1004 patients, and assessed their association with response, toxicity and survival using unconditional logistic regression and Cox proportional hazards regression analyses respectively. Nonsynonymous rs2231142 (odds ratio [OR] 2.07; 95 % confidence interval [CI] 1.26-3.63), rs1871744 (OR 0.60; 95 % CI 0.42-0.87) and their haplotype and diplotype were associated with objective response. Rs4148157 was associated with shorter overall survival (Log-rank = 0.002; hazard ratio [HR] 1.22; 95 % CI 1.05-1.42). Furthermore, the combined rs2233914 and rs1871744 genotype was significantly associated with poor response (OR 0.31; 95 % CI 0.17-0.56; = 0.003). And the combined genotypes of the functional rs10759637 of and the nonsynonymous rs2231142 (Log-rank = 5.20×10; HR 1.47; 95 % CI 1.19-1.81; = 0.007) or linked rs4148157 of were significantly associated with poor survival. This study reveals divergent association of polymorphism with response and survival of NSCLC patients receiving platinum-based chemotherapy, demonstrates the combined effects of functional variants of and on clinical outcomes, and highlights pharmacogenetic relevance of platinum transporter genes interaction.
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http://dx.doi.org/10.7150/jca.51621DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7847637PMC
January 2021

Phase 1/2 study of ceritinib in Chinese patients with advanced anaplastic lymphoma kinase-rearranged non-small cell lung cancer previously treated with crizotinib: Results from ASCEND-6.

Lung Cancer 2020 12 5;150:240-246. Epub 2020 Nov 5.

Sun Yat-Sen University Cancer Center, Guangzhou, China.

Background: Patients with anaplastic lymphoma kinase-rearranged (ALK+) non-small cell lung cancer (NSCLC) treated with crizotinib inevitably relapse, with brain as common site of progression.

Patients And Methods: ASCEND-6, a phase 1/2, single-arm study, included adult Chinese patients with stage IIIB or IV ALK+ NSCLC pretreated with crizotinib as the last therapy (irrespective of prior chemotherapies [≤2]). Primary endpoints were pharmacokinetics (PK), safety, and tolerability. Key secondary endpoint was overall response rate (ORR; investigator assessed).

Results: Of the 103 enrolled patients, all received prior crizotinib, 70 % received ≥1 prior chemotherapy regimen, and 63.1 % had brain metastases at baseline. In the phase 1 component, 20 patients completed a 5-day PK run-in period. Median T (n = 16) was ∼6 h; geometric means of AUC (n = 16) and C (n = 16) at steady state were 22,000 ng*h/mL and 1080 ng/mL, respectively. In the final analysis, median follow-up time was 34 months (range: 27.8-40.6). The ORR was 41.7 % (95 % confidence interval [CI]: 32.1-51.9), and median progression-free survival was 7.2 months (95 % CI: 4.1-7.5). Median overall survival was 17.5 months (95 % CI: 10.8-24.3). Most frequent adverse events, regardless of study drug relationship (mostly grade 1/2), were diarrhea (74.8 %), vomiting (62.1 %), alanine transaminase increased (59.2 %), aspartate transaminase increased (58.3 %), and nausea (58.3 %).

Conclusions: Ceritinib PK in Chinese patients is consistent with those observed in the global ASCEND-1 study. Ceritinib was well tolerated and showed durable responses in Chinese patients with ALK+ NSCLC who progressed after crizotinib and ≤2 prior lines of chemotherapy.
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http://dx.doi.org/10.1016/j.lungcan.2020.10.024DOI Listing
December 2020

High-throughput single-EV liquid biopsy: Rapid, simultaneous, and multiplexed detection of nucleic acids, proteins, and their combinations.

Sci Adv 2020 Nov 20;6(47). Epub 2020 Nov 20.

Department of Pulmonary Medicine, Shanghai Respiratory Research Institute, Zhongshan Hospital, Fudan University, Shanghai, China.

MicroRNAs (miRNAs), mRNA, and proteins in/on extracellular vesicles (EVs) represent potential cancer biomarkers. Concurrent detection of multiple biomarkers at a single-EV level would greatly improve prognosis and/or diagnosis and understanding of EV phenotypes, biogenesis, and functions. Here, we introduced a High-throughput Nano-bio Chip Integrated System for Liquid Biopsy (HNCIB) system for simultaneous detection of proteins and mRNA/miRNA in a single EV. Validated through systematic control experiments, HNCIB showed high reliability, sensitivity, and specificity. In a panel of 34 patients with lung adenocarcinoma (LUAD) and 35 healthy donors, HNCIB detected an up-regulated expression of programmed death-ligand 1 mRNA and protein and miR-21 in EVs derived from patients with LUAD compared to those from healthy donors. HNCIB has low sample requirement (~90 μl), fast assay time (~6 hours), and high throughput (up to 384 samples per assay) and would have great potential in the study of EVs and their clinical applications.
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http://dx.doi.org/10.1126/sciadv.abc1204DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7679165PMC
November 2020

Marked Reduction in 28-day Mortality Among Elderly Patients with Severe Community-acquired Pneumonia: Post Hoc Analysis of a Large Randomized Controlled Trial.

Clin Interv Aging 2020 9;15:2109-2115. Epub 2020 Nov 9.

Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, People's Republic of China.

Background: There were few studies on the case mortality of severe community-acquired pneumonia (CAP) in elderly people. Improved outcomes with XueBiJing (XBJ) injection vs placebo have been shown in overall trial populations. We investigated the efficacy and safety of XBJ vs placebo in subjects with severe CAP stratified by age (<65 and ≥65 years).

Methods: This post hoc analysis of a large randomized trial compared data from elderly and nonelderly patients with XBJ, 100 mL, q 12 h, or a visually indistinguishable placebo for five-to-seven days.

Results: Among subjects ≥65 years (n=291), 23 (16.0%) XBJ recipients and 41 (27.9%) placebo recipients (=0.014) died within 28 days. Among subjects <65 years (n=360), XBJ still had lower mortality (XBJ 15.6% vs placebo 22.8%; =0.082), without significantly statistical difference. Total duration of ICU stay and the time of mechanical ventilation were similar in both groups (>0.05). XBJ also had a favorable safety profile, with no clinically relevant differences between the two groups. The overall incidence of adverse events was similar in both groups.

Conclusion: XBJ was safe and effective for reduction in 28-day mortality among elderly patients with severe CAP. Additional confirmatory trials involving elderly patients are needed to further confirm the present results.

Trial Registration: http://www.chictr.org.cn/index.aspx. ChiCTR-TRC-13003534.
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http://dx.doi.org/10.2147/CIA.S268140DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7665517PMC
March 2021

Corticosteroid therapy for coronavirus disease 2019-related acute respiratory distress syndrome: a cohort study with propensity score analysis.

Crit Care 2020 11 10;24(1):643. Epub 2020 Nov 10.

Infection Division, Wuhan Jin Yin-Tan Hospital, Wuhan, China.

Background: The impact of corticosteroid therapy on outcomes of patients with coronavirus disease 2019 (COVID-19) is highly controversial. We aimed to compare the risk of death between COVID-19-related ARDS patients with corticosteroid treatment and those without.

Methods: In this single-center retrospective observational study, patients with ARDS caused by COVID-19 between January 20, 2020, and February 24, 2020, were enrolled. The primary outcome was 60-day in-hospital death. The exposure was prescribed systemic corticosteroids or not. Time-dependent Cox regression models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for 60-day in-hospital mortality.

Results: A total of 382 patients [60.7 ± 14.1 years old (mean ± SD), 61.3% males] were analyzed. The median of sequential organ failure assessment (SOFA) score was 2.0 (IQR 2.0-3.0). Of these cases, 94 (24.6%) patients had invasive mechanical ventilation. The number of patients received systemic corticosteroids was 226 (59.2%), and 156 (40.8%) received standard treatment. The maximum dose of corticosteroids was 80.0 (IQR 40.0-80.0) mg equivalent methylprednisolone per day, and duration of corticosteroid treatment was 7.0 (4.0-12.0) days in total. In Cox regression analysis using corticosteroid treatment as a time-varying variable, corticosteroid treatment was associated with a significant reduction in risk of in-hospital death within 60 days after adjusting for age, sex, SOFA score at hospital admission, propensity score of corticosteroid treatment, comorbidities, antiviral treatment, and respiratory supports (HR 0.42; 95% CI 0.21, 0.85; p = 0.0160). Corticosteroids were not associated with delayed viral RNA clearance in our cohort.

Conclusion: In this clinical practice setting, low-dose corticosteroid treatment was associated with reduced risk of in-hospital death within 60 days in COVID-19 patients who developed ARDS.
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http://dx.doi.org/10.1186/s13054-020-03340-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7655069PMC
November 2020

Updated guidance on the management of COVID-19: from an American Thoracic Society/European Respiratory Society coordinated International Task Force (29 July 2020).

Eur Respir Rev 2020 Sep 5;29(157). Epub 2020 Oct 5.

Dept of Medicine, Pulmonary, Critical Care, and Sleep Medicine, Yale University School of Medicine, New Haven CT, USA.

Background: Coronavirus disease 2019 (COVID-19) is a disease caused by severe acute respiratory syndrome-coronavirus-2. Consensus suggestions can standardise care, thereby improving outcomes and facilitating future research.

Methods: An International Task Force was composed and agreement regarding courses of action was measured using the Convergence of Opinion on Recommendations and Evidence (CORE) process. 70% agreement was necessary to make a consensus suggestion.

Results: The Task Force made consensus suggestions to treat patients with acute COVID-19 pneumonia with remdesivir and dexamethasone but suggested against hydroxychloroquine except in the context of a clinical trial; these are revisions of prior suggestions resulting from the interim publication of several randomised trials. It also suggested that COVID-19 patients with a venous thromboembolic event be treated with therapeutic anticoagulant therapy for 3 months. The Task Force was unable to reach sufficient agreement to yield consensus suggestions for the post-hospital care of COVID-19 survivors. The Task Force fell one vote shy of suggesting routine screening for depression, anxiety and post-traumatic stress disorder.

Conclusions: The Task Force addressed questions related to pharmacotherapy in patients with COVID-19 and the post-hospital care of survivors, yielding several consensus suggestions. Management options for which there is insufficient agreement to formulate a suggestion represent research priorities.
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http://dx.doi.org/10.1183/16000617.0287-2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7537943PMC
September 2020

Gut microbiota regulate tumor metastasis via circRNA/miRNA networks.

Gut Microbes 2020 11 18;12(1):1788891. Epub 2020 Jul 18.

Department of Respiratory and Critical Care Medicine, and Department of Infectious Disease, Tongji Hospital, Tongji University School of Medicine , Shanghai, China.

Background: Increasing evidence indicates that gut microbiota plays an important role in cancer progression. However, the underlying mechanism remains largely unknown. Here, we report that broad-spectrum antibiotics (ABX) treatment leads to enhanced metastasis by the alteration of gut microbiome composition.

Methods: Cancer LLC and B16-F10 cell metastasis mouse models, and microarray/RNA sequencing analysis were used to reveal the regulatory functions of microbiota-mediated circular RNA (circRNA)/microRNA (miRNA) networks that may contribute to cancer metastasis.

Results: The specific pathogen-free (SPF) mice with ABX treatment demonstrated enhanced lung metastasis. Fecal microbiota transplantation (FMT) from SPF mice or Bifidobacterium into germ-free mice significantly suppressed lung metastasis. Mechanistically, gut microbiota impacts circRNA expression to regulate levels of corresponding miRNAs. Specifically, such modulations of gut microbiota inhibit mmu_circ_0000730 expression in an IL-11-dependent manner. Bioinformatics analysis combined with luciferase reporter assays revealed reciprocal repression between mmu_circ_0000730 and mmu-miR-466i-3p. We further showed that both mmu-miR-466i-3p and mmu-miR-466 f-3p suppresses a number of genes involved in epithelial-mesenchymal transition (EMT) and stemness of cancer stem cells such as SOX9.

Conclusions: These results provide evidence of a previously unrecognized regulatory role of non-coding RNAs in microbiota-mediated cancer metastasis, and thus, the microbiome may serve as a therapeutic target.
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http://dx.doi.org/10.1080/19490976.2020.1788891DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7524358PMC
November 2020

Prevalence and risk factors of small airway dysfunction, and association with smoking, in China: findings from a national cross-sectional study.

Lancet Respir Med 2020 11 26;8(11):1081-1093. Epub 2020 Jun 26.

State Key Laboratory of Biotherapy of China and Department of Respiratory and Critical Care Medicine, West China Hospital of Sichuan University, Chengdu, China.

Background: Small airway dysfunction is a common but neglected respiratory abnormality. Little is known about its prevalence, risk factors, and prognostic factors in China or anywhere else in the world. We aimed to estimate the prevalence of small airway dysfunction using spirometry before and after bronchodilation, both overall and in specific population subgroups; assess its association with a range of lifestyle and environmental factors (particularly smoking); and estimate the burden of small airway dysfunction in China.

Methods: From June, 2012, to May, 2015, the nationally representative China Pulmonary Health study invited 57 779 adults to participate using a multistage stratified sampling method from ten provinces (or equivalent), and 50 479 patients with valid lung function testing results were included in the analysis. We diagnosed small airway dysfunction on the basis of at least two of the following three indicators of lung function being less than 65% of predicted: maximal mid-expiratory flow, forced expiratory flow (FEF) 50%, and FEF 75%. Small airway dysfunction was further categorised into pre-small airway dysfunction (defined as having normal FEV and FEV/forced vital capacity [FVC] ratio before bronchodilator inhalation), and post-small airway dysfunction (defined as having normal FEV and FEV/FVC ratio both before and after bronchodilator inhalation). Logistic regression yielded adjusted odds ratios (ORs) for small airway dysfunction associated with smoking and other lifestyle and environmental factors. We further estimated the total number of cases of small airway dysfunction in China by applying present study findings to national census data.

Findings: Overall the prevalence of small airway dysfunction was 43·5% (95% CI 40·7-46·3), pre-small airway dysfunction was 25·5% (23·6-27·5), and post-small airway dysfunction was 11·3% (10·3-12·5). After multifactor regression analysis, the risk of small airway dysfunction was significantly associated with age, gender, urbanisation, education level, cigarette smoking, passive smoking, biomass use, exposure to high particulate matter with a diameter less than 2·5 μm (PM) concentrations, history of chronic cough during childhood, history of childhood pneumonia or bronchitis, parental history of respiratory diseases, and increase of body-mass index (BMI) by 5 kg/m. The ORs for small airway dysfunction and pre-small airway dysfunction were similar, whereas larger effect sizes were generally seen for post-small airway dysfunction than for either small airway dysfunction or pre-small airway dysfunction. For post-small airway dysfunction, cigarette smoking, exposure to PM, and increase of BMI by 5 kg/m were significantly associated with increased risk, among preventable risk factors. There was also a dose-response association between cigarette smoking and post-small airway dysfunction among men, but not among women. We estimate that, in 2015, 426 (95% CI 411-468) million adults had small airway dysfunction, 253 (238-278) million had pre-small airway dysfunction, and 111 (104-126) million had post-small airway dysfunction in China.

Interpretation: In China, spirometry-defined small airway dysfunction is highly prevalent, with cigarette smoking being a major modifiable risk factor, along with PM exposure and increase of BMI by 5 kg/m. Our findings emphasise the urgent need to develop and implement effective primary and secondary prevention strategies to reduce the burden of this condition in the general population.

Funding: Ministry of Science and Technology of China; National Natural Science Foundation of China; National Health Commission of China.
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http://dx.doi.org/10.1016/S2213-2600(20)30155-7DOI Listing
November 2020

Novel visualized quantitative epigenetic imprinted gene biomarkers diagnose the malignancy of ten cancer types.

Clin Epigenetics 2020 05 24;12(1):71. Epub 2020 May 24.

Department of Pulmonary Medicine, Shanghai Respiratory Research Institute, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, China.

Background: Epigenetic alterations are involved in most cancers, but its application in cancer diagnosis is still limited. More practical and intuitive methods to detect the aberrant expressions from clinical samples using highly sensitive biomarkers are needed. In this study, we developed a novel approach in identifying, visualizing, and quantifying the biallelic and multiallelic expressions of an imprinted gene panel associated with cancer status. We evaluated the normal and aberrant expressions measured using the imprinted gene panel to formulate diagnostic models which could accurately distinguish the imprinting differences of normal and benign cases from cancerous tissues for each of the ten cancer types.

Results: The Quantitative Chromogenic Imprinted Gene In Situ Hybridization (QCIGISH) method developed from a 1013-case study which provides a visual and quantitative analysis of non-coding RNA allelic expressions identified the guanine nucleotide-binding protein, alpha-stimulating complex locus (GNAS), growth factor receptor-bound protein (GRB10), and small nuclear ribonucleoprotein polypeptide N (SNRPN) out of five tested imprinted genes as efficient epigenetic biomarkers for the early-stage detection of ten cancer types. A binary algorithm developed for cancer diagnosis showed that elevated biallelic expression (BAE), multiallelic expression (MAE), and total expression (TE) measurements for the imprinted gene panel were associated with cell carcinogenesis, with the formulated diagnostic models achieving consistently high sensitivities (91-98%) and specificities (86-98%) across the different cancer types.

Conclusions: The QCIGISH method provides an innovative way to visually assess and quantitatively analyze individual cells for cancer potential extending from hyperplasia and dysplasia until carcinoma in situ and invasion, which effectively supplements standard clinical cytologic and histopathologic diagnosis for early cancer detection. In addition, the diagnostic models developed from the BAE, MAE, and TE measurements of the imprinted gene panel GNAS, GRB10, and SNRPN could provide important predictive information which are useful in early-stage cancer detection and personalized cancer management.
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http://dx.doi.org/10.1186/s13148-020-00861-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7245932PMC
May 2020

Knockdown of enhances the anticancer effect of gefitinib in non-small cell lung cancer.

J Thorac Dis 2020 Mar;12(3):712-723

Department of Pulmonary Medicine, Shanghai Respiratory Research Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, China.

Background: Tyrosine kinase inhibitors (TKIs), such as gefitinib, are widely used as standard treatments for non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations. However, the subsequent inevitable drug resistance has become a major challenge in clinical treatment. The aim of this study was to investigate the role of tissue-type plasminogen activator () in gefitinib resistance in NSCLC.

Methods: The function of was determined using gefitinib-resistant cells and a nude mouse model. The gene knockdown was achieved by Lentivirus based RNA silence technique. Expression of relevant genes and proteins, cell viability, proliferation, apoptosis, cell cycle, reactive oxygen species levels, mitochondrial membrane potential and differential gene expression was detected by RT-qPCR, western blot, cell counting kit-8 assay, EdU incorporation, flow cytometry, JC-1 dye assay and complementary DNA arrays. The effects of knockdown on tumorigenesis was analyzed .

Results: Gefitinib-resistant cells expressed higher levels of and that knockdown of in resistant cells restored gefitinib sensitivity. Tumor proliferation was limited in vivo following knockdown. Moreover, knockdown affected mitochondrial function, caused caspase activation and cell cycle arrest, and activated TNF-α signaling, leading to apoptosis of gefitinib-resistant PC9 cells.

Conclusions: Our results suggest that reduces apoptosis of NSCLC cells and knockdown of enhances anticancer effect of gefitinib by upregulating TNF-α signaling.
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http://dx.doi.org/10.21037/jtd.2019.12.106DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7139041PMC
March 2020

CHD4 mediates proliferation and migration of non-small cell lung cancer via the RhoA/ROCK pathway by regulating PHF5A.

BMC Cancer 2020 Mar 30;20(1):262. Epub 2020 Mar 30.

Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, China.

Background: Chromodomain helicase DNA-binding protein 4 (CHD4) has been shown to contribute to DNA repair and cell cycle promotion; however, its roles in cancer initiation and progression remain largely unknown. This study aimed to demonstrate the role of CHD4 in the development of non-small cell lung cancer (NSCLC) and determine the potential mechanisms of action.

Methods: By using immunohistochemistry, the expression levels were evaluated in both cancer and non-cancerous tissues. Subsequently, CHD4 knockdown and overexpression strategies were employed to investigate the effects of CHD4 on cell proliferation, migration, along with the growth and formation of tumors in a xenografts mouse model. The protein expression levels of CHD4, PHF5A and ROCK/RhoA markers were determined by Western blot analysis.

Results: Compared with non-cancerous tissues, CHD4 was overexpressed in cancer tissues and CHD4 expression levels were closely related to clinical parameters of NSCLC patients. In H292 and PC-9 cell lines, CHD4 overexpression could promote the proliferative and migratory potential of NSCLC cells. Furthermore, down-regulation of CHD4 could reduce the proliferative and migratory ability in A549 and H1299 cell lines. Meanwhile, knockdown of CHD4 could decrease the tumorigenicity in nude mice. Finally, we demonstrated that one of the mechanisms underlying the promotive effect of CHD4 on NSCLC proliferation and migration may be through its interaction with PHD finger protein 5A (PHF5A) and subsequent activation of the RhoA/ROCK signaling pathway.

Conclusions: CHD4, which is highly expressed in cancer tissue, could be an independent prognostic factor for NSCLC patients. CHD4 plays an important role in regulating the proliferative and migratory abilities of NSCLC via likely the RhoA/ROCK pathway by regulating PHF5A.
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http://dx.doi.org/10.1186/s12885-020-06762-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7106713PMC
March 2020

Risk Factors Associated With Acute Respiratory Distress Syndrome and Death in Patients With Coronavirus Disease 2019 Pneumonia in Wuhan, China.

JAMA Intern Med 2020 07;180(7):934-943

Department of Pulmonary Medicine, QingPu Branch of Zhongshan Hospital Affiliated to Fudan University, Shanghai, China.

Importance: Coronavirus disease 2019 (COVID-19) is an emerging infectious disease that was first reported in Wuhan, China, and has subsequently spread worldwide. Risk factors for the clinical outcomes of COVID-19 pneumonia have not yet been well delineated.

Objective: To describe the clinical characteristics and outcomes in patients with COVID-19 pneumonia who developed acute respiratory distress syndrome (ARDS) or died.

Design, Setting, And Participants: Retrospective cohort study of 201 patients with confirmed COVID-19 pneumonia admitted to Wuhan Jinyintan Hospital in China between December 25, 2019, and January 26, 2020. The final date of follow-up was February 13, 2020.

Exposures: Confirmed COVID-19 pneumonia.

Main Outcomes And Measures: The development of ARDS and death. Epidemiological, demographic, clinical, laboratory, management, treatment, and outcome data were also collected and analyzed.

Results: Of 201 patients, the median age was 51 years (interquartile range, 43-60 years), and 128 (63.7%) patients were men. Eighty-four patients (41.8%) developed ARDS, and of those 84 patients, 44 (52.4%) died. In those who developed ARDS, compared with those who did not, more patients presented with dyspnea (50 of 84 [59.5%] patients and 30 of 117 [25.6%] patients, respectively [difference, 33.9%; 95% CI, 19.7%-48.1%]) and had comorbidities such as hypertension (23 of 84 [27.4%] patients and 16 of 117 [13.7%] patients, respectively [difference, 13.7%; 95% CI, 1.3%-26.1%]) and diabetes (16 of 84 [19.0%] patients and 6 of 117 [5.1%] patients, respectively [difference, 13.9%; 95% CI, 3.6%-24.2%]). In bivariate Cox regression analysis, risk factors associated with the development of ARDS and progression from ARDS to death included older age (hazard ratio [HR], 3.26; 95% CI 2.08-5.11; and HR, 6.17; 95% CI, 3.26-11.67, respectively), neutrophilia (HR, 1.14; 95% CI, 1.09-1.19; and HR, 1.08; 95% CI, 1.01-1.17, respectively), and organ and coagulation dysfunction (eg, higher lactate dehydrogenase [HR, 1.61; 95% CI, 1.44-1.79; and HR, 1.30; 95% CI, 1.11-1.52, respectively] and D-dimer [HR, 1.03; 95% CI, 1.01-1.04; and HR, 1.02; 95% CI, 1.01-1.04, respectively]). High fever (≥39 °C) was associated with higher likelihood of ARDS development (HR, 1.77; 95% CI, 1.11-2.84) and lower likelihood of death (HR, 0.41; 95% CI, 0.21-0.82). Among patients with ARDS, treatment with methylprednisolone decreased the risk of death (HR, 0.38; 95% CI, 0.20-0.72).

Conclusions And Relevance: Older age was associated with greater risk of development of ARDS and death likely owing to less rigorous immune response. Although high fever was associated with the development of ARDS, it was also associated with better outcomes among patients with ARDS. Moreover, treatment with methylprednisolone may be beneficial for patients who develop ARDS.
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http://dx.doi.org/10.1001/jamainternmed.2020.0994DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7070509PMC
July 2020

2019 novel coronavirus of pneumonia in Wuhan, China: emerging attack and management strategies.

Clin Transl Med 2020 Feb 20;9(1):19. Epub 2020 Feb 20.

Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, 180 Feng Lin Road, Shanghai, 200032, China.

An ongoing outbreak of 2019-nCoV pneumonia was first identified in Wuhan, Hubei province, China at the end of 2019. With the spread of the new coronavirus accelerating, person-to-person transmission in family homes or hospitals, and intercity spread of 2019-nCoV occurred. At least 40,261 cases confirmed, 23,589 cases suspected, 909 cases death and 3444 cases cured in China and worldwide 24 countries confirmed 383 cases being diagnosed, 1 case death in February 10th, 2020. At present, the mortality of 2019-nCoV in China is 2.3%, compared with 9.6% of SARS and 34.4% of MERS reported by WHO. It seems the new virus is not as fatal as many people thought. Chinese authorities improved surveillance network, made the laboratory be able to recognize the outbreak within a few weeks and announced the virus genome that provide efficient epidemiological control. More comprehensive information is required to understand 2019-nCoV feature, the epidemiology of origin and spreading, and the clinical phenomina. According to the current status, blocking transmission, isolation, protection, and alternative medication are the urgent management strategies against 2019-nCoV.
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http://dx.doi.org/10.1186/s40169-020-00271-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7033263PMC
February 2020

Helsinki by nature: The Nature Step to Respiratory Health.

Clin Transl Allergy 2019 30;9:57. Epub 2019 Oct 30.

29FILHA, Finnish Lung Health Association, Helsinki, Finland.

Background: was the overarching theme of the 12th General Meeting of the Global Alliance against Chronic Respiratory Diseases (GARD) in Helsinki, August 2018. New approaches are needed to improve respiratory health and reduce premature mortality of chronic diseases by 30% till 2030 (UN Sustainable Development Goals, SDGs). Planetary health is defined as the health of human civilization and the state of the natural systems on which it depends. Planetary health and human health are interconnected, and both need to be considered by individuals and governments while addressing several SDGs.

Results: The concept of the Nature Step has evolved from innovative research indicating, how changed lifestyle in urban surroundings reduces contact with biodiverse environments, impoverishes microbiota, affects immune regulation and increases risk of NCDs. The Nature Step calls for strengthening connections to nature. Physical activity in natural environments should be promoted, use of fresh vegetables, fruits and water increased, and consumption of sugary drinks, tobacco and alcohol restricted. Nature relatedness should be part of everyday life and especially emphasized in the care of children and the elderly. Taking "nature" to modern cities in a controlled way is possible but a challenge for urban planning, nature conservation, housing, traffic arrangements, energy production, and importantly for supplying and distributing food. Actions against the well-known respiratory risk factors, air pollution and smoking, should be taken simultaneously.

Conclusions: In Finland and elsewhere in Europe, successful programmes have been implemented to reduce the burden of respiratory disorders and other NCDs. Unhealthy behaviour can be changed by well-coordinated actions involving all stakeholders. The growing public health concern caused by NCDs in urban surroundings cannot be solved by health care alone; a multidisciplinary approach is mandatory.
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http://dx.doi.org/10.1186/s13601-019-0295-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6822361PMC
October 2019

Epidemiology of lung cancer and lung cancer screening programs in China and the United States.

Cancer Lett 2020 01 7;468:82-87. Epub 2019 Oct 7.

Division of Pulmonary, Critical Care and Sleep Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Electronic address:

Lung cancer is a heterogeneous disease that is impacted by environmental exposures and by constitutional genetic or epigenetic susceptibilities to disease development and progression. The United States and China have distinct and diverse populations and geographic environmental exposures that contribute to unique patterns of lung cancer incidence and mortality. In this paper, the authors compare trends of incidence and mortality of lung cancer in the US and China, and the impact on lung cancer screening programs in the two countries. It is worth noting that the mortality of lung cancer in the US has decreased gradually while in China it is still increasing over recent years. While decreasing smoking prevalence and the impact of clean air legislation have helped to mitigate the trend in the US relative to China, the increasingly widespread implementation of lung cancer chest CT screening is expected to impact lung cancer incidence and mortality in both countries. Currently there are few studies to compare the environmental and genetic risk factors for US and Chinese populations with regards to lung cancer incidence and mortality. The authors discuss the impact of gender and exposure risks, mainly smoking and environmental pollutants. Of high importance is the incidence of lung cancer in never smokers that is significantly higher in China than in the United States; this is particularly notable in women. These data suggest inclusion of ambient air pollution exposure and gender into lung cancer risk prognostic models to better capture high-risk individuals, especially for non-smoking women.
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http://dx.doi.org/10.1016/j.canlet.2019.10.009DOI Listing
January 2020

Tumor-derived DNA from pleural effusion supernatant as a promising alternative to tumor tissue in genomic profiling of advanced lung cancer.

Theranostics 2019 28;9(19):5532-5541. Epub 2019 Jul 28.

Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.

Pleural effusion (PE) is commonly observed in advanced lung cancer and was suggested to contain both cell-free tumor DNA and tumor cells. Molecular profiling of PE represents a minimally invasive approach of detecting tumor driver mutations for clinical decision making, especially when tumor tissues are not available. The objective of this study is to investigate the efficacy and precision of detecting gene alterations in PE samples to address the feasibility in clinical use. Sixty-three metastatic lung cancer patients with (n=30, cohort 1) or without (n=33, cohort 2) matched tumor tissues were enrolled in this study. PE and plasma samples of each patient were collected simultaneously. Supernatant and cell precipitate of PE were processed separately to extract cfDNA (PE-cfDNA) and sediment DNA (sDNA). All samples were subjected to targeted next-generation sequencing (NGS) of 416 cancer-related genes. PE supernatants contain more abundant tumor DNA than PE sediments and plasma samples, suggested by higher mutant allele frequencies (MAF) and elevated mutation detection rate in PE-cfDNA (98.4% vs. 90.5% in PE sDNA vs. 87% in plasma cfDNA). In Cohort 1 with matched tumor tissue, tumor mutational burden (TMB) of PE-cfDNA was similar as tumor tissues (6.4 vs. 5.6), but significantly higher than PE sDNA (median TMB: 3.3) and plasma cfDNA (median TMB: 3.4). Ninety-three percent (27 out of 29) of tissue-determined driver mutations were detected in PE-cfDNA, including alterations in , , , , , and , while only 62% were captured in plasma cfDNA. PE-cfDNA also has the highest detection rate of driver mutations in the full cohort (71% vs. 68% in PE sDNA vs. 59% in plasma cfDNA). Mutation detection from cytological negative and hemorrhagic PE is challenging. Comparatively, PE-cfDNA demonstrated absolute superiority than PE sDNA in such a scenario, suggesting that it is an independent source of tumor DNA and therefore less influenced by the abundance of tumor cells. Genomic profiling of PE-cfDNA offers an alternative, and potentially more meticulous approach in assessing tumor genomics in advanced lung cancer when tumor tissue is not available. Our data further demonstrate that in hemorrhagic or cytologically negative PE samples, PE-cfDNA has higher mutation detection sensitivity than sDNA and plasma cfDNA, and therefore is a more reliable source for genetic testing.
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http://dx.doi.org/10.7150/thno.34070DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6735385PMC
September 2020

[Interpretation of design ideas and implementation process of randomized controlled trial of Xuebijing injection in the treatment of severe community-acquired pneumonia].

Zhonghua Wei Zhong Bing Ji Jiu Yi Xue 2019 Jul;31(7):811-814

Institute of Field Surgery, General Hospital of PLA, Beijing 100853, China. Corresponding author: Bai Chunxue, Email:

Objective: A multicenter blinded randomized controlled trial (RCT) was conducted in accordance with international clinical trial standards to evaluate the efficacy and safety of Xuebijing injection in the treatment of severe community-acquired pneumonia (SCAP) under strict quality control condition. This article aims to illustrate key contents of the design ideas and implementation process of the RCT of Xuebijing injection in the treatment of SCAP, including the selection of research objects, design, implementation, and insights, etc., share experience with researchers of the respiratory and critical care, and provide reference for future studies in critical care.
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http://dx.doi.org/10.3760/cma.j.issn.2095-4352.2019.07.003DOI Listing
July 2019

Prevalence, risk factors, and management of asthma in China: a national cross-sectional study.

Lancet 2019 08 20;394(10196):407-418. Epub 2019 Jun 20.

Department of Respiratory and Critical Care Medicine, Beijing Hospital, Beijing, China; National Center of Gerontology, Beijing Hospital, Beijing, China.

Background: Asthma is a common chronic airway disease worldwide. Despite its large population size, China has had no comprehensive study of the national prevalence, risk factors, and management of asthma. We therefore aimed to estimate the national prevalence of asthma in a representative sample of the Chinese population.

Methods: A representative sample of 57 779 adults aged 20 years or older was recruited for the national cross-sectional China Pulmonary Health (CPH) study using a multi-stage stratified sampling method with parameters derived from the 2010 census. Ten Chinese provinces, representative of all socioeconomic settings, from six geographical regions were selected, and all assessments were done in local health centres. Exclusion criteria were temporary residence, inability to take a spirometry test, hospital treatment of cardiovascular conditions or tuberculosis, and pregnancy and breastfeeding. Asthma was determined on the basis of a self-reported history of diagnosis by a physician or by wheezing symptoms in the preceding 12 months. All participants were assessed with a standard asthma questionnaire and were classed as having or not having airflow limitation through pulmonary function tests before and after the use of a bronchodilator (400 μg of salbutamol). Risk factors for asthma were examined by multivariable-adjusted analyses done in all participants for whom data on the variables of interest were available. Disease management was assessed by the self-reported history of physician diagnosis, treatments, and hospital visits in people with asthma.

Findings: Between June 22, 2012, and May 25, 2015, 57 779 participants were recruited into the CPH study. 50 991 (21 446 men and 29 545 women) completed the questionnaire survey and had reliable post-bronchodilator pulmonary function test results and were thus included in the final analysis. The overall prevalence of asthma in our sample was 4·2% (95% CI 3·1-5·6), representing 45·7 million Chinese adults. The prevalence of asthma with airflow limitation was 1·1% (0·9-1·4), representing 13·1 million adults. Cigarette smoking (odds ratio [OR] 1·89, 95% CI 1·26-2·84; p=0·004), allergic rhinitis (3·06, 2·26-4·15; p<0·0001), childhood pneumonia or bronchitis (2·43, 1·44-4·10; p=0·002), parental history of respiratory disease (1·44, 1·02-2·04; p=0·040), and low education attainment (p=0·045) were associated with prevalent asthma. In 2032 people with asthma, only 28·8% (95% CI 19·7-40·0) reported ever being diagnosed by a physician, 23·4% (13·9-36·6) had a previous pulmonary function test, and 5·6% (3·1-9·9) had been treated with inhaled corticosteroids. Furthermore, 15·5% (11·4-20·8) people with asthma reported at least one emergency room visit and 7·2% (4·9-10·5) at least one hospital admission due to exacerbation of respiratory symptoms within the preceding year.

Interpretation: Asthma is prevalent but largely undiagnosed and undertreated in China. It is crucial to increase the awareness of asthma and disseminate standardised treatment in clinical settings to reduce the disease burden.

Funding: National Key R&D Program of China, Ministry of Science and Technology of China; the Special Research Foundation for Public Welfare of Health, Ministry of Health of China; the Chinese National Research Program for Key Issues in Air Pollution Control; and the National Natural Science Foundation of China.
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http://dx.doi.org/10.1016/S0140-6736(19)31147-XDOI Listing
August 2019

XueBiJing Injection Versus Placebo for Critically Ill Patients With Severe Community-Acquired Pneumonia: A Randomized Controlled Trial.

Crit Care Med 2019 09;47(9):e735-e743

Department of Emergency Medicine, The Second Hospital of Hebei Medical University, Shijiazhuang, China.

Objectives: To investigate whether XueBiJing injection improves clinical outcomes in critically ill patients with severe community-acquired pneumonia.

Design: Prospective, randomized, controlled study.

Setting: Thirty-three hospitals in China.

Patients: A total of 710 adults 18-75 years old with severe community-acquired pneumonia.

Interventions: Participants in the XueBiJing group received XueBiJing, 100 mL, q12 hours, and the control group received a visually indistinguishable placebo.

Measurements And Main Results: The primary outcome was 8-day improvement in the pneumonia severity index risk rating. Secondary outcomes were 28-day mortality rate, duration of mechanical ventilation and total duration of ICU stay. Improvement in the pneumonia severity index risk rating, from a previously defined endpoint, occurred in 203 (60.78%) participants receiving XueBiJing and in 158 (46.33%) participants receiving placebo (between-group difference [95% CI], 14.4% [6.9-21.8%]; p < 0.001). Fifty-three (15.87%) XueBiJing recipients and 84 (24.63%) placebo recipients (8.8% [2.4-15.2%]; p = 0.006) died within 28 days. XueBiJing administration also decreased the mechanical ventilation time and the total ICU stay duration. The median mechanical ventilation time was 11.0 versus 16.5 days for the XueBiJing and placebo groups, respectively (p = 0.012). The total duration of ICU stay was 12 days for XueBiJing recipients versus 16 days for placebo recipients (p = 0.004). A total of 256 patients experienced adverse events (119 [35.63%] vs 137 [40.18%] in the XueBiJing and placebo groups, respectively [p = 0.235]).

Conclusions: In critically ill patients with severe community-acquired pneumonia, XueBiJing injection led to a statistically significant improvement in the primary endpoint of the pneumonia severity index as well a significant improvement in the secondary clinical outcomes of mortality, duration of mechanical ventilation and duration of ICU stay.
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http://dx.doi.org/10.1097/CCM.0000000000003842DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6727951PMC
September 2019

Interventions to Reduce Personal Exposures to Air Pollution: A Primer for Health Care Providers.

Glob Heart 2019 03;14(1):47-60

Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, MI, USA.

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http://dx.doi.org/10.1016/j.gheart.2019.02.001DOI Listing
March 2019

Molecular characterization of clinical responses to PD-1/PD-L1 inhibitors in non-small cell lung cancer: Predictive value of multidimensional immunomarker detection for the efficacy of PD-1 inhibitors in Chinese patients.

Thorac Cancer 2019 05 23;10(5):1303-1309. Epub 2019 Apr 23.

Department of Respiratory Medicine, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical Sciences, Beijing, China.

According to multiple studies, the objective response rate of PD-1/PD-L1 inhibitors in the second-line treatment of unscreened non-small cell lung cancer (NSCLC) is only approximately 20%. Predictive biomarkers of treatment efficacies are still under investigation. In selected NSCLC patients with PD-L1 expression ≥ 50%, the response rate of pembrolizumab in first-line treatment can reach 44.8%. Moreover, patients with a higher tumor mutation burden (TMB) tend to achieve a better response with nivolumab. Besides PD-L1 expression and TMB, taking all these indicators into consideration would hypothetically maximize the clinical response in a specific subgroup of patients. Our study aims to accumulate large and complete samples and clinical data to verify the biomarkers and their cutoff values related to the efficacy of PD-1/PD-L1 inhibitors in Chinese NSCLC patients, and to construct a comprehensive predictive model by combining multi-omics data with contemporary machine learning techniques. NSCLC patients administered treatment of anti-PD-1/PD-L1 antibodies or a combination with other drugs have been enrolled. The estimated enrollment is 250 participants. A sophisticated predictive model of immunotherapy response in the Chinese population has not yet been developed. It is clinically and practically imperative to comprehensively evaluate the possible indicators of Chinese NSCLC patients through multiple test platforms, such as next generation sequencing, PCR, or immunohistochemistry. This study is registered in the Chinese Clinical Trial Registry (ChiCTR1900021395).
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http://dx.doi.org/10.1111/1759-7714.13078DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6500968PMC
May 2019

Glycerol kinase 5 confers gefitinib resistance through SREBP1/SCD1 signaling pathway.

J Exp Clin Cancer Res 2019 Feb 21;38(1):96. Epub 2019 Feb 21.

Department of Pulmonary Medicine, Shanghai Respiratory Research Institute, Zhongshan Hospital, Fudan University, Shanghai, China.

Background: Drug resistance is common in cancer chemotherapy. This study investigates the role of Glycerol kinase 5 (GK5) in mediating gefitinib resistance in NSCLC.

Methods: The exosomal mRNA of GK5 was detected using a tethered cationic lipoplex nanoparticle (TCLN) biochip. Real-time PCR and Western blot were used to examine the expression of GK5 mRNA and protein in gefitinib-sensitive and -resistant human lung adenocarcinoma cells. The cell counting kit-8, EdU assay, flow cytometry, and JC-1 dye were used to measure cell proliferation, cell cycle, and the mitochondrial membrane potential.

Results: We found that the exosomal mRNA of GK5 in the plasma of patients with gefitinib-resistant adenocarcinoma was significantly higher compared with that of gefitinib-sensitive patients. The mRNA and protein levels of GK5 were significantly upregulated in gefitinib-resistant human lung adenocarcinoma PC9R and H1975 cells compared with gefitinib-sensitive PC9 cells. Silencing GK5 in PC9R cells induced mitochondrial damage, caspase activation, cell cycle arrest, and apoptosis via SREBP1/SCD1 signaling pathway.

Conclusions: We demonstrated that GK5 confers gefitinib resistance in lung cancer by inhibiting apoptosis and cell cycle arrest. GK5 could be a novel therapeutic target for treatment of NSCLC with resistance to EGFR tyrosine kinase inhibitors.
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http://dx.doi.org/10.1186/s13046-019-1057-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6385389PMC
February 2019

Subgroup Analysis for Chinese Patients Included in the INPULSIS Trials on Nintedanib in Idiopathic Pulmonary Fibrosis.

Adv Ther 2019 03 7;36(3):621-631. Epub 2019 Feb 7.

Department of Respiratory Diseases, The First Hospital of China Medical University, Shenyang, China.

Purpose: To investigate the efficacy and safety of nintedanib versus placebo in Chinese patients with idiopathic pulmonary fibrosis (IPF).

Methods: The INPULSIS trials consisted of two replicate, randomized, placebo-controlled, double-blind trials comparing nintedanib 150 mg bid with placebo over a 52-week treatment period. The primary endpoint was annual rate of decline in forced vital capacity (FVC); key secondary endpoints were change from baseline in Saint George's Respiratory Questionnaire's total score and time to first investigator-reported acute exacerbation. Data from both trials were pooled for the Chinese subgroup analyses.

Results: A total of 101 Chinese patients (nintedanib/placebo: 61/40) were treated. The demographic characteristics were generally balanced between treatment arms. Over 52 weeks, the rate of decline in FVC was lower in nintedanib-treated patients compared with placebo-treated patients in the Chinese subgroup [- 126.43 vs. - 229.82 mL/year; ∆ = 103.39 mL/year (95% confidence interval, CI: - 19.40 to 226.18)]. The proportion of patients with adverse events (AEs) over 52 weeks was similar between treatment arms. The most commonly reported AEs with nintedanib treatment were gastrointestinal symptoms (diarrhoea, nausea, and vomiting).

Conclusions: Nintedanib is clinically efficacious in Chinese patients with IPF with approximately 50% reductions in the rate of decline in FVC, demonstrating slowed disease progression. Similar to the overall INPULSIS population, nintedanib has a favourable benefit/risk profile in Chinese patients with IPF. CLINICALTRIALS.

Gov Identifiers: NCT01335464, NCT01335477.

Funding: Boehringer Ingelheim. Plain language summary available for this article.
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http://dx.doi.org/10.1007/s12325-019-0887-1DOI Listing
March 2019
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