Publications by authors named "Huahao Shen"

129 Publications

Increasing NADPH Availability for Xylitol Production via Pentose-Phosphate-Pathway Gene Overexpression and Embden-Meyerhof-Parnas-Pathway Gene Deletion in .

J Agric Food Chem 2021 Aug 12;69(33):9625-9631. Epub 2021 Aug 12.

Key Laboratory of Biomass Chemical Engineering of the Ministry of Education, College of Chemical and Biological Engineering, Zhejiang University, Hangzhou 310027, PR China.

Cofactor availability is often a rate-limiting factor in the bioconversion of xylose to xylitol. The overexpression of pentose phosphate pathway genes and the deletion of Embden-Meyerhof-Parnas pathway genes can modulate the glucose metabolic flux and increase the intracellular NADPH supply, enabling cells to produce xylitol from corncob hydrolysates. The effects of and/or overexpression and , , and/or deletion on the intracellular redox environment and xylitol production were examined. The NADPH-enhanced strain 2bpgi produced 162 g/L xylitol from corncob hydrolysates after a 76 h fed-batch fermentation in a 15 L bioreactor, which was 13.3% greater than the 143 g/L xylitol produced by the IS5-d control strain. Additionally, the xylitol productivity and xylitol yield per glucose for 2bpgi were 2.13 g/L/h and 2.50 g/g, respectively. Thus, the genetic modifications in 2bpgi significantly enhanced NADPH regeneration, making 2bpgi a potentially useful strain for the industrial-scale production of xylitol from detoxified corncob hydrolysates.
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http://dx.doi.org/10.1021/acs.jafc.1c03283DOI Listing
August 2021

Effectiveness of omalizumab in patients with severe allergic asthma: A retrospective study in China.

Respir Med 2021 Jun 29;186:106522. Epub 2021 Jun 29.

Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China. Electronic address:

Background: We conducted the first real-world study of treatment with omalizumab, a humanized monoclonal anti-immunoglobulin E antibody, in Chinese patients with severe allergic asthma.

Objective: The primary objective was the steroid-sparing effect of omalizumab after 12 and 16 weeks of treatment. Characteristics of the patient population, treatment patterns, response rate, and other measures of therapeutic effectiveness were also reported.

Methods: This nationwide, retrospective, real-world study was conducted in patients with severe allergic asthma who were treated with omalizumab in China. Data, including demographics, Asthma Control Test (ACT) and laboratory and lung function test results, and omalizumab use information, were extracted from patient records collected as part of a previously conducted real-world survey (Asthma Group of the Respiratory Disease Society of the Chinese Medical Association).

Results: In total, 139 patient records were included; 131 and 118 patients remained on treatment at the ≥12- and ≥16-week time points, respectively. The mean ± standard deviation age and median asthma duration (interquartile range) were 47.4 ± 14.3 and 7 (4, 15) years, respectively; 75.6% of patients had a history of allergic disease. Reductions (versus baseline) in inhaled corticosteroid/long-acting β2 agonists or oral corticosteroids were reported in 61.1% and 63.6% of patients at ≥12 and ≥ 16 weeks, respectively. There were significant improvements in ACT scores (6.08, P < .001) and nitric oxide fraction in exhaled air (-13.0, P = .01) from baseline. Multivariate analysis revealed that age and allergic medical history were predictors of omalizumab treatment response. No serious adverse events were reported.

Conclusion: Real-world omalizumab treatment was efficacious and well-tolerated in Chinese patients with severe allergic asthma.
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http://dx.doi.org/10.1016/j.rmed.2021.106522DOI Listing
June 2021

-Mutated Squamous Cell Lung Cancer and Its Association With Outcomes.

Front Oncol 2021 14;11:680804. Epub 2021 Jun 14.

Key Laboratory of Respiratory Disease of Zhejiang Province, Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China.

Background: The therapeutic efficacy of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in advanced -mutant lung squamous cell carcinoma (SCC) patients remains uncertain. Furthermore, the factors underlying the responsiveness have not been fully investigated. We therefore investigated the link between genomic profiles and EGFR-TKI efficacy.

Material And Methods: We consecutively enrolled stage IV, -mutant, and EGFR-TKI-treated patients with SCC. Patients with wild-type lung SCC and -mutant lung adenocarcinoma were consecutively enrolled as controls, and next-generation sequencing (NGS) was performed.

Results: In total, 28 -mutant lung SCC, 41 -mutant lung adenocarcinoma, and 40 wild-type lung SCC patients were included. Among the patients with mutations, shorter progression-free survival (PFS) was observed in SCC compared to adenocarcinoma (4.6 11.0 months, P<0.001). Comparison of the genomic profiles revealed that -mutant SCC patients had similar mutation characteristics to -mutant adenocarcinoma patients, but differed from those with wild-type SCC. Further exploration of -mutant SCC revealed that mutations in (P = 0.005), (P = 0.016), and the Wnt (P = 0.027) pathway were negatively associated with PFS. Mutations in (P = 0.025) were associated with improved PFS.

Conclusions: -mutant lung SCC has a worse prognosis than -mutant adenocarcinoma. Mutations in other genes, such as , , , or Wnt that had implications on PFS raise the possibility of understanding mechanisms of resistance to EGFR-TKI in lung SCC, which will aid identification of potential beneficial subgroups of patients with -mutant SCCs receiving EGFR-TKIs.
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http://dx.doi.org/10.3389/fonc.2021.680804DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8236808PMC
June 2021

Epithelium-derived IL17A Promotes Cigarette Smoke-induced Inflammation and Mucus Hyperproduction.

Am J Respir Cell Mol Biol 2021 Jun 29. Epub 2021 Jun 29.

Zhejiang University School of Medicine, 26441, Respiratory Medicine, Hangzhou, China;

Airway epithelium is a central modulator of innate and adaptive immunity in the lung. Interleukin (IL)17A expression was found to be increased in airway epithelium; however, the role of epithelial-derived IL17A in chronic obstructive pulmonary disease (COPD) remains unclear. In this study, we aim to determine whether epithelial-derived IL17A regulates inflammation and mucus hyperproduction in COPD using a cultured human bronchial epithelial (HBE) cell line in vitro and airway epithelium IL17A-specific knockout mouse in vivo. Increased IL17A expression was observed in mouse airway epithelium upon cigarette smoke (CS) exposure or in a COPD mouse model that was induced by CS and elastin. CS extract (CSE) also triggered IL17A expression in HBE cells. Blocking IL17A or IL17RA effectively attenuated CSE-induced MUC5AC and the inflammatory cytokines IL6, tumor necrosis factor (TNF)-α, and IL1β in HBE cells, suggesting that IL17A mediates CSE-induced inflammation and mucin production in an autocrine manner. CSE activated p-JUN and p-JNK, which were also reduced by IL17RA-siRNA, and JUN-siRNA attenuated CSE-induced IL6 and MUC5AC. In vivo, selective knockout of IL17A in airway epithelium markedly reduced the neutrophilic infiltration in Bronchoalveolar Lavage Fluid (BALF), peribronchial inflammation, pro-inflammatory mediators (CXCL1 and CXCL2), and mucus production in a COPD mouse model. We showed a novel function of airway epithelium-derived IL17A, which can act locally in an autocrine manner to amplify inflammation and increase mucus production in COPD pathogenesis.
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http://dx.doi.org/10.1165/rcmb.2020-0424OCDOI Listing
June 2021

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

Environ Int 2021 11 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
November 2021

IL-17-Mediated Inflammation Promotes Cigarette Smoke-Induced Genomic Instability.

Cells 2021 05 12;10(5). Epub 2021 May 12.

Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310000, China.

(1) Background: Chronic inflammation has been regarded as a risk factor for the onset and progression of human cancer, but the critical molecular mechanisms underlying this pathological process have yet to be elucidated. (2) Methods: In this study, we investigated whether interleukin (IL)-17-mediated inflammation was involved in cigarette smoke-induced genomic instability. (3) Results: Higher levels of both IL-17 and the DNA damage response (DDR) were found in the lung tissues of smokers than in those of non-smokers. Similarly, elevated levels of IL-17 and the DDR were observed in mice after cigarette smoke exposure, and a positive correlation was observed between IL-17 expression and the DDR. In line with these observations, the DDR in the mouse lung was diminished in IL-17 KO when exposed to cigarette smoke. Besides this, the treatment of human bronchial epithelium cells with IL-17 led to increased levels of the DDR and chromosome breakage. (4) Conclusions: These results suggest that cigarette smoke induces genomic instability at least partially through IL-17-mediated inflammation, implying that IL-17 could play an important role in the development of lung cancer.
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http://dx.doi.org/10.3390/cells10051173DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8151076PMC
May 2021

Eosinophilic inflammation promotes CCL6-dependent metastatic tumor growth.

Sci Adv 2021 May 26;7(22). Epub 2021 May 26.

Key Laboratory of Respiratory Disease of Zhejiang Province, Department of Respiratory and Critical Care Medicine, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, China.

Compelling evidence suggests that inflammatory components contribute to cancer development. However, eosinophils, involved in several inflammatory diseases, were not fully explored in cancer metastasis. We show that airway inflammatory eosinophilia and colonic inflammation with eosinophil infiltration are both associated with increased metastasis in mice. Eosinophilia is responsible for increased bone metastasis in eosinophil-enriched δ transgenic ( Tg) mice. We also observe increased eosinophils in the malignant pleural effusion of cancer patients with pleural metastasis. Mechanistically, eosinophils promote tumor cell migration and metastasis formation through secreting C-C motif chemokine ligand 6 (CCL6). Genetic knockout of in Tg mice remarkably attenuates bone metastasis. Moreover, inhibition of C-C chemokine receptor 1 (CCR1, the receptor of CCL6) in tumor cells reduces tumor cell migration and metastasis. Thus, our study identifies a CCL6-dependent prometastatic activity of eosinophils, which can be inhibited by targeting CCR1 and represent an approach to preventing metastatic disease.
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http://dx.doi.org/10.1126/sciadv.abb5943DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8153717PMC
May 2021

Application of a classifier combining bronchial transcriptomics and chest computed tomography features facilitates the diagnostic evaluation of lung cancer in smokers and nonsmokers.

Int J Cancer 2021 09 25;149(6):1290-1301. Epub 2021 May 25.

Key Laboratory of Respiratory Disease of Zhejiang Province, Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China.

Lung cancer screening by computed tomography (CT) reduces mortality but exhibited high false-positive rates. We established a diagnostic classifier combining chest CT features with bronchial transcriptomics. Patients with CT-detected suspected lung cancer were enrolled. The sample collected by bronchial brushing was used for RNA sequencing. The e1071 and pROC packages in R software was applied to build the model. Eventually, a total of 283 patients, including 183 with lung cancer and 100 with benign lesions, were included into final analysis. When incorporating transcriptomic data with radiological characteristics, the advanced model yielded 0.903 AUC with 81.1% NPV. Moreover, the classifier performed well regardless of lesion size, location, stage, histologic type or smoking status. Pathway analysis showed enhanced epithelial differentiation, tumor metastasis, and impaired immunity were predominant in smokers with cancer, whereas tumorigenesis played a central role in nonsmokers with cancer. Apoptosis and oxidative stress contributed critically in metastatic lung cancer; by contrast, immune dysfunction was pivotal in locally advanced lung cancer. Collectively, we devised a minimal-to-noninvasive, efficient diagnostic classifier for smokers and nonsmokers with lung cancer, which provides evidence for different mechanisms of cancer development and metastasis associated with smoking. A negative classifier result will help the physician make conservative diagnostic decisions.
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http://dx.doi.org/10.1002/ijc.33675DOI Listing
September 2021

The value of small airway function parameters and fractional exhaled nitric oxide for predicting positive methacholine challenge test in asthmatics of different ages with FEV  ≥ 80% predicted.

Clin Transl Allergy 2021 Mar;11(1):e12007

Department of Respiratory and Critical Care Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

Background: Small airway function parameters (SAFPs) combined with fractional exhaled nitric oxide (FeNO) can predict a positive methacholine challenge test (MCT) for asthma diagnosis. However, their predictive utility in patients with forced expiratory volume in one second (FEV ) ≥80% predicted within different age ranges remains unclear. This study aimed to assess the utility of SAFPs, alone or combined with FeNO, to predict a positive MCT in patients in two age groups (<55 and ≥55 years) with asthma-suggestive symptoms and FEV  ≥80% predicted.

Methods: We enrolled 846 Chinese patients with suspected asthma and standard spirometry, FeNO, and MCT findings. Using the area under the curves (AUCs), the utility of SAFPs, alone or combined with FeNO, for predicting a positive MCT was analyzed in a discovery (n = 534) and validation cohort (n = 312) in both age groups with FEV ≥80% predicted.

Results: In the discovery cohort, the optimal cut-off values for predicting a positive MCT in patients aged <55 years (74.2% and 74.9% for forced expiratory flow (FEF) and FEF , respectively) were higher than those in patients aged ≥55 years (65.0% and 62.9% for FEF , FEF , respectively). However, the optimal FeNO value in patients aged <55 years (43 ppb) was lower than that in patients aged ≥55 years (48 ppb). FeNO combined with SAFPs (FEF , FEF ) significantly increased the AUCs in both groups (≥55 years [0.851 for FEF and 0.844 for FEF ]; <55 years [0.865 for FEF and 0.883 for FEF ]) compared with a single parameter (p < 0.05). These findings were confirmed in the validation cohort. Compared with patients ≥55 years, those aged <55 years had higher and lower optimal cut-off values for SAFPs and FeNO, respectively. The AUCs of FeNO combined with SAFPs for predicting a positive MCT for asthma diagnosis were significantly higher than those of the individual parameters (p < 0.05) in both age groups.

Conclusions: There were age-group differences in the utility of SAFPs combined with FeNO for predicting a positive MCT. Patients with an asthma-suggestive history and a normal FEV should be stratified by age when using SAFPs combined with FeNO to predict a positive MCT.
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http://dx.doi.org/10.1002/clt2.12007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8099229PMC
March 2021

Prenatal and postnatal exposure to Bisphenol A and Asthma: a systemic review and meta-analysis.

J Thorac Dis 2021 Mar;13(3):1684-1696

Key Laboratory of Respiratory Disease of Zhejiang Province, Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China.

Background: Bisphenol A (BPA) is a plasticizer with high production and ubiquitous usage in polycarbonate plastics and epoxy resins. The association between prenatal or postnatal exposure to BPA and childhood wheeze/asthma has not been well established. Our study aimed to provide further justification for the current studies.

Methods: Studies were searched from PubMed, Web of Science, Scopus and Embase from inception until Sep 15, 2020. Meta-analysis was performed to calculate pooled adjusted odds ratios (aOR). The methodological quality of included studies was assessed by using the Newcastle Ottawa Scale (NOS).

Results: Of 2,814 screened articles, 9 studies with 3,885 participants were included in the final analysis. When all studies were pooled, postnatal exposure to BPA was associated with a higher risk of childhood asthma (aOR =1.43; 95% CI: 1.28-1.59) or childhood wheeze (aOR =1.38; 95% CI: 1.18-1.62). Prenatal exposure to BPA had a small but significant increased risk of childhood asthma (aOR =1.17; 95% CI: 1.01-1.34). An increased risk of childhood wheeze was related to prenatal exposure to BPA at 16 weeks' gestation (aOR =1.29; 95% CI: 1.07-1.55), but not at 26 weeks' gestation (aOR =1.07; 95% CI: 0.88-1.29) nor at random-time gestation (aOR =1.02; 95% CI: 0.89-1.16).

Conclusions: Prenatal and postnatal exposure to BPA was related to an increased risk of childhood asthma. However, only postnatal and early gestational exposure (at 16 weeks) to BPA could induce the risk of childhood wheeze, but not late gestational exposure (at 26 weeks).
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http://dx.doi.org/10.21037/jtd-20-1550DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8024800PMC
March 2021

Eosinophil-derived chemokine (hCCL15/23, mCCL6) interacts with CCR1 to promote eosinophilic airway inflammation.

Signal Transduct Target Ther 2021 Feb 28;6(1):91. Epub 2021 Feb 28.

Key Laboratory of Respiratory Disease of Zhejiang Province, Department of Respiratory and Critical Care Medicine, the Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, 310009, China.

Eosinophils are terminally differentiated cells derived from hematopoietic stem cells (HSCs) in the bone marrow. Several studies have confirmed the effective roles of eosinophils in asthmatic airway pathogenesis. However, their regulatory functions have not been well elucidated. Here, increased C-C chemokine ligand 6 (CCL6) in asthmatic mice and the human orthologs CCL15 and CCL23 that are highly expressed in asthma patients are described, which are mainly derived from eosinophils. Using Ccl6 knockout mice, further studies revealed CCL6-dependent allergic airway inflammation and committed eosinophilia in the bone marrow following ovalbumin (OVA) challenge and identified a CCL6-CCR1 regulatory axis in hematopoietic stem cells (HSCs). Eosinophil differentiation and airway inflammation were remarkably decreased by the specific CCR1 antagonist BX471. Thus, the study identifies that the CCL6-CCR1 axis is involved in the crosstalk between eosinophils and HSCs during the development of allergic airway inflammation, which also reveals a potential therapeutic strategy for targeting G protein-coupled receptors (GPCRs) for future clinical treatment of asthma.
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http://dx.doi.org/10.1038/s41392-021-00482-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7914252PMC
February 2021

A rapid screening classifier for diagnosing COVID-19.

Int J Biol Sci 2021 9;17(2):539-548. Epub 2021 Jan 9.

Key Laboratory of Respiratory Disease of Zhejiang Province, Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.

Coronavirus disease 2019 (COVID-19) has caused a global pandemic. A classifier combining chest X-ray (CXR) with clinical features may serve as a rapid screening approach. The study included 512 patients with COVID-19 and 106 with influenza A/B pneumonia. A deep neural network (DNN) was applied, and deep features derived from CXR and clinical findings formed fused features for diagnosis prediction. The clinical features of COVID-19 and influenza showed different patterns. Patients with COVID-19 experienced less fever, more diarrhea, and more salient hypercoagulability. Classifiers constructed using the clinical features or CXR had an area under the receiver operating curve (AUC) of 0.909 and 0.919, respectively. The diagnostic efficacy of the classifier combining the clinical features and CXR was dramatically improved and the AUC was 0.952 with 91.5% sensitivity and 81.2% specificity. Moreover, combined classifier was functional in both severe and non-serve COVID-19, with an AUC of 0.971 with 96.9% sensitivity in non-severe cases, which was on par with the computed tomography (CT)-based classifier, but had relatively inferior efficacy in severe cases compared to CT. In extension, we performed a reader study involving three experienced pulmonary physicians, artificial intelligence (AI) system demonstrated superiority in turn-around time and diagnostic accuracy compared with experienced pulmonary physicians. The classifier constructed using clinical and CXR features is efficient, economical, and radiation safe for distinguishing COVID-19 from influenza A/B pneumonia, serving as an ideal rapid screening tool during the COVID-19 pandemic.
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http://dx.doi.org/10.7150/ijbs.53982DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7893593PMC
March 2021

Detection of Viruses by Multiplex Real-Time Polymerase Chain Reaction in Bronchoalveolar Lavage Fluid of Patients with Nonresponding Community-Acquired Pneumonia.

Can Respir J 2020 25;2020:8715756. Epub 2020 Nov 25.

Key Laboratory of Respiratory Disease of Zhejiang Province, Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, China.

Background: Nonresponding pneumonia is responsible for the most mortality of community-acquired pneumonia (CAP). However, thus far, it is not clear whether viral infection plays an important role in the etiology of nonresponding CAP and whether there is a significant difference in the clinical characteristics between viral and nonviral nonresponding CAP.

Methods: From 2016 to 2019, nonresponding CAP patients were retrospectively enrolled in our study. All patients received bronchoalveolar lavage (BAL) and virus detection in BAL fluid by multiplex real-time polymerase chain reaction (PCR), and clinical, laboratory, and radiographic data were collected.

Results: A total of 43 patients were included. The median age was 62 years, and 65.1% of patients were male. Overall, 20 patients (46.5%) were identified with viral infection. Of these viruses, influenza virus ( = 8) and adenovirus ( = 7) were more frequently detected, and others included herpes simplex virus, human enterovirus, cytomegalovirus, human coronavirus 229E, rhinovirus, and parainfluenza virus. Compared with nonviral nonresponding CAP, only ground-glass opacity combined with consolidation was a more common imaging manifestation in viral nonresponding CAP. However, no obvious differences were found in clinical and laboratory findings between the presence and the absence of viral infections.

Conclusions: Viral infections were particularly frequent in adults with nonresponding CAP. The ground-glass opacity combined with consolidation was a specific imaging manifestation for viral nonresponding CAP, while the clinical and laboratory data showed no obvious differences between viral and nonviral nonresponding CAP.
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http://dx.doi.org/10.1155/2020/8715756DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7714605PMC
December 2020

MTOR suppresses autophagy-mediated production of IL25 in allergic airway inflammation.

Thorax 2020 12 18;75(12):1047-1057. Epub 2020 Oct 18.

Key Laboratory of Respiratory Disease of Zhejiang Province, Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, China

Introduction: Airway epithelial cells are recognised as an essential controller for the initiation and perpetuation of asthmatic inflammation, yet the detailed mechanisms remain largely unknown. This study aims to investigate the roles and mechanisms of the mechanistic target of rapamycin (MTOR)-autophagy axis in airway epithelial injury in asthma.

Methods: We examined the MTOR-autophagy signalling in airway epithelium from asthmatic patients or allergic mice induced by ovalbumin or house dust mites, or in human bronchial epithelial (HBE) cells. Furthermore, mice with specific MTOR knockdown in airway epithelium and autophagy-related mice were used for allergic models.

Results: MTOR activity was decreased, while autophagy was elevated, in airway epithelium from asthmatic patients or allergic mice, or in HBE cells treated with IL33 or IL13. These changes were associated with upstream tuberous sclerosis protein 2 signalling. Specific MTOR knockdown in mouse bronchial epithelium augmented, while LC3B deletion diminished allergen-induced airway inflammation and mucus hyperproduction. The worsened inflammation caused by MTOR deficiency was also ameliorated in mice. Mechanistically, autophagy was induced later than the emergence of allergen-initiated inflammation, particularly IL33 expression. MTOR deficiency increased, while knocking out of LC3B abolished the production of IL25 and the eventual airway inflammation on allergen challenge. Blocking IL25 markedly attenuated the exacerbated airway inflammation in MTOR-deficiency mice.

Conclusion: Collectively, these results demonstrate that allergen-initiated inflammation suppresses MTOR and induces autophagy in airway epithelial cells, which results in the production of certain proallergic cytokines such as IL25, further promoting the type 2 response and eventually perpetuating airway inflammation in asthma.
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http://dx.doi.org/10.1136/thoraxjnl-2019-213771DOI Listing
December 2020

Elevated mortality of chronic diseases during COVID-19 pandemic: a cause for concern?

Ther Adv Chronic Dis 2020 26;11:2040622320961590. Epub 2020 Sep 26.

Department of Respiratory and Critical Care Medicine, Key Laboratory of Respiratory Disease of Zhejiang Province, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310009, China.

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http://dx.doi.org/10.1177/2040622320961590DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7534067PMC
September 2020

Mutation Revealed from Myofibroblastoma-Discordant Monozygotic Twins Leads to p53/p21 Deficit and WEE1 Inhibitor Sensitivity.

Adv Sci (Weinh) 2020 Oct 5;7(19):2001041. Epub 2020 Aug 5.

Key Laboratory of Respiratory Disease of Zhejiang Province, Department of Respiratory and Critical Care Medicine Second Affiliated Hospital of Zhejiang University School of Medicine Hangzhou Zhejiang 310009 China.

High-throughput gene sequencing has identified various genetic variants as the culprits for some common hereditary cancers. However, the heritability of a substantial proportion of cancers remains unexplained, which may result from rare deleterious mutations hidden in a myriad of nonsense genetic variations. This poses a great challenge to the understanding of the pathology and thus the rational design of effective treatments for affected patients. Here, whole genome sequencing is employed in a representative case in which one monozygotic twin is discordant for lung inflammatory myofibroblastoma to disclose rare tumor-related mutations. A missense single nucleotide variation rs61955126 T>C in the lysine methyltransferase SETD8 (accession: NM_020382, ) is exposed. It is shown that SETD8 is vital for genomic integrity by promoting faithful DNA replication, and its C302R mutation downregulates the p53/p21 pathway. Importantly, the mutation significantly increases the sensitivity of cancer cells to WEE1 inhibition. Given that WEE1 inhibitors have shown great promise for clinical approval, these results impart a potential therapeutic approach using WEE1 inhibitor for cancer patients carrying the same mutation, and indicate that genome sequencing and genetic functional studies can be integrated into individualized therapies.
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http://dx.doi.org/10.1002/advs.202001041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7539211PMC
October 2020

Response of patients with chest tightness variant asthma with routine asthma treatment regimen: A 1-year multicenter, prospective, real-world study.

Clin Transl Med 2020 Sep;10(5):e178

Department of Pulmonary Medicine, Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.

Background: Asthmatic patients with chest tightness as their only presenting symptom (chest tightness variant asthma [CTVA]) have clinical characteristics of eosinophilic airway inflammation similar to those of classic asthma (CA); however, whether CTVA has similar response to antiasthma treatment as compared with CA remains unclear.

Objective: The response of 76 CTVA patients to standard asthma treatments with inhaled corticosteroids with long-acting beta-agonists was explored in a 52-week multicenter, prospective, real-world study.

Results: After 52 weeks of treatment with therapy regimens used for CA, the mean 5-point Asthma Control Questionnaire (ACQ-5) score decreased markedly from 1.38(first administration) to 0.71 (52 weeks, mean decrease: 0.674, 95%CI: 0.447-0.900, P<.001).The mean asthma quality-of-life questionnaire (AQLQ) score increased from 5.77 (first administration) to 6.20 (52 weeks, mean increase: 0.441, 95% CI 0.258-0.625, P<.001). Furthermore, at week 52, FVC, FEV %, the diurnal variation in PEFand the PD20-FEV were significantly improved. Subgroup analysis revealed that the patients at first administration in the responsive group had higher ACQ-5 scores than those in the nonresponsive group (P < .05).

Conclusion: In conclusion, patients with CTVA had a good therapeutic response to the guideline-recommended routine treatment (containing inhaled corticosteroids). The association between the treatment response and the severity of CTVA suggested that CTVA patients with higher ACQ-5 scores had better therapeutic effects.
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http://dx.doi.org/10.1002/ctm2.178DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7503098PMC
September 2020

Induction of ferroptosis-like cell death of eosinophils exerts synergistic effects with glucocorticoids in allergic airway inflammation.

Thorax 2020 11 5;75(11):918-927. Epub 2020 Aug 5.

Key Laboratory of Respiratory Disease of Zhejiang Province, Department of Respiratory and Critical Care Medicine, Zhejiang University School of Medicine Second Affiliated Hospital, Hangzhou, Zhejiang, China

Introduction: Eosinophils are critical in allergic disorders, and promoting eosinophil death effectively attenuates allergic airway inflammation. Ferroptosis is a recently described novel form of cell death; however, little is known about ferroptosis in eosinophils and related diseases. This study aimed to investigate the effects of ferroptosis-inducing agents (FINs) on eosinophil death and allergic airway inflammation, and to explore their potential synergistic effect with glucocorticoids (GCs).

Methods: Eosinophils isolated from the peripheral blood of humans or mice were incubated with FINs, and eosinophil ferroptosis was assessed. The in vivo effects of FINs alone or in combination with dexamethasone (DXMS) were examined in a mouse model of allergic airway inflammation. Bronchoalveolar lavage fluid and lung tissue were collected to examine airway inflammation.

Results: Treatment with FINs time and dose dependency induced cell death in human and mouse eosinophils. Interestingly, FINs induced non-canonical ferroptosis in eosinophils, which generated morphological characteristics unique to ferroptosis and was iron dependent but was independent of lipid peroxidation. The antioxidants glutathione and N-acetylcysteine significantly attenuated FIN-induced cell death. Treatment with FINs triggered eosinophil death in vivo and eventually relieved eosinophilic airway inflammation in mice. Furthermore, FINs exerted a synergistic effect with DXMS to induce eosinophil death in vitro and to alleviate allergic airway inflammation in vivo.

Conclusions: FINs induced ferroptosis-like cell death of eosinophils, suggesting their use as a promising therapeutic strategy for eosinophilic airway inflammation, especially due to the advantage of their synergy with GCs in the treatment of allergic disorders.
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http://dx.doi.org/10.1136/thoraxjnl-2020-214764DOI Listing
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

Genome-wide high-resolution mapping of mitotic DNA synthesis sites and common fragile sites by direct sequencing.

Cell Res 2020 11 19;30(11):1009-1023. Epub 2020 Jun 19.

Department of Pharmacology & Department of Respiratory and Critical Care Medicine of the Second Affiliated Hospital, Zhejiang University School of Medicine, Key Laboratory of Respiratory Disease of Zhejiang Province, Hangzhou, Zhejiang, 310009, China.

Common fragile sites (CFSs) are genomic loci prone to the formation of breaks or gaps on metaphase chromosomes. They are hotspots for chromosome rearrangements and structural variations, which have been extensively implicated in carcinogenesis, aging, and other pathological processes. Although many CFSs were identified decades ago, a consensus is still lacking for why they are particularly unstable and sensitive to replication perturbations. This is in part due to the lack of high-resolution mapping data for the vast majority of the CFSs, which has hindered mechanistic interrogations. Here, we seek to map human CFSs with high resolution on a genome-wide scale by sequencing the sites of mitotic DNA synthesis (MiDASeq) that are specific for CFSs. We generated a nucleotide-resolution atlas of MiDAS sites (MDSs) that covered most of the known CFSs, and comprehensively analyzed their sequence characteristics and genomic features. Our data on MDSs tallied well with long-standing hypotheses to explain CFS fragility while highlighting the contributions of late replication timing and large transcription units. Notably, the MDSs also encompassed most of the recurrent double-strand break clusters previously identified in mouse neural stem/progenitor cells, thus bridging evolutionarily conserved break points across species. Moreover, MiDAseq provides an important resource that can stimulate future research on CFSs to further unravel the mechanisms and biological relevance underlying these labile genomic regions.
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http://dx.doi.org/10.1038/s41422-020-0357-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7785011PMC
November 2020

Replication Stress Induces ATR/CHK1-Dependent Nonrandom Segregation of Damaged Chromosomes.

Mol Cell 2020 05 29;78(4):714-724.e5. Epub 2020 Apr 29.

Department of Pharmacology and Department of Respiratory and Critical Care Medicine of the Second Affiliated Hospital, Zhejiang University School of Medicine, Key Laboratory of Respiratory Disease of Zhejiang Province, Hangzhou 310009, China. Electronic address:

Nonrandom DNA segregation (NDS) is a mitotic event in which sister chromatids carrying the oldest DNA strands are inherited exclusively by one of the two daughter cells. Although this phenomenon has been observed across various organisms, the mechanism and physiological relevance of this event remain poorly defined. Here, we demonstrate that DNA replication stress can trigger NDS in human cells. This biased inheritance of old template DNA is associated with the asymmetric DNA damage response (DDR), which derives at least in part from telomeric DNA. Mechanistically, we reveal that the ATR/CHK1 signaling pathway plays an essential role in mediating NDS. We show that this biased segregation process leads to cell-cycle arrest and cell death in damaged daughter cells inheriting newly replicated DNA. These data therefore identify a key role for NDS in the maintenance of genomic integrity within cancer cell populations undergoing replication stress due to oncogene activation.
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http://dx.doi.org/10.1016/j.molcel.2020.04.005DOI Listing
May 2020

Comparison of transbronchial needle aspiration with and without ultrasound guidance for diagnosing benign lymph node adenopathy.

Diagn Pathol 2020 Apr 15;15(1):36. Epub 2020 Apr 15.

Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310009, China.

Background: Transbronchial needle aspiration (TBNA) is a minimally invasive procedure performed to diagnose lymph node (LN) adenopathy. TBNA with and without endobronchial ultrasound (EBUS) guidance has a high diagnostic yield for malignant LN enlargement, but the value for diagnosing benign LN enlargement has been less thoroughly investigated.

Methods: We retrospectively evaluated 3540 patients with mediastinal LN enlargement who received TBNA. One hundred sixty-six patients with benign mediastinal lymphadenopathy were included and 293 LNs were biopsied. A positive result was defined as a specific histological abnormality. Conventional TBNA (cTBNA) and EBUS-TBNA, as well as cTBNA and transbronchial forceps biopsy (TBFB), were compared. The subgroup analysis was stratified by disease type and LN size.

Results: A diagnosis was made in 76.84% of the EBUS-TBNA and 61.31% of the cTBNA (P < 0.05). EBUS-TBNA was superior to cTBNA for both granulomatous (65.18% vs. 45.45%, P < 0.05) and non-granulomatous disease (96.92% vs. 84.06%, P < 0.05). In contrast, the diagnostic yield of EBUS-TBNA was higher than that of cTBNA for LNs < 20 mm (79.44% vs. 64.29%, P < 0.05), but for LNs > 20 mm the difference was marginal. These findings were confirmed in a group of independent patients who received cTBNA plus EBUS-TBNA. The diagnostic yield did not differ between cTBNA and TBFB, but significantly increased to 76.67% when both modalities were employed.

Conclusions: EBUS-TBNA is the preferred minimally invasive diagnostic method for benign mediastinal LN disease. Combined cTBNA and TBFB is a safe and feasible alternative when EBUS is unavailable.
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http://dx.doi.org/10.1186/s13000-020-00958-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7158000PMC
April 2020

Early recruited neutrophils promote asthmatic inflammation exacerbation by release of neutrophil elastase.

Cell Immunol 2020 06 3;352:104101. Epub 2020 Apr 3.

Key Laboratory of Respiratory Disease of Zhejiang Province, Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, China. Electronic address:

Neutrophils can regulate adaptive immune responses and contribute to chronic inflammation including asthma. However, the roles and mechanisms of neutrophils in initiating eosinophilic airway inflammation remain incompletely understood. Neutrophil elastase (NE) is a component of azurophilic granules and a serine protease with potent functions during inflammation. Here, we showed that neutrophils were early recruited at the onset of asthmatic inflammation by related chemokines. Furthermore, neutrophils could capture allergens and release NE to promote neutrophil aggregation at first. Then they prompt eosinophil infiltration and amplify type 2 immune responses in later phases. Also, this process can be rescued by administration of the NE inhibitor (GW311616). Our data collectively indicate that neutrophils could contribute to asthmatic inflammation by releasing NE.
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http://dx.doi.org/10.1016/j.cellimm.2020.104101DOI Listing
June 2020

Risk of COVID-19 for patients with cancer.

Lancet Oncol 2020 04 3;21(4):e180. Epub 2020 Mar 3.

Key Laboratory of Respiratory Disease of Zhejiang Province, Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang 310052, China. Electronic address:

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http://dx.doi.org/10.1016/S1470-2045(20)30150-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7130057PMC
April 2020

Airway Epithelial cGAS Is Critical for Induction of Experimental Allergic Airway Inflammation.

J Immunol 2020 03 7;204(6):1437-1447. Epub 2020 Feb 7.

Key Laboratory of Respiratory Disease of Zhejiang Province, Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, China; and

DNA damage could lead to the accumulation of cytosolic DNA, and the cytosolic DNA-sensing pathway has been implicated in multiple inflammatory diseases. However, the role of cytosolic DNA-sensing pathway in asthma pathogenesis is still unclear. This article explored the role of airway epithelial cyclic GMP-AMP synthase (cGAS), the major sensor of cytosolic dsDNA, in asthma pathogenesis. Cytosolic dsDNA accumulation in airway epithelial cells (ECs) was detected in the setting of allergic inflammation both in vitro and in vivo. Mice with cGAS deletion in airway ECs were used for OVA- or house dust mite (HDM)-induced allergic airway inflammation. Additionally, the effects of cGAS knockdown on IL-33-induced GM-CSF production and the mechanisms by which IL-33 induced cytosolic dsDNA accumulation in human bronchial epithelial (HBE) cells were explored. Increased accumulation of cytosolic dsDNA was observed in airway epithelium of OVA- or HDM-challenged mice and in HBE cells treated with IL-33. Deletion of cGAS in the airway ECs of mice significantly attenuated the allergic airway inflammation induced by OVA or HDM. Mechanistically, cGAS participates in promoting T2 immunity likely via regulating the production of airway epithelial GM-CSF. Furthermore, Mito-TEMPO could reduce IL-33-induced cytoplasmic dsDNA accumulation in HBE cells possibly through suppressing the release of mitochondrial DNA into the cytosol. In conclusion, airway epithelial cGAS plays an important role via sensing the cytosolic dsDNA in asthma pathogenesis and could serve as a promising therapeutic target against allergic airway inflammation.
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http://dx.doi.org/10.4049/jimmunol.1900869DOI Listing
March 2020

Combination of the CRP mutation and ptsG deletion in Escherichia coli to efficiently synthesize xylitol from corncob hydrolysates.

Appl Microbiol Biotechnol 2020 Mar 16;104(5):2039-2050. Epub 2020 Jan 16.

Key Laboratory of Biomass Chemical Engineering of Ministry of Education, College of Chemical and Biological Engineering, Zhejiang University, Hangzhou, 310027, People's Republic of China.

The biotechnology-based production of xylitol has received widespread attention because it can use cheap and renewable lignocellulose as a raw material, thereby decreasing costs and pollution. The simultaneous use of various sugars in lignocellulose hydrolysates is a primary prerequisite for efficient xylitol production. In this study, a ΔptsG and crp* combinatorial strategy was used to generate Escherichia coli W3110 strain IS5-dI, which completely eliminated glucose repression and simultaneously used glucose and xylose. This strain produced 164 g/L xylitol from detoxified corncob hydrolysates during a fed-batch fermentation in a 15-L bioreactor, which was 14.7% higher than the xylitol produced by the starting strain, IS5-d (143 g/L), and the xylitol productivity was 3.04 g/L/h. These results represent the highest xylitol concentration and productivity reported to date for bacteria and hemicellulosic sugars. Additionally, strain IS5-dG, which differs from IS5-dI at CRP amino acid residue 127 (I127G), was tolerant to the toxins in corncob hydrolysates. In a fed-batch fermentation experiment involving a 15-L bioreactor, IS5-dG produced 137 g/L xylitol from non-detoxified corncob hydrolysates, with a productivity of 1.76 g/L/h. On the basis of these results, we believe that IS5-dI and IS5-dG may be useful host strains for the industrial-scale production of xylitol from detoxified or non-detoxified corncob hydrolysates.
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http://dx.doi.org/10.1007/s00253-019-10324-0DOI Listing
March 2020

Corrigendum to "Nanoformulated ABT-199 to effectively target Bcl-2 at mitochondrial membrane alleviates airway inflammation by inducing apoptosis" [Biomaterials 192 (2019) 429-439].

Biomaterials 2020 Jan 22;227:119549. Epub 2019 Oct 22.

Key Laboratory of Respiratory Disease of Zhejiang Province, Hangzhou, Zhejiang, 310058, China; Department of Respiratory and Critical Care Medicine, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310009, China; Key Site of National Clinical Research Center for Respiratory Disease, Hangzhou, Zhejiang, 310009, China; State Key Laboratory of Respiratory Diseases, Guangzhou, Guangdong, 510120,China. Electronic address:

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http://dx.doi.org/10.1016/j.biomaterials.2019.119549DOI Listing
January 2020

Management of severe asthma: a European Respiratory Society/American Thoracic Society guideline.

Eur Respir J 2020 01 2;55(1). Epub 2020 Jan 2.

Division of Pulmonary and Critical Care, University of Wisconsin, Madison, WI, USA.

This document provides clinical recommendations for the management of severe asthma. Comprehensive evidence syntheses, including meta-analyses, were performed to summarise all available evidence relevant to the European Respiratory Society/American Thoracic Society Task Force's questions. The evidence was appraised using the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach and the results were summarised in evidence profiles. The evidence syntheses were discussed and recommendations formulated by a multidisciplinary Task Force of asthma experts, who made specific recommendations on six specific questions. After considering the balance of desirable and undesirable consequences, quality of evidence, feasibility, and acceptability of various interventions, the Task Force made the following recommendations: 1) suggest using anti-interleukin (IL)-5 and anti-IL-5 receptor α for severe uncontrolled adult eosinophilic asthma phenotypes; 2) suggest using a blood eosinophil cut-point ≥150 μL to guide anti-IL-5 initiation in adult patients with severe asthma; 3) suggest considering specific eosinophil (≥260 μL) and exhaled nitric oxide fraction (≥19.5 ppb) cut-offs to identify adolescents or adults with the greatest likelihood of response to anti-IgE therapy; 4) suggest using inhaled tiotropium for adolescents and adults with severe uncontrolled asthma despite Global Initiative for Asthma (GINA) step 4-5 or National Asthma Education and Prevention Program (NAEPP) step 5 therapies; 5) suggest a trial of chronic macrolide therapy to reduce asthma exacerbations in persistently symptomatic or uncontrolled patients on GINA step 5 or NAEPP step 5 therapies, irrespective of asthma phenotype; and 6) suggest using anti-IL-4/13 for adult patients with severe eosinophilic asthma and for those with severe corticosteroid-dependent asthma regardless of blood eosinophil levels. These recommendations should be reconsidered as new evidence becomes available.
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http://dx.doi.org/10.1183/13993003.00588-2019DOI Listing
January 2020

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

Lipid metabolism in chronic obstructive pulmonary disease.

Int J Chron Obstruct Pulmon Dis 2019 13;14:1009-1018. Epub 2019 May 13.

Key Laboratory of Respiratory Disease of Zhejiang Province, Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital of Zhejiang University School of Medicine, Institute of Respiratory Diseases, Hangzhou, Zhejiang, People's Republic of China.

Dysregulated lipid metabolism plays crucial roles in various diseases, including diabetes mellitus, cancer, and neurodegeneration. Recent studies suggest that alterations in major lipid metabolic pathways contribute to pathogenesis of lung diseases, including chronic obstructive pulmonary disease (COPD). These changes allow lung tissue to meet the energy needs and trigger anabolic pathways that initiate the synthesis of active molecules directly involved in the inflammation. In this review, we summarize the changes of catabolism and anabolism of lipids, lipid molecules including lipid mediators, lipid synthesis transcription factors, cholesterol, and phospholipids, and how those lipid molecules participate in the initiation and resolution of inflammation in COPD.
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http://dx.doi.org/10.2147/COPD.S196210DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6524761PMC
January 2020
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