Showing papers by "Huahao Shen published in 2021"

Eosinophilic inflammation promotes CCL6-dependent metastatic tumor growth

Abstract: 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 Cd3δ-Il-5 transgenic (Il-5 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 Ccl6 in Il-5 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.

A rapid screening classifier for diagnosing COVID-19.

Abstract: Rationale: 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 Methods: 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 Results: 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 0909 and 0919, respectively The diagnostic efficacy of the classifier combining the clinical features and CXR was dramatically improved and the AUC was 0952 with 915% sensitivity and 812% specificity Moreover, combined classifier was functional in both severe and non-serve COVID-19, with an AUC of 0971 with 969% 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 Conclusions: 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

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

Abstract: Background The therapeutic efficacy of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in advanced EGFR-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, EGFR-mutant, and EGFR-TKI-treated patients with SCC. Patients with EGFR wild-type lung SCC and EGFR-mutant lung adenocarcinoma were consecutively enrolled as controls, and next-generation sequencing (NGS) was performed. Results In total, 28 EGFR-mutant lung SCC, 41 EGFR-mutant lung adenocarcinoma, and 40 EGFR wild-type lung SCC patients were included. Among the patients with EGFR mutations, shorter progression-free survival (PFS) was observed in SCC compared to adenocarcinoma (4.6 vs. 11.0 months, P<0.001). Comparison of the genomic profiles revealed that EGFR-mutant SCC patients had similar mutation characteristics to EGFR-mutant adenocarcinoma patients, but differed from those with EGFR wild-type SCC. Further exploration of EGFR-mutant SCC revealed that mutations in CREBBP (P = 0.005), ZNF217 (P = 0.016), and the Wnt (P = 0.027) pathway were negatively associated with PFS. Mutations in GRM8 (P = 0.025) were associated with improved PFS. Conclusions EGFR-mutant lung SCC has a worse prognosis than EGFR-mutant adenocarcinoma. Mutations in other genes, such as CREBBP, ZNF217, GRM8, 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 EGFR-mutant SCCs receiving EGFR-TKIs.

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

Abstract: 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.

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

Abstract: (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.

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 1 ≥ 80% predicted.

Abstract: 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 (FEV1 ) ≥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 FEV1 ≥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 FEV1 ≥80% predicted RESULTS In the discovery cohort, the optimal cut-off values for predicting a positive MCT in patients aged <55 years (742% and 749% for forced expiratory flow (FEF)50% and FEF25%-75% , respectively) were higher than those in patients aged ≥55 years (650% and 629% for FEF50% , FEF25%-75% , 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 (FEF50% , FEF25%-75% ) significantly increased the AUCs in both groups (≥55 years [0851 for FEF50% and 0844 for FEF25%-75% ]; <55 years [0865 for FEF50% and 0883 for FEF25%-75% ]) compared with a single parameter (p < 005) 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 < 005) 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 FEV1 should be stratified by age when using SAFPs combined with FeNO to predict a positive MCT

Therapeutic Effects of the Bcl-2 Inhibitor on Bleomycin-induced Pulmonary Fibrosis in Mice.

Abstract: Idiopathic pulmonary fibrosis (IPF) is a distressing lung disorder with poor prognosis and high mortality rates. Limited therapeutic options for IPF is a major clinical challenge. Well-known for its anti-apoptotic properties, B-cell lymphoma 2 (Bcl-2) plays a critical role in the pathology of malignancies and inflammatory diseases, including IPF. In this study, we aimed to investigate the therapeutic effect of a Bcl-2 homology domain 3 mimetic inhibitor, ABT-199, on bleomycin (BLM)-induced pulmonary fibrosis in mice, and explore possible underlying mechanism. The lung inflammation and fibrosis model was established by intratracheal instillation of a single dose of BLM. We observed elevated Bcl-2 in the alveolar macrophages and fibroblasts derived from BLM-instilled mice from day 7. Further, we obtained in vivo evidence that early therapeutic treatment with Bcl-2 inhibitor ABT-199 from day 3, and late treatment from day 10, both alleviated airway inflammation and lung fibrosis induced by BLM. Our data suggest that ABT-199 might be an effective antifibrotic agent that interferes with profibrogenic cells, which may be a promising therapy in the treatment of clinical IPF patients.

Autophagy Promotes Cigarette Smoke-Initiated and Elastin-Driven Bronchitis-Like Airway Inflammation in Mice.

Abstract: Cigarette smoke (CS)-induced macrophage activation and airway epithelial injury are both critical for the development of chronic obstructive pulmonary disease (COPD), while the eventual functions of autophagy in these processes remain controversial. We have recently developed a novel COPD mouse model which is based on the autoimmune response sensitized by CS and facilitated by elastin. In the current study, we therefore utilized this model to investigate the roles of autophagy in different stages of the development of bronchitis-like airway inflammation. Autophagic markers were increased in airway epithelium and lung tissues, and Becn+/- or Lc3b-/- mice exhibited reduced neutrophilic airway inflammation and mucus hyperproduction in this COPD mouse model. Moreover, treatment of an autophagic inhibitor 3-methyladenine (3-MA) either during CS-initiated sensitization or during elastin provocation significantly inhibited the bronchitis-like phenotypes in mice. Short CS exposure rapidly induced expression of matrix metallopeptidase 12 (MMP12) in alveolar macrophages, and treatment of doxycycline, a pan metalloproteinase inhibitor, during CS exposure effectively attenuated the ensuing elastin-induced airway inflammation in mice. CS extract triggered MMP12 expression in cultured macrophages, which was attenuated by autophagy impairment (Becn+/- or Lc3b-/-) or inhibition (3-MA or Spautin-1). These data, taken together, demonstrate that autophagy mediates both the CS-initiated MMP12 activation in macrophages and subsequent airway epithelial injury, eventually contributing to development COPD-like airway inflammation. This study reemphasizes that inhibition of autophagy as a novel therapeutic strategy for CS-induced COPD.

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

Abstract: 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 non-smokers 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 non-smokers 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.

Perspectives and Management of Atypical Asthma in Chinese Specialists and Primary Care Practitioners-A Nationwide Questionnaire Survey.

Abstract: Background and objective: To evaluate the awareness/knowledge and clinical practice for the treatment of atypical asthma among respiratory specialists and primary care practitioners (PCPs) in China. Methods: A total number of 1,997 physicians participated in the survey via WeChat. The questionnaire included six main items: physician demographic characteristics, awareness, diagnosis, medical prescription, assessment/education, and proposal. Results: Cough variant asthma (CVA) was recognized by 97.51% of physicians (1,166 respiratory specialists and 799 PCPs), followed by chest tightness variant asthma (CTVA, 83.72%) and occult asthma (73.54%). Specialists were more likely to follow diagnostic recommendations than PCPs (P < 0.01); however, 34.15% of physicians reported the utility of bronchodilation tests, airway provocation tests, and peak expiratory flow monitoring. A total of 91.70% and 92.01% of physicians prescribed inhaled corticosteroids (ICS) or ICS plus long-acting beta-agonists (LABA) for CVA and CTVA, respectively. Physicians prescribed an ICS or ICS/LABA for 4 (2-8) or 8 (4-12) weeks for CVA and 4 (2-8) or 5 (4-12) weeks for CTVA, and the prescription durations were significantly shorter for PCPs than for specialists (P < 0.01). Further, 52.42% and 35.78% reported good control of CVA and CTVA, respectively, with significantly lower control rates for PCPs than for specialists (P < 0.01). Additionally, specialists exhibited better assessment and educational habits than PCPs. Conclusion: While atypical asthma was identified by most specialists and PCPs, there remains a gap between management in real clinical practice and guideline recommendations, especially for PCPs. Further training of PCPs and clinical studies of atypical asthma are required to improve practice.

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

Abstract: 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).

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

Abstract: The airway epithelium is a central modulator of innate and adaptive immunity in the lung. IL17A expression was found to be increased in the airway epithelium; however, the role of epithelium-derive...