The central cholinergic system regulates diverse neurological functions, learning, attention, arousal, sleep, emotion regulation and behavior control. As a close evolutionary relative of primates, the tree shrew is a valuable comparative model for neurobiological investigation. However, the anatomical distribution of choline acetyltransferase-immunoreactive (ChAT-ir) neurons in its brain remains poorly characterized. Using ChAT immunofluorescence, we systematically mapped the whole-brain distribution and morphology of ChAT-ir neurons in the tree shrew and compared them with those in the mouse. In the neocortex, ChAT-ir neurons were absent in the tree shrew, whereas the mouse showed sparse cortical labeling. Semi-quantitative analyses of subcortical regions revealed the overall distribution was largely conserved, whereas the tree shrew exhibited higher ChAT-ir neuronal density in the trochlear and prepositus nuclei compared to mice. ChAT-ir neurons were detected in the suprachiasmatic and supraoptic nuclei in the hypothalamus in the tree shrew but not in the mouse. Tree shrew ChAT-ir neurons showed greater dendritic complexity in the caudate nucleus, medial septum, pedunculopontine/dorsal tegmental nuclei, and prepositus nucleus, while the horizontal limb of the diagonal band and oculomotor nuclei exhibited similar complexity across species. In the putamen, the tree shrew has more complex distal dendrites but less complex proximal branches than mice. ChAT-ir neurons displayed a rostral-to-caudal density gradient in the caudate, while mice showed largely uniform distributions of ChAT-, CB-, PV-, and CR-positive neurons across the medial and lateral sides of the caudate putamen. These findings provide a comprehensive mapping of ChAT-ir neurons in the tree shrew brain, highlighting significant interspecies differences and offering a structural framework for investigating cholinergic roles in diverse neural functions.

Compromised cortical inhibition during threat processing contributes to individual vulnerability to stress-related psychiatric disorders. However, the precise underlying neurobiological circuits remain elusive. Here, by combining monosynaptic viral tracing, electrophysiology, in vivo calcium imaging, and functional manipulations in mice, we elucidated a functionally specialized monosynaptic pathway originating from glutamatergic pyramidal neurons in the ventromedial prefrontal cortex (vmPFCGlu) to corticotropin-releasing hormone (CRH)-expressing neurons in the paraventricular nucleus of the hypothalamus (PVNCRH). We found that activating medial prefrontal cortex (mPFC)-driven CRH "pacemaker" cells propagated calcium signals within the local CRH network of the PVN. Hyperactivity of this vmPFCGlu-PVNCRH circuit promoted persistent social avoidance, consolidated threat memory, facilitated auditory-cued fear acquisition, and impaired extinction. Conversely, inhibition of this circuit selectively reduced social stress‑induced avoidance. Our findings define a novel top-down circuit that specifically controls psychosocial stress responses and amplifies susceptibility to conditioned fear.

Neuroinflammation is recognized as a key mechanism underlying depression, with glial cells playing a central role in regulating neuronal activity and neuroimmune interactions. However, how microglia and astrocytes in distinct brain regions respond morphologically to peripheral inflammatory stimulation and how these changes contribute to depression remain poorly understood. Here, we established a lipopolysaccharide (LPS)-induced mouse model of inflammation-related depression and observed a significant increase in c-Fos expression in emotion- and stress-related brain regions, including the bed nucleus of the stria terminalis (BST), the paraventricular nucleus of hypothalamus (PVN), the ventrolateral periaqueductal gray (vlPAG), the locus coeruleus (LC) and the solitary nucleus (Sol). Using three-dimensional (3D) reconstruction and Sholl analysis, we quantified the process complexity, spatial coverage and filamentous architecture of both microglia and astrocytes. Microglia showed hypertrophy across all examined regions. BST and PVN exhibited thicker and straighter processes, LC and vlPAG displayed decreased spatial complexity, and Sol exhibited reactive hypertrophy characterized by increased filament volume and maximal intersections. Astrocytes generally exhibited reduced filament length, process diameter, or structural simplification in the BST, PVN, LC and vlPAG, whereas Sol astrocytes displayed increased process diameter but reduced filament length, area and maximal radius. Together, these findings provide a structural basis for understanding the cellular mechanisms underlying inflammation-related depression across different brain regions and suggest potential functional roles of glial remodeling in inflammatory depression.

Variations in individual coping styles have been linked to either resilience or vulnerability towards stress, thereby influencing the probability of developing stress-related disorders. The involvement of corticotropin-releasing factor (CRF) neurons within the medial prefrontal cortex (mPFC) plays a crucial role in modulating behavioral responses to stressful situations. In this study utilizing a mouse model of social defeat stress (SDS), we demonstrate how coordinated activation and localized release of CRF within the mPFC contribute to promoting adaptive responses under stressful conditions leading to enhanced resilience against subsequent challenges. Specifically, during SDS exposure, heightened activity levels were observed among mPFC CRF neurons coincide with increased local release triggered by active exploration and defensive behaviors, while decreased responses were detected upon exposure to aggression. Interestingly, the CRF neural activity and local release responding to coping behaviors throughout chronic social defeat stress (CSDS) differed between susceptible and resilient mice. Furthermore, activation of CRF receptor 1 (CRFR1) signaling in the mPFC enhanced active coping behaviors and conferred resilience to CSDS, while inhibition of CRF system promoted passive coping behaviors and induced susceptibility to sub-threshold SDS. Additionally, inhibition of CRFR1 in the mPFC nullified the pro-resilience effect elicited by activation of CRF neurons during CSDS. The collective findings provide evidence supporting the crucial role of local endogenous CRF derived from mPFC CRF neurons in maintaining resilience through active coping styles when confronted with social stress. Moreover, these results suggest that targeting the mPFC CRF system could hold promise as a therapeutic approach for managing stress-related disorders.

Astrocytes are associated with varying brain size between rodents and primates. As a close evolutionary relative of primates, the tree shrew ( Tupaia belangeri) provides a valuable comparative model for investigating glial architecture. However, the anatomical distribution and morphological characteristics of astrocytes in the tree shrew brain remain poorly characterized. In this study, glial fibrillary acidic protein (GFAP) immunofluorescence was employed to systematically examine the spatial distribution and morphology of astrocytes in the whole brain of tree shrews. Notably, GFAP-immunoreactive (ir) astrocytes were detected throughout the telencephalon, diencephalon, mesencephalon, metencephalon, and myelencephalon. Distinct laminar distribution was evident in regions such as the main olfactory bulb and hippocampus. Semi-quantitative comparisons revealed significant regional differences in astrocyte density between tree shrews and mice, encompassing the main olfactory bulb, accessory olfactory bulb, olfactory tubercle, cortex, hippocampus, cortical amygdaloid nucleus, hypothalamus, thalamus, superior colliculus, interpeduncular nucleus, median raphe nucleus, and parabrachial nucleus. Compared to mice, tree shrews exhibited higher astrocyte density with increased morphological complexity in the posterior hypothalamic nucleus, dorsomedial hypothalamic nucleus, ventromedial hypothalamic nucleus, and periaqueductal gray, but lower density with greater morphological complexity in the hippocampus and substantia nigra. In the paraventricular hypothalamic nucleus and lateral hypothalamic area, GFAP-ir astrocytes displayed comparable densities between tree shrews and mice but exhibited region-specific differences in morphological complexity. This study provides the first brain-wide mapping of GFAP-ir astrocytes in tree shrews, revealing marked interspecies differences in their distribution and morphology, and establishing a neuroanatomical framework for understanding astrocyte involvement in diverse physiological and behavioral functions.

Background Microglia-mediated neuroinflammation in Alzheimer’s disease (AD) is not only a response to pathophysiological events, but also plays a causative role in neurodegeneration. Cytoplasmic cysteinyl-tRNA synthetase (CARS) is considered to be a stimulant for immune responses to diseases; however, it remains unknown whether CARS is involved in the pathogenesis of AD. Methods Postmortem human temporal cortical tissues at different Braak stages and AD patient-derived serum samples were used to investigate the changes of CARS levels in AD by immunocytochemical staining, real-time PCR, western blotting and ELISA. After that, C57BL/6J and APP/PS1 transgenic mice and BV-2 cell line were used to explore the role of CARS protein in memory and neuroinflammation, as well as the underlying mechanisms. Finally, the associations of morphological features among CARS protein, microglia and dense-core plaques were examined by immunocytochemical staining. Results A positive correlation was found between aging and the intensity of CARS immunoreactivity in the temporal cortex. Both protein and mRNA levels of CARS were increased in the temporal cortex of AD patients. Immunocytochemical staining revealed increased CARS immunoreactivity in neurons of the temporal cortex in AD patients. Moreover, overexpression of CARS in hippocampal neurons induced and aggravated cognitive dysfunction in C57BL/6J and APP/PS1 mice, respectively, accompanied by activation of microglia and the TLR2/MyD88 signaling pathway as well as upregulation of proinflammatory cytokines. In vitro experiments showed that CARS treatment facilitated the production of proinflammatory cytokines and the activation of the TLR2/MyD88 signaling pathway of BV-2 cells. The accumulation of CARS protein occurred within dense-core Aβ plaques accompanied by recruitment of ameboid microglia. Significant upregulation of TLR2/MyD88 proteins was also observed in the temporal cortex of AD. Conclusions The findings suggest that the neuronal CARS drives neuroinflammation and induces memory deficits, which might be involved in the pathogenesis of AD.

Abstract Background ICS-based maintenance treatment was the basic treatment of asthma. Nevertheless, data of real-world study of ICS-based maintenance treatment on asthma outcome was limited. Methods Based on a national survey on asthma control and disease perception (CARN-2015-01 study), we analysed the impact of ICS-based maintenance treatment on asthma outcome: asthma control, annual incidence of asthma exacerbation hospitalization and emergency department visit in China. Results Altogether 3875 asthmatic outpatients were recruited. 66.7% (2583/3875) asthma patients chose ICS-based maintenance treatment as daily maintenance treatment. After adjusting for confounding factors (age, height, weight, BMI, smoking status, comorbidities, etc), ICS-based maintenance treatment was associated with better asthma control level [OR = 0.542, 95%CI (0.476, 0.617)], higher annual incidence of asthma exacerbation hospitalization [OR = 1.501, 95%CI (1.271, 1.773)] and higher annual incidence of emergency department visits [OR = 1.272, 95%CI (1.074, 1.507)]. In subgroup analysis, in well-controlled asthma patients, there was no statistical difference on annual incidence of asthma exacerbation hospitalization and emergency department visits. In partly controlled asthma patients, patients with ICS-based maintenance treatment have significantly higher annual incidence of asthma exacerbation hospitalization (31.9% vs. 22.5%, P < 0.001) and higher annual incidence of emergency department visits (24.1% vs. 19.1%, P = 0.013). In uncontrolled asthma patients, patients with ICS-based maintenance treatment have significantly higher annual incidence of asthma exacerbation hospitalization (44.7% vs. 28.5%, P < 0.001) but showed no statistical difference on annual incidence of emergency department visits (39.0% vs. 32.4%, P = 0.051). Conclusions ICS-based maintenance treatment was associated with better asthma control level, higher annual incidence of asthma exacerbation hospitalization and higher annual incidence of emergency department visits. During the process of ICS-based maintenance treatment, improvement of symptom control might be prior to the decrease of exacerbation risk.

BACKGROUND:Heat shock protein 90α (Hsp90α) is considered a tumor biomarker in many human malignancies. This study investigated the diagnostic value of Hsp90α combined with other traditional lung cancer biomarkers (CEA, CYFRA21-1, and NSE) and its role in monitoring the treatment response of lung cancer patients. METHODS:A total of 205 patients with lung cancer and 186 patients with lung benign disease who were admitted to our hospital were enrolled from 2018 to 2020. The 205 patients included 76 cases of squamous, 92 cases of adenocarcinoma, and 37 cases of small cell lung cancer. There were 49 patients with TNM I+II and 156 patients with TNM III+IV. A total of 10 mL baseline peripheral venous blood samples and subsequent peripheral venous blood samples (7 days after two cycles of chemotherapy) were collected, and the levels of Hsp90α, carcinoembryonic antigen (CEA), Cytokeratin 19 fragments (CYFRA21-1), and neuron-specific enolase (NSE) were detected by ELISA kit. RESULTS:Hsp90α was obviously higher in serum from patients with lung cancer than in patients with benign lung disease (p < 0.0001). Moreover, Hsp90α levels were higher in patients with advanced-stage (stage III-IV) lung cancer compared to those with early-stage (stage I-II). Hsp90α level was significantly decreased following treatment with chemotherapy in the progress partial response group (p = 0.017), whereas the level of Hsp90α was significantly higher after chemotherapy treatment in the progressive disease group (p < 0.0001). In addition, compared with CYFRA21-1, CEA, or NSE alone, the AUC of Hsp90α combined with CYFRA21-1, CEA, or NSE were significantly higher in the diagnosis of adenocarcinoma or small-cell lung cancer. DISCUSSION:Hsp90α combined with CYFRA21-1, CEA, and NSE can be used as diagnostic indicators of lung cancer. The Hsp90α level can be used to monitor treatment response.

Purpose: While asthma comorbidities are associated with higher health care utilisation, lower quality of life and poorer asthma control, the impact of asthma comorbidities on hospitalisation for asthma exacerbation (H-AX) remains less recognised. We aim to analyse the impact of asthma comorbidities on H-AX.Methods: Based on a national survey on asthma control and disease perception (CARN 2015 study), we analysed the impact of comorbidities on annual incidence and frequency of H-AX in China. Information on demographic characteristics, asthma comorbidities and annual incidence and frequency of H-AX were presented in this study. Results: Among 3875 ambulatory asthma patients, 75.9% (2941/3875) had comorbidities, and 26.4% (1017/3858) experienced H-AX during past year. After adjusting for confounding factors such as demographic data, smoking status and asthma control, COPD [OR=2.189, 95%CI (1.673, 2.863)] and coronary heart disease [OR=1.387, 95%CI (1.032, 1.864)] were associated with higher annual incidence, while allergic rhinitis [OR=0.692, 95%CI (0.588, 0.815)] was associated with lower annual incidence, of H-AX. In terms of frequency, allergic rhinitis [OR=1.630, 95%CI (1.214, 2.187)], COPD [OR=1.472, 95%CI (1.021, 2.122)] and anxiety [OR=2.609, 95%CI (1.051, 6.477)] showed statistically significant correlation with frequent H-AX.Conclusions: Comorbidities such as COPD, coronary heart disease and allergic rhinitis, may have an important role in the risk and/or frequency of annual hospitalisations due to asthma exacerbation. The goal of asthma control should rely on a multi-disciplinary treatment protocol but not merely on efforts of respiratory physicians.

Objective To analyze the relationship between medication compliance of patients with uncontrolled asthma and lung function,airway inflammation level, asthma control level and quality of life so as to obtain important references for improving patient compliance and asthma control level in the future. Methods Questionnaires were performed in asthma patients who did not achieve asthma control and had poor compliance in 32 third-class hospitals in 28 provinces of China mainland. All patients were tested for lung function and airway inflammation levels. So the relevant data of asthma compliance was investigated and analyzed. Results A total of 923 patients were investigated and the questionnaire recovery rate was 100%. Two hundred and forty-three（26.33%） answered cognitive related questions about asthma completely correctly. Treatment compliance in asthma patients was positively correlated with lung function and significantly negatively correlated with exhaled nitric oxide. Better treatment compliance in asthma has higher level of asthma control and quality of life. Poor compliance in asthma patients will lead to decreased lung function and elevated levels of airway inflammation, resulting in decreased asthma control and quality of life. Conclusion Asthma treatment compliance is related to lung function, airway inflammation, asthma control level and quality of life.

Objective:To evaluate the efficacy and safety of endoscopic stricturotomy (EST) under balloon-assisted enteroscopy (BAE) in treatment of benign jejuno-ileal stenosis.Methods:From December 2015 to August 2021, at the Air Force Medical Center, 41 patients who were diagnosed with benign jejuno-ileal stenosis underwent BAE deep small bowel EST and/or surgery due to ineffective or ineffective drug treatment were retrospectively analyzed. Twenty-one patients were treated with EST (EST group) and 20 patients were treated with surgery (surgery group). The etiology and follow-up time were analyzed, the general conditions (male proportion and age), the immediate technical success rate (the percentage of the stenosis that the enteroscope could pass through after EST in the total number of treated stenoses), the incidence of complications (including perforation, bleeding, etc.), the symptom remission rates at 3-month, 6-month, and 1-year after treatment (the percentage of patients with complete or partial remission in the total number of patients), cumulative symptom-free survival rate (no obstruction-related symptoms after EST or surgery till the last follow-up) and cumulative surgery-free survival rate of two groups were compared. Chi-square test, independent t-test, Fisher′s exact probability method and Kaplan-Meier analysis were used for statistical analysis. Results:The main etiology of stricture of EST group and surgery group was Crohn′s disease (71.4%, 15/21 and 60.0%, 12/20, respectively), and the median follow-up time was 12 months (6 to 46 months) and 45 months (14 to 73 months), respectively. There were no significant differences in male proportion, age, immediate technical success rate and incidence of complication between EST group and surgery group (57.1%, 12/21 vs. 65.0%, 13/20; (45.2±17.4) years old vs. (43.1±20.3) years old; 95.3%, 41/43 vs. 100.0%, 30/30; 26.9%, 7/26 vs. 10.0%, 2/20, all P>0.05). In the EST group, 9.5% (2/21) of the patients received surgery because of perforation during EST, 76.2% (16/21) of the patients did not need surgery after EST, and the median symptom-free survival time of patients without symptoms in EST group was 13.3 months. There was no significant difference in the symptom remission rate at 3-month after treatment between EST group and the surgery group (17/19 vs. 100.0%, 20/20, P>0.05). The symptom remission rate at 6-month and 1-year of EST group were lower than those of the surgery group (15/19 vs. 100.0%, 20/20; 8/11 vs. 100.0%, 20/20), and the differences were statistically significant (both were Fisher′s exact probability method, P=0.047 and 0.037). The cumulative symptom-free survival rates at 3-month, 6-month and 1-year of EST group and surgery group were 66.0% vs. 90.0%, 61.0% vs. 85.0% and 54.0% vs. 80.0%, respectively.The results of Kaplan-Meier analysis indicated that there was no significant difference in the symptom-free survival curve between two groups ( P>0.05). The 3-month, 6-month and 1-year cumulative surgery-free survival rates after treatment in EST group were 90.0%, 81.0% and 73.0%, respectively. The 3-month, 6-month and 1-year cumulative surgery-free survival rates after treatment in surgery group were all 100.0%. Conclusion:EST under BAE is technically feasible, and safe in the treatment of benign jejuno-ileal stenosis, and can effectively relieve clinical obstruction symptoms and avoid or delay surgery in the short term.

Purpose As stated in the Global Initiative for Asthma, there are still some asthmatic patients who have not achieved asthma control. Mobile is a useful tool for asthma management. We aimed to compare the advantages of mobile management with traditional management in improving adherence and control of asthma. Methods In this prospective, multicentre, randomized, controlled and parallel-group study, we enrolled patients with poor adherence and uncontrolled asthma at 32 hospitals in 28 provinces in China. Patients were randomly assigned to the mobile management or traditional management groups for 12 months. The primary endpoint was the proportion of patients with good adherence (Medication Adherence Report Scale for Asthma [MARS-A] score ≥ 45) for 6 months. This study is registered at ClinicalTrials.gov (NCT02917174). Results Between April 2017 and April 2018, 923 patients were eligible for randomization (mobile group, n = 461; traditional group, n = 462). Dropout was 84 (18.2%) in the mobile management group and 113 (24.4%) patients in the traditional management group. The proportion of patients with good adherence was significantly higher in the mobile management group than in the traditional management group (66.0% vs. 58.99%, P = 0.048). The mobile management group showed higher mean MARS-A score (at 1, 6, 9, and 12 months) and asthma control test scores (at 6 and 9 months), and lower total lost rate to follow-up within 12 months than the traditional management group. Conclusions Mobile asthma management can improve adherence and asthma control compared to traditional management. Trial Registration ClinicalTrials.gov Identifier: NCT02917174

目的 探讨三维CT定量测量小气道参数与肺功能相关性在慢性阻塞性肺疾病(COPD)患者评估中的价值.方法 回顾性纳入2020年1月至2021年3月于安徽医科大学第一附属医院和六安世立医院呼吸与危重症医学科就诊的146例急性加重期COPD患者,根据慢性阻塞性肺疾病全球倡议(GOLD)分级标准将患者分为GOLD1-2级(62例)、GOLD3-4级(84例),收集患者胸部CT、肺功能、临床评分和6 min步行距离等资料.定量测量患者肺气肿指数(LAA％-950HU),肺动脉与主动脉比值(PA:A)以及第3-8级气道参数壁面积百分比(WA％)、壁厚外径比(TDR).结果 GOLD3-4级患者WA％7.8、TDR7～8、全肺LAA％-950HU均高于GOLD1～2级(P＜0.001);小气道定量参数WA％7-8、TDR7-8与一秒率(FEV1/FVC)、第一秒用力呼气容积占预计值百分比(FEV1％pre)、用力呼气50％时的瞬间流速(FEF50％)、用力呼气75％时的瞬间流速(FEF75％)均负相关(P＜0.001),且相关性均高于大气道;每一肺叶LAA％-950HU与肺功能均负相关,且双肺下叶相关性最大;多元回归分析显示TDR7-8和全肺LAA％-950HU可共同预测患者肺功能FEV1/FVC、FEV1％pre下降(P＜0.001).结论 利用CT三维重建定量小气道参数,发现小气道WA％、TDR可较好预测COPD患者肺功能,对COPD的评估有一定价值.

BACKGROUND:Fibrotic hypersensitivity pneumonitis (FHP) is an allergic and diffuse pneumonia caused by repeated inhalation of antigenic substances, and sometimes developed in people working in specific environments. While novel antigens and exposures continued to be described, physicians should maintain a high suspicion of potential exposures. A detailed assessment of the patient's occupational exposures as well as living environment is necessary and complete allergen avoidance is the first and most important step in the management of FHP once the allergens are determined.CASE SUMMARY:A 35-year-old female was admitted to the hospital with a cough and breathing difficulties for more than one year. She was a nonsmoker and a manufacturer of halogen dishes, which are characteristic Chinese foods, for 15 years without any protection. High resolution computed tomography of the chest demonstrated an interstitial pneumonia pattern. Pulmonary function examination showed restricted ventilation dysfunction and a significant reduction in dispersion ability. Cell differentiation in bronchoalveolar lavage fluid demonstrated lymphocytosis (70.4%) with an increased lymphocyte CD4/CD8 ratio (0.94). Transbronchial lung biopsy combined with lung puncture pathology showed diffuse uniform alveolar interval thickening, chronic inflammatory cell infiltration, a proliferation of tissue in the bronchial wall fiber and alveolar epithelial follicle degeneration, resulting in fibrosis.CONCLUSION:Exposure to spices used for the production of halogen dishes may cause FHP.

Purpose While asthma comorbidities are associated with higher health care utilisation, lower quality of life and poorer asthma control, the impact of asthma comorbidities on hospitalisation for asthma exacerbation (H-AX) remains less recognised. We aim to analyse the impact of asthma comorbidities on H-AX. Methods Based on a national survey on asthma control and disease perception (CARN 2015 study), we analysed the impact of comorbidities on annual incidence and frequency of H-AX in China. Information on demographic characteristics, asthma comorbidities and annual incidence and frequency of H-AX were presented in this study. Results Among 3875 ambulatory asthma patients, 75.9% (2941/3875) had comorbidities, and 26.4% (1017/3858) experienced H-AX during past year. After adjusting for confounding factors such as demographic data, smoking status and asthma control, COPD [OR = 2.189, 95% CI (1.673, 2.863)] and coronary heart disease [OR = 1.387, 95% CI (1.032, 1.864)] were associated with higher annual incidence, while allergic rhinitis [OR = 0.692, 95% CI (0.588, 0.815)] was associated with lower annual incidence, of H-AX. In terms of frequency, allergic rhinitis [OR = 1.630, 95% CI (1.214, 2.187)], COPD [OR = 1.472, 95% CI (1.021, 2.122)] and anxiety [OR = 2.609, 95% CI (1.051, 6.477)] showed statistically significant correlation with frequent H-AX. Conclusions COPD and coronary heart disease were associated with higher annual incidence, while allergic rhinitis was associated with lower annual incidence of H-AX. Allergic rhinitis, COPD and anxiety were associated with frequent H-AX. Comorbidities may have an important role in the risk and frequency of annual hospitalisations due to asthma exacerbation. The goal of asthma control should rely on a multi-disciplinary treatment protocol.

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

PURPOSE:Details of patients hospitalized for asthma exacerbation in mainland China are lacking. To improve disease control and reduce economic burden, a large sample survey among this patient population is indispensable. This study aimed to investigate the clinical characteristics and outcomes of such patients.METHODS:A retrospective study was conducted on patients hospitalized for asthma exacerbation in 29 hospitals of 29 regions in mainland China during the period 2013 to 2014. Demographic features, pre-admission conditions, exacerbation details, and outcomes were summarized. Risk factors for exacerbation severity were analyzed.RESULTS:There were 3,240 asthmatic patients included in this study (57.7% females, 42.3% males). Only 28.0% used daily controller medications; 1,287 (39.7%) patients were not currently on inhaled corticosteroids. Acute upper airway infection was the most common trigger of exacerbation (42.3%). Patients with severe to life-threatening exacerbation tended to have a longer disease course, a smoking history, and had comorbidities such as hypertension, chronic obstructive pulmonary disease (COPD), and food allergy. The multivariate analysis showed that smoking history, comorbidities of hypertension, COPD, and food allergy were independent risk factors for more severe exacerbation. The number of patients hospitalized for asthma exacerbation varied with seasons, peaking in March and September. Eight patients died during the study period (mortality 0.25%).CONCLUSIONS:Despite enhanced education on asthma self-management in China during recent years, few patients were using daily controller medications before the onset of their exacerbation, indicating that more educational efforts and considerations are needed. The findings of this study may improve our understanding of hospital admission for asthma exacerbation in mainland China and provide evidence for decision-making.

Background: Exposure to particulate matters (PMs) can lead to an acute exacerbation of allergic airway diseases, increasing the severity of symptoms and mortality. However, little is known about the underlying molecular mechanism. This study aimed to investigate the effects of PMs on acute exacerbation of allergic airway inflammation and seek potential therapeutic targets. Methods: Non-allergic control and ovalbumin (OVA)-allergic wide-type (WT) and Toll-like receptor 2 knockout (Tlr2-/-) mice were exposed to 100 mu g of PM (diameter 5.85 mu m) or saline by the oropharyngeal instillation. The responses were examined three days after exposure. In the RAW264.7 macrophage cell line, Tlr2 was knocked down by small-interfering RNA or the NF-kappa B inhibitor JSH-23 was used, and then the cells were stimulated with PMs for 12 h before comparison of the inflammatory responses. Results: PM exposure led to increased inflammatory cell recruitment and airway intensity of PAS + staining in OVA-allergic WT mice, accompanied with an accumulation of inflammatory cells and elevated inflammatory cytokines, such as IL-6 and IL-18, in the bronchoalveolar lavage fluid (BALF). Furthermore, the protein levels of TLR2 and the NLRP3 inflammasome were elevated concomitantly with the airway inflammation post-OVA/PMs challenge. Tlr2 deficiency effectively inhibited the airway inflammation, including pulmonary inflammatory cell recruitment, mucus secretion, serum OVA-specific immunoglobulin E (IgE), and BALF inflammatory cytokine production. Additionally, the P-induced NLRP3 activation in the RAW 264.7 cell line was diminished by the knockdown of Tlr2 or JSH-23 treatment in vitro. Conclusion: Our results indicated that PMs exacerbate the allergic airway inflammation mediated by the TLR2/NF-kappa B/NLRP3 signaling pathway. Inhibition of NF-kappa B seems to be a possible treatment.

AIMS:Numerous studies indicate that toll-like receptor 2 (TLR2) led to divergent effects in asthma. The occurrence of autophagy in asthma pathogenesis is still incompletely understood. Here, we aimed to investigate the role of TLR2 and the underlying mechanisms in allergic airway inflammation and autophagy activation. MAIN METHODS:C57BL/6 and TLR2 knockout (TLR2-/-) mice were subjected to an ovalbumin (OVA)-immunized allergic airway model, and were treated with SP600125. Differential cell counts in bronchoalveolar lavage fluid were determined by Wright's staining. Histological analysis of airway inflammation was determined by haematoxylin and eosin (H&E) and periodic acid-Schiff (PAS) staining. The levels of OVA-specific immunoglobulin E (IgE), tumor necrosis factor α (TNF-α) and interleukin 10 (IL-10) were detected by enzyme-linked immunosorbent assay (ELISA). Proteins expression in lung tissues was detected by western blot, expression of TLR2 was further observed by immunofluorescence. Autophagy activation was determined by western blot and transmission electron microscopy (TEM). KEY FINDINGS:TLR2 expression was increased upon OVA challenge, and TLR2 deficiency was associated with decreased allergic airway inflammation. Meanwhile, TLR2 deficiency weakened autophagy activation. Moreover, inhibition of c-Jun N-terminal kinase (JNK) by SP600125 also suppressed OVA-induced allergic airway inflammation and autophagy activation. Interestingly, treating TLR2-/- mice with SP600125 showed similar OVA-induced allergic airway inflammation and autophagy activation compared to that in vehicle-treated TLR2-/- mice. SIGNIFICANCE:TLR2 might contribute to the maintenance of allergic airway inflammation through JNK signaling pathway accompanying with autophagy activation. These findings may provide a novel signal target for prevention of allergic airway inflammation.

Severe hemorrhagic shock and resuscitation (HS/R) can lead to lung injury, resulting in respiratory insufficiency. We investigated whether treatment with Alda-1, an ALDH2 activator, decreased lung injury induced by severe HS/R in a rat model. Male Sprague-Dawley rats were randomized into three groups, hemorrhagic shock + placebo, hemorrhagic shock + Alda-1, and sham. All animals were heparinized, and then 50% of the total calculated blood volume was collected over 60 minutes. After 40 minutes of hemorrhagic shock, animals were reinfused with the shed blood over 40 minutes and then observed for an additional 2 hours. Concentrations of 4-HNE, TNF-α, IL-6, and ALDH2 activity were detected; lung injury and lung wet-to-dry weight ratios were assessed. Expression of occludin and ZO-1 proteins in lung tissues was also determined. At 2 hours after resuscitation, lung injury was significantly reduced and the wet-to-dry weight ratio was notably decreased in the Alda-1 group compared with placebo (P<0.05). Alda-1 treatment also significantly increased the activity of ALDH2 and decreased the levels of toxic 4-HNE (P<0.05). In the Alda-1 group, IL-6 and TNF-α were dramatically decreased compared with placebo-treated animals (P<0.05). Expression of occludin and ZO-1 proteins was significantly decreased in the placebo group compared with the Alda-1 group (P<0.05). Thus, in a rat model of severe HS/R, treatment with Alda-1 increased the activity of ALDH2, significantly accelerated the clearance of reactive aldehydes, and concomitantly alleviated lung injury through improvement of pulmonary epithelial barrier integrity resulting in decreased alveolar epithelial tissue permeability, lung edema, and diffuse infiltration of inflammatory cells.