Expert Consensus on the Diagnosis and Treatment of Anticancer Drug-Induced Interstitial Lung Disease.

Drug-induced interstitial lung disease (DILD) is the most common pulmonary adverse event of anticancer drugs. In recent years, the incidence of anticancer DILD has gradually increased with the rapid development of novel anticancer agents. Due to the diverse clinical manifestations and the lack of specific diagnostic criteria, DILD is difficult to diagnose and may even become fatal if not treated properly. Herein, a multidisciplinary group of experts from oncology, respiratory, imaging, pharmacology, pathology, and radiology departments in China has reached the "expert consensus on the diagnosis and treatment of anticancer DILD" after several rounds of a comprehensive investigation. This consensus aims to improve the awareness of clinicians and provide recommendations for the early screening, diagnosis, and treatment of anticancer DILD. This consensus also emphasizes the importance of multidisciplinary collaboration while managing DILD.

Safety and accuracy of transbronchial lung cryobiopsy in diagnosing desquamative interstitial pneumonia.

INTRODUCTION: Transbronchial lung cryobiopsy (TBLC) is a new technique to obtain specimens for diagnosis of interstitial lung disease (ILD) in recent years. The objective of this study is to evaluate the safety and the diagnostic accuracy of TBLC in patients of desquamative interstitial pneumonia (DIP). METHODS: In this study twelve patients confirmed with DIP were selected from January 2019 to December 2020 at the department of pulmonary and critical care medicine in China-Japan Friendship Hospital. All cases underwent TBLC in a hybrid cone beam CT (CBCT) operation room with a single general anesthesia. The definitive diagnosis was made by a multidisciplinary team that involved clinicians, radiologists and pathologists. This study analyzed the biopsy sample surface areas, main complications and the consistency between TBLC pathology and multidisciplinary discussion (MDD) diagnosis for DIP. RESULTS: An average of 3.1 ± 1.1 specimens were obtained per patient. The mean surface area of the specimen was 23.7 ± 6.1 mm2 . None of the cases had pneumothorax or massive hemorrhage. Ten cases (83.3%) had no or mild bleeding and two cases (16.7%) had moderate bleeding. All cases had the typical pathologic characteristics of DIP, which was highly consistent with the diagnosis of MDD. CONCLUSION: TBLC can obtain sufficient samples for the pathological diagnosis of DIP, which has high security and accuracy in experienced specialist centers.

Inclusive Leadership and Career Sustainability: Mediating Roles of Supervisor Developmental Feedback and Thriving at Work.

Career sustainability is a well-researched issue in academics and other sectors. Technology advancements and COVID-19 have jeopardized career sustainability. Numerous studies have explored the influence of individual characteristics on career sustainability, but few have focused on leadership. In addition, cultural factors must be considered because leadership is rooted in culture. In particular, inclusive leadership reflects traditional Chinese culture. Therefore, based on self-determination social exchange theories, we analyzed the effects of inclusive leadership on career sustainability as well as the roles of thriving at work and supervisor developmental feedback (SDF) in career sustainability. In total, 363 samples were collected from China. The results revealed that inclusive leadership improves career sustainability through SDF and thriving at work. Theoretically, our study fills the research gap and establishes a mechanism and theoretical framework for inclusive leadership and career sustainability. Practically, we offer guidance for enterprises to cultivate inclusive leadership and improve career sustainability.

Erratum for Alveolar Type II Cells Escape Stress Failure Caused By Tonic Stretch Through Transient Focal Adhesion Disassembly.

[This corrects the article DOI: 10.7150/ijbs.7.588.].

Water-Soluble C60 Protects Against Bleomycin-Induced Pulmonary Fibrosis in Mice.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, fibrotic interstitial pneumonia. And, oxidation/antioxidant imbalance plays an important role in the progress of IPF. Fullerene is considered to be a novel "structural" antioxidant. This study aimed to explore if water-soluble C60 (C60(OH)22) can exhibit antifibrotic activity in its antioxidant role. METHODS: Healthy C57BL/6J mice were randomly grouped and induced pulmonary fibrosis by intratracheal injection of bleomycin. RESULTS: The survival rate of mice was observed and found that 10mg/kg was the optimal dose of water-soluble C60 for pulmonary fibrosis. We observed that water-soluble C60 can alleviate the severity of pulmonary fibrosis by observing the chest computed tomography, pulmonary pathology, and content of collagen, alpha smooth muscle actin and fibronectin in lung. Compared with bleomycin group, ROS, the content of TNF-α in BALF, and the number of fibroblasts was significantly decreased and the number of type Ⅱ alveolar epithelial cells was increased after treatment with C60. CONCLUSION: Therefore, thanks to its powerful antioxidant action, water-soluble C60 can reduce the severity of pulmonary fibrosis induced by bleomycin in mice.

[Significance of neutrophil extracellular trap and its markers in the early diagnosis of community-acquired pneumonia in children].

OBJECTIVE: To study the significance of plasma neutrophil extracellular trap (NET) and its markers in the diagnosis of community-acquired pneumonia (CAP) in children. METHODS: A total of 160 children with CAP were enrolled as the CAP group, and 50 healthy children were enrolled the control group. According to disease severity, the CAP group was further divided into a mild CAP subgroup with 137 children and a severe CAP subgroup with 23 children. According to the pathogen, the CAP group was further divided into a bacterial pneumonia subgroup with 78 children, a Mycoplasma pneumonia subgroup with 35 children, and a viral pneumonia subgroup with 47 children. The levels of plasma NET and its markers [antibacterial peptide (LL-37), extracellular free DNA (cfDNA), and deoxyribonuclease I (DNase I)] were measured. Receiver operating characteristic (ROC) curve was used to analyze the value of each index in diagnosing CAP and assessing its severity. RESULTS: Compared with the control group, the CAP group had significant increases in the levels of NET, LL-37, and cfDNA and a significant reduction in the activity of DNase I (P<0.05). Compared with the mild CAP subgroup, the severe CAP subgroup had significantly higher levels of NET, LL-37 and cfDNA and a significantly lower activity of DNase I (P<0.05). There were no significant differences in the levels of NET, LL-37, and cfDNA and the activity of DNase I among the bacterial pneumonia, Mycoplasma pneumonia, and viral pneumonia subgroups (P>0.05). In the CAP group, plasma NET levels were positively correlated with white blood cell count (WBC), percentage of neutrophils, and serum levels of C-reactive protein (CRP), procalcitonin and tumor necrosis factor-α (r=0.166, 0.168, 0.275, 0.181 and 0.173 respectively, P<0.05); LL-37 and cfDNA levels were positively correlated with WBC (r=0.186 and 0.338 respectively, P<0.05) and CRP levels (r=0.309 and 0.274 respectively, P<0.05); the activity of DNase I was negatively correlated with CRP levels (r=-0.482, P<0.05). The ROC curve analysis showed that NET, LL-37, cfDNA, and DNase I had an area under the ROC curve (AUC) of 0.844, 0.648, 0.727, and 0.913 respectively in the diagnosis of CAP, with optimal cut-off values of 182.89, 46.26 ng/mL, 233.13 ng/mL, and 0.39 U/mL respectively, sensitivities of 88.12%, 35.63%, 54.37%, and 91.25% respectively, and specificities of 74.00%, 92.00%, 86.00%, and 76.00% respectively. In the assessment of the severity of CAP, NET, LL-37, cfDNA, and DNase I had an AUC of 0.873, 0.924, 0.820, and 0.778 respectively, with optimal cut-off values of 257.7, 49.11 ng/mL, 252.54 ng/mL, and 0.29 U/mL respectively, sensitivities of 83.21%, 86.96%, 78.26%, and 95.65% respectively, and specificities of 78.26%, 83.94%, 76.64%, and 56.93% respectively. CONCLUSIONS: Plasma NET and its related markers have a certain value in diagnosing CAP and assessing its severity in children.

[Value of simultaneous amplification and testing in early diagnosis of Mycoplasma pneumoniae pneumonia and related influencing factors].

OBJECTIVE: To investigate the value of simultaneous amplification and testing (SAT) in the early diagnosis of Mycoplasma pneumoniae pneumonia (MPP) in children and related influencing factors. METHODS: A total of 526 children with community-acquired pneumonia who were hospitalized between December 2016 and December 2017 were enrolled. Particle agglutination was used to measure serum Mycoplasma pneumoniae (MP) antibody (MP-Ab). The value of SAT in the diagnosis of MPP was evaluated based on these results. RESULTS: Based on the results of serum MP-Ab measurement, 165 children were diagnosed with MPP. MP-SAT had a sensitivity of 90.9% (150/165), a specificity of 97.9% (368/376), and high accuracy (Youden index=0.89) in the diagnosis of MPP, suggesting that there was good consistency between these two methods (Kappa=0.90). The diagnostic sensitivity of MP-SAT in children with a short course of disease was significantly higher than that in children with a long course of disease (P=0.031). The diagnostic sensitivity of MP-SAT was significantly higher than that of single serum MP-Ab measurement (P=0.018), with poor consistency between these two methods (Kappa=0.039). MP-SAT had good consistency with double serum MP-Ab measurement (Kappa=0.91). The multivariate logistic regression analysis showed that course of disease (≥7 days) and out-of-hospital macrolide treatment were the main factors influencing the results of MP-SAT (P<0.05). CONCLUSIONS: MP-SAT has high value in the early diagnosis of MPP and can effectively cover the shortage of single serum MP-Ab test in the acute stage and thus provide help for early clinical diagnosis. MP-SAT test should be performed in the early stage of the disease (<7 days) and before the application of macrolide treatment.

Both Talin-1 and Talin-2 correlate with malignancy potential of the human hepatocellular carcinoma MHCC-97 L cell.

BACKGROUND: Talin-1 (TLN-1) and TLN-2 are implicated in many cellular processes, but their roles in hepatocellular carcinoma (HCC) remain unclear. This study aimed to assess cell cycle distribution, anoikis, invasion and migration in human HCC MHCC-97 L cells. METHODS: MHCC-97 L cells, which highly express TLN-1, were transduced with TLN-1 shRNA (experimental group) or scramble shRNA (negative control group); non-transduced MHCC-97 L cells were used as blank controls. TLN-1 and TLN-2 mRNA and protein levels were detected by real-time RT-PCR and western blot, respectively. Then, cell cycle distribution and anoikis were assessed by flow cytometry. In addition, migration and invasion abilities were assessed using Transwell and cell scratch assays. Finally, a xenograft nude mouse model was established to further assess cell tumorigenicity. RESULTS: Compared with the blank and negative control groups, TLN-1/2 mRNA and protein levels were significantly reduced in the experiment group. TLN-1/2 knockdown cells showed significantly more cells in the G0/G1 phase (79.24%) in comparison with both blank (65.36%) and negative (62.69%) control groups; conversely, less cells were found in G2/M and S phases in the experimental group compared with controls. Moreover, anoikis was enhanced (P < 0.05), while invasion and migration abilities were reduced (P < 0.05) in TLN-1/2 knockdown cells compared with controls. TLN-1/2 knockdown inhibited MHCC-97 L cell migration (Percentage of wound healing area: experimental group: 32.6 ± 0.7% vs. negative controls: 50.1 ± 0.6% and blank controls: 53.6 ± 0.6%, both P < 0.01). Finally, the tumors obtained with TLN-1/2 knockdown cells were smaller (P < 0.05) compared with controls. CONCLUSION: Both TLN-1 and TLN-2 levels correlate with tumorigenicity in human HCC, indicating that these molecules constitute important molecular targets for the diagnosis and/or treatment of HCC.

Talin-1 correlates with reduced invasion and migration in human hepatocellular carcinoma cells.

BACKGROUND: Talin-1 is a cytoskeleton protein that participates in cell migration and plays a role in tumor formation, migration, and metastasis in different types of cancer. Chinese investigators have observed that the levels of Talin-1 protein and mRNA expression in HCC tissues are significantly lower than in the adjacent non-cancerous tissue. However, Japanese investigators have reported that Talin-1 is upregulated in HCC. Tln2 as homologous gene of Tln-1, which encodes a very similar protein, but the role of Talin-2 is very little known in primary liver cancer (PLC). We investigated whether the expression of Talin-1 in PLC may be associated with the histological subtype as well as the role of Talin-1 in tumor cell invasion and migration using human hepatocellular carcinoma cell lines. MATERIALS AND METHODS: We measured the mRNA expression levels of Talin-1 and Talin-2 in five human liver cancer cell lines and normal human liver cell (LO2 cell line) by real-time PCR and the protein expression levels of Talin-1 by Western blot. Migration and invasion of the cells were assessed using transwell assays and cell scratch experiments, respectively, and proliferation was assessed by soft AGAR colony formation. RESULTS: Talin-1 and Talin-2 expression differed significantly between the five human liver cancer cell lines and LO2 cell line (p<0.05). Compared with the LO2 cell line, the invasion and migration capabilities of the five cancer cell lines differed significantly (p<0.05). Similarly, the colony-forming ability differed (p<0.05). CONCLUSIONS: High levels of Talin-1 expression are correlated with reduced invasion and migration as well as decreased malignancy in human liver cancer cell lines; the suppression of Talin-1 promotes invasion and migration. In addition, Talin-2 may be correlated with invasion and migration in human hepatocellular carcinoma.

Alveolar type II cells escape stress failure caused by tonic stretch through transient focal adhesion disassembly.

Mechanical ventilation-induced excessive stretch of alveoli is reported to induce cellular stress failure and subsequent lung injury, and is therefore an injurious factor to the lung. Avoiding cellular stress failure is crucial to ventilator-induced lung injury (VILI) treatment. In the present study, primary rat alveolar type II (ATII) cells were isolated to evaluate their viability and the mechanism of their survival under tonic stretch. By the annexin V/ PI staining and flow cytometry assay, we demonstrated that tonic stretch-induced cell death is an immediate injury of mechanical stress. In addition, immunofluorescence and immunoblots assay showed that the cells experienced an expansion-contraction-reexpansion process, accompanied by partial focal adhesion (FA) disassembly during contraction. Manipulation of integrin adherent affinity by altering bivalent cation levels in the culture medium and applying an integrin neutralizing antibody showed that facilitated adhesion affinity promoted cell death under tonic stretch, while lower level of adhesion protected the cells from stretch-induced stress failure. Finally, a simplified numerical model was established to reveal that adequate disassembly of FAs reduced the forces transmitting throughout the cell. Taken together, these results indicate that ATII cells escape stress failure caused by tonic stretch via active cell morphological remodeling, during which cells transiently disassemble FAs to unload mechanical forces.

[The temporal and spatial distribution of vasoactive intestinal peptide and its receptor in the development of airway hyperresponsiveness].

OBJECTIVE: To determine the possible involvement of vasoactive intestinal peptide (VIP) in the development of airway hyper responsiveness (AHR). METHODS: Twenty-five rabbits were randomly divided into five groups (5 animals each). Four groups were exposed to 2.0 ppm ozone 1 h/day for 1 (group B(0)), 2 (group B(1)), 4 (group B(2)), and 8 (group B(3)) days, respectively. The control group (group A) breathed only filtered room air. The changes of the VIP level and the mRNA expression of VIP receptor 1 (VIPR1) in the lung were detected at various ozone-stressing time points. In situ hybridization was performed to examine the distribution of VIPR1 in the lung. RESULTS: (1) The concentration of VIP in the lung increased slowly and were maximal at day 4, then returned to the normal level. (2) The changing pattern of the VIPR1 mRNA in the lung was similar to those observed for VIP. Increases in VIPR1 mRNA were detectable by 1 day and maximal by 2 - 4 days, and then decreased slowly. (3) In group A, VIPR1 was expressed on airway epithelium, in pulmonary interstitial and focal areas of airways and vascular smooth muscles. By days 2 to 4, hybridization staining increased and the majority of VIPR1-positive cells was located in the perivascular and peribronchiolar area. On day 8, very few positive cells were seen in the lung. CONCLUSION: VIP may play an important role in the development of AHR by binding with VIPR1.

Temporal and spatial distribution of VIP, CGRP and their receptors in the development of airway hyperresponsiveness in the lungs.

To explore the role of intrapulmonary neuropeptides in the development of airway hyperresponsiveness, we established an animal model of airway hyperresponsiveness (AHR) in rabbits by using ozone exposure. With the model, after test of the mechanics of respiration and bronchoalveolar lavage assay, the levels of vasoactive intestinal peptide (VIP) and calcitonin gene-related peptide (CGRP) in the lungs were determined by radioimmunoassay, and the expression of mRNA coding receptors of these two neuropeptides was evaluated by reverse transcriptional-polymerase chain reaction (RT-PCR). At the same time, the distribution of VIP receptor-1 (VIPR1) and CGRP receptor-1 (CGRPR1) in lung tissues and its time-course were examined by in situ hybridization. The results showed: (1) in ozone-stressing groups, airway resistance increased significantly and typical inflammatory pathological changes were observed in pulmonary tissue slides, including neutrophil and eosinophil infiltration, mucus exudation and bronchial epithelial cells (BECs) shedding; (2) with elongation of ozone exposure, the levels of VIP and CGRP in the lungs increased at first, reaching a peak on d 2 to 4, then decreased slowly, and CGRP peaked somewhat earlier than VIP; (3) mRNA expression of the two neuropeptide receptors in the lungs changed in a similar manner like VIP and CGRP, but the high level of mRNA expression of VIPR1 lasted longer than that of CGRPR1; and (4) in situ hybridization for neuropeptide receptors demonstrated that, in unstressed control, VIPR1 and CGRPR1 positive cells appeared in the airway epithelium, pulmonary interstitial and focal areas of airway and vascular smooth muscles. With the elongation of ozone exposure, hybridization stained deeper and the majority of positive cells were located around the vessels and bronchus except a few in the alveoli. At 8 d, only a small number of positive cells were seen in the lungs. From the results, it is concluded that ozone-stressing can induce the development of AHR, in which VIP and CGRP may play important roles. That implies, through binding to CGRPR1, CGRP stimulates an early inflammation response which contributes in cleaning up of irritants, while VIP exerts a later dampening of pulmonary inflammation response. These two neuropeptides may play sequential and complementary roles in the development of AHR.

[Influence of regulatory peptides on the secretion of interleukins from bronchial epithelial cells of the rabbit].

To explore the role of regulatory peptides in the secretion of bronchial epithelial cells (BECs), we observed the effects of four peptides, i.e.vasoactive intestinal peptide (VIP), epidermal growth factor (EGF), endothelin-1 (ET-1), and calcitonin gene-related peptide (CGRP), on the secretion of ILs from unstimulated or O3-stressed BECs. The results of the experiments showed that VIP exerted an inhibitory effect on the secretion of IL-1 and IL-8 from unstimulated and O3-stressed BECs, VIP also decreased the secretion of IL-5 from O3-stressed BECs; EGF promoted secretion of IL-1 and IL-8 from unstimulated BECs, but decreased the secretion of ILs from O3-stressed BECs; ET-1 and CGRP enhanced the secretion of IL-1, IL-5, and IL-8 from unstimlated BECs, CGRP also increased the secretion of ILs from O3-stressed BECs. The results obtained demonstrate that intrapulmonary regulatory peptides modulate the secretion of ILs from BECs, and may play an important part in transduction of inflammatory signals.