CD146 deficiency promotes inflammatory type 2 responses in pulmonary cryptococcosis.

Cryptococcus neoformans (C. neoformans) is an important opportunistic fungal pathogen for pulmonary cryptococcosis. Previously, we demonstrated that CD146 mediated the adhesion of C. neoformans to the airway epithelium. CD146 is more than an adhesion molecule. In the present study, we aimed to explore the roles of CD146 in the inflammatory response in pulmonary cryptococcosis. CD146 was decreased in lung tissues from patients with pulmonary cryptococcosis. Similarly, C. neoformans reduced pulmonary CD146 expression in mice following intratracheal inoculation. To explore the pathological roles of CD146 reduction in pulmonary cryptococcosis, CD146 knockout (KO) mice were inoculated with C. neoformans via intratracheal instillation. CD146 deficiency aggravated C. neoformans infection, as evidenced by a shortened survival time and increased fungal burdens in the lung. Inflammatory type 2 cytokines (IL-4, IL-5, and TNF-α) and alternatively activated macrophages were increased in the pulmonary tissues of CD146 KO-infected mice. CD146 is expressed in immune cells (macrophages, etc.) and nonimmune cells, i.e., epithelial cells and endothelial cells. Bone marrow chimeric mice were established and infected with C. neoformans. CD146 deficiency in immune cells but not in nonimmune cells increased fungal burdens in the lung. Mechanistically, upon C. neoformans challenge, CD146 KO macrophages produced more neutrophil chemokine KC and inflammatory cytokine TNF-α. Meanwhile, CD146 KO macrophages decreased the fungicidity and production of reactive oxygen species. Collectively, C. neoformans infection decreased CD146 in pulmonary tissues, leading to inflammatory type 2 responses, while CD146 deficiency worsened pulmonary cryptococcosis.

A comparative study of IL-33 and its receptor ST2 in a C57BL/6 J mouse model of pulmonary Cryptococcus neoformans infection.

It has been reported that IL-33 receptor ST2 deficiency mitigates Cryptococcus neoformans (C. neoformans) pulmonary infection in BALB/c mice. IL-33 may modulate immune responses in ST2-dependent and ST2-independent manners. The host genetic background (i.e., BALB/c, C57BL/6 J) influences immune responses against C. neoformans. In the present study, we aimed to explore the roles of IL-33 and ST2 in pulmonary C. neoformans-infected mice on a C57BL/6 J genetic background. C. neoformans infection increased IL-33 expression in lung tissues. IL-33 deficiency but not ST2 deficiency significantly extended the survival time of C. neoformans-infected mice. In contrast, either IL-33 or ST2 deficiency reduced fungal burdens in lung, spleen and brain tissues from the mice following C. neoformans intratracheal inoculation. Similarly, inflammatory responses in the lung tissues were more pronounced in both the IL-33-/- and ST2-/- infected mice. However, mucus production was decreased in IL-33-/- infected mice alone, and the level of IL-5 in bronchoalveolar lavage fluid (BALF) was substantially decreased in the IL-33-/- infected mice but not ST2-/- infected mice. Moreover, IL-33 deficiency but not ST2 deficiency increased iNOS-positive macrophages. At the early stage of infection, the reduced pulmonary fungal burden in the IL-33-/- and ST2-/- mice was accompanied by increased neutrophil infiltration. Collectively, IL-33 regulated pulmonary C. neoformans infection in an ST2-dependent and ST2-independent manner in C57BL/6 J mice.

Diagnostic value of endobronchial ultrasound combined with rapid on-site evaluation of transbronchial lung biopsy for peripheral pulmonary lesions.

BACKGROUND: Rapid on-site evaluation (ROSE) has the potential to increase endobronchial ultrasound (EBUS) guide transbronchial lung biopsy (TBLB) accuracy in the diagnosis of peripheral pulmonary lesions (PPLs). However, studies have reported controversial results. The aim of the study was to evaluate the diagnostic value of EBUS-TBLB combination with ROSE in PPLs. METHODS: A total of 152 patients with PPLs underwent EBUS were enrolled and completed this study. Patients were divided into EBUS combined with ROSE group (EBUS+ROSE group) and EBUS group (EBUS group). The diagnostic yield, operation time, and complications were compared between the two groups. RESULTS: The diagnostic yield in EBUS+ROSE group was 85.9%, the operation time was (24.6 ± 6.8) min, the diagnostic yield in EBUS group was 70.3%, and the operative time was (32.4 ± 8.7) min, there were significant differences in diagnostic yield (χ2 = 5.456, P = .016) and operation time (t = 3.167, P = .001) between the two groups. No severe procedure related complications were observed, such as, pneumothorax and hemorrhage. CONCLUSIONS: ROSE can improve the diagnostic yield and shorten the operation time. EBUS combined with ROSE is an effective diagnostic method for PPLs.

Diagnostic Value of Virtual Bronchoscopic Navigation Combined With Endobronchial Ultrasound Guided Transbronchial Lung Biopsy for Peripheral Pulmonary Lesions.

OBJECTIVE: X-ray guided transbronchial ultrasound-guided transbronchial lung biopsy (EBUS-TBLB) can improve the diagnostic yield of peripheral pulmonary lesions (PPLs), but it needs special requirements. The purpose of this study was to investigate the clinical value of virtual bronchoscopy navigation (VBN) combined with EBUS-TBLB in the diagnosis of PPLs without X-ray guidance. METHODS: The 105 patients with PPLs underwent EBUS-TBLB with or without VBN randomly. The diagnostic yield, the operation time and complications were evaluated in the 2 groups. RESULTS: No significant difference was found between the VBN+EBUS group and the EBUS group (76.0% vs. 65.5%, P = 0.287). The operation time of VBN+EBUS group was significantly shorter than that of EBUS group (20.6 ± 12.8 min vs. 28.6 ± 14.3 min, P = 0.023). No severe procedure related complications occurred. CONCLUSIONS: VBN can shorten the operation time. The combination of VBN and EBUS-TBLB is a safe and effective diagnosis technique for PPLs.

Pulmonary actinomycosis diagnosed by radial endobronchial ultrasound coupled with metagenomic next-generation sequencing: A case report and brief literature review.

Pulmonary actinomycosis (PA) is an uncommon pulmonary infectious disease that often is misdiagnosed. Metagenomic next-generation sequencing (mNGS) is a highly sensitive and culture-independent new molecular technology for precise infectious disease diagnosis. Here we report a PA case diagnosed by the combination of a radial endobronchial-ultrasonography guide sheath (R-EBUS-GS) and mNGS, along with a brief review of the literature.

Rapid On-Site Evaluation During Radial Endobronchial Ultrasound-Guided Transbronchial Lung Biopsy for the Diagnosis of Peripheral Pulmonary Lesions.

OBJECTIVE: To evaluate the diagnostic value of radial endobronchial ultrasound (R-EBUS) combination with rapid on-site evaluation (ROSE) guided transbronchial lung biopsy (TBLB) for peripheral pulmonary lesions. METHODS: Peripheral pulmonary lesions identified by computed tomography underwent R-EBUS with or without ROSE randomly from February 2016 to August 2017. The diagnostic yield and the operation time were compared. RESULTS: In total, 158 patients were involved in and completed this research, including 84 cases in the group of R-EBUS with ROSE, and 74 in the group without ROSE. The diagnostic yield of ROSE group was 85.7%. Among these positive cases, 69.4% cases were malignant tumors, and 30.6% cases were benign lesions. The operation time was (24.6 ± 6.3) min. In the group without ROSE, the diagnostic yield was 70.3%, including 35 malignant tumors (67.3%), and 17 benign lesions (32.7%). The operation time was (31.5 ± 6.8) min. There were significant differences between both groups in the diagnostic yield (χ2 = 5.556, P = 0.018) and in the operation time (t = 3.187, P < 0.01). No serious procedure related complications were observed, such as pneumothorax and hemorrhage. CONCLUSION: ROSE can improve the diagnostic yield, and shorten the operation time. R-EBUS combined with ROSE is a safe and effective technique for peripheral pulmonary lesions.

Expression of Cripto-1 predicts poor prognosis in stage I non-small cell lung cancer.

Cripto-1 (CR-1) is related to the biological behaviour and prognosis of carcinomas. The purpose of this study was to investigate the significance of CR-1 expression in surgically resected stage I non-small cell lung cancer (NSCLC). One hundred and forty-eight patients with completely resected stage I NSCLC and available clinical follow-up data were assessed. The protein expression of CR-1 in the tumours was detected by immunohistochemistry. CR-1 was highly expressed in 64 of 148 tumours. Among patients with high CR-1 expression, progression-free survival and overall survival rate were significantly lower than those of patients with low CR-1 levels (P = .013 and P = .019, respectively). The incidence of distant metastasis in patients with high CR-1 expression was significantly higher than that of in patients with low CR-1 expression (57.13% vs 21.43%, P = .001). The results of the multivariate analysis confirmed that a high CR-1 was a significant factor for poor prognosis. In conclusion, CR-1 could be a useful prognostic factor in patients with stage I NSCLC, likely as an indicator of the metastatic propensity of the tumour.

Effect of Endostar combined with angiopoietin-2 inhibitor on malignant pleural effusion in mice.

The present study was designed to investigate the synergetic effect of Endostar combined with an angiopoietin-2 specific inhibitor L1-10 on malignant pleural effusion (MPE) mouse model. A MPE mouse model was established by injecting Lewis lung carcinoma (LLC) cells into pleural cavity of C57BL/6 mice. The mice were randomly divided into four treatment groups: saline, Endostar, L1-10, and Endostar + L1-10. In the present study, we reported for the first time that Endostar combined with L1-10 had significant synergistic effects on the formation of MPE and tumor growth. Moreover, Endostar combined with L1-10 had additive effect on the attenuation of pleural inflammation, inhibition of tumor angiogenesis and pleural vascular hyperpermeability, which are central to the inhibition of MPE. Finally, these studies also found that Endostar combined with L1-10 could have complementary actions by reducing VEGF and IL-6 local release and downregulating VEGF expression in pleural tumors, which involved in the pathogenesis of MPE. Therefore, combined therapy with Endostar and L1-10 may be an encouraging strategy for the treatment of MPE.

Expression of the enhancer of zeste homolog 2 in biopsy specimen predicts chemoresistance and survival in advanced non-small cell lung cancer receiving first-line platinum-based chemotherapy.

OBJECTIVES: Enhancer of zeste homolog 2 (EZH2) plays a key role in tumorigenesis and cancer progression through epigenetic gene silencing and chromatin remodeling. The objective of this study was to investigate the correlation between EZH2 expression and platinum-based chemotherapy response as well as survival of patients with advanced non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: We identified 360 consecutive stage IIIB and IV NSCLC patients who underwent first-line platinum-based chemotherapy. Immunohistochemical analysis of EZH2 on the paraffin-embedded pre-treatment tumor samples was performed and correlated with chemotherapy response and survival. RESULTS: EZH2 was positive in 204 of 360 patients (56.7%). Of the 204 positive EZH2 patients, 72 (35.3%) responded to chemotherapy with either complete response, or partial remission. Of 156 negative EZH2 patients, 90 (57.7%) exhibited a response to chemotherapy. The difference in response to therapy between positive and negative EZH2 patients was statistically significant (p<0.01). Univariate survival analysis indicated that patients with positive EZH2 had a significantly lower disease-free survival (DFS) and overall survival (OS) than those patients with negative EZH2 expression. Multivariate Cox regression analysis demonstrated that positive EZH2 expression was an independent prognostic factor for both DFS and OS. Kaplan-Meier survival curves further confirmed that positive EZH2 expression correlates with poor survival in NSCLC patients. CONCLUSIONS: Our results indicate that advanced NSCLC patients with positive expression of EZH2 exhibited resistance to cisplatin-based chemotherapy. EZH2 may be a predictive and prognostic factor for cisplatin-based therapy response and disease survival in advanced NSCLC.

Elevated expression of Cripto-1 correlates with poor prognosis in non-small cell lung cancer.

Human Cripto-1 (CR-1) plays an important oncogenic role during tumorigenesis and is overexpressed in a wide range of carcinomas, yet little is known about CR-1 in non-small cell lung cancer (NSCLC). The aims of this study were to detect CR-1 expression in NSCLC and to analyze its association with prognosis of NSCLC patients. The expression of CR-1 messenger RNA (mRNA) and protein in 35 cases of NSCLC and corresponding noncancerous tissue samples was examined by quantitative real-time reverse transcription-polymerase chain reaction (qRT-PCR) and Western blotting. Immunohistochemistry was performed to detect the expression of CR-1 in 128 NSCLC tissues. The expression levels of CR-1 mRNA and protein in NSCLC tissues were significantly higher than those in corresponding noncancerous tissues (P < 0.001). A high level of CR-1 expression was correlated with poor tumor differentiation (P = 0.002), tumor-node-metastasis (TNM) stage (P = 0.004), and lymph node metastasis (P = 0.001). The results of the Kaplan-Meier analysis indicated that a high expression level of CR-1 resulted in a significantly poor prognosis of NSCLC patients. Multivariate Cox regression analysis revealed that CR-1 expression level was an independent prognostic parameter for the overall survival rate of NSCLC patients. Our data suggest that the high expression of CR-1 may play an important role in the progression of NSCLC, and CR-1 expression may offer a valuable marker for predicting the outcome of patients with NSCLC.

EZH2 regulates cancer cell migration through repressing TIMP-3 in non-small cell lung cancer.

Histone methylations play important roles in human cancer metastasis. Enhancer of zeste homolog 2 (EZH2) is a key component of the polycomb repressor complex 2, which is responsible for histone H3K27 methylation. EZH2 is overexpressed in lung cancer and epigenetically silences tumor suppressor genes. Here, we showed that EZH2 was up-regulated in lung cancer and had a positive correlation with pathologic stage, nodal involvement in lung cancer patients. Moreover, overexpression of EZH2 was correlated with reduced tissue inhibitor of metalloproteinase-3 (TIMP-3) expression, which was shown to be negatively associated with tumor metastasis. Of note, overall survival time of patients with high EZH2/low TIMP-3 expression was significantly shorter than that of patients with low EZH2/high TIMP-3 (P = 0.031). RNA interfering and pharmacologic inhibition of EZH2 reduced histone H3 lysine 27 tri-methylation level and increased TIMP-3 expression level. Knockdown of EZH2 by siRNA significantly reduced A549 cancer cell migration. In contrast, reduction of TIMP-3 in A549 cells partially rescued EZH2 deficiency-induced loss of cell migration capacity. Taken together, our findings indicate that EZH2 accelerates cancer cell migration, in part, via the repression of TIMP-3 expression, suggesting a potential mechanism by which EZH2 promotes lung cancer progression and metastasis.

Histological subtypes of solitary pulmonary nodules of adenocarcinoma and their clinical relevance.

OBJECTIVE: To explore the histological subtypes of solitary pulmonary nodules (SPNs) of invasive adenocarcinoma and their clinical relevance. METHODS: A total of 188 patients with pathologically confirmed invasive adenocarcinoma in our hospital from January 2007 to December 2011 were enrolled in this study. In accordance with the new classification of lung adenocarcinoma, all the histological sections were reviewed and classified, and the clinical data were collected and analyzed. RESULTS: Of these 188 patients who had been initially diagnosed as SPNs of adenocarcinoma, there were 6 cases of lepidic predominant adenocarcinoma (LPA), 71 cases of acinar predominant adenocarcinoma (APA), 74 cases of papillary predominant adenocarcinoma (PPA), 15 cases of micorpapillary predominant adenocarcinoma (MPA), and 22 cases of solid predominant adenocarcinoma (SPA) with mucin production. The incidence of lymph node metastasis was 80.0% and 81.8% in MPA and SPA, respectively, which was significantly higher than those in LPA, APA, and PPA (all P<0.01). The incidence of LPA was 83.3% (5/6) in women, which was significantly higher than that in men (P=0.037). CONCLUSIONS: According to the new classification, MPA and SPA have high incidence of lymph node metastasis. LPA is more likely to occur in women. Sub-typing of the lung adenocarcinoma based on the newest international classification criteria is helpful to identify the clinical features of this disease.