Adjacent Lung Research Articles

Recurrent Infections and Rash in a 6 Year Old Girl: A Case Report of Congenital C3 Defeciency

Primary complement deficiencies are very rare and a case of 6 year old girl with complement 3 deficiency is reported here who presented with recurrent infections and rash since her early childhood. She had several episodes of respiratory tract infections, urinary tract infections and various episodes of gastro enteritis and was treated subsequently every time with injectable antibiotics. Later she developed encysted hydropneumothorax with mild pleural thickening with compression collapse of adjacent right lung. On investigation complement 3 level was found below normal both in the patient and in her parents and younger sister. This case is reporting here in order to disseminate the message that underlying cause of recurrent infections could be primary immunodeficiency (C3).
 J Bangladesh Coll Phys Surg 2020; 38(2): 101-104

A safe and novel method for video-assisted thoracic surgery preoperative localization of small pulmonary nodules by using ZT medical glue (2-octyl cyanoacrylate)

BackgroundAccurate and fast localization of small pulmonary nodules is required for local pulmonary resection. In this study, we introduced and assessed a novel technique for the preoperative localization of small pulmonary nodules by using ZT medical glue (2-octyl cyanoacrylate). Methods101 patients who had a combined total of 106 small pulmonary nodules located by ZT glue and 53patients with 53 small pulmonary nodules located by hookwire were selected. Guided by computed tomography (CT), the surgeon injected certain volume ZT glue into an area adjacent to the small pulmonary nodule, then, the adjacent lung tissue infiltrated by ZT glue formed into a depressed hard nodule which can be used for preoperative localization with an obvious mark on lung surface or different hand touch. After localization, Wedge resection was performed via video-assisted thoracoscopic surgery and the specimen obtained from the procedure was immediately sent for pathological examination, followed by a standard surgical procedure. A contrast has been made between the ZT glue method and the hookwire. Results101 operations were successfully performed by using this novel technique, and 106 small pulmonary nodules were successfully located. Compared with the hookwire location, ZT glue method obviouslyextended the Time interval between localization and operation (P = 0.00) and a same complication rate (P = 0.07). ConclusionsThe use of ZT glue is a safe and effective method for the localization of small pulmonary nodules. Trial registrationThis study was approved by the ethics committee of Shaoxing People's Hospital (Number:2016-004, Date:2016,2,24), and informed consent was obtained from all enrolled patients.

Analysis of Wnt7B and BMP4 expression patterns in congenital pulmonary airway malformation.

Congenital pulmonary airway malformation (CPAM) is a rare disorder characterized by aberrant overgrowth of terminal bronchioles. The objective of this study was to describe wingless-type MMTV integration site family 7B (Wnt7B) and bone morphogenetic protein 4 (BMP4) expression patterns in human CPAM lesions and to explore the possible roles of Wnt7B and BMP4 in the pathogenesis of CPAM. Fifteen tissue samples from patients with CPAM were obtained from the Pathology Department of Shengjing Hospital of China Medical University. Samples representing CPAM lesions and adjacent normal lung tissues were collected and Wnt7B and BMP4 expression was detected through immunohistochemical (IHC) staining, quantitative real-time polymerase chain reaction (qRT-PCR), and Western blotting. IHC revealed that Wnt7B immunopositive cells were only detected in epithelial cells, whereas BMP4 immunopositive cells were detected in epithelial and mesenchymal cells. Expression of Wnt7B and BMP4 immunopositive cells was higher in CPAM lesions than that in adjacent normal lung tissue. qRT-PCR and Western blotting showed that Wnt7B and BMP4 mRNA and protein expression were significantly higher in CPAM lesions than in adjacent normal lung tissue (P < .05). Overall, the level of BMP4 was higher than that of Wnt7B. Increased expression of Wnt7B and BMP4 appear to be related to the pathogenesis of CPAM and abnormal pulmonary development. Upregulation of Wnt7B and BMP4 could play an important role in the development of the bronchial-alveolar structures that characterize CPAM.

Combined evaluation of the expression status of CD155 and TIGIT plays an important role in the prognosis of LUAD (lung adenocarcinoma)

The interaction between CD155 and its high-affinity ligand TIGIT is being increasingly investigated in various solid tumors. However, the prognostic significance of CD155 and TIGIT in lung adenocarcinoma (LUAD) remains unclear. In this study, immunohistochemistry was applied in 334 LUAD cases to evaluate the expression of CD155 and TIGIT. Western blotting was conducted in 5 paired primary LUAD and adjacent normal lung tissues. Our results reveal that CD155 and TIGIT are overexpressed in LUAD tissues and that aberrant overexpression is closely correlated with poor clinical outcomes (P < 0.01). The multivariate model also shows that CD155 expression is an independent risk factor for LUAD (RR, 1.34; P = 0.036). Moreover, patients expressing high CD155 and TIGIT simultaneously presented shorter overall survival (OS) (P < 0.01) and progression-free survival (PFS) (P < 0.01). These findings suggest that CD155 and TIGIT can make up a prognosticating tool to predict clinical outcomes, thereby contributing to personalized medical care in LUAD.

LncRNA-ATB Promotes Lung Squamous Carcinoma Cell Proliferation, Migration, and Invasion by Targeting microRNA-590-5p/NF90 Axis.

Lung cancer with highest morbidity and mortality seriously threatens human health worldwide. Long noncoding RNAs (lncRNAs) exert important biological functions by acting as microRNA, which is implicated in tumorigenesis and cancer development. Previous work has reported that lncRNA-ATB expression was significantly upregulated in lung adenocarcinoma tissues and promoted tumor progression; however, the mechanisms of lncRNA-ATB in lung squamous carcinoma (LSC) are still fairly elusive. In our study, lncRNA-ATB expression also markedly increases in LSC tissues and cell lines in comparison to the adjacent normal tissues and normal lung epithelial cells, respectively. Functional experiments indicate that lncRNA-ATB overexpression improves the proliferative, migratory, and invasive capabilities of normal lung epithelial cells compared with control group. Furthermore, the migratory and invasive abilities are strikingly inhibited in lncRNA-ATB silenced LSC cells. Mechanistically, lncRNA-ATB directly binds to microRNA-590-5p and downregulates microRNA-590-5p level, leading to the upregulation of NF-90 expression. In addition, lncRNA-ATB overexpression promotes the epithelial-mesenchymal transition process, where lncRNA-ATB overexpression facilitates the expression of mesenchymal phenotype related molecules N-cadherin and vimentin, while restrains the expression of epithelial phenotype related proteins E-cadherin and CK-19, compared to the control. Conversely, microRNA-590-5p mimics can reverse the results caused by lncRNA-ATB overexpression. Taken together, our initial data suggest that lncRNA-ATB overexpression may promote the progression of LSC by modulating the microRNA-590-5p/NF-90 axis.

Comprehensive Analysis of Aberrantly Expressed Profiles of lncRNAs and miRNAs with Associated ceRNA Network in Lung Adenocarcinoma and Lung Squamous Cell Carcinoma.

Lung cancer (LC) continues to be the leading cause of cancer-related deaths worldwide and the prognosis remains poor worldwide. At present, the long non-coding RNAs (lncRNAs) was considered as a part of competing endogenous RNA (ceRNA) network act as natural microRNA (miRNA) sponges to regulate protein-coding gene expression. However, functional roles of lncRNA-mediated ceRNAs in LC are insufficiently understood. To classify the specific mechanism of lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC), we comprehensively compared the expression profiles of mRNAs, lncRNAs and miRNAs obtained from 509 LUAD, 473 LUSC tissues and 49 adjacent non-cancerous lung tissues, based on The Cancer Genome Atlas (TCGA). After screening for differently expressed (DE) mRNAs, DEmiRNAs, DElncRNAs and weighted gene co-expression network analysis (WGCNA) (|log2FC| > 2.0 and an adjusted p value <0.05), a total of 4478 DEmRNAs, 526 DElncRNAs and 75 DEmiRNAs in LUAD, while 6237 DEmRNAs, 843 DElncRNAs and 117 DEmiRNAs in LUSC were discovered. Interaction (PPI) network analysis was performed to identify 656 nodes and 2987 edges (minimum required interaction score > 0.9), as well as 8 different protein-protein interactions. Gene ontology (GO) analysis mainly associated with cell proliferation. KEGG pathway enrichment analyses most partly associated with metabolism pathway and cytokine-cytokine receptor interaction. Finally, the dysregulated lncRNA-miRNA-ceRNA network was constructed based on correlation analyses and a total of 62 dysregulated lncRNAs, 28 DEmRNAs and 18 DEmiRNAs were involved. The most significant lncRNAs included DElncRNAs, LINC00641 and AC004947.2, miRNAs included miR-6860, miR-1285-3p, miR-767-3p and miR-7974, mRNAs included MAP3K3, FGD3 and ATP1B2. Then we analyzed and described the potential characteristics of biological function and pathological roles of the LUAD and LUSC ceRNA co-regulatory network. Our findings revealed ceRNA network will be beneficial for promoting the understanding of lncRNA-mediated ceRNA regulatory mechanisms in the pathogenesis of LUAD and LUSC.

Increases in mRNA and Protein Levels of the Genes for the Actin-Binding Proteins Profilin, Fascin, and Ezrin Promote Metastasis in Non-Small Cell Lung Cancer

The actin-binding proteins profilin, fascin, and ezrin were tested for involvement in metastasis of non-small cell lung cancer (NSCLC). The levels of the PFN1, FSCN1, and EZR mRNAs and respective proteins were determined by real-time PCR and Western blotting; tumor and adjacent normal lung tissue samples were obtained from 46 NSCLC patients. Patients with lymphatic metastasis had higher expression levels of the profilin, fascin, and ezrin mRNAs and the profilin and fascin proteins. Both mRNA and protein expression levels increased in patients with distant metastasis. The molecules may serve as predictors to evaluate the prognosis in NSCLC.

Cyclin K interacts with β-catenin to induce Cyclin D1 expression and facilitates tumorigenesis and radioresistance in lung cancer.

Rationale: Radioresistance remains the major cause of local relapse and distant metastasis in lung cancer. However, the underlying molecular mechanisms remain poorly defined. This study aimed to investigate the role and regulatory mechanism of Cyclin K in lung cancer radioresistance.Methods: Expression levels of Cyclin K were measured by immunohistochemistry in human lung cancer tissues and adjacent normal lung tissues. Cell growth and proliferation, neutral comet and foci formation assays, G2/M checkpoint and a xenograft mouse model were used for functional analyses. Gene expression was examined by RNA sequencing and quantitative real-time PCR. Protein-protein interaction was assessed by immunoprecipitation and GST pull-down assays.Results: We report that Cyclin K is frequently overexpressed and correlates with poor prognosis in lung cancer patients. Functionally, we demonstrate that Cyclin K depletion results in reduced proliferation, defective G2/M checkpoint and enhanced radiosensitivity in lung cancer. Mechanistically, we reveal that Cyclin K interacts with and promotes the stabilization of β-catenin protein, thereby upregulating the expression of Cyclin D1. More importantly, we show that Cyclin D1 is the major effector that mediates the biological functions of Cyclin K in lung cancer.Conclusions: These findings suggest that Cyclin K positively modulates the β-catenin/Cyclin D1 axis to promote tumorigenesis and radioresistance in lung cancer, indicating that Cyclin K may represent a novel attractive biomarker for lung cancer radiotherapy.

FANCI Cooperates with IMPDH2 to Promote Lung Adenocarcinoma Tumor Growth via a MEK/ERK/MMPs Pathway.

PurposeFanconi anemia complementation group I (FANCI) is a key protein in ribosome biogenesis and DNA repair. Here, we aimed to determine the clinical significance, prognostic value and biology functions of FANCI in lung adenocarcinoma (LUAD).MethodsThe expression of FANCI in LUAD tissue and its relationship with patient outcomes were assessed using bioinformatics analysis, as well as quantitative reverse-transcription PCR (qRT-PCR) and Western blot analysis of LUAD tissue and adjacent normal lung tissue. The chi-squared test and Cox regression analysis were used to analyze the clinical significance of FANCI expression. The biological effects of FANCI knockdown in human LUAD cell lines were investigated by analysis of proliferation, colony formation, cell cycle distribution, migration, and invasion in vitro, and monitoring of tumor xenograft growth in vivo. FANCI interactions with IMPDH2 and involvement in MEK/ERK/MMPs signaling were analyzed using co-immunoprecipitation assays, immunofluorescence microscopy, and Western blotting.ResultsFANCI was identified as a hub gene for LUAD. FANCI expression was upregulated in LUAD tissues compared with normal lung tissues and was positively associated with lymphatic metastasis, distant metastasis, and poor outcome. FANCI was also an independent prognostic factor in LUAD patients. Knockdown of FANCI in LUAD cell lines decreased their proliferation, migration, invasion, and cell cycle progression in vitro, and decreased the growth of xenografts in mice. Direct binding of FANCI to IMPDH2 decreased IMPDH2 degradation, regulated activation of MEK/ERK/MMPs signaling. Overexpression of IMPDH2 reversed the inhibitory effects of FANCI knockdown.ConclusionFANCI may act as an oncogene in LUAD by cooperating with IMPDH2 to promote cell proliferation via the MEK/ERK/MMPs pathway. These results identify FANCI as a potential prognostic biomarker and therapeutic target for LUAD.

Does Tumor FDG-PET Avidity Represent Enhanced Glycolytic Metabolism in Non-Small Cell Lung Cancer?

In non-small cell lung cancer (NSCLC), 18fluoro-2-deoxyglucose-positron emission tomography (FDG-PET) assists in diagnosis, staging, and evaluating treatment response. One variable of FDG-PET, the maximum standard uptake value (SUVm), is considered an objective measure of glucose uptake. However, little is known about the fate of glucose in FDG-avid lung tumors invivo. This study used stable glucose isotope tracing to determine whether the SUVm predicts glycolytic metabolism or other glucose fates in tumors. In this prospective Institutional Review Board-approved clinical trial, 52 untreated potentially resectable confirmed NSCLC patients underwent FDG-PET computed tomography. During the surgical procedure, the patients were infused with 13C-labeled glucose. Blood, tumor, and normal lung samples were analyzed by mass spectrometry to determine 13C enrichment in glycolytic intermediates. These values were compared with clinical variables, including SUVm, maximum tumor diameter, stage, grade, and MIB-1/Ki67 proliferation index. For each patient, 13C enrichment in each metabolite was compared between tumor and adjacent lung. Although all tumors metabolized glucose, SUVm did not correlate with glycolytic intermediate labeling. Rather, SUVm correlated with markers indicating the use of other respiratory substrates, including lactate, and with the proliferation index. SUVm does not correlate with glycolytic metabolism in human NSCLC but does correlate with the proliferation index, suggesting that SUVm predicts glucose use by pathways other than glycolysis. These pathways may offer alternative therapeutic targets, including biosynthetic pathways required for cell proliferation. The research techniques in this study offer the opportunity to understand the relationships between SUVm, tumor metabolism, and therapeutic vulnerabilities in human NSCLCs.

Identification and Integrated Analysis of Key Biomarkers for Diagnosis and Prognosis of Non-Small Cell Lung Cancer.

BackgroundNon-small cell lung cancer (NSCLC) is the main histologic form of lung cancer that affects human health, but biomarkers for therapeutic diagnosis and prognosis of the disease are currently lacking.Material/MethodsThe gene expression profile GSE18842 was downloaded from the Gene Expression Omnibus database in this prospective study, which consisted of 46 tumors and 45 controls. After screening differentially expressed genes (DEGs), we conducted functional enrichment analysis and KEGG analysis with upregulated differentially expressed genes (uDEGs) and downregulated differentially expressed genes (dDEGs), respectively. Protein–protein interaction (PPI) networks among DEGs and corresponding coding protein complexes, constructed using the STRING database, were analyzed using Cytoscape. Kaplan-Meier method was used to verify survival associated with hub genes. The GEPIA webserver was used to plot the gene expression level heat map of hub genes between NSCLC and adjacent lung tissues in the TCGA database.ResultsWe identified 368 DEGs (168 uDEGs and 200 dDEGs) in NSCLC samples relative to control samples after gene integration. We established a PPI network for the DEGs, which had 249 nodes and 1472 edges protein pairs. Ten undefined hub genes with the highest connectivity degree (CDK1, UBE2C, AURKA, CCNA2, CDC20, CCNB1, TOP2A, ASPM, MAD2L1, and KIF11) were verified by survival analysis, and 9 of them were associated with poorer overall survival in NSCLC. The expression reliability of hub genes was verified by use of the GEPIA web tool.ConclusionsThe results suggested that UBE2C, AURKA, CCNA2, CDC20, CCNB1, TOP2A, ASPM, MAD2L1, and KIF11 are inherent key biomarkers for diagnosis and prognosis, while KEGG analysis results showed the mitotic cell cycle pathway is a probable signaling pathway contributing to NSCLC progression. These genes could be promising biomarkers for diagnosis and provide a new approach for developing targeted therapeutic NSCLC drugs.

A Diagnostic Panel of DNA Methylation Biomarkers for Lung Adenocarcinoma.

Lung adenocarcinoma (LUAD) is one of the most common cancers and lethal diseases in the world. Recognition of the undetermined lung nodules at an early stage is useful for a favorable prognosis. However, there is no good method to identify the undetermined lung nodules and predict their clinical outcome. DNA methylation alteration is frequently observed in LUAD and may play important roles in carcinogenesis, diagnosis, and prediction. This study took advantage of publicly available methylation profiling resources and a machine learning method to investigate methylation differences between LUAD and adjacent non-malignant tissue. The prediction panel was first constructed using 338 tissue samples from LUAD patients including 149 non-malignant ones. This model was then validated with data from The Cancer Genome Atlas database and clinic samples. As a result, the methylation status of four CpG loci in homeobox A9 (HOXA9), keratin-associated protein 8-1 (KRTAP8-1), cyclin D1 (CCND1), and tubby-like protein 2 (TULP2) were highlighted as informative markers. A random forest classification model with an accuracy of 94.57% and kappa of 88.96% was obtained. To evaluate this panel for LUAD, the methylation levels of four CpG loci in HOXA9, KRTAP8-1, CCND1, and TULP2 of tumor samples and matched adjacent lung samples from 25 patients with LUAD were tested. In these LUAD patients, the methylation of HOXA9 was significantly upregulated, whereas the methylation of KRTAP8-1, CCND1, and TULP2 were downregulated obviously in tumor samples compared with adjacent tissues. Our study demonstrates that the methylation of HOXA9, KRTAP8-1, CCND1, and TULP2 has great potential for the early recognition of LUAD in the undetermined lung nodules. The findings also exhibit that the application of improved mathematic algorithms can yield accurate and particularly robust and widely applicable marker panels. This approach could greatly facilitate the discovery process of biomarkers in various fields.

Subclinical community‐acquired Acinetobacter pneumonia associated with mature cystic teratoma masquerading as lung abscess

A 22‐year‐old lady presented with fever and right pleuritic chest pain with chest X‐ray showing a right suprahilar shadow. Her symptoms largely subsided with antibiotic therapy but the shadow remained unresolved. Computerized tomography (CT) scan of thorax showed consolidation over the anterior segment of the right upper lobe with a hypodense area suspicious of a lung abscess. Fine needle aspirates of the lesion grew Acinetobacter baumannii twice but the shadow persisted despite multiple courses of antibiotics targeted at the organism. Right video‐assisted thoracoscopic surgery was done and the pathological diagnosis was a mature cystic teratoma with adjacent lung consolidation. Culture of the lung specimen also grew Acinetobacter baumannii. This was the first reported case of subclinical community‐acquired Acinetobacter pneumonia in association with a mature cystic teratoma, which masquerades as a lung abscess.

Prognostic model based on circular RNA circPDK1 for resected lung squamous cell carcinoma.

Circular RNA has been revealed as a potential biomarker in multiple malignancies. However, few studies have focused on its potential to be prognostic markers in lung squamous cell carcinoma (LSCC). In this work, we aimed to build a prognostic model of resected LSCC based on circular RNA pyruvate dehydrogenase kinase 1 (circPDK1) and other clinicopathological factors. circPDK1 was identified via next-generation sequencing. Three hundred two cases of LSCC tissue and their adjacent normal lung tissues were obtained from multiple medical centers and divided into study cohort (n=232) and validation cohort (n=70). The expression of circPDK1 was detected for analyzing its potential prognostic value for recurrence-free survival (RFS) and overall survival (OS) in LSCC. Finally, combined with circPDK1, T staging, lymph nodes (LN) metastasis status, age, and serum squamous cell Carcinoma Antigen (SCCAg), we built a prognostic model by nomograms method and confirmed it in the validation cohort. CircPDK1 was identified to be overexpressed (P<0.01) in LSCC. Through analysis in study cohort, circPDK1low patients (less than the mean expression, n=124) showed more lymph nodes metastasis (P=0.025), more vascular invasion (VI) (P=0.047), more visceral pleural invasion (VPI) (P=0.015) and poorer prognosis (P=0.003) than circPDK1high ones (n=108). Univariate and multivariate analysis showed that circPDK1, T staging, LN status, age, and SCCAg were significant prognostic factors for RFS and OS. The prognostic model based on these factors showed the concordance index (C-index) of 0.8214 and 0.8359 for predicting 5-year RFS and OS, respectively. Finally, the calibration curves were performed in the study cohort and a validation cohort to evaluate the model's efficiency. circPDK1 was identified as a potential biomarker of resected LSCC. The prognostic model including circPDK1, T staging, LN status, age, and SCCAg could effectively predict prognosis of resected LSCC.

New insights on congenital pulmonary airways malformations revealed by proteomic analyses

BackgroundCongenital Pulmonary Airway Malformation (CPAM) has an estimated prevalence between 0.87 and 1.02/10,000 live births and little is know about their pathogenesis. To improve our knowledge on these rare malformations, we analyzed the cellular origin of the two most frequent CPAM, CPAM types 1 and 2, and compared these malformations with adjacent healthy lung and human fetal lungs.MethodsWe prospectively enrolled 21 infants undergoing surgical resection for CPAM. Human fetal lung samples were collected after termination of pregnancy. Immunohistochemistry and proteomic analysis were performed on laser microdissected samples.ResultsCPAM 1 and 2 express mostly bronchial markers, such as cytokeratin 17 (Krt17) or α-smooth muscle actin (ACTA 2). CPAM 1 also expresses alveolar type II epithelial cell markers (SPC). Proteomic analysis on microlaser dissected epithelium confirmed these results and showed distinct protein profiles, CPAM 1 being more heterogeneous and displaying some similarities with fetal bronchi.ConclusionThis study provides new insights in CPAM etiology, showing clear distinction between CPAM types 1 and 2, by immunohistochemistry and proteomics. This suggests that CPAM 1 and CPAM 2 might occur at different stages of lung branching. Finally, the comparison between fetal lung structures and CPAMs shows clearly different protein profiles, thereby arguing against a developmental arrest in a localized part of the lung.

Ectonucleotidase CD39 and Checkpoint Signalling Receptor Programmed Death 1 are Highly Elevated in Intratumoral Immune Cells in Non–small-cell Lung Cancer

Lung cancer is the leading cause of cancer death in both sexes worldwide and has a predicted 5-year survival rate of <20%. Immunotherapy targeting immune checkpoints such as the programmed death 1 (PD-1) signaling pathway has led to a shift of paradigm in the treatment of advanced non–small-cell lung cancer (NSCLC) but remains without effect in ∼80% of patients. Accumulating evidence suggests that several immunosuppressive mechanisms may work together in NSCLC. The contribution and cooperation between different immunosuppressive mechanisms in NSCLC remain unknown. Recently, the CD39-adenosine pathway has gained increasing attention as a crucial immunosuppressive mechanism and possible target for immunotherapy. Immune cells were extracted from lung and tumor tissue after lung resection in 12 patients by combined enzymatic and mechanical tissue disaggregation. A multiparameter flow cytometry panel was established to investigate the expression and coexpression of CD39 and PD-1 on key lymphocyte subtypes. Frequencies of CD39+, PD-1+, and CD39+/PD-1+cells were higher among both CD4+ and CD8+ T cells isolated from NSCLC tumor tissue than in T cells from normal lung tissue. Similarly, the frequency of FoxP3+ CD4+ T cells (Tregs) was highly significantly elevated in tumor tissue compared to adjacent lung tissue. The consistent upregulation of CD39 on immune cells in tumor microenvironment indicates that the CD39 signaling pathway may, in addition to the PD-1 pathway, represent another important mechanism for tumor-induced immunosuppression in NSCLC. In addition, the present study indicates that a comprehensive immune response profiling with flow cytometry may be both feasible and clinically relevant.

Role of PET/CT in Management of Early Lung Adenocarcinoma.

OBJECTIVE. The purpose of this study was to explore the value of FDG PET combined with high-resolution CT (HRCT) in predicting the pathologic subtypes and growth patterns of early lung adenocarcinoma. MATERIALS AND METHODS. A retrospective analysis was conducted on the PET/CT data on ground-glass nodules (GGNs) resected from patients with stage IA lung adenocarcinoma. The efficacy of PET maximum standardized uptake value (SUVmax) combined with HRCT signs in prediction of histopathologic subtype and growth pattern of lung adeno-carcinoma was evaluated. RESULTS. SUVmax was significantly higher in GGNs with invasive HRCT signs. The diameter of GGN (odds ratio, 1.660; p = 0.000) and the difference in attenuation value (odds ratio, 1.012; p = 0.011) between ground-glass components and adjacent lung tissues were independent predictors of FDG uptake by GGNs. SUVmax was higher in invasive adenocarcinoma than in adenocarcinoma in situ (AIS)-minimally invasive adenocarcinoma (MIA) (median SUVmax, 2.0 vs 1.1; p = 0.008). An SUVmax of 2.0 was the optimal cutoff value for differentiating invasive adenocarcinoma from AIS-MIA. Acinar-papillary adenocarcinoma had a higher SUVmax than lepidic adenocarcinoma (median SUVmax, 2.1 vs 1.3; p = 0.037). An SUVmax of 1.4 was the optimal cutoff value for differentiating the growth pattern of adenocarcinoma. Use of PET/CT with HRCT significantly improved efficacy for differentiating invasive adeno-carcinoma from AIS-MIA. However, use of HRCT cannot significantly improve the diagnostic efficacy of FDG PET in the evaluation of tumors with different growth patterns. CONCLUSION. FDG PET can be used to predict the histopathologic subtypes and growth patterns of early lung adenocarcinoma. Combined with HRCT, it has value for predicting invasive histopathologic subtypes but no significance for predicting invasive growth patterns.

T-cell immunoglobulin and mucin domain 1 expression in human non-small-cell lung cancer tissues and its clinical significance

Objective To investigate the expression of T-cell immunoglobulin and mucin domain 1 (TIM-1) in non-small-cell lung cancer (NSCLC) tissues and to analyze its clinical significance. To further explore the regulatory effect of TIM-1 intervention on the biological function of NSCLC cell lines. Methods The immunohistochemistry assay and the tissue micro-array were used to examine the TIM-1 expression in lung cancer tissues as well as adjacent normal lung tissues. The correlation between the expression level of TIM-1 and patients’ clinic pathological parameters was evaluated by using chi-square test. The lung cancer cell lines A549 and SK-MES-1 were used to construct the stable knockdown expression of TIM-1 using RNA interference (RNAi) method. The cell counting kit-8 (CCK-8), wound healing, and Transwell were used to examine the cellular function after TIM-1 knockdown of these cells. Results Higher TIM-1 expression in lung squamous cell carcinoma tissues is significantly correlated with advanced TNM stage (Ⅲ+ Ⅳ: 33.3%, Ⅰ+ Ⅱ: 13.2%) (χ2=3.969, P<0.05), but not any other parameters. CCK-8 assay showed that, knockdown expression of TIM-1 make the cell proliferation rate decreased significantly. The wound healing assay showed that the cell migration abilities of LV-TIM-1-shRNA group was significantly lower than LV-NC group (A549, 24 h: t=17.540, P<0.01; SK-MES-1, 24 h: t=11.450, P<0.01). The Transwell assay showed that the cell invasion abilities was significantly decreased after knockdown expression of TIM-1. Conclusion Our results showed that the TIM-1 was highly expressed in non-small-cell lung cancer tissues, and its expression level was significantly correlated with TNM stage in squamous cell carcinoma patients. TIM-1 expression in lung adenocarcinoma tissues could be used as independent prognostic predictor for the patients, while higher TIM-1 expression in lung squamous cell carcinoma tissues trends significant for the prognostic prediction for the patients. Knockdown expression of TIM-1 could inhibit the cell viability, and the abilities of migration and invasion, and thus TIM-1 could be used as potential therapeutic target for lung cancer. Key words: T-cell immunoglobulin and mucin domain 1; Lung cancer; Immunohistochemistry; RNA interference; Prognosis

MicroRNA-182-5p regulates hedgehog signaling pathway and chemosensitivity of cisplatin-resistant lung adenocarcinoma cells via targeting GLI2.

Lung cancer is one of the deadliest cancers worldwide. Late diagnosis at an advanced, inoperable stage makes chemotherapy a treatment of choice, yet, with low response rates. The hedgehog signaling pathway (HHSP) is often reactivated in cancer. We identified miR-182-5p as a regulator of GLI2, a transcriptional regulator of the HHSP, and explored the role of the miR-182-5p/GLI2 axis in carcinogenesis and cisplatin resistance of lung adenocarcinoma (LADC). Expression of miRNAs and target genes was analyzed by RT-qPCR, expression of the GLI-protein family in LADC and adjacent lung tissue (n = 27 pairs) by immunohistochemistry. MiR-182-5p was manipulated, and data were generated by immunoblotting, immunofluorescence, apoptosis, proliferation/viability, dual-luciferase-, and colony forming assays. MiR-182-5p was down-regulated in cisplatin-resistant LADC cells and directly targeted GLI2. Interference with miR-182-5p or GLI2 silencing resulted in modulation of cell proliferation, clonogenic potential, and cisplatin-sensitivity. HHSP was markedly reactivated in LADC tissue compared to adjacent non-malignant lung tissue. Our results indicate that the miR-182-5p/GLI2 axis modulates tumorigenesis and cisplatin-resistance in LADC cells, by influencing the HHSP. Therefore, this axis might be considered as a potential biomarker and future therapeutic target in LADC patients.

Elevated FAM83A expression predicts poorer clincal outcome in lung adenocarcinoma.

Family with sequence similarity 83 member A (FAM83A) can promote tumor cell proliferation and facilitate epidermal growth factor tyrosine kinase inhibitor resistance in some malignant tumors, but its role in lung cancer has not been directly explored. We investigated FAM83A expression in lung adenocarcinoma (LUAD) and its significance in clinicopathologic characteristics and prognosis of the disease. We analyzed the mRNA expression of FAM83A in LUAD and normal (or adjacent) lung tissues from Oncomine database firstly. Then, we detected FAM83A protein expression in five paired fresh LUAD and adjacent lung tissue specimens from patients in our hospital by Western blotting. In addtion, FAM83A expression in 86 paraffin-embedded archived LUAD samples was evaluated by Immunohistochemistry, and the correlations between FAM83A expression and clinicopathologic characteristics and prognosis of the patients were analyzed. Oncomine data analysis manifested that FAM83A mRNA expression was increased in LUAD. Western blotting revealed higher FAM83A expression in fresh LUAD tissues than in the adjacent lung tissues (P= 0.036). Immunohistochemistry analysis on 86 paraffin samples further demonstrated that the LUAD tissue had higher FAM83A expression than adjacent lung tissue (P< 0.001). The correlation analysis revealed that advanced stage tumors (stage III-IV) had higher FAM83A expression than early stage tumors (stage I-II) (P= 0.004). High FAM83A expression was significantly associated with lymphnode involvement and clinical staging (P= 0.008 and 0.008 respectively). Univariate and multivariate Cox regression analysis manifested that FAM83A expression was an independent predictive factor for poor survival. Kaplan-Meier survival curves showed that patients with higher FAM83A expression had shorter overall survival than those with lower FAM83A expressions (P= 0.002). FAM83A is upregulated in advanced LUAD and is related to unfavorible prognosis. FAM83A might be a novel diagnostic and prognositic biomarker for LUAD.