Adjacent Lung Research Articles

MicroRNA-3692-3p is overexpressed in lung tumors but may not serve as a prognostic biomarker in lung cancer patients.

We previously reported overexpression of miR-3692-3p in the serum of non-small cell lung cancer patients. However, the expression profile and clinical utility of miR-3692-3p in the tumor tissues of lung cancer patients are not yet reported. We quantified the expression levels of miR-3692-3p in the tumors and adjacent normal lung tissues of early-stage (n = 29) and tissue biopsies of locally advanced and metastatic (n = 85) lung cancer patients using TaqMan advanced miRNA assay. We correlated miR-3692-3p expression with survival outcomes, therapeutic response, and other clinicopathological variables. We also predicted the target genes of miR-3692-3p, constructed a protein-protein interaction network, and performed functional enrichment analysis using various in silico tools. We found significant overexpression of miR-3692-3p in the tumors (Log2 fold change = 3.672; p < 0.0001) and tissue biopsies (Log2 fold change = 2.08; p = 0.0001) compared to normal lung tissues of lung cancer patients. The expression of miR-3692-3p did not correlate with overall survival (OS), progression-free survival (PFS), and response to therapy. In multivariate analysis, therapeutic response emerged as an independent prognostic biomarker of OS (HR = 3.47; p = 0.022) and PFS (HR = 19.86; p < 0.001). Our in silico analysis predicted 238 target genes of miR-3692-3p. Overexpression of miR-3692-3p could contribute to the development of lung cancer. However, mechanistic studies are warranted to shed further light on its role in lung carcinogenesis.

Study of Linear Energy Transfer Effect on Rib Fracture in Breast Patients Receiving Pencil-Beam-Scanning Proton Therapy

<h3>Purpose/Objective(s)</h3> To study the linear energy transfer (LET) effect upon rib fracture (RF) in breast cancer patients treated with pencil-beam scanning proton therapy (PBS) using dose-linear energy transfer volume histogram (DLVH). <h3>Materials/Methods</h3> After IRB approval, we retrospectively identified RF cases detected after workup of chest wall pain or incidentally on imaging in breast cancer patients treated with PBS to the breast/chest wall and regional nodes from 2015-2020. Control patients were selected to match the RF patients 2:1 considering prescription dose, boost location, reconstruction status, laterality, chest wall thickness, and treatment year. For all plans, a chest wall was contoured, incorporating ribs and intercostal muscles within the 50% prescription isodose line. Both dose and LET were calculated using a planning tool dose engine. DLVH was generated for each patient, using dose and LET as the two axes. The DLVH index, <i>V</i>(<i>d, l</i>), defined as <i>V</i>(% for normalized volume or cc for absolute volume) of the structure with a dose of at least <i>d</i> Gy[RBE] and an LET of at least <i>l</i> keV/µm, was calculated for all combinations of <i>d</i> and <i>l</i>. Conditional logistic regression model was used to establish the relation of <i>V</i>(<i>d, l</i>) and the observed RF at each combination of <i>d</i> and <i>l</i>. The derived <i>p values</i> constitute a <i>p value</i> map in the 2D dose and LET plane. Concordance and its standard error (se) maps were generated to evaluate the performances for all DLVH indices. A correlation coefficient map was obtained to determine the correlation between the featured DLVH indices. <h3>Results</h3> Eight RF cases were identified, and 16 controls were matched. Of RF patients, seven were treated with post-mastectomy (PMRT) and one was treated with post-lumpectomy radiotherapy. Six RF patients treated with PMRT received a dose of 50 Gy[RBE] in 25 fractions to the chest wall and regional lymph nodes; of these, four received a simultaneous integrated boost (SIB) of 56.25 Gy[RBE] to the chest wall (n=2) or axillary nodes (n=2), and one received a sequential boost of 14 Gy[RBE] in 7 fractions to the chest wall. One RF patient that received PMRT was treated with 40.05 Gy[RBE] in fifteen fractions to the chest wall and regional lymphatics. The post-lumpectomy patient received 50 Gy[RBE] in 25 fractions to the whole breast and regional nodes with a SIB of 56.25 Gy[RBE] to the lumpectomy cavity. Two characteristics correlated with RF (<i>p</i><0.2): 1) Smaller <i>V</i>(50-54 Gy[RBE], 0-4.4keV/µm) of the RF patients with a maximum concordance of 0.813 (se 0.114); 2) Larger <i>V</i>(0-36 Gy[RBE], 5.2-6.8keV/µm) of the RF patients with a maximum concordance of 0.875 (se 0.119) compared with controls. These two features were independent from each other with a weak negative correlation (-0.185). <h3>Conclusion</h3> The increase of high LET in moderate dose regions of the chest wall from constraining the adjacent heart and lung dose during PBS treatment planning may result in increased risk of RF.

Correlation Study on the Expression of INSR, IRS-1, and PD-L1 in Nonsmall Cell Lung Cancer.

Objective To study the expression and correlation of insulin receptor (INSR), insulin receptor substrate-1 (IRS-1), and programmed cell death ligand-1 (PD-L1) in nonsmall cell lung cancer (NSCLC). Methods 45 lung cancer tissues and 30 adjacent normal tissues of NSCLC patients diagnosed in the Second Affiliated Hospital of Shandong First Medical University from June 2019 to August 2020 were selected. The expressions of INSR, IRS-1, and PD-L1 proteins in tumor tissues and adjacent tissues of NSCLC were detected by immunohistochemical staining. Results The expression of INSR and IRS-1 in NSCLC was significantly higher than that in adjacent normal lung tissue (P < 0.05). INSR expression had statistical significance with the degree of pathological differentiation of nonsmall cell carcinoma (P = 0.031), but had no significant association with age, gender, pathological type, TNM stage, and lymph node metastasis status (P > 0.05). There was no significant correlation between IRS-1 positive expression and NSCLC patients' age, gender, pathological typing, degree of differentiation, TNM stage, and lymph node metastasis (P > 0.05). PD-L1 positive expression was correlated with lymph node metastasis of NSCLC (P = 0.028), while there was no significant correlation with gender, age, pathological type, TNM stage, and pathological differentiation degree of NSCLC patients (P > 0.05). Spearman correlation analysis showed that PD-L1 protein expression had a significant positive correlation with IRS-1 protein expression (r = 0.373), but was not correlated with the expression of INSR protein. Conclusion IRS-1 may be involved in the regulation of PD-L1 expression and mediate the occurrence of tumor immune escape, which is expected to become a new target for NSCLC immunotherapy and provide new clinical evidence for immunosuppressive therapy.

MiR-31/QKI-5 axis facilitates cell cycle progression of non-small-cell lung cancer cells by interacting and regulating p21 and CDK4/6 expressions.

RNA-binding protein Quaking-5 (QKI-5), a major isoform of QKIs, inhibits tumor progression in non-small cell lung cancer (NSCLC). However, the underlying molecular mechanisms of QKI-5 in the cell cycle of NSCLC are still largely unknown. MTT, flow cytometry, and colony formation assays were used to investigate cellular phenotypic changes. Mice xenograft model was used to evaluate the antitumor activities of QKI-5. Co-immunoprecipitation, RNA immunoprecipitation (RIP), and RIP sequencing were used to investigate protein-protein interaction and protein-mRNA interaction. The QKI-5 expression was downregulated in NSCLC tissues compared with that in paired normal adjacent lung tissues. Overexpression of QKI-5 inhibited NSCLC cell proliferative and colony forming ability. In addition, QKI-5 induced cell cycle arrest at G0/G1 phase through upregulating p21Waf1/Cip1 (p21) expression and downregulating cyclin D1, cyclin-dependent kinase 4 (CDK4), and CDK6 expressions. Further analyses showed that QKI-5 interacts with p21 protein and CDK4, CDK6 mRNAs, suggesting a critical function of QKI-5 in cell cycle regulation. In agreement with in vitro study, the mouse xenograft models validated tumor suppressive functions of QKI-5 in vivo through altering cell cycle G1-phase-associated proteins. Moreover, we demonstrated that QKI-5 is a direct target of miR-31. The QKI-5 expression was anticorrelated with the miR-31 expression in NSCLC patient samples. Our results suggest that the miR-31/QKI-5/p21-CDK4-CDK6 axis might have critical functions in the progression of NSCLC, and targeting this axis could serve as a potential therapeutic strategy for NSCLC.

Expression and clinical significance of CD31, CD34, and CD105 in pulmonary ground glass nodules with different vascular manifestations on CT.

Blood vessel passage on CT exerts a vital part in early diagnosis as well as treatment of carcinoma of the lungs. Intratumoral microvascular density (iMVD) has gradually become the focus of research on biological behavior, appearance, and evolution of malignant tumors nowadays. The aim of this paper was to verify whether there is a correlation between the iMVD and the vascular morphology of ground glass nodules (GGNs). A total of 109 patients with pulmonary GGN were classified into three groups (I,II, and III) according to the vascular morphology on CT, and their expression of CD31-, CD34-, and CD105-labeled iMVD was detected by the streptoavidin–biotin method, statistically analyzing the iMVD values of each group. The expression of CD31, CD34, and CD105 in different lung tissues was significantly different, with remarkably higher iMVD in lung cancer tissues than in adjacent normal lung tissues. In the imaging sort of types I, II, and III according to the means of vascular passage, the iMVD expression of CD31, CD34, and CD105 was significantly different between groups. These data suggest that the presence and the abnormal morphology of vessels seen within GGNs indicate the occurrence and progression of lung cancer in pathology. It offers a strong theoretical foundation for early diagnosis of carcinoma of the lungs, thus providing a more precise clinical diagnosis and prognosis of early-stage lung cancer.

Identification of NHLRC1 as a Novel AKT Activator from a Lung Cancer Epigenome-Wide Association Study (EWAS).

Changes in DNA methylation identified by epigenome-wide association studies (EWAS) have been recently linked to increased lung cancer risk. However, the cellular effects of these differentially methylated positions (DMPs) are often unclear. Therefore, we investigated top differentially methylated positions identified from an EWAS study. This included a putative regulatory region of NHLRC1. Hypomethylation of this gene was recently linked with decreased survival rates in lung cancer patients. HumanMethylation450 BeadChip array (450K) analysis was performed on 66 lung cancer case-control pairs from the European Prospective Investigation into Cancer and Nutrition Heidelberg lung cancer EWAS (EPIC HD) cohort. DMPs identified in these pre-diagnostic blood samples were then investigated for differential DNA methylation in lung tumor versus adjacent normal lung tissue from The Cancer Genome Atlas (TCGA) and replicated in two independent lung tumor versus adjacent normal tissue replication sets with MassARRAY. The EPIC HD top hypermethylated DMP cg06646708 was found to be a hypomethylated region in multiple data sets of lung tumor versus adjacent normal tissue. Hypomethylation within this region caused increased mRNA transcription of the closest gene NHLRC1 in lung tumors. In functional assays, we demonstrate attenuated proliferation, viability, migration, and invasion upon NHLRC1 knock-down in lung cancer cells. Furthermore, diminished AKT phosphorylation at serine 473 causing expression of pro-apoptotic AKT-repressed genes was detected in these knock-down experiments. In conclusion, this study demonstrates the powerful potential for discovery of novel functional mechanisms in oncogenesis based on EWAS DNA methylation data. NHLRC1 holds promise as a new prognostic biomarker for lung cancer survival and prognosis, as well as a target for novel treatment strategies in lung cancer patients.

Linc00996 is a favorable prognostic factor in LUAD: Results from bioinformatics analysis and experimental validation.

Background: Linc00996 has been reported in a variety of malignant tumors, but its potential role and significance in lung adenocarcinoma (LUAD) are not fully understood. The authors investigated the expression and biological behavior of Linc00996 in LUAD and elucidated the function of its potential target genes. Materials and methods: The data of Linc00996 expression in cancers were derived from GEPIA. GEO and TCGA datasets were used to identify the differential expression of Linc00996 in LUAD and analyze the respective correlation between different expression levels and LUAD stage and survival prognosis. We further elucidated the potential biological processes and pathways involved with Linc00996 in LAUD by GSEA. ssGSEA was applied to explore the relationship between Linc00996 and immune activity. Finally, the clinical impact of Linc00996 was assessed in 61 patients with LUAD, and the biological functions of Linc00996 were determined by a series of experiments in vitro, such as CCK8, colony formation, migration, and invasion assays. Results: Compared with adjacent normal lung tissues, Linc00996 was significantly downregulated in LUAD, and its expression was negatively correlated with T stage, N stage, and pathological stage. An in vitro study suggested that enhanced Linc00996 expression could inhibit cell proliferation, clonal formation, migration, and invasion in LUAD cell lines. Via GSEA and ssGSEA, we observed that Linc00996 might be connected with immune infiltration in LUAD, and Linc00996 might inhibit tumorigenesis and metastasis by regulating antigen processing and presentation, JAK-STAT3, and cell adhesion molecular signaling pathways. Conclusion: Linc00996 is a novel tumor suppressor in LUAD and may suppress the tumorigenesis and metastasis of LUAD via the tumor-related signaling pathway, such as antigen processing and presentation, JAK-STAT3, and cell adhesion molecular signaling pathways.

The microbiome of lower respiratory tract and tumor tissue in lung cancer manifested as radiological ground-glass opacity.

Recent studies have confirmed the existence of microbiota in the lungs. The relationship between lung ground-glass opacity (GGO) and microbiota in the lung microenvironment is not clear. In this study, we investigated the microbial composition and diversity in bronchoalveolar lavage fluid (BALF) of diseased lung segments and paired contralateral healthy lung segments from 11 GGO patients. Furthermore, lung GGO and paired normal tissues of 26 GGO patients were explored whether there are microbial characteristics related to GGO. Compared with the control group, the community richness of GGO tissue and BALF of GGO lung segment (α-diversity) and overall microbiome difference (β-diversity) had no significant difference. The microbiome composition of BALF of GGO segments is distinct from that of paired healthy lung segments [genus (Rothia), order (Lachnospiraceae), family (Lachnospiraceae), genus (Lachnospiraceae_NK4A136_group, Faecalibacterium), and species (Faecalibacterium prausnitzii, Bacteroides uniforms)]. GGO tissue and adjacent lung tissue had more significant differences at the levels of class, order, family, genus, and species level, and most of them are enriched in normal lung tissue. The area under the curve (AUC) using 10 genera-based biomarkers to predict GGO was 91.05% (95% CI: 81.93–100%). In conclusion, this study demonstrates there are significant differences in the lower respiratory tract and lung microbiome between GGO and the non-malignant control group through the BALF and lung tissues. Furthermore, some potential bacterial biomarkers showed good performance to predict GGO.

Local ablation of pulmonary malignancies abutting pleura: Evaluation of midterm local efficacy and safety.

ObjectiveTo retrospectively evaluate the efficacy and safety of local ablation treatment for adjacent pleural lung tumors.Materials and methodsSixty-two patients who underwent pulmonary nodule ablation at the Affiliated Cancer Hospital of Zhengzhou University were enrolled between January 2016 and December 2020. All patients were followed up with enhanced computed tomography or magnetic resonance imaging within 48 h after treatment and 2, 4, 6, 9, and 12 months after treatment. All patients were followed for at least 12 months.ResultsA total of 84 targeted tumors (62 patients) underwent 94 ablations. In the 12-month follow-up images, 69 of the 84 targeted tumors were completely ablated, 15 had incomplete ablation, and the 12-month incomplete ablation rate was 17.8% (15/84). Of the 15 incompletely ablated tumors, six had partial responses, five had stable disease, and four had progressive disease. The most common adverse event was pneumothorax, with an incidence of 54.8% (34/62). The second most common complication was pleural effusion, with an incidence rate of 41.9% (26/62). The incidence of needle-tract bleeding was 21% (13/62) and all patients were cured using hemostatic drugs. Serious complications were bronchopleural fistula in four patients (6.5%, 4/62) and needle tract metastasis in one patient. Four cases of bronchopleural fistula were found in the early stages and were cured after symptomatic treatment.ConclusionLocal ablation is effective for the treatment of adjacent pleural lung tumors, and its operation is safe and controllable.

Clinical significance of STING expression and methylation in lung adenocarcinoma based on bioinformatics analysis

The role of stimulator of interferon genes [STING, also known as transmembrane protein 173 (TMEM173)] in various human cancers has begun to emerge. However, the clinical value of STING in lung adenocarcinoma (LUAD) remains elusive. This study aims to elucidate the clinical significance of STING expression and methylation in LUAD. Here, through analyzing data from public resources, we found that both the mRNA and protein expression of STING were reduced in lung cancer. Moreover, lower expression of STING was associated with a worse prognosis in LUAD, but not lung squamous cell carcinoma (LUSC). Of note, higher methylation of STING was found in LUAD and had the potential to distinguish LUAD tissues from adjacent non-tumor lung tissues and correlated with unfavorable outcomes. Furthermore, the methylation of STING could serve as an independent prognostic indicator for both the overall survival (OS) and disease-free survival (DFS) of LUAD patients. Additionally, the constructed nomogram exhibited a favorable predictive accuracy in predicting the probability of 1- and 2-year OS. Our findings suggest that the mRNA expression, and especially the DNA methylation of STING, have the potential to be prognostic indicators for LUAD patients.

Identification of Hub Genes of Lung Adenocarcinoma Based on Weighted Gene Co-Expression Network in Chinese Population.

Purpose: Lung adenocarcinoma is one of the most common malignancies. Though some historic breakthroughs have been made in lung adenocarcinoma, its molecular mechanisms of development remain elusive. The aim of this study was to identify the potential genes associated with the lung adenocarcinoma progression and to provide new ideas for the prognosis evaluation of lung adenocarcinoma. Methods: The transcriptional profiles of ten pairs of snap-frozen tumor and adjacent normal lung tissues were obtained by performing RNA-seq. Weighted gene co-expression network analysis (WGCNA) was used to construct free-scale gene co-expression networks in order to explore the associations of gene sets with the clinical features and to investigate the functional enrichment analysis of co-expression genes. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway, and Gene Set Enrichment Analysis (GSEA) analyses were performed using clusterProfiler. The protein-protein network (PPI) was established using the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) and hub genes were identified using Cytohubba in Cytoscape. Transcription factor enrichment analysis was performed by the RcisTarget program in R language. Results: Based on RNA-seq data, 1,545 differentially expressed genes (DEGs) were found. Eight co-expression modules were identified among these DEGs. The blue module exhibited a strong correlation with LUAD, in which ADCY4, RXFP1, AVPR2, CALCRL, ADRB1, RAMP3, RAMP2 and VIPR1 were hub genes. A low expression level of RXFP1, AVPR2, ADRB1 and VIPR1 was detrimental to the survival of LUAD patients. Genes in the blue module enriched in 86 Gene Ontology terms and five KEGG pathways. We also found that transcription factors EGR3 and EXOSC3 were related to the biological function of the blue module. Overall, this study brings a new perspective to the understanding of LUAD and provides possible molecular biomarkers for prognosis evaluation of LUAD.

Associations of IFT20 and GM130 protein expressions with clinicopathological features and survival of patients with lung adenocarcinoma

BackgroundLung cancer is the leading cause of malignancy-related mortality and lung adenocarcinoma accounts for about 40% of lung malignancies. The aim of this study was to investigate the associations of intraflagellar transport protein 20 (IFT20) and Golgi matrix protein 130 (GM130) expression with clinicopathological features and survival in patients with lung adenocarcinoma.MethodsThe expressions of IFT20 and GM130 protein in cancerous and matched adjacent lung tissues of 235 patients with lung adenocarcinoma were assessed by tissue microarray and immunohistochemistry, which were indicated by the mean optical density (IOD/area), the rate of positive staining cells and staining intensity score. The correlation between IFT20 and GM130 protein was assessed by Spearman’s rank correlation. Associations of IFT20 and GM130 protein expression with clinicopathological features of patients were analyzed by multivariate logistic regression models. The survival analysis of patients was performed by Cox proportional hazard regression models.ResultsWith adjustment for multiple potential confounders, each one-point increase in IFT20 protein staining intensity score was significantly associated with 32% and 29% reduced risk for TNM stage in II ~ IV and lymphatic metastasis of patients, respectively (P < 0.05). And each one-point increase in GM130 protein staining intensity score was associated with a significant reduction in the risk of poor differentiation and tumors size > 7 cm by 29% and 38% for lung adenocarcinoma patients, respectively (P < 0.05). In stratified Cox model analysis, enhanced IFT20 staining intensity score was significantly decreased the risk of death by 16% for patients without distant metastasis. And elevated the IOD/area of GM130 expression significantly decreased the death risk of lung adenocarcinoma patients with tumor size > 7 cm or distant metastasis by 54% and 65%, respectively (P < 0.05).ConclusionIFT20 and GM130 protein expressions were negatively associated with tumor differentiated types, size, TNM stage and lymphatic metastasis of lung adenocarcinoma. Both IFT20 and GM130 proteins have some protective effects on the survival of lung adenocarcinoma patients with specific clinicopathological features.

Comparative Assessment of Morphological Changes in the Pleura and Lung Tissue after Pleurodesis with Various Solutions in the Experiment

Introduction. Currently, spontaneous pneumothorax occurs in 6,2-7,1% of patients with nonspecific lung diseases. There has been a steady increase in prevalence of this disease. The relevance of preventing recurrence of spontaneous pneumothorax is still beyond doubt. Most authors recommend performing chemical pleurodesis when nonspecific spontaneous pneumothorax occurs, especially if it is recurrent. At the present time, the issue of choosing the optimal chemical agent for performing pleurodesis remains important.The aim of the study was to analyse the nature and severity of the inflammatory reaction from the lungs, pleura and adjacent subpleural tissues of the chest wall in experimental animals during chemical pleurodesis with 4% sodium bicarbonate, 6% hydrogen peroxide and 5-fluorouracil solutions.Materials and methods. The experiment was conducted at the experimental laboratory of Voronezh Regional Clinical Hospital № 1. The study involved 200 experimental rats (WISTAR type) with simulated spontaneous pneumothorax; after a fixed time, one of the preparations was sprayed into the pleural cavity. All animals were divided into 3 groups depending on the method of pleurodesis (5-fluorouracil solution, 4% sodium bicarbonate solution and 6% hydrogen peroxide solution) and control (0,9% sodium chloride solution). Groups of animals were withdrawn from the experiment in accordance with the rules of humane treatment of animals in 3, 5, 7, 10, 30 days with sampling of organs and tissues of the chest for histological examination to compare severity of inflammatory reactions in the pleura and adjacent areas of the lungs depending on the drug used for pleurodesis. The main criterion for assessing the comparative effectiveness of chemical agents was the morphological picture of inflammation presented by counting free cell populations (lymphocytes, macrophages, neutrophils, histiocytes) in the pleura and adjacent areas of the lung tissue of the studied animals.Quantitative results were statistically processed using parametric and nonparametric methods with STATISTICA 10. The main statistical parameters of the studied data were estimated by the methods of descriptive statistics. Comparison of the studied samples was conducted with the Kruskal-Wallis test. Differences between the compared samples were considered significant at p0,05.Results. The morphology of the inflammatory reaction in the pleura and adjacent lung tissue in all the studied groups of animals was characterized by the predominance of neutrophils over other cells in the first days of the experiment; the fact supporting acute aseptic inflammation in response to drug administration. Further, the content of lymphocytes, macrophages and their inactive forms (histiocytes) increased, and the content of neutrophils decreased, which was typical for the transition of acute inflammation to chronic. Compared dynamics in the number of analyzed immunocompetent cells evidenced that the number of lymphocytes, macrophages and histiocytes increased faster. After pleurodesis with a 6% hydrogen peroxide solution, the lowest content of immunocompetent cells in the studied tissue samples was noted if compared with the samples obtained from other groups in the same period. In all cases, pleurodesis with 6% hydrogen peroxide resulted in the minimal number of neutrophils, and the dynamics of their decrease was the most pronounced. In the control group, the number of studied cells fluctuated within the average value for this group.Conclusion. The dynamics in the number of studied cell populations in all comparison groups was assessed as common. The method of pleurodesis significantly affects the number of cellular elements involved in the inflammatory response. Clinical outcomes of pleurodesis performed with a 6% hydrogen peroxide solution are characterized by a shorter duration and severity of the inflammatory response from the pleura and adjacent parts of the chest wall, compared with 5-fluorouracil and 4% sodium bicarbonate solutions.

Prognostic Significance of HMGA1 Expression in Lung Cancer Based on Bioinformatics Analysis.

High-mobility group protein 1 (HMGA1) participates in the processes of DNA transcription, replication, recombination, and repair. The HMGA1 gene is expressed abundantly during embryogenesis and is reactivated during carcinogenesis. HMGA1 gene expression has been associated with a high degree of malignancy, metastatic tendency, and poor survival in breast, colon, ovary, and pancreatic cancers. However, its prognostic significance in lung cancer remains unclear. Using publicly available data, HMGA1 was shown to be overexpressed in both small and non-small lung tumors, with higher expression compared to both the adjacent non-malignant lung tissues and non-tumor lung tissues of healthy individuals. Elevated HMGA1 expression could result from lowered HMGA1 methylation and was connected with some clinicopathological features like sex, age, and stage of the disease. The high HMGA1 expression level was connected with shorter overall and first progression survival time among lung adenocarcinoma patients, but not lung squamous cell carcinoma patients. HMGA1 could interact with proteins involved in cellular senescence and cell cycle control (TP53, RB1, RPS6KB1, and CDK1), transcription regulation (EP400 and HMGA2), chromatin assembly and remodeling (LMNB1), and cholesterol and isoprene biosynthesis (HMGCR and INSIG1). Taken together, HMGA1 overexpression could be an essential element of lung carcinogenesis and a prognostic feature in lung cancer.

PET/CT imaging of CSF1R in a mouse model of tuberculosis.

Macrophages represent an essential means of sequestration and immune evasion for Mycobacterium tuberculosis. Pulmonary tuberculosis (TB) is characterized by dense collections of tissue-specific and recruited macrophages, both of which abundantly express CSF1R on their outer surface. 4-Cyano-N-(5-(1-(dimethylglycyl)piperidin-4-yl)-2',3',4',5'-tetrahydro-[1,1'-biphenyl]-2-yl)-1H-imidazole-2-carboxamide (JNJ-28312141) is a reported high affinity, CSF1R-selective antagonist. We report the radiosynthesis of 4-cyano-N-(5-(1-(N-methyl-N-([11C]methyl)glycyl)piperidin-4-yl)-2',3',4',5'-tetrahydro-[1,1'-biphenyl]-2-yl)-1H-imidazole-2-carboxamide ([11C]JNJ-28312141) and non-invasive detection of granulomatous and diffuse lesions in a mouse model of TB using positron emission tomography (PET). Nor-methyl-JNJ-28312141 precursor was radiolabeled with [11C]iodomethane to produce [11C]JNJ-28312141. PET/CT imaging was performed in the C3HeB/FeJ murine model of chronic pulmonary TB to co-localize radiotracer uptake with granulomatous lesions observed on CT. Additionally, CSF1R, Iba1 fluorescence immunohistochemistry was performed to co-localize CSF1R target with reactive macrophages in infected and healthy mice. Radiosynthesis of [11C]JNJ-28312141 averaged a non-decay-corrected yield of 18.7 ± 2.1%, radiochemical purity of 99%, and specific activity averaging 658 ± 141GBq/µmol at the end-of-synthesis. PET/CT imaging in healthy mice showed hepatobiliary [13.39-25.34% ID/g, percentage of injected dose per gram of tissue (ID/g)] and kidney uptake (12.35% ID/g) at 40-50min post-injection. Infected mice showed focal pulmonary lesion uptake (5.58-12.49% ID/g), hepatobiliary uptake (15.30-40.50% ID/g), cervical node uptake, and renal uptake (11.66-29.33% ID/g). The ratio of infected lesioned lung/healthy lung uptake is 5.91:1, while the ratio of lesion uptake to adjacent infected radiolucent lung is 2.8:1. Pre-administration of 1mg/kg of unlabeled JNJ-28312141 with [11C]JNJ-28312141 in infected animals resulted in substantial blockade. Fluorescence microscopy of infected and uninfected whole lung sections exclusively co-localized CSF1R staining with abundant Iba1 + macrophages. Healthy lung exhibited no CSF1R staining and very few Iba1 + macrophages. [11C]JNJ-28312141 binds specifically to CSF1R + macrophages and delineates granulomatous foci of disease in a murine model of pulmonary TB.

DRAMATIC IMPROVEMENT OF ADULT PATIENTS WITH POST-TB PULMONARY PNEUMATOCELE AND BAD PULMONARY FUNCTION AFTER SURGICAL INTERVENTION

TYPE: Late Breaking Case Report TOPIC: Cardiothoracic Surgery INTRODUCTION: Pulmonary pneumatoceles (PCs) are thin walled air-filled cysts that develop within pulmonary parenchyma. PCs are developed after infection,or trauma. PCs caused as a complication of Staphylococcus pneumonia, and are more frequently in infants and children. Adult tuberculous pulmonary pneumatoceles are seldom [1]. PCs are asymptomatic. Large PCs may compress adjacent lung with mediastinal shift causing cardiopulmonary symptoms [2]. Surgical intervention is indicated when PCs cause cardiopulmonary compromise or rupture into the pleural space or unresolved infection [3]. CASE PRESENTATION: 60-years female patient presented by dry cough and shortness of breath (SOB). She was on corticosteroid therapy as treatment of bronchial asthma. She had history of resolved pulmonary TB. Clinical examination revealed diminished air entry . CXR showed translucent zone. CT with contrast showed large PC occupying >2/3 of hemithorax with mediastinal shift. During operation, rupture of PC by diathermy to avoid its over-inflation during ventilation , and wedge resection with fistula site repair through uniportal VATS.Closure of thoracotomy was performed as a routine with two ICT. Postoperative CXR revealed full inflated lung . They discharged with smooth postoperative course. DISCUSSION: PC in adult can occur during or after anti-TB treatment [3]. there was a history of resolved TB. Urgent surgery indicated in complicated PC (infection, tension, rupture). [6]. VATS procedure performed to PC excision and repair. CONCLUSIONS: Surgical excision of symptomatic complicated pulmonary pneumatocele with mini approach after well preparation gives marvelous improvement of respiratory condition. DISCLOSURE: Nothing to declare. KEYWORD: Pulmonary Pneumatocele, Pulmonary Tuberculosis, Fungal Ball, Cardiopulmonary Compromise.

Epigenome–wide DNA methylation signature of plasma zinc and their mediation roles in the association of zinc with lung cancer risk

Essential trace element zinc is associated with decreased lung cancer risk, but underlying mechanisms remain unclear. This study aimed to investigate role of DNA methylation in zinc-lung cancer association. We conducted a case-cohort study within prospective Dongfeng-Tongji cohort, including 359 incident lung cancer cases and a randomly selected sub–cohort of 1399 participants. Epigenome-wide association study (EWAS) was used to examine association of plasma zinc with DNA methylation in peripheral blood. For the zinc-related CpGs, their mediation effects on zinc-lung cancer association were assessed; their diagnostic performance for lung cancer was testified in the case-cohort study and further validated in another 126 pairs of lung cancer case-control study. We identified 28 CpGs associated with plasma zinc at P < 1.0 × 10−5 and seven of them (cg07077080, cg01077808, cg17749033, cg15554270, cg26125625, cg10669424, and cg15409013 annotated to GSR, CALR3, SLC16A3, PHLPP2, SLC12A8, VGLL4, and ADAMTS16, respectively) were associated with incident risk of lung cancer. Moreover, the above seven CpGs were differently methylated between 126 pairs of lung cancer and adjacent normal lung tissues and had the same directions with EWAS of zinc. They could mediate a separate 7.05%∼22.65% and a joint 29.42% of zinc-lung cancer association. Compared to using traditional factors, addition of methylation risk score exerted improved discriminations for lung cancer both in case-cohort study [area under the curve (AUC) = 0.818 vs. 0.738] and in case-control study (AUC = 0.816 vs. 0.646). Our results provide new insights for the biological role of DNA methylation in the inverse association of zinc with incident lung cancer.

Long Non-Coding RNA AP000695.2 Acts as a Novel Prognostic Biomarker and Regulates the Cell Growth and Migration of Lung Adenocarcinoma.

Long non-coding RNAs (lncRNAs) are tumor-associated biological molecules and have been found to be implicated in the progression of lung adenocarcinoma (LUAD). LncRNA-AP000695.2 (ENSG00000248538) is a long non-coding RNA (lncRNA) that is widely increased in many tumor types including lung adenocarcinoma (LUAD). However, the aberrant expression profile, clinical significance, and biological function of AP000695.2 in human lung adenocarcinoma (LUAD) need to be further investigated. This study mines key prognostic AP000695.2 and elucidates its potential role and molecular mechanism in regulating the proliferation and metastasis of LUAD. Here, we discovered that AP000695.2 was significantly upregulated in lung adenocarcinoma tissues compared with healthy adjacent lung tissue and higher in LUAD cell lines than in normal human bronchial epithelial cell lines. A higher expression of AP000695.2 was positively correlated with aggressive clinicopathological characteristics, and AP000695.2 served as an independent prognostic indicator for the overall survival, disease-free survival, and progression-free survival in patients with LUAD. Receiver operating curve (ROC) analysis revealed the significant diagnostic ability of AP000695.2 (AUC = 0.838). Our in vivo data confirmed that AP000695.2 promotes the proliferation, migration, and invasion of LUAD cells. GSEA results suggested that AP000695.2 co-expressed genes were mainly enriched in immune-related biological processes such as JAK-STAT signaling pathway and toll-like receptor signaling pathway. Single-sample GSEA analysis showed that AP000695.2 is correlated with tumor-infiltrating immune cells in lung adenocarcinoma. Our findings confirmed that AP000695.2 was involved in the progression of lung adenocarcinoma, providing a novel prognostic indicator and promising diagnostic biomarker in the future.

Downregulation of hsa-miR-30b-3p Inhibits the Oncogenicity of Lung Adenocarcinoma by Targeting the METTL7B Gene.

Objective Lung adenocarcinoma (LUAD) is one of the malignant tumors with the highest morbidity and mortality rates worldwide. Although surgery-based combination therapy can greatly improve the prognosis of LUAD patients, the overall outcome is still poor, and there is an urgent need to develop new and effective treatment alternatives for LUAD. The microRNA (miRNA) miR-30b-3p is a typical multifunctional miRNA that has been reported to promote the development of various malignancies. In this study, we investigated the effects of miR-30b-3p on the biological properties of LUAD and the possible mechanisms involved to provide new ideas for the development of more effective treatment options for LUAD. Methods Fluorescence quantitative real-time polymerase chain reaction (qRT-PCR) was used to measure the expression of miR-30b-3p and its target METTL7B gene in tumor tissues and adjacent noncancerous lung tissues of LUAD patients and to determine their correlation. The effect of miR-30b-3p on the biological properties of LUAD was investigated, after transfection of miR-30b-3p mimics or scramble miRNA (negative control) in LUAD cells, using various approaches, including by measuring cell proliferation using CCK-8 and Edu assays, cell invasion by Transwell assay, and apoptosis and cell cycle distribution by flow cytometry. Additionally, rescue assays were performed to verify the effect of METTL7B on miR-30b-3p function. Results In LUAD patients, low expression of miR-30b-3p and high expression of METTL7B in tumor tissues were significantly and negatively correlated with those in adjacent noncancerous lung tissues of the LUAD patients. It was also found that miR-30b-3p inhibits the proliferation and invasion of LUAD cells, promotes apoptosis, and changes the cell cycle distribution. METTL7B is a target gene of miR-30b-3p. METTL7B overexpression significantly reversed the biological effects of miR-30b-3p overexpression, including inhibition of cell proliferation and invasion, promotion of apoptosis, and alteration of the cell cycle distribution. Conclusions The miR-30b-3p alters the biology of LUAD by negatively regulating METTL7B expression, indicating the importance of the miR-30b-3p/METTL7B pathway in the development of LUAD.

FHL1 Overexpression as A Inhibitor of Lung Cancer Cell Invasion via Increasing RhoGDIß mRNA Expression.

Objective Four and a half Lin-11, Isl-1, Mac-3 (LIM) protein 1 (FHL1) is one of the FHL protein family, which is regarded as a tumor suppressor in the multiple malignant tumors. In this study, we aimed to explore the regulatory effects and mechanisms of FHL1 on lung cancer cell invasion. Materials and Methods In this experimental study, bioinformatics analysis of FHL1 transcripts in human lung adenocarcinomas of TCGA database was performed. Quantitative real-time polymerasechain reaction (PCR) was performed to detect FHL1 mRNA expression in 15 paired human lung cancer tissues and their adjacent normal lung tissues, or lung cancer cell lines (A549 and H1299) in comparison with human bronchial epithelial cell line (Beas- 2B). Moreover, western blot was used to analyze FHL1 and rho GDP-dissociation inhibitor beta (RhoGDIβ) protein expression in the indicated cell lines. Also, transwell assays were employed to measure the migrated, and invaded of indicated cell lines. Results FHL1 transcripts were downregulated in the human lung adenocarcinoma. The impaired FHL1 transcripts were positively correlated with advanced tumor node metastasis (TNM) stage. Moreover, as compared to the adjacent normal lung tissues, FHL1 mRNA was low expressed in 15 paired human lung cancer tissues than their adjacent normal lung tissues. Besides, FHL1 mRNA and protein expression were also reduced in H1299 and A549 cell lines in comparison with Beas-2B cell line. Overexpressed FHL1 protein inhibited the invasive ability of H1299 and A549 cell lines. Mechanically, FHL1 protein overexpression increased the RhoGDIβ protein and mRNA abundance, while knockdown of RhoGDIβ protein, completely restored the invasion ability of A549 (Flag-FHL1) cell line. ConclusionOur findings indicated that as a key FHL1 downstream regulator, RhoGDIβ is in charge of FHL1 inhibiting lung cancer cell invasion abilities, providing a critical insight into understanding the role of FHL1 for lung cancer development.