Angiomyomatous hamartoma of subglottic tracheal wall in a 12-year-old adolescent: a case report

Background Allergic rhinitis is the most common allergic disease encountered in a primary care setting. Diagnosis is often made clinically based on response to empiric therapy. However, with long-term treatment failure and/or atypical disease presentation, a differential diagnosis should be considered. The following is a report of an unusual and rare presentation of a subglottic tracheal angiomyomatous hamartoma in an adolescent, treated for many years as allergic rhinoconjunctivitis and asthma. Case presentation A 12-year-old Caucasian was referred to the allergy clinic with a lifetime history of bronchospasms and rhinoconjunctivitis symptoms, treated for many years for asthma and environmental allergies. Cough, posterior nasal drainage, self-described “choking on phlegm,” and a sensation of “a flap in the throat,”, worsened 5 months prior to the initial evaluation. Puncture skin testing for common environmental allergens was negative. Spirometry, performed due to history of chronic cough, showed blunting of the forced expiratory phase. A chest X-ray, immediately ordered to rule out possible extrapulmonary obstruction, showed bilateral bibasilar infiltrates. A noncontrast computerized tomographic scan of the chest, ordered to further elucidate X-ray findings, revealed a subglottic tracheal mass. Following a subsequent transfer and admission to a tertiary hospital center, microlaryngoscopy, bronchoscopy, and microsuspension laryngoscopy were performed to remove the tracheal mass. Pathology confirmed squamous mucosa with polypoid angiomyomatous changes and chronic inflammatory features consistent with angiomyomatous hamartoma. Surgical intervention was successful, and follow-up 1 year postoperatively revealed a healthy, asymptomatic adolescent child with normal lung function. Conclusions Although posterior nasal drainage and cough are typical presenting symptoms in the general patient population, they may be clinically impactful as they could disguise more serious medical conditions. A detailed history and careful physical examination may provide a high index of suspicion of disease, and can help work the differential diagnosis. This case presentation is the first documentation of subglottic hamartoma reported in the pediatric literature with clinical manifestation of environmental allergy and asthma symptoms.

Inhibition of Rac1 attenuates radiation-induced lung injury while suppresses lung tumor in mice

The lung is one of the most sensitive tissues to ionizing radiation, thus, radiation-induced lung injury (RILI) stays a key dose-limiting factor of thoracic radiotherapy. However, there is still little progress in the effective treatment of RILI. Ras-related C3 botulinum toxin substrate1, Rac1, is a small guanosine triphosphatases involved in oxidative stress and apoptosis. Thus, Rac1 may be an important molecule that mediates radiation damage, inhibition of which may produce a protective effect on RILI. By establishing a mouse model of radiation-induced lung injury and orthotopic lung tumor-bearing mouse model, we detected the role of Rac1 inhibition in the protection of RILI and suppression of lung tumor. The results showed that ionizing radiation induces the nuclear translocation of Rac1, the latter then promotes nuclear translocation of P53 and prolongs the residence time of p53 in the nucleus, thereby promoting the transcription of Trp53inp1 which mediates p53-dependent apoptosis. Inhibition of Rac1 significantly reduce the apoptosis of normal lung epithelial cells, thereby effectively alleviating RILI. On the other hand, inhibition of Rac1 could also significantly inhibit the growth of lung tumor, increase the radiation sensitivity of tumor cells. These differential effects of Rac1 inhibition were related to the mutation and overexpression of Rac1 in tumor cells.

Autophagy is impaired in fetal hypoplastic lungs and rescued by administration of amniotic fluid stem cell extracellular vesicles

Rationale: Pulmonary hypoplasia secondary to congenital diaphragmatic hernia (CDH) is characterized by reduced branching morphogenesis, which is responsible for poor clinical outcomes. Administration of amniotic fluid stem cell extracellular vesicles (AFSC-EVs) rescues branching morphogenesis in rodent fetal models of pulmonary hypoplasia. Herein, we hypothesized that AFSC-EVs exert their regenerative potential by affecting autophagy, a process required for normal lung development. Objectives: To evaluate autophagy in hypoplastic lungs throughout gestation and establish whether AFSC-EV administration improves branching morphogenesis through autophagy-mediated mechanisms. Methods: EVs were isolated from c-kit+ AFSC conditioned medium by ultracentrifugation and characterized for size, morphology, and EV markers. Branching morphogenesis was inhibited in rat fetuses by nitrofen administration to dams and in human fetal lung explants by blocking RAC1 activity with NSC23766. Expression of autophagy activators (BECN1 and ATG5) and adaptor (SQSTM1/p62) was analyzed in vitro (rat and human fetal lung explants) and in vivo (rat fetal lungs). Mechanistic studies on rat fetal primary lung epithelial cells were conducted using inhibitors for microRNA-17 and -20a contained in the AFSC-EV cargo and known to regulate autophagy. Measurements and Main Results: Rat and human models of fetal pulmonary hypoplasia showed reduced autophagy mainly at pseudoglandular and canalicular stages. AFSC-EV administration restored autophagy in both pulmonary hypoplasia models by transferring miR-17~92 cluster members contained in the EV cargo. Conclusions: AFSC-EV treatment rescues branching morphogenesis partly by restoring autophagy through miRNA cargo transfer. This study enhances our understanding of pulmonary hypoplasia pathogenesis and creates new opportunities for fetal therapeutic intervention in CDH babies.

Bullous Parametric Response Map for Functional Localization of COPD

Advanced bronchoscopic lung volume reduction treatment (BLVR) is now a routine care option for treating patients with severe emphysema. Patterns of low attenuation clusters indicating emphysema and functional small airway disease (fSAD) on paired CT, which may provide additional insights to the target selection of the segmental or subsegmental lobe of the treatments, require further investigation. The low attenuation clusters (LACS) were segmented to identify the scalar and spatial distribution of the lung destructions, in terms of 10 fractions scales of low attenuation density (LAD) located in upper lobes and lower lobes. The LACs of functional small airway disease (fSAD) were delineated by applying the technique of parametric response map (PRM) on the co-registered CT image data. Both emphysematous LACs of inspiratory CT and fSAD LACs on expiratory CT were used to derive the coefficients of the predictive model for estimating the airflow limitation. The voxel-wise severity is then predicted using the regional LACs on the co-registered CT to indicate the functional localization, namely, the bullous parametric response map (BPRM). A total of 100 subjects, 88 patients with mild to very severe COPD and 12 control participants with normal lung functions (FEV1/FVC % > 70%), were evaluated. Pearson’s correlations between FEV1/FVC% and LAV%HU-950 of severe emphysema are − 0.55 comparing to − 0.67 and − 0.62 of LAV%HU-856 of air-trapping and LAV%fSAD respectively. Pearson’s correlation between FEV1/FVC% and FEV1/FVC% predicted by the proposed model using LAD% of HU-950 and fSAD on BPRM is 0.82 (p < 0.01). The result of the Bullous Parametric Response Map (BPRM) is capable of identifying the less functional area of the lung, where the BLVR treatment is aimed at removing from a hyperinflated area of emphysematous regions.

Bioinformatics Analysis Identifies Potential Ferroptosis Key Genes in the Pathogenesis of Pulmonary Fibrosis

Objective: Ferroptosis has an important role in developing pulmonary fibrosis. The present project aimed to identify and validate the potential ferroptosis-related genes in pulmonary fibrosis by bioinformatics analyses and experiments.Methods: First, the pulmonary fibrosis tissue sequencing data were obtained from Gene Expression Omnibus (GEO) and FerrDb databases. Bioinformatics methods were used to analyze the differentially expressed genes (DEGs) between the normal control group and the pulmonary fibrosis group and extract ferroptosis-related DEGs. Hub genes were screened by enrichment analysis, protein-protein interaction (PPI) analysis, and random forest algorithm. Finally, mouse pulmonary fibrosis model was made for performing an exercise intervention and the hub genes’ expression was verified through qRT-PCR.Results: 13 up-regulated genes and 7 down-regulated genes were identified as ferroptosis-related DEGs by comparing 103 lung tissues with idiopathic pulmonary fibrosis (IPF) and 103 normal lung tissues. PPI results indicated the interactions among these ferroptosis-related genes. Kyoto Encyclopedia of Genes and Genomes (KEGG) Pathway enrichment and Genome-Ontology (GO) enrichment analyses showed that these ferroptosis-related genes involved in the organic anion transport, response to hypoxia, response to decrease oxygen level, HIF-1 signaling pathway, renal cell carcinoma, and arachidonic acid metabolism signaling pathway. The confirmed genes using PPI analysis and random forest algorithm included CAV1, NOS2, GDF15, HNF4A, and CDKN2A. qRT-PCR of the fibrotic lung tissues from the mouse model showed that the mRNA levels of NOS2 and GDF15 were up-regulated, while CAV1 and CDKN2A were down-regulated. Also, treadmill training led to an increased expression of CAV1 and CDKN2A and a decrease in the expression of NOS2 and GDF15.Conclusion: Using bioinformatics analysis, 20 potential genes were identified to be associated with ferroptosis in pulmonary fibrosis. CAV1, NOS2, GDF15, and CDKN2A were demonstrated to be influencing the development of pulmonary fibrosis by regulating ferroptosis. These findings suggested that, as an aerobic exercise treatment, treadmill training reduced ferroptosis in the pulmonary fibrosis tissues, and thus, reduces inflammation in the lungs. Aerobic exercise training initiate concomitantly with induction of pulmonary fibrosis reduces ferroptosis in lung. These results may develop our knowledge about pulmonary fibrosis and may contribute to its treatment.

Identification of Key Pathways and Genes Related to Immunotherapy Resistance of LUAD Based on WGCNA Analysis

Immunotherapy resistance is a major barrier in the application of immune checkpoint inhibitors (ICI) in lung adenocarcinoma (LUAD) patients. Although recent studies have found several mechanisms and potential genes responsible for immunotherapy resistance, ways to solve this problem are still lacking. Tumor immune dysfunction and exclusion (TIDE) algorithm is a newly developed method to calculate potential regulators and indicators of ICI resistance. In this article, we combined TIDE and weighted gene co-expression network analysis (WGCNA) to screen potential modules and hub genes that are highly associated with immunotherapy resistance using the Cancer Genome Atlas (TCGA) dataset of LUAD patients. We identified 45 gene co-expression modules, and the pink module was most correlated with TIDE score and other immunosuppressive features. After considering the potential factors in immunotherapy resistance, we found that the pink module was also highly related to cancer stemness. Further analysis showed enriched immunosuppressive cells in the extracellular matrix (ECM), immunotherapy resistance indicators, and common cancer-related signaling pathways in the pink module. Seven hub genes in the pink module were shown to be significantly upregulated in tumor tissues compared with normal lung tissue, and were related to poor survival of LUAD patients. Among them, THY1 was the gene most associated with TIDE score, a gene highly related to suppressive immune states, and was shown to be strongly expressed in late-stage patients. Immunohistochemistry (IHC) results demonstrated that THY1 level was higher in the progressive disease (PD) group of LUAD patients receiving a PD-1 monoclonal antibody (mAb) and positively correlated with SOX9. Collectively, we identified that THY1 could be a critical biomarker in predicting ICI efficiency and a potential target for avoiding tumor immunotherapy resistance.

Methyl Orange Biodegradation by Immobilized Consortium Microspheres: Experimental Design Approach, Toxicity Study and Bioaugmentation Potential

Methyl orange (MO) is categorized among the recalcitrant and refractory xenobiotics, representing a significant burden in the ecosystem. To clean-up the surrounding environment, advances in microbial degradation have been made. The main objective of this study was to investigate the extent to which an autochthonous consortium immobilized in alginate beads can promote an efficient biodegradation of MO. By employing response surface methodology (RSM), a parametric model explained the interaction of immobilized consortium (Raoultella planticola, Ochrobactrum thiophenivorans, Bacillus flexus and Staphylococcus xylosus) to assimilate 200 mg/L of MO in the presence of 40 g/L of NaCl within 120 h. Physicochemical analysis, including UV-Vis spectroscopy and FTIR, and monitoring of the degrading enzymes (azoreductase, DCIP reductase, NADH reductase, laccase, LiP, MnP, nitrate reductase and tyrosinase) were used to evaluate MO degradation. In addition, the toxicity of MO-degradation products was investigated by means of phytotoxicity and cytotoxicity. Chlorella vulgaris retained its photosynthetic performance (>78%), as shown by the contents of chlorophyll-a, chlorophyll-b and carotenoids. The viability of normal lung and kidney cell lines was recorded to be 90.63% and 99.23%, respectively, upon exposure to MO-metabolic outcomes. These results reflect the non-toxicity of treated samples, implying their utilization in ferti-irrigation applications and industrial cooling systems. Moreover, the immobilized consortium was employed in the bioremediation of MO from artificially contaminated agricultural and industrial effluents, in augmented and non-augmented systems. Bacterial consortium remediated MO by 155 and 128.5 mg/L in augmented systems of agricultural and industrial effluents, respectively, within 144 h, revealing its mutual synergistic interaction with both indigenous microbiotas despite differences in their chemical, physical and microbial contents. These promising results encourage the application of immobilized consortium in bioaugmentation studies using different resources.

Erythropoietin Receptor is a Risk Factor for Prognosis: A Potential Biomarker in Lung Adenocarcinoma

Background: Lung cancer has the highest mortality rate of all cancers, and LUAD's survival rate is particularly poor. Erythropoietin receptor (EPOR) is a member of the cytokine class I receptor family and can be detected in cancers such as lung adenocarcinoma (LUAD), however, the expression levels and prognostic value of EPOR in LUAD are still unclear.Methods: Multiple bioinformatics databases such as TIMER, Kaplan-Meier Plotter and TCGA databases, immunohistochemical method, and clinicopathological data of 92 LUADpatients between January 2008 and June 2016 were used to explore the EPOR expression, gene mutations affecting EPOR expression, EPOR-interacting or coexpressed genes, potential biological functions and the correlation of EPOR expression with prognosis, immune microenvironment and so on.All statistical analyses were performed in the R version 4.1.1.Results: In this study, the EPOR mRNA expression in LUAD tissues was possibly downregulated compared with that in normal lung tissues, but the EPOR protein expression in LUAD tissues was higher than that in paired normal lung tissues. Mutations in five genes, DDX60L, LGR6, POTEB3, RIF1 and SOX5, resulted in downregulation of EPOR expression, mutations in 10 genes includingC1orf168, DBX2 and EIF5B, resulted in upregulation of EPOR expression. Erichment analyses showed that EPOR is involved in neural tissue ligand-receptor interactions, MAPK and PI3K/Akt signaling pathways and cancer pathways. The KM Plotter and PrognoScan databases consistently concluded that EPOR was associated with prognosis in LUAD patients. Our clinicopathological data showed that high EPOR expression was associated with poorer OS (29.5 vs 46 months) and had a good predictive ability for 5-year survival probability. Conclusions: EPOR expression might be downregulated at the mRNA levels and significantly upregulated at the protein levels in LUAD, which showed that the mRNA and protein levels of EPOR are inconsistent.The high expression of EPOR was associated with poor prognosis and is expected to be a potential new prognostic marker for LUAD.

Analysis of the iodine distribution map in patients with diagnosis of pulmonary embolism: Initial results

Objectives: Analysing the iodine map distribution in patients with pulmonary embolism diagnosis by Dual Energy Computed Tomography. Materials and methods: Twenty-four images of pulmonary angiotomography by dual energy computed tomography were used to determinate the presence of pulmonary thrombi and identify the perfusion defects (PDs) in the Iodine Maps. Moreover, the iodine density (mg/ml) were measured in normal lung parenchyma and lung parenchyma with PDs areas. The documentary analysis was used thought the data collection sheet and the Likert scale questionnaire. The statistic software SPSS v.25 was used. Results: Thirty-four thrombi were found (21 occlusive and 13 partials occlusive) at monochromatic images. Forty-one perfusion defects (PD) were found at Iodine Maps, these have multiple origins: pulmonary thrombi (69.23%), artifacts (17.95%) and other alterations (12.82%). Furthermore, two new thrombi (5.56%) were identified, both were occlusive and segmental level. Mean Iodine density showed statistically significant differences among normal lung parenchyma (1.65 ± 0.66 mg/ml; [0.77-2.79 mg/ ml]) and parenchyma with PD areas (0.51 ± 0.26 mg/ml; [0.12-1.02 mg/ml])(p=0.000). Mean iodine density also had statistically significant differences between parenchyma with occlusive PD and partial occlusive PD (p=0.000). Iodine Map diagnostic quality was excellent (54.17%), good (33.33%), moderate (12.50%). Conclusion: The Iodine distribution Map offers a benefit greater than 5% in the diagnosis of pulmonary embolism by Dual-Energy Computed Tomography.

The Sulfotransferase SULT1C2 Is Epigenetically Activated and Transcriptionally Induced by Tobacco Exposure and Is Associated with Patient Outcome in Lung Adenocarcinoma

Lung cancer is the leading cause of cancer-related death. Tobacco exposure is associated with 80–90% of lung cancer cases. The SULT1C2 sulfotransferase modifies xenobiotic compounds to enhance secretion but can also render these compounds carcinogenic. To determine if SULT1C2 contributes to tobacco-related carcinogenesis in the lung, we analyzed the expression and epigenetic state of SULT1C2 in human lung adenocarcinoma (LUAD) samples and in LUAD cell lines exposed to cigarette smoke condensate (CSC). SULT1C2 expression was significantly positively correlated to overall LUAD patient survival in smokers, was elevated in LUAD tumors compared to adjacent non-tumor lung, and was significantly correlated with levels of patient exposure to tobacco smoke. SULT1C2 promoter DNA methylation was inversely correlated with expression in LUAD, and hypomethylation of the SULT1C2 promoter was observed in Asian patients, as compared to Caucasians. In vitro analysis of LUAD cell lines indicates that CSC stimulates expression of SULT1C2 in a dose-dependent and cell-line-specific manner. In vitro methylation of the SULT1C2 promoter significantly decreased transcriptional activity of a reporter plasmid, and SULT1C2 expression was activated by the DNA demethylating agent 5-Aza-2′-deoxycytidine in a cell line in which the SULT1C2 promoter was hypermethylated. An aryl hydrocarbon receptor (AHR) binding site was detected spanning critical methylation sites upstream of SULT1C2. CSC exposure significantly increased AHR binding to this predicted binding site in the SULT1C2 promoter in multiple lung cell lines. Our data suggest that CSC exposure leads to activation of the AHR transcription factor, increased binding to the SULT1C2 promoter, and upregulation of SULT1C2 expression and that this process is inhibited by DNA methylation at the SULT1C2 locus. Additionally, our results suggest that the level of SULT1C2 promoter methylation and gene expression in normal lung varies depending on the race of the patient, which could in part reflect the molecular mechanisms of racial disparities seen in lung cellular responses to cigarette smoke exposure.