Epithelioid angiosarcoma involving the lung is a rare entity that can present with nodules or consolidations on CT imaging. We describe the case of a 23-year-old woman who presented with chronic cough and pleuritic chest pain and consolidations on CT chest who ultimately underwent diagnostic biopsy. A high index of suspicion is required for this disease, and biopsy is essential for the diagnosis of angiosarcoma. Histological evaluation and immunohistochemical analysis are helpful for the diagnosis of epithelioid angiosarcoma, and expression of CD31 is supportive of the diagnosis.

"Pseudotumoral Calcinosis Causing Diaphragmatic Paralysis." American Journal of Respiratory and Critical Care Medicine, 209(4), pp. 454–455

JET, the world’s largest operating tokamak with unique Be/W wall and tritium handling capability, completed a Deuterium-Tritium (D-T) campaign in 2021 (Maggi et al 29th Fusion Energy Conf. ) following a decade of preparatory experiments, dedicated enhancements, technical rehearsals and training (Horton et al 2016 Fusion Eng. Des. 109–111 925). Operation with tritium raises significant technical, safety and scientific challenges not encountered in standard protium or deuterium operation. This contribution describes the tritium operational requirements, pulses and technical preparations, new operating procedures, lessons learned and details on the achieved operational availability and performance. The preparation and execution of the recent JET tritium experiments benefitted from the previous experience in 1991 (Preliminary Tritium Experiment), 1997 (DTE1 campaign) and 2003 (Trace Tritium Campaigns) and consisted of the following five phases: technical rehearsals and scenario preparation, tritium commissioning, 100% tritium campaign, D-T campaign (DTE2), tritium clean-up. Following the clean-up JET resumed normal operation and is currently undertaking a further D-T campaign (DTE3).

CASE PRESENTATION: A 44-year-old man with hyperthyroidism and no smoking history presented to his internist with 5 months of intermittent cough and hemoptysis. The patient's family history was remarkable only for non-Hodgkin's lymphoma in his father. He had a history of a 25-day exposure to a home renovation at work 2 years prior to presentation. He was treated with oral clarithromycin with no improvement in his symptoms. A chest radiograph showed bilateral nodular opacities with a left lower lobar consolidative opacity (Fig 1A, 1B); the patient underwent CT scanning of the chest, which showed areas of nodular infiltration in the lower lobes with tree-in-bud-like opacities. He was referred to a pulmonologist.

CASE PRESENTATION: A 51-year-old nonsmoking man presented to his general practitioner with a primary complaint of 4 months of progressive hoarseness, and was subsequently referred to an otolaryngologist. He had no relevant medical or surgical history. He did not take any chronic medications or supplements. He was born in the Dominican Republic and moved to New York City when he was 36 years old. He worked in construction. In his spare time, he would return to his home country. The patient was a lifelong nonsmoker and reported no alcohol consumption. He denied shortness of breath, cough, sputum expectoration, fevers, chills, and night sweats.

Although rare, inherited lung diseases provide important insights into disease pathogeneses. The two most common, cystic fibrosis (CF) and alpha-1 antitrypsin (alpha-1 AT) deficiency, are both monogenic, autosomal recessive disorders. CF is a multisystem disease that manifests in the lung with severe bronchitis, increased susceptibility to infection, progressive bronchiectasis, and lung function decline, whereas alpha-1 AT deficiency manifests primarily as panacinar lower lung zone emphysema, sometimes accompanied by bronchiectasis (1). Although CF and alpha-1 AT deficiency are the most prevalent, highly penetrant mutations leading to lung disease, many other mutations have been mapped for more than 20 rare familial lung diseases with diverse manifestations, including cystic, bronchiectatic, fibrotic, pulmonary vascular, ventilatory, hyper-IgE, or hypereosinophilic phenotypes (see Table E1 in the online supplement) (2–5). In contrast to the monogenic disorders, smoking-induced lung disease is far more prevalent (6). Although the classic lung phenotypes associated with smoking are bronchitis and/or emphysema, other smoking-induced lung phenotypes are now recognized, including variable degrees of cystic, bronchiectatic, fibrotic, and pulmonary vascular phenotypes (7). Because mutations lead to altered/absent gene expression in monogenic lung diseases, and as cigarette smoking is known to alter gene expression in lung cells, we hypothesized that smoking may affect the expression of genes involved in monogenic lung disorders, which might help explain the phenotypic diversity observed in cigarette smokers. One example of this concept is the smoking effect on alpha-1 AT protein function as a neutrophil elastase inhibitor: whereas alpha-1 AT deficiency is a relatively rare cause of emphysema, smoking induces a functional deficiency in the alpha-1 AT protein in the lower respiratory tract of smokers (8). Another example is that smoking induces dysfunction of the CF transmembrane conductance regulator (CFTR) protein in the respiratory tract and systemically (9). Because the most common smoking-related disease phenotypes start in the small airway epithelium (SAE), we asked, Are genes associated with monogenic lung disorders expressed in the SAE, and if so, does smoking alter expression levels? To address this question, we first assessed expression levels of 93 genes associated with monogenic lung disorders (10) (Table E1) in 230 SAE samples (>95% epithelial cells) obtained by bronchoscopic brushing, as previously described (11), from 87 healthy nonsmokers and 143 healthy smokers without clinical evidence of disease (normal lung function [FEV1, FVC, FEV1/FVC, total lung capacity, diffusing capacity of the lung for carbon monoxide, 6-minute-walk test], chest X-ray, alpha-1 AT levels, HIV-negative; smoking was verified by urine cotinine [all nonsmokers, ,5 ng/ml; smokers average 1,5306 1,066 ng/ml]). Of the 93 genes implicated in monogenic lung disorders, 92 were represented by 219 probesets on the Affymetrix HG-U133 Plus 2.0 microarray (Santa Clara, CA), and robust multiarray average–normalized data (GEO: GSE63127; Partek Genomics Suite 6.6, St. Louis, MO) were assessed by genome-wide analysis of variance, corrected for hybridization kit, sex, age, and ethnicity. Significance was determined by P, 0.05 after correction using Partek “step-up,” Benjamini-Hochberg, for multiple comparisons. Of the 92 genes assessed by microarray, 86 genes were expressed in the SAE. As expected, genes involved in airway diseases (i.e., bronchiectasis, CFTR of CF) were expressed. Surprisingly, many genes implicated in nonairway lung diseases were also expressed in healthy SAE, including genes related to parenchymal cystic/emphysema phenotypes, pulmonary fibrosis, pulmonary vascular disease, and others (Table E1). Assessing whether smoking alters expression of the 86 monogenic disease genes expressed in the SAE demonstrated that 37 (43%) of the genes were differentially expressed in healthy smokers versus healthy nonsmokers (P, 0.05; Table E1; Figure 1). In comparison, for 100 different random gene lists, an average of 26% of genes were differentially expressed (range, 0–42%; data not shown). Eighteen of the monogenic lung disorder genes (21%) were significantly down-regulated and 19 (22%) were significantly up-regulated in response to smoking, suggesting possible interplay between smoking effects and the function of monogenic lung disease-related genes. Among the 18 monogenic lung disorderrelated genes suppressed by smoking, the category with the greatest proportion of affected genes was the cystic/emphysema category, with 8 (57%) of 14 genes down-regulated, including genes related to Ehlers Danlos (CHST14, COL5A2), cutis laxa (EFEMP2, FBLN5), Marfan syndrome (FBN1), Loey-Dietz (SMAD3, TGFBR2), and lymphangioleiomyomatosis (TSC1). Genes in other disease categories were also down-regulated by smoking, including primary ciliary dyskinesia (PCD) (ARMC4, DNAAF2, DNAH5, HEATR2, and OFD1), non-PCD bronchiectasis (SCNN1G), familial fibrosis (MUC5B), Hermansky-Pudlak (DTNBP1, HPS4), and pulmonary hypertension (BMRP2). Among the 19 monogenic genes up-regulated by smoking, the cystic/emphysema category had the greatest proportion of affected genes, including Ehlers Danlos (COL1A1, COL5A1, FKBP14, TNXB), cutis laxa (LTBP4), and alpha-1 AT deficiency (SERPINA1). Genes in other categories of monogenic lung disorders were also up-regulated by smoking, including PCD (DNAL1), CF (CFTR), non-PCD bronchiectasis (SCNN1A, SCNN1B), familial pulmonary fibrosis (ELMOD2), Hermansky-Pudlak syndrome (HPS1, AP3B1), pulmonary hypertension (ENG, KCNK3, SMAD9), hyper-IgE syndrome (DOCK8), and syndromic hypoventilation (ASCL1, RET). To validate the microarray data, RNA sequencing was performed in a subset of SAE samples (n = 5 nonsmokers; n = 6 smokers; NIH Short Read Archive: SRP005411), and fold-change (defined as mean expression in smokers/mean expression in nonsmokers) of significant smoking-responsive genes correlated between the two methods (r = 0.54; P, 10; not shown). These studies were supported, in part, by U.S. National Institutes of Health (NIH) grants R01HL107882 and P20 HL113443. A.E.T. was supported, in part, by NIH grant K23HL103837.

Introduction Increasing evidence links COPD pathogenesis with pulmonary capillary apoptosis. We previously demonstrated that plasma levels of circulating microparticles released from endothelial cells (EMPs) due to apoptosis are elevated in smokers with normal spirometry but low diffusion capacity, that is, with early evidence of lung destruction. We hypothesised that pulmonary capillary apoptosis persists with the development of COPD and assessed its reversibility in healthy smokers and COPD smokers following smoking cessation.Methods Pulmonary function and high-resolution CT (HRCT) were assessed in 28 non-smokers, 61 healthy smokers and 49 COPD smokers; 17 healthy smokers and 18 COPD smokers quit smoking for 12 months following the baseline visit. Total EMP (CD42b(-)CD31(+)), pulmonary capillary EMP (CD42b(-)CD31(+)ACE(+)) and apoptotic EMP (CD42b(-)CD62E(+)/CD42b(-)CD31(+)) levels were quantified by flow cytometry.Results Compared with non-smokers, healthy smokers and COPD smokers had elevated levels of circulating EMPs due to active pulmonary capillary endothelial apoptosis. Levels remained elevated over 12 months in healthy smokers and COPD smokers who continued smoking, but returned to non-smoker levels in healthy smokers who quit. In contrast, levels remained significantly abnormal in COPD smokers who quit.Conclusions Pulmonary capillary apoptosis is reversible in healthy smokers who quit, but continues to play a role in COPD pathogenesis in smokers who progressed to airflow obstruction despite smoking cessation.

A characteristic feature of the human airway epithelium is the presence of ciliated cells bearing motile cilia, specialized cell surface projections containing axonemes composed of microtubules and dynein arms, which provide ATP-driven motility. In the airways, cilia function in concert with airway mucus to mediate the critical function of mucociliary clearance, cleansing the airways of inhaled particles and pathogens. The prototypical disorder of respiratory cilia is primary ciliary dyskinesia, an inherited disorder that leads to impaired mucociliary clearance, to repeated chest infections, and to the progressive destruction of lung architecture. Numerous acquired lung diseases are also marked by abnormalities in both cilia structure and function. In this review we summarize current knowledge regarding airway ciliated cells and cilia, how they function to maintain a healthy epithelium, and how disorders of cilia structure and function contribute to inherited and acquired lung disease.

Even after quitting smoking, the risk of the development of chronic obstructive pulmonary disease (COPD) and lung cancer remains significantly higher compared to healthy nonsmokers. Based on the knowledge that COPD and most lung cancers start in the small airway epithelium (SAE), we hypothesized that smoking modulates miRNA expression in the SAE linked to the pathogenesis of smoking-induced airway disease, and that some of these changes persist after smoking cessation. SAE was collected from 10th to 12th order bronchi using fiberoptic bronchoscopy. Affymetrix miRNA 2.0 arrays were used to assess miRNA expression in the SAE from 9 healthy nonsmokers and 10 healthy smokers, before and after they quit smoking for 3 months. Smoking status was determined by urine nicotine and cotinine measurement. There were significant differences in the expression of 34 miRNAs between healthy smokers and healthy nonsmokers (p<0.01, fold-change >1.5), with functions associated with lung development, airway epithelium differentiation, inflammation and cancer. After quitting smoking for 3 months, 12 out of the 34 miRNAs did not return to normal levels, with Wnt/β-catenin signaling pathway being the top identified enriched pathway of the target genes of the persistent dysregulated miRNAs. In the context that many of these persistent smoking-dependent miRNAs are associated with differentiation, inflammatory diseases or lung cancer, it is likely that persistent smoking-related changes in SAE miRNAs play a role in the subsequent development of these disorders.

Smoking and COPD are associated with decreased mucociliary clearance, and healthy smokers have shorter cilia in the large airway than nonsmokers. We hypothesized that changes in cilia length are consistent throughout the airway, and we further hypothesized that smokers with COPD have shorter cilia than healthy smokers. Because intraflagellar transport (IFT) is the process by which cilia of normal length are produced and maintained, and alterations in IFT lead to short cilia in model organisms, we also hypothesized that smoking induces changes in the expression of IFT-related genes in the airway epithelium of smokers and smokers with COPD. To assess these hypotheses, airway epithelium was obtained via bronchoscopic brushing. Cilia length was assessed by measuring 100 cilia (10 cilia on each of 10 cells) per subject and Affymetrix microarrays were used to evaluate IFT gene expression in nonsmokers and healthy smokers in 2 independent data sets from large and small airway as well as in COPD smokers in a data set from the small airway. In the large and small airway epithelium, cilia were significantly shorter in healthy smokers than nonsmokers, and significantly shorter in COPD smokers than in both healthy smokers and nonsmokers. The gene expression data confirmed that a set of 8 IFT genes were down-regulated in smokers in both data sets; however, no differences were seen in COPD smokers compared to healthy smokers. These results support the concept that loss of cilia length contributes to defective mucociliary clearance in COPD, and that smoking-induced changes in expression of IFT genes may be one mechanism of abnormally short cilia in smokers. Strategies to normalize cilia length may be an important avenue for novel COPD therapies.

Airway epithelium ciliated cells play a central role in clearing the lung of inhaled pathogens and xenobiotics, and cilia length and coordinated beating are important for airway clearance. Based on in vivo studies showing that the airway epithelium of healthy smokers has shorter cilia than that of healthy nonsmokers, we investigated the mechanisms involved in cigarette smoke-mediated inhibition of ciliogenesis by assessing normal human airway basal cell differentiation in air-liquid interface (ALI) cultures in the presence of nontoxic concentrations of cigarette smoke extract (CSE). Measurements of cilia length from Day 28 ALI cultures demonstrated that CSE exposure was associated with shorter cilia (P < 0.05), reproducing the effect of cigarette smoking on cilia length observed in vivo. This phenotype correlated with a broad CSE-mediated suppression of genes involved in cilia-related transcriptional regulation, intraflagellar transport, cilia motility, structural integrity, and basal body development but not of control genes or epithelial barrier integrity. The CSE-mediated inhibition of cilia growth could be prevented by lentivirus-mediated overexpression of FOXJ1, the major cilia-related transcription factor, which led to partial reversal of expression of cilia-related genes suppressed by CSE. Together, the data suggest that components of cigarette smoke are responsible for a broad suppression of genes involved in cilia growth, but, by stimulating ciliogenesis with the transcription factor FOXJ1, it may be possible to maintain close to normal cilia length despite the stress of cigarette smoking.