Validation of the Lung Subtyping Panel in Multiple Fresh-Frozen and Formalin-Fixed, Paraffin-Embedded Lung Tumor Gene Expression Data Sets.

PubMed

Faruki, Hawazin; Mayhew, Gregory M; Fan, Cheng; Wilkerson, Matthew D; Parker, Scott; Kam-Morgan, Lauren; Eisenberg, Marcia; Horten, Bruce; Hayes, D Neil; Perou, Charles M; Lai-Goldman, Myla

2016-06-01

Context .- A histologic classification of lung cancer subtypes is essential in guiding therapeutic management. Objective .- To complement morphology-based classification of lung tumors, a previously developed lung subtyping panel (LSP) of 57 genes was tested using multiple public fresh-frozen gene-expression data sets and a prospectively collected set of formalin-fixed, paraffin-embedded lung tumor samples. Design .- The LSP gene-expression signature was evaluated in multiple lung cancer gene-expression data sets totaling 2177 patients collected from 4 platforms: Illumina RNAseq (San Diego, California), Agilent (Santa Clara, California) and Affymetrix (Santa Clara) microarrays, and quantitative reverse transcription-polymerase chain reaction. Gene centroids were calculated for each of 3 genomic-defined subtypes: adenocarcinoma, squamous cell carcinoma, and neuroendocrine, the latter of which encompassed both small cell carcinoma and carcinoid. Classification by LSP into 3 subtypes was evaluated in both fresh-frozen and formalin-fixed, paraffin-embedded tumor samples, and agreement with the original morphology-based diagnosis was determined. Results .- The LSP-based classifications demonstrated overall agreement with the original clinical diagnosis ranging from 78% (251 of 322) to 91% (492 of 538 and 869 of 951) in the fresh-frozen public data sets and 84% (65 of 77) in the formalin-fixed, paraffin-embedded data set. The LSP performance was independent of tissue-preservation method and gene-expression platform. Secondary, blinded pathology review of formalin-fixed, paraffin-embedded samples demonstrated concordance of 82% (63 of 77) with the original morphology diagnosis. Conclusions .- The LSP gene-expression signature is a reproducible and objective method for classifying lung tumors and demonstrates good concordance with morphology-based classification across multiple data sets. The LSP panel can supplement morphologic assessment of lung cancers, particularly when classification by standard methods is challenging.

Protein profiles associated with survival in lung adenocarcinoma

PubMed Central

Chen, Guoan; Gharib, Tarek G; Wang, Hong; Huang, Chiang-Ching; Kuick, Rork; Thomas, Dafydd G.; Shedden, Kerby A.; Misek, David E.; Taylor, Jeremy M. G.; Giordano, Thomas J.; Kardia, Sharon L. R.; Iannettoni, Mark D.; Yee, John; Hogg, Philip J.; Orringer, Mark B.; Hanash, Samir M.; Beer, David G.

2003-01-01

Morphologic assessment of lung tumors is informative but insufficient to adequately predict patient outcome. We previously identified transcriptional profiles that predict patient survival, and here we identify proteins associated with patient survival in lung adenocarcinoma. A total of 682 individual protein spots were quantified in 90 lung adenocarcinomas by using quantitative two-dimensional polyacrylamide gel electrophoresis analysis. A leave-one-out cross-validation procedure using the top 20 survival-associated proteins identified by Cox modeling indicated that protein profiles as a whole can predict survival in stage I tumor patients (P = 0.01). Thirty-three of 46 survival-associated proteins were identified by using mass spectrometry. Expression of 12 candidate proteins was confirmed as tumor-derived with immunohistochemical analysis and tissue microarrays. Oligonucleotide microarray results from both the same tumors and from an independent study showed mRNAs associated with survival for 11 of 27 encoded genes. Combined analysis of protein and mRNA data revealed 11 components of the glycolysis pathway as associated with poor survival. Among these candidates, phosphoglycerate kinase 1 was associated with survival in the protein study, in both mRNA studies and in an independent validation set of 117 adenocarcinomas and squamous lung tumors using tissue microarrays. Elevated levels of phosphoglycerate kinase 1 in the serum were also significantly correlated with poor outcome in a validation set of 107 patients with lung adenocarcinomas using ELISA analysis. These studies identify new prognostic biomarkers and indicate that protein expression profiles can predict the outcome of patients with early-stage lung cancer. PMID:14573703

A Sphingosine-1 Phosphate agonist (FTY720) limits trauma/hemorrhagic shock induced multiple organ dysfunction syndrome

PubMed Central

Bonitz, Joyce A.; Son, Julie Y.; Chandler, Benjamin; Tomaio, Jacquelyn N.; Qin, Yong; Prescott, Lauriston M.; Feketeova, Eleonora; Deitch, Edwin A.

2014-01-01

BACKGROUND Trauma/hemorrhagic shock is one of the major consequences of battlefield injury as well as civilian trauma. FTY720 (sphingosine-1 phosphate agonist) has the capability to decrease the activity of the innate and adaptive immune systems and, at the same time, maintain endothelial cell barrier function and vascular homeostasis during stress. For this reason, we hypothesize that FTY720, as part of resuscitation therapy, would limit T/HS induced multiple organ dysfunction syndrome (MODS) in a rodent trauma-hemorrhagic shock (T/HS) model. METHODS Rats subjected to trauma/sham-shock (T/SS) or T/HS (30 mm Hg × 90 min), were administered FTY720 (1 mg/kg) post-T/HS during volume resuscitation. Lung injury (permeability to Evans Blue dye), PMN priming (respiratory burst activity), and RBC rigidity were measured. In addition, lymph duct cannulated rats were used to quantify the effect of FTY720 on gut injury (permeability and morphology) and the biologic activity of T/HS vs. T/SS lymph on PMN-RB and RBC deformability. RESULTS T/HS-induced increased lung permeability, PMN priming and RBC rigidity were all abrogated by FTY720. The systemic protective effect of FTY720 was only partially at the gut level, since FTY720 did not prevent T/HS-induced gut injury (morphology or permeability,) however, it did abrogate T/HS lymph-induced increased respiratory burst and RBC rigidity. CONCLUSION FTY720 limited T/HS-induced MODS (lung injury, red cell injury, and neutrophil priming) as well as T/HS lymph bioactivity, although it did not limit gut injury. PMID:25004059

Comprehensive Computational Pathological Image Analysis Predicts Lung Cancer Prognosis.

PubMed

Luo, Xin; Zang, Xiao; Yang, Lin; Huang, Junzhou; Liang, Faming; Rodriguez-Canales, Jaime; Wistuba, Ignacio I; Gazdar, Adi; Xie, Yang; Xiao, Guanghua

2017-03-01

Pathological examination of histopathological slides is a routine clinical procedure for lung cancer diagnosis and prognosis. Although the classification of lung cancer has been updated to become more specific, only a small subset of the total morphological features are taken into consideration. The vast majority of the detailed morphological features of tumor tissues, particularly tumor cells' surrounding microenvironment, are not fully analyzed. The heterogeneity of tumor cells and close interactions between tumor cells and their microenvironments are closely related to tumor development and progression. The goal of this study is to develop morphological feature-based prediction models for the prognosis of patients with lung cancer. We developed objective and quantitative computational approaches to analyze the morphological features of pathological images for patients with NSCLC. Tissue pathological images were analyzed for 523 patients with adenocarcinoma (ADC) and 511 patients with squamous cell carcinoma (SCC) from The Cancer Genome Atlas lung cancer cohorts. The features extracted from the pathological images were used to develop statistical models that predict patients' survival outcomes in ADC and SCC, respectively. We extracted 943 morphological features from pathological images of hematoxylin and eosin-stained tissue and identified morphological features that are significantly associated with prognosis in ADC and SCC, respectively. Statistical models based on these extracted features stratified NSCLC patients into high-risk and low-risk groups. The models were developed from training sets and validated in independent testing sets: a predicted high-risk group versus a predicted low-risk group (for patients with ADC: hazard ratio = 2.34, 95% confidence interval: 1.12-4.91, p = 0.024; for patients with SCC: hazard ratio = 2.22, 95% confidence interval: 1.15-4.27, p = 0.017) after adjustment for age, sex, smoking status, and pathologic tumor stage. The results suggest that the quantitative morphological features of tumor pathological images predict prognosis in patients with lung cancer. Copyright © 2016 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.

Structural-functional lung imaging using a combined CT-EIT and a Discrete Cosine Transformation reconstruction method.

PubMed

Schullcke, Benjamin; Gong, Bo; Krueger-Ziolek, Sabine; Soleimani, Manuchehr; Mueller-Lisse, Ullrich; Moeller, Knut

2016-05-16

Lung EIT is a functional imaging method that utilizes electrical currents to reconstruct images of conductivity changes inside the thorax. This technique is radiation free and applicable at the bedside, but lacks of spatial resolution compared to morphological imaging methods such as X-ray computed tomography (CT). In this article we describe an approach for EIT image reconstruction using morphologic information obtained from other structural imaging modalities. This leads to recon- structed images of lung ventilation that can easily be superimposed with structural CT or MRI images, which facilitates image interpretation. The approach is based on a Discrete Cosine Transformation (DCT) of an image of the considered transversal thorax slice. The use of DCT enables reduction of the dimensionality of the reconstruction and ensures that only conductivity changes of the lungs are reconstructed and displayed. The DCT based approach is well suited to fuse morphological image information with functional lung imaging at low computational costs. Results on simulated data indicate that this approach preserves the morphological structures of the lungs and avoids blurring of the solution. Images from patient measurements reveal the capabilities of the method and demonstrate benefits in possible applications.

Structural-functional lung imaging using a combined CT-EIT and a Discrete Cosine Transformation reconstruction method

PubMed Central

Schullcke, Benjamin; Gong, Bo; Krueger-Ziolek, Sabine; Soleimani, Manuchehr; Mueller-Lisse, Ullrich; Moeller, Knut

2016-01-01

Lung EIT is a functional imaging method that utilizes electrical currents to reconstruct images of conductivity changes inside the thorax. This technique is radiation free and applicable at the bedside, but lacks of spatial resolution compared to morphological imaging methods such as X-ray computed tomography (CT). In this article we describe an approach for EIT image reconstruction using morphologic information obtained from other structural imaging modalities. This leads to recon- structed images of lung ventilation that can easily be superimposed with structural CT or MRI images, which facilitates image interpretation. The approach is based on a Discrete Cosine Transformation (DCT) of an image of the considered transversal thorax slice. The use of DCT enables reduction of the dimensionality of the reconstruction and ensures that only conductivity changes of the lungs are reconstructed and displayed. The DCT based approach is well suited to fuse morphological image information with functional lung imaging at low computational costs. Results on simulated data indicate that this approach preserves the morphological structures of the lungs and avoids blurring of the solution. Images from patient measurements reveal the capabilities of the method and demonstrate benefits in possible applications. PMID:27181695

Axial segmentation of lungs CT scan images using canny method and morphological operation

NASA Astrophysics Data System (ADS)

Noviana, Rina; Febriani, Rasal, Isram; Lubis, Eva Utari Cintamurni

2017-08-01

Segmentation is a very important topic in digital image process. It is found simply in varied fields of image analysis, particularly within the medical imaging field. Axial segmentation of lungs CT scan is beneficial in designation of abnormalities and surgery planning. It will do to ascertain every section within the lungs. The results of the segmentation are accustomed discover the presence of nodules. The method which utilized in this analysis are image cropping, image binarization, Canny edge detection and morphological operation. Image cropping is done so as to separate the lungs areas, that is the region of interest. Binarization method generates a binary image that has 2 values with grey level, that is black and white (ROI), from another space of lungs CT scan image. Canny method used for the edge detection. Morphological operation is applied to smoothing the lungs edge. The segmentation methodology shows an honest result. It obtains an awfully smooth edge. Moreover, the image background can also be removed in order to get the main focus, the lungs.

Ex Vivo Artifacts and Histopathologic Pitfalls in the Lung.

PubMed

Thunnissen, Erik; Blaauwgeers, Hans J L G; de Cuba, Erienne M V; Yick, Ching Yong; Flieder, Douglas B

2016-03-01

Surgical and pathologic handling of lung physically affects lung tissue. This leads to artifacts that alter the morphologic appearance of pulmonary parenchyma. To describe and illustrate mechanisms of ex vivo artifacts that may lead to diagnostic pitfalls. In this study 4 mechanisms of ex vivo artifacts and corresponding diagnostic pitfalls are described and illustrated. The 4 patterns of artifacts are: (1) surgical collapse, due to the removal of air and blood from pulmonary resections; (2) ex vivo contraction of bronchial and bronchiolar smooth muscle; (3) clamping edema of open lung biopsies; and (4) spreading of tissue fragments and individual cells through a knife surface. Morphologic pitfalls include diagnostic patterns of adenocarcinoma, asthma, constrictive bronchiolitis, and lymphedema. Four patterns of pulmonary ex vivo artifacts are important to recognize in order to avoid morphologic misinterpretations.

Contribution of CT quantified emphysema, air trapping and airway wall thickness on pulmonary function in male smokers with and without COPD.

PubMed

Mohamed Hoesein, Firdaus A A; de Jong, Pim A; Lammers, Jan-Willem J; Mali, Willem P Th M; Mets, Onno M; Schmidt, Michael; de Koning, Harry J; Aalst, Carlijn van der; Oudkerk, Matthijs; Vliegenthart, Rozemarijn; Ginneken, Bram van; van Rikxoort, Eva M; Zanen, Pieter

2014-09-01

Emphysema, airway wall thickening and air trapping are associated with chronic obstructive pulmonary disease (COPD). All three can be quantified by computed tomography (CT) of the chest. The goal of the current study is to determine the relative contribution of CT derived parameters on spirometry, lung volume and lung diffusion testing. Emphysema, airway wall thickening and air trapping were quantified automatically on CT in 1,138 male smokers with and without COPD. Emphysema was quantified by the percentage of voxels below -950 Hounsfield Units (HU), airway wall thickness by the square root of wall area for a theoretical airway with 10 mm lumen perimeter (Pi10) and air trapping by the ratio of mean lung density at expiration and inspiration (E/I-ratio). Spirometry, residual volume to total lung capacity (RV/TLC) and diffusion capacity (Kco) were obtained. Standardized regression coefficients (β) were used to analyze the relative contribution of CT changes to pulmonary function measures. The independent contribution of the three CT measures differed per lung function parameter. For the FEV1 airway wall thickness was the most contributing structural lung change (β = -0.46), while for the FEV1/FVC this was emphysema (β = -0.55). For the residual volume (RV) air trapping was most contributing (β = -0.35). Lung diffusion capacity was most influenced by emphysema (β = -0.42). In a cohort of smokers with and without COPD the effect of different CT changes varies per lung function measure and therefore emphysema, airway wall thickness and air trapping need to be taken in account.

Design and physicochemical characterization of advanced spray-dried tacrolimus multifunctional particles for inhalation

PubMed Central

Wu, Xiao; Hayes, Don; Zwischenberger, Joseph B; Kuhn, Robert J; Mansour, Heidi M

2013-01-01

The aim of this study was to design, develop, and optimize respirable tacrolimus microparticles and nanoparticles and multifunctional tacrolimus lung surfactant mimic particles for targeted dry powder inhalation delivery as a pulmonary nanomedicine. Particles were rationally designed and produced at different pump rates by advanced spray-drying particle engineering design from organic solution in closed mode. In addition, multifunctional tacrolimus lung surfactant mimic dry powder particles were prepared by co-dissolving tacrolimus and lung surfactant mimic phospholipids in methanol, followed by advanced co-spray-drying particle engineering design technology in closed mode. The lung surfactant mimic phospholipids were 1,2-dipalmitoyl-sn-glycero-3-phosphocholine and 1,2-dipalmitoyl-sn-glycero-3-[phosphor-rac-1-glycerol]. Laser diffraction particle sizing indicated that the particle size distributions were suitable for pulmonary delivery, whereas scanning electron microscopy imaging indicated that these particles had both optimal particle morphology and surface morphology. Increasing the pump rate percent of tacrolimus solution resulted in a larger particle size. X-ray powder diffraction patterns and differential scanning calorimetry thermograms indicated that spray drying produced particles with higher amounts of amorphous phase. X-ray powder diffraction and differential scanning calorimetry also confirmed the preservation of the phospholipid bilayer structure in the solid state for all engineered respirable particles. Furthermore, it was observed in hot-stage micrographs that raw tacrolimus displayed a liquid crystal transition following the main phase transition, which is consistent with its interfacial properties. Water vapor uptake and lyotropic phase transitions in the solid state at varying levels of relative humidity were determined by gravimetric vapor sorption technique. Water content in the various powders was very low and well within the levels necessary for dry powder inhalation, as quantified by Karl Fisher coulometric titration. Conclusively, advanced spray-drying particle engineering design from organic solution in closed mode was successfully used to design and optimize solid-state particles in the respirable size range necessary for targeted pulmonary delivery, particularly for the deep lung. These particles were dry, stable, and had optimal properties for dry powder inhalation as a novel pulmonary nanomedicine. PMID:23403805

RECONSTRUCTION OF HUMAN LUNG MORPHOLOGY MODELS FROM MAGNETIC RESONANCE IMAGES

EPA Science Inventory

Reconstruction of Human Lung Morphology Models from Magnetic Resonance Images
T. B. Martonen (Experimental Toxicology Division, U.S. EPA, Research Triangle Park, NC 27709) and K. K. Isaacs (School of Public Health, University of North Carolina, Chapel Hill, NC 27514)

Lung volume quantified by MRI reflects extracellular-matrix deposition and altered pulmonary function in bleomycin models of fibrosis: effects of SOM230.

PubMed

Egger, Christine; Gérard, Christelle; Vidotto, Nella; Accart, Nathalie; Cannet, Catherine; Dunbar, Andrew; Tigani, Bruno; Piaia, Alessandro; Jarai, Gabor; Jarman, Elizabeth; Schmid, Herbert A; Beckmann, Nicolau

2014-06-15

Idiopathic pulmonary fibrosis is a progressive and lethal disease, characterized by loss of lung elasticity and alveolar surface area, secondary to alveolar epithelial cell injury, reactive inflammation, proliferation of fibroblasts, and deposition of extracellular matrix. The effects of oropharyngeal aspiration of bleomycin in Sprague-Dawley rats and C57BL/6 mice, as well as of intratracheal administration of ovalbumin to actively sensitized Brown Norway rats on total lung volume as assessed noninvasively by magnetic resonance imaging (MRI) were investigated here. Lung injury and volume were quantified by using nongated or respiratory-gated MRI acquisitions [ultrashort echo time (UTE) or gradient-echo techniques]. Lung function of bleomycin-challenged rats was examined additionally using a flexiVent system. Postmortem analyses included histology of collagen and hydroxyproline assays. Bleomycin induced an increase of MRI-assessed total lung volume, lung dry and wet weights, and hydroxyproline content as well as collagen amount. In bleomycin-treated rats, gated MRI showed an increased volume of the lung in the inspiratory and expiratory phases of the respiratory cycle and a temporary decrease of tidal volume. Decreased dynamic lung compliance was found in bleomycin-challenged rats. Bleomycin-induced increase of MRI-detected lung volume was consistent with tissue deposition during fibrotic processes resulting in decreased lung elasticity, whereas influences by edema or emphysema could be excluded. In ovalbumin-challenged rats, total lung volume quantified by MRI remained unchanged. The somatostatin analog, SOM230, was shown to have therapeutic effects on established bleomycin-induced fibrosis in rats. This work suggests MRI-detected total lung volume as readout for tissue-deposition in small rodent bleomycin models of pulmonary fibrosis. Copyright © 2014 the American Physiological Society.

The “dirty chest”—correlations between chest radiography, multislice CT and tobacco burden

PubMed Central

Kirchner, J; Goltz, J P; Lorenz, F; Obermann, A; Kirchner, E M; Kickuth, R

2012-01-01

Objectives Cigarette smoking-induced airway disease commonly results in an overall increase of non-specific lung markings on chest radiography. This has been described as “dirty chest”. As the morphological substrate of this condition is similar to the anthracosilicosis of coal workers, we hypothesised that it is possible to quantify the radiological changes using the International Labour Organization (ILO) classification of pneumoconiosis. The aims of this study were to evaluate whether there is a correlation between the extent of cigarette smoking and increased lung markings on chest radiography and to correlate the chest radiographic scores with findings on CT studies. Methods In a prospective analysis a cohort of 85 smokers was examined. The cigarette consumption was evaluated in pack years (defined as 20 cigarettes per day over 1 year). Film reading was performed by two board-certified radiologists. Chest radiographs were evaluated for the presence of thickening of bronchial walls, the presence of linear or nodular opacities, and emphysema. To correlate the smoking habits with the increase of overall lung markings in chest radiography, the ILO profusion score was converted to numbers ranging from zero to nine. Chest radiographs were rated according to the complete set of standard films of the revised ILO classification. Results 63/85 (74%) of the smokers showed an increase in overall lung markings on chest radiography; 32 (37%) had an ILO profusion score of <1/1, 29 (34%) had an ILO profusion score of <2/2 and 2 (2%) had an ILO score of ≥2/2. There was a significant positive linear correlation between the increase of overall lung markings on chest radiography and the cigarette consumption quantified as pack years (r=0.68). The majority of the heavy smokers (>40 pack years) showed emphysema; there was no significant difference between the prevalence of emphysema as diagnosed by CT (62%) or chest radiography (71%) (p<0.05).The most common findings in CT were thickening of bronchial walls (64%) and the presence of emphysema (62%) and of intralobular opacities (61%). Ground-glass opacities were seen in only 7% of our patients. Conclusion Bronchial wall thickening and intralobular opacities as seen in CT showed a positive linear correlation with the increase of overall lung markings on chest radiography. PMID:21937617

TRPA1 channels: expression in non-neuronal murine lung tissues and dispensability for hyperoxia-induced alveolar epithelial hyperplasia.

PubMed

Kannler, Martina; Lüling, Robin; Yildirim, Ali Önder; Gudermann, Thomas; Steinritz, Dirk; Dietrich, Alexander

2018-05-12

Transient receptor potential A1 (TRPA1) channels were originally characterized in neuronal tissues but also identified in lung epithelium by staining with fluorescently coupled TRPA1 antibodies. Its exact function in non-neuronal tissues, however, is elusive. TRPA1 is activated in vitro by hypoxia and hyperoxia and is therefore a promising TRP candidate for sensing hyperoxia in pulmonary epithelial cells and for inducing alveolar epithelial hyperplasia. Here, we isolated tracheal, bronchial, and alveolar epithelial cells and show low but detectable TRPA1 mRNA levels in all these cells as well as TRPA1 protein by Western blotting in alveolar type II (AT II) cells. We quantified changes in intracellular Ca 2+ ([Ca 2+ ] i ) levels induced by application of hyperoxic solutions in primary tracheal epithelial, bronchial epithelial, and AT II cells isolated from wild-type (WT) and TRPA1-deficient (TRPA1-/-) mouse lungs. In all cell types, we detected hyperoxia-induced rises in [Ca 2+ ] i levels, which were not significantly different in TRPA1-deficient cells compared to WT cells. We also tested TRPA1 function in a mouse model for hyperoxia-induced alveolar epithelial hyperplasia. A characteristic significant increase in thickening of alveolar tissues was detected in mouse lungs after exposure to hyperoxia, but not in normoxic WT and TRPA1-/- controls. Quantification of changes in lung morphology in hyperoxic WT and TRPA1-/- mice, however, again revealed no significant changes. Therefore, TRPA1 expression does neither appear to be a key player for hyperoxia-induced changes in [Ca 2+ ] i levels in primary lung epithelial cells, nor being essential for the development of hyperoxia-induced alveolar epithelial hyperplasia.

Implementation and evaluation of a new workflow for registration and segmentation of pulmonary MRI data for regional lung perfusion assessment.

PubMed

Böttger, T; Grunewald, K; Schöbinger, M; Fink, C; Risse, F; Kauczor, H U; Meinzer, H P; Wolf, Ivo

2007-03-07

Recently it has been shown that regional lung perfusion can be assessed using time-resolved contrast-enhanced magnetic resonance (MR) imaging. Quantification of the perfusion images has been attempted, based on definition of small regions of interest (ROIs). Use of complete lung segmentations instead of ROIs could possibly increase quantification accuracy. Due to the low signal-to-noise ratio, automatic segmentation algorithms cannot be applied. On the other hand, manual segmentation of the lung tissue is very time consuming and can become inaccurate, as the borders of the lung to adjacent tissues are not always clearly visible. We propose a new workflow for semi-automatic segmentation of the lung from additionally acquired morphological HASTE MR images. First the lung is delineated semi-automatically in the HASTE image. Next the HASTE image is automatically registered with the perfusion images. Finally, the transformation resulting from the registration is used to align the lung segmentation from the morphological dataset with the perfusion images. We evaluated rigid, affine and locally elastic transformations, suitable optimizers and different implementations of mutual information (MI) metrics to determine the best possible registration algorithm. We located the shortcomings of the registration procedure and under which conditions automatic registration will succeed or fail. Segmentation results were evaluated using overlap and distance measures. Integration of the new workflow reduces the time needed for post-processing of the data, simplifies the perfusion quantification and reduces interobserver variability in the segmentation process. In addition, the matched morphological data set can be used to identify morphologic changes as the source for the perfusion abnormalities.

Comparison of stochastic lung deposition fractions with experimental data.

PubMed

Majid, Hussain; Hofmann, Werner; Winkler-Heil, Renate

2012-04-01

Deposition fractions of inhaled particles predicted by different computational models vary with respect to physical and biological factors and mathematical modeling techniques. These models must be validated by comparison with available experimental data. Experimental data supplied by different deposition studies with surrogate airway models or lung casts were used in this study to evaluate the stochastic deposition model Inhalation, Deposition and Exhalation of Aerosols in the Lung at the airway generation level. Furthermore, different analytical equations derived for the three major deposition mechanisms, diffusion, impaction, and sedimentation, were applied to different cast or airway models to quantify their effect on calculated particle deposition fractions. The experimental results for ultrafine particles (0.00175 and 0.01) were found to be in close agreement with the stochastic model predictions; however, for coarse particles (3 and 8 μm), experimental deposition fractions became higher with increasing flow rate. An overall fair agreement among the calculated deposition fractions for the different cast geometries was found. However, alternative deposition equations resulted in up to 300% variation in predicted deposition fractions, although all equations predicted the same trends as functions of particle diameter and breathing conditions. From this comparative study, it can be concluded that structural differences in lung morphologies among different individuals are responsible for the apparent variability in particle deposition in each generation. The use of different deposition equations yields varying deposition results caused primarily by (i) different lung morphometries employed in their derivation and the choice of the central bifurcation zone geometry, (ii) the assumption of specific flow profiles, and (iii) different methods used in the derivation of these equations.

Investigation of alveolar tissue deformations using OCT combined with fluorescence microscopy

NASA Astrophysics Data System (ADS)

Gaertner, Maria; Cimalla, Peter; Knels, Lilla; Meissner, Sven; Schnabel, Christian; Kuebler, Wolfgang M.; Koch, Edmund

2011-06-01

In critical care medicine, artificial ventilation is a life saving tool providing sufficient blood oxygenation to patients suffering from respiratory failure. Essential for their survival is the use of protective ventilation strategies to prevent further lung damage due to ventilator induced lung injury (VILI). Since there is only little known about implications of lung tissue overdistension on the alveolar level, especially in the case of diseased lungs, this research deals with the investigation of lung tissue deformation on a microscale. A combined setup utilizing optical coherence tomography (OCT) and confocal fluorescence microscopy, is used to study the elastic behavior of the alveolar tissue. Three-dimensional geometrical information with voxel sizes of 6 μm × 6 μm × 11 μm (in air) is provided by OCT, structural information about localization of elastin fibers is elucidated via confocal fluorescence microscopy with a lateral resolution of around 1 μm. Imaging depths of 90 μm for OCT and 20 μm for confocal fluorescence microscopy were obtained. Dynamic studies of subpleural tissue were carried out on the basis of an in vivo mouse model post mortem, mimicking the physiological environment of an intact thorax and facilitating a window for the application of optical methods. Morphological changes were recorded by applying constant positive airway pressures of different values. With this, alveolar volume changes could clearly be recognized and quantified to form a compliance value of 3.5 • 10-6(see manuscript). The distribution of elastin fibers was detected and will be subject to further elasticity analysis.

DEVELOPMENT OF 3-D COMPUTER MODELS OF HUMAN LUNG MORPHOLOGY FOR IMPROOVED RISK ASSESSMENT OF INHALED PARTICULATE MATTER

EPA Science Inventory

DEVELOPMENT OF 3-D COMPUTER MODELS OF HUMAN LUNG MORPHOLOGY FOR IMPROVED RISK ASSESSMENT OF INHALED PARTICULATE MATTER

Jeffry D. Schroeter, Curriculum in Toxicology, University of North Carolina, Chapel Hill, NC 27599; Ted B. Martonen, ETD, NHEERL, USEPA, RTP, NC 27711; Do...

Intratracheal instillation of pravastatin for the treatment of murine allergic asthma: a lung-targeted approach to deliver statins

PubMed Central

Zeki, Amir A; Bratt, Jennifer M; Chang, Kevin Y; Franzi, Lisa M; Ott, Sean; Silveria, Mark; Fiehn, Oliver; Last, Jerold A; Kenyon, Nicholas J

2015-01-01

Systemic treatment with statins mitigates allergic airway inflammation, TH2 cytokine production, epithelial mucus production, and airway hyperreactivity (AHR) in murine models of asthma. We hypothesized that pravastatin delivered intratracheally would be quantifiable in lung tissues using mass spectrometry, achieve high drug concentrations in the lung with minimal systemic absorption, and mitigate airway inflammation and structural changes induced by ovalbumin. Male BALB/c mice were sensitized to ovalbumin (OVA) over 4 weeks, then exposed to 1% OVA aerosol or filtered air (FA) over 2 weeks. Mice received intratracheal instillations of pravastatin before and after each OVA exposure (30 mg/kg). Ultra performance liquid chromatography – mass spectrometry was used to quantify plasma, lung, and bronchoalveolar lavage fluid (BALF) pravastatin concentration. Pravastatin was quantifiable in mouse plasma, lung tissue, and BALF (BALF > lung > plasma for OVA and FA groups). At these concentrations pravastatin inhibited airway goblet cell hyperplasia/metaplasia, and reduced BALF levels of cytokines TNFα and KC, but did not reduce BALF total leukocyte or eosinophil cell counts. While pravastatin did not mitigate AHR, it did inhibit airway hypersensitivity (AHS). In this proof-of-principle study, using novel mass spectrometry methods we show that pravastatin is quantifiable in tissues, achieves high levels in mouse lungs with minimal systemic absorption, and mitigates some pathological features of allergic asthma. Inhaled pravastatin may be beneficial for the treatment of asthma by having direct airway effects independent of a potent anti-inflammatory effect. Statins with greater lipophilicity may achieve better anti-inflammatory effects warranting further research. PMID:25969462

Quantification of heterogeneity in lung disease with image-based pulmonary function testing.

PubMed

Stahr, Charlene S; Samarage, Chaminda R; Donnelley, Martin; Farrow, Nigel; Morgan, Kaye S; Zosky, Graeme; Boucher, Richard C; Siu, Karen K W; Mall, Marcus A; Parsons, David W; Dubsky, Stephen; Fouras, Andreas

2016-07-27

Computed tomography (CT) and spirometry are the mainstays of clinical pulmonary assessment. Spirometry is effort dependent and only provides a single global measure that is insensitive for regional disease, and as such, poor for capturing the early onset of lung disease, especially patchy disease such as cystic fibrosis lung disease. CT sensitively measures change in structure associated with advanced lung disease. However, obstructions in the peripheral airways and early onset of lung stiffening are often difficult to detect. Furthermore, CT imaging poses a radiation risk, particularly for young children, and dose reduction tends to result in reduced resolution. Here, we apply a series of lung tissue motion analyses, to achieve regional pulmonary function assessment in β-ENaC-overexpressing mice, a well-established model of lung disease. The expiratory time constants of regional airflows in the segmented airway tree were quantified as a measure of regional lung function. Our results showed marked heterogeneous lung function in β-ENaC-Tg mice compared to wild-type littermate controls; identified locations of airway obstruction, and quantified regions of bimodal airway resistance demonstrating lung compensation. These results demonstrate the applicability of regional lung function derived from lung motion as an effective alternative respiratory diagnostic tool.

Changes in Lung Capillary Permeability in Renal Failure

PubMed Central

Crosbie, W. A.; Snowden, S.; Parsons, V.

1972-01-01

Excess fluid in the lung can be quantified in chronic dialysis patients by using the double indicator dilution technique. The lung capillaries show an increased permeability to sodium when these patents develop pulmonary oedema. PMID:4564763

Lung function and pulmonary artery blood flow following prenatal maternal retinoic acid and imatinib in the nitrofen model of congenital diaphragmatic hernia.

PubMed

Burgos, Carmen Mesas; Davey, Marcus G; Riley, John S; Jia, Huimin; Flake, Alan W; Peranteau, William H

2017-12-19

Lung and pulmonary vascular maldevelopment in congenital diaphragmatic hernia (CDH) results in significant morbidity and mortality. Retinoic acid (RA) and imatinib have been shown to improve pulmonary morphology following prenatal administration in the rat nitrofen-induced CDH model. It remains unclear if these changes translate into improved function. We evaluated the effect of prenatal RA and imatinib on postnatal lung function, structure, and pulmonary artery (PA) blood flow in the rat CDH model. Olive oil or nitrofen was administered alone or in combination with RA or imatinib to pregnant rats. Pups were assessed for PA blood flow by ultrasound and pulmonary function/morphology following delivery, intubation, and short-term ventilation. Neither RA nor imatinib had a negative effect on lung and body growth. RA accelerated lung maturation indicated by increased alveoli number and thinner interalveolar septa and was associated with decreased PA resistance and improved oxygenation. With the exception of a decreased PA pulsatility index, no significant changes in morphology and pulmonary function were noted following imatinib. Prenatal treatment with RA but not imatinib was associated with improved pulmonary morphology and function, and decreased pulmonary vascular resistance. This study highlights the potential of prenatal pharmacologic therapies, such as RA, for management of CDH. Copyright © 2017 Elsevier Inc. All rights reserved.

SU-G-JeP3-01: A Method to Quantify Lung SBRT Target Localization Accuracy Based On Digitally Reconstructed Fluoroscopy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lafata, K; Ren, L; Cai, J

2016-06-15

Purpose: To develop a methodology based on digitally-reconstructed-fluoroscopy (DRF) to quantitatively assess target localization accuracy of lung SBRT, and to evaluate using both a dynamic digital phantom and a patient dataset. Methods: For each treatment field, a 10-phase DRF is generated based on the planning 4DCT. Each frame is pre-processed with a morphological top-hat filter, and corresponding beam apertures are projected to each detector plane. A template-matching algorithm based on cross-correlation is used to detect the tumor location in each frame. Tumor motion relative beam aperture is extracted in the superior-inferior direction based on each frame’s impulse response to themore » template, and the mean tumor position (MTP) is calculated as the average tumor displacement. The DRF template coordinates are then transferred to the corresponding MV-cine dataset, which is retrospectively filtered as above. The treatment MTP is calculated within each field’s projection space, relative to the DRF-defined template. The field’s localization error is defined as the difference between the DRF-derived-MTP (planning) and the MV-cine-derived-MTP (delivery). A dynamic digital phantom was used to assess the algorithm’s ability to detect intra-fractional changes in patient alignment, by simulating different spatial variations in the MV-cine and calculating the corresponding change in MTP. Inter-and-intra-fractional variation, IGRT accuracy, and filtering effects were investigated on a patient dataset. Results: Phantom results demonstrated a high accuracy in detecting both translational and rotational variation. The lowest localization error of the patient dataset was achieved at each fraction’s first field (mean=0.38mm), with Fx3 demonstrating a particularly strong correlation between intra-fractional motion-caused localization error and treatment progress. Filtering significantly improved tracking visibility in both the DRF and MV-cine images. Conclusion: We have developed and evaluated a methodology to quantify lung SBRT target localization accuracy based on digitally-reconstructed-fluoroscopy. Our approach may be useful in potentially reducing treatment margins to optimize lung SBRT outcomes. R01-184173.« less

Lung nodule malignancy classification using only radiologist-quantified image features as inputs to statistical learning algorithms: probing the Lung Image Database Consortium dataset with two statistical learning methods

PubMed Central

Hancock, Matthew C.; Magnan, Jerry F.

2016-01-01

Abstract. In the assessment of nodules in CT scans of the lungs, a number of image-derived features are diagnostically relevant. Currently, many of these features are defined only qualitatively, so they are difficult to quantify from first principles. Nevertheless, these features (through their qualitative definitions and interpretations thereof) are often quantified via a variety of mathematical methods for the purpose of computer-aided diagnosis (CAD). To determine the potential usefulness of quantified diagnostic image features as inputs to a CAD system, we investigate the predictive capability of statistical learning methods for classifying nodule malignancy. We utilize the Lung Image Database Consortium dataset and only employ the radiologist-assigned diagnostic feature values for the lung nodules therein, as well as our derived estimates of the diameter and volume of the nodules from the radiologists’ annotations. We calculate theoretical upper bounds on the classification accuracy that are achievable by an ideal classifier that only uses the radiologist-assigned feature values, and we obtain an accuracy of 85.74 (±1.14)%, which is, on average, 4.43% below the theoretical maximum of 90.17%. The corresponding area-under-the-curve (AUC) score is 0.932 (±0.012), which increases to 0.949 (±0.007) when diameter and volume features are included and has an accuracy of 88.08 (±1.11)%. Our results are comparable to those in the literature that use algorithmically derived image-based features, which supports our hypothesis that lung nodules can be classified as malignant or benign using only quantified, diagnostic image features, and indicates the competitiveness of this approach. We also analyze how the classification accuracy depends on specific features and feature subsets, and we rank the features according to their predictive power, statistically demonstrating the top four to be spiculation, lobulation, subtlety, and calcification. PMID:27990453

Lung nodule malignancy classification using only radiologist-quantified image features as inputs to statistical learning algorithms: probing the Lung Image Database Consortium dataset with two statistical learning methods.

PubMed

Hancock, Matthew C; Magnan, Jerry F

2016-10-01

In the assessment of nodules in CT scans of the lungs, a number of image-derived features are diagnostically relevant. Currently, many of these features are defined only qualitatively, so they are difficult to quantify from first principles. Nevertheless, these features (through their qualitative definitions and interpretations thereof) are often quantified via a variety of mathematical methods for the purpose of computer-aided diagnosis (CAD). To determine the potential usefulness of quantified diagnostic image features as inputs to a CAD system, we investigate the predictive capability of statistical learning methods for classifying nodule malignancy. We utilize the Lung Image Database Consortium dataset and only employ the radiologist-assigned diagnostic feature values for the lung nodules therein, as well as our derived estimates of the diameter and volume of the nodules from the radiologists' annotations. We calculate theoretical upper bounds on the classification accuracy that are achievable by an ideal classifier that only uses the radiologist-assigned feature values, and we obtain an accuracy of 85.74 [Formula: see text], which is, on average, 4.43% below the theoretical maximum of 90.17%. The corresponding area-under-the-curve (AUC) score is 0.932 ([Formula: see text]), which increases to 0.949 ([Formula: see text]) when diameter and volume features are included and has an accuracy of 88.08 [Formula: see text]. Our results are comparable to those in the literature that use algorithmically derived image-based features, which supports our hypothesis that lung nodules can be classified as malignant or benign using only quantified, diagnostic image features, and indicates the competitiveness of this approach. We also analyze how the classification accuracy depends on specific features and feature subsets, and we rank the features according to their predictive power, statistically demonstrating the top four to be spiculation, lobulation, subtlety, and calcification.

VEGF receptor expression decreases during lung development in congenital diaphragmatic hernia induced by nitrofen

PubMed Central

Sbragia, L.; Nassr, A.C.C.; Gonçalves, F.L.L.; Schmidt, A.F.; Zuliani, C.C.; Garcia, P.V.; Gallindo, R.M.; Pereira, L.A.V.

2014-01-01

Changes in vascular endothelial growth factor (VEGF) in pulmonary vessels have been described in congenital diaphragmatic hernia (CDH) and may contribute to the development of pulmonary hypoplasia and hypertension; however, how the expression of VEGF receptors changes during fetal lung development in CDH is not understood. The aim of this study was to compare morphological evolution with expression of VEGF receptors, VEGFR1 (Flt-1) and VEGFR2 (Flk-1), in pseudoglandular, canalicular, and saccular stages of lung development in normal rat fetuses and in fetuses with CDH. Pregnant rats were divided into four groups (n=20 fetuses each) of four different gestational days (GD) 18.5, 19.5, 20.5, 21.5: external control (EC), exposed to olive oil (OO), exposed to 100 mg nitrofen, by gavage, without CDH (N-), and exposed to nitrofen with CDH (CDH) on GD 9.5 (term=22 days). The morphological variables studied were: body weight (BW), total lung weight (TLW), left lung weight, TLW/BW ratio, total lung volume, and left lung volume. The histometric variables studied were: left lung parenchymal area density and left lung parenchymal volume. VEGFR1 and VEGFR2 expression were determined by Western blotting. The data were analyzed using analysis of variance with the Tukey-Kramer post hoc test. CDH frequency was 37% (80/216). All the morphological and histometric variables were reduced in the N- and CDH groups compared with the controls, and reductions were more pronounced in the CDH group (P<0.05) and more evident on GD 20.5 and GD 21.5. Similar results were observed for VEGFR1 and VEGFR2 expression. We conclude that N- and CDH fetuses showed primary pulmonary hypoplasia, with a decrease in VEGFR1 and VEGFR2 expression. PMID:24519134

Bioaccumulation and Subchronic Toxicity of 14 nm Gold Nanoparticles in Rats.

PubMed

Rambanapasi, Clinton; Zeevaart, Jan Rijn; Buntting, Hylton; Bester, Cornelius; Kotze, Deon; Hayeshi, Rose; Grobler, Anne

2016-06-10

Colloidal suspensions of 14 nm gold nanoparticles (AuNPs) were repeatedly administered intravenously at three dose levels (0.9, 9 and 90 µg) to male Sprague Dawley rats weekly for 7 weeks, followed by a 14-day washout period. After sacrificing, the amount of gold was quantified in the liver, lungs, spleen, skeleton and carcass using neutron activation analysis (NAA). During the study, pre- and post (24 h) administration blood samples were collected from both the test and control groups, the latter which received an equal injection volume of normal saline. General health indicators were monitored together with markers of kidney and liver damage for acute and subchronic toxicity assessment. Histopathological assessments were done on the heart, kidneys, liver, lungs and spleen to assess any morphological changes as a result of the exposure to AuNPs. The mass measurements of all the groups showed a steady increase with no signs of overt toxicity. The liver had the highest amount of gold (µg) per gram of tissue after 56 days followed by the spleen, lungs, skeleton and carcass. Markers of kidney and liver damage showed similar trends between the pre and post samples within each group and across groups. The histopathological examination also showed no hepatotoxicity and nephrotoxicity. There was accumulation of Au in tissues after repeated dosing, albeit with no observable overt toxicity, kidney or liver damage.

Random Walk Simulation of the MRI Apparent Diffusion Coefficient in a Geometrical Model of the Acinar Tree

PubMed Central

Pérez-Sánchez, José M.; Rodríguez, Ignacio; Ruiz-Cabello, Jesús

2009-01-01

Abstract Apparent diffusion coefficient (ADC) measurement in the lung using gas magnetic resonance imaging is a promising technique with potential for reflecting changes in lung microstructure. Despite some recent impressive human applications, full interpretation of ADC measures remains an elusive goal, due to a lack of detailed knowledge about the structure dependency of ADC. In an attempt to fill this gap we have performed random walk simulations in a three-dimensional geometrical model of the lung acinus, the distal alveolated sections of the lung tree accounting for ∼90% of the total lung volume. Simulations were carried out adjusting model parameters after published morphological data for the rat peripheral airway system, which predict an ADC behavior as microstructure changes with lung inflation in partial agreement with measured ADCs at different airway pressures. The approach used to relate experimental ADCs to lung microstructural changes does not make any assumption about the cause of the changes, so it could be applied to other scenarios such as chronic obstructive pulmonary disease, lung development, etc. The work presented here predicts numerically for the first time ADC values measured in the lung from independent morphological measures of lung microstructure taken at different inflation stages during the breath cycle. PMID:19619480

On-the-spot lung cancer differential diagnosis by label-free, molecular vibrational imaging and knowledge-based classification

NASA Astrophysics Data System (ADS)

Gao, Liang; Li, Fuhai; Thrall, Michael J.; Yang, Yaliang; Xing, Jiong; Hammoudi, Ahmad A.; Zhao, Hong; Massoud, Yehia; Cagle, Philip T.; Fan, Yubo; Wong, Kelvin K.; Wang, Zhiyong; Wong, Stephen T. C.

2011-09-01

We report the development and application of a knowledge-based coherent anti-Stokes Raman scattering (CARS) microscopy system for label-free imaging, pattern recognition, and classification of cells and tissue structures for differentiating lung cancer from non-neoplastic lung tissues and identifying lung cancer subtypes. A total of 1014 CARS images were acquired from 92 fresh frozen lung tissue samples. The established pathological workup and diagnostic cellular were used as prior knowledge for establishment of a knowledge-based CARS system using a machine learning approach. This system functions to separate normal, non-neoplastic, and subtypes of lung cancer tissues based on extracted quantitative features describing fibrils and cell morphology. The knowledge-based CARS system showed the ability to distinguish lung cancer from normal and non-neoplastic lung tissue with 91% sensitivity and 92% specificity. Small cell carcinomas were distinguished from nonsmall cell carcinomas with 100% sensitivity and specificity. As an adjunct to submitting tissue samples to routine pathology, our novel system recognizes the patterns of fibril and cell morphology, enabling medical practitioners to perform differential diagnosis of lung lesions in mere minutes. The demonstration of the strategy is also a necessary step toward in vivo point-of-care diagnosis of precancerous and cancerous lung lesions with a fiber-based CARS microendoscope.

Maternal deprivation decelerates postnatal morphological lung development of F344 rats.

PubMed

Hupa, Katharina Luise; Schmiedl, Andreas; Pabst, Reinhard; Von Hörsten, Stephan; Stephan, Michael

2014-02-01

Intensive medical care at premature born infants is often associated with separation of neonates from their mothers. Here, early artificial prolonged separation of rat pups from their dams (Maternal Deprivation, MD) was used to study potential impact on morphological lung maturation. Furthermore, we investigated the influence of an endogenous deficiency of the neuropeptide-cleaving dipeptidyl peptidase IV (DPP4), since the effects of MD are known to be partly mediated via neuropeptidergic effects, hypothesizing that MD will lead to a retardation of postnatal lung development, DPP4-dependendly. We used wild type and CD26/DPP4 deficient rats. For MD, the dam was placed each day into a separate cage for 2 h, while the pups remained in the nest on their own. Morphological lung maturation and cell proliferation at the postnatal days 7, 10, 14, and 21 were determined morphometrically. Maternally deprived wild types showed a retarded postnatal lung development compared with untreated controls in both substrains. During alveolarization, an increased thickness of alveolar septa and a decreased surface of septa about 50% were found. At the end of the morphological lung maturation, the surface of the alveolar septa was decreased at about 25% and the septal thickness remained increased about 20%. The proliferation rate was also decreased about 50% on day 14. However, the MD induced effects were less pronounced in DPP4-deficient rats, due to a significant deceleration already induced by DPP4-deficiency. Thus, MD as a model for postnatal stress experience influences remarkably postnatal development of rats, which is significantly modulated by the DPP4-system. Copyright © 2013 Wiley Periodicals, Inc.

Lung Volume Measured during Sequential Swallowing in Healthy Young Adults

ERIC Educational Resources Information Center

Hegland, Karen Wheeler; Huber, Jessica E.; Pitts, Teresa; Davenport, Paul W.; Sapienza, Christine M.

2011-01-01

Purpose: Outcomes from studying the coordinative relationship between respiratory and swallow subsystems are inconsistent for sequential swallows, and the lung volume at the initiation of sequential swallowing remains undefined. The first goal of this study was to quantify the lung volume at initiation of sequential swallowing ingestion cycles and…

COMPUTER SIMULATIONS OF LUNG AIRWAY STRUCTURES USING DATA-DRIVEN SURFACE MODELING TECHNIQUES

EPA Science Inventory

ABSTRACT

Knowledge of human lung morphology is a subject critical to many areas of medicine. The visualization of lung structures naturally lends itself to computer graphics modeling due to the large number of airways involved and the complexities of the branching systems...

Airway remodelling in the transplanted lung.

PubMed

Kuehnel, Mark; Maegel, Lavinia; Vogel-Claussen, Jens; Robertus, Jan Lukas; Jonigk, Danny

2017-03-01

Following lung transplantation, fibrotic remodelling of the small airways has been recognized for almost 5 decades as the main correlate of chronic graft failure and a major obstacle to long-term survival. Mainly due to airway fibrosis, pulmonary allografts currently show the highest attrition rate of all solid organ transplants, with a 5-year survival rate of 58 % on a worldwide scale. The observation that these morphological changes are not just the hallmark of chronic rejection but rather represent a manifestation of a multitude of alloimmune-dependent and -independent injuries was made more recently, as was the discovery that chronic lung allograft dysfunction manifests in different clinical phenotypes of respiratory impairment and corresponding morphological subentities. Although recent years have seen considerable advances in identifying and categorizing these subgroups on the basis of clinical, functional and histomorphological changes, as well as susceptibility to medicinal treatment, this process is far from over. Since the actual pathophysiological mechanisms governing airway remodelling are still only poorly understood, diagnosis and therapy of chronic lung allograft dysfunction presents a major challenge to clinicians, radiologists and pathologists alike. Here, we review and discuss the current state of the literature on chronic lung allograft dysfunction and shed light on classification systems, corresponding clinical and morphological changes, key cellular players and underlying molecular pathways, as well as on emerging diagnostic and therapeutic approaches.

Amyloid associated with elastin-staining laminar aggregates in the lungs of patients diagnosed with acute respiratory distress syndrome

PubMed Central

Fan, Kang; Nagle, William A

2002-01-01

Background The heterogeneity of conditions underlying respiratory distress, whether classified clinically as acute lung injury (ALI) or the more severe acute respiratory distress syndrome (ARDS), has hampered efforts to identify and more successfully treat these patients. Examination of postmortem lungs among cases clinically diagnosed as ARDS identified a cohort that showed a consistent morphology at the light and electron microscope levels, and featured pathognomonic structures which we termed elastin-staining laminar structures (ELS). Methods Postmortem tissues were stained using the Verhoeff-Van Gieson procedure for elastic fibers, and with Congo red for examination under a polarizing microscope. Similar samples were examined by transmission EM. Results The pathognomonic ELS presented as ordered molecular aggregates when stained using the Verhoeff-van Gieson technique for elastic fibers. In several postmortem lungs, the ELS also displayed apple-green birefringence after staining with Congo red, suggesting the presence of amyloid. Remarkably, most of the postmortem lungs with ELS exhibited no significant acute inflammatory cellular response such as neutrophilic reaction, and little evidence of widespread edema except for focal intra-alveolar hemorrhage. Conclusions Postmortem lungs that exhibit the ELS constitute a morphologically-identifiable subgroup of ARDS cases. The ordered nature of the ELS, as indicated by both elastin and amyloid stains, together with little morphological evidence of inflammation or edema, suggests that this cohort of ARDS may represent another form of conformational disease. If this hypothesis is confirmed, it will require a new approach in the diagnosis and treatment of patients who exhibit this form of acute lung injury. PMID:12377106

Biopersistence of man-made vitreous fibers and crocidolite asbestos in the rat lung following inhalation.

PubMed

Hesterberg, T W; Miiller, W C; Musselman, R P; Kamstrup, O; Hamilton, R D; Thevenaz, P

1996-02-01

This study investigated possible relationships between fiber bio-persistence in the lung and previously observed differences in pulmonary toxicity between asbestos and man-made vitreous fibers (MMVF) following inhalation exposure. Fischer 344/N rats were exposed nose only, 6 hr/day for 5 days to 30 mg/m3 MMVF (two fiberglass compositions, rock wool, or slag wool) or to 10 mg/m3 crocidolite asbestos. At eight time points up to 1 year postexposure, lung fiber burdens were analyzed for number/lung and bivariate dimensions using scanning electron microscopy (SEM) and for chemical composition using SEM energy dispersive spectroscopy. After 365 days, > 95% of long (> 20 microns) MMVFs had disappeared from the lung compared to only 17% of long crocidolite fibers. Longer MMVFs disappeared more rapidly than short MMVFs, suggesting that long fibers were dissolving or breaking. Mean diameters and lengths of the MMVFs decreased with time, while the mean diameter of crocidolite remained unchanged and its mean length showed an apparent increase, probably related to macrophage-mediated clearance of short fibers. Leaching of oxides occurred in the fibrous glasses and slag wool and correlated with morphological changes in the fibers over time. No chemical or morphological changes were observed in crocidolite fibers. These changes in MMVF number, chemistry, and morphology over time in lung tissue compared to crocidolite asbestos demonstrate the relatively low biological persistence of some MMVFs in the lung and may explain why these MMVFs are not tumorigenic in rats, even after chronic exposure at high concentrations.

Airspace Dimension Assessment with nanoparticles reflects lung density as quantified by MRI

PubMed Central

Jakobsson, Jonas K; Löndahl, Jakob; Olsson, Lars E; Diaz, Sandra; Zackrisson, Sophia; Wollmer, Per

2018-01-01

Background Airspace Dimension Assessment with inhaled nanoparticles is a novel method to determine distal airway morphology. This is the first empirical study using Airspace Dimension Assessment with nanoparticles (AiDA) to estimate distal airspace radius. The technology is relatively simple and potentially accessible in clinical outpatient settings. Method Nineteen never-smoking volunteers performed nanoparticle inhalation tests at multiple breath-hold times, and the difference in nanoparticle concentration of inhaled and exhaled gas was measured. An exponential decay curve was fitted to the concentration of recovered nanoparticles, and airspace dimensions were assessed from the half-life of the decay. Pulmonary tissue density was measured using magnetic resonance imaging (MRI). Results The distal airspace radius measured by AiDA correlated with lung tissue density as measured by MRI (ρ = −0.584; p = 0.0086). The linear intercept of the logarithm of the exponential decay curve correlated with forced expiratory volume in one second (FEV1) (ρ = 0.549; p = 0.0149). Conclusion The AiDA method shows potential to be developed into a tool to assess conditions involving changes in distal airways, eg, emphysema. The intercept may reflect airway properties; this finding should be further investigated.

Creb1 regulates late stage mammalian lung development via respiratory epithelial and mesenchymal-independent mechanisms

PubMed Central

Antony, N.; McDougall, A. R.; Mantamadiotis, T.; Cole, T. J.; Bird, A. D.

2016-01-01

During mammalian lung development, the morphological transition from respiratory tree branching morphogenesis to a predominantly saccular architecture, capable of air-breathing at birth, is dependent on physical forces as well as molecular signaling by a range of transcription factors including the cAMP response element binding protein 1 (Creb1). Creb1−/− mutant mice exhibit complete neonatal lethality consistent with a lack of lung maturation beyond the branching phase. To further define its role in the developing mouse lung, we deleted Creb1 separately in the respiratory epithelium and mesenchyme. Surprisingly, we found no evidence of a morphological lung defect nor compromised neonatal survival in either conditional Creb1 mutant. Interestingly however, loss of mesenchymal Creb1 on a genetic background lacking the related Crem protein showed normal lung development but poor neonatal survival. To investigate the underlying requirement for Creb1 for normal lung development, Creb1−/− mice were re-examined for defects in both respiratory muscles and glucocorticoid hormone signaling, which are also required for late stage lung maturation. However, these systems appeared normal in Creb1−/− mice. Together our results suggest that the requirement of Creb1 for normal mammalian lung morphogenesis is not dependent upon its expression in lung epithelium or mesenchyme, nor its role in musculoskeletal development. PMID:27150575

Tracking of Mesenchymal Stem Cells with Fluorescence Endomicroscopy Imaging in Radiotherapy-Induced Lung Injury

NASA Astrophysics Data System (ADS)

Perez, Jessica R.; Ybarra, Norma; Chagnon, Frederic; Serban, Monica; Lee, Sangkyu; Seuntjens, Jan; Lesur, Olivier; El Naqa, Issam

2017-01-01

Mesenchymal stem cells (MSCs) have potential for reducing inflammation and promoting organ repair. However, limitations in available techniques to track them and assess this potential for lung repair have hindered their applicability. In this work, we proposed, implemented and evaluated the use of fluorescence endomicroscopy as a novel imaging tool to track MSCs in vivo. MSCs were fluorescently labeled and injected into a rat model of radiation-induced lung injury via endotracheal (ET) or intravascular (IV) administration. Our results show that MSCs were visible in the lungs with fluorescence endomicroscopy. Moreover, we developed an automatic cell counting algorithm to quantify the number of detected cells in each condition. We observed a significantly higher number of detected cells in ET injection compared to IV and a slight increase in the mean number of detected cells in irradiated lungs compared to control, although the latter did not reach statistical significance. Fluorescence endomicroscopy imaging is a powerful new minimally invasive and translatable tool that can be used to track and quantify MSCs in the lungs and help assess their potential in organ repair.

Redistribution of pulmonary blood flow impacts thermodilution-based extravascular lung water measurements in a model of acute lung injury

PubMed Central

Easley, R. Blaine; Mulreany, Daniel G.; Lancaster, Christopher T.; Custer, Jason W.; Fernandez-Bustamante, Ana; Colantuoni, Elizabeth; Simon, Brett A.

2009-01-01

Background Studies using transthoracic thermodilution have demonstrated increased extravascular lung water (EVLW) measurements attributed to progression of edema and flooding during sepsis and acute lung injury. We hypothesize that redistribution of pulmonary blood flow can cause increased apparent EVLW secondary to increased perfusion of thermally silent tissue, not increased lung edema. Methods Anesthetized, mechanically ventilated canines were instrumented with PiCCO® (Pulsion Medical, Munich, Germany) catheters and underwent lung injury by repetitive saline lavage. Hemodynamic and respiratory physiologic data were recorded. After stabilized lung injury, endotoxin was administered to inactivate hypoxic pulmonary vasoconstriction. Computerized tomographic imaging was performed to quantify in vivo lung volume, total tissue (fluid) and air content, and regional distribution of blood flow. Results Lavage injury caused an increase in airway pressures and decreased arterial oxygen content with minimal hemodynamic effects. EVLW and shunt fraction increased after injury and then markedly following endotoxin administration. Computerized tomographic measurements quantified an endotoxin-induced increase in pulmonary blood flow to poorly aerated regions with no change in total lung tissue volume. Conclusions The abrupt increase in EVLW and shunt fraction after endotoxin administration is consistent with inactivation of hypoxic pulmonary vasoconstriction and increased perfusion to already flooded lung regions that were previously thermally silent. Computerized tomographic studies further demonstrate in vivo alterations in regional blood flow (but not lung water) and account for these alterations in shunt fraction and EVLW. PMID:19809280

Exaggerated Acute Lung Injury and Impaired Antibacterial Defenses During Staphylococcus aureus Infection in Rats with the Metabolic Syndrome

PubMed Central

Feng, Xiaomei; Maze, Mervyn; Koch, Lauren G.; Britton, Steven L.; Hellman, Judith

2015-01-01

Rats with Metabolic Syndrome (MetaS) have a dysregulated immune response to the aseptic trauma of surgery. We hypothesized that rats with MetaS would have dysregulated inflammation, increased lung injury, and less effective antibacterial defenses during Staphylococcus (S.) aureus sepsis as compared to rats without MetaS. Low capacity runner (LCR; a model of MetaS) and high capacity runner (HCR) rats were challenged intravenously with S. aureus bacteria. After 48 h, inflammatory mediators and bacteria were quantified in the blood, bronchoalveolar lavage fluid (BALF), and lung homogenates. Lungs were analyzed histologically. BALF protein and lung wet-dry ratios were quantified to assess for vascular leak. Endpoints were compared in infected LCR vs HCR rats. LCR rats had higher blood and lung S. aureus counts, as well as higher levels of IL-6 in plasma, lungs and BALF, MIP-2 in plasma and lung, and IL-17A in lungs. Conversely, LCR rats had lower levels of IL-10 in plasma and lungs. Although lactate levels, and liver and renal function tests were similar between groups, LCR rats had higher BALF protein and lung wet-dry ratios, and more pronounced acute lung injury histologically. During S. aureus bacteremia, as compared with HCR rats, LCR (MetaS) rats have heightened pro-inflammatory responses, accompanied by increased acute lung injury and vascular leak. Notably, despite an augmented pro-inflammatory phenotype, LCR rats have higher bacterial levels in their blood and lungs. The MetaS state may exacerbate lung injury and vascular leak by attenuating the inflammation-resolving response, and by weakening antimicrobial defenses. PMID:25978669

Controlled lung reperfusion to reduce pulmonary ischaemia/reperfusion injury after cardiopulmonary bypass in a porcine model.

PubMed

Slottosch, Ingo; Liakopoulos, Oliver; Kuhn, Elmar; Deppe, Antje; Lopez-Pastorini, Alberto; Schwarz, David; Neef, Klaus; Choi, Yeong-Hoon; Sterner-Kock, Anja; Jung, Kristina; Mühlfeld, Christian; Wahlers, Thorsten

2014-12-01

Ischaemia/reperfusion (I/R) injury of the lungs contributes to pulmonary dysfunction after cardiac surgery with cardiopulmonary bypass (CPB), leading to increased morbidity and mortality of patients. This study investigated the value of controlled lung reperfusion strategies on lung ischaemia-reperfusion injury in a porcine CPB model. Pigs were subjected to routine CPB for 120 min with 60 min of blood cardioplegic cardiac arrest (CCA). Following CCA, the uncontrolled reperfusion (UR, n = 6) group was conventionally weaned from CPB. Two groups underwent controlled lung reperfusion strategies (CR group: controlled reperfusion conditions, n = 6; MR group: controlled reperfusion conditions and modified reperfusate, n = 6) via the pulmonary artery before CPB weaning. Sham-operated pigs (n = 7) served as controls. Animals were followed up until 4 h after CPB. Pulmonary function, haemodynamics, markers of inflammation, endothelial injury and oxidative stress as well as morphological lung alterations were analysed. CPB (UR group) induced deterioration of pulmonary function (lung mechanics, oxygenation index and lung oedema). Also, controlled lung reperfusion groups (CR and MR) presented with pulmonary dysfunction after CPB. However, compared with UR, controlled lung reperfusion strategies (CR and MR) improved lung mechanics and reduced markers of oxidative stress, but without alteration of haemodynamics, oxygenation, inflammation, endothelial injury and lung morphology. Both controlled reperfusion groups were similar without relevant differences. Controlled lung reperfusion strategies attenuated a decrease in lung mechanics and an increase in oxidative stress, indicating an influence on CPB-related pulmonary injury. However, they failed to avoid completely CPB-related lung injury, implying the need for additional strategies given the multifactorial pathophysiology of postoperative pulmonary dysfunction. © The Author 2014. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.

[What is the prognostic significance of histomorphology in small cell lung carcinoma?].

PubMed

Facilone, F; Cimmino, A; Assennato, G; Sardelli, P; Colucci, G A; Resta, L

1993-01-01

What is the prognostic significant of the histomorphology in the small cell carcinomas of the lung? After the WHO classification of the lung cancer (1981), several studies criticized the subdivision of the small cell carcinoma in three sub-types (oat-cell, intermediate cell and combined types). The role of histology in the prognostic predition has been devaluated. In order to verify the prognostic value of the morphology of the small cell types of lung cancer, we performed a multivariate analysis in 62 patients. The survival rate was analytically compared with the following parameters: nuclear maximum diameter, nuclear form, nuclear chromatism, chromatine distribution, presence of nucleolus, evidence of cytoplasm. The results showed that none of these parameters are able to express a prognostic value. According to the recent studies, we think that the small cell carcinoma of the lung is a neoplasia with a multiform histologic pattern. Differences observed in clinical management are not correlate with the morphology, but with other biological parameters still unknown.

Automated diagnosis of interstitial lung diseases and emphysema in MDCT imaging

NASA Astrophysics Data System (ADS)

Fetita, Catalin; Chang Chien, Kuang-Che; Brillet, Pierre-Yves; Prêteux, Françoise

2007-09-01

Diffuse lung diseases (DLD) include a heterogeneous group of non-neoplasic disease resulting from damage to the lung parenchyma by varying patterns of inflammation. Characterization and quantification of DLD severity using MDCT, mainly in interstitial lung diseases and emphysema, is an important issue in clinical research for the evaluation of new therapies. This paper develops a 3D automated approach for detection and diagnosis of diffuse lung diseases such as fibrosis/honeycombing, ground glass and emphysema. The proposed methodology combines multi-resolution 3D morphological filtering (exploiting the sup-constrained connection cost operator) and graph-based classification for a full characterization of the parenchymal tissue. The morphological filtering performs a multi-level segmentation of the low- and medium-attenuated lung regions as well as their classification with respect to a granularity criterion (multi-resolution analysis). The original intensity range of the CT data volume is thus reduced in the segmented data to a number of levels equal to the resolution depth used (generally ten levels). The specificity of such morphological filtering is to extract tissue patterns locally contrasting with their neighborhood and of size inferior to the resolution depth, while preserving their original shape. A multi-valued hierarchical graph describing the segmentation result is built-up according to the resolution level and the adjacency of the different segmented components. The graph nodes are then enriched with the textural information carried out by their associated components. A graph analysis-reorganization based on the nodes attributes delivers the final classification of the lung parenchyma in normal and ILD/emphysematous regions. It also makes possible to discriminate between different types, or development stages, among the same class of diseases.

A Comparison of Two Commercial Volumetry Software Programs in the Analysis of Pulmonary Ground-Glass Nodules: Segmentation Capability and Measurement Accuracy

PubMed Central

Kim, Hyungjin; Lee, Sang Min; Lee, Hyun-Ju; Goo, Jin Mo

2013-01-01

Objective To compare the segmentation capability of the 2 currently available commercial volumetry software programs with specific segmentation algorithms for pulmonary ground-glass nodules (GGNs) and to assess their measurement accuracy. Materials and Methods In this study, 55 patients with 66 GGNs underwent unenhanced low-dose CT. GGN segmentation was performed by using 2 volumetry software programs (LungCARE, Siemens Healthcare; LungVCAR, GE Healthcare). Successful nodule segmentation was assessed visually and morphologic features of GGNs were evaluated to determine factors affecting segmentation by both types of software. In addition, the measurement accuracy of the software programs was investigated by using an anthropomorphic chest phantom containing simulated GGNs. Results The successful nodule segmentation rate was significantly higher in LungCARE (90.9%) than in LungVCAR (72.7%) (p = 0.012). Vascular attachment was a negatively influencing morphologic feature of nodule segmentation for both software programs. As for measurement accuracy, mean relative volume measurement errors in nodules ≥ 10 mm were 14.89% with LungCARE and 19.96% with LungVCAR. The mean relative attenuation measurement errors in nodules ≥ 10 mm were 3.03% with LungCARE and 5.12% with LungVCAR. Conclusion LungCARE shows significantly higher segmentation success rates than LungVCAR. Measurement accuracy of volume and attenuation of GGNs is acceptable in GGNs ≥ 10 mm by both software programs. PMID:23901328

Role of alveolar topology on acinar flows and convective mixing.

PubMed

Hofemeier, Philipp; Sznitman, Josué

2014-06-01

Due to experimental challenges, computational simulations are often sought to quantify inhaled aerosol transport in the pulmonary acinus. Commonly, these are performed using generic alveolar topologies, including spheres, toroids, and polyhedra, to mimic the complex acinar morphology. Yet, local acinar flows and ensuing particle transport are anticipated to be influenced by the specific morphological structures. We have assessed a range of acinar models under self-similar breathing conditions with respect to alveolar flow patterns, convective flow mixing, and deposition of fine particles (1.3 μm diameter). By tracking passive tracers over cumulative breathing cycles, we find that irreversible flow mixing correlates with the location and strength of the recirculating vortex inside the cavity. Such effects are strongest in proximal acinar generations where the ratio of alveolar to ductal flow rates is low and interalveolar disparities are most apparent. Our results for multi-alveolated acinar ducts highlight that fine 1 μm inhaled particles subject to alveolar flows are sensitive to the alveolar topology, underlining interalveolar disparities in particle deposition patterns. Despite the simplicity of the acinar models investigated, our findings suggest that alveolar topologies influence more significantly local flow patterns and deposition sites of fine particles for upper generations emphasizing the importance of the selected acinar model. In distal acinar generations, however, the alveolar geometry primarily needs to mimic the space-filling alveolar arrangement dictated by lung morphology.

Pulmonary nodule characterization, including computer analysis and quantitative features.

PubMed

Bartholmai, Brian J; Koo, Chi Wan; Johnson, Geoffrey B; White, Darin B; Raghunath, Sushravya M; Rajagopalan, Srinivasan; Moynagh, Michael R; Lindell, Rebecca M; Hartman, Thomas E

2015-03-01

Pulmonary nodules are commonly detected in computed tomography (CT) chest screening of a high-risk population. The specific visual or quantitative features on CT or other modalities can be used to characterize the likelihood that a nodule is benign or malignant. Visual features on CT such as size, attenuation, location, morphology, edge characteristics, and other distinctive "signs" can be highly suggestive of a specific diagnosis and, in general, be used to determine the probability that a specific nodule is benign or malignant. Change in size, attenuation, and morphology on serial follow-up CT, or features on other modalities such as nuclear medicine studies or MRI, can also contribute to the characterization of lung nodules. Imaging analytics can objectively and reproducibly quantify nodule features on CT, nuclear medicine, and magnetic resonance imaging. Some quantitative techniques show great promise in helping to differentiate benign from malignant lesions or to stratify the risk of aggressive versus indolent neoplasm. In this article, we (1) summarize the visual characteristics, descriptors, and signs that may be helpful in management of nodules identified on screening CT, (2) discuss current quantitative and multimodality techniques that aid in the differentiation of nodules, and (3) highlight the power, pitfalls, and limitations of these various techniques.

[Experimental approach to the prophylaxis and treatment of acute lung injury syndrome with proteinase inhibitors and corvitin].

PubMed

Moĭbenko, O O; Kubyshkin, A V; Kharchenko, V Z; Horokhova, N Iu; Semenets', P F

2003-01-01

The results of a combined study of the proteolysis on a model of post-ischemic toxemia in rats showed a decrease in antiproteinase potential and an activation of proteolysis. The activation of proteolysis and inhibition of antiproteinases was observed not only in the blood, but also in the bronchoalveolar secretion. Those changes were accompanied with the changes in the morphological structure of the lungs. The data obtained have shown a high effectiveness of proteinase inhibitor (contrical) and an antioxidant of flavonoid group (corvetine). Those drugs decreased the morphological changes in the lungs and prevented the development of imbalance in proteinase-inhibitor system. The prophylactic effect was more considerable when both drugs were used in a combined way.

Pathogens, patterns of pneumonia, and epidemiologic risk factors associated with respiratory disease in recently weaned cattle in Ireland.

PubMed

Murray, Gerard M; More, Simon J; Sammin, Dónal; Casey, Mìcheàl J; McElroy, Máire C; O'Neill, Rónan G; Byrne, William J; Earley, Bernadette; Clegg, Tracy A; Ball, Hywel; Bell, Colin J; Cassidy, Joseph P

2017-01-01

We examined the pathogens, morphologic patterns, and risk factors associated with bovine respiratory disease (BRD) in 136 recently weaned cattle ("weanlings"), 6-12 mo of age, that were submitted for postmortem examination to regional veterinary laboratories in Ireland. A standardized sampling protocol included routine microbiologic investigations as well as polymerase chain reaction and immunohistochemistry. Lungs with histologic lesions were categorized into 1 of 5 morphologic patterns of pneumonia. Fibrinosuppurative bronchopneumonia (49%) and interstitial pneumonia (48%) were the morphologic patterns recorded most frequently. The various morphologic patterns of pulmonary lesions suggest the involvement of variable combinations of initiating and compounding infectious agents that hindered any simple classification of the etiopathogenesis of the pneumonias. Dual infections were detected in 58% of lungs, with Mannheimia haemolytica and Histophilus somni most frequently recorded in concert. M. haemolytica (43%) was the most frequently detected respiratory pathogen; H. somni was also shown to be frequently implicated in pneumonia in this age group of cattle. Bovine parainfluenza virus 3 (BPIV-3) and Bovine respiratory syncytial virus (16% each) were the viral agents detected most frequently. Potential respiratory pathogens (particularly Pasteurella multocida, BPIV-3, and H. somni) were frequently detected (64%) in lungs that had neither gross nor histologic pulmonary lesions, raising questions regarding their role in the pathogenesis of BRD. The breadth of respiratory pathogens detected in bovine lungs by various detection methods highlights the diagnostic value of parallel analyses in respiratory disease postmortem investigation.

Longitudinal assessment of bleomycin-induced lung fibrosis by Micro-CT correlates with histological evaluation in mice.

PubMed

Ruscitti, Francesca; Ravanetti, Francesca; Essers, Jeroen; Ridwan, Yanto; Belenkov, Sasha; Vos, Wim; Ferreira, Francisca; KleinJan, Alex; van Heijningen, Paula; Van Holsbeke, Cedric; Cacchioli, Antonio; Villetti, Gino; Stellari, Franco Fabio

2017-01-01

The intratracheal instillation of bleomycin in mice induces early damage to alveolar epithelial cells and development of inflammation followed by fibrotic tissue changes and represents the most widely used model of pulmonary fibrosis to investigate human IPF. Histopathology is the gold standard for assessing lung fibrosis in rodents, however it precludes repeated and longitudinal measurements of disease progression and does not provide information on spatial and temporal distribution of tissue damage. Here we investigated the use of the Micro-CT technique to allow the evaluation of disease onset and progression at different time-points in the mouse bleomycin model of lung fibrosis. Micro-CT was throughout coupled with histological analysis for the validation of the imaging results. In bleomycin-instilled and control mice, airways and lung morphology changes were assessed and reconstructed at baseline, 7, 14 and 21 days post-treatment based on Micro-CT images. Ashcroft score, percentage of collagen content and percentage of alveolar air area were detected on lung slides processed by histology and subsequently compared with Micro-CT parameters. Extent (%) of fibrosis measured by Micro-CT correlated with Ashcroft score, the percentage of collagen content and the percentage of alveolar air area ( r 2  = 0.91; 0.77; 0.94, respectively). Distal airway radius also correlated with the Ashcroft score, the collagen content and alveolar air area percentage ( r 2  = 0.89; 0.78; 0.98, respectively). Micro-CT data were in good agreement with histological read-outs as micro-CT was able to quantify effectively and non-invasively disease progression longitudinally and to reduce the variability and number of animals used to assess the damage. This suggests that this technique is a powerful tool for understanding experimental pulmonary fibrosis and that its use could translate into a more efficient drug discovery process, also helping to fill the gap between preclinical setting and clinical practice.

Lung texture in serial thoracic CT scans: correlation with radiologist-defined severity of acute changes following radiation therapy

NASA Astrophysics Data System (ADS)

Cunliffe, Alexandra R.; Armato, Samuel G., III; Straus, Christopher; Malik, Renuka; Al-Hallaq, Hania A.

2014-09-01

This study examines the correlation between the radiologist-defined severity of normal tissue damage following radiation therapy (RT) for lung cancer treatment and a set of mathematical descriptors of computed tomography (CT) scan texture (‘texture features’). A pre-therapy CT scan and a post-therapy CT scan were retrospectively collected under IRB approval for each of the 25 patients who underwent definitive RT (median dose: 66 Gy). Sixty regions of interest (ROIs) were automatically identified in the non-cancerous lung tissue of each post-therapy scan. A radiologist compared post-therapy scan ROIs with pre-therapy scans and categorized each as containing no abnormality, mild abnormality, moderate abnormality, or severe abnormality. Twenty texture features that characterize gray-level intensity, region morphology, and gray-level distribution were calculated in post-therapy scan ROIs and compared with anatomically matched ROIs in the pre-therapy scan. Linear regression and receiver operating characteristic (ROC) analysis were used to compare the percent feature value change (ΔFV) between ROIs at each category of visible radiation damage. Most ROIs contained no (65%) or mild abnormality (30%). ROIs with moderate (3%) or severe (2%) abnormalities were observed in 9 patients. For 19 of 20 features, ΔFV was significantly different among severity levels. For 12 features, significant differences were observed at every level. Compared with regions with no abnormalities, ΔFV for these 12 features increased, on average, by 1.5%, 12%, and 30%, respectively, for mild, moderate, and severe abnormalitites. Area under the ROC curve was largest when comparing ΔFV in the highest severity level with the remaining three categories (mean AUC across features: 0.84). In conclusion, 19 features that characterized the severity of radiologic changes from pre-therapy scans were identified. These features may be used in future studies to quantify acute normal lung tissue damage following RT. Presented, in part at the IASLC 15th World Conference on Lung Conference, Sydney, AUS (2013).

Silencing hyperoxia-induced C/EBPα in neonatal mice improves lung architecture via enhanced proliferation of alveolar epithelial cells

PubMed Central

Yang, Guang; Hinson, Maurice D.; Bordner, Jessica E.; Lin, Qing S.; Fernando, Amal P.; La, Ping; Wright, Clyde J.

2011-01-01

Postnatal lung development requires proliferation and differentiation of specific cell types at precise times to promote proper alveolar formation. Hyperoxic exposure can disrupt alveolarization by inhibiting cell growth; however, it is not fully understood how this is mediated. The transcription factor CCAAT/enhancer binding protein-α (C/EBPα) is highly expressed in the lung and plays a role in cell proliferation and differentiation in many tissues. After 72 h of hyperoxia, C/EBPα expression was significantly enhanced in the lungs of newborn mice. The increased C/EBPα protein was predominantly located in alveolar type II cells. Silencing of C/EBPα with a transpulmonary injection of C/EBPα small interfering RNA (siRNA) prior to hyperoxic exposure reduced expression of markers of type I cell and differentiation typically observed after hyperoxia but did not rescue the altered lung morphology at 72 h. Nevertheless, when C/EBPα hyperoxia-exposed siRNA-injected mice were allowed to recover for 2 wk in room air, lung epithelial cell proliferation was increased and lung morphology was restored compared with hyperoxia-exposed control siRNA-injected mice. These data suggest that C/EBPα is an important regulator of postnatal alveolar epithelial cell proliferation and differentiation during injury and repair. PMID:21571903

Evidence for pleural epithelial-mesenchymal transition in murine compensatory lung growth

PubMed Central

Ysasi, Alexandra B.; Wagner, Willi L.; Valenzuela, Cristian D.; Kienzle, Arne; Servais, Andrew B.; Bennett, Robert D.; Tsuda, Akira; Ackermann, Maximilian; Mentzer, Steven J.

2017-01-01

In many mammals, including rodents and humans, removal of one lung results in the compensatory growth of the remaining lung; however, the mechanism of compensatory lung growth is unknown. Here, we investigated the changes in morphology and phenotype of pleural cells after pneumonectomy. Between days 1 and 3 after pneumonectomy, cells expressing α-smooth muscle actin (SMA), a cytoplasmic marker of myofibroblasts, were significantly increased in the pleura compared to surgical controls (p < .01). Scanning electron microscopy of the pleural surface 3 days post-pneumonectomy demonstrated regions of the pleura with morphologic features consistent with epithelial-mesenchymal transition (EMT); namely, cells with disrupted intercellular junctions and an acquired mesenchymal (rounded and fusiform) morphotype. To detect the migration of the transitional pleural cells into the lung, a biotin tracer was used to label the pleural mesothelial cells at the time of surgery. By post-operative day 3, image cytometry of post-pneumonectomy subpleural alveoli demonstrated a 40-fold increase in biotin+ cells relative to pneumonectomy-plus-plombage controls (p < .01). Suggesting a similar origin in space and time, the distribution of cells expressing biotin, SMA, or vimentin demonstrated a strong spatial autocorrelation in the subpleural lung (p < .001). We conclude that post-pneumonectomy compensatory lung growth involves EMT with the migration of transitional mesothelial cells into subpleural alveoli. PMID:28542402

Do nanoparticles provide a new opportunity for diagnosis of distal airspace disease?

PubMed Central

Löndahl, Jakob; Jakobsson, Jonas KF; Broday, David M; Aaltonen, H Laura; Wollmer, Per

2017-01-01

There is a need for efficient techniques to assess abnormalities in the peripheral regions of the lungs, for example, for diagnosis of pulmonary emphysema. Considerable scientific efforts have been directed toward measuring lung morphology by studying recovery of inhaled micron-sized aerosol particles (0.4–1.5 µm). In contrast, it is suggested that the recovery of inhaled airborne nanoparticles may be more useful for diagnosis. The objective of this work is to provide a theoretical background for the use of nanoparticles in measuring lung morphology and to assess their applicability based on a review of the literature. Using nanoparticles for studying distal airspace dimensions is shown to have several advantages over other aerosol-based methods. 1) Nanoparticles deposit almost exclusively by diffusion, which allows a simpler breathing maneuver with minor artifacts from particle losses in the oropharyngeal and upper airways. 2) A higher breathing flow rate can be utilized, making it possible to rapidly inhale from residual volume to total lung capacity (TLC), thereby eliminating the need to determine the TLC before measurement. 3) Recent studies indicate better penetration of nanoparticles than micron-sized particles into poorly ventilated and diseased regions of the lungs; thus, a stronger signal from the abnormal parts is expected. 4) Changes in airspace dimensions have a larger impact on the recovery of nanoparticles. Compared to current diagnostic techniques with high specificity for morphometric changes of the lungs, computed tomography and magnetic resonance imaging with hyperpolarized gases, an aerosol-based method is likely to be less time consuming, considerably cheaper, simpler to use, and easier to interpret (providing a single value rather than an image that has to be analyzed). Compared to diagnosis by carbon monoxide (DL,CO), the uptake of nanoparticles in the lung is not affected by blood flow, hemoglobin concentration or alterations of the alveolar membranes, but relies only on lung morphology. PMID:28053522

Do nanoparticles provide a new opportunity for diagnosis of distal airspace disease?

PubMed

Löndahl, Jakob; Jakobsson, Jonas Kf; Broday, David M; Aaltonen, H Laura; Wollmer, Per

There is a need for efficient techniques to assess abnormalities in the peripheral regions of the lungs, for example, for diagnosis of pulmonary emphysema. Considerable scientific efforts have been directed toward measuring lung morphology by studying recovery of inhaled micron-sized aerosol particles (0.4-1.5 µm). In contrast, it is suggested that the recovery of inhaled airborne nanoparticles may be more useful for diagnosis. The objective of this work is to provide a theoretical background for the use of nanoparticles in measuring lung morphology and to assess their applicability based on a review of the literature. Using nanoparticles for studying distal airspace dimensions is shown to have several advantages over other aerosol-based methods. 1) Nanoparticles deposit almost exclusively by diffusion, which allows a simpler breathing maneuver with minor artifacts from particle losses in the oropharyngeal and upper airways. 2) A higher breathing flow rate can be utilized, making it possible to rapidly inhale from residual volume to total lung capacity (TLC), thereby eliminating the need to determine the TLC before measurement. 3) Recent studies indicate better penetration of nanoparticles than micron-sized particles into poorly ventilated and diseased regions of the lungs; thus, a stronger signal from the abnormal parts is expected. 4) Changes in airspace dimensions have a larger impact on the recovery of nanoparticles. Compared to current diagnostic techniques with high specificity for morphometric changes of the lungs, computed tomography and magnetic resonance imaging with hyperpolarized gases, an aerosol-based method is likely to be less time consuming, considerably cheaper, simpler to use, and easier to interpret (providing a single value rather than an image that has to be analyzed). Compared to diagnosis by carbon monoxide ( D L,CO ), the uptake of nanoparticles in the lung is not affected by blood flow, hemoglobin concentration or alterations of the alveolar membranes, but relies only on lung morphology.

Nonlinear histogram binning for quantitative analysis of lung tissue fibrosis in high-resolution CT data

NASA Astrophysics Data System (ADS)

Zavaletta, Vanessa A.; Bartholmai, Brian J.; Robb, Richard A.

2007-03-01

Diffuse lung diseases, such as idiopathic pulmonary fibrosis (IPF), can be characterized and quantified by analysis of volumetric high resolution CT scans of the lungs. These data sets typically have dimensions of 512 x 512 x 400. It is too subjective and labor intensive for a radiologist to analyze each slice and quantify regional abnormalities manually. Thus, computer aided techniques are necessary, particularly texture analysis techniques which classify various lung tissue types. Second and higher order statistics which relate the spatial variation of the intensity values are good discriminatory features for various textures. The intensity values in lung CT scans range between [-1024, 1024]. Calculation of second order statistics on this range is too computationally intensive so the data is typically binned between 16 or 32 gray levels. There are more effective ways of binning the gray level range to improve classification. An optimal and very efficient way to nonlinearly bin the histogram is to use a dynamic programming algorithm. The objective of this paper is to show that nonlinear binning using dynamic programming is computationally efficient and improves the discriminatory power of the second and higher order statistics for more accurate quantification of diffuse lung disease.

Levels of circulating MMP-7 degraded elastin are elevated in pulmonary disorders.

PubMed

Kristensen, J H; Larsen, L; Dasgupta, B; Brodmerkel, C; Curran, M; Karsdal, M A; Sand, J M B; Willumsen, N; Knox, A J; Bolton, C E; Johnson, S R; Hägglund, P; Svensson, B; Leeming, D J

2015-11-01

Elastin is a signature protein of the lungs. Matrix metalloproteinase-7 (MMP-7) is important in lung defence mechanisms and degrades elastin. However, MMP-7 activity in regard to elastin degradation has never been quantified serologically in patients with lung diseases. An assay for the quantification of MMP-7 generated elastin fragments (ELM7) was therefore developed to investigate MMP-7 derived elastin degradation in pulmonary disorders such as idiopathic pulmonary fibrosis (IPF) and lung cancer. Monoclonal antibodies (mABs) were raised against eight carefully selected MMP-7 cleavage sites on elastin. After characterisation and validation of the mABs, one mAB targeting the ELM7 fragment was chosen. ELM7 fragment levels were assessed in serum samples from patients diagnosed with IPF (n=123, baseline samples, CTgov reg. NCT00786201), and lung cancer (n=40) and compared with age- and sex-matched controls. The ELM7 assay was specific towards in vitro MMP-7 degraded elastin and the ELM7 neoepitope but not towards other MMP-7 derived elastin fragments. Serum ELM7 levels were significantly increased in IPF (113%, p<0.0001) and lung cancer (96%, p<0.0001) compared to matched controls. MMP-7-generated elastin fragments can be quantified in serum and may reflect pathological lung tissue turnover in several important lung diseases. Copyright © 2015 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.

Radionuclide injury to the lung.

PubMed Central

Dagle, G E; Sanders, C L

1984-01-01

Radionuclide injury to the lung has been studied in rats, hamsters, dogs, mice and baboons. Exposure of the lung to high dose levels of radionuclides produces a spectrum of progressively more severe functional and morphological changes, ranging from radiation pneumonitis and fibrosis to lung tumors. These changes are somewhat similar for different species. Their severity can be related to the absorbed radiation dose (measured in rads) produced by alpha, beta or gamma radiation emanating from various deposited radionuclides. The chemicophysical forms of radionuclides and spatial-temporal factors are also important variables. As with other forms of injury to the lung, repair attempts are highlighted by fibrosis and proliferation of pulmonary epithelium. Lung tumors are the principal late effect observed in experimental animals following pulmonary deposition of radionuclides at dose levels that do not result in early deaths from radiation pneumonitis or fibrosis. The predominant lung tumors described have been of epithelial origin and have been classified, in decreasing frequency of occurrence, as adenocarcinoma, bronchioloalveolar carcinoma, epidermoid carcinomas and combined epidermoid and adenocarcinoma. Mesothelioma and fibrosarcoma have been observed in rats, but less commonly in other species. Hemangiosarcomas were frequency observed in dogs exposed to beta-gamma emitters, and occasionally in rats exposed to alpha emitters. These morphologic changes in the lungs of experimental animals were reviewed and issues relevant to the prediction of human hazards discussed. PMID:6376095

Non-invasive microstructure and morphology investigation of the mouse lung: qualitative description and quantitative measurement.

PubMed

Zhang, Lu; Li, Dongyue; Luo, Shuqian

2011-02-25

Early detection of lung cancer is known to improve the chances of successful treatment. However, lungs are soft tissues with complex three-dimensional configuration. Conventional X-ray imaging is based purely on absorption resulting in very low contrast when imaging soft tissues without contrast agents. It is difficult to obtain adequate information of lung lesions from conventional X-ray imaging. In this study, a recently emerged imaging technique, in-line X-ray phase contrast imaging (IL-XPCI) was used. This powerful technique enabled high-resolution investigations of soft tissues without contrast agents. We applied IL-XPCI to observe the lungs in an intact mouse for the purpose of defining quantitatively the micro-structures in lung. The three-dimensional model of the lung was successfully established, which provided an excellent view of lung airways. We highlighted the use of IL-XPCI in the visualization and assessment of alveoli which had rarely been studied in three dimensions (3D). The precise view of individual alveolus was achieved. The morphological parameters, such as diameter and alveolar surface area were measured. These parameters were of great importance in the diagnosis of diseases related to alveolus and alveolar scar. Our results indicated that IL-XPCI had the ability to represent complex anatomical structures in lung. This offered a new perspective on the diagnosis of respiratory disease and may guide future work in the study of respiratory mechanism on the alveoli level.

Assessment of pulmonary structure-function relationships in young children and adolescents with cystic fibrosis by multivolume proton-MRI and CT.

PubMed

Pennati, Francesca; Roach, David J; Clancy, John P; Brody, Alan S; Fleck, Robert J; Aliverti, Andrea; Woods, Jason C

2018-02-19

Lung disease is the most frequent cause of morbidity and mortality in patients with cystic fibrosis (CF), and there is a shortage of sensitive biomarkers able to regionally monitor disease progression and to assess early responses to therapy. To determine the feasibility of noncontrast-enhanced multivolume MRI, which assesses intensity changes between expiratory and inspiratory breath-hold images, to detect and quantify regional ventilation abnormalities in CF lung disease, with a focus on the structure-function relationship. Retrospective. Twenty-nine subjects, including healthy young children (n = 9, 7-37 months), healthy adolescents (n = 4, 14-22 years), young children with CF lung disease (n = 10, 7-47 months), and adolescents with CF lung disease (n = 6, 8-18 years) were studied. 3D spoiled gradient-recalled sequence at 1.5T. Subjects were scanned during breath-hold at functional residual capacity (FRC) and total lung capacity (TLC) through noncontrast-enhanced MRI and CT. Expiratory-inspiratory differences in MR signal-intensity (Δ 1 H-MRI) and CT-density (ΔHU) were computed to estimate regional ventilation. MR and CT images were also evaluated using a CF-specific scoring system. Quadratic regression, Spearman's correlation, one-way analysis of variance (ANOVA). Δ 1 H-MRI maps were sensitive to ventilation heterogeneity related to gravity dependence in healthy lung and to ventilation impairment in CF lung disease. A high correlation was found between MRI and CT ventilation maps (R 2  = 0.79, P < 0.001). Globally, Δ 1 H-MRI and ΔHU decrease with increasing morphological score (respectively, R 2  = 0.56, P < 0.001 and R 2  = 0.31, P < 0.001). Locally, Δ 1 H-MRI was higher in healthy regions (median 15%) compared to regions with bronchiectasis, air trapping, consolidation, and to segments fed by airways with bronchial wall thickening (P < 0.001). Multivolume noncontrast-enhanced MRI, as a nonionizing imaging modality that can be used on nearly any MRI scanner without specialized equipment or gaseous tracers, may be particularly valuable in CF care, providing a new imaging biomarker to detect early alterations in regional lung structure-function. 3 Technical Efficacy: Stage 3 J. Magn. Reson. Imaging 2018. © 2018 International Society for Magnetic Resonance in Medicine.

Automated scoring of regional lung perfusion in children from contrast enhanced 3D MRI

NASA Astrophysics Data System (ADS)

Heimann, Tobias; Eichinger, Monika; Bauman, Grzegorz; Bischoff, Arved; Puderbach, Michael; Meinzer, Hans-Peter

2012-03-01

MRI perfusion images give information about regional lung function and can be used to detect pulmonary pathologies in cystic fibrosis (CF) children. However, manual assessment of the percentage of pathologic tissue in defined lung subvolumes features large inter- and intra-observer variation, making it difficult to determine disease progression consistently. We present an automated method to calculate a regional score for this purpose. First, lungs are located based on thresholding and morphological operations. Second, statistical shape models of left and right children's lungs are initialized at the determined locations and used to precisely segment morphological images. Segmentation results are transferred to perfusion maps and employed as masks to calculate perfusion statistics. An automated threshold to determine pathologic tissue is calculated and used to determine accurate regional scores. We evaluated the method on 10 MRI images and achieved an average surface distance of less than 1.5 mm compared to manual reference segmentations. Pathologic tissue was detected correctly in 9 cases. The approach seems suitable for detecting early signs of CF and monitoring response to therapy.

[Comparative studies on toxicity of various dielectrics, petroleum derivatives, used in electroerosion technology. IV. Morphological and cytoenzymatic changes in the lungs and acid-base imbalance in rats chronically exposed to petroleum hydrocarbons].

PubMed

Starek, A; Kamiński, M

1981-01-01

In rats exposed to odourless kerosene of 75 and 300 mg/m3 concentration, for 14 weeks, morphologic and cytoenzymatic examinations of lungs have been carried out and acid-base equilibrium indices in blood have been determined. Passive congestion of lung parenchyma, subpleural blood extravasation, atelectasis foci, thickened interalveolar septa with infiltrates from neutrophils, lymphocytes, eosinophils and macrophages have been found. In addition a decrease in succinic dehydrogenase activity, NADPH -- tetrazolium reductase, and Mg++-ATP-ase and increase in acid phosphatase activity have been revealed. Those have been focal changes, involving, apart from bronchial tree (low exposure -- 75 mg/m3), the remaining lung parenchyma segments (high exposure -- 300 mg/m3). In addition, disturbances in acid-base equilibrium in form of compensated metabolic alkalosis (75 mg/m3) and compensated metabolic acidosis (300 mg/m3) have occurred. The obtained results demonstrate toxic effects of kerosene hydrocarbons on the function and structure of lungs.

Computerized analysis of cytology and fluorescence in situ hybridization (FISH) in induced sputum for lung cancer detection.

PubMed

Guber, Alexander; Greif, Joel; Rona, Roni; Fireman, Elizabeth; Madi, Lea; Kaplan, Tal; Yemini, Zipi; Gottfried, Maya; Katz, Ruth L; Daniely, Michal

2010-10-25

Lung cancer results from a multistep process, whereby genetic and epigenetic alterations lead to a malignant phenotype. Somatic mutations, deletions, and amplifications can be detected in the tumor itself, but they can also be found in histologically normal bronchial epithelium as a result of field cancerization. The present feasibility study describes a computer-assisted analysis of induced sputum employing morphology and fluorescence in situ hybridization (target-FISH), using 2 biomarkers located at chromosomes 3p22.1 and 10q22.3. Induced sputum samples were collected using a standardized protocol from 12 patients with lung cancer and from 15 healthy, nonsmoking controls. We used an automated scanning system that allows consecutive scans of morphology and FISH of the same slide. Cells derived for the lower airways were analyzed for the presence of genetic alterations in the 3p22.1 and 10q22.3 loci. The cutoff for a positive diagnosis was defined as >4% of cells showing genetic alterations. Eleven of 12 lung cancer patients and 12 of 15 controls were identified correctly, giving an overall sensitivity and specificity of 91.66% and 80%, respectively. This study describes a new technology for detecting lung cancer noninvasively in induced sputum via a combination of morphology and FISH analysis (target-FISH) using computer-assisted technology. This approach may potentially be utilized for mass screening of high-risk populations. © 2010 American Cancer Society.

Quantitative relation between emphysema and lung mineral content in coalworkers.

PubMed Central

Leigh, J; Driscoll, T R; Cole, B D; Beck, R W; Hull, B P; Yang, J

1994-01-01

The relation between quantified emphysema and measured lung content of coal and silica was investigated in the lungs of 264 deceased underground coalworkers who had been exposed to mixed coal and silica dust. Lung specimens obtained at postmortem and inflated and fixed under standard conditions were used to quantify the extent of emphysema and then to measure the amount of coal and silica present in the lungs at the time of death. These data were combined with clinical and other pathological information from the subjects. Multiple regression analysis showed that the extent of emphysema (E score) had a strong positive quantitative relation with coal content of the lungs (p < 0.0003), age (p < 0.0001), and smoking (p < 0.0001). There was a significant negative interaction of uncertain biological importance between coal content of the lungs and smoking (p < 0.004; E score = -1.79 + 0.62 coal + 0.06 age + 0.21 smoking -0.17 coal x smoking; adjusted R2 = 0.25). In lifelong non-smokers emphysema was particularly strongly related to coal content and age (coal: p < 0.001; age: p < 0.002; E score = -1.56 + 0.78 coal + 0.06 age; adjusted R2 = 0.66). The relation was basically unchanged by adding a lung silica content term. Emphysema score was highly negatively correlated with forced expiratory volume in one second (FEV1; % predicted, obtained within five years of death) (r = -0.44, p < 0.0001). Degree of lung fibrosis was highly positively associated with lung silica content (chi 2(1) = 12.9, p < 0.0003). These results provide strong evidence that emphysema in coalworkers is actually related to lung coal content. The role silica in development of emphysema, however remains unclear. PMID:8044232

Structural Development, Cellular Differentiation and Proliferation of the Respiratory Epithelium in the Bovine Fetal Lung.

PubMed

Drozdowska, J; Cousens, C; Finlayson, J; Collie, D; Dagleish, M P

2016-01-01

Fetal bovine lung samples of 11 different gestational ages were assigned to a classical developmental stage based on histological morphology. Immunohistochemistry was used to characterize the morphology of forming airways, proliferation rate of airway epithelium and the presence of epithelial cell types (i.e. ciliated cells, club cells, neuroepithelial cells (NECs) and type II pneumocytes). Typical structural organization of pseudoglandular (84-98 days gestational age [DGA]), canalicular (154-168 DGA) and alveolar (224-266 DGA) stages was recognized. In addition, transitional pseudoglandular-canalicular (112-126 DGA) and canalicular-saccular (182 DGA) morphologies were present. The embryonic stage was not observed. A significantly (P <0.05) higher proliferation rate of pulmonary epithelium, on average 5.5% and 4.4% in bronchi and bronchioles, respectively, was present in the transitional pseudoglandular-canalicular phase (112-126 DGA) compared with all other phases, while from 8 weeks before term (224-266 DGA) proliferation had almost ceased. The first epithelial cells identified by specific marker proteins in the earliest samples available for study (84 DGA) were ciliated cells and NECs. Club cells were present initially at 112 DGA and type II pneumocytes at 224 DGA. At the latest time points (224-226 DGA) these latter cell types were still present at a much lower percentage compared with adult cattle. This study characterized bovine fetal lung development by histological morphology and cellular composition of the respiratory epithelium and suggests that the apparent structural anatomical maturity of the bovine lung at term is not matched by functional maturity of the respiratory epithelium. Copyright © 2015 Elsevier Ltd. All rights reserved.

Biological effects of short-term, high-concentration exposure to methyl isocyanate. V. Morphologic evaluation of rat and guinea pig lungs

DOE Office of Scientific and Technical Information (OSTI.GOV)

Fowler, E.H.; Dodd, D.E.; Troup, C.M.

1987-06-01

The morphologic changes induced in the lungs of rats and guinea pigs exposed to high concentrations of MIC vapor (100, 600, and 1000 ppm in the rat and 25, 125, 225, and 675 ppm in the guinea pig) for a short time (15 min) in a static exposure chamber were evaluated at varying postexposure periods (0, 1, 2, and 4, and 16 hr). The 675 ppm-exposed guinea pigs were evaluated only immediately following removal from the chamber. Attention was primarily focused on the intrapulmonary conducting airways and the parenchyma (gas exchange region) of the lungs. The severity of morphologic changesmore » observed by light microscopy was directly correlated with exposure concentration and time postexposure in both species. Specifically, degenerative changes were observed in the bronchial, bronchiolar, and alveolar epithelium in both species. Quantitative differences were observed; 100 ppm of MIC in the rat resulted in much less damage than did 125 ppm of MIC in the guinea pig. Morphologic evidence of sloughing of large sheets of conducting airway epithelium with fibrin buildup and increased mucus production resulted in plugging of major airways and atelectasis. These observations support the hypothesis that tissue hypoxia was a major contributing factor resulting in death.« less

Quantifying EGFR alterations in the lung cancer genome with nanofluidic digital PCR arrays.

PubMed

Wang, Jun; Ramakrishnan, Ramesh; Tang, Zhe; Fan, Weiwen; Kluge, Amy; Dowlati, Afshin; Jones, Robert C; Ma, Patrick C

2010-04-01

The EGFR [epidermal growth factor receptor (erythroblastic leukemia viral (v-erb-b) oncogene homolog, avian)] gene is known to harbor genomic alterations in advanced lung cancer involving gene amplification and kinase mutations that predict the clinical response to EGFR-targeted inhibitors. Methods for detecting such molecular changes in lung cancer tumors are desirable. We used a nanofluidic digital PCR array platform and 16 cell lines and 20 samples of genomic DNA from resected tumors (stages I-III) to quantify the relative numbers of copies of the EGFR gene and to detect mutated EGFR alleles in lung cancer. We assessed the relative number of EGFR gene copies by calculating the ratio of the number of EGFR molecules (measured with a 6-carboxyfluorescein-labeled Scorpion assay) to the number of molecules of the single-copy gene RPP30 (ribonuclease P/MRP 30kDa subunit) (measured with a 6-carboxy-X-rhodamine-labeled TaqMan assay) in each panel. To assay for the EGFR L858R (exon 21) mutation and exon 19 in-frame deletions, we used the ARMS and Scorpion technologies in a DxS/Qiagen EGFR29 Mutation Test Kit for the digital PCR array. The digital array detected and quantified rare gefitinib/erlotinib-sensitizing EGFR mutations (0.02%-9.26% abundance) that were present in formalin-fixed, paraffin-embedded samples of early-stage resectable lung tumors without an associated increase in gene copy number. Our results also demonstrated the presence of intratumor molecular heterogeneity for the clinically relevant EGFR mutated alleles in these early-stage lung tumors. The digital PCR array platform allows characterization and quantification of oncogenes, such as EGFR, at the single-molecule level. Use of this nanofluidics platform may provide deeper insight into the specific roles of clinically relevant kinase mutations during different stages of lung tumor progression and may be useful in predicting the clinical response to EGFR-targeted inhibitors.

Lungeing on hard and soft surfaces: Movement symmetry of trotting horses considered sound by their owners.

PubMed

Pfau, T; Jennings, C; Mitchell, H; Olsen, E; Walker, A; Egenvall, A; Tröster, S; Weller, R; Rhodin, M

2016-01-01

Lungeing is often part of the clinical lameness examination. The difference in movement symmetry, which is a commonly employed lameness measure, has not been quantified between surfaces. To compare head and pelvic movement symmetry between surfaces and reins during lungeing. Quantitative gait analysis in 23 horses considered sound by their owners. Twenty-three horses were assessed in-hand and on the lunge on both reins on hard and soft surfaces with inertial sensors. Seven movement symmetry parameters were quantified and used to establish 2 groups, namely symmetrical (n = 9) and forelimb-lame horses (n = 14), based on values from straight-line assessment. Movement symmetry values for left rein measurements were side corrected to allow comparison of the amount of movement symmetry between reins. A mixed model (P<0.05) was used to study effects on movement symmetry of surface (hard/soft) and rein (inside/outside with respect to movement symmetry on the straight). In forelimb-lame horses, surface and rein were identified as significantly affecting all head movement symmetry measures (rein, all P<0.0001; surface, all P<0.042). In the symmetrical group, no significant influence of surface or rein was identified for head movement symmetry (rein, all P>0.245; surface, all P>0.073). No significant influence of surface or rein was identified for any of the pelvic movement symmetry measures in either group. While more symmetrical horses showed a consistent amount of movement symmetry across surfaces/reins, horses objectively quantified as lame on the straight showed decreased movement symmetry during lungeing, in particular with the lame limb on the inside of a hard circle. The variation within group questions straight-line movement symmetry as a sole measure of lameness without quantification of movement symmetry on the lunge, ideally on hard and soft surfaces to evaluate differences between reins and surfaces. In future, thresholds for lungeing need to be determined using simultaneous visual and objective assessment. © 2014 EVJ Ltd.

Intercellular Adhesion Molecule 1 Knockout Abrogates Radiation Induced Pulmonary Inflammation

NASA Astrophysics Data System (ADS)

Hallahan, Dennis E.; Virudachalam, Subbulakshmi

1997-06-01

Increased expression of intercellular adhesion molecule 1 (ICAM-1; CD54) is induced by exposure to ionizing radiation. The lung was used as a model to study the role of ICAM-1 in the pathogenesis of the radiation-induced inflammation-like response. ICAM-1 expression increased in the pulmonary microvascular endothelium and not in the endothelium of larger pulmonary vessels following treatment of mice with thoracic irradiation. To quantify radiation-induced ICAM-1 expression, we utilized fluorescence-activated cell sorting analysis of anti-ICAM-1 antibody labeling of pulmonary microvascular endothelial cells from human cadaver donors (HMVEC-L cells). Fluorochrome conjugates and UV microscopy were used to quantify the fluorescence intensity of ICAM in the irradiated lung. These studies showed a dose- and time-dependent increase in ICAM-1 expression in the pulmonary microvascular endothelium. Peak expression occurred at 24 h, while threshold dose was as low as 2 Gy. To determine whether ICAM-1 is required for inflammatory cell infiltration into the irradiated lung, the anti-ICAM-1 blocking antibody was administered by tail vein injection to mice following thoracic irradiation. Inflammatory cells were quantified by immunofluorescence for leukocyte common antigen (CD45). Mice treated with the anti-ICAM-1 blocking antibody showed attenuation of inflammatory cell infiltration into the lung in response to ionizing radiation exposure. To verify the requirement of ICAM-1 in the inflammation-like radiation response, we utilized the ICAM-1 knockout mouse. ICAM-1 was not expressed in the lungs of ICAM-1-deficient mice following treatment with thoracic irradiation. ICAM-1 knockout mice had no increase in the inflammatory cell infiltration into the lung in response to thoracic irradiation. These studies demonstrate a radiation dose-dependent increase in ICAM-1 expression in the pulmonary microvascular endothelium, and show that ICAM-1 is required for inflammatory cell infiltration into the irradiated lung.

Assessment of regional ventilation and deformation using 4D-CT imaging for healthy human lungs during tidal breathing

PubMed Central

Jahani, Nariman; Choi, Jiwoong; Iyer, Krishna; Hoffman, Eric A.

2015-01-01

This study aims to assess regional ventilation, nonlinearity, and hysteresis of human lungs during dynamic breathing via image registration of four-dimensional computed tomography (4D-CT) scans. Six healthy adult humans were studied by spiral multidetector-row CT during controlled tidal breathing as well as during total lung capacity and functional residual capacity breath holds. Static images were utilized to contrast static vs. dynamic (deep vs. tidal) breathing. A rolling-seal piston system was employed to maintain consistent tidal breathing during 4D-CT spiral image acquisition, providing required between-breath consistency for physiologically meaningful reconstructed respiratory motion. Registration-derived variables including local air volume and anisotropic deformation index (ADI, an indicator of preferential deformation in response to local force) were employed to assess regional ventilation and lung deformation. Lobar distributions of air volume change during tidal breathing were correlated with those of deep breathing (R2 ≈ 0.84). Small discrepancies between tidal and deep breathing were shown to be likely due to different distributions of air volume change in the left and the right lungs. We also demonstrated an asymmetric characteristic of flow rate between inhalation and exhalation. With ADI, we were able to quantify nonlinearity and hysteresis of lung deformation that can only be captured in dynamic images. Nonlinearity quantified by ADI is greater during inhalation, and it is stronger in the lower lobes (P < 0.05). Lung hysteresis estimated by the difference of ADI between inhalation and exhalation is more significant in the right lungs than that in the left lungs. PMID:26316512

Defective parasympathetic innervation is associated with airway branching abnormalities in experimental CDH

PubMed Central

Rhodes, Julie; Saxena, Deeksha; Zhang, GuangFeng; Gittes, George K.

2015-01-01

Developmental mechanisms leading to lung hypoplasia in congenital diaphragmatic hernia (CDH) remain poorly defined. Pulmonary innervation is defective in the human disease and in the rodent models of CDH. We hypothesize that defective parasympathetic innervation may contribute to airway branching abnormalities and, therefore, lung hypoplasia, during lung development in CDH. The murine nitrofen model of CDH was utilized to study the effect of the cholinergic agonist carbachol on embryonic day 11.5 (E11.5) lung explant cultures. Airway branching and contractions were quantified. In a subset of experiments, verapamil was added to inhibit airway contractions. Sox9 immunostaining and 5-bromo-2-deoxyuridine incorporation were used to identify and quantify the number and proliferation of distal airway epithelial progenitor cells. Intra-amniotic injections were used to determine the in vivo effect of carbachol. Airway branching and airway contractions were significantly decreased in nitrofen-treated lungs compared with controls. Carbachol resulted in increased airway contractions and branching in nitrofen-treated lungs. Nitrofen-treated lungs exhibited an increased number of proliferating Sox9-positive distal epithelial progenitor cells, which were decreased and normalized by treatment with carbachol. Verapamil inhibited the carbachol-induced airway contractions in nitrofen-treated lungs but had no effect on the carbachol-induced increase in airway branching, suggesting a direct carbachol effect independent of airway contractions. In vivo treatment of nitrofen-treated embryos via amniotic injection of carbachol at E10.5 resulted in modest increases in lung size and branching at E17.5. These results suggest that defective parasympathetic innervation may contribute to airway branching abnormalities in CDH. PMID:25934671

Morphological and ultrastructural evaluation of the golden retriever muscular dystrophy trachea, lungs, and diaphragm muscle.

PubMed

Lessa, Thais Borges; de Abreu, Dilayla Kelly; Rodrigues, Márcio Nogueira; Brólio, Marina Pandolphi; Miglino, Maria Angélica; Ambrósio, Carlos Eduardo

2014-11-01

Duchenne muscular dystrophy (DMD) is a genetic disease, characterized by atrophy and muscle weakness. The respiratory failure is a common cause of early death in patients with DMD. Golden retriever muscular dystrophy (GRMD) is a canine model which has been extensively used for many advances in therapeutics applications. As the patients with DMD, the GRMD frequently died from cardiac and respiratory failure. Observing the respiratory failure in DMD is one of the major causes of mortality we aimed to describe the morphological and ultrastructural data of trachea, lungs (conductive and respiratory portion of the system), and diaphragm muscle using histological and ultrastructural analysis. The diaphragm muscle showed discontinuous fibers architecture, with different diameter; a robust perimysium inflammatory infiltrate and some muscle cells displayed central nuclei. GRMD trachea and lungs presented collagen fibers and in addition, the GRMD lungs showed higher of levels collagen fibers that could limit the alveolar ducts and alveoli distension. Therefore, the most features observed were the collagen areas and fibrosis. We suggested in this study that the collagen remodeling in the trachea, lungs, and diaphragm muscle may increase fibrosis and affect the trachea, lungs, and diaphragm muscle function that can be a major cause of respiratory failure that occur in patients with DMD. © 2014 Wiley Periodicals, Inc.

Lung function imaging methods in Cystic Fibrosis pulmonary disease.

PubMed

Kołodziej, Magdalena; de Veer, Michael J; Cholewa, Marian; Egan, Gary F; Thompson, Bruce R

2017-05-17

Monitoring of pulmonary physiology is fundamental to the clinical management of patients with Cystic Fibrosis. The current standard clinical practise uses spirometry to assess lung function which delivers a clinically relevant functional readout of total lung function, however does not supply any visible or localised information. High Resolution Computed Tomography (HRCT) is a well-established current 'gold standard' method for monitoring lung anatomical changes in Cystic Fibrosis patients. HRCT provides excellent morphological information, however, the X-ray radiation dose can become significant if multiple scans are required to monitor chronic diseases such as cystic fibrosis. X-ray phase-contrast imaging is another emerging X-ray based methodology for Cystic Fibrosis lung assessment which provides dynamic morphological and functional information, albeit with even higher X-ray doses than HRCT. Magnetic Resonance Imaging (MRI) is a non-ionising radiation imaging method that is garnering growing interest among researchers and clinicians working with Cystic Fibrosis patients. Recent advances in MRI have opened up the possibilities to observe lung function in real time to potentially allow sensitive and accurate assessment of disease progression. The use of hyperpolarized gas or non-contrast enhanced MRI can be tailored to clinical needs. While MRI offers significant promise it still suffers from poor spatial resolution and the development of an objective scoring system especially for ventilation assessment.

Effects of alpha-tocopherol treatment on newborn rat lung development and injury in hyperoxia.

PubMed

Bucher, J R; Roberts, R J

1982-01-01

The efficacy of alpha-tocopherol treatment to influence the pattern or extent of lung injury resulting during exposure of newborn rats to hyperoxia was assessed following six-day exposures to FIO2 0.21, 0.4, and greater than 0.95. Alpha-Tocopherol treatment was found incapable of preventing the developmental arrest of the lung that occurs during hyperoxic exposure, shown by assessments of wet lung weights, lung DNA, lung volumes, and the progress of secondary septal and capillary development. However alpha-tocopherol treatment was found effective in preventing the hyperoxic-induced lessening of lung compliance and in preventing the deterioration of gas exchange capacity in the lung of the hyperoxic-exposed newborn rat. These findings suggest alpha-tocopherol treatment may not be capable of preventing major alterations in lung morphology in infants with chronic lung disease may be lessened by preserving gas exchange capabilities.

[The mechanism of docetaxel-induced apoptosis in human lung cancer cells].

PubMed

Li, Y; Shi, T; Zhao, W

2000-05-01

To study the mechanism of docetaxel-induced apoptosis. Morphological study, DNA gel electrophoresis, flow cytometry and fluorescin labeled Annexin V to detect apoptosis, RT-PCR to detect the gene related with apoptosis. Human lung cancer A549 cells treated with docetaxel induced cell cycle arrest at G2M phase, leading to apoptosis. The morphology of A549 showed nuclear chromatine condensation and fragmentation. Typical ladder pattern of DNA fragmentation was observed. Sub-G1 peak was found by flow cytometry. Transcription of Fas gene was enhanced, while no change in c-myc and bcl-2 genes. Annexin labeling results revealed the co-existence of cell apoptosis and necrosis in docetaxel-treated A549 cells. Docetaxel induces apoptosis and necrosis of human lung cancer. The induction of apoptosis may be related to expression of Fas.

Morphology of the Oligoryzomys nigripes respiratory system.

PubMed

Mario, Lara Carolina; Borghesi, Jéssica; G Hayashi, Rafael; O Favaron, Phelipe; N Rodrigues, Marcio; C Carvalho, Rafael; Miglino, Maria A

2018-06-04

Rodents are important in the transmission of infectious diseases that affect the respiratory tract, including simple infections and those caused by specific pathogens. These animals are natural reservoirs of zoonoses that cause many public health diseases. Basic knowledge on the morphology of these animals is important as basic research is useful for applied studies, such as the development of clinical, therapeutic, surgical and clinical models. Morphological data of respiratory tract in Oligoryzomys nigripes are absent in the literature. Therefore, the aim of this study was to perform a morphological analysis of the respiratory tract of O. nigripes. Five adult females from the environmental reserve in São Joaquim da Barra, São Paulo were used, donated to the Museum of Veterinary Anatomy (FMVZ/USP). Several morphological features follow the same pattern seen in rodents; however, this species showed some differences such as the presence of three lobar bronchi, nonlobed left lung and the right lung constituted by two lobes. Respiratory epithelium lined the whole respiratory tract and was seen using scanning electron microscopy the oval shape of the parenchyma and alveoli. © 2018 Blackwell Verlag GmbH.

A semi-automatic technique to quantify complex tuberculous lung lesions on 18F-fluorodeoxyglucose positron emission tomography/computerised tomography images.

PubMed

Malherbe, Stephanus T; Dupont, Patrick; Kant, Ilse; Ahlers, Petri; Kriel, Magdalena; Loxton, André G; Chen, Ray Y; Via, Laura E; Thienemann, Friedrich; Wilkinson, Robert J; Barry, Clifton E; Griffith-Richards, Stephanie; Ellman, Annare; Ronacher, Katharina; Winter, Jill; Walzl, Gerhard; Warwick, James M

2018-06-25

There is a growing interest in the use of 18 F-FDG PET-CT to monitor tuberculosis (TB) treatment response. However, TB causes complex and widespread pathology, which is challenging to segment and quantify in a reproducible manner. To address this, we developed a technique to standardise uptake (Z-score), segment and quantify tuberculous lung lesions on PET and CT concurrently, in order to track changes over time. We used open source tools and created a MATLAB script. The technique was optimised on a training set of five pulmonary tuberculosis (PTB) cases after standard TB therapy and 15 control patients with lesion-free lungs. We compared the proposed method to a fixed threshold (SUV > 1) and manual segmentation by two readers and piloted the technique successfully on scans of five control patients and five PTB cases (four cured and one failed treatment case), at diagnosis and after 1 and 6 months of treatment. There was a better correlation between the Z-score-based segmentation and manual segmentation than SUV > 1 and manual segmentation in terms of overall spatial overlap (measured in Dice similarity coefficient) and specificity (1 minus false positive volume fraction). However, SUV > 1 segmentation appeared more sensitive. Both the Z-score and SUV > 1 showed very low variability when measuring change over time. In addition, total glycolytic activity, calculated using segmentation by Z-score and lesion-to-background ratio, correlated well with traditional total glycolytic activity calculations. The technique quantified various PET and CT parameters, including the total glycolytic activity index, metabolic lesion volume, lesion volumes at different CT densities and combined PET and CT parameters. The quantified metrics showed a marked decrease in the cured cases, with changes already apparent at month one, but remained largely unchanged in the failed treatment case. Our technique is promising to segment and quantify the lung scans of pulmonary tuberculosis patients in a semi-automatic manner, appropriate for measuring treatment response. Further validation is required in larger cohorts.

Diffuse Alveolar Damage: A Common Phenomenon in Progressive Interstitial Lung Disorders

PubMed Central

Kaarteenaho, Riitta; Kinnula, Vuokko L.

2011-01-01

It has become obvious that several interstitial lung diseases, and even viral lung infections, can progress rapidly, and exhibit similar features in their lung morphology. The final histopathological feature, common in these lung disorders, is diffuse alveolar damage (DAD). The histopathology of DAD is considered to represent end stage phenomenon in acutely behaving interstitial pneumonias, such as acute interstitial pneumonia (AIP) and acute exacerbations of idiopathic pulmonary fibrosis (IPF). Acute worsening and DAD may occur also in patients with nonspecific interstitial pneumonias (NSIPs), and even in severe viral lung infections where there is DAD histopathology in the lung. A better understanding of the mechanisms underlying the DAD reaction is needed to clarify the treatment for these serious lung diseases. There is an urgent need for international efforts for studying DAD-associated lung diseases, since the prognosis of these patients has been and is still dismal. PMID:21637367

Amebic lung abscess with coexisting lung adenocarcinoma: a unusual case of amebiasis.

PubMed

Zhu, Hailong; Min, Xiangyang; Li, Shuai; Feng, Meng; Zhang, Guofeng; Yi, Xianghua

2014-01-01

Amebic lung abscess with concurrent lung cancer, but without either a liver abscess or amebic colitis, is extremely uncommon. Here, we report a 70-year-old man presenting with pulmonary amebiasis and coexisting lung adenocarcinoma. During his first-time hospitalization, the diagnosis of lung amebiasis was confirmed by morphological observation and PCR in formalin-fixed and paraffin-embedded sediments of pleural effusion. Almost four months later, the patient was readmitted to hospital for similar complaints. On readmission, lung adenocarcinoma was diagnosed by liquid-based sputum cytology and thought to be delayed because coexisting amebic lung abscess. This case demonstrated that sediments of pleural effusion may be used for further pathological examination after routine cytology has shown negative results. At the same time, we concluded that lung cancer may easily go undetected in the patients with pulmonary amebiasis and repetitive evaluation by cytology and imaging follow-up are useful to find potential cancer.

Amebic lung abscess with coexisting lung adenocarcinoma: a unusual case of amebiasis

PubMed Central

Zhu, Hailong; Min, Xiangyang; Li, Shuai; Feng, Meng; Zhang, Guofeng; Yi, Xianghua

2014-01-01

Amebic lung abscess with concurrent lung cancer, but without either a liver abscess or amebic colitis, is extremely uncommon. Here, we report a 70-year-old man presenting with pulmonary amebiasis and coexisting lung adenocarcinoma. During his first-time hospitalization, the diagnosis of lung amebiasis was confirmed by morphological observation and PCR in formalin-fixed and paraffin-embedded sediments of pleural effusion. Almost four months later, the patient was readmitted to hospital for similar complaints. On readmission, lung adenocarcinoma was diagnosed by liquid-based sputum cytology and thought to be delayed because coexisting amebic lung abscess. This case demonstrated that sediments of pleural effusion may be used for further pathological examination after routine cytology has shown negative results. At the same time, we concluded that lung cancer may easily go undetected in the patients with pulmonary amebiasis and repetitive evaluation by cytology and imaging follow-up are useful to find potential cancer. PMID:25550881

Importance of the lung perfusion scintigraphy in single lung transplantation.

PubMed

Rodríguez Mesa, N V; Guerrero Cancio, M C; Cordero Jiménez, M D; Alvarez Velázquez, I K

2012-01-01

Lung perfusion scintigraphy (LPS) with (99m)Tc-MAA gives valuable information about patients who will undergo a single lung transplantation. This technique makes it possible to evaluate and quantify the relative function of both lungs to select the organ to be transplanted. Once the surgery has been performed, the LPS represents a diagnostic method to study the status of the transplanted organ. Two patients who underwent single lung transplantation were studied in our hospital. In both cases, a pre-operative LPS was performed before surgery for selection of the organ to be transplanted and the scintigraphy study was performed a few months after transplantation to establish the perfusion function of the transplanted lung. Copyright © 2011 Elsevier España, S.L. y SEMNIM. All rights reserved.

Acute Depletion of Diacylglycerol from the Cis-Golgi Affects Localised Nuclear Envelope Morphology During Mitosis.

PubMed

Chung, Gary Hong Chun; Domart, Marie Charlotte; Peddie, Christopher; Mantell, Judith; Mclaverty, Kieran; Arabiotorre, Angela; Hodgson, Lorna; Byrne, Richard D; Verkade, Paul; Arkill, Kenton; Collinson, Lucy M; Larijani, Banafshe

2018-06-12

Dysregulation of nuclear envelope (NE) assembly results in various cancers; for example, renal and some lung carcinomas ensue due to NE malformation. The NE is a dynamic membrane compartment and its completion during mitosis, is a highly regulated process but the detailed mechanism still remains incompletely understood. Previous studies have found isolated diacylglycerol (DAG) containing vesicles are essential for completing the fusion of NE in non-somatic cells. We investigated the impact of DAG depletion from cis-Golgi in mammalian cells on NE reassembly. Using advanced electron microscopy, we observed an enriched DAG population of vesicles at the vicinity of the NE gaps of telophase mammalian cells. We applied a miniSOG-C1-domain tag that localized DAG-enriched vesicles at the perinuclear region, which suggested the existence of NE fusogenic vesicles. We quantified the impact of Golgi-DAG depletion by measuring the in situ NE rim curvature of the re-forming NE. The rim curvature in these cells was significantly reduced compared with controls, which indicated a localized defect in NE morphology. Our novel results demonstrate the significance of the role of DAG from cis-Golgi for the regulation of NE assembly. Published under license by The American Society for Biochemistry and Molecular Biology, Inc.

Methylene Blue Attenuates Lung Injury Induced by Hindlimb Ischemia Reperfusion in Rats

PubMed Central

Wang, Liangrong; Chen, Baihui; Lin, Bi; Ye, Yuzhu; Bao, Caiying; Zhao, Xiyue; Jin, Lida

2018-01-01

Objective This study was aimed to investigate the protective effect of methylene blue against lung injury induced by reperfusion of ischemic hindlimb in a rat model. Methods Twenty-four healthy adult male Sprague-Dawley rats were equally randomized into three groups: sham (SM) group, ischemia reperfusion (IR) group, and methylene blue (MB) group. Rats in both IR and MB groups were subjected to 4 h of ischemia by clamping the left femoral artery and then followed by 4 h of reperfusion. Treatment with 1% methylene blue (50 mg/kg) was administrated intraperitoneally at 10 min prior to reperfusion in the MB group. After 4 h of reperfusion, malondialdehyde (MDA) level, myeloperoxidase (MPO), and superoxide dismutase (SOD) activities in lung tissue were detected; inflammatory cytokines, including IL-1β and IL-6, were measured in bronchoalveolar lavage fluid (BALF); correspondingly, the morphological changes and water content in both gastrocnemius muscle and lung samples were evaluated. Results Hindlimb IR caused remarkable morphological abnormalities and edema in both muscle and lung tissues. SOD activity was decreased, both the MPO activity and MDA level in lung tissue, as well as IL-1β and IL-6 levels in BALF, were increased in the IR group (p < 0.05). Compared with the IR group, SOD activity was increased, whereas MPO activity and MDA level in lung tissue and IL-1β and IL-6 levels in BALF were decreased in the MB group (p < 0.05). Also, the histological damage and edema in both lung and muscle tissues were significantly attenuated by the treatment of methylene blue. Conclusion Methylene blue attenuates lung injury induced by hindlimb IR in rats, at least in part, by inhibiting oxidative stress. PMID:29713238

Determination of right ventricular ejection fraction in children with cystic fibrosis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Piepsz, A.; Ham, H.R.; Millet, E.

1987-01-01

The radionuclide right ventricular ejection fraction (RVEF) determined by means of Krypton-81m represents a simple, noninvasive, and accurate procedure to quantify the right ventricular contractility. This procedure was applied to 25 young patients with cystic fibrosis. The RVEF tended to decrease with the progression of the lung disease, as assessed by the clinical S-K score, the degree of the defects on lung scintigraphy, the PaO/sub 2/, and the lung function tests. However, the decrease of RVEF in patients with marked lung function tests. However, the decrease of RVEF in patients with marked lung involvement was moderate, and terminal lung diseasemore » was sometimes associated with normal right heart contractility.« less

Depiction of pneumothoraces in a large animal model using x-ray dark-field radiography.

PubMed

Hellbach, Katharina; Baehr, Andrea; De Marco, Fabio; Willer, Konstantin; Gromann, Lukas B; Herzen, Julia; Dmochewitz, Michaela; Auweter, Sigrid; Fingerle, Alexander A; Noël, Peter B; Rummeny, Ernst J; Yaroshenko, Andre; Maack, Hanns-Ingo; Pralow, Thomas; van der Heijden, Hendrik; Wieberneit, Nataly; Proksa, Roland; Koehler, Thomas; Rindt, Karsten; Schroeter, Tobias J; Mohr, Juergen; Bamberg, Fabian; Ertl-Wagner, Birgit; Pfeiffer, Franz; Reiser, Maximilian F

2018-02-08

The aim of this study was to assess the diagnostic value of x-ray dark-field radiography to detect pneumothoraces in a pig model. Eight pigs were imaged with an experimental grating-based large-animal dark-field scanner before and after induction of a unilateral pneumothorax. Image contrast-to-noise ratios between lung tissue and the air-filled pleural cavity were quantified for transmission and dark-field radiograms. The projected area in the object plane of the inflated lung was measured in dark-field images to quantify the collapse of lung parenchyma due to a pneumothorax. Means and standard deviations for lung sizes and signal intensities from dark-field and transmission images were tested for statistical significance using Student's two-tailed t-test for paired samples. The contrast-to-noise ratio between the air-filled pleural space of lateral pneumothoraces and lung tissue was significantly higher in the dark-field (3.65 ± 0.9) than in the transmission images (1.13 ± 1.1; p = 0.002). In case of dorsally located pneumothoraces, a significant decrease (-20.5%; p > 0.0001) in the projected area of inflated lung parenchyma was found after a pneumothorax was induced. Therefore, the detection of pneumothoraces in x-ray dark-field radiography was facilitated compared to transmission imaging in a large animal model.

Impact of airway morphological changes on pulmonary flows in scoliosis

NASA Astrophysics Data System (ADS)

Farrell, James; Garrido, Enrique; Valluri, Prashant

2016-11-01

The relationship between thoracic deformity in scoliosis and lung function is poorly understood. In a pilot study, we reviewed computed tomography (CT) routine scans of patients undergoing scoliosis surgery. The CT scans were processed to segment the anatomy of the airways, lung and spine. A three-dimensional model was created to study the anatomical relationship. Preliminary analysis showed significant airway morphological differences depending on the anterior position of the spine. A computational fluid dynamics (CFD) study was also conducted on the airway geometry using the inspiratory scans. The CFD model assuming non-compliant airway walls was capable of showing pressure drops in areas of high airway resistance, but was unable to predict regional ventilation differences. Our results indicate a dependence between the dynamic deformation of the airway during breathing and lung function. Dynamic structural deformation must therefore be incorporated within any modelling approaches to guide clinicians on the decision to perform surgical correction of the scoliosis.

Novel CT-based objective imaging biomarkers of long term radiation-induced lung damage.

PubMed

Veiga, Catarina; Landau, David; Devaraj, Anand; Doel, Tom; White, Jared; Ngai, Yenting; Hawkes, David J; McClelland, Jamie R

2018-06-14

and Purpose: Recent improvements in lung cancer survival have spurred an interest in understanding and minimizing long term radiation-induced lung damage (RILD). However, there is still no objective criteria to quantify RILD leading to variable reporting across centres and trials. We propose a set of objective imaging biomarkers to quantify common radiological findings observed 12-months after lung cancer radiotherapy (RT). Baseline and 12-month CT scans of 27 patients from a phase I/II clinical trial of isotoxic chemoradiation were included in this study. To detect and measure the severity of RILD, twelve quantitative imaging biomarkers were developed. These describe basic CT findings including parenchymal change, volume reduction and pleural change. The imaging biomarkers were implemented as semi-automated image analysis pipelines and assessed against visual assessment of the occurrence of each change. The majority of the biomarkers were measurable in each patient. Their continuous nature allows objective scoring of severity for each patient. For each imaging biomarker the cohort was split into two groups according to the presence or absence of the biomarker by visual assessment, testing the hypothesis that the imaging biomarkers were different in these two groups. All features were statistically significant except for rotation of the main bronchus and diaphragmatic curvature. The majority of the biomarkers were not strongly correlated with each other suggesting that each of the biomarkers is measuring a separate element of RILD pathology. We developed objective CT-based imaging biomarkers that quantify the severity of radiological lung damage after RT. These biomarkers are representative of typical radiological findings of RILD. Copyright © 2018. Published by Elsevier Inc.

Boosting CNN performance for lung texture classification using connected filtering

NASA Astrophysics Data System (ADS)

Tarando, Sebastián. Roberto; Fetita, Catalin; Kim, Young-Wouk; Cho, Hyoun; Brillet, Pierre-Yves

2018-02-01

Infiltrative lung diseases describe a large group of irreversible lung disorders requiring regular follow-up with CT imaging. Quantifying the evolution of the patient status imposes the development of automated classification tools for lung texture. This paper presents an original image pre-processing framework based on locally connected filtering applied in multiresolution, which helps improving the learning process and boost the performance of CNN for lung texture classification. By removing the dense vascular network from images used by the CNN for lung classification, locally connected filters provide a better discrimination between different lung patterns and help regularizing the classification output. The approach was tested in a preliminary evaluation on a 10 patient database of various lung pathologies, showing an increase of 10% in true positive rate (on average for all the cases) with respect to the state of the art cascade of CNNs for this task.

Three-dimensional visualization of morphology and ventilation procedure (air flow and diffusion) of a subdivision of the acinus using synchrotron radiation microtomography of the human lung specimens

NASA Astrophysics Data System (ADS)

Shimizu, Kenji; Ikura, Hirohiko; Ikezoe, Junpei; Nagareda, Tomofumi; Yagi, Naoto; Umetani, Keiji; Imai, Yutaka

2004-04-01

We have previously reported a synchrotron radiation (SR) microtomography system constructed at the bending magnet beamline at the SPring-8. This system has been applied to the lungs obtained at autopsy and inflated and fixed by Heitzman"s method. Normal lung and lung specimens with two different types of pathologic processes (fibrosis and emphysema) were included. Serial SR microtomographic images were stacked to yield the isotropic volumetric data with high-resolution (12 μm3 in voxel size). Within the air spaces of a subdivision of the acinus, each voxel is segmented three-dimensionally using a region growing algorithm ("rolling ball algorithm"). For each voxel within the segmented air spaces, two types of voxel coding have been performed: single-seeded (SS) coding and boundary-seeded (BS) coding, in which the minimum distance from an initial point as the only seed point and all object boundary voxels as a seed set were calculated and assigned as the code values to each voxel, respectively. With these two codes, combinations of surface rendering and volume rendering techniques were applied to visualize three-dimensional morphology of a subdivision of the acinus. Furthermore, sequentially filling process of air into a subdivision of the acinus was simulated under several conditions to visualize the ventilation procedure (air flow and diffusion). A subdivision of the acinus was reconstructed three-dimensionally, demonstrating the normal architecture of the human lung. Significant differences in appearance of ventilation procedure were observed between normal and two pathologic processes due to the alteration of the lung architecture. Three-dimensional reconstruction of the microstructure of a subdivision of the acinus and visualization of the ventilation procedure (air flow and diffusion) with SR microtomography would offer a new approach to study the morphology, physiology, and pathophysiology of the human respiratory system.

MRI of the lung: state of the art.

PubMed

Wielpütz, Mark; Kauczor, Hans-Ulrich

2012-01-01

Magnetic resonance imaging (MRI) of the lung is technically challenging due to the low proton density and fast signal decay of the lung parenchyma itself. Additional challenges consist of tissue loss, hyperinflation, and hypoxic hypoperfusion, e.g., in emphysema, a so-called "minus-pathology". However, pathological changes resulting in an increase of tissue ("plus-pathology"), such as atelectases, nodules, infiltrates, mucus, or pleural effusion, are easily depicted with high diagnostic accuracy. Although MRI is inferior or at best equal to multi-detector computed tomography (MDCT) for the detection of subtle morphological features, MRI now offers an increasing spectrum of functional imaging techniques such as perfusion assessment and measurement of ventilation and respiratory mechanics that are superior to what is possible with MDCT. Without putting patients at risk with ionizing radiation, repeated examinations allow for the evaluation of the course of lung disease and monitoring of the therapeutic response through quantitative imaging, providing a level of functional detail that cannot be obtained by any other single imaging modality. As such, MRI will likely be used for clinical applications beyond morphological imaging for many lung diseases. In this article, we review the technical aspects and protocol suggestions for chest MRI and discuss the role of MRI in the evaluation of nodules and masses, airway disease, respiratory mechanics, ventilation, perfusion and hemodynamics, and pulmonary vasculature.

Idiopathic interstitial pneumonias and emphysema: detection and classification using a texture-discriminative approach

NASA Astrophysics Data System (ADS)

Fetita, C.; Chang-Chien, K. C.; Brillet, P. Y.; Pr"teux, F.; Chang, R. F.

2012-03-01

Our study aims at developing a computer-aided diagnosis (CAD) system for fully automatic detection and classification of pathological lung parenchyma patterns in idiopathic interstitial pneumonias (IIP) and emphysema using multi-detector computed tomography (MDCT). The proposed CAD system is based on three-dimensional (3-D) mathematical morphology, texture and fuzzy logic analysis, and can be divided into four stages: (1) a multi-resolution decomposition scheme based on a 3-D morphological filter was exploited to discriminate the lung region patterns at different analysis scales. (2) An additional spatial lung partitioning based on the lung tissue texture was introduced to reinforce the spatial separation between patterns extracted at the same resolution level in the decomposition pyramid. Then, (3) a hierarchic tree structure was exploited to describe the relationship between patterns at different resolution levels, and for each pattern, six fuzzy membership functions were established for assigning a probability of association with a normal tissue or a pathological target. Finally, (4) a decision step exploiting the fuzzy-logic assignments selects the target class of each lung pattern among the following categories: normal (N), emphysema (EM), fibrosis/honeycombing (FHC), and ground glass (GDG). According to a preliminary evaluation on an extended database, the proposed method can overcome the drawbacks of a previously developed approach and achieve higher sensitivity and specificity.

The Creation and Statistical Evaluation of a Deterministic Model of the Human Bronchial Tree from HRCT Images.

PubMed

Montesantos, Spyridon; Katz, Ira; Pichelin, Marine; Caillibotte, Georges

2016-01-01

A quantitative description of the morphology of lung structure is essential prior to any form of predictive modeling of ventilation or aerosol deposition implemented within the lung. The human lung is a very complex organ, with airway structures that span two orders of magnitude and having a multitude of interfaces between air, tissue and blood. As such, current medical imaging protocols cannot provide medical practitioners and researchers with in-vivo knowledge of deeper lung structures. In this work a detailed algorithm for the generation of an individualized 3D deterministic model of the conducting part of the human tracheo-bronchial tree is described. Distinct initial conditions were obtained from the high-resolution computed tomography (HRCT) images of seven healthy volunteers. The algorithm developed is fractal in nature and is implemented as a self-similar space sub-division procedure. The expansion process utilizes physiologically realistic relationships and thresholds to produce an anatomically consistent human airway tree. The model was validated through extensive statistical analysis of the results and comparison of the most common morphological features with previously published morphometric studies and other equivalent models. The resulting trees were shown to be in good agreement with published human lung geometric characteristics and can be used to study, among other things, structure-function relationships in simulation studies.

Chemopreventive effects of NSAIDs as inhibitors of cyclooxygenase-2 and inducers of apoptosis in experimental lung carcinogenesis.

PubMed

Setia, Shruti; Vaish, Vivek; Sanyal, Sankar Nath

2012-07-01

Roles of cyclooxygenase (COX) enzyme and intrinsic pathway of apoptosis have been explored for the chemopreventive effects of non-steroidal anti-inflammatory drugs (NSAIDs) on 9,10-dimethyl benz(a)anthracene (DMBA)-induced lung cancer in rat model. 16 weeks after the administration of DMBA, morphological analysis revealed the occurrences of tumours and lesions, which were regressed considerably with the co-administration of indomethacin and etoricoxib, the two NSAIDs under investigation. DMBA group was marked by hyperplasia and dysplasia as observed by histological examination, and these features were corrected to a large extent by the two NSAIDs. Elevated levels of COX-2 were seen in the DMBA group, the enzyme responsible for prostaglandin synthesis during inflammation and cancer, whilst the expression of the constitutive isoform, COX-1, was equally expressed in all the groups. Apoptosis was quantified by studying the activities of apaf-1, caspase-9, and 3 by immunofluorescence and western blots. Their activities were found to diminish in the DMBA-treated animals as compared to the other groups. Fluorescent co-staining of the isolated broncho-alveolar lavage cells showed reduced number of apoptotic cells in the DMBA group, indicating decrease in apoptosis after carcinogen administration. The present results thus suggest that the mechanism of cancer chemoprevention of NSAIDs may include the suppression of COX-2 and the induction of apoptosis.

Effects of PEGylated paclitaxel nanocrystals on breast cancer and its lung metastasis

NASA Astrophysics Data System (ADS)

Zhang, Hua; Hu, Hongxiang; Zhang, Haoran; Dai, Wenbing; Wang, Xinglin; Wang, Xueqing; Zhang, Qiang

2015-06-01

As an attractive strategy developed rapidly in recent years, nanocrystals are used to deliver insoluble drugs. PEGylation may further prolong the circulation time of nanoparticles and improve the therapeutic outcome of drugs. In this study, paclitaxel (PTX) nanocrystals (PTX-NCs) and PEGylated PTX nanocrystals (PEG-PTX-NCs) were prepared using antisolvent precipitation augmented by probe sonication. The characteristics and antitumor efficacy of nanocrystals were investigated. The results indicated that the nanocrystals showed rod-like morphology, and the average particle size was 240 nm and 330 nm for PTX-NCs and PEG-PTX-NCs, respectively. The PEG molecules covered the surface of nanocrystals with an 11.54 nm fixed aqueous layer thickness (FALT), much higher than that of PTX-NCs (0.2 nm). PEG-PTX-NCs showed higher stability than PTX-NCs under both storage and physiological conditions. In breast cancer xenografted mice, PEG-PTX-NCs showed significantly better tumor inhibition compared to saline (p < 0.001) and PTX-NC groups (p < 0.05) after intravenous administration. In a model of lung tumor metastasis quantified by the luciferase activity, the PEG-PTX-NCs group showed higher anticancer efficacy not only than saline and PTX-NCs groups, but also than Taxol®, achieving an 82% reduction at the end of the experiment. These studies suggested the potential advantages of PEGylated PTX nanocrystals as alternative drug delivery systems for anticancer therapy.

Risk factors and survival outcome for non-elective referral in non-small cell lung cancer patients--analysis based on the National Lung Cancer Audit.

PubMed

Beckett, P; Tata, L J; Hubbard, R B

2014-03-01

Survival after diagnosis of lung cancer is poor and seemingly lower in the UK than other Western countries, due in large part to late presentation with advanced disease precluding curative treatment. Recent research suggests that around one-third of lung cancer patients reach specialist care after emergency presentation and have a worse survival outcome. Confirmation of these data and understanding which patients are affected may allow a targeted approach to improving outcomes. We used data from the UK National Lung Cancer Audit in a multivariate logistic regression model to quantify the association of non-elective referral in non-small cell lung cancer patients with covariates including age, sex, stage, performance status, co-morbidity and socioeconomic status and used the Kaplan-Meier method and Cox proportional hazards model to quantify survival by source of referral. In an analysis of 133,530 cases of NSCLC who presented 2006-2011, 19% of patients were referred non-electively (following an emergency admission to hospital or following an emergency presentation to A&E). This route of referral was strongly associated with more advanced disease stage (e.g. in Stage IV - OR: 2.34, 95% CI: 2.14-2.57, p<0.001) and worse performance status (e.g. in PS 4 - OR: 7.28, 95% CI: 6.75-7.86, p<0.001), but was also independently associated with worse socioeconomic status, and extremes of age. These patients were more likely to have died within 1 year of diagnosis (hazard ratio of 1.51 (95% CI: 1.49-1.54) after adjustment for key clinical variables. Our data confirm and quantify poorer survival in lung cancer patients who are referred non-electively to specialist care, which is more common in patients with poorer performance status, higher disease stage and less advantaged socioeconomic status. Work to tackle this late presentation should be urgently accelerated, since its realisation holds the promise of improved outcomes and better healthcare resource utilisation. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

GC-MS/MS Analyses of Biological Samples in Support of Developmental Toxic Effects on Percutaneous Exposure of Rats to VX

DTIC Science & Technology

2016-07-01

of blood, tissues, and organs (heart, lung, liver, kidney , brain, eye, diaphragm, and skin) that were obtained from rats (postnatal days 42 and 70...of blood, tissues, and organs (heart, lung, liver, kidney , brain, eye, and diaphragm) that were used to quantify the amounts of free and regenerated...Biosamples (brain, diaphragm, eye, heart, lung, liver, and kidney ) were collected at time of death or 48 h post-exposure for survivors. All

Lung cells support osteosarcoma cell migration and survival.

PubMed

Yu, Shibing; Fourman, Mitchell Stephen; Mahjoub, Adel; Mandell, Jonathan Brendan; Crasto, Jared Anthony; Greco, Nicholas Giuseppe; Weiss, Kurt Richard

2017-01-25

Osteosarcoma (OS) is the most common primary bone tumor, with a propensity to metastasize to the lungs. Five-year survival for metastatic OS is below 30%, and has not improved for several decades despite the introduction of multi-agent chemotherapy. Understanding OS cell migration to the lungs requires an evaluation of the lung microenvironment. Here we utilized an in vitro lung cell and OS cell co-culture model to explore the interactions between OS and lung cells, hypothesizing that lung cells would promote OS cell migration and survival. The impact of a novel anti-OS chemotherapy on OS migration and survival in the lung microenvironment was also examined. Three human OS cell lines (SJSA-1, Saos-2, U-2) and two human lung cell lines (HULEC-5a, MRC-5) were cultured according to American Type Culture Collection recommendations. Human lung cell lines were cultured in growth medium for 72 h to create conditioned media. OS proliferation was evaluated in lung co-culture and conditioned media microenvironment, with a murine fibroblast cell line (NIH-3 T3) in fresh growth medium as controls. Migration and invasion were measured using a real-time cell analysis system. Real-time PCR was utilized to probe for Aldehyde Dehydrogenase (ALDH1) expression. Osteosarcoma cells were also transduced with a lentivirus encoding for GFP to permit morphologic analysis with fluorescence microscopy. The anti-OS efficacy of Disulfiram, an ALDH-inhibitor previously shown to inhibit OS cell proliferation and metastasis in vitro, was evaluated in each microenvironment. Lung-cell conditioned medium promoted osteosarcoma cell migration, with a significantly higher attractive effect on all three osteosarcoma cell lines compared to basic growth medium, 10% serum containing medium, and NIH-3 T3 conditioned medium (p <0.05). Lung cell conditioned medium induced cell morphologic changes, as demonstrated with GFP-labeled cells. OS cells cultured in lung cell conditioned medium had increased alkaline phosphatase staining. Lung endothelial HULEC-5a cells are attractants for OS cell migration, proliferation, and survival. The SJSA-1 osteosarcoma cell line demonstrated greater metastatic potential than Saos-2 and U-2 cells. ALDH appears to be involved in the interaction between lung and OS cells, and ALP may be a valuable biomarker for monitoring functional OS changes during metastasis.

Comparison of tumor biology of two distinct cell sub-populations in lung cancer stem cells.

PubMed

Wang, Jianyu; Sun, Zhiwei; Liu, Yongli; Kong, Liangsheng; Zhou, Shixia; Tang, Junlin; Xing, Hongmei Rosie

2017-11-14

Characterization of the stem-like properties of cancer stem cells (CSCs) remain indirect and qualitative, especially the ability of CSCs to undergo asymmetric cell division for self renewal and differentiation, a unique property of cells of stem origin. It is partly due to the lack of stable cellular models of CSCs. In this study, we developed a new approach for CSC isolation and purification to derive a CSC-enriched cell line (LLC-SE). By conducting five consecutive rounds of single cell cloning using the LLC-SE cell line, we obtained two distinct sub-population of cells within the Lewis lung cancer CSCs that employed largely symmetric division for self-renewal (LLC-SD) or underwent asymmetric division for differentiation (LLC-ASD). LLC-SD and LLC-ASD cell lines could be stably passaged in culture and be distinguished by cell morphology, stem cell marker, spheroid formation and subcutaneous tumor initiation efficiency, as well as orthotopic lung tumor growth, progression and survival. The ability LLC-ASD cells to undergo asymmetric division was visualized and quantified by the asymmetric segregation of labeled BrdU and NUMB to one of the two daughter cells in anaphase cell division. The more stem-like LLC-SD cells exhibited higher capacity for tumorigenesis and progression and shorter survival. As few as 10 LLC-SD could initiate subcutaneous tumor growth when transplanted to the athymic mice. Collectively, these observations suggest that the SD-type of cells appear to be on the top of the hierarchical order of the CSCs. Furthermore, they have lead to generated cellular models of CSC self-renewal for future mechanistic investigations.

Intensity-Based Registration for Lung Motion Estimation

NASA Astrophysics Data System (ADS)

Cao, Kunlin; Ding, Kai; Amelon, Ryan E.; Du, Kaifang; Reinhardt, Joseph M.; Raghavan, Madhavan L.; Christensen, Gary E.

Image registration plays an important role within pulmonary image analysis. The task of registration is to find the spatial mapping that brings two images into alignment. Registration algorithms designed for matching 4D lung scans or two 3D scans acquired at different inflation levels can catch the temporal changes in position and shape of the region of interest. Accurate registration is critical to post-analysis of lung mechanics and motion estimation. In this chapter, we discuss lung-specific adaptations of intensity-based registration methods for 3D/4D lung images and review approaches for assessing registration accuracy. Then we introduce methods for estimating tissue motion and studying lung mechanics. Finally, we discuss methods for assessing and quantifying specific volume change, specific ventilation, strain/ stretch information and lobar sliding.

Morphological and morphometric specializations of the lung of the Andean goose, Chloephaga melanoptera: A lifelong high-altitude resident.

PubMed

Maina, John N; McCracken, Kevin G; Chua, Beverly; York, Julia M; Milsom, William K

2017-01-01

High altitude flight in rarefied, extremely cold and hypoxic air is a very challenging activity. Only a few species of birds can achieve it. Hitherto, the structure of the lungs of such birds has not been studied. This is because of the rarity of such species and the challenges of preparing well-fixed lung tissue. Here, it was posited that in addition to the now proven physiological adaptations, high altitude flying birds will also have acquired pulmonary structural adaptations that enable them to obtain the large amounts of oxygen (O2) needed for flight at high elevation, an environment where O2 levels are very low. The Andean goose (Chloephaga melanoptera) normally resides at altitudes above 3000 meters and flies to elevations as high as 6000 meters where O2 becomes limiting. In this study, its lung was morphologically- and morphometrically investigated. It was found that structurally the lungs are exceptionally specialized for gas exchange. Atypically, the infundibulae are well-vascularized. The mass-specific volume of the lung (42.8 cm3.kg-1), the mass-specific respiratory surface area of the blood-gas (tissue) barrier (96.5 cm2.g-1) and the mass-specific volume of the pulmonary capillary blood (7.44 cm3.kg-1) were some of the highest values so far reported in birds. The pulmonary structural specializations have generated a mass-specific total (overall) pulmonary morphometric diffusing capacity of the lung for oxygen (DLo2) of 0.119 mlO2.sec-1.mbar-1.kg-1, a value that is among some of the highest ones in birds that have been studied. The adaptations of the lung of the Andean goose possibly produce the high O2 conductance needed to live and fly at high altitude.

Live morphological analysis of taxol-induced cytoplasmic vacuolization [corrected] in human lung adenocarcinoma cells.

PubMed

Wang, Xiao-Ping; Chen, Tong-Sheng; Sun, Lei; Cai, Ji-Ye; Wu, Ming-Qian; Mok, Martin

2008-12-01

Taxol (paclitaxel), one of the most active cancer chemotherapeutic agents, can cause programmed cell death (PCD) and cytoplasmic vacuolization. The objective of this study was to analyze the morphological characteristics induced by taxol. Human lung adenocarcinoma (ASTC-a-1) cells were exposed to various concentration of taxol. CCK-8 was used to assay the cell viability. Atomic force microscopy (AFM), plasmid transfection and confocal fluorescence microscopy were performed to image the cells morphological change induced by taxol. Fluorescence resonance energy transfer (FRET) was used to monitor the caspase-3 activation in living cells during taxol-induced cell death. Cells treated with taxol exhibited significant swelling and cytoplasmic vacuolization which may be due to endoplasmic reticulum (ER) vacuolization. Caspase-3 was not activated during taxol-induced cytoplasmic vacuolization and cell death. These findings suggest that taxol induces caspase-3-independent cytoplasmic vacuolization, cell swelling and cell death through ER vacuolization.

Misidentification of Neosartorya pseudofischeri as Aspergillus fumigatus in a lung transplant patient.

PubMed

Khare, Reeti; Gupta, Sounak; Arif, Sana; Jentoft, Mark E; Deziel, Paul J; Roden, Anja C; Wilhelm, Mark P; Razonable, Raymund R; Wengenack, Nancy L

2014-07-01

We present a case of disseminated Neosartorya pseudofischeri infection in a bilateral lung transplant patient with cystic fibrosis. The organism was originally misidentified from respiratory specimens as Aspergillus fumigatus using colonial and microscopic morphology. DNA sequencing subsequently identified the organism correctly as N. pseudofischeri. Copyright © 2014, American Society for Microbiology. All Rights Reserved.

Fractal Geometry Enables Classification of Different Lung Morphologies in a Model of Experimental Asthma

NASA Astrophysics Data System (ADS)

Obert, Martin; Hagner, Stefanie; Krombach, Gabriele A.; Inan, Selcuk; Renz, Harald

2015-06-01

Animal models represent the basis of our current understanding of the pathophysiology of asthma and are of central importance in the preclinical development of drug therapies. The characterization of irregular lung shapes is a major issue in radiological imaging of mice in these models. The aim of this study was to find out whether differences in lung morphology can be described by fractal geometry. Healthy and asthmatic mouse groups, before and after an acute asthma attack induced by methacholine, were studied. In vivo flat-panel-based high-resolution Computed Tomography (CT) was used for mice's thorax imaging. The digital image data of the mice's lungs were segmented from the surrounding tissue. After that, the lungs were divided by image gray-level thresholds into two additional subsets. One subset contained basically the air transporting bronchial system. The other subset corresponds mainly to the blood vessel system. We estimated the fractal dimension of all sets of the different mouse groups using the mass radius relation (mrr). We found that the air transporting subset of the bronchial lung tissue enables a complete and significant differentiation between all four mouse groups (mean D of control mice before methacholine treatment: 2.64 ± 0.06; after treatment: 2.76 ± 0.03; asthma mice before methacholine treatment: 2.37 ± 0.16; after treatment: 2.71 ± 0.03; p < 0.05). We conclude that the concept of fractal geometry allows a well-defined, quantitative numerical and objective differentiation of lung shapes — applicable most likely also in human asthma diagnostics.

Microstructural consequences of blast lung injury characterised with digital volume correlation

NASA Astrophysics Data System (ADS)

Arora, Hari; Nila, Alex; Vitharana, Kalpani; Sherwood, Joseph M.; Nguyen, Thuy-Tien N.; Karunaratne, Angelo; Mohammed, Idris K.; Bodey, Andrew J.; Hellyer, Peter J.; Overby, Darryl R.; Schroter, Robert C.; Hollis, Dave

2017-12-01

This study focuses on microstructural changes that occur within the mammalian lung when subject to blast and how these changes influence strain distributions within the tissue. Shock tube experiments were performed to generate the blast injured specimens (cadaveric Sprague-Dawley rats). Blast overpressures of 100 kPa and 180 kPa were studied. Synchrotron tomography imaging was used to capture volumetric image data of lungs. Specimens were ventilated using a custom-built system to study multiple inflation pressures during each tomography scan. This data enabled the first digital volume correlation (DVC) measurements in lung tissue to be performed. Quantitative analysis was performed to describe the damaged architecture of the lung. No clear changes in the microstructure of the tissue morphology were observed due to controlled low to moderate level blast exposure. However, significant focal sites of injury were observed using DVC, which allowed detection of bias and concentration in the patterns of strain level. Morphological analysis corroborated the findings, illustrating that the focal damage caused by a blast can give rise to diffuse influence across the tissue. It is important to characterise the non-instantly fatal doses of blast, given the transient nature of blast lung in the clinical setting. This research has highlighted the need for better understanding of focal injury and its zone of influence (alveolar inter-dependency and neighbouring tissue burden as a result of focal injury). Digital volume correlation techniques show great promise as a tool to advance this endeavour, providing a new perspective on lung mechanics post-blast.

Rationale, study design and analysis plan of the lung imaging morphology for ventilator settings in acute respiratory distress syndrome study (LIVE study): Study protocol for a randomised controlled trial.

PubMed

Jabaudon, Matthieu; Godet, Thomas; Futier, Emmanuel; Bazin, Jean-Étienne; Sapin, Vincent; Roszyk, Laurence; Pereira, Bruno; Constantin, Jean-Michel

2017-10-01

Different acute respiratory distress syndrome (ARDS) phenotypes may explain controversial results in clinical trials. Lung-morphology is one of the ARDS-phenotypes and physiological studies suggest different responses in terms of positive-end-expiratory-pressure (PEEP) and recruitment-manoeuvres (RM) according to loss of aeration. To evaluate whether tailored ventilator regimens may impact ARDS outcomes, our group has designed a randomised-clinical-trial of ventilator settings according to lung morphology in moderate-to-severe ARDS (LIVE study). Patients will be enrolled within the first 12hours of ARDS onset. In both groups, volume-controlled ventilation with low tidal-volumes (Vt) will be used to target a plateau pressure≤30 cmH 2 O. In the control group, the PEEP level and inspired fraction of oxygen (FiO 2 ) will be set using the ARDSNet table; a Vt of 6 mL/kg of predicted body weight (PBW) will be set and prone position (PP) will be applied. In the intervention arm, the ventilator will be set according to lung morphology (focal/non-focal) that will be assessed according to CT-scan±chest x-ray+lung echography. For focal ARDS patients, a Vt of 8 mL/kg PBW will be used along with low PEEP and PP. For non-focal ARDS patients, a Vt of 6 mL/kg PBW will be used with RM and PEEP to reach a plateau pressure≤30 cmH 2 O. The primary outcome is all-cause 90-day mortality and the secondary outcomes are: in-hospital mortality, mortality at day 28, 60, 180 and 365; ventilator-free days at day 30, quality of life at one year; ventilator-associated pneumonia rate; barotrauma; ICU and hospital length of stay. This RCT is registered on Clinicaltrials.gov under identifier NCT02149589. Copyright © 2017 Société française d'anesthésie et de réanimation (Sfar). Published by Elsevier Masson SAS. All rights reserved.

Three-dimensional automatic computer-aided evaluation of pleural effusions on chest CT images

NASA Astrophysics Data System (ADS)

Bi, Mark; Summers, Ronald M.; Yao, Jianhua

2011-03-01

The ability to estimate the volume of pleural effusions is desirable as it can provide information about the severity of the condition and the need for thoracentesis. We present here an improved version of an automated program to measure the volume of pleural effusions using regular chest CT images. First, the lungs are segmented using region growing, mathematical morphology, and anatomical knowledge. The visceral and parietal layers of the pleura are then extracted based on anatomical landmarks, curve fitting and active contour models. The liver and compressed tissues are segmented out using thresholding. The pleural space is then fitted to a Bezier surface which is subsequently projected onto the individual two-dimensional slices. Finally, the volume of the pleural effusion is quantified. Our method was tested on 15 chest CT studies and validated against three separate manual tracings. The Dice coefficients were 0.74+/-0.07, 0.74+/-0.08, and 0.75+/-0.07 respectively, comparable to the variation between two different manual tracings.

Automation process for morphometric analysis of volumetric CT data from pulmonary vasculature in rats.

PubMed

Shingrani, Rahul; Krenz, Gary; Molthen, Robert

2010-01-01

With advances in medical imaging scanners, it has become commonplace to generate large multidimensional datasets. These datasets require tools for a rapid, thorough analysis. To address this need, we have developed an automated algorithm for morphometric analysis incorporating A Visualization Workshop computational and image processing libraries for three-dimensional segmentation, vascular tree generation and structural hierarchical ordering with a two-stage numeric optimization procedure for estimating vessel diameters. We combine this new technique with our mathematical models of pulmonary vascular morphology to quantify structural and functional attributes of lung arterial trees. Our physiological studies require repeated measurements of vascular structure to determine differences in vessel biomechanical properties between animal models of pulmonary disease. Automation provides many advantages including significantly improved speed and minimized operator interaction and biasing. The results are validated by comparison with previously published rat pulmonary arterial micro-CT data analysis techniques, in which vessels were manually mapped and measured using intense operator intervention. Published by Elsevier Ireland Ltd.

Quantifying the three-dimensional facial morphology of the laboratory rat with a focus on the vibrissae

PubMed Central

2018-01-01

The morphology of an animal’s face will have large effects on the sensory information it can acquire. Here we quantify the arrangement of cranial sensory structures of the rat, with special emphasis on the mystacial vibrissae (whiskers). Nearly all mammals have vibrissae, which are generally arranged in rows and columns across the face. The vibrissae serve a wide variety of important behavioral functions, including navigation, climbing, wake following, anemotaxis, and social interactions. To date, however, there are few studies that compare the morphology of vibrissal arrays across species, or that describe the arrangement of the vibrissae relative to other facial sensory structures. The few studies that do exist have exploited the whiskers’ grid-like arrangement to quantify array morphology in terms of row and column identity. However, relying on whisker identity poses a challenge for comparative research because different species have different numbers and arrangements of whiskers. The present work introduces an approach to quantify vibrissal array morphology regardless of the number of rows and columns, and to quantify the array’s location relative to other sensory structures. We use the three-dimensional locations of the whisker basepoints as fundamental parameters to generate equations describing the length, curvature, and orientation of each whisker. Results show that in the rat, whisker length varies exponentially across the array, and that a hard limit on intrinsic curvature constrains the whisker height-to-length ratio. Whiskers are oriented to “fan out” approximately equally in dorsal-ventral and rostral-caudal directions. Quantifying positions of the other sensory structures relative to the whisker basepoints shows remarkable alignment to the somatosensory cortical homunculus, an alignment that would not occur for other choices of coordinate systems (e.g., centered on the midpoint of the eyes). We anticipate that the quantification of facial sensory structures, including the vibrissae, will ultimately enable cross-species comparisons of multi-modal sensing volumes. PMID:29621356

Influence of airway wall compliance on epithelial cell injury and adhesion during interfacial flows

PubMed Central

Higuita-Castro, Natalia; Mihai, Cosmin; Hansford, Derek J.

2014-01-01

Interfacial flows during cyclic airway reopening are an important source of ventilator-induced lung injury. However, it is not known how changes in airway wall compliance influence cell injury during airway reopening. We used an in vitro model of airway reopening in a compliant microchannel to investigate how airway wall stiffness influences epithelial cell injury. Epithelial cells were grown on gel substrates with different rigidities, and cellular responses to substrate stiffness were evaluated in terms of metabolic activity, mechanics, morphology, and adhesion. Repeated microbubble propagations were used to simulate cyclic airway reopening, and cell injury and detachment were quantified via live/dead staining. Although cells cultured on softer gels exhibited a reduced elastic modulus, these cells experienced less plasma membrane rupture/necrosis. Cells on rigid gels exhibited a minor, but statistically significant, increase in the power law exponent and also exhibited a significantly larger height-to-length aspect ratio. Previous studies indicate that this change in morphology amplifies interfacial stresses and, therefore, correlates with the increased necrosis observed during airway reopening. Although cells cultured on stiff substrates exhibited more plasma membrane rupture, these cells experienced significantly less detachment and monolayer disruption during airway reopening. Western blotting and immunofluorescence indicate that this protection from detachment and monolayer disruption correlates with increased focal adhesion kinase and phosphorylated paxillin expression. Therefore, changes in cell morphology and focal adhesion structure may govern injury responses during compliant airway reopening. In addition, these results indicate that changes in airway compliance, as occurs during fibrosis or emphysema, may significantly influence cell injury during mechanical ventilation. PMID:25213636

Micro-CT image-derived metrics quantify arterial wall distensibility reduction in a rat model of pulmonary hypertension

NASA Astrophysics Data System (ADS)

Johnson, Roger H.; Karau, Kelly L.; Molthen, Robert C.; Haworth, Steven T.; Dawson, Christopher A.

2000-04-01

We developed methods to quantify arterial structural and mechanical properties in excised rat lungs and applied them to investigate the distensibility decrease accompanying chronic hypoxia-induced pulmonary hypertension. Lungs of control and hypertensive (three weeks 11% O2) animals were excised and a contrast agent introduced before micro-CT imaging with a special purpose scanner. For each lung, four 3D image data sets were obtained, each at a different intra-arterial contrast agent pressure. Vessel segment diameters and lengths were measured at all levels in the arterial tree hierarchy, and these data used to generate features sensitive to distensibility changes. Results indicate that measurements obtained from 3D micro-CT images can be used to quantify vessel biomechanical properties in this rat model of pulmonary hypertension and that distensibility is reduced by exposure to chronic hypoxia. Mechanical properties can be assessed in a localized fashion and quantified in a spatially-resolved way or as a single parameter describing the tree as a whole. Micro-CT is a nondestructive way to rapidly assess structural and mechanical properties of arteries in small animal organs maintained in a physiological state. Quantitative features measured by this method may provide valuable insights into the mechanisms causing the elevated pressures in pulmonary hypertension of differing etiologies and should become increasingly valuable tools in the study of complex phenotypes in small-animal models of important diseases such as hypertension.

Computed Tomographic Airway Morphology in Chronic Obstructive Pulmonary Disease. Remodeling or Innate Anatomy?

PubMed

Diaz, Alejandro A; Estépar, Raul San José; Washko, George R

2016-01-01

Computed tomographic measures of central airway morphology have been used in clinical, epidemiologic, and genetic investigation as an inference of the presence and severity of small-airway disease in smokers. Although several association studies have brought us to believe that these computed tomographic measures reflect airway remodeling, a careful review of such data and more recent evidence may reveal underappreciated complexity to these measures and limitations that prompt us to question that belief. This Perspective offers a review of seminal papers and alternative explanations of their data in the light of more recent evidence. The relationships between airway morphology and lung function are observed in subjects who never smoked, implying that native airway structure indeed contributes to lung function; computed tomographic measures of central airways such as wall area, lumen area, and total bronchial area are smaller in smokers with chronic obstructive pulmonary disease versus those without chronic obstructive pulmonary disease; and the airways are smaller as disease severity increases. The observations suggest that (1) native airway morphology likely contributes to the relationships between computed tomographic measures of airways and lung function; and (2) the presence of smaller airways in those with chronic obstructive pulmonary disease versus those without chronic obstructive pulmonary disease as well as their decrease with disease severity suggests that smokers with chronic obstructive pulmonary disease may simply have smaller airways to begin with, which put them at greater risk for the development of smoking-related disease.

Challenging embryological theories on congenital diaphragmatic hernia: future therapeutic implications for paediatric surgery.

PubMed Central

Jesudason, E. C.

2002-01-01

Lung hypoplasia is central to the poor prognosis of babies with congenital diaphragmatic hernia (CDH). Prolapse of abdominal organs through a diaphragmatic defect has traditionally been thought to impair lung growth by compression. The precise developmental biology of CDH remains unresolved. Refractory to fetal correction, lung hypoplasia in CDH may instead originate during embryogenesis and before visceral herniation. Resolving these conflicting hypotheses may lead to reappraisal of current clinical strategies. Genetic studies in murine models and the fruitfly, Drosophila melanogaster are elucidating the control of normal respiratory organogenesis. Branchless and breathless are Drosophila mutants lacking fibroblast growth factor (FGF) and its cognate receptor (FGFR), respectively. Sugarless and sulphateless mutants lack enzymes essential for heparan sulphate (HS) biosynthesis. Phenotypically, all these mutants share abrogated airway branching. Mammalian organ culture and transgenic models confirm the essential interaction of FGFs and HS during airway ramification. Embryonic airway development (branching morphogenesis) occurs in a defined spatiotemporal sequence. Unlike the surgically-created lamb model, the nitrofen rat model permits investigation of embryonic lung growth in CDH. Microdissecting embryonic lung primordia from the nitrofen CDH model and normal controls, we demonstrated that disruption of stereotyped airway branching correlates with and precedes subsequent CDH formation. To examine disturbed branching morphogenesis longitudinally, we characterised a system that preserves lung hypoplasia in organ culture. We tested FGFs and heparin (an HS analogue) as potential therapies on normal and hypoplastic lungs. Observing striking differences in morphological response to FGFs between normal and hypoplastic lung primordia, we postulated abnormalities of FGF/HS signalling in the embryonic CDH lung. Evaluating this hypothesis further, we examined effects of an HS-independent growth factor (epidermal growth factor, EGF) on hypoplastic lung development. Visible differences in morphological response indicate an intrinsic abnormality of hypoplastic lung primordia that may involve shared targets of FGFs and EGE. These studies indicate that lung hypoplasia precedes diaphragmatic hernia and may involve disturbances of mitogenic signalling pathways fundamental to embryonic lung development. What does this imply for human CDH? Fetal surgery may be 'too little, too late' to correct an established lung embryopathy. In utero growth factor therapy may permit antenatal lung rescue. Prevention of the birth defect by preconceptual prophylaxis may represent the ultimate solution. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 6 PMID:12215028

An integrated physiology model to study regional lung damage effects and the physiologic response

PubMed Central

2014-01-01

Background This work expands upon a previously developed exercise dynamic physiology model (DPM) with the addition of an anatomic pulmonary system in order to quantify the impact of lung damage on oxygen transport and physical performance decrement. Methods A pulmonary model is derived with an anatomic structure based on morphometric measurements, accounting for heterogeneous ventilation and perfusion observed experimentally. The model is incorporated into an existing exercise physiology model; the combined system is validated using human exercise data. Pulmonary damage from blast, blunt trauma, and chemical injury is quantified in the model based on lung fluid infiltration (edema) which reduces oxygen delivery to the blood. The pulmonary damage component is derived and calibrated based on published animal experiments; scaling laws are used to predict the human response to lung injury in terms of physical performance decrement. Results The augmented dynamic physiology model (DPM) accurately predicted the human response to hypoxia, altitude, and exercise observed experimentally. The pulmonary damage parameters (shunt and diffusing capacity reduction) were fit to experimental animal data obtained in blast, blunt trauma, and chemical damage studies which link lung damage to lung weight change; the model is able to predict the reduced oxygen delivery in damage conditions. The model accurately estimates physical performance reduction with pulmonary damage. Conclusions We have developed a physiologically-based mathematical model to predict performance decrement endpoints in the presence of thoracic damage; simulations can be extended to estimate human performance and escape in extreme situations. PMID:25044032

A review of cetacean lung morphology and mechanics.

PubMed

Piscitelli, Marina A; Raverty, Stephen A; Lillie, Margo A; Shadwick, Robert E

2013-12-01

Cetaceans possess diverse adaptations in respiratory structure and mechanics that are highly specialized for an array of surfacing and diving behaviors. Some of these adaptations and air management strategies are still not completely understood despite over a century of study. We have compiled the historical and contemporary knowledge of cetacean lung anatomy and mechanics in regards to normal lung function during ventilation and air management while diving. New techniques are emerging utilizing pulmonary mechanics to measure lung function in live cetaceans. Given the diversity of respiratory adaptations in cetaceans, interpretations of these results should consider species-specific anatomy, mechanics, and behavior. Copyright © 2013 Wiley Periodicals, Inc.

Cascade of convolutional neural networks for lung texture classification: overcoming ontological overlapping

NASA Astrophysics Data System (ADS)

Tarando, Sebastian Roberto; Fetita, Catalin; Brillet, Pierre-Yves

2017-03-01

The infiltrative lung diseases are a class of irreversible, non-neoplastic lung pathologies requiring regular follow-up with CT imaging. Quantifying the evolution of the patient status imposes the development of automated classification tools for lung texture. Traditionally, such classification relies on a two-dimensional analysis of axial CT images. This paper proposes a cascade of the existing CNN based CAD system, specifically tuned-up. The advantage of using a deep learning approach is a better regularization of the classification output. In a preliminary evaluation, the combined approach was tested on a 13 patient database of various lung pathologies, showing an increase of 10% in True Positive Rate (TPR) with respect to the best suited state of the art CNN for this task.

A role for MCP-1/CCR2 in interstitial lung disease in children

PubMed Central

Hartl, Dominik; Griese, Matthias; Nicolai, Thomas; Zissel, Gernot; Prell, Christine; Reinhardt, Dietrich; Schendel, Dolores J; Krauss-Etschmann, Susanne

2005-01-01

Background Interstitial lung diseases (ILD) are chronic inflammatory disorders leading to pulmonary fibrosis. Monocyte chemotactic protein 1 (MCP-1) promotes collagen synthesis and deletion of the MCP-1 receptor CCR2 protects from pulmonary fibrosis in ILD mouse models. We hypothesized that pulmonary MCP-1 and CCR2+ T cells accumulate in pediatric ILD and are related to disease severity. Methods Bronchoalveolar lavage fluid was obtained from 25 children with ILD and 10 healthy children. Levels of pulmonary MCP-1 and Th1/Th2-associated cytokines were quantified at the protein and the mRNA levels. Pulmonary CCR2+, CCR4+, CCR3+, CCR5+ and CXCR3+ T cells were quantified by flow-cytometry. Results CCR2+ T cells and MCP-1 levels were significantly elevated in children with ILD and correlated with forced vital capacity, total lung capacity and ILD disease severity scores. Children with lung fibrosis had significantly higher MCP-1 levels and CCR2+ T cells in bronchoalveolar lavage fluid compared to non-fibrotic children. Conclusion The results indicate that pulmonary CCR2+ T cells and MCP-1 contribute to the pathogenesis of pediatric ILD and might provide a novel target for therapeutic strategies. PMID:16095529

Classification of lung cancer patients and controls by chromatography of modified nucleosides in serum

USGS Publications Warehouse

McEntire, John E.; Kuo, Kenneth C.; Smith, Mark E.; Stalling, David L.; Richens, Jack W.; Zumwalt, Robert W.; Gehrke, Charles W.; Papermaster, Ben W.

1989-01-01

A wide spectrum of modified nucleosides has been quantified by high-performance liquid chromatography in serum of 49 male lung cancer patients, 35 patients with other cancers, and 48 patients hospitalized for nonneoplastic diseases. Data for 29 modified nucleoside peaks were normalized to an internal standard and analyzed by discriminant analysis and stepwise discriminant analysis. A model based on peaks selected by a stepwise discriminant procedure correctly classified 79% of the cancer and 75% of the noncancer subjects. It also demonstrated 84% sensitivity and 79% specificity when comparing lung cancer to noncancer subjects, and 80% sensitivity and 55% specificity in comparing lung cancer to other cancers. The nucleoside peaks having the greatest influence on the models varied dependent on the subgroups compared, confirming the importance of quantifying a wide array of nucleosides. These data support and expand previous studies which reported the utility of measuring modified nucleoside levels in serum and show that precise measurement of an array of 29 modified nucleosides in serum by high-performance liquid chromatography with UV scanning with subsequent data modeling may provide a clinically useful approach to patient classification in diagnosis and subsequent therapeutic monitoring.

Lung dosimetry for inhaled radon progeny in smokers.

PubMed

Baias, Paul F; Hofmann, Werner; Winkler-Heil, Renate; Cosma, Constantin; Duliu, Octavian G

2010-02-01

Cigarette smoking may change the morphological and physiological parameters of the lung. Thus the primary objective of the present study was to investigate to what extent these smoke-induced changes can modify deposition, clearance and resulting doses of inhaled radon progeny relative to healthy non-smokers (NSs). Doses to sensitive bronchial target cells were computed for four categories of smokers: (1) Light, short-term (LST) smokers, (2) light, long-term (LLT) smokers, (3) heavy, short-term (HST) smokers and (4) heavy, long-term (HLT) smokers. Because of only small changes of morphological and physiological parameters, doses for the LST smokers hardly differed from those for NSs. For LLT and HST smokers, even a protective effect could be observed, caused by a thicker mucus layer and increased mucus velocities. Only in the case of HLT smokers were doses higher by about a factor of 2 than those for NSs, caused primarily by impaired mucociliary clearance, higher breathing frequency, reduced lung volume and airway obstructions. These higher doses suggest that the contribution of inhaled radon progeny to the risk of lung cancer in smokers may be higher than currently assumed on the basis of NS doses.

Recent advances on the functional and evolutionary morphology of the amniote respiratory apparatus.

PubMed

Lambertz, Markus

2016-02-01

Increased organismic complexity in metazoans was achieved via the specialization of certain parts of the body involved in different faculties (structure-function complexes). One of the most basic metabolic demands of animals in general is a sufficient supply of all tissues with oxygen. Specialized structures for gas exchange (and transport) consequently evolved many times and in great variety among bilaterians. This review focuses on some of the latest advancements that morphological research has added to our understanding of how the respiratory apparatus of the primarily terrestrial vertebrates (amniotes) works and how it evolved. Two main components of the respiratory apparatus, the lungs as the "exchanger" and the ventilatory apparatus as the "active pump," are the focus of this paper. Specific questions related to the exchanger concern the structure of the lungs of the first amniotes and the efficiency of structurally simple snake lungs in health and disease, as well as secondary functions of the lungs in heat exchange during the evolution of sauropod dinosaurs. With regard to the active pump, I discuss how the unique ventilatory mechanism of turtles evolved and how understanding the avian ventilatory strategy affects animal welfare issues in the poultry industry. © 2016 New York Academy of Sciences.

Increased level of annexin A1 in bronchoalveolar lavage fluid as a potential diagnostic indicator for lung cancer.

PubMed

Biaoxue, Rong; Xiguang, Cai; Hua, Liu; Tian, Fu; Wenlong, Gao

2017-03-02

Annexin A1 has been implicated in various tumor types, but few studies have investigated its involvement in lung cancer. The purpose of this investigation was to quantify the annexin A1 level in bronchoalveolar lavage fluid (BALF) and analyze its usefulness in lung cancer diagnosis. Annexin A1 expression was measured by immunohistochemistry and enzyme immunoassay. The sensitivity and specificity of annexin A1 for distinguishing lung cancer were determined by receiver operator characteristic (ROC) curves. Tumor tissues, BALF and serum of patients with lung cancer contained higher levels of annexin A1 than those of the control group of patients with benign lung diseases. Moreover, an increased level of BALF annexin A1 was closely correlated with lymphatic invasion and malignant progression of lung cancer. The sensitivity and specificity of BALF annexin A1 for distinguishing lung cancer were 94.2% and 90.2%, respectively. Increased annexin A1 in BALF was correlated with lymphatic invasion and malignant progression of lung cancer, suggesting that it could be an indicator for discerning lung cancer and predicting outcome.

A neural network approach to lung nodule segmentation

NASA Astrophysics Data System (ADS)

Hu, Yaoxiu; Menon, Prahlad G.

2016-03-01

Computed tomography (CT) imaging is a sensitive and specific lung cancer screening tool for the high-risk population and shown to be promising for detection of lung cancer. This study proposes an automatic methodology for detecting and segmenting lung nodules from CT images. The proposed methods begin with thorax segmentation, lung extraction and reconstruction of the original shape of the parenchyma using morphology operations. Next, a multi-scale hessian-based vesselness filter is applied to extract lung vasculature in lung. The lung vasculature mask is subtracted from the lung region segmentation mask to extract 3D regions representing candidate pulmonary nodules. Finally, the remaining structures are classified as nodules through shape and intensity features which are together used to train an artificial neural network. Up to 75% sensitivity and 98% specificity was achieved for detection of lung nodules in our testing dataset, with an overall accuracy of 97.62%+/-0.72% using 11 selected features as input to the neural network classifier, based on 4-fold cross-validation studies. Receiver operator characteristics for identifying nodules revealed an area under curve of 0.9476.

Lung dynamic MRI deblurring using low-rank decomposition and dictionary learning.

PubMed

Gou, Shuiping; Wang, Yueyue; Wu, Jiaolong; Lee, Percy; Sheng, Ke

2015-04-01

Lung dynamic MRI (dMRI) has emerged to be an appealing tool to quantify lung motion for both planning and treatment guidance purposes. However, this modality can result in blurry images due to intrinsically low signal-to-noise ratio in the lung and spatial/temporal interpolation. The image blurring could adversely affect the image processing that depends on the availability of fine landmarks. The purpose of this study is to reduce dMRI blurring using image postprocessing. To enhance the image quality and exploit the spatiotemporal continuity of dMRI sequences, a low-rank decomposition and dictionary learning (LDDL) method was employed to deblur lung dMRI and enhance the conspicuity of lung blood vessels. Fifty frames of continuous 2D coronal dMRI frames using a steady state free precession sequence were obtained from five subjects including two healthy volunteer and three lung cancer patients. In LDDL, the lung dMRI was decomposed into sparse and low-rank components. Dictionary learning was employed to estimate the blurring kernel based on the whole image, low-rank or sparse component of the first image in the lung MRI sequence. Deblurring was performed on the whole image sequences using deconvolution based on the estimated blur kernel. The deblurring results were quantified using an automated blood vessel extraction method based on the classification of Hessian matrix filtered images. Accuracy of automated extraction was calculated using manual segmentation of the blood vessels as the ground truth. In the pilot study, LDDL based on the blurring kernel estimated from the sparse component led to performance superior to the other ways of kernel estimation. LDDL consistently improved image contrast and fine feature conspicuity of the original MRI without introducing artifacts. The accuracy of automated blood vessel extraction was on average increased by 16% using manual segmentation as the ground truth. Image blurring in dMRI images can be effectively reduced using a low-rank decomposition and dictionary learning method using kernels estimated by the sparse component.

Mathematics of Ventilator-induced Lung Injury.

PubMed

Rahaman, Ubaidur

2017-08-01

Ventilator-induced lung injury (VILI) results from mechanical disruption of blood-gas barrier and consequent edema and releases of inflammatory mediators. A transpulmonary pressure (P L ) of 17 cmH 2 O increases baby lung volume to its anatomical limit, predisposing to VILI. Viscoelastic property of lung makes pulmonary mechanics time dependent so that stress (P L ) increases with respiratory rate. Alveolar inhomogeneity in acute respiratory distress syndrome acts as a stress riser, multiplying global stress at regional level experienced by baby lung. Limitation of stress (P L ) rather than strain (tidal volume [V T ]) is the safe strategy of mechanical ventilation to prevent VILI. Driving pressure is the noninvasive surrogate of lung strain, but its relations to P L is dependent on the chest wall compliance. Determinants of lung stress (V T , driving pressure, positive end-expiratory pressure, and inspiratory flow) can be quantified in terms of mechanical power, and a safe threshold can be determined, which can be used in decision-making between safe mechanical ventilation and extracorporeal lung support.

Surfactant protein-A nanobody-conjugated liposomes loaded with methylprednisolone increase lung-targeting specificity and therapeutic effect for acute lung injury.

PubMed

Li, Nan; Weng, Dong; Wang, Shan-Mei; Zhang, Yuan; Chen, Shan-Shan; Yin, Zhao-Fang; Zhai, Jiali; Scoble, Judy; Williams, Charlotte C; Chen, Tao; Qiu, Hui; Wu, Qin; Zhao, Meng-Meng; Lu, Li-Qin; Mulet, Xavier; Li, Hui-Ping

2017-11-01

The advent of nanomedicine requires novel delivery vehicles to actively target their site of action. Here, we demonstrate the development of lung-targeting drug-loaded liposomes and their efficacy, specificity and safety. Our study focuses on glucocorticoids methylprednisolone (MPS), a commonly used drug to treat lung injuries. The steroidal molecule was loaded into functionalized nano-sterically stabilized unilamellar liposomes (NSSLs). Targeting functionality was performed through conjugation of surfactant protein A (SPANb) nanobodies to form MPS-NSSLs-SPANb. MPS-NSSLs-SPANb exhibited good size distribution, morphology, and encapsulation efficiency. Animal experiments demonstrated the high specificity of MPS-NSSLs-SPANb to the lung. Treatment with MPS-NSSLs-SPANb reduced the levels of TNF-α, IL-8, and TGF-β1 in rat bronchoalveolar lavage fluid and the expression of NK-κB in the lung tissues, thereby alleviating lung injuries and increasing rat survival. The nanobody functionalized nanoparticles demonstrate superior performance to treat lung injury when compared to that of antibody functionalized systems.

[Non-small cell lung cancer. Subtyping and predictive molecular marker investigations in cytology].

PubMed

Savic, S; Bihl, M P; Bubendorf, L

2012-07-01

The diagnosis and treatment of non-small cell lung cancer (NSCLC) have been revolutionized over the last few years. Requirements for cytopathologists in lung cancer diagnosis have therefore changed. The general diagnostic category of NSLC is no longer sufficient. In addition cytological specimens need to be evaluated for adequacy regarding predictive marker analyses. Accurate NSCLC subtyping with a distinction of adenocarcinoma from squamous cell carcinoma is crucial for treatment decisions as the subtype will decide on the chemotherapy regimen and the choice of predictive marker analyses for targeted treatment. In the majority of cases, the subtype can be diagnosed by morphology alone. Cytology is equally well suited as biopsy specimens for the assessment of molecular predictive markers. The best results are achieved when both cytology and biopsy specimens are compared to choose the most appropriate specimen for morphological subtyping and molecular testing. In this paper, we discuss special issues of NSCLC subtyping and currently recommended predictive molecular marker analyses.

Quantification of lung tumor rotation with automated landmark extraction using orthogonal cine MRI images

NASA Astrophysics Data System (ADS)

Paganelli, Chiara; Lee, Danny; Greer, Peter B.; Baroni, Guido; Riboldi, Marco; Keall, Paul

2015-09-01

The quantification of tumor motion in sites affected by respiratory motion is of primary importance to improve treatment accuracy. To account for motion, different studies analyzed the translational component only, without focusing on the rotational component, which was quantified in a few studies on the prostate with implanted markers. The aim of our study was to propose a tool able to quantify lung tumor rotation without the use of internal markers, thus providing accurate motion detection close to critical structures such as the heart or liver. Specifically, we propose the use of an automatic feature extraction method in combination with the acquisition of fast orthogonal cine MRI images of nine lung patients. As a preliminary test, we evaluated the performance of the feature extraction method by applying it on regions of interest around (i) the diaphragm and (ii) the tumor and comparing the estimated motion with that obtained by (i) the extraction of the diaphragm profile and (ii) the segmentation of the tumor, respectively. The results confirmed the capability of the proposed method in quantifying tumor motion. Then, a point-based rigid registration was applied to the extracted tumor features between all frames to account for rotation. The median lung rotation values were  -0.6   ±   2.3° and  -1.5   ±   2.7° in the sagittal and coronal planes respectively, confirming the need to account for tumor rotation along with translation to improve radiotherapy treatment.

Lung remodeling in a porcine model of cyanotic congenital heart defect with decreased pulmonary blood flow.

PubMed

Xu, Yaoqiang; Liu, Yinglong; Li, Zhiqiang; Su, Junwu; Li, Gang; Sun, Lizhong

2012-09-01

Hypoperfusion of the pulmonary vascular bed under the condition of congenital cardiac malformations may lead to progressive pulmonary vascular disease. To improve the mechanistic understanding of this disease, we examined the biochemical and morphological changes of the lung in a relevant animal model and provided valuable insights into the underlying mechanisms of the pathogenesis of pulmonary hypotension. A model of congenital heart defect with decreased pulmonary blood flow was implemented into 8 piglets (the cyanosis group). Another 8 piglets underwent a sham operation (the control group). Two months postoperatively, lung biopsy specimens were harvested for the measurement of the expression levels of MMP-2, MMP-9, TIMP-1, VEGF, and type I and type III collagens. Moreover, the light-microscopic morphology, morphometry, and ultrastructure of lobes were examined. Compared to the controls, the histopathological changes of the pulmonary vasculature in the cyanosis group showed evident hypoplasia and degeneration. The expression levels of MMP-2, MMP-9, TIMP-1, VEGF, and type I collagen, as well as the microvessel density, in the cyanosis group were significantly lower than those in the control group, whereas the level of type III collagen in the cyanosis group was significantly higher than that in the control group. The observed morphological changes may represent an adaptive reaction to the prolonged decrease of pulmonary blood flow. The underlying mechanism of lung remodeling may be attributed to the changes in the expression of structural proteins and cytokines in the pulmonary extracellular matrix induced by modulating factors.

Lung Matrix Metalloproteinase Activation following Partial Hepatic Ischemia/Reperfusion Injury in Rats

PubMed Central

Ferrigno, Andrea; Rizzo, Vittoria; Tarantola, Eleonora

2014-01-01

Purpose. Warm hepatic ischemia-reperfusion (I/R) injury can lead to multiorgan dysfunction. The aim of the present study was to investigate whether acute liver I/R does affect the function and/or structure of remote organs such as lung, kidney, and heart via modulation of extracellular matrix remodelling. Methods. Male Sprague-Dawley rats were subjected to 30 min partial hepatic ischemia by clamping the hepatic artery and the portal vein. After a 60 min reperfusion, liver, lung, kidney, and heart biopsies and blood samples were collected. Serum hepatic enzymes, creatinine, urea, Troponin I and TNF-alpha, and tissue matrix metalloproteinases (MMP-2, MMP-9), myeloperoxidase (MPO), malondialdehyde (MDA), and morphology were monitored. Results. Serum levels of hepatic enzymes and TNF-alpha were concomitantly increased during hepatic I/R. An increase in hepatic MMP-2 and MMP-9 activities was substantiated by tissue morphology alterations. Notably, acute hepatic I/R affect the lung inasmuch as MMP-9 activity and MPO levels were increased. No difference in MMPs and MPO was observed in kidney and heart. Conclusions. Although the underlying mechanism needs further investigation, this is the first study in which the MMP activation in a distant organ is reported; this event is probably TNF-alpha-mediated and the lung appears as the first remote organ to be involved in hepatic I/R injury. PMID:24592193

Serological assessment of neutrophil elastase activity on elastin during lung ECM remodeling.

PubMed

Kristensen, Jacob H; Karsdal, Morten A; Sand, Jannie Mb; Willumsen, Nicholas; Diefenbach, Claudia; Svensson, Birte; Hägglund, Per; Oersnes-Leeming, Diana J

2015-05-03

During the pathological destruction of lung tissue, neutrophil elastase (NE) degrades elastin, one of the major constituents of lung parenchyma. However there are no non-invasive methods to quantify NE degradation of elastin. We selected specific elastin fragments generated by NE for antibody generation and developed an ELISA assay (EL-NE) for the quantification of NE-degraded elastin. Monoclonal antibodies were developed against 10 NE-specific cleavage sites on elastin. One EL-NE assay was tested for analyte stability, linearity and intra- and inter-assay variation. The NE specificity was demonstrated using elastin cleaved in vitro with matrix metalloproteinases (MMPs), cathepsin G (CatG), NE and intact elastin. Clinical relevance was assessed by measuring levels of NE-generated elastin fragments in serum of patients diagnosed with idiopathic pulmonary fibrosis (IPF, n = 10) or lung cancer (n = 40). Analyte recovery of EL-NE for human serum was between 85% and 104%, the analyte was stable for four freeze/thaw cycles and after 24 h storage at 4°C. EL-NE was specific for NE-degraded elastin. Levels of NE-generated elastin fragments for elastin incubated in the presence of NE were 900% to 4700% higher than those seen with CatG or MMP incubation or in intact elastin. Serum levels of NE-generated elastin fragments were significantly increased in patients with IPF (137%, p = 0.002) and in patients with lung cancer (510%, p < 0.001) compared with age- and sex-matched controls. The EL-NE assay was specific for NE-degraded elastin. The EL-NE assay was able to specifically quantify NE-degraded elastin in serum. Serum levels of NE-degraded elastin might be used to detect excessive lung tissue degradation in lung cancer and IPF.

Pooled population pharmacokinetic model of imipenem in plasma and the lung epithelial lining fluid

PubMed Central

Rizk, Matthew L.; Lala, Mallika; Chavez‐Eng, Cynthia; Visser, Sandra A. G.; Kerbusch, Thomas; Danhof, Meindert; Rao, Gauri; van der Graaf, Piet H.

2016-01-01

Aims Several clinical trials have confirmed the therapeutic benefit of imipenem for treatment of lung infections. There is however no knowledge of the penetration of imipenem into the lung epithelial lining fluid (ELF), the site of action relevant for lung infections. Furthermore, although the plasma pharmacokinetics (PK) of imipenem has been widely studied, most studies have been based on selected patient groups. The aim of this analysis was to characterize imipenem plasma PK across populations and to quantify imipenem ELF penetration. Methods A population model for imipenem plasma PK was developed using data obtained from healthy volunteers, elderly subjects and subjects with renal impairment, in order to identify predictors for inter‐individual variability (IIV) of imipenem PK. Subsequently, a clinical study which measured plasma and ELF concentrations of imipenem was included in order to quantify lung penetration. Results A two compartmental model best described the plasma PK of imipenem. Creatinine clearance and body weight were included as subject characteristics predictive for IIV on clearance. Typical estimates for clearance, central and peripheral volume, and inter‐compartmental clearance were 11.5 l h–1, 9.37 l, 6.41 l, 13.7 l h–1, respectively (relative standard error (RSE) <8%). The distribution of imipenem into ELF was described using a time‐independent penetration coefficient of 0.44 (RSE 14%). Conclusion The identified lung penetration coefficient confirms the clinical relevance of imipenem for treatment of lung infections, while the population PK model provided insights into predictors of IIV for imipenem PK and may be of relevance to support dose optimization in various subject groups. PMID:26852277

Pooled population pharmacokinetic model of imipenem in plasma and the lung epithelial lining fluid.

PubMed

van Hasselt, J G Coen; Rizk, Matthew L; Lala, Mallika; Chavez-Eng, Cynthia; Visser, Sandra A G; Kerbusch, Thomas; Danhof, Meindert; Rao, Gauri; van der Graaf, Piet H

2016-06-01

Several clinical trials have confirmed the therapeutic benefit of imipenem for treatment of lung infections. There is however no knowledge of the penetration of imipenem into the lung epithelial lining fluid (ELF), the site of action relevant for lung infections. Furthermore, although the plasma pharmacokinetics (PK) of imipenem has been widely studied, most studies have been based on selected patient groups. The aim of this analysis was to characterize imipenem plasma PK across populations and to quantify imipenem ELF penetration. A population model for imipenem plasma PK was developed using data obtained from healthy volunteers, elderly subjects and subjects with renal impairment, in order to identify predictors for inter-individual variability (IIV) of imipenem PK. Subsequently, a clinical study which measured plasma and ELF concentrations of imipenem was included in order to quantify lung penetration. A two compartmental model best described the plasma PK of imipenem. Creatinine clearance and body weight were included as subject characteristics predictive for IIV on clearance. Typical estimates for clearance, central and peripheral volume, and inter-compartmental clearance were 11.5 l h(-1) , 9.37 l, 6.41 l, 13.7 l h(-1) , respectively (relative standard error (RSE) <8%). The distribution of imipenem into ELF was described using a time-independent penetration coefficient of 0.44 (RSE 14%). The identified lung penetration coefficient confirms the clinical relevance of imipenem for treatment of lung infections, while the population PK model provided insights into predictors of IIV for imipenem PK and may be of relevance to support dose optimization in various subject groups. © 2016 The British Pharmacological Society.

Changes in gene expression in lungs of mice exposed to traffic-related air pollution.

PubMed

Yang, Jie; Chen, Yi; Yu, Zhi; Ding, Hui; Ma, Zhongfu

2018-06-01

Long-term exposure to traffic-related pollutants can lead to a variety of respiratory diseases, including inflammation, asthma, and lung cancer; however, the underlying biological mechanisms are not fully understood. We focused on the effects of exposure to different air pollutants on the expression of genes associated with inflammatory immune responses, allergic reactions and asthma, and lung cancer. In order to understand the cellular responses induced by exposure to different traffic-related pollutants, we performed PCR array to evaluate the mRNA expression of genes associated with inflammatory immune responses, allergic reactions and asthma, and lung cancer in the lungs of mice exposed to three different environments, including the laboratory (clean air), and polluted parking garages in Foshan and Guangzhou for four weeks. Cytokines (IFN-γ, IL-4, and IL-17A) were analyzed by Flow cytometry; the morphological structures were detected by Haematoxylin and eosin (H&E) staining. Our results revealed that the main pollutant in Guangzhou was PM2.5, the main pollutants in Foshan were gaseous pollutants including CO, NO x and SO 2. IFN-γ was significantly lower, and IL-4, and IL-17A were significantly higher in mice in the Guangzhou and Foshan groups compared with laboratory group. The morphological structures were damaged in Guangzhou and Foshan groups. In addition, we found that exposure to traffic-related pollutants triggered the expression of inflammatory genes (Cxcl11 and Tnfs4), allergy and asthma genes (Clca3 and Prg2), and lung cancer genes (Agr2, Col11a1, and Sostdc1). As such, our results demonstrate that persistent exposure to traffic-related pollutants may elevate the incidence of immune disorders and asthma, and may be as a risk factor for lung cancer. Copyright © 2018. Published by Elsevier Ltd.

International review of cytology. Volume 106. A survey of cell biology

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bourne, G.H.; Jeon, K.W.; Friedlander, M.

1987-01-01

Contents: Morphology and Cytochemistry of the Endocrine Epthelial System in the Lung; Intrinsic Nerve Plexus of Mammalian Heart; Morphological Basis of Cardiac Rhythmical Activity. Structural and Functional Evolution of Gonadotropin-Releasing Hormone; Excitons and Solitons in Molecular Systems; The Centrosome and Its Role in the Organization of Microtubules. Each chapter includes references. Index.

Closed-loop mechanical ventilation for lung injury: a novel physiological-feedback mode following the principles of the open lung concept.

PubMed

Schwaiberger, David; Pickerodt, Philipp A; Pomprapa, Anake; Tjarks, Onno; Kork, Felix; Boemke, Willehad; Francis, Roland C E; Leonhardt, Steffen; Lachmann, Burkhard

2018-06-01

Adherence to low tidal volume (V T ) ventilation and selected positive end-expiratory pressures are low during mechanical ventilation for treatment of the acute respiratory distress syndrome. Using a pig model of severe lung injury, we tested the feasibility and physiological responses to a novel fully closed-loop mechanical ventilation algorithm based on the "open lung" concept. Lung injury was induced by surfactant washout in pigs (n = 8). Animals were ventilated following the principles of the "open lung approach" (OLA) using a fully closed-loop physiological feedback algorithm for mechanical ventilation. Standard gas exchange, respiratory- and hemodynamic parameters were measured. Electrical impedance tomography was used to quantify regional ventilation distribution during mechanical ventilation. Automatized mechanical ventilation provided strict adherence to low V T -ventilation for 6 h in severely lung injured pigs. Using the "open lung" approach, tidal volume delivery required low lung distending pressures, increased recruitment and ventilation of dorsal lung regions and improved arterial blood oxygenation. Physiological feedback closed-loop mechanical ventilation according to the principles of the open lung concept is feasible and provides low tidal volume ventilation without human intervention. Of importance, the "open lung approach"-ventilation improved gas exchange and reduced lung driving pressures by opening atelectasis and shifting of ventilation to dorsal lung regions.

New insights into lung diseases using hyperpolarized gas MRI.

PubMed

Flors, L; Altes, T A; Mugler, J P; de Lange, E E; Miller, G W; Mata, J F; Ruset, I C; Hersman, F W

2015-01-01

Hyperpolarized (HP) gases are a new class of contrast agents that permit to obtain high temporal and spatial resolution magnetic resonance images (MRI) of the lung airspaces. HP gas MRI has become important research tool not only for morphological and functional evaluation of normal pulmonary physiology but also for regional quantification of pathologic changes occurring in several lung diseases. The purpose of this work is to provide an introduction to MRI using HP noble gases, describing both the basic principles of the technique and the new information about lung disease provided by clinical studies with this method. The applications of the technique in normal subjects, smoking related lung disease, asthma, and cystic fibrosis are reviewed. Copyright © 2014 SERAM. Published by Elsevier España, S.L.U. All rights reserved.

Molecular Imaging and Precision Medicine in Lung Cancer.

PubMed

Zukotynski, Katherine A; Gerbaudo, Victor H

2017-01-01

Precision medicine allows tailoring of preventive or therapeutic interventions to avoid the expense and toxicity of futile treatment given to those who will not respond. Lung cancer is a heterogeneous disease functionally and morphologically. PET is a sensitive molecular imaging technique with a major role in the precision medicine algorithm of patients with lung cancer. It contributes to the precision medicine of lung neoplasia by interrogating tumor heterogeneity throughout the body. It provides anatomofunctional insight during diagnosis, staging, and restaging of the disease. It is a biomarker of tumoral heterogeneity that helps direct selection of the most appropriate treatment, the prediction of early response to cytotoxic and cytostatic therapies, and is a prognostic biomarker in patients with lung cancer. Crown Copyright © 2016. Published by Elsevier Inc. All rights reserved.

Liquid biopsy for early stage lung cancer.

PubMed

Liang, Wenhua; Zhao, Yi; Huang, Weizhe; Liang, Hengrui; Zeng, Haikang; He, Jianxing

2018-04-01

Liquid biopsy, which analyzes biological fluids especially blood specimen to detect and quantify circulating cancer biomarkers, have been rapidly introduced and represents a promising potency in clinical practice of lung cancer diagnosis and prognosis. Unlike conventional tissue biopsy, liquid biopsy is non-invasive, safe, simple in procedure, and is not influenced by manipulators' skills. Notably, some circulating cancer biomarkers are already detectable in disease with low-burden, making liquid biopsy feasible in detecting early stage lung cancer. In this review, we described a landscape of different liquid biopsy methods by highlighting the rationale and advantages, accessing the value of various circulating biomarkers and discussing their possible future development in the detection of early lung cancer.

COSMOS 2044: Lung morphology study, experiment K-7-28

NASA Technical Reports Server (NTRS)

Elliott, Ann R.; Mathieu-Costello, Odile; West, John B.

1991-01-01

Researchers examined the effect of microgravity during spaceflight on lung tissue. The ultrastructure of the left lungs of 5 Czechoslovakian Wister rats flown on the 13 day, 19+ hour Cosmos 2044 mission was examined and compared to 5 vivarium and 5 synchronous controls at 1-g conditions, and 5 rats exposed to 14 days of tail suspension. Pulmonary hemorrage and alveolar adema of unknown origin occurred to a greater extent in the flight, tail-suspended, and synchronous control animals, and in the dorsal regions of the lung when compared with the vivarium controls. The cause of these changes, which are possibly due to an increase in pulmonary vascular pressure, requires further investigation.

Modification of Rat Lung Decellularization Protocol Based on Dynamic Conductometry of Working Solution.

PubMed

Kuevda, E V; Gubareva, E A; Gumenyuk, I S; Sotnichenko, A S; Gilevich, I V; Nakokhov, R Z; Rusinova, T V; Yudina, T G; Red'ko, A N; Alekseenko, S N

2017-03-01

We modified the protocol of obtaining of biological scaffolds of rat lungs based on dynamic recording of specific resistivity of working detergent solution (conductometry) during perfusion decellularization. Termination of sodium deoxycholate exposure after attaining ionic equilibrium plateau did not impair the quality of decellularization and preserved structural matrix components, which was confirmed by morphological analysis and quantitative assay of residual DNA.

Fluid biopsy for circulating tumor cell identification in patients with early-and late-stage non-small cell lung cancer: a glimpse into lung cancer biology

NASA Astrophysics Data System (ADS)

Wendel, Marco; Bazhenova, Lyudmila; Boshuizen, Rogier; Kolatkar, Anand; Honnatti, Meghana; Cho, Edward H.; Marrinucci, Dena; Sandhu, Ajay; Perricone, Anthony; Thistlethwaite, Patricia; Bethel, Kelly; Nieva, Jorge; van den Heuvel, Michel; Kuhn, Peter

2012-02-01

Circulating tumor cell (CTC) counts are an established prognostic marker in metastatic prostate, breast and colorectal cancer, and recent data suggest a similar role in late stage non-small cell lung cancer (NSCLC). However, due to sensitivity constraints in current enrichment-based CTC detection technologies, there are few published data about CTC prevalence rates and morphologic heterogeneity in early-stage NSCLC, or the correlation of CTCs with disease progression and their usability for clinical staging. We investigated CTC counts, morphology and aggregation in early stage, locally advanced and metastatic NSCLC patients by using a fluid-phase biopsy approach that identifies CTCs without relying on surface-receptor-based enrichment and presents them in sufficiently high definition (HD) to satisfy diagnostic pathology image quality requirements. HD-CTCs were analyzed in blood samples from 78 chemotherapy-naïve NSCLC patients. 73% of the total population had a positive HD-CTC count (>0 CTC in 1 mL of blood) with a median of 4.4 HD-CTCs mL-1 (range 0-515.6) and a mean of 44.7 (±95.2) HD-CTCs mL-1. No significant difference in the medians of HD-CTC counts was detected between stage IV (n = 31, range 0-178.2), stage III (n = 34, range 0-515.6) and stages I/II (n = 13, range 0-442.3). Furthermore, HD-CTCs exhibited a uniformity in terms of molecular and physical characteristics such as fluorescent cytokeratin intensity, nuclear size, frequency of apoptosis and aggregate formation across the spectrum of staging. Our results demonstrate that despite stringent morphologic inclusion criteria for the definition of HD-CTCs, the HD-CTC assay shows high sensitivity in the detection and characterization of both early- and late-stage lung cancer CTCs. Extensive studies are warranted to investigate the prognostic value of CTC profiling in early-stage lung cancer. This finding has implications for the design of extensive studies examining screening, therapy and surveillance in lung cancer patients.

Small-animal dark-field radiography for pulmonary emphysema evaluation

NASA Astrophysics Data System (ADS)

Yaroshenko, Andre; Meinel, Felix G.; Hellbach, Katharina; Bech, Martin; Velroyen, Astrid; Müller, Mark; Bamberg, Fabian; Nikolaou, Konstantin; Reiser, Maximilian F.; Yildirim, Ali Ã.-.; Eickelberg, Oliver; Pfeiffer, Franz

2014-03-01

Chronic obstructive pulmonary disease (COPD) is one of the leading causes of morbidity and mortality worldwide and emphysema is one of its main components. The disorder is characterized by irreversible destruction of the alveolar walls and enlargement of distal airspaces. Despite the severe changes in the lung tissue morphology, conventional chest radiographs have only a limited sensitivity for the detection of mild to moderate emphysema. X-ray dark-field is an imaging modality that can significantly increase the visibility of lung tissue on radiographic images. The dark-field signal is generated by coherent, small-angle scattering of x-rays on the air-tissue interfaces in the lung. Therefore, morphological changes in the lung can be clearly visualized on dark-field images. This is demonstrated by a preclinical study with a small-animal emphysema model. To generate a murine model of pulmonary emphysema, a female C57BL/6N mouse was treated with a single orotracheal application of porcine pancreatic elastase (80 U/kg body weight) dissolved in phosphate-buffered saline (PBS). Control mouse received PBS. The mice were imaged using a small-animal dark-field scanner. While conventional x-ray transmission radiography images revealed only subtle indirect signs of the pulmonary disorder, the difference between healthy and emphysematous lungs could be clearly directly visualized on the dark-field images. The dose applied to the animals is compatible with longitudinal studies. The imaging results correlate well with histology. The results of this study reveal the high potential of dark-field radiography for clinical lung imaging.

Poster - Thur Eve - 16: Four-dimensional x-ray computed tomography and hyperpolarized 3 He magnetic resonance imaging of gas distribution in lung cancer.

PubMed

Mathew, L; Castillo, R; Castillo, E; Yaremko, B; Rodrigues, G; Etemad-Rezai, R; Guerrero, T; Parraga, G

2012-07-01

Dynamic imaging methods such as four-dimensional computed tomography (4DCT) and static imaging methods such as noble gas magnetic resonance imaging (MRI) deliver direct and regional measurements of lung function even in lung cancer patients in whom global lung function measurements are dominated by tumour burden. The purpose of this study was to directly compare quantitative measurements of gas distribution from static hyperpolarized 3 He MRI and dynamic 4DCT in a small group of lung cancer patients. MRI and 4DCT were performed in 11 subjects prior to radiation therapy. MRI was performed at 3.0T in breath-hold after inhalation 1L of hyperpolarized 3 He gas. Gas distribution in 3 He MRI was quantified using a semi-automated segmentation algorithm to generate percent-ventilated volume (PVV), reflecting the volume of gas in the lung normalized to the thoracic cavity volume. 4DCT pulmonary function maps were generated using deformable image registration of six expiratory phase images. The correspondence between identical tissue elements at inspiratory and expiratory phases was used to estimate regional gas distribution and PVV was quantified from these images. After accounting for differences in lung volumes between 3 He MRI (1.9±0.5L ipsilateral, 2.3±0.7 contralateral) and 4DCT (1.2±0.3L ipsilateral, 1.3±0.4L contralateral) during image acquisition, there was no statistically significant difference in PVV between 3 He MRI (72±11% ipsilateral, 79±12% contralateral) and 4DCT (74±3% ipsilateral, 75±4% contralateral). Our results indicate quantitative agreement in the regional distribution of inhaled gas in both static and dynamic imaging methods. PVV may be considered as a regional surrogate measurement of lung function or ventilation. © 2012 American Association of Physicists in Medicine.

A comprehensive computational model of sound transmission through the porcine lung

PubMed Central

Dai, Zoujun; Peng, Ying; Henry, Brian M.; Mansy, Hansen A.; Sandler, Richard H.; Royston, Thomas J.

2014-01-01

A comprehensive computational simulation model of sound transmission through the porcine lung is introduced and experimentally evaluated. This “subject-specific” model utilizes parenchymal and major airway geometry derived from x-ray CT images. The lung parenchyma is modeled as a poroviscoelastic material using Biot theory. A finite element (FE) mesh of the lung that includes airway detail is created and used in comsol FE software to simulate the vibroacoustic response of the lung to sound input at the trachea. The FE simulation model is validated by comparing simulation results to experimental measurements using scanning laser Doppler vibrometry on the surface of an excised, preserved lung. The FE model can also be used to calculate and visualize vibroacoustic pressure and motion inside the lung and its airways caused by the acoustic input. The effect of diffuse lung fibrosis and of a local tumor on the lung acoustic response is simulated and visualized using the FE model. In the future, this type of visualization can be compared and matched with experimentally obtained elastographic images to better quantify regional lung material properties to noninvasively diagnose and stage disease and response to treatment. PMID:25190415

A comprehensive computational model of sound transmission through the porcine lung.

PubMed

Dai, Zoujun; Peng, Ying; Henry, Brian M; Mansy, Hansen A; Sandler, Richard H; Royston, Thomas J

2014-09-01

A comprehensive computational simulation model of sound transmission through the porcine lung is introduced and experimentally evaluated. This "subject-specific" model utilizes parenchymal and major airway geometry derived from x-ray CT images. The lung parenchyma is modeled as a poroviscoelastic material using Biot theory. A finite element (FE) mesh of the lung that includes airway detail is created and used in comsol FE software to simulate the vibroacoustic response of the lung to sound input at the trachea. The FE simulation model is validated by comparing simulation results to experimental measurements using scanning laser Doppler vibrometry on the surface of an excised, preserved lung. The FE model can also be used to calculate and visualize vibroacoustic pressure and motion inside the lung and its airways caused by the acoustic input. The effect of diffuse lung fibrosis and of a local tumor on the lung acoustic response is simulated and visualized using the FE model. In the future, this type of visualization can be compared and matched with experimentally obtained elastographic images to better quantify regional lung material properties to noninvasively diagnose and stage disease and response to treatment.

Multiple image x-radiography for functional lung imaging

NASA Astrophysics Data System (ADS)

Aulakh, G. K.; Mann, A.; Belev, G.; Wiebe, S.; Kuebler, W. M.; Singh, B.; Chapman, D.

2018-01-01

Detection and visualization of lung tissue structures is impaired by predominance of air. However, by using synchrotron x-rays, refraction of x-rays at the interface of tissue and air can be utilized to generate contrast which may in turn enable quantification of lung optical properties. We utilized multiple image radiography, a variant of diffraction enhanced imaging, at the Canadian light source to quantify changes in unique x-ray optical properties of lungs, namely attenuation, refraction and ultra small-angle scatter (USAXS or width) contrast ratios as a function of lung orientation in free-breathing or respiratory-gated mice before and after intra-nasal bacterial endotoxin (lipopolysaccharide) instillation. The lung ultra small-angle scatter and attenuation contrast ratios were significantly higher 9 h post lipopolysaccharide instillation compared to saline treatment whereas the refraction contrast decreased in magnitude. In ventilated mice, end-expiratory pressures result in an increase in ultra small-angle scatter contrast ratio when compared to end-inspiratory pressures. There were no detectable changes in lung attenuation or refraction contrast ratio with change in lung pressure alone. In effect, multiple image radiography can be applied towards following optical properties of lung air-tissue barrier over time during pathologies such as acute lung injury.

Platelet kinetics and biodistribution in canine endotoxemia

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sostman, H.D.; Zoghbi, S.S.; Smith, G.J.

Kinetics and magnitudes of changes in indium-labeled platelet biodistribution were studied in dogs given E. coli endotoxin. Marked, reversible, dose-dependent shifts of platelets from blood to lung and apparently irreversible shifts to liver were demonstrated. These were contemporaneous with alterations in blood gases and in pulmonary and systemic hemodynamics. Morphologic studies revealed atelectasis, sequestration of leukocytes and platelets in the lungs, and mild interstitial pulmonary edema. This study provides in vivo quantification of labeled platelet response to a specific stimulus, and illustrates a method that could be applied to more extensive study of blood element participation in acute lung injury.

Micro-imaging of the Mouse Lung via MRI

NASA Astrophysics Data System (ADS)

Wang, Wei

Quantitative measurement of lung microstructure is of great significance in assessment of pulmonary disease, particularly in the earliest stages. Conventional stereological assessment of ex-vivo fixed tissue specimens under the microscope has a long and successful tradition and is regarded as a gold standard, but the invasive nature limits its applications and the practicality of use in longitudinal studies. The technique for diffusion MRI-based 3He lung morphometry was previously developed and validated for human lungs, and was recently extended to ex-vivo mouse lungs. The technique yields accurate, quantitative information about the microstructure and geometry of acinar airways. In this dissertation, the 3He lung morphometry technique is for the first time successfully implemented for in-vivo studies of mice. It can generate spatially-resolved maps of parameters that reveal the microstructure of mouse lung. Results in healthy mice indicate excellent agreement between in-vivo morphometry via 3He MRI and microscopic morphometry after sacrifice. The implementation and validation of 3He morphometry in healthy mice open up new avenues for application of the technique as a precise, noninvasive, in-vivo biomarker of changes in lung microstructure, within various mouse models of lung disease. We have applied 3He morphometry to the Sendai mouse model of lung disease. Specifically, the Sendai-virus model of chronic obstructive lung disease has demonstrated an innate immune response in mouse airways that exhibits similarities to the chronic airway inflammation in human COPD and asthma, but the effect on distal lung parenchyma had not been investigated. We imaged the time course and regional distribution of mouse lung microstructural changes in vivo after Sendai virus (SeV) infection with 1H and 3He diffusion MRI. 1H MR images detected the SeV-induced pulmonary inflammation in vivo and 3He lung morphometry showed modest increase in alveolar duct radius distal to airway inflammation, particularly in the lung periphery, indicating airspace enlargement after virus infection. Another important application of the imaging technique is the study of lung regeneration in a pneumonectomy (PNX) model. Partial resection of the lung by unilateral PNX is a robust model of compensatory lung growth. It is typically studied by postmortem morphometry in which longitudinal assessment in the same animal cannot be achieved. Here we successfully assess the microstructural changes and quantify the compensatory lung growth in vivo in the PNX mouse model via 1H and hyperpolarized 3He diffusion MRI. Our results show complete restoration in lung volume and total alveolar number with enlargement of alveolar size, which is consistent with prior histological studies conducted in different animals at various time points. This dissertation demonstrates that 3He lung morphometry has good sensitivity in quantifying small microstructural changes in the mouse lung and can be applied to a variety of mouse pulmonary models. Particularly, it has great potential to become a valuable tool in understanding the time course and the mechanism of lung growth in individual animals and may provide insight into post-natal lung growth and lung regeneration.

Gravity and the Evolution of Cardiopulmonary Morphology in Snakes

PubMed Central

Lillywhite, Harvey B.; Albert, James S.; Sheehy, Coleman M.; Seymour, Roger S.

2011-01-01

Physiological investigations of snakes have established the importance of heart position and pulmonary structure in contexts of gravity effects on blood circulation. Here we investigate morphological correlates of cardiopulmonary physiology in contexts related to ecology, behavior and evolution. We analyze data for heart position and length of vascular lung in 154 species of snakes that exhibit a broad range of characteristic behaviors and habitat associations. We construct a composite phylogeny for these species, and we codify gravitational stress according to species habitat and behavior. We use conventional regression and phylogenetically independent contrasts to evaluate whether trait diversity is correlated with gravitational habitat related to evolutionary transitions within the composite tree topology. We demonstrate that snake species living in arboreal habitats, or which express strongly climbing behaviors, possess relatively short blood columns between the heart and the head, as well as relatively short vascular lungs, compared to terrestrial species. Aquatic species, which experience little or no gravity stress in water, show the reverse – significantly longer heart–head distance and longer vascular lungs. These phylogenetic differences complement the results of physiological studies and are reflected in multiple habitat transitions during the evolutionary histories of these snake lineages, providing strong evidence that heart–to–head distance and length of vascular lung are co–adaptive cardiopulmonary features of snakes. PMID:22079804

Metastatic potential of lung squamous cell carcinoma associated with HSPC300 through its interaction with WAVE2.

PubMed

Cai, Xiongwei; Xiao, Ting; James, Sharon Y; Da, Jiping; Lin, Dongmei; Liu, Yu; Zheng, Yang; Zou, Shuangmei; Di, Xuebing; Guo, Suping; Han, Naijun; Lu, Yong-Jie; Cheng, Shujun; Gao, Yanning; Zhang, Kaitai

2009-09-01

The small protein, HSPC300 (haematopoietic stem/progenitor cell protein 300), is associated with reorganization of actin filaments and cell movement, but its activity has not been reported in human cancer cells. Here, we investigated the association of HSPC300 expression with clinical features of lung squamous cell carcinoma. High levels of HSPC300 protein were detected in 84.1% of tumour samples, and in 30.8% of adjacent morphologically normal tissues. The number of primary tumours with elevated HSPC300 levels was significantly higher in primary tumours with lymph node metastases as opposed to those without, and also in tumours from patients with more advanced disease. HSPC300 modulates the morphology and motility of cells, as siRNA knockdown caused the reorganization of actin filaments, decreased the formation of pseudopodia, and inhibited the migration of a lung cancer cell line. We further showed that HSPC300 interacted with the WAVE2 protein, and HSPC300 silencing resulted in the degradation of WAVE2 in vitro. HSPC300 and WAVE2 were co-expressed in approximately 85.7% of primary tumours with lymph node metastases. We hypothesize that HSPC300 is associated with metastatic potential of lung squamous cell carcinoma through its interaction with WAVE2.

From Curves to Trees: A Tree-like Shapes Distance Using the Elastic Shape Analysis Framework.

PubMed

Mottini, A; Descombes, X; Besse, F

2015-04-01

Trees are a special type of graph that can be found in various disciplines. In the field of biomedical imaging, trees have been widely studied as they can be used to describe structures such as neurons, blood vessels and lung airways. It has been shown that the morphological characteristics of these structures can provide information on their function aiding the characterization of pathological states. Therefore, it is important to develop methods that analyze their shape and quantify differences between their structures. In this paper, we present a method for the comparison of tree-like shapes that takes into account both topological and geometrical information. This method, which is based on the Elastic Shape Analysis Framework, also computes the mean shape of a population of trees. As a first application, we have considered the comparison of axon morphology. The performance of our method has been evaluated on two sets of images. For the first set of images, we considered four different populations of neurons from different animals and brain sections from the NeuroMorpho.org open database. The second set was composed of a database of 3D confocal microscopy images of three populations of axonal trees (normal and two types of mutations) of the same type of neurons. We have calculated the inter and intra class distances between the populations and embedded the distance in a classification scheme. We have compared the performance of our method against three other state of the art algorithms, and results showed that the proposed method better distinguishes between the populations. Furthermore, we present the mean shape of each population. These shapes present a more complete picture of the morphological characteristics of each population, compared to the average value of certain predefined features.

[Diagnosis, prognosis, and prediction of non-small cell lung cancer. Importance of morphology, immunohistochemistry and molecular pathology].

PubMed

Warth, A

2015-11-01

Tumor diagnostics are based on histomorphology, immunohistochemistry and molecular pathological analysis of mutations, translocations and amplifications which are of diagnostic, prognostic and/or predictive value. In recent decades only histomorphology was used to classify lung cancer as either small (SCLC) or non-small cell lung cancer (NSCLC), although NSCLC was further subdivided in different entities; however, as no specific therapy options were available classification of specific subtypes was not clinically meaningful. This fundamentally changed with the discovery of specific molecular alterations in adenocarcinoma (ADC), e.g. mutations in KRAS, EGFR and BRAF or translocations of the ALK and ROS1 gene loci, which now form the basis of targeted therapies and have led to a significantly improved patient outcome. The diagnostic, prognostic and predictive value of imaging, morphological, immunohistochemical and molecular characteristics as well as their interaction were systematically assessed in a large cohort with available clinical data including patient survival. Specific and sensitive diagnostic markers and marker panels were defined and diagnostic test algorithms for predictive biomarker assessment were optimized. It was demonstrated that the semi-quantitative assessment of ADC growth patterns is a stage-independent predictor of survival and is reproducibly applicable in the routine setting. Specific histomorphological characteristics correlated with computed tomography (CT) imaging features and thus allowed an improved interdisciplinary classification, especially in the preoperative or palliative setting. Moreover, specific molecular characteristics, for example BRAF mutations and the proliferation index (Ki-67) were identified as clinically relevant prognosticators. Comprehensive clinical, morphological, immunohistochemical and molecular assessment of NSCLCs allow an optimized patient stratification. Respective algorithms now form the backbone of the 2015 lung cancer World Health Organization (WHO) classification.

Isolation, in vitro culture and identification of a new type of mesenchymal stem cell derived from fetal bovine lung tissues.

PubMed

Hu, Pengfei; Pu, Yabin; Li, Xiayun; Zhu, Zhiqiang; Zhao, Yuhua; Guan, Weijun; Ma, Yuehui

2015-09-01

Lung‑derived mesenchymal stem cells (LMSCs) are considered to be important in lung tissue repair and regenerative processes. However, the biological characteristics and differentiation potential of LMSCs remain to be elucidated. In the present study, fetal lung‑derived mesenchymal stem cells (FLMSCs) were isolated from fetal bovine lung tissues by collagenase digestion. The in vitro culture conditions were optimized and stabilized and the self‑renewal ability and differentiation potential were evaluated. The results demonstrated that the FLMSCs were morphologically consistent with fibroblasts, were able to be cultured and passaged for at least 33 passages and the cell morphology and proliferative ability were stable during the first 10 passages. In addition, FLMSCs were found to express CD29, CD44, CD73 and CD166, however, they did not express hematopoietic cell specific markers, including CD34, CD45 and BOLA‑DRα. The growth kinetics of FLMSCs consisted of a lag phase, a logarithmic phase and a plateau phase, and as the passages increased, the proliferative ability of cells gradually decreased. The majority of FLMSCs were in G0/G1 phase. Following osteogenic induction, FLMSCs were positive for the expression of osteopontin and collagen type I α2. Following neurogenic differentiation, the cells were morphologically consistent with neuronal cells and positive for microtubule‑associated protein 2 and nestin expression. It was concluded that the isolated FLMSCs exhibited typical characteristics of mesenchymal stem cells and that the culture conditions were suitable for their proliferation and the maintenance of stemness. The present study illustrated the potential application of lung tissue as an adult stem cell source for regenerative therapies.

Exploiting unsupervised and supervised classification for segmentation of the pathological lung in CT

NASA Astrophysics Data System (ADS)

Korfiatis, P.; Kalogeropoulou, C.; Daoussis, D.; Petsas, T.; Adonopoulos, A.; Costaridou, L.

2009-07-01

Delineation of lung fields in presence of diffuse lung diseases (DLPDs), such as interstitial pneumonias (IP), challenges segmentation algorithms. To deal with IP patterns affecting the lung border an automated image texture classification scheme is proposed. The proposed segmentation scheme is based on supervised texture classification between lung tissue (normal and abnormal) and surrounding tissue (pleura and thoracic wall) in the lung border region. This region is coarsely defined around an initial estimate of lung border, provided by means of Markov Radom Field modeling and morphological operations. Subsequently, a support vector machine classifier was trained to distinguish between the above two classes of tissue, using textural feature of gray scale and wavelet domains. 17 patients diagnosed with IP, secondary to connective tissue diseases were examined. Segmentation performance in terms of overlap was 0.924±0.021, and for shape differentiation mean, rms and maximum distance were 1.663±0.816, 2.334±1.574 and 8.0515±6.549 mm, respectively. An accurate, automated scheme is proposed for segmenting abnormal lung fields in HRC affected by IP

Predictive capabilities of statistical learning methods for lung nodule malignancy classification using diagnostic image features: an investigation using the Lung Image Database Consortium dataset

NASA Astrophysics Data System (ADS)

Hancock, Matthew C.; Magnan, Jerry F.

2017-03-01

To determine the potential usefulness of quantified diagnostic image features as inputs to a CAD system, we investigate the predictive capabilities of statistical learning methods for classifying nodule malignancy, utilizing the Lung Image Database Consortium (LIDC) dataset, and only employ the radiologist-assigned diagnostic feature values for the lung nodules therein, as well as our derived estimates of the diameter and volume of the nodules from the radiologists' annotations. We calculate theoretical upper bounds on the classification accuracy that is achievable by an ideal classifier that only uses the radiologist-assigned feature values, and we obtain an accuracy of 85.74 (+/-1.14)% which is, on average, 4.43% below the theoretical maximum of 90.17%. The corresponding area-under-the-curve (AUC) score is 0.932 (+/-0.012), which increases to 0.949 (+/-0.007) when diameter and volume features are included, along with the accuracy to 88.08 (+/-1.11)%. Our results are comparable to those in the literature that use algorithmically-derived image-based features, which supports our hypothesis that lung nodules can be classified as malignant or benign using only quantified, diagnostic image features, and indicates the competitiveness of this approach. We also analyze how the classification accuracy depends on specific features, and feature subsets, and we rank the features according to their predictive power, statistically demonstrating the top four to be spiculation, lobulation, subtlety, and calcification.

Quantitative lung perfusion evaluation using Fourier decomposition perfusion MRI.

PubMed

Kjørstad, Åsmund; Corteville, Dominique M R; Fischer, Andre; Henzler, Thomas; Schmid-Bindert, Gerald; Zöllner, Frank G; Schad, Lothar R

2014-08-01

To quantitatively evaluate lung perfusion using Fourier decomposition perfusion MRI. The Fourier decomposition (FD) method is a noninvasive method for assessing ventilation- and perfusion-related information in the lungs, where the perfusion maps in particular have shown promise for clinical use. However, the perfusion maps are nonquantitative and dimensionless, making follow-ups and direct comparisons between patients difficult. We present an approach to obtain physically meaningful and quantifiable perfusion maps using the FD method. The standard FD perfusion images are quantified by comparing the partially blood-filled pixels in the lung parenchyma with the fully blood-filled pixels in the aorta. The percentage of blood in a pixel is then combined with the temporal information, yielding quantitative blood flow values. The values of 10 healthy volunteers are compared with SEEPAGE measurements which have shown high consistency with dynamic contrast enhanced-MRI. All pulmonary blood flow (PBF) values are within the expected range. The two methods are in good agreement (mean difference = 0.2 mL/min/100 mL, mean absolute difference = 11 mL/min/100 mL, mean PBF-FD = 150 mL/min/100 mL, mean PBF-SEEPAGE = 151 mL/min/100 mL). The Bland-Altman plot shows a good spread of values, indicating no systematic bias between the methods. Quantitative lung perfusion can be obtained using the Fourier Decomposition method combined with a small amount of postprocessing. Copyright © 2013 Wiley Periodicals, Inc.

[Immunohistochemical description of proliferative activity and apoptosis of lung squamous cell carcinoma (literature review)].

PubMed

Филенко, Борис Н; Ройко, Наталия В; Степанчук, Алла П; Проскурня, Сергей А

2016-01-01

The analysis of the publications are describe immunohistochemical study of proliferative activity and apoptosis of lung squamous cell carcinoma. Established that the imbalance between proliferation and cell death is a key process in the development of tumors. However, the value of tumor markers in histogenesis and morfogenesis of tumors and forecast their occurrence is not studied enough. Despite the significant amount of scientific literature devoted to this issue, has not yet established a clear link expression of immunohistochemical markers of proliferation and apoptosis with the degree of differentiation of squamous cell lung cancer. Analysis of the literature shows that the morphology of this histogenetics type lung cancer at the cellular, subcellular structural and functional levels are controversial and require detailed investigation.

Mitochondria in Lung Diseases

PubMed Central

Aravamudan, Bharathi; Thompson, Michael A.; Pabelick, Christina M.; Prakash, Y. S.

2014-01-01

Summary Mitochondria are autonomous cellular organelles that oversee a variety of functions such as metabolism, energy production, calcium buffering, and cell fate determination. Regulation of their morphology and diverse activities beyond energy production are being recognized as playing major roles in cellular health and dysfunction. This review is aimed at summarizing what is known regarding mitochondrial contributions to pathogenesis of lung diseases. Emphasis is given to understanding the importance of structural and functional aspects of mitochondria in both normal cellular function (based on knowledge from other cell types) and in development and modulation of lung diseases such as asthma, COPD, cystic fibrosis and cancer. Emerging techniques that allow examination of mitochondria, and potential strategies to target mitochondria in the treatment of lung diseases are also discussed. PMID:23978003

The evolution of morphological diversity in continental assemblages of passerine birds.

PubMed

Jønsson, Knud Andreas; Lessard, Jean-Philippe; Ricklefs, Robert E

2015-04-01

Understanding geographic variation in the species richness and lineage composition of regional biotas is a long-standing goal in ecology. Why do some evolutionary lineages proliferate while others do not, and how do new colonists fit into an established fauna? Here, we analyze the morphological structure of assemblages of passerine birds in four biogeographic regions to examine the relative influence of colonization history and niche-based processes on continental communities of passerine birds. Using morphological traits related to habitat choice, foraging technique, and movement, we quantify the morphological spaces occupied by different groups of passerine birds. We further quantify morphological overlap between groups by multivariate discriminant analysis and null model analyses of trait dispersion. Finally, we use subclade disparity through time to assess the temporal component of morphological evolution. We find mixed support for the prediction, based on priority, that first colonizers constrain subsequent colonizers. Indeed, our results show that the assembly of continental communities is idiosyncratic with regards to the diversification of new clades and the filling of morphospace. © 2015 The Author(s).

Using Image Processing to Determine Emphysema Severity

NASA Astrophysics Data System (ADS)

McKenzie, Alexander; Sadun, Alberto

2010-10-01

Currently X-rays and computerized tomography (CT) scans are used to detect emphysema, but other tests are required to accurately quantify the amount of lung that has been affected by the disease. These images clearly show if a patient has emphysema, but are unable by visual scan alone, to quantify the degree of the disease, as it presents as subtle, dark spots on the lung. Our goal is to use these CT scans to accurately diagnose and determine emphysema severity levels in patients. This will be accomplished by performing several different analyses of CT scan images of several patients representing a wide range of severity of the disease. In addition to analyzing the original CT data, this process will convert the data to one and two bit images and will then examine the deviation from a normal distribution curve to determine skewness. Our preliminary results show that this method of assessment appears to be more accurate and robust than the currently utilized methods, which involve looking at percentages of radiodensities in the air passages of the lung.

Correlation between Hox code and vertebral morphology in archosaurs.

PubMed

Böhmer, Christine; Rauhut, Oliver W M; Wörheide, Gert

2015-07-07

The relationship between developmental genes and phenotypic variation is of central interest in evolutionary biology. An excellent example is the role of Hox genes in the anteroposterior regionalization of the vertebral column in vertebrates. Archosaurs (crocodiles, dinosaurs including birds) are highly variable both in vertebral morphology and number. Nevertheless, functionally equivalent Hox genes are active in the axial skeleton during embryonic development, indicating that the morphological variation across taxa is likely owing to modifications in the pattern of Hox gene expression. By using geometric morphometrics, we demonstrate a correlation between vertebral Hox code and quantifiable vertebral morphology in modern archosaurs, in which the boundaries between morphological subgroups of vertebrae can be linked to anterior Hox gene expression boundaries. Our findings reveal homologous units of cervical vertebrae in modern archosaurs, each with their specific Hox gene pattern, enabling us to trace these homologies in the extinct sauropodomorph dinosaurs, a group with highly variable vertebral counts. Based on the quantifiable vertebral morphology, this allows us to infer the underlying genetic mechanisms in vertebral evolution in fossils, which represents not only an important case study, but will lead to a better understanding of the origin of morphological disparity in recent archosaur vertebral columns.

Correlation between Hox code and vertebral morphology in archosaurs

PubMed Central

Böhmer, Christine; Rauhut, Oliver W. M.; Wörheide, Gert

2015-01-01

The relationship between developmental genes and phenotypic variation is of central interest in evolutionary biology. An excellent example is the role of Hox genes in the anteroposterior regionalization of the vertebral column in vertebrates. Archosaurs (crocodiles, dinosaurs including birds) are highly variable both in vertebral morphology and number. Nevertheless, functionally equivalent Hox genes are active in the axial skeleton during embryonic development, indicating that the morphological variation across taxa is likely owing to modifications in the pattern of Hox gene expression. By using geometric morphometrics, we demonstrate a correlation between vertebral Hox code and quantifiable vertebral morphology in modern archosaurs, in which the boundaries between morphological subgroups of vertebrae can be linked to anterior Hox gene expression boundaries. Our findings reveal homologous units of cervical vertebrae in modern archosaurs, each with their specific Hox gene pattern, enabling us to trace these homologies in the extinct sauropodomorph dinosaurs, a group with highly variable vertebral counts. Based on the quantifiable vertebral morphology, this allows us to infer the underlying genetic mechanisms in vertebral evolution in fossils, which represents not only an important case study, but will lead to a better understanding of the origin of morphological disparity in recent archosaur vertebral columns. PMID:26085583

The association between endotoxin and lung function among children and adolescents living in a rural area

PubMed Central

Lawson, Joshua A; Dosman, James A; Rennie, Donna C; Beach, Jeremy; Newman, Stephen C; Senthilselvan, Ambikaipakan

2011-01-01

BACKGROUND/OBJECTIVES: Knowledge of the effects of domestic endotoxin on children’s lung function is limited. The association between domestic endotoxin and asthma or wheeze and lung function among school-age children (six to 18 years of age) was examined. The interaction between endotoxin and other personal and environmental characteristics and lung function was also assessed. METHODS: A case-control study was conducted in and around the rural community of Humboldt, Saskatchewan, between 2005 and 2007. Parents of cases reported either doctor-diagnosed asthma or wheeze in the previous year. Controls were randomly selected from those not reporting these conditions. Data were collected by questionnaire to ascertain symptoms and conditions, while spirometry was used to measure lung function including forced vital capacity and forced expiratory volume in 1 s. Dust collected from the child’s play area floor and the child’s mattress was used to quantify endotoxin, and saliva was collected to quantify cotinine levels and assess tobacco smoke exposure. RESULTS: There were 102 cases and 207 controls included in the present study. Lower forced expiratory volume in 1 s was associated with higher mattress endotoxin load among female cases (beta=−0.25, SE=0.07 [P<0.01]). There was a trend toward lower forced vital capacity, which was associated with higher play area endotoxin load among cases with high tobacco smoke exposure (beta=−0.17, SE=0.09 [P<0.10]). CONCLUSIONS: Findings indicated that high endotoxin levels present in common household areas of rural children with asthma or wheeze may also affect their lung function. These associations may be potentiated by tobacco smoke exposure and female sex. PMID:22187693

Risk Factors Associated with Quantitative Evidence of Lung Emphysema and Fibrosis in an HIV-infected Cohort

PubMed Central

Leader, Joseph K.; Crothers, Kristina; Huang, Laurence; King, Mark A.; Morris, Alison; Thompson, Bruce W.; Flores, Sonia C.; Drummond, M. Bradley; Rom, William N.; Diaz, Philip T.

2015-01-01

Introduction The disease spectrum for HIV-infected individuals has shifted towards co-morbid non-AIDS conditions including chronic lung disease, but quantitative image analysis of lung disease has not been performed. Objectives To quantify the prevalence of structural changes of the lung indicating emphysema or fibrosis on radiographic examination. Methods A cross-sectional analysis of 510 HIV-infected participants in the multi-center Lung-HIV study was performed. Data collected included: demographics, biological markers of HIV, pulmonary function testing, and chest CT examinations. Emphysema and fibrosis-like changes were quantified on CT images based on threshold approaches. Results In our cohort: 69% was on antiretroviral therapy, 13% had a current CD4 cell count less than 200 cells/μL, 39% had an HIV viral load greater than 500 copies/mL, 25% had at least a trace level of emphysema (defined as >2.5% of voxels <-950HU). Trace emphysema was significantly correlated with age, smoking, and pulmonary function. Neither current CD4 cell count nor HIV viral load was significantly correlated with emphysema. Fibrosis-like changes were detected in 29% of the participants and were significantly correlated with HIV viral load (Pearson correlation coefficient = 0.210, p<0.05); current CD4 cell count was not associated with fibrosis. In multivariable analyses including age, race, and smoking status, HIV viral load remained significantly correlated with fibrosis-like changes (coefficient = 0.107, P = 0.03). Conclusion A higher HIV viral load was significantly associated with fibrosis-like changes possibly indicating early interstitial lung disease, but emphysematous changes were not related to current CD4 cell count or HIV viral load. PMID:26914911

Loss of the endothelial glycocalyx is associated with increased E-selectin mediated adhesion of lung tumour cells to the brain microvascular endothelium.

PubMed

Rai, Srijana; Nejadhamzeeigilani, Zaynab; Gutowski, Nicholas J; Whatmore, Jacqueline L

2015-09-25

Arrest of metastasising lung cancer cells to the brain microvasculature maybe mediated by interactions between ligands on circulating tumour cells and endothelial E-selectin adhesion molecules; a process likely to be regulated by the endothelial glycocalyx. Using human cerebral microvascular endothelial cells and non-small cell lung cancer (NSCLC) cell lines, we describe how factors secreted by NSCLC cells i.e. cystatin C, cathepsin L, insulin-like growth factor-binding protein 7 (IGFBP7), vascular endothelial growth factor (VEGF) and tumour necrosis factor-alpha (TNF-α), damage the glycocalyx and enhance initial contacts between lung tumour and cerebral endothelial cells. Endothelial cells were treated with tumour secreted-proteins or lung tumour conditioned medium (CM). Surface levels of E-selectin were quantified by ELISA. Adhesion of A549 and SK-MES-1 cells was examined under flow conditions (1 dyne/cm(2)). Alterations in the endothelial glycocalyx were quantified by binding of fluorescein isothiocyanate-linked wheat germ agglutinin (WGA-FITC). A549 and SK-MES-1 CM and secreted-proteins significantly enhanced endothelial surface E-selectin levels after 30 min and 4 h and tumour cell adhesion after 30 min, 4 and 24 h. Both coincided with significant glycocalyx degradation; A549 and SK-MES-1 CM removing 55 ± 12 % and 58 ± 18.7 % of WGA-FITC binding, respectively. Inhibition of E-selectin binding by monoclonal anti-E-selectin antibody completely attenuated tumour cell adhesion. These data suggest that metastasising lung cancer cells facilitate their own adhesion to the brain endothelium by secreting factors that damage the endothelial glycocalyx, resulting in exposure of the previously shielded adhesion molecules and engagement of the E-selectin-mediated adhesion axis.

Cryopreservation of Viable Human Lung Tissue for Versatile Post-thaw Analyses and Culture

PubMed Central

Baatz, John E.; Newton, Danforth A.; Riemer, Ellen C.; Denlinger, Chadrick E.; Jones, E. Ellen; Drake, Richard R.; Spyropoulos, Demetri D.

2018-01-01

Clinical trials are currently used to test therapeutic efficacies for lung cancer, infections and diseases. Animal models are also used as surrogates for human disease. Both approaches are expensive and time-consuming. The utility of human biospecimens as models is limited by specialized tissue processing methods that preserve subclasses of analytes (e.g. RNA, protein, morphology) at the expense of others. We present a rapid and reproducible method for the cryopreservation of viable lung tissue from patients undergoing lobectomy or transplant. This method involves the pseudo-diaphragmatic expansion of pieces of fresh lung tissue with cryoprotectant formulation (pseudo-diaphragmatic expansion-cryoprotectant perfusion or PDX-CP) followed by controlled-rate freezing in cryovials. Expansion-perfusion rates, volumes and cryoprotectant formulation were optimized to maintain tissue architecture, decrease crystal formation and increase long-term cell viability. Rates of expansion of 4 cc/min or less and volumes ranging from 0.8–1.2 × tissue volume were well-tolerated by lung tissue obtained from patients with chronic obstructive pulmonary disease or idiopathic pulmonary fibrosis, showing minimal differences compared to standard histopathology. Morphology was greatly improved by the PDX-CP procedure compared to simple fixation. Fresh versus post-thawed lung tissue showed minimal differences in histology, RNA integrity numbers and post-translational modified protein integrity (2-dimensional differential gel electrophoresis). It was possible to derive numerous cell types, including alveolar epithelial cells, fibroblasts and stem cells, from the tissue for at least three months after cryopreservation. This new method should provide a uniform, cost-effective approach to the banking of biospecimens, with versatility to be amenable to any post-acquisition process applicable to fresh tissue samples. PMID:24982205

3He Lung Morphometry Technique: Accuracy Analysis and Pulse Sequence Optimization

PubMed Central

Sukstanskii, A.L.; Conradi, M.S.; Yablonskiy, D.A.

2010-01-01

The 3He lung morphometry technique (Yablonskiy et al, JAP, 2009), based on MRI measurements of hyperpolarized gas diffusion in lung airspaces, provides unique information on the lung microstructure at the alveolar level. 3D tomographic images of standard morphological parameters (mean airspace chord length, lung parenchyma surface-to-volume ratio, and the number of alveoli per unit lung volume) can be created from a rather short (several seconds) MRI scan. These parameters are most commonly used to characterize lung morphometry but were not previously available from in vivo studies. A background of the 3He lung morphometry technique is based on a previously proposed model of lung acinar airways, treated as cylindrical passages of external radius R covered by alveolar sleeves of depth h, and on a theory of gas diffusion in these airways. The initial works approximated the acinar airways as very long cylinders, all with the same R and h. The present work aims at analyzing effects of realistic acinar airway structures, incorporating airway branching, physiological airway lengths, a physiological ratio of airway ducts and sacs, and distributions of R and h. By means of Monte Carlo computer simulations, we demonstrate that our technique allows rather accurate measurements of geometrical and morphological parameters of acinar airways. In particular, the accuracy of determining one of the most important physiological parameter of acinar airways – surface-to-volume ratio – does not exceed several percent. Second, we analyze the effect of the susceptibility induced inhomogeneous magnetic field on the parameter estimate and demonstrate that this effect is rather negligible at B0 ≤ 3T and becomes substantial only at higher B0 Third, we theoretically derive an optimal choice of MR pulse sequence parameters, which should be used to acquire a series of diffusion attenuated MR signals, allowing a substantial decrease in the acquisition time and improvement in accuracy of the results. It is demonstrated that the optimal choice represents three not equidistant b-values: b1 = 0, b2 ~ 2 s/cm2, b3 ~ 8 s/cm2. PMID:20937564

Lung adenocarcinoma mimicking pulmonary fibrosis-a case report.

PubMed

Mehić, Bakir; Duranović Rayan, Lina; Bilalović, Nurija; Dohranović Tafro, Danina; Pilav, Ilijaz

2016-09-13

Lung cancer is usually presented with cough, dyspnea, pain and weight loss, which is overlapping with symptoms of other lung diseases such as pulmonary fibrosis. Pulmonary fibrosis shows characteristic reticular and nodular pattern, while lung cancers are mostly presented with infiltrative mass, thick-walled cavitations or a solitary nodule with spiculated borders. If the diagnosis is established based on clinical symptoms and CT findings, it would be a misapprehension. We report a case of lung adenocarcinoma whose symptoms as well as clinical images overlapped strongly with pulmonary fibrosis. The patient's non-productive cough, progressive dyspnea, restrictive pattern of pulmonary function test and CT scans (showing reticular interstitial opacities) were all indicative of pulmonary fibrosis. The patient underwent a treatment consisting of corticosteroids and antibiotics, to no avail. Histopathology of the lung showed that the patient suffered from mucinous adenocarcinoma. Albeit the immunohistochemical staining was not consistent with lung adenocarcinoma, tumor's morphological characteristics were consistent, and were used to make the definitive diagnosis. Given the fact that radiography cannot always make a clear-cut difference between pulmonary fibrosis and lung adenocarcinomas, and that clinical symptoms often overlap, histological examination should be considered as gold standard for diagnosis of lung adenocarcinoma.

Changes in Morphological and Elastic Properties of Patellar Tendon in Athletes with Unilateral Patellar Tendinopathy and Their Relationships with Pain and Functional Disability

PubMed Central

Zhang, Zhi Jie; Ng, Gabriel Yin-fat; Lee, Wai Chun; Fu, Siu Ngor

2014-01-01

Background Patellar tendinopathy (PT) is one of the most common knee disorders among athletes. Changes in morphology and elasticity of the painful tendon and how these relate to the self-perceived pain and dysfunction remain unclear. Objectives To compare the morphology and elastic properties of patellar tendons between athlete with and without unilateral PT and to examine its association with self-perceived pain and dysfunction. Methods In this cross-sectional study, 33 male athletes (20 healthy and 13 with unilateral PT) were enrolled. The morphology and elastic properties of the patellar tendon were assessed by the grey and elastography mode of supersonic shear imaging (SSI) technique while the intensity of pressure pain, self-perceived pain and dysfunction were quantified with a 10-lb force to the most painful site and the Victorian Institute of Sport Assessment-patella (VISA-P) questionnaire, respectively. Results In athletes with unilateral PT, the painful tendons had higher shear elastic modulus (SEM) and larger tendon than the non-painful side (p<0.05) or the dominant side of the healthy athletes (p<0.05). Significant correlations were found between tendon SEM ratio (SEM of painful over non-painful tendon) and the intensity of pressure pain (rho  = 0.62; p = 0.024), VISA-P scores (rho  = −0.61; p = 0.026), and the sub-scores of the VISA-P scores on going down stairs, lunge, single leg hopping and squatting (rho ranged from −0.63 to −0.67; p<0.05). Conclusions Athletes with unilateral PT had stiffer and larger tendon on the painful side than the non-painful side and the dominant side of healthy athletes. No significant differences on the patellar tendon morphology and elastic properties were detected between the dominant and non-dominant knees of the healthy control. The ratio of the SEM of painful to non-painful sides was associated with pain and dysfunction among athletes with unilateral PT. PMID:25303466

Quantifying the impact of respiratory-gated 4D CT acquisition on thoracic image quality: a digital phantom study.

PubMed

Bernatowicz, K; Keall, P; Mishra, P; Knopf, A; Lomax, A; Kipritidis, J

2015-01-01

Prospective respiratory-gated 4D CT has been shown to reduce tumor image artifacts by up to 50% compared to conventional 4D CT. However, to date no studies have quantified the impact of gated 4D CT on normal lung tissue imaging, which is important in performing dose calculations based on accurate estimates of lung volume and structure. To determine the impact of gated 4D CT on thoracic image quality, the authors developed a novel simulation framework incorporating a realistic deformable digital phantom driven by patient tumor motion patterns. Based on this framework, the authors test the hypothesis that respiratory-gated 4D CT can significantly reduce lung imaging artifacts. Our simulation framework synchronizes the 4D extended cardiac torso (XCAT) phantom with tumor motion data in a quasi real-time fashion, allowing simulation of three 4D CT acquisition modes featuring different levels of respiratory feedback: (i) "conventional" 4D CT that uses a constant imaging and couch-shift frequency, (ii) "beam paused" 4D CT that interrupts imaging to avoid oversampling at a given couch position and respiratory phase, and (iii) "respiratory-gated" 4D CT that triggers acquisition only when the respiratory motion fulfills phase-specific displacement gating windows based on prescan breathing data. Our framework generates a set of ground truth comparators, representing the average XCAT anatomy during beam-on for each of ten respiratory phase bins. Based on this framework, the authors simulated conventional, beam-paused, and respiratory-gated 4D CT images using tumor motion patterns from seven lung cancer patients across 13 treatment fractions, with a simulated 5.5 cm(3) spherical lesion. Normal lung tissue image quality was quantified by comparing simulated and ground truth images in terms of overall mean square error (MSE) intensity difference, threshold-based lung volume error, and fractional false positive/false negative rates. Averaged across all simulations and phase bins, respiratory-gating reduced overall thoracic MSE by 46% compared to conventional 4D CT (p ∼ 10(-19)). Gating leads to small but significant (p < 0.02) reductions in lung volume errors (1.8%-1.4%), false positives (4.0%-2.6%), and false negatives (2.7%-1.3%). These percentage reductions correspond to gating reducing image artifacts by 24-90 cm(3) of lung tissue. Similar to earlier studies, gating reduced patient image dose by up to 22%, but with scan time increased by up to 135%. Beam paused 4D CT did not significantly impact normal lung tissue image quality, but did yield similar dose reductions as for respiratory-gating, without the added cost in scanning time. For a typical 6 L lung, respiratory-gated 4D CT can reduce image artifacts affecting up to 90 cm(3) of normal lung tissue compared to conventional acquisition. This image improvement could have important implications for dose calculations based on 4D CT. Where image quality is less critical, beam paused 4D CT is a simple strategy to reduce imaging dose without sacrificing acquisition time.

Effect of Maternal Electroacupuncture on Perinatal Nicotine Exposure-Induced Lung Phenotype in Offspring.

PubMed

Ji, Bo; Zhao, Guo-Zhen; Sakurai, Reiko; Cao, Yu; Zhang, Zi-Jian; Wang, Dan; Yan, Ming-Na; Rehan, Virender K

2016-08-01

Pregnant women exposed to tobacco smoke predispose the offspring to many adverse consequences including an altered lung development and function. There is no effective therapeutic intervention to block the effects of smoke exposure on the developing lung. Clinical and animal studies demonstrate that acupuncture can modulate a variety of pathophysiological processes, including those involving the respiratory system; however, whether acupuncture affects the lung damage caused by perinatal smoke exposure is not known. To determine the effect of acupuncture on perinatal nicotine exposure on the developing lung, pregnant rat dams were administered (1) saline, (2) nicotine, or (3) nicotine + electroacupuncture (EA). Nicotine was administered (1 mg/kg subcutaneously) once a day and EA was applied to both "Zusanli" (ST 36) points. Both interventions were administered from gestational day 6 to postnatal day 21 (PND21), following which pups were sacrificed. Lungs, blood, and brain were collected to examine markers of lung injury, repair, and hypothalamic pituitary adrenal (HPA) axis. Concomitant EA application blocked nicotine-induced changes in lung morphology, lung peroxisome proliferator-activated receptor γ and wingless-int signaling, two key lung developmental signaling pathways, hypothalamic pituitary adrenal axis (hypothalamic corticotropic releasing hormone and lung glucocorticoid receptor levels), and plasma β-endorphin levels. Electroacupuncture blocks the nicotine-induced changes in lung developmental signaling pathways and the resultant myogenic lung phenotype, known to be present in the affected offspring. We conclude that EA is a promising novel intervention against the smoke exposed lung damage to the developing lung.

Preanalytics in lung cancer.

PubMed

Warth, Arne; Muley, Thomas; Meister, Michael; Weichert, Wilko

2015-01-01

Preanalytic sampling techniques and preparation of tissue specimens strongly influence analytical results in lung tissue diagnostics both on the morphological but also on the molecular level. However, in contrast to analytics where tremendous achievements in the last decade have led to a whole new portfolio of test methods, developments in preanalytics have been minimal. This is specifically unfortunate in lung cancer, where usually only small amounts of tissue are at hand and optimization in all processing steps is mandatory in order to increase the diagnostic yield. In the following, we provide a comprehensive overview on some aspects of preanalytics in lung cancer from the method of sampling over tissue processing to its impact on analytical test results. We specifically discuss the role of preanalytics in novel technologies like next-generation sequencing and in the state-of the-art cytology preparations. In addition, we point out specific problems in preanalytics which hamper further developments in the field of lung tissue diagnostics.

Individually programmable cell stretching microwell arrays actuated by a Braille display.

PubMed

Kamotani, Yoko; Bersano-Begey, Tommaso; Kato, Nobuhiro; Tung, Yi-Chung; Huh, Dongeun; Song, Jonathan W; Takayama, Shuichi

2008-06-01

Cell culture systems are often static and are therefore nonphysiological. In vivo, many cells are exposed to dynamic surroundings that stimulate cellular responses in a process known as mechanotransduction. To recreate this environment, stretchable cell culture substrate systems have been developed, however, these systems are limited by being macroscopic and low throughput. We have developed a device consisting of 24 miniature cell stretching chambers with flexible bottom membranes that are deformed using the computer-controlled, piezoelectrically actuated pins of a Braille display. We have also developed efficient image capture and analysis protocols to quantify morphological responses of the cells to applied strain. Human dermal microvascular endothelial cells (HDMECs) were found to show increasing degrees of alignment and elongation perpendicular to the radial strain in response to cyclic stretch at increasing frequencies of 0.2, 1, and 5 Hz, after 2, 4, and 12h. Mouse myogenic C2C12 cells were also found to align in response to the stretch, while A549 human lung adenocarcinoma epithelial cells did not respond to stretch.

Individually Programmable Cell Stretching Microwell Arrays Actuated by a Braille Display

PubMed Central

Kamotani, Yoko; Bersano-Begey, Tommaso; Kato, Nobuhiro; Tung, Yi-chung; Huh, Dongeun; Song, Jonathan W.; Takayama, Shuichi

2008-01-01

Cell culture systems are often static and are therefore nonphysiological. In vivo, many cells are exposed to dynamic surroundings that stimulate cellular responses in a process known as mechanotransduction. To recreate this environment, stretchable cell culture substrate systems have been developed, however these systems are limited by being macroscopic and low throughput. We have developed a device consisting of 24 miniature cell stretching chambers with flexible bottom membranes that are deformed using the computer-controlled, piezoelectrically actuated pins of a Braille display. We have also developed efficient image capture and analysis protocols to quantify morphological responses of the cells to applied strain. Human dermal microvascular endothelial cells (HDMECs) were found to show increasing degrees of alignment and elongation perpendicular to the radial strain in response to cyclic stretch at increasing frequencies of 0.2, 1, and 5 Hz, after 2, 4, and 12 hours. Mouse myogenic C2C12 cells were also found to align in response to the stretch, while A549 human lung adenocarcinoma epithelial cells did not respond to stretch. PMID:18342367

Dynamic MRI of Grid-Tagged Hyperpolarized Helium-3 for the Assessment of Lung Motion During Breathing

DOE Office of Scientific and Technical Information (OSTI.GOV)

Cai Jing; Sheng Ke; Benedict, Stanley H.

2009-09-01

Purpose: To develop a dynamic magnetic resonance imaging (MRI) tagging technique using hyperpolarized helium-3 (HP He-3) to track lung motion. Methods and Materials: An accelerated non-Cartesian k-space trajectory was used to gain acquisition speed, at the cost of introducing image artifacts, providing a viable strategy for obtaining whole-lung coverage with adequate temporal resolution. Multiple-slice two-dimensional dynamic images of the lung were obtained in three healthy subjects after inhaling He-3 gas polarized to 35%-40%. Displacement, strain, and ventilation maps were computed from the observed motion of the grid peaks. Results: Both temporal and spatial variations of pulmonary mechanics were observed inmore » normal subjects, including shear motion between different lobes of the same lung. Conclusion: These initial results suggest that dynamic imaging of grid-tagged hyperpolarized magnetization may potentially be a powerful tool for observing and quantifying pulmonary biomechanics on a regional basis and for assessing, validating, and improving lung deformable image registration algorithms.« less

A conserved post-transcriptional BMP2 switch in lung cells.

PubMed

Jiang, Shan; Fritz, David T; Rogers, Melissa B

2010-05-15

An ultra-conserved sequence in the bone morphogenetic protein 2 (BMP2) 3' untranslated region (UTR) markedly represses BMP2 expression in non-transformed lung cells. In contrast, the ultra-conserved sequence stimulates BMP2 expression in transformed lung cells. The ultra-conserved sequence functions as a post-transcriptional cis-regulatory switch. A common single-nucleotide polymorphism (SNP, rs15705, +A1123C), which has been shown to influence human morphology, disrupts a conserved element within the ultra-conserved sequence and altered reporter gene activity in non-transformed lung cells. This polymorphism changed the affinity of the BMP2 RNA for several proteins including nucleolin, which has an increased affinity for the C allele. Elevated BMP2 synthesis is associated with increased malignancy in mouse models of lung cancer and poor lung cancer patient prognosis. Understanding the cis- and trans-regulatory factors that control BMP2 synthesis is relevant to the initiation or progression of pathologies associated with abnormal BMP2 levels. (c) 2010 Wiley-Liss, Inc.

Prognostic importance of pleural attachment status measured by pretreatment CT images in patients with stage IA lung adenocarcinoma: measurement of the ratio of the interface between nodule and neighboring pleura to nodule surface area

NASA Astrophysics Data System (ADS)

Kawata, Y.; Niki, N.; Kusumoto, M.; Ohmatsu, H.; Aokage, K.; Ishii, G.; Matsumoto, Y.; Tsuchida, T.; Eguchi, K.; Kaneko, M.

2018-02-01

Screening for lung cancer with low-dose computed tomography (CT) has led to increased recognition of small lung cancers and is expected to increase the rate of detection of early-stage lung cancer. Major concerns in the implementation of the CT screening of large populations include determining the appropriate management of pulmonary nodules found on a scan. The identification of patients with early-stage lung cancer who have a higher risk for relapse and who require more aggressive surveillance has been a target of intense investigation. This study was performed to investigate whether image features of internal intensity in combination with surrounding structure characteristics are associated with an increased risk of relapse in patients with stage IA lung adenocarcinoma. We focused on pleural attachment status which is one of morphological characteristics associated with prognosis in three-dimensional thoracic CT images.

Pulmonary Abnormalities in Mice with Paracoccidioidomycosis: A Sequential Study Comparing High Resolution Computed Tomography and Pathologic Findings

PubMed Central

Hidalgo, José Miguel; de Oliveira Pascarelli, Bernardo Miguel; Patiño, Jairo Hernando; Lenzi, Henrique Leonel; Restrepo, Angela; Cano, Luz Elena

2010-01-01

Background Human paracoccidioidomycosis (PCM) is an endemic fungal disease of pulmonary origin. Follow-up of pulmonary lesions by image studies in an experimental model of PCM has not been previously attempted. This study focuses on defining patterns, topography and intensity of lung lesions in experimentally infected PCM mice by means of a comparative analysis between High Resolution Computed Tomography (HRCT) and histopathologic parameters. Methodology Male BALB/c mice were intranasally inoculated with 3×106 Paracoccidioides brasiliensis (Pb) conidia (n = 50) or PBS (n = 50). HRCT was done every four weeks to determine pulmonary lesions, quantify lung density, reconstruct and quantify lung air structure. Lungs were also analyzed by histopathology and histomorphometry. Results Three different patterns of lesions were evidenced by HRCT and histopathology, as follows: nodular-diffuse, confluent and pseudo-tumoral. The lesions were mainly located around the hilus and affected more frequently the left lung. At the 4th week post-challenge HRCT showed that 80% of the Pb-infected mice had peri-bronchial consolidations associated with a significant increase in upper lung density when compared with controls, (−263±25 vs. −422±10 HU, p<0.001). After the 8th and 12th weeks, consolidation had progressed involving also the middle regions. Histopathology revealed that consolidation as assessed by HRCT was equivalent histologically to a confluent granulomatous reaction, while nodules corresponded to individual compact granulomas. At the 16th week of infection, confluent granulomas formed pseudotumoral masses that obstructed large bronchi. Discrete focal fibrosis was visible gradually around granulomas, but this finding was only evident by histopathology. Conclusions/Significance This study demonstrated that conventional HRCT is a useful tool for evaluation and quantification of pulmonary damage occurring in experimental mouse PCM. The experimental design used decreases the need to sacrifice a large number of animals, and serves to monitor treatment efficacy by means of a more rational approach to the study of human lung disease. PMID:20614019

Lung Morphometry with Hyperpolarized 129Xe: Theoretical Background

PubMed Central

Sukstanskii, A.L.; Yablonskiy, D.A.

2011-01-01

The 3He lung morphometry technique, based on MRI measurements of hyperpolarized 3He gas diffusion in lung airspaces, provides unique information on the lung microstructure at the alveolar level. In vivo 3D tomographic images of standard morphological parameters (airspace chord length, lung parenchyma surface-to-volume ratio, number of alveoli per unit volume) can be generated from a rather short (several seconds) MRI scan. The technique is based on a theory of gas diffusion in lung acinar airways and experimental measurements of diffusion attenuated MRI signal. The present work aims at developing the theoretical background of a similar technique based on hyperpolarized 129Xe gas. As the diffusion coefficient and gyromagnetic ratio of 129Xe gas are substantially different from those of 3He gas, the specific details of the theory and experimental measurements with 129Xe should be amended. We establish phenomenological relationships between acinar airway geometrical parameters and the diffusion attenuated MR signal for human and small animal lungs, both normal lungs and lungs with mild emphysema. Optimal diffusion times are shown to be about 5 ms for human and 1.3 ms for small animals. The expected uncertainties in measuring main morphometrical parameters of the lungs are estimated in the framework of Bayesian probability theory. PMID:21713985

Correlation of lung surface area to apoptosis and proliferation in human emphysema.

PubMed

Imai, K; Mercer, B A; Schulman, L L; Sonett, J R; D'Armiento, J M

2005-02-01

Pulmonary emphysema is associated with alterations in matrix proteins and protease activity. These alterations may be linked to programmed cell death by apoptosis, potentially influencing lung architecture and lung function. To evaluate apoptosis in emphysema, lung tissue was analysed from 10 emphysema patients and six individuals without emphysema (normal). Morphological analysis revealed alveolar cells in emphysematous lungs with convoluted nuclei characteristic of apoptosis. DNA fragmentation was detected using terminal deoxynucleotide transferase-mediated dUTP nick-end labelling (TUNEL) and gel electrophoresis. TUNEL revealed higher apoptosis in emphysematous than normal lungs. Markers of apoptosis, including active caspase-3, proteolytic fragment of poly (ADP-ribose) polymerase, Bax and Bad, were detected in emphysematous lungs. Linear regression showed that apoptosis was inversely correlated with surface area. Emphysematous lungs demonstrated lower surface areas and increased cell proliferation. There was no correlation between apoptosis and proliferation, suggesting that, although both events increase during emphysema, they are not in equilibrium, potentially contributing to reduced lung surface area. In summary, cell-based mechanisms associated with emphysematous parenchymal damage include increased apoptosis and cell proliferation. Apoptosis correlated with airspace enlargement, supporting epidemiological evidence of the progressive nature of emphysema. These data extend the understanding of cell dynamics and structural changes within the lung during emphysema pathogenesis.

Inhaled Vitamin D: A Novel Strategy to Enhance Neonatal Lung Maturation.

PubMed

Taylor, Sneha K; Sakurai, Reiko; Sakurai, Tokusho; Rehan, Virender K

2016-12-01

The physiologic vitamin D (VD), 1α,25(OH) 2 D 3 (1,25D) is a local paracrine/autocrine effecter of fetal lung maturation. By stimulating alveolar type II cell and lipofibroblast proliferation and differentiation, parenterally administered 1,25D has been shown to enhance neonatal lung maturation; but due to the potential systemic side effects of the parenteral route, the translational value of these findings might be limited. To minimize the possibility of systemic toxicity, we examined the effects of VD on neonatal lung maturation, when delivered directly to lungs via nebulization. One-day-old rat pups were administered three different doses of 1,25D and its physiologic precursor 25(OH)D (25D), or the diluent, via nebulization daily for 14 days. Pups were sacrificed for lung, kidneys, and blood collection to determine markers of lung maturation, and serum 25D and calcium levels. Compared to controls, nebulized 25D and 1,25D enhanced lung maturation as evidenced by the increased expression of markers of alveolar epithelial (SP-B, leptin receptor), mesenchymal (PPARγ, C/EBPα), and endothelial (VEGF, FLK-1) differentiation, surfactant phospholipid synthesis, and lung morphology without any significant increases in serum 25D and calcium levels. Inhaled VD is a potentially safe and effective novel strategy to enhance neonatal lung maturation.

Three-dimensional quadratic modeling and quantitative evaluation of the diaphragm on a volumetric CT scan in patients with chronic obstructive pulmonary disease

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chang, Yongjun

Purpose: In patients with chronic obstructive pulmonary disease (COPD), diaphragm function may deteriorate due to reduced muscle fiber length. Quantitative analysis of the morphology of the diaphragm is therefore important. In the authors current study, they propose a diaphragm segmentation method for COPD patients that uses volumetric chest computed tomography (CT) data, and they provide a quantitative analysis of the diaphragmatic dimensions. Methods: Volumetric CT data were obtained from 30 COPD patients and 10 normal control patients using a 16-row multidetector CT scanner (Siemens Sensation 16) with 0.75-mm collimation. Diaphragm segmentation using 3D ray projections on the lower surface ofmore » the lungs was performed to identify the draft diaphragmatic lung surface, which was modeled using quadratic 3D surface fitting and robust regression in order to minimize the effects of segmentation error and parameterize diaphragm morphology. This result was visually evaluated by an expert thoracic radiologist. To take into consideration the shape features of the diaphragm, several quantification parameters—including the shape index on the apex (SIA) (which was computed using gradient set to 0), principal curvatures on the apex on the fitted diaphragm surface (CA), the height between the apex and the base plane (H), the diaphragm lengths along the x-, y-, and z-axes (XL, YL, ZL), quadratic-fitted diaphragm lengths on the z-axis (FZL), average curvature (C), and surface area (SA)—were measured using in-house software and compared with the pulmonary function test (PFT) results. Results: The overall accuracy of the combined segmentation method was 97.22% ± 4.44% while the visual accuracy of the models for the segmented diaphragms was 95.28% ± 2.52% (mean ± SD). The quantitative parameters, including SIA, CA, H, XL, YL, ZL, FZL, C, and SA were 0.85 ± 0.05 (mm{sup −1}), 0.01 ± 0.00 (mm{sup −1}), 17.93 ± 10.78 (mm), 129.80 ± 11.66 (mm), 163.19 ± 13.45 (mm), 71.27 ± 17.52 (mm), 61.59 ± 16.98 (mm), 0.01 ± 0.00 (mm{sup −1}), and 34 380.75 ± 6680.06 (mm{sup 2}), respectively. Several parameters were correlated with the PFT parameters. Conclusions: The authors propose an automatic method for quantitatively evaluating the morphological parameters of the diaphragm on volumetric chest CT in COPD patients. By measuring not only the conventional length and surface area but also the shape features of the diaphragm using quadratic 3D surface modeling, the proposed method is especially useful for quantifying diaphragm characteristics. Their method may be useful for assessing morphological diaphragmatic changes in COPD patients.« less

Multifactorial Analysis of Mortality in Screening Detected Lung Cancer.

PubMed

Digumarthy, Subba R; De Man, Ruben; Canellas, Rodrigo; Otrakji, Alexi; Wang, Ge; Kalra, Mannudeep K

2018-01-01

We hypothesized that severity of coronary artery calcification (CAC), emphysema, muscle mass, and fat attenuation can help predict mortality in patients with lung cancer participating in the National Lung Screening Trial (NLST). Following regulatory approval from the Cancer Data Access System (CDAS), all patients diagnosed with lung cancer at the time of the screening study were identified. These subjects were classified into two groups: survivors and nonsurvivors at the conclusion of the NLST trial. These groups were matched based on their age, gender, body mass index (BMI), smoking history, lung cancer stage, and survival time. CAC, emphysema, muscle mass, and subcutaneous fat attenuation were quantified on baseline low-dose chest CT (LDCT) for all patients in both groups. Nonsurvivor group had significantly greater CAC, decreased muscle mass, and higher fat attenuation compared to the survivor group ( p < 0.01). No significant difference in severity of emphysema was noted between the two groups ( p > 0.1). We thus conclude that it is possible to create a quantitative prediction model for lung cancer mortality for subjects with lung cancer detected on screening low-dose CT (LDCT).

Influence of Sinogram-Affirmed Iterative Reconstruction on Computed Tomography-Based Lung Volumetry and Quantification of Pulmonary Emphysema.

PubMed

Baumueller, Stephan; Hilty, Regina; Nguyen, Thi Dan Linh; Weder, Walter; Alkadhi, Hatem; Frauenfelder, Thomas

2016-01-01

The purpose of this study was to evaluate the influence of sinogram-affirmed iterative reconstruction (SAFIRE) on quantification of lung volume and pulmonary emphysema in low-dose chest computed tomography compared with filtered back projection (FBP). Enhanced or nonenhanced low-dose chest computed tomography was performed in 20 patients with chronic obstructive pulmonary disease (group A) and in 20 patients without lung disease (group B). Data sets were reconstructed with FBP and SAFIRE strength levels 3 to 5. Two readers semiautomatically evaluated lung volumes and automatically quantified pulmonary emphysema, and another assessed image quality. Radiation dose parameters were recorded. Lung volume between FBP and SAFIRE 3 to 5 was not significantly different among both groups (all P > 0.05). When compared with those of FBP, total emphysema volume was significantly lower among reconstructions with SAFIRE 4 and 5 (mean difference, 0.56 and 0.79 L; all P < 0.001). There was no nondiagnostic image quality. Sinogram-affirmed iterative reconstruction does not alter lung volume measurements, although quantification of lung emphysema is affected at higher strength levels.

Combined human papillomavirus typing and TP53 mutation analysis in distinguishing second primary tumors from lung metastases in patients with head and neck squamous cell carcinoma.

PubMed

Daher, Tamas; Tur, Mehmet Kemal; Brobeil, Alexander; Etschmann, Benjamin; Witte, Biruta; Engenhart-Cabillic, Rita; Krombach, Gabriele; Blau, Wolfgang; Grimminger, Friedrich; Seeger, Werner; Klussmann, Jens Peter; Bräuninger, Andreas; Gattenlöhner, Stefan

2018-06-01

In head and neck squamous cell carcinoma (HNSCC), the occurrence of concurrent lung malignancies poses a significant diagnostic challenge because metastatic HNSCC is difficult to discern from second primary lung squamous cell carcinoma (SCC). However, this differentiation is crucial because the recommended treatments for metastatic HNSCC and second primary lung SCC differ profoundly. We analyzed the origin of lung tumors in 32 patients with HNSCC using human papillomavirus (HPV) typing and targeted next generation sequencing of all coding exons of tumor protein 53 (TP53). Lung tumors were clearly identified as HNSCC metastases or second primary tumors in 29 patients, thus revealing that 16 patients had received incorrect diagnoses based on clinical and morphological data alone. The HPV typing and mutation analysis of all TP53 coding exons is a valuable diagnostic tool in patients with HNSCC and concurrent lung SCC, which can help to ensure that patients receive the most suitable treatment. © 2018 Wiley Periodicals, Inc.

Development of local complexity metrics to quantify the effect of anatomical noise on detectability of lung nodules in chest CT imaging

NASA Astrophysics Data System (ADS)

Solomon, Justin; Rubin, Geoffrey; Smith, Taylor; Harrawood, Brian; Choudhury, Kingshuk Roy; Samei, Ehsan

2017-03-01

The purpose of this study was to develop metrics of local anatomical complexity and compare them with detectability of lung nodules in CT. Data were drawn retrospectively from a published perception experiment in which detectability was assessed in cases enriched with virtual nodules (13 radiologists x 157 total nodules = 2041 responses). A local anatomical complexity metric called the distractor index was developed, defined as the Gaussian weighted proportion (i.e., average) of distracting local voxels (50 voxels in-plane, 5 slices). A distracting voxel was classified by thresholding image data that had been selectively filtered to enhance nodule-like features. The distractor index was measured for each nodule location in the nodule-free images. The local pixel standard deviation (STD) was also measured for each nodule. Other confounding factors of search fraction (proportion of lung voxels to total voxels in the given slice) and peripheral distance (defined as the 3D distance of the nodule from the trachea bifurcation) were measured. A generalized linear mixed-effects statistical model (no interaction terms, probit link function, random reader term) was fit to the data to determine the influence of each metric on detectability. In order of decreasing effect size: distractor index, STD, and search fraction all significantly affected detectability (P < 0.001). Distance to the trachea did not have a significant effect (P < 0.05). These data demonstrate that local lung complexity degrades detection of lung nodules and the distractor index could serve as a good surrogate metric to quantify anatomical complexity.

Molecular Testing in Multiple Synchronous Lung Adenocarcinomas: Case Report and Literature Review.

PubMed

Rafael, Oana C; Lazzaro, Richard; Hasanovic, Adnan

2016-02-01

Discovery of driver mutations in pulmonary adenocarcinoma has revolutionized the field of thoracic oncology with major impact on therapy and diagnosis. Testing for EGFR, ALK, and KRAS mutations has become part of everyday practice. We report a case with multiple synchronous primary pulmonary adenocarcinomas in a 72-year-old female with previous history of smoking. The patient presented with cough and bilateral lung ground glass opacities. A positron emission tomography/computed tomography scan showed no activity in mediastinal lymph nodes. She underwent a left upper lobe biopsy and a right upper lobe wedge resection. Pathology revealed 4 morphologically distinct adenocarcinoma foci, suggestive of synchronous primary lung tumors. Molecular testing demonstrated no mutation in the left tumor. Three different driver mutations were present in the right lung tumors: KRAS codon 12 G12D and G12V and EGFR exon 21 L858R mutation, confirming the initial histologic impression. Subsequently, left upper lobe lobectomy showed 3 additional foci of adenocarcinoma with different morphologies, suggestive of synchronous primaries as well. No additional molecular testing was performed. Synchronous pulmonary adenocarcinomas are not uncommon; however, 4 or more synchronous tumors are rare. Distinguishing multiple primary tumors from intrapulmonary metastases is a common problem in thoracic oncology with major implications for staging, prognosis, and treatment. Lung adenocarcinoma subclassification based on predominant and coexisting histologic patterns can greatly facilitate differentiation between intrapulmonary metastases and multiple synchronous tumors. Use of molecular profiling is recommended since it further increases confidence in the diagnostic workup of multiple pulmonary adenocarcinomas and helps guiding therapy. © The Author(s) 2015.

The effect of paraquat inhalation on parkinsonism, organ morphology and anatomy of mice and its recovery with the application of etliringea hemisphaerica (blume, r.m. smith) crude extract

NASA Astrophysics Data System (ADS)

Muslim, Choirul; Nurul Kamila, Santi

2018-03-01

This research is aimed to understand the effect of paraquat herbicide inhalation on Parkinsonism, morphology and anatomy change in mice, and its recovery with Etliringea hemisphaerica crude extract application. Sixty mice were placed into three following groups: group R0 were mice receiving standard food ransom, R1 were a group of mice receiving the regular food ransom plus inhalation of 1% paraquat, and R2 were a group of R1 plus obtaining 0,39mg/bw extract E. hemisphaerica (Bl.) R.M. Smith). After 2 X 7 days of sub-sequential application of both paraquat and “helani tulip” extract, we observed the effects. The examination included bradikinesia attitude, postural instability and rigidity, morphology and anatomy of brain, liver, blood, lung, and kidney. The data were tabulated and analyzed qualitative and semi quantitative description on the behavioural disorder, the alteration of morphology and anatomy, and their remedy based on Sander 2004, Junqueira and Carneiro, 2007. The results showed that the application of paraquat caused strong bradikinesia, postural instability and rigidity. The treatment of the extract was only resulting in the bradikinesia removal but was minor improving the consequence of postural instability and rigidity. Paraquat was not affecting the morphology of neural brain but was altering the morphology and anatomy of lung, liver, blood, and the kidney. In general, the negative impact of the paraquat was weakly eliminated by the treatment of “helani tulip” extract.

Increased levels of urinary PGE-M, a biomarker of inflammation, occur in association with obesity, aging and lung metastases in patients with breast cancer

PubMed Central

Morris, Patrick G.; Zhou, Xi Kathy; Milne, Ginger L.; Goldstein, Daniel; Hawks, Laura C.; Dang, Chau T.; Modi, Shanu; Fornier, Monica N.; Hudis, Clifford A.; Dannenberg, Andrew J.

2013-01-01

Elevated levels of cyclooxygenase (COX)-derived prostaglandin E2 (PGE2) occur in inflamed tissues. To evaluate the potential links between inflammation and breast cancer, levels of urinary prostaglandin E-metabolite (PGE-M), a stable end metabolite of PGE2, were quantified. We enrolled 400 patients with breast cancer: controls with early breast cancer (n=200), lung metastases (n=100) and metastases to other sites (n=100). Patients completed a questionnaire, provided urine and had measurements of height and weight. Urinary PGE-M was quantified by mass spectrometry. Ever smokers with lung metastasis who had not been exposed to NSAIDs had the highest PGE-M levels. PGE-M levels were increased in association with elevated BMI (p<0.001), aging (p<0.001), pack-year smoking history (p=0.02), lung metastases (p=0.02) and recent cytotoxic chemotherapy (p=0.03). Conversely, use of NSAIDs, prototypic inhibitors of COX activity, was associated with reduced PGE-M levels (p<0.001). Based on the current findings, PGE-M is likely to be a useful biomarker for the selection of high risk subgroups to determine the utility of interventions that aim to reduce inflammation and possibly the development and progression of breast cancer, especially in overweight and obese women. PMID:23531446

Diffusion of hyperpolarized 129Xe in the lung: a simplified model of 129Xe septal uptake and experimental results

NASA Astrophysics Data System (ADS)

Patz, Samuel; Muradyan, Iga; Hrovat, Mirko I.; Dabaghyan, Mikayel; Washko, George R.; Hatabu, Hiroto; Butler, James P.

2011-01-01

We used hyperpolarized 129Xe NMR to measure pulmonary alveolar surface area per unit gas volume SA/Vgas, alveolar septal thickness h and capillary transit time τ, three critical determinants of the lung's primary role as a gas exchange organ. An analytical solution for a simplified diffusion model is described, together with a modification of the xenon transfer contrast imaging technique utilizing 90° radio-frequency pulses applied to the dissolved phase, rather than traditional 180° pulses. With this approach, three-dimensional (3D) maps of SA/Vgas were obtained. We measured global SA/Vgas, h and τ in four normal subjects, two subjects with mild interstitial lung disease (ILD) and two subjects with mild chronic obstructive pulmonary disease (COPD). In normals, SA/Vgas decreased with increasing lung volume from ~320 to 80 cm-1 both h~13 μm and τ~1.5 s were relatively constant. For the two ILD subjects, h was, respectively, 36 and 97% larger than normal, quantifying an increased gas/blood tissue barrier; SA/Vgas and τ were normal. The two COPD subjects had SA/Vgas values ~25% that of normals, quantifying septal surface loss in emphysema; h and τ were normal. These are the first noninvasive, non-radiation-based, quantitative measurements of h and τ in patients with pulmonary disease.

Atorvastatin and Simvastatin Promoted Mouse Lung Repair After Cigarette Smoke-Induced Emphysema.

PubMed

Pinho-Ribeiro, Vanessa; Melo, Adriana Correa; Kennedy-Feitosa, Emanuel; Graca-Reis, Adriane; Barroso, Marina Valente; Cattani-Cavalieri, Isabella; Carvalho, Giovanna Marcella Cavalcante; Zin, Walter Araújo; Porto, Luis Cristóvão; Gitirana, Lycia Brito; Lanzetti, Manuella; Valença, Samuel Santos

2017-06-01

Cigarette smoke (CS) induces pulmonary emphysema by inflammation, oxidative stress, and metalloproteinase (MMP) activation. Pharmacological research studies have not focused on tissue repair after the establishment of emphysema but have instead focused on inflammatory stimulation. The aim of our study was to analyze the effects of atorvastatin and simvastatin on mouse lung repair after emphysema caused by CS. Male mice (C57BL/6, n = 45) were divided into the following groups: control (sham-exposed), CSr (mice exposed to 12 cigarettes a day for 60 days and then treated for another 60 days with the vehicle), CSr+A (CSr mice treated with atorvastatin for 60 days), and CSr+S (CSr mice treated with simvastatin for 60 days). The treatment with atorvastatin and simvastatin was administered via inhalation (15 min with 1 mg/mL once a day). Mice were sacrificed 24 h after the completion of the 120-day experimental procedure. We performed biochemical, morphological, and physiological analyses. We observed decreased levels of leukocytes and cytokines in statin-treated mice, accompanied by a reduction in oxidative stress markers. We also observed a morphological improvement confirmed by a mean linear intercept counting in statin-treated mice. Finally, statins also ameliorated lung function. We conclude that inhaled atorvastatin and simvastatin improved lung repair after cigarette smoke-induced emphysema in mice.

Rare discrepancies in a driver gene alteration within histologically heterogeneous primary lung cancers.

PubMed

Zhong, Wen-zhao; Su, Jian; Xu, Fang-ping; Zhai, Hao-ran; Zhang, Xu-chao; Yang, Xue-ning; Chen, Zhi-yong; Chen, Zhi-hong; Li, Wei; Dong, Song; Zhou, Qing; Yang, Jin-ji; Liu, Yan-hui; Wu, Yi-long

2015-11-01

Most lung adenocarcinomas consist of mixtures of histological subtypes harboring different frequencies of driver gene mutations. However, little is known about intratumoral heterogeneity(ITH) within histologically heterogeneous primary lung cancers. Investigating key driver genes in respective morphological pattern is crucial to personalized treatment. Morphologically different areas within the same surgically resected adenocarcinomas were extracted from tissues to analyze gene status in each growth pattern. Driver genes, epidermal growth factor receptor (EGFR), KRAS and EML4-ALK, were assessed by assays with different sensitivities. Seventy-nine consecutive eligible patients harboring a driver gene (EGFR=65; KRAS=10; EML4-ALK=4) were enrolled. For EGFR mutations, ITH occurred in 13.3% (8/60) by direct sequencing (DS) and 1.7% (1/60) by amplification refractory mutation system (ARMS) (P=0.016) among adenocarcinomas, but consistent within five adeno-squamous cell carcinomas by both methods. ITH among KRAS mutations were detected in 20% (2/10) by DS, whereas consistent (10/10) by high resolution melting. No discrepancies in EML4-ALK rearrangements existed according to fluorescence in situ hybridization. Rare ITHs of EGFR/KRAS/EML4-ALK alterations within histologically heterogeneous primary lung adenocarcinomas existed by methods with higher sensitivity. Discrepancies might be due to abundance of mutant tumor cells and detection assays. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Quantification of idiopathic pulmonary fibrosis using computed tomography and histology.

PubMed

Coxson, H O; Hogg, J C; Mayo, J R; Behzad, H; Whittall, K P; Schwartz, D A; Hartley, P G; Galvin, J R; Wilson, J S; Hunninghake, G W

1997-05-01

We used computed tomography (CT) and histologic analysis to quantify lung structure in idiopathic pulmonary fibrosis (IPF). CT scans were obtained from IPF and control patients and lung volumes were estimated from measurements of voxel size, and X-ray attenuation values of each voxel. Quantitative estimates of lung structure were obtained from biopsies obtained from diseased and normal CT regions using stereologic methods. CT density was used to calculate the proportion of tissue and air, and this value was used to correct the biopsy specimens to the level of inflation during the CT scan. The data show that IPF is associated with a reduction in airspace volume with no change in tissue volume or weight compared with control lungs. Lung surface area decreased two-thirds (p < 0.001) and mean parenchymal thickness increased tenfold (p < 0.001). An exudate of fluid and cells was present in the airspace of the diseased lung regions and the number of inflammatory cells, collagen, and proteoglycans was increased per 100 g of tissue in IPF. We conclude that IPF reorganized lung tissue content causing a loss of airspace and surface area without increasing the total lung tissue.

Longitudinal follow-up study of smoking-induced emphysema progression in low-dose CT screening of lung cancer

NASA Astrophysics Data System (ADS)

Suzuki, H.; Matsuhiro, M.; Kawata, Y.; Niki, N.; Nakano, Y.; Ohmatsu, H.; Kusumoto, M.; Tsuchida, T.; Eguchi, K.; Kaneko, Masahiro; Moriyama, N.

2014-03-01

Chronic obstructive pulmonary disease is a major public health problem that is predicted to be third leading cause of death in 2030. Although spirometry is traditionally used to quantify emphysema progression, it is difficult to detect the loss of pulmonary function by emphysema in early stage, and to assess the susceptibility to smoking. This study presents quantification method of smoking-induced emphysema progression based on annual changes of low attenuation volume (LAV) by each lung lobe acquired from low-dose CT images in lung cancer screening. The method consists of three steps. First, lung lobes are segmented using extracted interlobar fissures by enhancement filter based on fourdimensional curvature. Second, LAV of each lung lobe is segmented. Finally, smoking-induced emphysema progression is assessed by statistical analysis of the annual changes represented by linear regression of LAV percentage in each lung lobe. This method was applied to 140 participants in lung cancer CT screening for six years. The results showed that LAV progressions of nonsmokers, past smokers, and current smokers are different in terms of pack-year and smoking cessation duration. This study demonstrates effectiveness in diagnosis and prognosis of early emphysema in lung cancer CT screening.

Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress.

PubMed

Lu, Jun; Chen, Jian; Xu, Nianjun; Wu, Jun; Kang, Yani; Shen, Tingting; Kong, Hualei; Ma, Chao; Cheng, Ming; Shao, Zhifeng; Xu, Ling; Zhao, Xiaodong

2016-09-06

Application of cisplatin (DDP) for treating lung cancer is restricted due to its toxicity and lung cancer's drug resistance. In this study, we examined the effect of Jinfukang (JFK), an effective herbal medicine against lung cancer, on DDP-induced cytotoxicity in lung cancer cells. Morphologically, we observed that JFK increases DDP-induced pro-apoptosis in A549 cells in a synergistic manner. Transcriptome profiling analysis indicated that the combination of JFK and DDP regulates genes involved in apoptosis-related signaling pathways. Moreover, we found that the combination of JFK and DDP produces synergistic pro-apoptosis effect in other lung cancer cell lines, such as NCI-H1975, NCI-H1650, and NCI-H2228. Particularly, we demonstrated that AIFM2 is activated by the combined treatment of JFK and DDP and partially mediates the synergistic pro-apoptosis effect. Collectively, this study not only offered the first evidence that JFK promotes DDP-induced cytotoxicity, and activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress, but also provided a novel insight for improving cytotoxicity by combining JFK with DDP to treat lung cancer cells. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Sexual selection and the evolution of genital shape and complexity in water striders.

PubMed

Rowe, Locke; Arnqvist, Göran

2012-01-01

Animal genitalia show two striking but incompletely understood evolutionary trends: a great evolutionary divergence in the shape of genitalic structures, and characteristic structural complexity. Both features are thought to result from sexual selection, but explicit comparative tests are hampered by the fact that it is difficult to quantify both morphological complexity and divergence in shape. We undertake a comparative study of multiple nongenitalic and male genital traits in a clade of 15 water strider species to quantify complexity and shape divergence. We show that genital structures are more complex and their shape more divergent among species than nongenital traits. Further, intromittent genital traits are more complex and have evolved more divergently than nonintromittent genital traits. More importantly, shape and complexity of nonintromittent genital traits show correlated evolution with indices of premating sexual selection and intromittent genital traits with postmating sexual selection, suggesting that the evolution of different components of genital morphology are shaped independently by distinct forms of sexual selection. Our quantitative results provide direct comparative support for the hypothesis that sexual selection is associated with morphological complexity in genitalic traits and highlight the importance of quantifying morphological shape and complexity, rather than size in studies of genital evolution. © 2011 The Author(s). Evolution © 2011 The Society for the Study of Evolution.

Robust lung identification in MSCT via controlled flooding and shape constraints: dealing with anatomical and pathological specificity

NASA Astrophysics Data System (ADS)

Fetita, Catalin; Tarando, Sebastian; Brillet, Pierre-Yves; Grenier, Philippe A.

2016-03-01

Correct segmentation and labeling of lungs in thorax MSCT is a requirement in pulmonary/respiratory disease analysis as a basis for further processing or direct quantitative measures: lung texture classification, respiratory functional simulations, intrapulmonary vascular remodeling evaluation, detection of pleural effusion or subpleural opacities, are only few clinical applications related to this requirement. Whereas lung segmentation appears trivial for normal anatomo-pathological conditions, the presence of disease may complicate this task for fully-automated algorithms. The challenges come either from regional changes of lung texture opacity or from complex anatomic configurations (e.g., thin septum between lungs making difficult proper lung separation). They make difficult or even impossible the use of classic algorithms based on adaptive thresholding, 3-D connected component analysis and shape regularization. The objective of this work is to provide a robust segmentation approach of the pulmonary field, with individualized labeling of the lungs, able to overcome the mentioned limitations. The proposed approach relies on 3-D mathematical morphology and exploits the concept of controlled relief flooding (to identify contrasted lung areas) together with patient-specific shape properties for peripheral dense tissue detection. Tested on a database of 40 MSCT of pathological lungs, the proposed approach showed correct identification of lung areas with high sensitivity and specificity in locating peripheral dense opacities.

[Impact of multi-layer spiral CT angiography of bronchial artery and pulmonary artery in assessment of the main blood supply to the primary lung cancer].

PubMed

Xiao, Xiang-sheng; Yu, Hong; Li, Hui-min; Liu, Shi-yuan; Li, Cheng-zhou; Liu, Jing

2006-04-01

To investigate the blood supply of primary lung cancer (PLC) using CT angiography for bronchial artery (BA) and pulmonary artery (PA). Thin-section enhanced multi-layer spiral CT (MSCT) were carried out in 147 primary lung cancer patients and 46 healthy subjects as control. Three-dimensional images of bronchial artery and pulmonary artery were obtained using volume render (VR) and multi-planar reconstruction (MPR) or maximum intensity projection (MIP) at the workstation, and their morphological findings and relationship with the mass were assessed. 136 primary lung cancer patients and 32 healthy controls were evaluated for at least one bronchial artery displayed clearly in VR. The detective rate of the bronchial artery was 92.5% and 69.6%, respectively. The bronchial artery caliber and the total section area of lesion side in lung cancer patients were significantly larger than that on the contralateral side and that of the control (P < 0.05). Bronchial artery on the lesion side in lung cancer was dilated and tortuous, directly penetrating into the mass with reticularly anastomosed branches. In the PLC patients, all PA were shown clearly with normal morphological image though crossing over the masses in 54 patients; In 25 PLC patients, the PA being essentially intact, was pushed around and surrounded the mass, giving the "hold ball" sign; In 40 other PLC patients, PA being also intact, the mass surrounded and buried the PA from the outside, crushing the PA flat resulting in an eccentric or centrifugal shrinkage, forming the "dead branch" sign; In the rest 28 patients, the PA was surrounded and even compressed, forming the "residual root" sign. Primary lung cancer patient shows dilated bronchial arteries and increased bronchial artery blood flow, whereas pulmonary arteries just pass through the mass or are compressed by the mass. It is further demonstrated that the bronchial artery, instead of the pulmonary artery, is the main vessel of blood supply to the primary lung cancer as shown by MSCT angiography of bronchial artery and pulmonary artery.

Perfluorocarbon reduces cell damage from blast injury by inhibiting signal paths of NF-κB, MAPK and Bcl-2/Bax signaling pathway in A549 cells

PubMed Central

Li, Huaidong; Li, Chunsun; Yang, Zhen; Li, Yanqin; She, Danyang; Cao, Lu; Wang, Wenjie; Liu, Changlin; Chen, Liangan

2017-01-01

Background and objective Blast lung injury is a common type of blast injury and has very high mortality. Therefore, research to identify medical therapies for blast injury is important. Perfluorocarbon (PFC) is used to improve gas exchange in diseased lungs and has anti-inflammatory functions in vitro and in vivo. The aim of this study was to determine whether PFC reduces damage to A549 cells caused by blast injury and to elucidate its possible mechanisms of action. Study design and methods A549 alveolar epithelial cells exposed to blast waves were treated with and without PFC. Morphological changes and apoptosis of A549 cells were recorded. PCR and enzyme-linked immunosorbent assay (ELISA) were used to measure the mRNA or protein levels of IL-1β, IL-6 and TNF-α. Malondialdehyde (MDA) levels and superoxide dismutase (SOD) activity levels were detected. Western blot was used to quantify the expression of NF-κB, Bax, Bcl-2, cleaved caspase-3 and MAPK cell signaling proteins. Results A549 cells exposed to blast wave shrank, with less cell-cell contact. The morphological change of A549 cells exposed to blast waves were alleviated by PFC. PFC significantly inhibited the apoptosis of A549 cells exposed to blast waves. IL-1β, IL-6 and TNF-α cytokine and mRNA expression levels were significantly inhibited by PFC. PFC significantly increased MDA levels and decreased SOD activity levels. Further studies indicated that NF-κB, Bax, caspase-3, phospho-p38, phosphor-ERK and phosphor-JNK proteins were also suppressed by PFC. The quantity of Bcl-2 protein was increased by PFC. Conclusion Our research showed that PFC reduced A549 cell damage caused by blast injury. The potential mechanism may be associated with the following signaling pathways: 1) the signaling pathways of NF-κB and MAPK, which inhibit inflammation and reactive oxygen species (ROS); and 2) the signaling pathways of Bcl-2/Bax and caspase-3, which inhibit apoptosis. PMID:28323898

Physical activity alters limb bone structure but not entheseal morphology.

PubMed

Wallace, Ian J; Winchester, Julia M; Su, Anne; Boyer, Doug M; Konow, Nicolai

2017-06-01

Studies of ancient human skeletal remains frequently proceed from the assumption that individuals with robust limb bones and/or rugose, hypertrophic entheses can be inferred to have been highly physically active during life. Here, we experimentally test this assumption by measuring the effects of exercise on limb bone structure and entheseal morphology in turkeys. Growing females were either treated with a treadmill-running regimen for 10 weeks or served as controls. After the experiment, femoral cortical and trabecular bone structure were quantified with μCT in the mid-diaphysis and distal epiphysis, respectively, and entheseal morphology was quantified in the lateral epicondyle. The results indicate that elevated levels of physical activity affect limb bone structure but not entheseal morphology. Specifically, animals subjected to exercise displayed enhanced diaphyseal and trabecular bone architecture relative to controls, but no significant difference was detected between experimental groups in entheseal surface topography. These findings suggest that diaphyseal and trabecular structure are more reliable proxies than entheseal morphology for inferring ancient human physical activity levels from skeletal remains. Copyright © 2017 Elsevier Ltd. All rights reserved.

Quantitative CT Measures of Bronchiectasis in Smokers.

PubMed

Diaz, Alejandro A; Young, Thomas P; Maselli, Diego J; Martinez, Carlos H; Gill, Ritu; Nardelli, Pietro; Wang, Wei; Kinney, Gregory L; Hokanson, John E; Washko, George R; San Jose Estepar, Raul

2017-06-01

Bronchiectasis is frequent in smokers with COPD; however, there are only limited data on objective assessments of this process. The objective was to assess bronchovascular morphology, calculate the ratio of the diameters of bronchial lumen and adjacent artery (BA ratio), and identify those measurements able to discriminate bronchiectasis. We collected quantitative CT (QCT) measures of BA ratios, peak wall attenuation, wall thickness (WT), wall area, and wall area percent (WA%) at matched fourth through sixth airway generations in 21 ever smokers with bronchiectasis (cases) and 21 never-smoking control patients (control airways). In cases, measurements were collected at both bronchiectatic and nonbronchiectatic airways. Logistic analysis and the area under receiver operating characteristic curve (AUC) were used to assess the predictive ability of QCT measurements for bronchiectasis. The whole-lung and fourth through sixth airway generation BA ratio, WT, and WA% were significantly greater in bronchiectasis cases than control patients. The AUCs for the BA ratio to predict bronchiectasis ranged from 0.90 (whole lung) to 0.79 (fourth-generation). AUCs for WT and WA% ranged from 0.72 to 0.75 and from 0.71 to 0.75. The artery diameters but not bronchial diameters were smaller in bronchiectatic than both nonbronchiectatic and control airways (P < .01 for both). Smoking-related increases in the BA ratio appear to be driven by reductions in vascular caliber. QCT measures of BA ratio, WT, and WA% may be useful to objectively identify and quantify bronchiectasis in smokers. ClinicalTrials.gov; No.: NCT00608764; URL: www.clinicaltrials.gov. Copyright © 2016 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.

Mapping Candidate Ecological Restoration Areas Using Morphological Spatial Pattern Analysis (MSPA)

EPA Science Inventory

Morphological Spatial Pattern Analysis (MSPA) has been widely adopted by landscape ecologists over the past decade. A few examples of its many uses include: 1) quantifying landscape indicators and fragmentation in continental forest assessments, 2) explaining interior-exterior p...

Quantification of lung microstructure with hyperpolarized 3He diffusion MRI

PubMed Central

Sukstanskii, Alexander L.; Woods, Jason C.; Gierada, David S.; Quirk, James D.; Hogg, James C.; Cooper, Joel D.; Conradi, Mark S.

2009-01-01

The structure and integrity of pulmonary acinar airways and their changes in different diseases are of great importance and interest to a broad range of physiologists and clinicians. The introduction of hyperpolarized gases has opened a door to in vivo studies of lungs with MRI. In this study we demonstrate that MRI-based measurements of hyperpolarized 3He diffusivity in human lungs yield quantitative information on the value and spatial distribution of lung parenchyma surface-to-volume ratio, number of alveoli per unit lung volume, mean linear intercept, and acinar airway radii—parameters that have been used by lung physiologists for decades and are accepted as gold standards for quantifying emphysema. We validated our MRI-based method in six human lung specimens with different levels of emphysema against direct unbiased stereological measurements. We demonstrate for the first time MRI images of these lung microgeometric parameters in healthy lungs and lungs with different levels of emphysema (mild, moderate, and severe). Our data suggest that decreases in lung surface area per volume at the initial stages of emphysema are due to dramatic decreases in the depth of the alveolar sleeves covering the alveolar ducts and sacs, implying dramatic decreases in the lung's gas exchange capacity. Our novel methods are sufficiently sensitive to allow early detection and diagnosis of emphysema, providing an opportunity to improve patient treatment outcomes, and have the potential to provide safe and noninvasive in vivo biomarkers for monitoring drug efficacy in clinical trials. PMID:19661452

Quantifying the impact of respiratory-gated 4D CT acquisition on thoracic image quality: A digital phantom study

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bernatowicz, K., E-mail: kingab@student.ethz.ch; Knopf, A.; Lomax, A.

Purpose: Prospective respiratory-gated 4D CT has been shown to reduce tumor image artifacts by up to 50% compared to conventional 4D CT. However, to date no studies have quantified the impact of gated 4D CT on normal lung tissue imaging, which is important in performing dose calculations based on accurate estimates of lung volume and structure. To determine the impact of gated 4D CT on thoracic image quality, the authors developed a novel simulation framework incorporating a realistic deformable digital phantom driven by patient tumor motion patterns. Based on this framework, the authors test the hypothesis that respiratory-gated 4D CTmore » can significantly reduce lung imaging artifacts. Methods: Our simulation framework synchronizes the 4D extended cardiac torso (XCAT) phantom with tumor motion data in a quasi real-time fashion, allowing simulation of three 4D CT acquisition modes featuring different levels of respiratory feedback: (i) “conventional” 4D CT that uses a constant imaging and couch-shift frequency, (ii) “beam paused” 4D CT that interrupts imaging to avoid oversampling at a given couch position and respiratory phase, and (iii) “respiratory-gated” 4D CT that triggers acquisition only when the respiratory motion fulfills phase-specific displacement gating windows based on prescan breathing data. Our framework generates a set of ground truth comparators, representing the average XCAT anatomy during beam-on for each of ten respiratory phase bins. Based on this framework, the authors simulated conventional, beam-paused, and respiratory-gated 4D CT images using tumor motion patterns from seven lung cancer patients across 13 treatment fractions, with a simulated 5.5 cm{sup 3} spherical lesion. Normal lung tissue image quality was quantified by comparing simulated and ground truth images in terms of overall mean square error (MSE) intensity difference, threshold-based lung volume error, and fractional false positive/false negative rates. Results: Averaged across all simulations and phase bins, respiratory-gating reduced overall thoracic MSE by 46% compared to conventional 4D CT (p ∼ 10{sup −19}). Gating leads to small but significant (p < 0.02) reductions in lung volume errors (1.8%–1.4%), false positives (4.0%–2.6%), and false negatives (2.7%–1.3%). These percentage reductions correspond to gating reducing image artifacts by 24–90 cm{sup 3} of lung tissue. Similar to earlier studies, gating reduced patient image dose by up to 22%, but with scan time increased by up to 135%. Beam paused 4D CT did not significantly impact normal lung tissue image quality, but did yield similar dose reductions as for respiratory-gating, without the added cost in scanning time. Conclusions: For a typical 6 L lung, respiratory-gated 4D CT can reduce image artifacts affecting up to 90 cm{sup 3} of normal lung tissue compared to conventional acquisition. This image improvement could have important implications for dose calculations based on 4D CT. Where image quality is less critical, beam paused 4D CT is a simple strategy to reduce imaging dose without sacrificing acquisition time.« less

[Prevalence of tobacco smoking among phthisio-pulmonological inpatients].

PubMed

Ugriumov, A I

2001-01-01

A questionnaire survey of 222 phthisiopulmonological inpatients has indicated that 21.7 of the males and 4.05% of the females are smokers. Among clinical and morphological forms of tuberculosis, fibrocavernous tuberculosis is prevalent in smokers. Tuberculoma and post tuberculous fibrosis of varying severity are common in never smokers. Smokers are at high risk for lung cancer and at less risk for sarcoidosis with the equal incidence of chronic obstructive lung disease. The paper states that hospital physicians pay little attention to smoking among their patients.

Isolates of Sarcocystis falcatula-like organisms from South American opossums Didelphis marsupialis and Didelphis albiventris from São Paulo, Brazil.

PubMed

Dubey, J P; Lindsay, D S; Rosenthal, B M; Kerber, C E; Kasai, N; Pena, H F; Kwok, O C; Shen, S K; Gennari, S M

2001-12-01

Isolates of Sarcocystis falcatula-like organisms from South American opossums were characterized based on biological and morphological criteria. Sporocysts from intestinal scrapings of 1 Didelphis marsupialis and 8 Didelphis albiventris from São Paulo, Brazil, were fed to captive budgerigars (Melopsittacus undulatus). Budgerigars fed sporocysts from all 9 isolates became ill and S. falcatula-like schizonts were identified in sections of their lungs by immunohistochemical staining. Sarcocystis falcatula-like organisms were cultured from lungs of budgerigars fed sporocysts from D. marsupialis and from lungs of budgerigars fed sporocysts from 3 of 8 D. albiventris. The 33/54 locus amplified by polymerase chain reaction from culture-derived merozoites contained both a HinfI endonuclease recognition site previously suggested to diagnose S. falcatula and a DraI site thought to diagnosed S. neurona. Development of the isolate from D. marsupialis was studied in cell culture; its schizonts divided by endopolygeny, leaving a residual body. Morphological and genetic variation differentiated this Sarcocystis isolate originating in D. marsupialis from the Cornell I isolate of S. falcatula. This is the first report of a S. falcatula infection in the South American opossum, D. marsupialis.

Hydrogen-rich saline inhibits tobacco smoke-induced chronic obstructive pulmonary disease by alleviating airway inflammation and mucus hypersecretion in rats.

PubMed

Liu, Zibing; Geng, Wenye; Jiang, Chuanwei; Zhao, Shujun; Liu, Yong; Zhang, Ying; Qin, Shucun; Li, Chenxu; Zhang, Xinfang; Si, Yanhong

2017-09-01

Chronic obstructive pulmonary disease induced by tobacco smoke has been regarded as a great health problem worldwide. The purpose of this study is to evaluate the protective effect of hydrogen-rich saline, a novel antioxidant, on chronic obstructive pulmonary disease and explore the underlying mechanism. Sprague-Dawley rats were made chronic obstructive pulmonary disease models via tobacco smoke exposure for 12 weeks and the rats were treated with 10 ml/kg hydrogen-rich saline intraperitoneally during the last 4 weeks. Lung function testing indicated hydrogen-rich saline decreased lung airway resistance and increased lung compliance and the ratio of forced expiratory volume in 0.1 s/forced vital capacity in chronic obstructive pulmonary disease rats. Histological analysis revealed that hydrogen-rich saline alleviated morphological impairments of lung in tobacco smoke-induced chronic obstructive pulmonary disease rats. ELISA assay showed hydrogen-rich saline lowered the levels of pro-inflammatory cytokines (IL-8 and IL-6) and anti-inflammatory cytokine IL-10 in bronchoalveolar lavage fluid and serum of chronic obstructive pulmonary disease rats. The content of malondialdehyde in lung tissue and serum was also determined and the data indicated hydrogen-rich saline suppressed oxidative stress reaction. The protein expressions of mucin MUC5C and aquaporin 5 involved in mucus hypersecretion were analyzed by Western blot and ELISA and the data revealed that hydrogen-rich saline down-regulated MUC5AC level in bronchoalveolar lavage fluid and lung tissue and up-regulated aquaporin 5 level in lung tissue of chronic obstructive pulmonary disease rats. In conclusion, these results suggest that administration of hydrogen-rich saline exhibits significant protective effect on chronic obstructive pulmonary disease through alleviating inflammation, reducing oxidative stress and lessening mucus hypersecretion in tobacco smoke-induced chronic obstructive pulmonary disease rats. Impact statement This study was designed to evaluate protective effect of hydrogen-rich saline, a novel antioxidant, on tobacco smoke (TS)-induced chronic obstructive pulmonary disease (COPD) in rats and explore the underlying mechanism. Our results suggest that administration of hydrogen-rich saline improves lung function and alleviates morphological impairments of lung through alleviating inflammation, reducing oxidative stress and lessening mucus hypersecretion in TS-induced COPD rats.

Characteristics of new solid nodules detected in incidence screening rounds of low-dose CT lung cancer screening: the NELSON study.

PubMed

Walter, Joan E; Heuvelmans, Marjolein A; Bock, Geertruida H de; Yousaf-Khan, Uraujh; Groen, Harry J M; Aalst, Carlijn M van der; Nackaerts, Kristiaan; Ooijen, Peter M A van; Koning, Harry J de; Vliegenthart, Rozemarijn; Oudkerk, Matthijs

2018-04-16

New nodules after baseline are regularly found in low-dose CT lung cancer screening and have a high lung cancer probability. It is unknown whether morphological and location characteristics can improve new nodule risk stratification by size. Solid non-calcified nodules detected during incidence screening rounds of the randomised controlled Dutch-Belgian lung cancer screening (NELSON) trial and registered as new or previously below detection limit (15 mm 3 ) were included. A multivariate logistic regression analysis with lung cancer as outcome was performed, including previously established volume cut-offs (<30 mm 3 , 30-<200 mm 3 and ≥200 mm 3 ) and nodule characteristics (location, distribution, shape, margin and visibility <15 mm 3 in retrospect). Overall, 1280 new nodules were included with 73 (6%) being lung cancer. Of nodules ≥30 mm 3 at detection and visible <15 mm 3 in retrospect, 22% (6/27) were lung cancer. Discrimination based on volume cut-offs (area under the receiver operating characteristic curve (AUC): 0.80, 95% CI 0.75 to 0.84) and continuous volume (AUC: 0.82, 95% CI 0.77 to 0.87) was similar. After adjustment for volume cut-offs, only location in the right upper lobe (OR 2.0, P=0.012), central distribution (OR 2.4, P=0.001) and visibility <15 mm 3 in retrospect (OR 4.7, P=0.003) remained significant predictors for lung cancer. The Hosmer-Lemeshow test (P=0.75) and assessment of bootstrap calibration curves indicated adequate model fit. Discrimination based on the continuous model probability (AUC: 0.85, 95% CI 0.81 to 0.89) was superior to volume cut-offs alone, but when stratified into three risk groups (AUC: 0.82, 95% CI 0.78 to 0.86), discrimination was similar. Contrary to morphological nodule characteristics, growth-independent characteristics may further improve volume-based new nodule lung cancer prediction, but in a three-category stratification approach, this is limited. ISRCTN63545820; pre-results. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Comparison of three different methods for the detection of circulating tumor cells in mice with lung metastasis.

PubMed

Xu, Weifeng; Wu, Bing; Fu, Lengxi; Chen, Junying; Wang, Zeng; Huang, Fei; Chen, Jinrong; Zhang, Mei; Zhang, Zhenhuan; Lin, Jingan; Lan, Ruilong; Chen, Ruiqing; Chen, Wei; Chen, Long; Hong, Jinsheng; Zhang, Weijian; Ding, Yuxiong; Okunieff, Paul; Lin, Jianhua; Zhang, Lurong

2017-06-01

Circulating tumor cells (CTCs) represent the key step of cancer cell dissemination. The alteration of CTCs correlates with the treatment outcome and prognosis. To enrich and identify CTCs from billions of blood cells renders a very challenging task, which triggers development of several methods, including lysis of RBC plus negative or positive enrichment using antibodies, and filter membrane or spiral microfluidics to capture CTCs. To compare the advantages of different enrichment methods for CTCs, we utilized the 4T1 breast cancer cells transfected with both green fluorescent protein (GFP) and luciferase to trace CTCs in the experimental lung metastasis model. Three methods were used to detect CTCs at the same time: bioluminescence assay, smearing method, and membrane filter method. The in vivo alive mouse imaging was used to dynamically monitor the growth of lung metastases. The sensitivity and accuracy of three detection methods were compared side-by-side. Our results showed that 1) the sensitivity of bioluminescence assay was the highest, but there was no information of CTC morphology; 2) the smearing method and membrane filter method could observe the detail of CTC morphology, such as in single or in cluster, while their sensitivity was lower than bioluminescence assay; 3) A dynamic observation at a 7-day intervals, the lung metastatic cancer grew at a log speed, while CTCs were increased at a low speed. This might be due to the activated immune cells eliminating the CTCs at a speed much faster than CTCs were generated. This comparison of three CTC detection methods in mouse model suggests that bioluminescence assay could be used in quantitative study of the effect of certain agent on the suppression of CTCs, while GFP-based morphological assays could be used to study the dissemination mechanism of CTCs. The combination of both bioluminescence assay and GFP-based assay would generate more information for quantity and quality of CTCs.

A new functional method to choose the target lobe for lung volume reduction in emphysema - comparison with the conventional densitometric method.

PubMed

Hetzel, Juergen; Boeckeler, Michael; Horger, Marius; Ehab, Ahmed; Kloth, Christopher; Wagner, Robert; Freitag, Lutz; Slebos, Dirk-Jan; Lewis, Richard Alexander; Haentschel, Maik

2017-01-01

Lung volume reduction (LVR) improves breathing mechanics by reducing hyperinflation. Lobar selection usually focuses on choosing the most destroyed emphysematous lobes as seen on an inspiratory CT scan. However, it has never been shown to what extent these densitometric CT parameters predict the least deflation of an individual lobe during expiration. The addition of expiratory CT analysis allows measurement of the extent of lobar air trapping and could therefore provide additional functional information for choice of potential treatment targets. To determine lobar vital capacity/lobar total capacity (LVC/LTC) as a functional parameter for lobar air trapping using on an inspiratory and expiratory CT scan. To compare lobar selection by LVC/LTC with the established morphological CT density parameters. 36 patients referred for endoscopic LVR were studied. LVC/LTC, defined as delta volume over maximum volume of a lobe, was calculated using inspiratory and expiratory CT scans. The CT morphological parameters of mean lung density (MLD), low attenuation volume (LAV), and 15th percentile of Hounsfield units (15%P) were determined on an inspiratory CT scan for each lobe. We compared and correlated LVC/LTC with MLD, LAV, and 15%P. There was a weak correlation between the functional parameter LVC/LTC and all inspiratory densitometric parameters. Target lobe selection using lowest lobar deflation (lowest LVC/LTC) correlated with target lobe selection based on lowest MLD in 18 patients (50.0%), with the highest LAV in 13 patients (36.1%), and with the lowest 15%P in 12 patients (33.3%). CT-based measurement of deflation (LVC/LTC) as a functional parameter correlates weakly with all densitometric CT parameters on a lobar level. Therefore, morphological criteria based on inspiratory CT densitometry partially reflect the deflation of particular lung lobes, and may be of limited value as a sole predictor for target lobe selection in LVR.

No correlation between initial arterial carboxyhemoglobin level and degree of lung injury following ovine burn and smoke inhalation.

PubMed

Lange, Matthias; Cox, Robert A; Traber, Daniel L; Hamahata, Atsumori; Nakano, Yoshimitsu; Traber, Lillian D; Enkhbaatar, Perenlei

2014-04-01

Fire victims often suffer from burn injury and concomitant inhalation trauma, the latter significantly contributing to the morbidity and mortality in these patients. Measurement of blood carboxyhemoglobin levels has been proposed as a diagnostic marker to verify and, perhaps, quantify the degree of lung injury following inhalation trauma. However, this correlation has not yet been sufficiently validated. A total of 77 chronically instrumented sheep received sham injury, smoke inhalation injury, or combined burn and inhalation trauma following an established protocol. Arterial carboxyhemoglobin concentrations were determined directly after injury and correlated to several clinical and histopathological determinants of lung injury that were detected 48 hours post-injury. The injury induced severe impairment of pulmonary gas exchange and increases in transvascular fluid flux, lung water content, and airway obstruction scores. No significant correlations were detected between initial carboxyhemoglobin levels and all measured clinical and histopathological determinants of lung injury. In conclusion, the amount of arterial carboxyhemoglobin concentration cannot predict the degree of lung injury at 48 hours after ovine burn and smoke inhalation trauma.

Effects of tracheal occlusion with retinoic acid administration on normal lung development.

PubMed

Delabaere, Amélie; Marceau, Geoffroy; Coste, Karen; Blanchon, Loïc; Déchelotte, Pierre-Jean; Blanc, Pierre; Sapin, Vincent; Gallot, Denis

2017-05-01

Tracheal occlusion (TO) is an investigational therapy for severe congenital diaphragmatic hernia that decreases pulmonary hypoplasia, but sustained TO also induces deficient surfactant synthesis. Intramuscular maternal administration of retinoic acid (RA) in a surgical rabbit model of congenital diaphragmatic hernia showed a beneficial effect on lung maturation. We evaluated the potential of RA delivery into the trachea and studied the combined effects of TO and RA on normal lung development. Experiments were performed on normal rabbit fetuses. Liposomes and capric triglyceride (Miglyol ® ), alone and with RA, were administered in the trachea just before TO (d26). Lung morphology and surfactant production were studied at term (d30). Tracheal occlusion increased lung weight and enhanced alveolar development but increased apoptotic activity and decreased surfactant expression. Tracheal injection of RA improved surfactant production to levels of normal controls. We established the potential of liposome and Miglyol as RA vehicle for delivering this bioactive molecule in the fetal airways. Tracheal RA injection seems to oppose the effects of TO in fetuses with normal lungs. © 2017 John Wiley & Sons, Ltd. © 2017 John Wiley & Sons, Ltd.

Human embryonic lung epithelial tips are multipotent progenitors that can be expanded in vitro as long-term self-renewing organoids

PubMed Central

Nikolić, Marko Z; Caritg, Oriol; Jeng, Quitz; Johnson, Jo-Anne; Sun, Dawei; Howell, Kate J; Brady, Jane L; Laresgoiti, Usua; Allen, George; Butler, Richard; Zilbauer, Matthias; Giangreco, Adam; Rawlins, Emma L

2017-01-01

The embryonic mouse lung is a widely used substitute for human lung development. For example, attempts to differentiate human pluripotent stem cells to lung epithelium rely on passing through progenitor states that have only been described in mouse. The tip epithelium of the branching mouse lung is a multipotent progenitor pool that self-renews and produces differentiating descendants. We hypothesized that the human distal tip epithelium is an analogous progenitor population and tested this by examining morphology, gene expression and in vitro self-renewal and differentiation capacity of human tips. These experiments confirm that human and mouse tips are analogous and identify signalling pathways that are sufficient for long-term self-renewal of human tips as differentiation-competent organoids. Moreover, we identify mouse-human differences, including markers that define progenitor states and signalling requirements for long-term self-renewal. Our organoid system provides a genetically-tractable tool that will allow these human-specific features of lung development to be investigated. DOI: http://dx.doi.org/10.7554/eLife.26575.001 PMID:28665271

Calcineurin/Nfat signaling is required for perinatal lung maturation and function.

PubMed

Davé, Vrushank; Childs, Tawanna; Xu, Yan; Ikegami, Machiko; Besnard, Valérie; Maeda, Yutaka; Wert, Susan E; Neilson, Joel R; Crabtree, Gerald R; Whitsett, Jeffrey A

2006-10-01

Pulmonary surfactant proteins and lipids are required for lung function after birth. Lung immaturity and resultant surfactant deficiency cause respiratory distress syndrome, a common disorder contributing to morbidity and mortality in preterm infants. Surfactant synthesis increases prior to birth in association with formation of the alveoli that mediate efficient gas exchange. To identify mechanisms controlling perinatal lung maturation, the Calcineurin b1 (Cnb1) gene was deleted in the respiratory epithelium of the fetal mouse. Deletion of Cnb1 caused respiratory failure after birth and inhibited the structural maturation of the peripheral lung. Synthesis of surfactant and a lamellar body-associated protein, ABC transporter A3 (ABCA3), was decreased prior to birth. Nuclear factor of activated T cells (Nfat) calcineurin-dependent 3 (Nfatc3), a transcription factor modulated by calcineurin, was identified as a direct activator of Sftpa, Sftpb, Sftpc, Abca3, Foxa1, and Foxa2 genes. The calcineurin/Nfat pathway controls the morphologic maturation of lungs prior to birth and regulates expression of genes involved in surfactant homeostasis that are critical for adaptation to air breathing.

Morphological effects of chronic bilateral phrenectomy or vagotomy in the fetal lamb lung.

PubMed Central

Alcorn, D; Adamson, T M; Maloney, J E; Robinson, P M

1980-01-01

The relationship between fetal espiratory activity and fetal lung development has been studied at the cellular level using two experimental models. Chronic bilateral phrenectomy over a period of 20-28 days during the last trimester of the fetal lamb resulted in hypoplastic lungs, although cellular maturity, as indicated by the presence of alveolar epithelial Type II cells, was present. In the lungs from fetal lambs undergoing sham operations for a similar time course there was evidence of enhanced alveolar proliferation when compared with lungs from normal fetal sheep of a similar gastational age, most probably as a result of operative stress. Following chronic bilateral vagotomy no changes in size or histology of the fetal lamb lungs were detected. At an ultrastructural level, however, inclusions of Type II cells consistently showed the loss of the typical osmiophilic lamellated appearance. These results indicate the importance of the fetal breathing apparatus in maintaining a volume of lung liquid which is adequate for normal pulmonary development, particularly during the phase in which alveoli are formed. Images Fig. 1 Fig. 2 Fig. 3 Fig. 4 Fig. 5 Fig. 6 Fig. 7 Fig. 8 Fig. 9 Fig. 10 PMID:7429961

Applicability of avidin protein coated mesoporous silica nanoparticles as drug carriers in the lung

NASA Astrophysics Data System (ADS)

van Rijt, S. H.; Bölükbas, D. A.; Argyo, C.; Wipplinger, K.; Naureen, M.; Datz, S.; Eickelberg, O.; Meiners, S.; Bein, T.; Schmid, O.; Stoeger, T.

2016-04-01

Mesoporous silica nanoparticles (MSNs) exhibit unique drug delivery properties and are thus considered as promising candidates for next generation nano-medicines. In particular, inhalation into the lungs represents a direct, non-invasive delivery route for treating lung disease. To assess MSN biocompatibility in the lung, we investigated the bioresponse of avidin-coated MSNs (MSN-AVI), as well as aminated (uncoated) MSNs, after direct application into the lungs of mice. We quantified MSN distribution, clearance rate, cell-specific uptake, and inflammatory responses to MSNs within one week after instillation. We show that amine-functionalized (MSN-NH2) particles are not taken up by lung epithelial cells, but induced a prolonged inflammatory response in the lung and macrophage cell death. In contrast, MSN-AVI co-localized with alveolar epithelial type 1 and type 2 cells in the lung in the absence of sustained inflammatory responses or cell death, and showed preferential epithelial cell uptake in in vitro co-cultures. Further, MSN-AVI particles demonstrated uniform particle distribution in mouse lungs and slow clearance rates. Thus, we provide evidence that avidin functionalized MSNs (MSN-AVI) have the potential to serve as versatile biocompatible drug carriers for lung-specific drug delivery.Mesoporous silica nanoparticles (MSNs) exhibit unique drug delivery properties and are thus considered as promising candidates for next generation nano-medicines. In particular, inhalation into the lungs represents a direct, non-invasive delivery route for treating lung disease. To assess MSN biocompatibility in the lung, we investigated the bioresponse of avidin-coated MSNs (MSN-AVI), as well as aminated (uncoated) MSNs, after direct application into the lungs of mice. We quantified MSN distribution, clearance rate, cell-specific uptake, and inflammatory responses to MSNs within one week after instillation. We show that amine-functionalized (MSN-NH2) particles are not taken up by lung epithelial cells, but induced a prolonged inflammatory response in the lung and macrophage cell death. In contrast, MSN-AVI co-localized with alveolar epithelial type 1 and type 2 cells in the lung in the absence of sustained inflammatory responses or cell death, and showed preferential epithelial cell uptake in in vitro co-cultures. Further, MSN-AVI particles demonstrated uniform particle distribution in mouse lungs and slow clearance rates. Thus, we provide evidence that avidin functionalized MSNs (MSN-AVI) have the potential to serve as versatile biocompatible drug carriers for lung-specific drug delivery. Electronic supplementary information (ESI) available: Synthesis of MSN particles. Characterisation of MSN particles (Fig. S1 and S2), DLS measurements of MSNs over time, lymphocyte and PMN cell count after MSN exposure (Fig. S3). Toxicity in BAL cytospins controls, phalloidin staining on BAL cytospins of MSN-NH2 exposed mice (Fig. S4), nanoparticle distribution in lung cryo-slices of Balb/c mice exposed to 100 μg MSNs (Fig. S5). Balb/c mice cryo-slices exposed to MSN-AVI for 1 or 7 days, co-stained with alveolar epithelial cell type 1 marker or with alveolar epithelial cell type 2 marker (Fig. S6), DiD selective labeling in a co-culture set-up (Fig. S7). See DOI: 10.1039/c5nr04119h

Automated detection of lung nodules with three-dimensional convolutional neural networks

NASA Astrophysics Data System (ADS)

Pérez, Gustavo; Arbeláez, Pablo

2017-11-01

Lung cancer is the cancer type with highest mortality rate worldwide. It has been shown that early detection with computer tomography (CT) scans can reduce deaths caused by this disease. Manual detection of cancer nodules is costly and time-consuming. We present a general framework for the detection of nodules in lung CT images. Our method consists of the pre-processing of a patient's CT with filtering and lung extraction from the entire volume using a previously calculated mask for each patient. From the extracted lungs, we perform a candidate generation stage using morphological operations, followed by the training of a three-dimensional convolutional neural network for feature representation and classification of extracted candidates for false positive reduction. We perform experiments on the publicly available LIDC-IDRI dataset. Our candidate extraction approach is effective to produce precise candidates with a recall of 99.6%. In addition, false positive reduction stage manages to successfully classify candidates and increases precision by a factor of 7.000.

MO-DE-207B-10: Impact of Morphologic Characteristics On Radiomics Features From Contast-Enhanced CT for Primary Lung Tumors

DOE Office of Scientific and Technical Information (OSTI.GOV)

Fried, D; Zhang, L; Fave, X

Purpose: Determine the impact of morphologic characteristics (e.g. necrosis, vascular enhancement, and cavitation) on radiomic features from contrast enhanced CT (CE-CT) in primary lung tumors. Methods: We developed an auto-segmentation algorithm to separate lung tumors on contrast-enhanced CT into cavitation (air), necrosis, tissue, and enhancing vessels using a combination of thresholding and region-growing. An auto-segmentation algorithm was also designed to identify necrosis on FDG-PET scans. Wilcoxon rank-sum tests were used to determine if significant differences existed in radiomics features (histogram-uniformity and Laplacian-of-Gaussian average) from 249 patients, found to prognostic in previous work, based on the presence/absence of morphologic features. Featuremore » values were also compared between the original tumor contours and contours excluding a specific morphologic feature. Comparison of necrosis segmentation on CE-CT versus FDG-PET was performed in 78 patients to assess for agreement using the concordance correlation coefficient (CCC). Results: Tumors with cavitation and enhancing vasculature had lower uniformity values (p = 0.001 and p = 0.03, respectively). Tumors with enhancing vasculature and necrosis had higher Laplacian-of-Gaussian average values (measure of “edges” within the tumor) (p < 0.001). Removing these tissue types from regions-of-interest did not drastically alter either radiomic feature value (all scenarios had R{sup 2} > 0.8). This suggests there may be interactions between morphologic characteristics and the radiomic feature value of tumor tissue. Comparison of necrosis volume and percent necrosis volume of tumor were found to have CCC values of 0.85 and 0.76, respectively between CE-CT and FDG-PET segmentation methods. Conclusions: Tumors with enhancing vasculature, necrosis, and cavitation have higher radiomic feature values that are associated with poor prognosis than tumors without these features. Removing these tissue types from quantitative assessment did not drastically impact radiomic feature values. High reproducibility of CE-CT segmented necrosis compared to FDG-PET segmented necrosis provides a reasonable validation of segmentation accuracy on CE-CT.« less

Lung phenotype of juvenile and adult cystic fibrosis transmembrane conductance regulator-knockout ferrets.

PubMed

Sun, Xingshen; Olivier, Alicia K; Liang, Bo; Yi, Yaling; Sui, Hongshu; Evans, Turan I A; Zhang, Yulong; Zhou, Weihong; Tyler, Scott R; Fisher, John T; Keiser, Nicholas W; Liu, Xiaoming; Yan, Ziying; Song, Yi; Goeken, J Adam; Kinyon, Joann M; Fligg, Danielle; Wang, Xiaoyan; Xie, Weiliang; Lynch, Thomas J; Kaminsky, Paul M; Stewart, Zoe A; Pope, R Marshall; Frana, Timothy; Meyerholz, David K; Parekh, Kalpaj; Engelhardt, John F

2014-03-01

Chronic bacterial lung infections in cystic fibrosis (CF) are caused by defects in the CF transmembrane conductance regulator chloride channel. Previously, we described that newborn CF transmembrane conductance regulator-knockout ferrets rapidly develop lung infections within the first week of life. Here, we report a more slowly progressing lung bacterial colonization phenotype observed in juvenile to adult CF ferrets reared on a layered antibiotic regimen. Even on antibiotics, CF ferrets were still very susceptible to bacterial lung infection. The severity of lung histopathology ranged from mild to severe, and variably included mucus obstruction of the airways and submucosal glands, air trapping, atelectasis, bronchopneumonia, and interstitial pneumonia. In all CF lungs, significant numbers of bacteria were detected and impaired tracheal mucociliary clearance was observed. Although Streptococcus, Staphylococcus, and Enterococcus were observed most frequently in the lungs of CF animals, each animal displayed a predominant bacterial species that accounted for over 50% of the culturable bacteria, with no one bacterial taxon predominating in all animals. Matrix-assisted laser desorption-ionization time-of-flight mass spectrometry fingerprinting was used to quantify lung bacteria in 10 CF animals and demonstrated Streptococcus, Staphylococcus, Enterococcus, or Escherichia as the most abundant genera. Interestingly, there was significant overlap in the types of bacteria observed in the lung and intestine of a given CF animal, including bacterial taxa unique to the lung and gut of each CF animal analyzed. These findings demonstrate that CF ferrets develop lung disease during the juvenile and adult stages that is similar to patients with CF, and suggest that enteric bacterial flora may seed the lung of CF ferrets.

Cost drivers for breast, lung, and colorectal cancer care in a commercially insured population over a 6-month episode: an economic analysis from a health plan perspective.

PubMed

Sagar, Bhuvana; Lin, Yu Shen; Castel, Liana D

2017-10-01

In the absence of clinical data, accurate identification of cost drivers is needed for economic comparison in an alternate payment model. From a health plan perspective using claims data in a commercial population, the objective was to identify and quantify the effects of cost drivers in economic models of breast, lung, and colorectal cancer costs over a 6-month episode following initial chemotherapy. This study analyzed claims data from 9,748 Cigna beneficiaries with diagnosis of breast, lung, and colorectal cancer following initial chemotherapy from January 1, 2014 to December 31, 2015. We used multivariable regression models to quantify the impact of key factors on cost during the initial 6-month cancer care episode. Metastasis, facility provider affiliation, episode risk group (ERG) risk score, and radiation were cost drivers for all three types of cancer (breast, lung, and colorectal). In addition, younger age (p < .0001) and human epidermal growth factor receptor-2 oncogene overexpression (HER2+)-directed therapy (p < .0001) were associated with higher costs in breast cancer. Younger age (p < .0001) and female gender (p < .0001) were also associated with higher costs in colorectal cancer. Metastasis was also associated with 50% more hospital admissions and increased hospital length of stay (p < .001) in all three cancers over the 6-month episode duration. Chemotherapy and supportive drug therapies accounted for the highest proportion (48%) of total medical costs among beneficiaries observed. Value-based reimbursement models in oncology should appropriately account for key cost drivers. Although claims-based methodologies may be further augmented with clinical data, this study recommends adjusting for the factors identified in these models to predict costs in breast, lung, and colorectal cancers.

Reevaluation and reclassification of resected lung carcinomas originally diagnosed as squamous cell carcinoma using immunohistochemical analysis

PubMed Central

Kadota, Kyuichi; Nitadori, Jun-ichi; Rekhtman, Natasha; Jones, David R.; Adusumilli, Prasad S.; Travis, William D.

2015-01-01

Currently, non-small cell lung carcinomas are primarily classified by light microscopy. However, recent studies have shown that poorly-differentiated tumors are more accurately classified by immunohistochemistry. In this study, we investigated the use of immunohistochemical analysis in reclassifying lung carcinomas that were originally diagnosed as squamous cell carcinoma. Tumor slides and blocks were available for histologic evaluation, and tissue microarrays were constructed from 480 patients with resected lung carcinomas originally diagnosed as squamous cell carcinoma between 1999 and 2009. Immunohistochemistry for p40, p63, thyroid transcription factor-1 (TTF-1; clone SPT24 and 8G7G3/1), Napsin A, Chromogranin A, Synaptophysin, and CD56 were performed. Staining intensity (weak, moderate, or strong) and distribution (focal or diffuse) were also recorded. Of all, 449 (93.5%) patients were confirmed as having squamous cell carcinomas; the cases were mostly diffusely positive for p40 and negative for TTF-1 (8G7G3/1). Twenty cases (4.2%) were reclassified as adenocarcinoma since they were positive for TTF-1 (8G7G3/1 or SPT24) with either no or focal p40 expression, and all of them were poorly-differentiated with squamoid morphology. In addition, 1 case was reclassified as adenosquamous carcinoma, 4 cases as large cell carcinoma, 4 cases as large cell neuroendocrine carcinoma, and 2 cases as small cell carcinoma. In poorly-differentiated non-small cell lung carcinomas, an accurate distinction between squamous cell carcinoma and adenocarcinoma cannot be reliably determined by morphology alone and requires immunohistochemical analysis, even in resected specimens. Our findings suggest that TTF-1 8G7G3/1 may be better suited as the primary antibody in differentiating adenocarcinoma from squamous cell carcinoma. PMID:25871623

Automatic lung segmentation using control feedback system: morphology and texture paradigm.

PubMed

Noor, Norliza M; Than, Joel C M; Rijal, Omar M; Kassim, Rosminah M; Yunus, Ashari; Zeki, Amir A; Anzidei, Michele; Saba, Luca; Suri, Jasjit S

2015-03-01

Interstitial Lung Disease (ILD) encompasses a wide array of diseases that share some common radiologic characteristics. When diagnosing such diseases, radiologists can be affected by heavy workload and fatigue thus decreasing diagnostic accuracy. Automatic segmentation is the first step in implementing a Computer Aided Diagnosis (CAD) that will help radiologists to improve diagnostic accuracy thereby reducing manual interpretation. Automatic segmentation proposed uses an initial thresholding and morphology based segmentation coupled with feedback that detects large deviations with a corrective segmentation. This feedback is analogous to a control system which allows detection of abnormal or severe lung disease and provides a feedback to an online segmentation improving the overall performance of the system. This feedback system encompasses a texture paradigm. In this study we studied 48 males and 48 female patients consisting of 15 normal and 81 abnormal patients. A senior radiologist chose the five levels needed for ILD diagnosis. The results of segmentation were displayed by showing the comparison of the automated and ground truth boundaries (courtesy of ImgTracer™ 1.0, AtheroPoint™ LLC, Roseville, CA, USA). The left lung's performance of segmentation was 96.52% for Jaccard Index and 98.21% for Dice Similarity, 0.61 mm for Polyline Distance Metric (PDM), -1.15% for Relative Area Error and 4.09% Area Overlap Error. The right lung's performance of segmentation was 97.24% for Jaccard Index, 98.58% for Dice Similarity, 0.61 mm for PDM, -0.03% for Relative Area Error and 3.53% for Area Overlap Error. The segmentation overall has an overall similarity of 98.4%. The segmentation proposed is an accurate and fully automated system.

Ibuprofen-induced patent ductus arteriosus closure: physiologic, histologic, and biochemical effects on the premature lung.

PubMed

McCurnin, Donald; Seidner, Steven; Chang, Ling-Yi; Waleh, Nahid; Ikegami, Machiko; Petershack, Jean; Yoder, Brad; Giavedoni, Luis; Albertine, Kurt H; Dahl, Mar Janna; Wang, Zheng-ming; Clyman, Ronald I

2008-05-01

The goal was to study the pulmonary, biochemical, and morphologic effects of a persistent patent ductus arteriosus in a preterm baboon model of bronchopulmonary dysplasia. Preterm baboons (treated prenatally with glucocorticoids) were delivered at 125 days of gestation (term: 185 days), given surfactant, and ventilated for 14 days. Twenty-four hours after birth, newborns were randomly assigned to receive either ibuprofen (to close the patent ductus arteriosus; n = 8) or no drug (control; n = 13). After treatment was started, the ibuprofen group had significantly lower pulmonary/systemic flow ratio, higher systemic blood pressure, and lower left ventricular end diastolic diameter, compared with the control group. There were no differences in cardiac performance indices between the groups. Ventilation index and dynamic compliance were significantly improved with ibuprofen. The improved pulmonary mechanics in ibuprofen-treated newborns were not attributable to changes in levels of surfactant protein B, C, or D, saturated phosphatidylcholine, or surfactant inhibitory proteins. There were no differences in tracheal concentrations of cytokines commonly associated with the development of bronchopulmonary dysplasia. The groups had similar messenger RNA expression of genes that regulate inflammation and remodeling in the lung. Lungs from ibuprofen-treated newborns were significantly drier (lower wet/dry ratio) and expressed 2.5 times more epithelial sodium channel protein than did control lungs. By 14 days after delivery, control newborns had morphologic features of arrested alveolar development (decreased alveolar surface area and complexity), compared with age-matched fetuses. In contrast, there was no evidence of alveolar arrest in the ibuprofen-treated newborns. Ibuprofen-induced patent ductus arteriosus closure improved pulmonary mechanics, decreased total lung water, increased epithelial sodium channel expression, and decreased the detrimental effects of preterm birth on alveolarization.

Differential KrasV12 protein levels control a switch regulating lung cancer cell morphology and motility

PubMed Central

Schäfer, C.; Mohan, A.; Burford, W.; Driscoll, M. K.; Ludlow, A. T.; Wright, W. E.; Shay, J. W.; Danuser, G.

2016-01-01

Introduction Oncogenic Kras mutations are important drivers of lung cancer development and metastasis. They are known to activate numerous cellular signaling pathways implicated in enhanced proliferation, survival, tumorigenicity and motility during malignant progression. Objectives Most previous studies of Kras in cancer have focused on the comparison of cell states in the absence or presence of oncogenic Kras mutations. Here we show that differential expression of the constitutively active mutation KrasV12 has profound effects on cell morphology and motility that drive metastatic processes. Methods The study relies on lung cancer cell transformation models, patient-derived lung cancer cell lines, and human lung tumor sections combined with molecular biology techniques, live-cell imaging and staining methods. Results Our analysis shows two cell functional states driven by KrasV12 protein levels: a non-motile state associated with high KrasV12 levels and tumorigenicity, and a motile state associated with low KrasV12 levels and cell dissemination. Conversion between the states is conferred by differential activation of a mechano-sensitive double-negative feedback between KrasV12/ERK/Myosin II and matrix-adhesion signaling. KrasV12 expression levels change upon cues such as hypoxia and integrin-mediated cell-matrix adhesion, rendering KrasV12 levels an integrator of micro-environmental signals that translate into cellular function. By live cell imaging of tumor models we observe shedding of mixed high and low KrasV12 expressers forming multi-functional collectives with potentially optimal metastatic properties composed of a highly mobile and a highly tumorigenic unit. Discussion Together these data highlight previously unappreciated roles for the quantitative effects of expression level variation of oncogenic signaling molecules in conferring fundamental alterations in cell function regulation required for cancer progression. PMID:29057096

Intermedin Stabilized Endothelial Barrier Function and Attenuated Ventilator-induced Lung Injury in Mice

PubMed Central

Müller-Redetzky, Holger Christian; Kummer, Wolfgang; Pfeil, Uwe; Hellwig, Katharina; Will, Daniel; Paddenberg, Renate; Tabeling, Christoph; Hippenstiel, Stefan; Suttorp, Norbert; Witzenrath, Martin

2012-01-01

Background Even protective ventilation may aggravate or induce lung failure, particularly in preinjured lungs. Thus, new adjuvant pharmacologic strategies are needed to minimize ventilator-induced lung injury (VILI). Intermedin/Adrenomedullin-2 (IMD) stabilized pulmonary endothelial barrier function in vitro. We hypothesized that IMD may attenuate VILI-associated lung permeability in vivo. Methodology/Principal Findings Human pulmonary microvascular endothelial cell (HPMVEC) monolayers were incubated with IMD, and transcellular electrical resistance was measured to quantify endothelial barrier function. Expression and localization of endogenous pulmonary IMD, and its receptor complexes composed of calcitonin receptor-like receptor (CRLR) and receptor activity-modifying proteins (RAMPs) 1–3 were analyzed by qRT-PCR and immunofluorescence in non ventilated mouse lungs and in lungs ventilated for 6 h. In untreated and IMD treated mice, lung permeability, pulmonary leukocyte recruitment and cytokine levels were assessed after mechanical ventilation. Further, the impact of IMD on pulmonary vasoconstriction was investigated in precision cut lung slices (PCLS) and in isolated perfused and ventilated mouse lungs. IMD stabilized endothelial barrier function in HPMVECs. Mechanical ventilation reduced the expression of RAMP3, but not of IMD, CRLR, and RAMP1 and 2. Mechanical ventilation induced lung hyperpermeability, which was ameliorated by IMD treatment. Oxygenation was not improved by IMD, which may be attributed to impaired hypoxic vasoconstriction due to IMD treatment. IMD had minor impact on pulmonary leukocyte recruitment and did not reduce cytokine levels in VILI. Conclusions/Significance IMD may possibly provide a new approach to attenuate VILI. PMID:22563471

Shrinking lung syndrome as a manifestation of pleuritis: a new model based on pulmonary physiological studies.

PubMed

Henderson, Lauren A; Loring, Stephen H; Gill, Ritu R; Liao, Katherine P; Ishizawar, Rumey; Kim, Susan; Perlmutter-Goldenson, Robin; Rothman, Deborah; Son, Mary Beth F; Stoll, Matthew L; Zemel, Lawrence S; Sandborg, Christy; Dellaripa, Paul F; Nigrovic, Peter A

2013-03-01

The pathophysiology of shrinking lung syndrome (SLS) is poorly understood. We sought to define the structural basis for this condition through the study of pulmonary mechanics in affected patients. Since 2007, most patients evaluated for SLS at our institutions have undergone standardized respiratory testing including esophageal manometry. We analyzed these studies to define the physiological abnormalities driving respiratory restriction. Chest computed tomography data were post-processed to quantify lung volume and parenchymal density. Six cases met criteria for SLS. All presented with dyspnea as well as pleurisy and/or transient pleural effusions. Chest imaging results were free of parenchymal disease and corrected diffusing capacities were normal. Total lung capacities were 39%-50% of predicted. Maximal inspiratory pressures were impaired at high lung volumes, but not low lung volumes, in 5 patients. Lung compliance was strikingly reduced in all patients, accompanied by increased parenchymal density. Patients with SLS exhibited symptomatic and/or radiographic pleuritis associated with 2 characteristic physiological abnormalities: (1) impaired respiratory force at high but not low lung volumes; and (2) markedly decreased pulmonary compliance in the absence of identifiable interstitial lung disease. These findings suggest a model in which pleural inflammation chronically impairs deep inspiration, for example through neural reflexes, leading to parenchymal reorganization that impairs lung compliance, a known complication of persistently low lung volumes. Together these processes could account for the association of SLS with pleuritis as well as the gradual symptomatic and functional progression that is a hallmark of this syndrome.

Abnormal lung sounds in patients with asthma during episodes with normal lung function.

PubMed

Schreur, H J; Vanderschoot, J; Zwinderman, A H; Dijkman, J H; Sterk, P J

1994-07-01

Even in patients with clinically stable asthma with normal lung function, the airways are characterized by inflammatory changes, including mucosal swelling. In order to investigate whether lung sounds can distinguish these subjects from normal subjects, we compared lung sound characteristics between eight normal and nine symptom-free subjects with mild asthma. All subjects underwent simultaneous recordings of airflow, lung volume changes, and lung sounds during standardized quiet breathing, and during forced maneuvers. Flow-dependent power spectra were computed using fast Fourier transform. For each spectrum we determined lung sound intensity (LSI), frequencies (Q25%, Q50%, Q75%) wheezing (W), and W%. The results were analyzed by ANOVA. During expiration, LSI was lower in patients with asthma than in healthy controls, in particular at relatively low airflow values. During quiet expiration, Q25% to Q75% were higher in asthmatics than in healthy controls, while the change of Q25% to Q75% with flow was greater in asthmatic than in normal subjects. The W and W% were not different between the subject groups. The results indicate that at given airflows, lung sounds are lower in intensity and higher in pitch in asthmatics as compared with controls. This suggests that the generation and/or transmission of lung sounds in symptom-free patients with stable asthma differ from that in normal subjects, even when lung function is within the normal range. Therefore, airflow standardized phonopneumography might reflect morphologic changes in airways of patients with asthma.

A preclinical rodent model of acute radiation-induced lung injury after ablative focal irradiation reflecting clinical stereotactic body radiotherapy.

PubMed

Hong, Zhen-Yu; Lee, Hae-June; Choi, Won Hoon; Lee, Yoon-Jin; Eun, Sung Ho; Lee, Jung Il; Park, Kwangwoo; Lee, Ji Min; Cho, Jaeho

2014-07-01

In a previous study, we established an image-guided small-animal micro-irradiation system mimicking clinical stereotactic body radiotherapy (SBRT). The goal of this study was to develop a rodent model of acute phase lung injury after ablative irradiation. A radiation dose of 90 Gy was focally delivered to the left lung of C57BL/6 mice using a small animal stereotactic irradiator. At days 1, 3, 5, 7, 9, 11 and 14 after irradiation, the lungs were perfused with formalin for fixation and paraffin sections were stained with hematoxylin and eosin (H&E) and Masson's trichrome. At days 7 and 14 after irradiation, micro-computed tomography (CT) images of the lung were taken and lung functional measurements were performed with a flexiVent™ system. Gross morphological injury was evident 9 days after irradiation of normal lung tissues and dynamic sequential events occurring during the acute phase were validated by histopathological analysis. CT images of the mouse lungs indicated partial obstruction located in the peripheral area of the left lung. Significant alteration in inspiratory capacity and tissue damping were detected on day 14 after irradiation. An animal model of radiation-induced lung injury (RILI) in the acute phase reflecting clinical stereotactic body radiotherapy was established and validated with histopathological and functional analysis. This model enhances our understanding of the dynamic sequential events occurring in the acute phase of radiation-induced lung injury induced by ablative dose focal volume irradiation.

Conservative fluid management prevents age-associated ventilator induced mortality.

PubMed

Herbert, Joseph A; Valentine, Michael S; Saravanan, Nivi; Schneck, Matthew B; Pidaparti, Ramana; Fowler, Alpha A; Reynolds, Angela M; Heise, Rebecca L

2016-08-01

Approximately 800 thousand patients require mechanical ventilation in the United States annually with an in-hospital mortality rate of over 30%. The majority of patients requiring mechanical ventilation are over the age of 65 and advanced age is known to increase the severity of ventilator-induced lung injury (VILI) and in-hospital mortality rates. However, the mechanisms which predispose aging ventilator patients to increased mortality rates are not fully understood. Ventilation with conservative fluid management decreases mortality rates in acute respiratory distress patients, but to date there has been no investigation of the effect of conservative fluid management on VILI and ventilator associated mortality rates. We hypothesized that age-associated increases in susceptibility and incidence of pulmonary edema strongly promote age-related increases in ventilator associated mortality. 2month old and 20month old male C57BL6 mice were mechanically ventilated with either high tidal volume (HVT) or low tidal volume (LVT) for up to 4h with either liberal or conservative fluid support. During ventilation, lung compliance, total lung capacity, and hysteresis curves were quantified. Following ventilation, bronchoalveolar lavage fluid was analyzed for total protein content and inflammatory cell infiltration. Wet to dry ratios were used to directly measure edema in excised lungs. Lung histology was performed to quantify alveolar barrier damage/destruction. Age matched non-ventilated mice were used as controls. At 4h, both advanced age and HVT ventilation significantly increased markers of inflammation and injury, degraded pulmonary mechanics, and decreased survival rates. Conservative fluid support significantly diminished pulmonary edema and improved pulmonary mechanics by 1h in advanced age HVT subjects. In 4h ventilations, conservative fluid support significantly diminished pulmonary edema, improved lung mechanics, and resulted in significantly lower mortality rates in older subjects. Our study demonstrates that conservative fluid alone can attenuate the age associated increase in ventilator associated mortality. Copyright © 2016 Elsevier Inc. All rights reserved.

Conservative Fluid Management Prevents Age-Associated Ventilator Induced Mortality

PubMed Central

Herbert, Joseph A.; Valentine, Michael S.; Saravanan, Nivi; Schneck, Matthew B.; Pidaparti, Ramana; Fowler, Alpha A.; Reynolds, Angela M.; Heise, Rebecca L.

2017-01-01

Background Approximately 800 thousand patients require mechanical ventilation in the United States annually with an in-hospital mortality rate of over 30%. The majority of patients requiring mechanical ventilation are over the age of 65 and advanced age is known to increase the severity of ventilator-induced lung injury (VILI) and in-hosptial mortality rates. However, the mechanisms which predispose aging ventilator patients to increased mortality rates are not fully understood. Ventilation with conservative fluid management decreases mortality rates in acute respiratory distress patients, but to date there has been no investigation of the effect of conservative fluid management on VILI and ventilator associated mortality rates. We hypothesized that age-associated increases in susceptibility and incidence of pulmonary edema strongly promote age-related increases in ventilator associated mortality. Methods 2 month old and 20 month old male C57BL6 mice were mechanically ventilated with either high tidal volume (HVT) or low tidal volume (LVT) for up to 4 hours with either liberal or conservative fluid support. During ventilation, lung compliance, total lung capacity, and hysteresis curves were quantified. Following ventilation, bronchoalveolar lavage fluid was analyzed for total protein content and inflammatory cell infiltration. Wet to dry ratios were used to directly measure edema in excised lungs. Lung histology was performed to quantify alveolar barrier damage/destruction. Age matched non-ventilated mice were used as controls. Results At 4hrs, both advanced age and HVT ventilation significantly increased markers of inflammation and injury, degraded pulmonary mechanics, and decreased survival rates. Conservative fluid support significantly diminished pulmonary edema and improved pulmonary mechanics by 1hr in advanced age HVT subjects. In 4hr ventilations, conservative fluid support significantly diminished pulmonary edema, improved lung mechanics, and resulted in significantly lower mortality rates in older subjects. Conclusion Our study demonstrates that conservative fluid alone can attenuate the age associated increase in ventilator associated mortality. PMID:27188767

Differential cell reaction upon Toll-like receptor 4 and 9 activation in human alveolar and lung interstitial macrophages

PubMed Central

2010-01-01

Background Investigations on pulmonary macrophages (MΦ) mostly focus on alveolar MΦ (AM) as a well-defined cell population. Characteristics of MΦ in the interstitium, referred to as lung interstitial MΦ (IM), are rather ill-defined. In this study we therefore aimed to elucidate differences between AM and IM obtained from human lung tissue. Methods Human AM and IM were isolated from human non-tumor lung tissue from patients undergoing lung resection. Cell morphology was visualized using either light, electron or confocal microscopy. Phagocytic activity was analyzed by flow cytometry as well as confocal microscopy. Surface marker expression was measured by flow cytometry. Toll-like receptor (TLR) expression patterns as well as cytokine expression upon TLR4 or TLR9 stimulation were assessed by real time RT-PCR and cytokine protein production was measured using a fluorescent bead-based immunoassay. Results IM were found to be smaller and morphologically more heterogeneous than AM, whereas phagocytic activity was similar in both cell types. HLA-DR expression was markedly higher in IM compared to AM. Although analysis of TLR expression profiles revealed no differences between the two cell populations, AM and IM clearly varied in cell reaction upon activation. Both MΦ populations were markedly activated by LPS as well as DNA isolated from attenuated mycobacterial strains (M. bovis H37Ra and BCG). Whereas AM expressed higher amounts of inflammatory cytokines upon activation, IM were more efficient in producing immunoregulatory cytokines, such as IL10, IL1ra, and IL6. Conclusion AM appear to be more effective as a non-specific first line of defence against inhaled pathogens, whereas IM show a more pronounced regulatory function. These dissimilarities should be taken into consideration in future studies on the role of human lung MΦ in the inflammatory response. PMID:20843333

Epithelial–mesenchymal transition during oncogenic transformation induced by hexavalent chromium involves reactive oxygen species-dependent mechanism in lung epithelial cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ding, Song-Ze, E-mail: dingsongze@hotmail.com; Graduate Center for Toxicology, College of Medicine, University of Kentucky, Lexington, KY 40536; Yang, Yu-Xiu

2013-05-15

Hexavalent chromium [Cr(VI)] is an important human carcinogen associated with pulmonary diseases and lung cancer. Exposure to Cr(VI) induces DNA damage, cell morphological change and malignant transformation in human lung epithelial cells. Despite extensive studies, the molecular mechanisms remain elusive, it is also not known if Cr(VI)-induced transformation might accompany with invasive properties to facilitate metastasis. We aimed to study Cr(VI)-induced epithelial–mesenchymal transition (EMT) and invasion during oncogenic transformation in lung epithelial cells. The results showed that Cr(VI) at low doses represses E-cadherin mRNA and protein expression, enhances mesenchymal marker vimentin expression and transforms the epithelial cell into fibroblastoid morphology.more » Cr(VI) also increases cell invasion and promotes colony formation. Further studies indicated that Cr(VI) uses multiple mechanisms to repress E-cadherin expression, including activation of E-cadherin repressors such as Slug, ZEB1, KLF8 and enhancement the binding of HDAC1 in E-cadherin gene promoter, but DNA methylation is not responsible for the loss of E-cadherin. Catalase reduces Cr(VI)-induced E-cadherin and vimentin protein expression, attenuates cell invasion in matrigel and colony formation on soft agar. These results demonstrate that exposure to a common human carcinogen, Cr(VI), induces EMT and invasion during oncogenic transformation in lung epithelial cells and implicate in cancer metastasis and prevention. - Graphical abstract: Epithelial–mesenchymal transition during oncogenic transformation induced by hexavalent chromium involves reactive oxygen species-dependent mechanisms in lung epithelial cells. - Highlights: • We study if Cr(VI) might induce EMT and invasion in epithelial cells. • Cr(VI) induces EMT by altering E-cadherin and vimentin expression. • It also increases cell invasion and promotes oncogenic transformation. • Catalase reduces Cr(VI)-induced EMT, invasion and transformation.« less

TIPS: A system for automated image-based phenotyping of maize tassels

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gage, Joseph L.; Miller, Nathan D.; Spalding, Edgar P.

Here, the maize male inflorescence (tassel) produces pollen necessary for reproduction and commercial grain production of maize. The size of the tassel has been linked to factors affecting grain yield, so understanding the genetic control of tassel architecture is an important goal. Tassels are fragile and deform easily after removal from the plant, necessitating rapid measurement of any shape characteristics that cannot be retained during storage. Some morphological characteristics of tassels such as curvature and compactness are difficult to quantify using traditional methods, but can be quantified by image-based phenotyping tools. Lastly, these constraints necessitate the development of an efficientmore » method for capturing natural-state tassel morphology and complementary automated analytical methods that can quickly and reproducibly quantify traits of interest such as height, spread, and branch number.« less

TIPS: A system for automated image-based phenotyping of maize tassels

DOE PAGES

Gage, Joseph L.; Miller, Nathan D.; Spalding, Edgar P.; ...

2017-03-31

Here, the maize male inflorescence (tassel) produces pollen necessary for reproduction and commercial grain production of maize. The size of the tassel has been linked to factors affecting grain yield, so understanding the genetic control of tassel architecture is an important goal. Tassels are fragile and deform easily after removal from the plant, necessitating rapid measurement of any shape characteristics that cannot be retained during storage. Some morphological characteristics of tassels such as curvature and compactness are difficult to quantify using traditional methods, but can be quantified by image-based phenotyping tools. Lastly, these constraints necessitate the development of an efficientmore » method for capturing natural-state tassel morphology and complementary automated analytical methods that can quickly and reproducibly quantify traits of interest such as height, spread, and branch number.« less

Automatic detection of spiculation of pulmonary nodules in computed tomography images

NASA Astrophysics Data System (ADS)

Ciompi, F.; Jacobs, C.; Scholten, E. T.; van Riel, S. J.; W. Wille, M. M.; Prokop, M.; van Ginneken, B.

2015-03-01

We present a fully automatic method for the assessment of spiculation of pulmonary nodules in low-dose Computed Tomography (CT) images. Spiculation is considered as one of the indicators of nodule malignancy and an important feature to assess in order to decide on a patient-tailored follow-up procedure. For this reason, lung cancer screening scenario would benefit from the presence of a fully automatic system for the assessment of spiculation. The presented framework relies on the fact that spiculated nodules mainly differ from non-spiculated ones in their morphology. In order to discriminate the two categories, information on morphology is captured by sampling intensity profiles along circular patterns on spherical surfaces centered on the nodule, in a multi-scale fashion. Each intensity profile is interpreted as a periodic signal, where the Fourier transform is applied, obtaining a spectrum. A library of spectra is created by clustering data via unsupervised learning. The centroids of the clusters are used to label back each spectrum in the sampling pattern. A compact descriptor encoding the nodule morphology is obtained as the histogram of labels along all the spherical surfaces and used to classify spiculated nodules via supervised learning. We tested our approach on a set of nodules from the Danish Lung Cancer Screening Trial (DLCST) dataset. Our results show that the proposed method outperforms other 3-D descriptors of morphology in the automatic assessment of spiculation.

Differences of airway dimensions between patients with and without bronchiolitis obliterans syndrome after lung transplantation-Computer-assisted quantification of computed tomography.

PubMed

Doellinger, Felix; Weinheimer, Oliver; Zwiener, Isabella; Mayer, Eckhard; Buhl, Roland; Fahlenkamp, Ute Lina; Dueber, Christoph; Achenbach, Tobias

2016-08-01

The aim of our retrospective study was to determine whether a dedicated software for assessment of airway morphology can detect differences in airway dimensions between patients with and without bronchiolitis obliterans syndrome (BOS), regarded as the clinical correlate of chronic lung allograft rejection. 12 patients with and 14 patients without diagnosis of BOS were enrolled in the study. Evaluation of bronchial wall area percentage (WA%) and bronchial wall thickness (WT) in all follow-up CT scans was performed using a semiautomatic airway assessment tool. We assessed temporal changes (ΔWA%, ΔWT) and compared these morphological parameters with forced expiratory volume in one second (ΔFEV1). In patients with and without BOS, the temporal changes over the entire follow-up were 26.6% versus 16.2% for ΔFEV1 (p=0.034), 14.2% versus 5.4% for ΔWA% (p=0.003) and 0.212mm versus 0.064mm for ΔWT (p=0.011). We detected significant differences of the temporal changes of airway dimensions (ΔWA%, ΔWT) between lung transplant recipients with and without BOS. We conclude that computer-assisted bronchial wall measurements in CT scans might complement the information from pulmonary function tests and establish as a non-invasive method to confirm BOS in lung transplant recipients in the future. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Radiating despite a Lack of Character: Ecological Divergence among Closely Related, Morphologically Similar Honeyeaters (Aves: Meliphagidae) Co-occurring in Arid Australian Environments.

PubMed

Miller, Eliot T; Wagner, Sarah K; Harmon, Luke J; Ricklefs, Robert E

2017-02-01

Quantifying the relationship between form and function can inform use of morphology as a surrogate for ecology. How the strength of this relationship varies continentally can inform understanding of evolutionary radiations; for example, does the relationship break down when certain lineages invade and diversify in novel habitats? The 75 species of Australian honeyeaters (Meliphagidae) are morphologically and ecologically diverse, with species feeding on nectar, insects, fruit, and other resources. We investigated Meliphagidae ecomorphology and community structure by (1) quantifying the concordance between morphology and ecology (foraging behavior), (2) estimating rates of trait evolution in relation to the packing of ecological space, and (3) comparing phylogenetic and trait community structure across the broad environmental gradients of the continent. We found that morphology explained 37% of the variance in ecology (and 62% vice versa), and we uncovered well-known bivariate relationships among the multivariate ecomorphological data. Ecological trait diversity declined less rapidly than phylogenetic diversity along a gradient of decreasing precipitation. We employ a new method (trait fields) and extend another (phylogenetic fields) to show that while species in phylogenetically clustered, arid-environment assemblages are similar morphologically, they are as varied in foraging behavior as those from more diverse assemblages. Thus, although closely related and similar morphologically, these arid-adapted species have diverged in ecological space to a similar degree as their mesic counterparts.

Predicting Future Morphological Changes of Lesions from Radiotracer Uptake in 18F-FDG-PET Images

PubMed Central

Bagci, Ulas; Yao, Jianhua; Miller-Jaster, Kirsten; Chen, Xinjian; Mollura, Daniel J.

2013-01-01

We introduce a novel computational framework to enable automated identification of texture and shape features of lesions on 18F-FDG-PET images through a graph-based image segmentation method. The proposed framework predicts future morphological changes of lesions with high accuracy. The presented methodology has several benefits over conventional qualitative and semi-quantitative methods, due to its fully quantitative nature and high accuracy in each step of (i) detection, (ii) segmentation, and (iii) feature extraction. To evaluate our proposed computational framework, thirty patients received 2 18F-FDG-PET scans (60 scans total), at two different time points. Metastatic papillary renal cell carcinoma, cerebellar hemongioblastoma, non-small cell lung cancer, neurofibroma, lymphomatoid granulomatosis, lung neoplasm, neuroendocrine tumor, soft tissue thoracic mass, nonnecrotizing granulomatous inflammation, renal cell carcinoma with papillary and cystic features, diffuse large B-cell lymphoma, metastatic alveolar soft part sarcoma, and small cell lung cancer were included in this analysis. The radiotracer accumulation in patients' scans was automatically detected and segmented by the proposed segmentation algorithm. Delineated regions were used to extract shape and textural features, with the proposed adaptive feature extraction framework, as well as standardized uptake values (SUV) of uptake regions, to conduct a broad quantitative analysis. Evaluation of segmentation results indicates that our proposed segmentation algorithm has a mean dice similarity coefficient of 85.75±1.75%. We found that 28 of 68 extracted imaging features were correlated well with SUVmax (p<0.05), and some of the textural features (such as entropy and maximum probability) were superior in predicting morphological changes of radiotracer uptake regions longitudinally, compared to single intensity feature such as SUVmax. We also found that integrating textural features with SUV measurements significantly improves the prediction accuracy of morphological changes (Spearman correlation coefficient = 0.8715, p<2e-16). PMID:23431398

There is still a role for cytology in the 'liquid biopsy' era. A lesson from a TKI-treated patient showing adenocarcinoma to squamous cell carcinoma transition during disease progression.

PubMed

Clery, Eduardo; Pisapia, Pasquale; Feliciano, Salvatore; Vigliar, Elena; Marano, Antonio; De Luca, Caterina; Malapelle, Umberto; Troncone, Giancarlo; Bellevicine, Claudio

2017-09-01

Non-small cell lung carcinoma harbouring epidermal growth factor receptor ( EGFR ) mutation, usually progress after an initial response to tyrosine-kinase inhibitors (TKI). Liquid biopsy enables with a simple blood draw the accurate detection of EGFR p.T790M mutation, the most common resistance mechanism, avoiding the more invasive tissue re-biopsy. However, in a subset of cases, resistance mechanisms are more complex featuring both genetic and morphological changes. Here we report the case of a 67 years-old woman, affected by an EGFR mutated lung adenocarcinoma and treated by TKI. At disease progression, the patient developed a morphological transition to squamous cell carcinoma in association to the arising of a PIK3CA p.E542K mutant subclone. This case illustrates that, even in the "liquid biopsy" era, cytology can have still a role by providing an overall assessment of both morphology and genetic TKI resistance mechanisms. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

Estimating the asbestos-related lung cancer burden from mesothelioma mortality

PubMed Central

McCormack, V; Peto, J; Byrnes, G; Straif, K; Boffetta, P

2012-01-01

Background: Quantifying the asbestos-related lung cancer burden is difficult in the presence of this disease's multiple causes. We explore two methods to estimate this burden using mesothelioma deaths as a proxy for asbestos exposure. Methods: From the follow-up of 55 asbestos cohorts, we estimated ratios of (i) absolute number of asbestos-related lung cancers to mesothelioma deaths; (ii) excess lung cancer relative risk (%) to mesothelioma mortality per 1000 non-asbestos-related deaths. Results: Ratios varied by asbestos type; there were a mean 0.7 (95% confidence interval 0.5, 1.0) asbestos-related lung cancers per mesothelioma death in crocidolite cohorts (n=6 estimates), 6.1 (3.6, 10.5) in chrysotile (n=16), 4.0 (2.8, 5.9) in amosite (n=4) and 1.9 (1.4, 2.6) in mixed asbestos fibre cohorts (n=31). In a population with 2 mesothelioma deaths per 1000 deaths at ages 40–84 years (e.g., US men), the estimated lung cancer population attributable fraction due to mixed asbestos was estimated to be 4.0%. Conclusion: All types of asbestos fibres kill at least twice as many people through lung cancer than through mesothelioma, except for crocidolite. For chrysotile, widely consumed today, asbestos-related lung cancers cannot be robustly estimated from few mesothelioma deaths and the latter cannot be used to infer no excess risk of lung or other cancers. PMID:22233924

Pulmonary preinvasive neoplasia.

PubMed

Kerr, K M

2001-04-01

Advances in molecular biology have increased our knowledge of the biology of preneoplastic lesions in the human lung. The recently published WHO lung tumour classification defines three separate lesions that are regarded as preinvasive neoplasia. These are (1) squamous dysplasia and carcinoma in situ (SD/CIS), (2) atypical adenomatous hyperplasia (AAH), and (3) diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIP-NECH). SD/CIS is graded in four stages (mild, moderate, severe, and CIS), based upon the distribution of atypical cells and mitotic figures. Most airways showing SD/CIS demonstrate a range of grades; many epithelia are hard to assess and the reproducibility of this complex system remains to be established. Detailed criteria are, however, welcome and provide an objective framework on which to compare various molecular changes. Alterations in gene expression and chromosome structure known to be associated with malignant transformation can be demonstrated in CIS, less so in dysplasias, but also in morphologically normal epithelium. The changes might be sequential, and their frequency and number increase with atypia. Less is known of the "risk of progression" of SD/CIS to invasive "central" bronchial carcinoma. It may take between one and 10 years for invasion to occur, yet the lesion(s) may be reversible if carcinogen exposure ceases. AAH may be an important precursor lesion for peripheral "parenchymal" adenocarcinoma of the lung: the "adenoma" in an adenoma-carcinoma sequence. There is good morphological evidence that AAH may progress from low to high grade to bronchioloalveolar carcinoma (BAC; a non-invasive lesion by definition). Invasion then develops within BAC and peripheral lung adenocarcinoma evolves. The molecular events associated with this progression are not well understood and studies are hampered by a lack of clear criteria to distinguish high grade AAH from BAC. Nonetheless, as with SD/CIS, the patterns of expression of tumour associated genes are consistent with neoplastic progression. We have little idea of the incidence of AAH in the normal or "smoking" populations. It is found more frequently in cancer bearing lungs, especially in those with adenocarcinoma, and is more common in women. No data are available on the risk of progression of AAH. DIPNECH is an exceptionally rare lesion associated with the development of multiple carcinoid tumours. Almost nothing is known of its biology. Knowledge of these lesions will be crucial in the design and understanding of lung cancer screening programmes, where it is likely that the morphological and, more importantly perhaps, the molecular characteristics of these lesions will provide useful targets for detection and possibly even treatment.

Secondary flow measurements and passive tracer dispersion in multi-generational models of conducting airways of the lung

NASA Astrophysics Data System (ADS)

Fresconi, Frank; Prasad, Ajay

2006-11-01

A detailed knowledge of the flow and dispersion within the human respiratory tract is desirable for numerous reasons. Both risk assessments of exposure to toxic particles in the environment and the design of medical delivery systems targeting both lung-specific conditions (asthma, cystic fibrosis, and chronic obstructive pulmonary disease (COPD)) and system-wide ailments (diabetes, cancer, hormone replacement) would profit from such an understanding. The present work features experimental efforts aimed at elucidating the fluid mechanics of the lung. Particle image velocimetry (PIV) and laser induced fluorescence (LIF) measurements of steady and oscillatory flows were undertaken in anatomically accurate models (single and multi-generational) of the conductive region of the lung. PIV results captured primary and secondary velocity fields. LIF allowed visualization of the time-dependent deformation of a passive tracer and also quantified convective dispersion through the usage of a transport profile.

Isolation and Characterization of Human Lung Lymphatic Endothelial Cells

PubMed Central

Lorusso, Bruno; Falco, Angela; Madeddu, Denise; Frati, Caterina; Cavalli, Stefano; Graiani, Gallia; Gervasi, Andrea; Rinaldi, Laura; Lagrasta, Costanza; Maselli, Davide; Gnetti, Letizia; Silini, Enrico M.; Quaini, Eugenio; Ampollini, Luca; Carbognani, Paolo; Quaini, Federico

2015-01-01

Characterization of lymphatic endothelial cells from the respiratory system may be crucial to investigate the role of the lymphatic system in the normal and diseased lung. We describe a simple and inexpensive method to harvest, isolate, and expand lymphatic endothelial cells from the human lung (HL-LECs). Fifty-five samples of healthy lung selected from patients undergoing lobectomy were studied. A two-step purification tool, based on paramagnetic sorting with monoclonal antibodies to CD31 and Podoplanin, was employed to select a pure population of HL-LECs. The purity of HL-LECs was assessed by morphologic criteria, immunocytochemistry, flow cytometry, and functional assays. Interestingly, these cells retain in vitro several receptor tyrosine kinases (RTKs) implicated in cell survival and proliferation. HL-LECs represent a clinically relevant cellular substrate to study lymphatic biology, lymphoangiogenesis, interaction with microbial agents, wound healing, and anticancer therapy. PMID:26137493

Surfactant and pulmonary blood flow distributions following treatment of premature lambs with natural surfactant.

PubMed Central

Jobe, A; Ikegami, M; Jacobs, H; Jones, S

1984-01-01

Prematurely delivered lambs were treated with radiolabeled natural surfactant by either tracheal instillation at birth and before the onset of mechanical ventilation, or after 23 +/- 1 (+/- SE) min of mechanical ventilation. Right ventricular blood flow distributions, left ventricular outputs, and left-to-right ductal shunts were measured with radiolabeled microspheres. After sacrifice, the lungs of lambs receiving surfactant at birth inflated uniformly with constant distending pressure while the lungs of lambs treated after a period of ventilation had aerated, partially aerated, and atelectatic areas. All lungs were divided into pieces which were weighed and catalogued as to location. The amount of radiolabeled surfactant and microsphere-associated radioactivity in each piece of lung was quantified. Surfactant was relatively homogenously distributed to pieces of lung from lambs that were treated with surfactant at birth; 48% of lung pieces received amounts of surfactant within +/- 25% of the mean value. Surfactant was preferentially recovered from the aerated pieces of lungs of lambs treated after a period of mechanical ventilation, and the distribution of surfactant to these lungs was very nonhomogeneous. Right ventricular blood flow distributions to the lungs were quite homogeneous in both groups of lambs. However, in 8 of 12 lambs, pulmonary blood flow was preferentially directed away from those pieces of lung that received relatively large amounts of surfactant and toward pieces of lung that received less surfactant. This acute redirection of pulmonary blood flow distribution may result from the local changes in compliances within the lung following surfactant instillation. PMID:6546766

Automatic segmentation of tumor-laden lung volumes from the LIDC database

NASA Astrophysics Data System (ADS)

O'Dell, Walter G.

2012-03-01

The segmentation of the lung parenchyma is often a critical pre-processing step prior to application of computer-aided detection of lung nodules. Segmentation of the lung volume can dramatically decrease computation time and reduce the number of false positive detections by excluding from consideration extra-pulmonary tissue. However, while many algorithms are capable of adequately segmenting the healthy lung, none have been demonstrated to work reliably well on tumor-laden lungs. Of particular challenge is to preserve tumorous masses attached to the chest wall, mediastinum or major vessels. In this role, lung volume segmentation comprises an important computational step that can adversely affect the performance of the overall CAD algorithm. An automated lung volume segmentation algorithm has been developed with the goals to maximally exclude extra-pulmonary tissue while retaining all true nodules. The algorithm comprises a series of tasks including intensity thresholding, 2-D and 3-D morphological operations, 2-D and 3-D floodfilling, and snake-based clipping of nodules attached to the chest wall. It features the ability to (1) exclude trachea and bowels, (2) snip large attached nodules using snakes, (3) snip small attached nodules using dilation, (4) preserve large masses fully internal to lung volume, (5) account for basal aspects of the lung where in a 2-D slice the lower sections appear to be disconnected from main lung, and (6) achieve separation of the right and left hemi-lungs. The algorithm was developed and trained to on the first 100 datasets of the LIDC image database.

Potential for noninvasive assessment of lung inhomogeneity using highly precise, highly time-resolved measurements of gas exchange

PubMed Central

Mountain, James E.; Santer, Peter; O’Neill, David P.; Smith, Nicholas M. J.; Ciaffoni, Luca; Couper, John H.; Ritchie, Grant A. D.; Hancock, Gus; Whiteley, Jonathan P.

2018-01-01

Inhomogeneity in the lung impairs gas exchange and can be an early marker of lung disease. We hypothesized that highly precise measurements of gas exchange contain sufficient information to quantify many aspects of the inhomogeneity noninvasively. Our aim was to explore whether one parameterization of lung inhomogeneity could both fit such data and provide reliable parameter estimates. A mathematical model of gas exchange in an inhomogeneous lung was developed, containing inhomogeneity parameters for compliance, vascular conductance, and dead space, all relative to lung volume. Inputs were respiratory flow, cardiac output, and the inspiratory and pulmonary arterial gas compositions. Outputs were expiratory and pulmonary venous gas compositions. All values were specified every 10 ms. Some parameters were set to physiologically plausible values. To estimate the remaining unknown parameters and inputs, the model was embedded within a nonlinear estimation routine to minimize the deviations between model and data for CO2, O2, and N2 flows during expiration. Three groups, each of six individuals, were studied: young (20–30 yr); old (70–80 yr); and patients with mild to moderate chronic obstructive pulmonary disease (COPD). Each participant undertook a 15-min measurement protocol six times. For all parameters reflecting inhomogeneity, highly significant differences were found between the three participant groups (P < 0.001, ANOVA). Intraclass correlation coefficients were 0.96, 0.99, and 0.94 for the parameters reflecting inhomogeneity in deadspace, compliance, and vascular conductance, respectively. We conclude that, for the particular participants selected, highly repeatable estimates for parameters reflecting inhomogeneity could be obtained from noninvasive measurements of respiratory gas exchange. NEW & NOTEWORTHY This study describes a new method, based on highly precise measures of gas exchange, that quantifies three distributions that are intrinsic to the lung. These distributions represent three fundamentally different types of inhomogeneity that together give rise to ventilation-perfusion mismatch and result in impaired gas exchange. The measurement technique has potentially broad clinical applicability because it is simple for both patient and operator, it does not involve ionizing radiation, and it is completely noninvasive. PMID:29074714

The development of a 4D treatment planning methodology to simulate the tracking of central lung tumors in an MRI-linac.

PubMed

Al-Ward, Shahad M; Kim, Anthony; McCann, Claire; Ruschin, Mark; Cheung, Patrick; Sahgal, Arjun; Keller, Brian M

2018-01-01

Targeting and tracking of central lung tumors may be feasible on the Elekta MRI-linac (MRL) due to the soft-tissue visualization capabilities of MRI. The purpose of this work is to develop a novel treatment planning methodology to simulate tracking of central lung tumors with the MRL and to quantify the benefits in OAR sparing compared with the ITV approach. Full 4D-CT datasets for five central lung cancer patients were selected to simulate the condition of having 4D-pseudo-CTs derived from 4D-MRI data available on the MRL with real-time tracking capabilities. We used the MRL treatment planning system to generate two plans: (a) with a set of MLC-defined apertures around the target at each phase of the breathing ("4D-MRL" method); (b) with a fixed set of fields encompassing the maximum inhale and exhale of the breathing cycle ("ITV" method). For both plans, dose accumulation was performed onto a reference phase. To further study the potential benefits of a 4D-MRL method, the results were stratified by tumor motion amplitude, OAR-to-tumor proximity, and the relative OAR motion (ROM). With the 4D-MRL method, the reduction in mean doses was up to 3.0 Gy and 1.9 Gy for the heart and the lung. Moreover, the lung's V12.5 Gy was spared by a maximum of 300 cc. Maximum doses to serial organs were reduced by up to 6.1 Gy, 1.5 Gy, and 9.0 Gy for the esophagus, spinal cord, and the trachea, respectively. OAR dose reduction with our method depended on the tumor motion amplitude and the ROM. Some OARs with large ROMs and in close proximity to the tumor benefited from tracking despite small tumor amplitudes. We developed a novel 4D tracking methodology for the MRL for central lung tumors and quantified the potential dosimetric benefits compared with our current ITV approach. © 2017 The Authors. Journal of Applied Clinical Medical Physics published by Wiley Periodicals, Inc. on behalf of American Association of Physicists in Medicine.

Belowground competition from overstory trees influences Douglas-fir sapling morphology in thinned stands

Treesearch

Warren D. Devine; Timothy B. Harrington

2009-01-01

We evaluated effects of belowground competition on morphology of naturally established coast Douglas-fir (Pseudotsuga menziesii var. menziesii (Mirb.) Franco) saplings in 60- to 80-year-old thinned Douglas-fir stands in southwestern Washington. We separately quantified belowground competition from overstory and understory sources...

Novel end points for clinical trials in young children with cystic fibrosis.

PubMed

Simpson, Shannon J; Mott, Lauren S; Esther, Charles R; Stick, Stephen M; Hall, Graham L

2013-06-01

Cystic fibrosis (CF) lung disease commences early in the disease progression and is the most common cause of mortality. While new CF disease-modifying agents are currently undergoing clinical trial evaluation, the implementation of such trials in young children is limited by the lack of age-appropriate clinical trial end points. Advances in infant and preschool lung function testing, imaging of the chest and the development of biochemical biomarkers have led to increased possibility of quantifying mild lung disease in young children with CF and objectively monitoring disease progression over the course of an intervention. Despite this, further standardization and development of these techniques is required to provide robust objective measures for clinical trials in this age group.

Smoking-related interstitial lung diseases.

PubMed

Caminati, A; Graziano, P; Sverzellati, N; Harari, S

2010-12-01

In pulmonary pathology, a wide spectrum of morphological changes is related to the consequences of smoking, and recognizing them on surgical specimens and on small transbronchial biopsies represents a challenge for the pathologist. Respiratory bronchiolitis, also referred to as smoker's bronchiolitis, is a common histologic feature found in the lung tissue of cigarette smokers. When identified as the sole histopathologic finding in the clinical setting of symptomatic interstitial lung disease, a diagnosis of respiratory bronchiolitis-interstitial lung disease is made. Since smoking is recognized to cause a variety of histologic patterns encompassing respiratory bronchiolitis, respiratory bronchiolitis-interstitial lung disease, desquamative interstitial pneumonia and pulmonary Langerhans cell hystiocytosis, smoking-related interstitial lung disease may be a useful concept to keep in mind for the pathologists. The relationship of smoking with each of these entities has been largely established on the basis of epidemiologic evidence. Although they have been retained as distinct and separate conditions in various classifications of interstitial lung diseases, these entities share a number of clinical, radiologic, and pathologic features suggesting that they represent a spectrum of patterns of interstitial lung disease occurring in predisposed individuals who smoke. Evaluation of histologic features, particularly in surgical lung biopsy samples, is important in making the distinction between these disorders. However, even after tissue biopsy, it may sometimes be difficult to clearly separate these entities. Recently, respiratory bronchiolitis-interstitial lung disease with fibrosis has been described and postulated that this is a smoking-related condition distinct from fibrotic non-specific interstitial pneumonia.

Inhibiting Bruton's Tyrosine Kinase Rescues Mice from Lethal Influenza Induced Acute Lung Injury.

PubMed

Florence, Jon M; Krupa, Agnieszka; Booshehri, Laela M; Davis, Sandra A; Matthay, Michael A; Kurdowska, Anna K

2018-03-08

Infection with seasonal influenza A virus (IAV) leads to lung inflammation and respiratory failure, a main cause of death in influenza infected patients. Previous experiments in our laboratory indicated that Bruton's tyrosine kinase (Btk) plays a substantial role in regulating inflammation in the respiratory region during acute lung injury (ALI) in mice, therefore we sought to determine if blocking Btk activity had a protective effect in the lung during influenza induced inflammation. A Btk inhibitor (Btk Inh.) Ibrutinib (also known as PCI-32765) was administered intranasally to mice starting 72h after lethal infection with IAV. Our data indicates that treatment with the Btk inhibitor not only reduced weight loss and led to survival, but had a dramatic effect on morphological changes to the lungs of IAV infected mice. Attenuation of lung inflammation indicative of ALI such as alveolar hemorrhage, interstitial thickening, and the presence of alveolar exudate, together with reduced levels of inflammatory mediators TNFα, IL-1β, IL-6, KC, and MCP-1 strongly suggest amelioration of the pathological immune response in the lungs to promote resolution of the infection. Finally, we observed that blocking Btk specifically in the alveolar compartment led to significant attenuation of neutrophil extracellular traps (NET)s released into the lung in vivo, and NET formation in vitro. Our innovative findings suggest that Btk may be a new drug target for influenza induced lung injury, and in general immunomodulatory treatment may be key in treating lung dysfunction driven by excessive inflammation.

archiDART v3.0: A new data analysis pipeline allowing the topological analysis of plant root systems.

PubMed

Delory, Benjamin M; Li, Mao; Topp, Christopher N; Lobet, Guillaume

2018-01-01

Quantifying plant morphology is a very challenging task that requires methods able to capture the geometry and topology of plant organs at various spatial scales. Recently, the use of persistent homology as a mathematical framework to quantify plant morphology has been successfully demonstrated for leaves, shoots, and root systems. In this paper, we present a new data analysis pipeline implemented in the R package archiDART to analyse root system architectures using persistent homology. In addition, we also show that both geometric and topological descriptors are necessary to accurately compare root systems and assess their natural complexity.

archiDART v3.0: A new data analysis pipeline allowing the topological analysis of plant root systems

PubMed Central

Delory, Benjamin M.; Li, Mao; Topp, Christopher N.; Lobet, Guillaume

2018-01-01

Quantifying plant morphology is a very challenging task that requires methods able to capture the geometry and topology of plant organs at various spatial scales. Recently, the use of persistent homology as a mathematical framework to quantify plant morphology has been successfully demonstrated for leaves, shoots, and root systems. In this paper, we present a new data analysis pipeline implemented in the R package archiDART to analyse root system architectures using persistent homology. In addition, we also show that both geometric and topological descriptors are necessary to accurately compare root systems and assess their natural complexity. PMID:29636899

Nasal airflow simulations suggest convergent adaptation in Neanderthals and modern humans.

PubMed

de Azevedo, S; González, M F; Cintas, C; Ramallo, V; Quinto-Sánchez, M; Márquez, F; Hünemeier, T; Paschetta, C; Ruderman, A; Navarro, P; Pazos, B A; Silva de Cerqueira, C C; Velan, O; Ramírez-Rozzi, F; Calvo, N; Castro, H G; Paz, R R; González-José, R

2017-11-21

Both modern humans (MHs) and Neanderthals successfully settled across western Eurasian cold-climate landscapes. Among the many adaptations considered as essential to survival in such landscapes, changes in the nasal morphology and/or function aimed to humidify and warm the air before it reaches the lungs are of key importance. Unfortunately, the lack of soft-tissue evidence in the fossil record turns difficult any comparative study of respiratory performance. Here, we reconstruct the internal nasal cavity of a Neanderthal plus two representatives of climatically divergent MH populations (southwestern Europeans and northeastern Asians). The reconstruction includes mucosa distribution enabling a realistic simulation of the breathing cycle in different climatic conditions via computational fluid dynamics. Striking across-specimens differences in fluid residence times affecting humidification and warming performance at the anterior tract were found under cold/dry climate simulations. Specifically, the Asian model achieves a rapid air conditioning, followed by the Neanderthals, whereas the European model attains a proper conditioning only around the medium-posterior tract. In addition, quantitative-genetic evolutionary analyses of nasal morphology provided signals of stabilizing selection for MH populations, with the removal of Arctic populations turning covariation patterns compatible with evolution by genetic drift. Both results indicate that, departing from important craniofacial differences existing among Neanderthals and MHs, an advantageous species-specific respiratory performance in cold climates may have occurred in both species. Fluid dynamics and evolutionary biology independently provided evidence of nasal evolution, suggesting that adaptive explanations regarding complex functional phenotypes require interdisciplinary approaches aimed to quantify both performance and evolutionary signals on covariation patterns.

Using Dual Fluorescence Reporting Genes to Establish an In Vivo Imaging Model of Orthotopic Lung Adenocarcinoma in Mice.

PubMed

Lai, Cheng-Wei; Chen, Hsiao-Ling; Yen, Chih-Ching; Wang, Jiun-Long; Yang, Shang-Hsun; Chen, Chuan-Mu

2016-12-01

Lung adenocarcinoma is characterized by a poor prognosis and high mortality worldwide. In this study, we purposed to use the live imaging techniques and a reporter gene that generates highly penetrative near-infrared (NIR) fluorescence to establish a preclinical animal model that allows in vivo monitoring of lung cancer development and provides a non-invasive tool for the research on lung cancer pathogenesis and therapeutic efficacy. A human lung adenocarcinoma cell line (A549), which stably expressed the dual fluorescence reporting gene (pCAG-iRFP-2A-Venus), was used to generate subcutaneous or orthotopic lung cancer in nude mice. Cancer development was evaluated by live imaging via the NIR fluorescent signals from iRFP, and the signals were verified ex vivo by the green fluorescence of Venus from the gross lung. The tumor-bearing mice received miR-16 nucleic acid therapy by intranasal administration to demonstrate therapeutic efficacy in this live imaging system. For the subcutaneous xenografts, the detection of iRFP fluorescent signals revealed delicate changes occurring during tumor growth that are not distinguishable by conventional methods of tumor measurement. For the orthotopic xenografts, the positive correlation between the in vivo iRFP signal from mice chests and the ex vivo green fluorescent signal from gross lung tumors and the results of the suppressed tumorigenesis by miR-16 treatment indicated that lung tumor size can be accurately quantified by the emission of NIR fluorescence. In addition, orthotopic lung tumor localization can be accurately visualized using iRFP fluorescence tomography in vivo, thus revealing the trafficking of lung tumor cells. We introduced a novel dual fluorescence lung cancer model that provides a non-invasive option for preclinical research via the use of NIR fluorescence in live imaging of lung.

Lung Phenotype of Juvenile and Adult Cystic Fibrosis Transmembrane Conductance Regulator–Knockout Ferrets

PubMed Central

Sun, Xingshen; Olivier, Alicia K.; Liang, Bo; Yi, Yaling; Sui, Hongshu; Evans, Turan I. A.; Zhang, Yulong; Zhou, Weihong; Tyler, Scott R.; Fisher, John T.; Keiser, Nicholas W.; Liu, Xiaoming; Yan, Ziying; Song, Yi; Goeken, J. Adam; Kinyon, Joann M.; Fligg, Danielle; Wang, Xiaoyan; Xie, Weiliang; Lynch, Thomas J.; Kaminsky, Paul M.; Stewart, Zoe A.; Pope, R. Marshall; Frana, Timothy; Meyerholz, David K.; Parekh, Kalpaj

2014-01-01

Chronic bacterial lung infections in cystic fibrosis (CF) are caused by defects in the CF transmembrane conductance regulator chloride channel. Previously, we described that newborn CF transmembrane conductance regulator–knockout ferrets rapidly develop lung infections within the first week of life. Here, we report a more slowly progressing lung bacterial colonization phenotype observed in juvenile to adult CF ferrets reared on a layered antibiotic regimen. Even on antibiotics, CF ferrets were still very susceptible to bacterial lung infection. The severity of lung histopathology ranged from mild to severe, and variably included mucus obstruction of the airways and submucosal glands, air trapping, atelectasis, bronchopneumonia, and interstitial pneumonia. In all CF lungs, significant numbers of bacteria were detected and impaired tracheal mucociliary clearance was observed. Although Streptococcus, Staphylococcus, and Enterococcus were observed most frequently in the lungs of CF animals, each animal displayed a predominant bacterial species that accounted for over 50% of the culturable bacteria, with no one bacterial taxon predominating in all animals. Matrix-assisted laser desorption–ionization time-of-flight mass spectrometry fingerprinting was used to quantify lung bacteria in 10 CF animals and demonstrated Streptococcus, Staphylococcus, Enterococcus, or Escherichia as the most abundant genera. Interestingly, there was significant overlap in the types of bacteria observed in the lung and intestine of a given CF animal, including bacterial taxa unique to the lung and gut of each CF animal analyzed. These findings demonstrate that CF ferrets develop lung disease during the juvenile and adult stages that is similar to patients with CF, and suggest that enteric bacterial flora may seed the lung of CF ferrets. PMID:24074402

Cavin1; a Regulator of Lung Function and Macrophage Phenotype

PubMed Central

Govender, Praveen; Romero, Freddy; Shah, Dilip; Paez, Jesus; Ding, Shi-Ying; Liu, Libin; Gower, Adam; Baez, Elizabeth; Aly, Sherif Shawky; Pilch, Paul; Summer, Ross

2013-01-01

Caveolae are cell membrane invaginations that are highly abundant in adipose tissue, endothelial cells and the lung. The formation of caveolae is dependent on the expression of various structural proteins that serve as scaffolding for these membrane invaginations. Cavin1 is a newly identified structural protein whose deficiency in mice leads to loss of caveolae formation and to development of a lipodystrophic phenotype. In this study, we sought to investigate the functional role of Cavin1 in the lung. Cavin1 deficient mice possessed dramatically altered distal lung morphology and exhibited significant physiological alterations, notably, increased lung elastance. The changes in distal lung architecture were associated with hypercellularity and the accumulation of lung macrophages. The increases in lung macrophages occurred without changes to circulating numbers of mononuclear cells and without evidence for increased proliferation. However, the increases in lung macrophages were associated with higher levels of macrophage chemotactic factors CXCL2 and CCL2 in BAL fluid from Cavin1−/− mice suggesting a possible mechanism by which these cells accumulate. In addition, lung macrophages from Cavin1−/− mice were larger and displayed measurable differences in gene expression when compared to macrophages from wild-type mice. Interestingly, macrophages were also increased in adipose tissue but not in liver, kidney or skeletal muscle from Cavin1−/− mice, and similar tissue specificity for macrophage accumulation was observed in lungs and adipose tissue from Caveolin1−/− mice. In conclusion, this study demonstrates an important role for Cavin1 in lung homeostasis and suggests that caveolae structural proteins are necessary for regulating macrophage number and phenotype in the lung. PMID:23634221

Technical Note: Phantom study to evaluate the dose and image quality effects of a computed tomography organ-based tube current modulation technique.

PubMed

Gandhi, Diksha; Crotty, Dominic J; Stevens, Grant M; Schmidt, Taly Gilat

2015-11-01

This technical note quantifies the dose and image quality performance of a clinically available organ-dose-based tube current modulation (ODM) technique, using experimental and simulation phantom studies. The investigated ODM implementation reduces the tube current for the anterior source positions, without increasing current for posterior positions, although such an approach was also evaluated for comparison. Axial CT scans at 120 kV were performed on head and chest phantoms on an ODM-equipped scanner (Optima CT660, GE Healthcare, Chalfont St. Giles, England). Dosimeters quantified dose to breast, lung, heart, spine, eye lens, and brain regions for ODM and 3D-modulation (SmartmA) settings. Monte Carlo simulations, validated with experimental data, were performed on 28 voxelized head phantoms and 10 chest phantoms to quantify organ dose and noise standard deviation. The dose and noise effects of increasing the posterior tube current were also investigated. ODM reduced the dose for all experimental dosimeters with respect to SmartmA, with average dose reductions across dosimeters of 31% (breast), 21% (lung), 24% (heart), 6% (spine), 19% (eye lens), and 11% (brain), with similar results for the simulation validation study. In the phantom library study, the average dose reduction across all phantoms was 34% (breast), 20% (lung), 8% (spine), 20% (eye lens), and 8% (brain). ODM increased the noise standard deviation in reconstructed images by 6%-20%, with generally greater noise increases in anterior regions. Increasing the posterior tube current provided similar dose reduction as ODM for breast and eye lens, increased dose to the spine, with noise effects ranging from 2% noise reduction to 16% noise increase. At noise equal to SmartmA, ODM increased the estimated effective dose by 4% and 8% for chest and head scans, respectively. Increasing the posterior tube current further increased the effective dose by 15% (chest) and 18% (head) relative to SmartmA. ODM reduced dose in all experimental and simulation studies over a range of phantoms, while increasing noise. The results suggest a net dose/noise benefit for breast and eye lens for all studied phantoms, negligible lung dose effects for two phantoms, increased lung dose and/or noise for eight phantoms, and increased dose and/or noise for brain and spine for all studied phantoms compared to the reference protocol.

Novel cryomilled physically cross-linked biodegradable hydrogel microparticles as carriers for inhalation therapy.

PubMed

El-Sherbiny, I M; Smyth, H D C

2010-01-01

In this study, novel biodegradable physically cross-linked hydrogel microparticles were developed and evaluated in-vitro as potential carriers for inhalation therapy. These hydrogel microparticles were prepared to be respirable (desired aerodynamic size) when dry and also designed to avoid the macrophage uptake (attain large swollen size once deposited in lung). The swellable microparticles, prepared using cryomilling, were based on Pluronic® F-108 in combination with PEG grafted onto both chitosan (Cs) and its N-phthaloyl derivative (NPHCs). Polymers synthesized in the study were characterized using EA, FTIR, 2D-XRD and DSC. Morphology, particle size, density, biodegradation and moisture content of the microparticles were quantified. Swelling characteristics for both drug-free and drug-loaded microparticles showed excellent size increases (between 700-1300%) and the release profiles indicated sustained release could be achieved for up to 20 days. The respirable microparticles showed drug loading efficiency up to 92%. The enzymatic degradation of developed microparticles started within the first hour and only ∼10% weights were remaining after 10 days. In conclusion, these respirable microparticles demonstrated promising in-vitro performance for potential sustained release vectors in pulmonary drug delivery.

A 4DCT imaging-based breathing lung model with relative hysteresis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Miyawaki, Shinjiro; Choi, Sanghun; Hoffman, Eric A.

To reproduce realistic airway motion and airflow, the authors developed a deforming lung computational fluid dynamics (CFD) model based on four-dimensional (4D, space and time) dynamic computed tomography (CT) images. A total of 13 time points within controlled tidal volume respiration were used to account for realistic and irregular lung motion in human volunteers. Because of the irregular motion of 4DCT-based airways, we identified an optimal interpolation method for airway surface deformation during respiration, and implemented a computational solid mechanics-based moving mesh algorithm to produce smooth deforming airway mesh. In addition, we developed physiologically realistic airflow boundary conditions for bothmore » models based on multiple images and a single image. Furthermore, we examined simplified models based on one or two dynamic or static images. By comparing these simplified models with the model based on 13 dynamic images, we investigated the effects of relative hysteresis of lung structure with respect to lung volume, lung deformation, and imaging methods, i.e., dynamic vs. static scans, on CFD-predicted pressure drop. The effect of imaging method on pressure drop was 24 percentage points due to the differences in airflow distribution and airway geometry. - Highlights: • We developed a breathing human lung CFD model based on 4D-dynamic CT images. • The 4DCT-based breathing lung model is able to capture lung relative hysteresis. • A new boundary condition for lung model based on one static CT image was proposed. • The difference between lung models based on 4D and static CT images was quantified.« less

Improved biochemical preservation of lung slices during cold storage.

PubMed

Bull, D A; Connors, R C; Reid, B B; Albanil, A; Stringham, J C; Karwande, S V

2000-05-15

Development of lung preservation solutions typically requires whole-organ models which are animal and labor intensive. These models rely on physiologic rather than biochemical endpoints, making accurate comparison of the relative efficacy of individual solution components difficult. We hypothesized that lung slices could be used to assess preservation of biochemical function during cold storage. Whole rat lungs were precision cut into slices with a thickness of 500 microm and preserved at 4 degrees C in the following solutions: University of Wisconsin (UW), Euro-Collins (EC), low-potassium-dextran (LPD), Kyoto (K), normal saline (NS), or a novel lung preservation solution (NPS) developed using this model. Lung biochemical function was assessed by ATP content (etamol ATP/mg wet wt) and capacity for protein synthesis (cpm/mg protein) immediately following slicing (0 h) and at 6, 12, 18, and 24 h of cold storage. Six slices were assayed at each time point for each solution. The data were analyzed using analysis of variance and are presented as means +/- SD. ATP content was significantly higher in the lung slices stored in NPS compared with all other solutions at each time point (P < 0.0001). Protein synthesis was significantly higher in the lung slices stored in NPS compared with all other solutions at 6, 12, and 18 h of preservation (P < 0.05). This lung slice model allows the rapid and efficient screening of lung preservation solutions and their components using quantifiable biochemical endpoints. Using this model, we have developed a novel solution that improves the biochemical preservation of lung slices during cold storage. Copyright 2000 Academic Press.

The metastatic microenvironment: lung-derived factors control the viability of neuroblastoma lung metastasis.

PubMed

Maman, Shelly; Edry-Botzer, Liat; Sagi-Assif, Orit; Meshel, Tsipi; Yuan, Weirong; Lu, Wuyuan; Witz, Isaac P

2013-11-15

Recent data suggest that the mechanisms determining whether a tumor cell reaching a secondary organ will enter a dormant state, progress toward metastasis, or go through apoptosis are regulated by the microenvironment of the distant organ. In neuroblastoma, 60-70% of children with high-risk disease will ultimately experience relapse due to the presence of micrometastases. The main goal of this study is to evaluate the role of the lung microenvironment in determining the fate of neuroblastoma lung metastases and micrometastases. Utilizing an orthotopic mouse model for human neuroblastoma metastasis, we were able to generate two neuroblastoma cell populations-lung micrometastatic (MicroNB) cells and lung macrometastatic (MacroNB) cells. These two types of cells share the same genetic background, invade the same distant organ, but differ in their ability to create metastasis in the lungs. We hypothesize that factors present in the lung microenvironment inhibit the propagation of MicroNB cells preventing them from forming overt lung metastasis. This study indeed shows that lung-derived factors significantly reduce the viability of MicroNB cells by up regulating the expression of pro-apoptotic genes, inducing cell cycle arrest and decreasing ERK and FAK phosphorylation. Lung-derived factors affected various additional progression-linked cellular characteristics of neuroblastoma cells, such as the expression of stem-cell markers, morphology, and migratory capacity. An insight into the microenvironmental effects governing neuroblastoma recurrence and progression would be of pivotal importance as they could have a therapeutic potential for the treatment of neuroblastoma residual disease. Copyright © 2013 UICC.

Fourier decomposition pulmonary MRI using a variable flip angle balanced steady-state free precession technique.

PubMed

Corteville, D M R; Kjïrstad, Å; Henzler, T; Zöllner, F G; Schad, L R

2015-05-01

Fourier decomposition (FD) is a noninvasive method for assessing ventilation and perfusion-related information in the lungs. However, the technique has a low signal-to-noise ratio (SNR) in the lung parenchyma. We present an approach to increase the SNR in both morphological and functional images. The data used to create functional FD images are usually acquired using a standard balanced steady-state free precession (bSSFP) sequence. In the standard sequence, the possible range of the flip angle is restricted due to specific absorption rate (SAR) limitations. Thus, using a variable flip angle approach as an optimization is possible. This was validated using measurements from a phantom and six healthy volunteers. The SNR in both the morphological and functional FD images was increased by 32%, while the SAR restrictions were kept unchanged. Furthermore, due to the higher SNR, the effective resolution of the functional images was increased visibly. The variable flip angle approach did not introduce any new transient artifacts, and blurring artifacts were minimized. Both a gain in SNR and an effective resolution gain in functional lung images can be obtained using the FD method in conjunction with a variable flip angle optimized bSSFP sequence. © 2014 Wiley Periodicals, Inc.

Ceramides: a potential therapeutic target in pulmonary emphysema.

PubMed

Tibboel, Jeroen; Reiss, Irwin; de Jongste, Johan C; Post, Martin

2013-10-01

The aim of this manuscript was to characterize airway ceramide profiles in a rodent model of elastase-induced emphysema and to examine the effect of pharmacological intervention directed towards ceramide metabolism. Adult mice were anesthetized and treated with an intratracheal instillation of elastase. Lung function was measured, broncho-alveolar lavage fluid collected and histological and morphometrical analysis of lung tissue performed within 3 weeks after elastase injection, with and without sphingomyelinase inhibitors or serine palmitoyltransferase inhibitor. Ceramides in broncho-alveolar lavage (BAL) fluid were quantified by tandem mass spectrometry. BAL fluid showed a transient increase in total protein and IgM, and activated macrophages and neutrophils. Ceramides were transiently upregulated at day 2 after elastase treatment. Histology showed persistent patchy alveolar destruction at day 2 after elastase installation. Acid and neutral sphingomyelinase inhibitors had no effect on BAL ceramide levels, lung function or histology. Addition of a serine palmitoyltransferase inhibitor ameliorated lung function changes and reduced ceramides in BAL. Ceramides were increased during the acute inflammatory phase of elastase-induced lung injury. Since addition of a serine palmitoyltransferase inhibitor diminished the rise in ceramides and ameliorated lung function, ceramides likely contributed to the early phase of alveolar destruction and are a potential therapeutic target in the elastase model of lung emphysema.

Dynamic OCT monitoring and quantification of light penetration enhancement for normal, benign and cancerous human lung tissues at different concentrations of glycerol

DOE Office of Scientific and Technical Information (OSTI.GOV)

Shu-wen Tan; Ying Jin; Hui Yu

2013-10-31

We have evaluated the dynamic effects of the analyte diffusion on the 1/e light penetration depths of normal, benign and cancerous human lung tissue in vitro, as well as have monitored and quantified the dynamic change in the light penetration depths of the mentioned human lung tissue after application of 25 % and 50 % glycerol solution, respectively. The light penetration depths of the analyte diffusion in the lung tissue are measured using the Fourierdomain optical coherence tomography (FD-OCT). Experimental results show that the application of glycerol as a chemical agent can significantly enhance light penetration depths into the humanmore » normal lung (NL), lung benign granulomatosis (LBG) and lung squamous cell carcinoma (LSCC) tissue. In-depth transport of the glycerol molecules in the NL, LBG and LSCC tissue at a lower glycerol concentration (25 %) are faster than those at a higher glycerol concentration (50 %), and the 1/e light penetration depths at a lower glycerol concentration (25 %) are smaller than those at a higher glycerol concentration (50 %), respectively. Their differences in the maximal 1/e light penetration depths of the NL, LBG and LSCC tissue at a higher and a lower glycerol concentrations were only 8.8 %, 6.8 % and 4.7 %, respectively. (biophotonics)« less

Lung and Heart Sounds Analysis: State-of-the-Art and Future Trends.

PubMed

Padilla-Ortiz, Ana L; Ibarra, David

2018-01-01

Lung sounds, which include all sounds that are produced during the mechanism of respiration, may be classified into normal breath sounds and adventitious sounds. Normal breath sounds occur when no respiratory problems exist, whereas adventitious lung sounds (wheeze, rhonchi, crackle, etc.) are usually associated with certain pulmonary pathologies. Heart and lung sounds that are heard using a stethoscope are the result of mechanical interactions that indicate operation of cardiac and respiratory systems, respectively. In this article, we review the research conducted during the last six years on lung and heart sounds, instrumentation and data sources (sensors and databases), technological advances, and perspectives in processing and data analysis. Our review suggests that chronic obstructive pulmonary disease (COPD) and asthma are the most common respiratory diseases reported on in the literature; related diseases that are less analyzed include chronic bronchitis, idiopathic pulmonary fibrosis, congestive heart failure, and parenchymal pathology. Some new findings regarding the methodologies associated with advances in the electronic stethoscope have been presented for the auscultatory heart sound signaling process, including analysis and clarification of resulting sounds to create a diagnosis based on a quantifiable medical assessment. The availability of automatic interpretation of high precision of heart and lung sounds opens interesting possibilities for cardiovascular diagnosis as well as potential for intelligent diagnosis of heart and lung diseases.

Proton MRI as a noninvasive tool to assess elastase-induced lung damage in spontaneously breathing rats.

PubMed

Quintana, Harry Karmouty; Cannet, Catherine; Zurbruegg, Stefan; Blé, François-Xavier; Fozard, John R; Page, Clive P; Beckmann, Nicolau

2006-12-01

Elastase-induced changes in lung morphology and function were detected in spontaneously breathing rats using conventional proton MRI at 4.7 T. A single dose of porcine pancreatic elastase (75 U/100 g body weight) or vehicle (saline) was administered intratracheally (i.t.) to male Brown Norway (BN) rats. MRI fluid signals were detected in the lungs 24 hr after administration of elastase and resolved within 2 weeks. These results correlated with perivascular edema and cellular infiltration observed histologically. Reductions in MRI signal intensity of the lung parenchyma, and increases in lung volume were detected as early as 2 weeks following elastase administration and remained uniform throughout the study, which lasted 8 weeks. Observations were consistent with air trapping resulting from emphysema detected histologically. In a separate experiment, animals were treated daily intraperitoneally (i.p.) with all-trans-retinoic acid (ATRA; 500 microg/kg body weight) or its vehicle (triglyceride oil) starting on day 21 after elastase administration and continuing for 12 days. Under these conditions, ATRA did not elicit a reversal of elastase-induced lung damage as measured by MRI and histology. The present approach complements other validated applications of proton MRI in experimental lung research as a method for assessing drugs in rat models of respiratory diseases.

The epidemiology of lung cancer in Xuan Wei, China: current progress, issues, and research strategies.

PubMed

Chapman, R S; Mumford, J L; Harris, D B; He, Z Z; Jiang, W Z; Yang, R D

1988-01-01

In Xuan Wei, a rural Chinese county of about one million people, females' annual lung cancer mortality is China's highest, and males' is among China's highest. Xuan Wei's very high indoor air pollution levels (sometimes exceeding 20 mg/m3), residentially stable population, relatively uncomplicated lifestyle, and wide geographic variation in lung cancer mortality render it highly amenable to quantitative, interdisciplinary investigation of chemical carcinogens due to indoor air pollution. To date, epidemiologic findings reveal a closer association of lung cancer with the indoor burning of "smoky" coal (as opposed to "smokeless" coal or wood) than with tobacco use or occupation. Current aerometric, chemical, and toxicologic findings tend to confirm this association, though the specific carcinogenic constituents of Xuan Wei indoor air pollution have not yet been determined. Chinese and American investigators are conducting interdisciplinary field and laboratory investigations to quantify the lung cancer risk attendant on indoor air pollution relative to other factors, to measure and compare the characteristics of pollution from different Xuan Wei fuels, to determine the relative etiologic importance of pollution composition and concentration, and to develop quantitative relationships between air pollution dose and lung cancer risk.

Automated Image Analysis of Lung Branching Morphogenesis from Microscopic Images of Fetal Rat Explants

PubMed Central

Rodrigues, Pedro L.; Rodrigues, Nuno F.; Duque, Duarte; Granja, Sara; Correia-Pinto, Jorge; Vilaça, João L.

2014-01-01

Background. Regulating mechanisms of branching morphogenesis of fetal lung rat explants have been an essential tool for molecular research. This work presents a new methodology to accurately quantify the epithelial, outer contour, and peripheral airway buds of lung explants during cellular development from microscopic images. Methods. The outer contour was defined using an adaptive and multiscale threshold algorithm whose level was automatically calculated based on an entropy maximization criterion. The inner lung epithelium was defined by a clustering procedure that groups small image regions according to the minimum description length principle and local statistical properties. Finally, the number of peripheral buds was counted as the skeleton branched ends from a skeletonized image of the lung inner epithelia. Results. The time for lung branching morphometric analysis was reduced in 98% in contrast to the manual method. Best results were obtained in the first two days of cellular development, with lesser standard deviations. Nonsignificant differences were found between the automatic and manual results in all culture days. Conclusions. The proposed method introduces a series of advantages related to its intuitive use and accuracy, making the technique suitable to images with different lighting characteristics and allowing a reliable comparison between different researchers. PMID:25250057

Measurements of pulmonary vascular permeability with PET and gallium-68 transferrin

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mintun, M.A.; Dennis, D.R.; Welch, M.J.

1987-11-01

We quantified pulmonary vascular permeability with positron emission tomography (PET) and gallium-68-(/sup 68/Ga) labeled transferrin. Six dogs with oleic acid-induced lung injury confined to the left lower lobe, two normal human volunteers, and two patients with the adult respiratory distress syndrome (ARDS) were evaluated. Lung tissue-activity measurements were obtained from sequential 1-5 min PET scans collected over 60 min, after in vivo labeling of transferrin through intravenous administration of (/sup 68/Ga)citrate. Blood-activity measurements were measured from simultaneously obtained peripheral blood samples. A forward rate constant describing the movement of transferrin from pulmonary vascular to extravascular compartments, the pulmonary transcapillary escapemore » rate (PTCER), was then calculated from these data using a two-compartment model. In dogs, PTCER was 49 +/- 18 in normal lung tissue and 485 +/- 114 10(-4) min-1 in injured lung. A repeat study in these dogs 4 hr later showed no significant change. Values in the human subjects showed similarly marked differences between normal and abnormal lung tissue. We conclude that PET will be a useful method of evaluating vascular permeability changes after acute lung injury.« less

Regulatory T-Cell Distribution within Lung Compartments in COPD.

PubMed

Sales, Davi S; Ito, Juliana T; Zanchetta, Ivy A; Annoni, Raquel; Aun, Marcelo V; Ferraz, Luiz Fernando S; Cervilha, Daniela A B; Negri, Elnara; Mauad, Thais; Martins, Mílton A; Lopes, Fernanda D T Q S

2017-10-01

The importance of the adaptive immune response, specifically the role of regulatory T (Treg) cells in controlling the obstruction progression in smokers, has been highlighted. To quantify the adaptive immune cells in different lung compartments, we used lung tissues from 21 never-smokers without lung disease, 22 current and/or ex-smokers without lung disease (NOS) and 13 current and/or ex-smokers with chronic obstructive pulmonary disease (COPD) for histological analysis. We observed increased T, B, IL-17 and BAFF + cells in small and large airways of COPD individuals; however, in the NOS, we only observed increase in T and IL-17 + cells only in small airways. A decrease in the density of Treg + , TGF-β + and IL-10 + in small and large airways was observed only in COPD individuals. In the lymphoid tissues, Treg, T,B-cells and BAFF + cells were also increased in COPD; however, changes in Treg inhibitory associated cytokines were not observed in this compartment. Therefore, our results suggest that difference in Treg + cell distributions in lung compartments and the decrease in TGF-β + and IL-10 + cells in the airways may lead to the obstruction in smokers.

Automatic Approach for Lung Segmentation with Juxta-Pleural Nodules from Thoracic CT Based on Contour Tracing and Correction.

PubMed

Wang, Jinke; Guo, Haoyan

2016-01-01

This paper presents a fully automatic framework for lung segmentation, in which juxta-pleural nodule problem is brought into strong focus. The proposed scheme consists of three phases: skin boundary detection, rough segmentation of lung contour, and pulmonary parenchyma refinement. Firstly, chest skin boundary is extracted through image aligning, morphology operation, and connective region analysis. Secondly, diagonal-based border tracing is implemented for lung contour segmentation, with maximum cost path algorithm used for separating the left and right lungs. Finally, by arc-based border smoothing and concave-based border correction, the refined pulmonary parenchyma is obtained. The proposed scheme is evaluated on 45 volumes of chest scans, with volume difference (VD) 11.15 ± 69.63 cm 3 , volume overlap error (VOE) 3.5057 ± 1.3719%, average surface distance (ASD) 0.7917 ± 0.2741 mm, root mean square distance (RMSD) 1.6957 ± 0.6568 mm, maximum symmetric absolute surface distance (MSD) 21.3430 ± 8.1743 mm, and average time-cost 2 seconds per image. The preliminary results on accuracy and complexity prove that our scheme is a promising tool for lung segmentation with juxta-pleural nodules.

IN SILLICO LOBAR MODELS OF HUMAN LUNGS FOR TARGETED DELIVERY OF AEROSOLIZED PHARMACEUTICALS

EPA Science Inventory

The identification of factors affecting the deposition patterns of aerosolized pharmaceuticals has important implications to medicine (e.g., inhalation therapy regimens) and toxicology (e.g., drug testing protocols). Airway morphology is a critical element of the process, influen...

An efficient method to predict and include Bragg curve degradation due to lung-equivalent materials in Monte Carlo codes by applying a density modulation

NASA Astrophysics Data System (ADS)

Baumann, Kilian-Simon; Witt, Matthias; Weber, Uli; Engenhart-Cabillic, Rita; Zink, Klemens

2017-05-01

Sub-millimetre-sized heterogeneities such as lung parenchyma cause Bragg peak degradation which can lead to an underdose of the tumor and an overdose of healthy tissue when not accounted for in treatment planning. Since commonly used treatment-planning CTs do not resolve the fine structure of lungs, this degradation can hardly be considered. We present a mathematical model capable of predicting and describing Bragg peak degradation due to a lung-equivalent geometry consisting of sub-millimetre voxels filled with either lung tissue or air. The material characteristic ‘modulation power’ is introduced to quantify the Bragg peak degradation. A strategy was developed to transfer the modulating effects of such fine structures to rougher structures such as 2 mm thick CT voxels, which is the resolution of typically used CTs. This is done by using the modulation power to derive a density distribution applicable to these voxels. By replacing the previously used sub-millimetre voxels by 2 mm thick voxels filled with lung tissue and modulating the lung tissue’s density in each voxel individually, we were able to reproduce the Bragg peak degradation. Hence a solution is found to include Bragg curve degradation due to lung-equivalent materials in Monte Carlo-based treatment-planning systems.

Lung boundary detection in pediatric chest x-rays

NASA Astrophysics Data System (ADS)

Candemir, Sema; Antani, Sameer; Jaeger, Stefan; Browning, Renee; Thoma, George R.

2015-03-01

Tuberculosis (TB) is a major public health problem worldwide, and highly prevalent in developing countries. According to the World Health Organization (WHO), over 95% of TB deaths occur in low- and middle- income countries that often have under-resourced health care systems. In an effort to aid population screening in such resource challenged settings, the U.S. National Library of Medicine has developed a chest X-ray (CXR) screening system that provides a pre-decision on pulmonary abnormalities. When the system is presented with a digital CXR image from the Picture Archive and Communication Systems (PACS) or an imaging source, it automatically identifies the lung regions in the image, extracts image features, and classifies the image as normal or abnormal using trained machine-learning algorithms. The system has been trained on adult CXR images, and this article presents enhancements toward including pediatric CXR images. Our adult lung boundary detection algorithm is model-based. We note the lung shape differences during pediatric developmental stages, and adulthood, and propose building new lung models suitable for pediatric developmental stages. In this study, we quantify changes in lung shape from infancy to adulthood toward enhancing our lung segmentation algorithm. Our initial findings suggest pediatric age groupings of 0 - 23 months, 2 - 10 years, and 11 - 18 years. We present justification for our groupings. We report on the quality of boundary detection algorithm with the pediatric lung models.

A segmentation method for lung nodule image sequences based on superpixels and density-based spatial clustering of applications with noise

PubMed Central

Zhang, Wei; Zhang, Xiaolong; Qiang, Yan; Tian, Qi; Tang, Xiaoxian

2017-01-01

The fast and accurate segmentation of lung nodule image sequences is the basis of subsequent processing and diagnostic analyses. However, previous research investigating nodule segmentation algorithms cannot entirely segment cavitary nodules, and the segmentation of juxta-vascular nodules is inaccurate and inefficient. To solve these problems, we propose a new method for the segmentation of lung nodule image sequences based on superpixels and density-based spatial clustering of applications with noise (DBSCAN). First, our method uses three-dimensional computed tomography image features of the average intensity projection combined with multi-scale dot enhancement for preprocessing. Hexagonal clustering and morphological optimized sequential linear iterative clustering (HMSLIC) for sequence image oversegmentation is then proposed to obtain superpixel blocks. The adaptive weight coefficient is then constructed to calculate the distance required between superpixels to achieve precise lung nodules positioning and to obtain the subsequent clustering starting block. Moreover, by fitting the distance and detecting the change in slope, an accurate clustering threshold is obtained. Thereafter, a fast DBSCAN superpixel sequence clustering algorithm, which is optimized by the strategy of only clustering the lung nodules and adaptive threshold, is then used to obtain lung nodule mask sequences. Finally, the lung nodule image sequences are obtained. The experimental results show that our method rapidly, completely and accurately segments various types of lung nodule image sequences. PMID:28880916

Mechanisms and consequences of oxidative stress in lung disease: therapeutic implications for an aging populace.

PubMed

Hecker, Louise

2018-04-01

The rapid expansion of the elderly population has led to the recent epidemic of age-related diseases, including increased incidence and mortality of chronic and acute lung diseases. Numerous studies have implicated aging and oxidative stress in the pathogenesis of various pulmonary diseases; however, despite recent advances in these fields, the specific contributions of aging and oxidative stress remain elusive. This review will discuss the consequences of aging on lung morphology and physiology, and how redox imbalance with aging contributes to lung disease susceptibility. Here, we focus on three lung diseases for which aging is a significant risk factor: acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary disease (COPD), and idiopathic pulmonary fibrosis (IPF). Preclinical and clinical development for redox- and senescence-altering therapeutic strategies are discussed, as well as scientific advancements that may direct current and future therapeutic development. A deeper understanding of how aging impacts normal lung function, redox balance, and injury-repair processes will inspire the development of new therapies to prevent and/or reverse age-associated pulmonary diseases, and ultimately increase health span and longevity. This review is intended to encourage basic, clinical, and translational research that will bridge knowledge gaps at the intersection of aging, oxidative stress, and lung disease to fuel the development of more effective therapeutic strategies for lung diseases that disproportionately afflict the elderly.

Post-mortem CT: Hounsfield unit profiles obtained in the lungs with respect to the cause of death assessment.

PubMed

Schober, Daniel; Schwendener, Nicole; Zech, Wolf-Dieter; Jackowski, Christian

2017-01-01

Segmentation of the lungs using post-mortem computed tomography (PMCT) data was so far not feasible due to post-mortem changes such as internal livores. Recently, an Osirix plug-in has been developed allowing automatically segmenting lungs also in PMCT data. The aim of this study was to investigate if the Hounsfield unit (HU) profiles obtained in PMCT data of the segmented lung tissue present with specific behaviour in relation to the cause of death. In 105 PMCT data sets of forensic cases, the entire lung volumes were segmented using the Mia Lite plug-in on Osirix. HU profiles of the lungs were generated and correlated to cause of death groups as assessed after forensic autopsy (cardiac death, fatal haemorrhage, craniocerebral injury, intoxication, drowning, hypothermia, hanging and suffocation). Especially cardiac death cases, intoxication cases, fatal haemorrhage cases and hypothermia cases showed very specific HU profiles. In drowning, the profiles showed two different behaviours representing wet and dry drowning. HU profiles rather varied in craniocerebral injury cases, hanging cases as well as in suffocation cases. HU profiles of the lungs segmented from PMCT data may support the cause of death diagnosis as they represent specific morphological changes in the lungs such as oedema, congestion or blood loss. Especially in cardiac death, intoxication, fatal haemorrhage, hypothermia and drowning cases, HU profiles may be very supportive for the forensic pathologist.

[Occupational factors influencing lung cancer in women in epidemiological studies].

PubMed

Swiatkowska, Beata

2011-01-01

Lung cancer is the most common cancer in men, although the alarming statistics of recent years indicate that this pathology affects also more likely a group of women and in recent years has become the leading cause of cancer deaths among Polish women. This article presents the main issues relating to occupational determinants of lung cancer in women. The results of the analysis show that the number of neoplastic diseases, including the lung cancer, recognized as an occupational disease in Poland is low, particularly among women. A major factor hampering the certification of occupational etiology of lung cancer is a long latency period, no differences in terms of the clinical and morphological characteristics from lung cancer occurring in the general population, and relatively small number of identified occupational carcinogens. Analysis of the available literature on the adverse workplace conditions shows that only a few epidemiological studies focus on the problem of job-related risk among women, and only some of them provide detailed results for lung cancer. Moreover, the abundant literature on the subject concerning the male workers might not be fully relevant because of possible differences in hormonal, genetic and other gender-related biological differences that may significantly modify the risk of cancer in women. These aspects cause that the true contribution of occupational factors to the risk of lung cancer, particularly in women, is underestimated.

Analysis of Lung Microbiota in Bronchoalveolar Lavage, Protected Brush and Sputum Samples from Subjects with Mild-To-Moderate Cystic Fibrosis Lung Disease

PubMed Central

Hogan, Deborah A.; Willger, Sven D.; Dolben, Emily L.; Hampton, Thomas H.; Stanton, Bruce A.; Morrison, Hilary G.; Sogin, Mitchell L.; Czum, Julianna; Ashare, Alix

2016-01-01

Individuals with cystic fibrosis (CF) often acquire chronic lung infections that lead to irreversible damage. We sought to examine regional variation in the microbial communities in the lungs of individuals with mild-to-moderate CF lung disease, to examine the relationship between the local microbiota and local damage, and to determine the relationships between microbiota in samples taken directly from the lung and the microbiota in spontaneously expectorated sputum. In this initial study, nine stable, adult CF patients with an FEV1>50% underwent regional sampling of different lobes of the right lung by bronchoalveolar lavage (BAL) and protected brush (PB) sampling of mucus plugs. Sputum samples were obtained from six of the nine subjects immediately prior to the procedure. Microbial community analysis was performed on DNA extracted from these samples and the extent of damage in each lobe was quantified from a recent CT scan. The extent of damage observed in regions of the right lung did not correlate with specific microbial genera, levels of community diversity or composition, or bacterial genome copies per ml of BAL fluid. In all subjects, BAL fluid from different regions of the lung contained similar microbial communities. In eight out of nine subjects, PB samples from different regions of the lung were also similar in microbial community composition, and were similar to microbial communities in BAL fluid from the same lobe. Microbial communities in PB samples were more diverse than those in BAL samples, suggesting enrichment of some taxa in mucus plugs. To our knowledge, this study is the first to examine the microbiota in different regions of the CF lung in clinically stable individuals with mild-to-moderate CF-related lung disease. PMID:26943329

Lung inhomogeneities, inflation and [18F]2-fluoro-2-deoxy-D-glucose uptake rate in acute respiratory distress syndrome.

PubMed

Cressoni, Massimo; Chiumello, Davide; Chiurazzi, Chiara; Brioni, Matteo; Algieri, Ilaria; Gotti, Miriam; Nikolla, Klodiana; Massari, Dario; Cammaroto, Antonio; Colombo, Andrea; Cadringher, Paolo; Carlesso, Eleonora; Benti, Riccardo; Casati, Rosangela; Zito, Felicia; Gattinoni, Luciano

2016-01-01

The aim of the study was to determine the size and location of homogeneous inflamed/noninflamed and inhomogeneous inflamed/noninflamed lung compartments and their association with acute respiratory distress syndrome (ARDS) severity.In total, 20 ARDS patients underwent 5 and 45 cmH2O computed tomography (CT) scans to measure lung recruitability. [(18)F]2-fluoro-2-deoxy-d-glucose ([(18)F]FDG) uptake and lung inhomogeneities were quantified with a positron emission tomography-CT scan at 10 cmH2O. We defined four compartments with normal/abnormal [(18)F]FDG uptake and lung homogeneity.The homogeneous compartment with normal [(18)F]FDG uptake was primarily composed of well-inflated tissue (80±16%), double-sized in nondependent lung (32±27% versus 16±17%, p<0.0001) and decreased in size from mild, moderate to severe ARDS (33±14%, 26±20% and 5±9% of the total lung volume, respectively, p=0.05). The homogeneous compartment with high [(18)F]FDG uptake was similarly distributed between the dependent and nondependent lung. The inhomogeneous compartment with normal [(18)F]FDG uptake represented 4% of the lung volume. The inhomogeneous compartment with high [(18)F]FDG uptake was preferentially located in the dependent lung (21±10% versus 12±10%, p<0.0001), mostly at the open/closed interfaces and related to recruitability (r(2)=0.53, p<0.001).The homogeneous lung compartment with normal inflation and [(18)F]FDG uptake decreases with ARDS severity, while the inhomogeneous poorly/not inflated compartment increases. Most of the lung inhomogeneities are inflamed. A minor fraction of healthy tissue remains in severe ARDS. Copyright ©ERS 2016.

Non-Small-Cell Lung Cancer Molecular Signatures Recapitulate Lung Developmental Pathways

PubMed Central

Borczuk, Alain C.; Gorenstein, Lyall; Walter, Kristin L.; Assaad, Adel A.; Wang, Liqun; Powell, Charles A.

2003-01-01

Current paradigms hold that lung carcinomas arise from pleuripotent stem cells capable of differentiation into one or several histological types. These paradigms suggest lung tumor cell ontogeny is determined by consequences of gene expression that recapitulate events important in embryonic lung development. Using oligonucleotide microarrays, we acquired gene profiles from 32 microdissected non-small-cell lung tumors. We determined the 100 top-ranked marker genes for adenocarcinoma, squamous cell, large cell, and carcinoid using nearest neighbor analysis. Results were validated by immunostaining for 11 selected proteins using a tissue microarray representing 80 tumors. Gene expression data of lung development were accessed from a publicly available dataset generated with the murine Mu11k genome microarray. Self-organized mapping identified two temporally distinct clusters of murine orthologues. Supervised clustering of lung development data showed large-cell carcinoma gene orthologues were in a cluster expressed in pseudoglandular and canalicular stages whereas adenocarcinoma homologues were predominantly in a cluster expressed later in the terminal sac and alveolar stages of murine lung development. Representative large-cell genes (E2F3, MYBL2, HDAC2, CDK4, PCNA) are expressed in the nucleus and are associated with cell cycle and proliferation. In contrast, adenocarcinoma genes are associated with lung-specific transcription pathways (SFTPB, TTF-1), cell adhesion, and signal transduction. In sum, non-small-cell lung tumors histology gene profiles suggest mechanisms relevant to ontogeny and clinical course. Adenocarcinoma genes are associated with differentiation and glandular formation whereas large-cell genes are associated with proliferation and differentiation arrest. The identification of developmentally regulated pathways active in tumorigenesis provides insights into lung carcinogenesis and suggests early steps may differ according to the eventual tumor morphology. PMID:14578194

VESGEN Software for Mapping and Quantification of Vascular Regulators

NASA Technical Reports Server (NTRS)

Parsons-Wingerter, Patricia A.; Vickerman, Mary B.; Keith, Patricia A.

2012-01-01

VESsel GENeration (VESGEN) Analysis is an automated software that maps and quantifies effects of vascular regulators on vascular morphology by analyzing important vessel parameters. Quantification parameters include vessel diameter, length, branch points, density, and fractal dimension. For vascular trees, measurements are reported as dependent functions of vessel branching generation. VESGEN maps and quantifies vascular morphological events according to fractal-based vascular branching generation. It also relies on careful imaging of branching and networked vascular form. It was developed as a plug-in for ImageJ (National Institutes of Health, USA). VESGEN uses image-processing concepts of 8-neighbor pixel connectivity, skeleton, and distance map to analyze 2D, black-and-white (binary) images of vascular trees, networks, and tree-network composites. VESGEN maps typically 5 to 12 (or more) generations of vascular branching, starting from a single parent vessel. These generations are tracked and measured for critical vascular parameters that include vessel diameter, length, density and number, and tortuosity per branching generation. The effects of vascular therapeutics and regulators on vascular morphology and branching tested in human clinical or laboratory animal experimental studies are quantified by comparing vascular parameters with control groups. VESGEN provides a user interface to both guide and allow control over the users vascular analysis process. An option is provided to select a morphological tissue type of vascular trees, network or tree-network composites, which determines the general collections of algorithms, intermediate images, and output images and measurements that will be produced.

Quantifying spontaneous metastasis in a syngeneic mouse melanoma model using real time PCR.

PubMed

Deng, Wentao; McLaughlin, Sarah L; Klinke, David J

2017-08-07

Modeling metastasis in vivo with animals is a priority for both revealing mechanisms of tumor dissemination and developing therapeutic methods. While conventional intravenous injection of tumor cells provides an efficient and consistent system for studying tumor cell extravasation and colonization, studying spontaneous metastasis derived from orthotopic tumor sites has the advantage of modeling more aspects of the metastatic cascade, but is challenging as it is difficult to detect small numbers of metastatic cells. In this work, we developed an approach for quantifying spontaneous metastasis in the syngeneic mouse B16 system using real time PCR. We first transduced B16 cells with lentivirus expressing firefly luciferase Luc2 gene for bioluminescence imaging. Next, we developed a real time quantitative PCR (qPCR) method for the detection of luciferase-expressing, metastatic tumor cells in mouse lungs and other organs. To illustrate the approach, we quantified lung metastasis in both spontaneous and experimental scenarios using B16F0 and B16F10 cells in C57BL/6Ncrl and NOD-Scid Gamma (NSG) mice. We tracked B16 melanoma metastasis with both bioluminescence imaging and qPCR, which were found to be self-consistent. Using this assay, we can quantitatively detect one Luc2 positive tumor cell out of 10 4 tissue cells, which corresponds to a metastatic burden of 1.8 × 10 4 metastatic cells per whole mouse lung. More importantly, the qPCR method was at least a factor of 10 more sensitive in detecting metastatic cell dissemination and should be combined with bioluminescence imaging as a high-resolution, end-point method for final metastatic cell quantitation. Given the rapid growth of primary tumors in many mouse models, assays with improved sensitivity can provide better insight into biological mechanisms that underpin tumor metastasis.

Elevated levels of CXC chemokine connective tissue activating peptide (CTAP)-III in lung cancer patients.

PubMed

Lee, Gina; Gardner, Brian K; Elashoff, David A; Purcell, Colleen M; Sandha, Harpavan S; Mao, Jenny T; Krysan, Kostyantyn; Lee, Jay M; Dubinett, Steven M

2011-05-15

Despite advances in treatments, lung cancer has been the leading cause of cancer-related deaths in the United States for the past several decades. Recent findings from the National Lung Screening Trial reveal that low-dose helical computed tomography (CT) scan screening of high-risk individuals reduces lung cancer mortality. This suggests that early detection is of key importance to improving patient outcome. However, of those screened with CT scans, 25% had positive scans that require further follow-up studies which often involve more radiation exposure and invasive tests to reduce false positive results. The purpose of this study was to identify candidate plasma biomarkers to aid in diagnosis of lung cancer in at-risk individuals. We found increased expression of the CXC chemokine connective tissue-activating peptide (CTAP)-III from plasma specimens of lung cancer patients compared to at-risk control subjects. Identification of the peptide was confirmed by the addition of an anti-NAP-2 antibody that recognizes CTAP-III and NAP-2. We also quantified and verified the increased levels of plasma CTAP-III with ELISA in patients with lung cancer (mean ± SD, 1859 ± 1219 ng/mL) compared to controls (698 ± 434 ng/mL; P<0.001). Our findings demonstrate elevated plasma levels of CTAP-III occur in lung cancer patients. Further studies are required to determine if this chemokine could be utilized in a blood-based biomarker panel for the diagnosis of lung cancer.

Quantification of Age-Related Lung Tissue Mechanics under Mechanical Ventilation.

PubMed

Kim, JongWon; Heise, Rebecca L; Reynolds, Angela M; Pidaparti, Ramana M

2017-09-29

Elderly patients with obstructive lung diseases often receive mechanical ventilation to support their breathing and restore respiratory function. However, mechanical ventilation is known to increase the severity of ventilator-induced lung injury (VILI) in the elderly. Therefore, it is important to investigate the effects of aging to better understand the lung tissue mechanics to estimate the severity of ventilator-induced lung injuries. Two age-related geometric models involving human bronchioles from generation G10 to G23 and alveolar sacs were developed. The first is for a 50-year-old (normal) and second is for an 80-year old (aged) model. Lung tissue mechanics of normal and aged models were investigated under mechanical ventilation through computational simulations. Results obtained indicated that lung tissue strains during inhalation (t = 0.2 s) decreased by about 40% in the alveolar sac (G23) and 27% in the bronchiole (G20), respectively, for the 80-year-old as compared to the 50-year-old. The respiratory mechanics parameters (work of breathing per unit volume and maximum tissue strain) over G20 and G23 for the 80-year-old decreased by about 64% (three-fold) and 80% (four-fold), respectively, during the mechanical ventilation breathing cycle. However, there was a significant increase (by about threefold) in lung compliance for the 80-year-old in comparison to the 50-year-old. These findings from the computational simulations demonstrated that lung mechanical characteristics are significantly compromised in aging tissues, and these effects were quantified in this study.

Plant Proteinase Inhibitor BbCI Modulates Lung Inflammatory Responses and Mechanic and Remodeling Alterations Induced by Elastase in Mice.

PubMed

Almeida-Reis, Rafael; Theodoro-Junior, Osmar A; Oliveira, Bruno T M; Oliva, Leandro V; Toledo-Arruda, Alessandra C; Bonturi, Camila R; Brito, Marlon V; Lopes, Fernanda D T Q S; Prado, Carla M; Florencio, Ariana C; Martins, Mílton A; Owen, Caroline A; Leick, Edna A; Oliva, Maria L V; Tibério, Iolanda F L C

2017-01-01

Background. Proteinases play a key role in emphysema. Bauhinia bauhinioides cruzipain inhibitor (BbCI) is a serine-cysteine proteinase inhibitor. We evaluated BbCI treatment in elastase-induced pulmonary alterations. Methods.  C57BL / 6 mice received intratracheal elastase (ELA group) or saline (SAL group). One group of mice was treated with BbCI (days 1, 15, and 21 after elastase instillation, ELABC group). Controls received saline and BbCI (SALBC group). After 28 days, we evaluated respiratory mechanics, exhaled nitric oxide, and bronchoalveolar lavage fluid. In lung tissue we measured airspace enlargement, quantified neutrophils, TNF α -, MMP-9-, MMP-12-, TIMP-1-, iNOS-, and eNOS-positive cells, 8-iso-PGF2 α , collagen, and elastic fibers in alveolar septa and airways. MUC-5-positive cells were quantified only in airways. Results. BbCI reduced elastase-induced changes in pulmonary mechanics, airspace enlargement and elastase-induced increases in total cells, and neutrophils in BALF. BbCI reduced macrophages and neutrophils positive cells in alveolar septa and neutrophils and TNF α -positive cells in airways. BbCI attenuated elastic and collagen fibers, MMP-9- and MMP-12-positive cells, and isoprostane and iNOS-positive cells in alveolar septa and airways. BbCI reduced MUC5ac-positive cells in airways. Conclusions. BbCI improved lung mechanics and reduced lung inflammation and airspace enlargement and increased oxidative stress levels induced by elastase. BbCI may have therapeutic potential in chronic obstructive pulmonary disease.

Plant Proteinase Inhibitor BbCI Modulates Lung Inflammatory Responses and Mechanic and Remodeling Alterations Induced by Elastase in Mice

PubMed Central

Theodoro-Junior, Osmar A.; Oliveira, Bruno T. M.; Oliva, Leandro V.; Toledo-Arruda, Alessandra C.; Bonturi, Camila R.; Brito, Marlon V.; Prado, Carla M.; Florencio, Ariana C.; Martins, Mílton A.; Owen, Caroline A.; Oliva, Maria L. V.

2017-01-01

Background. Proteinases play a key role in emphysema. Bauhinia bauhinioides cruzipain inhibitor (BbCI) is a serine-cysteine proteinase inhibitor. We evaluated BbCI treatment in elastase-induced pulmonary alterations. Methods.  C57BL/6 mice received intratracheal elastase (ELA group) or saline (SAL group). One group of mice was treated with BbCI (days 1, 15, and 21 after elastase instillation, ELABC group). Controls received saline and BbCI (SALBC group). After 28 days, we evaluated respiratory mechanics, exhaled nitric oxide, and bronchoalveolar lavage fluid. In lung tissue we measured airspace enlargement, quantified neutrophils, TNFα-, MMP-9-, MMP-12-, TIMP-1-, iNOS-, and eNOS-positive cells, 8-iso-PGF2α, collagen, and elastic fibers in alveolar septa and airways. MUC-5-positive cells were quantified only in airways. Results. BbCI reduced elastase-induced changes in pulmonary mechanics, airspace enlargement and elastase-induced increases in total cells, and neutrophils in BALF. BbCI reduced macrophages and neutrophils positive cells in alveolar septa and neutrophils and TNFα-positive cells in airways. BbCI attenuated elastic and collagen fibers, MMP-9- and MMP-12-positive cells, and isoprostane and iNOS-positive cells in alveolar septa and airways. BbCI reduced MUC5ac-positive cells in airways. Conclusions. BbCI improved lung mechanics and reduced lung inflammation and airspace enlargement and increased oxidative stress levels induced by elastase. BbCI may have therapeutic potential in chronic obstructive pulmonary disease. PMID:28466019

Lung nodule detection in pediatric chest CT: quantitative relationship between image quality and radiologist performance.

PubMed

Li, Xiang; Samei, Ehsan; Barnhart, Huiman X; Gaca, Ana Maria; Hollingsworth, Caroline L; Maxfield, Charles M; Carrico, Caroline W T; Colsher, James G; Frush, Donald P

2011-05-01

To determine the quantitative relationship between image quality and radiologist performance in detecting small lung nodules in pediatric CT. The study included clinical chest CT images of 30 pediatric patients (0-16 years) scanned at tube currents of 55-180 mA. Calibrated noise addition software was used to simulate cases at three nominal mA settings: 70, 35, and 17.5 mA, resulting in quantum noise of 7-32 Hounsfield Unit (HU). Using a validated nodule simulation technique, lung nodules with diameters of 3-5 mm and peak contrasts of 200-500 HU were inserted into the cases, which were then randomized and rated independently by four experienced pediatric radiologists for nodule presence on a continuous scale from 0 (definitely absent) to 100 (definitely present). The receiver operating characteristic (ROC) data were analyzed to quantify the relationship between diagnostic accuracy (area under the ROC curve, AUC) and image quality (the product of nodule peak contrast and displayed diameter to noise ratio, CDNR display). AUC increased rapidly from 0.70 to 0.87 when CDNR display increased from 60 to 130 mm, followed by a slow increase to 0.94 when CDNR display further increased to 257 mm. For the average nodule diameter (4 mm) and contrast (350 HU), AUC decreased from 0.93 to 0.71 with noise increased from 7 to 28 HU. We quantified the relationship between image quality and the performance of radiologists in detecting lung nodules in pediatric CT. The relationship can guide CT protocol design to achieve the desired diagnostic performance at the lowest radiation dose.

Quantitative label-free multimodality nonlinear optical imaging for in situ differentiation of cancerous lesions

NASA Astrophysics Data System (ADS)

Xu, Xiaoyun; Li, Xiaoyan; Cheng, Jie; Liu, Zhengfan; Thrall, Michael J.; Wang, Xi; Wang, Zhiyong; Wong, Stephen T. C.

2013-03-01

The development of real-time, label-free imaging techniques has recently attracted research interest for in situ differentiation of cancerous lesions from normal tissues. Molecule-specific intrinsic contrast can arise from label-free imaging techniques such as Coherent Anti-Stokes Raman Scattering (CARS), Two-Photon Excited AutoFluorescence (TPEAF), and Second Harmonic Generation (SHG), which, in combination, would hold the promise of a powerful label-free tool for cancer diagnosis. Among cancer-related deaths, lung carcinoma is the leading cause for both sexes. Although early treatment can increase the survival rate dramatically, lesion detection and precise diagnosis at an early stage is unusual due to its asymptomatic nature and limitations of current diagnostic techniques that make screening difficult. We investigated the potential of using multimodality nonlinear optical microscopy that incorporates CARS, TPEAF, and SHG techniques for differentiation of lung cancer from normal tissue. Cancerous and non-cancerous lung tissue samples from patients were imaged using CARS, TPEAF, and SHG techniques for comparison. These images showed good pathology correlation with hematoxylin and eosin (H and E) stained sections from the same tissue samples. Ongoing work includes imaging at various penetration depths to show three-dimensional morphologies of tumor cell nuclei using CARS, elastin using TPEAF, and collagen using SHG and developing classification algorithms for quantitative feature extraction to enable lung cancer diagnosis. Our results indicate that via real-time morphology analyses, a multimodality nonlinear optical imaging platform potentially offers a powerful minimally-invasive way to differentiate cancer lesions from surrounding non-tumor tissues in vivo for clinical applications.

A volumetric pulmonary CT segmentation method with applications in emphysema assessment

NASA Astrophysics Data System (ADS)

Silva, José Silvestre; Silva, Augusto; Santos, Beatriz S.

2006-03-01

A segmentation method is a mandatory pre-processing step in many automated or semi-automated analysis tasks such as region identification and densitometric analysis, or even for 3D visualization purposes. In this work we present a fully automated volumetric pulmonary segmentation algorithm based on intensity discrimination and morphologic procedures. Our method first identifies the trachea as well as primary bronchi and then the pulmonary region is identified by applying a threshold and morphologic operations. When both lungs are in contact, additional procedures are performed to obtain two separated lung volumes. To evaluate the performance of the method, we compared contours extracted from 3D lung surfaces with reference contours, using several figures of merit. Results show that the worst case generally occurs at the middle sections of high resolution CT exams, due the presence of aerial and vascular structures. Nevertheless, the average error is inferior to the average error associated with radiologist inter-observer variability, which suggests that our method produces lung contours similar to those drawn by radiologists. The information created by our segmentation algorithm is used by an identification and representation method in pulmonary emphysema that also classifies emphysema according to its severity degree. Two clinically proved thresholds are applied which identify regions with severe emphysema, and with highly severe emphysema. Based on this thresholding strategy, an application for volumetric emphysema assessment was developed offering new display paradigms concerning the visualization of classification results. This framework is easily extendable to accommodate other classifiers namely those related with texture based segmentation as it is often the case with interstitial diseases.

Correlation between molecular analysis, diagnosis according to the 2015 WHO classification of unresected lung tumours and TTF1 expression in small biopsies and cytology specimens from 344 non-small cell lung carcinoma patients.

PubMed

Russell, Prudence A; Rogers, Toni-Maree; Solomon, Benjamin; Alam, Naveed; Barnett, Stephen A; Rathi, Vivek; Williams, Richard A; Wright, Gavin M; Conron, Matthew

2017-10-01

We investigated correlations between diagnosis according to the 2015 World Health Organization (WHO) classification of unresected lung tumours, molecular analysis and TTF1 expression in small biopsy and cytology specimens from 344 non-small cell lung carcinoma (NSCLC) patients. One case failed testing for EGFR, KRAS and ALK abnormalities and six had insufficient tumour for ALK testing. Overall mutation rate in 343 cases was 48% for the genes tested, with 19% EGFR, 33% KRAS and 4% BRAF mutations, and 5% ALK rearrangements detected. More EGFR-mutant (78%) and ALK-rearranged (75%) tumours had morphologic adenocarcinoma than KRAS-mutant (56%) tumours. Despite no significant difference in the overall rate of any molecular abnormality between morphologic adenocarcinoma (52%) and NSCLC, favour adenocarcinoma (47%) (p = 0.18), KRAS mutations were detected more frequently in the latter group. No significant difference in the overall rate of any molecular abnormality between TTF1 positive (49%) and TTF1 negative tumours (44%) (p = 0.92) was detected, but more EGFR-mutant (97%) and ALK-rearranged tumours (92%) were TTF1 positive than KRAS-mutant tumours (68%). Rates of EGFR, KRAS and BRAF mutations and ALK rearrangements in this Australian NSCLC patient population are consistent with the published international literature. Our findings suggest that 2015 WHO classification of unresected tumours may assist in identifying molecular subsets of advanced NSCLC. Copyright © 2017 Royal College of Pathologists of Australasia. Published by Elsevier B.V. All rights reserved.

Heterochrony and early left-right asymmetry in the development of the cardiorespiratory system of snakes.

PubMed

van Soldt, Benjamin J; Metscher, Brian D; Poelmann, Robert E; Vervust, Bart; Vonk, Freek J; Müller, Gerd B; Richardson, Michael K

2015-01-01

Snake lungs show a remarkable diversity of organ asymmetries. The right lung is always fully developed, while the left lung is either absent, vestigial, or well-developed (but smaller than the right). A 'tracheal lung' is present in some taxa. These asymmetries are reflected in the pulmonary arteries. Lung asymmetry is known to appear at early stages of development in Thamnophis radix and Natrix natrix. Unfortunately, there is no developmental data on snakes with a well-developed or absent left lung. We examine the adult and developmental morphology of the lung and pulmonary arteries in the snakes Python curtus breitensteini, Pantherophis guttata guttata, Elaphe obsoleta spiloides, Calloselasma rhodostoma and Causus rhombeatus using gross dissection, MicroCT scanning and 3D reconstruction. We find that the right and tracheal lung develop similarly in these species. By contrast, the left lung either: (1) fails to develop; (2) elongates more slowly and aborts early without (2a) or with (2b) subsequent development of faveoli; (3) or develops normally. A right pulmonary artery always develops, but the left develops only if the left lung develops. No pulmonary artery develops in relation to the tracheal lung. We conclude that heterochrony in lung bud development contributes to lung asymmetry in several snake taxa. Secondly, the development of the pulmonary arteries is asymmetric at early stages, possibly because the splanchnic plexus fails to develop when the left lung is reduced. Finally, some changes in the topography of the pulmonary arteries are consequent on ontogenetic displacement of the heart down the body. Our findings show that the left-right asymmetry in the cardiorespiratory system of snakes is expressed early in development and may become phenotypically expressed through heterochronic shifts in growth, and changes in axial relations of organs and vessels. We propose a step-wise model for reduction of the left lung during snake evolution.

["In vitro" interactions between influenza virus and mouse lung alveolar macrophages (author's transl)].

PubMed

Lemercier, G; Mavet, S; Burckhart, M F; Fontanges, R

1979-01-01

Interactions between influenza virus A/PR/8/34 (H0N1) and Balb/c mouse lung alveolar macrophages have been studied in vitro. One day after initiation of alveolar macrophage culture in 35 mm Falcon dishes, the virus suspension was allowed to adsorb to the cells for 1 h. Detachment of cells from the plastic substrate, morphological changes in adherent cells and decreased phagocytosis of heat-killed Candida albicans occured slowly as compared to control cultures. These facts appeared to be directly correlated to the concentration of viruses in the inoculum. Data yielded by virus titrations, electron microscopy and immunofluorescence suggest that mouse lung alveolar macrophages are able to take up a large amount of viral particles and inhibit their replication, allowing only an abortive viral cycle.

Quantification of lung perfusion blood volume (lung PBV) by dual-energy CT in patients with chronic thromboembolic pulmonary hypertension (CTEPH) before and after balloon pulmonary angioplasty (BPA): Preliminary results.

PubMed

Koike, Hirofumi; Sueyoshi, Eijun; Sakamoto, Ichiro; Uetani, Masataka; Nakata, Tomoo; Maemura, Kouji

2016-09-01

Balloon pulmonary angioplasty (BPA) is a treatment option for patients with chronic thromboembolic pulmonary hypertension (CTEPH). Its effect on pulmonary perfusion has not been quantified; we examined the clinical significance of pulmonary blood volume (PBV) using dual-energy computed tomography (DECT) in patients with CTEPH undergoing BPA. In this retrospective study of 16 BPAs in eight female patients with CTEPH, we evaluated both-lung (n=16), right- or left-lung (n=32), and three right- or left-segment (upper, middle, and lower) (n=96) PBVs before and after BPA, using DECT. We evaluated the relationships between improvement in lung PBV and pulmonary artery (PA) pressure (PAP), cardiac index (CI), pulmonary vascular resistance (PVR), and 6-min walking distance. We measured PA enhancement (PAenh) on DECT images and calculated lung PBV/PAenh to adjust timing. Pre- and post-BPA 6-segment lung PBV/PAenh were 0.067±0.021 and 0.077±0.019, respectively, in the treated segment (p<0.0001). There were significant positive correlations between pre- to post-BPA improvements in both-lung PBV/PAenh and PAP (R=0.69, p=0.005), PVR (R=0.56, p=0.03), and 6-min walking distance (R=0.67, p=0.01). Improved PBV after BPA, reflecting increased lung perfusion, was positively correlated with PAP, PVR, and 6-min walking distance. Lung PBV may be an indicator of BPA treatment effect. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Lung asbestos burden in shipyard and construction workers with mesothelioma: Comparison with burdens in subjects with asbestosis of lung cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Warnock, M.L.

1989-10-01

Although mesothelioma is generally considered to be caused by asbestos, epidemiologic studies indicate that some cases have another cause. In order to determine whether pulmonary asbestos burden can be used to define asbestos-related mesotheliomas, asbestos burden was quantified in 27 shipyard or construction workers with diffuse malignant mesothelioma of the pleura or peritoneum and a history of asbestos exposure. Their burden was significantly greater than the burden found in 19 unexposed men. The burdens were also compared to those of previously reported subjects with asbestosis or lung cancer. The median concentration for total amphibole fibers (2.7 million/g dry lung) inmore » subjects with mesothelioma did not differ significantly from our previously reported median values for 14 subjects with asbestosis (1.3 million/g dry lung) or for 60 asbestos workers with lung cancer (1.3 million/g dry lung). Fiber size distribution for amosite, the most prevalent fiber type, was similar in all three subject groups. Fifteen of 25 (60%) subjects with mesothelioma had mild asbestosis. Asbestos body (AB) concentrations were {ge} 1900/g dry lung, and total amphibole fiber concentrations were {ge}390,000/g dry lung. Counts of ABs{ge}0.5/cm{sup 2} in histologic sections always signified both of these concentrations in extracts. Thus, histologic sections showing {ge}0.5 ABs/cm{sup 2} or extracts containing asbestos body or amphibole fiber concentrations of at least 1900 or 390,000/g dry lung, respectively, will confirm an asbestos related mesothelioma.« less

A COMPUTER MODEL OF LUNG MORPHOLOGY TO ANALYZE SPECT IMAGES

EPA Science Inventory

Measurement of the three-dimensional (3-D) spatial distribution of aerosol deposition can be performed using Single Photon Emission Computed Tomography (SPECT). The advantage of using 3-D techniques over planar gamma imaging is that deposition patterns can be related to real lun...

The expression of HoxB5 and SPC in neonatal rat lung after exposure to fluoxetine.

PubMed

Taghizadeh, Razieh; Taghipour, Zahra; Karimi, Akbar; Shamsizadeh, Ali; Taghavi, Mohammad Mohsen; Shariati, Mahdi; Shabanizadeh, Ahmad; Jafari Naveh, Hamid Reza; Bidaki, Reza; Aminzadeh, Fariba

2016-01-01

Approximately 10% of pregnant women suffer from pregnancy-associated depression. Fluoxetine, as a selective serotonin reuptake inhibitor, is being employed as a therapy for depressive disorders. The present study aimed to determine the effects of fluoxetine on neonatal lung development. Thirty pregnant Wistar rats (weighing 200-250 g) were treated daily with 7 mg/kg fluoxetine from gestation day 0 to gestation day 21, via gavage. The control group received a similar volume of distilled water only. Following delivery, the newborns and their lungs were immediately weighed in both of the groups. The right lung was fixed for histological assessments while the left lung was used for evaluation of the expression of SPC and HoxB5 by the real-time polymerase chain reaction method. Results have indicated that even though the body weight and the number of neonatal rats in both groups were the same, the lung weight of neonates exposed to fluoxetine was significantly different compared to the control group ( P <0.05). Expression of both genes was increased, nonetheless, only elevation of HoxB5 was significant ( P <0.05). Histological studies demonstrated that lung tissue in the fluoxetine treatment group morphologically appears to be similar to the pseudoglandular phase, whereas the control group lungs experienced more development. According to the upregulated expression of HoxB5 concerning histological findings, results of the present study showed that fluoxetine can influence lung growth and may in turn lead to delay in lung development. So establishment of studies to identify the effects of antidepressant drugs during pregnancy is deserved.

Efficiency index: a new parameter to define breathing patterns during dynamic Xe-127 ventilation studies

DOE Office of Scientific and Technical Information (OSTI.GOV)

Slosman, D.; Susskind, H.; Bossuyt, A.

1986-03-01

Ventilation imaging can be improved by gating scintigraphic data with the respiratory cycle using temporal Fourier analysis (TFA) to quantify the temporal behavior of the ventilation. Sixteen consecutive images, representing equal-time increments of an average respiratory cycle, were produced by TFA in the posterior view on a pixel-by-pixel basis. An Efficiency Index (EFF), defined as the ratio of the summation of all the differences between maximum and minimum counts for each pixel to that for the entire lung during the respiratory cycle, was derived to describe the pattern of ventilation. The gated ventilation studies were carried out with Xe-127 inmore » 12 subjects: normal lung function (4), small airway disease (2), COPD (5), and restrictive disease (1). EFF for the first three harmonics correlated linearly with FEV1 (r = 0.701, p< 0.01). This approach is suggested as a very sensitive method to quantify the extent and regional distribution of airway obstruction.« less

Bronchoalveolar lavage in malignancy.

PubMed

Poletti, Venerino; Poletti, Giovanni; Murer, Bruno; Saragoni, Luca; Chilosi, Marco

2007-10-01

Bronchoalveolar lavage is a useful diagnostic tool in diffuse or disseminated lung malignancies that do not involve the bronchial structures visible by endoscopy. The neoplastic histotype and the intraparenchymal neoplastic growth pattern are good predictors for diagnostic yield; adenocarcinoma, and tumors with lymphangitic or lepidic growth patterns are more easily diagnosed by bronchoalveolar lavage; in these cases the diagnostic yield reported is higher than 80%. In hematologic malignancies the diagnostic yield is quite good in secondary diffuse indolent B cell lymphomas and in primary B cell lymphomas of mucosa-associated lymphoid tissue (MALT) type but low in Hodgkin disease. Morphological analysis may be implemented by immunocytochemical or molecular tests to identify the cell lineage and the presence of monoclonality. Disorders in which bronchioloalveolar cell hyperplasia/dysplasia is a significant morphological component may have cytological features in bronchoalveolar lavage fluid that mimic lung neoplasms: acute respiratory distress syndrome (ARDS), acute interstitial pneumonitis (AIP), and acute exacerbation of idiopathic pulmonary fibrosis are the most important clinical entities in this group.

Monitoring the process of pulmonary melanoma metastasis using large area and label-free nonlinear optical microscopy

NASA Astrophysics Data System (ADS)

Hua, Daozhu; Qi, Shuhong; Li, Hui; Zhang, Zhihong; Fu, Ling

2012-06-01

We performed large area nonlinear optical microscopy (NOM) for label-free monitoring of the process of pulmonary melanoma metastasis ex vivo with subcellular resolution in C57BL/6 mice. Multiphoton autofluorescence (MAF) and second harmonic generation (SHG) images of lung tissue are obtained in a volume of ~2.2 mm×2.2 mm×30 μm. Qualitative differences in morphologic features and quantitative measurement of pathological lung tissues at different time points are characterized. We find that combined with morphological features, the quantitative parameters, such as the intensity ratio of MAF and SHG between pathological tissue and normal tissue and the MAF to SHG index versus depth clearly shows the tissue physiological changes during the process of pulmonary melanoma metastasis. Our results demonstrate that large area NOM succeeds in monitoring the process of pulmonary melanoma metastasis, which can provide a powerful tool for the research in tumor pathophysiology and therapy evaluation.

Does immunohistochemistry affect response to therapy and survival of inoperable non-small cell lung carcinoma patients? A survey of 145 stage III-IV consecutive cases.

PubMed

Pelosi, Giuseppe; Haspinger, Eva Regina; Bimbatti, Manuela; Leone, Giorgia; Paolini, Biagio; Fabbri, Alessandra; Tamborini, Elena; Perrone, Federica; Testi, Adele; Garassino, Marina; Maisonneuve, Patrick; de Braud, Filippo; Pilotti, Silvana; Pastorino, Ugo

2014-04-01

Whether non-small cell lung carcinoma (NSCLC) unveiled by immunohistochemistry (IHC) has the same clinical outcome as those typed by morphology is still matter of debate. A total of 145 stage III-IV, consecutive inoperable NSCLC patients treated by chemotherapy (133 cases) or EGFR tyrosine kinase inhibitor (12 cases) and including 100 biopsies, 11 surgical specimens, and 34 cytological samples had originally accounted for 120 adenocarcinomas (ADs), 19 squamous cell carcinomas (SQCs), and 6 adenosquamous carcinomas (ADSQCs) by integrating morphology and thyroid transcription factor-1 (TTF1)/p40 IHC. Thirty-two NSCLC-not otherwise specified (NSCLC-NOS) cases were identified by morphology revision of the original diagnoses, which showed solid growth pattern (P < .001), 22 ADs, 5 SQCs, and 5 ADSQCs by IHC profiling (P < .001), and 10 gene-altered tumors (3 EGFR, 5 KRAS, and 2 ALK). While no significant relationships were observed between response to therapy and original, morphology or IHC diagnoses, driver mutations and tumor differentiation by TTF1 expression, AD run better progression-free survival (PFS) or overall survival (OS) than other tumor types by morphology (P = .010 and P = .047) and IHC (P = .033 and P = .046), respectively. Furthermore, patients with NSCLC-NOS confirmed as AD by IHC tended to have poorer OS (P = .179) and PFS (P = .193) similar to that of ADSQC and SQC (P = .702 and P = .540, respectively). A category of less differentiated AD with poorer prognosis on therapy could be identified by IHC, while there were no differences for SQC or ADSQC. The terminology of "NSCLC-NOS, favor by IHC" is appropriate to alert clinicians toward more aggressive tumors.

Strengthening Precipitate Morphologies Fully Quantified in Advanced Disk Superalloys

NASA Technical Reports Server (NTRS)

Gabb, Timothy P.

1998-01-01

Advanced aviation gas turbine engines will require disk superalloys that can operate at higher temperatures and stresses than current conditions. Such applications will be limited by the tensile, creep, and fatigue mechanical properties of these alloys. These mechanical properties vary with the size, shape, and quantity of the gamma precipitates that strengthen disk superalloys. It is therefore important to quantify these precipitate parameters and relate them to mechanical properties to improve disk superalloys. Favorable precipitate morphologies and practical processing approaches to achieve them can then be determined. A methodology has been developed at the NASA Lewis Research Center to allow the comprehensive quantification of the size, shape, and quantity of all types of gamma precipitates.

Immunohistowax processing, a new fixation and embedding method for light microscopy, which preserves antigen immunoreactivity and morphological structures: visualisation of dendritic cells in peripheral organs

PubMed Central

Pajak, B.; De Smedt, T.; Moulin, V.; De Trez, C.; Maldonado-Lopez, R.; Vansanten, G.; Briend, E.; Urbain, J.; Leo, O.; Moser, M.

2000-01-01

Aims—To describe a new fixation and embedding method for tissue samples, immunohistowax processing, which preserves both morphology and antigen immunoreactivity, and to use this technique to investigate the role of dendritic cells in the immune response in peripheral tissues. Methods—This technique was used to stain a population of specialised antigen presenting cells (dendritic cells) that have the unique capacity to sensitise naive T cells, and therefore to induce primary immune responses. The numbers of dendritic cells in peripheral organs of mice either untreated or injected with live Escherichia coli were compared. Results—Numbers of dendritic cells were greatly decreased in heart, kidney, and intestine after the inoculation of bacteria. The numbers of dendritic cells in the lung did not seem to be affected by the injection of E coli. However, staining of lung sections revealed that some monocyte like cells acquired morphological and phenotypic features of dendritic cells, and migrated into blood vessels. Conclusions—These observations suggest that the injection of bacteria induces the activation of dendritic cells in peripheral organs, where they play the role of sentinels, and/or their movement into lymphoid organs, where T cell priming is likely to occur. Key Words: dendritic cell • Escherichia coli • immunohistochemistry PMID:10961175

Analysis of airborne LiDAR surveys to quantify the characteristic morphologies of northern forested wetlands

Treesearch

Murray C. Richardson; Carl P. J. Mitchell; Brian A. Branfireun; Randall K. Kolka

2010-01-01

A new technique for quantifying the geomorphic form of northern forested wetlands from airborne LiDAR surveys is introduced, demonstrating the unprecedented ability to characterize the geomorphic form of northern forested wetlands using high-resolution digital topography. Two quantitative indices are presented, including the lagg width index (LWI) which objectively...

Testing microdensitometric ability to determine Monterey pine urban tree stress

Treesearch

David J. Nowak; Joe R. McBride

1993-01-01

Microdensitometric analysis of aerial photographs has been used to quantify urban tree stress of deciduous species. A test of this procedure applied to Monterey pine indicates that variations in ground cover beneath urban trees among cities and variations in crown morphology among tree species can limit the ability of microdensitometry to quantify urban tree stress....

Impact of scale on morphological spatial pattern of forest

Treesearch

Katarzyna Ostapowicz; Peter Vogt; Kurt H. Riitters; Jacek Kozak; Christine Estreguil

2008-01-01

Assessing and monitoring landscape pattern structure from multi-scale land-cover maps can utilize morphological spatial pattern analysis (MSPA), only if various influences of scale are known and taken into account. This paper lays part of the foundation for applying MSPA analysis in landscape monitoring by quantifying scale effects on six classes of spatial patterns...

Lung cancer incidence attributable to residential radon exposure in Alberta in 2012

PubMed Central

Grundy, Anne; Brand, Kevin; Khandwala, Farah; Poirier, Abbey; Tamminen, Sierra; Friedenreich, Christine M.; Brenner, Darren R.

2017-01-01

Background: Radon is carcinogenic, and exposure to radon has been shown to increase the risk of lung cancer. The objective of this study was to quantify the proportion and number of lung cancer cases in Alberta in 2012 that could be attributed to residential radon exposure. Methods: We estimated the population attributable risk of lung cancer for residential radon using radon exposure data from the Cross-Canada Survey of Radon Concentrations in Homes from 2009-2011 and data on all-cause and lung cancer mortality from Statistics Canada from 2008-2012. We used cancer incidence data from the Alberta Cancer Registry for 2012 to estimate the total number of lung cancers attributable to residential radon exposure. Estimates were also stratified by sex and smoking status. Results: The mean geometric residential radon level in Alberta in 2011 was 71.0 Bq/m3 (geometric standard deviation 2.14). Overall, an estimated 16.6% (95% confidence interval 9.4%-29.8%) of lung cancers were attributable to radon exposure, corresponding to 324 excess attributable cancer cases. The estimated population attributable risk of lung cancer due to radon exposure was higher among those who had never smoked (24.8%) than among ever smokers (15.6%). However, since only about 10% of cases of lung cancer occur in nonsmokers, the estimated total number of excess cases was higher for ever smokers (274) than for never smokers (48). Interpretation: With about 17% of lung cancer cases in Alberta in 2012 attributable to residential radon exposure, exposure reduction has the potential to substantially reduce Alberta's lung cancer burden. As such, home radon testing and remediation techniques represent important cancer prevention strategies. PMID:28663187

Postnatal lung mechanics, lung composition, and surfactant synthesis after tracheal occlusion vs prenatal intrapulmonary instillation of perfluorocarbon in fetal rabbits.

PubMed

Muensterer, Oliver J; Flemmer, Andreas W; Bergmann, Florian; Hajek, Kerstin S; Lu, Hui Qi; Simbruner, Georg; Deprest, Jan A; Till, Holger

2005-01-01

Fetal tracheal occlusion (TO) accelerates lung growth but decreases surfactant production. We have previously shown that instillation of perfluorooctylbromide (PFOB) into fetal rabbit lungs leads to lung growth similar to TO. This study compares neonatal lung mechanics and surfactant production after prenatal intrapulmonary PFOB instillation vs TO. In each of 18 pregnant rabbits on gestational day 27, sets of 4 fetuses underwent either (1) intrapulmonary instillation of 1 mL PFOB, (2) TO, (3) instillation of 1 mL 0.9% NaCl (saline), and (4) hysteroamniotomy without fetal manipulation (control). Fetuses were born by cesarean delivery after 48 hours. Fetuses of 12 rabbits were mechanically ventilated for 15 minutes to evaluate lung compliance and airway resistance. Pulmonary surfactant protein B (SP-B) was quantified by immunohistochemistry in fetuses of the remaining 6 rabbits. Compliance was decreased in the TO group after cesarean delivery (0.33 +/- 0.13 mL/cm H2O) compared with PFOB (0.59 +/- 0.12 mL/cm H2O), saline (0.50 +/- 0.12 mL/cm H2O), and control (0.52 +/- 0.10 mL/cm H2O) fetuses. Mean fetal lung to body weight ratio was higher in TO and PFOB fetuses compared with saline and control. Higher water content and lower numbers of surfactant protein B-positive cells were found in the TO-treated fetuses. Both prenatal intrapulmonary instillation of PFOB and TO accelerate lung growth, but TO is associated with decreased postnatal lung compliance, possibly influenced by decreased surfactant production and increased fluid retention. Conversely, instillation of PFOB preserved lung compliance and surfactant synthesis.

Curcumin protects the developing lung against long-term hyperoxic injury

PubMed Central

Sakurai, R.; Villarreal, P.; Husain, S.; Liu, Jie; Sakurai, T.; Tou, E.; Torday, J. S.

2013-01-01

Curcumin, a potent anti-inflammatory and antioxidant agent, modulates peroxisome proliferator-activated receptor-γ signaling, a key molecule in the etiology of bronchopulmonary dysplasia (BPD). We have previously shown curcumin's acute protection against neonatal hyperoxia-induced lung injury. However, its longer-term protection against BPD is not known. Hypothesizing that concurrent treatment with curcumin protects the developing lung against hyperoxia-induced lung injury long-term, we determined if curcumin protects against hyperoxic neonatal rat lung injury for the first 5 days of life, as determined at postnatal day (PND) 21. One-day-old rat pups were exposed to either 21 or 95% O2 for 5 days with or without curcumin treatment (5 mg/kg) administered intraperitoneally one time daily, following which the pups grew up to PND21 in room air. At PND21 lung development was determined, including gross and cellular structural and functional effects, and molecular mediators of inflammatory injury. To gain mechanistic insights, embryonic day 19 fetal rat lung fibroblasts were examined for markers of apoptosis and MAP kinase activation following in vitro exposure to hyperoxia for 24 h in the presence or absence of curcumin (5 μM). Curcumin effectively blocked hyperoxia-induced lung injury based on systematic analysis of markers for lung injury (apoptosis, Bcl-2/Bax, collagen III, fibronectin, vimentin, calponin, and elastin-related genes) and lung morphology (radial alveolar count and alveolar septal thickness). Mechanistically, curcumin prevented the hyperoxia-induced increases in cleaved caspase-3 and the phosphorylation of Erk1/2. Molecular effects of curcumin, both structural and cytoprotective, suggest that its actions against hyperoxia-induced lung injury are mediated via Erk1/2 activation and that it is a potential intervention against BPD. PMID:23812632

THE HUMAN FETAL LUNG XENOGRAFT: VALIDATION AS MODEL OF MICROVASCULAR REMODELING IN THE POSTGLANDULAR LUNG

PubMed Central

De Paepe, Monique E.; Chu, Sharon; Hall, Susan; Heger, Nicholas; Thanos, Chris; Mao, Quanfu

2012-01-01

Background Coordinated remodeling of epithelium and vasculature is essential for normal postglandular lung development. The value of the human-to-rodent lung xenograft as model of fetal microvascular development remains poorly defined. Aim The aim of this study was to determine the fate of the endogenous (human-derived) microvasculature in fetal lung xenografts. Methods Lung tissues were obtained from spontaneous pregnancy losses (14–22 weeks’ gestation) and implanted in the renal subcapsular or dorsal subcutaneous space of SCID-beige mice (T, B and NK-cell-deficient) and/or nude rats (T-cell-deficient). Informed parental consent was obtained. Lung morphogenesis, microvascular angiogenesis and epithelial differentiation were assessed at two and four weeks post-transplantation by light microscopy, immunohistochemical and gene expression studies. Archival age-matched postmortem lungs served as control. Results The vascular morphology, density and proliferation of renal subcapsular grafts in SCID-beige mice were similar to age-matched control lungs, with preservation of the physiologic association between epithelium and vasculature. The microvasculature of subcutaneous grafts in SCID-beige mice was underdeveloped and dysmorphic, associated with significantly lower VEGF, endoglin, and angiopoietin-2 mRNA expression than renal grafts. Grafts at both sites displayed mild airspace dysplasia. Renal subcapsular grafts in nude rats showed frequent infiltration by host lymphocytes and obliterating bronchiolitis-like changes, associated with markedly decreased endogenous angiogenesis. Conclusion This study demonstrates the critical importance of host and site selection to ensure optimal xenograft development. When transplanted to severely immune suppressed, NK-cell-deficient hosts and engrafted in the renal subcapsular site, the human-to-rodent fetal lung xenograft provides a valid model of postglandular microvascular lung remodeling. PMID:22811288

[Changes and role evaluation of TNF-α and IL-1β in lung tissues of ARDS mice].

PubMed

Liang, Jianing; Zhou, Qianqian; Zhang, Tianxiang; Wang, Xiaosu; Song, Liqiang

2017-02-01

Objective To study the expression levels of TNF-α and IL-1β in the lung tissues of acute respiratory distress syndrome (ARDS) mice and their relationships with the severity of lung injury in the mice. Methods A mouse model of ARDS was induced by lipopolysaccharide (LPS). The morphological changes of lung tissue was observed by HE staining, and the lung injury score was calculated. Quantitative real-time PCR was employed to detect the mRNA expression levels of TNF-α and IL-1β in lung tissues and ELISA was performed to test the protein levels of TNF-α and IL-1β in bronchoalveolar lavage fluid (BALF). Results Compared with the control group, the alveolar and interstitial tissue structure of ARDS model mice was impaired and filled with inflammatory cells. The lung injury score of ARDS model mice reached the peak at the third day. The mRNA levels of TNF-α and IL-1β in lung tissues of ARDS mice significantly increased, and respectively peaked at 30 minutes and 6 hours after LPS instillation. Simultaneously, the levels of TNF-α and IL-1β in BALF of ARDS mice significantly increased, and the tendency was consistent with mRNA levels in lung tissues. Conclusion LPS-induced lung injury and the expression levels of TNF-α and IL-1β in ARDS mice showed a similar "hump-like" increase over time. The high values of inflammatory mediators appeared before the peak of lung injury, which indicated that these inflammatory cytokines played an important role in the development of ARDS-caused inflammatory injury.

Heterochrony and Early Left-Right Asymmetry in the Development of the Cardiorespiratory System of Snakes

PubMed Central

van Soldt, Benjamin J.; Metscher, Brian D.; Poelmann, Robert E.; Vervust, Bart; Vonk, Freek J.; Müller, Gerd B.; Richardson, Michael K.

2015-01-01

Snake lungs show a remarkable diversity of organ asymmetries. The right lung is always fully developed, while the left lung is either absent, vestigial, or well-developed (but smaller than the right). A ‘tracheal lung’ is present in some taxa. These asymmetries are reflected in the pulmonary arteries. Lung asymmetry is known to appear at early stages of development in Thamnophis radix and Natrix natrix. Unfortunately, there is no developmental data on snakes with a well-developed or absent left lung. We examine the adult and developmental morphology of the lung and pulmonary arteries in the snakes Python curtus breitensteini, Pantherophis guttata guttata, Elaphe obsoleta spiloides, Calloselasma rhodostoma and Causus rhombeatus using gross dissection, MicroCT scanning and 3D reconstruction. We find that the right and tracheal lung develop similarly in these species. By contrast, the left lung either: (1) fails to develop; (2) elongates more slowly and aborts early without (2a) or with (2b) subsequent development of faveoli; (3) or develops normally. A right pulmonary artery always develops, but the left develops only if the left lung develops. No pulmonary artery develops in relation to the tracheal lung. We conclude that heterochrony in lung bud development contributes to lung asymmetry in several snake taxa. Secondly, the development of the pulmonary arteries is asymmetric at early stages, possibly because the splanchnic plexus fails to develop when the left lung is reduced. Finally, some changes in the topography of the pulmonary arteries are consequent on ontogenetic displacement of the heart down the body. Our findings show that the left-right asymmetry in the cardiorespiratory system of snakes is expressed early in development and may become phenotypically expressed through heterochronic shifts in growth, and changes in axial relations of organs and vessels. We propose a step-wise model for reduction of the left lung during snake evolution. PMID:25555231

Expression of profibrotic growth factors and their receptors by mouse lung macrophages and fibroblasts under conditions of acute viral inflammation in influenza A/H5N1 virus.

PubMed

Anikina, A G; Shkurupii, V A; Potapova, O V; Kovner, A V; Shestopalov, A M

2014-04-01

Morphological signs of early interstitial fibrosis, developing under conditions of acute viral inflammation (postinfection days 1-14), were observed in C57Bl/6 mice infected with influenza A/H5N1 A/goose/Krasnoozerskoye/627/05 virus. The development of fibrosis was confirmed by an increase in the number of lung cells expressing TNF-α. These changes were recorded in the presence of a many-fold increase in the counts of macrophages and fibroblasts expressing FGF, EGF, and their receptors.

Complement-mediated neutrophil activation in sepsis- and trauma-related adult respiratory distress syndrome. Clarification with radioaerosol lung scans

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tennenberg, S.D.; Jacobs, M.P.; Solomkin, J.S.

Complement-mediated neutrophil activation (CMNA) has been proposed as an important pathogenic mechanism causing acute microvascular lung injury in the adult respiratory distress syndrome (ARDS). To clarify the relationship between CMNA and evolving lung injury, we studied 26 patients with multiple trauma and sepsis within 24 hours of risk establishment for ARDS. Pulmonary alveolar-capillary permeability (PACP) was quantified as the clearance rate of a particulate radioaerosol. Seventeen patients (65%) had increased PACP (six developed ARDS) while nine (35%) had normal PACP (none developed ARDS; clearance rates of 3.4%/min and 1.5%/min, respectively). These patients, regardless of evidence of early lung injury, hadmore » elevated plasma C3adesArg levels and neutrophil chemotactic desensitization to C5a/C5adesArg. Plasma C3adesArg levels correlated weakly, but significantly, with PACP. Thus, CMNA may be a necessary, but not a sufficient, pathogenic mechanism in the evolution of ARDS.« less

A resource for the assessment of lung nodule size estimation methods: database of thoracic CT scans of an anthropomorphic phantom◊

PubMed Central

Gavrielides, Marios A.; Kinnard, Lisa M.; Myers, Kyle J.; Peregoy, Jennifer; Pritchard, William F.; Zeng, Rongping; Esparza, Juan; Karanian, John; Petrick, Nicholas

2010-01-01

A number of interrelated factors can affect the precision and accuracy of lung nodule size estimation. To quantify the effect of these factors, we have been conducting phantom CT studies using an anthropomorphic thoracic phantom containing a vasculature insert to which synthetic nodules were inserted or attached. Ten repeat scans were acquired on different multi-detector scanners, using several sets of acquisition and reconstruction protocols and various nodule characteristics (size, shape, density, location). This study design enables both bias and variance analysis for the nodule size estimation task. The resulting database is in the process of becoming publicly available as a resource to facilitate the assessment of lung nodule size estimation methodologies and to enable comparisons between different methods regarding measurement error. This resource complements public databases of clinical data and will contribute towards the development of procedures that will maximize the utility of CT imaging for lung cancer screening and tumor therapy evaluation. PMID:20640011

Feeding rates and under-ice foraging strategies of the smallest lunge filter feeder, the Antarctic minke whale (Balaenoptera bonaerensis).

PubMed

Friedlaender, A S; Goldbogen, J A; Nowacek, D P; Read, A J; Johnston, D; Gales, N

2014-08-15

Body size and feeding mode are two fundamental characteristics that determine foraging performance and ecological niche. As the smallest obligate lunge filter feeders, minke whales represent an ideal system for studying the physical and energetic limits of filter feeding in endotherms. We used multi-sensor suction cup tags to quantify the feeding performance of Antarctic minke whales. Foraging dives around and beneath sea ice contained up to 24 lunges per dive, the highest feeding rates for any lunge-feeding whale. Their small size allows minke whales access to krill in sea-ice environments not easily accessible to larger baleen whales. Furthermore, their ability to filter feed provides an advantage over other smaller sympatric krill predators such as penguins and seals that feed on individual prey. The unique combination of body size, feeding mechanism and sea-ice habitat of Antarctic minke whales defines a previously undocumented energetic niche that is unique among aquatic vertebrates. © 2014. Published by The Company of Biologists Ltd.

Concentrations of metallic elements in kidney, liver, and lung tissue of Indo-Pacific bottlenose dolphin Tursiops aduncus from coastal waters of Zanzibar, Tanzania.

PubMed

Mapunda, Edgar C; Othman, Othman C; Akwilapo, Leonard D; Bouwman, Hindrik; Mwevura, Haji

2017-09-15

Concentrations of metallic elements in kidney, liver and lung tissues of Indo-Pacific bottlenose dolphins Tursiops aduncus from coastal waters of Zanzibar were determined using inductively coupled plasma - optical emission spectroscopy. Cadmium, chromium, copper, and zinc were quantifiable in all tissues at concentration ranges of 0.10-150, 0.08-3.2, 1.1-88 and 14-210μg/g dry mass, respectively. Copper and zinc was significantly higher in liver, and females had significantly higher Cd in liver, and chromium in lung. Generally, T. aduncus dolphins from coastal waters around Zanzibar carry low concentrations of metals compared with dolphins from other areas. Cadmium increased significantly with age in kidney and lung. Copper decreased significantly with age in liver, probably due to foetal metallothionein. This study supplied baseline data against which future trends in marine mammals in the Indian Ocean, the world's third largest, can be assessed. Copyright © 2017 Elsevier Ltd. All rights reserved.

Supercomputer description of human lung morphology for imaging analysis.

PubMed

Martonen, T B; Hwang, D; Guan, X; Fleming, J S

1998-04-01

A supercomputer code that describes the three-dimensional branching structure of the human lung has been developed. The algorithm was written for the Cray C94. In our simulations, the human lung was divided into a matrix containing discrete volumes (voxels) so as to be compatible with analyses of SPECT images. The matrix has 3840 voxels. The matrix can be segmented into transverse, sagittal and coronal layers analogous to human subject examinations. The compositions of individual voxels were identified by the type and respective number of airways present. The code provides a mapping of the spatial positions of the almost 17 million airways in human lungs and unambiguously assigns each airway to a voxel. Thus, the clinician and research scientist in the medical arena have a powerful new tool to be used in imaging analyses. The code was designed to be integrated into diverse applications, including the interpretation of SPECT images, the design of inhalation exposure experiments and the targeted delivery of inhaled pharmacologic drugs.

Examples of Mesh and NURBS modelling for in vivo lung counting studies.

PubMed

Farah, Jad; Broggio, David; Franck, Didier

2011-03-01

Realistic calibration coefficients for in vivo counting installations are assessed using voxel phantoms and Monte Carlo calculations. However, voxel phantoms construction is time consuming and their flexibility extremely limited. This paper involves Mesh and non-uniform rational B-splines graphical formats, of greater flexibility, to optimise the calibration of in vivo counting installations. Two studies validating the use of such phantoms and involving geometry deformation and modelling were carried out to study the morphologic effect on lung counting efficiency. The created 3D models fitted with the reference ones, with volumetric differences of <5 %. Moreover, it was found that counting efficiency varies with the inverse of lungs' volume and that the latter primes when compared with chest wall thickness. Finally, a series of different thoracic female phantoms of various cup sizes, chest girths and internal organs' volumes were created starting from the International Commission on Radiological Protection (ICRP) adult female reference computational phantom to give correction factors for the lung monitoring of female workers.

Lung cancer diagnosis on ovary mass: a case report

PubMed Central

2013-01-01

Metastatic neoplasms to the ovary often cause diagnostic problems, in particular those large ovarian masses mimicking primary tumors. Most of these tumors arise from digestive system or breast, while 37-year-old woman diagnosed as right adnexal complex mass, with a subpleural nodule in the apical part of the left lower lobe, at preoperative chest computed tomography scan. The patient underwent total abdominal hysterectomy with right salpingo-oophorectomy (ovarian mass 220 × 200 mm), total omentectomy, left ovarian biopsy, peritoneal random biopsies, and peritoneal washings for cytology. Pathologic and immunohistochemical examination of ovarian specimen suggested morphology and expression of metastatic lung adenocarcinoma with an intense positivity for Thyroid Transcriptional Factor-1 (TTF-1) and Cytokeratin 7 (CK7) staining. Fine needle biopsy of the lung nodule found epithelioid like malignant cells, confirming the diagnosis of an ovarian metastasis from a primary lung cancer. This report focused on the clinical and pathologic diagnostic challenge of distinguishing secondary from primary ovarian neoplasms. Issues on useful immunohistochemical stains are also discussed. PMID:23663245

Cryptococcus neoformans of Unusual Morphology

PubMed Central

Cruickshank, J. G.; Cavill, R.; Jelbert, M.

1973-01-01

A case of primary cryptococcosis of the lungs was caused by an isolate of Cryptococcus neoformans that assumes a giant form in tissue but which has a normal appearance on artificial culture. Electron microscopy revealed gross enlargement of the capsule and plasma membranes in the tissue form. Images PMID:4121033

Effects of a Multidisciplinary Approach to Improve Volume of Diagnostic Material in CT-Guided Lung Biopsies.

PubMed

Ferguson, Philip E; Sales, Catherine M; Hodges, Dalton C; Sales, Elizabeth W

2015-01-01

Recent publications have emphasized the importance of a multidisciplinary strategy for maximum conservation and utilization of lung biopsy material for advanced testing, which may determine therapy. This paper quantifies the effect of a multidisciplinary strategy implemented to optimize and increase tissue volume in CT-guided transthoracic needle core lung biopsies. The strategy was three-pronged: (1) once there was confidence diagnostic tissue had been obtained and if safe for the patient, additional biopsy passes were performed to further increase volume of biopsy material, (2) biopsy material was placed in multiple cassettes for processing, and (3) all tissue ribbons were conserved when cutting blocks in the histology laboratory. This study quantifies the effects of strategies #1 and #2. This retrospective analysis comparing CT-guided lung biopsies from 2007 and 2012 (before and after multidisciplinary approach implementation) was performed at a single institution. Patient medical records were reviewed and main variables analyzed include biopsy sample size, radiologist, number of blocks submitted, diagnosis, and complications. The biopsy sample size measured was considered to be directly proportional to tissue volume in the block. Biopsy sample size increased 2.5 fold with the average total biopsy sample size increasing from 1.0 cm (0.9-1.1 cm) in 2007 to 2.5 cm (2.3-2.8 cm) in 2012 (P<0.0001). The improvement was statistically significant for each individual radiologist. During the same time, the rate of pneumothorax requiring chest tube placement decreased from 15% to 7% (P = 0.065). No other major complications were identified. The proportion of tumor within the biopsy material was similar at 28% (23%-33%) and 35% (30%-40%) for 2007 and 2012, respectively. The number of cases with at least two blocks available for testing increased from 10.7% to 96.4% (P<0.0001). The effect of this multidisciplinary strategy to CT-guided lung biopsies was effective in significantly increasing tissue volume and number of blocks available for advanced diagnostic testing.

A 3D human tissue-engineered lung model to study influenza A infection.

PubMed

Bhowmick, Rudra; Derakhshan, Mina; Liang, Yurong; Ritchey, Jerry; Liu, Lin; Gappa-Fahlenkamp, Heather

2018-05-05

Influenza A virus (IAV) claims approximately 250,000-500,000 lives annually worldwide. Currently, there are a few in vitro models available to study IAV immunopathology. Monolayer cultures of cell lines and primary lung cells (2D cell culture) is the most commonly used tool, however, this system does not have the in vivo-like structure of the lung and immune responses to IAV as it lacks the three-dimensional (3D) tissue structure. To recapitulate the lung physiology in vitro, a system that contains multiple cell types within a 3D environment that allows cell movement and interaction, would provide a critical tool. In this study, as a first step in designing a 3D-Human Tissue-Engineering Lung Model (3D-HTLM), we described the 3D culture of primary human small airway epithelial cells (HSAEpCs), and determined the immunophenotype of this system in response to IAV infections. We constructed a 3D chitosan-collagen scaffold and cultured HSAEpCs on these scaffolds at air-liquid interface (ALI). These 3D cultures were compared with 2D-cultured HSAEpCs for viability, morphology, marker protein expression, and cell differentiation. Results showed that the 3D-cultured HSAEpCs at ALI yielded maximum viable cells and morphologically resembled the in vivo lower airway epithelium. There were also significant increases in aquaporin-5 and cytokeratin-14 expression for HSAEpCs cultured in 3D compared to 2D. The 3D culture system was used to study the infection of HSAEpCs with two major IAV strains, H1N1 and H3N2.The HSAEpCs showed distinct changes in marker protein expression, both at mRNA and protein levels, and the release of proinflammatory cytokines. This study is the first step in the development of the 3D-HTLM, which will have wide applicability in studying pulmonary pathophysiology and therapeutics development.

[Morphological characteristics of inflammation in HIV-associated pulmonary tuberculosis with regard to the expression of myeloperoxidase].

PubMed

Bykhalov, L S; Smirnov, A V

2015-01-01

to characterize the morphological features of inflammation and the degree of myeloperoxidase expression in the lung of patients who died from HIV-associated tuberculosis (TB). Autopsy lung tissue specimens from 229 patients with HIV-associated TB were examined. A comparison group consisted of dead TB mono-infected patients (n = 30). Dead HIV/TB co-infected patients were divided into subgroups: 1) 50 patients with Stage 4A-4B and a CD4(+)-lymphocyte count of more than 200 cells/µl; 2) 54 with Stage 4B-4C and a CD4(+)-lymphocyte count of 100 to 200 cells/µl; 3) 125 with Stage 4C-5 and a CD4(+)-lymphocyte count of less than 100 cells/µl. Histological and immunohistochemical examinations of lung slices were performed using antibodies to myeloperoxidase (MPO). The predominant types of an inflammatory response were revealed according to the level of CD4+ lymphocytes. The lungs in Subgroup 1 showed a predominant typical granulomatous response (82%). Subgroup 2 exhibited an exudative-productive inflammatory response (57.4%) while Subgroup 3 displayed an alterative necrotic type (92.8%). Subgroup 3 showed the most marked reduction in lymphocyte numbers in the areas of inflammation, which was accompanied by a significant increase in the relative density and other morphometric parameters of MPO-positive macrophages and granulocytes in the inflammatory infiltration zones and alveolar walls. The identified changes in the lungs suggest that there is a decline in the magnitude of a delayed type hypersensitivity reaction, a progression of alterative necrotic processes as CD4(+) lymphocytes decrease in the systemic blood flow, and an increase in the proportion of functionally immature macrophages in the areas of inflammation, which reflects a substantially impaired local immune response to the persistence of M. tuberculosis in HIV infection.

The investigation of ceranib-2 on apoptosis and drug interaction with carboplatin in human non small cell lung cancer cells in vitro.

PubMed

Yildiz-Ozer, Merve; Oztopcu-Vatan, Pinar; Kus, Gokhan

2018-02-01

Ceramide is found to be involved in inhibition of cell division and induction of apoptosis in certain tumour cells. Ceranib-2 is an agent that increases ceramide levels by inhibiting ceramidase in cancer cells. Therefore, we aimed to investigate the effects of ceranib-2 on cell survival, apoptosis and interaction with carboplatin in human non-small cell lung cancer cells. The cytotoxic effect of ceranib-2 (1-100 µM) was determined by MTT assay in human lung adenocarcinoma (A549) and large cell lung carcinoma (H460) cells. Carboplatin (1-100 µM) and lung bronchial epithelial cells (BEAS-2B) were used as positive controls. Morphological and ultrastructural changes were analysed by light microscope and TEM. Apoptotic/necrotic cell death and acid ceramidase activity were analysed by ELISA. Combination effects of ceranib-2 and carboplatin were investigated by MTT. The expression levels of CASP3, CASP9, BAX and BCL-2 were examined by qRT-PCR. The IC 50 of ceranib-2 was determined as 22 μM in A549 cells and 8 μM in H460 cells for 24 h. Morphological changes and induction of DNA fragmentation have revealed apoptotic effects of ceranib-2 in both cell lines. Ceranib-2 and carboplatin has shown synergism in combined treatment at 10 and 25 μM doses in H460 cells for 24 h. Ceranib-2 inhibited acid ceramidase activity by 44% at 25 µM in H460 cells. Finally, CASP3, CASP9 and BAX expressions were increased while BCL-2 expression was reduced in both cells. Our results obtained some preliminary results about the cytotoxic and apoptotic effects of ceranib-2 for the first time in NSCLC cell lines.

MMP-13 In-Vivo Molecular Imaging Reveals Early Expression in Lung Adenocarcinoma

PubMed Central

Salaün, Mathieu; Peng, Jing; Hensley, Harvey H.; Roder, Navid; Flieder, Douglas B.; Houlle-Crépin, Solène; Abramovici-Roels, Olivia; Sabourin, Jean-Christophe; Thiberville, Luc; Clapper, Margie L.

2015-01-01

Introduction Several matrix metalloproteinases (MMPs) are overexpressed in lung cancer and may serve as potential targets for the development of bioactivable probes for molecular imaging. Objective To characterize and monitor the activity of MMPs during the progression of lung adenocarcinoma. Methods K-rasLSL-G12D mice were imaged serially during the development of adenocarcinomas using fluorescence molecular tomography (FMT) and a probe specific for MMP-2, -3, -9 and -13. Lung tumors were identified using FMT and MRI co-registration, and the probe concentration in each tumor was assessed at each time-point. The expression of Mmp2, -3, -9, -13 was quantified by qRT-PCR using RNA isolated from microdissected tumor cells. Immunohistochemical staining of overexpressed MMPs in animals was assessed on human lung tumors. Results In mice, 7 adenomas and 5 adenocarcinomas showed an increase in fluorescent signal on successive FMT scans, starting between weeks 4 and 8. qRT-PCR assays revealed significant overexpression of only Mmp-13 in mice lung tumors. In human tumors, a high MMP-13 immunostaining index was found in tumor cells from invasive lesions (24/27), but in none of the non-invasive (0/4) (p=0.001). Conclusion MMP-13 is detected in early pulmonary invasive adenocarcinomas and may be a potential target for molecular imaging of lung cancer. PMID:26193700

[Changes of 2015 WHO Histological Classification of Lung Cancer 
and the Clinical Significance].

PubMed

Yang, Xin; Lin, Dongmei

2016-06-20

Due in part to remarkable advances over the past decade in our understanding of lung cancer, particularly in area of medical oncology, molecular biology, and radiology, there is a pressing need for a revised classification, based not on pathology alone, but rather on an integrated multidisciplinary approach to classification of lung cancer. The 2015 World Health Organization (WHO) Classification of Tumors of the Lung, Pleura, Thymus and Heart has just been published with numerous important changes from the 2004 WHO classification. The revised classification has been greatly improved in helping advance the field, increasing the impact of research, improving patient care and assisting in predicting outcome. The most significant changes will be summarized in this paper as follows: (1) main changes of lung adenocarcinoma as proposed by the 2011 International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society (IASLC/ATS/ERS) classification, (2) reclassifying squamous cell carcinomas into keratinizing, nonkeratinizing, and basaloid subtypes with the nonkeratinizing tumors requiring immunohistochemistry proof of squamous differentiation, (3) restricting the diagnosis of large cell carcinoma only to resected tumors that lack any clear morphologic or immunohistochemical differentiation with reclassification of the remaining former large cell carcinoma subtypes into different categories, (4) grouping of neuroendocrine tumors together in one category, (5) and the current viewpoint of histologic grading of lung cancer.

Bronchial airway gene expression signatures in mouse lung squamous cell carcinoma and their modulation by cancer chemopreventive agents

PubMed Central

Szabo, Eva; Miller, Mark Steven; Lubet, Ronald A.; You, Ming; Wang, Yian

2017-01-01

Due to exposure to environmental toxicants, a “field cancerization” effect occurs in the lung resulting in the development of a field of initiated but morphologically normal appearing cells in the damaged epithelium of bronchial airways with dysregulated gene expression patterns. Using a mouse model of lung squamous cell carcinoma (SCC), we performed transcriptome sequencing (RNA-Seq) to profile bronchial airway gene expression and found activation of the PI3K and Myc signaling networks in cytologically normal bronchial airway epithelial cells of mice with preneopastic lung SCC lesions, which was reversed by treatment with the PI3K Inhibitor XL-147 and pioglitazone, respectively. Activated MYC signaling was also present in premalignant and tumor tissues from human lung SCC patients. In addition, we identified a key microRNA, mmu-miR-449c-5p, whose suppression significantly up-regulated Myc expression in the normal bronchial airway epithelial cells of mice with early stage SCC lesions. We developed a novel bronchial genomic classifier in mice and validated it in humans. In the classifier, Ppbp (pro-platelet basic protein) was overexpressed 115 fold in the bronchial airways of mice with preneoplastic lung SCC lesions. This is the first report that demonstrates Ppbp as a novel biomarker in the bronchial airway for lung cancer diagnosis. PMID:27935865

Identification of differentially expressed genes in human lung squamous cell carcinoma using suppression subtractive hybridization.

PubMed

Sun, Wenyue; Zhang, Kaitai; Zhang, Xinyu; Lei, Wendong; Xiao, Ting; Ma, Jinfang; Guo, Suping; Shao, Shujuan; Zhang, Husheng; Liu, Yan; Yuan, Jinsong; Hu, Zhi; Ma, Ying; Feng, Xiaoli; Hu, Songnian; Zhou, Jun; Cheng, Shujun; Gao, Yanning

2004-08-20

Lung cancer is one of the major causes of cancer-related deaths. Over the past decade, much has been known about the molecular changes associated with lung carcinogenesis; however, our understanding to lung tumorigenesis is still incomplete. To identify genes that are differentially expressed in squamous cell carcinoma (SCC) of the lung, we compared the expression profiles between primarily cultured SCC tumor cells and bronchial epithelial cells derived from morphologically normal bronchial epithelium of the same patient. Using suppression subtractive hybridization (SSH), two cDNA libraries containing up- and down-regulated genes in the tumor cells were constructed, named as LCTP and LCBP. The two libraries comprise 258 known genes and 133 unknown genes in total. The known up-regulated genes in the library LCTP represented a variety of functional groups; including metabolism-, cell adhesion and migration-, signal transduction-, and anti-apoptosis-related genes. Using semi-quantitative reverse transcription-polymerase chain reaction, seven genes chosen randomly from the LCTP were analyzed in the tumor tissue paired with its corresponding adjacent normal lung tissue derived from 16 cases of the SCC. Among them, the IQGAP1, RAP1GDS1, PAICS, MLF1, and MARK1 genes showed a consistent expression pattern with that of the SSH analysis. Identification and further characterization of these genes may allow a better understanding of lung carcinogenesis.

An Epithelial Integrin Regulates the Amplitude of Protective Lung Interferon Responses against Multiple Respiratory Pathogens.

PubMed

Meliopoulos, Victoria A; Van de Velde, Lee-Ann; Van de Velde, Nicholas C; Karlsson, Erik A; Neale, Geoff; Vogel, Peter; Guy, Cliff; Sharma, Shalini; Duan, Susu; Surman, Sherri L; Jones, Bart G; Johnson, Michael D L; Bosio, Catharine; Jolly, Lisa; Jenkins, R Gisli; Hurwitz, Julia L; Rosch, Jason W; Sheppard, Dean; Thomas, Paul G; Murray, Peter J; Schultz-Cherry, Stacey

2016-08-01

The healthy lung maintains a steady state of immune readiness to rapidly respond to injury from invaders. Integrins are important for setting the parameters of this resting state, particularly the epithelial-restricted αVβ6 integrin, which is upregulated during injury. Once expressed, αVβ6 moderates acute lung injury (ALI) through as yet undefined molecular mechanisms. We show that the upregulation of β6 during influenza infection is involved in disease pathogenesis. β6-deficient mice (β6 KO) have increased survival during influenza infection likely due to the limited viral spread into the alveolar spaces leading to reduced ALI. Although the β6 KO have morphologically normal lungs, they harbor constitutively activated lung CD11b+ alveolar macrophages (AM) and elevated type I IFN signaling activity, which we traced to the loss of β6-activated transforming growth factor-β (TGF-β). Administration of exogenous TGF-β to β6 KO mice leads to reduced numbers of CD11b+ AMs, decreased type I IFN signaling activity and loss of the protective phenotype during influenza infection. Protection extended to other respiratory pathogens such as Sendai virus and bacterial pneumonia. Our studies demonstrate that the loss of one epithelial protein, αVβ6 integrin, can alter the lung microenvironment during both homeostasis and respiratory infection leading to reduced lung injury and improved survival.

Postmortem CT investigation of air/gas distribution in the lungs and gastrointestinal tracts of newborn infants: a serial case study with regard to still- and live birth.

PubMed

Michiue, Tomomi; Ishikawa, Takaki; Kawamoto, Osamu; Sogawa, Nozomi; Oritani, Shigeki; Maeda, Hitoshi

2013-03-10

Flotation tests on the lungs and gastrointestinal tract to investigate aeration are classic procedures to examine the life of a newborn after birth; however, there are arguments about the reliability. The present study investigated serial forensic autopsy cases of newborn infants without marked decomposition (n=4) with regard to air/gas distribution in the lungs and gastrointestinal tracts by means of postmortem CT (PM-CT) as well as macromorphology and histology, compared with intrauterine and aborted fetuses (n=3). No gas was detected in the lungs or gastrointestinal tracts in all of three intrauterine fetal deaths. Gas was diffusely detected in the lungs of a newborn fatality attributed to smothering after birth; however, two neonatal fatalities had poor lung gas contents due to marked congestion with edema and diffuse atelectasis. In a case of unsuccessful cardiopulmonary resuscitation following possible birth asphyxia, pulmonary aeration was evidently localized on CT morphology, despite a larger amount of bowel gas, and was also uneven in histology, showing a membranous immunostaining pattern of pulmonary surfactant on the intra-alveolar surfaces of expanded alveoli. The combined use of PM-CT is useful to demonstrate air/gas distributions in the lungs and gastrointestinal tract for interpretation of spontaneous breathing after birth in newborn fatalities. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Lung injury pathways: Adenosine receptor 2B signaling limits development of ischemic bronchiolitis obliterans organizing pneumonia.

PubMed

Densmore, John C; Schaid, Terry R; Jeziorczak, Paul M; Medhora, Meetha; Audi, Said; Nayak, Shraddha; Auchampach, John; Dwinell, Melinda R; Geurts, Aron M; Jacobs, Elizabeth R

2017-02-01

Purpose/Aim of the Study: Adenosine signaling was studied in bronchiolitis obliterans organizing pneumonia (BOOP) resulting from unilateral lung ischemia. Ischemia was achieved by either left main pulmonary artery or complete hilar ligation. Sprague-Dawley (SD) rats, Dahl salt sensitive (SS) rats and SS mutant rat strains containing a mutation in the A 2B adenosine receptor gene (Adora2b) were studied. Adenosine concentrations were measured in bronchoalveolar lavage (BAL) by HPLC. A 2A (A 2A AR) and A 2B adenosine receptor (A 2B AR) mRNA and protein were quantified. Twenty-four hours after unilateral PA ligation, BAL adenosine concentrations from ischemic lungs were increased relative to contralateral lungs in SD rats. A 2B AR mRNA and protein concentrations were increased after PA ligation while miR27a, a negatively regulating microRNA, was decreased in ischemic lungs. A 2A AR mRNA and protein concentrations remained unchanged following ischemia. A 2B AR protein was increased in PA ligated lungs of SS rats after 7 days, and 4 h after complete hilar ligation in SD rats. SS-Adora2b mutants showed a greater extent of BOOP relative to SS rats, and greater inflammatory changes. Increased A 2B AR and adenosine following unilateral lung ischemia as well as more BOOP in A 2B AR mutant rats implicate a protective role for A 2B AR signaling in countering ischemic lung injury.

Lung Injury Pathways: Adenosine Receptor 2B Signaling Limits Development of Ischemic Bronchiolitis Obliterans Organizing Pneumonia

PubMed Central

Densmore, John C.; Schaid, Terry R.; Jeziorczak, Paul M.; Medhora, Meetha; Audi, Said; Nayak, Shraddha; Auchampach, John; Dwinell, Melinda R.; Geurts, Aron M.; Jacobs, Elizabeth R.

2018-01-01

Purpose/Aim of the study Adenosine signaling was studied in bronchiolitis obliterans organizing pneumonia (BOOP) resulting from unilateral lung ischemia. Materials and Methods Ischemia was achieved by either left main pulmonary artery or complete hilar ligation. Sprague Dawley (SD) rats, Dahl salt sensitive (SS) rats and SS mutant rat strain containing a mutation in the A2B adenosine receptor gene (Adora2b) were studied. Adenosine concentrations were measured in bronchoalveolar lavage (BAL) by HPLC. A2A (A2AAR) and A2B adenosine receptor (A2BAR) mRNA and protein were quantified. Results 24h after unilateral PA ligation, BAL adenosine concentrations from ischemic lungs were increased relative to contralateral lungs in SD rats. A2BAR mRNA and protein concentrations were increased after PA ligation while miR27a, a negatively regulating microRNA, was decreased in ischemic lungs. A2AAR mRNA and protein concentrations remained unchanged following ischemia. A2BAR protein was increased in PA ligated lungs of SS rats after 7d, and 4h after complete hilar ligation in SD rats. SS-Adora2b mutants showed a greater extent of BOOP relative to SS rats, and greater inflammatory changes. Conclusions Increased A2BAR and adenosine following unilateral lung ischemia as well as more BOOP in A2BAR mutant rats implicate a protective role for A2BAR signaling in countering ischemic lung injury. PMID:28266889

DOE Office of Scientific and Technical Information (OSTI.GOV)

Granton, Patrick V.; Dubois, Ludwig; Elmpt, Wouter van

Purpose: In lung cancer radiation therapy, the dose constraints are determined mostly by healthy lung toxicity. Preclinical microirradiators are a new tool to evaluate treatment strategies closer to clinical irradiation devices. In this study, we quantified local changes in lung density symptomatic of radiation-induced lung fibrosis (RILF) after partial lung irradiation in mice by using a precision image-guided small animal irradiator integrated with micro-computed tomography (CT) imaging. Methods and Materials: C57BL/6 adult male mice (n=76) were divided into 6 groups: a control group (0 Gy) and groups irradiated with a single fraction of 4, 8, 12, 16, or 20 Gy using 5-mmmore » circular parallel-opposed fields targeting the upper right lung. A Monte Carlo model of the small animal irradiator was used for dose calculations. Following irradiation, all mice were imaged at regular intervals over 39 weeks (10 time points total). Nonrigid deformation was used to register the initial micro-CT scan to all subsequent scans. Results: Significant differences could be observed between the 3 highest (>10 Gy) and 3 lowest irradiation (<10 Gy) dose levels. A mean difference of 120 ± 10 HU between the 0- and 20-Gy groups was observed at week 39. RILF was found to be spatially limited to the irradiated portion of the lung. Conclusions: The data suggest that the severity of RILF in partial lung irradiation compared to large field irradiation in mice for the same dose is reduced, and therefore higher doses can be tolerated.« less

Imaging Lung Function in Mice Using SPECT/CT and Per-Voxel Analysis

PubMed Central

Jobse, Brian N.; Rhem, Rod G.; McCurry, Cory A. J. R.; Wang, Iris Q.; Labiris, N. Renée

2012-01-01

Chronic lung disease is a major worldwide health concern but better tools are required to understand the underlying pathologies. Ventilation/perfusion (V/Q) single photon emission computed tomography (SPECT) with per-voxel analysis allows for non-invasive measurement of regional lung function. A clinically adapted V/Q methodology was used in healthy mice to investigate V/Q relationships. Twelve week-old mice were imaged to describe normal lung function while 36 week-old mice were imaged to determine how age affects V/Q. Mice were ventilated with Technegas™ and injected with 99mTc-macroaggregated albumin to trace ventilation and perfusion, respectively. For both processes, SPECT and CT images were acquired, co-registered, and quantitatively analyzed. On a per-voxel basis, ventilation and perfusion were moderately correlated (R = 0.58±0.03) in 12 week old animals and a mean log(V/Q) ratio of −0.07±0.01 and standard deviation of 0.36±0.02 were found, defining the extent of V/Q matching. In contrast, 36 week old animals had significantly increased levels of V/Q mismatching throughout the periphery of the lung. Measures of V/Q were consistent across healthy animals and differences were observed with age demonstrating the capability of this technique in quantifying lung function. Per-voxel analysis and the ability to non-invasively assess lung function will aid in the investigation of chronic lung disease models and drug efficacy studies. PMID:22870297

Kras, Egfr, and Tp53 Mutations in B6C3F1/N Mouse and F344/NTac Rat Alveolar/Bronchiolar Carcinomas Resulting from Chronic Inhalation Exposure to Cobalt Metal

PubMed Central

Hong, Hue-Hua L.; Hoenerhoff, Mark J.; Ton, Thai-Vu; Herbert, Ronald A.; Kissling, Grace E.; Hooth, Michelle J.; Behl, Mamta; Witt, Kristine L.; Smith-Roe, Stephanie L.; Sills, Robert C.; Pandiri, Arun R.

2015-01-01

Rodent lung tumors are morphologically similar to a subtype of human lung adenocarcinomas. The objective of this study was to evaluate Kras, Egfr and Tp53 mutations, which are relevant to human lung cancer, in cobalt metal dust (CMD) induced alveolar/bronchiolar tumors of B6C3F1/N mice and F344/NTac rats. Kras mutations were detected in 67% (mice) and 31% (rats) of CMD-induced lung tumors, and were predominantly exon 1 codon 12 G to T transversions (80% in mice and 57% in rats). Egfr mutations were detected in 17% (both mice and rats) of CMD-induced lung tumors, and were predominantly in exon 20 with 50% G to A transitions (mice and rats). Tp53 mutations were detected in 19% (mice) and 23% (rats) of CMD-induced lung tumors and were predominantly in exon 5 (mice, 69% transversions) and exon 6 (rats, all transitions). No mutations were observed for these genes in spontaneous lung tumors or normal lungs from untreated controls. Ames assays indicated that CMD is mutagenic in the absence but not in the presence of S9 mix. Thus, the mutation data (G to T transversions) and Ames assay results suggest that oxidative damage to DNA may be a contributing factor in CMD-induced pulmonary carcinogenesis in rodents. PMID:26059825

Bisphenol A stimulates human lung cancer cell migration via upregulation of matrix metalloproteinases by GPER/EGFR/ERK1/2 signal pathway.

PubMed

Zhang, Kun-Shui; Chen, Hui-Qing; Chen, Yi-Shen; Qiu, Kai-Feng; Zheng, Xiao-Bin; Li, Guo-Cheng; Yang, Hai-Di; Wen, Cui-Ju

2014-10-01

Lung cancer is one of the leading causes of cancer deaths worldwide. Recent evidences indicated that bisphenol A (BPA), a wide contaminant with endocrine disrupting activity, could enhance the susceptibility of carcinogenesis. Although there are increasing opportunities for lung cells exposure to BPA via inhalation, there is no study concerning the effects of BPA on the development of lung cancer. The present study revealed that BPA less than 10(-4)M had limited effects on the proliferation of lung cancer A549 cells, however, BPA treatment significantly stimulated the in vitro migration and invasion of cells combing with the morphological changes and up regulation of matrix metalloproteinase-2 (MMP-2) and MMP-9. G-protein-coupled estrogen receptor (GPER), while not estrogen receptor α/β (ERα/β), mediated the BPA induced up regulation of MMPs. Further, BPA treatment induced rapid activation of ERK1/2 via GPER/EGFR. GPER/ERFR/ERK1/2 mediated the BPA induced upregulation of MMPs and in vitro migration of lung cancer A549 cells. In summary, our data presented here revealed for the first time that BPA can promote the in vitro migration and invasion of lung cancer cells via upregulation of MMPs and GPER/EGFR/ERK1/2 signals, which mediated these effects. This study suggested that more attention should be paid on the BPA and other possible environmental estrogens induced development of lung cancer. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

Flow Cytometric Analysis of Mononuclear Phagocytes in Nondiseased Human Lung and Lung-Draining Lymph Nodes.

PubMed

Desch, A Nicole; Gibbings, Sophie L; Goyal, Rajni; Kolde, Raivo; Bednarek, Joe; Bruno, Tullia; Slansky, Jill E; Jacobelli, Jordan; Mason, Robert; Ito, Yoko; Messier, Elise; Randolph, Gwendalyn J; Prabagar, Miglena; Atif, Shaikh M; Segura, Elodie; Xavier, Ramnik J; Bratton, Donna L; Janssen, William J; Henson, Peter M; Jakubzick, Claudia V

2016-03-15

The pulmonary mononuclear phagocyte system is a critical host defense mechanism composed of macrophages, monocytes, monocyte-derived cells, and dendritic cells. However, our current characterization of these cells is limited because it is derived largely from animal studies and analysis of human mononuclear phagocytes from blood and small tissue resections around tumors. Phenotypic and morphologic characterization of mononuclear phagocytes that potentially access inhaled antigens in human lungs. We acquired and analyzed pulmonary mononuclear phagocytes from fully intact nondiseased human lungs (including the major blood vessels and draining lymph nodes) obtained en bloc from 72 individual donors. Differential labeling of hematopoietic cells via intrabronchial and intravenous administration of antibodies within the same lobe was used to identify extravascular tissue-resident mononuclear phagocytes and exclude cells within the vascular lumen. Multiparameter flow cytometry was used to identify mononuclear phagocyte populations among cells labeled by each route of antibody delivery. We performed a phenotypic analysis of pulmonary mononuclear phagocytes isolated from whole nondiseased human lungs and lung-draining lymph nodes. Five pulmonary mononuclear phagocytes were observed, including macrophages, monocyte-derived cells, and dendritic cells that were phenotypically distinct from cell populations found in blood. Different mononuclear phagocytes, particularly dendritic cells, were labeled by intravascular and intrabronchial antibody delivery, countering the notion that tissue and blood mononuclear phagocytes are equivalent systems. Phenotypic descriptions of the mononuclear phagocytes in nondiseased lungs provide a precedent for comparative studies in diseased lungs and potential targets for therapeutics.

The neocortex of cetartiodactyls. II. Neuronal morphology of the visual and motor cortices in the giraffe (Giraffa camelopardalis).

PubMed

Jacobs, Bob; Harland, Tessa; Kennedy, Deborah; Schall, Matthew; Wicinski, Bridget; Butti, Camilla; Hof, Patrick R; Sherwood, Chet C; Manger, Paul R

2015-09-01

The present quantitative study extends our investigation of cetartiodactyls by exploring the neuronal morphology in the giraffe (Giraffa camelopardalis) neocortex. Here, we investigate giraffe primary visual and motor cortices from perfusion-fixed brains of three subadults stained with a modified rapid Golgi technique. Neurons (n = 244) were quantified on a computer-assisted microscopy system. Qualitatively, the giraffe neocortex contained an array of complex spiny neurons that included both "typical" pyramidal neuron morphology and "atypical" spiny neurons in terms of morphology and/or orientation. In general, the neocortex exhibited a vertical columnar organization of apical dendrites. Although there was no significant quantitative difference in dendritic complexity for pyramidal neurons between primary visual (n = 78) and motor cortices (n = 65), there was a significant difference in dendritic spine density (motor cortex > visual cortex). The morphology of aspiny neurons in giraffes appeared to be similar to that of other eutherian mammals. For cross-species comparison of neuron morphology, giraffe pyramidal neurons were compared to those quantified with the same methodology in African elephants and some cetaceans (e.g., bottlenose dolphin, minke whale, humpback whale). Across species, the giraffe (and cetaceans) exhibited less widely bifurcating apical dendrites compared to elephants. Quantitative dendritic measures revealed that the elephant and humpback whale had more extensive dendrites than giraffes, whereas the minke whale and bottlenose dolphin had less extensive dendritic arbors. Spine measures were highest in the giraffe, perhaps due to the high quality, perfusion fixation. The neuronal morphology in giraffe neocortex is thus generally consistent with what is known about other cetartiodactyls.

Longitudinal In Vivo SPECT/CT Imaging Reveals Morphological Changes and Cardiopulmonary Apoptosis in a Rodent Model of Pulmonary Arterial Hypertension

PubMed Central

Paffett, Michael L.; Hesterman, Jacob; Candelaria, Gabriel; Lucas, Selita; Anderson, Tamara; Irwin, Daniel; Hoppin, Jack; Norenberg, Jeffrey; Campen, Matthew J.

2012-01-01

Pulmonary arterial hypertension (PAH) has a complex pathogenesis involving both heart and lungs. Animal models can reflect aspects of the human pathology and provide insights into the development and underlying mechanisms of disease. Because of the variability of most animal models of PAH, serial in vivo measurements of cardiopulmonary function, morphology, and markers of pathology can enhance the value of such studies. Therefore, quantitative in vivo SPECT/CT imaging was performed to assess cardiac function, morphology and cardiac perfusion utilizing 201Thallium (201Tl) in control and monocrotaline-treated rats. In addition, lung and heart apoptosis was examined with 99mTc-Annexin V (99mTc-Annexin) in these cohorts. Following baseline imaging, rats were injected with saline or monocrotaline (50 mg/kg, i.p.) and imaged weekly for 6 weeks. To assess a therapeutic response in an established pulmonary hypertensive state, a cohort of rats received resveratrol in drinking water (3 mg/kg/day) on days 28–42 post-monocrotaline injection to monitor regression of cardiopulmonary apoptosis. PAH in monocrotaline-treated rats was verified by conventional hemodynamic techniques on day 42 (right ventricular systolic pressure (RSVP) = 66.2 mmHg in monocrotaline vs 28.8 mmHg in controls) and in terms of right ventricular hypertrophy (RV/LVS = 0.70 in monocrotaline vs 0.32 in controls). Resveratrol partially reversed both RVSP (41.4 mmHg) and RV/LVS (0.46), as well as lung edema and RV contractility +dP/dtmax. Serial 99mTc-Annexin V imaging showed clear increases in pulmonary and cardiac apoptosis when compared to baseline, which regressed following resveratrol treatment. Monocrotaline induced modest changes in whole-heart perfusion as assessed by 201TI imaging and cardiac morphological changes consistent with septal deviation and enlarged RV. This study demonstrates the utility of functional in vivo SPECT/CT imaging in rodent models of PAH and further confirms the efficacy of resveratrol in reversing established monocrotaline-induced PAH presumably by attenuation of cardiopulmonary apoptosis. PMID:22815866

Corruption of the Fas Pathway Delays the Pulmonary Clearance of Murine Osteosarcoma Cells, Enhances Their Metastatic Potential, and Reduces the Effect of Aerosol Gemcitabine

PubMed Central

Gordon, Nancy; Koshkina, Nadezhda V.; Jia, Shu-Fang; Khanna, Chand; Mendoza, Arnulfo; Worth, Laura L.; Kleinerman, Eugenie S.

2015-01-01

Purpose Pulmonary metastases continue to be a significant problem in osteosarcoma. Apoptosis dysfunction is known to influence tumor development. Fas (CD95, APO-1)/FasL is one of the most extensively studied apoptotic pathways. Because FasL is constitutively expressed in the lung, cells that express Fas should be eliminated by lung endothelium. Cells with low or no cell surface Fas expression may be able to evade this innate defense mechanism. The purpose of these studies was to evaluate Fas expression in osteosarcoma lung metastases and the effect of gemcitabine on Fas expression and tumor growth. Experimental Design and Results Using the K7M2 murine osteosarcoma model, Fas expression was quantified using immunohistochemistry. High levels of Fas were present in primary tumors, but no Fas expression was present in actively growing lung metastases. Blocking the Fas pathway using Fas-associated death domain dominant-negative delayed tumor cell clearance from the lung and increased metastatic potential. Treatment of mice with aerosol gemcitabine resulted in increased Fas expression and subsequent tum or regression. Conclusions We conclude that corruption of the Fas pathway is critical to the ability of osteosarcoma cells to grow in the lung. Agents such as gemcitabine that up-regulate cell surface Fas expression may therefore be effective in treating osteosarcoma lung metastases. These data also suggest that an additional mechanism by which gemcitabine induces regression of osteosarcoma lung metastases is mediated by enhancing the sensitivity of the tumor cells to the constitutive FasL in the lung. PMID:17671136

Association of locally produced IL10 and TGFb1 with tumor size, histological type and presence of metastases in patients with lung carcinoma.

PubMed

Karlicic, Vukoica; Vukovic, Jelena; Stanojevic, Ivan; Sotirovic, Jelena; Peric, Aleksandar; Jovic, Milena; Cvijanovic, Vlado; Djukic, Mirjana; Banovic, Tatjana; Vojvodic, Danilo

2016-01-01

Advanced lung carcinoma is charasterized with fast disease progression. Interleukin (IL)10 and transforming growth factor (TGF)b1 are immunosuppressive mediators and their role in lung carcinoma pathogenesis and in the antitumor response has not yet been elucidated. The purpose of this study was to correlate IL10 and TGFb1 levels in the serum and lung tumor microcirculation with clinical stage, disease extent, histological features and TNM stage. The study included 41 lung cancer patients in clinical stage III and IV. Histological type was determined immunohistochemically, while tumor size, localization and dissemination were determined radiologically by multislice computerized tomography (MSCT). IL10 and TGFb1 levels were quantified with commercial flow cytometric test in serum and lung tumor microcirculation samples. Non small cell lung cancer (NSCLC) patients had significantly elevated TGFb1 while small cell lung cancer (SCLC) patients had significantly increased IL10 in tumor microcirculation. IL10 was significantly elevated in patients with the largest tumors, as well as in patients with III clinical stage and without metastases, both in the serum and tumor microcirculation. TGFb1 was significantly increased in serum and tumor microcirculation in patients with larger tumors. We found significant correlation between these two immunosuppressive cytokines, IL10 and TGFb1, in tumor microcirculation but not in patient serum samples. IL10 and TGFb1 in systemic and tumor microcirculation are significantly associated with particular histological type of lung cancer, tumor size and degree of disease extent.

When Is an Alveolar Type 2 Cell an Alveolar Type 2 Cell? A Conundrum for Lung Stem Cell Biology and Regenerative Medicine.

PubMed

Beers, Michael F; Moodley, Yuben

2017-07-01

Generating mature, differentiated, adult lung cells from pluripotent cells, such as induced pluripotent stem cells and embryonic stem cells, offers the hope of both generating disease-specific in vitro models and creating definitive and personalized therapies for a host of debilitating lung parenchymal and airway diseases. With the goal of advancing lung-regenerative medicine, several groups have developed and reported on protocols using defined media, coculture with mesenchymal components, or sequential treatments mimicking lung development, to obtain distal lung epithelial cells from stem cell precursors. However, there remains significant controversy about the degree of differentiation of these cells compared with their primary counterparts, coupled with a lack of consistency or uniformity in assessing the resultant phenotypes. Given the inevitable, exponential expansion of these approaches and the probable, but yet-to-emerge second and higher generation techniques to create such assets, we were prompted to pose the question, what makes a lung epithelial cell a lung epithelial cell? More specifically for this Perspective, we also posed the question, what are the minimum features that constitute an alveolar type (AT) 2 epithelial cell? In addressing this, we summarize a body of work spanning nearly five decades, amassed by a series of "lung epithelial cell biology pioneers," which carefully describes well characterized molecular, functional, and morphological features critical for discriminately assessing an AT2 phenotype. Armed with this, we propose a series of core criteria to assist the field in confirming that cells obtained following a differentiation protocol are indeed mature and functional AT2 epithelial cells.

Comparison of the gas-liquid dual support fixation and Heitzman fixation techniques for preparing lung specimens

PubMed Central

Yu, Dongsheng; Qu, Weili; Xia, Haipeng; Li, Xiaofeng; Luan, Zhenfeng; Yan, Renjie; Lu, Xiaodong; Zhao, Peng

2017-01-01

The aim of the present study was to compare the gas-liquid dual support fixation and Heitzman fixation techniques for the preparation of lung specimens. A total of 40 fresh lung samples were surgically collected from 40 male patients with lung cancer by biopsy. Patients were recruited from the Affiliated Hospital of Qingdao University Medical College (Qingdao, China) between July 2007 and June 2014. Samples were prepared using either the gas-liquid dual support fixation method (group A; n=26) or the Heitzman fixation method (group B; n=14). High-resolution computed tomography (HRCT) scanning was performed prior to surgery and corresponding postoperative HRCT scanning was conducted for the lung specimens; the gross transverse specimen section, cord photography images and histological sections were evaluated. Morphological observations of lung specimens indicated that there were 22 cases in group A with grade I (84.6%) and 4 cases with grade II (15.4%), whereas, in group B, there were 5 cases with grade II (35.7%) and 9 cases with grade III (64.3%). Statistical analysis demonstrated that the grades of specimens between the two groups were significantly different (P<0.01). Results from imaging and histological studies found that the quality of lung specimens was superior in group A, compared with group B. In conclusion, the present study demonstrated that, compared with the Heitzman fixation method, gas-liquid dual support fixation may be a superior technique for the preparation of lung specimens. This finding may facilitate the improvement of lung HRCT and pathological studies. PMID:28673006

Poster — Thur Eve — 70: Automatic lung bronchial and vessel bifurcations detection algorithm for deformable image registration assessment

DOE Office of Scientific and Technical Information (OSTI.GOV)

Labine, Alexandre; Carrier, Jean-François; Bedwani, Stéphane

2014-08-15

Purpose: To investigate an automatic bronchial and vessel bifurcations detection algorithm for deformable image registration (DIR) assessment to improve lung cancer radiation treatment. Methods: 4DCT datasets were acquired and exported to Varian treatment planning system (TPS) EclipseTM for contouring. The lungs TPS contour was used as the prior shape for a segmentation algorithm based on hierarchical surface deformation that identifies the deformed lungs volumes of the 10 breathing phases. Hounsfield unit (HU) threshold filter was applied within the segmented lung volumes to identify blood vessels and airways. Segmented blood vessels and airways were skeletonised using a hierarchical curve-skeleton algorithm basedmore » on a generalized potential field approach. A graph representation of the computed skeleton was generated to assign one of three labels to each node: the termination node, the continuation node or the branching node. Results: 320 ± 51 bifurcations were detected in the right lung of a patient for the 10 breathing phases. The bifurcations were visually analyzed. 92 ± 10 bifurcations were found in the upper half of the lung and 228 ± 45 bifurcations were found in the lower half of the lung. Discrepancies between ten vessel trees were mainly ascribed to large deformation and in regions where the HU varies. Conclusions: We established an automatic method for DIR assessment using the morphological information of the patient anatomy. This approach allows a description of the lung's internal structure movement, which is needed to validate the DIR deformation fields for accurate 4D cancer treatment planning.« less

Comparison of the gas-liquid dual support fixation and Heitzman fixation techniques for preparing lung specimens.

PubMed

Yu, Dongsheng; Qu, Weili; Xia, Haipeng; Li, Xiaofeng; Luan, Zhenfeng; Yan, Renjie; Lu, Xiaodong; Zhao, Peng

2017-07-01

The aim of the present study was to compare the gas-liquid dual support fixation and Heitzman fixation techniques for the preparation of lung specimens. A total of 40 fresh lung samples were surgically collected from 40 male patients with lung cancer by biopsy. Patients were recruited from the Affiliated Hospital of Qingdao University Medical College (Qingdao, China) between July 2007 and June 2014. Samples were prepared using either the gas-liquid dual support fixation method (group A; n=26) or the Heitzman fixation method (group B; n=14). High-resolution computed tomography (HRCT) scanning was performed prior to surgery and corresponding postoperative HRCT scanning was conducted for the lung specimens; the gross transverse specimen section, cord photography images and histological sections were evaluated. Morphological observations of lung specimens indicated that there were 22 cases in group A with grade I (84.6%) and 4 cases with grade II (15.4%), whereas, in group B, there were 5 cases with grade II (35.7%) and 9 cases with grade III (64.3%). Statistical analysis demonstrated that the grades of specimens between the two groups were significantly different (P<0.01). Results from imaging and histological studies found that the quality of lung specimens was superior in group A, compared with group B. In conclusion, the present study demonstrated that, compared with the Heitzman fixation method, gas-liquid dual support fixation may be a superior technique for the preparation of lung specimens. This finding may facilitate the improvement of lung HRCT and pathological studies.

Polyhexamethyleneguanidine phosphate induces severe lung inflammation, fibrosis, and thymic atrophy.

PubMed

Song, Jeong Ah; Park, Hyun-Ju; Yang, Mi-Jin; Jung, Kyung Jin; Yang, Hyo-Seon; Song, Chang-Woo; Lee, Kyuhong

2014-07-01

Polyhexamethyleneguanidine phosphate (PHMG-P) has been widely used as a disinfectant because of its strong bactericidal activity and low toxicity. However, in 2011, the Korea Centers for Disease Control and Prevention and the Ministry of Health and Welfare reported that a suspicious outbreak of pulmonary disease might have originated from humidifier disinfectants. The purpose of this study was to assess the toxicity of PHMG-P following direct exposure to the lung. PHMG-P (0.3, 0.9, or 1.5 mg/kg) was instilled into the lungs of mice. The levels of proinflammatory markers and fibrotic markers were quantified in lung tissues and flow cytometry was used to evaluate T cell distribution in the thymus. Administration of PHMG-P induced proinflammatory cytokines elevation and infiltration of immune cells into the lungs. Histopathological analysis revealed a dose-dependent exacerbation of both inflammation and pulmonary fibrosis on day 14. PHMG-P also decreased the total cell number and the CD4(+)/CD8(+) cell ratio in the thymus, with the histopathological examination indicating severe reduction of cortex and medulla. The mRNA levels of biomarkers associated with T cell development also decreased markedly. These findings suggest that exposure of lung tissue to PHMG-P leads to pulmonary inflammation and fibrosis as well as thymic atrophy. Copyright © 2014 Elsevier Ltd. All rights reserved.

Improved OCT imaging of lung tissue using a prototype for total liquid ventilation

NASA Astrophysics Data System (ADS)

Schnabel, Christian; Meissner, Sven; Koch, Edmund

2011-06-01

Optical coherence tomography (OCT) is used for imaging subpleural alveoli in animal models to gain information about dynamic and morphological changes of lung tissue during mechanical ventilation. The quality of OCT images can be increased if the refraction index inside the alveoli is matched to the one of tissue via liquid-filling. Thereby, scattering loss can be decreased and higher penetration depth and tissue contrast can be achieved. Until now, images of liquid-filled lungs were acquired in isolated and fixated lungs only, so that an in vivo measurement situation is not present. To use the advantages of liquid-filling for in vivo imaging of small rodent lungs, it was necessary to develop a liquid ventilator. Perfluorodecalin, a perfluorocarbon, was selected as breathing fluid because of its refraction index being similar to the one of water and the high transport capacity for carbon dioxide and oxygen. The setup is characterized by two independent syringe pumps to insert and withdraw the fluid into and from the lung and a custom-made control program for volume- or pressure-controlled ventilation modes. The presented results demonstrate the liquid-filling verified by optical coherence tomography and intravital microscopy (IVM) and the advantages of liquid-filling to OCT imaging of subpleural alveoli.

Morphology and Morphometry of the Lung in Corn Snakes (Pantherophis guttatus) Infected with Three Different Strains of Ferlavirus.

PubMed

Starck, J M; Neul, A; Schmidt, V; Kolb, T; Franz-Guess, S; Balcecean, D; Pees, M

2017-05-01

Ophidian paramyxovirus (ferlavirus) is a global threat to reptilian sauropsids in herpetological collections, with occasional but fatal effects. This study characterizes the effects of three different genetic strains of ferlavirus on the dynamic changes of histology and morphometry of the lung of corn snakes (Pantherophis guttatus). Lungs from 42 corn snakes were either sham-infected or infected experimentally under standardized conditions. From 4 to 49 days after intratracheal inoculation, the lungs were examined qualitatively and quantitatively. Progressive microscopical changes were seen in the lung. Initially, increased numbers of heterophils were observed in the interstitium followed by proliferation and vacuolation of epithelial cells lining faveoli. Electron microscopy revealed loss of type-I pneumocytes, hyperplasia of type-II pneumocytes, and interstitial infiltrates of heterophils and mononuclear cells. With progression of disease the respiratory epithelium was initially overgrown by transformed type-II pneumocytes and later became multilayered. The results of the study suggest that the respiratory capacity of the lungs declines with disease development. The dynamics of disease development and histopathology differed in snakes infected with different ferlavirus genogroups. Animals infected with virus genogroup B developed histopathological changes and morphometric changes more rapidly and of greater intensity than snakes infected with viruses from genogroups A or C. Copyright © 2017 Elsevier Ltd. All rights reserved.

Precision-cut vibratome slices allow functional live cell imaging of the pulmonary neuroepithelial body microenvironment in fetal mice.

PubMed

Schnorbusch, Kathy; Lembrechts, Robrecht; Brouns, Inge; Pintelon, Isabel; Timmermans, Jean-Pierre; Adriaensen, Dirk

2012-01-01

We recently developed an ex vivo lung slice model that allows for confocal live cell imaging (LCI) of neuroepithelial bodies (NEBs) in postnatal mouse lungs (postnatal days 1-21 and adult). NEBs are morphologically well-characterized, extensively innervated groups of neuroendocrine cells in the airway epithelium, which are shielded from the airway lumen by 'Clara-like' cells. The prominent presence of differentiated NEBs from early embryonic development onwards, strongly suggests that NEBs may exert important functions during late fetal and neonatal life. The main goal of the present study was to adapt the current postnatal LCI lung slice model to enable functional studies of fetal mouse lungs (gestational days 17-20).In vibratome lung slices of prenatal mice, NEBs could be unequivocally identified with the fluorescent stryryl pyridinium dye 4-Di-2-ASP. Changes in the intracellular free calcium concentration and in mitochondrial membrane potential could be monitored using appropriate functional fluorescent indicators (e.g. Fluo-4).It is clear that the described fetal mouse lung slice model is suited for LCI studies of Clara cells, ciliated cells, and the NEB microenvironment, and offers excellent possibilities to further unravel the significance of NEBs during the prenatal and perinatal period.

Analysis of intervention strategies for inhalation exposure to polycyclic aromatic hydrocarbons and associated lung cancer risk based on a Monte Carlo population exposure assessment model.

PubMed

Zhou, Bin; Zhao, Bin

2014-01-01

It is difficult to evaluate and compare interventions for reducing exposure to air pollutants, including polycyclic aromatic hydrocarbons (PAHs), a widely found air pollutant in both indoor and outdoor air. This study presents the first application of the Monte Carlo population exposure assessment model to quantify the effects of different intervention strategies on inhalation exposure to PAHs and the associated lung cancer risk. The method was applied to the population in Beijing, China, in the year 2006. Several intervention strategies were designed and studied, including atmospheric cleaning, smoking prohibition indoors, use of clean fuel for cooking, enhancing ventilation while cooking and use of indoor cleaners. Their performances were quantified by population attributable fraction (PAF) and potential impact fraction (PIF) of lung cancer risk, and the changes in indoor PAH concentrations and annual inhalation doses were also calculated and compared. The results showed that atmospheric cleaning and use of indoor cleaners were the two most effective interventions. The sensitivity analysis showed that several input parameters had major influence on the modeled PAH inhalation exposure and the rankings of different interventions. The ranking was reasonably robust for the remaining majority of parameters. The method itself can be extended to other pollutants and in different places. It enables the quantitative comparison of different intervention strategies and would benefit intervention design and relevant policy making.

Spreaders and Sponges define metastasis in lung cancer: A Markov chain Monte Carlo Mathematical Model

PubMed Central

Newton, Paul K.; Mason, Jeremy; Bethel, Kelly; Bazhenova, Lyudmila; Nieva, Jorge; Norton, Larry; Kuhn, Peter

2013-01-01

The classic view of metastatic cancer progression is that it is a unidirectional process initiated at the primary tumor site, progressing to variably distant metastatic sites in a fairly predictable, though not perfectly understood, fashion. A Markov chain Monte Carlo mathematical approach can determine a pathway diagram that classifies metastatic tumors as ‘spreaders’ or ‘sponges’ and orders the timescales of progression from site to site. In light of recent experimental evidence highlighting the potential significance of self-seeding of primary tumors, we use a Markov chain Monte Carlo (MCMC) approach, based on large autopsy data sets, to quantify the stochastic, systemic, and often multi-directional aspects of cancer progression. We quantify three types of multi-directional mechanisms of progression: (i) self-seeding of the primary tumor; (ii) re-seeding of the primary tumor from a metastatic site (primary re-seeding); and (iii) re-seeding of metastatic tumors (metastasis re-seeding). The model shows that the combined characteristics of the primary and the first metastatic site to which it spreads largely determine the future pathways and timescales of systemic disease. For lung cancer, the main ‘spreaders’ of systemic disease are the adrenal gland and kidney, whereas the main ‘sponges’ are regional lymph nodes, liver, and bone. Lung is a significant self-seeder, although it is a ‘sponge’ site with respect to progression characteristics. PMID:23447576

Asbestos exposure induces alveolar epithelial cell plasticity through MAPK/Erk signaling.

PubMed

Tamminen, Jenni A; Myllärniemi, Marjukka; Hyytiäinen, Marko; Keski-Oja, Jorma; Koli, Katri

2012-07-01

The inhalation of asbestos fibers is considered to be highly harmful, and lead to fibrotic and/or malignant disease. Epithelial-to-mesenchymal transition (EMT) is a common pathogenic mechanism in asbestos associated fibrotic (asbestosis) and malignant lung diseases. The characterization of molecular pathways contributing to EMT may provide new possibilities for prognostic and therapeutic applications. The role of asbestos as an inducer of EMT has not been previously characterized. We exposed cultured human lung epithelial cells to crocidolite asbestos and analyzed alterations in the expression of epithelial and mesenchymal marker proteins and cell morphology. Asbestos was found to induce downregulation of E-cadherin protein levels in A549 lung carcinoma cells in 2-dimensional (2D) and 3D cultures. Similar findings were made in primary small airway epithelial cells cultured in 3D conditions where the cells retained alveolar type II cell phenotype. A549 cells also exhibited loss of cell-cell contacts, actin reorganization and expression of α-smooth muscle actin (α-SMA) in 2D cultures. These phenotypic changes were not associated with increased transforming growth factor (TGF)-β signaling activity. MAPK/Erk signaling pathway was found to mediate asbestos-induced downregulation of E-cadherin and alterations in cell morphology. Our results suggest that asbestos can induce epithelial plasticity, which can be interfered by blocking the MAPK/Erk kinase activity. Copyright © 2012 Wiley Periodicals, Inc.

SU-G-BRC-08: Evaluation of Dose Mass Histogram as a More Representative Dose Description Method Than Dose Volume Histogram in Lung Cancer Patients

DOE Office of Scientific and Technical Information (OSTI.GOV)

Liu, J; Eldib, A; Ma, C

2016-06-15

Purpose: Dose-volume-histogram (DVH) is widely used for plan evaluation in radiation treatment. The concept of dose-mass-histogram (DMH) is expected to provide a more representative description as it accounts for heterogeneity in tissue density. This study is intended to assess the difference between DVH and DMH for evaluating treatment planning quality. Methods: 12 lung cancer treatment plans were exported from the treatment planning system. DVHs for the planning target volume (PTV), the normal lung and other structures of interest were calculated. DMHs were calculated in a similar way as DVHs expect that the voxel density converted from the CT number wasmore » used in tallying the dose histogram bins. The equivalent uniform dose (EUD) was calculated based on voxel volume and mass, respectively. The normal tissue complication probability (NTCP) in relation to the EUD was calculated for the normal lung to provide quantitative comparison of DVHs and DMHs for evaluating the radiobiological effect. Results: Large differences were observed between DVHs and DMHs for lungs and PTVs. For PTVs with dense tumor cores, DMHs are higher than DVHs due to larger mass weighing in the high dose conformal core regions. For the normal lungs, DMHs can either be higher or lower than DVHs depending on the target location within the lung. When the target is close to the lower lung, DMHs show higher values than DVHs because the lower lung has higher density than the central portion or the upper lung. DMHs are lower than DVHs for targets in the upper lung. The calculated NTCPs showed a large range of difference between DVHs and DMHs. Conclusion: The heterogeneity of lung can be well considered using DMH for evaluating target coverage and normal lung pneumonitis. Further studies are warranted to quantify the benefits of DMH over DVH for plan quality evaluation.« less

A Cost-Utility Analysis of Lung Cancer Screening and the Additional Benefits of Incorporating Smoking Cessation Interventions

PubMed Central

Villanti, Andrea C.; Jiang, Yiding; Abrams, David B.; Pyenson, Bruce S.

2013-01-01

Background A 2011 report from the National Lung Screening Trial indicates that three annual low-dose computed tomography (LDCT) screenings for lung cancer reduced lung cancer mortality by 20% compared to chest X-ray among older individuals at high risk for lung cancer. Discussion has shifted from clinical proof to financial feasibility. The goal of this study was to determine whether LDCT screening for lung cancer in a commercially-insured population (aged 50–64) at high risk for lung cancer is cost-effective and to quantify the additional benefits of incorporating smoking cessation interventions in a lung cancer screening program. Methods and Findings The current study builds upon a previous simulation model to estimate the cost-utility of annual, repeated LDCT screenings over 15 years in a high risk hypothetical cohort of 18 million adults between age 50 and 64 with 30+ pack-years of smoking history. In the base case, the lung cancer screening intervention cost $27.8 billion over 15 years and yielded 985,284 quality-adjusted life years (QALYs) gained for a cost-utility ratio of $28,240 per QALY gained. Adding smoking cessation to these annual screenings resulted in increases in both the costs and QALYs saved, reflected in cost-utility ratios ranging from $16,198 per QALY gained to $23,185 per QALY gained. Annual LDCT lung cancer screening in this high risk population remained cost-effective across all sensitivity analyses. Conclusions The findings of this study indicate that repeat annual lung cancer screening in a high risk cohort of adults aged 50–64 is highly cost-effective. Offering smoking cessation interventions with the annual screening program improved the cost-effectiveness of lung cancer screening between 20% and 45%. The cost-utility ratios estimated in this study were in line with other accepted cancer screening interventions and support inclusion of annual LDCT screening for lung cancer in a high risk population in clinical recommendations. PMID:23940744

Cerium oxide nanoparticles protect rodent lungs from hypobaric hypoxia-induced oxidative stress and inflammation.

PubMed

Arya, Aditya; Sethy, Niroj Kumar; Singh, Sushil Kumar; Das, Mainak; Bhargava, Kalpana

2013-01-01

Cerium oxide nanoparticles (nanoceria) are effective at quenching reactive oxygen species (ROS) in cell culture and animal models. Although nanoceria reportedly deposit in lungs, their efficacy in conferring lung protection during oxidative stress remains unexplored. Thus, the study evaluated the protective efficacy of nanoceria in rat lung tissue during hypobaric hypoxia. A total of 48 animals were randomly divided into four equal groups (control [C], nanoceria treated [T], hypoxia [H], and nanoceria treated plus hypoxia [T+H]). Animals were injected intraperitoneally with either a dose of 0.5 μg/kg body weight/week of nanoceria (T and T+H groups) or vehicle (C and H groups) for 5 weeks. After the final dose, H and T+H animals were challenged with hypobaric hypoxia, while C and T animals were maintained at normoxia. Lungs were isolated and homogenate was obtained for analysis of ROS, lipid peroxidation, glutathione, protein carbonylation, and 4-hydroxynonenal-adduct formation. Plasma was used for estimating major inflammatory cytokines using enzyme-linked immunosorbent assay. Intact lung tissues were fixed and both transmission electron microscopy and histopathological examinations were carried out separately for detecting internalization of nanoparticles as well as altered lung morphology. Spherical nanoceria of 7-10 nm diameter were synthesized using a microemulsion method, and the lung protective efficacy of the nanoceria evaluated during hypobaric hypoxia. With repeated intraperitoneal injections of low micromole concentration, we successfully localized the nanoceria in rodent lung without any inflammatory response. The lung-deposited nanoceria limited ROS formation, lipid peroxidation, and glutathione oxidation, and prevented oxidative protein modifications like nitration and carbonyl formation during hypobaric hypoxia. We also observed reduced lung inflammation in the nanoceria-injected lungs, supporting the anti-inflammatory properties of nanoceria. Cumulatively, these results suggest nanoceria deposit in lungs, confer protection by quenching noxious free radicals during hypobaric hypoxia, and do not evoke any inflammatory response.

IDENTIFICATION OF SPONTANEOUS FELINE IDIOPATHIC PULMONARY FIBROSIS: MORPHOLOGY AND ULTRASTRUCTURAL EVIDENCE FOR A TYPE II PNEUMOCYTE DEFECT

EPA Science Inventory

Abstract
Idiopathic pulmonary fibrosis currently lacks an animal model that develops the persistent, progressive lung fibrosis characteristic of the disease. Sixteen domestic cats developed dyspnea that was not responsive to therapy and which rapidly progressed until death/eu...

Analysis of poration-induced changes in cells from laser-activated plasmonic substrates

PubMed Central

Saklayen, Nabiha; Kalies, Stefan; Madrid, Marinna; Nuzzo, Valeria; Huber, Marinus; Shen, Weilu; Sinanan-Singh, Jasmine; Heinemann, Dag; Heisterkamp, Alexander; Mazur, Eric

2017-01-01

Laser-exposed plasmonic substrates permeabilize the plasma membrane of cells when in close contact to deliver cell-impermeable cargo. While studies have determined the cargo delivery efficiency and viability of laser-exposed plasmonic substrates, morphological changes in a cell have not been quantified. We porated myoblast C2C12 cells on a plasmonic pyramid array using a 532-nm laser with 850-ps pulse length and time-lapse fluorescence imaging to quantify cellular changes. We obtain a poration efficiency of 80%, viability of 90%, and a pore radius of 20 nm. We quantified area changes in the plasma membrane attached to the substrate (10% decrease), nucleus (5 – 10% decrease), and cytoplasm (5 – 10% decrease) over 1 h after laser treatment. Cytoskeleton fibers show a change of 50% in the alignment, or coherency, of fibers, which stabilizes after 10 mins. We investigate structural and morphological changes due to the poration process to enable the safe development of this technique for therapeutic applications. PMID:29082100

Root system morphology of Oregon white oak on a glacial outwash soil.

Treesearch

Warren D. Devine; Constance A. Harrington

2005-01-01

Oregon white oak is reportedly a deeply rooted species, but its rooting habit on coarse-textured soils is undocumented. In the Puget Trough of western Washington, Oregon white oak grows in coarse-textured glacial outwash soils on lowland sites. Our objective was to quantify the gross root system morphology of Oregon white oak in these soils, thereby improving our...

Towards a morphological metric of assemblage dynamics in the fossil record: a test case using planktonic foraminifera

PubMed Central

Hsiang, Allison Y.; Elder, Leanne E.; Hull, Pincelli M.

2016-01-01

With a glance, even the novice naturalist can tell you something about the ecology of a given ecosystem. This is because the morphology of individuals reflects their evolutionary history and ecology, and imparts a distinct ‘look’ to communities—making it possible to immediately discern between deserts and forests, or coral reefs and abyssal plains. Once quantified, morphology can provide a common metric for characterizing communities across space and time and, if measured rapidly, serve as a powerful tool for quantifying biotic dynamics. Here, we present and test a new high-throughput approach for analysing community shape in the fossil record using semi-three-dimensional (3D) morphometrics from vertically stacked images (light microscopic or photogrammetric). We assess the potential informativeness of community morphology in a first analysis of the relationship between 3D morphology, ecology and phylogeny in 16 extant species of planktonic foraminifera—an abundant group in the marine fossil record—and in a preliminary comparison of four assemblages from the North Atlantic. In the species examined, phylogenetic relatedness was most closely correlated with ecology, with all three ecological traits examined (depth habitat, symbiont ecology and biogeography) showing significant phylogenetic signal. By contrast, morphological trees (based on 3D shape similarity) were relatively distantly related to both ecology and phylogeny. Although improvements are needed to realize the full utility of community morphometrics, our approach already provides robust volumetric measurements of assemblage size, a key ecological characteristic. PMID:26977067

Towards a morphological metric of assemblage dynamics in the fossil record: a test case using planktonic foraminifera.

PubMed

Hsiang, Allison Y; Elder, Leanne E; Hull, Pincelli M

2016-04-05

With a glance, even the novice naturalist can tell you something about the ecology of a given ecosystem. This is because the morphology of individuals reflects their evolutionary history and ecology, and imparts a distinct 'look' to communities--making it possible to immediately discern between deserts and forests, or coral reefs and abyssal plains. Once quantified, morphology can provide a common metric for characterizing communities across space and time and, if measured rapidly, serve as a powerful tool for quantifying biotic dynamics. Here, we present and test a new high-throughput approach for analysing community shape in the fossil record using semi-three-dimensional (3D) morphometrics from vertically stacked images (light microscopic or photogrammetric). We assess the potential informativeness of community morphology in a first analysis of the relationship between 3D morphology, ecology and phylogeny in 16 extant species of planktonic foraminifera--an abundant group in the marine fossil record--and in a preliminary comparison of four assemblages from the North Atlantic. In the species examined, phylogenetic relatedness was most closely correlated with ecology, with all three ecological traits examined (depth habitat, symbiont ecology and biogeography) showing significant phylogenetic signal. By contrast, morphological trees (based on 3D shape similarity) were relatively distantly related to both ecology and phylogeny. Although improvements are needed to realize the full utility of community morphometrics, our approach already provides robust volumetric measurements of assemblage size, a key ecological characteristic. © 2016 The Authors.

Quantifying Morphological Features of α-U3O8 with Image Analysis for Nuclear Forensics.

PubMed

Olsen, Adam M; Richards, Bryony; Schwerdt, Ian; Heffernan, Sean; Lusk, Robert; Smith, Braxton; Jurrus, Elizabeth; Ruggiero, Christy; McDonald, Luther W

2017-03-07

Morphological changes in U 3 O 8 based on calcination temperature have been quantified enabling a morphological feature to serve as a signature of processing history in nuclear forensics. Five separate calcination temperatures were used to synthesize α-U 3 O 8 , and each sample was characterized using powder X-ray diffraction (p-XRD) and scanning electron microscopy (SEM). The p-XRD spectra were used to evaluate the purity of the synthesized U-oxide; the morphological analysis for materials (MAMA) software was utilized to quantitatively characterize the particle shape and size as indicated by the SEM images. Analysis comparing the particle attributes, such as particle area at each of the temperatures, was completed using the Kolmogorov-Smirnov two sample test (K-S test). These results illustrate a distinct statistical difference between each calcination temperature. To provide a framework for forensic analysis of an unknown sample, the sample distributions at each temperature were compared to randomly selected distributions (100, 250, 500, and 750 particles) from each synthesized temperature to determine if they were statistically different. It was found that 750 particles were required to differentiate between all of the synthesized temperatures with a confidence interval of 99.0%. Results from this study provide the first quantitative morphological study of U-oxides, and reveals the potential strength of morphological particle analysis in nuclear forensics by providing a framework for a more rapid characterization of interdicted uranium oxide samples.

Advances in tumor diagnosis using OCT and Raman spectroscopy

NASA Astrophysics Data System (ADS)

Zakharov, V. P.; Bratchenko, I. A.; Kozlov, S. V.; Moryatov, A. A.; Kornilin, D. V.; Myakinin, O. O.; Artemyev, D. N.

2014-05-01

Complex investigation of malignant tumors was performed with combined optical coherence tomography (OCT) and Raman spectroscopy (RS) setup: 22 ex vivo lung tissue samples and 23 in vivo experiments with skin tumors. It was shown that combined RS-OCT unit may be used for precise tissue morphology visualization with simultaneous tumor type determination (BCC, malignant melanoma of skin tissues, adenocarcinoma and squamous cell carcinoma of lung). Fast RS phase method for skin and lung tumors identification was proposed. It is based on alteration of Raman spectral intensity in 1300-1340, 1440-1460 and 1640-1680 cm-1 bands for healthy and malignant tissue. Complex method could identify: malignant melanoma with 88.9% sensitivity and 87.8% specificity; adenocarcinoma with 100% sensitivity and 81.5% specificity; squamous cell carcinomas with 90.9% sensitivity and 77.8% specificity.

99mTc-Hexamethylpropyleneamine Oxime Imaging for Early Detection of Acute Lung Injury in Rats Exposed to Hyperoxia or Lipopolysaccharide Treatment

PubMed Central

Audi, Said H.; Clough, Anne V.; Haworth, Steven T.; Medhora, Meetha; Ranji, Mahsa; Densmore, John C.; Jacobs, Elizabeth R.

2016-01-01

99mTc-Hexamethylpropyleneamine oxime (HMPAO) is a clinical single-photon emission computed tomography biomarker of tissue oxidoreductive state. Our objective was to investigate whether HMPAO lung uptake can serve as a pre-clinical marker of lung injury in two well-established rat models of human acute lung injury (ALI). Rats were exposed to >95% O2 (hyperoxia) or treated with intratracheal lipopolysaccharide (LPS), with first endpoints obtained 24 hours later. HMPAO was administered intravenously before and after treatment with the glutathione-depleting agent diethyl maleate (DEM), scintigraphy images were acquired, and HMPAO lung uptake was quantified from the images. We also measured breathing rates, heart rates, oxygen saturation, bronchoalveolar lavage (BAL) cell counts and protein, lung homogenate glutathione (GSH) content, and pulmonary vascular endothelial filtration coefficient (Kf). For hyperoxia rats, HMPAO lung uptake increased after 24 hours (134%) and 48 hours (172%) of exposure. For LPS-treated rats, HMPAO lung uptake increased (188%) 24 hours after injury and fell with resolution of injury. DEM reduced HMPAO uptake in hyperoxia and LPS rats by a greater fraction than in normoxia rats. Both hyperoxia exposure (18%) and LPS treatment (26%) increased lung homogenate GSH content, which correlated strongly with HMPAO uptake. Neither of the treatments had an effect on Kf at 24 hours. LPS-treated rats appeared healthy but exhibited mild tachypnea, BAL and histological evidence of inflammation, and increased wet and dry lung weights. These results suggest the potential utility of HMPAO as a tool for detecting ALI at a phase likely to exhibit minimal clinical evidence of injury. PMID:26974426

99MTc-Hexamethylpropyleneamine Oxime Imaging for Early Detection of Acute Lung Injury in Rats Exposed to Hyperoxia or Lipopolysaccharide Treatment.

PubMed

Audi, Said H; Clough, Anne V; Haworth, Steven T; Medhora, Meetha; Ranji, Mahsa; Densmore, John C; Jacobs, Elizabeth R

2016-10-01

Tc-Hexamethylpropyleneamine oxime (HMPAO) is a clinical single-photon emission computed tomography biomarker of tissue oxidoreductive state. Our objective was to investigate whether HMPAO lung uptake can serve as a preclinical marker of lung injury in two well-established rat models of human acute lung injury (ALI).Rats were exposed to >95% O2 (hyperoxia) or treated with intratracheal lipopolysaccharide (LPS), with first endpoints obtained 24 h later. HMPAO was administered intravenously before and after treatment with the glutathione-depleting agent diethyl maleate (DEM), scintigraphy images were acquired, and HMPAO lung uptake was quantified from the images. We also measured breathing rates, heart rates, oxygen saturation, bronchoalveolar lavage (BAL) cell counts and protein, lung homogenate glutathione (GSH) content, and pulmonary vascular endothelial filtration coefficient (Kf).For hyperoxia rats, HMPAO lung uptake increased after 24 h (134%) and 48 h (172%) of exposure. For LPS-treated rats, HMPAO lung uptake increased (188%) 24 h after injury and fell with resolution of injury. DEM reduced HMPAO uptake in hyperoxia and LPS rats by a greater fraction than in normoxia rats. Both hyperoxia exposure (18%) and LPS treatment (26%) increased lung homogenate GSH content, which correlated strongly with HMPAO uptake. Neither of the treatments had an effect on Kf at 24 h. LPS-treated rats appeared healthy but exhibited mild tachypnea, BAL, and histological evidence of inflammation, and increased wet and dry lung weights. These results suggest the potential utility of HMPAO as a tool for detecting ALI at a phase likely to exhibit minimal clinical evidence of injury.

Vasculature surrounding a nodule: A novel lung cancer biomarker.

PubMed

Wang, Xiaohua; Leader, Joseph K; Wang, Renwei; Wilson, David; Herman, James; Yuan, Jian-Min; Pu, Jiantao

2017-12-01

To investigate whether the vessels surrounding a nodule depicted on non-contrast, low-dose computed tomography (LDCT) can discriminate benign and malignant screen detected nodules. We collected a dataset consisting of LDCT scans acquired on 100 subjects from the Pittsburgh Lung Screening study (PLuSS). Fifty subjects were diagnosed with lung cancer and 50 subjects had suspicious nodules later proven benign. For the lung cancer cases, the location of the malignant nodule in the LDCT scans was known; while for the benign cases, the largest nodule in the LDCT scan was used in the analysis. A computer algorithm was developed to identify surrounding vessels and quantify the number and volume of vessels that were connected or near the nodule. A nonparametric receiver operating characteristic (ROC) analysis was performed based on a single nodule per subject to assess the discriminability of the surrounding vessels to provide a lung cancer diagnosis. Odds ratio (OR) were computed to determine the probability of a nodule being lung cancer based on the vessel features. The areas under the ROC curves (AUCs) for vessel count and vessel volume were 0.722 (95% CI=0.616-0.811, p<0.01) and 0.676 (95% CI=0.565-0.772), respectively. The number of vessels attached to a nodule was significantly higher in the lung cancer group 9.7 (±9.6) compared to the non-lung cancer group 4.0 (±4.3) CONCLUSION: Our preliminary results showed that malignant nodules are often surrounded by more vessels compared to benign nodules, suggesting that the surrounding vessel characteristics could serve as lung cancer biomarker for indeterminate nodules detected during LDCT lung cancer screening using only the information collected during the initial visit. Copyright © 2017 Elsevier B.V. All rights reserved.

Platelet Vascular Endothelial Growth Factor is a Potential Mediator of Transfusion-Related Acute Lung Injury.

PubMed

Maloney, James P; Ambruso, Daniel R; Voelkel, Norbert F; Silliman, Christopher C

The occurrence of non-hemolytic transfusion reactions is highest with platelet and plasma administration. Some of these reactions are characterized by endothelial leak, especially transfusion related acute lung injury (TRALI). Elevated concentrations of inflammatory mediators secreted by contaminating leukocytes during blood product storage may contribute to such reactions, but platelet-secreted mediators may also contribute. We hypothesized that platelet storage leads to accumulation of the endothelial permeability mediator vascular endothelial growth factor (VEGF), and that intravascular administration of exogenous VEGF leads to extensive binding to its lung receptors. Single donor, leukocyte-reduced apheresis platelet units were sampled over 5 days of storage. VEGF protein content of the centrifuged supernatant was determined by ELISA, and the potential contribution of VEGF from contaminating leukocytes was quantified. Isolated-perfused rat lungs were used to study the uptake of radiolabeled VEGF administered intravascularly, and the effect of unlabeled VEGF on lung leak. There was a time-dependent release of VEGF into the plasma fraction of the platelet concentrates (62 ± 9 pg/ml on day one, 149 ± 23 pg/ml on day 5; mean ± SEM, p<0.01, n=8) and a contribution by contaminating leukocytes was excluded. Exogenous 125I-VEGF bound avidly and specifically to the lung vasculature, and unlabeled VEGF in the lung perfusate caused vascular leak. Rising concentrations of VEGF occur during storage of single donor platelet concentrates due to platelet secretion or disintegration, but not due to leukocyte contamination. Exogenous VEGF at these concentrations rapidly binds to its receptors in the lung vessels. At higher VEGF concentrations, VEGF causes vascular leak in uninjured lungs. These data provide further evidence that VEGF may contribute to the increased lung permeability seen in TRALI associated with platelet products.

Developmental expression of Toll‑like receptors in the guinea pig lung.

PubMed

Ma, Lingjie; Yang, Jiali; Yang, Li; Shi, Juan; Xue, Jing; Li, Yong; Liu, Xiaoming

2017-03-01

The guinea pig is a useful model for investigating infectious and non‑infectious lung diseases due to the sensitivity of its respiratory system and susceptibility to infectious agents. Toll‑like receptors (TLRs) are important components of the innate immune response and are critical for lung immune function. In the present study, the differentiation of epithelial cells in the guinea pig lung was examined during gestation by studying anatomic morphology and the major epithelial cell types using cell type‑specific markers. The developmental expression of all 9 TLRs and the TLR signaling adaptors myeloid differentiation factor 88 (MyD88) and tumor necrosis factor receptor associated factor 6 (TRAF‑6) were investigated by reverse transcription‑quantitative polymerase chain reaction and western blotting analysis. The formation of lung lobes in guinea pigs was observed at 45 days of gestation (dGA), along with the expression of the basal cell marker keratin 14 and the alveolar type II cell marker pro‑surfactant protein. However, the cube cell marker secretoglobin family1A member 1 and ciliated cell marker b‑tubulin IV were only detected in the lungs from 52 dGA onward. The expression levels of all TLRs, MyD88 and TRAF‑6 were determined in lung tissues harvested from embryos, newborn, postnatal and adult animals. The expression levels of all TLR signaling components displayed similar dynamic expression patterns with gestation age and postnatal maturation time, except for TLR‑4 and TLR‑7. mRNA expression levels of TLR components were significantly increased in the lungs at 45 and 52 dGA, compared with later developmental stages. These results suggest that TLR expression in the guinea pig lung is developmentally regulated, enhancing the understanding of lung biology in guinea pig models.

Fibulin-1 functions as a prognostic factor in lung adenocarcinoma.

PubMed

Cui, Yuan; Liu, Jian; Yin, Hai-Bing; Liu, Yi-Fei; Liu, Jun-Hua

2015-09-01

Fibulin-1 is a member of the fibulin gene family, characterized by tandem arrays of epidermal growth factor-like domains and a C-terminal fibulin-type module. Fibulin-1 plays important roles in a range of cellular functions including morphology, growth, adhesion and mobility. It acts as a tumor suppressor gene in cutaneous melanoma, prostate cancer and gastric cancer. However, whether fibulin-1 also acts as a tumor suppressor gene in lung adenocarcinoma remains unknown. We also determined the association of fibulin-1 expression with various clinical and pathological parameters, which would show its potential role in clinical prognosis. We investigated and followed up 140 lung adenocarcinoma patients who underwent lung resection without pre- and post-operative systemic chemotherapy at the Affiliated Hospital of Nantong University from 2009 to 2013. Western blot assay and immunohistochemistry were used to evaluate the expression of fibulin-1 in lung adenocarcinoma tissues. We then analyzed the correlations between fibulin-1 expression and clinicopathological variables as well as the patients' overall survival rate. Both western blot assay and immunohistochemistry demonstrated that the level of fibulin-1 was downregulated in human lung adenocarcinoma tissues compared with that of normal lung tissues. Fibulin-1 expression significantly correlated with histological differentiation (P = 0.046), clinical stage (P< 0.01), lymph node status (P = 0.038) and expression of Ki-67 (P = 0.013). More importantly, multivariate analysis revealed that fibulin-1 was an independent prognostic marker for lung adenocarcinoma, and high expression of fibulin-1 was significantly associated with better prognosis of lung adenocarcinoma patients. The results supported our hypothesis that fibulin-1 can act as a prognostic factor in lung adenocarcinoma progression. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Quantification and visualization of relative local ventilation on dynamic chest radiographs

NASA Astrophysics Data System (ADS)

Tanaka, Rie; Sanada, Shigeru; Okazaki, Nobuo; Kobayashi, Takeshi; Nakayama, Kazuya; Matsui, Takeshi; Hayashi, Norio; Matsui, Osamu

2006-03-01

Recently-developed dynamic flat-panel detector (FPD) with a large field of view is possible to obtain breathing chest radiographs, which provide respiratory kinetics information. This study was performed to investigate the ability of dynamic chest radiography using FPD to quantify relative ventilation according to respiratory physiology. We also reported the results of primary clinical study and described the possibility of clinical use of our method. Dynamic chest radiographs of 12 subjects involving abnormal subjects during respiration were obtained using a modified FPD system (30 frames in 10 seconds). Imaging was performed in three different positions (standing, and right and left decubitus positions) to change the distribution of local ventilation by changing the lung's own gravity in each area. The distance from the lung apex to the diaphragm (abbr. DLD) was measured by the edge detection technique for use as an index of respiratory phase. We measured pixel values in each lung area and calculated correlation coefficients with DLD. Differences in the pixel values between the maximum inspiratory and expiratory frame were calculated, and the trend of distribution was evaluated by two-way analysis of variance. Pixel value in each lung area was strongly associated with respiratory phase and its time variation and distribution were consistent with known properties in respiratory physiology. Dynamic chest radiography using FPD combined with our computerized methods was capable of quantifying relative amount of ventilation during respiration, and of detecting regional differences in ventilation. In the subjects with emphysema, areas with decreased respiratory changes in pixel value are consisted with the areas with air trapping. This method is expected to be a useful novel diagnostic imaging method for supporting diagnosis and follow-up of pulmonary disease, which presents with abnormalities in local ventilation.

Technical Note: Phantom study to evaluate the dose and image quality effects of a computed tomography organ-based tube current modulation technique

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gandhi, Diksha; Schmidt, Taly Gilat, E-mail: taly.gilat-schmidt@marquette.edu; Crotty, Dominic J.

Purpose: This technical note quantifies the dose and image quality performance of a clinically available organ-dose-based tube current modulation (ODM) technique, using experimental and simulation phantom studies. The investigated ODM implementation reduces the tube current for the anterior source positions, without increasing current for posterior positions, although such an approach was also evaluated for comparison. Methods: Axial CT scans at 120 kV were performed on head and chest phantoms on an ODM-equipped scanner (Optima CT660, GE Healthcare, Chalfont St. Giles, England). Dosimeters quantified dose to breast, lung, heart, spine, eye lens, and brain regions for ODM and 3D-modulation (SmartmA) settings.more » Monte Carlo simulations, validated with experimental data, were performed on 28 voxelized head phantoms and 10 chest phantoms to quantify organ dose and noise standard deviation. The dose and noise effects of increasing the posterior tube current were also investigated. Results: ODM reduced the dose for all experimental dosimeters with respect to SmartmA, with average dose reductions across dosimeters of 31% (breast), 21% (lung), 24% (heart), 6% (spine), 19% (eye lens), and 11% (brain), with similar results for the simulation validation study. In the phantom library study, the average dose reduction across all phantoms was 34% (breast), 20% (lung), 8% (spine), 20% (eye lens), and 8% (brain). ODM increased the noise standard deviation in reconstructed images by 6%–20%, with generally greater noise increases in anterior regions. Increasing the posterior tube current provided similar dose reduction as ODM for breast and eye lens, increased dose to the spine, with noise effects ranging from 2% noise reduction to 16% noise increase. At noise equal to SmartmA, ODM increased the estimated effective dose by 4% and 8% for chest and head scans, respectively. Increasing the posterior tube current further increased the effective dose by 15% (chest) and 18% (head) relative to SmartmA. Conclusions: ODM reduced dose in all experimental and simulation studies over a range of phantoms, while increasing noise. The results suggest a net dose/noise benefit for breast and eye lens for all studied phantoms, negligible lung dose effects for two phantoms, increased lung dose and/or noise for eight phantoms, and increased dose and/or noise for brain and spine for all studied phantoms compared to the reference protocol.« less

Does the Consumption of Green Tea Reduce the Risk of Lung Cancer Among Smokers?

PubMed Central

Liang, Wenbin; Binns, Colin W.; Jian, Le

2007-01-01

Experimental and epidemiological studies were reviewed to assess whether the consumption of green tea could reduce the risk of lung cancer in smokers. Articles published since 1990 were located by searching electronic databases PubMed, Ovid and Science Direct, using keywords ‘lung cancer’, ‘tea’ and ‘smoking’ without any restriction on language. After relevant articles had been located, further papers were obtained from their reference lists. Evidence from experimental studies (in vitro animal and human trials) suggested that regular intake of green tea may be protective against tobacco carcinogens. However, the mechanism behind the protective effect is only partly understood. In most of the epidemiological studies reviewed, the green tea exposure was within 5 years of the interview or follow-up, which would coincide with the induction period and latent period of lung cancer. Longer term studies are thus needed to further quantify the cancer risk. There is some evidence suggesting regular intake of green tea at high level (>3 cups per day) may reduce the risk of smokers developing lung cancer. Improvement in measuring green tea intake is required in order to confirm the evidence from epidemiological studies. PMID:17342237

X-Ray based Lung Function measurement-a sensitive technique to quantify lung function in allergic airway inflammation mouse models

NASA Astrophysics Data System (ADS)

Dullin, C.; Markus, M. A.; Larsson, E.; Tromba, G.; Hülsmann, S.; Alves, F.

2016-11-01

In mice, along with the assessment of eosinophils, lung function measurements, most commonly carried out by plethysmography, are essential to monitor the course of allergic airway inflammation, to examine therapy efficacy and to correlate animal with patient data. To date, plethysmography techniques either use intubation and/or restraining of the mice and are thus invasive, or are limited in their sensitivity. We present a novel unrestrained lung function method based on low-dose planar cinematic x-ray imaging (X-Ray Lung Function, XLF) and demonstrate its performance in monitoring OVA induced experimental allergic airway inflammation in mice and an improved assessment of the efficacy of the common treatment dexamethasone. We further show that XLF is more sensitive than unrestrained whole body plethysmography (UWBP) and that conventional broncho-alveolar lavage and histology provide only limited information of the efficacy of a treatment when compared to XLF. Our results highlight the fact that a multi-parametric imaging approach as delivered by XLF is needed to address the combined cellular, anatomical and functional effects that occur during the course of asthma and in response to therapy.

Glycoproteomic analysis of bronchoalveolar lavage (BAL) fluid identifies tumor-associated glycoproteins from lung adenocarcinoma.

PubMed

Li, Qing Kay; Shah, Punit; Li, Yan; Aiyetan, Paul O; Chen, Jing; Yung, Rex; Molena, Daniela; Gabrielson, Edward; Askin, Frederic; Chan, Daniel W; Zhang, Hui

2013-08-02

Cytological examination of cells from bronchoalveolar lavage (BAL) is commonly used for the diagnosis of lung cancer. Proteins released from lung cancer cells into BAL may serve as biomarkers for cancer detection. In this study, N-glycoproteins in eight cases of BAL fluid, as well as eight lung adenocarcinoma tissues and eight tumor-matched normal lung tissues, were analyzed using the solid-phase extraction of N-glycoprotein (SPEG), iTRAQ labeling, and liquid chromatography tandem mass spectrometry (LC-MS/MS). Of 80 glycoproteins found in BAL specimens, 32 were identified in both cancer BAL and cancer tissues, with levels of 25 glycoproteins showing at least a 2-fold difference between cancer and benign BAL. Among them, eight glycoproteins showed greater than 2-fold elevations in cancer BAL, including Neutrophil elastase (NE), Integrin alpha-M, Cullin-4B, Napsin A, lysosome-associated membrane protein 2 (LAMP2), Cathepsin D, BPI fold-containing family B member 2, and Neutrophil gelatinase-associated lipocalin. The levels of Napsin A in cancer BAL were further verified in independently collected 39 BAL specimens using an ELISA assay. Our study demonstrates that potential protein biomarkers in BAL fluid can be detected and quantified.

Prognosis of phrenic nerve injury following thoracic interventions: four new cases and a review.

PubMed

Ostrowska, Monika; de Carvalho, Mamede

2012-04-01

Phrenic nerve lesion is a known complication of thoracic surgical intervention, but it is rarely described following thymectomy and lung surgery. To review the literature on thoracic intervention and phrenic nerve lesion and to describe four new cases, in which regular neurophysiological studies were performed. We reviewed the literature concerning phrenic nerve lesion after cardiac, lung and thymus surgical interventions. We described four cases of phrenic nerve lesion, three associated with thymectomy and one in lung surgery. The review shows that cryogenic or thermal injuries during cardiac surgeries are associated with good prognosis. The information on the outcome of phrenic nerve lesion in thymectomy or lung surgery is insufficient. Our cases and this review suggest that phrenic lesion in the last two interventions are associated with a poor recovery. Our data suggests that the prognosis of phrenic nerve lesion following thoracic intervention depends on the nature of the damage. Probably, in thymectomy and lung surgery, nerve stretch or laceration are involved, consequently the outcome is poorer in comparison with cardiac surgery, where cold lesion is more frequent. Neurophysiological tests give a direct, quantified and reliable assessment of nerve regeneration. Copyright © 2011 Elsevier B.V. All rights reserved.

A probabilistic model of emphysema based on granulometry analysis

NASA Astrophysics Data System (ADS)

Marcos, J. V.; Nava, R.; Cristobal, G.; Munoz-Barrutia, A.; Escalante-Ramírez, B.; Ortiz-de-Solórzano, C.

2013-11-01

Emphysema is associated with the destruction of lung parenchyma, resulting in abnormal enlargement of airspaces. Accurate quantification of emphysema is required for a better understanding of the disease as well as for the assessment of drugs and treatments. In the present study, a novel method for emphysema characterization from histological lung images is proposed. Elastase-induced mice were used to simulate the effect of emphysema on the lungs. A database composed of 50 normal and 50 emphysematous lung patches of size 512 x 512 pixels was used in our experiments. The purpose is to automatically identify those patches containing emphysematous tissue. The proposed approach is based on the use of granulometry analysis, which provides the pattern spectrum describing the distribution of airspaces in the lung region under evaluation. The profile of the spectrum was summarized by a set of statistical features. A logistic regression model was then used to estimate the probability for a patch to be emphysematous from this feature set. An accuracy of 87% was achieved by our method in the classification between normal and emphysematous samples. This result shows the utility of our granulometry-based method to quantify the lesions due to emphysema.

Type I collagen-targeted PET probe for pulmonary fibrosis detection and staging in preclinical models

PubMed Central

Désogère, Pauline; Tapias, Luis F.; Hariri, Lida P.; Rotile, Nicholas J.; Rietz, Tyson A.; Probst, Clemens K.; Blasi, Francesco; Day, Helen; Mino-Kenudson, Mari; Weinreb, Paul; Violette, Shelia M.; Fuchs, Bryan C.; Tager, Andrew M.; Lanuti, Michael; Caravan, Peter

2017-01-01

Pulmonary fibrosis is a scarring of the lungs that can arise from radiation injury, drug toxicity, environmental or genetic causes, and for unknown reasons [idiopathic pulmonary fibrosis (IPF)]. Overexpression of collagen is a hallmark of organ fibrosis. Here, we describe a peptide-based PET probe (68Ga-CBP8) that targets collagen type I. We evaluated 68Ga-CBP8 in vivo in the bleomycin-induced mouse model of pulmonary fibrosis. 68Ga-CBP8 showed high specificity for pulmonary fibrosis and high target:background ratios in diseased animals. The lung PET signal and lung 68Ga-CBP8 uptake (quantified ex vivo) correlated linearly (r2=0.80) with the amount of lung collagen in mice with fibrosis. We further demonstrated that the 68Ga-CBP8 probe could be used to monitor response to treatment in a second mouse model of pulmonary fibrosis associated with vascular leak. Ex vivo analysis of lung tissue from patients with IPF supported the animal findings. These studies indicate that 68Ga-CBP8 is a promising candidate for non-invasive imaging of human pulmonary fibrosis. PMID:28381537

Noncalcified Lung Nodules: Volumetric Assessment with Thoracic CT

PubMed Central

Gavrielides, Marios A.; Kinnard, Lisa M.; Myers, Kyle J.; Petrick, Nicholas

2009-01-01

Lung nodule volumetry is used for nodule diagnosis, as well as for monitoring tumor response to therapy. Volume measurement precision and accuracy depend on a number of factors, including image-acquisition and reconstruction parameters, nodule characteristics, and the performance of algorithms for nodule segmentation and volume estimation. The purpose of this article is to provide a review of published studies relevant to the computed tomographic (CT) volumetric analysis of lung nodules. A number of underexamined areas of research regarding volumetric accuracy are identified, including the measurement of nonsolid nodules, the effects of pitch and section overlap, and the effect of respiratory motion. The need for public databases of phantom scans, as well as of clinical data, is discussed. The review points to the need for continued research to examine volumetric accuracy as a function of a multitude of interrelated variables involved in the assessment of lung nodules. Understanding and quantifying the sources of volumetric measurement error in the assessment of lung nodules with CT would be a first step toward the development of methods to minimize that error through system improvements and to correctly account for any remaining error. © RSNA, 2009 PMID:19332844

Chitosan-folate decorated carbon nanotubes for site specific lung cancer delivery.

PubMed

Singh, Rahul Pratap; Sharma, Gunjan; Sonali; Singh, Sanjay; Bharti, Shreekant; Pandey, Bajarangprasad L; Koch, Biplob; Muthu, Madaswamy S

2017-08-01

The aim of this work was to formulate chitosan-folate conjugated multi-walled carbon nanotubes for the lung cancer targeted delivery of docetaxel. The chitosan-folate conjugate was synthesized and the conjugation was confirmed by Fourier transform infrared spectroscopy. The multi-walled carbon nanotubes were characterized for their particle size, polydispersity, zeta potential, surface morphology, drug encapsulation efficiency and in vitro release study. The in vitro cellular uptake, cytotoxicity, and cell cycle analysis of the docetaxel/coumarin-6 loaded multi-walled carbon nanotubes were carried out to compare the effectiveness of the formulations. The biocompatibility and safety of chitosan-folate conjugated multi-walled carbon nanotubes was analyzed by lung histopathology in comparison with marketed docetaxel formulation (Docel™) and acylated multi-walled carbon nanotubes. The cellular internalization study shown that the chitosan-folate conjugated multi-walled carbon nanotubes could be easily internalized into the lung cancer cells through a folate receptor-mediated endocytic pathway. The IC 50 values exhibited that chitosan-folate conjugated multi-walled carbon nanotubes could be 89-fold more effective than Docel™ in human lung cancer cells (A549 cells). Copyright © 2017 Elsevier B.V. All rights reserved.

Elderly male smokers with right lung tumors are viable candidates for KRAS mutation screening.

PubMed

Yang, Yang; Shi, Chun; Sun, Hui; Yin, Wei; Zhou, Xiao; Zhang, Lei; Jiang, Gening

2016-01-07

Genetic aberrations in tumor driver genes provide specific molecular targets for therapeutic intervention, which can greatly improve therapeutic outcomes. Here, we analyzed the mutational frequency of EGFR and KRAS gene, as well as EML4-ALK rearrangement, and summarized the clinicopathological characters of Chinese lung cancer patients. We detected the mutation spectrum of 1033 primary lung cancer patients. The analyzed clinicopathological parameters included gender, age at diagnosis, smoking status, pathological TNM stage, tumor morphology and location, visceral pleural invasion, and histological type. A total of 618 patients had mutations in EGFR or KRAS gene as well as rearrangement of EML4-ALK. Exon 19 deletions and L858R in the EGFR gene were the most frequent mutations. Left-side lung cancer was more common in female patients carrying the KRAS mutation. Rearrangement of EML4-ALK was more common in non-tobacco-using male patients, who also exhibited a higher likelihood of visceral pleura invasion. Elderly females who never smoked and possessed 1-20 mm stage I adenocarcinomas in the right side exhibited a higher frequency of EGFR mutations. Elderly male smokers with right lung tumors were viable candidates for KRAS mutation screening.

Spontaneous Epithelioid Hemangiosarcoma in a Rhesus Monkey (Macaca mulatta)

PubMed Central

Tsuchiya, Takayuki; Gray, Tasha L; Gatto, Nicholas T; Forest, Thomas; Machotka, Sam V; Troth, Sean P; Prahalada, Srinivasa

2014-01-01

Epithelioid hemangiosarcoma is a rare malignant endothelial neoplasia with a unique, predominantly epithelioid morphology. A 4-y-old rhesus monkey from our laboratory had multiple neoplastic nodules in a digit, limb skin, hindlimb muscle, and visceral organs including lung, heart, and brain. The nodules were composed of pleomorphic, polygonal, epithelioid, neoplastic cells that were arranged in sheets, nests, and cords and supported by variably dense fibrovascular connective tissue. The morphologic features of this tumor were predominantly epithelioid. However, some regions contained cystic spaces, clefts, and channel-like structures, all of which were lined with morphologically distinct neoplastic endothelial cells. These neoplastic cells, with or without epithelioid morphology, were positive immunohistochemically for CD31, factor VIII-related antigen, and vimentin. The presence of multiple metastatic nodules, high mitotic rate, and extensive Ki67-positive staining were consistent with malignancy. This report is the first description of epithelioid hemangiosarcoma in a rhesus monkey. PMID:25296017

Spontaneous epithelioid hemangiosarcoma in a rhesus monkey (Macaca mulatta).

PubMed

Tsuchiya, Takayuki; Gray, Tasha L; Gatto, Nicholas T; Forest, Thomas; Machotka, Sam V; Troth, Sean P; Prahalada, Srinivasa

2014-08-01

Epithelioid hemangiosarcoma is a rare malignant endothelial neoplasia with a unique, predominantly epithelioid morphology. A 4-y-old rhesus monkey from our laboratory had multiple neoplastic nodules in a digit, limb skin, hindlimb muscle, and visceral organs including lung, heart, and brain. The nodules were composed of pleomorphic, polygonal, epithelioid, neoplastic cells that were arranged in sheets, nests, and cords and supported by variably dense fibrovascular connective tissue. The morphologic features of this tumor were predominantly epithelioid. However, some regions contained cystic spaces, clefts, and channel-like structures, all of which were lined with morphologically distinct neoplastic endothelial cells. These neoplastic cells, with or without epithelioid morphology, were positive immunohistochemically for CD31, factor VIII-related antigen, and vimentin. The presence of multiple metastatic nodules, high mitotic rate, and extensive Ki67-positive staining were consistent with malignancy. This report is the first description of epithelioid hemangiosarcoma in a rhesus monkey.

Nuclear markers reveal that inter-lake cichlids' similar morphologies do not reflect similar genealogy.

PubMed

Kassam, Daud; Seki, Shingo; Horic, Michio; Yamaoka, Kosaku

2006-08-01

The apparent inter-lake morphological similarity among East African Great Lakes' cichlid species/genera has left evolutionary biologists asking whether such similarity is due to sharing of common ancestor or mere convergent evolution. In order to answer such question, we first used Geometric Morphometrics, GM, to quantify morphological similarity and then subsequently used Amplified Fragment Length Polymorphism, AFLP, to determine if similar morphologies imply shared ancestry or convergent evolution. GM revealed that not all presumed morphological similar pairs were indeed similar, and the dendrogram generated from AFLP data indicated distinct clusters corresponding to each lake and not inter-lake morphological similar pairs. Such results imply that the morphological similarity is due to convergent evolution and not shared ancestry. The congruency of GM and AFLP generated dendrograms imply that GM is capable of picking up phylogenetic signal, and thus GM can be potential tool in phylogenetic systematics.

A morphology independent methodology for quantifying planview river change and characteristics from remotely sensed imagery

DOE PAGES

Rowland, Joel C.; Shelef, Eitan; Pope, Paul A.; ...

2016-07-15

Remotely sensed imagery of rivers has long served as a means for characterizing channel properties and detection of planview change. In the last decade the dramatic increase in the availability of satellite imagery and processing tools has created the potential to greatly expand the spatial and temporal scale of our understanding of river morphology and dynamics. To date, the majority of GIS and automated analyses of planview changes in rivers from remotely sensed data has been developed for single-threaded meandering river systems. These methods have limited applicability to many of the earth's rivers with complex multi-channel planforms. Here we presentmore » the methodologies of a set of analysis algorithms collectively called Spatially Continuous Riverbank Erosion and Accretion Measurements (SCREAM). SCREAM analyzes planview river metrics regardless of river morphology. These algorithms quantify both the erosion and accretion rates of riverbanks from binary masks of channels generated from imagery acquired at two time periods. Additionally, the program quantifies the area of change between river channels and the surrounding floodplain and area of islands lost or formed between these two time periods. To examine variations in erosion rates in relation to local channel attributes and make rate comparisons between river systems of varying sizes, the program determines channel widths and bank curvature at every bank pixel. SCREAM was developed and tested on rivers with diverse and complex planform morphologies in imagery acquired from a range of observational platforms with varying spatial resolutions. Here, validation and verification of SCREAM-generated metrics against manual measurements show no significant measurement errors in determination of channel width, erosion, and bank aspects. SCREAM has the potential to provide data for both the quantitative examination of the controls on erosion rates and for the comparison of these rates across river systems ranging broadly in size and planform morphology.« less

Morphological transformation of soot: investigation of microphysical processes during the condensation of sulphuric acid and limonene ozonolysis products vapours

NASA Astrophysics Data System (ADS)

Pathak, R. K. P.; Pei, X.; Hallquist, M.; Pagels, J. H.

2017-12-01

Morphological transformation of soot particle by condensation of low volatility materials on it is a dominant atmospheric process with serious implications for its optical and hygroscopic properties, and atmospheric lifetime. In this study, the morphological transformation of soot agglomerate under the influence of condensation of vapours of sulphuric acid, and/or limonene ozonolysis products were investigated systematically using a Differential Mobility Analyser-Aerosol Particle Mass Analyser (DMA-APM) and the Tandem DMA techniques integrated with a laminar flow-tube system. We discovered that the morphology transformation of soot in general was a sequence of two-step process, i.e. (i) filling of void space within soot agglomerate; (ii) growth of particle diameter. These two steps followed and complimented each other. In the very beginning the filling was the dominant process followed by growth until it led to the accumulation of enough material that in turn exerted surface forces that eventually facilitated the further filling. The filling of void space was constrained by the initial morphology of fresh soot and the nature and amount of the material condensed. This process continued in several sequential steps until all void space within the soot agglomerate was filled completely and then growth of a spherical particle continued as long as mass was condensed on it. In this study, we developed a framework to quantify the microphysical transformation of soot upon the condensation of various materials. The framework utilized experimental data and hypothesis of ideal sphere growth and filling of voids to quantify the distribution of condensed materials in these two processes complimenting each other. Using this framework, we have quantified the percentage of material that went into processes of particle growth and void filling at each step. Using the same framework, we further estimated the fraction of internal voids and open voids and used this information to derive the volume equivalent diameter of soot agglomerate containing internal voids and calculated in-situ dynamic shape factor. Our study is the first study that tracks in situ microphysical changes in soot morphology quantitatively, providing the detailed status of both fresh and coated soot particles.

Recognition of Pneumocystis carinii by gram stain in impression smears of lung tissue.

PubMed Central

Felegie, T P; Pasculle, A W; Dekker, A

1984-01-01

In 12 of 20 (60%) biopsy-proven cases of Pneumocystis carinii pneumonia, the diagnosis was first suggested by examination of routine Gram stains of impression smears made from infected lung tissue and later confirmed by methenamine-silver staining. The cysts appeared as 5- to 7-microns unstained spheres, each containing six to eight intracystic gram-negative bodies (sporozoites). Although the Gram stain does not appear to be as sensitive as more traditional staining techniques for the detection of P. carinii, clinical microbiologists should be aware of the morphology of this organism in gram-stained specimens because this relatively simple procedure gives quick results. Images PMID:6084017

Quantifying temporal bone morphology of great apes and humans: an approach using geometric morphometrics.

PubMed

Lockwood, Charles A; Lynch, John M; Kimbel, William H

2002-12-01

The hominid temporal bone offers a complex array of morphology that is linked to several different functional systems. Its frequent preservation in the fossil record gives the temporal bone added significance in the study of human evolution, but its morphology has proven difficult to quantify. In this study we use techniques of 3D geometric morphometrics to quantify differences among humans and great apes and discuss the results in a phylogenetic context. Twenty-three landmarks on the ectocranial surface of the temporal bone provide a high level of anatomical detail. Generalized Procrustes analysis (GPA) is used to register (adjust for position, orientation and scale) landmark data from 405 adults representing Homo, Pan, Gorilla and Pongo. Principal components analysis of residuals from the GPA shows that the major source of variation is between humans and apes. Human characteristics such as a coronally orientated petrous axis, a deep mandibular fossa, a projecting mastoid process, and reduced lateral extension of the tympanic element strongly impact the analysis. In phenetic cluster analyses, gorillas and orangutans group together with respect to chimpanzees, and all apes group together with respect to humans. Thus, the analysis contradicts depictions of African apes as a single morphotype. Gorillas and orangutans lack the extensive preglenoid surface of chimpanzees, and their mastoid processes are less medially inflected. These and other characters shared by gorillas and orangutans are probably primitive for the African hominid clade.

Burden of lung cancer attributable to occupational diesel engine exhaust exposure in Canada.

PubMed

Kim, Joanne; Peters, Cheryl E; Arrandale, Victoria H; Labrèche, France; Ge, Calvin B; McLeod, Christopher B; Song, Chaojie; Lavoué, Jérôme; Davies, Hugh W; Nicol, Anne-Marie; Pahwa, Manisha; Demers, Paul A

2018-04-28

To estimate the population attributable fraction (PAF) and number of incident and fatal lung cancers in Canada from occupational exposure to diesel engine exhaust (DEE). DEE exposure prevalence and level estimates were used with Canadian Census and Labour Force Survey data to model the exposed population across the risk exposure period (REP, 1961-2001). Relative risks of lung cancer were calculated based on a meta-regression selected from the literature. PAFs were calculated using Levin's equation and applied to the 2011 lung cancer statistics obtained from the Canadian Cancer Registry. We estimated that 2.4% (95% CI 1.6% to 6.6%) of lung cancers in Canada are attributable to occupational DEE exposure, corresponding to approximately 560 (95% CI 380 to 1570) incident and 460 (95% CI 310 to 1270) fatal lung cancers in 2011. Overall, 1.6 million individuals alive in 2011 were occupationally exposed to DEE during the REP, 97% of whom were male. Occupations with the highest burden were underground miners, truck drivers and mechanics. Half of the attributable lung cancers occurred among workers with low exposure. This is the first study to quantify the burden of lung cancer attributable to occupational DEE exposure in Canada. Our results underscore a large potential for prevention, and a large public health impact from occupational exposure to low levels of DEE. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Lung cancer prevalence associated with radon exposure in Norwegian homes.

PubMed

Hassfjell, Christina Søyland; Grimsrud, Tom Kristian; Standring, William J F; Tretli, Steinar

2017-08-22

Radioactive radon gas is generated from uranium and thorium in underlying rocks and seeps into buildings. The gas and its decay products emit carcinogenic radiation and are regarded as the second most important risk factor for lung cancer after active tobacco smoking. The average radon concentration in Norwegian homes is higher than in most other Western countries. From a health and cost perspective, it is important to be able to quantify the risk of lung cancer posed by radon exposure. We estimated the radon-related risk of lung cancer in Norway based on risk estimates from the largest pooled analysis of European case-control studies, combined with the hitherto largest set of data on radon concentration measurements in Norwegian homes. Based on these estimates, we calculate that radon is a contributory factor in 12 % of all cases of lung cancer annually, assuming an average radon concentration of 88 Bq/m3 in Norwegian homes. For 2015, this accounted for 373 cases of lung cancer, with an approximate 95 % confidence interval of 145 – 682. Radon most likely contributes to a considerable number of cases of lung cancer. Since most cases of radon-associated lung cancer involve smokers or former smokers, a reduction of the radon concentration in homes could be a key measure to reduce the risk, especially for persons who are unable to quit smoking. The uncertainty in the estimated number of radon-associated cases can be reduced through a new national radon mapping study with an improved design.

H-1 Nuclear Magnetic Resonance Metabolomics Analysis Identifies Novel Urinary Biomarkers for Lung Function

DOE Office of Scientific and Technical Information (OSTI.GOV)

MCClay, Joseph L.; Adkins, Daniel E.; Isern, Nancy G.

2010-06-04

Chronic obstructive pulmonary disease (COPD), characterized by chronic airflow limitation, is a serious and growing public health concern. The major environmental risk factor for COPD is tobacco smoking, but the biological mechanisms underlying COPD are not well understood. In this study, we used proton nuclear magnetic resonance (1H-NMR) spectroscopy to identify and quantify metabolites associated with lung function in COPD. Plasma and urine were collected from 197 adults with COPD and from 195 adults without COPD. Samples were assayed using a 600 MHz NMR spectrometer, and the resulting spectra were analyzed against quantitative spirometric measures of lung function. After correctingmore » for false discoveries and adjusting for covariates (sex, age, smoking) several spectral regions in urine were found to be significantly associated with baseline lung function. These regions correspond to the metabolites trigonelline, hippurate and formate. Concentrations of each metabolite, standardized to urinary creatinine, were associated with baseline lung function (minimum p-value = 0.0002 for trigonelline). No significant associations were found with plasma metabolites. Two of the three urinary metabolites positively associated with baseline lung function, i.e. hippurate and formate, are often related to gut microflora. This suggests that the microbiome composition is variable between individuals with different lung function. Alternatively, the nature and origins of all three associated metabolites may reflect lifestyle differences affecting overall health. Our results will require replication and validation, but demonstrate the utility of NMR metabolomics as a screening tool for identifying novel biomarkers of lung disease or disease risk.« less

Chloride transport-driven alveolar fluid secretion is a major contributor to cardiogenic lung edema

PubMed Central

Solymosi, Esther A.; Kaestle-Gembardt, Stefanie M.; Vadász, István; Wang, Liming; Neye, Nils; Chupin, Cécile Julie Adrienne; Rozowsky, Simon; Ruehl, Ramona; Tabuchi, Arata; Schulz, Holger; Kapus, Andras; Morty, Rory E.; Kuebler, Wolfgang M.

2013-01-01

Alveolar fluid clearance driven by active epithelial Na+ and secondary Cl− absorption counteracts edema formation in the intact lung. Recently, we showed that impairment of alveolar fluid clearance because of inhibition of epithelial Na+ channels (ENaCs) promotes cardiogenic lung edema. Concomitantly, we observed a reversal of alveolar fluid clearance, suggesting that reversed transepithelial ion transport may promote lung edema by driving active alveolar fluid secretion. We, therefore, hypothesized that alveolar ion and fluid secretion may constitute a pathomechanism in lung edema and aimed to identify underlying molecular pathways. In isolated perfused lungs, alveolar fluid clearance and secretion were determined by a double-indicator dilution technique. Transepithelial Cl− secretion and alveolar Cl− influx were quantified by radionuclide tracing and alveolar Cl− imaging, respectively. Elevated hydrostatic pressure induced ouabain-sensitive alveolar fluid secretion that coincided with transepithelial Cl− secretion and alveolar Cl− influx. Inhibition of either cystic fibrosis transmembrane conductance regulator (CFTR) or Na+-K+-Cl− cotransporters (NKCC) blocked alveolar fluid secretion, and lungs of CFTR−/− mice were protected from hydrostatic edema. Inhibition of ENaC by amiloride reproduced alveolar fluid and Cl− secretion that were again CFTR-, NKCC-, and Na+-K+-ATPase–dependent. Our findings show a reversal of transepithelial Cl− and fluid flux from absorptive to secretory mode at hydrostatic stress. Alveolar Cl− and fluid secretion are triggered by ENaC inhibition and mediated by NKCC and CFTR. Our results characterize an innovative mechanism of cardiogenic edema formation and identify NKCC1 as a unique therapeutic target in cardiogenic lung edema. PMID:23645634

Hypoxic pulmonary vasoconstriction in reptiles: a comparative study of four species with different lung structures and pulmonary blood pressures.

PubMed

Skovgaard, Nini; Abe, Augusto S; Andrade, Denis V; Wang, Tobias

2005-11-01

Low O2 levels in the lungs of birds and mammals cause constriction of the pulmonary vasculature that elevates resistance to pulmonary blood flow and increases pulmonary blood pressure. This hypoxic pulmonary vasoconstriction (HPV) diverts pulmonary blood flow from poorly ventilated and hypoxic areas of the lung to more well-ventilated parts and is considered important for the local matching of ventilation to blood perfusion. In the present study, the effects of acute hypoxia on pulmonary and systemic blood flows and pressures were measured in four species of anesthetized reptiles with diverse lung structures and heart morphologies: varanid lizards (Varanus exanthematicus), caimans (Caiman latirostris), rattlesnakes (Crotalus durissus), and tegu lizards (Tupinambis merianae). As previously shown in turtles, hypoxia causes a reversible constriction of the pulmonary vasculature in varanids and caimans, decreasing pulmonary vascular conductance by 37 and 31%, respectively. These three species possess complex multicameral lungs, and it is likely that HPV would aid to secure ventilation-perfusion homogeneity. There was no HPV in rattlesnakes, which have structurally simple lungs where local ventilation-perfusion inhomogeneities are less likely to occur. However, tegu lizards, which also have simple unicameral lungs, did exhibit HPV, decreasing pulmonary vascular conductance by 32%, albeit at a lower threshold than varanids and caimans (6.2 kPa oxygen in inspired air vs. 8.2 and 13.9 kPa, respectively). Although these observations suggest that HPV is more pronounced in species with complex lungs and functionally divided hearts, it is also clear that other components are involved.

Embryonic Wnt gene expression in the nitrofen-induced hypoplastic lung using 3-dimensional imaging.

PubMed

Takayasu, Hajime; Murphy, Paula; Sato, Hideaki; Doi, Takashi; Puri, Prem

2010-11-01

Wnts have been reported to play a key role in the lung morphogenesis. We have previously reported that pulmonary gene expression of Wnt2 and Wnt7b is downregulated on day 15 of gestation in the nitrofen-induced congenital diaphragmatic hernia (CDH) model. However, the distribution pattern of gene expression of Wnts in the very early lung development remains unclear. Optical projection tomography (OPT) is a new technique for 3-dimensional imaging of small developing organs and gene distribution combined with whole-mount in situ hybridization. We designed this study to investigate the distribution pattern of Wnts gene expression in lung buds of nitrofen-induced CDH model using OPT. Embryos from normal and nitrofen-treated dams were harvested on embryonic day 10 (E10), and divided into controls and nitrofen group, respectively. Whole-mount in situ hybridization to detect transcripts of Wnt2 and Wnt7b was performed, analyzed, and reconstructed using OPT. The expression of Wnt2 transcripts was detected in the lung bud mesenchyme and markedly diminished in nitrofen group compared to controls, whereas Wnt7b transcripts were expressed in the mesoderm of bronchi and the lung bud with no detectable difference between 2 groups. We provide evidence for the first time that Wnt2 expression is downregulated at lung bud stage in the nitrofen model. Optical projection tomography is potentially a useful approach to visualize both gene expression and morphology during very early stages of lung development. Copyright © 2010 Elsevier Inc. All rights reserved.

The 10 Pillars of Lung Cancer Screening: Rationale and Logistics of a Lung Cancer Screening Program.

PubMed

Fintelmann, Florian J; Bernheim, Adam; Digumarthy, Subba R; Lennes, Inga T; Kalra, Mannudeep K; Gilman, Matthew D; Sharma, Amita; Flores, Efren J; Muse, Victorine V; Shepard, Jo-Anne O

2015-01-01

On the basis of the National Lung Screening Trial data released in 2011, the U.S. Preventive Services Task Force made lung cancer screening (LCS) with low-dose computed tomography (CT) a public health recommendation in 2013. The Centers for Medicare and Medicaid Services (CMS) currently reimburse LCS for asymptomatic individuals aged 55-77 years who have a tobacco smoking history of at least 30 pack-years and who are either currently smoking or had quit less than 15 years earlier. Commercial insurers reimburse the cost of LCS for individuals aged 55-80 years with the same smoking history. Effective care for the millions of Americans who qualify for LCS requires an organized step-wise approach. The 10-pillar model reflects the elements required to support a successful LCS program: eligibility, education, examination ordering, image acquisition, image review, communication, referral network, quality improvement, reimbursement, and research frontiers. Examination ordering can be coupled with decision support to ensure that only eligible individuals undergo LCS. Communication of results revolves around the Lung Imaging Reporting and Data System (Lung-RADS) from the American College of Radiology. Lung-RADS is a structured decision-oriented reporting system designed to minimize the rate of false-positive screening examination results. With nodule size and morphology as discriminators, Lung-RADS links nodule management pathways to the variety of nodules present on LCS CT studies. Tracking of patient outcomes is facilitated by a CMS-approved national registry maintained by the American College of Radiology. Online supplemental material is available for this article. (©)RSNA, 2015.

Ischaemia-reperfusion injury in orthotopic mouse lung transplants – a scanning electron microscopy study

PubMed Central

Draenert, Alice; Marquardt, Klaus; Inci, Ilhan; Soltermann, Alex; Weder, Walter; Jungraithmayr, Wolfgang

2011-01-01

Lung ischaemia-reperfusion (I/R) injury remains a major cause of graft failure in lung transplantation (Tx). With the implementation of orthotopic lung Tx in mice, a physiological model on the base of a perfused and ventilated graft became available for the investigation of I/R injury. Using the scanning electron microscopy (SEM) technique, we here present an analysis of early and late morphological changes of pulmonary I/R injury. Syngeneic lungs were orthotopically transplanted between C57BL/6 mice. Grafts were exposed to 2 h of cold ischaemia. Transplants and right lungs were examined by SEM with corresponding haematoxylin–eosin histology 30 min and 4 h after reperfusion. Thirty minutes after reperfusion, the alveolar surface of transplants showed a discontinued lining of surfactant, while the lining of the non-transplanted lung was normal. Within the graft, leucocytes displayed an irregular surface with development of pseudopodia, and microvilli were detected on the membrane of pneumocytes. At 4 h after reperfusion, leucocytes significantly increased in numbers within the alveolar space. Also, the number of microvilli on pneumocytes increased significantly. Similar to these, the endothelium of vessels increasingly developed microvilli from 30 min towards 4 h after reperfusion. The airways of transplanted grafts showed mild changes with thickening of the bronchial epithelium and a destruction of kinocilia. Taken together, SEM detects pathological events of I/R that are previously not described in normal histology. These findings may influence the interpretation of studies investigating the I/R injury in the mouse model of lung Tx. PMID:21272104

Protein Expression Profile of Rat Type Two Alveolar Epithelial Cells During Hyperoxic Stress and Recovery

NASA Astrophysics Data System (ADS)

Bhargava, Maneesh

Rationale: In rodent model systems, the sequential changes in lung morphology resulting from hyperoxic injury are well characterized, and are similar to changes in human acute respiratory distress syndrome (ARDS). In the injured lung, alveolar type two (AT2) epithelial cells play a critical role restoring the normal alveolar structure. Thus characterizing the changes in AT2 cells will provide insights into the mechanisms underpinning the recovery from lung injury. Methods: We applied an unbiased systems level proteomics approach to elucidate molecular mechanisms contributing to lung repair in a rat hyperoxic lung injury model. AT2 cells were isolated from rat lungs at predetermined intervals during hyperoxic injury and recovery. Protein expression profiles were determined by using iTRAQRTM with tandem mass spectrometry. Results: Of 959 distinct proteins identified, 183 significantly changed in abundance during the injury-recovery cycle. Gene Ontology enrichment analysis identified cell cycle, cell differentiation, cell metabolism, ion homeostasis, programmed cell death, ubiquitination, and cell migration to be significantly enriched by these proteins. Gene Set Enrichment Analysis of data acquired during lung repair revealed differential expression of gene sets that control multicellular organismal development, systems development, organ development, and chemical homeostasis. More detailed analysis identified activity in two regulatory pathways, JNK and miR 374. A Short Time-series Expression Miner (STEM) algorithm identified protein clusters with coherent changes during injury and repair. Conclusion: Coherent changes occur in the AT2 cell proteome in response to hyperoxic stress. These findings offer guidance regarding the specific molecular mechanisms governing repair of the injured lung.

Clinical value of CT-based preoperative software assisted lung lobe volumetry for predicting postoperative pulmonary function after lung surgery

NASA Astrophysics Data System (ADS)

Wormanns, Dag; Beyer, Florian; Hoffknecht, Petra; Dicken, Volker; Kuhnigk, Jan-Martin; Lange, Tobias; Thomas, Michael; Heindel, Walter

2005-04-01

This study was aimed to evaluate a morphology-based approach for prediction of postoperative forced expiratory volume in one second (FEV1) after lung resection from preoperative CT scans. Fifteen Patients with surgically treated (lobectomy or pneumonectomy) bronchogenic carcinoma were enrolled in the study. A preoperative chest CT and pulmonary function tests before and after surgery were performed. CT scans were analyzed by prototype software: automated segmentation and volumetry of lung lobes was performed with minimal user interaction. Determined volumes of different lung lobes were used to predict postoperative FEV1 as percentage of the preoperative values. Predicted FEV1 values were compared to the observed postoperative values as standard of reference. Patients underwent lobectomy in twelve cases (6 upper lobes; 1 middle lobe; 5 lower lobes; 6 right side; 6 left side) and pneumonectomy in three cases. Automated calculation of predicted postoperative lung function was successful in all cases. Predicted FEV1 ranged from 54% to 95% (mean 75% +/- 11%) of the preoperative values. Two cases with obviously erroneous LFT were excluded from analysis. Mean error of predicted FEV1 was 20 +/- 160 ml, indicating absence of systematic error; mean absolute error was 7.4 +/- 3.3% respective 137 +/- 77 ml/s. The 200 ml reproducibility criterion for FEV1 was met in 11 of 13 cases (85%). In conclusion, software-assisted prediction of postoperative lung function yielded a clinically acceptable agreement with the observed postoperative values. This method might add useful information for evaluation of functional operability of patients with lung cancer.

Anatomic and Pathologic Variability During Radiotherapy for a Hybrid Active Breath-Hold Gating Technique

DOE Office of Scientific and Technical Information (OSTI.GOV)

Glide-Hurst, Carri K.; Gopan, Ellen; Department of Radiation Oncology Wayne State University, Detroit, MI

2010-07-01

Purpose: To evaluate intra- and interfraction variability of tumor and lung volume and position using a hybrid active breath-hold gating technique. Methods and Materials: A total of 159 repeat normal inspiration active breath-hold CTs were acquired weekly during radiotherapy for 9 lung cancer patients (12-21 scans per patient). A physician delineated the gross tumor volume (GTV), lungs, and spinal cord on the first breath-hold CT, and contours were propagated semiautomatically. Intra- and interfraction variability of tumor and lung position and volume were evaluated. Tumor centroid and border variability were quantified. Results: On average, intrafraction variability of lung and GTV centroidmore » position was <2.0 mm. Interfraction population variability was 3.6-6.7 mm (systematic) and 3.1-3.9 mm (random) for the GTV centroid and 1.0-3.3 mm (systematic) and 1.5-2.6 mm (random) for the lungs. Tumor volume regressed 44.6% {+-} 23.2%. Gross tumor volume border variability was patient specific and demonstrated anisotropic shape change in some subjects. Interfraction GTV positional variability was associated with tumor volume regression and contralateral lung volume (p < 0.05). Inter-breath-hold reproducibility was unaffected by time point in the treatment course (p > 0.1). Increases in free-breathing tidal volume were associated with increases in breath-hold ipsilateral lung volume (p < 0.05). Conclusions: The breath-hold technique was reproducible within 2 mm during each fraction. Interfraction variability of GTV position and shape was substantial because of tumor volume and breath-hold lung volume change during therapy. These results support the feasibility of a hybrid breath-hold gating technique and suggest that online image guidance would be beneficial.« less

Mast-cell-releasing tryptase triggers acute lung injury induced by small intestinal ischemia-reperfusion by activating PAR-2 in rats.

PubMed

Gan, Xiaoliang; Liu, Dezhao; Huang, Pinjie; Gao, Wanling; Chen, Xinzhi; Hei, Ziqing

2012-06-01

Mast cell has been demonstrated to be involved in the small intestinal ischemia-reperfusion (IIR) injury, however, the precise role of tryptase released from mast cell on acute lung injury(ALI) induced by IIR remains to be elucidated, our study aimed to observe the roles of tryptase on ALI triggered by IIR and its underlying mechanism. Adult SD rats were randomized into sham-operated group, sole IIR group in which rats were subjected to 75 min superior mesenteric artery occlusion followed by 4 h reperfusion, or IIR being respectively treated with cromolyn sodium, protamine, and compound 48/80. The above agents were, respectively, administrated intravenously 5 min before reperfusion. At the end of experiment, lung tissue was obtained for assays for protein expressions of tryptase and mast cell protease 7 (MCP7) and protease-activated receptor 2 (PAR-2). Pulmonary mast cell number and levels of IL-8 were quantified. Lung histologic injury scores and lung water content were measured. IIR resulted in lung injury evidenced as significant increases in lung histological scores and lung water contents, accompanied with concomitant increases of expressions of tryptase and MCP7, and elevations in PAR-2 expressions and IL-8 levels in lungs. Stabilizing mast cell with cromolyn sodium and inhibiting tryptase with protamine significantly reduced IIR-mediated ALI and the above biochemical changes while activating mast cell with compound 48/80 further aggravated IIR-mediated ALI and the increases of above parameters. Tryptase released from mast cells mediates ALI induced by intestinal ischemia-reperfusion by activating PAR-2 to produce IL-8.

Diverse Epitope Specificity, Immunodominance Hierarchy, and Functional Avidity of Effector CD4 T Cells Established During Priming Is Maintained in Lung After Influenza A Virus Infection.

PubMed

Richards, Katherine A; DiPiazza, Anthony T; Rattan, Ajitanuj; Knowlden, Zackery A G; Yang, Hongmei; Sant, Andrea J

2018-01-01

One of the major contributions to protective immunity to influenza viruses that is provided by virus-specific CD4 T cells is delivery of effector function to the infected lung. However, there is little known about the selection and breadth of viral epitope-specific CD4 T cells that home to the lung after their initial priming. In this study, using a mouse model of influenza A infection and an unbiased method of epitope identification, the viral epitope-specific CD4 T cells elicited after infection were identified and quantified. We found that a very diverse specificity of CD4 T cells is primed by infection, including epitopes from hemagglutinin, neuraminidase, matrix protein, nucleoprotein, and non-structural protein-1. Using peptide-specific cytokine EliSpots, the diversity and immunodominance hierarchies established in the lung-draining lymph node were compared with specificities of CD4 T cells that home to the lung. Our studies revealed that CD4 T cells of all epitope specificities identified in peripheral lymphoid tissue home back to the lung and that most of these lung-homing cells are localized within the tissue rather than the pulmonary vasculature. There is a striking shift of CD4 T cell functionality that enriches for IFN-γ production as cells are primed in the lymph node, enter the lung vasculature, and finally establish residency in the tissue, but with no apparent shifts in their functional avidity. We conclude that CD4 T cells of broad viral epitope specificity are recruited into the lung after influenza infection, where they then have the opportunity to encounter infected or antigen-bearing antigen-presenting cells.

Alarmin S100A8 Activates Alveolar Epithelial Cells in the Context of Acute Lung Injury in a TLR4-Dependent Manner.

PubMed

Chakraborty, Deblina; Zenker, Stefanie; Rossaint, Jan; Hölscher, Anna; Pohlen, Michele; Zarbock, Alexander; Roth, Johannes; Vogl, Thomas

2017-01-01

Alveolar epithelial cells (AECs) are an essential part of the respiratory barrier in lungs for gas exchange and protection against pathogens. Damage to AECs occurs during lung injury and PAMPs/DAMPs have been shown to activate AECs. However, their interplay as well as the mechanism of AECs' activation especially by the alarmin S100A8/A9 is unknown. Thus, our aim was to study the mechanism of activation of AECs (type I and type II) by S100A8 and/or lipopolysaccharide (LPS) and to understand the role of endogenous S100A8/A9 in neutrophil recruitment in the lung. For our studies, we modified a previous protocol for isolation and culturing of murine AECs. Next, we stimulated the cells with S100A8 and/or LPS and analyzed cytokine/chemokine release. We also analyzed the contribution of the known S100-receptors TLR4 and RAGE in AEC activation. In a murine model of lung injury, we investigated the role of S100A8/A9 in neutrophil recruitment to lungs. S100A8 activates type I and type II cells in a dose- and time-dependent manner which could be quantified by the release of IL-6, KC, and MCP-1. We here clearly demonstrate that AEC s are activated by S100A8 via a TLR4-dependent pathway. Surprisingly, RAGE, albeit mainly expressed in lung tissue, plays no role. Additionally, we show that S100A8/A9 is an essential factor for neutrophil recruitment to lungs. We, therefore, conclude that S100A8 promotes acute lung injury via Toll-like receptor 4-dependent activation of AECs.

Alarmin S100A8 Activates Alveolar Epithelial Cells in the Context of Acute Lung Injury in a TLR4-Dependent Manner

PubMed Central

Chakraborty, Deblina; Zenker, Stefanie; Rossaint, Jan; Hölscher, Anna; Pohlen, Michele; Zarbock, Alexander; Roth, Johannes; Vogl, Thomas

2017-01-01

Alveolar epithelial cells (AECs) are an essential part of the respiratory barrier in lungs for gas exchange and protection against pathogens. Damage to AECs occurs during lung injury and PAMPs/DAMPs have been shown to activate AECs. However, their interplay as well as the mechanism of AECs’ activation especially by the alarmin S100A8/A9 is unknown. Thus, our aim was to study the mechanism of activation of AECs (type I and type II) by S100A8 and/or lipopolysaccharide (LPS) and to understand the role of endogenous S100A8/A9 in neutrophil recruitment in the lung. For our studies, we modified a previous protocol for isolation and culturing of murine AECs. Next, we stimulated the cells with S100A8 and/or LPS and analyzed cytokine/chemokine release. We also analyzed the contribution of the known S100-receptors TLR4 and RAGE in AEC activation. In a murine model of lung injury, we investigated the role of S100A8/A9 in neutrophil recruitment to lungs. S100A8 activates type I and type II cells in a dose- and time-dependent manner which could be quantified by the release of IL-6, KC, and MCP-1. We here clearly demonstrate that AEC s are activated by S100A8 via a TLR4-dependent pathway. Surprisingly, RAGE, albeit mainly expressed in lung tissue, plays no role. Additionally, we show that S100A8/A9 is an essential factor for neutrophil recruitment to lungs. We, therefore, conclude that S100A8 promotes acute lung injury via Toll-like receptor 4-dependent activation of AECs. PMID:29180999

Divergent Effects of Neutrophils on Fas-Induced Pulmonary Inflammation, Apoptosis, and Lung Damage.

PubMed

Bruns, Bastian; Hönle, Theresia; Kellermann, Philipp; Ayala, Alfred; Perl, Mario

2017-02-01

Pulmonary Fas activation is essential in the pathogenesis of the acute respiratory distress syndrome. It remains unclear whether Fas-induced lung injury is dependent on neutrophils or mainly triggered by epithelial cell apoptosis. The contribution of lung epithelial cells (LEC) and alveolar macrophages (AM) remains elusive.Mice were neutrophil reduced prior to intratracheal instillation of Fas-activating (Jo2) or isotype antibody for 6 or 18 h. LEC and AM were incubated with Jo2 and in the presence of nuclear factor kappa B, p-38 mitogen activated protein kinase (p38MAPK), or extracellular signal regulating kinase 1/2 (ERK1/2) inhibitors. Cytokines were assessed by cytometric bead array or ELISA. Apoptosis was quantified via active caspase-3 Western blotting and Terminal Deoxynucleotide Transferase dUTP Nick End Labeling (TUNEL). Lung injury was assessed by bronchoalveolar lavage fluid (BALF) protein concentration and lung histology.KC, IL-6, and MCP-1 were markedly increased in lung, plasma, and BALF 18 h after Jo2 in the presence of neutrophils; in neutrophil-reduced mice lungs, MCP-1, but not KC or IL-6, was even further enhanced. Six hours after Jo2, BALF protein was markedly increased only in the presence of neutrophils. Apoptosis remained unaffected by neutrophil reduction. AM released MCP-1 and underwent apoptosis at lower concentrations of Jo2 than LEC. Inhibition of p38MAPK significantly increased, while inhibition of ERK1/2 reduced AM and LEC apoptosis.In conclusion, neutrophils are a necessary component of Fas-induced lung damage, while not affecting lung apoptosis directly per se. LEC display higher resistance to Fas-triggered inflammation and apoptosis than AM.

Accuracy of transpulmonary thermodilution versus gravimetric measurement of extravascular lung water.

PubMed

Katzenelson, Rita; Perel, Azriel; Berkenstadt, Haiim; Preisman, Sergei; Kogan, Samuel; Sternik, Leonid; Segal, Eran

2004-07-01

Pulmonary edema is a severe and often life-threatening condition. The diagnosis of pulmonary edema and its quantification have great clinical significance and yet can be difficult. A new technique based on thermodilution measurement using a single indicator has recently been developed (PiCCO, Pulsion Medical Systems, AG Germany). This method allows the measurement of extravascular lung water and thus can quantify degree of pulmonary edema. The technique has not been compared with a gold standard, gravimetric measurement of extravascular lung water. Therefore, the objective of this study was to determine the ability of extravascular lung water measurement with the PiCCO to reflect the extravascular lung water as measured with a gravimetric technique in a dog model of pulmonary edema. Prospective, randomized animal study. A university animal research laboratory. Fifteen mongrel dogs (n = 5/group) weighing 20-30 kg. The dogs were anesthetized and mechanically ventilated. Five dogs served as controls; in five dogs hydrostatic pulmonary edema was induced using inflation of a left atrial balloon combined with fluid administration to maintain a high pulmonary artery occlusion pressure; and in five dogs pulmonary edema was induced by intravenous injection of oleic acid. After a period of stabilization in a state of pulmonary edema, extravascular lung water was measured with the PiCCO monitor. The animals were then killed, and extravascular lung water was measured using a gravimetric technique. There was a very close (r =.967, p <.001) relationship between transpulmonary thermodilution and gravimetric measurements. The measurement with the PiCCO was consistently higher, by 3.01 +/- 1.34 mL/kg, than the gravimetric measurement. Measurement of extravascular lung water using transpulmonary thermodilution with a single indicator is very closely correlated with gravimetric measurement of lung water in both increased permeability and hydrostatic pulmonary edema.

Heritability of Lung Disease Severity in Cystic Fibrosis

PubMed Central

Vanscoy, Lori L.; Blackman, Scott M.; Collaco, Joseph M.; Bowers, Amanda; Lai, Teresa; Naughton, Kathleen; Algire, Marilyn; McWilliams, Rita; Beck, Suzanne; Hoover-Fong, Julie; Hamosh, Ada; Cutler, Dave; Cutting, Garry R.

2007-01-01

Rationale: Obstructive lung disease, the major cause of mortality in cystic fibrosis (CF), is poorly correlated with mutations in the disease-causing gene, indicating that other factors determine severity of lung disease. Objectives: To quantify the contribution of modifier genes to variation in CF lung disease severity. Methods: Pulmonary function data from patients with CF living with their affected twin or sibling were converted into reference values based on both healthy and CF populations. The best measure of FEV1 within the last year was used for cross-sectional analysis. FEV1 measures collected over at least 4 years were used for longitudinal analysis. Genetic contribution to disease variation (i.e., heritability) was estimated in two ways: by comparing similarity of lung function in monozygous (MZ) twins (∼ 100% gene sharing) with that of dizygous (DZ) twins/siblings (∼ 50% gene sharing), and by comparing similarity of lung function measures for related siblings to similarity for all study subjects. Measurements and Main Results: Forty-seven MZ twin pairs, 10 DZ twin pairs, and 231 sibling pairs (of a total of 526 patients) with CF were studied. Correlations for all measures of lung function for MZ twins (0.82–0.91, p < 0.0001) were higher than for DZ twins and siblings (0.50–0.64, p < 0.001). Heritability estimates from both methods were consistent for each measure of lung function and ranged from 0.54 to 1.0. Heritability estimates generally increased after adjustment for differences in nutritional status (measured as body mass index z-score). Conclusions: Our heritability estimates indicate substantial genetic control of variation in CF lung disease severity, independent of CFTR genotype. PMID:17332481

Risk of Lung Cancer Mortality in Nuclear Workers from Internal Exposure to Alpha Particle-emitting Radionuclides

PubMed Central

Atkinson, Will; Bérard, Philippe; Bingham, Derek; Birchall, Alan; Blanchardon, Eric; Bull, Richard; Guseva Canu, Irina; Challeton-de Vathaire, Cécile; Cockerill, Rupert; Do, Minh T.; Engels, Hilde; Figuerola, Jordi; Foster, Adrian; Holmstock, Luc; Hurtgen, Christian; Laurier, Dominique; Puncher, Matthew; Riddell, Anthony E.; Samson, Eric; Thierry-Chef, Isabelle; Tirmarche, Margot; Vrijheid, Martine; Cardis, Elisabeth

2017-01-01

Background: Carcinogenic risks of internal exposures to alpha-emitters (except radon) are poorly understood. Since exposure to alpha particles—particularly through inhalation—occurs in a range of settings, understanding consequent risks is a public health priority. We aimed to quantify dose–response relationships between lung dose from alpha-emitters and lung cancer in nuclear workers. Methods: We conducted a case–control study, nested within Belgian, French, and UK cohorts of uranium and plutonium workers. Cases were workers who died from lung cancer; one to three controls were matched to each. Lung doses from alpha-emitters were assessed using bioassay data. We estimated excess odds ratio (OR) of lung cancer per gray (Gy) of lung dose. Results: The study comprised 553 cases and 1,333 controls. Median positive total alpha lung dose was 2.42 mGy (mean: 8.13 mGy; maximum: 316 mGy); for plutonium the median was 1.27 mGy and for uranium 2.17 mGy. Excess OR/Gy (90% confidence interval)—adjusted for external radiation, socioeconomic status, and smoking—was 11 (2.6, 24) for total alpha dose, 50 (17, 106) for plutonium, and 5.3 (−1.9, 18) for uranium. Conclusions: We found strong evidence for associations between low doses from alpha-emitters and lung cancer risk. The excess OR/Gy was greater for plutonium than uranium, though confidence intervals overlap. Risk estimates were similar to those estimated previously in plutonium workers, and in uranium miners exposed to radon and its progeny. Expressed as risk/equivalent dose in sieverts (Sv), our estimates are somewhat larger than but consistent with those for atomic bomb survivors. See video abstract at, http://links.lww.com/EDE/B232. PMID:28520643

[Arf6, RalA and BIRC5 protein expression in non small cell lung cancer].

PubMed

Knizhnik, A V; Kovaleva, O B; Laktionov, K K; Mochal'nikova, V V; Komel'kov, A V; Chevkina, E M; Zborovskaia, I B

2011-01-01

Evaluation of tumor markers expression pattern which determines individual progression parameters is one of the major topics in molecular oncopathology research. This work presents research on expression analysis of several Ras-Ral associated signal transduction pathway proteins (Arf6, RalA and BIRC5) in accordance with clinical criteria in non small cell lung cancer patients. Using Western-blot analysis and RT-PCR Arf6, RalA and BIRC5 expression has been analyzed in parallel in 53 non small cell lung cancer samples of different origin. Arf6 protein expression was elevated in 55% non small cell lung cancer tumor samples in comparison with normal tissue. In the group of squamous cell lung cancer Arf6 expression elevation was observed more often. RalA protein expression was decreased in comparison to normal tissue samples in 64% of non small cell lung cancer regardless to morphological structure. Correlation between RalA protein expression decrease and absence of regional metastases was revealed for squamous cell lung cancer. BIRC5 protein expression in tumor samples versus corresponding normal tissue was 1.3 times more often elevated in the squamous cell lung cancer group (in 76% tumor samples). At the same time elevation of BIRC5 expression was fixed only in 63% of adenocarcinoma tumor samples. A statistically significant decrease (p = 0.0158) of RalA protein expression and increase (p = 0.0498) of Arf6 protein expression in comparison with normal tissue was found for T1-2N0M0 and T1-2N1-2M0 groups of squamous cell lung cancer correspondingly.

Computer-aided pulmonary image analysis in small animal models

DOE Office of Scientific and Technical Information (OSTI.GOV)

Xu, Ziyue; Mansoor, Awais; Mollura, Daniel J.

Purpose: To develop an automated pulmonary image analysis framework for infectious lung diseases in small animal models. Methods: The authors describe a novel pathological lung and airway segmentation method for small animals. The proposed framework includes identification of abnormal imaging patterns pertaining to infectious lung diseases. First, the authors’ system estimates an expected lung volume by utilizing a regression function between total lung capacity and approximated rib cage volume. A significant difference between the expected lung volume and the initial lung segmentation indicates the presence of severe pathology, and invokes a machine learning based abnormal imaging pattern detection system next.more » The final stage of the proposed framework is the automatic extraction of airway tree for which new affinity relationships within the fuzzy connectedness image segmentation framework are proposed by combining Hessian and gray-scale morphological reconstruction filters. Results: 133 CT scans were collected from four different studies encompassing a wide spectrum of pulmonary abnormalities pertaining to two commonly used small animal models (ferret and rabbit). Sensitivity and specificity were greater than 90% for pathological lung segmentation (average dice similarity coefficient > 0.9). While qualitative visual assessments of airway tree extraction were performed by the participating expert radiologists, for quantitative evaluation the authors validated the proposed airway extraction method by using publicly available EXACT’09 data set. Conclusions: The authors developed a comprehensive computer-aided pulmonary image analysis framework for preclinical research applications. The proposed framework consists of automatic pathological lung segmentation and accurate airway tree extraction. The framework has high sensitivity and specificity; therefore, it can contribute advances in preclinical research in pulmonary diseases.« less

Volume error analysis for lung nodules attached to pulmonary vessels in an anthropomorphic thoracic phantom

NASA Astrophysics Data System (ADS)

Kinnard, Lisa M.; Gavrielides, Marios A.; Myers, Kyle J.; Zeng, Rongping; Peregoy, Jennifer; Pritchard, William; Karanian, John W.; Petrick, Nicholas

2008-03-01

High-resolution CT, three-dimensional (3D) methods for nodule volumetry have been introduced, with the hope that such methods will be more accurate and consistent than currently used planar measures of size. However, the error associated with volume estimation methods still needs to be quantified. Volume estimation error is multi-faceted in the sense that it is impacted by characteristics of the patient, the software tool and the CT system. The overall goal of this research is to quantify the various sources of measurement error and, when possible, minimize their effects. In the current study, we estimated nodule volume from ten repeat scans of an anthropomorphic phantom containing two synthetic spherical lung nodules (diameters: 5 and 10 mm; density: -630 HU), using a 16-slice Philips CT with 20, 50, 100 and 200 mAs exposures and 0.8 and 3.0 mm slice thicknesses. True volume was estimated from an average of diameter measurements, made using digital calipers. We report variance and bias results for volume measurements as a function of slice thickness, nodule diameter, and X-ray exposure.

Using Fractal And Morphological Criteria For Automatic Classification Of Lung Diseases

NASA Astrophysics Data System (ADS)

Vehel, Jacques Levy

1989-11-01

Medical Images are difficult to analyze by means of classical image processing tools because they are very complex and irregular. Such shapes are obtained for instance in Nuclear Medecine with the spatial distribution of activity for organs such as lungs, liver, and heart. We have tried to apply two different theories to these signals: - Fractal Geometry deals with the analysis of complex irregular shapes which cannot well be described by the classical Euclidean geometry. - Integral Geometry treats sets globally and allows to introduce robust measures. We have computed three parameters on three kinds of Lung's SPECT images: normal, pulmonary embolism and chronic desease: - The commonly used fractal dimension (FD), that gives a measurement of the irregularity of the 3D shape. - The generalized lacunarity dimension (GLD), defined as the variance of the ratio of the local activity by the mean activity, which is only sensitive to the distribution and the size of gaps in the surface. - The Favard length that gives an approximation of the surface of a 3-D shape. The results show that each slice of the lung, considered as a 3D surface, is fractal and that the fractal dimension is the same for each slice and for the three kind of lungs; as for the lacunarity and Favard length, they are clearly different for normal lungs, pulmonary embolisms and chronic diseases. These results indicate that automatic classification of Lung's SPECT can be achieved, and that a quantitative measurement of the evolution of the disease could be made.

Lung excision of non-small-cell lung cancer leaves cancer cells in residual lobe: cytological detection using pulmonary vein blood.

PubMed

Sawabata, Noriyoshi; Funaki, Soichiro; Shintani, Yasushi; Okumura, Meinosin

2016-02-01

Lung excision to treat non-small-cell lung cancer (NSCLC) is associated with a worse prognosis when compared with a lobectomy. Cancer relapse may be caused by tumour cells remaining in the residual lobe, the possibility of dislodged cancer cells in the residual lobe is assessed using pulmonary vein blood (PVB) from the resected lung. Twenty-eight patients with pathological stage I NSCLC who underwent lung excision followed by a lobectomy were evaluated according to the status of isolated tumour cells (ITCs) (origin of circulating tumour cells) in PVB from the resected lobe. Survival was also assessed according to the status of ITCs. The rate of ITC presence was 60.7% and depended on margin distance/tumour size (M/T) with a threshold of 1.0-30.8% (4/13) in M/T greater than or equal to 1.0 and 86.7% (13/15) in M/T smaller than 1.0 (P = 0.001). PVB-ITC status was no ITCs (N) in 11 (39.3%), only singular cells (S) in 13 (50.0%) and clustered cells (C) in 4 (14.3%). In addition, the survival status of patients with clustered cells was exclusively wrong. After pulmonary excision for lung cancer, tumour cells remain in the residual lobe and the morphology of which may indicate recurrence. © The Author 2015. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.

Early detection of lung cancer from CT images: nodule segmentation and classification using deep learning

NASA Astrophysics Data System (ADS)

Sharma, Manu; Bhatt, Jignesh S.; Joshi, Manjunath V.

2018-04-01

Lung cancer is one of the most abundant causes of the cancerous deaths worldwide. It has low survival rate mainly due to the late diagnosis. With the hardware advancements in computed tomography (CT) technology, it is now possible to capture the high resolution images of lung region. However, it needs to be augmented by efficient algorithms to detect the lung cancer in the earlier stages using the acquired CT images. To this end, we propose a two-step algorithm for early detection of lung cancer. Given the CT image, we first extract the patch from the center location of the nodule and segment the lung nodule region. We propose to use Otsu method followed by morphological operations for the segmentation. This step enables accurate segmentation due to the use of data-driven threshold. Unlike other methods, we perform the segmentation without using the complete contour information of the nodule. In the second step, a deep convolutional neural network (CNN) is used for the better classification (malignant or benign) of the nodule present in the segmented patch. Accurate segmentation of even a tiny nodule followed by better classification using deep CNN enables the early detection of lung cancer. Experiments have been conducted using 6306 CT images of LIDC-IDRI database. We achieved the test accuracy of 84.13%, with the sensitivity and specificity of 91.69% and 73.16%, respectively, clearly outperforming the state-of-the-art algorithms.

Effects of in vitro cultivated Calculus Bovis compound on pulmonary lesions in rabbits with schistosomiasis.

PubMed

Li, Tao; Yang, Zhen; Cai, Hong-Jiao; Song, Li-Wei; Lu, Ke-Yu; Zhou, Zheng; Wu, Zai-De

2010-02-14

To explore the interventional effects and mechanism of in vitro cultivated Calculus Bovis compound preparation (ICCBco) on pulmonary lesions in portal hypertensive rabbits with schistosomiasis. The experimental group included 20 portal hypertensive rabbits with schistosomiasis treated by ICCBco. The control group included 20 portal hypertensive rabbits with schistosomiasis treated by praziquantel. The morphological changes of the pulmonary tissues were observed under light and electron microscopy. The expression of fibronectin (FN) and laminin (LN) in the lung tissues was analyzed by immunohistochemistry. Under light microscope, the alveolar exudation in the lung tissue was more frequently observed in the control group, while the alveolar space was fairly dry in the lung tissue of ICCBco group. Under electron microscope, more alveolar exudation in the lung tissue, and more macrophages, alveolar angiotelectasis and the blurred three-tier structure of alveolar-capillary barrier could be seen in the control group. In ICCBco group, fibers within the alveolar interspace slightly increased in some lung regions, and the structure of type I epithelium, basement membrane and endodermis was complete, and no obvious exudation from the alveolar space, and novascular congestion could be observed. There was a positive or strong positive expression of FN and LN in the lung tissue of the control group, while there was a negative or weak positive expression of FN and LN in ICCBco group. ICCBco can effectively prevent pulmonary complications in portal hypertensive rabbits with schistosomiasis by means of improving lung microcirculation and lowering the content of extracellular matrix.

Man-made mineral fibers (MMMF): human exposures and health risk assessment.

PubMed

Lippmann, M

1990-03-01

MMMF are made by spraying or extruding molten glass, furnace slag, or mineral rock. Health concerns are based on the morphological and toxicological similarities between MMMF and asbestos, and the well-documented evidence that asbestos fibers can cause lung fibrosis (asbestosis), bronchial cancer, and mesothelioma in humans. Epidemiological evidence for human disease from inhalation exposures to fibrous glass is largely negative. Some positive associations have been reported for slag and rockwools. Most of the toxicological evidence for MMMF toxicity in laboratory animals is based on non-physiological exposures such as intratracheal instillation or intraperitoneal injection of fiber suspensions. The risks for lung fibrosis, lung cancer, and mesothelioma for industrial exposures to most fibrous glass products are either low or negligible for a variety of reasons. First, most commercial fibrous glass products have mean fiber diameters of approximately 7.5 microns, which results in mean aerodynamic diameters greater than 22 microns. Thus, most glass fibers, even if dispersed into the air, do not penetrate into the lung to any great extent. Second, the small fraction of smaller diameter fibers which do penetrate into the lungs are not persistent within the lungs for most fibrous glass products, due to mechanical breakage into shorter lengths and dissolution. Dissolution is most rapid for the smaller diameters (less than 0.1 micron) capable of producing mesothelioma. The greater hazards for slag and rockwools, in comparison to conventional fibrous glass, appear to be related to their smaller diameters and greater durability within the lungs.

Electrical impedance tomography

PubMed Central

Lobo, Beatriz; Hermosa, Cecilia; Abella, Ana

2018-01-01

Continuous assessment of respiratory status is one of the cornerstones of modern intensive care unit (ICU) monitoring systems. Electrical impedance tomography (EIT), although with some constraints, may play the lead as a new diagnostic and guiding tool for an adequate optimization of mechanical ventilation in critically ill patients. EIT may assist in defining mechanical ventilation settings, assess distribution of tidal volume and of end-expiratory lung volume (EELV) and contribute to titrate positive end-expiratory pressure (PEEP)/tidal volume combinations. It may also quantify gains (recruitment) and losses (overdistention or derecruitment), granting a more realistic evaluation of different ventilator modes or recruitment maneuvers, and helping in the identification of responders and non-responders to such maneuvers. Moreover, EIT also contributes to the management of life-threatening lung diseases such as pneumothorax, and aids in guiding fluid management in the critical care setting. Lastly, assessment of cardiac function and lung perfusion through electrical impedance is on the way. PMID:29430443

Quantifying parenchymal tethering in a finite element simulation of a human lung slice under bronchoconstriction.

PubMed

Breen, Barbara J; Donovan, Graham M; Sneyd, James; Tawhai, Merryn H

2012-08-15

Airway hyper-responsiveness (AHR), a hallmark of asthma, is a highly complex phenomenon characterised by multiple processes manifesting over a large range of length and time scales. Multiscale computational models have been derived to embody the experimental understanding of AHR. While current models differ in their derivation, a common assumption is that the increase in parenchymal tethering pressure P(teth) during airway constriction can be described using the model proposed by Lai-Fook (1979), which is based on intact lung experimental data for elastic moduli over a range of inflation pressures. Here we reexamine this relationship for consistency with a nonlinear elastic material law that has been parameterised to the pressure-volume behaviour of the intact lung. We show that the nonlinear law and Lai-Fook's relationship are consistent for small constrictions, but diverge when the constriction becomes large. Copyright © 2012 Elsevier B.V. All rights reserved.

High resolution propagation-based imaging system for in vivo dynamic computed tomography of lungs in small animals

NASA Astrophysics Data System (ADS)

Preissner, M.; Murrie, R. P.; Pinar, I.; Werdiger, F.; Carnibella, R. P.; Zosky, G. R.; Fouras, A.; Dubsky, S.

2018-04-01

We have developed an x-ray imaging system for in vivo four-dimensional computed tomography (4DCT) of small animals for pre-clinical lung investigations. Our customized laboratory facility is capable of high resolution in vivo imaging at high frame rates. Characterization using phantoms demonstrate a spatial resolution of slightly below 50 μm at imaging rates of 30 Hz, and the ability to quantify material density differences of at least 3%. We benchmark our system against existing small animal pre-clinical CT scanners using a quality factor that combines spatial resolution, image noise, dose and scan time. In vivo 4DCT images obtained on our system demonstrate resolution of important features such as blood vessels and small airways, of which the smallest discernible were measured as 55–60 μm in cross section. Quantitative analysis of the images demonstrate regional differences in ventilation between injured and healthy lungs.

Study of inflammatory responses to crocidolite and basalt wool in the rat lung.

PubMed

Adamis, Z; Kerényi, T; Honma, K; Jäckel, M; Tátrai, E; Ungváry, G

2001-03-09

The subacute effects of crocidolite and basalt wool dusts were studied by nmeans of biochemical, morphological. and histological methods 1 and .3 mo after intrabronchial instillation. The cell count, protein and phospholipid contents, and lactate dehydrogenase (LDH) activity were determined in the bronchoalveolar lavage (BAL). Both types of fibers induced a prolonged inflammatory reaction in the lung. All the parameters studied in the experimental groups were more markedly elevated after 3 mo. Relative to the control, the protein and LDH values were increased three- to fivefold, the phospholipid content twofold, and the number of free cells in the BAL exceeded the control level up to ninefold. The inflammatory responses to crocidolite and basalt wool in the lung did not differ significantly. In spite of this, basalt wool is recoinmended as an asbestos substitute, as the use of this man-nade fiber may result in a significantly lower release of dust than that from crocidolite.

Emphysema diagnosis using X-ray dark-field imaging at a laser-driven compact synchrotron light source

PubMed Central

Schleede, Simone; Meinel, Felix G.; Bech, Martin; Herzen, Julia; Achterhold, Klaus; Potdevin, Guillaume; Malecki, Andreas; Adam-Neumair, Silvia; Thieme, Sven F.; Bamberg, Fabian; Nikolaou, Konstantin; Bohla, Alexander; Yildirim, Ali Ö.; Loewen, Roderick; Gifford, Martin; Ruth, Ronald; Eickelberg, Oliver; Reiser, Maximilian; Pfeiffer, Franz

2012-01-01

In early stages of various pulmonary diseases, such as emphysema and fibrosis, the change in X-ray attenuation is not detectable with absorption-based radiography. To monitor the morphological changes that the alveoli network undergoes in the progression of these diseases, we propose using the dark-field signal, which is related to small-angle scattering in the sample. Combined with the absorption-based image, the dark-field signal enables better discrimination between healthy and emphysematous lung tissue in a mouse model. All measurements have been performed at 36 keV using a monochromatic laser-driven miniature synchrotron X-ray source (Compact Light Source). In this paper we present grating-based dark-field images of emphysematous vs. healthy lung tissue, where the strong dependence of the dark-field signal on mean alveolar size leads to improved diagnosis of emphysema in lung radiographs. PMID:23074250

Automated assessment of aortic and main pulmonary arterial diameters using model-based blood vessel segmentation for predicting chronic thromboembolic pulmonary hypertension in low-dose CT lung screening

NASA Astrophysics Data System (ADS)

Suzuki, Hidenobu; Kawata, Yoshiki; Niki, Noboru; Sugiura, Toshihiko; Tanabe, Nobuhiro; Kusumoto, Masahiko; Eguchi, Kenji; Kaneko, Masahiro

2018-02-01

Chronic thromboembolic pulmonary hypertension (CTEPH) is characterized by obstruction of the pulmonary vasculature by residual organized thrombi. A morphological abnormality inside mediastinum of CTEPH patient is enlargement of pulmonary artery. This paper presents an automated assessment of aortic and main pulmonary arterial diameters for predicting CTEPH in low-dose CT lung screening. The distinctive feature of our method is to segment aorta and main pulmonary artery using both of prior probability and vascular direction which were estimated from mediastinal vascular region using principal curvatures of four-dimensional hyper surface. The method was applied to two datasets, 64 lowdose CT scans of lung cancer screening and 19 normal-dose CT scans of CTEPH patients through the training phase with 121 low-dose CT scans. This paper demonstrates effectiveness of our method for predicting CTEPH in low-dose CT screening.

[Lung volume reduction surgery for emphysema and bullous pulmonary emphysema].

PubMed

Le Pimpec-Barthes, F; Das Neves-Pereira, J-C; Cazes, A; Arame, A; Grima, R; Hubsch, J-P; Zukerman, C; Hernigou, A; Badia, A; Bagan, P; Delclaux, C; Dusser, D; Riquet, M

2012-04-01

The improvement of respiratory symptoms for emphysematous patients by surgery is a concept that has evolved over time. Initially used for giant bullae, this surgery was then applied to patients with diffuse microbullous emphysema. The physiological and pathological concepts underlying these surgical procedures are the same in both cases: improve respiratory performance by reducing the high intrapleural pressure. The functional benefit of lung volume reduction surgery (LVRS) in the severe diffuse emphysema has been validated by the National Emphysema Treatment Trial (NETT) and the later studies which allowed to identify prognostic factors. The quality of the clinical, morphological and functional data made it possible to develop recommendations now widely used in current practice. Surgery for giant bullae occurring on little or moderately emphysematous lung is often a simpler approach but also requires specialised support to optimize its results. Copyright © 2012 Elsevier Masson SAS. All rights reserved.

Variations in Grain-Scale Sediment Structure in a Gravel-Bed Channel as a Function of Fine Sediment Content and Morphological Location

NASA Astrophysics Data System (ADS)

Voepel, H.; Ahmed, S. I.; Hodge, R. A.; Leyland, J.; Sear, D. A.

2016-12-01

One of the major causes of uncertainty in estimates of bedload transport rates in gravel bed rivers is a lack of understanding of grain-scale sediment structure, and the impact that this structure has on bed stability. Furthermore, grain-scale structure varies throughout a channel and over time in ways that have not been fully quantified. Our research aims to quantify variations in sediment structure caused by two key variables; morphological location within a riffle-pool sequence (reflecting variation in hydraulic conditions), and the fine sediment content of the gravel bed (sand and clay). We report results from a series of flume experiments in which we water-worked a gravel bed with a riffle-pool morphology. The fine sediment content of the bed was incrementally increased over a series of runs from gravel only, to coarse sand, fine sand and two concentrations of clay. After each experimental run intact samples of the bed at different locations were extracted and the internal structure of the bed was measured using non-destructive, micro-focus X-ray computed tomography (CT) imaging. The CT images were processed to measure the properties of individual grains, including volume, center of mass, dimension, and contact points. From these data we were able to quantify the sediment structure through metrics including measurement of grain pivot angles, grain exposure and protrusion, and vertical variation in bed porosity and fine sediment content. Metrics derived from the CT data were verified using data from grain counts and tilt-table measurements on co-located samples. Comparison of the metrics across different morphological locations and fine sediment content demonstrates how these factors affect the bed structure. These results have implications for the development of sediment entrainment models for gravel bed rivers.

Sustained Effects of Sirolimus on Lung Function and Cystic Lung Lesions in Lymphangioleiomyomatosis

PubMed Central

Yao, Jianhua; Jones, Amanda M.; Julien-Williams, Patricia; Stylianou, Mario; Moss, Joel

2014-01-01

Rationale: Sirolimus therapy stabilizes lung function and reduces the size of chylous effusions and lymphangioleiomyomas in patients with lymphangioleiomyomatosis. Objectives: To determine whether sirolimus has beneficial effects on lung function, cystic areas, and adjacent lung parenchyma; whether these effects are sustained; and whether sirolimus is well tolerated by patients. Methods: Lung function decline over time, lung volume occupied by cysts (cyst score), and lung tissue texture in the vicinity of the cysts were quantified with a computer-aided diagnosis system in 38 patients. Then we compared cyst scores from the last study on sirolimus with studies done on sirolimus therapy. In 12 patients, we evaluated rates of change in lung function and cyst scores off and on sirolimus. Measurements and Main Results: Sirolimus reduced yearly declines in FEV1 (−2.3 ± 0.1 vs. 1.0 ± 0.3% predicted; P < 0.001) and diffusing capacity of carbon monoxide (−2.6 ± 0.1 vs. 0.9 ± 0.2% predicted; P < 0.001). Cyst scores 1.2 ± 0.8 years (30.5 ± 11.9%) and 2.5 ± 2 years (29.7 ± 12.1%) after initiating sirolimus were not significantly different from pretreatment values (28.4 ± 12.5%). In 12 patients followed for 5 years, a significant reduction in rates of yearly decline in FEV1 (−1.4 ± 0.2 vs. 0.3 ± 0.4% predicted; P = 0.025) was observed. Analyses of 104 computed tomography scans showed a nonsignificant (P = 0.23) reduction in yearly rates of change of cyst scores (1.8 ± 0.2 vs. 0.3 ± 0.3%; P = 0.23) and lung texture features. Despite adverse events, most patients were able to continue sirolimus therapy. Conclusions: Sirolimus therapy slowed down lung function decline and increase in cystic lesions. Most patients were able to tolerate sirolimus therapy. PMID:25329516

Cigarette smoke condensate induces differential expression and promoter methylation profiles of critical genes involved in lung cancer in NL-20 lung cells in vitro: short-term and chronic exposure.

PubMed

Word, Beverly; Lyn-Cook, Lascelles E; Mwamba, Bibi; Wang, Honggang; Lyn-Cook, Beverly; Hammons, George

2013-01-01

Establishing early diagnostic markers of harm is critical for effective prevention programs and regulation of tobacco products. This study examined effects of cigarette smoke condensate (CSC) on expression and promoter methylation profile of critical genes (DAPK, ECAD, MGMT, and RASSF1A) involved in lung cancer development in different human lung cell lines. NL-20 cells were treated with 0.1-100 μg/ml of CSC for 24 to 72 hrs for short-term exposures. DAPK expression or methylation status was not significantly affected. However, CSC treatment resulted in changes in expression and promoter methylation profile of ECAD, MGMT, and RASSF1A. For chronic studies, cells were exposed to 1 or 10 μg/ml CSC up to 28 days. Cells showed morphological changes associated with transformation and changes in invasion capacities and global methylation status. This study provides critical data suggesting that epigenetic changes could serve as an early biomarker of harm due to exposure to cigarette smoke.

Peculiarities of the Inflammatory Process in the Reproductive Organs of C57Bl/6 Female Mice with Experimental Tuberculosis.

PubMed

Sukhikh, G T; Kayukova, S I; Bocharova, I V; Donnikov, A E; Lepekha, L N; Demikhova, O V; Uvarova, E V; Berezovskii, Yu S; Smirnova, T G

2016-04-01

Intravenous infection of C57Bl/6 female mice with M. tuberculosis H37Rv led to involvement of the lungs and dissemination of the tuberculous infection to the abdominal and pelvic organs. M. tuberculosis were detected in the lungs and spleen in 14, 35, and 90 days and in the uterine horns in 90 days after infection. Morphological analysis of organs showed successive development of exudative necrotic tuberculosis of the lungs, acute and chronic nonspecific inflammation in the reproductive organs (vagina, uterus, and uterine horns). The inflammatory process in the reproductive organs was associated with the development of anaerobic dysbiosis, that was most pronounced in 35 days after infection. Antituberculous therapy was followed by reduction of M. tuberculosis count in the lungs and spleen in 60 and 90 days after infection, eliminatation of M. tuberculosis in the uterine horns, arrest of nonspecific inflammation in female reproductive organs, recovery of the balance between aerobic and anaerobic microflora, and development of candidiasis of the urogenital mucosa.

[Immunohistochemistry of matrix metalloproteinases in different morphologic types of the lung cancer developed in the inhabitants of the Semipalatinsk Region].

PubMed

Sagindikova, G E; Kogan, E A; Satbaeva, E B

2008-01-01

The immunohistochemical characteristics of matrix metalloproteinases and their association with angiogenesis in different histological types of the lung cancer developed in the inhabitants of the Semipalatinsk Region (Kazakhstan) were investigated. The surgical and biopsy specimens from 87 patients with lung cancer, including 33 patients who had lived near the Semipalatinsk polygon from childhood to 2002 year and had been long exposed to radiation (annual radiation dose had been more than 0.1 Rem), were examined. Fifty-four control patients had lived in other Kazakhstan regions with the unchanged ionizing radiation background (n = 14) and in Moscow (n = 40). MMP-1, MMP-2, MMP-9, TIMP-1, VEGF, CD34, chromogranin, and CD68 were immunohistochemically detected. The increased expression of MMP-1, MMP-2, and MMP-9 in the cancer cells was ascertained in the study group as compared with the control one. Angiogenesis in the stroma of Semipalatinsk lung cancer was generally more pronounced, as judged by the expression of VEGF and the density of newly formed vessels.

Crizotinib-loaded polymeric nanoparticles in lung cancer chemotherapy.

PubMed

Jiang, Zhi-Ming; Dai, Shou-Ping; Xu, Yong-Qing; Li, Tao; Xie, Jian; Li, Chong; Zhang, Zhong-Hui

2015-07-01

The study describes the development of polylactide-tocopheryl polyethylene glycol 1000 succinate (PLA-TPGS)-based nanosystem as a carrier of crizotinib (CZT) to achieve superior anticancer efficacy in lung cancer therapy. We have demonstrated that block copolymer and hydrophobic drug is capable of self-assembling into a very stable nanocarrier, with suitable properties that allow their application for cancer drug delivery. Drug release study showed a sustained release pattern as a result of entrapment in the hydrophobic core of micelles. CZT/PT NP showed a noticeable cytotoxic effect in NCIH3122 lung cancer cells in a dose-dependent manner. Furthermore, morphological imaging and Live/Dead assay revealed a superior anticancer efficacy for nanoformulations. The polymeric nanoparticle showed a predominant presence in the cytoplasmic region of cell, indicating a typical endocytosis-mediated cellular uptake. The annexin V/PI staining-based apoptosis assay showed a remarkable ~40 % apoptosis (early and late apoptosis cells) comparing to only ~25 % apoptosis by free CZT. Taken together, Vitamin E TPGS-modified PLA nanoparticles would be a potential drug delivery system to increase the chemotherapeutic efficacy of CZT in lung cancer chemotherapy.

Extracting alveolar structure of human lung tissue specimens based on surface skeleton representation from 3D micro-CT images

NASA Astrophysics Data System (ADS)

Ishimori, Hiroyuki; Kawata, Yoshiki; Niki, Noboru; Nakaya, Yoshihiro; Ohmatsu, Hironobu; Matsui, Eisuke; Fujii, Masashi; Moriyama, Noriyuki

2007-03-01

We have developed a Micro CT system for understanding lung function at a high resolution of the micrometer order (up to 5µm in spatial resolution). Micro CT system enables the removal specimen of lungs to be observed at micro level, has expected a big contribution for micro internal organs morphology and the image diagnosis study. In this research, we develop system to visualize lung microstructures in three dimensions from micro CT images and analyze them. They characterize in that high CT value of the noise area is, and the difficulty of only using threshold processing to extract the alveolar wall of micro CT images. Thus, we are developing a method of extracting the alveolar wall with surface thinning algorithm. In this report, we propose the method which reduces the excessive degeneracy of figure which caused by surface thinning process. And, we apply this algorithm to the micro CT image of the actual pulmonary specimen. It is shown that the extraction of the alveolus wall becomes possible in the high precision.

LnPO 4 Nanoparticles Doped with Ac-225 and Sequestered Daughters for Targeted Alpha Therapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

McLaughlin, Mark F.; Robertson, David; Pevsner, Paul H.

2014-02-01

For targeted alpha therapy (TAT) with 225Ac, daughter radioisotopes from the parent emissions should be controlled. We report on a second-generation layered nanoparticle (NP) with improved daughter retention that can mediate TAT of lung tumor colonies. NPs of La 3+, Gd 3+, and 225Ac 3+ ions were coated with additional layers of GdPO 4 and then coated with gold via citrate reduction of NaAuCl 4. MAb 201b, targeting thrombomodulin in lung endothelium, was added to a polyethylene glycol (dPEG)-COOH linker. Furthermore, we quantified the NPs:mAb ratio by labeling the mAb with 125I. NPs showed 30% injected dose/organ antibody-mediated uptake inmore » the lung, which increased to 47% in mice pretreated with clodronate liposomes to reduce phagocytosis. Retention of daughter 213Bi in lung tissue was more than 70% at one hour and about 90% at 24 hours postinjection. Treatment of mice with lung-targeted 225Ac NP reduced EMT-6 lung colonies relative to cold antibody competition for targeting or phosphate-buffered saline injected controls. Finally, we show that LnPO 4 NPs represent a viable solution to deliver the 225Ac as an in vivo α generator. The NPs successfully retain a large percentage of the daughter products without compromising the tumoricidal properties of the α-radiation.« less

Adipose Gene Expression Profile Changes With Lung Allograft Reperfusion.

PubMed

Diamond, Joshua M; Arcasoy, Selim; McDonnough, Jamiela A; Sonett, Joshua R; Bacchetta, Matthew; D'Ovidio, Frank; Cantu, Edward; Bermudez, Christian A; McBurnie, Amika; Rushefski, Melanie; Kalman, Laurel H; Oyster, Michelle; D'Errico, Carly; Suzuki, Yoshikazu; Giles, Jon T; Ferrante, Anthony; Lippel, Matthew; Singh, Gopal; Lederer, David J; Christie, Jason D

2017-01-01

Obesity is a risk factor for primary graft dysfunction (PGD), a form of lung injury resulting from ischemia-reperfusion after lung transplantation, but the impact of ischemia-reperfusion on adipose tissue is unknown. We evaluated differential gene expression in thoracic visceral adipose tissue (VAT) before and after lung reperfusion. Total RNA was isolated from thoracic VAT sampled from six subjects enrolled in the Lung Transplant Body Composition study before and after allograft reperfusion and quantified using the Human Gene 2.0 ST array. Kyoto Encyclopedia of Genes and Genomes pathway analysis revealed enrichment for genes involved in complement and coagulation cascades and Jak-STAT signaling pathways. Overall, 72 genes were upregulated and 56 genes were downregulated in the postreperfusion time compared with baseline. Long pentraxin-3, a gene and plasma protein previously associated with PGD, was the most upregulated gene (19.5-fold increase, p = 0.04). Fibronectin leucine-rich transmembrane protein-3, a gene associated with cell adhesion and receptor signaling, was the most downregulated gene (4.3-fold decrease, p = 0.04). Ischemia-reperfusion has a demonstrable impact on gene expression in visceral adipose tissue in our pilot study of nonobese, non-PGD lung transplant recipients. Future evaluation will focus on differential adipose tissue gene expression and the development of PGD after transplant. © Copyright 2016 The American Society of Transplantation and the American Society of Transplant Surgeons.

Role of inflammatory cells and adenosine in lung ischemia reoxygenation injury using a model of lung donation after cardiac death.

PubMed

Smail, Hassiba; Baste, Jean-Marc; Gay, Arnaud; Begueret, Hugues; Noël, Romain; Morin, Jean-Paul; Litzler, Pierre-Yves

2016-04-01

The objective of this study is to analyze the role of inflammation in the lung ischemia reperfusion (IR) injury and determine the protective role of adenosine in an in vitro lung transplantation model. We used a hybrid model of lung donor after cardiac death, with warm ischemia in corpo of varying duration (2 h, 4 h) followed by in vitro lung slices culture for reoxygenation (1 h, 4 h and 24 h), in the presence or not of lymphocytes and of adenosine. To quantify the inflammatory lesions, we performed TNFα, IL2 assays, and histological analysis. In this model of a nonblood perfused system, the addition of lymphocytes during reoxygenation lead to higher rates of TNFα and IL2 after 4 h than after 2 h of warm ischemia (P < .05). These levels increased with the duration of reoxygenation and were maximum at 24 h (P < .05). In the presence of adenosine TNFα and IL2 decreased. After 2 h of warm ischemia, we observed a significant inflammatory infiltration, alveolar thickening and a necrosis of the bronchiolar cells. After 4 h of warm ischemia, alveolar cells necrosis was associated. This model showed that lymphocytes increased the inflammatory response and the histological lesions after 4 h of warm ischemia and that adenosine could have an anti-inflammatory role with potential reconditioning action when used in the pneumoplegia solution.

Simultaneous magnetic resonance imaging of ventilation distribution and gas uptake in the human lung using hyperpolarized xenon-129

PubMed Central

Mugler, John P.; Altes, Talissa A.; Ruset, Iulian C.; Dregely, Isabel M.; Mata, Jaime F.; Miller, G. Wilson; Ketel, Stephen; Ketel, Jeffrey; Hersman, F. William; Ruppert, Kai

2010-01-01

Despite a myriad of technical advances in medical imaging, as well as the growing need to address the global impact of pulmonary diseases, such as asthma and chronic obstructive pulmonary disease, on health and quality of life, it remains challenging to obtain in vivo regional depiction and quantification of the most basic physiological functions of the lung—gas delivery to the airspaces and gas uptake by the lung parenchyma and blood—in a manner suitable for routine application in humans. We report a method based on MRI of hyperpolarized xenon-129 that permits simultaneous observation of the 3D distributions of ventilation (gas delivery) and gas uptake, as well as quantification of regional gas uptake based on the associated ventilation. Subjects with lung disease showed variations in gas uptake that differed from those in ventilation in many regions, suggesting that gas uptake as measured by this technique reflects such features as underlying pathological alterations of lung tissue or of local blood flow. Furthermore, the ratio of the signal associated with gas uptake to that associated with ventilation was substantially altered in subjects with lung disease compared with healthy subjects. This MRI-based method provides a way to quantify relationships among gas delivery, exchange, and transport, and appears to have significant potential to provide more insight into lung disease. PMID:21098267

The Impact of Sources of Variability on Parametric Response Mapping of Lung CT Scans

PubMed Central

Boes, Jennifer L.; Bule, Maria; Hoff, Benjamin A.; Chamberlain, Ryan; Lynch, David A.; Stojanovska, Jadranka; Martinez, Fernando J.; Han, Meilan K.; Kazerooni, Ella A.; Ross, Brian D.; Galbán, Craig J.

2015-01-01

Parametric response mapping (PRM) of inspiration and expiration computed tomography (CT) images improves the radiological phenotyping of chronic obstructive pulmonary disease (COPD). PRM classifies individual voxels of lung parenchyma as normal, emphysematous, or nonemphysematous air trapping. In this study, bias and noise characteristics of the PRM methodology to CT and clinical procedures were evaluated to determine best practices for this quantitative technique. Twenty patients of varying COPD status with paired volumetric inspiration and expiration CT scans of the lungs were identified from the baseline COPD-Gene cohort. The impact of CT scanner manufacturer and reconstruction kernels were evaluated as potential sources of variability in PRM measurements along with simulations to quantify the impact of inspiration/expiration lung volume levels, misregistration, and image spacing on PRM measurements. Negligible variation in PRM metrics was observed when CT scanner type and reconstruction were consistent and inspiration/expiration lung volume levels were near target volumes. CT scanner Hounsfield unit drift occurred but remained difficult to ameliorate. Increasing levels of image misregistration and CT slice spacing were found to have a minor effect on PRM measurements. PRM-derived values were found to be most sensitive to lung volume levels and mismatched reconstruction kernels. As with other quantitative imaging techniques, reliable PRM measurements are attainable when consistent clinical and CT protocols are implemented. PMID:26568983

Regional Lung Ventilation Analysis Using Temporally Resolved Magnetic Resonance Imaging.

PubMed

Kolb, Christoph; Wetscherek, Andreas; Buzan, Maria Teodora; Werner, René; Rank, Christopher M; Kachelrie, Marc; Kreuter, Michael; Dinkel, Julien; Heuel, Claus Peter; Maier-Hein, Klaus

We propose a computer-aided method for regional ventilation analysis and observation of lung diseases in temporally resolved magnetic resonance imaging (4D MRI). A shape model-based segmentation and registration workflow was used to create an atlas-derived reference system in which regional tissue motion can be quantified and multimodal image data can be compared regionally. Model-based temporal registration of the lung surfaces in 4D MRI data was compared with the registration of 4D computed tomography (CT) images. A ventilation analysis was performed on 4D MR images of patients with lung fibrosis; 4D MR ventilation maps were compared with corresponding diagnostic 3D CT images of the patients and 4D CT maps of subjects without impaired lung function (serving as reference). Comparison between the computed patient-specific 4D MR regional ventilation maps and diagnostic CT images shows good correlation in conspicuous regions. Comparison to 4D CT-derived ventilation maps supports the plausibility of the 4D MR maps. Dynamic MRI-based flow-volume loops and spirograms further visualize the free-breathing behavior. The proposed methods allow for 4D MR-based regional analysis of tissue dynamics and ventilation in spontaneous breathing and comparison of patient data. The proposed atlas-based reference coordinate system provides an automated manner of annotating and comparing multimodal lung image data.

Hyperpolarized 129Xe MRI of the Human Lung

PubMed Central

Mugler, John P.; Altes, Talissa A.

2012-01-01

By permitting direct visualization of the airspaces of the lung, MR imaging using hyperpolarized gases provides unique strategies for evaluating pulmonary structure and function. Although the vast majority of research in humans has been performed using hyperpolarized 3He, recent contraction in the supply of 3He and consequent increases in price have turned attention to the alternative agent, hyperpolarized 129Xe. Compared to 3He, 129Xe yields reduced signal due to its smaller magnetic moment. Nonetheless, taking advantage of advances in gas-polarization technology, recent studies in humans using techniques for measuring ventilation, diffusion, and partial pressure of oxygen have demonstrated results for hyperpolarized 129Xe comparable to those previously demonstrated using hyperpolarized 3He. In addition, xenon has the advantage of readily dissolving in lung tissue and blood following inhalation, which makes hyperpolarized 129Xe particularly attractive for exploring certain characteristics of lung function, such as gas exchange and uptake, which cannot be accessed using 3He. Preliminary results from methods for imaging 129Xe dissolved in the human lung suggest that these approaches will provide new opportunities for quantifying relationships among gas delivery, exchange, and transport, and thus show substantial potential to broaden our understanding of lung disease. Finally, recent changes in the commercial landscape of the hyperpolarized-gas field now make it possible for this innovative technology to move beyond the research lab. PMID:23355432

Tensiometric and Phase Domain Behavior of Lung Surfactant on Mucus-like Viscoelastic Hydrogels.

PubMed

Schenck, Daniel M; Fiegel, Jennifer

2016-03-09

Lung surfactant has been observed at all surfaces of the airway lining fluids and is an important contributor to normal lung function. In the conducting airways, the surfactant film lies atop a viscoelastic mucus gel. In this work, we report on the characterization of the tensiometric and phase domain behavior of lung surfactant at the air-liquid interface of mucus-like viscoelastic gels. Poly(acrylic acid) hydrogels were formulated to serve as a model mucus with bulk rheological properties that matched those of tracheobronchial mucus secretions. Infasurf (Calfactant), a commercially available pulmonary surfactant derived from calf lung extract, was spread onto the hydrogel surface. The surface tension lowering ability and relaxation of Infasurf films on the hydrogels was quantified and compared to Infasurf behavior on an aqueous subphase. Infasurf phase domains during surface compression were characterized by fluorescence microscopy and phase shifting interferometry. We observed that increasing the bulk viscoelastic properties of the model mucus hydrogels reduced the ability of Infasurf films to lower surface tension and inhibited film relaxation. A shift in the formation of Infasurf condensed phase domains from smaller, more spherical domains to large, agglomerated, multilayer structures was observed with increasing viscoelastic properties of the subphase. These studies demonstrate that the surface behavior of lung surfactant on viscoelastic surfaces, such as those found in the conducting airways, differs significantly from aqueous, surfactant-laden systems.

In situ analysis of lung antigen-presenting cells during murine pulmonary infection with virulent Mycobacterium tuberculosis

PubMed Central

Pedroza-González, Alexander; García-Romo, Gina S; Aguilar-León, Diana; Calderon-Amador, Juana; Hurtado-Ortiz, Raquel; Orozco-Estevez, Hector; Lambrecht, Bart N; Estrada-García, Iris; Hernández-Pando, Rogelio; Flores-Romo, Leopoldo

2004-01-01

Scarce information exists about the role of lung antigen-presenting cells (APCs) in vivo during pulmonary tuberculosis. As APCs activate cellular immunity, following intratracheal inoculation with virulent Mycobacterium tuberculosis, we assessed in situ lung APC recruitment, distribution, granuloma involvement, morphology and mycobacterial burden by using MHC-CII, CD14, scavenger receptor class A (SRA), the murine dendritic cell (DC)-restricted marker CD11c and Ziehl–Neelsen staining. CD11c+ DC and CD14+ cell recruitment into lungs appeared by day 14, continuing until day 60. MHC-CII+ cells increased since day 7, persisting until day 60. Thus, virulent mycobacteria delays (14–21 days) lung APC recruitment compared to model antigens and nonvirulent bacilli (24–48 h). Regarding granuloma constitution, highly bacillary CD14+ and SRA+ cells were centrally located. MHC-CII+ cells were more peripheral, with less mycobacteria. CD11c+ cells were heterogeneously distributed within granulomas, with scarce bacilli. When labelling lung suspensions for MHC-CII and classifying cells as macrophages or DC, then staining for Ziehl–Neelsen, a remarkable segregation was found regarding bacillary burden. Most macrophage-like cells contained numerous bacilli, while DC had no or scarce mycobacteria. This implies differential APC contributions in situ during pulmonary tuberculosis regarding mycobacterial uptake, granuloma involvement and perhaps bacillary growth. PMID:15255967

Pathology of pulmonary tuberculosis and non-tuberculous mycobacterial lung disease: Facts, misconceptions, and practical tips for pathologists.

PubMed

Jain, Deepali; Ghosh, Subha; Teixeira, Lucileia; Mukhopadhyay, Sanjay

2017-11-01

Most pathologists are familiar with the microscopic features of tuberculosis and the need to examine special stains for acid-fast bacteria (AFB) in cases of granulomatous lung disease. However, misconceptions do exist, including the concept that finding AFB in "caseating granulomas" confirms the diagnosis of tuberculosis. This dogma is attributable to the high prevalence of tuberculosis in many countries, as well as unfamiliarity with the microscopic spectrum of non-tuberculous mycobacterial lung disease. This review aims to provide surgical pathologists with practical tips to identify AFB, illustrate the histologic overlap between pulmonary tuberculosis and non-tuberculous mycobacterial lung disease, and highlight the importance of cultures in this setting. M. tuberculosis and non-tuberculous mycobacteria cannot be reliably differentiated either on the basis of the tissue reaction or by bacterial morphology on acid-fast stains. Although a presumptive clinical diagnosis of tuberculosis can be made without culture-confirmation, the only definitive means to determine the true identity of AFB is by cultures or molecular methods. Making this distinction is most critical when AFB are found in incidentally detected lung nodules in geographic locations where the incidence of tuberculosis is low, because in such settings AFB in necrotizing granulomas of the lung are more likely to be non-tuberculous mycobacteria than M. tuberculosis. Copyright © 2017 Elsevier Inc. All rights reserved.

Identification of a Cell-of-Origin for Fibroblasts Comprising the Fibrotic Reticulum in Idiopathic Pulmonary Fibrosis

PubMed Central

Xia, Hong; Bodempudi, Vidya; Benyumov, Alexey; Hergert, Polla; Tank, Damien; Herrera, Jeremy; Braziunas, Jeff; Larsson, Ola; Parker, Matthew; Rossi, Daniel; Smith, Karen; Peterson, Mark; Limper, Andrew; Jessurun, Jose; Connett, John; Ingbar, David; Phan, Sem; Bitterman, Peter B.; Henke, Craig A.

2015-01-01

Idiopathic pulmonary fibrosis (IPF) is a progressive disease of the middle aged and elderly with a prevalence of one million persons worldwide. The fibrosis spreads from affected alveoli into contiguous alveoli, creating a reticular network that leads to death by asphyxiation. Lung fibroblasts from patients with IPF have phenotypic hallmarks, distinguishing them from their normal counterparts: pathologically activated Akt signaling axis, increased collagen and α-smooth muscle actin expression, distinct gene expression profile, and ability to form fibrotic lesions in model organisms. Despite the centrality of these fibroblasts in disease pathogenesis, their origin remains uncertain. Here, we report the identification of cells in the lungs of patients with IPF with the properties of mesenchymal progenitors. In contrast to progenitors isolated from nonfibrotic lungs, IPF mesenchymal progenitor cells produce daughter cells manifesting the full spectrum of IPF hallmarks, including the ability to form fibrotic lesions in zebrafish embryos and mouse lungs, and a transcriptional profile reflecting these properties. Morphological analysis of IPF lung tissue revealed that mesenchymal progenitor cells and cells with the characteristics of their progeny comprised the fibrotic reticulum. These data establish that the lungs of patients with IPF contain pathological mesenchymal progenitor cells that are cells of origin for fibrosis-mediating fibroblasts. These fibrogenic mesenchymal progenitors and their progeny represent an unexplored target for novel therapies to interdict fibrosis. PMID:24631025

Diphenyl ditelluride intoxication triggers histological changes in liver, kidney, and lung of mice.

PubMed

da Luz, Sônia Cristina Almeida; Daubermann, Melissa Falster; Thomé, Gustavo Roberto; Dos Santos, Matheus Mülling; Ramos, Angelica; Torres Salazar, Gerson; da Rocha, João Batista Teixeira; Barbosa, Nilda Vargas

2015-01-01

Tellurium compounds may be cytotoxic to different cells types. Thus, this work evaluated the effect of diphenyl ditelluride ((PhTe)2), an organotellurium commonly used in organic synthesis, on the morphology of liver, kidney, and lung. Adult mice were acutely (a subcutaneous single dose: 250 μmol/kg) or subchronically (one daily subcutaneous dose: 10 or 50 μmol/kg for 7 and 14 days) exposed to (PhTe)2. Afterwards, the histological analyses of liver, kidney, and lungs were performed. Liver histology revealed that the hepatocytes of mice subchronically exposed to (PhTe)2 presented cytoplasmic vacuolization, hydropic degeneration, and hyperchromatic nuclei. Subchronic exposure to 50 μmol/kg (PhTe)2 also caused hepatic necrosis. Microvesicular and macrovesicular steatosis were identified in liver of mice acutely exposed to (PhTe)2. Acute and subchronic intoxication with (PhTe)2 induced changes on epithelial cells of renal tubules, namely, loss of brush border and cytoplasmatic vacuolization. Atrophy and hypertrophy, cast proteinaceous formation, and acute tubular necrosis were also identified in renal tissue. Mice subchronically exposed to 50 μmol/kg (PhTe)2 developed intra-alveolar edema and alveolar wall congestion in some areas of lungs. Acute exposure to (PhTe)2 did not cause histological changes in lungs. Our data show that (PhTe)2 may be considered a histotoxic agent for liver, kidney, and lung.

Effect of the pulmonary deposition and in vitro permeability on the prediction of plasma levels of inhaled budesonide formulation.

PubMed

Salar-Behzadi, Sharareh; Wu, Shengqian; Mercuri, Annalisa; Meindl, Claudia; Stranzinger, Sandra; Fröhlich, Eleonore

2017-10-30

The growing interest in the inhalable pharmaceutical products requires advanced approaches to safe and fast product development, such as in silico tools that can be used for estimating the bioavailability and toxicity of developed formulation. GastroPlus™ is one of the few available software packages for in silico simulation of PBPK profile of inhalable products. It contains a complementary module for calculating the lung deposition, the permeability and the systemic absorption of inhalable products. Experimental values of lung deposition and permeability can also be used. This study aims to assess the efficiency of simulation by applying experimental permeability and deposition values, using budesonide as a model substance. The lung deposition values were obtained from the literature, the lung permeability data were experimentally determined by culturing Calu-3 cells under air-liquid interface and submersed conditions to morphologically resemble bronchial and alveolar epithelial cells, respectively. A two-compartment PK model was created for i.v. administration and used as a background for the in silico simulation of the plasma profile of budesonide after inhalation. The predicted plasma profile was compared with the in vivo data from the literature and the effects of experimental lung deposition and permeability on prediction were assessed. The developed model was significantly improved by using realistic lung deposition data combined with experimental data for peripheral permeability. Copyright © 2017 Elsevier B.V. All rights reserved.

Stimulatory effects of curcumin and quercetin on posttranslational modifications of p53 during lung carcinogenesis.

PubMed

Zhang, P; Zhang, Xy

2018-06-01

Lung cancer is responsible for increase in mortality due to cancer-related deaths, and new approaches are being explored for the betterment of the situation. In the present study, chemopreventive efficacy of curcumin and quercetin was investigated against benzo(a)pyrene (BP)-induced lung carcinogenesis. The mice were segregated into five groups, which included normal control, BP-treated, BP + curcumin-treated, BP + quercetin-treated, and BP + curcumin + quercetin-treated groups. The morphological and histological analyses of tumor nodules confirmed lung carcinogenesis22 weeks after weeks single intraperitoneal injection of BP at a dose of 100 mg/kg body weight to mice. Curcumin and quercetin when administered individually as well as in combination significantly elevated the expression of acetylated-p53, which was otherwise depressed due to BP treatment. Also, both the phytochemicals significantly reduced the BP-inflicted increased levels of phosphorylated-p53. Furthermore, observed increase in the number of apoptotic cells by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL), assay and increased activities of caspase 3 and 9 confirmed the induction of apoptosis by curcumin and quercetin. Moreover, the histological slides also showed noticeable improvement in the histoarchitecture of lungs by phytochemicals. The present study concludes that prophylactic treatment with curcumin and quercetin induces apoptosis in the lungs by modulation of p53 posttranslational modifications.

Bio-transformation of Graphene Oxide in Lung Fluids Significantly Enhances Its Photothermal Efficacy.

PubMed

Liu, Yun; Qi, Yu; Yin, Chunyang; Wang, Shunhao; Zhang, Shuping; Xu, An; Chen, Wei; Liu, Sijin

2018-01-01

Rationale: Graphene oxide (GO) has shown great promises in biomedical applications, such as drug delivery and thermotherapeutics, owing to its extraordinary physicochemical properties. Nonetheless, current biomedical applications of GO materials are premised on the basis of predesigned functions, and little consideration has been given to the influence of bio-transformation in the physiological environment on the physicochemical properties and predesigned functionalities of these materials. Hence, it is crucial to uncover the possible influence on GO's physicochemical properties and predesigned functionalities for better applications. Methods: Bio-transformed GOs were characterized by X-ray diffraction (XRD) spectra, Raman spectra, X-ray photoelectron spectroscopy (XPS) and Fourier transform infrared transmission (FT-IR) spectra. The morphologies of various GO materials were assessed via transmission electron microscopy (TEM), scanning electron microscopy (SEM) and atomic force microscopy (AFM) images. The photothermal (PTT) performance of different GO materials in vitro and in vivo were measured using 808 nm laser at a power density of 2 W/cm 2 . The PTT efficacy was determined using transplanted 4T1 cells-derived breast tumors in mice. Results: Bio-transformation of GO in the lung (a main target organ for GO to localize in vivo ) can induce dramatic changes to its physicochemical properties and morphology, and consequently, its performances in biomedical applications. Specifically, GO underwent significant reduction in two simulated lung fluids, Gamble's solution and artificial lysosomal fluid (ALF), as evidenced by the increase of C/O ratio (the ratio of C content to O content) relative to pristine GO. Bio-transformation also altered GO's morphology, characterized by sheet folding and wrinkle formation. Intriguingly, bio-transformation elevated the PTT performance of GO in vitro , and this elevation further facilitated PTT-based tumor-killing efficacy in tumor cells in vitro and in a mouse model with transplanted tumors. Bio-transformation also compromised the interaction between drug with GO, leading to reduced drug adsorption, as tested using doxorubicin (DOX). Conclusions: Transformation in Gamble's solution and ALF resulted in varied degrees of improved performances of GO, due to the differential effects on GO's physicochemical properties. Our findings unveiled an overlooked impact of GO bio-transformation, and unearthed a favorable trait of GO materials in thermotherapeutics and drug delivery in the lung microenvironment.

Non-invasive quantitative pulmonary V/Q imaging using Fourier decomposition MRI at 1.5T.

PubMed

Kjørstad, Åsmund; Corteville, Dominique M R; Henzler, Thomas; Schmid-Bindert, Gerald; Zöllner, Frank G; Schad, Lothar R

2015-12-01

Techniques for quantitative pulmonary perfusion and ventilation using the Fourier Decomposition method were recently demonstrated. We combine these two techniques and show that ventilation-perfusion (V/Q) imaging is possible using only a single MR acquisition of less than thirty seconds. The Fourier Decomposition method is used in combination with two quantification techniques, which extract baselines from within the images themselves and thus allows quantification. For the perfusion, a region assumed to consist of 100% blood is utilized, while for the ventilation the zero-frequency component is used. V/Q-imaging is then done by dividing the quantified ventilation map with the quantified perfusion map. The techniques were used on ten healthy volunteers and fifteen patients diagnosed with lung cancer. A mean V/Q-ratio of 1.15 ± 0.22 was found for the healthy volunteers and a mean V/Q-ratio of 1.93 ± 0.83 for the non-afflicted lung in the patients. Mean V/Q-ratio in the afflicted (tumor-bearing) lung was found to be 1.61 ± 1.06. Functional defects were clearly visible in many of the patient images, but 5 of 15 patient images had to be excluded due to artifacts or low SNR, indicating a lack of robustness. Non-invasive, quantitative V/Q-imaging is possible using Fourier Decomposition MRI. The method requires only a single acquisition of less than 30 seconds, but robustness in patients remains an issue. Copyright © 2015. Published by Elsevier GmbH.

A theranostic approach based on the use of a dual boron/Gd agent to improve the efficacy of Boron Neutron Capture Therapy in the lung cancer treatment.

PubMed

Alberti, Diego; Protti, Nicoletta; Toppino, Antonio; Deagostino, Annamaria; Lanzardo, Stefania; Bortolussi, Silva; Altieri, Saverio; Voena, Claudia; Chiarle, Roberto; Geninatti Crich, Simonetta; Aime, Silvio

2015-04-01

This study aims at developing an innovative theranostic approach for lung tumor and metastases treatment, based on Boron Neutron Capture Therapy (BNCT). It relies on to the use of low density lipoproteins (LDL) as carriers able to maximize the selective uptake of boron atoms in tumor cells and, at the same time, to quantify the in vivo boron distribution by magnetic resonance imaging (MRI). Tumor cells uptake was initially assessed by ICP-MS and MRI on four types of tumor (TUBO, B16-F10, MCF-7, A549) and one healthy (N-MUG) cell lines. Lung metastases were generated by intravenous injection of a Her2+ breast cancer cell line (i.e. TUBO) in BALB/c mice and transgenic EML4-ALK mice were used as primary tumor model. After neutron irradiation, tumor growth was followed for 30-40 days by MRI. Tumor masses of boron treated mice increased markedly slowly than the control group. From the clinical editor: In this article, the authors described an improvement to existing boron neutron capture therapy. The dual MRI/BNCT agent, carried by LDLs, was able to maximize the selective uptake of boron in tumor cells, and, at the same time, quantify boron distribution in tumor and in other tissues using MRI. Subsequent in vitro and in vivo experiments showed tumor cell killing after neutron irradiation. Copyright © 2015 Elsevier Inc. All rights reserved.

Analysis of Intervention Strategies for Inhalation Exposure to Polycyclic Aromatic Hydrocarbons and Associated Lung Cancer Risk Based on a Monte Carlo Population Exposure Assessment Model

PubMed Central

Zhou, Bin; Zhao, Bin

2014-01-01

It is difficult to evaluate and compare interventions for reducing exposure to air pollutants, including polycyclic aromatic hydrocarbons (PAHs), a widely found air pollutant in both indoor and outdoor air. This study presents the first application of the Monte Carlo population exposure assessment model to quantify the effects of different intervention strategies on inhalation exposure to PAHs and the associated lung cancer risk. The method was applied to the population in Beijing, China, in the year 2006. Several intervention strategies were designed and studied, including atmospheric cleaning, smoking prohibition indoors, use of clean fuel for cooking, enhancing ventilation while cooking and use of indoor cleaners. Their performances were quantified by population attributable fraction (PAF) and potential impact fraction (PIF) of lung cancer risk, and the changes in indoor PAH concentrations and annual inhalation doses were also calculated and compared. The results showed that atmospheric cleaning and use of indoor cleaners were the two most effective interventions. The sensitivity analysis showed that several input parameters had major influence on the modeled PAH inhalation exposure and the rankings of different interventions. The ranking was reasonably robust for the remaining majority of parameters. The method itself can be extended to other pollutants and in different places. It enables the quantitative comparison of different intervention strategies and would benefit intervention design and relevant policy making. PMID:24416436

In vitro evaluation of pulmonary deposition of airborne volcanic ash

NASA Astrophysics Data System (ADS)

Lähde, Anna; Sæunn Gudmundsdottir, Sigurbjörg; Joutsensaari, Jorma; Tapper, Unto; Ruusunen, Jarno; Ihalainen, Mika; Karhunen, Tommi; Torvela, Tiina; Jokiniemi, Jorma; Järvinen, Kristiina; Gíslason, Sigurður Reynir; Briem, Haraldur; Gizurarson, Sveinbjörn

2013-05-01

There has been an increasing interest in the effects of volcanic eruption on the environment, climate, and health following two recent volcanic eruptions in Iceland. Although health issues are mainly focused on subjects living close to the eruption due to the high concentration of airborne ash and gasses in close vicinity to the volcanoes, the ash may also reach high altitude and get distributed thousands of kilometers away from the volcano. Ash particles used in the studies were collected at the Eyjafjallajökull and Grímsvötn eruption sites. The composition, size, density and morphology of the particles were analyzed and the effect of particle properties on the re-dispersion and lung deposition were studied. The aerodynamic size and morphology of the particles were consistent with field measurement results obtained during the eruptions. Due to their size and structure, the ash particles can be re-suspended and transported into the lungs. The total surface area of submicron ash particles deposited into the alveolar and tracheobronchial regions of the lungs were 3-9% and 1-2%, respectively. Although the main fraction of the surface area is deposited in the head airways region, a significant amount of particles can deposit into the alveolar and tracheobronchial regions. The results indicate that a substantial increase in the concentration of respirable airborne ash particles and associated health hazard can take place if the deposited ash particles are re-suspended under dry, windy conditions or by outdoor human activity.

The influence of mannitol on morphology and disintegration of spray-dried nano-embedded microparticles.

PubMed

Torge, Afra; Grützmacher, Philipp; Mücklich, Frank; Schneider, Marc

2017-06-15

Nano-embedded microparticles represent a promising approach to deliver nanoparticles to the lungs. Microparticles with an appropriate aerodynamic diameter enable an application by dry powder inhaler and the transport of nanoparticles into the airways. By disintegration after deposition, nanoparticles can be released to exhibit their advantages such as a sustained drug release and delivery of the drug across the mucus barrier. The use of an appropriate matrix excipient to embed the nanoparticles is essential for the necessary disintegration and release of nanoparticles. In this context we investigated the influence of mannitol on the morphology, aerodynamic properties and disintegration behavior of nano-embedded microparticles. PLGA nanoparticles and mannitol were spray dried each as sole component and in combination in three different ratios. An influence of the mannitol content on the morphology was observed. Pure mannitol microparticles were solid and spherical, while the addition of nanoparticles resulted in raisin-shaped hollow particles. The different morphologies can be explained by diffusion processes of the compounds described by the Péclet-number. All powders showed suitable aerodynamic properties. By dispersion of the powders in simulated lung fluid, initial nanoparticle sizes could be recovered for samples containing mannitol. The fraction of redispersed nanoparticles was increased with increasing mannitol content. To evaluate the disintegration under conditions with higher comparability to the in vivo situation, spray-dried powders were exposed to >90% relative humidity. The disintegration behavior was monitored by analyzing roughness values by white light interferometry and supporting SEM imaging. The exposure to high relative humidity was shown to be sufficient for disintegration of the microparticles containing mannitol, releasing morphologically unchanged nanoparticles. With increasing mannitol content, the disintegration occurred faster and to a higher degree. Under these conditions, microparticles only composed of nanoparticles did not disintegrate. By enabling the release of nanoparticles from nano-embedded microparticles, mannitol was shown to be an ideal excipient to convert nanoparticles by spray drying into an inhalable dry power formulation. Copyright © 2017 Elsevier B.V. All rights reserved.

Quantitative analysis of lung elastic fibers in idiopathic pleuroparenchymal fibroelastosis (IPPFE): comparison of clinical, radiological, and pathological findings with those of idiopathic pulmonary fibrosis (IPF).

PubMed

Enomoto, Noriyuki; Kusagaya, Hideki; Oyama, Yoshiyuki; Kono, Masato; Kaida, Yusuke; Kuroishi, Shigeki; Hashimoto, Dai; Fujisawa, Tomoyuki; Yokomura, Koshi; Inui, Naoki; Nakamura, Yutaro; Suda, Takafumi

2014-05-28

The pathological appearance of idiopathic pleuroparenchymal fibroelastosis (IPPFE) with hematoxylin-eosin staining is similar to that of usual interstitial pneumonia (UIP) in patients with idiopathic pulmonary fibrosis (IPF). The amount of elastic fibers (EF) and detailed differences between IPPFE and IPF have not been fully elucidated. The aim of this study was to quantify the EF and identify the differences between IPPFE and IPF. We evaluated six patients with IPPFE and 28 patients with IPF who underwent surgical lung biopsy or autopsy. The patients' clinical history, physical findings, chest high-resolution computed tomography (HRCT) findings, and pathological features of lung specimens were retrospectively evaluated. The amounts of EF in lung specimens were quantified with Weigert's staining using a camera with a charge-coupled device and analytic software in both groups. Fewer patients with IPPFE than IPF had fine crackles (50.0% vs. 96.4%, p = 0.012). Patients with IPPFE had a lower forced vital capacity (62.7 ± 10.9% vs. 88.6 ± 21.9% predicted, p = 0.009), higher consolidation scores on HRCT (1.7 ± 0.8 vs. 0.3 ± 0.5, p < 0.0001), lower body mass indices (17.9 ± 0.9 vs. 24.3 ± 2.8, p < 0.0001), and more pneumothoraces than did patients with IPF (66.7 vs. 3.6%, p = 0.002). Lung specimens from patients with IPPFE had more than twice the amount of EF than did those from patients with IPF (28.5 ± 3.3% vs. 12.1 ± 4.4%, p < 0.0001). The amount of EF in the lower lobes was significantly lower than that in the upper lobes, even in the same patient with IPPFE (23.6 ± 2.4% vs. 32.4 ± 5.5%, p = 0.048). However, the amount of EF in the lower lobes of patients with IPPFE was still higher than that of patients with IPF (23.6 ± 2.4% vs. 12.2 ± 4.4%, p < 0.0001). More than twice the amount of EF was found in patients with IPPFE than in those with IPF. Even in the lower lobes, the amount of EF was higher in patients with IPPFE than in those with IPF, although the distribution of lung EF was heterogeneous in IPPFE specimens.

Impact of treatment planning with deformable image registration on dose distribution for carbon-ion beam lung treatment using a fixed irradiation port and rotating couch.

PubMed

Kumagai, M; Mori, S; Yamamoto, N

2015-06-01

When using a fixed irradiation port, treatment couch rotation is necessary to increase beam angle selection. We evaluated dose variations associated with positional morphological changes to organs. We retrospectively chose the data sets of ten patients with lung cancer who underwent respiratory-gated CT at three different couch rotation angles (0°, 20° and -20°). The respective CT data sets are referred to as CT0, CT20 and CT-20. Three treatment plans were generated as follows: in Plan 1, all compensating bolus designs and dose distributions were calculated using CT0. To evaluate the rotation effect without considering morphology changes, in Plan 2, the compensating boli designed using CT0 were applied to the CT±20 images. Plan 3 involved compensating boli designed using the CT±20 images. The accumulated dose distributions were calculated using deformable image registration (DIR). A sufficient prescribed dose was calculated for the planning target volume (PTV) in Plan 1 [minimum dose received by a volume ≥95% (D95) > 95.8%]. By contrast, Plan 2 showed degraded dose conformation to the PTV (D95 > 90%) owing to mismatch of the bolus design to the morphological positional changes in the respective CT. The dose assessment results of Plan 3 were very close to those of Plan 1. Dose distribution is significantly affected by whether or not positional organ morphology changes are factored into dose planning. In treatment planning using multiple CT scans with different couch positions, it is mandatory to calculate the accumulated dose using DIR.

Decreased Lung Perfusion After Breast/Chest Wall Irradiation: Quantitative Results From a Prospective Clinical Trial

DOE Office of Scientific and Technical Information (OSTI.GOV)

Liss, Adam L., E-mail: adamliss68@gmail.com; Marsh, Robin B.; Kapadia, Nirav S.

Purpose: To quantify lung perfusion changes after breast/chest wall radiation therapy (RT) using pre- and post-RT single photon emission computed tomography/computed tomography (SPECT/CT) attenuation-corrected perfusion scans; and correlate decreased perfusion with adjuvant RT dose for breast cancer in a prospective clinical trial. Methods and Materials: As part of an institutional review board–approved trial studying the impact of RT technique on lung function in node-positive breast cancer, patients received breast/chest wall and regional nodal irradiation including superior internal mammary node RT to 50 to 52.2 Gy with a boost to the tumor bed/mastectomy scar. All patients underwent quantitative SPECT/CT lung perfusion scanningmore » before RT and 1 year after RT. The SPECT/CT scans were co-registered, and the ratio of decreased perfusion after RT relative to the pre-RT perfusion scan was calculated to allow for direct comparison of SPECT/CT perfusion changes with delivered RT dose. The average ratio of decreased perfusion was calculated in 10-Gy dose increments from 0 to 60 Gy. Results: Fifty patients had complete lung SPECT/CT perfusion data available. No patient developed symptoms consistent with pulmonary toxicity. Nearly all patients demonstrated decreased perfusion in the left lung according to voxel-based analyses. The average ratio of lung perfusion deficits increased for each 10-Gy increment in radiation dose to the lung, with the largest changes in regions of lung that received 50 to 60 Gy (ratio 0.72 [95% confidence interval 0.64-0.79], P<.001) compared with the 0- to 10-Gy region. For each increase in 10 Gy to the left lung, the lung perfusion ratio decreased by 0.06 (P<.001). Conclusions: In the assessment of 50 patients with node-positive breast cancer treated with RT in a prospective clinical trial, decreased lung perfusion by SPECT/CT was demonstrated. Our study allowed for quantification of lung perfusion defects in a prospective cohort of breast cancer patients for whom attenuation-corrected SPECT/CT scans could be registered directly to RT treatment fields for precise dose estimates.« less

High spatiotemporal resolution measurement of regional lung air volumes from 2D phase contrast x-ray images.

PubMed

Leong, Andrew F T; Fouras, Andreas; Islam, M Sirajul; Wallace, Megan J; Hooper, Stuart B; Kitchen, Marcus J

2013-04-01

Described herein is a new technique for measuring regional lung air volumes from two-dimensional propagation-based phase contrast x-ray (PBI) images at very high spatial and temporal resolution. Phase contrast dramatically increases lung visibility and the outlined volumetric reconstruction technique quantifies dynamic changes in respiratory function. These methods can be used for assessing pulmonary disease and injury and for optimizing mechanical ventilation techniques for preterm infants using animal models. The volumetric reconstruction combines the algorithms of temporal subtraction and single image phase retrieval (SIPR) to isolate the image of the lungs from the thoracic cage in order to measure regional lung air volumes. The SIPR algorithm was used to recover the change in projected thickness of the lungs on a pixel-by-pixel basis (pixel dimensions ≈ 16.2 μm). The technique has been validated using numerical simulation and compared results of measuring regional lung air volumes with and without the use of temporal subtraction for removing the thoracic cage. To test this approach, a series of PBI images of newborn rabbit pups mechanically ventilated at different frequencies was employed. Regional lung air volumes measured from PBI images of newborn rabbit pups showed on average an improvement of at least 20% in 16% of pixels within the lungs in comparison to that measured without the use of temporal subtraction. The majority of pixels that showed an improvement was found to be in regions occupied by bone. Applying the volumetric technique to sequences of PBI images of newborn rabbit pups, it is shown that lung aeration at birth can be highly heterogeneous. This paper presents an image segmentation technique based on temporal subtraction that has successfully been used to isolate the lungs from PBI chest images, allowing the change in lung air volume to be measured over regions as small as the pixel size. Using this technique, it is possible to measure changes in regional lung volume at high spatial and temporal resolution during breathing at much lower x-ray dose than would be required using computed tomography.

Association between spirometry controlled chest CT scores using computer-animated biofeedback and clinical markers of lung disease in children with cystic fibrosis.

PubMed

Kongstad, Thomas; Green, Kent; Buchvald, Frederik; Skov, Marianne; Pressler, Tania; Nielsen, Kim Gjerum

2017-01-01

Background : Computed tomography (CT) of the lungs is the gold standard for assessing the extent of structural changes in the lungs. Spirometry-controlled chest CT (SCCCT) has improved the usefulness of CT by standardising inspiratory and expiratory lung volumes during imaging. This was a single-centre cross-sectional study in children with cystic fibrosis (CF). Using SCCCT we wished to investigate the association between the quantity and extent of structural lung changes and pulmonary function outcomes, and prevalence of known CF lung pathogens. Methods : CT images were analysed by CF-CT scoring (expressed as % of maximum score) to quantify different aspects of structural lung changes including bronchiectasis, airway wall thickening, mucus plugging, opacities, cysts, bullae and gas trapping. Clinical markers consisted of outcomes from pulmonary function tests, microbiological cultures from sputum and serological samples reflecting anti-bacterial and anti-fungal antibodies. Results : Sixty-four children with CF, median age (range) of 12.7 (6.4-18.1) years, participated in the study. The median (range) CF-CT total score in all children was 9.3% (0.4-46.8) with gas trapping of 40.7% (3.7-100) as the most abundant finding. Significantly higher median CF-CT total scores (21.9%) were found in patients with chronic infections ( N  = 12) including Gram-negative infection and allergic bronchopulmonary aspergillosis (ABPA) exhibiting CF-CT total scores of 14.2% (ns) and 24.0% ( p  < 0.01), respectively, compared to 8.0% in patients with no chronic lung infection. Lung clearance index (LCI) derived from multiple breath washout exhibited closest association with total CF-CT scores, compared to other pulmonary function outcomes. Conclusions : The most prominent structural lung change was gas trapping, while CF-CT total scores were generally low, both showing close association with LCI. Chronic lung infections, specifically in the form of ABPA, were associated with increased scores in lung changes. Further investigation of impact of infections with different microorganisms on extent and progression of structural CF lung disease is needed.

Positron Emission Tomography With 18F-Fluorodeoxyglucose in Patients With Sickle Cell Acute Chest Syndrome

PubMed Central

de Prost, Nicolas; Sasanelli, Myriam; Deux, Jean-François; Habibi, Anoosha; Razazi, Keyvan; Galactéros, Frédéric; Meignan, Michel; Maître, Bernard; Brun-Buisson, Christian; Itti, Emmanuel; Dessap, Armand Mekontso

2015-01-01

Abstract The acute chest syndrome (ACS) is the main cause of mortality among adult patients with sickle cell disease (SCD). Its pathophysiology is still unclear. Using positron emission tomography (PET) with 18F-fluorodeoxyglucose [18F-fluorodeoxyglucose (18F-FDG)], we explored the relationship between regional lung density and lung metabolism, as a reflection of lung neutrophilic infiltration during ACS. Patients were prospectively enrolled in a single-center study. Dual modality chest PET/computed tomography (CT) scans were performed, with 18F-FDG emission scans for quantification of regional 18F-FDG uptake and CT scans with radiocontrast agent to check for pulmonary artery thrombosis. Regional lung 18F-FDG uptake was quantified in ACS patients and in SCD patients without ACS (SCD non-ACS controls). Maximal (SUVmax) and mean (SUVmean) standardized uptake values were computed. Seventeen patients with ACS (mean age 28.3 ± 6.4 years) were included. None died nor required invasive mechanical ventilation. The main lung opacity on CT scans was lower lobe consolidation. Lungs of patients with ACS exhibited higher SUVmax than those of SCD non-ACS controls (2.5 [2.1–2.9] vs 0.8 [0.6–1.0]; P < 0.0001). Regional SUVmax and SUVmean was higher in lower than in upper lobes of ACS patients (P < 0.001) with a significant correlation between lung density and SUVmax (R2 = 0.78). SUVmean was higher in upper lobes of ACS patients than in lungs of SCD non-ACS controls (P < 0.001). Patients with SUVmax >2.5 had longer intensive care unit (ICU) stay than others (7 [6–11] vs 4 [3–6] days; P = 0.016). Lungs of patients with ACS exhibited higher 18F-FDG uptake than SCD non-ACS controls. Lung apices had normal aeration and lower 18F-FDG uptake than lung bases, but higher 18F-FDG uptake than lungs of SCD non-ACS controls. Patients with higher lung 18F-FDG uptake had longer ICU stay than others. PMID:25950690

Morphological imaging and quantification of axial xylem tissue in Fraxinus excelsior L. through X-ray micro-computed tomography.

PubMed

Koddenberg, Tim; Militz, Holger

2018-05-05

The popularity of X-ray based imaging methods has continued to increase in research domains. In wood research, X-ray micro-computed tomography (XμCT) is useful for structural studies examining the three-dimensional and complex xylem tissue of trees qualitatively and quantitatively. In this study, XμCT made it possible to visualize and quantify the spatial xylem organization of the angiosperm species Fraxinus excelsior L. on the microscopic level. Through image analysis, it was possible to determine morphological characteristics of the cellular axial tissue (vessel elements, fibers, and axial parenchyma cells) three-dimensionally. X-ray imaging at high resolutions provides very distinct visual insight into the xylem structure. Numerical analyses performed through semi-automatic procedures made it possible to quickly quantify cell characteristics (length, diameter, and volume of cells). Use of various spatial resolutions (0.87-5 μm) revealed boundaries users should be aware of. Nevertheless, our findings, both qualitative and quantitative, demonstrate XμCT to be a valuable tool for studying the spatial cell morphology of F. excelsior. Copyright © 2018. Published by Elsevier Ltd.

Discovery of potential protein biomarkers of lung adenocarcinoma in bronchoalveolar lavage fluid by SWATH MS data-independent acquisition and targeted data extraction.

PubMed

Ortea, I; Rodríguez-Ariza, A; Chicano-Gálvez, E; Arenas Vacas, M S; Jurado Gámez, B

2016-04-14

Lung cancer currently ranks as the neoplasia with the highest global mortality rate. Although some improvements have been introduced in recent years, new advances in diagnosis are required in order to increase survival rates. New mildly invasive endoscopy-based diagnostic techniques include the collection of bronchoalveolar lavage fluid (BALF), which is discarded after using a portion of the fluid for standard pathological procedures. BALF proteomic analysis can contribute to clinical practice with more sensitive biomarkers, and can complement cytohistological studies by aiding in the diagnosis, prognosis, and subtyping of lung cancer, as well as the monitoring of treatment response. The range of quantitative proteomics methodologies used for biomarker discovery is currently being broadened with the introduction of data-independent acquisition (DIA) analysis-related approaches that address the massive quantitation of the components of a proteome. Here we report for the first time a DIA-based quantitative proteomics study using BALF as the source for the discovery of potential lung cancer biomarkers. The results have been encouraging in terms of the number of identified and quantified proteins. A panel of candidate protein biomarkers for adenocarcinoma in BALF is reported; this points to the activation of the complement network as being strongly over-represented and suggests this pathway as a potential target for lung cancer research. In addition, the results reported for haptoglobin, complement C4-A, and glutathione S-transferase pi are consistent with previous studies, which indicates that these proteins deserve further consideration as potential lung cancer biomarkers in BALF. Our study demonstrates that the analysis of BALF proteins by liquid chromatography-tandem mass spectrometry (LC-MS/MS), combining a simple sample pre-treatment and SWATH DIA MS, is a useful method for the discovery of potential lung cancer biomarkers. Bronchoalveolar lavage fluid (BALF) analysis can contribute to clinical practice with more sensitive biomarkers, thus complementing cytohistological studies in order to aid in the diagnosis, prognosis, and subtyping of lung cancer, as well as the monitoring of treatment response. Here we report a panel of candidate protein biomarkers for adenocarcinoma in BALF. Forty-four proteins showed a fold-change higher than 3.75 among adenocarcinoma patients compared with controls. This report is the first DIA-based quantitative proteomics study to use bronchoalveolar lavage fluid (BALF) as a matrix for discovering potential biomarkers. The results are encouraging in terms of the number of identified and quantified proteins, demonstrating that the analysis of BALF proteins by a SWATH approach is a useful method for the discovery of potential biomarkers of pulmonary diseases. Copyright © 2016 Elsevier B.V. All rights reserved.

Cloning nanocrystal morphology with soft templates

NASA Astrophysics Data System (ADS)

Thapa, Dev Kumar; Pandey, Anshu

2016-08-01

In most template directed preparative methods, while the template decides the nanostructure morphology, the structure of the template itself is a non-general outcome of its peculiar chemistry. Here we demonstrate a template mediated synthesis that overcomes this deficiency. This synthesis involves overgrowth of silica template onto a sacrificial nanocrystal. Such templates are used to copy the morphologies of gold nanorods. After template overgrowth, gold is removed and silver is regrown in the template cavity to produce a single crystal silver nanorod. This technique allows for duplicating existing nanocrystals, while also providing a quantifiable breakdown of the structure - shape interdependence.

Identifying heterogeneity in rates of morphological evolution: discrete character change in the evolution of lungfish (Sarcopterygii; Dipnoi).

PubMed

Lloyd, Graeme T; Wang, Steve C; Brusatte, Stephen L

2012-02-01

Quantifying rates of morphological evolution is important in many macroevolutionary studies, and critical when assessing possible adaptive radiations and episodes of punctuated equilibrium in the fossil record. However, studies of morphological rates of change have lagged behind those on taxonomic diversification, and most authors have focused on continuous characters and quantifying patterns of morphological rates over time. Here, we provide a phylogenetic approach, using discrete characters and three statistical tests to determine points on a cladogram (branches or entire clades) that are characterized by significantly high or low rates of change. These methods include a randomization approach that identifies branches with significantly high rates and likelihood ratio tests that pinpoint either branches or clades that have significantly higher or lower rates than the pooled rate of the remainder of the tree. As a test case for these methods, we analyze a discrete character dataset of lungfish, which have long been regarded as "living fossils" due to an apparent slowdown in rates since the Devonian. We find that morphological rates are highly heterogeneous across the phylogeny and recover a general pattern of decreasing rates along the phylogenetic backbone toward living taxa, from the Devonian until the present. Compared with previous work, we are able to report a more nuanced picture of lungfish evolution using these new methods. © 2011 The Author(s). Evolution© 2011 The Society for the Study of Evolution.

The Morphology of the Rat Vibrissal Array: A Model for Quantifying Spatiotemporal Patterns of Whisker-Object Contact

PubMed Central

Gopal, Venkatesh; Solomon, Joseph H.; Hartmann, Mitra J. Z.

2011-01-01

In all sensory modalities, the data acquired by the nervous system is shaped by the biomechanics, material properties, and the morphology of the peripheral sensory organs. The rat vibrissal (whisker) system is one of the premier models in neuroscience to study the relationship between physical embodiment of the sensor array and the neural circuits underlying perception. To date, however, the three-dimensional morphology of the vibrissal array has not been characterized. Quantifying array morphology is important because it directly constrains the mechanosensory inputs that will be generated during behavior. These inputs in turn shape all subsequent neural processing in the vibrissal-trigeminal system, from the trigeminal ganglion to primary somatosensory (“barrel”) cortex. Here we develop a set of equations for the morphology of the vibrissal array that accurately describes the location of every point on every whisker to within ±5% of the whisker length. Given only a whisker's identity (row and column location within the array), the equations establish the whisker's two-dimensional (2D) shape as well as three-dimensional (3D) position and orientation. The equations were developed via parameterization of 2D and 3D scans of six rat vibrissal arrays, and the parameters were specifically chosen to be consistent with those commonly measured in behavioral studies. The final morphological model was used to simulate the contact patterns that would be generated as a rat uses its whiskers to tactually explore objects with varying curvatures. The simulations demonstrate that altering the morphology of the array changes the relationship between the sensory signals acquired and the curvature of the object. The morphology of the vibrissal array thus directly constrains the nature of the neural computations that can be associated with extraction of a particular object feature. These results illustrate the key role that the physical embodiment of the sensor array plays in the sensing process. PMID:21490724

Integrative analysis for the discovery of lung cancer serological markers and validation by MRM-MS

PubMed Central

An, Byung Chull; Choi, Yoo-Duk; Yang, Eun Gyeong; Na, Kook-Joo; Lee, Seung-Taek; Park, Jae-Il; Kim, Seon-Young; Lee, Cheolju

2017-01-01

Non-small-cell lung cancer (NSCLC) constitutes approximately 80% of all diagnosed lung cancers, and diagnostic markers detectable in the plasma/serum of NSCLC patients are greatly needed. In this study, we established a pipeline for the discovery of markers using 9 transcriptome datasets from publicly available databases and profiling of six lung cancer cell secretomes. Thirty-one out of 312 proteins that overlapped between two-fold differentially expressed genes and identified cell secretome proteins were detected in the pooled plasma of lung cancer patients. To quantify the candidates in the serum of NSCLC patients, multiple-reaction-monitoring mass spectrometry (MRM-MS) was performed for five candidate biomarkers. Finally, two potential biomarkers (BCHE and GPx3; AUC = 0.713 and 0.673, respectively) and one two-marker panel generated by logistic regression (BCHE/GPx3; AUC = 0.773) were identified. A validation test was performed by ELISA to evaluate the reproducibility of GPx3 and BCHE expression in an independent set of samples (BCHE and GPx3; AUC = 0.630 and 0.759, respectively, BCHE/GPx3 panel; AUC = 0.788). Collectively, these results demonstrate the feasibility of using our pipeline for marker discovery and our MRM-MS platform for verifying potential biomarkers of human diseases. PMID:28837649

Integrative analysis for the discovery of lung cancer serological markers and validation by MRM-MS.

PubMed

Shin, Jihye; Song, Sang-Yun; Ahn, Hee-Sung; An, Byung Chull; Choi, Yoo-Duk; Yang, Eun Gyeong; Na, Kook-Joo; Lee, Seung-Taek; Park, Jae-Il; Kim, Seon-Young; Lee, Cheolju; Lee, Seung-Won

2017-01-01

Non-small-cell lung cancer (NSCLC) constitutes approximately 80% of all diagnosed lung cancers, and diagnostic markers detectable in the plasma/serum of NSCLC patients are greatly needed. In this study, we established a pipeline for the discovery of markers using 9 transcriptome datasets from publicly available databases and profiling of six lung cancer cell secretomes. Thirty-one out of 312 proteins that overlapped between two-fold differentially expressed genes and identified cell secretome proteins were detected in the pooled plasma of lung cancer patients. To quantify the candidates in the serum of NSCLC patients, multiple-reaction-monitoring mass spectrometry (MRM-MS) was performed for five candidate biomarkers. Finally, two potential biomarkers (BCHE and GPx3; AUC = 0.713 and 0.673, respectively) and one two-marker panel generated by logistic regression (BCHE/GPx3; AUC = 0.773) were identified. A validation test was performed by ELISA to evaluate the reproducibility of GPx3 and BCHE expression in an independent set of samples (BCHE and GPx3; AUC = 0.630 and 0.759, respectively, BCHE/GPx3 panel; AUC = 0.788). Collectively, these results demonstrate the feasibility of using our pipeline for marker discovery and our MRM-MS platform for verifying potential biomarkers of human diseases.

Stereological analysis of bacterial load and lung lesions in nonhuman primates (rhesus macaques) experimentally infected with Mycobacterium tuberculosis.

PubMed

Luciw, Paul A; Oslund, Karen L; Yang, Xiao-Wei; Adamson, Lourdes; Ravindran, Resmi; Canfield, Don R; Tarara, Ross; Hirst, Linda; Christensen, Miles; Lerche, Nicholas W; Offenstein, Heather; Lewinsohn, David; Ventimiglia, Frank; Brignolo, Laurie; Wisner, Erik R; Hyde, Dallas M

2011-11-01

Infection with Mycobacterium tuberculosis primarily produces a multifocal distribution of pulmonary granulomas in which the pathogen resides. Accordingly, quantitative assessment of the bacterial load and pathology is a substantial challenge in tuberculosis. Such assessments are critical for studies of the pathogenesis and for the development of vaccines and drugs in animal models of experimental M. tuberculosis infection. Stereology enables unbiased quantitation of three-dimensional objects from two-dimensional sections and thus is suited to quantify histological lesions. We have developed a protocol for stereological analysis of the lung in rhesus macaques inoculated with a pathogenic clinical strain of M. tuberculosis (Erdman strain). These animals exhibit a pattern of infection and tuberculosis similar to that of naturally infected humans. Conditions were optimized for collecting lung samples in a nonbiased, random manner. Bacterial load in these samples was assessed by a standard plating assay, and granulomas were graded and enumerated microscopically. Stereological analysis provided quantitative data that supported a significant correlation between bacterial load and lung granulomas. Thus this stereological approach enables a quantitative, statistically valid analysis of the impact of M. tuberculosis infection in the lung and will serve as an essential tool for objectively comparing the efficacy of drugs and vaccines.

Cancer mortality in a cohort of asbestos textile workers

PubMed Central

Pira, E; Pelucchi, C; Buffoni, L; Palmas, A; Turbiglio, M; Negri, E; Piolatto, P G; La Vecchia, C

2005-01-01

A cohort of 889 men and 1077 women employed for at least 1 month between 1946 and 1984 by a former Italian leading asbestos (mainly textile) company, characterised by extremely heavy exposures often for short durations, was followed up to 1996, for a total of 53 024 person-years of observation. Employment data were obtained from factory personnel records, while vital status and causes of death were ascertained through municipality registers and local health units. We observed 222 cancer deaths compared with 116.4 expected (standardized mortality ratio, SMR=191). The highest ratios were found for pleural (SMR=4105), peritoneal (SMR=1817) and lung (SMR=282) cancers. We observed direct relationships with duration of employment for lung and peritoneal cancer, and with time since first employment for lung cancer and mesothelioma. Pleural cancer risk was independent from duration (SMR=3428 for employment <1 year, 7659 for 1–4 years, 2979 for 5–9 years and 2130 for ⩾10 years). Corresponding SMRs for lung cancer were 139, 251, 233 and 531. Nonsignificantly increased ratios were found for ovarian (SMR=261), laryngeal (SMR=238) and oro-pharyngeal (SMR=226) cancers. This study confirms and further quantifies the central role of latency in pleural mesothelioma and of cumulative exposure in lung cancer. PMID:15702125

A high-resolution imaging technique using a whole-body, research photon counting detector CT system

NASA Astrophysics Data System (ADS)

Leng, S.; Yu, Z.; Halaweish, A.; Kappler, S.; Hahn, K.; Henning, A.; Li, Z.; Lane, J.; Levin, D. L.; Jorgensen, S.; Ritman, E.; McCollough, C.

2016-03-01

A high-resolution (HR) data collection mode has been introduced to a whole-body, research photon-counting-detector CT system installed in our laboratory. In this mode, 64 rows of 0.45 mm x 0.45 mm detector pixels were used, which corresponded to a pixel size of 0.25 mm x 0.25 mm at the iso-center. Spatial resolution of this HR mode was quantified by measuring the MTF from a scan of a 50 micron wire phantom. An anthropomorphic lung phantom, cadaveric swine lung, temporal bone and heart specimens were scanned using the HR mode, and image quality was subjectively assessed by two experienced radiologists. High spatial resolution of the HR mode was evidenced by the MTF measurement, with 15 lp/cm and 20 lp/cm at 10% and 2% modulation. Images from anthropomorphic phantom and cadaveric specimens showed clear delineation of small structures, such as lung vessels, lung nodules, temporal bone structures, and coronary arteries. Temporal bone images showed critical anatomy (i.e. stapes superstructure) that was clearly visible in the PCD system. These results demonstrated the potential application of this imaging mode in lung, temporal bone, and vascular imaging. Other clinical applications that require high spatial resolution, such as musculoskeletal imaging, may also benefit from this high resolution mode.

A computational framework to detect normal and tuberculosis infected lung from H and E-stained whole slide images

NASA Astrophysics Data System (ADS)

Niazi, M. Khalid Khan; Beamer, Gillian; Gurcan, Metin N.

2017-03-01

Accurate detection and quantification of normal lung tissue in the context of Mycobacterium tuberculosis infection is of interest from a biological perspective. The automatic detection and quantification of normal lung will allow the biologists to focus more intensely on regions of interest within normal and infected tissues. We present a computational framework to extract individual tissue sections from whole slide images having multiple tissue sections. It automatically detects the background, red blood cells and handwritten digits to bring efficiency as well as accuracy in quantification of tissue sections. For efficiency, we model our framework with logical and morphological operations as they can be performed in linear time. We further divide these individual tissue sections into normal and infected areas using deep neural network. The computational framework was trained on 60 whole slide images. The proposed computational framework resulted in an overall accuracy of 99.2% when extracting individual tissue sections from 120 whole slide images in the test dataset. The framework resulted in a relatively higher accuracy (99.7%) while classifying individual lung sections into normal and infected areas. Our preliminary findings suggest that the proposed framework has good agreement with biologists on how define normal and infected lung areas.

Luteolin attenuates TGF-β1-induced epithelial-mesenchymal transition of lung cancer cells by interfering in the PI3K/Akt-NF-κB-Snail pathway.

PubMed

Chen, Kun-Chieh; Chen, Chiu-Yuan; Lin, Chih-Ru; Lin, Chih-Ju; Yang, Tsung-Ying; Chen, Tzu-Hsiu; Wu, Li-Chen; Wu, Chun-Chi

2013-12-05

Luteolin is a natural flavonoid that possesses a variety of pharmacological activities, such as anti-inflammatory and anti-cancer abilities. Whether luteolin regulates the transformation ability of lung cancer cells remains unclear. The current study aims to uncover the effects and underlying mechanisms of luteolin in regulation of and epithelial-mesenchymal transition of lung cancer cells. The lung adenocarcinoma A549 cells were used in this experiment; the cells were pretreated with luteolin followed by administration with TGF-β1. The expression levels of various cadherin and related upstream regulatory modules were examined. Pretreatment of luteolin prevented the morphological change and downregulation of E-cadherin of A549 cells induced by TGF-β1. In addition, the activation of PI3K-Akt-IκBa-NF-κB-Snail pathway which leads to the decline of E-cadherin induced by TGF-β1 was also attenuated under the pretreatment of luteolin. We provide the mechanisms about how luteolin attenuated the epithelial-mesenchymal transition of A549 lung cancer cells induced by TGF-β1. This finding will strengthen the anti-cancer effects of flavonoid compounds via the regulation of migration/invasion and EMT ability of various cancer cells. © 2013.

Technical Advance: Live-imaging analysis of human dendritic cell migrating behavior under the influence of immune-stimulating reagents in an organotypic model of lung

PubMed Central

Nguyen Hoang, Anh Thu; Chen, Puran; Björnfot, Sofia; Högstrand, Kari; Lock, John G.; Grandien, Alf; Coles, Mark; Svensson, Mattias

2014-01-01

This manuscript describes technical advances allowing manipulation and quantitative analyses of human DC migratory behavior in lung epithelial tissue. DCs are hematopoietic cells essential for the maintenance of tissue homeostasis and the induction of tissue-specific immune responses. Important functions include cytokine production and migration in response to infection for the induction of proper immune responses. To design appropriate strategies to exploit human DC functional properties in lung tissue for the purpose of clinical evaluation, e.g., candidate vaccination and immunotherapy strategies, we have developed a live-imaging assay based on our previously described organotypic model of the human lung. This assay allows provocations and subsequent quantitative investigations of DC functional properties under conditions mimicking morphological and functional features of the in vivo parental tissue. We present protocols to set up and prepare tissue models for 4D (x, y, z, time) fluorescence-imaging analysis that allow spatial and temporal studies of human DCs in live epithelial tissue, followed by flow cytometry analysis of DCs retrieved from digested tissue models. This model system can be useful for elucidating incompletely defined pathways controlling DC functional responses to infection and inflammation in lung epithelial tissue, as well as the efficacy of locally administered candidate interventions. PMID:24899587

Urinary excretion of the ß-adrenergic feed additives ractopamine and zilpaterol in breast and lung cancer patients

USDA-ARS?s Scientific Manuscript database

Background: ß-agonists have been legally used in the U.S. for almost two decades to increase lean muscle mass in meat animals. Despite a cardiotoxic effect after high-dose exposure, there has been limited research on human ß-agonist exposures related to meat consumption. Objectives: We quantified u...

Total Airway Count on Computed Tomography and the Risk of Chronic Obstructive Pulmonary Disease Progression. Findings from a Population-based Study.

PubMed

Kirby, Miranda; Tanabe, Naoya; Tan, Wan C; Zhou, Guohai; Obeidat, Ma'en; Hague, Cameron J; Leipsic, Jonathon; Bourbeau, Jean; Sin, Don D; Hogg, James C; Coxson, Harvey O

2018-01-01

Studies of excised lungs show that significant airway attrition in the "quiet" zone occurs early in chronic obstructive pulmonary disease (COPD). To determine if the total number of airways quantified in vivo using computed tomography (CT) reflects early airway-related disease changes and is associated with lung function decline independent of emphysema in COPD. Participants in the multicenter, population-based, longitudinal CanCOLD (Canadian Chronic Obstructive Lung Disease) study underwent inspiratory/expiratory CT at visit 1; spirometry was performed at four visits over 6 years. Emphysema was quantified as the CT inspiratory low-attenuation areas below -950 Hounsfield units. CT total airway count (TAC) was measured as well as airway inner diameter and wall area using anatomically equivalent airways. Participants included never-smokers (n = 286), smokers with normal spirometry at risk for COPD (n = 298), Global Initiative for Chronic Obstructive Lung Disease (GOLD) I COPD (n = 361), and GOLD II COPD (n = 239). TAC was significantly reduced by 19% in both GOLD I and GOLD II compared with never-smokers (P < 0.0001) and by 17% in both GOLD I and GOLD II compared with at-risk participants (P < 0.0001) after adjusting for low-attenuation areas below -950 Hounsfield units. Further analysis revealed parent airways with missing daughter branches had reduced inner diameters (P < 0.0001) and thinner walls (P < 0.0001) compared with those without missing daughter branches. Among all CT measures, TAC had the greatest influence on FEV 1 (P < 0.0001), FEV 1 /FVC (P < 0.0001), and bronchodilator responsiveness (P < 0.0001). TAC was independently associated with lung function decline (FEV 1 , P = 0.02; FEV 1 /FVC, P = 0.01). TAC may reflect the airway-related disease changes that accumulate in the "quiet" zone in early/mild COPD, indicating that TAC acquired with commercially available software across various CT platforms may be a biomarker to predict accelerated COPD progression.

Effects of a Multidisciplinary Approach to Improve Volume of Diagnostic Material in CT-Guided Lung Biopsies

PubMed Central

Ferguson, Philip E.; Sales, Catherine M.; Hodges, Dalton C.; Sales, Elizabeth W.

2015-01-01

Background Recent publications have emphasized the importance of a multidisciplinary strategy for maximum conservation and utilization of lung biopsy material for advanced testing, which may determine therapy. This paper quantifies the effect of a multidisciplinary strategy implemented to optimize and increase tissue volume in CT-guided transthoracic needle core lung biopsies. The strategy was three-pronged: (1) once there was confidence diagnostic tissue had been obtained and if safe for the patient, additional biopsy passes were performed to further increase volume of biopsy material, (2) biopsy material was placed in multiple cassettes for processing, and (3) all tissue ribbons were conserved when cutting blocks in the histology laboratory. This study quantifies the effects of strategies #1 and #2. Design This retrospective analysis comparing CT-guided lung biopsies from 2007 and 2012 (before and after multidisciplinary approach implementation) was performed at a single institution. Patient medical records were reviewed and main variables analyzed include biopsy sample size, radiologist, number of blocks submitted, diagnosis, and complications. The biopsy sample size measured was considered to be directly proportional to tissue volume in the block. Results Biopsy sample size increased 2.5 fold with the average total biopsy sample size increasing from 1.0 cm (0.9–1.1 cm) in 2007 to 2.5 cm (2.3–2.8 cm) in 2012 (P<0.0001). The improvement was statistically significant for each individual radiologist. During the same time, the rate of pneumothorax requiring chest tube placement decreased from 15% to 7% (P = 0.065). No other major complications were identified. The proportion of tumor within the biopsy material was similar at 28% (23%–33%) and 35% (30%–40%) for 2007 and 2012, respectively. The number of cases with at least two blocks available for testing increased from 10.7% to 96.4% (P<0.0001). Conclusions The effect of this multidisciplinary strategy to CT-guided lung biopsies was effective in significantly increasing tissue volume and number of blocks available for advanced diagnostic testing. PMID:26479367

Multi-Modal Imaging in a Mouse Model of Orthotopic Lung Cancer

PubMed Central

Patel, Priya; Kato, Tatsuya; Ujiie, Hideki; Wada, Hironobu; Lee, Daiyoon; Hu, Hsin-pei; Hirohashi, Kentaro; Ahn, Jin Young; Zheng, Jinzi; Yasufuku, Kazuhiro

2016-01-01

Background Investigation of CF800, a novel PEGylated nano-liposomal imaging agent containing indocyanine green (ICG) and iohexol, for real-time near infrared (NIR) fluorescence and computed tomography (CT) image-guided surgery in an orthotopic lung cancer model in nude mice. Methods CF800 was intravenously administered into 13 mice bearing the H460 orthotopic human lung cancer. At 48 h post-injection (peak imaging agent accumulation time point), ex vivo NIR and CT imaging was performed. A clinical NIR imaging system (SPY®, Novadaq) was used to measure fluorescence intensity of tumor and lung. Tumor-to-background-ratios (TBR) were calculated in inflated and deflated states. The mean Hounsfield unit (HU) of lung tumor was quantified using the CT data set and a semi-automated threshold-based method. Histological evaluation using H&E, the macrophage marker F4/80 and the endothelial cell marker CD31, was performed, and compared to the liposomal fluorescence signal obtained from adjacent tissue sections Results The fluorescence TBR measured when the lung is in the inflated state (2.0 ± 0.58) was significantly greater than in the deflated state (1.42 ± 0.380 (n = 7, p<0.003). Mean fluorescent signal in tumor was highly variable across samples, (49.0 ± 18.8 AU). CT image analysis revealed greater contrast enhancement in lung tumors (a mean increase of 110 ± 57 HU) when CF800 is administered compared to the no contrast enhanced tumors (p = 0.0002). Conclusion Preliminary data suggests that the high fluorescence TBR and CT tumor contrast enhancement provided by CF800 may have clinical utility in localization of lung cancer during CT and NIR image-guided surgery. PMID:27584018

Multi-Modal Imaging in a Mouse Model of Orthotopic Lung Cancer.

PubMed

Patel, Priya; Kato, Tatsuya; Ujiie, Hideki; Wada, Hironobu; Lee, Daiyoon; Hu, Hsin-Pei; Hirohashi, Kentaro; Ahn, Jin Young; Zheng, Jinzi; Yasufuku, Kazuhiro

2016-01-01

Investigation of CF800, a novel PEGylated nano-liposomal imaging agent containing indocyanine green (ICG) and iohexol, for real-time near infrared (NIR) fluorescence and computed tomography (CT) image-guided surgery in an orthotopic lung cancer model in nude mice. CF800 was intravenously administered into 13 mice bearing the H460 orthotopic human lung cancer. At 48 h post-injection (peak imaging agent accumulation time point), ex vivo NIR and CT imaging was performed. A clinical NIR imaging system (SPY®, Novadaq) was used to measure fluorescence intensity of tumor and lung. Tumor-to-background-ratios (TBR) were calculated in inflated and deflated states. The mean Hounsfield unit (HU) of lung tumor was quantified using the CT data set and a semi-automated threshold-based method. Histological evaluation using H&E, the macrophage marker F4/80 and the endothelial cell marker CD31, was performed, and compared to the liposomal fluorescence signal obtained from adjacent tissue sections. The fluorescence TBR measured when the lung is in the inflated state (2.0 ± 0.58) was significantly greater than in the deflated state (1.42 ± 0.380 (n = 7, p<0.003). Mean fluorescent signal in tumor was highly variable across samples, (49.0 ± 18.8 AU). CT image analysis revealed greater contrast enhancement in lung tumors (a mean increase of 110 ± 57 HU) when CF800 is administered compared to the no contrast enhanced tumors (p = 0.0002). Preliminary data suggests that the high fluorescence TBR and CT tumor contrast enhancement provided by CF800 may have clinical utility in localization of lung cancer during CT and NIR image-guided surgery.

Lung Microbiota Is Related to Smoking Status and to Development of Acute Respiratory Distress Syndrome in Critically Ill Trauma Patients.

PubMed

Panzer, Ariane R; Lynch, Susan V; Langelier, Chaz; Christie, Jason D; McCauley, Kathryn; Nelson, Mary; Cheung, Christopher K; Benowitz, Neal L; Cohen, Mitchell J; Calfee, Carolyn S

2018-03-01

Cigarette smoking is associated with increased risk of acute respiratory distress syndrome (ARDS) in patients after severe trauma; however, the mechanisms underlying this association are unknown. To determine whether cigarette smoking contributes to ARDS development after trauma by altering community composition of the lung microbiota. We studied the lung microbiota of mechanically ventilated patients admitted to the ICU after severe blunt trauma. To do so, we used 16S ribosomal RNA gene amplicon sequencing of endotracheal aspirate samples obtained on ICU admission (n = 74) and at 48 hours after admission (n = 30). Cigarette smoke exposure (quantified using plasma cotinine), ARDS development, and other clinical parameters were correlated with lung microbiota composition. Smoking status was significantly associated with lung bacterial community composition at ICU admission (P = 0.007 by permutational multivariate ANOVA [PERMANOVA]) and at 48 hours (P = 0.03 by PERMANOVA), as well as with significant enrichment of potential pathogens, including Streptococcus, Fusobacterium, Prevotella, Haemophilus, and Treponema. ARDS development was associated with lung community composition at 48 hours (P = 0.04 by PERMANOVA) and was characterized by relative enrichment of Enterobacteriaceae and of specific taxa enriched at baseline in smokers, including Prevotella and Fusobacterium. After severe blunt trauma, a history of smoking is related to lung microbiota composition, both at the time of ICU admission and at 48 hours. ARDS development is also correlated with respiratory microbial community structure at 48 hours and with taxa that are relatively enriched in smokers at ICU admission. The data derived from this pilot study suggest that smoking-related changes in the lung microbiota could be related to ARDS development after severe trauma.

Impact of occupational carcinogens on lung cancer risk in a general population

PubMed Central

De Matteis, Sara; Consonni, Dario; Lubin, Jay H; Tucker, Margaret; Peters, Susan; Vermeulen, Roel CH; Kromhout, Hans; Bertazzi, Pier Alberto; Caporaso, Neil E; Pesatori, Angela C; Wacholder, Sholom; Landi, Maria Teresa

2012-01-01

Background Exposure to occupational carcinogens is an important preventable cause of lung cancer. Most of the previous studies were in highly exposed industrial cohorts. Our aim was to quantify lung cancer burden attributable to occupational carcinogens in a general population. Methods We applied a new job–exposure matrix (JEM) to translate lifetime work histories, collected by personal interview and coded into standard job titles, into never, low and high exposure levels for six known/suspected occupational lung carcinogens in the Environment and Genetics in Lung cancer Etiology (EAGLE) population-based case–control study, conducted in Lombardy region, Italy, in 2002–05. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated in men (1537 cases and 1617 controls), by logistic regression adjusted for potential confounders, including smoking and co-exposure to JEM carcinogens. The population attributable fraction (PAF) was estimated as impact measure. Results Men showed an increased lung cancer risk even at low exposure to asbestos (OR: 1.76; 95% CI: 1.42–2.18), crystalline silica (OR: 1.31; 95% CI: 1.00–1.71) and nickel–chromium (OR: 1.18; 95% CI: 0.90–1.53); risk increased with exposure level. For polycyclic aromatic hydrocarbons, an increased risk (OR: 1.64; 95% CI: 0.99–2.70) was found only for high exposures. The PAFs for any exposure to asbestos, silica and nickel–chromium were 18.1, 5.7 and 7.0%, respectively, equivalent to an overall PAF of 22.5% (95% CI: 14.1–30.0). This corresponds to about 1016 (95% CI: 637–1355) male lung cancer cases/year in Lombardy. Conclusions These findings support the substantial role of selected occupational carcinogens on lung cancer burden, even at low exposures, in a general population. PMID:22467291

Impact of occupational carcinogens on lung cancer risk in a general population.

PubMed

De Matteis, Sara; Consonni, Dario; Lubin, Jay H; Tucker, Margaret; Peters, Susan; Vermeulen, Roel Ch; Kromhout, Hans; Bertazzi, Pier Alberto; Caporaso, Neil E; Pesatori, Angela C; Wacholder, Sholom; Landi, Maria Teresa

2012-06-01

Exposure to occupational carcinogens is an important preventable cause of lung cancer. Most of the previous studies were in highly exposed industrial cohorts. Our aim was to quantify lung cancer burden attributable to occupational carcinogens in a general population. We applied a new job-exposure matrix (JEM) to translate lifetime work histories, collected by personal interview and coded into standard job titles, into never, low and high exposure levels for six known/suspected occupational lung carcinogens in the Environment and Genetics in Lung cancer Etiology (EAGLE) population-based case-control study, conducted in Lombardy region, Italy, in 2002-05. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated in men (1537 cases and 1617 controls), by logistic regression adjusted for potential confounders, including smoking and co-exposure to JEM carcinogens. The population attributable fraction (PAF) was estimated as impact measure. Men showed an increased lung cancer risk even at low exposure to asbestos (OR: 1.76; 95% CI: 1.42-2.18), crystalline silica (OR: 1.31; 95% CI: 1.00-1.71) and nickel-chromium (OR: 1.18; 95% CI: 0.90-1.53); risk increased with exposure level. For polycyclic aromatic hydrocarbons, an increased risk (OR: 1.64; 95% CI: 0.99-2.70) was found only for high exposures. The PAFs for any exposure to asbestos, silica and nickel-chromium were 18.1, 5.7 and 7.0%, respectively, equivalent to an overall PAF of 22.5% (95% CI: 14.1-30.0). This corresponds to about 1016 (95% CI: 637-1355) male lung cancer cases/year in Lombardy. These findings support the substantial role of selected occupational carcinogens on lung cancer burden, even at low exposures, in a general population.

Effect of lungeing on head and pelvic movement asymmetry in horses with induced lameness.

PubMed

Rhodin, M; Pfau, T; Roepstorff, L; Egenvall, A

2013-12-01

Lungeing is an important part of lameness examinations, since the circular path enforced during lungeing is thought to accentuate low grade lameness. However, during lungeing the movement of sound horses becomes naturally asymmetric, which may mimic lameness. Also, compensatory movements in the opposite half of the body may mimic lameness. The aim of this study was to objectively study the presence of circle-dependent and compensatory movement asymmetries in horses with induced lameness. Ten horses were trotted in a straight line and lunged in both directions on a hard surface. Lameness was induced (reversible hoof pressure) in each limb, one at a time, in random order. Vertical head and pelvic movements were measured with body-mounted, uni-axial accelerometers. Differences between maximum and minimum height observed during/after left and right stance phases for the head (HDmax, HDmin) and pelvis (PDmax, PDmin) were measured. Mixed models were constructed to study the effect of lungeing direction and induction, and to quantify secondary compensatory asymmetry mechanisms in the forelimbs and hind limbs. Head and pelvic movement symmetries were affected by lungeing. Minimum pelvic height difference (PDmin) changed markedly, increasing significantly during lungeing, giving the impression of inner hind limb lameness. Primary hind limb lameness induced compensatory head movement, which mimicked an ipsilateral forelimb lameness of almost equal magnitude to the primary hind limb lameness. This could contribute to difficulty in correctly detecting hind limb lameness. Induced forelimb lameness caused both a compensatory contralateral (change in PDmax) and an ipsilateral (change in PDmin) hind limb asymmetry, potentially mimicking hind limb lameness, but of smaller magnitude. Both circle-dependent and compensatory movement mechanisms must be taken into account when evaluating lameness. Copyright © 2013 Elsevier Ltd. All rights reserved.

GM2-activator protein: a new biomarker for lung cancer.

PubMed

Potprommanee, Laddawan; Ma, Haou-Tzong; Shank, Lalida; Juan, Yi-Hsiu; Liao, Wei-Yu; Chen, Shui-Tein; Yu, Chong-Jen

2015-01-01

Effective biomarkers for early diagnosis of lung cancer are needed. A recent study demonstrated that urinary GM2-activator protein (GM2AP) level was increased in lung cancer patients. This study aims to validate the potential application of GM2AP as a biomarker for diagnosis of lung cancer. Serum and urine samples were obtained from 189 participants (133 patients for treatment naive lung cancer, 26 healthy volunteers for urine, and 30 healthy volunteers for serum). GM2AP level was detected by Western blotting and quantified using enzyme-linked immunosorbent assay (ELISA). The GM2AP expression in tumors and nontumor parts of lung tissues from 143 nonsmall cell lung cancers was detected by immunohistochemical stains. There was an 8.11 ± 1.36 folds increase in urine and a 5.41 ± 0.73 folds increase in serum level of GM2AP in lung cancer patients compared with healthy volunteers (p < 0.0001), achieving a 0.89 AUC value in urine and 0.90 AUC value in serum for the receiver-operating characteristic curves. Both serum and urine levels of GM2AP correlated significantly with pathology stages (urine, p = 0.009; serum, p < 0.0001). Using immunohistochemical, positive expression of GM2AP was found at 83.9% of nonsmall cell lung cancers patients and none in normal tissue. The GM2AP expression was significantly correlated with pathology stage (p = 0.0001). Patients with higher GM2AP expression had shorter overall survival (p = 0.045) and disease-free survival (p = 0.049) than lower GM2AP expression. Moreover, the multivariate analysis suggested GM2AP as an independent predictors of disease-free survival and overall survival. Our study demonstrates that GM2AP might serve as potential diagnostic and prognostic biomarkers in patients with lung cancer.

SU-E-J-86: Lobar Lung Function Quantification by PET Galligas and CT Ventilation Imaging in Lung Cancer Patients

DOE Office of Scientific and Technical Information (OSTI.GOV)

Eslick, E; Kipritidis, J; Keall, P

2014-06-01

Purpose: The purpose of this study was to quantify the lobar lung function using the novel PET Galligas ([68Ga]-carbon nanoparticle) ventilation imaging and the investigational CT ventilation imaging in lung cancer patients pre-treatment. Methods: We present results on our first three lung cancer patients (2 male, mean age 78 years) as part of an ongoing ethics approved study. For each patient a PET Galligas ventilation (PET-V) image and a pair of breath hold CT images (end-exhale and end-inhale tidal volumes) were acquired using a Siemens Biograph PET CT. CT-ventilation (CT-V) images were created from the pair of CT images usingmore » deformable image registration (DIR) algorithms and the Hounsfield Unit (HU) ventilation metric. A comparison of ventilation quantification from each modality was done on the lobar level and the voxel level. A Bland-Altman plot was used to assess the difference in mean percentage contribution of each lobe to the total lung function between the two modalities. For each patient, a voxel-wise Spearmans correlation was calculated for the whole lungs between the two modalities. Results: The Bland-Altman plot demonstrated strong agreement between PET-V and CT-V for assessment of lobar function (r=0.99, p<0.001; range mean difference: −5.5 to 3.0). The correlation between PET-V and CT-V at the voxel level was moderate(r=0.60, p<0.001). Conclusion: This preliminary study on the three patients data sets demonstrated strong agreement between PET and CT ventilation imaging for the assessment of pre-treatment lung function at the lobar level. Agreement was only moderate at the level of voxel correlations. These results indicate that CT ventilation imaging has potential for assessing pre-treatment lobar lung function in lung cancer patients.« less

Lung volume changes during cleaning of closed endotracheal suction catheters: a randomized crossover study using electrical impedance tomography.

PubMed

Corley, Amanda; Sharpe, Nicola; Caruana, Lawrence R; Spooner, Amy J; Fraser, John F

2014-04-01

Airway suctioning in mechanically ventilated patients is required to maintain airway patency. Closed suction catheters (CSCs) minimize lung volume loss during suctioning but require cleaning post-suction. Despite their widespread use, there is no published evidence examining lung volumes during CSC cleaning. The study objectives were to quantify lung volume changes during CSC cleaning and to determine whether these changes were preventable using a CSC with a valve in situ between the airway and catheter cleaning chamber. This prospective randomized crossover study was conducted in a metropolitan tertiary ICU. Ten patients mechanically ventilated via volume-controlled synchronized intermittent mandatory ventilation (SIMV-VC) and requiring manual hyperinflation (MHI) were included in this study. CSC cleaning was performed using 2 different brands of CSC (one with a valve [Ballard Trach Care 72, Kimberly-Clark, Roswell, Georgia] and one without [Portex Steri-Cath DL, Smiths Medical, Dublin, Ohio]). The maneuvers were performed during both SIMV-VC and MHI. Lung volume change was measured via impedance change using electrical impedance tomography. A mixed model was used to compare the estimated means. During cleaning of the valveless CSC, significant decreases in lung impedance occurred during MHI (-2563 impedance units, 95% CI 2213-2913, P < .001), and significant increases in lung impedance occurred during SIMV (762 impedance units, 95% CI 452-1072, P < .001). In contrast, cleaning of the CSC with a valve in situ resulted in non-significant lung volume changes and maintenance of normal ventilation during MHI and SIMV-VC, respectively (188 impedance units, 95% CI -136 to 511, P = .22; and 22 impedance units, 95% CI -342 to 299, P = .89). When there is no valve between the airway and suction catheter, cleaning of the CSC results in significant derangements in lung volume. Therefore, the presence of such a valve should be considered essential in preserving lung volumes and uninterrupted ventilation in mechanically ventilated patients.

The influence of gravity on regional lung blood flow in humans: SPECT in the upright and head-down posture.

PubMed

Ax, M; Sanchez-Crespo, A; Lindahl, S G E; Mure, M; Petersson, J

2017-06-01

Previous studies in humans have shown that gravity has little influence on the distribution of lung blood flow while changing posture from supine to prone. This study aimed to evaluate the maximal influence of posture by comparison of regional lung blood flow in the upright and head-down posture in 8 healthy volunteers, using a tilt table. Regional lung blood flow was marked by intravenous injection of macroaggregates of human albumin labeled with 99m Tc or 113m In, in the upright and head-down posture, respectively, during tidal breathing. Both radiotracers remain fixed in the lung after administration. The distribution of radioactivity was mapped using quantitative single photon emission computed tomography (SPECT) corrected for attenuation and scatter. All images were obtained supine during tidal breathing. A shift from upright to the head-down posture caused a clear redistribution of blood flow from basal to apical regions. We conclude that posture plays a role for the distribution of lung blood flow in upright humans, and that the influence of posture, and thereby gravity, is much greater in the upright and head-down posture than in horizontal postures. However, the results of the study demonstrate that lung structure is the main determinant of regional blood flow and gravity is a secondary contributor to the distribution of lung blood flow in the upright and head-down positions. NEW & NOTEWORTHY Using a dual-isotope quantitative SPECT method, we demonstrated that although a shift in posture redistributes blood flow in the direction of gravity, the results are also consistent with lung structure being a greater determinant of regional blood flow than gravity. To our knowledge, this is the first study to use modern imaging methods to quantify the shift in regional lung blood flow in humans at a change between the upright and head-down postures. Copyright © 2017 the American Physiological Society.

Lung Cancers Associated with Cystic Airspaces: Underrecognized Features of Early Disease.

PubMed

Sheard, Sarah; Moser, Joanna; Sayer, Charlie; Stefanidis, Konstantinos; Devaraj, Anand; Vlahos, Ioannis

2018-01-01

Early lung cancers associated with cystic airspaces are increasingly being recognized as a cause of delayed diagnoses-owing to data gathered from screening trials and encounters in routine clinical practice as more patients undergo serial imaging. Several morphologic subtypes of cancers associated with cystic airspaces exist and can exhibit variable patterns of progression as the solid elements of the tumor grow. Current understanding of the pathogenesis of these malignancies is limited, and the numbers of cases reported in the literature are small. However, several tumor cell types are represented in these lesions, with adenocarcinoma predominating. The features of cystic airspaces differ among cases and include emphysematous bullae, congenital or fibrotic cysts, subpleural blebs, bronchiectatic airways, and distended distal airspaces. Once identified, these cystic lesions pose management challenges to radiologists in terms of distinguishing them from benign mimics of cancer that are commonly seen in patients who also are at increased risk of lung cancer. Rendering a definitive tissue-based diagnosis can be difficult when the lesions are small, and affected patients tend to be in groups that are at higher risk of requiring biopsy or resection. In addition, the decision to monitor these cases can add to patient anxiety and cause the additional burden of strained departmental resources. The authors have drawn from their experience, emerging evidence from international lung cancer screening trials, and large databases of lung cancer cases from other groups to analyze the prevalence and evolution of lung cancers associated with cystic airspaces and provide guidance for managing these lesions. Although there are insufficient data to support specific management guidelines similar to those for managing small solid and ground-glass lung nodules, these data and guidelines should be the direction for ongoing research on early detection of lung cancer. © RSNA, 2018.