Mass preserving registration for lung CT

NASA Astrophysics Data System (ADS)

Gorbunova, Vladlena; Lo, Pechin; Loeve, Martine; Tiddens, Harm A.; Sporring, Jon; Nielsen, Mads; de Bruijne, Marleen

2009-02-01

In this paper, we evaluate a novel image registration method on a set of expiratory-inspiratory pairs of computed tomography (CT) lung scans. A free-form multi resolution image registration technique is used to match two scans of the same subject. To account for the differences in the lung intensities due to differences in inspiration level, we propose to adjust the intensity of lung tissue according to the local expansion or compression. An image registration method without intensity adjustment is compared to the proposed method. Both approaches are evaluated on a set of 10 pairs of expiration and inspiration CT scans of children with cystic fibrosis lung disease. The proposed method with mass preserving adjustment results in significantly better alignment of the vessel trees. Analysis of local volume change for regions with trapped air compared to normally ventilated regions revealed larger differences between these regions in the case of mass preserving image registration, indicating that mass preserving registration is better at capturing localized differences in lung deformation.

Tissue spray ionization mass spectrometry for rapid recognition of human lung squamous cell carcinoma

NASA Astrophysics Data System (ADS)

Wei, Yiping; Chen, Liru; Zhou, Wei; Chingin, Konstantin; Ouyang, Yongzhong; Zhu, Tenggao; Wen, Hua; Ding, Jianhua; Xu, Jianjun; Chen, Huanwen

2015-05-01

Tissue spray ionization mass spectrometry (TSI-MS) directly on small tissue samples has been shown to provide highly specific molecular information. In this study, we apply this method to the analysis of 38 pairs of human lung squamous cell carcinoma tissue (cancer) and adjacent normal lung tissue (normal). The main components of pulmonary surfactants, dipalmitoyl phosphatidylcholine (DPPC, m/z 757.47), phosphatidylcholine (POPC, m/z 782.52), oleoyl phosphatidylcholine (DOPC, m/z 808.49), and arachidonic acid stearoyl phosphatidylcholine (SAPC, m/z 832.43), were identified using high-resolution tandem mass spectrometry. Monte Carlo sampling partial least squares linear discriminant analysis (PLS-LDA) was used to distinguish full-mass-range mass spectra of cancer samples from the mass spectra of normal tissues. With 5 principal components and 30 - 40 Monte Carlo samplings, the accuracy of cancer identification in matched tissue samples reached 94.42%. Classification of a tissue sample required less than 1 min, which is much faster than the analysis of frozen sections. The rapid, in situ diagnosis with minimal sample consumption provided by TSI-MS is advantageous for surgeons. TSI-MS allows them to make more informed decisions during surgery.

Recipient-Matching of Passenger Leukocytes Prolongs Survival of Donor Lung Allografts in Miniature Swine

PubMed Central

Madariaga, Maria Lucia L.; Michel, Sebastian G.; La Muraglia, Glenn M.; Sihag, Smita; Leonard, David A.; Farkash, Evan A.; Colvin, Robert B.; Cetrulo, Curtis L.; Huang, Christene A.; Sachs, David H.; Madsen, Joren C.; Allan, James S.

2014-01-01

Background Allograft rejection continues to be a vexing problem in clinical lung transplantation, and the role played by passenger leukocytes in the rejection or acceptance of an organ is unclear. Here we tested whether recipient-matching of donor graft passenger leukocytes would impact graft survival in a preclinical model of orthotopic left lung transplantation. Methods In the experimental group (Group 1), donor lungs were obtained from chimeric swine, in which the passenger leukocytes (but not the parenchyma) were MHC-matched to the recipients (n=3). In the control group (Group 2), both the donor parenchyma and the passenger leukocytes were MHC-mismatched to the recipients (n = 3). Results Lungs harvested from swine previously rendered chimeric by hematopoietic stem cell transplantation using recipient-type cells showed a high degree of passenger leukocyte chimerism by immunohistochemistry and flow cytometry. The chimeric lungs containing passenger leukocytes matched to the lung recipient (Group 1) survived on average 107 days (range 80–156). Control lung allografts (Group 2) survived on average 45 days (range 29–64; p<0.05). Conclusion Our data indicate that recipient-matching of passenger leukocytes significantly prolongs lung allograft survival. PMID:25757217

Krypton-81m ventilation scanning: acute respiratory disease

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

Lavender, J.P.; Irving, H.; Armstrong, J.D. II

1981-02-01

From experience with 700 patients undergoing ventilation and perfusion lung scanning with krypton-81m/technetium-99m technique, 34 patients suffering from nonembolic acute respiratory disease were selected for review. In 16 patients with pneumonia, all had defects of ventilation corresponding to, or larger than, the radiologic consolidation. In 13 patients there was some preservation of perfusion in the consolidated region. In two of the three patients with matched defects, the pneumonia was of long standing. In seven patients with collapse or atelectasis and in 11 patients with acute reversible bronchial obstruction and normal volume lungs, a similar pattern or ventillation and perfusion wasmore » observed.« less

Fibroblast growth factor 10 haploinsufficiency causes chronic obstructive pulmonary disease.

PubMed

Klar, Joakim; Blomstrand, Peter; Brunmark, Charlott; Badhai, Jitendra; Håkansson, Hanna Falk; Brange, Charlotte Sollie; Bergendal, Birgitta; Dahl, Niklas

2011-10-01

Genetic factors influencing lung function may predispose to chronic obstructive pulmonary disease (COPD). The fibroblast growth factor 10 (FGF10) signalling pathway is critical for lung development and lung epithelial renewal. The hypothesis behind this study was that constitutive FGF10 insufficiency may lead to pulmonary disorder. Therefore investigation of the pulmonary functions of patients heterozygous for loss of function mutations in the FGF10 gene was performed. The spirometric measures of lung function from patients and non-carrier siblings were compared and both groups were related to matched reference data for normal human lung function. The patients show a significant decrease in lung function parameters when compared to control values. The average FEV1/IVC quota (FEV1%) for the patients is 0.65 (80% of predicted) and reversibility test using Terbutalin resulted in a 3.7% increase in FEV1. Patients with FGF10 haploinsufficiency have lung function parameters indicating COPD. A modest response to Terbutalin confirms an irreversible obstructive lung disease. These findings support the idea that genetic variants affecting the FGF10 signalling pathway are important determinants of lung function that may ultimately contribute to COPD. Specifically, the results show that FGF10 haploinsufficiency affects lung function measures providing a model for a dosage sensitive effect of FGF10 in the development of COPD.

The microbiome of the lung and its extracellular vesicles in nonsmokers, healthy smokers and COPD patients

PubMed Central

Kim, Hyun Jung; Kim, You-Sun; Kim, Kang-Hyun; Choi, Jun-Pyo; Kim, Yoon-Keun; Yun, Sunmi; Sharma, Lokesh; Dela Cruz, Charles S; Lee, Jae Seung; Oh, Yeon-Mok; Lee, Sang-Do; Lee, Sei Won

2017-01-01

Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory disease, and bacterial infection plays a role in its pathogenesis. Bacteria secrete nanometer-sized extracellular vesicles (EVs), which may induce more immune dysfunction and inflammation than the bacteria themselves. We hypothesized that the microbiome of lung EVs might have distinct characteristics depending on the presence of COPD and smoking status. We analyzed and compared the microbiomes of 13 nonsmokers with normal spirometry, 13 smokers with normal spirometry (healthy smokers) and 13 patients with COPD by using 16S ribosomal RNA gene sequencing of surgical lung tissue and lung EVs. Subjects were matched for age and sex in all groups and for smoking levels in the COPD and healthy smoker groups. Each group included 12 men and 1 woman with the same mean age of 65.5 years. In all groups, EVs consistently showed more operational taxonomic units (OTUs) than lung tissue. In the healthy smoker and COPD groups, EVs had a higher Shannon index and a lower Simpson index than lung tissue and this trend was more prominent in the COPD group. Principal component analysis (PCA) showed clusters based on sample type rather than participants' clinical characteristics. Stenotrophomonas, Propionibacterium and Alicyclobacillus were the most commonly found genera. Firmicutes were highly present in the EVs of the COPD group compared with other samples or groups. Our analysis of the lung microbiome revealed that the bacterial communities present in the EVs and in the COPD group possessed distinct characteristics with differences in the OTUs, diversity indexes and PCA clustering. PMID:28408748

SU-E-J-23: An Accurate Algorithm to Match Imperfectly Matched Images for Lung Tumor Detection Without Markers

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

Rozario, T; Bereg, S; Chiu, T

Purpose: In order to locate lung tumors on projection images without internal markers, digitally reconstructed radiograph (DRR) is created and compared with projection images. Since lung tumors always move and their locations change on projection images while they are static on DRRs, a special DRR (background DRR) is generated based on modified anatomy from which lung tumors are removed. In addition, global discrepancies exist between DRRs and projections due to their different image originations, scattering, and noises. This adversely affects comparison accuracy. A simple but efficient comparison algorithm is reported. Methods: This method divides global images into a matrix ofmore » small tiles and similarities will be evaluated by calculating normalized cross correlation (NCC) between corresponding tiles on projections and DRRs. The tile configuration (tile locations) will be automatically optimized to keep the tumor within a single tile which has bad matching with the corresponding DRR tile. A pixel based linear transformation will be determined by linear interpolations of tile transformation results obtained during tile matching. The DRR will be transformed to the projection image level and subtracted from it. The resulting subtracted image now contains only the tumor. A DRR of the tumor is registered to the subtracted image to locate the tumor. Results: This method has been successfully applied to kV fluoro images (about 1000 images) acquired on a Vero (Brainlab) for dynamic tumor tracking on phantom studies. Radiation opaque markers are implanted and used as ground truth for tumor positions. Although, other organs and bony structures introduce strong signals superimposed on tumors at some angles, this method accurately locates tumors on every projection over 12 gantry angles. The maximum error is less than 2.6 mm while the total average error is 1.0 mm. Conclusion: This algorithm is capable of detecting tumor without markers despite strong background signals.« less

SU-F-T-150: Comparing Normal Tissue Irradiated Volumes for Proton Vs. Photon Treatment Plans On Lung Patients

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

Liu, A; Mohan, R; Liao, Z

Purpose: The aim of this work is to compare the “irradiated volume” (IRV) of normal tissues receiving 5, 20, 50, 80 and 90% or higher of the prescription dose with passively scattered proton therapy (PSPT) vs. IMRT of lung cancer patients. The overall goal of this research is to understand the factors affecting outcomes of a randomized PSPT vs. IMRT lung trial. Methods: Thirteen lung cancer patients, selected randomly, were analyzed. Each patient had PSPT and IMRT 74 Gy (RBE) plans meeting the same normal tissue constraints generated. IRVs were created for pairs of IMRT and PSPT plans on eachmore » patient. The volume of iGTV, (respiratory motion-incorporated GTV) was subtracted from each IRV to create normal tissue irradiated volume IRVNT. The average of IRVNT DVHs over all patients was also calculated for both modalities and inter-compared as were the selected dose-volume indices. Probability (p value) curves were calculated based on the Wilcoxon matched-paired signed-rank test to determine the dose regions where the statistically significant differences existed. Results: As expected, the average 5, 20 and 50% IRVNT’s for PSPT was found to be significantly smaller than for IMRT (p < 0.001, 0.01, and 0.001 respectively). However, the average 90% IRVNT for PSPT was greater than for IMRT (p = 0.003) presumably due to larger penumbra of protons and the long range of protons in lower density media. The 80% IRVNT for PSPT was also larger but not statistically distinguishable (p = .224). Conclusion: PSPT modality has smaller irradiated volume at lower doses, but larger volume at high doses. A larger cohort of lung patients will be analyzed in the future and IRVNT of patients treated with PSPT and IMRT will be compared to determine if the irradiated volumes (the magnitude of “dose bath”) correlate with outcomes.« less

Identification of somatic mutations in non-small cell lung carcinomas using whole-exome sequencing

PubMed Central

Liu, Pengyuan; Morrison, Carl; Wang, Liang; Xiong, Donghai; Vedell, Peter; Cui, Peng; Hua, Xing; Ding, Feng; Lu, Yan; James, Michael; Ebben, John D.; Xu, Haiming; Adjei, Alex A.; Head, Karen; Andrae, Jaime W.; Tschannen, Michael R.; Jacob, Howard; Pan, Jing; Zhang, Qi; Van den Bergh, Francoise; Xiao, Haijie; Lo, Ken C.; Patel, Jigar; Richmond, Todd; Watt, Mary-Anne; Albert, Thomas; Selzer, Rebecca; Anderson, Marshall; Wang, Jiang; Wang, Yian; Starnes, Sandra; Yang, Ping; You, Ming

2012-01-01

Lung cancer is the leading cause of cancer-related death, with non-small cell lung cancer (NSCLC) being the predominant form of the disease. Most lung cancer is caused by the accumulation of genomic alterations due to tobacco exposure. To uncover its mutational landscape, we performed whole-exome sequencing in 31 NSCLCs and their matched normal tissue samples. We identified both common and unique mutation spectra and pathway activation in lung adenocarcinomas and squamous cell carcinomas, two major histologies in NSCLC. In addition to identifying previously known lung cancer genes (TP53, KRAS, EGFR, CDKN2A and RB1), the analysis revealed many genes not previously implicated in this malignancy. Notably, a novel gene CSMD3 was identified as the second most frequently mutated gene (next to TP53) in lung cancer. We further demonstrated that loss of CSMD3 results in increased proliferation of airway epithelial cells. The study provides unprecedented insights into mutational processes, cellular pathways and gene networks associated with lung cancer. Of potential immediate clinical relevance, several highly mutated genes identified in our study are promising druggable targets in cancer therapy including ALK, CTNNA3, DCC, MLL3, PCDHIIX, PIK3C2B, PIK3CG and ROCK2. PMID:22510280

Gene mutation analysis in non-small cell lung cancer patients using bronchoalveolar lavage fluid and tumor tissue as diagnostic markers.

PubMed

Li, Jian; Hu, Yi-Ming; Wang, Yi; Tang, Xing-Ping; Shi, Wei-Lin; Du, Yong-Jie

2014-12-09

Non-small cell lung cancer (NSCLC) is one of the main causes of cancer death in the world. Early detection of NSCLC can improve its outcome. The aim of this study was to identify the mutations of the KRAS and p53 genes in bronchoalveoar lavage (BAL) fluid for the early detection of peripheral NSCLC. We examined the DNA obtained from the tumor, nearby normal lung tissue, and matched BAL fluid for mutations in the KRAS and p53 genes; the material was obtained from 48 patients with peripheral NSCLC, and was analyzed by PCR-single strand conformation polymorphism and DNA sequencing. BAL fluids from 26 patients with benign lung disease were used as controls. Positive rates of KRAS and p53 mutations were distributed as follows: in NSCLC tissue, 52% and 58%; in BAL fluid of NSCLC patients, 38% and 44%; in normal lung tissue, 6% and 4%; and in BAL fluid of patients with benign lung disease, 8% and 4%. The combined detection of both KRAS and p53 mutations yielded a sensitivity of 66% for the diagnosis of peripheral NSCLC, which is markedly higher than that of cytology plus histology by first bronchoscopy (38%, p=0.008). In each patient with the 2 gene mutations in BAL fluid, mutation type and location were the same as those of the primary tumor. Our study indicates that the detection of the KRAS and p53 mutations in BAL fluids could be a helpful addition to cytology and histology examination for the diagnosis of peripheral NSCLC.

Elevated soluble CD30 correlates with development of bronchiolitis obliterans syndrome following lung transplantation.

PubMed

Fields, Ryan C; Bharat, Ankit; Steward, Nancy; Aloush, Aviva; Meyers, Brian F; Trulock, Elbert P; Chapman, William C; Patterson, G Alexander; Mohanakumar, Thalachallour

2006-12-27

The long-term function of lung transplants is limited by chronic rejection (bronchiolitis obliterans syndrome, BOS). Due to lack of specific markers, BOS is diagnosed clinically. Because there is strong evidence that alloimmunity plays a significant role in the pathogenesis of BOS, we investigated whether soluble CD30 (sCD30), a T-cell activation marker, would correlate with BOS. Sera collected serially from BOS+ (n = 20) and matched BOS- (n = 20) lung transplant (LT) patients were analyzed for sCD30 by enzyme-linked immunosorbent assay. Pretransplant sera and sera from normal donors were also analyzed. PreLT levels were comparable to normal subjects. However, posttransplant there was a significant elevation in sCD30 levels during BOS development in all BOS+ patients, compared to BOS- (mean 139.8+/-10.7 vs. 14.8+/-2.7 U/ml, P < 0.001). sCD30 levels declined in the BOS+ patients but were still elevated compared to BOS- (48.52+/-5.04 vs. 7.19+/-2.9, P < 0.0001). We conclude that sCD30 may represent a novel marker to monitor the development of BOS.

Pulmonary functions of narghile smokers compared to cigarette smokers: a case-control study.

PubMed

Ben Saad, Helmi; Khemiss, Mehdi; Nhari, Saida; Ben Essghaier, Mejda; Rouatbi, Sonia

2013-01-01

Studies of the lung function profiles of exclusive narghile smokers (ENS) are few, have some methodological limits, and present contradictory conclusions. The present study aimed to compare the plethysmographic profiles of ENS with age- and height-matched exclusive cigarette smokers (ECS). Males aged 35-60 living in Sousse, Tunisia, who have been smoking narghile exclusively for more than 10 narghile-years (n = 36) or cigarettes exclusively for more than 10 pack-years (n = 106) were recruited to participate in this case-control study. The anthropometric and plethysmographic data were measured according to international recommendations using a body plethysmograph (ZAN 500 Body II, Meβgreräte GmbH, Germany). Large-airway-obstructive-ventilatory-defect (LAOVD) was defined as: first second forced expiratory volume/forced vital capacity (FEV1/FVC) below the lower-limit-of-normal (LLN). Restrictive-ventilatory-defect (RVD) was defined as total lung capacity < LLN. Lung hyperinflation was defined as residual volume > upper-limit-of-normal. Student t-test and χ(2) test were used to compare plethysmographic data and profiles of the two groups. The subjects in the ENS and ECS groups are well matched in age (45±7 vs. 47±5 years) and height (1.73±0.06 vs. 1.72±0.06 m) and used similar quantities of tobacco (36±22 narghile-years vs. 35±19 pack-years). Compared to the ENS group, the ECS group had significantly lower FEV1 (84±12 vs. 60±21%), FVC (90±12 vs. 76±18%), and FEV1/FVC (99±7 vs. 83±17%). The two groups had similar percentages of RVD (31 vs. 36%), while the ECS group had a significantly higher percentage of LAOVD (8 vs. 58%) and lung hyperinflation (36 vs.57%). Chronic exclusive narghile smoking has less adverse effects on pulmonary function tests than chronic exclusive cigarette smoking.

Pulmonary functions of narghile smokers compared to cigarette smokers: a case-control study.

PubMed

Saad, Helmi Ben; Khemiss, Mehdi; Nhari, Saida; Essghaier, Mejda Ben; Rouatbi, Sonia

2013-01-01

Background Studies of the lung function profiles of exclusive narghile smokers (ENS) are few, have some methodological limits, and present contradictory conclusions. The present study aimed to compare the plethysmographic profiles of ENS with age- and height-matched exclusive cigarette smokers (ECS). Methods Males aged 35-60 living in Sousse, Tunisia, who have been smoking narghile exclusively for more than 10 narghile-years (n = 36) or cigarettes exclusively for more than 10 pack-years (n = 106) were recruited to participate in this case-control study. The anthropometric and plethysmographic data were measured according to international recommendations using a body plethysmograph (ZAN 500 Body II, Meβgreräte GmbH, Germany). Large-airway-obstructive-ventilatory-defect (LAOVD) was defined as: first second forced expiratory volume/forced vital capacity (FEV 1 /FVC) below the lower-limit-of-normal (LLN). Restrictive-ventilatory-defect (RVD) was defined as total lung capacity < LLN. Lung hyperinflation was defined as residual volume > upper-limit-of-normal. Student t-test and χ 2 test were used to compare plethysmographic data and profiles of the two groups. Results The subjects in the ENS and ECS groups are well matched in age (45±7 vs. 47±5 years) and height (1.73±0.06 vs. 1.72±0.06 m) and used similar quantities of tobacco (36±22 narghile-years vs. 35±19 pack-years). Compared to the ENS group, the ECS group had significantly lower FEV 1 (84±12 vs. 60±21%), FVC (90±12 vs. 76±18%), and FEV 1 /FVC (99±7 vs. 83±17%). The two groups had similar percentages of RVD (31 vs. 36%), while the ECS group had a significantly higher percentage of LAOVD (8 vs. 58%) and lung hyperinflation (36 vs.57%). Conclusion Chronic exclusive narghile smoking has less adverse effects on pulmonary function tests than chronic exclusive cigarette smoking.

Reduced exercise capacity in untreated adults with primary growth hormone resistance (Laron syndrome).

PubMed

Ben-Dov, Issahar; Gaides, Mark; Scheinowitz, Mickey; Wagner, Rivka; Laron, Zvi

2003-12-01

Primary IGF-I deficiency (Laron syndrome, LS) may decrease exercise capacity as a result of a lack of an IGF-I effect on heart, peripheral muscle or lung structure and/or function. Eight patients (six females) who had never received treatment with IGF-I, with mean age of 36 +/- 10 (SD) years (range 21-48), weight 47 +/- 9 kg (31-61), height 126 +/- 12 cm (112-140) and body mass index of 29 +/- 4 kg/m2 (24-34), and 12 age-matched controls, underwent lung function tests and incremental cycling to the limit of tolerance (CPX, MedGraphics). Predicted values for the patients were derived from adult equations based on height. In LS patients, lung function was near normal; vital capacity was 84 +/- 11% of expected (66-103). Peak exercise O2-uptake and the anaerobic threshold were reduced, 57 +/- 20% of predicted and 33 +/- 9% of predicted peak (P = 0.005 vs. controls), despite normal mean exercise breathing reserve. All parameters were normal in the controls. Exercise capacity in untreated adults with LS is significantly reduced. The limitation for most patients was not ventilatory but resulted either from low cardiac output and/or from dysfunction of the peripheral muscles. However, the relative contribution of each of these elements and/or the role of poor fitness needs further study.

Radiographic abnormalities and the risk of lung cancer among workers exposed to silica dust in Ontario.

PubMed Central

Finkelstein, M M

1995-01-01

OBJECTIVE: To determine whether workers in Ontario who had been exposed to silica dust and who have radiographic abnormalities are at increased risk of lung cancer. DESIGN: Cohort and case-control studies of rates of death from lung cancer and cancer incidence rates; data were obtained from the Ontario Silicosis Surveillance Registry. Follow-up was through linkage to the Ontario mortality and cancer registries. SETTING: Ontario. PARTICIPANTS: A total of 523 workers with radiographic abnormalities and 1568 control subjects with normal radiographic findings who had been exposed to silica dust. Matching criteria were year of birth and the requirement that the control subject have a normal radiographic finding either later than or in the same year that the radiographic abnormality was identified in the silicosis subject. OUTCOME MEASURES: Standardized mortality ratios (SMRs), standardized incidence ratios (SIRs) and odds ratios for lung cancer. RESULTS: In the cohort analysis, with the Ontario population rates as reference, the all-cause SMR was 0.96 among the workers with radiographic abnormalities and 0.51 among the control subjects. The corresponding SIRs for lung cancer were 2.49 and 0.87 (p < 0.001). In the case-control analysis the workers with silicosis were more likely than the control subjects to have been smokers, but this difference likely accounted for only a small part of the difference in the incidence of lung cancer. The relative risk of lung cancer was elevated among the workers with silicosis from the foundry, mining and nonmetallic-minerals industries; however, the number of subjects was too small for a significant difference to be detected. Among the miners exposure to radon daughters did not affect the risk of lung cancer attributable to radiographic abnormalities. CONCLUSIONS: Radiographic abnormalities suggestive of exposure to silica dust are markers for increased risk of lung cancer. Physicians might thus wish to warn their patients with silica-associated radiographic abnormalities about the increased risk and to counsel those who smoke to stop. PMID:7804920

Clinical significance of laryngopharyngeal reflux in patients with chronic obstructive pulmonary disease.

PubMed

Jung, Young Ho; Lee, Doh Young; Kim, Dong Wook; Park, Sung Soo; Heo, Eun Young; Chung, Hee Soon; Kim, Deog Kyeom

2015-01-01

Although chronic obstructive pulmonary disease (COPD) is closely associated with gastroesophageal reflux disease (GERD), the clinical significance of laryngopharyngeal reflux (LPR) is not fully understood in COPD. Prospective cohorts were established among 118 patients with COPD from March 2013 to July 2014. Thirty-two age-matched and sex-matched normal controls, who had routine health check-ups during the study period, were included. Laryngopharyngeal reflux finding scores (RFS) and reflux symptom index (RSI) for LPR were subjected to association analysis with severity and acute exacerbation of COPD during the 1-year follow-up. The mean age of patients enrolled in the study was 69.2±8.8 years, with 93.2% being male. Positive RFS (>7) and RSI (>13) were observed in 51 (42.5%) and six patients (5.0%), respectively. RFS and RSI were significantly higher in patients with COPD than in normal, healthy patients (P<0.001). RFS was significantly correlated with residual volume/total lung capacity (%, P=0.048). Scores for diffuse laryngeal edema, erythema, and hyperemia were significantly higher in the high-risk group (Global Initiative for Chronic Obstructive Lung Disease classification C and D; P=0.025 and P=0.049, respectively), while RSI was significantly higher in the more symptomatic group (Global Initiative for Chronic Obstructive Lung Disease classification B and D; P=0.047). RSI and RFS were significant predictors for severe acute exacerbation of COPD (P=0.03 and P=0.047, respectively), while only RSI was associated with severity of dyspnea. Laryngeal examination and evaluation of laryngeal reflux symptom could be a surrogate clinical indicator related to severe acute exacerbation of COPD. Further studies of LPR in COPD patients should be considered.

Lung Parenchymal Assessment in Primary and Secondary Pneumothorax.

PubMed

Bintcliffe, Oliver J; Edey, Anthony J; Armstrong, Lynne; Negus, Ian S; Maskell, Nick A

2016-03-01

The definition of primary spontaneous pneumothorax excludes patients with known lung disease; however, the assumption that the underlying lung is normal in these patients is increasingly contentious. The purpose of this study was to assess lung structure and compare the extent of emphysema in patients with primary versus secondary spontaneous pneumothorax and to patients with no pneumothorax in an otherwise comparable control group. We identified patients treated for pneumothorax by screening inpatient and outpatient medical records at one medical center in the United Kingdom. From this group, 20 patients had no clinically apparent underlying lung disease and were classified as having a primary spontaneous pneumothorax, and 20 patients were classified as having a secondary spontaneous pneumothorax. We assembled a control group composed of 40 subjects matched for age and smoking history who had a unilateral pleural effusion or were suspected to have a thoracic malignancy and had a chest computed tomography scan suitable for quantitative analysis. Demographics and smoking histories were collected. Quantitative evaluation of low-attenuation areas of the lung on computed tomography imaging was performed using semiautomated software, and the extent of emphysema-like destruction was assessed visually. The extent of emphysema and percentage of low-attenuation areas was greater for patients with primary spontaneous pneumothorax than for control subjects matched for age and smoking history (median, 0.25 vs. 0.00%; P = 0.019) and was also higher for patients with secondary pneumothorax than those with primary spontaneous pneumothorax (16.15 vs. 0.25%, P < 0.001). Patients with primary pneumothorax who smoked had significantly greater low-attenuation area than patients with primary pneumothorax who were nonsmokers (0.7 vs. 0.1%, P = 0.034). The majority of patients with primary spontaneous pneumothorax had quantifiable evidence of parenchymal destruction and emphysema. The exclusion of patients with underlying lung disease from the definition of primary spontaneous pneumothorax should be reappraised.

Lung diffusing capacity for nitric oxide as a marker of fibrotic changes in idiopathic interstitial pneumonias.

PubMed

Barisione, Giovanni; Brusasco, Claudia; Garlaschi, Alessandro; Baroffio, Michele; Brusasco, Vito

2016-05-01

Lung diffusing capacity for carbon monoxide (DLCO) is decreased in both usual interstitial pneumonia-idiopathic pulmonary fibrosis (UIP-IPF) and nonspecific interstitial pneumonia (NSIP), but is moderately related to computed tomography (CT)-determined fibrotic changes. This may be due to the relative insensitivity of DLCO to changes in alveolar membrane diffusive conductance (DMCO). The purpose of this study was to determine whether measurement of lung diffusing capacity for nitric oxide (DLNO) better reflects fibrotic changes than DLCO DLNO-DLCO were measured simultaneously in 30 patients with UIP-IPF and 30 with NSIP. Eighty-one matched healthy subjects served as a control group. The amount of pulmonary fibrosis was estimated by CT volumetric analysis of visually bounded areas showing reticular opacities and honeycombing. DMCO and pulmonary capillary volume (VC) were calculated. DLNO was below the lower limit of normal in all patients irrespective of extent and nature of disease, whereas DLCO was within the normal range in a nonnegligible number of patients. Both DLNO and DLCO were significantly correlated with visual assessment of fibrosis but DLNO more closely than DLCO DMCO was also below the lower limit of normal in all UIP-IPF and NSIP patients and significantly correlated with fibrosis extent in both diseases, whereas VC was weakly correlated with fibrosis in UIP-IPF and uncorrelated in NSIP, with normal values in half of patients. In conclusion, measurement of DLNO may provide a more sensitive evaluation of fibrotic changes than DLCO in either UIP-IPF or NSIP, because it better reflects DMCO. Copyright © 2016 the American Physiological Society.

Expression of the receptor for hyaluronic acid mediated motility (RHAMM) is associated with poor prognosis and metastasis in non-small cell lung carcinoma

PubMed Central

Azzopardi, Stephanie; Smith, Roger S.; Nasar, Abu; Altorki, Nasser K.; Mittal, Vivek; Somwar, Romel; Stiles, Brendon M.; Du, Yi-Chieh Nancy

2016-01-01

The receptor for hyaluronic acid-mediated motility (RHAMM) is upregulated in various cancers, but its role in primary and metastatic non-small cell lung carcinoma (NSCLC) remains to be determined. Here, we investigate the clinical relevance of RHAMM expression in NSCLC. RHAMM protein expression correlates with histological differentiation stages and extent of the primary tumor (T stages) in 156 patients with primary NSCLC. Importantly, while focal RHAMM staining pattern is present in 57% of primary NSCLC, intense RHAMM protein expression is present in 96% of metastatic NSCLC cases. In a publicly available database, The Cancer Genome Atlas (TCGA), RHAMM mRNA expression is 12- and 10-fold higher in lung adenocarcinoma and squamous lung carcinoma than in matched normal lung tissues, respectively. RHAMM mRNA expression correlates with stages of differentiation and inferior survival in more than 400 cases of lung adenocarcinoma in the Director's Challenge cohort. Of 4 RHAMM splice variants, RHAMMv3 (also known as RHAMMB) is the dominant variant in NSCLC. Moreover, shRNA-mediated knockdown of RHAMM reduced the migratory ability of two lung adenocarcinoma cell lines, H1975 and H3255. Taken together, RHAMM, most likely RHAMMv3 (RHAMMB), can serve as a prognostic factor for lung adenocarcinomas and a potential therapeutic target in NSCLC to inhibit tumor migration. PMID:27220886

Clinical Study of Orthogonal-View Phase-Matched Digital Tomosynthesis for Lung Tumor Localization.

PubMed

Zhang, You; Ren, Lei; Vergalasova, Irina; Yin, Fang-Fang

2017-01-01

Compared to cone-beam computed tomography, digital tomosynthesis imaging has the benefits of shorter scanning time, less imaging dose, and better mechanical clearance for tumor localization in radiation therapy. However, for lung tumors, the localization accuracy of the conventional digital tomosynthesis technique is affected by the lack of depth information and the existence of lung tumor motion. This study investigates the clinical feasibility of using an orthogonal-view phase-matched digital tomosynthesis technique to improve the accuracy of lung tumor localization. The proposed orthogonal-view phase-matched digital tomosynthesis technique benefits from 2 major features: (1) it acquires orthogonal-view projections to improve the depth information in reconstructed digital tomosynthesis images and (2) it applies respiratory phase-matching to incorporate patient motion information into the synthesized reference digital tomosynthesis sets, which helps to improve the localization accuracy of moving lung tumors. A retrospective study enrolling 14 patients was performed to evaluate the accuracy of the orthogonal-view phase-matched digital tomosynthesis technique. Phantom studies were also performed using an anthropomorphic phantom to investigate the feasibility of using intratreatment aggregated kV and beams' eye view cine MV projections for orthogonal-view phase-matched digital tomosynthesis imaging. The localization accuracy of the orthogonal-view phase-matched digital tomosynthesis technique was compared to that of the single-view digital tomosynthesis techniques and the digital tomosynthesis techniques without phase-matching. The orthogonal-view phase-matched digital tomosynthesis technique outperforms the other digital tomosynthesis techniques in tumor localization accuracy for both the patient study and the phantom study. For the patient study, the orthogonal-view phase-matched digital tomosynthesis technique localizes the tumor to an average (± standard deviation) error of 1.8 (0.7) mm for a 30° total scan angle. For the phantom study using aggregated kV-MV projections, the orthogonal-view phase-matched digital tomosynthesis localizes the tumor to an average error within 1 mm for varying magnitudes of scan angles. The pilot clinical study shows that the orthogonal-view phase-matched digital tomosynthesis technique enables fast and accurate localization of moving lung tumors.

Increased Lymphatic Vessel Length Is Associated With the Fibroblast Reticulum and Disease Severity in Usual Interstitial Pneumonia and Nonspecific Interstitial Pneumonia

PubMed Central

Cosgrove, Gregory P.; Janssen, William J.; Huie, Tristan J.; Burnham, Ellen L.; Heinz, David E.; Curran-Everett, Douglas; Sahin, Hakan; Schwarz, Marvin I.; Cool, Carlyne D.; Groshong, Steve D.; Geraci, Mark W.; Tuder, Rubin M.; Hyde, Dallas M.; Henson, Peter M.

2012-01-01

Background: Lymphangiogenesis responds to tissue injury as a key component of normal wound healing. The development of fibrosis in the idiopathic interstitial pneumonias may result from abnormal wound healing in response to injury. We hypothesize that increased lymphatic vessel (LV) length, a marker of lymphangiogenesis, is associated with parenchymal components of the fibroblast reticulum (organizing collagen, fibrotic collagen, and fibroblast foci), and its extent correlates with disease severity. Methods: We assessed stereologically the parenchymal structure of fibrotic lungs and its associated lymphatic network, which was highlighted immunohistochemically in age-matched samples of usual interstitial pneumonia (UIP), nonspecific interstitial pneumonia (NSIP) with FVC < 80%, COPD with a Global Initiative for Obstructive Lung Disease stage 0, and normal control lungs. Results: LV length density, as opposed to vessel volume density, was found to be associated with organizing and fibrotic collagen density (P < .0001). Length density of LVs and the volume density of organizing and fibrotic collagen were significantly associated with severity of both % FVC (P < .001) and diffusing capacity of the lung for carbon monoxide (P < .001). Conclusions: Severity of disease in UIP and NSIP is associated with increased LV length and is strongly associated with components of the fibroblast reticulum, namely organizing and fibrotic collagen, which supports a pathogenic role of LVs in these two diseases. Furthermore, the absence of definable differences between UIP and NSIP suggests that LVs are a unifying mechanism for the development of fibrosis in these fibrotic lung diseases. PMID:22797508

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.

Expiratory flow limitation and operating lung volumes during exercise in older and younger adults.

PubMed

Smith, Joshua R; Kurti, Stephanie P; Meskimen, Kayla; Harms, Craig A

2017-06-01

We determined the effect of aging on expiratory flow limitation (EFL) and operating lung volumes when matched for lung size. We hypothesized that older adults will exhibit greater EFL and increases in EELV during exercise compared to younger controls. Ten older (5M/5W; >60years old) and nineteen height-matched young adults (10M/9W) were recruited. Young adults were matched for%predicted forced vital capacity (FVC) (Y-matched%Pred FVC; n=10) and absolute FVC (Y-matched FVC; n=10). Tidal flow-volume loops were recorded during the incremental exercise test with maximal flow-volume loops measured pre- and post-exercise. Compared to younger controls, older adults exhibited more EFL at ventilations of 26, 35, 51, and 80L/min. The older group had higher end-inspiratory lung volume compared to Y-matched%Pred FVC group during submaximal ventilations. The older group increased EELV during exercise, while EELV stayed below resting in the Y-matched%Pred FVC group. These data suggest older adults exhibit more EFL and increase EELV earlier during exercise compared to younger adults. Copyright © 2017 Elsevier B.V. All rights reserved.

SU-F-R-31: Identification of Robust Normal Lung CT Texture Features for the Prediction of Radiation-Induced Lung Disease

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

Choi, W; Riyahi, S; Lu, W

Purpose: Normal lung CT texture features have been used for the prediction of radiation-induced lung disease (radiation pneumonitis and radiation fibrosis). For these features to be clinically useful, they need to be relatively invariant (robust) to tumor size and not correlated with normal lung volume. Methods: The free-breathing CTs of 14 lung SBRT patients were studied. Different sizes of GTVs were simulated with spheres placed at the upper lobe and lower lobe respectively in the normal lung (contralateral to tumor). 27 texture features (9 from intensity histogram, 8 from grey-level co-occurrence matrix [GLCM] and 10 from grey-level run-length matrix [GLRM])more » were extracted from [normal lung-GTV]. To measure the variability of a feature F, the relative difference D=|Fref -Fsim|/Fref*100% was calculated, where Fref was for the entire normal lung and Fsim was for [normal lung-GTV]. A feature was considered as robust if the largest non-outlier (Q3+1.5*IQR) D was less than 5%, and considered as not correlated with normal lung volume when their Pearson correlation was lower than 0.50. Results: Only 11 features were robust. All first-order intensity-histogram features (mean, max, etc.) were robust, while most higher-order features (skewness, kurtosis, etc.) were unrobust. Only two of the GLCM and four of the GLRM features were robust. Larger GTV resulted greater feature variation, this was particularly true for unrobust features. All robust features were not correlated with normal lung volume while three unrobust features showed high correlation. Excessive variations were observed in two low grey-level run features and were later identified to be from one patient with local lung diseases (atelectasis) in the normal lung. There was no dependence on GTV location. Conclusion: We identified 11 robust normal lung CT texture features that can be further examined for the prediction of radiation-induced lung disease. Interestingly, low grey-level run features identified normal lung diseases. This work was supported in part by the National Cancer Institute Grants R01CA172638.« less

Effect of Phase Lag on Fluid Flow and Particle Dispersion in a Single Human Alveolus

NASA Astrophysics Data System (ADS)

Chhabra, Sudhaker; Prasad, Ajay

2007-11-01

The human lung can be divided into (1) the conducting airways, and (2) the acini. The acini are responsible for gas exchange and consist of alveoli and bronchioles. The acini are useful delivery sites for inhaled therapeutic aerosols. In normal lung function the alveolus expands and contracts in phase with the bronchiole airflow oscillation. Lung diseases such as emphysema compromise the elasticity of the lung. Consequently, the alveolus may not oscillate in-phase with the oscillating bronchiole airflow. We have previously studied flow and particle transport in an alveolus for in-phase flow. The current work focuses on measuring out-of-phase airflow patterns and particle transport in an in-vitro model of a single expanding/contracting human alveolus. The model consists of a transparent, elastic, oscillating alveolus (represented by a 5/6th hemisphere) attached to a rigid circular tube. Realistic tidal breathing conditions were achieved by matching Reynolds and Womersley numbers. Flow patterns were measured using PIV; these velocity maps were subsequently used to calculate particle transport and deposition on the alveolar wall.

Analysis of point-to-point lung motion with full inspiration and expiration CT data using non-linear optimization method: optimal geometric assumption model for the effective registration algorithm

NASA Astrophysics Data System (ADS)

Kim, Namkug; Seo, Joon Beom; Heo, Jeong Nam; Kang, Suk-Ho

2007-03-01

The study was conducted to develop a simple model for more robust lung registration of volumetric CT data, which is essential for various clinical lung analysis applications, including the lung nodule matching in follow up CT studies, semi-quantitative assessment of lung perfusion, and etc. The purpose of this study is to find the most effective reference point and geometric model based on the lung motion analysis from the CT data sets obtained in full inspiration (In.) and expiration (Ex.). Ten pairs of CT data sets in normal subjects obtained in full In. and Ex. were used in this study. Two radiologists were requested to draw 20 points representing the subpleural point of the central axis in each segment. The apex, hilar point, and center of inertia (COI) of each unilateral lung were proposed as the reference point. To evaluate optimal expansion point, non-linear optimization without constraints was employed. The objective function is sum of distances from the line, consist of the corresponding points between In. and Ex. to the optimal point x. By using the nonlinear optimization, the optimal points was evaluated and compared between reference points. The average distance between the optimal point and each line segment revealed that the balloon model was more suitable to explain the lung expansion model. This lung motion analysis based on vector analysis and non-linear optimization shows that balloon model centered on the center of inertia of lung is most effective geometric model to explain lung expansion by breathing.

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

Horie, Masafumi; Saito, Akira, E-mail: asaitou-tky@umin.ac.jp; Mikami, Yu

Highlights: Black-Right-Pointing-Pointer We established three patient-paired sets of CAFs and NFs. Black-Right-Pointing-Pointer CAFs and NFs were analyzed using three-dimensional co-culture experiments. Black-Right-Pointing-Pointer CAFs clearly enhanced collagen gel contraction. Black-Right-Pointing-Pointer CAFs showed higher {alpha}-SMA expression than NFs. Black-Right-Pointing-Pointer CAFs were implicated in invasion and differentiation of lung cancer cells. -- Abstract: Lung cancer is the most common cause of cancer-related death worldwide. Stromal cancer-associated fibroblasts (CAFs) play crucial roles in carcinogenesis, proliferation, invasion, and metastasis of non-small cell lung carcinoma, and targeting of CAFs could be a novel strategy for cancer treatment. However, the characteristics of human CAFs still remain tomore » be better defined. In this study, we established patient-matched CAFs and normal fibroblasts (NFs), from tumoral and non-tumoral portions of resected lung tissue from lung cancer patients. CAFs showed higher {alpha}-smooth muscle actin ({alpha}-SMA) expression than NFs, and CAFs clearly enhanced collagen gel contraction. Furthermore, we employed three-dimensional co-culture assay with A549 lung cancer cells, where CAFs were more potent in inducing collagen gel contraction. Hematoxylin and eosin staining of co-cultured collagen gel revealed that CAFs had the potential to increase invasion of A549 cells compared to NFs. These observations provide evidence that lung CAFs have the tumor-promoting capacity distinct from NFs.« less

Reprogramming of Normal Fibroblasts into Cancer-Associated Fibroblasts by miRNAs-Mediated CCL2/VEGFA Signaling

PubMed Central

Shen, Hua; Yu, Xiaobo; Yang, Fengming; Zhang, Zhihua; Shen, Jianxin; Sun, Jin; Choksi, Swati; Jitkaew, Siriporn; Shu, Yongqian

2016-01-01

Cancer-associated fibroblasts (CAFs), the most common constituent of the tumor stoma, are known to promote tumor initiation, progression and metastasis. However, the mechanism of how cancer cells transform normal fibroblasts (NFs) into CAFs is largely unknown. In this study, we determined the contribution of miRNAs in the transformation of NFs into CAFs. We found that miR-1 and miR-206 were down-regulated, whereas miR-31 was up-regulated in lung CAFs when compared with matched NFs. Importantly, modifying the expression of these three deregulated miRNAs induced a functional conversion of NFs into CAFs and vice versa. When the miRNA-reprogrammed NFs and CAFs were co-cultured with lung cancer cells (LCCs), a similar pattern of cytokine expression profiling were observed between two groups. Using a combination of cytokine expression profiling and miRNAs algorithms, we identified VEGFA/CCL2 and FOXO3a as direct targets of miR-1, miR-206 and miR-31, respectively. Importantly, systemic delivery of anti-VEGFA/CCL2 or pre-miR-1, pre-miR-206 and anti-miR-31 significantly inhibited tumor angiogenesis, TAMs accumulation, tumor growth and lung metastasis. Our results show that miRNAs-mediated FOXO3a/VEGF/CCL2 signaling plays a prominent role in LCCs-mediated NFs into CAFs, which may have clinical implications for providing novel biomarker(s) and potential therapeutic target(s) of lung cancer in the future. PMID:27541266

Local allocation of lung donors results in transplanting lungs in lower priority transplant recipients.

PubMed

Russo, Mark J; Meltzer, David; Merlo, Aurelie; Johnson, Elizabeth; Shariati, Nazly M; Sonett, Joshua R; Gibbons, Robert

2013-04-01

Under the current lung allocation system, if organs are accepted for a candidate within the local donor service area (DSA), they are never offered to candidates at the broader regional level who are potentially more severely ill, even if the nonlocal candidate has a higher lung allocation score (LAS). The purpose of this study was to determine the frequency with which organs were allocated to a local lung recipient while a blood group-matched and size-matched candidate with a higher LAS existed in the same region. United Network for Organ Sharing (UNOS) provided deidentified patient-level data. The study population included all locally allocated organs for double-lung transplants (DLTs) performed in 2009 in the United States (n=580). All occurrences of an ABO blood group-matched, height-matched (±10 cm), double-lung candidate in the same region, with a higher LAS than the local candidate who actually received the organs, were calculated; these occurrences were termed events. In 2009, 3,454 events occurred when a local DLT recipient candidate received a DLT while a DLT candidate in the same region had a higher LAS. With a mean of 5.96 events per transplant, this impacted 480 (82.8%) of the 580 DLTs. Further, 555 (16.1%) of these events involved 1 (or more) of the 185 regional candidates who ultimately did not receive transplants and died while on the waiting list. This analysis suggests that the locally based lung allocation system results in a high frequency of events whereby an organ is allocated to a lower-priority candidate while an appropriately matched higher priority candidate exists regionally. Copyright © 2013 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.

A simplified interventional mapping system (SIMS) for the selection of combinations of targeted treatments in non-small cell lung cancer

PubMed Central

Lazar, Vladimir; Martini, Jean-François; Gomez-Navarro, Jesus; Yver, Antoine; Kan, Zhengyin; Dry, Jonathan R.; Kehren, Jeanne; Validire, Pierre; Rodon, Jordi; Vielh, Philippe; Ducreux, Michel; Galbraith, Susan; Lehnert, Manfred; Onn, Amir; Berger, Raanan; Pierotti, Marco A.; Porgador, Angel; Pramesh, CS; Ye, Ding-wei; Carvalho, Andre L.; Batist, Gerald; Le Chevalier, Thierry; Morice, Philippe; Besse, Benjamin; Vassal, Gilles; Mortlock, Andrew; Hansson, Johan; Berindan-Neagoe, Ioana; Dann, Robert; Haspel, Joel; Irimie, Alexandru; Laderman, Steve; Nechushtan, Hovav; Al Omari, Amal S.; Haywood, Trent; Bresson, Catherine; Soo, Khee Chee; Osman, Iman; Mata, Hilario; Lee, Jack J.; Jhaveri, Komal; Meurice, Guillaume; Palmer, Gary; Lacroix, Ludovic; Koscielny, Serge; Eterovic, Karina Agda; Blay, Jean-Yves; Buller, Richard; Eggermont, Alexander; Schilsky, Richard L.; Mendelsohn, John; Soria, Jean-Charles; Rothenberg, Mace

2015-01-01

Non-small cell lung cancer (NSCLC) is a leading cause of death worldwide. Targeted monotherapies produce high regression rates, albeit for limited patient subgroups, who inevitably succumb. We present a novel strategy for identifying customized combinations of triplets of targeted agents, utilizing a simplified interventional mapping system (SIMS) that merges knowledge about existent drugs and their impact on the hallmarks of cancer. Based on interrogation of matched lung tumor and normal tissue using targeted genomic sequencing, copy number variation, transcriptomics, and miRNA expression, the activation status of 24 interventional nodes was elucidated. An algorithm was developed to create a scoring system that enables ranking of the activated interventional nodes for each patient. Based on the trends of co-activation at interventional points, combinations of drug triplets were defined in order to overcome resistance. This methodology will inform a prospective trial to be conducted by the WIN consortium, aiming to significantly impact survival in metastatic NSCLC and other malignancies. PMID:25944621

Systematic Identification of Molecular Subtype-Selective Vulnerabilities in Non Small Cell Lung Cancer

PubMed Central

Kim, Hyun Seok; Mendiratta, Saurabh; Kim, Jiyeon; Pecot, Chad Victor; Larsen, Jill E.; Zubovych, Iryna; Seo, Bo Yeun; Kim, Jimi; Eskiocak, Banu; Chung, Hannah; McMillan, Elizabeth; Wu, Sherry; De Brabander, Jef; Komurov, Kakajan; Toombs, Jason E.; Wei, Shuguang; Peyton, Michael; Williams, Noelle; Gazdar, Adi F.; Posner, Bruce A.; Brekken, Rolf; Sood, Anil K.; Deberardinis, Ralph J.; Roth, Michael G.; Minna, John D.; White, Michael A.

2013-01-01

SUMMARY Context-specific molecular vulnerabilities that arise during tumor evolution represent an attractive intervention target class. However, the frequency and diversity of somatic lesions detected among lung tumors can confound efforts to identify these targets. To confront this challenge, we have applied parallel screening of chemical and genetic perturbations within a panel of molecularly annotated NSCLC lines to identify intervention opportunities tightly linked to molecular response indicators predictive of target sensitivity. Anchoring this analysis on a matched tumor/normal cell model from a lung adenocarcinoma patient identified three distinct target/response-indicator pairings that are represented with significant frequencies (6–16%) in the patient population. These include NLRP3 mutation/inflammasome activation-dependent FLIP addiction, co-occuring KRAS and LKB1 mutation-driven COPI addiction, and selective sensitivity to a synthetic indolotriazine that is specified by a 7-gene expression signature. Target efficacies were validated in vivo, and mechanism of action studies uncovered new cancer cell biology. PMID:24243015

Systematic identification of molecular subtype-selective vulnerabilities in non-small-cell lung cancer.

PubMed

Kim, Hyun Seok; Mendiratta, Saurabh; Kim, Jiyeon; Pecot, Chad Victor; Larsen, Jill E; Zubovych, Iryna; Seo, Bo Yeun; Kim, Jimi; Eskiocak, Banu; Chung, Hannah; McMillan, Elizabeth; Wu, Sherry; De Brabander, Jef; Komurov, Kakajan; Toombs, Jason E; Wei, Shuguang; Peyton, Michael; Williams, Noelle; Gazdar, Adi F; Posner, Bruce A; Brekken, Rolf A; Sood, Anil K; Deberardinis, Ralph J; Roth, Michael G; Minna, John D; White, Michael A

2013-10-24

Context-specific molecular vulnerabilities that arise during tumor evolution represent an attractive intervention target class. However, the frequency and diversity of somatic lesions detected among lung tumors can confound efforts to identify these targets. To confront this challenge, we have applied parallel screening of chemical and genetic perturbations within a panel of molecularly annotated NSCLC lines to identify intervention opportunities tightly linked to molecular response indicators predictive of target sensitivity. Anchoring this analysis on a matched tumor/normal cell model from a lung adenocarcinoma patient identified three distinct target/response-indicator pairings that are represented with significant frequencies (6%-16%) in the patient population. These include NLRP3 mutation/inflammasome activation-dependent FLIP addiction, co-occurring KRAS and LKB1 mutation-driven COPI addiction, and selective sensitivity to a synthetic indolotriazine that is specified by a seven-gene expression signature. Target efficacies were validated in vivo, and mechanism-of-action studies informed generalizable principles underpinning cancer cell biology. Copyright © 2013 Elsevier Inc. All rights reserved.

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

Quantitative CT characterization of pediatric lung development using routine clinical imaging

PubMed Central

Stein, Jill M.; Walkup, Laura L.; Brody, Alan S.; Fleck, Robert J.

2016-01-01

Background The use of quantitative CT analysis in children is limited by lack of normal values of lung parenchymal attenuation. These characteristics are important because normal lung development yields significant parenchymal attenuation changes as children age. Objective To perform quantitative characterization of normal pediatric lung parenchymal X-ray CT attenuation under routine clinical conditions in order to establish a baseline comparison to that seen in pathological lung conditions. Materials and methods We conducted a retrospective query of normal CT chest examinations in children ages 0–7 years from 2004 to 2014 using standard clinical protocol. During these examinations semi-automated lung parenchymal segmentation was performed to measure lung volume and mean lung attenuation. Results We analyzed 42 CT examinations in 39 children, ages 3 days to 83 months (mean ± standard deviation [SD] = 42±27 months). Lung volume ranged 0.10–1.72 liters (L). Mean lung attenuation was much higher in children younger than 12 months, with values as high as −380 Hounsfield units (HU) in neonates (lung volume 0.10 L). Lung volume decreased to approximately −650 HU by age 2 years (lung volume 0.47 L), with subsequently slower exponential decrease toward a relatively constant value of −860 HU as age and lung volume increased. Conclusion Normal lung parenchymal X-ray CT attenuation decreases with increasing lung volume and age; lung attenuation decreases rapidly in the first 2 years of age and more slowly thereafter. This change in normal lung attenuation should be taken into account as quantitative CT methods are translated to pediatric pulmonary imaging. PMID:27576458

An accurate algorithm to match imperfectly matched images for lung tumor detection without markers

PubMed Central

Rozario, Timothy; Bereg, Sergey; Yan, Yulong; Chiu, Tsuicheng; Liu, Honghuan; Kearney, Vasant; Jiang, Lan

2015-01-01

In order to locate lung tumors on kV projection images without internal markers, digitally reconstructed radiographs (DRRs) are created and compared with projection images. However, lung tumors always move due to respiration and their locations change on projection images while they are static on DRRs. In addition, global image intensity discrepancies exist between DRRs and projections due to their different image orientations, scattering, and noises. This adversely affects comparison accuracy. A simple but efficient comparison algorithm is reported to match imperfectly matched projection images and DRRs. The kV projection images were matched with different DRRs in two steps. Preprocessing was performed in advance to generate two sets of DRRs. The tumors were removed from the planning 3D CT for a single phase of planning 4D CT images using planning contours of tumors. DRRs of background and DRRs of tumors were generated separately for every projection angle. The first step was to match projection images with DRRs of background signals. This method divided global images into a matrix of small tiles and similarities were evaluated by calculating normalized cross‐correlation (NCC) between corresponding tiles on projections and DRRs. The tile configuration (tile locations) was automatically optimized to keep the tumor within a single projection tile that had a bad matching with the corresponding DRR tile. A pixel‐based linear transformation was determined by linear interpolations of tile transformation results obtained during tile matching. The background DRRs were transformed to the projection image level and subtracted from it. The resulting subtracted image now contained only the tumor. The second step was to register DRRs of tumors to the subtracted image to locate the tumor. This method was successfully applied to kV fluoro images (about 1000 images) acquired on a Vero (BrainLAB) for dynamic tumor tracking on phantom studies. Radiation opaque markers were implanted and used as ground truth for tumor positions. Although other organs and bony structures introduced strong signals superimposed on tumors at some angles, this method accurately located tumors on every projection over 12 gantry angles. The maximum error was less than 2.2 mm, while the total average error was less than 0.9 mm. This algorithm was capable of detecting tumors without markers, despite strong background signals. PACS numbers: 87.57.cj, 87.57.cp87.57.nj, 87.57.np, 87.57.Q‐, 87.59.bf, 87.63.lm

Quantitative Computerized Two-Point Correlation Analysis of Lung CT Scans Correlates With Pulmonary Function in Pulmonary Sarcoidosis

PubMed Central

Erdal, Barbaros Selnur; Yildiz, Vedat; King, Mark A.; Patterson, Andrew T.; Knopp, Michael V.; Clymer, Bradley D.

2012-01-01

Background: Chest CT scans are commonly used to clinically assess disease severity in patients presenting with pulmonary sarcoidosis. Despite their ability to reliably detect subtle changes in lung disease, the utility of chest CT scans for guiding therapy is limited by the fact that image interpretation by radiologists is qualitative and highly variable. We sought to create a computerized CT image analysis tool that would provide quantitative and clinically relevant information. Methods: We established that a two-point correlation analysis approach reduced the background signal attendant to normal lung structures, such as blood vessels, airways, and lymphatics while highlighting diseased tissue. This approach was applied to multiple lung fields to generate an overall lung texture score (LTS) representing the quantity of diseased lung parenchyma. Using deidentified lung CT scan and pulmonary function test (PFT) data from The Ohio State University Medical Center’s Information Warehouse, we analyzed 71 consecutive CT scans from patients with sarcoidosis for whom simultaneous matching PFTs were available to determine whether the LTS correlated with standard PFT results. Results: We found a high correlation between LTS and FVC, total lung capacity, and diffusing capacity of the lung for carbon monoxide (P < .0001 for all comparisons). Moreover, LTS was equivalent to PFTs for the detection of active lung disease. The image analysis protocol was conducted quickly (< 1 min per study) on a standard laptop computer connected to a publicly available National Institutes of Health ImageJ toolkit. Conclusions: The two-point image analysis tool is highly practical and appears to reliably assess lung disease severity. We predict that this tool will be useful for clinical and research applications. PMID:22628487

Ultrahigh resolution optical coherence tomography imaging of diseased rat lung using Gaussian shaped super continuum sources

NASA Astrophysics Data System (ADS)

Nishizawa, N.; Ishida, S.; Kitatsuji, M.; Ohshima, H.; Hasegawa, Y.; Matsushima, M.; Kawabe, T.

2012-02-01

We have been investigating ultrahigh resolution optical coherence tomography (UHR-OCT) imaging of lung tissues using fiber super continuum sources. The high power, low-noise, Gaussian shaped supercontinuum generated with ultrashort pulses and optical fibers at several wavelengths were used as the broadband light sources for UHR-OCT. For the 800 nm wavelength region, the axial resolution was 3.0 um in air and 2.0 um in tissue. Since the lung consists of tiny alveoli which are separated by thin wall, the UHR-OCT is supposed to be effective for lung imaging. The clear images of alveoli of rat were observed with and without index matching effects by saline. In this work, we investigated the UHR-OCT imaging of lung disease model. The lipopolysaccharide (LPS) induced acute lung injury / acute respiratory distress syndrome (ALI/ARDS) model of rat was prepared as the sample with disease and the UHR-OCT imaging of the disease part was demonstrated. The increment of signal intensity by pleural thickening was observed. The accumulation of exudative fluid in alveoli was also observed for two samples. By the comparison with normal lung images, we can obviously show the difference in the ALI/ARDS models. Since the lung consists of alveolar surrounded by capillary vessels, the effect of red-blood cells (RBC) is considered to be important. In this work, ex-vivo UHR-OCT imaging of RBC was demonstrated. Each RBC was able to be observed individually using UHR-OCT. The effect of RBC was estimated with the rat lung perfused with PBS.

Aberrant systemic arterial supply to normal lung arising from the proper hepatic artery discovered during transarterial chemoembolization.

PubMed

Walsworth, Matthew K; Yap, Felix Y; McWilliams, Justin P

2015-11-01

We report a rare case of dual arterial supply to an otherwise normal lung discovered incidentally during initial angiography performed with the intent of chemoembolization of hepatocellular carcinoma. In addition to normal hepatic arterial supply, the proper hepatic artery provided systemic arterial supply to the lower lobe of the left lung. Subsequent chest computed tomography angiography demonstrated a normal tracheobronchial tree and normal pulmonary arterial supply to the lung. Although other anatomic variants have been reported, there are no other reported cases of systemic arterial supply from the proper hepatic artery to the lung. Identifying systemic arterial supply to the lung during angiography is important while performing transcatheter chemoembolization or radioembolization in the liver in order to minimize non-target embolization of the lung.

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.

Genomic Landscape of Atypical Adenomatous Hyperplasia Reveals Divergent Modes to Lung Adenocarcinoma.

PubMed

Sivakumar, Smruthy; Lucas, F Anthony San; McDowell, Tina L; Lang, Wenhua; Xu, Li; Fujimoto, Junya; Zhang, Jianjun; Futreal, P Andrew; Fukuoka, Junya; Yatabe, Yasushi; Dubinett, Steven M; Spira, Avrum E; Fowler, Jerry; Hawk, Ernest T; Wistuba, Ignacio I; Scheet, Paul; Kadara, Humam

2017-11-15

There is a dearth of knowledge about the pathogenesis of premalignant lung lesions, especially for atypical adenomatous hyperplasia (AAH), the only known precursor for the major lung cancer subtype adenocarcinoma (LUAD). In this study, we performed deep DNA and RNA sequencing analyses of a set of AAH, LUAD, and normal tissues. Somatic BRAF variants were found in AAHs from 5 of 22 (23%) patients, 4 of 5 of whom had matched LUAD with driver EGFR mutations. KRAS mutations were present in AAHs from 4 of 22 (18%) of patients. KRAS mutations in AAH were only found in ever-smokers and were exclusive to BRAF -mutant cases. Integrative analysis revealed profiles expressed in KRAS -mutant cases ( UBE2C, REL ) and BRAF -mutant cases ( MAX ) of AAH, or common to both sets of cases (suppressed AXL ). Gene sets associated with suppressed antitumor (Th1; IL12A, GZMB ) and elevated protumor ( CCR2, CTLA-4 ) immune signaling were enriched in AAH development and progression. Our results reveal potentially divergent BRAF or KRAS pathways in AAH as well as immune dysregulation in the pathogenesis of this premalignant lung lesion. Cancer Res; 77(22); 6119-30. ©2017 AACR . ©2017 American Association for Cancer Research.

Association of thymidylate synthase gene 3'-untranslated region polymorphism with sensitivity of non-small cell lung cancer to pemetrexed treatment: TS gene polymorphism and pemetrexed sensitivity in NSCLC.

PubMed

Wang, Xia; Wang, Yadi; Wang, Yue; Cheng, Jian; Wang, Yanyun; Ha, Minwen

2013-01-25

Thymidylate synthase (TS) is a key enzyme responsible for DNA synthesis and repair. Altered expression of TS protein or TS gene polymorphisms has been associated with cancer progression and treatment response. This study investigated the expressions of TS and its gene SNPs in non-small cell lung cancer (NSCLC), and then its association with sensitivity to pemetrexed treatment. Immunohistochemistry and qRT-PCR were performed on 160 resected NSCLC specimens and corresponding normal tissues to assess the expressions of TS protein and TS mRNA, and for associations with clinicopathological data. Blood samples of 106 lung adenocarcinoma patients were examined for polymorphisms of the TS gene 3'-UTR 1494del 6 bp, which was then investigated for associations with responses of the patients to pemetrexed treatment and survival. Expression of both TS protein and its mRNA was elevated in NSCLC tissues compared with matched normal tissues, and significantly higher in lung squamous cell carcinoma than in lung adenocarcinoma. TS expression was associated with poor tumor differentiation. Furthermore, the genotyping data showed that 56% of lung adenocarcinoma patients had the TS gene 3'-UTR 1494 bp (-6 bp/-6 bp) genotype and the rest had TS gene 3'-UTR 1494 bp (-6 bp/+6 bp). There was no TS 3'-UTR 1494 bp (+6 bp/+6 bp) genotype in any patients. Statistical analysis revealed that gender, tumor stage, and TS 3'-UTR 1494del 6 bp polymorphism were significant prognostic factors after short-term pemetrexed treatment. Log-rank analysis revealed that patients with the (-6 bp/-6 bp) genotype had significantly better progression-free and overall survival than patients with (-6 bp/+6 bp). This study showed that TS protein is highly expressed in NSCLC and that polymorphisms of TS 3'-UTR 1494del 6 bp are associated with sensitivity of lung adenocarcinoma patients to pemetrexed treatment. This suggests that TS gene polymorphisms should be further evaluated as prognostic markers for personalized therapy in lung adenocarcinoma.

Preferential reduction of quadriceps over respiratory muscle strength and bulk after lung transplantation for cystic fibrosis.

PubMed

Pinet, C; Scillia, P; Cassart, M; Lamotte, M; Knoop, C; Mélot, C; Estenne, M

2004-09-01

In the absence of complications, recipients of lung transplants for cystic fibrosis have normal pulmonary function but the impact of the procedure on the strength and bulk of respiratory and limb muscles has not been studied. Twelve stable patients who had undergone lung transplantation for cystic fibrosis 48 months earlier (range 8-95) and 12 normal subjects matched for age, height, and sex were studied. The following parameters were measured: standard lung function, peak oxygen uptake by cycle ergometry, diaphragm surface area by computed tomographic (CT) scanning, diaphragm and abdominal muscle thickness by ultrasonography, twitch transdiaphragmatic and gastric pressures, quadriceps isokinetic strength, and quadriceps cross section by CT scanning, and lean body mass. Diaphragm mass was computed from diaphragm surface area and thickness. Twitch transdiaphragmatic and gastric pressures, diaphragm mass, and abdominal muscle thickness were similar in the two groups but quadriceps strength and cross section were decreased by nearly 30% in the patients. Patients had preserved quadriceps strength per unit cross section but reduced quadriceps cross section per unit lean body mass. The cumulative dose of corticosteroids was an independent predictor of quadriceps atrophy. Peak oxygen uptake showed positive correlations with quadriceps strength and cross section in the two groups, but peak oxygen uptake per unit quadriceps strength or cross section was reduced in the patient group. The diaphragm and abdominal muscles have preserved strength and bulk in patients transplanted for cystic fibrosis but the quadriceps is weak due to muscle atrophy. This atrophy is caused in part by corticosteroid therapy and correlates with the reduction in exercise capacity.

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.

Study of computerized spirometric parameters of traffic police personnel of Saurashtra region, Gujarat, India.

PubMed

Makwana, Amit H; Solanki, Jayesh D; Gokhale, Pradnya A; Mehta, Hemant B; Shah, Chinmay J; Gadhavi, Bhakti P

2015-01-01

Air pollution due to road traffic is a serious health hazard and air quality crisis in cities is mainly due to vehicular emission. Thus the persons who are continuously exposed are at an increased risk. The study was carried out to evaluate the extent of impairment in lung function in traffic police personnel compared to matched unexposed control group. A cross-sectional study was conducted to measure the spirometric parameters of 100 traffic police personnel, aged 20-55 years, working in Saurashtra region, as compared to matched control group, consisting of 100 unexposed males. Measurement of lung volumes and capacities was done with SPIROEXCEL. The statistical analysis was carried out with Graph pad instat 3. Traffic police personnel had significantly declined forced vital capacity (FVC), forced expiratory volume in one second (FEV 1), slow vital capacity (SVC) and maximum voluntary ventilation (MVV) when compared with predictive normal values, which is probably due to exposure to vehicular exhaust. Comparison of test values between groups showed significantly reduced FVC, MVV and increased FEV1/FVC ratio and insignificantly declined FEV1 and SVC in cases as compared to controls. Traffic personnel with longer duration of exposure showed significantly reduced lung functions than those with shorter duration. Smokers showed lower test values as compared to non-smokers with significance only in unexposed group. The effect of pollution by vehicular exhausts may be responsible for these pulmonary function impairments and traffic police personnel should be offered personal protective or preventive measures.

Multiscale image-based modeling and simulation of gas flow and particle transport in the human lungs

PubMed Central

Tawhai, Merryn H; Hoffman, Eric A

2013-01-01

Improved understanding of structure and function relationships in the human lungs in individuals and sub-populations is fundamentally important to the future of pulmonary medicine. Image-based measures of the lungs can provide sensitive indicators of localized features, however to provide a better prediction of lung response to disease, treatment and environment, it is desirable to integrate quantifiable regional features from imaging with associated value-added high-level modeling. With this objective in mind, recent advances in computational fluid dynamics (CFD) of the bronchial airways - from a single bifurcation symmetric model to a multiscale image-based subject-specific lung model - will be reviewed. The interaction of CFD models with local parenchymal tissue expansion - assessed by image registration - allows new understanding of the interplay between environment, hot spots where inhaled aerosols could accumulate, and inflammation. To bridge ventilation function with image-derived central airway structure in CFD, an airway geometrical modeling method that spans from the model ‘entrance’ to the terminal bronchioles will be introduced. Finally, the effects of turbulent flows and CFD turbulence models on aerosol transport and deposition will be discussed. CFD simulation of airflow and particle transport in the human lung has been pursued by a number of research groups, whose interest has been in studying flow physics and airways resistance, improving drug delivery, or investigating which populations are most susceptible to inhaled pollutants. The three most important factors that need to be considered in airway CFD studies are lung structure, regional lung function, and flow characteristics. Their correct treatment is important because the transport of therapeutic or pollutant particles is dependent on the characteristics of the flow by which they are transported; and the airflow in the lungs is dependent on the geometry of the airways and how ventilation is distributed to the peripheral tissue. The human airway structure spans more than 20 generations, beginning with the extra-thoracic airways (oral or nasal cavity, and through the pharynx and larynx to the trachea), then the conducting airways, the respiratory airways, and to the alveoli. The airways in individuals and sub-populations (by gender, age, ethnicity, and normal vs. diseased states) may exhibit different dimensions, branching patterns and angles, and thickness and rigidity. At the local level, one would like to capture detailed flow characteristics, e.g. local velocity profiles, shear stress, and pressure, for prediction of particle transport in an airway (lung structure) model that is specific to the geometry of an individual, to understand how inter-subject variation in airway geometry (normal or pathological) influences the transport and deposition of particles. In a systems biology – or multiscale modeling – approach, these local flow characteristics can be further integrated with epithelial cell models for the study of mechanotransduction. At the global (organ) level, one would like to match regional ventilation (lung function) that is specific to the individual, thus ensuring that the flow that transports inhaled particles is appropriately distributed throughout the lung model. Computational models that do not account for realistic distribution of ventilation are not capable of predicting realistic particle distribution or targeted drug deposition. Furthermore, the flow in the human lung can be transitional or turbulent in the upper and proximal airways, and becomes laminar in the distal airways. The flows in the laminar, transitional and turbulent regimes have different temporal and spatial scales. Therefore, modeling airway structure and predicting gas flow and particle transport at both local and global levels require image-guided multiscale modeling strategies. In this article, we will review the aforementioned three key aspects of CFD studies of the human lungs: airway structure (conducting airways), lung function (regional ventilation and boundary conditions), and flow characteristics (modeling of turbulent flow and its effect on particle transport). For modeling airway structure, we will focus on the conducting airways, and review both symmetric vs. asymmetric airway models, idealized vs. CT-based airway models, and multiscale subject-specific airway models. Imposition of physiological subject-specific boundary conditions (BCs) in CFD is essential to match regional ventilation in individuals, which is also critical in studying preferential deposition of inhaled aerosols in sub-populations, e.g. normals vs. asthmatics that may exhibit different ventilation patterns. Subject-specific regional ventilation defines flow distributions and characteristics in airway segments and bifurcations, which subsequently determines the transport and deposition of aerosols in the entire lungs. Turbulence models are needed to capture the transient and turbulent nature of the gas flow in the human lungs. Thus, the advantages and disadvantages of different turbulence models as well as their effects on particle transport will be discussed. The ultimate goal of the development is to identify sensitive structural and functional variables in sub-populations of normal and diseased lungs for potential clinical applications. PMID:23843310

Detection of Promoter DNA Methylation of APC, DAPK, and GSTP1 Genes in tissue Biopsy and Matched Serum of Advanced-Stage Lung Cancer Patients.

PubMed

Ali, Ashraf; Kumar, Sachin; Kakaria, Vinod Kumar; Mohan, Anant; Luthra, Kalpana; Upadhyay, Ashish Dutt; Guleria, Randeep

2017-07-03

Promoter DNA hypermethylation of APC, DAPK, and GSTP1 genes was evaluated in biopsy and matched serum of 160 lung cancer patients and 70 controls. In biopsy, 83.1, 83.1, and 78.1% of lung cancer patients and 72.9, 70, and 70% of controls, while in serum, 52.5, 30.6, and 65.6% of lung cancer patients and 14.3, 18.6, and 30% of controls were positive for APC, DAPK, and GSTP1 hypermethylation respectively. We couldn't find any significant role of DNA hypermethylation in lung cancer. However, long follow-up of methylation positive controls will be required to confirm its role for the prediction of lung cancer.

SU-E-J-111: Finite Element-Based Deformable Image Registration of Pleural Cavity for Photodynamic Therapy

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

Penjweini, R; Zhu, T

Purpose: The pleural volumes will deform during surgery portion of the pleural photodynamic therapy (PDT) of lung cancer when the pleural cavity is opened. This impact the delivered dose when using highly conformal treatment techniques. In this study, a finite element-based (FEM) deformable image registration is used to quantify the anatomical variation between the contours for the pleural cavities obtained in the operating room and those determined from pre-surgery computed tomography (CT) scans. Methods: An infrared camera-based navigation system (NDI) is used during PDT to track the anatomical changes and contour the lung and chest cavity. A series of CTsmore » of the lungs, in the same patient, are also acquired before the surgery. The structure contour of lung and the CTs are processed and contoured in Matlab and MeshLab. Then, the contours are imported into COMSOL Multiphysics 5.0, where the FEM-based deformable image registration is obtained using the deformed mesh - moving mesh (ALE) model. The NDI acquired lung contour is considered as the reference contour, and the CT contour is used as the target one, which will be deformed. Results: The reconstructed three-dimensional contours from both NDI and CT can be converted to COMSOL so that a three-dimensional ALE model can be developed. The contours can be registered using COMSOL ALE moving mesh model, which takes into account the deformation along x, y and z-axes. The deformed contour has good matches to the reference contour after the dynamic matching process. The resulting 3D deformation map can be used to obtain the locations of other critical anatomic structures, e.g., heart, during surgery. Conclusion: Deformable image registration can fuse images acquired by different modalities. It provides insights into the development of phenomenon and variation in normal anatomical structures over time. The initial assessments of three-dimensional registration show good agreement.« less

Whole exome sequencing identifies driver mutations in asymptomatic computed tomography-detected lung cancers with normal karyotype.

PubMed

Belloni, Elena; Veronesi, Giulia; Rotta, Luca; Volorio, Sara; Sardella, Domenico; Bernard, Loris; Pece, Salvatore; Di Fiore, Pier Paolo; Fumagalli, Caterina; Barberis, Massimo; Spaggiari, Lorenzo; Pelicci, Pier Giuseppe; Riva, Laura

2015-04-01

The efficacy of curative surgery for lung cancer could be largely improved by non-invasive screening programs, which can detect the disease at early stages. We previously showed that 18% of screening-identified lung cancers demonstrate a normal karyotype and, following high-density genome scanning, can be subdivided into samples with 1) numerous; 2) none; and 3) few copy number alterations. Whole exome sequencing was applied to the two normal karyotype, screening-detected lung cancers, constituting group 2, as well as normal controls. We identified mutations in both tumors, including KEAP1 (commonly mutated in lung cancers) in one, and TP53, PMS1, and MSH3 (well-characterized DNA-repair genes) in the other. The two normal karyotype screening-detected lung tumors displayed a typical lung cancer mutational profile that only next generation sequencing could reveal, which offered an additional contribution to the over-diagnosis bias concept hypothesized within lung cancer screening programs. Copyright © 2015 Elsevier Inc. All rights reserved.

Structural basis for pulmonary functional imaging.

PubMed

Itoh, H; Nakatsu, M; Yoxtheimer, L M; Uematsu, H; Ohno, Y; Hatabu, H

2001-03-01

An understanding of fine normal lung morphology is important for effective pulmonary functional imaging. The lung specimens must be inflated. These include (a) unfixed, inflated lung specimen, (b) formaldehyde fixed lung specimen, (c) fixed, inflated dry lung specimen, and (d) histology specimen. Photography, magnified view, radiograph, computed tomography, and histology of these specimens are demonstrated. From a standpoint of diagnostic imaging, the main normal lung structures consist of airways (bronchi and bronchioles), alveoli, pulmonary vessels, secondary pulmonary lobules, and subpleural pulmonary lymphatic channels. This review summarizes fine radiologic normal lung morphology as an aid to effective pulmonary functional imaging.

PDRG1, a novel tumor marker for multiple malignancies that is selectively regulated by genotoxic stress

PubMed Central

Jiang, Lingyan; Luo, Xiuquan; Shi, Jingxue; Sun, Hong; Sun, Qing; Sheikh, M Saeed

2011-01-01

We have previously cloned and characterized a novel p53 and DNA damage-regulated gene named PDRG1. PDRG1 was found to be differentially regulated by ultraviolet (UV) radiation and p53. In this study, we further investigated stress regulation of PDRG1 and found it to be selectively regulated by agents that induce genotoxic stress (DNA damage). Using cancer profiling arrays, we also investigated PDRG1 expression in matching normal and tumor samples representing various malignancies and found its expression to be upregulated in multiple malignancies including cancers of the colon, rectum, ovary, lung, stomach, breast and uterus when compared to their respective matched normal tissues. Western blot and immunohistochemical analyses were also performed on select specimen sets of colon cancers and matching normal tissues and the results also indicated PDRG1 overexpression in tumors relative to normal tissues. To gain insight into the function of PDRG1, we performed PDRG1 knockdown in human colon cancer cells and found its depletion to result in marked slowdown of tumor cell growth. These results suggest that PDRG1 may be linked to cell growth regulation. Yeast two-hybrid screening also led to the identification of PDCD7, CIZ1 and MAP1S as PDRG1-interacting proteins that are involved in apoptosis and cell cycle regulation which further implicate PDRG1 in controlling cell growth regulation. Taken together, our results indicate that PDRG1 expression is increased in multiple human malignancies suggesting it to be a high-value novel tumor marker that could play a role in cancer development and/or progression. PMID:21193842

I Vivo Characterization of Ultrasonic Backscattering from Normal and Abnormal Lungs.

NASA Astrophysics Data System (ADS)

Jafari, Farhad

The primary goal of this project has been to characterize the lung tissue in its in vivo ultrasonic backscattering properties in normal human subjects, and study the changes in the lung echo characteristics under various pathological conditions. Such a characterization procedure is used to estimate the potential of ultrasound for providing useful diagnostic information about the superficial region of the lung. The results of this study may be divided into three categories: (1) This work has resulted in the ultrasonic characterization of lung tissue, in vivo, and has investigated the various statistical features of the lung echo properties in normal human subjects. The echo properties of the lungs are characterized with respect to the mean echo amplitude relative to a perfect reflector and the mean autocorrelation of normalized echo signals. (2) A theoretical model is developed to simulate the ultrasonic backscattering properties of the lung under normal and various simulated abnormal conditions. This model has been tested on various phantoms simulating the strong acoustic interactions of the lung. When applied to the lung this model has shown excellent agreement to experimental data gathered on a population of normal human subjects. By varying a few of the model parameters, the effect of changes in the lung structural parameters on the detected ultrasonic echoes is investigated. It is found that alveoli size changes of about 50 percent and concentration changes of 40 percent may produce spectral changes exceeding the variability exhibited by normal lungs. (3) Ultrasonic echoes from the lungs of 4 groups of patients were studied. The groups included patients with edema, emphysema, pneumothorax, and patients undergoing radiation therapy for treatment of lung cancer. Significant deviations from normal lung echo characteristics is observed in more than 80 percent of the patients studied. These deviations are intercompared and some qualitative associations between the echo characteristics on each patient group and their pulmonary pathology is made. It is concluded that the technique may provide a potential tool in detecting pulmonary abnormalities. More controlled patient studies, however, are indicated as necessary to determine the sensitivity of the ultrasound technique.

Family with sequence similarity 83, member B is a predictor of poor prognosis and a potential therapeutic target for lung adenocarcinoma expressing wild-type epidermal growth factor receptor.

PubMed

Yamaura, Takumi; Ezaki, Junji; Okabe, Naoyuki; Takagi, Hironori; Ozaki, Yuki; Inoue, Takuya; Watanabe, Yuzuru; Fukuhara, Mitsuro; Muto, Satoshi; Matsumura, Yuki; Hasegawa, Takeo; Hoshino, Mika; Osugi, Jun; Shio, Yutaka; Waguri, Satoshi; Tamura, Hirosumi; Imai, Jun-Ichi; Ito, Emi; Yanagisawa, Yuka; Honma, Reiko; Watanabe, Shinya; Suzuki, Hiroyuki

2018-02-01

Lung adenocarcinoma (ADC) patients with tumors that harbor no targetable driver gene mutation, such as epidermal growth factor receptor ( EGFR ) gene mutations, have unfavorable prognosis, and thus, novel therapeutic targets are required. Family with sequence similarity 83, member B ( FAM83B ) is a biomarker for squamous cell lung cancer. FAM83B has also recently been shown to serve an important role in the EGFR signaling pathway. In the present study, the molecular and clinical impact of FAM83B in lung ADC was investigated. Matched tumor and adjacent normal tissue samples were obtained from 216 patients who underwent complete lung resection for primary lung ADC and were examined for FAM83B expression using cDNA microarray analysis. The associations between FAM83B expression and clinicopathological parameters, including patient survival, were examined. FAM83B was highly expressed in tumors from males, smokers and in tumors with wild-type EGFR . Multivariate analyses further confirmed that wild-type EGFR tumors were significantly positively associated with FAM83B expression. In survival analysis, FAM83B expression was associated with poor outcomes in disease-free survival and overall survival, particularly when stratified against tumors with wild-type EGFR . Furthermore, FAM83B knockdown was performed to investigate its phenotypic effect on lung ADC cell lines. Gene silencing by FAM83B RNA interference induced growth suppression in the HLC-1 and H1975 lung ADC cell lines. FAM83B may be involved in lung ADC tumor proliferation and can be a predictor of poor survival. FAM83B is also a potential novel therapeutic target for ADC with wild-type EGFR .

Lung texture in serial thoracic CT scans: Assessment of change introduced by image registration1

PubMed Central

Cunliffe, Alexandra R.; Al-Hallaq, Hania A.; Labby, Zacariah E.; Pelizzari, Charles A.; Straus, Christopher; Sensakovic, William F.; Ludwig, Michelle; Armato, Samuel G.

2012-01-01

Purpose: The aim of this study was to quantify the effect of four image registration methods on lung texture features extracted from serial computed tomography (CT) scans obtained from healthy human subjects. Methods: Two chest CT scans acquired at different time points were collected retrospectively for each of 27 patients. Following automated lung segmentation, each follow-up CT scan was registered to the baseline scan using four algorithms: (1) rigid, (2) affine, (3) B-splines deformable, and (4) demons deformable. The registration accuracy for each scan pair was evaluated by measuring the Euclidean distance between 150 identified landmarks. On average, 1432 spatially matched 32 × 32-pixel region-of-interest (ROI) pairs were automatically extracted from each scan pair. First-order, fractal, Fourier, Laws’ filter, and gray-level co-occurrence matrix texture features were calculated in each ROI, for a total of 140 features. Agreement between baseline and follow-up scan ROI feature values was assessed by Bland–Altman analysis for each feature; the range spanned by the 95% limits of agreement of feature value differences was calculated and normalized by the average feature value to obtain the normalized range of agreement (nRoA). Features with small nRoA were considered “registration-stable.” The normalized bias for each feature was calculated from the feature value differences between baseline and follow-up scans averaged across all ROIs in every patient. Because patients had “normal” chest CT scans, minimal change in texture feature values between scan pairs was anticipated, with the expectation of small bias and narrow limits of agreement. Results: Registration with demons reduced the Euclidean distance between landmarks such that only 9% of landmarks were separated by ≥1 mm, compared with rigid (98%), affine (95%), and B-splines (90%). Ninety-nine of the 140 (71%) features analyzed yielded nRoA > 50% for all registration methods, indicating that the majority of feature values were perturbed following registration. Nineteen of the features (14%) had nRoA < 15% following demons registration, indicating relative feature value stability. Student's t-tests showed that the nRoA of these 19 features was significantly larger when rigid, affine, or B-splines registration methods were used compared with demons registration. Demons registration yielded greater normalized bias in feature value change than B-splines registration, though this difference was not significant (p = 0.15). Conclusions: Demons registration provided higher spatial accuracy between matched anatomic landmarks in serial CT scans than rigid, affine, or B-splines algorithms. Texture feature changes calculated in healthy lung tissue from serial CT scans were smaller following demons registration compared with all other algorithms. Though registration altered the values of the majority of texture features, 19 features remained relatively stable after demons registration, indicating their potential for detecting pathologic change in serial CT scans. Combined use of accurate deformable registration using demons and texture analysis may allow for quantitative evaluation of local changes in lung tissue due to disease progression or treatment response. PMID:22894392

A GPU-based symmetric non-rigid image registration method in human lung.

PubMed

Haghighi, Babak; D Ellingwood, Nathan; Yin, Youbing; Hoffman, Eric A; Lin, Ching-Long

2018-03-01

Quantitative computed tomography (QCT) of the lungs plays an increasing role in identifying sub-phenotypes of pathologies previously lumped into broad categories such as chronic obstructive pulmonary disease and asthma. Methods for image matching and linking multiple lung volumes have proven useful in linking structure to function and in the identification of regional longitudinal changes. Here, we seek to improve the accuracy of image matching via the use of a symmetric multi-level non-rigid registration employing an inverse consistent (IC) transformation whereby images are registered both in the forward and reverse directions. To develop the symmetric method, two similarity measures, the sum of squared intensity difference (SSD) and the sum of squared tissue volume difference (SSTVD), were used. The method is based on a novel generic mathematical framework to include forward and backward transformations, simultaneously, eliminating the need to compute the inverse transformation. Two implementations were used to assess the proposed method: a two-dimensional (2-D) implementation using synthetic examples with SSD, and a multi-core CPU and graphics processing unit (GPU) implementation with SSTVD for three-dimensional (3-D) human lung datasets (six normal adults studied at total lung capacity (TLC) and functional residual capacity (FRC)). Success was evaluated in terms of the IC transformation consistency serving to link TLC to FRC. 2-D registration on synthetic images, using both symmetric and non-symmetric SSD methods, and comparison of displacement fields showed that the symmetric method gave a symmetrical grid shape and reduced IC errors, with the mean values of IC errors decreased by 37%. Results for both symmetric and non-symmetric transformations of human datasets showed that the symmetric method gave better results for IC errors in all cases, with mean values of IC errors for the symmetric method lower than the non-symmetric methods using both SSD and SSTVD. The GPU version demonstrated an average of 43 times speedup and ~5.2 times speedup over the single-threaded and 12-threaded CPU versions, respectively. Run times with the GPU were as fast as 2 min. The symmetric method improved the inverse consistency, aiding the use of image registration in the QCT-based evaluation of the lung.

Synergistic role of HSP90α and HSP90β to promote myofibroblast persistence in lung fibrosis.

PubMed

Bellaye, Pierre-Simon; Shimbori, Chiko; Yanagihara, Toyoshi; Carlson, David A; Hughes, Philip; Upagupta, Chandak; Sato, Seidai; Wheildon, Nolan; Haystead, Timothy; Ask, Kjetil; Kolb, Martin

2018-02-01

Idiopathic pulmonary fibrosis (IPF) is a progressive disease of the lung parenchyma, causing significant morbidity through worsening dyspnoea and overall functional decline. IPF is characterised by apoptosis-resistant myofibroblasts, which are a major source for the excessive production of extracellular matrix (ECM) overtaking normal lung tissue. We sought to study the role of heat shock protein (HSP) isoforms HSP90α and HSP90β, whose distinct roles in lung fibrogenesis remain elusive.We determined the level of circulating HSP90α in IPF patients (n=31) and age-matched healthy controls (n=9) by ELISA. The release of HSP90α and HSP90β was evaluated in vitro in primary IPF and control lung fibroblasts and ex vivo after mechanical stretch on fibrotic lung slices from rats receiving adenovector-mediated transforming growth factor-β1.We demonstrate that circulating HSP90α is upregulated in IPF patients in correlation with disease severity. The release of HSP90α is enhanced by the increase in mechanical stress of the fibrotic ECM. This increase in extracellular HSP90α signals through low-density lipoprotein receptor-related protein 1 (LRP1) to promote myofibroblast differentiation and persistence. In parallel, we demonstrate that the intracellular form of HSP90β stabilises LRP1, thus amplifying HSP90α extracellular action.We believe that the specific inhibition of extracellular HSP90α is a promising therapeutic strategy to reduce pro-fibrotic signalling in IPF. Copyright ©ERS 2018.

Magnetic resonance assessment of parenchymal elasticity in normal and edematous, ventilator-injured lung.

PubMed

McGee, Kiaran P; Mariappan, Yogesh K; Hubmayr, Rolf D; Carter, Rickey E; Bao, Zhonghao; Levin, David L; Manduca, Armando; Ehman, Richard L

2012-08-15

Magnetic resonance elastography (MRE) is a MR imaging method capable of spatially resolving the intrinsic mechanical properties of normal lung parenchyma. We tested the hypothesis that the mechanical properties of edematous lung exhibit local properties similar to those of a fluid-filled lung at transpulmonary pressures (P(tp)) up to 25 cm H(2)O. Pulmonary edema was induced in anesthetized female adult Sprague-Dawley rats by mechanical ventilation to a pressure of 40 cm H(2)O for ≈ 30 min. Prior to imaging the wet weight of each ex vivo lung set was measured. MRE, high-resolution T(1)-weighted spin echo and T(2)* gradient echo data were acquired at each P(tp) for both normal and injured ex vivo lungs. At P(tp)s of 6 cm H(2)O and greater, the shear stiffness of normal lungs was greater than injured lungs (P ≤ 0.0003). For P(tp)s up to 12 cm H(2)O, shear stiffness was equal to 1.00, 1.07, 1.16, and 1.26 kPa for the injured and 1.31, 1.89, 2.41, and 2.93 kPa for normal lungs at 3, 6, 9, and 12 cm H(2)O, respectively. For injured lungs MRE magnitude signal and shear stiffness within regions of differing degrees of alveolar flooding were calculated as a function of P(tp). Differences in shear stiffness were statistically significant between groups (P < 0.001) with regions of lower magnitude signal being stiffer than those of higher signal. These data demonstrate that when the alveolar space filling material is fluid, MRE-derived parenchymal shear stiffness of the lung decreases, and the lung becomes inherently softer compared with normal lung.

Lipidomics reveals dramatic lipid compositional changes in the maturing postnatal lung

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

Dautel, Sydney E.; Kyle, Jennifer E.; Clair, Geremy

Lung immaturity is a major cause of morbidity and mortality in premature infants. Understanding the molecular mechanisms driving normal lung development could provide insights on how to ameliorate disrupted development. While transcriptomic and proteomic analyses of normal lung development have been previously reported, characterization of changes in the lipidome is lacking. Lipids play significant roles in the lung, such as dipalmitoylcholine in pulmonary surfactant; however, many of the roles of specific lipid species in normal lung development, as well as in disease states, are not well defined. In this study, we used liquid chromatography-mass spectrometry (LC-MS/MS) to investigate the murinemore » lipidome during normal postnatal lung development. Lipidomics analysis of lungs from post-natal day 7, day 14 and 6-8 week mice (adult) identified 928 unique lipids across 21 lipid subclasses, with dramatic alterations in the lipidome across developmental stages. Our data confirmed previously recognized aspects of post-natal lung development and revealed several insights, including in sphingolipid-mediated apoptosis, inflammation and energy storage/usage. Complementary proteomics, metabolomics and chemical imaging corroborated these observations. Finally, this multi-omic view provides a unique resource and deeper insight into normal pulmonary development.« less

Lipidomics reveals dramatic lipid compositional changes in the maturing postnatal lung

DOE PAGES

Dautel, Sydney E.; Kyle, Jennifer E.; Clair, Geremy; ...

2017-02-01

Lung immaturity is a major cause of morbidity and mortality in premature infants. Understanding the molecular mechanisms driving normal lung development could provide insights on how to ameliorate disrupted development. While transcriptomic and proteomic analyses of normal lung development have been previously reported, characterization of changes in the lipidome is lacking. Lipids play significant roles in the lung, such as dipalmitoylcholine in pulmonary surfactant; however, many of the roles of specific lipid species in normal lung development, as well as in disease states, are not well defined. In this study, we used liquid chromatography-mass spectrometry (LC-MS/MS) to investigate the murinemore » lipidome during normal postnatal lung development. Lipidomics analysis of lungs from post-natal day 7, day 14 and 6-8 week mice (adult) identified 928 unique lipids across 21 lipid subclasses, with dramatic alterations in the lipidome across developmental stages. Our data confirmed previously recognized aspects of post-natal lung development and revealed several insights, including in sphingolipid-mediated apoptosis, inflammation and energy storage/usage. Complementary proteomics, metabolomics and chemical imaging corroborated these observations. Finally, this multi-omic view provides a unique resource and deeper insight into normal pulmonary development.« less

Deregulation of the lysyl hydroxylase matrix cross-linking system in experimental and clinical bronchopulmonary dysplasia.

PubMed

Witsch, Thilo J; Turowski, Pawel; Sakkas, Elpidoforos; Niess, Gero; Becker, Simone; Herold, Susanne; Mayer, Konstantin; Vadász, István; Roberts, Jesse D; Seeger, Werner; Morty, Rory E

2014-02-01

Bronchopulmonary dysplasia (BPD) is a common and serious complication of premature birth, characterized by a pronounced arrest of alveolar development. The underlying pathophysiological mechanisms are poorly understood although perturbations to the maturation and remodeling of the extracellular matrix (ECM) are emerging as candidate disease pathomechanisms. In this study, the expression and regulation of three members of the lysyl hydroxylase family of ECM remodeling enzymes (Plod1, Plod2, and Plod3) in clinical BPD, as well as in an experimental animal model of BPD, were addressed. All three enzymes were localized to the septal walls in developing mouse lungs, with Plod1 also expressed in the vessel walls of the developing lung and Plod3 expressed uniquely at the base of developing septa. The expression of plod1, plod2, and plod3 was upregulated in the lungs of mouse pups exposed to 85% O2, an experimental animal model of BPD. Transforming growth factor (TGF)-β increased plod2 mRNA levels and activated the plod2 promoter in vitro in lung epithelial cells and in lung fibroblasts. Using in vivo neutralization of TGF-β signaling in the experimental animal model of BPD, TGF-β was identified as the regulator of aberrant plod2 expression. PLOD2 mRNA expression was also elevated in human neonates who died with BPD or at risk for BPD, compared with neonates matched for gestational age at birth or chronological age at death. These data point to potential roles for lysyl hydroxylases in normal lung development, as well as in perturbed late lung development associated with BPD.

Interpretation of normal anatomic structures on chest radiography: Comparison of Fuji Computed Radiography (FCR) 5501D with FCR 5000 and screen‐film system

PubMed Central

Nakashima, Kazuaki; Ashizawa, Kazuto; Ochi, Makoto; Hashmi, Rashid; Hayashi, Kuniaki; Gotoh, Shinichi; Honda, Sumihisa; Igarashi, Akito; Komaki, Takao

2003-01-01

The purpose of this study was to investigate the usefulness of Fuji Computed Radiography (FCR) 5501D by comparing it with FCR 5000 and a screen‐film system (S/F). Posteroanterior chest radiographs often patients with no abnormality on chest CT scans were obtained with FCR 5501D, FCR 5000, and S/F. Six observers (three radiologists and three radio‐technologists) evaluated the visibility of nine normal anatomic structures (including lungs, soft tissue, and bones) and overall visibility on each image. Observers scored using a five‐point scale on each structure. FCR 5000 showed a significantly higher score in soft tissue and bone structures, and overall visibility compared with S/F, but, there was no significant difference between them in the visibility of all four normal lung structures. Compared with S/F, the score for FCR 5501D was higher in eight of the nine normal structures, including three of the four lung structures (unobscured lung, retrocardiac lung, and subdiaphragmatic lung), and overall visibility. Compared with FCR 5000, the score for FCR 5501D was higher in three normal structures, including two of the four lung structures (unobscured lung and subdiaphragmatic lung), and overall visibility. FCR 5501D was the best among the three techniques to visualize normal anatomic structures, particularly the obscured and unobscured lung. © 2003 American College of Medical Physics. PACS number(s): 87.57.–s, 87.62.+n PMID:12540822

Musashi-2 (MSI2) supports TGF-β signaling and inhibits claudins to promote non-small cell lung cancer (NSCLC) metastasis.

PubMed

Kudinov, Alexander E; Deneka, Alexander; Nikonova, Anna S; Beck, Tim N; Ahn, Young-Ho; Liu, Xin; Martinez, Cathleen F; Schultz, Fred A; Reynolds, Samuel; Yang, Dong-Hua; Cai, Kathy Q; Yaghmour, Khaled M; Baker, Karmel A; Egleston, Brian L; Nicolas, Emmanuelle; Chikwem, Adaeze; Andrianov, Gregory; Singh, Shelly; Borghaei, Hossein; Serebriiskii, Ilya G; Gibbons, Don L; Kurie, Jonathan M; Golemis, Erica A; Boumber, Yanis

2016-06-21

Non-small cell lung cancer (NSCLC) has a 5-y survival rate of ∼16%, with most deaths associated with uncontrolled metastasis. We screened for stem cell identity-related genes preferentially expressed in a panel of cell lines with high versus low metastatic potential, derived from NSCLC tumors of Kras(LA1/+);P53(R172HΔG/+) (KP) mice. The Musashi-2 (MSI2) protein, a regulator of mRNA translation, was consistently elevated in metastasis-competent cell lines. MSI2 was overexpressed in 123 human NSCLC tumor specimens versus normal lung, whereas higher expression was associated with disease progression in an independent set of matched normal/primary tumor/lymph node specimens. Depletion of MSI2 in multiple independent metastatic murine and human NSCLC cell lines reduced invasion and metastatic potential, independent of an effect on proliferation. MSI2 depletion significantly induced expression of proteins associated with epithelial identity, including tight junction proteins [claudin 3 (CLDN3), claudin 5 (CLDN5), and claudin 7 (CLDN7)] and down-regulated direct translational targets associated with epithelial-mesenchymal transition, including the TGF-β receptor 1 (TGFβR1), the small mothers against decapentaplegic homolog 3 (SMAD3), and the zinc finger proteins SNAI1 (SNAIL) and SNAI2 (SLUG). Overexpression of TGFβRI reversed the loss of invasion associated with MSI2 depletion, whereas overexpression of CLDN7 inhibited MSI2-dependent invasion. Unexpectedly, MSI2 depletion reduced E-cadherin expression, reflecting a mixed epithelial-mesenchymal phenotype. Based on this work, we propose that MSI2 provides essential support for TGFβR1/SMAD3 signaling and contributes to invasive adenocarcinoma of the lung and may serve as a predictive biomarker of NSCLC aggressiveness.

Decreased expression of 14-3-3 σ, an early event of malignant transformation of respiratory epithelium, also facilitates progression of squamous cell lung cancer

PubMed Central

Sun, Nan; Wu, Yongkai; Huang, Bo; Liu, Qian; Dong, Yinan; Ding, Jianqiao; Liu, Yongyu

2015-01-01

Background It has been shown that 14-3-3 σ serves as a tumor suppressor gene, and is downregulated in various tumor tissues. However, the role of 14-3-3 σ during the initiation and progression of lung squamous cell carcinoma (SqCC) is not well understood. Methods The expression status of 14-3-3 σ in archival tissue samples from 40 lung SqCC patients (36 with normal bronchia, 19 squamous metaplasia, and 17 dysplasia/carcinoma in situ, in their tissue samples) was examined by immunohistochemical analysis. The proliferation rate and tumor formation ability of the H520 cell transfected with 14-3-3 σ was tested with methyl thiazolyl tetrazolium assay and nude mice subcutaneous injection, respectively. Results In the normal bronchial epithelia, 14-3-3 σ was highly expressed, whereas it was significantly decreased in precancerous and cancerous tissues. Compared with matched invasive cancer tissues, the expression level of 14-3-3 σ in squamous metaplasia was significantly higher (P = 0.049), while that in dysplasia/carcinoma in situ showed no significant changes (P = 0.135). Statistical analysis showed that the expression level of 14-3-3 σ in tumor tissue was associated with the differentiation grade of the tumor (P = 0.001) and the prognosis of the patient (P = 0.003). The overexpression of 14-3-3 σ significantly suppressed the proliferation of H520 cells in vitro and in vivo. Conclusion The inactivation of 14-3-3 σ may be a very early event in tumorigenesis and could facilitate the initiation and progression of lung SqCC in a sustainable way. PMID:26557909

Measurement of Lung Cancer Tumor Markers in a Glass Wool Company Workers Exposed to Respirable Synthetic Vitreous Fiber and Dust.

PubMed

Abtahi, Shabnam; Malekzadeh, Mahyar; Nikravan, Ghafour; Ghaderi, Abbas

2018-01-01

Occupational exposures to respirable synthetic vitreous fiber (SVF) and dust are associated with many lung diseases including lung cancer. Low-dose computed tomography is used for screening patients who are highly suspicious of having lung carcinoma. However, it seems not to be cost-effective. Serum biomarkers could be a useful tool for the surveillance of occupational exposure, by providing the possibility of diagnosing lung cancer in its early stages. To determine if serum carcinoembryonic antigen (CEA) and cytokeratin fragment (CYFRA) 21-1 levels in workers exposed more than normal population to respirable SVF and dust may be used as indicators of progression towards lung cancer. An analytic cross-sectional study, including 145 personnel of a glass wool company, along with 25 age-matched healthy individuals, was conducted to investigate the relationship between occupational exposure to respirable SVFs and dust and serum levels of two lung/pleura serum tumor markers, CEA and CYFRA 21-1, measured by ELISA. Individuals exposed to higher than the recommended levels of respirable SVF had higher serum concentrations of CEA and CYFRA 21-1, compared to controls (p=0.008 and 0.040, respectively), as well as in comparison to those exposed to lower than recommended OSHA levels (p=0.046 and 0.033, respectively). Workers with >9 years work experience, had significantly (p=0.045) higher levels of serum CYFRA 21-1 than those with ≤9 years of experience. It seems that working for >9 years in sites with detectable levels of respirable SVF and dust would increase the levels of known lung cancer serum tumor markers. Transferring these workers to sites with respirable SVF concentrations lower than the limit of detection in the air is recommended.

Methylation of Wnt7a Is Modulated by DNMT1 and Cigarette Smoke Condensate in Non-Small Cell Lung Cancer

PubMed Central

Tennis, Meredith A.; VanScoyk, Michelle M.; Wilson, Lora A.; Kelley, Nicole; Winn, Robert A.

2012-01-01

Wnt7a is known to be a tumor suppressor that is lost in NSCLC, but no mechanism of loss has been established. Methylation of promoter regions has been established as a common mechanism of loss of tumor suppressor expression in NSCLC. We previously demonstrated that loss of Wnt7a in non-transformed lung epithelial cell lines led to increased cell growth, altered 3-D culture growth, and increased migration. The Wnt7a promoter has a higher percentage of methylation in NSCLC tumor tissue compared to matched normal lung tissue and methylation of the promoter region leads to decreased activity. We treated H157 and H1299 NSCLC cell lines with 5-Aza-2′-deoxycytidine and detected loss of Wnt7a promoter methylation, increased Wnt7a expression, and increased activity of the Wnt7a lung signaling pathway. When DNMT1 expression was knocked down by shRNA, expression of Wnt7a increased and methylation decreased. Together these data suggest that in NSCLC, Wnt7a is lost by methylation in a subset of tumors and that this methylation is maintained by DNMT1. Restoration of Wnt7a expression through demethylation could be an important therapeutic approach in the treatment of NSCLC. PMID:22403725

Immersing lungs in hydrogen-rich saline attenuates lung ischaemia-reperfusion injury.

PubMed

Takahashi, Mamoru; Chen-Yoshikawa, Toyofumi F; Saito, Masao; Tanaka, Satona; Miyamoto, Ei; Ohata, Keiji; Kondo, Takeshi; Motoyama, Hideki; Hijiya, Kyoko; Aoyama, Akihiro; Date, Hiroshi

2017-03-01

Anti-oxidant effects of hydrogen have been reported in studies examining ischaemia-reperfusion injury (IRI). In this study, we evaluated the therapeutic efficacy of immersing lungs in hydrogen-rich saline on lung IRI. Lewis rats were divided into three groups: (i) sham, (ii) normal saline and (iii) hydrogen-rich saline. In the first experiment, the left thoracic cavity was filled with either normal saline or hydrogen-rich saline for 1 h. Then, we measured the hydrogen concentration in the left lung using a sensor gas chromatograph ( N = 3 per group). In the second experiment, lung IRI was induced by occlusion of the left pulmonary hilum for 1 h, followed by reperfusion for 3 h. During the ischaemic period, the left thoracic cavity was filled with either normal saline or hydrogen-rich saline. After reperfusion, we assessed lung function, histological changes and cytokine production ( N = 5-7 per group). Immersing lungs in hydrogen-rich saline resulted in an elevated hydrogen concentration in the lung (6.9 ± 2.9 μmol/1 g lung). After IRI, pulmonary function (pulmonary compliance and oxygenation levels) was significantly higher in the hydrogen-rich saline group than in the normal saline group ( P  < 0.05). Similarly, pro-inflammatory cytokine levels (interleukin-1β and interleukin-6) in the left lung were significantly lower in the hydrogen-rich saline group than in the normal saline group ( P  < 0.05). Immersing lungs in hydrogen-rich saline delivered hydrogen into the lung and consequently attenuated lung IRI. Hydrogen-rich solution appears to be a promising approach to managing lung IRI. © The Author 2016. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.

Matched-pair analysis of a multi-institutional cohort reveals that epidermal growth factor receptor mutation is not a risk factor for postoperative recurrence of lung adenocarcinoma.

PubMed

Matsumura, Yuki; Suzuki, Hiroyuki; Ohira, Tetsuya; Shiono, Satoshi; Abe, Jiro; Sagawa, Motoyasu; Sakurada, Akira; Katahira, Masato; Machida, Yuichiro; Takahashi, Satomi; Okada, Yoshinori

2017-12-01

It is unclear whether epidermal growth factor receptor (EGFR) mutation status is a risk factor for postoperative recurrence of surgically resected lung adenocarcinoma (ADC). Therefore, we conducted a multi-institutional study employing matched-pair analysis to compare recurrence-free survival (RFS) and overall survival (OS) of patients with lung ADC according to EGFR mutation status. We collected the records of 909 patients who underwent surgical resection for lung ADC between 2005 and 2012 at five participating institutions and were also examined their EGFR mutation status. For each patient with an EGFR mutation, we selected one with the wild-type EGFR sequence and matched them according to institution, age, gender, smoking history, pathological stage (pStage), and adjuvant treatment. We compared RFS and OS of the matched cohort. The patients were allocated into groups (n=181 each) with mutated or wild-type EGFR sequences. Both cohorts had identical characteristics as follows: institution, median age (68 years), men (85, 47%), ever smokers (77, 43%), and pStage (IA, 108, 60%; IB, 48, 27%; II, 14, 8%; III, 11, 6%). The 3- and 5-year RFS rates of patients with mutated or wild-type EGFR sequence were 79%, 68% and 77%, 68%, respectively (p=0.557). The respective OS rates were 92%, 81%, and 89%, 79% (p=0.574). Matched-pair and multi-institutional analysis reveals that an EGFR mutation was not a significant risk factor for recurrence of patients with surgically resected lung adenocarcinoma. Copyright © 2017 Elsevier B.V. All rights reserved.

Epidermal growth factor receptor gene mutation as risk factor for recurrence in patients with surgically resected lung adenocarcinoma: a matched-pair analysis.

PubMed

Matsumura, Yuki; Owada, Yuki; Yamaura, Takumi; Muto, Satoshi; Osugi, Jun; Hoshino, Mika; Higuchi, Mitsunori; Ohira, Tetsuya; Suzuki, Hiroyuki; Gotoh, Mitsukazu

2016-08-01

Epidermal growth factor receptor (EGFR) mutation is a robust prognostic factor in patients with lung adenocarcinoma (ADC). However, the role of EGFR mutation status as a recurrence-risk factor remains unknown because the presence of such mutations is associated with other background characteristics. We therefore conducted a matched-pair analysis to compare recurrence-free survival (RFS) in matched cohorts of patients with lung ADC. We enrolled 379 patients who underwent surgical resection for lung ADC between 2005 and 2012. We determined the EGFR mutation status of each tumour. Matching their age, gender, smoking history and pathological stage (pStage), we compared RFS between matched cohorts with and without EGFR mutation (n = 86 each). The median age was 67 years, there were 39 (45%) men, 39 (45%) ex- or current smokers and pStage I: 71 (83%), II: 5 (6%), III: 8 (9%), IV: 2 (2%) in each group. The 3- and 5-year RFS rates in patients with mutant and wild-type EGFR were 85 and 78%, and 74 and 60%, respectively, with significant differences between the groups (P = 0.040). Multivariate analysis identified vascular invasion and lymphatic permeation, but not EGFR mutation status, as independent risk factors for recurrence. EGFR-gene mutation might be a favourable recurrence-risk factor in patients with surgically resected lung ADC, but further studies in larger cohorts are needed to verify this hypothesis. © The Author 2016. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.

Incidence of late atrial fibrillation in bilateral lung versus heart transplants.

PubMed

Magruder, J Trent; Plum, William; Crawford, Todd C; Grimm, Joshua C; Borja, Marvin C; Berger, Ronald D; Tandri, Harikrishna; Calkins, Hugh; Cameron, Duke E; Mandal, Kaushik

2016-10-01

We compared the incidence of late-onset atrial fibrillation in orthotopic heart transplant recipients and bilateral orthotopic lung transplant recipients. We reviewed the records of all heart and lung transplant operations carried out in our institution between 1995 and 2015. We performed 1:1 propensity-matching based on patient age, sex, body mass index, and hypertension. Our primary outcome, late-onset atrial fibrillation, was defined as atrial fibrillation occurring after discharge following hospitalization for transplantation. Over the study period, 397 orthotopic heart transplants and 240 bilateral orthotopic lung transplants were performed. Propensity matching resulted in 173 pairs who were matched with respect to age, sex, body mass index, and preoperative hypertension. The median follow-up was 5.3 years for heart transplant patients and 3.1 years for lung transplant patients. Late-onset atrial fibrillation occurred in 11 heart transplant patients (5 of whom had biopsy-proven evidence of rejection) and 19 lung transplant patients (2 of whom had biopsy-proven evidence of rejection). On Kaplan-Meier analysis, the probability of late-onset atrial fibrillation at 5 years was 4.3% for heart transplant patients vs. 13.9% for lung transplant patients (log-rank p = 0.01). We documented an increased probability of late-onset atrial fibrillation among bilateral orthotopic lung transplant patients compared to orthotopic heart transplant patients. This was a hypothesis-generating study that suggests a potential role for cardiac autonomic innervation in the genesis of atrial fibrillation. © The Author(s) 2016.

Assessing breathing motion by shape matching of lung and diaphragm surfaces

NASA Astrophysics Data System (ADS)

Urschler, Martin; Bischof, Horst

2005-04-01

Studying complex thorax breating motion is an important research topic for accurate fusion of functional and anatomical data, radiotherapy planning or reduction of breathing motion artifacts. We investigate segmented CT lung, airway and diaphragm surfaces at several different breathing states between Functional Residual and Total Lung Capacity. In general, it is hard to robustly derive corresponding shape features like curvature maxima from lung and diaphragm surfaces since diaphragm and rib cage muscles tend to deform the elastic lung tissue such that e.g. ridges might disappear. A novel registration method based on the shape context approach for shape matching is presented where we extend shape context to 3D surfaces. The shape context approach was reported as a promising method for matching 2D shapes without relying on extracted shape features. We use the point correspondences for a non-rigid thin-plate-spline registration to get deformation fields that describe the movement of lung and diaphragm. Our validation consists of experiments on phantom and real sheep thorax data sets. Phantom experiments make use of shapes that are manipulated with known transformations that simulate breathing behaviour. Real thorax data experiments use a data set showing lungs and diaphragm at 5 distinct breathing states, where we compare subsets of the data sets and qualitatively and quantitatively asses the registration performance by using manually identified corresponding landmarks.

Case Studies in Physiology: Ventilation and perfusion in a giraffe-does size matter?

PubMed

Nyman, Görel; Röken, Bengt; Hedin, Eva-Maria; Hedenstierna, Göran

2016-12-01

The trachea in the giraffe is long but narrow, and dead space ventilation is considered to be of approximately the same size as in other mammals. Less is known about the matching between ventilation and lung blood flow. The lungs in the giraffe are large, up to 1 m high and 0.7 m wide, and this may cause considerable ventilation/perfusion (V A /Q) mismatch due to the influence of gravitational forces, which could lead to hypoxemia. We studied a young giraffe under anesthesia using the multiple inert gas elimination technique to analyze the VA/Q distribution and arterial oxygenation and compared the results with those obtained in other species of different sizes, including humans. V A /Q distribution was broad but unimodal, and the shunt of blood flow through nonventilated lung regions was essentially absent, suggesting no lung collapse. The V A /Q match was as good as in the similarly sized horse and was even comparable to that in smaller sized animals, including rabbit and rat. The match was also similar to that in anesthetized humans. Arterial oxygenation was essentially similar in all studied species. The findings suggest that the efficiency of V A /Q matching is independent of lung size in the studied mammals that vary in weight from less than 1 to more than 400 kg. Copyright © 2016 the American Physiological Society.

Normal expiratory flow rate and lung volumes in patients with combined emphysema and interstitial lung disease: a case series and literature review.

PubMed

Heathcote, Karen L; Cockcroft, Donald W; Fladeland, Derek A; Fenton, Mark E

2011-01-01

Pulmonary function tests in patients with idiopathic pulmonary fibrosis characteristically show a restrictive pattern including small lung volumes and increased expiratory flow rates resulting from a reduction in pulmonary compliance due to diffuse fibrosis. Conversely, an obstructive pattern with hyperinflation results in emphysema by loss of elastic recoil, expiratory collapse of the peripheral airways and air trapping. When the diseases coexist, pulmonary volumes are compensated, and a smaller than expected reduction or even normal lung volumes can be found. The present report describes 10 patients with progressive breathlessness, three of whom experienced severe limitation in their quality of life. All patients showed lung interstitial involvement and emphysema on computed tomography scan of the chest. The 10 patients showed normal spirometry and lung volumes with severe compromise of gas exchange. Normal lung volumes do not exclude diagnosis of idiopathic pulmonary fibrosis in patients with concomitant emphysema. The relatively preserved lung volumes may underestimate the severity of idiopathic pulmonary fibrosis and attenuate its effects on lung function parameters.

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).

MO-G-17A-06: Kernel Based Dosimetry for 90Y Microsphere Liver Therapy Using 90Y Bremsstrahlung SPECT/CT

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

Mikell, J; Siman, W; Kappadath, S

2014-06-15

Purpose: 90Y microsphere therapy in liver presents a situation where beta transport is dominant and the tissue is relatively homogenous. We compare voxel-based absorbed doses from a 90Y kernel to Monte Carlo (MC) using quantitative 90Y bremsstrahlung SPECT/CT as source distribution. Methods: Liver, normal liver, and tumors were delineated by an interventional radiologist using contrast-enhanced CT registered with 90Y SPECT/CT scans for 14 therapies. Right lung was segmented via region growing. The kernel was generated with 1.04 g/cc soft tissue for 4.8 mm voxel matching the SPECT. MC simulation materials included air, lung, soft tissue, and bone with varying densities.more » We report percent difference between kernel and MC (%Δ(K,MC)) for mean absorbed dose, D70, and V20Gy in total liver, normal liver, tumors, and right lung. We also report %Δ(K,MC) for heterogeneity metrics: coefficient of variation (COV) and D10/D90. The impact of spatial resolution (0, 10, 20 mm FWHM) and lung shunt fraction (LSF) (1,5,10,20%) on the accuracy of MC and kernel doses near the liver-lung interface was modeled in 1D. We report the distance from the interface where errors become <10% of unblurred MC as d10(side of interface, dose calculation, FWHM blurring, LSF). Results: The %Δ(K,MC) for mean, D70, and V20Gy in tumor and liver was <7% while right lung differences varied from 60–90%. The %Δ(K,MC) for COV was <4.8% for tumor and liver and <54% for the right lung. The %Δ(K,MC) for D10/D90 was <5% for 22/23 tumors. d10(liver,MC,10,1–20) awere <9mm and d10(liver,MC,20,1–20) awere <15mm; both agreed within 3mm to the kernel. d10(lung,MC,10,20), d10(lung,MC,10,1), d10(lung,MC,20,20), and d10(lung,MC,20,1) awere 6, 25, 15, and 34mm, respectively. Kernel calculations on blurred distributions in lung had errors > 10%. Conclusions: Liver and tumor voxel doses with 90Y kernel and MC agree within 7%. Large differences exist between the two methods in right lung. Research reported in this publication was supported by the National Cancer Institute of the National Institutes of Health under Award Number R01CA138986. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.« less

Bronchopulmonary dysplasia: improvement in lung function between 7 and 10 years of age.

PubMed

Blayney, M; Kerem, E; Whyte, H; O'Brodovich, H

1991-02-01

To evaluate the natural history of bronchopulmonary dysplasia, we studied the same 32 patients at a mean age of 7 and 10 years. The group as a whole had normal height and weight percentiles, and each child grew along his or her established somatic growth curve. Although some children had abnormal values, the group maintained a normal mean total lung capacity and functional residual capacity. The mean residual volume and the residual volume/total lung capacity ratios were elevated at both ages. At age 7 years the 19 patients (59%) who had a forced expiratory volume in 1 second (FEV1) of less than 80% had "catch up" improvement by 10 years of age (65 +/- 11% to 72 +/- 16% of predicted value; p less than 0.05). All the children who had a normal FEV1 at 7 years of age continued to have a normal FEV1 at age 10 years. Resting single-breath carbon monoxide uptake by the lung was normal when measured at age 10 years. The majority of patients had a positive methacholine challenge test result at both ages, although there was a low incidence of clinically diagnosed asthma. This study demonstrates that patients with bronchopulmonary dysplasia who have normal lung function at age 7 have had normal lung growth and that those with evidence of mild to moderate lung disease have continued lung growth or repair, or both, during their school years.

Unique spatial and cellular expression patterns of Hoxa5, Hoxb4 and Hoxb6 proteins in normal developing murine lung are modified in pulmonary hypoplasia

PubMed Central

Volpe, MaryAnn Vitoria; Wang, Karen Ting Wai; Nielsen, Heber Carl; Chinoy, Mala Romeshchandra

2009-01-01

Background Hox transcription factors modulate signaling pathways controlling organ morphogenesis and maintain cell fate and differentiation in adults. Retinoid signaling, key in regulating Hox expression, is altered in pulmonary hypoplasia. Information on pattern-specific expression of Hox proteins in normal lung development and in pulmonary hypoplasia is minimal. Our objective was to determine how pulmonary hypoplasia alters temporal, spatial and cellular expression of Hoxa5, Hoxb4 and Hoxb6 proteins compared to normal lung development. Methods Temporal, spatial and cellular Hoxa5, Hoxb4 and Hoxb6 expression was studied in normal (untreated) and nitrofen-induced hypoplastic (NT-PH) lungs from gestational day 13.5, 16, 19 fetuses and neonates using western blot and immunohistochemistry. Results Modification of protein levels and spatial and cellular Hox expression patterns in NT-PH lungs was consistent with delayed lung development. Distinct protein isoforms were detected for each Hox protein. Expression levels of the Hoxa5 and Hoxb6 isoforms changed with development and further in NT-PH lungs. Compared to normal lungs, Gd19 and neonatal NT-PH lungs had decreased Hoxb6 and increased Hoxa5 and Hoxb4. Hoxa5 cellular localization changed from mesenchyme to epithelia earlier in normal lungs. Hoxb4 was expressed in mesenchyme and epithelial cells throughout development. Hoxb6 remained mainly in mesenchymal cells around distal airways. Conclusions Unique spatial and cellular expression of Hoxa5, Hoxb4 and Hoxb6 participates in branching morphogenesis and terminal sac formation. Altered Hox protein temporal and cellular balance of expression either contributes to pulmonary hypoplasia or functions as a compensatory mechanism attempting to correct abnormal lung development and maturation in this condition. PMID:18553509

Frequency and number of ultrasound lung rockets (B-lines) using a regionally based lung ultrasound examination named vet BLUE (veterinary bedside lung ultrasound exam) in dogs with radiographically normal lung findings.

PubMed

Lisciandro, Gregory R; Fosgate, Geoffrey T; Fulton, Robert M

2014-01-01

Lung ultrasound is superior to lung auscultation and supine chest radiography for many respiratory conditions in human patients. Ultrasound diagnoses are based on easily learned patterns of sonographic findings and artifacts in standardized images. By applying the wet lung (ultrasound lung rockets or B-lines, representing interstitial edema) versus dry lung (A-lines with a glide sign) concept many respiratory conditions can be diagnosed or excluded. The ultrasound probe can be used as a visual stethoscope for the evaluation of human lungs because dry artifacts (A-lines with a glide sign) predominate over wet artifacts (ultrasound lung rockets or B-lines). However, the frequency and number of wet lung ultrasound artifacts in dogs with radiographically normal lungs is unknown. Thus, the primary objective was to determine the baseline frequency and number of ultrasound lung rockets in dogs without clinical signs of respiratory disease and with radiographically normal lung findings using an 8-view novel regionally based lung ultrasound examination called Vet BLUE. Frequency of ultrasound lung rockets were statistically compared based on signalment, body condition score, investigator, and reasons for radiography. Ten left-sided heart failure dogs were similarly enrolled. Overall frequency of ultrasound lung rockets was 11% (95% confidence interval, 6-19%) in dogs without respiratory disease versus 100% (95% confidence interval, 74-100%) in those with left-sided heart failure. The low frequency and number of ultrasound lung rockets observed in dogs without respiratory disease and with radiographically normal lungs suggests that Vet BLUE will be clinically useful for the identification of canine respiratory conditions. © 2014 American College of Veterinary Radiology.

The effect of lung-size mismatch on mechanical ventilation tidal volumes after bilateral lung transplantation.

PubMed

Dezube, Rebecca; Arnaoutakis, George J; Reed, Robert M; Bolukbas, Servet; Shah, Ashish S; Orens, Jonathan B; Brower, Roy G; Eberlein, Michael

2013-03-01

Mechanical ventilation tidal volumes are usually set according to an estimate of patient size in millilitres (ml) per kilogram (kg) body weight. We describe the relationship between donor-recipient lung-size mismatch and postoperative mechanical ventilation tidal volumes according to recipient- and donor-predicted body weights in a cohort of bilateral lung transplant patients. A most-undersized (10 patients with lowest predicted total lung capacity [pTLC] ratio = pTLC-donor/pTLC-recipient), a most-oversized (10 patients with highest pTLC ratio) and best-matched subset (10 patients with predicted total lung capacity ratio closest to 1.0) were selected within a cohort of 70 patients. All tidal volumes during mechanical ventilation in the first 96 h after bilateral lung transplantation were recorded. Tidal volumes were expressed in ml and ml/kg-recipient-predicted body weights and ml/kg-donor-predicted body weights. Postoperative absolute tidal volumes (in ml) were comparable between subsets of patients with undersized, matched and oversized allografts (552 ± 103 vs 581 ± 107 vs 582 ± 104 ml), and tidal volumes in ml/kg-recipient-predicted body weights were also similar (8.8 ± 1.4 vs 9.3 ± 1.1 vs 9.8 ± 2.1). However, tidal volumes in ml/kg-donor-predicted body weights revealed significant differences between undersized, matched, and oversized subsets (11.4 ± 3.1 vs 9.4 ± 1.2 vs 8.1 ± 2.1, respectively; P < 0.05). Two patients developed primary graft dysfunction grade 3, both in the undersized subset. Four patients in the undersized group underwent tracheotomy (vs none in matched and one in oversized subset). During mechanical ventilation after bilateral lung transplantation, undersized allografts received relatively higher tidal volumes compared with oversized allografts when the tidal volumes were related to donor-predicted body weights.

Efficacy of a Self-expanding Tract Sealant Device in the Reduction of Pneumothorax and Chest Tube Placement Rates After Percutaneous Lung Biopsy: A Matched Controlled Study Using Propensity Score Analysis.

PubMed

Ahrar, Judy U; Gupta, Sanjay; Ensor, Joe E; Mahvash, Armeen; Sabir, Sharjeel H; Steele, Joseph R; McRae, Stephen E; Avritscher, Rony; Huang, Steven Y; Odisio, Bruno C; Murthy, Ravi; Ahrar, Kamran; Wallace, Michael J; Tam, Alda L

2017-02-01

To evaluate the use of a self-expanding tract sealant device (BioSentry™) on the rates of pneumothorax and chest tube insertion after percutaneous lung biopsy. In this retrospective study, we compared 318 patients who received BioSentry™ during percutaneous lung biopsy (treated group) with 1956 patients who did not (control group). Patient-, lesion-, and procedure-specific variables, and pneumothorax and chest tube insertion rates were recorded. To adjust for potential selection bias, patients in the treated group were matched 1:1 to patients in the control group using propensity score matching based on the above-mentioned variables. Patients were considered a match if the absolute difference in their propensity scores was ≤equal to 0.02. Before matching, the pneumothorax and chest tube rates were 24.5 and 13.1% in the control group, and 21.1 and 8.5% in the treated group, respectively. Using propensity scores, a match was found for 317 patients in the treatment group. Chi-square contingency matched pair analysis showed the treated group had significantly lower pneumothorax (20.8 vs. 32.8%; p = 0.001) and chest tube (8.2 vs. 20.8%; p < 0.0001) rates compared to the control group. Sub-analysis including only faculty who had >30 cases of both treatment and control cases demonstrated similar findings: the treated group had significantly lower pneumothorax (17.6 vs. 30.2%; p = 0.002) and chest tube (7.2 vs. 18%; p = 0.001) rates. The self-expanding tract sealant device significantly reduced the pneumothorax rate, and more importantly, the chest tube placement rate after percutaneous lung biopsy.

Application of a High Throughput Method of Biomarker Discovery to Improvement of the EarlyCDT®-Lung Test

PubMed Central

Macdonald, Isabel K.; Murray, Andrea; Healey, Graham F.; Parsy-Kowalska, Celine B.; Allen, Jared; McElveen, Jane; Robertson, Chris; Sewell, Herbert F.; Chapman, Caroline J.; Robertson, John F. R.

2012-01-01

Background The National Lung Screening Trial showed that CT screening for lung cancer led to a 20% reduction in mortality. However, CT screening has a number of disadvantages including low specificity. A validated autoantibody assay is available commercially (EarlyCDT®-Lung) to aid in the early detection of lung cancer and risk stratification in patients with pulmonary nodules detected by CT. Recent advances in high throughput (HTP) cloning and expression methods have been developed into a discovery pipeline to identify biomarkers that detect autoantibodies. The aim of this study was to demonstrate the successful clinical application of this strategy to add to the EarlyCDT-Lung panel in order to improve its sensitivity and specificity (and hence positive predictive value, (PPV)). Methods and Findings Serum from two matched independent cohorts of lung cancer patients were used (n = 100 and n = 165). Sixty nine proteins were initially screened on an abridged HTP version of the autoantibody ELISA using protein prepared on small scale by a HTP expression and purification screen. Promising leads were produced in shake flask culture and tested on the full assay. These results were analyzed in combination with those from the EarlyCDT-Lung panel in order to provide a set of re-optimized cut-offs. Five proteins that still displayed cancer/normal differentiation were tested for reproducibility and validation on a second batch of protein and a separate patient cohort. Addition of these proteins resulted in an improvement in the sensitivity and specificity of the test from 38% and 86% to 49% and 93% respectively (PPV improvement from 1 in 16 to 1 in 7). Conclusion This is a practical example of the value of investing resources to develop a HTP technology. Such technology may lead to improvement in the clinical utility of the EarlyCDT­-Lung test, and so further aid the early detection of lung cancer. PMID:23272083

Analysis of the Plasma Proteome in COPD: Novel Low Abundance Proteins Reflect the Severity of Lung Remodeling

PubMed Central

Merali, Salim; Barrero, Carlos A.; Bowler, Russell P.; Chen, Diane Er; Criner, Gerard; Braverman, Alan; Litwin, Samuel; Yeung, Anthony; Kelsen, Steven G.

2015-01-01

The search for COPD biomarkers has largely employed a targeted approach that focuses on plasma proteins involved in the systemic inflammatory response and in lung injury and repair. This proof of concept study was designed to test the idea that an open, unbiased, in-depth proteomics approach could identify novel, low abundance plasma proteins i.e., ng/mL concentration, which could serve as potential biomarkers. Differentially expressed proteins were identified in a discovery group with severe COPD (FEV1 <45% predicted; n = 10). Subjects with normal lung function matched for age, sex, ethnicity and smoking history served as controls (n = 10). Pooled plasma from each group was exhaustively immunodepleted of abundant proteins, d separated by 1-D gel electrophoresis and extensively fractionated prior to LC-tandem mass spectroscopy (GeLC-MS). Thirty one differentially expressed proteins were identified in the discovery group including markers of lung defense against oxidant stress, alveolar macrophage activation, and lung tissue injury and repair. Four of the 31 proteins (i.e., GRP78, soluble CD163, IL1AP and MSPT9) were measured in a separate verification group of 80 subjects with varying COPD severity by immunoassay. All 4 were significantly altered in COPD and 2 (GRP78 and soluble CD163) correlated with both FEV1 and the extent of emphysema. In-depth, plasma proteomic analysis identified a group of novel, differentially expressed, low abundance proteins that reflect known pathogenic mechanisms and the severity of lung remodeling in COPD. These proteins may also prove useful as COPD biomarkers. PMID:24111704

Analysis of the plasma proteome in COPD: Novel low abundance proteins reflect the severity of lung remodeling.

PubMed

Merali, Salim; Barrero, Carlos A; Bowler, Russell P; Chen, Diane Er; Criner, Gerard; Braverman, Alan; Litwin, Samuel; Yeung, Anthony; Kelsen, Steven G

2014-04-01

The search for COPD biomarkers has largely employed a targeted approach that focuses on plasma proteins involved in the systemic inflammatory response and in lung injury and repair. This proof of concept study was designed to test the idea that an open, unbiased, in-depth proteomics approach could identify novel, low abundance plasma proteins i.e., ng/mL concentration, which could serve as potential biomarkers. Differentially expressed proteins were identified in a discovery group with severe COPD (FEV1 <45% predicted; n = 10). Subjects with normal lung function matched for age, sex, ethnicity and smoking history served as controls (n = 10). Pooled plasma from each group was exhaustively immunodepleted of abundant proteins, d separated by 1-D gel electrophoresis and extensively fractionated prior to LC-tandem mass spectroscopy (GeLC-MS). Thirty one differentially expressed proteins were identified in the discovery group including markers of lung defense against oxidant stress, alveolar macrophage activation, and lung tissue injury and repair. Four of the 31 proteins (i.e., GRP78, soluble CD163, IL1AP and MSPT9) were measured in a separate verification group of 80 subjects with varying COPD severity by immunoassay. All 4 were significantly altered in COPD and 2 (GRP78 and soluble CD163) correlated with both FEV1 and the extent of emphysema. In-depth, plasma proteomic analysis identified a group of novel, differentially expressed, low abundance proteins that reflect known pathogenic mechanisms and the severity of lung remodeling in COPD. These proteins may also prove useful as COPD biomarkers.

3D cine magnetic resonance imaging of rat lung ARDS using gradient-modulated SWIFT with retrospective respiratory gating

NASA Astrophysics Data System (ADS)

Kobayashi, Naoharu; Lei, Jianxun; Utecht, Lynn; Garwood, Michael; Ingbar, David H.; Bhargava, Maneesh

2015-03-01

SWeep Imaging with Fourier Transformation (SWIFT) with gradient modulation and DC navigator retrospective gating is introduced as a 3D cine magnetic resonance imaging (MRI) method for the lung. In anesthetized normal rats, the quasi-simultaneous excitation and acquisition in SWIFT enabled extremely high sensitivity to the fast-decaying parenchymal signals (TE=~4 μs), which are invisible with conventional MRI techniques. Respiratory motion information was extracted from DC navigator signals and the SWIFT data were reconstructed to 3D cine images with 16 respiratory phases. To test this technique's capabilities, rats exposed to > 95% O2 for 60 hours for induction of acute respiratory distress syndrome (ARDS), were imaged and compared with normal rat lungs (N=7 and 5 for ARDS and normal groups, respectively). SWIFT images showed lung tissue density differences along the gravity direction. In the cine SWIFT images, a parenchymal signal drop at the inhalation phase was consistently observed for both normal and ARDS rats due to lung inflation (i.e. decrease of the proton density), but the drop was less for ARDS rats. Depending on the respiratory phase and lung region, the lungs from the ARDS rats showed 1-24% higher parenchymal signal intensities relative to the normal rat lungs, likely due to accumulated extravascular water (EVLW). Those results demonstrate that SWIFT has high enough sensitivity for detecting the lung proton density changes due to gravity, different phases of respiration and accumulation of EVLW in the rat ARDS lungs.

Dynamic expression of chymotrypsin-like elastase 1 over the course of murine lung development

PubMed Central

Liu, Sheng; Young, Sarah Marie

2014-01-01

Postnatal lung development requires coordination of three processes (surface area expansion, microvascular growth, and matrix remodeling). Because normal elastin structure is important for lung morphogenesis, because physiological remodeling of lung elastin has never been defined, and because elastin remodeling is angiogenic, we sought to test the hypothesis that, during lung development, elastin is remodeled in a defined temporal-spatial pattern, that a novel protease is associated with this remodeling, and that angiogenesis is associated with elastin remodeling. By elastin in situ zymography, lung elastin remodeling increased 24-fold between embryonic day (E) 15.5 and postnatal day (PND) 14. Remodeling was restricted to major vessels and airways on PND1 with a sevenfold increase in alveolar wall elastin remodeling from PND1 to PND14. By inhibition assays and literature review, we identified chymotrypsin-like elastase 1 (CELA1) as a potential mediator of elastin remodeling. CELA1 mRNA levels increased 12-fold from E15.5 to PND9, and protein levels increased 3.4-fold from E18.5 to PND9. By costaining experiments, the temporal-spatial pattern of CELA1 expression matched that of elastin remodeling, and 58–85% of CELA1+ cells were <10 μm from an elastase signal. An association between elastin remodeling and angiogenesis was tested by similar methods. At PND7 and PND14, 60–95% of angiogenin+ cells were associated with elastin remodeling. Both elastase inhibition and CELA1 silencing impaired angiogenesis in vitro. Our data defines the temporal-spatial pattern of elastin remodeling during lung development, demonstrates an association of this remodeling with CELA1, and supports a role for elastin remodeling in regulating angiogenesis. PMID:24793170

Wnt5a Is Associated with Cigarette Smoke-Related Lung Carcinogenesis via Protein Kinase C

PubMed Central

Sung, Jae Sook; Ju, Hyun Jung; Kim, Hyun Kyung; Park, Kyong Hwa; Lee, Jong Won; Koh, In Song; Kim, Yeul Hong

2013-01-01

Wnt5a is overexpressed during the progression of human non-small cell lung cancer. However, the roles of Wnt5a during smoking-related lung carcinogenesis have not been clearly elucidated. We investigated the associations between Wnt5a and the early development of cigarette smoke related lung cancer using human bronchial epithelial (HBE) cells (NHBE, BEAS-2B, 1799, 1198 and 1170I) at different malignant stages established by exposure to cigarette smoke condensate (CSC). Abnormal up-regulation of Wnt5a mRNA and proteins was detected in CSC-exposed transformed 1198 and tumorigenic 1170I cells as compared with other non-CSC exposed HBE cells. Tumor tissues obtained from smokers showed higher Wnt5a expressions than matched normal tissues. In non-CSC exposed 1799 cells, treatment of recombinant Wnt5a caused the activations of PKC and Akt, and the blockage of Wnt5a and PKC significantly decreased the viabilities of CSC-transformed 1198 cells expressing high levels of Wnt5a. This reduced cell survival rate was associated with increased apoptosis via the down-regulation of Bcl2 and the induction of cleaved poly ADP-ribose polymerase. Moreover, CSC-treated 1799 cells showed induction of Wnt5a expression and enhanced colony-forming capacity. The CSC-induced colony forming efficiency was suppressed by the co-incubation with a PKC inhibitor. In conclusion, these results suggest that cigarette smoke induces Wnt5a-coupled PKC activity during lung carcinogenesis, which causes Akt activity and anti-apoptosis in lung cancer. Therefore, current study provides novel clues for the crucial role of Wnt5a in the smoking-related lung carcinogenesis. PMID:23349696

Wnt5a is associated with cigarette smoke-related lung carcinogenesis via protein kinase C.

PubMed

Whang, Young Mi; Jo, Ukhyun; Sung, Jae Sook; Ju, Hyun Jung; Kim, Hyun Kyung; Park, Kyong Hwa; Lee, Jong Won; Koh, In Song; Kim, Yeul Hong

2013-01-01

Wnt5a is overexpressed during the progression of human non-small cell lung cancer. However, the roles of Wnt5a during smoking-related lung carcinogenesis have not been clearly elucidated. We investigated the associations between Wnt5a and the early development of cigarette smoke related lung cancer using human bronchial epithelial (HBE) cells (NHBE, BEAS-2B, 1799, 1198 and 1170I) at different malignant stages established by exposure to cigarette smoke condensate (CSC). Abnormal up-regulation of Wnt5a mRNA and proteins was detected in CSC-exposed transformed 1198 and tumorigenic 1170I cells as compared with other non-CSC exposed HBE cells. Tumor tissues obtained from smokers showed higher Wnt5a expressions than matched normal tissues. In non-CSC exposed 1799 cells, treatment of recombinant Wnt5a caused the activations of PKC and Akt, and the blockage of Wnt5a and PKC significantly decreased the viabilities of CSC-transformed 1198 cells expressing high levels of Wnt5a. This reduced cell survival rate was associated with increased apoptosis via the down-regulation of Bcl2 and the induction of cleaved poly ADP-ribose polymerase. Moreover, CSC-treated 1799 cells showed induction of Wnt5a expression and enhanced colony-forming capacity. The CSC-induced colony forming efficiency was suppressed by the co-incubation with a PKC inhibitor. In conclusion, these results suggest that cigarette smoke induces Wnt5a-coupled PKC activity during lung carcinogenesis, which causes Akt activity and anti-apoptosis in lung cancer. Therefore, current study provides novel clues for the crucial role of Wnt5a in the smoking-related lung carcinogenesis.

Quantifying the impact of immediate reconstruction in postmastectomy radiation: a large, dose-volume histogram-based analysis.

PubMed

Ohri, Nisha; Cordeiro, Peter G; Keam, Jennifer; Ballangrud, Ase; Shi, Weiji; Zhang, Zhigang; Nerbun, Claire T; Woch, Katherine M; Stein, Nicholas F; Zhou, Ying; McCormick, Beryl; Powell, Simon N; Ho, Alice Y

2012-10-01

To assess the impact of immediate breast reconstruction on postmastectomy radiation (PMRT) using dose-volume histogram (DVH) data. Two hundred forty-seven women underwent PMRT at our center, 196 with implant reconstruction and 51 without reconstruction. Patients with reconstruction were treated with tangential photons, and patients without reconstruction were treated with en-face electron fields and customized bolus. Twenty percent of patients received internal mammary node (IMN) treatment. The DVH data were compared between groups. Ipsilateral lung parameters included V20 (% volume receiving 20 Gy), V40 (% volume receiving 40 Gy), mean dose, and maximum dose. Heart parameters included V25 (% volume receiving 25 Gy), mean dose, and maximum dose. IMN coverage was assessed when applicable. Chest wall coverage was assessed in patients with reconstruction. Propensity-matched analysis adjusted for potential confounders of laterality and IMN treatment. Reconstruction was associated with lower lung V20, mean dose, and maximum dose compared with no reconstruction (all P<.0001). These associations persisted on propensity-matched analysis (all P<.0001). Heart doses were similar between groups (P=NS). Ninety percent of patients with reconstruction had excellent chest wall coverage (D95 >98%). IMN coverage was superior in patients with reconstruction (D95 >92.0 vs 75.7%, P<.001). IMN treatment significantly increased lung and heart parameters in patients with reconstruction (all P<.05) but minimally affected those without reconstruction (all P>.05). Among IMN-treated patients, only lower lung V20 in those without reconstruction persisted (P=.022), and mean and maximum heart doses were higher than in patients without reconstruction (P=.006, P=.015, respectively). Implant reconstruction does not compromise the technical quality of PMRT when the IMNs are untreated. Treatment technique, not reconstruction, is the primary determinant of target coverage and normal tissue doses. Published by Elsevier Inc.

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.

Increased vital and total lung capacities in Tibetan compared to Han residents of Lhasa (3,658 m).

PubMed

Droma, T; McCullough, R G; McCullough, R E; Zhuang, J G; Cymerman, A; Sun, S F; Sutton, J R; Moore, L G

1991-11-01

Larger chest dimensions and lung volumes have been reported for Andean high-altitude natives compared with sea-level residents and implicated in raising lung diffusing capacity. Studies conducted in Nepal suggested that lifelong Himalayan residents did not have enlarged chest dimensions. To determine if high-altitude Himalayans (Tibetans) had larger lung volumes than acclimatized newcomers (Han "Chinese"), we studied 38 Tibetan and 43 Han residents of Lhasa, Tibet Autonomous Region, China (elevation 3,658 m) matched for age, height, weight, and smoking history. The Tibetan compared with the Han subjects had a larger total lung capacity [6.80 +/- 0.19 (mean +/- SEM) vs 6.24 +/- 0.18 l BTPS, P less than 0.05], vital capacity (5.00 +/- 0.08 vs 4.51 +/- 0.10 1 BTPS, P less than 0.05), and tended to have a greater residual volume (1.86 +/- 0.12 vs 1.56 +/- 0.09 1 BTPS, P less than 0.06). Chest circumference was greater in the Tibetan than the Han subjects (85 +/- 1 vs 82 +/- 1 cm, P less than 0.05) and correlated with vital capacity in each group as well as in the two groups combined (r = 0.69, P less than 0.05). Han who had migrated to high altitude as children (less than or equal to 5 years old, n = 6) compared to Han adult migrants (greater than or equal to 18 years old, n = 26) were shorter but had similar lung volumes and capacities when normalized for body size. The Tibetans' vital capacity and total lung capacity in relation to body size were similar to values reported previously for lifelong residents of high altitude in South and North America. Thus, Tibetans, like North and South American high-altitude residents, have larger lung volumes. This may be important for raising lung diffusing capacity and preserving arterial oxygen saturation during exercise.

Embryonic essential myosin light chain regulates fetal lung development in rats.

PubMed

Santos, Marta; Moura, Rute S; Gonzaga, Sílvia; Nogueira-Silva, Cristina; Ohlmeier, Steffen; Correia-Pinto, Jorge

2007-09-01

Congenital diaphragmatic hernia (CDH) is currently the most life-threatening congenital anomaly the major finding of which is lung hypoplasia. Lung hypoplasia pathophysiology involves early developmental molecular insult in branching morphogenesis and a late mechanical insult by abdominal herniation in maturation and differentiation processes. Since early determinants of lung hypoplasia might appear as promising targets for prenatal therapy, proteomics analysis of normal and nitrofen-induced hypoplastic lungs was performed at 17.5 days after conception. The major differentially expressed protein was identified by mass spectrometry as myosin light chain 1a (MLC1a). Embryonic essential MLC1a and regulatory myosin light chain 2 (MLC2) were characterized throughout normal and abnormal lung development by immunohistochemistry and Western blot. Disruption of MLC1a expression was assessed in normal lung explant cultures by antisense oligodeoxynucleotides. Since early stages of normal lung development, MLC1a was expressed in vascular smooth muscle (VSM) cells of pulmonary artery, and MLC2 was present in parabronchial smooth muscle and VSM cells of pulmonary vessels. In addition, early smooth muscle differentiation delay was observed by immunohistochemistry of alpha-smooth muscle actin and transforming growth factor-beta1. Disruption of MLC1a expression during normal pulmonary development led to significant growth and branching impairment, suggesting a role in branching morphogenesis. Both MLC1a and MLC2 were absent from hypoplastic fetal lungs during pseudoglandular stage of lung development, whereas their expression partially recovered by prenatal treatment with vitamin A. Thus, a deficiency in contractile proteins MLC1a and MLC2 might have a role among the early molecular determinants of lung hypoplasia in the rat model of nitrofen-induced CDH.

Glycogen Synthase Kinase 3 Protein Kinase Activity Is Frequently Elevated in Human Non-Small Cell Lung Carcinoma and Supports Tumour Cell Proliferation

PubMed Central

O′Flaherty, Linda; Pardo, Olivier E.; Dzien, Piotr; Phillips, Lois; Morgan, Carys; Pawade, Joya; May, Margaret T.; Sohail, Muhammad; Hetzel, Martin R.; Seckl, Michael J.; Tavaré, Jeremy M.

2014-01-01

Background Glycogen synthase kinase 3 (GSK3) is a central regulator of cellular metabolism, development and growth. GSK3 activity was thought to oppose tumourigenesis, yet recent studies indicate that it may support tumour growth in some cancer types including in non-small cell lung carcinoma (NSCLC). We examined the undefined role of GSK3 protein kinase activity in tissue from human NSCLC. Methods The expression and protein kinase activity of GSK3 was determined in 29 fresh frozen samples of human NSCLC and patient-matched normal lung tissue by quantitative immunoassay and western blotting for the phosphorylation of three distinct GSK3 substrates in situ (glycogen synthase, RelA and CRMP-2). The proliferation and sensitivity to the small-molecule GSK3 inhibitor; CHIR99021, of NSCLC cell lines (Hcc193, H1975, PC9 and A549) and non-neoplastic type II pneumocytes was further assessed in adherent culture. Results Expression and protein kinase activity of GSK3 was elevated in 41% of human NSCLC samples when compared to patient-matched control tissue. Phosphorylation of GSK3α/β at the inhibitory S21/9 residue was a poor biomarker for activity in tumour samples. The GSK3 inhibitor, CHIR99021 dose-dependently reduced the proliferation of three NSCLC cell lines yet was ineffective against type II pneumocytes. Conclusion NSCLC tumours with elevated GSK3 protein kinase activity may have evolved dependence on the kinase for sustained growth. Our results provide further important rationale for exploring the use of GSK3 inhibitors in treating NSCLC. PMID:25486534

Global Profiling and Molecular Characterization of Alternative Splicing Events Misregulated in Lung Cancer ▿ †

PubMed Central

Misquitta-Ali, Christine M.; Cheng, Edith; O'Hanlon, Dave; Liu, Ni; McGlade, C. Jane; Tsao, Ming Sound; Blencowe, Benjamin J.

2011-01-01

Alternative splicing (AS) is a widespread mechanism underlying the generation of proteomic and regulatory complexity. However, which of the myriad of human AS events play important roles in disease is largely unknown. To identify frequently occurring AS events in lung cancer, we used AS microarray profiling and reverse transcription-PCR (RT-PCR) assays to survey patient-matched normal and adenocarcinoma tumor tissues from the lungs of 29 individuals diagnosed with non-small cell lung cancer (NSCLC). Of 5,183 profiled alternative exons, four displayed tumor-associated changes in the majority of the patients. These events affected transcripts from the VEGFA, MACF1, APP, and NUMB genes. Similar AS changes were detected in NUMB and APP transcripts in primary breast and colon tumors. Tumor-associated increases in NUMB exon 9 inclusion correlated with reduced levels of NUMB protein expression and activation of the Notch signaling pathway, an event that has been linked to tumorigenesis. Moreover, short hairpin RNA (shRNA) knockdown of NUMB followed by isoform-specific rescue revealed that expression of the exon 9-skipped (nontumor) isoform represses Notch target gene activation whereas expression of the exon 9-included (tumor) isoform lacks this activity and is capable of promoting cell proliferation. The results thus reveal widespread AS changes in NSCLC that impact cell signaling in a manner that likely contributes to tumorigenesis. PMID:21041478

Global profiling and molecular characterization of alternative splicing events misregulated in lung cancer.

PubMed

Misquitta-Ali, Christine M; Cheng, Edith; O'Hanlon, Dave; Liu, Ni; McGlade, C Jane; Tsao, Ming Sound; Blencowe, Benjamin J

2011-01-01

Alternative splicing (AS) is a widespread mechanism underlying the generation of proteomic and regulatory complexity. However, which of the myriad of human AS events play important roles in disease is largely unknown. To identify frequently occurring AS events in lung cancer, we used AS microarray profiling and reverse transcription-PCR (RT-PCR) assays to survey patient-matched normal and adenocarcinoma tumor tissues from the lungs of 29 individuals diagnosed with non-small cell lung cancer (NSCLC). Of 5,183 profiled alternative exons, four displayed tumor-associated changes in the majority of the patients. These events affected transcripts from the VEGFA, MACF1, APP, and NUMB genes. Similar AS changes were detected in NUMB and APP transcripts in primary breast and colon tumors. Tumor-associated increases in NUMB exon 9 inclusion correlated with reduced levels of NUMB protein expression and activation of the Notch signaling pathway, an event that has been linked to tumorigenesis. Moreover, short hairpin RNA (shRNA) knockdown of NUMB followed by isoform-specific rescue revealed that expression of the exon 9-skipped (nontumor) isoform represses Notch target gene activation whereas expression of the exon 9-included (tumor) isoform lacks this activity and is capable of promoting cell proliferation. The results thus reveal widespread AS changes in NSCLC that impact cell signaling in a manner that likely contributes to tumorigenesis.

[Normal lung volumes in patients with idiopathic pulmonary fibrosis and emphysema].

PubMed

Casas, Juan Pablo; Abbona, Horacio; Robles, Adriana; López, Ana María

2008-01-01

Pulmonary function tests in idiopathic pulmonary fibrosis characteristically show a restrictive pattern, resulting from reduction of pulmonary compliance due to diffuse fibrosis. Conversely, an obstructive pattern with hyperinflation results in emphysema by loss of elastic recoil, expiratory collapse of the peripheral airways and air trapping. Previous reports suggest that when both diseases coexist, pulmonary volumes are compensated and a smaller than expected reduction or even normal lung volumes can be found. We report 4 male patients of 64, 60, 73 and 70 years, all with heavy cigarette smoking history and progressive breathlessness. Three of them had severe limitation in their quality of life. All four showed advanced lung interstitial involvement, at high resolution CT scan, fibrotic changes predominantly in the subpleural areas of lower lung fields and concomitant emphysema in the upper lobes. Emphysema and pulmonary fibrosis was confirmed by open lung biopsy in one patient. The four patients showed normal spirometry and lung volumes with severe compromise of gas exchange and poor exercise tolerance evaluated by 6 minute walk test. Severe pulmonary arterial hypertension was also confirmed in three patients. Normal lung volumes does not exclude diagnosis of idiopathic pulmonary fibrosis in patients with concomitant emphysema. The relatively preserved lung volumes may underestimate the severity of idiopathic pulmonary fibrosis and attenuate its effects on lung function parameters.

Parametric Response Mapping as an Indicator of Bronchiolitis Obliterans Syndrome following Hematopoietic Stem Cell Transplantation

PubMed Central

Galbán, Craig J.; Boes, Jennifer L.; Bule, Maria; Kitko, Carrie L; Couriel, Daniel R; Johnson, Timothy D.; Lama, Vihba; Telenga, Eef D.; van den Berge, Maarten; Rehemtulla, Alnawaz; Kazerooni, Ella A.; Ponkowski, Michael J.; Ross, Brian D.; Yanik, Gregory A.

2014-01-01

The management of bronchiolitis obliterans syndrome (BOS) following hematopoietic cell transplantation (HCT) presents many challenges, both diagnostically and therapeutically. We have developed a computed tomography (CT) voxel-wise methodology termed Parametric Response Mapping (PRM) that quantifies normal parenchyma (PRMNormal), functional small airway disease (PRMfSAD), emphysema (PRMEmph) and parenchymal disease (PRMPD) as relative lung volumes. We now investigate the use of PRM as an imaging biomarker in the diagnosis of BOS. PRM was applied to CT data from four patient cohorts: acute infection (n=11), BOS at onset (n=34), BOS plus infection (n=9), and age-matched, non-transplant controls (n=23). Pulmonary function tests and broncho-alveolar lavage (BAL) were used for group classification. Mean values for PRMfSAD were significantly greater in patients with BOS (38±2%) when compared to those with infection alone (17±4%, p<0.0001) and age-matched controls (8.4±1%, p<0.0001). Patients with BOS had similar PRMfSAD profiles, whether a concurrent infection was present or not. An optimal cut-point for PRMfSAD of 28% of the total lung volume was identified, with values >28% highly indicative of BOS occurrence. PRM may provide a major advance in our ability to identify the small airway obstruction that characterizes BOS, even in the presence of concurrent infection. PMID:24954547

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

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

Environment impacts the metabolic dependencies of Ras-driven non-small cell lung cancer

PubMed Central

Davidson, Shawn M.; Papagiannakopoulos, Thales; Olenchock, Benjamin A.; Heyman, Julia E.; Keibler, Mark A.; Luengo, Alba; Bauer, Matthew R.; Jha, Abhishek K.; O’Brien, James P.; Pierce, Kerry A.; Gui, Dan Y.; Sullivan, Lucas B.; Wasylenko, Thomas M.; Subbaraj, Lakshmipriya; Chin, Christopher R.; Stephanopolous, Gregory; Mott, Bryan T.; Jacks, Tyler; Clish, Clary B.; Vander Heiden, Matthew G.

2016-01-01

SUMMARY Cultured cells convert glucose to lactate and glutamine is the major source of tricarboxylic acid (TCA) cycle carbon, but whether the same metabolic phenotype is found in tumors is less studied. We infused mice with lung cancers with isotope-labeled glucose or glutamine and compared the fate of these nutrients in tumor and normal tissue. As expected, lung tumors exhibit increased lactate production from glucose. However, glutamine utilization by both lung tumors and normal lung was minimal, with lung tumors showing increased glucose contribution to the TCA cycle relative to normal lung tissue. Deletion of enzymes involved in glucose oxidation demonstrates that glucose carbon contribution to the TCA cycle is required for tumor formation. These data suggest that understanding nutrient utilization by tumors can predict metabolic dependencies of cancers in vivo. Furthermore, these data argue that the in vivo environment is an important determinant of the metabolic phenotype of cancer cells. PMID:26853747

The clinical and prognostic value of polo-like kinase 1 in lung squamous cell carcinoma patients: immunohistochemical analysis

PubMed Central

Li, Hefei; Sun, Zhenqing; Guo, Qiang; Shi, Hongyun; Jia, Youchao

2017-01-01

Polo-like kinase 1 (PLK1) has been suggested to serve as an oncogene in most human cancers. The aim of our study is to present more evidence about the clinical and prognostic value of PLK1 in lung squamous cell carcinoma patients. The status of PLK1 was observed in lung adenocarcinoma, lung squamous cell carcinoma, and normal lung tissues through analyzing microarray dataset (GEO accession numbers: GSE1213 and GSE 3627). PLK1 mRNA and protein expressions were detected in lung squamous cell carcinoma and normal lung tissues by using quantitative real-time PCR (qRT-PCR) and immunohistochemistry. In our results, the levels of PLK1 in lung squamous cell carcinoma tissues were higher than that in lung adenocarcinoma tissues. Compared with paired adjacent normal lung tissues, the PLK1 expression was increased in lung squamous cell carcinoma tissues. Furthermore, high expression of PLK1 protein was correlated with differentiated degree, clinical stage, tumor size, lymph node metastasis, and distant metastasis. The univariate and multivariate analyses showed PLK1 protein high expression was an unfavorable prognostic biomarker for lung squamous cell carcinoma patients. In conclusion, high expression of PLK1 is associated with the aggressive progression and poor prognosis in lung squamous cell carcinoma patients. PMID:28724602

Incidental Prophylactic Nodal Irradiation and Patterns of Nodal Relapse in Inoperable Early Stage NSCLC Patients Treated With SBRT: A Case-Matched Analysis

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

Lao, Louis; Department of Radiation Oncology, Auckland City Hospital, Auckland; Hope, Andrew J.

2014-09-01

Purpose: Reported rates of non-small cell lung cancer (NSCLC) nodal failure following stereotactic body radiation therapy (SBRT) are lower than those reported in the surgical series when matched for stage. We hypothesized that this effect was due to incidental prophylactic nodal irradiation. Methods and Materials: A prospectively collected group of medically inoperable early stage NSCLC patients from 2004 to 2010 was used to identify cases with nodal relapses. Controls were matched to cases, 2:1, controlling for tumor volume (ie, same or greater) and tumor location (ie, same lobe). Reference (normalized to equivalent dose for 2-Gy fractions [EQD2]) point doses atmore » the ipsilateral hilum and carina, demographic data, and clinical outcomes were extracted from the medical records. Univariate conditional logistical regression analyses were performed with variables of interest. Results: Cases and controls were well matched except for size. The controls, as expected, had larger gross tumor volumes (P=.02). The mean ipsilateral hilar doses were 9.6 Gy and 22.4 Gy for cases and controls, respectively (P=.014). The mean carinal doses were 7.0 Gy and 9.2 Gy, respectively (P=.13). Mediastinal nodal relapses, with and without ipsilateral hilar relapse, were associated with mean ipsilateral hilar doses of 3.6 Gy and 19.8 Gy, respectively (P=.01). The conditional density plot appears to demonstrate an inverse dose-effect relationship between ipsilateral hilar normalized total dose and risk of ipsilateral hilar relapse. Conclusions: Incidental hilar dose greater than 20 Gy is significantly associated with fewer ipsilateral hilar relapses in inoperable early stage NSCLC patients treated with SBRT.« less

Esophagus and Contralateral Lung-Sparing IMRT for Locally Advanced Lung Cancer in the Community Hospital Setting.

PubMed

Kao, Johnny; Pettit, Jeffrey; Zahid, Soombal; Gold, Kenneth D; Palatt, Terry

2015-01-01

The optimal technique for performing lung IMRT remains poorly defined. We hypothesize that improved dose distributions associated with normal tissue-sparing IMRT can allow safe dose escalation resulting in decreased acute and late toxicity. We performed a retrospective analysis of 82 consecutive lung cancer patients treated with curative intent from 1/10 to 9/14. From 1/10 to 4/12, 44 patients were treated with the community standard of three-dimensional conformal radiotherapy or IMRT without specific esophagus or contralateral lung constraints (standard RT). From 5/12 to 9/14, 38 patients were treated with normal tissue-sparing IMRT with selective sparing of contralateral lung and esophagus. The study endpoints were dosimetry, toxicity, and overall survival. Despite higher mean prescribed radiation doses in the normal tissue-sparing IMRT cohort (64.5 vs. 60.8 Gy, p = 0.04), patients treated with normal tissue-sparing IMRT had significantly lower lung V20, V10, V5, mean lung, esophageal V60, and mean esophagus doses compared to patients treated with standard RT (p ≤ 0.001). Patients in the normal tissue-sparing IMRT group had reduced acute grade ≥3 esophagitis (0 vs. 11%, p < 0.001), acute grade ≥2 weight loss (2 vs. 16%, p = 0.04), and late grade ≥2 pneumonitis (7 vs. 21%, p = 0.02). The 2-year overall survival was 52% with normal tissue-sparing IMRT arm compared to 28% for standard RT (p = 0.015). These data provide proof of principle that suboptimal radiation dose distributions are associated with significant acute and late lung and esophageal toxicity that may result in hospitalization or even premature mortality. Strict attention to contralateral lung and esophageal dose-volume constraints are feasible in the community hospital setting without sacrificing disease control.

Stem cells are dispensable for lung homeostasis but restore airways after injury.

PubMed

Giangreco, Adam; Arwert, Esther N; Rosewell, Ian R; Snyder, Joshua; Watt, Fiona M; Stripp, Barry R

2009-06-09

Local tissue stem cells have been described in airways of the lung but their contribution to normal epithelial maintenance is currently unknown. We therefore developed aggregation chimera mice and a whole-lung imaging method to determine the relative contributions of progenitor (Clara) and bronchiolar stem cells to epithelial maintenance and repair. In normal and moderately injured airways chimeric patches were small in size and not associated with previously described stem cell niches. This finding suggested that single, randomly distributed progenitor cells maintain normal epithelial homeostasis. In contrast we found that repair following severe lung injury resulted in the generation of rare, large clonal cell patches that were associated with stem cell niches. This study provides evidence that epithelial stem cells are dispensable for normal airway homeostasis. We also demonstrate that stem cell activation and robust clonal cellular expansion occur only during repair from severe lung injury.

Clinical significance of preoperative serum albumin level for prognosis in surgically resected patients with non-small cell lung cancer: Comparative study of normal lung, emphysema, and pulmonary fibrosis.

PubMed

Miura, Kentaro; Hamanaka, Kazutoshi; Koizumi, Tomonobu; Kitaguchi, Yoshiaki; Terada, Yukihiro; Nakamura, Daisuke; Kumeda, Hirotaka; Agatsuma, Hiroyuki; Hyogotani, Akira; Kawakami, Satoshi; Yoshizawa, Akihiko; Asaka, Shiho; Ito, Ken-Ichi

2017-09-01

This study was performed to clarify whether preoperative serum albumin level is related to the prognosis of non-small cell lung cancer patients undergoing surgical resection, and the relationships between serum albumin level and clinicopathological characteristics of lung cancer patients with emphysema or pulmonary fibrosis. We retrospectively evaluated 556 patients that underwent surgical resection for non-small cell lung cancer. The correlation between preoperative serum albumin level and survival was evaluated. Patients were divided into three groups according to the findings on chest high-resolution computed tomography (normal lung, emphysema, and pulmonary fibrosis), and the relationships between serum albumin level and clinicopathological characteristics, including prognosis, were evaluated. The cut-off value of serum albumin level was set at 4.2g/dL. Patients with low albumin levels (albumin <4.2) had significantly poorer prognosis than those with high albumin levels (albumin ≥4.2) with regard to both overall survival and recurrence-free survival. Serum albumin levels in the emphysema group (n=48) and pulmonary fibrosis group (n=45) were significantly lower than that in the normal lung group (n=463) (p=0.009 and <0.001, respectively). Low serum albumin level was a risk factor in normal lung and pulmonary fibrosis groups, but not in the emphysema group. Preoperative serum albumin level was an important prognostic factor for overall survival and recurrence-free survival in patients with resected non-small cell lung cancer. Divided into normal lung, emphysema, and pulmonary fibrosis groups, serum albumin level showed no influence only in patients in the emphysema group. Copyright © 2017 Elsevier B.V. All rights reserved.

Novel algorithm to identify and differentiate specific digital signature of breath sound in patients with diffuse parenchymal lung disease.

PubMed

Bhattacharyya, Parthasarathi; Mondal, Ashok; Dey, Rana; Saha, Dipanjan; Saha, Goutam

2015-05-01

Auscultation is an important part of the clinical examination of different lung diseases. Objective analysis of lung sounds based on underlying characteristics and its subsequent automatic interpretations may help a clinical practice. We collected the breath sounds from 8 normal subjects and 20 diffuse parenchymal lung disease (DPLD) patients using a newly developed instrument and then filtered off the heart sounds using a novel technology. The collected sounds were thereafter analysed digitally on several characteristics as dynamical complexity, texture information and regularity index to find and define their unique digital signatures for differentiating normality and abnormality. For convenience of testing, these characteristic signatures of normal and DPLD lung sounds were transformed into coloured visual representations. The predictive power of these images has been validated by six independent observers that include three physicians. The proposed method gives a classification accuracy of 100% for composite features for both the normal as well as lung sound signals from DPLD patients. When tested by independent observers on the visually transformed images, the positive predictive value to diagnose the normality and DPLD remained 100%. The lung sounds from the normal and DPLD subjects could be differentiated and expressed according to their digital signatures. On visual transformation to coloured images, they retain 100% predictive power. This technique may assist physicians to diagnose DPLD from visual images bearing the digital signature of the condition. © 2015 Asian Pacific Society of Respirology.

Combined Ventilation and Perfusion Imaging Correlates With the Dosimetric Parameters of Radiation Pneumonitis in Radiation Therapy Planning for Lung Cancer

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

Kimura, Tomoki, E-mail: tkkimura@hiroshima-u.ac.jp; Doi, Yoshiko; Nakashima, Takeo

2015-11-15

Purpose: The purpose of this study was to prospectively investigate clinical correlations between dosimetric parameters associated with radiation pneumonitis (RP) and functional lung imaging. Methods and Materials: Functional lung imaging was performed using four-dimensional computed tomography (4D-CT) for ventilation imaging, single-photon emission computed tomography (SPECT) for perfusion imaging, or both (V/Q-matched region). Using 4D-CT, ventilation imaging was derived from a low attenuation area according to CT numbers below different thresholds (vent-860 and -910). Perfusion imaging at the 10th, 30th, 50th, and 70th percentile perfusion levels (F10-F70) were defined as the top 10%, 30%, 50%, and 70% hyperperfused normal lung, respectively.more » All imaging data were incorporated into a 3D planning system to evaluate correlations between RP dosimetric parameters (where fV20 is the percentage of functional lung volume irradiated with >20 Gy, or fMLD, the mean dose administered to functional lung) and the percentage of functional lung volume. Radiation pneumonitis was evaluated using Common Terminology Criteria for Adverse Events version 4.0. Statistical significance was defined as a P value of <.05. Results: Sixty patients who underwent curative radiation therapy were enrolled (48 patients for non-small cell lung cancer, and 12 patients for small cell lung cancer). Grades 1, 2, and ≥3 RP were observed in 16, 44, and 6 patients, respectively. Significant correlations were observed between the percentage of functional lung volume and fV20 (r=0.4475 in vent-860 and 0.3508 in F30) or fMLD (r=0.4701 in vent-860 and 0.3128 in F30) in patients with grade ≥2 RP. F30∩vent-860 results exhibited stronger correlations with fV20 and fMLD in patients with grade ≥2 (r=0.5509 in fV20 and 0.5320 in fMLD) and grade ≥3 RP (r=0.8770 in fV20 and 0.8518 in fMLD). Conclusions: RP dosimetric parameters correlated significantly with functional lung imaging.« less

Efficacy of a Self-expanding Tract Sealant Device in the Reduction of Pneumothorax and Chest Tube Placement Rates After Percutaneous Lung Biopsy: A Matched Controlled Study Using Propensity Score Analysis

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

Ahrar, Judy U., E-mail: judy.ahrar@mdanderson.org; Gupta, Sanjay; Ensor, Joe E.

PurposeTo evaluate the use of a self-expanding tract sealant device (BioSentry™) on the rates of pneumothorax and chest tube insertion after percutaneous lung biopsy.Materials and MethodsIn this retrospective study, we compared 318 patients who received BioSentry™ during percutaneous lung biopsy (treated group) with 1956 patients who did not (control group). Patient-, lesion-, and procedure-specific variables, and pneumothorax and chest tube insertion rates were recorded. To adjust for potential selection bias, patients in the treated group were matched 1:1 to patients in the control group using propensity score matching based on the above-mentioned variables. Patients were considered a match if themore » absolute difference in their propensity scores was ≤equal to 0.02.ResultsBefore matching, the pneumothorax and chest tube rates were 24.5 and 13.1% in the control group, and 21.1 and 8.5% in the treated group, respectively. Using propensity scores, a match was found for 317 patients in the treatment group. Chi-square contingency matched pair analysis showed the treated group had significantly lower pneumothorax (20.8 vs. 32.8%; p = 0.001) and chest tube (8.2 vs. 20.8%; p < 0.0001) rates compared to the control group. Sub-analysis including only faculty who had >30 cases of both treatment and control cases demonstrated similar findings: the treated group had significantly lower pneumothorax (17.6 vs. 30.2%; p = 0.002) and chest tube (7.2 vs. 18%; p = 0.001) rates.ConclusionsThe self-expanding tract sealant device significantly reduced the pneumothorax rate, and more importantly, the chest tube placement rate after percutaneous lung biopsy.« less

Post-Inhaled Corticosteroid Pulmonary Tuberculosis Increases Lung Cancer in Patients with Asthma.

PubMed

Jian, Zhi-Hong; Huang, Jing-Yang; Lin, Frank Cheau-Feng; Nfor, Oswald Ndi; Jhang, Kai-Ming; Ku, Wen-Yuan; Ho, Chien-Chang; Lung, Chia-Chi; Pan, Hui-Hsien; Wu, Min-Chen; Wu, Ming-Fang; Liaw, Yung-Po

2016-01-01

To evaluate the association between post-inhaled corticosteroid (ICS) pulmonary tuberculosis (TB), pneumonia and lung cancer in patients with asthma. The study samples were collected from the National Health Insurance Database. Asthmatic patients who were first-time users of ICS between 2003 and 2005 were identified as cases. For each case, 4 control individuals were randomly matched for sex, age and date of ICS use. Cases and matched controls were followed up until the end of 2010. Cox proportional hazard regression was used to determine the hazard ratio for pulmonary infections and lung cancer risk in the ICS users and non-users. A total of 10,904 first-time users of ICS were matched with 43,616 controls. The hazard ratios for lung cancer were: 2.52 (95% confidence interval [CI], 1.22-5.22; p = 0.012) for individuals with post-ICS TB, 1.28 (95%CI, 0.73-2.26; p = 0.389) for post-ICS pneumonia, 2.31(95%CI, 0.84-6.38; p = 0.105) for post-ICS pneumonia+TB, 1.08 (95%CI, 0.57-2.03; p = 0.815) for TB, 0.99 (95%CI, 0.63-1.55; p = 0.970) for pneumonia, and 0.32 (95%CI, 0.05-2.32; p = 0.261) for pneumonia+ TB, respectively. Post-ICS TB increased lung cancer risk in patients with asthma. Because of the high mortality associated with lung cancer, screening tests are recommended for patients with post-ICS TB.

Primary cilia are increased in number and demonstrate structural abnormalities in human cancer.

PubMed

Yasar, Binnaz; Linton, Kim; Slater, Christian; Byers, Richard

2017-07-01

Primary cilia play an important role in the regulation of cell signalling pathways and are thought to have a role in cancer but have seldom been studied in human cancer samples. Primary cilia were visualised by dual immunofluorescence for anti-CROCC (ciliary rootlet coiled-coil) and anti-tubulin in a range of human cancers (including carcinomas of stomach, pancreas, prostate, lung and colon, lobular and ductal breast cancers and follicular lymphoma) and in matched normal tissue (stomach, pancreas, lung, large and small intestines, breast and reactive lymph nodes) samples using a tissue microarray; their frequency, association with proliferation, was measured by Ki-67 staining and their structure was analysed. Compared with normal tissues, primary cilia frequency was significantly elevated in adenocarcinoma of the lung (2.75% vs 1.85%, p=0.016), adenocarcinoma of the colon (3.80% vs 2.43%, respectively, p=0.017), follicular lymphoma (1.18% vs 0.83%, p=0.003) and pancreatic adenocarcinoma (7.00% vs 5.26%, p=0.002); there was no statistically significant difference compared with normal control tissue for gastric and prostatic adenocarcinomas or for lobular and ductal breast cancers. Additionally, structural abnormalities of primary cilia were identified in cancer tissues, including elongation of the axoneme, multiple basal bodies and branching of the axoneme. Ki-67 scores ranged from 0.7% to 78.4% and showed no statistically significant correlation with primary cilia frequency across all tissues (p=0.1501). The results show upregulation of primary cilia and the presence of structural defects in a wide range of human cancer tissue samples demonstrating association of dysregulation of primary cilia with human cancer. 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/.

Correlation of circular RNA abundance with proliferation--exemplified with colorectal and ovarian cancer, idiopathic lung fibrosis, and normal human tissues.

PubMed

Bachmayr-Heyda, Anna; Reiner, Agnes T; Auer, Katharina; Sukhbaatar, Nyamdelger; Aust, Stefanie; Bachleitner-Hofmann, Thomas; Mesteri, Ildiko; Grunt, Thomas W; Zeillinger, Robert; Pils, Dietmar

2015-01-27

Circular RNAs are a recently (re-)discovered abundant RNA species with presumed function as miRNA sponges, thus part of the competing endogenous RNA network. We analysed the expression of circular and linear RNAs and proliferation in matched normal colon mucosa and tumour tissues. We predicted >1,800 circular RNAs and proved the existence of five randomly chosen examples using RT-qPCR. Interestingly, the ratio of circular to linear RNA isoforms was always lower in tumour compared to normal colon samples and even lower in colorectal cancer cell lines. Furthermore, this ratio correlated negatively with the proliferation index. The correlation of global circular RNA abundance (the circRNA index) and proliferation was validated in a non-cancerous proliferative disease, idiopathic pulmonary fibrosis, ovarian cancer cells compared to cultured normal ovarian epithelial cells, and 13 normal human tissues. We are the first to report a global reduction of circular RNA abundance in colorectal cancer cell lines and cancer compared to normal tissues and discovered a negative correlation of global circular RNA abundance and proliferation. This negative correlation seems to be a general principle in human tissues as validated with three different settings. Finally, we present a simple model how circular RNAs could accumulate in non-proliferating cells.

Correlation of circular RNA abundance with proliferation – exemplified with colorectal and ovarian cancer, idiopathic lung fibrosis, and normal human tissues

PubMed Central

Bachmayr-Heyda, Anna; Reiner, Agnes T.; Auer, Katharina; Sukhbaatar, Nyamdelger; Aust, Stefanie; Bachleitner-Hofmann, Thomas; Mesteri, Ildiko; Grunt, Thomas W.; Zeillinger, Robert; Pils, Dietmar

2015-01-01

Circular RNAs are a recently (re-)discovered abundant RNA species with presumed function as miRNA sponges, thus part of the competing endogenous RNA network. We analysed the expression of circular and linear RNAs and proliferation in matched normal colon mucosa and tumour tissues. We predicted >1,800 circular RNAs and proved the existence of five randomly chosen examples using RT-qPCR. Interestingly, the ratio of circular to linear RNA isoforms was always lower in tumour compared to normal colon samples and even lower in colorectal cancer cell lines. Furthermore, this ratio correlated negatively with the proliferation index. The correlation of global circular RNA abundance (the circRNA index) and proliferation was validated in a non-cancerous proliferative disease, idiopathic pulmonary fibrosis, ovarian cancer cells compared to cultured normal ovarian epithelial cells, and 13 normal human tissues. We are the first to report a global reduction of circular RNA abundance in colorectal cancer cell lines and cancer compared to normal tissues and discovered a negative correlation of global circular RNA abundance and proliferation. This negative correlation seems to be a general principle in human tissues as validated with three different settings. Finally, we present a simple model how circular RNAs could accumulate in non-proliferating cells. PMID:25624062

Molecular Profiles for Lung Cancer Pathogenesis and Detection in U.S. Veterans

DTIC Science & Technology

2014-12-01

smokers [7]. In addition, modulation of global gene expression in the normal epithelium in health smokers is similar in the large and small airways...previously shown that gene-expression profiles in cytologically normal mainstem bronchus epithelium can distinguish smokers with and without lung cancer...spatially mapping the molecular field of injury associated with smoking-related lung cancer. In smokers undergoing resection of lung lesions, high

Evaluation of normal lung tissue complication probability in gated and conventional radiotherapy using the 4D XCAT digital phantom.

PubMed

Shahzadeh, Sara; Gholami, Somayeh; Aghamiri, Seyed Mahmood Reza; Mahani, Hojjat; Nabavi, Mansoure; Kalantari, Faraz

2018-06-01

The present study was conducted to investigate normal lung tissue complication probability in gated and conventional radiotherapy (RT) as a function of diaphragm motion, lesion size, and its location using 4D-XCAT digital phantom in a simulation study. Different time series of 3D-CT images were generated using the 4D-XCAT digital phantom. The binary data obtained from this phantom were then converted to the digital imaging and communication in medicine (DICOM) format using an in-house MATLAB-based program to be compatible with our treatment planning system (TPS). The 3D-TPS with superposition computational algorithm was used to generate conventional and gated plans. Treatment plans were generated for 36 different XCAT phantom configurations. These included four diaphragm motions of 20, 25, 30 and 35 mm, three lesion sizes of 3, 4, and 5 cm in diameter and each tumor was placed in four different lung locations (right lower lobe, right upper lobe, left lower lobe and left upper lobe). The complication of normal lung tissue was assessed in terms of mean lung dose (MLD), the lung volume receiving ≥20 Gy (V20), and normal tissue complication probability (NTCP). The results showed that the gated RT yields superior outcomes in terms of normal tissue complication compared to the conventional RT. For all cases, the gated radiation therapy technique reduced the mean dose, V20, and NTCP of lung tissue by up to 5.53 Gy, 13.38%, and 23.89%, respectively. The results of this study showed that the gated RT provides significant advantages in terms of the normal lung tissue complication, compared to the conventional RT, especially for the lesions near the diaphragm. Copyright © 2018 Elsevier Ltd. All rights reserved.

The effect of lung deformation on the spatial distribution of pulmonary blood flow.

PubMed

Arai, Tatsuya J; Theilmann, Rebecca J; Sá, Rui Carlos; Villongco, Michael T; Hopkins, Susan R

2016-11-01

Pulmonary perfusion measurement using magnetic resonance imaging combined with deformable image registration enabled us to quantify the change in the spatial distribution of pulmonary perfusion at different lung volumes. The current study elucidated the effects of tidal volume lung inflation [functional residual capacity (FRC) + 500 ml and FRC + 1 litre] on the change in pulmonary perfusion distribution. Changes in hydrostatic pressure distribution as well as transmural pressure distribution due to the change in lung height with tidal volume inflation are probably bigger contributors to the redistribution of pulmonary perfusion than the changes in pulmonary vasculature resistance caused by lung tissue stretch. Tidal volume lung inflation results in structural changes in the pulmonary circulation, potentially affecting pulmonary perfusion. We hypothesized that perfusion is recruited to regions receiving the greatest deformation from a tidal breath, thus ensuring ventilation-perfusion matching. Density-normalized perfusion (DNP) magnetic resonance imaging data were obtained in healthy subjects (n = 7) in the right lung at functional residual capacity (FRC), FRC+500 ml, and FRC+1.0 l. Using deformable image registration, the displacement of a sagittal lung slice acquired at FRC to the larger volumes was calculated. Registered DNP images were normalized by the mean to estimate perfusion redistribution (nDNP). Data were evaluated across gravitational regions (dependent, middle, non-dependent) and by lobes (upper, RUL; middle, RML; lower, RLL). Lung inflation did not alter mean DNP within the slice (P = 0.10). The greatest expansion was seen in the dependent region (P < 0.0001: dependent vs non-dependent, P < 0.0001: dependent vs middle) and RLL (P = 0.0015: RLL vs RUL, P < 0.0001: RLL vs RML). Neither nDNP recruitment to RLL [+500 ml = -0.047(0.145), +1 litre = 0.018(0.096)] nor to dependent lung [+500 ml = -0.058(0.126), +1 litre = -0.023(0.106)] were found. Instead, redistribution was seen in decreased nDNP in the non-dependent [+500 ml = -0.075(0.152), +1 litre = -0.137(0.167)) and increased nDNP in the gravitational middle lung [+500 ml = 0.098(0.058), +1 litre = 0.093(0.081)] (P = 0.01). However, there was no significant lobar redistribution (P < 0.89). Contrary to our hypothesis, based on the comparison between gravitational and lobar perfusion data, perfusion was not redistributed to the regions of the most inflation. This suggests that either changes in hydrostatic pressure or transmural pressure distribution in the gravitational direction are implicated in the redistribution of perfusion away from the non-dependent lung. © 2016 The Authors. The Journal of Physiology © 2016 The Physiological Society.

The effect of lung deformation on the spatial distribution of pulmonary blood flow

PubMed Central

Arai, Tatsuya J.; Theilmann, Rebecca J.; Sá, Rui Carlos; Villongco, Michael T.

2016-01-01

Key points Pulmonary perfusion measurement using magnetic resonance imaging combined with deformable image registration enabled us to quantify the change in the spatial distribution of pulmonary perfusion at different lung volumes.The current study elucidated the effects of tidal volume lung inflation [functional residual capacity (FRC) + 500 ml and FRC + 1 litre] on the change in pulmonary perfusion distribution.Changes in hydrostatic pressure distribution as well as transmural pressure distribution due to the change in lung height with tidal volume inflation are probably bigger contributors to the redistribution of pulmonary perfusion than the changes in pulmonary vasculature resistance caused by lung tissue stretch. Abstract Tidal volume lung inflation results in structural changes in the pulmonary circulation, potentially affecting pulmonary perfusion. We hypothesized that perfusion is recruited to regions receiving the greatest deformation from a tidal breath, thus ensuring ventilation–perfusion matching. Density‐normalized perfusion (DNP) magnetic resonance imaging data were obtained in healthy subjects (n = 7) in the right lung at functional residual capacity (FRC), FRC+500 ml, and FRC+1.0 l. Using deformable image registration, the displacement of a sagittal lung slice acquired at FRC to the larger volumes was calculated. Registered DNP images were normalized by the mean to estimate perfusion redistribution (nDNP). Data were evaluated across gravitational regions (dependent, middle, non‐dependent) and by lobes (upper, RUL; middle, RML; lower, RLL). Lung inflation did not alter mean DNP within the slice (P = 0.10). The greatest expansion was seen in the dependent region (P < 0.0001: dependent vs non‐dependent, P < 0.0001: dependent vs middle) and RLL (P = 0.0015: RLL vs RUL, P < 0.0001: RLL vs RML). Neither nDNP recruitment to RLL [+500 ml = −0.047(0.145), +1 litre = 0.018(0.096)] nor to dependent lung [+500 ml = −0.058(0.126), +1 litre = −0.023(0.106)] were found. Instead, redistribution was seen in decreased nDNP in the non‐dependent [+500 ml = −0.075(0.152), +1 litre = −0.137(0.167)) and increased nDNP in the gravitational middle lung [+500 ml = 0.098(0.058), +1 litre = 0.093(0.081)] (P = 0.01). However, there was no significant lobar redistribution (P < 0.89). Contrary to our hypothesis, based on the comparison between gravitational and lobar perfusion data, perfusion was not redistributed to the regions of the most inflation. This suggests that either changes in hydrostatic pressure or transmural pressure distribution in the gravitational direction are implicated in the redistribution of perfusion away from the non‐dependent lung. PMID:27273807

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.

Listening panel agreement and characteristics of lung sounds digitally recorded from children aged 1–59 months enrolled in the Pneumonia Etiology Research for Child Health (PERCH) case–control study

PubMed Central

Park, Daniel E; Watson, Nora L; Buck, W Chris; Bunthi, Charatdao; Devendra, Akash; Ebruke, Bernard E; Elhilali, Mounya; Emmanouilidou, Dimitra; Garcia-Prats, Anthony J; Githinji, Leah; Hossain, Lokman; Madhi, Shabir A; Moore, David P; Mulindwa, Justin; Olson, Dan; Awori, Juliet O; Vandepitte, Warunee P; Verwey, Charl; West, James E; Knoll, Maria D; O'Brien, Katherine L; Feikin, Daniel R; Hammit, Laura L

2017-01-01

Introduction Paediatric lung sound recordings can be systematically assessed, but methodological feasibility and validity is unknown, especially from developing countries. We examined the performance of acoustically interpreting recorded paediatric lung sounds and compared sound characteristics between cases and controls. Methods Pneumonia Etiology Research for Child Health staff in six African and Asian sites recorded lung sounds with a digital stethoscope in cases and controls. Cases aged 1–59 months had WHO severe or very severe pneumonia; age-matched community controls did not. A listening panel assigned examination results of normal, crackle, wheeze, crackle and wheeze or uninterpretable, with adjudication of discordant interpretations. Classifications were recategorised into any crackle, any wheeze or abnormal (any crackle or wheeze) and primary listener agreement (first two listeners) was analysed among interpretable examinations using the prevalence-adjusted, bias-adjusted kappa (PABAK). We examined predictors of disagreement with logistic regression and compared case and control lung sounds with descriptive statistics. Results Primary listeners considered 89.5% of 792 case and 92.4% of 301 control recordings interpretable. Among interpretable recordings, listeners agreed on the presence or absence of any abnormality in 74.9% (PABAK 0.50) of cases and 69.8% (PABAK 0.40) of controls, presence/absence of crackles in 70.6% (PABAK 0.41) of cases and 82.4% (PABAK 0.65) of controls and presence/absence of wheeze in 72.6% (PABAK 0.45) of cases and 73.8% (PABAK 0.48) of controls. Controls, tachypnoea, >3 uninterpretable chest positions, crying, upper airway noises and study site predicted listener disagreement. Among all interpretable examinations, 38.0% of cases and 84.9% of controls were normal (p<0.0001); wheezing was the most common sound (49.9%) in cases. Conclusions Listening panel and case–control data suggests our methodology is feasible, likely valid and that small airway inflammation is common in WHO pneumonia. Digital auscultation may be an important future pneumonia diagnostic in developing countries. PMID:28883927

Listening panel agreement and characteristics of lung sounds digitally recorded from children aged 1-59 months enrolled in the Pneumonia Etiology Research for Child Health (PERCH) case-control study.

PubMed

McCollum, Eric D; Park, Daniel E; Watson, Nora L; Buck, W Chris; Bunthi, Charatdao; Devendra, Akash; Ebruke, Bernard E; Elhilali, Mounya; Emmanouilidou, Dimitra; Garcia-Prats, Anthony J; Githinji, Leah; Hossain, Lokman; Madhi, Shabir A; Moore, David P; Mulindwa, Justin; Olson, Dan; Awori, Juliet O; Vandepitte, Warunee P; Verwey, Charl; West, James E; Knoll, Maria D; O'Brien, Katherine L; Feikin, Daniel R; Hammit, Laura L

2017-01-01

Paediatric lung sound recordings can be systematically assessed, but methodological feasibility and validity is unknown, especially from developing countries. We examined the performance of acoustically interpreting recorded paediatric lung sounds and compared sound characteristics between cases and controls. Pneumonia Etiology Research for Child Health staff in six African and Asian sites recorded lung sounds with a digital stethoscope in cases and controls. Cases aged 1-59 months had WHO severe or very severe pneumonia; age-matched community controls did not. A listening panel assigned examination results of normal, crackle, wheeze, crackle and wheeze or uninterpretable, with adjudication of discordant interpretations. Classifications were recategorised into any crackle, any wheeze or abnormal (any crackle or wheeze) and primary listener agreement (first two listeners) was analysed among interpretable examinations using the prevalence-adjusted, bias-adjusted kappa (PABAK). We examined predictors of disagreement with logistic regression and compared case and control lung sounds with descriptive statistics. Primary listeners considered 89.5% of 792 case and 92.4% of 301 control recordings interpretable. Among interpretable recordings, listeners agreed on the presence or absence of any abnormality in 74.9% (PABAK 0.50) of cases and 69.8% (PABAK 0.40) of controls, presence/absence of crackles in 70.6% (PABAK 0.41) of cases and 82.4% (PABAK 0.65) of controls and presence/absence of wheeze in 72.6% (PABAK 0.45) of cases and 73.8% (PABAK 0.48) of controls. Controls, tachypnoea, >3 uninterpretable chest positions, crying, upper airway noises and study site predicted listener disagreement. Among all interpretable examinations, 38.0% of cases and 84.9% of controls were normal (p<0.0001); wheezing was the most common sound (49.9%) in cases. Listening panel and case-control data suggests our methodology is feasible, likely valid and that small airway inflammation is common in WHO pneumonia. Digital auscultation may be an important future pneumonia diagnostic in developing countries.

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.

Lung sound intensity in patients with emphysema and in normal subjects at standardised airflows.

PubMed Central

Schreur, H J; Sterk, P J; Vanderschoot, J; van Klink, H C; van Vollenhoven, E; Dijkman, J H

1992-01-01

BACKGROUND: A common auscultatory finding in pulmonary emphysema is a reduction of lung sounds. This might be due to a reduction in the generation of sounds due to the accompanying airflow limitation or to poor transmission of sounds due to destruction of parenchyma. Lung sound intensity was investigated in normal and emphysematous subjects in relation to airflow. METHODS: Eight normal men (45-63 years, FEV1 79-126% predicted) and nine men with severe emphysema (50-70 years, FEV1 14-63% predicted) participated in the study. Emphysema was diagnosed according to pulmonary history, results of lung function tests, and radiographic criteria. All subjects underwent phonopneumography during standardised breathing manoeuvres between 0.5 and 2 1 below total lung capacity with inspiratory and expiratory target airflows of 2 and 1 l/s respectively during 50 seconds. The synchronous measurements included airflow at the mouth and lung volume changes, and lung sounds at four locations on the right chest wall. For each microphone airflow dependent power spectra were computed by using fast Fourier transformation. Lung sound intensity was expressed as log power (in dB) at 200 Hz at inspiratory flow rates of 1 and 2 l/s and at an expiratory flow rate of 1 l/s. RESULTS: Lung sound intensity was well repeatable on two separate days, the intraclass correlation coefficient ranging from 0.77 to 0.94 between the four microphones. The intensity was strongly influenced by microphone location and airflow. There was, however, no significant difference in lung sound intensity at any flow rate between the normal and the emphysema group. CONCLUSION: Airflow standardised lung sound intensity does not differ between normal and emphysematous subjects. This suggests that the auscultatory finding of diminished breath sounds during the regular physical examination in patients with emphysema is due predominantly to airflow limitation. Images PMID:1440459

Breath sounds

MedlinePlus

The lung sounds are best heard with a stethoscope. This is called auscultation. Normal lung sounds occur ... the bottom of the rib cage. Using a stethoscope, the doctor may hear normal breathing sounds, decreased ...

Use of Lung Allografts from Brain-Dead Donors after Cardiopulmonary Arrest and Resuscitation

PubMed Central

Worni, Mathias; Osho, Asishana A.; Snyder, Laurie D.; Palmer, Scott M.; Pietrobon, Ricardo; Davis, R. Duane; Hartwig, Matthew G.

2013-01-01

Rationale: Patients who progress to brain death after resuscitation from cardiac arrest have been hypothesized to represent an underused source of potential organ donors; however, there is a paucity of data regarding the viability of lung allografts after a period of cardiac arrest in the donor. Objectives: To analyze postoperative complications and survival after lung transplant from brain-dead donors resuscitated after cardiac arrest. Methods: The United Network for Organ Sharing database records donors with cardiac arrest occurring after brain death. Adult recipients of lung allografts from these arrest/resuscitation donors between 2005 and 2011 were compared with nonarrest donors. Propensity score matching was used to reduce the effect of confounding. Postoperative complications and overall survival were assessed using McNemar’s test for correlated binary proportions and Kaplan–Meier methods. Measurements and Main Results: A total of 479 lung transplant recipients from arrest/resuscitation donors were 1:1 propensity matched from a cohort of 9,076 control subjects. Baseline characteristics in the 1:1-matched cohort were balanced. There was no significant difference in perioperative mortality, airway dehiscence, dialysis requirement, postoperative length of stay (P ≥ 0.38 for all), or overall survival (P = 0.52). A subanalysis of the donor arrest group demonstrated similar survival when stratified by resuscitation time quartile (P = 0.38). Conclusions: There is no evidence of inferior outcomes after lung transplant from brain-dead donors who have had a period of cardiac arrest provided that good lung function is preserved and the donor is otherwise deemed acceptable for transplantation. Potential expansion of the donor pool to include cardiac arrest as the cause of brain death requires further study. PMID:23777361

Transarterial Embolization of Anomalous Systemic Arterial Supply to Normal Basal Segments of the Lung.

PubMed

Jiang, Sen; Yu, Dong; Jie, Bing

2016-09-01

To evaluate transarterial embolization (TAE) for the management of anomalous systemic arterial (ASA) supply to normal basal segments of the lung. Thirteen patients with ASA supply to normal basal segments of the lung underwent TAE. All patients presented with hemoptysis and had complete-type anomalies on pre-TAE or post-TAE computed tomography (CT). The anomaly was unilateral in all patients; 11 lesions were located in the left lung and 2 in the right. All patients underwent embolization with coils (n = 10) or a vascular plug (n = 3). Procedural success, clinical efficacy, and complications were assessed. Mean post-TAE CT and clinical follow-up was 25.4 and 42.1 months, respectively. Technical success was achieved in 100 % of cases. Several changes were noted on follow-up CT: complete obstruction of the ASA in all cases, normal (n = 11) or decreased (n = 2) density of the affected lung parenchyma, reduction of the primary enlarged inferior pulmonary vein in all cases, and pulmonary infarction and thickening of the corresponding bronchial artery (n = 4). The main complication was pulmonary infarction in four cases. TAE is a safe, effective, and minimally invasive therapeutic option for patients with ASA supply to normal basal segments of the lung.

Implant breast reconstruction followed by radiotherapy: Can helical tomotherapy become a standard irradiation treatment?

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

Massabeau, Carole, E-mail: cmassabeau@hotmail.com; Fournier-Bidoz, Nathalie; Wakil, Georges

2012-01-01

To evaluate the benefits and limitations of helical tomotherapy (HT) for loco-regional irradiation of patients after a mastectomy and immediate implant-based reconstruction. Ten breast cancer patients with retropectoral implants were randomly selected for this comparative study. Planning target volumes (PTVs) 1 (the volume between the skin and the implant, plus margin) and 2 (supraclavicular, infraclavicular, and internal mammary nodes, plus margin) were 50 Gy in 25 fractions using a standard technique and HT. The extracted dosimetric data were compared using a 2-tailed Wilcoxon matched-pair signed-rank test. Doses for PTV1 and PTV2 were significantly higher with HT (V95 of 98.91 andmore » 97.91%, respectively) compared with the standard technique (77.46 and 72.91%, respectively). Similarly, the indexes of homogeneity were significantly greater with HT (p = 0.002). HT reduced ipsilateral lung volume that received {>=}20 Gy (16.7 vs. 35%), and bilateral lungs (p = 0.01) and neighboring organs received doses that remained well below tolerance levels. The heart volume, which received 25 Gy, was negligible with both techniques. HT can achieve full target coverage while decreasing high doses to the heart and ipsilateral lung. However, the low doses to normal tissue volumes need to be reduced in future studies.« less

WE-AB-303-01: FEATURED PRESENTATION: A Dual-Detector Phase-Matched Digital Tomosynthesis (DTS) Imaging Scheme Using Aggregated KV and MV Projections for Intra-Treatment Lung Tumor Tracking

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

Zhang, Y; Yin, F; Mao, R

2015-06-15

Purpose: To develop a dual-detector phase-matched DTS technique for continuous and fast intra-treatment lung tumor localization. Methods: Tumor localization accuracy of limited-angle DTS imaging is affected by low inter-slice resolution. The dual-detector DTS technique aims to overcome this limitation through combining orthogonally acquired beam’s eye view MV projections and kV projections for intra-treatment DTS reconstruction and localization. To aggregate the kV and MV projections for reconstruction, the MV projections were linearly converted to synthesize corresponding kV projections. To further address the lung motion induced localization errors, this technique uses respiratory phase-matching to match the motion information between on-board DTS andmore » reference DTS to offset the adverse effects of motion blurriness in tumor localization.A study was performed using the CIRS008A lung phantom to simulate different on-board target variation scenarios for localization. The intra-treatment kV and MV acquisition was achieved through the Varian TrueBeam Developer Mode. Four methods were compared for their localization accuracy: 1. the proposed dual-detector phase-matched DTS technique; 2. the single-detector phase-matched DTS technique; 3. the dual-detector 3D-DTS technique without phase-matching; and 4. the single-detector 3D-DTS technique without phase-matching. Results: For scan angles of 2.5°, 5°, 10°, 20° and 30°, the dual-detector phase-matched DTS technique localized the tumor with average(±standard deviations) errors of 0.4±0.3 mm, 0.5±0.3 mm, 0.6±0.2 mm, 0.9±0.4 mm and 1.0±0.3 mm, respectively. The corresponding values of single-detector phase-matched DTS technique were 4.0±2.5 mm, 2.7±1.1 mm, 1.7±1.2 mm, 2.2±0.9 mm and 1.5±0.8 mm, respectively. The values of dual-detector 3D-DTS technique were 6.2±1.7 mm, 6.3±1.2 mm, 5.3±1.3 mm, 2.0±2.2 mm and 1.5±0.5 mm, respectively. And the values of single-detector 3D-DTS technique were 9.7±8.9 mm, 9.8±8.8 mm, 10.0±9.7 mm, 3.9±2.7 mm and 2.2±1.3 mm, respectively. Conclusion: The dual-detector phase-matched DTS technique substantially improves the tumor localization accuracy, which can be applied to real-time intra-treatment lung tumor localization. The research was funded by the National Institutes of Health Grant No. R01-CA184173 and a grant from Varian Medical Systems.« less

Protective Lung Ventilation and Morbidity After Pulmonary Resection: A Propensity Score-Matched Analysis.

PubMed

Amar, David; Zhang, Hao; Pedoto, Alessia; Desiderio, Dawn P; Shi, Weiji; Tan, Kay See

2017-07-01

Protective lung ventilation (PLV) during one-lung ventilation (OLV) for thoracic surgery is frequently recommended to reduce pulmonary complications. However, limited outcome data exist on whether PLV use during OLV is associated with less clinically relevant pulmonary morbidity after lung resection. Intraoperative data were prospectively collected in 1080 patients undergoing pulmonary resection with OLV, intentional crystalloid restriction, and mechanical ventilation to maintain inspiratory peak airway pressure <30 cm H2O. Other ventilator settings and all aspects of anesthetic management were at the discretion of the anesthesia care team. We defined PLV and non-PLV as <8 or ≥8 mL/kg (predicted body weight) mean tidal volume. The primary outcome was the occurrence of pneumonia and/or acute respiratory distress syndrome (ARDS). Propensity score matching was used to generate PLV and non-PLV groups with comparable characteristics. Associations between outcomes and PLV status were analyzed by exact logistic regression, with matching as cluster in the anatomic and nonanatomic lung resection cohorts. In the propensity score-matched analysis, the incidence of pneumonia and/or ARDS among patients who had an anatomic lung resection was 9/172 (5.2%) in the non-PLV compared to the PLV group 7/172 (4.1%; odds ratio, 1.29; 95% confidence interval, 0.48-3.45, P= .62). The incidence of pneumonia and/or ARDS in patients who underwent nonanatomic resection was 3/118 (2.5%) in the non-PLV compared to the PLV group, 1/118 (0.9%; odds ratio, 3.00; 95% confidence interval, 0.31-28.84, P= .34). In this prospective observational study, we found no differences in the incidence of pneumonia and/or ARDS between patients undergoing lung resection with tidal volumes <8 or ≥8 mL/kg. Our data suggest that when fluid restriction and peak airway pressures are limited, the clinical impact of PLV in this patient population is small. Future randomized trials are needed to better understand the benefits of a small tidal volume strategy during OLV on clinically important outcomes.

The non-specificity of the left/right ventricular amplitude ratio (LV/RV) for mitral insufficiency

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

Preston, D.F.; Reinsel, M.S.; Martin, N.L.

1984-01-01

The purpose of this study was to determine the specificity of the LV/RV for mitral insufficiency. One hundred and sixty patients underwent MUGA studies as part of their diagnostic evaluation. Phase analysis was performed. In the amplitude image, the LV/RV was measured. Patients were divided into 11 clinical groups based on chart review after adequate follow-up. The groups were compared by Duncan's Multiple Comparsion Test. Patients with mitral insufficiency (N = 12, mean LV/RV = 2.36), those with idiopathic myocardiopathy (8, 2.29) and those with normal hearts having lung disease on chest x-ray (22, 1.78) formed a group which atmore » the p < .05 level were not different from one another. Patients with idiopathic myocardiography, normal hearts with lung disease on chest x-ray, normal hearts with lung disease (23, 1.71) formed a second group which partially overlapped with both the first and third groups. The third group consisted of normal hearts with lung disease, normal hearts not taking adriamycin (18, 1.53), normal hearts taking adriamycin (22, 1.50), congestive heart failure (19, 1.50), arteriosclerotic heart disease, normal hearts (15, 1.29), chronic obstructive pulmonary disease and acute myocardial infarction. The LV/RV is not specific for mitral insufficiency. Idiopathic myocardiography, and normal hearts with lung disease on chest x-ray (metastases, cancer of the lung, infiltrates, fibrosis, and/or COPD) cannot be differentiated on a statistical basis. The mitral insufficiency group had the greatest values of LV/RV. It appears that decreased RV amplitude seen with diseases causing strain on the right ventricle will result in elevated LV/RV ratios.« less

Post-Inhaled Corticosteroid Pulmonary Tuberculosis Increases Lung Cancer in Patients with Asthma

PubMed Central

Lin, Frank Cheau-Feng; Nfor, Oswald Ndi; Jhang, Kai-Ming; Ku, Wen-Yuan; Ho, Chien-Chang; Lung, Chia-Chi; Pan, Hui-Hsien; Wu, Min-Chen; Wu, Ming-Fang; Liaw, Yung-Po

2016-01-01

Purpose To evaluate the association between post-inhaled corticosteroid (ICS) pulmonary tuberculosis (TB), pneumonia and lung cancer in patients with asthma. Methods The study samples were collected from the National Health Insurance Database. Asthmatic patients who were first-time users of ICS between 2003 and 2005 were identified as cases. For each case, 4 control individuals were randomly matched for sex, age and date of ICS use. Cases and matched controls were followed up until the end of 2010. Cox proportional hazard regression was used to determine the hazard ratio for pulmonary infections and lung cancer risk in the ICS users and non-users. Results A total of 10,904 first-time users of ICS were matched with 43,616 controls. The hazard ratios for lung cancer were: 2.52 (95% confidence interval [CI], 1.22–5.22; p = 0.012) for individuals with post-ICS TB, 1.28 (95%CI, 0.73–2.26; p = 0.389) for post-ICS pneumonia, 2.31(95%CI, 0.84–6.38; p = 0.105) for post-ICS pneumonia+TB, 1.08 (95%CI, 0.57–2.03; p = 0.815) for TB, 0.99 (95%CI, 0.63–1.55; p = 0.970) for pneumonia, and 0.32 (95%CI, 0.05–2.32; p = 0.261) for pneumonia+ TB, respectively. Conclusions Post-ICS TB increased lung cancer risk in patients with asthma. Because of the high mortality associated with lung cancer, screening tests are recommended for patients with post-ICS TB. PMID:27448321

HOX genes in human lung: altered expression in primary pulmonary hypertension and emphysema.

PubMed

Golpon, H A; Geraci, M W; Moore, M D; Miller, H L; Miller, G J; Tuder, R M; Voelkel, N F

2001-03-01

HOX genes belong to the large family of homeodomain genes that function as transcription factors. Animal studies indicate that they play an essential role in lung development. We investigated the expression pattern of HOX genes in human lung tissue by using microarray and degenerate reverse transcriptase-polymerase chain reaction survey techniques. HOX genes predominantly from the 3' end of clusters A and B were expressed in normal human adult lung and among them HOXA5 was the most abundant, followed by HOXB2 and HOXB6. In fetal (12 weeks old) and diseased lung specimens (emphysema, primary pulmonary hypertension) additional HOX genes from clusters C and D were expressed. Using in situ hybridization, transcripts for HOXA5 were predominantly found in alveolar septal and epithelial cells, both in normal and diseased lungs. A 2.5-fold increase in HOXA5 mRNA expression was demonstrated by quantitative reverse transcriptase-polymerase chain reaction in primary pulmonary hypertension lung specimens when compared to normal lung tissue. In conclusion, we demonstrate that HOX genes are selectively expressed in the human lung. Differences in the pattern of HOX gene expression exist among fetal, adult, and diseased lung specimens. The altered pattern of HOX gene expression may contribute to the development of pulmonary diseases.

HOX Genes in Human Lung

PubMed Central

Golpon, Heiko A.; Geraci, Mark W.; Moore, Mark D.; Miller, Heidi L.; Miller, Gary J.; Tuder, Rubin M.; Voelkel, Norbert F.

2001-01-01

HOX genes belong to the large family of homeodomain genes that function as transcription factors. Animal studies indicate that they play an essential role in lung development. We investigated the expression pattern of HOX genes in human lung tissue by using microarray and degenerate reverse transcriptase-polymerase chain reaction survey techniques. HOX genes predominantly from the 3′ end of clusters A and B were expressed in normal human adult lung and among them HOXA5 was the most abundant, followed by HOXB2 and HOXB6. In fetal (12 weeks old) and diseased lung specimens (emphysema, primary pulmonary hypertension) additional HOX genes from clusters C and D were expressed. Using in situ hybridization, transcripts for HOXA5 were predominantly found in alveolar septal and epithelial cells, both in normal and diseased lungs. A 2.5-fold increase in HOXA5 mRNA expression was demonstrated by quantitative reverse transcriptase-polymerase chain reaction in primary pulmonary hypertension lung specimens when compared to normal lung tissue. In conclusion, we demonstrate that HOX genes are selectively expressed in the human lung. Differences in the pattern of HOX gene expression exist among fetal, adult, and diseased lung specimens. The altered pattern of HOX gene expression may contribute to the development of pulmonary diseases. PMID:11238043

Conditionally reprogrammed normal and primary tumor prostate epithelial cells: a novel patient-derived cell model for studies of human prostate cancer

PubMed Central

Timofeeva, Olga A.; Palechor-Ceron, Nancy; Li, Guanglei; Yuan, Hang; Krawczyk, Ewa; Zhong, Xiaogang; Liu, Geng; Upadhyay, Geeta; Dakic, Aleksandra; Yu, Songtao; Fang, Shuang; Choudhury, Sujata; Zhang, Xueping; Ju, Andrew; Lee, Myeong-Seon; Dan, Han C.; Ji, Youngmi; Hou, Yong; Zheng, Yun-Ling; Albanese, Chris; Rhim, Johng; Schlegel, Richard; Dritschilo, Anatoly; Liu, Xuefeng

2017-01-01

Our previous study demonstrated that conditional reprogramming (CR) allows the establishment of patient-derived normal and tumor epithelial cell cultures from a variety of tissue types including breast, lung, colon and prostate. Using CR, we have established matched normal and tumor cultures, GUMC-29 and GUMC-30 respectively, from a patient's prostatectomy specimen. These CR cells proliferate indefinitely in vitro and retain stable karyotypes. Most importantly, only tumor-derived CR cells (GUMC-30) produced tumors in xenografted SCID mice, demonstrating maintenance of the critical tumor phenotype. Characterization of cells with DNA fingerprinting demonstrated identical patterns in normal and tumor CR cells as well as in xenografted tumors. By flow cytometry, both normal and tumor CR cells expressed basal, luminal, and stem cell markers, with the majority of the normal and tumor CR cells expressing prostate basal cell markers, CD44 and Trop2, as well as luminal marker, CD13, suggesting a transit-amplifying phenotype. Consistent with this phenotype, real time RT-PCR analyses demonstrated that CR cells predominantly expressed high levels of basal cell markers (KRT5, KRT14 and p63), and low levels of luminal markers. When the CR tumor cells were injected into SCID mice, the expression of luminal markers (AR, NKX3.1) increased significantly, while basal cell markers dramatically decreased. These data suggest that CR cells maintain high levels of proliferation and low levels of differentiation in the presence of feeder cells and ROCK inhibitor, but undergo differentiation once injected into SCID mice. Genomic analyses, including SNP and INDEL, identified genes mutated in tumor cells, including components of apoptosis, cell attachment, and hypoxia pathways. The use of matched patient-derived cells provides a unique in vitro model for studies of early prostate cancer. PMID:28009986

Interpretation of indeterminate lung scintigrams. [/sup 99m/Tc, /sup 133/Xe

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

Biello, D.R.; Mattar, A.G.; Osei-Wusu, A.

1979-10-01

Lung scintigrams and pulmonary angiograms of 111 patients with suspected pulmonary embolism who had matching perfusion defects and radiographic abnormalities (infiltrate, atelectasis, or effusion) were reviewed. In 14 patients perfusion defects were substantially smaller than the corresponding radiographic opacity; only 1 (7%) had pulmonary embolism. In 77 the opacities and perfusion defects were of similar size; the abnormality was due to embolism in 20 (26%). In 18 patients perfusion defects were substantially larger than the radiographic opacities and were not associated with matching ventilation abnormalities; of these, 16 (89%) had pulmonary embolism. Evaluation of the relative size of perfusion defectsmore » and radiographic abnormalities occurring in the same region improves the ability of lung scintigrams to predict pulmonary emboli.« less

Chronic Hypoxia Accentuates Dysanaptic Lung Growth.

PubMed

Llapur, Conrado J; Martínez, Myriam R; Grassino, Pedro T; Stok, Ana; Altieri, Héctor H; Bonilla, Federico; Caram, María M; Krowchuk, Natasha M; Kirby, Miranda; Coxson, Harvey O; Tepper, Robert S

2016-08-01

Adults born and raised at high altitudes have larger lung volumes and greater pulmonary diffusion capacity compared with adults at low altitude; however, it remains unclear whether the air and tissue volumes have comparable increases and whether there is a difference in airway size. To assess the effect of chronic hypoxia on lung growth using in vivo high-resolution computed tomography measurements. Healthy adults born and raised at moderate altitude (2,000 m above sea level; n = 19) and at low altitude (400 m above sea level; n = 23) underwent high-resolution computed tomography. Differences in total lung, air, and tissue volume, mean lung density, as well as airway lumen and wall areas in anatomically matched airways were compared between groups. No significant differences for age, sex, weight, or height were found between the two groups (P > 0.05). In a multivariate regression model, altitude was a significant contributor for total lung volume (P = 0.02), air volume (P = 0.03), and tissue volume (P = 0.03), whereby the volumes were greater for the moderate- versus the low-altitude group. However, altitude was not a significant contributor for mean lung density (P = 0.35) or lumen and wall areas in anatomically matched segmental, subsegmental, and subsubsegmental airways. Our findings suggest that the adult lung did not increase lung volume later in life by expansion of an existing number of alveoli, but rather from increased alveolarization early in life. In addition, chronic hypoxia accentuates dysanaptic lung growth by increasing the lung parenchyma but not the airways.

SU-E-T-632: A Dosimetric Comparison of the 3D-CRT Planning of Chest Wall in Post-Mastectomy Breast Cancer Patients, with and Without Breast Board Setup

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

Muzaffar, Ambreen; Masood, Asif; Ullah, Haseeb

2014-06-15

Purpose: Breast boards are used in breast radiation which increases normal lung and heart doses, when supraclavicular field is included. Therefore, in this study through dose volume histogram (DVHs), lung and heart doses comparison was done between two different setups i.e. with and without breast board, for the treatment of left chest wall and supraclavicular fossa in postmastectomy left breast cancer. Methods: In this study, CT-Simulation scans of ten breast cancer patients were done with and without breast board, at Shifa International Hospitals Islamabad, to investigate the differences between the two different setups of the irradiation of left chest wallmore » in terms of lung and heart doses. For immobilization, support under the neck, shoulders and arms was used. Precise PLAN 2.15 treatment planning system (TPS) was used for 3D-CRT planning. The total prescribed dose for both the plans was 5000 cGy/25 fractions. The chest wall was treated with a pair of tangential photon fields and the upper supraclavicular nodal regions were treated with an anterior photon field. A mono-isocentric technique was used to match the tangential fields with the anterior field at the isocentre. The dose volume histogram was used to compare the doses of heart and ipsilateral lung. Results: Both the plans of each patient were generated and compared. DVH results showed that for the same PTV dose coverage, plans without breast board resulted in a reduction of lung and heart doses compared with the plans with breast board. There was significant reductions in V20, V<25 and mean doses for lung and V<9 and mean doses for heart. Conclusion: In comparison of both the plans, setup without breast board significantly reduced the dose-volume of the ipsilateral lung and heart in left chest wall patients. Waived registration request has been submitted.« less

The concept of "baby lung".

PubMed

Gattinoni, Luciano; Pesenti, Antonio

2005-06-01

The "baby lung" concept originated as an offspring of computed tomography examinations which showed in most patients with acute lung injury/acute respiratory distress syndrome that the normally aerated tissue has the dimensions of the lung of a 5- to 6-year-old child (300-500 g aerated tissue). The respiratory system compliance is linearly related to the "baby lung" dimensions, suggesting that the acute respiratory distress syndrome lung is not "stiff" but instead small, with nearly normal intrinsic elasticity. Initially we taught that the "baby lung" is a distinct anatomical structure, in the nondependent lung regions. However, the density redistribution in prone position shows that the "baby lung" is a functional and not an anatomical concept. This provides a rational for "gentle lung treatment" and a background to explain concepts such as baro- and volutrauma. From a physiological perspective the "baby lung" helps to understand ventilator-induced lung injury. In this context, what appears dangerous is not the V(T)/kg ratio but instead the V(T)/"baby lung" ratio. The practical message is straightforward: the smaller the "baby lung," the greater is the potential for unsafe mechanical ventilation.

The effect of methacholine-induced acute airway narrowing on lung sounds in normal and asthmatic subjects.

PubMed

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

1995-02-01

The association between lung sound alterations and airways obstruction has long been recognized in clinical practice, but the precise pathophysiological mechanisms of this relationship have not been determined. Therefore, we examined the changes in lung sounds at well-defined levels of methacholine-induced airway narrowing in eight normal and nine asthmatic subjects with normal baseline lung function. All subjects underwent phonopneumography at baseline condition and at > or = 20% fall in forced expiratory volume in one second (FEV1), and in asthmatic subjects also at > or = 40% fall in FEV1. Lung sounds were recorded at three locations on the chest wall during standardized quiet breathing, and during maximal forced breathing. Airflow-dependent power spectra were computed using fast Fourier transform. For each spectrum, we determined the intensity and frequency content of lung sounds, together with the extent of wheezing. The results were analysed using analysis of variance (ANOVA). During acute airway narrowing, the intensity and frequency content of the recorded sounds, as well as the extent of wheezing, were higher than at baseline in both groups of subjects. At similar levels of obstruction, both the pitch and the change in sound intensity with airflow were higher in asthmatics than in normal subjects. Wheezing, being nondiscriminative between the subject groups at baseline, was more prominent in asthmatics than in normal subjects at 20% fall in FEV1. We conclude that, at given levels of acute airway narrowing, lung sounds differ between asthmatics and normal subjects. This suggests that airflow-standardized phonopneumography is a sensitive method for detecting abnormalities in airway dynamics in asthma.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

Automatic tracking of arbitrarily shaped implanted markers in kilovoltage projection images: A feasibility study

PubMed Central

Regmi, Rajesh; Lovelock, D. Michael; Hunt, Margie; Zhang, Pengpeng; Pham, Hai; Xiong, Jianping; Yorke, Ellen D.; Goodman, Karyn A.; Rimner, Andreas; Mostafavi, Hassan; Mageras, Gig S.

2014-01-01

Purpose: Certain types of commonly used fiducial markers take on irregular shapes upon implantation in soft tissue. This poses a challenge for methods that assume a predefined shape of markers when automatically tracking such markers in kilovoltage (kV) radiographs. The authors have developed a method of automatically tracking regularly and irregularly shaped markers using kV projection images and assessed its potential for detecting intrafractional target motion during rotational treatment. Methods: Template-based matching used a normalized cross-correlation with simplex minimization. Templates were created from computed tomography (CT) images for phantom studies and from end-expiration breath-hold planning CT for patient studies. The kV images were processed using a Sobel filter to enhance marker visibility. To correct for changes in intermarker relative positions between simulation and treatment that can introduce errors in automatic matching, marker offsets in three dimensions were manually determined from an approximately orthogonal pair of kV images. Two studies in anthropomorphic phantom were carried out, one using a gold cylindrical marker representing regular shape, another using a Visicoil marker representing irregular shape. Automatic matching of templates to cone beam CT (CBCT) projection images was performed to known marker positions in phantom. In patient data, automatic matching was compared to manual matching as an approximate ground truth. Positional discrepancy between automatic and manual matching of less than 2 mm was assumed as the criterion for successful tracking. Tracking success rates were examined in kV projection images from 22 CBCT scans of four pancreas, six gastroesophageal junction, and one lung cancer patients. Each patient had at least one irregularly shaped radiopaque marker implanted in or near the tumor. In addition, automatic tracking was tested in intrafraction kV images of three lung cancer patients with irregularly shaped markers during 11 volumetric modulated arc treatments. Purpose-built software developed at our institution was used to create marker templates and track the markers embedded in kV images. Results: Phantom studies showed mean ± standard deviation measurement uncertainty of automatic registration to be 0.14 ± 0.07 mm and 0.17 ± 0.08 mm for Visicoil and gold cylindrical markers, respectively. The mean success rate of automatic tracking with CBCT projections (11 frames per second, fps) of pancreas, gastroesophageal junction, and lung cancer patients was 100%, 99.1% (range 98%–100%), and 100%, respectively. With intrafraction images (approx. 0.2 fps) of lung cancer patients, the success rate was 98.2% (range 97%–100%), and 94.3% (range 93%–97%) using templates from 1.25 mm and 2.5 mm slice spacing CT scans, respectively. Correction of intermarker relative position was found to improve the success rate in two out of eight patients analyzed. Conclusions: The proposed method can track arbitrary marker shapes in kV images using templates generated from a breath-hold CT acquired at simulation. The studies indicate its feasibility for tracking tumor motion during rotational treatment. Investigation of the causes of misregistration suggests that its rate of incidence can be reduced with higher frequency of image acquisition, templates made from smaller CT slice spacing, and correction of changes in intermarker relative positions when they occur. PMID:24989384

Automatic tracking of arbitrarily shaped implanted markers in kilovoltage projection images: A feasibility study

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

Regmi, Rajesh; Lovelock, D. Michael; Hunt, Margie

Purpose: Certain types of commonly used fiducial markers take on irregular shapes upon implantation in soft tissue. This poses a challenge for methods that assume a predefined shape of markers when automatically tracking such markers in kilovoltage (kV) radiographs. The authors have developed a method of automatically tracking regularly and irregularly shaped markers using kV projection images and assessed its potential for detecting intrafractional target motion during rotational treatment. Methods: Template-based matching used a normalized cross-correlation with simplex minimization. Templates were created from computed tomography (CT) images for phantom studies and from end-expiration breath-hold planning CT for patient studies. Themore » kV images were processed using a Sobel filter to enhance marker visibility. To correct for changes in intermarker relative positions between simulation and treatment that can introduce errors in automatic matching, marker offsets in three dimensions were manually determined from an approximately orthogonal pair of kV images. Two studies in anthropomorphic phantom were carried out, one using a gold cylindrical marker representing regular shape, another using a Visicoil marker representing irregular shape. Automatic matching of templates to cone beam CT (CBCT) projection images was performed to known marker positions in phantom. In patient data, automatic matching was compared to manual matching as an approximate ground truth. Positional discrepancy between automatic and manual matching of less than 2 mm was assumed as the criterion for successful tracking. Tracking success rates were examined in kV projection images from 22 CBCT scans of four pancreas, six gastroesophageal junction, and one lung cancer patients. Each patient had at least one irregularly shaped radiopaque marker implanted in or near the tumor. In addition, automatic tracking was tested in intrafraction kV images of three lung cancer patients with irregularly shaped markers during 11 volumetric modulated arc treatments. Purpose-built software developed at our institution was used to create marker templates and track the markers embedded in kV images. Results: Phantom studies showed mean ± standard deviation measurement uncertainty of automatic registration to be 0.14 ± 0.07 mm and 0.17 ± 0.08 mm for Visicoil and gold cylindrical markers, respectively. The mean success rate of automatic tracking with CBCT projections (11 frames per second, fps) of pancreas, gastroesophageal junction, and lung cancer patients was 100%, 99.1% (range 98%–100%), and 100%, respectively. With intrafraction images (approx. 0.2 fps) of lung cancer patients, the success rate was 98.2% (range 97%–100%), and 94.3% (range 93%–97%) using templates from 1.25 mm and 2.5 mm slice spacing CT scans, respectively. Correction of intermarker relative position was found to improve the success rate in two out of eight patients analyzed. Conclusions: The proposed method can track arbitrary marker shapes in kV images using templates generated from a breath-hold CT acquired at simulation. The studies indicate its feasibility for tracking tumor motion during rotational treatment. Investigation of the causes of misregistration suggests that its rate of incidence can be reduced with higher frequency of image acquisition, templates made from smaller CT slice spacing, and correction of changes in intermarker relative positions when they occur.« less

Single-energy computed tomography-based pulmonary perfusion imaging: Proof-of-principle in a canine model

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

Yamamoto, Tokihiro, E-mail: toyamamoto@ucdavis.edu

Purpose: Radiotherapy (RT) that selectively avoids irradiating highly functional lung regions may reduce pulmonary toxicity, which is substantial in lung cancer RT. Single-energy computed tomography (CT) pulmonary perfusion imaging has several advantages (e.g., higher resolution) over other modalities and has great potential for widespread clinical implementation, particularly in RT. The purpose of this study was to establish proof-of-principle for single-energy CT perfusion imaging. Methods: Single-energy CT perfusion imaging is based on the following: (1) acquisition of end-inspiratory breath-hold CT scans before and after intravenous injection of iodinated contrast agents, (2) deformable image registration (DIR) for spatial mapping of those twomore » CT image data sets, and (3) subtraction of the precontrast image data set from the postcontrast image data set, yielding a map of regional Hounsfield unit (HU) enhancement, a surrogate for regional perfusion. In a protocol approved by the institutional animal care and use committee, the authors acquired CT scans in the prone position for a total of 14 anesthetized canines (seven canines with normal lungs and seven canines with diseased lungs). The elastix algorithm was used for DIR. The accuracy of DIR was evaluated based on the target registration error (TRE) of 50 anatomic pulmonary landmarks per subject for 10 randomly selected subjects as well as on singularities (i.e., regions where the displacement vector field is not bijective). Prior to perfusion computation, HUs of the precontrast end-inspiratory image were corrected for variation in the lung inflation level between the precontrast and postcontrast end-inspiratory CT scans, using a model built from two additional precontrast CT scans at end-expiration and midinspiration. The authors also assessed spatial heterogeneity and gravitationally directed gradients of regional perfusion for normal lung subjects and diseased lung subjects using a two-sample two-tailed t-test. Results: The mean TRE (and standard deviation) was 0.6 ± 0.7 mm (smaller than the voxel dimension) for DIR between pre contrast and postcontrast end-inspiratory CT image data sets. No singularities were observed in the displacement vector fields. The mean HU enhancement (and standard deviation) was 37.3 ± 10.5 HU for normal lung subjects and 30.7 ± 13.5 HU for diseased lung subjects. Spatial heterogeneity of regional perfusion was found to be higher for diseased lung subjects than for normal lung subjects, i.e., a mean coefficient of variation of 2.06 vs 1.59 (p = 0.07). The average gravitationally directed gradient was strong and significant (R{sup 2} = 0.99, p < 0.01) for normal lung dogs, whereas it was moderate and nonsignificant (R{sup 2} = 0.61, p = 0.12) for diseased lung dogs. Conclusions: This canine study demonstrated the accuracy of DIR with subvoxel TREs on average, higher spatial heterogeneity of regional perfusion for diseased lung subjects than for normal lung subjects, and a strong gravitationally directed gradient for normal lung subjects, providing proof-of-principle for single-energy CT pulmonary perfusion imaging. Further studies such as comparison with other perfusion imaging modalities will be necessary to validate the physiological significance.« less

[Horseshoe lung with normal pulmonary venous return].

PubMed

Gondra Sangroniz, A; Elorz Lambarri, J; Villar Alvarez, M A; Lecumberri Cortes, I; Ayala Curiel, J

2010-09-01

Horseshoe lung is a rare congenital anomaly characterised by a midline isthmus of pulmonary parenchyma connecting the posterior basal segments of the lungs behind the heart in conjunction with unilateral pulmonary hypoplasia. Of all cases, 80% are associated with scimitar syndrome, consisting of right anomalous pulmonary venous drainage, pulmonary hypoplasia of the right lung and systemic arterial perfusion to some lung areas. A six year old girl who had recurrent lower respiratory infections since birth. Chest Rx, angioCT and MR showed: hypoplasia of the right lung, dextrocardia and pulmonary isthmus bridging both lungs behind the pericardium. The right hypoplastic lung had little systemic supply coming from the abdominal aorta. The right pulmonary artery was hypoplastic. The right pulmonary venous drainage was normal. We present a case of horseshoe lung without abnormal venous drainage. 2010 Asociación Española de Pediatría. Published by Elsevier Espana. All rights reserved.

Relationship between thoracic auscultation and lung pathology detected by ultrasonography in sheep.

PubMed

Scott, Phil; Collie, Dave; McGorum, Bruce; Sargison, Neil

2010-10-01

The utility of routine auscultation to detect and characterise the nature of a range of superficial lung and pleural pathologies in domestic sheep was assessed using ultrasonographic examination to indicate and localise pathologies pre-mortem. Necropsy examination was then used to fully characterise the nature and extent of the lesions. Auscultation recordings were made from 10 normal sheep with no clinical evidence of respiratory disease and with absence of significant superficial lung pathology, which was confirmed initially by ultrasound examination and subsequently at necropsy examination. A further two sheep with endotoxaemia and 30 sheep with well-defined lung lesions were also examined. Increased audibility of normal lung sounds in 4/10 normal sheep was associated with tachypnoea as a consequence of handling and transport during hot weather and was also observed in the two sheep with endotoxaemia. Moderate to severe coarse crackles detected in all advanced cases of ovine pulmonary adenocarcinoma (n=16) were audible over an area larger than the lesion distribution identified during ultrasound examination, and confirmed later at necropsy. Auscultation did not detect abnormal sounds in any of the five sheep with focal pleural abscesses (up to 10 cm diameter). Unilateral pyothorax caused attenuation of sounds relative to the contra-lateral normal lung in all three sheep with this condition. Marked fibrinous pleurisy caused attenuation of sounds relative to normal areas of lung in six sheep. No sounds resembling the description of pleural frictions rubs were heard in the sheep with marked fibrinous pleurisy (n=6) or associated with focal pleural abscesses (n=5). Routine interpretation of auscultated sound did not allow the presence of superficial lung pathology or its distribution to be accurately defined in the respiratory diseases represented in this study. Copyright © 2009 Elsevier Ltd. All rights reserved.

Midkine and pleiotrophin concentrations in needle biopsies of breast and lung masses.

PubMed

Giamanco, Nicole M; Jee, Youn Hee; Wellstein, Anton; Shriver, Craig D; Summers, Thomas A; Baron, Jeffrey

2017-09-07

Midkine (MDK) and pleiotrophin (PTN) are two closely related heparin-binding growth factors which are overexpressed in a wide variety of human cancers. We hypothesized that the concentrations of these factors in washout of biopsy needles would be higher in breast and lung cancer than in benign lesions. Seventy subjects underwent pre-operative core needle biopsies of 78 breast masses (16 malignancies). In 11 subjects, fine needle aspiration was performed ex vivo on 7 non-small cell lung cancers and 11 normal lung specimens within surgically excised lung tissue. The biopsy needle was washed with buffer for immunoassay. The MDK/DNA and the PTN/DNA ratio in most of the malignant breast masses were similar to the ratios in benign masses except one lobular carcinoma in situ (24-fold higher PTN/DNA ratio than the average benign mass). The MDK/DNA and PTN/DNA ratio were similar in most malignant and normal lung tissue except one squamous cell carcinoma (38-fold higher MDK/DNA ratio than the average of normal lung tissue). Both MDK and PTN are readily measurable in washout of needle biopsy samples from breast and lung masses and levels are highly elevated only in a specific subset of these malignancies.

Transarterial Embolization of Anomalous Systemic Arterial Supply to Normal Basal Segments of the Lung

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

Jiang, Sen, E-mail: jasfly77@vip.163.com; Yu, Dong; Jie, Bing

PurposeTo evaluate transarterial embolization (TAE) for the management of anomalous systemic arterial (ASA) supply to normal basal segments of the lung.MethodsThirteen patients with ASA supply to normal basal segments of the lung underwent TAE. All patients presented with hemoptysis and had complete-type anomalies on pre-TAE or post-TAE computed tomography (CT). The anomaly was unilateral in all patients; 11 lesions were located in the left lung and 2 in the right. All patients underwent embolization with coils (n = 10) or a vascular plug (n = 3). Procedural success, clinical efficacy, and complications were assessed. Mean post-TAE CT and clinical follow-up was 25.4 and 42.1 months,more » respectively.ResultsTechnical success was achieved in 100 % of cases. Several changes were noted on follow-up CT: complete obstruction of the ASA in all cases, normal (n = 11) or decreased (n = 2) density of the affected lung parenchyma, reduction of the primary enlarged inferior pulmonary vein in all cases, and pulmonary infarction and thickening of the corresponding bronchial artery (n = 4). The main complication was pulmonary infarction in four cases.ConclusionTAE is a safe, effective, and minimally invasive therapeutic option for patients with ASA supply to normal basal segments of the lung.« less

Photodynamic therapy: a promising alternative in oncology

NASA Astrophysics Data System (ADS)

Nelius, Thomas; de Riese, Werner T. W.; Filleur, Stephanie

2004-07-01

Photodynamic Therapy (PDT) is a treatment modality that is based on the administration of a photosensitizer and the following application of light in a wavelength range matching the absorption spectrum of the photosensitizer. Ideally the photosensitizer retains in the tumor tissue more than in normal tissue and thus allows targeted destruction of cancerous tissue. The use of PDT is slowly being accepted as a standard treatment for certain types of cancer. This includes mainly treatment strategies with only palliative intentions (obstructive esophageal cancer and advanced lung cancer) while for certain malignant conditions new applications exists that are already intended for cure (e.g. early stage of lung cancer). The main advantage of PDT is that the treatment can be repeated multiple times safely without major side effects. PDT can be safely combined with already established treatment options like surgery, chemotherapy or radiotherapy. A disadvantage of PDT is the only localized effect of the therapy, which usually cannot significantly alter the outcome of a systemic disease. In this paper we review the history of PDT as well as current clinical applications in oncology and future directions.

The role of high airway pressure and dynamic strain on ventilator-induced lung injury in a heterogeneous acute lung injury model.

PubMed

Jain, Sumeet V; Kollisch-Singule, Michaela; Satalin, Joshua; Searles, Quinn; Dombert, Luke; Abdel-Razek, Osama; Yepuri, Natesh; Leonard, Antony; Gruessner, Angelika; Andrews, Penny; Fazal, Fabeha; Meng, Qinghe; Wang, Guirong; Gatto, Louis A; Habashi, Nader M; Nieman, Gary F

2017-12-01

Acute respiratory distress syndrome causes a heterogeneous lung injury with normal and acutely injured lung tissue in the same lung. Improperly adjusted mechanical ventilation can exacerbate ARDS causing a secondary ventilator-induced lung injury (VILI). We hypothesized that a peak airway pressure of 40 cmH 2 O (static strain) alone would not cause additional injury in either the normal or acutely injured lung tissue unless combined with high tidal volume (dynamic strain). Pigs were anesthetized, and heterogeneous acute lung injury (ALI) was created by Tween instillation via a bronchoscope to both diaphragmatic lung lobes. Tissue in all other lobes was normal. Airway pressure release ventilation was used to precisely regulate time and pressure at both inspiration and expiration. Animals were separated into two groups: (1) over-distension + high dynamic strain (OD + H DS , n = 6) and (2) over-distension + low dynamic strain (OD + L DS , n = 6). OD was caused by setting the inspiratory pressure at 40 cmH 2 O and dynamic strain was modified by changing the expiratory duration, which varied the tidal volume. Animals were ventilated for 6 h recording hemodynamics, lung function, and inflammatory mediators followed by an extensive necropsy. In normal tissue (N T ), OD + L DS caused minimal histologic damage and a significant reduction in BALF total protein (p < 0.05) and MMP-9 activity (p < 0.05), as compared with OD + H DS . In acutely injured tissue (ALI T ), OD + L DS resulted in reduced histologic injury and pulmonary edema (p < 0.05), as compared with OD + H DS . Both N T and ALI T are resistant to VILI caused by OD alone, but when combined with a H DS , significant tissue injury develops.

Upregulated INHBA Expression May Promote Cell Proliferation and Is Associated with Poor Survival in Lung Adenocarcinoma1

PubMed Central

Seder, Christopher W; Hartojo, Wibisono; Lin, Lin; Silvers, Amy L; Wang, Zhuwen; Thomas, Dafydd G; Giordano, Thomas J; Chen, Guoan; Chang, Andrew C; Orringer, Mark B; Beer, David G

2009-01-01

Introduction The expression, mechanisms of regulation, and functional impact of INHBA (activin A) in lung adenocarcinoma (AD) have not been fully elucidated. Methods INHBA expression was examined in 96 lung samples (86 ADs, 10 normal lung) using oligonucleotide microarrays and 187 lung samples (164 ADs, 6 bronchioalveolar carcinomas, and 17 normal lung) using immunohistochemistry. The proliferation of AD cell lines H460 and SKLU1 was examined with WST-1 assays after treatment with recombinant activin A, follistatin, and INHBA-targeting small-interfering RNA. Cells were also treated with 5-aza-2′ deoxycytidine and trichostatin A to investigate the role of epigenetic regulation in INHBA expression. Results Primary ADs expressed 3.1 times more INHBA mRNA than normal lung. In stage I AD patients, high levels of primary tumor INHBA transcripts were associated with worse prognosis. Immunohistochemistry confirmed higher inhibin βA protein expression in ADs (78.7%) and bronchioalveolar carcinomas (66.7%) compared with normal lung (11.8%). H460 and SKLU1 demonstrated increased proliferation when treated with exogenous activin A and reduced proliferation when treated with follistatin or INHBA-targeting small-interfering RNA. INHBA mRNA expression in H460 cells was upregulated after treatment with trichostatin A and 5-aza-2′ deoxycytidine. Conclusions INHBA is overexpressed in AD relative to controls. Inhibin βA may promote cell proliferation, and its overexpression is associated with worse survival in stage I AD patients. In addition, overexpression of INHBA may be affected by promoter methylation and histone acetylation in a subset of lung ADs. PMID:19308293

Identification of Importin 8 (IPO8) as the most accurate reference gene for the clinicopathological analysis of lung specimens

PubMed Central

Nguewa, Paul A; Agorreta, Jackeline; Blanco, David; Lozano, Maria Dolores; Gomez-Roman, Javier; Sanchez, Blas A; Valles, Iñaki; Pajares, Maria J; Pio, Ruben; Rodriguez, Maria Jose; Montuenga, Luis M; Calvo, Alfonso

2008-01-01

Background The accurate normalization of differentially expressed genes in lung cancer is essential for the identification of novel therapeutic targets and biomarkers by real time RT-PCR and microarrays. Although classical "housekeeping" genes, such as GAPDH, HPRT1, and beta-actin have been widely used in the past, their accuracy as reference genes for lung tissues has not been proven. Results We have conducted a thorough analysis of a panel of 16 candidate reference genes for lung specimens and lung cell lines. Gene expression was measured by quantitative real time RT-PCR and expression stability was analyzed with the softwares GeNorm and NormFinder, mean of |ΔCt| (= |Ct Normal-Ct tumor|) ± SEM, and correlation coefficients among genes. Systematic comparison between candidates led us to the identification of a subset of suitable reference genes for clinical samples: IPO8, ACTB, POLR2A, 18S, and PPIA. Further analysis showed that IPO8 had a very low mean of |ΔCt| (0.70 ± 0.09), with no statistically significant differences between normal and malignant samples and with excellent expression stability. Conclusion Our data show that IPO8 is the most accurate reference gene for clinical lung specimens. In addition, we demonstrate that the commonly used genes GAPDH and HPRT1 are inappropriate to normalize data derived from lung biopsies, although they are suitable as reference genes for lung cell lines. We thus propose IPO8 as a novel reference gene for lung cancer samples. PMID:19014639

[Testing and analyzing the lung functions in the normal population in Hebei province].

PubMed

Chen, Li; Zhao, Ming; Han, Shao-mei; Li, Zhong-ming; Zhu, Guang-jin

2004-08-01

To investigate the lung function of the normal subjects living in Hebei province and its correlative factors such as living circumstance, age, height, and body weight. The lung volumes and breath capacities of 1,587 normal subjects were tested by portable spirometers (Scope Rotry) from August to October in 2002. The influences of living circumstance, age, gender, height, and body weight on lung functions were observed and analyzed. No significant difference was found between urban and rural areas in all indexes (P > 0.05); however, significant difference existed between male and female subjects (P = 0.000). The change trends of lung function in male and female subjects were similar. Growth spurt appeared at the age of 12-16 years in male subjects and 12-14 years in female subjects. Vital capacity (VC), forced vital capacity (FVC), and forced expiratory volume in one second (FEV1) reached their peaks at the age of 26-34 years and then decreased with age. Peak expiratory flow (PEF), 25% forced expiratory flow (FEF50%), and 75% forced expiratory flow (FEF75%) appeared at the age of 18 and then went down with age. Both height and weight had a correlation with all the indexes of lung functions, although the influence of height is stronger than weight. All the indexes of lung function have correlations with age, height, and weight. Lung function changes with aging, therefore different expected values shall be available for the adolescence, young adults, and middle-aged and old people. This study provides reference values of lung function for normal population.

Enhanced expression of G-protein coupled estrogen receptor (GPER/GPR30) in lung cancer

PubMed Central

2012-01-01

Background G-protein-coupled estrogen receptor (GPER/GPR30) was reported to bind 17β-estradiol (E2), tamoxifen, and ICI 182,780 (fulvestrant) and promotes activation of epidermal growth factor receptor (EGFR)-mediated signaling in breast, endometrial and thyroid cancer cells. Although lung adenocarcinomas express estrogen receptors α and β (ERα and ERβ), the expression of GPER in lung cancer has not been investigated. The purpose of this study was to examine the expression of GPER in lung cancer. Methods The expression patterns of GPER in various lung cancer lines and lung tumors were investigated using standard quantitative real time PCR (at mRNA levels), Western blot and immunohistochemistry (IHC) methods (at protein levels). The expression of GPER was scored and the pairwise comparisons (cancer vs adjacent tissues as well as cancer vs normal lung tissues) were performed. Results Analysis by real-time PCR and Western blotting revealed a significantly higher expression of GPER at both mRNA and protein levels in human non small cell lung cancer cell (NSCLC) lines relative to immortalized normal lung bronchial epithelial cells (HBECs). The virally immortalized human small airway epithelial cell line HPL1D showed higher expression than HBECs and similar expression to NSCLC cells. Immunohistochemical analysis of tissue sections of murine lung adenomas as well as human lung adenocarcinomas, squamous cell carcinomas and non-small cell lung carcinomas showed consistently higher expression of GPER in the tumor relative to the surrounding non-tumor tissue. Conclusion The results from this study demonstrate increased GPER expression in lung cancer cells and tumors compared to normal lung. Further evaluation of the function and regulation of GPER will be necessary to determine if GPER is a marker of lung cancer progression. PMID:23273253

Enhanced expression of G-protein coupled estrogen receptor (GPER/GPR30) in lung cancer.

PubMed

Jala, Venkatakrishna Rao; Radde, Brandie N; Haribabu, Bodduluri; Klinge, Carolyn M

2012-12-28

G-protein-coupled estrogen receptor (GPER/GPR30) was reported to bind 17β-estradiol (E2), tamoxifen, and ICI 182,780 (fulvestrant) and promotes activation of epidermal growth factor receptor (EGFR)-mediated signaling in breast, endometrial and thyroid cancer cells. Although lung adenocarcinomas express estrogen receptors α and β (ERα and ERβ), the expression of GPER in lung cancer has not been investigated. The purpose of this study was to examine the expression of GPER in lung cancer. The expression patterns of GPER in various lung cancer lines and lung tumors were investigated using standard quantitative real time PCR (at mRNA levels), Western blot and immunohistochemistry (IHC) methods (at protein levels). The expression of GPER was scored and the pairwise comparisons (cancer vs adjacent tissues as well as cancer vs normal lung tissues) were performed. Analysis by real-time PCR and Western blotting revealed a significantly higher expression of GPER at both mRNA and protein levels in human non small cell lung cancer cell (NSCLC) lines relative to immortalized normal lung bronchial epithelial cells (HBECs). The virally immortalized human small airway epithelial cell line HPL1D showed higher expression than HBECs and similar expression to NSCLC cells. Immunohistochemical analysis of tissue sections of murine lung adenomas as well as human lung adenocarcinomas, squamous cell carcinomas and non-small cell lung carcinomas showed consistently higher expression of GPER in the tumor relative to the surrounding non-tumor tissue. The results from this study demonstrate increased GPER expression in lung cancer cells and tumors compared to normal lung. Further evaluation of the function and regulation of GPER will be necessary to determine if GPER is a marker of lung cancer progression.

Serum antioxidant levels and nutritional status in early and advanced stage lung cancer patients.

PubMed

Klarod, Kultida; Hongsprabhas, Pranithi; Khampitak, Tueanjit; Wirasorn, Kosin; Kiertiburanakul, Sasisopin; Tangrassameeprasert, Roongpet; Daduang, Jureerut; Yongvanit, Puangrat; Boonsiri, Patcharee

2011-01-01

Malnutrition frequently occurs in lung cancer patients. We aimed to determine nutritional status and antioxidant and mineral levels in Thai patients with lung cancer. A prospective study with matched case-control was conducted. Nutritional status was assessed by body mass index (BMI) and subjective global assessment (SGA). Eastern Cooperative Oncology Group (ECOG) performance status was used to assess the performance. The serum antioxidant and mineral levels were determined. Forty-nine patients with a mean age of 58.8 (range, 35-82) who were first diagnosed with lung cancer were enrolled. They were compared with 60 healthy controls, and levels of retinol, α-tocopherol, β-carotene, lycopene, β-cryptoxanthin, selenium, and zinc were lower (P < 0.05). However, peroxidase activity was higher (P = 0.002) in patients. Selenium levels were higher in early stage compared to advanced stage patients (P = 0.041). Overweight patients had higher selenium levels (0.04 mg/L) than normal BMI patients (β = 0.04, P = 0.035). Patients with SGA class C had lower selenium levels (0.03 mg/L) than those with class A (β = -0.03, P = 0.035). The poorer ECOG performance patients had significantly lower β-carotene (β = -0.192, P = 0.003) and selenium (β = -0.031, P = 0.011) levels compared with those with good ECOG performance status. Significantly lower levels of antioxidants and selenium were found in lung cancer patients compared to healthy controls. Levels of some antioxidants and minerals differed among categories of BMI, SGA categories, or ECOG performance status. These findings may be helpful for further studies, such as the effect of nutritional supplementation on clinical outcomes. Copyright © 2011 Elsevier Inc. All rights reserved.

Suberoylanilide hydroxamic acid increases anti-cancer effect of tumor necrosis factor-α through up-regulation of TNF receptor 1 in lung cancer cells.

PubMed

You, Bo Ra; Han, Bo Ram; Park, Woo Hyun

2017-03-14

Suberoylanilide hydroxamic acid (SAHA) as a histone deacetylase (HDAC) inhibitor has anti-cancer effect. Here, we evaluated the effect of SAHA on HDAC activity and cell growth in many normal lung and cancer cells. We observed that the HDAC activities of lung cancer cells were higher than that of normal lung cells. SAHA inhibited the growth of lung cancer cells regardless of the inhibitory effect on HDAC. This agent induced a G2/M phase arrest and apoptosis, which was accompanied by mitochondrial membrane potential (MMP: ΔΨm) loss in lung cancer cells. However, SAHA did not induce cell death in normal lung cells. All tested caspase inhibitors prevented apoptotic cell death in SAHA-treated A549 and Calu-6 lung cancer cells. Treatment with tumor necrosis factor-alpha (TNF-α) enhanced apoptosis in SAHA-treated lung cancer cells through caspase-8 and caspase-9 activations. Especially, SAHA increased the expression level of TNF-α receptor 1 (TNFR1), especially acetylation of the region of TNFR1 promoter -223/-29 in lung cancer cells. The down-regulation of TNFR1 suppressed apoptosis in TNF-α and SAHA-treated lung cancer cells. In conclusion, SAHA inhibited the growth of lung cancer cells via a G2/M phase arrest and caspase-dependent apoptosis. SAHA also enhanced apoptotic effect of TNF-α in human lung cancer cells through up-regulation of TNFR1. TNF-α may be a key to improve anti-cancer effect of HDAC inhibitors.

Suberoylanilide hydroxamic acid increases anti-cancer effect of tumor necrosis factor-α through up-regulation of TNF receptor 1 in lung cancer cells

PubMed Central

You, Bo Ra; Han, Bo Ram; Park, Woo Hyun

2017-01-01

Suberoylanilide hydroxamic acid (SAHA) as a histone deacetylase (HDAC) inhibitor has anti-cancer effect. Here, we evaluated the effect of SAHA on HDAC activity and cell growth in many normal lung and cancer cells. We observed that the HDAC activities of lung cancer cells were higher than that of normal lung cells. SAHA inhibited the growth of lung cancer cells regardless of the inhibitory effect on HDAC. This agent induced a G2/M phase arrest and apoptosis, which was accompanied by mitochondrial membrane potential (MMP: ΔΨm) loss in lung cancer cells. However, SAHA did not induce cell death in normal lung cells. All tested caspase inhibitors prevented apoptotic cell death in SAHA-treated A549 and Calu-6 lung cancer cells. Treatment with tumor necrosis factor-alpha (TNF-α) enhanced apoptosis in SAHA-treated lung cancer cells through caspase-8 and caspase-9 activations. Especially, SAHA increased the expression level of TNF-α receptor 1 (TNFR1), especially acetylation of the region of TNFR1 promoter −223/-29 in lung cancer cells. The down-regulation of TNFR1 suppressed apoptosis in TNF-α and SAHA-treated lung cancer cells. In conclusion, SAHA inhibited the growth of lung cancer cells via a G2/M phase arrest and caspase-dependent apoptosis. SAHA also enhanced apoptotic effect of TNF-α in human lung cancer cells through up-regulation of TNFR1. TNF-α may be a key to improve anti-cancer effect of HDAC inhibitors. PMID:28099148

SU-E-T-572: Normal Lung Tissue Sparing in Radiation Therapy for Locally Advanced Non-Small Cell Lung Cancer

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

Hong, C; Ju, S; Ahn, Y

2015-06-15

Purpose: To compare normal lung-sparing capabilities of three advanced radiation therapy techniques for locally advanced non-small cell lung cancer (LA-NSCLC). Methods: Four-dimensional computed tomography (4DCT) was performed in 10 patients with stage IIIb LA-NSCLC. The internal target volume (ITV); planning target volume (PTV); and organs at risks (OARs) such as spinal cord, total normal lung, heart, and esophagus were delineated for each CT data set. Intensity-modulated radiation therapy (IMRT), Tomohelical-IMRT (TH-IMRT), and TomoDirect-IMRT (TD-IMRT) plans were generated (total prescribed dose, 66 Gy in 33 fractions to the PTV) for each patient. To reduce the normal lung dose, complete and directionalmore » block function was applied outside the normal lung far from the target for both TH-IMRT and TD-IMRT, while pseudo- OAR was set in the same region for IMRT. Dosimetric characteristics of the three plans were compared in terms of target coverage, the sparing capability for the OAR, and the normal tissue complication probability (NTCP). Beam delivery efficiency was also compared. Results: TH-IMRT and TD-IMRT provided better target coverage than IMRT plans. Lung volume receiving ≥–30 Gy, mean dose, and NTCP were significant with TH-IMRT than with IMRT (p=0.006), and volume receiving ≥20–30 Gy was lower in TD-IMRT than in IMRT (p<0.05). Compared with IMRT, TH-IMRT had better sparing effect on the spinal cord (Dmax, NTCP) and heart (V45) (p<0.05). NTCP for the spinal cord, V45 and V60 for the heart, and Dmax for the esophagus were significantly lower in TD-IMRT than in IMRT. The monitor units per fraction were clearly smaller for IMRT than for TH-IMRT and TD-IMRT (p=0.006). Conclusion: In LA-NSCLC, TH-IMRT gave superior PTV coverage and OAR sparing compared to IMRT. TH-IMRT provided better control of the lung volume receiving ≥5–30 Gy. The delivery time and monitor units were lower in TD-IMRT than in TH-IMRT.« less

Lung Transplant Outcomes in Systemic Sclerosis with Significant Esophageal Dysfunction. A Comprehensive Single-Center Experience

PubMed Central

Schwab, Kristin; Saggar, Rajeev; Duffy, Erin; Elashoff, David; Tseng, Chi-Hong; Weigt, Sam; Charan, Deepshikha; Abtin, Fereidoun; Johannes, Jimmy; Derhovanessian, Ariss; Conklin, Jeffrey; Ghassemi, Kevin; Khanna, Dinesh; Siddiqui, Osama; Ardehali, Abbas; Hunter, Curtis; Kwon, Murray; Biniwale, Reshma; Lo, Michelle; Volkmann, Elizabeth; Torres Barba, David; Belperio, John A.; Mahrer, Thomas; Furst, Daniel E.; Kafaja, Suzanne; Clements, Philip; Shino, Michael; Gregson, Aric; Kubak, Bernard; Lynch, Joseph P.; Ross, David

2016-01-01

Rationale: Consideration of lung transplantation in patients with systemic sclerosis (SSc) remains guarded, often due to the concern for esophageal dysfunction and the associated potential for allograft injury and suboptimal post–lung transplantation outcomes. Objectives: The purpose of this study was to systematically report our single-center experience regarding lung transplantation in the setting of SSc, with a particular focus on esophageal dysfunction. Methods: We retrospectively reviewed all lung transplants at our center from January 1, 2000 through August 31, 2012 (n = 562), comparing the SSc group (n = 35) to the following lung transplant diagnostic subsets: all non-SSc (n = 527), non-SSc diffuse fibrotic lung disease (n = 264), and a non-SSc matched group (n = 109). We evaluated post–lung transplant outcomes, including survival, primary graft dysfunction, acute rejection, bronchiolitis obliterans syndrome, and microbiology of respiratory isolates. In addition, we defined severe esophageal dysfunction using esophageal manometry and esophageal morphometry criteria on the basis of chest computed tomography images. For patients with SSc referred for lung transplant but subsequently denied (n = 36), we queried the reason(s) for denial with respect to the concern for esophageal dysfunction. Measurements and Main Results: The 1-, 3-, and 5-year post–lung transplant survival for SSc was 94, 77, and 70%, respectively, and similar to the other groups. The remaining post–lung transplant outcomes evaluated were also similar between SSc and the other groups. Approximately 60% of the SSc group had severe esophageal dysfunction. Pre–lung transplant chest computed tomography imaging demonstrated significantly abnormal esophageal morphometry for SSc when compared with the matched group. Importantly, esophageal dysfunction was the sole reason for lung transplant denial in a single case. Conclusions: Relative to other lung transplant indications, our SSc group experienced comparable survival, primary graft dysfunction, acute rejection, bronchiolitis obliterans syndrome, and microbiology of respiratory isolates, despite the high prevalence of severe esophageal dysfunction. Esophageal dysfunction rarely precluded active listing for lung transplantation. PMID:27078625

Survival in patients with metachronous second primary lung cancer.

PubMed

Ha, Duc; Choi, Humberto; Chevalier, Cory; Zell, Katrina; Wang, Xiao-Feng; Mazzone, Peter J

2015-01-01

Four to 10% of patients with non-small cell lung cancer subsequently develop a metachronous second primary lung cancer. The decision to perform surveillance or screening imaging for patients with potentially cured lung cancer must take into account the outcomes expected when detecting metachronous second primaries. To assess potential survival differences between patients with metachronous second primary lung cancer compared to matched patients with first primary lung cancer. We retrospectively reviewed patients diagnosed with lung cancer at the Cleveland Clinic (2006-2010). Metachronous second primary lung cancer was defined as lung cancer diagnosed after a 4-year, disease-free interval from the first lung cancer, or if there were two different histologic subtypes diagnosed at different times. Patients with first primary lung cancer diagnosed in the same time period served as control subjects. Propensity score matching was performed using age, sex, smoking history, histologic subtype, and collaborative stage, with a 1:3 case-control ratio. Survival analyses were performed by Cox proportional hazards modeling and Kaplan-Meier estimates. Forty-four patients met criteria for having a metachronous second primary lung cancer. There were no statistically significant differences between case subjects and control subjects in prognostic variables. The median survival time and 2-year overall survival rate for the metachronous second primary group, compared with control subjects, were as follows: 11.8 versus 18.4 months (P = 0.18) and 31.0 versus 40.9% (P = 0.28). The survival difference was largest in those with stage I metachronous second primaries (median survival time, 26.8 vs. 60.4 mo, P = 0.09; 2-year overall survival, 56.3 vs. 71.2%, P = 0.28). Patients with stage I metachronous second primary lung cancer may have worse survival than those who present with a first primary lung cancer. This could influence the benefit-risk balance of screening the high-risk cohort with a previously treated lung cancer.

Estimation of regional lung expansion via 3D image registration

NASA Astrophysics Data System (ADS)

Pan, Yan; Kumar, Dinesh; Hoffman, Eric A.; Christensen, Gary E.; McLennan, Geoffrey; Song, Joo Hyun; Ross, Alan; Simon, Brett A.; Reinhardt, Joseph M.

2005-04-01

A method is described to estimate regional lung expansion and related biomechanical parameters using multiple CT images of the lungs, acquired at different inflation levels. In this study, the lungs of two sheep were imaged utilizing a multi-detector row CT at different lung inflations in the prone and supine positions. Using the lung surfaces and the airway branch points for guidance, a 3D inverse consistent image registration procedure was used to match different lung volumes at each orientation. The registration was validated using a set of implanted metal markers. After registration, the Jacobian of the deformation field was computed to express regional expansion or contraction. The regional lung expansion at different pressures and different orientations are compared.

The lung in space.

PubMed

Prisk, G Kim

2005-09-01

The lung is exquisitely sensitive to gravity, which induces gradients in ventilation, blood flow, and gas exchange. Studies of lungs in microgravity provide a means of elucidating the effects of gravity. They suggest a mechanism by which gravity serves to match ventilation to perfusion, making for a more efficient lung than anticipated. Despite predictions, lungs do not become edematous, and there is no disruption to, gas exchange in microgravity. Sleep disturbances in microgravity are not a result of respiratory-related events; obstructive sleep apnea is caused principally by the gravitational effects on the upper airways. In microgravity, lungs may be at greater risk to the effects of inhaled aerosols.

The lung in space

NASA Technical Reports Server (NTRS)

Prisk, G. Kim

2005-01-01

The lung is exquisitely sensitive to gravity, which induces gradients in ventilation, blood flow, and gas exchange. Studies of lungs in microgravity provide a means of elucidating the effects of gravity. They suggest a mechanism by which gravity serves to match ventilation to perfusion, making for a more efficient lung than anticipated. Despite predictions, lungs do not become edematous, and there is no disruption to, gas exchange in microgravity. Sleep disturbances in microgravity are not a result of respiratory-related events; obstructive sleep apnea is caused principally by the gravitational effects on the upper airways. In microgravity, lungs may be at greater risk to the effects of inhaled aerosols.

Microscopic FTIR studies of lung cancer cells in pleural fluid.

PubMed

Wang, H P; Wang, H C; Huang, Y J

1997-10-01

Structural changes associated with lung cancer and tuberculous cells in pleural fluid were studied by microscopic FTIR spectroscopy. Infrared spectra demonstrate significant spectral differences between normal, lung cancer and tuberculous cells. The ratio of the peak intensities of the 1030 and 1080 cm-1 bands (originated mainly in glycogen and phosphodiester groups of nucleic acids) differs greatly between normal and lung cancer samples. Such findings prompt the consideration that recording infrared spectra from lung cancer and tuberculous cells may be of diagnostic value. Since measurements of IR spectra of lung cancer cells in the pleural fluid can be a very rapid inexpensive process, our finding warrant exploration of this possibility in the investigation of the mechanism whereby the environmental pollution related cancers develop.

Hand ultrasound: a high-fidelity simulation of lung sliding.

PubMed

Shokoohi, Hamid; Boniface, Keith

2012-09-01

Simulation training has been effectively used to integrate didactic knowledge and technical skills in emergency and critical care medicine. In this article, we introduce a novel model of simulating lung ultrasound and the features of lung sliding and pneumothorax by performing a hand ultrasound. The simulation model involves scanning the palmar aspect of the hand to create normal lung sliding in varying modes of scanning and to mimic ultrasound features of pneumothorax, including "stratosphere/barcode sign" and "lung point." The simple, reproducible, and readily available simulation model we describe demonstrates a high-fidelity simulation surrogate that can be used to rapidly illustrate the signs of normal and abnormal lung sliding at the bedside. © 2012 by the Society for Academic Emergency Medicine.

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

Sattarivand, Mike; Summers, Clare; Robar, James

Purpose: To evaluate the validity of using spine as a surrogate for tumor positioning with ExacTrac stereoscopic imaging in lung stereotactic body radiation therapy (SBRT). Methods: Using the Novalis ExacTrac x-ray system, 39 lung SBRT patients (182 treatments) were aligned before treatment with 6 degrees (6D) of freedom couch (3 translations, 3 rotations) based on spine matching on stereoscopic images. The couch was shifted to treatment isocenter and pre-treatment CBCT was performed based on a soft tissue match around tumor volume. The CBCT data were used to measure residual errors following ExacTrac alignment. The thresholds for re-aligning the patients basedmore » on CBCT were 3mm shift or 3° rotation (in any 6D). In order to evaluate the effect of tumor location on residual errors, correlations between tumor distance from spine and individual residual errors were calculated. Results: Residual errors were up to 0.5±2.4mm. Using 3mm/3° thresholds, 80/182 (44%) of the treatments required re-alignment based on CBCT soft tissue matching following ExacTrac spine alignment. Most mismatches were in sup-inf, ant-post, and roll directions which had larger standard deviations. No correlation was found between tumor distance from spine and individual residual errors. Conclusion: ExacTrac stereoscopic imaging offers a quick pre-treatment patient alignment. However, bone matching based on spine is not reliable for aligning lung SBRT patients who require soft tissue image registration from CBCT. Spine can be a poor surrogate for lung SBRT patient alignment even for proximal tumor volumes.« less

Automated pulmonary lobar ventilation measurements using volume-matched thoracic CT and MRI

NASA Astrophysics Data System (ADS)

Guo, F.; Svenningsen, S.; Bluemke, E.; Rajchl, M.; Yuan, J.; Fenster, A.; Parraga, G.

2015-03-01

Objectives: To develop and evaluate an automated registration and segmentation pipeline for regional lobar pulmonary structure-function measurements, using volume-matched thoracic CT and MRI in order to guide therapy. Methods: Ten subjects underwent pulmonary function tests and volume-matched 1H and 3He MRI and thoracic CT during a single 2-hr visit. CT was registered to 1H MRI using an affine method that incorporated block-matching and this was followed by a deformable step using free-form deformation. The resultant deformation field was used to deform the associated CT lobe mask that was generated using commercial software. 3He-1H image registration used the same two-step registration method and 3He ventilation was segmented using hierarchical k-means clustering. Whole lung and lobar 3He ventilation and ventilation defect percent (VDP) were generated by mapping ventilation defects to CT-defined whole lung and lobe volumes. Target CT-3He registration accuracy was evaluated using region- , surface distance- and volume-based metrics. Automated whole lung and lobar VDP was compared with semi-automated and manual results using paired t-tests. Results: The proposed pipeline yielded regional spatial agreement of 88.0+/-0.9% and surface distance error of 3.9+/-0.5 mm. Automated and manual whole lung and lobar ventilation and VDP were not significantly different and they were significantly correlated (r = 0.77, p < 0.0001). Conclusion: The proposed automated pipeline can be used to generate regional pulmonary structural-functional maps with high accuracy and robustness, providing an important tool for image-guided pulmonary interventions.

Protanomaly-without-darkened-red is deuteranopia with rods

PubMed Central

Shevell, Steven K.; Sun, Yang; Neitz, Maureen

2008-01-01

The Rayleigh match, a color match between a mixture of 545+670 nm lights and 589 nm light in modern instruments, is the definitive measurement for the diagnosis of inherited red/green color defects. All trichromats, whether normal or anomalous, have a limited range of 545+670 nm mixtures they perceive to match 589 nm: a typical color-normal match-range is about 50–55% of 670 nm in the mixture (deutan mode), while deuteranomals have a range that includes mixtures with less 670 nm than normal and protanomals a range that includes mixtures with more 670 nm than normal. Further, the matching luminance of the 589 nm light for deuteranomals is the same as for normals but for protanomals is below normal. An example of an unexpected Rayleigh match, therefore, is a match range above normal (typical of protanomaly) and a normal luminance setting for 589 nm (typical of deuteranomaly), a match that Pickford (1950) called protanomaly “when the red end of the spectrum is not darkened”. In this case, Rayleigh matching does not yield a clear diagnosis. Aside from Pickford, we are aware of only one other report of a similar observer (Pokorny and Smith, 1981); this study predated modern genetic techniques that can reveal the cone photopigment(s) in the red/green range. We recently had the opportunity to conduct genetic and psychophysical tests on such an observer. Genetic results predict he is a deuteranope. His Rayleigh match is consistent with L cones and a contribution from rods. Further, with a rod-suppressing background, his Rayleigh match is characteristic of a single L-cone photopigment (deuteranopia). PMID:18423511

Protanomaly without darkened red is deuteranopia with rods.

PubMed

Shevell, Steven K; Sun, Yang; Neitz, Maureen

2008-11-01

The Rayleigh match, a color match between a mixture of 545+670 nm lights and 589 nm light in modern instruments, is the definitive measurement for the diagnosis of inherited red-green color defects. All trichromats, whether normal or anomalous, have a limited range of 545+670 nm mixtures they perceive to match 589 nm: a typical color-normal match range is about 50-55% of 670 nm in the mixture (deutan mode), while deuteranomals have a range that includes mixtures with less 670 nm than normal and protanomals a range that includes mixtures with more 670 nm than normal. Further, the matching luminance of the 589 nm light for deuteranomals is the same as for normals but for protanomals is below normal. An example of an unexpected Rayleigh match, therefore, is a match range above normal (typical of protanomaly) and a normal luminance setting for 589 nm (typical of deuteranomaly), a match called protanomaly "when the red end of the spectrum is not darkened" [Pickford, R.W. (1950). Three pedigrees for color blindness. Nature, 165, 182.]. In this case, Rayleigh matching does not yield a clear diagnosis. Aside from Pickford, we are aware of only one other report of a similar observer [Pokorny, J., & Smith, V. C. (1981). A variant of red-green color defect. Vision Research, 21, 311-317]; this study predated modern genetic techniques that can reveal the cone photopigment(s) in the red-green range. We recently had the opportunity to conduct genetic and psychophysical tests on such an observer. Genetic results predict he is a deuteranope. His Rayleigh match is consistent with L cones and a contribution from rods. Further, with a rod-suppressing background, his Rayleigh match is characteristic of a single L-cone photopigment (deuteranopia).

[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.

Computerized scheme for detection of diffuse lung diseases on CR chest images

NASA Astrophysics Data System (ADS)

Pereira, Roberto R., Jr.; Shiraishi, Junji; Li, Feng; Li, Qiang; Doi, Kunio

2008-03-01

We have developed a new computer-aided diagnostic (CAD) scheme for detection of diffuse lung disease in computed radiographic (CR) chest images. One hundred ninety-four chest images (56 normals and 138 abnormals with diffuse lung diseases) were used. The 138 abnormal cases were classified into three levels of severity (34 mild, 60 moderate, and 44 severe) by an experienced chest radiologist with use of five different patterns, i.e., reticular, reticulonodular, nodular, air-space opacity, and emphysema. In our computerized scheme, the first moment of the power spectrum, the root-mean-square variation, and the average pixel value were determined for each region of interest (ROI), which was selected automatically in the lung fields. The average pixel value and its dependence on the location of the ROI were employed for identifying abnormal patterns due to air-space opacity or emphysema. A rule-based method was used for determining three levels of abnormality for each ROI (0: normal, 1: mild, 2: moderate, and 3: severe). The distinction between normal lungs and abnormal lungs with diffuse lung disease was determined based on the fractional number of abnormal ROIs by taking into account the severity of abnormalities. Preliminary results indicated that the area under the ROC curve was 0.889 for the 44 severe cases, 0.825 for the 104 severe and moderate cases, and 0.794 for all cases. We have identified a number of problems and reasons causing false positives on normal cases, and also false negatives on abnormal cases. In addition, we have discussed potential approaches for improvement of our CAD scheme. In conclusion, the CAD scheme for detection of diffuse lung diseases based on texture features extracted from CR chest images has the potential to assist radiologists in their interpretation of diffuse lung diseases.

Patterns of Growth and Decline in Lung Function in Persistent Childhood Asthma.

PubMed

McGeachie, M J; Yates, K P; Zhou, X; Guo, F; Sternberg, A L; Van Natta, M L; Wise, R A; Szefler, S J; Sharma, S; Kho, A T; Cho, M H; Croteau-Chonka, D C; Castaldi, P J; Jain, G; Sanyal, A; Zhan, Y; Lajoie, B R; Dekker, J; Stamatoyannopoulos, J; Covar, R A; Zeiger, R S; Adkinson, N F; Williams, P V; Kelly, H W; Grasemann, H; Vonk, J M; Koppelman, G H; Postma, D S; Raby, B A; Houston, I; Lu, Q; Fuhlbrigge, A L; Tantisira, K G; Silverman, E K; Tonascia, J; Weiss, S T; Strunk, R C

2016-05-12

Tracking longitudinal measurements of growth and decline in lung function in patients with persistent childhood asthma may reveal links between asthma and subsequent chronic airflow obstruction. We classified children with asthma according to four characteristic patterns of lung-function growth and decline on the basis of graphs showing forced expiratory volume in 1 second (FEV1), representing spirometric measurements performed from childhood into adulthood. Risk factors associated with abnormal patterns were also examined. To define normal values, we used FEV1 values from participants in the National Health and Nutrition Examination Survey who did not have asthma. Of the 684 study participants, 170 (25%) had a normal pattern of lung-function growth without early decline, and 514 (75%) had abnormal patterns: 176 (26%) had reduced growth and an early decline, 160 (23%) had reduced growth only, and 178 (26%) had normal growth and an early decline. Lower baseline values for FEV1, smaller bronchodilator response, airway hyperresponsiveness at baseline, and male sex were associated with reduced growth (P<0.001 for all comparisons). At the last spirometric measurement (mean [±SD] age, 26.0±1.8 years), 73 participants (11%) met Global Initiative for Chronic Obstructive Lung Disease spirometric criteria for lung-function impairment that was consistent with chronic obstructive pulmonary disease (COPD); these participants were more likely to have a reduced pattern of growth than a normal pattern (18% vs. 3%, P<0.001). Childhood impairment of lung function and male sex were the most significant predictors of abnormal longitudinal patterns of lung-function growth and decline. Children with persistent asthma and reduced growth of lung function are at increased risk for fixed airflow obstruction and possibly COPD in early adulthood. (Funded by the Parker B. Francis Foundation and others; ClinicalTrials.gov number, NCT00000575.).

Contribution of Fetal, but Not Adult, Pulmonary Mesothelium to Mesenchymal Lineages in Lung Homeostasis and Fibrosis.

PubMed

von Gise, Alexander; Stevens, Sean M; Honor, Leah B; Oh, Jin Hee; Gao, Chi; Zhou, Bin; Pu, William T

2016-02-01

The lung is enveloped by a layer of specialized epithelium, the pulmonary mesothelium. In other organs, mesothelial cells undergo epithelial-mesenchymal transition and contribute to organ stromal cells. The contribution of pulmonary mesothelial cells (PMCs) to the developing lung has been evaluated with differing conclusions. PMCs have also been indirectly implicated in lung fibrosis in the progressive, fatal lung disease idiopathic pulmonary fibrosis. We used fetal or postnatal genetic pulse labeling of PMCs to assess their fate in murine development, normal lung homeostasis, and models of pulmonary fibrosis. We found that most fetal PMC-derived mesenchymal cells (PMCDCs) expressed markers of pericytes and fibroblasts, only a small minority expressed smooth muscle markers, and none expressed endothelial cell markers. Postnatal PMCs did not contribute to lung mesenchyme during normal lung homeostasis or in models of lung fibrosis. However, fetal PMCDCs were abundant and actively proliferating within fibrotic regions in lung fibrosis models, suggesting that they actively participate in the fibrotic process. These data clarify the role of fetal and postnatal PMCDCs in lung development and disease.

Modeling of lung cancer risk due to radon exhalation of granite stone in dwelling houses.

PubMed

Abbasi, Akbar

2017-01-01

Due to increasing occurrences of lung cancer, radon exhalation rates, radon concentrations, and lung cancer risks in several types of commonly used granite stone, samples used for flooring in buildings, have been investigated. We measured the radon exhalation rates due to granite stones by means of an AlphaGUARD Model PQ2000 in a cube container with changeable floor by various granite stones. The lung cancer risk and percentage of lung cancer deaths (LCRn) due to those conditions were calculated using Darby's model. The radon exhalation rates ranged from 1.59 ± 0.41 to 9.43 ± 0.74 Bq/m 2/h. The radon concentrations in the standard room with poor and normal ventilation were calculated 20.10-71.09 Bq/m 3 and 16.12-47.01 Bq/m 3, respectively. The estimated numbers of lung cancer deaths attributable to indoor radon due to granite stones in 2013 were 145 (3.33%) and 103 (2.37%) for poor and normal ventilation systems, respectively. According to our estimations, the values of 3.33% and 2.37% of lung cancer deaths in 2013 are attributed to radon exhalation of granite stones with poor and normal ventilation systems, respectively.

Lung lobe segmentation based on statistical atlas and graph cuts

NASA Astrophysics Data System (ADS)

Nimura, Yukitaka; Kitasaka, Takayuki; Honma, Hirotoshi; Takabatake, Hirotsugu; Mori, Masaki; Natori, Hiroshi; Mori, Kensaku

2012-03-01

This paper presents a novel method that can extract lung lobes by utilizing probability atlas and multilabel graph cuts. Information about pulmonary structures plays very important role for decision of the treatment strategy and surgical planning. The human lungs are divided into five anatomical regions, the lung lobes. Precise segmentation and recognition of lung lobes are indispensable tasks in computer aided diagnosis systems and computer aided surgery systems. A lot of methods for lung lobe segmentation are proposed. However, these methods only target the normal cases. Therefore, these methods cannot extract the lung lobes in abnormal cases, such as COPD cases. To extract lung lobes in abnormal cases, this paper propose a lung lobe segmentation method based on probability atlas of lobe location and multilabel graph cuts. The process consists of three components; normalization based on the patient's physique, probability atlas generation, and segmentation based on graph cuts. We apply this method to six cases of chest CT images including COPD cases. Jaccard index was 79.1%.

LINKING LUNG AIRWAY STRUCTURE TO PULMONARY FUNCTION VIA COMPOSITE BRIDGE REGRESSION

PubMed Central

Chen, Kun; Hoffman, Eric A.; Seetharaman, Indu; Jiao, Feiran; Lin, Ching-Long; Chan, Kung-Sik

2017-01-01

The human lung airway is a complex inverted tree-like structure. Detailed airway measurements can be extracted from MDCT-scanned lung images, such as segmental wall thickness, airway diameter, parent-child branch angles, etc. The wealth of lung airway data provides a unique opportunity for advancing our understanding of the fundamental structure-function relationships within the lung. An important problem is to construct and identify important lung airway features in normal subjects and connect these to standardized pulmonary function test results such as FEV1%. Among other things, the problem is complicated by the fact that a particular airway feature may be an important (relevant) predictor only when it pertains to segments of certain generations. Thus, the key is an efficient, consistent method for simultaneously conducting group selection (lung airway feature types) and within-group variable selection (airway generations), i.e., bi-level selection. Here we streamline a comprehensive procedure to process the lung airway data via imputation, normalization, transformation and groupwise principal component analysis, and then adopt a new composite penalized regression approach for conducting bi-level feature selection. As a prototype of composite penalization, the proposed composite bridge regression method is shown to admit an efficient algorithm, enjoy bi-level oracle properties, and outperform several existing methods. We analyze the MDCT lung image data from a cohort of 132 subjects with normal lung function. Our results show that, lung function in terms of FEV1% is promoted by having a less dense and more homogeneous lung comprising an airway whose segments enjoy more heterogeneity in wall thicknesses, larger mean diameters, lumen areas and branch angles. These data hold the potential of defining more accurately the “normal” subject population with borderline atypical lung functions that are clearly influenced by many genetic and environmental factors. PMID:28280520

Intermittent Fluorescence Oscillations in Lipid Droplets in a Live Normal and Lung Cancer Cell: Time-Resolved Confocal Microscopy.

PubMed

Chowdhury, Rajdeep; Amin, Md Asif; Bhattacharyya, Kankan

2015-08-27

Intermittent structural oscillation in the lipid droplets of live lung cells is monitored using time-resolved confocal microscopy. Significant differences are observed between the lung cancer cell (A549) and normal (nonmalignant) lung cell (WI38). For this study, the lipid droplets are covalently labeled with a fluorescent dye, coumarin maleimide (7-diethylamino-3-(4-maleimido-phenyl)-4-methylcoumarin, CPM). The number of lipid droplets in the cancer cell is found to be ∼20-fold higher than that in the normal (nonmalignant) cell. The fluctuation in the fluorescence intensity of the dye (CPM) is attributed to the red-ox processes and periodic formation/rupture of the S-CPM bond. The amount of reactive oxygen species (ROS) is much higher in a cancer cell. This is manifested in faster oscillations (0.9 ± 0.3 s) in cancer cells compared to that in the normal cells (2.8 ± 0.7 s). Solvation dynamics in the lipid droplets of cancer cells is slower compared to that in the normal cell.

A propensity score-matched comparison of the efficacies of OK-432 and talc slurry for pleurodesis for malignant pleural effusion induced by lung adenocarcinoma.

PubMed

Nohara, Kango; Takada, Kazuto; Kojima, Eiji; Ninomiya, Kiyoko; Miyamatsu, Shoko; Shimizu, Takahiro; Sakurai, Tsutomu; Mizuno, Takaaki; Yamashita, Yuuki

2016-09-01

The choice of an optimal sclerosant for pleurodesis for malignant pleural effusion remains controversial. This retrospective clinical study compared the efficacy and safety of two sclerosants; talc slurry (talc-s) and OK-432. We compared the characteristics, 30/90-day success rates, and adverse events in patients with lung adenocarcinoma who underwent pleurodesis by using either OK-432 or talc-s. Propensity score matching was used to compare the two scelrosants. Ninety-four patients (mean age=71.6±9.6 years) were included in this retrospective study, of whom 64 received OK-432 and 30 received talc-s. Seventy-three patients (77.6%) were initially diagnosed with clinical stage IV lung cancer, with a 28.7% epidermal growth factor receptor mutation frequency. The propensity score-matched cohort included 26 patients from each group. The 30-day success rates for OK-432 and talc-s were 80.7% and 76.9%, respectively (odds ratio: 1.26, 95% confidence interval: 0.33-4.77, p=0.73). Neither the overall incidence of adverse events nor the 90-day success rates differed significantly. Multivariate logistic regression revealed that the predictors of 30-day success were lower drainage volume on the previous day, particularly <250mL/day, the presence of full lung expansion, and pre-therapy with an epidermal growth factor receptor-tyrosine kinase inhibitor. The median post-pleurodesis survival time was 6.9 months, which was not significantly different between the study groups. Propensity score-matched analyses showed that pleurodesis using OK-432 and talc-s demonstrated comparable efficacy and safety profiles in patients with lung adenocarcinoma. This indicated that OK-432 could be a viable alternative to talc-s in this procedure. Copyright © 2016. Published by Elsevier B.V.

STATs in Lung Development: Distinct Early and Late Expression, Growth Modulation and Signaling Dysregulation in Congenital Diaphragmatic Hernia.

PubMed

Piairo, Paulina; Moura, Rute S; Baptista, Maria João; Correia-Pinto, Jorge; Nogueira-Silva, Cristina

2018-01-01

Congenital diaphragmatic hernia (CDH) is a life-threatening developmental anomaly, intrinsically combining severe pulmonary hypoplasia and hypertension. During development, signal transducers and activators of transcription (STAT) are utilized to elicit cell growth, differentiation, and survival. We used the nitrofen-induced CDH rat model. At selected gestational time points, lungs were divided into two experimental groups, i.e., control or CDH. We performed immunohistochemistry and western blotting analysis to investigate the developmental expression profile of the complete family of STATs (STAT1-6), plus specific STATs activation (p-STAT3, p-STAT6) and regulation by SOCS (SOCS3) in normal lungs against those of diseased lungs. The normal fetal lung explants were treated with piceatannol (STAT3 inhibitor) in vitro followed by morphometrical analysis. Molecular profiling of STATs during the lung development revealed distinct early and late expression signatures. Experimental CDH altered the STATs expression, activation, and regulation in the fetal lungs. In particular, STAT3 and STAT6 were persistently over-expressed and early over-activated. Piceatannol treatment dose-dependently stimulated the fetal lung growth. These findings suggest that STATs play an important role during normal fetal lung development and CDH pathogenesis. Moreover, functionally targeting STAT signaling modulates fetal lung growth, which highlights that STAT3 and STAT6 signaling might be promising therapeutic targets in reducing or preventing pulmonary hypoplasia in CDH. © 2018 The Author(s). Published by S. Karger AG, Basel.

Quantitative features in the computed tomography of healthy lungs.

PubMed Central

Fromson, B H; Denison, D M

1988-01-01

This study set out to determine whether quantitative features of lung computed tomography scans could be identified that would lead to a tightly defined normal range for use in assessing patients. Fourteen normal subjects with apparently healthy lungs were studied. A technique was developed for rapid and automatic extraction of lung field data from the computed tomography scans. The Hounsfield unit histograms were constructed and, when normalised for predicted lung volumes, shown to be consistent in shape for all the subjects. A three dimensional presentation of the data in the form of a "net plot" was devised, and from this a logarithmic relationship between the area of each lung slice and its mean density was derived (r = 0.9, n = 545, p less than 0.0001). The residual density, calculated as the difference between measured density and density predicted from the relationship with area, was shown to be normally distributed with a mean of 0 and a standard deviation of 25 Hounsfield units (chi 2 test: p less than 0.05). A presentation combining this residual density with the net plot is described. PMID:3353883

The Evolving MCART Multimodal Imaging Core: Establishing a protocol for Computed Tomography and Echocardiography in the Rhesus macaque to perform longitudinal analysis of radiation-induced organ injury

PubMed Central

de Faria, Eduardo B.; Barrow, Kory R.; Ruehle, Bradley T.; Parker, Jordan T.; Swartz, Elisa; Taylor-Howell, Cheryl; Kieta, Kaitlyn M.; Lees, Cynthia J.; Sleeper, Meg M.; Dobbin, Travis; Baron, Adam D.; Mohindra, Pranshu; MacVittie, Thomas J.

2015-01-01

Computed Tomography (CT) and Echocardiography (EC) are two imaging modalities that produce critical longitudinal data that can be analyzed for radiation-induced organ-specific injury to the lung and heart. The Medical Countermeasures Against Radiological Threats (MCART) consortium has a well-established animal model research platform that includes nonhuman primate (NHP) models of the acute radiation syndrome and the delayed effects of acute radiation exposure. These models call for a definition of the latency, incidence, severity, duration, and resolution of different organ-specific radiation-induced subsyndromes. The pulmonary subsyndromes and cardiac effects are a pair of inter-dependent syndromes impacted by exposure to potentially lethal doses of radiation. Establishing a connection between these will reveal important information about their interaction and progression of injury and recovery. Herein, we demonstrate the use of CT and EC data in the rhesus macaque models to define delayed organ injury thereby establishing: a) consistent and reliable methodology to assess radiation-induced damage to the lung and heart, b) an extensive database in normal age-matched NHP for key primary and secondary endpoints, c) identified problematic variables in imaging techniques and proposed solutions to maintain data integrity and d) initiated longitudinal analysis of potentially lethal radiation-induced damage to the lung and heart. PMID:26425907

Dimethyl Sulfoxide Attenuates Acute Lung Injury Induced by Hemorrhagic Shock/Resuscitation in Rats.

PubMed

Tsung, Yu-Chi; Chung, Chih-Yang; Wan, Hung-Chieh; Chang, Ya-Ying; Shih, Ping-Cheng; Hsu, Han-Shui; Kao, Ming-Chang; Huang, Chun-Jen

2017-04-01

Inflammation following hemorrhagic shock/resuscitation (HS/RES) induces acute lung injury (ALI). Dimethyl sulfoxide (DMSO) possesses anti-inflammatory and antioxidative capacities. We sought to clarify whether DMSO could attenuate ALI induced by HS/RES. Male Sprague-Dawley rats were allocated to receive either a sham operation, sham plus DMSO, HS/RES, or HS/RES plus DMSO, and these were denoted as the Sham, Sham + DMSO, HS/RES, or HS/RES + DMSO group, respectively (n = 12 in each group). HS/RES was achieved by drawing blood to lower mean arterial pressure (40-45 mmHg for 60 min) followed by reinfusion with shed blood/saline mixtures. All rats received an intravenous injection of normal saline or DMSO immediately before resuscitation or at matching points relative to the sham groups. Arterial blood gas and histological assays (including histopathology, neutrophil infiltration, and lung water content) confirmed that HS/RES induced ALI. Significant increases in pulmonary expression of tumor necrosis factor-α (TNF-α), malondialdehyde, nuclear factor-kappa B (NF-κB), inducible nitric oxide synthase (iNOS), and cyclooxygenase 2 (COX-2) confirmed that HS/RES induced pulmonary inflammation and oxidative stress. DMSO significantly attenuated the pulmonary inflammation and ALI induced by HS/RES. The mechanisms for this may involve reducing inflammation and oxidative stress through inhibition of pulmonary NF-κB, TNF-α, iNOS, and COX-2 expression.

Correlation of 68Ga Ventilation-Perfusion PET/CT with Pulmonary Function Test Indices for Assessing Lung Function.

PubMed

Le Roux, Pierre-Yves; Siva, Shankar; Steinfort, Daniel P; Callahan, Jason; Eu, Peter; Irving, Lou B; Hicks, Rodney J; Hofman, Michael S

2015-11-01

Pulmonary function tests (PFTs) are routinely used to assess lung function, but they do not provide information about regional pulmonary dysfunction. We aimed to assess correlation of quantitative ventilation-perfusion (V/Q) PET/CT with PFT indices. Thirty patients underwent V/Q PET/CT and PFT. Respiration-gated images were acquired after inhalation of (68)Ga-carbon nanoparticles and administration of (68)Ga-macroaggregated albumin. Functional volumes were calculated by dividing the volume of normal ventilated and perfused (%NVQ), unmatched and matched defects by the total lung volume. These functional volumes were correlated with forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), FEV1/FVC, and diffusing capacity for carbon monoxide (DLCO). All functional volumes were significantly different in patients with chronic obstructive pulmonary disease (P < 0.05). FEV1/FVC and %NVQ had the highest correlation (r = 0.82). FEV1 was also best correlated with %NVQ (r = 0.64). DLCO was best correlated with the volume of unmatched defects (r = -0.55). Considering %NVQ only, a cutoff value of 90% correctly categorized 28 of 30 patients with or without significant pulmonary function impairment. Our study demonstrates strong correlations between V/Q PET/CT functional volumes and PFT parameters. Because V/Q PET/CT is able to assess regional lung function, these data support the feasibility of its use in radiation therapy and preoperative planning and assessing pulmonary dysfunction in a variety of respiratory diseases. © 2015 by the Society of Nuclear Medicine and Molecular Imaging, Inc.

SU-E-J-18: Evaluation of the Effectiveness of Compression Methods in SBRT for Lung.

PubMed

Liao, Y; Tolekids, G; Yao, R; Templeton, A; Sensakovic, W; Chu, J

2012-06-01

This study aims to evaluate the effectiveness of compression in immobilizing tumor during stereotactic body radiotherapy (SBRT) for lung cancer. Published data have demonstrated bigger respiratory motion in lower lobe than in upper lobe during normal breathing. We hypothesize that 4DCT-based patient selection and abdominal compression would immobilize lung tumor volumes effectively, regardless of their location. We retrospectively reviewed 12 SBRT lung cases treated with Trilogy® (Varian Medical System, Palo Alto, CA). Either compression plate or Vac-LokTM was used as abdomen compression of the SBRT immobilization system (Body Pro-LokTM, CIVCO) to restrict patients' breathing during CT simulation and treatment delivery. These cases are grouped into 2 categories: lower and upper lobe tumor, each with 6 cases. Records for 33 treatments were studied. On each treatment day, the patient was set up to the bony anatomy using kV-kV-match. A CBCT was performed to further set up the patient to the tumor based on the soft tissue information. The shifts from CBCT-setup were analyzed as displacement vectors demonstrating the magnitude of the tumor motion relative to the bony anatomy. The mean magnitude of displacement vectors for upper lobe and lower lobe were 3.7±2.7 and 4.2±6.3, [1S.D.] mm, respectively. The Wilcoxon rank sum test indicates that the difference in the displacement vector between the two groups is not statistically significant (p-value = 0.33). The magnitude of shifts from CBCT were small with mean value <5mm in SBRT lung treatments. No statistically significant difference were observed in the displacement of tumor between lower and upper lobes. With limited sample size, this suggests that our current 4DCT screening/abdominal compression approach is effective in restricting the respiration-induced tumor motion despite its location within the lung. We plan to confirm this Result in additional patients. © 2012 American Association of Physicists in Medicine.

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

Molecular Profiles for Lung Cancer Pathogenesis and Detection in U.S. Veterans

DTIC Science & Technology

2014-12-18

that the adjacent field cancerization extends to relatively less invasive large airways and harbors markers that can detect lung cancer in smokers ; 5...profiles have been described in the normal-appearing bronchial epithelium of healthy smokers (9) including those that were diagnostic of lung cancer...10). In addition, modulation of global gene expression in the normal epithelium in health smokers is similar in the large and small airways and the

SU-F-T-134: Can We Use the Same Dose Constrains Learnt From Photon World to Plan Proton for Lung Cancer?

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

Xiao, Z; Zou, J; Yue, N

Purpose: To evaluate if the same DVH constrains used in photon plans can be safely used to plan proton therapy for lung cancer. Since protons and photons have different dose deposition patterns, the hypothesis is following DVH constrains derived from photon world is not safe for proton. Methods: We retrospectively evaluated plans for 11 lung cancer patients. Each patient was planned with photon and proton following the same dose constrains. Dose statistics on PTV, normal lung, heart and esophagus were extracted for comparison. gEUD for normal lung was calculated and compared between proton and photon plans. We calculated series ofmore » gEUDs for each plan by varying the parameter “a” in gEUD formula from 0.1 to 3, covering the whole confidence interval. Results: For all patients, proton plans yield similar PTV coverage and lower dose to heart and esophagus than photon plans. Normal lung V5 was 32.3 % on average in proton plans than 55.4 % in photon. Normal lung gEUD monotonically increased with increasing “a” for all proton and photon plans. For a given patient, the gEUD-proton(a) had a steeper slope than gEUD-photon(a). The two curves crossed for 8 out of 11 patients when “a” = [0.1, 3]. a-crossing ranged from 0.8 to 2.44 with an average of 1.15. For a« less

Differential expression patterns of housekeeping genes increase diagnostic and prognostic value in lung cancer

PubMed Central

Chang, Yu-Chun; Ding, Yan; Dong, Lingsheng; Zhu, Lang-Jing; Jensen, Roderick V.

2018-01-01

Background Using DNA microarrays, we previously identified 451 genes expressed in 19 different human tissues. Although ubiquitously expressed, the variable expression patterns of these “housekeeping genes” (HKGs) could separate one normal human tissue type from another. Current focus on identifying “specific disease markers” is problematic as single gene expression in a given sample represents the specific cellular states of the sample at the time of collection. In this study, we examine the diagnostic and prognostic potential of the variable expressions of HKGs in lung cancers. Methods Microarray and RNA-seq data for normal lungs, lung adenocarcinomas (AD), squamous cell carcinomas of the lung (SQCLC), and small cell carcinomas of the lung (SCLC) were collected from online databases. Using 374 of 451 HKGs, differentially expressed genes between pairs of sample types were determined via two-sided, homoscedastic t-test. Principal component analysis and hierarchical clustering classified normal lung and lung cancers subtypes according to relative gene expression variations. We used uni- and multi-variate cox-regressions to identify significant predictors of overall survival in AD patients. Classifying genes were selected using a set of training samples and then validated using an independent test set. Gene Ontology was examined by PANTHER. Results This study showed that the differential expression patterns of 242, 245, and 99 HKGs were able to distinguish normal lung from AD, SCLC, and SQCLC, respectively. From these, 70 HKGs were common across the three lung cancer subtypes. These HKGs have low expression variation compared to current lung cancer markers (e.g., EGFR, KRAS) and were involved in the most common biological processes (e.g., metabolism, stress response). In addition, the expression pattern of 106 HKGs alone was a significant classifier of AD versus SQCLC. We further highlighted that a panel of 13 HKGs was an independent predictor of overall survival and cumulative risk in AD patients. Discussion Here we report HKG expression patterns may be an effective tool for evaluation of lung cancer states. For example, the differential expression pattern of 70 HKGs alone can separate normal lung tissue from various lung cancers while a panel of 106 HKGs was a capable class predictor of subtypes of non-small cell carcinomas. We also reported that HKGs have significantly lower variance compared to traditional cancer markers across samples, highlighting the robustness of a panel of genes over any one specific biomarker. Using RNA-seq data, we showed that the expression pattern of 13 HKGs is a significant, independent predictor of overall survival for AD patients. This reinforces the predictive power of a HKG panel across different gene expression measurement platforms. Thus, we propose the expression patterns of HKGs alone may be sufficient for the diagnosis and prognosis of individuals with lung cancer. PMID:29761043

Lung gallium scan

MedlinePlus

... the lungs. This is most often due to sarcoidosis or a certain type of pneumonia. Normal Results ... it may mean any of the following problems: Sarcoidosis (disease in which inflammation occurs in the lungs ...

Tissue-dependent differences in the asynchronous appearance of mast cells in normal mice and in congenic mast cell-deficient mice after infusion of normal bone marrow cells

PubMed Central

DU, T; FRIEND, D S; AUSTEN, K F; KATZ, H R

1996-01-01

The time courses of the appearance of tissue mast cells in six sites were compared in normal WBB6F1-+/+ mice (+/+) and in congenic mast cell-deficient WBB6F1-W/Wv mice (W/Wv) that received an intravenous infusion of bone marrow cells from +/+mice (BM→W/Wv). As assessed by morphometric analysis of Carnoy's solution-fixed, methylene blue-stained tissue sections, the density of mast cells in the stomach mucosa, stomach submucosa, and spleen of +/+ mice reached maximal levels by 8 weeks of age, whereas the density of mast cells in the skin, extraparenchymal airway walls, and lung parenchyma did not reach maximal levels until 18 weeks of age. When 8-week-old W/Wv mice were infused with 2×107 bone marrow cells from +/+ mice, mast cells appeared in the stomach mucosa and submucosa after 2.5 weeks, in the spleen and extraparenchymal airway walls after 5 weeks, and in the lung parenchyma after 10 weeks. Twenty weeks after bone marrow infusion, the mast cell densities in the spleen, stomach mucosa, and stomach submucosa were seven-, 13-, and five-fold greater, respectively, than those in age-matched +/+ mice, but were eight-, two-, and five-fold lower in the skin, extraparenchymal airway walls, and lung parenchyma, respectively. Thus, those tissues that in +/+ mice reached maximal mast cell densities earlier exhibited abnormally high mast cell densities in BM→W/Wv mice, and those that reached maximal mast cell densities later in +/+ mice had abnormally low mast cell densities in BM→W/Wv mice. Immunological and inflammatory responses are often compared in W/Wv and BM→W/Wv mice to assess mast cell dependency. Our results indicate that the capacity to restore a mast cell-dependent response in a particular tissue of the latter mice may relate to the local mast cell density and whether the immunological challenge activates mast cells only in that tissue or systematically with attendant widespread release of proinflammatory mediators. PMID:8565318

Association of High-Dose Ibuprofen Use, Lung Function Decline, and Long-Term Survival in Children with Cystic Fibrosis.

PubMed

Konstan, Michael W; VanDevanter, Donald R; Sawicki, Gregory S; Pasta, David J; Foreman, Aimee J; Neiman, Evgueni A; Morgan, Wayne J

2018-04-01

Cystic fibrosis deaths result primarily from lung function loss, so chronic respiratory therapies, intended to preserve lung function, are cornerstones of cystic fibrosis care. Although treatment-associated reduction in rate of lung function loss should ultimately improve cystic fibrosis survival, no such relationship has been described for any chronic cystic fibrosis therapy. In part, this is because the ages of most rapid lung function decline-early adolescence-precede the median age of cystic fibrosis deaths by more than a decade. To study associations of high-dose ibuprofen treatment with the rate of forced expiratory volume in 1 second decline and mortality among children followed in the Epidemiologic Study of Cystic Fibrosis and subsequently in the U.S. Cystic Fibrosis Foundation Patient Registry. We performed a matched cohort study using data from Epidemiologic Study of Cystic Fibrosis. Exposure was defined as high-dose ibuprofen use reported at ≥80% of encounters over 2 years. Unexposed children were matched to exposed children 5:1 using propensity scores on the basis of demographic, clinical, and treatment covariates. The rate of decline of percent predicted forced expiratory volume in 1 second during the 2-year follow-up period was estimated by mixed-effects modeling with random slopes and intercepts. Survival over 16 follow-up years in the U.S. Cystic Fibrosis Foundation Patient Registry was compared between treatment groups by using proportional hazards modeling controlling for matching and covariates. We included 775 high-dose ibuprofen users and 3,665 nonusers who were well matched on demographic, clinical, and treatment variables. High-dose ibuprofen users declined on average 1.10 percent predicted forced expiratory volume in 1 second/yr (95% confidence interval; 0.51, 1.69) during the 2-year treatment period, whereas nonusers declined at a rate of 1.76% percent predicted forced expiratory volume in 1 second/yr (95% confidence interval; 1.48, 2.04) during the corresponding 2-year period, a 37.5% slower decline among users compared with nonusers (95% confidence interval; 0.4%, 71.3%; P = 0.046). The users had better subsequent survival (P < 0.001): the unadjusted and adjusted hazard ratios for mortality (high-dose ibuprofen/non-high-dose ibuprofen) (95% confidence interval) were 0.75 (0.64, 0.87) and 0.82 (0.69, 0.96). In a propensity-score matched cohort study of children with cystic fibrosis, we observed an association between high-dose ibuprofen use and both slower lung function decline and improved long-term survival. These results are consistent with the hypothesis that treatment-associated reduction of lung function decline in children with cystic fibrosis leads to improved survival.

Inactivation of LLC1 gene in nonsmall cell lung cancer

PubMed Central

Hong, Kyeong-Man; Yang, Sei-Hoon; Chowdhuri, Sinchita R.; Player, Audrey; Hames, Megan; Fukuoka, Junya; Meerzaman, Daoud; Dracheva, Tatiana; Sun, Zhifu; Yang, Ping; Jen, Jin

2007-01-01

Serial analysis of gene expression studies led us to identify a previously unknown gene, c20orf85, that is present in the normal lung epithelium, but absent or downregulated in most primary non-small cell lung cancers and lung cancer cell lines. We named this gene LLC1 for Low in Lung Cancer 1. LLC1 is located on chromosome 20q13.3 and has a 70% GC content in the promoter region. It has 4 exons and encodes a protein containing 137 amino acids. By in situ hybridization, we observed that LLC1 message is localized in normal lung bronchial epithelial cells, but absent in 13 of 14 lung adenocarcinoma and 9 out of 10 lung squamous carcinoma samples. Methylation at CpG sites of the LLC1 promoter was frequently observed in lung cancer cell lines and in a fraction of primary lung cancer tissues. Treatment with 5-aza deoxycytidine resulted in a reduced methylation of the LLC1 promoter concomitant with the increase of LLC1 expression. These results suggest that inactivation of LLC1 by means of promoter methylation is a frequent event in nonsmall cell lung cancer and may play a role in lung tumorigenesis. PMID:17304513

Protein regulator of cytokinesis-1 expression: prognostic value in lung squamous cell carcinoma patients

PubMed Central

Zhan, Ping; Xi, Guang-Min; Liu, Hong-Bing; Liu, Ya-Fang; Xu, Wu-Jian; Zhu, Qingqing; Zhou, Ze-Jun; Miao, Ying-Ying; Wang, Xiao-Xia; Jin, Jia-Jia

2017-01-01

Background Protein regulator of cytokinesis-1 (PRC1) has been shown to participate in the completion of cytokinesis, and it is dysregulated in cancer processes. However, its relevance in lung squamous cell carcinoma (SCC) remained largely unknown. We aimed to study the expression pattern of PRC1 and assess its clinical significance in lung SCC. Methods PRC1 protein expression in human lung SCC and adjacent normal lung tissues was detected by immunohistochemistry. PRC1 expression was assessed in association with clinicopathological features and clinical outcomes of lung SCC patients. Results In lung SCC tissues, PRC1 protein expression was significantly higher than those in paired normal lung tissues. The lung SCC patients with PRC1 overexpression had an advanced pathological stage (TNM stage), positive lymph node metastasis, and a shorter overall survival (OS) time more frequently than patients with low PRC1 expression. Additional, PRC1 expression was also shown to be poor as a prognostic factor for OS in patients with lung SCC. Conclusions Our study indicated that aberrant expression of PRC1 may point to biochemical recurrence in lung SCC. This highlights its potential as a valuable prognostic marker for lung SCC. PMID:28840006

MOLECULAR AND CYTOGENETIC ANALYSIS OF LUNG TUMOR CELL LINES

EPA Science Inventory

We have measured the levels of amplification of oncogenes and tumor marker genes or other genes of interest in nine human lung tumor cell lines in comparison to normal human bronchial epithelial cells or normal blood lymphocytes to test the hypothesis that aberrant amplification ...

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

Che, Magnus M.; Conti, Michele; Chanda, Soma

We evaluated the protective efficacy of nasal atropine methyl bromide (AMB) which does not cross the blood-brain barrier against sarin inhalation exposure. Age and weight matched male guinea pigs were exposed to 846.5 mg/m{sup 3} sarin using a microinstillation inhalation exposure technique for 4 min. The survival rate at this dose was 20%. Post-exposure treatment with nasal AMB (2.5 mg/kg, 1 min) completely protected against sarin induced toxicity (100% survival). Development of muscular tremors was decreased in animals treated with nasal AMB. Post-exposure treatment with nasal AMB also normalized acute decrease in blood oxygen saturation and heart rate following sarinmore » exposure. Inhibition of blood AChE and BChE activities following sarin exposure was reduced in animals treated with nasal AMB, indicating that survival increases the metabolism of sarin or expression of AChE. The body weight loss of animals exposed to sarin and treated with nasal AMB was similar to saline controls. No differences were observed in lung accessory lobe or tracheal edema following exposure to sarin and subsequent treatment with nasal AMB. Total bronchoalveolar lavage fluid (BALF) protein, a biomarker of lung injury, showed trends similar to saline controls. Surfactant levels post-exposure treatment with nasal AMB returned to normal, similar to saline controls. Alkaline phosphatase levels post-exposure treatment with nasal AMB were decreased. Taken together, these data suggest that nasal AMB blocks the copious airway secretion and peripheral cholinergic effects and protects against lethal inhalation exposure to sarin thus increasing survival.« less

An Integrated Analysis of miRNA and mRNA Expressions in Non-Small Cell Lung Cancers

PubMed Central

Ma, Lina; Huang, Yanyan; Zhu, Wangyu; Zhou, Shiquan; Zhou, Jihang; Zeng, Fang; Liu, Xiaoguang; Zhang, Yongkui; Yu, Jun

2011-01-01

Using DNA microarrays, we generated both mRNA and miRNA expression data from 6 non-small cell lung cancer (NSCLC) tissues and their matching normal control from adjacent tissues to identify potential miRNA markers for diagnostics. We demonstrated that hsa-miR-96 is significantly and consistently up-regulated in all 6 NSCLCs. We validated this result in an independent set of 35 paired tumors and their adjacent normal tissues, as well as their sera that are collected before surgical resection or chemotherapy, and the results suggested that hsa-miR-96 may play an important role in NSCLC development and has great potential to be used as a noninvasive marker for diagnosing NSCLC. We predicted potential miRNA target mRNAs based on different methods (TargetScan and miRanda). Further classification of miRNA regulated genes based on their relationship with miRNAs revealed that hsa-miR-96 and certain other miRNAs tend to down-regulate their target mRNAs in NSCLC development, which have expression levels permissive to direct interaction between miRNAs and their target mRNAs. In addition, we identified a significant correlation of miRNA regulation with genes coincide with high density of CpG islands, which suggests that miRNA may represent a primary regulatory mechanism governing basic cellular functions and cell differentiations, and such mechanism may be complementary to DNA methylation in repressing or activating gene expression. PMID:22046296

Volumetric Image Guidance Using Carina vs Spine as Registration Landmarks for Conventionally Fractionated Lung Radiotherapy

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

Lavoie, Caroline; Higgins, Jane; Bissonnette, Jean-Pierre

2012-12-01

Purpose: To compare the relative accuracy of 2 image guided radiation therapy methods using carina vs spine as landmarks and then to identify which landmark is superior relative to tumor coverage. Methods and Materials: For 98 lung patients, 2596 daily image-guidance cone-beam computed tomography scans were analyzed. Tattoos were used for initial patient alignment; then, spine and carina registrations were performed independently. A separate analysis assessed the adequacy of gross tumor volume, internal target volume, and planning target volume coverage on cone-beam computed tomography using the initial, middle, and final fractions of radiation therapy. Coverage was recorded for primary tumormore » (T), nodes (N), and combined target (T+N). Three scenarios were compared: tattoos alignment, spine registration, and carina registration. Results: Spine and carina registrations identified setup errors {>=}5 mm in 35% and 46% of fractions, respectively. The mean vector difference between spine and carina matching had a magnitude of 3.3 mm. Spine and carina improved combined target coverage, compared with tattoos, in 50% and 34% (spine) to 54% and 46% (carina) of the first and final fractions, respectively. Carina matching showed greater combined target coverage in 17% and 23% of fractions for the first and final fractions, respectively; with spine matching, this was only observed in 4% (first) and 6% (final) of fractions. Carina matching provided superior nodes coverage at the end of radiation compared with spine matching (P=.0006), without compromising primary tumor coverage. Conclusion: Frequent patient setup errors occur in locally advanced lung cancer patients. Spine and carina registrations improved combined target coverage throughout the treatment course, but carina matching provided superior combined target coverage.« less

SU-F-T-600: Influence of Acuros XB and AAA Dose Calculation Algorithms On Plan Quality Metrics and Normal Lung Doses in Lung SBRT

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

Yaparpalvi, R; Mynampati, D; Kuo, H

Purpose: To study the influence of superposition-beam model (AAA) and determinant-photon transport-solver (Acuros XB) dose calculation algorithms on the treatment plan quality metrics and on normal lung dose in Lung SBRT. Methods: Treatment plans of 10 Lung SBRT patients were randomly selected. Patients were prescribed to a total dose of 50-54Gy in 3–5 fractions (10?5 or 18?3). Doses were optimized accomplished with 6-MV using 2-arcs (VMAT). Doses were calculated using AAA algorithm with heterogeneity correction. For each plan, plan quality metrics in the categories- coverage, homogeneity, conformity and gradient were quantified. Repeat dosimetry for these AAA treatment plans was performedmore » using AXB algorithm with heterogeneity correction for same beam and MU parameters. Plan quality metrics were again evaluated and compared with AAA plan metrics. For normal lung dose, V{sub 20} and V{sub 5} to (Total lung- GTV) were evaluated. Results: The results are summarized in Supplemental Table 1. PTV volume was mean 11.4 (±3.3) cm{sup 3}. Comparing RTOG 0813 protocol criteria for conformality, AXB plans yielded on average, similar PITV ratio (individual PITV ratio differences varied from −9 to +15%), reduced target coverage (−1.6%) and increased R50% (+2.6%). Comparing normal lung doses, the lung V{sub 20} (+3.1%) and V{sub 5} (+1.5%) were slightly higher for AXB plans compared to AAA plans. High-dose spillage ((V105%PD - PTV)/ PTV) was slightly lower for AXB plans but the % low dose spillage (D2cm) was similar between the two calculation algorithms. Conclusion: AAA algorithm overestimates lung target dose. Routinely adapting to AXB for dose calculations in Lung SBRT planning may improve dose calculation accuracy, as AXB based calculations have been shown to be closer to Monte Carlo based dose predictions in accuracy and with relatively faster computational time. For clinical practice, revisiting dose-fractionation in Lung SBRT to correct for dose overestimates attributable to algorithm may very well be warranted.« less

Signs of antimetastatic activity of palladium complexes of methylenediphosphonic acid in IR spectra

NASA Astrophysics Data System (ADS)

Tolstorozhev, G. B.; Skornyakov, I. V.; Pekhnio, V. I.; Kozachkova, A. N.; Sharykina, N. I.

2012-07-01

We have used Fourier transform IR spectroscopy methods to study normal mouse lung tissue and also after subcutaneous transplantation of a B-16 melanoma tumor in the tissue. We also studied tissues with B-16 melanoma after they were treated with coordination compounds based on palladium complexes of methylenediphosphonic acid. The IR spectra of the lung tissues with metastases in the region of the C = O stretching vibrations are different from the IR spectra of normal tissue. We identified spectroscopic signs of the presence of metastases in the lung. We show that when a cancerous tumor is treated with a preparation of palladium complexes of methylenediphosphonic acid, the spectroscopic signs of the presence of metastases in the lung are missing. After treatment with the optimal dose of this drug, the IR spectrum of the lung tissue in which multiple metastases were present before treatment corresponds to the spectrum of normal tissue. We have determined the efficacy of the antitumor activity of coordination compounds based on palladium complexes of methylenediphosphonic acid.

Deformation of a flexible disk bonded to an elastic half space-application to the lung.

PubMed

Lai-Fook, S J; Hajji, M A; Wilson, T A

1980-08-01

An analysis is presented of the deformation of a homogeneous, isotropic, elastic half space subjected to a constant radial strain in a circular area on the boundary. Explicit analytic expressions for the normal and radial displacements and the shear stress on the boundary are used to interpret experiments performed on inflated pig lungs. The boundary strain was induced by inflating or deflating the lung after bonding a flexible disk to the lung surface. The prediction that the surface bulges outward for positive boundary strain and inward for negative strain was observed in the experiments. Poisson's ratio at two transpulmonary pressures was measured, by use of the normal displacement equation evaluated at the surface. A direct estimate of Poisson's ratio was possible because the normal displacement of the surface depended uniquely on the compressibility of the material. Qualitative comparisons between theory and experiment support the use of continuum analyses in evaluating the behavior of the lung parenchyma when subjected to small local distortions.

Laryngeal Aerodynamics in Children with Hearing Impairment versus Age and Height Matched Normal Hearing Peers.

PubMed

Das, Barshapriya; Chatterjee, Indranil; Kumar, Suman

2013-01-01

Lack of proper auditory feedback in hearing-impaired subjects results in functional voice disorder. It is directly related to discoordination of intrinsic and extrinsic laryngeal muscles and disturbed contraction and relaxation of antagonistic muscles. A total of twenty children in the age range of 5-10 years were considered for the study. They were divided into two groups: normal hearing children and hearing aid user children. Results showed a significant difference in the vital capacity, maximum sustained phonation, and fast adduction abduction rate having equal variance for normal and hearing aid user children, respectively, but no significant difference was found in the peak flow value with being statistically significant. A reduced vital capacity in hearing aid user children suggests a limited use of the lung volume for speech production. It may be inferred from the study that the hearing aid user children have poor vocal proficiency which is reflected in their voice. The use of voicing component in hearing impaired subjects is seen due to improper auditory feedback. It was found that there was a significant difference in the vital capacity, maximum sustained phonation (MSP), and fast adduction abduction rate and no significant difference in the peak flow.

NEUTROPHIL DEPLETION ATTENUATES INTERLEUKIN-8 PRODUCTION IN MILD-OVERSTRETCHED VENTILATED NORMAL RABBIT LUNG

EPA Science Inventory

OBJECTIVE: Acute lung injury induced by lung overstretch is associated with neutrophil influx, but the pathogenic role of neutrophils in overstretch-induced lung injury remains unclear. DESIGN: To assess the contribution of neutrophils, we compared the effects of noninjurious lar...

TH-CD-207A-08: Simulated Real-Time Image Guidance for Lung SBRT Patients Using Scatter Imaging

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

Redler, G; Cifter, G; Templeton, A

2016-06-15

Purpose: To develop a comprehensive Monte Carlo-based model for the acquisition of scatter images of patient anatomy in real-time, during lung SBRT treatment. Methods: During SBRT treatment, images of patient anatomy can be acquired from scattered radiation. To rigorously examine the utility of scatter images for image guidance, a model is developed using MCNP code to simulate scatter images of phantoms and lung cancer patients. The model is validated by comparing experimental and simulated images of phantoms of different complexity. The differentiation between tissue types is investigated by imaging objects of known compositions (water, lung, and bone equivalent). A lungmore » tumor phantom, simulating materials and geometry encountered during lung SBRT treatments, is used to investigate image noise properties for various quantities of delivered radiation (monitor units(MU)). Patient scatter images are simulated using the validated simulation model. 4DCT patient data is converted to an MCNP input geometry accounting for different tissue composition and densities. Lung tumor phantom images acquired with decreasing imaging time (decreasing MU) are used to model the expected noise amplitude in patient scatter images, producing realistic simulated patient scatter images with varying temporal resolution. Results: Image intensity in simulated and experimental scatter images of tissue equivalent objects (water, lung, bone) match within the uncertainty (∼3%). Lung tumor phantom images agree as well. Specifically, tumor-to-lung contrast matches within the uncertainty. The addition of random noise approximating quantum noise in experimental images to simulated patient images shows that scatter images of lung tumors can provide images in as fast as 0.5 seconds with CNR∼2.7. Conclusions: A scatter imaging simulation model is developed and validated using experimental phantom scatter images. Following validation, lung cancer patient scatter images are simulated. These simulated patient images demonstrate the clinical utility of scatter imaging for real-time tumor tracking during lung SBRT.« less

Lung density change after SABR: A comparative study between tri-Co-60 magnetic resonance-guided system and linear accelerator

PubMed Central

Kim, Eunji; Wu, Hong-Gyun; Park, Jong Min; Kim, Jung-in; Kim, Hak Jae

2018-01-01

Radiation-induced lung damage is an important treatment-related toxicity after lung stereotactic ablative radiotherapy (SABR). After implementing a tri-60Co magnetic-resonance image guided system, ViewRayTM, we compared the associated early radiological lung density changes to those associated with a linear accelerator (LINAC). Eight patients treated with the tri-60Co system were matched 1:1 with patients treated with LINAC. Prescription doses were 52 Gy or 60 Gy in four fractions, and lung dose-volumetric parameters were calculated from each planning system. The first two follow-up computed tomography (CT) were co-registered with the planning CT through deformable registration software, and lung density was measured by isodose levels. Tumor size was matched between the two groups, but the planning target volume of LINAC was larger than that of the tri-60Co system (p = 0.036). With regard to clinically relevant dose-volumetric parameters in the lungs, the ipsilateral lung mean dose, V10Gy and V20Gy were significantly poorer in tri-60Co plans compared to LINAC plans (p = 0.012, 0.036, and 0.017, respectively). Increased lung density was not observed in the first follow-up scan compared to the planning scan. A significant change of lung density was shown in the second follow-up scan and there was no meaningful difference between the tri-60Co system and LINAC for all dose regions. In addition, no patient developed clinical radiation pneumonitis until the second follow-up scan. Therefore, there was no significant difference in the early radiological lung damage between the tri-60Co system and LINAC for lung SABR despite of the inferior plan quality of the tri-60Co system compared to that of LINAC. Further studies with a longer follow-up period are needed to confirm our findings. PMID:29608606

Sex differences in chronic obstructive pulmonary disease evaluated using optical coherence tomography

NASA Astrophysics Data System (ADS)

Kirby, Miranda; Zhang, Wei; Laratta, Peter K.; Sin, Don D.; Lam, Stephen; Coxson, Harvey O.

2014-03-01

Although there are more women than men dying of chronic obstructive pulmonary disease (COPD) in the United States and elsewhere, we still do not have a clear understanding of the differences in the pathophysiology of airflow obstruction between the sexes. Optical coherence tomography (OCT) is an emerging imaging technology that has the capability of imaging small bronchioles with resolution approaching histology. Therefore, our objective was to compare OCT-derived airway wall measurements between males and females matched for lung size and in anatomically matched small airways. Subjects 50-80 yrs were enrolled in the British Columbia Lung Health Study and underwent OCT and spirometry. OCT was performed using a 1.5mm diameter probe/sheath in anatomically matched airways for males and females; the right lower lobe (RB8 or RB9) or left lower lobe (LB8 or LB9) during end-expiration. OCT airway wall area (Aaw) was obtained by manual segmentation. For males and females there was no significant difference in OCT Aaw (p=0.12). Spearman correlation coefficients indicated that the forced expiratory volume in 1 second (FEV1) and Aaw were significantly correlated for males (r=-0.78, p=0.004) but not for females (r=-0.20, p=0.49) matched for lung size. These novel OCT findings demonstrate that while there were no overall sex differences in airway wall thickness, the relationship between lung function and airway wall thickness was correlated only in men. Therefore, factors other than airway remodeling may be driving COPD pathogenesis in women and OCT may provide important information for investigating airway remodeling and its relationship with COPD progression.

Optical measurement of isolated canine lung filtration coefficients at normal hematocrits.

PubMed

Klaesner, J W; Pou, N A; Parker, R E; Finney, C; Roselli, R J

1997-12-01

In this study, lung filtration coefficient (Kfc) values were measured in eight isolated canine lung preparations at normal hematocrit values using three methods: gravimetric, blood-corrected gravimetric, and optical. The lungs were kept in zone 3 conditions and subjected to an average venous pressure increase of 10.24 +/- 0.27 (SE) cmH2O. The resulting Kfc (ml . min-1 . cmH2O-1 . 100 g dry lung wt-1) measured with the gravimetric technique was 0.420 +/- 0.017, which was statistically different from the Kfc measured by the blood-corrected gravimetric method (0.273 +/- 0.018) or the product of the reflection coefficient (sigmaf) and Kfc measured optically (0. 272 +/- 0.018). The optical method involved the use of a Cellco filter cartridge to separate red blood cells from plasma, which allowed measurement of the concentration of the tracer in plasma at normal hematocrits (34 +/- 1.5). The permeability-surface area product was measured using radioactive multiple indicator-dilution methods before, during, and after venous pressure elevations. Results showed that the surface area of the lung did not change significantly during the measurement of Kfc. These studies suggest that sigmafKfc can be measured optically at normal hematocrits, that this measurement is not influenced by blood volume changes that occur during the measurement, and that the optical sigmafKfc agrees with the Kfc obtained via the blood-corrected gravimetric method.

Heart-lung transplant - slideshow

MedlinePlus

... page: //medlineplus.gov/ency/presentations/100147.htm Heart-lung transplant - series—Normal anatomy To use the sharing features ... Editorial team. Related MedlinePlus Health Topics Heart Transplantation Lung Transplantation A.D.A.M., Inc. is accredited by ...

DNA methylation in lung tissues of mouse offspring exposed in utero to polycyclic aromatic hydrocarbons.

PubMed

Fish, Trevor J; Benninghoff, Abby D

2017-11-01

Polycyclic aromatic hydrocarbons (PAHs) comprise an important class of environmental pollutants that are known to cause lung cancer in animals and are suspected lung carcinogens in humans. Moreover, evidence from cell-based studies points to PAHs as modulators of the epigenome. The objective of this work was to assess patterns of genome-wide DNA methylation in lung tissues of adult offspring initiated in utero with the transplacental PAH carcinogens dibenzo [def,p]chrysene (DBC) or benzo [a]pyrene (BaP). Genome-wide methylation patterns for normal (not exposed), normal adjacent and lung tumor tissues obtained from adult offspring were determined using methylated DNA immunoprecipitation (MeDIP) with the NimbleGen mouse DNA methylation CpG island array. Lung tumor incidence in 45-week old mice initiated with BaP was 32%, much lower than that of the DBC-exposed offspring at 96%. Also, male offspring appeared more susceptible to BaP as compared to females. Distinct patterns of DNA methylation were associated with non-exposed, normal adjacent and adenocarcinoma lung tissues, as determined by principal components, hierarchical clustering and gene ontology analyses. From these methylation profiles, a set of genes of interest was identified that includes potential important targets for epigenetic modification during the process of lung tumorigenesis in animals exposed to environmental PAHs. Copyright © 2017 Elsevier Ltd. All rights reserved.

Production and Assessment of Decellularized Pig and Human Lung Scaffolds

PubMed Central

Niles, Jean; Riddle, Michael; Vargas, Gracie; Schilagard, Tuya; Ma, Liang; Edward, Kert; La Francesca, Saverio; Sakamoto, Jason; Vega, Stephanie; Ogadegbe, Marie; Mlcak, Ronald; Deyo, Donald; Woodson, Lee; McQuitty, Christopher; Lick, Scott; Beckles, Daniel; Melo, Esther; Cortiella, Joaquin

2013-01-01

The authors have previously shown that acellular (AC) trachea-lung scaffolds can (1) be produced from natural rat lungs, (2) retain critical components of the extracellular matrix (ECM) such as collagen-1 and elastin, and (3) be used to produce lung tissue after recellularization with murine embryonic stem cells. The aim of this study was to produce large (porcine or human) AC lung scaffolds to determine the feasibility of producing scaffolds with potential clinical applicability. We report here the first attempt to produce AC pig or human trachea-lung scaffold. Using a combination of freezing and sodium dodecyl sulfate washes, pig trachea-lungs and human trachea-lungs were decellularized. Once decellularization was complete we evaluated the structural integrity of the AC lung scaffolds using bronchoscopy, multiphoton microscopy (MPM), assessment of the ECM utilizing immunocytochemistry and evaluation of mechanics through the use of pulmonary function tests (PFTs). Immunocytochemistry indicated that there was loss of collagen type IV and laminin in the AC lung scaffold, but retention of collagen-1, elastin, and fibronectin in some regions. MPM scoring was also used to examine the AC lung scaffold ECM structure and to evaluate the amount of collagen I in normal and AC lung. MPM was used to examine the physical arrangement of collagen-1 and elastin in the pleura, distal lung, lung borders, and trachea or bronchi. MPM and bronchoscopy of trachea and lung tissues showed that no cells or cell debris remained in the AC scaffolds. PFT measurements of the trachea-lungs showed no relevant differences in peak pressure, dynamic or static compliance, and a nonrestricted flow pattern in AC compared to normal lungs. Although there were changes in content of collagen I and elastin this did not affect the mechanics of lung function as evidenced by normal PFT values. When repopulated with a variety of stem or adult cells including human adult primary alveolar epithelial type II cells both pig and human AC scaffolds supported cell attachment and cell viability. Examination of scaffolds produced using a variety of detergents indicated that detergent choice influenced human immune response in terms of T cell activation and chemokine production. PMID:23638920

Production and assessment of decellularized pig and human lung scaffolds.

PubMed

Nichols, Joan E; Niles, Jean; Riddle, Michael; Vargas, Gracie; Schilagard, Tuya; Ma, Liang; Edward, Kert; La Francesca, Saverio; Sakamoto, Jason; Vega, Stephanie; Ogadegbe, Marie; Mlcak, Ronald; Deyo, Donald; Woodson, Lee; McQuitty, Christopher; Lick, Scott; Beckles, Daniel; Melo, Esther; Cortiella, Joaquin

2013-09-01

The authors have previously shown that acellular (AC) trachea-lung scaffolds can (1) be produced from natural rat lungs, (2) retain critical components of the extracellular matrix (ECM) such as collagen-1 and elastin, and (3) be used to produce lung tissue after recellularization with murine embryonic stem cells. The aim of this study was to produce large (porcine or human) AC lung scaffolds to determine the feasibility of producing scaffolds with potential clinical applicability. We report here the first attempt to produce AC pig or human trachea-lung scaffold. Using a combination of freezing and sodium dodecyl sulfate washes, pig trachea-lungs and human trachea-lungs were decellularized. Once decellularization was complete we evaluated the structural integrity of the AC lung scaffolds using bronchoscopy, multiphoton microscopy (MPM), assessment of the ECM utilizing immunocytochemistry and evaluation of mechanics through the use of pulmonary function tests (PFTs). Immunocytochemistry indicated that there was loss of collagen type IV and laminin in the AC lung scaffold, but retention of collagen-1, elastin, and fibronectin in some regions. MPM scoring was also used to examine the AC lung scaffold ECM structure and to evaluate the amount of collagen I in normal and AC lung. MPM was used to examine the physical arrangement of collagen-1 and elastin in the pleura, distal lung, lung borders, and trachea or bronchi. MPM and bronchoscopy of trachea and lung tissues showed that no cells or cell debris remained in the AC scaffolds. PFT measurements of the trachea-lungs showed no relevant differences in peak pressure, dynamic or static compliance, and a nonrestricted flow pattern in AC compared to normal lungs. Although there were changes in content of collagen I and elastin this did not affect the mechanics of lung function as evidenced by normal PFT values. When repopulated with a variety of stem or adult cells including human adult primary alveolar epithelial type II cells both pig and human AC scaffolds supported cell attachment and cell viability. Examination of scaffolds produced using a variety of detergents indicated that detergent choice influenced human immune response in terms of T cell activation and chemokine production.

Scribble is required for normal epithelial cell–cell contacts and lumen morphogenesis in the mammalian lung

PubMed Central

Yates, Laura L.; Schnatwinkel, Carsten; Hazelwood, Lee; Chessum, Lauren; Paudyal, Anju; Hilton, Helen; Romero, M. Rosario; Wilde, Jonathan; Bogani, Debora; Sanderson, Jeremy; Formstone, Caroline; Murdoch, Jennifer N.; Niswander, Lee A.; Greenfield, Andy; Dean, Charlotte H.

2013-01-01

During lung development, proper epithelial cell arrangements are critical for the formation of an arborized network of tubes. Each tube requires a lumen, the diameter of which must be tightly regulated to enable optimal lung function. Lung branching and lumen morphogenesis require close epithelial cell–cell contacts that are maintained as a result of adherens junctions, tight junctions and by intact apical–basal (A/B) polarity. However, the molecular mechanisms that maintain epithelial cohesion and lumen diameter in the mammalian lung are unknown. Here we show that Scribble, a protein implicated in planar cell polarity (PCP) signalling, is necessary for normal lung morphogenesis. Lungs of the Scrib mouse mutant Circletail (Crc) are abnormally shaped with fewer airways, and these airways often lack a visible, ‘open’ lumen. Mechanistically we show that Scrib genetically interacts with the core PCP gene Vangl2 in the developing lung and that the distribution of PCP pathway proteins and Rho mediated cytoskeletal modification is perturbed in ScribCrc/Crc lungs. However A/B polarity, which is disrupted in Drosophila Scrib mutants, is largely unaffected. Notably, we find that Scrib mediates functions not attributed to other PCP proteins in the lung. Specifically, Scrib localises to both adherens and tight junctions of lung epithelia and knockdown of Scrib in lung explants and organotypic cultures leads to reduced cohesion of lung epithelial cells. Live imaging of Scrib knockdown lungs shows that Scrib does not affect bud bifurcation, as previously shown for the PCP protein Celsr1, but is required to maintain epithelial cohesion. To understand the mechanism leading to reduced cell–cell association, we show that Scrib associates with β-catenin in embryonic lung and the sub-cellular distribution of adherens and tight junction proteins is perturbed in mutant lung epithelia. Our data reveal that Scrib is required for normal lung epithelial organisation and lumen morphogenesis by maintaining cell–cell contacts. Thus we reveal novel and important roles for Scrib in lung development operating via the PCP pathway, and in regulating junctional complexes and cell cohesion. PMID:23195221

Integrative transcriptome analysis identifies deregulated microRNA-transcription factor networks in lung adenocarcinoma

PubMed Central

Cinegaglia, Naiara C.; Andrade, Sonia Cristina S.; Tokar, Tomas; Pinheiro, Maísa; Severino, Fábio E.; Oliveira, Rogério A.; Hasimoto, Erica N.; Cataneo, Daniele C.; Cataneo, Antônio J.M.; Defaveri, Júlio; Souza, Cristiano P.; Marques, Márcia M.C.; Carvalho, Robson F.; Coutinho, Luiz L.; Gross, Jefferson L.; Rogatto, Silvia R.; Lam, Wan L.; Jurisica, Igor; Reis, Patricia P.

2016-01-01

Herein, we aimed at identifying global transcriptome microRNA (miRNA) changes and miRNA target genes in lung adenocarcinoma. Samples were selected as training (N = 24) and independent validation (N = 34) sets. Tissues were microdissected to obtain >90% tumor or normal lung cells, subjected to miRNA transcriptome sequencing and TaqMan quantitative PCR validation. We further integrated our data with published miRNA and mRNA expression datasets across 1,491 lung adenocarcinoma and 455 normal lung samples. We identified known and novel, significantly over- and under-expressed (p ≤ 0.01 and FDR≤0.1) miRNAs in lung adenocarcinoma compared to normal lung tissue: let-7a, miR-10a, miR-15b, miR-23b, miR-26a, miR-26b, miR-29a, miR-30e, miR-99a, miR-146b, miR-181b, miR-181c, miR-421, miR-181a, miR-574 and miR-1247. Validated miRNAs included let-7a-2, let-7a-3, miR-15b, miR-21, miR-155 and miR-200b; higher levels of miR-21 expression were associated with lower patient survival (p = 0.042). We identified a regulatory network including miR-15b and miR-155, and transcription factors with prognostic value in lung cancer. Our findings may contribute to the development of treatment strategies in lung adenocarcinoma. PMID:27081085

Methods for Measuring Lung Volumes: Is There a Better One?

PubMed

Tantucci, Claudio; Bottone, Damiano; Borghesi, Andrea; Guerini, Michele; Quadri, Federico; Pini, Laura

2016-01-01

Accurate measurement of lung volumes is of paramount importance to establish the presence of ventilatory defects and give insights for diagnostic and/or therapeutic purposes. It was the aim of this study to measure lung volumes in subjects with respiratory disorders and in normal controls by 3 different techniques (plethysmographic, dilutional and radiographic methods), in an attempt to clarify the role of each of them in performing such a task, without any presumptive 'a priori' superiority of one method above others. Patients andMethods: In different groups of subjects with obstructive and restrictive ventilatory defects and in a normal control group, total lung capacity, functional residual capacity (FRC) and residual volume were measured by body plethysmography, multi-breath helium (He) dilution and radiographic CT scan method with spirometric gating. The 3 methods gave comparable results in normal subjects and in patients with a restrictive defect. In patients with an obstructive defect, CT scan and plethysmography showed similar lung volumes, while on average significantly lower lung volumes were obtained with the He dilution technique. Taking into account that the He dilution technique does primarily measure FRC during tidal breathing, our data suggest that in some patients with an obstructive defect, a number of small airways can be functionally closed at end-expiratory lung volume, preventing He to reach the lung regions subserved by these airways. In all circumstances, both CT scan with spirometric gating and plethysmographic methods provide similar values of lung volumes. In contrast, the He dilution method can measure lower lung volumes in some patients with chronic airflow obstruction. © 2016 S. Karger AG, Basel.

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

Humidifier Disinfectants Are a Cause of Lung Injury among Adults in South Korea: A Community-Based Case-Control Study

PubMed Central

Kwon, Geun-Yong; Gwack, Jin; Park, Young-Joon; Youn, Seung-Ki; Kwon, Jun-Wook; Yang, Byung-Guk; Lee, Moo-Song; Jung, Miran; Lee, Hanyi; Jun, Byung-Yool; Lim, Hyun-Sul

2016-01-01

Backgrounds An outbreak of lung injury among South Korean adults was examined in a hospital-based case-control study, and the suspected cause was exposure to humidifier disinfectant (HD). However, a case-control study with community-dwelling controls was needed to validate the previous study’s findings, and to confirm the exposure-response relationship between HD and lung injury. Methods Each case of lung injury was matched with four community-dwelling controls, according to age (±3 years), sex, residence, and history of childbirth since 2006 (for women). Environmental risk factors, which included type and use of humidifier and HD, were investigated using a structured questionnaire during August 2011. The exposure to HD was calculated for both cases and controls, and the corresponding risks of lung injury were compared. Results Among 28 eligible cases, 16 patients agreed to participate, and 60 matched controls were considered eligible for this study. The cases were more likely to have been exposed to HD (odds ratio: 116.1, 95% confidence interval: 6.5–2,063.7). All cases were exposed to HDs containing polyhexamethyleneguanidine phosphate, and the risk of lung injury increased with the cumulative exposure, duration of exposure, and exposure per day. Conclusions This study revealed a statistically significant exposure-response relationship between HD and lung injury. Therefore, continuous monitoring and stricter evaluation of environmental chemicals’ safety should be conducted. PMID:26990641

Lung Structure and the Intrinsic Challenges of Gas Exchange

PubMed Central

Hsia, Connie C.W.; Hyde, Dallas M.; Weibel, Ewald R.

2016-01-01

Structural and functional complexities of the mammalian lung evolved to meet a unique set of challenges, namely, the provision of efficient delivery of inspired air to all lung units within a confined thoracic space, to build a large gas exchange surface associated with minimal barrier thickness and a microvascular network to accommodate the entire right ventricular cardiac output while withstanding cyclic mechanical stresses that increase several folds from rest to exercise. Intricate regulatory mechanisms at every level ensure that the dynamic capacities of ventilation, perfusion, diffusion, and chemical binding to hemoglobin are commensurate with usual metabolic demands and periodic extreme needs for activity and survival. This article reviews the structural design of mammalian and human lung, its functional challenges, limitations, and potential for adaptation. We discuss (i) the evolutionary origin of alveolar lungs and its advantages and compromises, (ii) structural determinants of alveolar gas exchange, including architecture of conducting bronchovascular trees that converge in gas exchange units, (iii) the challenges of matching ventilation, perfusion, and diffusion and tissue-erythrocyte and thoracopulmonary interactions. The notion of erythrocytes as an integral component of the gas exchanger is emphasized. We further discuss the signals, sources, and limits of structural plasticity of the lung in alveolar hypoxia and following a loss of lung units, and the promise and caveats of interventions aimed at augmenting endogenous adaptive responses. Our objective is to understand how individual components are matched at multiple levels to optimize organ function in the face of physiological demands or pathological constraints. PMID:27065169

Ventilatory protective strategies during thoracic surgery: effects of alveolar recruitment maneuver and low-tidal volume ventilation on lung density distribution.

PubMed

Kozian, Alf; Schilling, Thomas; Schütze, Hartmut; Senturk, Mert; Hachenberg, Thomas; Hedenstierna, Göran

2011-05-01

The increased tidal volume (V(T)) applied to the ventilated lung during one-lung ventilation (OLV) enhances cyclic alveolar recruitment and mechanical stress. It is unknown whether alveolar recruitment maneuvers (ARMs) and reduced V(T) may influence tidal recruitment and lung density. Therefore, the effects of ARM and OLV with different V(T) on pulmonary gas/tissue distribution are examined. Eight anesthetized piglets were mechanically ventilated (V(T) = 10 ml/kg). A defined ARM was applied to the whole lung (40 cm H(2)O for 10 s). Spiral computed tomographic lung scans were acquired before and after ARM. Thereafter, the lungs were separated with an endobronchial blocker. The pigs were randomized to receive OLV in the dependent lung with a V(T) of either 5 or 10 ml/kg. Computed tomography was repeated during and after OLV. The voxels were categorized by density intervals (i.e., atelectasis, poorly aerated, normally aerated, or overaerated). Tidal recruitment was defined as the addition of gas to collapsed lung regions. The dependent lung contained atelectatic (56 ± 10 ml), poorly aerated (183 ± 10 ml), and normally aerated (187 ± 29 ml) regions before ARM. After ARM, lung volume and aeration increased (426 ± 35 vs. 526 ± 69 ml). Respiratory compliance enhanced, and tidal recruitment decreased (95% vs. 79% of the whole end-expiratory lung volume). OLV with 10 ml/kg further increased aeration (atelectasis, 15 ± 2 ml; poorly aerated, 94 ± 24 ml; normally aerated, 580 ± 98 ml) and tidal recruitment (81% of the dependent lung). OLV with 5 ml/kg did not affect tidal recruitment or lung density distribution. (Data are given as mean ± SD.) The ARM improves aeration and respiratory mechanics. In contrast to OLV with high V(T), OLV with reduced V(T) does not reinforce tidal recruitment, indicating decreased mechanical stress.

Excited state proton transfer in the lysosome of live lung cells: normal and cancer cells.

PubMed

Chowdhury, Rajdeep; Saha, Abhijit; Mandal, Amit Kumar; Jana, Batakrishna; Ghosh, Surajit; Bhattacharyya, Kankan

2015-02-12

Dynamics of excited state proton transfer (ESPT) in the lysosome region of live lung cells (normal and cancer) is studied by picosecond time-resolved confocal microscopy. For this, we used a fluorescent probe, pyranine (8-hydroxy-pyrene-1,3,6-trisulfonate, HPTS). From the colocalization of HPTS with a lysotracker dye (lysotracker yellow), we confirmed that HPTS resides in the lysosome for both of the cells. The diffusion coefficient (Dt) in the lysosome region was obtained from fluorescence correlation spectroscopy (FCS). From Dt, the viscosity of lysosome is estimated to be ∼40 and ∼30 cP in the cancer and normal cells, respectively. The rate constants of the elementary steps of ESPT in a normal lung cell (WI38) are compared with those in a lung cancer cell (A549). It is observed that the time constant of the initial proton transfer process in a normal cell (τ(PT) = 40 ps) is similar to that in a cancer cell. The recombination of the geminate ion pair is slightly faster (τ(rec) = 25 ps) in the normal cell than that (τ(rec) = 30 ps) in a cancer cell. The time constant of the dissociation (τ(diss)) of the geminate ion pair for the cancer cell (τ(diss) = 80 ps) is 1.5 times faster compared to that (τ(diss) = 120 ps) in a normal cell.

Exponential analysis of the lung pressure-volume curve in patients with chronic pigeon-breeder's lung.

PubMed

Sansores, R; Perez-Padilla, R; Paré, P D; Selman, M

1992-05-01

Pigeon-breeder's lung (PBL) is extremely common in Mexico City and often progresses to irreversible pulmonary fibrosis. The exponential analysis of the lung pressure-volume (PV) curve (V = A - Be-kp) has been suggested as a method to separate the lung restriction caused by inflammation from that caused by pulmonary fibrosis; a significantly decreased value for the exponential constant, k, suggests a change in the mechanical properties of the functioning lung parenchyma, while a normal value accompanied by restriction suggests subtraction of lung units without a change in the mechanical properties of the functioning units. We measured lung volumes and static PV curves in 29 patients who had persistent lung restriction following a biopsy-proven diagnosis of PBL. Mean values in the 29 subjects were as follows: age, 43 +/- 13 years; TLC, 61 +/- 15 percent of predicted; VC, 46 +/- 19 percent of predicted; and k, 55 +/- 17 percent of predicted. Twenty-four of the 29 patients had values for k that were below the 95 percent confidence level, and five had "normal" values. There was no difference in TLC and VC (percent of predicted) between those with or without a decreased value for k. Four of five patients with a normal value for k improved subsequent to diagnosis, while only one of 21 patients with a decreased k improved. We conclude that increased lung elasticity manifested by a low value for k is common in patients with chronic PBL. These results support the observation of frequent irreversible lung fibrosis in these patients. Measurements of k could prove a good prognostic indicator at the time of initial diagnosis.

Cell-surface marker discovery for lung cancer

PubMed Central

Cohen, Allison S.; Khalil, Farah K.; Welsh, Eric A.; Schabath, Matthew B.; Enkemann, Steven A.; Davis, Andrea; Zhou, Jun-Min; Boulware, David C.; Kim, Jongphil; Haura, Eric B.; Morse, David L.

2017-01-01

Lung cancer is the leading cause of cancer deaths in the United States. Novel lung cancer targeted therapeutic and molecular imaging agents are needed to improve outcomes and enable personalized care. Since these agents typically cannot cross the plasma membrane while carrying cytotoxic payload or imaging contrast, discovery of cell-surface targets is a necessary initial step. Herein, we report the discovery and characterization of lung cancer cell-surface markers for use in development of targeted agents. To identify putative cell-surface markers, existing microarray gene expression data from patient specimens were analyzed to select markers with differential expression in lung cancer compared to normal lung. Greater than 200 putative cell-surface markers were identified as being overexpressed in lung cancers. Ten cell-surface markers (CA9, CA12, CXorf61, DSG3, FAT2, GPR87, KISS1R, LYPD3, SLC7A11 and TMPRSS4) were selected based on differential mRNA expression in lung tumors vs. non-neoplastic lung samples and other normal tissues, and other considerations involving known biology and targeting moieties. Protein expression was confirmed by immunohistochemistry (IHC) staining and scoring of patient tumor and normal tissue samples. As further validation, marker expression was determined in lung cancer cell lines using microarray data and Kaplan–Meier survival analyses were performed for each of the markers using patient clinical data. High expression for six of the markers (CA9, CA12, CXorf61, GPR87, LYPD3, and SLC7A11) was significantly associated with worse survival. These markers should be useful for the development of novel targeted imaging probes or therapeutics for use in personalized care of lung cancer patients. PMID:29371917

Further Development of an Exhaled microRNA Biomarker of Lung Cancer Risk

DTIC Science & Technology

2017-08-01

devise a non -invasive airway based exhaled microRNA metric for lung cancer risk, initial work to be tested in a case control study. We expanded the...control study. We also expanded the assessment of lung cancer subjects to also include limited (3-month) prospective follow-up of non -cancer controls...follow-up of non -cancer controls in order to minimize control contamination/misclassification, and improved matching on age, smoking status, and

Calcium and magnesium in drinking-water and risk of death from lung cancer in women.

PubMed

Cheng, Meng-Hsuan; Chiu, Hui-Fen; Tsai, Shang-Shyue; Chen, Chih-Cheng; Yang, Chun-Yuh

2012-01-01

The possible association between the risk of lung cancer in women and the levels of calcium (Ca) and magnesium (Mg) in drinking-water from municipal supplies was investigated in a matched, case-control study in Taiwan. All eligible female lung cancer deaths (3,532 cases) of Taiwan residents, from 2000 through to 2008, were compared with deaths from other causes (3,532 controls), and the levels of Ca and Mg in drinking-water of these residents were determined. Data on Ca and Mg levels in drinking-water throughout Taiwan were obtained from the Taiwan Water Supply Corporation (TWSC). The control group consisted of people who died from other causes, and the controls were pair-matched to the cases by sex, year of birth, and year of death. The adjusted odd ratios were not statistically significant for the relationship between Ca levels in drinking-water and lung cancer in women. The adjusted odd ratios for female lung cancer deaths for those with higher Mg levels in their drinking-water, as compared to the lowest tertile, were 0.82 (95% CI = 0.72-0.93) and 0.80 (95% CI = 0.69-0.93), respectively. The results of the present study show that there is a significant trend toward a decreased risk of lung cancer in women with increasing Mg levels in drinking-water.

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

Ultrashort Echo-Time Magnetic Resonance Imaging Is a Sensitive Method for the Evaluation of Early Cystic Fibrosis Lung Disease

PubMed Central

Roach, David J.; Crémillieux, Yannick; Fleck, Robert J.; Brody, Alan S.; Serai, Suraj D.; Szczesniak, Rhonda D.; Kerlakian, Stephanie; Clancy, John P.

2016-01-01

Rationale: Recent advancements that have been made in magnetic resonance imaging (MRI) improve our ability to assess pulmonary structure and function in patients with cystic fibrosis (CF). A nonionizing imaging modality that can be used as a serial monitoring tool throughout life can positively affect patient care and outcomes. Objectives: To compare an ultrashort echo-time MRI method with computed tomography (CT) as a biomarker of lung structure abnormalities in young children with early CF lung disease. Methods: Eleven patients with CF (mean age, 31.8 ± 5.7 mo; median age, 33 mo; 7 male and 4 female) were imaged via CT and ultrashort echo-time MRI. Eleven healthy age-matched patients (mean age, 22.5 ± 10.2 mo; median age, 23 mo; 5 male and 6 female) were imaged via ultrashort echo-time MRI. CT scans of 13 additional patients obtained for clinical indications not affecting the heart or lungs and interpreted as normal provided a CT control group (mean age, 24.1 ± 11.7 mo; median age, 24 mo; 6 male and 7 female). Studies were scored by two experienced radiologists using a well-validated CF-specific scoring system for CF lung disease. Measurements and Main Results: Correlations between CT and ultrashort echo-time MRI scores of patients with CF were very strong, with P values ≤0.001 for bronchiectasis (r = 0.96) and overall score (r = 0.90), and moderately strong for bronchial wall thickening (r = 0.62, P = 0.043). MRI easily differentiated CF and control groups via a reader CF-specific scoring system. Conclusions: Ultrashort echo-time MRI detected structural lung disease in very young patients with CF and provided imaging data that correlated well with CT. By quantifying early CF lung disease without using ionizing radiation, ultrashort echo-time MRI appears well suited for pediatric patients requiring longitudinal imaging for clinical care or research studies. Clinical Trial registered with www.clinicaltrials.gov (NCT01832519). PMID:27551814

Alteration of lung atrial natriuretic peptide receptors in genetic cardiomyopathy.

PubMed

Mukaddam-Daher, S; Tremblay, J; Fujio, N; Koch, C; Jankowski, M; Quillen, E W; Gutkowska, J

1996-07-01

These studies were designed to characterize the atrial natriuretic peptide (ANF) receptor subtypes [guanylyl cyclase natriuretic peptide receptors (NPR-A, NPR-B) and NPR-C] in lungs of normal hamsters and to evaluate alterations in receptor kinetics in genetic cardiomyopathy (CMO), a model of human congestive heart failure. Lung membranes were obtained from normal and CMO 200-to 230-day-old hamsters. Cross-linking and competitive binding receptor assays using 125I-labeled human ANF showed that lung membranes exhibit NPR, mainly guanylyl cyclase NPR-A and clearance NPR-C receptors. Stimulation of guanylyl cyclase by ANF and C-type natriuretic peptide (CNP) confirmed the presence of NPR-A and NPR-B. The maximum binding capacity of total ANF binding sites (442 +/- 68 vs. 271 +/- 57 fmol/mg protein, P < 0.05) was reduced, but dissociation constant (0.26 +/- 0.04 vs. 0.41 +/- 0.08 nM) was not altered in CMO animals. Similar reductions were observed in the binding sites for brain natriuretic peptide (BNP; 438 +/- 83 vs. 236 +/- 53 fmol/mg protein) and CNP (321 +/- 80 vs. 165 +/- 56 fmol/mg protein, P < 0.05) which may reflect a decline in NPR-A and NPR-B and/or NPR-C. Acid wash improved binding of 125I-labeled rat ANF to lung membranes of both normal and CMO hamsters, but the tendency towards reduced binding in CMO hamsters did not reach statistical significance, implying that downregulation may not have been due only to prior occupancy of the receptors. Transcripts of NPR-A, NPR-B, and NPR-C receptors in hamster lungs were detected by quantitative polymerase chain reaction. Compared with normal controls, the CMO hamster lung NPR-A mRNA was reduced by 50%, but NPR-B mRNA and NPR-C mRNA were not altered. Moreover, CMO hamster lungs showed less activation of guanylyl cyclase by ANF. These studies demonstrate that lung NPR are downregulated in hamster CMO.

General practice consultations, diagnostic investigations, and prescriptions in the year preceding a lung cancer diagnosis.

PubMed

Guldbrandt, Louise M; Møller, Henrik; Jakobsen, Erik; Vedsted, Peter

2017-01-01

Patterns of general practice utilization in the period before lung cancer (LC) diagnosis may provide new knowledge to ensure timelier and earlier diagnosis of LC. This study aimed to explore the prediagnostic activity in general practice in the year preceding LC diagnosis. The activity was compared to a matched comparison group. We compared LC patients with different stage, and patients with and without chronic obstructive pulmonary disease (COPD). Using Danish registers, we performed a population-based matched cohort study including lung cancer patients (n = 34,017) and matched comparison subjects (n = 340,170). During months 12 to 1 prior to diagnosis, 92.6% of LC patients and 88.4% of comparison subjects had one or more contacts with general practice. 13.0% of LC patients and 3.3% of comparison subjects had two or more X-rays. 20.8% of LC patients and 8.5% of comparison subjects had two or more first-time antibiotics prescriptions. The incidence rate ratio for having a contact to general practice was similar for LC patients with localized disease compared to LC patients with metastatic disease. LC patients with COPD had more frequent contacts, lung functions tests, X-rays, and prescriptions than COPD patients without lung cancer, but not as pronounced as compared to patients without COPD. There was a significant increase in healthcare seeking and diagnostic activity in the year prior to a LC diagnosis, regardless of stage at diagnosis. COPD may mask the symptoms of LC. This indicates the presence of a "diagnostic time window" and a potential for more timely diagnosis of LC based on clinical signs and symptoms. © 2016 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

Mass-size distribution and concentration of metals from personal exposure to arc welding fume in pipeline construction: a case report.

PubMed

Yang, Show-Yi; Lin, Jia-Ming; Young, Li-Hao; Chang, Ching-Wen

2018-04-07

We investigate exposure to welding fume metals in pipeline construction, which are responsible for severe respiratory problems. We analyzed air samples obtained using size-fractioning cascade impactors that were attached to the welders performing shielded metal and gas tungsten arc welding outdoors. Iron, aluminum, zinc, chromium, manganese, copper, nickel, and lead concentrations in the water-soluble (WS) and water-insoluble (WI) portions were determined separately, using inductively coupled plasma mass spectrometry. The mass-size distribution of welding fume matches a log-normal distribution with two modes. The metal concentrations in the welding fume were ranked as follows: Fe > Al > Zn > Cr > Mn > Ni > Cu > Pb. In the WS portion, the capacities of metals dissolving in water are correlated with the metal species but particle sizes. Particularly, Zn, Mn, and Pb exhibit relatively higher capacities than Cu, Cr, Al, Fe, and Ni. Exposure of the gas-exchange region of the lungs to WS metals were in the range of 4.9% to 34.6% of the corresponding metals in air by considering the particle-size selection in lungs, metal composition by particle size, and the capacities of each metal dissolving in water.

Power Flow in Phonation

NASA Astrophysics Data System (ADS)

Zhang, Lucy; Yu, Feimi; Krane, Michael

2017-11-01

The control volume analysis of power flow during sustained phonation is performed using results of a fully-coupled aeroelastic-aeroacoustic simulation. The control volumes consist of the laryngeal region, and the larynx and the vocal tract. Two cases are considered: an effectively infinite length vocal tract, where sound produced in the larynx radiates away and is not reflected back, and a constant-area vocal tract of normal adult human dimensions, in which phonatory sound resonates before radiating from the mouth opening. In both cases the lungs are modeled to absorb all incident sound, while providing a constant volume flow toward the larynx. Control of the acoustic boundary conditions is accomplished using perfectly matched- layers, and flow from the lungs is provided by a source distribution near the entrance to the trachea region. For both cases the power flow for the larynx and larynx plus vocal tract control volumes are computed using the integral form of the mechanical energy equation, expanded to consider power exchanges between slightly compressible flow in the larynx and the acoustic fields in the vocal tract and trachea. The funding from NIH 2R01DC005642-10A1 is greatly acknowledged.

Combining deep learning and coherent anti-Stokes Raman scattering imaging for automated differential diagnosis of lung cancer

NASA Astrophysics Data System (ADS)

Weng, Sheng; Xu, Xiaoyun; Li, Jiasong; Wong, Stephen T. C.

2017-10-01

Lung cancer is the most prevalent type of cancer and the leading cause of cancer-related deaths worldwide. Coherent anti-Stokes Raman scattering (CARS) is capable of providing cellular-level images and resolving pathologically related features on human lung tissues. However, conventional means of analyzing CARS images requires extensive image processing, feature engineering, and human intervention. This study demonstrates the feasibility of applying a deep learning algorithm to automatically differentiate normal and cancerous lung tissue images acquired by CARS. We leverage the features learned by pretrained deep neural networks and retrain the model using CARS images as the input. We achieve 89.2% accuracy in classifying normal, small-cell carcinoma, adenocarcinoma, and squamous cell carcinoma lung images. This computational method is a step toward on-the-spot diagnosis of lung cancer and can be further strengthened by the efforts aimed at miniaturizing the CARS technique for fiber-based microendoscopic imaging.

Neutral endopeptidase: variable expression in human lung, inactivation in lung cancer, and modulation of peptide-induced calcium flux.

PubMed

Cohen, A J; Bunn, P A; Franklin, W; Magill-Solc, C; Hartmann, C; Helfrich, B; Gilman, L; Folkvord, J; Helm, K; Miller, Y E

1996-02-15

Neutral endopeptidase (NEP; CALLA, CD10, EC 3.4.24.11) is a cell surface endopeptidase that hydrolyses bioactive peptides, including the bombesin-like peptides, as well as other neuropeptides. Bombesin-like peptides and other neuropeptides are autocrine growth factors for both small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). Low expression of NEP has been reported in SCLC and NSCLC cell lines. NEP inhibition has been shown to increase proliferation in one cell line. To date, NEP expression has not been quantitatively evaluated in normal adult lung, SCLC or NSCLC tumors, paired uninvolved lung from the same patient, or in other pulmonary neoplasms such as mesotheliomas and carcinoids. We examined the expression of NEP in these tissues and human cell lines using immunohistochemistry, flow cytometry, enzyme activity, ELISA, Western blot, and reverse transcription (RT)-PCR. Uninvolved lung tissue from different individuals displayed considerable variation in NEP activity and protein. By immunohistochemistry, NEP expression was detectable in alveolar and airway epithelium, fibroblasts of normal lung, and in mesotheliomas, whereas it was undetectable in most SCLC, adenocarcinoma, squamous cell carcinoma, and carcinoid tumors of the lung. NEP activity and protein levels were lower in all SCLC and adenocarcinoma tumors when compared to adjacent uninvolved lung, often at levels consistent with expression derived from contaminating stroma. NEP expression and activity were reduced or undetectable in most SCLC and lung adenocarcinoma cell lines. NEP mRNA by RT-PCR was not expressed or was in low abundance in the majority of lung cancer cell lines. The majority of lung tumors did not express NEP by RT-PCR as compared with normal adjacent lung. In addition, recombinant NEP abolished, whereas an NEP inhibitor potentiated, the calcium flux generated by neuropeptides in some lung cancer cell lines, demonstrating potential physiological significance for low NEP expression. NEP, therefore, is a signal transduction and possibly a growth modulator for both SCLC and NSCLC, emphasizing the role of neuropeptides in the pathogenesis of the major histological forms of lung cancer.

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.

A General Approach to the Evaluation of Ventilation-Perfusion Ratios in Normal and Abnormal Lungs

ERIC Educational Resources Information Center

Wagner, Peter D.

1977-01-01

Outlines methods for manipulating multiple gas data so as to gain the greatest amount of insight into the properties of ventilation-perfusion distributions. Refers to data corresponding to normal and abnormal lungs. Uses a two-dimensional framework with the respiratory gases of oxygen and carbon dioxide. (CS)

Cystic Fibrosis Associated with Worse Survival After Liver Transplantation.

PubMed

Black, Sylvester M; Woodley, Frederick W; Tumin, Dmitry; Mumtaz, Khalid; Whitson, Bryan A; Tobias, Joseph D; Hayes, Don

2016-04-01

Survival in cystic fibrosis patients after liver transplantation and liver-lung transplantation is not well studied. To discern survival rates after liver transplantation and liver-lung transplantation in patients with and without cystic fibrosis. The United Network for Organ Sharing database was queried from 1987 to 2013. Univariate Cox proportional hazards, multivariate Cox models, and propensity score matching were performed. Liver transplant and liver-lung transplant were performed in 212 and 53 patients with cystic fibrosis, respectively. Univariate Cox proportional hazards regression identified lower survival in cystic fibrosis after liver transplant compared to a reference non-cystic fibrosis liver transplant cohort (HR 1.248; 95 % CI 1.012, 1.541; p = 0.039). Supplementary analysis found graft survival was similar across the 3 recipient categories (log-rank test: χ(2) 2.68; p = 0.262). Multivariate Cox models identified increased mortality hazard among cystic fibrosis patients undergoing liver transplantation (HR 2.439; 95 % CI 1.709, 3.482; p < 0.001) and liver-lung transplantation (HR 2.753; 95 % CI 1.560, 4.861; p < 0.001). Propensity score matching of cystic fibrosis patients undergoing liver transplantation to non-cystic fibrosis controls identified a greater mortality hazard in the cystic fibrosis cohort using a Cox proportional hazards model stratified on matched pairs (HR 3.167; 95 % CI 1.265, 7.929, p = 0.014). Liver transplantation in cystic fibrosis is associated with poorer long-term patient survival compared to non-cystic fibrosis patients, although the difference is not due to graft survival.

Validation of the plain chest radiograph for epidemiologic studies of airflow obstruction

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

Musk, A.W.

The chest radiographs of 125 industrial workers from rural New South Wales were examined for overinflated lungs, with and without attenuated midzonal vessels. Although the mean values of a comprehensive range of pulmonary function tests in the whole group were within normal limits, the nine subjects whose radiographs showed overinflated lungs and attenuated vessels had significantly impaired pulmonary function in comparison with 85 subjects with normal radiographs. The mean values for these nine subjects, expressed as a percentage of the mean value for subjects with normal radiographs, were: forced expiratory volume in 1 second, 75%; total lung capacity, 107%; residualmore » volume, 143%; transpulmonary pressure at maximum inspiration, 60%; static deflation compliance, 158%; lung volume at transpulmonary pressure 10 cm H/sub 2/O, 132%; transfer factor, 79%; and transfer factor/alveolar volume, 77%. Similar results were obtained by a second observer. Those subjects with overinflation but no vascular attenuation had significantly larger mean values for vital capacity and alveolar volume but no significant difference in total lung capacity or other tests of the mechanical properties of the lungs. Agreement on the presence of a positive sign between the two observers expressed as a percentage of those considered positive by either was 81% for overinflation and 62% for attenuated midzonal vessels. The results indicate that in groups of subjects with normal-average values of pulmonary function, the plain chest radiograph may provide information concerning pulmonary structure that is reflected in tests of function.« less

Extracting the normal lung dose-response curve from clinical DVH data: a possible role for low dose hyper-radiosensitivity, increased radioresistance

NASA Astrophysics Data System (ADS)

Gordon, J. J.; Snyder, K.; Zhong, H.; Barton, K.; Sun, Z.; Chetty, I. J.; Matuszak, M.; Ten Haken, R. K.

2015-09-01

In conventionally fractionated radiation therapy for lung cancer, radiation pneumonitis’ (RP) dependence on the normal lung dose-volume histogram (DVH) is not well understood. Complication models alternatively make RP a function of a summary statistic, such as mean lung dose (MLD). This work searches over damage profiles, which quantify sub-volume damage as a function of dose. Profiles that achieve best RP predictive accuracy on a clinical dataset are hypothesized to approximate DVH dependence. Step function damage rate profiles R(D) are generated, having discrete steps at several dose points. A range of profiles is sampled by varying the step heights and dose point locations. Normal lung damage is the integral of R(D) with the cumulative DVH. Each profile is used in conjunction with a damage cutoff to predict grade 2 plus (G2+) RP for DVHs from a University of Michigan clinical trial dataset consisting of 89 CFRT patients, of which 17 were diagnosed with G2+ RP. Optimal profiles achieve a modest increase in predictive accuracy—erroneous RP predictions are reduced from 11 (using MLD) to 8. A novel result is that optimal profiles have a similar distinctive shape: enhanced damage contribution from low doses (<20 Gy), a flat contribution from doses in the range ~20-40 Gy, then a further enhanced contribution from doses above 40 Gy. These features resemble the hyper-radiosensitivity / increased radioresistance (HRS/IRR) observed in some cell survival curves, which can be modeled using Joiner’s induced repair model. A novel search strategy is employed, which has the potential to estimate RP dependence on the normal lung DVH. When applied to a clinical dataset, identified profiles share a characteristic shape, which resembles HRS/IRR. This suggests that normal lung may have enhanced sensitivity to low doses, and that this sensitivity can affect RP risk.

Lung cancer in shipbuilding and related industries in Louisiana.

PubMed

Gottlieb, M S; Stedman, R B

1979-09-01

The relationship between shipbuilding and related industries and risk of fatal lung cancer (1960-1975) is described for selected Louisiana parishes. Deaths from lung cancer were matched to deaths not caused by cancer. Shipbuilders had a significantly increased risk (greater than twofold) of dying of lung cancer as compared with other causes. The risk of dying of lung cancer in related occupations (seamen and longshoremen) was also increased. Information on laterality of lung cancer was not supportive of particulate substances contributing to causality due to the large number of unspecified cases. The preponderance of deaths appears to be occurring in men with a greater number of years of exposure to this industry and in those aged 20 to 34 years in 1940. These common occupations in Louisiana could contribute to the high rate of lung cancer.

Signs of Gas Trapping in Normal Lung Density Regions in Smokers.

PubMed

Bodduluri, Sandeep; Reinhardt, Joseph M; Hoffman, Eric A; Newell, John D; Nath, Hrudaya; Dransfield, Mark T; Bhatt, Surya P

2017-12-01

A substantial proportion of subjects without overt airflow obstruction have significant respiratory morbidity and structural abnormalities as visualized by computed tomography. Whether regions of the lung that appear normal using traditional computed tomography criteria have mild disease is not known. To identify subthreshold structural disease in normal-appearing lung regions in smokers. We analyzed 8,034 subjects with complete inspiratory and expiratory computed tomographic data participating in the COPDGene Study, including 103 lifetime nonsmokers. The ratio of the mean lung density at end expiration (E) to end inspiration (I) was calculated in lung regions with normal density (ND) by traditional thresholds for mild emphysema (-910 Hounsfield units) and gas trapping (-856 Hounsfield units) to derive the ND-E/I ratio. Multivariable regression analysis was used to measure the associations between ND-E/I, lung function, and respiratory morbidity. The ND-E/I ratio was greater in smokers than in nonsmokers, and it progressively increased from mild to severe chronic obstructive pulmonary disease severity. A proportion of 26.3% of smokers without airflow obstruction had ND-E/I greater than the 90th percentile of normal. ND-E/I was independently associated with FEV 1 (adjusted β = -0.020; 95% confidence interval [CI], -0.032 to -0.007; P = 0.001), St. George's Respiratory Questionnaire scores (adjusted β = 0.952; 95% CI, 0.529 to 1.374; P < 0.001), 6-minute-walk distance (adjusted β = -10.412; 95% CI, -12.267 to -8.556; P < 0.001), and body mass index, airflow obstruction, dyspnea, and exercise capacity index (adjusted β = 0.169; 95% CI, 0.148 to 0.190; P < 0.001), and also with FEV 1 change at follow-up (adjusted β = -3.013; 95% CI, -4.478 to -1.548; P = 0.001). Subthreshold gas trapping representing mild small airway disease is prevalent in normal-appearing lung regions in smokers without airflow obstruction, and it is associated with respiratory morbidity. Clinical trial registered with www.clinicaltrials.gov (NCT00608764).

[Tripartite-motif protein 25 and pyruvate kinase M2 protein expression in non-small cell lung cancer].

PubMed

Jing, Huai-Zhi; Qiu, Feng; Chen, Shi-Zhi; Su, Lin; Qu, Can

2015-03-01

To investigate the expression of tripartite-motif protein 25 (TRIM25) and pyruvate kinase M2 (PKM2) protein in non-small cell lung cancer (NSCLC) and explore their role in the occurrence and progression of NSCLC. The expressions of TRIM25 and PKM2 protein were detected in 60 NSCLC specimens and 20 adjacent normal lung tissue (>5 cm from the lesions) with immunofluorescence histochemical method and in 10 fresh specimens of NSCLC with Western blotting. The results were analyzed in relation with the clinicopathological features of the patients. The positivity rates of TRIM25 expression was 45% in the 60 lung carcinoma specimens, significantly higher than that in the 20 normal lung tissues (10%, P=0.005). TRIM25 protein was expressed in 28.6% of lung adenocarcinoma tissues and in 59.4% of squamous carcinoma tissues (P=0.017). TRIM25 protein expression was positively correlated with the TNM stages and lymph node metastasis of NSCLC (P<0.05). The expressions of PKM2 protein in 60 cases of lung carcinoma was 73.3%,while in 20 cases of normal lung tissues the expressions was 30%(P=0.001). The positivity rates of PKM2 expression differed significantly between lung adenocarcinoma and squamous carcinoma (57.1% vs 87.5%, P=0.008). An inverse correlation was noted between TRIM25 and PKM2 expressions (P=0.026). TRIM25 and PKM2 protein may participate in the occurrence and progression of NSCLC, and their expressions are inversely correlated.

Improved throughput traction microscopy reveals pivotal role for matrix stiffness in fibroblast contractility and TGF-β responsiveness

PubMed Central

Marinković, Aleksandar; Mih, Justin D.; Park, Jin-Ah; Liu, Fei

2012-01-01

Lung fibroblast functions such as matrix remodeling and activation of latent transforming growth factor-β1 (TGF-β1) are associated with expression of the myofibroblast phenotype and are directly linked to fibroblast capacity to generate force and deform the extracellular matrix. However, the study of fibroblast force-generating capacities through methods such as traction force microscopy is hindered by low throughput and time-consuming procedures. In this study, we improved at the detail level methods for higher-throughput traction measurements on polyacrylamide hydrogels using gel-surface-bound fluorescent beads to permit autofocusing and automated displacement mapping, and transduction of fibroblasts with a fluorescent label to streamline cell boundary identification. Together these advances substantially improve the throughput of traction microscopy and allow us to efficiently compute the forces exerted by lung fibroblasts on substrates spanning the stiffness range present in normal and fibrotic lung tissue. Our results reveal that lung fibroblasts dramatically alter the forces they transmit to the extracellular matrix as its stiffness changes, with very low forces generated on matrices as compliant as normal lung tissue. Moreover, exogenous TGF-β1 selectively accentuates tractions on stiff matrices, mimicking fibrotic lung, but not on physiological stiffness matrices, despite equivalent changes in Smad2/3 activation. Taken together, these results demonstrate a pivotal role for matrix mechanical properties in regulating baseline and TGF-β1-stimulated contraction of lung fibroblasts and suggest that stiff fibrotic lung tissue may promote myofibroblast activation through contractility-driven events, whereas normal lung tissue compliance may protect against such feedback amplification of fibroblast activation. PMID:22659883

Glucose Transporter-1 Distribution in Fibrotic Lung Disease

PubMed Central

Malide, Daniela; Yao, Jianhua; Nathan, Steven D.; Rosas, Ivan O.; Gahl, William A.; Moss, Joel; Gochuico, Bernadette R.

2013-01-01

Background: [18F]-2-fluoro-2-deoxyglucose (FDG)-PET scan uptake is increased in areas of fibrosis and honeycombing in patients with idiopathic pulmonary fibrosis (IPF). Glucose transporter-1 (Glut-1) is known to be the main transporter for FDG. There is a paucity of data regarding the distribution of Glut-1 and the cells responsible for FDG binding in fibrotic lung diseases. Methods: We applied immunofluorescence to localize Glut-1 in normal, IPF, and Hermansky-Pudlak syndrome (HPS) pulmonary fibrosis lung tissue specimens as well as an array of 19 different lung neoplasms. In addition, we investigated Glut-1 expression in inflammatory cells from BAL fluid (BALF) from healthy volunteers, subjects with IPF, and subjects with HPS pulmonary fibrosis. Results: In normal lung tissue, Glut-1 immunoreactivity was seen on the surface of erythrocytes. In tissue sections from fibrotic lung diseases (IPF and HPS pulmonary fibrosis), Glut-1 immunoreactivity was present on the surface of erythrocytes and inflammatory cells. BALF inflammatory cells from healthy control subjects showed no immunoreactivity; BALF cells from subjects with IPF and HPS pulmonary fibrosis showed Glut-1 immunoreactivity associated with neutrophils and alveolar macrophages. Conclusions: Glut-1 transporter expression in normal lung is limited to erythrocytes. In fibrotic lung, erythrocytes and inflammatory cells express Glut-1. Together, these data suggest that FDG-PET scan uptake in IPF could be explained by enhanced inflammatory and erythrocytes uptake due to neovascularization seen in IPF and not an upregulation of metabolic rate in pneumocytes. Thus, FDG-PET scan may detect inflammation and neovascularization in lung fibrosis. PMID:23699745

[Estimation of pulmonary hypertension in lung and valvular heart diseases by perfusion lung scintigraphy].

PubMed

Fujii, T; Tanaka, M; Yazaki, Y; Kitabayashi, H; Koizumi, T; Kubo, K; Sekiguchi, M; Yano, K

1999-06-01

To estimate pulmonary hypertension, we measured postural differences in pulmonary blood flow for the lateral decubitus positions on perfusion lung scintigrams with Tc-99 m macro-aggregated albumin, applying the method devised by Tanaka et al (Eur J Nucl Med 17: 320-326, 1990). Utilizing a scintillation camera coupled to a minicomputer system, changes in the distribution of pulmonary blood flow caused by gravitational effects, namely, changes in the total count ratios for the right lung versus the left lung in the right and left lateral decubitus positions (R/L), were obtained for 44 patients with lung disease, 95 patients with valvular heart disease, and 23 normal subjects. Mean standard deviation in the R/L ratios was 3.09 +/- 1.28 for the normal subjects, 1.97 +/- 0.89 for the patients with lung disease, and 1.59 +/- 0.59 for the patients with valvular heart disease. The R/L ratios correlated with mean pulmonary arterial pressure and cardio-thoracic ratios in the lung disease and valvular heart disease groups, with pulmonary arteriolar resistance in the former, and with pulmonary capillary wedge pressure in the latter. Defining pulmonary hypertension (> 20 mmHg) as an R/L ratio of less than 1.81, which is the mean-1 standard deviation for normal subjects, the sensitivity and the specificity of the R/L ratio for the diagnosis of pulmonary hypertension were 62.9% and 76.2%, respectively, for the lung disease patients, and 80.3% and 61.8%, respectively, for the valvular heart disease patients. This method seems to be useful for the pathophysiologic evaluation of pulmonary perfusion in cases of lung disease and valvular heart disease.

Effect of cadmium on the expression levels of interleukin-1α and interleukin-10 cytokines in human lung cells.

PubMed

Odewumi, Caroline; Latinwo, Lekan M; Sinclair, Andre; Badisa, Veera L D; Abdullah, Ahkinyala; Badisa, Ramesh B

2015-11-01

Cadmium is an environmentally hazardous metal, which causes toxicity in humans. Inhalation of cigarette smoke and industrial fumes containing cadmium are sources of cadmium exposure. It is responsible for the malfunction of various organs, leading to disease particularly in the lungs, liver and kidneys. In the present study, the effect of cadmium chloride (CdCl2) on cell viability, and the expression levels of interleukin (IL)‑1α and IL‑10 cytokines at various concentrations and incubation durations were assessed in MRC‑9 human normal lung and A549 human lung cancer cells to elucidate the mechanism of cadmium toxicity. Cell viability was measured using a crystal violet dye binding assay. The expression levels of the cytokines were measured by cytokine specific enzyme‑linked immunosorbent assay kits. The viability assay results revealed higher sensitivity of the A549 lung cancer cells to CdCl2 compared with the normal MRC‑9 lung cells. In the normal MRC‑9 lung cells, higher expression levels of the cytokines were observed at the lowest CdCl2 concentration at a shorter exposure time compared with the lung cancer cells. Higher levels of the cytokines were observed in the A549 lung cancer cells at all other times and concentrations compared with the MRC‑9 cells, indicating higher levels of inflammation. The cytokine levels were reduced at higher CdCl2 concentrations and longer exposure durations, demonstrating the toxic effect of cadmium. The results indicated that CdCl2 affected the expression levels of the cytokines and led to cytotoxicity in human lung cells, and suggested that compounds which reduce inflammation may prevent cadmium toxicity.

Alterations in gene expression and DNA methylation during murine and human lung alveolar septation.

PubMed

Cuna, Alain; Halloran, Brian; Faye-Petersen, Ona; Kelly, David; Crossman, David K; Cui, Xiangqin; Pandit, Kusum; Kaminski, Naftali; Bhattacharya, Soumyaroop; Ahmad, Ausaf; Mariani, Thomas J; Ambalavanan, Namasivayam

2015-07-01

DNA methylation, a major epigenetic mechanism, may regulate coordinated expression of multiple genes at specific time points during alveolar septation in lung development. The objective of this study was to identify genes regulated by methylation during normal septation in mice and during disordered septation in bronchopulmonary dysplasia. In mice, newborn lungs (preseptation) and adult lungs (postseptation) were evaluated by microarray analysis of gene expression and immunoprecipitation of methylated DNA followed by sequencing (MeDIP-Seq). In humans, microarray gene expression data were integrated with genome-wide DNA methylation data from bronchopulmonary dysplasia versus preterm and term lung. Genes with reciprocal changes in expression and methylation, suggesting regulation by DNA methylation, were identified. In mice, 95 genes with inverse correlation between expression and methylation during normal septation were identified. In addition to genes known to be important in lung development (Wnt signaling, Angpt2, Sox9, etc.) and its extracellular matrix (Tnc, Eln, etc.), genes involved with immune and antioxidant defense (Stat4, Sod3, Prdx6, etc.) were also observed. In humans, 23 genes were differentially methylated with reciprocal changes in expression in bronchopulmonary dysplasia compared with preterm or term lung. Genes of interest included those involved with detoxifying enzymes (Gstm3) and transforming growth factor-β signaling (bone morphogenetic protein 7 [Bmp7]). In terms of overlap, 20 genes and three pathways methylated during mouse lung development also demonstrated changes in methylation between preterm and term human lung. Changes in methylation correspond to altered expression of a number of genes associated with lung development, suggesting that DNA methylation of these genes may regulate normal and abnormal alveolar septation.

Aerosol bolus dispersion in acinar airways—influence of gravity and airway asymmetry

PubMed Central

Ma, Baoshun

2012-01-01

The aerosol bolus technique can be used to estimate the degree of convective mixing in the lung; however, contributions of different lung compartments to measured dispersion cannot be differentiated unambiguously. To estimate dispersion in the distal lung, we studied the effect of gravity and airway asymmetry on the dispersion of 1 μm-diameter particle boluses in three-dimensional computational models of the lung periphery, ranging from a single alveolar sac to four-generation (g4) structures of bifurcating airways that deformed homogeneously during breathing. Boluses were introduced at the beginning of a 2-s inhalation, immediately followed by a 3-s exhalation. Dispersion was estimated by the half-width of the exhaled bolus. Dispersion was significantly affected by the spatial orientation of the models in normal gravity and was less in zero gravity than in normal gravity. Dispersion was strongly correlated with model volume in both normal and zero gravity. Predicted pulmonary dispersion based on a symmetric g4 acinar model was 391 ml and 238 ml under normal and zero gravity, respectively. These results accounted for a significant amount of dispersion measured experimentally. In zero gravity, predicted dispersion in a highly asymmetric model accounted for ∼20% of that obtained in a symmetric model with comparable volume and number of alveolated branches, whereas normal gravity dispersions were comparable in both models. These results suggest that gravitational sedimentation and not geometrical asymmetry is the dominant factor in aerosol dispersion in the lung periphery. PMID:22678957

Aerosol bolus dispersion in acinar airways--influence of gravity and airway asymmetry.

PubMed

Ma, Baoshun; Darquenne, Chantal

2012-08-01

The aerosol bolus technique can be used to estimate the degree of convective mixing in the lung; however, contributions of different lung compartments to measured dispersion cannot be differentiated unambiguously. To estimate dispersion in the distal lung, we studied the effect of gravity and airway asymmetry on the dispersion of 1 μm-diameter particle boluses in three-dimensional computational models of the lung periphery, ranging from a single alveolar sac to four-generation (g4) structures of bifurcating airways that deformed homogeneously during breathing. Boluses were introduced at the beginning of a 2-s inhalation, immediately followed by a 3-s exhalation. Dispersion was estimated by the half-width of the exhaled bolus. Dispersion was significantly affected by the spatial orientation of the models in normal gravity and was less in zero gravity than in normal gravity. Dispersion was strongly correlated with model volume in both normal and zero gravity. Predicted pulmonary dispersion based on a symmetric g4 acinar model was 391 ml and 238 ml under normal and zero gravity, respectively. These results accounted for a significant amount of dispersion measured experimentally. In zero gravity, predicted dispersion in a highly asymmetric model accounted for ∼20% of that obtained in a symmetric model with comparable volume and number of alveolated branches, whereas normal gravity dispersions were comparable in both models. These results suggest that gravitational sedimentation and not geometrical asymmetry is the dominant factor in aerosol dispersion in the lung periphery.

The cough response to ultrasonically nebulized distilled water in heart-lung transplantation patients

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

Higenbottam, T.; Jackson, M.; Woolman, P.

1989-07-01

As a result of clinical heart-lung transplantation, the lungs are denervated below the level of the tracheal anastomosis. It has been questioned whether afferent vagal reinnervation occurs after surgery. Here we report the cough frequency, during inhalation of ultrasonically nebulized distilled water, of 15 heart-lung transplant patients studied 6 wk to 36 months after surgery. They were compared with 15 normal subjects of a similar age and sex. The distribution of the aerosol was studied in five normal subjects using /sup 99m/technetium diethylene triamine pentaacetate (/sup 99m/Tc-DTPA) in saline. In seven patients, the sensitivity of the laryngeal mucosa to instilledmore » distilled water (0.2 ml) was tested at the time of fiberoptic bronchoscopy by recording the cough response. Ten percent of the aerosol was deposited onto the larynx and trachea, 56% on the central airways, and 34% in the periphery of the lung. The cough response to the aerosol was strikingly diminished in the patients compared with normal subjects (p less than 0.001), but all seven patients coughed when distilled water was instilled onto the larynx. As expected, the laryngeal mucosa of heart-lung transplant patients remains sensitive to distilled water. However, the diminished coughing when the distilled water is distributed by aerosol to the central airways supports the view that vagal afferent nerves do not reinnervate the lungs after heart-lung transplantation, up to 36 months after surgery.« less

Measurement of xenon diffusing capacity in the rat lung by hyperpolarized 129Xe MRI and dynamic spectroscopy in a single breath-hold.

PubMed

Abdeen, Nishard; Cross, Albert; Cron, Gregory; White, Steven; Rand, Thomas; Miller, David; Santyr, Giles

2006-08-01

We used the dual capability of hyperpolarized 129Xe for spectroscopy and imaging to develop new measures of xenon diffusing capacity in the rat lung that (analogously to the diffusing capacity of carbon monoxide or DLCO) are calculated as a product of total lung volume and gas transfer rate constants divided by the pressure gradient. Under conditions of known constant pressure breath-hold, the volume is measured by hyperpolarized 129Xe MRI, and the transfer rate is measured by dynamic spectroscopy. The new quantities (xenon diffusing capacity in lung parenchyma (DLXeLP)), xenon diffusing capacity in RBCs (DLXeRBC), and total lung xenon diffusing capacity (DLXe)) were measured in six normal rats and six rats with lung inflammation induced by instillation of fungal spores of Stachybotrys chartarum. DLXeLP, DLXeRBC, and DLXe were 56 +/- 10 ml/min/mmHg, 64 +/- 35 ml/min/mmHg, and 29 +/- 9 ml/min/mmHg, respectively, for normal rats, and 27 +/- 9 ml/min/mmHg, 42 +/- 27 ml/min/mmHg, and 16 +/- 7 ml/min/mmHg, respectively, for diseased rats. Lung volumes and gas transfer times for LP (TtrLP) were 16 +/- 2 ml and 22 +/- 3 ms, respectively, for normal rats and 12 +/- 2 ml and 35 +/- 8 ms, respectively, for diseased rats. Xenon diffusing capacities may be useful for measuring changes in gas exchange associated with inflammation and other lung diseases. Copyright 2006 Wiley-Liss, Inc.

New formulas for calculating the lung-to-head ratio in healthy fetuses between 20 and 40 weeks' gestation.

PubMed

Kehl, Sven; Eckert, Sven; Berlit, Sebastian; Tuschy, Benjamin; Sütterlin, Marc; Siemer, Jörn

2013-11-01

The purpose of this study was to develop new formulas for the expected fetal lung area-to-head circumference ratio in normal singleton pregnancies between 20 and 40 weeks' gestation. The lung-to-head ratio and complete fetal biometric parameters of 126 fetuses between 20 and 40 weeks' gestation were prospectively measured. The lung-to-head ratio was measured by 3 different methods (longest diameter, anteroposterior diameter, and tracing). Formulas for predicting right and left lung-to-head ratios with regard to gestational age and biometric parameters were derived by stepwise regression analysis. New formulas for calculating right and left lung-to-head ratios by each measurement method were derived. The formulas included gestational age only and no biometric parameters. The new formulas for estimating the expected lung-to-head ratio by the 3 different methods in normal singleton pregnancies up to 40 weeks' gestation may help improve the prognostic power of observed-to-expected lung-to-head ratio assessment in fetuses with congenital diaphragmatic hernias.

Unilateral lung transplantation for pulmonary fibrosis.

PubMed

1986-05-01

Improvements in immunosuppression and surgical techniques have made unilateral lung transplantation feasible in selected patients with end-stage interstitial lung disease. We report two cases of successful unilateral lung transplantation for end-stage respiratory failure due to pulmonary fibrosis. The patients, both oxygen-dependent, had progressive disease refractory to all treatment, with an anticipated life expectancy of less than one year on the basis of the rate of progression of the disease. Both patients were discharged six weeks after transplantation and returned to normal life. They are alive and well at 26 months and 14 months after the procedure. Pulmonary-function studies have shown substantial improvement in their lung volumes and diffusing capacities. For both patients, arterial oxygen tension is now normal and there is no arterial oxygen desaturation with exercise. This experience shows that unilateral lung transplantation, for selected patients with end-stage interstitial lung disease, provides a good functional result. Moreover, it avoids the necessity for cardiac transplantation, as required by the combined heart-lung procedure, and permits the use of the donor heart for another recipient.

Normal Variability of Weekly Musculoskeletal Screening Scores and the Influence of Training Load across an Australian Football League Season.

PubMed

Esmaeili, Alireza; Stewart, Andrew M; Hopkins, William G; Elias, George P; Lazarus, Brendan H; Rowell, Amber E; Aughey, Robert J

2018-01-01

Aim: The sit and reach test (S&R), dorsiflexion lunge test (DLT), and adductor squeeze test (AST) are commonly used in weekly musculoskeletal screening for athlete monitoring and injury prevention purposes. The aim of this study was to determine the normal week to week variability of the test scores, individual differences in variability, and the effects of training load on the scores. Methods: Forty-four elite Australian rules footballers from one club completed the weekly screening tests on day 2 or 3 post-main training (pre-season) or post-match (in-season) over a 10 month season. Ratings of perceived exertion and session duration for all training sessions were used to derive various measures of training load via both simple summations and exponentially weighted moving averages. Data were analyzed via linear and quadratic mixed modeling and interpreted using magnitude-based inference. Results: Substantial small to moderate variability was found for the tests at both season phases; for example over the in-season, the normal variability ±90% confidence limits were as follows: S&R ±1.01 cm, ±0.12; DLT ±0.48 cm, ±0.06; AST ±7.4%, ±0.6%. Small individual differences in variability existed for the S&R and AST (factor standard deviations between 1.31 and 1.66). All measures of training load had trivial effects on the screening scores. Conclusion: A change in a test score larger than the normal variability is required to be considered a true change. Athlete monitoring and flagging systems need to account for the individual differences in variability. The tests are not sensitive to internal training load when conducted 2 or 3 days post-training or post-match, and the scores should be interpreted cautiously when used as measures of recovery.

Impact of combined pulmonary fibrosis and emphysema on surgical complications and long-term survival in patients undergoing surgery for non-small-cell lung cancer.

PubMed

Hata, Atsushi; Sekine, Yasuo; Kota, Ohashi; Koh, Eitetsu; Yoshino, Ichiro

2016-01-01

The outcome of radical surgery for lung cancer was investigated in patients with combined pulmonary fibrosis and emphysema (CPFE). A retrospective chart review involved 250 patients with lung cancer who underwent pulmonary resection at Tokyo Women's Medical University Yachiyo Medical Center between 2008 and 2012. Based on the status of nontumor-bearing lung evaluated by preoperative computed tomography (CT), the patients were divided into normal, emphysema, interstitial pneumonia (IP), and CPFE groups, and their clinical characteristics and surgical outcome were analyzed. The normal, emphysema, IP, and CPFE groups comprised 124 (49.6%), 108 (43.2%), seven (2.8%), and eleven (4.4%) patients, respectively. The 5-year survival rate of the CPFE group (18.7%) was significantly lower than that of the normal (77.5%) and emphysema groups (67.1%) (P<0.0001 and P=0.0027, respectively) but equivalent to that of the IP group (44.4%) (P=0.2928). In a subset analysis of cancer stage, the 5-year overall survival rate of the CPFE group in stage I (n=8, 21.4%) was also lower than that of the normal group and emphysema group in stage I (n=91, 84.9% and n=70, 81.1%; P<0.0001 and P<0.0001, respectively). During entire observation period, the CPFE group was more likely to die of respiratory failure (27.2%) compared with the normal and emphysema groups (P<0.0001). Multivariate analysis of prognostic factors using Cox proportional hazard model identified CPFE as an independent risk factor (P=0.009). CPFE patients have a poorer prognosis than those with emphysema alone or with normal lung on CT finding. The intensive evaluation of preoperative CT images is important, and radical surgery for lung cancer should be decided carefully when patients concomitantly harbor CPFE, because of unfavorable prognosis.

Probing the regional distribution of pulmonary gas exchange through single-breath gas- and dissolved-phase 129Xe MR imaging.

PubMed

Kaushik, S Sivaram; Freeman, Matthew S; Cleveland, Zackary I; Davies, John; Stiles, Jane; Virgincar, Rohan S; Robertson, Scott H; He, Mu; Kelly, Kevin T; Foster, W Michael; McAdams, H Page; Driehuys, Bastiaan

2013-09-01

Although some central aspects of pulmonary function (ventilation and perfusion) are known to be heterogeneous, the distribution of diffusive gas exchange remains poorly characterized. A solution is offered by hyperpolarized 129Xe magnetic resonance (MR) imaging, because this gas can be separately detected in the lung's air spaces and dissolved in its tissues. Early dissolved-phase 129Xe images exhibited intensity gradients that favored the dependent lung. To quantitatively corroborate this finding, we developed an interleaved, three-dimensional radial sequence to image the gaseous and dissolved 129Xe distributions in the same breath. These images were normalized and divided to calculate "129Xe gas-transfer" maps. We hypothesized that, for healthy volunteers, 129Xe gas-transfer maps would retain the previously observed posture-dependent gradients. This was tested in nine subjects: when the subjects were supine, 129Xe gas transfer exhibited a posterior-anterior gradient of -2.00 ± 0.74%/cm; when the subjects were prone, the gradient reversed to 1.94 ± 1.14%/cm (P < 0.001). The 129Xe gas-transfer maps also exhibited significant heterogeneity, as measured by the coefficient of variation, that correlated with subject total lung capacity (r = 0.77, P = 0.015). Gas-transfer intensity varied nonmonotonically with slice position and increased in slices proximal to the main pulmonary arteries. Despite substantial heterogeneity, the mean gas transfer for all subjects was 1.00 ± 0.01 while supine and 1.01 ± 0.01 while prone (P = 0.25), indicating good "matching" between gas- and dissolved-phase distributions. This study demonstrates that single-breath gas- and dissolved-phase 129Xe MR imaging yields 129Xe gas-transfer maps that are sensitive to altered gas exchange caused by differences in lung inflation and posture.

Scintigraphy at 3 months after single lung transplantation and observations of primary graft dysfunction and lung function.

PubMed

Belmaati, Esther Okeke; Iversen, Martin; Kofoed, Klaus F; Nielsen, Michael B; Mortensen, Jann

2012-06-01

Scintigraphy has been used as a tool to detect dysfunction of the lung before and after transplantation. The aims of this study were to evaluate the development of the ventilation-perfusion relationships in single lung transplant recipients in the first year, at 3 months after transplantation, and to investigate whether scintigraphic findings at 3 months were predictive for the outcome at 12 months in relation to primary graft dysfunction (PGD) and lung function. A retrospective study was carried out on all patients who prospectively and consecutively were referred for a routine lung scintigraphy procedure 3 months after single lung transplantation (SLTX). A total of 41 patients were included in the study: 20 women and 21 men with the age span of patients at transplantation being 38-66 years (mean ± SD: 54.2 ± 6.0). Patient records also included lung function tests and chest X-ray images. We found no significant correlation between lung function distribution at 3 months and PGD at 72 h. There was also no significant correlation between PGD scores at 72 h and lung function at 6 and 12 months. The same applied to scintigraphic scores for heterogeneity at 3 months compared with lung function at 6 and 12 months. Fifty-five percent of all patients had decreased ventilation function measured in the period from 6 to 12 months. Forty-nine percent of the patients had normal perfusion evaluations, and 51% had abnormal perfusion evaluations at 3 months. For ventilation evaluations, 72% were normal and 28% were abnormal. There was a significant difference in the normal versus abnormal perfusion and ventilation scintigraphic images evaluated from the same patients. Ventilation was distributed more homogenously in the transplanted lung than perfusion in the same lung. The relative distribution of perfusion and ventilation to the transplanted lung of patients with and without a primary diagnosis of fibrosis did not differ significantly from each other. We conclude that PGD defined at 72 h does not lead to recognizable changes in ventilation-perfusion scintigrapy at 3 months, and scintigraphic findings do not correlate with development in lung function in the first 12 months.

Three distinct pneumotypes characterize the microbiome of the lung in BALB/cJ mice.

PubMed

Scheiermann, Julia; Klinman, Dennis M

2017-01-01

Bacteria can rarely be isolated from normal healthy lungs using conventional culture techniques, supporting the traditional belief that the lungs are sterile. Yet recent studies using next generation sequencing report that bacterial DNA commonly found in the upper respiratory tract (URT) is present at lower levels in the lungs. Interpretation of that finding is complicated by the technical limitations and potential for contamination introduced when dealing with low biomass samples. The current work sought to overcome those limitations to clarify the number, type and source of bacteria present in the lungs of normal mice. Results showed that the oral microbiome is diverse and highly conserved whereas murine lung samples fall into three distinct patterns. 33% of the samples were sterile, as they lacked culturable bacteria and their bacterial DNA content did not differ from background. 9% of samples contained comparatively higher amounts of bacterial DNA whose composition mimicked that detected in the URT. A final group (58%) contained smaller amounts of microbial DNA whose composition was correlating to that of rodent chow and cage bedding, likely acquired by inspiration of food and bedding fragments. By analyzing each sample independently rather than working with group averages, this work eliminated the bias introduced by aspiration-contaminated samples to establish that three distinct microbiome pneumotypes are present in normal murine lungs.

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

Expression of apoptosis-regulatory genes in lung tumour cell lines: relationship to p53 expression and relevance to acquired drug resistance.

PubMed Central

Reeve, J. G.; Xiong, J.; Morgan, J.; Bleehen, N. M.

1996-01-01

As a first step towards elucidating the potential role(s) of bcl-2 and bcl-2-related genes in lung tumorigenesis and therapeutic responsiveness, the expression of these genes has been examined in a panel of lung cancer cell lines derived from untreated and treated patients, and in cell lines selected in vitro for multidrug resistance. Bcl-2 was hyperexpressed in 15 of 16 small-cell lung cancer (SCLC) cell lines and two of five non-small-cell lung cancer (NSCLC) lines compared with normal lung and brain, and hyperexpression was not chemotherapy related. Bcl-x was hyperexpressed in the majority of SCLC and NSCLC cell lines as compared with normal tissues, and all lung tumour lines preferentially expressed bcl-x1-mRNA, the splice variant form that inhibits apoptosis. Bax gene transcripts were hyperexpressed in most SCLC and NSCLC cell lines examined compared with normal adult tissues. Mutant p53 gene expression was detected in the majority of the cell lines and no relationship between p53 gene expression and the expression of either bcl-2, bcl-x or bax was observed. No changes in bcl-2, bcl-x and bax gene expression were observed in multidrug-resistant cell lines compared with their drug-sensitive counterparts. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 PMID:8630278

Three Dimensional Imaging of Paraffin Embedded Human Lung Tissue Samples by Micro-Computed Tomography

PubMed Central

Scott, Anna E.; Vasilescu, Dragos M.; Seal, Katherine A. D.; Keyes, Samuel D.; Mavrogordato, Mark N.; Hogg, James C.; Sinclair, Ian; Warner, Jane A.; Hackett, Tillie-Louise; Lackie, Peter M.

2015-01-01

Background Understanding the three-dimensional (3-D) micro-architecture of lung tissue can provide insights into the pathology of lung disease. Micro computed tomography (µCT) has previously been used to elucidate lung 3D histology and morphometry in fixed samples that have been stained with contrast agents or air inflated and dried. However, non-destructive microstructural 3D imaging of formalin-fixed paraffin embedded (FFPE) tissues would facilitate retrospective analysis of extensive tissue archives of lung FFPE lung samples with linked clinical data. Methods FFPE human lung tissue samples (n = 4) were scanned using a Nikon metrology µCT scanner. Semi-automatic techniques were used to segment the 3D structure of airways and blood vessels. Airspace size (mean linear intercept, Lm) was measured on µCT images and on matched histological sections from the same FFPE samples imaged by light microscopy to validate µCT imaging. Results The µCT imaging protocol provided contrast between tissue and paraffin in FFPE samples (15mm x 7mm). Resolution (voxel size 6.7 µm) in the reconstructed images was sufficient for semi-automatic image segmentation of airways and blood vessels as well as quantitative airspace analysis. The scans were also used to scout for regions of interest, enabling time-efficient preparation of conventional histological sections. The Lm measurements from µCT images were not significantly different to those from matched histological sections. Conclusion We demonstrated how non-destructive imaging of routinely prepared FFPE samples by laboratory µCT can be used to visualize and assess the 3D morphology of the lung including by morphometric analysis. PMID:26030902

Using rule-based natural language processing to improve disease normalization in biomedical text.

PubMed

Kang, Ning; Singh, Bharat; Afzal, Zubair; van Mulligen, Erik M; Kors, Jan A

2013-01-01

In order for computers to extract useful information from unstructured text, a concept normalization system is needed to link relevant concepts in a text to sources that contain further information about the concept. Popular concept normalization tools in the biomedical field are dictionary-based. In this study we investigate the usefulness of natural language processing (NLP) as an adjunct to dictionary-based concept normalization. We compared the performance of two biomedical concept normalization systems, MetaMap and Peregrine, on the Arizona Disease Corpus, with and without the use of a rule-based NLP module. Performance was assessed for exact and inexact boundary matching of the system annotations with those of the gold standard and for concept identifier matching. Without the NLP module, MetaMap and Peregrine attained F-scores of 61.0% and 63.9%, respectively, for exact boundary matching, and 55.1% and 56.9% for concept identifier matching. With the aid of the NLP module, the F-scores of MetaMap and Peregrine improved to 73.3% and 78.0% for boundary matching, and to 66.2% and 69.8% for concept identifier matching. For inexact boundary matching, performances further increased to 85.5% and 85.4%, and to 73.6% and 73.3% for concept identifier matching. We have shown the added value of NLP for the recognition and normalization of diseases with MetaMap and Peregrine. The NLP module is general and can be applied in combination with any concept normalization system. Whether its use for concept types other than disease is equally advantageous remains to be investigated.

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.

3D temporal subtraction on multislice CT images using nonlinear warping technique

NASA Astrophysics Data System (ADS)

Ishida, Takayuki; Katsuragawa, Shigehiko; Kawashita, Ikuo; Kim, Hyounseop; Itai, Yoshinori; Awai, Kazuo; Li, Qiang; Doi, Kunio

2007-03-01

The detection of very subtle lesions and/or lesions overlapped with vessels on CT images is a time consuming and difficult task for radiologists. In this study, we have developed a 3D temporal subtraction method to enhance interval changes between previous and current multislice CT images based on a nonlinear image warping technique. Our method provides a subtraction CT image which is obtained by subtraction of a previous CT image from a current CT image. Reduction of misregistration artifacts is important in the temporal subtraction method. Therefore, our computerized method includes global and local image matching techniques for accurate registration of current and previous CT images. For global image matching, we selected the corresponding previous section image for each current section image by using 2D cross-correlation between a blurred low-resolution current CT image and a blurred previous CT image. For local image matching, we applied the 3D template matching technique with translation and rotation of volumes of interests (VOIs) which were selected in the current and the previous CT images. The local shift vector for each VOI pair was determined when the cross-correlation value became the maximum in the 3D template matching. The local shift vectors at all voxels were determined by interpolation of shift vectors of VOIs, and then the previous CT image was nonlinearly warped according to the shift vector for each voxel. Finally, the warped previous CT image was subtracted from the current CT image. The 3D temporal subtraction method was applied to 19 clinical cases. The normal background structures such as vessels, ribs, and heart were removed without large misregistration artifacts. Thus, interval changes due to lung diseases were clearly enhanced as white shadows on subtraction CT images.

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.

Effects of body position on lung density estimated from EIT data

NASA Astrophysics Data System (ADS)

Noshiro, Makoto; Ebihara, Kei; Sato, Ena; Nebuya, Satoru; Brown, Brian H.

2010-04-01

Normal subjects took the sitting, supine, prone, right lateral and left lateral positions during the measurement procedure. One minute epochs of EIT data were collected at the levels of the 3rd, 4th, 5th and 6th intercostal spaces in each position during normal tidal breathing. Lung density was then determined from the EIT data using the method proposed by Brown5. Lung density at the electrode level of the 6th intercostal space was different from that at almost any other levels in both male and female subjects, and lung density at the electrode levels of the 4th and 5th intercostal spaces in male subjects did not depend upon position.

Deep neural network convolution (NNC) for three-class classification of diffuse lung disease opacities in high-resolution CT (HRCT): consolidation, ground-glass opacity (GGO), and normal opacity

NASA Astrophysics Data System (ADS)

Hashimoto, Noriaki; Suzuki, Kenji; Liu, Junchi; Hirano, Yasushi; MacMahon, Heber; Kido, Shoji

2018-02-01

Consolidation and ground-glass opacity (GGO) are two major types of opacities associated with diffuse lung diseases. Accurate detection and classification of such opacities are crucially important in the diagnosis of lung diseases, but the process is subjective, and suffers from interobserver variability. Our study purpose was to develop a deep neural network convolution (NNC) system for distinguishing among consolidation, GGO, and normal lung tissue in high-resolution CT (HRCT). We developed ensemble of two deep NNC models, each of which was composed of neural network regression (NNR) with an input layer, a convolution layer, a fully-connected hidden layer, and a fully-connected output layer followed by a thresholding layer. The output layer of each NNC provided a map for the likelihood of being each corresponding lung opacity of interest. The two NNC models in the ensemble were connected in a class-selection layer. We trained our NNC ensemble with pairs of input 2D axial slices and "teaching" probability maps for the corresponding lung opacity, which were obtained by combining three radiologists' annotations. We randomly selected 10 and 40 slices from HRCT scans of 172 patients for each class as a training and test set, respectively. Our NNC ensemble achieved an area under the receiver-operating-characteristic (ROC) curve (AUC) of 0.981 and 0.958 in distinction of consolidation and GGO, respectively, from normal opacity, yielding a classification accuracy of 93.3% among 3 classes. Thus, our deep-NNC-based system for classifying diffuse lung diseases achieved high accuracies for classification of consolidation, GGO, and normal opacity.

Lung Structure and the Intrinsic Challenges of Gas Exchange.

PubMed

Hsia, Connie C W; Hyde, Dallas M; Weibel, Ewald R

2016-03-15

Structural and functional complexities of the mammalian lung evolved to meet a unique set of challenges, namely, the provision of efficient delivery of inspired air to all lung units within a confined thoracic space, to build a large gas exchange surface associated with minimal barrier thickness and a microvascular network to accommodate the entire right ventricular cardiac output while withstanding cyclic mechanical stresses that increase several folds from rest to exercise. Intricate regulatory mechanisms at every level ensure that the dynamic capacities of ventilation, perfusion, diffusion, and chemical binding to hemoglobin are commensurate with usual metabolic demands and periodic extreme needs for activity and survival. This article reviews the structural design of mammalian and human lung, its functional challenges, limitations, and potential for adaptation. We discuss (i) the evolutionary origin of alveolar lungs and its advantages and compromises, (ii) structural determinants of alveolar gas exchange, including architecture of conducting bronchovascular trees that converge in gas exchange units, (iii) the challenges of matching ventilation, perfusion, and diffusion and tissue-erythrocyte and thoracopulmonary interactions. The notion of erythrocytes as an integral component of the gas exchanger is emphasized. We further discuss the signals, sources, and limits of structural plasticity of the lung in alveolar hypoxia and following a loss of lung units, and the promise and caveats of interventions aimed at augmenting endogenous adaptive responses. Our objective is to understand how individual components are matched at multiple levels to optimize organ function in the face of physiological demands or pathological constraints. Copyright © 2016 John Wiley & Sons, Inc.

Effect of prolonged bed rest on lung volume in normal individuals

NASA Technical Reports Server (NTRS)

Beckett, W. S.; Vroman, N. B.; Nigro, D.; Thompson-Gorman, S.; Wilkerson, J. E.

1986-01-01

The effect of prolonged bed rest on the lung function was studied by measuring forced vital capacity (FVC) and total lung capacity (TLC) in normal subjects before, during, and after 11- to 12-day rest periods. It was found that both FVC and TLC increased during bed rest (compared with the ambulatory controls), while residual volume and functional residual capacity of the respiratory system did not change. It is concluded that the increase in TLC by prolonged bed rest is not dependent on alterations in plasma volume.

Improved quantitation and reproducibility in multi-PET/CT lung studies by combining CT information.

PubMed

Holman, Beverley F; Cuplov, Vesna; Millner, Lynn; Endozo, Raymond; Maher, Toby M; Groves, Ashley M; Hutton, Brian F; Thielemans, Kris

2018-06-05

Matched attenuation maps are vital for obtaining accurate and reproducible kinetic and static parameter estimates from PET data. With increased interest in PET/CT imaging of diffuse lung diseases for assessing disease progression and treatment effectiveness, understanding the extent of the effect of respiratory motion and establishing methods for correction are becoming more important. In a previous study, we have shown that using the wrong attenuation map leads to large errors due to density mismatches in the lung, especially in dynamic PET scans. Here, we extend this work to the case where the study is sub-divided into several scans, e.g. for patient comfort, each with its own CT (cine-CT and 'snap shot' CT). A method to combine multi-CT information into a combined-CT has then been developed, which averages the CT information from each study section to produce composite CT images with the lung density more representative of that in the PET data. This combined-CT was applied to nine patients with idiopathic pulmonary fibrosis, imaged with dynamic 18 F-FDG PET/CT to determine the improvement in the precision of the parameter estimates. Using XCAT simulations, errors in the influx rate constant were found to be as high as 60% in multi-PET/CT studies. Analysis of patient data identified displacements between study sections in the time activity curves, which led to an average standard error in the estimates of the influx rate constant of 53% with conventional methods. This reduced to within 5% after use of combined-CTs for attenuation correction of the study sections. Use of combined-CTs to reconstruct the sections of a multi-PET/CT study, as opposed to using the individually acquired CTs at each study stage, produces more precise parameter estimates and may improve discrimination between diseased and normal lung.

3D printer generated thorax phantom with mobile tumor for radiation dosimetry

NASA Astrophysics Data System (ADS)

Mayer, Rulon; Liacouras, Peter; Thomas, Andrew; Kang, Minglei; Lin, Liyong; Simone, Charles B.

2015-07-01

This article describes the design, construction, and properties of an anthropomorphic thorax phantom with a moving surrogate tumor. This novel phantom permits detection of dose both inside and outside a moving tumor and within the substitute lung tissue material. A 3D printer generated the thorax shell composed of a chest wall, spinal column, and posterior regions of the phantom. Images of a computed tomography scan of the thorax from a patient with lung cancer provided the template for the 3D printing. The plastic phantom is segmented into two materials representing the muscle and bones, and its geometry closely matches a patient. A surrogate spherical plastic tumor controlled by a 3D linear stage simulates a lung tumor's trajectory during normal breathing. Sawdust emulates the lung tissue in terms of average and distribution in Hounsfield numbers. The sawdust also provides a forgiving medium that permits tumor motion and sandwiching of radiochromic film inside the mobile surrogate plastic tumor for dosimetry. A custom cork casing shields the film and tumor and eliminates film bending during extended scans. The phantom, lung tissue surrogate, and radiochromic film are exposed to a seven field plan based on an ECLIPSE plan for 6 MV photons from a Trilogy machine delivering 230 cGy to the isocenter. The dose collected in a sagittal plane is compared to the calculated plan. Gamma analysis finds 8.8% and 5.5% gamma failure rates for measurements of large amplitude trajectory and static measurements relative to the large amplitude plan, respectively. These particular gamma analysis results were achieved using parameters of 3% dose and 3 mm, for regions receiving doses >150 cGy. The plan assumes a stationary detection grid unlike the moving radiochromic film and tissues. This difference was experimentally observed and motivated calculated dose distributions that incorporated the phase of the tumor periodic motion. These calculations modestly improve agreement between the measured and intended doses.

3D printer generated thorax phantom with mobile tumor for radiation dosimetry.

PubMed

Mayer, Rulon; Liacouras, Peter; Thomas, Andrew; Kang, Minglei; Lin, Liyong; Simone, Charles B

2015-07-01

This article describes the design, construction, and properties of an anthropomorphic thorax phantom with a moving surrogate tumor. This novel phantom permits detection of dose both inside and outside a moving tumor and within the substitute lung tissue material. A 3D printer generated the thorax shell composed of a chest wall, spinal column, and posterior regions of the phantom. Images of a computed tomography scan of the thorax from a patient with lung cancer provided the template for the 3D printing. The plastic phantom is segmented into two materials representing the muscle and bones, and its geometry closely matches a patient. A surrogate spherical plastic tumor controlled by a 3D linear stage simulates a lung tumor's trajectory during normal breathing. Sawdust emulates the lung tissue in terms of average and distribution in Hounsfield numbers. The sawdust also provides a forgiving medium that permits tumor motion and sandwiching of radiochromic film inside the mobile surrogate plastic tumor for dosimetry. A custom cork casing shields the film and tumor and eliminates film bending during extended scans. The phantom, lung tissue surrogate, and radiochromic film are exposed to a seven field plan based on an ECLIPSE plan for 6 MV photons from a Trilogy machine delivering 230 cGy to the isocenter. The dose collected in a sagittal plane is compared to the calculated plan. Gamma analysis finds 8.8% and 5.5% gamma failure rates for measurements of large amplitude trajectory and static measurements relative to the large amplitude plan, respectively. These particular gamma analysis results were achieved using parameters of 3% dose and 3 mm, for regions receiving doses >150 cGy. The plan assumes a stationary detection grid unlike the moving radiochromic film and tissues. This difference was experimentally observed and motivated calculated dose distributions that incorporated the phase of the tumor periodic motion. These calculations modestly improve agreement between the measured and intended doses.

3D printer generated thorax phantom with mobile tumor for radiation dosimetry

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

Mayer, Rulon; Liacouras, Peter; Thomas, Andrew

2015-07-15

This article describes the design, construction, and properties of an anthropomorphic thorax phantom with a moving surrogate tumor. This novel phantom permits detection of dose both inside and outside a moving tumor and within the substitute lung tissue material. A 3D printer generated the thorax shell composed of a chest wall, spinal column, and posterior regions of the phantom. Images of a computed tomography scan of the thorax from a patient with lung cancer provided the template for the 3D printing. The plastic phantom is segmented into two materials representing the muscle and bones, and its geometry closely matches amore » patient. A surrogate spherical plastic tumor controlled by a 3D linear stage simulates a lung tumor’s trajectory during normal breathing. Sawdust emulates the lung tissue in terms of average and distribution in Hounsfield numbers. The sawdust also provides a forgiving medium that permits tumor motion and sandwiching of radiochromic film inside the mobile surrogate plastic tumor for dosimetry. A custom cork casing shields the film and tumor and eliminates film bending during extended scans. The phantom, lung tissue surrogate, and radiochromic film are exposed to a seven field plan based on an ECLIPSE plan for 6 MV photons from a Trilogy machine delivering 230 cGy to the isocenter. The dose collected in a sagittal plane is compared to the calculated plan. Gamma analysis finds 8.8% and 5.5% gamma failure rates for measurements of large amplitude trajectory and static measurements relative to the large amplitude plan, respectively. These particular gamma analysis results were achieved using parameters of 3% dose and 3 mm, for regions receiving doses >150 cGy. The plan assumes a stationary detection grid unlike the moving radiochromic film and tissues. This difference was experimentally observed and motivated calculated dose distributions that incorporated the phase of the tumor periodic motion. These calculations modestly improve agreement between the measured and intended doses.« less

Bombesin-like peptides and receptors in normal fetal baboon lung: roles in lung growth and maturation.

PubMed

Emanuel, R L; Torday, J S; Mu, Q; Asokananthan, N; Sikorski, K A; Sunday, M E

1999-11-01

Previously, we have shown that bombesin-like peptide (BLP) promotes fetal lung development in rodents and humans but mediates postnatal lung injury in hyperoxic baboons. The present study analyzed the normal ontogeny of BLP and BLP receptors as well as the effects of BLP on cultured normal fetal baboon lungs. Transcripts encoding gastrin-releasing peptide (GRP), a pulmonary BLP, were detectable on gestational day 60 (ED60), peaked on approximately ED90, and then declined before term (ED180). Numbers of BLP-immunopositive neuroendocrine cells peaked from ED80 to ED125 and declined by ED160, preceding GRP-receptor mRNAs detected from ED125 until birth. BLP (0.1-10 nM) stimulated type II cell differentiation in organ cultures as assessed by [(3)H]choline incorporation into surfactant phospholipids, electron microscopy, and increased surfactant protein (SP) A- and/or SP-C-immunopositive cells and SP-A mRNA. BLP also induced neuroendocrine differentiation on ED60. Cell proliferation was induced by GRP, peaking on ED90. Similarly, blocking BLP degradation stimulated lung growth and maturation, which was completely reversed by a BLP-specific antagonist. The dissociation between GRP and GRP-receptor gene expression during ontogeny suggests that novel BLP receptors and/or peptides might be implicated in these responses.

Effect of SO/sub 2/ on the clearance of Listeria monocytogenes from the lungs of emphysematous hamsters

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

Trimpe, K.L.; Weiss, H.; Zwilling, B.S.

1986-10-01

The effect of sulfur dioxide on the clearance of Listeria monocytogenes from normal and emphysematous hamsters was assessed by measuring the number of colony forming units recovered from whole lung homogenates. Continuous exposure to SO/sub 2/ after intratracheal instillation of Listeria significantly altered the clearance of viable bacteria from the lungs of emphysematous but not normal hamsters. Pre-exposure of hamsters to SO/sub 2/ for 2 weeks prior to respiratory infection had similar effects. The emphysematous hamsters exposed to SO/sub 2/ had a lower average number of Listeria in the lungs after the first week of infection than control groups. Thismore » effect appears to result from the combined influence of the SO/sub 2/, the Listeria infection, and the emphysematous condition within the lungs.« less

Strigolactone analogues induce apoptosis through activation of p38 and the stress response pathway in cancer cell lines and in conditionally reprogrammed primary prostate cancer cells.

PubMed

Pollock, Claire B; McDonough, Sara; Wang, Victor S; Lee, Hyojung; Ringer, Lymor; Li, Xin; Prandi, Cristina; Lee, Richard J; Feldman, Adam S; Koltai, Hinanit; Kapulnik, Yoram; Rodriguez, Olga C; Schlegel, Richard; Albanese, Christopher; Yarden, Ronit I

2014-03-30

Strigolactones are a novel class of plant hormones produced in roots and regulate shoot and root development. We have previously shown that synthetic strigolactone analogues potently inhibit growth of breast cancer cells and breast cancer stem cells. Here we show that strigolactone analogues inhibit the growth and survival of an array of cancer-derived cell lines representing solid and non-solid cancer cells including: prostate, colon, lung, melanoma, osteosarcoma and leukemic cell lines, while normal cells were minimally affected. Treatment of cancer cells with strigolactone analogues was hallmarked by activation of the stress-related MAPKs: p38 and JNK and induction of stress-related genes; cell cycle arrest and apoptosis evident by increased percentages of cells in the sub-G1 fraction and Annexin V staining. In addition, we tested the response of patient-matched conditionally reprogrammed primary prostate normal and cancer cells. The tumor cells exhibited significantly higher sensitivity to the two most potent SL analogues with increased apoptosis confirmed by PARP1 cleavage compared to their normal counterpart cells. Thus, Strigolactone analogues are promising candidates for anticancer therapy by their ability to specifically induce cell cycle arrest, cellular stress and apoptosis in tumor cells with minimal effects on growth and survival of normal cells.

Automatic quantitative computed tomography segmentation and analysis of aerated lung volumes in acute respiratory distress syndrome-A comparative diagnostic study.

PubMed

Klapsing, Philipp; Herrmann, Peter; Quintel, Michael; Moerer, Onnen

2017-12-01

Quantitative lung computed tomographic (CT) analysis yields objective data regarding lung aeration but is currently not used in clinical routine primarily because of the labor-intensive process of manual CT segmentation. Automatic lung segmentation could help to shorten processing times significantly. In this study, we assessed bias and precision of lung CT analysis using automatic segmentation compared with manual segmentation. In this monocentric clinical study, 10 mechanically ventilated patients with mild to moderate acute respiratory distress syndrome were included who had received lung CT scans at 5- and 45-mbar airway pressure during a prior study. Lung segmentations were performed both automatically using a computerized algorithm and manually. Automatic segmentation yielded similar lung volumes compared with manual segmentation with clinically minor differences both at 5 and 45 mbar. At 5 mbar, results were as follows: overdistended lung 49.58mL (manual, SD 77.37mL) and 50.41mL (automatic, SD 77.3mL), P=.028; normally aerated lung 2142.17mL (manual, SD 1131.48mL) and 2156.68mL (automatic, SD 1134.53mL), P = .1038; and poorly aerated lung 631.68mL (manual, SD 196.76mL) and 646.32mL (automatic, SD 169.63mL), P = .3794. At 45 mbar, values were as follows: overdistended lung 612.85mL (manual, SD 449.55mL) and 615.49mL (automatic, SD 451.03mL), P=.078; normally aerated lung 3890.12mL (manual, SD 1134.14mL) and 3907.65mL (automatic, SD 1133.62mL), P = .027; and poorly aerated lung 413.35mL (manual, SD 57.66mL) and 469.58mL (automatic, SD 70.14mL), P=.007. Bland-Altman analyses revealed the following mean biases and limits of agreement at 5 mbar for automatic vs manual segmentation: overdistended lung +0.848mL (±2.062mL), normally aerated +14.51mL (±49.71mL), and poorly aerated +14.64mL (±98.16mL). At 45 mbar, results were as follows: overdistended +2.639mL (±8.231mL), normally aerated 17.53mL (±41.41mL), and poorly aerated 56.23mL (±100.67mL). Automatic single CT image and whole lung segmentation were faster than manual segmentation (0.17 vs 125.35seconds [P<.0001] and 10.46 vs 7739.45seconds [P<.0001]). Automatic lung CT segmentation allows fast analysis of aerated lung regions. A reduction of processing times by more than 99% allows the use of quantitative CT at the bedside. Copyright © 2016 Elsevier Inc. All rights reserved.

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.

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.

Membrane-bound (MUC1) and secretory (MUC2, MUC3, and MUC4) mucin gene expression in human lung cancer.

PubMed

Nguyen, P L; Niehans, G A; Cherwitz, D L; Kim, Y S; Ho, S B

1996-01-01

Abnormalities of mucin-type glycoproteins have been described in lung cancers, but their molecular basis is unknown. In this study, mucin-core-peptide-specific antibodies and cDNA probes were used to determine the relative expression of mucin genes corresponding to one membrane-bound mucin (MUC1), two intestinal mucins (MUC2 and MUC3), and one tracheobronchial mucin (MUC4) in normal (nonneoplastic) lung, and in lung neoplasms. Normal lung tissues exhibited a distinct pattern of mucin gene expression, with high levels of MUC1 and MUC4 mRNA and low to absent levels of MUC2 and MUC3 mucin immunoreactivity and mRNA. In contrast, lung adenocarcinomas, especially well-differentiated cancers, exhibited increased MUC1, MUC3, and MUC4 mRNA levels. Lung squamous-cell, adenosquamous, and large-cell carcinomas were characterized by increased levels of MUC4 mucin only. We conclude that the expression of one membrane-bound and several secretory-type mucins is independently regulated and markedly altered in lung neoplasms. The frequent occurrence of increased MUC4 transcripts in a variety of non-small-cell lung cancers indicates the potential importance of this type of mucin in lung cancer biology.

Losartan Attenuates Degradation of Aorta and Lung Tissue Micromechanics in a Mouse Model of Severe Marfan Syndrome

PubMed Central

Lee, Jia-Jye; Galatioto, Josephine; Rao, Satish; Ramirez, Francesco; Costa, Kevin D.

2018-01-01

Marfan syndrome (MFS) is an autosomal dominant disease of the connective tissue due to mutations in the fibrillin-1 gene (FBN1). This study aimed at characterizing microelastic properties of the ascending aorta wall and lung parenchyma tissues from wild type (WT) and age-matched Fbn1 hypomorphic mice (Fbn1mgR/mgR mice) to identify tissue-specific biomechanical effects of aging and disease in MFS. Atomic force microscopy (AFM) was used to indent lung parenchyma and aortic wall tissues, using Hybrid Eshelby Decomposition analysis to extract layer-specific properties of the intima and media. The intima stiffened with age and was not different between WT and Fbn1mgR/mgR tissues, whereas the media layer of mutant aortas showed progressive structural and mechanical degradation with a modulus that was 50% softer than WT by 3.5 months of age. Similarly, mutant mice displayed progressive structural and mechanical deterioration of lung tissue, which was over 85% softer than WT by 3.5 months of age. Chronic treatment with the angiotensin type I receptor antagonist, losartan, attenuated the aorta and lung tissue degradation, resulting in structural and mechanical properties not significantly different from age-matched WT controls. By revealing micromechanical softening of elastin-rich aorta and lung tissues with disease progression in fibrillin-1 deficient mice, our findings support the use of losartan as a prophylactic treatment that may abrogate the life-threatening symptoms of MFS. PMID:27090893

Losartan Attenuates Degradation of Aorta and Lung Tissue Micromechanics in a Mouse Model of Severe Marfan Syndrome.

PubMed

Lee, Jia-Jye; Galatioto, Josephine; Rao, Satish; Ramirez, Francesco; Costa, Kevin D

2016-10-01

Marfan syndrome (MFS) is an autosomal dominant disease of the connective tissue due to mutations in the fibrillin-1 gene (FBN1). This study aimed at characterizing microelastic properties of the ascending aortic wall and lung parenchyma tissues from wild type (WT) and age-matched Fbn1 hypomorphic mice (Fbn1(mgR/mgR) mice) to identify tissue-specific biomechanical effects of aging and disease in MFS. Atomic force microscopy was used to indent lung parenchyma and aortic wall tissues, using Hybrid Eshelby Decomposition analysis to extract layer-specific properties of the intima and media. The intima stiffened with age and was not different between WT and Fbn1(mgR/mgR) tissues, whereas the media layer of MFS aortas showed progressive structural and mechanical degradation with a modulus that was 50% softer than WT by 3.5 months of age. Similarly, MFS mice displayed progressive structural and mechanical deterioration of lung tissue, which was over 85% softer than WT by 3.5 months of age. Chronic treatment with the angiotensin type I receptor antagonist, losartan, attenuated the aorta and lung tissue degradation, resulting in structural and mechanical properties not significantly different from age-matched WT controls. By revealing micromechanical softening of elastin-rich aorta and lung tissues with disease progression in fibrillin-1 deficient mice, our findings support the use of losartan as a prophylactic treatment that may abrogate the life-threatening symptoms of MFS.

Graft downsizing during ex vivo lung perfusion: case report and technical notes.

PubMed

Nosotti, M; Rosso, L; Mendogni, P; Tosi, D; Palleschi, A; Righi, I; Froio, S; Valenza, F; Santambrogio, L

2014-09-01

Among patients with respiratory insufficiency awaiting lung transplantation, small adult patients have a lower opportunity of receiving size-matched pulmonary grafts, because of the shortage of donors, particularly those of small size. Reducing the size of an oversized graft is one of the methods to increase the donor pool; similarly, ex vivo lung perfusion is an emerging technique aimed toward the same purpose. We describe how we combined the 2 techniques (lobar transplantation plus contralateral nonanatomic graft reduction during ex vivo lung perfusion) to overcome graft shortage in a clinical case. For the 1st time, this case report demonstrates that surgical manipulation during ex vivo lung perfusion does not affect the functional improvement in a lung previously judged to be not suitable for transplantation. The 6-month follow-up results are similar to those of standard bilateral lung transplantation. Copyright © 2014 Elsevier Inc. All rights reserved.

Anthropometric and physiological profiles of active blind Malaysian males.

PubMed

Singh, R; Singh, H J

1993-12-01

Cardiopulmonary capacities of twelve adults (aged between 14 to 44 years) with varying degrees of blindness engaged in regular recreational activities were compared with twelve age-matched normal sighted healthy males (control group) who were also involved in regular recreational activities. Maximum oxygen consumption (VO2max) was measured directly during exhaustive exercise test on a cycle ergometer. Forced vital capacity, leg strength and power were determined by spirometry, standing long jump and vertical jump respectively. No significant differences in VO2max, forced vital capacity and leg strength and power were observed between the blind and the control groups. No anthropometric differences were evident between the two groups. The results show therefore that the visually handicapped who are active can have a similar level of physical fitness, lung function and explosive leg strength as those of their active sighted counterparts.

Indirect measurement of lung density and air volume from electrical impedance tomography (EIT) data.

PubMed

Nebuya, Satoru; Mills, Gary H; Milnes, Peter; Brown, Brian H

2011-12-01

This paper describes a method for estimating lung density, air volume and changes in fluid content from a non-invasive measurement of the electrical resistivity of the lungs. Resistivity in Ω m was found by fitting measured electrical impedance tomography (EIT) data to a finite difference model of the thorax. Lung density was determined by comparing the resistivity of the lungs, measured at a relatively high frequency, with values predicted from a published model of lung structure. Lung air volume can then be calculated if total lung weight is also known. Temporal changes in lung fluid content will produce proportional changes in lung density. The method was implemented on EIT data, collected using eight electrodes placed in a single plane around the thorax, from 46 adult male subjects and 36 adult female subjects. Mean lung densities (±SD) of 246 ± 67 and 239 ± 64 kg m(-3), respectively, were obtained. In seven adult male subjects estimates of 1.68 ± 0.30, 3.42 ± 0.49 and 4.40 ± 0.53 l in residual volume, functional residual capacity and vital capacity, respectively, were obtained. Sources of error are discussed. It is concluded that absolute differences in lung density of about 30% and changes over time of less than 30% should be detected using the current technology in normal subjects. These changes would result from approximately 300 ml increase in lung fluid. The method proposed could be used for non-invasive monitoring of total lung air and fluid content in normal subjects but needs to be assessed in patients with lung disease.

An optimized two-photon method for in vivo lung imaging reveals intimate cell collaborations during infection

NASA Astrophysics Data System (ADS)

Fiole, Daniel; Deman, Pierre; Trescos, Yannick; Douady, Julien; Tournier, Jean-Nicolas

2013-02-01

Lung tissue motion arising from breathing and heart beating has been described as the largest annoyance of in vivo imaging. Consequently, infected lung tissue has never been imaged in vivo thus far, and little is known concerning the kinetics of the mucosal immune system at the cellular level. We have developed an optimized post-processing strategy to overcome tissue motion, based upon two-photon and second harmonic generation (SHG) microscopy. In contrast to previously published data, we have freed the lung parenchyma from any strain and depression in order to maintain the lungs under optimal physiological parameters. Excitation beams swept the sample throughout normal breathing and heart movements, allowing the collection of many images. Given that tissue motion is unpredictably, it was essential to sort images of interest. This step was enhanced by using SHG signal from collagen as a reference for sampling and realignment phases. A normalized cross-correlation criterion was used between a manually chosen reference image and rigid transformations of all others. Using CX3CR1+/gfp mice this process allowed the collection of high resolution images of pulmonary dendritic cells (DCs) interacting with Bacillus anthracis spores, a Gram-positive bacteria responsible for anthrax disease. We imaged lung tissue for up to one hour, without interrupting normal lung physiology. Interestingly, our data revealed unexpected interactions between DCs and macrophages, two specialized phagocytes. These contacts may participate in a better coordinate immune response. Our results not only demonstrate the phagocytizing task of lung DCs but also infer a cooperative role of alveolar macrophages and DCs.

Evaluation of three presets for four-dimensional cone beam CT in lung radiotherapy verification by visual grading analysis.

PubMed

Kember, Sally A; Hansen, Vibeke N; Fast, Martin F; Nill, Simeon; McDonald, Fiona; Ahmed, Merina; Thomas, Karen; McNair, Helen A

2016-07-01

To evaluate three image acquisition presets for four-dimensional cone beam CT (CBCT) to identify an optimal preset for lung tumour image quality while minimizing dose and acquisition time. Nine patients undergoing radical conventionally fractionated radiotherapy for lung cancer had verification CBCTs acquired using three presets: Preset 1 on Day 1 (11 mGy dose, 240 s acquisition time), Preset 2 on Day 2 (9 mGy dose, 133 s acquisition time) and Preset 3 on Day 3 (9 mGy dose, 67 s acquisition time). The clarity of the tumour and other thoracic structures, and the acceptability of the match, were retrospectively graded by visual grading analysis (VGA). Logistic regression was used to identify the most appropriate preset and any factors that might influence the result. Presets 1 and 2 met a clinical requirement of 75% of structures to be rated "Clear" or above and 75% of matches to be rated "Acceptable" or above. Clarity is significantly affected by preset, patient, observer and structure. Match acceptability is significantly affected by preset. The application of VGA in this initial study enabled a provisional selection of an optimal preset (Preset 2) to be made. This was the first application of VGA to the investigation of presets for CBCT.

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

Alhenc-Gelas, F.; Weare, J.A.; Johnson, R.L. Jr.

CE was purified from human lung, and antisera were raised in rabbits. Antisera inhibited the activity of the purified enzyme from lung and kidney and the plasma CE of normal persons and sarcoid patients. With antisera at a titer of 1:100,000, a sensitive, direct RIA was developed. CE purified from lung or kidney and CE present in normal and in sarcoid plasma gave parallel logit-log displacement lines, suggesting immunological identity. The level of CE in normal human plasma was 400 +/- 131 ng/ml. In untreated sarcoid patients, the enzyme level and activity increased in parallel. There was a negative correlationmore » (r . -0.81) between enzyme level and diffusing capacity of the lung for CO in sarcoid patients. Synthetic inhibitors such as captopril or MK 421 did not interfere with the RIA, permitting enzyme levels to be monitored in patients undergoing acute inhibitor therapy. During administration of MK 421, CE activity was negligible and plasma levels of CE did not change. In contrast, renin activity increased eightfold during the inhibitor therapy.« less

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

Alhenc-Gelas, F.; Weare, J.A.; Johnson, R.L. Jr.

CE (converting enzyme) was purified from human lung, and antisera were raised in rabbits. Antisera inhibited the activity of the purified enzyme from lung and kidney and the plasma CE of normal persons and sarcoid patients. With antisera at a titer of 1:100,000, a sensitive, direct RIA was developed. CE purified from lung or kidney and CE present in normal and in sarcoid plasma gave parallel logit-log displacement lines, suggesting immunological identity. The level of CE in normal human plasma was 400 +/- 131 ng/ml. In untreated sarcoid patients, the enzyme level and activity increased in parallel. There was amore » negative correlation between enzyme level and diffusing capacity of the lung for CO in sarcoid patients. Synthetic inhibitors such as captopril or MK 421 did not interfere with the RIA, permitting enzyme levels to be monitored in patients undergoing acute inhibitor therapy. During administration of MK 421, CE activity was negligible and plasma levels of CE did not change. In contrast, renin activity increased eightfold during the inhibitor therapy.« less

[Lung dysfunction in patients with mild chronic obstructive bronchitis].

PubMed

Nefedov, V B; Popova, L A; Shergina, E A

2004-01-01

VC, FVC, FEV1, FEV1/VC%, PEF, MEF25, MEF50, MEF75, TCL, TGV, RV, Ravt, Riin, Rex, DLCO-SS, PaO2, and PaO2 were determined in 33 patients with mild chronic obstructive lung disease (FEV1 > 70% of the normal value). All the patients were found to have impaired bronchial patency; most (63.6%) patients had lung volume and capacity changes, almost half (45.5%) the patients had pulmonary gas exchange dysfunction. Impaired bronchial patency mainly appeared as decreased MEF50, MEF15, and FEV1/VC%; altered lung volumes and capacities manifested chiefly by increased RV and decreased VC; pulmonary gas exchange dysfunction showed up primarily as lowered PaO2. The magnitude of the observed functional changes was generally slight. MEF50, MEF75, FEV1/VC%, and VC dropped to 59-20 and 79-70% of the normal value, respectively. RV increased up to 142-196% of the normal value; PaO2 reduced up to 79-60% mm Hg.

Lung function not affected by asbestos exposure in workers with normal Computed Tomography scan.

PubMed

Schikowsky, Christian; Felten, Michael K; Eisenhawer, Christian; Das, Marco; Kraus, Thomas

2017-05-01

It has been suggested that asbestos exposure affects lung function, even in the absence of asbestos-related pulmonary interstitial or pleural changes or emphysema. We analyzed associations between well-known asbestos-related risk factors, such as individual cumulative asbestos exposure, and key lung function parameters in formerly asbestos-exposed power industry workers (N = 207) with normal CT scans. For this, we excluded participants with emphysema, fibrosis, pleural changes, or any combination of these. The lung function parameters of FVC, FEV1, DLCO/VA, and airway resistance were significantly associated with the burden of smoking, BMI and years since end of exposure (only DLCO/VA). However, they were not affected by factors directly related to amount (eg, cumulative exposure) or duration of asbestos exposure. Our results confirm the well-known correlation between lung function, smoking habits, and BMI. However, we found no significant association between lung function and asbestos exposure. © 2017 Wiley Periodicals, Inc.

Algorithm of pulmonary emphysema extraction using thoracic 3-D CT images

NASA Astrophysics Data System (ADS)

Saita, Shinsuke; Kubo, Mitsuru; Kawata, Yoshiki; Niki, Noboru; Nakano, Yasutaka; Ohmatsu, Hironobu; Tominaga, Keigo; Eguchi, Kenji; Moriyama, Noriyuki

2008-03-01

Emphysema patients have the tendency to increase due to aging and smoking. Emphysematous disease destroys alveolus and to repair is impossible, thus early detection is essential. CT value of lung tissue decreases due to the destruction of lung structure. This CT value becomes lower than the normal lung- low density absorption region or referred to as Low Attenuation Area (LAA). So far, the conventional way of extracting LAA by simple thresholding has been proposed. However, the CT value of CT image fluctuates due to the measurement conditions, with various bias components such as inspiration, expiration and congestion. It is therefore necessary to consider these bias components in the extraction of LAA. We removed these bias components and we proposed LAA extraction algorithm. This algorithm has been applied to the phantom image. Then, by using the low dose CT(normal: 30 cases, obstructive lung disease: 26 cases), we extracted early stage LAA and quantitatively analyzed lung lobes using lung structure.

Combining deep learning and coherent anti-Stokes Raman scattering imaging for automated differential diagnosis of lung cancer.

PubMed

Weng, Sheng; Xu, Xiaoyun; Li, Jiasong; Wong, Stephen T C

2017-10-01

Lung cancer is the most prevalent type of cancer and the leading cause of cancer-related deaths worldwide. Coherent anti-Stokes Raman scattering (CARS) is capable of providing cellular-level images and resolving pathologically related features on human lung tissues. However, conventional means of analyzing CARS images requires extensive image processing, feature engineering, and human intervention. This study demonstrates the feasibility of applying a deep learning algorithm to automatically differentiate normal and cancerous lung tissue images acquired by CARS. We leverage the features learned by pretrained deep neural networks and retrain the model using CARS images as the input. We achieve 89.2% accuracy in classifying normal, small-cell carcinoma, adenocarcinoma, and squamous cell carcinoma lung images. This computational method is a step toward on-the-spot diagnosis of lung cancer and can be further strengthened by the efforts aimed at miniaturizing the CARS technique for fiber-based microendoscopic imaging. (2017) COPYRIGHT Society of Photo-Optical Instrumentation Engineers (SPIE).

A PERFECT MATCH CONDITION FOR POINT-SET MATCHING PROBLEMS USING THE OPTIMAL MASS TRANSPORT APPROACH

PubMed Central

CHEN, PENGWEN; LIN, CHING-LONG; CHERN, I-LIANG

2013-01-01

We study the performance of optimal mass transport-based methods applied to point-set matching problems. The present study, which is based on the L2 mass transport cost, states that perfect matches always occur when the product of the point-set cardinality and the norm of the curl of the non-rigid deformation field does not exceed some constant. This analytic result is justified by a numerical study of matching two sets of pulmonary vascular tree branch points whose displacement is caused by the lung volume changes in the same human subject. The nearly perfect match performance verifies the effectiveness of this mass transport-based approach. PMID:23687536

SU-E-J-178: A Normalization Method Can Remove Discrepancy in Ventilation Function Due to Different Breathing Patterns

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

Qu, H; Yu, N; Stephans, K

2014-06-01

Purpose: To develop a normalization method to remove discrepancy in ventilation function due to different breathing patterns. Methods: Twenty five early stage non-small cell lung cancer patients were included in this study. For each patient, a ten phase 4D-CT and the voluntarily maximum inhale and exhale CTs were acquired clinically and retrospectively used for this study. For each patient, two ventilation maps were calculated from voxel-to-voxel CT density variations from two phases of the quiet breathing and two phases of the extreme breathing. For the quiet breathing, 0% (inhale) and 50% (exhale) phases from 4D-CT were used. An in-house toolmore » was developed to calculate and display the ventilation maps. To enable normalization, the whole lung of each patient was evenly divided into three parts in the longitude direction at a coronal image with a maximum lung cross section. The ratio of cumulated ventilation from the top one-third region to the middle one-third region of the lung was calculated for each breathing pattern. Pearson's correlation coefficient was calculated on the ratios of the two breathing patterns for the group. Results: For each patient, the ventilation map from the quiet breathing was different from that of the extreme breathing. When the cumulative ventilation was normalized to the middle one-third of the lung region for each patient, the normalized ventilation functions from the two breathing patterns were consistent. For this group of patients, the correlation coefficient of the normalized ventilations for the two breathing patterns was 0.76 (p < 0.01), indicating a strong correlation in the ventilation function measured from the two breathing patterns. Conclusion: For each patient, the ventilation map is dependent of the breathing pattern. Using a regional normalization method, the discrepancy in ventilation function induced by the different breathing patterns thus different tidal volumes can be removed.« less

A case of systemic arterial supply to the right lower lobe of the lung: imaging findings and review of the literature.

PubMed

Mautone, Marcela; Naidoo, Parm

2014-03-01

Systemic arterialization of the lung without pulmonary sequestration is the rarest form of anomalous systemic arterial supply to the lung. This condition is characterised by an aberrant arterial branch arising from the aorta which supplies an area of lung parenchyma with normal bronchopulmonary anatomy. It is often diagnosed following investigation of an incidental cardiac murmur or based on abnormal imaging, as most patients are asymptomatic or minimally symptomatic. Thoracic computed tomography and computed tomography angiography are generally the most useful diagnostic tests. We present a case of a 22-year old female who was diagnosed with systemic arterial supply to a portion of otherwise normal right lower lobe following investigation of low volume haemoptysis.

Patient-specific dose estimation for pediatric chest CT

PubMed Central

Li, Xiang; Samei, Ehsan; Segars, W. Paul; Sturgeon, Gregory M.; Colsher, James G.; Frush, Donald P.

2008-01-01

Current methods for organ and effective dose estimations in pediatric CT are largely patient generic. Physical phantoms and computer models have only been developed for standard/limited patient sizes at discrete ages (e.g., 0, 1, 5, 10, 15years old) and do not reflect the variability of patient anatomy and body habitus within the same size/age group. In this investigation, full-body computer models of seven pediatric patients in the same size/protocol group (weight: 11.9–18.2kg) were created based on the patients’ actual multi-detector array CT (MDCT) data. Organs and structures in the scan coverage were individually segmented. Other organs and structures were created by morphing existing adult models (developed from visible human data) to match the framework defined by the segmented organs, referencing the organ volume and anthropometry data in ICRP Publication 89. Organ and effective dose of these patients from a chest MDCT scan protocol (64 slice LightSpeed VCT scanner, 120kVp, 70 or 75mA, 0.4s gantry rotation period, pitch of 1.375, 20mm beam collimation, and small body scan field-of-view) was calculated using a Monte Carlo program previously developed and validated to simulate radiation transport in the same CT system. The seven patients had normalized effective dose of 3.7–5.3mSv∕100mAs (coefficient of variation: 10.8%). Normalized lung dose and heart dose were 10.4–12.6mGy∕100mAs and 11.2–13.3mGy∕100mAs, respectively. Organ dose variations across the patients were generally small for large organs in the scan coverage (<7%), but large for small organs in the scan coverage (9%–18%) and for partially or indirectly exposed organs (11%–77%). Normalized effective dose correlated weakly with body weight (correlation coefficient:r=−0.80). Normalized lung dose and heart dose correlated strongly with mid-chest equivalent diameter (lung: r=−0.99, heart: r=−0.93); these strong correlation relationships can be used to estimate patient-specific organ dose for any other patient in the same size/protocol group who undergoes the chest scan. In summary, this work reported the first assessment of dose variations across pediatric CT patients in the same size/protocol group due to the variability of patient anatomy and body habitus and provided a previously unavailable method for patient-specific organ dose estimation, which will help in assessing patient risk and optimizing dose reduction strategies, including the development of scan protocols. PMID:19175138

Patient-specific dose estimation for pediatric chest CT

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

Li Xiang; Samei, Ehsan; Segars, W. Paul

2008-12-15

Current methods for organ and effective dose estimations in pediatric CT are largely patient generic. Physical phantoms and computer models have only been developed for standard/limited patient sizes at discrete ages (e.g., 0, 1, 5, 10, 15 years old) and do not reflect the variability of patient anatomy and body habitus within the same size/age group. In this investigation, full-body computer models of seven pediatric patients in the same size/protocol group (weight: 11.9-18.2 kg) were created based on the patients' actual multi-detector array CT (MDCT) data. Organs and structures in the scan coverage were individually segmented. Other organs and structuresmore » were created by morphing existing adult models (developed from visible human data) to match the framework defined by the segmented organs, referencing the organ volume and anthropometry data in ICRP Publication 89. Organ and effective dose of these patients from a chest MDCT scan protocol (64 slice LightSpeed VCT scanner, 120 kVp, 70 or 75 mA, 0.4 s gantry rotation period, pitch of 1.375, 20 mm beam collimation, and small body scan field-of-view) was calculated using a Monte Carlo program previously developed and validated to simulate radiation transport in the same CT system. The seven patients had normalized effective dose of 3.7-5.3 mSv/100 mAs (coefficient of variation: 10.8%). Normalized lung dose and heart dose were 10.4-12.6 mGy/100 mAs and 11.2-13.3 mGy/100 mAs, respectively. Organ dose variations across the patients were generally small for large organs in the scan coverage (<7%), but large for small organs in the scan coverage (9%-18%) and for partially or indirectly exposed organs (11%-77%). Normalized effective dose correlated weakly with body weight (correlation coefficient: r=-0.80). Normalized lung dose and heart dose correlated strongly with mid-chest equivalent diameter (lung: r=-0.99, heart: r=-0.93); these strong correlation relationships can be used to estimate patient-specific organ dose for any other patient in the same size/protocol group who undergoes the chest scan. In summary, this work reported the first assessment of dose variations across pediatric CT patients in the same size/protocol group due to the variability of patient anatomy and body habitus and provided a previously unavailable method for patient-specific organ dose estimation, which will help in assessing patient risk and optimizing dose reduction strategies, including the development of scan protocols.« less

A Compendium of Canine Normal Tissue Gene Expression

PubMed Central

Chen, Qing-Rong; Wen, Xinyu; Khan, Javed; Khanna, Chand

2011-01-01

Background Our understanding of disease is increasingly informed by changes in gene expression between normal and abnormal tissues. The release of the canine genome sequence in 2005 provided an opportunity to better understand human health and disease using the dog as clinically relevant model. Accordingly, we now present the first genome-wide, canine normal tissue gene expression compendium with corresponding human cross-species analysis. Methodology/Principal Findings The Affymetrix platform was utilized to catalogue gene expression signatures of 10 normal canine tissues including: liver, kidney, heart, lung, cerebrum, lymph node, spleen, jejunum, pancreas and skeletal muscle. The quality of the database was assessed in several ways. Organ defining gene sets were identified for each tissue and functional enrichment analysis revealed themes consistent with known physio-anatomic functions for each organ. In addition, a comparison of orthologous gene expression between matched canine and human normal tissues uncovered remarkable similarity. To demonstrate the utility of this dataset, novel canine gene annotations were established based on comparative analysis of dog and human tissue selective gene expression and manual curation of canine probeset mapping. Public access, using infrastructure identical to that currently in use for human normal tissues, has been established and allows for additional comparisons across species. Conclusions/Significance These data advance our understanding of the canine genome through a comprehensive analysis of gene expression in a diverse set of tissues, contributing to improved functional annotation that has been lacking. Importantly, it will be used to inform future studies of disease in the dog as a model for human translational research and provides a novel resource to the community at large. PMID:21655323

ATP promotes cell survival via regulation of cytosolic [Ca2+] and Bcl-2/Bax ratio in lung cancer cells

PubMed Central

Song, Shanshan; Jacobson, Krista N.; McDermott, Kimberly M.; Reddy, Sekhar P.; Cress, Anne E.; Tang, Haiyang; Dudek, Steven M.; Black, Stephen M.; Garcia, Joe G. N.; Makino, Ayako

2015-01-01

Adenosine triphosphate (ATP) is a ubiquitous extracellular messenger elevated in the tumor microenvironment. ATP regulates cell functions by acting on purinergic receptors (P2X and P2Y) and activating a series of intracellular signaling pathways. We examined ATP-induced Ca2+ signaling and its effects on antiapoptotic (Bcl-2) and proapoptotic (Bax) proteins in normal human airway epithelial cells and lung cancer cells. Lung cancer cells exhibited two phases (transient and plateau phases) of increase in cytosolic [Ca2+] ([Ca2+]cyt) caused by ATP, while only the transient phase was observed in normal cells. Removal of extracellular Ca2+ eliminated the plateau phase increase of [Ca2+]cyt in lung cancer cells, indicating that the plateau phase of [Ca2+]cyt increase is due to Ca2+ influx. The distribution of P2X (P2X1-7) and P2Y (P2Y1, P2Y2, P2Y4, P2Y6, P2Y11) receptors was different between lung cancer cells and normal cells. Proapoptotic P2X7 was nearly undetectable in lung cancer cells, which may explain why lung cancer cells showed decreased cytotoxicity when treated with high concentration of ATP. The Bcl-2/Bax ratio was increased in lung cancer cells following treatment with ATP; however, the antiapoptotic protein Bcl-2 demonstrated more sensitivity to ATP than proapoptotic protein Bax. Decreasing extracellular Ca2+ or chelating intracellular Ca2+ with BAPTA-AM significantly inhibited ATP-induced increase in Bcl-2/Bax ratio, indicating that a rise in [Ca2+]cyt through Ca2+ influx is the critical mediator for ATP-mediated increase in Bcl-2/Bax ratio. Therefore, despite high ATP levels in the tumor microenvironment, which would induce cell apoptosis in normal cells, the decreased P2X7 and elevated Bcl-2/Bax ratio in lung cancer cells may enable tumor cells to survive. Increasing the Bcl-2/Bax ratio by exposure to high extracellular ATP may, therefore, be an important selective pressure promoting transformation and cancer progression. PMID:26491047

Beta-cryptoxanthin restores nicotine-reduced lung SIRT1 to normal levels and inhibits nicotine-promoted lung tumorigenesis and emphysema in A/J mice

USDA-ARS?s Scientific Manuscript database

Nicotine, a large constituent of cigarette smoke, is associated with an increased risk of lung cancer, but the data supporting this relationship are inconsistent. Here, we found that nicotine treatment not only induced emphysema but also increased both lung tumor multiplicity and volume in 4-nitrosa...

The role of integrin α8β1 in fetal lung morphogenesis and injury

PubMed Central

Benjamin, John T.; Gaston, David C.; Halloran, Brian A.; Schnapp, Lynn M.; Zent, Roy; Prince, Lawrence S.

2009-01-01

Prenatal inflammation prevents normal lung morphogenesis and leads to bronchopulmonary dysplasia (BPD), a common complication of preterm birth. We previously demonstrated in a bacterial endotoxin mouse model of BPD that disrupting fibronectin localization in the fetal lung mesenchyme causes arrested saccular airway branching. In this study we show that expression of the fibronectin receptor, integrin α8β1, is decreased in the lung mesenchyme in the same inflammation model suggesting it is required for normal lung development. We verified a role for integrin α8β1 in lung development using integrin α8-null mice, which develop fusion of the medial and caudal lobes as well as abnormalities in airway division. We further show in vivo and vitro that α8-null fetal lung mesenchymal cells fail to form stable adhesions and have increased migration. Thus we propose that integrin α8β1 plays a critical role in lung morphogenesis by regulating mesenchymal cell adhesion and migration. Furthermore, our data suggests that disruption of the interactions between extracellular matrix and integrin α8β1 may contribute to the pathogenesis of BPD. PMID:19769957

Sensitivity and specificity of 3-D texture analysis of lung parenchyma is better than 2-D for discrimination of lung pathology in stage 0 COPD

NASA Astrophysics Data System (ADS)

Xu, Ye; Sonka, Milan; McLennan, Geoffrey; Guo, Junfeng; Hoffman, Eric

2005-04-01

Lung parenchyma evaluation via multidetector-row CT (MDCT), has significantly altered clinical practice in the early detection of lung disease. Our goal is to enhance our texture-based tissue classification ability to differentiate early pathologic processes by extending our 2-D Adaptive Multiple Feature Method (AMFM) to 3-D AMFM. We performed MDCT on 34 human volunteers in five categories: emphysema in severe Chronic Obstructive Pulmonary Disease (COPD) as EC, emphysema in mild COPD (MC), normal appearing lung in COPD (NC), non-smokers with normal lung function (NN), smokers with normal function (NS). We volumetrically excluded the airway and vessel regions, calculated 24 volumetric texture features for each Volume of Interest (VOI); and used Bayesian rules for discrimination. Leave-one-out and half-half methods were used for testing. Sensitivity, specificity and accuracy were calculated. The accuracy of the leave-one-out method for the four-class classification in the form of 3-D/2-D is: EC: 84.9%/70.7%, MC: 89.8%/82.7%; NC: 87.5.0%/49.6%; NN: 100.0%/60.0%. The accuracy of the leave-one-out method for the two-class classification in the form of 3-D/2-D is: NN: 99.3%/71.6%; NS: 99.7%/74.5%. We conclude that 3-D AMFM analysis of the lung parenchyma improves discrimination compared to 2-D analysis of the same images.

Insulin-like growth factor I, IGF-binding protein 3, and lung cancer risk in a prospective study of men in China.

PubMed

London, Stephanie J; Yuan, Jian-Min; Travlos, Gregory S; Gao, Yu-Tang; Wilson, Ralph E; Ross, Ronald K; Yu, Mimi C

2002-05-15

Insulin-like growth factor I (IGF-I) stimulates cell proliferation and inhibits apoptosis in the lung and other tissues by interacting with the IGF-I receptor. The major binding protein for IGF-I, insulin-like growth factor-binding protein 3 (IGFBP-3), modulates the effects of IGF-I but also inhibits cell growth and induces apoptosis independent of IGF-I and its receptor. In a prospective study of men in Shanghai, China, we examined the association between serum levels of IGF-I and IGFBP-3 and the subsequent risk of lung cancer. From 1986 to 1989, serum was collected from 18,244 men aged 45-64 years living in Shanghai without a history of cancer. We analyzed IGF-I and IGFBP-3 levels in serum from 230 case patients who developed incident lung cancer during follow-up and from 740 control subjects. Among 230 case patients and 659 matched control subjects, increased IGF-I levels were not associated with increased risk of lung cancer. However, for subjects in the highest quartile relative to the lowest quartile of IGFBP-3, the odds ratio (OR) for lung cancer, adjusted for smoking and IGF-I, was 0.50 (95% confidence interval [CI] = 0.25 to 1.02). When the analysis was restricted to ever smokers (184 case patients and 344 matched control subjects), the OR for lung cancer in men in the highest quartile of IGFBP-3 relative to those in the lowest quartile, adjusted for smoking and IGF-I, was 0.41 (95% CI = 0.18 to 0.92). In this prospective study of Chinese men, higher serum levels of IGF-I did not increase the risk of lung cancer. However, subjects with higher serum levels of IGFBP-3 were at reduced risk of lung cancer. This finding is consistent with experimental data that indicate that IGFBP-3 can inhibit cellular proliferation and induce apoptosis independent of IGF-I and the IGF-I receptor.

Evaluation of computed tomography numbers for treatment planning of lung cancer

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

Mira, J.G.; Fullerton, G.D.; Ezekiel, J.

1982-09-01

Computerized tomography numbers (CTN) were evaluated in 32 computerized tomography scans performed on patients with carcinoma of the lung, with the aim of evaluating CTN in normal (lung, blood, muscle, etc) and pathologic tissues (tumor, atelectasis, effusion, post-radiation fibrosis). Our main findings are: 1. Large individual CTN variations are encountered in both normal and pathologic tissues, above and below mean values. Hence, absolute numbers are meaningless. Measurements of any abnormal intrathoracic structure should be compared in relation to normal tissue CTN values in the same scan. 2. Tumor and complete atelectasis have CTN basically similar to soft tissue. Hence, thesemore » numbers are not useful for differential diagnosis. 3. Effusions usually have lower CTN and can be distinguished from previous situations. 4. Dosimetry based on uniform lung density assumptions (i.e., 300 mg/cm/sup 3/) might produce substantial dose errors as lung CTN exhibit variations indicating densities well above and below this value. 5. Preliminary information indicates that partial atelectasis and incipient post-radiation fibrosis can have very low CTN. Hence, they can be differentiated from solid tumors in certain cases, and help in differential diagnosis of post radiation recurrence within the radiotherapy field versus fibrosis.« less

Discrimination and quantification of autofluorescence spectra of human lung cells

NASA Astrophysics Data System (ADS)

Rahmani, Mahya; Khani, Mohammad Mehdi; Khazaei Koohpar, Zeinab; Molik, Paria

2016-10-01

To study laser-induced autofluorescence spectroscopy of the human lung cell line, we evaluated the native fluorescence properties of cancer QU-DB and normal MRC-5 human lung cells during continuous exposure to 405 nm laser light. Two emission bands centered at ~470 nm and ~560 nm were observed. These peaks are most likely attributable to mitochondrial fluorescent reduced nicotinamide adenine dinucleotide and riboflavin fluorophores, respectively. This article highlights lung cell autofluorescence characterization and signal discrimination by collective investigation of different spectral features. The absolute intensity, the spectral shape factor or redox ratio, the full width of half-maximum and the full width of quarter maximum was evaluated. Moreover, the intensity ratio, the area under the peak and the area ratio as a contrast factor for normal and cancerous cells were also calculated. Among all these features it seems that the contrast factor precisely and significantly discriminates the spectral differences of normal and cancerous lung cells. On the other hand, the relative quantum yield for both cell types were found by comparing the quantum yield of an unknown compound with known fluorescein sodium as a reference solution.

Applying the technique of volume-modulated arc radiotherapy to upper esophageal carcinoma.

PubMed

Ma, Pan; Wang, Xiaozhen; Xu, Yingjie; Dai, Jianrong; Wang, Luhua

2014-05-08

This study aims to evaluate the possibility of using the technique of volume-modulated arc therapy (VMAT) to combine the advantages of simplified intensity-modulated radiation therapy (sIMRT) with that of regular intensity-modulated radiation therapy (IMRT) in upper esophageal cancer. Ten patients with upper esophageal carcinoma were randomly chosen in this retrospective study. sIMRT, IMRT, and VMAT plans were generated to deliver 60 Gy in 30 fractions to the planning target volume (PTV). For each patient, with the same clinical requirements (target dose prescription, and dose/dose-volume constraints to organs at risk (OARs)), three plans were designed for sIMRT (five equispaced coplanar beams), IMRT (seven equispaced coplanar beams), and VMAT (two complete arcs). Comparisons were performed for dosimetric parameters of PTV and of OARs (lungs, spinal cord PRV, heart and normal tissue (NT)). All the plans were delivered to a phantom to evaluate the treatment time. The Wilcoxon matched-pairs, signed-rank test was used for intragroup comparison. For all patients, compared to sIMRT plans, VMAT plans statistically provide: a) significant improvement in HI and CI for PTV; b) significant decrease in delivery time, lung V20, MLD, heart V30 and spinal cord PRV D1cc; c) significant increase in NT V5; and d) no significant reduction in lung V5, V10, and heart MD. For all patients, compared to IMRT plans, VMAT plans statistically provide: a) significant improvement in CI for PTV; b) significant decrease in delivery time, lung V20, MLD, NT and spinal cord PRV D1cc; c) significant increase in NT V5; and d) no significant reduction in HI for PTV, lung V5, V10, heart V30 and heart MD. For patients with upper esophageal carcinoma, using VMAT significantly reduces the delivery time and the dose to the lungs compared with IMRT, and consequently saves as much treatment time as sIMRT. Considering those significant advantages, compared to sIMRT and IMRT, VMAT is the first choice of radiotherapy techniques for upper esophageal carcinoma.

Detection of early subclinical lung disease in children with cystic fibrosis by lung ventilation imaging with hyperpolarised gas MRI.

PubMed

Marshall, Helen; Horsley, Alex; Taylor, Chris J; Smith, Laurie; Hughes, David; Horn, Felix C; Swift, Andrew J; Parra-Robles, Juan; Hughes, Paul J; Norquay, Graham; Stewart, Neil J; Collier, Guilhem J; Teare, Dawn; Cunningham, Steve; Aldag, Ina; Wild, Jim M

2017-08-01

Hyperpolarised 3 He ventilation-MRI, anatomical lung MRI, lung clearance index (LCI), low-dose CT and spirometry were performed on 19 children (6-16 years) with clinically stable mild cystic fibrosis (CF) (FEV 1 >-1.96), and 10 controls. All controls had normal spirometry, MRI and LCI. Ventilation-MRI was the most sensitive method of detecting abnormalities, present in 89% of patients with CF, compared with CT abnormalities in 68%, LCI 47% and conventional MRI 22%. Ventilation defects were present in the absence of CT abnormalities and in patients with normal physiology, including LCI. Ventilation-MRI is thus feasible in young children, highly sensitive and provides additional information about lung structure-function relationships. 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/.

Toothguide Trainer tests with color vision deficiency simulation monitor.

PubMed

Borbély, Judit; Varsányi, Balázs; Fejérdy, Pál; Hermann, Péter; Jakstat, Holger A

2010-01-01

The aim of this study was to evaluate whether simulated severe red and green color vision deficiency (CVD) influenced color matching results and to investigate whether training with Toothguide Trainer (TT) computer program enabled better color matching results. A total of 31 color normal dental students participated in the study. Every participant had to pass the Ishihara Test. Participants with a red/green color vision deficiency were excluded. A lecture on tooth color matching was given, and individual training with TT was performed. To measure the individual tooth color matching results in normal and color deficient display modes, the TT final exam was displayed on a calibrated monitor that served as a hardware-based method of simulating protanopy and deuteranopy. Data from the TT final exams were collected in normal and in severe red and green CVD-simulating monitor display modes. Color difference values for each participant in each display mode were computed (∑ΔE(ab)(*)), and the respective means and standard deviations were calculated. The Student's t-test was used in statistical evaluation. Participants made larger ΔE(ab)(*) errors in severe color vision deficient display modes than in the normal monitor mode. TT tests showed significant (p<0.05) difference in the tooth color matching results of severe green color vision deficiency simulation mode compared to normal vision mode. Students' shade matching results were significantly better after training (p=0.009). Computer-simulated severe color vision deficiency mode resulted in significantly worse color matching quality compared to normal color vision mode. Toothguide Trainer computer program improved color matching results. Copyright © 2010 Elsevier Ltd. All rights reserved.

The PCP genes Celsr1 and Vangl2 are required for normal lung branching morphogenesis

PubMed Central

Yates, Laura L.; Schnatwinkel, Carsten; Murdoch, Jennifer N.; Bogani, Debora; Formstone, Caroline J.; Townsend, Stuart; Greenfield, Andy; Niswander, Lee A.; Dean, Charlotte H.

2010-01-01

The lungs are generated by branching morphogenesis as a result of reciprocal signalling interactions between the epithelium and mesenchyme during development. Mutations that disrupt formation of either the correct number or shape of epithelial branches affect lung function. This, in turn, can lead to congenital abnormalities such as cystadenomatoid malformations, pulmonary hypertension or lung hypoplasia. Defects in lung architecture are also associated with adult lung disease, particularly in cases of idiopathic lung fibrosis. Identifying the signalling pathways which drive epithelial tube formation will likely shed light on both congenital and adult lung disease. Here we show that mutations in the planar cell polarity (PCP) genes Celsr1 and Vangl2 lead to disrupted lung development and defects in lung architecture. Lungs from Celsr1Crsh and Vangl2Lp mouse mutants are small and misshapen with fewer branches, and by late gestation exhibit thickened interstitial mesenchyme and defective saccular formation. We observe a recapitulation of these branching defects following inhibition of Rho kinase, an important downstream effector of the PCP signalling pathway. Moreover, epithelial integrity is disrupted, cytoskeletal remodelling perturbed and mutant endoderm does not branch normally in response to the chemoattractant FGF10. We further show that Celsr1 and Vangl2 proteins are present in restricted spatial domains within lung epithelium. Our data show that the PCP genes Celsr1 and Vangl2 are required for foetal lung development thereby revealing a novel signalling pathway critical for this process that will enhance our understanding of congenital and adult lung diseases and may in future lead to novel therapeutic strategies. PMID:20223754

Lung motion estimation using dynamic point shifting: An innovative model based on a robust point matching algorithm

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

Yi, Jianbing, E-mail: yijianbing8@163.com; Yang, Xuan, E-mail: xyang0520@263.net; Li, Yan-Ran, E-mail: lyran@szu.edu.cn

2015-10-15

Purpose: Image-guided radiotherapy is an advanced 4D radiotherapy technique that has been developed in recent years. However, respiratory motion causes significant uncertainties in image-guided radiotherapy procedures. To address these issues, an innovative lung motion estimation model based on a robust point matching is proposed in this paper. Methods: An innovative robust point matching algorithm using dynamic point shifting is proposed to estimate patient-specific lung motion during free breathing from 4D computed tomography data. The correspondence of the landmark points is determined from the Euclidean distance between the landmark points and the similarity between the local images that are centered atmore » points at the same time. To ensure that the points in the source image correspond to the points in the target image during other phases, the virtual target points are first created and shifted based on the similarity between the local image centered at the source point and the local image centered at the virtual target point. Second, the target points are shifted by the constrained inverse function mapping the target points to the virtual target points. The source point set and shifted target point set are used to estimate the transformation function between the source image and target image. Results: The performances of the authors’ method are evaluated on two publicly available DIR-lab and POPI-model lung datasets. For computing target registration errors on 750 landmark points in six phases of the DIR-lab dataset and 37 landmark points in ten phases of the POPI-model dataset, the mean and standard deviation by the authors’ method are 1.11 and 1.11 mm, but they are 2.33 and 2.32 mm without considering image intensity, and 1.17 and 1.19 mm with sliding conditions. For the two phases of maximum inhalation and maximum exhalation in the DIR-lab dataset with 300 landmark points of each case, the mean and standard deviation of target registration errors on the 3000 landmark points of ten cases by the authors’ method are 1.21 and 1.04 mm. In the EMPIRE10 lung registration challenge, the authors’ method ranks 24 of 39. According to the index of the maximum shear stretch, the authors’ method is also efficient to describe the discontinuous motion at the lung boundaries. Conclusions: By establishing the correspondence of the landmark points in the source phase and the other target phases combining shape matching and image intensity matching together, the mismatching issue in the robust point matching algorithm is adequately addressed. The target registration errors are statistically reduced by shifting the virtual target points and target points. The authors’ method with consideration of sliding conditions can effectively estimate the discontinuous motion, and the estimated motion is natural. The primary limitation of the proposed method is that the temporal constraints of the trajectories of voxels are not introduced into the motion model. However, the proposed method provides satisfactory motion information, which results in precise tumor coverage by the radiation dose during radiotherapy.« less

Lung motion estimation using dynamic point shifting: An innovative model based on a robust point matching algorithm.

PubMed

Yi, Jianbing; Yang, Xuan; Chen, Guoliang; Li, Yan-Ran

2015-10-01

Image-guided radiotherapy is an advanced 4D radiotherapy technique that has been developed in recent years. However, respiratory motion causes significant uncertainties in image-guided radiotherapy procedures. To address these issues, an innovative lung motion estimation model based on a robust point matching is proposed in this paper. An innovative robust point matching algorithm using dynamic point shifting is proposed to estimate patient-specific lung motion during free breathing from 4D computed tomography data. The correspondence of the landmark points is determined from the Euclidean distance between the landmark points and the similarity between the local images that are centered at points at the same time. To ensure that the points in the source image correspond to the points in the target image during other phases, the virtual target points are first created and shifted based on the similarity between the local image centered at the source point and the local image centered at the virtual target point. Second, the target points are shifted by the constrained inverse function mapping the target points to the virtual target points. The source point set and shifted target point set are used to estimate the transformation function between the source image and target image. The performances of the authors' method are evaluated on two publicly available DIR-lab and POPI-model lung datasets. For computing target registration errors on 750 landmark points in six phases of the DIR-lab dataset and 37 landmark points in ten phases of the POPI-model dataset, the mean and standard deviation by the authors' method are 1.11 and 1.11 mm, but they are 2.33 and 2.32 mm without considering image intensity, and 1.17 and 1.19 mm with sliding conditions. For the two phases of maximum inhalation and maximum exhalation in the DIR-lab dataset with 300 landmark points of each case, the mean and standard deviation of target registration errors on the 3000 landmark points of ten cases by the authors' method are 1.21 and 1.04 mm. In the EMPIRE10 lung registration challenge, the authors' method ranks 24 of 39. According to the index of the maximum shear stretch, the authors' method is also efficient to describe the discontinuous motion at the lung boundaries. By establishing the correspondence of the landmark points in the source phase and the other target phases combining shape matching and image intensity matching together, the mismatching issue in the robust point matching algorithm is adequately addressed. The target registration errors are statistically reduced by shifting the virtual target points and target points. The authors' method with consideration of sliding conditions can effectively estimate the discontinuous motion, and the estimated motion is natural. The primary limitation of the proposed method is that the temporal constraints of the trajectories of voxels are not introduced into the motion model. However, the proposed method provides satisfactory motion information, which results in precise tumor coverage by the radiation dose during radiotherapy.

Is cancer history really an exclusion criterion for clinical trial of lung cancer? Influence of gastrointestinal tract cancer history on the outcomes of lung cancer surgery.

PubMed

Aokage, Keiju; Okada, Morihito; Suzuki, Kenji; Nomura, Shogo; Suzuki, Shigeki; Tsubokawa, Norifumi; Mimae, Takahiro; Hattori, Aritoshi; Hishida, Tomoyuki; Yoshida, Junji; Tsuboi, Masahiro

2017-02-15

Exclusion of patients with a history of other cancer treatment except in situ situation has been considered to be inevitable for clinical trials investigating survival outcome. However, there have been few reports confirming these influences on surgical outcome of lung cancer patients ever. Multi-institutional, individual data from patients with non–small cell lung cancer resected between 2000 and 2013 were collected. The patients were divided into two groups: those with a history of gastrointestinal tract cancer (GI group) and those without any history (non-GI group). We compared the outcomes with well-matched groups using propensity scoring to minimize bias related to the nonrandomness. The influence of gastrointestinal tract cancer stage, disease-free interval, and treatment method for gastrointestinal tract cancer on the surgical outcome of non–small cell lung cancer was examined. We analyzed 196 patients in the GI group and 3732 in the non-GI group. In unmatched cohort, multivariate analyses showed that a history of gastrointestinal tract cancer did not affect overall survival or recurrence-free survival. Independent predictors of poor prognosis included older age, male sex, high carcinoembryonic antigen levels and advanced clinical stage of non–small cell lung cancer. The two groups in the matched cohort demonstrated equivalent overall survival and recurrence-free survival, even in patients with clinical stage I. Gastrointestinal tract cancer stage, disease-free interval and treatment method for gastrointestinal tract cancer were not associated with outcomes. History of early gastrointestinal tract cancer completely resected is not always necessary for exclusion criteria in clinical trial of lung cancer.

Lung size mismatch and primary graft dysfunction after bilateral lung transplantation *

PubMed Central

Eberlein, Michael; Reed, Robert M.; Bolukbas, Servet; Wille, Keith M.; Orens, Jonathan B.; Brower, Roy G.; Christie, Jason D.

2014-01-01

BACKGROUND Donor to recipient lung size matching at lung transplantation (LTx) can be estimated by the predicted total lung capacity (pTLC)ratio (donor pTLC/recipient pTLC). We aimed to determine whether the pTLC-ratio is associated with the risk of primary graft dysfunction (PGD) after bilateral LTx (BLT). METHODS We calculated the pTLC-ratio for 812 adult BLTs from the Lung Transplant Outcomes Group between 3/2002-12/2010. Patients were stratified by pTLC-ratio>1.0 (“oversized”) and pTLC-ratio≤1.0 (“undersized”). PGD was defined as any ISHLT grade 3 PGD within 72 hours of reperfusion (PGD 3). We analyzed the association between risk factors and PGD using multivariable conditional logistic regression. As transplant diagnoses can influence the size matching decisions and also modulate the risk for PGD, we performed pre-specified analyses by assessing the impact of lung size mismatch within diagnostic categories. RESULTS In univariate analyses oversizing was associated with a 39% lower odds of PGD3 (OR 0.61, 95% CI, p=0.003). In a multivariate model accounting for center effects and known PGD risks, oversizing remained independently associated with a decreased odds of PGD3 (OR 0.58, 95% CI 0.38-0.88, p=0.01). The risk adjusted point estimate was similar for the non-COPD diagnoses groups (OR 0.52, 95%CI 0.32-0.86, p=0.01); however there was no detected association within the COPD group (OR 0.72, 95% CI 0.29-1.78, p=0.5). CONCLUSION Oversized allografts are associated with a decreased risk of PGD3 after BLT; this effect appears most apparent in non-COPD patients. PMID:25447586

Aspergillus fumigatus chronic colonization and lung function decline in cystic fibrosis may have a two-way relationship.

PubMed

Noni, M; Katelari, A; Dimopoulos, G; Doudounakis, S-E; Tzoumaka-Bakoula, C; Spoulou, V

2015-11-01

Aspergillus fumigatus is commonly found in cystic fibrosis (CF) airways. Our aim was to assess the relationship between A. fumigatus chronic colonization and lung function in CF patients. A case-control study of CF patients born from 1989 to 2002 was performed. Medical records were reviewed from the time of initial diagnosis until December 2013. Chronic colonization was defined as two or more positive sputum cultures in a given year. Each patient chronically colonized with A. fumigatus was matched with three control patients (never colonized by A. fumigatus) for age, sex, and year of birth (±3 years). A number of parameters were recorded and analyzed prospectively. The primary outcome measure was the difference in forced expiratory volume in 1 s (FEV1) in percent predicted between groups. Linear mixed models were used for longitudinal analyses to evaluate the relationship between A. fumigatus chronic colonization and lung function during a 7-year period and study the lung function 4 years before the time of enrollment (t0). Twenty patients had chronic colonization and were matched with 60 controls. A significant difference in lung function was detected throughout the 7-year period after adjustment for confounders (est = 8.66, p = 0.020). Four years before t0, FEV1 baseline was the only factor associated with the course of lung function (est = 0.64, p < 0.001) and was significantly different between groups (p = 0.001). In conclusion, a decreased FEV1 baseline appears to be a risk factor for chronic colonization by A. fumigatus, which, in turn, may cause a faster deterioration of lung function.

Comparison of flow and gas washout characteristics between pressure control and high-frequency percussive ventilation using a test lung

PubMed Central

Dutta, Rabijit; Xing, Tao; Swanson, Craig; Heltborg, Jeff; Murdoch, Gordon K

2018-01-01

Objective A comparison between flow and gas washout data for high-frequency percussive ventilation (HFPV) and pressure control ventilation (PCV) under similar conditions is currently not available. This bench study aims to compare and describe the flow and gas washout behavior of HFPV and PCV in a newly designed experimental setup and establish a framework for future clinical and animal studies. Approach We studied gas washout behavior using a newly designed experimental setup that is motivated by the multi-breath nitrogen washout measurements. In this procedure, a test lung was filled with nitrogen gas before it was connected to a ventilator. Pressure, volume, and oxygen concentrations were recorded under different compliance and resistance conditions. PCV was compared with two settings of HFPV, namely, HFPV-High and HFPV-Low, to simulate the different variations in its clinical application. In the HFPV-Low mode, the peak pressures and drive pressures of HFPV and PCV are matched, whereas in the HFPV-High mode, the mean airway pressures (MAP) are matched. Main results HFPV-Low mode delivers smaller tidal volume (VT) as compared to PCV under all lung conditions, whereas HFPV-High delivers a larger VT. HFPV-High provides rapid washout as compared to PCV under all lung conditions. HFPV-Low takes a longer time to wash out nitrogen except at a low compliance, where it expedites washout at a smaller VT and MAP compared to PCV washout. Significance Various flow parameters for HFPV and PCV are mathematically defined. A shorter washout time at a small VT in low compliant test lungs for HFPV could be regarded as a hypothesis for lung protective ventilation for animal or human lungs. PMID:29369819

Comparison of flow and gas washout characteristics between pressure control and high-frequency percussive ventilation using a test lung.

PubMed

Dutta, Rabijit; Xing, Tao; Swanson, Craig; Heltborg, Jeff; Murdoch, Gordon K

2018-03-15

A comparison between flow and gas washout data for high-frequency percussive ventilation (HFPV) and pressure control ventilation (PCV) under similar conditions is currently not available. This bench study aims to compare and describe the flow and gas washout behavior of HFPV and PCV in a newly designed experimental setup and establish a framework for future clinical and animal studies. We studied gas washout behavior using a newly designed experimental setup that is motivated by the multi-breath nitrogen washout measurements. In this procedure, a test lung was filled with nitrogen gas before it was connected to a ventilator. Pressure, volume, and oxygen concentrations were recorded under different compliance and resistance conditions. PCV was compared with two settings of HFPV, namely, HFPV-High and HFPV-Low, to simulate the different variations in its clinical application. In the HFPV-Low mode, the peak pressures and drive pressures of HFPV and PCV are matched, whereas in the HFPV-High mode, the mean airway pressures (MAP) are matched. HFPV-Low mode delivers smaller tidal volume (V T ) as compared to PCV under all lung conditions, whereas HFPV-High delivers a larger V T . HFPV-High provides rapid washout as compared to PCV under all lung conditions. HFPV-Low takes a longer time to wash out nitrogen except at a low compliance, where it expedites washout at a smaller V T and MAP compared to PCV washout. Various flow parameters for HFPV and PCV are mathematically defined. A shorter washout time at a small V T in low compliant test lungs for HFPV could be regarded as a hypothesis for lung protective ventilation for animal or human lungs.

Development and validation of automated 2D-3D bronchial airway matching to track changes in regional bronchial morphology using serial low-dose chest CT scans in children with chronic lung disease.

PubMed

Raman, Pavithra; Raman, Raghav; Newman, Beverley; Venkatraman, Raman; Raman, Bhargav; Robinson, Terry E

2010-12-01

To address potential concern for cumulative radiation exposure with serial spiral chest computed tomography (CT) scans in children with chronic lung disease, we developed an approach to match bronchial airways on low-dose spiral and low-dose high-resolution CT (HRCT) chest images to allow serial comparisons. An automated algorithm matches the position and orientation of bronchial airways obtained from HRCT slices with those in the spiral CT scan. To validate this algorithm, we compared manual matching vs automatic matching of bronchial airways in three pediatric patients. The mean absolute percentage difference between the manually matched spiral CT airway and the index HRCT airways were 9.4 ± 8.5% for the internal diameter measurements, 6.0 ± 4.1% for the outer diameter measurements, and 10.1 ± 9.3% for the wall thickness measurements. The mean absolute percentage difference between the automatically matched spiral CT airway measurements and index HRCT airway measurements were 9.2 ± 8.6% for the inner diameter, 5.8 ± 4.5% for the outer diameter, and 9.9 ± 9.5% for the wall thickness. The overall difference between manual and automated methods was 2.1 ± 1.2%, which was significantly less than the interuser variability of 5.1 ± 4.6% (p<0.05). Tests of equivalence had p<0.05, demonstrating no significant difference between the two methods. The time required for matching was significantly reduced in the automated method (p<0.01) and was as accurate as manual matching, allowing efficient comparison of airways obtained on low-dose spiral CT imaging with low-dose HRCT scans.

Reduction of observer variation using matched CT-PET for lung cancer delineation: A three-dimensional analysis

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

Steenbakkers, Roel; Duppen, Joop C.; Fitton, Isabelle

2006-02-01

Purpose: Target delineation using only CT information introduces large geometric uncertainties in radiotherapy for lung cancer. Therefore, a reduction of the delineation variability is needed. The impact of including a matched CT scan with 2-[{sup 18}F]fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) and adaptation of the delineation protocol and software on target delineation in lung cancer was evaluated in an extensive multi-institutional setting and compared with the delineations using CT only. Methods and Materials: The study was separated into two phases. For the first phase, 11 radiation oncologists (observers) delineated the gross tumor volume (GTV), including the pathologic lymph nodes of 22more » lung cancer patients (Stages I-IIIB) on CT only. For the second phase (1 year later), the same radiation oncologists delineated the GTV of the same 22 patients on a matched CT-FDG-PET scan using an adapted delineation protocol and software (according to the results of the first phase). All delineated volumes were analyzed in detail. The observer variation was computed in three dimensions by measuring the distance between the median GTV surface and each individual GTV. The variation in distance of all radiation oncologists was expressed as a standard deviation. The observer variation was evaluated for anatomic regions (lung, mediastinum, chest wall, atelectasis, and lymph nodes) and interpretation regions (agreement and disagreement; i.e., >80% vs. <80% of the radiation oncologists delineated the same structure, respectively). All radiation oncologist-computer interactions were recorded and analyzed with a tool called 'Big Brother.' Results: The overall three-dimensional observer variation was reduced from 1.0 cm (SD) for the first phase (CT only) to 0.4 cm (SD) for the second phase (matched CT-FDG-PET). The largest reduction in the observer variation was seen in the atelectasis region (SD 1.9 cm reduced to 0.5 cm). The mean ratio between the common and encompassing volume was 0.17 and 0.29 for the first and second phases, respectively. For the first phase, the common volume was 0 in 4 patients (i.e., no common point for all GTVs). In the second phase, the common volume was always >0. For all anatomic regions, the interpretation differences among the radiation oncologists were reduced. The amount of disagreement was 45% and 18% for the first and second phase, respectively. Furthermore, the mean delineation time (12 vs. 16 min, p < 0.001) and mean number of corrections (25 vs. 39, p < 0.001) were reduced in the second phase compared with the first phase. Conclusion: For high-precision radiotherapy, the delineation of lung target volumes using only CT introduces too great a variability among radiation oncologists. Implementing matched CT-FDG-PET and adapted delineation protocol and software reduced observer variation in lung cancer delineation significantly with respect to CT only. However, the remaining observer variation was still large compared with other geometric uncertainties (setup variation and organ motion)« less

ANG-1 TIE-2 and BMPR Signalling Defects Are Not Seen in the Nitrofen Model of Pulmonary Hypertension and Congenital Diaphragmatic Hernia

PubMed Central

Corbett, Harriet Jane; Connell, Marilyn Gwen; Fernig, David Garth

2012-01-01

Background Pulmonary hypertension (PH) is a lethal disease that is associated with characteristic histological abnormalities of the lung vasculature and defects of angiopoetin-1 (ANG-1), TIE-2 and bone morphogenetic protein receptor (BMPR)-related signalling. We hypothesized that if these signalling defects cause PH generically, they will be readily identifiable perinatally in congenital diaphragmatic hernia (CDH), where the typical pulmonary vascular changes are present before birth and are accompanied by PH after birth. Methods CDH (predominantly left-sided, LCDH) was created in Sprague-Dawley rat pups by e9.5 maternal nitrofen administration. Left lungs from normal and LCDH pups were compared at fetal and postnatal time points for ANG-1, TIE-2, phosphorylated-TIE-2, phosphorylated-SMAD1/5/8 and phosphorylated-ERK1/2 by immunoprecipitation and Western blotting of lung protein extracts and by immunohistochemistry on lung sections. Results In normal lung, pulmonary ANG-1 protein levels fall between fetal and postnatal life, while TIE-2 levels increase. Over the corresponding time period, LCDH lung retained normal expression of ANG-1, TIE-2, phosphorylated-TIE-2 and, downstream of BMPR, phosphorylated-SMAD1/5/8 and phosphorylated-p44/42. Conclusion In PH and CDH defects of ANG-1/TIE-2/BMPR-related signalling are not essential for the lethal vasculopathy. PMID:22539968

Characterizing the lung tissue mechanical properties using a micromechanical model of alveolar sac

NASA Astrophysics Data System (ADS)

Karami, Elham; Seify, Behzad; Moghadas, Hadi; Sabsalinejad, Masoomeh; Lee, Ting-Yim; Samani, Abbas

2017-03-01

According to statistics, lung disease is among the leading causes of death worldwide. As such, many research groups are developing powerful tools for understanding, diagnosis and treatment of various lung diseases. Recently, biomechanical modeling has emerged as an effective tool for better understanding of human physiology, disease diagnosis and computer assisted medical intervention. Mechanical properties of lung tissue are important requirements for methods developed for lung disease diagnosis and medical intervention. As such, the main objective of this study is to develop an effective tool for estimating the mechanical properties of normal and pathological lung parenchyma tissue based on its microstructure. For this purpose, a micromechanical model of the lung tissue was developed using finite element (FE) method, and the model was demonstrated to have application in estimating the mechanical properties of lung alveolar wall. The proposed model was developed by assembling truncated octahedron tissue units resembling the alveoli. A compression test was simulated using finite element method on the created geometry and the hyper-elastic parameters of the alveoli wall were calculated using reported alveolar wall stress-strain data and an inverse optimization framework. Preliminary results indicate that the proposed model can be potentially used to reconstruct microstructural images of lung tissue using macro-scale tissue response for normal and different pathological conditions. Such images can be used for effective diagnosis of lung diseases such as Chronic Obstructive Pulmonary Disease (COPD).

Thoracic Insufficiency Syndrome

MedlinePlus

... Patients with this condition can't maintain normal respiration or lung growth. The thorax (spine, rib cage, and sternum) is the engine of respiration. It must have adequate space for the lungs ...

The Prognosis of Small Cell Lung Cancer in Patients with Pulmonary Fibrosis.

PubMed

Matsumoto, Yoko; Ohara, Sayaka; Furukawa, Ryutaro; Usui, Kazuhiro

2017-10-01

The purpose of this study was to assess the prognosis of small cell lung cancer (SCLC) based on the underlying pulmonary disease. A total of 204 patients with SCLC were reviewed and categorized into three groups: normal, emphysema and fibrosis. The median overall survival duration (OS) in patients with normal lungs (n=57), with emphysema (n=105) and fibrosis (n=42) was 21.3, 16.4 and 10.8 months (p=0.063). In limited-stage disease (LD), the median OS in patients with fibrosis (7.4 months) was shorter than normal (52.7 months) or emphysema patients (26.4 months) (p=0.034). In extensive-stage disease (ED), the median OS in patients with fibrosis (12.7 months) was not significantly different from normal (11.4 months) or emphysema patients (13.5 months) (p=0.600). Patients with fibrosis had a poorer prognosis than normal or emphysema patients in LD-SCLC, but the coexistence of pulmonary fibrosis did not affect the prognostic outcomes in ED-SCLC. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

Diagnosing and Mapping Pulmonary Emphysema on X-Ray Projection Images: Incremental Value of Grating-Based X-Ray Dark-Field Imaging

PubMed Central

Meinel, Felix G.; Schwab, Felix; Schleede, Simone; Bech, Martin; Herzen, Julia; Achterhold, Klaus; Auweter, Sigrid; Bamberg, Fabian; Yildirim, Ali Ö.; Bohla, Alexander; Eickelberg, Oliver; Loewen, Rod; Gifford, Martin; Ruth, Ronald; Reiser, Maximilian F.; Pfeiffer, Franz; Nikolaou, Konstantin

2013-01-01

Purpose To assess whether grating-based X-ray dark-field imaging can increase the sensitivity of X-ray projection images in the diagnosis of pulmonary emphysema and allow for a more accurate assessment of emphysema distribution. Materials and Methods Lungs from three mice with pulmonary emphysema and three healthy mice were imaged ex vivo using a laser-driven compact synchrotron X-ray source. Median signal intensities of transmission (T), dark-field (V) and a combined parameter (normalized scatter) were compared between emphysema and control group. To determine the diagnostic value of each parameter in differentiating between healthy and emphysematous lung tissue, a receiver-operating-characteristic (ROC) curve analysis was performed both on a per-pixel and a per-individual basis. Parametric maps of emphysema distribution were generated using transmission, dark-field and normalized scatter signal and correlated with histopathology. Results Transmission values relative to water were higher for emphysematous lungs than for control lungs (1.11 vs. 1.06, p<0.001). There was no difference in median dark-field signal intensities between both groups (0.66 vs. 0.66). Median normalized scatter was significantly lower in the emphysematous lungs compared to controls (4.9 vs. 10.8, p<0.001), and was the best parameter for differentiation of healthy vs. emphysematous lung tissue. In a per-pixel analysis, the area under the ROC curve (AUC) for the normalized scatter value was significantly higher than for transmission (0.86 vs. 0.78, p<0.001) and dark-field value (0.86 vs. 0.52, p<0.001) alone. Normalized scatter showed very high sensitivity for a wide range of specificity values (94% sensitivity at 75% specificity). Using the normalized scatter signal to display the regional distribution of emphysema provides color-coded parametric maps, which show the best correlation with histopathology. Conclusion In a murine model, the complementary information provided by X-ray transmission and dark-field images adds incremental diagnostic value in detecting pulmonary emphysema and visualizing its regional distribution as compared to conventional X-ray projections. PMID:23555692

Diagnosing and mapping pulmonary emphysema on X-ray projection images: incremental value of grating-based X-ray dark-field imaging.

PubMed

Meinel, Felix G; Schwab, Felix; Schleede, Simone; Bech, Martin; Herzen, Julia; Achterhold, Klaus; Auweter, Sigrid; Bamberg, Fabian; Yildirim, Ali Ö; Bohla, Alexander; Eickelberg, Oliver; Loewen, Rod; Gifford, Martin; Ruth, Ronald; Reiser, Maximilian F; Pfeiffer, Franz; Nikolaou, Konstantin

2013-01-01

To assess whether grating-based X-ray dark-field imaging can increase the sensitivity of X-ray projection images in the diagnosis of pulmonary emphysema and allow for a more accurate assessment of emphysema distribution. Lungs from three mice with pulmonary emphysema and three healthy mice were imaged ex vivo using a laser-driven compact synchrotron X-ray source. Median signal intensities of transmission (T), dark-field (V) and a combined parameter (normalized scatter) were compared between emphysema and control group. To determine the diagnostic value of each parameter in differentiating between healthy and emphysematous lung tissue, a receiver-operating-characteristic (ROC) curve analysis was performed both on a per-pixel and a per-individual basis. Parametric maps of emphysema distribution were generated using transmission, dark-field and normalized scatter signal and correlated with histopathology. Transmission values relative to water were higher for emphysematous lungs than for control lungs (1.11 vs. 1.06, p<0.001). There was no difference in median dark-field signal intensities between both groups (0.66 vs. 0.66). Median normalized scatter was significantly lower in the emphysematous lungs compared to controls (4.9 vs. 10.8, p<0.001), and was the best parameter for differentiation of healthy vs. emphysematous lung tissue. In a per-pixel analysis, the area under the ROC curve (AUC) for the normalized scatter value was significantly higher than for transmission (0.86 vs. 0.78, p<0.001) and dark-field value (0.86 vs. 0.52, p<0.001) alone. Normalized scatter showed very high sensitivity for a wide range of specificity values (94% sensitivity at 75% specificity). Using the normalized scatter signal to display the regional distribution of emphysema provides color-coded parametric maps, which show the best correlation with histopathology. In a murine model, the complementary information provided by X-ray transmission and dark-field images adds incremental diagnostic value in detecting pulmonary emphysema and visualizing its regional distribution as compared to conventional X-ray projections.

How absolute EIT reflects the dependence of unilateral lung aeration on hyper-gravity and weightlessness?

PubMed

Hahn, G; Just, A; Hellige, G; Dittmar, J; Quintel, M

2013-09-01

We studied the influence of three gravity levels (0, 1 and 1.8 g) on unilateral lung aeration in a left lateral position by the application of absolute electrical impedance tomography. The electrical resistivity of the lung tissue was considered to be a meaningful indicator for lung aeration since changes in resistivity have already been validated in other studies to be proportional to changes in lung volume. Twenty-two healthy volunteers were studied during parabolic flights with three phases of different gravity, each lasting ∼20-22 s. Spontaneous breathing at normal tidal volume VT and at increased VT was performed. During transition to hyper-gravity mean expiratory resistivities (±SD in Ωm) increased at normal VT in the upper (right) lung from 7.6 ± 1.5 to 8.0 ± 1.7 and decreased from 5.8 ± 1.2 to 5.7 ± 1.2 in the lower (left) lung. Inspiratory resistivity values are 8.3 ± 1.6 to 8.8 ± 1.8 (right) and 6.3 ± 1.3 to 6.0 ± 1.3 (left). At increased VT, the changes in resistivities at end-expiration were 7.7 ± 1.5 to 8.0 ± 1.7 (right) and 5.8 ± 1.2 to 5.7 ± 1.2 (left). Corresponding end-inspiratory values are 9.9 ± 1.9 to 10.0 ± 2.0 (right) and 8.6 ± 2.1 to 7.9 ± 2.0 (left). During weightlessness, the distortion in the lungs disappeared and both lungs showed a nearly identical aeration, which was between the levels displayed at normal gravity. The small increase in resistivity for the upper lung during transition to hyper-gravity from 1 to 1.8 g at increased VT suggests that the degressive part of the pressure-volume curve has already been reached at end-inspiration. The results for a left lateral position are in agreement with West's lung model which has been introduced for cranio-caudal gravity dependence in the lungs.

Immunohistochemical quantification of expression of a tight junction protein, claudin-7, in human lung cancer samples using digital image analysis method.

PubMed

Lu, Zhe; Liu, Yi; Xu, Junfeng; Yin, Hongping; Yuan, Haiying; Gu, Jinjing; Chen, Yan-Hua; Shi, Liyun; Chen, Dan; Xie, Bin

2018-03-01

Tight junction proteins are correlated with cancer development. As the pivotal proteins in epithelial cells, altered expression and distribution of different claudins have been reported in a wide variety of human malignancies. We have previously reported that claudin-7 was strongly expressed in benign bronchial epithelial cells at the cell-cell junction while expression of claudin-7 was either altered with discontinued weak expression or completely absent in lung cancers. Based on these results, we continued working on the expression pattern of claudin-7 and its relationship with lung cancer development. We herein proposed a new Digital Image Classification, Fragmentation index, Morphological analysis (DICFM) method for differentiating the normal lung tissues and lung cancer tissues based on the claudin-7 immunohistochemical staining. Seventy-seven lung cancer samples were obtained from the Second Affiliated Hospital of Zhejiang University and claudin-7 immunohistochemical staining was performed. Based on C++ and Open Source Computer Vision Library (OpenCV, version 2.4.4), the DICFM processing module was developed. Intensity and fragmentation of claudin-7 expression, as well as the morphological parameters of nuclei were calculated. Evaluation of results was performed using Receiver Operator Characteristic (ROC) analysis. Agreement between these computational results and the results obtained by two pathologists was demonstrated. The intensity of claudin-7 expression was significantly decreased while the fragmentation was significantly increased in the lung cancer tissues compared to the normal lung tissues and the intensity was strongly positively associated with the differentiation of lung cancer cells. Moreover, the perimeters of the nuclei of lung cancer cells were significantly greater than that of the normal lung cells, while the parameters of area and circularity revealed no statistical significance. Taken together, our DICFM approach may be applied as an appropriate approach to quantify the immunohistochemical staining of claudin-7 on the cell membrane and claudin-7 may serve as a marker for identification of lung cancer. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

Pleural plaques and their effect on lung function in Libby vermiculite miners.

PubMed

Clark, Kathleen A; Flynn, J Jay; Goodman, Julie E; Zu, Ke; Karmaus, Wilfried J J; Mohr, Lawrence C

2014-09-01

Multiple studies have investigated the relationship between asbestos-related pleural plaques (PPs) and lung function, with disparate and inconsistent results. Most use chest radiographs to identify PPs and simple spirometry to measure lung function. High-resolution CT (HRCT) scanning improves the accuracy of PP identification. Complete pulmonary function tests (PFTs), including spirometry, lung volumes, and diffusing capacity of the lung for carbon monoxide, provide a more definitive assessment of lung function. The goal of this study was to determine, using HRCT scanning and complete PFTs, the effect of PPs on lung function in Libby vermiculite miners. The results of HRCT scanning and complete PFTs performed between January 2000 and August 2012 were obtained from the medical records of 166 Libby vermiculite miners. Multivariate regression analyses with Tukey multivariate adjustment were used to assess statistical associations between the presence of PPs and lung function. Adjustments were made for age, BMI, smoking history, duration of employment, and years since last occupational asbestos exposure. Nearly 90% of miners (n = 149) had evidence of PPs on HRCT scan. No significant differences in spirometry results, lung volumes, or diffusing capacity of the lung for carbon monoxide were found between miners with PPs alone and miners with normal HRCT scans. Miners with both interstitial fibrosis and the presence of PPs had a significantly decreased total lung capacity in comparison with miners with normal HRCT scans (P = .02). Age, cumulative smoking history, and BMI were significant covariates that contributed to abnormal lung function. Asbestos-related PPs alone have no significant effect on lung function in Libby vermiculite miners.

Four SNPs and Systemic Level of FOXP3 in Smokers and Patients with Chronic Obstructive Pulmonary Disease.

PubMed

Chu, Shuyuan; Zhong, Xiaoning; Zhang, Jianquan; Lai, Xiaoying; Xie, Jiajun; Li, Yu

2016-12-01

Forkhead box P3 (FOXP3) is the essential transcription factor for the function of regulatory T-cell (Treg). However, the gene mutation of FOXP3 in patients with chronic obstructive pulmonary disease (COPD) at different stages has not been reported. We aim to investigate four single nucleotide polymorphisms (SNPs) and the mRNA expression of FOXP3 in smokers with normal lung function and smokers with COPD at different stages. FOXP3 mRNA expression and SNPs in FOXP3 were assessed in nonsmokers with normal lung function (N), smokers with normal lung function (S), smokers with COPD in the Global Initiative for Chronic Obstructive Lung Disease (GOLD) 1 or 2 grade (COPD 1-2), and smokers with COPD in GOLD 3 or 4 grade (COPD 3-4). In peripheral blood sample, FOXP3 mRNA was assessed using real-time quantitative PCR and SNPs were analyzed by TaqMan PCR. FOXP3 mRNA level in peripheral blood sample was decreased when COPD was aggravated. The frequency of FOXP3 rs5902434 genotype del/del and allele del are lower in COPD 1-2 and COPD 3-4 than that in N or S. The rs5902434 genotype del/del and allele del were, respectively, associated with decreased risk of COPD and lung function decline. The rs5902434 genotypic distribution was correlated with FOXP3 mRNA level. In conclusion, both FOXP3 rs5902434 genotypes and alleles were differently distributed in COPD patients and smokers with normal lung function. The distribution of del/del genotype was associated with systemic expression of FOXP3 mRNA. More research is needed to explore the role of FOXP3 gene polymorphism in immunoinflammation of COPD.

Developing a Reference of Normal Lung Sounds in Healthy Peruvian Children

PubMed Central

Ellington, Laura E.; Emmanouilidou, Dimitra; Elhilali, Mounya; Gilman, Robert H.; Tielsch, James M.; Chavez, Miguel A.; Marin-Concha, Julio; Figueroa, Dante; West, James

2018-01-01

Purpose Lung auscultation has long been a standard of care for the diagnosis of respiratory diseases. Recent advances in electronic auscultation and signal processing have yet to find clinical acceptance; however, computerized lung sound analysis may be ideal for pediatric populations in settings, where skilled healthcare providers are commonly unavailable. We described features of normal lung sounds in young children using a novel signal processing approach to lay a foundation for identifying pathologic respiratory sounds. Methods 186 healthy children with normal pulmonary exams and without respiratory complaints were enrolled at a tertiary care hospital in Lima, Peru. Lung sounds were recorded at eight thoracic sites using a digital stethoscope. 151 (81 %) of the recordings were eligible for further analysis. Heavy-crying segments were automatically rejected and features extracted from spectral and temporal signal representations contributed to profiling of lung sounds. Results Mean age, height, and weight among study participants were 2.2 years (SD 1.4), 84.7 cm (SD 13.2), and 12.0 kg (SD 3.6), respectively; and, 47 % were boys. We identified ten distinct spectral and spectro-temporal signal parameters and most demonstrated linear relationships with age, height, and weight, while no differences with genders were noted. Older children had a faster decaying spectrum than younger ones. Features like spectral peak width, lower-frequency Mel-frequency cepstral coefficients, and spectro-temporal modulations also showed variations with recording site. Conclusions Lung sound extracted features varied significantly with child characteristics and lung site. A comparison with adult studies revealed differences in the extracted features for children. While sound-reduction techniques will improve analysis, we offer a novel, reproducible tool for sound analysis in real-world environments. PMID:24943262

Developing a reference of normal lung sounds in healthy Peruvian children.

PubMed

Ellington, Laura E; Emmanouilidou, Dimitra; Elhilali, Mounya; Gilman, Robert H; Tielsch, James M; Chavez, Miguel A; Marin-Concha, Julio; Figueroa, Dante; West, James; Checkley, William

2014-10-01

Lung auscultation has long been a standard of care for the diagnosis of respiratory diseases. Recent advances in electronic auscultation and signal processing have yet to find clinical acceptance; however, computerized lung sound analysis may be ideal for pediatric populations in settings, where skilled healthcare providers are commonly unavailable. We described features of normal lung sounds in young children using a novel signal processing approach to lay a foundation for identifying pathologic respiratory sounds. 186 healthy children with normal pulmonary exams and without respiratory complaints were enrolled at a tertiary care hospital in Lima, Peru. Lung sounds were recorded at eight thoracic sites using a digital stethoscope. 151 (81%) of the recordings were eligible for further analysis. Heavy-crying segments were automatically rejected and features extracted from spectral and temporal signal representations contributed to profiling of lung sounds. Mean age, height, and weight among study participants were 2.2 years (SD 1.4), 84.7 cm (SD 13.2), and 12.0 kg (SD 3.6), respectively; and, 47% were boys. We identified ten distinct spectral and spectro-temporal signal parameters and most demonstrated linear relationships with age, height, and weight, while no differences with genders were noted. Older children had a faster decaying spectrum than younger ones. Features like spectral peak width, lower-frequency Mel-frequency cepstral coefficients, and spectro-temporal modulations also showed variations with recording site. Lung sound extracted features varied significantly with child characteristics and lung site. A comparison with adult studies revealed differences in the extracted features for children. While sound-reduction techniques will improve analysis, we offer a novel, reproducible tool for sound analysis in real-world environments.

Fast correspondences search in anatomical trees

NASA Astrophysics Data System (ADS)

dos Santos, Thiago R.; Gergel, Ingmar; Meinzer, Hans-Peter; Maier-Hein, Lena

2010-03-01

Registration of multiple medical images commonly comprises the steps feature extraction, correspondences search and transformation computation. In this paper, we present a new method for a fast and pose independent search of correspondences using as features anatomical trees such as the bronchial system in the lungs or the vessel system in the liver. Our approach scores the similarities between the trees' nodes (bifurcations) taking into account both, topological properties extracted from their graph representations and anatomical properties extracted from the trees themselves. The node assignment maximizes the global similarity (sum of the scores of each pair of assigned nodes), assuring that the matches are distributed throughout the trees. Furthermore, the proposed method is able to deal with distortions in the data, such as noise, motion, artifacts, and problems associated with the extraction method, such as missing or false branches. According to an evaluation on swine lung data sets, the method requires less than one second on average to compute the matching and yields a high rate of correct matches compared to state of the art work.

Function of the Dräger Oxylog ventilator at high altitude.

PubMed

Thomas, G; Brimacombe, J

1994-06-01

We have assessed the performance of the Dräger Oxylog ventilator at high altitude using a decompression chamber and a lung simulator set to mimic the normal and non-compliant lung. In the normal lung, tidal volume increased by 28% at 2040 metres and by 106% at 9120 metres. A lesser change, but in the opposite direction, occurred in respiratory rate. The net effect was a linear increase in minute volume with altitude. At 2040 and 9144 metres minute volume increased by 13% and by 45%, and rate decreased by 10% and 30% respectively. In the abnormal lung stimulation, similar, but slightly less marked, changes occurred in all variables. These changes are of sufficient magnitude to require frequent observation of tidal volume and respiratory rate during aircraft ascent and descent.

Markerless positional verification using template matching and triangulation of kV images acquired during irradiation for lung tumors treated in breath-hold

NASA Astrophysics Data System (ADS)

Hazelaar, Colien; Dahele, Max; Mostafavi, Hassan; van der Weide, Lineke; Slotman, Ben; Verbakel, Wilko

2018-06-01

Lung tumors treated in breath-hold are subject to inter- and intra-breath-hold variations, which makes tumor position monitoring during each breath-hold important. A markerless technique is desirable, but limited tumor visibility on kV images makes this challenging. We evaluated if template matching  +  triangulation of kV projection images acquired during breath-hold stereotactic treatments could determine 3D tumor position. Band-pass filtering and/or digital tomosynthesis (DTS) were used as image pre-filtering/enhancement techniques. On-board kV images continuously acquired during volumetric modulated arc irradiation of (i) a 3D-printed anthropomorphic thorax phantom with three lung tumors (n  =  6 stationary datasets, n  =  2 gradually moving), and (ii) four patients (13 datasets) were analyzed. 2D reference templates (filtered DRRs) were created from planning CT data. Normalized cross-correlation was used for 2D matching between templates and pre-filtered/enhanced kV images. For 3D verification, each registration was triangulated with multiple previous registrations. Generally applicable image processing/algorithm settings for lung tumors in breath-hold were identified. For the stationary phantom, the interquartile range of the 3D position vector was on average 0.25 mm for 12° DTS  +  band-pass filtering (average detected positions in 2D  =  99.7%, 3D  =  96.1%, and 3D excluding first 12° due to triangulation angle  =  99.9%) compared to 0.81 mm for band-pass filtering only (55.8/52.9/55.0%). For the moving phantom, RMS errors for the lateral/longitudinal/vertical direction after 12° DTS  +  band-pass filtering were 1.5/0.4/1.1 mm and 2.2/0.3/3.2 mm. For the clinical data, 2D position was determined for at least 93% of each dataset and 3D position excluding first 12° for at least 82% of each dataset using 12° DTS  +  band-pass filtering. Template matching  +  triangulation using DTS  +  band-pass filtered images could accurately determine the position of stationary lung tumors. However, triangulation was less accurate/reliable for targets with continuous, gradual displacement in the lateral and vertical directions. This technique is therefore currently most suited to detect/monitor offsets occurring between initial setup and the start of treatment, inter-breath-hold variations, and tumors with predominantly longitudinal motion.

Genetics and Genomics of Longitudinal Lung Function Patterns in Individuals with Asthma

PubMed Central

Yates, Katherine P.; Zhou, Xiaobo; Guo, Feng; Sternberg, Alice L.; Van Natta, Mark L.; Wise, Robert A.; Szefler, Stanley J.; Sharma, Sunita; Kho, Alvin T.; Cho, Michael H.; Croteau-Chonka, Damien C.; Castaldi, Peter J.; Jain, Gaurav; Sanyal, Amartya; Zhan, Ye; Lajoie, Bryan R.; Dekker, Job; Stamatoyannopoulos, John; Covar, Ronina A.; Zeiger, Robert S.; Adkinson, N. Franklin; Williams, Paul V.; Kelly, H. William; Grasemann, Hartmut; Vonk, Judith M.; Koppelman, Gerard H.; Postma, Dirkje S.; Raby, Benjamin A.; Houston, Isaac; Lu, Quan; Fuhlbrigge, Anne L.; Tantisira, Kelan G.; Silverman, Edwin K.; Tonascia, James; Strunk, Robert C.; Weiss, Scott T.

2016-01-01

Rationale: Patterns of longitudinal lung function growth and decline in childhood asthma have been shown to be important in determining risk for future respiratory ailments including chronic airway obstruction and chronic obstructive pulmonary disease. Objectives: To determine the genetic underpinnings of lung function patterns in subjects with childhood asthma. Methods: We performed a genome-wide association study of 581 non-Hispanic white individuals with asthma that were previously classified by patterns of lung function growth and decline (normal growth, normal growth with early decline, reduced growth, and reduced growth with early decline). The strongest association was also measured in two additional cohorts: a small asthma cohort and a large chronic obstructive pulmonary disease metaanalysis cohort. Interaction between the genomic region encompassing the most strongly associated single-nucleotide polymorphism and nearby genes was assessed by two chromosome conformation capture assays. Measurements and Main Results: An intergenic single-nucleotide polymorphism (rs4445257) on chromosome 8 was strongly associated with the normal growth with early decline pattern compared with all other pattern groups (P = 6.7 × 10−9; odds ratio, 2.8; 95% confidence interval, 2.0–4.0); replication analysis suggested this variant had opposite effects in normal growth with early decline and reduced growth with early decline pattern groups. Chromosome conformation capture experiments indicated a chromatin interaction between rs4445257 and the promoter of the distal CSMD3 gene. Conclusions: Early decline in lung function after normal growth is associated with a genetic polymorphism that may also protect against early decline in reduced growth groups. Clinical trial registered with www.clinicaltrials.gov (NCT00000575). PMID:27367781

Non-Essential Role for TLR2 and Its Signaling Adaptor Mal/TIRAP in Preserving Normal Lung Architecture in Mice

PubMed Central

Ruwanpura, Saleela M.; McLeod, Louise; Lilja, Andrew R.; Brooks, Gavin; Dousha, Lovisa F.; Seow, Huei J.; Bozinovski, Steven; Vlahos, Ross; Hertzog, Paul J.; Anderson, Gary P.; Jenkins, Brendan J.

2013-01-01

Myeloid differentiation factor 88 (MyD88) and MyD88-adaptor like (Mal)/Toll-interleukin 1 receptor domain containing adaptor protein (TIRAP) play a critical role in transducing signals downstream of the Toll-like receptor (TLR) family. While genetic ablation of the TLR4/MyD88 signaling axis in mice leads to pulmonary cell death and oxidative stress culminating in emphysema, the involvement of Mal, as well as TLR2 which like TLR4 also signals via MyD88 and Mal, in the pathogenesis of emphysema has not been studied. By employing an in vivo genetic approach, we reveal here that unlike the spontaneous pulmonary emphysema which developed in Tlr4−/− mice by 6 months of age, the lungs of Tlr2−/− mice showed no physiological or morphological signs of emphysema. A more detailed comparative analysis of the lungs from these mice confirmed that elevated oxidative protein carbonylation levels and increased numbers of alveolar cell apoptosis were only detected in Tlr4−/− mice, along with up-regulation of NADPH oxidase 3 (Nox3) mRNA expression. With respect to Mal, the architecture of the lungs of Mal−/− mice was normal. However, despite normal oxidative protein carbonylation levels in the lungs of emphysema-free Mal−/− mice, these mice displayed increased levels of apoptosis comparable to those observed in emphysematous Tlr4−/− mice. In conclusion, our data provide in vivo evidence for the non-essential role for TLR2, unlike the related TLR4, in maintaining the normal architecture of the lung. In addition, we reveal that Mal differentially facilitates the anti-apoptotic, but not oxidant suppressive, activities of TLR4 in the lung, both of which appear to be essential for TLR4 to prevent the onset of emphysema. PMID:24205107

Energy normalization of TV viewed optical correlation (automated correlation plane analyzer for an optical processor)

NASA Technical Reports Server (NTRS)

Grumet, A.

1981-01-01

An automatic correlation plane processor that can rapidly acquire, identify, and locate the autocorrelation outputs of a bank of multiple optical matched filters is described. The read-only memory (ROM) stored digital silhouette of each image associated with each matched filter allows TV video to be used to collect image energy to provide accurate normalization of autocorrelations. The resulting normalized autocorrelations are independent of the illumination of the matched input. Deviation from unity of a normalized correlation can be used as a confidence measure of correct image identification. Analog preprocessing circuits permit digital conversion and random access memory (RAM) storage of those video signals with the correct amplitude, pulse width, rising slope, and falling slope. TV synchronized addressing of 3 RAMs permits on-line storage of: (1) the maximum unnormalized amplitude, (2) the image x location, and (3) the image y location of the output of each of up to 99 matched filters. A fourth RAM stores all normalized correlations. A normalization approach, normalization for cross correlations, a system's description with block diagrams, and system's applications are discussed.

Classification algorithm of lung lobe for lung disease cases based on multislice CT images

NASA Astrophysics Data System (ADS)

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

2011-03-01

With the development of multi-slice CT technology, to obtain an accurate 3D image of lung field in a short time is possible. To support that, a lot of image processing methods need to be developed. In clinical setting for diagnosis of lung cancer, it is important to study and analyse lung structure. Therefore, classification of lung lobe provides useful information for lung cancer analysis. In this report, we describe algorithm which classify lungs into lung lobes for lung disease cases from multi-slice CT images. The classification algorithm of lung lobes is efficiently carried out using information of lung blood vessel, bronchus, and interlobar fissure. Applying the classification algorithms to multi-slice CT images of 20 normal cases and 5 lung disease cases, we demonstrate the usefulness of the proposed algorithms.

SU-E-T-573: Normal Tissue Dose Effect of Prescription Isodose Level Selection in Lung Stereotactic Body Radiation Therapy

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

Zhang, Q; Lei, Y; Zheng, D

Purpose: To evaluate dose fall-off in normal tissue for lung stereotactic body radiation therapy (SBRT) cases planned with different prescription isodose levels (IDLs), by calculating the dose dropping speed (DDS) in normal tissue on plans computed with both Pencil Beam (PB) and Monte-Carlo (MC) algorithms. Methods: The DDS was calculated on 32 plans for 8 lung SBRT patients. For each patient, 4 dynamic conformal arc plans were individually optimized for prescription isodose levels (IDL) ranging from 60% to 90% of the maximum dose with 10% increments to conformally cover the PTV. Eighty non-overlapping rind structures each of 1mm thickness weremore » created layer by layer from each PTV surface. The average dose in each rind was calculated and fitted with a double exponential function (DEF) of the distance from the PTV surface, which models the steep- and moderate-slope portions of the average dose curve in normal tissue. The parameter characterizing the steep portion of the average dose curve in the DEF quantifies the DDS in the immediate normal tissue receiving high dose. Provided that the prescription dose covers the whole PTV, a greater DDS indicates better normal tissue sparing. The DDS were compared among plans with different prescription IDLs, for plans computed with both PB and MC algorithms. Results: For all patients, the DDS was found to be the lowest for 90% prescription IDL and reached a highest plateau region for 60% or 70% prescription. The trend was the same for both PB and MC plans. Conclusion: Among the range of prescription IDLs accepted by lung SBRT RTOG protocols, prescriptions to 60% and 70% IDLs were found to provide best normal tissue sparing.« less

[A case-control study of the risk factors for lung cancer among Chinese women who have never smoked].

PubMed

Fang, Jun; Gan, De-kun; Zheng, Su-hua; Zhang, Hong-wei

2006-07-01

To investigate the risk factors for lung cancer among women who had never smoked. Methods A 1:2 matched case-control study was carried out. The cases are the no-smoking female patients with the primary lung cancer diagnosed by pathology mothed from hospitals in Beijing, Shanghai and Chengdu between September 2001 and February 2004. One hospital control and one population control matched for age, sex and no-smoking et al., were enrolled. The case and control were interviewed about the exposure information of related factors using the uniform questionnaire. Statistical analysis of single-factor and multivariate conditional Logistic regression were performed to screen the risk factors of lung cancer. During the single-factoranalysis, 28 exposure factors were identified as risk factors for lung cancer. The multivariate conditional Logistic regression show that passive smoking index > or = 50 person * year (OR = 1.77,95% CI, 1.07 - 2.92), consumption of internal organs of animals (OR = 1.85,95% CI, 1.06 - 3.22), and occupational exposure to dust (OR = 2.47,95% CI, 1.21 - 5.03) and bad ventilation in workplace( OR = 4.02,95% CI, 1.74 - 9.29) are risk factors for lung cancer, but consumption of vegetables( OR = 0.26, 95% CI, 0.12 - 0.59), taking vitamins often (OR = 0.53, 95% CI, 0.30 - 0.93), average month income per person after married > or = 500 yuan ( OR = 0.50, 95% CI, 0.28 - 0.91) and the first procreation occurred between 24 and 30 years old (OR = 0.53, 95% CI, 0.32 - 0.90) are the protective factors for lung cancer. The dose-response were observed between passive smoking and risk rate of lung cancer by trend test. Some factors such as passive smoking, consumption of internal organs of animals, occupational exposure to dust and bad ventilation in workplace can increase the risk of lung cancer for women who had never smoked. Other factors such as consumption of vegetables, taking vitamins, and so on, can reduce the risk of lung cancer for women who had never smoked.

Pulmonary veins in the normal lung and pulmonary hypertension due to left heart disease

PubMed Central

Hunt, James M.; Bethea, Brian; Liu, Xiang; Gandjeva, Aneta; Mammen, Pradeep P. A.; Stacher, Elvira; Gandjeva, Marina R.; Parish, Elisabeth; Perez, Mario; Smith, Lynelle; Graham, Brian B.; Kuebler, Wolfgang M.

2013-01-01

Despite the importance of pulmonary veins in normal lung physiology and the pathobiology of pulmonary hypertension with left heart disease (PH-LHD), pulmonary veins remain largely understudied. Difficult to identify histologically, lung venous endothelium or smooth muscle cells display no unique characteristic functional and structural markers that distinguish them from pulmonary arteries. To address these challenges, we undertook a search for unique molecular markers in pulmonary veins. In addition, we addressed the expression pattern of a candidate molecular marker and analyzed the structural pattern of vascular remodeling of pulmonary veins in a rodent model of PH-LHD and in lung tissue of patients with PH-LHD obtained at time of placement on a left ventricular assist device. We detected urokinase plasminogen activator receptor (uPAR) expression preferentially in normal pulmonary veins of mice, rats, and human lungs. Expression of uPAR remained elevated in pulmonary veins of rats with PH-LHD; however, we also detected induction of uPAR expression in remodeled pulmonary arteries. These findings were validated in lungs of patients with PH-LHD. In selected patients with sequential lung biopsy at the time of removal of the left ventricular assist device, we present early data suggesting improvement in pulmonary hemodynamics and venous remodeling, indicating potential regression of venous remodeling in response to assist device treatment. Our data indicate that remodeling of pulmonary veins is an integral part of PH-LHD and that pulmonary veins share some key features present in remodeled yet not normotensive pulmonary arteries. PMID:24039255

Are there sex differences in the capillary blood volume and diffusing capacity response to exercise?

PubMed

Bouwsema, Melissa M; Tedjasaputra, Vincent; Stickland, Michael K

2017-03-01

Previous work suggests that women may exhibit a greater respiratory limitation in exercise compared with height-matched men. Diffusion capacity (Dl CO ) increases with incremental exercise, and the smaller lungs of women may limit membrane diffusing capacity (Dm) and pulmonary capillary blood volume (Vc) in response to the increased oxygen demand. We hypothesized that women would have lower Dl CO , Dl CO relative to cardiac output (Dl CO /Q̇), Dm, Vc, and pulmonary transit time, secondary to lower Vc at peak exercise. Sixteen women (112 ± 12% predicted relative V̇o 2peak ) and sixteen men (118 ± 22% predicted relative V̇o 2peak ) were matched for height and weight. Hemoglobin-corrected diffusing capacity (Dl CO ), Vc, and Dm were determined via the multiple-[Formula: see text] Dl CO technique at rest and during incremental exercise up to 90% of V̇o 2peak Both groups increased Dl CO , Vc, and Dm with exercise intensity, but women had 20% lower Dl CO ( P < 0.001), 18% lower Vc ( P = 0.002), and 22% lower Dm ( P < 0.001) compared with men across all workloads, and neither group exhibited a plateau in Vc. When expressed relative to alveolar volume (Va), the between-sex difference was eliminated. The drop in Dl CO /Q̇ was proportionally less in women than men, and mean pulmonary transit time did not drop below 0.3 s in either group. Women demonstrate consistently lower Dl CO , Vc, and Dm compared with height-matched men during exercise; however, these differences disappear with correction for lung size. These results suggest that after differences in lung volume are accounted for there is no intrinsic sex difference in the Dl CO , Vc, or Dm response to exercise. NEW & NOTEWORTHY Women demonstrate lower diffusing capacity-to-cardiac output ratio (Dl CO /Q̇), pulmonary capillary blood volume (Vc), and membrane diffusing capacity (Dm) compared with height-matched men during exercise. However, these differences disappear after correction for lung size. The drop in Dl CO /Q̇ was proportionally less in women, and pulmonary transit time did not drop below 0.3 s in either group. After differences in lung volume are accounted for, there is no intrinsic sex difference in Dl CO , Vc, or Dm response to exercise. Copyright © 2017 the American Physiological Society.

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

Lung volume is a determinant of aerosol bolus dispersion.

PubMed

Schulz, Holger; Eder, Gunter; Heyder, Joachim

2003-01-01

The technique of inhaling a small volume element labeled with particles ("aerosol bolus") can be used to assess convective gas mixing in the lung. While a bolus undergoes mixing in the lung, particles are dispersed in an increasing volume of the respired air. However, determining factors of bolus dispersion are not yet completely understood. The present study tested the hypothesis that bolus dispersion is related, among others, to the total volume in which the bolus is allowed to mix--i.e., to the individual lung size. Bolus dispersion was measured in 32 anesthetized, mechanically ventilated dogs with total lung capacities (TLCs) of 1.1-2.5 L. Six-milliliter aerosol boluses were introduced at various preselected time-points during inspiration to probe different volumetric lung depths. Dispersion (SD) was determined by moment analysis of particle concentrations in the expired air. We found linear correlations between SD at a given lung depth and the individual end-inspiratory lung volume (V(L)). The relationship was tightest for boluses inhaled deepest into the lungs: SD(40) = 0.068 V(L) - 1.77, r(2) = 0.59. Normalizing SD to V(L) abolished this dependency and resulted in a considerable reduction of inter-individual variability as compared to the uncorrected measurements. These data indicate that lung size influences measurements of bolus dispersion. It therefore appears reasonable to apply a normalization procedure before interpreting the data. Apart from a reduction in measurement variability, this should help to separate the effects on bolus dispersion of altered lung volumes and altered mixing processes in diseased lungs.

Mechanobiology in Lung Epithelial Cells: Measurements, Perturbations, and Responses

PubMed Central

Waters, Christopher M.; Roan, Esra; Navajas, Daniel

2015-01-01

Epithelial cells of the lung are located at the interface between the environment and the organism and serve many important functions including barrier protection, fluid balance, clearance of particulate, initiation of immune responses, mucus and surfactant production, and repair following injury. Because of the complex structure of the lung and its cyclic deformation during the respiratory cycle, epithelial cells are exposed to continuously varying levels of mechanical stresses. While normal lung function is maintained under these conditions, changes in mechanical stresses can have profound effects on the function of epithelial cells and therefore the function of the organ. In this review, we will describe the types of stresses and strains in the lungs, how these are transmitted, and how these may vary in human disease or animal models. Many approaches have been developed to better understand how cells sense and respond to mechanical stresses, and we will discuss these approaches and how they have been used to study lung epithelial cells in culture. Understanding how cells sense and respond to changes in mechanical stresses will contribute to our understanding of the role of lung epithelial cells during normal function and development and how their function may change in diseases such as acute lung injury, asthma, emphysema, and fibrosis. PMID:23728969

Respiratory mechanics and breathing pattern in the neonatal foal.

PubMed

Koterba, A M; Kosch, P C

1987-01-01

Breathing pattern, respiratory muscle activation pattern, lung volumes and volume-pressure characteristics of the respiratory system of normal, term, neonatal foals on Days 2 and 7 of age were determined to test the hypothesis that the foal actively maintains end-expiratory lung volume (EEV) greater than the relaxation volume of the respiratory system (Vrx) because of a highly compliant chest wall. Breathing pattern was measured in the awake, unsedated foal during quiet breathing in lateral and standing positions. The typical neonatal foal breathing pattern was characterized by a monophasic inspiratory and expiratory flow pattern. Both inspiration and expiration were active, with onset of Edi activity preceding onset of inspiratory flow, and phasic abdominal muscle activity detectable throughout most of expiration. No evidence was found to support the hypothesis that the normal, term neonatal foal actively maintains EEV greater than Vrx. In the neonatal foal, normalized lung volume and lung compliance values were similar to those reported for neonates of other species, while normalized chest wall compliance was considerably lower. We conclude that the chest wall of the term neonatal foal is sufficiently rigid to prevent a low Vrx. This characteristic probably prevents the foal from having to use a breathing strategy which maintains an EEV greater than Vrx.

Early Assessment of Treatment Responses During Radiation Therapy for Lung Cancer Using Quantitative Analysis of Daily Computed Tomography

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

Paul, Jijo; Yang, Cungeng; Wu, Hui

Purpose: To investigate early tumor and normal tissue responses during the course of radiation therapy (RT) for lung cancer using quantitative analysis of daily computed tomography (CT) scans. Methods and Materials: Daily diagnostic-quality CT scans acquired using CT-on-rails during CT-guided RT for 20 lung cancer patients were quantitatively analyzed. On each daily CT set, the contours of the gross tumor volume (GTV) and lungs were generated and the radiation dose delivered was reconstructed. The changes in CT image intensity (Hounsfield unit [HU]) features in the GTV and the multiple normal lung tissue shells around the GTV were extracted from themore » daily CT scans. The associations between the changes in the mean HUs, GTV, accumulated dose during RT delivery, and patient survival rate were analyzed. Results: During the RT course, radiation can induce substantial changes in the HU histogram features on the daily CT scans, with reductions in the GTV mean HUs (dH) observed in the range of 11 to 48 HU (median 30). The dH is statistically related to the accumulated GTV dose (R{sup 2} > 0.99) and correlates weakly with the change in GTV (R{sup 2} = 0.3481). Statistically significant increases in patient survival rates (P=.038) were observed for patients with a higher dH in the GTV. In the normal lung, the 4 regions proximal to the GTV showed statistically significant (P<.001) HU reductions from the first to last fraction. Conclusion: Quantitative analysis of the daily CT scans indicated that the mean HUs in lung tumor and surrounding normal tissue were reduced during RT delivery. This reduction was observed in the early phase of the treatment, is patient specific, and correlated with the delivered dose. A larger HU reduction in the GTV correlated significantly with greater patient survival. The changes in daily CT features, such as the mean HU, can be used for early assessment of the radiation response during RT delivery for lung cancer.« less

SU-E-J-86: Functional Conformal Planning for Stereotactic Body Radiation Therapy with CT-Pulmonary Ventilation Imaging

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

Kurosawa, T; Moriya, S; Sato, M

2015-06-15

Purpose: To evaluate the functional planning using CT-pulmonary ventilation imaging for conformal SBRT. Methods: The CT-pulmonary ventilation image was generated using the Jacobian metric in the in-house program with the NiftyReg software package. Using the ventilation image, the normal lung was split into three lung regions for functionality (high, moderate and low). The anatomical plan (AP) and functional plan (FP) were made for ten lung SBRT patients. For the AP, the beam angles were optimized with the dose-volume constraints for the normal lung sparing and the PTV coverage. For the FP, the gantry angles were also optimized with the additionalmore » constraint for high functional lung. The MLC aperture shapes were adjusted to the PTV with the additional 5 mm margin. The dosimetric parameters for PTV, the functional volumes, spinal cord and so on were compared in both plans. Results: Compared to the AP, the FP showed better dose sparing for high- and moderate-functional lungs with similar PTV coverage while not taking care of the low functional lung (High:−12.9±9.26% Moderate: −2.0±7.09%, Low: +4.1±12.2%). For the other normal organs, the FP and AP showed similar dose sparing in the eight patients. However, the FP showed that the maximum doses for spinal cord were increased with the significant increment of 16.4Gy and 21.0Gy in other two patients, respectively. Because the beam direction optimizer chose the unexpected directions passing through the spinal cord. Conclusion: Even the functional conformal SBRT can selectively reduce high- and moderatefunctional lung while keeping the PTV coverage. However, it would be careful that the optimizer would choose unexpected beam angles and the dose sparing for the other normal organs can be worse. Therefore, the planner needs to control the dose-volume constraints and also limit the beam angles in order to achieve the expected dose sparing and coverage.« less

Early Assessment of Treatment Responses During Radiation Therapy for Lung Cancer Using Quantitative Analysis of Daily Computed Tomography.

PubMed

Paul, Jijo; Yang, Cungeng; Wu, Hui; Tai, An; Dalah, Entesar; Zheng, Cheng; Johnstone, Candice; Kong, Feng-Ming; Gore, Elizabeth; Li, X Allen

2017-06-01

To investigate early tumor and normal tissue responses during the course of radiation therapy (RT) for lung cancer using quantitative analysis of daily computed tomography (CT) scans. Daily diagnostic-quality CT scans acquired using CT-on-rails during CT-guided RT for 20 lung cancer patients were quantitatively analyzed. On each daily CT set, the contours of the gross tumor volume (GTV) and lungs were generated and the radiation dose delivered was reconstructed. The changes in CT image intensity (Hounsfield unit [HU]) features in the GTV and the multiple normal lung tissue shells around the GTV were extracted from the daily CT scans. The associations between the changes in the mean HUs, GTV, accumulated dose during RT delivery, and patient survival rate were analyzed. During the RT course, radiation can induce substantial changes in the HU histogram features on the daily CT scans, with reductions in the GTV mean HUs (dH) observed in the range of 11 to 48 HU (median 30). The dH is statistically related to the accumulated GTV dose (R 2  > 0.99) and correlates weakly with the change in GTV (R 2  = 0.3481). Statistically significant increases in patient survival rates (P=.038) were observed for patients with a higher dH in the GTV. In the normal lung, the 4 regions proximal to the GTV showed statistically significant (P<.001) HU reductions from the first to last fraction. Quantitative analysis of the daily CT scans indicated that the mean HUs in lung tumor and surrounding normal tissue were reduced during RT delivery. This reduction was observed in the early phase of the treatment, is patient specific, and correlated with the delivered dose. A larger HU reduction in the GTV correlated significantly with greater patient survival. The changes in daily CT features, such as the mean HU, can be used for early assessment of the radiation response during RT delivery for lung cancer. Copyright © 2017 Elsevier Inc. All rights reserved.

Real-Time Reverse-Transcription Quantitative Polymerase Chain Reaction Assay Is a Feasible Method for the Relative Quantification of Heregulin Expression in Non-Small Cell Lung Cancer Tissue.

PubMed

Kristof, Jessica; Sakrison, Kellen; Jin, Xiaoping; Nakamaru, Kenji; Schneider, Matthias; Beckman, Robert A; Freeman, Daniel; Spittle, Cindy; Feng, Wenqin

2017-01-01

In preclinical studies, heregulin ( HRG ) expression was shown to be the most relevant predictive biomarker for response to patritumab, a fully human anti-epidermal growth factor receptor 3 monoclonal antibody. In support of a phase 2 study of erlotinib ± patritumab in non-small cell lung cancer (NSCLC), a reverse-transcription quantitative polymerase chain reaction (RT-qPCR) assay for relative quantification of HRG expression from formalin-fixed paraffin-embedded (FFPE) NSCLC tissue samples was developed and validated and described herein. Test specimens included matched FFPE normal lung and NSCLC and frozen NSCLC tissue, and HRG -positive and HRG -negative cell lines. Formalin-fixed paraffin-embedded tissue was examined for functional performance. Heregulin distribution was also analyzed across 200 NSCLC commercial samples. Applied Biosystems TaqMan Gene Expression Assays were run on the Bio-Rad CFX96 real-time PCR platform. Heregulin RT-qPCR assay specificity, PCR efficiency, PCR linearity, and reproducibility were demonstrated. The final assay parameters included the Qiagen FFPE RNA Extraction Kit for RNA extraction from FFPE NSCLC tissue, 50 ng of RNA input, and 3 reference (housekeeping) genes ( HMBS, IPO8 , and EIF2B1 ), which had expression levels similar to HRG expression levels and were stable among FFPE NSCLC samples. Using the validated assay, unimodal HRG distribution was confirmed across 185 evaluable FFPE NSCLC commercial samples. Feasibility of an RT-qPCR assay for the quantification of HRG expression in FFPE NSCLC specimens was demonstrated.

Shade matching performance of normal and color vision-deficient dental professionals with standard daylight and tungsten illuminants.

PubMed

Gokce, Hasan Suat; Piskin, Bulent; Ceyhan, Dogan; Gokce, Sila Mermut; Arisan, Volkan

2010-03-01

The lighting conditions of the environment and visual deficiencies such as red-green color vision deficiency affect the clinical shade matching performance of dental professionals. The purpose of this study was to evaluate the shade matching performance of normal and color vision-deficient dental professionals with standard daylight and tungsten illuminants. Two sets of porcelain disc replicas of 16 shade guide tabs (VITA Lumin) were manufactured to exact L*a*b* values by using a colorimeter. Then these twin porcelain discs (13 mm x 2.4 mm) were mixed up and placed into a color-matching cabinet that standardized the lighting conditions for the observation tests. Normal and red-green color vision-deficient dental professionals were asked to match the 32 porcelain discs using standard artificial daylight D65 (high color temperature) and tungsten filament lamp light (T) (low color temperature) illuminants. The results were analyzed by repeated-measures ANOVA and paired and independent samples t tests for the differences between dental professionals and differences between the illuminants (alpha=.05). Regarding the sum of the correct shade match scores of all observations with both illuminants, the difference between normal vision and red-green color vision-deficient dental professional groups was not statistically significant (F=4.132; P=.054). However, the correct shade match scores of each group were significantly different for each illuminant (P<.005). The correct shade matching scores of normal color vision dental professionals were significantly higher with D65 illuminant (t=7.004; P<.001). Color matching scores of red-green color vision-deficient dental professionals (approximately 5.7 more pairs than with D65) were significantly higher with T illuminant (t=5.977; P<.001). CONCLUSIONS.: Within the limitations of this study, the shade matching performance of dental professionals was affected by color vision deficiency and the color temperature of the illuminant. The color vision-deficient group was notably unsuccessful with the D65 illuminant in shade matching. In contrast, there was a significant increase in the shade matching performance of the color vision-deficient group with T illuminant. The lower color temperature illuminant dramatically decreased the normal color vision groups' correct shade matching score. (c) 2010 The Editorial Council of the Journal of Prosthetic Dentistry. Published by Mosby, Inc. All rights reserved.

Taxonomic Knowledge of Children with and without Cochlear Implants

ERIC Educational Resources Information Center

Lund, Emily; Dinsmoor, Jessica

2016-01-01

Purpose: The purpose of this study was to compare the taxonomic vocabulary knowledge and organization of children with cochlear implants to (a) children with normal hearing matched for age, and (b) children matched for vocabulary development. Method: Ten children with cochlear implants, 10 age-matched children with normal hearing, and 10…

Fetal and post-natal lung defects reveal a novel and required role for Fgf8 in lung development

PubMed Central

Yu, Shibin; Poe, Bryan; Schwarz, Margaret; Elliot, Sarah; Albertine, Kurt H.; Fenton, Stephen; Garg, Vidu; Moon, Anne M.

2016-01-01

The fibroblast growth factor, FGF8, has been shown to be essential for vertebrate cardiovascular, craniofacial, brain and limb development. Here we report that Fgf8 function is required for normal progression through the late fetal stages of lung development that culminate in alveolar formation. Budding, lobation and branching morphogenesis are unaffected in early stage Fgf8 hypomorphic and conditional mutant lungs. Excess proliferation during fetal development disrupts distal airspace formation, mesenchymal and vascular remodeling, and Type I epithelial cell differentiation resulting in postnatal respiratory failure and death. Our findings reveal a previously unknown, critical role for Fgf8 function in fetal lung development and suggest that this factor may also contribute to postnatal alveologenesis. Given the high number of premature infants with alveolar dysgenesis and lung dysplasia, and the accumulating evidence that short-term benefits of available therapies may be outweighed by long term detrimental effects on postnatal alveologenesis, the therapeutic implications of identifying a factor or pathway that can be targeted to stimulate normal alveolar development are profound. PMID:20727874

Incidental Transient Cortical Blindness after Lung Resection.

PubMed

Oncel, Murat; Sunam, Guven Sadi; Varoglu, Asuman Orhan; Karabagli, Hakan; Yildiran, Huseyin

2016-03-01

Transient vision loss after major surgical procedures is a rare clinical complication. The most common etiologies are cardiac, spinal, head, and neck surgeries. There has been no report on vision loss after lung resection. A 65-year-old man was admitted to our clinic with lung cancer. Resection was performed using right upper lobectomy with no complications. Cortical blindness developed 12 hours later in the postoperative period. Results from magnetic resonance imaging and diffusion-weighted investigations were normal. The neurologic examination was normal. The blood glucose level was 92 mg/dL and blood gas analysis showed a PO 2 of 82 mm Hg. After 24 hours, the patient began to see and could count fingers, and his vision was fully restored within 72 hours after this point. Autonomic dysfunction due to impaired microvascular structures in diabetes mellitus may induce posterior circulation dysfunction, even when the hemodynamic state is normal in the perioperative period. The physician must keep in mind that vision loss may occur after lung resection due to autonomic dysfunction, especially in older patients with diabetes mellitus.

Finite element analysis of a percussion device for pulmonary diagnostics

NASA Astrophysics Data System (ADS)

Dhar, Aneesh

A pneumothorax is a medical condition where one or both lungs are unable to remain expanded due to air in the pleural space. Finite Element Analysis simulations were conducted on a Percussion Device, which is able to diagnose a pneumothorax using an automated percussion technique. The simulations helped determine the natural modes of vibration of the Percussion Device. These modes were then compared to the motion experimentally measured by an accelerometer on the Percussion Device. It was observed that the modes of the percussion head occurred in the range of 0 to 100 Hz, while the sensor membrane modes occurred in the range of 600 to 900 Hz. Most of these modes were found to match with peaks in the experimental spectra. The simulations performed are reliable and provide an understanding of the contribution of the normal modes to the complex signals measured using the Percussion Device.

Inhibition of mTOR enhances radiosensitivity of lung cancer cells and protects normal lung cells against radiation.

PubMed

Zheng, Hang; Wang, Miao; Wu, Jing; Wang, Zhi-Ming; Nan, Hai-Jun; Sun, He

2016-06-01

Radiotherapy has been used for a long time as a standard therapy for cancer; however, there have been no recent research breakthroughs. Radioresistance and various side-effects lead to the unexpected outcomes of radiation therapy. Specific and accurate targeting as well as reduction of radioresistance have been major challenges for irradiation therapy. Recent studies have shown that rapamycin shows promise for inhibiting tumorigenesis by suppressing mammalian target of rapamycin (mTOR). We found that the combination of rapamycin with irradiation significantly diminished cell viability and colony formation, and increased cell apoptosis, as compared with irradiation alone in lung cancer cell line A549, suggesting that rapamycin can enhance the effectiveness of radiation therapy by sensitizing cancer cells to irradiation. Importantly, we observed that the adverse effects of irradiation on a healthy lung cell line (WI-38) were also offset. No enhanced protein expression of mTOR signaling was observed in WI-38 cells, which is normally elevated in lung cancer cells. Moreover, DNA damage was significantly less with the combination therapy than with irradiation therapy alone. Our data suggest that the incorporation of rapamycin during radiation therapy could be a potent way to improve the sensitivity and effectiveness of radiation therapy as well as to protect normal cells from being damaged by irradiation.

Ghrelin expression in human and rat fetal lungs and the effect of ghrelin administration in nitrofen-induced congenital diaphragmatic hernia.

PubMed

Santos, Marta; Bastos, Pedro; Gonzaga, Silvia; Roriz, José-Mário; Baptista, Maria J; Nogueira-Silva, Cristina; Melo-Rocha, Gustavo; Henriques-Coelho, Tiago; Roncon-Albuquerque, Roberto; Leite-Moreira, Adelino F; De Krijger, Ronald R; Tibboel, Dick; Rottier, Robbert; Correia-Pinto, Jorge

2006-04-01

Ghrelin is a strong physiologic growth hormone secretagogue that exhibits endocrine and non-endocrine actions. In this study, ghrelin expression in humans and rats was evaluated throughout development of normal and hypoplastic lungs associated with congenital diaphragmatic hernia (CDH). Additionally, the effect of antenatal treatment with ghrelin in the nitrofen-induced CDH rat model was tested. In normal lungs, ghrelin was expressed in the primitive epithelium at early stages of development and decreased in levels of expression with gestational age. In hypoplastic lungs ghrelin was overexpressed in both human and rat CDH fetuses when compared with controls. Exogenous administration of ghrelin to nitrofen-treated dams led to an attenuation of pulmonary hypoplasia of CDH pups. Furthermore, the growth hormone, secretagogue receptor (GHSR1a), could not be amplified from human or rat fetal lungs by RT-PCR. In conclusion, of all the lungs studied so far, the fetal lung is one of the first to express ghrelin during development and might be considered a new source of circulating fetal ghrelin. Overexpression of ghrelin in hypoplastic lungs and the effect of exogenous administration of ghrelin to nitrofen-treated dams strongly suggest a role for ghrelin in mechanisms involved in attenuation of fetal lung hypoplasia, most likely through a GHSR1a-independent pathway.

Altered monocyte and fibrocyte phenotype and function in scleroderma interstitial lung disease: reversal by caveolin-1 scaffolding domain peptide.

PubMed

Tourkina, Elena; Bonner, Michael; Oates, James; Hofbauer, Ann; Richard, Mathieu; Znoyko, Sergei; Visconti, Richard P; Zhang, Jing; Hatfield, Corey M; Silver, Richard M; Hoffman, Stanley

2011-07-01

Interstitial lung disease (ILD) is a major cause of morbidity and mortality in scleroderma (systemic sclerosis, or SSc). Fibrocytes are a monocyte-derived cell population implicated in the pathogenesis of fibrosing disorders. Given the recently recognized importance of caveolin-1 in regulating function and signaling in SSc monocytes, in the present study we examined the role of caveolin-1 in the migration and/or trafficking and phenotype of monocytes and fibrocytes in fibrotic lung disease in human patients and an animal model. These studies fill a gap in our understanding of how monocytes and fibrocytes contribute to SSc-ILD pathology. We found that C-X-C chemokine receptor type 4-positive (CXCR4+)/collagen I-positive (ColI+), CD34+/ColI+ and CD45+/ColI+ cells are present in SSc-ILD lungs, but not in control lungs, with CXCR4+ cells being most prevalent. Expression of CXCR4 and its ligand, stromal cell-derived factor 1 (CXCL12), are also highly upregulated in SSc-ILD lung tissue. SSc monocytes, which lack caveolin-1 and therefore overexpress CXCR4, exhibit almost sevenfold increased migration toward CXCL12 compared to control monocytes. Restoration of caveolin-1 function by administering the caveolin scaffolding domain (CSD) peptide reverses this hypermigration. Similarly, transforming growth factor β-treated normal monocytes lose caveolin-1, overexpress CXCR4 and exhibit 15-fold increased monocyte migration that is CSD peptide-sensitive. SSc monocytes exhibit a different phenotype than normal monocytes, expressing high levels of ColI, CD14 and CD34. Because ColI+/CD14+ cells are prevalent in SSc blood, we looked for such cells in lung tissue and confirmed their presence in SSc-ILD lungs but not in normal lungs. Finally, in the bleomycin model of lung fibrosis, we show that CSD peptide diminishes fibrocyte accumulation in the lungs. Our results suggest that low caveolin-1 in SSc monocytes contributes to ILD via effects on cell migration and phenotype and that the hyperaccumulation of fibrocytes in SSc-ILD may result from the altered phenotype and migratory activity of their monocyte precursors.

Altered monocyte and fibrocyte phenotype and function in scleroderma interstitial lung disease: reversal by caveolin-1 scaffolding domain peptide

PubMed Central

2011-01-01

Interstitial lung disease (ILD) is a major cause of morbidity and mortality in scleroderma (systemic sclerosis, or SSc). Fibrocytes are a monocyte-derived cell population implicated in the pathogenesis of fibrosing disorders. Given the recently recognized importance of caveolin-1 in regulating function and signaling in SSc monocytes, in the present study we examined the role of caveolin-1 in the migration and/or trafficking and phenotype of monocytes and fibrocytes in fibrotic lung disease in human patients and an animal model. These studies fill a gap in our understanding of how monocytes and fibrocytes contribute to SSc-ILD pathology. We found that C-X-C chemokine receptor type 4-positive (CXCR4+)/collagen I-positive (ColI+), CD34+/ColI+ and CD45+/ColI+ cells are present in SSc-ILD lungs, but not in control lungs, with CXCR4+ cells being most prevalent. Expression of CXCR4 and its ligand, stromal cell-derived factor 1 (CXCL12), are also highly upregulated in SSc-ILD lung tissue. SSc monocytes, which lack caveolin-1 and therefore overexpress CXCR4, exhibit almost sevenfold increased migration toward CXCL12 compared to control monocytes. Restoration of caveolin-1 function by administering the caveolin scaffolding domain (CSD) peptide reverses this hypermigration. Similarly, transforming growth factor β-treated normal monocytes lose caveolin-1, overexpress CXCR4 and exhibit 15-fold increased monocyte migration that is CSD peptide-sensitive. SSc monocytes exhibit a different phenotype than normal monocytes, expressing high levels of ColI, CD14 and CD34. Because ColI+/CD14+ cells are prevalent in SSc blood, we looked for such cells in lung tissue and confirmed their presence in SSc-ILD lungs but not in normal lungs. Finally, in the bleomycin model of lung fibrosis, we show that CSD peptide diminishes fibrocyte accumulation in the lungs. Our results suggest that low caveolin-1 in SSc monocytes contributes to ILD via effects on cell migration and phenotype and that the hyperaccumulation of fibrocytes in SSc-ILD may result from the altered phenotype and migratory activity of their monocyte precursors. PMID:21722364

Emphysema (image)

MedlinePlus

Emphysema is a lung disease involving damage to the air sacs (alveoli). There is progressive destruction of alveoli and the surrounding tissue that supports the alveoli. With more advanced disease, large air cysts develop where normal lung ...

Automatic lung nodule matching for the follow-up in temporal chest CT scans

NASA Astrophysics Data System (ADS)

Hong, Helen; Lee, Jeongjin; Shin, Yeong Gil

2006-03-01

We propose a fast and robust registration method for matching lung nodules of temporal chest CT scans. Our method is composed of four stages. First, the lungs are extracted from chest CT scans by the automatic segmentation method. Second, the gross translational mismatch is corrected by the optimal cube registration. This initial registration does not require extracting any anatomical landmarks. Third, initial alignment is step by step refined by the iterative surface registration. To evaluate the distance measure between surface boundary points, a 3D distance map is generated by the narrow-band distance propagation, which drives fast and robust convergence to the optimal location. Fourth, nodule correspondences are established by the pairs with the smallest Euclidean distances. The results of pulmonary nodule alignment of twenty patients are reported on a per-center-of mass point basis using the average Euclidean distance (AED) error between corresponding nodules of initial and follow-up scans. The average AED error of twenty patients is significantly reduced to 4.7mm from 30.0mm by our registration. Experimental results show that our registration method aligns the lung nodules much faster than the conventional ones using a distance measure. Accurate and fast result of our method would be more useful for the radiologist's evaluation of pulmonary nodules on chest CT scans.

Measurement of lung function using Electrical Impedance Tomography (EIT) during mechanical ventilation

NASA Astrophysics Data System (ADS)

Nebuya, Satoru; Koike, Tomotaka; Imai, Hiroshi; Noshiro, Makoto; Brown, Brian H.; Soma, Kazui

2010-04-01

The consistency of regional lung density measurements as estimated by Electrical Impedance Tomography (EIT), in eleven patients supported by a mechanical ventilator, was validated to verify the feasibility of its use in intensive care medicine. There were significant differences in regional lung densities between the normal lung and diseased lungs associated with pneumonia, atelectasis and pleural effusion (Steel-Dwass test, p < 0.05). Temporal changes in regional lung density of patients with atelectasis were observed to be in good agreement with the results of clinical diagnosis. These results indicate that it is feasible to obtain a quantitative value for regional lung density using EIT.

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.

TU-H-207A-08: Estimating Radiation Dose From Low-Dose Lung Cancer Screening CT Exams Using Tube Current Modulation

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

Hardy, A; Bostani, M; McMillan, K

Purpose: The purpose of this work is to estimate effective and lung doses from a low-dose lung cancer screening CT protocol using Tube Current Modulation (TCM) across patient models of different sizes. Methods: Monte Carlo simulation methods were used to estimate effective and lung doses from a low-dose lung cancer screening protocol for a 64-slice CT (Sensation 64, Siemens Healthcare) that used TCM. Scanning parameters were from the AAPM protocols. Ten GSF voxelized patient models were used and had all radiosensitive organs identified to facilitate estimating both organ and effective doses. Predicted TCM schemes for each patient model were generatedmore » using a validated method wherein tissue attenuation characteristics and scanner limitations were used to determine the TCM output as a function of table position and source angle. The water equivalent diameter (WED) was determined by estimating the attenuation at the center of the scan volume for each patient model. Monte Carlo simulations were performed using the unique TCM scheme for each patient model. Lung doses were tallied and effective doses were estimated using ICRP 103 tissue weighting factors. Effective and lung dose values were normalized by scanspecific 32 cm CTDIvol values based upon the average tube current across the entire simulated scan. Absolute and normalized doses were reported as a function of WED for each patient. Results: For all ten patients modeled, the effective dose using TCM protocols was below 1.5 mSv. Smaller sized patient models experienced lower absolute doses compared to larger sized patients. Normalized effective and lung doses showed some dependence on patient size (R2 = 0.77 and 0.78, respectively). Conclusion: Effective doses for a low-dose lung screening protocol using TCM were below 1.5 mSv for all patient models used in this study. Institutional research agreement, Siemens Healthcare; Past recipient, research grant support, Siemens Healthcare; Consultant, Toshiba America Medical Systems; Consultant, Samsung Electronics.« less

CT analysis of lung density changes in patients undergoing total body irradiation prior to bone marrow transplantation.

PubMed

Lee, J Y; Shank, B; Bonfiglio, P; Reid, A

1984-10-01

Sequential changes in lung density measured by CT are potentially sensitive and convenient monitors of lung abnormalities following total body irradiation (TBI). Methods have been developed to compare pre- and post-TBI CT of lung. The average local features of a cross-sectional lung slice are extracted from three peripheral regions of interest in the anterior, posterior, and lateral portions of the CT image. Also, density profiles across a specific region may be obtained. These may be compared first for verification of patient position and breathing status and then for changes between pre- and post-TBI. These may also be compared with radiation dose profiles through the lung. A preliminary study on 21 leukemia patients undergoing total body irradiation indicates the following: (a) Density gradients of patients' lungs in the antero-posterior direction show a marked heterogeneity before and after transplantation compared with normal lungs. The patients with departures from normal density gradients pre-TBI correlate with later pulmonary complications. (b) Measurements of average peripheral lung densities have demonstrated that the average lung density in the younger age group is substantially higher: pre-TBI, the average CT number (1,000 scale) is -638 +/- 39 Hounsfield unit (HU) for 0-10 years old and -739 +/- 53 HU for 21-40 years old. (c) Density profiles showed no post-TBI regional changes in lung density corresponding to the dose profile across the lung, so no differentiation of a radiation-specific effect has yet been possible. Computed tomographic density profiles in the antero-posterior direction are successfully used to verify positioning of the CT slice and the breathing level of the lung.

Lung epithelial stem cells and their niches: Fgf10 takes center stage.

PubMed

Volckaert, Thomas; De Langhe, Stijn

2014-01-01

Throughout life adult animals crucially depend on stem cell populations to maintain and repair their tissues to ensure life-long organ function. Stem cells are characterized by their capacity to extensively self-renew and give rise to one or more differentiated cell types. These powerful stem cell properties are key to meet the changing demand for tissue replacement during normal lung homeostasis and regeneration after lung injury. Great strides have been made over the last few years to identify and characterize lung epithelial stem cells as well as their lineage relationships. Unfortunately, knowledge on what regulates the behavior and fate specification of lung epithelial stem cells is still limited, but involves communication with their microenvironment or niche, a local tissue environment that hosts and influences the behaviors or characteristics of stem cells and that comprises other cell types and extracellular matrix. As such, an intimate and dynamic epithelial-mesenchymal cross-talk, which is also essential during lung development, is required for normal homeostasis and to mount an appropriate regenerative response after lung injury. Fibroblast growth factor 10 (Fgf10) signaling in particular seems to be a well-conserved signaling pathway governing epithelial-mesenchymal interactions during lung development as well as between different adult lung epithelial stem cells and their niches. On the other hand, disruption of these reciprocal interactions leads to a dysfunctional epithelial stem cell-niche unit, which may culminate in chronic lung diseases such as chronic obstructive pulmonary disease (COPD), chronic asthma and idiopathic pulmonary fibrosis (IPF).

Pathophysiology of Pulmonary Hypertension in Chronic Parenchymal Lung Disease.

PubMed

Singh, Inderjit; Ma, Kevin Cong; Berlin, David Adam

2016-04-01

Pulmonary hypertension commonly complicates chronic obstructive pulmonary disease and interstitial lung disease. The association of chronic lung disease and pulmonary hypertension portends a worse prognosis. The pathophysiology of pulmonary hypertension differs in the presence or absence of lung disease. We describe the physiological determinants of the normal pulmonary circulation to better understand the pathophysiological factors implicated in chronic parenchymal lung disease-associated pulmonary hypertension. This review will focus on the pathophysiology of 3 forms of chronic lung disease-associated pulmonary hypertension: idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease, and sarcoidosis. Copyright © 2016 Elsevier Inc. All rights reserved.

Bombesin-like peptide receptors in human bronchial epithelial cells.

PubMed

Kane, M A; Toi-Scott, M; Johnson, G L; Kelley, K K; Boose, D; Escobedo-Morse, A

1996-01-01

Northern blot and RNAse protection assays previously failed to detect bombesin-like peptide (BLP) receptors in normal human lung tissue, but by RT/PCR cultured human bronchial epithelial (HBE) cells expressed all three BLP receptor subtypes, predominantly neuromedin B (NMB) receptor. By RT/PCR, we found expression of all three BLP receptor subtypes by human lung tissue and confirmed NMB receptor expression in six out of six HBE samples. However, transformed HBE BEAS B2B cells expressed only gastrin-releasing peptide (GRP) receptors; saturable, high-affinity (Kd = 3.5 nM) specific [125I]GRP binding confirmed functional GRP receptor, with M(r) = 75 kDa and immunologic cross-reactivity with GRP receptor from human small-cell lung carcinoma (SCLC) NCI-H345 cells. Altered regulation of BLP receptors may accompany transformation of normal lung cells to cancer.

Preservation of normal lung regions in the adult respiratory distress syndrome

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

Maunder, R.J.; Shuman, W.P.; McHugh, J.W.

1986-05-09

In this report, the authors challenge the commonly held assumption that the adult respiratory distress syndrome (ARDS) is a homogeneous process associated with generalized and relatively uniform damage to the alveolar capillary membrane. They studied 13 patients with ARDS, comparing the pulmonary parenchymal changes seen by standard bedside chest roentgenograms with those seen by computed tomography of the chest. Three patients demonstrated generalized lung involvement by both radiologic techniques. In another eight patients, despite the appearance of generalized involvement on the standard chest x-ray film, the computed tomographic scans showed patchy infiltrates interspersed with areas of normal-appearing lung. Two patientsmore » showed patchy involvement by both techniques. The fact that ARDS spares some regions of lung parenchyma is useful knowledge in understanding the gas-exchange abnormalities of ARDS, the variable responsiveness to positive end-expiratory pressure, and the occurrence of oxygen toxicity. The problem of regional inhomogeneity should also be kept in mind when interpreting lung biopsy specimens or bronchoalveolar lavage fluid in patients with ARDS.« less

Transbronchial biopsies safely diagnose amyloid lung disease

PubMed Central

Govender, Praveen; Keyes, Colleen M.; Hankinson, Elizabeth A.; O’Hara, Carl J.; Sanchorawala, Vaishali; Berk, John L.

2018-01-01

Background Autopsy identifies lung involvement in 58–92% of patients with the most prevalent forms of systemic amyloidoses. In the absence of lung biopsies, amyloid lung disease often goes unrecognized. Report of a death following transbronchial biopsies in a patient with systemic amyloidosis cautioned against the procedure in this patient cohort. We reviewed our experience with transbronchial biopsies in patients with amyloidosis to determine the safety and utility of bronchoscopic lung biopsies. Methods We identified patients referred to the Amyloidosis Center at Boston Medical Center with lung amyloidosis diagnosed by transbronchial lung biopsies (TBBX). Amyloid typing was determined by immunohistochemistry or mass spectrometry. Standard end organ assessments, including pulmonary function test (PFT) and chest tomography (CT) imaging, and extra-thoracic biopsies established the extent of disease. Results Twenty-five (21.7%) of 115 patients with lung amyloidosis were diagnosed by TBBX. PFT classified 33.3% with restrictive physiology, 28.6% with obstructive disease, and 9.5% mixed physiology; 9.5% exhibited isolated diffusion defects while 19% had normal pulmonary testing. Two view chest or CT imaging identified focal opacities in 52% of cases and diffuse interstitial disease in 48%. Amyloid type and disease extent included 68% systemic AL disease, 16% localized (lung limited) AL disease, 12% ATTR disease, and 4% AA amyloidosis. Fluoroscopy was not used during biopsy. No procedure complications were reported. Conclusions Our case series of 25 patients supports the use of bronchoscopic transbronchial biopsies for diagnosis of parenchymal lung amyloidosis. Normal PFTs do not rule out the histologic presence of amyloid lung disease. PMID:28393574

Estimation of Lung Ventilation

NASA Astrophysics Data System (ADS)

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

Since the primary function of the lung is gas exchange, ventilation can be interpreted as an index of lung function in addition to perfusion. Injury and disease processes can alter lung function on a global and/or a local level. MDCT can be used to acquire multiple static breath-hold CT images of the lung taken at different lung volumes, or with proper respiratory control, 4DCT images of the lung reconstructed at different respiratory phases. Image registration can be applied to this data to estimate a deformation field that transforms the lung from one volume configuration to the other. This deformation field can be analyzed to estimate local lung tissue expansion, calculate voxel-by-voxel intensity change, and make biomechanical measurements. The physiologic significance of the registration-based measures of respiratory function can be established by comparing to more conventional measurements, such as nuclear medicine or contrast wash-in/wash-out studies with CT or MR. An important emerging application of these methods is the detection of pulmonary function change in subjects undergoing radiation therapy (RT) for lung cancer. During RT, treatment is commonly limited to sub-therapeutic doses due to unintended toxicity to normal lung tissue. Measurement of pulmonary function may be useful as a planning tool during RT planning, may be useful for tracking the progression of toxicity to nearby normal tissue during RT, and can be used to evaluate the effectiveness of a treatment post-therapy. This chapter reviews the basic measures to estimate regional ventilation from image registration of CT images, the comparison of them to the existing golden standard and the application in radiation therapy.

Fibrocytes Regulate Wilms’ Tumor 1-Positive Cell Accumulation in Severe Fibrotic Lung Disease

PubMed Central

Sontake, Vishwaraj; Shanmukhappa, Shiva K.; DiPasquale, Betsy A.; Reddy, Geereddy B.; Medvedovic, Mario; Hardie, William D.; White, Eric S.; Madala, Satish K.

2015-01-01

Collagen-producing myofibroblast transdifferentiation is considered a crucial determinant in the formation of scar tissue in the lungs of patients with idiopathic pulmonary fibrosis (IPF). Multiple resident pulmonary cell types and bone marrow-derived fibrocytes have been implicated as contributors to fibrotic lesions due to the transdifferentiation potential of these cells into myofibroblasts. In this study, we assessed the expression of Wilms’ tumor 1 (WT1), a known marker of mesothelial cells, in various cell types in normal and fibrotic lungs. We demonstrate that WT1 is expressed by both mesothelial and mesenchymal cells in IPF lungs, but has limited or no expression in normal human lungs. We also demonstrate that WT1-positive cells accumulate in fibrotic lung lesions, using two different mouse models of pulmonary fibrosis and WT1 promoter-driven fluorescent reporter mice. Reconstitution of bone-marrow cells into a transforming growth factor-α transgenic-mouse model demonstrated that fibrocytes do not transform into WT1-positive mesenchymal cells, but do augment accumulation of WT1-positive cells in severe fibrotic lung disease. Importantly, the number of WT1-positive cells in fibrotic lesions were correlated with severity of lung disease as assessed by changes in lung function, histology, and hydroxyproline levels in mice. Finally, inhibition of WT1 expression was sufficient to attenuate collagen and other extracellular-matrix gene production by mesenchymal cells from both murine and human fibrotic lungs. Thus, the results of this study demonstrate a novel association between fibrocyte-driven WT1-positive cell accumulation and severe fibrotic lung disease. PMID:26371248

Lobar lung transplantation from deceased donors: A systematic review

PubMed Central

Eberlein, Michael; Reed, Robert M; Chahla, Mayy; Bolukbas, Servet; Blevins, Amy; Van Raemdonck, Dirk; Stanzi, Alessia; Inci, Ilhan; Marasco, Silvana; Shigemura, Norihisa; Aigner, Clemens; Deuse, Tobias

2017-01-01

AIM To systematically review reports on deceased-donor-lobar lung transplantation (ddLLTx) and uniformly describe size matching using the donor-to-recipient predicted-total lung-capacity (pTLC) ratio. METHODS We set out to systematically review reports on ddLLTx and uniformly describe size matching using the donor-to-recipient pTLC ratio and to summarize reported one-year survival data of ddLLTx and conventional-LTx. We searched in PubMed, CINAHL via EBSCO, Cochrane Database of Systematic Reviews via Wiley (CDSR), Database of Abstracts of Reviews of Effects via Wiley (DARE), Cochrane Central Register of Controlled Trials via Wiley (CENTRAL), Scopus (which includes EMBASE abstracts), and Web of Science for original reports on ddLLTx. RESULTS Nine observational cohort studies reporting on 301 ddLLTx met our inclusion criteria for systematic review of size matching, and eight for describing one-year-survival. The ddLLTx-group was often characterized by high acuity; however there was heterogeneity in transplant indications and pre-operative characteristics between studies. Data to calculate the pTLC ratio was available for 242 ddLLTx (80%). The mean pTLCratio before lobar resection was 1.25 ± 0.3 and the transplanted pTLCratio after lobar resection was 0.76 ± 0.2. One-year survival in the ddLLTx-group ranged from 50%-100%, compared to 72%-88% in the conventional-LTx group. In the largest study ddLLTx (n = 138) was associated with a lower one-year-survival compared to conventional-LTx (n = 539) (65.1% vs 84.1%, P < 0.001). CONCLUSION Further investigations of optimal donor-to-recipient size matching parameters for ddLLTx could improve outcomes of this important surgical option. PMID:28280698

Lobar lung transplantation from deceased donors: A systematic review.

PubMed

Eberlein, Michael; Reed, Robert M; Chahla, Mayy; Bolukbas, Servet; Blevins, Amy; Van Raemdonck, Dirk; Stanzi, Alessia; Inci, Ilhan; Marasco, Silvana; Shigemura, Norihisa; Aigner, Clemens; Deuse, Tobias

2017-02-24

To systematically review reports on deceased-donor-lobar lung transplantation (ddLLTx) and uniformly describe size matching using the donor-to-recipient predicted-total lung-capacity (pTLC) ratio. We set out to systematically review reports on ddLLTx and uniformly describe size matching using the donor-to-recipient pTLC ratio and to summarize reported one-year survival data of ddLLTx and conventional-LTx. We searched in PubMed, CINAHL via EBSCO, Cochrane Database of Systematic Reviews via Wiley (CDSR), Database of Abstracts of Reviews of Effects via Wiley (DARE), Cochrane Central Register of Controlled Trials via Wiley (CENTRAL), Scopus (which includes EMBASE abstracts), and Web of Science for original reports on ddLLTx. Nine observational cohort studies reporting on 301 ddLLTx met our inclusion criteria for systematic review of size matching, and eight for describing one-year-survival. The ddLLTx-group was often characterized by high acuity; however there was heterogeneity in transplant indications and pre-operative characteristics between studies. Data to calculate the pTLC ratio was available for 242 ddLLTx (80%). The mean pTLCratio before lobar resection was 1.25 ± 0.3 and the transplanted pTLCratio after lobar resection was 0.76 ± 0.2. One-year survival in the ddLLTx-group ranged from 50%-100%, compared to 72%-88% in the conventional-LTx group. In the largest study ddLLTx ( n = 138) was associated with a lower one-year-survival compared to conventional-LTx ( n = 539) (65.1% vs 84.1%, P < 0.001). Further investigations of optimal donor-to-recipient size matching parameters for ddLLTx could improve outcomes of this important surgical option.

Population effect model identifies gene expression predictors of survival outcomes in lung adenocarcinoma for both Caucasian and Asian patients

PubMed Central

Cai, Guoshuai; Xiao, Feifei; Cheng, Chao; Li, Yafang; Amos, Christopher I.; Whitfield, Michael L.

2017-01-01

Background We analyzed and integrated transcriptome data from two large studies of lung adenocarcinomas on distinct populations. Our goal was to investigate the variable gene expression alterations between paired tumor-normal tissues and prospectively identify those alterations that can reliably predict lung disease related outcomes across populations. Methods We developed a mixed model that combined the paired tumor-normal RNA-seq from two populations. Alterations in gene expression common to both populations were detected and validated in two independent DNA microarray datasets. A 10-gene prognosis signature was developed through a l1 penalized regression approach and its prognostic value was evaluated in a third independent microarray cohort. Results Deregulation of apoptosis pathways and increased expression of cell cycle pathways were identified in tumors of both Caucasian and Asian lung adenocarcinoma patients. We demonstrate that a 10-gene biomarker panel can predict prognosis of lung adenocarcinoma in both Caucasians and Asians. Compared to low risk groups, high risk groups showed significantly shorter overall survival time (Caucasian patients data: HR = 3.63, p-value = 0.007; Asian patients data: HR = 3.25, p-value = 0.001). Conclusions This study uses a statistical framework to detect DEGs between paired tumor and normal tissues that considers variances among patients and ethnicities, which will aid in understanding the common genes and signalling pathways with the largest effect sizes in ethnically diverse cohorts. We propose multifunctional markers for distinguishing tumor from normal tissue and prognosis for both populations studied. PMID:28426704

WE-FG-202-03: Quantitative CT-Based Analysis to Assess Lung Injury Following Proton Radiotherapy

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

Underwood, T; University College London, London; Grassberger, C

2016-06-15

Purpose: Relative to photon alternatives, the increased dose-conformity associated with proton therapy is expected to reduce the extent of radiation-induced lung toxicity. However, analysis of follow-up data is yet to be published in this area. In this study we retrospectively analyzed late-phase HU changes for proton therapy cohorts of chest wall and lung patients. Methods: From our institution’s register of patients treated using double-scattered protons, all chest wall and stereotactic lung cases (treated 2011–2012 and 2008–2014 respectively) were initially considered. Follow-up CT data were accessible for 10 chest wall cases (prescribed 50.4 GyRBE in 28 fractions) and 16 lung casesmore » (prescribed 42–50 GyRBE in 3–4 fractions). CT time-points ranged from 0.5–3.5 years post-treatment. Planning doses were recalculated using TOPAS Monte Carlo simulations and mapped onto the follow-up images using deformable registration. Excluding internal target volumes, changes in HU between each patient’s planning and follow-up CT(s) were evaluated for dose bins of 2–30 GyRBE (2 GyRBE increments). Results: Linear increases in HU per unit dose, with correlations statistically significant at the 1% level (one-sided Spearman’s rank test), were evident for all 10 chest wall cases and 14/16 lung cases. The mean changes in HU/Gy were: 1.76 (SD=0.73) for the chest wall cohort, and 1.40 (SD=0.87) for the lung cohort. The median scan times post treatment were 21 and 12 months respectively. All 26 patients developed solid consolidation (scar-like radiographic opacities) within the exposed lung(s). Conclusion: Analysis of follow-up CTs revealed statistically significant correlations in HU-change/dose for two proton cohorts (lung and chest wall). Quantitatively, the late-phase changes we report broadly match published photon data. Further analysis of such radiographic changes, particularly via matched cohort studies drawing upon consistent imaging protocols, could play an important role in elucidating inter-modality differences and provide insight into proton RBE for lung injury. Tracy Underwood gratefully acknowledges the support of the European Commission under an FP7 Marie Curie International Outgoing Fellowship for Career Development (#630064). This work was also funded under U19 grant CA 021239 (PI: Delaney).« less

Preliminary study of brain glucose metabolism changes in patients with lung cancer of different histological types.

PubMed

Li, Wei-Ling; Fu, Chang; Xuan, Ang; Shi, Da-Peng; Gao, Yong-Ju; Zhang, Jie; Xu, Jun-Ling

2015-02-05

Cerebral glucose metabolism changes are always observed in patients suffering from malignant tumors. This preliminary study aimed to investigate the brain glucose metabolism changes in patients with lung cancer of different histological types. One hundred and twenty patients with primary untreated lung cancer, who visited People's Hospital of Zhengzhou University from February 2012 to July 2013, were divided into three groups based on histological types confirmed by biopsy or surgical pathology, which included adenocarcinoma (52 cases), squamous cell carcinoma (43 cases), and small-cell carcinoma (25 cases). The whole body 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET)/computed tomography (CT) of these cases was retrospectively studied. The brain PET data of three groups were analyzed individually using statistical parametric maps (SPM) software, with 50 age-matched and gender-matched healthy controls for comparison. The brain resting glucose metabolism in all three lung cancer groups showed regional cerebral metabolic reduction. The hypo-metabolic cerebral regions were mainly distributed at the left superior and middle frontal, bilateral superior and middle temporal and inferior and middle temporal gyrus. Besides, the hypo-metabolic regions were also found in the right inferior parietal lobule and hippocampus in the small-cell carcinoma group. The area of the total hypo-metabolic cerebral regions in the small-cell carcinoma group (total voxel value 3255) was larger than those in the adenocarcinoma group (total voxel value 1217) and squamous cell carcinoma group (total voxel value 1292). The brain resting glucose metabolism in patients with lung cancer shows regional cerebral metabolic reduction and the brain hypo-metabolic changes are related to the histological types of lung cancer.

Cohort mortality study of North American industrial sand workers. II. Case-referent analysis of lung cancer and silicosis deaths.

PubMed

Hughes, J M; Weill, H; Rando, R J; Shi, R; McDonald, A D; McDonald, J C

2001-04-01

A cohort mortality study of 2670 men in nine North American industrial sand plants resulted in 83 deaths from lung cancer 20 or more years after hire (standardized mortality ratio 139) and 37 deaths from silicosis (including seven from silico-tuberculosis). The lung cancer excess was unrelated to duration of employment and not found in all plants. The primary aim was to determine whether lung cancer risk among these employees was related to quantitative estimates of crystalline silica exposure, after allowance for cigarette smoking. A secondary aim was to do the same for silicosis mortality, partly as a means of validating the estimated levels of exposure. A nested case-referent study was undertaken with cases matched with up to two controls on plant, age and date of first employment from men who survived the case. Exposures were estimated by linking work histories to a job-exposure matrix, undertaken separately. Cigarette smoking information was obtained from medical records and other sources, blind as to case-control status. Matched statistical analyses were conducted using conditional logistic regression. Odds ratios for silicosis mortality were significantly related to cumulative silica exposures and tended to a relationship with category of average crystalline silica concentration, but inconsistently with length of employment. After accounting for a strong effect of cigarette smoking, odds ratios for lung cancer were related to cumulative crystalline silica exposure and to average silica concentration, but not to length of employment. These findings support a causal relationship between lung cancer and quartz exposure after allowance for cigarette smoking, in the absence of cristobalite or other known occupational carcinogens.

Positive end-expiratory pressure at minimal respiratory elastance represents the best compromise between mechanical stress and lung aeration in oleic acid induced lung injury.

PubMed

Carvalho, Alysson Roncally S; Jandre, Frederico C; Pino, Alexandre V; Bozza, Fernando A; Salluh, Jorge; Rodrigues, Rosana; Ascoli, Fabio O; Giannella-Neto, Antonio

2007-01-01

Protective ventilatory strategies have been applied to prevent ventilator-induced lung injury in patients with acute lung injury (ALI). However, adjustment of positive end-expiratory pressure (PEEP) to avoid alveolar de-recruitment and hyperinflation remains difficult. An alternative is to set the PEEP based on minimizing respiratory system elastance (Ers) by titrating PEEP. In the present study we evaluate the distribution of lung aeration (assessed using computed tomography scanning) and the behaviour of Ers in a porcine model of ALI, during a descending PEEP titration manoeuvre with a protective low tidal volume. PEEP titration (from 26 to 0 cmH2O, with a tidal volume of 6 to 7 ml/kg) was performed, following a recruitment manoeuvre. At each PEEP, helical computed tomography scans of juxta-diaphragmatic parts of the lower lobes were obtained during end-expiratory and end-inspiratory pauses in six piglets with ALI induced by oleic acid. The distribution of the lung compartments (hyperinflated, normally aerated, poorly aerated and non-aerated areas) was determined and the Ers was estimated on a breath-by-breath basis from the equation of motion of the respiratory system using the least-squares method. Progressive reduction in PEEP from 26 cmH2O to the PEEP at which the minimum Ers was observed improved poorly aerated areas, with a proportional reduction in hyperinflated areas. Also, the distribution of normally aerated areas remained steady over this interval, with no changes in non-aerated areas. The PEEP at which minimal Ers occurred corresponded to the greatest amount of normally aerated areas, with lesser hyperinflated, and poorly and non-aerated areas. Levels of PEEP below that at which minimal Ers was observed increased poorly and non-aerated areas, with concomitant reductions in normally inflated and hyperinflated areas. The PEEP at which minimal Ers occurred, obtained by descending PEEP titration with a protective low tidal volume, corresponded to the greatest amount of normally aerated areas, with lesser collapsed and hyperinflated areas. The institution of high levels of PEEP reduced poorly aerated areas but enlarged hyperinflated ones. Reduction in PEEP consistently enhanced poorly or non-aerated areas as well as tidal re-aeration. Hence, monitoring respiratory mechanics during a PEEP titration procedure may be a useful adjunct to optimize lung aeration.

CD10/neutral endopeptidase 24.11 in developing human fetal lung. Patterns of expression and modulation of peptide-mediated proliferation.

PubMed

Sunday, M E; Hua, J; Torday, J S; Reyes, B; Shipp, M A

1992-12-01

The cell membrane-associated enzyme CD10/neutral endopeptidase 24.11 (CD10/NEP) functions in multiple organ systems to downregulate responses to peptide hormones. Recently, CD10/NEP was found to hydrolyze bombesin-like peptides (BLP), which are mitogens for normal bronchial epithelial cells and small cell lung carcinomas. Growth of BLP-responsive small cell lung carcinomas was potentiated by CD10/NEP inhibition, implicating CD10/NEP in regulation of BLP-mediated tumor growth. BLP are also likely to participate in normal lung development because high BLP levels are found in fetal lung, and bombesin induces proliferation and maturation of human fetal lung in organ cultures and murine fetal lung in utero. To explore potential roles for CD10/NEP in regulating peptide-mediated human fetal lung development, we have characterized temporal and cellular patterns of CD10/NEP expression and effects of CD10/NEP inhibition in organ cultures. Peak CD10/NEP transcript levels are identified at 11-13 wk gestation by Northern blots and localized to epithelial cells and mesenchyme of developing airways by in situ hybridization. CD10/NEP immunostaining is most intense in undifferentiated airway epithelium. In human fetal lung organ cultures, inhibition of CD10/NEP with either phosphoramidon or SCH32615 increases thymidine incorporation by 166-182% (P < 0.025). The specific BLP receptor antagonist, [Leu13-psi(CH2NH)Leu14]bombesin abolishes these effects on fetal lung growth, suggesting that CD10/NEP modulates BLP-mediated proliferation. CD10/NEP expression in the growing front of airway epithelium and the effects of CD10/NEP inhibitors in lung explants implicate the enzyme in the regulation of peptide-mediated fetal lung growth.

Vitamin D Receptor Expression in Normal, Premalignant, and Malignant Human Lung Tissue

PubMed Central

Menezes, Ravi J.; Cheney, Richard T.; Husain, Aliya; Tretiakova, Maria; Loewen, Gregory; Johnson, Candace S.; Jayaprakash, Vijay; Moysich, Kirsten B.; Salgia, Ravi; Reid, Mary E.

2009-01-01

Background There is a strong interest in identifying chemopreventive agents that might help decrease the burden of lung cancer. The active metabolite of vitamin D, 1,25-dihydroxycholecalciferol (calcitriol), has been shown to have antiproliferative effects in several tumor types, mediated by the vitamin D receptor (VDR). This is the first comprehensive survey of VDR expression in a series of human lung tissues, including normal and premalignant central airway biopsies and lung tumors. Methods Immunohistochemical expression of nuclear and cytoplasmic VDR was examined in 180 premalignant or malignant bronchial biopsies from bronchoscopy of 78 high-risk individuals at the Roswell Park Cancer Institute and also in 63 tumor samples from 35 lung cancer patients from the University of Chicago Hospitals. Associations between clinicopathologic data and VDR expression were examined. Results VDR expression was present in many samples. In biopsies, VDR was commonly detected throughout the full epithelial layer. Most histologically normal (60%, 53 of 88) and metaplastic (61%, 39 of 64) samples had moderate to high nuclear intensity; dysplastic samples mostly had low nuclear intensity (10 of 18, 55%). In tumor samples, 62% (38 of 61) were lacking cytoplasmic VDR, with nuclear expression present in 79%(49 of 62). Analysis of all samples revealed a positive linear trend between proportion of samples with greater nuclear than cytoplasmic intensity and increasing histologic grade (P < 0.01). Conclusions VDR expression spanned the lung carcinogenesis spectrum. Nuclear expression was similar across various histologies, whereas cytoplasmic expression decreased with increasing histologic grade. These results indicate that there is potential for the use of calcitriol as a chemopreventive agent against the development of lung cancer. (Cancer Epidemiol Bio-markers Prev 2008;17(5):1104–10) PMID:18483332

Chronic electronic cigarette exposure in mice induces features of COPD in a nicotine-dependent manner

PubMed Central

Garcia-Arcos, Itsaso; Geraghty, Patrick; Baumlin, Nathalie; Campos, Michael; Dabo, Abdoulaye Jules; Jundi, Bakr; Cummins, Neville; Eden, Edward; Grosche, Astrid; Salathe, Matthias; Foronjy, Robert

2016-01-01

Background The use of electronic (e)-cigarettes is increasing rapidly, but their lung health effects are not established. Clinical studies examining the potential long-term impact of e-cigarette use on lung health will take decades. To address this gap in knowledge, this study investigated the effects of exposure to aerosolised nicotine-free and nicotine-containing e-cigarette fluid on mouse lungs and normal human airway epithelial cells. Methods Mice were exposed to aerosolised phosphate-buffered saline, nicotine-free or nicotine-containing e-cigarette solution, 1-hour daily for 4 months. Normal human bronchial epithelial (NHBE) cells cultured at an air-liquid interface were exposed to e-cigarette vapours or nicotine solutions using a Vitrocell smoke exposure robot. Results Inhalation of nicotine-containing e-cigarettes increased airway hyper-reactivity, distal airspace enlargement, mucin production, cytokine and protease expression. Exposure to nicotine-free e-cigarettes did not affect these lung parameters. NHBE cells exposed to nicotine-containing e-cigarette vapour showed impaired ciliary beat frequency, airway surface liquid volume, cystic fibrosis transmembrane regulator and ATP-stimulated K+ ion conductance and decreased expression of FOXJ1 and KCNMA1. Exposure of NHBE cells to nicotine for 5 days increased interleukin (IL)-6 and IL-8 secretion. Conclusions Exposure to inhaled nicotine-containing e-cigarette fluids triggered effects normally associated with the development of COPD including cytokine expression, airway hyper-reactivity and lung tissue destruction. These effects were nicotine-dependent both in the mouse lung and in human airway cells, suggesting that inhaled nicotine contributes to airway and lung disease in addition to its addictive properties. Thus, these findings highlight the potential dangers of nicotine inhalation during e-cigarette use. PMID:27558745

FTIR characterization of animal lung cells: normal and precancerous modified e10 cell line

NASA Astrophysics Data System (ADS)

Zezell, D. M.; Pereira, T. M.; Mennecier, G.; Bachmann, L.; Govone, A. B.; Dagli, M. L. Z.

2012-06-01

The chemical carcinogens from tobacco are related to over 90% of lung cancers around the world. The risk of death of this kind of cancer is high because the diagnosis usually is made only in advanced stages. Therefore, it is necessary to develop new diagnostic methods for detecting the lung cancer in earlier stages. The Fourier Transform Infrared Spectroscopy (FTIR) can offer high sensibility and accuracy to detect the minimal chemical changes into the biological sample. The aim of this study is to evaluate the differences on infrared spectra between normal lung cells and precancerous lung cells transformed by NNK. Non-cancerous lung cell line e10 (ATCC) and NNK-transformed e10 cell lines were maintained in complete culture medium (1:1 mixture of Dulbecco's modified Eagle's medium and Ham's F12 [DMEM/Ham's F12], supplemented with 100 ng/ml cholera enterotoxin, 10 lg/ml insulin, 0.5 lg/ml. hydrocortisol, 20 ng/ml epidermal growth factor, and 5% horse serum. The cultures were maintained in alcohol 70%. The infrared spectra were acquired on ATR-FTIR Nicolet 6700 spectrophotometer at 4 cm-1 resolution, 30 scans, in the 1800-900 cm-1 spectral range. Each sample had 3 spectra recorded, 30 infrared spectra were obtained from each cell line. The second derivate of spectra indicates that there are displacement in 1646 cm-1 (amine I) and 1255 cm-1(DNA), allowing the possibility to differentiate the two king of cells, with accuracy of 89,9%. These preliminary results indicate that ATR-FTIR is useful to differentiate normal e10 lung cells from precancerous e10 transformed by NNK.

[Combined pulmonary fibrosis and emphysema (CPFE)--limitation of usual lung function test and challenge at practice].

PubMed

Takai, Daiya

2014-12-01

Spirometry and the flow-volume curve test are commonly performed lung function tests. However, a unique clinical entity occasionally shows almost normal data in these tests, and is therefore missed on screening tests. The clinical entity of combined pulmonary emphysema and pulmdoary fibrosis was recognized and documented in the 90's in Japan, the USA, and Europe. Typical emphysema shows obstructive disorders, and pulmonary fibrosis shows restrictive disorders. Thus, the combination of both should lead to a combined disorder pattern in lung function tests, but this is not the case. In 2005, Cottin reported and redefined this combination of emphysema and fibrosis of the lung as "Combined Pulmonary Fibrosis and Emphysema" (CPFE). The patients are typically heavily smoking males who show an almost normal lung function. The upper lobe of these patients usually shows severe emphysema, which contributes to a static volume and a late phase in the forced volume test. On the other hand their lower lobe shows fibrotic change. The fibrotic portion contributes to early phase flow in the flow-volume curve. These mechanisms are a reason for the normal pattern appearance in lung function tests in CPFE patients. As a matter of course, these patients have damaged upper and lower lobes: their diffusing capacity of the lung shows a low performance, their saturation of blood hemoglobin decreases soon after light exercise, and their KL-6 (a blood marker of pulmonary fibrosis) usually shows a high value. They are considered a high risk group regarding complications of post-surgical treatment. Thus, when medical technologists identify suspicious cases, they should advise doctors to add diffusing capacity and KL-6 tests. (Review).

Simulation of late inspiratory rise in airway pressure during pressure support ventilation.

PubMed

Yu, Chun-Hsiang; Su, Po-Lan; Lin, Wei-Chieh; Lin, Sheng-Hsiang; Chen, Chang-Wen

2015-02-01

Late inspiratory rise in airway pressure (LIRAP, Paw/ΔT) caused by inspiratory muscle relaxation or expiratory muscle contraction is frequently seen during pressure support ventilation (PSV), although the modulating factors are unknown. We investigated the effects of respiratory mechanics (normal, obstructive, restrictive, or mixed), inspiratory effort (-2, -8, or -15 cm H2O), flow cycle criteria (5-40% peak inspiratory flow), and duration of inspiratory muscle relaxation (0.18-0.3 s) on LIRAP during PSV using a lung simulator and 4 types of ventilators. LIRAP occurred with all lung models when inspiratory effort was medium to high and duration of inspiratory muscle relaxation was short. The normal lung model was associated with the fastest LIRAP, whereas the obstructive lung model was associated with the slowest. Unless lung mechanics were normal or mixed, LIRAP was unlikely to occur when inspiratory effort was low. Different ventilators were also associated with differences in LIRAP speed. Except for within the restrictive lung model, changes in flow cycle level did not abolish LIRAP if inspiratory effort was medium to high. Increased duration of inspiratory relaxation also led to the elimination of LIRAP. Simulation of expiratory muscle contraction revealed that LIRAP occurred only when expiratory muscle contraction occurred sometime after the beginning of inspiration. Our simulation study reveals that both respiratory resistance and compliance may affect LIRAP. Except for under restrictive lung conditions, LIRAP is unlikely to be abolished by simply lowering flow cycle criteria when inspiratory effort is strong and relaxation time is rapid. LIRAP may be caused by expiratory muscle contraction when it occurs during inspiration. Copyright © 2015 by Daedalus Enterprises.

Socioeconomic Status and Lung Cancer: Unraveling the Contribution of Genetic Admixture

PubMed Central

Selvin, Steve; Wrensch, Margaret R.; Sison, Jennette D.; Hansen, Helen M.; Quesenberry, Charles P.; Seldin, Michael F.; Barcellos, Lisa F.; Buffler, Patricia A.; Wiencke, John K.

2013-01-01

Objectives. We examined the relationship between genetic ancestry, socioeconomic status (SES), and lung cancer among African Americans and Latinos. Methods. We evaluated SES and genetic ancestry in a Northern California lung cancer case–control study (1998–2003) of African Americans and Latinos. Lung cancer case and control participants were frequency matched on age, gender, and race/ethnicity. We assessed case–control differences in individual admixture proportions using the 2-sample t test and analysis of covariance. Logistic regression models examined associations among genetic ancestry, socioeconomic characteristics, and lung cancer. Results. Decreased Amerindian ancestry was associated with higher education among Latino control participants and greater African ancestry was associated with decreased education among African lung cancer case participants. Education was associated with lung cancer among both Latinos and African Americans, independent of smoking, ancestry, age, and gender. Genetic ancestry was not associated with lung cancer among African Americans. Conclusions. Findings suggest that socioeconomic factors may have a greater impact than genetic ancestry on lung cancer among African Americans. The genetic heterogeneity and recent dynamic migration and acculturation of Latinos complicate recruitment; thus, epidemiological analyses and findings should be interpreted cautiously. PMID:23948011

Diagnosis and treatment of pulmonary hypertension in infancy

PubMed Central

Steinhorn, Robin H.

2013-01-01

Normal pulmonary vascular development in infancy requires maintenance of low pulmonary vascular resistance after birth, and is necessary for normal lung function and growth. The developing lung is subject to multiple genetic, pathological and/or environmental influences that can adversely affect lung adaptation, development, and growth, leading to pulmonary hypertension. New classifications of pulmonary hypertension are beginning to account for these diverse phenotypes, and or pulmonary hypertension in infants due to PPHN, congenital diaphragmatic hernia, and bronchopulmonary dysplasia (BPD). The most effective pharmacotherapeutic strategies for infants with PPHN are directed at selective reduction of PVR, and take advantage of a rapidly advancing understanding of the altered signaling pathways in the remodeled vasculature. PMID:24083892

Chemical composition of PM10 and its in vitro toxicological impacts on lung cells during the Middle Eastern Dust (MED) storms in Ahvaz, Iran.

PubMed

Naimabadi, Abolfazl; Ghadiri, Ata; Idani, Esmaeil; Babaei, Ali Akbar; Alavi, Nadali; Shirmardi, Mohammad; Khodadadi, Ali; Marzouni, Mohammad Bagherian; Ankali, Kambiz Ahmadi; Rouhizadeh, Ahmad; Goudarzi, Gholamreza

2016-04-01

Reports on the effects of PM10 from dust storm on lung cells are limited. The main purpose of this study was to investigate the chemical composition and in vitro toxicological impacts of PM10 suspensions, its water-soluble fraction, and the solvent-extractable organics extracted from Middle Eastern Dust storms on the human lung epithelial cell (A549). Samples of dust storms and normal days (PM10 < 200 μg m(-3)) were collected from December 2012 until June 2013 in Ahvaz, the capital of Khuzestan Province in Iran. The chemical composition and cytotoxicity were analyzed by ICP- OES and Lactase Dehydrogenase (LDH) reduction assay, respectively. The results showed that PM10 suspensions, their water-soluble fraction and solvent-extractable organics from both dust storm and normal days caused a decrease in the cell viability and an increase in LDH in supernatant in a dose-response manner. Although samples of normal days showed higher cytotoxicity than those of dust storm at the highest treated dosage, T Test showed no significant difference in cytotoxicity between normal days and dust event days (P value > 0.05). These results led to the conclusions that dust storm PM10 as well as normal day PM10 could lead to cytotoxicity, and the organic compounds (PAHs) and the insoluble particle-core might be the main contributors to cytotoxicity. Our results showed that cytotoxicity and the risk of PM10 to human lung may be more severe during dust storm than normal days due to inhalation of a higher mass concentration of airborne particles. Further research on PM dangerous fractions and the most responsible components to make cytotoxicity in exposed cells is recommended. Copyright © 2016 Elsevier Ltd. All rights reserved.

Impact of geocoding methods on associations between long-term exposure to urban air pollution and lung function.

PubMed

Jacquemin, Bénédicte; Lepeule, Johanna; Boudier, Anne; Arnould, Caroline; Benmerad, Meriem; Chappaz, Claire; Ferran, Joane; Kauffmann, Francine; Morelli, Xavier; Pin, Isabelle; Pison, Christophe; Rios, Isabelle; Temam, Sofia; Künzli, Nino; Slama, Rémy; Siroux, Valérie

2013-09-01

Errors in address geocodes may affect estimates of the effects of air pollution on health. We investigated the impact of four geocoding techniques on the association between urban air pollution estimated with a fine-scale (10 m × 10 m) dispersion model and lung function in adults. We measured forced expiratory volume in 1 sec (FEV1) and forced vital capacity (FVC) in 354 adult residents of Grenoble, France, who were participants in two well-characterized studies, the Epidemiological Study on the Genetics and Environment on Asthma (EGEA) and the European Community Respiratory Health Survey (ECRHS). Home addresses were geocoded using individual building matching as the reference approach and three spatial interpolation approaches. We used a dispersion model to estimate mean PM10 and nitrogen dioxide concentrations at each participant's address during the 12 months preceding their lung function measurements. Associations between exposures and lung function parameters were adjusted for individual confounders and same-day exposure to air pollutants. The geocoding techniques were compared with regard to geographical distances between coordinates, exposure estimates, and associations between the estimated exposures and health effects. Median distances between coordinates estimated using the building matching and the three interpolation techniques were 26.4, 27.9, and 35.6 m. Compared with exposure estimates based on building matching, PM10 concentrations based on the three interpolation techniques tended to be overestimated. When building matching was used to estimate exposures, a one-interquartile range increase in PM10 (3.0 μg/m3) was associated with a 3.72-point decrease in FVC% predicted (95% CI: -0.56, -6.88) and a 3.86-point decrease in FEV1% predicted (95% CI: -0.14, -3.24). The magnitude of associations decreased when other geocoding approaches were used [e.g., for FVC% predicted -2.81 (95% CI: -0.26, -5.35) using NavTEQ, or 2.08 (95% CI -4.63, 0.47, p = 0.11) using Google Maps]. Our findings suggest that the choice of geocoding technique may influence estimated health effects when air pollution exposures are estimated using a fine-scale exposure model.

IL-22 Is Essential for Lung Epithelial Repair following Influenza Infection

PubMed Central

Pociask, Derek A.; Scheller, Erich V.; Mandalapu, Sivanarayana; McHugh, Kevin J.; Enelow, Richard I.; Fattman, Cheryl L.; Kolls, Jay K.; Alcorn, John F.

2014-01-01

Influenza infection is widespread in the United States and the world. Despite low mortality rates due to infection, morbidity is common and little is known about the molecular events involved in recovery. Influenza infection results in persistent distal lung remodeling, and the mechanism(s) involved are poorly understood. Recently IL-22 has been found to mediate epithelial repair. We propose that IL-22 is critical for recovery of normal lung function and architecture after influenza infection. Wild-type and IL-22−/− mice were infected with influenza A PR8/34 H1N1 and were followed up for up to 21 days post infection. IL-22 receptor was localized to the airway epithelium in naive mice but was expressed at the sites of parenchymal lung remodeling induced by influenza infection. IL-22−/− mice displayed exacerbated lung injury compared with wild-type mice, which correlated with decreased lung function 21 days post infection. Epithelial metaplasia was observed in wild-type mice but was not evident in IL-22−/− animals that were characterized with an increased fibrotic phenotype. Gene expression analysis revealed aberrant expression of epithelial genes involved in repair processes, among changes in several other biological processes. These data indicate that IL-22 is required for normal lung repair after influenza infection. IL-22 represents a novel pathway involved in interstitial lung disease. PMID:23490254

Tobacco smoke induces production of chemokine CCL20 to promote lung cancer.

PubMed

Wang, Gui-Zhen; Cheng, Xin; Li, Xin-Chun; Liu, Yong-Qiang; Wang, Xian-Quan; Shi, Xu; Wang, Zai-Yong; Guo, Yong-Qing; Wen, Zhe-Sheng; Huang, Yun-Chao; Zhou, Guang-Biao

2015-07-10

Tobacco kills nearly 6 million people each year, and 90% of the annual 1.59 million lung cancer deaths worldwide are caused by cigarette smoke. Clinically, a long latency is required for individuals to develop lung cancer since they were first exposed to smoking. In this study, we aimed to identify clinical relevant inflammatory factors that are critical for carcinogenesis by treating normal human lung epithelial cells with tobacco carcinogen nicotine-derived nitrosaminoketone (NNK) for a long period (60 days) and systematic screening in 84 cytokines/chemokines. We found that a chemokine CCL20 was significantly up-regulated by NNK, and in 78/173 (45.1%) patients the expression of CCL20 was higher in tumor samples than their adjacent normal lung tissues. Interestingly, CCL20 was up-regulated in 48/92 (52.2%) smoker and 29/78 (37.2%) nonsmoker patients (p = 0.05), and high CCL20 was associated with poor prognosis. NNK induced the production of CCL20, which promoted lung cancer cell proliferation and migration. In addition, an anti-inflammation drug, dexamethasone, inhibited NNK-induced CCL20 production and suppressed lung cancer in vitro and in vivo. These results indicate that CCL20 is crucial for tobacco smoke-caused lung cancer, and anti-CCL20 could be a rational approach to fight against this deadly disease. Copyright © 2015 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.

Mast cells in the human lung at high altitude

NASA Astrophysics Data System (ADS)

Heath, Donald

1992-12-01

Mast cell densities in the lung were measured in five native highlanders of La Paz (3600 m) and in one lowlander dying from high-altitude pulmonary oedema (HAPO) at 3440 m. Two of the highlanders were mestizos with normal pulmonary arteries and the others were Aymara Indians with muscular remodelling of their pulmonary vasculature. The aim of the investigation was to determine if accumulation of mast cells in the lung at high altitude (HA) is related to alveolar hypoxia alone, to a combination of hypoxia and muscularization of the pulmonary arterial tree, or to oedema of the lung. The lungs of four lowlanders were used as normoxic controls. The results showed that the mast cell density of the two Mestizos was in the normal range of lowlanders (0.6-8.8 cells/mm2). In the Aymara Indians the mast cell counts were raised (25.6-26.0 cells/mm2). In the lowlander dying from HAPO the mast cell count was greatly raised to 70.1 cells/mm2 lung tissue. The results show that in native highlanders an accumulation of mast cells in the lung is not related to hypoxia alone but to a combination of hypoxia and muscular remodelling of the pulmonary arteries. However, the most potent cause of increased mast cell density in the lung at high altitude appears to be high-altitude pulmonary oedema.

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.

Normal versus sickle red blood cells: hemodynamic and permeability characteristics in reperfusion lung injury.

PubMed

Haynes, J; Seibert, A; Shah, A; Taylor, A

1990-01-01

Decreased deformability and increased internal viscosity of the sickle red blood cell (SRBC) contribute to abnormal flow in the microcirculation. Since the lungs are commonly affected in sickle cell disease, we compared the hemodynamics of the normal human red blood cell (NRBC) with the SRBC in the pulmonary circulation. The SRBC has decreased antioxidant enzyme activities compared with the NRBC. Thus, using the capillary filtration coefficient (Kfc), we determined the ability of the NRBC and the SRBC to attenuate the increased permeability and resulting edema seen in the oxidant stress of reperfusion lung injury (RLI). We found that lungs perfused with a 5% SRBC perfusate had higher pulmonary arterial pressures (Ppa) and resistances than lungs perfused with a 5% NRBC perfusate. Lungs made ischemic and reperfused with a physiologic cell-free perfusate resulted in a significant increase (P less than .05) in Kfc compared with the preischemic Kfc (.45 +/- .06 to 1.4 +/- 22 mL.min-1.cm H2O.100 g-1). In lungs reperfused with 5% RBC-containing perfusates, the Kfc did not change from preischemic Kfc with NRBCs and decreased from the preischemic Kfc with SRBCs. These findings suggest that the SRBC causes physiologically significant increases in Ppa and resistances and the SRBC, like the NRBC, offers apparent protection in RLI.

Synthetic Secoisolariciresinol Diglucoside (LGM2605) Protects Human Lung in an Ex Vivo Model of Proton Radiation Damage.

PubMed

Velalopoulou, Anastasia; Chatterjee, Shampa; Pietrofesa, Ralph A; Koziol-White, Cynthia; Panettieri, Reynold A; Lin, Liyong; Tuttle, Stephen; Berman, Abigail; Koumenis, Constantinos; Christofidou-Solomidou, Melpo

2017-11-25

Radiation therapy for the treatment of thoracic malignancies has improved significantly by directing of the proton beam in higher doses on the targeted tumor while normal tissues around the tumor receive much lower doses. Nevertheless, exposure of normal tissues to protons is known to pose a substantial risk in long-term survivors, as confirmed by our work in space-relevant exposures of murine lungs to proton radiation. Thus, radioprotective strategies are being sought. We established that LGM2605 is a potent protector from radiation-induced lung toxicity and aimed in the current study to extend the initial findings of space-relevant, proton radiation-associated late lung damage in mice by looking at acute changes in human lung. We used an ex vivo model of organ culture where tissue slices of donor living human lung were kept in culture and exposed to proton radiation. We exposed donor human lung precision-cut lung sections (huPCLS), pretreated with LGM2605, to 4 Gy proton radiation and evaluated them 30 min and 24 h later for gene expression changes relevant to inflammation, oxidative stress, and cell cycle arrest, and determined radiation-induced senescence, inflammation, and oxidative tissue damage. We identified an LGM2605-mediated reduction of proton radiation-induced cellular senescence and associated cell cycle changes, an associated proinflammatory phenotype, and associated oxidative tissue damage. This is a first report on the effects of proton radiation and of the radioprotective properties of LGM2605 on human lung.

Synthetic Secoisolariciresinol Diglucoside (LGM2605) Protects Human Lung in an Ex Vivo Model of Proton Radiation Damage

PubMed Central

Velalopoulou, Anastasia; Chatterjee, Shampa; Pietrofesa, Ralph A.; Koziol-White, Cynthia; Panettieri, Reynold A.; Lin, Liyong; Tuttle, Stephen; Berman, Abigail; Koumenis, Constantinos; Christofidou-Solomidou, Melpo

2017-01-01

Radiation therapy for the treatment of thoracic malignancies has improved significantly by directing of the proton beam in higher doses on the targeted tumor while normal tissues around the tumor receive much lower doses. Nevertheless, exposure of normal tissues to protons is known to pose a substantial risk in long-term survivors, as confirmed by our work in space-relevant exposures of murine lungs to proton radiation. Thus, radioprotective strategies are being sought. We established that LGM2605 is a potent protector from radiation-induced lung toxicity and aimed in the current study to extend the initial findings of space-relevant, proton radiation-associated late lung damage in mice by looking at acute changes in human lung. We used an ex vivo model of organ culture where tissue slices of donor living human lung were kept in culture and exposed to proton radiation. We exposed donor human lung precision-cut lung sections (huPCLS), pretreated with LGM2605, to 4 Gy proton radiation and evaluated them 30 min and 24 h later for gene expression changes relevant to inflammation, oxidative stress, and cell cycle arrest, and determined radiation-induced senescence, inflammation, and oxidative tissue damage. We identified an LGM2605-mediated reduction of proton radiation-induced cellular senescence and associated cell cycle changes, an associated proinflammatory phenotype, and associated oxidative tissue damage. This is a first report on the effects of proton radiation and of the radioprotective properties of LGM2605 on human lung. PMID:29186841

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.

AMBIENT PARTICULATE MATTER DECREASED IN HUMAN ALVEOLAR MACHROPHAGE CYTOKINE RELEASE

EPA Science Inventory

Human exposure to ambient airborne particulate matter (PM) is associated with cardiopulmonary mortality and morbidity, including increased hospitalizations for lung infection. Normal lung immune responses to bacterial infection include alveolar macrophage cytokine production and...

Distribution and function of the peptide transporter PEPT2 in normal and cystic fibrosis human lung.

PubMed

Groneberg, D A; Eynott, P R; Döring, F; Dinh, Q Thai; Oates, T; Barnes, P J; Chung, K F; Daniel, H; Fischer, A

2002-01-01

Aerosol administration of peptide based drugs has an important role in the treatment of various pulmonary and systemic diseases. The characterisation of pulmonary peptide transport pathways can lead to new strategies in aerosol drug treatment. Immunohistochemistry and ex vivo uptake studies were established to assess the distribution and activity of the beta-lactam transporting high affinity proton coupled peptide transporter PEPT2 in normal and cystic fibrosis human airway tissue. PEPT2 immunoreactivity in normal human airways was localised to cells of the tracheal and bronchial epithelium and the endothelium of small vessels. In peripheral lung immunoreactivity was restricted to type II pneumocytes. In sections of cystic fibrosis lung a similar pattern of distribution was obtained with signals localised to endothelial cells, airway epithelium, and type II pneumocytes. Functional ex vivo uptake studies with fresh lung specimens led to an uptake of the fluorophore conjugated dipeptide derivative D-Ala-L-Lys-AMCA into bronchial epithelial cells and type II pneumocytes. This uptake was competitively inhibited by dipeptides and cephalosporins but not ACE inhibitors, indicating a substrate specificity as described for PEPT2. These findings provide evidence for the expression and function of the peptide transporter PEPT2 in the normal and cystic fibrosis human respiratory tract and suggest that PEPT2 is likely to play a role in the transport of pulmonary peptides and peptidomimetics.

Distribution and function of the peptide transporter PEPT2 in normal and cystic fibrosis human lung

PubMed Central

Groneberg, D; Eynott, P; Doring, F; Thai, D; Oates, T; Barnes, P; Chung, K; Daniel, H; Fischer, A

2002-01-01

Background: Aerosol administration of peptide based drugs has an important role in the treatment of various pulmonary and systemic diseases. The characterisation of pulmonary peptide transport pathways can lead to new strategies in aerosol drug treatment. Methods: Immunohistochemistry and ex vivo uptake studies were established to assess the distribution and activity of the ß-lactam transporting high affinity proton coupled peptide transporter PEPT2 in normal and cystic fibrosis human airway tissue. Results: PEPT2 immunoreactivity in normal human airways was localised to cells of the tracheal and bronchial epithelium and the endothelium of small vessels. In peripheral lung immunoreactivity was restricted to type II pneumocytes. In sections of cystic fibrosis lung a similar pattern of distribution was obtained with signals localised to endothelial cells, airway epithelium, and type II pneumocytes. Functional ex vivo uptake studies with fresh lung specimens led to an uptake of the fluorophore conjugated dipeptide derivative D-Ala-L-Lys-AMCA into bronchial epithelial cells and type II pneumocytes. This uptake was competitively inhibited by dipeptides and cephalosporins but not ACE inhibitors, indicating a substrate specificity as described for PEPT2. Conclusions: These findings provide evidence for the expression and function of the peptide transporter PEPT2 in the normal and cystic fibrosis human respiratory tract and suggest that PEPT2 is likely to play a role in the transport of pulmonary peptides and peptidomimetics. PMID:11809991

Single-cell RNA sequencing identifies diverse roles of epithelial cells in idiopathic pulmonary fibrosis

PubMed Central

Mizuno, Takako; Sridharan, Anusha; Du, Yina; Guo, Minzhe; Wikenheiser-Brokamp, Kathryn A.; Perl, Anne-Karina T.; Funari, Vincent A.; Gokey, Jason J.; Stripp, Barry R.; Whitsett, Jeffrey A.

2016-01-01

Idiopathic pulmonary fibrosis (IPF) is a lethal interstitial lung disease characterized by airway remodeling, inflammation, alveolar destruction, and fibrosis. We utilized single-cell RNA sequencing (scRNA-seq) to identify epithelial cell types and associated biological processes involved in the pathogenesis of IPF. Transcriptomic analysis of normal human lung epithelial cells defined gene expression patterns associated with highly differentiated alveolar type 2 (AT2) cells, indicated by enrichment of RNAs critical for surfactant homeostasis. In contrast, scRNA-seq of IPF cells identified 3 distinct subsets of epithelial cell types with characteristics of conducting airway basal and goblet cells and an additional atypical transitional cell that contributes to pathological processes in IPF. Individual IPF cells frequently coexpressed alveolar type 1 (AT1), AT2, and conducting airway selective markers, demonstrating “indeterminate” states of differentiation not seen in normal lung development. Pathway analysis predicted aberrant activation of canonical signaling via TGF-β, HIPPO/YAP, P53, WNT, and AKT/PI3K. Immunofluorescence confocal microscopy identified the disruption of alveolar structure and loss of the normal proximal-peripheral differentiation of pulmonary epithelial cells. scRNA-seq analyses identified loss of normal epithelial cell identities and unique contributions of epithelial cells to the pathogenesis of IPF. The present study provides a rich data source to further explore lung health and disease. PMID:27942595

Mutation profiles in early-stage lung squamous cell carcinoma with clinical follow-up and correlation with markers of immune function.

PubMed

Choi, M; Kadara, H; Zhang, J; Parra, E R; Rodriguez-Canales, J; Gaffney, S G; Zhao, Z; Behrens, C; Fujimoto, J; Chow, C; Kim, K; Kalhor, N; Moran, C; Rimm, D; Swisher, S; Gibbons, D L; Heymach, J; Kaftan, E; Townsend, J P; Lynch, T J; Schlessinger, J; Lee, J; Lifton, R P; Herbst, R S; Wistuba, I I

2017-01-01

Lung squamous cell carcinoma (LUSC) accounts for 20–30% of non-small cell lung cancers (NSCLCs). There are limited treatment strategies for LUSC in part due to our inadequate understanding of the molecular underpinnings of the disease. We performed whole-exome sequencing (WES) and comprehensive immune profiling of a unique set of clinically annotated early-stage LUSCs to increase our understanding of the pathobiology of this malignancy. Matched pairs of surgically resected stage I-III LUSCs and normal lung tissues (n = 108) were analyzed by WES. Immunohistochemistry and image analysis-based profiling of 10 immune markers were done on a subset of LUSCs (n = 91). Associations among mutations, immune markers and clinicopathological variables were statistically examined using analysis of variance and Fisher’s exact test. Cox proportional hazards regression models were used for statistical analysis of clinical outcome. This early-stage LUSC cohort displayed an average of 209 exonic mutations per tumor. Fourteen genes exhibited significant enrichment for somatic mutation: TP53, MLL2, PIK3CA, NFE2L2, CDH8, KEAP1, PTEN, ADCY8, PTPRT, CALCR, GRM8, FBXW7, RB1 and CDKN2A. Among mutated genes associated with poor recurrence-free survival, MLL2 mutations predicted poor prognosis in both TP53 mutant and wild-type LUSCs. We also found that in treated patients, FBXW7 and KEAP1 mutations were associated with poor response to adjuvant therapy, particularly in TP53-mutant tumors. Analysis of mutations with immune markers revealed that ADCY8 and PIK3CA mutations were associated with markedly decreased tumoral PD-L1 expression, LUSCs with PIK3CA mutations exhibited elevated CD45ro levels and CDKN2A-mutant tumors displayed an up-regulated immune response. Our findings pinpoint mutated genes that may impact clinical outcome as well as personalized strategies for targeted immunotherapies in early-stage LUSC.

Assessment of regional lung functional impairment with co-registered respiratory-gated ventilation/perfusion SPET-CT images: initial experiences.

PubMed

Suga, Kazuyoshi; Yasuhiko, Kawakami; Zaki, Mohammed; Yamashita, Tomio; Seto, Aska; Matsumoto, Tsuneo; Matsunaga, Naofumi

2004-02-01

In this study, respiratory-gated ventilation and perfusion single-photon emission tomography (SPET) were used to define regional functional impairment and to obtain reliable co-registration with computed tomography (CT) images in various lung diseases. Using a triple-headed SPET unit and a physiological synchroniser, gated perfusion SPET was performed in a total of 78 patients with different pulmonary diseases, including metastatic nodules (n = 15); in 34 of these patients, it was performed in combination with gated technetium-99m Technegas SPET. Projection data were acquired using 60 stops over 120 degrees for each detector. Gated end-inspiration and ungated images were reconstructed from 1/8 data centered at peak inspiration for each regular respiratory cycle and full respiratory cycle data, respectively. Gated images were registered with tidal inspiration CT images using automated three-dimensional (3D) registration software. Registration mismatch was assessed by measuring 3D distance of the centroid of the nine selected round perfusion-defective nodules. Gated SPET images were completed within 29 min, and increased the number of visible ventilation and perfusion defects by 9.7% and 17.2%, respectively, as compared with ungated images; furthermore, lesion-to-normal lung contrast was significantly higher on gated SPET images. In the nine round perfusion-defective nodules, gated images yielded a significantly better SPET-CT match compared with ungated images (4.9 +/- 3.1 mm vs 19.0 +/- 9.1 mm, P<0.001). The co-registered SPET-CT images allowed accurate perception of the location and extent of each ventilation/perfusion defect on the underlying CT anatomy, and characterised the pathophysiology of the various diseases. By reducing respiratory motion effects and enhancing perfusion/ventilation defect clarity, gated SPET can provide reliable co-registered images with CT images to accurately characterise regional functional impairment in various lung diseases.

Quantification of neonatal lung parenchymal density via ultrashort echo time MRI with comparison to CT.

PubMed

Higano, Nara S; Fleck, Robert J; Spielberg, David R; Walkup, Laura L; Hahn, Andrew D; Thomen, Robert P; Merhar, Stephanie L; Kingma, Paul S; Tkach, Jean A; Fain, Sean B; Woods, Jason C

2017-10-01

To demonstrate that ultrashort echo time (UTE) magnetic resonance imaging (MRI) can achieve computed tomography (CT)-like quantification of lung parenchyma in free-breathing, non-sedated neonates. Because infant CTs are used sparingly, parenchymal disease evaluation via UTE MRI has potential for translational impact. Two neonatal control cohorts without suspected pulmonary morbidities underwent either a research UTE MRI (n = 5; 1.5T) or a clinically-ordered CT (n = 9). Whole-lung means and anterior-posterior gradients of UTE-measured image intensity (arbitrary units, au, normalized to muscle) and CT-measured density (g/cm 3 ) were compared (Mann-Whitney U-test). Separately, a diseased neonatal cohort (n = 5) with various pulmonary morbidities underwent both UTE MRI and CT. UTE intensity and CT density were compared with Spearman correlations within ∼33 anatomically matched regions of interest (ROIs) in each diseased subject, spanning low- to high-density tissues. Radiological classifications were evaluated in all ROIs, with mean UTE intensities and CT densities compared in each classification. In control subjects, whole-lung UTE intensities (0.51 ± 0.04 au) were similar to CT densities (0.44 ± 0.09 g/cm 3 ) (P = 0.062), as were UTE (0.021 ± 0.020 au/cm) and CT (0.034 ± 0.024 [g/cm 3 ]/cm) anterior-posterior gradients (P = 0.351). In diseased subjects' ROIs, significant correlations were observed between UTE and CT (P ≤0.007 in each case). Relative differences between UTE and CT were small in all classifications (4-25%). These results demonstrate a strong association between UTE image intensity and CT density, both between whole-lung tissue in control patients and regional radiological pathologies in diseased patients. This indicates the potential for UTE MRI to longitudinally evaluate neonatal pulmonary disease and to provide visualization of pathologies similar to CT, without sedation/anesthesia or ionizing radiation. 3 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2017;46:992-1000. © 2017 International Society for Magnetic Resonance in Medicine.

Lung scintigraphy in differential diagnosis of peripheral lung cancer and community-acquired pneumonia

NASA Astrophysics Data System (ADS)

Krivonogov, Nikolay G.; Efimova, Nataliya Y.; Zavadovsky, Konstantin W.; Lishmanov, Yuri B.

2016-08-01

Ventilation/perfusion lung scintigraphy was performed in 39 patients with verified diagnosis of community-acquired pneumonia (CAP) and in 14 patients with peripheral lung cancer. Ventilation/perfusion ratio, apical-basal gradients of ventilation (U/L(V)) and lung perfusion (U/L(P)), and alveolar capillary permeability of radionuclide aerosol were determined based on scintigraphy data. The study demonstrated that main signs of CAP were increases in ventilation/perfusion ratio, perfusion and ventilation gradient on a side of the diseased lung, and two-side increase in alveolar capillary permeability rate for radionuclide aerosol. Unlike this, scintigraphic signs of peripheral lung cancer comprise an increase in ventilation/perfusion ratio over 1.0 on a side of the diseased lung with its simultaneous decrease on a contralateral side, normal values of perfusion and ventilation gradients of both lungs, and delayed alveolar capillary clearance in the diseased lung compared with the intact lung.

Lung scintigraphy in differential diagnosis of peripheral lung cancer and community-acquired pneumonia

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

Krivonogov, Nikolay G., E-mail: kng@cardio-tomsk.ru; Efimova, Nataliya Y., E-mail: efimova@cardio-tomsk.ru; Zavadovsky, Konstantin W.

Ventilation/perfusion lung scintigraphy was performed in 39 patients with verified diagnosis of community-acquired pneumonia (CAP) and in 14 patients with peripheral lung cancer. Ventilation/perfusion ratio, apical-basal gradients of ventilation (U/L(V)) and lung perfusion (U/L(P)), and alveolar capillary permeability of radionuclide aerosol were determined based on scintigraphy data. The study demonstrated that main signs of CAP were increases in ventilation/perfusion ratio, perfusion and ventilation gradient on a side of the diseased lung, and two-side increase in alveolar capillary permeability rate for radionuclide aerosol. Unlike this, scintigraphic signs of peripheral lung cancer comprise an increase in ventilation/perfusion ratio over 1.0 on amore » side of the diseased lung with its simultaneous decrease on a contralateral side, normal values of perfusion and ventilation gradients of both lungs, and delayed alveolar capillary clearance in the diseased lung compared with the intact lung.« less

Reconstruction of Internal Doses for the Alpha-Risk Case-Control Study of Lung Cancer and Leukaemia Among European Nuclear Workers.

PubMed

Bingham, Derek; Bérard, Philippe; Birchall, Alan; Bull, Richard; Cardis, Elisabeth; Challeton-de Vathaire, Cécile; Grellier, James; Hurtgen, Christian; Puncher, Matthew; Riddell, Anthony; Thierry-Chef, Isabelle

2017-05-01

The Alpha-Risk study required the reconstruction of doses to lung and red bone marrow for lung cancer and leukaemia cases and their matched controls from cohorts of nuclear workers in the UK, France and Belgium. The dosimetrists and epidemiologists agreed requirements regarding the bioassay data, biokinetic and dosimetric models and dose assessment software to be used and doses to be reported. The best values to use for uncertainties on the monitoring data, setting of exposure regimes and characteristics of the exposure material, including lung solubility, were the responsibility of the dosimetrist responsible for each cohort. Among 1721 subjects, the median absorbed dose to the lung from alpha radiations was 2.1 mGy, with a maximum dose of 316 mGy. The lung doses calculated reflect the higher levels of exposure seen among workers in the early years of the nuclear industry compared to today. © Crown copyright 2016.

Abnormal lung function in adults with congenital heart disease: prevalence, relation to cardiac anatomy, and association with survival.

PubMed

Alonso-Gonzalez, Rafael; Borgia, Francesco; Diller, Gerhard-Paul; Inuzuka, Ryo; Kempny, Aleksander; Martinez-Naharro, Ana; Tutarel, Oktay; Marino, Philip; Wustmann, Kerstin; Charalambides, Menelaos; Silva, Margarida; Swan, Lorna; Dimopoulos, Konstantinos; Gatzoulis, Michael A

2013-02-26

Restrictive lung defects are associated with higher mortality in patients with acquired chronic heart failure. We investigated the prevalence of abnormal lung function, its relation to severity of underlying cardiac defect, its surgical history, and its impact on outcome across the spectrum of adult congenital heart disease. A total of 1188 patients with adult congenital heart disease (age, 33.1±13.1 years) undergoing lung function testing between 2000 and 2009 were included. Patients were classified according to the severity of lung dysfunction based on predicted values of forced vital capacity. Lung function was normal in 53% of patients with adult congenital heart disease, mildly impaired in 17%, and moderately to severely impaired in the remainder (30%). Moderate to severe impairment of lung function related to complexity of underlying cardiac defect, enlarged cardiothoracic ratio, previous thoracotomy/ies, body mass index, scoliosis, and diaphragm palsy. Over a median follow-up period of 6.7 years, 106 patients died. Moderate to severe impairment of lung function was an independent predictor of survival in this cohort. Patients with reduced force vital capacity of at least moderate severity had a 1.6-fold increased risk of death compared with patients with normal lung function (P=0.04). A reduced forced vital capacity is prevalent in patients with adult congenital heart disease; its severity relates to the complexity of the underlying heart defect, surgical history, and scoliosis. Moderate to severe impairment of lung function is an independent predictor of mortality in contemporary patients with adult congenital heart disease.

Sex Differences and Sex Steroids in Lung Health and Disease

PubMed Central

Townsend, Elizabeth A.; Miller, Virginia M.

2012-01-01

Sex differences in the biology of different organ systems and the influence of sex hormones in modulating health and disease are increasingly relevant in clinical and research areas. Although work has focused on sex differences and sex hormones in cardiovascular, musculoskeletal, and neuronal systems, there is now increasing clinical evidence for sex differences in incidence, morbidity, and mortality of lung diseases including allergic diseases (such as asthma), chronic obstructive pulmonary disease, pulmonary fibrosis, lung cancer, as well as pulmonary hypertension. Whether such differences are inherent and/or whether sex steroids play a role in modulating these differences is currently under investigation. The purpose of this review is to define sex differences in lung structure/function under normal and specific disease states, with exploration of whether and how sex hormone signaling mechanisms may explain these clinical observations. Focusing on adult age groups, the review addresses the following: 1) inherent sex differences in lung anatomy and physiology; 2) the importance of certain time points in life such as puberty, pregnancy, menopause, and aging; 3) expression and signaling of sex steroid receptors under normal vs. disease states; 4) potential interplay between different sex steroids; 5) the question of whether sex steroids are beneficial or detrimental to the lung; and 6) the potential use of sex steroid signaling as biomarkers and therapeutic avenues in lung diseases. The importance of focusing on sex differences and sex steroids in the lung lies in the increasing incidence of lung diseases in women and the need to address lung diseases across the life span. PMID:22240244

Production of Fibronectin by the Human Alveolar Macrophage: Mechanism for the Recruitment of Fibroblasts to Sites of Tissue Injury in Interstitial Lung Diseases

NASA Astrophysics Data System (ADS)

Rennard, Stephen I.; Hunninghake, Gary W.; Bitterman, Peter B.; Crystal, Ronald G.

1981-11-01

Because cells of the mononuclear phagocyte system are known to produce fibronectin and because alveolar macrophages are activated in many interstitial lung diseases, the present study was designed to evaluate a role for the alveolar macrophage as a source of the increased levels of fibronectin found in the lower respiratory tract in interstitial lung diseases and to determine if such fibronectin might contribute to the development of the fibrosis found in these disorders by being a chemoattractant for human lung fibroblasts. Production of fibronectin by human alveolar macrophages obtained by bronchoalveolar lavage and maintained in short-term culture in serum-free conditions was demonstrated; de novo synthesis was confirmed by the incorporation of [14C]proline. This fibronectin had a monomer molecular weight of 220,000 and was antigenically similar to plasma fibronectin. Macrophages from patients with idiopathic pulmonary fibrosis produced fibronectin at a rate 20 times higher than did normal macrophages; macrophages from patients with pulmonary sarcoidosis produced fibronectin at 10 times the normal rate. Macrophages from 6 of 10 patients with various other interstitial disorders produced fibronectin at rates greater than the rate of highest normal control. Human alveolar macrophage fibronectin was chemotactic for human lung fibroblasts, suggesting a functional role for this fibronectin in the derangement of the alveolar structures that is characteristic of these disorders.

Identification of Immunogenic Targets for Lung Cancer Vaccines

DTIC Science & Technology

2017-09-01

quantitative proteomic analysis to identify proteins overexpressed in non-small cell lung cancer cell lines compared with normal lung epithelial...Army Medical Research and Materiel Command Fort Detrick, Maryland 21702-5012 DISTRIBUTION STATEMENT: Approved for Public Release; Distribution...Department of the Army position, policy or decision unless so designated by other documentation. REPORT DOCUMENTATION PAGE Form Approved OMB No. 0704-0188

Accuracy of shade matching performed by colour blind and normal dental students using 3D Master and Vita Lumin shade guides.

PubMed

Vafaee, F; Rakhshan, V; Vafaei, M; Khoshhal, M

2012-03-01

The purpose of this study was to investigate whether 3D Master or VitaLumin shade guides could improve colour selection in individuals with normal and defective colour vision. First, colour perception of 260 dental students was evaluated. Afterwards, 9 colour blind and 9 matched normal subjects tried to detect colours of 10 randomly selected tabs from each kit and the correct/false answers were counted. Of the colour-defective subjects, 47.8% and 33.3% correctly detected the shade using 3D Master and VitaLumin, respectively. These statistics were 62.2% and 42.2% in normal subjects. In normal participants, but not in colour blind ones, 3D Master significantly improved shade matching accuracy compared to VitaLumin.

The Influence of Type 1 Diabetes Mellitus on Pulmonary Function and Exercise Capacity - Results from the Study of Health in Pomerania (SHIP).

PubMed

Stubbe, Beate; Schipf, Sabine; Schäper, Christoph; Felix, Stephan B; Steveling, Antje; Nauck, Matthias; Völzke, Henry; Wallaschofski, Henri; Friedrich, Nele; Ewert, Ralf; Ittermann, Till; Gläser, Sven

2017-01-01

Background: Diabetes mellitus Type 1 (T1DM) is associated with metabolic and microvascular diseases as part of a multi-organ and multi-systemic disorder. The dense network of capillary vessels in the lungs may change during the course of the development of microangiopathy. The connective tissue as well as alveoli may be subjected to non-enzymatic glycosylation of proteins which may in turn affect pulmonary function. Previous studies investigating lung function in patients with type 1 diabetes have only been performed on small numbers of patients. Our study is based on population data of the Study of Health in Pomerania (SHIP). Objective: To investigate the influence of metabolic control on pulmonary system function and to establish a decreased pulmonary system function as a late complication of T1DM in a population based setting. Methods: The study is a case matched study with multiple controls based on participants with T1DM (SHIP-DM-1, n=73) and non-diabetics (SHIP-1, n=292) from the population based study of Pomerania. Data on lung function and exercise performance stratified by age, sex, body mass index and smoking habits in participants with T1DM and without diabetes were matched. Results: Participants with T1DM showed a significantly lower total lung capacity, residual volume and forced vital capacity. The transfer factor for carbon monoxide, the maximum power output and oxygen uptake during exercise were significantly decreased in comparison to the general population without diabetes. Conclusion: The pattern of abnormal pulmonary function as observed in the present study with a reduction in lung volume parameters and reduced oxygen uptake in participants with T1DM suggests a restrictive type of lung disease caused by an intrinsic lung tissue derangement as well as pulmonary microangiopathy. © Georg Thieme Verlag KG Stuttgart · New York.

Using gEUD based plan analysis method to evaluate proton vs. photon plans for lung cancer radiation therapy.

PubMed

Xiao, Zhiyan; Zou, Wei J; Chen, Ting; Yue, Ning J; Jabbour, Salma K; Parikh, Rahul; Zhang, Miao

2018-03-01

The goal of this study was to exam the efficacy of current DVH based clinical guidelines draw from photon experience for lung cancer radiation therapy on proton therapy. Comparison proton plans and IMRT plans were generated for 10 lung patients treated in our proton facility. A gEUD based plan evaluation method was developed for plan evaluation. This evaluation method used normal lung gEUD(a) curve in which the model parameter "a" was sampled from the literature reported value. For all patients, the proton plans delivered lower normal lung V 5 Gy with similar V 20 Gy and similar target coverage. Based on current clinical guidelines, proton plans were ranked superior to IMRT plans for all 10 patients. However, the proton and IMRT normal lung gEUD(a) curves crossed for 8 patients within the tested range of "a", which means there was a possibility that proton plan would be worse than IMRT plan for lung sparing. A concept of deficiency index (DI) was introduced to quantify the probability of proton plans doing worse than IMRT plans. By applying threshold on DI, four patients' proton plan was ranked inferior to the IMRT plan. Meanwhile if a threshold to the location of curve crossing was applied, 6 patients' proton plan was ranked inferior to the IMRT plan. The contradictory ranking results between the current clinical guidelines and the gEUD(a) curve analysis demonstrated there is potential pitfalls by applying photon experience directly to the proton world. A comprehensive plan evaluation based on radio-biological models should be carried out to decide if a lung patient would really be benefit from proton therapy. © 2018 The Authors. Journal of Applied Clinical Medical Physics published by Wiley Periodicals, Inc. on behalf of American Association of Physicists in Medicine.

Impact of Upfront Cellular Enrichment by Laser Capture Microdissection on Protein and Phosphoprotein Drug Target Signaling Activation Measurements in Human Lung Cancer: Implications for Personalized Medicine

PubMed Central

Elisa, Baldelli; B., Haura Eric; Lucio, Crinò; Douglas, Cress W.; Vienna, Ludovini; B., Schabath Matthew; A., Liotta Lance; F., Petricoin Emanuel; Mariaelena, Pierobon

2015-01-01

Purpose The aim of this study was to evaluate whether upfront cellular enrichment via laser capture microdissection is necessary for accurately quantifying predictive biomarkers in non-small cell lung cancer tumors. Experimental design Fifteen snap frozen surgical biopsies were analyzed. Whole tissue lysate and matched highly enriched tumor epithelium via laser capture microdissection (LCM) were obtained for each patient. The expression and activation/phosphorylation levels of 26 proteins were measured by reverse phase protein microarray. Differences in signaling architecture of dissected and undissected matched pairs were visualized using unsupervised clustering analysis, bar graphs, and scatter plots. Results Overall patient matched LCM and undissected material displayed very distinct and differing signaling architectures with 93% of the matched pairs clustering separately. These differences were seen regardless of the amount of starting tumor epithelial content present in the specimen. Conclusions and clinical relevance These results indicate that LCM driven upfront cellular enrichment is necessary to accurately determine the expression/activation levels of predictive protein signaling markers although results should be evaluated in larger clinical settings. Upfront cellular enrichment of the target cell appears to be an important part of the workflow needed for the accurate quantification of predictive protein signaling biomarkers. Larger independent studies are warranted. PMID:25676683

Changes of air-tissue ratio evaluated by EBCT after cardiopulmonary resuscitation (CPR): validation in swine

NASA Astrophysics Data System (ADS)

Recheis, Wolfgang A.; Schuster, Antonius H.; Kleinsasser, Axel; Loeckinger, Alexander; Hoermann, Christoph; zur Nedden, Dieter

2001-05-01

The purpose was to evaluate changes of the air-tissue ratio (ATR) in previously defined regions of interest after cardiopulmonary resuscitation (CPR) in porcine model. Eight anesthetized and ventilated pigs we scanned in supine position before and 30 minutes after CPR at two different constant PEEP levels (5 cm H2O, 15 cm H2O). Volume scans were obtained using 6 mm slices. The gray values of the lung were divided into steps of 100 HU in order to get access to the changes of ATR. ATR was evaluated in ventral, intermediate and dorsal regions of the lung. CPR for 9 minutes led to an uneven distribution of ventilation. In the ventral region, areas with high ATR increased. Areas with normal ATR decreased. In contrast the dorsal regions with low ATR increased. ATR in the intermediate regions remained almost unchanged. Using the higher PEEP level, areas with normal ATR showed a marked increase accompanied by a decrease of areas with low ATR. After CPR, an uneven distribution of lung aeration was detected. According to the impaired hemodynamics, areas with normal ATR decreased and areas with high and low ATR increased. Using higher PEEP levels improved lung aeration.

Metachronous Lung Cancer: Clinical Characteristics and Effects of Surgical Treatment.

PubMed

Rzechonek, Adam; Błasiak, Piotr; Muszczyńska-Bernhard, Beata; Pawełczyk, Konrad; Pniewski, Grzegorz; Ornat, Maciej; Grzegrzółka, Jędrzej; Brzecka, Anna

2018-01-01

The occurrence of a second lung tumor after surgical removal of lung cancer usually indicates a lung cancer metastasis, but sometimes a new lesion proves to be a new primary lung cancer, i.e., metachronous lung cancer. The goal of the present study was to conduct a clinical evaluation of patients with metachronous lung cancer and lung cancer metastasis, and to compare the early and distant outcomes of surgical treatment in both cancer types. There were 26 age-matched patients with lung cancer metastases and 23 patients with metachronous lung cancers, who underwent a second lung cancer resection. We evaluated the histological type of a resected cancer, the extent of thoracosurgery, the frequency of early postoperative complications, and the probability of 5-year survival after the second operation. The findings were that metachronous lung cancer was adenocarcinoma in 52% of patients, with a different histopathological pattern from that of the primary lung cancer in 74% of patients. In both cancer groups, mechanical resections were the most common surgery type (76% of all cases), with anatomical resections such as segmentectomy, lobectomy, or pneumectomy being much rarer conducted. The incidence of early postoperative complications in metachronous lung cancer and lung cancer metastasis (30% vs. 31%, respectively) and the probability of 5-year survival after resection of either cancer tumor (60.7% vs. 50.9%, respectively) were comparable. In conclusion, patients undergoing primary lung cancer surgery require a long-term follow-up due to the risk of metastatic or metachronous lung cancer. The likelihood of metachronous lung cancer and pulmonary lung cancer metastases, the incidence of postoperative complications, and the probability of 5-year survival after resection of metachronous lung cancer or lung cancer metastasis are similar.

Individualized Radical Radiotherapy of Non-Small-Cell Lung Cancer Based on Normal Tissue Dose Constraints: A Feasibility Study

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

Baardwijk, Angela van; Bosmans, Geert; Boersma, Liesbeth

2008-08-01

Purpose: Local recurrence is a major problem after (chemo-)radiation for non-small-cell lung cancer. We hypothesized that for each individual patient, the highest therapeutic ratio could be achieved by increasing total tumor dose (TTD) to the limits of normal tissues, delivered within 5 weeks. We report first results of a prospective feasibility trial. Methods and Materials: Twenty-eight patients with medically inoperable or locally advanced non-small-cell lung cancer, World Health Organization performance score of 0-1, and reasonable lung function (forced expiratory volume in 1 second > 50%) were analyzed. All patients underwent irradiation using an individualized prescribed TTD based on normal tissuemore » dose constraints (mean lung dose, 19 Gy; maximal spinal cord dose, 54 Gy) up to a maximal TTD of 79.2 Gy in 1.8-Gy fractions twice daily. No concurrent chemoradiation was administered. Toxicity was scored using the Common Terminology Criteria for Adverse Events criteria. An {sup 18}F-fluoro-2-deoxy-glucose-positron emission tomography-computed tomography scan was performed to evaluate (metabolic) response 3 months after treatment. Results: Mean delivered dose was 63.0 {+-} 9.8 Gy. The TTD was most often limited by the mean lung dose (32.1%) or spinal cord (28.6%). Acute toxicity generally was mild; only 1 patient experienced Grade 3 cough and 1 patient experienced Grade 3 dysphagia. One patient (3.6%) died of pneumonitis. For late toxicity, 2 patients (7.7%) had Grade 3 cough or dyspnea; none had severe dysphagia. Complete metabolic response was obtained in 44% (11 of 26 patients). With a median follow-up of 13 months, median overall survival was 19.6 months, with a 1-year survival rate of 57.1%. Conclusions: Individualized maximal tolerable dose irradiation based on normal tissue dose constraints is feasible, and initial results are promising.« less

Identification of early-stage usual interstitial pneumonia from low-dose chest CT scans using fractional high-density lung distribution

NASA Astrophysics Data System (ADS)

Xie, Yiting; Salvatore, Mary; Liu, Shuang; Jirapatnakul, Artit; Yankelevitz, David F.; Henschke, Claudia I.; Reeves, Anthony P.

2017-03-01

A fully-automated computer algorithm has been developed to identify early-stage Usual Interstitial Pneumonia (UIP) using features computed from low-dose CT scans. In each scan, the pre-segmented lung region is divided into N subsections (N = 1, 8, 27, 64) by separating the lung from anterior/posterior, left/right and superior/inferior in 3D space. Each subsection has approximately the same volume. In each subsection, a classic density measurement (fractional high-density volume h) is evaluated to characterize the disease severity in that subsection, resulting in a feature vector of length N for each lung. Features are then combined in two different ways: concatenation (2*N features) and taking the maximum in each of the two corresponding subsections in the two lungs (N features). The algorithm was evaluated on a dataset consisting of 51 UIP and 56 normal cases, a combined feature vector was computed for each case and an SVM classifier (RBF kernel) was used to classify them into UIP or normal using ten-fold cross validation. A receiver operating characteristic (ROC) area under the curve (AUC) was used for evaluation. The highest AUC of 0.95 was achieved by using concatenated features and an N of 27. Using lung partition (N = 27, 64) with concatenated features had significantly better result over not using partitions (N = 1) (p-value < 0.05). Therefore this equal-volume partition fractional high-density volume method is useful in distinguishing early-stage UIP from normal cases.

Prospective longitudinal evaluation of lung function during the first year of life after extracorporeal membrane oxygenation.

PubMed

Hofhuis, Ward; Hanekamp, Manon N; Ijsselstijn, Hanneke; Nieuwhof, Eveline M; Hop, Wim C J; Tibboel, Dick; de Jongste, Johan C; Merkus, Peter J F M

2011-03-01

To collect longitudinal data on lung function in the first year of life after extracorporeal membrane oxygenation and to evaluate relationships between lung function and perinatal factors. Longitudinal data on lung function in the first year of life after extracorporeal membrane oxygenation are lacking. Prospective longitudinal cohort study. Outpatient clinic of a tertiary level pediatric hospital. The cohort consisted of 64 infants; 33 received extracorporeal membrane oxygenation for meconium aspiration syndrome, 14 for congenital diaphragmatic hernia, four for sepsis, six for persistent pulmonary hypertension of the neonate, and seven for respiratory distress syndrome of infancy. Evaluation was at 6 mos and 12 mos; 39 infants were evaluated at both time points . None. Functional residual capacity and forced expiratory flow at functional residual capacity were measured and expressed as z score. Mean (sem) functional residual capacities in z score were 0.0 (0.2) and 0.2 (0.2) at 6 mos and 12 mos, respectively. Mean (sem) forced expiratory flow was significantly below average (z score = 0) (p < .001) at 6 mos and 12 mos: -1.1 (0.1) and -1.2 (0.1), respectively. At 12 mos, infants with diaphragmatic hernia had a functional residual capacity significantly above normal: mean (sem) z score = 1.2 (0.5). Infants treated with extracorporeal membrane oxygenation have normal lung volumes and stable forced expiratory flows within normal range, although below average, within the first year of life. There is reason to believe, therefore, that extracorporeal membrane oxygenation either ameliorates the harmful effects of mechanical ventilation or somehow preserves lung function in the very ill neonate.

Asbestos-associated genome-wide DNA methylation changes in lung cancer.

PubMed

Kettunen, Eeva; Hernandez-Vargas, Hector; Cros, Marie-Pierre; Durand, Geoffroy; Le Calvez-Kelm, Florence; Stuopelyte, Kristina; Jarmalaite, Sonata; Salmenkivi, Kaisa; Anttila, Sisko; Wolff, Henrik; Herceg, Zdenko; Husgafvel-Pursiainen, Kirsti

2017-11-15

Previous studies have revealed a robust association between exposure to asbestos and human lung cancer. Accumulating evidence has highlighted the role of epigenome deregulation in the mechanism of carcinogen-induced malignancies. We examined the impact of asbestos on DNA methylation. Our genome-wide studies (using Illumina HumanMethylation450K BeadChip) of lung cancer tissue and paired normal lung from 28 asbestos-exposed or non-exposed patients, mostly smokers, revealed distinctive DNA methylation changes. We identified a number of differentially methylated regions (DMR) and differentially variable, differentially methylated CpGs (DVMC), with individual CpGs further validated by pyrosequencing in an independent series of 91 non-small cell lung cancer and paired normal lung. We discovered and validated BEND4, ZSCAN31 and GPR135 as significantly hypermethylated in lung cancer. DMRs in genes such as RARB (FDR 1.1 × 10 -19 , mean change in beta [Δ] -0.09), GPR135 (FDR 1.87 × 10 -8 , mean Δ -0.09) and TPO (FDR 8.58 × 10 -5 , mean Δ -0.11), and DVMCs in NPTN, NRG2, GLT25D2 and TRPC3 (all with p <0.05, t-test) were significantly associated with asbestos exposure status in exposed versus non-exposed lung tumors. Hypomethylation was characteristic to DVMCs in lung cancer tissue from asbestos-exposed subjects. When DVMCs related to asbestos or smoking were analyzed, 96% of the elements were unique to either of the exposures, consistent with the concept that the methylation changes in tumors may be specific for risk factors. In conclusion, we identified novel DNA methylation changes associated with lung tumors and asbestos exposure, suggesting that changes may be present in causal pathway from asbestos exposure to lung cancer. © 2017 UICC.

Preferential elevation of Prx I and Trx expression in lung cancer cells following hypoxia and in human lung cancer tissues.

PubMed

Kim, H J; Chae, H Z; Kim, Y J; Kim, Y H; Hwangs, T S; Park, E M; Park, Y M

2003-10-01

Transient/chronic microenvironmental hypoxia that exists within a majority of solid tumors has been suggested to have a profound influence on tumor growth and therapeutic outcome. Since the functions of novel antioxidant proteins, peroxiredoxin I (Prx I) and II, have been implicated in regulating cell proliferation, differentiation, and apoptosis, it was of our special interest to probe a possible role of Prx I and II in the context of hypoxic tumor microenvironment. Since both Prx I and II use thioredoxin (Trx) as an electron donor and Trx is a substrate for thioredoxin reductase (TrxR), we investigated the regulation of Trx and TrxR as well as Prx expression following hypoxia. Here we show a dynamic change of glutathione homeostasis in lung cancer A549 cells and an up-regulation of Prx I and Trx following hypoxia. Western blot analysis of 10 human lung cancer and paired normal lung tissues also revealed an elevated expression of Prx I and Trx proteins in lung cancer tissues. Immunohistochemical analysis of the lung cancer tissues confirmed an augmented Prx I and Trx expression in cancer cells with respect to the parenchymal cells in adjacent normal lung tissue. Based on these results, we suggest that the redox changes in lung tumor microenvironment could have acted as a trigger for the up-regulation of Prx I and Trx in lung cancer cells. Although the clinical significance of our finding awaits more rigorous future study, preferential augmentation of the Prx I and Trx in lung cancer cells may well represent an attempt of cancer cells to manipulate a dynamic redox change in tumor microenvironment in a manner that is beneficial for their proliferation and malignant progression.

Transpulmonary pressures and lung mechanics with glossopharyngeal insufflation and exsufflation beyond normal lung volumes in competitive breath-hold divers.

PubMed

Loring, Stephen H; O'Donnell, Carl R; Butler, James P; Lindholm, Peter; Jacobson, Francine; Ferrigno, Massimo

2007-03-01

Throughout life, most mammals breathe between maximal and minimal lung volumes determined by respiratory mechanics and muscle strength. In contrast, competitive breath-hold divers exceed these limits when they employ glossopharyngeal insufflation (GI) before a dive to increase lung gas volume (providing additional oxygen and intrapulmonary gas to prevent dangerous chest compression at depths recently greater than 100 m) and glossopharyngeal exsufflation (GE) during descent to draw air from compressed lungs into the pharynx for middle ear pressure equalization. To explore the mechanical effects of these maneuvers on the respiratory system, we measured lung volumes by helium dilution with spirometry and computed tomography and estimated transpulmonary pressures using an esophageal balloon after GI and GE in four competitive breath-hold divers. Maximal lung volume was increased after GI by 0.13-2.84 liters, resulting in volumes 1.5-7.9 SD above predicted values. The amount of gas in the lungs after GI increased by 0.59-4.16 liters, largely due to elevated intrapulmonary pressures of 52-109 cmH(2)O. The transpulmonary pressures increased after GI to values ranging from 43 to 80 cmH(2)O, 1.6-2.9 times the expected values at total lung capacity. After GE, lung volumes were reduced by 0.09-0.44 liters, and the corresponding transpulmonary pressures decreased to -15 to -31 cmH(2)O, suggesting closure of intrapulmonary airways. We conclude that the lungs of some healthy individuals are able to withstand repeated inflation to transpulmonary pressures far greater than those to which they would normally be exposed.

Trunk position influences the kinematics, kinetics, and muscle activity of the lead lower extremity during the forward lunge exercise.

PubMed

Farrokhi, Shawn; Pollard, Christine D; Souza, Richard B; Chen, Yu-Jen; Reischl, Stephen; Powers, Christopher M

2008-07-01

Experimental laboratory study. To examine how a change in trunk position influences the kinematics, kinetics, and muscle activity of the lead lower extremity during the forward lunge exercise. Altering the position of the trunk during the forward lunge exercise is thought to affect the muscular actions of the lead lower extremity. However, no studies have compared the biomechanical differences between the traditional forward lunge and its variations. Ten healthy adults (5 males, 5 females; mean age +/- SD, 26.7 +/- 3.2 years) participated. Lower extremity kinematics, kinetics, and surface electromyographic (EMG) data were obtained while subjects performed 3 lunge exercises: normal lunge with the trunk erect (NL), lunge with the trunk forward (LTF), and lunge with trunk extension (LTE). A 1-way analysis of variance with repeated measures was used to compare lower extremity kinematics, joint impulse (area under the moment-time curve), and normalized EMG (highest 1-second window of activity for selected lower extremity muscles) among the 3 lunge conditions. During the LTF condition, significant increases were noted in peak hip flexion angle, hip extensor and ankle plantar flexor impulse, as well as gluteus maximus and biceps femoris EMG (P<.015) when compared to the NL condition. During the LTE condition, a significant increase was noted in peak ankle dorsiflexion and a significant decrease was noted in peak hip flexion angle (P<.015) compared to the NL condition. Performing a lunge with the trunk forward increased the hip extensor impulse and the recruitment of the hip extensors. In contrast, performing a forward lunge with the trunk extended did not alter joint impulse or activation of the lower extremity musculature. Therapy, level 5.

The axonal guidance cue semaphorin 3C contributes to alveolar growth and repair.

PubMed

Vadivel, Arul; Alphonse, Rajesh S; Collins, Jennifer J P; van Haaften, Tim; O'Reilly, Megan; Eaton, Farah; Thébaud, Bernard

2013-01-01

Lung diseases characterized by alveolar damage such as bronchopulmonary dysplasia (BPD) in premature infants and emphysema lack efficient treatments. Understanding the mechanisms contributing to normal and impaired alveolar growth and repair may identify new therapeutic targets for these lung diseases. Axonal guidance cues are molecules that guide the outgrowth of axons. Amongst these axonal guidance cues, members of the Semaphorin family, in particular Semaphorin 3C (Sema3C), contribute to early lung branching morphogenesis. The role of Sema3C during alveolar growth and repair is unknown. We hypothesized that Sema3C promotes alveolar development and repair. In vivo Sema3C knock down using intranasal siRNA during the postnatal stage of alveolar development in rats caused significant air space enlargement reminiscent of BPD. Sema3C knock down was associated with increased TLR3 expression and lung inflammatory cells influx. In a model of O2-induced arrested alveolar growth in newborn rats mimicking BPD, air space enlargement was associated with decreased lung Sema3C mRNA expression. In vitro, Sema3C treatment preserved alveolar epithelial cell viability in hyperoxia and accelerated alveolar epithelial cell wound healing. Sema3C preserved lung microvascular endothelial cell vascular network formation in vitro under hyperoxic conditions. In vivo, Sema3C treatment of hyperoxic rats decreased lung neutrophil influx and preserved alveolar and lung vascular growth. Sema3C also preserved lung plexinA2 and Sema3C expression, alveolar epithelial cell proliferation and decreased lung apoptosis. In conclusion, the axonal guidance cue Sema3C promotes normal alveolar growth and may be worthwhile further investigating as a potential therapeutic target for lung repair.

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).

Cigarette smoke–induced induction of antioxidant enzyme activities in airway leukocytes is absent in active smokers with COPD

PubMed Central

Dove, Rosamund E.; Leong-Smith, Pheneatia; Roos-Engstrand, Ester; Pourazar, Jamshid; Shah, Mittal; Behndig, Annelie F.; Mudway, Ian S.; Blomberg, Anders

2015-01-01

Background Oxidative injury to the airway has been proposed as an important underlying mechanism in the pathogenesis of chronic obstructive pulmonary disease (COPD). As the extent of oxidant-mediated damage is dependent on the endogenous antioxidant defences within the airways, we examined whether COPD was associated with deficiencies in the antioxidant network within the respiratory tract lining fluids (RTLFs) and resident airway leukocytes. We hypothesised that COPD would be associated with both basal depression of antioxidant defences and impaired adaptive antioxidant responses to cigarette smoke. Methods Low molecular weight and enzymatic antioxidants together with metal-handling proteins were quantified in bronchoalveolar lavage fluid and airway leukocytes, derived from current (n=9) and ex-smoking COPD patients (n=15), as well as from smokers with normal lung function (n=16) and healthy never smokers (n=13). Results Current cigarette smoking was associated with an increase in ascorbate and glutathione within peripheral RTLFs in both smokers with normal lung function compared with healthy never smokers and in COPD smokers compared with COPD ex-smokers. In contrast, intra-cellular antioxidant enzyme activities (glutathione peroxidase, glutathione reductase, and catalase) were only up-regulated in smokers with normal lung function compared with healthy never smokers and not in actively smoking COPD patients relative to COPD ex-smokers. Conclusions We found no evidence of impaired basal antioxidant defences, within either the RTLFs or airway leukocytes in stable ex-smoking COPD patients compared with healthy never smoking controls. Current cigarette smoking induced an up-regulation of low molecular weight antioxidants in the RTLFs of both control subjects with normal lung function and patients with COPD. Importantly, the present data demonstrated a cigarette smoke–induced increase in intra-cellular antioxidant enzyme activities only within the smokers with normal lung function, implying that patients with COPD who continue to smoke will experience enhanced oxidative stress, prompting disease progression. PMID:26557249

A Multicenter Study on Long-Term Outcomes After Lung Transplantation Comparing Donation After Circulatory Death and Donation After Brain Death.

PubMed

van Suylen, V; Luijk, B; Hoek, R A S; van de Graaf, E A; Verschuuren, E A; Van De Wauwer, C; Bekkers, J A; Meijer, R C A; van der Bij, W; Erasmus, M E

2017-10-01

The implementation of donation after circulatory death category 3 (DCD3) was one of the attempts to reduce the gap between supply and demand of donor lungs. In the Netherlands, the total number of potential lung donors was greatly increased by the availability of DCD3 lungs in addition to the initial standard use of donation after brain death (DBD) lungs. From the three lung transplant centers in the Netherlands, 130 DCD3 recipients were one-to-one nearest neighbor propensity score matched with 130 DBD recipients. The primary end points were primary graft dysfunction (PGD), posttransplant lung function, freedom from chronic lung allograft dysfunction (CLAD), and overall survival. PGD did not differ between the groups. Posttransplant lung function was comparable after bilateral lung transplantation, but seemed worse after DCD3 single lung transplantation. The incidence of CLAD (p = 0.17) nor the freedom from CLAD (p = 0.36) nor the overall survival (p = 0.40) were significantly different between both groups. The presented multicenter results are derived from a national context where one third of the lung transplantations are performed with DCD3 lungs. We conclude that the long-term outcome after lung transplantation with DCD3 donors is similar to that of DBD donors and that DCD3 donation can substantially enlarge the donor pool. © 2017 The American Society of Transplantation and the American Society of Transplant Surgeons.

Perioperative Management of Patients on Clopidogrel (Plavix) Undergoing Major Lung Resection

PubMed Central

Ceppa, DuyKhanh P.; Welsby, Ian J.; Wang, Tracy Y.; Onaitis, Mark W.; Tong, Betty C.; Harpole, David H.; D’Amico, Thomas A.; Berry, Mark F.

2014-01-01

BACKGROUND Management of patients requiring antiplatelet therapy with clopidogrel (Plavix) and major lung resection must balance the risks of bleeding and cardiovascular events. We reviewed our experience with patients treated with clopidogrel perioperatively to examine outcomes, including results of a new strategy for high-risk patients. METHODS Patients who underwent major lung resection and received perioperative clopidogrel between January 2005 and September 2010 were reviewed. Initially, clopidogrel management consisted of discontinuation approximately 5 days before surgery and resumption immediately after surgery. Following July 2010, high-risk patients (drug-eluting coronary stent placement within prior year or previous coronary event after clopidogrel discontinuation) were admitted 2–3 days preoperatively and bridged with the intravenous GP IIb/IIIa receptor inhibitor eptifibatide (Integrilin) according to a multidisciplinary cardiology/anesthesiology/thoracic surgery protocol. Outcomes were compared to control patients (matched for preoperative risk factors and extent of pulmonary resection) who did not receive perioperative clopidogrel. RESULTS Fifty-four patients who had major lung resection between January 2005 and September 2010 and received clopidogrel perioperatively were matched with 108 controls. Both groups had similar mortality, postoperative length of stay, and no differences in the rates of perioperative transfusions, reoperations for bleeding, myocardial infarctions, and strokes. Seven of the 54 clopidogrel patients were admitted preoperatively for an eptifibatide bridge. Two of these patients received perioperative transfusions, but there were no mortalities, reoperations, myocardial infarctions, or stroke. CONCLUSIONS Patients taking clopidogrel can safely undergo major lung resection. Treatment with an eptifibatide bridge may minimize the risk of cardiovascular events in higher risk patients. PMID:21978871

Adenocarcinoma predominant pattern subtyping and nuclear grading in cytology: Is there a role in prognostication of advanced pulmonary adenocarcinomas?

PubMed

Nambirajan, A; Kaur, H; Jangra, K; Kaur, K; Madan, K; Mathur, S R; Iyer, V K; Jain, D

2018-04-01

Primary lung adenocarcinomas (ADs) show varied architectural patterns, and pattern-based subtyping of ADs is currently recommended due to prognostic implications. Predicting AD patterns on cytology is challenging; however, cytological nuclear features appear to correlate with histological grade and survival in early stage lung ADs. The feasibility and value of AD pattern prediction and nuclear grading on cytology in advanced lung ADs is not known. We aimed to predict patterns and analyse nuclear features on cytology and evaluate their role in prognostication. One-hundred patients of Stage III/IV lung AD with available matched cytology and histology samples were included. Cyto-patterns based on cell arrangement patterns (flat sheets vs three-dimensional clusters vs papillae) and cyto-nuclear score based on nuclear features (size, shape, contour), nucleoli (macronucleoli vs prominent vs inconspicuous), and nuclear chromatin were determined, and correlated with predominant histological-pattern observed on the matched small biopsy and outcome. Higher cyto-nuclear scores were observed with high-grade histo-patterns (solid, micropapillary and cribriform), while the predicted cyto-patterns did not correspond to the predominant pattern on histology in 77% cases. Highest cyto-histo agreement was observed for solid pattern (72%). High grade histo-patterns and cyto-nuclear scores > 3 showed a trend towards inferior survival (not significant). Nuclear grade scoring on cytology is simple to perform, and is predictive of high grade patterns. Its inclusion in routine reporting of cytology samples of lung ADs may be valuable. © 2018 John Wiley & Sons Ltd.

Bmi-1 expression modulates non-small cell lung cancer progression

PubMed Central

Xiong, Dan; Ye, Yunlin; Fu, Yujie; Wang, Jinglong; Kuang, Bohua; Wang, Hongbo; Wang, Xiumin; Zu, Lidong; Xiao, Gang; Hao, Mingang; Wang, Jianhua

2015-01-01

Previous studies indicate that the role of B lymphoma Mo-MLV insertion region 1 homolog (Bmi-1) is responsible for multiple cancer progression. However, Bmi-1 in controlling gene expression in non-small cell lung cancer (NSCLC) development is not well explored. Here we report that the Bmi-1 level is highly increased in primary NSCLC tissues compared to matched adjacent non-cancerous tissues and required for lung tumor growth in xenograft model. Furthermore, we also demonstrate that Bmi-1 level is lower in matched involved lymph node cancerous tissues than the respective primary NSCLC tissues. We find that Bmi-1 does not affect cell cycle and apoptosis in lung cancer cell lines as it does not affect the expression of p16/p19, Pten, AKT and P-AKT. Mechanistic analyses note that reduction of Bmi-1 expression inversely regulates invasion and metastasis of NSCLC cells in vitro and in vivo, followed by induction of epithelial-mesenchymal transition (EMT). Using genome microarray assays, we find that RNAi-mediated silence of Bmi-1 modulates some important molecular genetics or signaling pathways, potentially associated with NSCLC development. Taken together, our findings disclose for the first time that Bmi-1 level accumulates strongly in early stage and then declines in late stage, which is potentially important for NSCLC cell invasion and metastasis during progression. PMID:25880371

Effect of Radiotherapy Planning Complexity on Survival of Elderly Patients With Unresected Localized Lung Cancer

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

Park, Chang H.; Bonomi, Marcelo; Cesaretti, Jamie

2011-11-01

Purpose: To evaluate whether complex radiotherapy (RT) planning was associated with improved outcomes in a cohort of elderly patients with unresected Stage I-II non-small-cell lung cancer (NSCLC). Methods and Materials: Using the Surveillance, Epidemiology, and End Results registry linked to Medicare claims, we identified 1998 patients aged >65 years with histologically confirmed, unresected stage I-II NSCLC. Patients were classified into an intermediate or complex RT planning group using Medicare physician codes. To address potential selection bias, we used propensity score modeling. Survival of patients who received intermediate and complex simulation was compared using Cox regression models adjusting for propensity scoresmore » and in a stratified and matched analysis according to propensity scores. Results: Overall, 25% of patients received complex RT planning. Complex RT planning was associated with better overall (hazard ratio 0.84; 95% confidence interval, 0.75-0.95) and lung cancer-specific (hazard ratio 0.81; 95% confidence interval, 0.71-0.93) survival after controlling for propensity scores. Similarly, stratified and matched analyses showed better overall and lung cancer-specific survival of patients treated with complex RT planning. Conclusions: The use of complex RT planning is associated with improved survival among elderly patients with unresected Stage I-II NSCLC. These findings should be validated in prospective randomized controlled trials.« less

Pulmonary anatomy and a case of unilateral aplasia in a common snapping turtle (Chelydra serpentina): developmental perspectives on cryptodiran lungs.

PubMed

Schachner, E R; Sedlmayr, J C; Schott, R; Lyson, T R; Sanders, R K; Lambertz, M

2017-12-01

The common snapping turtle (Chelydra serpentina) is a well studied and broadly distributed member of Testudines; however, very little is known concerning developmental anomalies and soft tissue pathologies of turtles and other reptiles. Here, we present an unusual case of unilateral pulmonary aplasia, asymmetrical carapacial kyphosis, and mild scoliosis in a live adult C. serpentina. The detailed three-dimensional (3D) anatomy of the respiratory system in both the pathological and normal adult C. serpentina, and a hatchling are visualized using computed tomography (CT), microCT, and 3D digital anatomical models. In the pathological turtle, the right lung consists of an extrapulmonary bronchus that terminates in a blind stump with no lung present. The left lung is hyperinflated relative to the normal adult, occupying the extra coelomic space facilitated by the unusual mid-carapacial kyphotic bulge. The bronchial tree of the left lung retains the overall bauplan of the normal specimens, with some minor downstream variation in the number of secondary airways. The primary difference between the internal pulmonary structure of the pathological individual and that of a normal adult is a marked increase in the surface area and density of the parenchymal tissue originating from the secondary airways, a 14.3% increase in the surface area to volume ratio. Despite this, the aplasia has not had an impact upon the ability of the turtle to survive; however, it did interfere with aquatic locomotion and buoyancy control under water. This turtle represents a striking example of a non-fatal congenital defect and compensatory visceral hypertrophy. © 2017 Anatomical Society.

CCAAT/Enhancer Binding Protein–α Regulates the Protease/Antiprotease Balance Required for Bronchiolar Epithelium Regeneration

PubMed Central

Sato, Atsuyasu; Xu, Yan; Whitsett, Jeffrey A.

2012-01-01

Many transcription factors that regulate lung morphogenesis during development are reactivated to mediate repairs of the injured adult lung. We hypothesized that CCAAT/enhancer binding protein–α (C/EBPα), a transcription factor critical for perinatal lung maturation, regulates genes required for the normal repair of the bronchiolar epithelium after injury. Transgenic CebpαΔ/Δ mice, in which Cebpa was conditionally deleted from Clara cells and Type II cells after birth, were used in this study. Airway injury was induced in mice by the intraperitoneal administration of naphthalene to ablate bronchiolar epithelial cells. Although the deletion of C/EBPα did not influence lung structure and function under unstressed conditions, C/EBPα was required for the normal repair of terminal bronchiolar epithelium after naphthalene injury. To identify cellular processes that are influenced by C/EBPα during repair, mRNA microarray was performed on terminal bronchiolar epithelial cells isolated by laser-capture microdissection. Normal repair of the terminal bronchiolar epithelium was highly associated with the mRNAs regulating antiprotease activities, and their induction required C/EBPα. The defective deposition of fibronectin in CebpαΔ/Δ mice was associated with increased protease activity and delayed differentiation of FoxJ1-expressing ciliated cells. The fibronectin and ciliated cells were restored by the intratracheal treatment of CebpαΔ/Δ mice with the serine protease inhibitor. In conclusion, C/EBPα regulates the expression of serine protease inhibitors that are required for the normal increase of fibronectin and the restoration of ciliated cells after injury. Treatment with serine protease inhibitor may aid in the recovery of injured bronchiolar epithelial cells, and prevent common chronic lung diseases. PMID:22652201

Four-Dimensional CT of the Diaphragm in Children: Initial Experience

PubMed Central

2018-01-01

Objective To evaluate the technical feasibility of four-dimensional (4D) CT for the functional evaluation of the pediatric diaphragm. Materials and Methods In 22 consecutive children (median age 3.5 months, age range 3 days–3 years), 4D CT was performed to assess diaphragm motion. Diaphragm abnormalities were qualitatively evaluated and diaphragm motion was quantitatively measured on 4D CT. Lung density changes between peak inspiration and expiration were measured in the basal lung parenchyma. The diaphragm motions and lung density changes measured on 4D CT were compared between various diaphragm conditions. In 11 of the 22 children, chest sonography was available for comparison. Results Four-dimensional CT demonstrated normal diaphragm (n = 8), paralysis (n = 10), eventration (n = 3), and diffusely decreased motion (n = 1). Chest sonography demonstrated normal diaphragm (n = 2), paralysis (n = 6), eventration (n = 2), and right pleural effusion (n = 1). The sonographic findings were concordant with the 4D CT findings in 90.9% (10/11) of the patients. In diaphragm paralysis, the affected diaphragm motion was significantly decreased compared with the contralateral normal diaphragm motion (−1.1 ± 2.2 mm vs. 7.6 ± 3.8 mm, p = 0.005). The normal diaphragms showed significantly greater motion than the paralyzed diaphragms (4.5 ± 2.1 mm vs. −1.1 ± 2.2 mm, p < 0.0001), while the normal diaphragm motion was significantly smaller than the motion of the contralateral normal diaphragm in paralysis (4.5 ± 2.1 mm vs. 7.6 ± 3.8 mm, p = 0.01). Basal lung density change of the affected side was significantly smaller than that of the contralateral side in diaphragm paralysis (89 ± 73 Hounsfield units [HU] vs. 180 ± 71 HU, p = 0.03), while no significant differences were found between the normal diaphragms and the paralyzed diaphragms (136 ± 66 HU vs. 89 ± 73 HU, p = 0.1) or between the normal diaphragms and the contralateral normal diaphragms in paralysis (136 ± 66 HU vs. 180 ± 71 HU, p = 0.1). Conclusion The functional evaluation of the pediatric diaphragm is feasible with 4D CT in select children. PMID:29354007

Localized Energy-Based Normalization of Medical Images: Application to Chest Radiography.

PubMed

Philipsen, R H H M; Maduskar, P; Hogeweg, L; Melendez, J; Sánchez, C I; van Ginneken, B

2015-09-01

Automated quantitative analysis systems for medical images often lack the capability to successfully process images from multiple sources. Normalization of such images prior to further analysis is a possible solution to this limitation. This work presents a general method to normalize medical images and thoroughly investigates its effectiveness for chest radiography (CXR). The method starts with an energy decomposition of the image in different bands. Next, each band's localized energy is scaled to a reference value and the image is reconstructed. We investigate iterative and local application of this technique. The normalization is applied iteratively to the lung fields on six datasets from different sources, each comprising 50 normal CXRs and 50 abnormal CXRs. The method is evaluated in three supervised computer-aided detection tasks related to CXR analysis and compared to two reference normalization methods. In the first task, automatic lung segmentation, the average Jaccard overlap significantly increased from 0.72±0.30 and 0.87±0.11 for both reference methods to with normalization. The second experiment was aimed at segmentation of the clavicles. The reference methods had an average Jaccard index of 0.57±0.26 and 0.53±0.26; with normalization this significantly increased to . The third experiment was detection of tuberculosis related abnormalities in the lung fields. The average area under the Receiver Operating Curve increased significantly from 0.72±0.14 and 0.79±0.06 using the reference methods to with normalization. We conclude that the normalization can be successfully applied in chest radiography and makes supervised systems more generally applicable to data from different sources.

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

Lieske, T.R.; Sunderrajan, E.V.; Passamonte, P.M.

A patient with chronic eosinophilic pneumonia was evaluated using bronchoalveolar lavage, technetium-99m glucoheptonate, and transbronchial lung biopsy. Bronchoalveolar lavage revealed 43 percent eosinophils and correlated well with results of transbronchial lung biopsy. Technetium-99m glucoheptonate lung imaging demonstrated intense parenchymal uptake. After eight weeks of corticosteroid therapy, the bronchoalveolar lavage eosinophil population and the technetium-99m glucoheptonate uptake had returned to normal. We suggest that bronchoalveolar lavage, with transbronchial lung biopsy, is a less invasive way than open lung biopsy to diagnose chronic eosinophilic pneumonia. The mechanism of uptake of technetium-99m glucoheptonate in this disorder remains to be defined.

Involvement of MicroRNAs in Lung Cancer Biology and Therapy

PubMed Central

Liu, Xi; Sempere, Lorenzo F.; Guo, Yongli; Korc, Murray; Kauppinen, Sakari; Freemantle, Sarah J.; Dmitrovsky, Ethan

2011-01-01

MicroRNAs (miRNAs) are a class of small RNAs that regulate gene expression. Expression profiles of specific miRNAs have improved cancer diagnosis and classification and even provided prognostic information in many human cancers, including lung cancer. Tumor suppressive and oncogenic miRNAs were uncovered in lung carcinogenesis. The biological functions of these miRNAs in lung cancer were recently validated in well characterized cellular, murine transgenic as well as transplantable lung cancer models and in human paired normal-malignant lung tissue banks and tissue arrays. Tumor suppressive and oncogenic miRNAs that were identified in lung cancer will be reviewed here. Emphasis is placed on highlighting those functionally validated miRNAs that are not only biomarkers of lung carcinogenesis, but also candidate pharmacologic targets. How these miRNA findings advance an understanding of lung cancer biology and could improve lung cancer therapy are discussed in this article. PMID:21420030

Estimation of regional gas and tissue volumes of the lung in supine man using computed tomography.

PubMed

Denison, D M; Morgan, M D; Millar, A B

1986-08-01

This study was intended to discover how well computed tomography could recover the volume and weight of lung like foams in a body like shell, and then how well it could recover the volume and weight of the lungs in supine man. Model thoraces were made with various loaves of bread submerged in water. Computed tomography scans recovered the volume of the model lungs (true volume range 250-12,500 ml) within +0.2 (SD 68) ml and their weights (true range 72-3125 g) within +30 (78) g. Scans also recovered successive injections of 50 ml of water, within +/- 5 ml. Scans in 12 healthy supine men recovered their vital capacities, total lung capacities (TLC), and predicted tissue volumes with comparable accuracy. At total lung capacity the mean tissue volume of single lungs was 431 (64) ml and at residual volume (RV) it was 427 (63) ml. Tissue volume was then used to match inspiratory and expiratory slices and calculate regional ventilation. Throughout the mid 90% of lung the RV/TLC ratio was fairly constant--mean 21% (5%). New methods of presenting such regional data graphically and automatically are also described.

Lung mass density analysis using deep neural network and lung ultrasound surface wave elastography.

PubMed

Zhou, Boran; Zhang, Xiaoming

2018-05-23

Lung mass density is directly associated with lung pathology. Computed Tomography (CT) evaluates lung pathology using the Hounsfield unit (HU) but not lung density directly. We have developed a lung ultrasound surface wave elastography (LUSWE) technique to measure the surface wave speed of superficial lung tissue. The objective of this study was to develop a method for analyzing lung mass density of superficial lung tissue using a deep neural network (DNN) and synthetic data of wave speed measurements with LUSWE. The synthetic training dataset of surface wave speed, excitation frequency, lung mass density, and viscoelasticity from LUSWE (788,000 in total) was used to train the DNN model. The DNN was composed of 3 hidden layers of 1024 neurons for each layer and trained for 10 epochs with a batch size of 4096 and a learning rate of 0.001 with three types of optimizers. The test dataset (4000) of wave speeds at three excitation frequencies (100, 150, and 200 Hz) and shear elasticity of superficial lung tissue was used to predict the lung density and evaluate its accuracy compared with predefined lung mass densities. This technique was then validated on a sponge phantom experiment. The obtained results showed that predictions matched well with test dataset (validation accuracy is 0.992) and experimental data in the sponge phantom experiment. This method may be useful to analyze lung mass density by using the DNN model together with the surface wave speed and lung stiffness measurements. Copyright © 2018 Elsevier B.V. All rights reserved.

Expression of LLT1 and its receptor CD161 in lung cancer is associated with better clinical outcome.

PubMed

Braud, Véronique M; Biton, Jérôme; Becht, Etienne; Knockaert, Samantha; Mansuet-Lupo, Audrey; Cosson, Estelle; Damotte, Diane; Alifano, Marco; Validire, Pierre; Anjuère, Fabienne; Cremer, Isabelle; Girard, Nicolas; Gossot, Dominique; Seguin-Givelet, Agathe; Dieu-Nosjean, Marie-Caroline; Germain, Claire

2018-01-01

Co-stimulatory and inhibitory receptors expressed by immune cells in the tumor microenvironment modulate the immune response and cancer progression. Their expression and regulation are still not fully characterized and a better understanding of these mechanisms is needed to improve current immunotherapies. Our previous work has identified a novel ligand/receptor pair, LLT1/CD161, that modulates immune responses. Here, we extensively characterize its expression in non-small cell lung cancer (NSCLC). We show that LLT1 expression is restricted to germinal center (GC) B cells within tertiary lymphoid structures (TLS), representing a new hallmark of the presence of active TLS in the tumor microenvironment. CD161-expressing immune cells are found at the vicinity of these structures, with a global enrichment of NSCLC tumors in CD161 + CD4 + and CD8 + T cells as compared to normal distant lung and peripheral blood. CD161 + CD4 + T cells are more activated and produce Th1-cytokines at a higher frequency than their matched CD161-negative counterparts. Interestingly, CD161 + CD4 + T cells highly express OX40 co-stimulatory receptor, less frequently 4-1BB, and display an activated but not completely exhausted PD-1-positive Tim-3-negative phenotype. Finally, a meta-analysis revealed a positive association of CLEC2D (coding for LLT1) and KLRB1 (coding for CD161) gene expression with favorable outcome in NSCLC, independently of the size of T and B cell infiltrates. These data are consistent with a positive impact of LLT1/CD161 on NSCLC patient survival, and make CD161-expressing CD4 + T cells ideal candidates for efficient anti-tumor recall responses.

Diffusion limitations of the lung - comparison of different measurement methods.

PubMed

Preisser, A M; Seeber, M; Harth, V

2015-01-01

Pulmonary fibrosis leads to a decrease of oxygen diffusion, in particular during exercise. Bronchial obstruction also could decrease the partial pressure of oxygen (P(a)O(2)). In this study we investigated the validity of blood gas content, especially P(a)O(2) and P(a)O(2) affected by hyperventilation (P(a)O(2corr)) and alveolo-arterial oxygen gradient (P(A-a)O(2)) in comparison with the CO diffusion capacity (DLCO) in different lung diseases. A total of 250 subjects were studied (52.3 ± 12.5 year; F/M 40/210), among which there were 162 subjects with different lung disorders and 88 healthy controls. Pearson's correlation coefficients (r) of DLCO with P(a)O(2), P(a)O(2corr), and PA-aO(2) were analyzed in each group. The results show that the diagnostic power of P(A-a)O(2) against P(a)O(2corr) was equivalent, especially during exercise (r = -0.89 and -0.92, respectively). DLCO showed only weak correlations with P(a)O(2corr) and P(A-a)O(2) (r = 0.17 and -0.19, respectively). In conclusion, DLCO shows a better match with blood gas content during exercise than at rest during which it is routinely tested. Thus, the exercise test is advisable. The P(A-a)O(2) takes into account the level of ventilation, which makes it correlate better with DLCO rather than with blood gas content. The most significant problems in clinical evaluation of blood gas parameters during exercise are the insufficiently defined limits of normal-to-pathological range.

Serum nitric oxide metabolites and disease activity in patients with systemic sclerosis.

PubMed

Mok, Mo Yin; Fung, Peter Chin Wah; Ooi, Clara; Tse, Hung Fat; Wong, Yik; Lam, Yui Ming; Wong, Woon Sing; Lau, Chak Sing

2008-03-01

There is no surrogate marker in serum for defining disease activity in scleroderma (SSc). Nitric oxide (NO), which regulates vasodilation and possesses pro-inflammatory actions, has been implicated in the pathogenesis of SSc. We compared serum NO(x) (total nitrate and nitrite) level in SSc patients to healthy controls and evaluated its correlation with detailed symptomatology and scoring systems for various organ involvement. Symptoms and physical findings that suggested disease activity in regard to various organs were documented. Lung function test, high-resolution computed tomographic (HRCT) scan of thorax and echocardiography were performed. Serum NO(x) was measured by chemiluminescence. Serum NO(x) levels in SSc (n = 43) were significantly higher (72.4 +/- 47.8 microM) than age- and sex-matched controls (n = 41; 37.1 +/- 13.5 microM; p < 0.001). Serum NO(x) were not found to be associated with lung fibrosis defined by lung function parameters or inflammation and fibrosis scores on HRCT. Twenty-two patients were found to have elevated serum NO(x) level defined as mean +/- 2 SD of normal controls. Logistic regression analysis revealed that age (OR 1.12, p = 0.02) and elevated pulmonary arterial pressure (PAP) (n = 9; OR 145.3, p = 0.01) were predictive factors for elevated serum NO(x). Prednisolone use was associated with lower serum NO(x) level (OR 0.06, p = 0.04). Elevated PAP of increasing severity was found to be associated with higher level of serum NO(x) (p = 0.004 by trend). Serum NO(x) in SSc patients were elevated compared to healthy controls. Serum NO(x) level was determined by multiple factors including age, prednisolone use, and elevated PAP.

Validation of SCT Methylation as a Hallmark Biomarker for Lung Cancers.

PubMed

Zhang, Yu-An; Ma, Xiaotu; Sathe, Adwait; Fujimoto, Junya; Wistuba, Ignacio; Lam, Stephen; Yatabe, Yasushi; Wang, Yi-Wei; Stastny, Victor; Gao, Boning; Larsen, Jill E; Girard, Luc; Liu, Xiaoyun; Song, Kai; Behrens, Carmen; Kalhor, Neda; Xie, Yang; Zhang, Michael Q; Minna, John D; Gazdar, Adi F

2016-03-01

The human secretin gene (SCT) encodes secretin, a hormone with limited tissue distribution. Analysis of the 450k methylation array data in The Cancer Genome Atlas (TCGA) indicated that the SCT promoter region is differentially hypermethylated in lung cancer. Our purpose was to validate SCT methylation as a potential biomarker for lung cancer. We analyzed data from TCGA and developed and applied SCT-specific bisulfite DNA sequencing and quantitative methylation-specific polymerase chain reaction assays. The analyses of TCGA 450K data for 801 samples showed that SCT hypermethylation has an area under the curve (AUC) value greater than 0.98 that can be used to distinguish lung adenocarcinomas or squamous cell carcinomas from nonmalignant lung tissue. Bisulfite sequencing of lung cancer cell lines and normal blood cells allowed us to confirm that SCT methylation is highly discriminative. By applying a quantitative methylation-specific polymerase chain reaction assay, we found that SCT hypermethylation is frequently detected in all major subtypes of malignant non-small cell lung cancer (AUC = 0.92, n = 108) and small cell lung cancer (AUC = 0.93, n = 40) but is less frequent in lung carcinoids (AUC = 0.54, n = 20). SCT hypermethylation appeared in samples of lung carcinoma in situ during multistage pathogenesis and increased in invasive samples. Further analyses of TCGA 450k data showed that SCT hypermethylation is highly discriminative in most other types of malignant tumors but less frequent in low-grade malignant tumors. The only normal tissue with a high level of methylation was the placenta. Our findings demonstrated that SCT methylation is a highly discriminative biomarker for lung and other malignant tumors, is less frequent in low-grade malignant tumors (including lung carcinoids), and appears at the carcinoma in situ stage. Copyright © 2015 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.

Distinct biological effects of low-dose radiation on normal and cancerous human lung cells are mediated by ATM signaling

PubMed Central

Li, Wei; Zhao, Yuguang; Wen, Xue; Liang, Xinyue; Zhang, Xiaoying; Zhou, Lei; Hu, Jifan; Niu, Chao; Tian, Huimin; Han, Fujun; Chen, Xiao; Dong, Lihua; Cai, Lu; Cui, Jiuwei

2016-01-01

Low-dose radiation (LDR) induces hormesis and adaptive response in normal cells but not in cancer cells, suggesting its potential protection of normal tissue against damage induced by conventional radiotherapy. However, the underlying mechanisms are not well established. We addressed this in the present study by examining the role of the ataxia telangiectasia mutated (ATM) signaling pathway in response to LDR using A549 human lung adenocarcinoma cells and HBE135-E6E7 (HBE) normal lung epithelial cells. We found that LDR-activated ATM was the initiating event in hormesis and adaptive response to LDR in HBE cells. ATM activation increased the expression of CDK4/CDK6/cyclin D1 by activating the AKT/glycogen synthase kinase (GSK)-3β signaling pathway, which stimulated HBE cell proliferation. Activation of ATM/AKT/GSK-3β signaling also increased nuclear accumulation of nuclear factor erythroid 2-related factor 2, leading to increased expression of antioxidants, which mitigated cellular damage from excessive reactive oxygen species production induced by high-dose radiation. However, these effects were not observed in A549 cells. Thus, the failure to activate these pathways in A549 cells likely explains the difference between normal and cancer cells in terms of hormesis and adaptive response to LDR. PMID:27708248

Technetium-fibrinogen lung scanning in canine lung contusion

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

Geller, E.; Khaw, B.A.; Strauss, H.W.

1984-07-01

To detect experimentally induced acute lung contusion in anesthetized dogs, serial radionuclide images of the lung were recorded following intravenous infusion of 99mTc-labelled human fibrinogen (Tc-HF). The accumulation of Tc-HF in canine lungs was serially quantitated for up to 20 hours after lung contusion. A contusion (number1) was produced in one lung, Tc-HF was injected IV after 15 minutes, and 75 minutes later a contralateral lung contusion (number2) was produced in a series of 14 dogs. At autopsy the excised lungs were scanned, sectioned, and counted for radioactivity. Radiolabelled fibrinogen accumulated within 2-4 minutes of contusion number2 and remained stablemore » over the next 20 hours in 14 dogs; contusion number1 was barely visible in four dogs. Lung Tc-HF activity in the central region of contusion number2 remained sixfold higher than in normal lung tissue. These data suggest that following lung contusion, fibrinogen deposition occurs rapidly and remains stable over a 20-hour interval of observation.« less

SU-F-T-85: Energy Modulated Electron Postmastectomy Unreconstructed (PU) Chest Wall (CW) Irradiation Technique to Achieve Heart Sparing

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

Hong, L; Ballangrud, A; Mechalakos, J

Purpose: For left-sided PU patients requiring CW and nodal irradiation, sometimes partial wide tangents (PWT) are not feasible due to abnormal chest wall contour or heart position close to the anterior chest wall or unusual wide excision scar. We developed an energy modulated electron chest wall irradiation technique that will achieve heart sparing. Methods: Ten left-sided PU patients were selected for this dosimetry study. If PWT were used, the amount of the ipsilateral lung would be ranged 3.4 to 4.4 cm, and the amount of heart would be ranged 1.3 to 3.8 cm. We used electron paired fields that matchedmore » on the skin to achieve dose conformity to the chest wall. The enface electron fields were designed at extended SSD from a single isocenter and gantry angle with different energy beams using different cutout. Lower energy was used in the central chest wall part and higher energy was used in the periphery of the chest wall. Bolus was used for the electron fields to ensure adequate skin dose coverage. The electron fields were matched to the photon supra-clavicle field in the superior region. Daily field junctions were used to feather the match lines between all the fields. Target volumes and normal tissues were drawn according to institutional protocols. Prescription dose was 2Gy per fraction for a total 50Gy. Dose calculations were done with Eclipse EMC-11031 for Electron and AAA-11031 for photons. Results: Six patients were planned using 6/9MeV, three using 9/12MeV and one 6/12MeV. Target volumes achieved adequate coverage. For heart, V30Gy, V20Gy and Mean Dose were 0.6%±0.6%, 2.7%±1.7%, and 3.0Gy±0.8Gy respectively. For ipsilateral lung, V50Gy, V20Gy, V10Gy and V5Gy were 0.9%±1.1%, 34.3%±5.1%, 51.6%±6.3% and 64.1%±7.5% respectively. Conclusion: For left-sided PU patients with unusual anatomy, energy modulated electron CW irradiation technique can achieve heart sparing with acceptable lung dose.« less

Evaluation of pulmonary function using single-breath-hold dual-energy computed tomography with xenon

PubMed Central

Kyoyama, Hiroyuki; Hirata, Yusuke; Kikuchi, Satoshi; Sakai, Kosuke; Saito, Yuriko; Mikami, Shintaro; Moriyama, Gaku; Yanagita, Hisami; Watanabe, Wataru; Otani, Katharina; Honda, Norinari; Uematsu, Kazutsugu

2017-01-01

Abstract Xenon-enhanced dual-energy computed tomography (xenon-enhanced CT) can provide lung ventilation maps that may be useful for assessing structural and functional abnormalities of the lung. Xenon-enhanced CT has been performed using a multiple-breath-hold technique during xenon washout. We recently developed xenon-enhanced CT using a single-breath-hold technique to assess ventilation. We sought to evaluate whether xenon-enhanced CT using a single-breath-hold technique correlates with pulmonary function testing (PFT) results. Twenty-six patients, including 11 chronic obstructive pulmonary disease (COPD) patients, underwent xenon-enhanced CT and PFT. Three of the COPD patients underwent xenon-enhanced CT before and after bronchodilator treatment. Images from xenon-CT were obtained by dual-source CT during a breath-hold after a single vital-capacity inspiration of a xenon–oxygen gas mixture. Image postprocessing by 3-material decomposition generated conventional CT and xenon-enhanced images. Low-attenuation areas on xenon images matched low-attenuation areas on conventional CT in 21 cases but matched normal-attenuation areas in 5 cases. Volumes of Hounsfield unit (HU) histograms of xenon images correlated moderately and highly with vital capacity (VC) and total lung capacity (TLC), respectively (r = 0.68 and 0.85). Means and modes of histograms weakly correlated with VC (r = 0.39 and 0.38), moderately with forced expiratory volume in 1 second (FEV1) (r = 0.59 and 0.56), weakly with the ratio of FEV1 to FVC (r = 0.46 and 0.42), and moderately with the ratio of FEV1 to its predicted value (r = 0.64 and 0.60). Mode and volume of histograms increased in 2 COPD patients after the improvement of FEV1 with bronchodilators. Inhalation of xenon gas caused no adverse effects. Xenon-enhanced CT using a single-breath-hold technique depicted functional abnormalities not detectable on thin-slice CT. Mode, mean, and volume of HU histograms of xenon images reflected pulmonary function. Xenon images obtained with xenon-enhanced CT using a single-breath-hold technique can qualitatively depict pulmonary ventilation. A larger study comprising only COPD patients should be conducted, as xenon-enhanced CT is expected to be a promising technique for the management of COPD. PMID:28099359

Evaluation of pulmonary function using single-breath-hold dual-energy computed tomography with xenon: Results of a preliminary study.

PubMed

Kyoyama, Hiroyuki; Hirata, Yusuke; Kikuchi, Satoshi; Sakai, Kosuke; Saito, Yuriko; Mikami, Shintaro; Moriyama, Gaku; Yanagita, Hisami; Watanabe, Wataru; Otani, Katharina; Honda, Norinari; Uematsu, Kazutsugu

2017-01-01

Xenon-enhanced dual-energy computed tomography (xenon-enhanced CT) can provide lung ventilation maps that may be useful for assessing structural and functional abnormalities of the lung. Xenon-enhanced CT has been performed using a multiple-breath-hold technique during xenon washout. We recently developed xenon-enhanced CT using a single-breath-hold technique to assess ventilation. We sought to evaluate whether xenon-enhanced CT using a single-breath-hold technique correlates with pulmonary function testing (PFT) results.Twenty-six patients, including 11 chronic obstructive pulmonary disease (COPD) patients, underwent xenon-enhanced CT and PFT. Three of the COPD patients underwent xenon-enhanced CT before and after bronchodilator treatment. Images from xenon-CT were obtained by dual-source CT during a breath-hold after a single vital-capacity inspiration of a xenon-oxygen gas mixture. Image postprocessing by 3-material decomposition generated conventional CT and xenon-enhanced images.Low-attenuation areas on xenon images matched low-attenuation areas on conventional CT in 21 cases but matched normal-attenuation areas in 5 cases. Volumes of Hounsfield unit (HU) histograms of xenon images correlated moderately and highly with vital capacity (VC) and total lung capacity (TLC), respectively (r = 0.68 and 0.85). Means and modes of histograms weakly correlated with VC (r = 0.39 and 0.38), moderately with forced expiratory volume in 1 second (FEV1) (r = 0.59 and 0.56), weakly with the ratio of FEV1 to FVC (r = 0.46 and 0.42), and moderately with the ratio of FEV1 to its predicted value (r = 0.64 and 0.60). Mode and volume of histograms increased in 2 COPD patients after the improvement of FEV1 with bronchodilators. Inhalation of xenon gas caused no adverse effects.Xenon-enhanced CT using a single-breath-hold technique depicted functional abnormalities not detectable on thin-slice CT. Mode, mean, and volume of HU histograms of xenon images reflected pulmonary function. Xenon images obtained with xenon-enhanced CT using a single-breath-hold technique can qualitatively depict pulmonary ventilation. A larger study comprising only COPD patients should be conducted, as xenon-enhanced CT is expected to be a promising technique for the management of COPD.

PET scan

MedlinePlus

... in your lung is cancerous or harmless Normal Results A normal result means there were no problems ... which the tracer has abnormally collected. What Abnormal Results Mean Abnormal results depend on the part of ...

Composite recovery type curves in normalized time from Theis' exact solution

USGS Publications Warehouse

Goode, Daniel J.

1997-01-01

Type curves derived from Theis’ exact nonequilibrium well function solution are proposed for graphical estimation of aquifer hydraulic properties, transmissivity (T), and storage coefficient (S), from water-level recovery data after cessation of a constant-rate discharge test. Drawdown (on log scale) is plotted versus the ratio of time since pumping stopped to duration of pumping, a normalized time. Under Theis conditions, individual type curves depend on only the dimensionless pumping duration, which depends in turn on S and radial distance from the pumping well. Type curve matching, in contrast to the Theis procedure for pumping data, is performed by shifting only the drawdown axis; the time axis is fixed because it is a relative or normalized time. The match-point for the drawdown axis is used to compute T, and S is determined from matching the curve shape, which depends on early dimensionless-time data. Multiple well data can be plotted and matched simultaneously (a composite plot), with drawdown at different radial distances matching different curves. The ratio of dimensionless pumping durations for any two matched curves is equal to one over the squared ratio of radial distances. Application to two recovery datasets from the literature confirm the utility of these type curves in normalized time for composite estimation of T and S.

Genetic polymorphisms in the vitamin D pathway in relation to lung cancer risk and survival

PubMed Central

Kong, Jinyu; Xu, Fangxiu; Qu, Jinli; Wang, Yu; Gao, Ming; Yu, Herbert; Qian, Biyun

2015-01-01

Studies have suggested that vitamin D may have protective effects against cancer development or tumor progression. To search for additional evidence, we investigated the role of genetic polymorphisms involved in the vitamin D pathway in non-small cell lung cancer (NSCLC). We evaluated common genetic polymorphisms associated with the vitamin D pathway in relation to NSCLC in a case-control study of 603 newly diagnosed NSCLC patients and 661 matched healthy controls. Seven single nucleotide polymorphisms (SNPs) were genotyped, the expression of CYP27B1 and CYP24A1 were measured in 153 tumor samples and their associations with genotypes and patient survival were also analyzed. In the case-control comparison, we found SNP rs3782130 (CYP27B1), rs7041 (GC), rs6068816 and rs4809957 (CYP24A1) associated with NSCLC risk. The risk of NSCLC was increased with the number of risk alleles. CYP27B1 and CYP24A1 expression were significantly different between tumor and normal tissues in NSCLC. High CYP27B1 expression was associated with better overall survival, and the expression was different by the rs3782130 genotype. The study suggests that some genetic polymorphisms involved in the vitamin D pathway may associate with NSCLC risk, and one of the polymorphisms (rs3782130) may affect gene expression and patient survival. PMID:25544771

The development and plasticity of alveolar type 1 cells

PubMed Central

Yang, Jun; Hernandez, Belinda J.; Martinez Alanis, Denise; Narvaez del Pilar, Odemaris; Vila-Ellis, Lisandra; Akiyama, Haruhiko; Evans, Scott E.; Ostrin, Edwin J.; Chen, Jichao

2016-01-01

Alveolar type 1 (AT1) cells cover >95% of the gas exchange surface and are extremely thin to facilitate passive gas diffusion. The development of these highly specialized cells and its coordination with the formation of the honeycomb-like alveolar structure are poorly understood. Using new marker-based stereology and single-cell imaging methods, we show that AT1 cells in the mouse lung form expansive thin cellular extensions via a non-proliferative two-step process while retaining cellular plasticity. In the flattening step, AT1 cells undergo molecular specification and remodel cell junctions while remaining connected to their epithelial neighbors. In the folding step, AT1 cells increase in size by more than 10-fold and undergo cellular morphogenesis that matches capillary and secondary septa formation, resulting in a single AT1 cell spanning multiple alveoli. Furthermore, AT1 cells are an unexpected source of VEGFA and their normal development is required for alveolar angiogenesis. Notably, a majority of AT1 cells proliferate upon ectopic SOX2 expression and undergo stage-dependent cell fate reprogramming. These results provide evidence that AT1 cells have both structural and signaling roles in alveolar maturation and can exit their terminally differentiated non-proliferative state. Our findings suggest that AT1 cells might be a new target in the pathogenesis and treatment of lung diseases associated with premature birth. PMID:26586225

A Population-Based Comparative Effectiveness Study of Radiation Therapy Techniques in Stage III Non-Small Cell Lung Cancer

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

Harris, Jeremy P.; Murphy, James D.; Hanlon, Alexandra L.

2014-03-15

Purpose: Concerns have been raised about the potential for worse treatment outcomes because of dosimetric inaccuracies related to tumor motion and increased toxicity caused by the spread of low-dose radiation to normal tissues in patients with locally advanced non-small cell lung cancer (NSCLC) treated with intensity modulated radiation therapy (IMRT). We therefore performed a population-based comparative effectiveness analysis of IMRT, conventional 3-dimensional conformal radiation therapy (3D-CRT), and 2-dimensional radiation therapy (2D-RT) in stage III NSCLC. Methods and Materials: We used the Surveillance, Epidemiology, and End Results (SEER)-Medicare database to identify a cohort of patients diagnosed with stage III NSCLC frommore » 2002 to 2009 treated with IMRT, 3D-CRT, or 2D-RT. Using Cox regression and propensity score matching, we compared survival and toxicities of these treatments. Results: The proportion of patients treated with IMRT increased from 2% in 2002 to 25% in 2009, and the use of 2D-RT decreased from 32% to 3%. In univariate analysis, IMRT was associated with improved overall survival (OS) (hazard ratio [HR] 0.90, P=.02) and cancer-specific survival (CSS) (HR 0.89, P=.02). After controlling for confounders, IMRT was associated with similar OS (HR 0.94, P=.23) and CSS (HR 0.94, P=.28) compared with 3D-CRT. Both techniques had superior OS compared with 2D-RT. IMRT was associated with similar toxicity risks on multivariate analysis compared with 3D-CRT. Propensity score matched model results were similar to those from adjusted models. Conclusions: In this population-based analysis, IMRT for stage III NSCLC was associated with similar OS and CSS and maintained similar toxicity risks compared with 3D-CRT.« less

Aberrant pulmonary lymphatic development in the nitrofen mouse model of congenital diaphragmatic hernia

PubMed Central

Shue, Eveline; Wu, Jianfeng; Schecter, Samuel; Miniati, Doug

2013-01-01

Purpose Many infants develop a postsurgical chylothorax after diaphragmatic hernia repair. The pathogenesis remains elusive but may be due to dysfunctional lymphatic development. This study characterizes pulmonary lymphatic development in the nitrofen mouse model of CDH. Methods CD1 pregnant mice were fed nitrofen/bisdiamine (N/B) or olive oil at E8.5. At E14.5 and E15.5, lung buds were categorized by phenotype: normal, N/B without CDH (N/B−CDH), or N/B with CDH (N/B+CDH). Anti-CD31 was used to localize all endothelial cells, while anti-LYVE-1 was used to identify lymphatic endothelial cells in lung buds using immunofluorescence. Differential protein expression of lymphatic-specific markers was analyzed. Results Lymphatic endothelial cells localized to the mesenchyme surrounding the airway epithelium at E15.5. CD31 and LYVE-1 colocalization identified lymphatic endothelial cells. LYVE-1 expression was upregulated in N/B+CDH lung buds in comparison to N/B−CDH and normal lung buds by immunofluorescence. Western blotting shows that VEGF-D, LYVE-1, Prox-1, and VEGFR-3 expression was upregulated in N/B+CDH lung buds in comparison to N/B−CDH or control lung buds at E14.5. Conclusions Lung lymphatics are hyperplastic in N/B+CDH. Upregulation of lymphatic-specific genes suggest that lymphatic hyperplasia plays an important role in dysfunctional lung lymphatic development in the nitrofen mouse model of CDH. PMID:23845607

Aberrant pulmonary lymphatic development in the nitrofen mouse model of congenital diaphragmatic hernia.

PubMed

Shue, Eveline; Wu, Jianfeng; Schecter, Samuel; Miniati, Doug

2013-06-01

Many infants develop a postsurgical chylothorax after diaphragmatic hernia repair. The pathogenesis remains elusive but may be owing to dysfunctional lymphatic development. This study characterizes pulmonary lymphatic development in the nitrofen mouse model of CDH. CD1 pregnant mice were fed nitrofen/bisdiamine (N/B) or olive oil at E8.5. At E14.5 and E15.5, lung buds were categorized by phenotype: normal, N/B without CDH (N/B - CDH), or N/B with CDH (N/B+CDH). Anti-CD31 was used to localize all endothelial cells, while anti-LYVE-1 was used to identify lymphatic endothelial cells in lung buds using immunofluorescence. Differential protein expression of lymphatic-specific markers was analyzed. Lymphatic endothelial cells localized to the mesenchyme surrounding the airway epithelium at E15.5. CD31 and LYVE-1 colocalization identified lymphatic endothelial cells. LYVE-1 expression was upregulated in N/B+CDH lung buds in comparison to N/B - CDH and normal lung buds by immunofluorescence. Western blotting shows that VEGF-D, LYVE-1, Prox-1, and VEGFR-3 expression was upregulated in N/B+CDH lung buds in comparison to N/B - CDH or control lung buds at E14.5. Lung lymphatics are hyperplastic in N/B+CDH. Upregulation of lymphatic-specific genes suggests that lymphatic hyperplasia plays an important role in dysfunctional lung lymphatic development in the nitrofen mouse model of CDH. Copyright © 2013 Elsevier Inc. All rights reserved.

Identification of Alternative Splicing and Fusion Transcripts in Non-Small Cell Lung Cancer by RNA Sequencing.

PubMed

Hong, Yoonki; Kim, Woo Jin; Bang, Chi Young; Lee, Jae Cheol; Oh, Yeon-Mok

2016-04-01

Lung cancer is the most common cause of cancer related death. Alterations in gene sequence, structure, and expression have an important role in the pathogenesis of lung cancer. Fusion genes and alternative splicing of cancer-related genes have the potential to be oncogenic. In the current study, we performed RNA-sequencing (RNA-seq) to investigate potential fusion genes and alternative splicing in non-small cell lung cancer. RNA was isolated from lung tissues obtained from 86 subjects with lung cancer. The RNA samples from lung cancer and normal tissues were processed with RNA-seq using the HiSeq 2000 system. Fusion genes were evaluated using Defuse and ChimeraScan. Candidate fusion transcripts were validated by Sanger sequencing. Alternative splicing was analyzed using multivariate analysis of transcript sequencing and validated using quantitative real time polymerase chain reaction. RNA-seq data identified oncogenic fusion genes EML4-ALK and SLC34A2-ROS1 in three of 86 normal-cancer paired samples. Nine distinct fusion transcripts were selected using DeFuse and ChimeraScan; of which, four fusion transcripts were validated by Sanger sequencing. In 33 squamous cell carcinoma, 29 tumor specific skipped exon events and six mutually exclusive exon events were identified. ITGB4 and PYCR1 were top genes that showed significant tumor specific splice variants. In conclusion, RNA-seq data identified novel potential fusion transcripts and splice variants. Further evaluation of their functional significance in the pathogenesis of lung cancer is required.

Expression of WNT5A in Idiopathic Pulmonary Fibrosis and Its Control by TGF-β and WNT7B in Human Lung Fibroblasts.

PubMed

Newman, Donna R; Sills, W Shane; Hanrahan, Katherine; Ziegler, Amanda; Tidd, Kathleen McGinnis; Cook, Elizabeth; Sannes, Philip L

2016-02-01

The wingless (Wnt) family of signaling ligands contributes significantly to lung development and is highly expressed in patients with usual interstitial pneumonia (UIP). We sought to define the cellular distribution of Wnt5A in the lung tissue of patients with idiopathic pulmonary fibrosis (IPF) and the signaling ligands that control its expression in human lung fibroblasts and IPF myofibroblasts. Tissue sections from 40 patients diagnosed with IPF or UIP were probed for the immunolocalization of Wnt5A. Further, isolated lung fibroblasts from normal or IPF human lungs, adenovirally transduced for the overexpression or silencing of Wnt7B or treated with TGF-β1 or its inhibitor, were analyzed for Wnt5A protein expression. Wnt5A was expressed in IPF lungs by airway and alveolar epithelium, smooth muscle cells, endothelium, and myofibroblasts of fibroblastic foci and throughout the interstitium. Forced overexpression of Wnt7B with or without TGF-β1 treatment significantly increased Wnt5A protein expression in normal human smooth muscle cells and fibroblasts but not in IPF myofibroblasts where Wnt5A was already highly expressed. The results demonstrate a wide distribution of Wnt5A expression in cells of the IPF lung and reveal that it is significantly increased by Wnt7B and TGF-β1, which, in combination, could represent key signaling pathways that modulate the pathogenesis of IPF. © 2016 The Histochemical Society.

Identification of Key Transcription Factors Associated with Lung Squamous Cell Carcinoma

PubMed Central

Zhang, Feng; Chen, Xia; Wei, Ke; Liu, Daoming; Xu, Xiaodong; Zhang, Xing; Shi, Hong

2017-01-01

Background Lung squamous cell carcinoma (lung SCC) is a common type of lung cancer, but its mechanism of pathogenesis is unclear. The aim of this study was to identify key transcription factors in lung SCC and elucidate its mechanism. Material/Methods Six published microarray datasets of lung SCC were downloaded from Gene Expression Omnibus (GEO) for integrated bioinformatics analysis. Significance analysis of microarrays was used to identify differentially expressed genes (DEGs) between lung SCC and normal controls. The biological functions and signaling pathways of DEGs were mapped in the Gene Otology and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway database, respectively. A transcription factor gene regulatory network was used to obtain insights into the functions of DEGs. Results A total of 1,011 genes, including 539 upregulated genes and 462 downregulated genes, were filtered as DEGs between lung SCC and normal controls. DEGs were significantly enriched in cell cycle, DNA replication, p53 signaling pathway, pathways in cancer, adherens junction, and cell adhesion molecules signaling pathways. There were 57 transcription factors identified, which were used to construct a regulatory network. The network consisted of 736 interactions between 49 transcription factors and 486 DEGs. NFIC, BRCA1, and NFATC2 were the top 3 transcription factors that had the highest connectivity with DEGs and that regulated 83, 82, and 75 DEGs in the network, respectively. Conclusions NFIC, BRCA1, and NFATC2 might be the key transcription factors in the development of lung SCC by regulating the genes involved in cell cycle and DNA replication pathways. PMID:28081052

Fetal MRI lung volumes are predictive of perinatal outcomes in fetuses with congenital lung masses.

PubMed

Zamora, Irving J; Sheikh, Fariha; Cassady, Christopher I; Olutoye, Oluyinka O; Mehollin-Ray, Amy R; Ruano, Rodrigo; Lee, Timothy C; Welty, Stephen E; Belfort, Michael A; Ethun, Cecilia G; Kim, Michael E; Cass, Darrell L

2014-06-01

The purpose of this study was to evaluate fetal magnetic resonance imaging (MRI) as a modality for predicting perinatal outcomes and lung-related morbidity in fetuses with congenital lung masses (CLM). The records of all patients treated for CLM from 2002 to 2012 were reviewed retrospectively. Fetal MRI-derived lung mass volume ratio (LMVR), observed/expected normal fetal lung volume (O/E-NFLV), and lesion-to-lung volume ratio (LLV) were calculated. Multivariate regression and receiver operating characteristic analyses were applied to determine the predictive accuracy of prenatal imaging. Of 128 fetuses with CLM, 93% (n=118) survived. MRI data were available for 113 fetuses. In early gestation (<26weeks), MRI measurements of LMVR and LLV correlated with risk of fetal hydrops, mortality, and/or need for fetal intervention. In later gestation (>26weeks), LMVR, LLV, and O/E-NFLV correlated with neonatal respiratory distress, intubation, NICU admission and need for neonatal surgery. On multivariate regression, LMVR was the strongest predictor for development of fetal hydrops (OR: 6.97, 1.58-30.84; p=0.01) and neonatal respiratory distress (OR: 12.38, 3.52-43.61; p≤0.001). An LMVR >2.0 predicted worse perinatal outcome with 83% sensitivity and 99% specificity (AUC=0.94; p<0.001). Fetal MRI volumetric measurements of lung masses and residual normal lung are predictive of perinatal outcomes in fetuses with CLM. These data may assist in perinatal risk stratification, counseling, and resource utilization. Copyright © 2014 Elsevier Inc. All rights reserved.

The spleen can influence the metastasis of AH130 hepatoma cells in rats.

PubMed

Toyonaga, M; Hiraoka, T; Tanaka, H; Miyauchi, Y

1993-06-01

The effect of pathophysiological conditions due to disturbance of the spleen is still unclear. We studied the effects of splenectomy in normal and methylcellulose-induced hypersplenic rats on the development of pulmonary metastases created by intravenous injection of ascites containing AH130 hepatoma cells from male Hos-Donryu rats. Growth of metastatic lesions in the lung was not affected by splenectomy in normal rats, but was increased by splenectomy in hypersplenic rats. Overall, there were fewer pulmonary metastases in rats with hypersplenism, but after splenectomy rats with hypersplenism had a significantly greater number of metastases than did normal rats. The metastases rate correlated somewhat with changes in the blood coagulation and T lymphocyte profile. There is a relationship between the spleen and formation of metastases in cancer. Formation of metastases in the lung was affected most by splenectomy in hypersplenism. To elucidate the mechanism by which metastases are formed in the lung under these pathologic conditions, further studies on the exact role of the spleen are required.

Targeted inactivation of the murine Abca3 gene leads to respiratory failure in newborns with defective lamellar bodies

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

Hammel, Markus; Michel, Geert; Hoefer, Christina

2007-08-10

Mutations in the human ABCA3 gene, encoding an ABC-transporter, are associated with respiratory failure in newborns and pediatric interstitial lung disease. In order to study disease mechanisms, a transgenic mouse model with a disrupted Abca3 gene was generated by targeting embryonic stem cells. While heterozygous animals developed normally and were fertile, individuals homozygous for the altered allele (Abca3-/-) died within one hour after birth from respiratory failure, ABCA3 protein being undetectable. Abca3-/- newborns showed atelectasis of the lung in comparison to a normal gas content in unaffected or heterozygous littermates. Electron microscopy demonstrated the absence of normal lamellar bodies inmore » type II pneumocytes. Instead, condensed structures with apparent absence of lipid content were found. We conclude that ABCA3 is required for the formation of lamellar bodies and lung surfactant function. The phenotype of respiratory failure immediately after birth corresponds to the clinical course of severe ABCA3 mutations in human newborns.« less

A new algorithm for distorted fingerprints matching based on normalized fuzzy similarity measure.

PubMed

Chen, Xinjian; Tian, Jie; Yang, Xin

2006-03-01

Coping with nonlinear distortions in fingerprint matching is a challenging task. This paper proposes a novel algorithm, normalized fuzzy similarity measure (NFSM), to deal with the nonlinear distortions. The proposed algorithm has two main steps. First, the template and input fingerprints were aligned. In this process, the local topological structure matching was introduced to improve the robustness of global alignment. Second, the method NFSM was introduced to compute the similarity between the template and input fingerprints. The proposed algorithm was evaluated on fingerprints databases of FVC2004. Experimental results confirm that NFSM is a reliable and effective algorithm for fingerprint matching with nonliner distortions. The algorithm gives considerably higher matching scores compared to conventional matching algorithms for the deformed fingerprints.

Genetic variation at the microRNA binding site of CAV1 gene is associated with lung cancer susceptibility

PubMed Central

Fang, Xue; Li, Xuelian; Yin, Zhihua; Xia, Lingzi; Quan, Xiaowei; Zhao, Yuxia; Zhou, Baosen

2017-01-01

Single nucleotide polymorphism (SNP) may influence the genesis and development of cancer in a variety of ways depending on their location. Here we conducted a study in Chinese female non-smokers to investigate the relationship between rs1049337, rs926198 and the risk or survival of lung cancer. Further, we explored whether rs1049337 could alter the binding affinity between the mRNA of CAV1 and the corresponding microRNAs. Finally, we evaluated the relationship between expression level of CAV1 and prognosis of lung cancer. The results showed that the rs1049337-C allele and rs926198-C allele were the protective alleles of lung cancer risk. Haplotype analysis indicated that the C-C haplotype (constructed by rs1049337 and rs926198) was a protective haplotype for lung cancer risk. The result of luciferase reporter assay showed that rs1049337 can affect the binding affinity of CAV1 mRNA to the corresponding microRNAs both in A549 cell line and H1299 cell line. Compared with C allele, T allele had a relatively decreased luciferase activity. Compared with paired normal adjacent tissue or normal lung tissue, lung cancer tissue showed a relatively low level of CAV1. Refer to those patients at early stage of lung cancer, the expression level of CAV1 in patients at late stage of lung cancer was relatively low. In conclusion, the results indicated that rs1049337, it's a SNP located at 3′UTR region of CAV1 may affect lung cancer risk by altering the binding affinity between the mRNA of CAV1 and the corresponding microRNAs. PMID:29190968

Intrinsic catch-up growth of hypoplastic fetal lungs is mediated by interleukin-6.

PubMed

Nogueira-Silva, Cristina; Moura, Rute S; Esteves, Nuno; Gonzaga, Sílvia; Correia-Pinto, Jorge

2008-07-01

Fetal lung hypoplasia is a common finding in several fetal conditions such as congenital diaphragmatic hernia (CDH). Interestingly, previous studies have demonstrated that hypoplastic lungs have the ability to recover to normal size, when relieved from mechanical factors. However, the underlying mechanisms remain largely unknown. Recently, interleukin-6 (IL-6) has been involved in catch-up growth phenomenon in children. Thus, we hypothesized that IL-6 could mediate fetal growth recover from hypoplastic lungs. Control and nitrofen-induced hypoplastic lung explants were cultured either in normal conditions or with IL-6 neutralizing antibodies. The total number of peripheral airway buds, epithelial perimeter, and total explant area were analyzed and daily branching rates were calculated. Additionally, IL-6 mRNA and protein expression was assessed both in qualitative (by in situ hybridization and immunohistochemistry) and in quantitative (by real-time PCR and Western blot) approaches, in control and hypoplastic lungs (nitrofen and CDH groups). Nitrofen-induced hypoplastic lungs showed in vitro, out of systemic environment, the ability to recover from hypoplasia and presented daily branching rates significantly higher than controls. Blocking IL-6 activity significantly diminished the intrinsic capacity of hypoplastic fetal lungs to recover from hypoplasia and attenuated their daily branching rates. Although more exacerbated in CDH, both nitrofen-exposed lungs presented significant IL-6 mRNA and protein over-expression throughout all studied gestational ages. The present study suggests, for the first time, that fetal lung is able to recover from growth retardation through a way that resembles the catch-up growth phenomenon, and it seems to be, at least partially, orchestrated by intrinsic mechanisms implicating IL-6.

Rac3 Regulates Cell Invasion, Migration and EMT in Lung Adenocarcinoma through p38 MAPK Pathway

PubMed Central

Zhang, Chenlei; Liu, Tieqin; Wang, Gebang; Wang, Huan; Che, Xiaofang; Gao, Xinghua; Liu, Hongxu

2017-01-01

Background: The role of Rac3 in cell proliferation in lung adenocarcinoma has been tackled in our previous study. However, the role of Rac3 in cell invasion and migration of lung adenocarcinoma is still not clear. Methods: The expression of Rac3 in lung adenocarcinoma specimens and paired noncancerous normal tissues were evaluated by immunohistochemistry. Lentivirus-mediated RNA interference (RNAi) was employed to silence Rac3 in lung adenocarcinoma cell lines A549 and H1299. A p38 MAPK inhibitor (LY2228820) was employed to inhibit activity of p38 MAPK pathway. Cell invasion and migration in vitro were examined by invasion and migration assays, respectively. PathScan® intracellular signaling array kit and western blot were employed in mechanism investigation. Results: Rac3 expression was frequently higher in lung adenocarcinoma than paired noncancerous normal tissues. Rac3 expression was an independent risk factor for lymphonode metastasis, and was associated with worse survival outcome. Silencing of Rac3 inhibited cell invasion and cell migration in lung adenocarcinoma cell lines. Knockdown of Rac3 decreased activity of p38 MAPK pathway. LY2228820, which was an important p38 MAPK inhibitor, inhibited Rac3-induced cell invasion and migration of lung adenocarcinoma. E-cadherin expression was increased and vimentin expression was decreased after silencing of Rac3 or following the treatment of LY2228820. Conclusions: Our findings suggest that Rac3 regulates cell invasion, migration and EMT via p38 MAPK pathway. Rac3 may be a potential biomarker of invasion and metastasis for lung adenocarcinoma, and knockdown of Rac3 may potentially serve as a promising therapeutic target for lung adenocarcinoma. PMID:28900489

Coiled-coil domain-containing protein 8 inhibits the invasiveness and migration of non-small cell lung cancer cells.

PubMed

Jiang, Gui-Yang; Zhang, Xiu-Peng; Zhang, Yong; Xu, Hong-Tao; Wang, Liang; Li, Qing-Chang; Wang, En-Hua

2016-10-01

Lung cancer has always been the leading cause of death among patients with malignant tumors, and the majority of these patients die because of cancer cell invasion and metastasis. Previous studies have implicated coiled-coil domain-containing protein 8 (CCDC8) as a tumor suppressor in several types of cancer, such as breast and prostate cancers. However, the expression levels or functions of CCDC8 in lung cancer have not been elucidated. Here, we used immunohistochemical staining to measure CCDC8 expression in 147 samples from tumors and 30 samples from the adjacent normal lung tissues of patients with non-small cell lung cancer. CCDC8 was shown to be located predominantly in the cytoplasm and partially on the cell membrane, and its expression level was significantly lower in lung cancer samples than that in the adjacent normal lung tissues (P=.001). CCDC8 expression was closely related to tumor differentiation (P=.039), tumor-node-metastasis stage (P=.009), lymph node metastasis (P=.038), and prognosis (P=.043) of lung cancer. Transfection of A549 cells with CCDC8 significantly reduced cell invasion and migration (P<.05), whereas the invasiveness and migration capacity in CCDC8-knockdown A549 cells were significantly increased in comparison with the control cells (P<.05). Furthermore, we demonstrated that CCDC8 can downregulate the expression of Snail and upregulate the expression of E-cadherin by inhibiting p-P38 and p-IκBα. Collectively, CCDC8 may suppress the invasion and metastasis of lung cancer cells, and it may represent a promising therapeutic target for non-small cell lung cancer. Copyright © 2016 Elsevier Inc. All rights reserved.

Overexpression of IL-38 protein in anticancer drug-induced lung injury and acute exacerbation of idiopathic pulmonary fibrosis.

PubMed

Tominaga, Masaki; Okamoto, Masaki; Kawayama, Tomotaka; Matsuoka, Masanobu; Kaieda, Shinjiro; Sakazaki, Yuki; Kinoshita, Takashi; Mori, Daisuke; Inoue, Akira; Hoshino, Tomoaki

2017-09-01

Interleukin (IL)-38, a member of the IL-1 family, shows high homology to IL-1 receptor antagonist (IL-1Ra) and IL-36 receptor antagonist (IL-36Ra). Its function in interstitial lung disease (ILD) is still unknown. To determine the expression pattern of IL-38 mRNA, a panel of cDNAs derived from various tissues was analyzed by quantitative real-time PCR. Immunohistochemical reactivity with anti-human IL-38 monoclonal antibody (clone H127C) was evaluated semi-quantitatively in lung tissue samples from 12 patients with idiopathic pulmonary fibrosis/usual interstitial pneumonia (IPF/UIP), 5 with acute exacerbation of IPF, and 10 with anticancer drug-induced ILD (bleomycin in 5 and epidermal growth factor receptor-tyrosine kinase inhibitor in 5). Control lung tissues were obtained from areas of normal lung in 22 lung cancer patients who underwent extirpation surgery. IL-38 transcripts were strongly expressed in the lung, spleen, synoviocytes, and peripheral blood mononuclear cells, and at a lower level in pancreas and muscle. IL-38 protein was not strongly expressed in normal pulmonary alveolar tissues in all 22 control lungs. In contrast, IL-38 was overexpressed in the lungs of 4 of 5 (80%) patients with acute IPF exacerbation and 100% (10/10) of the patients with drug-induced ILD. IL-38 overexpression was limited to hyperplastic type II pneumocytes, which are considered to reflect regenerative change following diffuse alveolar damage in ILD. IL-38 may play an important role in acute and/or chronic inflammation in anticancer drug-induced lung injury and acute exacerbation of IPF. Copyright © 2017 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.

Immunomodulatory Effects of Mixed Hematopoietic Chimerism: Immune Tolerance in Canine Model of Lung Transplantation

PubMed Central

Nash;, Richard A.; Yunosov;, Murad; Abrams;, Kraig; Hwang;, Billanna; Castilla-Llorente;, Cristina; Chen;, Peter; Farivar;, Alexander S.; Georges;, George E.; Hackman;, Robert C.; Lamm;, Wayne J.E.; Lesnikova;, Marina; Ochs;, Hans D.; Randolph-Habecker;, Julie; Ziegler;, Stephen F.; Storb;, Rainer; Storer;, Barry; Madtes;, David K.; Glenny;, Robb; Mulligan, Michael S.

2010-01-01

Long-term survival after lung transplantation is limited by acute and chronic graft rejection. Induction of immune tolerance by first establishing mixed hematopoietic chimerism (MC) is a promising strategy to improve outcomes. In a preclinical canine model, stable MC was established in recipients after reduced-intensity conditioning and hematopoietic cell transplantation from a DLA-identical donor. Delayed lung transplantation was performed from the stem cell donor without pharmacological immunosuppression. Lung graft survival without loss of function was prolonged in chimeric (n=5) vs. nonchimeric (n=7) recipients (p≤0.05, Fisher’s test). There were histological changes consistent with low grade rejection in 3/5 of the lung grafts in chimeric recipients at ≥1 year. Chimeric recipients after lung transplantation had a normal immune response to a T-dependent antigen. Compared to normal dogs, there were significant increases of CD4+INFγ+, CD4+IL-4+ and CD8+ INFγ+ T-cell subsets in the blood (p <0.0001 for each of the 3 T-cell subsets). Markers for regulatory T-cell subsets including foxP3, IL10 and TGFβ were also increased in CD3+ T cells from the blood and peripheral tissues of chimeric recipients after lung transplantation. Establishing MC is immunomodulatory and observed changes were consistent with activation of both the effector and regulatory immune response. PMID:19422333

Correlation between the clinical pretest probability score and the lung ventilation and perfusion scan probability.

PubMed

Bhoobalan, Shanmugasundaram; Chakravartty, Riddhika; Dolbear, Gill; Al-Janabi, Mazin

2013-10-01

Aim of the study was to determine the accuracy of the clinical pretest probability (PTP) score and its association with lung ventilation and perfusion (VQ) scan. A retrospective analysis of 510 patients who had a lung VQ scan between 2008 and 2010 were included in the study. Out of 510 studies, the number of normal, low, and high probability VQ scans were 155 (30%), 289 (57%), and 55 (11%), respectively. A total of 103 patients underwent computed tomography pulmonary angiography (CTPA) scan in which 21 (20%) had a positive scan, 81 (79%) had a negative scan and one (1%) had an equivocal result. The rate of PE in the normal, low-probability, and high-probability scan categories were: 2 (9.5%), 10 (47.5%), and 9 (43%) respectively. A very low correlation (Pearson correlation coefficient r = 0.20) between the clinical PTP score and lung VQ scan. The area under the curve (AUC) of the clinical PTP score was 52% when compared with the CTPA results. However, the accuracy of lung VQ scan was better (AUC = 74%) when compared with CTPA scan. The clinical PTP score is unreliable on its own; however, it may still aid in the interpretation of lung VQ scan. The accuracy of the lung VQ scan was better in the assessment of underlying pulmonary embolism (PE).

Correlation between the clinical pretest probability score and the lung ventilation and perfusion scan probability

PubMed Central

Bhoobalan, Shanmugasundaram; Chakravartty, Riddhika; Dolbear, Gill; Al-Janabi, Mazin

2013-01-01

Purpose: Aim of the study was to determine the accuracy of the clinical pretest probability (PTP) score and its association with lung ventilation and perfusion (VQ) scan. Materials and Methods: A retrospective analysis of 510 patients who had a lung VQ scan between 2008 and 2010 were included in the study. Out of 510 studies, the number of normal, low, and high probability VQ scans were 155 (30%), 289 (57%), and 55 (11%), respectively. Results: A total of 103 patients underwent computed tomography pulmonary angiography (CTPA) scan in which 21 (20%) had a positive scan, 81 (79%) had a negative scan and one (1%) had an equivocal result. The rate of PE in the normal, low-probability, and high-probability scan categories were: 2 (9.5%), 10 (47.5%), and 9 (43%) respectively. A very low correlation (Pearson correlation coefficient r = 0.20) between the clinical PTP score and lung VQ scan. The area under the curve (AUC) of the clinical PTP score was 52% when compared with the CTPA results. However, the accuracy of lung VQ scan was better (AUC = 74%) when compared with CTPA scan. Conclusion: The clinical PTP score is unreliable on its own; however, it may still aid in the interpretation of lung VQ scan. The accuracy of the lung VQ scan was better in the assessment of underlying pulmonary embolism (PE). PMID:24379532

miR-133 involves in lung adenocarcinoma cell metastasis by targeting FLOT2.

PubMed

Wei, Guangxia; Xu, Yahuan; Peng, Tao; Yan, Jie

2018-03-01

Dysregulated microRNAs (miRNAs) reported to involve into the oncogenesis and progression in various human cancers. However, the roles and mechanism of miR-133 in lung adenocarcinoma remain largely unclear. In this study, qPCR assay and western blot were used to detect the expression levels of miR-133, Akt and FLOT2. Luciferase reporter assay was used to identify the target role of miR-133 on FLOT2. The cell invasion and the migration capability were performed using the transwell invasion assay and wound healing assay. We found that miR-133 expression levels were downregulated in human lung adenocarcinoma specimens and cell lines compared with the adjacent normal tissues and normal human bronchial epithelial cell. miR-133 significantly suppressed metastasis of lung adenocarcinoma cells in vitro. Furthermore, FLOT2 (flotillin-2) identified as a direct target of miR-133, and FLOT2 expression levels were inversely correlated with miR-133 expression levels in human lung adenocarcinoma specimens. And the restoration studies suggested FGF2 as a downstream effector of miR-133 which acted through Akt signalling pathway. Our study revealed the mechanism that miR-133 suppresses lung adenocarcinoma metastasis by targeting FLOT2 via Akt signalling pathway, implicating a potential prognostic biomarker and therapeutic target for lung adenocarcinoma treatment.

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.

A biomechanical approach for in vivo diaphragm muscle motion prediction during normal respiration

NASA Astrophysics Data System (ADS)

Coelho, Brett; Karami, Elham; Haddad, Seyyed M. H.; Seify, Behzad; Samani, Abbas

2017-03-01

Lung cancer is one of the leading causes of cancer death in men and women. External Beam Radiation Therapy (EBRT) is a commonly used primary treatment for the condition. A major challenge with such treatments is the delivery of sufficient radiation dose to the lung tumor while ensuring that surrounding healthy lung parenchyma receives only minimal dose. This can be achieved by coupling EBRT with respiratory computer models which can predict the tumour location as a function of phase during the breathing cycle1. The diaphragm muscle contraction is mainly responsible for a large portion of the lung tumor motion during normal breathing, especially when tumours are in the lower lobes, therefore the importance of accurately modelling the diaphragm is paramount in lung tumour motion prediction. The goal of this research is to develop a biomechanical model of the diaphragm, including its active and passive response, using detailed geometric, biomechanical and anatomical information that mimics the diaphragmatic behaviour in a patient specific manner. For this purpose, a Finite Element Model (FEM) of the diaphragm was developed in order to predict the in vivo motion of the diaphragm, paving the way for computer assisted lung cancer tumor tracking in EBRT. Preliminary results obtained from the proposed model are promising and they indicate that it can be used as a plausible tool for effective lung cancer EBRT to improve patient care.

The hedgehog system machinery controls transforming growth factor-β-dependent myofibroblastic differentiation in humans: involvement in idiopathic pulmonary fibrosis.

PubMed

Cigna, Natacha; Farrokhi Moshai, Elika; Brayer, Stéphanie; Marchal-Somme, Joëlle; Wémeau-Stervinou, Lidwine; Fabre, Aurélie; Mal, Hervé; Lesèche, Guy; Dehoux, Monique; Soler, Paul; Crestani, Bruno; Mailleux, Arnaud A

2012-12-01

Idiopathic pulmonary fibrosis (IPF) is a devastating disease of unknown cause. Key signaling developmental pathways are aberrantly expressed in IPF. The hedgehog pathway plays a key role during fetal lung development and may be involved in lung fibrogenesis. We determined the expression pattern of several Sonic hedgehog (SHH) pathway members in normal and IPF human lung biopsies and primary fibroblasts. The effect of hedgehog pathway inhibition was assayed by lung fibroblast proliferation and differentiation with and without transforming growth factor (TGF)-β1. We showed that the hedgehog pathway was reactivated in the IPF lung. Importantly, we deciphered the cross talk between the hedgehog and TGF-β pathway in human lung fibroblasts. TGF-β1 modulated the expression of key components of the hedgehog pathway independent of Smoothened, the obligatory signal transducer of the pathway. Smoothened was required for TGF-β1-induced myofibroblastic differentiation of control fibroblasts, but differentiation of IPF fibroblasts was partially resistant to Smoothened inhibition. Furthermore, functional hedgehog pathway machinery from the primary cilium, as well as GLI-dependent transcription in the nucleus, was required for the TGF-β1 effects on normal and IPF fibroblasts during myofibroblastic differentiation. These data identify the GLI transcription factors as potential therapeutic targets in lung fibrosis. Copyright © 2012 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Lung plethysmography

MedlinePlus

... it is not often used because of its technical difficulties. Normal Results Normal results depend on your ... Duplication for commercial use must be authorized in writing by ADAM Health Solutions. About MedlinePlus Site Map ...

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

Suzuki, Minoru; Sakurai, Yoshinori; Masunaga, Shinichiro

Purpose: To investigate the feasibility of boron neutron capture therapy (BNCT) for malignant pleural mesothelioma (MPM) from a viewpoint of dose distribution analysis using Simulation Environment for Radiotherapy Applications (SERA), a currently available BNCT treatment planning system. Methods and Materials: The BNCT treatment plans were constructed for 3 patients with MPM using the SERA system, with 2 opposed anterior-posterior beams. The {sup 1}B concentrations in the tumor and normal lung in this study were assumed to be 84 and 24 ppm, respectively, and were derived from data observed in clinical trials. The maximum, mean, and minimum doses to the tumorsmore » and the normal lung were assessed for each plan. The doses delivered to 5% and 95% of the tumor volume, D{sub 05} and D{sub 95}, were adopted as the representative dose for the maximum and minimum dose, respectively. Results: When the D{sub 05} to the normal ipsilateral lung was 5 Gy-Eq, the D{sub 95} and mean doses delivered to the normal lung were 2.2-3.6 and 3.5-4.2 Gy-Eq, respectively. The mean doses delivered to the tumors were 22.4-27.2 Gy-Eq. The D{sub 05} and D{sub 95} doses to the tumors were 9.6-15.0 and 31.5-39.5 Gy-Eq, respectively. Conclusions: From a viewpoint of the dose-distribution analysis, BNCT has the possibility to be a promising treatment for MPM patients who are inoperable because of age and other medical illnesses.« less

Mast cell phenotypes in the allograft after lung transplantation.

PubMed

Banga, Amit; Han, Yingchun; Wang, Xiaofeng; Hsieh, Fred H

2016-07-01

The burden of mast cell (MC) infiltration and their phenotypes, MC-tryptase (MCT ) and MC-tryptase/chymase (MCTC ), after lung transplantation (LT) has not been evaluated in human studies. We reviewed 20 transbronchial lung biopsy (TBLB) specimen from patients with early normal allograft (<6 months post-LT, n=5), late normal allograft (>6 months, n=5), A2 or worse acute cellular rejection (ACR, n=5), and chronic lung allograft dysfunction (CLAD, n=5). Slides were immunostained for tryptase and chymase. Total MC, MCT , MCTC and MCTC to-MCT ratio were compared between the four groups using a generalized linear mixed model. Irrespective of clinicopathologic diagnosis, MC burden tends to increase with time (r(2) =.56, P=.009). MCTC phenotype was significantly increased in the CLAD group (8.2±4.9 cells per HPF) in comparison with the other three groups (early normal: 1.6±1.7, P=.0026; late normal: 2.5±2.3, P=.048; ACR: 2.7±3.5, P=.021). Further, the ratio of MCTC to MCT was significantly increased in CLAD group as compared to the other three groups (P<.001 for all comparisons). The burden of MC may increase in the allograft as function of time. Patients with CLAD have an increased relative and absolute burden of MCTC phenotype MC. Future studies are needed to confirm these findings and evaluate the potential pathologic role of MCTC in allograft dysfunction. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Neonatal lungs--can absolute lung resistivity be determined non-invasively?

PubMed

Brown, B H; Primhak, R A; Smallwood, R H; Milnes, P; Narracott, A J; Jackson, M J

2002-07-01

The electrical resistivity of lung tissue can be related to the structure and composition of the tissue and also to the air content. Conditions such as pulmonary oedema and emphysema have been shown to change lung resistivity. However, direct access to the lungs to enable resistivity to be measured is very difficult. We have developed a new method of using electrical impedance tomographic (EIT) measurements on a group of 142 normal neonates to determine the absolute resistivity of lung tissue. The methodology involves comparing the measured EIT data with that from a finite difference model of the thorax in which lung tissue resistivity can be changed. A mean value of 5.7 +/- 1.7 omega(m) was found over the frequency range 4 kHz to 813 kHz. This value is lower than that usually given for adult lung tissue but consistent with the literature on the composition of the neonatal lung and with structural modelling.

SYNERGY-AI: Artificial Intelligence Based Precision Oncology Clinical Trial Matching and Registry

ClinicalTrials.gov

2018-02-24

Cancer, Metastatic; Cancer; Cancer of Pancreas; Cancer of Liver; Cancer of Stomach; Cancer Liver; Cancer of Rectum; Cancer of Kidney; Cancer of Esophagus; Cancer of Cervix; Cancer of Colon; Cancer of Larynx; Cancer, Lung; Cancer, Breast; Cancer, Advanced; Cancer Prostate; Cancer of Neck; Cancer of Skin; Neuroendocrine Tumors; Carcinoma; Mismatch Repair Deficiency; BRCA Gene Rearrangement; Non Hodgkin Lymphoma; Leukemia; Non Small Cell Lung Cancer; Cholangiocarcinoma; Glioblastoma; Central Nervous System Tumor; Melanoma; Urothelial Carcinoma; Bladder Cancer; Ovarian Cancer; Endometrial Cancer; Testicular Cancer; Breast Cancer

In vivo imaging of pulmonary nodule and vasculature using endoscopic co-registered optical coherence tomography and autofluorescence imaging (Conference Presentation)

NASA Astrophysics Data System (ADS)

Pahlevaninezhad, Hamid; Lee, Anthony; Hohert, Geoffrey; Schwartz, Carely; Shaipanich, Tawimas; Ritchie, Alexander J.; Zhang, Wei; MacAulay, Calum E.; Lam, Stephen; Lane, Pierre M.

2016-03-01

Peripheral lung nodules found by CT-scans are difficult to localize and biopsy bronchoscopically particularly for those ≤ 2 cm in diameter. In this work, we present the results of endoscopic co-registered optical coherence tomography and autofluorescence imaging (OCT-AFI) of normal and abnormal peripheral airways from 40 patients using 0.9 mm diameter fiber optic rotary pullback catheter. Optical coherence tomography (OCT) can visualize detailed airway morphology endoscopically in the lung periphery. Autofluorescence imaging (AFI) can visualize fluorescing tissue components such as collagen and elastin, enabling the detection of airway lesions with high sensitivity. Results indicate that AFI of abnormal airways is different from that of normal airways, suggesting that AFI can provide a sensitive visual presentation for rapidly identifying possible sites of pulmonary nodules. AFI can also rapidly visualize in vivo vascular networks using fast scanning parameters resulting in vascular-sensitive imaging with less breathing/cardiac motion artifacts compared to Doppler OCT imaging. It is known that tumor vasculature is structurally and functionally different from normal vessels. Thus, AFI can be potentially used for differentiating normal and abnormal lung vasculature for studying vascular remodeling.

A concordance index for matched case-control studies with applications in cancer risk.

PubMed

Brentnall, Adam R; Cuzick, Jack; Field, John; Duffy, Stephen W

2015-02-10

In unmatched case-control studies, the area under the receiver operating characteristic (ROC) curve (AUC) may be used to measure how well a variable discriminates between cases and controls. The AUC is sometimes used in matched case-control studies by ignoring matching, but it lacks interpretation because it is not based on an estimate of the ROC for the population of interest. We introduce an alternative measure of discrimination that is the concordance of risk factors conditional on the matching factors. Parametric and non-parametric estimators are given for different matching scenarios, and applied to real data from breast and lung cancer case-control studies. Diagnostic plots to verify the constancy of discrimination over matching factors are demonstrated. The proposed simple measure is easy to use, interpret, more efficient than unmatched AUC statistics and may be applied to compare the conditional discrimination performance of risk factors. Copyright © 2014 John Wiley & Sons, Ltd.

Expression of TMPRSS4 in non-small cell lung cancer and its modulation by hypoxia

PubMed Central

NGUYEN, TRI-HUNG; WEBER, WILLIAM; HAVARI, EVIS; CONNORS, TIMOTHY; BAGLEY, REBECCA G.; McLAREN, RAJASHREE; NAMBIAR, PRASHANT R.; MADDEN, STEPHEN L.; TEICHER, BEVERLY A.; ROBERTS, BRUCE; KAPLAN, JOHANNE; SHANKARA, SRINIVAS

2012-01-01

Overexpression of TMPRSS4, a cell surface-associated transmembrane serine protease, has been reported in pancreatic, colorectal and thyroid cancers, and has been implicated in tumor cell migration and metastasis. Few reports have investigated both TMPRSS4 gene expression levels and the protein products. In this study, quantitative RT-PCR and protein staining were used to assess TMPRSS4 expression in primary non-small cell lung carcinoma (NSCLC) tissues and in lung tumor cell lines. At the transcriptional level, TMPRSS4 message was significantly elevated in the majority of human squamous cell and adenocarcinomas compared with normal lung tissues. Staining of over 100 NSCLC primary tumor and normal specimens with rabbit polyclonal anti-TMPRSS4 antibodies confirmed expression at the protein level in both squamous cell and adenocarcinomas with little or no staining in normal lung tissues. Human lung tumor cell lines expressed varying levels of TMPRSS4 mRNA in vitro. Interestingly, tumor cell lines with high levels of TMPRSS4 mRNA failed to show detectable TMPRSS4 protein by either immunoblotting or flow cytometry. However, protein levels were increased under hypoxic culture conditions suggesting that hypoxia within the tumor microenvironment may upregulate TMPRSS4 protein expression in vivo. This was supported by the observation of TMPRSS4 protein in xenograft tumors derived from the cell lines. In addition, staining of human squamous cell carcinoma samples for carbonic anhydrase IX (CAIX), a hypoxia marker, showed TMPRSS4 positive cells adjacent to CAIX positive cells. Overall, these results indicate that the cancer-associated TMPRSS4 protein is overexpressed in NSCLC and may represent a potential therapeutic target. PMID:22692880

Collagen and elastin cross-linking is altered during aberrant late lung development associated with hyperoxia.

PubMed

Mižíková, Ivana; Ruiz-Camp, Jordi; Steenbock, Heiko; Madurga, Alicia; Vadász, István; Herold, Susanne; Mayer, Konstantin; Seeger, Werner; Brinckmann, Jürgen; Morty, Rory E

2015-06-01

Maturation of the lung extracellular matrix (ECM) plays an important role in the formation of alveolar gas exchange units. A key step in ECM maturation is cross-linking of collagen and elastin, which imparts stability and functionality to the ECM. During aberrant late lung development in bronchopulmonary dysplasia (BPD) patients and animal models of BPD, alveolarization is blocked, and the function of ECM cross-linking enzymes is deregulated, suggesting that perturbed ECM cross-linking may impact alveolarization. In a hyperoxia (85% O2)-based mouse model of BPD, blunted alveolarization was accompanied by alterations to lung collagen and elastin levels and cross-linking. Total collagen levels were increased (by 63%). The abundance of dihydroxylysinonorleucine collagen cross-links and the dihydroxylysinonorleucine-to-hydroxylysinonorleucine ratio were increased by 11 and 18%, respectively, suggestive of a profibrotic state. In contrast, insoluble elastin levels and the abundance of the elastin cross-links desmosine and isodesmosine in insoluble elastin were decreased by 35, 30, and 21%, respectively. The lung collagen-to-elastin ratio was threefold increased. Treatment of hyperoxia-exposed newborn mice with the lysyl oxidase inhibitor β-aminopropionitrile partially restored normal collagen levels, normalized the dihydroxylysinonorleucine-to-hydroxylysinonorleucine ratio, partially normalized desmosine and isodesmosine cross-links in insoluble elastin, and partially restored elastin foci structure in the developing septa. However, β-aminopropionitrile administration concomitant with hyperoxia exposure did not improve alveolarization, evident from unchanged alveolar surface area and alveoli number, and worsened septal thickening (increased by 12%). These data demonstrate that collagen and elastin cross-linking are perturbed during the arrested alveolarization of developing mouse lungs exposed to hyperoxia. Copyright © 2015 the American Physiological Society.

Lung pair phantom

DOEpatents

Olsen, Peter C.; Gordon, N. Ross; Simmons, Kevin L.

1993-01-01

The present invention is a material and method of making the material that exhibits improved radiation attenuation simulation of real lungs, i.e., an "authentic lung tissue" or ALT phantom. Specifically, the ALT phantom is a two-part polyurethane medium density foam mixed with calcium carbonate, potassium carbonate if needed for K-40 background, lanthanum nitrate, acetone, and a nitrate or chloride form of a radionuclide. This formulation is found to closely match chemical composition and linear attenuation of real lungs. The ALT phantom material is made according to established procedures but without adding foaming agents or preparing thixotropic concentrate and with a modification for ensuring uniformity of density of the ALT phantom that is necessary for accurate simulation. The modification is that the polyurethane chemicals are mixed at a low temperature prior to pouring the polyurethane mixture into the mold.

Lung pair phantom

DOEpatents

Olsen, P.C.; Gordon, N.R.; Simmons, K.L.

1993-11-30

The present invention is a material and method of making the material that exhibits improved radiation attenuation simulation of real lungs, i.e., an ``authentic lung tissue`` or ALT phantom. Specifically, the ALT phantom is a two-part polyurethane medium density foam mixed with calcium carbonate, potassium carbonate if needed for K-40 background, lanthanum nitrate, acetone, and a nitrate or chloride form of a radionuclide. This formulation is found to closely match chemical composition and linear attenuation of real lungs. The ALT phantom material is made according to established procedures but without adding foaming agents or preparing thixotropic concentrate and with a modification for ensuring uniformity of density of the ALT phantom that is necessary for accurate simulation. The modification is that the polyurethane chemicals are mixed at a low temperature prior to pouring the polyurethane mixture into the mold.

Relationship between linear and nonlinear dynamics of heart rate and impairment of lung function in COPD patients.

PubMed

Mazzuco, Adriana; Medeiros, Wladimir Musetti; Sperling, Milena Pelosi Rizk; de Souza, Aline Soares; Alencar, Maria Clara Noman; Arbex, Flávio Ferlin; Neder, José Alberto; Arena, Ross; Borghi-Silva, Audrey

2015-01-01

In chronic obstructive pulmonary disease (COPD), functional and structural impairment of lung function can negatively impact heart rate variability (HRV); however, it is unknown if static lung volumes and lung diffusion capacity negatively impacts HRV responses. We investigated whether impairment of static lung volumes and lung diffusion capacity could be related to HRV indices in patients with moderate to severe COPD. Sixteen sedentary males with COPD were enrolled in this study. Resting blood gases, static lung volumes, and lung diffusion capacity for carbon monoxide (DLCO) were measured. The RR interval (RRi) was registered in the supine, standing, and seated positions (10 minutes each) and during 4 minutes of a respiratory sinus arrhythmia maneuver (M-RSA). Delta changes (Δsupine-standing and Δsupine-M-RSA) of the standard deviation of normal RRi, low frequency (LF, normalized units [nu]) and high frequency (HF [nu]), SD1, SD2, alpha1, alpha2, and approximate entropy (ApEn) indices were calculated. HF, LF, SD1, SD2, and alpha1 deltas significantly correlated with forced expiratory volume in 1 second, DLCO, airway resistance, residual volume, inspiratory capacity/total lung capacity ratio, and residual volume/total lung capacity ratio. Significant and moderate associations were also observed between LF/HF ratio versus total gas volume (%), r=0.53; LF/HF ratio versus residual volume, %, r=0.52; and HF versus total gas volume (%), r=-0.53 (P<0.05). Linear regression analysis revealed that ΔRRi supine-M-RSA was independently related to DLCO (r=-0.77, r (2)=0.43, P<0.05). Responses of HRV indices were more prominent during M-RSA in moderate to severe COPD. Moreover, greater lung function impairment was related to poorer heart rate dynamics. Finally, impaired lung diffusion capacity was related to an altered parasympathetic response in these patients.

Noninvasive Tissue Characterization of Lung Tumors Using Integrated Backscatter Intravascular Ultrasound: An Ex Vivo Comparative Study With Pathological Diagnosis.

PubMed

Ito, Fumitaka; Kawasaki, Masanori; Ohno, Yasushi; Toyoshi, Sayaka; Morishita, Megumi; Kaito, Daizo; Yanase, Komei; Funaguchi, Norihiko; Asano, Masahiro; Endo, Junki; Mori, Hidenori; Kobayashi, Kazuhiro; Nishigaki, Kazuhiko; Miyazaki, Tatsuhiko; Takemura, Genzou; Minatoguchi, Shinya

2016-05-01

Endobronchial ultrasonography (EBUS) facilitates a lung cancer diagnosis. However, qualitative tissue characterization of lung tumors is difficult using EBUS. Integrated backscatter (IBS) is an ultrasound technique that calculates the power of the ultrasound signal to characterize tissue components in coronary arteries. We hypothesized that qualitative diagnosis of lung tumors is possible using the IBS technique. The aim of the present study was to elucidate whether the IBS technique can be used in lung tissue diagnoses. Thirty-five consecutive patients who underwent surgery for lung cancer were prospectively enrolled. Surgical specimens of the lung and the tumor tissue were obtained, and the IBS values were measured within 48 h after surgery. Histologic images of lung and tumor tissues were compared with IBS values, and the relative interstitial area according to results of Masson's trichrome staining were determined by using an imaging processor. The IBS values in tumor tissue were significantly lower than those in normal lung tissue (-50.9 ± 2.6 dB and -47.6 ± 2.6 dB, respectively; P < .001). The IBS values of adenocarcinomas associated with a good 5-year survival rate were higher than those of non-adenocarcinomas (-48.1 ± 1.6 dB and -52.6 ± 1.4 dB; P < .001). There were significant correlations between the IBS values and the relative interstitial area or micro air area in tumor (r = 0.53 and r = 0.67; P < .01). After combining normal lung tissue and adenocarcinomas with a good prognosis, the sensitivity and specificity for establishing the presence of lung tumors were 84% and 85%. Qualitative diagnosis of lung tumors was possible, with a sensitivity of 84% and a specificity of 85%, using the ultrasound IBS technique. Copyright © 2016 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.