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1.  Updates and Controversies in the Rapidly Evolving Field of Lung Cancer Screening, Early Detection, and Chemoprevention 
Cancers  2014;6(2):1157-1179.
Lung cancer remains the leading cause of cancer-related death in the United States. Cigarette smoking is a well-recognized risk factor for lung cancer, and a sustained elevation of lung cancer risk persists even after smoking cessation. Despite identifiable risk factors, there has been minimal improvement in mortality for patients with lung cancer primarily stemming from diagnosis at a late stage when there are few effective therapeutic options. Early detection of lung cancer and effective screening of high-risk individuals may help improve lung cancer mortality. While low dose computerized tomography (LDCT) screening of high risk smokers has been shown to reduce lung cancer mortality, the high rates of false positives and potential for over-diagnosis have raised questions on how to best implement lung cancer screening. The rapidly evolving field of lung cancer screening and early-detection biomarkers may ultimately improve the ability to diagnose lung cancer in its early stages, identify smokers at highest-risk for this disease, and target chemoprevention strategies. This review aims to provide an overview of the opportunities and challenges related to lung cancer screening, the field of biomarker development for early lung cancer detection, and the future of lung cancer chemoprevention.
PMCID: PMC4074822  PMID: 24840047
lung cancer; screening; early detection; chemoprevention
2.  Airway PI3K Pathway Activation Is an Early and Reversible Event in Lung Cancer Development 
Science translational medicine  2010;2(26):26ra25.
Although only a subset of smokers develop lung cancer, we cannot determine which smokers are at highest risk for cancer development, nor do we know the signaling pathways altered early in the process of tumorigenesis in these individuals. On the basis of the concept that cigarette smoke creates a molecular field of injury throughout the respiratory tract, this study explores oncogenic pathway deregulation in cytologically normal proximal airway epithelial cells of smokers at risk for lung cancer. We observed a significant increase in a genomic signature of phosphatidylinositol 3-kinase (PI3K) pathway activation in the cytologically normal bronchial airway of smokers with lung cancer and smokers with dysplastic lesions, suggesting that PI3K is activated in the proximal airway before tumorigenesis. Further, PI3K activity is decreased in the airway of high-risk smokers who had significant regression of dysplasia after treatment with the chemopreventive agent myo-inositol, and myo-inositol inhibits the PI3K pathway in vitro. These results suggest that deregulation of the PI3K pathway in the bronchial airway epithelium of smokers is an early, measurable, and reversible event in the development of lung cancer and that genomic profiling of these relatively accessible airway cells may enable personalized approaches to chemoprevention and therapy. Our work further suggests that additional lung cancer chemoprevention trials either targeting the PI3K pathway or measuring airway PI3K activation as an intermediate endpoint are warranted.
PMCID: PMC3694402  PMID: 20375364
3.  The Field of Tissue Injury in the Lung and Airway 
The concept of field cancerization was first introduced over six decades ago in the setting of oral cancer. Later, field cancerization involving histologic and molecular changes of neoplasms and adjacent tissue began to be characterized in smokers with or without lung cancer. Investigators also described a diffuse, non-neoplastic field of molecular injury throughout the respiratory tract that is attributable to cigarette smoking and susceptibility to smoking-induced lung disease. The potential molecular origins of field cancerization and the field of injury following cigarette smoke exposure in lung and airway epithelia are critical to understanding the impact of the field of injury on clinical diagnostics and therapeutics for smoking-induced lung disease.
PMCID: PMC2705781  PMID: 19138985
field of injury; field cancerization; lung cancer; tobacco smoke; molecular diagnosis and prognosis
4.  Comparison of Proteomic and Transcriptomic Profiles in the Bronchial Airway Epithelium of Current and Never Smokers 
PLoS ONE  2009;4(4):e5043.
Although prior studies have demonstrated a smoking-induced field of molecular injury throughout the lung and airway, the impact of smoking on the airway epithelial proteome and its relationship to smoking-related changes in the airway transcriptome are unclear.
Methodology/Principal Findings
Airway epithelial cells were obtained from never (n = 5) and current (n = 5) smokers by brushing the mainstem bronchus. Proteins were separated by one dimensional polyacrylamide gel electrophoresis (1D-PAGE). After in-gel digestion, tryptic peptides were processed via liquid chromatography/ tandem mass spectrometry (LC-MS/MS) and proteins identified. RNA from the same samples was hybridized to HG-U133A microarrays. Protein detection was compared to RNA expression in the current study and a previously published airway dataset. The functional properties of many of the 197 proteins detected in a majority of never smokers were similar to those observed in the never smoker airway transcriptome. LC-MS/MS identified 23 proteins that differed between never and current smokers. Western blotting confirmed the smoking-related changes of PLUNC, P4HB1, and uteroglobin protein levels. Many of the proteins differentially detected between never and current smokers were also altered at the level of gene expression in this cohort and the prior airway transcriptome study. There was a strong association between protein detection and expression of its corresponding transcript within the same sample, with 86% of the proteins detected by LC-MS/MS having a detectable corresponding probeset by microarray in the same sample. Forty-one proteins identified by LC-MS/MS lacked detectable expression of a corresponding transcript and were detected in ≤5% of airway samples from a previously published dataset.
1D-PAGE coupled with LC-MS/MS effectively profiled the airway epithelium proteome and identified proteins expressed at different levels as a result of cigarette smoke exposure. While there was a strong correlation between protein and transcript detection within the same sample, we also identified proteins whose corresponding transcripts were not detected by microarray. This noninvasive approach to proteomic profiling of airway epithelium may provide additional insights into the field of injury induced by tobacco exposure.
PMCID: PMC2664466  PMID: 19357784
5.  Smoking-induced gene expression changes in the bronchial airway are reflected in nasal and buccal epithelium 
BMC Genomics  2008;9:259.
Cigarette smoking is a leading cause of preventable death and a significant cause of lung cancer and chronic obstructive pulmonary disease. Prior studies have demonstrated that smoking creates a field of molecular injury throughout the airway epithelium exposed to cigarette smoke. We have previously characterized gene expression in the bronchial epithelium of never smokers and identified the gene expression changes that occur in the mainstem bronchus in response to smoking. In this study, we explored relationships in whole-genome gene expression between extrathorcic (buccal and nasal) and intrathoracic (bronchial) epithelium in healthy current and never smokers.
Using genes that have been previously defined as being expressed in the bronchial airway of never smokers (the "normal airway transcriptome"), we found that bronchial and nasal epithelium from non-smokers were most similar in gene expression when compared to other epithelial and nonepithelial tissues, with several antioxidant, detoxification, and structural genes being highly expressed in both the bronchus and nose. Principle component analysis of previously defined smoking-induced genes from the bronchus suggested that smoking had a similar effect on gene expression in nasal epithelium. Gene set enrichment analysis demonstrated that this set of genes was also highly enriched among the genes most altered by smoking in both nasal and buccal epithelial samples. The expression of several detoxification genes was commonly altered by smoking in all three respiratory epithelial tissues, suggesting a common airway-wide response to tobacco exposure.
Our findings support a relationship between gene expression in extra- and intrathoracic airway epithelial cells and extend the concept of a smoking-induced field of injury to epithelial cells that line the mouth and nose. This relationship could potentially be utilized to develop a non-invasive biomarker for tobacco exposure as well as a non-invasive screening or diagnostic tool providing information about individual susceptibility to smoking-induced lung diseases.
PMCID: PMC2435556  PMID: 18513428
6.  Reversible and permanent effects of tobacco smoke exposure on airway epithelial gene expression 
Genome Biology  2007;8(9):R201.
Oligonucleotide microarray analysis revealed 175 genes that are differentially expressed in large airway epithelial cells of people who currently smoke compared with those who never smoked, with 28 classified as irreversible, 6 as slowly reversible, and 139 as rapidly reversible.
Tobacco use remains the leading preventable cause of death in the US. The risk of dying from smoking-related diseases remains elevated for former smokers years after quitting. The identification of irreversible effects of tobacco smoke on airway gene expression may provide insights into the causes of this elevated risk.
Using oligonucleotide microarrays, we measured gene expression in large airway epithelial cells obtained via bronchoscopy from never, current, and former smokers (n = 104). Linear models identified 175 genes differentially expressed between current and never smokers, and classified these as irreversible (n = 28), slowly reversible (n = 6), or rapidly reversible (n = 139) based on their expression in former smokers. A greater percentage of irreversible and slowly reversible genes were down-regulated by smoking, suggesting possible mechanisms for persistent changes, such as allelic loss at 16q13. Similarities with airway epithelium gene expression changes caused by other environmental exposures suggest that common mechanisms are involved in the response to tobacco smoke. Finally, using irreversible genes, we built a biomarker of ever exposure to tobacco smoke capable of classifying an independent set of former and current smokers with 81% and 100% accuracy, respectively.
We have categorized smoking-related changes in airway gene expression by their degree of reversibility upon smoking cessation. Our findings provide insights into the mechanisms leading to reversible and persistent effects of tobacco smoke that may explain former smokers increased risk for developing tobacco-induced lung disease and provide novel targets for chemoprophylaxis. Airway gene expression may also serve as a sensitive biomarker to identify individuals with past exposure to tobacco smoke.
PMCID: PMC2375039  PMID: 17894889
7.  Detection of fibrinogen-fibrin degradation products by counterelectrophoresis  
Journal of Clinical Pathology  1972;25(9):754-756.
Counterelectrophoresis using a discontinuous buffer system permits detection of fibrinogen-fibrin degradation products (FDP) under a variety of clinical circumstances. The method is sensitive, reliable, and is easily performed using conventional equipment in any clinical laboratory assuming the responsibility for assaying fibrinogen-fibrin degradation products.
PMCID: PMC477503  PMID: 5086217
8.  Acromegalic pneumonomegaly: lung growth in the adult 
Journal of Clinical Investigation  1970;49(6):1051-1060.
Lung size was evaluated with pulmonary function tests in 10 patients with acromegaly, 1 pituitary giant, and 1 patient who had acromegaly but now has hypopituitarism. In the six acromegalic men all lung volumes were increased. The average values and per cent of predicted were total lung capacity 9.1 liters. 139%; functional residual capacity 5.2 liters, 145%; vital capacity 6.0 liters, 134%; and tissue volume 1.1 liters. There was no evidence of airflow obstruction or air trapping. Anatomic dead space was increased in proportion to the large lung volumes. Lung compliance was increased, averaging 0.43 liters/cm H2O, but lung elastic recoil was normal. These studies show that the lung is involved in the general visceromegaly of acromegaly and that lung size increases in acromegalic men as a result of actual lung growth. Despite the large lung volumes, diffusing capacity was normal suggesting that lung growth resulted from an increase in the size rather than from an increase in the number of alveoli. In contrast to the acromegalic men, lung volumes, anatomic dead space and tissue volume were normal in four acromegalic women, suggesting that sex hormones may modify the effect of growth hormone on the lung. Lung size was large in the pituitary giant but lung volumes were normal according to predicted values based on the patient's great height. Lung volumes were normal in the one male who had been acromegalic but who has been hypopituitary for 21 yr. The role of growth hormone in normal postnatal lung growth and in the maintainance of normal lung size remains to be defined.
PMCID: PMC322573  PMID: 5422011
9.  Differential reactivity in the pulmonary circulation 
Journal of Clinical Investigation  1968;47(4):800-808.
A new method for relating regional intravascular resistance to pulmonary arterial, capillary, and venous pressure and volume was used to evaluate local differences of reactivity in the pulmonary blood vessels in the isolated lung lobe of the dog.
Intravascular infusion of isoproterenol caused active dilatation of pulmonary arteries and veins. Capillary conductance (1/resistance) and volume increased, possibly as a result of the opening of previously closed capillaries. Serotonin infusion caused active constriction of both the pulmonary arteries and veins. A low dose of serotonin (1.5 μg/min per kg) caused predominant constriction of whichever vessels were upstream (arteries during forward perfusion, veins during reverse perfusion). A high dose of serotonin (4.5-5.0 μg/min per kg) caused constriction of both upstream and downstream vessels. Metabolic inactivation of serotonin by the lung is suggested as an explanation for these observations. Histamine infusion caused predominant venous constriction whether veins were upstream or downstream. Capillary volume and conductance decreased during forward and reverse perfusion, perhaps as a result of pericapillary edema formation. Large arterial vessels constricted slightly, whereas small arterial vessels appeared to be passively dilated.
PMCID: PMC297230  PMID: 5641619
10.  Longitudinal distribution of vascular resistance in the pulmonary arteries, capillaries, and veins 
Journal of Clinical Investigation  1968;47(4):783-799.
A new method has been described for measuring the pressure and resistance to blood flow in the pulmonary arteries, capillaries, and veins. Studies were performed in dog isolated lung lobes perfused at constant flow with blood from a donor dog. Pulmonary artery and vein volume and total lobar blood volume were measured by the ether plethysmograph and dyedilution techniques. The longitudinal distribution of vascular resistance was determined by analyzing the decrease in perfusion pressure caused by a bolus of low viscosity liquid introduced into the vascular inflow of the lobe.
The pulmonary arteries were responsible for 46% of total lobar vascular resistance, whereas the pulmonary capillaries and veins accounted for 34 and 20% of total lobar vascular resistance respectively. Vascular resistance was 322 dynes ·sec·cm-5/ml of vessel in the lobar pulmonary arteries, 112 dynes·sec·cm-5/ml in the pulmonary capillaries, and 115 dynes·sec·cm-5/ml in the lobar pulmonary veins. Peak vascular resistivity (resistance per milliliter of volume) was in an area 2 ml proximal to the capillary bed, but resistivity was high throughout the pulmonary arterial tree. The pulmonary arteries accounted for approximately 50% of vascular resistance upstream from the sluice point when alveolar pressure exceeded venous pressure.
The method described provides the first measurements of pulmonary capillary pressure. Mid-capillary pressure averaged 13.3 cm H2O, pulmonary artery pressure averaged 20.4 cm H2O, and pulmonary vein pressure averaged 9.2 cm H2O. These techniques also provide a way of analyzing arterial, capillary, and venous responses to various pharmacologic and physiologic stimuli.
PMCID: PMC297229  PMID: 4868032

Results 1-14 (14)