Diseases Commons^™

Web Tool For Estimating The Cancer Hazard Rates In Aging., Tengiz Mdzinarishvili, Alexander Sherman, Oleg Shats, Simon Sherman

Journal Articles: Eppley Institute

A computational approach for estimating the overall, population, and individual cancer hazard rates was developed. The population rates characterize a risk of getting cancer of a specific site/type, occurring within an age-specific group of individuals from a specified population during a distinct time period. The individual rates characterize an analogous risk but only for the individuals susceptible to cancer. The approach uses a novel regularization and anchoring technique to solve an identifiability problem that occurs while determining the age, period, and cohort (APC) effects. These effects are used to estimate the overall rate, and to estimate the population and individual …

The Omega-3 Fatty Acid Docosahexaenoic Acid Attenuates Organic Dust-Induced Airway Inflammation., Tara M. Nordgren, Taylor D. Friemel, Art J. Heires, Jill A. Poole, Todd A. Wyatt, Debra J. Romberger

Journal Articles: Pulmonary & Critical Care Med

Workers exposed to organic dusts from concentrated animal feeding operations (CAFOs) are at risk for developing airway inflammatory diseases. Available preventative and therapeutic measures for alleviating dust-induced lung disease are inadequate. Because omega-3 fatty acids can mitigate inflammatory processes, we aimed to determine whether nutritional supplementation with the omega-3 fatty acid docosahexaenoic acid (DHA) could reduce the airway inflammatory consequences of exposures to organic dust. Aqueous extracts of organic dusts from swine CAFOs (ODE) were utilized. In DHA-pretreated human bronchial epithelial cells, lung fibroblasts, monocyte cell cultures, and precision-cut murine lung slices, we found that DHA pretreatment dose-dependently decreased ODE-induced …

Nerve Growth Factor Regulates Neurolymphatic Remodeling During Corneal Inflammation And Resolution., Darci M. Fink, Alicia L. Connor, Philip M. Kelley, Maria M. Steele, Michael A. Hollingsworth, Richard M. Tempero

Journal Articles: Eppley Institute

The cellular and physiologic mechanisms that regulate the resolution of inflammation remain poorly defined despite their widespread importance in improving inflammatory disease outcomes. We studied the resolution of two cardinal signs of inflammation-pain and swelling-by investigating molecular mechanisms that regulate neural and lymphatic vessel remodeling during the resolution of corneal inflammation. A mouse model of corneal inflammation and wound recovery was developed to study this process in vivo. Administration of nerve growth factor (NGF) increased pain sensation and inhibited neural remodeling and lymphatic vessel regression processes during wound recovery. A complementary in vivo approach, the corneal micropocket assay, revealed that …

Family-Specific, Novel, Deleterious Germline Variants Provide A Rich Resource To Identify Genetic Predispositions For Brcax Familial Breast Cancer., Hongxiu Wen, Yeong C. Kim, Carrie Snyder, Fengxia Xiao, Elizabeth A. Fleissner, Dina Becirovic, Jiangtao Luo, Bradley Downs, Simon Sherman, Kenneth Cowan, Henry T. Lynch, San Ming Wang

Journal Articles: Eppley Institute

BACKGROUND: Genetic predisposition is the primary risk factor for familial breast cancer. For the majority of familial breast cancer, however, the genetic predispositions remain unknown. All newly identified predispositions occur rarely in disease population, and the unknown genetic predispositions are estimated to reach up to total thousands. Family unit is the basic structure of genetics. Because it is an autosomal dominant disease, individuals with a history of familial breast cancer must carry the same genetic predisposition across generations. Therefore, focusing on the cases in lineages of familial breast cancer, rather than pooled cases in disease population, is expected to provide …

Heuristic Modeling Of Carcinogenesis For The Population With Dichotomous Susceptibility To Cancer: A Pancreatic Cancer Example., Tengiz Mdzinarishvili, Simon Sherman

Journal Articles: Eppley Institute

At present, carcinogenic models imply that all individuals in a population are susceptible to cancer. These models either ignore a fall of the cancer incidence rate at old ages, or use some poorly identifiable parameters for its accounting. In this work, a new heuristic model is proposed. The model assumes that, in a population, only a small fraction (pool) of individuals is susceptible to cancer and decomposes the problem of the carcinogenic modeling on two sequentially solvable problems: (i) determination of the age-specific hazard rate in individuals susceptible to cancer (individual hazard rate) from the observed hazard rate in the …

Metabolic Reprogramming Induced By Ketone Bodies Diminishes Pancreatic Cancer Cachexia, Surendra K. Shukla, Teklab Gebregiworgis, Vinee Purohit, Nina V. Chaika, Venugopal Gunda, Prakash Radhakrishnan, Kamiya Mehla, Iraklis I. Pipinos, Robert Powers, Fang Yu, Pankaj K. Singh

Journal Articles: Eppley Institute

BACKGROUND: Aberrant energy metabolism is a hallmark of cancer. To fulfill the increased energy requirements, tumor cells secrete cytokines/factors inducing muscle and fat degradation in cancer patients, a condition known as cancer cachexia. It accounts for nearly 20% of all cancer-related deaths. However, the mechanistic basis of cancer cachexia and therapies targeting cancer cachexia thus far remain elusive. A ketogenic diet, a high-fat and low-carbohydrate diet that elevates circulating levels of ketone bodies (i.e., acetoacetate, β-hydroxybutyrate, and acetone), serves as an alternative energy source. It has also been proposed that a ketogenic diet leads to systemic metabolic changes. Keeping in …

Non-Emphysematous Chronic Obstructive Pulmonary Disease Is Associated With Diabetes Mellitus, Craig P. Hersh, Barry J. Make, David A. Lynch, R. Graham Barr, Russell P. Bowler, Peter M.A. Calverley, Peter J. Castaldi, Michael H. Cho, Harvey O. Coxson, Dawn L. Demeo, Marilyn G. Foreman, Meilan K. Han, Benjamin J. Harshfield, John E. Hokanson, Sharon Lutz, Joe W. Ramsdell, Elizabeth A. Regan, Stephen I. Rennard, Joyce D. Schroeder, Frank C. Sciurba, Robert M. Steiner, Ruth Tal-Singer, Edwin Van Beek, Edwin K. Silverman, James D. Crapo, Copdgene And Eclipse Investigators

Journal Articles: Pulmonary & Critical Care Med

BACKGROUND: Chronic obstructive pulmonary disease (COPD) has been classically divided into blue bloaters and pink puffers. The utility of these clinical subtypes is unclear. However, the broader distinction between airway-predominant and emphysema-predominant COPD may be clinically relevant. The objective was to define clinical features of emphysema-predominant and non-emphysematous COPD patients.

METHODS: Current and former smokers from the Genetic Epidemiology of COPD Study (COPDGene) had chest computed tomography (CT) scans with quantitative image analysis. Emphysema-predominant COPD was defined by low attenuation area at -950 Hounsfield Units (LAA-950) ≥10%. Non-emphysematous COPD was defined by airflow obstruction with minimal to no emphysema (LAA-950 …

Sexually-Dimorphic Targeting Of Functionally-Related Genes In Copd, Kimberly Glass, John Quackenbush, Edwin K. Silverman, Bartolome Celli, Stephen I. Rennard, Guo-Cheng Yuan, Dawn L. Demeo

Journal Articles: Pulmonary & Critical Care Med

BACKGROUND: There is growing evidence that many diseases develop, progress, and respond to therapy differently in men and women. This variability may manifest as a result of sex-specific structures in gene regulatory networks that influence how those networks operate. However, there are few methods to identify and characterize differences in network structure, slowing progress in understanding mechanisms driving sexual dimorphism.

RESULTS: Here we apply an integrative network inference method, PANDA (Passing Attributes between Networks for Data Assimilation), to model sex-specific networks in blood and sputum samples from subjects with Chronic Obstructive Pulmonary Disease (COPD). We used a jack-knifing approach to …

The Association Of Plasma Biomarkers With Computed Tomography-Assessed Emphysema Phenotypes, Brendan J. Carolan, Grant Hughes, Jarrett Morrow, Craig P. Hersh, Wanda K. O'Neal, Stephen I. Rennard, Sreekumar G. Pillai, Paula Belloni, Debra A. Cockayne, Alejandro P. Comellas, Meilan Han, Rachel L. Zemans, Katerina Kechris, Russell P. Bowler

Journal Articles: Pulmonary & Critical Care Med

RATIONALE: Chronic obstructive pulmonary disease (COPD) is a phenotypically heterogeneous disease. In COPD, the presence of emphysema is associated with increased mortality and risk of lung cancer. High resolution computed tomography (HRCT) scans are useful in quantifying emphysema but are associated with radiation exposure and high incidence of false positive findings (i.e., nodules). Using a comprehensive biomarker panel, we sought to determine if there was a peripheral blood biomarker signature of emphysema.

METHODS: 114 plasma biomarkers were measured using a custom assay in 588 individuals enrolled in the COPDGene study. Quantitative emphysema measurements included percent low lung attenuation (%LAA) ≤ …

Randomized Study Of The Safety, Pharmacokinetics, And Bronchodilatory Efficacy Of A Proprietary Glycopyrronium Metered-Dose Inhaler In Study Patients With Chronic Obstructive Pulmonary Disease, Stephen I. Rennard, Charles Fogarty, Colin Reisner, Carlos Fernandez, Tracy Fischer, Michael Golden, Earl St Rose, Patrick Darken, Gregory Tardie, Chadwick Orevillo

Journal Articles: Pulmonary & Critical Care Med

BACKGROUND: Bronchodilator medications are central to the symptomatic management of chronic obstructive pulmonary disease (COPD). Metered-dose inhalers (MDIs) are the most commonly used devices to deliver treatment to patients with COPD and asthma, comprising approximately 70% of bronchodilator prescriptions. Proprietary porous-particle technology permits the formulation of long-acting muscarinic antagonists, long-acting β2-agonists, and a combination of both in hydrofluoroalkane (HFA) MDIs, providing a solution to formulation challenges inherent to the development of HFA MDIs, which have contributed to the development of dry-powder inhalers.

METHODS: In this randomized, double-blind, 4-period, 6-treatment, placebo- and active-controlled, multicenter, crossover study, 4 ascending single doses of …

Analyzing Networks Of Phenotypes In Complex Diseases: Methodology And Applications In Copd, Jen-Hwa Chu, Craig P. Hersh, Peter J. Castaldi, Michael H. Cho, Benjamin A. Raby, Nan Laird, Russell Bowler, Stephen I. Rennard, Joseph Loscalzo, John Quackenbush, Edwin K. Silverman

Journal Articles: Pulmonary & Critical Care Med

BACKGROUND: The investigation of complex disease heterogeneity has been challenging. Here, we introduce a network-based approach, using partial correlations, that analyzes the relationships among multiple disease-related phenotypes.

RESULTS: We applied this method to two large, well-characterized studies of chronic obstructive pulmonary disease (COPD). We also examined the associations between these COPD phenotypic networks and other factors, including case-control status, disease severity, and genetic variants. Using these phenotypic networks, we have detected novel relationships between phenotypes that would not have been observed using traditional epidemiological approaches.

CONCLUSION: Phenotypic network analysis of complex diseases could provide novel insights into disease susceptibility, disease …

Clinical And Computed Tomographic Predictors Of Chronic Bronchitis In Copd: A Cross Sectional Analysis Of The Copdgene Study, Victor Kim, Adam Davey, Alejandro P. Comellas, Meilan K. Han, George Washko, Carlos H. Martinez, David Lynch, Jin Hwa Lee, Edwin K. Silverman, James D. Crapo, Barry J. Make, Gerard J. Criner, The Copdgene® Investigators

Journal Articles: Pulmonary & Critical Care Med

BACKGROUND: Chronic bronchitis (CB) has been related to poor outcomes in Chronic Obstructive Pulmonary Disease (COPD). From a clinical standpoint, we have shown that subjects with CB in a group with moderate to severe airflow obstruction were younger, more likely to be current smokers, male, Caucasian, had worse health related quality of life, more dyspnea, and increased exacerbation history compared to those without CB. We sought to further refine our clinical characterization of chronic bronchitics in a larger cohort and analyze the CT correlates of CB in COPD subjects. We hypothesized that COPD patients with CB would have thicker airways …

Comparison Of Serum, Edta Plasma And P100 Plasma For Luminex-Based Biomarker Multiplex Assays In Patients With Chronic Obstructive Pulmonary Disease In The Spiromics Study, Wanda K. O'Neal, Wayne Anderson, Patricia V. Basta, Elizabeth E. Carretta, Claire M. Doerschuk, R. Graham Barr, Eugene R. Bleecker, Stephanie A. Christenson, Jeffrey L. Curtis, Meilan K. Han, Nadia N. Hansel, Richard E. Kanner, Eric C. Kleerup, Fernando J. Martinez, Bruce E. Miller, Stephen P. Peters, Stephen I. Rennard, Mary Beth Scholand, Ruth Tal-Singer, Prescott G. Woodruff, David J. Couper, Sonia M. Davis, Spiromics Investigators

Journal Articles: Pulmonary & Critical Care Med

BACKGROUND: As a part of the longitudinal Chronic Obstructive Pulmonary Disease (COPD) study, Subpopulations and Intermediate Outcome Measures in COPD study (SPIROMICS), blood samples are being collected from 3200 subjects with the goal of identifying blood biomarkers for sub-phenotyping patients and predicting disease progression. To determine the most reliable sample type for measuring specific blood analytes in the cohort, a pilot study was performed from a subset of 24 subjects comparing serum, Ethylenediaminetetraacetic acid (EDTA) plasma, and EDTA plasma with proteinase inhibitors (P100).

METHODS: 105 analytes, chosen for potential relevance to COPD, arranged in 12 multiplex and one simplex platform …

Dnah5 Is Associated With Total Lung Capacity In Chronic Obstructive Pulmonary Disease, Jin Hwa Lee, Merry-Lynn N Mcdonald, Michael H. Cho, Emily S. Wan, Peter J. Castaldi, Gary M. Hunninghake, Nathaniel Marchetti, David A. Lynch, James D. Crapo, David A. Lomas, Harvey O. Coxson, Per S. Bakke, Edwin K. Silverman, Craig P. Hersh, The Copdgene And Eclipse Investigators

Journal Articles: Pulmonary & Critical Care Med

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is characterized by expiratory flow limitation, causing air trapping and lung hyperinflation. Hyperinflation leads to reduced exercise tolerance and poor quality of life in COPD patients. Total lung capacity (TLC) is an indicator of hyperinflation particularly in subjects with moderate-to-severe airflow obstruction. The aim of our study was to identify genetic variants associated with TLC in COPD.

METHODS: We performed genome-wide association studies (GWASs) in white subjects from three cohorts: the COPDGene Study; the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE); and GenKOLS (Bergen, Norway). All subjects were current or ex-smokers …

Influence Of Diet And Obesity On Copd Development And Outcomes, Corrine K. Hanson, Erica P. Rutten, Emiel F.M. Wouters, Stephen I. Rennard

Journal Articles: Pulmonary & Critical Care Med

The global increase in the prevalence and incidence of obesity has called serious attention to this issue as a major public health concern. Obesity is associated with many chronic diseases, including cardiovascular disease and diabetes, and recently the role of overweight and obesity in lung disease has received new interest. Independently of obesity, diet also plays a role as a risk factor for many chronic diseases, and evidence is accumulating to support a role for diet in the prevention and management of several lung diseases. Chronic obstructive lung disease is the third-leading cause of death globally, and both obesity and …

Roflumilast And Dyspnea In Patients With Moderate To Very Severe Chronic Obstructive Pulmonary Disease: A Pooled Analysis Of Four Clinical Trials, Stephen I. Rennard, Shawn X. Sun, Stavros Tourkodimitris, Paul Rowe, Udo M. Goehring, Dirk Bredenbröker, Peter M.A. Calverley

Journal Articles: Pulmonary & Critical Care Med

PURPOSE: Breathlessness is a predominant symptom of chronic obstructive pulmonary disease (COPD), making it a valuable outcome in addition to lung function to assess treatment benefit. The phosphodiesterase-4 inhibitor roflumilast has been shown to provide small but significant improvements in dyspnea, as measured by the transition dyspnea index (TDI), in two 1-year studies in patients with severe to very severe COPD.

PATIENTS AND METHODS: To provide a more comprehensive assessment of the impact of roflumilast on dyspnea, post hoc analyses of four 1-year roflumilast studies (M2-111, M2-112, M2-124, and M2-125) in patients with moderate to very severe COPD were conducted. …

Efficacy And Safety Of Fixed-Dose Combinations Of Aclidinium Bromide/Formoterol Fumarate: The 24-Week, Randomized, Placebo-Controlled Augment Copd Study, Anthony D. D'Urzo, Stephen I. Rennard, Edward M. Kerwin, Victor Mergel, Anne R. Leselbaum, Cynthia F. Caracta, Augment Copd Study Investigators

Journal Articles: Pulmonary & Critical Care Med

BACKGROUND: Combining two long-acting bronchodilators with complementary mechanisms of action may provide treatment benefits to patients with chronic obstructive pulmonary disease (COPD) that are greater than those derived from either treatment alone. The efficacy and safety of a fixed-dose combination (FDC) of aclidinium bromide, a long-acting muscarinic antagonist, and formoterol fumarate, a long-acting β2-agonist, in patients with moderate to severe COPD are presented.

METHODS: In this 24-week double-blind study, 1692 patients with stable COPD were equally randomized to twice-daily treatment with FDC aclidinium 400 μg/formoterol 12 μg (ACL400/FOR12 FDC), FDC aclidinium 400 μg/formoterol 6 μg (ACL400/FOR6 FDC), aclidinium 400 μg, …

Muc1 Regulates Cyclin D1 Gene Expression Through P120 Catenin And Β-Catenin, X. Liu, Thomas C. Caffrey, M. M. Steele, Ashley M. Mohr, Pankaj K. Singh, Prakash Radhakrishnan, David L. Kelly, Y. Wen, Michael A. Hollingsworth

Journal Articles: Eppley Institute

MUC1 interacts with β-catenin and p120 catenin to modulate WNT signaling. We investigated the effect of overexpressing MUC1 on the regulation of cyclin D1, a downstream target for the WNT/β-catenin signaling pathway, in two human pancreatic cancer cell lines, Panc-1 and S2-013. We observed a significant enhancement in the activation of cyclin D1 promoter-reporter activity in poorly differentiated Panc1.MUC1F cells that overexpress recombinant MUC1 relative to Panc-1.NEO cells, which express very low levels of endogenous MUC1. In stark contrast, cyclin D1 promoter activity was not affected in moderately differentiated S2-013.MUC1F cells that overexpressed recombinant MUC1 relative to S2-013.NEO cells that …

A Simplified Score To Quantify Comorbidity In Copd, Nirupama Putcha, Milo A. Puhan, M. Bradley Drummond, Meilan K. Han, Elizabeth A. Regan, Nicola A. Hanania, Carlos H. Martinez, Marilyn Foreman, Surya P. Bhatt, Barry Make, Joe Ramsdell, Dawn L. Demeo, R. Graham Barr, Stephen I. Rennard, Fernando Martinez, Edwin K. Silverman, James Crapo, Robert A. Wise, Nadia N. Hansel

Journal Articles: Pulmonary & Critical Care Med

IMPORTANCE: Comorbidities are common in COPD, but quantifying their burden is difficult. Currently there is a COPD-specific comorbidity index to predict mortality and another to predict general quality of life. We sought to develop and validate a COPD-specific comorbidity score that reflects comorbidity burden on patient-centered outcomes.

MATERIALS AND METHODS: Using the COPDGene study (GOLD II-IV COPD), we developed comorbidity scores to describe patient-centered outcomes employing three techniques: 1) simple count, 2) weighted score, and 3) weighted score based upon statistical selection procedure. We tested associations, area under the Curve (AUC) and calibration statistics to validate scores internally with outcomes …

A Divisive Shuffling Approach (Vista) For Gene Expression Analysis To Identify Subtypes In Chronic Obstructive Pulmonary Disease, Jörg Menche, Amitabh Sharma, Michael H. Cho, Ruth J. Mayer, Stephen I. Rennard, Bartolome Celli, Bruce E. Miller, Nick Locantore, Ruth Tal-Singer, Soumitra Ghosh, Chris Larminie, Glyn Bradley, John H. Riley, Alvar Agusti, Edwin K. Silverman, Albert-László Barabási

Journal Articles: Pulmonary & Critical Care Med

BACKGROUND: An important step toward understanding the biological mechanisms underlying a complex disease is a refined understanding of its clinical heterogeneity. Relating clinical and molecular differences may allow us to define more specific subtypes of patients that respond differently to therapeutic interventions.

RESULTS: We developed a novel unbiased method called diVIsive Shuffling Approach (VIStA) that identifies subgroups of patients by maximizing the difference in their gene expression patterns. We tested our algorithm on 140 subjects with Chronic Obstructive Pulmonary Disease (COPD) and found four distinct, biologically and clinically meaningful combinations of clinical characteristics that are associated with large gene expression …

Vest Chest Physiotherapy Airway Clearance Is Associated With Nitric Oxide Metabolism., Joseph H. Sisson, Todd A. Wyatt, Jacqueline A. Pavlik, Pawanjit S. Sarna, Peter J. Murphy

Journal Articles: Pulmonary & Critical Care Med

Background. Vest chest physiotherapy (VCPT) enhances airway clearance in cystic fibrosis (CF) by an unknown mechanism. Because cilia are sensitive to nitric oxide (NO), we hypothesized that VCPT enhances clearance by changing NO metabolism. Methods. Both normal subjects and stable CF subjects had pre- and post-VCPT airway clearance assessed using nasal saccharin transit time (NSTT) followed by a collection of exhaled breath condensate (EBC) analyzed for NO metabolites (NO x ). Results. VCPT shorted NSTT by 35% in normal and stable CF subjects with no difference observed between the groups. EBC NO x concentrations decreased 68% in control subjects after …

Asymmetric Dimethylarginine Blocks Nitric Oxide-Mediated Alcohol-Stimulated Cilia Beating., Todd A. Wyatt, S . M. Wells, Z . A. Alsaidi, Jane M. Devasure, E. B. Klein, Kristina L. Bailey, Joseph H. Sisson

Journal Articles: Pulmonary & Critical Care Med

The airway epithelium is exposed to alcohol during drinking through direct exhalation of volatized ethanol from the bronchial circulation. Alcohol exposure leads to a rapid increase in the cilia beat frequency (CBF) of bronchial epithelial cells followed by a chronic desensitization of cilia stimulatory responses. This effect is governed in part by the nitric oxide regulation of cyclic guanosine and adenosine monophosphate-dependent protein kinases (PKG and PKA) and is not fully understood. Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, is implicated in the pathogenesis of several pulmonary disorders. We hypothesized that the inhibition of nitric oxide synthase …

Ron Knockdown And Ron Monoclonal Antibody Imc-Ron8 Sensitize Pancreatic Cancer To Histone Deacetylase Inhibitors (Hdaci)., Yi Zou, Gillian M. Howell, Lisa E. Humphrey, J. Wang, Michael G. Brattain

Journal Articles: Eppley Institute

Recepteur d'origine nantais (Ron) is overexpressed in a panel of pancreatic cancer cells and tissue samples from pancreatic cancer patients. Ron can be activated by its ligand macrophage stimulating protein (MSP), thereby activating oncogenic signaling pathways. Crosstalk between Ron and EGFR, c-Met, or IGF-1R may provide a mechanism underlying drug resistance. Thus, targeting Ron may represent a novel therapeutic strategy. IMC-RON8 is the first Ron monoclonal antibody (mAb) entering clinical trial for targeting Ron overexpression. Our studies show IMC-RON8 downmodulated Ron expression in pancreatic cancer cells and significantly blocked MSP-stimulated Ron activation, downstream Akt and ERK phosphorylation, and survivin mRNA …

Maresin-1 Reduces The Pro-Inflammatory Response Of Bronchial Epithelial Cells To Organic Dust., Tara M. Nordgren, Art J. Heires, Todd A. Wyatt, Jill A. Poole, Tricia D. Levan, D. Roselyn Cerutis, Debra J. Romberger

Journal Articles: Pulmonary & Critical Care Med

BACKGROUND: Exposure to organic dust causes detrimental airway inflammation. Current preventative and therapeutic measures do not adequately treat resulting disease, necessitating novel therapeutic interventions. Recently identified mediators derived from polyunsaturated fatty acids exhibit anti-inflammatory and pro-resolving actions. We tested the potential of one of these mediators, maresin-1 (MaR1), in reducing organic dust-associated airway inflammation.

METHODS: As bronchial epithelial cells (BECs) are pivotal in initiating organic dust-induced inflammation, we investigated the in vitro effects of MaR1 on a human BEC cell line (BEAS-2B). Cells were pretreated for 1 hour with 0-200 nM MaR1, followed by 1-24 hour treatment with 5% hog …

Intra-Tumoral Heterogeneity In Metastatic Potential And Survival Signaling Between Iso-Clonal Hct116 And Hct116b Human Colon Carcinoma Cell Lines., Sanjib Chowdhury, Melanie Ongchin, Elizabeth Sharratt, Ivan Dominguez, J. Wang, Michael G. Brattain, Ashwani Rajput

Journal Articles: Eppley Institute

BACKGROUND: Colorectal cancer (CRC) metastasis is a leading cause of cancer-related deaths in the United States. The molecular mechanisms underlying this complex, multi-step pathway are yet to be completely elucidated. Recent reports have stressed the importance of intra-tumoral heterogeneity in the development of a metastatic phenotype. The purpose of this study was to characterize the intra-tumoral phenotypic heterogeneity between two iso-clonal human colon cancer sublines HCT116 and HCT116b on their ability to undergo metastatic colonization and survive under growth factor deprivation stress (GFDS).

MATERIALS AND METHODS: HCT116 and HCT116b cells were transfected with green fluorescence protein and subcutaneously injected into …

Tgf-Beta Suppresses Vegfa-Mediated Angiogenesis In Colon Cancer Metastasis., Liying Geng, Anathbandhu Chaudhuri, G. Talmon, James L. Wisecarver, J. Wang

Journal Articles: Eppley Institute

The FET cell line, derived from an early stage colon carcinoma, is non-tumorigenic in athymic nude mice. Engineered FET cells that express TGF-α (FETα) display constitutively active EGFR/ErbB signaling. These cells readily formed xenograft tumors in athymic nude mice. Importantly, FETα cells retained their response to TGF-beta-mediated growth inhibition, and, like the parental FET cells, expression of a dominant negative TGF-beta type II receptor (DNRII) in FETα cells (FETα/DNRII) abrogated responsiveness to TGF-beta-induced growth inhibition and apoptosis under stress conditions in vitro and increased metastatic potential in an orthotopic model in vivo, which indicates metastasis suppressor activity of TGF-beta signaling …

Effect Of Budesonide On Fibroblast-Mediated Collagen Gel Contraction And Degradation, Qiuhong Fang, Nancy A. Schulte, Huijung Kim, Tetsu Kobayashi, Xingqi Wang, Anna Miller-Larsson, Elisabet Wieslander, Myron L. Toews, Xiangde Liu, Stephen I. Rennard

Journal Articles: Pulmonary & Critical Care Med

BACKGROUND: The balance between production and degradation of extracellular matrix is crucial in maintaining normal tissue structure. This study was designed to investigate the effect of budesonide on fibroblast-mediated tissue repair and remodeling.

METHODS: Using human fetal lung fibroblasts in a three-dimensional collagen gel culture system, we investigated the effect of budesonide (1-1000 nM) on collagen gel contraction and degradation in the presence or absence of Inflammatory cytokines (interleukin-1β and tumor necrosis factor α; 5 ng/mL each) and, in order to activate latent proteases, serine protease trypsin 0.25 μg/mL. The effects of budesonide on metalloproteinase production and activation were also …

Pge 2 Desensitizes Β -Agonist Effect On Human Lung Fibroblast-Mediated Collagen Gel Contraction Through Opregulating Pde4, Qiuhong Fang, Yingmin Ma, Jing Wang, Joel Michalski, Stephen I. Rennard, Xiangde Liu

Journal Articles: Pulmonary & Critical Care Med

In the current study, we investigated the effect of a long-acting β -agonist (salmeterol) and a phosphodiesterase 4 (PDE4) inhibitor (cilomilast) on human lung fibroblast-mediated collagen gel contraction. Higher concentrations of salmeterol (10(-7) and 10(-6) M) inhibited fibroblast-mediated collagen gel contraction. No effect was observed with cilomilast alone (up to 10(-5) M). In the presence of 10(-8) M salmeterol, however, cilomilast could significantly inhibit fibroblast-mediated collagen gel contraction in a concentration-dependent manner (10(-7) ~10(-5) M). Blockade of endogenous PGE2 by indomethacin further potentiated the inhibitory effect of salmeterol on fibroblast-mediated collagen gel contraction, but it did not affect cilomilast's effect. …

Anti-Inflammatory Effects Of Budesonide In Human Lung Fibroblast Are Independent Of Histone Deacetylase 2, Xingqi Wang, Amy J. Nelson, Zachary M. Weiler, Amol Patil, Tadashi Sato, Nobuhiro Kanaji, Masanori Nakanishi, Joel Michalski, Maha Farid, Hesham Basma, Tricia D. Levan, Anna Miller-Larsson, Elisabet Wieslander, Kai-Christian Muller, Olaf Holz, Helgo Magnussen, Klaus F. Rabe, Xiangde Liu, Stephen I. Rennard

Journal Articles: Pulmonary & Critical Care Med

OBJECTIVE AND DESIGN: Reduced expression of histone deacetylase 2 (HDAC2) in alveolar macrophages and epithelial cells may account for reduced response of chronic obstructive pulmonary disease (COPD) patients to glucocorticoids. HDAC2 expression and its role in mediating glucocorticoid effects on fibroblast functions, however, has not been fully studied. This study was designed to investigate whether HDAC2 mediates glucocorticoid effects on release of inflammatory cytokines and matrix metalloproteinases (MMPs) from human lung fibroblasts.

METHODS: Human lung fibroblasts (HFL-1 cells) were stimulated with interleukin (IL)-1 β plus tumor necrosis factor (TNF)-α in the presence or absence of the glucocorticoid budesonide. Cytokines (IL-6 …

Breast Cancer Incidence In Black And White Women Stratified By Estrogen And Progesterone Receptor Statuses., Michael X. Gleason, Tengiz Mdzinarishvili, Simon Sherman

Journal Articles: Eppley Institute

BACKGROUND: There is increasing evidence that breast cancer is a heterogeneous disease presented by different phenotypes and that white women have a higher breast cancer incidence rate, whereas black women have a higher mortality rate. It is also well known that white women have lower incidence rates than black women until approximately age 40, when rate curves cross over and white women have higher rates. The goal of this study was to validate the risk of white and black women to breast cancer phenotypes, stratified by statuses of the estrogen (ER) and progesterone (PR) receptors.

METHODOLOGY/PRINCIPAL FINDINGS: SEER17 data were …