William N. Rom, M.D., M.P.H.

A case of acute exacerbation of IPF following orthopedic surgery
Basavaraj A.; Steiger D.; Callahan C.; Rom W.; Dweck E.
2011 ;140(4):?-?, Chest
INTRODUCTION: Acute exacerbation of IPF is increasingly being recognized as a common clinical event in the IPF population. The exact etiology remains unknown. Previous reports have shown an association between lung surgery, bronchoalveolar lavage, and surgical lung biopsies as a potential trigger for exacerbations of IPF. To our knowledge, there are no known cases in the literature reporting an exacerbation of IPF following a non-thoracic surgical procedure. We report a case of acute exacerbation of IPF following orthopedic surgery. CASE PRESENTATION: 78 year old male with a history of COPD (thirty pack year smoking history) and severe osteoarthritis was admitted to the NYU Hospital for Joint Diseases to undergo evaluation for total hip arthroplasty. Pre-operative evaluation was significant for a restrictive pattern with low DLCO on pulmonary function testing, as well increased interstitial markings on chest x-ray concerning for a fibrotic process. The patient reported no pulmonary symptoms, and underwent successful total hip arthroplasty without complication. On Post op day #6, the patient developed dyspnea on exertion and at rest, requiring increasing amounts of oxygen supplementation. A Chest CT was negative for pulmonary embolism, however did show bronchiectasis and evidence of fibrosis. An echocardiogram did not show evidence of heart failure. The patient was started on broad spectrum antibiotics with Vancomycin, Zosyn and Azithromycin. He also was started on high dose IV steroids (Solumedrol 60mg IV every 6 hours) for a potential COPD exacerbation. Sputum culture was positive only for Candida glabrata, and the patient completed a course of Anidulafungin. However, the patient's respiratory status continued to deteriorate, eventually requiring noninvasive positive pressure ventilation. High dose steroids were continued, as well as therapeutic anticoagulation. A repeat CT chest showed increased groundglass opacities, worsening bronchiectasis and fibrosis diffusely in a UIP pattern. A repeat echocardiogram showed new evidence for pulmonary hypertension, however otherwise normal. A trial of diuretics was initiated without a response. The patient eventually required intubation and tracheostomy, and later passed away. An autopsy revealed evidence for diffuse alveolar damage on a background of honeycombing and bronchiectasis. DISCUSSION: The etiology and pathogenesis of IPF exacerbations remains unknown. One hypothesis involves the loss of alveolar cell integrity following injury, leading to extrusion of fibrin into the alveolar spaces and remodeling. Fibrocytes can be recruited in response to chemokines generated by infection and injury and may potentiate fibrogenesis, leading to diffuse alveolar damage. This process may be triggered by pulmonary procedures, as previously reported. However, a similar inflammatory response may occur after a non-thoracic procedure, leading to the fibrogenic process. The above patient suffered an unexplained worsening fibrotic process, as evidenced by imaging, respiratory failure, and autopsy findings. Alternative causes, such as left heart failure and pulmonary embolism, were excluded. Potential infections were treated with antibiotics. Commonly proposed diagnostic criteria for IPF exacerbation were met. This is the first case to our knowledge of a non-pulmonary procedure triggering the disease process. Cases such as this are likely more common than realized and remain underreported. Clinicians should be aware of the potential for exacerbation of IPF following non-thoracic surgical procedures. CONCLUSIONS: Acute exacerbation of IPF is increasingly being recognized as a common clinical event and may occur after non-thoracic procedures, such as orthopedic surgery
— id: 149979, year: 2011, vol: 140, page: ?, stat: Journal Article,

NF-kappaB in lung tumorigenesis
Cai Z.; Tchou-Wong K.-M.; Rom W.N.
2011 ;3(4):4258-4268, Cancers
The development of lung cancer in humans can be divided into three steps: initiation, promotion and progression. This process is driven by alterations in related signal transduction pathways. These pathways signal the aberrant activation of NF-kappaB, a transcription factor that regulates the expression of genes important for lung tumorigenesis. Our current knowledge about the role of the NF-kappaB signaling pathway in the development of lung cancer has been bolstered by animal models demonstrating the connection between K-ras and tobacco induced lung transformation with NF-kappaB. Activation of downstream genes leads to cell proliferation, inhibition of apoptosis, angiogenesis, inflammation, invasion, and metastasis. 2011 by the authors; licensee MDPI, Basel, Switzerland
— id: 149824, year: 2011, vol: 3, page: 4258, stat: Journal Article,

Pulmonary Disability Evaluations In Fdny Rescue Workers Exposed To Wtc Particulates: A Pilot Study
Comfort AL; Weiden M; Naveed B; Ferrier N; Webber MP; Berger KI; Rom WN; Prezant DJ; Nolan A
2011 ;183:?-? #A4799, American journal of respiratory & critical care medicine
— id: 137900, year: 2011, vol: 183, page: ?, stat: Journal Article,

HIV-associated lung infections and complications in the era of combination antiretroviral therapy
Crothers, Kristina; Thompson, Bruce W; Burkhardt, Kathryn; Morris, Alison; Flores, Sonia C; Diaz, Philip T; Chaisson, Richard E; Kirk, Gregory D; Rom, William N; Huang, Laurence
2011 Jun;8(3):275-281, Proceedings of the American Thoracic Society
The spectrum of lung diseases associated with HIV is broad, and many infectious and noninfectious complications of HIV infection have been recognized. The nature and prevalence of lung complications have not been fully characterized since the Pulmonary Complications of HIV Infection Study more than 15 years ago, before antiretroviral therapy (ART) increased life expectancy. Our understanding of the global epidemiology of these diseases in the current ART era is limited, and the mechanisms for the increases in the noninfectious conditions, in particular, are not well understood. The Longitudinal Studies of HIV-Associated Lung Infections and Complications (Lung HIV) Study (ClinicalTrials.gov number NCT00933595) is a collaborative multi-R01 consortium of research projects established by the National Heart, Lung, and Blood Institute to examine a diverse range of infectious and noninfectious pulmonary diseases in HIV-infected persons. This article reviews our current state of knowledge of the impact of HIV on lung health and the development of pulmonary diseases, and highlights ongoing research within the Lung HIV Study
— id: 137958, year: 2011, vol: 8, page: 275, stat: Journal Article,

Low Serum Iga And Igg4 Levels Predict Accelerated Decline In Lung Function Of WTC Dust Exposed Firefighters
Ferrier NV; Nolan A; Naveed B; Rom WN; Comfort AL; Prezant DJ; Weiden MD
2011 ;183:?-? #A4773, American journal of respiratory & critical care medicine
— id: 137903, year: 2011, vol: 183, page: ?, stat: Journal Article,

Sputum-based molecular biomarkers for the early detection of lung cancer: Limitations and promise
Kim C.E.; Tchou-Wong K.-M.; Rom W.N.
2011 ;3(3):2975-2989, Cancers
Lung cancer is the leading cause of cancer deaths, with an overall survival of 15% at five years. Biomarkers that can sensitively and specifically detect lung cancer at early stage are crucial for improving this poor survival rate. Sputum has been the target for the discovery of non-invasive biomarkers for lung cancer because it contains airway epithelial cells, and molecular alterations identified in sputum are most likely to reflect tumor-associated changes or field cancerization caused by smoking in the lung. Sputumbased molecular biomarkers include morphology, allelic imbalance, promoter hypermethylation, gene mutations and, recently, differential miRNA expression. To improve the sensitivity and reproducibility of sputum-based biomarkers, we recommend standardization of processing protocols, bronchial epithelial cell enrichment, and identification of field cancerization biomarkers. 2011 by the authors; licensee MDPI, Basel, Switzerland
— id: 138725, year: 2011, vol: 3, page: 2975, stat: Journal Article,

Neutrophils Activate Alveolar Macrophages by Producing Caspase-6-Mediated Cleavage of IL-1 Receptor-Associated Kinase-M
Kobayashi, Hiroshi; Nolan, Anna; Naveed, Bushra; Hoshino, Yoshihiko; Segal, Leopoldo N; Fujita, Yoko; Rom, William N; Weiden, Michael D
2011 Jan 1;186(1):403-410, Journal of immunology
Alveolar macrophages (AMs) are exposed to respirable microbial particles. Similar to phagocytes in the gastrointestinal tract, AMs can suppress inflammation after exposure to nonpathogenic organisms. IL-1R-associated kinase-M (IRAK-M) is one inhibitor of innate immunity, normally suppressing pulmonary inflammation. During pneumonia, polymorphonuclear neutrophils (PMNs) are recruited by chemotactic factors released by AMs to produce an intense inflammation. We report that intact IRAK-M is strongly expressed in resting human AMs but is cleaved in patients with pneumonia via PMN-mediated induction of caspase-6 (CASP-6) activity. PMN contact is necessary and PMN membranes are sufficient for CASP-6 induction in macrophages. PMNs fail to induce TNF-alpha fully in macrophages expressing CASP-6 cleavage-resistant IRAK-M. Without CASP-6 expression, PMN stimulation fails to cleave IRAK-M, degrade IkappaBalpha, or induce TNF-alpha. CASP-6(-/-) mice subjected to cecal ligation and puncture have impaired TNF-alpha production in the lung and decreased mortality. LPS did not induce or require CASP-6 activity demonstrating that TLR2/4 signaling is independent from the CASP-6 regulated pathway. These data define a central role for CASP-6 in PMN-driven macrophage activation and identify IRAK-M as an important target for CASP-6. PMNs de-repress AMs via CASP-6-mediated IRAK-M cleavage. This regulatory system will blunt lung inflammation unless PMNs infiltrate the alveolar spaces
— id: 116209, year: 2011, vol: 186, page: 403, stat: Journal Article,

Resection of non-small cell lung cancers reverses tumor-induced gene expression changes in the peripheral immune system
Kossenkov, Andrew V; Vachani, Anil; Chang, Celia; Nichols, Calen; Billouin, Shere; Horng, Wenhwai; Rom, William N; Albelda, Steven M; Showe, Michael K; Showe, Louise C
2011 Sep 15;17(18):5867-5877, Clinical cancer research
PURPOSE: To characterize the interactions of non-small cell lung cancer (NSCLC) tumors with the immune system at the level of mRNA and microRNA (miRNA) expression and to define expression signatures that characterize the presence of a malignant tumor versus a nonmalignant nodule. EXPERIMENTAL DESIGN: We have examined the changes of both mRNA and miRNA expression levels in peripheral blood mononuclear cells (PBMC) between paired samples collected from NSCLC patients before and after tumor removal using Illumina gene expression arrays. RESULTS: We found that malignant tumor removal significantly changes expression of more than 3,000 protein-coding genes, especially genes in pathways associated with suppression of the innate immune response, including natural killer cell signaling and apoptosis-associated ceramide signaling. Binding sites for the ETS domain transcription factors ELK1, ELK4, and SPI1 were enriched in promoter regions of genes upregulated in the presence of a tumor. Additional important regulators included five miRNAs expressed at significantly higher levels before tumor removal. Repressed protein-coding targets of those miRNAs included many transcription factors, several involved in immunologically important pathways. Although there was a significant overlap in the effects of malignant tumors and benign lung nodules on PBMC gene expression, we identified one gene panel which indicates a tumor or nodule presence and a second panel that can distinguish malignant from nonmalignant nodules. CONCLUSIONS: A tumor presence in the lung influences mRNA and miRNA expression in PBMC and this influence is reversed by tumor removal. These results suggest that PBMC gene expression signatures could be used for lung cancer diagnosis. Clin Cancer Res; 17(18); 5867-77. (c)2011 AACR
— id: 137838, year: 2011, vol: 17, page: 5867, stat: Journal Article,

Biomarkers of metabolic syndrome predict accelerated decline of lung function in NYC firefighters that were exposed to world trade center particulates
Naveed B.; Comfort A.; Ferrier N.; Kwon S.; Rom W.N.; Prezant D.J.; Weiden M.D.; Nolan A.
2011 ;4(2):99-99, Clinical & Translational Science
OBJECTIVES/SPECIFIC AIMS: The first year post 9/11/2001, the FEV1 of FDNY rescue workers declined 439 mL, stabilizing to a 25 ml/yr decline in the subsequent 7 years. Airflow obstruction predominated in firefighters who sought a subspecialty pulmonary evaluation for treatment. We are investigating the relationship between biomarkers of metabolic syndrome (MS) and decline in lung function. METHODS/ STUDY POPULATION: Treatment cohort (N = 1720) was stratified by FEV1 into obstructed, FEV1 < 76% predicted (LLN), or normal airflow, FEV1>76%. A pilot analysis assayed 41 patients' serum drawn 5 months post 9/11 for 15 biomarkers of MS by Luminex, (obstructed N = 10, normal N = 31). All patients had normal pre-9/11 lung function. Serum cholesterol (CHOL) and triglycerides (TG) were available on 157 patients, 20/157 were obstructed. Data presented as means +/- SD; p values -0.05 by t-test considered significant. RESULTS/ANTICIPATED RESULTS: BMIs at time of serum sampling were no different between normal and obstructed individuals. At subspecialty PFT, obstructed patients had higher BMIs with an accelerated decline in lung function post 9/11, increased airway reactivity, and evidence of air trapping based on elevated RV when compared to normals. Obstructed subjects had significantly greater CHOL and CHOL/HDL ratios; higher levels of sE-Selectin, tPAI-1, and s-ICAM; and a trend towards elevated levels of TG and C-peptide. DISCUSSION/SIGNIFICANCE OF IMPACT: Blood drawn post-WTC exposure identified a subgroup of patients with markers of MS. This subgroup had subsequent increased weight gain and decline in lung function. The finding of MS biomarkers prior to lung function decline raises the possibility that the combination of irritant exposure and mediators of MS interact and promote lung injury
— id: 142066, year: 2011, vol: 4, page: 99, stat: Journal Article,

Biomarkers Of Metabolic Syndrome Predict Accelerated Decline Of Lung Function In NYC Firefighters That Were Exposed To Wtc Particulates
Naveed B; Comfort AL; Ferrier N; Kasturiarachchi KJ; Rom WN; Prezant DJ; Weiden MD; Nolan A
2011 ;183:?-? #A4795, American journal of respiratory & critical care medicine
— id: 137902, year: 2011, vol: 183, page: ?, stat: Journal Article,

WTC Dust Induces Gm-Csf In Serum Of Fdny Rescue Workers With Accelerated Decline Of Lung Function And In Cultured Alveolar Macrophages
Naveed B; Comfort AL; Ferrier N; Segal LN; Kasturiarachchi KJ; Kwon S; Chen LC; Gordon T; Cohen MD; Prophete C; Rom WN; Prezant DJ; Nolan A; Weiden M
2011 ;183:?-? #A4770, American journal of respiratory & critical care medicine
— id: 137901, year: 2011, vol: 183, page: ?, stat: Journal Article,

Metabolic Syndrome Biomarkers Predict Lung Function Impairment: A Nested Case-Control Study
Naveed B; Weiden MD; Kwon S; Gracely EJ; Comfort AL; Ferrier N; Kasturiarachchi KJ; Cohen HW; Aldrich TK; Rom WN; Kelly K; Prezant DJ; Nolan A
2011 Nov 17;:?-? #, American journal of respiratory & critical care medicine
RATIONALE: Cross-sectional studies demonstrate an association between metabolic syndrome and impaired lung function. OBJECTIVE: Define if metabolic syndrome biomarkers are risk factors for loss of lung function after irritant exposure. METHODS: A nested case-control study of FDNY personnel with normal pre-9/11 FEV1 and who presented for subspecialty pulmonary evaluation before 3/10/2008. We correlated metabolic syndrome biomarkers obtained within six months of World Trade Center Dust exposure with subsequent FEV1. FEV1 at subspecialty pulmonary evaluation within 6.5 years defined disease status; cases had FEV1<lower limit of normal (LLN) while controls had FEV1>/=LLN. MEASUREMENTS: Clinical data and serum sampled at the first monitoring exam within six months of 9/11/2001 assessed BMI, heart rate, serum glucose, Triglycerides/High Density Lipoprotein (HDL), Leptin, Pancreatic Polypeptide and Amylin. MAIN RESULTS: Cases and controls had significant differences in HDL<40 mg/dL with Triglycerides >/=150 mg/dL, heart rate >/=66 bpm, and Leptin >/=10,300 pg/mL. Each increased the odds of abnormal FEV1 at pulmonary evaluation by more than 2 fold, while Amylin >/=116 pg/mL decreased the odds by 84%, in a multi-biomarker model adjusting for age, race, BMI and WTC arrival time. This model had a sensitivity of 41%, a specificity of 86% and a ROC AUC of 0.77. CONCLUSION: Abnormal triglycerides and HDL, elevated heart rate and Leptin are independent risk factors of greater susceptibility to lung function impairment after 9/11/2001 while elevated Amylin is protective. Metabolic biomarkers are predictors of lung disease, and may be useful for assessing risk of impaired lung function in response to particulate inhalation
— id: 149814, year: 2011, vol: , page: ?, stat: Journal Article,

Inflammatory Biomarkers Predict Airflow Obstruction After Exposure to World Trade Center Dust
Nolan A; Naveed B; Comfort AL; Ferrier N; Hall CB; Kwon S; Kasturiarachchi KJ; Cohen HW; Zeig-Owens R; Glaser MS; Webber MP; Aldrich TK; Rom WN; Kelly K; Prezant DJ; Weiden MD
2011 Oct 13;:?-? #, Chest
Abstract BACKGROUND:The World Trade Center (WTC) collapse produced airflow obstruction in a majority of firefighters receiving subspecialty pulmonary evaluation (SPE) within 6.5 years post-9/11. METHODS:In a cohort of 801 never smokers with normal pre-9/11 FEV(1), we correlated inflammatory biomarkers and complete blood counts at monitoring entry within 6 months of 9/11/2001 with a median FEV(1) at SPE (34 months, IQR 25-57). Cases of airflow obstruction had FEV(1) < LLN (100/801; 70/100 had serum) while controls had FEV(1) >/= LLN (153/801; 124/153 had serum). RESULTS:From monitoring entry to SPE, years later, FEV(1) declined 12% in cases and increased 3% in controls. Cases had elevated serum MDC, GM-CSF, G-CSF and IP-10. Elevated GM-CSF and MDC increased the risk for subsequent FEV(1) < LLN by 2.5 fold (95% CI; 1.2-5.3) and 3.0 fold (1.4-6.1) in a logistic model adjusted for exposure, BMI, age on 9/11, and polymorphonuclear neutrophils. The model had sensitivity of 38% (95% CI 27-51), specificity of 88% (80-93). CONCLUSIONS:Inflammatory biomarkers can be risk factors for airflow obstruction following dust and smoke exposure. Elevated serum GM-CSF and MDC soon after WTC exposure were associated with increased risk of airflow obstruction in subsequent years. Biomarkers of inflammation may help identify pathways producing obstruction after irritant exposure
— id: 138730, year: 2011, vol: , page: ?, stat: Journal Article,

Role of oxidants in interstitial lung diseases: pneumoconioses, constrictive bronchiolitis, and chronic tropical pulmonary eosinophilia
Rom, William N
2011 ;2011:407657-407657, Mediators of inflammation
Oxidants such as superoxide anion, hydrogen peroxide, and myeloperoxidase from activated inflammatory cells in the lower respiratory tract contribute to inflammation and injury. Etiologic agents include inorganic particulates such as asbestos, silica, or coal mine dust or mixtures of inorganic dust and combustion materials found in World Trade Center dust and smoke. These etiologic agents are phagocytosed by alveolar macrophages or bronchial epithelial cells and release chemotactic factors that recruit inflammatory cells to the lung. Chemotactic factors attract and activate neutrophils, eosinophils, mast cells, and lymphocytes and further activate macrophages to release more oxidants. Inorganic dusts target alveolar macrophages, World Trade Center dust targets bronchial epithelial cells, and eosinophils characterize tropical pulmonary eosinophilia (TPE) caused by filarial organisms. The technique of bronchoalveolar lavage in humans has recovered alveolar macrophages (AMs) in dust diseases and eosinophils in TPE that release increased amounts of oxidants in vitro. Interestingly, TPE has massively increased eosinophils in the acute form and after treatment can still have ongoing eosinophilic inflammation. A course of prednisone for one week can reduce the oxidant burden and attendant inflammation and may be a strategy to prevent chronic TPE and interstitial lung disease
— id: 141997, year: 2011, vol: 2011, page: 407657, stat: Journal Article,

Biomarker Discovery and Verification of a Lung Cancer Signature with SOMAmer Proteomic Technology
Rom, William N; Ostroff, Rachel M; Pass, Harvey I; Bigbee, William L; Franklin, Wilbur; Gold, Larry; Mehan, Mike; Miller, York; Siegfried, Jill M; Stewart, Alex; Walker, Jeffrey J; Weissfeld, Joel L; Williams, Stephen; Zichi, Dom; Brody, Edward
2011 May;8(2):209-210, Proceedings of the American Thoracic Society
— id: 131977, year: 2011, vol: 8, page: 209, stat: Journal Article,

Regulatory t cells and th17 cells in bronchoalveolar lavage
Segal L; Kulkarni R; Nolan A; Weiden MD; Tse DB; Rom WN
2011 ;183:?-? #A4799, American journal of respiratory & critical care medicine
— id: 137898, year: 2011, vol: 183, page: ?, stat: Journal Article,

Disparity between proximal and distal airway reactivity during methacholine challenge
Segal, Leopoldo N; Goldring, Roberta M; Oppenheimer, Beno W; Stabile, Alexandra; Reibman, Joan; Rom, William N; Weiden, Michael D; Berger, Kenneth I
2011 Jun;8(3):145-152, COPD: Journal of Chronic Obstructive Pulmonary Disease
There is an increasing awareness of the role of distal airways in the pathophysiology of obstructive lung diseases including asthma and chronic obstructive pulmonary disease. We hypothesize that during induced bronchoconstriction: 1) disparity between distal and proximal airway reactivity may occur; and 2) changes in distal airway function may explain symptom onset in subjects with minimal FEV(1) change. 185 subjects underwent methacholine challenge testing (MCT). In addition to spirometry, oscillometry was performed at baseline and after maximum dose of methacholine; 33/185 also underwent oscillometry after each dose. Oscillometric parameters included resistance at 5 and 20 Hz (R(5,) R(20)) and heterogeneity of distal airway mechanics assessed by frequency dependence of resistance 5-20 Hz (R(5-20)) and reactance area (AX). R(5) varied widely during MCT (range -0.8 - 11.3 cmH(2)O/L/s) and correlated poorly with change in FEV(1) (r = 0.17). Changes in R(5) reflected changes in both R(20) and R(5-20) (r = 0.59, p<0.05; r = 0.87, p<0.0001). However, R(20) increased only 0.3 cmH(2)O/L/s, while R(5-20) increased 0.7 cmH(2)O/L/s for every 1cmH(2)O/L/s change in R(5,) indicating predominant effect of distal airway mechanics. 9/33 subjects developed symptoms despite minimal FEV(1) change (<5%), while R(5) increased 42% due to increased distal airway heterogeneity. These data indicate disparate behavior of proximal airway resistance (FEV(1) and R(20)) and distal airway heterogeneity (R(5-20) and AX). Distal airway reactivity may be associated with methacholine-induced symptoms despite absence of change in FEV(1). This study highlights the importance of disparity between proximal and distal airway behavior, which has implications in understanding pathophysiology of obstructive pulmonary diseases and their response to treatment
— id: 134171, year: 2011, vol: 8, page: 145, stat: Journal Article,

HIV-1 and Bacterial Pneumonia in the Era of Antiretroviral Therapy
Segal, Leopoldo N; Methe, Barbara A; Nolan, Anna; Hoshino, Yoshihiko; Rom, William N; Dawson, Rod; Bateman, Eric; Weiden, Michael D
2011 Jun;8(3):282-287, Proceedings of the American Thoracic Society
Community-acquired pneumonia affects approximately 4 million people in the United States, with 40,000 deaths per year. The incidence is increased about 35-fold in HIV-infected individuals, and this rate has decreased since the antiretroviral era has begun. Bacterial pneumonia has decreased from 5 to 20 cases per 100 person-years to less than 1 to 5 cases per 100 person-years in the era of antiretroviral therapy. HIV-1 infection impairs the function of neutrophils in the lung and infects CD4(+) cells and alveolar macrophages. Opportunistic infections dramatically increase local HIV replication in the lung cells, especially alveolar macrophages and CD4(+) cells. This enhanced replication increases viral mutations and provides opportunities for viral escape from latent reservoirs. Mortality is increased with more comorbidities in this highly susceptible population. Immunization with vaccines is recommended, especially pneumococcal vaccines, although the vaccine itself may stimulate viral replication. Recent studies show that the lower respiratory tract is a microbial reservoir in HIV-infected individuals rather than being a sterile environment, as originally thought. This may provide new opportunities for preventing opportunistic infections in HIV-infected subjects. Bacterial pneumonia presents an ongoing challenge in these high-risk individuals, particularly in studying the functions of the innate and acquired immune response
— id: 134318, year: 2011, vol: 8, page: 282, stat: Journal Article,

Azithromycin suppresses inflammatory cytokines and induces inhibatory transcription factors in alveolar macrophages
Segal, Leopoldo; Kulkarni, Rohan; Fujita, Yoko; Nolan, Anna; Rom, William N; Weiden, Michael
2011 ;183:?-? #A2853, American journal of respiratory & critical care medicine
— id: 137899, year: 2011, vol: 183, page: ?, stat: Journal Article,

Similar Exposure To World Trade Center (WTC) Dust Produced Variable Lung Function Decline: Defining Most And Least Effected Subgroups In The FDNY Cohort
Ferrier, Natalia; Nolan, Anna; Rom, Wiliam N; Comfort, Ashley L; Prezant, David J; Weiden, Michael D
2010 ;181:- #A1252, American journal of respiratory & critical care medicine
— id: 113679, year: 2010, vol: 181, page: , stat: Journal Article,

Neutrophils Activate Alveolar Macrophages By Producing Caspase-6 Mediated Cleavage Of Interleukin-1 Associated Kinase-M (IRAK-M) In Tuberculosis
Kobayashi, Hiroshi; Nolan, Anna; Naveed, Bushra; Comfort, Ashley L; Rom, William N; Hoshino, Yoshihiko; Weiden, Michael D
2010 ;181:- #A3221, American journal of respiratory & critical care medicine
— id: 113677, year: 2010, vol: 181, page: , stat: Journal Article,

The use of linezolid and nebulized amikacin in a case of Mycobacterium chelonae/Mycobacterium abscessus pulmonary disease
Lee R.A.; Rom W.N.; Addrizzo-Harris D.J.
2010 ;138(4):?-?, Chest
INTRODUCTION: Traditionally, Mycobacterium abscessus pulmonary disease has poor long term response to current antibiotic regimens. The data regarding the clinical efficacy of linezolid and aerosolized amikacin in M. abscessus pulmonary disease is limited. CASE PRESENTATION: A 52 year-old Caucasian female presented in 2004 with scant hemoptysis and intermittent night sweats. Her past medical history was unremarkable. She denied history of pneumonias. She did not smoke tobacco. She worked as a middle school secretary. Computed tomographic (CT) evaluation of the chest showed significant bronchiectasis in the right middle lobe with irregular opacities throughout the right upper lobe and right lower lobe. She was treated empirically with levofloxacin for recurrent episodes of infection with a presumed response. In 2007, she had more severe hemoptysis with several teaspoons of bright red blood that woke her up from sleep at night. M. chelonae and M. abscessus were identified in her sputum and she was started on clarithromycin combined with ciprofloxacin. In 2008, pulmonary function tests showed evidence of decreasing diffusing capacity. Chest CT showed interval increase in the nodular densities primarily in the right middle lobe and many were cavitating. She required hospitalization in 2009 for increasing hemoptysis and underwent IR embolization of branches of the right bronchial artery and right internal mammary artery. Nebulized amikacin 250 mg daily was started along with linezolid 600 mg daily. After 6 months of moxifloxacin, clarithromycin, nebulized amikacin, and linezolid, chest CT in late 2009 showed improvement and there was no further hemoptysis. DISCUSSIONS: Intermittent courses of parenteral therapy combined with and followed by an oral macrolide, aerosolized amikacin, and linezolid may be used to suppress infection and control disease progression of M. abscessus pulmonary disease. (1) Cost and side effects may limit the feasibility of prolonged treatment with parenteral antibiotic therapy. Aminoglycosides exhibit significant concentration-dependent bactericidal activity against nontuberculous mycobacteria. Extended parenteral therapy with aminoglycosides has been avoided due to the substantial risks of nephrotoxicity, ototoxicity, and vestibular toxicity. Aerosolized antibiotic delivery offers the potential advantage of achieving high drug concentrations in the lung with low systemic absorption and diminished risk of systemic toxicities. Aerosolized antibiotics have been used with notable success in the treatment of chronic Pseudomonas aeruginosa infection in patients with cystic fibrosis. In an observational case series, six HIV-negative patients with Mycobacterium avium intracellulare pulmonary infections who had failed standard therapy were administered aerosolized amikacin at 15 mg/kg daily in addition to standard multi-drug macrolide-based oral therapy. Five responded to therapy and achieved symptomatic improvement. Four were sputum culture negative after 6 months of therapy. (2) Approximately 50% of M. abscessus isolates are susceptible or exhibit intermediate susceptibility in vitro to the oxazolidinone linezolid. A small number of patients with M. abscessus lung disease have been treated with linezolid and a companion drug, usually a macrolide, with varied results. Impediments to long-term use of linezolid include the cost and potential side effects of chronic therapy which include peripheral neuropathy and anemia. Once daily dosing of linezolid 600mg instead of the traditional twice daily dosing is currently used by some to treat mycobacterial disease with seemingly fewer side effects and retained antimycobacterial activity. CONCLUSION: Preliminary case series suggest that nonparenteral agents including oral macrolides, aerosolized amikacin, and linezolid may be effective for the treatment of M. abscessus pulmonary disease
— id: 127241, year: 2010, vol: 138, page: ?, stat: Journal Article,

New drugs and regimens for treatment of TB
Leibert, Eric; Rom, William N
2010 Jul;8(7):801-813, Expert review of anti-infective therapy
Tools for effective TB control have been available for years. Case finding, active medications, case management and directly observed therapy are the foundations for the management of TB. The current TB epidemic, centered in resource-limited settings is fueled by the HIV-1 epidemic. Lack of ability to diagnose and treat drug-resistant TB has led to development of more extensive patterns of resistance. Among the currently available drugs, there is reason to hope that rifamycins paired with fluoroquinolones will lead to shorter treatment regimens for drug-susceptible TB. As the result of novel public-private collaborations and investments of resources, new drugs are being developed. These include TMC207, already shown to have activity early in the treatment of multidrug-resistant TB and others that are likely to be active against persistor organisms, and have the prospect to dramatically shorten treatment courses for active and latent TB. Given that these drugs have novel mechanisms of action, combinations have the prospect to be highly active even against multidrug-resistant organisms
— id: 111618, year: 2010, vol: 8, page: 801, stat: Journal Article,

Does asbestos exposure (asbestosis) cause (clinical) airway obstruction (small airway disease)?
Miller, Albert; Rom, William N
2010 Aug 15;182(4):444-445, American journal of respiratory & critical care medicine
— id: 133824, year: 2010, vol: 182, page: 444, stat: Journal Article,

WTC PM2.5 stimulates a more intense inflammatory response in human BAL cells than other ambient PM2.5 from NYC and surrounding environs
Naveed B.; Weiden M.D.; Rom W.N.; Prezant D.J.; Comfort A.; Chen L.; Kwon S.; Chen Y.; Gordon T.; Nolan A.
2010 ;3(2):S48-S48, Clinical & Translational Science
OBJECTIVES: Particulate matter (PM) exposure causes adverse health effects. The WTC collapse led to significant PM exposure and lung injury (Weiden et al. Chest 2009). The mechanism by which WTC PM causes pulmonary morbidity is not understood. We are investigating the differential cytokine effects on human alveolar cells, comparing ambient PM of WTC to ambient PM from NYC, South Bronx (SB) and Sterling Forest (SF), a rural area northwest of NYC. METHODS AND POPULATION: AM were obtained from Bronchoalveolar lavage (BAL) by adherence overnight. AM were exposed to 50mug/mL suspensions of WTC, SB, and SF PM2.5. Media alone was the negative control and 40 ng/mL of LPS was the positive control. After 24hrs, supernatants were collected and analyzed in duplicate using Human Cytokine Panel I (Millipore) on a Luminex-200. RESULTS: Fold induction of mediators was expressed as ratios of PM exposure/media alone. Exposure to WTC PM was markedly more inflammatory than SB and SF. The most significant inductions were of the leukocyte growth factors (GM-CSF, G-CSF), a promoter of angiogenesis (VEGF), the chemokine (RANTES) and the potent multifunctional cytokine IL-6. LPS caused a greater induction for all of the analytes when compared to WTC PM except for IL-1ra. SIGNIFICANCE OF STUDY: WTC PM2.5 produces a marked inflammatory effect in comparison to PM2.5 from both NYC, SB and rural sites. The large number of cytokines induced by WTC PM may drive airway injury and may be biomarkers for lung injury. WTC PM has been observed in induced sputum obtained 9 months after 9/11/2001 and so the elaboration of cytokines may underlie the severe and long lasting health effects produced by exposure to WTC PM
— id: 111408, year: 2010, vol: 3, page: S48, stat: Journal Article,

Microparticle Activity Is Increased In Murine Polymicrobial Sepsis
Naveed, Bushra; Weiden, Michael D; Comfort, Ashley L; Chen, Yingdi; Kwon, Sophia; Rom, William N; Nolan, Anna
2010 ;181:- #1375, American journal of respiratory & critical care medicine
— id: 113680, year: 2010, vol: 181, page: , stat: Journal Article,

WTC PM2.5 Stimulates A More Intense Inflammatory Response In Human BAL Cells Than Other Ambient PM2.5 From NYC And Surrounding Environs
Naveed, Bushra; Weiden, Michael D; Rom, William N; Prezant, David J; Comfort, Ashley L; Chen, Yingdi; Kwon, Sophia; Chen, Lung Chi; Gordon, Terry; Nolan, Anna
2010 ;181:- #A1158, American journal of respiratory & critical care medicine
— id: 113678, year: 2010, vol: 181, page: , stat: Journal Article,

UNLOCKING BIOMARKER DISCOVERY FOR EARLY DETECTION OF LUNG CANCER
Ostroff, R.; Bigbee, W.; Franklin, W.; Gold, L.; Mehan, M.; Miller, Y.; Pass, H.; Rom, W.; Siegfried, J.; Stewart, A.; Walker, J.; Weissfeld, J.; Williams, S.; Zichi, D.; Brody, E.
2010 AUG ;31:S14-S14, Tumour biology
— id: 132750, year: 2010, vol: 31, page: S14, stat: Journal Article,

Unlocking biomarker discovery: large scale application of aptamer proteomic technology for early detection of lung cancer
Ostroff, Rachel M; Bigbee, William L; Franklin, Wilbur; Gold, Larry; Mehan, Mike; Miller, York E; Pass, Harvey I; Rom, William N; Siegfried, Jill M; Stewart, Alex; Walker, Jeffrey J; Weissfeld, Joel L; Williams, Stephen; Zichi, Dom; Brody, Edward N
2010 ;5(12):e15003-e15003, PLoS ONE
BACKGROUND: Lung cancer is the leading cause of cancer deaths worldwide. New diagnostics are needed to detect early stage lung cancer because it may be cured with surgery. However, most cases are diagnosed too late for curative surgery. Here we present a comprehensive clinical biomarker study of lung cancer and the first large-scale clinical application of a new aptamer-based proteomic technology to discover blood protein biomarkers in disease. METHODOLOGY/PRINCIPAL FINDINGS: We conducted a multi-center case-control study in archived serum samples from 1,326 subjects from four independent studies of non-small cell lung cancer (NSCLC) in long-term tobacco-exposed populations. Sera were collected and processed under uniform protocols. Case sera were collected from 291 patients within 8 weeks of the first biopsy-proven lung cancer and prior to tumor removal by surgery. Control sera were collected from 1,035 asymptomatic study participants with >/= 10 pack-years of cigarette smoking. We measured 813 proteins in each sample with a new aptamer-based proteomic technology, identified 44 candidate biomarkers, and developed a 12-protein panel (cadherin-1, CD30 ligand, endostatin, HSP90alpha, LRIG3, MIP-4, pleiotrophin, PRKCI, RGM-C, SCF-sR, sL-selectin, and YES) that discriminates NSCLC from controls with 91% sensitivity and 84% specificity in cross-validated training and 89% sensitivity and 83% specificity in a separate verification set, with similar performance for early and late stage NSCLC. CONCLUSIONS/SIGNIFICANCE: This study is a significant advance in clinical proteomics in an area of high unmet clinical need. Our analysis exceeds the breadth and dynamic range of proteome interrogated of previously published clinical studies of broad serum proteome profiling platforms including mass spectrometry, antibody arrays, and autoantibody arrays. The sensitivity and specificity of our 12-biomarker panel improves upon published protein and gene expression panels. Separate verification of classifier performance provides evidence against over-fitting and is encouraging for the next development phase, independent validation. This careful study provides a solid foundation to develop tests sorely needed to identify early stage lung cancer
— id: 119198, year: 2010, vol: 5, page: e15003, stat: Journal Article,

Molecular Analysis of Plasma DNA for the Early Detection of Lung Cancer by Quantitative Methylation-Specific PCR
Ostrow, KL; Hoque, MO; Loyo, M; Brait, M; Greenberg, A; Siegfried, JM; Grandis, JR; Davis, AG; Bigbee, WL; Rom, W; Sidransky, D
2010 JUL 1 ;16(13):3463-3472, Clinical cancer research
Purpose: Aberrant promoter hypermethylation of tumor suppressor genes is a promising marker for lung cancer detection. We investigated the likelihood of detecting aberrant DNA methylation of tumor suppressor genes in plasma samples of patients with abnormalities of the lung detected upon computed tomography (CT) scan. Experimental Design: In a small evaluation cohort, four gene promoters (DCC, Kif1a, NISCH, and Rarb) were found to be methylated with increased frequency in samples from cancer patients specifically. We then examined DNA from 93 plasma samples from patients with abnormal findings in the lung detected upon CT scan for aberrant methylation of these four gene promoters by quantitative fluorogenic real-time PCR. The patients were divided into two groups, ground glass opacity (n = 23) and cancerous tumors (n = 70). Plasma DNA from age-matched nodule-free individuals were used as controls (n = 80). Results: In plasma, 73% of patients with cancerous tumors showed methylation of at least one gene with a specificity of 71% (P = 0.0001). Only 22% patients with ground glass opacity exhibited methylation of at least one gene. When smoking history was taken into account, 72% of cancer patients with no smoking history or those who smoked < 20 pack-years showed methylation of at least one gene with 100% specificity (P = 0.05) when compared with matched controls. Among heavy smokers with 20+ pack-years of smoking history, 30% of the control group and 73% of the patients with cancerous tumors showed methylation (P = 0.0001). Conclusions: These biomarkers can distinguish between cancerous and noncancerous abnormal CT findings. Clin Cancer Res; 16(13); 3463-72. (C) 2010 AACR
— id: 110858, year: 2010, vol: 16, page: 3463, stat: Journal Article,

Fissural Nodular Densities: Inherent Stability and Benignity and Variability in Descriptive Nomenclature
Pryluck, D; Shiau, M; Wnorowski, A; Naidich, D; Sanger, J; Rom, W
2010 MAY ;194(5):-, American journal of roentgenology
— id: 111950, year: 2010, vol: 194, page: , stat: Journal Article,

Identification of an autoantibody panel to separate lung cancer from smokers and nonsmokers
Rom, William N; Goldberg, Judith D; Addrizzo-Harris, Doreen; Watson, Heather N; Khilkin, Michael; Greenberg, Alissa K; Naidich, David P; Crawford, Bernard; Eylers, Ellen; Liu, Daorong; Tan, Eng M
2010 ;10:234-234, BMC cancer
BACKGROUND: Sera from lung cancer patients contain autoantibodies that react with tumor associated antigens (TAAs) that reflect genetic over-expression, mutation, or other anomalies of cell cycle, growth, signaling, and metabolism pathways. METHODS: We performed immunoassays to detect autoantibodies to ten tumor associated antigens (TAAs) selected on the basis of previous studies showing that they had preferential specificity for certain cancers. Sera examined were from lung cancer patients (22); smokers with ground-glass opacities (GGOs) (46), benign solid nodules (55), or normal CTs (35); and normal non-smokers (36). Logistic regression models based on the antibody biomarker levels among the high risk and lung cancer groups were developed to identify the combinations of biomarkers that predict lung cancer in these cohorts. RESULTS: Statistically significant differences in the distributions of each of the biomarkers were identified among all five groups. Using Receiver Operating Characteristic (ROC) curves based on age, c-myc, Cyclin A, Cyclin B1, Cyclin D1, CDK2, and survivin, we obtained a sensitivity = 81% and specificity = 97% for the classification of cancer vs smokers(no nodules, solid nodules, or GGO) and correctly predicted 31/36 healthy controls as noncancer. CONCLUSION: A pattern of autoantibody reactivity to TAAs may distinguish patients with lung cancer versus smokers with normal CTs, stable solid nodules, ground glass opacities, or normal healthy never smokers
— id: 110098, year: 2010, vol: 10, page: 234, stat: Journal Article,

Emerging exposures and respiratory health: world trade center dust
Rom, William N; Reibman, Joan; Rogers, Linda; Weiden, Michael D; Oppenheimer, Beno; Berger, Kenneth; Goldring, Roberta; Harrison, Denise; Prezant, David
2010 May;7(2):142-145, Proceedings of the American Thoracic Society
The attack on the World Trade Center (WTC) on 9/11/2001 produced a massive dust cloud with acute exposure, and the rubble pile burning over 3 months exposed more than 300,000 residents, rescue workers, and clean-up workers. Firefighters in the New York City Fire Department had significant respiratory symptoms characterized by cough, dyspnea, gastroesophageal reflux, and nasal stuffiness with a significant 1-year decline in FVC and FEV(1). Bronchial hyperreactivity measured by methacholine challenge correlated with bronchial wall thickening on CT scans. Compared with the NHANES III data for FVC and FEV(1), 32% of 2,000 WTC dust-exposed residents and clean-up workers were below the lower 5th percentile. The most common abnormality was a low FVC pattern, a finding similar to that also described for individuals in rescue and recovery activities. Among those complaining of respiratory symptoms and normal spirometry, almost half had abnormalities detected with impedance oscillometry consistent with distal airways' disease. Follow-up with the WTC Health Registry and the WTC Environmental Health Center will help discern whether treatment with anti-inflammatory medications or bronchodilators in those with respiratory symptoms may prevent the development of chronic obstructive pulmonary disease
— id: 109531, year: 2010, vol: 7, page: 142, stat: Journal Article,

Optical detection of buccal epithelial nanoarchitectural alterations in patients harboring lung cancer: implications for screening
Roy, Hemant K; Subramanian, Hariharan; Damania, Dhwanil; Hensing, Thomas A; Rom, William N; Pass, Harvey I; Ray, Daniel; Rogers, Jeremy D; Bogojevic, Andrej; Shah, Maitri; Kuzniar, Tomasz; Pradhan, Prabhakar; Backman, Vadim
2010 Oct 15;70(20):7748-7754, Cancer research
We have recently developed a novel optical technology, partial wave spectroscopic (PWS) microscopy, which is exquisitely sensitive to the nanoarchitectural manifestation of the genetic/epigenetic alterations of field carcinogenesis. Our approach was to screen for lung cancer by assessing the cheek cells based on emerging genetic/epigenetic data which suggests that the buccal epithelium is altered in lung field carcinogenesis. We performed PWS analysis from microscopically normal buccal epithelial brushings from smokers with and without lung cancer (n = 135). The PWS parameter, disorder strength of cell nanoarchitecture (L(d)), was markedly (>50%) elevated in patients harboring lung cancer compared with neoplasia-free smokers. The performance characteristic was excellent with an area under the receiver operator characteristic curve of >0.80 and was equivalent for both disease stage (early versus late) and histologies (small cell versus non-small cell lung cancers). An independent data set validated the findings with only a minimal degradation of performance characteristics. Our results offer proof of concept that buccal PWS may potentially herald a minimally intrusive prescreening test that could be integral to the success of lung cancer population screening programs
— id: 135525, year: 2010, vol: 70, page: 7748, stat: Journal Article,

Obstructive airways disease with air trapping among firefighters exposed to World Trade Center dust
Weiden, Michael D; Ferrier, Natalia; Nolan, Anna; Rom, William N; Comfort, Ashley; Gustave, Jackson; Zeig-Owens, Rachel; Zheng, Shugi; Goldring, Roberta M; Berger, Kenneth I; Cosenza, Kaitlyn; Lee, Roy; Webber, Mayris P; Kelly, Kerry J; Aldrich, Thomas K; Prezant, David J
2010 Mar;137(3):566-574, Chest
BACKGROUND: The World Trade Center (WTC) collapse produced a massive exposure to respirable particulates in New York City Fire Department (FDNY) rescue workers. This group had spirometry examinations pre-September 11, 2001, and post-September 11, 2001, demonstrating declines in lung function with parallel declines in FEV(1) and FVC. To date, the underlying pathophysiologic cause for this has been open to question. METHODS: Of 13,234 participants in the FDNY-WTC Monitoring Program, 1,720 (13%) were referred for pulmonary subspecialty evaluation at a single institution. Evaluation included 919 full pulmonary function tests, 1,219 methacholine challenge tests, and 982 high-resolution chest CT scans. RESULTS: At pulmonary evaluation (median 34 months post-September 11, 2001), median values were FEV(1) 93% predicted (interquartile range [IQR], 83%-101%), FVC 98% predicted (IQR, 89%-106%), and FEV(1)/FVC 0.78 (IQR, 0.72-0.82). The residual volume (RV) was 123% predicted (IQR, 106%-147%) with nearly all participants having normal total lung capacity, functional residual capacity, and diffusing capacity of carbon monoxide. Also, 1,051/1,720 (59%) had obstructive airways disease based on at least one of the following: FEV(1)/FVC, bronchodilator responsiveness, hyperreactivity, or elevated RV. After adjusting for age, gender, race, height and weight, and tobacco use, the decline in FEV(1) post-September 11, 2001, was significantly correlated with increased RV percent predicted (P < .0001), increased bronchodilator responsiveness (P < .0001), and increased hyperreactivity (P = .0056). CT scans demonstrated bronchial wall thickening that was significantly associated with the decline in FEV(1) post-September 11, 2001 (P = .024), increases in hyperreactivity (P < .0001), and increases in RV (P < .0001). Few had evidence for interstitial disease. CONCLUSIONS: Airways obstruction was the predominant physiologic finding underlying the reduction in lung function post-September 11, 2001, in FDNY WTC rescue workers presenting for pulmonary evaluation
— id: 109029, year: 2010, vol: 137, page: 566, stat: Journal Article,

Immunomodulation with recombinant interferon-gamma1b in pulmonary tuberculosis
Dawson, Rod; Condos, Rany; Tse, Doris; Huie, Maryann L; Ress, Stanley; Tseng, Chi-Hong; Brauns, Clint; Weiden, Michael; Hoshino, Yoshihiko; Bateman, Eric; Rom, William N
2009 ;4(9):e6984-e6984, PLoS ONE
BACKGROUND: Current treatment regimens for pulmonary tuberculosis require at least 6 months of therapy. Immune adjuvant therapy with recombinant interferon-gamma1b (rIFN-gammab) may reduce pulmonary inflammation and reduce the period of infectivity by promoting earlier sputum clearance. METHODOLOGY/PRINCIPAL FINDINGS: We performed a randomized, controlled clinical trial of directly observed therapy (DOTS) versus DOTS supplemented with nebulized or subcutaneously administered rIFN-gamma1b over 4 months to 89 patients with cavitary pulmonary tuberculosis. Bronchoalveolar lavage (BAL) and blood were sampled at 0 and 4 months. There was a significant decline in levels of inflammatory cytokines IL-1beta, IL-6, IL-8, and IL-10 in 24-hour BAL supernatants only in the nebulized rIFN-gamma1b group from baseline to week 16. Both rIFN-gamma1b groups showed significant 3-fold increases in CD4+ lymphocyte response to PPD at 4 weeks. There was a significant (p = 0.03) difference in the rate of clearance of Mtb from the sputum smear at 4 weeks for the nebulized rIFN-gamma1b adjuvant group compared to DOTS or DOTS with subcutaneous rIFN-gamma1b. In addition, there was significant reduction in the prevalence of fever, wheeze, and night sweats at 4 weeks among patients receiving rFN-gamma1b versus DOTS alone. CONCLUSION: Recombinant interferon-gamma1b adjuvant therapy plus DOTS in cavitary pulmonary tuberculosis can reduce inflammatory cytokines at the site of disease, improve clearance of Mtb from the sputum, and improve constitutional symptoms. TRIAL REGISTRATION: ClinicalTrials.gov NCT00201123
— id: 104334, year: 2009, vol: 4, page: e6984, stat: Journal Article,

Caspase 6 cleaves the macrophage inhibitor IRAK-M in contact dependent innate immune activation
Kobayashi H; Nolan A; Naveed B; Hoshino Y; Hoshino S; Rom WN; Weiden MD
2009 April;179:A5689-A5689, American journal of respiratory & critical care medicine
— id: 101390, year: 2009, vol: 179, page: A5689, stat: Journal Article,

Wnt pathway in pulmonary fibrosis in the bleomycin mouse model
Liu, Li; Carron, Benjamin; Yee, Herman T; Yie, Ting-An; Hajjou, Mustapha; Rom, William
2009 ;28(2):99-108, Journal of environmental pathology, toxicology & oncology
BACKGROUND: The Wnt/beta-catenin signaling pathway plays an important role in regulating cellular differentiation, proliferation, and polarity. METHODS: We used bleomycin to induce lung fibrosis in a transgenic Wnt reporter mouse to characterize the expression pattern of cyclin D1, MMP-7, and TGF-beta in conjunction with the Wnt/beta-catenin signaling pathway. LacZ expression reveals the Wnt/beta-catenin signaling pathway through the activated (nuclear) beta-catenin and coactivation of LEF/TCF transcription factors. X-gal staining and immunohistochemical staining of beta-catenin, cyclin D1, MMP-7, and TGF-beta were assessed after bleomycin administration. RESULTS: We observed LacZ expression in bronchiolar proliferative lesions and the epithelium in remodeled cystic and fibrotic areas at both 1 and 3 weeks. Nuclear beta-catenin staining was prominent in epithelial cells of remodeled and fibrotic areas at 3 weeks. MMP-7 was faint in basement membranes of airways and matrix zones in fibrotic areas at 3 weeks. Cyclin D1 was observed in alveolar macrophages (AM), alveolar epithelium, and fibrotic areas consistent with rapid cell turnover in these areas at both 1 and 3 weeks. TGF-beta was faintly staining in alveolar macrophages and epithelial cells at 3 weeks. CONCLUSION: The Wnt/beta-catenin pathway is activated in bleomycin-induced lung fibrosis, and downstream genes were localized in AM, alveolar epithelium, and interstitium
— id: 104353, year: 2009, vol: 28, page: 99, stat: Journal Article,

CD80 mediates the innate inflammatory response in murine polymicrobial sepsis
Naveed B; Nolan A; Weiden WN; Rom WN; Gold JA
2009 April;179:A1142-A1142, American journal of respiratory & critical care medicine
— id: 101392, year: 2009, vol: 179, page: A1142, stat: Journal Article,

Costimulatory molecules in the inflammatory response to PM2.5 exposure
Naveed B; Weiden MD; Nolan A; Kang GS; Rom WN; Chen LC
2009 April;179:A3138-A3138, American journal of respiratory & critical care medicine
— id: 101389, year: 2009, vol: 179, page: A3138, stat: Journal Article,

Differential role for CD80 and CD86 in the regulation of the innate immune response in murine polymicrobial sepsis
Nolan, Anna; Kobayashi, Hiroshi; Naveed, Bushra; Kelly, Ann; Hoshino, Yoshihiko; Hoshino, Satomi; Karulf, Matthew R; Rom, William N; Weiden, Michael D; Gold, Jeffrey A
2009 ;4(8):e6600-e6600, PLoS ONE
BACKGROUND: Inflammation in the early stages of sepsis is governed by the innate immune response. Costimulatory molecules are a receptor/ligand class of molecules capable of regulation of inflammation in innate immunity via macrophage/neutrophil contact. We recently described that CD80/86 ligation is required for maximal macrophage activation and CD80/86(-/-) mice display reduced mortality and inflammatory cytokine production after cecal ligation and puncture (CLP). However, these data also demonstrate differential regulation of CD80 and CD86 expression in sepsis, suggesting a divergent role for these receptors. Therefore, the goal of this study was to determine the individual contribution of CD80/86 family members in regulating inflammation in sepsis. METHODOLOGY/PRINCIPAL FINDINGS: CD80(-/-) mice had improved survival after CLP when compared to WT or CD86(-/-) mice. This was associated with preferential attenuation of inflammatory cytokine production in CD80(-/-) mice. Results were confirmed with pharmacologic blockade, with anti-CD80 mAb rescuing mice when administered before or after CLP. In vitro, activation of macrophages with neutrophil lipid rafts caused selective disassociation of IRAK-M, a negative regulator of NF-kappaB signaling from CD80; providing a mechanism for preferential regulation of cytokine production by CD80. Finally, in humans, upregulation of CD80 and loss of constitutive CD86 expression on monocytes was associated with higher severity of illness and inflammation confirming the findings in our mouse model. CONCLUSIONS: In conclusion, our data describe a differential role for CD80 and CD86 in regulation of inflammation in the innate immune response to sepsis. Future therapeutic strategies for blockade of the CD80/86 system in sepsis should focus on direct inhibition of CD80
— id: 101388, year: 2009, vol: 4, page: e6600, stat: Journal Article,

Characteristics of a residential and working community with diverse exposure to World Trade Center dust, gas, and fumes
Reibman, Joan; Liu, Mengling; Cheng, Qinyi; Liautaud, Sybille; Rogers, Linda; Lau, Stephanie; Berger, Kenneth I; Goldring, Roberta M; Marmor, Michael; Fernandez-Beros, Maria Elena; Tonorezos, Emily S; Caplan-Shaw, Caralee E; Gonzalez, Jaime; Filner, Joshua; Walter, Dawn; Kyng, Kymara; Rom, William N
2009 May;51(5):534-541, Journal of occupational & environmental medicine
OBJECTIVE: To describe physical symptoms in those local residents, local workers, and cleanup workers who were enrolled in a treatment program and had reported symptoms and exposure to the dust, gas, and fumes released with the destruction of the World Trade Center (WTC) on September 11, 2001. METHODS: Symptomatic individuals underwent standardized evaluation and subsequent treatment. RESULTS: One thousand eight hundred ninety-eight individuals participated in the WTC Environmental Health Center between September 2005 and May 2008. Upper and lower respiratory symptoms that began after September 11, 2001 and persisted at the time of examination were common in each exposure population. Many (31%) had spirometry measurements below the lower limit of normal. CONCLUSIONS: Residents and local workers as well as those with work-associated exposure to WTC dust have new and persistent respiratory symptoms with lung function abnormalities 5 or more years after the WTC destruction
— id: 98897, year: 2009, vol: 51, page: 534, stat: Journal Article,

Preliminary validation of a lung cancer diagnostic biomarker panel identified through mass spectrometry-based discovery in cancer tissues and cell lines
Rom, WN; Pass, HI; FitzHugh, W; Dhariwal, G; Heidbrink, J; Ruben, SM; Birse, CE
2009 SEP ;4(9):S380-S381, Journal of thoracic oncology
— id: 102465, year: 2009, vol: 4, page: S380, stat: Journal Article,

Gene expression profiles in peripheral blood mononuclear cells can distinguish patients with non-small cell lung cancer from patients with nonmalignant lung disease
Showe, Michael K; Vachani, Anil; Kossenkov, Andrew V; Yousef, Malik; Nichols, Calen; Nikonova, Elena V; Chang, Celia; Kucharczuk, John; Tran, Bao; Wakeam, Elliot; Yie, Ting An; Speicher, David; Rom, William N; Albelda, Steven; Showe, Louise C
2009 Dec 15;69(24):9202-9210, Cancer research
Early diagnosis of lung cancer followed by surgery presently is the most effective treatment for non-small cell lung cancer (NSCLC). An accurate, minimally invasive test that could detect early disease would permit timely intervention and potentially reduce mortality. Recent studies have shown that the peripheral blood can carry information related to the presence of disease, including prognostic information and information on therapeutic response. We have analyzed gene expression in peripheral blood mononuclear cell samples including 137 patients with NSCLC tumors and 91 patient controls with nonmalignant lung conditions, including histologically diagnosed benign nodules. Subjects were primarily smokers and former smokers. We have identified a 29-gene signature that separates these two patient classes with 86% accuracy (91% sensitivity, 80% specificity). Accuracy in an independent validation set, including samples from a new location, was 78% (sensitivity of 76% and specificity of 82%). An analysis of this NSCLC gene signature in 18 NSCLCs taken presurgery, with matched samples from 2 to 5 months postsurgery, showed that in 78% of cases, the signature was reduced postsurgery and disappeared entirely in 33%. Our results show the feasibility of using peripheral blood gene expression signatures to identify early-stage NSCLC in at-risk populations
— id: 149815, year: 2009, vol: 69, page: 9202, stat: Journal Article,

Standard operating procedures for serum and plasma collection: early detection research network consensus statement standard operating procedure integration working group
Tuck, Melissa K; Chan, Daniel W; Chia, David; Godwin, Andrew K; Grizzle, William E; Krueger, Karl E; Rom, William; Sanda, Martin; Sorbara, Lynn; Stass, Sanford; Wang, Wendy; Brenner, Dean E
2009 Jan;8(1):113-117, Journal of proteome research
Specimen collection is an integral component of clinical research. Specimens from subjects with various stages of cancers or other conditions, as well as those without disease, are critical tools in the hunt for biomarkers, predictors, or tests that will detect serious diseases earlier or more readily than currently possible. Analytic methodologies evolve quickly. Access to high-quality specimens, collected and handled in standardized ways that minimize potential bias or confounding factors, is key to the 'bench to bedside' aim of translational research. It is essential that standard operating procedures, 'the how' of creating the repositories, be defined prospectively when designing clinical trials. Small differences in the processing or handling of a specimen can have dramatic effects in analytical reliability and reproducibility, especially when multiplex methods are used. A representative working group, Standard Operating Procedures Internal Working Group (SOPIWG), comprised of members from across Early Detection Research Network (EDRN) was formed to develop standard operating procedures (SOPs) for various types of specimens collected and managed for our biomarker discovery and validation work. This report presents our consensus on SOPs for the collection, processing, handling, and storage of serum and plasma for biomarker discovery and validation
— id: 135219, year: 2009, vol: 8, page: 113, stat: Journal Article,

Diagnosis of non-small cell lung cancer from peripheral blood gene expression
Vachani, A; Kossenkov, A; Rom, WN; Albelda, SM; Showe, MK; Showe, LC
2009 SEP ;4(9):S515-S516, Journal of thoracic oncology
— id: 102467, year: 2009, vol: 4, page: S515, stat: Journal Article,

World Trade Center collapse produced airway injury and air trapping
Weiden MD; Ferrier N; Nolan A; Rom WN; Comfort A; Gustave J; Zheng S; Goldring R; Berger K; Cosenz K; Beringer A; Glass L; Lee R; Zeig-Owens R; Webber M; Prezant DJ
2009 ;179:A5852-A5852, American journal of respiratory & critical care medicine
— id: 101391, year: 2009, vol: 179, page: A5852, stat: Journal Article,

Case series report of a linezolid-containing regimen for extensively drug-resistant tuberculosis
Condos, Rany; Hadgiangelis, Nicos; Leibert, Eric; Jacquette, Germaine; Harkin, Timothy; Rom, William N
2008 Jul;134(1):187-192, Chest
OBJECTIVE: To determine whether linezolid is safe and well tolerated in the treatment of extensively drug-resistant tuberculosis (XDR-TB). MATERIALS AND METHODS: The was conducted in a specialized tuberculosis ward for multidrug-resistant tuberculosis (MDR-TB) on the Chest Service of Bellevue Hospital Center, which is a 768-bed public hospital in New York City. Seven patients with confirmed MDR-TB or XDR-TB who were still culture positive despite appropriate directly observed therapy were treated with a regimen containing linezolid and at least one other active agent. RESULTS: The linezolid-containing regimen led to sustained negative conversion of sputum cultures and radiographic improvement in all patients. Long-term therapy (longest duration of therapy, 28 months) was well tolerated in most patients. Neutropenia developed in three patients, but was reversible, and peripheral neuropathy developed in two patients. CONCLUSIONS: Linezolid remains a promising possible addition to our therapeutic armamentarium against XDR-TB. Linezolid is associated with side effects that can be adequately managed. Further studies to define the mechanism of action and optimum dose should be performed
— id: 81065, year: 2008, vol: 134, page: 187, stat: Journal Article,

Mycobacterium tuberculosis induces CCL18 expression in human macrophages
Ferrara, G; Bleck, B; Richeldi, L; Reibman, J; Fabbri, L M; Rom, W N; Condos, R
2008 Dec;68(6):668-674, Scandinavian journal of immunology
The interaction of Mycobacterium tuberculosis (MTB) with the immune system is mediated by cytokine and chemokine responses of macrophages and/or dendritic cells. Chemokine (C-C motif) ligand 18 (CCL18) and interleukin (IL)-10 are major factors secreted by phagocytes, postulated to recruit naive T lymphocytes and inhibit pro-inflammatory cells. Our study investigated the role of CCL18 and IL-10 in an in vitro model of infection by MTB in human macrophages. CD14(+) monocytes, obtained from the peripheral blood of eight healthy donors, differentiated in monocyte-derived macrophages (MDM) with monocyte-colony stimulating factor (100 ng/ml) for 6 days, were stimulated in vitro with lipopolysaccharide (LPS) (1 microg/ml) and with heat killed MTB Hv37Ra (multiplicity of infection 1:5) for 24 h. Alveolar macrophages from five healthy donors were infected with MTB Hv37RA. CCL18 protein and mRNA were detected by enzyme-linked immunosorbent assay (ELISA) and real-time PCR, IL-10 levels by ELISA. Stimulation of MDM with LPS or MTB led to a significant increase in CCL18 protein (control 2.67 +/- 0.46 ng/ml, LPS 4.05 +/- 0.56 ng/ml, with MTB 6.70 +/- 1.59 ng/ml, n = 5, P < 0.05) and specific mRNA levels (control 0.09 +/- 0.01, LPS 0.24 +/- 0.11, with MTB 0.34 +/- 0.08 CCL18/Glyceraldehyde 3-phosphate dehydrogenase (GAPDH), n = 3, P < 0.05). A significant increase of the production of CCL18 was observed in infected alveolar macrophages. IL-10 levels increased from 38.52 +/- 26.38 pg/ml in control cells to 1129.32 +/- 235.00 and 974.25 +/- 164.46 pg/ml in LPS and MTB treated cells, respectively (P < 0.05). Up-regulation of CCL18 and IL-10 in macrophages by MTB may be involved in the recruitment of naive T cells in association with local suppressive immunity against intracellular pathogens. This could represent a mechanism of tolerance during the early phases of infection
— id: 91453, year: 2008, vol: 68, page: 668, stat: Journal Article,

The burden of exposure-related diffuse lung disease
Goldyn, Sheryl R; Condos, Rany; Rom, William N
2008 Dec;29(6):591-602, Seminars in respiratory & critical care medicine
Estimating the burden of exposure-related diffuse lung disease in terms of health effects and economic burden remains challenging. Labor statistics are inadequate to define the scope of the problem, and few studies have analyzed the prevalence of exposure-related illnesses and the subsequent health care cost. Well-defined exposures, such as those associated with coal mines, asbestos mines, and stonecutting, have led to more accurate assessment of prevalence and cost. As governmental regulation of workplace exposure has increased, the prevalence of diseases such as silicosis and coal workers' pneumoconiosis has diminished. However, the health and economic effects of diseases with long latency periods, such as asbestosis and mesothelioma, continue to increase in the short term. Newer exposures, such as those related to air pollution, nylon flock, and the World Trade Center collapse, have added to these costs. As a result, estimates of cost for occupational diseases, including respiratory illnesses, exceed $26 billion annually, and the true economic burden is likely much higher
— id: 94493, year: 2008, vol: 29, page: 591, stat: Journal Article,

Performance of mitochondrial DNA mutations detecting early stage cancer
Jakupciak, John P; Maragh, Samantha; Markowitz, Maura E; Greenberg, Alissa K; Hoque, Mohammad O; Maitra, Anirban; Barker, Peter E; Wagner, Paul D; Rom, William N; Srivastava, Sudhir; Sidransky, David; O'Connell, Catherine D
2008 ;8:285-285, BMC cancer
BACKGROUND: Mutations in the mitochondrial genome (mtgenome) have been associated with cancer and many other disorders. These mutations can be point mutations or deletions, or admixtures (heteroplasmy). The detection of mtDNA mutations in body fluids using resequencing microarrays, which are more sensitive than other sequencing methods, could provide a strategy to measure mutation loads in remote anatomical sites. METHODS: We determined the mtDNA mutation load in the entire mitochondrial genome of 26 individuals with different early stage cancers (lung, bladder, kidney) and 12 heavy smokers without cancer. MtDNA was sequenced from three matched specimens (blood, tumor and body fluid) from each cancer patient and two matched specimens (blood and sputum) from smokers without cancer. The inherited wildtype sequence in the blood was compared to the sequences present in the tumor and body fluid, detected using the Affymetrix Genechip Human Mitochondrial Resequencing Array 1.0 and supplemented by capillary sequencing for noncoding region. RESULTS: Using this high-throughput method, 75% of the tumors were found to contain mtDNA mutations, higher than in our previous studies, and 36% of the body fluids from these cancer patients contained mtDNA mutations. Most of the mutations detected were heteroplasmic. A statistically significantly higher heteroplasmy rate occurred in tumor specimens when compared to both body fluid of cancer patients and sputum of controls, and in patient blood compared to blood of controls. Only 2 of the 12 sputum specimens from heavy smokers without cancer (17%) contained mtDNA mutations. Although patient mutations were spread throughout the mtDNA genome in the lung, bladder and kidney series, a statistically significant elevation of tRNA and ND complex mutations was detected in tumors. CONCLUSION: Our findings indicate comprehensive mtDNA resequencing can be a high-throughput tool for detecting mutations in clinical samples with potential applications for cancer detection, but it is unclear the biological relevance of these detected mitochondrial mutations. Whether the detection of tumor-specific mtDNA mutations in body fluidsy this method will be useful for diagnosis and monitoring applications requires further investigation
— id: 94495, year: 2008, vol: 8, page: 285, stat: Journal Article,

Molecular origin of endemic leprosy in New York City
Keo, Thormika; Martiniuk, Frank; Latkowski, JoAnn; Cabrera, Aloys; Rom, William; Levis, William R
2008 Mar 15;46(6):899-901, Clinical infectious diseases
We report an indigenous case of leprosy in New York City in an immunocompetent patient who was infected with a Mycobacterium leprae genotype that is consistent with an exogenous origin. Physicians in the eastern United States should be alerted that, although most patients who develop leprosy in the United States are foreign born, native-born Americans are also susceptible to the infection
— id: 76393, year: 2008, vol: 46, page: 899, stat: Journal Article,

Identification of annexin 1 as a novel autoantigen in acute exacerbation of idiopathic pulmonary fibrosis
Kurosu, Katsushi; Takiguchi, Yuichi; Okada, Osamu; Yumoto, Norio; Sakao, Seiichiro; Tada, Yuji; Kasahara, Yasunori; Tanabe, Nobuhiro; Tatsumi, Koichiro; Weiden, Michael; Rom, William N; Kuriyama, Takayuki
2008 Jul 1;181(1):756-767, Journal of immunology
Consistent with the hypothesis that pulmonary epithelial apoptosis is the key to the acute exacerbation of idiopathic pulmonary fibrosis (IPF), we conducted serological identification of Ags by recombinant expression cloning (SEREX) analysis using type II alveolar cell carcinoma (A549) cell lines to identify disease-related Abs. In a survey of Abs to the recombinant autoantigens identified by SEREX analysis, five Abs were identified as novel candidates for the acute exacerbation of IPF. Abs to annexin 1 were detected in 47 and 53% of the sera and bronchoalveolar lavage materials from patients with acute exacerbation of IPF. Some identical TCR Vbeta genes were identified in sequential materials obtained at 1-3 mo in all 10 acute exacerbation IPF cases, suggesting that some infiltrating CD4-positive T cells sharing limited epitopes expand by Ag-driven stimulation during disease extension. The CDR3 region of these identical TCR Vbeta genes showed high homology with the N-terminal portion of annexin 1, including in the HLA-DR ligand epitopes predicted by TEPITOPE analysis. By Western blotting analysis and observation of the CD4-positive T cell responses in bronchoalveolar lavage samples, the N-terminal portion of annexin 1 was cleaved and found to induce marked proliferative responses of CD4-positive T cells in three patients. Our study demonstrates that annexin 1 is an autoantigen that raises both Ab production and T cell response in patients with acute exacerbation of IPF, and that the N-terminal portion of annexin 1 plays some role in the pathogenesis of acute exacerbation in IPF patients
— id: 94496, year: 2008, vol: 181, page: 756, stat: Journal Article,

In vitro mechanisms of lovastatin on lung cancer cell lines as a potential chemopreventive agent
Maksimova, Elena; Yie, Ting-An; Rom, William N
2008 Jan-Feb;186(1):45-54, Lung
Lung cancer causes over one million deaths per year worldwide and cigarette smoking, the proximate cause, results in a field cancerization of the respiratory track. Lung cancer cells or premalignant cells may be susceptible to apoptosis or necrosis-inducing agents. Statins inhibit the acetyl coenzyme A pathway reducing L-mevalonate that is a precursor to isoprenoids necessary for post-translational processing, resulting in apoptosis. Lovastatin was added to four lung cancer cell lines and normal human bronchial epithelial cells followed by Western blots to evaluate proteins in the cell cycle, oxidant, and apoptotic pathways. Flow cytometry revealed significant increases in three of four lung cancer cell lines in apoptosis and necrosis after lovastatin treatment at 10 microM for 72 h. Lovastatin adversely affected lung cancer cell survival with increases in cell-cycle check-point inhibitors p21WAF and/or p27KIP and a decrease in cyclin D1. All four lung cancer cell lines had a decrease in glutathione after lovastatin treatment consistent with reduced protection against reactive oxidant species. Three of four lung cancer cell lines had increased cytochrome c release with reduced pro-caspase-3 and increases in activated caspase-3. Lovastatin induces apoptosis and necrosis in lung cancer cell lines by causing alterations in the cell cycle, reducing glutathione, and activating p53, Bax protein, and caspases while increasing cytochrome c in apoptosis pathways. Targeting HMG-CoA reductase may represent an approach to lung cancer chemotherapy, e.g., reversing ground glass opacities detected on CT scans or resolving airway preneoplasias detected by bronchoscopy before they progress to malignant transformation
— id: 78016, year: 2008, vol: 186, page: 45, stat: Journal Article,

Multiple strand displacement amplification of mitochondrial DNA from clinical samples
Maragh, Samantha; Jakupciak, John P; Wagner, Paul D; Rom, William N; Sidransky, David; Srivastava, Sudhir; O'Connell, Catherine D
2008 ;9:7-7, BMC medical genetics
BACKGROUND: Whole genome amplification (WGA) methods allow diagnostic laboratories to overcome the common problem of insufficient DNA in patient specimens. Further, body fluid samples useful for cancer early detection are often difficult to amplify with traditional PCR methods. In this first application of WGA on the entire human mitochondrial genome, we compared the accuracy of mitochondrial DNA (mtDNA) sequence analysis after WGA to that performed without genome amplification. We applied the method to a small group of cancer cases and controls and demonstrated that WGA is capable of increasing the yield of starting DNA material with identical genetic sequence. METHODS: DNA was isolated from clinical samples and sent to NIST. Samples were amplified by PCR and those with no visible amplification were re-amplified using the Multiple Displacement Amplificaiton technique of whole genome amplification. All samples were analyzed by mitochip for mitochondrial DNA sequence to compare sequence concordance of the WGA samples with respect to native DNA. Real-Time PCR analysis was conducted to determine the level of WGA amplification for both nuclear and mtDNA. RESULTS: In total, 19 samples were compared and the concordance rate between WGA and native mtDNA sequences was 99.995%. All of the cancer associated mutations in the native mtDNA were detected in the WGA amplified material and heteroplasmies in the native mtDNA were detected with high fidelity in the WGA material. In addition to the native mtDNA sequence present in the sample, 13 new heteroplasmies were detected in the WGA material. CONCLUSION: Genetic screening of mtDNA amplified by WGA is applicable for the detection of cancer associated mutations. Our results show the feasibility of this method for: 1) increasing the amount of DNA available for analysis, 2) recovering the identical mtDNA sequence, 3) accurately detecting mtDNA point mutations associated with cancer
— id: 78888, year: 2008, vol: 9, page: 7, stat: Journal Article,

Particulate matter inhibits DNA repair and enhances mutagenesis
Mehta, Manju; Chen, Lung-Chi; Gordon, Terry; Rom, William; Tang, Moon-Shong
2008 Dec 8;657(2):116-121, Mutation research
Exposure to ambient air pollution has been associated with adverse health effects including lung cancer. A recent epidemiology study has established that each 10mug/m(3) elevation in long-term exposure to average PM(2.5) ambient concentration was associated with approximately 8% of lung cancer mortality. The underlying mechanisms of how PM contributes to lung carcinogenesis, however, remain to be elucidated. We have recently found that transition metals such as nickel and chromium and oxidative stress induced lipid peroxidation metabolites such as aldehydes can greatly inhibit nucleotide excision repair (NER) and enhance carcinogen-induced mutations. Because PM is rich in metal and aldehyde content and can induce oxidative stress, we tested the effect of PM on DNA repair capacity in cultured human lung cells using in vitro DNA repair synthesis and host cell reactivation assays. We found that PM greatly inhibits NER for ultraviolet (UV) light and benzo(a)pyrene diol epoxide (BPDE) induced DNA damage in human lung cells. We further demonstrated that PM exposure can significantly increase both spontaneous and UV-induced mutagenesis. These results together suggest that the carcinogenicity of PM may act through its combined effect on suppression of DNA repair and enhancement of DNA replication errors
— id: 90028, year: 2008, vol: 657, page: 116, stat: Journal Article,

Survival after surgery in stage IA and IB non-small cell lung cancer
Ost, David; Goldberg, Judith; Rolnitzky, Linda; Rom, William N
2008 Mar 1;177(5):516-523, American journal of respiratory & critical care medicine
RATIONALE: Whether histologic subtype of non-small cell lung cancer (NSCLC) has an important effect on prognosis after surgery is unknown. OBJECTIVES: We hypothesized that we could predict mortality more effectively by integrating precise tumor size and histology rather than relying on conventional staging. METHODS: We used the SEER (Surveillance, Epidemiology, and End Results) registry. Inclusion criteria were as follows: (1) primary squamous cell or adenocarcinoma; (2) potentially curative surgery, defined as a lobectomy or bilobectomy; (3) lymph node dissection performed; and (4) pathologic stage IA or IB. MEASUREMENTS AND MAIN RESULTS: From 1988 to 2000, 7,965 patients were included. For both all-cause and lung cancer-associated mortality, tumor size demonstrated the strongest association (log-rank P < 0.0001 for each). When tumors were small (</=2 cm), lung cancer-associated mortality was similar for adenocarcinoma when compared with squamous cell carcinoma. When tumors were 3 cm or larger in size, lung cancer-associated mortality was higher for adenocarcinoma. The increased risk of lung cancer-associated mortality with adenocarcinoma was more pronounced in those younger than 65 years. Survival prediction using precise size and histology had much better discriminatory power than conventional TNM (tumor-node-metastasis) staging (P = 0.005). CONCLUSIONS: Staging that takes into account size, histology, late recurrence risk, and patient age is more accurate than the current TNM system and is clinically relevant because improved prediction can facilitate better decisions on the use of adjuvant chemotherapy
— id: 76334, year: 2008, vol: 177, page: 516, stat: Journal Article,

Detection of lung cancer using weighted digital analysis of breath biomarkers
Phillips, Michael; Altorki, Nasser; Austin, John H M; Cameron, Robert B; Cataneo, Renee N; Kloss, Robert; Maxfield, Roger A; Munawar, Muhammad I; Pass, Harvey I; Rashid, Asif; Rom, William N; Schmitt, Peter; Wai, James
2008 Jul;393(2):76-84, Clinica chimica acta
BACKGROUND: A combination of biomarkers in a multivariate model may predict disease with greater accuracy than a single biomarker employed alone. We developed a non-linear method of multivariate analysis, weighted digital analysis (WDA), and evaluated its ability to predict lung cancer employing volatile biomarkers in the breath. METHODS: WDA generates a discriminant function to predict membership in disease vs no disease groups by determining weight, a cutoff value, and a sign for each predictor variable employed in the model. The weight of each predictor variable was the area under the curve (AUC) of the receiver operating characteristic (ROC) curve minus a fixed offset of 0.55, where the AUC was obtained by employing that predictor variable alone, as the sole marker of disease. The sign (+/-) was used to invert the predictor variable if a lower value indicated a higher probability of disease. When employed to predict the presence of a disease in a particular patient, the discriminant function was determined as the sum of the weights of all predictor variables that exceeded their cutoff values. The algorithm that generates the discriminant function is deterministic because parameters are calculated from each individual predictor variable without any optimization or adjustment. We employed WDA to re-evaluate data from a recent study of breath biomarkers of lung cancer, comprising the volatile organic compounds (VOCs) in the alveolar breath of 193 subjects with primary lung cancer and 211 controls with a negative chest CT. RESULTS: The WDA discriminant function accurately identified patients with lung cancer in a model employing 30 breath VOCs (ROC curve AUC=0.90; sensitivity=84.5%, specificity=81.0%). These results were superior to multilinear regression analysis of the same data set (AUC=0.74, sensitivity=68.4, specificity=73.5%). WDA test accuracy did not vary appreciably with TNM (tumor, node, metastasis) stage of disease, and results were not affected by tobacco smoking (ROC curve AUC=0.92 in current smokers, 0.90 in former smokers). WDA was a robust predictor of lung cancer: random removal of 1/3 of the VOCs did not reduce the AUC of the ROC curve by >10% (99.7% CI). CONCLUSIONS: A test employing WDA of breath VOCs predicted lung cancer with accuracy similar to chest computed tomography. The algorithm identified dependencies that were not apparent with traditional linear methods. WDA appears to provide a useful new technique for non-linear multivariate analysis of data
— id: 78887, year: 2008, vol: 393, page: 76, stat: Journal Article,

Using high throughput resequencing microarrays to detect mutations in genes involved in lung cancer
Piao, LC; Gunnison, A; Nadas, A; Chen, WC; Nonaka, D; Spivack, S; Pass, H; Rom, WN; Tang, MS
2008 DEC 11 ;4(3):159-159, Cancer biomarkers : section A of Disease markers
— id: 91475, year: 2008, vol: 4, page: 159, stat: Journal Article,

Gene expression profiles of bronchoalveolar cells in pulmonary TB
Raju, Bindu; Hoshino, Yoshihiko; Belitskaya-Levy, Ilana; Dawson, Rod; Ress, Stanley; Gold, Jeffrey A; Condos, Rany; Pine, Richard; Brown, Stuart; Nolan, Anna; Rom, William N; Weiden, Michael D
2008 Jan;88(1):39-51, Tuberculosis (Edinburgh, Scotland)
The host response to Mycobacterium tuberculosis includes macrophage activation, inflammation with increased immune effector cells, tissue necrosis, and cavity formation, and fibrosis, distortion, and bronchiectasis. To evaluate the molecular basis of the immune response in the lungs of patients with active pulmonary tuberculosis (TB), we used bronchoalveolar lavage to obtain cells at the site of infection. Affymetrix GeneChip microarrays and cDNA nylon filter microarrays interrogated gene expression in bronchoalveolar lavage (BAL) cells from 11 healthy controls and 17 patients with active pulmonary TB. We found altered gene expression for 69 genes in TB versus normal controls that included cell surface markers, cytokines, chemokines, receptors, transcription factors, and complement components. In addition, TB BAL cell gene expression patterns segregated into 2 groups: one suggestive of a T helper type 1 (Th1) cellular immune response with increased signal transducer and activator of transcription-4 (STAT-4), interferon-gamma (IFN-gamma receptor), and monokine induced by IFN-gamma (MIG) expression with increased IFN-gamma protein levels in BAL fluid; the other group displayed characteristics of Th2 immunity with increased STAT-6, CD81, and IL-10 receptor expression. We were able to demonstrate that a Th2 presentation could change to a Th1 pattern after anti-tuberculous treatment in 1 TB patient studied serially. These gene expression data support the conclusion that pulmonary TB produces a global change in the BAL cell transcriptome with manifestations of either Th1 or Th2 immunity
— id: 74211, year: 2008, vol: 88, page: 39, stat: Journal Article,

Global warming: a challenge to all American Thoracic Society members
Rom, William N; Pinkerton, Kent E; Martin, William J; Forastiere, Francesco
2008 May 15;177(10):1053-1054, American journal of respiratory & critical care medicine
— id: 78886, year: 2008, vol: 177, page: 1053, stat: Journal Article,

Immunohistochemical study of fibrosis and adenocarcinoma in dominant-negative p53 transgenic mice exposed to chrysotile asbestos and benzo(a)pyrene
Yee, Herman; Yie, Ting-An; Goldberg, Judith; Wong, Kam Meng Tchou; Rom, William N
2008 ;27(4):267-276, Journal of environmental pathology, toxicology & oncology
We evaluated the mechanisms using immunohistochemistry whereby chrysotile asbestos and benzo(a)pyrene (BaP) instilled intratracheally into lung-specific dominant-negative p53 (dnp53) mice might interact in causing lung carcinomas and fibrosis. Chrysotile asbestos and benzo(a)pyrene (BaP) were instilled intratracheally into lung-specific dominant-negative p53 (dnp53) and control mice. The mice were sacrificed at 12 months and their lungs examined for lung carcinomas and fibrosis. Immunostains for proteins related to apoptosis, fibrogenesis, matrix remodeling and inflammation were performed. The dnp53 mice had increased numbers of lung adenocarcinomas with BaP alone and the combination of chrysotile and BaP (the latter was additive but not significant). Several atypical adenomatous hyperplasia lesions were found in the combined treatment group. dnp53 and FVBN control mice developed nodular buds of fibrotic lung tissue after chrysotile asbestos exposure that were localized in respiratory bronchioles; these lesions had significant increases in immunohistochemical staining for TGF-beta, MMP-7 and -9, MIG-1, and SDF-1. Fibrotic lesions in mice exposed to chrysotile had increased collagen demonstrated by picrosirius red staining. The dnp53 mice with adenocarcinomas had increased SDF-1, TGF-beta, MMP-9 and -7, Cyclin D, and MIG-1 immunostaining in the chrysotile and combined treatment groups. We conclude that BaP and the combination of BaP plus chrysotile asbestos are potent inducers of adenocarcinoma in dnp53 mice and that the inflammatory cytokines and proteases MMP-7 and -9, MIG-1, and SDF-1, and growth factors Cyclin D and TGF-beta are increased in the specific lesions
— id: 94494, year: 2008, vol: 27, page: 267, stat: Journal Article,

Gene profiling of normal human bronchial epithelial cells in response to asbestos and benzo(a)pyrene diol epoxide (BPDE)
Belitskaya-Levy, Ilana; Hajjou, Mustapha; Su, Wei-cheng; Yie, Ting-An; Tchou-Wong, Kam-Meng; Tang, Moon-shong; Goldberg, Judith D; Rom, William N
2007 ;26(4):281-294, Journal of environmental pathology, toxicology & oncology
Asbestos and benzo(a)pyrene diol epoxide (BPDE) are pulmonary carcinogens with synergistic interaction in causing lung cancer. We used Affymetrix microarrays to study gene modulation in vitro using normal human bronchial epithelial cells exposed to chrysotile asbestos and/or BPDE for 4 or 24 h. Linear models were used to compare treated cells to controls at each time point to identify statistically significant up- or downregulation of genes. Profiles of genes regulated by chrysotile were dominated by cytokines, growth factors, and DNA damage. Profiles of genes with BPDE and chrysotile regulation were correlated with proliferation, DNA damage recognition and nucleotide-excision repair, cytokines, and apoptosis. Chemokines, growth-regulated oncogene-alpha (Gro-alpha, CXCL-1), and IL-8, were significantly increased, and these had previously been observed in bronchoalveolar lavage from asbestos workers or in animal models. Interestingly, the Hermansky-Pudlak gene, which is mutated in an autosomal recessive form of pulmonary fibrosis, was downregulated threefold by BPDE at 4 h. This is an interesting example of gene (Hermansky-Pudlak syndrome) and environment (BPDE) interaction. Transcription factors, including activating transcription factor 3 and Cbp/p300-interacting transactivator, were upregulated by chrysotile. Real Time PCR for IL-8, ATF-3, GADD45B, CXC Ligand 1, and CTGF compared to GAPDH validated microarray findings at 24 h. These in vitro findings in NHBE cells model environment-gene interaction for asbestos and BPDE, highlighting effects of inflammation, fibrosis, proliferation, and DNA damage recognition and repair
— id: 76391, year: 2007, vol: 26, page: 281, stat: Journal Article,

Human matrix metalloproteinase-8 gene delivery increases the oncolytic activity of a replicating adenovirus
Cheng, Jin; Sauthoff, Harald; Huang, YaoQi; Kutler, David I; Bajwa, Sofia; Rom, William N; Hay, John G
2007 Nov;15(11):1982-1990, Molecular therapy
The success of replicating adenoviruses for cancer therapy is limited by inefficient virus delivery and poor distribution within the tumor mass. Stromal matrix within the tumor may hinder the free cell-to-cell spread of the virus. In this study, in vitro cell culture experiments showed that collagen I blocked the passage of an adenoviral vector through a membrane. On the basis of reports of the effective collagen I-degrading activity of matrix metalloproteinase-8 (MMP-8), we constructed an adenovirus to express the MMP-8 transgene (AdMMP8). A549 cells infected in vitro with AdMMP8 did not show altered growth but were able to modify a fibrillar collagen substrate to allow viral diffusion. Further, AdMMP8 did not affect replication of the wild-type virus (Adwt300). Established human A549 lung cancer and BxPC-3 pancreatic cancer xenograft tumors that were injected with Adwt300 together with the non-replicating AdMMP8 virus showed significantly reduced growth compared with control tumors. Histochemical analysis showed reduced amounts of collagen within necrotic areas of MMP-8-injected tumors compared with controls. These results demonstrate that intra-tumoral expression of MMP-8 is a possible strategy for improving viral spread and improving the oncolytic activity of replicating adenovirus
— id: 75471, year: 2007, vol: 15, page: 1982, stat: Journal Article,

Utility of retrievable inferior vena cava filters for primary prophylaxis of pulmonary embolism in high-risk preoperative orthopedic patients
Dweck, E; Bashar, M; Hansen, D; Clark, TW; Rom, WN; Steiger, D
2007 OCT ;132(4):627S-627S, Chest
— id: 87207, year: 2007, vol: 132, page: 627S, stat: Journal Article,

S-adenosylmethionine as a biomarker for the early detection of lung cancer
Greenberg, Alissa K; Rimal, Binaya; Felner, Kevin; Zafar, Subooha; Hung, Jerry; Eylers, Ellen; Phalan, Brendan; Zhang, Meng; Goldberg, Judith D; Crawford, Bernard; Rom, William N; Naidich, David; Merali, Salim
2007 Oct;132(4):1247-1252, Chest
BACKGROUND: S-Adenosylmethionine (AdoMet) is a major methyl donor for transmethylation reactions and propylamine donor for the biosynthesis of polyamines in biological systems, and therefore may play a role in lung cancer development. We hypothesized that AdoMet levels were elevated in patients with lung cancer and may prove useful as a biomarker for early lung cancer. METHODS: High-performance liquid chromatography was used to analyze plasma AdoMet levels in triplicate samples from 68 patients. This included 13 patients with lung cancer, 33 smokers with benign lung disease, and 22 healthy nonsmokers. The three groups of subjects were compared with respect to the distribution of demographic and disease characteristics and AdoMet levels. Distributions were examined using summary statistics and box plots, and nonparametric analysis of variance procedures. RESULTS: Serum AdoMet levels were elevated in patients with lung cancer as compared to smokers with benign lung disorders and healthy nonsmokers. There were no significant correlations between AdoMet levels and tumor cell types, nodule size, or other demographic variables. CONCLUSIONS: Our data demonstrate that plasma levels of AdoMet are significantly elevated in patients with lung cancer. Plasma AdoMet levels may prove to be a useful tool for the diagnosis of early lung cancer, in combination with chest CT. Registered at: clinicaltrials.gov (NCT00301119)
— id: 74778, year: 2007, vol: 132, page: 1247, stat: Journal Article,

Mechanisms of polymorphonuclear neutrophil-mediated induction of HIV-1 replication in macrophages during pulmonary tuberculosis
Hoshino, Yoshihiko; Hoshino, Satomi; Gold, Jeffrey A; Raju, Bindu; Prabhakar, Savita; Pine, Richard; Rom, William N; Nakata, Koh; Weiden, Michael
2007 May 1;195(9):1303-1310, Journal of infectious diseases
BACKGROUND: Pulmonary tuberculosis (TB) can present with polymorphonuclear neutrophil (PMN)-predominant alveolitis. TB accelerates acquired immunodeficiency syndrome by increasing human immunodeficiency virus type 1 (HIV-1) replication and mutation in alveolar macrophages. A 16-kDa CCAAAT/enhancer-binding protein beta (C/EBP beta ) isoform is a strong transcriptional repressor of the HIV long terminal repeat (LTR) in resting alveolar macrophages, leading to latent viral infection; its expression is lost during TB, derepressing the HIV LTR. METHODS: Lung segments were sampled from HIV/Mycobacterium tuberculosis-coinfected patients by means of bronchoalveolar lavage. In vitro coculture experiments defined the mechanism of induction of HIV-1 infection in macrophages by PMNs. RESULTS: Lung segments from patients with PMN-predominant TB had a markedly elevated viral load. Direct contact between activated PMNs and macrophages stimulated HIV-1 replication and LTR transcription and down-regulated inhibitory C/EBP beta . Isolated PMN membranes substituted for PMN contact, derepressing the HIV-1 LTR. The lipid raft fraction of PMN membranes expressed CD40 ligand (CD40L), CD28, and leukocyte function-associated antigen 1 (LFA-1 [i.e., CD11a and CD18]), and PMN activation increased lipid raft expression of CD40L and CD28. Blocking antibodies to CD40L, CD28, and LFA-1 inhibited PMN membrane-mediated HIV-1 LTR derepression. Alternately, cross-linking of macrophage receptors for CD40L, CD28, and LFA-1 (CD40, CD80/86, and intercellular adhesion molecule 1) abolished inhibitory C/EBP beta expression. CONCLUSION: PMN-macrophage contact derepresses the HIV-1 LTR and enhances HIV-1 replication in alveolar macrophages during pulmonary TB. Derepression is mediated through costimulatory molecule signaling.
— id: 72865, year: 2007, vol: 195, page: 1303, stat: Journal Article,

Integration of HIV-1 caused STAT3-associated B cell lymphoma in an AIDS patient
Katano, Harutaka; Sato, Yuko; Hoshino, Satomi; Tachikawa, Natsuo; Oka, Shinichi; Morishita, Yasuyuki; Ishida, Takaomi; Watanabe, Toshiki; Rom, William N; Mori, Shigeo; Sata, Tetsutaro; Weiden, Michael D; Hoshino, Yoshihiko
2007 Nov-Dec;9(14-15):1581-1589, Microbes & infection
Signal transducer and activator of transcription 3 (STAT3) is a DNA-binding transcription factor activated by multiple cytokines and interferons. High expression of STAT3 has also been implicated in cancer and lymphoma. Here, we show a case of B cell lymphoma in which a defective human immunodeficiency virus 1 (HIV-1) integrated upstream of the first STAT3 coding exon. The lymphoma cells with anaplastic large cell morphology formed multiple nodular lesions in the lung of an acquired immunodeficiency syndrome (AIDS) patient with Kaposi's sarcoma. The provirus had a 5' long terminal repeat (LTR) deletion, but the 3' LTR had stronger promoter activity than the STAT3 promoter in reporter assays. Immunohistochemistry showed increased expression of STAT3 in the nuclei of lymphoma cells. Transfection of STAT3 resulted in transient cell proliferation in primary B cells in vitro. Although this is a very rare case of HIV-1-integrated lymphoma, these data suggest that up-regulation of STAT3 caused by HIV-1 integration resulted in the development of B cell lymphoma in this special case
— id: 78803, year: 2007, vol: 9, page: 1581, stat: Journal Article,

Leprosy as immune reconstitution inflammatory syndrome in HIV-positive persons
Martiniuk, Frank; Rao, Shaline D; Rea, Thomas H; Glickman, Michael S; Giovinazzo, Jerome; Rom, William N; Cabrera, Aloys; Levis, William R
2007 Sep;13(9):1438-1440, Emerging infectious diseases
— id: 78889, year: 2007, vol: 13, page: 1438, stat: Journal Article,

Identification of novel hsp65 RFLPs for Mycobacterium leprae
Martiniuk, Frank; Tambini, Marc; Rahimian, Joseph; Moreira, Andre; Yee, Herman; Tchou-Wong, Kam-Meng; Hanna, Bruce A; Rom, William N; Levis, William R
2007 Mar;6(3):268-274, Journal of drugs in dermatology : JDD
Leprosy or Hansen's disease is a chronic infectious disease caused by an acid-fast bacillus, Mycobacterium leprae (M. leprae). The bacilli proliferate in macrophages infiltrating the skin and gain entry to the dermal nerves via the laminar surface of Schwann cells where they replicate. After entry, the Schwann cells proliferate and then die. Conclusive identification of M. leprae DNA in a sample can be obtained by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) for the heat shock 65 gene (hsp65). Molecular epidemiology will make it possible to study the global distributions of M. leprae, explore the relationship between genotypes-incidence rates, mode of transmission, and the type of disease (tuberculoid vs. lepromatous). We amplified DNA using PCR for the hsp65 gene from 24 skin lesions from patients diagnosed with various types of leprosy. Fifteen out of 24 were positive for the hsp65 gene. Digestion with HaeIII-PAGE for the RFLP confirmation of the presence of M. leprae DNA showed the typical pattern in 5 out of 24 and 2 novel patterns in 10 out of 24 patients. We confirmed the presence of M. leprae DNA by sequencing the genes for gyraseA or B and folP, which contained only M. leprae specific single nucleotide polymorphisms (SNPs). Thus, we describe novel hsp65 RFLPs for M. leprae found in a high frequency making them ideal for future epidemiology and transmission studies
— id: 71866, year: 2007, vol: 6, page: 268, stat: Journal Article,

Distal airway function in symptomatic subjects with normal spirometry following World Trade Center dust exposure
Oppenheimer, Beno W; Goldring, Roberta M; Herberg, Matthew E; Hofer, Ira S; Reyfman, Paul A; Liautaud, Sybille; Rom, William N; Reibman, Joan; Berger, Kenneth I
2007 Oct;132(4):1275-1282, Chest
RATIONALE: Following collapse of the World Trade Center (WTC), individuals reported new-onset respiratory symptoms. Despite symptoms, spirometry often revealed normal airway function. However, bronchial wall thickening and air trapping were seen radiographically in some subjects. We hypothesized that symptomatic individuals following exposure to WTC dust may have functional abnormalities in distal airways not detectable with routine spirometry. METHODS: One hundred seventy-four subjects with respiratory symptoms and normal spirometry results were evaluated. Impedance oscillometry (IOS) was performed to determine resistance at 5 Hz, 5 to 20 Hz, and reactance area. Forty-three subjects were also tested for frequency dependence of compliance (FDC). Testing was repeated after bronchodilation. RESULTS: Predominant symptoms included cough (67%) and dyspnea (65%). Despite normal spirometry results, mean resistance at 5 Hz, 5 to 20 Hz, and reactance area were elevated (4.36 +/- 0.12 cm H(2)O/L/s, 0.86 +/- 0.05 cm H(2)O/L/s, and 6.12 +/- 0.50 cm H(2)O/L, respectively) [mean +/- SE]. Resistance and reactance normalized after bronchodilation. FDC was present in 37 of 43 individuals with improvement after bronchodilation. CONCLUSIONS: Symptomatic individuals with presumed WTC dust/fume exposure and normal spirometry results displayed airway dysfunction based on the following: (1) elevated airway resistance and frequency dependence of resistance determined by IOS; (2) heterogeneity of distal airway function demonstrated by elevated reactance area on oscillometry and FDC; and (3) reversibility of these functional abnormalities to or toward normal following administration of a bronchodilator. Since spirometry results were normal in all subjects, these abnormalities likely reflect dysfunction in airways more distal to those evaluated by spirometry. Examination of distal airway function when spirometry results are normal may be important in the evaluation of subjects exposed to occupational and environmental hazards
— id: 75380, year: 2007, vol: 132, page: 1275, stat: Journal Article,

Prediction of lung cancer using volatile biomarkers in breath
Phillips, Michael; Altorki, Nasser; Austin, John H M; Cameron, Robert B; Cataneo, Renee N; Greenberg, Joel; Kloss, Robert; Maxfield, Roger A; Munawar, Muhammad I; Pass, Harvey I; Rashid, Asif; Rom, William N; Schmitt, Peter
2007 ;3(2):95-109, Cancer biomarkers : section A of Disease markers
BACKGROUND: Normal metabolism generates several volatile organic compounds (VOCs) that are excreted in the breath (e.g. alkanes). In patients with lung cancer, induction of high-risk cytochrome p450 genotypes may accelerate catabolism of these VOCs, so that their altered abundance in breath may provide biomarkers of lung cancer. METHODS: VOCs in 1.0 L alveolar breath were analyzed in 193 subjects with primary lung cancer and 211 controls with a negative chest CT. Subjects were randomly assigned to a training set or to a prediction set in a 2:1 split. A fuzzy logic model of breath biomarkers of lung cancer was constructed in the training set and then tested in subjects in the prediction set by generating their typicality scores for lung cancer. RESULTS: Mean typicality scores employing a 16 VOC model were significantly higher in lung cancer patients than in the control group (p<0.0001 in all TNM stages). The model predicted primary lung cancer with 84.6% sensitivity, 80.0% specificity, and 0.88 area under curve (AUC) of the receiver operating characteristic (ROC) curve. Predictive accuracy was similar in TNM stages 1 through 4, and was not affected by current or former tobacco smoking. The predictive model achieved near-maximal performance with six breath VOCs, and was progressively degraded by random classifiers. Predictions with fuzzy logic were consistently superior to multilinear analysis. If applied to a population with 2% prevalence of lung cancer, a screening breath test would have a negative predictive value of 0.985 and a positive predictive value of 0.163 (true positive rate =0.277, false positive rate =0.029). CONCLUSIONS: A two-minute breath test predicted lung cancer with accuracy comparable to screening CT of chest. The accuracy of the test was not affected by TNM stage of disease or tobacco smoking. Alterations in breath VOCs in lung cancer were consistent with a non-linear pathophysiologic process, such as an off-on switch controlling high-risk cytochrome p450 activity. Further research is needed to determine if detection of lung cancer with this test will reduce mortality
— id: 78891, year: 2007, vol: 3, page: 95, stat: Journal Article,

Ozone, a malady for all ages
Pinkerton, Kent E; Balmes, John R; Fanucchi, Michelle V; Rom, William N
2007 Jul 15;176(2):107-108, American journal of respiratory & critical care medicine
— id: 78890, year: 2007, vol: 176, page: 107, stat: Journal Article,

Asbestosis, pleural fibrosis, and lung cancer
Rom, William N
Environmental and occupational medicine Philadelphia : Wolters Kluwer/Lippincott Williams & Wilkins, 2007,
— id: 5361, year: 2007, vol: , page: ?, stat: Chapter,

High-altitude illnesses
Rom, William N
Environmental and occupational medicine Philadelphia : Wolters Kluwer/Lippincott Williams & Wilkins, 2007,
— id: 5372, year: 2007, vol: , page: ?, stat: Chapter,

The discipline of environmental and occupational medicine
Rom, William N
Environmental and occupational medicine Philadelphia : Wolters Kluwer/Lippincott Williams & Wilkins, 2007,
— id: 5359, year: 2007, vol: , page: ?, stat: Chapter,

Environmental and occupational medicine
Rom, William N; Markowitz, Steven
Philadelphia : Wolters Kluwer/Lippincott Williams & Wilkins, 2007,
— id: 1302, year: 2007, vol: , page: , stat: ,

Rapid chemokinetic movement and the invasive potential of lung cancer cells; a functional molecular study (vol 6, pg 151, 2006)
Tchou-Wong, KM; Fok, SYY; Rubin, JS; Pixley, F; Condeelis, J; Braet, F; Rom, W; Soon, LL
2007 FEB 22 ;7(1):111-117, BMC cancer
— id: 71053, year: 2007, vol: 7, page: 111, stat: Journal Article,

Mycobacterium tuberculosis malate synthase- and MPT51-based serodiagnostic assay as an adjunct to rapid identification of pulmonary tuberculosis
Achkar, Jacqueline M; Dong, Yuxin; Holzman, Robert S; Belisle, John; Kourbeti, Irene S; Sherpa, Tsering; Condos, Rany; Rom, William N; Laal, Suman
2006 Nov;13(11):1291-1293, Clinical & vaccine immunology
The 81-kDa malate synthase (MS; Rv 1837c) and the 27-kDa MPT51 (Rv 3803c) of Mycobacterium tuberculosis are immunodominant antigens recognized by serum antibodies from approximately 80% of human immunodeficiency virus-negative smear-positive tuberculosis patients from India. We now provide evidence that the use of the MS/MPT51-based serodiagnostic assay can serve as an adjunct to sputum microscopy in the rapid diagnosis of pulmonary tuberculosis
— id: 70310, year: 2006, vol: 13, page: 1291, stat: Journal Article,

Sequence specificity of Cr(III)-DNA adduct formation in the p53 gene: NGG sequences are preferential adduct-forming sites
Arakawa, Hirohumi; Wu, Feng; Costa, Max; Rom, William; Tang, Moon-Shong
2006 Mar;27(3):639-645, Carcinogenesis
Hexavalent chromium [Cr(VI)] is a known etiological factor in human lung cancer. Cr(VI) exposure-related lung cancer has a high mutation incidence in the p53 gene. Upon intake in human cells Cr(VI) is reduced to Cr(III), which is able to conjugate with amino acids and consequently form either binary Cr(III)-DNA or ternary Cr(III)-amino acid-DNA adducts. Both binary and ternary Cr(III)-DNA adducts are mutagenic. We have found that the Escherichia coli nucleotide excision enzyme UvrABC nuclease is able to incise Cr(III)- and Cr(III)-histidine-modified plasmid DNA and the extent of incision is proportional to the amount of Cr(III)-DNA adducts in the plasmid. In order to determine the role of Cr(III)-DNA adducts in the mutagenesis of the p53 gene in human cancer using the UvrABC nuclease incision method, we have mapped the Cr(III)-DNA distribution in PCR DNA fragments amplified from exons 5, 7 and 8 of the p53 gene. We have found that the sequence specificities of Cr(III)-DNA and Cr(III)-histidine-DNA adducts in the p53 gene sequence are identical and that both types of adducts are preferentially formed at -NGG- sequences, including codons 245, 248 and 249, the mutational hotspots in human lung cancer. It has been found that Cr(III)-DNA adducts induce mainly G to T mutations. Therefore, these results suggest that Cr(III)-DNA adduct formation contributes to the p53 gene mutations in lung carcinogenesis
— id: 63597, year: 2006, vol: 27, page: 639, stat: Journal Article,

Prevalence of workplace exacerbation of asthma symptoms in an urban working population of asthmatics
Berger, Zackary; Rom, W N; Reibman, J; Kim, M; Zhang, S; Luo, L; Friedman-Jimenez, George
2006 Aug;48(8):833-839, Journal of occupational & environmental medicine
OBJECTIVES: We used an interviewer-administered questionnaire to investigate workplace exacerbation of asthma symptoms (WEAS) among low-income, minority, working asthmatics admitted Bellevue Hospital Center in New York City from 2001 to 2002. We hypothesized that a high prevalence of WEAS would be found in this population among all jobs held and a subset of individual occupational classifications. MEASUREMENTS AND MAIN RESULTS: Of 301 subjects, 51% reported WEAS in their current or most recent job; 71% reported WEAS in any job. Prevalences (95% confidence intervals) of WEAS in common job classifications were 61% (49-73%) in janitorial jobs, 50% (33-67%) in garment and textile manufacturing jobs, and 38% (23-55%) in construction jobs. CONCLUSION: WEAS is prevalent in this urban minority population
— id: 69582, year: 2006, vol: 48, page: 833, stat: Journal Article,

Transbronchial needle aspiration in HIV-infected patients with intrathoracic adenopathy: A 15-year experience at a major teaching hospital
Herscovici, P; Harkin, TJ; Naidich, DP; Rom, WN; Addrizzo-Harris, DJ
2006 ;130(4):275S-275S, Chest
— id: 134681, year: 2006, vol: 130, page: 275S, stat: Journal Article,

Interaction of iron and calcium minerals in coals and their roles in coal dust-induced health and environmental problems
Huang, X; Gordon, T; Rom, WN; Finkelman, RB
2006 NOV-DEC ;64(6):153-178, Reviews in mineralogy & geochemistry
Epidemiological studies using pollutant gases (e.g., SO2) and particle characteristics (e.g., elemental carbon) indicate that products of fossil fuel combustion are important contributors to particulate matter (PM)-associated hospital admissions and mortality. Coal is one of the world's most important fossil fuels, providing 40% of electricity worldwide. Besides individuals exposed to PM in ambient air, coal mining can cause adverse health effects in workers exposed to coal dusts at the workplace. Among the respiratory diseases, coal workers' pneumoconiosis (CWP) has received the most attention because of its clear occupational association. The field of CWP research is one of the few areas in occupational health in which considerable epidemiological data are available. This offers a good opportunity to focus on the relationship between epidemiological data and physico-chemical and/or biological characteristics of coals. The objective of this review is to assess whether some physico-chemical parameters play a role in the observed regional differences in the prevalence of CWP among various coalmine regions. We mainly concentrate on the chemical interaction of two minerals, pyrite (FeS2) and calcite (CaCO3) in the coals and their role in causing occupational lung diseases (e.g., pneumoconiosis) and other environmental problems (e.g., acid mine drainage). Therefore, understanding the chemical interaction of the two minerals in the coal may lead to the identification of the causal components in coal dusts as well as in PM. Examples from U.S.A. coals are used to illustrate the chemical interaction and geological distribution of iron and calcium minerals in various coalmine regions and how the differences in levels of these types of minerals contribute to the observed regional differences in the prevalence of CWP. Molecular mechanisms leading to the CWP development are also discussed, particular in the aspects of oxidative stress and inflammation
— id: 70749, year: 2006, vol: 64, page: 153, stat: Journal Article,

Small particles with big effects
Rom, William N; Samet, Jonathan M
2006 Feb 15;173(4):365-366, American journal of respiratory & critical care medicine
— id: 78892, year: 2006, vol: 173, page: 365, stat: Journal Article,

Modification of the p53 transgene of a replication-competent adenovirus prevents mdm2- and E1b-55kD-mediated degradation of p53
Sauthoff, H; Pipiya, T; Chen, S; Heitner, S; Cheng, J; Huang, Y Q; Rom, W N; Hay, J G
2006 Jul;13(7):686-695, Cancer gene therapy
Clinical efficacy of adenovirus-mediated cancer gene therapy has been limited thus far. To improve its oncolytic effect, a replication-competent adenoviral vector was previously constructed to express high levels of p53 at a late time point in the viral life cycle. p53 expression from this vector improved tumor cell killing and viral spread in vitro. However, p53 function is antagonized by cellular mdm2 and adenoviral E1b-55kD, both of which are known to bind to and inactivate p53. Therefore, a new vector (Adp53W23S) that expresses a modified p53 transgene, which does not bind to E1b-55kd and mdm2, was constructed. The modified p53 protein was demonstrated to have a substantially prolonged half-life, and its localization was predominantly nuclear. Viral replication was unaffected by expression of the modified p53 and cancer cell killing was improved in vitro. However, in a xenograft model, efficacy was not significantly different from control virus. In conclusion, expression of a degradation-resistant p53 transgene late in the life cycle of a replication-competent adenovirus improves p53 stability and cancer cell killing in vitro. However, other factors, such as the adenoviral E1b-19kD and E1a proteins, which oppose p53 function, and limitations to viral spread need to be addressed to further improve in vivo efficacy
— id: 67944, year: 2006, vol: 13, page: 686, stat: Journal Article,

Rapid chemokinetic movement and the invasive potential of lung cancer cells; a functional molecular study
Tchou-Wong, Kam-Meng; Fok, Sandra Y Y; Rubin, Jeffrey S; Pixley, Fiona; Condeelis, John; Braet, Filip; Rom, William; Soon, Lilian L
2006 ;6:151-151, BMC cancer
BACKGROUND: Non-small cell lung cancer is the most common cause of early casualty from malignant disease in western countries. The heterogeneous nature of these cells has been identified by histochemical and microarray biomarker analyses. Unfortunately, the morphological, molecular and biological variation within cell lines used as models for invasion and metastasis are not well understood. In this study, we test the hypothesis that heterogeneous cancer cells exhibit variable motility responses such as chemokinesis and chemotaxis that can be characterized molecularly. METHODS: A subpopulation of H460 lung cancer cells called KINE that migrated under chemokinetic (no gradient) conditions was harvested from Boyden chambers and cultured. Time-lapsed microscopy, immunofluorescence microscopy and microarray analyses were then carried out comparing chemokinetic KINE cells with the unselected CON cell population. RESULTS: Time-lapsed microscopy and analysis showed that KINE cells moved faster but less directionally than the unselected control population (CON), confirming their chemokinetic character. Of note was that chemokinetic KINE cells also chemotaxed efficiently. KINE cells were less adhesive to substrate than CON cells and demonstrated loss of mature focal adhesions at the leading edge and the presence of non-focalized cortical actin. These characteristics are common in highly motile amoeboid cells that may favour faster motility speeds. KINE cells were also significantly more invasive compared to CON. Gene array studies and real-time PCR showed the downregulation of a gene called, ROM, in highly chemokinetic KINE compared to mainly chemotactic CON cells. ROM was also reduced in expression in a panel of lung cancer cell lines compared to normal lung cells. CONCLUSION: This study shows that cancer cells that are efficient in both chemokinesis and chemotaxis demonstrate high invasion levels. These cells possess different morphological, cytoskeletal and adhesive properties from another population that are only efficient at chemotaxis, indicating a loss in polarity. Understanding the regulation of polarity in the context of cell motility is important in order to improve control and inhibition of invasion and metastasis
— id: 72107, year: 2006, vol: 6, page: 151, stat: Journal Article,

Distinctive serum protein profiles involving abundant proteins in lung cancer patients based upon antibody microarray analysis
Gao, Wei-Min; Kuick, Rork; Orchekowski, Randal P; Misek, David E; Qiu, Ji; Greenberg, Alissa K; Rom, William N; Brenner, Dean E; Omenn, Gilbert S; Haab, Brian B; Hanash, Samir M
2005 ;5:110-110, BMC cancer
BACKGROUND: Cancer serum protein profiling by mass spectrometry has uncovered mass profiles that are potentially diagnostic for several common types of cancer. However, direct mass spectrometric profiling has a limited dynamic range and difficulties in providing the identification of the distinctive proteins. We hypothesized that distinctive profiles may result from the differential expression of relatively abundant serum proteins associated with the host response. METHODS: Eighty-four antibodies, targeting a wide range of serum proteins, were spotted onto nitrocellulose-coated microscope slides. The abundances of the corresponding proteins were measured in 80 serum samples, from 24 newly diagnosed subjects with lung cancer, 24 healthy controls, and 32 subjects with chronic obstructive pulmonary disease (COPD). Two-color rolling-circle amplification was used to measure protein abundance. RESULTS: Seven of the 84 antibodies gave a significant difference (p < 0.01) for the lung cancer patients as compared to healthy controls, as well as compared to COPD patients. Proteins that exhibited higher abundances in the lung cancer samples relative to the control samples included C-reactive protein (CRP; a 13.3 fold increase), serum amyloid A (SAA; a 2.0 fold increase), mucin 1 and alpha-1-antitrypsin (1.4 fold increases). The increased expression levels of CRP and SAA were validated by Western blot analysis. Leave-one-out cross-validation was used to construct Diagonal Linear Discriminant Analysis (DLDA) classifiers. At a cutoff where all 56 of the non-tumor samples were correctly classified, 15/24 lung tumor patient sera were correctly classified. CONCLUSION: Our results suggest that a distinctive serum protein profile involving abundant proteins may be observed in lung cancer patients relative to healthy subjects or patients with chronic disease and may have utility as part of strategies for detecting lung cancer
— id: 65900, year: 2005, vol: 5, page: 110, stat: Journal Article,

Should renal insufficiency be a relative contraindication to bronchoscopic biopsy?
Mehta NL; Harkin TJ; Rom WN; Graap W; Addrizzo-Harris DJ
2005 ;12(2):81-83, Journal of Bronchology
In 1977, Cunningham et al reported a 45% risk of hemorrhage in azotemic patients undergoing flexible bronchoscopy (FB) with biopsy. There have been no recent studies evaluating renal insufficiency as a relative contraindication to biopsy. We reviewed all charts of Bellevue Hospital bronchoscopies from October 1997 to October 2002 for blood urea nitrogen (BUN), creatinine (Cr), hemogram, and coagulation studies as well as the type of biopsy performed, pretreatment medications, and complications from the FB. Patients were included if they had a BUN >=30 mg/dL and/or a Cr >=2 mg/dL. Seventy-two patients met criteria. Twenty-five of 72 (35%) patients had bronchoscopic biopsy. Seven of 25 (28%) were hemodialysis (HD) patients and 18 of 25 (72%) were nondialysis (ND) patients. All HD patients received FB within 24 hours after HD and were given desmopressin (DDAVP) prebronchoscopy. One patient with coagulopathy also received platelets and fresh-frozen plasma. Six of 7 HD patients had forceps biopsy (BX) (BUN range 31-65; Cr range 5.2-18.7) and 1 had transbronchial needle aspiration (TBNA) (BUN 32; Cr 4.3). Twelve of 18 ND patients had BX (BUN 20-69; Cr 0.9-2.5), 4 had TBNA (BUN 20-62; Cr 1.1-4.5), and 2 had BX and TBNA (BUN 30-35; Cr 1.4-1.5). One of 25 (4%) ND patients had a major complication of massive bleeding that required intervention. One of 25 (4%) ND patients had minor bleeding. There were no complications in the HD group. These findings suggest a low complication rate of bleeding in patients undergoing biopsy during FB if screened for coagulation abnormalities and, if receiving HD, done after HD with prebronchoscopy DDAVP. Our hemorrhagic complication rate was much lower than that reported in 1977. These data advocate further studies to evaluate whether bronchoscopic biopsy should be considered a relative contraindication in patients with renal insufficiency.
— id: 51794, year: 2005, vol: 12, page: 81, stat: Journal Article,

Prediction of lung cancer using volatile biomarkers in breath
Phillips, M; Altorki, N; Austin, JHM; Cameron, RB; Cataneo, RN; Greenberg, J; Kloss, R; Maxfield, RA; Pass, HI; Rom, WN; Tietje, O
2005 JUN 1 ;23(16):839S-839S, Journal of clinical oncology
— id: 57805, year: 2005, vol: 23, page: 839S, stat: Journal Article,

Hypoxia reduces adenoviral replication in cancer cells by downregulation of viral protein expression
Pipiya, T; Sauthoff, H; Huang, Y Q; Chang, B; Cheng, J; Heitner, S; Chen, S; Rom, W N; Hay, J G
2005 Jun;12(11):911-917, Gene therapy
Successful cancer therapy using replicating viral vectors relies on the spread of virus from infected to uninfected cells. To date, there has been limited clinical success in the use of replicating adenoviruses. In animal models, established xenograft tumors are rarely eliminated despite the persistence of high viral titers within the tumor. Hypoxia is a prevalent characteristic of solid tumors, whereas adenovirus naturally infects tissues exposed to ambient oxygen concentrations. Here, we report that hypoxia (1% oxygen) reduces adenoviral replication in H1299 and A549 lung cancer cells, BxPC-3 pancreatic cancer cells, LNCaP prostate cancer cells and HCT116 colon cancer cells. However, hypoxia does not reduce cell viability or restrict S-phase entry. Importantly, the production of E1a and fiber proteins under hypoxic conditions was substantially decreased at 24 and 48 h compared to room air controls. In contrast, Northern analysis showed similar levels of E1a mRNA in room air and hypoxic conditions. In conclusion, a level of hypoxia similar to that found within solid tumors reduces the replication of adenoviral vectors by reduction of viral protein expression without a reduction in mRNA levels. To further improve oncolytic therapy using a replicating adenovirus, it is important to understand the mechanism through which hypoxia and the virus interact to control expression of viral and cellular proteins, and consequently to develop means to overcome decreased viral production in hypoxic conditions
— id: 57889, year: 2005, vol: 12, page: 911, stat: Journal Article,

Basic pathogenetic mechanisms in silicosis: current understanding
Rimal, Binaya; Greenberg, Alissa K; Rom, William N
2005 Mar;11(2):169-173, Current opinion in pulmonary medicine
PURPOSE OF REVIEW: Silicosis continues to be a common cause of chronic lung diseases, despite evidence that these diseases can be prevented by environmental dust control. Silicosis has been studied extensively by basic and clinical scientists, yet little is known about the crucial cellular and molecular mechanisms that initiate and propagate the process of inflammation and scarring. RECENT FINDINGS: Recent in vivo, in vitro, and human studies have focused on several main areas of investigation into the causes and processes of the development of silicosis. These areas of investigation include the variability of pathogenic potential of different varieties of silica; the role of activated alveolar macrophages products in the development and progression of silicosis; and the direct role played by the silica particle surface in triggering adverse biologic reactions, such as generating ROS and RNS. The generation of oxidants by silica particles and by silica-activated cells results in cell and lung damage; increased expression of inflammatory cytokines, including TNF-alpha, IL 1 beta, and TGF-beta; activation of cell signaling pathways, including the MAP kinase pathways; and phosphorylation and activation of specific transcription factors (e.g., NFkB). The ROS, RNS, and NO generated by the silica particles also induce apoptosis in macrophages and other cells. SUMMARY: Further research on the molecular mechanisms involved in the inflammatory processes important for progression to fibrotic diseases is needed for the development of effective treatment of silicosis. Potential therapeutic strategies include inhibition of cytokines such as IL-1, TNF alpha, the use of anti-oxidants, and the inhibition of apoptosis
— id: 56043, year: 2005, vol: 11, page: 169, stat: Journal Article,

Interleukin-10 induces inhibitory C/EBPbeta through STAT-3 and represses HIV-1 transcription in macrophages
Tanaka, Naohiko; Hoshino, Yoshihiko; Gold, Jeffrey; Hoshino, Satomi; Martiniuk, Frank; Kurata, Takeshi; Pine, Richard; Levy, David; Rom, William N; Weiden, Michael
2005 Oct;33(4):406-411, American journal of respiratory cell & molecular biology
Pulmonary tuberculosis (TB) has been characterized by inflammation with increased pro- or anti-inflammatory cytokines produced by macrophages. We have reported that IFN produces inhibitory C/EBPbeta and represses transcription of the HIV-1 LTR in macrophages. STAT-1 and type I IFN receptor knockout mice have macrophages that are defective in IFN signaling, yet LPS stimulation induces inhibitory C/EBPbeta, demonstrating that other cytokines can induce this repressor. LPS or Mycobacterium tuberculosis-derived lipoarabinomannan induce the anti-inflammatory cytokine interleukin (IL)-10, which represses the HIV-1 LTR in differentiated THP-1 macrophages by inducing inhibitory C/EBPbeta. In contrast, in undifferentiated THP-1 monocytes, IL-10 did not inhibit HIV-1 replication or induce C/EBPbeta. IL-10 signal transduction uses STAT-3, and macrophages from STAT-3-/- mice fail to produce inhibitory C/EBPbeta after LPS or IL-10 stimulation. Transfection of STAT-3 into THP-1 cells enhances C/EBPbeta promoter activity. THP-1 differentiation also increases STAT-3 protein, but not STAT-3 gene transcription, and induces a translational regulator, CUG-binding protein, that was essential for production of C/EBPbeta. Differentiation induced post-transcriptional regulation is required to produce inhibitory C/EBPbeta in response to IL-10. Only macrophages are able to repress HIV-1 LTR promoter activity and inhibit viral replication in response to IL-10 or type I IFN
— id: 58745, year: 2005, vol: 33, page: 406, stat: Journal Article,

Cytokine response in tuberculosis
Condos R; Rom WN
Tuberculosis Philadelphia : Lippincott Williams & Wilkins, 2004,
— id: 3965, year: 2004, vol: , page: 285, stat: Chapter,

Regional deposition of aerosolized interferon-gamma in pulmonary tuberculosis
Condos, Rany; Hull, Frank P; Schluger, Neil W; Rom, William N; Smaldone, Gerald C
2004 Jun;125(6):2146-2155, Chest
STUDY OBJECTIVES: Aerosol interferon-gamma (IFN-gamma) is a potential immunomodulator in the treatment of pulmonary tuberculosis (TB). Previous investigations demonstrated conversion of sputum smears in five patients with multidrug-resistant TB after 12 treatments over 1 month, and induction of signaling molecules in 10 of 11 drug-sensitive TB patients using BAL. The objective of the current study was to evaluate particle size and deposition pattern in patients with TB receiving aerosol IFN-gamma treatment. DESIGN: Particle size was determined with a cascade impactor, and deposition of IFN-gamma mixed with (99m)Tc-labeled human serum albumin was assessed using a gamma camera. Local levels of IFN-gamma were measured in BAL using enzyme-linked immunosorbent assays. Study patients/intervention: Fourteen patients with pulmonary TB received IFN-gamma aerosol (500 micro g) for 12 treatments in addition to antimycobacterial therapy with BAL before and after IFN-gamma aerosol treatment. Eight patients with minimal-to-moderate parenchymal involvement underwent deposition studies. Deposited (99m)Tc-labeled IFN-gamma aerosol was partitioned between upper airways and lungs using attenuation correction measurements. (133)Xe equilibrium scanning, (133)Xe washout, and (99m)Tc- macroaggregate injection defined regional lung volume, ventilation, and perfusion. RESULTS: Upper airway deposition was significant often exceeding lung deposition (53.9 +/- 7.09 micro g vs 35.8 +/- 2.73 micro g, respectively [mean +/- SE]). IFN-gamma levels measured in BAL fluid were significantly increased with aerosol treatment (0.83 +/- 0.43 micro g before vs 24.76 +/- 8.71 micro g after, p </= 0.017), and IFN-gamma levels correlated with regional deposition of IFN-gamma aerosol (r = 0.823). Four-quadrant analysis of regional lung deposition best correlated with regional perfusion (r = 0.422, p = 0.013) with penetration of aerosol into areas of obvious radiographic infiltration on chest radiograph. CONCLUSIONS: Aerosol therapy with IFN-gamma in patients with pulmonary TB is widely distributed and results in significant enhancement of IFN-gamma levels in the lower respiratory tract. In patients without lung destruction, IFN-gamma aerosol may be an adjuvant to enhance the local immune response
— id: 44955, year: 2004, vol: 125, page: 2146, stat: Journal Article,

HLA-A2-restricted CD8+-cytotoxic-T-cell responses to novel epitopes in Mycobacterium tuberculosis superoxide dismutase, alanine dehydrogenase, and glutamine synthetase
Dong, Yuzhi; Demaria, Sandra; Sun, Xuming; Santori, Fabio R; Jesdale, Bill M; De Groot, Anne S; Rom, William N; Bushkin, Yuri
2004 Apr;72(4):2412-2415, Infection & immunity
Major histocompatibility complex class I-restricted CD8(+) cytotoxic T lymphocytes (CTL) are implicated in protective Th1 immunity to Mycobacterium tuberculosis infection. We report the identification of three novel HLA-A*0201-restricted CTL epitopes within mycobacterial superoxide dismutase (SodA), L-alanine dehydrogenase (AlaDH), and L-glutamine synthetase (GlnS) proteins
— id: 44727, year: 2004, vol: 72, page: 2412, stat: Journal Article,

Gender and lung cancer
Gasperino, James; Rom, William N
2004 May;5(6):353-359, Clinical lung cancer
Although lung cancer is the leading cause of cancer death among men and women in the United States, female smokers appear to be at increased risk. After controlling for the number of cigarettes smoked, female sex imparts a significant, independent risk for most histologic types of lung cancer. Cigarette smoking, genetics, and endocrine factors may interact to contribute to the disparity in lung cancer risk between the sexes. Estrogens have direct and indirect actions in the lung, and estrogen has been implicated in lung carcinogenesis in female smokers. This review of the literature will focus on endocrine factors and tobacco carcinogens as risk factors for lung cancer in women
— id: 44954, year: 2004, vol: 5, page: 353, stat: Journal Article,

Surfactant protein A modulates the inflammatory response in macrophages during tuberculosis
Gold, Jeffrey A; Hoshino, Yoshihiko; Tanaka, Naohiko; Rom, William N; Raju, Bindu; Condos, Rany; Weiden, Michael D
2004 Feb;72(2):645-650, Infection & immunity
Tuberculosis leads to immune activation and increased human immunodeficiency virus type 1 (HIV-1) replication in the lung. However, in vitro models of mycobacterial infection of human macrophages do not fully reproduce these in vivo observations, suggesting that there are additional host factors. Surfactant protein A (SP-A) is an important mediator of innate immunity in the lung. SP-A levels were assayed in the human lung by using bronchoalveolar lavage (BAL). There was a threefold reduction in SP-A levels during tuberculosis only in the radiographically involved lung segments, and the levels returned to normal after 1 month of treatment. The SP-A levels were inversely correlated with the percentage of neutrophils in BAL fluid, suggesting that low SP-A levels were associated with increased inflammation in the lung. Differentiated THP-1 macrophages were used to test the effect of decreasing SP-A levels on immune function. In the absence of infection with Mycobacterium tuberculosis, SP-A at doses ranging from 5 to 0.01 micro g/ml inhibited both interleukin-6 (IL-6) production and HIV-1 long terminal repeat (LTR) activity. In macrophages infected with M. tuberculosis, SP-A augmented both IL-6 production and HIV-1 LTR activity. To better understand the effect of SP-A, we measured expression of CAAT/enhancer binding protein beta (C/EBPbeta), a transcription factor central to the regulation of IL-6 and the HIV-1 LTR. In macrophages infected with M. tuberculosis, SP-A reduced expression of a dominant negative isoform of C/EBPbeta. These data suggest that SP-A has pleiotropic effects even at the low concentrations found in tuberculosis patients. This protein augments inflammation in the presence of infection and inhibits inflammation in uninfected macrophages, protecting uninvolved lung segments from the deleterious effects of inflammation
— id: 42242, year: 2004, vol: 72, page: 645, stat: Journal Article,

Diagnosis and initial management of nonmalignant diseases related to asbestos
Guidotti, TL; Miller, A; Christiani, D; Wagner, G; Balmes, J; Harber, P; Brodkin, CA; Rom, W; Hillerdal, G; Harbut, M; Green, FHY
2004 SEP 15 ;170(6):691-715, American journal of respiratory & critical care medicine
— id: 46519, year: 2004, vol: 170, page: 691, stat: Journal Article,

Mycobacterium tuberculosis-induced CXCR4 and chemokine expression leads to preferential X4 HIV-1 replication in human macrophages
Hoshino, Yoshihiko; Tse, Doris B; Rochford, Gemma; Prabhakar, Savita; Hoshino, Satomi; Chitkara, Nishay; Kuwabara, Kenichi; Ching, Elbert; Raju, Bindu; Gold, Jeffrey A; Borkowsky, William; Rom, William N; Pine, Richard; Weiden, Michael
2004 May 15;172(10):6251-6258, Journal of immunology
Opportunistic infections such as pulmonary tuberculosis (TB) increase local HIV-1 replication and mutation. As AIDS progresses, alteration of the HIV-1 gp120 V3 sequence is associated with a shift in viral coreceptor use from CCR5 (CD195) to CXCR4 (CD184). To better understand the effect of HIV/TB coinfection, we screened transcripts from bronchoalveolar lavage cells with high density cDNA arrays and found that CXCR4 mRNA is increased in patients with TB. Surprisingly, CXCR4 was predominately expressed on alveolar macrophages (AM). Mycobacterium tuberculosis infection of macrophages in vitro increased CXCR4 surface expression, whereas amelioration of disease reduced CXCR4 expression in vivo. Bronchoalveolar lavage fluid from TB patients had elevated levels of CCL4 (macrophage inflammatory protein-1beta), CCL5 (RANTES), and CX3CL1 (fractalkine), but not CXCL12 (stromal-derived factor-1alpha). We found that M. tuberculosis infection of macrophages in vitro increased viral entry and RT of CXCR4, using HIV-1, but not of CCR5, using HIV-1. Lastly, HIV-1 derived from the lung contains CD14, suggesting that they were produced in AM. Our results demonstrate that TB produces a permissive environment for replication of CXCR4-using virus by increasing CXCR4 expression in AM and for suppression of CCR5-using HIV-1 by increasing CC chemokine expression. These changes explain in part why TB accelerates the course of AIDS. CXCR4 inhibitors are a rational therapeutic approach in HIV/TB coinfection
— id: 42732, year: 2004, vol: 172, page: 6251, stat: Journal Article,

Angiopoietin-1 reduces lung edema and mortality induced by bacterial endotoxin
Huang, YQ; Sauthoff, H; Pipiya, T; Chen, S; Rom, WN; Hay, JG
2004 MAY ;9(1-2):S262-S262, Molecular therapy
— id: 46544, year: 2004, vol: 9, page: S262, stat: Journal Article,

BCL-6 mutations in pulmonary lymphoproliferative disorders: demonstration of an aberrant immunological reaction in HIV-related lymphoid interstitial pneumonia
Kurosu, Katsushi; Weiden, Michael D; Takiguchi, Yuichi; Rom, William N; Yumoto, Norio; Jaishree, Jagirdar; Nakata, Koh; Kasahara, Yasunori; Tanabe, Nobuhiro; Tatsumi, Koichiro; Mikata, Atsuo; Kuriyama, Takayuki
2004 Jun 1;172(11):7116-7122, Journal of immunology
We used a PCR and sequence procedure to analyze the Ig V(H) gene and the mutations in the 5' regulatory regions of BCL-6 genes in pulmonary lymphoproliferative disorders (mucosa-associated lymphoid tissue (MALT) lymphoma, HIV-related, EBV-related, and virus-negative lymphocytic interstitial pneumonia (LIP)). Eight of 20 (40%) pulmonary MALT lymphoma and 10 of 20 LIP (5 of 5 (100%) HIV-related, 2 of 5 (40%) EBV-related, and 3 of 10 (30%) virus-negative LIP) cases showed BCL-6 gene mutations. Intraclonal heterogeneity of the BCL-6 mutations was observed only in pulmonary MALT lymphoma cases whose Ig V(H) genes also showed intraclonal heterogeneity. Ongoing BCL-6 mutations might reflect re-entry into a germinal center pathway to further mutations. BCL-6 mutations in pulmonary MALT lymphoma and HIV-negative LIP showed some features (high transition to transversion ratio, standard polarity, and RGYW/WRCY bias) of Ig V(H) gene hypermutation, leading to the view that pulmonary MALT lymphomas and HIV-negative LIP are under the influence of germinal center hypermutation mechanisms. Because BCL-6 mutations in HIV-related LIP cases did not demonstrate features of Ig V(H) gene hypermutation, immunological reactions in HIV-related LIP are the result of a process different from that found in HIV-negative pulmonary lymphoproliferative disorders
— id: 42731, year: 2004, vol: 172, page: 7116, stat: Journal Article,

Principles of tuberculosis management
Leibert E; Rom WN
Tuberculosis Philadelphia : Lippincott Williams & Wilkins, 2004,
— id: 3985, year: 2004, vol: , page: 714, stat: Chapter,

Hypoxia reduces adenoviral replication in cancer cells by down-regulation of viral protein expression
Pipiya, T; Sauthoff, H; Huang, YQ; Chang, B; Rom, WN; Hay, JG
2004 MAY ;9(1-2):S106-S107, Molecular therapy
— id: 46542, year: 2004, vol: 9, page: S106, stat: Journal Article,

Aerosolized gamma interferon (IFN-gamma) induces expression of the genes encoding the IFN-gamma-inducible 10-kilodalton protein but not inducible nitric oxide synthase in the lung during tuberculosis
Raju, Bindu; Hoshino, Yoshihiko; Kuwabara, Kenichi; Belitskaya, Ilana; Prabhakar, Savita; Canova, Antony; Gold, Jeffrey A; Condos, Rany; Pine, Richard I; Brown, Stuart; Rom, William N; Weiden, Michael D
2004 Mar;72(3):1275-1283, Infection & immunity
Gamma interferon (IFN-gamma) is critical in the immune response against Mycobacterium tuberculosis. In an ongoing trial of aerosol IFN-gamma in conjunction with standard drug therapy, we have observed activation of IFN signaling in bronchoalveolar lavage (BAL) cells from tuberculosis (TB) patients. We hypothesized that aerosol IFN-gamma treatment of pulmonary TB would increase expression of genes important for the control of TB. We investigated the expression of downstream genes by measuring inducible nitric oxide synthase (iNOS) and the chemokine IFN-inducible 10-kDa protein (IP-10) by real-time quantitative reverse transcription-PCR. In vitro, M. tuberculosis induced IP-10, and IFN-gamma stimulated this further, with no effect on iNOS expression. We studied 21 patients with pulmonary TB and 7 healthy subjects. Similar to the in vitro model, IP-10 mRNA was increased in BAL cells from TB patients and was augmented after treatment with aerosolized IFN-gamma. TB was also associated with elevated iNOS mRNA, but aerosolized IFN-gamma did not further enhance expression. Genomic analysis identified 1,300 of 4,058 genes expressed in BAL cells from six TB patients before and after 1 month of therapy, including aerosolized IFN-gamma. However, only 15 genes were differentially regulated by IFN-gamma. We conclude that iNOS and IP-10 mRNA expression is increased in TB but that aerosol IFN-gamma treatment increases expression of few genes in the human lung
— id: 42241, year: 2004, vol: 72, page: 1275, stat: Journal Article,

Tuberculosis
Rom, William N; Garay, Stuart M
Philadelphia : Lippincott Williams & Wilkins, 2004,
— id: 968, year: 2004, vol: , page: , stat: ,

Modification of the p53 transgene of a replication-competent adenovirus improves p53 stability and cancer cell killing
Sauthoff, H; Pipiya, T; Chen, S; Heitner, S; Huang, YQ; Rom, WN; Hay, JG
2004 MAY ;9(1-2):S112-S112, Molecular therapy
— id: 46543, year: 2004, vol: 9, page: S112, stat: Journal Article,

Impact of E1a modifications on tumor-selective adenoviral replication and toxicity
Sauthoff, Harald; Pipiya, Teona; Heitner, Sheila; Chen, Shu; Bleck, Bertram; Reibman, Joan; Chang, William; Norman, Robert G; Rom, William N; Hay, John G
2004 Oct;10(4):749-757, Molecular therapy
Replicating adenoviral vectors are capable of multiplying up to a thousandfold in the target cell, a property that might prove to be of tremendous potential for cancer therapy. However, restricting viral replication and toxicity to cancer cells is essential to optimize safety. It has been proposed that modifications of the E1a protein that impair binding to Rb or p300 will prevent S-phase induction in normal cells, resulting in selective viral replication in tumor cells. However, it remains uncertain which of the several possible E1a modifications would be most effective at protecting normal cells without compromising the oncolytic effect of the vector. In this study, we have expressed several E1a-deletion mutants at high levels using the CMV promoter and tested them for their ability to facilitate S-phase induction, viral replication, and cytotoxicity in both normal and cancer cells. Deletion of the Rb-binding domain within E1a only slightly decreased the ability of the virus to induce S phase in growth-arrested cells. The effect of this deletion on viral replication and cytotoxicity was variable. There was reduced cytotoxicity in normal bronchial epithelial cells; however, in some normal cell types there was equal viral replication and cytotoxicity compared with wild type. Deletions in both the N-terminus and the Rb-binding domain were required to block S-phase induction effectively in growth-arrested normal cells; in addition, this virus demonstrated reduced viral replication and cytotoxicity in normal cells. An equally favorable replication and cytotoxicity profile was induced by a virus expressing E1a that is incapable of binding to the transcriptional adapter motif (TRAM) of p300. All viruses were equally cytotoxic to cancer cells compared with wild-type virus. In conclusion, deletion of the Rb-binding site alone within E1a may not be the most efficacious means of targeting viral replication and toxicity. However, deletion within the N-terminus in conjunction with a deletion within the Rb-binding domain, or deletion of the p300-TRAM binding domain, induces a more favorable cytotoxicity profile
— id: 51518, year: 2004, vol: 10, page: 749, stat: Journal Article,

Clinical Correlation of Asbestos Bodies in BAL Fluid
Vathesatogkit, Pratan; Harkin, Timothy J; Addrizzo-Harris, Doreen J; Bodkin, Marion; Crane, Michael; Rom, William N
2004 Sep;126(3):966-971, Chest
BACKGROUND: Asbestos bodies (AB) in BAL cells are specific markers of asbestos exposure. METHODS: We retrospectively reviewed BAL cytocentrifuge slides of 30 utility workers with a history of asbestos exposure and 30 normal volunteers. BAL cytocentrifuge slides were blinded and scanned under 40 x light microscope. RESULTS: AB were found more frequently in subjects with a history of asbestos exposure compared to normal volunteers (10 of 30 subjects, 33%, vs 0 of 30 subjects). The mean number of AB seen in the AB-positive group was 2.7 per slide. Demographic data were comparable including age, gender, and smoking. Exposure histories were also similar: duration > 20 years, onset > 30 years ago, and time since last exposure > 7 years. More AB-positive patients reported respiratory symptoms (70% vs 26%, p < 0.05). High-resolution CT scans of AB-positive patients revealed a higher prevalence of parenchymal disease (70% vs 26%, p < 0.05). AB-positive subjects had reduced pulmonary function compared to AB-negative subjects: FVC (86% vs 97% predicted), FEV(1) (77% vs 92% predicted, p < 0.05), and diffusion capacity of the lung for carbon monoxide (76% vs 104% predicted, p < 0.01). CONCLUSION: In individuals with a history of asbestos exposure, the presence of AB in BAL cells is associated with higher prevalence of parenchymal abnormalities, respiratory symptoms, and reduced pulmonary function
— id: 44704, year: 2004, vol: 126, page: 966, stat: Journal Article,

Candidate secreted biomarkers in plasma for the early detection of stage I lung cancer
Chavany, C; Chen, S; Yamaguchi, K; Schramm, S; Zafar, S; Greenberg, A; Crawford, B; Zervos, M; Rom, W; Jendoubi, M
2003 NOV ;12(11):1331S-1331S, Cancer epidemiology biomarkers & prevention
— id: 55377, year: 2003, vol: 12, page: 1331S, stat: Journal Article,

Recombinant gamma interferon stimulates signal transduction and gene expression in alveolar macrophages in vitro and in tuberculosis patients
Condos, Rany; Raju, Bindu; Canova, Antony; Zhao, Ben-Yang; Weiden, Michael; Rom, William N; Pine, Richard
2003 Apr;71(4):2058-2064, Infection & immunity
Tuberculosis is the seventh leading cause of morbidity and mortality in the world, with eight million cases per year. Animal and human studies demonstrate an enrichment of CD4 cells at sites of disease, with a more favorable clinical course when there is a Th1 response with the presence of gamma interferon (IFN-gamma). We previously treated patients who had multidrug-resistant tuberculosis with recombinant IFN-gamma (rIFN-gamma) in aerosol form and were able to convert smear-positive cases to smear negative with 12 treatments over 1 month. We hypothesized that rIFN-gamma would induce signal transducer and activator of transcription (STAT) and interferon regulatory factor (IRF) binding activity in alveolar macrophages (AM). AM treated in vitro showed clear upregulation of STAT-1 and IRF-1 by rIFN-gamma. STAT-1 was not activated and IRF-1 was only weakly induced after 1 day of infection by Mycobacterium tuberculosis TN913. In bronchoalveolar lavage (BAL) cells obtained from 10 of 10 tuberculosis patients 10 +/- 2 days post-antituberculosis treatment, there was no detectable STAT-1 or IRF-1 DNA-binding activity. After 4 weeks of treatment with rIFN-gamma aerosol in addition to the antituberculosis drugs, 10 of 10 patients had increased STAT-1, IRF-1, and/or IRF-9 DNA-binding activity in BAL cells from lung segments shown radiographically to be involved and in those shown to be uninvolved. Symptoms and chest radiographs improved, and amounts of macrophage inflammatory cytokines and human immunodeficiency virus type 1 (HIV-1) viral loads (in five of five HIV-1-coinfected patients) declined in the second BAL specimens. rIFN-gamma aerosol induces signal transduction and gene expression in BAL cells and should be evaluated for efficacy in a randomized, controlled clinical trial
— id: 44958, year: 2003, vol: 71, page: 2058, stat: Journal Article,

Chromium(VI) exposure enhances polycyclic aromatic hydrocarbon-DNA binding at the p53 gene in human lung cells
Feng, Zhaohui; Hu, Wenwei; Rom, William N; Costa, Max; Tang, Moon-Shong
2003 Apr;24(4):771-778, Carcinogenesis
Chromium(VI) [Cr(VI)] is a ubiquitous environmental and industrial contaminant. Cr(VI) exposure is strongly associated with a higher incidence of human lung cancer, but the mechanism of Cr(VI) carcinogenicity remains unclear. Cigarette smoking has been known as the prominent cause of lung cancer, and polycyclic aromatic hydrocarbons (PAHs), the major carcinogens in cigarette smoke, have been suggested as being responsible for the initiation and development of lung cancer. It has been reported that lung cancer from workers exposed to Cr(VI) has a high percentage of G to T transversion mutations in the non-transcribed strand of the p53 gene, a hallmark of PAH-induced mutation. Cr(VI) is a weak mutagen although it can induce a high percentage of G to T transversion mutations. These results raise the possibility that Cr(VI) may enhance PAH binding at the p53 gene in lung tissue. To test this possibility, we have determined the effect of Cr(VI) exposure on benzo[a]pyrene diol epoxides (BPDE)-DNA binding at total genomic DNA level and at the p53 gene in normal human lung fibroblast cells. We found that in lung cells Cr(VI) pre-exposure does not affect the BPDE-DNA binding at the total genomic DNA level or at exons 5, 6 and 9 of the p53 gene; however, it greatly enhances BPDE-DNA binding at exons 7 and 8 of the p53 gene, especially at mutational hotspots of lung cancer: codons 248, 273 and 282 of the p53 gene. No enhancement of BPDE-DNA binding in the p53 was observed when naked genomic DNA isolated from Cr(VI)-exposed cells was modified with BPDE in vitro. These results suggest that Cr(VI) exposure may enhance chromatin structure-dependent carcinogen-DNA binding. This effect may contribute to the synergism of Cr(VI) and BPDE on mutagenesis and cell transformation, and may also contribute to the higher incidence of lung cancer in Cr(VI)-exposed populations
— id: 39234, year: 2003, vol: 24, page: 771, stat: Journal Article,

Gene expression of primary human bronchial epithelial cells in response to coal dusts with different prevalence of coal workers' pneumoconiosis
Hu, Wenwei; Zhang, Qi; Su, Wei Cheng; Feng, Zhaohui; Rom, William; Chen, Lung Chi; Tang, Moonshong; Huang, Xi
2003 Jul 11;66(13):1249-1265, Journal of toxicology & environmental health. Pt. A
Striking regional differences in the prevalence of coal workers' pneumoconiosis (CWP) have been observed but not fully understood. This study investigated the early biological responses of primary lung cells to treatment with coal dusts from various seams. High-density oligoarray technology (GeneChip, Affymetrix, Santa Clara, CA) was used to compile gene expression profiles of primary human bronchial epithelial cells to low concentrations (2 microg/cm(2)) of coals for 6 h or 24 h of treatment. Data showed that a total of 1050 out of 12,000 genes on the chip were altered by 2 coal dusts. The coal from the Pennsylvania (PA) coal-mine region with a high prevalence of CWP altered 908 genes, many more than the coal from Utah (UT) with a low prevalence of CWP, which affected 356 genes. Many genes decreased their expression levels in response to the PA coal at 6 h and/or 24 h of treatment. For example, transferrin receptor, a gene known to control cellular iron uptake, was downregulated in the cells treated with the iron-containing PA coal in order to protect cells from iron overload. The UT coal without bioavailable iron had no such effect. The downregulation patterns of genes were confirmed by reverse-transcription polymerase chain reaction (RT-PCR). This study is one of the first in profiling gene expressions of primary bronchial epithelial cells treated with coals from various seams, which may set stages for future studies on specific genes
— id: 39145, year: 2003, vol: 66, page: 1249, stat: Journal Article,

Detection of lung cancer with volatile markers in the breath
Phillips, Michael; Cataneo, Renee N; Cummin, Andrew R C; Gagliardi, Anthony J; Gleeson, Kevin; Greenberg, Joel; Maxfield, Roger A; Rom, William N
2003 Jun;123(6):2115-2123, Chest
STUDY OBJECTIVES: To evaluate volatile organic compounds (VOCs) in the breath as tumor markers in lung cancer. Alkanes and monomethylated alkanes are oxidative stress products that are excreted in the breath, the catabolism of which may be accelerated by polymorphic cytochrome p450-mixed oxidase enzymes that are induced in patients with lung cancer. DESIGN: Combined case-control and cross-sectional study. SETTING: Five academic pulmonary medicine services in the United States and the United Kingdom. Patients and participants: One hundred seventy-eight bronchoscopy patients and 41 healthy volunteers. INTERVENTION: Breath samples were analyzed by gas chromatography and mass spectroscopy to determine alveolar gradients (ie, the abundance in breath minus the abundance in room air) of C4-C20 alkanes and monomethylated alkanes. MEASUREMENTS: Patients with primary lung cancer (PLC) were compared to healthy volunteers, and a predictive model was constructed using forward stepwise discriminant analysis of the alveolar gradients. This model was cross-validated with a leave-one-out jackknife technique and was tested in two additional groups of patients who had not been used to develop the model (ie, bronchoscopy patients in whom cancer was not detected, and patients with metastatic lung cancer [MLC]). RESULTS: Eighty-seven of 178 patients had lung cancer (PLC, 67 patients; MLC, 15 patients; undetermined, 5 patients). A predictive model employing nine VOCs identified PLC with a sensitivity of 89.6% (60 of 67 patients) and a specificity of 82.9% (34 of 41 patients). On cross-validation, the sensitivity was 85.1% (57 of 67 patients) and the specificity was 80.5% (33 of 41 patients). The stratification of patients by tobacco smoking status, histologic type of cancer, and TNM stage of cancer revealed no marked effects. In the two additional tests, the model predicted MLC with a sensitivity of 66.7% (10 of 15 patients), and it classified the cancer-negative bronchoscopy patients with a specificity of 37.4% (34 of 91 patients). CONCLUSIONS: Compared to healthy volunteers, patients with PLC had abnormal breath test findings that were consistent with the accelerated catabolism of alkanes and monomethylated alkanes. A predictive model employing nine of these VOCs exhibited sufficient sensitivity and specificity to be considered as a screen for lung cancer in a high-risk population such as adult smokers
— id: 44957, year: 2003, vol: 123, page: 2115, stat: Journal Article,

Hypoxia reduces adenoviral replication in cancer cells
Pipiya, T; Sauthoff, H; Heitner, S; Chen, S; Rom, W; Hay, JG
2003 MAY ;7(5):S174-S175, Molecular therapy
— id: 38566, year: 2003, vol: 7, page: S174, stat: Journal Article,

Functional genomics in lung cancer and biomarker detection
Rom, William N; Tchou-Wong, Kam-Meng
2003 Aug;29(2):153-156, American journal of respiratory cell & molecular biology
— id: 44956, year: 2003, vol: 29, page: 153, stat: Journal Article,

Molecular and genetic aspects of lung cancer
Rom, William N; Tchou-Wong, Kam-Meng
2003 ;75(10):3-26, Methods in molecular medicine
— id: 44960, year: 2003, vol: 75, page: 3, stat: Journal Article,

Comparison of E1a modifications to achieve tumor cell selective viral replication and toxicity
Sauthoff, H; Pipiya, T; Heitner, S; Chang, W; Chen, S; Rom, WN; Hay, JG
2003 MAY ;7(5):S453-S454, Molecular therapy
— id: 38567, year: 2003, vol: 7, page: S453, stat: Journal Article,

Intratumoral spread of wild-type adenovirus is limited after local injection of human xenograft tumors: virus persists and spreads systemically at late time points
Sauthoff, Harald; Hu, Jing; Maca, Cielo; Goldman, Michael; Heitner, Sheila; Yee, Herman; Pipiya, Teona; Rom, William N; Hay, John G
2003 Mar 20;14(5):425-433, Human gene therapy
Oncolytic replicating adenoviruses are a promising new modality for the treatment of cancer. Despite the assumed biologic advantage of continued viral replication and spread from infected to uninfected cancer cells, early clinical trials demonstrate that the efficacy of current vectors is limited. In xenograft tumor models using immune-incompetent mice, wild-type adenovirus is also rarely able to eradicate established tumors. This suggests that innate immune mechanisms may clear the virus or that barriers within the tumor prevent viral spread. The aim of this study was to evaluate the kinetics of viral distribution and spread after intratumoral injection of virus in a human tumor xenograft model. After intratumoral injection of wild-type virus, high levels of titratable virus persisted within the xenograft tumors for at least 8 weeks. Virus distribution within the tumors as determined by immunohistochemistry was patchy, and virus-infected cells appeared to be flanked by tumor necrosis and connective tissue. The close proximity of virus-infected cells to the tumor-supporting structure, which is of murine origin, was clearly demonstrated using a DNA probe that specifically hybridizes to the B1 murine DNA repeat. Importantly, although virus was cleared from the circulation 6 hr after intratumoral injection, after 4 weeks systemic spread of virus was detected. In addition, vessels of infected tumors were surrounded by necrosis and an advancing rim of virus-infected tumor cells, suggesting reinfection of the xenograft tumor through the vasculature. These data suggest that human adenoviral spread within tumor xenografts is impaired by murine tumor-supporting structures. In addition, there is evidence for continued viral replication within the tumor, with subsequent systemic dissemination and reinfection of tumors via the tumor vasculature. Despite the limitations of immune-incompetent models, an understanding of the interactions between the virus and the tumor-bearing host is important in the design of effective therapies
— id: 37579, year: 2003, vol: 14, page: 425, stat: Journal Article,

Lung-specific expression of mutant p53 as mouse model for lung cancer
Tchou-Wong, Kam-Meng; Rom, William N
2003 ;74(10):465-480, Methods in molecular medicine
— id: 44959, year: 2003, vol: 74, page: 465, stat: Journal Article,

Preferential DNA damage and poor repair determine ras gene mutational hotspot in human cancer
Feng, Zhaohui; Hu, Wenwei; Chen, James X; Pao, Annie; Li, Haiying; Rom, William; Hung, Mien-Chie; Tang, Moon-shong
2002 Oct 16;94(20):1527-1536, Journal of the National Cancer Institute
BACKGROUND: Mutations in ras genes are commonly found in human cancers and in animal models. Although mutations at codons 12, 13, and 61 of H-, N- and K-ras genes can activate their oncogenic function, mutations at codon 12 of K-ras are the most common mutations found among the three ras genes in human cancers. To investigate whether codon 12 of human K-ras is especially susceptible to carcinogens and/or whether carcinogen-DNA adducts at this codon are repaired less efficiently, we examined tobacco smoke carcinogen-induced DNA damage in normal human bronchial epithelial and fibroblast cells. METHODS: We used the UvrABC nuclease incision method in combination with ligation-mediated polymerase chain reaction to map the distribution of DNA adducts induced by benzo[a]pyrene diol epoxide (BPDE) and other bulky carcinogens within exons 1 and 2 in H-ras, N-ras, and K-ras. We also analyzed BPDE-DNA adduct repair efficiency in these three genes using the same method. RESULTS: Codons 12 and 14 of the K-ras gene were hotspots for carcinogen-DNA adduct formation, with little and no adduct formation at codons 13 and 61, respectively. The BPDE-DNA adducts formed at codon 14 were repaired almost twice as quickly as those formed at codon 12. There was some BPDE-DNA adduct formation at codons 12 of H-ras and N-ras, but this codon was not a hotspot. Furthermore, no substantial difference in repair rates between codon 12 and the other codons analyzed (codons 3 and 18) was observed in either the H-ras or N-ras genes. CONCLUSION: These findings link the human cancer mutational hotspot at codon 12 of K-ras to preferential DNA damage and poor repair
— id: 39575, year: 2002, vol: 94, page: 1527, stat: Journal Article,

4-aminobiphenyl is a major etiological agent of human bladder cancer: evidence from its DNA binding spectrum in human p53 gene
Feng, Zhaohui; Hu, Wenwei; Rom, William N; Beland, Frederick A; Tang, Moon-shong
2002 Oct;23(10):1721-1727, Carcinogenesis
4-aminobiphenyl (4-ABP) is a major etiological agent of human bladder cancer, and its metabolites are able to form DNA adducts that may induce mutation and initiate bladder carcinogenesis. Thirty to sixty percent of human bladder cancer has a mutation in the p53 gene, and the mutational spectrum bears two characteristics: compared with other cancers, the pattern of mutations is more evenly distributed along the p53 gene, and the mutational hotspots occur at both CpG sites, such as codons 175, 248 and 273, and non-CpG sites, such as codons 280 and 285, the latter two being unique mutational hotspots for bladder and other urinary tract cancers. These findings raise the possibility that the special p53 mutational features in human bladder cancer are due to the unique binding spectrum of metabolically activated 4-ABP in bladder cells. To address this question, here we have mapped the 4-ABP-DNA adduct distribution in the p53 gene at the nucleotide sequence level in human bladder cells. We found that, unlike benzo[a]pyrene trans-7,8-dihydrodiol-9,10-epoxide-DNA adduction, which preferentially occurs at CpG sites, 4-ABP-DNA adduction is not biased for CpG sites, and the adducts are more evenly distributed along the p53 gene; nonetheless, the p53 mutational hotspots in bladder cancer at codons 175, 248, 280 and 285 are also the preferential sites for 4-ABP adduct formation. These results strongly suggest that the unique binding spectrum of 4-ABP contributes greatly to the unique mutational spectrum in the p53 gene of human bladder cancer, and provide further molecular evidence to directly link 4-ABP to bladder cancer
— id: 39577, year: 2002, vol: 23, page: 1721, stat: Journal Article,

N-hydroxy-4-aminobiphenyl-DNA binding in human p53 gene: sequence preference and the effect of C5 cytosine methylation
Feng, Zhaohui; Hu, Wenwei; Rom, William N; Beland, Frederick A; Tang, Moon-shong
2002 May 21;41(20):6414-6421, Biochemistry
4-Aminobiphenyl (4-ABP) is a major etiological agent for human bladder cancer. Metabolically activated 4-ABP is able to interact with DNA to form adducts that may induce mutations and initiate carcinogenesis. Thirty to sixty percent of bladder cancer has a mutation in the tumor suppressor p53 gene, and the mutational spectrum bears unique features. To date the DNA binding spectrum of 4-ABP in the p53 gene is not known due to the lack of methodology to detect 4-ABP-DNA adducts at nucleotide sequence level. We have found that UvrABC nuclease, a nucleotide excision repair complex isolated from Escherichia coli, is able to incise specifically and quantitatively DNA fragments modified with N-hydroxy-4-aminobiphenyl (N-OH-4-ABP), an activated intermediate of 4-ABP. Using the UvrABC nuclease incision method, we mapped the binding spectrum of N-OH-4-ABP in DNA fragments containing exons 5, 7, and 8 of the human p53 gene and also determined the effect of C5 cytosine methylation on N-OH-4-ABP-DNA binding. We found that codon 285, a mutational hotspot at a non-CpG site in bladder cancer, is the preferential binding site for N-OH-4-ABP. We also found that C5 cytosine methylation greatly enhanced N-OH-4-ABP binding at CpG sites, and that two mutational hotspots at CpG sites, codons 175 and 248, became preferential binding sites for N-OH-4-ABP only after being methylated. These results suggest that both the unique DNA binding specificity of 4-ABP and cytosine methylation contribute to the mutational spectrum of the p53 gene in human bladder cancer
— id: 32120, year: 2002, vol: 41, page: 6414, stat: Journal Article,

Significance of abnormal chest radiograph findings in patients with HIV-1 infection without respiratory symptoms
Gold, Jeffrey A; Rom, William N; Harkin, Timothy J
2002 May;121(5):1472-1477, Chest
STUDY OBJECTIVES: Patients with HIV-1 infection or AIDS may present with abnormal chest radiograph (CXR) findings in the absence of symptoms specific to the lung. The objective was to determine the spectrum of disease and the diagnostic modalities employed in these patients. METHODS: From 1996 to 1998, we identified patients with HIV-1 infection presenting to the Bellevue Hospital Chest Service with abnormal CXR findings, and absence of specific pulmonary symptoms. Charts were reviewed for presence of constitutional symptoms, CD4 lymphocyte count, use of Pneumocystis carinii pneumonia (PCP) prophylaxis, eventual diagnosis, and all diagnostic modalities employed. CXR findings were classified according to their predominant abnormalities: nodules, infiltrates, cavity, mass, adenopathy, or effusion. RESULTS: Forty-four patients were eligible for inclusion. Eight-six percent of patients had a CD4 lymphocyte count < 200 cells/microL, and 57% were receiving PCP prophylaxis. Nodular disease was the most common radiographic abnormality (57%), followed by adenopathy (17%). A definitive diagnosis was obtained in 86% of the patients. The most common diagnosis was tuberculosis (26%), followed by nontuberculous mycobacteria (NTM; 23%) and Kaposi sarcoma (12%). No patients had PCP or bacterial pneumonia. Sixty-two percent of patients required an invasive modality to establish a diagnosis. Only 18% of patients with tuberculosis (2 of 11 patients) received diagnoses by sputum analysis. CONCLUSIONS: Patients with HIV-1 infection, abnormal CXR findings, and lack of pulmonary symptoms have a high incidence of infectious disorders, especially pulmonary tuberculosis and infection due to NTM. The high prevalence of treatable and potentially communicable disorders warrants an aggressive diagnostic approach in these patients
— id: 38691, year: 2002, vol: 121, page: 1472, stat: Journal Article,

Selective p38 activation in human non-small cell lung cancer
Greenberg, Alissa K; Basu, Sharmila; Hu, Jing; Yie, Ting-an; Tchou-Wong, Kam Meng; Rom, William N; Lee, Theodore C
2002 May;26(5):558-564, American journal of respiratory cell & molecular biology
The mitogen-activated protein kinase (MAPK) pathways transmit signals from the cell membrane to the nucleus. Activation of MAPK cascades may play a role in malignant transformation. We hypothesized that enhanced expression of one or more of these pathways would occur in human lung cancers. Using Western blot analysis of tissue homogenates from resected non- small cell lung cancers and matched non-neoplastic lung tissue, we determined that only activated p38 was consistently increased in tumor compared with normal tissue. In vitro kinase assays confirmed that the levels of activated MAPK correlated with the activity of the enzymes, and immunohistochemical analysis confirmed the cellular localization of the activated MAPKs. We incubated a lung cancer cell line in a hypoxic chamber to simulate the hypoxic environment in solid lung tumors, but found no increase in p38 activation. Contrary to our expectations, ERK and JNK, the MAPK pathways traditionally associated with cell growth and perhaps malignant transformation, were not consistently activated in the human lung tumor samples. However, p38, a MAPK usually associated with stress responses, growth arrest, and apoptosis, was activated in all of the human lung cancer samples, suggesting an additional role for this pathway in malignant cell growth or transformation
— id: 39668, year: 2002, vol: 26, page: 558, stat: Journal Article,

Glucocorticoids inhibit lung cancer cell growth through both the extracellular signal-related kinase pathway and cell cycle regulators
Greenberg, Alissa K; Hu, Jing; Basu, Sharmila; Hay, John; Reibman, Joan; Yie, Ting-An; Tchou-Wong, Kam Meng; Rom, William N; Lee, Theodore C
2002 Sep;27(3):320-328, American journal of respiratory cell & molecular biology
Glucocorticoids inhibit the proliferation of various cell types, but the mechanism of this inhibition remains unclear. We investigated the effect of dexamethasone on non-small cell lung cancer cell growth and cell cycle progression. We showed that dexamethasone suppresses the proliferation of A549 and Calu-1 cells, with accumulation of cells in G1/G0 stage of the cell cycle, as determined by fluorescence-activated cell sorter analysis. Western blot analysis confirmed that this is associated with hypophosphorylation of retinoblastoma protein. Using Western blot analysis and in vitro kinase assays, we found that dexamethasone results in decreased activity of CDK2 and 4, decreased levels of cyclin D, E2F, and Myc, and increased levels of the CDK inhibitor p21(Cip1). In addition, we found that dexamethasone decreases activity of extracellular signal-related kinase (ERK)/mitogen-activated protein kinase (MAPK). The kinetics of all these changes indicate that inhibition of the ERK/MAPK pathway precedes the cell cycle effects, suggesting that regulation of this MAPK-signaling pathway may be an alternative mechanism for glucocorticoid-induced cell cycle arrest and growth inhibition
— id: 39599, year: 2002, vol: 27, page: 320, stat: Journal Article,

Clinical presentation of pulmonary mycetoma in HIV-infected patients
Greenberg, Alissa K; Knapp, Jocelyn; Rom, William N; Addrizzo-Harris, Doreen J
2002 Sep;122(3):886-892, Chest
STUDY OBJECTIVE:s: Although pulmonary mycetoma has been well-described in immunocompetent hosts, the only description in HIV-infected patients has been of 10 patients from our institution, from 1992 to 1995. To further investigate the impact of HIV status on the presentation and course of pulmonary mycetoma, we conducted a follow-up study. DESIGN: Retrospective review of all cases of pulmonary mycetoma at Bellevue Hospital from 1992 to 1999. SETTING: Patients were evaluated on the inpatient chest service and in the outpatient chest and HIV clinics of Bellevue Hospital in New York City. PATIENTS: We identified 74 patients with pulmonary mycetoma; 20 of them were HIV-infected (27%). INTERVENTIONS: The 20 HIV-infected patients were treated with antiretroviral and/or antifungal therapy. MEASUREMENTS AND RESULTS: Predisposing diseases were pulmonary tuberculosis (TB), Pneumocystis carinii pneumonia (PCP), or both TB and PCP. Seventeen patients had a CD4+ cell count of < 100 cells/ micro L at presentation. Hemoptysis was present in 13 patients, but was massive in only 1 patient. Cough was common. Of the 18 patients for whom follow-up was available, 11 received antifungal treatment and 7 were observed without therapy. Six patients received both antiretroviral and antifungal therapy. Disease progression occurred in 50%. Only five patients exhibited radiographic or clinical improvement. All five were treated with both antiretroviral and antifungal therapy. CONCLUSIONS: PCP is a risk factor for pulmonary mycetoma in the HIV-infected individual. HIV-infected patients with mycetomas have a significant rate of disease progression, although they rarely have life-threatening hemoptysis. A combination of antifungal and antiretroviral therapy may improve the clinical outcome in HIV-infected patients with pulmonary mycetoma
— id: 34534, year: 2002, vol: 122, page: 886, stat: Journal Article,

Preneoplastic lesions of the lung
Greenberg, Alissa K; Yee, Herman; Rom, William N
2002 ;3(1):20-20, Respiratory research
Lung cancer is the leading cause of cancer deaths worldwide. If we can define and detect preneoplastic lesions, we might have a chance of improving survival. The World Health Organization has defined three preneoplastic lesions of the bronchial epithelium: squamous dysplasia/carcinoma in situ; atypical adenomatous hyperplasia; and diffuse idiopathic pulmonary neuroendocrine cell hyperplasia. These lesions are believed to progress to squamous cell carcinoma, adenocarcinoma and carcinoid tumors, respectively. In this review we summarize the data supporting the preneoplastic nature of these lesions, and delve into some of the genetic changes found in atypical adenomatous hyperplasia and squamous dysplasia/carcinoma in situ
— id: 39661, year: 2002, vol: 3, page: 20, stat: Journal Article,

Maximal HIV-1 replication in alveolar macrophages during tuberculosis requires both lymphocyte contact and cytokines
Hoshino, Yoshihiko; Nakata, Koh; Hoshino, Satomi; Honda, Yoshihiro; Tse, Doris B; Shioda, Tatsuo; Rom, William N; Weiden, Michael
2002 Feb 18;195(4):495-505, Journal of experimental medicine
HIV-1 replication is markedly upregulated in alveolar macrophages (AM) during pulmonary tuberculosis (TB). This is associated with loss of an inhibitory CCAAT enhancer binding protein beta (C/EBPbeta) transcription factor and activation of nuclear factor (NF)-kappaB. Since the cellular immune response in pulmonary TB requires lymphocyte--macrophage interaction, a model system was developed in which lymphocytes were added to AM. Contact between lymphocytes and AM reduced inhibitory C/EBPbeta, activated NF-kappaB, and enhanced HIV-1 replication. If contact between lymphocytes and macrophages was prevented, inhibitory C/EBPbeta expression was maintained and the HIV-1 long terminal repeat (LTR) was not maximally stimulated although NF-kappaB was activated. Antibodies that cross-linked macrophage expressed B-7, and vascular cell adhesion molecule and CD40 were used to mimic lymphocyte contact. All three cross-linking antibodies were required to abolish inhibitory C/EBPbeta expression. However, the HIV-1 LTR was not maximally stimulated and NF-kappaB was not activated. Maximal HIV-1--LTR stimulation required both lymphocyte-derived soluble factors, and cross-linking of macrophage expressed costimulatory molecules. High level HIV-1--LTR stimulation was also achieved when IL-1beta, IL-6, and TNF-beta were added to macrophages with cross-linked costimulatory molecules. Contact between activated lymphocytes and macrophages is necessary to down-regulate inhibitory C/EBPbeta, thereby derepressing the HIV-1 LTR. Lymphocyte-derived cytokines activate NF-kappaB, further enhancing the HIV-1 LTR
— id: 39706, year: 2002, vol: 195, page: 495, stat: Journal Article,

Oligoclonal T cell expansions in pulmonary lymphoproliferative disorders: demonstration of the frequent occurrence of oligoclonal T cells in human immunodeficiency virus-related lymphoid interstitial pneumonia
Kurosu, Katsushi; Yumoto, Norio; Rom, William N; Takiguchi, Yuichi; Jaishree, Jagirdai; Nakata, Koh; Tatsumi, Koichiro; Mikata, Aatsuo; Kuriyama, Takatyuki; Weiden, Michael D
2002 Jan 15;165(2):254-259, American journal of respiratory & critical care medicine
We used a denaturing gradient gel electrophoresis (DGGE) procedure with 40-nucleotide guanine- and cytosine-rich sequences in the polymerase chain reaction (PCR) and sequencing analysis to analyze the T cell antigen receptor (TCR)-Vgamma gene repertoire of infiltrating T lymphocytes in pulmonary lymphoproliferative disorders. Six of 15 low-grade mucosa-associated lymphoid tissue (MALT) lymphomas and 8 of 15 cases of lymphocytic interstitial pneumonia (LIP) showed some oligoclonal bands for TCR-Vgamma genes on DGGE. Sequencing analysis demonstrated plural oligoclonal TCR-Vgamma clones among the oligoclonal PCR products on DGGE, leading to the conclusion that conventional antigen-specific oligoclonal expansions may play some role in the pathogenesis of pulmonary lymphoproliferative disorders. The frequency of oligoclonal infiltrating T cell expansions in human immunodeficiency virus (HIV)-related LIP (100%) was significantly higher than in low-grade pulmonary MALT lymphomas (40%) or in HIV-negative LIP (30%). Because recent evidence demonstrates that the V3 loop in the proviral amino acid sequences of mononuclear cells from bronchoalveolar lavage is more homogeneous than those from peripheral blood, this homogeneity might result in oligoclonal expansions of infiltrating T lymphocytes as a consequence of ongoing reactions against lung-specific viral strains
— id: 42264, year: 2002, vol: 165, page: 254, stat: Journal Article,

Helios gene gun particle delivery for therapy of acid maltase deficiency
Martiniuk, Frank; Chen, Agnes; Mack, Adra; Donnabella, Vincent; Slonim, Alfred; Bulone, Linda; Arvanitopoulos, Eleni; Raben, Nina; Plotz, Paul; Rom, William N
2002 Oct;21(10):717-725, DNA & cell biology
Autosomal recessive deficiency of lysosomal acid maltase (GAA) or glycogen storage disease type II (GSDII) results in a spectrum of phenotypes including a rapidly fatal infantile disorder (Pompe's), juvenile, and a late-onset adult myopathy. The infantile onset form presents as hypotonia with massive accumulation of glycogen in skeletal and heart muscle, with death due to cardiorespiratory failure. Adult patients with the slowly progressive form develop severe skeletal muscle weakness and respiratory failure. Particle bombardment is a safe, efficient physical method in which high-density, subcellular-sized particles are accelerated to high velocity to carry DNA into cells. Because it does not depend on a specific ligand, receptor, or biochemical features on cell surfaces, particle-mediated gene transfer can be readily applied to a variety of systems. We evaluated particle bombardment as a delivery system for therapy of GSDII. We utilized a vector carrying the CMV promoter linked to the human GAA cDNA. Human GSDII cell lines (fibroblasts and lymphoid) as well as ex vivo with adult-onset peripheral blood cells (lymphocytes and monocytes) were transiently transfected by bombardment with a Helios gene gun delivering gold particles coated with the GAA expression plasmid. All cell types showed an increase in human GAA activity greater than 50% of normal activity. Subsequently, GAA -/- mice were treated every 2 weeks for 4 months by particle bombardment to the epidermis of the lower back and hind limbs. Muscle weakness in the hind and forelimbs was reversed. These data suggest that particle delivery of the GAA cDNA by the Helios gene gun may be a safe, effective treatment for GSDII
— id: 39560, year: 2002, vol: 21, page: 717, stat: Journal Article,

Mycobacterial antigens exacerbate disease manifestations in Mycobacterium tuberculosis-infected mice
Moreira, Andre L; Tsenova, Liana; Aman, Melles Haile; Bekker, Linda-Gail; Freeman, Sherry; Mangaliso, Bande; Schroder, Ulf; Jagirdar, Jaishree; Rom, William N; Tovey, Michael G; Freedman, Victoria H; Kaplan, Gilla
2002 Apr;70(4):2100-2107, Infection & immunity
To control tuberculosis worldwide, the burden of adult pulmonary disease must be reduced. Although widely used, Mycobacterium bovis BCG vaccination given at birth does not protect against adult pulmonary disease. Therefore, postexposure vaccination of adults with mycobacterial antigens is being considered. We examined the effect of various mycobacterial antigens on mice with prior M. tuberculosis infection. Subcutaneous administration of live or heat-treated BCG with or without lipid adjuvants to infected mice induced increased antigen-specific T-cell proliferation but did not reduce the bacterial load in the lungs and caused larger lung granulomas. Similarly, additional mycobacterial antigen delivered directly to the lungs by aerosol infection with viable M. tuberculosis mixed with heat-killed Mycobacterium tuberculosis (1:1) also did not reduce the bacillary load but caused increased expression of tumor necrosis factor alpha (TNF-alpha) and interleukin 6 (IL-6), which was associated with larger granulomas in the lungs. When M. tuberculosis-infected mice were treated with recombinant BCG that secreted cytokines shown to reduce disease in a preinfection vaccine model, the BCG secreting TNF-alpha, and to a lesser extent, IL-2 and gamma interferon (IFN-gamma), caused a significant increase in granuloma size in the lungs. Moreover, treatment of M. tuberculosis-infected mice with recombinant murine TNF-alpha resulted in increased inflammation in the lungs and accelerated mortality without affecting the bacillary load. Taken together, these studies suggest that administration of mycobacterial antigens to mice with prior M. tuberculosis infection leads to immune activation that may exacerbate lung pathology via TNF-alpha-induced inflammation without reducing the bacillary load
— id: 35027, year: 2002, vol: 70, page: 2100, stat: Journal Article,

Correlation of PPD status of immunocompetent tuberculosis patients and bronchoalveolar lavage (BAL) cell differential
Nolan A; Rom WN; Condos R; Raju B
2002 ;165:A288-A288, American journal of respiratory & critical care medicine
— id: 101405, year: 2002, vol: 165, page: A288, stat: Journal Article,

Cough and bronchial responsiveness in firefighters at the World Trade Center site
Prezant, David J; Weiden, Michael; Banauch, Gisela I; McGuinness, Georgeann; Rom, William N; Aldrich, Thomas K; Kelly, Kerry J
2002 Sep 12;347(11):806-815, New England journal of medicine
BACKGROUND: Workers from the Fire Department of New York City were exposed to a variety of inhaled materials during and after the collapse of the World Trade Center. We evaluated clinical features in a series of 332 firefighters in whom severe cough developed after exposure and the prevalence and severity of bronchial hyperreactivity in firefighters without severe cough classified according to the level of exposure. METHODS: 'World Trade Center cough' was defined as a persistent cough that developed after exposure to the site and was accompanied by respiratory symptoms severe enough to require medical leave for at least four weeks. Evaluation of exposed firefighters included completion of a standard questionnaire, spirometry, airway-responsiveness testing, and chest imaging. RESULTS: In the first six months after September 11, 2001, World Trade Center cough occurred in 128 of 1636 firefighters with a high level of exposure (8 percent), 187 of 6958 with a moderate level of exposure (3 percent), and 17 of 1320 with a low level of exposure (1 percent). In addition, 95 percent had symptoms of dyspnea, 87 percent had gastroesophageal reflux disease, and 54 percent had nasal congestion. Of those tested before treatment of World Trade Center cough, 63 percent of firefighters (149 of 237) had a response to a bronchodilator and 24 percent (9 of 37) had bronchial hyperreactivity. Chest radiographs were unchanged from precollapse findings in 319 of the 332 with World Trade Center cough. Among the cohort without severe cough, bronchial hyperreactivity was present in 77 firefighters with a high level of exposure (23 percent) and 26 with a moderate level of exposure (8 percent). CONCLUSIONS: Intense, short-term exposure to materials generated during the collapse of the World Trade Center was associated with bronchial responsiveness and the development of cough. Clinical and physiological severity was related to the intensity of exposure
— id: 42262, year: 2002, vol: 347, page: 806, stat: Journal Article,

Acute eosinophilic pneumonia in a New York City firefighter exposed to World Trade Center dust
Rom, William N; Weiden, Michael; Garcia, Roberto; Yie, Ting An; Vathesatogkit, Pratan; Tse, Doris B; McGuinness, Georgeann; Roggli, Victor; Prezant, David
2002 Sep 15;166(6):797-800, American journal of respiratory & critical care medicine
We report a sentinel case of acute eosinophilic pneumonia in a firefighter exposed to high concentrations of World Trade Center dust during the rescue effort from September 11 to 24. The firefighter presented with a Pa(O2) of 53 mm Hg and responded to oxygen and corticosteroids. Computed tomography scan showed patchy ground glass density, thickened bronchial walls, and bilateral pleural effusions. Bronchoalveolar lavage recovered 70% eosinophils, with only 1% eosinophils in peripheral blood. Eosinophils were not degranulated and increased levels of interleukin-5 were measured in bronchoalveolar lavage and serum. Mineralogic analysis counted 305 commercial asbestos fibers/10(6) macrophages including those with high aspect ratios, and significant quantities of fly ash and degraded fibrous glass. Acute eosinophilic pneumonia is a rare consequence of acute high dust exposure. World Trade Center dust consists of large particle-size silicates, but fly ash and asbestos fibers may be found in bronchoalveolar lavage cells
— id: 39593, year: 2002, vol: 166, page: 797, stat: Journal Article,

Late expression of p53 from a replicating adenovirus improves tumor cell killing and is more tumor cell specific than expression of the adenoviral death protein
Sauthoff, Harald; Pipiya, Teona; Heitner, Sheila; Chen, Shu; Norman, Robert G; Rom, William N; Hay, John G
2002 Oct 10;13(15):1859-1871, Human gene therapy
Gene transfer of p53 induces cell death in most cancer cells, and replication-defective adenoviral vectors expressing p53 are being evaluated in clinical trials. However, low transduction efficiency limits the efficacy of replication-defective vector systems for cancer therapy. The use of replication-competent vectors for gene delivery may have several advantages, holding the potential to multiply and spread the therapeutic agent after infection of only a few cells. However, expression of a transgene may adversely affect viral replication. We have constructed a replicating adenoviral vector (Adp53rc) that expresses high levels of p53 at a late time point in the viral life cycle and also contains a deletion of the adenoviral death protein (ADP). Adp53rc-infected cancer cells demonstrated high levels of p53 expression in parallel with the late expression pattern of the adenoviral fiber protein. p53 expression late in the viral life cycle did not impair effective virus propagation. Survival of several lung cancer cell lines was significantly diminished after infection with Adp53rc, compared with an identical p53-negative control virus. p53 expression also improved virus release and spread. Interestingly, p53 was more cytotoxic than the ADP in cancer cells but less cytotoxic than the ADP in normal cells. In conclusion, late expression of p53 from a replicating virus improves tumor cell killing and viral spread without impairing viral replication. In addition, in combination with a deletion of the ADP, specificity of tumor cell killing is improved
— id: 37580, year: 2002, vol: 13, page: 1859, stat: Journal Article,

Crucial role of interleukin-1beta and nitric oxide synthase in silica-induced inflammation and apoptosis in mice
Srivastava, Kamal D; Rom, William N; Jagirdar, Jaishree; Yie, Ting-An; Gordon, Terry; Tchou-Wong, Kam-Meng
2002 Feb 15;165(4):527-533, American journal of respiratory & critical care medicine
Crystalline silica stimulates macrophages in vitro to release interleukin-1beta (IL-1beta), tumor necrosis factor-alpha (TNF-alpha), and nitric oxide (NO) and induces apoptosis of macrophages. Because the fibrogenic potential of a particulate paralleled its ability to induce apoptosis in macrophages, we investigated the underlying mechanisms by which IL-1beta and NO mediate apoptosis and inflammation in murine silicosis. First, we demonstrated that silica induced NO production and apoptosis in vitro using the IC-21 macrophage cell line. Both NO release and apoptosis could be inhibited by neutralizing anti-IL-1beta antibody or the NO synthase (NOS) inhibitor N(G)-nitro-L-arginine-methyl ester (L-NAME), demonstrating the requirement for IL-1beta-mediated NO release in silica-induced apoptosis. We exposed IL-1beta knockout (IL-1beta(-/-)) mice, inducible NOS knockout (iNOS(-/-)) mice, and wild-type mice to 250 mg/m(3) silica for 5 h/d for 10 d using an inhalation chamber. Exposure of wild-type mice to silica resulted in lung inflammation, apoptosis, and significantly larger and more numerous silicotic lesions than in IL-1beta(-/-) mice over a 12-wk course. We also exposed iNOS(-/-) mice via inhalation in the same protocol and compared with wild-type mice and demonstrated that iNOS(-/-) mice had significantly reduced apoptosis and inflammation. These results demonstrated an association between apoptosis and inflammation in murine silicosis and support a potential role for IL-1beta-dependent NO-mediated apoptosis in the evolution of silicosis
— id: 39712, year: 2002, vol: 165, page: 527, stat: Journal Article,

Lung-specific expression of dominant-negative mutant p53 in transgenic mice increases spontaneous and benzo(a)pyrene-induced lung cancer
Tchou-Wong, Kam-Meng; Jiang, Yixing; Yee, Herman; LaRosa, Jennifer; Lee, Theodore C; Pellicer, Angel; Jagirdar, Jaishree; Gordon, Terry; Goldberg, Judith D; Rom, William N
2002 Aug;27(2):186-193, American journal of respiratory cell & molecular biology
Mutations in the p53 gene have been implicated to play an important role in the development of various human cancers. To evaluate the importance of p53 in lung cancer, a transgenic mouse model was established by utilizing the Clara cell secretory protein (CCSP) promoter to target the expression of a dominant-negative mutant form of p53 (dnp53) in the lung. In two transgenic CCSP-dnp53 founder lines, the dnp53 protein was expressed exclusively in the lungs. The incidence of spontaneous lung cancer in 18-month-old transgenic mice was 45%, whereas that in age-matched control mice was 20%. The relative risk of lung tumors in CCSP-dnp53 mice was 2.3 times that of wild-type mice (exact confidence limits of 0.69, 17.5). In addition to the increased incidence of spontaneous lung tumor, these mice were more susceptible to the development of lung adenocarcinoma after exposure to benzo(a)pyrene (BaP). Six months after intratracheal instillation of benzo(a)pyrene, the tumor incidence in wild-type and CCSP-dnp53 mice was 39% and 73%, respectively. The risk of lung tumors was 25.3 times greater in BaP-treated mice adjusted for transgene expression (95% confidence limits of 3.29, 678, mid-p corrected). These results suggest that p53 function is important for protecting mice from both spontaneous and BaP-induced lung cancers
— id: 32452, year: 2002, vol: 27, page: 186, stat: Journal Article,

Increased incidence of multidrug-resistant tuberculosis in diabetic patients on the Bellevue Chest Service, 1987 to 1997
Bashar M; Alcabes P; Rom WN; Condos R
2001 Nov;120(5):1514-1519, Chest
STUDY OBJECTIVES: To investigate the characteristics of tuberculosis infection in diabetic patients at Bellevue Hospital. DESIGN: We conducted a case-control study retrospectively reviewing the records of patients at Bellevue Hospital Center from 1987 to 1997 with a discharge diagnosis of tuberculosis and diabetes mellitus. SETTING: Bellevue Hospital Center is a 1,200-bed, inner-city municipal hospital located in the Lower East Side of New York City. PATIENTS: Fifty-three identified patients had verified tuberculosis infection and diabetes; of these, 50 charts were available for review. One hundred five control cases were selected from nondiabetic patients with a discharge diagnosis of tuberculosis during the same time period. MEASUREMENTS AND RESULTS: Thirty-six percent (18 cases) of the patients with diabetes and tuberculosis had multidrug-resistant tuberculosis (MDR-TB) compared to only 10% (10 cases) in the control group (p < 0.01) Controlling for homelessness, HIV status, and directly observed therapy, the relative risk of MDR-TB was calculated to be 8.6 (confidence interval, 3.1 to 23.6) in the diabetic group compared to the control group. CONCLUSIONS: There was a significant association between diabetes and MDR-TB. Diabetes continues to be a risk factor for tuberculosis and was associated with MDR-TB in our patients
— id: 26564, year: 2001, vol: 120, page: 1514, stat: Journal Article,

Wild-type adenovirus decreases tumor xenograft growth, but despite viral persistence complete tumor responses are rarely achieved-deletion of the viral e1b-19-kd gene increases the viral oncolytic effect
Harrison D; Sauthoff H; Heitner S; Jagirdar J; Rom WN; Hay JG
2001 Jul;12(10):1323-1332, Human gene therapy
Strategies to target viral replication to tumor cells hold great promise for the treatment of cancer, but even with replicating adenoviruses complete tumor responses are rarely achieved. To evaluate replicating adenoviral vectors, we have used A549 human lung cancer nude mouse xenografts as a model system. Intratumoral injection of wild-type adenovirus (Ad309) significantly reduced tumor growth from day 14 (p = 0.04) onward; however, tumor volumes reached a plateau at day 50. At 100 days, high levels of titratable virus were present within persistent viable tumors. In contrast to viral injection into established tumors, when tumor cells were infected in vitro with wild-type virus and then mixed with uninfected tumor cells, 1% of infected cells was sufficient to prevent tumor establishment. An E1b-19kD-deleted viral mutant (Ad337) was more efficient than Ad309 in this cell-mixing model. Just 1 cell in 1000 infected with Ad337 prevented tumor growth. However, although better than wild-type virus, Ad337 was unable to eradicate established flank tumors. These data suggest that although replicating adenoviruses exhibit significant oncolytic activity, barriers within the established tumor, such as connective tissue and tumor matrix, may limit the spread of virus. Strategies to enhance viral spread through established tumors are therefore likely to greatly improve the therapeutic efficacy of replicating adenoviruses
— id: 21145, year: 2001, vol: 12, page: 1323, stat: Journal Article,

Inhibition of anchorage-independent growth and lung metastasis of A549 lung carcinoma cells by IkappaBbeta
Jiang Y; Cui L; Yie TA; Rom WN; Cheng H; Tchou-Wong KM
2001 Apr 26;20(18):2254-2263, Oncogene
To evaluate the role of the NF-kappaB signaling pathway in oncogenic transformation, we expressed IkappaBbeta, a specific inhibitor of NF-kappaB, in two human lung adenocarcinoma cell lines, A549 and H441. Expression of IkappaBbeta significantly reduced NF-kappaB activation induced by cotransfection with p65/RelA or TNF-alpha and abrogated the basal NF-kappaB activity in A549 cells. Transfection of IkappaBbeta into A549, H441 and K-ras-transformed NIH3T3 cells suppressed anchorage-independent growth as measured by colony formation in soft agar. Anchorage-independent growth of vector-transfected A549 cells in reduced serum could be enhanced by both EGF and IGF-I. In contrast, only EGF but not IGF-I could induce anchorage-independent growth of IkappaBbeta-expressing A549 cells, suggesting that the IGF-I signaling pathway regulating growth and survival may be blocked by IkappaBbeta. Interestingly, expression of IkappaBbeta suppressed growth of A549 cells in low serum in vitro without affecting in vivo growth subcutaneously in nude mice. However, metastatic growth of IkappaBbeta-expressing A549 cells in the lungs of nude mice was significantly inhibited. These results provide evidence that NFkappaB plays an important role in anchorage-independent growth and metastatic growth of lung carcinoma cells
— id: 20612, year: 2001, vol: 20, page: 2254, stat: Journal Article,

In situ activation of helper t cells in the lung
Raju B; Tung CF; Cheng D; Yousefzadeh N; Condos R; Rom WN; Tse DB
2001 Aug;69(8):4790-4798, Infection & immunity
To better understand the lung and systemic responses of helper T cells mediating memory immunity to Mycobacterium tuberculosis, we used three- and four-color flow cytometry to study the surface phenotype of CD4(+) lymphocytes. Bronchoalveolar lavage (BAL) fluid and peripheral blood (PB) samples were obtained from a total of 25 subjects, including 10 tuberculosis (TB)-infected subjects, 8 purified-protein-derivative-negative subjects, and 7 purified-protein-derivative-positive subjects. In marked contrast to CD4(+) lymphocytes from PB (9% +/- 5% expressing CD45RA and CD29), the majority (55% +/- 16%) of CD4(+) lymphocytes in BAL (ALs) simultaneously expressed CD45RA, a naive T-cell marker, and CD29, members of the very late activation family. Further evaluation revealed that CD4(+) ALs expressed both CD45RA and CD45RO, a memory T-cell marker. In addition, the proportion of CD4(+) lymphocytes expressing CD69, an early activation marker, was drastically increased in BAL fluid (83% +/- 9%) compared to PB (1% +/- 1%), whereas no significant difference was seen in the expression of CD25, the low-affinity interleukin 2 receptor (34% +/- 15% versus 40% +/- 16%). More importantly, we identified a minor population of CD69(bright) CD25(bright) CD4(+) lymphocytes in BAL (10% +/- 6%) that were consistently absent from PB (1% +/- 1%). Thus, CD4(+) lymphocytes in the lung paradoxically coexpress surface molecules characteristic of naive and memory helper T cells as well as surface molecules commonly associated with early and late stages of activation. No difference was observed for ALs obtained from TB-infected and uninfected lung segments in this regard. It remains to be determined if these surface molecules are induced by the alveolar environment or if CD4(+) lymphocytes coexpressing this unusual combination of surface molecules are selectively recruited from the circulation. Our data suggest that ex vivo experiments on helper T-cell subsets that display distinctive phenotypes may be pivotal to studies on the human immune response to potential TB vaccines
— id: 21134, year: 2001, vol: 69, page: 4790, stat: Journal Article,

Malignant mesothelioma from neighborhood exposure to anthophyllite asbestos
Rom WN; Hammar SP; Rusch V; Dodson R; Hoffman S
2001 Aug;40(2):211-214, American journal of industrial medicine
BACKGROUND: Anthophyllite asbestos has been reported to cause asbestosis, lung cancer, mesothelioma, and pleural plaques in occupationally exposed workers. Anthophyllite has also been associated with pleural plaques in Finland and Japan among those who live near mines and mills and have neighborhood or environmental exposure. METHODS: We evaluated a 38-year-old patient with pleural mesothelioma who lived, attended school, and delivered newspapers near a manufacturing facility that used exclusively anthophyllite asbestos fiber from ages 8-17 years. He had no work exposure to asbestos. RESULTS: The pleural mesothelioma was an epithelial type with tubulopapillary structures and was treated with an extrapleural pneumonectomy followed by radiation therapy. The malignant cells were positive by immunohistochemistry for cytokeratin but negative for carcinoembryonic antigen, S100, B72.3, and leu M1 antigen. Anthophyllite fibers were > 5 microm in length in lung tissue compared to 3 microm from a general population study. CONCLUSIONS: Anthophyllite asbestos has been associated with neighborhood environmental exposure and pleural plaques; we now report a neighborhood exposure and pleural mesothelioma
— id: 26707, year: 2001, vol: 40, page: 211, stat: Journal Article,

Medical aspects of global warming
Yoganathan D; Rom WN
2001 Aug;40(2):199-210, American journal of industrial medicine
BACKGROUND: Global warming is caused by increased carbon dioxide (CO2)resulting in a greenhouse effect with enhanced warming of the earth. Measurements of CO2 show a steady increase over the past 30 years caused by the burning of fossil fuels and from the loss of natural CO2 sinks. A 100-year increase in global temperature by 0.3 to 0.6 degrees C is reflected in atmospheric warming, glacier shrinkage, and rising sea levels. OBJECTIVES: Planetary ecosystem dynamics are being altered, challenging public health. It is predicted that morbidity and mortality will increase as a result of heat stress, as seen in recent heat waves in the U.S. Weather disaster effects will increase in number and magnitude, and both noninfectious and infectious diseases may flourish. A significant challenge will be the changes in life cycles of microbial species due to the warmer environs. Specific increases in incidence have been noted for vector-borne diseases, in addition to pulmonary findings, cardiovascular morbidity, neurological diseases, and occupational diseases. CONCLUSIONS: Warming can be demonstrated by the observed changes that have already occurred in the environment, particularly the thinning of polar ice caps. The United States Global Research Program has been established to coordinate research activities, which responds to issues deemed important by the United Nations Framework Convention on Climate Change. Research issues pertain to the scientific uncertainties in the greenhouse effect, temperature measurements at various atmospheric levels and latitudes, and impact on biota redistribution. The Kyoto Protocol has mandated specific solutions, e.g., a 7% reduction in CO2 levels within 10 years. Future recommendations involve supporting new technologies that are available to decrease emissions as well as understanding the role that occupational and environmental specialists have in global warming recognition
— id: 26708, year: 2001, vol: 40, page: 199, stat: Journal Article,

Lung-specific immune response in tuberculosis
Condos R; Rom WN; Weiden M
2000 Feb;4(2 Suppl 1):S11-S17, International journal of tuberculosis & lung disease
— id: 11825, year: 2000, vol: 4, page: S11, stat: Journal Article,

Increasing incidence of mycobacterium xenopi at bellevue hospital : An emerging pathogen or a product of improved laboratory methods? [In Process Citation]
Donnabella V; Salazar-Schicchi J; Bonk S; Hanna B; Rom WN
2000 Nov;118(5):1365-1370, Chest
Study objectives: To investigate the dramatic rise in number of Mycobacterium xenopi isolates identified in our mycobacteriology laboratory, and to determine if this increase was due to emerging clinical pathology or to changes in culture technique. DESIGN: Retrospective chart and laboratory review. SETTING: University-affiliated tertiary-care city hospital. PATIENTS: Eighty-one patients with a single culture positive for M xenopi from 1975 to 1994 (period 1), and 47 patients with two or more cultures positive from 1994 to 1998 (period 2). INTERVENTIONS: The Bellevue mycobacteriology laboratory changed the culture medium from solid Lowenstein-Jensen medium (used from 1975 to 1990) to the Septi-Check AFB System (Becton-Dickinson; Glencoe, MD; used from 1991 to 1994), to the Mycobacteria Growth Indication Tube (MGIT; Becton-Dickinson; used from 1995 to 1998). Measurements and results: We recovered 29 M xenopi isolates from 1975 to 1990, 12 isolates from 1991 to 1994, and 381 isolates from 1995 to 1998. We subsequently identified and reviewed the medical records of all 81 patients who were culture positive for M xenopi from 1975 to 1994 (period 1), and 46 patients who had two or more isolates culture positive for M xenopi from 1995 to 1998 (period 2). For period 1, 75% of the subjects were male, 80% were minority, and at least 43% were HIV positive. Only one patient had clinical M xenopi lung disease during this period. For period 2, 79% of the subjects were male, 83% were minority, and at least 58% were HIV positive; two additional patients were identified who had clinical M xenopi lung disease. CONCLUSIONS: The dramatic increase in M xenopi isolates noted in our hospital was due to a more sensitive laboratory isolation technique, rather than a true increase in clinical disease. Other hospitals utilizing MGIT systems for mycobacterial recovery should interpret positive M xenopi cultures with caution
— id: 15396, year: 2000, vol: 118, page: 1365, stat: Journal Article,

Hut lung. A domestically acquired particulate lung disease [In Process Citation]
Gold JA; Jagirdar J; Hay JG; Addrizzo-Harris DJ; Naidich DP; Rom WN
2000 Sep;79(5):310-317, Medicine (Baltimore)
We report an illustrative case of advanced 'hut lung,' or domestically acquired particulate lung disease (DAPLD), in a recently emigrated nonsmoking Bangladeshi woman with a history of 171 hour-years of exposure to biomass smoke. She presented with symptoms of chronic cough, dyspnea, and early parenchymal lung disease. High-resolution computed tomography (CT) of the chest demonstrated numerous 2- to 3-mm nodules, sparing the pleural surface. To our knowledge, this is the first such report of CT findings in the literature. Bronchoscopy yielded typical anthracotic plaques and diffuse anthracosis with interstitial inflammation on histopathologic examination of biopsy specimens. DAPLD is potentially the largest environmentally attributable disorder in the world, with an estimated 3 billion people at risk. Caused by the inhalation of particles liberated from the combustion of biomass fuel, DAPLD results in significant morbidity from infancy to adulthood. Clinically, DAPLD manifests a broad range of disorders from chronic bronchitis and dyspnea to advanced interstitial lung disease and malignancy. While a detailed environmental history is essential for making the diagnosis in most individuals, for patients with advanced DAPLD, invasive modalities such as bronchoscopy with transbronchial biopsy and examination of bronchoalveolar lavage fluid help differentiate it from other diseases. Recognition of this syndrome and removal of the patient from the environment is the only treatment. The development of well-controlled interventional trials and the commitment of sufficient resources to educate local populaces and develop alternative fuel sources, stove designs, and ventilation are essential toward reducing the magnitude of DAPLD
— id: 15397, year: 2000, vol: 79, page: 310, stat: Journal Article,

Aberrant expression of immunoglobulin heavy chain genes in Epstein-Barr virus-negative, human immunodeficiency virus-related lymphoid interstitial pneumonia.[In Process Citation]
Kurosu K; Yumoto N; Rom WN; Jaishree J; Nakata K; Kuriyama T; Mikata A; Weiden MD
2000 Dec;80(12):1891-1903, Laboratory investigation
The two-step polymerase chain reaction (PCR) and sequencing analysis was used to analyze the immunoglobulin heavy chain variable (Ig V(H)) genes of open-chest biopsy or autopsy samples from five patients with Epstein-Barr virus-negative human immunodeficiency virus (HIV)-related lymphoid interstitial pneumonia (LIP), and the results were compared with those for Ig V(H) genes from five HIV-negative LIP patients. The findings of this study are consistent with the different immunological situations of HIV-related and HIV-negative LIP. (a) The Ig V(H)3 subgroup was underexpressed in three of five cases of HIV-related LIP. In contrast, none of the HIV-negative cases showed this abnormality. Because the Ig V(H)3 subgroup encodes the largest portion of Ig V(H) genes, a depletion of B cells expressing Ig V(H)3 genes reflects a major alteration in the B-cell compartment. (b) All HIV-related LIP cases demonstrated two or three oligoclonal populations. HIV-negative cases showed minor monoclonal or polyclonal populations, but not oligoclonal ones. These oligoclonal populations suggest the coexistence of several occult clonal B-cell populations in HIV-related LIP. (c) Some oligoclonal clones in HIV-related LIP showed mutated framework regions not demonstrated in HIV-negative clones. This degree of variation exceeds the usual mutation rate for frameworks, suggesting a role for framework residues in antigen binding. (d) The frequency of D-D fusions of minor oligoclonal clones (HIV-related LIP) is higher than that of minor monoclonal clones (HIV-negative LIP). Such D-D fusions may enhance the probability of expression of antibodies capable of binding HIV glycoproteins
— id: 15395, year: 2000, vol: 80, page: 1891, stat: Journal Article,

Correction of glycogen storage disease type II by enzyme replacement with a recombinant human acid maltase produced by over-expression in a CHO-DHFR(neg) cell line [In Process Citation]
Martiniuk F; Chen A; Donnabella V; Arvanitopoulos E; Slonim AE; Raben N; Plotz P; Rom WN
2000 Oct 5;276(3):917-923, Biochemical & biophysical research communications
Inherited genetic deficiency of lysosomal acid alpha glucosidase or acid maltase (GAA) results in the autosomal recessive glycogen storage disease type II (GSD II). To investigate whether we could generate a functional recombinant human GAA (rhGAA) for enzyme replacement therapy, we subcloned the cDNAs for human GAA and mouse dihydrofolate reductase (DHFR) into DHFR(neg) Chinese hamster ovary cells and established a stable cotransformant that expressed rhGAA. We cultured the recombinant cells in media with progressively increasing concentrations of methotrexate and found that human GAA enzyme activity increased to over 2,000 IU per gram protein. Importantly, the human GAA enzyme activity correlated to equivalent amounts of human GAA protein by rocketimmunoelectrophoresis. We confirmed that the human GAA enzyme activity corresponded to an amplification in human GAA mRNA by Northern analysis and human GAA cDNA copy number by Southern analysis. Exposing the rhGAA to human GSDII fibroblast cells or patient's lymphocytes or monocytes resulted in uptake of the rhGAA and reversal of the enzymatic defect. Mannose-6-phosphate in the media blocked uptake. GAA -/- mice were treated with the rhGAA at 1 mg/kg, which resulted in heterozygous levels of GAA in tissues, most notably skeletal muscle, heart and diaphragm after two infusions. More importantly, after multiple infusions, hind, and fore-limb muscle weakness was reversed. This rhGAA would be ideal for enzyme replacement therapy in GSD II.
— id: 15196, year: 2000, vol: 276, page: 917, stat: Journal Article,

Molecular and genetic aspects of lung cancer
Rom WN; Hay JG; Lee TC; Jiang Y; Tchou-Wong KM
2000 Apr;161(4 Pt 1):1355-1367, American journal of respiratory & critical care medicine
— id: 11754, year: 2000, vol: 161, page: 1355, stat: Journal Article,

Deletion of the adenoviral E1b-19kD gene enhances tumor cell killing of a replicating adenoviral vector
Sauthoff H; Heitner S; Rom WN; Hay JG
2000 Feb 10;11(3):379-388, Human gene therapy
Replicating adenoviral vectors are a promising new modality for cancer treatment and clinical trials with such vectors are ongoing. Targeting these vectors to cancer cells has been the focus of research. However, even if perfect targeting were to be achieved, a vector still must effectively kill cancer cells and spread throughout the bulk of the tumor. The adenoviral E1b-19kD protein is a potent inhibitor of apoptosis and may therefore compromise the therapeutic efficacy of an adenoviral vector. In this study we have investigated if an E1b-19kD gene deletion could improve the ability of a replicating adenoviral vector to spread through and kill cancer cells. In several lung cancer cell lines an E1b-19kD-deleted virus (Ad337) induced substantially more apoptosis than did a wild-type virus (Ad309), and tumor cell survival was significantly reduced in three of four cell lines. In addition, the apoptotic effects of cisplatin or paclitaxel were augmented by Ad337, but inhibited by wild-type virus. The number of infectious virus particles in the supernatant of infected cells was increased with Ad337 compared with wild-type virus, indicating enhanced early viral release. Ad337, in contrast to Ad309, induced significantly larger plaques after infection of A549 cells. This well-described large plaque phenotype of an E1b-19kD mutant virus is likely the result of early viral release and enhanced cell-to-cell viral spread. Loss of E1b-19kD function caused only minor cell line-specific increase or decrease in viral yield. We conclude that deletion of the E1b-19kD gene may enhance the tumoricidal effects of a replicating adenoviral vector
— id: 8543, year: 2000, vol: 11, page: 379, stat: Journal Article,

Replicating adenoviral vectors persist in tumor xenographs for up to 100 days but viral spread is insufficient to support tumor eradication
Sauthoff, H; Harrison, D; Heitner, S; Rom, WN; Hay, JG
2000 DEC ;7(12):S13-S14, Cancer gene therapy
— id: 54416, year: 2000, vol: 7, page: S13, stat: Journal Article,

Differentiation of monocytes to macrophages switches the Mycobacterium tuberculosis effect on HIV-1 replication from stimulation to inhibition: modulation of interferon response and CCAAT/enhancer binding protein beta expression
Weiden M; Tanaka N; Qiao Y; Zhao BY; Honda Y; Nakata K; Canova A; Levy DE; Rom WN; Pine R
2000 Aug 15;165(4):2028-2039, Journal of immunology
HIV-1 replication is inhibited in uninflamed lung macrophages and is stimulated during tuberculosis. Attempts to recapitulate activation of HIV-1 replication in primary monocytes and macrophages ex vivo and in the untreated and PMA-treated THP-1 cell line model in vitro have produced opposite results depending on the state of differentiation of the cells. After infection with Mycobacterium tuberculosis, monocytes enhanced HIV-1 replication and produced a stimulatory 37-kDa CCAAT/enhancer binding protein beta (C/EBPbeta) transcription factor, whereas macrophages suppressed HIV-1 replication and produced an inhibitory 16-kDa C/EBPbeta transcription factor. IFN-beta induced inhibitory 16-kDa C/EBPbeta in macrophages, but had no effect on C/EBPbeta expression in monocytes. Macrophages, but not monocytes, were able to activate IFN-stimulated gene factor-3 (ISGF-3), a transcription factor composed of STAT-1, STAT-2, and IFN regulatory factor (IRF)-9, after infection with M. tuberculosis or stimulation with type I IFN. Macrophages expressed IRF-9 DNA-binding activity, but monocytes did not, and addition of the IRF-9 component reconstituted ISGF-3 in extracts of IFN-treated monocytes. Modulation of IFN responsiveness upon differentiation occurred at least in part through a post-transcriptionally regulated increase in IRF-9 expression. Both monocytes and macrophages maintained IFN responsiveness, activating STAT-1 homodimer formation and transcription of the STAT-1 gene after IFN stimulation. In addition, both monocytes and macrophages were able to activate NF-kappaB upon infection with M. tuberculosis. These results show that induction of ISGF-3, expression of the inhibitory 16-kDa C/EBPbeta, and suppression of HIV-1 replication via a transcriptional mechanism are macrophage-specific responses to infection with M. tuberculosis
— id: 11568, year: 2000, vol: 165, page: 2028, stat: Journal Article,

Specific cell targeting for delivery of toxins into small-cell lung cancer using a streptavidin fusion protein complex
Yu A; Choi J; Ohno K; Levin B; Rom WN; Meruelo D
2000 Jul;19(7):383-388, DNA & cell biology
New modalities of treatment for small-cell lung cancer (SCLC) are needed, because the majority of patients continue to die of disseminated disease despite an initial response to conventional chemotherapy. Abnormal surface expression of the neural-cell adhesion molecule (NCAM) has been noted to be highly associated with SCLC. We examined the ability and efficiency of a streptavidin-Protein A (ST-PA) fusion protein complexed with an anti-NCAM monoclonal antibody (Mab) to transfer biotinylated beta-galactosidase into human SCLC cell lines NCI-H69, NCI-H526, and NCI-H446. When the surface molecule NCAM was targeted with this system, more than 99% of the targeted cells internalized and exhibited beta-galactosidase activity. In addition, we evaluated cytotoxic activity against SCLC lines NCI-H69 and NCI-H526 by efficient delivery of biotinylated glucose oxidase using the same ST-PA/anti-NCAM Mab complex. Cytotoxicity of the transduced cells (SCLC) was 10-fold and 100-fold greater, respectively, than the glucose oxidase control. This system could be widely applied for specific therapy of cancer cells by targeting unique surface molecules (antigens) using the corresponding Mab/ST-PA complex to transfer a variety of effector molecules; e.g., immunotoxic compounds, into target cells with a high degree of efficiency and specificity
— id: 11544, year: 2000, vol: 19, page: 383, stat: Journal Article,

Diabetes mellitus and tuberculosis on the Bellevue chest service 1987-1997: A case control study
Bashar, M; Lan, A; Alcabes, P; Rom, WN; Condos, R
1999 MAR ;159(3):A748-A748, American journal of respiratory & critical care medicine
— id: 53891, year: 1999, vol: 159, page: A748, stat: Journal Article,

Induction of IRF-1 STAT-1 by IFN-gamma in tuberculosis infection
Condos, R; Raju, B; Lubin, AS; Rom, WN; Pine, RI
1999 MAR ;159(3):A740-A740, American journal of respiratory & critical care medicine
— id: 53890, year: 1999, vol: 159, page: A740, stat: Journal Article,

Induction of STAT-1 and IRF-1 by IFN-gamma in tuberculosis patients
Condos, Rany; Zhao, Ben Yang; Raju, Bindu; Lubin, Andrew S; Canova, Antony; Rom William N; Pine, Richard
1999 Sept;19(Supl. 1):S95-S95, Journal of interferon & cytokine research
— id: 15939, year: 1999, vol: 19, page: S95, stat: Journal Article,

Significance of abnormal chest radiographs in HIV-infected patients without respiratory symptoms
Gold, JA; Rom, WN; Harkin, TJ
1999 MAR ;159(3):A561-A561, American journal of respiratory & critical care medicine
— id: 53886, year: 1999, vol: 159, page: A561, stat: Journal Article,

Targeting the replication of adenoviral gene therapy vectors to lung cancer cells: the importance of the adenoviral E1b-55kD gene
Hay JG; Shapiro N; Sauthoff H; Heitner S; Phupakdi W; Rom WN
1999 Mar 1;10(4):579-590, Human gene therapy
It has been proposed that an adenovirus with the E1b-55kD gene deleted has a selective advantage in replicating in cancer cells that have mutations in the p53 gene (Bischoff et al., 1996). We have explored this hypothesis in several lung cancer cell lines, and evaluated potential mechanisms that might regulate the replication of Ad338, an E1b-55kD-deleted virus, with the objective of developing a rational approach for targeting gene therapy to lung tumors. Our data show that Ad338 replicates poorly in three lung cancer cell lines with various p53 mutations (H441, H446, and Calu1), yet this virus replicates to a high level in a lung cancer cell line with wild-type p53 (A549) and in a normal lung fibroblast line (IMR90). Viral DNA replication, expression of viral proteins, and shutoff of host cell proteins were not important variables in limiting the replication of the E1b-55kD-deleted virus. However, the cell lines resistant to host cell protein shutoff were also the most resistant to the cytopathic effect induced by mutant and wild-type virus and the only cells to survive for 8 days following infection. The E1b-55kD protein clearly has an important role in viral replication beyond its interaction with p53. Thus, an E1b-55kD-deleted virus cannot be used to specifically target viral replication to p53-mutated lung cancer cells
— id: 7342, year: 1999, vol: 10, page: 579, stat: Journal Article,

High levels of plasma IL-10 does not diminish purified protein derivative (PPD) skin induration size
Hull, FP; Condos, R; Rom, WN
1999 MAR ;159(3):A555-A555, American journal of respiratory & critical care medicine
— id: 53884, year: 1999, vol: 159, page: A555, stat: Journal Article,

Induction of tumor suppression and glandular differentiation of A549 lung carcinoma cells by dominant-negative IGF-I receptor
Jiang Y; Rom WN; Yie TA; Chi CX; Tchou-Wong KM
1999 Oct 28;18(44):6071-6077, Oncogene
Overexpression or activation of insulin-like growth factor I receptor (IGF-IR) has been observed in many human cancers including breast, lung, colon and gastric carcinomas. We demonstrate that inhibition of the endogenous insulin-like growth factor I receptor by stable expression of a dominant-negative IGF-IR represses the transforming activity in vitro and tumorigenicity of human lung carcinoma cells A549 in vivo. The suppression of tumorigenicity in nude mice is correlated with the induction of glandular differentiation. In addition, functional inhibition of the endogenous receptor dramatically increases the sensitivity of A549 cells to a variety of apoptotic signals including UV irradiation and proteasome inhibitors. These effects are due to the formation of a stable heterocomplex of the dominant-negative receptor with the endogenous wild type receptor which reduces the kinase activity of the latter by twofold. Thus, inhibition of the IGF-IR signaling pathway not only suppresses tumorigenicity but also enhances sensitivity to apoptosis-inducing agents. Antagonizing IGF-IR signaling by promoting tumor differentiation and enhancing sensitivity to apoptotic death are potential cancer therapeutic approaches
— id: 6239, year: 1999, vol: 18, page: 6071, stat: Journal Article,

Functional disruption of IGF-I receptor reverses tumorigenicity of human lung adenocarcinoma cells
Jiang, Y; Rom, WN; Yie, TA; Chi, C; Tchou-Wong, KM
1999 MAR ;159(3):A206-A206, American journal of respiratory & critical care medicine
— id: 53871, year: 1999, vol: 159, page: A206, stat: Journal Article,

Aberrant expression of immunoglobulin genes in human immunodeficiency virus lymphoid interstitial pneumonia (LIP)
Kurosu, K; Yumoto, N; Jaqirdar, J; Nakata, K; Tanaka, N; Mikata, A; Kuriyama, T; Rom, WN; Weiden, M
1999 MAR ;159(3):A393-A393, American journal of respiratory & critical care medicine
— id: 53880, year: 1999, vol: 159, page: A393, stat: Journal Article,

Helios gene gun delivery for gene therapy of acid maltase deficiency
Martiniuk, F; Chen, A; Mack, A; Donnabella, V; Arvanitopoulos, E; Rom, WN
1999 MAR ;159(3):A435-A435, American journal of respiratory & critical care medicine
— id: 53881, year: 1999, vol: 159, page: A435, stat: Journal Article,

Evaluating mechanisms responsible for mutation rates in clinical isolates of TB
Martiniuk, F; Chen, A; Weiden, M; Mack, A; Donnabella, V; Rom, WN
1999 MAR ;159(3):A16-A16, American journal of respiratory & critical care medicine
— id: 53868, year: 1999, vol: 159, page: A16, stat: Journal Article,

Deletion of the E1b-19-kDa gene enhances the tumoricidal effect of a replicating adenoviral vector
Sauthoff K; Heitner S; Rom WN; Hay JG
1999 Nov-Dec;6(6 Suppl S):S10-S10 Abstract #O38, Cancer gene therapy
BACKGROUND, Fine-needle aspiration biopsy (FNA) has been successful in diagnosing epithelial lesions of the breast. Its role in the evaluation of spindle cell and mesenchymal lesions of the breast, which include a variety of benign and malignant conditions, is less clear. This article discusses the cytologic features and differential diagnosis of these lesions, as well as the potential diagnostic pitfalls associated with them. METHODS, FNAs of the breast, in which a spindle cell or mesenchymal component was a key or dominant feature, were retrieved. Fibroadenomas without cellular stroma and typical lipomas were excluded. RESULTS. Forty-six aspirates (0<87%) in a series of 5306 breast FNAs contained a significant spindle cell or mesenchymal component. The aspirates were classified into 4 categories: 1) reactive conditions, including 2 diabetic mastopathies, 3 granulation tissue specimens, and 7 granulomatous lesions; 2) benign neoplastic conditions, including 1 mammary hamartoma, 1 dermatofibroma, 1 fibromatosis, 2 granular cell tumors, 2 angiolipomas, and 7 cellular fibroadenomas; 3) low grade malignant neoplastic lesions, including 10 low grade phyllodes tumors; and 4) high grade malignant neoplastic lesions, including 1 metaplastic carcinoma with chondroid stroma, 1 pleomorphic liposarcoma, 2 malignant fibrous histiocytomas, 2 osteosarcomas, and 4 metastatic melanomas. A specific diagnosis was rendered in 38 cases (82<6%). The mammary hamartoma was diagnosed as fibrocystic changes; the dermatofibroma as benign spindle cell lesion, not otherwise specified (NOS); and the primary osteosarcoma as an atypical spindle cell proliferation, NOS. The reactive ductal epithelial cells in one of the granulomatous mastitis specimens, as well as the hyperplastic ductal epithelial cells in one of the phyllodes tumors, were interpreted as atypical ductal proliferation. The marked cytologic atypia displayed by one granular cell tumor was interpreted as low grade adenocarcinoma and the primary liposarcoma as poorly differentiated carcinoma. CONCLUSIONS. Breast lesions with a significant spindle cell or mesenchymal component are rarely encountered in FNA and constitute a heterogeneous group that may pose a diagnostic dilemma FNA should be the initial diagnostic procedure for investigating these lesions, as a specific diagnosis was rendered in the majority of cases. Cancer (Cancer Cytopathol) 1999;87:359-71. (C) 1999 American Cancer Society
— id: 8605, year: 1999, vol: 6, page: S10, stat: Journal Article,

Efficacy and complications of inferior vena cava filter placement in orthopedic patients with pulmonary embolism or deep vein thrombosis
Sauthoff, H; Addrizzo-Harris, DJ; DellaValle, C; Schlossberg, P; Rosen, R; Gold, J; Fallar, E; Rom, WN; Steiger, D
1999 MAR ;159(3):A360-A360, American journal of respiratory & critical care medicine
— id: 53879, year: 1999, vol: 159, page: A360, stat: Journal Article,

An E1b-55kD deleted adenovirus vector does not target p53 mutated lung cancer cells by specific viral replication
Sauthoff, H; Shapiro, N; Heitner, S; Phupakdi, W; Rom, WN; Hay, JG
1999 MAR ;159(3):A237-A237, American journal of respiratory & critical care medicine
— id: 53872, year: 1999, vol: 159, page: A237, stat: Journal Article,

Screening for infection and disease as a tuberculosis control measure among indigents in New York City, 1994-1997
Schluger NW; Huberman R; Holzman R; Rom WN; Cohen DI
1999 Apr;3(4):281-286, International journal of tuberculosis & lung disease
SETTING: Several social service agencies in New York City, and the Chest Clinic of Bellevue Hospital, a large public hospital. OBJECTIVE: To determine the utility of screening as a preventive and control measure among persons at risk for tuberculosis. DESIGN: Persons seeking social services at several private agencies in New York City were screened, and those with a positive skin test or symptoms suggestive of active tuberculosis were referred to the Chest Clinic for evaluation. RESULTS: Of 3828 persons evaluated, 20 had active tuberculosis, and 33% of the screened cohort were tuberculin skin test positive. Of 466 persons with tuberculosis infection who were evaluated, only 55 persons were given isoniazid (INH), and only 20 completed preventive therapy. Most patients who were not given INH had taken it previously, were older than 35 years, or had continuing alcohol use which made physicians reluctant to prescribe isoniazid. CONCLUSION: Screening for tuberculosis may detect a significant number of cases of active disease when the background prevalence of the disease is very high. However, screening for infection as a means to prevent future cases is unlikely to be effective unless rates of administration and completion of isoniazid preventive therapy are increased
— id: 6091, year: 1999, vol: 3, page: 281, stat: Journal Article,

The role of interleukin 1-beta-mediated nitric oxide release in silica-induced apoptosis in macrophages
Srivastava, K; Rom, WN; Chi, C; Gordon, T; Tchou-Wong, KM
1999 MAR ;159(3):A697-A697, American journal of respiratory & critical care medicine
— id: 53888, year: 1999, vol: 159, page: A697, stat: Journal Article,

Inhibitory C/EBP beta suppress viral and cytokine promoters alter an inflammatory stimulus
Tanaka, N; Nakata, K; Honda, Y; Rogers, L; Rom, WN; Weiden, M
1999 MAR ;159(3):A660-A660, American journal of respiratory & critical care medicine
— id: 53887, year: 1999, vol: 159, page: A660, stat: Journal Article,

Role of c-Jun N-terminal kinase 1 (JNK1) in cell cycle checkpoint activated by the protease inhibitor N-acetyl-leucinyl-leucinyl-norleucinal
Tchou WW; Yie TA; Tan TH; Rom WN; Tchou-Wong KM
1999 Nov 25;18(50):6974-6980, Oncogene
The cysteine protease inhibitor N-acetyl-leucinyl-leucinyl-norleucinal (LLnL) inhibited the growth of the Calu-1 lung carcinoma cells and induced a prolonged cell cycle arrest in the S phase. c-Jun N-terminal kinases (JNKs) participate in cellular responses to mitogenic stimuli, environmental stresses, and apoptotic signals but its role in cell cycle checkpoint control has not been elucidated. In this report, we examined the role of JNK in LLnL-induced S phase checkpoint by overexpression of a dominant-negative mutant of JNK1 (JNK1-APF) in Calu-1 cells. Expression of high levels of JNK1-APF blocked the growth-inhibitory effects of LLnL and abrogated S phase arrest induced by LLnL. These results support the role of JNK in the activation of cell cycle checkpoint induced by LLnL
— id: 11907, year: 1999, vol: 18, page: 6974, stat: Journal Article,

Activation of NF-kappaB in Mycobacterium tuberculosis- induced interleukin-2 receptor expression in mononuclear phagocytes
Tchou-Wong KM; Tanabe O; Chi C; Yie TA; Rom WN
1999 Apr;159(4 Pt 1):1323-1329, American journal of respiratory & critical care medicine
Soluble interleukin-2 receptor-alpha (IL-2Ralpha) has been reported to be increased in the sera of patients with advanced tuberculosis, and levels decline after therapy in accordance with improvement of radiologic findings. We investigated expression of the IL-2Ralpha in bronchoalveolar lavage (BAL) cells in active pulmonary tuberculosis, and evaluated the mechanism Mycobacterium tuberculosis induces in the IL-2Ralpha using the THP-1 mononuclear phagocyte cell line. We found IL-2Ralpha expression to be increased in BAL cells from involved sites of active pulmonary tuberculosis. Expression of the alpha-chain of IL-2Ralpha on peripheral blood monocytes (PBM) was induced by M. tuberculosis by flow cytometry evaluation. Northern analysis demonstrated increased IL-2Ralpha gene expression after stimulation with M. tuberculosis which was further induced by interferon-gamma (IFN-gamma). The IL-2Ralpha promoter containing the nuclear factor kappa B (NF-kappaB) site was transcriptionally induced by M. tuberculosis and this NF-kappaB site could confer inducibility to a heterologous herpes thymidine kinase (TK) promoter by M. tuberculosis. Electrophoretic mobility shift assays (EMSAs) revealed specific binding of nuclear protein to the NF-kappaB site upon induction with M. tuberculosis. Using antibodies against the p50 and p65 subunits of NF-kappaB in EMSAs, the involvement of both p50 and p65 proteins was further demonstrated. Functional expression of the IL-2Ralpha on mononuclear phagocytes in M. tuberculosis infection may play an important immunomodulatory role in the host response
— id: 6078, year: 1999, vol: 159, page: 1323, stat: Journal Article,

Phenotypic analysis of alveolar helper T cells demonstrates in situ activation in the lung
Tse, DB; Raju, B; Tung, CF; Chan, DS; Condos, R; Rom, WN
1999 MAR ;159(3):A555-A555, American journal of respiratory & critical care medicine
— id: 53885, year: 1999, vol: 159, page: A555, stat: Journal Article,

The gene for lysosomal protein CD63 is normal in patients with Hermansky-Pudlak syndrome
Armstrong LW; Rom WN; Martiniuk FT
1998 ;176(4):249-256, Lung
Hermansky-Pudlak syndrome (HPS) is one of the few genetic disorders associated with severe pulmonary fibrosis. Fifty percent of affected patients die as a result of respiratory insufficiency. Fibrosis is thought to be caused by the accumulation of ceroid, an insoluble fluorescent lipoprotein, both extracellularly and in the lysosomes of alveolar macrophages. In addition to pulmonary fibrosis, HPS is characterized by oculocutaneous albinism and a reduction in the number of platelet dense bodies. CD63 is a protein that was described originally in platelet lysosomes. It localizes to the membranes of melanosomes and platelet dense bodies. CD63 is decreased dramatically in the lysosomes and dense bodies of patients with HPS. We theorized that CD63, a membrane protein common to lysosomes, melanosomes, and platelet dense bodies, may play a role in HPS. We sought to characterize the gene coding for this protein in HPS lymphoid cell lines. The coding region for CD63 was sequenced in control and HPS cell lines. Messenger RNA from HPS and normal cell lines was examined by Northern analysis. Genomic DNA from the same cell lines was examined by Southern analysis and polymerase chain reaction (PCR). CD63 protein in lymphoid cell lines and peripheral blood monocytes was compared by Western analysis. We found no mutations in the coding region of CD63 in an HPS cell line. We also found no diminution in the quantity of CD63 RNA by Northern analysis and no gross defects in the structural gene by PCR and Southern analysis, suggesting that the CD63 structural gene, promoter, and untranslated regions were normal. Western analysis showed that the 43-kDa protein was present in control and HPS lymphoid cell lines and peripheral blood monocytes in equivalent amounts. Although CD63 is an attractive candidate for the primary defect of HPS, the disease is probably not caused by a mutation in the CD63 gene
— id: 7490, year: 1998, vol: 176, page: 249, stat: Journal Article,

Early inhibition of mycobacterial growth by human alveolar macrophages is not due to nitric oxide
Aston C; Rom WN; Talbot AT; Reibman J
1998 Jun;157(6 Pt 1):1943-1950, American journal of respiratory & critical care medicine
Phagocytic cells provide the first line of defense against mycobacteria. We examined the relative mycobacteriostatic contributions of normal human alveolar macrophages (HAM), peripheral blood monocytes (PBM), and polymorphonuclear leukocytes (PMN) in the early time period after infection with mycobacteria (48 h). Cells were infected with Mycobacterium bovis (BCG) or M. tuberculosis H37Ra and their ability to inhibit growth was determined by mycobacterial incorporation of [3H]uracil. HAM inhibited the growth of both mycobacteria (44.2 +/- 7.9 and 37.6 +/- 10.5% inhibition, respectively). Two populations of HAM donors were subsequently defined: inhibitors and noninhibitors. The ability to inhibit growth of H37Ra correlated with that of BCG. In contrast to HAM, PBM and PMN did not inhibit mycobacterial growth. Because nitric oxide (NO) has been proposed to mediate growth inhibition in murine models, we examined whether NO was responsible for the early growth inhibition of mycobacteria by HAM. As expected, in murine peritoneal macrophages (MPM) IFN-gamma (2,500 U/ml) enhanced growth inhibition of BCG; the effect was abolished by the nitric oxide synthase (NOS) inhibitor NMMA. In contrast, IFN-gamma failed to enhance growth inhibition by HAM or PBM and NMMA had no effect. MPM expressed inducible nitric oxide synthase (NOS2) mRNA in response to LPS and IFN-gamma and produced NO. Neither NOS2 mRNA nor NO could be detected in HAM stimulated with LPS and IFN-gamma or mycobacteria. These data demonstrate that HAM, but not PBM or PMN, have NO-independent mycobacteriostatic activity in the early time period after infection with mycobacteria
— id: 7492, year: 1998, vol: 157, page: 1943, stat: Journal Article,

Physiological effects of reduced barometric pressure
Berger KI; Rom WN
Encyclopedia of Occupational Health & Safety Geneva : International Labour Office, 1998,
— id: 2770, year: 1998, vol: , page: 375, stat: Chapter,

Local immune responses correlate with presentation and outcome in tuberculosis
Condos R; Rom WN; Liu YM; Schluger NW
1998 Mar;157(3 Pt 1):729-735, American journal of respiratory & critical care medicine
Local cellular immune responses may affect presentation and outcome in tuberculosis (TB). To investigate this hypothesis, we performed bronchoalveolar lavage (BAL) on 30 patients with untreated pulmonary tuberculosis and assessed the type of cellular inflammatory response and cytokine production. We then correlated BAL findings and cytokine production with clinical findings. We also performed BAL on a subset of patients to examine changes in cytokine production by BAL cells over time. We found that at presentation patients with less clinically and radiographically advanced TB (smear-negative, noncavitary disease) had a local immune response characterized by a predominance of lymphocytes. Furthermore, BAL cells from these patients secreted interferon (IFNgamma), and not Interleukin-4, suggesting a Th 1-type lymphocytic response. In patients with smear-positive and/or cavitary disease, macrophages or polymorphonuclear leukocytes were the predominant BAL cell type, but with treatment and clinical improvement these patients went on to recruit IFNgamma producing cells to the lung. We conclude that the type of cellular immune response that occurs locally in the lung may affect presentation and outcome in pulmonary TB, and an understanding of the development of this response may lead to insights into pathogenesis and novel therapies for TB
— id: 7536, year: 1998, vol: 157, page: 729, stat: Journal Article,

Heterozygote frequency for Glycogenosis Type II in Italy
Danesino, C; Martiniuk, F; Dellavecchia, C; Chen, A; Mack, A; Arvanitopoulos, E; Minelli, A; Alcabes, P; Rom, WN
1998 JUL ;6(1):155-155, European journal of human genetics
— id: 53419, year: 1998, vol: 6, page: 155, stat: Journal Article,

Angular and fibrous particles in lung in relation to silica-induced diseases
Dufresne A; Begin R; Dion C; Jagirdar J; Rom WN; Loosereewanich P; Muir DC; Ritchie AC; Perrault G
1998 Jun;71(4):263-269, International archives of occupational & environmental health
INTRODUCTION: The lung concentration of angular and fibrous particles was measured in cases of lung fibrosis only, in cases of lung fibrosis and lung cancer, and in cases of lung cancer only. These patients worked in different trades (mining, foundries, construction and were not a homogeneous group of exposed workers. MATERIAL AND METHODS: Particles, both angular and fibrous, were extracted from lung parenchyma by a bleach digestion method, mounted on copper microscopic grids by a carbon replica technique, and analyzed by transmission electron microscopy (TEM) and energy-dispersive spectroscopy (EDS). The quartz concentration was also determined by X-ray diffraction (XRD) on a silver membrane filter after extraction from the lung parenchyma. RESULTS: (1) Lung cancer and lung fibrosis cases retained more metal-rich particles (P = 0.02) and more angular particles of all sorts (P = 0.009) than did lung fibrosis cases only, and the differences were statistically significant. (2) However, more quartz was retained in the lungs in lung fibrosis cases than in lung fibrosis or lung cancer cases, but the difference in the concentrations was not statistically significant. (3) More ferruginous bodies were retained in the lungs in lung cancer and lung fibrosis cases than in cases of lung fibrosis only, and the difference in the concentrations was statistically significant (P = 0.02). CONCLUSION: Results obtained from lung tissue must always be interpreted cautiously. However, these results are consistent with the hypothesis that workers in some trades such as foundries were exposed not only to quartz but also to asbestos, ceramic fibers, metal-rich non fibrous particles, and other likely carcinogenic chemicals. The wide range of particle types identified in the lungs of these workers illustrates the complexity of trying to determine disease origins in these work environments. Epidemiology studies have to control for the exposure to these carcinogens as well as for smoking habits
— id: 57139, year: 1998, vol: 71, page: 263, stat: Journal Article,

Time to detection of Mycobacterium tuberculosis in sputum culture correlates with outcome in patients receiving treatment for pulmonary tuberculosis
Epstein MD; Schluger NW; Davidow AL; Bonk S; Rom WN; Hanna B
1998 Feb;113(2):379-386, Chest
STUDY OBJECTIVE: The purpose of this study was to determine whether the time to detection (TTD) of Mycobacterium tuberculosis in sputum culture correlates with the response to antituberculous treatment in patients with pulmonary tuberculosis. STUDY DESIGN: Twenty-six consecutive patients were studied who had active pulmonary tuberculosis and sufficient sputum cultures and clinical follow-up to allow adequate assessment. RESULTS: Following initiation of antituberculous therapy, 13 patients (group 1, responders) had a complete response to treatment, and the TTD of M tuberculosis using the mycobacterial growth indicator tube increased steadily. The remaining 13 patients (group 2, nonresponders) had persistent evidence of active disease and demonstrated little or no increase in the TTD with treatment unless an additional therapeutic intervention was implemented (surgery, improved compliance with medications, or a change in medications). The presence of HIV infection, intravenous drug use, multidrug resistance, treatment with second-line therapy, extensive radiographic involvement, and cavitary disease were associated with a delayed increase in the TTD. CONCLUSIONS: The TTD was superior to clinical, radiographic, or conventional bacteriologic evaluation in determining treatment outcome. The TTD closely correlates with the overall response to treatment for pulmonary tuberculosis and may represent a useful adjunct to predict outcome in these patients
— id: 7556, year: 1998, vol: 113, page: 379, stat: Journal Article,

Transbronchial needle aspiration (TBNA) in patients infected with HIV
Harkin TJ; Ciotoli C; Addrizzo-Harris DJ; Naidich DP; Jagirdar J; Rom WN
1998 Jun;157(6 Pt 1):1913-1918, American journal of respiratory & critical care medicine
Transbronchial needle aspiration (TBNA) of intrathoracic lymph nodes has been shown to be useful in the diagnosis and staging of bronchogenic carcinoma. With the exception of sarcoidosis, the usefulness of TBNA has not been widely investigated in other clinical settings. We investigated the utility of TBNA with a 19-gauge histology needle in HIV-infected patients with mediastinal and hilar adenopathy at Bellevue Hospital Center. We performed 44 procedures in 41 patients. Adequate lymph node sampling was obtained in 35 of 44 (80%), and diagnostic material was obtained in 23 of 44 (52%) procedures. TBNA was the exclusive means of diagnosis in 13 of 41 (32%) patients. Of the 44 procedures, 23 (52%) were performed in patients with mycobacterial disease, with TBNA providing the diagnosis in 20 of 23 (87%). In these patients, positive TBNA specimens included smears of aspirated materials for acid-fast bacilli in 11, mycobacterial culture in 14, and histology in 15. In other diseases, TBNA diagnosed sarcoidosis with noncaseating granulomata in 2 of 4 patients and non-small cell lung cancer in 1 of 2 patients. TBNA was not helpful in other diseases including Pneumocystis carinii pneumonia, infection with Cryptococcus or Nocardia, bacterial pneumonia, viral pneumonia, and Kaposi's sarcoma. No pulmonary diagnosis was established in five patients. No complications of TBNA occurred. We conclude that TBNA through the flexible bronchoscope is safe and effective in the diagnosis of intrathoracic adenopathy in HIV-infected patients, and is particularly efficacious in the diagnosis of mycobacterial disease. Furthermore, TBNA may provide the only diagnostic specimen in almost one-third of HIV-infected patients, thereby sparing these patients more invasive procedures such as mediastinoscopy
— id: 8034, year: 1998, vol: 157, page: 1913, stat: Journal Article,

Type I interferon induces inhibitory 16-kD CCAAT/ enhancer binding protein (C/EBP)beta, repressing the HIV-1 long terminal repeat in macrophages: pulmonary tuberculosis alters C/EBP expression, enhancing HIV-1 replication
Honda Y; Rogers L; Nakata K; Zhao BY; Pine R; Nakai Y; Kurosu K; Rom WN; Weiden M
1998 Oct 5;188(7):1255-1265, Journal of experimental medicine
We have previously observed that HIV-1 replication is suppressed in uninflamed lung and increased during tuberculosis. In vitro THP-1 cell-derived macrophages inhibited HIV-1 replication after infection with Mycobacterium tuberculosis. Suppression of HIV-1 replication was associated with inhibition of the HIV-1 long terminal repeat (LTR) and induction of ISGF-3, a type I interferon (IFN)-specific transcription factor. Repression of the HIV-1 LTR required intact CCAAT/enhancer binding protein (C/EBP) sites. THP-1 cell-derived macrophages infected with M. tuberculosis, lipopolysaccharide, or IFN-beta induced the 16-kD inhibitory C/EBPbeta isoform and coincidentally repressed HIV-1 LTR transcription. C/EBPbeta was the predominant C/EBP family member produced in THP-1 macrophages during HIV-1 LTR repression. In vivo, alveolar macrophages from uninflamed lung strongly expressed inhibitory 16-kD C/EBPbeta, but pulmonary tuberculosis abolished inhibitory C/EBPbeta expression and induced a novel C/EBP DNA binding protein. Therefore, in vitro, proinflammatory stimulation produces an IFN response inhibiting viral replication by induction of a C/EBPbeta transcriptional repressor. THP-1 cell-derived macrophages stimulated with type I IFN are similar to alveolar macrophages in the uninflamed lung in vivo. In contrast, the cellular immune response in active pulmonary tuberculosis disrupts this innate immunity, switching C/EBP expression and allowing high level viral replication
— id: 8036, year: 1998, vol: 188, page: 1255, stat: Journal Article,

Valvular endocarditis due to Mycobacterium tuberculosis
Klingler K; Brandli O; Doerfler M; Schluger N; Rom WN
1998 May;2(5):435-437, International journal of tuberculosis & lung disease
Granulomas due to Mycobacterium tuberculosis are rarely observed in valvular structures. When observed, they are associated with disseminated tuberculosis in immunocompromised patients. We report the first case of tuberculous valvular endocarditis isolated in an immunocompetent patient. The patient had severe mitral valve regurgitation due to a perforation of the anterior leaflet of the mitral valve. M. tuberculosis was cultured from the vegetations and no other tuberculous foci were identified. This case exemplifies the protean manifestations of M. tuberculosis infections
— id: 7629, year: 1998, vol: 2, page: 435, stat: Journal Article,

Carrier frequency for glycogen storage disease type II in New York and estimates of affected individuals born with the disease
Martiniuk F; Chen A; Mack A; Arvanitopoulos E; Chen Y; Rom WN; Codd WJ; Hanna B; Alcabes P; Raben N; Plotz P
1998 Aug 27;79(1):69-72, American journal of medical genetics
— id: 7965, year: 1998, vol: 79, page: 69, stat: Journal Article,

Isoniazid levels in the bronchoalveolar lavage fluid of patients with pulmonary tuberculosis
O'Brien JK; Doerfler ME; Harkin TJ; Rom WN
1998 ;176(3):205-211, Lung
Isoniazid (INH) is one of the most important first line drugs in the treatment of tuberculosis. We utilized high performance liquid chromatography with a hydrazone extraction technique to measure INH in bronchoalveolar lavage (BAL) fluid specimens from six patients with active pulmonary tuberculosis. We found BAL fluid INH levels to be similar to 2-h peak serum levels. The concentration of INH in BAL fluid from lobes with infiltrate was similar to the concentration of INH in BAL fluid from lobes without infiltrate (0.062 microgram/ml and 0.073 microgram/ml, respectively). After adjusting for protein concentration in the BAL fluid, INH levels in lobes with infiltrate were threefold lower than in lobes without infiltrate. The correlation between the concentration of INH in serum and BAL fluid approached significance after correcting for protein (lobes with infiltrate, r2 = 0.60 (p = 0.07); lobes without infiltrate, r2 = 0.50 (p = 0.12). INH penetrates into bronchoalveolar fluid, and concentrations of INH in the BAL fluid suggest that assessment of the INH serum concentration is adequate to evaluate bioavailability of the drug in patients with pulmonary tuberculosis
— id: 7721, year: 1998, vol: 176, page: 205, stat: Journal Article,

Assessment of activation, differentiation, and carcinogenesis of lung cells by quantitative competitive RT-PCR
Rom WN
1998 Jul;19(1):3-5, American journal of respiratory cell & molecular biology
— id: 7766, year: 1998, vol: 19, page: 3, stat: Journal Article,

Environmental & occupational medicine
Rom, William N
Philadelphia : Lippincott-Raven Publishers, 1998,
— id: 588, year: 1998, vol: , page: , stat: ,

The host immune response to tuberculosis
Schluger NW; Rom WN
1998 Mar;157(3 Pt 1):679-691, American journal of respiratory & critical care medicine
— id: 7782, year: 1998, vol: 157, page: 679, stat: Journal Article,

Radio-opaque punctate opacities on the chest radiograph following intravenous injection of a bismuth compound
Addrizzo-Harris DJ; Churg A; Rom WN
1997 Mar;52(3):303-304, Thorax
The case history is described of a patient who presented with small rounded punctate metallic opacities widely dispersed on the chest radiograph with accumulation of metallic particles in the right ventricle. Energy dispersive x ray spectroscopy of alveolar macrophages identified a major predominant peak as bismuth. The patient had been injected with a health tonic in Honduras two years earlier
— id: 12365, year: 1997, vol: 52, page: 303, stat: Journal Article,

Pulmonary aspergilloma and AIDS. A comparison of HIV-infected and HIV-negative individuals
Addrizzo-Harris DJ; Harkin TJ; McGuinness G; Naidich DP; Rom WN
1997 Mar;111(3):612-618, Chest
OBJECTIVE AND METHODS: While pulmonary aspergilloma has been well described in immunocompetent hosts, to date and to our knowledge, there has not been a description of pulmonary aspergilloma in the HIV-infected individual. A retrospective review of cases seen by the Bellevue Hospital Chest Service from January 1992 through June 1995 identified 25 patients with aspergilloma. To investigate the impact of HIV status on pulmonary aspergilloma, we compared clinical presentation, progression of disease, treatment, and outcome in the HIV-infected patient vs the HIV-negative patient with aspergilloma. RESULTS: Of the 25 patients identified, 10 were HIV-infected and 15 were HIV-negative. Predisposing diseases included tuberculosis (18/25, 72%), sarcoidosis (4/25, 16%), and Pneumocystis carinii pneumonia (3/25, 12%). All 25 patients had evidence of aspergilloma on chest CT. In addition, 17 of 25 patients had evidence of Aspergillus species in fungal culture, pathologic specimens, or immunoprecipitins. Hemoptysis was present in 15 of 25 (60%) (11/15 [73%] of the HIV-negative group vs 4/10 [40%] of the HIV-infected group). Severe hemoptysis (> 150 mL/d) occurred in 5 of 15 (33%) of the HIV-negative group vs 1 of 10 (10%) of the HIV-infected group. Disease progression occurred more frequently among the HIV-infected group (4/8, 50% vs 1/13, 8% in HIV-negative individuals). All patients with disease progression had lymphocyte subset CD4+ < 100 cells per microliter. Four of eight (50%) of the HIV-infected group vs 1 of 13 (8%) of the HIV-negative group died. SUMMARY AND CONCLUSIONS: We conclude the following: (1) although tuberculosis and sarcoidosis are the most prevalent predisposing diseases, P carinii pneumonia in the HIV-infected individual is a risk factor for pulmonary aspergilloma; (2) HIV-infected individuals with CD4+ < 100 cells per microliter are more likely to have disease progression despite treatment; and (3) HIV-negative patients are more likely to have hemoptysis requiring intervention
— id: 12362, year: 1997, vol: 111, page: 612, stat: Journal Article,

Treatment of multidrug-resistant pulmonary tuberculosis with interferon-gamma via aerosol
Condos R; Rom WN; Schluger NW
1997 May 24;349(9064):1513-1515, Lancet
BACKGROUND: Multidrug-resistant tuberculosis (MDR-TB) is associated with substantial morbidity, despite drug therapy. Interferon-gamma, a cytokine produced mainly by CD4 T lymphocytes, can activate alveolar macrophages, important effector cells in host immunity against Mycobacterium tuberculosis. We investigated safety and tolerability of aerosolised interferon-gamma in patients with MDR-TB, and assessed its efficacy in terms of sputum-smear grades. METHODS: We did an open-label trial of aerosol interferon-gamma given to five patients with smears and cultures positive for pulmonary MDR-TB, despite documented adherence to therapy. The patients received aerosol interferon-gamma 500 micrograms three times a week for 1 month. Safety and tolerability were assessed, and, as well as routine clinical assessments, sputum samples for smear and culture were collected at entry and weekly. Computed tomography scans of the chest were done at baseline and after therapy ended. FINDINGS: Interferon-gamma was well tolerated by all patients. In all five, bodyweight stabilised or increased. Sputum acid-fast-bacillus smears became negative in all patients, and the time to positive culture increased (from 17 to 24 days, not significant), which suggested that the mycobacterial burden had decreased. The size of cavitary lesions was reduced in all patients, 2 months after treatment had ended. INTERPRETATION: Preliminary data suggest that aerosol interferon-gamma is a well-tolerated treatment that may be useful as adjunctive therapy in patients with MDR-TB who are otherwise not responding well to therapy
— id: 56933, year: 1997, vol: 349, page: 1513, stat: Journal Article,

Occupational and environmental medicine in New York State
de la Hoz RE; London M; Friedman-Jimenez G; Rom WN
1997 ;70(1):1-8, International archives of occupational & environmental health
New York State (NYS) is home to 7.2% of the population and producer of 8.4% of the gross domestic product of the United States. The history and the current status of occupational and environmental medicine (OEM) research, educational resources, clinical practice patterns, and regulatory framework in NYS are reviewed. Changes anticipated or already taking place in health care financing, clinical practice patterns, occupational safety and health regulations and enforcement, and funding for research and medical education at the national level, are already having an impact in OEM activities in NYS
— id: 12405, year: 1997, vol: 70, page: 1, stat: Journal Article,

Angular and fibrous particles in lung are markers of job categories
Dufresne A; Begin R; Dion C; Jagirdar J; Rom WN; Loosereewanich P; Muir DC; Ritchie AC; Perrault G
1997 Nov 5;206(2-3):127-136, Science of the total environment
INTRODUCTION: The lung concentration of angular and fibrous particles has been measured when cases are stratified into their job categories; 21 miners (metallic mines such as gold, zinc and copper), 18 iron foundrymen, 22 non-iron foundrymen, four welders, three sand-blast workers, four construction workers, three technicians and professionals, seven workers in other trades excluding welding. Twelve asbestos miners representing a positive exposure to asbestos and 20 people representing a background population were added to the previous groups. MATERIAL AND METHODS: Particles, both angular and fibrous, were extracted from lung parenchyma by a bleach digestion method, mounted on copper microscopic grids by a carbon replica technique and analyzed by transmission electron microscopy (TEM) and energy dispersive spectroscopy (EDS). Quartz concentration was also determined by X-ray diffraction (XRD) on a silver membrane filter after the extraction from the lung parenchyma. RESULTS: (1) The highest concentrations of quartz were found in mines (metallic mines), iron foundrymen and sand-blast workers. Notable amounts quartz were found in welders and professionals. (2) The highest concentrations of short fibres were found in non-iron foundrymen, asbestos miners and construction workers. (3) The highest concentrations of long fibres were found in non-iron foundry men and asbestos miners. (4) The highest concentrations of ferruginous bodies were found in non-iron foundrymen and asbestos miners. (5) The non-iron foundrymen were exposed to ceramic fibres and asbestos fibres. CONCLUSION: The results of the study may not be representative of the broad spectrum of workers in the industrial activities in which they have been involved. However, the detailed composition of the retained particles of our workers is explained both qualitatively and quantitatively by their work histories. Finally, the broad range of particle types identified in the lungs of these workers illustrate the complexity or trying to determine disease origins in these occupational settings
— id: 15398, year: 1997, vol: 206, page: 127, stat: Journal Article,

The significance of Mycobacterium avium complex cultivation in the sputum of patients with pulmonary tuberculosis
Epstein MD; Aranda CP; Bonk S; Hanna B; Rom WN
1997 Jan;111(1):142-147, Chest
Mycobacterium avium-intracellulare complex (MAC) is a ubiquitous environmental microorganism whose pathogenicity ranges from innocuous colonization to disease, in immunocompetent as well as immunocompromised individuals. We sought to determine the clinical significance of MAC in sputum cultures of patients with pulmonary tuberculosis (TB). A retrospective analysis between January 1994 and March 1995 at Bellevue Hospital Center revealed both Mycobacterium tuberculosis and MAC in 35 patients (11% of all patients with TB). Of 27 patients reviewed, 52% were HIV-1 infected (median CD4 + 25 cells per microliter). Radiographic manifestations in patients with TB and MAC were similar to those seen in patients with TB alone. Both mycobacteria were cultured primarily from respiratory sources. M tuberculosis was usually cultured first or concurrent with MAC, and in nearly all cases, both species were recovered within 2 months of each other. Most patients improved clinically, bacteriologically, and radiographically with standard antituberculous therapy, except those with advanced AIDS, multidrug-resistant TB (MDR-TB), or disseminated MAC. We conclude that recovery of MAC in sputum is common in patients with pulmonary TB, regardless of HIV-1 infection, MDR-TB, or other clinical, bacteriologic, or radiographic attributes. MAC cultivation in most of these patients likely represents transient colonization, and in most cases is not clinically significant
— id: 12430, year: 1997, vol: 111, page: 142, stat: Journal Article,

Immunohistochemical localization of transforming growth factor beta isoforms in asbestos-related diseases
Jagirdar J; Lee TC; Reibman J; Gold LI; Aston C; Begin R; Rom WN
1997 Sep;105 Suppl 5:1197-1203, Environmental health perspectives
Transforming growth factor beta (TGF-beta), a multifunctional cytokine and growth factor, plays a key role in scarring and fibrotic processes because of its ability to induce extracellular matrix proteins and modulate the growth and immune function of many cell types. These effects are important in inflammatory disorders with fibrosis and cancer. The asbestos-related diseases are characterized by fibrosis in the lower respiratory tract and pleura and increased occurrence of lung cancer and mesothelioma. We performed immunohistochemistry with isoform-specific antibodies to the three TGF-beta isoforms on 16 autopsy lungs from Quebec, Canada, asbestos miners and millers. There was increased immunolocalization of all three TGF-beta isoforms in the fibrotic lesions of asbestosis and pleural fibrosis. The hyperplastic type II pneumocytes contained all three isoforms. By contrast, there was differential spatial immunostaining for the TGF-beta isoforms in malignant mesothelioma, with TGF-beta 1 in the stroma but TGF-beta 2 in the tumor cells. These data are consistent with an important role for TGF-beta in accumulation of extracellular matrix and cell proliferation in asbestos-related diseases
— id: 12204, year: 1997, vol: 105 Suppl 5, page: 1197, stat: Journal Article,

Effects of mycobacteria on regulation of apoptosis in mononuclear phagocytes
Klingler K; Tchou-Wong KM; Brandli O; Aston C; Kim R; Chi C; Rom WN
1997 Dec;65(12):5272-5278, Infection & immunity
Since apoptosis is observed in tuberculous granulomata, we investigated the molecular mechanisms underlying the apoptotic pathway in an in vitro model of mycobacterial infection of mononuclear phagocytes. We postulated that Mycobacterium tuberculosis could trigger the apoptotic pathway in macrophages, resulting in death of the microorganism by modulating the expression of bcl-2, bax, bcl-xL, and bcl-xS. We found that the mRNA of bcl-2, an inhibitor of apoptosis, was downregulated in peripheral blood monocytes (PBM) between 2 and 6 h following infection with M. bovis BCG or induction with heat-killed M. tuberculosis H37Ra. Western analysis showed a downregulation of the Bcl-2 protein, with a half-life of 24 h. At the same time points, there was no change in the expression of Bax or Bcl-xS, inducers of apoptosis, but Bcl-xL, another inhibitor of apoptosis, was minimally upregulated by BCG. To determine if apoptosis could be a mechanism for growth inhibition in vivo, we obtained alveolar macrophages by bronchoalveolar lavage from involved sites in patients with active pulmonary tuberculosis. Using the TUNEL (terminal deoxynucleotidyltransferase mediated nick end labeling) technique, we observed significantly more apoptosis in involved segments of five tuberculosis patients (14.8 +/- 1.9%) than in those of normal controls (<1%, P = 0.02) or in uninvolved segments (4.3 +/- 0.9%, P < 0.05). We conclude that apoptosis of mononuclear phagocytes induced by M. tuberculosis occurs in vivo and that in an in vitro model of mycobacterial infection, apoptosis may be mediated by downregulation of Bcl-2
— id: 56887, year: 1997, vol: 65, page: 5272, stat: Journal Article,

Immunohistochemical localization of transforming growth factor-beta and insulin-like growth factor-I in asbestosis in the sheep model
Lee TC; Gold LI; Reibman J; Aston C; Begin R; Rom WN; Jagirdar J
1997 ;69(3):157-164, International archives of occupational & environmental health
Asbestosis is characterized by increased collagen deposition along the walls of terminal respiratory bronchioles that extends into the alveolar ducts and septae. Alveolar macrophages are activated and release growth factors that stimulate mesenchymal cell proliferation and enhanced formation of extracellular matrix. Both insulin-like growth factor-I (IGF-I), and transforming growth factor beta (TGF-beta) regulate cellular growth and promote matrix accumulation and are hypothesized to play important roles in asbestosis. We performed immunohistochemistry using polyclonal antibodies to specific synthetic peptides of the three mammalian isoforms of TGF-beta (TGF-beta 1, -beta 2, -beta 3) and to IGF-I on lungs of sheep treated intratracheally with chrysotile asbestos. All three TGF-beta isoforms were found in bronchial and bronchiolar epithelium, macrophages, and bronchial and vascular smooth muscle in control lungs. The distribution of TGF-beta was increased in these lung constituents as fibrotic lesions developed. Fibrotic lesions additionally demonstrated intense immunostaining of all three TGF-beta isoforms that localized to the extracellular matrix zones with little staining of interstitial cells. In the control sheep lungs, IGF-I staining was detected in bronchial and bronchiolar epithelium, bronchial glands, bronchial and vascular smooth muscle, endothelium, and macrophages. IGF-I immunostaining was detected in macrophages in peribronchial fibrosis and in fibroblasts along the periphery of and within lesions, but not in the extracellular matrix. Metaplastic proliferating epithelium and macrophages were strongly immunoreactive for IGF-I in advanced lesions. Our data demonstrate different immunostaining patterns for IGF-I and TGF-beta in asbestosis, with IGF-I in the cellular periphery and TGF-beta in the extracellular matrix consistent with a complementary role in stimulating interstitial fibroblast proliferation and new collagen deposition in areas of active fibrosis
— id: 12416, year: 1997, vol: 69, page: 157, stat: Journal Article,

Mycobacterium tuberculosis enhances human immunodeficiency virus-1 replication in the lung
Nakata K; Rom WN; Honda Y; Condos R; Kanegasaki S; Cao Y; Weiden M
1997 Mar;155(3):996-1003, American journal of respiratory & critical care medicine
We investigated the in vivo effect of coinfection of Mycobacterium tuberculosis on human immunodeficiency virus type 1 (HIV-1) replication using bronchoalveolar lavage (BAL) of 11 HIV-1-infected patients with pulmonary tuberculosis and 10 patients with no lung disease. Lung segments involved with pulmonary tuberculosis had significantly elevated HIV-1 branched DNA (bDNA) levels and p24 in BAL compared with lung segments uninvolved with tuberculosis or with BAL from patients with no lung disease. The BAL viral burden was higher than plasma HIV-1 in tuberculosis patients, indicating local production of virus. BAL HIV-1 bDNA declined over the course of treatment for tuberculosis in three patients who underwent serial bronchoscopies. Tumor necrosis factor-alpha (TNF-alpha) and HIV-1 bDNA particles were strongly correlated (r2 = 0.9, p < 0.01) in lung segments involved with tuberculosis. The deduced amino acid sequence of HIV-1 gp120 V3 region from involved segments of three patients with pulmonary tuberculosis showed basic substitutions associated with altered viral phenotype. Phylogenetic analysis of V3 sequences demonstrated that BAL HIV-1 RNA had diverged from plasma. These data support the conclusion that pulmonary tuberculosis enhances local HIV-1 replication in vivo
— id: 12363, year: 1997, vol: 155, page: 996, stat: Journal Article,

DNA fingerprints from Mycobacterium tuberculosis isolates of patients confined for therapy noncompliance show frequent clustering
O'Brien JK; Sandman LA; Kreiswirth BN; Rom WN; Schluger NW
1997 Aug;112(2):387-392, Chest
STUDY OBJECTIVE: To test the hypothesis that individuals chronically noncompliant with antituberculous chemotherapy are vectors for ongoing transmission of the disease in the community. DESIGN: Cohort study. SETTING: A large public hospital with a tuberculosis detention unit for patients with repeated and prolonged nonadherence to therapy. PATIENTS: Mycobacterium tuberculosis isolates from patients confined on the detention unit were obtained from the hospital's mycobacteriology laboratory. INTERVENTIONS: None. MEASUREMENTS AND RESULTS: A standardized IS6110-based Southern blot hybridization protocol was used to genotype M tuberculosis isolates recovered from patients confined on the detention unit at the hospital. Each DNA fingerprint pattern was compared with the IS6110-fingerprint database at the Public Health Research Institute Tuberculosis Center, which has archived fingerprint patterns from over 2,500 M tuberculosis isolates collected from New York City patients in the past 5 years. Eighty percent of available isolates from detained patients belonged to an identifiable DNA fingerprint cluster, suggesting an epidemiologic link between the detainees and other New York City tuberculosis patients. CONCLUSIONS: Chronic noncompliance with therapy is associated with ongoing spread of tuberculosis in the community. Aggressive measures, including detention, for the small number of recalcitrant, noncompliant patients may interrupt a chain of transmission and contribute to a decline in the spread of tuberculosis in urban areas
— id: 7228, year: 1997, vol: 112, page: 387, stat: Journal Article,

Development of a suicide gene as a novel approach to killing Mycobacterium tuberculosis
Rom WN; Yie TA; Tchou-Wong KM
1997 Dec;156(6):1993-1998, American journal of respiratory & critical care medicine
The increase in multidrug-resistant tuberculosis and high mortality among those co-infected with HIV-1 necessitates new therapeutic approaches directed at Mycobacterium tuberculosis. We hypothesized that a dominant-negative mutation in the DNA-dependent RNA polymerase gene would inhibit transcription of all genes by blocking access of the wild-type enzyme to promoters. An evolutionarily invariant lysine was substituted with arginine by site-directed mutagenesis in the rpoB gene. The dominant-negative rpoB gene product inhibited a transposon-derived kanamycin-resistance gene in both M. smegmatis and M. tuberculosis H37Rv, leading to growth inhibition of the mycobacteria on solid media containing kanamycin. The dominant-negative mutant rpoB gene is a potential suicide gene especially for the treatment of multidrug-resistant tuberculosis once a delivery strategy is also developed
— id: 12189, year: 1997, vol: 156, page: 1993, stat: Journal Article,

Tuberculosis infection and disease among persons seeking social services in New York City
Schluger NW; Huberman R; Wolinsky N; Dooley R; Rom WN; Holzman RS
1997 Feb;1(1):31-37, International journal of tuberculosis & lung disease
SETTING: A large public hospital in New York City. OBJECTIVE: To determine the prevalence of tuberculosis infection and disease in a cohort of indigent persons in New York. DESIGN: Persons seeking social services at any of five community-based organizations in New York City were screened for tuberculosis infection using tuberculin skin testing and a symptom questionnaire. Skin test or symptom positive persons were referred to the Bellevue Hospital Chest Clinic for a chest radiograph and medical evaluation. After this evaluation, patients were classified into a diagnostic category (e.g. tuberculosis infection, tuberculosis disease, no evidence of tuberculosis infection or disease). RESULTS: Of 651 persons screened, 591 (91%) completed the initial evaluation. The tuberculosis infection prevalence for the entire cohort was 41% (95% Confidence Interval [CI], 37% to 45%). Risk factors for infection included residence in a congregate setting, drug use, and birth outside the United States. Human immunodeficiency virus (HIV) infection was not a risk factor for infection. Eleven cases of active tuberculosis were also detected (disease prevalence of 1.7%, 95% CI, 0.85% to 3%). Most of the patients with active tuberculosis had documented HIV infection or clear risk factors for HIV. CONCLUSION: We conclude that tuberculosis infection and disease remain common in populations characterized by poor housing conditions, drug use, and HIV infection. Linking a major medical provider with community-based organizations is an effective means to provide highly targeted screening services to a population at serious risk for disease acquisition and transmission
— id: 12178, year: 1997, vol: 1, page: 31, stat: Journal Article,

Early responses to infection: chemokines as mediators of inflammation [see comments]
Schluger NW; Rom WN
1997 Aug;9(4):504-508, Current opinion in immunology
Chemokines are a superfamily of small related protein molecules that are secreted by a variety of cells and that have, among their diverse biological properties, the ability to recruit a wide range of immune cells to the sites of infection and disease. Chemokines are secreted in response to bacterial, viral, parasitic, and mycobacterial pathogens. Our recent progress in understanding the patterns of chemokine secretion in response to various pathogens and their impact on disease manifestations is likely to lead to the development of novel therapeutic approaches for a variety of serious infections
— id: 12296, year: 1997, vol: 9, page: 504, stat: Journal Article,

Molecular regulation of IL-6 activation by asbestos in lung epithelial cells: role of reactive oxygen species
Simeonova PP; Toriumi W; Kommineni C; Erkan M; Munson AE; Rom WN; Luster MI
1997 Oct 15;159(8):3921-3928, Journal of immunology
IL-6 has been characterized as a pleiotropic cytokine with multiple biologic activities, but its induction and role in asbestos diseases have not been studied. Asbestos fibers were found to stimulate IL-6 expression and secretion in pulmonary type II-like epithelial A549 cells as well as in normal human bronchial epithelial cells. IL-6 induction was dependent on the intracellular redox-oxidative state, since intracellular hydroxyl scavengers and N-acetylcysteine, a precursor of glutathione, abrogated IL-6 secretion by asbestos or H2O2. IL-6 induction paralleled increased DNA binding activity to the nuclear factor-kappa B (NF-kappa B)- and NF-IL-6-recognized sites in the IL-6 promoter. The NF-kappa B and NF-IL-6 DNA binding proteins were immunochemically characterized as a heterodimer p65/p50 and a homodimer C/EBP beta, respectively. Stimulation of DNA binding activity to the NF-kappa B and NF-IL-6 binding sites of the IL-6 promoter by asbestos or H2O2 were inhibited by tetramethylthiourea, a hydroxyl radical scavenger. The role of local IL-6 production in the pathophysiologic processes of fiber-induced lung disorders was examined. Although less active than fibroblast growth factor, human rIL-6 also stimulated lung fibroblast growth, as evidenced by increased [3H]thymidine incorporation. Furthermore, elevated IL-6 levels were found in bronchoalveolar lavage fluids from patients diagnosed with lung fibrosis and work-related histories of long term asbestos exposure. Taken together, the results suggest that asbestos-induced oxidative stress is involved in the activation of NF-kappa B and NF-IL-6 transcription factors, which recognize the IL-6 promoter. The resulting increase in IL-6 expression may be involved in both inflammatory and fibrotic processes in the lung
— id: 15399, year: 1997, vol: 159, page: 3921, stat: Journal Article,

GM-CSF gene expression is normal but protein release is absent in a patient with pulmonary alveolar proteinosis [published erratum appears in Am J Respir Crit Care Med 1998 Apr;157(4 Pt 1):1353]
Tchou-Wong KM; Harkin TJ; Chi C; Bodkin M; Rom WN
1997 Dec;156(6):1999-2002, American journal of respiratory & critical care medicine
Pulmonary alveolar proteinosis (PAP) is a rare disease characterized by an excessive accumulation of surfactant lipids and proteins in the alveolar space. In mice with a homozygous deletion of granulocyte macrophage-colony stimulating factor (GM-CSF), their phenotype mimics PAP. To evaluate whether the knockout mouse model mimics human disease, we evaluated GM-CSF expression in alveolar macrophages from a patient with PAP. We performed multiple whole lung lavages on a patient with PAP, and cultured BAL cells in the presence or absence of LPS. In contrast to the GM-CSF knockout mouse, human BAL cells from a patient with PAP expressed mRNA for GM-CSF following LPS stimulation. However, similar to the knockout mouse, GM-CSF protein release from BAL cells was undetectable with or without LPS. BAL cells from normal human controls released GM-CSF in abundance after LPS stimulation. In BAL cells from the patient with PAP, neutralization of interleukin-10 (IL-10) by anti-IL-10 antibody, resulted in enhanced GM-CSF production. Thus, alveolar macrophages from a PAP lung have deficient GM-CSF production analogous to the GM-CSF knockout mice; in contrast, human cells from a PAP lung have an intact GM-CSF gene. This case report illustrates an important difference between the knockout mouse model of PAP and the human disease
— id: 12188, year: 1997, vol: 156, page: 1999, stat: Journal Article,

Nicotine enhances expression of the neutrophil elastase gene and protein in a human myeloblast/promyelocyte cell line
Armstrong LW; Rom WN; Martiniuk FT; Hart D; Jagirdar J; Galdston M
1996 Nov;154(5):1520-1524, American journal of respiratory & critical care medicine
The pathogenesis of emphysema is considered to be an imbalance of protease and antiprotease activity in the lower respiratory tract leading to uninhibited degradation of lung interstitium by elastolytic enzymes. An increased amount of the serine protease neutrophil elastase (NE) is though to play a major role in this degradation. Because the expression of NE is limited to neutrophil precursors in the bone marrow, we hypothesized that nicotine, which is readily absorbed from lung and distributed to tissue, including bone marrow, would increase expression of the NE gene and protein. HL-60 cells, a myeloblast/promyelocyte cell line, were cultured in the presence or absence of 0.06 and 0.8 microM nicotine for 5 d. Both concentrations of nicotine caused a 2.4- to 3.3-fold increase, respectively, in NE gene expression over unstimulated cells, and NE protein increased 4.8- to 3.4-fold over unstimulated cells, respectively, similar to our positive control DMSO. Nicotine did not induce upregulation of the NE gene by initiating cell differentiation. Both low and high nicotine concentrations upregulate the NE gene in HL-60 cells leading to increased NE protein concentration per cell suggesting a pathophysiologic mechanism for emphysema
— id: 12496, year: 1996, vol: 154, page: 1520, stat: Journal Article,

Cytokine production in tuberculosis
Barnes, Peter F; Rom, William N
Tuberculosis Boston : Little Brown, 1996,
— id: 4833, year: 1996, vol: , page: ?, stat: Chapter,

Elevated interleukin-8 in the alveolitis of individuals with asbestos exposure
Broser M; Zhang Y; Aston C; Harkin T; Rom WN
1996 ;68(2):109-114, International archives of occupational & environmental health
Asbestosis is a fibrotic and inflammatory interstitial lung disease occurring after chronic occupational exposure to asbestos. An alveolitis has been described with activated alveolar macrophages and increased neutrophils as sampled by bronchoalveolar lavage (BAL). Animal models and in vitro studies demonstrate that asbestos can stimulate alveolar macrophages to release neutrophil chemotactic factor. We performed BAL on 18 nonsmoking individuals with asbestos exposure and observed a twofold increase in percent neutrophils recovered. Alveolar macrophages cultured in vitro from the asbestos-exposed individuals spontaneously released significant amounts of the neutrophil chemotaxin, interleukin-8 (IL-8). In addition, the alveolar macrophages expressed a 2.7-fold increase in steady state mRNA levels compared to unexposed normal controls utilizing the reverse transcriptase/polymerase chain reaction. In vitro experiments confirmed that crocidolite or chrysotile asbestos could stimulate the release of IL-8 from mononuclear phagocytes in a dose-dependent fashion. We conclude that asbestos exposure causes a mild neutrophilic alveolitis, and that IL-8 is one potential mediator capable of contributing to this inflammation in the lower respiratory tract
— id: 12690, year: 1996, vol: 68, page: 109, stat: Journal Article,

Effect of Mycobacterium tuberculosis and its components on macrophages and the release of matrix metalloproteinases
Chang JC; Wysocki A; Tchou-Wong KM; Moskowitz N; Zhang Y; Rom WN
1996 Mar;51(3):306-311, Thorax
BACKGROUND: Pulmonary tuberculosis is associated with caseating necrosis, parenchymal lung destruction, and cavity formation. It was hypothesised that tuberculous lung destruction is mediated, at least in part, by the participation of matrix metalloproteinases released by mononuclear phagocytes. METHODS: Cells of the myelomonocytic leukaemia cell line THP-1 were incubated with lipoarabinomannan (LAM), the major antigenic cell wall component, and with Mycobacterium tuberculosis and analysed by Northern blot analysis. Two patients with active cavitary tuberculosis also underwent bronchoalveolar lavage and the cells were analysed by Northern blotting. RESULTS: Incubation of THP-1 cells with LAM resulted in the stimulated release of matrix metalloproteinase-9 (MMP-9), a 92 kDa gelatinase, by 24 hours in a dose-dependent fashion. In addition, Northern analysis revealed that LAM upregulated the gene for MMP-9 by 24 hours, but not the gene for the 72 kDa gelatinase MMP-2. Heat killed M tuberculosis H37Ra also upregulated the MMP-9 gene. Bronchoalveolar lavage of the two patients with active cavitary tuberculosis showed striking upregulation of the MMP-9 gene compared with a normal control using Northern analysis. LAM also upregulated the type I interstitial collagenase (MMP-1) gene by 24 hours in both THP-1 cells and peripheral blood monocytes. CONCLUSIONS: These data suggest that M tuberculosis and its major cell antigenic component, LAM, stimulate the release of MMP-9 and upregulate the expression of genes for MMP-1 and MMP-9. It is possible that M tuberculosis and its components contribute directly to cavity formation by their ability to stimulate macrophages to release matrix metallo-proteinases that digest collagens I-IV, and indirectly by stimulating the release of the cytokines interleukin 1 beta and tumour necrosis factor alpha that induce fibroblasts to amplify the release of matrix metalloproteinases
— id: 56806, year: 1996, vol: 51, page: 306, stat: Journal Article,

Peripheral-blood-based PCR assay to identify patients with active pulmonary tuberculosis
Condos R; McClune A; Rom WN; Schluger NW
1996 Apr 20;347(9008):1082-1085, Lancet
BACKGROUND: There is a need for rapid diagnosis of pulmonary tuberculosis. We have previously used a PCR to detect circulating Mycobacterium tuberculosis DNA in blood samples from patients (mostly HIV-infected) with pulmonary tuberculosis. We have now prospectively investigated the role of this blood-based PCR assay for diagnosis of this disease in a clinical setting. METHODS: Our PCR assay is specific for the IS6110 insertion element of the M tuberculosis complex of organisms. We used it to test peripheral blood from 88 consecutive patients admitted to a chest ward with suspected pulmonary tuberculosis. Personnel who carried out the assay did not know the results of any clinical investigations and ultimate diagnosis, and clinicians did not know the PCR results. Results of the PCR assay were compared with the final clinical diagnosis. A subgroup of 15 patients had blood samples assayed serially to track the PCR signal over time. FINDINGS: 41 patients had a final clinical diagnosis of tuberculosis, and the cases were typical of those seen at our hospital: HIV infection was common, and most cases were not sputum-smear positive for acid-fast bacilli. The PCR assay correctly identified 39 of 41 patients with proven pulmonary tuberculosis, 26 (63%) of whom were sputum-smear negative. There were five patients in whom a positive PCR result did not accord with the final clinical diagnosis, and two of the 44 negative PCR results were classified as false negatives. The overall sensitivity and specificity of the PCR assay for a diagnosis of tuberculosis was 95% and 89%, respectively. In 15 patients with pulmonary tuberculosis and a positive blood assay,the PCR result remained positive after 1 month of therapy, but had reverted to negative in 13 of the 15 by 4 months of therapy. INTERPRETATION: We conclude that peripheral-blood-based PCR detection for the diagnosis of tuberculosis is a technically feasible approach that has a potentially important role in the diagnosis of pulmonary tuberculosis
— id: 56864, year: 1996, vol: 347, page: 1082, stat: Journal Article,

Chronic lung disease secondary to ammonia inhalation injury: a report on three cases
de la Hoz RE; Schlueter DP; Rom WN
1996 Feb;29(2):209-214, American journal of industrial medicine
Inhalation of highly hydrosoluble toxicants, like ammonia, can be associated with chronic lung diseases, which have been partially characterized. We present the case of three patients who were evaluated 2 years after massive exposure to ammonia in occupational settings. They presented with chronic dyspnea, and clinical pictures consistent with restrictive lung dysfunction, obstructive lung disease, and bronchial hyper-reactivity and small airways disease, respectively. The findings in 94 reported cases of inhalation injury due to massive exposure to ammonia are reviewed; in 35 cases follow-up for at least 1 year was available. The range of chronic pulmonary diseases associated with ammonia inhalation injury is reviewed, and suggestions for appropriate diagnostic evaluation are made
— id: 7066, year: 1996, vol: 29, page: 209, stat: Journal Article,

Differentiation of the ILO boundary chest roentgenograph (0/1 to 1/0) in asbestosis by high-resolution computed tomography scan, alveolitis, and respiratory impairment
Harkin TJ; McGuinness G; Goldring R; Cohen H; Parker JE; Crane M; Naidich DP; Rom WN
1996 Jan;38(1):46-52, Journal of occupational & environmental medicine
High-resolution computed tomography (HRCT) scans have been advocated as providing greater sensitivity in detecting parenchymal opacities in asbestos-exposed individuals, especially in the presence of pleural fibrosis, and having excellent inter- and intraobserver reader interpretation. We compared the 1980 International Labor Organization (ILO) International Classification of the Radiographs of the Pneumoconioses for asbestosis with the high-resolution CT scan using a grid scoring system to better differentiate normal versus abnormal in the ILO boundary 0/1 to 1/0 chest roentgenograph. We studied 37 asbestos-exposed individuals using the ILO classification, HRCT grid scores, respiratory symptom questionnaires, pulmonary function tests, and bronchoalveolar lavage. We used Pearson correlation coefficients to evaluate the linear relationship between outcome variables and each roentgenographic method. The normal HRCT scan proved to be an excellent predictor of 'normality,' with pulmonary function values close to 100% for forced vital capacity (FVC), forced expiratory volume in 1 second (FEV1), total lung capacity (TLC), and carbon monoxide diffusing capacity (DLCO) and no increase in BAL inflammatory cells. Concordant HRCT/ILO abnormalities were associated with reduced FEV1/FVC ratio, reduced diffusing capacity, and alveolitis consistent with a definition of asbestosis. In our study, the ILO classification and HRCT grid scores were both excellent modalities for the assessment of asbestosis and its association with impaired physiology and alveolitis, with their combined use providing statistical associations with alveolitis and reduced diffusing capacity
— id: 56819, year: 1996, vol: 38, page: 46, stat: Journal Article,

Lipophosphoglycan from Leishmania suppresses agonist-induced interleukin 1 beta gene expression in human monocytes via a unique promoter sequence
Hatzigeorgiou DE; Geng J; Zhu B; Zhang Y; Liu K; Rom WN; Fenton MJ; Turco SJ; Ho JL
1996 Dec 10;93(25):14708-14713, Proceedings of the National Academy of Sciences of the United States of America
Leishmania are parasites that survive within macrophages by mechanism(s) not entirely known. Depression of cellular immunity and diminished production of interleukin 1 beta (IL-1 beta) and tumor necrosis factor alpha are potential ways by which the parasite survives within macrophages. We examined the mechanism(s) by which lipophosphoglycan (LPG), a major glycolipid of Leishmania, perturbs cytokine gene expression. LPG treatment of THP-1 monocytes suppressed endotoxin induction of IL-1 beta steady-state mRNA by greater than 90%, while having no effect on the expression of a control gene. The addition of LPG 2 h before or 2 h after endotoxin challenge significantly suppressed steady-state IL-1 beta mRNA by 90% and 70%, respectively. LPG also inhibited tumor necrosis factor alpha and Staphylococcus induction of IL-1 beta gene expression. The inhibitory effect of LPG is agonist-specific because LPG did not suppress the induction of IL-1 beta mRNA by phorbol 12-myristate 13-acetate. A unique DNA sequence located within the -310 to -57 nucleotide region of the IL-1 beta promoter was found to mediate LPG's inhibitory activity. The requirement for the -310 to -57 promoter gene sequence for LPG's effect is demonstrated by the abrogation of LPG's inhibitory activity by truncation or deletion of the -310 to -57 promoter gene sequence. Furthermore, the minimal IL-1 beta promoter (positions -310 to +15) mediated LPG's inhibitory activity with dose and kinetic profiles that were similar to LPG's suppression of steady-state IL-1 beta mRNA. These findings delineated a promoter gene sequence that responds to LPG to act as a 'gene silencer', a function, to our knowledge, not previously described. LPG's inhibitory activity for several mediators of inflammation and the persistence of significant inhibitory activity 2 h after endotoxin challenge suggest that LPG has therapeutic potential and may be exploited for therapy of sepsis, acute respiratory distress syndrome, and autoimmune diseases
— id: 15400, year: 1996, vol: 93, page: 14708, stat: Journal Article,

Transforming growth factor-beta (TGF-beta) in silicosis
Jagirdar J; Begin R; Dufresne A; Goswami S; Lee TC; Rom WN
1996 Oct;154(4 Pt 1):1076-1081, American journal of respiratory & critical care medicine
Silicosis is characterized by fibrosing nodular lesions that may eventually develop into progressive massive fibrosis (PMF). Cytokines (interleukin-1beta [IL-1beta], tumor necrosis factor-alpha [TNF-alpha] and growth factors insulin-like growth factor-1 [IGF-1] platelet-derived growth factor [PDGF]) have been implicated in the formation of these lesions. TGF-beta promotes extracellular matrix accumulation by upregulating collagen and fibronectin gene expression, and inhibits matrix degradation by decreasing secretion of proteases and increasing secretion of protease inhibitors. We hypothesized that TGF-beta is associated with matrix deposition and fibrosis in silicosis. To test this hypothesis we studied early and late nodular lesions and PMF (11 cases and two controls) with immunohistochemistry, using rabbit polyclonal antibody to the purified whole molecule of TGF-beta in Bouin's fixed lung tissue. This antibody is reactive with both intra- and extracellular forms of TGF-beta. In the control lungs, small amounts of TGF-beta were present in the bronchial epithelium, macrophages, bronchial and vascular smooth muscle, and bronchial glands. There was minimal to moderate staining in the early silicotic peribronchiolar lesions. In the nodular lesions of silicosis, central hyalinized areas contained the maximum staining for TGF-beta. Fibroblasts in the periphery of the nodular lesions were also positive. In acute silicosis, there was marked staining of hyperplastic alveolar epithelium. Macrophages were markedly positive. In the PMF lesions, large areas of scar tissue contained TGF-beta. These data suggest a major role for TGF-beta in silicosis, particularly in the formation of silicotic nodules and the development of PMF
— id: 12531, year: 1996, vol: 154, page: 1076, stat: Journal Article,

Cell cycle regulation in lung carcinoma: Correlation between cyclin kinase inhibitor p21, p53 and proliferation
Kaplan, P; Kim, J; Lee, TC; Rom, W; Jagirdar, J
1996 ;74(Suppl 1):922-922, Laboratory investigation
— id: 53088, year: 1996, vol: 74, page: 922, stat: Journal Article,

Biomarkers of lung inflammation in recreational joggers exposed to ozone
Kinney PL; Nilsen DM; Lippmann M; Brescia M; Gordon T; McGovern T; El-Fawal H; Devlin RB; Rom WN
1996 Nov;154(5):1430-1435, American journal of respiratory & critical care medicine
Humans exhibit an acute inflammatory response in the lungs after controlled laboratory exposure to ozone. The present study was designed to test whether biomarkers of inflammation are detectable in humans exposed to ozone and associated copollutants under natural conditions outdoors. Bronchoscopy with bronchoalveolar lavage (BAL) was carried out on 19 normal volunteer joggers from Governors Island, NY, who exercised in the afternoon during the 1992 summer (S1) season. Fifteen subjects were retested during the following, low ozone, winter season (W). The BAL protocol involved an initial instillation of 20 ml saline followed by four sequential 50-ml saline washes carried out in both the right middle lobe and the lingula. The eight 50-ml samples were pooled as the 'alveolar' sample. Analyses performed on the alveolar lavage samples included cell differentials, release of IL-8, TNF-alpha, and reactive oxygen species (ROS) by pooled cells, and levels of IL-8, protein, LDH, fibronectin, alpha1-antitrypsin (alpha1-AT), complement fragment 3a (C3a), and prostaglandin E2 (PGE2) in lavage fluids. Release of ROS by stimulated BAL cells was lower in S1 than in W (p = 0.03). In contrast, LDH levels in BAL fluids were 2-fold higher in S1 than in W (p = 0.02), as were IL-8 (p = 0.12) and PGE2 (p = 0.06). These results suggest a possible ongoing inflammatory response in the lungs of recreational joggers exposed to ozone and associated copollutants during the summer months
— id: 12497, year: 1996, vol: 154, page: 1430, stat: Journal Article,

Increased release of interleukin-1 beta, interleukin-6, and tumor necrosis factor-alpha by bronchoalveolar cells lavaged from involved sites in pulmonary tuberculosis
Law K; Weiden M; Harkin T; Tchou-Wong K; Chi C; Rom WN
1996 Feb;153(2):799-804, American journal of respiratory & critical care medicine
Mycobacterium tuberculosis and its components have been shown to stimulate mononuclear phagocytes in vitro to release interleukin-1 beta (IL-1 beta), tumor necrosis factor-alpha (TNF-alpha), and interleukin-6 (IL-6). Animal models of tuberculosis (TB) also demonstrate the presence of cytokines in granulomas. We hypothesized that bronchoalveolar lavage (BAL) cells from patients with pulmonary TB would have increased spontaneous release of IL-1 beta, IL-6, and TNF-alpha and would have a concomitant alveolitis. We performed BAL on 26 patients with active TB and on six normal volunteers. BAL fluid from radiographically involved and uninvolved sites was evaluated separately for cell types and the spontaneous release of cytokines. The alveolar inflammation in involved sites was characterized by an increase in lymphocytes (miliary TB, 38 +/- 10%; involved sites, 22 +/- 4%; uninvolved sites, 13 +/- 2%; normal, 5 +/- 2%) and neutrophils (involved sites, 21 +/- 7%; uninvolved sites, 3 +/- 2%). There was a significant increase in the spontaneous release of IL-1 beta (501 +/- 280 pg/ml), TNF-alpha (782 +/- 165 pg/ml), and IL-6 (473 +/- 157 pg/ml) from involved sites of TB patients that was 5- to 20-fold greater than uninvolved sites, normal controls, or miliary TB. Northern analysis revealed increased gene expression of IL-1 beta, TNF-alpha, and IL-6 from the involved sites from two patients with TB compared with two negative controls. We conclude that BAL cells, especially alveolar macrophages, are activated in the alveolar inflammation of active TB and spontaneously release increased quantities of IL-1 beta, IL-6, and TNF-alpha, and that these cytokines are likely to be involved in directing granuloma formation and control of M. tuberculosis infection
— id: 8003, year: 1996, vol: 153, page: 799, stat: Journal Article,

Tuberculosis in HIV-positive patients: cellular response and immune activation in the lung
Law KF; Jagirdar J; Weiden MD; Bodkin M; Rom WN
1996 Apr;153(4 Pt 1):1377-1384, American journal of respiratory & critical care medicine
The host response to Mycobacterium tuberculosis is dependent on the accumulation and activation of cytotoxic and memory CD4+ T cells, resulting in granuloma formation and delayed type hypersensitivity. We characterized the cellular response of radiographically involved lung segments from 17 HIV-positive and 11 HIV-negative patients with acute tuberculosis (TB) using bronchoalveolar lavage (BAL) and compared the response to uninvolved segments, normal control subjects and peripheral blood. In both HIV-positive and HIV-negative patients, radiographically involved segments had significantly increased numbers of total cells per milliliter, percent of neutrophils recovered, and percent of lymphocytes recovered compared with uninvolved segments or normal control subjects, but HIV-positive patients had a lower proportion of lymphocytes in the involved segments than HIV-negative patients with tuberculosis (19 +/- 5% versus 33 +/- 5%; p < 0.05). Lymphocyte subset analysis demonstrated that HIV-positive patients had markedly reduced percentages of CD4+ lymphocytes (CD4+ lymphocytes in HIV-positive TB involved site 25 +/- 6%; HIV-negative TB involved site 73 +/- 2%; p < 0.01) and an increase in the percentage of CD8+ lymphocytes (HIV positive involved site 61 +/- 6% versus HIV negative involved site 19 +/- 3%; p < 0.01). Immunohistochemistry of lung biopsy tissue in five HIV-negative patients showed similar lymphocyte subset profiles as BAL, indicating that BAL reflects cell populations in tissue granulomas. BAL lymphocytes from four HIV-positive and four HIV-negative tuberculosis patients demonstrated immune activation by staining with a murine antibody to TIA-1, a cytoplasmic protein associated with cytotoxicity and apoptosis (HIV positive 48 +/- 6%, HIV negative 31 +/- 7%, normals 11 +/- 5%). Steady state mRNA for gamma-interferon was decreased in four HIV-positive patients when compared with four HIV-negative patients. IL-8 production was comparable in HIV-negative and HIV-positive patients with focal disease but reduced in two patients with miliary tuberculosis. We conclude that HIV-positive patients with+ tuberculosis have a reduced enrichment and activation of immune cells in the lung, and this failure of a CD4+ alveolitis limits an effective immune response
— id: 6926, year: 1996, vol: 153, page: 1377, stat: Journal Article,

Spinal tuberculosis in patients with human immunodeficiency virus infection: clinical presentation, therapy and outcome
Leibert E; Schluger NW; Bonk S; Rom WN
1996 Aug;77(4):329-334, Tubercle & lung disease
SETTING: Bellevue Hospital, a large public hospital in New York City. OBJECTIVE: To discern the clinical characteristics of spinal tuberculosis (Pott's disease) in patients with the human immunodeficiency virus (HIV). DESIGN: Review of all cases of spinal tuberculosis seen at the hospital from 1988 to 1995, with comparison of HIV-positive and HIV-negative cases. Chart reviews for all cases were performed and information regarding signs and symptoms, neurological findings, laboratory and radiographic data, medical and surgical treatment and eventual outcome were recorded. RESULTS: We collected 26 cases of tuberculosis of the spine between July 1988 and June 1995. Seven of our 26 patients (27%) were HIV seropositive. Six of these were PPD+ on presentation. When compared with HIV-negative patients, those with HIV and spinal tuberculosis had similar clinical presentations; most patients had a diagnosis made with percutaneous needle aspiration biopsy of clinically involved areas, and open procedures added little diagnostic information. Most were treated without surgery, and response to antituberculosis therapy was uniformly good. CONCLUSION: We conclude that clinical presentations of spinal tuberculosis are similar in HIV-positive and -negative patients, and good outcomes can be expected with regard to mycobacterial disease
— id: 12570, year: 1996, vol: 77, page: 329, stat: Journal Article,

Latency-associated peptide (LAP), which binds and confers latency upon transforming growth factor-beta (TGF-beta), is a substrate for protein kinase C and thrombin-stimulated platelet kinase(s)
Munger, JS; Harpel, JG; Rom, WN; Rifkin, DB
1996 MAR ;44(3):A231-A231, Journal of investigative medicine
— id: 52943, year: 1996, vol: 44, page: A231, stat: Journal Article,

Inducible nitric oxide synthase in pulmonary alveolar macrophages from patients with tuberculosis
Nicholson, S; BoneciniAlmeida, MDG; Silva, JRLE; Nathan, C; Xie, QW; Mumford, R; Weidner, JR; Calaycay, J; Geng, J; Boechat, N; Linhares, C; Rom, W; Ho, JL
1996 MAY 1 ;183(5):2293-2302, Journal of experimental medicine
The high-output pathway of nitric oxide production helps protect mice from infection by several pathogens, including Mycobacterium tuberculosis. However, based on studies of cells cultured from blood, it is controversial whether human mononuclear phagocytes can express the corresponding inducible nitric oxide synthase (iNOS; NOS2). The present study examined alveolar macrophages tired directly after bronchopulmonary lavage. An average of 65% of the macrophages from 11 of 11 patients with untreated, culture-positive pulmonary tuberculosis reacted with an antibody documented herein to be monospecific for human NOS2. In contrast, a mean of 10% of bronchoalveolar lavage cells were positive from each of five clinically normal subjects. Tuberculosis patients' macrophages displayed diaphorase activity in the same proportion that they stained for NOS2, under assay conditions wherein die diaphorase reaction was strictly dependent on NOS2 expression. Bronchoalveolar lavage specimens also contained NOS2 mRNA. Thus, macrophages in the lungs of people with clinically active Mycobacterium tuberculosis infection often express catalytically competent NOS2
— id: 52898, year: 1996, vol: 183, page: 2293, stat: Journal Article,

Outcome of MDR-TB patients, 1983-1993. Prolonged survival with appropriate therapy
Park MM; Davis AL; Schluger NW; Cohen H; Rom WN
1996 Jan;153(1):317-324, American journal of respiratory & critical care medicine
We analyzed the clinical and laboratory findings and outcome of 173 patients hospitalized at our institution from 1983 to 1994 with multidrug-resistant tuberculosis (MDR-TB) and evaluated outcome. The 173 patients (mean age 40 +/- 1 yr) were predominantly male (92%), African American or Hispanic (80%), and mostly undomiciled. Over half (52%) were known to be HIV-infected. HIV-positive MDR-TB patients had significantly more pulmonary and constitutional symptoms, more extrapulmonary disease, and fewer cavitary lesions on chest radiographs. Fifty-five percent of the patients in the cohort have died; mortality was significantly greater for HIV-positive than HIV-negative (72% versus 20%, p < 0.01). The median duration of survival of MDR-TB patients was 22 +/- 1 mo. Overall, extrapulmonary involvement was a risk factor for shorter survival, while a cavitary lesion on initial chest film and institution of appropriate treatment were positive predictors of survival. In HIV+ patients, only appropriate therapy was associated with prolonged survival (median of 14.1 mo). Interestingly, there was a trend toward better outcome in the first half of the decade reviewed. We conclude that although mortality from MDR-TB is high in both HIV-positive and HIV-negative patients, institution of appropriate therapy is the factor most strongly associated with a favorable outcome. Development of new diagnostic and therapeutic strategies for MDR-TB are urgently needed
— id: 12698, year: 1996, vol: 153, page: 317, stat: Journal Article,

Review: pneumothorax in patients with AIDS-related Pneumocystis carinii pneumonia
Pastores SM; Garay SM; Naidich DP; Rom WN
1996 Nov;312(5):229-234, American journal of the medical sciences
A retrospective review was performed to describe the clinical characteristics, course, and outcome of pneumothorax for all patients admitted to Bellevue Hospital, New York, with AIDS who had Pneumocystis carinii pneumonia (PCP) diagnosed between January 1985, through July 1991. Of 1360 patients with AIDS and PCP, 67 patients (4.9%) were identified with pneumothorax; a group of 50 is the subject of this review. Of these 50 patients, 22 patients (44%) developed spontaneous pneumothorax, 15 patients (30%) developed pneumothorax during mechanical ventilation, and 13 patients (26%) had pneumothorax after an invasive procedure. Of the 22 patients with spontaneous pneumothorax, 8 had cystic parenchymal abnormalities on the chest radiograph and 6 had a history of PCP. The majority of patients were treated with tube thoracostomy and/or surgical intervention. All 15 patients who developed pneumothorax during mechanical ventilation died. Results of pathologic studies revealed varying degrees of interstitial inflammation and fibrosis interspersed with areas of hemorrhage and necrosis, and presence of P carinii cysts. Autopsy specimens obtained in two cases demonstrated multiple parenchymal cavities and evidence of an alveolar eosinophilic exudate with P carinii organisms. Spontaneous pneumothorax in patients with AIDS usually occurs in association with PCP and is associated with significant morbidity. Patients at risk include those with cystic lesions on chest radiograph and those patients with a history of PCP. Patients with AIDS and PCP who develop pneumothorax during mechanical ventilation have a poor outcome
— id: 12507, year: 1996, vol: 312, page: 229, stat: Journal Article,

Prospects for a tuberculosis vaccine
Rom, William N
Tuberculosis Boston : Little Brown, 1996,
— id: 4865, year: 1996, vol: , page: ?, stat: Chapter,

Tuberculosis
Rom, William N.; Garay, Stuart M
Boston : Little, Brown, c1996,
— id: 520, year: 1996, vol: , page: , stat: ,

Firefly luciferase for tuberculosis diagnosis
Rom, William N; Jacobs, William R, Jr.
Tuberculosis Boston : Little Brown, 1996,
— id: 4832, year: 1996, vol: , page: ?, stat: Chapter,

Potential new therapies for tuberculosis
Rom, William N; Kinney, Dennis
Tuberculosis Boston : Little Brown, 1996,
— id: 4864, year: 1996, vol: , page: ?, stat: Chapter,

Design and support for national tuberculosis programs
Rom, William N; O'Brien, Richard; Spinaci, Sergio
Tuberculosis Boston : Little Brown, 1996,
— id: 4867, year: 1996, vol: , page: ?, stat: Chapter,

Multidrug-resistant tuberculosis in children: two cases and a review of the literature
Schluger NW; Lawrence RM; McGuiness G; Park M; Rom WN
1996 Feb;21(2):138-142, Pediatric pulmonology
— id: 12649, year: 1996, vol: 21, page: 138, stat: Journal Article,

Principles of therapy of tuberculosis in the modern era
Schluger, Neil W; Harkin, Timothy J; Rom, William N
Tuberculosis Boston : Little Brown, 1996,
— id: 4855, year: 1996, vol: , page: ?, stat: Chapter,

Novel form of p21(WAF1/CIP1/SDI1) protein in phorbol ester-induced G2/M arrest
Tchou WW; Rom WN; Tchou-Wong KM
1996 Nov 22;271(47):29556-29560, Journal of biological chemistry
Cell cycle progression requires activation of different cyclin-dependent kinases (CDKs) which are positively regulated by cyclins and negatively regulated by CDK inhibitors. Growth inhibition of the Calu-1 lung carcinoma cells induced with the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA), a potent activator of protein kinase C, is associated with G2/M arrest and induction of expression of a novel, faster-migrating form of p21(WAF1/CIP1/SDI1) (p21) protein, an inhibitor of cyclin-dependent kinases. This faster-migrating p21 protein was also expressed in TPA-treated A549 lung carcinoma cells which also exhibited G2/M arrest but not in TPA-treated U937 leukemia cells, which only expressed a slower-migrating form of p21 protein. However, reverse transcriptase-polymerase chain reaction and Southern analysis demonstrated no evidence of novel splice in TPA-treated Calu-1 cells. On the other hand, immunoblotting analysis demonstrated that the faster-migrating p21 protein could be detected only by peptide antibody directed against the N terminus but not the C terminus, suggestive of truncation of the latter or protein modification that results in the loss of the C-terminal epitope. Correlation of G2/M arrest with expression of the faster-migrating p21 protein suggests that this novel form of p21 protein may be a mediator of G2/M arrest and growth inhibition
— id: 12469, year: 1996, vol: 271, page: 29556, stat: Journal Article,

Enhanced insulin-like growth factor molecules in idiopathic pulmonary fibrosis
Aston C; Jagirdar J; Lee TC; Hur T; Hintz RL; Rom WN
1995 May;151(5):1597-1603, American journal of respiratory & critical care medicine
Idiopathic pulmonary fibrosis (IPF) is characterized by activated alveolar macrophages (AM), alveolar epithelial cell proliferation and interstitial matrix, and immune complex deposition. Spontaneous release of competence and progression-type growth factors and their associated binding proteins may contribute to the pathologic features of IPF. To study the role of insulin-like growth factor (IGF) molecules in IPF we evaluated spontaneous release of IGF-I and IGFBP-3 in bronchoalveolar lavage cells from control subjects and from patients with IPF. IGF-I levels were similar compared with those in control subjects. In contrast, IGFBP-3 was significantly increased in IPF. In situ hybridization of open lung biopsies showed IGF-I to be abundant in IPF lung tissue in alveolar macrophages, interstitial mesenchymal cells, and epithelial cells. Northern, Western ligand blotting, reverse transcription PCR, and radioimmunoassay suggested that immune complexes stimulate expression of IGFBP-3 in mononuclear phagocytes in a time- and dose-dependent manner bearing strong similarities to stimulation by LPS. These data are compatible with the hypothesis that IGFBP-3 increases the bioactivity of IGF-I derived from a variety of lung tissues contributing to the fibrosis and remodeling seen in IPF
— id: 6569, year: 1995, vol: 151, page: 1597, stat: Journal Article,

Increased prevalence of K-ras oncogene mutations in lung adenocarcinoma
Mills NE; Fishman CL; Rom WN; Dubin N; Jacobson DR
1995 Apr 1;55(7):1444-1447, Cancer research
Reported estimates of ras mutation prevalence in lung adenocarcinoma of 15-24% may be underestimates because of the insensitivity of the assays used. We have devised a rapid, non-radioactive assay for ras mutations, which detects 1 mutant allele/10(3) normal alleles and have used it to study DNA isolated from 53 lung tumor samples (including 28 adenocarcinomas) previously analyzed by PCR/allele specific oligonucleotide hybridization, which is less sensitive. We detected mutations in 13 of 28 samples, including 7 not detected by PCR/allele specific oligonucleotide hybridization. We also found ras mutations in 14 of 25 previously unstudied samples (56%). Our results indicate that the prevalence of K-ras codon 12 mutations in lung adenocarcinoma is higher than previously reported; thus, ras mutations may be more clinically useful as molecular markers for lung cancer than has been appreciated
— id: 56686, year: 1995, vol: 55, page: 1444, stat: Journal Article,

Detection of K-ras oncogene mutations in bronchoalveolar lavage fluid for lung cancer diagnosis
Mills NE; Fishman CL; Scholes J; Anderson SE; Rom WN; Jacobson DR
1995 Jul 19;87(14):1056-1060, Journal of the National Cancer Institute
BACKGROUND: Lung cancer is the leading cause of cancer deaths in the United States. A long-standing goal of cancer researchers has been to develop tests that would facilitate earlier diagnosis and treatment of lung cancer and thereby decrease mortality from this disease. Because cancer results from the accumulation of a variety of genetic events (e.g., mutations, rearrangements, and deletions) in genes controlling cell growth and differentiation, these changes might serve as diagnostically useful molecular markers. Activation of the K-ras oncogene by point mutations in codon 12, which occurs in many cases of lung adenocarcinoma, may serve as one such clinically useful molecular marker. For detection of K-ras point mutations in bronchoalveolar lavage fluid, in which small numbers of malignant cells are mixed with a population of predominantly genetically normal cells, the sensitivity of commonly used assays for ras mutations risks false-negative results. PURPOSE: By applying a highly sensitive assay, we investigated whether detection of K-ras codon 12 mutations in samples of bronchoalveolar lavage fluid could be clinically useful in diagnosing lung cancer. METHODS: We developed a highly sensitive assay for detecting K-ras codon 12 mutations based on an enriched polymerase chain reaction (PCR) technique. This technique was applied to 87 specimens of bronchoalveolar lavage fluid specimens that were obtained from 86 patients, and associated tumor biopsy specimens obtained from 35 of these patients who underwent diagnostic bronchoscopy for clinically suspected lung cancer. Statistical comparisons were performed by using the two-tailed Fisher's exact test [corrected]. RESULTS: Of 52 patients with confirmed lung cancer, samples of bronchoalveolar lavage fluid from 16 patients contained K-ras codon 12 mutations, including 14 (56%) of 25 patients with lung adenocarcinomas, one (33%) of three with bronchoalveolar carcinomas, one (20%) of five with large-cell carcinomas, and none of the 14 with squamous cell carcinomas. Mutations were detected in four additional cases in which cancer was suspected but had not been histologically confirmed. Tissue samples from 35 of the patients all yielded the identical K-ras codon 12 genotype found in the corresponding samples of bronchoalveolar lavage fluid. No mutation was found in any sample from 30 patients with diagnoses other than non-small-cell lung cancer. Thus, for those cases in which tissue was available and tested, the sensitivity and specificity of detecting K-ras mutations in bronchoalveolar lavage fluid for diagnosing K-ras mutation-positive lung cancer were both 100%. For nine patients, K-ras mutations were detected in bronchoalveolar lavage fluid obtained during otherwise nondiagnostic bronchoscopies. CONCLUSIONS: Our data demonstrate that sensitive detection of K-ras codon 12 mutations can serve as an important adjunct to cytology in the diagnosis of lung cancer. IMPLICATIONS: Detection of these mutations could lead to earlier cancer diagnosis and less need for invasive diagnostic procedures
— id: 56489, year: 1995, vol: 87, page: 1056, stat: Journal Article,

Low copy number and limited variability of proviral DNA in alveolar macrophages from HIV-1-infected patients: evidence for genetic differences in HIV-1 between lung and blood macrophage populations
Nakata K; Weiden M; Harkin T; Ho D; Rom WN
1995 Nov;1(7):744-757, Molecular medicine
BACKGROUND: We investigated the human immunodeficiency virus (HIV) proviral DNA sequence and copy number in alveolar macrophages (AM) and peripheral blood monocytes (PBM) from 10 HIV-positive patients without any active concurrent pulmonary disease to understand the nature of HIV-1 infection in vivo in the lung microenvironment. MATERIALS AND METHODS: The 10 seropositive patients without active pulmonary disease were selected based on chest roentegenography and pathological/cytological test of bronchoalveolar (BAL) fluid. In order to determine accurate proviral copy numbers, AM and PBM were isolated to 99 and 94% purity, respectively, and quantitative polymerase chain reaction (PCR), with a sensitivity to detect three copies of HIV proviral DNA per 10(5) cells, was applied. For analysis of genetic variation in HIV-1, PCR-amplified HIV-1 DNA from AM and PBM of five patients were subcloned and 2-12 clones from each sample underwent DNA sequence analysis of HIV-1 gp120 V3-V5. Heteroduplex mobility assays were performed to confirm the results of the sequence analysis. RESULTS: The proviral copy number in AM or PBM were less than 20 copies/10(5) cells in all patients, and five patients had less than the detection limit. There was no significant difference in HIV copy number between AM and PBM. No correlation was found between PBM/AM HIV copy number and CD4+ lymphocyte count in the peripheral blood. Sequence analysis revealed that the mean intrapatient genetic similarity in AM was 97.5 +/- 0.18% (n = 107), which was significantly higher than that in PBM (96.2 +/- 0.26% (n = 94), p < 0.001), suggesting that variability of HIV-1 DNA in AM was relatively limited. Divergence occurred when AM derived HIV-1 sequence was compared with PBM derived sequence from the same patient (95.8 +/- 0.17% (n = 223) p < 0.001). Phylogenetic analysis of DNA sequence demonstrated complete separation of HIV lineages from lung and blood in four of five patients. CONCLUSIONS: The results suggest the HIV-1 infection in AM is restricted in vivo with low viral burden and homogenous genotype. We propose that the pulmonary microenvironment may limit the extent of HIV-1 infection
— id: 7024, year: 1995, vol: 1, page: 744, stat: Journal Article,

LIMITED VARIABILITY AND COPY NUMBER OF HIV-1 IN HUMAN ALVEOLAR MACROPHAGES
NAKATA, K; WEIDEN, M; HARKIN, T; HO, D; ROM, WN
1995 APR 2 ;54(3):241-241, Journal of cellular biochemistry
— id: 87325, year: 1995, vol: 54, page: 241, stat: Journal Article,

Human host response to Mycobacterium tuberculosis
Rom WN; Schluger N; Law K; Condos R; Zhang Y; Weiden M; Harkin T; Tchou-Wong KM
1995 Nov 11;125(45):2178-2185, Schweizerische medizinische wochenschrift = Journal suisse de medecine
Despite the importance of tuberculosis as the leading cause of death due to infectious disease in the world, it has only been recently that an understanding of the human host response in this infection has begun to emerge. The key components of this response are cytokines and components of cellular immunity, predominantly T-lymphocytes and macrophages. Though the relationships among the components of the immune response are complex, it seems likely that in response to mycobacterial infection associated with active disease, cytokines such as TNF-alpha and IL-1 beta are produced; these cytokines serve to recruit more lymphocytes, generally of the T(H) (T helper) phenotype, which then produces substances such as the macrophage activating factor interferon-gamma. Macrophages activated by IFN-gamma ar thus stimulating to enhance intracellular killing of mycobacteria. The role of other cytokines, such as IL-6 and IL-8, both of which are induced by M. tuberculosis or its cell was components, is less clear. Further elucidation of the human host response to tuberculosis should help in the development of new vaccines and treatment strategies
— id: 12714, year: 1995, vol: 125, page: 2178, stat: Journal Article,

Comprehensive tuberculosis control for patients at high risk for noncompliance
Schluger N; Ciotoli C; Cohen D; Johnson H; Rom WN
1995 May;151(5):1486-1490, American journal of respiratory & critical care medicine
The current tuberculosis epidemic in the United States is marked, in many areas, by high rates of noncompliance with antituberculous regimens. In response to this, a comprehensive program of medical, nursing, social services, and supervised therapy was developed at Bellevue Hospital. Most patients were referred to the on-site directly observed therapy program (DOT) located in the hospital. Patients on DOT received daily or twice weekly therapy, and were given incentives to enhance compliance. Outreach was used to track patients who missed appointments. From November 1992 through July 1993, 113 patients were referred. HIV infection, homelessness, illicit drug use, and alcoholism were common. Follow-up revealed that 11 patients were noncompliant and completely lost to follow-up; of the remaining 102, 99% achieved bacteriologic cure. Of the 102 patients who received therapy, 74 attended the Bellevue DOT clinic, 16 attended other DOT programs in the city or received medication at home, and three died of HIV-related, nontuberculous illness. Nine patients were self-medicated and judged treatment successes. We conclude that a comprehensive hospital-based tuberculosis control program is capable of achieving a high degree of success, even in a population at high risk for noncompliance
— id: 6744, year: 1995, vol: 151, page: 1486, stat: Journal Article,

The polymerase chain reaction in the diagnosis and evaluation of pulmonary infections
Schluger NW; Rom WN
1995 Jul;152(1):11-16, American journal of respiratory & critical care medicine
One of the most heralded developments in basic science to reach clinical application in recent years has been the polymerase chain reaction (PCR). This technique of DNA amplification, which has already had an enormous effect on the way in which molecular biology research is done (and whose inventor, Kary Mullis, was awarded the Nobel Prize in Chemistry in 1993 in recognition of the extraordinary impact of PCR technology on scientific research generally), was quickly appreciated by clinical investigators as having potentially widespread utility in the early diagnosis of a wide range of disorders, such as inherited illnesses and infectious diseases (1). This Commentary will review the application of PCR to the diagnosis and evaluation of respiratory infections. The underlying principle guiding this Commentary is that the ideal diagnostic test for respiratory infectious disease should have the following characteristics: high sensitivity and specificity, high positive and negative predictive value, rapid turnaround time, ease of performance, reliability across samples (the same sample tested repeatedly should give the same result) and across those performing the assay (different laboratories performing the assay on the same specimen will report the same result), and low cost. It is against these criteria that PCR will be measured in this review
— id: 6865, year: 1995, vol: 152, page: 11, stat: Journal Article,

Thalidomide treatment reduces tumor necrosis factor alpha production and enhances weight gain in patients with pulmonary tuberculosis
Tramontana, J M; Utaipat, U; Molloy, A; Akarasewi, P; Burroughs, M; Makonkawkeyoon, S; Johnson, B; Klausner, J D; Rom, W; Kaplan, G
1995 May;1(4):384-397, Molecular medicine
BACKGROUND: The monocyte-derived cytokine, tumor necrosis factor alpha (TNF alpha), is essential for host immunity, but overproduction of this cytokine may have serious pathologic consequences. Excess TNF alpha produced in pulmonary tuberculosis may cause fevers, weakness, night sweats, necrosis, and progressive weight loss. Thalidomide (alpha-N-phthalimidoglutarimide) has recently been shown to suppress TNF alpha production by human monocytes in vitro and to reduce serum TNF alpha in leprosy patients. We have therefore conducted a two-part placebo-controlled pilot study of thalidomide in patients with active tuberculosis to determine its effects on clinical response, immune reactivity, TNF alpha levels, and weight. MATERIALS AND METHODS: 30 male patients with active tuberculosis, either human immunodeficiency virus type 1 positive (HIV-1+) or HIV-1-, received thalidomide or placebo for single or multiple 14 day cycles. Toxicity of the study drug, delayed type hypersensitivity (DTH), cytokine production, and weight gain were evaluated. RESULTS: Thalidomide treatment was well tolerated, without serious adverse events. The drug did not adversely affect the DTH response to purified protein derivative (PPD), total leukocyte, or differential cell counts. TNF alpha production was significantly reduced during thalidomide treatment while interferon-gamma (IFN gamma) production was enhanced. Daily administration of thalidomide resulted in a significant enhancement of weight gain. CONCLUSIONS: The results indicate that thalidomide is well tolerated by patients receiving anti-tuberculosis therapy. Thalidomide treatment reduces TNF alpha production both in vivo and in vitro and is associated with an accelerated weight gain during the study period
— id: 132221, year: 1995, vol: 1, page: 384, stat: Journal Article,

Enhanced interleukin-8 release and gene expression in macrophages after exposure to Mycobacterium tuberculosis and its components
Zhang Y; Broser M; Cohen H; Bodkin M; Law K; Reibman J; Rom WN
1995 Feb;95(2):586-592, Journal of clinical investigation
Mycobacterium tuberculosis infection is accompanied by acute and chronic inflammatory infiltrates associated with necrotizing granulomas in lung tissue. The cellular infiltrate is characterized by inflammatory cells which include neutrophils, lymphocytes, and macrophages. In animal and in vitro models of mycobacterial infection, cytokines including tumor necrosis factor-alpha (TNF-alpha), interferon gamma (IFN-gamma), and interleukin-1 beta (IL-1 beta) participate in granulomatous inflammation. We hypothesized that interleukin-3, a potent chemoattractant for neutrophils and lymphocytes, could be released by activated alveolar macrophages after exposure to M. tuberculosis or its components and contribute to granulomatous lung inflammation. A quantitative immunoassay revealed that IL-8 protein release was significantly elevated in supernatants of macrophages and in lavage fluid obtained from patients with pulmonary tuberculosis compared to normal controls. In addition, Northern blots demonstrated striking up-regulation of IL-8 mRNA in macrophages from these patients. M. tuberculosis and its cell wall components lipoarabinomannan (LAM), lipomannan (LM), and phosphoinositolmannoside (PIM) stimulated IL-8 protein release and mRNA expression in vitro from alveolar macrophages, but deacylated LAM did not. Neutralizing antibodies to TNF-alpha and/or IL-1-alpha and beta blocked 83% of the stimulation. IL-8 synthesis and release is an early response of macrophages after phagocytosis of M. tuberculosis. Its production serves to attract both acute and chronic inflammatory cells of active infection and thus participates in the process of containment of the pathogen
— id: 56733, year: 1995, vol: 95, page: 586, stat: Journal Article,

Mycobacterium tuberculosis enhances human immunodeficiency virus-1 replication by transcriptional activation at the long terminal repeat
Zhang Y; Nakata K; Weiden M; Rom WN
1995 May;95(5):2324-2331, Journal of clinical investigation
Tuberculosis has emerged as an epidemic fueled by the large number of individuals infected with the human immunodeficiency virus, especially those who are injecting drug users. We found a striking increase from 4- to 208-fold in p24 levels in bronchoalveolar lavage fluid from involved sites of Mycobacterium tuberculosis infection vs uninvolved sites in three HIV+ patients. We used an in vitro cell culture model to determine if tuberculosis could activate replication of HIV-1. Mononuclear phagocyte cell lines U937 and THP-1 infected with HIV-1JR-CSF, in vitro and stimulated with live M. tuberculosis H37Ra, had a threefold increase in p24 in culture supernatants. Using the HIV-1 long terminal repeat with a chloramphenicol acetyltransferase (CAT) reporter construct, live M. tuberculosis increased transcription 20-fold in THP-1 cells, and cell wall components stimulated CAT expression to a lesser extent. The nuclear factor-kappa B enhancer element was responsible for the majority of the increased CAT activity although two upstream nuclear factor-IL6 sites may also contribute to enhanced transcription. Antibodies to TNF-alpha and IL-1 inhibited the increase in CAT activity of the HIV-1 long terminal repeat by M. tuberculosis from 21-fold to 8-fold. Stimulation of HIV-1 replication by M. tuberculosis may exacerbate dysfunction of the host immune response in dually infected individuals
— id: 6794, year: 1995, vol: 95, page: 2324, stat: Journal Article,

Endemic tuberculosis among homeless men in New York City
Concato J; Rom WN
1994 Sep 26;154(18):2069-2073, Archives of internal medicine
OBJECTIVES: The purpose of the study was to describe demographic and clinical characteristics of patients at the only long-term care facility for homeless men with tuberculosis in New York City, and to evaluate the outcome of a directly observed therapy program for these men. METHODS: The study population included residents at the 'tuberculosis unit' for men in the New York City municipal shelter system. A cross-sectional survey described the characteristics of 76 men in the unit during November 1991. A retrospective cohort study evaluated 104 consecutive admissions to the facility from October 1, 1990, through March 30, 1991, and determined the outcome of directly observed therapy. RESULTS: Cross-sectional survey (n = 76). The median age was 43 years (range, 25 to 60 years); 67 patients (88%) had pulmonary tuberculosis. Among 58 isolates of Mycobacterium tuberculosis, eight were resistant to one drug (14%) and an additional nine were resistant to at least two drugs (16%). A history of previous treatment was associated with an odds ratio of 5.1 for having multiple drug-resistant tuberculosis (exact 95% confidence interval, 0.8 to 53.5). Retrospective cohort (n = 104). Excluding 21 men whose care was transferred to other agencies or institutions, 39 (47%) of 83 subjects completed or were still receiving treatment after 12 months and 44 (53%) of 83 subjects failed to complete the program. CONCLUSIONS: As expected, previous treatment for tuberculosis among homeless men is associated with an increased risk of having multiple-drug resistance. A directly observed therapy program successfully treated less than half of the enrolled subjects. Increased efforts are needed to control the spread of tuberculosis among homeless individuals
— id: 12891, year: 1994, vol: 154, page: 2069, stat: Journal Article,

Isolation of the gene for the beta subunit of RNA polymerase from rifampicin-resistant Mycobacterium tuberculosis and identification of new mutations
Donnabella V; Martiniuk F; Kinney D; Bacerdo M; Bonk S; Hanna B; Rom WN
1994 Dec;11(6):639-643, American journal of respiratory cell & molecular biology
Tuberculosis (TB) is one of the most important infections worldwide, with an estimated incidence of 10 million active cases per year. Rifampicin is a key component of the first-line therapy used in the treatment of tuberculosis. In Escherichia coli and Mycobacterium leprae, rifampicin has been shown to inhibit the beta subunit of RNA polymerase. The gene (rpoB) encoding this enzyme has been described in both species. We report the isolation of the homologous functional rifampicin resistance gene from M. tuberculosis. A library was constructed with 15 to 25 kb BamHI-digested DNA fragments from a rifampicin-resistant M. tuberculosis clinical isolate that was ligated into an E. coli-mycobacterial shuttle plasmid. Southern analysis of BamHI-digested DNA from 200 recombinant plasmids was performed and filters were hybridized to a 411 bp fragment of the beta subunit of RNA polymerase from M. tuberculosis. Only DNA from one plasmid (#86) hybridized, which suggested that the gene is found as a single copy per genome. This plasmid was able to transfer rifampicin resistance to sensitive M. smegmatis and thus codes for a functional genetic unit. Sequence analysis in the expected 'hotspot' region in eight rifampicin-resistant M. tuberculosis strains (including one multidrug-resistant strain) revealed two novel mutations as well as others previously described
— id: 12859, year: 1994, vol: 11, page: 639, stat: Journal Article,

ALLELIC FREQUENCY AT THE NATURAL-RESISTANCE ASSOCIATED MACROPHAGE PROTEIN (NRAMP) LOCUS FROM PATIENTS AT RISK FOR TB
DONNABELLA, V; LAW, K; BODKIN, M; CHEN, Y; ROM, WN; MARTINIUK, F
1994 APR ;42(2):A187-A187, Clinical research
— id: 52491, year: 1994, vol: 42, page: A187, stat: Journal Article,

EXAGGERATED RELEASE OF IL-1-BETA, IL-6, AND TNF-ALPHA AND INCREASED GENE-EXPRESSION BY ALVEOLAR MACROPHAGES LAVAGED FROM PATIENTS WITH ACTIVE TUBERCULOSIS
LAW, KF; WEIDEN, MD; ROM, WN
1994 APR ;42(2):A301-A301, Clinical research
— id: 52499, year: 1994, vol: 42, page: A301, stat: Journal Article,

Mycobacterium tuberculosis alters expression of adhesion molecules on monocytic cells
Lopez Ramirez GM; Rom WN; Ciotoli C; Talbot A; Martiniuk F; Cronstein B; Reibman J
1994 Jun;62(6):2515-2520, Infection & immunity
The host response to Mycobacterium tuberculosis is characterized by interactions between mononuclear cells, with recruitment and fusion of these cells culminating in granuloma formation. In addition, the host response to M. tuberculosis requires CD4+ T-cell reactivity, mediated by antigen-independent as well as antigen-dependent mechanisms. Thus, we hypothesized that cell adhesion molecules such as intercellular adhesion molecule 1 (ICAM-1; CD54) would participate in the response to infection with M. tuberculosis. Exposure of THP-1 cells derived from a monocyte/macrophage cell line to M. tuberculosis (1:1 bacterium/cell ratio) elicited a sustained increase (660% +/- 49% above resting level) in the expression of ICAM-1 that continued for at least 72 h. Neither the expression of vascular cell adhesion molecule 1 (VCAM-1; CD106) nor that of the integrins lymphocyte function-associated antigen 1 (LFA-1; CD11a/CD18) or CR3 (CD11b/CD18) was increased to a similar extent at corresponding time points. The increase in ICAM-1 protein expression was accompanied by an increase in steady-state mRNA (Northern [RNA] analysis). Neutralizing monoclonal antibodies directed against tumor necrosis factor alpha but not interleukin 1 alpha or interleukin 1 beta substantially abrogated the response to M. tuberculosis consistent with a paracrine or autocrine response. Continuous upregulation of the expression of ICAM-1 on mononuclear phagocytes induced by M. tuberculosis may mediate the recruitment of monocytes and enhance the antigen presentation of M. tuberculosis, thus permitting the generation and maintenance of the host response
— id: 56558, year: 1994, vol: 62, page: 2515, stat: Journal Article,

Hemoptysis: prospective high-resolution CT/bronchoscopic correlation [see comments]
McGuinness G; Beacher JR; Harkin TJ; Garay SM; Rom WN; Naidich DP
1994 Apr;105(4):1155-1162, Chest
The precise roles of fiberoptic bronchoscopy (FOB) and computed tomography (CT) of the chest in the evaluation of patients presenting with hemoptysis have not been clearly defined. On the assumption that both procedures would likely provide unique and complementary information, a prospective study with blinded interpreters using a modified high-resolution CT technique (HRCT) and FOB was designed to evaluate 57 consecutive patients admitted to Bellevue Hospital with hemoptysis. Etiologies included bronchiectasis (25 percent), tuberculosis (16 percent), lung cancer (12 percent), aspergilloma (12 percent), and bronchitis (5 percent): in an additional 5 percent of cases, hemoptysis proved to be due miscellaneous causes, while in 19 percent hemoptysis proved to be cryptogenic. Patients with lung cancer all were at least 50 years old, smoked an average of 78 pack-years, and had less severe hemoptysis but of longer duration. All had conditions diagnosed both by HRCT and FOB. High-resolution CT proved of particular value in diagnosing bronchiectasis and aspergillomas, while FOB was diagnostic of bronchitis and mucosal lesions such as Kaposi's sarcoma. Fiberoptic bronchoscopy localized bleeding in only 51 percent of cases. The high sensitivity of CT in identifying both the intraluminal and extraluminal extent of central lung cancers in conjunction with its value in diagnosing bronchiectasis suggest that CT should be obtained prior to bronchoscopy in all patients presenting with hemoptysis
— id: 6451, year: 1994, vol: 105, page: 1155, stat: Journal Article,

The third epidemic--multidrug-resistant tuberculosis
Neville K; Bromberg A; Bromberg R; Bonk S; Hanna BA; Rom WN
1994 Jan;105(1):45-48, Chest
We recently observed a striking increase in multidrug-resistant tuberculosis (MDR-TB) among patients admitted to the Chest Service at Bellevue Hospital Center in New York. We reviewed the laboratory susceptibility test results of 4,681 tuberculosis (TB) cases over the past 20 years, Combined resistance to isoniazid and rifampin increased from 2.5 percent in 1971 to 16 percent in 1991 with higher rates noted for individual drugs. We reviewed the medical records of 100 patients with drug-resistant TB, finding that these individuals were predominantly less than 40 years of age, minority, male, jobless, undomiciled, with a high percentage of drug abuse and human immunodeficiency virus infection. We conclude that the epidemics of AIDS and TB are complicated by a third epidemic of MDR-TB. This third epidemic requires urgent attention to achieve more rapid diagnosis, to develop new therapeutic regimens, and to address the social and hospital environment ot care for these individuals
— id: 6466, year: 1994, vol: 105, page: 45, stat: Journal Article,

Pleural tuberculosis and HIV infection [see comments]
Relkin F; Aranda CP; Garay SM; Smith R; Berkowitz KA; Rom WN
1994 May;105(5):1338-1341, Chest
Human immunodeficiency virus infection changes the clinical presentation of tuberculosis infection with atypical radiographs and more common extra-pulmonary involvement. We retrospectively studied pleural tuberculosis in HIV-positive patients over a 5-year period. We identified 70 patients with pleural tuberculosis by positive Mycobacterium tuberculosis cultures of pleural fluid and/or pleural tissue, including 43 HIV-positive and 27 HIV-negative patients. The HIV-positive patients were significantly younger (mean age, 38 +/- 1 years in HIV-positive vs 52 +/- 3 years in HIV-negative patients, p < 0.05). There were more intravenous drug abusers in the HIV-positive group (74 vs 30 percent, p < 0.01). The HIV-positive group had significantly fewer positive tuberculin skin tests (41 percent vs 76 percent, p < 0.03). Both groups had similar pleural fluid cellularity and pleural biopsy histologic conditions, but the HIV-positive patients demonstrated significantly more acid-fast bacteria identifiable in pleural tissue (69 percent vs 21 percent, p < 0.01), and a higher incidence of positive M tuberculosis cultures of sputum (53 percent vs 23 percent, p = 0.02). Pleural tuberculosis in HIV-positive patients presented more often as a manifestation of a greater burden of microorganisms and impaired host response
— id: 6493, year: 1994, vol: 105, page: 1338, stat: Journal Article,

Amplification of DNA of Mycobacterium tuberculosis from peripheral blood of patients with pulmonary tuberculosis
Schluger NW; Condos R; Lewis S; Rom WN
1994 Jul 23;344(8917):232-233, Lancet
Sputum examination for rapid diagnosis of pulmonary tuberculosis is not always satisfactory. We examined peripheral blood with the polymerase chain reaction (PCR). Blood samples were collected from 8 consecutive patients with suspected pulmonary tuberculosis and from 18 healthy controls, half of whom were tuberculin skin-test positive. All 8 patients had evidence of circulating Mycobacterium tuberculosis DNA in the lymphocyte fraction of peripheral blood, and positive sputum cultures indicating active pulmonary tuberculosis. None of the healthy controls had positive PCR results. This PCR technique may prove useful for the rapid diagnosis of tuberculosis
— id: 56708, year: 1994, vol: 344, page: 232, stat: Journal Article,

Clinical utility of the polymerase chain reaction in the diagnosis of infections due to Mycobacterium tuberculosis
Schluger NW; Kinney D; Harkin TJ; Rom WN
1994 Apr;105(4):1116-1121, Chest
OBJECTIVE: To evaluate the clinical utility of the polymerase chain reaction (PCR) in the diagnosis of infections due to Mycobacterium tuberculosis. DESIGN: Clinical specimens were assayed by PCR for the presence of the insertion element IS6110, a DNA sequence unique to the M tuberculosis complex of organisms. The PCR results were then correlated with acid-fast bacilli (AFB) smears, cultures, pathology, and clinical histories. SETTING: Bellevue Hospital, a large municipal teaching hospital. PATIENTS: Inpatients on the Bellevue Chest Service. MEASUREMENTS AND RESULTS: Sixty-five patients were evaluated. The PCR for M tuberculosis was positive in 37 patients and negative in 28. When correlated with smears, cultures, pathology, and clinical history, the sensitivity of PCR for a diagnosis of active tuberculosis (TB) was 100 percent. However, the specificity for a diagnosis of active TB was only 70 percent, as the PCR assay was positive in a number of patients with only prior, treated TB, or asymptomatic tuberculous infection. For a diagnosis of any TB infection (active, treated, or asymptomatic), sensitivity of PCR was 87.5 percent and specificity was 90 percent. CONCLUSIONS: The PCR assay for TB is extremely sensitive, but it lacks specificity for a diagnosis of active TB. Its role in clinical practice will likely be limited to well-defined situations, such as HIV-positive patients with intrathoracic adenopathy, and it may be most useful in excluding active TB from consideration in selected patients. Given the cost of the assay and the labor intensity it requires, it should not be part of the routine initial evaluation of patients with suspected pulmonary TB
— id: 6513, year: 1994, vol: 105, page: 1116, stat: Journal Article,

Current approaches to the diagnosis of active pulmonary tuberculosis
Schluger NW; Rom WN
1994 Jan;149(1):264-267, American journal of respiratory & critical care medicine
— id: 6514, year: 1994, vol: 149, page: 264, stat: Journal Article,

THE GENETICS OF MULTIDRUG-RESISTANCE IN MYCOBACTERIUM-TUBERCULOSIS
WEIDEN, MD; ROM, WN; KREISWIRTH, B; DONNABELLA, V; MARTINIUK, F
1994 APR ;42(2):A302-A302, Clinical research
— id: 52500, year: 1994, vol: 42, page: A302, stat: Journal Article,

Activation of the interleukin 6 gene by Mycobacterium tuberculosis or lipopolysaccharide is mediated by nuclear factors NF-IL6 and NF-kappa B
Zhang Y; Broser M; Rom WN
1994 Mar 15;91(6):2225-2229, Proceedings of the National Academy of Sciences of the United States of America
The host response to Mycobacterium tuberculosis includes granuloma formation at sites of infection and systemic symptoms. Cytokines have been identified by immunohistochemistry in granulomas in animal models of bacillus Calmette-Guerin (BCG) infection and are released by mononuclear phagocytes upon stimulation by mycobacterial proteins. In this regard, the cytokine interleukin 6 (IL-6) may play a role in the clinical manifestations and pathological events of tuberculosis infection. We have demonstrated that lipoarabinomannan (LAM) from the mycobacterial cell wall, which was virtually devoid of lipopolysaccharide (LPS), stimulated mononuclear phagocytes to release IL-6 in a dose-response manner. LAM and LPS were potent inducers of IL-6 gene expression in peripheral blood monocytes. Both LAM- and LPS-inducible IL-6 promoter activity was localized to a DNA fragment, positions -158 to -49, by deletion analysis and chloramphenicol acetyltransferase assay. Two nuclear factor NF-IL6 (positions -153 to -145 and -83 to -75) and one nuclear factor NF-kappa B (positions -72 to -63) motifs are present within this fragment. Site-directed mutagenesis of one or more of these motifs within the IL-6 promoter demonstrated that each has positive regulatory activity and that they could act in a function- and orientation-independent manner. Deletion of all three elements abolished inducibility of IL-6 promoter activity by both LAM and LPS. We conclude that the NF-IL6 and NF-kappa B sites mediate IL-6 induction in response to both LPS and LAM, acting as bacterial or mycobacterial response elements
— id: 57404, year: 1994, vol: 91, page: 2225, stat: Journal Article,

THE ROLE OF INSULIN-LIKE GROWTH-FACTOR MOLECULES IN IDIOPATHIC PULMONARY FIBROSIS (IPF)
ASTON, C; LEE, TC; JAGIRDAR, J; HUR, T; HINTZ, RL; ROM, WN
1993 APR ;147(4):A481-A481, American review of respiratory disease
— id: 54158, year: 1993, vol: 147, page: A481, stat: Journal Article,

Bronchogenic carcinoma in young patients at risk for acquired immunodeficiency syndrome
Chan TK; Aranda CP; Rom WN
1993 Mar;103(3):862-864, Chest
Several case reports have suggested that bronchogenic carcinoma occurs more frequently in young patients who are human immunodeficiency virus (HIV) seropositive. We investigated the incidence of bronchogenic carcinoma and its clinical presentations in young patients at risk for HIV infection. The tumor registry of Bellevue Hospital was reviewed, and 261 cases of bronchogenic carcinoma during the period from 1976 to 1979 (pre-AIDS period) and 232 during the period from 1987 to 1990 (AIDS period) were identified. These cases were stratified into age groups: 45 or younger, 46 to 55, 56 to 65, and 66 years or older. All patients aged 45 years or younger in the AIDS period were subdivided by HIV risk, and clinical characteristics were compared among the subgroups. Results revealed no increased incidence of bronchogenic carcinoma from the pre-AIDS period compared with the AIDS period. These results suggest that HIV seropositivity is not a risk factor for bronchogenic carcinoma
— id: 13230, year: 1993, vol: 103, page: 862, stat: Journal Article,

DIRECTLY OBSERVED THERAPY FOR HOMELESS MEN WITH TUBERCULOSIS
CONCATO, J; ROM, WN
1993 APR ;147(4):A917-A917, American review of respiratory disease
— id: 54171, year: 1993, vol: 147, page: A917, stat: Journal Article,

TUBERCULOSIS INFECTIONS AMONG HOUSESTAFF AT BELLEVUE HOSPITAL IN AN EPIDEMIC PERIOD
CONDOS, R; SCHLUGER, N; LACOUTURE, R; ROM, W
1993 APR ;147(4):A124-A124, American review of respiratory disease
— id: 54154, year: 1993, vol: 147, page: A124, stat: Journal Article,

ISOLATION OF THE GENE FOR THE BETA-SUBUNIT OF RNA-POLYMERASE FROM RIFAMPICIN RESISTANT MYCOBACTERIUM-TUBERCULOSIS
DONNABELLA, V; MARTINIUK, F; KINNEY, D; BRESCIA, M; BONK, S; HANNA, B; ROM, WN
1993 APR ;41(2):A196-A196, Clinical research
— id: 54263, year: 1993, vol: 41, page: A196, stat: Journal Article,

TRANSBRONCHIAL NEEDLE ASPIRATION IN THE DIAGNOSIS OF MEDIASTINAL MYCOBACTERIAL INFECTION
HARKIN, TJ; KARP, J; CIOTOLI, C; FISHMAN, C; NAIDICH, DP; GRAAP, W; ROM, WN
1993 APR ;147(4):A801-A801, American review of respiratory disease
— id: 54169, year: 1993, vol: 147, page: A801, stat: Journal Article,

LIPOPHOSPHOGLYCAN FROM LEISHMANIA DONOVANI DOWN-REGULATES IL-1-BETA GENE-EXPRESSION IN THP-1 CELLS
HATZIGEORGIOU, DH; ZHANG, Y; TURCO, S; ROM, WN; HO, JL
1993 APR ;41(2):A322-A322, Clinical research
— id: 54280, year: 1993, vol: 41, page: A322, stat: Journal Article,

TRANSFORMING GROWTH-FACTOR-BETA (TGF-BETA) 1,2,3 IN SHEEP AND HUMAN ASBESTOSIS
JAGIRDAR, J; BEGIN, R; MASSE, S; SAXENA, B; LEE, TC; GOSWANI, S; GOLD, L; ROM, W
1993 ;68(Suppl 1):A132-A132, Laboratory investigation
— id: 54389, year: 1993, vol: 68, page: A132, stat: Journal Article,

Normal human mesothelial cells and mesothelioma cell lines express insulin-like growth factor I and associated molecules
Lee TC; Zhang Y; Aston C; Hintz R; Jagirdar J; Perle MA; Burt M; Rom WN
1993 Jun 15;53(12):2858-2864, Cancer research
Insulin-like growth factor (IGF) I has important growth regulatory functions in normal growth and development. IGF-I is also a mitogen for a number of cancer cell lines; however, its autocrine effect has not been well established. In this study, the expression of IGF-I, its receptor, and its major serum-binding protein were examined in 5 normal human mesothelial (NHM) cell samples and 11 pleural mesothelioma cell lines. All NHM cells and mesothelioma cell lines expressed IGF-I, IGF-binding protein 3 (IGFBP-3), and IGF-I receptor mRNA by either Northern blot or reverse transcription polymerase chain reaction analysis. IGF-I (0.136 +/- 0.024 ng/ml, mean +/- SEM) and IGFBP-3 (18.5 +/- 3.2 ng/ml) proteins were readily detected in the conditioned medium of mesothelioma cell lines but were not greater than corresponding measurements in that of NHM cells (IGF-I, 0.120 +/- 0.080 ng/ml; IGFBP-3, 15.9 +/- 1.3 ng/ml). Exogenous recombinant IGF-I stimulated cell proliferation of NHM cells, demonstrating the presence of a functional IGF-I receptor. Our results suggest that IGF-I may function as an autocrine growth stimulus in normal proliferating mesothelial cells, which may contribute to their malignant transformation
— id: 57504, year: 1993, vol: 53, page: 2858, stat: Journal Article,

THE ROLE OF IGF-I AND TGF-BETA IN A SHEEP MODEL OF ASBESTOSIS
LEE, TC; JAGIRDAR, J; ASTON, C; REIBMAN, J; GOLD, L; BEGIN, R; ROM, WN
1993 APR ;147(4):A758-A758, American review of respiratory disease
— id: 54167, year: 1993, vol: 147, page: A758, stat: Journal Article,

TRANSFORMING GROWTH-FACTOR-BETA (TGF-BETA) ISOFORMS IN ASBESTOS-RELATED DISEASES
LEE, TC; JAGIRDAR, J; REIBMAN, J; GOLD, L; ASTON, C; BEGIN, R; ROM, WN
1993 APR ;147(4):A759-A759, American review of respiratory disease
— id: 54168, year: 1993, vol: 147, page: A759, stat: Journal Article,

Intrathoracic adenopathy associated with pulmonary tuberculosis in patients with human immunodeficiency virus infection
Pastores SM; Naidich DP; Aranda CP; McGuinnes G; Rom WN
1993 May;103(5):1433-1437, Chest
The role of computed tomography (CT) in the diagnosis of mediastinal tuberculous lymphadenitis was evaluated retrospectively in 25 human immunodeficiency virus (HIV)-infected patients (19 had AIDS). In all cases, the diagnosis of tuberculosis was established by mycobacterial culture and/or histologic evaluation. The most characteristic CT finding was the presence of low-density mediastinal and hilar lymph nodes in 16 of 19 (84 percent) patients with AIDS and four of six (67 percent) HIV-seropositive patients without AIDS. Marked enhancement of the periphery of nodes was identified in five cases, all in patients with documented AIDS. In most cases, lymphadenopathy proved to be massive, presenting as extensive, heterogenous soft-tissue lesions, presumably the result of coalescence of groups of matted nodes. We conclude that low-density mediastinal and/or hilar lymph nodes on CT, while not pathognomonic, is sufficiently characteristic for tuberculosis to warrant empiric antituberculosis therapy pending results of cultures
— id: 15402, year: 1993, vol: 103, page: 1433, stat: Journal Article,

PLEURAL TUBERCULOSIS (PLTB) AND HUMAN-IMMUNODEFICIENCY-VIRUS INFECTION (HIV)
RELKIN, F; SMITH, R; ARANDA, C; BERKOWITZ, K; BHOLA, A; ROM, W
1993 APR ;147(4):A488-A488, American review of respiratory disease
— id: 54160, year: 1993, vol: 147, page: A488, stat: Journal Article,

The rising tide of tuberculosis and the human host response to Mycobacterium tuberculosis
Rom WN; Zhang Y
1993 Jun;121(6):737-741, Journal of laboratory & clinical medicine
— id: 13141, year: 1993, vol: 121, page: 737, stat: Journal Article,

Cytokine gene activation and modified responsiveness to interleukin-2 in the blood of tuberculosis patients
Schauf V; Rom WN; Smith KA; Sampaio EP; Meyn PA; Tramontana JM; Cohn ZA; Kaplan G
1993 Oct;168(4):1056-1059, Journal of infectious diseases
Selected parameters of cellular immunity relating to cytokine gene activation and responsiveness to interleukin-2 (IL-2) were analyzed in 27 patients with active pulmonary tuberculosis and no human immunodeficiency virus type 1 infection. Cytokine mRNAs were not expressed by peripheral blood mononuclear cells (PBMC) of normal controls. In PBMC of tuberculosis patients, messages for IL-1, IL-8, and tumor necrosis factor-alpha were uniformly expressed, whereas PBMC of only 5 of 18 patients expressed IL-6. PBMC of 7 patients (all of those with systemic symptoms) expressed interferon-gamma mRNA and none expressed IL-2 mRNA. Most patients' cells demonstrated IL-4 mRNA. Limiting dilution analysis of IL-2-responsive cells in PBMC revealed that tuberculosis patients had 10-fold fewer IL-2-responsive cells than did controls
— id: 15401, year: 1993, vol: 168, page: 1056, stat: Journal Article,

Mechanisms of stimulation of interleukin-1 beta and tumor necrosis factor-alpha by Mycobacterium tuberculosis components
Zhang Y; Doerfler M; Lee TC; Guillemin B; Rom WN
1993 May;91(5):2076-2083, Journal of clinical investigation
The granulomatous immune response in tuberculosis is characterized by delayed hypersensitivity and is mediated by various cytokines released by the stimulated mononuclear phagocytes, including tumor necrosis factor-alpha (TNF alpha) and IL-1 beta. We have demonstrated that Mycobacterium tuberculosis cell wall component lipoarabinomannan (LAM), mycobacterial heat shock protein-65 kD, and M. tuberculosis culture filtrate, devoid of LPS as assessed by the Amebocyte Lysate assay, stimulate the production of TNF alpha and IL-1 beta proteins and mRNA from mononuclear phagocytes (THP-1 cells). The effect of LAM on the release of these cytokines was specific, as only LAM stimulation was inhibited by anti-LAM monoclonal antibody. Interestingly, we found that LAM and Gram-negative bacterial cell wall-associated endotoxin LPS may share a similar mechanism in their stimulatory action as demonstrated by inhibition of TNF alpha and IL-1 beta release by monoclonal antibodies to CD14. Anti-CD14 monoclonal antibody MY4 inhibited both TNF alpha and IL-1 beta release with LAM and LPS but no effect was observed with other mycobacterial proteins. An isotype antibody control did not inhibit release of cytokines under the same experimental conditions. M. tuberculosis and its components upregulated IL-1 beta and TNF alpha mRNAs in THP-1 cells. Nuclear run-on assay for IL-1 beta demonstrated that LAM increased the transcription rate. The induction of IL-1 beta was regulated at the transcriptional level, in which these stimuli acted through cis-acting element(s) on the 5' flanking region of the IL-1 beta genomic DNA. M. tuberculosis cell wall component LAM acts similarly to LPS in activating mononuclear phagocyte cytokine TNF alpha and IL-1 beta release through CD14 and synthesis at the transcriptional level; both cytokines are key participants in the host immune response to tuberculosis
— id: 13187, year: 1993, vol: 91, page: 2076, stat: Journal Article,

Enhanced IL-1 beta and tumor necrosis factor-alpha release and messenger RNA expression in macrophages from idiopathic pulmonary fibrosis or after asbestos exposure
Zhang Y; Lee TC; Guillemin B; Yu MC; Rom WN
1993 May 1;150(9):4188-4196, Journal of immunology
Idiopathic pulmonary fibrosis (IPF) and asbestosis are fibrotic interstitial lung diseases characterized by alveolar wall fibrosis with accumulation of extracellular matrix, interstitial remodeling, and increased numbers of activated alveolar macrophages. Animal models and in vitro studies have shown that macrophage cytokines, namely IL-1 beta and TNF-alpha, play significant roles in the development of fibrosis. We found significant increases for TNF-alpha release in both diseases (p < 0.01) and a significant increase for IL-1 beta release in asbestosis compared to normal controls (p < 0.01). Also, the mRNA expression of these cytokines was increased in alveolar macrophages from patients with IPF or asbestosis compared with normals. The level of TNF-alpha release in macrophage supernatants correlated with the number of neutrophils per milliliter bronchoalveolar lavage fluid returned. Chrysotile, crocidolite, amosite asbestos, and silica stimulated IL-1 beta and TNF-alpha release and up-regulated their respective mRNA in macrophages or monocytes. To evaluate the role of IL-1 beta and TNF-alpha in the accumulation of extracellular matrix, we studied collagen types I and III and fibronectin gene expression in human diploid lung fibroblasts after short term (2 h) serum-free exposure to recombinant cytokines. Both cytokines up-regulated these genes 1.5- to 3.6-fold. These cytokines have the potential to influence the remodeling and fibrosis observed in the lower respiratory tract in IPF and asbestosis
— id: 13178, year: 1993, vol: 150, page: 4188, stat: Journal Article,

Regulation of the interleukin-1 beta (IL-1 beta) gene by mycobacterial components and lipopolysaccharide is mediated by two nuclear factor-IL6 motifs
Zhang Y; Rom WN
1993 Jun;13(6):3831-3837, Molecular & cellular biology
The cytokines interleukin-1 beta (IL-1 beta) and tumor necrosis factor alpha (TNF-alpha) are released by mononuclear phagocytes in vitro after stimulation with mycobacteria and are considered to mediate pathophysiologic events, including granuloma formation and systemic symptoms. We demonstrated that the Mycobacterium tuberculosis cell wall component lipoarabinomannan (LAM) is a very potent inducer of IL-1 beta gene expression in human monocytes and investigated the mechanism of this effect. We localized the LAM-, lipopolysaccharide (LPS)-, and TNF-alpha-inducible promoter activity to a -131/+15 (positions -131 to +15) DNA fragment of the IL-1 beta gene by deletion analysis and chloramphenicol acetyltransferase assay. Within this DNA fragment, there were two novel 9-bp motifs (-90/-82 and -40/-32) with high homology to the nuclear factor-IL6 (NF-IL6) binding site. Site-directed mutagenesis demonstrated that the two NF-IL-6 motifs could be independently activated by LAM, LPS, or TNF-alpha and that they acted in an orientation-independent manner. DNA mobility shift assay revealed specific binding of nuclear protein(s) from LAM-, LPS-, or TNF-alpha-stimulated THP-1 cells to the NF-IL6 motifs. We conclude that the two NF-IL6 sites mediate induction of IL-1 beta in response to the stimuli LAM, LPS, and TNF-alpha
— id: 13156, year: 1993, vol: 13, page: 3831, stat: Journal Article,

STIMULATION OF LONG TERMINAL REPEAT SEQUENCES FROM THE HUMAN-IMMUNODEFICIENCY-VIRUS BY COMPONENTS FROM MYCOBACTERIUM-TUBERCULOSIS
ZHANG, Y; ROM, WN
1993 APR ;41(2):A282-A282, Clinical research
— id: 54274, year: 1993, vol: 41, page: A282, stat: Journal Article,

MULTIPLE HOSPITAL ADMISSIONS AND MULTIPLE-DRUG RESISTANT TUBERCULOSIS AMONG HOMELESS MEN IN NEW-YORK-CITY
CONCATO, J; ADLER, JJ; ROM, WN
1992 APR ;40(2):A139-A139, Clinical research
— id: 51973, year: 1992, vol: 40, page: A139, stat: Journal Article,

Accelerated loss of lung function and alveolitis in a longitudinal study of non-smoking individuals with occupational exposure to asbestos
Rom WN
1992 ;21(6):835-844, American journal of industrial medicine
Long-term asbestos workers who insulate pipes and boilers may develop interstitial lung disease associated with loss of lung function. To quantitate annual loss of lung function, 77 individuals with chest X-rays greater than or equal to 1/0 ILO category who were life-long non-smokers or ex-smokers for greater than 5 years were evaluated. Study parameters included pulmonary function tests and bronchoalveolar lavage for a mean of 3 visits over 30 +/- 2 months. The study participants were 56 +/- 1 years old and had 31 +/- 1 years' occupational exposure to asbestos. At the first visit, multiple regression analysis revealed significant associations between rales or radiographic opacities and VC, FEV1, and total lung capacity; significant associations were also found between neutrophils/ml lavage fluid with FEV1 and diffusing capacity (all p less than 0.05). Annual declines for the asbestos-exposed were VC -92 +/- 28 ml/yr and FEV1 -66 +/- 21 ml/yr. Declines in VC and FEV1 were less in those with reduced lung function at the initial visit. There were no significant associations between any of the annual declines and cells recovered by bronchoalveolar lavage. Compared to other asbestos-exposed cohorts followed longitudinally, asbestos insulators with radiographs greater than or equal to 1/0 and exposure greater than or equal to 20 years have larger rates of FVC and FEV1 decline for both non-smokers and ex-smokers
— id: 13737, year: 1992, vol: 21, page: 835, stat: Journal Article,

Lymphocyte-macrophage alveolitis in nonsmoking individuals occupationally exposed to asbestos
Rom WN; Travis WD
1992 Mar;101(3):779-786, Chest
A disordered immunologic activity has been observed in humans and animal models of asbestosis and silicosis. To characterize the lung immunologic response following long-term occupational exposure to asbestos, bronchoalveolar lavage (BAL) was performed on 28 nonsmoking individuals. Increased BAL lymphocytes were observed in one third. Lung lymphocytes were predominantly of the CD4+ helper-inducer subtype with increased CD4+/CD8+ ratio and increased surface expression of DR antigen consistent with the activation phenotype. Histologic evaluation of lung tissue from two individuals with lymphocytic-macrophage alveolitis and asbestos exposure revealed an infiltration of alveolar walls with chronic inflammatory mononuclear cells (lymphocytes). Interferon gamma was spontaneously released by BAL cells from 19 (76 percent) of 25 of the individuals with asbestos exposure and only one of ten normal controls. The release of interferon gamma by BAL cells could be further stimulated with concanavalin A and suppressed by cyclosporine. Although asbestosis is characterized by a predominant alveolar macrophage alveolitis, there is a subgroup with lymphocytic alveolitis and activated lymphocytes participating in the inflammatory response, especially in those without respiratory impairment early in the course of the disease process
— id: 13679, year: 1992, vol: 101, page: 779, stat: Journal Article,

Environmental and occupational medicine
Rom, William N
Boston : Little, Brown, 1992,
— id: 401, year: 1992, vol: , page: , stat: ,

CELLULAR AND MOLECULAR-BASIS OF THE ASBESTOS-RELATED DISEASES - REPLY
ROM, WN; TRAVIS, WD; BRODY, AR
1992 JAN ;145(1):238-239, American review of respiratory disease
— id: 52117, year: 1992, vol: 145, page: 238, stat: Journal Article,

Lung inflammation in coal miners assessed by uptake of 67Ga-citrate and clearance of inhaled 99mTc-labeled diethylenetriamine pentaacetate aerosol
Susskind H; Rom WN
1992 Jul;146(1):47-52, American review of respiratory disease
We compared the diffuse lung uptake of 67Ga-citrate, an index of inflammatory lung activity, with the lung clearance of inhaled 99mTc-labeled diethylenetriamine pentaacetate (DTPA) aerosol, an index of pulmonary epithelial permeability, in a group of 19 West Virginia coal miners whose pulmonary status was compatible with coal worker's pneumoconiosis. 99mTc-DTPA clearance alone and 67Ga-citrate uptake alone were measured in nine and five additional subjects, respectively. The objective of this study was to determine if increased 99mTc-DTPA lung clearance was caused by inflammation at the lung epithelial surfaces. Subjects inhaled approximately 150 microCi (approximately 5.6 MBq) of 99mTc-DTPA aerosol, and quantitative gamma camera images of the lungs were acquired at 1-min increments for 25 min. Regions of interest (ROI) were selected to include (1) both lungs; (2) each individual lung; and (3) the upper, middle, and lower thirds of each lung. 99mTc-DTPA clearance was determined from the slopes of the respective time-activity plots for the different ROI. Each subject was intravenously administered 50 miCroCk (1.9 MBq)/kg 67Ga-citrate 48 to 72 h before imaging the body between neck and pelvis. The extent of 67Ga-citrate lung uptake was expressed as the gallium index (GI). Mean radioaerosol clearance half-time (T1/2) for the six nonsmoking coal miners (60.6 +/- 16.0 min) was significantly shorter (p less than 0.001) than for the nonsmoking control group (123.8 +/- 28.7 min). T1/2 for the 12 smoking miners (18.4 +/- 10.2 min) was shorter than for the smoking control group (33.1 +/- 17.8 min), but the difference did not attain statistical significance.(ABSTRACT TRUNCATED AT 250 WORDS)
— id: 15403, year: 1992, vol: 146, page: 47, stat: Journal Article,

LIPOARABINOMANNAN FROM MYCOBACTERIUM-TUBERCULOSIS ACTIVATES NF-IL-6 AND NF-KB BINDING-SITES ON THE INTERLEUKIN-6 GENE
ZHANG, Y; ROM, WN
1992 APR ;40(2):A215-A215, Clinical research
— id: 51980, year: 1992, vol: 40, page: A215, stat: Journal Article,

LIPOARABINOMANNAN FROM MYCOBACTERIUM-TUBERCULOSIS REGULATES THE IL-1-BETA GENE BY 2 NOVEL 9-BASE PAIR MOTIFS
ZHANG, Y; ROM, WN
1992 APR ;40(2):A305-A305, Clinical research
— id: 51999, year: 1992, vol: 40, page: A305, stat: Journal Article,

ASBESTOS FIBERS ARE MUTAGENIC AFTER ALL - NEW SIGNS OF ORTHODOXY FOR A PARADOXICAL GROUP OF CARCINOGENS
FASY, TM; DAVIS, JMG; MYINT, T; JAURAND, MC; ESMEN, N; SCHWARTZ, A; ROM, WN; KANE, A; MARK, E
1991 DEC 31 ;643(5):271-282, Annals of the New York Academy of Sciences
— id: 51885, year: 1991, vol: 643, page: 271, stat: Journal Article,

Role of peptide growth factors in asbestos-related human lung cancer
Guillemin B; Zhang Y; Lee TC; Rom WN
1991 Dec 31;643:245-257, Annals of the New York Academy of Sciences
— id: 15404, year: 1991, vol: 643, page: 245, stat: Journal Article,

Human mononuclear phagocytes express the insulin-like growth factor-II/mannose-6-phosphate receptor
Rom WN
1991 Jun;4(6):555-559, American journal of respiratory cell & molecular biology
The insulin-like growth factor (IGF)-II/mannose-6-phosphate (M6P) receptor, which targets acid hydrolases to lysosomes, is a multifunctional protein with separate binding sites for IGF-II and M6P. The purpose of this study was to determine if alveolar macrophages (AM) and their precursor cells, blood monocytes, expressed this receptor. AM expressed IGF-II/M6P receptors as detected by [125]IGF-II surface binding that was not reduced by recombinant IGF-I or IGF-I receptor monoclonal antibody (alpha IR3). Surface binding was also detected on blood monocytes and could be upregulated approximately 4-fold by incubation with lipopolysaccharide. There were no differences in surface binding by AM lavaged from individuals with asbestos exposure or from normal volunteers. Using the polymerase chain reaction and reverse transcriptase to reverse-transcribe mRNA from mononuclear phagocytes, specific IGF-II/M6P receptor cDNA was amplified and detected by agarose gel electrophoresis from both AM and blood monocytes. The IGF-II/M6P receptor has an intracellular transport role in many cells cycling from the cell surface to the cytoplasm, or binding to phosphorylated acid hydrolases in the Golgi and transporting them to an acidic prelysosomal site where they dissociate and fuse to the lysosomes and IGF-II/M6P recycles to the trans-Golgi. These functions may be particularly important in asbestosis and other interstitial lung diseases where AM are activated, intracellular lysosomes are a prominent morphologic feature, and acid hydrolases are found in recovered lavage fluid
— id: 14017, year: 1991, vol: 4, page: 555, stat: Journal Article,

Relationship of inflammatory cell cytokines to disease severity in individuals with occupational inorganic dust exposure
Rom WN
1991 ;19(1):15-27, American journal of industrial medicine
The pneumoconioses due to chronic occupational exposure to asbestos, coal, or silica are characterized by an alveolar macrophage-dominated alveolitis with exaggerated spontaneous release of mediators: oxidants, chemotaxins for neutrophils, and fibroblast growth factors. Bronchoalveolar lavage was performed on 66 non-smoking inorganic dust-exposed individuals with a chest x-ray greater than or equal to 1/0 stratified by presence or absence of restrictive respiratory impairment, and 28 unexposed non-smoking controls. Both dust-exposed groups stratified by presence or not of impairment had increased numbers of total cells recovered by lavage compared to normals, and those with respiratory impairment (n = 40) had a significant increase in percent and number of neutrophils recovered. Similarly, only those with respiratory impairment had macrophages that spontaneously released significant amounts of the oxidants superoxide anion and hydrogen peroxide. There was a significant trend for the release of fibronectin by macrophages from controls to dust-exposed without impairment to those with impairment. Both dust-exposed groups also had increased release of alveolar macrophage-derived progression growth factor, but this was significantly less than macrophages from patients with idiopathic pulmonary fibrosis. Since occupational exposure was virtually identical in inorganic dust-exposed individuals with versus without respiratory impairment, the quantitative differences in the release of macrophage mediators may be due to factors in host susceptibility
— id: 14200, year: 1991, vol: 19, page: 15, stat: Journal Article,

Dehydroepiandrosterone inhibits the spontaneous release of superoxide radical by alveolar macrophages in vitro in asbestosis
Rom WN; Harkin T
1991 Aug;55(2):145-156, Environmental research
Asbestosis is characterized by an alveolar macrophage alveolitis with injury and fibrosis of the lower respiratory tract. Alveolar macrophages recovered by bronchoalveolar lavage spontaneously release exaggerated amounts of oxidants including superoxide anion and hydrogen peroxide that may mediate alveolar epithelial cell injury. Dehydroepiandrosterone (DHEA) is a normally occurring adrenal androgen that inhibits glucose-6-phosphate dehydrogenase, the initial enzyme in the pentose phosphate shunt necessary for NADPH generation and superoxide anion formation. In this regard, we hypothesized that DHEA may reduce asbestos-induced oxidant release. DHEA added in vitro to alveolar macrophages lavaged from 11 nonsmoking asbestos workers significantly reduced superoxide anion release. DHEA was measured in bronchoalveolar lavage and found to be similar to serum concentrations. DHEA is an antioxidant and potential anticarcinogenic agent that may have a therapeutic role in reducing the increased oxidant burden in asbestos-induced alveolitis of the lower respiratory tract
— id: 13961, year: 1991, vol: 55, page: 145, stat: Journal Article,

Activated alveolar macrophages express the insulin-like growth factor-I receptor
Rom WN; Paakko P
1991 May;4(5):432-439, American journal of respiratory cell & molecular biology
Alveolar macrophages (AM) recovered from the lower respiratory tract of individuals with interstitial lung disease (ILD) proliferate at a 2- to 15-fold increased rate (P.B. Bitterman et al. 1984. J. Clin. Invest. 74:460-469). Normal AM stimulated with immune complexes or asbestos release platelet-derived growth factor and insulin-like growth factor-I (IGF-I), and AM activated in vivo in ILD release these growth factors. We evaluated normal unstimulated and activated AM for the receptor for IGF-I to determine if macrophage IGF-I could be involved in the enhanced macrophage proliferation. Although normal AM did not have specific 125I-labeled recombinant IGF-I binding, AM activated by chrysotile asbestos or lipopolysaccharide in vitro or from individuals with ILD had detectable binding that could be inhibited by an anti-IGF-I receptor monoclonal antibody in a dose-dependent fashion. Autoradiography with 125I-labeled recombinant IGF-I revealed binding to the IGF-I receptor on the surface of activated AM, and the percentage of labeled cells was reduced with anti-IGF-I receptor monoclonal antibody or excess unlabeled recombinant IGF-I. Hybridization of total AM RNA to a 32P-labeled IGF-I receptor riboprobe using solution hybridization demonstrated IGF-I receptor mRNA transcripts in AM from an individual with asbestosis, consistent with active expression of the IGF-I receptor gene. In the context of the known role of IGF-I as a growth factor for many cells, these data are consistent with the concept that IGF-I and its receptor may play an important role in the proliferation of AM in the inflamed lower respiratory tract
— id: 14051, year: 1991, vol: 4, page: 432, stat: Journal Article,

Cellular and molecular basis of the asbestos-related diseases [see comments]
Rom WN; Travis WD; Brody AR
1991 Feb;143(2):408-422, American review of respiratory disease
Asbestosis is an inflammatory and fibrotic process of the alveolar structures mediated, at least in part, by cytokines released by 'activated' alveolar macrophages. The process of phagocytosis and 'activation' of alveolar macrophages is poorly understood. Are all macrophages activated or only subpopulations? Which cytokines are up-regulated? How does the local milieu modulate profibrotic and antifibrotic mediators? Is protein release accompanied by up-regulation of gene transcription? Is there an ordered sequence of cytokine activity? What roles do neutrophils and lymphocytes play? How can disease progression best be quantified absent further exposure? Answers to these questions are important to direct rational strategies at interdicting the fibrotic process. The question of cancer and asbestos is more vexing. The processes of inflammation, fibrosis, and carcinogenesis appear to be closely intertwined. For example, proto-oncogenes such as c-sis (PDGF B-chain) are up-regulated in activated alveolar macrophages from fibrotic lungs; these and possibly others may play an important role in asbestos carcinogenesis. Second, asbestos can transfect DNA into cells. Furthermore, DNA can adhere to asbestos fibers, and these fibers are capable of direct transmigration into cells. The questions of the mechanisms of cigarette smoke cocarcinogenicity and latency remain. Lastly, if the bronchial epithelium is highly metaplastic throughout from cigarette smoking, what triggers a single (or several) nidus of cells to transform into carcinoma? Malignant mesothelioma poses the most challenging questions because of association with brief asbestos exposure by history. Mesothelial cells are susceptible to minute environmental manipulations, and changes occur after exposure to all fiber types. Yet epidemiologic studies point toward long amphiboles as having greater mesothelioma risk. To test this hypothesis, experimental data must be generated differentiating tumorigenesis risk from short, chrysotile fibers that can migrate to the parietal pleura from the associations of long amphiboles persisting in lung tissue. Despite the future decreasing numbers of clinical cases of asbestos-related disease, solving the important mechanistic questions remaining will contribute significantly to our understanding of fibrosis and cancer
— id: 14142, year: 1991, vol: 143, page: 408, stat: Journal Article,

REGULATION OF IL-BETA GENE BY MYCOBACTERIA TUBERCULOSIS PROTEINS
ZHANG, Y; YU, M; ROM, WN
1991 APR ;39(2):A289-A289, Clinical research
— id: 51615, year: 1991, vol: 39, page: A289, stat: Journal Article,

Basic mechanisms leading to focal emphysema in coal workers' pneumoconiosis
Rom WN
1990 Oct;53(1):16-28, Environmental research
Coal miners develop focal emphysema characterized by dilatation of second- and third-order respiratory bronchioles with coal mine dust-laden macrophages infiltrating the wall. A reticulin network with small amounts of collagen and atrophy of smooth muscle occurs. To evaluate the mechanisms of lung injury associated with this lesion, 17 long-term non- or ex-smoking West Virginia underground coal miners underwent bronchoalveolar lavage (BAL) and were compared to healthy nonsmoker and smoker controls. The coal miners had evidence of an alveolar macrophage-neutrophil alveolitis with a significant increase in neutrophils/microliter of epithelial lining fluid and an increased gallium lung scan index (206 +/- 26 units). Alveolar macrophages lavaged from coal miners spontaneously released exaggerated amounts of superoxide anion and hydrogen peroxide in vitro compared to nonsmoking controls. Coal workers had significantly elevated levels of neutrophil elastase in BAL fluid complexed with alpha 1-antitrypsin (P less than 0.01) and normal levels of alpha 1-antitrypsin. An accumulation of activated, dust-laden inflammatory cells with increased release of oxidants and elastase may contribute to the development of focal emphysema identified at postmortem in miners with coal workers' pneumoconiosis
— id: 15406, year: 1990, vol: 53, page: 16, stat: Journal Article,

Persistent lower respiratory tract inflammation associated with interstitial lung disease in patients with tropical pulmonary eosinophilia following conventional treatment with diethylcarbamazine
Rom WN; Vijayan VK; Cornelius MJ; Kumaraswami V; Prabhakar R; Ottesen EA; Crystal RG
1990 Nov;142(5):1088-1092, American review of respiratory disease
Tropical pulmonary eosinophilia (TPE) presents as an acute syndrome with dyspnea, fluffy infiltrates, and rounded opacities on the chest radiograph, reduced lung function, marked eosinophilia in the blood and lower respiratory tract, and high titers of specific IgE and IgG antifilarial antibodies. The standard therapy for TPE is a 3-wk course of diethylcarbamazine (DEC) following which there is almost always a marked improvement in all parameters. However, clinical observations suggest that the disease can persist despite DEC therapy and lead to chronic dyspnea with restrictive lung impairment. To evaluate the concept that DEC therapy is not completely 'curative' for TPE, but rather leaves most individuals with a mild, chronic form of TPE defined by persistent inflammation of the lower respiratory tract, we evaluated 23 individuals an average of 12 +/- 2 months following a standard 3-wk course of diethylcarbamazine for acute TPE. In the majority there were mild, persistent symptoms referrable to the lung, chest X-ray abnormalities, blood eosinophilia, and elevated serum IgE and filarial specific IgG. On the average, lung function was consistent with the presence of chronic, mild interstitial lung disease. When the inflammatory cells from the lower respiratory tract were examined, there was a persistent eosinophilic alveolitis (TPE/post-DEC 1769 +/- 376 eosinophils/microliters epithelial lining fluid; normal subjects 256 +/- 38, p less than 0.02). Evaluation of the lower respiratory tract inflammatory cells recovered from the TPE/post-DEC-treated individuals demonstrated spontaneous release of exaggerated amounts of O2-. and H2O2 compared to normal subjects (p less than 0.05, both comparisons).(ABSTRACT TRUNCATED AT 250 WORDS)
— id: 15405, year: 1990, vol: 142, page: 1088, stat: Journal Article,

EVALUATION OF ALVEOLAR MACROPHAGE PARTICLE BURDEN IN INDIVIDUALS OCCUPATIONALLY EXPOSED TO INORGANIC DUSTS
Rom, WN; Churg, A; Leapman, R; Fiori, C; Swyt, C
1990 Dec;3(12):S43-S56, Journal of aerosol medicine
Alveolar macrophages recovered by bronchoalveolar lavage from individuals with occupational inorganic dust exposure are laden with particles. We evaluated 42 non-smoking males with long- term exposure to asbestos (27), coal (7), or silica (8) and normals (8) to determine a particle burden per 10(6) alveolar macrophages. Scanning/transmission electron microscopy and energy-dispersive x-ray analysis were utilized to evaluate the particles following bleach digestion of the cells, or of alveolar macrophage sections. There was a four-fold (p < 0.01) increase in the number of particles in the dust-exposed. There was also a striking increase in silica particle number in the silica-exposed (p < 0.02) but not in the other dust-exposed groups. One-third of the coal miner's cells contained silica particles predominantly < 0.5 mu-m. In the asbestos-exposed, there was one chrysotile fiber per 35 cells, and one amosite fiber per 215 cells consistent with the known mixed exposure of workers exposed to insulation products in the United States. No crocidolite was observed in any of the cells and tremolite was identified in two controls and two workers. Computer- generated maps of elements comprising the particles demonstrated the in situ localization of the particles and identified many very small alumino-silicates, particularly in coal miners. Particle analysis is a useful technique to evaluate type and amount of exposure, to evaluate alveolar clearance, and may be useful to investigate macrophage activation
— id: 32195, year: 1990, vol: 3, page: S43, stat: Journal Article,

Morphologic characterization of alveolar macrophages from subjects with occupational exposure to inorganic particles
Takemura T; Rom WN; Ferrans VJ; Crystal RG
1989 Dec;140(6):1674-1685, American review of respiratory disease
Alveolar macrophages recovered by bronchoalveolar lavage from 43 nonsmoking or greater than 5-yr ex-smoking subjects with occupational exposure to inorganic particles (asbestos, n 1/2 19; silica, n 1/2 10; coal, n 1/2 14) were evaluated by light microscopy and transmission and scanning electron microscopy to determine the morphologic changes resulting in these cells from chronic inorganic particulate inhalation. Alveolar macrophages from dust-exposed subjects, including those who had been free of exposure to particles for more than 1 yr, contained particles of higher proportion than did those of normal unexposed subjects. Most of these particles were located within phagolysosomes. The frequency of multinucleated alveolar macrophages was significantly higher in the dust-exposed groups. Ultrastructural studies showed alterations of the morphologic aspects of the surfaces of alveolar macrophages from the dust-exposed subjects, including increased numbers of rufflings, filopodia, pinocytotic vesicles, subplasmalemmal linear densities, and increased frequency of macrophage-macrophage and macrophage-lymphocyte interactions. Furthermore, the numbers of lysosomes were significantly increased in alveolar macrophages from the dust-exposed subjects. Together, these morphologic changes are consistent with the sequelae of phagocytosis, and they emphasize both the role of alveolar macrophages in eliminating inorganic particles from the alveolar spaces and the consequences this role has in alveolar macrophage activation
— id: 15407, year: 1989, vol: 140, page: 1674, stat: Journal Article,

The lung matrix and inflammation: Part II. Biochemical and molecular mechanisms of fibrogenesis: implications for environmental lung disease
Brody AR; Bitterman PB; Adler KB; Rannels DE; Thet LA; Rom WN; Rennard SI
1988 Oct;138(4):1056-1057, American review of respiratory disease
— id: 15409, year: 1988, vol: 138, page: 1056, stat: Journal Article,

Colchicine suppresses the release of fibroblast growth factors from alveolar macrophages in vitro. The basis of a possible therapeutic approach ot the fibrotic disorders
Rennard SI; Bitterman PB; Ozaki T; Rom WN; Crystal RG
1988 Jan;137(1):181-185, American review of respiratory disease
Fibrosis is the accumulation of fibroblasts and the connective tissue products secreted by these cells, usually subsequent to tissue injury. While fibrosis can be useful in preserving the general structural integrity of a tissue, it often alters cell-cell and cell-connective tissue interactions, which leads to loss of tissue function. On the basis of the concept that mononuclear phagocytes can direct the development of fibrosis through the release of specific mediators that stimulate fibroblast proliferation, we propose a therapeutic strategy to prevent fibrosis by preventing the release of these specific mediators. The present study demonstrated that colchicine, a widely used and well-tolerated drug, can block alveolar macrophage release of 2 mediators associated with the development of fibrosis in interstitial lung diseases, fibronectin, and the alveolar-macrophage-derived growth factor (AMDGF). Colchicine blocked the spontaneous release of fibronectin by alveolar macrophages obtained from patients with fibrotic lung disease by 23 +/- 4% after 24 h and by greater than 90% after 72 h. AMDGF release was blocked by 68 +/- 10% after 4 h (p less than 0.01, all comparisons). The effect of colchicine was not due to nonspecific toxicity since [14C]proline tracer studies demonstrated that macrophages treated with colchicine were capable of de novo protein synthesis and the secretion of several protein products, despite the fact that fibronectin and AMDGF release were suppressed. The effect of colchicine on the spontaneous release of both fibronectin and AMDGF could be observed at concentrations less than 10 ng/ml, levels that can be achieved in vivo.(ABSTRACT TRUNCATED AT 250 WORDS)
— id: 15410, year: 1988, vol: 137, page: 181, stat: Journal Article,

Alveolar macrophages release an insulin-like growth factor I-type molecule
Rom WN; Basset P; Fells GA; Nukiwa T; Trapnell BC; Crysal RG
1988 Nov;82(5):1685-1693, Journal of clinical investigation
Human alveolar macrophages, when activated, release a progression-type growth factor for fibroblasts that signals 'competent' fibroblasts to replicate. The present study demonstrates that this growth activity is an insulin-like growth factor I (IGF-I)-type molecule. Partial purification of medium conditioned by activated alveolar macrophages using ion exchange and gel filtration chromatography revealed an IGF-I molecule as detected by an anti-IGF-I polyclonal antibody and that the specific activity of the progression-type growth activity tracked with the amount of IGF-I present. In a serum-free complementation test, the increase in fibroblast proliferation by alveolar macrophage IGF-I was reduced in a dose-response manner with an anti-IGF-I monoclonal antibody. The alveolar macrophage IGF-I displaced 125I-IGF-I from its receptor in a binding assay utilizing human lung fibroblasts and it stimulated type I IGF receptors purified from human lung fibroblasts to phosphorylate a tyrosine-containing artificial substrate. In contrast to the 7.6-kD serum IGF-I, gel chromatography revealed that the alveolar macrophage IGF-I had an apparent molecular mass of 26 kD, similar to other tissue IGF-Is. Alveolar macrophages expressed IGF-I mRNA transcripts as detected by solution hybridization using a 32P-labeled riboprobe complementary to exons I-II-III of the IGF-I gene. In the context of the known functions of the family of IGF-I molecules in cell growth, IGF-I released by activated alveolar macrophages may play a role in acute and chronic inflammatory disorders
— id: 15408, year: 1988, vol: 82, page: 1685, stat: Journal Article,

Exaggerated spontaneous release of platelet-derived growth factor by alveolar macrophages from patients with idiopathic pulmonary fibrosis
Martinet Y; Rom WN; Grotendorst GR; Martin GR; Crystal RG
1987 Jul 23;317(4):202-209, New England journal of medicine
Idiopathic pulmonary fibrosis is a fibrotic lung disease characterized by an increased number of mesenchymal cells in the alveolar walls. Alveolar macrophages constitutively express low levels of c-sis, the protooncogene coding for the B chain of platelet-derived growth factor, a protein with chemotactic and mitogenic activity toward mesenchymal cells. We therefore hypothesized that alveolar macrophages in patients with idiopathic pulmonary fibrosis may release increased amounts of platelet-derived growth factor, which might help to explain the accumulation of mesenchymal cells and the fibrosis of the lower respiratory tract in the disease. Evaluation of alveolar macrophages recovered from the lungs of patients with idiopathic pulmonary fibrosis demonstrated that these cells spontaneously released four times more platelet-derived growth factor than did alveolar macrophages recovered from normal persons (P less than 0.01). That the platelet-derived growth factor molecules were potentially active was shown by their chemotactic activity for smooth-muscle cells and their ability to act as a 'competence' factor for fibroblast growth. These observations suggest the possibility that the accumulation of mesenchymal cells within the alveolar walls in patients with idiopathic pulmonary fibrosis may result partly from the exaggerated release of the potent mitogen platelet-derived growth factor by mononuclear phagocytes in the lower respiratory tract
— id: 15412, year: 1987, vol: 317, page: 202, stat: Journal Article,

Acute tropical pulmonary eosinophilia. Characterization of the lower respiratory tract inflammation and its response to therapy
Pinkston P; Vijayan VK; Nutman TB; Rom WN; O'Donnell KM; Cornelius MJ; Kumaraswami V; Ferrans VJ; Takemura T; Yenokida G; et al
1987 Jul;80(1):216-225, Journal of clinical investigation
Although acute tropical pulmonary eosinophilia (TPE) is well recognized as a manifestation of filarial infection, the processes that mediate the abnormalities of the lung in TPE are unknown. To evaluate the hypothesis that the derangements of the lower respiratory tract in this disorder are mediated by inflammatory cells in the local milieu, we utilized bronchoalveolar lavage to evaluate affected individuals before and after therapy. Inflammatory cells recovered from the lower respiratory tract of individuals with acute, untreated TPE (n = 8) revealed a striking eosinophilic alveolitis, with marked elevations in both the proportion of eosinophils (TPE 54 +/- 5%; normal 2 +/- 5%; P less than 0.001) and the concentration of eosinophils in the recovered epithelial lining fluid (ELF) (TPE 63 +/- 20 X 10(3)/microliter; normal 0.3 +/- 0.1 X 10(3)/microliter; P less than 0.01). Importantly, when individuals (n = 5) with acute TPE were treated with diethylcarbamazine (DEC), there was a marked decrease of the lung eosinophils and concomitant increase in lung function. These observations are consistent with the concept that at least some of the abnormalities found in the lung in acute TPE are mediated by an eosinophil-dominated inflammatory process in the lower respiratory tract
— id: 15413, year: 1987, vol: 80, page: 216, stat: Journal Article,

Characterization of the lower respiratory tract inflammation of nonsmoking individuals with interstitial lung disease associated with chronic inhalation of inorganic dusts
Rom WN; Bitterman PB; Rennard SI; Cantin A; Crystal RG
1987 Dec;136(6):1429-1434, American review of respiratory disease
The pneumoconioses, interstitial lung disorders resulting from the inhalation of inorganic dusts, are associated with chronic inflammatory processes in the lower respiratory tract. To characterize these inflammatory processes in relation to the pathogenesis of these disorders, we studied 39 nonsmoking individuals with long-term occupational exposures to inorganic dust and functional evidence of interstitial disease (asbestosis, n = 18; coal workers' pneumoconiosis, n = 15; silicosis, n = 6). In all 3 disorders, the inflammation was dominated by alveolar macrophages. Because a common feature of these interstitial lung diseases is concurrent injury and fibrosis of alveolar walls, we assessed whether these alveolar macrophages were spontaneously releasing mediators capable of giving rise to these changes. Alveolar macrophages from the study population were spontaneously releasing increased amounts of superoxide anion and hydrogen peroxide (both p less than 0.01 compared to normals), oxidants capable of injuring lung parenchymal cells. The alveolar macrophages were also spontaneously releasing significantly increased amounts of fibronectin and alveolar macrophage-derived growth factor (both p less than 0.01 compared to normals), mediators that act synergistically to signal fibroblast replication. Taken together, these findings define a major role for the alveolar macrophage in mediating the alveolar wall injury and fibrosis that characterize the common pneumoconioses and suggest that the alveolar macrophage is an important 'target' for developing strategies designed to prevent loss of lung function in these individuals
— id: 15411, year: 1987, vol: 136, page: 1429, stat: Journal Article,

Canoe country wilderness : a guide's canoe trails through the BWCA and Quetico
Rom, William N
Minneapolis MN : Voyageur Press, 1987,
— id: 1303, year: 1987, vol: , page: , stat: ,

Health effects among refrigeration repair workers exposed to fluorocarbons
Campbell DD; Lockey JE; Petajan J; Gunter BJ; Rom WN
1986 Feb;43(2):107-111, British journal of industrial medicine
Refrigeration repair workers may be intermittently exposed to fluorocarbons and their thermal decomposition products. A case of peripheral neuropathy (distal axonopathy) in a commercial refrigeration repairman prompted an epidemiological investigation of the health of refrigeration repair workers. No additional cases of peripheral neuropathy were identified among the 27 refrigeration repair workers studied. A reference group of 14 non-refrigeration repair workers was also studied. No differences were noted between groups for the ulnar (motor and sensory), median (motor and sensory), peroneal, sural, or tibial nerve conduction velocities. Refrigeration repair workers reported palpitations and lightheadedness significantly more often than workers in the reference group. No clinical neurological or electroneurophysiological abnormalities were detected in eight refrigeration repair workers followed up for three years during continuous employment
— id: 15415, year: 1986, vol: 43, page: 107, stat: Journal Article,

Longitudinal evaluation of pulmonary function in copper smelter workers exposed to sulfur dioxide
Rom WN; Wood SD; White GL; Bang KM; Reading JC
1986 May;133(5):830-833, American review of respiratory disease
From 1973 to 1974, a longitudinal study of pulmonary function in 113 Utah copper smelter workers reported significant declines in FVC and FEV1 related to sulfur dioxide exposure. In 1980, we performed a 7-yr follow-up study, finding significant increases in FVC and FEV1. The 66 follow-up participants were similar to those 47 lost to follow-up with regard to age and initial pulmonary function. Subgroups of smelter workers with initial higher exposures to sulfur dioxide and FEV1 less than 90% predicted did not show an accelerated rate of decline. To reconcile these differences between the 2 studies, we reevaluated the spirometry curves from 1973 and 1974. All had short expiratory times, with none 6 s or longer, whereas all of the curves from the spirograms obtained in 1980 exceeded 6 s. In addition, from 1980 to 1983, we performed a longitudinal study of 48 of the original workers, finding small annual mean declines for FVC of 6 ml and FEV1 of 5 ml. Personal exposures to sulfur dioxide were not significantly different in 1982 than in 1976; thus, we were unable to corroborate the findings of the initial longitudinal study
— id: 15414, year: 1986, vol: 133, page: 830, stat: Journal Article,

Zeolite exposure and associated pneumoconiosis
Casey KR; Shigeoka JW; Rom WN; Moatamed F
1985 Jun;87(6):837-840, Chest
Naturally occurring zeolite minerals are aluminum silicates widespread in the earth's crust. Several of these minerals have fibrous forms and have been implicated as a possible cause of benign and malignant diseases of the lung and pleura in Turkey. This report describes a patient, living in an area of Nevada rich in zeolites, who presented with idiopathic pleural thickening and pulmonary fibrosis associated with extensive pulmonary deposition of zeolites
— id: 15417, year: 1985, vol: 87, page: 837, stat: Journal Article,

Gallium-67 citrate imaging in underground coal miners
Kanner RE; Barkman HW Jr; Rom WN; Taylor AT Jr
1985 ;8(1):49-55, American journal of industrial medicine
Twenty-two underground coal workers with 27 or more years of coal dust exposure were studied with gallium-67 citrate (Ga-67) imaging. Radiographic evidence of coal workers pneumoconiosis (CWP) was present in 12 subjects. The Ga-67 scan was abnormal in 11 of 12 with, and 9 of 10 without, CWP. The Ga-67 uptake index was significantly correlated with total dust exposure (p less than 0.01) and approached significant correlation with the radiographic profusion of the nodules (0.10 greater than p greater than 0.05). There was no correlation between Ga-67 uptake and spirometric function, which was normal in this group of patients; furthermore, increased lung uptake of gallium did not indicate a poor prognosis in subjects no longer exposed to coal dust. While coal dust exposure may be associated with positive Ga-67 lung scan in coal miners with many years of coal dust exposure, the scan provided no information not already available from a careful exposure history and a chest radiograph. Since Ga-67 scanning is a relatively expensive procedure we would recommend that its use in subjects with asymptomatic CWP be limited to an investigative role and not be made part of a routine evaluation
— id: 15418, year: 1985, vol: 8, page: 49, stat: Journal Article,

Morbidity survey of U.S. oil shale workers employed during 1948-1969
Rom WN; Krueger G; Zone J; Attfield MD; Costello J; Burkart J; Turner ER
1985 Jan-Feb;40(1):58-62, Archives of environmental health
The health status of 325 oil shale workers employed at the Anvil Points, Colorado, demonstration facility from 1948 to 1969 was evaluated. As a comparison population, 323 Utah coal miners frequency matched for age were studied. The prevalence of respiratory symptoms among oil shale workers who smoked were similar to the coal miners who smoked, although nonsmoking oil shale workers had fewer symptoms compared to nonsmoking coal workers. Four cases of skin cancers were found on the oil shale workers and eight cases in the controls. Similar numbers of nevi, telangiectasiae, possible pitch warts, pigment changes (solar/senile lentigo), and papillomata (seborrheic keratoses and skin tags) were seen in both groups, while actinic keratoses were more frequent in the oil shale workers. The prevalence of actinic keratoses was significantly associated with oil shale work after allowing for age, sun exposure, and other exposures. The prevalence of pulmonary cytology metaplasia was associated with years of production work in oil shale among both smokers and exsmokers. More of the oil shale workers had atypical cells in the urine, but the excess was mostly found among exsmokers. Although these workers had short-term and limited oil shale exposure work exposure, we recommend that medical surveillance of oil shale workers consider the skin, respiratory, and urinary systems for special observation
— id: 15419, year: 1985, vol: 40, page: 58, stat: Journal Article,

Circulating immune complexes in asbestos workers
Zone JJ; Rom WN
1985 Aug;37(2):383-389, Environmental research
Circulating immune complexes, rheumatoid factor, and antinuclear antibodies were evaluated in 25 asbestos insulation workers and 32 brick mason controls. There were 10 asbestos workers with radiographic parenchymal or pleural changes, consistent with their asbestos exposure. There were no differences in antinuclear antibodies or rheumatoid factor between asbestos workers and controls. The asbestos workers had significantly increased levels of IgG and IgA circulating immune complexes. There was a significant correlation between IgA circulating immune complexes and radiographic changes
— id: 15416, year: 1985, vol: 37, page: 383, stat: Journal Article,

Basophilic stippling of red blood cells: a nonspecific finding of multiple etiology
Cheson BD; Rom WN; Webber RC
1984 ;5(4):327-334, American journal of industrial medicine
Basophilic stippling of red blood cells (BSC) has been noted in lead intoxication since 1899 and has been considered a classic laboratory sign of lead poisoning since that time. BSC are inclusions of aggregated ribosomes found only in the red blood cells and may be confused with siderotic (iron) granules. Heinz Bodies, or even reticulocytes. BSC are an inconstant finding in lead intoxication. In a review of peripheral blood smears from 1,000 consecutive internal medicine patients, we found BSC in 27%. These occurred in a variety of malignant, rheumatologic, hematologic, cardiovascular, and other diseases, frequently with an associated anemia. BSC may even be found in a small percentage of normal people; thus, it must be emphasized that BSC is a nonspecific finding. Furthermore, BSC has been replaced by blood lead (since the 1940s) and zinc protoporphyrin (since the 1970s) levels for biologic monitoring of lead-exposed workers
— id: 15423, year: 1984, vol: 5, page: 327, stat: Journal Article,

Commentary: research on the mechanisms of the occupational lung diseases
Rom WN
1984 May-Jun;39(3):186-189, Archives of environmental health
— id: 15421, year: 1984, vol: 39, page: 186, stat: Journal Article,

Pneumoconiosis and exposures of dental laboratory technicians
Rom WN; Lockey JE; Lee JS; Kimball AC; Bang KM; Leaman H; Johns RE Jr; Perrota D; Gibbons HL
1984 Nov;74(11):1252-1257, American journal of public health. AJPH
One hundred and seventy-eight dental laboratory technicians and 69 non-exposed controls participated in an epidemiological respiratory study. Eight technicians who had a mean of 28 years' grinding nonprecious metal alloys were diagnosed as having a simple pneumoconiosis by chest radiograph. Mean values for per cent predicted FVC and FEV1 were reduced among male nonsmoker technicians compared to male nonsmoker controls; after controlling for age, there was also a reduction in spirometry with increasing work-years. An industrial hygiene survey was conducted in 13 laboratories randomly selected from 42 laboratories stratified by size and type of operation in the Salt Lake City, Utah metropolitan area. Personal exposures to beryllium and cobalt exceeded the Threshold Limit Values (TLVs) in one laboratory. Occupational exposures in dental laboratories need to be controlled to prevent beryllium-related lung disorders as well as simple pneumoconiosis
— id: 15420, year: 1984, vol: 74, page: 1252, stat: Journal Article,

The use of asbestos-cement pipe for public water supply and the incidence of cancer in selected communities in Utah
Sadler TD; Rom WN; Lyon JL; Mason JO
1984 Summer;9(4):285-293, Journal of community health
We tested the hypothesis that there is an association between the use of asbestos-cement piping for drinking water supplies and the incidence of gastrointestinal and kidney cancer. Cancer incidence in 14 Utah communities that had used predominantly asbestos-cement piping for transporting their drinking water supplies for 20 years or more were compared to 27 Utah communities that had never used asbestos-cement piping. Cancer incidence was tabulated for 11 cancer sites for the years 1967-1976. Increased Standard Incidence Ratios (SIRs) were found for cancer of the kidney in men (SIR 192) and leukemia (a control site) in women (SIR 203). No increased SIRs were found for the opposite sex at these sites or for the other gastrointestinal sites singly or in combination. There was no increase in age-adjusted cancer incidence for the 11 sites in 4 of the 14 study communities that had used asbestos-cement piping for 30 years or more. Limitations of the study were that the water supplies were nonaggressive, and leaching from the pipes was minimal if at all. Furthermore, the latent period for observation was very short, suggesting that these results should be considered preliminary
— id: 15422, year: 1984, vol: 9, page: 285, stat: Journal Article,

Trends in mortality of diffuse malignant mesothelioma of pleura
Archer VE; Rom WN
1983 Jul 9;2(8341):112-113, Lancet
— id: 15426, year: 1983, vol: 2, page: 112, stat: Journal Article,

Dental laboratory health hazards
Lee JS; Kimball AC; Rom WN
1983 Nov;58(11):23-26, Dental laboratory review
— id: 15424, year: 1983, vol: 58, page: 23, stat: Journal Article,

Preventing disease and injury in the work place: issues and solutions
Lee JS; Rom WN; Craft BF
1983 May;6(1):1-15, Family & community health
— id: 15429, year: 1983, vol: 6, page: 1, stat: Journal Article,

Lymphocyte sister chromatid exchange (SCE) frequencies in coke oven workers
Miner JK; Rom WN; Livingston GK; Lyon JL
1983 Jan;25(1):30-33, Journal of occupational medicine
Lymphocyte sister chromatid exchange (SCE) frequencies were determined for 12 long-term coke oven workers and 12 other age-matched steelworkers with no coke oven work exposure. All study participants were nonsmokers. The exposed group had a mean of 28.9 years' exposure to the coke oven emissions. SCE frequencies for the exposed individuals ranged from 7.97 to 11.20 SCEs per cell while the control individuals ranged from 6.73 to 10.60 SCEs per cell. The mean SCE frequency for the exposed group was 9.54 +/- SD 1.15 SCEs per cell, and was 14% higher than the 8.35 +/- SD 1.09 SCEs per cell of the control group (p = .016). The long-term exposure to coke oven emissions experienced by the coke oven workers may be the explanation for this small difference
— id: 15435, year: 1983, vol: 25, page: 30, stat: Journal Article,

Health implications of natural fibrous zeolites for the Intermountain West
Rom WN; Casey KR; Parry WT; Mjaatvedt CH; Moatamed F
1983 Feb;30(1):1-8, Environmental research
— id: 15434, year: 1983, vol: 30, page: 1, stat: Journal Article,

An epidemiologic study of the respiratory effects of trona dust
Rom WN; Greaves W; Bang KM; Holthouser M; Campbell D; Bernstein R
1983 Mar-Apr;38(2):86-92, Archives of environmental health
Trona (sodium sesquicarbonate) is mined from an underground deposit in Wyoming and processed for use in glass, paper, detergent, and chemical applications. Trona dust is alkaline (pH 10.5) and can have an irritant effect on respiratory airways, mucous membranes, and the skin. A study population of 142 underground miners and 88 surface workers from one facility volunteered for an epidemiologic study. Their mean age was 37.6 yr and mean duration of employment was 10.0 yr. The percentage with chronic cough and phlegm was 23%; both symptoms were more common among smokers than nonsmokers. Thirty-three percent of the workers complained of dyspnea when hurrying on level ground or walking up a slight hill. Half of the workers complained of upper respiratory tract symptoms and eye irritation. Both smokers and exsmokers had significant declines of forced expiratory volume in 1 sec (FEV1.0) with age; exsmokers also had declines with work-years when compared to a nonsmoking comparison population. Nonsmokers with personal dust measurements had a significant decline of FEV1.0 related to respirable dust exposure. A shift study of 104 workers revealed a significant fall in FEV1.0 among nonsmokers and surface workers. Significance was approached in the high dust exposure group. An increase in the mean percent predicted forced vital capacity and FEV1.0 was shown for the 125 workers who had a 5-yr follow-up of pulmonary function. There was no correlation between the shift study decrements and the longitudinal 5-yr follow-up. Industrial hygiene dust sampling found elevated levels of total dust but lower respirable dust, with no detectable free silica
— id: 15433, year: 1983, vol: 38, page: 86, stat: Journal Article,

Sister chromatid exchange frequency in asbestos workers
Rom WN; Livingston GK; Casey KR; Wood SD; Egger MJ; Chiu GL; Jerominski L
1983 Jan;70(1):45-48, Journal of the National Cancer Institute
In vitro cytogenetic studies of amosite, chrysotile, and crocidolite asbestos have shown that these fibers may induce chromosome abnormalities and an elevated sister chromatid exchange (SCE) rate in mammalian cells. Twenty-five asbestos insulators (6 with radiographic asbestosis) were compared to 14 controls frequency matched for age and were found to have a marginally increased SCE rate in circulating lymphocytes with increasing years of exposure (P= 0.057). There was a significant association between SCE rate and smoking (P=0.002) after controlling for years of asbestos exposure and age. Smoking asbestos insulators had the highest SCE rate. Sister chromatid exchanges in chromosomes of group A, i.e., the group with the longest chromosomes, were significantly associated with asbestos exposure and cigarette smoking, with an interaction between the two
— id: 15436, year: 1983, vol: 70, page: 45, stat: Journal Article,

Reversible beryllium sensitization in a prospective study of beryllium workers
Rom WN; Lockey JE; Bang KM; Dewitt C; Johns RE Jr
1983 Sep-Oct;38(5):302-307, Archives of environmental health
Chronic beryllium disease is a granulomatous and fibrotic pulmonary disorder with increased numbers and percentage of lymphocytes in bronchoalveolar lavage fluid similar to that found in hypersensitivity pneumonitis. Blastogenic lymphocyte transformation (LT) to beryllium salts has been described in lavage and blood lymphocytes in patients with chronic beryllium disease. We conducted a 3-yr prospective study to evaluate the relationship between LT and beryllium exposure and pulmonary changes consistent with chronic beryllium disease. There were 15.9% (13/82) positive LTs in 1979 and 8.2% (5/61) in 1982. Of 11 positive LTs in 1979, 8 were negative in 1982, concomitant with a significant reduction in exposure. A positive LT was not associated with reduced pulmonary function, and no radiographic changes consistent with beryllium disease were identified. We propose that LT in beryllium workers is related to exposure and is reversible when exposure levels are reduced through diligent industrial hygiene measures
— id: 15425, year: 1983, vol: 38, page: 302, stat: Journal Article,

A study of dermatitis in trona miners and millers
Rom WN; Moshell A; Greaves W; Bang KM; Holthouser M; Campbell D; Bernstein R
1983 Apr;25(4):295-299, Journal of occupational medicine
Trona (sodium sesquicarbonate) is mined from an underground deposit in Wyoming and processed for use in the manufacture of glass, paper, and detergents, and in chemical applications. Trona dust is alkaline (pH 10.5) and may have an irritant effect on the respiratory airways, mucous membranes, and the skin. One hundred forty-two underground miners and 88 surface workers from one trona facility participated voluntarily in an epidemiologic and clinical study. Their mean age was 37.6 and their mean working period, 10.0 years. One half of the study participants complained of skin symptoms; dermatologic symptoms increased from twofold to fifteenfold after the subjects began trona mining. Trona dermatitis consists of pruritic, erythematous, raised, dry, and fissured lesions commonly affecting the hands, arms, and legs. A dose-response relationship was observed among underground workers. Patch testing with 10% aqueous trona and sodium carbonate was negative, suggesting that the dermatitis was primarily irritant in nature
— id: 15430, year: 1983, vol: 25, page: 295, stat: Journal Article,

Antinuclear antibodies in Utah coal miners
Rom WN; Turner WG; Kanner RE; Renzetti AD Jr; Peebles C; Tan E; Olsen DM
1983 Mar;83(3):515-519, Chest
Antinuclear antibodies (ANA) were detected using a mouse kidney substrate in 69 of 238 (29 percent) underground Utah coal miners at a titer of 1:16. At titers of 1:4 and higher, 52 percent were positive. The majority had a speckled pattern and were not directed against any previously characterized antigens. Fifteen of 28 with high titer ANA had reduced complement. The ANA was more apt to be present in those with coal workers' pneumoconiosis (CWP), and as ANA titer increased, the percentage with CWP increased. The ANA increased with both age and coal mine dust exposure. It is hypothesized that ANA and CWP both result from long-term dust exposure, but that there is insufficient evidence to implicate ANA in the pathogenesis of CWP
— id: 15431, year: 1983, vol: 83, page: 515, stat: Journal Article,

Environmental and occupational medicine
Rom, William N.; Renzetti, Attilio D.; Lee, Jeffrey S.; Archer, Victor E.; Selikoff, Irving J
Boston : Little, Brown, c1983,
— id: 223, year: 1983, vol: , page: , stat: ,

Occupational health and safety
Rom, William N; Lee, Jeffrey S
Gaithersburg MD : Aspen Systems, 1983,
— id: 1298, year: 1983, vol: , page: , stat: ,

Health issues related to metal and nonmetallic mining
Wagner, William L; Rom, William N; Merchant, James A
Boston : Butterworth, 1983,
— id: 1304, year: 1983, vol: , page: , stat: ,

Prevalence of antinuclear antibodies in a normal male population
White GL Jr; Wood SD; Rom WN
1983 Jun;148(6):536-538, Military medicine
— id: 15428, year: 1983, vol: 148, page: 536, stat: Journal Article,

Pentachlorophenol poisoning
Wood S; Rom WN; White GL Jr; Logan DC
1983 Jul;25(7):527-530, Journal of occupational medicine
Pentachlorophenol (PCP) is a pesticide commonly used as a wood preservative. Although exposure has been well controlled in large chemical manufacturing plants, over-exposures have recently becomes a concern at smaller facilities. Five cases of PCP poisoning, including two fatalities, occurred in two small wood preservative plants. All cases presented with fever, including severe hyperpyrexia in two; an increased anion gap and renal insufficiency were noted in two others. PCP may uncouple oxidative phosphorylation, resulting in a poisoning syndrome characterized by hyperpyrexia, diaphoresis, tachycardia, tachypnea, abdominal pain, nausea, and even death
— id: 15427, year: 1983, vol: 25, page: 527, stat: Journal Article,

Characterization of zeolite fiber sizes using scanning electron microscopy
Wright WE; Rom WN; Moatamed F
1983 Mar-Apr;38(2):99-103, Archives of environmental health
A synthetic zeolite and four natural zeolites from the western United States were examined for fibers using a scanning electron microscope. The distributions of fiber sizes were compared to distributions of fiber sizes of erionite and fibrous glass to determine if the fiber sizes were similar to those associated with mesothelioma in humans and animals. Fibers were abundant in two samples of natural erionite, rare in two samples of natural mordenite, and not present in the sample of synthetic mordenite. Although the majority of the erionite fibers were short (less than 8 mu long) and thicker than the tumorigenic erionite (greater than 0.25 mu wide), 6% and 11% of the fibers corresponded to fiber size categories of fibrous glass that have correlated with pleural mesothelioma production in rats. Even a single species of zeolite (erionite) is not uniform in its distribution of fiber sizes. On the basis of fiber size, these natural zeolites should be evaluated because of their potential carcinogenic risk
— id: 15432, year: 1983, vol: 38, page: 99, stat: Journal Article,

Diffuse malignant mesothelioma: a review
Rom WN; Lockey JE
1982 Dec;137(6):548-554, Western journal of medicine
— id: 15437, year: 1982, vol: 137, page: 548, stat: Journal Article,

Lung cancer mortality among residents living near the El Paso smelter
Rom WN; Varley G; Lyon JL; Shopkow S
1982 Aug;39(3):269-272, British journal of industrial medicine
Occupational exposure to arsenic has been associated with cancer of the lung, but epidemiological studies of cancer of the lung and environmental exposure to arsenic have produced conflicting results. Case-control studies about point sources of pollution have been useful in identifying environmental hazards. This technique was used to evaluate the risk for lung cancer near a smelter in El Paso, Texas, that uses an arsenic-containing ore and has been in continuous operation since 1887. A comparison of 575 cases of lung cancer with 1490 breast and prostate controls collected from 1944 to 1973 found no significant associations with distance using 2-km concentric circles out to 20 km from the smelter
— id: 15438, year: 1982, vol: 39, page: 269, stat: Journal Article,

Legal and ethical dilemmas in occupational health
Rom, William N; Lee, Jeffrey S
Ann Arbor MI : Ann Arbor Science, 1982,
— id: 1301, year: 1982, vol: , page: , stat: ,

Environmental/occupational lung disease
Rom, William N; Lockey, James E; Casey, Kenneth R
Salt Lake City UT : Rocky Mountain Center for Occupational Health, 1982,
— id: 1305, year: 1982, vol: , page: , stat: ,

Asbestos-related diseases
Casey KR; Rom WN; Moatamed F
1981 May;2(2):179-202, Clinics in chest medicine
— id: 15440, year: 1981, vol: 2, page: 179, stat: Journal Article,

Relationship between lung cancer and distance of residence from nonferrous smelter stack effluent
Greaves WW; Rom WN; Lyon JL; Varley G; Wright DD; Chiu G
1981 ;2(1):15-23, American journal of industrial medicine
Because of a reported association between residence in counties with nonferrous smelters and increased risk of lung cancer, we studied the relationship between distance of residence from nonferrous smelters and lung cancer. Patients with lung cancer and patients with other cancers not known to be associated with smelter effluent (breast, prostate, and colon) were compared. All patients lived within a 20-kilometer radius around one of 10 nonferrous smelters in five western states during 1970-1977. Data were obtained from cancer registries or death certificates and were examined separately for each area. Addresses at the time of diagnosis or death were plotted on U.S. Geological Survey maps to calculate distance from each smelter. The distribution of lung cancer near the smelters was not significantly different from the distribution of control cancers in any of the areas studied
— id: 15442, year: 1981, vol: 2, page: 15, stat: Journal Article,

Occupational and environmental health programs in a medical school: should they be a department?
Rom WN
1981 Nov;56(11):914-916, Journal of medical education
— id: 15439, year: 1981, vol: 56, page: 914, stat: Journal Article,

Respiratory disease in Utah coal miners
Rom WN; Kanner RE; Renzetti AD Jr; Shigeoka JW; Barkman HW; Nichols M; Turner WA; Coleman M; Wright WE
1981 Apr;123(4 Pt 1):372-377, American review of respiratory disease
Two hundred forty-two Utah underground coal miners volunteered to participate in a respiratory disease study. They were an older group (mean, 56 years of age) and had spent a mean of 29 years in the coal-mining industry. The prevalence of chronic bronchitis was 57%, and that of coal worker's pneumoconiosis, 25%; only one worker had progressive massive fibrosis. Significant impairment of pulmonary function was found among those with a history of cigarette smoking. Chronic bronchitis or coal worker's penumoconiosis among nonsmokers did not impair pulmonary function. There was a significant association among the nonsmokers between increasing exposure to coal dust and coal worker's pneumoconiosis, but not for changes in pulmonary function. Coal mine dust had a significant influence in causing the symptom complex of chronic cough and sputum production, and coal worker's pneumoconiosis
— id: 15441, year: 1981, vol: 123, page: 372, stat: Journal Article,

Occupational and environmental health problems of the developing oil shale industry: a review
Rom WN; Lee JS; Craft BF
1981 ;2(3):247-260, American journal of industrial medicine
The American oil shale industry is on the threshold of commercial industrial development. Potential occupational hazards include shalosis or oil shale pneumoconiosis, dermatoses, cancer of the skin, lung, and possibly other sites, and accidents. Air, water, and solid waste pollution problems are complicated by the aridity of the Green River oil shale formation located in Utah, Colorado, and Wyoming. The region currently lacks the schools, health facilities, community services, and skilled labor required for large-scale development. The oil shale industry faces an opportunity and a challenge of prudently assessing and controlling exposures and contributing to the social development of the region
— id: 15443, year: 1981, vol: 2, page: 247, stat: Journal Article,

... Second Annual Park City Environmental Health Conference
Rom, William N; Peters, John M
New York : Alan R Liss, 1981,
— id: 1299, year: 1981, vol: , page: , stat: ,

Asbestos-induced sister chromatid exchanges in cultured Chinese hamster ovarian fibroblast cells
Livingston GK; Rom WN; Morris MV
1980 Sep;4(2-3):373-382