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1.
Artigo em Inglês | MEDLINE | ID: mdl-37372732

RESUMO

INTRODUCTION: Environmental Health in a Global World at New York University was re-designed as a class participatory effort, challenging undergraduate students to understand environmental hazards and the resultant adverse health outcomes by embracing the inherent complexity of environmental risks and proposing solutions. METHODS: Following introductory lectures, students are placed into teams and assigned a specific perspective, or avatar, which includes learning to see the challenge from the perspective of a technical expert such as a biologist, an engineer, or an anthropologist. The teams then design specific systems maps to visualize the complex interactions that lead to adverse health outcomes after a given environmental exposure. The maps highlight potential leverage points where relatively minor interventions can provide a disproportionate benefit in health outcomes. The teams then explore potential interventions and identify the potential unintended consequences of those actions, develop and advocate for innovative new strategies to mitigate risk and improve outcomes. RESULTS AND DISCUSSION: Over the past 5 years, we have taught this methodology to over 680 students with strong, student-oriented results. The teams created and presented more than 100 strategies, addressing a diverse set of environmental challenges that include water contamination, gun violence, air pollution, environmental justice, health security, and climate change. Developing the strategies helped the students understand environmental threats in a more holistic way, provided them with some agency in finding solutions, and offered an opportunity for them to improve their presentation skills. The responses in course evaluations have been enthusiastic, with many students reporting a deep impact on their college experience.


Assuntos
Aprendizagem , Estudantes , Humanos , Exposição Ambiental , New York , Saúde Ambiental
2.
Artigo em Inglês | MEDLINE | ID: mdl-38248506

RESUMO

The climate crisis is a health emergency: breaking temperature records every successive month, increasing mortality from hurricanes/cyclones resulting in >USD150 billion/year in damages, and mounting global loss of life from floods, droughts, and food insecurity. An entire course on climate change and global public health was envisioned, designed for students in public health, and delivered to Masters level students. The course content included the physical science behind global heating, heat waves, extreme weather disasters, arthropod-related diseases, allergies, air pollution epidemiology, melting ice and sea level rise, climate denialism, renewable energy and economics, social cost of carbon, and public policy. The methods included student engagement in presenting two air pollution epidemiological or experimental papers on fossil fuel air pollution. Second, they authored a mid-term paper on a specific topic in the climate crisis facing their locale, e.g., New York City. Third, they focused on a State, evaluating their climate change laws and their plans to harness renewable wind, solar, storage, nuclear, and geothermal energy. Students elsewhere covered regional entities' approach to renewable energy. Fourth, the global impact was presented by student teams presenting a country's nationally determined contribution to the Paris Climate Agreement. Over 200 Master's students completed the course; the participation and feedback demonstrated markedly improved knowledge and evaluation of the course over time.


Assuntos
Mudança Climática , Saúde Pública , Humanos , Escolaridade , Estudantes , Temperatura
3.
Am J Ind Med ; 65(4): 286-320, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35156722

RESUMO

A tribute to Dr. Irving J. Selikoff MD, the founder of this journal, is indeed welcome now more than two decades after his passing. He was known during his lifetime as the US Father of Environmental Medicine which at the time encompassed occupational medicine and much more as industry also polluted the general environment. The 1970s were a busy time as OSHA and the EPA were newly formed and high exposures to workers were no exception. Dr. Selikoff was a brave pioneer examining workers throughout the country and Canada, publicizing their exposures, and writing and presenting the scientific results. Industry was not always receptive and controlled an astounding amount of narrative, with the creation of the American Journal of Industrial Medicine filling a void of scientific need. We four authors write about the ethics of occupational health, the plight of nuclear energy workers, the climate crisis and opportunity for unions to engage workers, and the global march toward educating medical students on workers' health and safety. All four of us interacted with Dr. Selikoff during his tenure at Mount Sinai, and over the years joined each other in promoting his legacy. Toward that end we have written articles honoring his memory.


Assuntos
Medicina Ambiental , Administração Financeira , Neoplasias , Saúde Ocupacional , Medicina do Trabalho , Humanos , Masculino , Estados Unidos
4.
Cancer Discov ; 11(2): 293-307, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33177060

RESUMO

In lung cancer, enrichment of the lower airway microbiota with oral commensals commonly occurs, and ex vivo models support that some of these bacteria can trigger host transcriptomic signatures associated with carcinogenesis. Here, we show that this lower airway dysbiotic signature was more prevalent in the stage IIIB-IV tumor-node-metastasis lung cancer group and is associated with poor prognosis, as shown by decreased survival among subjects with early-stage disease (I-IIIA) and worse tumor progression as measured by RECIST scores among subjects with stage IIIB-IV disease. In addition, this lower airway microbiota signature was associated with upregulation of the IL17, PI3K, MAPK, and ERK pathways in airway transcriptome, and we identified Veillonella parvula as the most abundant taxon driving this association. In a KP lung cancer model, lower airway dysbiosis with V. parvula led to decreased survival, increased tumor burden, IL17 inflammatory phenotype, and activation of checkpoint inhibitor markers. SIGNIFICANCE: Multiple lines of investigation have shown that the gut microbiota affects host immune response to immunotherapy in cancer. Here, we support that the local airway microbiota modulates the host immune tone in lung cancer, affecting tumor progression and prognosis.See related commentary by Zitvogel and Kroemer, p. 224.This article is highlighted in the In This Issue feature, p. 211.


Assuntos
Adenocarcinoma/mortalidade , Disbiose/complicações , Neoplasias Pulmonares/mortalidade , Adenocarcinoma/complicações , Adenocarcinoma/microbiologia , Adenocarcinoma/secundário , Animais , Estudos de Coortes , Modelos Animais de Doenças , Progressão da Doença , Feminino , Humanos , Neoplasias Pulmonares/complicações , Neoplasias Pulmonares/microbiologia , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Transgênicos , Microbiota , Metástase Neoplásica , Estadiamento de Neoplasias , New York , Modelos de Riscos Proporcionais , Análise de Sobrevida
5.
Respir Res ; 21(1): 228, 2020 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-32878618

RESUMO

BACKGROUND: Emphysema in asymptomatic heavy smokers can be detected during CT-scan screening for lung cancer. Metalloproteinases (MMPs) have been found to play a role in the pathogenesis of chronic obstructive pulmonary disease and to possibly serve as biomarkers for emphysema. METHODS: The NYU Lung Cancer Biomarker Center enrolled study subjects over 50 years of age with lung cancer risk factors from January 1, 2010, to December 31, 2015. These subjects received chest multi-detector computed tomography, spirometry, and provided serum for immunoassays for metalloproteinases (MMP) -1, -2, -7, -9, -10 and tissue inhibitor of metalloproteinases (TIMP) -1 and -2. RESULTS: Three hundred sixteen study subjects were enrolled. Of the 222 patients who met the inclusion criteria, 46% had emphysema. Smokers with emphysema had increased pack-years of smoking compared to smokers without emphysema (51 ± 24 pack-years (mean ± sd) versus 37 ± 20; p < 0.0001). Smokers with emphysema also had lower FEV1/FVC percent compared to smokers without emphysema (68 ± 11 (mean ± sd) versus 75 ± 8; p < 0.0001). Increased age and pack-years of smoking were associated with increased odds of emphysema. None of the metalloproteinases or tissue inhibitors of metalloproteinases were useful to predict the presence of emphysema in smokers. CONCLUSION: Emphysema was detected by CT in almost half of heavy urban smokers. Serum MMP levels provided minimal additional information to improve the detection of mild emphysema among smokers given their clinical characteristics (age, pack-years, and FEV1/FVC ratio).


Assuntos
Metaloproteases/sangue , Doença Pulmonar Obstrutiva Crônica/sangue , Doença Pulmonar Obstrutiva Crônica/epidemiologia , Fumar Tabaco/sangue , Fumar Tabaco/epidemiologia , População Urbana , Idoso , Biomarcadores/sangue , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Doença Pulmonar Obstrutiva Crônica/diagnóstico por imagem , Fumantes , Fumar Tabaco/efeitos adversos , Tomografia Computadorizada por Raios X/métodos
6.
Cancer Res ; 79(1): 263-273, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-30487137

RESUMO

Low-dose CT (LDCT) is widely accepted as the preferred method for detecting pulmonary nodules. However, the determination of whether a nodule is benign or malignant involves either repeated scans or invasive procedures that sample the lung tissue. Noninvasive methods to assess these nodules are needed to reduce unnecessary invasive tests. In this study, we have developed a pulmonary nodule classifier (PNC) using RNA from whole blood collected in RNA-stabilizing PAXgene tubes that addresses this need. Samples were prospectively collected from high-risk and incidental subjects with a positive lung CT scan. A total of 821 samples from 5 clinical sites were analyzed. Malignant samples were predominantly stage 1 by pathologic diagnosis and 97% of the benign samples were confirmed by 4 years of follow-up. A panel of diagnostic biomarkers was selected from a subset of the samples assayed on Illumina microarrays that achieved a ROC-AUC of 0.847 on independent validation. The microarray data were then used to design a biomarker panel of 559 gene probes to be validated on the clinically tested NanoString nCounter platform. RNA from 583 patients was used to assess and refine the NanoString PNC (nPNC), which was then validated on 158 independent samples (ROC-AUC = 0.825). The nPNC outperformed three clinical algorithms in discriminating malignant from benign pulmonary nodules ranging from 6-20 mm using just 41 diagnostic biomarkers. Overall, this platform provides an accurate, noninvasive method for the diagnosis of pulmonary nodules in patients with non-small cell lung cancer. SIGNIFICANCE: These findings describe a minimally invasive and clinically practical pulmonary nodule classifier that has good diagnostic ability at distinguishing benign from malignant pulmonary nodules.


Assuntos
Biomarcadores Tumorais/genética , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Perfilação da Expressão Gênica , Neoplasias Pulmonares/diagnóstico , Nódulos Pulmonares Múltiplos/diagnóstico , Tomografia Computadorizada por Raios X/métodos , Idoso , Algoritmos , Biomarcadores Tumorais/sangue , Carcinoma Pulmonar de Células não Pequenas/sangue , Carcinoma Pulmonar de Células não Pequenas/diagnóstico por imagem , Carcinoma Pulmonar de Células não Pequenas/genética , Diagnóstico Diferencial , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/genética , Masculino , Pessoa de Meia-Idade , Nódulos Pulmonares Múltiplos/sangue , Nódulos Pulmonares Múltiplos/diagnóstico por imagem , Nódulos Pulmonares Múltiplos/genética , Estudos Prospectivos
7.
Oncogene ; 37(45): 5967-5981, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-29980786

RESUMO

It remains unclear whether PAX6 acts as a crucial transcription factor for lung cancer stem cell (CSC) traits. We demonstrate that PAX6 acts as an oncogene responsible for induction of cancer stemness properties in lung adenocarcinoma (LUAD). Mechanistically, PAX6 promotes GLI transcription, resulting in SOX2 upregulation directly by the binding of GLI to the proximal promoter region of the SOX2 gene. The overexpressed SOX2 enhances the expression of key pluripotent factors (OCT4 and NANOG) and suppresses differentiation lineage factors (HOPX and NKX2-1), driving cancer cells toward a stem-like state. In contrast, in the differentiated non-CSCs, PAX6 is transcriptionally silenced by its promoter methylation. In human lung cancer tissues, the positive linear correlations of PAX6 expression with GLI and SOX2 expression and its negative correlations with HOPX and NKX2-1 expression were observed. Therapeutically, the blockade of the PAX6-GLI-SOX2 signaling axis elicits a long-lasting therapeutic efficacy by limiting CSC expansion following chemotherapy. Furthermore, a methylation panel including the PAX6 gene yielded a sensitivity of 79.1% and specificity of 83.3% for cancer detection using serum DNA from stage IA LUAD. Our findings provide a rationale for targeting the PAX6-GLI-SOX2 signaling axis with chemotherapy as an effective therapeutic strategy and support the clinical utility of PAX6 gene promoter methylation as a biomarker for early lung cancer detection.


Assuntos
Adenocarcinoma de Pulmão/patologia , Neoplasias Pulmonares/patologia , Células-Tronco Neoplásicas/metabolismo , Fator de Transcrição PAX6/genética , Fatores de Transcrição SOXB1/metabolismo , Proteína GLI1 em Dedos de Zinco/metabolismo , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/metabolismo , Animais , Metilação de DNA , Epigênese Genética , Regulação Neoplásica da Expressão Gênica , Xenoenxertos , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Camundongos , Células-Tronco Neoplásicas/patologia , Oncogenes , Fator de Transcrição PAX6/metabolismo , Transdução de Sinais/fisiologia
8.
Proc Natl Acad Sci U S A ; 115(27): E6152-E6161, 2018 07 03.
Artigo em Inglês | MEDLINE | ID: mdl-29915082

RESUMO

Tobacco smoke (TS) contains numerous cancer-causing agents, with polycyclic aromatic hydrocarbons (PAHs) and nitrosamines being most frequently cited as the major TS human cancer agents. Many lines of evidence seriously question this conclusion. To resolve this issue, we determined DNA adducts induced by the three major TS carcinogens: benzo(a)pyrene (BP), 4-(methylnitrosamine)-1-(3-pyridyl)-1-butanoe (NNK), and aldehydes in humans and mice. In mice, TS induces abundant aldehyde-induced γ-hydroxy-propano-deoxyguanosine (γ-OH-PdG) and α-methyl-γ-OH-PdG adducts in the lung and bladder, but not in the heart and liver. TS does not induce the BP- and NNK-DNA adducts in lung, heart, liver, and bladder. TS also reduces DNA repair activity and the abundance of repair proteins, XPC and OGG1/2, in lung tissues. These TS effects were greatly reduced by diet with polyphenols. We found that γ-OH-PdG and α-methyl-γ-OH-PdG are the major adducts formed in tobacco smokers' buccal cells as well as the normal lung tissues of tobacco-smoking lung cancer patients, but not in lung tissues of nonsmokers. However, the levels of BP- and NNK-DNA adducts are the same in lung tissues of smokers and nonsmokers. We found that while BP and NNK can induce BPDE-dG and O6-methyl-dG adducts in human lung and bladder epithelial cells, these inductions can be inhibited by acrolein. Acrolein also can reduce DNA repair activity and repair proteins. We propose a TS carcinogenesis paradigm. Aldehydes are major TS carcinogens exerting dominant effect: Aldehydes induce mutagenic PdG adducts, impair DNA repair functions, and inhibit many procarcinogens in TS from becoming DNA-damaging agents.


Assuntos
Aldeídos/toxicidade , Benzo(a)pireno/toxicidade , Carcinógenos/toxicidade , Transformação Celular Neoplásica , Dano ao DNA , Reparo do DNA/efeitos dos fármacos , Neoplasias Pulmonares , Nitrosaminas/toxicidade , Poluição por Fumaça de Tabaco/efeitos adversos , Fumar Tabaco , Animais , Linhagem Celular , Transformação Celular Neoplásica/induzido quimicamente , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Transformação Celular Neoplásica/patologia , Humanos , Neoplasias Pulmonares/induzido quimicamente , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Camundongos , Fumar Tabaco/efeitos adversos , Fumar Tabaco/patologia
9.
Am J Respir Crit Care Med ; 198(9): 1188-1198, 2018 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-29864375

RESUMO

RATIONALE: In lung cancer, upregulation of the PI3K (phosphoinositide 3-kinase) pathway is an early event that contributes to cell proliferation, survival, and tissue invasion. Upregulation of this pathway was recently described as associated with enrichment of the lower airways with bacteria identified as oral commensals. OBJECTIVES: We hypothesize that host-microbe interactions in the lower airways of subjects with lung cancer affect known cancer pathways. METHODS: Airway brushings were collected prospectively from subjects with lung nodules at time of diagnostic bronchoscopy, including 39 subjects with final lung cancer diagnoses and 36 subjects with noncancer diagnoses. In addition, samples from 10 healthy control subjects were included. 16S ribosomal RNA gene amplicon sequencing and paired transcriptome sequencing were performed on all airway samples. In addition, an in vitro model with airway epithelial cells exposed to bacteria/bacterial products was performed. MEASUREMENTS AND MAIN RESULTS: The composition of the lower airway transcriptome in the patients with cancer was significantly different from the control subjects, which included up-regulation of ERK (extracellular signal-regulated kinase) and PI3K signaling pathways. The lower airways of patients with lung cancer were enriched for oral taxa (Streptococcus and Veillonella), which was associated with up-regulation of the ERK and PI3K signaling pathways. In vitro exposure of airway epithelial cells to Veillonella, Prevotella, and Streptococcus led to upregulation of these same signaling pathways. CONCLUSIONS: The data presented here show that several transcriptomic signatures previously identified as relevant to lung cancer pathogenesis are associated with enrichment of the lower airway microbiota with oral commensals.


Assuntos
Neoplasias Pulmonares/enzimologia , Microbiota/fisiologia , Fosfatidilinositol 3-Quinases/metabolismo , Sistema Respiratório/enzimologia , Regulação para Cima/fisiologia , Adulto , Idoso , Broncoscopia , Estudos Transversais , Feminino , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/microbiologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Sistema Respiratório/metabolismo , Sistema Respiratório/microbiologia
10.
Int J Cancer ; 142(11): 2355-2362, 2018 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-29313979

RESUMO

While long-term survival rates for early-stage lung cancer are high, most cases are diagnosed in later stages that can negatively impact survival rates. We aim to design a simple, single biomarker blood test for early-stage lung cancer that is robust to preclinical variables and can be readily implemented in the clinic. Whole blood was collected in PAXgene tubes from a training set of 29 patients, and a validation set of 260 patients, of which samples from 58 patients were prospectively collected in a clinical trial specifically for our study. After RNA was extracted, the expressions of FPR1 and a reference gene were quantified by an automated one-step Taqman RT-PCR assay. Elevated levels of FPR1 mRNA in whole blood predicted lung cancer status with a sensitivity of 55% and a specificity of 87% on all validation specimens. The prospectively collected specimens had a significantly higher 68% sensitivity and 89% specificity. Results from patients with benign nodules were similar to healthy volunteers. No meaningful correlation was present between our test results and any clinical characteristic other than lung cancer diagnosis. FPR1 mRNA levels in whole blood can predict the presence of lung cancer. Using this as a reflex test for positive lung cancer screening computed tomography scans has the potential to increase the positive predictive value. This marker can be easily measured in an automated process utilizing off-the-shelf equipment and reagents. Further work is justified to explain the source of this biomarker.


Assuntos
Biomarcadores Tumorais , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Carcinoma Pulmonar de Células não Pequenas/genética , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/genética , RNA Mensageiro , Receptores de Formil Peptídeo/genética , Carcinoma de Pequenas Células do Pulmão/diagnóstico , Carcinoma de Pequenas Células do Pulmão/genética , Estudos de Casos e Controles , Comorbidade , Detecção Precoce de Câncer , Feminino , Humanos , Masculino , Estadiamento de Neoplasias , Curva ROC
11.
Clin Cancer Res ; 23(22): 7141-7152, 2017 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-28855354

RESUMO

Purpose: To establish a novel panel of cancer-specific methylated genes for cancer detection and prognostic stratification of early-stage non-small cell lung cancer (NSCLC).Experimental Design: Identification of differentially methylated regions (DMR) was performed with bumphunter on "The Cancer Genome Atlas (TCGA)" dataset, and clinical utility was assessed using quantitative methylation-specific PCR assay in multiple sets of primary NSCLC and body fluids that included serum, pleural effusion, and ascites samples.Results: A methylation panel of 6 genes (CDO1, HOXA9, AJAP1, PTGDR, UNCX, and MARCH11) was selected from TCGA dataset. Promoter methylation of the gene panel was detected in 92.2% (83/90) of the training cohort with a specificity of 72.0% (18/25) and in 93.0% (40/43) of an independent cohort of stage IA primary NSCLC. In serum samples from the later 43 stage IA subjects and population-matched 42 control subjects, the gene panel yielded a sensitivity of 72.1% (31/41) and specificity of 71.4% (30/42). Similar diagnostic accuracy was observed in pleural effusion and ascites samples. A prognostic risk category based on the methylation status of CDO1, HOXA9, PTGDR, and AJAP1 refined the risk stratification for outcomes as an independent prognostic factor for an early-stage disease. Moreover, the paralog group for HOXA9, predominantly overexpressed in subjects with HOXA9 methylation, showed poor outcomes.Conclusions: Promoter methylation of a panel of 6 genes has potential for use as a biomarker for early cancer detection and to predict prognosis at the time of diagnosis. Clin Cancer Res; 23(22); 7141-52. ©2017 AACR.


Assuntos
Biomarcadores Tumorais , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/mortalidade , DNA Tumoral Circulante , Metilação de DNA , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Pulmonar de Células não Pequenas/sangue , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Terapia Combinada , Ilhas de CpG , Detecção Precoce de Câncer , Epigênese Genética , Feminino , Perfilação da Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/diagnóstico , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Derrame Pleural Maligno/genética , Derrame Pleural Maligno/metabolismo , Prognóstico , Regiões Promotoras Genéticas
12.
Clin Proteomics ; 14: 25, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28694742

RESUMO

BACKGROUND: The number of pulmonary nodules detected in the US is expected to increase substantially following recent recommendations for nationwide CT-based lung cancer screening. Given the low specificity of CT screening, non-invasive adjuvant methods are needed to differentiate cancerous lesions from benign nodules to help avoid unnecessary invasive procedures in the asymptomatic population. We have constructed a serum-based multi-biomarker panel and assessed its clinical accuracy in a retrospective analysis of samples collected from participants with suspicious radiographic findings in the Prostate, Lung, Chest and Ovarian (PLCO) cancer screening trial. METHODS: Starting with a set of 9 candidate biomarkers, we identified 8 that exhibited limited pre-analytical variability with increasing clotting time, a key pre-analytical variable associated with the collection of serum. These 8 biomarkers were evaluated in a training study consisting of 95 stage I NSCLC patients and 186 smoker controls where a 5-biomarker pulmonary nodule classifier (PNC) was selected. The clinical accuracy of the PNC was determined in a blinded study of asymptomatic individuals comprising 119 confirmed malignant nodule cases and 119 benign nodule controls selected from the PLCO screening trial. RESULTS: A PNC comprising 5 biomarkers: CEA, CYFRA 21-1, OPN, SCC, and TFPI, was selected in the training study. In an independent validation study, the PNC resolved lung cancer cases from benign nodule controls with an AUC of 0.653 (p < 0.0001). CEA and CYFRA 21-1, two of the markers included in the PNC, also accurately distinguished malignant lesions from benign controls. CONCLUSIONS: A 5-biomarker blood test has been developed for the diagnostic evaluation of asymptomatic individuals with solitary pulmonary nodules.

13.
Oncoimmunology ; 6(5): e1310359, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28638733

RESUMO

Identification of biomarkers for early detection of lung cancer (LC) is important, in turn leading to more effective treatment and reduction of mortality. Serological proteome analysis (SERPA) was used to identify proteins around 34 kD as ECH1 and HNRNPA2B1, which had been recognized by serum autoantibody from 25 LC patients. In the validation study, including 90 sera from LC patients and 89 sera from normal individuals, autoantibody to ECH1 achieved an area under the curve (AUC) of 0.799 with sensitivity of 62.2% and specificity of 95.5% in discriminating LC from normal individuals, and showed negative correlation with tumor size (rs = -0.256, p = 0.023). Autoantibody to HNRNPA2B1 performed an AUC of 0.874 with sensitivity of 72.2% and specificity of 95.5%, and showed negative correlation with lymph node metastasis (rs = -0.279, p = 0.012). By using longitudinal preclinical samples, autoantibody to ECH1 showed an AUC of 0.763 with sensitivity of 60.0% and specificity of 89.3% in distinguishing early stage LC from matched normal controls, and elevated autoantibody levels could be detected greater than 2 y before LC diagnosis. ECH1 and HNRNPA2B1 are autoantigens that elicit autoimmune responses in LC and their autoantibody can be the potential biomarkers for the early detection of LC.

14.
Cell Host Microbe ; 21(4): 530-537.e4, 2017 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-28366509

RESUMO

Despite the immune-reconstitution with antiretroviral therapy (ART), HIV-infected individuals remain highly susceptible to tuberculosis (TB) and have an enrichment of oral anaerobes in the lung. Products of bacterial anaerobic metabolism, like butyrate and other short-chain fatty acids (SCFAs), induce regulatory T cells (Tregs). We tested whether SCFAs contribute to poor TB control in a longitudinal cohort of ART-treated HIV-infected South Africans. Increase in serum SCFAs was associated with increased TB susceptibility. SCFAs inhibited IFN-γ and IL-17A production in peripheral blood mononuclear cells from HIV-infected ART-treated individuals in response to M. tuberculosis antigen stimulation. Pulmonary SCFAs correlated with increased oral anaerobes, such as Prevotella in the lung, and with M. tuberculosis antigen-induced Tregs. Metabolites from anaerobic bacterial fermentation may, therefore, increase TB susceptibility by suppressing IFN-γ and IL-17A production during the cellular immune response to M. tuberculosis.


Assuntos
Bactérias Anaeróbias/metabolismo , Suscetibilidade a Doenças , Ácidos Graxos Voláteis/sangue , Infecções por HIV/tratamento farmacológico , Fatores Imunológicos/sangue , Mycobacterium tuberculosis/imunologia , Tuberculose Pulmonar/imunologia , Antirretrovirais/uso terapêutico , Bactérias Anaeróbias/crescimento & desenvolvimento , Ácidos Graxos Voláteis/metabolismo , Infecções por HIV/complicações , Humanos , Fatores Imunológicos/metabolismo , Interferon gama/metabolismo , Interleucina-17/metabolismo , Leucócitos Mononucleares/imunologia , Estudos Longitudinais , Pulmão/microbiologia , África do Sul , Linfócitos T Reguladores/imunologia , Tuberculose Pulmonar/epidemiologia
15.
Carcinogenesis ; 38(3): 271-280, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-28049629

RESUMO

Lung cancer is the leading cause of cancer mortality in the United States with non-small cell lung cancer (NSCLC) adenocarcinoma being the most common histological type. Early perturbations in cellular metabolism are a hallmark of cancer, but the extent of these changes in early stage lung adenocarcinoma remains largely unknown. In the current study, an integrated metabolomics and proteomics approach was utilized to characterize the biochemical and molecular alterations between malignant and matched control tissue from 27 subjects diagnosed with early stage lung adenocarcinoma. Differential analysis identified 71 metabolites and 1102 proteins that delineated tumor from control tissue. Integrated results indicated four major metabolic changes in early stage adenocarcinoma: (1) increased glycosylation and glutaminolysis; (2) elevated Nrf2 activation; (3) increase in nicotinic and nicotinamide salvaging pathways; and (4) elevated polyamine biosynthesis linked to differential regulation of the SAM/nicotinamide methyl-donor pathway. Genomic data from publicly available databases were included to strengthen proteomic findings. Our findings provide insight into the biochemical and molecular biological reprogramming that may accompanies early stage lung tumorigenesis and highlight potential therapeutic targets.

16.
Thorax ; 72(1): 13-22, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27486204

RESUMO

INTRODUCTION: Azithromycin (AZM) reduces pulmonary inflammation and exacerbations in patients with COPD having emphysema. The antimicrobial effects of AZM on the lower airway microbiome are not known and may contribute to its beneficial effects. Here we tested whether AZM treatment affects the lung microbiome and bacterial metabolites that might contribute to changes in levels of inflammatory cytokines in the airways. METHODS: 20 smokers (current or ex-smokers) with emphysema were randomised to receive AZM 250 mg or placebo daily for 8 weeks. Bronchoalveolar lavage (BAL) was performed at baseline and after treatment. Measurements performed in acellular BAL fluid included 16S rRNA gene sequences and quantity; 39 cytokines, chemokines and growth factors and 119 identified metabolites. The response to lipopolysaccharide (LPS) by alveolar macrophages after ex-vivo treatment with AZM or bacterial metabolites was assessed. RESULTS: Compared with placebo, AZM did not alter bacterial burden but reduced α-diversity, decreasing 11 low abundance taxa, none of which are classical pulmonary pathogens. Compared with placebo, AZM treatment led to reduced in-vivo levels of chemokine (C-X-C) ligand 1 (CXCL1), tumour necrosis factor (TNF)-α, interleukin (IL)-13 and IL-12p40 in BAL, but increased bacterial metabolites including glycolic acid, indol-3-acetate and linoleic acid. Glycolic acid and indol-3-acetate, but not AZM, blunted ex-vivo LPS-induced alveolar macrophage generation of CXCL1, TNF-α, IL-13 and IL-12p40. CONCLUSION: AZM treatment altered both lung microbiota and metabolome, affecting anti-inflammatory bacterial metabolites that may contribute to its therapeutic effects. TRIAL REGISTRATION NUMBER: NCT02557958.


Assuntos
Antibacterianos/farmacologia , Azitromicina/farmacologia , Citocinas/análise , Pulmão/microbiologia , Metaboloma/efeitos dos fármacos , Microbiota/efeitos dos fármacos , RNA Ribossômico 16S/análise , Idoso , Antibacterianos/uso terapêutico , Azitromicina/uso terapêutico , Líquido da Lavagem Broncoalveolar/química , Líquido da Lavagem Broncoalveolar/microbiologia , Quimiocina CXCL1/análise , Método Duplo-Cego , Feminino , Glicolatos/metabolismo , Humanos , Ácidos Indolacéticos/metabolismo , Inflamação/tratamento farmacológico , Subunidade p40 da Interleucina-12/análise , Interleucina-13/análise , Ácido Linoleico/metabolismo , Macrófagos Alveolares , Masculino , Pessoa de Meia-Idade , Enfisema Pulmonar , Fator de Necrose Tumoral alfa/análise
17.
ERJ Open Res ; 2(4)2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27995132

RESUMO

Smoking induced inflammation leads to distal airway destruction. However, the relationship between distal airway dysfunction and inflammation remains unclear, particularly in smokers prior to the development of airway obstruction. Seven normal controls and 16 smokers without chronic obstructive pulmonary disease (COPD) were studied. Respiratory function was assessed using the forced oscillation technique (FOT). Abnormal FOT was defined as elevated resistance at 5 Hz (R5). Parameters reflecting distal lung function included frequency dependence of resistance (R5-20) and dynamic elastance (X5). Inflammation was quantified in concentrated bronchoalveolar lavage utilising cell count differential and cytokines expressed as concentration per mL epithelial lining fluid. All control subjects and seven smokers had normal R5. Nine smokers had elevated R5 with abnormal R5-20 and X5, indicating distal lung dysfunction. The presence of abnormal FOT was associated with two-fold higher lymphocyte and neutrophil counts (p<0.025) and with higher interleukin (IL)-8, eotaxin and fractalkine levels (p<0.01). Reactivity of R5-20 and X5 correlated with levels of IL-8, eotaxin, fractalkine, IL-12p70 and transforming growth factor-α (r>0.47, p<0.01). Distal airway dysfunction in smokers without COPD identifies the presence of distal lung inflammation that parallel reported observations in established COPD. These findings were not evident on routine pulmonary function testing and may allow the identification of smokers at risk of progression to COPD.

18.
Lung Cancer ; 99: 172-9, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27565936

RESUMO

OBJECTIVES: Autoantibodies against tumor-associated antigens (TAAs) identified in patients with advanced lung cancer may be detected in subjects with early lung cancer or even predate the diagnosis. The purpose of this study is to address the temporal relationship between lung cancer development and serum autoantibody response. MATERIALS AND METHODS: Two cohorts of patients with newly diagnosed lung cancer were included. The first cohort included 90 sera from patients with lung cancer (Stages I-III) and 89 normal control sera. In the second cohort, 93 serial serum samples from 25 patients with CT-scan screen-detected stage I lung cancer were collected before the diagnosis of lung cancer (average 32 months) and 56 controls were matched on age, gender, and smoking. Autoantibody levels were measured by immunoassay. RESULTS: Measurement of autoantibodies against seven TAAs (14-3-3ζ, c-Myc, MDM2, NPM1, p16, p53 and cyclin B1) individually could discriminate lung cancer patients from normal individuals in the first cohort and the area under curve (AUC) was 0.863 based on a panel of seven autoantibodies, with sensitivity of 68.9% and specificity of 79.5%. Autoantibodies in serial pre-diagnostic serum samples against the same panel of seven TAAs were detected prior to lung cancer diagnosis with sensitivity of 76.0% and specificity of 73.2% (AUC) (95%CI): 0.885 (0.797-0.973)). Elevated autoantibody levels could be detected greater than four years prior to lung cancer diagnosis. CONCLUSION: A panel of seven TAAs may enhance the early detection of lung cancer, consistent with a humoral immune response to TAAs that can be detected months to years prior to the diagnosis.


Assuntos
Antígenos de Neoplasias/imunologia , Autoanticorpos/imunologia , Biomarcadores Tumorais , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos de Neoplasias/sangue , Autoanticorpos/sangue , Estudos de Casos e Controles , Detecção Precoce de Câncer , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Neoplasias Pulmonares/sangue , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Nucleofosmina , Curva ROC , Sensibilidade e Especificidade , Carga Tumoral
19.
Nat Microbiol ; 1: 16031, 2016 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-27572644

RESUMO

Microaspiration is a common phenomenon in healthy subjects, but its frequency is increased in chronic inflammatory airway diseases, and its role in inflammatory and immune phenotypes is unclear. We have previously demonstrated that acellular bronchoalveolar lavage samples from half of the healthy people examined are enriched with oral taxa (here called pneumotypeSPT) and this finding is associated with increased numbers of lymphocytes and neutrophils in bronchoalveolar lavage. Here, we have characterized the inflammatory phenotype using a multi-omic approach. By evaluating both upper airway and acellular bronchoalveolar lavage samples from 49 subjects from three cohorts without known pulmonary disease, we observed that pneumotypeSPT was associated with a distinct metabolic profile, enhanced expression of inflammatory cytokines, a pro-inflammatory phenotype characterized by elevated Th-17 lymphocytes and, conversely, a blunted alveolar macrophage TLR4 response. The cellular immune responses observed in the lower airways of humans with pneumotypeSPT indicate a role for the aspiration-derived microbiota in regulating the basal inflammatory status at the pulmonary mucosal surface.


Assuntos
Microbiota , Pneumonia/microbiologia , Pneumonia/patologia , Aspiração Respiratória/complicações , Células Th17/imunologia , Líquido da Lavagem Broncoalveolar/citologia , Líquido da Lavagem Broncoalveolar/microbiologia , Humanos
20.
Neuromuscul Disord ; 26(8): 481-9, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27297666

RESUMO

To identify determinants of respiratory disease progression in late-onset Pompe disease (LOPD), we studied relationships between pulmonary function, respiratory muscle strength, gas exchange, and respiratory control. Longitudinal evaluation of 22 LOPD patients (mean age 38 years) was performed at 6-month intervals for 6-24 months. Measurements included vital capacity (VC), maximum inspiratory pressure (MIP), maximum expiratory pressure (MEP), tidal volume (VT), dead space (VD), and ventilatory response to CO2. Although reduction in VC correlated with MIP and MEP (p < 0.0001), some patients had normal VC despite reduced MIP and MEP (5 [23%] and 9 [41%] patients, respectively). Daytime hypercapnia was associated with reduced VC (<60% predicted) and MIP (<40% predicted). Moreover, chronic hypercapnia was associated with elevated VD/VT (≥0.44) due to falling VT (≈300 ml), compatible with reduced efficiency of CO2 clearance. The presence of hypercapnia and/or ventilatory support was associated with reduced ventilatory responsiveness to CO2 (≤0.7 l/min/mmHg). We conclude that daytime hypercapnia, an indicator of chronic respiratory failure, is tightly linked to the degree of respiratory muscle weakness and severity of pulmonary dysfunction in LOPD patients. Reductions in CO2 clearance efficiency and ventilatory responsiveness may contribute to the development of chronic daytime hypercapnia.


Assuntos
Doença de Depósito de Glicogênio Tipo II/complicações , Doença de Depósito de Glicogênio Tipo II/fisiopatologia , Insuficiência Respiratória/complicações , Insuficiência Respiratória/fisiopatologia , Adulto , Idade de Início , Pressão do Ar , Gasometria , Dióxido de Carbono/metabolismo , Progressão da Doença , Feminino , Humanos , Hipercapnia/complicações , Hipercapnia/fisiopatologia , Inalação/fisiologia , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Músculos Respiratórios/fisiopatologia , Volume de Ventilação Pulmonar , Capacidade Vital , Adulto Jovem
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