26 results on '"Sonja Rust"'
Search Results
2. Cytotoxicity, mutagenicity and genotoxicity of electronic cigarettes emission aerosols compared to cigarette smoke: the REPLICA project
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Rosalia Emma, Virginia Fuochi, Alfio Distefano, Konstantinos Partsinevelos, Sonja Rust, Fahad Zadjali, Mohammed Al Tobi, Razan Zadjali, Zaina Alharthi, Roberta Pulvirenti, Pio Maria Furneri, Riccardo Polosa, Ang Sun, Massimo Caruso, Giovanni Li Volti, and the Replica Project Group
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Medicine ,Science - Abstract
Abstract Concerns have recently increased that the integrity of some scientific research is questionable due to the inability to reproduce the claimed results of some experiments and thereby confirm that the original researcher's conclusions were justified. This phenomenon has been described as 'reproducibility crisis' and affects various fields from medicine to basic applied sciences. In this context, the REPLICA project aims to replicate previously conducted in vitro studies on the toxicity of cigarette smoke and e-cigarette aerosol, sometimes adding experiments or conditions where necessary, in order to verify the robustness and replicability of the data. In this work the REPLICA Team replicated biological and toxicological assessment published by Rudd and colleagues in 2020. As in the original paper, we performed Neutral Red Uptake (NRU) assay for the evaluation of cytotoxicity, Ames test for the evaluation of mutagenesis and In Vitro Micronuclei (IVMN) assay for the evaluation of genotoxicity on cells treated with cigarette smoke or e-cigarette aerosol. The results showed high cytotoxicity, mutagenicity and genotoxicity induced by cigarette smoke, but slight or no cytotoxic, mutagenic and genotoxic effects induced by the e-cigarette aerosol. Although the two studies presented some methodological differences, the findings supported those previously presented by Rudd and colleagues.
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- 2023
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3. Electronic nicotine delivery systems exhibit reduced bronchial epithelial cells toxicity compared to cigarette: the Replica Project
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Massimo Caruso, Rosalia Emma, Alfio Distefano, Sonja Rust, Konstantinos Poulas, Fahad Zadjali, Antonio Giordano, Vladislav Volarevic, Konstantinos Mesiakaris, Mohammed Al Tobi, Silvia Boffo, Aleksandar Arsenijevic, Pietro Zuccarello, Cesarina Giallongo, Margherita Ferrante, Riccardo Polosa, Giovanni Li Volti, and the Replica Project Group
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Medicine ,Science - Abstract
Abstract Electronic nicotine delivery systems (ENDS) may reduce health risks associated with chronic exposure to smoke and their potential benefits have been the matter of intense scientific debate. We aimed to replicate three published studies on cytotoxic and inflammatory effects of cigarette smoke and ENDS aerosol in an independent multi-center ring study. We aimed to establish the reliability of results and the robustness of conclusions by replicating the authors’ experimental protocols and further validating them with different techniques. Human bronchial epithelial cells (NCI-H292) were exposed to cigarette whole smoke and vapor phase and to aerosol from ENDS. We also assessed the inflammatory cytokines interleukin-6 and interleukin-8 and the remodeling mediator matrix metalloproteinase-1. We replicated cell viability results and confirmed that almost 80% of cytotoxic effects are due to volatile compounds in the vapor phase of smoke. Our findings substantiated the reduced cytotoxic effects of ENDS aerosol. However, our data on inflammatory and remodeling activity triggered by smoke differed significantly from those in the original reports. Taken together, independent data from multiple laboratories clearly demonstrated the reduced toxicity of ENDS products compared to cigarettes.
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- 2021
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4. Seroepidemiological Survey on the Impact of Smoking on SARS-CoV-2 Infection and COVID-19 Outcomes: Protocol for the Troina Study
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Riccardo Polosa, Venera Tomaselli, Pietro Ferrara, Alba Corina Romeo, Sonja Rust, Daniela Saitta, Filippo Caraci, Corrado Romano, Murugesan Thangaraju, Pietro Zuccarello, Jed Rose, Giulio Giacomo Cantone, Margherita Ferrante, Jonathan Belsey, Fabio Cibella, Elisa Interlandi, and Raffaele Ferri
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Medicine ,Computer applications to medicine. Medical informatics ,R858-859.7 - Abstract
BackgroundAfter the global spread of SARS-CoV-2, research has highlighted several aspects of the pandemic, focusing on clinical features and risk factors associated with infection and disease severity. However, emerging results on the role of smoking in SARS-CoV-2 infection susceptibility or COVID-19 outcomes are conflicting, and their robustness remains uncertain. ObjectiveIn this context, this study aims at quantifying the proportion of SARS-CoV-2 antibody seroprevalence, studying the changes in antibody levels over time, and analyzing the association between the biochemically verified smoking status and SARS-CoV-2 infection. MethodsThe research design involves a 6-month prospective cohort study with a serial sampling of the same individuals. Each participant will be surveyed about their demographics and COVID-19–related information, and blood sampling will be collected upon recruitment and at specified follow-up time points (ie, after 8 and 24 weeks). Blood samples will be screened for the presence of SARS-CoV-2–specific antibodies and serum cotinine, being the latter of the principal metabolite of nicotine, which will be used to assess participants’ smoking status. ResultsThe study is ongoing. It aims to find a higher antibody prevalence in individuals at high risk for viral exposure (ie, health care personnel) and to refine current estimates on the association between smoking status and SARS-CoV-2/COVID-19. ConclusionsThe added value of this research is that the current smoking status of the population to be studied will be biochemically verified to avoid the bias associated with self-reported smoking status. As such, the results from this survey may provide an actionable metric to study the role of smoking in SARS-CoV-2 infection and COVID-19 outcomes, and therefore to implement the most appropriate public health measures to control the pandemic. Results may also serve as a reference for future clinical research, and the methodology could be exploited in public health sectors and policies. International Registered Report Identifier (IRRID)DERR1-10.2196/32285
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- 2021
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5. Role of Cigarette Smoke on Angiotensin-Converting Enzyme-2 Protein Membrane Expression in Bronchial Epithelial Cells Using an Air-Liquid Interface Model
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Massimo Caruso, Alfio Distefano, Rosalia Emma, Michelino Di Rosa, Giuseppe Carota, Sonja Rust, Riccardo Polosa, Pietro Zuccarello, Margherita Ferrante, Giuseppina Raciti, and Giovanni Li Volti
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ACE-2 ,nicotine ,smoke ,cigarette ,epithelial cells ,Therapeutics. Pharmacology ,RM1-950 - Abstract
Prevalence studies of current smoking, among hospitalized COVID-19 patients, demonstrated an unexpectedly low prevalence among patients with COVID-19. The aim of the present study was to evaluate the effect of smoke from cigarettes on ACE-2 in bronchial epithelial cells. Normal bronchial epithelial cells (H292) were exposed to smoke by an air-liquid-interface (ALI) system and ACE-2 membrane protein expression was evaluated after 24 h from exposure. Our transcriptomics data analysis showed a significant selective reduction of membrane ACE-2 expression (about 25%) following smoking exposure. Interestingly, we observed a positive direct correlation between ACE-2 reduction and nicotine delivery. Furthermore, by stratifying GSE52237 as a function of ACE-2 gene expression levels, we highlighted 1,012 genes related to ACE-2 in smokers and 855 in non-smokers. Furthermore, we showed that 161 genes involved in the endocytosis process were highlighted using the online pathway tool KEGG. Finally, 11 genes were in common between the ACE-2 pathway in smokers and the genes regulated during endocytosis, while 12 genes with non-smokers. Interestingly, six in non-smokers and four genes in smokers were closely involved during the viral internalization process. Our data may offer a pharmaceutical role of nicotine as potential treatment option in COVID-19.
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- 2021
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6. Data from Zinc Protoporphyrin IX Stimulates Tumor Immunity by Disrupting the Immunosuppressive Enzyme Indoleamine 2,3-Dioxygenase
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George C. Prendergast, Mario Mautino, Alexander J. Muller, David H. Munn, Sonja Rust, James B. DuHadaway, and Richard Metz
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The tryptophan catabolic enzyme indoleamine 2,3-dioxygenase (IDO) has emerged as an important driver of immune escape in a growing number of cancers and cancer-associated chronic infections. In this study, we define novel immunotherapeutic applications for the heme precursor compound zinc protoporphyrin IX (ZnPP) based on our discovery that it is a potent small-molecule inhibitor of IDO. Inhibitory activity was determined using in vitro and in-cell enzyme assays as well as a novel in vivo pharmacodynamic system. An irreversible mechanism of inhibition was documented, consistent with competition for heme binding in newly synthesized cellular protein. siRNA methodology and an IDO-deficient mouse strain were used to verify the specificity of ZnPP as an IDO inhibitor. In a preclinical model of melanoma, ZnPP displayed antitumor properties that relied on T-cell function and IDO integrity. ZnPP also phenocopied the known antitumor properties of IDO inhibitors in preclinical models of skin and breast carcinoma. Our results suggest clinical evaluation of ZnPP as an adjuvant immunochemotherapy in chronic infections and cancers in which there is emerging recognition of a pathophysiologic role for IDO dysregulation. Mol Cancer Ther; 9(6); 1864–71. ©2010 AACR.
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- 2023
7. Supplementary Data from Zinc Protoporphyrin IX Stimulates Tumor Immunity by Disrupting the Immunosuppressive Enzyme Indoleamine 2,3-Dioxygenase
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George C. Prendergast, Mario Mautino, Alexander J. Muller, David H. Munn, Sonja Rust, James B. DuHadaway, and Richard Metz
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Supplementary Data from Zinc Protoporphyrin IX Stimulates Tumor Immunity by Disrupting the Immunosuppressive Enzyme Indoleamine 2,3-Dioxygenase
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- 2023
8. Correction to: Health outcomes in COPD smokers using heated tobacco products: a 3‑year follow‑up
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Riccardo Polosa, Jaymin B. Morjaria, Umberto Prosperini, Barbara Busà, Alfio Pennisi, Gualberto Gussoni, Sonja Rust, Marilena Maglia, and Pasquale Caponnetto
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In the acknowledgment section for JBM in the original publication of the article, the donation was not made to ASH but various charities. Hence, the correct sentence should read as “All proceeds of the work were donated to a number of charities”. The original article has been corrected.
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- 2022
9. Cytotoxicity, Mutagenicity and Genotoxicity of Electronic Cigarettes Emission Aerosols Compared to Cigarette Smoke: the REPLICA project
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Rosalia Emma, Virginia Fuochi, Alfio Distefano, Sonja Rust, Fahad Zadjali, Mohammed Al Tobi, Razan Zadjali, Zaina Alharthi, Roberta Pulvirenti, Pio Maria Furneri, Riccardo Polosa, Massimo Caruso, and Giovanni Li Volti
- Abstract
During the last decade electronic cigarettes (e-cigarettes) have been studied as an alternative devices to the tobacco cigarette, but with better safety for the health of smokers, so as to create a new approach to smoking addiction, such as the “smoking harm reduction”. This new approach, suggested by a part of the scientific world, aroused interest and debates in the regulatory field, involving all the major regulatory bodies and often creating divergences from nation to nation on the rules driving the production, distribution and consumption of these alternative products. Many studies have been conducted both in vitro and in vivo, to clarify the effects of the e-cigarette compared to the classic one. In this context, the Center of Excellence for the Acceleration of HArm Reduction (CoEHAR) was established within the University of Catania (Italy) and the multi-center project, created under its leadership, the REPLICA project, which aims to replicate in vitro studies originally conducted by tobacco and e-cigarette manufacturers, in order to verify the robustness and replicability of the data. In this work the REPLICA Team replicated part of the work published by Rudd and colleagues in 2020, which aims to establish the aerosol-induced cytotoxicity, mutagenesis and genotoxicity of a pod system e-cigarette aerosol compared to tobacco cigarette smoke. As in the original paper, we performed Neutral Red Test (NRU) for the evaluation of cytotoxicity, AMES test for the evaluation of mutagenesis and In Vitro Micronuclei (IVM) assay for the evaluation of genotoxicity on cells treated with cigarette smoke or e-cigarette aerosol. The results obtained showed high cytotoxicity, mutagenicity and genotoxicity induced by cigarette smoke, but slight or no cytotoxic, mutagenic and genotoxic effects induced by the e-cigarette aerosol. The data obtained support those previously presented by Rudd and colleagues, although we have highlighted some methodological flaws of their work. Overall, we can affirm that the results obtained by Rudd and colleagues have been established and our data also confirm the idea that e-cigarette aerosol is much safer and less harmful than cigarette smoking, making it a useful device in smoking harm reduction.
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- 2022
10. Comparative assessment of electronic nicotine delivery systems aerosol and cigarette smoke on endothelial cell migration: The Replica Project
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Massimo Caruso, Rosalia Emma, Alfio Distefano, Sonja Rust, Konstantinos Poulas, Antonio Giordano, Vladislav Volarevic, Konstantinos Mesiakaris, Silvia Boffo, Aleksandar Arsenijevic, Georgios Karanasios, Roberta Pulvirenti, Aleksandar Ilic, Angelo Canciello, Pietro Zuccarello, Margherita Ferrante, Riccardo Polosa, and Giovanni Li Volti
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ENDS ,ENDS, cells migration, cigarette smoke, e-cigarette, endothelial cells, wound healing ,cells migration ,cigarette smoke ,Pharmaceutical Science ,Environmental Chemistry ,wound healing ,e-cigarette ,Spectroscopy ,endothelial cells ,Analytical Chemistry - Abstract
Cigarette smoking is associated with impairment of repair mechanisms necessary for vascular endothelium homeostasis. Reducing the exposure to smoke toxicants may result in the mitigation of the harmful effect on the endothelium and cardiovascular disease development. Previous investigations evaluated in vitro the effect of electronic cigarette (EC) compared with cigarette smoke demonstrating a significant reduction in human umbilical vein endothelial cells (HUVECs) migration inhibition following EC aerosol exposure. In the present study, we replicated one of these studies, evaluating the effects of cigarette smoke on endothelial cell migration compared with aerosol from EC and heated tobacco products (HTPs). We performed an in vitro scratch wound assay on endothelial cells with a multi-center approach (ring-study) to verify the robustness and reliability of the results obtained in the replicated study, also testing the effect of aerosol from two HTPs on endothelial cells. Consistently with the original study, we observed a substantial reduction of the effects of aerosol from EC and HTPs on endothelial cell migration compared with cigarette smoke. While cigarette smoke reduced endothelial wound healing ability already at low concentrations (12.5%) and in a concentration-dependent manner, EC and HTPs aerosol showed no effect on endothelial cells until 80%-100% concentrations. In conclusion, our study further confirms the importance of EC and tobacco heated products as a possible harm reduction strategy for cardiovascular diseases development in smokers.
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- 2022
11. Health outcomes in COPD smokers using heated tobacco products: a 3-year follow-up
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Pasquale Caponnetto, Alfio Pennisi, Jaymin B. Morjaria, Riccardo Polosa, Sonja Rust, Barbara Busà, Marilena Maglia, Umberto Prosperini, and Gualberto Gussoni
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Male ,Complete data ,medicine.medical_specialty ,Glo ,medicine.medical_treatment ,Walk Test ,Disease ,Smoking cessation ,Electronic Nicotine Delivery Systems ,Health outcomes ,Pulmonary Disease, Chronic Obstructive ,03 medical and health sciences ,0302 clinical medicine ,Quality of life ,Internal medicine ,Tobacco harm reduction ,Internal Medicine ,COPD ,Humans ,Medicine ,In patient ,Patient Reported Outcome Measures ,030212 general & internal medicine ,Lung function ,Aged ,IQOS ,Smokers ,Heated tobacco products ,business.industry ,Walk distance ,Middle Aged ,medicine.disease ,Im - Original ,Respiratory Function Tests ,Italy ,030228 respiratory system ,Cohort ,Disease Progression ,Emergency Medicine ,Female ,business ,Follow-Up Studies - Abstract
BackgroundGiven that many patients with chronic obstructive pulmonary disease (COPD) smoke despite their symptoms, it is important to understand the long term health impact of cigarette substitution with heated tobacco products (HTPs). We monitored health parameters for 3-years in COPD patients who substantially attenuated or ceased cigarette consumption after switching to HTPs.MethodsChanges in daily cigarette smoking, annualized disease exacerbations, lung function indices, patients reported outcomes (CAT scores) and 6-minute walk distance (6MWD) from baseline were measured in COPD patients using HTPs at 12, 24 and 36 months. These were compared to a group of age- and sex-matched COPD patients who continued smoking.ResultsComplete data sets were available for 38 patients (19 in each group). Subjects using HTPs had a substantial decrease in annualized COPD exacerbations within the group mean (±SD) from 2.1 (±0.9) at baseline to 1.4 (±0.8), 1.2 (±0.8) and 1.3 (±0.8) at 12-, 24- and 36-month follow-up (pConclusionsThis study is the first to describe the long-term health effects of HTP use in COPD patients. Consistent improvements in respiratory symptoms, exercise tolerance, quality of life, and rate of disease exacerbations were observed in patients with COPD who abstained from smoking or substantially reduced their cigarette consumption by switching to HTP use.
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- 2021
12. In vitro cytoxicity profile of e-cigarette liquid samples on primary human bronchial epithelial cells
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Massimo Caruso, Alfio Distefano, Rosalia Emma, Pietro Zuccarello, Chiara Copat, Margherita Ferrante, Giuseppe Carota, Roberta Pulvirenti, Riccardo Polosa, Gesualdo Antonio Missale, Sonja Rust, Giuseppina Raciti, and Giovanni Li Volti
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microplastics ,smoke ,aerosol ,Pharmaceutical Science ,Environmental Chemistry ,cytotoxicity ,metals ,Spectroscopy ,Analytical Chemistry - Abstract
Cigarette smoke is associated to severe chronic diseases. The most harmful components of cigarette smoke derive from the combustion process, which are significantly reduced in the electronic cigarette aerosol, thus providing a valid option in harm reduction strategies. To develop safer products, it is therefore necessary to screen electronic cigarette liquids (e-liquids) to meet high safety standards defined by government regulations. The aim of the present study was to evaluate the presence of metal- and plastic-derived contaminants in four different commercial e-liquids with high concentration of nicotine and their cytotoxic effect in normal human bronchial epithelial cells by a number of in vitro assays, in comparison with the 1R6F reference cigarette, using an air-liquid interface (ALI) exposure system. Moreover, we evaluated the effect of aerosol exposure on oxidative stress by measuring the production of reactive oxygen species and mitochondrial potential. Our results showed no contaminants in all e-liquids and a significantly reduced cytotoxic effect of e-liquid aerosol compared to cigarette smoke as well as a maintained mitochondria integrity. Moreover, no production of reactive oxygen species was detected with e-cigarette aerosol. In conclusion, these results support the reduced toxicity potential of e-cigs compared to tobacco cigarettes in an in vitro model resembling real life smoke exposure.
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- 2022
13. Electronic Nicotine Delivery Systems Exhibit LowerToxicity Compared to Cigarettes: 'The Replica Study Experience'
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Alfio Distefano, Massimo Caruso, Rosalia Emma, Sonja Rust, Konstantinos Poulas, Fahad Zadjali, Silvia Boffo, Vladislav Volarevic, Konstantinos Mesiakaris, Georgios Karanasios, Mohammed Al Tobi, Najwa Albalushi, Antonio Giordano, Angelo Canciello, Aleksandar Arsenijevic, Aleksandar Ilic, Tancredi Caruso, Giuseppe Carota, Maria R. Spampinato, Pietro Zuccarello, Margherita Ferrante, Riccardo Polosa, and Giovanni Li Volti
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Genetics ,Molecular Biology ,Biochemistry ,Biotechnology - Published
- 2022
14. Seroepidemiological Survey on the Impact of Smoking on SARS-CoV-2 Infection and COVID-19 Outcomes: Protocol for the Troina Study (Preprint)
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Riccardo Polosa, Venera Tomaselli, Pietro Ferrara, Alba Corina Romeo, Sonja Rust, Daniela Saitta, Filippo Caraci, Corrado Romano, Murugesan Thangaraju, Pietro Zuccarello, Jed Rose, Giulio Giacomo Cantone, Margherita Ferrante, Jonathan Belsey, Fabio Cibella, Elisa Interlandi, and Raffaele Ferri
- Abstract
BACKGROUND After the global spread of SARS-CoV-2, research has highlighted several aspects of the pandemic, focusing on clinical features and risk factors associated with infection and disease severity. However, emerging results on the role of smoking in SARS-CoV-2 infection susceptibility or COVID-19 outcomes are conflicting, and their robustness remains uncertain. OBJECTIVE In this context, this study aims at quantifying the proportion of SARS-CoV-2 antibody seroprevalence, studying the changes in antibody levels over time, and analyzing the association between the biochemically verified smoking status and SARS-CoV-2 infection. METHODS The research design involves a 6-month prospective cohort study with a serial sampling of the same individuals. Each participant will be surveyed about their demographics and COVID-19–related information, and blood sampling will be collected upon recruitment and at specified follow-up time points (ie, after 8 and 24 weeks). Blood samples will be screened for the presence of SARS-CoV-2–specific antibodies and serum cotinine, being the latter of the principal metabolite of nicotine, which will be used to assess participants’ smoking status. RESULTS The study is ongoing. It aims to find a higher antibody prevalence in individuals at high risk for viral exposure (ie, health care personnel) and to refine current estimates on the association between smoking status and SARS-CoV-2/COVID-19. CONCLUSIONS The added value of this research is that the current smoking status of the population to be studied will be biochemically verified to avoid the bias associated with self-reported smoking status. As such, the results from this survey may provide an actionable metric to study the role of smoking in SARS-CoV-2 infection and COVID-19 outcomes, and therefore to implement the most appropriate public health measures to control the pandemic. Results may also serve as a reference for future clinical research, and the methodology could be exploited in public health sectors and policies. INTERNATIONAL REGISTERED REPORT DERR1-10.2196/32285
- Published
- 2021
15. Electronic nicotine delivery systems exhibit reduced bronchial epithelial cells toxicity compared to cigarette: The Replica Project
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Arsenijevic A, Boffo S, Li Volti G, Antonio Giordano, Massimo Caruso, Riccardo Polosa, Volarevic, K. Mesiakaris, Alfio Distefano, Konstantinos Poulas, Sonja Rust, Rosalia Emma, Fahad Zadjali, Pietro Zuccarello, Tobi Ma, and Margherita Ferrante
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Smoke ,Cigarette smoking ,Nicotine delivery ,business.industry ,Reduced toxicity ,Toxicity ,Vapor phase ,Cigarette smoke ,Medicine ,Pharmacology ,business ,Bronchial Epithelial Cell - Abstract
Cigarette smoking is the leading cause of preventable deaths worldwide. Electronic Nicotine Delivery Systems (ENDS) may reduce health risks associated with chronic exposure to smoke and their potential benefits have been the matter of intense scientific debate. Here we replicated three key published studies from the Tobacco Industry on cytotoxic and inflammatory effects of cigarette smoke and ENDS aerosol in an independent multicentric study. We aimed to establish the reliability of results and the robustness of conclusions by replicating the authors’ experimental protocols and further validating them with different techniques. We exposed human bronchial epithelial cell (NCI-H292) to cigarette smoke and to aerosol from ENDS. All the exposure were conducted at air-liquid interface to assess cytotoxicity effects of smoke and aerosol. Moreover, we aimed to assess different inflammatory mediators release (IL-6, IL-8 and MMP-1) from cells exposed to whole smoke and to smoke without particulate matter (vapor phase). We were able to replicate the results obtained in the original studies on cytotoxicity confirming that almost 80% of the cytotoxic effect of smoke is due to the vapor phase of smoke. Moreover, our results substantiated the reduced cytotoxic effects of ENDS aerosol in respect to cigarette smoke. However, our data are significantly different from the original ones in terms of inflammatory and remodeling activity triggered by smoke. Taken all together, the data obtained independently in different laboratories clearly demonstrate the reduced toxicity of ENDS products compared to cigarettes and thus providing a valuable tool to the harm reduction strategies in smokers. Competing Interest Statement Riccardo Polosa is full tenured professor of Internal Medicine at the University of Catania (Italy) and Medical Director of the Institute for Internal Medicine and Clinical Immunology at the same University. In relation to his recent work in the area of respiratory diseases, clinical immunology, and tobacco control, RP has received has received lecture fees and research funding from Pfizer, GlaxoSmithKline, CV Therapeutics, NeuroSearch A/S, Sandoz, MSD, Boehringer Ingelheim, Novartis, Duska Therapeutics, and Forest Laboratories. Lecture fees from a number of European EC industry and trade associations (including FIVAPE in France and FIESEL in Italy) were directly donated to vaper advocacy no-profit organizations. RP has also received grants from European Commission initiatives (U-BIOPRED and AIRPROM) and from the Integral Rheumatology & Immunology Specialists Network (IRIS) initiative. He has also served as a consultant for Pfizer, Global Health Alliance for treatment of tobacco dependence, CV Therapeutics, Boehringer Ingelheim, Novartis, Duska Therapeutics, ECITA (Electronic Cigarette Industry Trade Association, in the UK), Arbi Group Srl., and Health Diplomats. RP has served on the Medical and Scientific Advisory Board of Cordex Pharma, Inc., CV Therapeutics, Duska Therapeutics Inc, Pfizer, and PharmaCielo. RP is also founder of the Center for Tobacco prevention and treatment (CPCT) at the University of Catania and of the Center of Excellence for the acceleration of HArm Reduction (CoEHAR) at the same University, which has received support from Foundation for a Smoke Free World to conduct 8 independent investigator-initiated research projects on harm reduction. RP is also currently involved in the following pro bono activities: scientific advisor for LIAF, Lega Italiana Anti Fumo (Italian acronym for Italian Anti-Smoking League), the Consumer Advocates for Smoke-free Alternatives (CASAA) and the International Network of Nicotine Consumers Organizations (INNCO); Chair of the European Technical Committee for standardization on -Requirements and test methods for emissions of electronic cigarettes- (CEN/TC 437; WG4). Giovanni Li Volti is currently elected Director of the Center of Excellence for the acceleration of HArm Reduction. Konstantinos Poulas has received service grants and research funding from a number of Vaping Companies. He is the Head of the Institute of Research and Innovations, which has received a grant from the Foundation for a Smoke Free World. All the other authors declare no conflicts of interest., This investigator-initiated experimental research was produced with the help of a grant from the Foundation for a Smoke Free World. The funder had no role in the study design, or the writing of the experimental research. The contents, selection and presentation of facts, as well as any opinions expressed in the experimental research are the sole responsibility of the author and under no circumstances shall be regarded as reflecting the positions of the funder.
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- 2021
- Full Text
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16. POPULATION-BASED SERO-EPIDEMIOLOGICAL STUDY PROTOCOL FOR THE IMPACT OF SMOKING ON SARS-COV-2 INFECTION AND COVID-19 OUTCOMES – THE TROINA STUDY
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A. C. Romeo, Raffaele Ferri, Carmelo Romano, Riccardo Polosa, Valerio Tomaselli, Fabio Cibella, Juliana Lundgren Rose, Sonja Rust, Margherita Ferrante, Filippo Caraci, Jonathan Belsey, M. Thangaraju, Daniela Saitta, Pietro Ferrara, E. Interlandi, and Pietro Zuccarello
- Subjects
Research design ,medicine.medical_specialty ,education.field_of_study ,business.industry ,Public health ,Population ,Context (language use) ,Environmental health ,Epidemiology ,medicine ,Seroprevalence ,Prospective cohort study ,education ,business ,Blood sampling - Abstract
After the global spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), research has highlighted several aspects of the pandemic, focusing on clinical features and risk factors associated with infection and disease severity. However, emerging results on the role of smoking in SARS-CoV-2 infection susceptibility or COVID-19 outcomes are conflicting, and their robustness remains uncertain. In this context, this project aims at quantifying the proportion of SARS-CoV-S antibody seroprevalence, studying the changes in antibody levels over time, and analyzing the association between smoking status and infection using seroprevalence data.The added value of this research is that the current smoking status of the population to be studied will be biochemically verified, in order to avoid the bias associated with self-reported smoking status. As such, the results from this survey may provide actionable metric to study the role of smoking in SARS-CoV-2 spread, and therefore implement the most appropriate public health measures to control the pandemic.The research design involves a 6-month prospective cohort study with serial sampling of the same individuals. Each participant will be surveyed about their demographics and COVID-19-related information, and blood sampling will be collected upon recruitment and at specified follow-up time points (namely, after 8 and 24 weeks). Blood samples will be screened for the presence of SARS-CoV-2 specific antibodies and serum cotinine.Overall, we expect to find a higher prevalence of antibodies in individuals at high-risk for viral exposure (i.e., healthcare or other essential workers), according to previous literature, and to refine current estimates on the association between smoking status and SARS-CoV-2/COVID-19. Our results may serve as a reference for future clinical research and the methodology could be exploited in public health sectors and policies.
- Published
- 2021
17. Screening of different cytotoxicity methods for the assessment of ENDS toxicity relative tobacco cigarettes
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Giuseppe Carota, Roberta Pulvirenti, Massimo Caruso, Sonja Rust, Alfio Distefano, Rosalia Emma, Riccardo Polosa, and Giovanni Li Volti
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Neutral red ,chemistry.chemical_compound ,Chemistry ,Annexin ,Apoptosis ,High-content screening ,Toxicity ,media_common.cataloged_instance ,Viability assay ,European union ,Pharmacology ,Cytotoxicity ,media_common - Abstract
Electronic Nicotine Delivery Systems (ENDS), i.e., electronic cigarettes (e-cigs) and Tobacco Heating Products (THPs), are rapidly growing in popularity. The marketing of these products is regulated by specific rules in the European Union and in the US, which permit their legal sales. Nonetheless, comprehensive quality and safety requirements for regulatory purposes are still under development. Cytotoxicity studies are an important initial step in appraising the potential toxicity of ENDS. The aim of the present study was to screen a battery of different in vitro cytotoxicity methods for the assessment of toxicity induced by ENDS. We evaluated different cytotoxicity assays, including neutral red uptake (NRU), 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), Annexin V apoptosis, High Content Screening (HCS) assays and Real Time Cell Analysis (RTCA), to compare two e-cigs (Vype ePen 3 and Vype eStick Maxx) and two THPs (IQOS and GLO™) with the 1R6F reference tobacco cigarette. Human bronchial epithelial cells (H292) were exposed to 1R6F smoke (5 puffs by HCI regime), ePen vapor (10 puffs by modified HCI regime), eStick vapor (25 puffs by CRM81 regime), IQOS vapor (7 puffs by HCI regime) and GLO vapor (8 puffs by HCI regime) at air-liquid interface. All tests showed reduced cell viability following 1R6F smoke exposure and slight or no reduction with ENDS at 24 hours compared to controls. In addition, Annexin V and RTCA exhibited a further significant reduction in cell viability following 1R6F exposure compared with other assays. Furthermore, Annexin V allowed to discriminate viable cells from those in early/late apoptosis. Finally, RTCA and HCS being time-resolved analyses allowed also to determine the kinetic dependency parameter for toxicity of smoke/vapor chemicals on cell viability. In conclusion, NRU assay may be considered a suitable test, especially when combined with a time-resolved test, for assessing the kinetic of cytotoxicity induced by these products.
- Published
- 2021
18. Seroepidemiological Survey on the Impact of Smoking on SARS-CoV-2 Infection and COVID-19 Outcomes: Protocol for the Troina Study
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Margherita Ferrante, Filippo Caraci, Elisa Interlandi, Venera Tomaselli, Riccardo Polosa, Murugesan Thangaraju, Jonathan Belsey, Sonja Rust, Alba Corina Romeo, Jed E. Rose, Pietro Zuccarello, Corrado Romano, Giulio Giacomo Cantone, Fabio Cibella, Raffaele Ferri, Daniela Saitta, Pietro Ferrara, Polosa, R, Tomaselli, V, Ferrara, P, Romeo, A, Rust, S, Saitta, D, Caraci, F, Romano, C, Thangaraju, M, Zuccarello, P, Rose, J, Cantone, G, Ferrante, M, Belsey, J, Cibella, F, Interlandi, E, and Ferri, R
- Subjects
Research design ,medicine.medical_specialty ,Population ,Context (language use) ,antibody persistence ,cotinine ,COVID-19 ,SARS-CoV-2 ,seroprevalence ,smoking impact ,smoking status ,chemistry.chemical_compound ,Environmental health ,Health care ,Protocol ,Medicine ,Prospective cohort study ,education ,education.field_of_study ,business.industry ,Public health ,General Medicine ,chemistry ,Smoking statu ,business ,Cotinine ,Blood sampling - Abstract
Background After the global spread of SARS-CoV-2, research has highlighted several aspects of the pandemic, focusing on clinical features and risk factors associated with infection and disease severity. However, emerging results on the role of smoking in SARS-CoV-2 infection susceptibility or COVID-19 outcomes are conflicting, and their robustness remains uncertain. Objective In this context, this study aims at quantifying the proportion of SARS-CoV-2 antibody seroprevalence, studying the changes in antibody levels over time, and analyzing the association between the biochemically verified smoking status and SARS-CoV-2 infection. Methods The research design involves a 6-month prospective cohort study with a serial sampling of the same individuals. Each participant will be surveyed about their demographics and COVID-19–related information, and blood sampling will be collected upon recruitment and at specified follow-up time points (ie, after 8 and 24 weeks). Blood samples will be screened for the presence of SARS-CoV-2–specific antibodies and serum cotinine, being the latter of the principal metabolite of nicotine, which will be used to assess participants’ smoking status. Results The study is ongoing. It aims to find a higher antibody prevalence in individuals at high risk for viral exposure (ie, health care personnel) and to refine current estimates on the association between smoking status and SARS-CoV-2/COVID-19. Conclusions The added value of this research is that the current smoking status of the population to be studied will be biochemically verified to avoid the bias associated with self-reported smoking status. As such, the results from this survey may provide an actionable metric to study the role of smoking in SARS-CoV-2 infection and COVID-19 outcomes, and therefore to implement the most appropriate public health measures to control the pandemic. Results may also serve as a reference for future clinical research, and the methodology could be exploited in public health sectors and policies. International Registered Report Identifier (IRRID) DERR1-10.2196/32285
- Published
- 2021
19. Nicotine dosimetry and stability in cambridge filter PADs (CFPs) following different smoking regime protocols and storage conditions
- Author
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Massimo Caruso, Claudia Favara, Pietro Zuccarello, Sonja Rust, Riccardo Polosa, Roberta Pulvirenti, Margherita Ferrante, Giovanni Li Volti, and Rosalia Emma
- Subjects
Normalization (statistics) ,Nicotine ,Post exposure ,010501 environmental sciences ,Electronic Nicotine Delivery Systems ,Toxicology ,030226 pharmacology & pharmacy ,01 natural sciences ,law.invention ,03 medical and health sciences ,0302 clinical medicine ,Drug Stability ,law ,medicine ,Dosimetry ,Food science ,Electronic cigarette ,0105 earth and related environmental sciences ,Smoke ,Principal Component Analysis ,Time zero ,Chemistry ,Cambridge filter pad ,Methodology ,Temperature ,General Medicine ,Reference Standards ,Tobacco constituents ,Smoking regimes ,Nicotine delivery ,Particulate Matter ,medicine.drug - Abstract
Despite the growing numbers of studies on cigarettes and electronic nicotine delivery products (ENDs), no standard assessment of nicotine stability in various matrix post exposure is currently available. The aim of the present study was to evaluate the optimal standard condition to store Cambridge Filter Pads (CFPs) before chemical analysis in order to guarantee the titer of nicotine.We further performed data normalization according to different smoking or vaping runs. Smoke and vapor generated respectively by a reference tobacco cigarette (1R6F) and ENDs under different exposure regimes (ISO, HCI and CRM81) were collected on CFPs as totalparticulate matter(TPM) and subsequently analyzed for nicotine content. For each exposure, some CFPs were analyzed at time zero, whereas the others were stored under different conditions for nicotine assessment after 30 days. Principal Component Analysis (PCA) showed the best correlation between nicotine on CFPs and TPM for normalization. This study suggests that different exposure regimes and products can affect the preservation of nicotine titer on CFPs while samples storage at −80°C may prevent the loss of nicotine. Finally, normalization of nicotine with TPM is strongly recommended for regulatory purpose.
- Published
- 2020
20. Nicotine dosimetry and stability in Cambridge Filter PADs (CFPs) following different smoking regimen protocols and condition storage
- Author
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Roberta Pulvirenti, Sonja Rust, Claudia Favara, Massimo Caruso, Giovanni Li Volti, Margherita Ferrante, Rosalia Emma, Pietro Zuccarello, and Riccardo Polosa
- Subjects
Time zero ,Chemistry ,law.invention ,Nicotine ,Regimen ,Nicotine delivery ,law ,nicotine, electronic cigarette, stability, Cambridge Filter Pad, smoking regimen, storage ,Nicotine concentration ,medicine ,Dosimetry ,Food science ,Electronic cigarette ,medicine.drug - Abstract
Despite the growing numbers of studies with cigarettes and other electronic nicotine delivery products (ENDs), there is no standard covering nicotine dosimetry and its stability in various matrix. The aim of the present study was to provide a protocol to normalize nicotine concentration adsorbed in Cambridge Filter PADs (CFPs) and their storage method. Smoke/vapor generated by a reference tobacco cigarette (1R6F) and ENDs with different exposure regimes (ISO, HCI and CRM81) was collected in CFPs. For each exposure, some CFPs were analyzed at time zero, whereas the others were stored under different conditions for nicotine assessment after 30 days. Principal Component Analysis (PCA) was also performed to establish the best parameter for nicotine normalization. PCA showed the best correlation between nicotine in CFPs and TPM. Our results showed differences between products and puffing regimes, but storage of CFPs at −80°C was always effective in maintaining the nicotine content. In conclusion, this study highlights that different exposure regimens and products can affect the preservation of nicotine titer in CFPs and samples storage at −80°C may prevent the loss of nicotine. These conditions are recommended and should be adopted for Inter-laboratory comparison studies on ENDs to ensure harmonization between participating laboratories.
- Published
- 2020
21. Role of Cigarette Smoke on ACE-2 Protein Membrane Expression in Bronchial Epithelial Cells Using an Air-Liquid Interface Model
- Author
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Michelino Di Rosa, Riccardo Polosa, Giuseppina Raciti, Rosalia Emma, Pietro Zuccarello, Giuseppe Carota, Margherita Ferrante, Massimo Caruso, Giovanni Li Volti, Sonja Rust, and Alfio Distefano
- Subjects
Smoke ,Nicotine ,Membrane ,Chemistry ,Interface model ,ACE-2 ,nicotine ,smoke ,cigarette ,epithelial cells ,medicine ,biochemistry ,Cigarette smoke ,medicine.drug ,Cell biology - Abstract
Prevalence studies of current smoking among hospitalized COVID-19 patients demonstrated an unexpectedly low prevalence of current smoking among patients with COVID-19. The aim of the present proposal was to evaluate the effect of smoke from cigarettes on ACE-2 in bronchial epithelial cells. Normal bronchial epithelial cells (H292) were exposed to smoke by an air-liquid-interface (ALI) system and ACE-2 membrane protein expression was evaluated after 24 hours from exposure. Our transcriptomics data analysis showed a significant selective reduction of membrane ACE-2 expression (about 25%) following smoking exposure. Interestingly, we observed a positive direct correlation between ACE-2 reduction and nicotine delivery. Furthermore, by stratifying GSE52237 as a function of ACE-2 gene expression levels, we highlighted 1012 genes related to ACE-2 in smokers and 855 in non-smokers. Furthermore, we showed that 161 genes involved in the endocytosis process were highlighted using the online pathway tool KEGG. Finally, 11 genes were in common between the ACE-2 pathway in smokers and the genes regulated during endocytosis, while 12 genes with non-smokers. Interestingly, six in non-smokers and four genes in smokers were closely involved during the viral internalization process. Our data may offer a pharmaceutical role of nicotine as potential treatment option in COVID-19.
- Published
- 2020
22. Screening of different cytotoxicity methods for the assessment of ENDS toxicity relative to tobacco cigarettes
- Author
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Sonja Rust, Roberta Pulvirenti, Giuseppe Carota, Massimo Caruso, Alfio Distefano, Giovanni Li Volti, Rosalia Emma, and Riccardo Polosa
- Subjects
Neutral red ,Cell Survival ,Cytotoxicity ,Cigarette smoke ,ENDS ,Electronic cigarette ,THP ,Electronic Nicotine Delivery Systems ,Pharmacology ,Toxicology ,Tobacco smoke ,Cell Line ,law.invention ,chemistry.chemical_compound ,Annexin ,law ,Humans ,Viability assay ,Chemistry ,Epithelial Cells ,Tobacco Products ,General Medicine ,Apoptosis ,Toxicity - Abstract
Electronic Nicotine Delivery Systems (ENDS), i.e., electronic-cigarettes (e-cigs) and Tobacco Heating Products (THPs), are rapidly growing in popularity. Nonetheless, comprehensive quality and safety requirements for regulatory purposes are still under development. Cytotoxicity studies are important initial steps in appraising the potential ENDS toxicity. The aim of the present study was to screen different in vitro cytotoxicity methods for the assessment of ENDS toxicity. We evaluated NRU, MTT, Annexin V apoptosis (AN-V), High-Content Screening (HCS) assays and Real-Time Cell Analysis (RTCA), to compare two e-cigs and two THPs with the 1R6F reference tobacco cigarette. Human adenocarcinoma lung epithelial cells (H292) were exposed to tobacco smoke and ENDS vapor at air-liquid interface. All tests showed reduced cell viability following 1R6F smoke exposure and slight or no reduction with ENDS at 24 h. AN-V and RTCA exhibited a further significant reduction in cell viability following 1R6F exposure. AN-V allowed to discriminate viable cells from those in early/late apoptosis. RTCA and HCS being time-resolved analyses elucidate the kinetic dependency parameter for toxicity of smoke/vapor chemicals on cell viability. In conclusion, NRU assay may be considered a suitable test, especially when combined with a time-resolved analysis, for assessing the kinetic of cytotoxicity induced by these products.
- Published
- 2021
23. Corrigendum: IDO2 is critical for IDO1-mediated T-cell regulation and exerts a non-redundant function in inflammation
- Author
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Elizabeth Pigott, Laura Mandik-Nayak, Babak Baban, George C. Prendergast, Phillip Chandler, Andrew L. Mellor, Sonja Rust, Richard P. Metz, James B. DuHadaway, Lauren M.F. Merlo, Martin P. Keough, Courtney Smith, and Alexander J. Muller
- Subjects
medicine.anatomical_structure ,Chemistry ,T cell ,Immunology ,medicine ,Immunology and Allergy ,Inflammation ,General Medicine ,medicine.symptom ,Function (biology) ,Cell biology - Published
- 2019
24. IDO2 is critical for IDO1-mediated T-cell regulation and exerts a non-redundant function in inflammation
- Author
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Andrew L. Mellor, Richard P. Metz, Elizabeth Pigott, George C. Prendergast, Martin P. Keough, James B. DuHadaway, Alexander J. Muller, Lauren M.F. Merlo, Phillip Chandler, Courtney Smith, Sonja Rust, Laura Mandik-Nayak, and Babak Baban
- Subjects
Male ,medicine.medical_specialty ,Skin Neoplasms ,9,10-Dimethyl-1,2-benzanthracene ,medicine.medical_treatment ,T cell ,Immunology ,Spleen ,Inflammation ,Biology ,T-Lymphocytes, Regulatory ,Mice ,Immune system ,Blood serum ,Immunity ,Internal medicine ,medicine ,Animals ,Indoleamine-Pyrrole 2,3,-Dioxygenase ,Immunology and Allergy ,Th1-Th2 Balance ,Kynurenine ,Mice, Knockout ,Papilloma ,Dendritic Cells ,General Medicine ,Acquired immune system ,Cell biology ,Endocrinology ,Cytokine ,medicine.anatomical_structure ,Gene Expression Regulation ,Carcinogens ,Cytokines ,Tetradecanoylphorbol Acetate ,Female ,Featured Article of the Month ,Lymphocyte Culture Test, Mixed ,medicine.symptom ,Corrigendum ,Signal Transduction - Abstract
IDO2 is implicated in tryptophan catabolism and immunity but its physiological functions are not well established. Here we report the characterization of mice genetically deficient in IDO2, which develop normally but exhibit defects in IDO-mediated T-cell regulation and inflammatory responses. Construction of this strain was prompted in part by our discovery that IDO2 function is attenuated in macrophages from Ido1−/− mice due to altered message splicing, generating a functional mosaic with implications for interpreting findings in Ido1–/– mice. No apparent defects were observed in Ido2–/– mice in embryonic development or hematopoietic differentiation, with wild-type profiles documented for kynurenine in blood serum and for immune cells in spleen, lymph nodes, peritoneum, thymus and bone marrow of naive mice. In contrast, upon immune stimulation we determined that IDO1-dependent T regulatory cell generation was defective in Ido2−/− mice, supporting Ido1–Ido2 genetic interaction and establishing a functional role for Ido2 in immune modulation. Pathophysiologically, both Ido1−/− and Ido2−/− mice displayed reduced skin contact hypersensitivity responses, but mechanistic distinctions were apparent, with only Ido2 deficiency associated with a suppression of immune regulatory cytokines that included GM-CSF, G-CSF, IFN-γ, TNF-α, IL-6 and MCP-1/CCL2. Different contributions to inflammation were likewise indicated by the finding that Ido2−/− mice did not phenocopy Ido1−/− mice in the reduced susceptibility of the latter to inflammatory skin cancer. Taken together, our results offer an initial glimpse into immune modulation by IDO2, revealing its genetic interaction with IDO1 and distinguishing its non-redundant contributions to inflammation.
- Published
- 2014
25. Zinc Protoporphyrin IX Stimulates Tumor Immunity by Disrupting the Immunosuppressive Enzyme Indoleamine 2,3-Dioxygenase
- Author
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George C. Prendergast, Alexander J. Muller, Sonja Rust, Mario R. Mautino, James B. Duhadaway, David H. Munn, and Richard Metz
- Subjects
Cancer Research ,Heme binding ,T cell ,Protoporphyrins ,Biology ,Article ,Cell Line ,Immune tolerance ,Mice ,chemistry.chemical_compound ,In vivo ,Neoplasms ,Immune Tolerance ,medicine ,Animals ,Humans ,Indoleamine-Pyrrole 2,3,-Dioxygenase ,Indoleamine 2,3-dioxygenase ,Heme ,chemistry.chemical_classification ,Melanoma ,Immunity ,medicine.disease ,Enzyme ,medicine.anatomical_structure ,Oncology ,chemistry ,Biochemistry ,Cancer research ,Heme Oxygenase-1 - Abstract
The tryptophan catabolic enzyme indoleamine 2,3-dioxygenase (IDO) has emerged as an important driver of immune escape in a growing number of cancers and cancer-associated chronic infections. In this study, we define novel immunotherapeutic applications for the heme precursor compound zinc protoporphyrin IX (ZnPP) based on our discovery that it is a potent small-molecule inhibitor of IDO. Inhibitory activity was determined using in vitro and in-cell enzyme assays as well as a novel in vivo pharmacodynamic system. An irreversible mechanism of inhibition was documented, consistent with competition for heme binding in newly synthesized cellular protein. siRNA methodology and an IDO-deficient mouse strain were used to verify the specificity of ZnPP as an IDO inhibitor. In a preclinical model of melanoma, ZnPP displayed antitumor properties that relied on T-cell function and IDO integrity. ZnPP also phenocopied the known antitumor properties of IDO inhibitors in preclinical models of skin and breast carcinoma. Our results suggest clinical evaluation of ZnPP as an adjuvant immunochemotherapy in chronic infections and cancers in which there is emerging recognition of a pathophysiologic role for IDO dysregulation. Mol Cancer Ther; 9(6); 1864–71. ©2010 AACR.
- Published
- 2010
26. IDO inhibits a tryptophan sufficiency signal that stimulates mTOR: A novel IDO effector pathway targeted by D-1-methyl-tryptophan
- Author
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David H. Munn, Nicholas N. Vahanian, George C. Prendergast, Charles J. Link, Sonja Rust, Richard Metz, James B. DuHadaway, and Mario R. Mautino
- Subjects
autophagy ,Immunology ,P70-S6 Kinase 1 ,Biology ,immunomodulation ,IDO ,amino acid starvation ,03 medical and health sciences ,0302 clinical medicine ,PKC-θ ,TDO ,IDO2 ,medicine ,Immunology and Allergy ,Integrated stress response ,S6K ,PI3K/AKT/mTOR pathway ,030304 developmental biology ,0303 health sciences ,Catabolism ,Kinase ,Effector ,Autophagy ,3. Good health ,Oncology ,Mechanism of action ,Biochemistry ,Cancer research ,mTOR ,stress signaling ,medicine.symptom ,030215 immunology ,Research Paper - Abstract
Tryptophan catabolism by indoleamine 2,3-dioxygenase (IDO) alters inflammation and favors T-cell tolerance in cancer, but the underlying molecular mechanisms remain poorly understood. The integrated stress response kinase GCN2, a sensor of uncharged tRNA that is activated by amino acid deprivation, is recognized as an important effector of the IDO pathway. However, in a mouse model of inflammatory carcinogenesis, ablation of Gcn2 did not promote resistance against tumor development like the absence of IDO does, implying the existence of additional cancer-relevant pathways that operate downstream of IDO. Addressing this gap in knowledge, we report that the IDO-mediated catabolism of tryptophan also inhibits the immunoregulatory kinases mTOR and PKC-Θ, along with the induction of autophagy. These effects were relieved specifically by tryptophan but also by the experimental agent 1-methyl-D-tryptophan (D-1MT, also known as NLG8189), the latter of which reversed the inhibitory signals generated by IDO with higher potency. Taken together, our results implicate mTOR and PKC-Θ in IDO-mediated immunosuppressive signaling, and they provide timely insights into the unique mechanism of action of D-1MT as compared with traditional biochemical inhibitors of IDO. These findings are important translationally, because they suggest broader clinical uses for D-1MT against cancers that overexpress any tryptophan catabolic enzyme (IDO, IDO2 or TDO). Moreover, they define mTOR and PKC-Θ as candidate pharmacodynamic markers for D-1MT responses in patients recruited to ongoing phase IB/II cancer trials, addressing a current clinical need.
- Published
- 2012
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