Publications by authors named "Massimo Caruso"

64 Publications

Screening of different cytotoxicity methods for the assessment of ENDS toxicity relative to tobacco cigarettes.

Regul Toxicol Pharmacol 2021 Oct 24;125:105018. Epub 2021 Jul 24.

Department of Biomedical and Biotechnological Sciences, University of Catania, Via S. Sofia, 97, 95123, Catania, Italy; Center of Excellence for the Acceleration of Harm Reduction (CoEHAR), University of Catania, Via S. Sofia, 97, 95123, Catania, Italy. Electronic address:

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.
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http://dx.doi.org/10.1016/j.yrtph.2021.105018DOI Listing
October 2021

Mapping atopic dermatitis and anti-IL-22 response signatures to type 2-low severe neutrophilic asthma.

J Allergy Clin Immunol 2021 Apr 20. Epub 2021 Apr 20.

Clinical and Experimental Sciences and Human Development in Health, University of Southampton Faculty of Medicine, Southampton, United Kingdom; NIHR Southampton Biomedical Research Centre, University Hospital Southampton NHS Foundation Trust, Southampton, United Kingdom; David Hide Asthma and Allergy Research Centre, St Mary's Hospital, Newport, Isle of Wight, United Kingdom.

Background: Transcriptomic changes in patients who respond clinically to biological therapies may identify responses in other tissues or diseases.

Objective: We sought to determine whether a disease signature identified in atopic dermatitis (AD) is seen in adults with severe asthma and whether a transcriptomic signature for patients with AD who respond clinically to anti-IL-22 (fezakinumab [FZ]) is enriched in severe asthma.

Methods: An AD disease signature was obtained from analysis of differentially expressed genes between AD lesional and nonlesional skin biopsies. Differentially expressed genes from lesional skin from therapeutic superresponders before and after 12 weeks of FZ treatment defined the FZ-response signature. Gene set variation analysis was used to produce enrichment scores of AD and FZ-response signatures in the Unbiased Biomarkers for the Prediction of Respiratory Disease Outcomes asthma cohort.

Results: The AD disease signature (112 upregulated genes) encompassing inflammatory, T-cell, T2, and T17/T22 pathways was enriched in the blood and sputum of patients with asthma with increasing severity. Patients with asthma with sputum neutrophilia and mixed granulocyte phenotypes were the most enriched (P < .05). The FZ-response signature (296 downregulated genes) was enriched in asthmatic blood (P < .05) and particularly in neutrophilic and mixed granulocytic sputum (P < .05). These data were confirmed in sputum of the Airway Disease Endotyping for Personalized Therapeutics cohort. IL-22 mRNA across tissues did not correlate with FZ-response enrichment scores, but this response signature correlated with T22/IL-22 pathways.

Conclusions: The FZ-response signature in AD identifies severe neutrophilic asthmatic patients as potential responders to FZ therapy. This approach will help identify patients for future asthma clinical trials of drugs used successfully in other chronic diseases.
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http://dx.doi.org/10.1016/j.jaci.2021.04.010DOI Listing
April 2021

Role of Cigarette Smoke on Angiotensin-Converting Enzyme-2 Protein Membrane Expression in Bronchial Epithelial Cells Using an Air-Liquid Interface Model.

Front Pharmacol 2021 30;12:652102. Epub 2021 Mar 30.

Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy.

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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http://dx.doi.org/10.3389/fphar.2021.652102DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8042260PMC
March 2021

Nicotine dosimetry and stability in cambridge filter PADs (CFPs) following different smoking regime protocols and storage conditions.

Regul Toxicol Pharmacol 2021 Jun 18;122:104917. Epub 2021 Mar 18.

Department of Medical, Surgical Sciences and Advanced Technologies "G.F. Ingrassia", Via S. Sofia, 87, 95123, Catania, Italy; Center of Excellence for the Acceleration of Harm Reduction (CoEHAR), University of Catania, Via S. Sofia, 97, 95123, Catania, Italy. Electronic address:

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 total particulate 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.
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http://dx.doi.org/10.1016/j.yrtph.2021.104917DOI Listing
June 2021

Medication Adherence in Patients With Severe Asthma Prescribed Oral Corticosteroids in the U-BIOPRED Cohort.

Chest 2021 Jul 19;160(1):53-64. Epub 2021 Feb 19.

Department of Respiratory Medicine, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.

Background: Although estimates of suboptimal adherence to oral corticosteroids in asthma range from 30% to 50%, no ideal method for measurement exists; the impact of poor adherence in severe asthma is likely to be particularly high.

Research Questions: What is the prevalence of suboptimal adherence detected by self-reporting and direct measures? Is suboptimal adherence associated with disease activity?

Study Design And Methods: Data were included from individuals with severe asthma taking part in the U-BIOPRED (Unbiased Biomarkers for the Prediction of Respiratory Disease Outcomes) study and prescribed daily oral corticosteroids. Participants completed the Medication Adherence Report Scale, a five-item questionnaire used to grade adherence on a scale from 1 to 5, and provided a urine sample for analysis of prednisolone and metabolites by liquid chromatography-mass spectrometry.

Results: Data from 166 participants were included in this study: mean (SD) age, 54.2 (± 11.9) years; FEV, 65.1% (± 20.5%) predicted; female, 58%; 37% completing the Medication Adherence Report Scale reported suboptimal adherence; and 43% with urinary corticosteroid data did not have detectable prednisolone or metabolites in their urine. Good adherence by both methods was detected in 49 of the 142 (35%) of participants in whom both methods were performed; adherence detection did not match between methods in 53%. Self-reported high adherers had better asthma control and quality of life, whereas directly measured high adherers had lower blood eosinophil levels.

Interpretation: Low adherence is a common problem in severe asthma, whether measured directly or self-reported. We report poor agreement between the two methods, suggesting some disassociation between self-assessment of medication adherence and regular oral corticosteroid use, which suggests that each approach may provide complementary information in clinical practice.
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http://dx.doi.org/10.1016/j.chest.2021.02.023DOI Listing
July 2021

Short and Long Term Repeatability of Saccharin Transit Time in Current, Former, and Never Smokers.

Front Physiol 2020 18;11:1109. Epub 2020 Sep 18.

Centre for the Prevention and Treatment of Tobacco Addiction (CPCT), Teaching Hospital "Policlinico-V. Emanuele", University of Catania, Catania, Italy.

Smoking progressively damages the efficiency of mucociliary clearance (MCC) defense mechanisms, thus contributing to increased susceptibility to respiratory infections. Prolonged mucociliary clearance transit time (MCCTT) caused by chronic smoking has been investigated by saccharin test, but little data is available about its short- and long-term reproducibility. Moreover, it is not known if MCC impairment can be reversed when stopping smoking. Objective of the study is to investigate and compare short (3 days) and long term (30 days) repeatability of baseline saccharin transit time (STT) among current, former, and never smokers. STT results were analyzed in 39 current, 40 former, and 40 never smokers. Significant ( < 0.0001) short-term and long-term repeatability of STT were observed in current (R squared = 0.398 and 0.672, for short- and long-term, respectively) and former smokers (R squared = 0.714 and 0.595, for short- and long-term, respectively). Significant differences in MCCTT were observed among the three study groups ( < 0.0001); the median (IQR) MCCTT being 13.15 (10.24-17.25), 7.26 (6.18-9.17), and 7.24 (5.73-8.73) minutes for current, former and never smokers, respectively. Comparison between current smokers and former smokers was significantly different ( < 0.0001). There was no significant difference between former and never smokers. The Saccharin test was well tolerated by all participants. We have shown for the first time high level repeatability in both current and former smokers. Moreover, MCC impairment can be completely reversed, former smokers exhibiting similar STT as never smokers. Measurement of STT is a sensitive biomarker of physiological effect for the detection of early respiratory health changes and may be useful for clinical research.
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http://dx.doi.org/10.3389/fphys.2020.01109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7537769PMC
September 2020

Investigation on the Antibacterial Activity of Electronic Cigarette Liquids (ECLs): A Proof of Concept Study.

Curr Pharm Biotechnol 2021 ;22(7):983-994

Department of Biomedical and Biotechnological Sciences (BIOMETEC), University of Catania, Catania, Italy.

Background: The key ingredients of e-cigarettes liquid are commonly propane-1,2-diol (also called propylene glycol) and propane-1,2,3-triol (vegetal glycerol) and their antimicrobial effects are already established. The nicotine and flavors which are often present in e-liquids can interfere with the growth of some microorganisms.

Objective: The effect of combining these elements in e-liquids is unknown. The aim of the study was to investigate the possible effects of these liquids on bacterial growth in the presence or absence of nicotine and flavors.

Methods: Susceptibilities of pathogenic strains (Klebsiella pneumoniae, Staphylococcus aureus, Pseudomonas aeruginosa, Acinetobacter baumannii, Escherichia coli, Enterococcus faecalis and Sarcina lutea) were studied by means of a multidisciplinary approach. Cell viability and antioxidant assays were also evaluated.

Results: All e-liquids investigated showed antibacterial activity against at least one pathogenic strain. Higher activity was correlated to the presence of flavors and nicotine.

Discussion: In most cases, the value of minimal bactericidal concentration is equal to the value of minimal inhibitory concentration showing that these substances have a bactericidal effect. This effect was observed in concentrations up to 6.25% v/v. Antioxidant activity was also correlated to the presence of flavors. Over time, the viability assay in human epithelial lung A549 cells showed a dose-dependent inhibition of cell growth.

Conclusion: Our results have shown that flavors considerably enhance the antibacterial activity of propane-1,2-diol and propane-1,2,3-triol. This study provides important evidence that should be taken into consideration in further investigative approaches, to clarify the different sensitivity of the various bacterial species to e-liquids, including the respiratory microbiota, to highlight the possible role of flavors and nicotine.
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http://dx.doi.org/10.2174/1389201021666200903121624DOI Listing
June 2021

Urinary Leukotriene E and Prostaglandin D Metabolites Increase in Adult and Childhood Severe Asthma Characterized by Type 2 Inflammation. A Clinical Observational Study.

Am J Respir Crit Care Med 2021 01;203(1):37-53

The Center for Allergy Research.

New approaches are needed to guide personalized treatment of asthma. To test if urinary eicosanoid metabolites can direct asthma phenotyping. Urinary metabolites of prostaglandins (PGs), cysteinyl leukotrienes (CysLTs), and isoprostanes were quantified in the U-BIOPRED (Unbiased Biomarkers for the Prediction of Respiratory Diseases Outcomes) study including 86 adults with mild-to-moderate asthma (MMA), 411 with severe asthma (SA), and 100 healthy control participants. Validation was performed internally in 302 participants with SA followed up after 12-18 months and externally in 95 adolescents with asthma. Metabolite concentrations in healthy control participants were unrelated to age, body mass index, and sex, except for the PGE pathway. Eicosanoid concentrations were generally greater in participants with MMA relative to healthy control participants, with further elevations in participants with SA. However, PGE metabolite concentrations were either the same or lower in male nonsmokers with asthma than in healthy control participants. Metabolite concentrations were unchanged in those with asthma who adhered to oral corticosteroid treatment as documented by urinary prednisolone detection, whereas those with SA treated with omalizumab had lower concentrations of LTE and the PGD metabolite 2,3-dinor-11β-PGF. High concentrations of LTE and PGD metabolites were associated with lower lung function and increased amounts of exhaled nitric oxide and eosinophil markers in blood, sputum, and urine in U-BIOPRED participants and in adolescents with asthma. These type 2 (T2) asthma associations were reproduced in the follow-up visit of the U-BIOPRED study and were found to be as sensitive to detect T2 inflammation as the established biomarkers. Monitoring of urinary eicosanoids can identify T2 asthma and introduces a new noninvasive approach for molecular phenotyping of adult and adolescent asthma.Clinical trial registered with www.clinicaltrials.gov (NCT01976767).
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http://dx.doi.org/10.1164/rccm.201909-1869OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7781128PMC
January 2021

Heme-Oxygenase and Kidney Transplantation: A Potential for Target Therapy?

Biomolecules 2020 05 30;10(6). Epub 2020 May 30.

Organ Transplant Unit, University Hospital of Catania, 95123 Catania, Italy.

Kidney transplantation is a well-established therapy for patients with end-stage renal disease. While a significant improvement of short-term results has been achieved in the short-term, similar results were not reported in the long-term. Heme-oxygenase (HO) is the rate-limiting enzyme in heme catabolism, converting heme to iron, carbon monoxide, and biliverdin. Heme-oxygenase overexpression may be observed in all phases of transplant processes, including brain death, recipient management, and acute and chronic rejection. HO induction has been proved to provide a significant reduction of inflammatory response and a reduction of ischemia and reperfusion injury in organ transplantation, as well as providing a reduction of incidence of acute rejection. In this review, we will summarize data on HO and kidney transplantation, suggesting possible clinical applications in the near future to improve the long-term outcomes.
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http://dx.doi.org/10.3390/biom10060840DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7355572PMC
May 2020

A new standardized phytoextract from red orange and lemon wastes (red orange and lemon extract) reduces basophil degranulation and activation.

Nat Prod Res 2020 May 6:1-6. Epub 2020 May 6.

Research Centre for Olive, Citrus and Tree Fruit, Council for Agricultural Research and Economics (CREA), Acireale, Italy.

Citrus fruits are rich sources of bioactive compounds and their consumption is associated to health-promoting effects. Citrus processing wastes contain bioflavonoids and other high added value compounds. The aim of this study was to evaluate the antiallergic properties of a new phytoextract obtained by citrus wastes and peels. Blood orange and lemon processing wastes were used to produce a Red orange and Lemon Extract (RLE). Blood samples from 30 allergic donors were collected and used to evaluate the basophil activation (CD203c) and degranulation (CD63) by stimulation trough allergen with and without the RLE. Reduced basophil expression of CD203c and CD63 were observed in RLE + Allergen treated samples, with -20.21% of CD203c expression ( < 0.0001) and -54.11% of CD63 expression ( < 0.0001), compared to Allergen treated samples. The RLE evidenced a good antiallergic activity, mainly acting on basophils degranulation, and therefore reducing the key event of pro-inflammatory mediators release after allergic stimuli.
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http://dx.doi.org/10.1080/14786419.2020.1761355DOI Listing
May 2020

Smoking and SARS-CoV-2 Disease (COVID-19): Dangerous Liaisons or Confusing Relationships?

J Clin Med 2020 May 2;9(5). Epub 2020 May 2.

Center of Excellence for the acceleration of Harm reduction - CoEHAR; University of Catania, Via S. Sofia, 97 95131 Catania, Italy.

We read with great interest the article by Brake SJ and colleagues [...].
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http://dx.doi.org/10.3390/jcm9051321DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7290834PMC
May 2020

Role of 17-Estradiol on Cell Proliferation and Mitochondrial Fitness in Glioblastoma Cells.

J Oncol 2020 14;2020:2314693. Epub 2020 Feb 14.

Department of Biomedical and Biotechnological Sciences, University of Catania, Via S. Sofia 97, 95125 Catania, Italy.

Gliomas are the most common primary tumors of the central nervous system (CNS) in the adult. Previous data showed that estrogen affects cancer cells, but its effect is cell-type-dependent and controversial. The present study aimed to analyze the effects of estradiol (E2, 5 nM) in human glioblastoma multiforme U87-MG cells and how it may impact on cell proliferation and mitochondrial fitness. We monitored cell proliferation by xCELLigence technology and mitochondrial fitness by assessing the expression of genes involved in mitochondrial biogenesis (PGC1α, SIRT1, and TFAM), oxidative phosphorylation (ND4, Cytb, COX-II, COX IV, NDUFA6, and ATP synthase), and dynamics (OPA1, MNF2, MNF1, and FIS1). Finally, we evaluated Nrf2 nuclear translocation by immunocytochemical analysis. Our results showed that E2 resulted in a significant increase in cell proliferation, with a significant increase in the expression of genes involved in various mechanisms of mitochondrial fitness. Finally, E2 treatment resulted in a significant increase of Nrf2 nuclear translocation with a significant increase in the expression of one of its target genes (i.e., heme oxygenase-1). Our results suggest that E2 promotes proliferation in glioblastoma cells and regulate the expression of genes involved in mitochondrial fitness and chemoresistance pathway.
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http://dx.doi.org/10.1155/2020/2314693DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7042539PMC
February 2020

Heme Oxygenase-1 and Carbon Monoxide Regulate Growth and Progression in Glioblastoma Cells.

Mol Neurobiol 2020 May 27;57(5):2436-2446. Epub 2020 Feb 27.

Department of Biomedical and Biotechnological Sciences, University of Catania, Via S. Sofia 97, 95125, Catania, Italy.

In human glioma tumours, heme oxygenase-1 (HO-1) is overexpressed when compared with normal brain tissues and during oligodendroglioma progression. However, the molecular mechanisms mediated by HO-1 to promote glioblastoma remain unknown. We therefore aimed at investigating the effect of HO-1 expression and its selective enzymatic inhibition in two different cell lines (i.e. A172 and U87-MG). HO-1 was induced by hemin treatment (10 μM), and VP13/47 (100 μM) was used as a specific non-competitive inhibitor of HO-1 activity. Cell proliferation was measured by cell index measurement (xCelligence technology) and clonogenic assay, whereas cell migration was assessed by wound healing assay. Carbon monoxide-releasing molecules (CORMs) (i.e. CORM-3 and CORM-A1) were also used in a separate set of experiments to confirm the effect of HO-1 by-product in glioblastoma progression further. Our results were further validated using GSE4412 microarray dataset analysis and comparing biopsies overexpressing HO-1 with the rest of the cases. Our results showed that hemin was able to induce both HO-1 gene and protein expression in a cell-dependent manner being A172 more responsive to pharmacological upregulation of HO-1. Hemin, but not CORMs treatment, resulted in a significant increase of cell proliferation following 24 h of treatment as measured by increased cell index and colony formation capacity and such effect was abolished by VP13/47. Interestingly, both hemin and CORMs showed a significant effect on the wound healing assay also exhibiting cell specificity. Finally, our dataset analysis showed a positive correlation of HO-1 gene expression with ITGBI and ITGBII which are membrane receptors involved in cell adhesion, embryogenesis, tissue repair, immune response and metastatic diffusion of tumour cells. In conclusion, our data suggest that HO-1 and its by-product CO exhibit a cell-specific effect on various aspects of disease progression and are associated with a complex series of molecular mechanisms driving cell proliferation, survival and metastasis.
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http://dx.doi.org/10.1007/s12035-020-01869-7DOI Listing
May 2020

Non-inferiority trial comparing cigarette consumption, adoption rates, acceptability, tolerability, and tobacco harm reduction potential in smokers switching to Heated Tobacco Products or electronic cigarettes: Study protocol for a randomized controlled trial.

Contemp Clin Trials Commun 2020 Mar 8;17:100518. Epub 2020 Jan 8.

Centro per La Prevenzione e Cura Del Tabagismo (CPCT), Azienda Ospedaliero-Universitaria "Policlinico-V. Emanuele", Università di Catania, Catania, Italy.

Background: Despite the introduction of tobacco control measures, smoking remains highly prevalent in most EU countries. In Italy, one in four adults were still regular smokers in 2017. Increasing use of combustion-free delivering nicotine technologies for cigarette substitution may accelerate the current downward trends in smoking prevalence. Whether Heated Tobacco Products (HTPs) are more effective tobacco smoking substitutes that may potentially facilitate adoption and full conversion compared to e-cigarettes (ECs) is not known.We have designed a prospective study to compare changes in cigarette consumption and adoption rates among smokers randomized to either HTPs or ECs. Product acceptability, tolerability, and their tobacco harm reduction potential will be also compared.

Methods: 220 healthy smokers, not motivated to quit, will be randomized into a 12-weeks single-center, open label, non-inferiority trial comparing study outcomes from HTPs vs. ECs use. The primary outcome will be biochemically verified self-reported continuous abstinence at 12-weeks from the previous visit. Secondary outcomes will include: smoking reduction from baseline, adoption rates and product acceptability, tolerability, changes in step test values and in the level of selected biomarkers of exposure in exhaled breath (i.e. eCO) and in spot urine samples. A follow-up visit will be also included at 24-weeks to review product usage and smoking behavior under naturalistic condition of use.Recruitment of participants started in May 2019 and enrolment is expected to be completed in November 2019.

Discussion: This will be the first study directly comparing Heated Tobacco Products with Electronic Cigarettes in term of reduction in cigarette consumption, adoption rates, product acceptability, tolerability, and tobacco harm reduction potential. This knowledge can contribute to a better understanding of the potential role of this new technology in the evolving nicotine consumer market.

Trial Registration: ClinicalTrials.gov ID: NCT03569748.Registered June 25, 2018.https://register.clinicaltrials.gov/prs/app/action/LoginUser?ts=1&cx=-jg9qo4.
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http://dx.doi.org/10.1016/j.conctc.2020.100518DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6962654PMC
March 2020

High nicotine exposure in rodents is unlikely to inform about its toxicity in humans.

Eur Respir J 2019 Aug 29;54(2). Epub 2019 Aug 29.

Dept of Clinical and Experimental Medicine, University of Catania, Catania, Italy

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http://dx.doi.org/10.1183/13993003.01073-2018DOI Listing
August 2019

The effect of e-cigarette aerosol emissions on respiratory health: a narrative review.

Expert Rev Respir Med 2019 09 2;13(9):899-915. Epub 2019 Aug 2.

Dipartimento di Medicina Clinica e Sperimentale (MEDCLIN), University of Catania , Catania , Italy.

: Due to the uptake in the use of e-cigarettes (ECs), evidence on their health effects is needed to inform health care and policy. Some regulators and health professionals have raised concerns that the respirable aerosols generated by ECs contain several constituents of potential toxicological and biological relevance to respiratory health. : We critically assess published research on the respiratory system investigating the effects of ECs in preclinical models, clinical studies of people who switched to ECs from tobacco cigarettes, and population surveys. We assess the studies for the quality of their methodology and accuracy of their interpretation. To adequately assess the impact of EC use on human health, addressing common mistakes and developing robust and realistic methodological recommendations is an urgent priority. The findings of this review indicate that ECs under normal conditions of use demonstrate far fewer respiratory risks than combustible tobacco cigarettes. EC users and smokers considering ECs have the right to be informed about the relative risks of EC use, and to be made aware that findings of studies published by the media are not always reliable. : Growing evidence supports the relative safety of EC emission aerosols for the respiratory tract compared to tobacco smoke.
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http://dx.doi.org/10.1080/17476348.2019.1649146DOI Listing
September 2019

Sensitization of chondrosarcoma cells with PARP inhibitor and high-LET radiation.

J Bone Oncol 2019 Aug 20;17:100246. Epub 2019 Jun 20.

LARIA, iRCM, François JACOB Institute, DRF-CEA, Caen, France.

Chondrosarcoma is a malignant tumor that arises from cartilaginous tissue and is radioresistant and chemoresistant to conventional treatments. The preferred treatment consists of surgical resection, which might cause severe disabilities for the patient; in addition, this procedure might be impossible for inoperable locations, such as the skull base. Carbon ion irradiation (hadron therapy) has been proposed as an alternative treatment, primarily due to its greater biological effectiveness and improved ballistic properties compared with conventional radiotherapy with X-rays. The goal of this study was to characterize the genetic mutations of a grade III chondrosarcoma cell line (CH2879) and examine the cellular responses to conventional radiotherapy (X-rays) and hadron therapy (proton and carbon ions) in the presence of the PARP inhibitor Olaparib. To better understand PARP inhibition, we first analyzed the formation of poly-ADP ribose chains by western blot; we observed an increase in its signal after irradiation, which disappeared on addition of the PARP inhibitor. PARPi enhanced ratio of approximately 1.3, 1.8, and 1.5 following irradiation of cells with X-rays, protons, and C-ions, respectively, as detected by clonogenic assay. The decrease in cell survival was confirmed by proliferation assay. The radiosensitivity of CH2879 cells was associated with mutations in homologous recombination repair genes, such as and . This study demonstrates the capacity of the PARP inhibitor Olaparib to radiosensitize mutated chondrosarcoma cells to conventional photon irradiation, proton and carbon ion irradiation.
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http://dx.doi.org/10.1016/j.jbo.2019.100246DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6609837PMC
August 2019

Metabolic Characterization of Supernatants Produced by spp. With Anti- Activity.

Front Microbiol 2019 26;10:1403. Epub 2019 Jun 26.

Department of Biomedical and Biotechnological Sciences (BIOMETEC), University of Catania, Catania, Italy.

is an organism of public health interest for its presence in water supply systems and other humid thermal habitats. In this study, ten cell-free supernatants produced by strains were evaluated for their ability to inhibit strains isolated from hot tap water. Production of antimicrobial substances by strains were assessed by agar well diffusion test on BCYE agar plates pre-inoculated with Cell-free supernatants (CFS) showed antimicrobial activity against all strains tested: and showed the highest activity. By means of a proton-based nuclear magnetic resonance (H-NMR) spectroscopy, we detected and quantified the metabolites of these CFSs, so to gain information about which metabolic pathway was likely to be connected to the observed inhibition activity. A panel of metabolites with variations in concentration were revealed, but considerable differences among inter-species were not showed as reported in a similar work by Foschi et al. (2018). More than fifty molecules belonging mainly to the groups of amino acids, organic acids, monosaccharides, ketones, and alcohols were identified in the metabolome. Significant differences were recorded comparing the metabolites found in the supernatants of strains grown in MRS with glycerol and the same strains grown in MRS without supplements. Indeed, pathway analysis revealed that glycine, serine and threonine, pyruvate, and sulfur metabolic pathways had a higher impact when strains were grown in MRS medium with a supplement such as glycerol. Among the metabolites identified, many were amino acids, suggesting the possible presence of bacteriocins which could be linked to the anti- activity shown by cell-free supernatants.
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http://dx.doi.org/10.3389/fmicb.2019.01403DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6606692PMC
June 2019

An evaluation of mepolizumab for the treatment of severe asthma.

Expert Opin Biol Ther 2019 06 7;19(6):491-500. Epub 2019 May 7.

c Department of Clinical and Experimental Medicine , University of Catania , Catania (CT) , Italy.

: Asthma is considered one of the most common chronic conditions globally, characterized by variable airflow obstruction and symptoms. Severe asthma is diagnosed when asthma control requires high-intensity therapy or continues to remain uncontrolled despite treatment. Eosinophilic inflammation is known to be perpetuated by the activity of IL-5 in a proportion of severe asthma subjects, and targeting IL-5 may offer a therapeutic option. : In this review, we discuss the role and pathogenesis of IL-5 and eosinophils in asthma and rationale of antagonizing IL-5 in severe eosinophilic asthma. Mepolizumab is the first of three anti-IL-5 biologics licensed in 2015 for use in this subgroup of patients. We discuss clinical and real-life studies leading up to its approval and post-marketing outcomes in terms of efficacy and safety to-date, as well as its pros and cons. : IL-5 antagonism has paved the way for an additional personalized therapeutic opportunity for use in severe asthma with eosinophilic inflammation, though there is limited evidence on the long-term implications of suppressing/depleting eosinophils and the duration for which they should be administered.
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http://dx.doi.org/10.1080/14712598.2019.1610382DOI Listing
June 2019

IL-17-high asthma with features of a psoriasis immunophenotype.

J Allergy Clin Immunol 2019 11 15;144(5):1198-1213. Epub 2019 Apr 15.

Respiratory, Inflammation, Autoimmunity IMED Biotech Unit, AstraZeneca, Gothenburg, Sweden.

Background: The role of IL-17 immunity is well established in patients with inflammatory diseases, such as psoriasis and inflammatory bowel disease, but not in asthmatic patients, in whom further study is required.

Objective: We sought to undertake a deep phenotyping study of asthmatic patients with upregulated IL-17 immunity.

Methods: Whole-genome transcriptomic analysis was performed by using epithelial brushings, bronchial biopsy specimens (91 asthmatic patients and 46 healthy control subjects), and whole blood samples (n = 498) from the Unbiased Biomarkers for the Prediction of Respiratory Disease Outcomes (U-BIOPRED) cohort. Gene signatures induced in vitro by IL-17 and IL-13 in bronchial epithelial cells were used to identify patients with IL-17-high and IL-13-high asthma phenotypes.

Results: Twenty-two of 91 patients were identified with IL-17, and 9 patients were identified with IL-13 gene signatures. The patients with IL-17-high asthma were characterized by risk of frequent exacerbations, airway (sputum and mucosal) neutrophilia, decreased lung microbiota diversity, and urinary biomarker evidence of activation of the thromboxane B2 pathway. In pathway analysis the differentially expressed genes in patients with IL-17-high asthma were shared with those reported as altered in psoriasis lesions and included genes regulating epithelial barrier function and defense mechanisms, such as IL1B, IL6, IL8, and β-defensin.

Conclusion: The IL-17-high asthma phenotype, characterized by bronchial epithelial dysfunction and upregulated antimicrobial and inflammatory response, resembles the immunophenotype of psoriasis, including activation of the thromboxane B2 pathway, which should be considered a biomarker for this phenotype in further studies, including clinical trials targeting IL-17.
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http://dx.doi.org/10.1016/j.jaci.2019.03.027DOI Listing
November 2019

Stratification of asthma phenotypes by airway proteomic signatures.

J Allergy Clin Immunol 2019 07 28;144(1):70-82. Epub 2019 Mar 28.

European Institute for Systems Biology and Medicine, CNRS-ENS-UCBL-INSERM, Université de Lyon, Lyon, France.

Background: Stratification by eosinophil and neutrophil counts increases our understanding of asthma and helps target therapy, but there is room for improvement in our accuracy in prediction of treatment responses and a need for better understanding of the underlying mechanisms.

Objective: We sought to identify molecular subphenotypes of asthma defined by proteomic signatures for improved stratification.

Methods: Unbiased label-free quantitative mass spectrometry and topological data analysis were used to analyze the proteomes of sputum supernatants from 246 participants (206 asthmatic patients) as a novel means of asthma stratification. Microarray analysis of sputum cells provided transcriptomics data additionally to inform on underlying mechanisms.

Results: Analysis of the sputum proteome resulted in 10 clusters (ie, proteotypes) based on similarity in proteomic features, representing discrete molecular subphenotypes of asthma. Overlaying granulocyte counts onto the 10 clusters as metadata further defined 3 of these as highly eosinophilic, 3 as highly neutrophilic, and 2 as highly atopic with relatively low granulocytic inflammation. For each of these 3 phenotypes, logistic regression analysis identified candidate protein biomarkers, and matched transcriptomic data pointed to differentially activated underlying mechanisms.

Conclusion: This study provides further stratification of asthma currently classified based on quantification of granulocytic inflammation and provided additional insight into their underlying mechanisms, which could become targets for novel therapies.
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http://dx.doi.org/10.1016/j.jaci.2019.03.013DOI Listing
July 2019

Lipid phenotyping of lung epithelial lining fluid in healthy human volunteers.

Metabolomics 2018 09 17;14(10):123. Epub 2018 Sep 17.

Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, UK.

Background: Lung epithelial lining fluid (ELF)-sampled through sputum induction-is a medium rich in cells, proteins and lipids. However, despite its key role in maintaining lung function, homeostasis and defences, the composition and biology of ELF, especially in respect of lipids, remain incompletely understood.

Objectives: To characterise the induced sputum lipidome of healthy adult individuals, and to examine associations between different ELF lipid phenotypes and the demographic characteristics within the study cohort.

Methods: Induced sputum samples were obtained from 41 healthy non-smoking adults, and their lipid compositions analysed using a combination of untargeted shotgun and liquid chromatography mass spectrometry methods. Topological data analysis (TDA) was used to group subjects with comparable sputum lipidomes in order to identify distinct ELF phenotypes.

Results: The induced sputum lipidome was diverse, comprising a range of different molecular classes, including at least 75 glycerophospholipids, 13 sphingolipids, 5 sterol lipids and 12 neutral glycerolipids. TDA identified two distinct phenotypes differentiated by a higher total lipid content and specific enrichments of diacyl-glycerophosphocholines, -inositols and -glycerols in one group, with enrichments of sterols, glycolipids and sphingolipids in the other. Subjects presenting the lipid-rich ELF phenotype also had significantly higher BMI, but did not differ in respect of other demographic characteristics such as age or gender.

Conclusions: We provide the first evidence that the ELF lipidome varies significantly between healthy individuals and propose that such differences are related to weight status, highlighting the potential impact of (over)nutrition on lung lipid metabolism.
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http://dx.doi.org/10.1007/s11306-018-1412-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6153688PMC
September 2018

Identification and prospective stability of electronic nose (eNose)-derived inflammatory phenotypes in patients with severe asthma.

J Allergy Clin Immunol 2019 05 6;143(5):1811-1820.e7. Epub 2018 Dec 6.

Respiratory Research Unit, University of Nottingham, Nottingham, United Kingdom.

Background: Severe asthma is a heterogeneous condition, as shown by independent cluster analyses based on demographic, clinical, and inflammatory characteristics. A next step is to identify molecularly driven phenotypes using "omics" technologies. Molecular fingerprints of exhaled breath are associated with inflammation and can qualify as noninvasive assessment of severe asthma phenotypes.

Objectives: We aimed (1) to identify severe asthma phenotypes using exhaled metabolomic fingerprints obtained from a composite of electronic noses (eNoses) and (2) to assess the stability of eNose-derived phenotypes in relation to within-patient clinical and inflammatory changes.

Methods: In this longitudinal multicenter study exhaled breath samples were taken from an unselected subset of adults with severe asthma from the U-BIOPRED cohort. Exhaled metabolites were analyzed centrally by using an assembly of eNoses. Unsupervised Ward clustering enhanced by similarity profile analysis together with K-means clustering was performed. For internal validation, partitioning around medoids and topological data analysis were applied. Samples at 12 to 18 months of prospective follow-up were used to assess longitudinal within-patient stability.

Results: Data were available for 78 subjects (age, 55 years [interquartile range, 45-64 years]; 41% male). Three eNose-driven clusters (n = 26/33/19) were revealed, showing differences in circulating eosinophil (P = .045) and neutrophil (P = .017) percentages and ratios of patients using oral corticosteroids (P = .035). Longitudinal within-patient cluster stability was associated with changes in sputum eosinophil percentages (P = .045).

Conclusions: We have identified and followed up exhaled molecular phenotypes of severe asthma, which were associated with changing inflammatory profile and oral steroid use. This suggests that breath analysis can contribute to the management of severe asthma.
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http://dx.doi.org/10.1016/j.jaci.2018.10.058DOI Listing
May 2019

Mepolizumab in the management of severe eosinophilic asthma in adults: current evidence and practical experience.

Ther Adv Respir Dis 2018 Jan-Dec;12:1753466618808490

Department of Biomedical and Biotechnological Sciences, Department of Clinical and Experimental Medicine, University of Catania, Via S. Sofia, 97, 95123 Catania (CT), Italy.

Asthma is a chronic inflammatory condition involving the airways with varying pathophysiological mechanisms, clinical symptoms and outcomes, generally controlled by conventional therapies including inhaled corticosteroids and long-acting β agonists. However, these therapies are unable to successfully control symptoms in about 5-10% of severe asthma patients. Atopic asthma, characterized by high immunoglobulin (Ig)E or eosinophilia, represents about 50% of asthmatic patients. Interleukin (IL)-5 is the main cytokine responsible of activation of eosinophils, hence therapeutic strategies have been investigated and developed for clinical use. Biologics targeting IL-5 and its receptor (first mepolizumab and subsequently, reslizumab and benralizumab), have been recently approved and used as add-on therapy for severe eosinophilic asthma resulting in a reduction in the circulating eosinophil count, improvement in lung function and exacerbation reduction in asthma patients. Despite these biologics having been approved for stratified severe asthma patients that remain uncontrolled with high doses of conventional therapy, a number of patients may be eligible for more than one biologic. Presently, the lack of head-to-head studies comparing the biological agents among themselves and with conventional therapy make the choice of optimal therapy for each patient a challenge for clinicians. Moreover, discontinuation of these treatments, implications for efficacy or adverse events, in particular in long-term treatment, and needs for useful biomarkers are still matters of debate. In this review we evaluate to date, the evidence on mepolizumab that seems to demonstrate it is a well-tolerated and efficacious regimen for use in severe eosinophilic asthma, though more studies are still required.
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http://dx.doi.org/10.1177/1753466618808490DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6204623PMC
March 2019

Enhanced oxidative stress in smoking and ex-smoking severe asthma in the U-BIOPRED cohort.

PLoS One 2018 21;13(9):e0203874. Epub 2018 Sep 21.

Dept of Respiratory Medicine, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands.

Oxidative stress is believed to be a major driver of inflammation in smoking asthmatics. The U-BIOPRED project recruited a cohort of Severe Asthma smokers/ex-smokers (SAs/ex) and non-smokers (SAn) with extensive clinical and biomarker information enabling characterization of these subjects. We investigated oxidative stress in severe asthma subjects by analysing urinary 8-iso-PGF2α and the mRNA-expression of the main pro-oxidant (NOX2; NOSs) and anti-oxidant (SODs; CAT; GPX1) enzymes in the airways of SAs/ex and SAn. All the severe asthma U-BIOPRED subjects were further divided into current smokers with severe asthma (CSA), ex-smokers with severe asthma (ESA) and non-smokers with severe asthma (NSA) to deepen the effect of active smoking. Clinical data, urine and sputum were obtained from severe asthma subjects. A bronchoscopy to obtain bronchial biopsy and brushing was performed in a subset of subjects. The main clinical data were analysed for each subset of subjects (urine-8-iso-PGF2α; IS-transcriptomics; BB-transcriptomics; BBr-transcriptomics). Urinary 8-iso-PGF2α was quantified using mass spectrometry. Sputum, bronchial biopsy and bronchial brushing were processed for mRNA expression microarray analysis. Urinary 8-iso-PGF2α was increased in SAs/ex, median (IQR) = 31.7 (24.5-44.7) ng/mmol creatinine, compared to SAn, median (IQR) = 26.6 (19.6-36.6) ng/mmol creatinine (p< 0.001), and in CSA, median (IQR) = 34.25 (24.4-47.7), vs. ESA, median (IQR) = 29.4 (22.3-40.5), and NSA, median (IQR) = 26.5 (19.6-16.6) ng/mmol creatinine (p = 0.004). Sputum mRNA expression of NOX2 was increased in SAs/ex compared to SAn (probe sets 203922_PM_s_at fold-change = 1.05 p = 0.006; 203923_PM_s_at fold-change = 1.06, p = 0.003; 233538_PM_s_at fold-change = 1.06, p = 0.014). The mRNA expression of antioxidant enzymes were similar between the two severe asthma cohorts in all airway samples. NOS2 mRNA expression was decreased in bronchial brushing of SAs/ex compared to SAn (fold-change = -1.10; p = 0.029). NOS2 mRNA expression in bronchial brushing correlated with FeNO (Kendal's Tau = 0.535; p< 0.001). From clinical and inflammatory analysis, FeNO was lower in CSA than in ESA in all the analysed subject subsets (p< 0.01) indicating an effect of active smoking. Results about FeNO suggest its clinical limitation, as inflammation biomarker, in severe asthma active smokers. These data provide evidence of greater systemic oxidative stress in severe asthma smokers as reflected by a significant changes of NOX2 mRNA expression in the airways, together with elevated urinary 8-iso-PGF2α in the smokers/ex-smokers group. Trial registration ClinicalTrials.gov-Identifier: NCT01976767.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0203874PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6150501PMC
March 2019

Health effects in COPD smokers who switch to electronic cigarettes: a retrospective-prospective 3-year follow-up.

Int J Chron Obstruct Pulmon Dis 2018 22;13:2533-2542. Epub 2018 Aug 22.

Department of Clinical & Experimental Medicine, University of Catania, Catania, Italy.

Background: Health effects of electronic cigarette (EC) use in patients with chronic obstructive pulmonary disease (COPD) are largely unexplored.

Aim: We present findings from a long-term prospective assessment of respiratory parameters in a cohort of COPD patients who ceased or substantially reduced conventional cigarette use with ECs.

Methods: We prospectively re-evaluated COPD exacerbations, spirometric indices, subjective assessments (using the COPD Assessment Tool [CAT] scores), physical activity (measured by the 6-minute walk distance [6MWD]), and conventional cigarette use in EC users with COPD who were retrospectively assessed previously. Baseline measurements prior to switching to EC use were compared to follow-up visits at 12, 24, and 36 months. Age- and sex-matched regularly smoking COPD patients who were not using ECs were included as reference (control) group.

Results: Complete data were available from 44 patients. Compared to baseline in the EC-user group, there was a marked decline in the use of conventional cigarettes. Although there was no change in lung function, significant improvements in COPD exacerbation rates, CAT scores, and 6MWD were observed consistently in the EC user group over the 3-year period (<0.01). Similar findings were noted in COPD EC users who also smoked conventional cigarettes ("dual users").

Conclusion: The present study suggests that EC use may ameliorate objective and subjective COPD outcomes and that the benefits gained may persist long-term. EC use may reverse some of the harm resulting from tobacco smoking in COPD patients.
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http://dx.doi.org/10.2147/COPD.S161138DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6113943PMC
January 2019

Electronic cigarette vapour enhances pneumococcal adherence to airway epithelial cells under abnormal conditions of exposure.

Eur Respir J 2018 09 6;52(3). Epub 2018 Sep 6.

Dept of Clinical and Experimental Medicine (MEDCLIN), University of Catania, Catania, Italy.

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http://dx.doi.org/10.1183/13993003.00915-2018DOI Listing
September 2018
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