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Tobacco smoking is highly prevalent among patients with psychosis and associated with worse clinical outcomes. Neurometabolites, such as glutamate and choline, are both implicated in psychosis and tobacco smoking. However, the specific associations between smoking and neurometabolites have yet to be investigated in patients with psychosis. The current study examines associations of chronic smoking and neurometabolite levels in the anterior cingulate cortex (ACC) in first-episode psychosis (FEP) patients and controls. Proton magnetic resonance spectroscopy ( 1 H MRS) data of 59 FEP patients and 35 controls were analysed. Associations between smoking status (i.e., smoker yes/no) or cigarettes per day and Glx (glutamate + glutamine, as proxy for glutamate) and total choline (tCh) levels were assessed at baseline in both groups separately. For patients, six months follow-up data were acquired for multi-cross-sectional analysis using linear mixed models. No significant differences in ACC Glx levels were found between smoking (n = 28) and non-smoking (n = 31) FEP patients. Smoking patients showed lower tCh levels compared to non-smoking patients at baseline, although not surving multiple comparisons correction, and in multi-cross-sectional analysis (p FDR  = 0.08 and p FDR  = 0.044, respectively). Negative associations were observed between cigarettes smoked per day, and ACC Glx (p FDR  = 0.02) and tCh levels (p FDR  = 0.02) in controls. Differences between patients and controls regarding Glx might be explained by pre-existing disease-related glutamate deficits or alterations at nicotine acetylcholine receptor level, resulting in differences in tobacco-related associations with neurometabolites. Additionally, observed alterations in tCh levels, suggesting reduced cellular proliferation processes, might result from exposure to the neurotoxic effects of smoking., Competing Interests: Declaration of competing interest None., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Tobacco smoking is positively correlated with non-alcoholic fatty liver disease (NAFLD) 1-5 , but the underlying mechanism for this association is unclear. Here we report that nicotine accumulates in the intestine during tobacco smoking and activates intestinal AMPKα. We identify the gut bacterium Bacteroides xylanisolvens as an effective nicotine degrader. Colonization of B. xylanisolvens reduces intestinal nicotine concentrations in nicotine-exposed mice, and it improves nicotine-exacerbated NAFLD progression. Mechanistically, AMPKα promotes the phosphorylation of sphingomyelin phosphodiesterase 3 (SMPD3), stabilizing the latter and therefore increasing intestinal ceramide formation, which contributes to NAFLD progression to non-alcoholic steatohepatitis (NASH). Our results establish a role for intestinal nicotine accumulation in NAFLD progression and reveal an endogenous bacterium in the human intestine with the ability to metabolize nicotine. These findings suggest a possible route to reduce tobacco smoking-exacerbated NAFLD progression., (© 2022. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Introduction: Cigarette smoke triggers many cellular and signaling responses in the lung and the resulting inflammation plays a central role in smoke-related lung diseases, such as COPD. We explored the effects of smoking on the small airway proteome in samples obtained by collection of exhaled particles with the aim to identify specific proteins dysregulated by smoking., Methods: Exhaled particles were obtained from 38 current smokers, 47 former smokers and 22 healthy controls with the PExA method. 120 ng of sample was collected from individual subjects and analyzed with the SOMAscan proteomics platform. General linear model-based statistics were performed., Results: Two hundred and three proteins were detected in at least half of 107 total samples. Active smoking exerted a significant impact on the protein composition of respiratory tract lining fluid (RTLF), with 81 proteins altered in current smokers compared to never smokers (p < 0.05, q < 0.124). Among the proteins most clearly discriminating between current and never smokers were sRAGE, FSTL3, SPOCK2 and protein S, all of them being less abundant in current smokers. Analysis stratified for sex unveiled sex differences with more pronounced proteomic alterations due to active smoking in females than males. Proteins whose abundance was altered by active smoking in women were to a larger extent related to the complement system. The small airway protein profile of former smokers appeared to be more similar to that observed in never smokers., Conclusions: The study shows that smoking has a strong impact on protein expression in the small airways, and that smoking affects men and women differently, suggesting PExA sampling combined with high sensitivity protein analysis offers a promising platform for early detection of COPD and identification of novel COPD drug targets., (© 2021. The Author(s).)

Background: Melanocytic nevi have a complex evolution influenced by several endogenous and exogenous factors and are known risk factors for malignant melanoma. Interestingly, tobacco use seems to be inversely associated with melanoma risk. However, the association between tobacco use and nevi and lentigines has not yet been evaluated., Methods: We investigated the prevalence of nevi, atypical nevi, and lentigines in relation to tobacco smoking in a cohort of 59 smokers and 60 age- and sex-matched nonsmokers, using a questionnaire and performing a total body skin examination by experts., Results: No significant differences were detected between smokers and nonsmokers in the numbers of nevi, atypical nevi, and lentigines in sun-exposed areas (p = 0.966, 0.326, and 0.241, respectively) and in non-sun-exposed areas (p = 0.095, 0.351, and 0.546, respectively)., Conclusion: Our results revealed no significant differences in the prevalence of nevi, atypical nevi, and lentigines between smokers and nonsmokers in sun-exposed and non-sun-exposed areas., Competing Interests: The authors have declared no competing interests.

Tobacco smoking is associated with an increased risk of oral leukoplakia and head and neck cancer. Although it has recently been reported that the establishment of an immunosuppressive microenvironment in oral potentially malignant disorders may lead to malignant transformation, it is unclear whether the microenvironments of oral potentially malignant disorders differ according to smoking status. We examined differences in programmed death-ligand 1 (PD-L1) expression and subepithelial CD163+ TAM and CD8+ cell/lymphocyte counts in the microenvironment of oral leukoplakia of smoking and non-smoking patients and investigated their associations with malignant transformation. Pathology reports and original biopsy request forms from 1995-2015 were retrospectively reviewed. Lesions clinically characterized as white plaques/lesions of the oral mucosa and pathologically diagnosed as oral epithelial dysplasia were included. Immunohistochemistry was performed to evaluate PD-L1 expression and subepithelial CD163+/CD8+ cell counts. The significance of prognostic factors in predicting malignant transformation was determined using Cox regression analysis. Statistical significance was defined as P<0.05. In total, 200 patients with oral leukoplakia were selected. The mean age at diagnosis was higher in non-smoking patients (n = 141; 66.9 years) than in smoking patients (n = 59; 60.5 years). The 5-year cumulative malignant transformation rate was higher in non-smoking patients than in smoking patients (9.3% vs. 3.0%, respectively). Oral leukoplakia was associated with significantly higher PD-L1 expression and increased numbers of subepithelial CD163+ cells in the non-smoking group compared with the smoking group. Non-smoking-related oral leukoplakia with positive PD-L1 expression was associated with a 6.97-fold (95% confidence interval: 2.14-22.7) increased risk of malignant transformation. The microenvironment of oral leukoplakia differed according to smoking status. A combination of smoking status and PD-L1 expression may predict malignant transformation in oral leukoplakia patients. This study highlights the importance of understanding the interaction between smoking and the microenvironment in oral leukoplakia., Competing Interests: The authors have declared that no competing interests exist.

BACKGROUNDClear cell renal cell carcinoma (ccRCC) is the most common histologically defined renal cancer. However, it is not a uniform disease and includes several genetic subtypes with different prognoses. ccRCC is also characterized by distinctive metabolic reprogramming. Tobacco smoking (TS) is an established risk factor for ccRCC, with unknown effects on tumor pathobiology.METHODSWe investigated the landscape of ccRCCs and paired normal kidney tissues using integrated transcriptomic, metabolomic, and metallomic approaches in a cohort of white males who were long-term current smokers (LTS) or were never smokers (NS).RESULTSAll 3 Omics domains consistently identified a distinct metabolic subtype of ccRCCs in LTS, characterized by activation of oxidative phosphorylation (OXPHOS) coupled with reprogramming of the malate-aspartate shuttle and metabolism of aspartate, glutamate, glutamine, and histidine. Cadmium, copper, and inorganic arsenic accumulated in LTS tumors, showing redistribution among intracellular pools, including relocation of copper into the cytochrome c oxidase complex. A gene expression signature based on the LTS metabolic subtype provided prognostic stratification of The Cancer Genome Atlas ccRCC tumors that was independent of genomic alterations.CONCLUSIONThe work identified the TS-related metabolic subtype of ccRCC with vulnerabilities that can be exploited for precision medicine approaches targeting metabolic pathways. The results provided rationale for the development of metabolic biomarkers with diagnostic and prognostic applications using evaluation of OXPHOS status. The metallomic analysis revealed the role of disrupted metal homeostasis in ccRCC, highlighting the importance of studying effects of metals from e-cigarettes and environmental exposures.FUNDINGDepartment of Defense, Veteran Administration, NIH, ACS, and University of Cincinnati Cancer Institute.

People living with HIV (PLWH) in the antiretroviral therapy (ART) era may lose more life-years to tobacco use than to HIV. Yet, smoking rates are more than twice as high among PLWH than the general population, contributing not just to mortality but to other adverse health outcomes, including neurocognitive deficits (neuroHIV). There is growing evidence that synergy with chronic inflammation and immune dysregulation that persists despite ART may be one mechanism by which tobacco smoking contributes to neuroHIV. This review will summarize the differential effects of nicotine vs tobacco smoking on inflammation in addition to the effects of tobacco smoke components on HIV disease progression. We will also discuss biomarkers of inflammation via neuroimaging as well as biomarkers of nicotine dependence (e.g., nicotine metabolite ratio). Tobacco smoking and nicotine may impact ART drug metabolism and conversely, certain ARTs may impact nicotine metabolism. Thus, we will review these bidirectional relationships and how they may contribute to neuroHIV and other adverse outcomes. We will also discuss the effects of tobacco use on the interaction between peripheral organs (lungs, heart, kidney) and subsequent CNS function in the context of HIV. Lastly, given the dramatic rise in the use of electronic nicotine delivery systems, we will discuss the implications of vaping on these processes. Despite the growing recognition of the importance of addressing tobacco use among PLWH, more research is necessary at both the preclinical and clinical level to disentangle the potentially synergistic effects of tobacco use, nicotine, HIV, cognition and immune dysregulation, as well as identify optimal approaches to reduce tobacco use. Graphical Abstract Proposed model of the relationships among HIV, ART, smoking, inflammation, and neurocognition. Solid lines represent relationships supported by evidence. Dashed lines represent relationships for which there is not enough evidence to make a conclusion. (a) HIV infection produces elevated levels of inflammation even among virally suppressed individuals. (b) HIV is associated with deficits in cognition function. (c) Smoking rates are higher among PLWH, compared to the general population. (d) The nicotine metabolite ratio (NMR) is associated with smoking behavior. (e) HIV and tobacco use are both associated with higher rates of psychiatric comorbidities, such as depression, and elevated levels of chronic stress. These factors may represent other mechanisms linking HIV and tobacco use. (f) The relationship between nicotine, tobacco smoking, and inflammation is complex, but it is well-established that smoking induces inflammation; the evidence for nicotine as anti-inflammatory is supported in some studies, but not others. (g) The relationship between tobacco use and neurocognition may differ for the effects of nicotine (acute nicotine use may have beneficial effects) vs. tobacco smoking (chronic use may impair cognition). (h) Elevated levels of inflammation may be associated with deficits in cognition. (i) PLWH may metabolize nicotine faster than those without HIV; the mechanism is not yet known and the finding needs validation in larger samples. We also hypothesize that if HIV-infection increases nicotine metabolism, then we should observe an attenuation effect once ART is initiated. (j) It is possible that the increase in NMR is due to ART effects on CYP2A6. (k) We hypothesize that faster nicotine metabolism may result in higher levels of inflammation since nicotine has anti-inflammatory properties.

To improve the clinical outcome of adoptive NK cell therapy in patients with solid tumors, NK cells need to persist within the tumor microenvironment (TME) in which the abundance of ROS could dampen antitumor immune responses. In the present study, we demonstrated that IL-15-primed NK cells acquired resistance against oxidative stress through the thioredoxin system activated by mTOR. Mechanistically, the activation of thioredoxin showed dependence on localization of thioredoxin-interacting protein. We show that NK cells residing in the tumor core expressed higher thiol densities that could aid in protecting other lymphocytes against ROS within the TME. Furthermore, the prognostic value of IL15 and the NK cell gene signature in tumors may be influenced by tobacco smoking history in patients with non-small-cell lung cancer (NSCLC). Collectively, the levels of reducing antioxidants in NK cells may not only predict better tumor penetrance but potentially even the immune therapy response.

The effects of tobacco smoking on the immune system of the brain are not well elucidated. Although nicotine is immunosuppressive, other constituents in tobacco smoke have inflammatory effects. PET imaging of the 18-kDa translocator protein (TSPO) provides a biomarker for microglia, the primary immunocompetent cells of the brain. This work compared brain TSPO levels in 20 tobacco smokers (abstinent for at least 2 h) and 20 nonsmokers using a fully quantitative modeling approach for the first time, to our knowledge. Methods: 11 C-PBR28 ( N -((2-(methoxy- 11 C)-phenyl)methyl)- N -(6-phenoxy-3-pyridinyl)acetamide) PET scans were acquired with arterial blood sampling to estimate the metabolite-corrected input function. 11 C-PBR28 volumes of distribution were estimated throughout the brain with multilinear analysis. Results: Statistical analyses revealed no evidence of significant differences in regional 11 C-PBR28 volumes of distribution between smokers and nonsmokers (whole-brain Cohen d = 0.09) despite adequate power to detect medium effect sizes. Conclusion: These findings inform previous PET studies reporting lower TSPO radiotracer concentrations in the brain (measured as SUV) for tobacco smokers than for nonsmokers by demonstrating the importance of accounting for radiotracer concentrations in plasma. These findings suggest that nonsmokers and smokers have comparable TSPO levels in the brain. Additional work with other biomarkers is needed to fully characterize the effects of tobacco smoking on the brain immune system., (© 2020 by the Society of Nuclear Medicine and Molecular Imaging.)

Introduction: The rate of nicotine metabolism, estimated by the nicotine metabolite ratio (NMR), is an important determinant of tobacco dependence. This study investigated the effect of NMR on smoking behavior due to nicotine reinforcement during ad libitum smoking., Aims and Methods: As part of a larger study, participants were stratified based on saliva NMR as fast and slow metabolizers. After smoking a cigarette and measuring nicotine blood concentrations, participants smoked as desired over a 90-minute period. Analysis included time to first cigarette, total number of cigarettes, total number of puffs, and weight of tobacco consumed., Results: Sixty-one (48%) participants were fast metabolizers and 66 (52%) slow metabolizers by NMR. No significant differences were found regarding the smoking topography variables by NMR. Normal metabolizers by genotype (n = 79) had a shorter time to first cigarette than reduced metabolizers (n = 39; p = .032). Blacks smoked fewer cigarettes (p = .008) and took fewer total puffs (p = .002) compared with Whites. Among Whites, fast metabolizers by NMR had a shorter time to first cigarette compared with slow metabolizers (p = .014). Among fast metabolizers, Whites had, compared with Blacks, shorter latency to first cigarette (p = .003) and higher number of total puffs (p = .014) and cigarettes smoked (p = .014). Baseline cigarettes per day and nicotine elimination half-life significantly predicted topography outcomes., Conclusions: Saliva NMR did not predict cigarette reinforcement during a relatively brief period of ad libitum smoking. Differences were seen by race, with White fast metabolizers by NMR having shorter time to first cigarettes compared with slow metabolizers., Implications: After a 90-minute period of nicotine abstinence, NMR was not significantly associated with smoking reinforcement. Slow and fast metabolizers had similar time to first cigarette, number of cigarettes smoked, total number of puffs, and tobacco consumed; however, within-race differences show that within Whites, fast metabolizers had a faster time to first cigarette than slow metabolizers., (© The Author(s) 2019. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The factors mediating fatal SARS-CoV-2 infections are poorly understood. Here, we show that cigarette smoke causes a dose-dependent upregulation of angiotensin converting enzyme 2 (ACE2), the SARS-CoV-2 receptor, in rodent and human lungs. Using single-cell sequencing data, we demonstrate that ACE2 is expressed in a subset of secretory cells in the respiratory tract. Chronic smoke exposure triggers the expansion of this cell population and a concomitant increase in ACE2 expression. In contrast, quitting smoking decreases the abundance of these secretory cells and reduces ACE2 levels. Finally, we demonstrate that ACE2 expression is responsive to inflammatory signaling and can be upregulated by viral infections or interferon treatment. Taken together, these results may partially explain why smokers are particularly susceptible to severe SARS-CoV-2 infections. Furthermore, our work identifies ACE2 as an interferon-stimulated gene in lung cells, suggesting that SARS-CoV-2 infections could create positive feedback loops that increase ACE2 levels and facilitate viral dissemination., Competing Interests: Declaration of Interests J.C.S. is a co-founder of Meliora Therapeutics and is an employee of Google, Inc. This work was performed outside of her affiliation with Google and used no proprietary knowledge or materials from Google. J.M.S. has received consulting fees from Ono Pharmaceuticals, is a member of the Advisory Board of Tyra Biosciences, and is a co-founder of Meliora Therapeutics., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Incidence of oropharyngeal squamous cell carcinoma (OPSCC) is rising rapidly in many western countries due to Human papillomavirus (HPV) and tobacco smoking, with a considerable overlap. Immunotherapy directed at the PD1/PD-L1 axis have shown promise in head and neck cancer and other cancer types. PD-L1 expression may indicate a poorer prognosis, and at the same time indicate a possible benefit of anti-PD-L1 immunotherapeutic agents. The primary aim of this study was to establish the prognostic effect of PD-L1 expression after primary curative radiotherapy alone. Material and methods: A cohort of 303 OPSCC patients treated with primary, curative intended radiotherapy was established. PD-L1 expression was evaluated by immunohistochemistry on formalin fixed, paraffin embedded tissue sections. PD-L1 positivity was defined as a Combined Positive Score (CPS) ≥1, indicating staining of either tumor cells, lymphocytes or macrophages. Results: Median follow-up was 5.3 years. With 199 deaths, there was no difference in overall survival between patients with PD-L1+ and PD-L1- tumors (adjusted hazard ratio [aHR] and 95% confidence interval [CI]: 1.0 [0.71-1.4]). Also, locoregional failure was similar between the two groups (aHR 1.1 [CI: 0.68 - 1.7]). Tumors were PD-L1+ in 76% of cases, significantly more among HPV p16+ tumors (82% vs. 70%, p  = .01). Interestingly, higher prevalence of PD-L1+ expression was seen in HPV p16+ patients with <10 pack-years of tobacco-smoking (93%) compared to HPV p16+ smokers (76%) or HPV p16-negative patients (70%) ( p  = .003). Conclusion: PD-L1 expression had no prognostic significance in OPSCC patients treated with primary radiotherapy alone. A substantial proportion of OPSCC tumors show PD-L1 overexpression, especially in HPV p16+ tumors in patients with little or no smoking history.

Chronic obstructive pulmonary disease (COPD) is related to smoking and anti-inflammatory therapy is indicated. Among the mediators with anti-inflammatory properties, we highlight piperlongumine (PL), an alkaloid/amide of Piper longum. Here we evaluated the PL administration on an experimental model of respiratory inflammation resulting from exposure to cigarette smoke. Male Balb/c mice were exposed to burning of 10 commercial cigarettes, 2x/day, for five weeks on specific equipment. PL efficacy was evaluated in control, exposed to smoke without treatment and PL treated (2.0 mg/kg, 3x/week) groups. Animals were weighed and plethysmographic analyses performed at the end of the exposure protocol. Inflammatory cells were evaluated in the bronchoalveolar lavage (BAL) and hemoglobin and glucose in the blood. Lung fragments were processed for histopathological studies and AnxA1, COX-2, NF-kB and neutrophil elastase expressions. Plethysmography revealed that PL maintained pulmonary frequency, volume and ventilation parameters similar to controls, with respiratory volume reduction compared to untreated animals. Final weight was reduced in both exposed groups. PL decreased hemoglobin concentration, attenuated the reduction of glucose levels and reduced influx of lymphocytes, neutrophils and macrophages in BAL. Histopathologically occured infiltration of inflammatory cells, increase of the interalveolar septa and intra-alveolar spaces in untreated animals. But, PL administration recovered lung tissues and, immunohistochemically, promoted increased expression of AnxA1 and reduction of COX-2, NF-kB and neutrophil elastase. Together the results indicate that PL attenuates systemic and pulmonary inflammatory changes, partially by modulating the expression the endogenous AnxA1, and may represent a promising therapy in preventing the inflammation induced by cigarette smoke., (Copyright © 2020. Published by Elsevier Ltd.)

Despite health risks associated with smoking, up to 20% of the US population persist in this behavior; many smoke to control body weight or appetite, and fear of post-cessation weight gain can motivate continued smoking. Nicotine and tobacco use is associated with lower body weight, and cessation yields an average weight gain of about 4 kg, which is thought to reflect a return to the body weight of a typical nonsmoker. Nicotine replacement therapies can delay this weight gain but do not prevent it altogether, and the underlying mechanism for how nicotine is able to reduce weight is not fully understood. In rodent models, nicotine reduces weight gain, reduces food consumption, and alters energy expenditure, but these effects vary with duration and route of nicotine administration. Nicotine, acting through nicotinic acetylcholine receptors (nAChRs), increases the firing rate of both orexigenic agouti-related peptide and anorexigenic proopiomelanocortin neurons in the arcuate nucleus of the hypothalamus (ARC). Manipulation of nAChR subunit expression within the ARC can block the ability of nicotine and the nicotinic agonist cytisine from decreasing food intake; however, it is unknown exactly how this reduces food intake. This review summarizes the clinical and preclinical work on nicotine, food intake, and weight gain, then explores the feeding circuitry of the ARC and how it is regulated by nicotine. Finally, we propose a novel hypothesis for how nicotine acts on this hypothalamic circuit to reduce food intake. Implications: This review provides a comprehensive and updated summary of the clinical and preclinical work examining nicotine and food intake, as well as a summary of recent work examining feeding circuits of the hypothalamus. Synthesis of these two topics has led to new understanding of how nAChR signaling regulates food intake circuits in the hypothalamus., (© The Author(s) 2019. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved.For permissions, please e-mail: journals.permissions@oup.com.)

Introduction: Alcohol may influence the nicotine metabolite ratio (NMR), an index of the rate of nicotine metabolism that is associated smoking level and lapses. We examined if NMR changes during alcohol use disorder (AUD) treatment and how changes in NMR relate to reductions in drinking., Methods: Using an observational design, 22 daily smokers [63.64% male, Mage = 46.77 (11.37)] receiving AUD treatment completed baseline and follow-up appointments 3 weeks apart. At each appointment, daily alcohol and cigarette use, salivary and urinary NMR, nicotine exposure via urinary total nicotine equivalents, and carbon monoxide were assessed. Multilevel models examined the change over time in NMR and its within-person relations with changes in drinks per week. Sex differences were evaluated., Results: There were significant reductions in both salivary and urinary NMR over time for men (p = .02; p = .01, respectively) but not for women (p = .54; p = .90, respectively). There were no changes over time in total nicotine equivalents (p = .09), carbon monoxide (p = .44), or cigarette use (p = .44) in either sex. Drinks per week were significantly reduced for men (29.12 drink reduction, p < .001) but not for women (2.28 drink reduction, p = .80); however, within-person changes in drinking were not associated with changes in salivary or urinary NMR (p = .99; p = .19)., Conclusions: The reduction in alcohol use and NMR in men provides indirect support for alcohol increasing NMR. In contrast, the low baseline drinking and lack of alcohol reduction likely underlie the lack of change in NMR in females. Reasons for NMR reductions during AUD treatment and its effects on smoking require further study., Implications: Three weeks of alcohol use disorder treatment among daily smokers coincided with a significant reduction in both alcohol use and NMR for men; however, neither drinking level nor NMR changed for women. The findings indirectly support that heavy drinking increases NMR, which is reversed with reduced drinking. Additional research is needed to establish if these changes in NMR correlate with smoking and cessation outcomes., (© The Author(s) 2018. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Squamous cell carcinomas of the head and neck (HNSCC) arise from mucosal keratinocytes of the upper aero-digestive tract. Despite a common cell of origin and similar driver-gene mutations which divert cell fate from differentiation to proliferation, HNSCC are considered a heterogeneous group of tumors categorized by site of origin within the aero-digestive mucosa, and the presence or absence of HPV infection. Tobacco use is a major driver of carcinogenesis in HNSCC and is a poor prognosticator that has previously been associated with poor immune cell infiltration and higher mutation numbers. Here, we study patterns of mutations in HNSCC that are derived from the specific nucleotide changes and their surrounding nucleotide context (also known as mutation signatures). We identify that mutations linked to DNA adducts associated with tobacco smoke exposure are predominantly found in the larynx. Presence of this class of mutation, termed COSMIC signature 4, is responsible for the increased burden of mutation in this anatomical sub-site. In addition, we show that another mutation pattern, COSMIC signature 5, is positively associated with age in HNSCC from non-smokers and that larynx SCC from non-smokers have a greater number of signature 5 mutations compared with other HNSCC sub-sites. Immunohistochemistry demonstrates a significantly lower Ki-67 proliferation index in size matched larynx SCC compared with oral cavity SCC and oropharynx SCC. Collectively, these observations support a model where larynx SCC are characterized by slower growth and increased susceptibility to mutations from tobacco carcinogen DNA adducts.

Background: Asthma is closely associated with tobacco smoking (TS) and is more difficult to effectively treat after exposure to TS., Objective: To observe the effects of TS on the expression of endothelin-2 (ET-2) and airway inflammation in asthmatic rats and to explore the related mechanisms., Methods: We established an animal model of asthma with ovalbumin (OVA)/Al(OH) 3 and subjected different animal groups to TS and/or dexamethasone/bosentan. The differences in the inflammatory cell infiltration, the pathological changes to the bronchial wall and the bronchial smooth muscle thickness, and the expression of ET-2, c-Jun amino terminal kinase (JNK1/2), malondialdehyde (MDA), and glutathione peroxidase (GSH) in the lung tissue and of interleukin (IL)-7 in bronchoalveolar lavage fluid (BALF) were assessed., Results: Exposure to TS or OVA caused an obvious increase in the inflammatory cells in the BALF over what was observed in the control group. In asthma models, the expression of ET-1, JNK1/2, MDA, and GSH in the lung tissues, as well as that of IL-17 in the BALF, was increased. After treatment with dexamethasone/bosentan, the expression of IL-17, JNK1/2, MDA, and GSH decreased compared to the smoking group; airway inflammation and the staining intensity in the lung tissue were also reduced., Conclusion: TS exposure can clearly exacerbate airway inflammation in asthmatic rats, while bosentan can alleviate airway inflammation through regulation of the ET-2/JNK1/2 signalling pathway., (Copyright © 2019 Elsevier B.V. All rights reserved.)

It is well known that smoking is the risk factor in the development and clinical course of Crohn s disease (CD), but on the other hand, smoking is a protective factor against ulcerative colitis (UC). The pathways that are influenced by smoking in CD and UC are poorly understood. The aim of our study was to analyse the influence of smoking on the mRNA expression of cytokines in mucosa in patients with CD and UC. We performed a cross-sectional study. The cohort consisted of 86 IBD patients (48 CD patients and 38 UC patients) and took place at the IBD Centre at the University Hospital Bratislava-Ružinov. We took the demographic and clinical data of each patient, including information about their smoking habits. We performed a colonoscopy on each patient and took biopsies from both inflamed and non-inflamed sigma (CD, UC) and terminal ileum (CD). mRNA was extracted from mucosal biopsy samples for each cytokine and was normalized to a housekeeping gene (GAPDH). Finally, we compared the mRNA expression of target cytokines in the mucosa of smokers and non-smokers in IBD patients. Smokers with Crohn s disease have a significantly higher mRNA expression of pro-inflammatory cytokine TNF ? (p=0.003) in inflamed mucosa in sigma compared with non-smokers. In smokers with ulcerative colitis, we observed significantly higher mRNA expression of anti-inflammatory cytokine IL 10 (p=0.022) in non-inflamed mucosa of sigma. Similarly, smokers with UC have a significantly decreased mRNA expression of cytokine TLR 2 (p=0.024) and CCR1 (p=0.049) in non-inflamed mucosa of sigma. Based on our results, smoking has a positive influence on cessation and the clinical course of UC due to the stimulation of anti-inflammatory cytokine IL 10 in mucosa. On the other hand, smokers with CD have a higher expression of pro-inflammatory cytokine TNF ?, which could be associated with a worsening of the disease and response to therapy.

Background: Tobacco smoking rates in depressive patients are higher compared with the general population. Smoking was demonstrated to accelerate the metabolism of different drugs metabolized by CYP1A2, but possibly also by CYP2C19 and CYP3A4. The principle aim of the present investigation from 2015 to 2018 was to determine the differences in the pharmacokinetics of escitalopram between smokers and nonsmokers., Methods: A group of nonsmokers (n = 88) was compared with smokers (n = 36), both receiving escitalopram, using the Mann-Whitney U test. Linear regression analysis was used to account for the impact of escitalopram dose, age, and sex in addition to smoking on the steady-state serum concentration of escitalopram., Results: Smokers received by mean 17.6% higher doses of escitalopram (P = 0.026) but showed 31.9% lower serum concentrations (P = 0.031). To control for confounders, linear regression analysis showed that dose (P < 0.001), sex (P = 0.03), and smoking tobacco (P = 0.027) did significantly influence serum concentrations of escitalopram with higher levels in women and nonsmokers., Conclusions: Notwithstanding higher daily doses, smokers had significantly lower serum concentrations of escitalopram. In concordance with previous results, besides CYP1A2, a possible induction of CYP2C19 and CYP3A4 by tobacco smoke, resulting in lower serum concentrations of escitalopram in smokers than in nonsmokers, is suggested. Therefore, to provide personalized therapy, clinicians should consider smoking status and inform patients on the interactions of smoking and escitalopram metabolism.

Introduction: Currently, there is no widely accepted, non-self-report measure that simultaneously reflects smoking behaviors and is molecularly informative of general disease processes. Recently, researchers developed a smoking index (SI) using nucleated blood cells and a multi-tissue DNA methylation-based predictor of chronological age and disease (DNA methylation age [DNAm-age]). To better understand the utility of this novel SI in readily accessible cell types, we used buccal cell DNA methylation to examine SI relationships with long-term tobacco smoking and moist snuff consumption., Methods: We used a publicly available dataset composed of buccal cell DNA methylation values from 120 middle-aged men (40 long-term smokers, 40 moist snuff consumers, and 40 nonsmokers). DNAm-age (353-CpGs) and SI (66-CpGs) were calculated using CpG sites measured using the Illumina HumanMethylation450 BeadChip. We estimated associations of tobacco consumption habits with both SI and DNAm-age using linear regression models adjusted for chronological age, race, and methylation technical covariates., Results: In fully adjusted models with nonsmokers as the reference, smoking (β = 1.08, 95% CI = 0.82 to 1.33, p < .0001) but not snuff consumption (β = .06, 95% CI = -0.19 to 0.32, p = .63) was significantly associated with SI. SI was an excellent predictor of smoking versus nonsmoking (area under the curve = 0.92, 95% CI = 0.85 to 0.98). Four DNAm-age CpGs were differentially methylated between smokers and nonsmokers including cg14992253 [EIF3I], which has been previously shown to be differentially methylated with exposure to long-term fine-particle air pollution (PM2.5)., Conclusions: The 66-CpG SI appears to be a useful tool for measuring smoking-specific behaviors in buccal cells. Still, further research is needed to broadly confirm our findings and SI relationships with DNAm-age., Implications: Our findings demonstrate that this 66-CpG blood-derived SI can reflect long-term tobacco smoking, but not long-term snuff consumption, in buccal cells. This evidence will be useful as the field works to identify an accurate non-self-report smoking biomarker that can be measured in an easily accessible tissue. Future research efforts should focus on (1) optimizing the relationship of the SI with DNAm-age so that the metric can maximize its utility as a tool for understanding general disease processes, and (2) determining normal values for the SI CpGs so that the measure is not as study sample specific., (© The Author(s) 2018. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Expression of the Receptor for Advanced Glycation Endproducts (RAGE) initiates pro-inflammatory pathways resulting in lung destruction. We hypothesized that RAGE directed imaging demonstrates increased lung uptake in smoke-exposure., Methods: After exposure to room air or to cigarette smoke for 4-weeks or 16-weeks, rabbits were injected with 99m Tc-anti-RAGE F(ab') 2 and underwent Single-Photon Emission Computed Tomography/Computed Tomography (SPECT/CT) imaging. Lung radiotracer uptake was calculated as percent injected dose (%ID). Lungs were dissected for gamma well counting and histological analysis., Results: 99m Tc-anti-RAGE F(ab') 2 SPECT/CT imaging demonstrated increased lung expression of RAGE with smoke exposure compared to room air control at 4-weeks: Room air right (R) 0.75 ± 0.38%ID, left (L) 0.62 ± 0.32%ID vs. Smoke exposed R 0.17 ± 0.03, L 0.17 ± 0.02%ID (p = 0.02 and 0.028, respectively). By 16-weeks of smoke exposure, the uptake decreased to 0.19 ± 0.05%ID R and 0.17 ± 0.05%ID L, significantly lower than 4-week imaging (p = 0.0076 and 0.0129 respectively). Staining for RAGE confirmed SPECT results, with the RAGE ligand HMGB1 upregulated in the macrophages of 4-week smoke-exposed rabbits., Conclusions: RAGE-directed imaging identified pulmonary RAGE expression acutely in vivo in an animal model of emphysema early after smoke exposure, with diminution over time. These studies document the extent and time course of RAGE expression under smoke exposure conditions and could be utilized for disease monitoring and examining response to future RAGE-targeted therapies.

Aims: Tobacco smoking is associated with a vast range of adverse health effects, including diminished cognitive and anti-oxidative capabilities. Conversely, vitamin E (VitE) is known to enhance data acquisition and retention and hippocampal oxidative defense. No studies, however, examined the protective effect of VitE with tobacco administration. Therefore, this study examined the protective effect of VitE on the cognitive and oxidative debilitating effects induced by waterpipe smoking., Materials and Methods: Wistar male rats were divided into four groups: waterpipe smoking, VitE, waterpipe combined with VitE, and control group. The exposure to waterpipe and VitE was for one month and then spatial learning and memory were assesses using Radial Arms Water Maze. Additionally, oxidative stress biomarkers (Catalase, GPx, and TBARS, GSH, GSSG, and GSH/GSSG ratio) were assessed in the hippocampus., Key Findings: The results revealed that waterpipe smoking impaired short-term and long-term memory (P < 0.05). Waterpipe smoking reduced activity of catalase (P < 0.05), GPx (P < 0.05) and GSH/GSSG ratio (P < 0.05) in the hippocampus. Administration of VitE prevented memory impairment and alterations in oxidative stress biomarkers., Significance: waterpipe smoking induces short-term and long-term memory impairments, which were prevented by administration of VitE via its anti-oxidative properties., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Rationale: About 1.1 billion people smoke tobacco globally and tobacco-related health care costs 1.8% of GDP in many countries. The majority of people are unable to quit smoking despite pharmacological intervention, highlighting the need to understand the pathophysiology associated with tobacco smoking to aid the development of new therapeutics. The reinforcing effects of tobacco smoking are thought to be mediated by the dopamine system. However, the nature of dopamine dysfunction seen in smokers is unclear., Objective: To determine the nature and robustness of the evidence for dopaminergic alterations in smokers., Methods: The entire MEDLINE, EMBASE, and PsycINFO databases were searched for studies from inception date to November 18, 2018. In vivo human molecular imaging studies of dopamine measures (dopamine synthesis or release capacity, transporter levels, receptor levels) in tobacco smokers were selected. Demographic, clinical, and imaging measures were extracted from each study and meta-analyses, and sensitivity analyses were conducted., Results: Fourteen studies met inclusion criteria comprising a total sample of 219 tobacco smokers and 297 controls. The meta-analysis showed a significant reduction in dopamine transporter availability in the smokers relative to controls with an effect size of - 0.72 ([95% CI, - 1.38 to - 0.05], p = 0.03). However, there was no difference in D2/3 receptor availability in smokers relative to controls (d = -0.16 ([95% CI, - 0.42 to 0.1], p = 0.23). There were insufficient studies for meta-analysis of other measures. However, findings from the published studies indicated blunted dopamine release and lower D1 receptor availability, while findings for dopamine synthesis capacity were inconsistent., Conclusion: Our data indicate that striatal dopamine transporter availability is lower but D2/3 receptors are unaltered in smokers relative to controls. We discuss the putative mechanisms underlying this and their implications.

Oral cancer and smoking are closely related, because the oral cavity, which is the route of ingestion of tobacco smoke, is in direct contact with the oral mucosa. Nicotine, one of the components of tobacco, can diffuse rapidly to the central nervous system and is responsible for tobacco addiction. Nicotine is present in high concentrations in the bloodstream of smokers; while the addictive effects of this alkaloid have extensively been studied, its effect on tumorigenesis is not clear yet. Therefore, in this study, we examined the effect of nicotine on cell proliferation and the signaling pathways it activates. The human oral squamous cell carcinoma cell line HSC-2 was used as a model system. We demonstrated the correlation between nicotine and epidermal growth factor receptor (EGFR) signaling. Nicotine treatment induced HSC-2 cell proliferation and migration and the phosphorylation of EGFR. Furthermore, nicotine treatment activated the EGFR downstream effectors phosphatidylinositol-3 kinase/AKT and p44/42 mitogen-activated protein kinases (ERK), which, in turn, promoted cell proliferation. Overall, our study suggests that nicotine promotes cell growth and migration through epidermal growth factor (EGF) signaling and plays an important role in oral cancer progression., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Free radicals (FRs) are active chemical substances having unpaired electron(s) which participate in the causation of precancerous lesions or cancer in tobacco habituates. Alterations in the antioxidant levels are reflected throughout the antioxidant enzyme activities in blood, wherein erythrocytes are considered highly sensitive to those enzymes. Our study was therefore aimed to assess the effects of tobacco consumption on erythrocyte antioxidant enzyme- Superoxide dismutase (E-SOD) and evaluate its defensive action., Methods: E-SOD was estimated in 32 participants categorized in 2 groups (tobacco users and controls). 3 mL venous blood was withdrawn and antioxidant levels were assessed using RANSOD kit (Randox, Catalogue No.-125) as per the manufacturer's instructions. The E-SOD activity was then determined using spectrophotometry and the data was statistically evaluated., Results: The Two-tailed Paired t-test was applied in smokers-SOD intergroup (mean=-124.45, P<0.0001) and chewers-SOD intergroup (mean=-66.70, P=0.1017). The mean SOD values (139.72±36.94) in cases were found to be significantly lower as compared to controls (212.75±37.04). The lowest SOD level was seen with chewers compared to other groups., Conclusions: E-SOD was found to be lowest among tobacco chewers probably due to the fact of excessive enzyme activity against prolonged release of carcinogens. The variability in the enzyme activity envisaged its potential as a biomarker in establishing the oral potentially malignant disorders (OPMDs) much before the lesions arises or detect the progression of existing lesion to malignancy.

Background : Existing theories hold that chronic tobacco smoking leads to the development of adverse psychological symptoms, thus producing a compulsive urge to smoke in order to alleviate these sensations. Sleep disturbances are often considered among the negative consequences of chronic smoking. Objectives : The current study aimed at examining whether dysregulation of the hypothalamic-pituitary-adrenocortical (HPA) axis may be involved in this disruption of sleep quality among smokers. Methods : Smokers and non-smokers provided saliva samples following awakening for assessment of cortisol concentrations as a measure of HPA activity. Subsequently the participants completed the State-Trait Anxiety Inventory, Brief Questionnaire on Smoking Urges, the Fagerstrom Test for Nicotine Dependence, and the Pittsburgh Sleep Quality Index. Next, their sleep was monitored objectively for one week using an actigraph. Results : While smokers' self-reported sleep quality was similar to that of non-smokers, their sleep recording data pointed to diminished sleep continuity (increased wake time after sleep onset; WASO), while total sleep time and sleep onset latency were similar to that of non-smokers. Cortisol secretion was higher among smokers. However, among smokers only, cortisol was negatively correlated with WASO, suggesting that the direct enhancing effect of smoking on WASO is somewhat balanced by an indirect process related to higher cortisol levels. Possible interpretations for this inconsistent mediation are discussed. Conclusions/Importance : Smoking is associated with reduced sleep continuity and the relationship between smoking and sleep continuity may involve the HPA axis.

Background: The morbidity and mortality associated with tobacco smoking is well established. Nicotine is the addictive component of tobacco. Nicotine, through the non-neuronal α7nicotinic receptor, induces cell proliferation, neo-angiogenesis, epithelial to mesenchymal transition, and inhibits drug-induced apoptosis., Objective: To understand the genetic, molecular and cellular biology of addiction, chronic obstructive pulmonary disease and lung cancer., Methods: The search for papers to be included in the review was performed during the months of July- September 2018 in the following databases: PubMed (http://www.ncbi.nlm.nih.gov), Scopus (http://www.scopus.com), EMBASE (http://www.elsevier.com/online-tools/embase), and ISI Web of Knowledge (http://apps.webofknowledge.com/). The following searching terms: "nicotine", "nicotinic receptor", and "addiction" or "COPD" or "lung cancer" were used. Patents were retrieved in clinicaltrials.gov (https://clinicaltrials.gov/). All papers written in English were evaluated. The reference list of retrieved articles was also reviewed to identify other eligible studies that were not indexed by the above-mentioned databases. New experimental data on the ability of nicotine to promote transformation of human bronchial epithelial cells, exposed for one hour to Benzo[a]pyrene-7,8-diol-9-10-epoxide, are reported., Results: Nicotinic receptors variants and nicotinic receptors upregulation are involved in addiction, chronic obstructive pulmonary disease and/or lung cancer. Nicotine through α7nicotinic receptor upregulation induces complete bronchial epithelial cells transformation., Conclusion: Genetic studies highlight the involvement of nicotinic receptors variants in addiction, chronic obstructive pulmonary disease and/or lung cancer. A future important step will be to translate these genetic findings to clinical practice. Interventions able to help smoking cessation in nicotine dependence subjects, under patent, are reported., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Introduction : Research from Philip Morris International's science division on its Heat-not-Burn product IQOS TM focused on its chemical, toxicological, clinical, and behavioral aspects. Independent research on the experiences and behavioral aspects of using IQOS TM , and how it compares to e-cigarettes, is largely lacking. The current randomized, cross-over behavioral trial tried to bridge the latter gaps. Methods : Participants ( n = 30) came to the lab on three consecutive days after being overnight smoking abstinent. During each session, participants used one of three products (cigarette, e-cigarette, or IQOS TM ) for five minutes. Exhaled CO (eCO) measurements and questionnaires were repeatedly administered throughout the session. Results : Smoking a cigarette for five minutes resulted in a significant increase of eCO, whereas using an IQOS TM resulted in a small but reliable increase (0.3 ppm). Vaping did not affect eCO. Cigarette craving reduced significantly after product use, with the decline being stronger for smoking than for e-cigarettes or IQOS TM . Withdrawal symptoms declined immediately after smoking or using IQOS TM , and with some delay after vaping. IQOS TM scored higher in terms of subjective reward/satisfaction and was slightly preferred to the e-cigarette. Discussion : Short-term use of IQOS TM has a minimal impact on eCO, is equally effective in reducing cigarette craving and withdrawal symptoms as an e-cigarette, and is slightly preferred., Competing Interests: The authors declare no conflict of interest but are advocates for Tobacco Harm Reduction (THR).

Beyond promoting smoking initiation and preventing smokers from quitting, nicotine can reduce food intake and body weight and thus is viewed as desirable by some smokers, especially many women. During the last several decades, the molecular mechanisms underlying the inverse correlation between smoking and body weight have been investigated extensively in both animals and humans. Nicotine's weight effects appear to result especially from the drug's stimulation of α3β4 nicotine acetylcholine receptors (nAChRs), which are located on pro-opiomelanocortin (POMC) neurons in the arcuate nucleus (ARC), leading to activation of the melanocortin circuit, which is associated with body weight. Further, α7- and α4β2-containing nAChRs have been implicated in weight control by nicotine. This review summarizes current understanding of the regulatory effects of nicotine on food intake and body weight according to the findings from pharmacological, molecular genetic, electrophysiological, and feeding studies on these appetite-regulating molecules, such as α3β4, α7, and α4β2 nAChRs; neuropeptide Y (NPY); POMC; melanocortin 4 receptor (MC4R); agouti-related peptide (AgRP); leptin, ghrelin, and protein YY (PYY).

Introduction: Varenicline doubles cessation over nicotine replacement therapy (NRT) patch for "normal," but not "slow," nicotine metabolizers, as assessed by the nicotine metabolite ratio (NMR). Metabolism-informed care (MIC) could improve outcomes by matching normal metabolizers with non-nicotine medication (e.g., varenicline) and slow metabolizers with NRT patch., Methods: We conducted a feasibility randomized controlled trial of MIC versus guideline based care (GBC) among 81 outpatient adult daily smokers with medical comorbidity. Participants reported perceptions of MIC, underwent blood draw for NMR, and received expert cessation counseling. For MIC participants, medication selection was informed by NMR result (normal (≥0.31) vs. slow (< 0.31)). The primary outcome was MIC feasibility, reflected by attitudes toward MIC and by match rates between NMR and medication. Secondary endpoints (cessation confidence, medication use, smoking status) were assessed over 6 months to inform future studies., Results: Participants were median age 53 years, 46% female, 28% black, and ~90% endorsed MIC. Despite high varenicline prescription rates (~60%) in both arms, NMR-medication matching was higher in MIC (84%) versus GBC (58%) participants (p=0.02); unadjusted odds ratio (OR) 3.67, 95% confidence interval [1.33, 11.00; p-value=0.02]. Secondary endpoints were similar at 1, 3, and 6 months., Conclusions: MIC, an NMR-based precision approach to smoking cessation, was acceptable to 90% of smokers and improved NMR-medication match rates more than 3-fold compared to GBC, even with generally high use of varenicline. These data support the feasibility of MIC, which could maximize efficacy of smoking cessation medication while minimizing side effects and cost., Implications: Among treatment-seeking daily smokers with medical comorbidity, most viewed metabolism-informed care (MIC), guided by the nicotine metabolism ratio (NMR), favorably, and were willing to accept MIC-guided medication. Compared to GBC participants (58%), more MIC participants (84%) were prescribed NMR-matched medication (i.e., normal metabolizers received varenicline; slow metabolizers received NRT patch). MIC increased the odds of optimized matching between NMR and medication more than 3-fold over GBC. Because the number needed to treat (NNT) to help one normal metabolizer quit smoking is only 4.9 for varenicline versus 26 for patch, broad implementation of MIC will improve drug efficacy in normal metabolizers as well as minimize side effects in slow metabolizers.

Aim: The study investigated the extent to which tobacco smoke exposure causes changes in lipids biochemistry through measurement blood concentrations of: paraoxonase-1 (PON-1) activities as lipid-bound enzyme into cell membrane, concentration of malonyldialdehyde (MDA), protein adducts of 4-hydroxynonenal (HNE-adducts), oxidized low density lipoproteins (oxLDL), total cholesterol (CH) and high-density lipoprotein cholesterol (HDL). Additionally, the activity of P isoform of glutathione S-transferase (GST-π) was measured. Methods: Investigations were performed in the blood of patients with acute pancreatitis (AP) on the 1 st , 3 rd and 7 th day of hospitalization and in healthy volunteers. The activities of PON-1 forms, GST-π were determined spectrophotometrically. Concentrations of PON-1, MDA, HNE-adducts, oxLDL, HDL, CH were measured using commercial tests. Results: Near 2-fold higher concentrations of MDA, HNE-adducts, oxLDL, correlating with inflammatory markers in AP patients compared to healthy subjects were demonstrated, which were accompanied by gradually increasing CH/HDL ratio during hospitalization. During hospital treatment, decreased activities of all PON-1 subtypes were observed in AP patients compared to healthy subjects, more pronounced in tobacco smokers. A decreased PON-1 phosphotriesterase activity in non-AP control group smokers compared to non-smokers was noted. In non-smoking AP patients GST-π activity normalized during hospitalization in contrast to smokers. Conclusions: GST-π and PON-1 phosphotriesterase activities seem to be a sensitive marker of pro/antioxidative imbalance in smokers. Lipids peroxidation products generated during AP can intensify preexisting inflammation. Increasing stay in the hospital was associated with worsening of lipids peroxidation markers and the parameters of lipid profile, in both non-smoking and smoking AP patients, what can indicate that the oxidative-inflammatory process are not extinguished., Competing Interests: Competing Interests: The authors have declared that no competing interest exists.

Understanding the stimulatory effects of nicotine on cardiovascular function in humans is of great interest given the wide-spread use of different forms of combustible and smokeless products that deliver nicotine. An intravenous nicotine infusion procedure was used to evaluate factors associated with the acute heart rate (HR) response to nicotine (0.5 mg per 70 kg bodyweight) in a sample of 213 smokers. We tested for differential response to nicotine based on demographic characteristics (race [European American vs African America], sex, body mass index and age); a set of blood-based biomarkers (baseline nicotine, cotinine and cortisol levels and nicotine metabolite ratio); and a set of self-reported measures related to tobacco use. Nicotine infusion was first noted to increase HR approximately 10 beats per minute (95% CI: 7.8-12.3) one minute post-infusion, and 13 beats per minute (95% CI: 11.0-15.2) two minutes post-infusion. Higher cortisol, lower nicotine levels, higher nicotine metabolite ratio, being female and greater withdrawal symptoms were independently associated with a potentiated increase in HR 1 or 2 min after nicotine infusion. Factors associated with the acute HR effects of nicotine warrant further investigation given their potential to inform the development of nicotine delivery systems as tobacco harm reduction approaches for smokers., (Copyright © 2018 Elsevier Inc. All rights reserved.)

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&#95;PM&#95;s&#95;at fold-change = 1.05 p = 0.006; 203923&#95;PM&#95;s&#95;at fold-change = 1.06, p = 0.003; 233538&#95;PM&#95;s&#95;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., Competing Interests: M. Caruso, R. Emma, A.T. Bansal, C.E. Wheelock, M.J. Loza, L. Fabbella, T. Sandstrom, F. Singer, A.R. Sousa, D.E. Shaw, R. Lutter, S.J. Fowler, I. Horvath, I. Pandis, P. Montuschi declare non conflict of interest. J. Kolmert, B. De Meulder, D. Lefaudeux, C. Auffray, P.J. Sterk, N. Krug, M. Sanak, J. Corfield declare grants from IMI (Innovative Medicine Initiatives) during the conduct of the study. S.E. Dahlen declares financial supporting by Swedish Research Academic Foundations, RSPS Incentive, AZ, Teva and GSK consultancies. B. Dahlen declares consultancies for TEVA. P. Chanez reports grants and personal fees from Almirall, BI, Centocor, GSK, MSD, AstraZeneca, Novartis, Teva, Chiesi, Schering Plough, outside the submitted work. P.S. Bakke reports personal fees from GlaxoSmithKline, Boehringer-Ingelheim, AstraZeneca, Orionpharma, Mundipharma, outside the submitted work. R. Djukanovic reports receiving fees for lectures at symposia organised by Novartis and TEVA and consultation for these two companies as member of advisory boards. He is a co-founder and current consultant, and has shares in Synairgen, a University of Southampton spin out company. P.H. Howarth reports fees from GSK, outside the submitted work. L. Fleming reports personal fees and other from Vectura, Novartis, Boehringer ingelheim, outside the submitted work. I. Adcock reports grants from EU-IMI, during the conduct of the study; grants from MRC, BHF, Dunhill Medical Trust, personal fees from Chiesi, GSK, Boehringer Ingelheim, outside the submitted work. K.F. Chung reports personal fees from Advisory Board membership, grants for research, and personal fees from payments for lectures, outside the submitted work. ATB is employed by Acclarogen Ltd., MJL by Janssen Research & Development, LLC., ARS by GSK and JC by Astra Zeneca R&D and Areteva R&D. There are no patents, products in development or marketed products to declare. This does not alter our adherence to all the PLOS ONE policies on sharing data and materials, as detailed online in the guide for authors.

Cancer is the second leading cause of death in the world, causing 8.8 million deaths in 2015 according to the World Health Organization (WHO). Risk factors for cancer include smoking and alcohol con sumption. In Chile, 33.6% of the population and 21.2% of young people smokes. Alcohol consump tion in the Chilean population is 74.5% and 12.2% in young people. Among the physiological factors that influence the development of cancer, the genetic factor plays a relevant role. It has been shown that the presence of genetic polymorphisms that alter the ability of the body to eliminate contami nants increase the risk of developing cancer. The same applies to polymorphisms that prevent DNA repair due to damage caused by environmental pollutants such as cigarette smoke. The objective of this review is to analyze the state of the art of the relationship between pharmacogenetics, smoking, and alcohol consumption as risk factors for the development of cancer. In conclusion, the results suggest that the presence of polymorphisms that alter the function of biotransformation enzymes phase I (CYP1A1, CYP1E1) and phase II (GST), as well as polymorphisms in DNA repair enzymes (ERCC1 / ERCC2), increase the risk of cancer induced by smoking and alcohol consumption. This association is important considering that smoking and drinking alcohol are highly prevalent among the Chilean population.

Introduction: To propose a hypothesis theory to establish a linkage between cigarette smoking and cluster headache pathogenesis., Background: Cluster headache is a primary headache syndrome grouped under the trigeminal autonomic cephalalgias. What distinguishes cluster headache from all other primary headache conditions is its inherent connection to cigarette smoking. It is undeniable that tobacco exposure is in some manner related to cluster headache. The connection to tobacco exposure for cluster headache is so strong that even if an individual sufferer never smoked, then that individual typically had significant secondary smoke exposure as a child from parental smoking behavior and in many instances both scenarios exist. The manner by which cigarette smoking is connected to cluster headache pathogenesis is unknown at present. If this could be determined this may contribute to advancing our understanding of cluster headache pathophysiology., Methods/results: Hypothesis statement., Conclusion: The hypothesis theory will include several principles: (1) the need of double lifetime tobacco exposure, (2) that cadmium is possibly the primary agent in cigarette smoke that leads to hypothalamic-pituitary-gonadal axis toxicity promoting cluster headache, (3) that the estrogenization of the brain and its specific sexually dimorphic nuclei is necessary to develop cluster headache with tobacco exposure, and (4) that the chronic effects of smoking and its toxic metabolites including cadmium and nicotine on the cortex are contributing to the morphometric and orexin alterations that have been previously attributed to the primary headache disorder itself., (© 2018 American Headache Society.)

Background: Identifying the biological basis of smoking cessation success is of growing interest. The rate of nicotine metabolism, measured by the nicotine metabolite ratio, affects multiple aspects of nicotine dependence. Fast nicotine metabolizers tend to smoke more, experience more withdrawal and craving, and have lower cessation rates compared with slow metabolizers. The nicotine metabolite ratio predicts treatment response, and differences in brain activation between fast metabolizers and slow metabolizers have been reported in fMRI studies. As reinforcing/rewarding effects of tobacco are associated with dopamine transmission, the purpose of the present study was to study the dopaminergic system in human smokers based on their nicotine metabolite ratio., Methods: The first aim of the study was to explore if there were differences in D2 and D3 receptor binding between fast metabolizers and slow metabolizers during abstinence. The second aim was to explore smoking-induced dopamine release in both groups. Participants underwent 2 [11C]-(+)-PHNO PET scans: one scan during abstinence and the other after smoking a tobacco cigarette. Subjective measures were recorded and blood was drawn for measurement of nicotine and cotinine levels., Results: During abstinence, slow metabolizers (n = 13) had lower [11C]-(+)-PHNO binding potential than fast metabolizers (n = 15) restricted to the D2 regions of the associative striatum and sensorimotor striatum. After smoking a cigarette, [11C]-(+)-PHNO binding potential was decreased in the limbic striatum and ventral pallidum, suggestive of increases in dopamine, but there were no nicotine metabolite ratio differences., Conclusions: Further studies are required to delineate if differences in [11C]-(+)-PHNO binding between slow metabolizers and fast metabolizers at abstinence baseline are preexisting traits or induced by prolonged tobacco use.

Long-term tobacco smokers with chronic obstructive pulmonary disease (COPD) or chronic bronchitis display an excessive accumulation of neutrophils in the airways; an inflammation that responds poorly to established therapy. Thus, there is a need to identify new molecular targets for the development of effective therapy. Here, we hypothesized that the neutrophil-mobilizing cytokine interleukin (IL)-26 (IL-26) is involved in airway inflammation amongst long-term tobacco smokers with or without COPD, chronic bronchitis or colonization by pathogenic bacteria. By analyzing bronchoalveolar lavage (BAL), bronchail wash (BW) and induced sputum (IS) samples, we found increased extracellular IL-26 protein in the airways of long-term smokers in vivo without further increase amongst those with clinically stable COPD. In human alveolar macrophages (AM) in vitro , the exposure to water-soluble tobacco smoke components (WTC) enhanced IL-26 gene and protein. In this cell model, the same exposure increased gene expression of the IL-26 receptor complex ( IL10R2 and IL20R1 ) and nuclear factor κ B (NF-κB); a proven regulator of IL-26 production. In the same cell model, recombinant human IL-26 in vitro caused a concentration-dependent increase in the gene expression of NF-κB and several pro-inflammatory cytokines. In the long-term smokers, we also observed that extracellular IL-26 protein in BAL samples correlates with measures of lung function, tobacco load, and several markers of neutrophil accumulation. Extracellular IL-26 was further increased in long-term smokers with exacerbations of COPD (IS samples), with chronic bronchitis (BAL samples ) or with colonization by pathogenic bacteria (IS and BW samples). Thus, IL-26 in the airways emerges as a promising target for improving the understanding of the pathogenic mechanisms behind several pulmonary morbidities in long-term tobacco smokers., (© 2018 The Author(s).)

Introduction: Waterpipe tobacco smoking has increased in prevalence worldwide, including among pregnant women. In this study, we investigated the effect of prenatal maternal waterpipe tobacco smoke (WTS) exposure during different stages of pregnancy on learning and memory of adult offspring rats., Methods: Pregnant rats received either fresh air or mainstream WTS (2 hours daily) during early, mid, late, or whole gestational period. Male offspring rats were followed through 20 weeks. Outcomes included (1) spatial learning and memory using the radial arm water maze (RAWM), (2) levels of brain derived neurotrophic factor (BDNF) in the hippocampus, and (3) oxidative stress biomarkers (superoxide dismutase, catalase, glutathione peroxidase and thiobarbituric acid reactive substances)., Results: Relative to offspring whose mothers were exposed to fresh air, prenatal exposure to WTS at any stage of pregnancy resulted in short- and long-term memory impairment in adult offspring rats (p < .05). This impairment was associated with reduced levels of BDNF in hippocampus (p < .05). However, prenatal WTS did not affect the level of oxidative stress biomarkers in hippocampus. Prenatal WTS during late gestation increased the activity of catalase as compared to control., Conclusion: Prenatal maternal WTS exposure can impair the memory of adult male offspring. These results support development of interventions that target pregnant women who smoke waterpipe during pregnancy., Implications: We examined for the first time the effect of prenatal waterpipe tobacco smoke exposure on learning and memory of offspring. The results showed that in utero exposure to waterpipe tobacco smoke was associated with impaired memory and decreased brain derived neurotrophic factor in hippocampus of adult male offspring rats.

Introduction: Nicotine acts as an agonist at presynaptic nicotinic acetylcholine receptors and to facilitate synaptic release of several neurotransmitters including dopamine and glutamate. The thalamus has the highest density of nicotinic acetylcholine receptors in the brain, which may make this area more vulnerable to the addictive effects of nicotine. However, the volume of thalamus abnormalities and the association with smoking behaviors in young smokers remains unknown., Methods: Thirty-six young male smokers and 36 age-, gender- and education-matched nonsmokers participated in the current study. The nicotine dependence severity and cumulative effect were assessed with the Fagerström test for nicotine dependence (FTND) and pack-years. We used subcortical volume analyses method in FreeSurfer to investigate the thalamus volume differences between young smokers and nonsmokers. Correlation analysis was used to investigate the relationship between thalamus volume and smoking behaviors (pack-years and FTND) in young smokers., Results and Conclusions: Relative to nonsmokers, the young smokers showed reduced volume of bilateral thalamus. In addition, the left thalamus volume was correlated with FTND in young smokers. It is hoped that our findings can shed new insights into the neurobiology of young smokers., Implications: In this article, we investigated the changes of thalamus volume in young male smokers compared with nonsmokers. Reduced left thalamus volume was correlated with FTND in young smokers, which may reflect nicotine severity in young male smokers.

The present study was designed to explore the easy and fast method diagnosis of tobacco products in saliva of tobacco users (TU) by FTIR. Sixty four male tobacco users (TU) with mean age range 15.3 to 30.7 years were randomly selected for collection of saliva samples before and after tobacco use (smoking, chewing and dipping tobacco). Twenty were the smoking tobacco users (STU), 24 were chewing tobacco users (CTU) and 20 were dipping tobacco users (DTU). CTU were the users of Mainpuri (n=10) and users of PEN, FIT, 2100 (n=14). Forty eight saliva samples of age and gender matched healthy individuals with negative personal or family history of any addiction were also collected for comparison which served as controls. All were analyzed for their salivary flow rate, salivary pH and salivary diagnostic bands by FTIR. Significantly increased SFR (p<0.05) and salivary pH were found in after chewing tobacco as compared to before its chewing. The comparison between after tobacco use and controls we found decreased SFR and salivary pH for STU. Significant decreased SFR and increased salivary pH were found before or after use of dipping tobacco as compared to controls. Sharp bands at 735-745 cm-1 were found and may be used as salivary diagnostic bands for STU, 945-949 cm-1 for DTU and 900-915 cm-1 for CTU as well as DTU. In conclusion, the salivary diagnostic bands were found at 735-745 cm -1 , 900-915 cm -1 and 945-949 cm -1 for TU by easy and fast method using FTIR.

Study Design: ADAMTS5-deficient and wild type (WT) mice were chronically exposed to tobacco smoke to investigate effects on intervertebral disc degeneration (IDD)., Objective: The aim of this study was to demonstrate a role for ADAMTS5 in mediating tobacco smoking-induced IDD., Summary of Background Data: We previously demonstrated that chronic tobacco smoking causes IDD in mice because, in part, of proteolytic destruction of disc aggrecan. However, it was unknown which matrix proteinase(s) drive these detrimental effects., Methods: Three-month-old WT (C57BL/6) and ADAMTS5 mice were chronically exposed to tobacco smoke (four cigarettes/day, 5 day/week for 6 months). ADAMTS-mediated cleavage of disc aggrecan was analyzed by Western blot. Disc total glycosaminoglycan (GAG) content was assessed by dimethyl methylene blue assay and safranin O/fast green histology. Vertebral osteoporosity was measured by microcomputed tomography. Human nucleus pulposus (hNP) cell cultures were also exposed directly to tobacco smoke extract (TSE), a condensate containing the water-soluble compounds inhaled by smokers, to measure ADAMTS5 expression and ADAMTS-mediated cleavage of aggrecan. Activation of nuclear factor (NF)-κB, a family of transcription factors essential for modulating the cellular response to stress, was measured by immunofluorescence assay., Results: Genetic depletion of ADAMTS5 prevented vertebral bone loss, substantially reduced loss of disc GAG content, and completely obviated ADAMTS-mediated proteolysis of disc aggrecan within its interglobular domain (IGD) in mice following exposure to tobacco smoke. hNP cell cultures exposed to TSE also resulted in upregulation of ADAMTS5 protein expression and a concomitant increase in ADAMTS-mediated cleavage within aggrecan IGD. Activation of NF-κB, known to be required for ADAMTS5 gene expression, was observed in both TSE-treated hNP cell cultures and disc tissue of tobacco smoke-exposed mice., Conclusion: The findings demonstrate that ADAMTS5 is the primary aggrecanase mediating smoking-induced disc aggrecanolysis and IDD. Mouse models of chronic tobacco smoking are important and useful for probing the mechanisms of disc aggrecan catabolism and IDD., Level of Evidence: N/A.

Smoking is a crucial factor in respiratory diseases and lung inflammation, which are the reasons for high mortality worldwide. Despite the negative impact that tobacco consumption causes on health, few metabolomics studies have compared the composition of biofluids from smoker and non-smoker individuals. Exhaled breath condensate (EBC) is one of the biofluids less employed for clinical studies despite its non-invasive sampling and the foreseeable relationship between its composition and respiratory diseases. EBC was used in this research as clinical sample to compare three groups of individuals: current smokers (CS), former smokers (FS) and never smokers (NS). Special attention was paid to the cumulative consumption expressed as smoked pack-year. The levels of 12 metabolites found statistically significant among the three groups of individuals were discussed to find an explanation to their altered levels. Significant compounds included monoacylglycerol derivatives, terpenes and other compounds, the presence of which could be associated to the influence of smoking on the qualitative and quantitative composition of the microbiome.