An immunogenetic basis for lung cancer risk.

Cancer risk is influenced by inherited mutations, DNA replication errors, and environmental factors. However, the influence of genetic variation in immunosurveillance on cancer risk is not well understood. Leveraging population-level data from the UK Biobank and FinnGen, we show that heterozygosity at the human leukocyte antigen (HLA)-II loci is associated with reduced lung cancer risk in smokers. Fine-mapping implicated amino acid heterozygosity in the HLA-II peptide binding groove in reduced lung cancer risk, and single-cell analyses showed that smoking drives enrichment of proinflammatory lung macrophages and HLA-II+ epithelial cells. In lung cancer, widespread loss of HLA-II heterozygosity (LOH) favored loss of alleles with larger neopeptide repertoires. Thus, our findings nominate genetic variation in immunosurveillance as a critical risk factor for lung cancer.

Smoking changes adaptive immunity with persistent effects.

Individuals differ widely in their immune responses, with age, sex and genetic factors having major roles in this inherent variability1-6. However, the variables that drive such differences in cytokine secretion-a crucial component of the host response to immune challenges-remain poorly defined. Here we investigated 136 variables and identified smoking, cytomegalovirus latent infection and body mass index as major contributors to variability in cytokine response, with effects of comparable magnitudes with age, sex and genetics. We find that smoking influences both innate and adaptive immune responses. Notably, its effect on innate responses is quickly lost after smoking cessation and is specifically associated with plasma levels of CEACAM6, whereas its effect on adaptive responses persists long after individuals quit smoking and is associated with epigenetic memory. This is supported by the association of the past smoking effect on cytokine responses with DNA methylation at specific signal trans-activators and regulators of metabolism. Our findings identify three novel variables associated with cytokine secretion variability and reveal roles for smoking in the short- and long-term regulation of immune responses. These results have potential clinical implications for the risk of developing infections, cancers or autoimmune diseases.

Central obesity, smoking habit, and hypertension are associated with lower antibody titres in response to COVID-19 mRNA vaccine.

AIMS: To explore variables associated with the serological response following COVID-19 mRNA vaccine. METHODS: Eighty-six healthcare workers adhering to the vaccination campaign against COVID-19 were enrolled in January-February 2021. All subjects underwent two COVID-19 mRNA vaccine inoculations (Pfizer/BioNTech) separated by 3 weeks. Blood samples were collected before the 1st and 1-4 weeks after the second inoculation. Clinical history, demographics, and vaccine side effects were recorded. Baseline anthropometric parameters were measured, and body composition was performed through dual-energy-X-ray absorptiometry. RESULTS: Higher waist circumference was associated with lower antibody (Ab) titres (R = -0.324, p = 0.004); smokers had lower levels compared to non-smokers [1099 (1350) vs. 1921 (1375), p = 0.007], as well as hypertensive versus normotensive [650 ± 1192 vs. 1911 (1364), p = 0.001] and dyslipideamic compared to those with normal serum lipids [534 (972) vs 1872 (1406), p = 0.005]. Multivariate analysis showed that higher waist circumference, smoking, hypertension, and longer time elapsed since second vaccine inoculation were associated with lower Ab titres, independent of BMI, age. and gender. CONCLUSIONS: Central obesity, hypertension, and smoking are associated with lower Ab titres following COVID-19 vaccination. Although it is currently impossible to determine whether lower SARS-CoV-2 Abs lead to higher likelihood of developing COVID-19, it is well-established that neutralizing antibodies correlate with protection against several viruses including SARS-CoV-2. Our findings, therefore, call for a vigilant approach, as subjects with central obesity, hypertension, and smoking could benefit from earlier vaccine boosters or different vaccine schedules.

Smoking History Predicts High Presence of TILs and Efficacy of PD-1 Blockade in PD-L1 Expression-negative Non-small Cell Lung Cancer Patients.

BACKGROUND/AIM: Programmed death-ligand 1 (PD-L1) expression on tumor cells is a predictive biomarker of programmed cell death 1 (PD-1) blockade therapy. This study sought to clarify predictors of the efficacy of nivolumab in non-small cell lung cancer (NSCLC) patients with PD-L1 expression-negative tumors. PATIENTS AND METHODS: We retrospectively reviewed the records of advanced NSCLC patients between January 2016 and April 2019, and investigated the predictive marker of nivolumab including the status of CD8+ tumor infiltrating lymphocytes (TILs). RESULTS: A total of 70 NSCLC patients were included. Overall response rate (ORR) and progression-free survival (PFS) were better in patients with a heavy smoking history (smoking index: SI≥600) than in those without (SI<600) [ORR: 20.6% vs. 2.8%, (p=0.02), and PFS: 2.4 months vs. 1.8 months, (p=0.04)]. A high density of CD8+ TILs was significantly associated with a heavy smoking history (p=0.04). Conlusion: Heavy smoking history (SI≥600), which was correlated with a large number of CD8+ TILs, could be a predictor of the efficacy of nivolumab in NSCLC patients with PD-L1 expression-negative tumors.

Determinants and Reference Ranges of Serum Immunoglobulins in Middle-Aged and Elderly Individuals: a Population-Based Study.

PURPOSE: In clinical practice, currently one reference range for serum immunoglobulin (Ig) A, G, and M is applied to all adults, although various factors may influence Ig serum levels. Population-based data on determinants of IgA, IgG, and IgM and recommendations for subgroup specific reference ranges are lacking. We aimed to provide an overview of determinants of IgA, IgG, and IgM in community-dwelling middle-aged and elderly individuals and explore determinants that influence Ig reference ranges. METHODS: Within the Rotterdam Study, we performed linear regression analyses for the association of demographic, lifestyle, and cardiovascular factors with serum IgA, IgG, and IgM. We furthermore calculated Ig reference ranges (based on percentiles), both overall and within relevant subgroups. RESULTS: We included 8768 participants (median age 62 years). IgA and IgG increased non-linearly with higher age (P < .0001 for both). Women had lower IgA (beta: - 0.24; 95% confidence interval [95% CI]: - 0.29; - 0.20) and IgG (beta: - 0.33; 95% CI: - 0.44; - 0.23), but higher IgM levels (beta: 0.08; 95% CI: 0.04;0.13) than men. Former and particularly current smoking were associated with lower IgA and IgG (betas between - 0.07 and - 1.03). Higher alcohol consumption was associated with lower IgG (beta for heavy drinking: - 0.70; 95% CI: - 0.91; - 0.48). Corticosteroid use was associated with lower IgG (beta: - 1.12; 95% CI: - 1.58; - 0.66). Associations with cardiovascular factors were heterogeneous and differed between sexes. CONCLUSION: Age, sex, smoking, alcohol consumption, corticosteroid use, and cardiovascular factors are determinants that should be considered when interpreting serum Ig levels in middle-aged and elderly individuals and may require adjusted reference ranges.

Serum levels of TGF-ß1, cytokines, angiogenic, and anti-angiogenic factors in pregnant women who smoke.

INTRODUCTION: Women who smoke during pregnancy have a reduced risk of preeclampsia. The mechanism of this association is poorly understood. Preeclampsia is an anti-angiogenic and inflammatory state. Transforming growth factor beta 1 (TGF-ß1) is a multi-functional anti-inflammatory cytokine that activates membrane bound endoglin on endothelial cells causing a myriad of vascular actions including vasorelaxation. The objective of the study was to determine serum levels of cytokines, angiogenic factors, placental growth factor (PlGF), TGF-ß-1 and anti-angiogenic factors, soluble endoglin (sEng) and soluble vascular endothelial growth factor 1 (sVEGFR1) in smoking and non-smoking pregnant women. METHODS: Using enzyme-linked immunosorbent and multiplex assays we prospectively analyzed serum levels of PIGF, TGF-ß1, sEng, sVEGFR1 and cytokines in normotensive pregnant smokers and non-smokers. Exclusion criteria included maternal hypertension, autoimmune disorders, rupture of membranes, evidence of labor and drug use. RESULTS: There were 59 women in the smoking and 66 in the non-smoking group. Compared to non-smoking mothers. maternal age was lower in smoking mothers with no significant difference in other demographic variables. There was no difference in levels of cytokines, anti-angiogenic factors and PlGF between the two groups. Median TGF-ß1 levels were significantly higher in the smoking group (8120 pg/mL vs 6040 pg/mL, p < 0.001) and remained significant after controlling for confounders. TGF-ß1 levels correlated positively with cotinine levels in the smoking group. CONCLUSIONS: We speculate that higher TGF-ß1 levels may explain the reduced incidence of preeclampsia in mothers who smoke by being available for action on maternal endothelium even after inactivation by circulating maternal sEng.

Long-term tobacco exposure and immunosenescence: Paradoxical effects on T-cells telomere length and telomerase activity.

Immunosenescence are alterations on immune system that occurs throughout an individual life. The main characteristic of this process is replicative senescence, evaluated by telomere shortening. Several factors implicate on telomere shortening, such as smoking. In this study, we evaluated the influence of smoking and Chronic Obstructive Pulmonary Disease (COPD) on cytokines, telomere length and telomerase activity. Blood samples were collected from subjects aged over 60 years old: Healthy (never smokers), Smokers (smoking for over 30 years) and COPDs (ex-smokers for ≥15 years). A young group was included as control. PBMCs were cultured for assessment of telomerase activity using RT-PCR, and cytokines secretion flow cytometry. CD4+ and CD8+ purified lymphocytes were used to assess telomere length using FlowFISH. We observed that COPD patients have accelerated telomere shortening. Paradoxically, smokers without lung damage showed preserved telomere length, suggesting that tobacco smoking may affect regulatory mechanisms, such as telomerase. Telomerase activity showed diminished activity in COPDs, while Smokers showed increased activity compared to COPDs and Healthy groups. Extracellular environment reflected this unbalance, indicated by an anti-inflammatory profile in Smokers, while COPDs showed an inflammatory prone profile. Further studies focusing on telomeric maintenance may unveil mechanisms that are associated with cancer under long-term smoking.

Low-Blood Lymphocyte Number and Lymphocyte Decline as Key Factors in COPD Outcomes: A Longitudinal Cohort Study.

BACKGROUND: Smokers with and without chronic obstructive pulmonary disease (COPD) are at risk of severe outcomes like exacerbations, cancer, respiratory failure, and decreased survival. The mechanisms for these outcomes are unclear; however, there is evidence that blood lymphocytes (BL) number might play a role. OBJECTIVE: The objective of this study is to investigate the relationship between BL and their possible decline over time with long-term outcomes in smokers with and without COPD. METHODS: In 511 smokers, 302 with COPD (COPD) and 209 without COPD (noCOPD), followed long term, we investigated whether BL number and BL decline over time might be associated with long-term outcomes. Smokers were divided according to BL number in high-BL (≥1,800 cells/µL) and low-BL (<1,800 cells/µL). Clinical features, cancer incidence, and mortality were recorded during follow-up. BL count in multiple samples and BL decline over time were calculated and related to outcomes. RESULTS: BL count was lower in COPD (1,880 cells/µL) than noCOPD (2,300 cells/µL; p < 0.001). 43% of COPD and 23% of noCOPD had low-BL count (p < 0.001). BL decline over time was higher in COPD than noCOPD (p = 0.040). 22.5% of the whole cohort developed cancer which incidence was higher in low-BL subjects and in BL decliners than high-BL (31 vs. 18%; p = 0.001) and no decliners (32 vs. 19%; p = 0.002). 26% in the cohort died during follow-up. Furthermore, low-BL count, BL decline, and age were independent risk factors for mortality by Cox regression analysis. CONCLUSION: BL count and BL decline are related to worse outcomes in smokers with and without COPD, which suggests that BL count and decline might play a mechanistic role in outcomes deterioration. Insights into mechanisms inducing the fall in BL count could improve the understanding of COPD pathogenesis and point toward new therapeutic measures.

Melatonin attenuates smoking-induced atherosclerosis by activating the Nrf2 pathway via NLRP3 inflammasomes in endothelial cells.

Substantial evidence suggests that the effects of smoking in atherosclerosis are associated with inflammation mediated by endothelial cells. However, the mechanisms and potential drug therapies for smoking-induced atherosclerosis remain to be clarified. Considering that melatonin exerts beneficial effects in cardiovascular diseases, we examined its effects on cigarette smoke-induced vascular injury. We found that cigarette smoke extract (CSE) treatment induced NLRP3-related pyroptosis in human aortic endothelial cells (HAECs). CSE also induced ROS generation and upregulated the Nrf2 pathway in HAECs. Furthermore, pretreatment of HAECs with Nrf2-specific siRNA and an Nrf2 activator revealed that Nrf2 can inhibit CSE-induced ROS/NLRP3 activation. Nrf2 also improved cell viability and the expression of VEGF and eNOS in CSE-treated HAECs. In balloon-induced carotid artery injury model rats exposed to cigarette smoke, melatonin treatment reduced intimal hyperplasia in the carotid artery. Mechanistic studies revealed that compared with the control group, Nrf2 activation was increased in the melatonin group, whereas ROS levels and the NLRP3 inflammasome pathway were inhibited. These results reveal that melatonin might effectively protect against smoking-induced vascular injury and atherosclerosis through the Nrf2/ROS/NLRP3 signaling pathway. Overall, these observations provide compelling evidence for the clinical use of melatonin to reduce smoking-related inflammatory vascular injury and atherosclerosis.

Association of plasma netrin-1 level with inflammatory balance and comorbidities in patients with acute exacerbation of COPD.

INTRODUCTION: Chronic obstructive pulmonary disease (COPD) is a common lung disease characterized by airflow restriction and systemic inflammation. Netrin-1 is a protein mainly produced in the central nervous system and has proven anti-inflammatory activity. The aim of this study was to determine netrin-1 level and its relationship with comorbidities in patients with acute exacerbation of COPD. MATERIALS AND METHODS: The study included 232 patients aged over 40 years who were divided into 3 groups: Group 1: ex-smokers (≥ 20 pack-years) with COPD hospitalized for COPD exacerbation (n= 142), Group 2: current-smokers (≥ 20 pack-years) without COPD (n= 30), Group 3: a control group comprising healthy non-smokers (n= 60). Plasma netrin-1 levels were measured using commercial enzyme-linked immunosorbent assay (ELISA) kit. RESULT: There were significant differences in forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), FEV1/FVC, C-reactive protein (CRP), and plasma netrin-1 levels between patients with acute exacerbation of COPD and current smokers without COPD, healthy controls (p= 0.001 for all). Netrin-1 levels at discharge were lower in COPD patients with diabetes mellitus (DM) compared to nondiabetic COPD patients (p= 0.01). Weak correlation was observed between netrin-1 level at admission and FEV1, FVC, partial pressure of oxygen, and CRP levels (r= 0.394, p= 0.01; r= -0.366, p= 0.01; r= -0.19, p= 0.05; r= 0.306, p= 0.01). Netrin-1 level at admission was also moderately correlated with smoking history (pack-years) (r= 0.579, p= 0.01). CONCLUSIONS: Netrin-1 was elevated in acute exacerbation of COPD and may be an important element in inflammatory balance. Patients with both COPD and DM were found to have lower netrin-1 levels at discharge after resolution of the acute exacerbation.

Immune Trait Shifts in Association With Tobacco Smoking: A Study in Healthy Women.

Tobacco smoking is known to impact circulating levels of major immune cells populations, but its effect on specific immune cell subsets remains poorly understood. Here, using high-resolution data from 223 healthy women (25 current and 198 never smokers), we investigated the association between smoking status and 35,651 immune traits capturing immune cell subset frequencies. Our results confirmed that active tobacco smoking is associated with increased frequencies of circulating CD8+ T cells expressing the CD25 activation marker. Moreover, we identified novel associations between smoking status and relative abundances of CD8+ CD25+ memory T cells, CD8+ memory T cells expressing the CCR4 chemokine receptor, and CD4+CD8+ (double-positive) CD25+ T cells. We also observed, in current smokers, a decrease in the relative frequencies of CD4+ T cells expressing the CD38 activation marker and an increase in class-switched memory B cell isotypes IgA, IgG, and IgE. Finally, using data from 135 former female smokers, we showed that the relative frequencies of immune traits associated with active smoking are usually completely restored after smoking cessation, with the exception of subsets of CD8+ and CD8+ memory T cells, which persist partially altered. Our results are consistent with previous findings and provide further evidence on how tobacco smoking shapes leukocyte cell subsets proportion toward chronic inflammation.

A Comprehensive View on the Human Antibody Repertoire Against Staphylococcus aureus Antigens in the General Population.

Our goal was to provide a comprehensive overview of the antibody response to Staphylococcus aureus antigens in the general population as a basis for defining disease-specific profiles and diagnostic signatures. We tested the specific IgG and IgA responses to 79 staphylococcal antigens in 996 individuals from the population-based Study of Health in Pomerania. Using a dilution-based multiplex suspension array, we extended the dynamic range of specific antibody detection to seven orders of magnitude, allowing the precise quantification of high and low abundant antibody specificities in the same sample. The observed IgG and IgA antibody responses were highly heterogeneous with differences between individuals as well as between bacterial antigens that spanned several orders of magnitude. Some antigens elicited significantly more IgG than IgA and vice versa. We confirmed a strong influence of colonization on the antibody response and quantified the influence of sex, smoking, age, body mass index, and serum glucose on anti-staphylococcal IgG and IgA. However, all host parameters tested explain only a small part of the extensive variability in individual response to the different antigens of S. aureus.

The Role of Human Leukocyte Antigen-DR in Regulatory T Cells in Patients with Virus-Induced Acute Exacerbation of Chronic Obstructive Pulmonary Disease.

BACKGROUND This study assessed the role of different immune phenotypes of T cells in virus-induced acute exacerbation of chronic obstructive pulmonary disease (AECOPD). MATERIAL AND METHODS The study involved 103 participants, including individuals with virus-induced AECOPD (n=32), non-virus-induced AECOPD (n=31), and stable COPD (n=20) and individuals who were healthy smokers (n=20). The immune phenotypes of T cells in peripheral blood were evaluated via flow cytometry analysis, and the differences were analyzed. RESULTS Patients with virus-induced AECOPD (virus group) had a higher COPD assessment test score on admission than those in the group with non-virus-induced AECOPD (nonvirus group; 25.6±3.8 vs 21.9±4.8, P=0.045). A lower CD4⁺ human leukocyte antigen-DR (HLA-DR)+ frequency was found in the peripheral blood of the virus group compared with the nonvirus group (2.2 vs 4.2, P=0.015), and the frequency of CD4⁺ CD25high CD127low HLA-DR⁺ in CD4⁺ in the virus group was lower than in the nonvirus group (1.1 vs 3.6, P=0.011). The CD3⁺, CD4⁺, CD8⁺, CD4⁺ central memory T cell, CD4⁺ effector memory T cell (Tem), CD4⁺ end-stage T cell, and CD8⁺ Tem levels in lymphocytes of peripheral blood were lower in exacerbation groups relative to those in the stable COPD and healthy smoking groups, but similar between exacerbation groups. Similar frequencies and levels of T cells between different stagings of COPD were also identified. CONCLUSIONS The expression of HLA-DR on the cell surface of CD4⁺ regulatory T cells (Tregs) was lower in the peripheral blood of patients with virus-induced AECOPD. The expression of HLA-DR in CD4⁺ Tregs suggested the effect of respiratory viruses on adaptive immunity of patients with AECOPD to some extent.

The Exposome and Immune Health in Times of the COVID-19 Pandemic.

Growing evidence supports the importance of lifestyle and environmental exposures-collectively referred to as the 'exposome'-for ensuring immune health. In this narrative review, we summarize and discuss the effects of the different exposome components (physical activity, body weight management, diet, sun exposure, stress, sleep and circadian rhythms, pollution, smoking, and gut microbiome) on immune function and inflammation, particularly in the context of the current coronavirus disease 2019 (COVID-19) pandemic. We highlight the potential role of 'exposome improvements' in the prevention-or amelioration, once established-of this disease as well as their effect on the response to vaccination. In light of the existing evidence, the promotion of a healthy exposome should be a cornerstone in the prevention and management of the COVID-19 pandemic and other eventual pandemics.

IL-36 Cytokines Promote Inflammation in the Lungs of Long-Term Smokers.

Chronic obstructive pulmonary disease (COPD) is a progressive inflammatory lung disease with high morbidity and mortality. The IL-36 family are proinflammatory cytokines that are known to shape innate immune responses, including those critical to bacterial pneumonia. The objective of this study was to determine whether IL-36 cytokines promote a proinflammatory milieu in the lungs of long-term smokers with and without COPD. Concentrations of IL-36 cytokines were measured in plasma and BAL fluid from subjects in a pilot study (n = 23) of long-term smokers with and without COPD in vivo and from a variety of lung cells (from 3-5 donors) stimulated with bacteria or cigarette smoke components in vitro. Pulmonary macrophages were stimulated with IL-36 cytokines in vitro, and chemokine and cytokine production was assessed. IL-36α and IL-36γ are produced to varying degrees in murine and human lung cells in response to bacterial stimuli and cigarette smoke components in vitro. Moreover, whereas IL-36γ production is upregulated early after cigarette smoke stimulation and wanes over time, IL-36α production requires a longer duration of exposure. IL-36α and IL-36γ are enhanced systemically and locally in long-term smokers with and without COPD, and local IL-36α concentrations display a positive correlation with declining ventilatory lung function and increasing proinflammatory cytokine concentrations. In vitro, IL-36α and IL-36γ induce proinflammatory chemokines and cytokines in a concentration-dependent fashion that requires IL-36R and MyD88. IL-36 cytokine production is altered in long-term smokers with and without COPD and contributes to shaping a proinflammatory milieu in the lungs.

Combined oral contraceptives modify the effect of smoking on inflammatory cellular indexes and endothelial function in healthy subjects.

Little information is available on the influence of sex in combination with smoking habits and combined oral contraceptives (COC) use on cellular inflammatory indexes such as neutrophil/lymphocyte ratio (NLR), derived NRL (dNLR), platelet/lymphocyte ratio (PLR), monocyte/lymphocyte ratio (MLR), mean platelet volume/platelet count (MPV/PLT), aggregate inflammation systemic index (AISI), and systemic inflammation response index (SIRI), which are cost-effective biomarkers to assessing inflammation. Therefore, the effect of COC was studied alone or in association with smoking and compared with results from healthy COC-free women and men. Furthermore, the association of cellular inflammatory indexes with endothelial function (arginine (Arg), asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA) and lipid peroxidation (malondialdehyde MDA) biomarkers was evaluated. Blood was collected for hematological and biochemical analysis, which were used to calculate PLR, NLR, dNLR, MLR, MPV/PLT, AISI, and SIRI. Serum samples were assayed for Arg, ADMA, SDMA, and MDA. Monocytes, MLR, SIRI, and MPV/PLT were higher in men, while PLT count was higher in women. COC use increased lymphocytes and lowered PLR and MLR. Smoking reduced sexually divergent parameters, especially in COC users: smoking and non-smoking COC-free women displayed six divergent parameters, while COC users displayed only two (monocytes and MPV). In addition, COC affected endothelial function, reducing ADMA and Arg. Moreover, COC-free women had lower Arg levels than men. In conclusion, COC use strongly influence the effects of tobacco smoking, which are sex and parameter specific. Further, these data stress that COC use and smoking attitude select different cohorts indicating that sex and gender studies need intersectionality.

Airway regulatory T cells are decreased in COPD with a rapid decline in lung function.

BACKGROUND: Differences in the expression of regulatory T cells (Tregs) have been suggested to explain why some smokers develop COPD and some do not. Upregulation of Tregs in response to smoking would restrain airway inflammation and thus the development of COPD; while the absense of such upregulation would over time lead to chronic inflammation and COPD. We hypothesized that-among COPD patients-the same mechanism would affect rate of decline in lung function; specifically, that a decreased expression of Tregs would be associated with a more rapid decline in FEV1. METHODS: Bronchoscopy with BAL was performed in 52 subjects recruited from the longitudinal OLIN COPD study; 12 with COPD and a rapid decline in lung function (loss of FEV1 ≥ 60 ml/year), 10 with COPD and a non-rapid decline in lung function (loss of FEV1 ≤ 30 ml/year), 15 current and ex-smokers and 15 non-smokers with normal lung function. BAL lymphocyte subsets were determined using flow cytometry. RESULTS: The proportions of Tregs with regulatory function (FoxP3+/CD4+CD25bright) were significantly lower in COPD subjects with a rapid decline in lung function compared to those with a non-rapid decline (p = 0.019). This result was confirmed in a mixed model regression analysis in which adjustments for inhaled corticosteroid usage, smoking, sex and age were evaluated. No significant difference was found between COPD subjects and smokers or non-smokers with normal lung function. CONCLUSIONS: COPD subjects with a rapid decline in lung function had lower proportions of T cells with regulatory function in BAL fluid, suggesting that an inability to suppress the inflammatory response following smoking might lead to a more rapid decline in FEV1. Trial registration Clinicaltrials.gov identifier NCT02729220.

Clinical significance of preoperative inflammatory markers in non-small cell lung cancer patients: A multicenter retrospective study.

Inflammatory biomarkers have been associated with clinical outcomes in non-small cell lung cancer (NSCLC). However, the best prognostic marker(s) has not been identified, and the association between inflammatory markers and clinical characteristics is poorly understood. We selected 1,237 patients with resected NSCLC from Kyushu University (2003-2015) and Kyushu Cancer Center (2009-2015) in Japan. Pearson product-moment correlation coefficient among inflammatory markers and area under curve (AUC) of receiver operating characteristic (ROC) curve analyses for overall survival (OS) were calculated. We analyzed the associations between inflammatory markers and clinical factors using Student's t-test. Univariate and multivariate analyses with Cox proportional hazards regression analyses were performed to evaluate the relationship between survival and clinical factors. The cut-off values for neutrophil-lymphocyte ratio (NLR), lymphocyte-monocyte ratio (LMR), platelet-lymphocyte ratio, and derived NLR (dNLR) were determined by ROC curve analyses for OS. We found a strong positive correlation between NLR and dNLR (r = 0.9629). The AUC of LMR was the highest amongst the measured metrics, and the AUC of NLR was higher than dNLR. Levels of some inflammatory markers were associated with sex, smoking, squamous cell carcinoma, and pathological stage. LMR ≥ 5.11 and lactate dehydrogenase (LDH) concentration ≥ 222 (U/L) were independent predictors of both disease-free survival (DFS) and OS (LMR; P = 0.0009 and 0.0008, LDH; P = 0.0195 and 0.0187, respectively). Certain inflammatory markers, potentially linked to smoking, were associated with an advanced pathological stage in NSCLC. LMR and LDH were independent predictors of both DFS and OS.

Periodontal Conditions and Whole Salivary IL-17A and -23 Levels among Young Adult Cannabis sativa (Marijuana)-Smokers, Heavy Cigarette-Smokers and Non-Smokers.

In the United States, prevalence of marijuana-use has doubled in the past 2 decades. The aim was to compare the periodontal conditions and whole-salivary IL-17A and IL-23 levels among young adult marijuana-smokers, heavy cigarette-smokers and non-smokers. Self-reported marijuana-smokers, heavy-cigarette-smokers, non-smokers with periodontitis and periodontally-healthy non-smokers were included. Demographic data was recorded and full-mouth plaque index (PI), bleeding on probing (BoP), probing depth (PD) and clinical attachment loss (AL), marginal bone loss (MBL) and missing teeth were recorded. Levels of IL-17A and IL-23 levels were measured in the whole saliva. p < 0.01 was considered statistically significant. Fifteen-marijuana-smokers, 15 heavy-cigarette-smokers, 16 non-smokers-with-periodontitis and 15 periodontally-healthy-non-smokers) were included. The clinicoradiographic parameters were worse among marijuana-smokers (p < 0.01), cigarette-smokers (p < 0.01) and non-smokers-with-periodontitis (p < 0.01) than periodontally-healthy-non-smokers. Marijuana- and cigarette-smokers had Stage-IV/Grade C and non-smokers with periodontitis had Stage-III/Grade-C. Salivary IL-17A and IL-23 levels were higher in marijuana-smokers than cigarette-smokers (p < 0.01) and non-smokers-with-periodontitis (p < 0.01). Whole salivary IL-17A and IL-23 levels were higher among cigarette-smokers than non-smokers with periodontitis (p < 0.01) and periodontally-healthy-individuals (p < 0.01). Marijuana- and heavy cigarette-smokers have comparable clinicoradiographic periodontal statuses. This rejects hypothesis-1. However, whole salivary immunoinflammatory response may be moderately worse in marijuana-smokers compared with heavy cigarette-smokers and non-smoker with periodontitis thereby supporting hypothesis-2.

Smoking status-based efficacy difference in anti-PD-1/PD-L1 immunotherapy: a systematic review and meta-analysis.

Aim: This study aimed to evaluate the relationship between smoking status and efficacy of PD-1/PD-L1 inhibitors compared with conventional agents. Materials & methods: We reviewed Phase II/III trials of PD-1/PD-L1 inhibitors that reported hazard ratio (HR) in current/former and never smoking patients. Results: 15 qualifying trials comprising 9073 patients were eligible in this study. Compared with conventional agents, PD-1/PD-L1 inhibitors correlated with prolonged progression-free survival (HR: 0.73; 0.58-0.92) and overall survival (HR: 0.75; 0.71-0.80) in current/former smoker patients but not in never-smoker patients (HR: 1.15 and 0.86 for progression-free survival and overall survival, respectively; both p > 0.05) irrespective of cancer type, target of experimental agents and treatment strategy. Conclusion: There exit smoking status-based efficacy difference in anti-PD-1/PD-L1 immunotherapy.