Shared and distinct mechanisms of UBA1 inactivation across different diseases.

Most cellular ubiquitin signaling is initiated by UBA1, which activates and transfers ubiquitin to tens of E2 enzymes. Clonally acquired UBA1 missense mutations cause an inflammatory-hematologic overlap disease called VEXAS (vacuoles, E1, X-linked, autoinflammatory, somatic) syndrome. Despite extensive clinical investigation into this lethal disease, little is known about the underlying molecular mechanisms. Here, by dissecting VEXAS-causing UBA1 mutations, we discovered that p.Met41 mutations alter cytoplasmic isoform expression, whereas other mutations reduce catalytic activity of nuclear and cytoplasmic isoforms by diverse mechanisms, including aberrant oxyester formation. Strikingly, non-p.Met41 mutations most prominently affect transthioesterification, revealing ubiquitin transfer to cytoplasmic E2 enzymes as a shared property of pathogenesis amongst different VEXAS syndrome genotypes. A similar E2 charging bottleneck exists in some lung cancer-associated UBA1 mutations, but not in spinal muscular atrophy-causing UBA1 mutations, which instead, render UBA1 thermolabile. Collectively, our results highlight the precision of conformational changes required for faithful ubiquitin transfer, define distinct and shared mechanisms of UBA1 inactivation in diverse diseases, and suggest that specific E1-E2 modules control different aspects of tissue differentiation and maintenance.

Predicting Lung Cancer in Korean Never-Smokers With Polygenic Risk Scores.

In the last few decades, genome-wide association studies (GWAS) with more than 10,000 subjects have identified several loci associated with lung cancer and these loci have been used to develop novel risk prediction tools for cancer. The present study aimed to establish a lung cancer prediction model for Korean never-smokers using polygenic risk scores (PRSs); PRSs were calculated using a pruning-thresholding-based approach based on 11 genome-wide significant single nucleotide polymorphisms (SNPs). Overall, the odds ratios tended to increase as PRSs were larger, with the odds ratio of the top 5% PRSs being 1.71 (95% confidence interval: 1.31-2.23) using the 40%-60% percentile group as the reference, and the area under the curve (AUC) of the prediction model being of 0.76 (95% confidence interval: 0.747-0.774). The receiver operating characteristic (ROC) curves of the prediction model with and without PRSs as covariates were compared using DeLong's test, and a significant difference was observed. Our results suggest that PRSs can be valuable tools for predicting the risk of lung cancer.

Meta-Analysis and DIA-MS-Based Proteomic Investigation of COPD Patients and Asymptomatic Smokers in the Indian Population.

Chronic obstructive pulmonary disease (COPD) is India's second largest cause of death and is largely caused by smoking. Asymptomatic smokers develop COPD due to genetic, environmental, and molecular variables, making early screening crucial. Data-independent acquisition mass spectrometry (DIA-MS) based-proteomics offers an unbiased method to analyze proteomic profiles. This study is the first to use DIA-based proteomics to analyze individual serum samples from three distinct male cohorts: healthy individuals (n = 10), asymptomatic smokers (n = 10), and COPD patients (n = 10). This comprehensive approach identified 667 proteins with a 1% false discovery rate. Differentially expressed proteins included 40 in the normal versus asymptomatic comparison, 88 in the COPD versus normal comparison, and 40 in the COPD versus asymptomatic comparison. Among them, protein-associated genes such as PRDX6, ELANE, PRKCSH, PRTN3, and MNDA could help differentiate COPD from asymptomatic smokers, while ELANE, H3-3A, IGHE, SLC4A1, and SERPINA11 could differentiate COPD from healthy subjects. Pathway enrichment and protein-protein interaction analyses revealed significant alterations in hemostasis, immune system functions, fibrin clot formation, and post-translational protein modifications. Key proteins were validated using a parallel reaction monitoring assay. DIA data are available via ProteomeXchange with identifier PXD055242. Our findings reveal key protein classifiers in COPD patients, asymptomatic smokers, and healthy individuals, helping clinicians understand disease pathobiology and improve disease management and quality of life.

A nested case-control study of untargeted plasma metabolomics and lung cancer among never-smoking women within the prospective Shanghai Women's Health Study.

The etiology of lung cancer in never-smokers remains elusive, despite 15% of lung cancer cases in men and 53% in women worldwide being unrelated to smoking. Here, we aimed to enhance our understanding of lung cancer pathogenesis among never-smokers using untargeted metabolomics. This nested case-control study included 395 never-smoking women who developed lung cancer and 395 matched never-smoking cancer-free women from the prospective Shanghai Women's Health Study with 15,353 metabolic features quantified in pre-diagnostic plasma using liquid chromatography high-resolution mass spectrometry. Recognizing that metabolites often correlate and seldom act independently in biological processes, we utilized a weighted correlation network analysis to agnostically construct 28 network modules of correlated metabolites. Using conditional logistic regression models, we assessed the associations for both metabolic network modules and individual metabolic features with lung cancer, accounting for multiple testing using a false discovery rate (FDR) < 0.20. We identified a network module of 121 features inversely associated with all lung cancer (p = .001, FDR = 0.028) and lung adenocarcinoma (p = .002, FDR = 0.056), where lyso-glycerophospholipids played a key role driving these associations. Another module of 440 features was inversely associated with lung adenocarcinoma (p = .014, FDR = 0.196). Individual metabolites within these network modules were enriched in biological pathways linked to oxidative stress, and energy metabolism. These pathways have been implicated in previous metabolomics studies involving populations exposed to known lung cancer risk factors such as traffic-related air pollution and polycyclic aromatic hydrocarbons. Our results suggest that untargeted plasma metabolomics could provide novel insights into the etiology and risk factors of lung cancer among never-smokers.

Reproductive factors and risk of lung cancer among 300,000 Chinese female never-smokers: evidence from the China Kadoorie Biobank study.

BACKGROUND: Lung cancer is the leading cause of cancer mortality among Chinese females despite the low smoking prevalence among this population. This study assessed the roles of reproductive factors in lung cancer development among Chinese female never-smokers. METHODS: The prospective China Kadoorie Biobank (CKB) recruited over 0.5 million Chinese adults (0.3 million females) from 10 geographical areas in China in 2004-2008 when information on socio-demographic/lifestyle/environmental factors, physical measurements, medical history, and reproductive history collected through interviewer-administered questionnaires. Cox proportional hazard regression was used to estimate adjusted hazard ratios (HRs) of lung cancer by reproductive factors. Subgroup analyses by menopausal status, birth year, and geographical region were performed. RESULTS: During a median follow-up of 11 years, 2,284 incident lung cancers occurred among 282,558 female never-smokers. Ever oral contraceptive use was associated with a higher risk of lung cancer (HR = 1.16, 95% CI: 1.02-1.33) with a significant increasing trend associated with longer duration of use (p-trend = 0.03). Longer average breastfeeding duration per child was associated with a decreased risk (0.86, 0.78-0.95) for > 12 months compared with those who breastfed for 7-12 months. No statistically significant association was detected between other reproductive factors and lung cancer risk. CONCLUSION: Oral contraceptive use was associated with an increased risk of lung cancer in Chinese female never-smokers. Further studies are needed to assess lung cancer risk related to different types of oral contraceptives in similar populations.

Aberrant glycosylation of secretory mucin from the oral cavity in tobacco consumers: a pilot study.

Mucins are a family of high-molecular-weight O-linked glycoproteins which are the primary structural components of mucus and maintain homeostasis in the oral cavity. The present study was conducted as the first step towards establishing a correlation of aberrant mucin glycosylation with tobacco-associated clinical conditions. Tobacco habituates for the study were identified on the basis of type, duration, amount, and frequency of using tobacco products. The secretory mucin and its saccharides were determined from the saliva collected from smokers, smokeless tobacco habituates, and healthy, nonsmoking individuals. On the one hand, the salivary mucin content was markedly reduced in smokeless tobacco habituates with respect to smokers. On the other hand, the amount of sialic acid and fucose moieties of salivary mucin was increased in both smokers and smokeless tobacco habituates compared to the healthy cohort. Furthermore, the duration of tobacco exposure have been identified as the main factor influencing the extent of damage to the oral mucosa in terms of mucin secretion. The reduced secretory mucin content with aberrant glycosylation in the oral cavity may have a significant role in the further development or progression of oral diseases.

Combined assessment of lysine and N-acetyl cadaverine levels assist as a potential biomarker of the smoker periodontitis.

Periodontitis is an inflammatory condition of supporting structures of teeth leading to attachment and bone loss. Cigarette smoking is the single most important and modifiable risk factor with 5 to 20-fold susceptibility for periodontal diseases. Reverse smoking is a peculiar habit of smoking where the lit end is kept inside the mouth, which is predominant in the northern coastal districts of Andhra Pradesh. Polyamines are biologically active amines involved in tissue regeneration and modulation of inflammation. The study aimed to evaluate polyamines and check their utility as a marker in detection of periodontitis among different groups. Total polyamine levels showed significant increase in reverse smokers with periodontitis when compared to the other groups. Qualitative analysis by thin layer chromatography showed three polyamine bands with varying intensity among the different groups. Mass spectrometric and NMR analyses of the three bands identified them as N1, N8-diacetyl spermidine, N-acetyl cadaverine and lysine. Most significantly elevated levels of lysine was observed in the smoker and reverse smoker periodontitis groups when compared to healthy and non-smoker periodontitis groups. The significantly elevated levels of N-acetyl cadaverine could be responsible for the more destruction of periodontium in the reverse smoker group. Antioxidant potential decreased significantly in different smoker periodontitis groups. The present study suggests that the quantitative analysis of salivary polyamines, lysine and N-acetyl cadaverine can aid as an easy noninvasive diagnostic method for assessing the periodontal status, especially in smokers.

Circulating levels of galectin-9 are a potential biomarker of survival in advanced non-small-cell lung cancer.

BACKGROUND: The immune system is recognized to have therapeutic potential to destroy cancer cells. Soluble T-cell immunoglobulin mucin domain-3 (sTIM-3) and its ligand galectin 9 (Gal-9) cause suppression of cytokine production, cell cycle arrest and cell death. sTIM-3 and Gal-9 levels may have prognostic implications in non-small-cell lung cancer (NSCLC) patients. METHODS: This prospective cohort study was performed at Instituto de Medicina Integral Prof. Fernando Figueira, Recife, Pernambuco, Brazil. Fifty-eight patients were diagnosed with advanced NSCLC from January 2019 to January 2020. RESULTS: The age median was of 64.0 years. Soluble galectin-9 (sGal-9) levels in the smokers compared to nonsmoker patients (p < 0.0001). By using the receiver operating characteristic curve, we found that a baseline of 1694 pg/mL (cutoff). sGAL9 with specificity (72.2%), sensitivity (83.2%) and area under the curve = 0.8497 (p < 0.0004). Until 18.2 months, 46.8% and 72.9% were alive in the sGAL9low and sGAL9high groups, respectively (log-rank test; p = 0.02). The median survival was 15.9 months for sGAL9low (≤1694 pg/mL). CONCLUSION: This study indicated an association of tobacco with the release of circulating sGal-9 levels and the accuracy of sGal-9 as a potential biomarker predictive of survival time in advanced NSCLC patients. Furthermore, sGal-9 has may be a potential therapeutic target in the advanced NSCLC.

Chronic Electronic Cigarette Use and Atherosclerosis Risk in Young People: A Cross-Sectional Study-Brief Report.

BACKGROUND: Little is known whether electronic cigarettes (ECIG) increase vulnerability to future atherosclerotic cardiovascular disease. We determined, using an ex vivo mechanistic atherogenesis assay, whether proatherogenic changes including monocyte transendothelial migration and monocyte-derived foam cell formation are increased in people who use ECIGs. METHODS: In a cross-sectional single-center study using plasma and peripheral blood mononuclear cells from healthy participants who are nonsmokers or with exclusive use of ECIGs or tobacco cigarettes (TCIGs), autologous peripheral blood mononuclear cells with patient plasma and pooled peripheral blood mononuclear cells from healthy nonsmokers with patient plasma were utilized to dissect patient-specific ex vivo proatherogenic circulating factors present in plasma and cellular factors present in monocytes. Our main outcomes were monocyte transendothelial migration (% of blood monocyte cells that undergo transendothelial migration through a collagen gel) and monocyte-derived foam cell formation as determined by flow cytometry and the median fluorescence intensity of the lipid-staining fluorochrome BODIPY in monocytes of participants in the setting of an ex vivo model of atherogenesis. RESULTS: Study participants (N=60) had median age of 24.0 years (interquartile range [IQR], 22.0-25.0 years), and 31 were females. Monocyte transendothelial migration was increased in people who exclusively used TCIGs (n=18; median [IQR], 2.30 [ 1.29-2.82]; P<0.001) and in people who exclusively used ECIGs (n=21; median [IQR], 1.42 [ 0.96-1.91]; P<0.01) compared with nonsmoking controls (n=21; median [IQR], 1.05 [0.66-1.24]). Monocyte-derived foam cell formation was increased in people who exclusively used TCIGs (median [IQR], 2.01 [ 1.59-2.49]; P<0.001) and in people who exclusively used ECIGs (median [IQR], 1.54 [ 1.10-1.86]; P<0.001) compared with nonsmoker controls (median [IQR], 0.97 [0.86-1.22]). Both monocyte transendothelial migration and monocyte-derived foam cell formation were higher in TCIG smokers compared with ECIG users and in ECIG users who were former smokers versus ECIG users who were never smokers (P<0.05 for all comparisons). CONCLUSIONS: The finding of alterations in proatherogenic properties of blood monocytes and plasma in TCIG smokers compared with nonsmokers validates this assay as a strong ex vivo mechanistic tool with which to measure proatherogenic changes in people who use ECIGs. Similar yet significantly less severe alterations in proatherogenic properties of monocytes and plasma were detected in the blood from ECIG users. Future studies are necessary to determine whether these findings are attributable to a residual effect of prior smoking or are a direct effect of current ECIG use.

Risk-stratified Approach for Never- and Ever-Smokers in Lung Cancer Screening: A Prospective Cohort Study in China.

Rationale: Over 40% of lung cancer cases occurred in never-smokers in China. However, high-risk never-smokers were precluded from benefiting from lung cancer screening as most screening guidelines did not consider them. Objectives: We sought to develop and validate prediction models for 3-year lung cancer risks for never- and ever-smokers, named the China National Cancer Center Lung Cancer models (China NCC-LCm2021 models). Methods: 425,626 never-smokers and 128,952 ever-smokers from the National Lung Cancer Screening program were used as the training cohort and analyzed using multivariable Cox models. Models were validated in two independent prospective cohorts: one included 369,650 never-smokers and 107,678 ever-smokers (841 and 421 lung cancers), and the other included 286,327 never-smokers and 78,469 ever-smokers (503 and 127 lung cancers). Measurements and Main Results: The areas under the receiver operating characteristic curves in the two validation cohorts were 0.698 and 0.673 for never-smokers and 0.728 and 0.752 for ever-smokers. Our models had higher areas under the receiver operating characteristic curves than other existing models and were well calibrated in the validation cohort. The China NCC-LCm2021 ⩾0.47% threshold was suggested for never-smokers and ⩾0.51% for ever-smokers. Moreover, we provided a range of threshold options with corresponding expected screening outcomes, screening targets, and screening efficiency. Conclusion: The construction of the China NCC-LCm2021 models can accurately reflect individual risk of lung cancer, regardless of smoking status. Our models can significantly increase the feasibility of conducting centralized lung cancer screening programs because we provide justified thresholds to define the high-risk population of lung cancer and threshold options to adapt different configurations of medical resources.

Causes of and Clinical Features Associated with Death in Tobacco Cigarette Users by Lung Function Impairment.

Rationale: Cigarette smoking contributes to the risk of death through different mechanisms. Objectives: To determine how causes of and clinical features associated with death vary in tobacco cigarette users by lung function impairment. Methods: We stratified current and former tobacco cigarette users enrolled in Genetic Epidemiology of Chronic Obstructive Pulmonary Disease (COPDGene) into normal spirometry, PRISm (Preserved Ratio Impaired Spirometry), Global Initiative for Chronic Obstructive Lung Disease (GOLD) 1-2 COPD, and GOLD 3-4 COPD. Deaths were identified via longitudinal follow-up and Social Security Death Index search. Causes of death were adjudicated after a review of death certificates, medical records, and next-of-kin interviews. We tested associations between baseline clinical variables and all-cause mortality using multivariable Cox proportional hazards models. Measurements and Main Results: Over a 10.1-year median follow-up, 2,200 deaths occurred among 10,132 participants (age 59.5 ± 9.0 yr; 46.6% women). Death from cardiovascular disease was most frequent in PRISm (31% of deaths). Lung cancer deaths were most frequent in GOLD 1-2 (18% of deaths vs. 9-11% in other groups). Respiratory deaths outpaced competing causes of death in GOLD 3-4, particularly when BODE index ⩾7. St. George's Respiratory Questionnaire score ⩾25 was associated with higher mortality in all groups: Hazard ratio (HR), 1.48 (1.20-1.84) normal spirometry; HR, 1.40 (1.05-1.87) PRISm; HR, 1.80 (1.49-2.17) GOLD 1-2; HR, 1.65 (1.26-2.17) GOLD 3-4. History of respiratory exacerbations was associated with higher mortality in GOLD 1-2 and GOLD 3-4, quantitative emphysema in GOLD 1-2, and airway wall thickness in PRISm and GOLD 3-4. Conclusions: Leading causes of death vary by lung function impairment in tobacco cigarette users. Worse respiratory-related quality of life is associated with all-cause mortality regardless of lung function.

Smoking cessation and mortality risk reduction in older adults with long-term smoking history.

BACKGROUND: The association between smoking cessation and decreased mortality existed among former smokers has been well documented. However, evidence is limited for smokers with long-term exposure. This study aims to quantify the association between smoking cessation and mortality by years since quitting in older adults with long-term smoking history. METHODS: Data from Beijing Healthy Aging Cohort Study (BHACS), conducted among communities aged over 55 years old at recruitment, were collected via questionnaire between July 2009 and September 2015 and followed up for all-cause and cancer mortality until March 2021. Self-reported smoking status and years since quitting were collected at baseline. Cox proportional hazards models were used to examine the association between smoking cessation and all-cause and cancer mortality. RESULTS: A total of 11 235 participants (43.9% male) were included, with a mean age of 70.35 (SD 7.71) years. Former smokers comprised 31.7% of the cohort, with a median smoking duration of 43 (IQR: 34-50) years. During 71 573 person-years of follow-up, there were 1 617 deaths (14.4% of the total cohort), of which 872 (17.7%) occurred among male participants. Compared with never smokers, HR (95%CI) for participants who current smoked was 2.898 (2.092-4.013); quit smoking less than 10 years (medians [quartiles] 4 [1, 7] years) before recruitment was 2.738(1.972-3.802); 10 to 20 years (16 [13, 20] years), 1.807(1.286-2.540); and 20 years or more (30 [25, 37] years), 1.293(0.981-1.705). The risk of all-cause and cancer mortality decreased gradually over years since quitting. Quitting less than 10 years, 10 to 20 years and 20 years or more, former smokers avoided an estimated 8.4%, 57.5% and 84.6% of excess all-cause mortality associated with current smoking, respectively. The association between smoking cessation and decreased mortality was observed among former smokers regardless of smoking history. CONCLUSIONS: In this study, current smoking was associated with nearly triple the mortality risk compared to never smoking. Smoking cessation, even after a long-term smoking history, was associated with significant decreases in the relative excess mortality linked to continuing smoking. The association were more pronounced in men.

Diet quality as assessed by the healthy eating index-2020 among different smoking status: an analysis of national health and nutrition examination survey (NHANES) data from 2005 to 2018.

BACKGROUND: Combining smoking with poor eating habits significantly elevates the risk of chronic illnesses and early death. Understanding of how dietary quality shifts post-smoking cessation remains limited. The objective of this study is to examine dietary quality - using Healthy Eating Index (HEI - 2020) and its 13 components, among current, former, and never smokers, and particularly the impact of quitting and the duration of cessation on dietary habits. METHODS: A cross-sectional analysis of 31,569 adults from the National Health and Nutrition Examination Survey (NHANES) 2005-2018 was conducted. Dietary quality was assessed using HEI-2020 scores, which were determined by NIH developed - simple HEI scoring algorithm per person. Smoking status was categorized into current, former, and never smokers, with further subdivisions for current (heavy/light smokers) and former smokers (duration post-cessation). Descriptive analysis and multiple regression models weighted to represent the US population were performed. RESULTS: The current smoking rate was 19.4%, with a higher prevalence in males (22.5%) than females (17.5%). Current smokers reported statistically significantly lower HEI total score than both former and never smokers. Former smokers exhibited HEI scores similar to those of never smokers. The adjusted HEI total scores for current, former, and never smokers were 49.2, 54.0, and 53.3, respectively, with a statistically significant difference (p < 0.001). Moreover, light smokers had better total HEI score than heavy smokers (46.8 vs. 50.8, p < 0.001, respectively), but former and never smokers scored even higher. Quitting smoking immediately improved dietary quality, with former smokers reaching the dietary levels of never smokers within 5-10 years (53.8 vs. 53.3, p > 0.05, respectively). Compared to current smokers, former smokers tended to consume more beneficial foods (e.g., fruits, vegetables, greens and beans, whole grains, proteins, and fatty acids), while also consuming more sodium and less added sugar. CONCLUSIONS: Current smokers, particularly heavy smokers, exhibit poorer dietary habits than former and never smokers. The dietary quality of former smokers aligns with never smokers over time, highlighting the positive impact of smoking cessation on diet. This has implications for reducing chronic disease risks associated with poor diet and smoking.

The enhancing effect of social reward on inhibitory control in smokers: Evidence from behaviour and ERP studies.

OBJECTIVE: Prior research has revealed impaired inhibitory control as a pivotal factor contributing to smokers' struggle to control smoking impulses. However, few studies focus on enhancing smokers' inhibitory control. This study investigates the potential of social rewards to bolster inhibitory control among smokers and elucidates the underlying mechanisms. METHODS: In Experiment 1, a reward-based Go/Nogo paradigm assessed error rates and reaction times for 30 smokers exposed to social reward and neutral feedback in distinct contexts (smoking-related and neutral). Experiment 2 used a modified paradigm, incorporating cognitive load manipulation, to investigate error rates, reaction times, N2, and P3 ERPs among 32 smokers facing social reward and neutral feedback under different cognitive loads (high and low). RESULTS: Smokers exhibit lower Nogo error rates with social reward feedback; higher error rates occur with smoking cues and high cognitive load; increased N2, P3 amplitudes under social reward versus neutral feedback; low cognitive load enhances P3 amplitude under social reward. CONCLUSION: Social reward improves smokers' inhibitory control, but this effect weakens with exposure to smoking cues; higher cognitive load further diminishes the enhancement of smokers' inhibitory control by social reward under smoking cues.

Higher Risk of Wound Complications but no Clinically Significant Increase in Operative Time for Smokers Receiving Myomectomy for Uterine Fibroids.

Myomectomy is a common procedure to remove uterine fibroids. Smoking impacts outcomes across various surgeries; however, may limit fibroid growth. We sought to determine if smoking impacts myomectomy for uterine fibroid removal outcomes. Patients with and without a history of tobacco smoking receiving a myomectomy for uterine fibroid removal were compared. Compared to patients with no history of tobacco smoking, tobacco smokers had a significantly increased risk of wound complications. No other variables analyzed demonstrated a clinically significant difference. Future research is needed to examine how different frequency of tobacco smoking impacts outcomes.

Attentional Bias Toward Cigarette-Related Cues in Male Smokers is Modulated by Cognitive Control Mechanisms.

Background: Many studies have found that smokers' attentional bias toward cigarette-related cues and cognitive control impairment significantly impacts their cigarette use. However, there is limited research on how the interaction between attentional bias and cognitive control may modulate smokers' cigarette-seeking behavior. Objectives: This study used a cigarette Stroop task to examine whether smokers with different attentional control ability had different levels of attentional bias toward cigarette-related cues. Methods: A total of 130 male smokers completed the Flanker task to measure their attentional control ability. The attentional control scores of all participants were ranked from low to high, with the top 27% placed in the high attentional control group and the bottom 27% in the low attentional control group. Subsequently, both groups completed the cigarette Stroop task to measure their attentional bias toward cigarette-related cues. Results: Smokers with low attentional control responded more slowly to cigarette-related cues than to neutral cues, while smokers with high attentional control showed no significant difference in their response time to either condition. Conclusions/Importance: Attentional control ability can regulate smokers' attentional bias toward cigarette-related cues. Smokers with low attentional control ability are more likely to have attentional bias toward cigarette-related cues, offering insights for targeted prevention of cigarette addiction.

Squamous Cell Carcinoma in Never Smokers: An Insight into SMARCB1 Loss.

Lung cancer remains the leading cause of cancer-related mortality worldwide, with non-small cell lung cancer (NSCLC) constituting 85% of cases. Among NSCLCs, squamous cell carcinoma (SqCC) is strongly associated with smoking. However, lung cancer in never smokers (LCINS) represents approximately 25% of lung cancer cases globally and shows increasing incidence, particularly in East Asia. LCINS-SqCC is less well-characterized, especially regarding its genomic alterations and their impact on clinical outcomes. We conducted a retrospective analysis over a 20-year period (July 2003-July 2023) at two major tertiary centers in the UK. The cohort included 59 patients with LCINS-SqCC who underwent radical surgical resection. Data collected included demographic information, comorbidities, histopathological details, and outcome metrics such as disease-free and overall survival. Molecular sequencing of tumor specimens was performed to identify genomic aberrations. The cohort had a median age of 71 years (IQR 62-77) and a median BMI of 25.4 (IQR 22.8-27.8), with a slight male predominance (53%). The majority of patients (93%) had a preoperative MRC of 1-2. Recurrent disease was observed in 23 patients (39%), and 32 patients (54%) had died at a median follow-up of 3 years. Median disease-free survival was 545 days (IQR 132-1496), and overall survival was 888 days (IQR 443-2071). Preoperative creatinine levels were higher in patients who experienced recurrence (p = 0.037). Molecular analysis identified biallelic SMARCB1 loss in two younger patients, associated with rapid disease progression despite R0 resection. These patients' tumors were PDL1-negative, TTF-1-negative, and positive for cytokeratin, CD56, and p40. SMARCB1-deficient SqCC in never smokers represents a highly aggressive variant with poor disease-free survival, highlighting the importance of integrating advanced molecular diagnostics in clinical practice. This study underscores the necessity for personalized treatment strategies, including targeted therapies such as EZH2 inhibitors and immune checkpoint blockade, to address the unique molecular pathways in SMARCB1-deficient cancers. Further clinical trials are essential to optimize therapeutic approaches for this challenging subgroup of lung cancer.

The Fagerström Test for Nicotine Dependence, as a prognostic factor, in current smokers with and without COPD: A cross-sectional study in northern Greece.

BACKGROUND: Smoking poses the most common risk factor for chronic obstructive pulmonary disease (COPD) and aggravates disease progression. Tobacco dependence inhibits smoking cessation and may affect smoking patterns that increase tobacco exposure and predispose to lung function decline. AIMS AND OBJECTIVES: We aimed to assess tobacco dependence in current smokers with and without COPD and evaluate its role in disease development. METHOD: This cross-sectional study was conducted in Greek rural areas. Current smokers completed the Fagerström Test for Nicotine Dependence and were classified into COPD and non-COPD groups based on spirometry parameters. RESULTS: Among current smokers, 288 participants comprised the non-COPD and 71 the COPD group. Both presented moderate tobacco dependence, but smokers with COPD started to smoke earlier in the morning. Multiple logistic regression analysis revealed higher COPD prevalence in smokers with higher scores in the Fagerström test (odds ratio OR = 1.12, 95% confidence interval [1.01 - 1.24]) and older age (OR = 1.06 [1.03 - 1.09]), independently of pack-years smoking index. Multiple linear regression analysis in smokers with COPD showed that the forced expiratory volume in the 1st second decreased by 2.3% of the predicted value for each point increase in the Fagerström Test and 0.59% for each year of age, independently of participants' sex and pack-years smoking index. CONCLUSION: The Fagerström score appears to indicate a higher probability for COPD and lung function deterioration when assessed along with age in current smokers. Smoking cessation support programs are fundamental to COPD prevention and management.

Prevalence of breakthrough COVID-19 infection among healthcare workers in Baghdad.

Objective: To determine the prevalence and severity of breakthrough coronavirus disease-2019 infection among health workers, and to assess health workers' post-vaccination adherence to preventive guidelines. METHODS: The cross-sectional study was conducted from December 2021 to March 2022 at 2 major hospitals in Baghdad, Iraq, and comprised physicians, pharmacists, dentists and paramedical staff present at time of data collection. The participants were classified according to vaccination status with history of infection. Unvaccinated meant infected before vaccination; partially vaccinated meant infected after the first dose; and fully vaccinated meant breakthrough infection after the second dose. Data was analysed using SPSS 28. RESULTS: Of the 506 participants aged 20-59 years, 327(64.6%) were females, 247(48.8%) were physicians, 72(14.2%) were smokers, and 21(4.1%) had asthma. All the 506(100%) participants had been infected after vaccination; 430(85%) after the second dose, and 76(15%) after the first dose. In 445(88.6%) cases, the infection was mild to moderate, while admission was required in 21(4.1%). With respect to adherence to preventive guidelines, 229(45.3%) subjects were always wearing masks before the vaccination, but 119(23.7%) continued doing that after receiving the second dose of the vaccine. CONCLUSIONS: The majority of the participants had fallen victim to breakthrough coronavirus disease-2019 infection. Adherence to preventive guidelines was found to be reduced after the second dose of the vaccination.

Smoking has detrimental effects on voice related Quality of Life of University Teachers.

Objective: To compare voice related quality of life of smoker and non-smoker university teachers. Method: This Cross-Sectional descriptive study was conducted at Riphah International University over a period of six months January to June, 2022. A sample of N=352 University teachers of both genders, aged 25 to 65 years, who were faculty members and working at least 8 hours per day in teaching positions with at least one-year experience were included in the study. Demographic sheet, Voice Related Quality of Life (VRQOL) and Voice Handicap Index (VHI) were used for data collection and analysis conducted on SPSS Version 21. Mean scores of VRQOL and VHI for smokers and non-smokers were compared using Mann Whitney U Test. & Spearman's correlation was utilized to determine any association between the tool scores. P<0.01 was considered significant. Results: Results reveal that the mean score of Voice related quality of life scale was significantly (p=0.000) higher in smokers compared to non-smokers indicating worse voice quality in smokers. Similarly, voice handicap index scores were much higher in smokers (p=0.000) indicating more handicap in the smokers. Conclusion: The study concludes that smoking has a detrimental effect on voice and voice related quality of life of university teachers and voice related quality of life as determined by VRQOL scale is significantly better in non-smokers.