Smoking-associated Lung Research Articles

Why making smoking cessation a priority for rare interstitial lung disease smokers?

This review aims to discuss the complex relationship between smoking and interstitial lung diseases (ILDs), emphasizing the significant morbidity and mortality associated with these conditions. While the etiology of ILDs remains multifactorial, cigarette smoking emerges as a prominent modifiable risk factor implicated in their pathogenesis and progression. This narrative review will provide insight into smoking-associated interstitial lung diseases and personalised approaches to smoking cessation. Epidemiological studies consistently link smoking to ILDs such as idiopathic pulmonary fibrosis (IPF), respiratory bronchiolitis-associated ILD (RB-ILD), and desquamative interstitial pneumonia (DIP), highlighting the urgent need for comprehensive tobacco cessation strategies. Despite the established benefits of smoking cessation, adherence to cessation programs remains challenging due to nicotine addiction, psychological factors, and social influences. The modest success rates of smoking cessation in ILD patients, emphasises the importance of tailored interventions and ongoing support is needed to overcome barriers and to improve outcomes of quitting smoking in this category of vulnerable patients.

Role of Insulin-like Growth Factor-1 Receptor in Tobacco Smoking-Associated Lung Cancer Development.

Cancer remains a significant global health concern, with lung cancer consistently leading as one of the most common malignancies. Genetic aberrations involving receptor tyrosine kinases (RTKs) are known to be associated with cancer initiation and development, but RTK involvement in smoking-associated lung cancer cases is not well understood. The Insulin-like Growth Factor 1 Receptor (IGF-1R) is a receptor that plays a critical role in lung cancer development. Its signaling pathway affects the growth and survival of cancer cells, and high expression is linked to poor prognosis and resistance to treatment. Several reports have shown that by activating IGF-1R, tobacco smoke-related carcinogens promote lung cancer and chemotherapy resistance. However, the relationship between IGF-1R and cancer is complex and can vary depending on the type of cancer. Ongoing investigations are focused on developing therapeutic strategies to target IGF-1R and overcome chemotherapy resistance. Overall, this review explores the intricate connections between tobacco smoke-specific carcinogens and the IGF-1R pathway in lung carcinogenesis. This review further highlights the challenges in using IGF-1R inhibitors as targeted therapy for lung cancer due to structural similarities with insulin receptors. Overcoming these obstacles may require a comprehensive approach combining IGF-1R inhibition with other selective agents for successful cancer treatment.

Lung cancer in patients who have never smoked - an emerging disease.

Lung cancer is the most common cause of cancer-related deaths globally. Although smoking-related lung cancers continue to account for the majority of diagnoses, smoking rates have been decreasing for several decades. Lung cancer in individuals who have never smoked (LCINS) is estimated to be the fifth most common cause of cancer-related deaths worldwide in 2023, preferentially occurring in women and Asian populations. As smoking rates continue to decline, understanding the aetiology and features of this disease, which necessitate unique diagnostic and treatment paradigms, will be imperative. New data have provided important insights into the molecular and genomic characteristics of LCINS, which are distinct from those of smoking-associated lung cancers and directly affect treatment decisions and outcomes. Herein, we review the emerging data regarding the aetiology and features of LCINS, particularly the genetic and environmental underpinnings of this disease as well as their implications for treatment. In addition, we outline the unique diagnostic and therapeutic paradigms of LCINS and discuss future directions in identifying individuals at high risk of this disease for potential screening efforts.

Tobacco smoke exposure recruits inflammatory airspace monocytes that establish permissive lung niches for Mycobacterium tuberculosis.

Tobacco smoking doubles the risk of active tuberculosis (TB) and accounts for up to 20% of all active TB cases globally. How smoking promotes lung microenvironments permissive to Mycobacterium tuberculosis (Mtb) growth remains incompletely understood. We investigated primary bronchoalveolar lavage cells from current and never smokers by performing single-cell RNA sequencing (scRNA-seq), flow cytometry, and functional assays. We observed the enrichment of immature inflammatory monocytes in the lungs of smokers compared with nonsmokers. These monocytes exhibited phenotypes consistent with recent recruitment from blood, ongoing differentiation, increased activation, and states similar to those with chronic obstructive pulmonary disease. Using integrative scRNA-seq and flow cytometry, we identified CD93 as a marker for a subset of these newly recruited smoking-associated lung monocytes and further provided evidence that the recruitment of monocytes into the lung was mediated by CCR2-binding chemokines, including CCL11. We also show that these cells exhibit elevated inflammatory responses upon exposure to Mtb and accelerated intracellular growth of Mtb compared with mature macrophages. This elevated Mtb growth could be inhibited by anti-inflammatory small molecules, providing a connection between smoking-induced pro-inflammatory states and permissiveness to Mtb growth. Our findings suggest a model in which smoking leads to the recruitment of immature inflammatory monocytes from the periphery to the lung, which results in the accumulation of these Mtb-permissive cells in the airway. This work defines how smoking may lead to increased susceptibility to Mtb and identifies host-directed therapies to reduce the burden of TB among those who smoke.

Early Detection of Lung Cancer Using Small RNAs

IntroductionLung cancer remains the deadliest cancer in the world, and lung cancer survival is heavily dependent on tumor stage at the time of detection. Low-dose computed tomography screening can reduce mortality; however, annual screening is limited by low adherence in the United States of America and still not broadly implemented in Europe. As a result, less than 10% of lung cancers are detected through existing programs. Thus, there is a great need for additional screening tests, such as a blood test, that could be deployed in the primary care setting. MethodsWe prospectively recruited 1384 individuals meeting the National Lung Screening Trial demographic eligibility criteria for lung cancer and collected stabilized whole blood to enable the pipetting-free collection of material, thus minimizing preanalytical noise. Ultra-deep small RNA sequencing (20 million reads per sample) was performed with the addition of a method to remove highly abundant erythroid RNAs, and thus open bandwidth for the detection of less abundant species originating from the plasma or the immune cellular compartment. We used 100 random data splits to train and evaluate an ensemble of logistic regression classifiers using small RNA expression of 943 individuals, discovered an 18-small RNA feature consensus signature (miLung), and validated this signature in an independent cohort (441 individuals). Blood cell sorting and tumor tissue sequencing were performed to deconvolve small RNAs into their source of origin. ResultsWe generated diagnostic models and report a median receiver-operating characteristic area under the curve of 0.86 (95% confidence interval [CI]: 0.84–0.86) in the discovery cohort and generalized performance of 0.83 in the validation cohort. Diagnostic performance increased in a stage-dependent manner ranging from 0.73 (95% CI: 0.71–0.76) for stage I to 0.90 (95% CI: 0.89–0.90) for stage IV in the discovery cohort and from 0.76 to 0.86 in the validation cohort. We identified a tumor-shed, plasma-bound ribosomal RNA fragment of the L1 stalk as a dominant predictor of lung cancer. The fragment is decreased after surgery with curative intent. In additional experiments, results of dried blood spot collection and sequencing revealed that small RNA analysis could potentially be conducted through home sampling. ConclusionsThese data suggest the potential of a small RNA-based blood test as a viable alternative to low-dose computed tomography screening for early detection of smoking-associated lung cancer.

Early detection of lung cancer using small RNAs.

3035 Background: Low-dose computed tomography (LDCT) screening can significantly reduce lung cancer mortality. However, annual screening is limited by low adherence in the USA and still not broadly implemented in Europe. As a result, <10% of lung cancers are detected through existing programs. Thus, there is great need for additional diagnostic modalities, such as a blood test that could be deployed in the primary care setting. Methods: We prospectively recruited 1,189 patients meeting the 2013 USPSTF screening criteria for lung cancer and collected stabilized whole blood. Ultra-deep small RNA sequencing was performed with a method to remove highly abundant erythroid RNAs, opening bandwidth for the detection of less abundant species originating from plasma or the immune cellular compartment. We utilized 100 random data splits to train and evaluate logistic regression classifiers using small RNA expression, discovered an 18-small RNA feature consensus signature (miLung), and validated this in an independent cohort (246 patients). Blood cell sorting and tumor tissue sequencing were performed to deconvolve small RNAs into their source of origin. Results: We generated diagnostic models and report a median ROC AUC of 0.86 (95% CI 0.84-0.86) in the discovery cohort, and generalized performance of 0.84 in the validation cohort. Diagnostic performance increased stage-dependently from 0.73 (95% CI 0.71-0.76) for Stage I to 0.90 (95% CI 0.89-0.90) for Stage IV. We identified a tumor-shed, plasma-bound ribosomal RNA fragment of the L1 stalk as a dominant predictor of lung cancer. The fragment is decreased following surgery with curative intent. In additional experiments, dried blood spot collection and sequencing revealed that small RNA analysis could potentially be conducted via home-sampling. Conclusions: These data suggest the potential of a small RNA-based blood test as a viable alternative to LDCT screening for early detection of smoking-associated lung cancer. Clinical trial information: NCT03452514 . [Table: see text]

Impact of sub-acute acrolein inhalation on the molecular regulation of mitochondrial metabolism in rat lung

Nowadays, mitochondria are recognized as key players in the pathogenesis of a variety of smoking-associated lung diseases. Acrolein, a component of cigarette smoke, is a known driver of biological mechanisms underlying smoking-induced respiratory toxicity. The impact of sub-acute acrolein inhalation in vivo on key processes controlling mitochondrial homeostasis in cells of the airways however is unknown. In this study, we investigated the activity/abundance of a myriad of molecules critically involved in mitochondrial metabolic pathways and mitochondrial quality control processes (mitochondrial biogenesis and mitophagy) in the lungs of Sprague-Dawley rats that were sub-acutely exposed to filtered air or 3 ppm acrolein by whole-body inhalation (5 h/day, 5 days/week for 4 weeks). Acrolein exposure induced a general inflammatory response in the lung as gene expression analysis revealed an increased expression of Icam1 and Cinc1 (p < 0.1; p < 0.05). Acrolein significantly decreased enzyme activity of hydroxyacyl-Coenzyme A dehydrogenase (p < 0.01), and decreased Pdk4 transcript levels (p < 0.05), suggestive of acrolein-induced changes in metabolic processes. Investigation of constituents of the mitochondrial biogenesis pathways and mitophagy machinery revealed no pronounced alterations. In conclusion, sub-acute inhalation of acrolein did not affect the regulation of mitochondrial metabolism and quality control, which is in contrast to more profound changes after acute exposure in other studies.

Disruption of the Molecular Regulation of Mitochondrial Metabolism in Airway and Lung Epithelial Cells by Cigarette Smoke: Are Aldehydes the Culprit?

Chronic obstructive pulmonary disease (COPD) is a devastating lung disease for which cigarette smoking is the main risk factor. Acetaldehyde, acrolein, and formaldehyde are short-chain aldehydes known to be formed during pyrolysis and combustion of tobacco and have been linked to respiratory toxicity. Mitochondrial dysfunction is suggested to be mechanistically and causally involved in the pathogenesis of smoking-associated lung diseases such as COPD. Cigarette smoke (CS) has been shown to impair the molecular regulation of mitochondrial metabolism and content in epithelial cells of the airways and lungs. Although it is unknown which specific chemicals present in CS are responsible for this, it has been suggested that aldehydes may be involved. Therefore, it has been proposed by the World Health Organization to regulate aldehydes in commercially-available cigarettes. In this review, we comprehensively describe and discuss the impact of acetaldehyde, acrolein, and formaldehyde on mitochondrial function and content and the molecular pathways controlling this (biogenesis versus mitophagy) in epithelial cells of the airways and lungs. In addition, potential therapeutic applications targeting (aldehyde-induced) mitochondrial dysfunction, as well as regulatory implications, and the necessary required future studies to provide scientific support for this regulation, have been covered in this review.

Comprehensive analysis of molecular features, prognostic values, and immune landscape association of m6A-regulated immune-related lncRNAs in smoking-associated lung squamous cell carcinoma.

Lung squamous cell carcinoma (LUSC) is the second most common histopathological subtype of lung cancer, and smoking is the leading cause of this type of cancer. However, the critical factors that directly affect the survival rate and sensitivity to immunotherapy of smoking LUSC patients are still unknown. Previous studies have highlighted the role of N6-methyladenosine (m6A) RNA modification, the most common epigenetic modification in eukaryotic species, together with immune-related long non-coding RNAs (lncRNAs) in promoting the development and progression of tumors. Thus, elucidating m6A-modified immune lncRNAs in LUSC patients with smoking history is vital. In this study, we described the expression and mutation features of the 24 m6A-related regulators in the smoking-associated LUSC cohort from The Cancer Genome Atlas (TCGA) database. Then, two distinct subtypes based on the expression levels of the prognostic m6A-regulated immune lncRNAs were defined, and differentially expressed genes (DEGs) between the subtypes were identified. The distributions of clinical characteristics and the tumor microenvironment (TME) between clusters were analyzed. Finally, we established a lncRNA-associated risk model and exhaustively clarified the clinical features, prognosis, immune landscape, and drug sensitivity on the basis of this scoring system. Our findings give insight into potential mechanisms of LUSC tumorigenesis and development and provide new ideas in offering LUSC patients with individual and effective immunotherapies.

Revisiting the role of pulmonary surfactant in chronic inflammatory lung diseases and environmental exposure.

Pulmonary surfactant is a crucial and dynamic lung structure whose primary functions are to reduce alveolar surface tension and facilitate breathing. Though disruptions in surfactant homeostasis are typically thought of in the context of respiratory distress and premature infants, many lung diseases have been noted to have significant surfactant abnormalities. Nevertheless, preclinical and clinical studies of pulmonary disease too often overlook the potential contribution of surfactant alterations - whether in quantity, quality or composition - to disease pathogenesis and symptoms. In inflammatory lung diseases, whether these changes are cause or consequence remains a subject of debate. This review will outline 1) the importance of pulmonary surfactant in the maintenance of respiratory health, 2) the diseases associated with primary surfactant dysregulation, 3) the surfactant abnormalities observed in inflammatory pulmonary diseases and, finally, 4) the available research on the interplay between surfactant homeostasis and smoking-associated lung disease. From these published studies, we posit that changes in surfactant integrity and composition contribute more considerably to chronic inflammatory pulmonary diseases and that more work is required to determine the mechanisms underlying these alterations and their potential treatability.

Abstract 2214: The genomic landscape of lung cancer in post-menopausal never-smoker women

Abstract Lung cancer is the deadliest form of cancer worldwide. Cigarette smoking is the primary risk factor for developing lung cancer, fueling global tobacco cessation programs. In the United States, it is projected that by 2065 there will be a 63% reduction in smoking-associated lung cancer burden. However, even with this decline, lung cancer will still account for a significant proportion of cancer-associate mortality, suggesting that factors beyond smoking contribute to lung tumorigenesis. Lung cancer in never smokers is a distinct sub-group that needs specific exploration. It is the 7th highest cause of cancer-deaths worldwide, with an increasing trend in its incidence. Thus far, the majority of tumor genome-wide sequencing efforts in lung cancer have been focused on patient cohorts with a smoking history. We know that LCNS is distinct from lung adenocarcinoma found in smokers at the genetic level, however large gaps in our understanding of this population persist. Through a unique collaboration with the Women's Health Initiative (WHI) we now have access to a large repository of tumor tissue from LCNS patients. We have performed exome-sequencing on this cohort and here we describe novel mutations, structural variants and copy number changes in this cohort. Whole-exome sequencing of 75 tumor-normal pairs was performed. Mutations were identified for the entire cohort using different computational methods. For the identification of single nucleotide variants a consensus dual-caller and filtering methodology was employed. Variants were then analyzed to identify genes with significant mutations using MutSig2CV. Structural variant analysis was performed using SvABA and copy number analysis was performed using TITAN. Finally, we perform correlative analysis of mutations with the metadata curated by the WHI and highlight key features of this cohort. Our mutational analysis reveals showed that there is an enrichment of known oncogenes including KRAS, EGFR and TP53. Additionally, we identified mutations in STK11. Here we describe novel genes and mutations previously unknown to occur in LCNS cohort and describe their potential functional implications. We also report novel structural variants and copy number alterations. Additionally we performed mutational signature analysis and identified novel signatures specific to this cohort. Mutational analysis of our LCNS cohort reveals that this cohort in general has a lower tumor mutational burden compared to their control cohort with a history of smoking. Additionally, we find that this cohort has mutations that have been previously reported in studies in LCNS patients. However, the existence of novel mutations and structural alterations may offer a unique opportunity for future target identification and therapeutic intervention. Citation Format: Sitapriya Moorthi, Amy Paguirigan, Garnet Anderson, Gavin Ha, Alice Berger. The genomic landscape of lung cancer in post-menopausal never-smoker women [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2214.

Ethnic Differences of Urinary Cadmium in Cigarette Smokers from the Multiethnic Cohort Study.

The Multiethnic Cohort Study (MEC) has demonstrated racial/ethnic differences in smoking-associated lung cancer risk. As part of the ongoing effort to characterize exposure to cigarette smoke constituents and better understand risk differences, we evaluated Cd exposure as it is a known lung carcinogen. We quantified urinary cadmium (Cd) by inductively coupled plasma mass spectrometry in a subset of 1956 current smokers from MEC. Ethnic-specific geometric means (GM) were compared adjusting for age at urine collection, sex, creatinine (natural log), education, and smoking (urinary total nicotine equivalents [TNE] and smoking duration). Self-reported questionnaire data, including occupation, were also considered. Latinos and Native Hawaiians had the highest GM urinary Cd (0.871 and 0.836 ng/mL, respectively) followed by Japanese Americans and African Americans (0.811 ng/mL and 0.807, respectively) and Whites (0.736 ng/mL). Patterns in race/ethnicity were consistent by sex such that females had the highest GM urinary Cd. When further adjusting for categorical occupational Cd exposure, racial/ethnic differences of Cd remained (p = 0.009). Findings suggest differences in urinary Cd among smokers across different racial/ethnic groups exist and highlight the importance in considering environmental sources of Cd exposure beyond smoking. These finding lay ground for future studies of individual characteristics that are associated with lower risk for cancer despite higher carcinogenic exposures.

Trajectory of smoking behavior change among Chinese immigrant smokers.

BackgroundThe incidence and mortality rates of smoking-associated lung cancer are high among Chinese immigrant smokers. Coming from a country with different smoking policies, culture, and economic background than the U.S., Chinese smokers may change their smoking behaviors after immigrating to the U.S.ObjectivesThis study aims to explore the trajectory of smoking behavior change among Chinese immigrant smokers migrating to the U.S.MethodsThis qualitative study was guided by the Grounded theory. Semi-structured intensive individual interviews were conducted among 10 eligible participants. A purposive theoretical sampling method was used to recruit participants through a website. Individual interviews were conducted online, via telephone, or in-person in Mandarin. Data were transcribed verbatim in Mandarin, translated into English, and triangulated with follow-up interviews and dialogues among authors to enhance trustworthiness and consistency of the study. Process coding and content analysis were used to analyze data.ResultsA total of 10 participants, 7 males and 3 females, were interviewed. Results showed the trajectory of smoking behavior change among Chinese immigrant smokers went through three phases: 1) Beginning to smoke, which included learning to smoke from others, trying to smoke and learning to smoke, and hiding their smoking behaviors from others; 2) maintaining smoking, which included setting boundary around smoking, smoking as a facilitator or barrier to social interaction, feeling pressures related to smoking behavior, and making others happy: Collective smoking and controlling smoking desire; and 3) changing smoking behaviors, which included experiencing life events that were triggers to changing smoking behavior, boredom as a reason for relapses, personal will as a key to quitting smoking, and quitting smoking for a loved one. Although some differences existed between male and female Chinese immigrant smokers’ smoking behaviors, their trajectories of smoking behavior change were generally similar.DiscussionFindings from this study can help health care providers to extend their understanding toward smoking behavior change among Chinese immigrant smokers across different socio-cultural contexts.

Impact of emphysema on sputum culture conversion in male patients with pulmonary tuberculosis: a retrospective analysis

BackgroundAlthough cigarette smoking may have a negative impact on the clinical outcome of pulmonary tuberculosis (PTB), few studies have investigated the impact of smoking-associated lung diseases. Emphysema is a major pathological finding of smoking-related lung damage. We aimed to clarify the effect of emphysema on sputum culture conversion rate for Mycobacterium tuberculosis (MTB).MethodsWe retrospectively studied 79 male patients with PTB confirmed by acid-fast bacillus smear and culture at Jikei University Daisan Hospital between January 2015 and December 2018. We investigated the sputum culture conversion rates for MTB after starting standard anti-TB treatment in patients with or without emphysema. Emphysema was defined as Goddard score ≥ 1 based on low attenuation area < − 950 Hounsfield Unit (HU) using computed tomography (CT). We also evaluated the effect on PTB-related CT findings prior to anti-TB treatment.ResultsMycobacterial median time to culture conversion (TCC) in 38 PTB patients with emphysema was 52.0 days [interquartile range (IQR) 29.0–66.0 days], which was significantly delayed compared with that in 41 patients without emphysema (28.0 days, IQR 14.0–42.0 days) (p < 0.001, log-rank test). Multivariate Cox proportional hazards analysis showed that the following were associated with delayed TCC: emphysema [hazard ratio (HR): 2.43; 95% confidence interval (CI): 1.18–4.97; p = 0.015), cavities (HR: 2.15; 95% CI: 1.83–3.89; p = 0.012) and baseline time to TB detection within 2 weeks (HR: 2.95; 95% CI: 1.64–5.31; p < 0.0001). Cavities and consolidation were more often identified by CT in PTB patients with than without emphysema (71.05% vs 43.90%; p = 0.015, and 84.21% vs 60.98%; p = 0.021, respectively).ConclusionsThis study suggests that emphysema poses an increased risk of delayed TCC in PTB. Emphysema detection by CT might be a useful method for prediction of the duration of PTB treatment required for sputum negative conversion.

Abstract 3349: Evolution of the gut Amicrobiome during the pathogenesis of smoking-associated Kras-mutant lung cancer

Abstract Relative to other tumors in smokers, KRAS-mutant lung adenocarcinomas (LUADs) display dismal prognosis warranting the need for early management of this disease. Limiting these advances is our gap in knowledge of events that drive KRAS-mutant LUAD oncogenesis. Host defense systems, such as those elicited by the gut microbiome, were recently shown to influence tumors external to the gastrointestinal tract (e.g. melanomas), thus highlighting the microbiome as an orchestrator of oncogenesis. Yet, gut microbiome changes in early stages of KRAS-mutant LUAD development are not known. We recently reported that mice with knockout of G-protein coupled receptor 5A (Gprc5a-/-), in contrast to wild type (WT) littermates, develop LUADs which are accelerated following exposure to tobacco carcinogen (nicotine-specific nitrosamine ketone/NNK). LUADs in the tobacco exposed Gprc5a-/- mouse model exhibit high somatic mutation burdens, driver Kras variants and other co-occurring drivers, features constituting a “perfect storm” for LUAD pathogenesis in smokers. Using this human-relevant model, we performed 16S-Seq of fecal samples collected prior to and at several time points post-NNK exposure during LUAD development. We found significant, some progressive, microbial changes during the pathogenesis of LUAD, including abolishment of phylum Verrucomicrobia, progressive increase in tumor-promoting genera Odoribacter spp., gradual decrease in Akkermansia spp., which was previously shown to be associated with response to PD-1 blockade, as well as reduced abundance of Ruminococcus which was previously reported to be suppressed during colon carcinogenesis. Additionally, and prior to tumor onset, lungs and immune cells of these Gprc5a-/- mice exhibited markedly elevated expression of lipocalin 2 (LCN2), an antimicrobial protein released from host cells during microbiome imbalance and inflammation. We further found that Gprc5a-/- mice with knockout of Lcn2 exhibited increased tumors compared to similarly exposed Gprc5a-/- with intact Lcn2. These effects were accompanied by widespread changes in the gut microbiome including increased abundance of tumor-promoting Alistipes spp. and, conversely, reduced abundance of Lactobacillus spp. Our data show that host defense mediated by LCN2 counteracts Kras-mutant LUAD development by restricting gut microbiome imbalance (i.e., maintaining gut microbiome homeostasis and diversity), suggesting a protective role during Kras-mutant LUAD development. Our overall findings inform on novel pathways implicating antimicrobial host defense mechanisms in the development of smoking-associated Kras-mutant LUAD. Efforts are underway to discern specific microbiome profiles that are likely causally related to smoking-associated Kras-mutant LUAD development as well as to develop and test preclinical microbiome intervention strategies for this malignancy. Citation Format: Warapen Treekitkarnmongkol, Casey Finnicum, Ansam Sinjab, Maya Hassane, Christel Davis, Gareth E. Davies, Kristi L. Hoffman, Junya Fujimoto, Florencia McAllister, Boris Sepesi, Tina Cascone, Robert R. Jenq, Joseph Petrosino, Erik Ehli, Seyed J. Moghaddam, Humam Kadara. Evolution of the gut microbiome during the pathogenesis of smoking-associated Kras-mutant lung cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3349.

Assessing the Current State of Lung Cancer Chemoprevention: A Comprehensive Overview.

Chemoprevention of lung cancer is thought to significantly reduce the risk of acquiring these conditions in the subpopulation of patients with underlying health issues, such as chronic obstructive pulmonary disorder and smoking-associated lung problems. Many strategies have been tested in the previous decades, with very few translating to successful clinical trials in specific subpopulations of patients. In this review, we analyze these strategies, as well as new approaches that have emerged throughout the last few years, including synthetic lethality concept and microbiome-induced regulation of lung carcinogenesis. Overall, the continuous effort in the area of lung chemoprevention is required to develop practical therapeutical approaches. Given the inconsistency of results obtained in clinical trials targeting lung cancer chemoprevention in various subgroups of patients that differ in the underlying health condition, race, and gender, we believe that individualized approaches will have more promise than generalized treatments.

P19Arf Exacerbates Cigarette Smoke-Induced Pulmonary Dysfunction.

Senescent cells accumulate in tissues during aging or pathological settings. The semi-genetic or pharmacological targeting of senescent cells revealed that cellular senescence underlies many aspects of the aging-associated phenotype and diseases. We previously reported that cellular senescence contributes to aging- and disease-associated pulmonary dysfunction. We herein report that the elimination of Arf-expressing cells ameliorates cigarette smoke-induced lung pathologies in mice. Cigarette smoke induced the expression of Ink4a and Arf in lung tissue with concomitant increases in lung tissue compliance and alveolar airspace. The elimination of Arf-expressing cells prior to cigarette smoke exposure protected against these changes. Furthermore, the administration of cigarette smoke extract lead to pulmonary dysfunction, which was ameliorated by subsequent senescent cell elimination. Collectively, these results suggest that senescent cells are a potential therapeutic target for cigarette smoking-associated lung disease.

Bioinformatics and functional analyses of key genes in smoking-associated lung adenocarcinoma.

Smoking is one of the most important factors associated with the development of lung cancer. However, the signaling pathways and driver genes in smoking-associated lung adenocarcinoma remain unknown. The present study analyzed 433 samples of smoking-associated lung adenocarcinoma and 75 samples of non-smoking lung adenocarcinoma from the Cancer Genome Atlas database. Gene Ontology (GO) analysis was performed using the Database for Annotation, Visualization and Integrated Discovery and the ggplot2 R/Bioconductor package. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis was performed using the R packages RSQLite and org.Hs.eg.db. Multivariate Cox regression analysis was performed to screen factors associated with patient survival. Kaplan-Meier and receiver operating characteristic curves were used to analyze the potential clinical significance of the identified biomarkers as molecular prognostic markers for the five-year overall survival time. A total of 373 differentially expressed genes (DEGs; |log2-fold change|≥2.0 and P<0.01) were identified, of which 71 were downregulated and 302 were upregulated. These DEGs were associated with 28 significant GO functions and 11 significant KEGG pathways (false discovery rate <0.05). Two hundred thirty-eight proteins were associated with the 373 differentially expressed genes, and a protein-protein interaction network was constructed. Multivariate regression analysis revealed that 7 mRNAs, cytochrome P450 family 17 subfamily A member 1, PKHD1 like 1, retinoid isomerohydrolase RPE65, neurotensin receptor 1, fetuin B, insulin-like growth factor binding protein 1 and glucose-6-phosphatase catalytic subunit, significantly distinguished between non-smoking and smoking-associated adenocarcinomas. Kaplan-Meier analysis demonstrated that patients in the 7 mRNAs-high-risk group had a significantly worse prognosis than those of the low-risk group. The data obtained in the current study suggested that these genes may serve as potential novel prognostic biomarkers of smoking-associated lung adenocarcinoma.

Network analysis of differentially expressed smoking-associated mRNAs, lncRNAs and miRNAs reveals key regulators in smoking-associated lung cancer.

Lung cancer is the leading cause of cancer-associated mortality worldwide. Smoking is one of the most significant etiological contributors to lung cancer development. However, the molecular mechanisms underlying smoking-induced induction and progression of lung cancer have remained to be fully elucidated. Furthermore, long non-coding RNAs (lncRNAs) are increasingly recognized to have important roles in diverse biological processes. The present study focused on identifying differentially expressed mRNAs, lncRNAs and micro (mi)RNAs in smoking-associated lung cancer. Smoking-associated co-expression networks and protein-protein interaction (PPI) networks were constructed to identify hub lncRNAs and genes in smoking-associated lung cancer. Furthermore, Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses of differentially expressed lncRNAs were performed. A total of 314 mRNAs, 24 lncRNAs and 4 miRNAs were identified to be deregulated in smoking-associated lung cancer. PPI network analysis identified 20 hub genes in smoking-associated lung cancer, including dynein axonemal heavy chain 7, dynein cytoplasmic 2 heavy chain 1, WD repeat domain 78, collagen type III α 1 chain (COL3A1), COL1A1 and COL1A2. Furthermore, co-expression network analysis indicated that relaxin family peptide receptor 1, receptor activity modifying protein 2-antisense RNA 1, long intergenic non-protein coding RNA 312 (LINC00312) and LINC00472 were key lncRNAs in smoking-associated lung cancer. A bioinformatics analysis indicated these smoking-associated lncRNAs have a role in various processes and pathways, including cell proliferation and the cyclic guanosine monophosphate cGMP)/protein kinase cGMP-dependent 1 signaling pathway. Of note, these hub genes and lncRNAs were identified to be associated with the prognosis of lung cancer patients. In conclusion, the present study provides useful information for further exploring the diagnostic and prognostic value of the potential candidate biomarkers, as well as their utility as drug targets for smoking-associated lung cancer.

Sport as applied therapy in patients with schizophrenic psychoses

Sport as applied therapy in patients with schizophrenic psychoses Abstract. Schizophrenic psychoses are serious mental illnesses associated with low life expectancy compared with healthy individuals and other psychiatric disorders. Overweight and associated health problems such as diabetes mellitus, cardiovascular disease and smoking-associated lung disease have been shown to be risk factors related to high mortality. Low physical activity and increased sedentary behavior have been identified as the most important behavioral risk factors for cardiovascular diseases in people with schizophrenia. Numerous research results show a positive influence of sport on mental symptoms as well as on physical health. In the studies, however, different types of guided movement with divergent intensity were used in group or single setting. The Deutsche Gesellschaft für Psychiatrie und Psychotherapie, Psychosomatik und Nervenheilkunde [German Association for Psychiatry, Psychotherapy and Psychosomatics] recommends sports and physical exercise interventions for patients with severe mental illnesses. Still, further large randomized controlled trials are needed to investigate the nature, extent and duration, as well as the effect of the methods used in the various stages of the disease. One goal should be the evidence-based implementation of specific and systematic sport and movement interventions as a complementary module in addition to psychopharmacological and psychotherapeutic treatment in people with schizophrenia.