The cerebellum is causally involved in episodic memory under aging.

Episodic memory decline is a major signature of both normal and pathological aging. Many neural regions have been implicated in the processes subserving both episodic memory and typical aging decline. Here, we demonstrate that the cerebellum is causally involved episodic memory under aging. We show that a 12-day neurostimulation program delivered to the right cerebellum led to improvements in episodic memory performance under healthy aging that long outlast the stimulation period - healthy elderly individuals show episodic memory improvement both immediately after the intervention program and in a 4-month follow-up. These results demonstrate the causal relevance of the cerebellum in processes associated with long-term episodic memory, potentially highlighting its role in regulating and maintaining cognitive processing. Moreover, they point to the importance of non-pharmacological interventions that prevent or diminish cognitive decline in healthy aging.

NeuroAIreh@b: an artificial intelligence-based methodology for personalized and adaptive neurorehabilitation.

Cognitive impairments are a prevalent consequence of acquired brain injury, dementia, and age-related cognitive decline, hampering individuals' daily functioning and independence, with significant societal and economic implications. While neurorehabilitation represents a promising avenue for addressing these deficits, traditional rehabilitation approaches face notable limitations. First, they lack adaptability, offering one-size-fits-all solutions that may not effectively meet each patient's unique needs. Furthermore, the resource-intensive nature of these interventions, often confined to clinical settings, poses barriers to widespread, cost-effective, and sustained implementation, resulting in suboptimal outcomes in terms of intervention adaptability, intensity, and duration. In response to these challenges, this paper introduces NeuroAIreh@b, an innovative cognitive profiling and training methodology that uses an AI-driven framework to optimize neurorehabilitation prescription. NeuroAIreh@b effectively bridges the gap between neuropsychological assessment and computational modeling, thereby affording highly personalized and adaptive neurorehabilitation sessions. This approach also leverages virtual reality-based simulations of daily living activities to enhance ecological validity and efficacy. The feasibility of NeuroAIreh@b has already been demonstrated through a clinical study with stroke patients employing a tablet-based intervention. The NeuroAIreh@b methodology holds the potential for efficacy studies in large randomized controlled trials in the future.

Prioritizing research challenges and funding for allergy and asthma and the need for translational research-The European Strategic Forum on Allergic Diseases.

The European Academy of Allergy and Clinical Immunology (EAACI) organized the first European Strategic Forum on Allergic Diseases and Asthma. The main aim was to bring together all relevant stakeholders and decision-makers in the field of allergy, asthma and clinical Immunology around an open debate on contemporary challenges and potential solutions for the next decade. The Strategic Forum was an upscaling of the EAACI White Paper aiming to integrate the Academy's output with the perspective offered by EAACI's partners. This collaboration is fundamental for adapting and integrating allergy and asthma care into the context of real-world problems. The Strategic Forum on Allergic Diseases brought together all partners who have the drive and the influence to make positive change: national and international societies, patients' organizations, regulatory bodies and industry representatives. An open debate with a special focus on drug development and biomedical engineering, big data and information technology and allergic diseases and asthma in the context of environmental health concluded that connecting science with the transformation of care and a joint agreement between all partners on priorities and needs are essential to ensure a better management of allergic diseases and asthma in the advent of precision medicine together with global access to innovative and affordable diagnostics and therapeutics.

Triple therapy in COPD: new evidence with the extrafine fixed combination of beclomethasone dipropionate, formoterol fumarate, and glycopyrronium bromide.

The goals of COPD therapy are to prevent and control symptoms, reduce the frequency and severity of exacerbations, and improve exercise tolerance. The triple combination therapy of inhaled corticosteroids (ICSs), long-acting beta2 agonists (LABAs), and long-acting muscarinic antagonists (LAMAs) has become an option for maintenance treatment of COPD and as a "step-up" therapy from single or double combination treatments. There is evidence that triple combination ICS/LABA/LAMA with different inhalers improves lung function, symptoms, and health status and reduces exacerbations. A new triple fixed-dose combination of extrafine beclomethasone dipropionate (100 µg/puff)/formoterol fumarate (6 µg/puff)/glycopyrronium bromide (12.5 µg/puff) has been developed as a hydrofluoroalkane pressurized metered dose inhaler. Two large pivotal studies showed that this extrafine fixed ICS/LABA/LAMA triple combination is superior to fixed ICS/LABA combined therapy and also superior to the LAMA tiotropium in terms of lung function and exacerbation prevention in COPD patients at risk of exacerbation. This review considers the new information provided by these clinical trials of extrafine triple therapy and the implications for the clinical management of COPD patients.

High-dose beclometasone dipropionate/formoterol fumarate in fixed-dose combination for the treatment of asthma.

The high-strength formulation of extrafine beclometasone dipropionate/formoterol fumarate (BDP/Form) 200/6 µg has been developed to step up inhaled corticosteroid treatment, without increasing the dose of the bronchodilator, in patients who are not controlled with previous therapies. Two clinical studies have evaluated efficacy of high-strength BDP/Form as compared with another high-dose fixed combination and BDP monotherapy. Overall, data show that BDP/Form 200/6 µg improves lung function and has beneficial effects on symptoms, use of rescue medication and asthma control, with an acceptable safety profile comparable with that of high-dose fluticasone propionate/salmeterol. Therefore, BDP/Form 200/6 µg could be considered as an effective and safe treatment for patients with asthma who are not adequately controlled with high doses of inhaled corticosteroid monotherapy or medium doses of inhaled corticosteroid/long-acting ß2-agonist combinations.

Extrafine beclometasone diproprionate/formoterol fumarate: a review of its effects in chronic obstructive pulmonary disease.

A fixed-dose inhaled corticosteroid/long-acting ß2-agonist (ICS/LABA) combination of extrafine beclometasone dipropionate and formoterol fumarate (BDP/FF) has been recently approved for use in chronic obstructive pulmonary disease (COPD). Small airway inflammation and remodelling are cardinal features of COPD; therefore, the ability of this extrafine formulation to reach the small, as well as the large, airways is likely to be therapeutically important by enabling treatment of inflammatory processes in the whole bronchial tree. The clinical development of extrafine BDP/FF has demonstrated significant benefits over extrafine FF in terms of lung function improvement and reduction of the exacerbation rate, thus supporting the beneficial effect of an ICS combined to a LABA in COPD patients. Head-to-head comparison studies versus other ICS/LABA combinations have shown that the extrafine formulation enables the clinical benefits to be achieved with a lower dose of ICS. Extrafine BDP/FF showed lung function and dyspnoea improvements comparable to other ICS/LABAs, and a significantly faster onset of action was observed when compared with a salmeterol-containing fixed-dose combination. This review summarises the clinical evidence supporting the efficacy of extrafine BDP/FF in COPD and confirming that extrafine BDP/FF achieves the type of health benefit expected from such a targeted ICS/LABA combination in COPD.

The prevalence of small airways disease in adult asthma: A systematic literature review.

BACKGROUND: Small airways dysfunction and inflammation contribute significantly to the clinical impact of asthma, yet conventional methods of assessing airways function in the clinic cannot reliably evaluate its presence. However, most recently, promising methods of assessment are being utilised. METHODS: We conducted a systematic literature review, using PubMed, with the aim of determining the prevalence of small airways disease in adult patients with asthma. We ascertained how small airways disease prevalence compared between different studies when measured using distinct techniques of small airways assessment. RESULTS: Fifteen publications were identified determining the prevalence of small airways disease in asthma. Methods of assessments included impulse oscillometry, spirometry, body plethysmography, multiple-breath nitrogen washout, and high-resolution computed tomography. These studies used differing inclusion characteristics and recruited patients with a broad range of asthma severity, yet collectively they reported an overall prevalence of small airways disease of 50-60%. Small airways disease was present across all asthma severities, with evidence of distal airway disease even in the absence of proximal airway obstruction. CONCLUSIONS: Small airways disease is highly prevalent in asthma, even in patients with milder disease. Given the clinical impact of small airways disease, its presence should not be underestimated or overlooked as part of the daily management of patients with asthma.

Treatment response according to small airway phenotypes: a real-life observational study.

OBJECTIVE: Scant clinical data are available on the effects of current treatments for asthma on different subgroups of patients with this disease. We conducted a prospective, noninterventional, multicenter real-life study in adult patients with persistent asthma, and we specifically analyzed the effects of treatment with extrafine beclometasone dipropionate/formoterol (BDP/F) in asthma patients categorized by phenotypes related to small airways (i.e. smoking habits, disease duration, and air trapping). METHODS: Patients received BDP/F as a fixed combination (100/6 µg), administered in 1-2 inhalations twice daily over a period of 12 weeks. Peak expiratory flow (PEF), forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), number of asthma attacks, asthma control, and severity of asthma symptoms were evaluated in the overall population and in different subgroups at three different time points. RESULTS: Overall, 213 patients were enrolled. In the overall population the treatment resulted in a significant increase in the proportion of well controlled patients (from 6.1% to 66.3%; p<0.001), and a reduction of uncontrolled subjects (70.3% versus 10.0%; p<0.001). BDP/F was also associated with a reduction in asthma attacks and an improvement of symptoms. These results were confirmed in specific subgroups of patients identified as small airway phenotypes: smokers, elderly patients, those with long duration of disease and air trapping. CONCLUSIONS: This real-life observational study indicates that extrafine BDP/F in a fixed combination improves asthma control and symptoms in the overall population as well as specific subgroups of patients.

NEXThaler, an innovative dry powder inhaler delivering an extrafine fixed combination of beclometasone and formoterol to treat large and small airways in asthma.

INTRODUCTION: Airway inflammation and remodelling in asthma occur in the large airways and also in the small airways. The small airways are those < 2 mm in diameter and are significant sites of chronic asthmatic inflammation. It is important, therefore, to target the small as well as the large airways in any strategy for effective treatment of this disease. AREAS COVERED: The present review deals with the recently developed fixed dose drug combination of beclometasone dipropionate/formoterol fumarate that emits extrafine particles when delivered from an innovative dry powder inhaler (DPI), NEXThaler®. The aim is to present the technical and clinical aspects of aerosolized drug delivery to the lungs. EXPERT OPINION: The data show that the NEXThaler DPI is an efficient device for the management of persistent asthma. The evaluation of the inhalation profiles through the NEXThaler DPI demonstrates that device activation and consistent dose delivery occurs at patient achievable inhalation flow rates, and supports the broad utility of the NEXThaler DPI in patients with asthma. Overall, all the effectiveness, efficiency and satisfaction outcomes demonstrate the NEXThaler DPI is easy to use.

Comparing usability of NEXThaler(®) with other inhaled corticosteroid/long-acting ß2-agonist fixed combination dry powder inhalers in asthma patients.

BACKGROUND: Inhaler mishandling is a common issue among patients suffering from asthma and is associated with poor clinical outcomes and greater consumption of health-care resources. Ease of use can improve inhaler technique and, possibly, patients' preference for their inhaler device, which in turn may lead to better adherence to therapy. METHODS: This study investigated usability characteristics of NEXThaler(®) versus two other dry powder inhalers (DPIs; Diskus(®) and Turbuhaler(®)). Sixty-six adult patients with asthma (mean age 42.9±17.7 years) and with no previous experience of using a DPI were included in a randomized crossover comparison of the three devices. The main measures of usability were the number of steps failed for each device and the number of people who were able to use the device successfully (effectiveness), the time it took patients to set up the device and the time to read the instructions for use (IFU; efficiency), and patient preferences (satisfaction). Inhaler technique was evaluated after the IFU leaflet was read. RESULTS: NEXThaler was found to be superior to the other two DPIs in terms of the number of device use failures (p<0.001), time to set up (p<0.001), and time to read IFU (p<0.001). Additionally, the proportion of participants who completed a successful inhalation without any errors at all was significantly higher for NEXThaler than for Diskus and Turbuhaler (p<0.001). Patients rated NEXThaler as the easiest to use and most preferred inhaler to own (p<0.001). CONCLUSIONS: NEXThaler displayed better usability compared with Diskus and Turbuhaler. The improved usability and higher satisfaction with the device may contribute to increased patient adherence to asthma treatment.

Do inhaled corticosteroid/long-acting beta2-agonist fixed combinations provide superior clinical benefits compared with separate inhalers? A literature reappraisal.

Current asthma management guidelines emphasize the importance of disease control. Although effective drug therapies are available, real-life data indicate that the general level of asthma control is still low. Fixed-dose combinations of inhaled corticosteroids/long-acting beta(2)-agonists (ICS/LABAs) are now increasingly used in the management of asthma. A number of studies have compared the clinical benefits of ICS/LABA fixed combinations with the monocomponents administered using two separate inhalers. We conducted a database search to identify all published studies that have assessed whether fixed-dose combinations achieve greater asthma control compared with administration by separate inhalers. Among fixed combinations, only extrafine beclomethasone/formoterol provided significantly greater asthma control compared with separate inhalers administered as larger aerosol particles. This greater effect may be explained by increased delivery to the small airways by the extrafine formulation.

Rapid effects of extrafine beclomethasone dipropionate/formoterol fixed combination inhaler on airway inflammation and bronchoconstriction in asthma: a randomised controlled trial.

BACKGROUND: The dose-dependent anti-inflammatory effects of a recent fixed combination of extrafine beclomethasone dipropionate/formoterol (BDP/F) were investigated using non-invasive markers of inflammation, exhaled nitric oxide (NO) and adenosine monophosphate (AMP) provocative challenge. The aim was to assess the onset of the anti-inflammatory action of low and high doses and evaluate the suitability of non-invasive assessments to demonstrate dose response. METHODS: Steroid naïve adult out-patients with mild asthma, sensitive to AMP with baseline exhaled NO > 25 parts per billion entered a double-blind, placebo-controlled, 3-way, cross-over study. Patients were randomised to low dose (1 actuation) or high dose (4 actuations) extrafine BDP/F 100/6 µg, or placebo administered twice daily on Days 1 and 2 and once in the morning on Day 3 of each period. Exhaled NO was measured pre-dose on Day 1, then 2 and 4 hours post-administration on Day 3. The AMP challenge was performed 4 hours post-administration on Day 3 and forced expiratory volume in 1 second (FEV1, L) was measured from 0 to 4 hours post-dose on Day 1. Endpoints were NO at 2 and 4 hours, AMP challenge at 4 hours after the fifth dose on Day 3 and FEV1 area under the curve from 0 to 4 h post-dose on Day 1. Analysis of covariance was performed for NO and FEV1 and analysis of variance for AMP challenge. RESULTS: Eighteen patients were randomised and completed the study. Exhaled NO was significantly lower for both doses of extrafine BDP/F versus placebo at 2 and 4 hours (high dose LS mean difference: -22.5 ppb, p < 0.0001 and -20.5 ppb, p < 0.0001; low dose: -14.1 ppb, p = 0.0006 and -12.1 ppb, p = 0.0043) with a significant dose response (p = 0.0342 and p = 0.0423). Likewise, AMP challenge revealed statistically significant differences between both doses of extrafine BDP/F and placebo (high dose LS mean difference: 4.8 mg/mL, p < 0.0001; low dose: 3.7 mg/mL, p < 0.0001), and a significant dose response (p = 0.0185). FEV1 was significantly improved versus placebo for both doses (high dose LS mean difference: 0.2 L, p = 0.0001; low dose: 0.2 L p = 0.0001), but without a significant dose response. CONCLUSIONS: The fixed combination inhaler of extrafine BDP/F has early dose-dependent anti-inflammatory effects with a rapid onset of bronchodilatation in mild asthmatic patients. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01343745.

Multipotent capacity of immortalized human bronchial epithelial cells.

While the adult murine lung utilizes multiple compartmentally restricted progenitor cells during homeostasis and repair, much less is known about the progenitor cells from the human lung. Translating the murine stem cell model to humans is hindered by anatomical differences between species. Here we show that human bronchial epithelial cells (HBECs) display characteristics of multipotent stem cells of the lung. These HBECs express markers indicative of several epithelial types of the adult lung when experimentally tested in cell culture. When cultured in three different three-dimensional (3D) systems, subtle changes in the microenvironment result in unique responses including the ability of HBECs to differentiate into multiple central and peripheral lung cell types. These new findings indicate that the adult human lung contains a multipotent progenitor cell whose differentiation potential is primarily dictated by the microenvironment. The HBEC system is not only important in understanding mechanisms for specific cell lineage differentiation, but also for examining changes that correlate with human lung diseases including lung cancer.

Aldehyde dehydrogenase activity selects for lung adenocarcinoma stem cells dependent on notch signaling.

Aldehyde dehydrogenase (ALDH) is a candidate marker for lung cancer cells with stem cell-like properties. Immunohistochemical staining of a large panel of primary non-small cell lung cancer (NSCLC) samples for ALDH1A1, ALDH3A1, and CD133 revealed a significant correlation between ALDH1A1 (but not ALDH3A1 or CD133) expression and poor prognosis in patients including those with stage I and N0 disease. Flow cytometric analysis of a panel of lung cancer cell lines and patient tumors revealed that most NSCLCs contain a subpopulation of cells with elevated ALDH activity, and that this activity is associated with ALDH1A1 expression. Isolated ALDH(+) lung cancer cells were observed to be highly tumorigenic and clonogenic as well as capable of self-renewal compared with their ALDH(-) counterparts. Expression analysis of sorted cells revealed elevated Notch pathway transcript expression in ALDH(+) cells. Suppression of the Notch pathway by treatment with either a γ-secretase inhibitor or stable expression of shRNA against NOTCH3 resulted in a significant decrease in ALDH(+) lung cancer cells, commensurate with a reduction in tumor cell proliferation and clonogenicity. Taken together, these findings indicate that ALDH selects for a subpopulation of self-renewing NSCLC stem-like cells with increased tumorigenic potential, that NSCLCs harboring tumor cells with ALDH1A1 expression have inferior prognosis, and that ALDH1A1 and CD133 identify different tumor subpopulations. Therapeutic targeting of the Notch pathway reduces this ALDH(+) component, implicating Notch signaling in lung cancer stem cell maintenance.

MFSD2A is a novel lung tumor suppressor gene modulating cell cycle and matrix attachment.

BACKGROUND: MFSD2A (major facilitator superfamily domain containing 2) gene maps on chromosome 1p34 within a linkage disequilibrium block containing genetic elements associated with progression of lung cancer. RESULTS: Here we show that MFSD2A expression is strongly downregulated in non-small cell lung cancer cell lines of different histotypes and in primary lung adenocarcinomas. Experimental modulation of MFSD2A in lung cancer cells is associated with alteration of mRNA levels of genes involved in cell cycle control and interaction with the extracellular matrix. Exogenous expression of MFSD2A in lung cancer cells induced a G1 block, impaired adhesion and migration in vitro, and significantly reduced tumor colony number in vitro (4- to 27-fold, P < 0.0001) and tumor volume in vivo (approximately 3-fold, P < 0.0001). siRNA knockdown studies in normal human bronchial epithelial cells confirmed the role of MFSD2A in G1 regulation. CONCLUSION: Together these data suggest that MFSD2A is a novel lung cancer tumor suppressor gene that regulates cell cycle progression and matrix attachment.

Sex determining region Y-Box 2 (SOX2) is a potential cell-lineage gene highly expressed in the pathogenesis of squamous cell carcinomas of the lung.

BACKGROUND: Non-small cell lung cancer (NSCLC) represents the majority (85%) of lung cancers and is comprised mainly of adenocarcinomas and squamous cell carcinomas (SCCs). The sequential pathogenesis of lung adenocarcinomas and SCCs occurs through dissimilar phases as the former tumors typically arise in the lung periphery whereas the latter normally arise near the central airway. METHODOLOGY/PRINCIPAL FINDINGS: We assessed the expression of SOX2, an embryonic stem cell transcriptional factor that also plays important roles in the proliferation of basal tracheal cells and whose expression is restricted to the main and central airways and bronchioles of the developing and adult mouse lung, in NSCLC by various methodologies. Here, we found that SOX2 mRNA levels, from various published datasets, were significantly elevated in lung SCCs compared to adenocarcinomas (all p<0.001). Moreover, a previously characterized OCT4/SOX2/NANOG signature effectively separated lung SCCs from adenocarcinomas in two independent publicly available datasets which correlated with increased SOX2 mRNA in SCCs. Immunohistochemical analysis of various histological lung tissue specimens demonstrated marked nuclear SOX2 protein expression in all normal bronchial epithelia, alveolar bronchiolization structures and premalignant lesions in SCC development (hyperplasia, dysplasia and carcinoma in situ) and absence of expression in all normal alveoli and atypical adenomatous hyperplasias. Moreover, SOX2 protein expression was greatly higher in lung SCCs compared to adenocarcinomas following analyses in two independent large TMA sets (TMA set I, n = 287; TMA set II, n = 511 both p<0.001). Furthermore, amplification of SOX2 DNA was detected in 20% of lung SCCs tested (n = 40) and in none of the adenocarcinomas (n = 17). CONCLUSIONS/SIGNIFICANCE: Our findings highlight a cell-lineage gene expression pattern for the stem cell transcriptional factor SOX2 in the pathogenesis of lung SCCs and suggest a differential activation of stem cell-related pathways between squamous cell carcinomas and adenocarcinomas of the lung.

Genome-wide association study in discordant sibships identifies multiple inherited susceptibility alleles linked to lung cancer.

We analyzed a series of young (median age = 52 years) non-smoker lung cancer patients and their unaffected siblings as controls, using a genome-wide 620 901 single-nucleotide polymorphism (SNP) array analysis and a case-control DNA pooling approach. We identified 82 putatively associated SNPs that were retested by individual genotyping followed by use of the sib transmission disequilibrium test, pointing to 36 SNPs associated with lung cancer risk in the discordant sibs series. Analysis of these 36 SNPs in a polygenic model characterized by additive and interchangeable effects of rare alleles revealed a highly statistically significant dosage-dependent association between risk allele carrier status and proportion of cancer cases. Replication of the same 36 SNPs in a population-based series confirmed the association with lung cancer for three SNPs, suggesting that phenocopies and genetic heterogeneity can play a major role in the complex genetics of lung cancer risk in the general population.

FGFR4 Gly388Arg polymorphism may affect the clinical stage of patients with lung cancer by modulating the transcriptional profile of normal lung.

The association of the fibroblast growth factor receptor 4 (FGFR4) Gly388Arg polymorphism with clinical stage and overall survival in a series of 541 Italian lung adenocarcinoma (ADCA) patients indicated a significantly decreased survival in patients carrying the rare Arg388 allele as compared to that in Gly/Gly homozygous patients [hazard ratio (HR) = 1.5; 95% confidence interval (CI) 1.1-1.9], with the decrease related to the association of the same polymorphism with clinical stage (HR = 1.8, 95% CI 1.3-2.6). By contrast, no significant association was detected in small series of either Norwegian lung ADCA patients or Italian lung squamous cell carcinoma (SQCC) patients. Single nucleotide polymorphisms of known FGFR4 ligands expressed in lung (FGF9, FGF18 and FGF19) were not associated with clinical stage or survival and showed no interaction with FGFR4. Analysis of gene expression profile in normal lungs according to FGFR4 genotype indicated a specific transcript pattern associated with the allele carrier status, suggesting a functional role for the FGFR4 polymorphism already detectable in normal lung. These findings confirm the significant association of the FGFR4 Gly388Arg polymorphism with clinical stage and overall survival in an Italian lung ADCA population and demonstrate a FGFR4 genotype-dependent transcriptional profile present in normal lung tissue.

Transcription deregulation at the 15q25 locus in association with lung adenocarcinoma risk.

PURPOSE: We characterized the candidacy of the six candidate genes mapping in the chromosome 15q25 locus, which was previously reported as associated with lung cancer risk, and confirmed the locus association with lung cancer risk in an Italian population of lung adenocarcinoma patients and controls. EXPERIMENTAL DESIGN: We did a quantitative analysis of mRNA levels of IREB2 (iron-responsive element-binding protein 2), LOC123688, PMSA4 [proteasome (prosome, macropain) subunit alpha type 4], CHRNB4 (cholinergic receptor nicotinic beta 4), CHRNA3 (cholinergic receptor nicotinic alpha 3), and CHRNA5 (cholinergic receptor nicotinic alpha 5) genes in paired normal lung and lung adenocarcinoma tissue, and an immunohistochemical localization of CHRNA3- and CHRNA5-encoded proteins. We also examined the association of CHRNA5 D398N polymorphism with lung cancer risk and with CHRNA5 mRNA levels in the normal lung. RESULTS: Expression analysis of the six candidate genes mapping in the lung cancer risk-associated chromosome 15q25 locus revealed a 30-fold up-regulation of the gene encoding the CHRNA5 subunit and a 2-fold down-regulation of the CHRNA3 subunit in lung adenocarcinoma as compared with the normal lung. The expression of the four other candidate genes resulted either unchanged or absent. The carrier status of the 398N allele at the D398N polymorphism of the CHRNA5 gene was associated with lung adenocarcinoma risk (odds ratio, 1.5; 95% confidence interval, 1.2-2.0) in a population-based series of lung adenocarcinoma patients (n=467) and healthy controls (n=739). Analysis of a family-based series of nonsmoker lung cancer cases (n=80) and healthy sib controls (n=80) indicated a similar trend. In addition, the same D398N variation correlated with CHRNA5 mRNA levels in normal lung of adenocarcinoma patients. CONCLUSIONS: Our results point to the candidacy of the CHRNA5 gene for the 15q25 locus.

A polygenic model with common variants may predict lung adenocarcinoma risk in humans.

Genome-wide screening for genetic loci associated with risk of lung adenocarcinoma (ADCA) was carried out in pooled DNA using the Illumina 300K single-nucleotide polymorphism (SNP) array, in a joint analysis of 2 Italian case-control series matched by age, gender and smoking habit. The rare allele carrier status of 8 SNPs was associated with a decreased lung ADCA risk [odds ratios (OR): 0.6-0.8]. In a polygenic model characterized by additive and interchangeable effects, individuals carrying 2 to 6 rare alleles at these 8 SNPs showed a significant trend toward a decreased risk of lung ADCA (up to OR of 0.3). These results suggest the relevance of a polygenic model in the modulation of individual risk of lung ADCA in the general population.