Citations

Abstract Rationale: Adverse social determinants of health (SDOH) are common in COPD and associated with increased mortality. However, cause-specific mortality is understudied. We evaluated associations of neighborhood-level SDOH with all-cause and cause-specific mortality among individuals with or at-risk for COPD. Methods: SPIROMICS is an ongoing, multi-center, longitudinal observational study of individuals across the US with current or former personal smoking histories (≥20 pack-years), with or without spirometrically-defined COPD. We established geocoded neighborhood-level SDOH at baseline using 2010 census tract data, including specifically, area deprivation index (ADI) (range 0-100, 100 = most disadvantaged), poverty level (percentage of households below the poverty line), poor food access (>1/3 of residents with no access to fresh food stores within 1 mile in urban areas and 10 miles in rural areas), and food desert (low income plus poor food access). We ascertained all-cause and cause-specific mortality through 12/31/2021 using the National Death Index. Using Cox proportional hazards models, we evaluated the risk of all-cause mortality for each SDOH. We utilized competing-risk regression models to evaluate the risk of cardiovascular, respiratory, COPD (a subset of respiratory), and neoplastic causes of death individually with each SDOH. Models were adjusted for demographics, smoking status, pack-years, BMI categories, coronary heart disease, FEV1% predicted and study site. Effect modification by lung function was assessed using multiplicative interactions between SDOH and FEV1% predicted. Results: Among 2977 participants, mean ADI was 40.1±27.8. Within a participant's neighborhood, on average 10.4±10.4% of households were below the poverty line, 933 (31.3%) had poor food access, and 220 (7.4%) resided in a food desert. During a median follow-up of 7.8 years (IQR 5.6-9.2), 744 (25.0%) participants died, most commonly from respiratory causes including COPD. Neither ADI nor neighborhood poverty level were associated with all-cause mortality or any specific cause of death (Table). Despite lack of associations between food access and mortality (Table), individuals residing in a food desert had elevated risks of all-cause (HR: 1.36 [95%CI: 1.03-1.79]) and cardiovascular (HR: 2.62 [95%CI: 1.5-4.35]) deaths. There was no significant effect modification by lung function. Conclusions: In a large cohort of individuals with personal smoking histories, with or without COPD, living in a food desert was associated with increased all-cause and cardiovascular mortality. However, neighborhood poverty level and food access, the two components of food desert, were not independently associated with mortality, suggesting the association of multimodal SDOH variables with mortality in this population.

Abstract Rationale: MUC5B and MUC5AC are neighboring genes on chromosome 11p15 that encode the two predominant mucins secreted in the respiratory airways. Increased airway mucin concentrations and an imbalance between these two mucins drive COPD symptoms and the development of airflow obstruction or COPD, but the epigenomic regulation of this loci has not been characterized in the airways. Methods: We isolated DNA from bronchial airway brushings of 72 participants with >20 pack-years smoking history from the Subpopulations and Intermediate Outcomes Measures in COPD Study (SPIROMICS). 36 participants had GOLD-based moderate-to-severe COPD (FEV1/FVC<0.70, FEV1<80%) and 36 were without or with mild COPD. We used the Illumina Infinium Methylation EPIC BeadChip Array to assess proportion of DNA methylation (β) spanning 689,937 CpG sites. We evaluated proportional DNA methylation (β) at 96 CpG loci within a 103kB region using matrixQTL for cis-expression quantitative trait methylation (eQTM: 10kB flanks relative to MUC5AC/MUC5B) integrating bulk RNA-seq data and mQTL models integrating gene sequencing data to identify DNA variation associated with proportion eQTM methylation. Models included age, sex, BMI, clinical site, current smoking vs past smoking, total pack-years, three ancestral components of ancestry, chipset, and position. Results: We identified a top eQTM, cg00524486, marginally associated with MUC5B expression (coefficient estimate=8.75, punadjusted=0.0014, pFDR=0.065, Figure 1B). This eQTM was associated with CT scan parametric response mapping-based functional small airways disease (PRM-fSAD, beta coefficient[β]=3.64, p=0.011). We tested for DNA variation associated with methylation of this top eQTM which identified two methylation quantitative trait loci (mQTL: rs885454 [β=0.044, minor allele frequency[MAF]=0.09, pFDR=0.01], rs868902 [β=0.020, MAF=0.43, pFDR=0.08, Figure 1A) associated with cg00524486 methylation, of which the more frequent mQTL, rs868902, was marginally associated with PRM-fSAD (p=0.07) in the larger SPIROMICS cohort with MUC5B DNA sequencing data. Conclusions: This preliminary multi-omic study of the lower airway epithelium demonstrates that the expression of MUC5B is epigenetically regulated by neighboring CpG probe methylation (eQTM) represented by DNA variation (mQTL). These studies require further confirmation in a larger dataset of airway samples and support a role for epigenetic variation as a biologic contributor and biomarker of early COPD pathogenesis.

Abstract RATIONALE: Airway-to-lung ratio (AirLR), calculated as the mean of airway lumen diameters at standard anatomic locations divided by the cube-root of total lung volume, is associated with COPD risk regardless of smoking status, and we have previously shown an association between total-pulmonary-vascular-volume-to-lung-size relationship with AirLR. [PMCID: PMC11284327] Using dual energy computed tomography (DECT), we recently developed a deep learning-based algorithm for pulmonary arterial segmentation to compute pulmonary-arterial-to-lung ratio (ArtLR) which correlated significantly with AirLR and markers COPD. Here we automate image processing in a larger cohort to estimate ArtLR, introduce an alternative ArtLR standardization and correlate it to COPD-related measures of lung structure and function. METHODS: Using a SPIROMICS sub-cohort (110 participants), imaged via contrast enhanced DECT at functional residual capacity (FRC), an automatic deep learning pipeline segmented the arteries from the pulmonary vascular tree. Another pipeline automatically extracted the centerlines and calculated average arterial segment diameters. A paired non-contrast total lung capacity (TLC) scan was registered to the DECT FRC scan to transfer airway segment labels from the TLC to FRC domain. AirLR was calculated as the mean of airway lumen diameters at standard anatomic locations (trachea-to-subsegments) divided by cube root of lung volume [TLC or FRC]. A simple Long Short-Term Memory (LSTM) network was used to find corresponding anatomic arterial segments. Associations between ArtLR and %Emphysema, AirLR, pre- and post-bronchodilator FEV1/FVC, and a texture-based (AMFM) measure of %broncho-vascular bundles was assessed using linear regression to adjust for age, sex and BMI. RESULTS: In adjusted analyses, a 1-SD decrement in ArtLR-TLC was associated with 4.198 units increase in %Emphysema-910 (95%CI: 1.360-7.037; p = 0.0041), and 0.8198 units decrease in %Bronchovascular (95%CI: 0.5037-1.136; p < 0.0001). A 1-SD increment in ArtLR-TLC was associated with 0.2515 SD increase in AirLR-Outer (95%CI: 0.04947SD-0.4536SD; p = 0.0152), and 0.02083 units increase in PreBronch-FEV1FVC (95%CI: 0.001814-0.03984; p = 0.0321). Sex and BMI show significant associations with ArtLR-TLC, where female is associated with 1.068 SD decrease in ArtLR, and a unit increase in BMI is associated with 0.05788 SD increase in ArtLR (both p-values < 0.0001), and age was not association with ArtLR. CONCLUSIONS: An automated pipeline for pulmonary arterial tree segmentation and standardization from contrast enhanced DECT FRC scans demonstrates a significant relationship between ArtLR and AirLR as well as between ArtLR and %emphysema, and FEV1/FVC. A standardized method of arterial tree size assessment provides for expanded exploration of vascular vs airway disease etiologies.

Abstract Rationale: Individuals with chronic obstructive pulmonary disease (COPD) have different clinical trajectories, some with minimal symptom burden, others experiencing recurrent exacerbations, the most severe of which require hospitalization. Existing diagnostics, including spirometry and symptom assessments, lack the precision to identify high-risk patients who may benefit from timely preventive therapies. Nuclear cell-free DNA (ncfDNA) is a well-established marker of systemic tissue injury, implicated in amplifying inflammation by triggering type 1 interferon release by activating DNA-sensing pathways. Because COPD is accompanied by inflammation and tissue injury systemically, we hypothesized that ncfDNA is associated with increased risk of severe exacerbations requiring hospitalization. Methods: Design: We utilized baseline plasma samples randomly selected from 672 individuals with COPD from the Subpopulations and Intermediate Outcomes Measures in COPD Study (SPIROMICS) cohort, which prospectively collected exacerbation numbers and type. The primary endpoint was exacerbation requiring hospitalization. Secondary endpoints included total number of exacerbations (defined as use of oral steroids, antibiotics, or healthcare utilization) and severe exacerbations (defined as requiring emergency room care or hospitalization). Measure: We measured plasma ncfDNA using digital droplet PCR. Analysis: We assessed the association of ncfDNA with exacerbation outcomes using negative binomial regression or Cox regression, adjusting for age, percent post-bronchodilator forced expiratory volume in one second (FEV1), supplemental oxygen use, and smoking status. Results: In total, 57% (n=383) of COPD participants experienced exacerbations, 29% (n=197) at least one severe, and 22% (n=145) requiring hospitalization, the latter at a median of 622 days from enrollment (IQR=287-997). Higher ncfDNA levels at enrollment correlated with measures of COPD severity, including baseline FEV1 (beta = -0.12, 95% CI -0.18 to -0.049, p <0.001). Higher ncfDNA associated with increased risk of COPD exacerbation requiring hospitalization (incidence rate ratio (IRR) 1.40, 95% CI 1.12-1.75, p =0.003) and severe exacerbations (IRR 1.36, 95% CI 1.11-1.67, p=0.002) and a trend towards total exacerbations (IRR 1.11, 95% CI 0.98-1.26, p= 0.09). The primary outcome, risk of time-to-first hospitalization, correlated significantly with higher ncfDNA with hazard ratio (HR) 1.23, 95% CI 1.01-1.49, p=0.037. Conclusion: These results suggest that ncfDNA may serve as a predictor for severe and hospitalization-associated COPD exacerbations. To better understand the relationship between ncfDNA and COPD pathophysiology, follow-up studies should explore longitudinal trends and cfDNA tissue sources, and their link to COPD exacerbations.

Abstract Rationale: We have previously shown reduced total IgG, IgG subclasses, and levels/function of pneumococcal-specific antibodies are associated with increased risk for exacerbations of COPD (ECOPD). The binding of IgG to its receptor, the Fc receptor for IgG (FcγR) on immune cells, has a critical role in determining antibody levels and function. In addition to our research demonstrating that IgG heavy chain gene (IGHG) variants are associated with ECOPD, single nucleotide variants (SNVs) in genes encoding FcγR (FCGR1-3, which encode receptor subtypes FcγRI, FcγRIIa/b/c, and FcγRIIIa/b) may also result in antibody deficiency and increased exacerbation risk. Due to technical challenges in accurately identifying SNVs in FCGR, this region has not been well-characterized. The limited data that exist are from people of European descent, and prior studies have not included African American participants. We therefore sought to investigate the hypothesis that distinct SNVs in genes encoding FcγR are associated with disease severity and history of exacerbations in African American people with COPD. Methods: We developed a novel pipeline to identify SNVs in the coding (CDS) regions of chromosome 1 using short-read whole genome sequence data. The pipeline was benchmarked using paired long-read samples from Genome in a Bottle. SNVs were called within CDS regions and analyzed in a meta-analysis of self-reported African American participants in SPIROMICS and COPDGene (n=3063). Genetic variants were tested for association with COPD severity (GOLD spirometry stage 1-2 vs 3-4) as well as COPD exacerbations, adjusting for age, sex and principal components controlling for population structure. Results: Eight SNVs were significantly associated with frequent ECOPD (≥2 in one year) in the meta-analysis of African American COPDGene and SPIROMICS participants (Table). Seven of these 8 SNVs were found in FCGR3; 4 in the activating FCGR3A subtype, and 3 in FCGR3B. Seven of 11 SNVs associated with COPD severity were in FCGR3 (4 in FCGR3A; 3 in FCGR3B). One SNV (rs371849) was associated with both frequent exacerbations (P=0.002) and COPD severity (P=0.044). Conclusions: We used a cutting-edge variant calling pipeline to identify multiple SNVs in FCGR, primarily involving FcγRIII receptor subtypes, associated with COPD severity and exacerbations in African American participants in SPIROMICS and COPDGene. FcγRIII variants are known to cause impaired antibody levels and function in people of European descent. The structural and functional importance of newly recognized variants in African American cohorts require further study, as they may represent immunogenetic risk factors for antibody deficiency and exacerbations.

Abstract Background: Effective treatments (Tx) are needed for MTAP-del cancers (10-15% of all cancers). BMS-986504 (formerly MRTX1719) is a potential first-in-class MTA-cooperative protein arginine methyltransferase 5 (PRMT5) inhibitor that selectively binds to the PRMT5-MTA complex, a synthetic lethal target in MTAP-del but not MTAP-wild-type cells. In the first-in-human phase 1/2 CA240-0007 study, BMS-986504 was well tolerated and showed clinical activity in heavily pretreated pts across multiple advanced solid tumors with homozygous MTAP-del. Here, we report results of exploratory PD analyses of PRMT5 inhibition with BMS-986504 in CA240-0007. Methods: Pts with advanced, unresectable or metastatic solid tumors with homozygous MTAP-del received BMS-986504 (50 to 800 mg) in 3-wk cycles. Symmetric dimethylarginine (SDMA) and intron retention are known PD BMs of PRMT5 inhibition. Therefore, PD effects of BMS-986504 were assessed via changes in plasma and tumor SDMA levels (mass spec and IHC), intron retention, and gene expression (RNASeq) based on samples collected at baseline (BL) and cycle 2 day 1 (C2D1). Additional analyses correlating efficacy outcomes with PD results and select mutations at BL were performed in clinically evaluable pts as of 19-SEP-24. Results: Robust PD modulation of the PRMT5 pathway was observed with BMS-986504. Among pts with matched samples (n = 63), median plasma SDMA levels were reduced by 56% from BL (122.6 ng/mL) to C2D1 (53.8 ng/mL). There were dose-dependent reductions in median plasma SDMA with the greatest reductions at 400 mg QD (59.7% [n = 20]), 400 mg BID (61.9% [n = 9]) and 600 mg QD (59.1% [n = 14]). These PD effects were corroborated in the tumor. Median tumor SDMA levels decreased from an HScore of 285 at BL to 0 at C2D1. Consistent with the SDMA decreases, increased intron retention was observed in 9/11 pts with matched samples. BMS-986504 led to downregulation of several gene pathways including DNA repair and mitotic spindle formation, and MYC and E2F targets, as assessed by RNASeq. There was no significant change in expression of MAT2A, PRMT5, or other PRMT genes, suggesting a lack of compensation for PRMT5 inhibition through these genes. Responses were observed with BMS-986504 across EGFR, KRAS, and TP53 mutation subgroups. Additional correlative analyses among BMs and efficacy outcomes will be presented. Conclusions: BMS-986504 demonstrated robust PD effects across multiple doses and solid tumors which is consistent with the proposed mechanism of action. There was a trend of increasing plasma SDMA reduction across doses, with the greatest reductions observed at 400 mg QD and above. Together these results support further investigation of BMS-986504 at 400 mg QD and higher doses as a potential first-in-class synthetic lethal Tx option in pts with advanced solid tumors with MTAP-del. Citation Format: Jordi Rodón, Tyler Simpson, Ben George, Pasi A. Jänne, Kathryn C. Arbour, Konstantinos Leventakos, Kyriakos P. Papadopoulos, Melissa L. Johnson, Alexander I. Spira, Cesar A. Perez, Hani M. Babiker, Richard Zuniga, Candace L. Haddox, Tapsi Kumar, Yidi Qin, Wen-Chi Chou, Peter Olson, Kenna Anderes, Alice Wozniak, Curtis Chin, Ming Lei, Jason T. Henry. Pharmacodynamic (PD) and exploratory biomarker (BM) analysis of the PRMT5 inhibitor BMS-986504 in patients (pts) with advanced solid tumors with homozygous MTAP deletion (MTAP-del) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr CT079.

Abstract Rationale Reliable data about the natural history of lung function decline in alpha-1 antitrypsin (AAT)-deficient Pi*MZ heterozygotes is largely missing. Objectives We hypothesized that, in adults with a tobacco smoking history, lung function deteriorates faster in Pi*MZ compared with the Pi*MM genotype. Methods We identified 1,856 Pi*MM and 79 Pi*MZ participants with ⩾20 pack-years tobacco smoking history from the SPIROMICS (Subpopulations and Intermediate Outcomes Measures in COPD Study) cohort by DNA sequencing and followed them over a median of 4.8 years, comparing radiographic and clinical characteristics between the two groups over time using regression models. Results Adjusted for age, sex, race, smoking pack-year history, and smoking status, Pi*MZ participants had a lower baseline percent predicted forced expiratory volume in 1 second (FEV1) (65.4% vs. 75.1%; difference 95% confidence interval [CI], −15.4% to −3.9%), more radiographic emphysema (<−950 Hounsfield units%, 12.9% vs. 7.8%; difference 95% CI, 2.8% to 7.5%), and nonsignificantly lower lung density. In the longitudinal analysis, the FEV1 annual rate of decline was similar in both groups over the course of the study (−34.5 ml/yr vs. −34.6 ml/yr for Pi*MZ and Pi*MM; difference 95% CI, −16.9 to 17.1 ml/yr). There were no significant differences between Pi*MZ and Pi*MM individuals in the annualized change in lung density, emphysema, patient-reported outcomes, exacerbations, or survival. The proportion with faster FEV1 decline (annual loss ⩾40 ml) was similar in Pi*MZ and Pi*MM groups. In both groups, faster FEV1 decline was associated with more air trapping and small airway disease at baseline. In Pi*MZ only, faster decline was associated with higher blood eosinophil counts (310 vs. 220 cells/μl; difference 95% CI, 30 to 140 cells/μl). In the subgroup analysis limited to a small number of currently smoking participants, no significant differences in longitudinal outcomes were found. Conclusions Despite a lower FEV1 and more emphysema at enrollment, the longitudinal analysis did not demonstrate significantly greater lung function decline or lung density loss in Pi*MZ compared with Pi*MM participants with tobacco smoking history. Limited sample size and duration of longitudinal follow-up constrain generalizability of our findings, thus prohibiting the conclusion that longitudinal trajectories did not differ between these groups. However, our results may suggest that earlier life events could be responsible for more extensive lung disease at enrollment in Pi*MZ compared with Pi*MM tobacco-exposed individuals.

AbstractThe vascular system is an intricate system that develops during early periods of embryogenesis. Through a complex signaling pathway of vasculogenesis and angiogenesis, embryonic vessels grow and coalesce, which allows nutrient and waste management. Dysfunction in these endothelial cells gives rise to vascular variants. Throughout gestational development, vascular variants can form in different organ systems such as the thoracic cavity, hepatic, renal, and lower pelvis. It is clinically very important for physicians to recognize these variants, as these variants can predispose to certain illnesses and treatment of patients surgically. This article discusses the embryology and vascular variants of the arterial system with a focus on the thoracic cavity, hepatic, renal, and pelvic variations to help aid in minimizing technical complications during procedures.

Increased infiltration of CD3 + and CD8 + T cells into ovarian cancer (OC) is linked to better prognosis, but the specific antigens involved are unclear. Recent reports suggest that HLA class I can present peptides from noncoding genomic regions, known as noncanonical or cryptic peptides, but their immunogenicity is underexplored. To address this, we used immunopeptidomic analysis and RNA sequencing on five metastatic OC samples, which identified 311 cryptic peptides (40 to 83 per patient). Despite comprising less than 1% of total peptides, cryptic peptides from noncoding transcripts emerged as the predominant antigen class when compared to the other major classes of known tumor-specific and tumor-associated antigens in OC samples. Notably, nearly 70% of the prioritized cryptic peptides elicited T cell activation, as evidenced by increased 4-1BB and IFN-γ expression in autologous CD8 + T cells. This study reveals noncoding cryptic peptides as an important class of immunogenic antigens in OC.