Faculty Bibliography

BACKGROUND/UNASSIGNED:Coronary heart disease (CHD) is the leading cause of morbidity and mortality worldwide, yet current prediction tools do not fully capture sex differences in risk. Menopause further modifies women's risk of CHD, but underlying molecular mechanisms are not well understood. Proteomic profiling may provide new insights into these mechanisms. METHODS/UNASSIGNED:We analyzed 4,877 SomaScan™-based plasma proteins in 10,034 Atherosclerosis Risk in Communities (ARIC) participants. Using linear regression, we identified sex- and menopause-related differences in circulating protein concentrations. We performed pathway enrichment analyses to capture underlying biological mechanisms. To evaluate the associations between proteins and incident CHD and differences by sex or menopause status, we applied Cox regression. Finally, we used LASSO regression to identify proteins that improve CHD risk prediction beyond an established clinical model. RESULTS/UNASSIGNED:We observed significant differences in circulating proteins by sex and menopausal status, including early changes during the menopausal transition. We found protein associations with incident CHD differed markedly by sex and menopausal stage: eight proteins were associated with CHD in men, compared with 54 in women, and six and 17 proteins in peri‑ and postmenopausal women, respectively. In risk prediction analyses, adding sex-specific protein panels improved CHD prediction (ΔC-statistic=0.05 in men and 0.03 in women), with similar improvement across menopausal stages. CONCLUSIONS/UNASSIGNED:Proteomic profiles underlying CHD risk differ substantially by sex and menopausal stage. These findings suggest potential biological heterogeneity in CHD and support the study of sex- and menopause-related differences in underlying mechanisms.

This study explored the effects of three diets differing in the amount and type of carbohydrates on peripheral immune markers. After a 15% weight loss with a very-low-carbohydrate diet (VLCD), participants were randomized to isocaloric diets: VLCD, high-carbohydrate diet with high starch content (HC-Starch), or high-carbohydrate diet with high sugar content (HC-Sugar). Changes in peripheral immune markers were assessed in 44 participants using multimodal analyses before randomization and after 10 weeks on the diet. In HC-Starch, cytometry by time of flight (CyTOF) revealed significant shifts in proportions of circulating natural killer (NK) cells and increased activation markers in NK cells, monocytes, T cells, dendritic cells, and neutrophils. In agreement, transcriptomics showed upregulation of immune and metabolic pathways with HC-Starch but reductions with HC-Sugar. Cytokine analysis and mouse experiments suggested that increased adipsin and complement activation could underlie these changes. Following weight loss with VLCD, starch-rich diets serve as an unrecognized driver of inflammation. This study was registered at ClinicalTrials.gov: NCT03394664.

OBJECTIVE:Psoriatic arthritis (PsA) is a chronic immune-mediated arthritis affecting approximately 30% of individuals with psoriasis. The mechanisms driving PsA joint inflammation remain incompletely defined. METHODS:To address this gap, we performed multimodal single-cell sequencing of immune cells from matched peripheral blood and synovial fluid (SF) from 6 PsA patients, with comparisons to a rheumatoid arthritis (RA) patient and 6 healthy controls (HC). RESULTS:T cells. Cell-cell communication analysis highlighted CXCR6-CXCL16 and CXCR3-CXCL10 chemokine axes as mediators of immune cell recruitment and retention, while in vitro assays showed enhanced migration of PsA SF T cells toward a CXCL16 gradient relative to paired blood. CONCLUSION/CONCLUSIONS:CD4 T cells in PsA are cytotoxic and antigen-responsive, contributing to joint inflammation following recruitment by CXCL16-producing dendritic cells.

BACKGROUND:Major breakthroughs in the clinical application of liquid biopsies, such as the use of salivary samples to detect biomarkers for the early detection of diseases and conditions, are on the horizon. Historically, late detection of oral cancer has contributed to high morbidity and mortality, making scientific advancements in this field particularly impactful. This guideline evaluates and provides recommendations for commercially available salivary adjunct tests in the United States designed specifically for screening adults without mucosal abnormalities and for determining the need for biopsy among adults with mucosal abnormalities of the oral cavity or lip. TYPES OF STUDIES REVIEWED/METHODS:The researchers used living systematic review methodology to identify evidence on the benefits and harms of salivary adjunct tests. They also conducted a scoping review of patient and clinician values and preferences regarding the use of these adjuncts and evaluated data on other contextual factors, including costs, equity, acceptability, and feasibility of these tests. The guideline panel formulated a recommendation after applying the Grading of Recommendations Assessment, Development and Evaluation Evidence to Decision framework. RESULTS:The panel issued 2 research-only recommendations, limiting the use of salivary adjunct tests for early oral cancer detection to research settings: 1 for adults with oral mucosal or lip abnormalities, and 1 for adults without mucosal abnormalities. Three good practice statements were also formulated: 2 recommending the performance of clinical oral examinations for all adult patients, and 1 recommending biopsy or referral for adult patients with persistent oral mucosal abnormalities. PRACTICAL IMPLICATIONS/CONCLUSIONS:All adult patients should receive a clinical oral examination. When a mucosal abnormality is identified, biopsy remains the reference standard for establishing a definitive diagnosis. Salivary diagnostic adjuncts, whether used to screen asymptomatic adults or to determine the need for biopsy in adults with mucosal abnormalities, should not be used in regular clinical practice or as a public health screening measure outside of a research setting. Further research is needed to establish the potential role of salivary adjunct tests in clinical practice.

BACKGROUND/UNASSIGNED:Treatment options for refractory gastric cancer are limited. Preclinical data suggest interplay between angiogenesis and immune regulation, with vascular endothelial growth factor impairing antitumor immunity through decreasing antigen presentation, effector function, and immune cell trafficking. This phase II study evaluated lenvatinib plus pembrolizumab in the refractory setting. PATIENTS AND METHODS/UNASSIGNED:Eligible patients had advanced gastric or gastroesophageal junction adenocarcinoma with measurable disease, Eastern Cooperative Oncology Group ≤ 1, and progression after ≥1 prior therapy, without prior immune checkpoint inhibitor exposure. Patients received pembrolizumab 200 mg i.v. every 21 days and lenvatinib 20 mg orally daily, with a 7-day lead-in. Primary endpoint was objective response rate. Using Simon optimal two-stage design, 29 patients were planned; the study would be considered positive if ≥6 responses were observed. Secondary endpoints included safety, progression-free survival (PFS), and overall survival (OS). RESULTS/UNASSIGNED:Enrollment was prematurely suspended at 24 patients due to evolving practice patterns. Median age was 63 years; 75% were male; 63% were White. Seven patients (29%) received ≥2 lines of therapy. Among 20 assessable patients, 5 (25%) achieved partial responses, including 2 with combined positive score (CPS) <1 tumors. Median duration of response was 31.6 weeks. Median PFS and OS were 12.9 and 21.4 weeks, respectively. Treatment was well tolerated with no new safety signals. CONCLUSIONS/UNASSIGNED:Lenvatinib plus pembrolizumab did not meet the predefined efficacy threshold in the overall cohort. However, treatment was well tolerated and encouraging responses were seen in patients with CPS <1 tumors. Although the sample size was limited, these findings suggest that further investigation of this treatment strategy in patients with CPS < 1 disease may be warranted.

Treatment strategies for relapsed/refractory large B-cell lymphoma (R/R LBCL) have evolved rapidly, yet relationships between therapy selection and outcomes remain poorly defined. The LEO CReWE study evaluated disease characteristics, patterns of care, and outcomes in 1504 patients with R/R LBCL from 2002 to 2022. Of these, 64% received chemoimmunotherapy at second-line (2L). Autologous stem cell transplant (ASCT) and/or chimeric antigen receptor T-cell therapy (CAR-T) were planned at 2L for 984 patients (65%), with 471 (31%) ultimately receiving ASCT and 94 (6%) receiving CAR-T. Complete response (CR) rates at 2L ranged from 24% for lenalidomide-based regimens to 49% for CAR-T; salvage chemotherapy achieved a 44% CR rate overall and 60% among patients who eventually underwent ASCT. Median event-free and overall survival from 2L were 4.3 months and 18.3 months, respectively; survival improved in eras during which CAR-T was available. Patients intended for but unable to receive ASCT or CAR-T experienced poor outcomes comparable to those never intended for curative therapy at 2L. The LEO CReWE study represents the first large-scale depiction of 2L treatment patterns and outcomes for LBCL in the modern era, inclusive of all treatment approaches, and underscores the ongoing need for more effective therapies despite the advent of CAR-T.

BACKGROUND:Most eligible patients are not prescribed guideline-directed medical therapy for heart failure with reduced ejection fraction (EF). Increased time pressures for providers in the ambulatory setting may contribute to these shortfalls. We assessed the association between cardiologist ambulatory workload and guideline-directed medical therapy prescription for patients with heart failure with reduced EF. METHODS:This was a cross-sectional study of patients with heart failure with reduced EF (EF ≤40%) seen by a cardiologist from October 1, 2022, to September 30, 2023, using deidentified administrative and electronic health record data from Optum Labs Data Warehouse, which includes data from multiple health systems across the United States. The primary exposure was ambulatory workload, measured as the average number of visits per day, categorized into quartiles. The primary outcome was "comprehensive quadruple therapy," defined as prescription for all 4 guideline-directed medical therapies: β-blocker; angiotensin receptor-neprilysin inhibitor; mineralocorticoid receptor antagonist; and sodium-glucose cotransporter 2 inhibitor. Analyses were conducted using generalized estimating equations, adjusted for demographic and clinical variables. RESULTS:value=quartile 1: 1.35 [1.09-1.66], 0.008; quartile 2: 1.20 [1.00-1.43], 0.050; quartile 3: 1.11 [0.93-1.32], 0.28; quartile 4 [reference]). CONCLUSIONS:Seeing a cardiologist with lower ambulatory workload was associated with increased prescribing of guideline-recommended, life-saving therapy in patients with heart failure with reduced EF. Current models that incentivize more visits per day may negatively impact care in the ambulatory setting.

AIMS/OBJECTIVE:Plaque erosion accounts for up to 40% of acute coronary syndromes. Unlike plaque rupture, erosion is characterized by thrombus formation on an intact fibrous cap following endothelial denudation. Rupture is associated with broad inflammatory activation, whereas erosion features accumulation of specific immune cells, particularly CD4+ and CD8+ T cells. Their functional programming remains insufficiently defined.The objective was to characterize intracoronary and peripheral T cell phenotypes, activation programs, and clonal architecture in acute coronary syndromes caused by plaque erosion compared with plaque rupture. METHODS AND RESULTS/RESULTS:We prospectively enrolled 133 consecutive patients with acute coronary syndromes in whom plaque erosion or rupture was classified by optical coherence tomography. Blood was sampled from the coronary segment proximal to the lesion and from the peripheral circulation. T cell phenotypes were assessed by flow cytometry and plasma proteomics. In a subgroup, intracoronary samples underwent CITE-seq, integrating single-cell transcriptomics with surface protein profiling, together with paired T cell receptor sequencing. RESULTS:Flow cytometry demonstrated enrichment of activated memory helper and cytotoxic T cells with anti-inflammatory features at erosion sites, in contrast to predominantly naive and pro-inflammatory T cells in rupture. CITE-seq revealed erosion-specific activation of pathways related to proliferation, adhesion, and tissue repair, whereas T cells in rupture displayed enhanced inflammatory pathways. Functional validation confirmed greater IL-2/IFN-γ induction in rupture-associated memory T cells and greater IL-10 induction in erosion-associated Tregs. T cell receptor sequencing showed greater clonal expansion in erosion, suggesting antigen-experienced clonal selection, whereas rupture exhibited broader and less focused clonal diversity. CONCLUSIONS:Plaque erosion and plaque rupture show fundamentally different T cell immune profiles. Erosion is marked by memory-skewed, clonally expanded regulatory and cytotoxic T cell subsets, while rupture is characterized by proinflammatory phenotypes, diverse T cell receptor repertoires, and heightened inflammatory signaling. These findings support morphology-tailored immunotherapeutic approaches, including established anti-inflammatory strategies for rupture and selective T cell-directed interventions for erosion.

BackgroundLupus nephritis (LN) affects over 60% of patients with systemic lupus erythematosus and is a risk factor for progression to end stage kidney disease. Guidelines recommend high dose parenteral methylprednisolone "pulses" for induction, although intravenous pulse therapy has not been rigorously compared to oral therapy. In this observational study, we report the outcomes of 17 patients who initiated therapy for LN with high dose oral dexamethasone.MethodsLN patients treated with oral dexamethasone between December 2021, and January 2025, were identified and baseline characteristics were recorded. Patients were assessed for a complete renal response (CRR, uPCR < 500, eGFR > 80%), satisfactory renal response (SRR, uPCR < 700, eGFR > 80%), or partial renal response (PRR, uPCR ≤ half of baseline uPCR, eGFR > 80%) at 1 year after receipt of dexamethasone. Responses were compared to outcomes in the BLISS-LN, AURORA and REGENCY trials.ResultsSeventeen patients with LN treated with induction dexamethasone were identified. The average age was 40 years old, and 15 patients were female. Six patients were of African ancestry, four Hispanic ethnicity, and three were White. Fourteen patients had proliferative LN. 47% of patients achieved a CRR, 59% obtained a SRR, and 53% obtained a PRR. Renal outcomes compared favorably to outcomes in the active arms of the BLISS-LN, AURORA 1, and REGENCY studies. Biomarkers including C3, C4, and dsDNA antibodies improved throughout the period. Proteinuria declined in 14 of 17 patients.ConclusionPatients with LN initially treated with oral dexamethasone in place of intravenous pulse methylprednisolone achieved responses similar to outcomes in recent LN trials. Dexamethasone is a promising potential oral option to initiate treatment for LN obviating need for parenteral therapy.

Immune checkpoint inhibitors (ICIs) have transformed the treatment of advanced non-small cell lung cancer (NSCLC), yet a large proportion of patients do not respond. The lung microbiome is a key modulator of antitumor immunity, however, the functional contribution of active microbial communities and their interaction with host transcriptional programs in shaping ICI outcomes remain poorly defined. Here, we prospectively analyzed bronchoalveolar lavage (BAL) samples from 71 NSCLC patients prior to ICI initiation. We profiled the microbiome and host transcriptome in the BAL to look for microbial and host signatures in the lower airways associated with treatment response. We found that enrichment of the lower airway microbiome with oral commensals was associated with disease progression and worse prognosis of patients treated with ICI. Metatranscriptomics-derived microbial clustering revealed distinct functional profiles. The microbial cluster enriched with oral commensals, which was only present among patients with poor response to ICI, had differential regulation of pathways involved in the metabolism of short-chain fatty acids, methane, and pyruvate. This cluster also correlated with host immune pathways including upregulation of interferon signaling, neutrophil degranulation, and mitophagy, all of which could contribute to the poor response to immunotherapy. In a preclinical murine model of lung cancer with dysbiosis, inoculating lung tumor-bearing mice with oral commensals increased intratumoral neutrophils and Th17 responses and impaired ICI efficacy. Our findings support the concept that microbial communities in the lower airways influence tumor-immune interactions via defined metabolic-immune axes.