Citations

Abstract Aims To assess the performance of an artificial intelligence-enabled electrocardiogram (AI-ECG) algorithm in identifying patients with moderate to severe aortic stenosis (AS) in an Asian cohort from a tertiary care centre. Methods and results We identified a randomly selected patients ≥60 years old who underwent echocardiography and ECG within in 31 days between 2012 and 2021 at the Samsung Medical Center in Korea. Patients with previous cardiac surgery, prosthetic valves, or pacemakers were excluded. The AI-ECG model, originally developed and validated by Mayo Clinic in the USA, was applied without fine-tuning. Performance metrics, including the area under the curve (AUC), sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy, were calculated to compare AI-ECG predictions with TTE-confirmed AS status. Among 5425 patients, 1095 had moderate to severe AS, and 4330 age- and sex-matched patients without AS were included as controls. The AI-ECG model achieved an AUC of 0.85 (95% CI: 0.84–0.87) in detecting moderate to severe AS. Sensitivity, specificity, PPV, NPV, and accuracy were 0.83, 0.65, 0.37, 0.94, and 68.29%, respectively. The model's performance was consistent across various age and sex subgroups, with sensitivity increasing in older patients. Conclusion The AI-ECG model developed in the USA demonstrated comparable performance in detecting moderate to severe AS in an Asian cohort compared with its original validation population. These findings highlight the potential utility of AI-ECG as a non-invasive screening tool for AS across diverse patient populations.

ABSTRACT Bipolar disorder’s (BD) clinical heterogeneity has an unresolved genetic basis. We meta-analyzed genome-wide association studies (GWAS) of 16 BD subphenotypes in 226,032 individuals from 57 cohorts (38,022 cases); 10 advanced to multivariate and multi-trait analyses. Four factors (compulsive, psychotic, dysregulated, internalizing) explained 82.8% of shared genetic variance. BD1 and BD2 loaded on distinct factors despite a high genetic correlation; 87.0% of common-factor loci were significant in neither subtype. Unipolar mania aligned with psychosis over internalizing, and was distinguishable from BD1, and rapid cycling showed heritable cross-domain liability. We identified 356 risk loci, 158 novel, including the first univariate-GWAS associations for psychosis, unipolar mania, rapid cycling and schizoaffective disorder—and 249 credible genes (89 high-confidence), 12 with approved-drug or clinical-phase annotations. Cell-type association showed a midbrain dopaminergic–GABAergic gradient along the psychotic factor. BD’s genetic architecture appears hierarchical—a general liability resolving into dimensions of course and comorbidity beyond diagnostic subtypes.

Abstract Introduction: Opioid use disorder constitutes a significant health crisis in the United States, contributing to high rates of opioid overdose-related deaths. A major driver of these fatalities is fentanyl, a potent synthetic opioid with both sedative and analgesic properties. These properties that make fentanyl clinically effective also increase its addictive potential. Early in opioid addiction, abnormal increases in extracellular dopamine in the nucleus accumbens (NAc) reinforce excessive drug-seeking behaviors which can lead to fatal respiratory depression. Given this mechanism, we investigated whether high frequency stimulation (HFS), mimicking human deep brain stimulation (DBS) of the ventral tegmental area (VTA) could block NAc dopamine increase following an acute lethal dose of fentanyl. We hypothesized that VTA DBS would mitigate these dopaminergic responses and prevent fentanyl-induced respiratory failure. Methods: Multiple cyclic square wave voltammetry (M-CSWV), was applied via a carbon fiber microelectrode in the NAc of urethane-anesthetized male Sprague-Dawley rats. Dopamine levels were recorded at baseline and following acute fentanyl (30 µg/kg, i.v.). HFS (130 Hz frequency, 200 µsec pulse width, and 0.2 mA amplitude) was administered to the VTA before and during fentanyl exposure. Results: Acute fentanyl administration resulted in a 178.2% increase in NAc dopamine levels from baseline, accompanied by a decline in respiratory rates to critically low levels (45 breaths per minute vs. 102 bpm), eventually resulting in 100% mortality. HFS of the VTA did not significantly alter baseline tonic dopamine levels or prevent fentanyl-induced dopamine increase in the NAc but was able to fully rescue fentanyl-induced respiratory failure.

Abstract Predicting host phenotypes from shotgun metagenomic data is essential for translating microbiome research into clinical practice)Despite the development of numerous computational tools for this task, researchers often default to traditional machine learning methods such as Random Forest)This hesitancy to adopt newer methods stems from their complexity as well as the lack of standardized evaluations, as most tools are assessed on different datasets and compared against a limited set of methods)Here, we introduce LAMPP, a standardized benchmark for evaluating methods for predicting host phenotypes from gut metagenomic data)LAMPP features a diverse range of prediction tasks and enables consistent, comparative assessments across prediction tools)Our systematic evaluation of existing tools shows that classic machine learning methods (e.g., Random Forest) perform competitively, offering both ease of use and state-of-the-art results)At the same time, it demonstrates that microbiome-based phenotype prediction remains a challenging problem)By providing a consistent platform for ongoing evaluation and access to raw sequencing data, LAMPP motivates the development of novel prediction pipelines from raw sequencing data to phenotype prediction, including novel sample representation and data augmentation strategies)LAMPP is publicly available for ongoing benchmarking at https://lampp.yassourlab.com/ .

PURPOSE Tumor treating fields (TTFields) use alternating electric fields to disrupt cancer cell proliferation. Feasibility of TTFields therapy with gemcitabine/nab-paclitaxel was previously demonstrated in patients with advanced pancreatic adenocarcinoma. PANOVA-3 was designed to confirm safety and efficacy of TTFields in patients with unresectable locally advanced pancreatic adenocarcinoma (LA-PAC). METHODS In this global phase III trial, 571 patients with newly diagnosed LA-PAC were randomly assigned to receive gemcitabine 1,000 mg/m 2 and nab-paclitaxel 125 mg/m 2 by intravenous infusion once a day on days 1, 8, and 15 of a 28-day cycle with or without TTFields. The primary end point was overall survival (OS). Secondary end points included progression-free survival (PFS), local PFS, pain-free survival, and overall response rate (ORR). Distant PFS was analyzed post hoc. RESULTS OS was significantly prolonged using TTFields with gemcitabine/nab-paclitaxel versus gemcitabine/nab-paclitaxel (median, 16.2 months [95% CI, 15.0 to 18.0] v 14.2 months [95% CI, 12.8 to 15.4]; hazard ratio [HR], 0.82 [95% CI, 0.68 to 0.99]; P = .039). PFS, local PFS, and ORR were not improved. Pain-free survival was significantly prolonged with TTFields with gemcitabine/nab-paclitaxel (median, 15.2 months [95% CI, 10.3 to 22.8] v 9.1 months [95% CI, 7.4 to 12.7]; HR, 0.74 [95% CI, 0.56 to 0.97]; P = .027), as was distant PFS (median, 13.9 months [95% CI, 12.2 to 16.8] v 11.5 months [95% CI, 10.4 to 12.9]; HR, 0.74 [95% CI, 0.57 to 0.96]; P = .022). Device-related skin adverse events (AEs) were experienced by 76.3% of patients. Most device-related skin AEs were mild to moderate, with 7.7% of patients reporting a grade 3 AE. CONCLUSION This study demonstrated significant OS, pain-free survival, and distant PFS benefits for TTFields with gemcitabine/nab-paclitaxel versus gemcitabine/nab-paclitaxel in patients with unresectable LA-PAC, with no additive systemic toxicity.

1001 Background: Imlunestrant (imlu) is a next-generation, brain-penetrant, oral selective estrogen receptor degrader. The EMBER-3 trial, in patients (pts) with ER+, HER2- ABC who had disease progression on or after aromatase inhibitor-based therapy, showed significant progression free survival (PFS) improvement with imlu vs standard therapy (SOC, fulvestrant or exemestane) in pts with ESR1 mutations ( ESR1 m), and with imlunestrant+abemaciclib (imlu+abema) vs imlu in all pts, regardless of ESR1 m. Exploratory PRO analyses are presented here. Methods: EORTC QLQ-C30 was administered at baseline (BL) and every 8 weeks until treatment discontinuation. Prespecified QLQ-C30 analysis used a longitudinal mixed model for repeated measures to calculate mean change from BL in pts with BL and ≥1 post-BL score. PRO-CTCAE (diarrhea frequency) was administered weekly, reporting 0 (never) to 4 (almost constantly). PRO-CTCAE (injection site reaction [ISR]) was administered to fulvestrant recipients weekly for 2 weeks post-injection, reporting yes/no (pain, swelling, redness). Descriptive analysis was used for PRO-CTCAE. Results: In pts with ESR1 m, imlu monotherapy was associated with many improved or maintained EORTC QLQ-C30 scores, whereas scores with SOC were declined or maintained. Specifically, pts with ESR1 m on imlu had improved global health status (GHS)/quality of life (QOL) and physical function (PF) scores, while scores with SOC declined (mean change differences between treatments: 9.9 [0.1, 19.7] and 6.2 [-0.8, 13.1], respectively). These PRO findings mirror the PFS findings in this group. In the overall population, GHS/QOL scores declined similarly with imlu vs SOC (mean change differences: 0.5 [-4.7, 5.7]), while PF scores were maintained with imlu vs a slight decline with SOC (mean change difference: 2.5 [-1.1, 6.1]). Most fulvestrant recipients (72%) reported ISR at any time while on treatment, with a mean of 31% during the first week of the first 6 cycles. Imlu+abema vs imlu showed broadly similar declines in all pts, with minimal mean change differences in GHS/QOL and PF scores (0.8 [-7.4, 5.9]; -2.2 [-6.6, 2.2], respectively). Pts reported similarly low rates of “frequent” or “almost constant” diarrhea with imlu (3%) and SOC (2%) and higher rates with imlu+abema (22%). Conclusions: PROs from EMBER-3 demonstrated that patients with ESR1 m had better GHS/QOL and PF with imlu vs SOC, mirroring efficacy results. While the frequency of CTCAE defined ISRs was low, the high rate of PRO-CTCAE ISR demonstrates that this clinically relevant adverse event is underappreciated by physicians. Additionally, all pts had generally comparable GHS/QOL and PF with imlu+abema vs imlu. Overall, these results support the efficacy and safety of imlu compared to existing SOC. Clinical trial information: NCT04975308 .

AbstractINTRODUCTIONThis study investigated the role of the ubiquitin–proteasome system (UPS) in dominantly inherited Alzheimer's disease (DIAD) by examining cerebrospinal fluid (CSF) levels of UPS proteins.METHODThe SOMAscan assay was used to detect changes in UPS proteins in mutation carriers (MCs) relative to disease progression; imaging and CSF biomarkers of amyloid, tau, and neurodegeneration measures; and Clinical Dementia Rating scale.RESULTSSubtle increases in specific ubiquitin enzymes were detected in MCs up to two decades before symptom onset, with more pronounced elevations in UPS‐activating enzymes near symptom onset. Significant correlations were found between UPS proteins and Alzheimer's disease (AD) biomarkers, especially between autophagy markers and late‐stage tau biomarkers, microglia, and axonal degeneration.DISCUSSIONThe rise in UPS proteins alongside tau‐related markers suggests UPS involvement in tau neurofibrillary tangles. Elevated CSF UPS proteins in DIAD MCs may serve as indicators of disease progression, and may support the UPS as a therapeutic target in AD.Highlights This study investigates the ubiquitin‐proteasome system (UPS) in Dominantly Inherited Alzheimer's Disease (DIAD), highlighting early molecular changes linked to disease progression. Using SOMAscan proteomics, we identified significant UPS protein alterations in cerebrospinal fluid of mutation carriers, notably up to 20 years before clinical symptom onset. Correlations between UPS protein levels and Alzheimer's biomarkers, particularly tau and neurodegeneration markers, suggest a strong association between UPS dysregulation and tau pathology in DIAD. Dynamic UPS changes align with A/T biological staging: UPS proteins were shown to increase across Aβ/tau (A/T) groups, with largest increases in the A+/T+ group, reinforcing their role in late‐stage tau pathology and disease progression. These findings underscore the potential of UPS proteins as early biomarkers for Alzheimer's disease progression and as novel therapeutic targets, especially in tau‐pathology‐driven neurodegeneration. This work contributes to understanding AD pathogenesis, by emphasizing the importance of protein quality control systems and by offering avenues for future biomarker discovery and therapeutic development in Alzheimer's disease.

Abstract Background:Chronic obstructive pulmonary disease (COPD) is a major global health burden, with genome-wide association studies explaining only a fraction of its heritability. Recent advancements, including large-scale, multi-ancestry whole-genome sequencing and a focus on severe, early-onset cases, offer promising avenues to identify additional COPD-related variants. Furthermore, recent studies show that adjusting for polygenic risk scores (PRS) enhances statistical power to detect rare variants, advancing efforts to understand COPD's genetic basis. Methods:We performed a whole genome sequencing association study of severe, early-onset COPD (FEV1 < 50%, age ≤ 55), FEV1 and FEV1/FVC in eight population-based studies (ARIC, CARDIA, CFS, CHS, FHS, HCHS/SOL, JHS, MESA) and seven COPD-enriched studies (COPDGene, ECLIPSE, Boston Early-Onset COPD Study, LTRC, TCGS (Poland), ICGN, SPIROMICS). We performed single-variant analyses using regenie software, applying a genome-wide significance threshold of P < 5.0 x 10-8. For rare variant set (MAF <1%) analysis, we annotated variants with loss of function or deleterious missense using WGS Annotator and prediction tools LOFTEE, SIFT, and PolyPhen2, then analyzed these variants with SKATO-ACAT method in regenie, adjusting for covariates including sex, sequencing center, and principal components of ancestry. We additionally evaluated adjusting the analyses for PRSs for lung function traits. Results: We analyzed 53,028 participants including 34,751 European, 12,508 African, 1,088 Latino American, and 674 East Asian ancestry. Across cohorts, we analyzed 5,063 severe (FEV1 < 50%) COPD cases, among whom 1,103 were early-onset (age ≤ 55). Excluding variants within 1 Mbp of known variants, single-variant analysis identified 68 novel associations (MAC ≥ 30), with 8 common associations (MAF ≥ 1%) in 6 genomic regions. Our most significant novel association for severe early-onset COPD was rs74297390 (intergenic to POM121L12, MAF = 9.6%, Beta = 0.41, P = 3.5 x 10-8). For FEV1 and FEV1/FVC ratio, variants near DKK2 and AKR1E2 were significantly associated and were replicated in an independent dataset (Shrine et al., 2019). DKK2 is an antagonist in the Wnt pathway. In a preliminary variant set analysis, CHRM3-AS1 was associated with severe early-onset COPD, GPAT with FEV1, and COL8A1I and HMCN1 with FEV1/FVC. With PRS adjustment, ST6GALNAC5 was associated with FEV1/FVC. Conclusions: In a whole genome sequencing study of lung function and severe early-onset COPD, we identified new loci for COPD-related phenotypes, including two novel loci that replicated in an independent dataset. Ongoing work involves variant set-based analyses with additional covariate adjustments, as well as PRS adjustments for binary traits.

PURPOSE The combination of the Bruton tyrosine kinase inhibitor ibrutinib with bendamustine-rituximab for first-line treatment of mantle cell lymphoma (MCL) prolonged progression-free survival (PFS), but without improvement in overall survival (OS), likely because of toxicity. Acalabrutinib was shown to be efficacious and less toxic than ibrutinib in a head-to-head trial in chronic lymphocytic leukemia and therefore might lead to better outcomes in MCL. METHODS Patients 65 years and older with previously untreated MCL received acalabrutinib (100 mg twice daily) or placebo (until disease progression or unacceptable toxicity), plus six cycles of bendamustine (90 mg/m 2 once daily; days 1 and 2) and rituximab (375 mg/m 2 as a single dose; day 1) followed by rituximab maintenance in responding patients for 2 years. Crossover to acalabrutinib at disease progression was permitted. The primary end point was PFS per the independent review committee; overall response rate and OS were secondary end points. RESULTS In total, 598 patients were randomly assigned, with 299 in each arm. At a median follow-up of 49.8 months using the reverse Kaplan-Meier method, the median PFS was 66.4 months in the acalabrutinib arm and 49.6 months in the placebo arm (hazard ratio [HR], 0.73 [95% CI, 0.57 to 0.94]; P = .0160). Benefit was seen across all subgroups, including those with high-risk features. Overall response/complete response rates were 91.0%/66.6% and 88.0%/53.5% in the acalabrutinib and placebo arms, respectively. OS was not significantly different (HR, 0.86 [95% CI, 0.65 to 1.13]; P = .27). Grade 3 or greater adverse events were reported in 88.9% and 88.2% in the acalabrutinib and placebo arms, respectively. CONCLUSION The combination of acalabrutinib with bendamustine-rituximab significantly improved PFS. Clinical benefit of acalabrutinib with bendamustine-rituximab was achieved with manageable toxicity.

Background: Tumor immune microenvironment (TIME) organization fundamentally shapes cancer progression and immunotherapy outcomes. Traditional 2D spatial molecular approaches inadequately capture the complex three-dimensional architecture and cellular interactions within TIME. We developed an AI-driven platform integrating multiple spatial molecular datasets, enabling comprehensive 3D visualization for therapeutic discovery and patient selection. Methods: Our platform combines holotomography imaging, providing 3D refractive index maps, with diverse spatial molecular data: in situ molecular imaging, spatial proteomics, multiplex immunohistochemistry, and spatial transcriptomics. AI algorithms align datasets within a unified 3D coordinate system, while Poisson implicit surface reconstruction generates subcellular-resolution models. Platform validation used clinical samples from immunotherapy-treated patients. Results: The platform integrated multimodal spatial data into high-resolution 3D TIME representations, revealing novel relationships between protein expression, transcriptional patterns, and cellular architecture. 3D surface protein analysis with subcellular morphology identified patients with target protein expression outside tight junctions, indicating higher risk for adverse effects from antibody-drug conjugates and cellular therapies. This insight, unavailable through 2D analysis, enabled precise patient selection. Conclusions: This platform provides detailed subcellular-resolution TIME architecture analysis, offering actionable insights for therapeutic targeting, biomarker discovery, and patient selection. AI-driven 3D spatial multimodal TIME analysis advances precision medicine across multiple therapeutic approaches, including immunotherapy, targeted therapy, and drug delivery optimization. AI Disclosure: Original abstract content was written by the authors. Claude was used for editorial assistance and formatting without altering the scientific content or context of the work. Citation Format: Inyeop Jang, Yoonho Choi, Minji Kim, Jeonghwan Park, Jiyeon Sung, Byungsoo Ann, Clemenceau R. Jean, TaeHyun Hwang. AI-enabled 3D multimodal integration platform reveals subcellular architecture of tumor immune microenvironment for therapeutic target and biomarker discovery and patient selection [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3648.