Citations

Abstract Introduction Alzheimer’s disease (AD) is characterized by pathologies including amyloid, tau, neurodegeneration reflected in established blood biomarkers and track with clinical changes. However, the association between peripheral cell-specific signatures and AD-related phenotypes remain poorly characterized. Methods We analyzed bulk blood transcriptome data from the Mayo Clinic Study of Aging (MCSA) and Emory University Vascular study. We used BayesPrism, CIBERSORTx, and an in-house pipeline CNNreg to deconvolute these data and obtain peripheral cell proportions. Cell type specific transcripts were estimated with BayesPrism. We compared cell proportions between cases (AD/MCI) and controls. Association analysis was performed between cell type specific transcripts and AD-related phenotypes including diagnosis and cognition. Meta-analysis of transcripts associations and gene ontology analysis were conducted to assess the enriched pathways for significant genes. Results In MCSA, B and CD4+ T cells proportions are significantly lower while that of myeloid cells higher in cases. The Emory cohort had similar trends. We identified transcripts associated with AD-related phenotypes in CD4+ T and CD8+ T cells. In CD4+ T cells, transcripts downregulated in case are enriched in response to stimulus pathway, whereas those upregulated in negative regulation of immune response. Downregulation of CD4+ T genes enriched in extracellular matrix disassembly and epigenetic regulation and upregulation of those in protein localization associate with better cognition. In CD8+T cells, genes pertinent to vascular development were downregulated while those to metabolic processes were upregulated in cases. Downregulation of CD8+T genes involved in lipid transportation and upregulation of those in mitochondria associate with better cognition. Conclusion We identified peripheral cellular transcriptional changes associated with AD/MCI phenotypes and involved in important biological pathways, revealing potential disease mechanisms in AD. Funding Source RF1 AG051504 Topic Categories Neuroimmunology (NEUR)

Abstract Introduction Despite its prevalence, risk stratification for tachycardia-induced cardiomyopathy remains poorly understood. A deep learning model developed at Mayo Clinic uses standard 12-lead electrocardiograms (ECGs) to predict reduced LVEF (≤35%) in the general population with high accuracy (AUC 0.93) Purpose We investigated the performance of AI-ECG in predicting systolic dysfunction among patients with atrial fibrillation and rapid ventricular response, and compared it with NT-proBNP. Methods We conducted a retrospective study (IRB approval #25-000904) of adult patients (age ≥ 18 years) evaluated across our Clinic enterprise with atrial fibrillation and rapid ventricular response (heart rate >100 bpm), including AF occurring in-hospital and AF at presentation, between January 2017 and May 2025. We excluded patients with a known history of heart failure with reduced EF (<50%). We also collected data on NT-proBNP levels when available within one week of the ECG and echocardiogram. Results A total of 11,801 patients were included, with a mean age of 73.2 +- 12.6 years, 48.6% female and 94.8% White. A combination of AI ECG low EF probability cutoff of 75% had specificity of 96% and 98% NPV in ruling out LVEF < 35%. A combination of AI ECG low EF probability cutoff of 17% and LVEF <35% provided the best balance of sensitivity and specificity, 66% and 78%, respectively with an accuracy of 78%. NT-proBNP data was available on 5,279 patients (48%). Mean NT-proBNP level was 4090 pg/mL. Based on ROC curve analysis, AI ECG was superior to NT-proBNP in predicting LVEF <35% (AUC 0.72 vs 0.59), with accuracy of 77% versus 47% at Youden’s cutpoints of AI-ECG probability of 17% and NT-proBNP level of 1767 pg/mL, respectively Conclusions Our study demonstrates the utility of AI-ECG in predicting reduced LVEF among patients with AF RVR. AI-ECG demonstrated excellent specificity and NPV in ruling out reduced LVEF, serving as a powerful clinical screening tool to assist with the pharmacologic choice of rate control and could change the timing of further echocardiographic evaluation. Our study offers novel insights paving the way for future investigations to help fine-tune and further delineate the role of AI ECG in risk stratifying patients with suspected tachycardia-induced cardiomyopathy, guiding therapeutic and diagnostic clinical decisions

Abstract The trabecular meshwork (TM) and ciliary body (CB) regulate aqueous humor dynamics and intraocular pressure (IOP), and TM/Schlemm’s canal (SC) dysfunction underlies glaucoma. Here, we present a spatially resolved multi-omics atlas of human TM and CB, integrating snRNA-seq, scRNA-seq, and snATAC-seq from over one million cells and nuclei across 112 donors with Xenium spatial transcriptomics. We identified 9 major cell classes and 21 cell types, revealing heterogeneity, including undercharacterized fibroblast and epithelial subpopulations. Spatial mapping supported TM fibroblast zonation and CB epithelial organization. Regulatory analyses identified cell type–specific programs, including OTX/PAX networks in CB epithelium and SMAD3/TGF-β signaling in fibroblasts. Integration with glaucoma loci showed enrichment of non-coding variants in regulatory elements associated with POAG and PACG. Age- and ancestry-associated remodeling revealed divergent fibroblast aging with increased PIEZO1 , suggesting impaired outflow and elevated IOP. Together, this high-resolution atlas links cellular, regulatory, and genetic variation to anterior segment function and glaucoma susceptibility.

TPS6138 Background: Patients with early-stage oral cavity cancer (OCC; T1-2N0M0; AJCC 8th edition) have a 20-30% risk of occult nodal metastases despite clinical and radiographic evaluations. Standard-of-care treatment for most patients includes elective neck dissection (END), which requires surgical removal of the regional cervical lymph nodes, even though 70-80% of these necks are disease-free. Sentinel lymph node biopsy (SLN Bx), a less invasive procedure, could assess the first echelon lymph nodes as an alternative to END, potentially reducing morbidity and costs. A pivotal clinical trial comparing SLN Bx to END (NCT#04333537) is underway to inform efforts to establish optimal disease management for early-stage OCC. Methods: To assess the efficacy of SLN Bx in this population, we activated an international, multi-institutional, prospective phase II/III trial in July 2020, randomizing patients to two surgical arms: SLN Bx and END. A node-negative 18 F-FDG PET/CT imaging biomarker study with centralized read was required before randomization. OCC patients with a positive PET/CT remained in a registry to compare imaging findings with final neck pathology. Given the current evidence on morbidity for SLN Bx versus END, the phase II was designed to determine whether the change in patient-reported neck and shoulder function and related quality of life (QOL) from baseline to 6 months after surgery, using the Neck Dissection Impairment Index (NDII), showed a signal of superiority of SLN Bx compared to END (minimum important difference ³ 7.5; one-sided a = 0.10; 90% power). As of December 2024, 261 patients had been randomized and 203 were analyzed for the “Go/No-Go” decision to move forward into phase III. The phase III portion is a non-inferiority (NI) trial with disease-free survival (DFS) as the primary endpoint (NI margin hazard ratio 1.34 based on a 5% absolute difference in 2-year DFS; one-sided a = 0.05; 80% power, and two interim looks). The change in NDII from baseline to 6 months after surgery is a hierarchical co-primary endpoint for phase III. Phase III opened in October 2025 upon receiving a “Go” signal from phase II. Target accrual for phase III is 686 node-negative PET/CT patients, including those randomized in phase II (425 additional patients). In addition to sites requiring radiotherapy and imaging credentialing, quality assurance will include central pathology review of all negative SLN Bx cases and surgeon credentialing through an education course with SLN Bx and END case review by the surgical co-chairs. A surgical quality assurance working group will review all trial SLN Bx and END procedures. As of 01/12/26, 351 patients have been screened, and 273 of the planned 686 have been randomized. Clinical trial information: NCT#04333537 .

8579 Background: LOH may provide a means to target tumor versus normal cells, to augment the efficacy and safety of MSLN-targeted programs (Hecht et al. JCO . 2022). A2B694 is an autologous, logic-gated, Tmod CAR T therapy designed to improve tumor selectivity and decrease toxicity by integrating an MSLN CAR activator with an HLA-A*02 blocker (Hamburger et al. Mol Imm. 2020). Methods: The first-in-human, open-label, phase 1/2 EVEREST-2 (NCT06051695) study of A2B694 in patients with recurrent/metastatic MSLN-expressing cancers with tumor-associated HLA-A*02 LOH. The prescreening study BASECAMP-1 (NCT04981119) identifies eligible patients and cryopreserves leukapheresis product. Upon progression, A2B694 is manufactured and administered after lymphodepletion. Phase 1 primary objective: evaluate the safety and tolerability of A2B694 and identify a recommended phase 2 dose. Results: As of 05 January 2026, 13 patients were enrolled: 8 women/5 men, median age 59 years, 11 non-Hispanic White/2 Hispanic with unknown race. Tumor types included colorectal (n = 4), ovarian (n = 3), pancreatic (n = 3), non–small cell lung adenocarcinoma (NSCLC), gastro-esophageal, and mesothelioma (n = 1 each). A2B694 dose level (DL) groups were: DL1: 1×10 8 cells (n = 3), DL2: 2×10 8 cells (n = 4), DL3: 4×10 8 cells (n = 5), and DL4: 6×10 8 cells plus low-dose IL-2 (n = 1). Lymphodepletion prior to administration of A2B694 was well-tolerated, with expected, transient cytopenias. The only adverse event reported in more than 1 patient was grade 3 neutropenia. One patient had grade 3 ICANS and 1 patient had grade 1 CRS. There were no dose-limiting toxicities or new safety signals after up to 17 months follow-up. All 13 patients received A2B694, were efficacy-evaluable, and had A2B694 detected post-infusion in peripheral blood. While A2B694 was not detected in tumor biopsies collected in patients treated at DL1 (0/2), all patients treated at DL2-DL4 with available biopsies (3/3) had detectable A2B694 in the tumor microenvironment. A patient with KRAS G12V /STK11 co-mutated NSCLC who had progressed on carboplatin, pemetrexed, and pembrolizumab achieved a complete response (CR) at D90 post-infusion per RECIST 1.1 by central review and had a confirmed CR at D180. In addition, PET-CT scan and ctDNA on D190 demonstrated no evidence of disease. On D243, the patient had a CNS relapse, with an ongoing non-CNS CR per RANO-BM at D284. At M12, the patient's CT showed no new findings and persistence of A2B694 in the blood was confirmed by ddPCR. Conclusions: We report the first patient with NSCLC to have a CR after CAR T. Overall, A2B694 demonstrated manageable safety and tolerability in patients with advanced solid MSLN-expressing tumors with tumor-associated HLA-A*02 LOH. The maximum tolerated dose has not been reached; dose-escalation continues. Clinical trial information: NCT06051695 .

Abstract Introduction Biliary fibrosis and inflammation are central to the pathogenesis of cholangiopathies such as primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC). Inflammatory and fibrogenic stimuli, such as transforming growth factor-β (TGFβ) and lipopolysaccharide (LPS) signaling, drive these processes, but their underlying transcriptional mechanisms in cholangiocytes remain incompletely defined. We investigated the role of Runt-related transcription factor 1 (RUNX1) as a transcriptional co-regulator of fibroinflammatory signaling in cholangiocytes. Methods Human PSC-derived cholangiocytes (PSC-Cs) and mouse large biliary epithelial cells (MLEs) were subjected to RUNX1 knockdown or pharmacologic inhibition (Ro5-3335 or AI-10-104). Cytokine secretion was profiled by Luminex multiplexing; RUNX1 genomic binding and protein interactome were assessed by ChIP-qPCR, ChIP-seq, and LC-MS/MS. In vivo , Mdr2 −/− mice received Ro5-3335, and cholangiocyte-selective Runx1 knockout mice (Krt19-CreERT) were challenged with a DDC diet, followed by evaluation of fibrosis and inflammation. Results RUNX1 expression was significantly increased in cholangiocytes from PSC and PBC patients, and Mdr2 −/− mice. RUNX1 knockdown or inhibition reduced IL6, TNFα, and other proinflammatory cytokines in PSC-Cs and attenuated TGFβ-, LPS-, and TNFα-induced Il6 and Ccl2 expression in MLEs. ChIP-qPCR and ChIP-seq revealed TGFβ-induced RUNX1 binding to the Il6 promoter and 727 additional genomic sites enriched for fibrosis and inflammatory pathways; predicted upstream regulators included TGFβ, TNF, and NFκB signaling. Proteomic analysis identified TGFβ-induced RUNX1 interactions with SMAD2 and NFκB2. In vivo , Ro5-3335 treatment in Mdr2 −/− mice reduced hepatic collagen, ECM gene expression, immune cell infiltration, and serum liver injury markers and bile acids. Similarly, cholangiocyte-specific Runx1 deletion mitigated fibrosis, inflammation, and liver injury in DDC-fed mice. Conclusion RUNX1 is a central transcriptional hub integrating TGFβ and inflammatory signals in cholangiocytes. Its inhibition attenuates biliary fibrosis and inflammation in cholestatic models, supporting RUNX1 as a potential therapeutic target in fibroinflammatory cholangiopathies.

Introduction The unproven stem cell intervention (SCI) industry markets stem cell products to patients navigating chronic and serious conditions who seek alternative options when conventional treatments no longer offer relief or improvement. This market is often characterized by providers using deceptive advertising to misinform potential consumers to seek stem cells that have not been shown to be safe and/or effective through clinical studies. Objective This study examines how patients describe interpersonal and institutional trust in relation to their interest in and decisions about unproven SCIs among two distinct and divergent chronic disease patient groups: patients with little or no interest in unproven SCIs (low seekers) and those with high interest or have undertaken an unproven SCI (high seekers). Methods A semi-structured interview guide was developed deductively and modified inductively based on the Unified Theory of Health Behavior. Qualitative interviews among 36 patients and carers were conduct and transcripts were analyzed using constant comparison based on the principles of grounded theory. Results Trust varies across social contexts as low seekers expressed strong reservations about the commercialization elements of the SCI industry placing greater confidence in conventional medicine. In contrast, high seekers questioned the advice of conventional providers and motives of medical regulators. Across both, personal relationships were commonly described as influential in how participants evaluated unproven SCIs. Conclusion These findings suggest that communication efforts in clinical settings should account for the relational and emotional dimensions of trust. Interventions aimed at countering misleading information and promoting informed choices should engage trusted messengers and address the broader social and psychological contexts in which patients may seek unproven SCIs.

Abstract Background Lumbar puncture is a routinely performed procedure, yet it presents significant challenges in patients with abnormal spinal anatomy, such as severe scoliosis or obesity. Conventional ultrasound-assisted neuraxial techniques, while superior to landmark-based methods, are constrained by two fundamental limitations: inaccurate projection of the probe’s geometric center onto the skin when the probe is tilted or rocked, and the difficulty of consistently replicating the exact probe angle during needle insertion. These limitations contribute to multiple needle passes, prolonged procedure time, and increased patient discomfort and complication risk. To address these issues, we developed a novel angle-free ultrasound-assisted technique designed to eliminate the need for replicating probe angulation during needle insertion. Case presentation: This angle-free approach was utilized for serial lumbar punctures in two patients with spinal muscular atrophy requiring repeated intrathecal nusinersen administration. Both patients presented with extreme anatomical complexity, including high body mass index (30 and 35.1 kg/m²) and severe scoliosis (Cobb angles 90° and 83°). The technique follows a three-step protocol: (1) Preprocedural imaging to select the optimal interlaminar space; (2) Ultrasound-guided postural adjustment until the probe could be held perpendicular to the bed edge and parallel to the floor while maintaining target visualization; (3) Needle insertion along this orthogonal trajectory. All 22 procedures (11 per patient) were completed successfully without persistent neurological complications. Procedural outcomes demonstrated a first-attempt success rate of 81.8% (Case 1) and 100% (Case 2), with first-pass success rates of 45.5% and 54.5%, respectively. Longitudinal analysis across sequential procedures revealed a consistent reduction in both the number of needle passes and needling time, reflecting a favorable learning curve. Conclusions The angle-free ultrasound-assisted neuraxial technique offers a valuable alternative for patients with complex spinal anatomy. By using real-time postural adjustments to achieve a needle trajectory, it enhances procedural precision and eliminates the technical hurdle of replicating probe angulation. The structured "4P" framework (Planning, Positioning, Perpendicular, Parallel) offers a practical guide for clinical adoption. The observed learning curve suggests that clinicians can readily acquire and apply this technique to manage such challenging cases.

Abstract Background Health-related quality of life (HRQoL) is impaired in patients with Crohn’s disease (CD). Upadacitinib (UPA), a Janus kinase inhibitor, demonstrated efficacy and safety in the phase 3 U-EXCEED (NCT03345836) and U-EXCEL (NCT03345849) induction, and U-ENDURE (NCT03345823) maintenance trials in patients with moderately to severely active CD. We assessed the effect of UPA maintenance treatment on HRQoL in patients with moderately to severely active CD from the U-ENDURE long-term extension (LTE) study. Methods Patients who completed the 52-week U-ENDURE maintenance study were eligible to participate in the LTE study, continuing their previously assigned maintenance treatment. Of the 337 patients receiving UPA (168, UPA 30 mg; 169, UPA 15 mg) in the U-ENDURE maintenance trial, a total of 244 patients (137, UPA 30 mg; 107, UPA 15 mg) were included in this analysis. All 244 patients completed week 96 of the LTE. Endpoints included percentage of patients who achieved Inflammatory Bowel Disease Questionnaire (IBDQ) response (≥16-point increase from induction baseline), IBDQ remission (total score ≥170 points), a meaningful within-person change (MWPC) of ≥ 9point increase from baseline in the Functional Assessment of Chronic Illness Therapy – Fatigue Scale (FACIT-F) and a MWPC of ≥ 4.1- and ≥3.9-point increase from baseline on the 36-item Short Form Health Survey (SF-36) physical (PCS) and mental (MCS) component summary score, respectively, at maintenance week 52 and LTE week 96. We also assessed MWPC in Work Productivity and Activity Impairment in CD (WPAI-CD) domains defined as a decrease of ≥ 6.1% in presenteeism, ≥6.5% in absenteeism, ≥7.3% in overall work impairment and ≥8.5% in activity impairment. Data were reported using nonresponder imputation. Results The proportion of patients in the UPA 30 mg group achieving HRQoL outcomes was maintained from maintenance week 52 to LTE week 96, including achievement of IBDQ response (61.3% vs 57.7%), IBDQ remission (53.3% vs 53.3%), MWPC improvement in FACIT-F (50.4% vs 40.9%), SF-36 PCS (56.9% vs 56.2%), SF-36 MCS (47.4% vs 40.9%) and MWPC improvements in WPAI-CD domains presenteeism (45.6% vs 48.1%), overall work impairment (49.4% vs 51.9%) and daily activity impairment (57.7% vs 56.9%). Patients in the UPA 15 mg group also maintained achievement of these HRQoL outcomes over time (Table). Conclusion UPA (15 and 30 mg) maintenance treatment over a 3-year period was associated with sustained and clinically meaningful disease-specific and generic HRQoL improvement in patients with moderately to severely active CD. Despite the overall trend favouring UPA 30 mg, differences in patient-reported outcomes between the 2 dose groups were small. Conflict of interest: Panés, Julián: Personal Fees: J. Panés received consultancy fees/honorarium from AbbVie, Alimentiv, Boehringer Ingelheim, Ferring, Galapagos, Genentech/Roche, GlaxoSmithKline, Janssen, Mirum, Nimbus, Pfizer, Progenity, Prometheus, Protagonist, Revolo, Sanofi, Sorriso, Spyre Therapeutics, Surrozen, Takeda, and Wasserman, and has served on data safety monitoring boards for Alimentiv, Mirum, Roche, Sorriso, Sanofi, and Surrozen Louis, Edouard: Education and Reserach Grants for my department: Abbvie, Takeda, Johnson and Johnson, Pfizer, Fresenius-Kabi, Celltrion, EG pharma, Sandoz, Falk Personal Fees for conferences, advisory boards and consultancy: Abbvie, Takeda, Ferring, Pfizer, Johnson and Johnson, Lilly, Galapagos, Celltrion, Arena, BMS, Falk, Biokuris, Fresenius-Kabi, Thabor Bossuyt, Peter: Grant support for research from AbbVie, EG Consulting fee from AbbVie, Bristol Meyers Squibb, CIRC, Galapagos, Janssen, Jeito capital, Lilly, Pentax, Pfizer, PSI-CRO, Roche, Takeda, Tetrameros Speakers fee from AbbVie, AMC ICP, Amgen, Bristol Myers Squibb, Celltrion, Dr Falk Benelux, EG, Galapagos, Globalport, Lilly, Medtalks, Materia Prima, Pentax, Springer Media Joshi, Namita: Namita Joshi is a full-time employees/contractor of AbbVie and may own AbbVie stock or options. Xuan, Si: Full-time employee/contractor of AbbVie and may own AbbVie stock or options. Shukla, Nidhi: Full-time employee/contractor of AbbVie and may own AbbVie stock or options. Dubcenco, Elena: Full-time employee/contractor of AbbVie and may own AbbVie stock or options. Aponte, Fernando: Full-time employee/contractor of AbbVie and may own AbbVie stock or options. Perkovic, Ashley: Full-time employee/contractor of AbbVie and may own AbbVie stock or options. Loftus, Jr, Edward: Grant: AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Genentech, Gilead, Janssen, Pfizer, Receptos, Robarts Clinical Trials, Takeda, Theravance, UCB. Personal Fees: AbbVie, Allergan, Amgen, Arena, Boehringer Ingelheim, Bristol-Myers Squibb, Calibr, Celgene, Celltrion, Eli Lilly, Genentech, Gilead, Iterative Scopes, Janssen, Ono Pharma, Pfizer, Sun Pharma, Takeda, UCB.

800 Background: Primary squamous cell carcinoma (SCC) of the small intestine is exceedingly rare and associated with poor prognosis. Literature is currently limited to a few case reports, and, to our knowledge, this is the first population-based analysis of patients with small intestine SCC. This study aimed to identify patient demographics and predictors of survival outcomes. Methods: Patients with histologically confirmed primary SCC of the small intestine diagnosed between 2000 and 2022 were identified from the SEER database; autopsy-only cases were excluded. Patient demographics, tumor site, stage (SEER summary stage), and initial treatments were summarized. Overall survival (OS) was defined from diagnosis to death, with one-year OS estimated by Kaplan–Meier methods. Multivariate Cox proportional hazards models evaluated associations between patient variables (age, sex, race, residence, year of diagnosis, surgery, and chemotherapy) and mortality. All statistical analyses were performed using R version 4.4.2. Results: A total of 89 patients diagnosed with primary small intestine SCC were identified. The median age at diagnosis was 68 years; 43 % were female, and 67 % were non-Hispanic White. Most patients (82 %) resided in urban counties. Tumor site was mostly the duodenum (37 %), followed by ileum (16 %) and jejunum (10 %); 33 % were not otherwise specified. Among patients with a recorded stage, 45 % had localized disease, 38 % regional disease, and 17 % distant metastases. Initial treatment comprised surgery in 60 % of patients, chemotherapy in 25 %, and radiation in 10%. The median OS was approximately six months, and the one-year OS was 36.7 % (95 % CI 27.9–48.3). Women had a higher one-year OS (42 %) than men (33 %), although this difference was not statistically significant. In multivariable analysis, surgical resection was associated with a markedly lower hazard of death (HR = 0.43, 95 % CI 0.25–0.74). Chemotherapy was associated with an insignificantly improved survival (HR 0.54, 95 % CI 0.27–1.09). Additionally, rural residence (HR ≈ 2.9) and older age (HR ≈ 1.03) were independently associated with worse survival (p<0.05). Conclusions: This population-based study highlights the rarity and aggressiveness of primary small bowel SCC, with a median OS of six months. Surgical resection was strongly associated with improved survival (adjusted HR ≈ 0.43), reinforcing its role as the cornerstone of management. Chemotherapy showed a nonsignificant survival benefit, highlighting the need for prospective studies. The association of rural residence with higher mortality suggests disparities in access to care and underscores the need for strategies to improve early detection and referral. Overall, these findings support a multimodal approach centered on surgery and warrant further studies to elucidate pathogenesis and optimize systemic therapy.