Citations

PURPOSE In immunoglobulin light chain (AL) amyloidosis, amyloid fibrils cause organ dysfunction. Anselamimab, a monoclonal antibody, selectively binds to amyloid fibrils, accelerating their clearance. METHODS Newly diagnosed patients with European modification of Mayo 2004 stage IIIa or IIIb AL amyloidosis were randomly assigned to receive anselamimab or placebo with cyclophosphamide, bortezomib, and dexamethasone (with or without daratumumab). The primary end point was a hierarchical composite of time to all-cause mortality (ACM) and frequency of cardiovascular hospitalizations (CVHs), analyzed using the Finkelstein-Schoenfeld test and win ratio estimation. RESULTS Among 406 randomly assigned patients, the primary end point win ratio for anselamimab versus placebo was 1.11 (95% CI, 0.83, 1.50; P = .332) and the hazard ratio (HR) for ACM was 0.80 (95% CI, 0.57, 1.13; P = .290). CVH rates in the anselamimab and placebo groups were 0.59 (95% CI, 0.42, 0.83) and 0.89 (95% CI, 0.55, 1.43), respectively ( P = .145). Among patients with kappa isotype (n = 72), the win ratio was 2.06 (95% CI, 0.98, 4.31; P = .100) and anselamimab reduced ACM by 62% versus placebo (HR, 0.38; 95% CI, 0.17 to 0.86; nominal P = .012), and CVH by 71% (IRR, 0.29; 95% CI, 0.10 to 0.87; nominal P = .028) with improvements in Kansas City Cardiomyopathy Questionnaire-Overall Score. There was no clinical benefit observed in the lambda population. Anselamimab was generally well-tolerated; safety data were comparable between treatment arms overall. CONCLUSION Treatment with anselamimab, an antifibril antibody used alongside antiplasma cell dyscrasia therapy, while not meeting the primary end point in the overall population, significantly improved ACM and CVH in patients with kappa AL, potentially offering a new therapeutic option for this isotype.

4013 Background: Pancreatic ductal adenocarcinoma (PDAC) is driven predominantly by oncogenic KRAS signaling, yet prior attempts to target the MAPK pathway have been limited by toxicity and emergence of resistance. Atebimetinib is a next-generation, deep cyclic inhibitor (DCI) of MEK designed to achieve pulsatile pathway inhibition with improved tolerability. We report a Phase 2a cohort evaluating atebimetinib in combination with modified gemcitabine/nab-paclitaxel (mGnP) in the first-line treatment of advanced or metastatic PDAC (NCT05585320). Methods: In this multicenter, open-label, nonrandomized Phase 2a study, patients with previously untreated advanced or metastatic PDAC were eligible for participation and were treated with orally administered atebimetinib daily in combination with mGnP (modification: every other week dosing). The primary endpoint was objective response rate (ORR) per investigator assessment using RECIST 1.1 criteria in response-evaluable patients. The cohort was powered (~80%, one sided alpha 0.05) using an optimal Simon’s 2-stage design. Results: Fifty-five patients were enrolled and treated with 320 mg atebimetinib daily + mGnP. ECOG performance status was 0-1 (100%); median age was 68 years (range 42-85 years), 62% were ≥65 years, and 55% were male. No grade 5 treatment-related adverse events (AE) were observed. No AE related to atebimetinib were higher than grade 3. Grade 3 AE related to atebimetinib occurred in 29% of participants, with the most frequent being rash (5%), ALT increased (5%), and AST increased (5%). Among the 50 response-evaluable patients, best overall response (BOR) achieved were 21 PR, 21 SD, 7 PD, 1 NE. The ORR was 42%, and DCR was 84%. With a median follow-up of 10.4 months (data cutoff Jan 7, 2026), 6- and 9-month OS rates were 88% and 79%, respectively; median PFS was 8.3 months and median OS was not reached. Conclusions: Atebimetinib in combination with mGnP demonstrated favorable safety and promising efficacy compared to historic standard-of-care (SoC) GnP. 1 A phase 3 registrational trial is planned to start in mid-2026 for evaluation of atebimetinib + mGnP versus SoC GnP. 1. Von Hoff DD, Ervin T, Arena FP, et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med . 2013;369(18):1691-1703. doi:10.1056/NEJMoa1304369 (PMID: 24131140). Clinical trial information: NCT05585320 .

Abstract Rationale Respiratory disease is a major cause of mortality in Down syndrome (DS; trisomy 21, T21). DS is considered a progeroid syndrome, with elevated cellular senescence (SEN) and oxidative stress. Because SEN shapes organogenesis, its dysregulation may impair lung morphogenesis. We previously found SEN/SASP (senescence-associated secretory phenotype) abnormalities in prenatal human T21 lungs. Here, we test whether these alterations persist and change after birth. Methods We analyzed human lung single-nuclear RNA (snRNA-seq) datasets (prenatal and postnatal) to quantify epithelial and mesenchymal SEN/SASP signatures. Sex- and age-matched T21 and non-T21 prenatal and postnatal lungs were studied; fibroblasts were isolated as prenatal human lung fibroblasts (HFLF) and postnatal human lung fibroblasts (HLF). SEN/SASP were measured by RT-qPCR and immunofluorescence (IF) in tissue and HFLF/HLF. HFLF/HLF were assayed for SA-β-gal, oxidative stress (CellROX/MitoSOX), and Ca²+ dynamics (Fura-2 AM). 48h treatments with tunicamycin (1µM, SEN inducer), 4-phenylbutyrate (4-PBA, 2 mM, ER Stress inhibitor), or pyrroloquinoline quinone (PQQ, 20 μM, antioxidant) were performed on T21 and non-T21 HFLF/HLF. Conditioned media (CM) were collected after 48h from untreated cultures and then applied to cells of the opposite genotype for 24, 48, and 72h. Results Overall SEN profile was similar in epithelium and mesenchyme across ages, but pathway signatures differed. Epithelium shows an inflammatory SASP, while mesenchyme shows a less-inflammatory, remodeling/growth-factor SASP. These lineage patterns were more evident postnatally. Whole-tissue IF showed increased γ-H2AX and p21 in T21 vs non-T21 both prenatally and postnatally (p < 0.05). At baseline, T21 HFLF/HLF had higher CDKN1A, CDKN2A, TP53, CDKN2B, and SERPINE1 (p < 0.05; n = 5-6), with increased γ-H2AX/p21 IF (p < 0.01; n = 6), SA-β-gal (p < 0.05; n = 5-6), and ER/mitochondrial stress (p < 0.05; n = 5-6). Fura-2 AM showed greater Ca²+ release in T21 HFLF/HLF at baseline and after acetylcholine (10 μM, p < 0.01; n = 5). Mitochondrial-morphology genes (FIS1, DNM1L, MFN1) were elevated in T21 HFLF/HLF (p < 0.05; n = 6). In T21 HFLF, 4-PBA and PQQ each reduced SA-β-gal (p < 0.01; n = 6). In postnatal HLF, PQQ had the stronger effect (p < 0.05; n = 5). T21 CM induced progressively greater SEN/SASP over 24/48/72h in non-T21 cells (p < 0.05; n = 5-6), while non-T21 CM partially rescued T21-HLF phenotypes at 24h only (p < 0.05; n = 5-6). Conclusion These data indicate that lung senescence in T21 initiates in utero and intensifies after birth and reflects lineage-specific pathways. ER-stress-related mechanisms are more prominent prenatally, while mitochondrial/redox mechanisms are predominant postnatally. This evidence suggests age and lineage-dependent drivers of senescence that may help explain DS lung disease and highlight potential new mechanistic targets. This abstract is funded by: NIH/NHLBI

Abstract Respiratory viral infections such as influenza and SARS-CoV-2 can lead to the development of chronic lung disease and impaired pulmonary function long after the recovery from acute illness. However, the mechanisms underlying these post-acute sequelae remain poorly understood. Using human lung samples from patients with post-acute sequelae of COVID-19 with pulmonary fibrosis (PASC-PF) and an aged mouse model of chronic lung disease following acute viral infection, we found that CD4+ T cells were enriched near the dysplastic Krt8Hi epithelial regions of the lung. Similarly, in aged mice, CD4+ T cells localized to Krt8Hi areas, and their spatial distribution correlated positively with the extent of epithelial dysplasia. Further analysis of bronchoalveolar lavage (BAL) fluid from COVID-19 convalescent individuals revealed a distinct population of FoxP3−PD-1HiCD4+ T cells highly expressing ICOS, CD69, and CD103 - markers characteristic of both T follicular helper (TFH) and tissue-resident memory (TRM) cells, which we have defined as tissue-resident helper (TRH) cells previously. Notably, the frequency of these TRH-like cells correlated positively with the extent of reticulate or consolidated regions on chest CT scans, indicative of lung fibrosis. Furthermore, the frequency of these cells was negatively associated with lung functional parameters including forced vital capacity (FVC). These findings suggest that PD-1HiCD4+ TRH-like cells expand in PASC and may contribute to chronic lung sequelae. Given that Bcl6 is required for TRH differentiation, we employed an aged, CD4-specific, inducible Bcl6-deficient (Bcl6iΔCD4) mouse model to evaluate the functional contribution of these cells to post viral lung fibrosis. Bcl6 deficiency led to a marked reduction in total and antigen-specific PD-1HiCD4+ TRH cells, as confirmed by flow cytometry and immunofluorescence. Strikingly, Bcl6 iΔCD4 mice displayed significantly decreased inflammatory and fibrotic lesions in the lung compared to wild-type controls. Moreover, Bcl6 iΔCD4 mice exhibited enhanced lung regeneration, evidenced by increased AT1 and AT2 epithelial cells and improved pulmonary function. Together, these findings identify Bcl6-dependent CD4+ TRH responses as key drivers of post-viral chronic lung sequelae. This study reveals a novel immunopathogenic mechanism linking persistent tissue helper memory T-cell responses to impaired lung repair and fibrosis, providing new insight into the development of post-viral lung disease and potential therapeutic targets for conditions such as respiratory long COVID. This abstract is funded by: American Lung Association, NIH

Abstract Objectives To examine the extent to which heat-related causes of death are recorded in fatal drug overdoses, how these patterns vary across states and over time, and how overdose characteristics differ between deaths with, versus without, heat involvement recorded. Methods Death certificate data for all drug overdose deaths in US residents from 2001 to 2024 (from the National Center for Health Statistics) were analyzed to identify whether a heat-related cause of death was also listed on the death certificate. Joinpoint regression, descriptive statistics, and nonparametric tests were used to examine temporal trends and compare overdose deaths with versus without recorded heat involvement. Results In 2001, fewer than 10 drug overdose deaths with recorded heat involvement were identified, but this number increased to 558 in 2024. From 2013 to 2024, mortality rates increased significantly, with an estimated annual percent change of 30.1 (95% Confidence Interval, 26.5–47.1). The highest mortality rates and numbers of deaths were observed in residents of Arizona and Nevada. American Indian/Alaska Native, Mexican-heritage, and foreign-born populations accounted for larger shares of overdose deaths with, compared to without, heat involvement recorded. A street or highway was more frequently identified as the place of injury in overdose deaths with (18.9%), versus without (2.2%) heat involvement reported. Psychostimulants such as methamphetamine were involved in 85.9% of overdose deaths with, compared to 28.9% without, recorded heat involvement. Conclusions Although representing only a fraction of all overdose deaths, fatal overdoses involving heat exposure have increased markedly over time and disproportionately impact certain states and demographic groups.

Rationale: Respiratory disease is a major cause of mortality in Down syndrome (DS; trisomy 21, T21). DS is considered a progeroid syndrome, with elevated cellular senescence (SEN) and oxidative stress. Because SEN shapes organogenesis, its dysregulation may impair lung morphogenesis. We previously found SEN/SASP (senescence-associated secretory phenotype) abnormalities in prenatal human T21 lungs. Here, we test whether these alterations persist and change after birth. Methods: We analyzed human lung single-nuclear RNA (snRNA-seq) datasets (prenatal and postnatal) to quantify epithelial and mesenchymal SEN/SASP signatures. Sex- and age-matched T21 and non-T21 prenatal and postnatal lungs were studied; fibroblasts were isolated as prenatal human lung fibroblasts (HFLF) and postnatal human lung fibroblasts (HLF). SEN/SASP were measured by RT-qPCR and immunofluorescence (IF) in tissue and HFLF/HLF. HFLF/HLF were assayed for SA-β-gal, oxidative stress (CellROX/MitoSOX), and Ca 2 + dynamics (Fura-2 AM). 48h treatments with tunicamycin (1µM, SEN inducer), 4-phenylbutyrate (4-PBA, 2 mM, ER Stress inhibitor), or pyrroloquinoline quinone (PQQ, 20 μM, antioxidant) were performed on T21 and non-T21 HFLF/HLF. Conditioned media (CM) were collected after 48h from untreated cultures and then applied to cells of the opposite genotype for 24, 48, and 72h. Results: Overall SEN profile was similar in epithelium and mesenchyme across ages, but pathway signatures differed. Epithelium shows an inflammatory SASP, while mesenchyme shows a less-inflammatory, remodeling/growth-factor SASP. These lineage patterns were more evident postnatally. Whole-tissue IF showed increased γ-H2AX and p21 in T21 vs non-T21 both prenatally and postnatally (p< 0.05). At baseline, T21 HFLF/HLF had higher CDKN1A, CDKN2A, TP53, CDKN2B, and SERPINE1 (p< 0.05; n=5–6), with increased γ-H2AX/p21 IF (p< 0.01; n=6), SA-β-gal (p< 0.05; n=5–6), and ER/mitochondrial stress (p< 0.05; n=5–6). Fura-2 AM showed greater Ca 2 + release in T21 HFLF/HLF at baseline and after acetylcholine (10 μM, p< 0.01; n=5). Mitochondrial-morphology genes (FIS1, DNM1L, MFN1) were elevated in T21 HFLF/HLF (p< 0.05; n=6). In T21 HFLF, 4-PBA and PQQ each reduced SA-β-gal (p< 0.01; n=6). In postnatal HLF, PQQ had the stronger effect (p< 0.05; n=5). T21 CM induced progressively greater SEN/SASP over 24/48/72h in non-T21 cells (p< 0.05; n=5-6), while non-T21 CM partially rescued T21-HLF phenotypes at 24h only (p< 0.05; n=5-6). Conclusion: These data indicate that lung senescence in T21 initiates in utero and intensifies after birth and reflects lineage-specific pathways. ER-stress-related mechanisms are more prominent prenatally, while mitochondrial/redox mechanisms are predominant postnatally. This evidence suggests age and lineage-dependent drivers of senescence that may help explain DS lung disease and highlight potential new mechanistic targets. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

Autoimmune diseases arise when B and T lymphocytes lose tolerance to self. Yet in most disorders, the underlying molecular determinants, including autoantibodies, epitopes and lymphocyte clones that drive tissue injury remain undefined. Rapid-onset obesity with hypothalamic dysfunction, hypoventilation and autonomic dysregulation (ROHHAD) is a rare and often fatal pediatric neuroendocrine syndrome with strong evidence of antigen-driven paraneoplastic autoimmunity, including association with the intracellular autoantigen ZSCAN1. However, the effector immune circuit and the epitope-level determinants operating within the hypothalamus and brainstem have remained unknown. To address this challenge in ROHHAD and more broadly in autoimmune disease, we developed the Autoimmune Epitope and immunoGlobulin/Immune-receptor identification System (AEGIS), an integrated framework that links immune repertoires to their cognate self-epitopes. AEGIS combines B cell and T cell receptor profiling from sites of tissue injury with high-resolution epitope mapping, direct sequencing of antigen-specific autoantibodies, in silico antibody-antigen folding, selection, and T cell antigen discovery. Applied to a deeply phenotyped child with ROHHAD, AEGIS revealed a compartmentalized, clonally restricted immune response in which brain-deposited IgG and expanded cerebrospinal fluid B cell and CD4 T cell clonotypes converged on shared ZSCAN1 epitopes, resolved to minimal determinants and peptide-MHC ligands. These findings provide a clone- and epitope-linked mechanistic map of ROHHAD autoimmunity and establish a generalizable framework for identifying candidate pathogenic clones and antigens across diverse autoimmune diseases.

Abstract Patients with extremely rare pathogenic variants pose unique challenges to current healthcare systems. Nano-rare mutations have been defined as mutations with a known prevalence of &lt;30 patients worldwide, but because of the small fraction of humans who have undergone genetic testing, neither the precise prevalence of individual mutations nor the total prevalence of patients with nano-rare mutations is known. n-Lorem is a non-profit founded in 2020 with the mission of equitably discovering, developing, and providing bespoke experimental antisense oligonucleotides (ASOs) for free, for life, to patients with nano-rare mutations that are amenable to ASO treatment. In this perspective, we provide an overview of the n-Lorem processes and systems, the characteristics of the first 329 patients who have applied for treatment for whom initial assessment was completed and suitability for ASO treatment determined, and a summary of the results of ASO treatment for patients treated to date. Detailed data on individual patients and the overall clinical safety and tolerability profiles of the ASOs for which there are clinical data are the subjects of other manuscripts.

Abstract Pancreatic cancer disproportionately affects Black individuals in the United States, but they have limited representation in genetic studies of pancreatic ductal adenocarcinoma (PDAC). To address this gap, we performed admixture mapping and genome-wide association analysis (GWAS) in genetically inferred African ancestry individuals (1,030 cases and 889 controls). Admixture mapping identified three regions with a significantly higher proportion of African ancestry in cases compared to controls (5q33.3, 10p1, 22q12.3). GWAS identified a genome-wide significant association at 5p15.33 ( CLPTM1L , rs383009:T>C, T Allele Frequency=0.51, OR:1.45, P value=1.24×10 -8 ), a locus previously associated with PDAC. Known loci at 5p15.33, 7q32.3, 8q24.21 and 7q25.1 also replicated (P value <0.01). Multi-ancestral fine-mapping identified two potential causal SNPs (rs3830069 and rs2735940) at 5p15.33. Collectively these findings identified novel PDAC risk loci and expanded our understanding of this deadly cancer in underrepresented populations, emphasizing the multifactorial nature of PDAC risk including inherited genetic and non-genetic factors. Statement of Significance To understand how genetic variation contributes to PDAC risk in Black people in North American, we studied individuals of genetically-inferred African ancestry. We identified novel risk loci and differences in the contribution of known loci. This demonstrates that ancestry-informed genetic analyses improve our understanding of PDAC risk and enhances discovery.