Citations

Abstract Neuroblastoma (NB) accounts for 10% of pediatric cancer-related deaths. High-risk NB is frequently metastatic at diagnosis and has a poor 5-year survival rate (<50%) despite aggressive treatment. GD2, a disialoganglioside glycolipid that is expressed in nearly all NBs, has been validated as a promising immunotherapy target. Although GD2-CAR-T cells have been clinically evaluated, their efficacy has been limited by poor tumor infiltration and the immunosuppressive tumor microenvironment (TME), highlighting the need for alternative immune-based strategies. With inherent capacity of macrophages to infiltrate tumors, phagocytose cancer cells, and modulate TME, they represent a promising alternative strategy for immunotherapy in NB. In this study, we developed and evaluated GD2-CAR-macrophages (GD2-CAR-Ms) as a novel therapeutic approach for NB. GD2-specific CAR constructs were designed, validated, and introduced into multiple human and murine monocyte/macrophage cell lines via lentiviral transduction. Fluorescent microscopy and flow cytometry confirmed a significant enhancement in the phagocytosis of GD2-high NB cells by GD2-CAR-Ms containing Hu3F8 single-chain variable fragment (scFv). A strong positive correlation was observed between GD2 expression levels on the target cells and phagocytosis efficiency of GD2-CAR-Ms, indicating that the phagocytic activity of GD2-CAR-Ms is antigen-specific. Anti-tumor efficacy was further evaluated in vivo using an immunocompetent Mycn-expressing NB non-genetically engineered mouse model (MYCN-NGEMM). Mice treated with GD2-CAR-Ms exhibited significantly reduced tumor burden and prolonged survival compared to control groups. Notably, treatment of mice bearing GD2-high tumors resulted in markedly improved survival, including one complete remission among ten treated animals, underscoring the therapeutic potential of GD2-targeted macrophage therapy. Histological analysis showed increased deposition of connective tissues and decreased tumor cells density, suggesting TME remodeling. Furthermore, immunohistochemistry reveals increased immune cell infiltration, particularly of macrophages, neutrophils and T cells, indicating a favorable shift in the immune TME from “cold” to “hot” following GD2-CAR-M treatment. Additionally, inhibition of tumor growth was also observed in our zebrafish NB model after GD2-CAR-Ms treatment, further supporting their therapeutic potential. Together, our findings demonstrate that GD2-CAR-Ms exhibit potent antitumor activity and reshape the tumor immune microenvironment, supporting their translational potential as a therapeutic strategy for high-risk NB. Citation Format: Ke-En Tan, Kok Siong Yeo, Cheng Zhang, Caleb Baker, Shyang Hong Tan, Alexis M. Sosic, Yat-Yuen Lim, Choong-Yong Ung, Cristina Correia, Stephanie F. Polites, Yi Lin, William A. Weiss, Hu Li, Shizhen Zhu. Engineering macrophages as a novel therapeutic approach for high-risk neuroblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 7810.

Abstract Background: Symmetry principles, a long foundational framework in physics and chemistry, have rarely been applied to understand biological phenotypes especially in cancers. Here we examine whether symmetric relationships in gene expression can characterize and differentiate healthy from disease conditions. Method: To test this concept, we built a hybrid machine-learning framework, Learning-Based Invariant Feature Engineering (LIFE), that applies two symmetric invariant feature functions, IFF1 and IFF2, to all possible gene pairs in bulk transcriptomic datasets to identify invariant feature genes (IFGs) - gene pairs whose transformed expression values by either IFF1 or IFF2 produce quasi-constant single-value outputs within a phenotype despite inter-individual variability. Results: Using bulk transcriptomes from 25 normal organs (GTEx) and 25 cancer types (TCGA), we computed IFF values for all normally distributed gene pairs, selected the 1000 most stable pairs per phenotype, and evaluated their performance in multiclass classification with five-fold cross-validation and independent hold-out testing. IFGs generated >70% accuracy across organs and cancers, establishing the existence of robust phenotype-specific symmetry “fingerprints.” Mapping approved and experimental drug targets onto networks construction from IFGs (IF-Nets) showed strong enrichment of hubs in cancer networks and highlighted the use of IF-Nets as drug discovery platforms in cancer treatment. Conclusion: Our findings demonstrate that gene-expression symmetry as a unifying organizing principle for phenotype definition and illustrate how IFGs and IF-Nets can guide biomarker design and symmetry-aware pharmacological intervention via “symmetry breaking.” Citation Format: Cristina Correia, Choong-Yong Ung, Cheng Zhang, Shizhen Zhu, Hu Li, . Learning-based invariant feature engineering reveals symmetry-encoded fingerprints of cancers that facilitate drug discovery [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 5516.

Abstract Cholesterol has long been viewed as a structural component of cellular membranes, yet its role in DNA damage response remains poorly defined. Here, we show that ionizing radiation (IR) induces broad transcriptional upregulation of cholesterol biosynthesis, transport, and storage pathways, leading to sustained intracellular accumulation of cholesterol. BODIPY-cholesterol imaging, Filipin III staining, and quantitative subcellular fractionation confirmed selective nuclear enrichment of cholesterol following IR, coinciding with extensive chromatin remodeling. Proteomic profiling of cholesterol-interacting proteins revealed a strong enrichment of chromatin-associated factors, suggesting a previously unrecognized lipid-chromatin interface in irradiated cells. Functionally, cholesterol accumulation promoted chromatin compaction and repressive histone modification patterns, impairing DNA damage sensing and checkpoint activation despite increased underlying DNA lesions. These alterations facilitated aberrant mitotic entry, formation of cytoplasmic chromatin fragments (CCFs), and activation of cGAS-STING-NF-κB signaling. Cholesterol exposure ultimately diverted damaged cells toward a senescent fate, marked by Lamin B1 loss, p21 induction, and a robust senescence-associated secretory phenotype (SASP) enriched for IL-1 and TNF family cytokines. In vivo, dietary cholesterol exacerbated radiation-induced inflammation and weakened systemic anti-tumor immunity. Transcriptomic analyses of immunotherapy-treated patients revealed that tumors enriched for cholesterol import and senescence signatures were associated with poor response to PD-L1 blockade and worse survival. Together, these findings identify a cholesterol-chromatin-senescence axis that links metabolic remodeling to defective DNA damage signaling and immune suppression after radiation, highlighting cholesterol metabolism as a potential therapeutic vulnerability in cancer therapy. Citation Format: Yiqun Han, Yaobin Ouyang, Shouhai Zhu, Hangcheng Xu, Bin Chen, Ping Yin, Qin Zhou, Jinzhou Huang, Kuntian Luo, Zheming Wu, Huaping Xiao, Xinyi Tu, Jake A. Kloeber, Jiajun Jing, Xiaofeng Huang, Meng Xu Welliver, Zhenkun Lou, Robert Mutter. Cholesterol triggers chromatin stress to drive senescence and inflammation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 539.

The regulation of the cardiomyocyte cell cycle is central to understanding heart regeneration. In adult mammals, cardiomyocytes withdraw from the cell cycle, limiting their ability to proliferate and repair heart tissue after injury. This process is controlled by intrinsic genetic programs and extrinsic signals, which together restrict the regenerative response in mature hearts. Understanding the mechanisms that regulate cardiomyocyte cell cycle activity is therefore critical for advancing cardiac regenerative medicine. In this review, we provide a comparative and integrated overview of cardiomyocyte cell cycle regulation in lower vertebrates and mammals, and discuss the major intrinsic factors that govern this process, including cyclin/CDK pathways, transcription factors and co-activators, oxygen and metabolic regulation, and epigenetic mechanisms. We also review the influence of hormones and growth factors, as well as the supportive roles of nonmyocyte populations in heart regeneration. By integrating findings across species, developmental stages, and regulatory levels, these findings highlight the complex regulatory network controlling cardiomyocyte proliferation and provide insight into potential therapeutic strategies for stimulating cardiac repair in the adult mammalian heart.

The underlying immunopathogenesis of inflammatory arthritis (IA) immune-related adverse event (irAE) remains obscure. Unlike rheumatoid arthritis (RA), where autoantibodies and B cell dysfunction are central features, the contribution of humoral immunity to IA-irAE is unclear. Here, we performed immunophenotyping of peripheral blood from patients with IA-irAE and compared them with patients with seronegative RA, immune checkpoint inhibition–treated patients without irAE, and healthy controls. IA-irAE was marked with increased cytotoxic gene expression and metabolic activation in T cells and reduced CXCR3 and CCR6 expression in CD4 + T cells. Contrary to seronegative RA, patients with IA-irAE displayed no substantial elevation in autoantibody levels or atypical CD11c + CD21 − B cells. IA-irAE was further characterized by elevated levels of interleukin-6 (IL-6), IL-12, and type I interferon, which correlated with the T cell activation phenotypes. Together, our findings define IA-irAE as a disease with certain immunological features distinctive from RA, representing a potentially T cell–driven, autoantibody-independent autoimmunity. These results offer insights into immune tolerance breakdown and therapeutic targeting in irAEs.

Human diseases are complex and arise from the coordinated action of multiple genes and their protein products. Genes’ behaviors extend beyond genetic variants, mutations, and differential expressions. Their coordinated activity across biological scales (molecules, cells, tissues, organs) produces emergent behaviors that shape health and disease. These emergent behaviors span time and space and are often hard to measure directly from observation when using standard experimental measurements. Yet these “hidden” or latent gene characteristics can be powerful drivers of disease. We propose a Mini-Galaxy Model (MGM), a systems-level AI-driven network framework that models cells as “mini-galaxies” composed of multilayered biological information, with each layer encoding a different dimension of genes’ behavior. Here, we delineate a strategy on how to construct and compare MGMs across health and disease and map their etiological relatedness. We also operationalize the MGM as a discovery platform for translational medicine, offering modules to allow target prioritization and editing. By reframing human diseases as the result of emergent behavior of multilayered multimode biological networks and their perturbations, the MGM yields actionable rules to streamline biomarker discovery, guide target selection and enable rational design of combinatorial interventions, and accelerate drug repurposing.

Abstract Background The van Herk margin formula, derived for 3‐D conformal radiotherapy with a uniform 3.2 mm dose penumbra and no intrinsic dose buffer, remains widely used to design CTV‐to‐PTV expansions in contemporary image‐guided prostate radiotherapy. However, coplanar VMAT techniques often feature broader penumbrae and explicit PTV–isodose clearances, potentially violating the assumptions underlying the original formulation and leading to overly conservative margins. Purpose We investigated whether the widely adopted van Herk margin formula overestimates clinical target volume (CTV)‐to‐planning target volume (PTV) expansions for contemporary coplanar volumetric modulated arc therapy (VMAT) prostate treatments. Methods Fifty consecutive intact‐prostate VMAT radiotherapy plans (two coplanar arcs; clinical margins 3 mm, except for 2 mm posterior) were exported. Direction‐specific 90% isodose–to‐PTV gaps and penumbra widths were measured. Candidate anisotropic margins were tested by eroding the PTV to create CTV_eval. Monte‐Carlo simulations combined systematic (Σ) shifts with Gaussian random (σ′) blurring kernels of 0–2 mm were performed. Acceptability criteria of (i) CTV Dmin0.03 cc ≥ 90% Rx in ≥ 90% of simulated scenarios or (ii) population tumor‐control probability (TCP) loss < 1 % were used. Results VMAT plans exhibited intrinsic 90% isodose clearances of 3–5 mm laterally/anteriorly and 1–2 mm superior–inferiorly, while axial‐plane penumbras were up to fivefold broader than van Herk's assumption. With a [0, 0, 2] mm (LR/AP/SI) margin, ≥ 90% of patients maintained Dmin0.03 cc ≥ 90% Rx provided Σ lay within an ellipsoid of [2.0, 1.5, 1.8] mm and σ′ ≤ [1.5, 2.0, 1.5] mm. Under TCP criteria the safe Σ ellipsoid for high‐risk disease was [2.5, 1.9, 2.2] mm, while low‐intermediate risk was even less sensitive. Conclusions For image‐guided coplanar VMAT prostate radiotherapy, an anisotropic [0, 0, 2] mm CTV‐to‐PTV margin is sufficient for target coverage. A modified margin expression that subtracts the measured isodose–to‐PTV gap and uses reduced random‐error coefficients better reflects modern practice.

ABSTRACT Background Driving supports independence and quality of life in later life but is vulnerable to age‐related and/or disease‐related decline. While cognitive impairment is a well‐recognized risk for unsafe mobility, the contribution of sensorimotor function is less understood. Methods We studied 374 cognitively normal older adults (Clinical Dementia Rating = 0 at baseline) enrolled in the DRIVES Project. A SensoryMotor Impairment Index (SMI) was constructed from six domains (grip strength, gait speed, reaction time, hearing, vision, olfaction) and categorized as 0, 1, 2, or ≥ 3 impairments. Naturalistic driving was continuously monitored using in‐vehicle GPS dataloggers between 2019 and 2025. Linear mixed‐effects models tested whether longitudinal driving trajectories differed by baseline SMI, adjusting for age, sex, race, education, body mass index, and cognition (Preclinical Alzheimer's Cognitive Composite). Results At baseline, participants with higher SMI burden were older and had lower cognitive scores (both p < 0.01). Over time, greater sensorymotor impairment was associated with faster declines in driving exposure and spatial range. Compared with SMI = 0, participants with SMI ≥ 3 showed steeper reductions in nighttime trips (−0.050 vs. −0.037 trips/month), long‐distance trips (> 20 miles; p < 0.001), and maximum trip distance ( p = 0.009), and greater contraction of driving space (entropy and radius of gyration; p < 0.001). Self‐reported driving behaviors showed that participants with higher SMI drove fewer days per‐week and were more likely to avoid night driving ( p < 0.01). Rates of self‐reported adverse driving events (e.g., crashes or citations) did not differ significantly across SMI groups, consistent with compensatory self‐regulatory behaviors. Conclusion Greater sensorymotor impairment predicts accelerated decline in naturalistic driving among cognitively normal older adults, independent of cognition. A composite SMI may provide a feasible, low‐cost approach to identify older drivers at risk for declining mobility and support timely interventions to prolong safe driving.

PURPOSE Gastroesophageal carcinoma (GEC) is increasingly managed using biomarker-guided therapies. Although both tissue DNA (tDNA) and circulating tumor DNA (ctDNA) testing are used clinically, the concordance of genomic alterations between primary tumors, metastatic sites, and liquid biopsy remains incompletely understood. METHODS We retrospectively analyzed 345 patients with GEC who underwent ctDNA testing at Mayo Clinic. tDNA next-generation sequencing and immunohistochemistry (IHC) for human epidermal growth factor receptor 2 (HER2)/erb-b2 receptor tyrosine kinase 2 ( ERBB2 ) and mismatch repair (MMR) were collected. Concordance was evaluated between ctDNA and tDNA, ctDNA and IHC, and across all three modalities, using 60-day and 30-day intervals. RESULTS Among 345 patients with ctDNA testing, 186 had tDNA testing, and 310 underwent IHC. ctDNA testing showed a shorter turnaround time than tDNA (median 6 v 13 days). The most frequent alteration in ctDNA, primary tDNA, and metastatic tDNA was TP53. Concordance between ctDNA and primary tDNA was ≥78.8% for key genes; between ctDNA and metastatic tDNA, it was ≥84.8%. IHC-ctDNA concordance was higher in metastatic tumors, with 91.1% for HER2/ ERBB2 and 97.7% for mismatch repair (MMR)/microsatellite instability (MSI) compared with 81.1% and 95.8%, respectively, in primary tumors. Triplet concordance for MSI/MMR was 97.6% in primary tumors and 100% in metastatic tumors, while ERBB2 /HER2 showed 84.4% and 93.9% concordance, respectively. ctDNA temporal heterogeneity analysis revealed 14 patients with fluctuating ERBB2 status and 3 with fluctuating MSI-H status. CONCLUSION ctDNA testing demonstrates high concordance with tDNA and IHC and offers faster turnaround. Given its minimally invasive nature and strong concordance with tissue-based testing, ctDNA is a reliable tool for genomic profiling and longitudinal monitoring in GEC.

ABSTRACT Cataract is a leading cause of visual impairment worldwide, and its prevalence is increasing with population aging. The majority are age‐related cataracts (ARC), clinically classified into nuclear, cortical, and posterior subcapsular cataracts (PSC) by opacity location. Mechanisms of cataractogenesis remain incompletely understood. While cortical and nuclear cataracts are largely attributed to crystallin aggregation, such protein‐centric mechanisms fail to explain the early onset and axial location of PSC. Morphologically, PSC resembles posterior capsule opacification (PCO), a secondary cataract driven by epithelial–mesenchymal transition (EMT) of lens epithelial cells (LECs), suggesting LEC‐EMT may also contribute to PSC. Using clinically stratified human lens samples, we confirmed EMT marker expression across PSC subtypes. Transcriptomic profiling revealed that LECs, the lens's sole metabolically active cells, in age‐related PSC (ARC‐PSC), compared with age‐related nuclear cataract (ANC) and clear lenses, exhibit elevated EMT signatures tightly linked to senescence‐associated inflammatory signaling. Aqueous humor (AqH) profiling demonstrated a pro‐inflammatory milieu across PSC subtypes, with IL‐17A uniquely elevated in ARC‐PSC, consistent with transcriptomic findings. Integrated analyses support a model in which senescence functions as an upstream driver, whereby senescent LECs release SASP factors, including IL‐17A, that activate NF‐κB signaling to amplify inflammation, reinforce senescence, and drive EMT. In vitro, senolysis and IL‐17A blockade disrupted this loop, attenuating senescence‐ and EMT‐associated phenotypes. Collectively, our study demonstrates that senescent LECs sustain an IL‐17A–NF‐κB circuit that drives EMT and accelerates ARC‐PSC progression, positioning ARC‐PSC as a unique human context to study senescence‐induced epithelial remodeling in aging tissues.