Citations

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.

Background: Hepatorenal syndrome–acute kidney injury (HRS-AKI) is associated with high mortality in cirrhosis. Recent FDA approval of terlipressin and updated clinical guidance have expanded management options, but real-world practice patterns remain unknown. Methods: We conducted a nationwide survey of U.S. hepatology providers regarding HRS-AKI management practices. The 33-question survey assessed provider demographics, vasoconstrictor selection, treatment timing, and adherence to guideline recommendations. Results: Among 162 respondents, most were hepatologists (94%) at academic centers (83%). Only 11% obtained a nephrology consultation at AKI detection, with 44% waiting until worsening renal function. Terlipressin was available at 80% of institutions but more commonly at academic centers (84% vs. 53%, p =0.003). Consistent with guideline recommendations, 77% of providers initiate vasoconstrictors only after completing a trial of volume expansion (if no renal improvement), particularly in academic centers (80% vs. 60% non-academic, p =0.03). Terlipressin (49%) and midodrine/octreotide (44%) were preferred first-line treatments, with providers at academic centers more likely to use midodrine/octreotide (46% vs. 30%, p =0.008). Mean arterial pressure was used by 62% of providers to guide vasoconstrictor dosing. Most providers (73%) discontinued vasoconstrictor treatment after 4 days if no improvement. Conclusions: Significant variations exist between guideline recommendations and real-world HRS-AKI management, especially first-line treatment choice, treatment monitoring, and nephrology consultation. These findings highlight opportunities to improve guideline implementation and identify areas where practice patterns might inform provider education and future guidance updates.

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.

Abstract Methods that map genetic risk to cells do not directly test whether spatially organized ligand–receptor (LR) gene annotations carry conditional heritability association. Here we introduce EdgeMap, which scores each gene by the spatial activity of its LR contexts in spatial transcriptomics data, maps these scores alongside cell-intrinsic annotations to SNP-level LD scores, and tests both jointly against GWAS summary statistics. Across 17 traits and five human tissues, edge z -scores are systematically higher in biologically matched tissues: all 15 traits with both matched and unmatched tissue classes show this ordering (median Δ z = 1.51 ; sign P = 3.1 × 10 −5 ), and 11 of 13 nominal-positive associations concentrate in the biologically matched set ( P = 1 × 10 −4 ). The pattern survives broad LR-gene-class and cell-type composition controls. Donor-level cross-section summaries, independent GWAS replication for LDL and CAD, and cell-segmented Visium HD liver data provide convergent support. A secondary analysis prioritizes constituent genes within active LR contexts; sixteen of 31 prioritized genes are absent from standard gene-level methods. These results establish spatially weighted LR-gene annotations as a complementary layer for interpreting complex-trait genetic architecture.

Abstract Background and Aims Stroke and systemic embolism are recognized but poorly characterized complications of atrial fibrillation (AF) and left atrial flutter (AFL) catheter ablation. Their incidence, outcomes, and procedural associations remain insufficiently defined. Methods Retrospective global registry was initiated by the European Heart Rhythm Association Scientific Committee. A secure database captured data from ablation centres worldwide on general AF and left AFL ablation activity, as well as detailed information on patients with symptomatic embolic events between 2017 and 2024. Results Overall, 204 centres reported 335 743 ablation procedures and 550 embolic events (incidence 0.16%). Centre-level rate ranged from 0% to 3.1%. Most events were cerebral (94%), followed by peripheral (5%), and combined (1%). Coronary air embolism accounted for 62% of all peripheral events. Intraprocedural events occurred in 93 patients (17%), within 72 h in 357 (78%) and beyond 72 h in 100 (22%); 128 cases (23%) were diagnosed after hospital discharge. Nonparoxysmal AF (0.23% vs 0.15%; P < .001), centre experience, and ablation energy source (radiofrequency, 0.16%; cryoballoon, 0.16%; pulsed field ablation, 0.25%; laserballoon, 0.88%; P < .001) were associated with embolic risk. Median NIHSS score after stroke was 4 (interquartile range, 2–9). Three-month follow-up was available for 518 patients with embolism (95%): 181 (35%) had sequelae and 16 (3%) died. Conclusions Symptomatic embolic events are infrequent but associated with significant morbidity and mortality. Most events occur early, though a substantial proportion arise later. Higher event rates were observed with laser and possibly with pulsed field ablation. A greater centre experience was associated with a lower embolism incidence.

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.