Citations

Introduction: Atherosclerotic lesions preferentially form in arterial regions exposed to disturbed flow (DF), where ECs exhibit mitochondrial (mt) dysfunction, metabolic reprogramming, and senescence. Hippo pathway kinases LATS1/2 maintain EC homeostasis, but how DF–mediated LATS1/2 suppression drives EC metabolic remodeling remains unclear. Hypothesis: We propose that DF activates CD38, leading to mt dysfunction and metabolic reprogramming that promotes EC senescence and aberrant proliferation by LATS1/2 inhibition. Methods: EC-specific Lats1/2 knockout mice were generated using tamoxifen-inducible Cre systems, and DF was induced by partial carotid ligation. Murine and human plaques were analyzed using COMET™ immunofluorescence, and spatial metabolomics. Bioenergetic profiling included Seahorse XF analysis, 13 C-glucose/ 13 C-glutamine tracing, and pharmacologic modulation of CD38, mtROS, and ATP synthase. Results: Complete Lats1/2 deletion caused fatal edema and vascular leakage, while partial loss produced fragile, highly neovascularized plaques. Spatial proteomics revealed a CD38-driven senescence-associated stemness (SAS) phenotype under LATS1/2 deficiency. Metabolomics showed sulfite and taurine accumulation, consistent with SUOX deficiency. Mechanistically, CD38 suppressed SUOX, induced Complex V reverse-mode , increased succinate flux, and accelerated ATP consumption. Despite ATP depletion, glutamate metabolism and TCA cycle flux were enhanced, sustaining EC proliferation under energetic stress. LATS1/2 knockdown reduced mt respiratory capacity (lower OCR peak) without significantly increasing glycolysis, and DF suppressed both OCR and ECAR, indicating impaired energy metabolism under pathological shear stress. CD38 inhibition restored mt respiration and glycolytic capacity by preserving NAD, and rescuing LATS1/2 and DF-mediated defects. Blocking reverse-mode Complex V reduced DF- and LATS1/2-dependent EC senescence and proliferation. Conclusion: Complete LATS1/2 deletion causes fatal vascular leakage, while partial loss drives plaque formation with fragile neovessels through a CD38-dependent SAS phenotype. CD38 suppresses SUOX, induces Complex V reverse-mode , increases succinate flux, and accelerates ATP consumption, enabling EC proliferation despite energy stress. DF and LATS1/2 loss impair mt and glycolytic function, whereas CD38 inhibition restores mt respiration and reduces EC senescence and proliferation to prevent atherothrombosis in DF regions.

Most genetic variants associated with complex traits are hypothesized to regulate gene expression. To understand the genetics underlying gene expression variability, we characterized 14,324 RNA-sequencing samples from the Trans-Omics for Precision Medicine program and performed expression and splicing quantitative trait locus (e/sQTL) analyses in six tissues and cell types, including whole blood ( n = 6454) and lung ( n = 1291). We detected tens of thousands of secondary cis-e/sQTLs, showing that secondary cis-e/sQTL discovery remains unsaturated. We fine-mapped UK Biobank–derived genome-wide association study (GWAS) signals from 164 traits and identified e/sQTL colocalizations for 10,611 GWAS signals, including 7096 that colocalize with secondary e/sQTLs. Our results suggest that even larger e/sQTL analyses will uncover additional secondary e/sQTLs, further benefiting GWAS interpretation.

Abstract Recent single-cell transcriptomic studies of follicular lymphoma (FL) have revealed heterogeneity among malignant B (MB) cells and selected components of the tumor microenvironment (TME), but have been constrained by relatively small sample sizes and a lack of spatial context. We performed comprehensive cellular profiling and spatial dissection of over five million cells by integrating single-nucleus RNA sequencing (snRNA-seq) from 182 samples (FL, n = 167; control, n = 15) with single-cell spatial transcriptomics (ST) from 386 samples (FL, n = 365; control, n = 21). After stringent quality control, 1,289,073 and 3,968,427 cells from snRNA-seq and ST data, respectively, were analyzed. Unsupervised clustering of snRNA-seq data identified 58 TME cell subtypes. To extend this classification to the ST dataset, we integrated snRNA-seq and ST data by co-embedding them into a shared principal component space, enabling robust batch correction and cell-type label transfer across modalities. Using this supervised annotation framework, ST data recapitulated 54 TME cell subtypes. MB, proliferating MB (MBprolif), and healthy B (HB) cells were classified using sample-level unsupervised clustering in ST. Macrophages exhibited previously uncharacterized heterogeneity in transcriptomic profiles and spatial distribution. We identified CXCL13-expressing macrophage subtypes with high intra- and peri-follicular abundance, termed follicular macrophages (FMs). Non-negative matrix factorization of intrafollicular cell fractions identified five TME archetypes: FM, follicular stroma, two follicular T, and HB archetypes. The FM archetype was enriched for intrafollicular macrophages, including FMs, and showed a significantly higher proportion of grade 3A/3B cases (53.4%) compared to other archetypes (≤16.5%). It was also associated with a higher frequency of high tumor burden requiring treatment initiation rather than a watch-and-wait (WW) approach. Among patients managed by WW, those with the FM archetype showed significantly shorter event-free survival (EFS) compared to those with non-FM archetypes, whereas this association was not observed among treated patients. The percentage of intrafollicular macrophages (IFMP) showed excellent predictive performance for the FM archetype (area under the curve: 0.90). IFMP calculated in a published multiplex spatial protein imaging dataset from an independent cohort of 242 FL patients validated the associations between high IFMP and both pathology grade 3A/3B and shorter EFS in WW patients. Consistently, spatial neighborhood and cell–cell communication analyses revealed co-localization of FMs and MBprolif cells, forming a distinct niche with activated signaling mediated by FM-derived CXCL13, APRIL, and BAFF. Our integrative multi-modal analysis defines previously unrecognized cellular heterogeneity and spatial architecture in FL and highlights macrophage-enriched follicular ecosystems associated with aggressive clinicopathological features, providing a framework for improved biological understanding and patient management. Citation Format: Yoshiaki Abe, Bijal Thakkar, Atish Kizhakeyil, Ashley Wilson, Andrew L. Feldman, Jared Henderson, Amy Ayers, Sara Borgschatz, R. Andrew Harkins, Priya Lakra, Daisuke Kaji, Jonathon B. Cohen, David Russler-Germain, Eric Mou, Francisco Vega, Jennifer Chapman, Giorgio Inghirami, Carla Casulo, Izidore S. Lossos, Jean L. Koff, Chijioke Nze, Peter Martin, Sergei Syrbu, Kiran Vij, David L. Jaye, James R. Cerhan, Christopher R. Flowers, Anne J. Novak, Richard Burack, Dai Chihara, Mamiko Sakata-Yanagimoto, Joshua Tobin, Xubin Li, Michael R. Green. Spatially resolved microenvironment profiling reveals distinct follicular lymphoma archetypes [abstract]. In: Proceedings of the Fifth AACR International Meeting on Advances in Malignant Lymphoma: From Discovery to Clinical Impact; 2026 Jun 24-27; Philadelphia, PA. Philadelphia (PA): AACR; Blood Cancer Discov 2026;7(3_Suppl):Abstract nr A049.

Abstract Background Ionizing radiation (IR) accelerates atherosclerosis through induction of cellular senescence, DNA damage, defective efferocytosis, and dysregulation of clonal hematopoiesis (CH) drivers. Although low-dose colchicine reduces ischemic cardiovascular events in coronary artery disease, the precise molecular mechanisms underlying its vasculoprotective effects remain incompletely defined, and whether it mitigates radiation-associated vascular injury is unknown. Methods Bone marrow–derived macrophages (BMDMs) were pretreated with low-dose colchicine and exposed to 2 Gy IR. Molecular effects were assessed by RNA-seq, immunoblotting, and molecular docking. In vivo effects were tested in a partial carotid ligation (PLCL) model using spatial proteomics. Human monocyte-derived macrophages (HMDMs) from thoracic malignancy patients were analyzed before and after radiation therapy (RT). Results Low-dose colchicine suppressed IR-induced macrophage senescence signaling while preserving NRF2 activity. In a cell-free assay, colchicine directly activated aldehyde dehydrogenase 2 (ALDH2) in a dose-dependent manner (EC 50 1–5 nM), identifying ALDH2 as a direct molecular target of colchicine. Following irradiation, colchicine restored ALDH2, reduced mitochondrial (mt)ROS - dependent p90 ribosomal S6 kinase ( p90RSK ) activation and lipid peroxidation, preserved TET2 and DNMT3A expression, and rescued impaired efferocytosis while preventing nicotinamide adenine dinucleotide (NAD⁺) and adenosine triphosphate (ATP) depletion. These protective effects were ALDH2-dependent, as they were lost with ALDH2 inhibition or depletion and were mimicked by pharmacologic ALDH2 activation. In vivo, colchicine attenuated radiation-induced atherosclerosis and macrophage senescence-associated stemness (SAS). Consistently, macrophages from patients after RT showed reduced ALDH2 with increased mtROS, lipid peroxidation, and senescence. Conclusion These findings identify ALDH2 as a previously unrecognized molecular target of colchicine that links mitochondrial redox control to suppression of radiation-induced macrophage senescence and atherosclerosis and may contribute to the efficacy of low-dose colchicine in cardiovascular disease.

BACKGROUND: Atherothrombosis, which underlies most acute coronary syndromes and is driven by intraplaque thrombosis, preferentially occurs in regions of disturbed blood flow (d-flow). Although LATS1/2 (large tumor suppressor kinases 1 and 2) are known regulators of endothelial mechanotransduction, the mechanisms by which d-flow connects endothelial senescence, proliferation, and intraplaque thrombosis remain poorly understood. METHODS: We investigated endothelial cell (EC)-specific roles of Lats1/2 using inducible EC-specific knockout mice in a partial carotid ligation model. Spatial multiomics of human and mouse plaques was performed using imaging mass cytometry, COMET sequential immunofluorescence, and spatial metabolomics. RESULTS: Tamoxifen-induced deletion of both Lats1 and Lats2 (homozygous) in ECs caused fatal edema and increased vascular permeability. In contrast, Lats1 het ( ± ) / Lats2 homo ( −/−) -EC-specific knockout mice survived and developed spontaneous atherothrombotic plaques with neovascularization. Spatial proteomics revealed that LATS1/2 loss induced a senescence-associated stemness phenotype driven by CD38 upregulation. Spatial metabolomics showed sulfite and taurine accumulation, indicating SUOX (sulfite oxidase) deficiency. CD38 suppressed SUOX, demonstrated a switch into the reverse mode of mitochondrial complex V, increased succinate dehydrogenase activity, and promoted ATP consumption. Despite ATP depletion, glutamate metabolism and the citric acid cycle flux increased, sustaining EC proliferation under energetic stress. This senescence-associated stemness state promoted both proliferation and senescence, leading to fragile, leaky neovessels and intraplaque thrombotic lesions. Pharmacological CD38 inhibition attenuated these phenotypes. Similar EC states were observed in human plaques. CONCLUSIONS: Loss of Lats1/2 in ECs induces a CD38-associated senescence-associated stemness-like phenotype that promotes intraplaque thrombosis through mitochondrial metabolic reprogramming, including changes consistent with reverse-mode operation of mitochondrial complex V. These findings define a mechanistic link between disturbed flow, endothelial metabolic reprogramming, and intraplaque thrombosis and hemorrhage.

A new systems approach to diseased states and wellness result in a new branch in the healthcare services, namely, Personalized and Precision Medicine (PPM). To achieve the implementation of PPM concept, it is necessary to create a fundamentally new strategy based upon the recogni-tion of biomarkers and thus the targets to secure the grand future of drug design and drug dis-covery.Each decision-maker values the impact of their decision to use PPM on their own budget and well-being, which may not necessarily be optimal for society as a whole. It would be extremely useful to integrate data harvesting from different databanks for applications to provide more tai-lored measures for the patients resulting in improved patient outcomes, reduced adverse events, and more cost-effective use of the latest health care resources including diagnostic (companion ones or theranostics), preventive and therapeutic (targeted molecular and cellular) etc.Meanwhile, along with the impact of genomics and bioinformatics, pathology is the central specialty of PPM-related resources. Coupled with IT, the upgraded tools are ever more efficient and robust within clinical cancer settings. The latest algorithms may be able to identify and vali-date patterns which humans are not capable of quantifying easily, such as slight differences in textures or morphologies. In this sense, the impact of pathology allows a modular approach, as its various aspects are under development in several areas of PPM.Among the above-mentioned medical specialists involved in PPM, the pathologists play an im-portant and key role in the implementation and development of PPM-driven resources that are in the center of decision of many therapeutic choices. Recent advances in systems biology have tremendously affected the practice of precision pathology, gradually transforming it from a morphology-based into a precise molecular-based discipline. The enormous development of precision pathology research (integrating molecular OMICS and digital approaches) has raised great expectations concerning its impact on PPM aiming to custom-ize medical practice with a focus on the individual, based on the use of molecular tests, identifi-cation of genomic biomarkers, and development of targeted drugs.The precision pathology process introduces a new paradigm in pathology by leveraging digital imaging and IT technologies, and provides significant advancements in accuracy, efficiency, and collaboration. Among the latest innovations the precision pathology supported by digital tools, would dictate the implementation of high-resolution imaging, image analysis tools and integra-tion with molecular OMICS data. Integration of the approaches and resources will provide a true challenge for the future, requiring collaboration between oncologists, pathologists, biodesigners and bioengineers and remaining a challenge to precision cancer practice and profiled bioindustry.The latter requires precision pathologists highly trained in pre-analytic processes, tumor area mi-crodissection for tumor cell enrichment, methodology analysis and results. The in-depth study of molecular alterations in patients allows optimizing molecular diagnosis and selecting candidates for receive novel treatments against specific molecular targets. These patients would benefit from multidisciplinary approach and learning. In this sense, molecular diagnostics has a long tradition in pathology, especially in clinical one, where various OMICS-analyses of cancers are incorpo-rated into diagnostic and decision-making algorithms to secure a way where the pathologists con-tinue to play an essential role in developing and implementing molecular profiling tests in practice and communicate the results and their relevance with cancer practitioners.Cancer pathology is the central specialty of personalized and precision oncology (PPO). Meanwhile, the combination of comprehensive biobanking and the next wave of theranostic pathology technologies provides a natural, externally visible infrastructure that now allows pa-thology as a discipline – to engage directly with the biotechnology and pharma sector. We’re at an exciting junction in precision cancer pathology’s growth as a medical specialty, and pathology-driven biobanking is becoming both central to our core expertise and, even more importantly, a powerful enabler for many of the most promising growth areas of our discipline: PPM healthcare, clinical trials and drug development, theranostics, and functional assessment and monitoring of disease. In the context of these changes and challenges, the precision cancer pathology can play a fundamental role in both PPO-guided clinical practice and biodesign-driven cancer research.

Significance: Immune checkpoint inhibitors (ICIs) have transformed cancer therapy by reactivating antitumor immunity and improving outcomes across multiple malignancies. Yet, clinical observations and preclinical studies suggest that ICIs may increase long-term cardiovascular disease risk, including hypertension, atherosclerosis, and thrombosis. The underlying mechanisms remain incompletely defined, highlighting the need for focused investigation into the vascular consequences of immune activation. Recent Advances: ICI-induced immune activation disrupts vascular and immune homeostasis through persistent production of reactive oxygen species (ROS), mitochondrial dysfunction, and accumulation of cell-free DNA (cfDNA). Sustained T-cell activation enhances ROS generation, driving DNA damage and senescence in both endothelial and immune cells. ICIs may also promote endothelial-to-mesenchymal transition (EndoMT) through chronic oxidative and inflammatory signaling, contributing to fibrosis, vascular stiffness, and chronic inflammation. Transforming growth factor-beta, although immunosuppressive in many contexts, can drive profibrotic and EndoMT programs within the vasculature. Other cytokines and regulators, including interleukin-17 and regulator of calcineurin 1, have been implicated in vascular remodeling, atherosclerosis, and hypertension. Critical Issues: The relative roles of ROS, mitochondrial dysfunction, cfDNA-driven inflammation, and EndoMT in ICI-associated vascular senescence remain unclear. While inflammation-induced vascular damage is well-recognized, direct ICI-specific mechanisms require stronger evidence. How senescent endothelial and immune cells influence therapy resistance and remodeling of the tumor microenvironment also remains to be defined. Future Directions: Mitochondrial and cytosolic ROS sources—arising from electron leakage during oxidative phosphorylation and NADPH oxidases activity—shape immune signaling and sustain T-cell activation during checkpoint blockade. The DNA damage response kinases ataxia-telangiectasia mutated and ATM- and Rad3-related, activated by oxidative and replicative stress, engage p53-dependent senescence pathways in endothelial and immune cells. Future studies should evaluate biomarkers such as cfDNA and thrombospondin-1 and explore senescence-targeting or redox-modulating interventions that may alleviate cardiovascular toxicity without diminishing antitumor efficacy. This review outlines mechanistic pathways linking ICIs to vascular dysfunction and senescence, integrating preclinical data with emerging clinical insights. It distinguishes established processes from ICI-specific hypotheses and identifies key gaps requiring clinical validation. Antioxid. Redox Signal. 00, 000–000.

ABSTRACT Background and Aims Chronic inflammatory demyelinating polyradiculoneuropathy ( CIDP ) is a common, treatable, autoimmune, neuropathy frequently misdiagnosed. The complex electrodiagnostic ( EDX ) criteria required for diagnosis are challenging to apply in routine practice. This study evaluates the effectiveness of a machine‐assisted EDX tool in real‐time identification of demyelinating nerve conduction studies ( NCS ) stipulated by 2021‐ EAN / PNS CIDP criteria in conjunction with an online CIDP clinical probability calculator. Methods We prospectively evaluated 100 consecutive patients with referral or EDX diagnosis of polyradiculoneuropathy beginning January 1, 2024. Fifty patients were included, each from Jacksonville and Rochester Mayo Clinics. Routine electromyography ( EMG ) reports were compared to a machine‐assisted support tool applying 2021‐ EAN / PNS CIDP EDX criteria to NCS assessing demyelination. The EDX ‐assistant performance was compared to the final clinical diagnosis and our previously reported online CIDP clinical prediction tool ( https://news.mayocliniclabs.com/cidp‐calculator/ ). Results Among 100 patients (60% male; median age 64), 30 had a final clinical CIDP diagnosis with 29 having intravenous immunoglobulin follow‐up; 27 (93%) improved and 2 (7%) stabilized. Routine EMGs reported demyelination in 14 of 30 (47%), with 46% sensitivity and 79% specificity. The EDX ‐assistant identified CIDP demyelination in 28 of 30 (93%), with 93% sensitivity and 57% specificity. The clinical calculator detected CIDP in 30 of 30 (100%) with 86% specificity, increasing to 94% after excluding false positives lacking demyelinating features on the EDX tool. Interpretation A real‐time machine‐assisted EDX support tool, used with a clinical web‐based calculator, streamlines CIDP assessment by improving standardized identification of 2021‐EAN/PNS CIDP demyelinating NCS criteria and aiding clinical decisions.