Citations

Abstract Colorectal cancer develops through a normal-adenoma-carcinoma sequence, yet only 5-10% of adenomas progress to malignancy, and the cellular programs governing that sequence remain poorly defined. Here we generate a spatial multi-omics atlas of human colon adenomas, combining Visium CytAssist and protein co-detection across 24 nonadvanced and advanced tubular adenomas with single-cell resolution Xenium Prime 5K profiling of 101 patient-matched normal, adenoma, and carcinoma cores from 16 patients. Integrating whole-transcriptome and 31-plex protein data identifies nine spatial clusters and two dysplastic epithelial populations that co-express stemness, proliferation, and senescence programs. These programs occupy a shared, spatially confined epithelial niche that expands from adenoma to carcinoma. Spatial analysis revealed GDF15, a senescence-associated secretory factor, mediated the coupling between senescence and stemness in advanced adenomas, and that GDF15-high epithelium locally excludes CD8+ T cells in adenoma and, more broadly, in carcinoma. These findings position senescence as a spatially instructive rather than merely tumor-suppressive program during colorectal carcinogenesis and suggest GDF15 might be a potential candidate target for cancer prevention and interception in the colon.

Importance Elevated low-density lipoprotein cholesterol (LDL-C) is a modifiable risk factor for cardiovascular disease, the leading cause of premature death worldwide. Assessing the LDL-C–related burden is critical for guiding prevention and treatment strategies. Objectives To estimate the global, regional, and national burden of ischemic heart disease and ischemic stroke attributable to elevated LDL-C (relative to 35-54 mg/dL) from 1990 to 2023 and to quantify the contributions of population growth, aging, risk-deleted burden, and exposure changes to burden trends. Design, Setting, and Population This comparative risk assessment, part of the Global Burden of Disease Study 2023, estimated population-level LDL-C exposure and associated health loss in 204 countries and territories. Mean LDL-C levels were estimated using spatiotemporal gaussian process regression based on 806 studies across 161 countries. Relative risks were derived from meta-analyses of 38 randomized clinical trials. Population-attributable fractions for deaths and disability-adjusted life-years (DALYs) were estimated by age and sex for adults aged 25 years or older from 1990 to 2023, with 95% uncertainty intervals. Exposure Population-level LDL-C concentrations. Main Outcomes and Measures Population-attributable fractions, counts, and rates (all ages and age standardized per 100 000) of LDL-C–attributable deaths and DALYs from ischemic heart disease and ischemic stroke, with uncertainty intervals. Results In 2023, elevated LDL-C accounted for 3.6 million deaths (95% uncertainty interval, 2.2-5.4 million; 6.0% of global mortality) and 90.7 million DALYs (95% uncertainty interval, 58.9-123.3 million; 3.2% of DALYs). Although global all-ages rates remained stable, age-standardized death and DALY rates decreased by 45.6% and 39.5%, respectively, since 1990. In 2023, age-standardized LDL-C–attributable DALY rates were highest in Eastern Europe and lowest in high-income Asia-Pacific. One-third of the global LDL-C burden occurred in India and China. Population growth and aging drove the increasing burden, with notable regional disparities in LDL-C exposure and risk-deleted DALY rates shifting toward middle-sociodemographic settings. Conclusions and Relevance Despite declining age-standardized rates, the absolute LDL-C burden has increased since 1990 due to demographic changes and has shifted toward middle-sociodemographic countries. Measurement and surveillance gaps persist. Strengthened prevention, diagnosis, and treatment access strategies are essential to mitigate the health burden of LDL-C.

Background: Noninvasive tests are well validated in metabolic dysfunction–associated steatotic liver disease, but evidence in metabolic dysfunction and alcohol-associated liver disease (MetALD) and alcohol-associated liver disease (ALD) is limited. We evaluated noninvasive test–based clinical care pathways for fibrosis risk stratification in MetALD and ALD. Methods: This is a multinational, multicenter, cross-sectional study across 35 centers in 16 countries (2013–2025), including adults with MetALD or ALD. Fibrosis was assessed by liver biopsy and/or vibration-controlled transient elastography (VCTE). In biopsy-proven participants, we analyzed the sequential pathway (Fibrosis-4 [FIB-4] first, followed by VCTE for indeterminate FIB-4) to identify advanced fibrosis (≥F3). Diagnostic accuracy was assessed using the AUC. Results: Among 893 participants (41.3% MetALD and 58.7% ALD), the median age was 52 [43.0–61.0] years, and 79.4% were male. The estimated prevalence of advanced fibrosis was 45% (32.2% in MetALD and 54.0% in ALD). Participants with MetALD had a more dysmetabolic profile but lower fibrosis stages than ALD. Among biopsy-proven participants, FIB-4 AUC was 0.720, and VCTE AUC was 0.833. FIB-4 performed better in MetALD than ALD (AUC 0.773 vs. 0.540), while VCTE accuracy was similar across groups. In the sequential pathways, the false-negative rate for advanced fibrosis (misclassified as low risk) was 6.8% (4.9% MetALD and 11.3% ALD). Conclusions: In biopsy-proven patients, FIB-4 performance was acceptable in MetALD but substantially weaker in ALD. The standard 2-step pathway performed adequately in MetALD but missed a clinically meaningful proportion of advanced fibrosis in ALD.

Abstract Introduction It is critical for the immune system to destroy cells harboring intracellular infection to remove pathogen burden. This function is widely attributed to cytotoxic T cells, which can physically engage with their targets through the T cell receptor complex, releasing cytotoxic granules, resulting in a specific death of infected targets. However, effector cytokines tumor necrosis factor-α (TNF) and interferon-γ (IFNγ), secreted by T cells, are themselves cytotoxic in combination to a degree. While TNF has appreciated cell death function through the TNF receptor 1 (TNFR1) signaling pathway, no clear cytotoxic function is attributed to IFNγ. Because of the diffusible nature of these cytokines, it is possible for T cells to elicit cytotoxicity without requiring direct contact with their targets, termed paracrine killing. Whether paracrine killing occurs during viral infection and how it is regulated is unclear. Paracrine killing poses issues of both sensitivity to these cytokines in that high concentrations of these cytokines are needed to affect target cells, as well as specificity in discriminating infected from uninfected host cells. Accounting for both issues, we hypothesize that paracrine killing is elicited through pathogen restriction whereby only infected cells are susceptible to death. Methods Analysis was performed in vitro using the Incucyte live cell imaging system and Western blots with fibroblast targets and a VSV infection model and OT1 T cells were leveraged ex vivo. Results TNF and IFNγ protect cells against the cytopathic effect of the virus. TNF specifically synergizes with VSV resulting in death of the infected cells and the two cytokines have distinct roles that work in concert. We demonstrate that TNF and IFNγ released by activated T cells suppress viral infection of nearby cells in a paracrine manner. Conclusion Here we provide insight and context into how distinct cytokines function in a cooperative manner for immune protection during an infection. Funding Source Mayo Clinic Graduate School of Biomedical Sciences Topic Categories Viral Immunology (VIR)

Abstract Introduction Mucosal immunization and respiratory IgA offer significant promise in protecting against airborne pathogens, including SARS-CoV-2. However, the conditions and mechanisms that lead to the robust induction of respiratory IgA responses following mucosal vaccination remain poorly understood. Methods In this project, we established SARS-CoV-2 breakthrough infection and mucosal adenovirus-based booster vaccination models. Using genetic mouse models and various in vivo and in vitro blockade or depletion approaches, we further investigated the mechanisms regulating respiratory IgA responses. Results Here we found that a mucosal adenovirus-based booster vaccination in mouse models revealed that respiratory booster immunization elicited markedly stronger and more durable respiratory IgA, T cell response, and protective immunity against SARS-CoV-2, supporting the promise of respiratory mucosal vaccination. Mechanistically, we identified that local CD4+ T cells support respiratory IgA production by promoting IgA+ B cell class switching, proliferation, and survival in situ. This T cell help depended on interactions between local Blimp-1+ T-bet+ Th1 cells and B cells, mediated through ICOS/CD40L/MHC-II engagement and IL-21 signaling. Furthermore, lung macrophages contributed to the mucosal IgA response via TGF-β production. Consequently, mucosal administration of SARS-CoV-2 Spike-encoding mRNA encapsulated in pulmonary surfactant (PS)- incorporated lipid nanoparticles designed to target lung macrophages elicited a stronger mucosal IgA response. Conclusion Our results uncover a local cellular network supporting enhanced mucosal IgA responses, with implications for the development of optimal mucosal immunization strategies against SARS-CoV-2 and other respiratory pathogens such as H5N1 influenza. Funding Source AI147394, AG069264, AI112844, HL170961, AI154598, AI176171 to J.S., AI67986, AI177467 to Hui.H; U54CA260582 to S.L.L; R01AI168684 to G. Z.; S.L.L was also supported by a fund provided by an anonymous private donor to The Ohio State University. Topic Categories Mucosal and Regional Immunology (MUC)

Introduction: Co-stimulatory proteins are master regulators of the immune system. We identified the co-stimulatory CD40-CD40L dyad as a key driver of inflammation during atherosclerosis and have shown that CD40 and CD40L exert cell-type divergent functions. Hypothesis: CD40 is abundantly expressed on endothelial cells (EC) undergoing endothelial mesenchymal transition (EndMT). We hypothesize that EC CD40 drives atherosclerosis via EndMT. Methods: We analyzed scRNAseq data from human carotid plaques, performed multiplex IHC, and used human aortic endothelial cells (HAECs) for in vitro studies. A tamoxifen-inducible EC specific CD40 deficient atherosclerotic mouse model (cadherin5 (cdh5)ERT2-CD40 flfl -ApoE -/- ) was generated. Results: Besides its presence on immune cells, CD40 is expressed on endothelial cells in both human and mouse atherosclerotic plaques. Analysis of scRNAseq data of human carotid atherosclerotic plaques showed that CD40 is highly expressed in COL1A2/FN1 expressing endothelial cells (ECs), a subset undergoing EndMT. Multiplex staining revealed that CD40 colocalized with the EndMT markers αSMA, NOTCH3, TWIST and VCAM1 in human plaques. In vitro , stimulation of human arterial endothelial cells (HAECs) with CD40L resulted in an increase in the EndMT markers markers fibronectin, vimentin, sm22α, FSP1 and snail. Using phosphoproteomics, CD40L was found to decrease phosphorylation of the junctional integrity proteins CTNNA1 [S652; S655] and ARHGAP21 [S1383]. To investigate the endothelial-specific effects of CD40 in atherosclerosis, 8-week-old cdh5ERT2-CD40 flfl -ApoE -/- mice and their CD40 flfl -ApoE -/- littermate controls were treated with tamoxifen and fed a high cholesterol diet for 10 wks. Deletion of EC-CD40 resulted in a significant reduction in plaque size. This reduction was accompanied by a shift from fibrous cap atheromas (FCA) towards intimal xanthoma (IX) and pathological intimal thickening (PIT). Flow cytometry analysis of the spleen showed that CD40 deletion in ECs results in a significant decrease in CD8 and CD4 effector T cells. This decrease in CD8 and CD4 effector T cells was accompanied by a diminished activation status, shown by a decrease in CD69 + CD8 + CD62 - CD44 + T cells, CD40L + CD8 + CD62 - CD44 + T cells and CD40L + CD4 + CD62 - CD44 + T cells. These findings demonstrate that endothelial CD40 drives atherosclerosis by inducing EndMT-driven plaque inflammation.

ABSTRACT Introduction Cardiogenic shock (CS) carries high morbidity and mortality. However, evidence for mechanical circulatory support (MCS) in non‐ischemic CS remains limited, as prior trials have focused on infarct‐related shock. Methods We performed a retrospective cross‐sectional study using the Nationwide Inpatient Sample (2017–2019), identifying hospitalizations with a principal diagnosis of CS and excluding acute myocardial infarction. Patients were categorized into mutually exclusive groups: no MCS, intra‐aortic balloon pump (IABP) only, Impella only, or extracorporeal membrane oxygenation (ECMO) only. Primary outcomes were in‐hospital mortality, length of stay (LOS), and total hospital cost. Survey‐weighted multivariable models adjusted for demographics, hospital characteristics, and comorbidity burden using Elixhauser and Charlson indices. Results Among 104 045 hospitalizations, 6040 received MCS. IABP was most common, followed by Impella and ECMO. Among patients receiving a single MCS strategy, overall in‐hospital mortality was 29.5%., with lower mortality in the IABP group (19.9%) compared with Impella (37.4%) and ECMO (44.3%). After adjustment, IABP was associated with lower observed in‐hospital mortality versus no MCS (aOR 0.58, 95% CI 0.53–0.64; p < 0.01), whereas Impella and ECMO showed increased aOR. IABP and ECMO were associated with longer LOS, while Impella was not. All MCS strategies were associated with higher costs, with ECMO showing the greatest increase (cost ratio 3.30, 95% CI 3.12–3.50). Conclusion In non‐ischemic CS, MCS strategies demonstrate distinct profiles of mortality and resource utilization. IABP was associated with lower observed in‐hospital mortality, whereas all MCS were linked to higher costs, highlighting heterogeneity in outcomes and the need for further research.

Vascular stents are crucial devices in the treatment of cardiovascular diseases, and their structural design and function critically affect therapeutic efficacy and patient prognosis. Conventional stents can effectively restore vascular patency by providing mechanical support to blood vessels. However, they still face significant challenges including restenosis, thrombosis, and limited adaptability to complex patient-specific lesion characteristics. To address these limitations, drug delivery offers an important strategy to modulate the pathological microenvironment, enhance long-term vascular healing, and reduce systemic side effects. Meanwhile, advances in computational simulations have provided powerful tools for optimizing stent design through structural mechanics, hemodynamics, and drug release modeling. Computational approaches enable the rational design of stent architectures with improved mechanical stability, vascular compatibility, and therapeutic regulation. Consequently, the development of vascular stents is evolving toward the synergistic integration of drug delivery, structural optimization, and intelligent design. This review summarizes the latest advances in functional vascular stents, clinical applications and computational design. This work aims to provide valuable insights for the engineering of efficient, precise, and intelligent vascular stents for cardiovascular therapies.

Functional constipation (FC) and irritable bowel syndrome with constipation (IBS-C) are prevalent disorders of gut–brain interaction with limited effective treatments. The vagus nerve exerts considerable influence on the gastrointestinal (GI) tract, indicating that noninvasive electrical neuromodulation targeting this nerve could provide a promising therapeutic avenue for both FC and IBS-C. This review explores several emerging noninvasive neuromodulation techniques involving the vagus nerve, such as transcutaneous auricular vagal nerve stimulation, percutaneous electrical nerve field stimulation, and transcutaneous electrical acustimulation. The clinical applications of these methods in managing FC and IBS-C are evaluated. Existing evidence supports the efficacy and safety of noninvasive neuromodulation in relieving symptoms of these conditions. Future investigations should aim to refine these techniques, advance device technology, and further clarify the mechanisms of action.