Citations

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.

Abstract In many cancers, a major barrier to effective immunotherapy is the dominance of tumor-associated myeloid cells (TAMs), which establish a profoundly immunosuppressive tumor microenvironment (TME). This challenge is particularly pronounced in glioblastoma (GBM), where myeloid cells represent the predominant immune population and actively suppress antitumor immunity. Identifying targets that can reprogram TAMs from an immunosuppressive state toward a pro-inflammatory, antigen-presenting phenotype remains a critical unmet need. Here, we identify the voltage-gated proton channel Hv1 as an immune-restricted regulator of glioma-associated macrophage function. Hv1 is notable not only for its immune-specific expression but also for its established roles in central nervous system (CNS) pathologies, where Hv1 depletion alters microglial and macrophage polarization, reduces myeloid accumulation, dampens inflammatory cytokine production, and limits secondary tissue damage. However, Hv1’s role in shaping the GBM immune landscape—particularly in vivo—has remained poorly understood due to low Hvcn1 transcript abundance and the lack of reliable antibodies and genetic tools. Given the dominance of myeloid cells in GBM and their central role in tumor immune regulation, we sought to define Hv1 function within this highly immunosuppressive brain TME. Analysis of patient datasets revealed that elevated Hv1 expression correlates with poor clinical prognosis. Consistently, Hv1 loss significantly prolonged survival in multiple murine glioma models. Using in vivo two-photon imaging and spectral flow cytometry, we show that Hv1 depletion reprograms TAMs toward an anti-tumor phenotype characterized by enhanced tumor cell phagocytosis, improved antigen presentation, and increased T cell infiltration. By generating new Hv1 reporter and conditional mouse lines, we further demonstrate that tumor-associated microglia and infiltrating macrophages are the principal sources of Hv1 and markedly upregulate its expression in response to glioma. Notably, selective deletion of Hv1 in infiltrating macrophages phenocopied the survival benefit observed with global Hv1 loss. Mechanistically, using mass spectrometry and genetic models, we identify the Stimulator of Interferon Genes (STING) as a previously unrecognized binding partner of Hv1, placing Hv1 within the STING signaling pathway, a central regulator of innate and adaptive immune responses. Together, these findings fill a critical gap in understanding myeloid Hv1 function in GBM and identify Hv1 as a promising target for reprogramming the tumor immune microenvironment. Citation Format: Jiaying Zheng, Lingxiao Wang, Shunyi Zhao, Katayoun Ayasoufi, Meijie Wang, Praveen N. Pallegar, Peter R. Strege, Langni Liu, Yushan Wan, Wenjing Zhang, Emma N. Goddery, Manling Xie, Arthur Beyder, Aaron J. Johnson, Long-Jun Wu. Myeloid Hv1-STING axis tunes glioma immunity [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Brain Cancer; 2026 Mar 23-25; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2026;86(6_Suppl):Abstract nr A016.

Abstract Purpose: The Pancreatic Cancer Detection Consortium (PCDC) performed a blinded Early Detection Research Network–defined phase II biomarker bakeoff study of blood-based biomarker panels. The aims were to evaluate panel performance, to compare the panels’ performance with that of cancer antigen 19-9 (CA19-9) alone, and to evaluate the performance of new combinations of the individual biomarkers. Experimental Design: Ten biomarkers representing eight biomarker panels and CA19-9 were evaluated using plasma, serum, and germline DNA from 140 stage I to IV pancreatic ductal adenocarcinoma (PDAC) cases and 140 controls from three tertiary care institutions, with controls frequency matched to cases on age and sex. LASSO regression was employed to explore new biomarker combinations. The primary metric was area under the receiver operating characteristic curve (AUC). Results: The study population was 51% female, with median age 67.3 (minimum: 45, maximum: 90) years. Biomarker panel AUCs ranged from 89.9 to 96.3; the AUC for serum CA19-9 alone was 91.7 [95% confidence interval (CI), 87.8–95.6]. Two panels had significantly higher AUCs than serum CA19-9 alone, the CA19-9/FUT2/3 panel (AUC = 96.3, P = 0.002), and the tissue factor pathway inhibitor/tenascin C (TFPI/TNC-FNIII-C) panel (AUC = 95, P = 0.01). Exploratory models to recombine biomarkers retained all but two biomarkers [optimism-corrected AUC = 96.4 (94–98.9)]. Conclusions: The CA19-9/FUT2/3 panel was the best performing panel in this biomarker bakeoff. Its evaluation in larger studies is warranted. Biomarker bakeoffs are an effective strategy for comparing the performance of promising biomarkers for pancreatic cancer early detection, and the PCDC is well poised to conduct such studies. Recommendations for performing such studies are provided.

ABSTRACT Background Antiplatelet management in patients hospitalised for gastrointestinal bleeding (GIB) after percutaneous coronary intervention (PCI) requires balancing risks of rebleeding and clinical vascular events. Aims Evaluate the impact of antiplatelet resumption timing post‐endoscopy on rebleeding and clinical vascular events. Methods We performed a retrospective nationwide cohort study of patients hospitalised with post‐PCI GIB on dual antiplatelet therapy (DAPT) using the Vizient Clinical Database. Co‐primary outcomes were 30‐day rebleeding and 90‐day clinical vascular events after endoscopy. Multivariable Cox proportional hazards regression analysis was performed. Results Among 2979 patients with both antiplatelet agents held before endoscopy for GIB (46.0% upper; 34.8% lower), antiplatelet resumption > 7 days post‐endoscopy was associated with decreased 30‐day rebleeding (hazard ratio [HR] 0.66; 95% confidence interval [CI] [0.49–0.87]) and increased 90‐day clinical vascular events (HR 1.18 [1.02–1.36]) compared to restarting ≤ 1 day post‐endoscopy. Among 869 patients with one antiplatelet agent held before endoscopy for GIB (47.3% upper; 36.3% lower), resumption at > 7 days vs. ≤ 1 day had HR 0.69 (0.41–1.14) for rebleeding and HR 1.41 (0.97–2.04) for clinical vascular events. HRs for antiplatelet resumption > 3 days vs. ≤ 1 day post‐endoscopy were similar. Conclusions Antiplatelet resumption > 7 days after endoscopy in patients hospitalised with post‐PCI GIB is associated with decreased 30‐day rebleeding but increased 90‐day clinical vascular events compared with resumption ≤ 1 day post‐endoscopy. Similar tradeoffs were noted with antiplatelet resumption > 3 days post‐endoscopy. To optimise competing risks of rebleeding versus clinical vascular events, antiplatelet therapy should be resumed no later than 7 days post‐endoscopy, and preferably within 3–4 days.

Abstract Lentigo maligna (LM) is a subtype of cutaneous melanoma in situ that develops on chronically sun‐damaged skin in elderly individuals. Its diagnosis and management remain challenging due to its slow progression, frequent occurrence on cosmetically sensitive areas in frail individuals, and tendency for subclinical peripheral extension. Despite its potential for invasive transformation, the natural history of LM remains incompletely understood and evidence‐based management strategies for this specific entity remain limited. This work aims to bridge the gap between scarce high‐quality evidence and the clinicians' need for practical guidance on LM management by formulating evidence‐based and expert consensus‐driven recommendations for diagnosis, treatment and follow‐up. Under the coordination of the International Dermoscopy Society, a global, multidisciplinary consortium of 53 experts—including dermatologists, dermato‐oncologists, dermatologic surgeons, radiologists, radiotherapists, pathologists and epidemiologists—formulated recommendations through structured consensus, informed by a comprehensive review of current scientific evidence and clinical practice standards. Optimal management of LM requires accurate diagnosis and individualized treatment planning. Non‐invasive skin imaging techniques, especially dermoscopy and reflectance confocal microscopy, aid in diagnosis, biopsy orientation, lesion delineation and post‐treatment monitoring. Multiple partial biopsies help confirm diagnosis and rule out invasion. Complete surgical excision remains the first treatment option. No definitive safety margins can be recommended for standard surgery; margin‐controlled techniques are preferable for large or ill‐defined lesions. Topical imiquimod and radiotherapy are effective alternatives where surgery is unsuitable. Topical imiquimod is useful as primary, adjuvant or neoadjuvant therapy. Blind destructive methods should be avoided. Close clinical and imaging follow‐up is needed. Patient‐centred care, shared decision‐making, and a multidisciplinary approach are critical for optimal outcomes. These international consensus recommendations summarize current best practices for LM management, offering practical, evidence‐informed guidance to clinicians while acknowledging the potential of future research in refining these conclusions.

Cellular and molecular heterogeneity in the liver has been increasingly recognized to drive liver fibrosis progression, but the particular events that occur initially in response to liver injury and trigger immune cell recruitment remain unclear. Here, we identify epigenetically aberrant liver sinusoidal endothelial cells (LSECs) as key players in this process. Mechanistically, the epigenetic readers like bromodomain-containing protein 4–dependent (BRD4-dependent) super enhancers (SEs) activate proinflammatory genes, including promyelocytic leukemia (PML). The PML protein, in turn, binds BRD4 and amplifies proinflammatory angiocrine signaling through phase separation–dependent SE activation via PML/BRD4 condensate formation. In mouse models, LSEC-specific depletion of the PML/BRD4 complex mitigates liver inflammation and fibrosis. Single-cell RNA-seq reveals that epigenetically aberrant LSECs exhibit a reprogrammed proinflammatory angiocrine landscape in mouse fibrotic livers. TIMP1 + LSECs promote the recruitment of CD63 + monocyte–derived macrophages (MoMFs) during liver fibrosis progression. Thereby, PML/BRD4 in LSECs governs inflammatory immune cell recruitment in liver fibrosis. Pharmacological BRD4 inhibition or epigenetic PML-SE repression alleviates liver inflammation and fibrosis. In conclusion, PML/BRD4-mediated SE activation via phase separation drives proinflammatory angiocrine signaling in LSECs, initiating the inflammatory cascade and subsequent immune cell recruitment during liver fibrosis.

ABSTRACT Glucagon‐like peptide‐1 (GLP‐1) receptor agonists (GLP‐1 RAs) improve glycaemia and reduce body weight, yet their organ‐level actions on skeletal muscle remain incompletely defined. Framing skeletal muscle as an integrated unit of vasculature and muscle cells, we synthesize evidence with emphasis on glucose and protein metabolism. GLP‐1 and GLP‐1 RAs recruit microvasculature in muscle, expanding capillary surface area and increasing delivery of insulin, glucose, and amino acids. Microvascular recruitment increases interstitial insulin availability and potentiates insulin‐stimulated glucose uptake and glycogen synthesis, whereas direct effects of GLP‐1 on muscle cells remain under investigation. For protein metabolism, microvascular recruitment can enhance muscle protein synthesis when plasma amino acid availability is elevated, whereas effects under basal (fasted) conditions remain unclear. Elucidating the uncertainty regarding GLP‐1 receptor localization in human muscle cells will clarify whether direct signaling occurs within muscle cells, thereby improving our understanding of the relative contribution of direct versus perfusion‐mediated actions of GLP‐1 RAs. Clinically, GLP‐1 RAs reduce lean body mass, likely reflecting energy‐deficit–mediated effects, but studies directly assessing muscle mass are still limited. Overall, current evidence indicates that GLP‐1 RAs exert beneficial effects on muscle vasculature and muscle glucose metabolism. However, their influence on muscle protein turnover remains unclear—primarily due to observed reductions in muscle mass—despite preclinical data suggesting potential favorable effects on muscle protein metabolism that remain to be confirmed in humans.

Abstract Acute kidney injury (AKI) causes rapid loss of renal function with high morbidity and mortality. Our previous research showed that neuronal nitric oxide synthase (NOS1) mediates nitric oxide-dependent dilation of the afferent arteriole, inhibiting tubuloglomerular feedback (TGF), which critically regulates single nephron glomerular filtration rate (GFR). This mechanism could affect how vulnerable the organ is to ischemic injury, but this has not been directly tested. In the present study, we generated inducible macula densa (MD)-specific NOS1 knockout mice (NKCC2-Cre-NOS1 flox/flox) using a new inducible NKCC2-Cre line crossed with NOS1 flox mice. AKI was induced by 18-min bilateral renal pedicle clamping at 37°C, followed by 48-h reperfusion. Kidney injury was assessed by measuring GFR, plasma creatinine, histology, cytokines, apoptosis, fibrotic factors, and proteomics. Complete NOS1 deletion in MD cells was confirmed through NKCC2/NOS1 immunofluorescence. MD NOS1 deletion enhanced the TGF response, which was further amplified following AKI compared with control (Cre −/−). Following AKI, compared with controls (Cre −/−), NOS1 knockouts showed a significantly lower GFR (236 ± 66 to 24 ± 22 μl/min) and higher plasma creatinine levels, alongside more severe tubular damage evidenced by H&E staining. Cytokine array analysis showed chemokines such as MCP-1 and CXCL1 and macrophage marker CD68 were significantly increased; Western blot analysis showed cleaved caspase-3 levels were significantly increased, indicating enhanced apoptosis. Additionally, fibrosis markers TIMP-1, collagen-3, and α-SMA were significantly up-regulated at both mRNA and protein levels. We further observed increased hypoxia marker hypoxia-inducible factor-1α in MD-specific NOS1 knockout mice (Cre +/−). Global label-free proteomic profiling with targeted validation identified genotype-dependent responses involving haptoglobin, Tacstd2, and Cyp20a1, linking NOS1 deficiency to exaggerated inflammatory, fibrotic, and metabolic pathways. These findings highlight a novel role of MD NOS1 and TGF in AKI pathophysiology, suggesting NOS1 targeting as a therapeutic strategy. Haptoglobin was identified as a downstream plasma signal of NOS1-dependent AKI responses, indicating potential translational value.