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11064 Background: Local and state paid sick leave (PSL) mandates have been associated with increased use of preventive services, including cancer screening, and reduced emergency care utilization. Little research has examined PSL policies and cancer after diagnosis. This study evaluates associations of PSL policies and timely treatment initiation among women with early-stage breast cancer. Methods: We identified patients aged 18-64 years newly diagnosed with stages 0-II breast cancer from the National Cancer Database in 2004-2023 and linked then to area-level policy implementation, measured as the month and year the state, county, or city required PSL. Primary outcomes were receipt of definitive surgery or neoadjuvant therapy within 30, 60, and 90 days of diagnosis. We compared changes in treatment initiation between patients residing in areas with and without PSL policies during and after the month and year of diagnosis. We used a staggered difference-in-differences design to account for differential timing of implementation, adjusting for patient demographics, clinical, and area-level characteristics. Random errors were clustered at the state level. Supplemental analyses stratified by county-level unemployment rates and individual insurance coverage. Results: The study included 1,891,411 patients, of whom 249,313 (13.2%) resided in an area with PSL policies at diagnosis. Patients in areas with PSL policies were more likely to have Medicaid, reside in higher-income and metropolitan areas. PSL policy implementation was significantly associated with a 3.4 percentage point (PPT) increase in the probability of treatment ≤30 days (95% CI: 1.1-5.7), 3.0 PPT increase ≤60 days (95% CI: 1.6-4.3), 1.3 PPT increase ≤90 days (95% CI: 0.5-2.1) (Table). Improvements in timely treatment were concentrated in low-unemployment areas; no significant improvements were observed in high-unemployment areas. The magnitude of associations between PSL policies and treatment initiation was stronger among patients without private insurance than with private insurance. Conclusions: Local and state PSL mandates were associated with earlier treatment initiation among working-age patients with early-stage breast cancer, especially in areas with low female unemployment rate. Findings suggest that PSL policies play an important role in timely cancer treatment for employed women who may not have PSL through their jobs. Association of paid sick leave policies and breast cancer treatment initiation. Time from diagnosis to surgery/neoadjuvant therapy (days) DID PPT Lower 95% CI Upper 95% CI P-value Overall ≤30 3.4 1.1 5.7 0.004 ≤60 3.0 1.6 4.3 0.000 ≤90 1.3 0.5 2.1 0.001 Low female unemployment ≤30 2.2 -0.7 5.0 0.136 ≤60 3.8 1.8 5.8 0.000 ≤90 1.2 0.3 2.2 0.012 High female unemployment ≤30 1.8 -0.6 4.2 0.145 ≤60 -1.2 -4.5 2.0 0.459 ≤90 -1.4 -3.7 0.9 0.232

Abstract Introduction Biliary fibrosis and inflammation are central to the pathogenesis of cholangiopathies such as primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC). Inflammatory and fibrogenic stimuli, such as transforming growth factor-β (TGFβ) and lipopolysaccharide (LPS) signaling, drive these processes, but their underlying transcriptional mechanisms in cholangiocytes remain incompletely defined. We investigated the role of Runt-related transcription factor 1 (RUNX1) as a transcriptional co-regulator of fibroinflammatory signaling in cholangiocytes. Methods Human PSC-derived cholangiocytes (PSC-Cs) and mouse large biliary epithelial cells (MLEs) were subjected to RUNX1 knockdown or pharmacologic inhibition (Ro5-3335 or AI-10-104). Cytokine secretion was profiled by Luminex multiplexing; RUNX1 genomic binding and protein interactome were assessed by ChIP-qPCR, ChIP-seq, and LC-MS/MS. In vivo , Mdr2 −/− mice received Ro5-3335, and cholangiocyte-selective Runx1 knockout mice (Krt19-CreERT) were challenged with a DDC diet, followed by evaluation of fibrosis and inflammation. Results RUNX1 expression was significantly increased in cholangiocytes from PSC and PBC patients, and Mdr2 −/− mice. RUNX1 knockdown or inhibition reduced IL6, TNFα, and other proinflammatory cytokines in PSC-Cs and attenuated TGFβ-, LPS-, and TNFα-induced Il6 and Ccl2 expression in MLEs. ChIP-qPCR and ChIP-seq revealed TGFβ-induced RUNX1 binding to the Il6 promoter and 727 additional genomic sites enriched for fibrosis and inflammatory pathways; predicted upstream regulators included TGFβ, TNF, and NFκB signaling. Proteomic analysis identified TGFβ-induced RUNX1 interactions with SMAD2 and NFκB2. In vivo , Ro5-3335 treatment in Mdr2 −/− mice reduced hepatic collagen, ECM gene expression, immune cell infiltration, and serum liver injury markers and bile acids. Similarly, cholangiocyte-specific Runx1 deletion mitigated fibrosis, inflammation, and liver injury in DDC-fed mice. Conclusion RUNX1 is a central transcriptional hub integrating TGFβ and inflammatory signals in cholangiocytes. Its inhibition attenuates biliary fibrosis and inflammation in cholestatic models, supporting RUNX1 as a potential therapeutic target in fibroinflammatory cholangiopathies.

Multiple sclerosis (MS) is an immune-mediated chronic inflammatory and degenerative disease of the central nervous system (CNS). Typically occurring in young and middle-aged individuals, untreated MS can have high rates of disability and recurrence, thereby imposing a significant burden on the patient, their family, and society. Many factors are implicated in the etiology of MS, with the relationship between Epstein-Barr Virus (EBV) infection and the development of MS being the subject of extensive research recently. When the human body experiences a decline in immune function, it may trigger reactivation of EBV, and this reactivation is also believed to increase the risk of onset or relapse of MS. Currently, the phenomenon of cross-reactivity resulting from molecular mimicry following EBV infection (including reactivation status) is theorized as a contributing etiology. EBV-mediated abnormalities in T cells and B cells also play a key role in the development of MS. However, the underlying mechanisms have not been thoroughly understood. Meanwhile, the limited availability of effective treatment options for MS, in particular MS progression, underscores the urgent need for novel therapeutic strategies. Here, we discuss the pathophysiological mechanisms underlying MS, specifically emphasizing the relationship between EBV infection and the disease pathology. Furthermore, we introduced relevant pharmacological targets in order to propose a broader range of therapeutic alternatives for individuals diagnosed with MS.

PURPOSE We tested the hypothesis that adding metastasis-directed therapy (MDT) to standard-of-care (SOC) systemic therapy improves progression-free survival (PFS) among patients with oligometastatic disease. METHODS EXTEND was a multicenter randomized phase II trial. Patients with 1-5 metastases were randomly assigned to MDT + SOC versus SOC in one of the six baskets (breast, pancreas, kidney, two prostate baskets, and an other basket) with basket-specific stratification and powering. PFS, the primary end point, was prespecified in the per-protocol set within each basket, across all baskets, and across all baskets excluding the prostate baskets. Exploratory end points included circulating tumor DNA (ctDNA) and immune profiling. RESULTS From 2018 through 2023, 521 patients were screened, 350 were randomly assigned, and 334 were analyzed per protocol (MDT + SOC, n = 166; SOC, n = 168). Radiotherapy was used as MDT for 98% of metastases (370/379). Overall, after a median follow-up of 53 months, PFS was improved with MDT + SOC (hazard ratio [HR], 0.54 [95% CI, 0.41 to 0.72], P < .001). Similarly, PFS was improved when excluding the prostate baskets (HR, 0.60 [95% CI, 0.40 to 0.89]). Within each basket, PFS superiority was identified for the pancreas, prostate, and other baskets, whereas the breast and kidney baskets were inconclusive. At enrollment, detectable ctDNA correlated with shorter PFS and survival; by contrast, ctDNA clearance 3 months postenrollment correlated with improved survival. MDT + SOC-induced systemic immune activation was most pronounced among baskets demonstrating PFS superiority. CONCLUSION The phase II EXTEND trial supports the addition of MDT to SOC for oligometastatic disease. Histology-specific efficacy signals were identified for phase III testing. Translational insights suggest the potential for optimizing the definition of oligometastasis using ctDNA and point to systemic immune responses as a possible mechanism of benefit from MDT.

Introduction: Endothelial cell (EC) dysfunction, driven by comorbidities of heart failure with preserved ejection fraction (HFpEF), has emerged as a potential contributor to disease progression, yet the EC specific molecular mediators in HFpEF remain poorly defined. Purpose: To identify EC-specific molecular mediators that are involved in HFpEF and determine their functional roles in disease pathogenesis. Hypothesis: Based on omics analysis of a murine HFpEF model, we hypothesized that EC plasminogen activator inhibitor-1 (PAI-1) is a key mediator of HFpEF pathogenesis. Methods: Male RiboTagEC (Cdh5CreERT2+/Rpl22HA/+) mice were used in a HFpEF model induced by hypertensive/metabolic stresses (60% calories from lard and L-NAME 0.5 g/L in water) or administrated with normal water and diet as controls. Hearts and skeletal muscle were collected for both bulk RNA sequencing (Bulk-seq) and EC-specific translatome analysis using translating ribosome affinity purification assay followed by RNA-sequencing (TRAP-seq). The functional roles of EC PAI-1 were tested using male tamoxifen-inducible, endothelial specific PAI-1 knockout (Cdh5CreERT2+/PAI-1flox/flox, PAI-1iEC KO) and control mice (PAI-1flox/flox, PAI-1iEC+/+) subjected to HFpEF induction. Cardiac function was assessed by echocardiography, pressure–volume (PV) loop analysis, and treadmill exercise testing. Student’s t-test was used (p < 0.05). Results: Bulk-seq and EC-specific TRAP-seq identified PAI-1 as one of the most upregulated genes in both heart and skeletal muscle EC in HFpEF. Bulk-seq demonstrated a 2.5-fold change (FC, log 2 FC=1.35) increases in the heart and 12.2-fold increases (log 2 FC = 3.61) in the skeletal muscle. TRAP-seq showed a 1.75-fold change (log 2 FC=0.81) increases in the heart and 4.76-fold increases (log 2 FC = 2.25) in the skeletal muscle. These consistent findings led us to investigate the functional role of EC PAI-1 in the pathogenesis of HFpEF. With similar body weight (Control: 40±4 g, n=10; KO: 38±6 g, n=11; p=0.319) and ejection fraction (Control: 54±6 %, n=10; KO: 54±5 %, n=12; p=0.686), we found that PAI-1iEC KO mice exhibited improved diastolic function after 10 weeks of HFpEF induction. Specifically, echocardiography demonstrated a significant reduction in E/e′ in KO mice (Control: 27±4, n=10; KO: 24±3, n=12; p=0.018). PV analysis confirmed this improvement with lower end-diastolic pressure (Control: 19±2 mmHg, n=8; KO: 13±5 mmHg, n=10; p=0.009), reduced Tau (Control: 9.7±1.2 ms, n=8; KO: 8.6±1.0 ms, n=10; p=0.047), and a reduced EDPVR constant β (Control: 0.20±0.05, n=6; KO: 0.10±0.03, n=6; p=0.017). KO mice also exhibited improved treadmill running distance (Control: 179±35 m, n=10; KO: 214±40 m, n=12; p=0.043). Conclusion: Endothelial PAI-1 contributes to diastolic dysfunction and reduced exercise capacity in HFpEF. These findings highlight endothelial PAI-1 as a potential therapeutic target for HFpEF. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

Abstract Prostate adenocarcinomas (PRAD) can acquire resistance to androgen receptor signaling inhibitors through lineage transition to a cell state known as neuroendocrine prostate cancer (NEPC). Using a panel of isogenic PRAD and NEPC mouse tumoroids, we show that NEPC cells acquire new transcription factor (TF) dependencies that function in a previously undefined network. Through selective perturbation of each TF, we identify ASCL1 as a key regulator of NE lineage fate whereas MYCL functions downstream to drive NEPC growth/survival by recruitment of the TIP60/KAT5 acetyltransferase. Interestingly, while dependencies on specific TF family paralogs can vary across NEPC models, all show markedly enhanced dependency on TIP60. Moreover, the H2A.Z-acetyltransferase activity of the TIP60 complex (TIP60-C) is required for NEPC as well as the acetyl-reader BRD8, which is newly incorporated as a TIP60-C subunit with the NEPC transition. Targeted degradation studies in isogenic tumoroids reveal increased dependence on MYCL in NEPC relative to its paralog MYC in PRAD. In addition to a paralog switch (MYC to MYCL), the MYC pathway-addicted NE state is accompanied by a chaperone switch (from TIP60-C to SRCAP) for H2A.Z histone exchange and a coactivator switch (to TIP60) for MYC target gene expression. The NE-specific coupling of MYCL with TIP60 reveals a previously unappreciated opportunity to target MYC-driven NE diseases through pharmacological inhibition of TIP60.

Inflammatory bowel disease (IBD) is driven by a breakdown in immune regulation and epithelial barrier function, yet the contribution of eosinophils to this process has remained poorly defined and controversial. While eosinophils infiltrate the intestinal mucosa during both flares and remission, their role in shaping disease outcomes is unclear. Our RNA-seq analyses of colonic eosinophils isolated from dextran sulfate sodium (DSS)-treated mice revealed a significant upregulation of cyclooxygenase (COX)-2 (gene name, Ptgs2 ). Eosinophil-specific deletion of COX-2 (Ptgs2 fl/fl eoCre +/− ) reduced IL-22 production and exacerbated DSS- and trinitrobenzene sulfonic acid (TNBS)-induced colitis, characterized by greater weight loss, higher disease activity, colon shortening, and epithelial injury. Administration of recombinant IL-22 reversed these phenotypes. Mechanistically, eosinophil-derived COX-2 enhanced IL-22 production by type 3 Innate lymphoid cells (ILC3s) through prostaglandin E2 (PGE 2 ) signaling. Consistently, Ptgs2 fl/fl eoCre +/− mice exhibited reduced colonic PGE 2 levels, while PGE 2 analog treatment restored IL-22 production and mucosal protection. Our findings identify eosinophil-derived COX-2 and PGE 2 as a critical regulator of IL-22 production during colitis, uncovering a eosinophil–ILC3 cross talk that safeguards the intestinal barrier and represents a promising therapeutic target in IBD.

Abstract Minimal residual disease (MRD) has been endorsed by the FDA Oncology Drugs Advisory Committee as an endpoint for accelerated approval in multiple myeloma based on individual patient data collected from randomized trials. However, emerging data from recent trials were not included. A novel artificial intelligence (AI)–assisted framework is proposed, which automates information identification and extraction, providing up-to-date analyses that confirm moderate trial-level and strong individual patient–level associations between MRD− rates at suspected complete response (MRD-CR) and survival endpoints in multiple myeloma. Specifically, this study utilized an AI-assisted framework that identifies relevant studies and filters critical information to analyze published data via 2 independent objectives. First, we examined the trial-level association using the coefficients of determination (R2) and its 95% confidence intervals (CI) based on published statistics of treatment effects on MRD and various endpoints. Next, we generated synthetic individual patient data with covariates through AI-curated tools to estimate the individual-level association. The AI tool searched for eligible randomized clinical trials (RCT). A total of 20 two-arm comparisons from 19 RCTs were analyzed. Trial-level analysis showed an R2 of 0.71 (95% CI, 0.52–0.89) pooling disease subpopulations. Furthermore, AI techniques were applied to create synthetic individual data, combining information extracted from Kaplan–Meier curves and subgroup analyses from published literatures. Using generated synthetic data, we estimated the individual-level correlation between MRD-CR rates and progression-free survival outcomes with a bivariate copula model and calculated a global odds ratio of 7.28 (95% CI, 5.60–8.95). Significance: (i) A novel AI-assisted framework is proposed, which automates information identification and extraction, providing rapid up-to-date analyses. (ii) Moderate trial-level and strong individual patient–level associations between MRD and various clinical endpoints in multiple myeloma are confirmed.