Cheng Hsin General Hospital

Bladder urothelial carcinoma (BLCA) remains a clinical challenge because of its high recurrence rate and the persistence of cancer stem cells (CSCs) within the tumor microenvironment (TME). Neuropilin-1 (NRP1) is recognized as a key orchestrator of epithelial–mesenchymal transition (EMT) and stemness in several malignancies; however, its specific mechanism in driving BLCA aggressiveness and CSC maintenance has not been fully elucidated. This study aimed to characterize the regulatory role of NRP1 in bladder cancer progression and identify potential therapeutic options. The clinical significance of NRP1 was first assessed using TCGA patient datasets and tissue microarrays. The functional roles of NRP1 were determined through CRISPR/Cas9-mediated knockout, shRNA-mediated knockdown, and overexpression of NRP1 in the T24 and 5637 cell lines. Bulk RNA sequencing and GSEA were utilized to identify downstream pathways, and ELISA and Western blotting were used to validate signaling interactions. Finally, a synergistic therapeutic strategy was tested using a subcutaneous xenograft nude mouse model. High NRP1 expression was significantly associated with advanced tumor stage, chemoresistance, and poor overall survival in patients with BLCA. Mechanistically, NRP1 regulated the IL-6–STAT3 signaling axis; NRP1 depletion significantly reduced IL-6 secretion and phosphorylated STAT3 levels, thereby impairing sphere formation and EMT features. Conversely, exogenous IL-6 treatment rescued the CSC phenotype in NRP1-deficient cells. Clinically, NRP1 expression strongly correlated with IL-6 and STAT3 levels, and patients with high expression of NRP1 and IL-6 had significantly worse survival outcomes, identifying NRP1–IL-6 coexpression as a novel prognostic biomarker in BLCA. Based on these findings, we demonstrated that dual targeting with the NRP1 inhibitor EG00229 and the IL-6-neutralizing antibody siltuximab synergistically suppressed CSC self-renewal and inhibited tumor growth in vivo. This study provides a comprehensive characterization of the NRP1–IL-6–STAT3 axis as a fundamental driver of bladder cancer stemness. Our findings establish a foundational mechanistic proof-of-concept for a dual-targeting approach. By simultaneously inhibiting NRP1 and neutralizing IL-6, we demonstrated profound suppression of tumor-initiating capacity and CSC self-renewal. This strategy offers significant translational potential for improving clinical outcomes and overcoming therapeutic resistance in patients with aggressive BLCA.

White matter microdissection represents a valuable method for studying the three-dimensional organization of the human brain. Building on Klingler's classical technique, this approach has regained importance as both a research and educational tool in microneurosurgery. While the white matter dissection of the lateral aspect of the brain has been extensively described, the medial surface has received comparatively less attention. This article represents the second part of a three-paper series on white matter microdissection. It provides a structured, step-by-step demonstration of the dissection of the medial aspect of the brain, with a specific focus on the limbic lobe. As in the first paper, the core content is the supplementary video, which, through editing and annotation, has an enhanced didactic value. The dissection was performed according to the Klingler technique and recorded during the 8th Sulci, Gyri, Ventricles and Fiber Dissection Hands-on Course (Taipei, 2025). The procedure was conducted under microscopic magnification and edited into a didactic video presentation. All identifiable participants provided informed consent for publication. The dissection proceeds through nine main stages, beginning with the identification of the medial sulci and gyri and continuing with the sequential removal of cortical layers and white matter bundles. This systematic approach exposes the cingulum, inferior longitudinal fasciculus, callosal fibers, hippocampal formation, tapetum, thalamic peduncles, and mammillothalamic tract, illustrating the organization of the limbic lobe and the relationships between major white matter tracts and the ventricular walls. This work presents a comprehensive and didactic video demonstration of the medial hemispheric white matter dissection, highlighting the continuity and spatial relationships of limbic and periventricular structures. It contributes to a systematic and anatomically grounded understanding of cerebral white matter organization and supports the educational role of white matter microdissection in neurosurgical anatomy.

Patients with benign prostatic hyperplasia (BPH) have an increased risk of developing cardiovascular disease. Taking alpha-1 blockers is associated with an increased risk of major adverse cardiovascular events. Patients suffering from ischemic stroke (IS) may develop baroreflex and parasympathetic dysfunction-induced cerebral autoregulation impairment. The relationship between pharmacotherapy for BPH and the risk of recurrent IS remains unclear. The purpose of this study was to determine whether medications for BPH increase the risk of recurrent IS. This is a retrospective cohort study. Data from patients diagnosed with IS between 2000 and 2015 was collected from Taiwan National Health Insurance Database. Newly diagnosed IS patients were identified (International Classification of Diseases, Ninth Edition, Clinical Modification (ICD-9-CM): 433-437). BPH patients with an ICD-9-CM of 600 were identified. The event observed was recurrent IS after the firstever IS. The factors associated with recurrent IS were assessed via Cox proportional hazards regression. Recurrent IS was associated with BPH with an adjusted hazard ratio (HR) of 1.505 and a 95% confidence interval (CI) of 1.112-1.829, p < 0.001), and a competing risk model showed an adjusted HR of 1.544 (95% CI: 1.128-1.896, p < 0.001). The adjusted HR for treatment with alpha-1 blockers was 1.581 (95% CI: 1.16-1.915, p < 0.001), and increased risk with adjusted HR for treatment with high doses of 5-alpha reductase inhibitors over a long period of time are also at risk of recurrent IS. These findings highlight the association between BPH incidence and the risk of recurrent IS. The pharmacotherapy for BPH in IS patients should take great care.

BackgroundFine particulate matter 2.5 (PM2.5), a key indicator of air pollution, is classified as a human carcinogen. However, the link between air pollution and bladder cancer (BC) progression remains unclear. Dysregulation of the Wingless-related integration site (Wnt)/β-catenin and mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathways is a key driver of tumorigenesis in multiple cancers, including BC.ResultsThis study demonstrated that PM2.5 exposure enhances BC cell migration and invasion. Ribonucleic acid (RNA) sequencing identified the Wnt signaling pathway as a key regulator in PM2.5-exposed BC cells. Elevated protein levels of Wnt3A, Wnt5A, and β-catenin, along with the nuclear translocation of β-catenin, further highlighted the role of the PM2.5-activated Wnt/β-catenin pathway in promoting BC progression. The interaction between the Wnt/β-catenin and MAPK/ ERK pathways was examined using inhibitors and shRNAs. MEK or ERK inhibition not only suppressed PM2.5-induced upregulation of Wnt3A, Wnt5A, and β-catenin nuclear translocation but also significantly reduced the migration and invasion of PM2.5-exposed BC cells. Both pathways represent promising therapeutic targets, and several existing pathway-specific inhibitors may be repurposed for the future clinical management of PM2.5-induced BC progression.ConclusionsPM2.5 promotes BC progression through both the MAPK/ERK and Wnt/β-catenin signaling pathways. MEK/ERK inhibition suppressed PM2.5-induced nuclear translocation of β-catenin, suggesting that the MAPK/ERK pathway functions upstream of the Wnt/β-catenin pathway. This study provides mechanistic insights into how PM2.5 exposure drives BC progression and offers a potential foundation for developing targeted therapies for PM2.5-associated BC.Supplementary InformationThe online version contains supplementary material available at 10.1186/s12989-025-00656-3.

Colorectal cancer (CRC) remains a formidable clinical challenge due to immune escape, metastasis, and resistance to conventional therapies. This study engineered a tumor microenvironment (TME)-responsive platform of orthogonally masked polyethylene glycol (omPEG)-coated solid lipid nanoparticles (SLNs) for targeted combinatorial immunotherapy in EGFR/PD-L1/CTLA-4-dysregulated CRC. The formulation co-delivered NMS-873 (NM), a VCP/p97 inhibitor, to induce endoplasmic reticulum stress (ERS) and proteostasis collapse, together with bispecific PD-L1/CTLA-4 aptamers (P1C4) for dual checkpoint blockade. A complementary SLN formulation encapsulating galunisertib (G) and DNase (DN) degraded neutrophil extracellular traps (NETs) and suppressed tumor-associated neutrophils (TANs), thereby reshaping the immunosuppressive TME. The pH-sensitive omPEG shell preserved peptide ligand activity in circulation and enabled tumor-localized exposure of moieties targeting EGFR, ER, PD-L1, and CXCR2, thereby directing delivery toward CRC cells, tumor-associated macrophages (TAMs), and TANs. NM-induced ERS led to immunogenic cell death, G1 arrest, and apoptosis, while P1C4 co-loading suppressed epithelial-mesenchymal transition (EMT) and cancer stem cell (CSC)-like traits by downregulating N-cadherin/Slug/Snail/Smad and CD44/Oct4/Nanog/c-Myc/MMP-9 and restoring E-cadherin, thereby mitigating tumor migration and aggressiveness. The combinatorial treatment provoked potent antitumor immunity, reactivated dendritic and CD8⁺/CD4⁺ T cells, and enhanced proinflammatory cytokines (IL-1α, IL-2, IL-9, IL-12, IFN-γ, TNF-α, MIP-1β), while suppressing TGF-β, IL-4, IL-5, IL-10, Tregs, TAMs, and TANs. In vivo PET/MRI imaging and immunohistopathological analyses confirmed selective tumor accumulation and effective tumor regression. This peptide-guided, TME-tailored SLN strategy achieves coordinated immune reprogramming, ERS induction, EMT/CSC reversal, NET disruption, and dual checkpoint blockade, offering a clinically translatable platform to overcome chemoimmunotherapy resistance in EGFR/PD-L1/CTLA-4-driven CRC.

Purpose Translate the Western Ontario Rotator Cuff (WORC) Index into Traditional Chinese (WORC-TC), validate its psychometric properties, and adapt it to rotator cuff tears (RCTs) in patients who only understand Traditional Chinese. Methods Translation and psychometric validation were performed. A total of 210 patients completed the WORC-TC, Quick Disability of the Arm, Shoulder, and Hand (QuickDASH), 12-item Short-Form Health Survey (SF-12), Numerical Pain Rating Scale (NPRS), and State Anger Scale (SAS) questionnaires. Construct validity and internal consistency were evaluated. Test–retest reliability analyses were conducted on a 30-patient sub-sample. Results The translation and linguistic validation process modified one item. Exploratory factor analysis identified a four-factor structure explaining 66.132% variance. The WORC-TC demonstrated convergent validity with QuickDASH (r = 0.834, p < 0.001), NPRS (r = 0.754, p < 0.001), and SF-12 (r = −0.702, p < 0.001), and divergent validity with the SAS (r = 0.286, p < 0.001). Known-group validity was confirmed, with significant differences between high- and low-pain groups (p < 0.001). The WORC-TC showed satisfactory internal consistency (Cronbach’s alpha: 0.94) and good test–retest reliability (intraclass correlation coefficient: 0.79). Conclusion The WORC-TC can reliably evaluate quality of life in patients with RCTs who exclusively use Traditional Chinese.