Jiangsu Cancer Hospital

High-grade meningiomas remain clinically challenging due to their aggressive behavior and limited therapeutic options. Although mutations and dysregulation of KMT2 family members have been implicated in various cancers, their functional significance in meningioma remains unclear. While NF2 alterations are the most common drivers of meningioma pathogenesis, the mechanisms regulating NF2 transcription in NF2-intact tumors are poorly understood. Here, we demonstrate that KMT2C expression is markedly reduced in high-grade meningiomas and that loss of KMT2C promotes proliferation and invasion in NF2-wild-type meningioma cells. Mechanistically, KMT2C deficiency suppresses NF2 transcription and inactivates Hippo signaling, leading to enhanced oncogenic activity and increased sensitivity to ferroptosis. Loss of KMT2C impairs the acetyltransferase activity of CBP/EP300, resulting in a global reduction of H3K27ac and transcriptional silencing of NF2. Pharmacological restoration of histone acetylation with the HDAC inhibitor Trichostatin A (TSA) effectively suppressed tumor growth. Collectively, our findings identify KMT2C as a key epigenetic regulator linking promoter histone acetylation, NF2-Hippo pathway activity, and ferroptosis susceptibility. These results provide mechanistic insights into high-grade meningioma progression and highlight ferroptosis induction and epigenetic modulation as promising therapeutic strategies for NF2-wild-type, KMT2C-deficient meningiomas.

PurposeThis study aimed to develop a synergistic photodynamic therapy/sonodynamic therapy (PDT/SDT) system that utilises novel NBDPBr nanoparticles (NPs). These NBDPBr NPs are composed of the aza-boron-dipyrromethene (Aza-BODIPY) dye NBDPBr, which is encapsulated in amphiphilic polymer F-127 (Pluronic®). The system is intended for the treatment of triple-negative breast cancer (TNBC), and simultaneously establishes a multimodal imaging platform for real-time monitoring of the therapeutic effect.MethodsThe photophysical properties of the NBDPBr NPs were characterised. Singlet oxygen (1O2) generation was assessed under laser (L) and ultrasound (US) irradiation. In vitro cytotoxicity and reactive oxygen species (ROS) production were evaluated in 4T1 TNBC cells. The therapeutic effect and biosafety in vivo were tested by using a syngeneic TNBC mouse model, and it was monitored by ultra-resolution micro-imaging (URM) and photoacoustic imaging (PAI).ResultsThe spherical NBDPBr NPs showed excellent stability, with an average diameter of about 82.9 nm. Combined laser and ultrasound irradiation induced the highest 1O2 production, leading to 96.02% cell death in vitro and near-complete tumor suppression in vivo, with no significant systemic toxicity. URM revealed decreased tumor microvascular density and PAI indicated reduced blood oxygen saturation post-treatment, confirming synergistic PDT/SDT-induced vascular disruption and tumor hypoxia.ConclusionNBDPBr NPs mediate potent synergistic PDT/SDT against TNBC, supported by a dual-modal URM/PAI imaging platform for treatment monitoring. This study presents a promising theranostic strategy with high translational potential for TNBC management.

This study aims to evaluate the impact of four SNPs of human 8-oxoguanine DNA glycosylase 1 (hOGG1) gene, and its interaction with smoking and alcohol drinking on the risk of nasopharyngeal carcinoma (NPC). Hardy-Weinberg equilibrium (HWE) and the relationship between four SNPs of the hOGG1 gene and the risk of NPC were tested using the SNPStats online software ( https://www.snpstats.net/start.htm ). Generalized multifactor dimensionality reduction (GMDR) was utilized to screen the optimal interaction combinations among four hOGG1 gene SNPs, smoking, and alcohol drinking. We found that rs1052133- Cys allele was associated with increased NPC risk, ORs (95% CI) were 1.42 (1.12-1.85) for Ser/Cys genotype, 1.95 (1.51-2.48) for Cys/Cys genotype, 1.57 (1.18-2.05) for Ser/Cys or Cys/Cys genotype, compared to Ser/Ser genotype. We also found that rs159153- T allele was associated with increased NPC risk, ORs (95% CI) were 1.35 (1.06-1.73) for CT genotype, 2.18 (1.62-2.85) for TT genotype, 1.45 (1.09-1.90) for CT or TT genotype, compared to CC genotype. However, we did not find any statistically significant impact of the minor alleles of rs3219008 and rs293795 on the risk of NPC. GMDR model found a significant gene-environment interaction combination (two-locus model with P = 0.018) between rs1052133 and smoking. Compared to never smokers with rs1052133 Ser/Ser genotype, ever or currently smokers with rs1052133- Ser/Cys or Cys/Cys genotype have the highest NPC risk, OR (95% CI) = 3.18 (1.94-4.42). The rs1052133 and rs159153 minor alleles, the interaction between rs1052133 and smoking, were all associated with increased NPC risk.

Artificial intelligence (AI) is transforming the diagnostic landscape of malignant tumors in the urinary system, including prostate cancer, bladder cancer, and renal cell carcinoma (RCC). By integrating imaging, pathology, and molecular data, AI enhances the precision and reproducibility of tumor detection, grading, and risk stratification. In prostate cancer, AI-assisted multiparametric Magnetic resonance imaging (MRI) and digital pathology systems improve lesion localization and Gleason scoring. For bladder cancer, deep learning-based cystoscopy and radiomics models from Computed tomography/magnetic resonance imaging (CT/MRI) enable real-time lesion segmentation and non-invasive biomarker prediction, such as Programmed Cell Death-Ligand 1 (PD-L1) expression. In RCC, AI, combined with CT/MRI and multi-omics data, aids in subtype classification and prognostic prediction, supporting personalized therapy. However, despite these promising advances, challenges such as data standardization, model generalizability, interpretability, and regulatory compliance hinder AI's clinical translation. This review outlines the current state of AI in urological cancer diagnosis and prognosis, its technological innovations, and the clinical challenges and opportunities that lie ahead.

To elucidate the mechanism by which icaritin—a novel agent for hepatocellular carcinoma (HCC)—remodels the tumor microenvironment (TME) by inhibiting HCC cell metabolism-mediated M2 polarization of tumor-associated macrophages (TAMs). Integrative approaches spanning in vitro Transwell cocultures, RNA-seq, LC3-based autophagy tracing, STX16 gene edition, and orthotopic xenografts mechanistically dissected the affective and mechanism of icaritin in remodeling TME. Our results indicate that icaritin transcriptionally suppresses ALDOB in HCC cells to reduce lactate production. Consequently, the lactylation of histone H3 at lysine 9 and lysine 18 (H3K9/H3K18la) on the STX16 promoter is diminished, thereby ablating STX16 transcription. STX16 deficiency blocks autophagolysosome biogenesis, leading to the accumulation of autophagosomes in HCC cells. These autophagosomes are subsequently delivered to macrophages via extracellular vesicle (EVs) and then triggers autophagic cell death and p62-guided STAT3 destruction within the macrophages, thereby eliminating M2 TAMs and reprograming the tumor immune microenvironment. In vivo validation confirmed icaritin suppressed tumor growth and M2 macrophage infiltration via the ALDOB/STX16/autophagy/STAT3 axis. These results indicate that by orchestrating a novel "metabolism-epigenetics-autophagy-EVs" cascade to eliminate TAMs, icaritin targets ALDOB, STX16, and STAT3, revealing key nodes for therapeutic intervention.

Abstract Background: The management of human epidermal growth factor receptor 2-negative metastatic breast cancer (HER2-negative MBC) in second-line or later settings remains challenging due to the absence of standardized treatment regimens and the limited therapeutic efficacy of chemotherapy. Anlotinib, a novel multi-target tyrosine kinase inhibitor, exerts its effects by inhibiting angiogenesis. This study prospectively evaluated the efficacy and safety of anlotinib combined with chemotherapy as a second-line or later therapeutic option for HER2-negative MBC. Methods: Between August 2022 and August 2023, we prospectively enrolled 33 HER2-negative MBC patients who had experienced treatment failure following at least one line of systemic therapy in the metastatic setting. All participants received anlotinib in combination with chemotherapy. The primary endpoint was median progression-free survival (mPFS), while secondary endpoints included overall survival (OS), objective response rate (ORR), clinical benefit rate (CBR), disease control rate (DCR), and safety. Exploratory analyses utilized the Olink Target 96 Immuno-Oncology Panel to identify proteomic predictors of therapeutic response from serum samples collected from participants. Results: The cohort consisted of patients with hormone receptor-positive (HR+) /HER2-negative breast cancer (N=23) and triple-negative breast cancer (TNBC) (N=10). After a median follow-up duration of 25.9 months (95% CI: 19.9-32.0), the overall mPFS was 8.3 months, and the median OS was 22.2 months. In the HR+ and TNBC subgroups, mPFS was 7.4 months versus 10.6months, respectively. The ORR was 33.3%, DCR reached 90.9% and CBR stood at 60.6%. The analysis of Olink revealed that five proteins, namely CSF-1, VEGF, IL-6, IL-10, and IL-12, exhibited statistically significant differences between the sensitive and non-sensitive groups (P < 0.05), and higher expression levels of these proteins experienced shorter PFS.Grade≥3 treatment- related adverse events were reported in 21.2% of patients including hypertriglyceridemia and neutropenia, with no treatment-related fatalities documented during the study period. Conclusion: Anlotinib combined with chemotherapy demonstrated promising efficacy and an acceptable safety profile for second-line or later treatment of patients with HER2-negative MBC. Baseline serum levels of VEGFA, CSF-1, IL-6, IL-10, and IL-12 identified through proteomic analysis show potential as predictive biomarkers for therapeutic response. These findings necessitate validation in larger randomized clinical trials. Citation Format: Y. Yuan, T. Xu, Q. Gu, L. Zhang, S. Li. Phase II Trial of Anlotinib-Chemotherapy Combination in HER2-Negative Metastatic Breast Cancer: Therapeutic Efficacy and Proteomic Biomarker Profiling [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS1-09-26.

<title>Abstract</title> <bold>Objective:</bold> To examine whether educational attainment is associated with activities of daily living (ADL) limitation among U.S. adults aged ≥50 years after accounting for health status. <bold>Methods:</bold> We conducted a cross-sectional analysis using data from a nationally representative survey, the 2022 Health and Retirement Study. The analytic sample included 1,695 participants (complete-case analysis). ADL limitation was defined as difficulty in ≥1 of dressing, walking across a room, bathing, or using the toilet. Education was measured as years completed. Logistic regression estimated odds ratios (ORs) and 95% confidence intervals (CIs) adjusting for sex, hypertension, and self-rated health, with sex-stratified and rescaled-education sensitivity analyses. <bold>Results:</bold> ADL limitation was reported by 857/1,695 (50.6%) participants. Those with ADL limitation had fewer years of education (12.61 vs 13.89; p &lt; 0.001). Higher education was associated with lower odds of ADL limitation, but the association was attenuated after adjustment for self-rated health (fully adjusted OR per 1-year = 0.961, 95% CI: 0.928–0.996; per 5-year = 0.822, 95% CI: 0.690–0.978). Poorer self-rated health (OR = 2.379 per category, 95% CI: 2.102–2.692) and hypertension (OR = 1.364, 95% CI: 1.099–1.694) were strongly associated with higher odds of ADL limitation. <bold>Conclusion:</bold> Educational attainment was modestly associated with lower odds of ADL limitation, and the association was substantially attenuated after accounting for self-rated health, suggesting that differences in health status may partly explain the observed education–ADL gradient. Targeting chronic disease management and incorporating scalable health measures may support prevention of functional decline, with education serving as a marker of social vulnerability.

Poly (ADP‒ribose) polymerase inhibitors (PARPis) are widely used in maintenance therapy for various platinum-sensitive cancers regardless of the occurrence of BRCA mutations. However, the mechanisms of action and treatment resistance associated with the use of PARPis for maintenance therapy in pancreatic cancer remain unclear. In this study, in addition to the induction of apoptosis, the use of PARPis (olaparib and niraparib) as maintenance therapies inhibited cell proliferation by causing cellular senescence to exert potent anticancer effects on Capan-1 (BRCA mutated) and PANC-1 (BRCA wild-type) cells. Mechanistically, the cellular senescence caused by PARPis relies on the Chk2‒p21 pathway but not in a p53-dependent manner. Interestingly, in addition to directly causing DNA damage, PARPis also exacerbate DNA damage through the generation of ROS via the positive feedback pathway, thereby inducing cellular senescence. Unfortunately, PARPis therapy-induced senescence is a reversible anticancer mechanism in which senescent cancer cells lose their senescence-like phenotype and continue proliferating upon drug withdrawal. This potentially explains the requirement for sustained PARPi therapy in the clinic. Furthermore, the expression of Bcl-2 was increased in PARPi-induced senescent cancer cells, providing a window for opportunistic elimination via synergistic senolytic drugs. The inhibition of Bcl-2 through the sequence-dependent combination of navitoclax enhanced the anticancer effects of PARPis by removing senescent cells. Collectively, data from our study demonstrate that the clinical application of PARPis as maintenance therapy could be achieved through the induction of cellular senescence. Furthermore, sequence-dependent combination with senescence-targeting drugs can potentiate pancreatic cancer treatment effects of PARPis regardless of the BRCA status.