Fudan University Shanghai Cancer Center

AG10 is a molecule that can bind to the thyroxine (T4) binding pocket of transthyretin (TTR). The reversible association between the hydrophilic peptides and TTR using AG10 could increase the circulation half-life (t1/2). We hypothesized that modifying PSMA-617 with AG10 could extend the t1/2 of PSMA-617 and mitigate the limitations caused by insufficient uptake. The aim of this study was to develop an optimal AG10-modified radiotherapeutic agent that could maximize both tumor uptake and absorbed dose, thereby enhancing therapeutic efficacy for the treatment of tumors, even with moderate PSMA expression. Lysine was used as a linker for the conjugation of PSMA-617 and AG10 to synthesize AG10-PSMA-617 (AP-01). AP-01 was labeled with 68Ga to image prostate carcinoma xenografts with moderate PSMA expression, serving as a reference for PSMA radio-ligand therapy (PRLT) based treatments. AP-01 was labeled with 177Lu for the treatment of prostate carcinoma xenografts with moderate PSMA expression. The binding properties and biodistribution of 68Ga-AP-01 and 177Lu-AP-01 were studied both in vitro and in vivo. The cytotoxic effects of the 177Lu-AP-01 were evaluated in prostate carcinoma xenografts. PSMA-617 was successfully conjugated with AG10 using lysine as the linker and labeled with 177Lu to produce PRLT radiopharmaceuticals-177Lu-AP-01. AP-01 was labeled with 68Ga for imaging prostate carcinoma with moderate PSMA expression. AP-01 demonstrated a high binding affinity (IC50 = 3.42 nM) for PSMA in vitro, comparable to that of PSMA-617 (IC50 = 3.38 nM) (P = 0.324). PET/CT imaging of 68Ga-AP-01 demonstrated significantly improved tumor uptake and retention as compared with 68Ga-PSMA-617. The maximum uptake of 68Ga-AP-01 and 68Ga-PSMA-617 by 22Rv1 tumors was 18.07 ± 1.19%ID/g and 9.27 ± 1.20%ID/g at 4h pi, respectively (P < 0.05). The in vivo targeting abilities of 177Lu-AP-01 were evaluated through SPECT/CT imaging. The tumor (maximum)-to-muscle (maximum) (T/Mmax) ratio of 177Lu-AP-01 was 49.28 ± 7.18 at 72h pi. However, the T/Mmax ratio of 177Lu-PSMA-617 was 8.39 ± 8.57 at 48h pi. Biodistribution studies further confirmed the significantly higher tumor uptake of 177Lu-AP-01 (4.87 ± 0.91%ID/g) compared to 177Lu-PSMA-617 (1.12 ± 0.01%ID/g) at 96h post-injection (P < 0.05). The inhibitory efficiency of 177Lu-AP-01 on 22Rv1 tumor xenografts was 88.36%, which was superior to that of 177Lu-PSMA-617 (73.36%) (P < 0.05). 177Lu-AP-01 demonstrated no toxic effects on hepatorenal function, routine blood tests, or major organs in mice when compared to the control group. In this study, AP-01 was successfully synthesized. 68Ga-AP-01 and 177Lu-AP-01 were obtained with high radiochemical purity and stability. High binding affinity and PSMA targeting specificity were identified in vitro and in vivo. With significantly enhanced tumor uptake and retention, 177Lu-AP-01 has the potential to improve therapeutic efficacy for the treatment of prostate cancer with moderate PSMA expression.

Peritoneal metastasis is the most lethal manifestation of gastric cancer, with a median survival of less than one year, highlighting the need for new therapeutic targets. Through an in vivo genome-wide CRISPR/Cas9 screen, we identified GRIA2, an AMPA-type glutamate receptor subunit, as a key driver of peritoneal metastasis. GRIA2 promotes gastric cancer cell migration, invasion, stemness, and adhesion to mesothelial cells in a glutamate-dependent manner. Mechanistically, glutamate activates GRIA2, enhancing its interaction with GSK-3β and inducing calcium influx, inhibiting GSK-3β kinase activity and stabilizing β-catenin, thereby activating the Wnt/β-catenin signaling pathway. Single-cell RNA sequencing revealed that cancer-associated fibroblasts are the primary source of glutamate in the peritoneal microenvironment, which establishes a paracrine axis that enhances GRIA2-driven metastasis. Pharmacological inhibition of AMPA receptors with NBQX and Selurampanel suppressed peritoneal metastasis in both cell line-derived and patient-derived organoid xenograft (PDOX) mouse models. In clinical analysis, GRIA2 expression in peritoneal metastases correlated with the levels of β-catenin and phosphorylated GSK-3β (serine 9), with high GRIA2 expression predicting poor prognosis. These findings suggest that GRIA2 is a novel therapeutic target, and AMPA receptor antagonists are promising agents for treating gastric cancer peritoneal metastasis.

Apostichopus japonicus is a traditional medicinal and culinary species, with existing anti-aging research primarily focusing on its bioactive peptides. In contrast, the anti-aging potential of its major polysaccharide, fucoidan (Aj-FUC), remains largely unexplored. Since the intestine is a central target in the aging process and the primary site for polysaccharide interaction, this study investigates the protective effects and underlying mechanisms of Aj-FUC against d-galactose (d-Gal)-induced intestinal senescence in mice. Aj-FUC significantly improved intestinal function, including restoration of villus structure and colon length, as well as enhancement of motility, absorption, and digestive enzyme activity. Additionally, Aj-FUC ameliorated the senescence-associated secretory phenotype, reduced oxidative stress levels, and downregulated mRNA expression of P16, P21, and P53, showing strong anti-aging effects. Meanwhile, Aj-FUC increased mRNA and protein levels of tight junction proteins, indicating improved intestinal barrier function. Further research revealed that Aj-FUC activated the Wnt/β-catenin pathway and promoted the proliferation of intestinal stem cells (ISCs). Moreover, Aj-FUC remodeled the gut microbiota and enriched Lactobacillus, thereby promoting ISC growth. Aj-FUC mitigates intestinal aging primarily by modulating the gut microbiota and subsequently promoting ISC-mediated epithelial renewal via the Wnt/β-catenin pathway. These findings highlight the promise of Aj-FUC as a marine-based prebiotic functional food ingredient for improving intestinal health during aging. © 2026 Society of Chemical Industry.

The study aimed to explore how patients with late-stage cancer, their spouses and their dependent children communicate about parents' cancer from parents' perspectives, and to develop a theory of family communication within the context of late-stage cancer. This qualitative study was conducted from a grounded theory perspective. Forty-nine participants, including patients with late-stage cancer (n=27) and their spouses (n=22), were interviewed between November 2024 and September 2025. Data analysis followed the framework of Charmaz's constructivist grounded theory, including initial coding, focused coding and theory coding. This study found that family communication in the context of late-stage cancer constituted a stage-based process of relational reconstitution. This process progressed from dyadic buffering through triadic transition to collective reconstitution, and was driven by strategic communication, including proactive engagement, avoidant regulation and receptive waiting across verbal and non-verbal modes. The communication topics families navigated were multifaceted, centering on illness and treatment management, daily living and care coordination, financial burden and resource allocation, reassurance and emotional support, existential concerns of death and the future, and the education and development for children. The family communication was influenced by individual, family, and societal factors. Ultimately, this process led to collective coping, transforming an individual crisis into a manageable collective experience. This study developed a grounded theory of family communication from parental perspectives within the context of late-stage cancer. The findings emphasized the importance of family-centered clinical support, including personalized communication guidance for patients, spouses and children. Further research integrating children's perspectives and exploring contextual variations is needed to further develop this theoretical model and inform supportive interventions.

Cancer-associated fibroblasts (CAFs) are the predominant stromal components within the tumor microenvironment (TME), playing multifaceted roles in cancer progression through dynamic interactions with neoplastic and immune cells. Emerging evidence has revealed remarkable heterogeneity and plasticity of CAFs, which originate from diverse cellular precursors. This cellular diversity, coupled with dynamic epigenetic reprogramming and bidirectional cross-talk with tumor cells, generates distinct CAF subsets with specialized functional outputs. Here, we systematically review the current understanding of CAF biology, encompassing their cellular origins, molecular heterogeneity, and the complex signaling networks. We discuss the functional of CAFs, detailing their protumorigenic roles in extracellular matrix (ECM) remodeling, immunosuppressive niche formation, metabolic reprogramming, angiogenesis, therapy resistance, and maintenance of cancer stem cell properties, while also highlighting emerging evidence for tumor-restrictive CAF subsets. We critically evaluate therapeutic strategies targeting CAFs, including direct depletion approaches, ECM modulation, disruption of CAF-tumor cross-talk, and emphasis on clinical trials and associated challenges. Finally, we outline future directions leveraging single-cell multiomics, patient-derived models and combinatorial regimens to translate current understanding of CAF biology into effective stroma-targeted therapies. This comprehensive framework not only positions CAFs as central architects of tumor ecosystems but also reveals actionable therapeutic vulnerabilities at the intersection of stromal biology and precision oncology.

This study developed an active packaging material by incorporating tea tree oil (TTO)-loaded lotus stalk biochar (BC@TTO) into a chitosan (CS) matrix. Biochar was prepared from lotus stalks via pyrolysis at 600 °C and characterized, revealing a mesoporous structure with a specific surface area of 35.9 m2/g. Adsorption studies demonstrated that BC exhibited high affinity for TTO, following pseudo-first-order kinetics and the Langmuir isotherm model, with a maximum adsorption capacity of 295.6 mg/g. Chitosan-based composite membranes with varying BC@TTO contents (1-7 wt%) were fabricated by solution casting. The incorporation of BC@TTO significantly enhanced the tensile strength, elongation at break, barrier properties (water vapor and oxygen), and antioxidant/antibacterial activities of the membranes, with optimal performance observed at 3 wt% loading. However, higher loadings led to filler aggregation, reduced transparency, and compromised mechanical properties. In vitro release studies indicated that TTO release followed the Avrami model, suggesting a diffusion-controlled mechanism. Preservation tests on blueberries showed that the CS-3BC@TTO membrane effectively reduced weight loss and maintained fruit quality during storage. This work presents a promising strategy for designing bioactive packaging materials with sustained release functionality for food preservation applications.