Zhongshan Hospital

5-Fluorouracil (5-FU) remains a cornerstone of first-line chemotherapy for gastric cancer, yet the emergence of resistance severely compromises its clinical efficacy. Although ferroptosis suppression has been recognized as a pivotal mechanism of chemoresistance, the mitochondrial regulatory processes involved remain poorly understood. We integrated clinical specimen analysis, in vitro and in vivo functional assays, multi-omics profiling, and molecular docking to delineate the role of the mitochondrial oxidoreductase OXNAD1 in mediating 5-FU resistance in gastric cancer, and to assess the therapeutic potential of the natural polyphenol resveratrol as a chemosensitizing agent. OXNAD1 was found to be significantly overexpressed in gastric cancer tissues and cell lines, correlating with unfavorable prognosis and enhanced 5-FU resistance. Mechanistically, OXNAD1 directly bound to and suppressed the ferroptosis driver PTGS2, thereby attenuating lipid peroxidation and mitochondrial damage, ultimately restraining ferroptosis and promoting drug resistance. Notably, resveratrol disrupted the OXNAD1-PTGS2 interaction by directly binding OXNAD1, reinstating ferroptotic activity, markedly enhancing the cytotoxic effect of 5-FU in resistant cells, and potentiating the antitumor efficacy of 5-FU in xenograft models. The OXNAD1-PTGS2 axis constitutes a critical metabolic-cell death cross-regulatory pathway underlying 5-FU resistance in gastric cancer. Targeting this axis with resveratrol provides a promising combinatorial strategy to overcome chemoresistance.

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.

To analyze the diagnostic performance of tissue attenuation imaging (TAI), tissue scatter-distribution imaging (TSI) and ultrasound-based fat fraction (USFF) in suspected metabolic-associated fatty liver disease (MASLD), using histopathological hepatic steatosis as the reference standard. This was a retrospective analysis of prospectively recruited participants with suspected MASLD from August 2022 to November 2023. TAI, TSI and USFF were measured. Spearman correlation analysis was used to evaluate the correlation of TAI, TSI and USFF with hepatic steatosis. The diagnostic performance for detecting hepatic steatosis was evaluated by multiclass or binary receiver operating characteristic (ROC) curves. A total of 264 participants were enrolled, including 227 with biopsy-confirmed MASLD and 37 with normal liver biopsy results. Compared with TAI and TSI, USFF had a better positive correlation with hepatic steatosis in the overall set (rUSFF = 0.62, rTAI = 0.57, rTSI = 0.56; all p < 0.001). Multiclass ROC analysis indicated TAI, TSI and USFF exhibited only modest to suboptimal diagnostic performance for all hepatic steatosis (S0-S3) in index (volume under surface (VUS) 0.21-0.51) and validation set (VUS 0.18-0.34). However, binary ROC curves revealed TAI, TSI and USFF yielded the highest AUCs in detecting mild or greater hepatic steatosis in index (AUC 0.95-0.98) and validation set (AUC 0.92-0.96). USFF has a good correlation with histopathological hepatic steatosis grade. TAI, TSI and USFF might be potential quantitative diagnostic tools for detecting mild hepatic steatosis in MASLD, though further validation in larger and more balanced cohorts is needed. Question How is the diagnostic performance of quantitative ultrasound parameters in suspected metabolic dysfunction-associated steatotic liver disease using liver biopsy as the reference standard? Findings Tissue attenuation imaging, tissue scatter-distribution imaging and ultrasound-based fat fraction show promising diagnostic potential for mild hepatic steatosis in metabolic dysfunction-associated steatotic liver disease. Clinical relevance Tissue attenuation imaging, tissue scatter-distribution imaging, and ultrasound-based fat fraction might be potential noninvasive tools for detecting mild hepatic steatosis and conducting large-scale follow-ups in metabolic dysfunction-associated steatotic liver disease.

To provide recommendations for the most appropriate endovascular intervention of femoropopliteal (FP) arterial disease based on plaque characterization. A panel of 22 physicians from multiple disciplines participated in a modified Delphi consensus, leveraging the RAND/UCLA Appropriateness Method. Panelists engaged in 2 rounds of voting, following a literature review, with an in-person discussion prior to the second round of voting. A rigorous statistical approach was used to analyze the points of agreement and disagreement. Consensus-based recommendations on the most appropriate endovascular approaches for treating patients with FP lesions, stratified by lesion morphology, were generated. Overall, 490 individual items were included in the voting, 458 (93%) of which achieved consensus and 32 (7%) were nonconsensus items, based on a priori criteria under the following categories: (a) recommendations on method for determining plaque morphology, (b) preferred endovascular devices for vessel preparation and definitive treatment stratified by (i) plaque morphology and (ii) Tosaka classification of in-stent restenosis, and (c) vessel preparation device safety-related considerations. This international, multidisciplinary consensus provides evidence- and expert-informed recommendations for vessel preparation and definitive treatment of FP arterial disease, tailored to plaque morphology. These consensus recommendations aim to support clinical decision making and promote best interventional practices by serving as an expert opinion supplement to existing guideline-based care pathways.

ABSTRACT Primary liver cancer remains a significant global public health challenge, characterized by persistently high incidence and mortality. This review synthesizes current epidemiological data to analyze trends and etiological shifts, with particular emphasis on China, which bears over 40% of the global burden. Findings highlight a transition in dominant risk factors from viral hepatitis to metabolic dysfunction‐associated steatotic liver disease (MASLD), alongside persistent threats from aflatoxin exposure and lifestyle behaviors. Evidence‐based prevention strategies, including universal hepatitis B virus (HBV) vaccination, antiviral therapy expansion, aflatoxin control, and early metabolic intervention, are critical to reducing disease burden. The integration of artificial intelligence into screening and management represents a promising advancement. A multi‐faceted approach combining vaccination, surveillance, lifestyle modification, and technological innovation is essential for effective global liver cancer control.

The increasing resistance of pathogenic bacteria challenges current skin disinfection strategies, while the non-degradability of traditional cationic antimicrobials limits their clinical safety. Conventional photodynamic therapy is limited by complex application requirements. To address these limitations, we developed a biodegradable, sunlight-activated photodynamic cationic nanospray (NPPORPMn). Under environmentally friendly and readily accessible sunlight irradiation (NPPORPMn+L), NPPORPMn efficiently generates reactive oxygen species and works synergistically with its quaternary ammonium cations to exert potent antibacterial effects. This dual-action significantly reduces the inflammatory response in infected microenvironments and accelerates wound healing in infections caused by Staphylococcus aureus (S. aureus) and methicillin-resistant Staphylococcus aureus (MRSA). Skin disinfection experiments further demonstrate that NPPORPMn+L can eliminate pathogenic bacteria and resident microbial communities on the skin surface. This study presents an innovative, biodegradable, and clinically safe nanospray platform that harnesses the convenience of sunlight activation to provide a promising strategy for combating antibiotic-resistant infections.

Despite treatment, many hypertensive patients with coronary heart disease (CHD) have blood pressure (BP) that remains above guideline targets. However, less is known about patients in whom on-treatment BP is below target and major European guidelines differ substantially in their recommendations for such patients. Specifically, 2023 European Society of Hypertension (ESH) guidelines provide a Class 3 recommendation to proactively avoid BP below target whereas 2024 European Society of Cardiology (ESC) guidelines do not. Between 2020 and 2023, adults hospitalised in the previous 6-24 months with incident or recurrent CHD were sampled in 14 countries from all six WHO regions and invited for a standardised interview and examination as part of the International Action on Secondary and Primary Prevention by Intervention to Reduce Events (INTERASPIRE) study. We measured seated BP twice using an automated oscillometric device after 5 min of rest. We defined participants as having BP above target (BP ≥130/80 mm Hg), at target (BP 120-129/70-79 mm Hg) or below target (<120/70 mm Hg); according to both 2023 ESH and 2024 ESC guidelines. Among 4548 participants (21.1% female), the mean age (±SD) was 60.0 (±10.3) years. At a median (IQR) of 1.05 (0.76-1.45) years after index CHD hospitalisation, 10.3% of patients had BP readings within the target range of 120-129/70-79 mm Hg, with 53.9% above target and 35.7% below target. Patients with below-target BP were more likely to have heart failure (13.6% vs 10.0%, p=0.041) and estimated glomerular filtration rate <60 mL/min/1.73 m² (18.9% vs 10.7%, p<0.001), when compared with those at target. They were also statistically more likely to be severely frail (p=0.030). The median number of BP-lowering medications did not differ significantly between the 3 BP target groups. Cumulative dosing of BP-lowering medications in the below-target group was also not more intensive than that in the at-target group. More than one-third of INTERASPIRE patients with CHD presented with BP <120/70 mm Hg, which is below target per current European hypertension guidelines. Further research is needed in this population to resolve discordant guideline recommendations and determine whether de-escalation of BP-lowering therapies is beneficial or even harmful in this setting.