Cardioembolic stroke (CS) and atherosclerosis (AS) are closely related diseases. Ferroptosis, a novel form of programmed cell death, may play a key role in CS and AS. However, the pathophysiological mechanisms underlying their coexistence remain unclear. This study aims to identify the hub genes and pathways involved in developing both diseases.

CS (GSE58294) and AS (GSE20129) datasets were obtained from the Gene Expression Omnibus database, and a ferroptosis (FR)-related gene dataset was downloaded from the FR database. A study was conducted to examine differentially expressed genes (DEGs) in healthy individuals and patients diagnosed with CS and AS. Gene ontology and Kyoto encyclopedia of genes and genomes analyses were performed to explore the functions of common FR-related DEGs (FRDEGs). Two machine learning algorithms, Least Absolute Shrinkage and Selection Operator (LASSO) regression and Support Vector Machine Recursive Feature Elimination (SVM-RFE), were used to screen for overlapping FRDEGs in CS and AS. To validate the prediction results, blood samples were collected from healthy controls and patients with CS and AS for quantitative real-time PCR. The correlation between biomarkers and clinical features was also evaluated.

A total of 69 and 39 FRDEGs were identified in CS and AS, respectively. The hub genes, CIRBP, CREB5, MAPK14, PEBP1, and PTGS2, were identified using multiple methods. The area under the curve was > 0.7 for both models constructed using CS and AS datasets. A strong correlation was observed between neutrophil levels and expression of the hub genes. Additionally, several types of cancer indicated elevated expression of these hub genes compared to normal tissues.

In summary, the diagnostic model based on the FR-related gene PTGS2 demonstrated significant and specific diagnostic value for CS and AS, reflecting the status of blood lymphocytes, monocytes, and neutrophils. A pan-cancer study suggested it could serve as a new clinical prognostic marker and therapeutic target across various cancer types. This model may aid in the diagnosis of CS and AS. The findings offer new insights into the pathogenesis of these diseases.

Ovarian cancer (OC) is the most lethal gynecological tumor, primarily due to resistance to chemotherapy. Cyclin L2 (CCNL2) is a novel member of the cyclin family and mainly localized in nucleus. It regulates transcription and alternative splicing by interacting with cyclin-dependent kinases. However, its role in OC chemoresistance remains unknown.

Here, we demonstrated that the expression level of CCNL2 was higher in OC tissues as well as in various other tumor types. Furthermore, elevated expression of CCNL2 indicated a poor prognosis in ovarian cancer. Functionally, CCNL2 promoted OC cell proliferation and xenograft growth. Depletion of CCNL2 enhanced chemotherapy sensitivity in OC cells. Mechanistically, YBX1 directly bound to CCNL2 mRNA, and its depletion reduced CCNL2 mRNA stability and protein expression. MeRIP assays revealed that YBX1 regulated CCNL2 via 5-methylcytosine (m⁵C) modification. Mutation of the key residue of YBX1 required for m⁵C function led to decreased CCNL2 expression. Further investigation of the YBX1 regulatory network identified a direct interaction between YBX1 and MATR3, which cooperatively modulated downstream targets. Notably, MATR3 knockdown reversed the YBX1-induced upregulation of CCNL2. Virtual screening identified YB-B1 as a YBX1 inhibitor that effectively downregulated both YBX1 and CCNL2 expression. In vitro, YB-B1 suppressed ovarian cancer cell proliferation and enhanced cisplatin cytotoxicity. Furthermore, patient-derived tumor xenograft (PDX) model also confirmed its chemosensitizing effect.

In summary, we demonstrated that CCNL2 promoted OC cell proliferation and chemoresistance, with its expression regulated by YBX1 via m⁵C methylation. The small molecule inhibitor YB-B1 was identified as a promising solution to overcome chemotherapy resistance.

Not applicable.

Tumor-associated macrophages (TAMs) have a significant impact on the prognosis and treatment outcomes of Wilms tumor (WT) patients. To explore the key mechanisms underlying WT progression and immune therapy, this study used CIBERSORT to analyze the immune cell infiltration of 120 WT patients. Combined with single-cell RNA sequencing (scRNA-seq) data, the heterogeneity of macrophages in WT and adjacent tissues was revealed, identifying a subpopulation of tissue-resident macrophages with specific expression of BCL2A1. Further validation through immunohistochemistry (IHC) and immunofluorescence (IF) experiments confirmed the presence of BCL2A1⁺tissue-resident macrophages and elevated BCL2A1 expression is associated with advanced tumors and poor prognosis. Functional enrichment analysis suggests that BCL2A1⁺tissue-resident macrophages may promote WT progression through immune regulation and apoptosis pathways. This study is the first to identify the presence of a BCL2A1⁺tissue-resident macrophage subset in WT and reveal its critical role in tumor progression, potentially providing a novel target for personalized immunotherapy.

Radionuclide therapy and chemotherapy are effective for pancreatic cancer, yet their efficacy is often limited by tumor hypoxia. In this study, manganese porphyrin (MnTTP) and tirapazamine (TPZ) were encapsulated in polylactic-co-glycolic acid (PLGA) spheres, which were subsequently coated with polydopamine to label the radionuclide ¹³¹I, forming a theranostic nanoplatform. The nanoplatform demonstrated excellent biocompatibility, stable labeling efficiency, and dual-modal MRI/SPECT imaging capabilities. The nanoplatform generated reactive oxygen species (ROS) under ultrasound(US) activation, in combination with the β-rays emitted by ¹³¹I, synergistically eradicate tumor cells and exacerbate hypoxia in the tumor microenvironment. Furthermore, TPZ was activated to produce toxic free radicals under hypoxic conditions, enabling a synergistic therapeutic approach that combined radionuclide therapy and sonodynamic therapy. This approach effectively inhibited tumor stem cell formation and enhanced anti-tumor efficacy. Additionally, the nanoplatform's metabolism in vivo and the therapeutic effect were monitored in real-time under MRI/SPECT dual-modality imaging. This therapeutic strategy offers a promising solution for overcoming tumor hypoxia and achieving efficient combination therapy for tumors.

Immunomodulatory agents benefit a small percentage of patients with oral cancer (OC), a subset of head and neck cancer. Cathepsin S (CTSS), a lysosomal protease, has been frequently associated with tumor immunity. This study aimed to investigate the mechanism by which tumor CTSS affects anti-tumor immunity through the regulation of interleukin-7 (IL-7) to overcome this obstacle.

OC patients' samples were used to disclose the correlation among CTSS and CD8⁺ T cell infiltration levels. The cytokine array was used to investigate the effect of CTSS on the secretion of cytokine/chemokines. We utilized various cell biology experiments to investigate the molecular mechanism of CTSS that mediates IL-7 secretion in OC cell lines, including fluorescence resonance energy transfer, immunogold-labeled transmission electron microscopy, IL-7-enzyme-linked immunosorbent assay, immunofluorescence staining, and pull-down assay. Two syngeneic OC mice models were utilized to investigate the anti-cancer effects and the tumor immunity modulation effects of RJW-58, a CTSS activity inhibitor, and the combination with the anti-PD-1 antibody.

CTSS expression was inversely correlated with CD8⁺ T-cell infiltration in clinical samples. In vivo and in vitro studies using a mouse OC tumor model showed that CTSS-knockdown inhibited tumor growth and enhanced CD8⁺ T cell proliferation. These results were counteracted by co-treatment with anti-CD8 or anti-IL-7 antibodies. CTSS inhibition also remodeled the memory CD8⁺ T cell subsets within tumor tissues in vivo. Mechanistically, CTSS inhibited IL-7 secretion by disrupting its intracellular transport route. This was achieved by recognizing the intracellular domain of the IL-7 receptor (IL-7R), which bound IL-7 in granular vesicles. RJW-58 enhanced IL-7 secretion and exerted an anti-tumor effect. RJW-58 enhanced the therapeutic effect of the anti-PD-1 antibody in syngeneic mouse models.

The findings indicate that CTSS negatively regulates IL-7 secretion by interacting with IL-7R. The CTSS-targeting strategy has the potential to reinvigorate IL-7-directed anti-tumor T cell immunity and enhance the therapeutic effect of the anti-PD-1 antibody.

Endometrial cancer ranks among the most prevalent gynecological malignancies, with a notable increase in incidence, especially among women under 40. Although most patients are diagnosed at an early stage and have an excellent prognosis, the outcome for metastatic and recurrent cases remains poor. Current treatment for advanced-stage disease includes chemotherapy, hormonal therapy and checkpoint inhibitors. The clinical response rate to immunotherapy varies depending on the molecular subtype of endometrial carcinoma. Novel immunotherapeutic strategies are needed to improve patient survival, particularly across molecular subtypes. CD276 (cluster of differentiation 276, B7-H3) is emerging as a promising immunotherapy target due to its expression across multiple tumor types. Therapeutic targeting of CD276 may enhance immune cell infiltration into the tumor site by affecting its expression on tumor cells and tumor vasculature, which addresses a critical challenge for the successful treatment of solid tumors.

We developed a novel, IgG-based CD276xCD3 bispecific antibody termed CC-3, which has demonstrated pronounced preclinical efficacy in stimulating T cell antitumor responses and is presently undergoing evaluation in a Phase I clinical trial (NCT05999396). In this study, CC-3-induced T cell activation and proliferation was analyzed using flow cytometry. We also used a LegendPlex assay to measure the secretion of cytokines and effector molecules induced by CC-3. Finally, these processes culminated in target cell lysis which was analyzed using a flow cytometry-based cytotoxicity assay.

CD276 is abundantly expressed in endometrial cancer. Treatment with CC-3 activated T cells, stimulated degranulation, and induced the secretion of cytokines and effector molecules, demonstrating CC-3-mediated T cell reactivity against endometrial cancer cells. Furthermore, CC-3 promoted robust T cell proliferation and memory T cell subset formation, culminating in potent target cell lysis.

Overall, our findings highlight the potential of CC-3 for clinical evaluation as a therapeutic option for patients with endometrial cancer.

This article focuses on ovarian cancer (OC), the most lethal gynecological malignancy, whose risk is influenced by multiple factors, including genetic background, age, reproductive history, parity, obesity status, and smoking habits. Mitochondria, as the core organelles in eukaryotic cells, play a pivotal role in the initiation and progression of OC. In recent years, growing evidence has revealed a close relationship between mitochondrial dysfunction and the accelerated proliferation, enhanced invasiveness, metastasis ability, and therapy resistance of OC. This paper provides an in-depth analysis of the complex interactions between mitochondrial dysfunction and the malignant biological characteristics of OC, as well as the underlying regulatory mechanisms of mitochondrial function. Furthermore, it elaborates on how genetic variations, regulatory factors, and the tumor microenvironment (TME) influence mitochondrial function and drive the malignant progression of OC. Additionally, this paper comprehensively summarizes therapeutic strategies targeting mitochondrial dysfunction in OC, aiming to provide novel insights and strategies for clinical research and treatment.

Metabolic and stress response adaptations in prostate cancer (PCa) mediate tumor resistance to radiation therapy (RT). Our study investigated the roles of glutamine (Gln) transporters SLC1A5, SLC7A5, and SLC38A1 in regulating NUPR1-mediated stress response, PCa cell survival, metabolic reprogramming, and response to RT.

The radiosensitizing potential of GLS inhibition with CB-839 was analyzed in prostate cancer xenograft models. The level of gene expression was analyzed by RNA sequencing and RT-qPCR in the established cell lines or patient-derived tumor and adjacent non-cancerous tissues. Phosphoproteomic analysis was employed to identify the underlying signaling pathways. The publicly available PCa patient datasets, and a dataset for the patients treated with RT were analyzed by SUMO software. The key parameters of mitochondrial functions were measured by Seahorse analysis. Analysis of the general oxidative stress level and mitochondrial superoxide detection were conducted using flow cytometry. γH2A.X foci analysis was used to assess the DNA double strand break. Relative cell sensitivity to RT was evaluated by radiobiological clonogenic assays. Aldefluor assay and sphere-forming analysis were used to determine cancer stem cell (CSC) phenotype.

A siRNA-mediated knockdown of Gln transporters SLC1A5, SLC7A5, and SLC38A1 resulted in significant radiosensitization of PCa cells. Consistently, the first-in-clinic glutaminase (GLS) inhibitor CB-839, combined with RT, demonstrated a synergistic effect with radiotherapy in vivo, significantly delaying tumor growth. Inhibition of Gln metabolism or knockdown of Gln transporters SLC1A5, SLC7A5, or SLC38A1 induces expression of NUPR1, a stress response transcriptional regulator, but simultaneously uncouples the NUPR1-driven metabolic stress-adaptation program. Similarly to the effect from NUPR1 knockdown, depletion of these Gln transporters led to reduced cell viability, accumulation of mitochondrial ROS, and increased PCa radiosensitivity. This effect is more pronounced in PCa cells with high dependency on OXPHOS for energy production.

Our work underscores the role of Gln transporters and the NUPR1-mediated stress response in PCa cell survival, oxidative stress, mitochondrial functions, and radioresistance. Our findings provide a potential therapeutic in vivo strategy to enhance the efficacy of RT and suggest a potential synergism between the depletion of Gln transporters or NUPR1 and OXPHOS inhibition.

Birt-Hogg-Dubé (BHD) syndrome is a rare autosomal dominant inherited disease caused by germline mutations in the FLCN (folliculin) gene. It often presents as skin fibrofolliculoma, pneumothorax and renal cell carcinoma. BHD syndrome-associated renal cell carcinoma usually presents with an inert course, but some cases may be associated with sarcomatoid dedifferentiation, suggesting a higher aggressiveness and poor prognosis.

A 66-year-old female patient presented with a left renal mass and underwent open radical left nephrectomy with lymph node dissection. Postoperative pathology confirmed the diagnosis of renal cell carcinoma with sarcomatoid dedifferentiation, classified as Stage IV pT4N0M0. Immunohistochemical analysis revealed vimentin (+), CD10 (+), and Ki67 (approximately 80% +), which aided in the diagnosis. Initial treatment with first-line targeted immunotherapy (axitinib plus toripalimab) was unsuccessful. Following treatment failure, genetic testing was performed and identified FLCN and BRCA2 mutations. Based on these findings, second-line therapy with anlotinib combined with toripalimab was initiated, demonstrating significant efficacy. Imaging assessments consistently indicated a partial response according to RECIST1.1 criteria. Additionally, olaparib was considered as a potential therapeutic option due to the BRCA2 mutation, and one cycle of olaparib was administered during the second-line treatment. At seven months post-operation, intra-abdominal metastatic lesions remained well-controlled, with no significant pulmonary metastasis. Routine monitoring of blood counts, liver and kidney function, thyroid function, myocardial enzymes, and cortisol levels revealed no significant adverse effects, underscoring the safety and efficacy of the treatment regimen.

This case not only reveals the complexity and treatment challenges of BHD syndrome-associated renal cell carcinoma with sarcomatoid dedifferentiation but also provides an important basis for the development of individualized treatment strategies. The successful treatment of this case suggests that targeted immunotherapy may have potential advantages in refractory cases and emphasizes the important role of gene testing in guiding individualized treatment. In the future, it is necessary to further explore the molecular mechanism of BHD syndrome-associated renal cell carcinoma and sarcomatoid renal cell carcinoma and verify the efficacy of targeted immunotherapy.

Lysosomes are monolayer membrane-encapsulated organelles containing acid hydrolases, crucial for intracellular substance breakdown and cellular homeostasis. They are also involved in autophagy. Although autophagy is linked to cancer, the role of lysosome-related genes in cervical cancer prognosis remains unclear. This study aimed to develop a prognostic model for cervical cancer based on lysosome-related genes and explore its applications in the tumor microenvironment, radiotherapy prognosis, and clinical pharmacology.

We identified differentially expressed lysosome-related genes in cervical cancer and normal tissues using the TCGA database. A prognostic model was constructed using LASSO-Cox regression, validated with ROC curves and PCA analysis, and further verified using the GEO dataset GSE63514. In vitro and in vivo experiments were conducted to explore key genes, and their biological significance and pharmacological potential were analyzed.

A five-gene (AP1B1, DNASE2, LAMP3, NPC1, and LAPTM4A) lysosome-associated prognostic model was developed. LAMP3 was identified as the most differentially expressed gene. Knockdown of LAMP3 significantly reduced cervical cancer cell migration and invasion through lysosomal and autophagic pathways. Daidzein was found to have high binding affinity for LAMP3, suggesting its therapeutic potential.

Lysosome-related gene modeling has significant clinical value. LAMP3 knockdown inhibits cervical cancer progression by reducing autophagy and lysosomal function. Daidzein shows potential as a novel therapeutic agent. However, further validation in larger cohorts is needed due to the limited sample size in this study.