Integration of photomagnetic bimodal imaging to monitor an autogenous exosome loaded platform: unveiling strong targeted retention effects for guiding the photothermal and magnetothermal therapy in a mouse prostate cancer model.

BACKGROUND: Prostate cancer (PCa) is the most prevalent cancer among males, emphasizing the critical need for precise diagnosis and treatment to enhance patient prognosis. Recent studies have extensively utilized urine exosomes from patients with cancer for targeted delivery. This study aimed to employ highly sensitive magnetic particle imaging (MPI) and fluorescence molecular imaging (FMI) to monitor the targeted delivery of an exosome-loaded platform at the tumour site, offering insights into a potential combined photothermal and magnetic thermal therapy regime for PCa. RESULTS: MPI and FMI were utilized to monitor the in vivo retention performance of exosomes in a prostate tumour mouse model. The exosome-loaded platform exhibited robust homologous targeting ability during imaging (SPIONs@EXO-Dye:66·48%±3·85%; Dye-SPIONs: 34·57%±7·55%, **P<0·01), as verified by in vitro imaging and in vitro tissue Prussian blue staining. CONCLUSIONS: The experimental data underscore the feasibility of using MPI for in vivo PCa imaging. Furthermore, the exosome-loaded platform may contribute to the precise diagnosis and treatment of PCa.

Clinical-imaging metrics for the diagnosis of prostate cancer in PI-RADS 3 lesions.

OBJECTIVE: To explore the feasibility and efficacy of clinical-imaging metrics in the diagnosis of prostate cancer (PCa) and clinically significant prostate cancer (csPCa) in prostate imaging-reporting and data system (PI-RADS) category 3 lesions. METHODS: A retrospective analysis was conducted on lesions diagnosed as PI-RADS 3. They were categorized into benign, non-csPCa and csPCa groups. Apparent diffusion coefficient (ADC), T2-weighted imaging signal intensity (T2WISI), coefficient of variation of ADC and T2WISI, prostate-specific antigen density (PSAD), ADC density (ADCD), prostate-specific antigen lesion volume density (PSAVD) and ADC lesion volume density (ADCVD) were measured and calculated. Univariate and multivariate analyses were used to identify risk factors associated with PCa and csPCa. Receiver operating characteristic curve (ROC) and decision curves were utilized to assess the efficacy and net benefit of independent risk factors. RESULTS: Among 202 patients, 133 had benign prostate disease, 25 non-csPCa and 44 csPCa. Age, PSA and lesion location showed no significant differences (P > 0.05) among the groups. T2WISI and coefficient of variation of ADC (ADCcv) were independent risk factors for PCa in PI-RADS 3 lesions, yielding an area under the curve (AUC) of 0.68. ADC was an independent risk factor for csPCa in PI-RADS 3 lesions, yielding an AUC of 0.65. Decision curve analysis showed net benefit for patients at certain probability thresholds. CONCLUSIONS: T2WISI and ADCcv, along with ADC, respectively showed considerable promise in enhancing the diagnosis of PCa and csPCa in PI-RADS 3 lesions.

Emerging and anticipated innovations in prostate cancer MRI and their impact on patient care.

Prostate cancer (PCa) remains the leading malignancy affecting men, with over 3 million men living with the disease in the US, and an estimated 288,000 new cases and almost 35,000 deaths in 2023 in the United States alone. Over the last few decades, imaging has been a cornerstone in PCa care, with a crucial role in the detection, staging, and assessment of PCa recurrence or by guiding diagnostic or therapeutic interventions. To improve diagnostic accuracy and outcomes in PCa care, remarkable advancements have been made to different imaging modalities in recent years. This paper focuses on reviewing the main innovations in the field of PCa magnetic resonance imaging, including MRI protocols, MRI-guided procedural interventions, artificial intelligence algorithms and positron emission tomography, which may impact PCa care in the future.

Lethal pulmonary thromboembolism in mice induced by intravenous human umbilical cord mesenchymal stem cell-derived large extracellular vesicles in a dose- and tissue factor-dependent manner.

Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) have obvious advantages over MSC therapy. But the strong procoagulant properties of MSC-EVs pose a potential risk of thromboembolism, an issue that remains insufficiently explored. In this study, we systematically investigated the procoagulant activity of large EVs derived from human umbilical cord MSCs (UC-EVs) both in vitro and in vivo. UC-EVs were isolated from cell culture supernatants. Mice were injected with UC-EVs (0.125, 0.25, 0.5, 1, 2, 4 µg/g body weight) in 100 µL PBS via the tail vein. Behavior and mortality were monitored for 30 min after injection. We showed that these UC-EVs activated coagulation in a dose- and tissue factor-dependent manner. UC-EVs-induced coagulation in vitro could be inhibited by addition of tissue factor pathway inhibitor. Notably, intravenous administration of high doses of the UC-EVs (1 µg/g body weight or higher) led to rapid mortality due to multiple thrombus formations in lung tissue, platelets, and fibrinogen depletion, and prolonged prothrombin and activated partial thromboplastin times. Importantly, we demonstrated that pulmonary thromboembolism induced by the UC-EVs could be prevented by either reducing the infusion rate or by pre-injection of heparin, a known anticoagulant. In conclusion, this study elucidates the procoagulant characteristics and mechanisms of large UC-EVs, details the associated coagulation risk during intravenous delivery, sets a safe upper limit for intravenous dose, and offers effective strategies to prevent such mortal risks when high doses of large UC-EVs are needed for optimal therapeutic effects, with implications for the development and application of large UC-EV-based as well as other MSC-EV-based therapies.

Targeting Senescent Alveolar Epithelial Cells Using Engineered Mesenchymal Stem Cell-Derived Extracellular Vesicles To Treat Pulmonary Fibrosis.

Type 2 alveolar epithelial cell (AEC2) senescence is crucial to the pathogenesis of pulmonary fibrosis (PF). The nicotinamide adenine dinucleotide (NAD+)-consuming enzyme cluster of differentiation 38 (CD38) is a marker of senescent cells and is highly expressed in AEC2s of patients with PF, thus rendering it a potential treatment target. Umbilical cord mesenchymal stem cell (MSC)-derived extracellular vesicles (MSC-EVs) have emerged as a cell-free treatment with clinical application prospects in antiaging and antifibrosis treatments. Herein, we constructed CD38 antigen receptor membrane-modified MSC-EVs (CD38-ARM-MSC-EVs) by transfecting MSCs with a lentivirus loaded with a CD38 antigen receptor-CD8 transmembrane fragment fusion plasmid to target AEC2s and alleviate PF. Compared with MSC-EVs, the CD38-ARM-MSC-EVs engineered in this study showed a higher expression of the CD38 antigen receptor and antifibrotic miRNAs and targeted senescent AEC2s cells highly expressing CD38 in vitro and in naturally aged mouse models after intraperitoneal administration. CD38-ARM-MSC-EVs effectively restored the NAD+ levels, reversed the epithelial-mesenchymal transition phenotype, and rejuvenated senescent A549 cells in vitro, thereby mitigating multiple age-associated phenotypes and alleviating PF in aged mice. Thus, this study provides a technology to engineer MSC-EVs and support our CD38-ARM-MSC-EVs to be developed as promising agents with high clinical potential against PF.

P-450-dependent Epoxygenase Pathway of Arachidonic Acid Is Involved in Myeloma-induced Angiogenesis of Endothelial Cells / 华中科技大学学报（医学）（英德文版）

P-450-dependent epoxygenase pathway of arachidonic acid and the products of epoxyeicosatrienoic acids (EETs) have been demonstrated to be involved in angiogenesis and tumor progression.This study examined the expression of EETs and the role of the pathway in the angiogenesis of multiple myeloma (MM).MM cell lines of U266 and RPMI8226 were cultured,and the EETs levels (11,12-EET and 14,15-EET) in the supematant were determined by ELISA.Human umbilical vein endothelial cells (HUVECs) were cultured and used for analysis of the angiogenesis activity of the two MM cell lines,which was examined both in vitro and in vivo by employing MTT,chemotaxis,tube formation and matrigel plug assays.11,12-EET and 14,15-EET were found in the supematant of the cultured MM cells.The levels of the two EETs in the supernatant of U266 cells were significantly higher than those in the RPMI8226 cell supematant (P＜0.05),and the levels paralleled the respective angiogenesis activity of the two different MM cell lines.17-octadecynoic acid (17-ODYA),as a specific inhibitor of P450 enzyme,suppressed HUVECs proliferation and tube formation induced by MM cells.Furthermore,17-ODYA decreased the EET levels in the supernatant of MM cells.These results suggest that EETs may play an important role in the angiogenesis of MM,and the inhibitor 17-ODYA suppresses this effect.

Inhibitory Effects of Parthenolide on the Angiogenesis Induced by Human Multiple Myeloma Cells and the Mechanism / 华中科技大学学报（医学）（英德文版）

Summary: The inhibitory effects ofparthenolide (PTL) on angiogenesis induced by multiple myeloma (MM) cells in vitro, and the mechanism were investigated. Human MM line RPMI8226 cells were cultured in vitro. The effects of MM culture supernatant on the migration and tubule formation ability of human umbilical vein endothelial cells (HUVECs) treated with PTL were observed. By using Western blot, the expression of p65 and IκB-α in MM cells was detected. RT-PCR was used to assay the expression of VEGF, IL-6, MMP2 and MMP9 mRNA in MM cells. ELISA was used to measure the levels of VEGF and IL-6 in MM cell culture supernatant. The expression of MMP2 and MMP9 in MM cells was examined by immunohistochemistry. (1) In 3.5, 5.0, 7.5 and 10 μmol/L PTL groups the number of migrated cells was 310±56, 207±28, 127±21 and 49±10 respectively, which was significantly different from that in positive control group (598±47) (P<0.01). In 3.5 and 5.0 μmol/L PTL groups the areas of capillary-like structures were 0.092±0.003 and 0.063±0.002 mm2, significantly less than in positive control group (0.262±0.012 mm2) (P<0.01), but in 7.5 and 10 μmol/L PTL groups no capillary-like structures were found;(2) After treatment with different concentrations of PTL for 48 h, the expression of p65 protein was gradually decreased, while that of IκB-α was gradually enhanced with the increased concentration of PTL;(3) After treatment with 3.5,5.0, 7.5 and 10 μmol/L PTL for 48 h, the VEGF levels in the supematant were 2373.4±392.2,1982.3±293.3, 1247.0±338.4 and 936.5±168.5 pg/mL respectively, significantly different from those in positive control group (2729±440.0 pg/mL) (P<0.05). After treatment with 7.5 and 10 μmol/L PTL, the IL-6 levels in the culture supernatant were 59.6±2.8 and 41.4±9.8 pg/mL respectively, significantly lower than in positive control group (1287.3±43.5 pg/mL) (P<0.05);(4) RT-PCR revealed that PTL could significantly inhibit the expression of VEGF and IL-6 mRNA in MM cells, but not influence the expression of MMP2 and MMP9 mRNA.;(5) Immunohisto chemistry indicated that PTL had no significant effects on the expression of MMP2 and MMP9 protein in MM cells. It was concluded that the abilities of the culture supematant of MM cells treated with PTL to induce endothelial cells migration and tubule formation were significantly reduced, suggesting PTL could obviously inhibit the angiogenesis induced by MM cells. PTL could decrease NF-kappaB activity and significantly suppress the expression of VEGF and IL-6 mRNA and protein, which might contribute to the mechanism by which PTL inhibited the angiogenesis induced by MM cells.