Conventional immunotherapy exhibits low response rates due to the immunosuppressive tumor microenvironment (TME). To overcome this limitation, this study introduces ZFPG nanoparticles (ZFPG NPs) with ZnFe₂O₄@Pt cores and glucose oxidase (GOx) shells. The ZFPG NPs possess five-enzyme activities, good sonosensitivity, and remarkable magnetic targeting properties, which facilitate sono-metallo-immunotherapy for prostate cancer treatment in male mice. Specifically, the magnetic targeting ability effectively improves their accumulation in tumors while still showing enrichment in the liver and kidneys. The multienzyme cascade catalysis and sonosensitivity of these NPs effectively deplete glutathione and glucose, and enhance the generation and utilization of H₂O₂, thereby inducing multiple ROS bursts. Furthermore, these comprehensive effects up-regulate the HMOX1 to promote the Fe²⁺ and lipid peroxides accumulation, thereby inducing immunogenic ferroptosis. This strategy facilitates anti-tumor immunity by ameliorating the immunosuppressive TME and inhibiting lung metastatic progression. This joint warfare strategy offers a powerful solution to address conventional immunotherapy limitations.

The administration of mesenchymal stem cells (MSCs) through intracavernous injection is a potential therapeutic approach for managing diabetes mellitus-induced erectile dysfunction (DMED). However, pulmonary embolism and tumorigenicity are fatal adverse events that limit the clinical application of MSCs. In this study, we examined the therapeutic efficacy and potential mechanism of MSC-derived extracellular vesicles (MSC-EVs). In this study, forty 8-week-old male SpragueDawley (SD) rats were utilised. In the control group, ten rats were administered an intraperitoneal injection of PBS. STZ (60 mg/kg) was intraperitoneally injected into the remaining rats to establish a diabetes mellitus (DM) model. Afterwards, the diabetic rats were divided into three groups at random: the DM group (intracavernosal injection of PBS), the EVs group (intracavernosal injection of MSC-EVs), and the EVs-200a group (intracavernosal injection of miR-200a-3p-enriched extracellular vesicles). Erectile function was determined by measuring intracavernous pressure in real time and utilising electrical stimulation of the cavernous nerves. The smooth muscle content was evaluated through the investigation of penile tissue using immunofluorescence staining, Masson's trichrome staining, and western blotting after euthanasia. Superoxide dismutase (SOD), malondialdehyde (MDA), and glutathione (GSH) levels in the corpus cavernosum were measured via ELISA. In vitro, hydrogen peroxide (H₂O₂) was used to induce oxidative stress. The viability of corpus cavernosum smooth muscle cells (ccSMCs) incubated with or without H₂O₂ was measured using a CCK8 assay. Flow cytometry was used to assess the levels of reactive oxygen species (ROS) and apoptosis in ccSMCs. Furthermore, a dual-luciferase reporter assay was performed to validate the relationship between miR-200a-3p and Keap1. Reversal of erectile function was observed in the EVs groups, especially in the EVs-200a group. DM increased the MDA level and decreased the SOD and GSH levels. In the DM group, the expression of alpha-smooth muscle actin (α-SMA) and smooth muscle 22 alpha (SM22α) was decreased, and the expression of osteopontin (OPN) was increased. Western blotting revealed decreased Nrf2, HO-1, and Bcl2 expression and increased Keap1, Bax and cleaved caspase3 expression in the cavernous tissue. miR-200a-3p-enriched extracellular vesicles (EVs-200a) reversed these changes and inhibited the loss of smooth muscle content and cavernous fibrosis. In vitro, H₂O₂ induced high ROS levels in ccSMCs and increased apoptosis, and these effects reversed by EVs-200a. H₂O₂ reduced Nrf2, HO-1, and Bcl2 expression and increased Keap1, Bax and cleaved caspase-3 expression, and these effects were reversed by MSC-EVs, especially EVs-200a. The of dual-luciferase reporter assay results indicated that miR-200a-3p directly targeted Keap1 in a negative manner. MSC-EVs, especially EVs-200a, alleviated erectile dysfunction in diabetic rats through the regulation of phenotypic switching, apoptosis and fibrosis. Mechanistically, miR-200a-3p targeted the Keap1/Nrf2 pathway to attenuate oxidative stress in diabetic rats.

BACKGROUND:Clinical cases of nonmedullary thyroid carcinoma (NMTC) in combination with primary hyperparathyroidism (PHPT) have been reported occasionally. However, the clinical characteristics and risk factors of concomitant NMTC in PHPT patients rem...

(1) Background: The study aimed to construct nomograms to improve the detection rates of prostate cancer (PCa) and clinically significant prostate cancer (CSPCa) in the Asian population. (2) Methods: This multicenter prospective study included a group of 293 patients from three hospitals. Univariable and multivariable logistic regression analysis was performed to identify potential risk factors and construct nomograms. Discrimination, calibration, and clinical utility were used to assess the performance of the nomogram. The web-based dynamic nomograms were subsequently built based on multivariable logistic analysis. (3) Results: A total of 293 patients were included in our study with 201 negative and 92 positive results in PCa. Four independent predictive factors (age, prostate health index (PHI), prostate volume, and prostate imaging reporting and data system score (PI-RADS)) for PCa were included, and four factors (age, PHI, PI-RADS, and Log PSA Density) for CSPCa were included. The area under the ROC curve (AUC) for PCa was 0.902 in the training cohort and 0.869 in the validation cohort. The AUC for CSPCa was 0.896 in the training cohort and 0.890 in the validation cohort. (4) Conclusions: The combined diagnosis of PHI and PI-RADS can avoid more unnecessary biopsies and improve the detection rate of PCa and CSPCa. The nomogram with the combination of age, PHI, PV, and PI-RADS could improve the detection of PCa, and the nomogram with the combination of age, PHI, PI-RADS, and Log PSAD could improve the detection of CSPCa.

The aim of the present study was to investigate the tropism of mesenchymal stem cells (MSCs) to the tumor microenvironment, and to evaluate the feasibility of bone marrow mesenchymal stem cells differentiating into myofibroblasts in vitro. A total of 1 ml bone marrow was extracted from the greater trochanter of one male New Zealand rabbit, and MSCs were obtained by density gradient centrifugation and cultured routinely. The surface markers were analyzed by flow cytometry. A VX2 tumor was aseptically excised from another male New Zealand rabbit and primary cultured. The tropism of MSCs for 30% and 50% VX2 conditioned medium was determined by using Transwell migration assays. MSCs were incubated in 30% VX2 conditioned medium for 7 or 14 days. The messenger (m)RNA levels and protein expression of α-smooth muscle actin (α-SMA) and vimentin were measured by reverse transcription-polymerase chain reaction and western blotting. MSCs were observed to have a spindle shape. The cultured MSCs were cluster of differentiation (CD)44+, CD105+, CD106+ and CD34−. VX2 cells demonstrated a spindle or polygon shape. In the Transwell assay, it was observed that the migrated cells appeared more frequently in the 30% VX2 conditioned medium group compared with the other groups when microscopically examined, which was additionally confirmed by the results of a colorimetric assay. The mRNA levels and protein expression of α-SMA and vimentin significantly increased in the test group compared with the control group at 7 days (P<0.01), and further increased in the test group at 14 days (P<0.01). The results of the present study demonstrated that MSCs have tropism for the tumor microenvironment and furthermore, may differentiate into myofibroblasts in the tumor microenvironment in vitro. The present study suggested that MSCs may migrate to the tumor and subsequently differentiate into myofibroblasts due to the tumor microenvironment, which may lead to promotion of the growth of the tumor. The present study additionally suggested that MSCs may be the precursors of tumor/carcinoma-associated myofibroblasts.

To improve conventional chemotherapeutic efficacy, it is significant to identify novel molecular markers for chemosensitivity as well as possible molecules accelerating cell-killing mechanisms. In this study, we attempted to elucidate how MK2206, an allosteric Akt inhibitor, enhances the cisplatin (CDDP)-induced cytotoxicity and apoptosis in testicular cancer. We checked three testicular cancer cell lines for the expression of phospho(p)-Akt and its downstream molecules targets by Western blot. The potential antitumor effects were analyzed by MTT assay in vitro and by subcutaneous xenograft models in vivo. The cell invasion was analyzed by transwell invasion assay, and the activities of Akt signaling pathway and expression of apoptosis-related proteins were measured by Western blot. Our results indicated that there was overactivation of p-Akt and its downstream molecules in testicular cancer cell lines compared with normal testis epithelium cells. MK2206 (600 nM) inhibited cell invasion in TCAM-2 and P19 cell lines and significantly increased the susceptibility of testicular cancer to CDDP. Combined with CDDP, MK2206 potentiated CDDP-induced cytotoxicity and apoptosis, with repressed expression of p-Akt and its downstream targets. The subcutaneous xenograft models also showed that a combined CDDP/MK2206 therapy completely suppressed tumor growth without any side effects. These results suggested that the concomitant use of MK2206 could enhance the CDDP-induced cytotoxicity and apoptosis in testicular cancer with the suppressed expression of Akt pathway.