FePt/MnO2@PEG Nanoparticles as Multifunctional Radiosensitizers for Enhancing Ferroptosis and Alleviating Hypoxia in Osteosarcoma Therapy.

Radiotherapy (RT) is a widely used cancer treatment, and the use of metal-based nanoradiotherapy sensitizers has demonstrated promise in enhancing its efficacy. However, achieving effective accumulation of these sensitizers within tumors and overcoming resistance induced by the hypoxic tumor microenvironment remain challenging issues. In this study, we developed FePt/MnO2@PEG nanoparticles with multiple radiosensitizing mechanisms, including high-atomic-number element-mediated radiation capture, catalase-mimicking oxygenation, and GSH depletion-induced ferroptosis. Both in vitro and in vivo experiments were conducted to validate the radiosensitizing mechanisms and therapeutic efficacy of FePt/MnO2@PEG. In conclusion, this study presents a novel and clinically relevant strategy and establishes a safe and effective combination radiotherapy approach for cancer treatment. These findings hold significant potential for improving radiotherapy outcomes and advancing the field of nanomedicine in cancer therapy.

Exosomal miR-181a-5p derived from SAOS-2 cells promotes macrophages M2 polarization by targeting RORA.

Although the interaction between tumor cells and tumor-associated macrophages (TAMs) has been widely studied; however, the mechanism of osteosarcoma cells in regulating the polarization of TAMs remains unclear. Exosomes from SAOS-2 cells were isolated and validated by electron microscopy and Western blot. Transfection of indicated plasmids was applied to modify the expressions of miR-181a-5p and RAR-related orphan receptor alpha (RORA). Flow cytometric analysis was carried out to analyze M1/M2 macrophage polarization. Quantitative real-time PCR was performed to determine the levels of miR-181a-5p and RORA. Protein levels of CD63, CD81, RORA, CD163, CD206, IL-10, CXCL10, and IL-1ß were evaluated by Western blot. The direct interaction of miR-181a-5p and RORA was validated by dual-luciferase activity assay. The expression of miR-181a-5p was upregulated in osteosarcoma tissues and presented in SAOS-2-derived exosomes. SAOS-2-derived exosomes promoted the polarization of M2 macrophages by transferring miR-181a-5p. In addition, RORA was downregulated in osteosarcoma tissues and showed a negative correlation with miR-181a-5p. RORA was found to be the downstream target of miR-181a-5p in SAOS-2 cells. Inhibition of RORA reversed the effects of miR-181a-5p knockdown on the polarization of M2 macrophages. The results showed that exosomal miR-181a-5p derived from osteosarcoma cells induced polarization of M2 macrophages via targeting RORA.

Hsa_circ_0079530/AQP4 Axis Is Related to Non-Small Cell Lung Cancer Development and Radiosensitivity.

BACKGROUND: Circular RNAs are associated with non-small cell lung cancer (NSCLC) development and radiosensitivity. Nevertheless, the function and regulation mechanism of hsa_circ_0079530 (circ_0079530) in NSCLC development and radiosensitivity are largely unknown. METHODS: The abundances of circ_0079530, microRNA (miR-409-3p), aquaporin 4 (AQP4), E-cadherin, intercellular adhesion molecule-1, vitronectin, proliferating cell nuclear antigen, and matrix metalloproteinase 9 were determined via quantitative reverse transcription polymerase chain reaction or western blotting. Cell proliferation, survival fraction, cycle process, migration, invasion, and in vivo growth were examined by cell counting kit-8, colony formation, flow cytometry, transwell, and xenograft analyses. The binding relationship was assessed via dual-luciferase reporter assay and RNA immunoprecipitation assay. RESULTS: Circ_0079530 expression was increased in NSCLC tissues and radioresistant samples. Circ_0079530 knockdown restrained cell proliferation, migration, and invasion, and facilitated radiosensitivity. Circ_0079530 silence decreased tumor growth with or without radiation treatment. Circ_0079530 was verified as a miR-409-3p sponge, and miR-409-3p downregulation mitigated the effects of circ_0079530 interference on NSCLC cell malignancy and radiosensitivity. AQP4 was directly targeted by miR-409-3p. MiR-409-3p restrained cell proliferation, migration, and invasion, and enhanced radiosensitivity by decreasing AQP4 expression. Notably, circ_0079530 silence decreased AQP4 expression by regulating miR-409-3p expression. CONCLUSION: Circ_0079530 silence repressed cell proliferation, migration, and invasion, and facilitated radiosensitivity in NSCLC cells by mediating miR-409-3p/AQP4 axis.

The Role of miR-31-5p in the Development of Intervertebral Disc Degeneration and Its Therapeutic Potential.

Intervertebral disc degeneration (IDD) refers to the abnormal response of cell-mediated progressive structural failure. In order to understand the molecular mechanism of the maintenance and destruction of the intervertebral disc, new IDD treatment methods are developed. Here, we first analyzed the key regulators of IDD through microRNAs microarrays. Then, the level of miR-31-5p was evaluated by qRT-PCR. The association between miR-31-5p and Stromal cell-derived factor 1 (SDF-1)/CXCR7 axis was assessed by 3'-untranslated region (UTR) cloning and luciferase assay. The apoptosis of cells under different treatments was evaluated by flow cytometer. The cell proliferation was assessed by EdU assay. After IDD model establishment, the discs of mice tail were harvested for histological and radiographic evaluation in each group. Finally, the protein levels of SDF-1, CXCR7, ADAMTS-5, Col II, Aggrecan, and MMP13 were assessed by western blot. The results show that miR-31-5p is a key regulator of IDD and its level is down-regulated in IDD. Overexpression of miR-31-5p facilitates nucleus pulposus cell proliferation, inhibits apoptosis, facilitates ECM formation, and inhibits the level of matrix degrading enzymes in NP cells. The SDF-1/CXCR7 axis is the direct target of miR-31-5p. miR-31-5p acts on IDD by regulating SDF-1/CXCR7. In vitro experiments further verified that the up-regulation of miR-31-5p prevented the development of IDD. In conclusion, overexpression of miR-31-5p can inhibit IDD by regulating SDF-1/CXCR7.

Different setup errors assessed by weekly cone-beam computed tomography on different registration in nasopharyngeal carcinoma treated with intensity-modulated radiation therapy.

The study aimed to investigate the difference of setup errors on different registration in the treatment of nasopharyngeal carcinoma based on weekly cone-beam computed tomography (CBCT). Thirty nasopharyngeal cancer patients scheduled to undergo intensity-modulated radiotherapy (IMRT) were prospectively enrolled in the study. Each patient had a weekly CBCT before radiation therapy. In the entire study, 201 CBCT scans were obtained. The scans were registered to the planning CT to determine the difference of setup errors on different registration sites. Different registration sites were represented by bony landmarks. Nasal septum and pterygoid process represent head, cervical vertebrae 1-3 represent upper neck, and cervical vertebrae 4-6 represent lower neck. Patient positioning errors were recorded in the right-left (RL), superior-inferior (SI), and anterior-posterior (AP) directions over the course of radiotherapy. Planning target volume margins were calculated from the systematic and random errors. In this study, we can make a conclusion that there are setup errors in RL, SI, and AP directions of nasopharyngeal carcinoma patients undergoing IMRT. In addition, the head and neck setup error has the difference, with statistical significance, while patient setup error of neck is greater than that of head during the course of radiotherapy. In our institution, we recommend a planning target volume margin of 3.0 mm in RL direction, 1.3 mm in SI direction, and 2.6 mm in AP direction for nasopharyngeal cancer patients undergoing IMRT with weekly CBCT scans.

[Intensity modulated radiation therapy for 90 untreated nasopharyngeal carcinoma].

OBJECTIVE: To observe the clinical results and the toxicities of normal tissues in untreated nasopharyngeal carcinoma (NPC) treated with intensity modulated radiation therapy (IMRT). METHODS: A total of 90 patients with untreated NPC received IMRT. According to the 1992 Fuzhou staging system, 3 patients were in stage I, 29 in stage II, 26 in stage III, and 32 in stage IVa. For IMRT,the prescription dose was 71.94-77.88 Gy/33f for the planning target volume of the gross tumor volume in the nasopharynx (PGTVnx); 69.96 Gy/33f for the positive neck lymph nodes (GTVnd); 60-66 Gy/33f for the planning target volume of the high risk regions (PTV1); and 50.4-56 Gy/28f for the planning target volume of the low risk regions (PTV2). Chemotherapy included concurrent and adjuvant protocols. The overall survival rate, local control rate, and distant metastasis-free survival rate were estimated by Kaplan-Meier method. Cox regression was used for multivariate analysis. Acute and 1ate toxicities were graded according to RTOG radiation morbidity scoring criteria. RESULTS: The median follow-up time was 33 months (12-56 months). The 1-, 2-, 3- and 4-year survival rate was 97.8%, 90.6%, 86% and 80%; the local control tate was 98.8%, 97.5%, 92.1% and 77.4%; and the distant metastasis-free survival rate was 95.3%, 90.7%, 88.4% and 85.8%, respectively. The most serious acute toxicity was irradiated inflammation of mocosa with Grade 1 to 4 of 16.7%, 60%, 23.3% and 0, respectively. In the multivariate analysis, clinical stages were the prognostic factors for the survival rate. The most serious toxicity was salivary gland. The rate of grade xerostomia 1-year after the radiotherapy with Grade 1 to 4 was 18.1%, 9.6%, 0 and 0, respectively. CONCLUSION: IMRT combined chemotherapy can improve the survival rate, and late adverse reaction is obviously decreased. Local recurrence and distant metastasis are the main reasons for low survival rate.